International Journal of Molecular Sciences

22 pages, 1319 KiB

Open AccessReview

State of Art of Cancer Pharmacogenomics in Latin American Populations

by Andrés López-Cortés¹

, Santiago Guerrero²

, María Ana Redal³, Angel Tito Alvarado⁴ and Luis Abel Quiñones^5,*

¹ Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad Tecnológica Equinoccial, Quito 170527, Ecuador

² Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain

³ Instituto de Fisiopatología y Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Centro de Diagnóstico Molecular, MEDgenomica, Buenos Aires 1000-1499, Argentina

⁴ Unidad de Bioequivalencia y Medicina Personalizada, Facultad de Medicina, Universidad de San Martín de Porres, Lima 12, Peru

⁵ Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology, Faculty of Medicine, University of Chile, Santiago 70111, Chile

Int. J. Mol. Sci. 2017, 18(6), 639; https://doi.org/10.3390/ijms18060639 - 23 May 2017

Cited by 26 | Viewed by 9342

Abstract

Over the past decades, several studies have shown that tumor-related somatic and germline alterations predicts tumor prognosis, drug response and toxicity. Latin American populations present a vast geno-phenotypic diversity due to the great interethnic and interracial mixing. This genetic flow leads to the [...] Read more.

Over the past decades, several studies have shown that tumor-related somatic and germline alterations predicts tumor prognosis, drug response and toxicity. Latin American populations present a vast geno-phenotypic diversity due to the great interethnic and interracial mixing. This genetic flow leads to the appearance of complex characteristics that allow individuals to adapt to endemic environments, such as high altitude or extreme tropical weather. These genetic changes, most of them subtle and unexplored, could establish a mutational profile to develop new pharmacogenomic therapies specific for Latin American populations. In this review, we present the current status of research on somatic and germline alterations in Latin America compared to those found in Caucasian and Asian populations. Full article

(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2016)

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16 pages, 16758 KiB

Open AccessArticle

B-Myb Is Up-Regulated and Promotes Cell Growth and Motility in Non-Small Cell Lung Cancer

by Yuelei Jin^1,2, Huifang Zhu^1,2, Wei Cai^1,2, Xiaoyan Fan^1,2, Yitao Wang^1,2, Yulong Niu², Fangzhou Song^1,2,* and Youquan Bu^1,2,*

¹ Department of Biochemistry and Molecular Biology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, Chongqing 400016, China

² Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China

Int. J. Mol. Sci. 2017, 18(6), 860; https://doi.org/10.3390/ijms18060860 - 27 May 2017

Cited by 43 | Viewed by 6906

Abstract

B-Myb is a transcription factor that is overexpressed and plays an oncogenic role in several types of human cancers. However, its potential implication in lung cancer remains elusive. In the present study, we have for the first time investigated the expression profile of [...] Read more.

B-Myb is a transcription factor that is overexpressed and plays an oncogenic role in several types of human cancers. However, its potential implication in lung cancer remains elusive. In the present study, we have for the first time investigated the expression profile of B-Myb and its functional impact in lung cancer. Expression analysis by quantificational real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry demonstrated that B-Myb expression is aberrantly overexpressed in non-small cell lung cancer (NSCLC), and positively correlated with pathologic grade and clinical stage of NSCLC. A gain-of-function study revealed that overexpression of B-Myb significantly increases lung cancer cell growth, colony formation, migration, and invasion. Conversely, a loss-of-function study showed that knockdown of B-Myb decreases cell growth, migration, and invasion. B-Myb overexpression also promoted tumor growth in vivo in a NSCLC xenograft nude mouse model. A molecular mechanistic study by RNA-sequencing (RNA-seq) analysis showed that B-Myb overexpression causes up-regulation of various downstream genes (e.g., COL11A1, COL6A1, FN1, MMP2, NID1, FLT4, INSR, and CCNA1) and activation of multiple critical pathways (e.g., extracellular signal-regulated kinases (ERK) and phosphorylated-protein kinase B (Akt) signaling pathways) involved in cell proliferation, tumorigenesis, and metastasis. Collectively, our results indicate a tumor-promoting role for B-Myb in NSCLC and thus imply its potential as a target for the diagnosis and/or treatment of NSCLC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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11 pages, 249 KiB

Open AccessReview

Message in a Bottle: Dialog between Intestine and Skin Modulated by Probiotics

by Adrián D. Friedrich^1,*, Mariela L. Paz^1,2, Juliana Leoni² and Daniel H. González Maglio^1,2,*

¹ Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Inmunología, 1053 Buenos Aires, Argentina

² CONICET-Universidad de Buenos Aires, Instituto de Estudios de la Inmunidad Humoral (IDEHU), LIBAP, 1053 Buenos Aires, Argentina

Int. J. Mol. Sci. 2017, 18(6), 1067; https://doi.org/10.3390/ijms18061067 - 9 Jun 2017

Cited by 27 | Viewed by 9430

Abstract

At the beginning, probiotics were used exclusively for gastrointestinal conditions. However, over the years, evidence has shown that probiotics exert systemic effects. In this review article, we will summarize recent reports that postulate probiotic treatment as an efficient one against skin pathologies, such [...] Read more.

At the beginning, probiotics were used exclusively for gastrointestinal conditions. However, over the years, evidence has shown that probiotics exert systemic effects. In this review article, we will summarize recent reports that postulate probiotic treatment as an efficient one against skin pathologies, such as cancer, allergy, photoaging and skin infections. The focus will be restricted to oral probiotics that could potentially counteract the ultraviolet irradiation-induced skin alterations. Moreover, the possible underlying mechanisms by which probiotics can impact on the gut and exert their skin effects will be reviewed. Furthermore, how the local and systemic immune system is involved in the intestine-cutaneous crosstalk will be analyzed. In conclusion, this article will be divided into three core ideas: (a) probiotics regulate gut homeostasis; (b) gut and skin homeostasis are connected; (c) probiotics are a potentially effective treatment against skin conditions. Full article

(This article belongs to the Special Issue Nutrients and Phytochemicals for Skin Health)

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27 pages, 7983 KiB

Open AccessArticle

Ficus umbellata Vahl. (Moraceae) Stem Bark Extracts Exert Antitumor Activities In Vitro and In Vivo

by Kevine Kamga Silihe¹, Stéphane Zingue^2,3,4,5

, Evelyn Winter⁴, Charline Florence Awounfack³, Anupam Bishayee^6,*

, Nishil N. Desai⁶, Leônidas João Mello, Jr.⁴, Thomas Michel⁷, Francine Nzufo Tankeu¹, Derek Tantoh Ndinteh⁵, Sara Honorine Riwom¹, Dieudonné Njamen^3,5 and Tânia Beatriz Creczynski-Pasa^4,*

¹ Department of Biochemistry, Faculty of Sciences, University of Yaounde 1, Yaounde 812, Cameroon

² Department of Life and Earth Sciences, Higher Teachers’ Training College, University of Maroua, Maroua 55, Cameroon

³ Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, Yaounde 812, Cameroon

⁴ Department of Pharmaceutical Sciences and Department of Biochemistry, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil

⁵ Department of Applied Chemistry, Faculty of Sciences, University of Johannesburg, Doornfontein 2028, South Africa

⁶ Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA

⁷ Institute of Chemistry of Nice, Faculty of Sciences, University Côte d’Azur, Nice F-06108 Nice Cedex 2, France

Int. J. Mol. Sci. 2017, 18(6), 1073; https://doi.org/10.3390/ijms18061073 - 23 May 2017

Cited by 24 | Viewed by 6422

Abstract

A Ficus umbellata is used to treat cancer. The present work was therefore designed to assess antitumor potentials of F. umbellata extracts in nine different cell lines. Cell cycle, apoptosis, cell migration/invasion, levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), caspases [...] Read more.

A Ficus umbellata is used to treat cancer. The present work was therefore designed to assess antitumor potentials of F. umbellata extracts in nine different cell lines. Cell cycle, apoptosis, cell migration/invasion, levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), caspases activities as well as Bcl-2 and Bcl-xL protein content were assessed in MDA-MB-231 cells. The 7,12-dimethylbenz(a)anthracene (DMBA)-induced carcinogenesis in rats were also used to investigate antitumor potential of F. umbellata extracts. The F. umbellata methanol extract exhibited a CC₅₀ of 180 μg/mL in MDA-MB-231 cells after 24 h. It induced apoptosis in MCF-7 and MDA-MB-231 cells, while it did not alter their cell cycle phases. Further, it induced a decrease in MMP, an increase in ROS levels and caspases activities as well as a downregulation in Bcl-2 and Bcl-xL protein contents in MDA-MB-231 cells. In vivo, F. umbellata aqueous (200 mg/kg) and methanol (50 mg/kg) extracts significantly (p < 0.001) reduced ovarian tumor incidence (10%), total tumor burden (58% and 46%, respectively), average tumor weight (57.8% and 45.6%, respectively) as compared to DMBA control group. These results suggest antitumor potential of F. umbellata constituents possibly due to apoptosis induction mediated through ROS-dependent mitochondrial pathway. Full article

(This article belongs to the Special Issue Nutraceuticals in Human Health and Disease)

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16 pages, 5644 KiB

Open AccessArticle

by Haijian Sun^1,†, Xuexue Zhu^1,†, Yuetao Zhou¹, Weiwei Cai¹ and Liying Qiu^1,2,*

¹ Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China

² Department of Basic Medicine, Wuxi Medical School, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1097; https://doi.org/10.3390/ijms18061097 - 26 May 2017

Cited by 48 | Viewed by 9942

Abstract

Oxidized low-density lipoprotein (ox-LDL) accumulation is one of the critical determinants in endothelial dysfunction in many cardiovascular diseases such as atherosclerosis. C1q/TNF-related protein 9 (CTRP9) is identified to be an adipocytokine with cardioprotective properties. However, the potential roles of CTRP9 in endothelial function [...] Read more.

Oxidized low-density lipoprotein (ox-LDL) accumulation is one of the critical determinants in endothelial dysfunction in many cardiovascular diseases such as atherosclerosis. C1q/TNF-related protein 9 (CTRP9) is identified to be an adipocytokine with cardioprotective properties. However, the potential roles of CTRP9 in endothelial function remain largely elusive. In the present study, the effects of CTRP9 on the proliferation, apoptosis, migration, angiogenesis, nitric oxide (NO) production and oxidative stress in human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL were investigated. We observed that treatment with ox-LDL inhibited the proliferation, migration, angiogenesis and the generation of NO, while stimulated the apoptosis and reactive oxygen species (ROS) production in HUVECs. Incubation of HUVECs with CTRP9 rescued ox-LDL-induced endothelial injury. CTRP9 treatment reversed ox-LDL-evoked decreases in antioxidant enzymes including heme oxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase quinone 1, and glutamate-cysteine ligase (GCL), as well as endothelial nitric oxide synthase (eNOS). Furthermore, CTRP9 induced activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC1-α) and phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Of interest, AMPK inhibition or PGC1-α silencing abolished CTRP9-mediated antioxidant enzymes levels, eNOS expressions, and endothelial protective effects. Collectively, we provided the first evidence that CTRP9 attenuated ox-LDL-induced endothelial injury by antioxidant enzyme inductions dependent on PGC-1α/AMPK activation. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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11 pages, 1377 KiB

Open AccessArticle

Emergence of CD26+ Cancer Stem Cells with Metastatic Properties in Colorectal Carcinogenesis

by Alvin Ho-Kwan Cheung^1,2,†, Deepak Narayanan Iyer^1,2,†, Colin Siu-Chi Lam^1,2,†, Lui Ng^1,2, Sunny K. M. Wong^1,2, Hung-Sing Lee^1,2, Timothy Wan^1,2, Johnny Man^1,2, Ariel K. M. Chow^1,2, Ronnie T. Poon^1,2, Roberta Pang^1,2,* and Wai-Lun Law^1,2,*

¹ Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong and Queen Mary Hospital, Sassoon Road, Pokfulam, Hong Kong

² Centre for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1106; https://doi.org/10.3390/ijms18061106 - 23 May 2017

Cited by 14 | Viewed by 4712

Abstract

Colorectal cancer results from genetic aberrations which accumulate over a long period of time, with malignant and metastatic properties acquired at a relatively late stage. A subpopulation of CD26+ colorectal cancer stem cells are known to be implicated in metastasis. We quantified CD26+ [...] Read more.

Colorectal cancer results from genetic aberrations which accumulate over a long period of time, with malignant and metastatic properties acquired at a relatively late stage. A subpopulation of CD26+ colorectal cancer stem cells are known to be implicated in metastasis. We quantified CD26+ cancer cells in 11 primary tumor samples by flow cytometry, and showed that tumors having confirmed or suspected metastases harbored a relatively high CD26+ level in these samples. We hypothesized that this subpopulation of cancer stem cells arises in the late stage of carcinogenesis from the bulk of tumor daughter cells which are CD26−. The manipulation of PIK3CA and TP53, two genes commonly deregulated in the late stage, had an effect on the maintenance of the CD26+ cell population. When CD26− tumor daughter cells were sorted and cultured, the emergence of tumor spheres containing CD26+ cells occurred. These findings shed light to the origin of colorectal cancer stem cells with metastatic properties, which has an implication on conventional treatments by surgery or adjuvant chemotherapy for tumor debulking. Full article

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16 pages, 5195 KiB

Open AccessArticle

NANOG Plays a Hierarchical Role in the Transcription Network Regulating the Pluripotency and Plasticity of Adipose Tissue-Derived Stem Cells

by Maria Pitrone¹, Giuseppe Pizzolanti^1,*

, Laura Tomasello¹, Antonina Coppola¹, Lorenzo Morini², Gianni Pantuso², Romina Ficarella³, Valentina Guarnotta¹, Sebastio Perrini³, Francesco Giorgino³ and Carla Giordano^1,4,*

¹ Aldo Galluzzo Laboratory of Regenerative Medicine, Section of Endocrinology, Diabetology and Metabolism, Di.Bi.M.I.S, University of Palermo, 90127 Palermo, Italy

² Oncology Surgery, University of Palermo, 90127 Palermo, Italy

³ Endocrinology and Metabolic Diseases, University of Bari, 70124 Bari, Italy

⁴ ATeN (Advanced Technologies Network Center), University of Palermo, 90127 Palermo, Italy

Int. J. Mol. Sci. 2017, 18(6), 1107; https://doi.org/10.3390/ijms18061107 - 23 May 2017

Cited by 27 | Viewed by 9171

Abstract

The stromal vascular cell fraction (SVF) of visceral and subcutaneous adipose tissue (VAT and SAT) has increasingly come into focus in stem cell research, since these compartments represent a rich source of multipotent adipose-derived stem cells (ASCs). ASCs exhibit a self-renewal potential and [...] Read more.

The stromal vascular cell fraction (SVF) of visceral and subcutaneous adipose tissue (VAT and SAT) has increasingly come into focus in stem cell research, since these compartments represent a rich source of multipotent adipose-derived stem cells (ASCs). ASCs exhibit a self-renewal potential and differentiation capacity. Our aim was to study the different expression of the embryonic stem cell markers NANOG (homeobox protein NANOG), SOX2 (SRY (sex determining region Y)-box 2) and OCT4 (octamer-binding transcription factor 4) and to evaluate if there exists a hierarchal role in this network in ASCs derived from both SAT and VAT. ASCs were isolated from SAT and VAT biopsies of 72 consenting patients (23 men, 47 women; age 45 ± 10; BMI between 25 ± 5 and 30 ± 5 range) undergoing elective open-abdominal surgery. Sphere-forming capability was evaluated by plating cells in low adhesion plastic. Stem cell markers CD90, CD105, CD29, CD31, CD45 and CD146 were analyzed by flow cytometry, and the stem cell transcription factors NANOG, SOX2 and OCT4 were detected by immunoblotting and real-time PCR. NANOG, SOX2 and OCT4 interplay was explored by gene silencing. ASCs from VAT and SAT confirmed their mesenchymal stem cell (MSC) phenotype expressing the specific MSC markers CD90, CD105, NANOG, SOX2 and OCT4. NANOG silencing induced a significant OCT4 (70 ± 0.05%) and SOX2 (75 ± 0.03%) downregulation, whereas SOX2 silencing did not affect NANOG gene expression. Adipose tissue is an important source of MSC, and siRNA experiments endorse a hierarchical role of NANOG in the complex transcription network that regulates pluripotency. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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12 pages, 1421 KiB

Open AccessReview

Epigenetic Strategies to Boost Cancer Immunotherapies

by Maria J. Barrero

CNIO-Lilly Epigenetics Laboratory, Spanish National Cancer Research Center (CNIO), C/Melchor Fernández Almagro, 3. 28029 Madrid, Spain

Int. J. Mol. Sci. 2017, 18(6), 1108; https://doi.org/10.3390/ijms18061108 - 23 May 2017

Cited by 32 | Viewed by 7445

Abstract

Recently, immunotherapeutic approaches have shown impressive responses in a subset of cancer patients. However, the rate of success is low and a large percentage of treated patients do not experience clinical benefits. Therefore, additional strategies are needed to improve responses and select responsive [...] Read more.

Recently, immunotherapeutic approaches have shown impressive responses in a subset of cancer patients. However, the rate of success is low and a large percentage of treated patients do not experience clinical benefits. Therefore, additional strategies are needed to improve responses and select responsive patients. Emerging data suggest that epigenetic drugs can improve the responses to immunotherapy. Understanding the mechanisms of resistance to immunotherapy and the epigenetic events that take place during immune evasion is critical to providing a rational combined use of immunotherapies and epigenetic drugs. This review focuses in the epigenetic mechanisms involved in the responses to immunotherapy and how current drugs that target epigenetic regulators impact on them. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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15 pages, 1941 KiB

Open AccessArticle

Marker-Assisted Molecular Profiling, Deletion Mutant Analysis, and RNA-Seq Reveal a Disease Resistance Cluster Associated with Uromyces appendiculatus Infection in Common Bean Phaseolus vulgaris L.

by Antonette R. Todd¹, Nicole Donofrio², Venkateswara R. Sripathi^1,3, Phillip E. McClean⁴, Rian K. Lee⁴, Marcial Pastor-Corrales⁵ and Venu (Kal) Kalavacharla^1,6,*

¹ Department of Agriculture and Natural Resources, Delaware State University, Dover, DE 19901, USA

² Department of Plant and Soil Sciences, University of Delaware, Newark, DE 19716, USA

³ Center for Molecular Biology, Department of Biological & Environmental Sciences, College of Agricultural, Life & Natural Sciences, Alabama A&M University, Normal, AL 35762, USA

⁴ Department of Plant Sciences, North Dakota State University, Fargo, ND 58105, USA

⁵ United States Department of Agriculture-Agricultural Research Service, Soybean Genomics and Improvement Laboratory, Beltsville Agricultural Research Center, Beltsville, MD 20170, USA

⁶ Center for Integrated and Environmental Research (CIBER), Delaware State University, Dover, DE 19901, USA

Int. J. Mol. Sci. 2017, 18(6), 1109; https://doi.org/10.3390/ijms18061109 - 23 May 2017

Cited by 6 | Viewed by 5031

Abstract

Common bean (Phaseolus vulgaris L.) is an important legume, useful for its high protein and dietary fiber. The fungal pathogen Uromyces appendiculatus (Pers.) Unger can cause major loss in susceptible varieties of the common bean. The Ur-3 locus provides race specific resistance [...] Read more.

Common bean (Phaseolus vulgaris L.) is an important legume, useful for its high protein and dietary fiber. The fungal pathogen Uromyces appendiculatus (Pers.) Unger can cause major loss in susceptible varieties of the common bean. The Ur-3 locus provides race specific resistance to virulent strains or races of the bean rust pathogen along with Crg, (Complements resistance gene), which is required for Ur-3-mediated rust resistance. In this study, we inoculated two common bean genotypes (resistant “Sierra” and susceptible crg) with rust race 53 of U. appendiculatus, isolated leaf RNA at specific time points, and sequenced their transcriptomes. First, molecular markers were used to locate and identify a 250 kb deletion on chromosome 10 in mutant crg (which carries a deletion at the Crg locus). Next, we identified differential expression of several disease resistance genes between Mock Inoculated (MI) and Inoculated (I) samples of “Sierra” leaf RNA within the 250 kb delineated region. Both marker assisted molecular profiling and RNA-seq were used to identify possible transcriptomic locations of interest regarding the resistance in the common bean to race 53. Identification of differential expression among samples in disease resistance clusters in the bean genome may elucidate significant genes underlying rust resistance. Along with preserving favorable traits in the crop, the current research may also aid in global sustainability of food stocks necessary for many populations. Full article

(This article belongs to the Special Issue Plant Defense Genes Against Biotic Stresses)

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23 pages, 1035 KiB

Open AccessArticle

Validation of Splicing Events in Transcriptome Sequencing Data

by Wolfgang Kaisers^1,2,*

, Johannes Ptok³, Holger Schwender^2,4 and Heiner Schaal^2,3

¹ Department for Anaesthesiology, University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany

² BMFZ (Biologisch-Medizinisches Forschungszentrum), Heinrich Heine University, 40225 Düsseldorf, Germany

³ Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany

⁴ Mathematical Institute, Heinrich Heine University, 40225 Düsseldorf, Germany

Int. J. Mol. Sci. 2017, 18(6), 1110; https://doi.org/10.3390/ijms18061110 - 23 May 2017

Cited by 6 | Viewed by 4342

Abstract

Genomic alignments of sequenced cellular messenger RNA contain gapped alignments which are interpreted as consequence of intron removal. The resulting gap-sites, genomic locations of alignment gaps, are landmarks representing potential splice-sites. As alignment algorithms report gap-sites with a considerable false discovery rate, validations [...] Read more.

Genomic alignments of sequenced cellular messenger RNA contain gapped alignments which are interpreted as consequence of intron removal. The resulting gap-sites, genomic locations of alignment gaps, are landmarks representing potential splice-sites. As alignment algorithms report gap-sites with a considerable false discovery rate, validations are required. We describe two quality scores, gap quality score (gqs) and weighted gap information score (wgis), developed for validation of putative splicing events: While gqs solely relies on alignment data wgis additionally considers information from the genomic sequence. FASTQ files obtained from 54 human dermal fibroblast samples were aligned against the human genome (GRCh38) using TopHat and STAR aligner. Statistical properties of gap-sites validated by gqs and wgis were evaluated by their sequence similarity to known exon-intron borders. Within the 54 samples, TopHat identifies 1,000,380 and STAR reports 6,487,577 gap-sites. Due to the lack of strand information, however, the percentage of identified GT-AG gap-sites is rather low. While gap-sites from TopHat contain ≈89% GT-AG, gap-sites from STAR only contain ≈42% GT-AG dinucleotide pairs in merged data from 54 fibroblast samples. Validation with gqs yields 156,251 gap-sites from TopHat alignments and 166,294 from STAR alignments. Validation with wgis yields 770,327 gap-sites from TopHat alignments and 1,065,596 from STAR alignments. Both alignment algorithms, TopHat and STAR, report gap-sites with considerable false discovery rate, which can drastically be reduced by validation with gqs and wgis. Full article

(This article belongs to the Section Biochemistry)

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10 pages, 660 KiB

Open AccessReview

Aberrant DNA Methylation as a Biomarker and a Therapeutic Target of Cholangiocarcinoma

by Toshiaki Nakaoka, Yoshimasa Saito^* and Hidetsugu Saito

Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan

Int. J. Mol. Sci. 2017, 18(6), 1111; https://doi.org/10.3390/ijms18061111 - 23 May 2017

Cited by 49 | Viewed by 8724

Abstract

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients [...] Read more.

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, death-associated protein kinase (DAPK), miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for the diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors holds considerable promise for the treatment of cholangiocarcinoma through the reactivation of tumor suppressor genes and miRNAs as well as the induction of an anti-viral immune response. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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15 pages, 891 KiB

Open AccessReview

Oxidative Stress: Promoter of Allergic Sensitization to Protease Allergens?

by Leonie S. Van Rijt^1,*,†, Lara Utsch^1,†, René Lutter^1,2 and Ronald Van Ree^1,3

¹ Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

² Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

³ Department of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1112; https://doi.org/10.3390/ijms18061112 - 23 May 2017

Cited by 35 | Viewed by 7243

Abstract

Allergies arise from aberrant T helper type 2 responses to allergens. Several respiratory allergens possess proteolytic activity, which has been recognized to act as an adjuvant for the development of a Th2 response. Allergen source-derived proteases can activate the protease-activated receptor-2, have specific [...] Read more.

Allergies arise from aberrant T helper type 2 responses to allergens. Several respiratory allergens possess proteolytic activity, which has been recognized to act as an adjuvant for the development of a Th2 response. Allergen source-derived proteases can activate the protease-activated receptor-2, have specific effects on immune cells by cleaving cell membrane-bound regulatory molecules, and can disrupt tight junctions. The protease activity can induce a non-allergen-specific inflammatory response in the airways, which will set the stage for an allergen-specific Th2 response. In this review, we will discuss the evidence for the induction of oxidative stress as an underlying mechanism in Th2 sensitization to proteolytic allergens. We will discuss recent data linking the proteolytic activity of an allergen to its potential to induce oxidative stress and how this can facilitate allergic sensitization. Based on experimental data, we propose that a less proficient anti-oxidant response to allergen-induced oxidative stress contributes to the susceptibility to allergic sensitization. Besides the effect of oxidative stress on the immune response, we will also discuss how oxidative stress can increase the immunogenicity of an allergen by chemical modification. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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15 pages, 2158 KiB

Open AccessArticle

Regulatory Plasticity of Earthworm wMT-2 Gene Expression

by Victoria Drechsel¹, Karl Schauer¹, Maja Šrut² and Martina Höckner^1,*

¹ Institute of Zoology, Center for Molecular Biosciences, University of Innsbruck, Technikerstr. 25, 6020 Innsbruck, Austria

² Division of Zoology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia

Int. J. Mol. Sci. 2017, 18(6), 1113; https://doi.org/10.3390/ijms18061113 - 24 May 2017

Cited by 16 | Viewed by 6003

Abstract

Metallothioneins (MTs) are multifunctional proteins occurring throughout the animal kingdom. While the expression and transcriptional regulation of MTs is well-studied in vertebrates, the mechanism of MT activation is still unknown for most invertebrates. Therefore, we examined wMT-2 gene regulation and expression patterns in [...] Read more.

Metallothioneins (MTs) are multifunctional proteins occurring throughout the animal kingdom. While the expression and transcriptional regulation of MTs is well-studied in vertebrates, the mechanism of MT activation is still unknown for most invertebrates. Therefore, we examined wMT-2 gene regulation and expression patterns in Lumbricus rubellus and L. terrestris. Transcription levels, the occupation of DNA binding sites, the expression of putative transcriptional regulators, and promotor DNA methylation were determined. We found that wMT-2 expression does not follow a circadian pattern. However, Cd-induced wMT-2 induction was observed, and was, interestingly, suppressed by physical injury. Moreover, the promotor region that is responsible for the wMT-2 gene regulation was elucidated. ATF, a putative transcriptional regulator, showed increased phosphorylation upon Cd exposure, suggesting that it plays a major role in wMT-2 gene activation. The promotor methylation of wMT-2, on the other hand, is probably not involved in transcriptional regulation. Elucidating the regulatory mechanism of the earthworm MT gene activation might provide insights into the molecular coordination of the environmental stress response in invertebrates, and might also reveal a link to wound repair and, in a broader sense, to immunity. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

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14 pages, 2055 KiB

Open AccessArticle

Mass Spectrometry Based Profiling and Imaging of Various Ginsenosides from Panax ginseng Roots at Different Ages

by Jae Won Lee¹

, Seung-Heon Ji¹, Young-Seob Lee¹, Doo Jin Choi¹, Bo-Ram Choi¹, Geum-Soog Kim¹, Nam-In Baek²

and Dae Young Lee^1,*

¹ Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration (RDA), Eumseong 27709, Korea

² Department of Oriental Medicinal Materials and Processing, Kyung Hee University, Yongin 17104, Korea

Int. J. Mol. Sci. 2017, 18(6), 1114; https://doi.org/10.3390/ijms18061114 - 24 May 2017

Cited by 40 | Viewed by 6684

Abstract

(1) Background: Panax ginseng root is one of the most important herbal products, and the profiling of ginsenosides is critical for the quality control of ginseng roots at different ages in the herbal markets. Furthermore, interest in assessing the contents as well as [...] Read more.

(1) Background: Panax ginseng root is one of the most important herbal products, and the profiling of ginsenosides is critical for the quality control of ginseng roots at different ages in the herbal markets. Furthermore, interest in assessing the contents as well as the localization of biological compounds has been growing. The objective of this study is to carry out the mass spectrometry (MS)-based profiling and imaging of ginsenosides to assess ginseng roots at different ages; (2) Methods: Optimal ultra performance liquid chromatography coupled to quadrupole time of flight/MS (UPLC-QTOF/MS) was used to profile various ginsenosides from P. ginseng roots. Matrix-assisted laser desorption ionization (MALDI)-time of flight (TOF)/MS-based imaging was also optimized to visualize ginsenosides in ginseng roots; (3) Results: UPLC-QTOF/MS was used to profile 30 ginsenosides with high mass accuracy, with an in-house library constructed for the fast and exact identification of ginsenosides. Using this method, the levels of 14 ginsenosides were assessed in P. ginseng roots cultivated for 4, 5, and 6 years. The optimal MALDI-imaging MS (IMS) was also applied to visualize the 14 ginsenosides in ginseng roots. As a result, the MSI cross sections showed the localization of 4 ginsenoside ions ([M + K]⁺) in P. ginseng roots at different ages; (4) Conclusions: The contents and localization of various ginsenosides differ depending on the cultivation years of P. ginseng roots. Furthermore, this study demonstrated the utility of MS-based profiling and imaging of ginsenosides for the quality control of ginseng roots. Full article

(This article belongs to the Special Issue Metabolomics in the Plant Sciences 2017)

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23 pages, 1692 KiB

Open AccessReview

The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis

by Panagiotis Tsapogas^1,*, Ciaran James Mooney², Geoffrey Brown^2,3 and Antonius Rolink¹

¹ Developmental and Molecular Immunology, Department of Biomedicine, University of Basel, Mattenstrasse 28, Basel 4058, Switzerland

² Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edbgaston, Birmingham B15 2TT, UK

³ Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edbgaston, Birmingham B15 2TT, UK

Int. J. Mol. Sci. 2017, 18(6), 1115; https://doi.org/10.3390/ijms18061115 - 24 May 2017

Cited by 92 | Viewed by 14192

Abstract

The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 [...] Read more.

The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 are frequently found in acute myeloid leukemia (AML) patients and associated with a poor clinical prognosis. In the present review we provide an overview of our current knowledge on the role of FL in the generation of blood cell lineages. We examine recent studies on Flt3 expression by hematopoietic stem cells and its potential instructive action at early stages of hematopoiesis. In addition, we review current findings on the role of mutated FLT3 in leukemia and the development of FLT3 inhibitors for therapeutic use to treat AML. The importance of mouse models in elucidating the role of Flt3-ligand in normal and malignant hematopoiesis is discussed. Full article

(This article belongs to the Special Issue The Biology and Treatment of Myeloid Leukaemias)

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16 pages, 771 KiB

Open AccessReview

Molecular Basis of Alcohol-Related Gastric and Colon Cancer

by Hye-Kyung Na^* and Ja Young Lee

Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women’s University, Seoul 01133, Korea

Int. J. Mol. Sci. 2017, 18(6), 1116; https://doi.org/10.3390/ijms18061116 - 24 May 2017

Cited by 123 | Viewed by 16779

Abstract

Many meta-analysis, large cohort studies, and experimental studies suggest that chronic alcohol consumption increases the risk of gastric and colon cancer. Ethanol is metabolized by alcohol dehydrogenases (ADH), catalase or cytochrome P450 2E1 (CYP2E1) to acetaldehyde, which is then further oxidized to acetate [...] Read more.

Many meta-analysis, large cohort studies, and experimental studies suggest that chronic alcohol consumption increases the risk of gastric and colon cancer. Ethanol is metabolized by alcohol dehydrogenases (ADH), catalase or cytochrome P450 2E1 (CYP2E1) to acetaldehyde, which is then further oxidized to acetate by aldehyde dehydrogenase (ALDH). Acetaldehyde has been classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen to humans. The acetaldehyde level in the stomach and colon is locally influenced by gastric colonization by Helicobacter pylori or colonic microbes, as well as polymorphisms in the genes encoding tissue alcohol metabolizing enzymes, especially ALDH2. Alcohol stimulates the uptake of carcinogens and their metabolism and also changes the composition of enteric microbes in a way to enhance the aldehyde level. Alcohol also undergoes chemical coupling to membrane phospholipids and disrupts organization of tight junctions, leading to nuclear translocation of β-catenin and ZONAB, which may contributes to regulation of genes involved in proliferation, invasion and metastasis. Alcohol also generates reactive oxygen species (ROS) by suppressing the expression of antioxidant and cytoprotective enzymes and inducing expression of CYP2E1 which contribute to the metabolic activation of chemical carcinogens. Besides exerting genotoxic effects by directly damaging DNA, ROS can activates signaling molecules involved in inflammation, metastasis and angiogenesis. In addition, alcohol consumption induces folate deficiency, which may result in aberrant DNA methylation profiles, thereby influencing cancer-related gene expression. Full article

(This article belongs to the Special Issue Gene-Diet Interactions in Chronic Diseases)

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15 pages, 869 KiB

Open AccessReview

Mammalian Metallothionein-3: New Functional and Structural Insights

by Milan Vašák^1,* and Gabriele Meloni^2,*

¹ Department of Chemistry B, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

² Department of Chemistry and Biochemistry, University of Texas at Dallas, 800 W Campbell Road, Richardson, TX 75080-3021, USA

Int. J. Mol. Sci. 2017, 18(6), 1117; https://doi.org/10.3390/ijms18061117 - 24 May 2017

Cited by 83 | Viewed by 8816

Abstract

Metallothionein-3 (MT-3), a member of the mammalian metallothionein (MT) family, is mainly expressed in the central nervous system (CNS). MT-3 possesses a unique neuronal growth inhibitory activity, and the levels of this intra- and extracellularly occurring metalloprotein are markedly diminished in the brain [...] Read more.

Metallothionein-3 (MT-3), a member of the mammalian metallothionein (MT) family, is mainly expressed in the central nervous system (CNS). MT-3 possesses a unique neuronal growth inhibitory activity, and the levels of this intra- and extracellularly occurring metalloprotein are markedly diminished in the brain of patients affected by a number of metal-linked neurodegenerative disorders, including Alzheimer’s disease (AD). In these pathologies, the redox cycling of copper, accompanied by the production of reactive oxygen species (ROS), plays a key role in the neuronal toxicity. Although MT-3 shares the metal-thiolate clusters with the well-characterized MT-1 and MT-2, it shows distinct biological, structural and chemical properties. Owing to its anti-oxidant properties and modulator function not only for Zn, but also for Cu in the extra- and intracellular space, MT-3, but not MT-1/MT-2, protects neuronal cells from the toxicity of various Cu(II)-bound amyloids. In recent years, the roles of zinc dynamics and MT-3 function in neurodegeneration are slowly emerging. This short review focuses on the recent developments regarding the chemistry and biology of MT-3. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

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14 pages, 984 KiB

Open AccessArticle

Essential Role of Growth Hormone and IGF-1 in Therapeutic Effect of Ghrelin in the Course of Acetic Acid-Induced Colitis

by Piotr Ceranowicz¹

, Zygmunt Warzecha^1,*

, Jakub Cieszkowski¹, Dagmara Ceranowicz^1,2, Beata Kuśnierz-Cabala³, Joanna Bonior⁴

, Jolanta Jaworek⁴, Tadeusz Ambroży⁵

, Krzysztof Gil⁶

, Rafał Olszanecki⁷, Małgorzata Pihut⁸ and Artur Dembiński¹

¹ Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland

² Department of Pediatrics, Gastroenterology and Nutrition, University Children’s Hospital, Faculty of Medicine, Jagiellonian University Medical College, 30-663 Cracow, Poland

³ Department of Diagnostics, Chair of Clinical Biochemistry, Faculty of Medicine Jagiellonian University Medical College, 31-501 Cracow, Poland

⁴ Department of Medical Physiology Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Cracow, Poland

⁵ Department of Theory of Sport and Kinesiology, Faculty of Physical Education, University of Physical Education, 31-571 Cracow, Poland

⁶ Department of Pathophysiology, Faculty of Medicine, Jagiellonian University Medical College, 31-121 Cracow, Poland

⁷ Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland

⁸ Department of Prosthetic Dentistry, Faculty of Medicine, Jagiellonian University Medical College, 31-155 Cracow, Poland

Int. J. Mol. Sci. 2017, 18(6), 1118; https://doi.org/10.3390/ijms18061118 - 24 May 2017

Cited by 27 | Viewed by 5691

Abstract

Previous studies have shown that ghrelin exhibits a protective and therapeutic effect in the gut. The aim of the present study was to examine whether administration of ghrelin affects the course of acetic acid-induced colitis and to determine what is the role of [...] Read more.

Previous studies have shown that ghrelin exhibits a protective and therapeutic effect in the gut. The aim of the present study was to examine whether administration of ghrelin affects the course of acetic acid-induced colitis and to determine what is the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in this effect. In sham-operated or hypophysectomized male Wistar rats, colitis was induced by enema with 1 mL of 3% solution of acetic acid. Saline or ghrelin (given at the dose of 8 nmol/kg/dose) was administered intraperitoneally twice a day. Seven days after colitis induction, rats were anesthetized and the severity of the colitis was assessed. Treatment with ghrelin reduced the area of colonic mucosa damage in pituitary-intact rat. This effect was associated with increase in serum levels of GH and IGF-1. Moreover, administration of ghrelin improved blood flow in colonic mucosa and mucosal cell proliferation, as well as reduced mucosal concentration of proinflammatory interleukin-1β (IL-1β) and activity of myeloperoxidase. Hypophysectomy reduced serum levels of GH and IGF-1 and increased the area of colonic damage in rats with colitis. These effects were associated with additional reduction in mucosal blood follow and DNA synthesis when compared to pituitary-intact rats. Mucosal concentration of IL-1β and mucosal activity of myeloperoxidase were maximally increased. Moreover, in hypophysectomized rats, administration of ghrelin failed to affect serum levels of GH or IGF-1, as well as the healing rate of colitis, mucosal cell proliferation, and mucosal concentration of IL-1β, or activity of myeloperoxidase. We conclude that administration of ghrelin accelerates the healing of the acetic acid-induced colitis. Therapeutic effect of ghrelin in experimental colitis is mainly mediated by the release of endogenous growth hormone and IGF-1. Full article

(This article belongs to the Special Issue Growth Hormone: Therapeutic Possibilities)

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17 pages, 474 KiB

Open AccessReview

Melatonin Scavenger Properties against Oxidative and Nitrosative Stress: Impact on Gamete Handling and In Vitro Embryo Production in Humans and Other Mammals

by Pía Loren¹

, Raúl Sánchez^1,2, María-Elena Arias^1,2,3, Ricardo Felmer^1,4, Jennie Risopatrón^1,5 and Carolina Cheuquemán^1,*

¹ Centro de Biotecnología de la Reproducción (BIOREN-CEBIOR), Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile

² Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile

³ Departamento de Producción Agropecuaria, Facultad de Ciencias Agropecuarias y Forestales, Universidad de La Frontera, Temuco 4811230, Chile

⁴ Departamento de Ciencias Agronómicas y Recursos Naturales, Facultad de Ciencias Agropecuarias y Forestales, Universidad de La Frontera, Temuco 4811230, Chile

⁵ Departamento de Ciencias Básicas, Universidad de La Frontera, Temuco 4811230, Chile

Int. J. Mol. Sci. 2017, 18(6), 1119; https://doi.org/10.3390/ijms18061119 - 14 Jun 2017

Cited by 72 | Viewed by 6458

Abstract

Oxidative and nitrosative stress are common problems when handling gametes in vitro. In vitro development in mammalian embryos is highly affected by culture conditions, especially by reactive oxygen species (ROS) and reactive nitrogen species (RNS), because their absence or overproduction causes embryo arrest [...] Read more.

Oxidative and nitrosative stress are common problems when handling gametes in vitro. In vitro development in mammalian embryos is highly affected by culture conditions, especially by reactive oxygen species (ROS) and reactive nitrogen species (RNS), because their absence or overproduction causes embryo arrest and changes in gene expression. Melatonin in gamete co-incubation during in vitro fertilization (IVF) has deleterious or positive effects, depending on the concentration used in the culture medium, demonstrating the delicate balance between antioxidant and pro-oxidant activity. Further research is needed to better understand the possible impact of melatonin on the different IVP steps in humans and other mammals, especially in seasonal breeds where this neuro-hormone system highly regulates its reproduction physiology. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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12 pages, 721 KiB

Open AccessReview

Cholesterol Crystal Embolism and Chronic Kidney Disease

by Xuezhu Li¹, George Bayliss² and Shougang Zhuang^1,2,*

¹ Division of Nephrology, Tongji University School of Medicine, Shanghai 200120, China

² Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI 02903, USA

Int. J. Mol. Sci. 2017, 18(6), 1120; https://doi.org/10.3390/ijms18061120 - 24 May 2017

Cited by 49 | Viewed by 14636

Abstract

Renal disease caused by cholesterol crystal embolism (CCE) occurs when cholesterol crystals become lodged in small renal arteries after small pieces of atheromatous plaques break off from the aorta or renal arteries and shower the downstream vascular bed. CCE is a multisystemic disease [...] Read more.

Renal disease caused by cholesterol crystal embolism (CCE) occurs when cholesterol crystals become lodged in small renal arteries after small pieces of atheromatous plaques break off from the aorta or renal arteries and shower the downstream vascular bed. CCE is a multisystemic disease but kidneys are particularly vulnerable to atheroembolic disease, which can cause an acute, subacute, or chronic decline in renal function. This life-threatening disease may be underdiagnosed and overlooked as a cause of chronic kidney disease (CKD) among patients with advanced atherosclerosis. CCE can result from vascular surgery, angiography, or administration of anticoagulants. Atheroembolic renal disease has various clinical features that resemble those found in other kidney disorders and systemic diseases. It is commonly misdiagnosed in clinic, but confirmed by characteristic renal biopsy findings. Therapeutic options are limited, and prognosis is considered to be poor. Expanding knowledge of atheroembolic renal disease due to CCE opens perspectives for recognition, diagnosis, and treatment of this cause of progressive renal insufficiency. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease 2017)

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15 pages, 2272 KiB

Open AccessArticle

Stability Profiles and Therapeutic Effect of Cu/Zn Superoxide Dismutase Chemically Coupled to O-Quaternary Chitosan Derivatives against Dextran Sodium Sulfate-Induced Colitis

by Nan Zhao¹, Zhaolong Feng¹, Meng Shao¹, Jichao Cao^1,2, Fengshan Wang^1,2 and Chunhui Liu^1,2,*

¹ Key Laboratory of Chemical Biology (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China

² National Glycoengineering Research Center, Shandong University, Jinan 250012, China

Int. J. Mol. Sci. 2017, 18(6), 1121; https://doi.org/10.3390/ijms18061121 - 24 May 2017

Cited by 12 | Viewed by 5683

Abstract

Superoxide dismutase (SOD) has attracted considerable attention on treatment of reactive oxygen species (ROS)-related disorders. We previously conjugated Cu/Zn SOD to O-quaternary chitosan derivatives (O-HTCC) to yield a polymer–enzyme conjugate O-HTCC-SOD that demonstrated superior therapeutic effect to native SOD. [...] Read more.

Superoxide dismutase (SOD) has attracted considerable attention on treatment of reactive oxygen species (ROS)-related disorders. We previously conjugated Cu/Zn SOD to O-quaternary chitosan derivatives (O-HTCC) to yield a polymer–enzyme conjugate O-HTCC-SOD that demonstrated superior therapeutic effect to native SOD. The present study demonstrated that O-HTCC-SOD had wider pH activity range, better thermal stability, excellent long-term stability for storage, as well as unique reinstatement of activity exposure to proteolytic degradation that was helpful for longer half-life in vivo. O-HTCC-SOD exerted significant anti-inflammatory effects on lipopolysaccharides (LPS)-stimulated mouse peritoneal macrophages by down-regulating production of pro-inflammatory cytokines and intracellular ROS. O-HTCC-SOD significantly attenuated dextran sodium (DSS)-induced colitis in mice as observed by the colitis severity, neutrophil infiltration and histopathological damage, whereas native SOD failed to do so. In conclusion, conjugation of O-HTCC conferred SOD with better stability and enhanced therapeutic potential, offering a promising option in treatment of inflammatory bowel disease. Full article

(This article belongs to the Special Issue Dissecting Mechanisms of Action of Biologics in Inflammatory Bowel Diseases)

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12 pages, 215 KiB

Open AccessReview

Engineering Exosomes for Cancer Therapy

by Katie E. Gilligan

and Róisín M. Dwyer^*

Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway (NUIG), Galway H91 YR71, Ireland

Int. J. Mol. Sci. 2017, 18(6), 1122; https://doi.org/10.3390/ijms18061122 - 24 May 2017

Cited by 248 | Viewed by 18349

Abstract

There remains an urgent need for novel therapeutic strategies to treat metastatic cancer, which results in over 8 million deaths annually worldwide. Following secretion, exosomes are naturally taken up by cells, and capable of the stable transfer of drugs, therapeutic microRNAs and proteins. [...] Read more.

There remains an urgent need for novel therapeutic strategies to treat metastatic cancer, which results in over 8 million deaths annually worldwide. Following secretion, exosomes are naturally taken up by cells, and capable of the stable transfer of drugs, therapeutic microRNAs and proteins. As knowledge of the biogenesis, release and uptake of exosomes continues to evolve, and thus also has interest in these extracellular vesicles as potential tumor-targeted vehicles for cancer therapy. The ability to engineer exosome content and migratory itinerary holds tremendous promise. Studies to date have employed viral and non-viral methods to engineer the parent cells to secrete modified exosomes, or alternatively, to directly manipulate exosome content following secretion. The majority of studies have demonstrated promising results, with decreased tumor cell invasion, migration and proliferation, along with enhanced immune response, cell death, and sensitivity to chemotherapy observed. The studies outlined in this review highlight the exciting potential for exosomes as therapeutic vehicles for cancer treatment. Successful implementation in the clinical setting will be dependent upon establishment of rigorous standards for exosome manipulation, isolation, and characterisation. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

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17 pages, 3188 KiB

Open AccessArticle

Chlorpromazine Increases the Expression of Polysialic Acid (PolySia) in Human Neuroblastoma Cells and Mouse Prefrontal Cortex

by Chikara Abe^1,2,†, Saki Nishimura^1,2,†, Airi Mori^1,2, Yuki Niimi^1,2, Yi Yang^1,2, Masaya Hane^1,2, Ken Kitajima^1,2 and Chihiro Sato^1,2,*

¹ Bioscience and Biotechnology Center, Nagoya University, Nagoya 464-8601, Japan

² Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1123; https://doi.org/10.3390/ijms18061123 - 24 May 2017

Cited by 20 | Viewed by 7558

Abstract

The neural cell adhesion molecule (NCAM) is modified by polysialic acid (polySia or PSA) in embryonic brains. In adult brains, polySia modification of NCAM is only observed in restricted areas where neural plasticity, remodeling of neural connections, or neural generation is ongoing although [...] Read more.

The neural cell adhesion molecule (NCAM) is modified by polysialic acid (polySia or PSA) in embryonic brains. In adult brains, polySia modification of NCAM is only observed in restricted areas where neural plasticity, remodeling of neural connections, or neural generation is ongoing although the amount of NCAM remains unchanged. Impairments of the polySia-expression and several single nucleotide polymorphisms (SNPs) of the polysialyltransferase (polyST) ST8SIA2 gene are reported to be associated with schizophrenia and bipolar disorder. Chlorpromazine (CPZ) is well-known as an agent for treating schizophrenia, and our hypothesis is that CPZ may affect the polySia expression or the gene expression of polySTs or NCAM. To test this hypothesis, we analyzed the effects of CPZ on the expression of polySia-NCAM on human neuroblastoma cell line, IMR-32 cells, by immunochemical and chemical methods. Interestingly, the cell surface expression of polySia, especially those with lower chain lengths, was significantly increased on the CPZ-treated cells, while mRNAs for polySTs and NCAM, and the amounts of total polySia-NCAM remained unchanged. The addition of brefeldin A, an inhibitor of endocytosis, suppressed the CPZ-induced cell surface polySia expression. In addition, polySia-NCAM was also observed in the vesicle compartment inside the cell. All these data suggest that the level of cell surface expression of polySia in IMR-32 is highly regulated and that CPZ changes the rate of the recycling of polySia-NCAM, leading to the up-regulation of polySia-NCAM on the cell surface. We also analyzed the effect of CPZ on polySia-expression in various brain regions in adult mice and found that CPZ only influenced the total amounts of polySia-NCAM in prefrontal cortex. These results suggest a brain-region-specific effect of CPZ on the expression of total polySia in mouse brain. Collectively, anti-schizophrenia agent CPZ consistently up-regulates the expression polySia at both cellular and animal levels. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins 2017)

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12 pages, 241 KiB

Open AccessReview

Translational Development and Application of (1→3)-β-d-Glucan for Diagnosis and Therapeutic Monitoring of Invasive Mycoses

by Matthew W. McCarthy^1,*, Ruta Petraitiene²

and Thomas J. Walsh³

¹ Division of General Internal Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA

² Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA

³ Departments of Pediatrics, and Microbiology & Immunology, Weill Cornell Medicine, New York, NY 10065, USA

Int. J. Mol. Sci. 2017, 18(6), 1124; https://doi.org/10.3390/ijms18061124 - 24 May 2017

Cited by 21 | Viewed by 6659

Abstract

Early diagnosis and prompt initiation of appropriate antimicrobial therapy are crucial steps in the management of patients with invasive fungal infections. However, the diagnosis of invasive mycoses remains a major challenge in clinical practice, because presenting symptoms may be subtle and non-invasive diagnostic [...] Read more.

Early diagnosis and prompt initiation of appropriate antimicrobial therapy are crucial steps in the management of patients with invasive fungal infections. However, the diagnosis of invasive mycoses remains a major challenge in clinical practice, because presenting symptoms may be subtle and non-invasive diagnostic assays often lack sensitivity and specificity. Diagnosis is often expressed on a scale of probability (proven, probable and possible) based on a constellation of imaging findings, microbiological tools and histopathology, as there is no stand-alone assay for diagnosis. Recent data suggest that the carbohydrate biomarker (1→3)-β-d-glucan may be useful in both the diagnosis and therapeutic monitoring of invasive fungal infections due to some yeasts, molds, and dimorphic fungi. In this paper, we review recent advances in the use of (1→3)-β-d-glucan to monitor clinical response to antifungal therapy and explore how this assay may be used in the future. Full article

(This article belongs to the Special Issue Glucan: New Perspectives on Biochemistry and Application)

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10 pages, 5680 KiB

Open AccessArticle

Melatonin Attenuates Pulmonary Hypertension in Chronically Hypoxic Rats

by Ming Wai Hung, Hang Mee Yeung, Chi Fai Lau

, Angela Ming See Poon, George L. Tipoe and Man Lung Fung^*

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China

Int. J. Mol. Sci. 2017, 18(6), 1125; https://doi.org/10.3390/ijms18061125 - 24 May 2017

Cited by 45 | Viewed by 6360

Abstract

Chronic hypoxia induces pulmonary hypertension and vascular remodeling, which are clinically relevant to patients with chronic obstructive pulmonary disease (COPD) associated with a decreased level of nitric oxide (NO). Oxidative stress and inflammation play important roles in the pathophysiological processes in COPD. We [...] Read more.

Chronic hypoxia induces pulmonary hypertension and vascular remodeling, which are clinically relevant to patients with chronic obstructive pulmonary disease (COPD) associated with a decreased level of nitric oxide (NO). Oxidative stress and inflammation play important roles in the pathophysiological processes in COPD. We examined the hypothesis that daily administration of melatonin (10 mg/kg) mitigates the pulmonary hypertension and vascular remodeling in chronically hypoxic rats. The right ventricular systolic pressure (RVSP) and the thickness of pulmonary arteriolar wall were measured from normoxic control, vehicle- and melatonin-treated hypoxic rats exposed to 10% O₂ for 14 days. Levels of markers for oxidative stress (malondialdhyde) and inflammation (tumor necrosis factor-α (TNFα), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2)) and the expressions of total endothelial NO synthase (eNOS) and phosphorylated eNOS at serine1177 (ser1177) were determined in the lung tissue. We found that the RVSP and the thickness of the arteriolar wall were significantly increased in the vehicle-treated hypoxic animals with elevated levels of malondialdhyde and mRNA expressions of the inflammatory mediators, when compared with the normoxic control. In addition, the phosphorylated eNOS (ser1177) level was significantly decreased, despite an increased eNOS expression in the vehicle-treated hypoxic group. Melatonin treatment significantly attenuated the levels of RVSP, thickness of the arteriolar wall, oxidative and inflammatory markers in the hypoxic animals with a marked increase in the eNOS phosphorylation in the lung. These results suggest that melatonin attenuates pulmonary hypertension by antagonizing the oxidative injury and restoration of NO production. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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24 pages, 1150 KiB

Open AccessReview

The Peroxisome-Mitochondria Connection: How and Why?

by Marc Fransen^1,*, Celien Lismont¹ and Paul Walton²

¹ Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine, KU Leuven, University of Leuven, 3000 Leuven, Belgium

² Department of Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 3K7, Canada

Int. J. Mol. Sci. 2017, 18(6), 1126; https://doi.org/10.3390/ijms18061126 - 24 May 2017

Cited by 252 | Viewed by 23495

Abstract

Over the past decades, peroxisomes have emerged as key regulators in overall cellular lipid and reactive oxygen species metabolism. In mammals, these organelles have also been recognized as important hubs in redox-, lipid-, inflammatory-, and innate immune-signaling networks. To exert these activities, peroxisomes [...] Read more.

Over the past decades, peroxisomes have emerged as key regulators in overall cellular lipid and reactive oxygen species metabolism. In mammals, these organelles have also been recognized as important hubs in redox-, lipid-, inflammatory-, and innate immune-signaling networks. To exert these activities, peroxisomes must interact both functionally and physically with other cell organelles. This review provides a comprehensive look of what is currently known about the interconnectivity between peroxisomes and mitochondria within mammalian cells. We first outline how peroxisomal and mitochondrial abundance are controlled by common sets of cis- and trans-acting factors. Next, we discuss how peroxisomes and mitochondria may communicate with each other at the molecular level. In addition, we reflect on how these organelles cooperate in various metabolic and signaling pathways. Finally, we address why peroxisomes and mitochondria have to maintain a healthy relationship and why defects in one organelle may cause dysfunction in the other. Gaining a better insight into these issues is pivotal to understanding how these organelles function in their environment, both in health and disease. Full article

(This article belongs to the Special Issue Mitochondria Crosstalks with other Organelles in Pathophysiology)

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20 pages, 12906 KiB

Open AccessArticle

Tdrd12 Is Essential for Germ Cell Development and Maintenance in Zebrafish

by Xiangyan Dai¹, Yuqin Shu^2,3, Qiyong Lou², Qiang Tian¹, Gang Zhai², Jia Song^2,3, Suxiang Lu^2,3, Hong Yu¹, Jiangyan He² and Zhan Yin^2,*

¹ Department of Medical Cell Biology and Genetics, College of Preclinical Medicine, Southwest Medical University, Luzhou 646000, China

² State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China

³ University of Chinese Academy of Sciences, Beijing 100049, China

Int. J. Mol. Sci. 2017, 18(6), 1127; https://doi.org/10.3390/ijms18061127 - 7 Jun 2017

Cited by 21 | Viewed by 8059

Abstract

The regularity of Piwi-interacting RNA (piRNA) biogenesis is crucial to germline development. Functioning as Piwi-interacting proteins, Tudor domain-related proteins (Tdrds) have been demonstrated to be involved in spermatogenesis and the piRNA pathway. In this study, zebrafish tdrd12 was identified, and the maternal and [...] Read more.

The regularity of Piwi-interacting RNA (piRNA) biogenesis is crucial to germline development. Functioning as Piwi-interacting proteins, Tudor domain-related proteins (Tdrds) have been demonstrated to be involved in spermatogenesis and the piRNA pathway. In this study, zebrafish tdrd12 was identified, and the maternal and germ cell-specific expression patterns of zebrafish tdrd12 were observed. Utilizing TALEN (transcription activator-like effector nuclease) techniques, two independent tdrd12 mutant zebrafish lines were generated. Although no defects were found during the generation of the primordial germ cells (PGCs) in the tdrd12-null fish progenies obtained from the heterozygous tdrd12 mutant parents, all Tdrd12-deficient fish developed into infertile males. The reduced numbers and eventually loss of the germ cells by 35 days post fertilization (dpf) led to masculinization and infertility of the Tdrd12-deficient fish. Meiosis defects of the germ cells in the tdrd12 mutants during the gonad-transitioning period were observed, revealing the indispensable functions of Tdrd12 in gametogenesis. Our studies demonstrated that zebrafish Tdrd12 is essential for germ cell development and maintenance. Full article

(This article belongs to the Section Biochemistry)

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11 pages, 257 KiB

Open AccessArticle

Inducible Nitric Oxide Synthase Polymorphisms and Nitric Oxide Levels in Individuals with Chronic Periodontitis

by Raquel M. Scarel-Caminaga^1,*

, Flávia F. Cera¹, Suzane C. Pigossi²

, Livia S. Finoti³, Yeon J. Kim⁴, Aline C. Viana², Rodrigo Secolin⁵, Marcelo F. Montenegro⁶, José E. Tanus-Santos⁶, Silvana R. P. Orrico² and Joni A. Cirelli²

¹ Department of Morphology, School of Dentistry at Araraquara, São Paulo State University (UNESP), Humaita St., 1680, Araraquara CEP 14801-903, São Paulo, Brazil

² Department of Diagnosis and Surgery, School of Dentistry at Araraquara, São Paulo State University (UNESP), Humaita St., 1680, Araraquara CEP 14801-903, São Paulo, Brazil

³ Department of Periodontics, School of Dental Medicine, University of Pennsylvania, 240 S 40th St., Philadelphia, PA 19104, USA

⁴ Department of Implantology, University of Santo Amaro, Professor Enéas de Siqueira Neto, St., 340, Santo Amaro CEP 04829-300, São Paulo, Brazil

⁵ Department of Medical Genetics, University of Campinas—UNICAMP, Tessália Vieira de Camargo St., 126 Campinas CEP 13083-887, São Paulo, Brazil

⁶ Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Avenue, 3900, Ribeirão Preto CEP 14.049-900, São Paulo, Brazil

Int. J. Mol. Sci. 2017, 18(6), 1128; https://doi.org/10.3390/ijms18061128 - 15 Jun 2017

Cited by 14 | Viewed by 3952

Abstract

This study aimed to investigate whether the −1026(A>C)(rs2779249) and +2087(A>G)(2297518) polymorphisms in the NOS2 gene were associated with chronic periodontitis (CP) and with salivary levels of nitrite (NO₂⁻) and/or nitrate + nitrite (NOx). A group of 113 mixed-race patients were [...] Read more.

This study aimed to investigate whether the −1026(A>C)(rs2779249) and +2087(A>G)(2297518) polymorphisms in the NOS2 gene were associated with chronic periodontitis (CP) and with salivary levels of nitrite (NO₂⁻) and/or nitrate + nitrite (NOx). A group of 113 mixed-race patients were subjected to periodontal, genetic, and biochemical evaluations (65 CP/48 periodontally healthy subjects). DNA was extracted from oral epithelial cells and used for genotyping by polymerase chain reaction (real-time). Salivary NOx concentrations were determined using an ozone-based chemiluminescence assay. Association of CP with alleles and genotypes of the −1026(A>C) polymorphism was found (X² test, p = 0.0075; 0.0308), but this was not maintained after multiple logistic regression, performed to estimate the effect of covariates and polymorphisms in CP. This analysis demonstrated, after correction for multiple comparisons, that only the female gender was significantly associated with CP. Polymorphisms analyzed as haplotypes were not associated with CP. NOx levels were significantly higher in the control group of heterozygous individuals for both polymorphisms. In conclusion, the female gender was significantly associated with CP, and higher levels of salivary NOx were found in control subjects and associated with the heterozygous state of the NOS2 polymorphisms, reinforcing the potential of NO metabolites as markers of periodontitis status. Full article

(This article belongs to the Section Biochemistry)

14 pages, 450 KiB

Open AccessReview

The Importance of Pericytes in Healing: Wounds and other Pathologies

by Hannah M. Thomas^1,2,3, Allison J. Cowin^1,2,3

and Stuart J. Mills^1,2,3,*

¹ Centre for Regenerative Medicine, Future Industries Institute, University of South Australia, Mawson Lakes 5095, Australia

² School of Pharmacy and Medical Sciences, University of South Australia, Adelaide 5000, Australia

³ Cooperative Research Centre for Cell Therapy Manufacturing, North Terrace, Adelaide 5000, Australia

Int. J. Mol. Sci. 2017, 18(6), 1129; https://doi.org/10.3390/ijms18061129 - 24 May 2017

Cited by 56 | Viewed by 9021

Abstract

Much of current research investigates the beneficial properties of mesenchymal stem cells (MSCs) as a treatment for wounds and other forms of injury. In this review, we bring attention to and discuss the role of the pericyte, a cell type which shares much [...] Read more.

Much of current research investigates the beneficial properties of mesenchymal stem cells (MSCs) as a treatment for wounds and other forms of injury. In this review, we bring attention to and discuss the role of the pericyte, a cell type which shares much of the differentiation potential and regenerative properties of the MSC as well as specific roles in the regulation of angiogenesis, inflammation and fibrosis. Pericytes have been identified as dysfunctional or depleted in many disease states, and observing the outcomes of pericyte perturbation in models of disease and wound healing informs our understanding of overall pericyte function and identifies these cells as an important target in the development of therapies to encourage healing. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration)

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13 pages, 3737 KiB

Open AccessArticle

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy

by Vincent Wing Sun Liu¹

, Wing Lung Yau², Chun Wai Tam², Kwok-Ming Yao¹ and Stephen Yuen Wing Shiu^1,*

¹ School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China

² Division of Nursing and Health Studies, School of Science and Technology, Open University of Hong Kong, Hong Kong, China

Int. J. Mol. Sci. 2017, 18(6), 1130; https://doi.org/10.3390/ijms18061130 - 31 May 2017

Cited by 38 | Viewed by 8656

Abstract

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we [...] Read more.

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT₁ receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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17 pages, 1545 KiB

Open AccessReview

Is There a Role for Genomics in the Management of Hypertension?

by Jacopo Burrello¹, Silvia Monticone¹

, Fabrizio Buffolo¹, Martina Tetti¹, Franco Veglio¹, Tracy A. Williams^1,2 and Paolo Mulatero^1,*

¹ Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Turin, 10126 Turin, Italy

² Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, 80336 Munich, Germany

Int. J. Mol. Sci. 2017, 18(6), 1131; https://doi.org/10.3390/ijms18061131 - 26 May 2017

Cited by 43 | Viewed by 7286

Abstract

Hypertension (HTN) affects about 1 billion people worldwide and the lack of a single identifiable cause complicates its treatment. Blood pressure (BP) levels are influenced by environmental factors, but there is a strong genetic component. Linkage analysis has identified several genes involved in [...] Read more.

Hypertension (HTN) affects about 1 billion people worldwide and the lack of a single identifiable cause complicates its treatment. Blood pressure (BP) levels are influenced by environmental factors, but there is a strong genetic component. Linkage analysis has identified several genes involved in Mendelian forms of HTN and the associated pathophysiological mechanisms have been unravelled, leading to targeted therapies. The majority of these syndromes are due to gain-of-function or loss-of-functions mutations, resulting in an alteration of mineralocorticoid, glucocorticoid, or sympathetic pathways. The diagnosis of monogenic forms of HTN has limited practical implications on the population and a systematic genetic screening is not justifiable. Genome-wide linkage and association studies (GWAS) have identified single nucleotide polymorphisms (SNPs), which influence BP. Forty-three variants have been described with each SNP affecting systolic and diastolic BP by 1.0 and 0.5 mmHg, respectively. Taken together Mendelian inheritance and all GWAS-identified HTN-associated variants explain 2–3% of BP variance. Epigenetic modifications, such as DNA methylation, histone modification and non-coding RNAs, have become increasingly recognized as important players in BP regulation and may justify a further part of missing heritability. In this review, we will discuss how genetics and genomics may assist clinicians in managing patients with HTN. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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16 pages, 5427 KiB

Open AccessArticle

Prostaglandin E2-Induced COX-2 Expressions via EP2 and EP4 Signaling Pathways in Human LoVo Colon Cancer Cells

by Hsi-Hsien Hsu^1,2, Yueh-Min Lin^3,4, Chia-Yao Shen⁵, Marthandam Asokan Shibu⁶, Shin-Yi Li⁶, Sheng-Huang Chang⁷, Chien-Chung Lin⁸, Ray-Jade Chen⁹, Vijaya Padma Viswanadha¹⁰, Hui-Nung Shih^1,6 and Chih-Yang Huang^6,11,12,*

¹ Division of Colorectal Surgery, Mackay Memorial Hospital, Freshwater 25160, Taiwan

² Mackay Medicine, Nursing and Management College, Taipei 10449, Taiwan

³ Department of pathology, Changhua Christian Hospital, Changhua 500, Taiwan

⁴ Medical Technology, Jen-The Junior College of Medicine, Nursing and Management, Miaoli 35664, Taiwan

⁵ Department of Nursing, Mei Ho University, Pingguang Road, Pingtung 912, Taiwan

⁶ Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan

⁷ Tsao-Tun Psychiatric Center, Department of Health, Executive Yuan, Taipei 10058, Taiwan

⁸ Orthopaedic Department, Armed Forces General Hospital, Taichung 404, Taiwan

⁹ Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

¹⁰ Department of Biotechnology, Bharathiar University, Coimbatore-641 046, India

¹¹ Graduate Institute of Chinese Medical Science, China Medical University, Taichung 40402, Taiwan

¹² Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan

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Int. J. Mol. Sci. 2017, 18(6), 1132; https://doi.org/10.3390/ijms18061132 - 25 May 2017

Cited by 51 | Viewed by 9893

Abstract

Metastasis is the most dangerous risk faced by patients with hereditary non-polyposis colon cancer (HNPCC). The expression of matrix metalloproteinases (MMPs) has been observed in several types of human cancers and regulates the efficacy of many therapies. Here, we show that treatment with [...] Read more.

Metastasis is the most dangerous risk faced by patients with hereditary non-polyposis colon cancer (HNPCC). The expression of matrix metalloproteinases (MMPs) has been observed in several types of human cancers and regulates the efficacy of many therapies. Here, we show that treatment with various concentrations of prostaglandin E2 (PGE2; 0, 1, 5 or 10 μM) promotes the migration ability of the human LoVo colon cancer cell line. As demonstrated by mRNA and protein expression analyses, EP2 and EP4 are the major PGE2 receptors expressed on the LoVo cell membrane. The Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt cell survival pathway was upregulated by EP2 and EP4 activation. Following the activation of the PI3K/Akt pathway, β-catenin translocated into the nucleus and triggered COX2 transcription via LEF-1 and TCF-4 and its subsequent translation. COX2 expression correlated with the elevation in the migration ability of LoVo cells. The experimental evidence shows a possible mechanism by which PGE2 induces cancer cell migration and further suggests PGE2 to be a potential therapeutic target in colon cancer metastasis. On inhibition of PGE2, in order to determine the downstream pathway, the levels of PI3K/Akt pathway were suppressed and the β-catenin expression was also modulated. Inhibition of EP2 and EP4 shows that PGE2 induces protein expression of COX-2 through EP2 and EP4 receptors in LoVo colon cancer cells. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 1448 KiB

Open AccessArticle

Function of Metallothionein-3 in Neuronal Cells: Do Metal Ions Alter Expression Levels of MT3?

by Jamie Bousleiman¹, Alexa Pinsky¹, Sohee Ki¹, Angela Su¹, Irina Morozova², Sergey Kalachikov², Amen Wiqas³, Rae Silver^4,5,6,*, Mary Sever^1,* and Rachel Narehood Austin^1,*

¹ Department of Chemistry, Barnard College of Columbia University, New York, NY 10027, USA

² Center for Genome Technology and Biomolecular Engineering, Department of Chemical Engineering, Columbia University, New York, NY 10027, USA

³ Department of Biology, Barnard College of Columbia University, New York, NY 10027, USA

⁴ Department of Psychology and Program in Neuroscience, Barnard College of Columbia University, New York, NY 10027, USA

⁵ Department of Psychology, Columbia University, New York, NY 10027, USA

⁶ Department of Pathology and Cell Biology Columbia Health Sciences, New York, NY 10027, USA

Int. J. Mol. Sci. 2017, 18(6), 1133; https://doi.org/10.3390/ijms18061133 - 25 May 2017

Cited by 22 | Viewed by 7075

Abstract

A study of factors proposed to affect metallothionein-3 (MT3) function was carried out to elucidate the opaque role MT3 plays in human metalloneurochemistry. Gene expression of Mt2 and Mt3 was examined in tissues extracted from the dentate gyrus of mouse brains and in [...] Read more.

A study of factors proposed to affect metallothionein-3 (MT3) function was carried out to elucidate the opaque role MT3 plays in human metalloneurochemistry. Gene expression of Mt2 and Mt3 was examined in tissues extracted from the dentate gyrus of mouse brains and in human neuronal cell cultures. The whole-genome gene expression analysis identified significant variations in the mRNA levels of genes associated with zinc homeostasis, including Mt2 and Mt3. Mt3 was found to be the most differentially expressed gene in the identified groups, pointing to the existence of a factor, not yet identified, that differentially controls Mt3 expression. To examine the expression of the human metallothioneins in neurons, mRNA levels of MT3 and MT2 were compared in BE(2)C and SH-SY5Y cell cultures treated with lead, zinc, cobalt, and lithium. MT2 was highly upregulated by Zn²⁺ in both cell cultures, while MT3 was not affected, and no other metal had an effect on either MT2 or MT3. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

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15 pages, 386 KiB

Open AccessArticle

A Relative Deficiency of Lysosomal Acid Lypase Activity Characterizes Non-Alcoholic Fatty Liver Disease

by Francesco Tovoli^1,*, Lucia Napoli¹, Giulia Negrini¹, Sergio D’Addato¹

, Giulia Tozzi², Jessica D’Amico², Fabio Piscaglia¹

and Luigi Bolondi¹

¹ Unit of Internal Medicine, Departmentt of Medical and Surgical Sciences, University of Bologna, 40136 Bologna, Italy

² Unit of Neuromuscolar and Neurodegenerative Diseases, Children’s Hospital and Research Institute “Bambino Gesù”, 00165 Rome, Italy

Int. J. Mol. Sci. 2017, 18(6), 1134; https://doi.org/10.3390/ijms18061134 - 25 May 2017

Cited by 30 | Viewed by 6703

Abstract

Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)—however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to [...] Read more.

Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)—however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to determine LAL activity in a cohort of NAFLD subjects and in a control group of hepatitis C virus (HCV)-infected patients, investigating the role of liver cirrhosis. A total of 81 patients with a diagnosis of NAFLD, and 78 matched controls with HCV-related liver disease were enrolled. For each patient, LAL activity was determined on peripheral dried blood spots (DBS) and correlated with clinical and laboratory data. A subgroup analysis among cirrhotic patients was also performed. LAL activity is significantly reduced in NAFLD, compared to that in HCV patients. This finding is particularly evident in the pre-cirrhotic stage of disease. LAL activity is also correlated with platelet and white blood cell count, suggesting an analytic interference of portal-hypertension-induced pancytopenia on DBS-determined LAL activity. NAFLD is characterized by a specific deficit in LAL activity, suggesting a pathogenetic role of LAL. We propose that future studies on this topic should rely on tissue specific analyses, as peripheral blood tests are also influenced by confounding factors. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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18 pages, 2842 KiB

Open AccessArticle

Predicting Zoonotic Risk of Influenza A Viruses from Host Tropism Protein Signature Using Random Forest

by Christine L. P. Eng^1,*, Joo Chuan Tong² and Tin Wee Tan³

¹ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore

² Institute of High Performance Computing, A*Star, 138632 Singapore, Singapore

³ National Supercomputing Centre, 138632 Singapore, Singapore

Int. J. Mol. Sci. 2017, 18(6), 1135; https://doi.org/10.3390/ijms18061135 - 25 May 2017

Cited by 20 | Viewed by 8113

Abstract

Influenza A viruses remain a significant health problem, especially when a novel subtype emerges from the avian population to cause severe outbreaks in humans. Zoonotic viruses arise from the animal population as a result of mutations and reassortments, giving rise to novel strains [...] Read more.

Influenza A viruses remain a significant health problem, especially when a novel subtype emerges from the avian population to cause severe outbreaks in humans. Zoonotic viruses arise from the animal population as a result of mutations and reassortments, giving rise to novel strains with the capability to evade the host species barrier and cause human infections. Despite progress in understanding interspecies transmission of influenza viruses, we are no closer to predicting zoonotic strains that can lead to an outbreak. We have previously discovered distinct host tropism protein signatures of avian, human and zoonotic influenza strains obtained from host tropism predictions on individual protein sequences. Here, we apply machine learning approaches on the signatures to build a computational model capable of predicting zoonotic strains. The zoonotic strain prediction model can classify avian, human or zoonotic strains with high accuracy, as well as providing an estimated zoonotic risk. This would therefore allow us to quickly determine if an influenza virus strain has the potential to be zoonotic using only protein sequences. The swift identification of potential zoonotic strains in the animal population using the zoonotic strain prediction model could provide us with an early indication of an imminent influenza outbreak. Full article

(This article belongs to the Special Issue Molecular Research of Emerging Viruses: Viral Evolution, Diagnostics and Pathogenesis and Therapeutics)

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29 pages, 12743 KiB

Open AccessArticle

Comparative Study of Lectin Domains in Model Species: New Insights into Evolutionary Dynamics

by Sofie Van Holle^1,†

, Kristof De Schutter^1,2,†

, Lore Eggermont¹, Mariya Tsaneva¹, Liuyi Dang¹ and Els J. M. Van Damme^1,*

¹ Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium

² Department of Crop Protection, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1136; https://doi.org/10.3390/ijms18061136 - 25 May 2017

Cited by 34 | Viewed by 7074

Abstract

Lectins are present throughout the plant kingdom and are reported to be involved in diverse biological processes. In this study, we provide a comparative analysis of the lectin families from model species in a phylogenetic framework. The analysis focuses on the different plant [...] Read more.

Lectins are present throughout the plant kingdom and are reported to be involved in diverse biological processes. In this study, we provide a comparative analysis of the lectin families from model species in a phylogenetic framework. The analysis focuses on the different plant lectin domains identified in five representative core angiosperm genomes (Arabidopsis thaliana, Glycine max, Cucumis sativus, Oryza sativa ssp. japonica and Oryza sativa ssp. indica). The genomes were screened for genes encoding lectin domains using a combination of Basic Local Alignment Search Tool (BLAST), hidden Markov models, and InterProScan analysis. Additionally, phylogenetic relationships were investigated by constructing maximum likelihood phylogenetic trees. The results demonstrate that the majority of the lectin families are present in each of the species under study. Domain organization analysis showed that most identified proteins are multi-domain proteins, owing to the modular rearrangement of protein domains during evolution. Most of these multi-domain proteins are widespread, while others display a lineage-specific distribution. Furthermore, the phylogenetic analyses reveal that some lectin families evolved to be similar to the phylogeny of the plant species, while others share a closer evolutionary history based on the corresponding protein domain architecture. Our results yield insights into the evolutionary relationships and functional divergence of plant lectins. Full article

(This article belongs to the Special Issue Plant Lectins: From Model Species to Crop Plants)

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37 pages, 936 KiB

Open AccessReview

Therapeutic Applications of Rose Hips from Different Rosa Species

by Inés Mármol¹, Cristina Sánchez-de-Diego², Nerea Jiménez-Moreno³, Carmen Ancín-Azpilicueta^3,* and María Jesús Rodríguez-Yoldi^1,*

¹ Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza 50013, Spain

² Department of Physiological Sciences II, University of Barcelona, Barcelona 08907, Spain

³ Department of Applied Chemistry, Public University of Navarra, Pamplona 31006, Spain

Int. J. Mol. Sci. 2017, 18(6), 1137; https://doi.org/10.3390/ijms18061137 - 25 May 2017

Cited by 150 | Viewed by 36308

Abstract

Rosa species, rose hips, are widespread wild plants that have been traditionally used as medicinal compounds for the treatment of a wide variety of diseases. The therapeutic potential of these plants is based on its antioxidant effects caused by or associated with its [...] Read more.

Rosa species, rose hips, are widespread wild plants that have been traditionally used as medicinal compounds for the treatment of a wide variety of diseases. The therapeutic potential of these plants is based on its antioxidant effects caused by or associated with its phytochemical composition, which includes ascorbic acid, phenolic compounds and healthy fatty acids among others. Over the last few years, medicinal interest in rose hips has increased as a consequence of recent research that has studied its potential application as a treatment for several diseases including skin disorders, hepatotoxicity, renal disturbances, diarrhoea, inflammatory disorders, arthritis, diabetes, hyperlipidaemia, obesity and cancer. In this review, the role of different species of Rosa in the prevention of treatment of various disorders related to oxidative stress, is examined, focusing on new therapeutic approaches from a molecular point of view. Full article

(This article belongs to the Special Issue Correlation between Nutrition, Oxidative Stress and Disease)

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21 pages, 646 KiB

Open AccessReview

Perturbations in the Replication Program Contribute to Genomic Instability in Cancer

by Britny Blumenfeld¹, Micha Ben-Zimra^1,2 and Itamar Simon^1,*

¹ Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel

² Pharmacology and Experimental Therapeutics Unit, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel

Int. J. Mol. Sci. 2017, 18(6), 1138; https://doi.org/10.3390/ijms18061138 - 25 May 2017

Cited by 28 | Viewed by 5211

Abstract

Cancer and genomic instability are highly impacted by the deoxyribonucleic acid (DNA) replication program. Inaccuracies in DNA replication lead to the increased acquisition of mutations and structural variations. These inaccuracies mainly stem from loss of DNA fidelity due to replication stress or due [...] Read more.

Cancer and genomic instability are highly impacted by the deoxyribonucleic acid (DNA) replication program. Inaccuracies in DNA replication lead to the increased acquisition of mutations and structural variations. These inaccuracies mainly stem from loss of DNA fidelity due to replication stress or due to aberrations in the temporal organization of the replication process. Here we review the mechanisms and impact of these major sources of error to the replication program. Full article

(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)

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13 pages, 1263 KiB

Open AccessCommunication

Transfection of Antisense Oligonucleotides Mediated by Cationic Vesicles Based on Non-Ionic Surfactant and Polycations Bearing Quaternary Ammonium Moieties

by Judith Mayr¹, Santiago Grijalvo^2,3, Jürgen Bachl¹, Ramon Pons², Ramon Eritja^2,3,*

and David Díaz Díaz^1,2,*

¹ Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, Regensburg 93053, Germany

² Institute of Advanced Chemistry of Catalonia-Spanish National Research Council (IQAC-CSIC), Jordi Girona 18-26, Barcelona 08034, Spain

³ Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Jordi Girona 18-26, Barcelona 08034, Spain

Int. J. Mol. Sci. 2017, 18(6), 1139; https://doi.org/10.3390/ijms18061139 - 26 May 2017

Cited by 9 | Viewed by 8345

Abstract

Three different ionene polymers with varying quaternary ammonium moieties were used as a proof of concept for the formulation of antisense oligonucleotides, which are capable of inhibiting Renilla luciferase messenger ribonucleic acid (mRNA). Cationic vesicles, consisting of cationic polymer, antisense oligonucleotide (Luc [...] Read more.

Three different ionene polymers with varying quaternary ammonium moieties were used as a proof of concept for the formulation of antisense oligonucleotides, which are capable of inhibiting Renilla luciferase messenger ribonucleic acid (mRNA). Cationic vesicles, consisting of cationic polymer, antisense oligonucleotide (Luc) and non-ionic surfactant polysorbate 80, were investigated regarding their ζ potential, cytotoxicity and transfection efficiency. Deoxyribonucleic acid- (DNA) forming complexes in the presence of cationic vesicles were also investigated in terms of small-angle X-ray scattering (SAXS). The studied cationic vesicles showed very little, if any, toxicity against HeLa cells. Transfection abilities proved to vary strongly depending on the present quaternary ammonium moiety. Full article

(This article belongs to the Section Materials Science)

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13 pages, 1999 KiB

Open AccessArticle

Changes of Microrna Levels in Plasma of Patients with Rectal Cancer during Chemoradiotherapy

by Peter Jo¹, Azadeh Azizian¹, Junius Salendo¹, Frank Kramer², Markus Bernhardt¹, Hendrik A. Wolff³, Jens Gruber⁴

, Marian Grade¹, Tim Beißbarth², B. Michael Ghadimi¹ and Jochen Gaedcke^1,*

¹ Department of General-, Visceral-, and Pediatric Surgery, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany

² Department of Medical Statistics, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany

³ Department of Radiology, Nuclear Medicine and Radiotherapy, Radiology Munich, Burgstr. 7, 80333 Munich, Germany

⁴ German Primate Center, Medical RNA Biology, Kellnerweg 4, 37075 Goettingen, Germany

Int. J. Mol. Sci. 2017, 18(6), 1140; https://doi.org/10.3390/ijms18061140 - 27 May 2017

Cited by 14 | Viewed by 7141

Abstract

Since the response to chemoradiotherapy in patients with locally advanced rectal cancer is heterogeneous, valid biomarkers are needed to monitor tumor response. Circulating microRNAs are promising candidates, however analyses of circulating microRNAs in rectal cancer are still rare. 111 patients with rectal cancer [...] Read more.

Since the response to chemoradiotherapy in patients with locally advanced rectal cancer is heterogeneous, valid biomarkers are needed to monitor tumor response. Circulating microRNAs are promising candidates, however analyses of circulating microRNAs in rectal cancer are still rare. 111 patients with rectal cancer and 46 age-matched normal controls were enrolled. The expression levels of 30 microRNAs were analyzed in 17 pre-treatment patients’ plasma samples. Differentially regulated microRNAs were validated in 94 independent patients. For 52 of the 94 patients a paired comparison between pre-treatment and post-treatment samples was performed. miR-17, miR-18b, miR-20a, miR-31, and miR-193a_3p, were significantly downregulated in pre-treatment plasma samples of patients with rectal cancer (p < 0.05). miR-29c, miR-30c, and miR-195 showed a trend of differential regulation. After validation, miR-31 and miR-30c were significantly deregulated by a decrease of expression. In 52 patients expression analyses of the 8 microRNAs in matched pre-treatment and post-treatment samples showed a significant decrease for all microRNAs (p < 0.05) after treatment. Expression levels of miR-31 and miR-30c could serve as valid biomarkers if validated in a prospective study. Plasma microRNA expression levels do not necessarily represent miRNA expression levels in tumor tissue. Also, expression levels of microRNAs change during multimodal therapy. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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14 pages, 2647 KiB

Open AccessArticle

Anti-Inflammatory Properties of Brazilian Green Propolis Encapsulated in a γ-Cyclodextrin Complex in Mice Fed a Western-Type Diet

by Gerald Rimbach^1,*

, Alexandra Fischer¹, Anke Schloesser¹, Gerold Jerz², Naoko Ikuta^3,4, Yoshiyuki Ishida⁴, Ryota Matsuzawa⁵, Seiichi Matsugo⁵, Patricia Huebbe¹ and Keiji Terao⁴

¹ Institute of Human Nutrition and Food Science, Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany

² Institute of Food Chemistry, Technical University Braunschweig, Schleinitzstrasse 20, 38106 Braunschweig, Germany

³ Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, 650-0017 Kobe, Japan

⁴ CycloChem Bio Co., Ltd., 7-4-5 Minatojima-minamimachi, Chuo-ku, 650-0047 Kobe, Japan

⁵ School of Natural System, Kanazawa University, Kakuma-machi, 920-1192 Kanazawa, Japan

Int. J. Mol. Sci. 2017, 18(6), 1141; https://doi.org/10.3390/ijms18061141 - 26 May 2017

Cited by 26 | Viewed by 7813

Abstract

Ageing is often accompanied by chronic inflammation. A fat- and sugar-rich Western-type diet (WTD) may accelerate the ageing phenotype. Cell culture studies have indicated that artepillin C-containing Brazilian green propolis exhibits anti-inflammatory properties. However, little is known regarding its anti-inflammatory potential in mouse [...] Read more.

Ageing is often accompanied by chronic inflammation. A fat- and sugar-rich Western-type diet (WTD) may accelerate the ageing phenotype. Cell culture studies have indicated that artepillin C-containing Brazilian green propolis exhibits anti-inflammatory properties. However, little is known regarding its anti-inflammatory potential in mouse liver in vivo. In this study, female C57BL/6NRj wild-type mice were fed a WTD, a WTD supplemented with Brazilian green propolis supercritical extract (GPSE) encapsulated in γ-cyclodextrin (γCD) or a WTD plus γCD for 10 weeks. GPSE-γCD did not affect the food intake, body weight or body composition of the mice. However, mRNA levels of the tumour necrosis factor α were significantly downregulated (p < 0.05) in these mice compared to those in the WTD-fed controls. Furthermore, the gene expression levels of other pro-inflammatory markers, including serum amyloid P, were significantly (p < 0.001) decreased following GPSE-γCD treatment. GPSE-γCD significantly induced hepatic ferritin gene expression (p < 0.01), which may contribute to its anti-inflammatory properties. Conversely, GPSE-γCD did not affect the biomarkers of endogenous antioxidant defence, including catalase, glutathione peroxidase-4, paraoxonase-1, glutamate cysteine ligase and nuclear factor erythroid 2-related factor-2 (Nrf2). Overall, the present data suggest that dietary GPSE-γCD exhibits anti-inflammatory, but not antioxidant activity in mouse liver in vivo. Thus, GPSE-γCD has the potential to serve as a natural hepatoprotective bioactive compound for dietary-mediated strategies against chronic inflammation. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 1969 KiB

Open AccessArticle

Suppression of Osteoclastogenesis by Melatonin: A Melatonin Receptor-Independent Action

by Hyung Joon Kim¹, Ha Jin Kim¹, Moon-Kyoung Bae¹ and Yong-Deok Kim^2,*

¹ Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 626-870, Korea

² Department of Oral and Maxillofacial Surgery, Dental Research Institute and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 626-870, Korea

Int. J. Mol. Sci. 2017, 18(6), 1142; https://doi.org/10.3390/ijms18061142 - 26 May 2017

Cited by 54 | Viewed by 7921

Abstract

In vertebrates, melatonin is primarily secreted from the pineal gland but it affects various biological processes including the sleep-wake cycle, vasomotor control, immune system and bone homeostasis. Melatonin has been known to promote osteoblast differentiation and bone maturation, but a direct role of [...] Read more.

In vertebrates, melatonin is primarily secreted from the pineal gland but it affects various biological processes including the sleep-wake cycle, vasomotor control, immune system and bone homeostasis. Melatonin has been known to promote osteoblast differentiation and bone maturation, but a direct role of melatonin on osteoclast differentiation is still elusive. The present study investigated the effect of melatonin on the differentiation of macrophages to osteoclasts. The presence of melatonin significantly reduced receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and the siRNA-mediated knockdown of the melatonin receptor failed to overcome the anti-osteoclastogenic effect of melatonin. Although melatonin treatment did not affect the phosphorylation of extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK), it markedly inhibited the activation of NF-κB and subsequent induction of nuclear factor of activated T cell cytoplasmic 1(NFATc1). Thus, our results suggest that melatonin could suppress osteoclast differentiation through downregulation of NF-κB pathway with concomitant decrease in the NFATc1 transcription factor induction. Furthermore, melatonin seems to have an anti-osteoclastogenic effect independent of plasma membrane melatonin receptors. In addition to previously reported properties of melatonin, our study proposes another aspect of melatonin and bone homeostasis. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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11 pages, 3532 KiB

Open AccessEditorial

Nerve Growth Factor and Related Substances: A Brief History and an Introduction to the International NGF Meeting Series

by Ralph A. Bradshaw^1,2, William Mobley³ and Robert A. Rush^4,*

¹ Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA

² Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA

³ Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA

⁴ Department of Human Physiology, Flinders University, Adelaide, SA 5001, Australia

Int. J. Mol. Sci. 2017, 18(6), 1143; https://doi.org/10.3390/ijms18061143 - 26 May 2017

Cited by 24 | Viewed by 6128

Abstract

Nerve growth factor (NGF) is a protein whose importance to research and its elucidation of fundamental mechanisms in cell and neurobiology far outstrips its basic physiological roles. It was the first of a broad class of cell regulators, largely acting through autocrine and [...] Read more.

Nerve growth factor (NGF) is a protein whose importance to research and its elucidation of fundamental mechanisms in cell and neurobiology far outstrips its basic physiological roles. It was the first of a broad class of cell regulators, largely acting through autocrine and paracrine interactions which will be described herein. It was of similar significance in establishing the identity and unique roles of neurotrophic factors in the development and maintenance of the peripheral and central nervous systems. Finally, it contributed to many advances in the elaboration of cell surface receptor mechanisms and intracellular cell signaling. As such, it can be considered to be a “molecular Rosetta Stone”. In this brief review, the highlights of these various studies are summarized, particularly as illustrated by their coverage in the 13 NGF international meetings that have been held since 1986. Full article

(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)

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27 pages, 2990 KiB

Open AccessArticle

Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-Amidino and Amidino N²-Thiophenecarbonyl- and N²-Tosylanthranilamides

by Soo Hyun Lee^1,†, Wonhwa Lee^2,†, ThiHa Nguyen¹, Il Soo Um¹, Jong-Sup Bae^2,* and Eunsook Ma^1,*

¹ College of Pharmacy, Catholic University of Daegu, Hayang-ro 13-13, Hayang-eup, Gyeongsan-si, Gyeongbuk 712-702, Korea

² College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1144; https://doi.org/10.3390/ijms18061144 - 31 May 2017

Cited by 7 | Viewed by 5075

Abstract

Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non-amidino N²-thiophencarbonyl- and N²-tosyl anthranilamides [...] Read more.

Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non-amidino N²-thiophencarbonyl- and N²-tosyl anthranilamides 1–20 and six amidino N²-thiophencarbonyl- and N²-tosylanthranilamides 21–26 were synthesized to evaluate their activated partial thromboplastin time (aPTT) and prothrombin time (PT) using human plasma at a concentration of 30 µg/mL in vitro. As a result, compounds 5, 9, and 21–23 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 21–23 significantly exhibited a concentration-dependent prolongation of in vitro PT and aPTT, in vivo bleeding time, and ex vivo clotting time. These compounds concentration-dependently inhibited the activities of thrombin and FXa and inhibited the generation of thrombin and FXa in human endothelial cells. In addition, data showed that 5, 9, and 21–23 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced by U46619 in vitro and ex vivo. Among the derivatives evaluated, N-(3′-amidinophenyl)-2-((thiophen-2′′-yl)carbonylamino)benzamide (21) was the most active compound. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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13 pages, 533 KiB

Open AccessReview

Biological and Physicochemical Functions of Ubiquitylation Revealed by Synthetic Chemistry Approaches

by Daichi Morimoto¹

, Erik Walinda²

, Kenji Sugase¹

and Masahiro Shirakawa^1,*

¹ Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan

² Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

Int. J. Mol. Sci. 2017, 18(6), 1145; https://doi.org/10.3390/ijms18061145 - 27 May 2017

Cited by 5 | Viewed by 5906

Abstract

Most intracellular proteins are subjected to post-translational modification by ubiquitin. Accordingly, it is of fundamental importance to investigate the biological and physicochemical effects of ubiquitylation on substrate proteins. However, preparation of ubiquitylated proteins by an enzymatic synthesis bears limitations in terms of yield [...] Read more.

Most intracellular proteins are subjected to post-translational modification by ubiquitin. Accordingly, it is of fundamental importance to investigate the biological and physicochemical effects of ubiquitylation on substrate proteins. However, preparation of ubiquitylated proteins by an enzymatic synthesis bears limitations in terms of yield and site-specificity. Recently established chemical ubiquitylation methodologies can overcome these problems and provide a new understanding of ubiquitylation. Herein we describe the recent chemical ubiquitylation procedures with a focus on the effects of ubiquitylation on target proteins revealed by the synthetic approach. Full article

(This article belongs to the Special Issue Ubiquitin System)

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10 pages, 449 KiB

Open AccessReview

Epigenetic Signature: A New Player as Predictor of Clinically Significant Prostate Cancer (PCa) in Patients on Active Surveillance (AS)

by Matteo Ferro¹

, Paola Ungaro^2,*, Amelia Cimmino^3,*

, Giuseppe Lucarelli⁴

, Gian Maria Busetto⁵

, Francesco Cantiello⁶, Rocco Damiano⁶ and Daniela Terracciano^7,*

¹ Urologic Surgery Unit, European Institute of Oncology, 20141 Milan, Italy

² Institute of Experimental Endocrinology and Oncology (IEOS-CNR) “G. Salvatore”, Via Sergio Pansini, 5, 80131 Naples, Italy

³ Institute of Genetics and Biophysics “A. Buzzati Traverso”, National Research Council (CNR), Via Pietro Castellino 111, 80131 Naples, Italy

⁴ Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, 70124 Bari, Italy

⁵ Department of Gynecological-Obstetrics Sciences and Urological Sciences, Sapienza Rome University Policlinico Umberto I, 00161 Rome, Italy

⁶ Department of Urology, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy

⁷ Department of Translational Medical Sciences, University of Naples Federico II, Via Sergio Pansini, 5, 80131 Naples, Italy

Int. J. Mol. Sci. 2017, 18(6), 1146; https://doi.org/10.3390/ijms18061146 - 27 May 2017

Cited by 26 | Viewed by 5525

Abstract

Widespread prostate-specific antigen (PSA) testing notably increased the number of prostate cancer (PCa) diagnoses. However, about 30% of these patients have low-risk tumors that are not lethal and remain asymptomatic during their lifetime. Overtreatment of such patients may reduce quality of life and [...] Read more.

Widespread prostate-specific antigen (PSA) testing notably increased the number of prostate cancer (PCa) diagnoses. However, about 30% of these patients have low-risk tumors that are not lethal and remain asymptomatic during their lifetime. Overtreatment of such patients may reduce quality of life and increase healthcare costs. Active surveillance (AS) has become an accepted alternative to immediate treatment in selected men with low-risk PCa. Despite much progress in recent years toward identifying the best candidates for AS in recent years, the greatest risk remains the possibility of misclassification of the cancer or missing a high-risk cancer. This is particularly worrisome in men with a life expectancy of greater than 10–15 years. The Prostate Cancer Research International Active Surveillance (PRIAS) study showed that, in addition to age and PSA at diagnosis, both PSA density (PSA-D) and the number of positive cores at diagnosis (two compared with one) are the strongest predictors for reclassification biopsy or switching to deferred treatment. However, there is still no consensus upon guidelines for placing patients on AS. Each institution has its own protocol for AS that is based on PRIAS criteria. Many different variables have been proposed as tools to enrol patients in AS: PSA-D, the percentage of freePSA, and the extent of cancer on biopsy (number of positive cores or percentage of core involvement). More recently, the Prostate Health Index (PHI), the 4 Kallikrein (4K) score, and other patient factors, such as age, race, and family history, have been investigated as tools able to predict clinically significant PCa. Recently, some reports suggested that epigenetic mapping differs significantly between cancer patients and healthy subjects. These findings indicated as future prospect the use of epigenetic markers to identify PCa patients with low-grade disease, who are likely candidates for AS. This review explores literature data about the potential of epigenetic markers as predictors of clinically significant disease. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)

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15 pages, 12019 KiB

Open AccessCommunication

Mutual Regulation of NOD2 and RIG-I in Zebrafish Provides Insights into the Coordination between Innate Antibacterial and Antiviral Signaling Pathways

by Li Nie¹, Xiao-Xiao Xu², Li-Xin Xiang², Jian-Zhong Shao^2,3,* and Jiong Chen^1,*

¹ Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China

² College of Life Sciences, Zhejiang University, Hangzhou 310058, China

³ Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China

Int. J. Mol. Sci. 2017, 18(6), 1147; https://doi.org/10.3390/ijms18061147 - 27 May 2017

Cited by 16 | Viewed by 4574

Abstract

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and retinoic acid-inducible gene I (RIG-I) are two important cytosolic pattern recognition receptors (PRRs) in the recognition of pathogen-associated molecular patterns (PAMPs), initiating innate antibacterial and antiviral signaling pathways. However, the relationship between these PRRs, especially in [...] Read more.

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and retinoic acid-inducible gene I (RIG-I) are two important cytosolic pattern recognition receptors (PRRs) in the recognition of pathogen-associated molecular patterns (PAMPs), initiating innate antibacterial and antiviral signaling pathways. However, the relationship between these PRRs, especially in teleost fish models, is rarely reported. In this article, we describe the mutual regulation of zebrafish NOD2 (DrNOD2) and RIG-I (DrRIG-I) in innate immune responses. Luciferase assays were conducted to determine the activation of NF-κB and interferon signaling. Morpholino-mediated knockdown and mRNA-mediated rescue were performed to further confirm the regulatory roles between DrNOD2 and DrRIG-I. Results showed that DrNOD2 and DrRIG-I shared conserved structural hallmarks with their mammalian counterparts, and activated DrRIG-I signaling can induce DrNOD2 production. Surprisingly, DrNOD2-initiated signaling can also induce DrRIG-I expression, indicating that a mutual regulatory mechanism may exist between them. Studies conducted using HEK293T cells and zebrafish embryos showed that DrRIG-I could negatively regulate DrNOD2-activated NF-κB signaling, and DrNOD2 could inhibit DrRIG-I-induced IFN signaling. Moreover, knocking down DrRIG-I expression by morpholino could enhance DrNOD2-initiated NF-κB activation, and vice versa, which could be rescued by their corresponding mRNAs. Results revealed a mutual feedback regulatory mechanism underlying NOD2 and RIG-I signaling pathways in teleosts. This mechanism reflects the coordination between cytosolic antibacterial and antiviral PRRs in the complex network of innate immunity. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 1570 KiB

Open AccessArticle

N-Caffeoyltryptamine, a Potent Anti-Inflammatory Phenolic Amide, Suppressed MCP-1 Expression in LPS-stimulated THP-1 Cells and Rats Fed a High-Fat Diet

by Jae B. Park

Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, The Agricultural Research Service, The United States Department of Agriculture, Bldg. 307C, Rm. 131, Beltsville, MD 20705, USA

Int. J. Mol. Sci. 2017, 18(6), 1148; https://doi.org/10.3390/ijms18061148 - 27 May 2017

Cited by 4 | Viewed by 4215

Abstract

Monocyte chemoattractant protein-1 (MCP-1) is a well-known chemokine critically involved in the pathophysiological progression of several inflammatory diseases including arthrosclerosis. N-caffeoyltryptamine is a phenolic amide with strong anti-inflammatory effects. Therefore, in this paper, the potential effect of N-caffeoyltryptamine on MCP-1 expression [...] Read more.

Monocyte chemoattractant protein-1 (MCP-1) is a well-known chemokine critically involved in the pathophysiological progression of several inflammatory diseases including arthrosclerosis. N-caffeoyltryptamine is a phenolic amide with strong anti-inflammatory effects. Therefore, in this paper, the potential effect of N-caffeoyltryptamine on MCP-1 expression was investigated as a potential p38 mitogen-activated protein (MAP) kinase inhibitor in vitro and in vivo. At the concentration of 20 μM, N-caffeoyltryptamine significantly inhibited p38 MAP kinase α, β, γ and δ by 15–50% (p < 0.05), particularly p38 MAP kinase α (IC₅₀ = 16.7 μM) and β (IC₅₀ = 18.3 μM). Also, the pretreatment of the lipopolysaccharide (LPS)-stimulated THP-1 cells with N-caffeoyltryptamine (10, 20 and 40 μM) led to significant suppression of MCP-1 production by 10–45% (p < 0.05) in the cells. Additionally, N-caffeoyltryptamine was also able to significantly downregulate MCP-1 mRNA expression in the THP-1 cells (p < 0.05). On the basis of this strong inhibition in vitro, an animal study was conducted to confirm this inhibitory effect in vivo. Rats were divided into three groups (n = 8): a normal control diet (C), a high-fat diet (HF), or a high-fat diet supplemented with N-caffeoyltryptamine (2 mg per day) (HFS). After 16 weeks, blood samples were collected from the rats in each group, and MCP-1 levels were determined in plasma with other atherogenic markers (C-reactive protein and soluble E-selectin (sE-selectin)). As expected, the average MCP-1 levels of the HF group were found to be higher than those of the C group (p < 0.05). However, the MCP-1 levels of the HFS group were significantly lower than those of the HF group (p < 0.05), suggesting that N-caffeoyltryptamine could decrease MCP-1 expression in vivo. Related to other atherogenic markers such as C-reactive protein and sE-selectin, there was no significant difference in their levels between the HF and HFS groups. These data suggest that N-caffeoyltryptamine may specifically suppress MCP-1 expression in vitro and in vivo, possibly by inhibiting p38 MAP kinase. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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17 pages, 4315 KiB

Open AccessArticle

Strawberry (cv. Romina) Methanolic Extract and Anthocyanin-Enriched Fraction Improve Lipid Profile and Antioxidant Status in HepG2 Cells

by Tamara Y. Forbes-Hernández^1,2

, Massimiliano Gasparrini¹, Sadia Afrin¹

, Danila Cianciosi¹, Ana M. González-Paramás³, Celestino Santos-Buelga³

, Bruno Mezzetti⁴, José L. Quiles⁵

, Maurizio Battino^1,6

, Francesca Giampieri^1,*

and Stefano Bompadre^7,*

¹ Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche (DISCO)-Sez. Biochimica, Facoltà di Medicina, Università Politecnica delle Marche, 60131 Ancona, Italy

² Área de Nutrición y Salud, Universidad Internacional Iberoamericana (UNINI), Campeche C.P. 24040, Mexico

³ Grupo de Investigación en Polifenoles (GIP-USAL), Faculty of Pharmacy, Campus Miguel de Unamuno, Salamanca University, Salamanca E-37007, Spain

⁴ Dipartimento di Scienze Agrarie, Alimentari e Ambientali, Università Politecnica delle Marche, 60131 Ancona, Italy

⁵ Department of Physiology, Institute of Nutrition and Food Technology “José Mataix”, Biomedical Research Centre, University of Granada, Granada C.P. 18000, Spain

⁶ Centre for Nutrition & Health, Universidad Europea del Atlantico (UEA), Santander 39011, Spain

⁷ Dipartimento di Scienze Biomediche e Sanità Pubblica, Università Politecnica delle Marche, 60131 Ancona, Italy

Int. J. Mol. Sci. 2017, 18(6), 1149; https://doi.org/10.3390/ijms18061149 - 28 May 2017

Cited by 47 | Viewed by 9145

Abstract

Dyslipidemia and oxidation of low density lipoproteins (LDL) are recognized as critical factors in the development of atherosclerosis. Healthy dietary patterns, with abundant fruit and vegetable consumption, may prevent the onset of these risk factors due to the presence of phytochemical compounds. Strawberries [...] Read more.

Dyslipidemia and oxidation of low density lipoproteins (LDL) are recognized as critical factors in the development of atherosclerosis. Healthy dietary patterns, with abundant fruit and vegetable consumption, may prevent the onset of these risk factors due to the presence of phytochemical compounds. Strawberries are known for their high content of polyphenols; among them, flavonoids are the major constituents, and it is presumed that they are responsible for the biological activity of the fruit. Nevertheless, there are only a few studies that actually evaluate the effects of different fractions isolated from strawberries. In order to assess the effects of two different strawberry extracts (whole methanolic extract/anthocyanin-enriched fraction) on the lipid profile and antioxidant status in human hepatocellular carcinoma (HepG2) cells, the triglycerides and LDL-cholesterol content, lipid peroxidation, intracellular reactive oxygen species (ROS) content and antioxidant enzymes’ activity on cell lysates were determined. Results demonstrated that both strawberry extracts not only improved the lipid metabolism by decreasing triglycerides and LDL-cholesterol contents, but also improved the redox state of HepG2 cells by modulating thiobarbituric acid-reactive substances production, antioxidant enzyme activity and ROS generation. The observed effects were more pronounced for the anthocyanin-enriched fraction. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2016)

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14 pages, 5596 KiB

Open AccessArticle

The Effect of Dry Eye Disease on Scar Formation in Rabbit Glaucoma Filtration Surgery

by Hong Ji, Yingting Zhu, Yingying Zhang, Yu Jia, Yiqing Li, Jian Ge and Yehong Zhuo^*

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China

Int. J. Mol. Sci. 2017, 18(6), 1150; https://doi.org/10.3390/ijms18061150 - 28 May 2017

Cited by 10 | Viewed by 9013

Abstract

The success rate of glaucoma filtration surgery is closely related to conjunctival inflammation, and the main mechanism of dry eye disease (DED) is inflammation. The aim of this study was to evaluate the effect of DED on bleb scar formation after rabbit glaucoma [...] Read more.

The success rate of glaucoma filtration surgery is closely related to conjunctival inflammation, and the main mechanism of dry eye disease (DED) is inflammation. The aim of this study was to evaluate the effect of DED on bleb scar formation after rabbit glaucoma filtration surgery. Sixteen New Zealand white rabbits were randomly divided into control and DED groups. A DED model was induced by twice-daily topical administration of 0.1% benzalkonium chloride (BAC) drops for three weeks. Ocular examinations were performed to verify the DED model. Surgical effects were assessed, and histologic assessments were performed on the 28th postoperative day. Higher fluorescein staining scores, lower basal tear secretion levels and goblet cell counts, and increased interleukin 1β (IL-1β) levels were observed in the DED group. The DED eyes displayed significantly higher intraocular pressure (IOP)% on the 14th postoperative day; a smaller bleb area on days 14, 21 and 28; and a shorter bleb survival time. Moreover, proliferating cell nuclear antigen (PCNA) and alpha-smooth muscle actin (α-SMA) levels were significantly increased in the DED group. These results demonstrate that DED promotes filtering bleb scar formation and shortens bleb survival time; these effects may be mediated via IL-1β. Full article

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9 pages, 10414 KiB

Open AccessArticle

Sensitivity of HOXB13 as a Diagnostic Immunohistochemical Marker of Prostatic Origin in Prostate Cancer Metastases: Comparison to PSA, Prostein, Androgen Receptor, ERG, NKX3.1, PSAP, and PSMA

by Ilka Kristiansen¹, Carsten Stephan², Klaus Jung³

, Manfred Dietel⁴, Anja Rieger⁴, Yuri Tolkach^1,† and Glen Kristiansen^1,*,†

¹ Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany

² Department of Urology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany

³ Berlin Institute of Urologic Research, Berlin, Germany

⁴ Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1151; https://doi.org/10.3390/ijms18061151 - 29 May 2017

Cited by 39 | Viewed by 6917

Abstract

Aims: Determining the origin of metastases is an important task of pathologists to allow for the initiation of a tumor-specific therapy. Recently, homeobox protein Hox-B13 (HOXB13) has been suggested as a new marker for the detection of prostatic origin. The aim of this [...] Read more.

Aims: Determining the origin of metastases is an important task of pathologists to allow for the initiation of a tumor-specific therapy. Recently, homeobox protein Hox-B13 (HOXB13) has been suggested as a new marker for the detection of prostatic origin. The aim of this study was to evaluate the diagnostic sensitivity of HOXB13 in comparison to commonly used immunohistochemical markers for prostate cancer. Materials and methods: Histologically confirmed prostate cancer lymph node metastases from 64 cases were used to test the diagnostic value of immunohistochemical markers: prostate specific antigen (PSA), Prostatic acid phosphatase (PSAP), prostate specific membrane antigen (PSMA), homeobox gene NKX3.1, prostein, androgen receptor (AR), HOXB13, and ETS-related gene (ERG). All markers were evaluated semi-quantitatively using Remmele's immune reactive score. Results: The detection rate of prostate origin of metastasis for single markers was 100% for NKX3.1, 98.1% for AR, 84.3% for PSMA, 80.8% for PSA, 66% for PSAP, 60.4% for HOXB13, 59.6% for prostein, and 50.0% for ERG. Conclusions: Our data suggest that HOXB13 on its own lacks sensitivity for the detection of prostatic origin. Therefore, this marker should be only used in conjunction with other markers, preferably the highly specific PSA. The combination of PSA with NKX3.1 shows a higher sensitivity and thus appears preferable in this setting. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)

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13 pages, 2857 KiB

Open AccessArticle

Knockdown of XBP1 by RNAi in Mouse Granulosa Cells Promotes Apoptosis, Inhibits Cell Cycle, and Decreases Estradiol Synthesis

by Nan Wang¹

, Fan Zhao¹, Pengfei Lin¹, Guangle Zhang¹, Keqiong Tang¹, Aihua Wang² and Yaping Jin^1,*

¹ Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest Agriculture and Forestry University, Yangling 712100, China

² College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling 712100, China

Int. J. Mol. Sci. 2017, 18(6), 1152; https://doi.org/10.3390/ijms18061152 - 29 May 2017

Cited by 30 | Viewed by 6450

Abstract

Granulosa cells are crucial for follicular growth, development, and follicular atresia. X-box binding protein 1 (XBP1), a basic region-leucine zipper protein, is widely involved in cell differentiation, proliferation, apoptosis, cellular stress response, and other signaling pathways. In this study, RNA interference, flow cytometry, [...] Read more.

Granulosa cells are crucial for follicular growth, development, and follicular atresia. X-box binding protein 1 (XBP1), a basic region-leucine zipper protein, is widely involved in cell differentiation, proliferation, apoptosis, cellular stress response, and other signaling pathways. In this study, RNA interference, flow cytometry, western blot, real-time PCR, Cell Counting Kit (CCK8), and ELISA were used to investigate the effect of XBP1 on steroidogenesis, apoptosis, cell cycle, and proliferation of mouse granulosa cells. ELISA analysis showed that XBP1 depletion significantly decreased the concentrations of estradiol (E2). Additionally, the expression of estrogen synthesis enzyme Cyp19a1 was sharply downregulated. Moreover, flow cytometry showed that knockdown of XBP1 increased the apoptosis rate and arrests the cell cycle in S-phase in granulosa cells (GCs). Further study confirmed these results. The expression of CCAAT-enhancer-binding protein homologous protein (CHOP), cysteinyl aspartate specific proteases-3 (caspase-3), cleaved caspase-3, and Cyclin E was upregulated, while that of Bcl-2, Cyclin A1, and Cyclin B1 was downregulated. Simultaneously, CCK8 analysis indicated that XBP1 disruption inhibited cell proliferation. In addition, XBP1 knockdown also alters the expression of Has2 and Ptgs2, two essential genes for folliculogenesis. Collectively, these data reveal a novel critical role of XBP1 in folliculogenesis by regulating the cell cycle, apoptosis, and steroid synthesis of mouse granulosa cells. Full article

(This article belongs to the Section Biochemistry)

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18 pages, 3476 KiB

Open AccessReview

The Methods of Choice for Extracellular Vesicles (EVs) Characterization

by Rafal Szatanek¹, Monika Baj-Krzyworzeka¹, Jakub Zimoch², Malgorzata Lekka³, Maciej Siedlar¹

and Jarek Baran^1,*

¹ Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland

² Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, 8032 Zurich, Switzerland

³ Department of Research of Biophysical Microstructure, Institute of Nuclear Physics Polish Academy of Sciences, 31-342 Krakow, Poland

Int. J. Mol. Sci. 2017, 18(6), 1153; https://doi.org/10.3390/ijms18061153 - 29 May 2017

Cited by 439 | Viewed by 22858

Abstract

In recent years, extracellular vesicles (EVs) have become a subject of intense study. These membrane-enclosed spherical structures are secreted by almost every cell type and are engaged in the transport of cellular content (cargo) from parental to target cells. The impact of EVs [...] Read more.

In recent years, extracellular vesicles (EVs) have become a subject of intense study. These membrane-enclosed spherical structures are secreted by almost every cell type and are engaged in the transport of cellular content (cargo) from parental to target cells. The impact of EVs transfer has been observed in many vital cellular processes including cell-to-cell communication and immune response modulation; thus, a fast and precise characterization of EVs may be relevant for both scientific and diagnostic purposes. In this review, the most popular analytical techniques used in EVs studies are presented with the emphasis on exosomes and microvesicles characterization. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

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15 pages, 457 KiB

Open AccessReview

Non-Coding RNAs in Hodgkin Lymphoma

by Anna Cordeiro

, Mariano Monzó and Alfons Navarro^*

Molecular Oncology and Embryology Laboratory, Human Anatomy and Embryology Unit, School of Medicine, University of Barcelona, C/Casanova 143, 08032 Barcelona, Spain

Int. J. Mol. Sci. 2017, 18(6), 1154; https://doi.org/10.3390/ijms18061154 - 29 May 2017

Cited by 16 | Viewed by 6045

Abstract

MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression by binding to the 3’-UTR of their target genes, can act as oncogenes or tumor suppressors. Recently, other types of non-coding RNAs—piwiRNAs and long non-coding RNAs—have also been identified. Hodgkin lymphoma (HL) is a [...] Read more.

MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression by binding to the 3’-UTR of their target genes, can act as oncogenes or tumor suppressors. Recently, other types of non-coding RNAs—piwiRNAs and long non-coding RNAs—have also been identified. Hodgkin lymphoma (HL) is a B cell origin disease characterized by the presence of only 1% of tumor cells, known as Hodgkin and Reed-Stenberg (HRS) cells, which interact with the microenvironment to evade apoptosis. Several studies have reported specific miRNA signatures that can differentiate HL lymph nodes from reactive lymph nodes, identify histologic groups within classical HL, and distinguish HRS cells from germinal center B cells. Moreover, some signatures are associated with survival or response to chemotherapy. Most of the miRNAs in the signatures regulate genes related to apoptosis, cell cycle arrest, or signaling pathways. Here we review findings on miRNAs in HL, as well as on other non-coding RNAs. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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16 pages, 2223 KiB

Open AccessArticle

De Novo Transcriptome Sequencing and the Hypothetical Cold Response Mode of Saussurea involucrata in Extreme Cold Environments

by Jin Li¹, Hailiang Liu², Wenwen Xia¹, Jianqiang Mu¹, Yujie Feng¹, Ruina Liu¹, Panyao Yan³, Aiying Wang¹, Zhongping Lin^1,4, Yong Guo⁵, Jianbo Zhu^1,* and Xianfeng Chen^1,3,*

¹ College of Life Sciences, Shihezi University, Shihezi 832000, China

² Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China

³ ShengTing Bioinformatics Institute, Christiansburg, VA 24073, USA

⁴ College of Life Sciences, Perking University, Beijing 100871, China

⁵ Institute of Crop Science, Chinese Academy of Agricultural Sciences, Beijing 100081, China

Int. J. Mol. Sci. 2017, 18(6), 1155; https://doi.org/10.3390/ijms18061155 - 7 Jun 2017

Cited by 25 | Viewed by 5827

Abstract

Saussurea involucrata grows in high mountain areas covered by snow throughout the year. The temperature of this habitat can change drastically in one day. To gain a better understanding of the cold response signaling pathways and molecular metabolic reactions involved in cold stress [...] Read more.

Saussurea involucrata grows in high mountain areas covered by snow throughout the year. The temperature of this habitat can change drastically in one day. To gain a better understanding of the cold response signaling pathways and molecular metabolic reactions involved in cold stress tolerance, genome-wide transcriptional analyses were performed using RNA-Seq technologies. A total of 199,758 transcripts were assembled, producing 138,540 unigenes with 46.8 Gb clean data. Overall, 184,416 (92.32%) transcripts were successfully annotated. The 365 transcription factors identified (292 unigenes) belonged to 49 transcription factor families associated with cold stress responses. A total of 343 transcripts on the signal transduction (132 upregulated and 212 downregulated in at least any one of the conditions) were strongly affected by cold temperature, such as the CBL-interacting serine/threonine-protein kinase (CIPKs), receptor-like protein kinases, and protein kinases. The circadian rhythm pathway was activated by cold adaptation, which was necessary to endure the severe temperature changes within a day. There were 346 differentially expressed genes (DEGs) related to transport, of which 138 were upregulated and 22 were downregulated in at least any one of the conditions. Under cold stress conditions, transcriptional regulation, molecular transport, and signal transduction were involved in the adaptation to low temperature in S. involucrata. These findings contribute to our understanding of the adaptation of plants to harsh environments and the survival traits of S. involucrata. In addition, the present study provides insight into the molecular mechanisms of chilling and freezing tolerance. Full article

(This article belongs to the Section Molecular Plant Sciences)

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11 pages, 911 KiB

Open AccessArticle

Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR^+/−-IRS-1^+/− Double Heterozygous (IR-IRS1dh) Mice

by Andras Franko^1,2,*

, Alexander Kunze³, Marlen Böse¹, Jürgen-Christoph Von Kleist-Retzow^1,4, Mats Paulsson^3,5,6, Ursula Hartmann³ and Rudolf J. Wiesner^1,5,6

¹ Institute of Vegetative Physiology, Medical Faculty, University of Köln, Robert-Koch-Str. 39, D-50931 Cologne, Germany

² Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany

³ Center for Biochemistry, Medical Faculty, University of Köln, Joseph-Stelzmann-Str. 52, D-50931 Cologne, Germany

⁴ Department of Pediatrics, University Hospital Cologne, Kerpener Str. 62, D-50937 Cologne, Germany

⁵ Center for Molecular Medicine Cologne (CMMC), University of Köln, D-50931 Cologne, Germany

⁶ Cologne Excellence Cluster on Cellular Stress Responses in Ageing-associated Diseases (CECAD), University of Köln, D-50931 Cologne, Germany

Int. J. Mol. Sci. 2017, 18(6), 1156; https://doi.org/10.3390/ijms18061156 - 30 May 2017

Cited by 6 | Viewed by 5395

Abstract

Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR)^+/− [...] Read more.

Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR)^+/−-insulin receptor substrate-1 (IRS-1)^+/− double heterozygous (IR-IRS1dh) mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver. Full article

(This article belongs to the Special Issue Mitochondria Crosstalks with other Organelles in Pathophysiology)

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13 pages, 3136 KiB

Open AccessArticle

Loss of BAX by miR-365 Promotes Cutaneous Squamous Cell Carcinoma Progression by Suppressing Apoptosis

by Liang Zhou^†, Ruirui Gao^†, Yinghui Wang, Meijuan Zhou and Zhenhua Ding^*

¹ Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1157; https://doi.org/10.3390/ijms18061157 - 30 May 2017

Cited by 30 | Viewed by 5690

Abstract

Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level. However, the posttranscriptional regulation of BAX is under explored. In this study, we identified BAX as the novel downstream [...] Read more.

Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level. However, the posttranscriptional regulation of BAX is under explored. In this study, we identified BAX as the novel downstream target of miR-365, which is supported by gain- and loss-of-function studies of onco-miR-365. Loss of BAX by either RNA interference or highly-expressed miR-365 in cells of cutaneous squamous cell carcinoma (CSCC) enhanced the tumor resistance against apoptosis, while repressing cell proliferation, migration, and invasiveness. In vivo experiment confirmed that BAX knockdown promotes the growth of CSCC xenografts. Collectively, our results find a miR-365-BAX axis for alleviating the pro-apoptotic effects of BAX, which promotes CSCC development and may facilitate the generation of novel therapeutic regimens to the clinical treatment of CSCC. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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9 pages, 1826 KiB

Open AccessArticle

The Instrumentation of a Microfluidic Analyzer Enabling the Characterization of the Specific Membrane Capacitance, Cytoplasm Conductivity, and Instantaneous Young’s Modulus of Single Cells

by Ke Wang^1,2,†, Yang Zhao^3,†

, Deyong Chen^1,2, Chengjun Huang³, Beiyuan Fan^1,2, Rong Long⁴, Chia-Hsun Hsieh⁵

, Junbo Wang^1,2,*, Min-Hsien Wu^5,6,* and Jian Chen^1,2,*

¹ State Key Laboratory of Transducer Technology, Institute of Electronics, Chinese Academy of Sciences, Beijing 100190, China

² School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100190, China

³ Institute of Microelectronics of Chinese Academy of Sciences, Beijing 100029, China

⁴ Department of Mechanical Engineering, University of Colorado, Boulder, CO 80309, USA

⁵ Division of Haematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33302, Taiwan

⁶ Graduate Institute of Biochemical and Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1158; https://doi.org/10.3390/ijms18061158 - 19 Jun 2017

Cited by 4 | Viewed by 4903

Abstract

This paper presents the instrumentation of a microfluidic analyzer enabling the characterization of single-cell biophysical properties, which includes seven key components: a microfluidic module, a pressure module, an imaging module, an impedance module, two LabVIEW platforms for instrument operation and raw data processing, [...] Read more.

This paper presents the instrumentation of a microfluidic analyzer enabling the characterization of single-cell biophysical properties, which includes seven key components: a microfluidic module, a pressure module, an imaging module, an impedance module, two LabVIEW platforms for instrument operation and raw data processing, respectively, and a Python code for data translation. Under the control of the LabVIEW platform for instrument operation, the pressure module flushes single cells into the microfluidic module with raw biophysical parameters sampled by the imaging and impedance modules and processed by the LabVIEW platform for raw data processing, which were further translated into intrinsic cellular biophysical parameters using the code developed in Python. Based on this system, specific membrane capacitance, cytoplasm conductivity, and instantaneous Young’s modulus of three cell types were quantified as 2.76 ± 0.57 μF/cm², 1.00 ± 0.14 S/m, and 3.79 ± 1.11 kPa for A549 cells (n_cell = 202); 1.88 ± 0.31 μF/cm², 1.05 ± 0.16 S/m, and 3.74 ± 0.75 kPa for 95D cells (n_cell = 257); 2.11 ± 0.38 μF/cm², 0.87 ± 0.11 S/m, and 5.39 ± 0.89 kPa for H460 cells (n_cell = 246). As a semi-automatic instrument with a throughput of roughly 1 cell per second, this prototype instrument can be potentially used for the characterization of cellular biophysical properties. Full article

(This article belongs to the Special Issue Single Cell Technology)

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13 pages, 1506 KiB

Open AccessArticle

Significance of Phosphorylated Epidermal Growth Factor Receptor and Its Signal Transducers in Human Soft Tissue Sarcoma

by Jia-Lin Yang^1,2,*, Romi Das Gupta³, David Goldstein^2,4 and Philip J. Crowe^1,2

¹ Department of Surgery, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney 2001, Australia

² Sarcoma and Nanooncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney 2001, Australia

³ Department of Paediatric and Burns Surgery, Lady Cilento Children’s Hospital, Children’s Health Queensland, Brisbane 4000, Australia

⁴ Department of Medical Oncology, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney 2001, Australia

Int. J. Mol. Sci. 2017, 18(6), 1159; https://doi.org/10.3390/ijms18061159 - 30 May 2017

Cited by 14 | Viewed by 5468

Abstract

Previous studies have shown that total epidermal growth factor receptor (EGFR) protein is highly expressed in soft tissue sarcoma (STS). We aimed to investigate the significance of phosphorylated-EGFR (pEGFR) and its activated-downstream signal transducers in STS tissue samples. A tissue microarray comprising 87 [...] Read more.

Previous studies have shown that total epidermal growth factor receptor (EGFR) protein is highly expressed in soft tissue sarcoma (STS). We aimed to investigate the significance of phosphorylated-EGFR (pEGFR) and its activated-downstream signal transducers in STS tissue samples. A tissue microarray comprising 87 STS samples was assessed for total EGFR, pEGFR and its phosphorylated signal transducers and expression was correlated with clinicopathlogical parameters including patient outcome. Although the expression of total EGFR was significantly associated with adverse STS histologic grade (p = 0.004) and clinical stage (p = 0.012) similar to pEGFR, phosphorylated protein kinase B (pAkt) and phosphorylated extracellular signal regulated kinase (pERK), it is not a prognostic factor for survival. By contrast, the expression of pEGFR is an independent factor for cancer specific survival, while pERK is an independent prognostic factor for both overall and cancer specific survival in STS (p < 0.05, Cox proportional hazard model and log-rank test) in addition to the recognised factors of tumour grade and clinical stage. pERK and pEGFR are new independent prognostic factors for overall and/or cancer specific survival in STS. The expression of EGFR/pEGFR, and their associated downstream signal transducers, was associated with STS progression, suggesting that EGFR downstream signalling pathways may jointly support STS cell survival. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)

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23 pages, 2912 KiB

Open AccessArticle

Sugar-Binding Profiles of Chitin-Binding Lectins from the Hevein Family: A Comprehensive Study

by Yoko Itakura^1,2

, Sachiko Nakamura-Tsuruta¹, Junko Kominami¹, Hiroaki Tateno¹ and Jun Hirabayashi^1,*

¹ Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, AIST Tsukuba Central 2, 1-1-1, Umezono, Tsukuba, Ibaraki 305-8568, Japan

² Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan

Int. J. Mol. Sci. 2017, 18(6), 1160; https://doi.org/10.3390/ijms18061160 - 30 May 2017

Cited by 61 | Viewed by 8293

Abstract

Chitin-binding lectins form the hevein family in plants, which are defined by the presence of single or multiple structurally conserved GlcNAc (N-acetylglucosamine)-binding domains. Although they have been used as probes for chito-oligosaccharides, their detailed specificities remain to be investigated. In this [...] Read more.

Chitin-binding lectins form the hevein family in plants, which are defined by the presence of single or multiple structurally conserved GlcNAc (N-acetylglucosamine)-binding domains. Although they have been used as probes for chito-oligosaccharides, their detailed specificities remain to be investigated. In this study, we analyzed six chitin-binding lectins, DSA, LEL, PWM, STL, UDA, and WGA, by quantitative frontal affinity chromatography. Some novel features were evident: WGA showed almost comparable affinity for pyridylaminated chitotriose and chitotetraose, while LEL and UDA showed much weaker affinity, and DSA, PWM, and STL had no substantial affinity for the former. WGA showed selective affinity for hybrid-type N-glycans harboring a bisecting GlcNAc residue. UDA showed extensive binding to high-mannose type N-glycans, with affinity increasing with the number of Man residues. DSA showed the highest affinity for highly branched N-glycans consisting of type II LacNAc (N-acetyllactosamine). Further, multivalent features of these lectins were investigated by using glycoconjugate and lectin microarrays. The lectins showed substantial binding to immobilized LacNAc as well as chito-oligosaccharides, although the extents to which they bound varied among them. WGA showed strong binding to heavily sialylated glycoproteins. The above observations will help interpret lectin-glycoprotein interactions in histochemical studies and glyco-biomarker investigations. Full article

(This article belongs to the Special Issue Plant Lectins: From Model Species to Crop Plants)

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16 pages, 6472 KiB

Open AccessArticle

Identification of Differentially Expressed Micrornas Associate with Glucose Metabolism in Different Organs of Blunt Snout Bream (Megalobrama amblycephala)

by Ling-Hong Miao^1,2

, Yan Lin², Wen-Jing Pan¹, Xin Huang¹, Xian-Ping Ge^1,2,*, Ming-Chun Ren², Qun-Lan Zhou² and Bo Liu^1,2

¹ Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China

² Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China

Int. J. Mol. Sci. 2017, 18(6), 1161; https://doi.org/10.3390/ijms18061161 - 31 May 2017

Cited by 30 | Viewed by 5557

Abstract

Blunt snout bream (Megalobrama amblycephala) is a widely favored herbivorous fish species and is a frequentlyused fish model for studying the metabolism physiology. This study aimed to provide a comprehensive illustration of the mechanisms of a high-starch diet (HSD) induced lipid [...] Read more.

Blunt snout bream (Megalobrama amblycephala) is a widely favored herbivorous fish species and is a frequentlyused fish model for studying the metabolism physiology. This study aimed to provide a comprehensive illustration of the mechanisms of a high-starch diet (HSD) induced lipid metabolic disorder by identifying microRNAs (miRNAs) controlled pathways in glucose and lipid metabolism in fish using high-throughput sequencing technologies. Small RNA libraries derived from intestines, livers, and brains of HSD and normal-starch diet (NSD) treated M. amblycephala were sequenced and 79, 124 and 77 differentially expressed miRNAs (DEMs) in intestines, livers, and brains of HSD treated fish were identified, respectively. Bioinformatics analyses showed that these DEMs targeted hundreds of predicted genes were enriched into metabolic pathways and biosynthetic processes, including peroxisome proliferator-activated receptor (PPAR), glycolysis/gluconeogenesis, and insulin signaling pathway. These analyses confirmed that miRNAs play crucial roles in glucose and lipid metabolism related to high wheat starch treatment. These results provide information on further investigation of a DEM-related mechanism dysregulated by a high carbohydrate diet. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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12 pages, 1381 KiB

Open AccessArticle

TRAV7-2*02 Expressing CD8⁺ T Cells Are Responsible for Palladium Allergy

by Yuri Takeda^1,2, Yoshiko Suto¹, Koyu Ito¹, Wataru Hashimoto², Tadashi Nishiya³, Kyosuke Ueda⁴, Takayuki Narushima⁴, Tetsu Takahashi² and Kouetsu Ogasawara^1,*

¹ Department of Immunobiology, Institute of Development, Aging and Cancer, Tohoku University 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan

² Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan

³ Department of Pharmacology, School of Pharmaceutical Sciences, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima 963-8611, Japan

⁴ Department of Materials Processing, Graduate School of Engineering, Tohoku University, 6-6-02 Aza Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8579, Japan

Int. J. Mol. Sci. 2017, 18(6), 1162; https://doi.org/10.3390/ijms18061162 - 31 May 2017

Cited by 10 | Viewed by 4713

Abstract

While metallic biomaterials have led to an improvement in the quality of life, metal allergies, especially to palladium (Pd), has caused a recent increase in allergic patients. Metal allergy is known to be a T cell-mediated delayed-type hypersensitivity (DTH); however, the pathogenic T [...] Read more.

While metallic biomaterials have led to an improvement in the quality of life, metal allergies, especially to palladium (Pd), has caused a recent increase in allergic patients. Metal allergy is known to be a T cell-mediated delayed-type hypersensitivity (DTH); however, the pathogenic T cell subsets and the specific T cell receptor (TCR) have not been identified. Therefore, we attempted to identify the pathogenic T cells responsible for Pd allergy. We found that activating CD8⁺ T cells significantly increased and that the TRAV (TCRα variable) 7-2*02 chain skewed in Pd allergic mice. Furthermore, adoptive transfer experiments revealed that in vitro-cultured Pd-stimulated antigen presenting cells (APCs) function as memory APCs with recipient mice developing Pd allergy and that the frequency of TRAV7-2*02 increases the same as conventional Pd allergic mice. In contrast, neither proliferation of CD8⁺ T cells nor increasing of TRAV7-2*02 was observed in major histocompatibility complex I (MHC I)-deficient Pd-APCs transferred to mice. Taken together, we revealed that TRAV7-2*02-expressing CD8⁺ T cells are the pathogenic T cells for the development of Pd allergy. We also identified the CDR3 consensus motif of pathogenic TCRs as CAAXSGSWQLIF in TRAV7-2*02/TRAJ (TCRα junction)22*01 positive cells. These results suggest that the specific TCRs represent novel targets for the development of diagnostics and treatments for metal allergy. Full article

(This article belongs to the Special Issue Metal Metabolism in Animals II)

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10 pages, 1505 KiB

Open AccessArticle

The Complete Structure of the Core Oligosaccharide from Edwardsiella tarda EIB 202 Lipopolysaccharide

by Marta Kaszowska^1,*,†, Elena De Mendoza-Barberá^2,†, Anna Maciejewska¹, Susana Merino²

, Czeslaw Lugowski^1,3 and Juan M. Tomás²

¹ Department of Immunochemistry, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, PL-53-114 Wroclaw, Poland

² Department of Microbiology, University of Barcelona, Diagonal 643, 08071 Barcelona, Spain

³ Department of Biotechnology and Molecular Biology, University of Opole, PL-45-035 Opole, Poland

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1163; https://doi.org/10.3390/ijms18061163 - 31 May 2017

Cited by 6 | Viewed by 4489

Abstract

The chemical structure and genomics of the lipopolysaccharide (LPS) core oligosaccharide of pathogenic Edwardsiella tarda strain EIB 202 were studied for the first time. The complete gene assignment for all LPS core biosynthesis gene functions was acquired. The complete structure of core oligosaccharide [...] Read more.

The chemical structure and genomics of the lipopolysaccharide (LPS) core oligosaccharide of pathogenic Edwardsiella tarda strain EIB 202 were studied for the first time. The complete gene assignment for all LPS core biosynthesis gene functions was acquired. The complete structure of core oligosaccharide was investigated by ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy, electrospray ionization mass spectrometry MSⁿ, and matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry. The following structure of the undecasaccharide was established:

The heterogeneous appearance of the core oligosaccharide structure was due to the partial lack of β-d-Galp and the replacement of α-d-GlcpNAcGly by α-d-GlcpNGly. The glycine location was identified by mass spectrometry. Full article

(This article belongs to the Special Issue Lipopolysaccharides (LPSs))

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25 pages, 2302 KiB

Open AccessReview

Plant Lectins and Lectin Receptor-Like Kinases: How Do They Sense the Outside?

by Kevin Bellande¹, Jean-Jacques Bono², Bruno Savelli¹, Elisabeth Jamet¹ and Hervé Canut^1,*

¹ Laboratoire de Recherche en Sciences Végétales, Université de Toulouse, CNRS, UPS, 24 Chemin de Borde Rouge, Auzeville, BP 42617, 31326 Castanet-Tolosan, France

² LIPM, Université de Toulouse, INRA, CNRS, 31326 Castanet-Tolosan, France

Int. J. Mol. Sci. 2017, 18(6), 1164; https://doi.org/10.3390/ijms18061164 - 31 May 2017

Cited by 113 | Viewed by 15856

Abstract

Lectins are fundamental to plant life and have important roles in cell-to-cell communication; development and defence strategies. At the cell surface; lectins are present both as soluble proteins (LecPs) and as chimeric proteins: lectins are then the extracellular domains of receptor-like kinases (LecRLKs) [...] Read more.

Lectins are fundamental to plant life and have important roles in cell-to-cell communication; development and defence strategies. At the cell surface; lectins are present both as soluble proteins (LecPs) and as chimeric proteins: lectins are then the extracellular domains of receptor-like kinases (LecRLKs) and receptor-like proteins (LecRLPs). In this review; we first describe the domain architectures of proteins harbouring G-type; L-type; LysM and malectin carbohydrate-binding domains. We then focus on the functions of LecPs; LecRLKs and LecRLPs referring to the biological processes they are involved in and to the ligands they recognize. Together; LecPs; LecRLKs and LecRLPs constitute versatile recognition systems at the cell surface contributing to the detection of symbionts and pathogens; and/or involved in monitoring of the cell wall structure and cell growth. Full article

(This article belongs to the Special Issue Plant Lectins: From Model Species to Crop Plants)

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18 pages, 3480 KiB

Open AccessArticle

Role of Free Radicals and Biotransformation in Trichloronitrobenzene-Induced Nephrotoxicity In Vitro

by Gary O. Rankin^*, Connor Tyree, Deborah Pope, Jordan Tate, Christopher Racine, Dianne K. Anestis, Kathleen C. Brown, Mason Dial and Monica A. Valentovic

Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA

Int. J. Mol. Sci. 2017, 18(6), 1165; https://doi.org/10.3390/ijms18061165 - 31 May 2017

Cited by 2 | Viewed by 4697

Abstract

This study determined the comparative nephrotoxic potential of four trichloronitrobenzenes (TCNBs) (2,3,4-; 2,4,5-; 2,4,6-; and 3,4,5-TCNB) and explored the effects of antioxidants and biotransformation inhibitors on TCNB-induced cytotoxicity in isolated renal cortical cells (IRCC) from male Fischer 344 rats. IRCC were incubated with [...] Read more.

This study determined the comparative nephrotoxic potential of four trichloronitrobenzenes (TCNBs) (2,3,4-; 2,4,5-; 2,4,6-; and 3,4,5-TCNB) and explored the effects of antioxidants and biotransformation inhibitors on TCNB-induced cytotoxicity in isolated renal cortical cells (IRCC) from male Fischer 344 rats. IRCC were incubated with a TCNB up to 1.0 mM for 15–120 min. Pretreatment with an antioxidant or cytochrome P450 (CYP), flavin monooxygenase (FMO), or peroxidase inhibitor was used in some experiments. Among the four TCNBs, the order of decreasing nephrotoxic potential was approximately 3,4,5- > 2,4,6- > 2,3,4- > 2,4,5-TCNB. The four TCNBs exhibited a similar profile of attenuation of cytotoxicity in response to antioxidant pretreatments. 2,3,4- and 3,4,5-TCNB cytotoxicity was attenuated by most of the biotransformation inhibitors tested, 2,4,5-TCNB cytotoxicity was only inhibited by isoniazid (CYP 2E1 inhibitor), and 2,4,6-TCNB-induced cytotoxicity was inhibited by one CYP inhibitor, one FMO inhibitor, and one peroxidase inhibitor. All of the CYP specific inhibitors tested offered some attenuation of 3,4,5-TCNB cytotoxicity. These results indicate that 3,4,5-TCNB is the most potent nephrotoxicant, free radicals play a role in the TCNB cytotoxicity, and the role of biotransformation in TCNB nephrotoxicity in vitro is variable and dependent on the position of the chloro groups. Full article

(This article belongs to the Special Issue Nephrotoxicity)

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15 pages, 845 KiB

Open AccessReview

Transcriptomics, NF-κB Pathway, and Their Potential Spaceflight-Related Health Consequences

by Ye Zhang¹, Maria Moreno-Villanueva^2,3, Stephanie Krieger^2,4, Govindarajan T. Ramesh⁵, Srujana Neelam^1,6 and Honglu Wu^2,*

¹ NASA Kennedy Space Center, Cape Canaveral, FL 32899, USA

² NASA Johnson Space Center, Houston, TX 77058, USA

³ University of Konstanz, 78464 Konstanz, Germany

⁴ KBR Wyle, Houston, TX 77058, USA

⁵ Norfolk State University, Norfolk, VA 23504, USA

⁶ University Space Research Association, Columbia, MD 21046, USA

Int. J. Mol. Sci. 2017, 18(6), 1166; https://doi.org/10.3390/ijms18061166 - 31 May 2017

Cited by 35 | Viewed by 7025

Abstract

In space, living organisms are exposed to multiple stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as bone loss and immune dysfunction. Understanding the mechanisms by which spaceflight impacts [...] Read more.

In space, living organisms are exposed to multiple stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as bone loss and immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures. Over the years, a number of studies have been conducted under real or simulated space conditions. RNA and protein levels in cellular and animal models have been targeted in order to identify pathways affected by spaceflight. Of the many pathways responsive to the space environment, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) network appears to commonly be affected across many different cell types under the true or simulated spaceflight conditions. NF-κB is of particular interest, as it is associated with many of the spaceflight-related health consequences. This review intends to summarize the transcriptomics studies that identified NF-κB as a responsive pathway to ground-based simulated microgravity or the true spaceflight condition. These studies were carried out using either human cell or animal models. In addition, the review summarizes the studies that focused specifically on NF-κB pathway in specific cell types or organ tissues as related to the known spaceflight-related health risks including immune dysfunction, bone loss, muscle atrophy, central nerve system (CNS) dysfunction, and risks associated with space radiation. Whether the NF-κB pathway is activated or inhibited in space is dependent on the cell type, but the potential health impact appeared to be always negative. It is argued that more studies on NF-κB should be conducted to fully understand this particular pathway for the benefit of crew health in space. Full article

(This article belongs to the Special Issue Transcriptome Profiling in Human Diseases)

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11 pages, 810 KiB

Open AccessReview

Implications of Extracellular Matrix Production by Adipose Tissue-Derived Stem Cells for Development of Wound Healing Therapies

by Kathrine Hyldig, Simone Riis, Cristian Pablo Pennisi

, Vladimir Zachar and Trine Fink^*

Laboratory for Stem Cell Research, Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark

Int. J. Mol. Sci. 2017, 18(6), 1167; https://doi.org/10.3390/ijms18061167 - 31 May 2017

Cited by 71 | Viewed by 9821

Abstract

The synthesis and deposition of extracellular matrix (ECM) plays an important role in the healing of acute and chronic wounds. Consequently, the use of ECM as treatment for chronic wounds has been of special interest—both in terms of inducing ECM production by resident [...] Read more.

The synthesis and deposition of extracellular matrix (ECM) plays an important role in the healing of acute and chronic wounds. Consequently, the use of ECM as treatment for chronic wounds has been of special interest—both in terms of inducing ECM production by resident cells and applying ex vivo produced ECM. For these purposes, using adipose tissue-derived stem cells (ASCs) could be of use. ASCs are recognized to promote wound healing of otherwise chronic wounds, possibly through the reduction of inflammation, induction of angiogenesis, and promotion of fibroblast and keratinocyte growth. However, little is known regarding the importance of ASC-produced ECM for wound healing. In this review, we describe the importance of ECM for wound healing, and how ECM production by ASCs may be exploited in developing new therapies for the treatment of chronic wounds. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration)

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28 pages, 1616 KiB

Open AccessReview

Can Co-Activation of Nrf2 and Neurotrophic Signaling Pathway Slow Alzheimer’s Disease?

by Kelsey E. Murphy and Joshua J. Park^*

Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA

Int. J. Mol. Sci. 2017, 18(6), 1168; https://doi.org/10.3390/ijms18061168 - 31 May 2017

Cited by 45 | Viewed by 14654

Abstract

Alzheimer’s disease (AD) is a multifaceted disease that is hard to treat by single-modal treatment. AD starts with amyloid peptides, mitochondrial dysfunction, and oxidative stress and later is accompanied with chronic endoplasmic reticulum (ER) stress and autophagy dysfunction, resulting in more complicated pathogenesis. [...] Read more.

Alzheimer’s disease (AD) is a multifaceted disease that is hard to treat by single-modal treatment. AD starts with amyloid peptides, mitochondrial dysfunction, and oxidative stress and later is accompanied with chronic endoplasmic reticulum (ER) stress and autophagy dysfunction, resulting in more complicated pathogenesis. Currently, few treatments can modify the complicated pathogenic progress of AD. Compared to the treatment with exogenous antioxidants, the activation of global antioxidant defense system via Nrf2 looks more promising in attenuating oxidative stress in AD brains. Accompanying the activation of the Nrf2-mediated antioxidant defense system that reduce the AD-causative factor, oxidative stress, it is also necessary to activate the neurotrophic signaling pathway that replaces damaged organelles and molecules with new ones. Thus, the dual actions to activate both the Nrf2 antioxidant system and neurotrophic signaling pathway are expected to provide a better strategy to modify AD pathogenesis. Here, we review the current understanding of AD pathogenesis and neuronal defense systems and discuss a possible way to co-activate the Nrf2 antioxidant system and neurotrophic signaling pathway with the hope of helping to find a better strategy to slow AD. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2017)

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15 pages, 1031 KiB

Open AccessArticle

Utilization of Multi-Immunization and Multiple Selection Strategies for Isolation of Hapten-Specific Antibodies from Recombinant Antibody Phage Display Libraries

by Antti Tullila^* and Tarja K. Nevanen

VTT Technical Research Centre of Finland, Tietotie 2, FI-02150 Espoo, Finland

Int. J. Mol. Sci. 2017, 18(6), 1169; https://doi.org/10.3390/ijms18061169 - 31 May 2017

Cited by 16 | Viewed by 4807

Abstract

Phage display technology provides a powerful tool for the development of novel recombinant antibodies. In this work, we optimized and streamlined the recombinant antibody discovery process for haptens as an example. A multi-immunization approach was used in order to avoid the need for [...] Read more.

Phage display technology provides a powerful tool for the development of novel recombinant antibodies. In this work, we optimized and streamlined the recombinant antibody discovery process for haptens as an example. A multi-immunization approach was used in order to avoid the need for construction of multiple antibody libraries. Selection methods were developed to utilize the full potential of the recombinant antibody library by applying four different elution conditions simultaneously. High-throughput immunoassays were used to analyse the binding properties of the individual antibody clones. Different carrier proteins were used in the immunization, selection, and screening phases to avoid enrichment of the antibodies for the carrier protein epitopes. Novel recombinant antibodies against mycophenolic acid and ochratoxin A, with affinities up to 39 nM and 34 nM, respectively, were isolated from a multi-immunized fragment antigen-binding (Fab) library. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 2478 KiB

Open AccessReview

Local Actions of Melatonin in Somatic Cells of the Testis

by Mónica Beatriz Frungieri^*

, Ricardo Saúl Calandra and Soledad Paola Rossi

Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, Buenos Aires 1428, Argentina

Int. J. Mol. Sci. 2017, 18(6), 1170; https://doi.org/10.3390/ijms18061170 - 31 May 2017

Cited by 82 | Viewed by 9680

Abstract

The pineal hormone melatonin regulates testicular function through the hypothalamic-adenohypophyseal axis. In addition, direct actions of melatonin in somatic cells of the testis have been described. Melatonin acts as a local modulator of the endocrine activity in Leydig cells. In Sertoli cells, melatonin [...] Read more.

The pineal hormone melatonin regulates testicular function through the hypothalamic-adenohypophyseal axis. In addition, direct actions of melatonin in somatic cells of the testis have been described. Melatonin acts as a local modulator of the endocrine activity in Leydig cells. In Sertoli cells, melatonin influences cellular growth, proliferation, energy metabolism and the oxidation state, and consequently may regulate spermatogenesis. These data pinpoint melatonin as a key player in the regulation of testicular physiology (i.e., steroidogenesis, spermatogenesis) mostly in seasonal breeders. In patients with idiopathic infertility, melatonin exerts anti-proliferative and anti-inflammatory effects on testicular macrophages, and provides protective effects against oxidative stress in testicular mast cells. Consequently, melatonin is also involved in the modulation of inflammatory and oxidant/anti-oxidant states in testicular pathology. Overall, the literature data indicate that melatonin has important effects on testicular function and male reproduction. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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22 pages, 1188 KiB

Open AccessArticle

Ontogeny of Sex-Related Differences in Foetal Developmental Features, Lipid Availability and Fatty Acid Composition

by Consolacion Garcia-Contreras¹, Marta Vazquez-Gomez²

, Susana Astiz¹

, Laura Torres-Rovira¹, Raul Sanchez-Sanchez¹, Ernesto Gomez-Fidalgo¹, Jorge Gonzalez³, Beatriz Isabel², Ana Rey², Cristina Ovilo¹ and Antonio Gonzalez-Bulnes^1,*

¹ Subdirección General de Investigación y Tecnología, Instituto Nacional de Investigación y TecnologíaAgraria y Alimentaria, Madrid 28040, Spain

² Faculty of Veterinary Sciences, Universidad Complutense de Madrid, Madrid 28040, Spain

³ Micros Veterinaria, Leon 24007, Spain

Int. J. Mol. Sci. 2017, 18(6), 1171; https://doi.org/10.3390/ijms18061171 - 31 May 2017

Cited by 17 | Viewed by 6511

Abstract

Sex-related differences in lipid availability and fatty acid composition during swine foetal development were investigated. Plasma cholesterol and triglyceride concentrations in the mother were strongly related to the adequacy or inadequacy of foetal development and concomitant activation of protective growth in some organs [...] Read more.

Sex-related differences in lipid availability and fatty acid composition during swine foetal development were investigated. Plasma cholesterol and triglyceride concentrations in the mother were strongly related to the adequacy or inadequacy of foetal development and concomitant activation of protective growth in some organs (brain, heart, liver and spleen). Cholesterol and triglyceride availability was similar in male and female offspring, but female foetuses showed evidence of higher placental transfer of essential fatty acids and synthesis of non-essential fatty acids in muscle and liver. These sex-related differences affected primarily the neutral lipid fraction (triglycerides), which may lead to sex-related postnatal differences in energy partitioning. These results illustrate the strong influence of the maternal lipid profile on foetal development and homeorhesis, and they confirm and extend previous reports that female offspring show better adaptive responses to maternal malnutrition than male offspring. These findings may help guide dietary interventions to ensure adequate fatty acid availability for postnatal development. Full article

(This article belongs to the Special Issue Nutrigenomics of Risk Factors for Disease)

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22 pages, 585 KiB

Open AccessReview

EZH2 in Cancer Progression and Potential Application in Cancer Therapy: A Friend or Foe?

by Ke-Sin Yan¹, Chia-Yuan Lin¹, Tan-Wei Liao², Cheng-Ming Peng³, Shou-Chun Lee⁴, Yi-Jui Liu^4,5, Wing P. Chan⁶ and Ruey-Hwang Chou^1,2,7,*

¹ Graduate Institute of Biomedical Sciences, China Medical University, No.91, Hsueh-Shih Rd., North Dist., Taichung 40402, Taiwan

² Center for Molecular Medicine, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung 40402, Taiwan

³ Da Vinci Minimally Invasive Surgery Center, Chung Shan Medical University Hospital, No. 110, Sec. 1, Chien-Kuo N. Rd., Taichung 40201, Taiwan

⁴ Master’s Program of Biomedical Informatics and Biomedical Engineering, Feng Chia University, No. 100, Wenhwa Rd., Seatwen Dist., Taichung 40724, Taiwan

⁵ Department of Automatic Control Engineering, Feng Chia University, No.100, Wenhwa Rd., Seatwen Dist., Taichung 40724, Taiwan

⁶ Department of Radiology, Wan Fang Hospital, Taipei Medical University, No. 111, Sec. 3, Singlong Rd., Taipei 11696, Taiwan

⁷ Department of Biotechnology, Asia University, No. 500, Lioufeng Rd., Wufeng Dist., Taichung 41354, Taiwan

Int. J. Mol. Sci. 2017, 18(6), 1172; https://doi.org/10.3390/ijms18061172 - 31 May 2017

Cited by 87 | Viewed by 9924

Abstract

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 functions as a double-facet molecule in regulation of gene expression via repression or activation mechanisms, depending on [...] Read more.

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 functions as a double-facet molecule in regulation of gene expression via repression or activation mechanisms, depending on the different cellular contexts. EZH2 interacts with both histone and non-histone proteins to modulate diverse physiological functions including cancer progression and malignancy. In this review article, we focused on the updated information regarding microRNAs (miRNAs) and long non coding RNAs (lncRNAs) in regulation of EZH2, the oncogenic and tumor suppressive roles of EZH2 in cancer progression and malignancy, as well as current pre-clinical and clinical trials of EZH2 inhibitors. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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16 pages, 3378 KiB

Open AccessArticle

Differential Sarcomere and Electrophysiological Maturation of Human iPSC-Derived Cardiac Myocytes in Monolayer vs. Aggregation-Based Differentiation Protocols

by Dorota Jeziorowska^1,2, Vincent Fontaine^1,2, Charlène Jouve^1,2, Eric Villard¹, Sébastien Dussaud¹, David Akbar³, Valérie Letang⁴, Pauline Cervello⁴, Jean-Michiel Itier⁵, Marie-Pierre Pruniaux⁴ and Jean-Sébastien Hulot^1,2,*

¹ Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, Pitié-Salpêtrière Hospital, F-75013 Paris, France

² Institute of Cardiometabolism and Nutrition (ICAN), F-75013 Paris, France

³ Institut du Cerveau et de la Moelle épinière, ICM, CNRS UMR 7225, Inserm U 1127, UPMC-P6 UMR S 1127, Plateforme d’exploration cellulaire, CELIS-Culture Cellulaire, F-75013 Paris, France

⁴ Sanofi Recherche et Développement, F-91380 Chilly-Mazarin, France

⁵ Sanofi Recherche et Développement, F-94403 Vitry, France

Int. J. Mol. Sci. 2017, 18(6), 1173; https://doi.org/10.3390/ijms18061173 - 1 Jun 2017

Cited by 25 | Viewed by 9133

Abstract

Human induced pluripotent stem cells (iPSCs) represent a powerful human model to study cardiac disease in vitro, notably channelopathies and sarcomeric cardiomyopathies. Different protocols for cardiac differentiation of iPSCs have been proposed either based on embroid body formation (3D) or, more recently, on [...] Read more.

Human induced pluripotent stem cells (iPSCs) represent a powerful human model to study cardiac disease in vitro, notably channelopathies and sarcomeric cardiomyopathies. Different protocols for cardiac differentiation of iPSCs have been proposed either based on embroid body formation (3D) or, more recently, on monolayer culture (2D). We performed a direct comparison of the characteristics of the derived cardiomyocytes (iPSC-CMs) on day 27 ± 2 of differentiation between 3D and 2D differentiation protocols with two different Wnt-inhibitors were compared: IWR1 (inhibitor of Wnt response) or IWP2 (inhibitor of Wnt production). We firstly found that the level of Troponin T (TNNT2) expression measured by FACS was significantly higher for both 2D protocols as compared to the 3D protocol. In the three methods, iPSC-CM show sarcomeric structures. However, iPSC-CM generated in 2D protocols constantly displayed larger sarcomere lengths as compared to the 3D protocol. In addition, mRNA and protein analyses reveal higher cTNi to ssTNi ratios in the 2D protocol using IWP2 as compared to both other protocols, indicating a higher sarcomeric maturation. Differentiation of cardiac myocytes with 2D monolayer-based protocols and the use of IWP2 allows the production of higher yield of cardiac myocytes that have more suitable characteristics to study sarcomeric cardiomyopathies. Full article

(This article belongs to the Special Issue Stem Cell Research)

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19 pages, 9726 KiB

Open AccessArticle

The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma

by Angkana Thongkum^1,2, Chunjing Wu³, Ying-Ying Li^3,4, Medhi Wangpaichitr^3,5, Panida Navasumrit^1,2,6, Varabhorn Parnlob¹, Thaniya Sricharunrat⁷, Vajarabhongsa Bhudhisawasdi^8,9, Mathuros Ruchirawat^1,6,* and Niramol Savaraj^3,4,*

¹ Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand

² Chulabhorn Graduate Institute, Laksi, Bangkok 10210, Thailand

³ Division of Hematology/Oncology, Miami Veterans Affairs Healthcare System, Miami, FL 33125, USA

⁴ Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA

⁵ Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA

⁶ Center of Excellence on Environmental Health, Toxicology (EHT), Ministry of Education, Bangkok 10300, Thailand

⁷ Laboratory Unit of Pathology, Chulabhorn Hospital, Laksi, Bangkok 10210, Thailand

⁸ Department of Surgery, Faculty of Medicine, Khonkaen University, Khonkaen 40000, Thailand

⁹ Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand

Int. J. Mol. Sci. 2017, 18(6), 1175; https://doi.org/10.3390/ijms18061175 - 1 Jun 2017

Cited by 28 | Viewed by 7441

Abstract

Argininosuccinate synthetase (ASS), a key enzyme to synthesize arginine is down regulated in many tumors including hepatocellular carcinoma (HCC). Similar to previous reports, we have found the decrease in ASS expression in poorly differentiated HCC. These ASS(-) tumors are auxotrophic for arginine. Pegylated [...] Read more.

Argininosuccinate synthetase (ASS), a key enzyme to synthesize arginine is down regulated in many tumors including hepatocellular carcinoma (HCC). Similar to previous reports, we have found the decrease in ASS expression in poorly differentiated HCC. These ASS(-) tumors are auxotrophic for arginine. Pegylated arginine deiminase (ADI-PEG20), which degrades arginine, has shown activity in these tumors, but the antitumor effect is not robust and hence combination treatment is needed. Herein, we have elucidated the effectiveness of ADI-PEG20 combined with 5-Fluorouracil (5-FU) in ASS(-)HCC by targeting urea cycle and pyrimidine metabolism using four HCC cell lines as model. SNU398 and SNU387 express very low levels of ASS or ASS(-) while Huh-1, and HepG2 express high ASS similar to normal cells. Our results showed that the augmented cytotoxic effect of combination treatment only occurs in SNU398 and SNU387, and not in HepG2 and Huh-1 (ASS(+)) cells, and is partly due to reduced anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP), myeloid leukemia cell differentiation protein (Mcl-1) and B-cell lymphoma-2 (Bcl-2). Importantly, lack of ASS also influences essential enzymes in pyrimidine synthesis (carbamoyl-phosphate synthetase2, aspartate transcarbamylase and dihydrooratase (CAD) and thymidylate synthase (TS)) and malate dehydrogenase-1 (MDH-1) in TCA cycle. ADI-PEG20 treatment decreased these enzymes and made them more vulnerable to 5-FU. Transfection of ASS restored these enzymes and abolished the sensitivity to ADI-PEG20 and combination treatment. Overall, our data suggest that ASS influences multiple enzymes involved in 5-FU sensitivity. Combining ADI-PEG20 and 5-FU may be effective to treat ASS(-)hepatoma and warrants further clinical investigation. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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16 pages, 3603 KiB

Open AccessArticle

Dynamic In Vivo Profiling of DNA Damage and Repair after Radiotherapy Using Canine Patients as a Model

by Nadine Schulz¹, Hassan Chaachouay¹, Katarzyna J. Nytko^1,2, Mathias S. Weyland³, Malgorzata Roos⁴, Rudolf M. Füchslin³, Franco Guscetti⁵, Stephan Scheidegger³ and Carla Rohrer Bley^1,2,*

¹ Division of Radiation Oncology, Vetsuisse Faculty University of Zurich, CH-8057 Zurich, Switzerland

² Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, CH-8057 Zurich, Switzerland

³ ZHAW School of Engineering, Zurich University of Applied Sciences, CH-8400 Winterthur, Switzerland

⁴ Department of Biostatistics, Epidemiology Biostatistics and Prevention Institute, Faculty of Medicine, University of Zurich, CH-8001 Zurich, Switzerland

⁵ Institute of Veterinary Pathology, Vetsuisse Faculty University of Zurich, CH-8057 Zurich, Switzerland

Int. J. Mol. Sci. 2017, 18(6), 1176; https://doi.org/10.3390/ijms18061176 - 1 Jun 2017

Cited by 14 | Viewed by 6968

Abstract

Time resolved data of DNA damage and repair after radiotherapy elucidates the relation between damage, repair, and cell survival. While well characterized in vitro, little is known about the time-course of DNA damage response in tumors sampled from individual patients. Kinetics of DNA [...] Read more.

Time resolved data of DNA damage and repair after radiotherapy elucidates the relation between damage, repair, and cell survival. While well characterized in vitro, little is known about the time-course of DNA damage response in tumors sampled from individual patients. Kinetics of DNA damage after radiotherapy was assessed in eight dogs using repeated in vivo samples of tumor and co-irradiated normal tissue analyzed with comet assay and phosphorylated H2AX (γH2AX) immunohistochemistry. In vivo results were then compared (in silico) with a dynamic mathematical model for DNA damage formation and repair. Maximum %DNA in tail was observed at 15–60 min after irradiation, with a rapid decrease. Time-courses of γH2AX-foci paralleled these findings with a small time delay and were not influenced by covariates. The evolutionary parameter search based on %DNA in tail revealed a good fit of the DNA repair model to in vivo data for pooled sarcoma time-courses, but fits for individual sarcoma time-courses suffer from the heterogeneous nature of the in vivo data. It was possible to follow dynamics of comet tail intensity and γH2AX-foci during a course of radiation using a minimally invasive approach. DNA repair can be quantitatively investigated as time-courses of individual patients by integrating this resulting data into a dynamic mathematical model. Full article

(This article belongs to the Special Issue DNA Injury and Repair Systems)

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9 pages, 1259 KiB

Open AccessArticle

Low-Symmetry Mixed Fluorinated Subphthalocyanines as Fluorescence Imaging Probes in MDA-MB-231 Breast Tumor Cells

by Katherine J. McAuliffe, Megan A. Kaster, Regina G. Szlag and Evan R. Trivedi^*

Department of Chemistry, Oakland University, Rochester, MI 48309, USA

Int. J. Mol. Sci. 2017, 18(6), 1177; https://doi.org/10.3390/ijms18061177 - 1 Jun 2017

Cited by 18 | Viewed by 5440

Abstract

Boron subphthalocyanines (SPcs) are aromatic macrocycles that possess a combination of physical and optical properties that make them excellent candidates for application as fluorescent imaging probes. These molecules have intense electronic absorption and emission, and structural versatility that allows for specific tuning of [...] Read more.

Boron subphthalocyanines (SPcs) are aromatic macrocycles that possess a combination of physical and optical properties that make them excellent candidates for application as fluorescent imaging probes. These molecules have intense electronic absorption and emission, and structural versatility that allows for specific tuning of physical properties. Herein, we report the synthesis of a series of low-symmetry fluorinated SPcs and compare them to analogous compounds with varying numbers of peripheral fluorine atoms and varied aromaticity. Across the series, with increasing addition of fluorine atoms to the periphery of the ring, a downfield chemical shift in ¹⁹F NMR and a bathochromic shift of electronic absorption were observed. Expanding the size of the aromatic ring by replacing peripheral benzo- groups with naphtho- groups prompted a far more drastic bathochromic shift to absorption and emission. Fluorescence quantum yields (Φ_f) proved to be sufficiently high to observe intracellular fluorescence from MDA-MB-231 breast tumor cells in vitro by epifluorescence microscopy; fluorination proved vital for this purpose to improve solubility. This report lays the groundwork for the future development of these promising SPcs for their ultimate application as near-infrared (NIR) fluorescent imaging probes in biological systems. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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25 pages, 2360 KiB

Open AccessReview

Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer

by Liviuta Budisan¹, Diana Gulei², Oana Mihaela Zanoaga¹, Alexandra Iulia Irimie³, Sergiu Chira¹, Cornelia Braicu¹, Claudia Diana Gherman^4,5,* and Ioana Berindan-Neagoe^1,2,6

¹ Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy “Iuliu-Hatieganu”, 400012 Cluj-Napoca, Romania

² MEDFUTURE-Research Center for Advanced Medicine, University of Medicine and Pharmacy “Iuliu-Hatieganu”, 400012 Cluj-Napoca, Romania

³ Department of Prosthodontics and Dental Materials, Faculty of Dental Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 23 Marinescu Street, 400012 Cluj-Napoca, Romania

⁴ Surgical Clinic II, 4–6 Clinicilor Street, 400006 Cluj-Napoca, Romania

⁵ Department of Surgery, University of Medicine and Pharmacy “Iuliu Haţieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania

⁶ Department of Functional Genomics and Experimental Pathology, Oncological Institute “Prof. Dr. Ion Chiricuţă”, 400015 Cluj-Napoca, Romania

Int. J. Mol. Sci. 2017, 18(6), 1178; https://doi.org/10.3390/ijms18061178 - 1 Jun 2017

Cited by 89 | Viewed by 9932

Abstract

Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression [...] Read more.

Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression of coding and non-coding transcripts with an oncogenic or tumour suppressor role. These natural agents are currently exploited for the development of therapeutic strategies alone or in tandem with conventional treatments for cancer. The aim of this paper is to review the recent studies regarding the role of these natural phytochemicals in different processes related to cancer inhibition, including apoptosis activation, angiogenesis and metastasis suppression. From the large palette of phytochemicals we selected epigallocatechin gallate (EGCG), caffeic acid phenethyl ester (CAPE), genistein, morin and kaempferol, due to their increased activity in modulating multiple coding and non-coding genes, targeting the main hallmarks of cancer. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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76 pages, 4470 KiB

Open AccessReview

A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

by Craig L. Parfett^1,* and Daniel Desaulniers²

¹ Mechanistic Studies Division, Environmental Health Science and Research Bureau,HealthyEnvironments and Consumer Safety Branch, Health Canada, 50 Columbine Driveway,Tunney’s Pasture, Ottawa, ON K1A 0K9, Canada

² Hazard Identification Division, Environmental Health Science and Research Bureau,HealthyEnvironments and Consumer Safety Branch, Health Canada, 50 Columbine Driveway,Tunney’s Pasture, Ottawa, ON K1A 0K9, Canada

Int. J. Mol. Sci. 2017, 18(6), 1179; https://doi.org/10.3390/ijms18061179 - 1 Jun 2017

Cited by 30 | Viewed by 10563

Abstract

An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed [...] Read more.

An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs. effect data extrapolated to human in vivo concentrations. Much direct experimental evidence now shows that disruption of epigenetic processes by chemicals is a carcinogenic mode of action that leads to altered gene functions playing causal roles in cancer initiation and progression. In assessing chemical safety, it would therefore be advantageous to consider an emerging class of carcinogens, the epigenotoxicants, with the ability to change chromatin and/or DNA marks by direct or indirect effects on the activities of enzymes (writers, erasers/editors, remodelers and readers) that convey the epigenetic information. Evidence is reviewed supporting a strategy for in vitro hazard identification of carcinogens that induce toxicity through disturbance of functional epigenetic pathways in human somatic cells, leading to inactivated tumour suppressor genes and carcinogenesis. In the context of human cell transformation models, these in vitro pathway measurements ensure high biological relevance to the apical endpoint of cancer. Four causal mechanisms participating in pathways to persistent epigenetic gene silencing were considered: covalent histone modification, nucleosome remodeling, non-coding RNA interaction and DNA methylation. Within these four interacting mechanisms, 25 epigenetic toxicity pathway components (SET1, MLL1, KDM5, G9A, SUV39H1, SETDB1, EZH2, JMJD3, CBX7, CBX8, BMI, SUZ12, HP1, MPP8, DNMT1, DNMT3A, DNMT3B, TET1, MeCP2, SETDB2, BAZ2A, UHRF1, CTCF, HOTAIR and ANRIL) were found to have experimental evidence showing that functional perturbations played “driver” roles in human cellular transformation. Measurement of epigenotoxicants presents challenges for short-term carcinogenicity testing, especially in the high-throughput modes emphasized in the Tox21 chemicals testing approach. There is need to develop and validate in vitro tests to detect both, locus-specific, and genome-wide, epigenetic alterations with causal links to oncogenic cellular phenotypes. Some recent examples of cell-based high throughput chemical screening assays are presented that have been applied or have shown potential for application to epigenetic endpoints. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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21 pages, 1685 KiB

Open AccessArticle

Meta-Analyses of QTLs Associated with Protein and Oil Contents and Compositions in Soybean [Glycine max (L.) Merr.] Seed

by Kyujung Van¹ and Leah K. McHale^1,2,3,*

¹ Department of Horticulture and Crop Science, The Ohio State University, Columbus, OH 43210, USA

² Center for Soybean Research, The Ohio State University, Columbus, OH 43210, USA

³ Center for Applied Plant Sciences, The Ohio State University, Columbus, OH 43210, USA

Int. J. Mol. Sci. 2017, 18(6), 1180; https://doi.org/10.3390/ijms18061180 - 1 Jun 2017

Cited by 76 | Viewed by 7987

Abstract

Soybean [Glycine max (L.) Merr.] is a valuable and nutritious crop in part due to the high protein meal and vegetable oil produced from its seed. Soybean producers desire cultivars with both elevated seed protein and oil concentrations as well as specific [...] Read more.

Soybean [Glycine max (L.) Merr.] is a valuable and nutritious crop in part due to the high protein meal and vegetable oil produced from its seed. Soybean producers desire cultivars with both elevated seed protein and oil concentrations as well as specific amino acid and fatty acid profiles. Numerous studies have identified quantitative trait loci (QTLs) associated with seed composition traits, but validation of these QTLs has rarely been carried out. In this study, we have collected information, including genetic location and additive effects, on each QTL for seed contents of protein and oil, as well as amino acid and fatty acid compositions from over 80 studies. Using BioMercator V. 4.2, a meta-QTL analysis was performed with genetic information comprised of 175 QTLs for protein, 205 QTLs for oil, 156 QTLs for amino acids, and 113 QTLs for fatty acids. A total of 55 meta-QTL for seed composition were detected on 6 out of 20 chromosomes. Meta-QTL possessed narrower confidence intervals than the original QTL and candidate genes were identified within each meta-QTL. These candidate genes elucidate potential natural genetic variation in genes contributing to protein and oil biosynthesis and accumulation, providing meaningful information to further soybean breeding programs. Full article

(This article belongs to the Special Issue Pulses)

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12 pages, 482 KiB

Open AccessArticle

Qualitative and Quantitative Assessment of Vascular Changes in Diabetic Macular Edema after Dexamethasone Implant Using Optical Coherence Tomography Angiography

by Lisa Toto¹, Rossella D’Aloisio^2,*, Marta Di Nicola³

, Giuseppe Di Martino⁴

, Silvio Di Staso⁵, Marco Ciancaglini⁵, Daniele Tognetto² and Leonardo Mastropasqua¹

¹ Ophthalmology Clinic, Department of Medicine and Science of Ageing, University “G. D’Annunzio” Chieti-Pescara, Chieti 66100, Italy

² Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste 34100, Italy

³ Department of Medical, Oral and Biotechnological Sciences, Laboratory of Biostatistics, University “G. D’Annunzio” Chieti-Pescara, Chieti 66100, Italy

⁴ School of Hygiene and Preventive Medicine, Department of Medicine and Science of Ageing, University “G. D’Annunzio” Chieti-Pescara, Chieti 66100, Italy

⁵ Ophthalmology Clinic, Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila 67100, Italy

Int. J. Mol. Sci. 2017, 18(6), 1181; https://doi.org/10.3390/ijms18061181 - 2 Jun 2017

Cited by 65 | Viewed by 6057

Abstract

The aim of this study was to investigate retinal and choriocapillaris vessel changes in diabetic macular edema (DME) after the intravitreal dexamethasone implant (IDI) using optical coherence tomography angiography (OCTA). Moreover, a comparison between morphological and functional parameters of DME and healthy patients [...] Read more.

The aim of this study was to investigate retinal and choriocapillaris vessel changes in diabetic macular edema (DME) after the intravitreal dexamethasone implant (IDI) using optical coherence tomography angiography (OCTA). Moreover, a comparison between morphological and functional parameters of DME and healthy patients was performed. Twenty-five eyes of 25 type 2 diabetic retinopathy patients complicated by macular edema (DME group) and 25 healthy subjects (control group) were enrolled. Superficial capillary plexus density (SCPD) and deep capillary plexus density (DCPD) in the foveal and parafoveal areas, choricapillary density (CCD) and optic disc vessel density (ODVD) were detected using OCTA at baseline and after 7, 30, 60, 90 and 120 days post injection. Best corrected visual acuity (BCVA), retinal sensitivity, and central retinal thickness (CMT) were also evaluated in both groups of patients. A statistically significant difference between the two groups (DME and controls) was found in terms of functional (MP, p < 0.001 and BCVA, p < 0.001) and morphological (CMT, p < 0.001; SCPD in the parafoveal area, p < 0.001; DCPD in the foveal area, p < 0.05 and parafoveal area, p < 0.001; CCD, p < 0.001) parameters. After the treatment, SCPD and DCPD in the foveal and parafoveal areas did not modify significantly during the follow up. Full article

(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)

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22 pages, 863 KiB

Open AccessReview

Micro-RNAs as Potential Predictors of Response to Breast Cancer Systemic Therapy: Future Clinical Implications

by Alma D. Campos-Parra^1,*, Gerardo Cuamani Mitznahuatl¹, Abraham Pedroza-Torres^1,2, Rafael Vázquez Romo³, Fany Iris Porras Reyes⁴, Eduardo López-Urrutia⁵ and Carlos Pérez-Plasencia⁵

¹ Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, C.P. 14080 Tlalpan, Ciudad de México, Mexico

² CATEDRA-CONACyT, Av. De los Insurgente Sur 1582, Col. Crédito Constructor., C.P. 03940 Benito Juárez, Ciudad de México, Mexico

³ Departamento de Cirugia de Tumores mamarios, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, C.P. 14080 Tlalpan, Ciudad de México, Mexico

⁴ Servicio de Anatomia Patologica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, C.P. 14080 Tlalpan, Ciudad de México, Mexico

⁵ Unidad de Biomedicina, FES-IZTACALA, Universidad Nacional Autónoma de Mexico (UNAM), Av. De Los Barrios 1, Col. Los Reyes Iztacala, C.P. 54090 Tlalnepantla, México, Mexico

Int. J. Mol. Sci. 2017, 18(6), 1182; https://doi.org/10.3390/ijms18061182 - 2 Jun 2017

Cited by 45 | Viewed by 7251

Abstract

Despite advances in diagnosis and new treatments such as targeted therapies, breast cancer (BC) is still the most prevalent tumor in women worldwide and the leading cause of death. The principal obstacle for successful BC treatment is the acquired or de novo resistance [...] Read more.

Despite advances in diagnosis and new treatments such as targeted therapies, breast cancer (BC) is still the most prevalent tumor in women worldwide and the leading cause of death. The principal obstacle for successful BC treatment is the acquired or de novo resistance of the tumors to the systemic therapy (chemotherapy, endocrine, and targeted therapies) that patients receive. In the era of personalized treatment, several studies have focused on the search for biomarkers capable of predicting the response to this therapy; microRNAs (miRNAs) stand out among these markers due to their broad spectrum or potential clinical applications. miRNAs are conserved small non-coding RNAs that act as negative regulators of gene expression playing an important role in several cellular processes, such as cell proliferation, autophagy, genomic stability, and apoptosis. We reviewed recent data that describe the role of miRNAs as potential predictors of response to systemic treatments in BC. Furthermore, upon analyzing the collected published information, we noticed that the overexpression of miR-155, miR-222, miR-125b, and miR-21 predicts the resistance to the most common systemic treatments; nonetheless, the function of these particular miRNAs must be carefully studied and further analyses are still necessary to increase knowledge about their role and future potential clinical uses in BC. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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23 pages, 702 KiB

Open AccessReview

Extracellular Vesicles in Hematological Malignancies: From Biology to Therapy

by Antonella Caivano^1,*, Francesco La Rocca²

, Ilaria Laurenzana¹, Stefania Trino¹, Luciana De Luca¹

, Daniela Lamorte¹

, Luigi Del Vecchio^3,4,† and Pellegrino Musto^5,†

¹ Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 858028 Rionero in Vulture, Italy

² Laboratory of Clinical Research and Advanced Diagnostics, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture, Italy

³ CEINGE-Biotecnologie Avanzate scarl, Federico II University, 80138 Naples, Italy

⁴ Department of Molecular Medicine and Medical Biotechnologies, Federico II University, 80138 Naples, Italy

⁵ Scientific Direction, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1183; https://doi.org/10.3390/ijms18061183 - 2 Jun 2017

Cited by 35 | Viewed by 7237

Abstract

Extracellular vesicles (EVs) are a heterogeneous group of particles, between 15 nanometers and 10 microns in diameter, released by almost all cell types in physiological and pathological conditions, including tumors. EVs have recently emerged as particularly interesting informative vehicles, so that they could [...] Read more.

Extracellular vesicles (EVs) are a heterogeneous group of particles, between 15 nanometers and 10 microns in diameter, released by almost all cell types in physiological and pathological conditions, including tumors. EVs have recently emerged as particularly interesting informative vehicles, so that they could be considered a true “cell biopsy”. Indeed, EV cargo, including proteins, lipids, and nucleic acids, generally reflects the nature and status of the origin cells. In some cases, EVs are enriched of peculiar molecular cargo, thus suggesting at least a degree of specific cellular packaging. EVs are identified as important and critical players in intercellular communications in short and long distance interplays. Here, we examine the physiological role of EVs and their activity in cross-talk between bone marrow microenvironment and neoplastic cells in hematological malignancies (HMs). In these diseases, HM EVs can modify tumor and bone marrow microenvironment, making the latter “stronger” in supporting malignancy, inducing drug resistance, and suppressing the immune system. Moreover, EVs are abundant in biologic fluids and protect their molecular cargo against degradation. For these and other “natural” characteristics, EVs could be potential biomarkers in a context of HM liquid biopsy and therapeutic tools. These aspects will be also analyzed in this review. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

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19 pages, 2372 KiB

Open AccessArticle

Gene Expression (mRNA) Markers for Differentiating between Malignant and Benign Follicular Thyroid Tumours

by Bartosz Wojtas^1,2,†, Aleksandra Pfeifer^1,3,†, Malgorzata Oczko-Wojciechowska¹, Jolanta Krajewska¹, Agnieszka Czarniecka⁴, Aleksandra Kukulska¹, Markus Eszlinger⁵, Thomas Musholt⁶, Tomasz Stokowy^1,3,7, Michal Swierniak^1,8, Ewa Stobiecka⁹, Ewa Chmielik⁹, Dagmara Rusinek¹, Tomasz Tyszkiewicz¹, Monika Halczok¹, Steffen Hauptmann¹⁰, Dariusz Lange⁹, Michal Jarzab¹¹

, Ralf Paschke¹² and Barbara Jarzab^1,*

¹ Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute—Oncology Center, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland

² Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warsaw, Poland

³ Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Akademicka 2A, 44-100 Gliwice, Poland

⁴ The Oncologic and Reconstructive Surgery Clinic, Maria Sklodowska-Curie Institute—Oncology Center, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland

⁵ Department of Oncology & Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada

⁶ Department of General, Visceral, and Transplantation Surgery, University Medical Center of the Johannes Gutenberg University, D55099 Mainz, Germany

⁷ Department of Clinical Science, University of Bergen, 5020 Bergen, Norway

⁸ Genomic Medicine, Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-093 Warsaw, Poland

⁹ Tumor Pathology Department, Maria Sklodowska-Curie Institute—Oncology Center, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland

¹⁰ Department of Pathology, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany

¹¹ III Department of Radiotherapy and Chemotherapy, Maria Sklodowska-Curie Institute—Oncology Center, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland

¹² Division of Endocrinology, Departments of Medicine, Pathology, Biochemistry & Molecular Biology, and Oncology, and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2017, 18(6), 1184; https://doi.org/10.3390/ijms18061184 - 2 Jun 2017

Cited by 30 | Viewed by 7426

Abstract

Distinguishing between follicular thyroid cancer (FTC) and follicular thyroid adenoma (FTA) constitutes a long-standing diagnostic problem resulting in equivocal histopathological diagnoses. There is therefore a need for additional molecular markers. To identify molecular differences between FTC and FTA, we analyzed the gene expression [...] Read more.

Distinguishing between follicular thyroid cancer (FTC) and follicular thyroid adenoma (FTA) constitutes a long-standing diagnostic problem resulting in equivocal histopathological diagnoses. There is therefore a need for additional molecular markers. To identify molecular differences between FTC and FTA, we analyzed the gene expression microarray data of 52 follicular neoplasms. We also performed a meta-analysis involving 14 studies employing high throughput methods (365 follicular neoplasms analyzed). Based on these two analyses, we selected 18 genes differentially expressed between FTA and FTC. We validated them by quantitative real-time polymerase chain reaction (qRT-PCR) in an independent set of 71 follicular neoplasms from formaldehyde-fixed paraffin embedded (FFPE) tissue material. We confirmed differential expression for 7 genes (CPQ, PLVAP, TFF3, ACVRL1, ZFYVE21, FAM189A2, and CLEC3B). Finally, we created a classifier that distinguished between FTC and FTA with an accuracy of 78%, sensitivity of 76%, and specificity of 80%, based on the expression of 4 genes (CPQ, PLVAP, TFF3, ACVRL1). In our study, we have demonstrated that meta-analysis is a valuable method for selecting possible molecular markers. Based on our results, we conclude that there might exist a plausible limit of gene classifier accuracy of approximately 80%, when follicular tumors are discriminated based on formalin-fixed postoperative material. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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21 pages, 801 KiB

Open AccessReview

Utilizing Zebrafish Visual Behaviors in Drug Screening for Retinal Degeneration

by Logan Ganzen^1,†, Prahatha Venkatraman^1,†, Chi Pui Pang², Yuk Fai Leung^1,3,4,5,* and Mingzhi Zhang^6,*

¹ Department of Biological Sciences, Purdue University, 915 W. State Street, West Lafayette, IN 47907, USA

² Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China

³ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine Lafayette, 625 Harrison Street, West Lafayette, IN 47907, USA

⁴ Purdue Institute for Integrative neuroscience, 610 Purdue Mall, Purdue University, West Lafayette, IN 47907, USA

⁵ Purdue Institute for Drug Discovery, 610 Purdue Mall, Purdue University, West Lafayette, IN 47907, USA

⁶ Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou 515041, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1185; https://doi.org/10.3390/ijms18061185 - 2 Jun 2017

Cited by 49 | Viewed by 10871

Abstract

Zebrafish are a popular vertebrate model in drug discovery. They produce a large number of small and rapidly-developing embryos. These embryos display rich visual-behaviors that can be used to screen drugs for treating retinal degeneration (RD). RD comprises blinding diseases such as Retinitis [...] Read more.

Zebrafish are a popular vertebrate model in drug discovery. They produce a large number of small and rapidly-developing embryos. These embryos display rich visual-behaviors that can be used to screen drugs for treating retinal degeneration (RD). RD comprises blinding diseases such as Retinitis Pigmentosa, which affects 1 in 4000 people. This disease has no definitive cure, emphasizing an urgency to identify new drugs. In this review, we will discuss advantages, challenges, and research developments in using zebrafish behaviors to screen drugs in vivo. We will specifically discuss a visual-motor response that can potentially expedite discovery of new RD drugs. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

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12 pages, 2208 KiB

Open AccessArticle

Expression Profiling of Strawberry Allergen Fra a during Fruit Ripening Controlled by Exogenous Auxin

by Misaki Ishibashi, Hiroki Yoshikawa and Yuichi Uno^*

Department of Plant Resource Science, Graduate School of Agricultural Science, Kobe University, Rokko, Kobe, Hyogo 657-8501, Japan

Int. J. Mol. Sci. 2017, 18(6), 1186; https://doi.org/10.3390/ijms18061186 - 2 Jun 2017

Cited by 14 | Viewed by 8775

Abstract

Strawberry fruit contain the allergenic Fra a proteins, members of the pathogenesis-related 10 protein family that causes oral allergic syndrome symptoms. Fra a proteins are involved in the flavonoid biosynthesis pathway, which might be important for color development in fruits. Auxin is an [...] Read more.

Strawberry fruit contain the allergenic Fra a proteins, members of the pathogenesis-related 10 protein family that causes oral allergic syndrome symptoms. Fra a proteins are involved in the flavonoid biosynthesis pathway, which might be important for color development in fruits. Auxin is an important plant hormone in strawberry fruit that controls fruit fleshiness and ripening. In this study, we treated strawberry fruits with exogenous auxin or auxin inhibitors at pre- and post-harvest stages, and analyzed Fra a transcriptional and translational expression levels during fruit development by real-time PCR and immunoblotting. Pre-harvest treatment with 1-naphthaleneacetic acid (NAA) alone did not affect Fra a expression, but applied in conjunction with achene removal NAA promoted fruit pigmentation and Fra a protein accumulation. The response was developmental stage-specific: Fra a 1 was highly expressed in immature fruit, whereas Fra a 2 was expressed in young to ripe fruit. In post-harvest treatments, auxin did not contribute to Fra a induction. Auxin inhibitors delayed fruit ripening; as a result, they seemed to influence Fra a 1 expression. Thus, Fra a expression was not directly regulated by auxin, but might be associated with the ripening process and/or external factors in a paralog-specific manner. Full article

(This article belongs to the Special Issue Ripening Control and Induction of the Defence and Antioxidant Systems)

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19 pages, 7200 KiB

Open AccessReview

Deciphering Structural Photophysics of Fluorescent Proteins by Kinetic Crystallography

by Dominique Bourgeois

Institut de Biologie Structurale, Univ. Grenoble Alpes, CNRS, CEA, CNRS, IBS, F-38000 Grenoble, France

Int. J. Mol. Sci. 2017, 18(6), 1187; https://doi.org/10.3390/ijms18061187 - 2 Jun 2017

Cited by 13 | Viewed by 6178

Abstract

Because they enable labeling of biological samples in a genetically-encoded manner, Fluorescent Proteins (FPs) have revolutionized life sciences. Photo-transformable fluorescent proteins (PTFPs), in particular, recently attracted wide interest, as their fluorescence state can be actively modulated by light, a property central to the [...] Read more.

Because they enable labeling of biological samples in a genetically-encoded manner, Fluorescent Proteins (FPs) have revolutionized life sciences. Photo-transformable fluorescent proteins (PTFPs), in particular, recently attracted wide interest, as their fluorescence state can be actively modulated by light, a property central to the emergence of super-resolution microscopy. PTFPs, however, exhibit highly complex photophysical behaviours that are still poorly understood, hampering the rational engineering of variants with improved performances. We show that kinetic crystallography combined with in crystallo optical spectroscopy, modeling approaches and single-molecule measurements constitutes a powerful tool to decipher processes such as photoactivation, photoconversion, photoswitching, photoblinking and photobleaching. Besides potential applications for the design of enhanced PTFPs, these investigations provide fundamental insight into photoactivated protein dynamics. Full article

(This article belongs to the Special Issue Fluorescent Proteins)

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40 pages, 688 KiB

Open AccessReview

Gene-Diet Interactions in Type 2 Diabetes: The Chicken and Egg Debate

by Ángeles Ortega^1,2, Genoveva Berná^1,2,3, Anabel Rojas^1,2,3, Franz Martín^1,2,3,* and Bernat Soria^1,3,*

¹ Centro Andaluz de Biología Molecular y Medicina Regenerativa–CABIMER, 41092 Seville, Spain

² Universidad Pablo Olavide, 41013 Seville, Spain

³ Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain

Int. J. Mol. Sci. 2017, 18(6), 1188; https://doi.org/10.3390/ijms18061188 - 2 Jun 2017

Cited by 58 | Viewed by 14578

Abstract

Consistent evidence from both experimental and human studies indicates that Type 2 diabetes mellitus (T2DM) is a complex disease resulting from the interaction of genetic, epigenetic, environmental, and lifestyle factors. Nutrients and dietary patterns are important environmental factors to consider in the prevention, [...] Read more.

Consistent evidence from both experimental and human studies indicates that Type 2 diabetes mellitus (T2DM) is a complex disease resulting from the interaction of genetic, epigenetic, environmental, and lifestyle factors. Nutrients and dietary patterns are important environmental factors to consider in the prevention, development and treatment of this disease. Nutritional genomics focuses on the interaction between bioactive food components and the genome and includes studies of nutrigenetics, nutrigenomics and epigenetic modifications caused by nutrients. There is evidence supporting the existence of nutrient-gene and T2DM interactions coming from animal studies and family-based intervention studies. Moreover, many case-control, cohort, cross-sectional cohort studies and clinical trials have identified relationships between individual genetic load, diet and T2DM. Some of these studies were on a large scale. In addition, studies with animal models and human observational studies, in different countries over periods of time, support a causative relationship between adverse nutritional conditions during in utero development, persistent epigenetic changes and T2DM. This review provides comprehensive information on the current state of nutrient-gene interactions and their role in T2DM pathogenesis, the relationship between individual genetic load and diet, and the importance of epigenetic factors in influencing gene expression and defining the individual risk of T2DM. Full article

(This article belongs to the Special Issue Gene-Diet Interactions in Chronic Diseases)

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11 pages, 3649 KiB

Open AccessArticle

Stability of BDNF in Human Samples Stored Up to 6 Months and Correlations of Serum and EDTA-Plasma Concentrations

by Maryna Polyakova^1,2,3,*,†, Haiko Schlögl^4,*,†, Julia Sacher^1,3, Maren Schmidt-Kassow⁵, Jochen Kaiser⁵, Michael Stumvoll⁴, Jürgen Kratzsch^3,6,† and Matthias L. Schroeter^1,3,7,†

¹ Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany

² Clinic for Psychiatry and Psychotherapy, University of Leipzig, 04103 Leipzig, Germany

³ LIFE—Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103 Leipzig, Germany

⁴ Department of Endocrinology, University Hospital Leipzig, 04103 Leipzig, Germany

⁵ Institute of Medical Psychology, Goethe University Frankfurt, 60528 Frankfurt, Germany

⁶ Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, 04103 Leipzig, Germany

⁷ Clinic for Cognitive Neurology, University of Leipzig, 04103 Leipzig, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1189; https://doi.org/10.3390/ijms18061189 - 3 Jun 2017

Cited by 44 | Viewed by 9841

Abstract

Brain-derived neurotrophic factor (BDNF), an important neural growth factor, has gained growing interest in neuroscience, but many influencing physiological and analytical aspects still remain unclear. In this study we assessed the impact of storage time at room temperature, repeated freeze/thaw cycles, and storage [...] Read more.

Brain-derived neurotrophic factor (BDNF), an important neural growth factor, has gained growing interest in neuroscience, but many influencing physiological and analytical aspects still remain unclear. In this study we assessed the impact of storage time at room temperature, repeated freeze/thaw cycles, and storage at −80 °C up to 6 months on serum and ethylenediaminetetraacetic acid (EDTA)-plasma BDNF. Furthermore, we assessed correlations of serum and plasma BDNF concentrations in two independent sets of samples. Coefficients of variations (CVs) for serum BDNF concentrations were significantly lower than CVs of plasma concentrations (n = 245, p = 0.006). Mean serum and plasma concentrations at all analyzed time points remained within the acceptable change limit of the inter-assay precision as declared by the manufacturer. Serum and plasma BDNF concentrations correlated positively in both sets of samples and at all analyzed time points of the stability assessment (r = 0.455 to r_s = 0.596; p < 0.004). In summary, when considering the acceptable change limit, BDNF was stable in serum and in EDTA-plasma up to 6 months. Due to a higher reliability, we suggest favoring serum over EDTA-plasma for future experiments assessing peripheral BDNF concentrations. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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19 pages, 261 KiB

Open AccessOpinion

Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use

by Mario Gimona^1,2,3, Karin Pachler^1,2,3, Sandra Laner-Plamberger^1,3

, Katharina Schallmoser^1,3 and Eva Rohde^1,3,*

¹ GMP Unit, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria

² Research Program Nanovesicular Therapies, Paracelsus Medical University (PMU), 5020 Salzburg, Austria

³ Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University (PMU), 5020 Salzburg, Austria

Int. J. Mol. Sci. 2017, 18(6), 1190; https://doi.org/10.3390/ijms18061190 - 3 Jun 2017

Cited by 249 | Viewed by 14897

Abstract

Extracellular vesicles (EVs) derived from stem and progenitor cells may have therapeutic effects comparable to their parental cells and are considered promising agents for the treatment of a variety of diseases. To this end, strategies must be designed to successfully translate EV research [...] Read more.

Extracellular vesicles (EVs) derived from stem and progenitor cells may have therapeutic effects comparable to their parental cells and are considered promising agents for the treatment of a variety of diseases. To this end, strategies must be designed to successfully translate EV research and to develop safe and efficacious therapies, whilst taking into account the applicable regulations. Here, we discuss the requirements for manufacturing, safety, and efficacy testing of EVs along their path from the laboratory to the patient. Development of EV-therapeutics is influenced by the source cell types and the target diseases. In this article, we express our view based on our experience in manufacturing biological therapeutics for routine use or clinical testing, and focus on strategies for advancing mesenchymal stromal cell (MSC)-derived EV-based therapies. We also discuss the rationale for testing MSC-EVs in selected diseases with an unmet clinical need such as critical size bone defects, epidermolysis bullosa and spinal cord injury. While the scientific community, pharmaceutical companies and clinicians are at the point of entering into clinical trials for testing the therapeutic potential of various EV-based products, the identification of the mode of action underlying the suggested potency in each therapeutic approach remains a major challenge to the translational path. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

21 pages, 3325 KiB

Open AccessArticle

Cross-Kingdom Regulation of Putative miRNAs Derived from Happy Tree in Cancer Pathway: A Systems Biology Approach

by Dinesh Kumar^†, Swapnil Kumar^†, Garima Ayachit, Shivarudrappa B. Bhairappanavar, Afzal Ansari

, Priyanka Sharma, Subhash Soni and Jayashankar Das^*

¹ Gujarat Institute of Bioinformatics, Gujarat State Biotechnology Mission, Department of Science & Technology, Government of Gujarat, Gandhinagar 382011, India

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1191; https://doi.org/10.3390/ijms18061191 - 3 Jun 2017

Cited by 40 | Viewed by 8028

Abstract

MicroRNAs (miRNAs) are well-known key regulators of gene expression primarily at the post-transcriptional level. Plant-derived miRNAs may pass through the gastrointestinal tract, entering into the body fluid and regulate the expression of endogenous mRNAs. Camptotheca acuminata, a highly important medicinal plant known [...] Read more.

MicroRNAs (miRNAs) are well-known key regulators of gene expression primarily at the post-transcriptional level. Plant-derived miRNAs may pass through the gastrointestinal tract, entering into the body fluid and regulate the expression of endogenous mRNAs. Camptotheca acuminata, a highly important medicinal plant known for its anti-cancer potential was selected to investigate cross-kingdom regulatory mechanism and involvement of miRNAs derived from this plant in cancer-associated pathways through in silico systems biology approach. In this study, total 33 highly stable putative novel miRNAs were predicted from the publically available 53,294 ESTs of C. acuminata, out of which 14 miRNAs were found to be regulating 152 target genes in human. Functional enrichment, gene-disease associations and network analysis of these target genes were carried out and the results revealed their association with prominent types of cancers like breast cancer, leukemia and lung cancer. Pathways like focal adhesion, regulation of lipolysis in adipocytes and mTOR signaling pathways were found significantly associated with the target genes. The regulatory network analysis showed the association of some important hub proteins like GSK3B, NUMB, PEG3, ITGA2 and DLG2 with cancer-associated pathways. Based on the analysis results, it can be suggested that the ingestion of the C. acuminata miRNAs may have a functional impact on tumorigenesis in a cross-kingdom way and may affect the physiological condition at genetic level. Thus, the predicted miRNAs seem to hold potentially significant role in cancer pathway regulation and therefore, may be further validated using in vivo experiments for a better insight into their mechanism of epigenetic action of miRNA. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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15 pages, 2436 KiB

Open AccessArticle

Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms

by Sarina Grutsch^1,†, Julian E. Fuchs^2,†,‡, Linda Ahammer¹, Anna S. Kamenik², Klaus R. Liedl^2,* and Martin Tollinger^1,*

¹ Institute of Organic Chemistry & Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria

² Institute of Inorganic and Theoretical Chemistry & Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria

^† These authors contributed equally to this work.

^‡ Current Address: Department of Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG, Doktor-Boehringer-Gasse 5-11, A-1120 Vienna, Austria.

Int. J. Mol. Sci. 2017, 18(6), 1192; https://doi.org/10.3390/ijms18061192 - 3 Jun 2017

Cited by 18 | Viewed by 6204

Abstract

The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility [...] Read more.

The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a) and Bet v 1.0102 (Bet v 1d), are conformationally flexible. Inaccessible cleavage sites in helices and strands are highly flexible on the microsecond-millisecond time scale, whereas those located in loops display faster nanosecond-microsecond flexibility. The data consistently show that Bet v 1.0102 is more flexible and conformationally heterogeneous than Bet v 1.0101. Moreover, NMR hydrogen-deuterium exchange measurements reveal that the backbone amides in Bet v 1.0102 are significantly more solvent exposed, in agreement with this isoform’s higher susceptibility to proteolytic cleavage. The differential conformational flexibility of Bet v 1 isoforms, along with the transient exposure of inaccessible sites to the protein surface, may be linked to proteolytic susceptibility, representing a potential structure-based rationale for the observed differences in Th2 polarization and allergic sensitization. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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21 pages, 716 KiB

Open AccessReview

Resveratrol, 4′ Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health

by Edwin D. Lephart

Department of Physiology and Developmental Biology and The Neuroscience Center, LS 4005, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA

Int. J. Mol. Sci. 2017, 18(6), 1193; https://doi.org/10.3390/ijms18061193 - 3 Jun 2017

Cited by 44 | Viewed by 8277

Abstract

Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best-known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17β-estradiol. Human skin gene expression was reviewed for [...] Read more.

Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best-known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17β-estradiol. Human skin gene expression was reviewed for 28 different biomarkers when resveratrol, 4′ acetoxy resveratrol (4AR), R-equol, racemic equol or S-equol were tested. Sirtuin 1 activator (SIRT 1) was stimulated by resveratrol and 4AR only. Resveratrol, R-equol and racemic equol were effective on the aging biomarkers proliferating cell nuclear factor (PCNA), nerve growth factor (NGF), 5α-reductase and the calcium binding proteins S100 A8 and A9. Racemic equol and 4AR displayed among the highest levels for the collagens, elastin and tissue inhibitor of the matrix metalloproteinase 1 (TIMP 1). S-equol displayed the lowest level of effectiveness compared to the other compounds. The 4AR analog was more effective compared to resveratrol by 1.6-fold. R-equol and racemic equol were almost equal in potency displaying greater inhibition vs. resveratrol or its 4′ analog for the matrix metalloproteinases (MMPs), but among the inflammatory biomarkers, resveratrol, 4AR, R-equol and racemic equol displayed high inhibition. Thus, these cosmeceuticals display promise to improve dermal health; however, further study is warranted to understand how phytochemicals protect/enhance the skin. Full article

(This article belongs to the Special Issue Nutrients and Phytochemicals for Skin Health)

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13 pages, 2611 KiB

Open AccessArticle

Photoreceptor PhyB Involved in Arabidopsis Temperature Perception and Heat-Tolerance Formation

by Junyi Song^1,†, Qijun Liu^1,†, Biru Hu^1,* and Wenjian Wu^1,2

¹ College of Science, National University of Defense Technology, Changsha 410073, China

² State Key Lab of Nuclear, Biological and Chemical Protection for Civilian, Beijing 102205, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1194; https://doi.org/10.3390/ijms18061194 - 5 Jun 2017

Cited by 54 | Viewed by 7598

Abstract

The influence of temperature on plants is essential. However, our knowledge on the intricate regulation process underlying heat stress (HS) response in plants is limited. Recently, information about thermal sensors in vivo has begun to emerge. In this study, another primary environmental stimulus, [...] Read more.

The influence of temperature on plants is essential. However, our knowledge on the intricate regulation process underlying heat stress (HS) response in plants is limited. Recently, information about thermal sensors in vivo has begun to emerge. In this study, another primary environmental stimulus, light, was verified once again to work with temperature synergistically on plants, through the modulation of numerous biological processes. With the application of transcriptomic analysis, a substantial number of heat-responsive genes were detected involved in both light- and phytohormone-mediated pathways in Arabidopsis. During this process, phytoreceptor phyB acts as a molecular switch to turn on or turn off several other genes HS response, under different light conditions. Furthermore, a morphological study showed the afunction of phyB enhanced plants thermal tolerance, confirming the important role of this phytochrome in temperature perception and response in plants. This study adds data to the picture of light and temperature signaling cross-talk in plants, which is important for the exploration of complicated HS responses or light-mediated mechanisms. Furthermore, based on its influence on Arabidopsis thermal response in both morphological and physiological levels, phyB is a photoreceptor, as revealed before, as well as an essential thermal sensor in plants. Full article

(This article belongs to the Special Issue Abiotic Stress and Gene Networks in Plants 2017)

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14 pages, 8239 KiB

Open AccessArticle

Aronia melanocarpa (Black Chokeberry) Reduces Ethanol-Induced Gastric Damage via Regulation of HSP-70, NF-κB, and MCP-1 Signaling

by Antonisamy Paulrayer^1,†, Aravinthan Adithan^1,†, Jeong Ho Lee^2,†, Kwang Hyun Moon², Dae Geun Kim², So Yeon Im², Chang-Won Kang¹, Nam Soo Kim¹ and Jong-Hoon Kim^1,*

¹ College of Veterinary Medicine, BK21PLUS project, Chonbuk National University, 79 Gobong-ro, Iksan-city, Jeollabuk-do 54596, Korea

² Sunchang Reserch Institute of Health and Longevity, Ingye-myeon Indeok-ro, Sunchang-gun, Jeollabuk-do 56015, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1195; https://doi.org/10.3390/ijms18061195 - 5 Jun 2017

Cited by 40 | Viewed by 10944

Abstract

Aronia melanocarpa (Michx.) Ell. belongs to the Rosaceae family. The purpose of this study is to explore the gastroprotective effect of the Aronia melanocarpa hydro-alcoholic extract (AMHAE) against ethanol-induced gastric ulcer in a rat model. Different concentrations (50, 100, and 200 mg/kg) of [...] Read more.

Aronia melanocarpa (Michx.) Ell. belongs to the Rosaceae family. The purpose of this study is to explore the gastroprotective effect of the Aronia melanocarpa hydro-alcoholic extract (AMHAE) against ethanol-induced gastric ulcer in a rat model. Different concentrations (50, 100, and 200 mg/kg) of AMHAE, or 30 mg/kg of omeprazole, significantly inhibited the gastric injury formation. The ethanol-induced ulcer group showed significant increases of malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, nuclear factor-kappaB p65 (NF-κB p65), and monocyte chemoattractant protein (MCP)-1, and decreased activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-px), and interleukin (IL)-4. However, AMHAE (200 mg/kg) pretreatment significantly reversed the altered pathophysiological levels of these biomolecules to near normal stages. The gastroprotective activity of AMHAE was abolished by pretreatment with l-NAME, naloxone, capsazepine, and indomethacin, demonstrating the participation of nitric oxide (NO), opioids, TRPV (vanilloid receptor-related transient receptor potential), and prostaglandins in AMHAE-assisted gastroprotection against ethanol-induced gastric injuries. This gastroprotective effect of AMHAE might be due to the downregulation of TNF-α-based NF-κB, MCP-1 signaling and strong antioxidant properties. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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20 pages, 1697 KiB

Open AccessReview

Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

by Sigrun Lange^1,2,*, Mark Gallagher³, Sharad Kholia⁴, Uchini S. Kosgodage³, Mariya Hristova⁵, John Hardy⁶ and Jameel M. Inal³

¹ Department of Biomedical Sciences, University of Westminster, 115, New Cavendish Street, London W1W 6UW, UK

² School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK

³ Cellular and Molecular Immunology Research Centre, School of Human Sciences, London Metropolitan University, 166-220 Holloway Road, London N7 8DB, UK

⁴ Molecular Biotechnology Center, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy

⁵ Institute for Women’s Health, University College London, 74 Huntley Street, London WC1N 6HX, UK

⁶ Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK

Int. J. Mol. Sci. 2017, 18(6), 1196; https://doi.org/10.3390/ijms18061196 - 5 Jun 2017

Cited by 60 | Viewed by 9591

Abstract

Exosomes and microvesicles (EMVs) are lipid bilayer-enclosed structures released from cells and participate in cell-to-cell communication via transport of biological molecules. EMVs play important roles in various pathologies, including cancer and neurodegeneration. The regulation of EMV biogenesis is thus of great importance and [...] Read more.

Exosomes and microvesicles (EMVs) are lipid bilayer-enclosed structures released from cells and participate in cell-to-cell communication via transport of biological molecules. EMVs play important roles in various pathologies, including cancer and neurodegeneration. The regulation of EMV biogenesis is thus of great importance and novel ways for manipulating their release from cells have recently been highlighted. One of the pathways involved in EMV shedding is driven by peptidylarginine deiminase (PAD) mediated post-translational protein deimination, which is calcium-dependent and affects cytoskeletal rearrangement amongst other things. Increased PAD expression is observed in various cancers and neurodegeneration and may contribute to increased EMV shedding and disease progression. Here, we review the roles of PADs and EMVs in cancer and neurodegeneration. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

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16 pages, 4929 KiB

Open AccessArticle

Hepatoprotective Effect of Aqueous Extract from the Seeds of Orychophragmus violaceus against Liver Injury in Mice and HepG2 Cells

by Xiaowei Huo^1,†, Chenqi Liu^1,2,†, Li Gao¹, Xudong Xu¹, Nailiang Zhu^1,*

and Li Cao^1,*

¹ Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China

² Research Center on Life Sciences and Environmental Sciences, Harbin University of Commerce, Harbin 150076, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1197; https://doi.org/10.3390/ijms18061197 - 15 Jun 2017

Cited by 31 | Viewed by 6533

Abstract

Orychophragmus violaceus (O. violaceus) is a kind of edible wild herb in north China and its seeds have medical potential, however, the effect of O. violaceus seeds on liver injury and the mechanism of action remains poorly understood. Thus, the purpose [...] Read more.

Orychophragmus violaceus (O. violaceus) is a kind of edible wild herb in north China and its seeds have medical potential, however, the effect of O. violaceus seeds on liver injury and the mechanism of action remains poorly understood. Thus, the purpose of the present study is to investigate the effect of O. violaceus seeds on liver injury and further explore the molecular mechanism of the beneficial effects using aqueous extract from the seeds of O. violaceus (AEOV). Mice were orally administrated with saline, AEOV, and biphenyldicarboxylate for 4 days, and were then injected subcutaneously with 0.1% carbon tetrachloride (CCl₄) dissolved in corn oil. Sixteen hours later, mice were sacrificed and blood samples were collected. Then, the serum was separated and used for biochemical assay. Livers were excised and were routinely processed for histological examinations. Enzyme activities and protein levels in liver homogenates were detected using commercial kits or by western blot analysis. Additionally, the hepatoprotective effect of AEOV in vitro was evaluated using epigoitrin, the major alkaloid compound isolated from AEOV. We found that AEOV attenuated liver injury induced by CCl₄ as evidenced by decreased levels of alanine aminotransferase (ALT) and aminotransferase (AST) in serum, improvement of liver histopathological changes, and substantial attenuation of oxidative stress and inflammation via regulation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and nuclear factor κB (NFκB) pathways. These effects of AEOV were comparable to that of biphenyldicarboxylate which was commonly used as a hepatoprotective reference. Moreover, pretreatment of HepG2 cells with epigoitrin improved cell viability, decreased lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, attenuated the NFκB pathway, and elevated the Nrf2 pathway after exposure to H₂O₂. These results suggest that AEOV could effectively prevent CCl₄-induced liver injury in mice via regulating the Nrf2 and NFκB pathways, and reveal the cytoprotective effects of epigoitrin against H₂O₂-induced oxidative stress in HepG2 cells. Full article

(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food 2017)

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16 pages, 5790 KiB

Open AccessArticle

Biochemical and Computational Insights on a Novel Acid-Resistant and Thermal-Stable Glucose 1-Dehydrogenase

by Haitao Ding^1,*, Fen Gao², Yong Yu¹ and Bo Chen¹

¹ Key Laboratory for Polar Science of State Oceanic Administration, Polar Research Institute of China, Shanghai 200136, China

² East China Sea Fisheries Research Institute, Shanghai 200090, China

Int. J. Mol. Sci. 2017, 18(6), 1198; https://doi.org/10.3390/ijms18061198 - 5 Jun 2017

Cited by 9 | Viewed by 4781

Abstract

Due to the dual cofactor specificity, glucose 1-dehydrogenase (GDH) has been considered as a promising alternative for coenzyme regeneration in biocatalysis. To mine for potential GDHs for practical applications, several genes encoding for GDH had been heterogeneously expressed in Escherichia coli BL21 (DE3) [...] Read more.

Due to the dual cofactor specificity, glucose 1-dehydrogenase (GDH) has been considered as a promising alternative for coenzyme regeneration in biocatalysis. To mine for potential GDHs for practical applications, several genes encoding for GDH had been heterogeneously expressed in Escherichia coli BL21 (DE3) for primary screening. Of all the candidates, GDH from Bacillus sp. ZJ (BzGDH) was one of the most robust enzymes. BzGDH was then purified to homogeneity by immobilized metal affinity chromatography and characterized biochemically. It displayed maximum activity at 45 °C and pH 9.0, and was stable at temperatures below 50 °C. BzGDH also exhibited a broad pH stability, especially in the acidic region, which could maintain around 80% of its initial activity at the pH range of 4.0–8.5 after incubating for 1 hour. Molecular dynamics simulation was conducted for better understanding the stability feature of BzGDH against the structural context. The in-silico simulation shows that BzGDH is stable and can maintain its overall structure against heat during the simulation at 323 K, which is consistent with the biochemical studies. In brief, the robust stability of BzGDH made it an attractive participant for cofactor regeneration on practical applications, especially for the catalysis implemented in acidic pH and high temperature. Full article

(This article belongs to the Special Issue Special Protein Molecules Computational Identification)

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14 pages, 829 KiB

Open AccessArticle

Identification of Proteases and Protease Inhibitors in Allergenic and Non-Allergenic Pollen

by Barbara Höllbacher^1,†

, Armin O. Schmitt²

, Heidi Hofer¹, Fatima Ferreira¹

and Peter Lackner^1,*,†

¹ Deptartment of Molecular Biology, University of Salzburg, A-5020 Salzburg, Austria

² Faculty of Agricultural Sciences, Georg-August-Universität Göttingen, D-37075 Göttingen, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1199; https://doi.org/10.3390/ijms18061199 - 5 Jun 2017

Cited by 18 | Viewed by 5968

Abstract

Pollen is one of the most common causes of allergy worldwide, making the study of their molecular composition crucial for the advancement of allergy research. Despite substantial efforts in this field, it is not yet clear why some plant pollens strongly provoke allergies [...] Read more.

Pollen is one of the most common causes of allergy worldwide, making the study of their molecular composition crucial for the advancement of allergy research. Despite substantial efforts in this field, it is not yet clear why some plant pollens strongly provoke allergies while others do not. However, proteases and protease inhibitors from allergen sources are known to play an important role in the development of pollen allergies. In this study, we aim to uncover differences in the transcriptional pattern of proteases and protease inhibitors in Betula verrucosa and Pinus sylvestris pollen as models for high and low allergenic potential, respectively. We applied RNA sequencing to Betula verrucosa and Pinus sylvestris pollen. After de-novo assembly we derived general functional profiles of the protein coding transcripts. By utilization of domain based functional annotation we identified potential proteases and protease inhibitors and compared their expression in the two types of pollen. Functional profiles are highly similar between Betula verrucosa and Pinus sylvestris pollen. Both pollen contain proteases and inhibitors from 53 and 7 Pfam families, respectively. Some of the members comprised within those families are implicated in facilitating allergen entry, while others are known allergens themselves. Our work revealed several candidate proteins which, with further investigation, represent exciting new leads in elucidating the process behind allergic sensitization. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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14 pages, 2558 KiB

Open AccessArticle

Ulmus macrocarpa Hance Extracts Attenuated H₂O₂ and UVB-Induced Skin Photo-Aging by Activating Antioxidant Enzymes and Inhibiting MAPK Pathways

by Sun-Il Choi¹, Jin-Ha Lee¹, Jae-Min Kim¹, Tae-Dong Jung¹, Bong-Yeon Cho¹, Seung-Hyun Choi¹, Dae-Won Lee², Jinkyung Kim², Jong-Yea Kim¹ and Ok-Hawn Lee^1,*

¹ Department of Food Science and Biotechnology, Kangwon National University, Chuncheon 24341, Korea

² Jeongseon Yaccho Co., Ltd., Jeongseon 26125, Korea

Int. J. Mol. Sci. 2017, 18(6), 1200; https://doi.org/10.3390/ijms18061200 - 5 Jun 2017

Cited by 40 | Viewed by 9154

Abstract

To protect from reactive oxygen species (ROS) damages, skin cells have evolved to have antioxidant enzymes, such as copper and zinc-dependent superoxide dismutase (SOD1), mitochondrial manganese-dependent superoxide dismutase (SOD2), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR), and suppressed the expression of [...] Read more.

To protect from reactive oxygen species (ROS) damages, skin cells have evolved to have antioxidant enzymes, such as copper and zinc-dependent superoxide dismutase (SOD1), mitochondrial manganese-dependent superoxide dismutase (SOD2), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR), and suppressed the expression of matrix metalloproteinases (MMPs) through the mitogen-activated protein kinase (MAPK) signaling pathways, such as c-Jun N-terminal kinase (JNK) and p38. Bioactive compounds analyses were performed using a high-performance liquid chromatography-photodiode array detector (HPLC-PDA) system. The antioxidant activity of Ulmus macrocarpa Hance (UMH) extracts was estimated in vitro. The anti-aging activity of UMH extracts was estimated in vivo using the SKH-1 hairless mice. The UMH extracts reduced the H₂O₂-induced intracellular ROS production and the cell damages in human dermal fibroblasts (HDFs). Moreover, the H₂O₂-induced phosphorylation of JNK and p38 was detected in HDF and UMH extracts blocked the phosphorylation. These results suggest that UMH extracts can reduce the expression of MMPs and the reduced MMPs lead to the inhibition of collagen degradation. In addition, oral administration of the UMH extracts decreased the depth, thickness, and length of wrinkles on UVB exposed hairless mice. Therefore, UMH extracts play an advantage of the functional materials in antioxidant and anti-aging of skin. Full article

(This article belongs to the Special Issue Nutrients and Phytochemicals for Skin Health)

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20 pages, 710 KiB

Open AccessReview

Genomic Variations in Pancreatic Cancer and Potential Opportunities for Development of New Approaches for Diagnosis and Treatment

by Shuangshuang Lu¹, Tasqeen Ahmed², Pan Du¹ and Yaohe Wang^1,2,*

¹ National Center for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China

² Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK

Int. J. Mol. Sci. 2017, 18(6), 1201; https://doi.org/10.3390/ijms18061201 - 5 Jun 2017

Cited by 14 | Viewed by 6442

Abstract

Human pancreatic cancer has a very poor prognosis with an overall five-year survival rate of less than 5% and an average median survival time of six months. This is largely due to metastatic disease, which is already present in the majority of patients [...] Read more.

Human pancreatic cancer has a very poor prognosis with an overall five-year survival rate of less than 5% and an average median survival time of six months. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Although our understanding of the molecular events underlying multi-step carcinogenesis in pancreatic cancer has steadily increased, translation into more effective therapeutic approaches has been inefficient in recent decades. Therefore, it is imperative that novel and targeted approaches are designed to facilitate the early detection and treatment of pancreatic cancer. Presently, there are numerous ongoing studies investigating the types of genomic variations in pancreatic cancer and their impact on tumor initiation and growth, as well as prognosis. This has led to the development of therapeutics to target these genetic variations for clinical benefit. Thus far, there have been minimal clinical successes directly targeting these genomic alterations; however research is ongoing to ultimately discover an innovative approach to tackle this devastating disease. This review will discuss the genomic variations in pancreatic cancer, and the resulting potential diagnostic and therapeutic implications. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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23 pages, 683 KiB

Open AccessReview

Molecular, Genetic and Agronomic Approaches to Utilizing Pulses as Cover Crops and Green Manure into Cropping Systems

by Eleni Tani^1,*,†, Eleni Abraham^2,†

, Demosthenis Chachalis³ and Ilias Travlos⁴

¹ Laboratory of Plant Breeding and Biometry, Department of Crop Science, Agricultural University of Athens, IeraOdos 75, Athens 11855, Greece

² Laboratory of Range Science, Faculty of Agriculture, Forestry and Natural Environment, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece

³ Laboratory of Weed Science, BenakiPhytopathological Institute, S. Delta 8, Athens 14561, Greece

⁴ Laboratory of Agronomy, Department of Crop Science, Agricultural University of Athens, IeraOdos 75, Athens 11855, Greece

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1202; https://doi.org/10.3390/ijms18061202 - 5 Jun 2017

Cited by 13 | Viewed by 6195

Abstract

Cover crops constitute one of the most promising agronomic practices towards a more sustainable agriculture. Their beneficial effects on main crops, soil and environment are many and various, while risks and disadvantages may also appear. Several legumes show a high potential but further [...] Read more.

Cover crops constitute one of the most promising agronomic practices towards a more sustainable agriculture. Their beneficial effects on main crops, soil and environment are many and various, while risks and disadvantages may also appear. Several legumes show a high potential but further research is required in order to suggest the optimal legume cover crops for each case in terms of their productivity and ability to suppress weeds. The additional cost associated with cover crops should also be addressed and in this context the use of grain legumes such as cowpea, faba bean and pea could be of high interest. Some of the aspects of these grain legumes as far as their use as cover crops, their genetic diversity and their breeding using conventional and molecular approaches are discussed in the present review. The specific species seem to have a high potential for use as cover crops, especially if their noticeable genetic diversity is exploited and their breeding focuses on several desirable traits. Full article

(This article belongs to the Section Molecular Plant Sciences)

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12 pages, 1852 KiB

Open AccessArticle

Insulin Treatment May Alter Fatty Acid Carriers in Placentas from Gestational Diabetes Subjects

by Maria Ruiz-Palacios¹, Maria Teresa Prieto-Sánchez²

, Antonio José Ruiz-Alcaraz³

, José Eliseo Blanco-Carnero², Maria Sanchez-Campillo¹

, Juan José Parrilla² and Elvira Larqué^1,*

¹ Department of Physiology, Faculty of Biology, Campus Mare Nostrum, University of Murcia, Murcia 30100, Spain

² Obstetrics and Gynecology Service, Virgen de la Arrixaca Clinical Hospital, University of Murcia, Murcia 30120, Spain

³ Department of Biochemistry, Molecular Biology B and Immunology, Campus Mare Nostrum, University of Murcia, Murcia 30100, Spain

Int. J. Mol. Sci. 2017, 18(6), 1203; https://doi.org/10.3390/ijms18061203 - 6 Jun 2017

Cited by 32 | Viewed by 5580

Abstract

There is little information available on the effect of Gestational diabetes mellitus (GDM) treatment (diet or insulin) on placental lipid carriers, which may influence fetal fat accretion. Insulin may activate placental insulin receptors protein kinase (AKT) and extracellular signal regulated kinase ERK mediators, [...] Read more.

There is little information available on the effect of Gestational diabetes mellitus (GDM) treatment (diet or insulin) on placental lipid carriers, which may influence fetal fat accretion. Insulin may activate placental insulin receptors protein kinase (AKT) and extracellular signal regulated kinase ERK mediators, which might affect lipid metabolism. Placenta was collected from 25 control women, 23 GDM-Diet and 20 GDM-Insulin. Western blotting of insulin signaling mediators and lipid carriers was performed. The human choricarcinoma-derived cell line BeWo was preincubated with insulin inhibitors protein kinase (AKT) and extracellular signal regulated kinase (ERK) and ERK inhibitors to evaluate insulin regulation of lipid carriers. Maternal serum insulin at recruitment correlated to ultrasound fetal abdominal circumference in offspring of GDM and placental endothelial lipase (EL). Lipoprotein lipase in placenta was significantly reduced in both GDM, while most of the other lipid carriers tended to higher values, although not significantly. There was a significant increase in both phosphorylated-Akt and ERK in placentas from GDM-Insulin patients; both were associated to placental fatty acid translocase (FAT), fatty acid binding protein (A-FABP), and EL. BeWo cells treated with insulin pathway inhibitors significantly reduced A-FABP, fatty acid transport protein (FATP-1), and EL levels, confirming the role of insulin on these carriers. We conclude that insulin promotes the phosphorylation of placental insulin mediators contributing to higher levels of some specific fatty acid carriers in the placenta and fetal adiposity in GDM. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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12 pages, 2403 KiB

Open AccessArticle

Proteases of Dermatophagoides pteronyssinus

by Thomas A. Randall¹

, Robert E. London², Michael C. Fitzgerald³ and Geoffrey A. Mueller^2,*

¹ Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA

² Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr., Research Triangle Park, NC 27709, USA

³ Chemistry Department, Duke Univeristy, Durham, NC, 27708, USA

Int. J. Mol. Sci. 2017, 18(6), 1204; https://doi.org/10.3390/ijms18061204 - 6 Jun 2017

Cited by 15 | Viewed by 5736

Abstract

Since the discovery that Der p 1 is a cysteine protease, the role of proteolytic activity in allergic sensitization has been explored. There are many allergens with proteolytic activity; however, exposure from dust mites is not limited to allergens. In this paper, genomic, [...] Read more.

Since the discovery that Der p 1 is a cysteine protease, the role of proteolytic activity in allergic sensitization has been explored. There are many allergens with proteolytic activity; however, exposure from dust mites is not limited to allergens. In this paper, genomic, transcriptomic and proteomic data on Dermatophagoides pteronyssinus (DP) was mined for information regarding the complete degradome of this house dust mite. D. pteronyssinus has more proteases than the closely related Acari, Dermatophagoides farinae (DF) and Sarcoptes scabiei (SS). The group of proteases in D. pteronyssinus is found to be more highly transcribed than the norm for this species. The distribution of protease types is dominated by the cysteine proteases like Der p 1 that account for about half of protease transcription by abundance, and Der p 1 in particular accounts for 22% of the total protease transcripts. In an analysis of protease stability, the group of allergens (Der p 1, Der p 3, Der p 6, and Der p 9) is found to be more stable than the mean. It is also statistically demonstrated that the protease allergens are simultaneously more highly expressed and more stable than the group of D. pteronyssinus proteases being examined, consistent with common assumptions about allergens in general. There are several significant non-allergen outliers from the normal group of proteases with high expression and high stability that should be examined for IgE binding. This paper compiles the first holistic picture of the D. pteronyssinus degradome to which humans may be exposed. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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21 pages, 12429 KiB

Open AccessArticle

Genetic Variation Controlling Wrinkled Seed Phenotypes in Pisum: How Lucky Was Mendel?

by Tracey Rayner^1,†, Carol Moreau^1,†, Mike Ambrose¹, Peter G. Isaac², Noel Ellis^3,4 and Claire Domoney^1,*

¹ John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK

² IDna Genetics Ltd, Centrum, Norwich Research Park, Norwich NR4 7UG, UK

³ Department of Biology Sciences, University of Auckland, Auckland 1142, New Zealand

⁴ Department of Crop Physiology, International Centre for Agricultural Research in the Dry Areas (ICARDA), Rabat 10106, Morocco

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1205; https://doi.org/10.3390/ijms18061205 - 6 Jun 2017

Cited by 16 | Viewed by 9206

Abstract

One of the traits studied by Mendel in pea (Pisum sativum L.) was the wrinkled-seeded phenotype, and the molecular basis for a mutation underlying this phenotype was discovered in the 1990s. Although the starch-branching enzyme gene mutation identified at the genetic locus [...] Read more.

One of the traits studied by Mendel in pea (Pisum sativum L.) was the wrinkled-seeded phenotype, and the molecular basis for a mutation underlying this phenotype was discovered in the 1990s. Although the starch-branching enzyme gene mutation identified at the genetic locus r is most likely to be that in seeds available to Mendel in the mid-1800s, it has remained an open question as to whether or not additional natural mutations in this gene exist within Pisum germplasm collections. Here, we explore this question and show that all but two wrinkled-seeded variants in one such collection correspond to either the mutant allele described previously for the r locus or a mutation at a second genetic locus, rb, affecting the gene encoding the large subunit of Adenosine diphosphoglucose (ADP-glucose) pyrophosphorylase; the molecular basis for the rb mutation is described here. The genetic basis for the phenotype of one (JI 2110) of the two lines which are neither r nor rb has been studied in crosses with a round-seeded variant (JI 281); for which extensive genetic marker data were expected. In marked contrast to the trait studied by Mendel and the rb phenotype; the data suggest that the wrinkled-seeded phenotype in JI 2110 is maternally determined, controlled by two genetic loci, and the extent to which it is manifested is very sensitive to the environment. Metabolite analysis of the cotyledons of JI 2110 revealed a profile for sucrose and sucrose-derived compounds that was more similar to that of wild-type round-seeded, than that of wrinkled-seeded r, pea lines. However, the metabolite profile of the seed coat (testa) of JI 2110 was distinct from that of other round-seeded genotypes tested which, together with analysis of recombinant inbred progeny lines, suggests an explanation for the seed phenotype. Full article

(This article belongs to the Special Issue Pulses)

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12 pages, 925 KiB

Open AccessReview

Dendritic Cell-Airway Epithelial Cell Cross-Talk Changes with Age and Contributes to Chronic Lung Inflammatory Diseases in the Elderly

by Anshu Agrawal

Division of Basic and Clinical Immunology, Department of Medicine, University of California Irvine, Irvine, CA 92697, USA

Int. J. Mol. Sci. 2017, 18(6), 1206; https://doi.org/10.3390/ijms18061206 - 6 Jun 2017

Cited by 23 | Viewed by 6717

Abstract

Age-associated dysregulated immune and inflammatory responses are one of the major factors responsible for the prevalence of chronic respiratory diseases in the older population. Pulmonary dendritic cells (DCs) are present below the airway epithelial cells (AECs) and are critical in initiating effective immune [...] Read more.

Age-associated dysregulated immune and inflammatory responses are one of the major factors responsible for the prevalence of chronic respiratory diseases in the older population. Pulmonary dendritic cells (DCs) are present below the airway epithelial cells (AECs) and are critical in initiating effective immune responses to harmful pathogens while maintaining tolerance against harmless antigens. The interaction between DCs and AECs plays a crucial role in lung immunity at homeostasis and during infections. The functions of both DCs and AECs are impacted with age. The present report reviews how the potential crosstalk between pulmonary DCs and AECs is dysregulated in the elderly impairing the capacity to maintain tolerance at the respiratory surfaces, which results in severe and chronic respiratory inflammatory diseases. We also discuss how such DC-AECs crosstalk will provide insight into the mechanisms underlying the increased susceptibility of the elderly to pulmonary inflammatory diseases. Full article

(This article belongs to the Special Issue Immunology of Aging)

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20 pages, 1116 KiB

Open AccessReview

The Functions of MicroRNA-200 Family in Ovarian Cancer: Beyond Epithelial-Mesenchymal Transition

by Pui-Wah Choi and Shu-Wing Ng^*

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA

Int. J. Mol. Sci. 2017, 18(6), 1207; https://doi.org/10.3390/ijms18061207 - 6 Jun 2017

Cited by 65 | Viewed by 9348

Abstract

The majority of studies on microRNA-200 family members (miR-200s) in human cancers are based on the premise that miR-200s maintain epithelial cell integrity by suppressing epithelial-mesenchymal transition (EMT) through direct inhibition of mesenchymal transcription factors zinc finger E-box-binding homeobox 1/2 (ZEB1/ZEB2) and transforming [...] Read more.

The majority of studies on microRNA-200 family members (miR-200s) in human cancers are based on the premise that miR-200s maintain epithelial cell integrity by suppressing epithelial-mesenchymal transition (EMT) through direct inhibition of mesenchymal transcription factors zinc finger E-box-binding homeobox 1/2 (ZEB1/ZEB2) and transforming growth factor-β (TGF-β), a potent inducer of EMT. Hence, downregulation of miR-200 in cancer cells promotes EMT and cancer metastasis. Yet, miR-200s are highly expressed in ovarian cancer, and ovarian cancer metastasizes primarily by dissemination within the pelvic cavity. In this review, we will refocus the epithelial property of ovarian cancer cells and the role of miR-200s in safeguarding this property, as well as the diverse roles of miR-200s in inclusion cyst formation, cancer cell growth, collective movement, angiogenesis, exosome-mediated cell communication, and chemoresponse. Taken together, miR-200s play a significant role in the initiation, progression and metastasis of ovarian cancer and may serve as diagnostic biomarkers and a target in therapeutic development. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies)

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12 pages, 7217 KiB

Open AccessArticle

RETRACTED: MicroRNA-223-3p Regulates Ovarian Cancer Cell Proliferation and Invasion by Targeting SOX11 Expression

by Gang Fang, Jiao Liu, Qianna Wang, Xueqiong Huang, Runwen Yang, Yuzhou Pang and Meichun Yang^*

Laboratory of Zhuang Medicine Prescriptions Basis and Application Research, Guangxi University of Chinese Medicine, Nanning 530200, China

Int. J. Mol. Sci. 2017, 18(6), 1208; https://doi.org/10.3390/ijms18061208 - 6 Jun 2017

Cited by 70 | Viewed by 5035 | Retraction

Abstract

MicroRNAs (miRNAs) often display different expression in many cancers and other diseases in current research studies. miR-223 expression is upregulated in rheumatoid arthritis. Also, miR-223 expression has been demonstrated to be highly expressed in pancreatic cancer and gastric cancer in comparison with normal [...] Read more.

MicroRNAs (miRNAs) often display different expression in many cancers and other diseases in current research studies. miR-223 expression is upregulated in rheumatoid arthritis. Also, miR-223 expression has been demonstrated to be highly expressed in pancreatic cancer and gastric cancer in comparison with normal tissue. However, whether miR-223 displays different expression in ovarian cancer and what its underlying functions are in ovarian cancer have remained unclear. In this study, we demonstrated that miR-223-3p was upregulated in ovarian cancer tissue. Next, we explored the functional role of miR-223-3p in ovarian cancer using SKOV3 and OVCAR3 cell lines. Our results suggested that miR-223-3p mimic promoted ovarian cancer cell proliferation, migration, and invasion in vitro. However, miR-223-3p inhibitor displayed the opposite effects. In addition, we demonstrated that miR-223-3p mimic promoted tumor growth in vivo. Furthermore, we found SOX11 (sex determining region Y-box 11) was inversely expressed with miR-223-3p in ovarian cancer (OC) cell lines and tissue specimens. miR-223-3p mimic decreased SOX11 expression. Overexpressing SOX11 inhibited ovarian cancer cell proliferation and invasion, which indicated that miR-223-3p regulated OC cell proliferation and invasion through targeting SOX11 expression. In conclusion, the findings of the present study demonstrated that miR-223-3p could be a potential therapeutic for ovarian cancer. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 5183 KiB

Open AccessArticle

Pathological Analysis of Ocular Lesions in a Murine Model of Sjögren’s Syndrome

by Aya Ushio¹, Rieko Arakaki¹, Hiroshi Eguchi², Fumika Hotta², Akiko Yamada¹, Yasusei Kudo¹ and Naozumi Ishimaru^1,*

¹ Departmant of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan

² Department of Ophtalmology, Sakai Hospital Kindai University, Osaka 590-0132, Japan

Int. J. Mol. Sci. 2017, 18(6), 1209; https://doi.org/10.3390/ijms18061209 - 6 Jun 2017

Cited by 18 | Viewed by 6693

Abstract

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by severe inflammation of exocrine glands such as the salivary and lacrimal glands. When it affects the lacrimal glands, many patients experience keratoconjunctivitis due to severely dry eyes. This study investigated the pathological and [...] Read more.

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by severe inflammation of exocrine glands such as the salivary and lacrimal glands. When it affects the lacrimal glands, many patients experience keratoconjunctivitis due to severely dry eyes. This study investigated the pathological and immunological characteristics of ocular lesions in a mouse model of SS. Corneal epithelial injury and hyperplasia were confirmed pathologically. The number of conjunctival mucin-producing goblet cells was significantly decreased in the SS model mice compared with control mice. Expression levels of transforming growth factor (TGF)-β, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-X-C motif chemokine (CXCL) 12 were significantly higher in the corneal epithelium of the SS model mice than in control mice. Inflammatory lesions were observed in the Harderian, intraorbital, and extraorbital lacrimal glands in the SS model mice, suggesting that the ocular glands were targeted by an autoimmune response. The lacrimal glands of the SS model mice were infiltrated by cluster of differentiation (CD)4⁺ T cells. Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed significantly increased mRNA expression of TNF-α, TGF-β, CXCL9, and lysozyme in the extraorbital lacrimal glands of the SS model mice compared with control mice. These results add to the understanding of the complex pathogenesis of SS and may facilitate development of new therapeutic strategies. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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15 pages, 253 KiB

Open AccessReview

Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers

by Tong-Hong Wang^1,2,3,4,†

, Shih-Min Hsia^5,6,†

, Yin-Hwa Shih^7,* and Tzong-Ming Shieh^8,*

¹ Tissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan

² Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan

³ Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan

⁴ Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan

⁵ School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan

⁶ Nutrition Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan

⁷ Department of Oral Hygiene, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

⁸ Department of Dental Hygiene, College of Health Care, China Medical University, Taichung 40402, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1210; https://doi.org/10.3390/ijms18061210 - 6 Jun 2017

Cited by 51 | Viewed by 8352

Abstract

Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, [...] Read more.

Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, is increasing: oral cancer and nasopharyngeal carcinoma are ranked fourth and tenth respectively, among the top ten cancers in this group, and a major cause of cancer-related deaths in Taiwanese males. Previous studies have identified smoking, alcohol use, and betel quid chewing as the three major causes of head and neck cancers; these three social habits are commonly observed in Taiwanese males, resulting in an increasing morbidity rate of head and neck cancers in this population. In this literature review, we discuss the association between specific components of betel quid, alcohol, and tobacco, and the occurrence of head and neck cancers, lung cancer, gastrointestinal cancers, and urethral cancer. We focus on regulatory mechanisms at the epigenetic level and their oncogenic effects. The review further discusses the application of FDA-approved epigenetic drugs as therapeutic strategies against cancer. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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17 pages, 1644 KiB

Open AccessArticle

Novel Structurally Related Flavones Augment Cell Death Induced by rhsTRAIL

by Joanna Bronikowska^1,*, Ewelina Szliszka¹, Edyta Kostrzewa-Susłow², Dagmara Jaworska¹

, Zenon P. Czuba¹, Piotr Bednarski³ and Wojciech Król^1,3,†

¹ Department of Microbiology and Immunology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Jordana 19, Zabrze 41808, Poland

² Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, Wrocław 50375, Poland

³ Institute of Rheumatology in Warsaw, Spartańska 1, Warszawa 02637, Poland

^† Deceased on 10 May 2016.

Int. J. Mol. Sci. 2017, 18(6), 1211; https://doi.org/10.3390/ijms18061211 - 6 Jun 2017

Cited by 11 | Viewed by 4440

Abstract

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) was identified as a powerful activator of apoptosis in tumor cells and one of the most promising candidates for cancer therapy with no toxicity against normal tissues. However, many tumor cells are resistant to TRAIL-induced apoptosis. The [...] Read more.

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) was identified as a powerful activator of apoptosis in tumor cells and one of the most promising candidates for cancer therapy with no toxicity against normal tissues. However, many tumor cells are resistant to TRAIL-induced apoptosis. The aim of this work was to analyze the improvement of the anticancer effect of rhsTRAIL (recombinant human soluble TRAIL) by nine flavones: 5-Hydroxyflavone, 6-Hydroxyflavone, 7-Hydroxyflavone and their new synthetic derivatives 5-acetoxyflavone, 5-butyryloxyflavone, 6-acetoxyflavone, 6-butyryloxyflavone, 7-acetoxyflavone and 7-butyryloxyflavone. We examined the cytotoxic and apoptotic effects of rhsTRAIL enhanced by novel structurally-related flavones on SW480 and SW620 colon cancer cells using the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test, the lactate dehydrogenase assay and annexin V-FITC fluorescence staining. We observed a slight difference in the activities of the flavones that was dependent on their chemical structure. Our study indicates that all nine flavones significantly augment cell death by rhsTRAIL (cytotoxicity range 36.8 ± 1.7%–91.4 ± 1.7%; apoptosis increase of 33.0 ± 0.7%–78.5 ± 0.9%). Our study demonstrates the potential use of tested flavones in TRAIL-based anticancer therapy and prevention. Full article

(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)

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13 pages, 1410 KiB

Open AccessArticle

In Vitro Evaluation of the Antioxidant, Cytoprotective, and Antimicrobial Properties of Essential Oil from Pistacia vera L. Variety Bronte Hull

by Antonella Smeriglio

, Marcella Denaro, Davide Barreca^*, Antonella Calderaro, Carlo Bisignano, Giovanna Ginestra, Ersilia Bellocco and Domenico Trombetta

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, , Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy

Int. J. Mol. Sci. 2017, 18(6), 1212; https://doi.org/10.3390/ijms18061212 - 6 Jun 2017

Cited by 83 | Viewed by 7037

Abstract

Although the chemical composition and biological properties of some species of the genus Pistacia has been investigated, studies on hull essential oil of Pistacia vera L. variety Bronte (HEO) are currently lacking. In this work, we have carried out an in-depth phytochemical profile [...] Read more.

Although the chemical composition and biological properties of some species of the genus Pistacia has been investigated, studies on hull essential oil of Pistacia vera L. variety Bronte (HEO) are currently lacking. In this work, we have carried out an in-depth phytochemical profile elucidation by Gas Chromatography-Mass Spectrometry (GC-MS) analysis, and an evaluation of antioxidant scavenging properties of HEO, using several different in vitro methods, checking also its cytoprotective potential on lymphocytes treated with tert-butyl hydroperoxide. Moreover, the antimicrobial activity against Gram-positive and Gram-negative strains, both American Type Culture Collection (ATCC) and clinical isolates, was also investigated. GC-MS analysis highlighted the richness of this complex matrix, with the identification of 40 derivatives. The major components identified were 4-Carene (31.743%), α-Pinene (23.584%), d-Limonene (8.002%), and 3-Carene (7.731%). The HEO showed a strong iron chelating activity and was found to be markedly active against hydroxyl radical, while scarce effects were found against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. Moreover, pre-treatment with HEO was observed to significantly increase the cell viability, decreasing the lactate dehydrogenase (LDH) release. HEO was bactericidal against all the tested strains at the concentration of 7.11 mg/mL, with the exception of Pseudomonas aeruginosa ATCC 9027. The obtained results demonstrate the strong free-radical scavenging activity of HEO along with remarkable cytoprotective and antimicrobial properties. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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11 pages, 4230 KiB

Open AccessArticle

Depigmenting Effect of Resveratrol Is Dependent on FOXO3a Activation without SIRT1 Activation

by Soon-Hyo Kwon, Hye-Ryung Choi, Youn-A Kang and Kyoung-Chan Park^*

College of Medicine, Seoul National University, Seoul National University Bundang Hospital, Gyeonggi 13620, Korea

Int. J. Mol. Sci. 2017, 18(6), 1213; https://doi.org/10.3390/ijms18061213 - 7 Jun 2017

Cited by 18 | Viewed by 6891

Abstract

Resveratrol exhibits not only anti-melanogenic property by inhibiting microphthalmia-associated transcription factor (MITF), but also anti-aging property by activating sirtuin-1 (SIRT1). In this study, the relationship between depigmenting effect of resveratrol and SIRT1/forkhead box O (FOXO) 3a activation and was investigated. Resveratrol suppressed melanogenesis [...] Read more.

Resveratrol exhibits not only anti-melanogenic property by inhibiting microphthalmia-associated transcription factor (MITF), but also anti-aging property by activating sirtuin-1 (SIRT1). In this study, the relationship between depigmenting effect of resveratrol and SIRT1/forkhead box O (FOXO) 3a activation and was investigated. Resveratrol suppressed melanogenesis by the downregulation of MITF and tyrosinase via ERK pathway. Results showed that the expression of both SIRT1 and FOXO3a were increased. It is reported that SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. However in our study, FOXO3a activation appeared earlier than that of SIRT1. Furthermore, the effect of resveratrol on the levels of MITF and tyrosinase was suppressed when melanocytes were pre-treated with SP600125 (JNK inhibitor). However, pre-treatment with SIRT1 inhibitor (EX527, or sirtinol) did not affect the levels of MITF and tyrosinase. Therefore, resveratrol inhibits melanogenesis through the activation of FOXO3a but not by the activation of SIRT1. Although SIRT1 activation by resveratrol is a well-known mechanism of resveratrol-induced antiaging effects, our study showed that not SIRT1 but FOXO3a activation is involved in depigmenting effects of resveratrol. Full article

(This article belongs to the Section Biochemistry)

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11 pages, 3649 KiB

Open AccessArticle

A Conjugate of Pentamethine Cyanine and ¹⁸F as a Positron Emission Tomography/Near-Infrared Fluorescence Probe for Multimodality Tumor Imaging

by Fei-Fei An¹, Harikrishna Kommidi¹

, Nandi Chen^1,2 and Richard Ting^1,*

¹ Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medical College, 413 East 69th Street, New York, NY 10065, USA

² State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha 410082, China

Int. J. Mol. Sci. 2017, 18(6), 1214; https://doi.org/10.3390/ijms18061214 - 7 Jun 2017

Cited by 20 | Viewed by 6077 | Correction

Abstract

The novel synthesis of a dual-modality, pentamethine cyanine (Cy5) fluorescent, ¹⁸F positron emission tomography (PET) imaging probe is reported. The probe shows a large extinction coefficient and large quantum yield in the biologically transparent, near-infrared window (650–900 nm) for in vivo fluorescent [...] Read more.

The novel synthesis of a dual-modality, pentamethine cyanine (Cy5) fluorescent, ¹⁸F positron emission tomography (PET) imaging probe is reported. The probe shows a large extinction coefficient and large quantum yield in the biologically transparent, near-infrared window (650–900 nm) for in vivo fluorescent imaging. This fluorophore bears the isotope, ¹⁸F, giving a ¹⁸F-PET/near-infrared fluorescent (NIRF), bi-modal imaging probe, that combines the long-term stability of NIRF and the unlimited penetration depth of PET imaging. The bi-modal probe is labeled with ¹⁸F in a quick, one-step reaction, which is important in working with the rapid decay of ¹⁸F. The bi-modal probe bears a free carboxyl group, highlighting a PET/NIRF synthon that can be conjugated onto many advanced biomolecules for biomarker-specific in vivo dual-modal PET/NIR tumor imaging, confocal histology, and utility in multi-fluorophore, fluorescence-guided surgery. Its potential in vivo biocompatibility is explored in a quick proof-of-principal in vivo study. The dye is delivered to A549 xenograft flank-tumors to generate PET and NIRF signals at the tumor site. The tumor distribution is confirmed in ex vivo gamma counting and imaging. Pentamethine cyanine (Cy5) has the ability to preferentially accumulate in tumor xenografts. We substitute the PET/NIRF probe for Cy5, and explore this phenomenon. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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29 pages, 7993 KiB

Open AccessArticle

Design and Synthesis of Non-Peptide Mimetics Mapping the Immunodominant Myelin Basic Protein (MBP_83–96) Epitope to Function as T-Cell Receptor Antagonists

by Mary-Patricia Yannakakis^1,2, Carmen Simal¹

, Haralambos Tzoupis¹, Maria Rodi³

, Narges Dargahi⁴, Monica Prakash⁴, Athanasia Mouzaki³

, James A. Platts²

, Vasso Apostolopoulos^4,*,†

and Theodore V. Tselios^1,*,†

¹ Department of Chemistry, University of Patras, 26504 Rion Patras, Greece

² School of Chemistry, Cardiff University, Park Place, Cardiff CF103AT, Wales, UK

³ Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Rion, 26500 Patras, Greece

⁴ Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, St. Albans, VIC 3021, Australia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1215; https://doi.org/10.3390/ijms18061215 - 8 Jun 2017

Cited by 15 | Viewed by 6586

Abstract

Encephalitogenic T cells are heavily implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Their stimulation is triggered by the formation of a trimolecular complex between the human leukocyte antigen (HLA), an immunodominant myelin basic [...] Read more.

Encephalitogenic T cells are heavily implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Their stimulation is triggered by the formation of a trimolecular complex between the human leukocyte antigen (HLA), an immunodominant myelin basic protein (MBP) epitope, and the T cell receptor (TCR). We detail herein our studies directed towards the rational design and synthesis of non-peptide mimetic molecules, based on the immunodominant MBP_83–96 epitope that is recognized by the TCR in complex with HLA. We focused our attention on the inhibition of the trimolecular complex formation and consequently the inhibition of proliferation of activated T cells. A structure-based pharmacophore model was generated, in view of the interactions between the TCR and the HLA-MBP_83–96 complex. As a result, new candidate molecules were designed based on lead compounds obtained through the ZINC database. Moreover, semi-empirical and density functional theory methods were applied for the prediction of the binding energy between the proposed non-peptide mimetics and the TCR. We synthesized six molecules that were further evaluated in vitro as TCR antagonists. Analogues 15 and 16 were able to inhibit to some extent the stimulation of T cells by the immunodominant MBP_83–99 peptide from immunized mice. Inhibition was followed to a lesser degree by analogues 17 and 18 and then by analogue 19. These studies show that lead compounds 15 and 16 may be used for immunotherapy against MS. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2017)

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12 pages, 745 KiB

Open AccessReview

The Spleen: A Hub Connecting Nervous and Immune Systems in Cardiovascular and Metabolic Diseases

by Andrea Lori¹, Marialuisa Perrotta¹, Giuseppe Lembo^1,2,* and Daniela Carnevale^1,2,*

¹ Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, 86077 Pozzilli, Italy

² Department of Molecular Medicine, “Sapienza” University of Rome, 00161 Rome, Italy

Int. J. Mol. Sci. 2017, 18(6), 1216; https://doi.org/10.3390/ijms18061216 - 7 Jun 2017

Cited by 49 | Viewed by 9970

Abstract

Metabolic disorders have been identified as major health problems affecting a large portion of the world population. In addition, obesity and insulin resistance are principal risk factors for the development of cardiovascular diseases. Altered immune responses are common features of both hypertension and [...] Read more.

Metabolic disorders have been identified as major health problems affecting a large portion of the world population. In addition, obesity and insulin resistance are principal risk factors for the development of cardiovascular diseases. Altered immune responses are common features of both hypertension and obesity and, moreover, the involvement of the nervous system in the modulation of immune system is gaining even more attention in both pathophysiological contexts. For these reasons, during the last decades, researches focused their efforts on the comprehension of the molecular mechanisms connecting immune system to cardiovascular and metabolic diseases. On the other hand, it has been reported that in these pathological conditions, central neural pathways modulate the activity of the peripheral nervous system, which is strongly involved in onset and progression of the disease. It is interesting to notice that neural reflex can also participate in the modulation of immune functions. In this scenario, the spleen becomes the crucial hub allowing the interaction of different systems differently involved in metabolic and cardiovascular diseases. Here, we summarize the major findings that dissect the role of the immune system in disorders related to metabolic and cardiovascular dysfunctions, and how this could also be influenced by neural reflexes. Full article

(This article belongs to the Special Issue Spleen: Crossroad between Immune System, Metabolic Asset and Endocrine Function)

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13 pages, 3599 KiB

Open AccessArticle

Machine-Learned Data Structures of Lipid Marker Serum Concentrations in Multiple Sclerosis Patients Differ from Those in Healthy Subjects

by Jörn Lötsch^1,2,*

, Michael Thrun³

, Florian Lerch², Robert Brunkhorst⁴, Susanne Schiffmann^1,2, Dominique Thomas¹

, Irmgard Tegder¹, Gerd Geisslinger^1,2 and Alfred Ultsch³

¹ Institute of Clinical Pharmacology, Goethe-University, Theodor Stern Kai 7, Frankfurt am Main 60590, Germany

² Fraunhofer Institute of Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany

³ DataBionics Research Group, University of Marburg, Hans-Meerwein-Strasse 6, Marburg 35032, Germany

⁴ Department of Neurology, Goethe-University Hospital, Schleusenweg 2-16, Frankfurt am Main 60528, Germany

Int. J. Mol. Sci. 2017, 18(6), 1217; https://doi.org/10.3390/ijms18061217 - 7 Jun 2017

Cited by 22 | Viewed by 5735

Abstract

Lipid signaling has been suggested to be a major pathophysiological mechanism of multiple sclerosis (MS). With the increasing knowledge about lipid signaling, acquired data become increasingly complex making bioinformatics necessary in lipid research. We used unsupervised machine-learning to analyze lipid marker serum concentrations, [...] Read more.

Lipid signaling has been suggested to be a major pathophysiological mechanism of multiple sclerosis (MS). With the increasing knowledge about lipid signaling, acquired data become increasingly complex making bioinformatics necessary in lipid research. We used unsupervised machine-learning to analyze lipid marker serum concentrations, pursuing the hypothesis that for the most relevant markers the emerging data structures will coincide with the diagnosis of MS. Machine learning was implemented as emergent self-organizing feature maps (ESOM) combined with the U*-matrix visualization technique. The data space consisted of serum concentrations of three main classes of lipid markers comprising eicosanoids (d = 11 markers), ceramides (d = 10), and lyosophosphatidic acids (d = 6). They were analyzed in cohorts of MS patients (n = 102) and healthy subjects (n = 301). Clear data structures in the high-dimensional data space were observed in eicosanoid and ceramides serum concentrations whereas no clear structure could be found in lysophosphatidic acid concentrations. With ceramide concentrations, the structures that had emerged from unsupervised machine-learning almost completely overlapped with the known grouping of MS patients versus healthy subjects. This was only partly provided by eicosanoid serum concentrations. Thus, unsupervised machine-learning identified distinct data structures of bioactive lipid serum concentrations. These structures could be superimposed with the known grouping of MS patients versus healthy subjects, which was almost completely possible with ceramides. Therefore, based on the present analysis, ceramides are first-line candidates for further exploration as drug-gable targets or biomarkers in MS. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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9 pages, 3438 KiB

Open AccessCase Report

Down’s Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship

by Nandini Dey^1,2, Amy Krie¹, Jessica Klein¹, Kirstin Williams¹, Amanda McMillan¹, Rachel Elsey¹, Yuliang Sun¹, Casey Williams^1,2, Pradip De^1,2 and Brian Leyland-Jones^1,*

¹ Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA

² Departmental of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA

Int. J. Mol. Sci. 2017, 18(6), 1218; https://doi.org/10.3390/ijms18061218 - 7 Jun 2017

Cited by 4 | Viewed by 6543

Abstract

Down’s syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual [...] Read more.

Down’s syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient’s tumor are RUNX1 and ERG genes. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. During the time of writing of this report, no metastatic lesions were identified. The patient currently has no evidence of disease. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)

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15 pages, 3739 KiB

Open AccessReview

Lignins and Their Derivatives with Beneficial Effects on Human Health

by Maria Pilar Vinardell^*

and Montserrat Mitjans

Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Avinguda Joan XXIII 27-31, 08028 Barcelona, Spain

Int. J. Mol. Sci. 2017, 18(6), 1219; https://doi.org/10.3390/ijms18061219 - 7 Jun 2017

Cited by 207 | Viewed by 11351

Abstract

A review of the pharmacological applications of lignins provides evidence of their protective role against the development of different diseases. In many cases, the effects of lignins could be explained by their antioxidant capacity. Here, we present a systematic review of the literature [...] Read more.

A review of the pharmacological applications of lignins provides evidence of their protective role against the development of different diseases. In many cases, the effects of lignins could be explained by their antioxidant capacity. Here, we present a systematic review of the literature from the period 2010–2016 which provides information concerning new applications of lignins derived from recent research. The most promising findings are reported, including the methodologies employed and results obtained with lignins or their derivatives which may improve human health. We highlight potential applications in the treatment of obesity, diabetes, thrombosis, viral infections and cancer. Moreover, we report both that lignins can be used in the preparation of nanoparticles to deliver different drugs and also their use in photoprotection. Full article

(This article belongs to the Special Issue The Lignin Challenge: Exploring Innovative Applications)

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16 pages, 5579 KiB

Open AccessArticle

mtDNA as a Mediator for Expression of Hypoxia-Inducible Factor 1α and ROS in Hypoxic Neuroblastoma Cells

by Chung-Wen Kuo^1,2,†, Meng-Han Tsai^1,†, Tsu-Kung Lin^1,6, Mao-Meng Tiao³, Pei-Wen Wang⁴, Jiin-Haur Chuang⁵, Shang-Der Chen¹ and Chia-Wei Liou^1,6,*

¹ Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

² Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan

³ Departments of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

⁴ Department of Metabolism, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

⁵ Departments of Pediatrics Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

⁶ Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1220; https://doi.org/10.3390/ijms18061220 - 7 Jun 2017

Cited by 24 | Viewed by 7137

Abstract

Mitochondria consume O₂ to produce ATP and are critical for adaption of hypoxia, but the role of mitochondria in HIF-1α pathway is as yet unclear. In this study, mitochondrial DNA (mtDNA) enriched (SK-N-AS) and depleted (ρ⁰) cells of neuroblastoma were [...] Read more.

Mitochondria consume O₂ to produce ATP and are critical for adaption of hypoxia, but the role of mitochondria in HIF-1α pathway is as yet unclear. In this study, mitochondrial DNA (mtDNA) enriched (SK-N-AS) and depleted (ρ⁰) cells of neuroblastoma were cultured in a hypoxic chamber to simulate a hypoxic condition and then the major components involved in mitochondrial related pathways, hypoxia-inducible factor 1α (HIF-1α) and reactive oxygen species (ROS) were measured. The results showed that hypoxia-stimulated exposure elevated expression of HIF-1α, which was additionally influenced by level of generated ROS within the cytosol. Moreover, elevation of HIF-1α also resulted in increases of lactate dehydrogenase A (LDH-A) and pyruvate dehydrogenase kinase 1 (PDK1) in both hypoxic cells. The expression of mitochondrial biogenesis related proteins and metabolic components were noted to increase significantly in hypoxic SK-N-AS cells, indicating that mtDNA was involved in mitochondrial retrograde signaling and metabolic pathways. An analysis of dynamic proteins found elevated levels of HIF-1α causing an increased expression of dynamin-related protein 1 (DRP1) during hypoxia; further, the existence of mtDNA also resulted in higher expression of DRP1 during hypoxia. By using siRNA of HIF-1α or DRP1, expression of DRP1 decreased after suppression of HIF-1α; moreover, the expression of HIF-1α was also affected by the suppression of DRP1. In this study, we demonstrated that mtDNA is a mediator of HIF-1α in eliciting metabolic reprogramming, and mitochondrial biogenesis. Identification of a mutual relationship between HIF-1α and DRP1 may be a critical tool in the future development of clinical applications. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 1217 KiB

Open AccessReview

Melatonin and Fertoprotective Adjuvants: Prevention against Premature Ovarian Failure during Chemotherapy

by Hoon Jang¹

, Kwonho Hong^2,* and Youngsok Choi^1,*

¹ Department of Biomedical Science, Cha University, 335 Pangyo, Bundang, Seongnami, Gyeonggi 13488, Korea

² Department of Stem Cell and Regenerative Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea

Int. J. Mol. Sci. 2017, 18(6), 1221; https://doi.org/10.3390/ijms18061221 - 7 Jun 2017

Cited by 43 | Viewed by 9670

Abstract

Premature ovarian failure is one of the side effects of chemotherapy in pre-menopausal cancer patients. Preservation of fertility has become increasingly important in improving the quality of life of completely recovered cancer patients. Among the possible strategies for preserving fertility such as ovarian [...] Read more.

Premature ovarian failure is one of the side effects of chemotherapy in pre-menopausal cancer patients. Preservation of fertility has become increasingly important in improving the quality of life of completely recovered cancer patients. Among the possible strategies for preserving fertility such as ovarian tissue cryopreservation, co-treatment with a pharmacological adjuvant is highly effective and poses less of a burden on the human body. Melatonin is generally produced in various tissues and acts as a universally acting antioxidant in cells. Melatonin is now more widely used in various biological processes including treating insomnia and an adjuvant during chemotherapy. In this review, we summarize the information indicating that melatonin may be useful for reducing and preventing premature ovarian failure in chemotherapy-treated female patients. We also mention that many adjuvants other than melatonin are developed and used to inhibit chemotherapy-induced infertility. This information will give us novel insights on the clinical use of melatonin and other agents as fertoprotective adjuvants for female cancer patients. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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20 pages, 1493 KiB

Open AccessReview

The Value of In Vitro Tests to Diminish Drug Challenges

by Cristobalina Mayorga^1,2,*, Inmaculada Doña², Ezequiel Perez-Inestrosa^3,4, Tahia D. Fernández¹ and Maria J. Torres^2,4

¹ Research Laboratory-Allergy Unit, Biomedical Institute of Málaga-IBIMA, Regional University Hospital of Malaga-UMA, Málaga 29009, Spain

² Allergy Service, IBIMA-Regional University Hospital of Malaga-UMA, Málaga 29009, Spain

³ Department of Organic Chemistry, University of Málaga, Biomedical Institute of Málaga-IBIMA, Málaga 29071, Spain

⁴ Andalusian Center for Nanomedicine and Biotechnology-BIONAND, Málaga 29590, Spain

Int. J. Mol. Sci. 2017, 18(6), 1222; https://doi.org/10.3390/ijms18061222 - 7 Jun 2017

Cited by 60 | Viewed by 5808

Abstract

Drug hypersensitivity reactions have multiple implications for patient safety and health system costs, thus it is important to perform an accurate diagnosis. The diagnostic procedure includes a detailed clinical history, often unreliable; followed by skin tests, sometimes with low sensitivity or unavailable; and [...] Read more.

Drug hypersensitivity reactions have multiple implications for patient safety and health system costs, thus it is important to perform an accurate diagnosis. The diagnostic procedure includes a detailed clinical history, often unreliable; followed by skin tests, sometimes with low sensitivity or unavailable; and drug provocation testing, which is not risk-free for the patient, especially in severe reactions. In vitro tests could help to identify correctly the responsible agent, thus improving the diagnosis of these reactions, helping the physician to find safe alternatives, and reducing the need to perform drug provocation testing. However, it is necessary to confirm the sensitivity, specificity, negative and positive predictive values for these in vitro tests to enable their implementation in clinical practice. In this review, we have analyzed these parameters from different studies that have used in vitro test for evaluating drug hypersensitivity reactions and estimated the added value of these tests to the in vivo diagnosis. Full article

(This article belongs to the Special Issue Drug Hypersensitivity)

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14 pages, 718 KiB

Open AccessReview

Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or “Innate Hypersensitivity”?

by David Spoerl^1,*, Haig Nigolian¹, Christoph Czarnetzki² and Thomas Harr¹

¹ Division of Clinical Immunology and Allergy, Department of Medical Specialties, University Hospital and Faculty of Medicine, University of Geneva, rue Gabrielle-Perret-Gentil 4, CH-1205 Geneva, Switzerland

² Department of Anesthesiology, University Hospital and Faculty of Medicine, University of Geneva, rue Gabrielle-Perret-Gentil 4, CH-1205 Geneva, Switzerland

Int. J. Mol. Sci. 2017, 18(6), 1223; https://doi.org/10.3390/ijms18061223 - 7 Jun 2017

Cited by 66 | Viewed by 18233

Abstract

Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological [...] Read more.

Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related) may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA) are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2). In light of this new insight into the patho-mechanism of pseudo-allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE-mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions. Full article

(This article belongs to the Special Issue Drug Hypersensitivity)

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19 pages, 3708 KiB

Open AccessArticle

Activation of Magnesium Lignosulfonate and Kraft Lignin: Influence on the Properties of Phenolic Resin-Based Composites for Potential Applications in Abrasive Materials

by Lukasz Klapiszewski^1,*

, Artur Jamrozik^1,2, Beata Strzemiecka¹, Danuta Matykiewicz³, Adam Voelkel¹ and Teofil Jesionowski¹

¹ Poznan University of Technology, Faculty of Chemical Technology, Institute of Chemical Technology and Engineering, Berdychowo 4, PL-60965 Poznan, Poland

² Wielkopolska Centre of Advanced Technologies, Umultowska 89 C, PL-61614 Poznan, Poland

³ Poznan University of Technology, Institute of Material Technology, Division of Plastic Processing, Piotrowo 3, PL-61138 Poznan, Poland

Int. J. Mol. Sci. 2017, 18(6), 1224; https://doi.org/10.3390/ijms18061224 - 8 Jun 2017

Cited by 51 | Viewed by 7490

Abstract

Magnesium lignosulfonate and kraft lignin were activated by different oxidizing agents for use in phenolic resin composites used for the production of abrasive components. The physicochemical properties of the oxidized materials were analyzed by Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), [...] Read more.

Magnesium lignosulfonate and kraft lignin were activated by different oxidizing agents for use in phenolic resin composites used for the production of abrasive components. The physicochemical properties of the oxidized materials were analyzed by Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), dynamic mechanical-thermal analysis (DMTA) and inverse gas chromatography (IGC). The homogeneity of the model abrasive composites containing the studied products was assessed based on observations obtained using a scanning electron microscope (SEM). FTIR and XPS analysis of the oxidized products indicated that the activation process leads mainly to the formation of carbonyl groups. The IGC technique was used to assess changes in the surface energy and the acid–base properties of the studied biopolymers. The changes in the acid–base properties suggest that more groups acting as electron donors appear on the oxidized surface of the materials. DMTA studies showed that the model composites with 5% magnesium lignosulfonate oxidized by H₂O₂ had the best thermomechanical properties. Based on the results it was possible to propose a hypothetical mechanism of the oxidation of the natural polymers. The use of such oxidized products may improve the thermomechanical properties of abrasive articles. Full article

(This article belongs to the Special Issue The Lignin Challenge: Exploring Innovative Applications)

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12 pages, 4904 KiB

Open AccessArticle

Comparing Proteolytic Fingerprints of Antigen-Presenting Cells during Allergen Processing

by Heidi Hofer^1,†, Tamara Weidinger^1,†, Peter Briza^1,†, Claudia Asam¹, Martin Wolf¹, Teresa E. Twaroch², Frank Stolz², Angela Neubauer², Elfriede Dall¹, Peter Hammerl¹, Alain Jacquet³

and Michael Wallner^1,*

¹ Department of Molecular Biology, University of Salzburg, Salzburg 5020, Austria

² Biomay AG, Vienna 1090, Austria

³ Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1225; https://doi.org/10.3390/ijms18061225 - 8 Jun 2017

Cited by 4 | Viewed by 5222

Abstract

Endolysosomal processing has a critical influence on immunogenicity as well as immune polarization of protein antigens. In industrialized countries, allergies affect around 25% of the population. For the rational design of protein-based allergy therapeutics for immunotherapy, a good knowledge of T cell-reactive regions [...] Read more.

Endolysosomal processing has a critical influence on immunogenicity as well as immune polarization of protein antigens. In industrialized countries, allergies affect around 25% of the population. For the rational design of protein-based allergy therapeutics for immunotherapy, a good knowledge of T cell-reactive regions on allergens is required. Thus, we sought to analyze endolysosomal degradation patterns of inhalant allergens. Four major allergens from ragweed, birch, as well as house dust mites were produced as recombinant proteins. Endolysosomal proteases were purified by differential centrifugation from dendritic cells, macrophages, and B cells, and combined with allergens for proteolytic processing. Thereafter, endolysosomal proteolysis was monitored by protein gel electrophoresis and mass spectrometry. We found that the overall proteolytic activity of specific endolysosomal fractions differed substantially, whereas the degradation patterns of the four model allergens obtained with the different proteases were extremely similar. Moreover, previously identified T cell epitopes were assigned to endolysosomal peptides and indeed showed a good overlap with known T cell epitopes for all four candidate allergens. Thus, we propose that the degradome assay can be used as a predictor to determine antigenic peptides as potential T cell epitopes, which will help in the rational design of protein-based allergy vaccine candidates. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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18 pages, 8140 KiB

Open AccessArticle

Cellular Consequences of Diminished Protein O-Mannosyltransferase Activity in Baker’s Yeast

by Ewa Zatorska¹, Lihi Gal²

, Jaro Schmitt¹, Daniela Bausewein¹, Maya Schuldiner²

and Sabine Strahl^1,*

¹ Centre for Organismal Studies (COS), Heidelberg University, 69120 Heidelberg, Germany

² Department of Molecular Genetics, Weizmann Institute of Science, 7610001 Rehovot, Israel

Int. J. Mol. Sci. 2017, 18(6), 1226; https://doi.org/10.3390/ijms18061226 - 9 Jun 2017

Cited by 5 | Viewed by 8108

Abstract

O-Mannosylation is a type of protein glycosylation initiated in the endoplasmic reticulum (ER) by the protein O-mannosyltransferase (PMT) family. Despite the vital role of O-mannosylation, its molecular functions and regulation are not fully characterized. To further explore the cellular impact [...] Read more.

O-Mannosylation is a type of protein glycosylation initiated in the endoplasmic reticulum (ER) by the protein O-mannosyltransferase (PMT) family. Despite the vital role of O-mannosylation, its molecular functions and regulation are not fully characterized. To further explore the cellular impact of protein O-mannosylation, we performed a genome-wide screen to identify Saccharomyces cerevisiae mutants with increased sensitivity towards the PMT-specific inhibitor compound R3A-5a. We identified the cell wall and the ER as the cell compartments affected most upon PMT inhibition. Especially mutants with defects in N-glycosylation, biosynthesis of glycosylphosphatidylinositol-anchored proteins and cell wall β-1,6-glucan showed impaired growth when O-mannosylation became limiting. Signaling pathways that counteract cell wall defects and unbalanced ER homeostasis, namely the cell wall integrity pathway and the unfolded protein response, were highly crucial for the cell growth. Moreover, among the most affected mutants, we identified Ost3, one of two homologous subunits of the oligosaccharyltransferase complexes involved in N-glycosylation, suggesting a functional link between the two pathways. Indeed, we identified Pmt2 as a substrate for Ost3 suggesting that the reduced function of Pmt2 in the absence of N-glycosylation promoted sensitivity to the drug. Interestingly, even though S. cerevisiae Pmt1 and Pmt2 proteins are highly similar on the sequence, as well as the structural level and act as a complex, we identified only Pmt2, but not Pmt1, as an Ost3-specific substrate protein. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins 2017)

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21 pages, 3937 KiB

Open AccessArticle

Identification of Novel Placentally Expressed Aspartic Proteinase in Humans

by Marta Majewska^1,*

, Aleksandra Lipka²

, Grzegorz Panasiewicz³, Marek Gowkielewicz²

, Marcin Jozwik², Mariusz Krzysztof Majewski¹

and Bozena Szafranska³

¹ Department of Human Physiology, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Warszawska Str 30, 10-082 Olsztyn, Poland

² Department of Gynecology and Obstetrics, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Niepodleglosci Str 44, 10-045 Olsztyn, Poland

³ Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str 1A, 10-719 Olsztyn, Poland

Int. J. Mol. Sci. 2017, 18(6), 1227; https://doi.org/10.3390/ijms18061227 - 8 Jun 2017

Cited by 4 | Viewed by 4356

Abstract

This study presents pioneering data concerning the human pregnancy-associated glycoprotein-Like family, identified in the genome, of the term placental transcriptome and proteome. RNA-seq allowed the identification of 1364 bp hPAG-L/pep cDNA with at least 56.5% homology with other aspartic proteinases (APs). In silico [...] Read more.

This study presents pioneering data concerning the human pregnancy-associated glycoprotein-Like family, identified in the genome, of the term placental transcriptome and proteome. RNA-seq allowed the identification of 1364 bp hPAG-L/pep cDNA with at least 56.5% homology with other aspartic proteinases (APs). In silico analyses revealed 388 amino acids (aa) of full-length hPAG-L polypeptide precursor, with 15 aa-signal peptide, 47 aa-blocking peptide and 326 aa-mature protein, and two Asp residues (D), specific for a catalytic cleft of the APs (VVFDTGSSNLWV91-102 and AIVDTGTSLLTG274-285). Capillary sequencing identified 9330 bp of the hPAG-L gene (Gen Bank Acc. No. KX533473), composed of nine exons and eight introns. Heterologous Western blotting revealed the presence of one dominant 60 kDa isoform of the hPAG-L amongst cellular placental proteins. Detection with anti-pPAG-P and anti-Rec pPAG2 polyclonals allowed identification of the hPAG-L proteins located within regions of chorionic villi, especially within the syncytiotrophoblast of term singleton placentas. Our novel data extend the present knowledge about the human genome, as well as placental transcriptome and proteome during term pregnancy. Presumably, this may contribute to establishing a new diagnostic tool for examination of some disturbances during human pregnancy, as well as growing interest from both scientific and clinical perspectives. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 4984 KiB

Open AccessArticle

BrWRKY65, a WRKY Transcription Factor, Is Involved in Regulating Three Leaf Senescence-Associated Genes in Chinese Flowering Cabbage

by Zhong-Qi Fan, Xiao-Li Tan, Wei Shan, Jian-Fei Kuang, Wang-Jin Lu and Jian-Ye Chen^*

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources/Guangdong Provincial Key Laboratory of Postharvest Science of Fruits and Vegetables/Key Laboratory of Biology and Genetic Improvement of Horticultural Crops-South China, Ministry of Agriculture, College of Horticulture, South China Agricultural University, Guangzhou 510642, China

Int. J. Mol. Sci. 2017, 18(6), 1228; https://doi.org/10.3390/ijms18061228 - 8 Jun 2017

Cited by 53 | Viewed by 8093

Abstract

Plant-specific WRKY transcription factors (TFs) have been implicated to function as regulators of leaf senescence, but their association with postharvest leaf senescence of economically important leafy vegetables, is poorly understood. In this work, the characterization of a Group IIe WRKY TF, BrWRKY65, from [...] Read more.

Plant-specific WRKY transcription factors (TFs) have been implicated to function as regulators of leaf senescence, but their association with postharvest leaf senescence of economically important leafy vegetables, is poorly understood. In this work, the characterization of a Group IIe WRKY TF, BrWRKY65, from Chinese flowering cabbage (Brassica rapa var. parachinensis) is reported. The expression of BrWRKY65 was up-regulated following leaf chlorophyll degradation and yellowing during postharvest senescence. Subcellular localization and transcriptional activation assays showed that BrWRKY65 was localized in the nucleus and exhibited trans-activation ability. Further electrophoretic mobility shift assay (EMSA) and transient expression analysis clearly revealed that BrWRKY65 directly bound to the W-box motifs in the promoters of three senescence-associated genes (SAGs) such as BrNYC1 and BrSGR1 associated with chlorophyll degradation, and BrDIN1, and subsequently activated their expressions. These findings demonstrate that BrWRKY65 may be positively associated with postharvest leaf senescence, at least partially, by the direct activation of SAGs. Taken together, these findings provide new insights into the transcriptional regulatory mechanism of postharvest leaf senescence in Chinese flowering cabbage. Full article

(This article belongs to the Special Issue Abiotic Stress and Gene Networks in Plants 2017)

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13 pages, 5354 KiB

Open AccessArticle

The Roles of Reactive Oxygen Species and Nitric Oxide in Perfluorooctanoic Acid-Induced Developmental Cardiotoxicity and l-Carnitine Mediated Protection

by Meng Zhao^1,†, Qixiao Jiang^1,*,†, Wencheng Wang², Min Geng¹, Meng Wang¹, Yantao Han¹ and Chunbo Wang^1,*

¹ Department of Pharmacology, Qingdao University Medical College, 308 Ning Xia Road, Qingdao 266071, China

² Qingdao Municipal Center for Disease Control & Prevention, 175 Shandong Road, Qingdao 266071, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1229; https://doi.org/10.3390/ijms18061229 - 8 Jun 2017

Cited by 18 | Viewed by 6383

Abstract

Perfluorooctanoic acid (PFOA) is an environmental contaminant that could induce developmental cardiotoxicity in a chicken embryo, which may be alleviated by l-carnitine. To explore the roles of reactive oxygen species (ROS) and nitric oxide (NO) in such changes and the potential effects [...] Read more.

Perfluorooctanoic acid (PFOA) is an environmental contaminant that could induce developmental cardiotoxicity in a chicken embryo, which may be alleviated by l-carnitine. To explore the roles of reactive oxygen species (ROS) and nitric oxide (NO) in such changes and the potential effects of l-carnitine, fertile chicken eggs were exposed to PFOA via an air cell injection, with or without l-carnitine co-treatment. The ROS and NO levels in chicken embryo hearts were determined with electron spin resonance (ESR), and the protein levels of the nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) p65 and inducible nitric oxide synthase (iNOS) in chicken embryo hearts were assessed with western blotting. The results of ESR indicated that PFOA exposure induced an elevation in the ROS levels in ED19 chicken embryo hearts and hatchling chicken hearts, while l-carnitine could alleviate such changes. Meanwhile, increased NO levels were observed in ED19 embryo hearts and hatchling hearts following PFOA exposure, while l-carnitine co-treatment exerted modulatory effects. Western blotting revealed that p65 translocation in ED19 embryo hearts and hatchling hearts was enhanced by PFOA, while l-carnitine co-treatment alleviated such changes. iNOS expression levels in ED19 embryo hearts followed the same pattern as NO levels, while a suppression of expression was observed in hatchling hearts exposed to PFOA. ROS/NF-κB p65 and iNOS/NO seem to be involved in the late stage (ED19 and post hatch) of PFOA-induced developmental cardiotoxicity in a chicken embryo. l-carnitine could exert anti-oxidant and NO modulatory effects in the developing chicken embryo hearts, which likely contribute to its cardioprotective effects. Full article

(This article belongs to the Special Issue Correlation between Nutrition, Oxidative Stress and Disease)

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12 pages, 3923 KiB

Open AccessArticle

Galectins-1, -3, and -7 Are Prognostic Markers for Survival of Ovarian Cancer Patients

by Heiko Schulz¹, Elisa Schmoeckel²

, Christina Kuhn¹, Simone Hofmann¹, Doris Mayr², Sven Mahner¹ and Udo Jeschke^1,*

¹ Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistr. 15, 81377 Munich and Campus Innenstadt: Maistr. 11, Munich 80337, Germany

² LMU Munich, Department of Pathology, Ludwig Maximilians University of Munich, Thalkirchner Str. 142, Munich 80337, Germany

Int. J. Mol. Sci. 2017, 18(6), 1230; https://doi.org/10.3390/ijms18061230 - 8 Jun 2017

Cited by 41 | Viewed by 6687

Abstract

There is a tremendous need for developing new useful prognostic factors in ovarian cancer. Galectins are a family of carbohydrate binding proteins which have been suggested to serve as prognostic factors for various cancer types. In this study, the presence of Galectin-1, -3, [...] Read more.

There is a tremendous need for developing new useful prognostic factors in ovarian cancer. Galectins are a family of carbohydrate binding proteins which have been suggested to serve as prognostic factors for various cancer types. In this study, the presence of Galectin-1, -3, and -7 was investigated in 156 ovarian cancer specimens by immunochemical staining. Staining was evaluated in the cytoplasm and nucleus of cancer cells as well as the peritumoral stroma using a semi quantitative score (Remmele (IR) score). Patients’ overall survival was compared between different groups of Galectin expression. Galectin (Gal)-1 and -3 staining was observed in the peritumoral stroma as well as the nucleus and cytoplasm of tumor cells, while Gal-7 was only present in the cytoplasm of tumor cells. Patients with Gal-1 expression in the cytoplasm or high Gal-1 expression in the peritumoral stroma showed reduced overall survival. Nuclear Gal-3 staining correlated with a better outcome. We observed a significantly reduced overall survival for cases with high Gal-7 expression and a better survival for Gal-7 negative cases, when compared to cases with low expression of Gal-7. We were able to show that both tumor and stroma staining of Gal-1 could serve as negative prognostic factors for ovarian cancer. We were able to confirm cytoplasmic Gal-7 as a negative prognostic factor. Gal-3 staining in the nucleus could be a new positive prognosticator for ovarian cancer. Full article

(This article belongs to the Special Issue Galectins in Cancer and Translational Medicine)

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25 pages, 506 KiB

Open AccessReview

Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes

by Marie Rouanet^1,2, Marine Lebrin³, Fabian Gross³

, Barbara Bournet^1,2,4, Pierre Cordelier² and Louis Buscail^1,2,3,4,*

¹ Department of Gastroenterology, CHU Rangueil, 1 avenue Jean Poulhès, Toulouse 31059, France

² INSERM UMR 1037, Cancer Research Center of Toulouse, Toulouse 31037, France

³ Center for Clinical Investigation 1436, Module of Biotherapy, CHU Rangueil, 1 avenue Jean Poulhès, Toulouse Cedex 9, France

⁴ University of Toulouse III, Medical School of Medicine Rangueil, Toulouse 31062, France

Int. J. Mol. Sci. 2017, 18(6), 1231; https://doi.org/10.3390/ijms18061231 - 8 Jun 2017

Cited by 34 | Viewed by 11344

Abstract

A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments [...] Read more.

A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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30 pages, 2728 KiB

Open AccessReview

Plant Lectins Targeting O-Glycans at the Cell Surface as Tools for Cancer Diagnosis, Prognosis and Therapy

by Guillaume Poiroux¹, Annick Barre², Els J. M. Van Damme³

, Hervé Benoist² and Pierre Rougé^2,*

¹ Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche, Centre de Recherche en Cancérologie de Toulouse, 31037 Toulouse, France

² Unité Mixte de Recherche, 152 PharmaDev, Institut de Recherche et Développement, Faculté de Pharmacie, 35 Chemin des Maraîchers Université Paul Sabatier, 31062 Toulouse, France

³ Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium

Int. J. Mol. Sci. 2017, 18(6), 1232; https://doi.org/10.3390/ijms18061232 - 9 Jun 2017

Cited by 82 | Viewed by 10947

Abstract

Aberrant O-glycans expressed at the surface of cancer cells consist of membrane-tethered glycoproteins (T and Tn antigens) and glycolipids (Lewis a, Lewis x and Forssman antigens). All of these O-glycans have been identified as glyco-markers of interest for the diagnosis and [...] Read more.

Aberrant O-glycans expressed at the surface of cancer cells consist of membrane-tethered glycoproteins (T and Tn antigens) and glycolipids (Lewis a, Lewis x and Forssman antigens). All of these O-glycans have been identified as glyco-markers of interest for the diagnosis and the prognosis of cancer diseases. These epitopes are specifically detected using T/Tn-specific lectins isolated from various plants such as jacalin from Artocarpus integrifola, and fungi such as the Agaricus bisporus lectin. These lectins accommodate T/Tn antigens at the monosaccharide-binding site; residues located in the surrounding extended binding-site of the lectins often participate in the binding of more extended epitopes. Depending on the shape and size of the extended carbohydrate-binding site, their fine sugar-binding specificity towards complex O-glycans readily differs from one lectin to another, resulting in a great diversity in their sugar-recognition capacity. T/Tn-specific lectins have been extensively used for the histochemical detection of cancer cells in biopsies and for the follow up of the cancer progression and evolution. T/Tn-specific lectins also induce a caspase-dependent apoptosis in cancer cells, often associated with a more or less severe inhibition of proliferation. Moreover, they provide another potential source of molecules adapted to the building of photosensitizer-conjugates allowing a specific targeting to cancer cells, for the photodynamic treatment of tumors. Full article

(This article belongs to the Special Issue Plant Lectins: From Model Species to Crop Plants)

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25 pages, 1681 KiB

Open AccessReview

Interactive Roles of DNA Helicases and Translocases with the Single-Stranded DNA Binding Protein RPA in Nucleic Acid Metabolism

by Sanket Awate and Robert M. Brosh, Jr.^*

Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health,NIH Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD 21224, USA

Int. J. Mol. Sci. 2017, 18(6), 1233; https://doi.org/10.3390/ijms18061233 - 8 Jun 2017

Cited by 25 | Viewed by 14335

Abstract

Helicases and translocases use the energy of nucleoside triphosphate binding and hydrolysis to unwind/resolve structured nucleic acids or move along a single-stranded or double-stranded polynucleotide chain, respectively. These molecular motors facilitate a variety of transactions including replication, DNA repair, recombination, and transcription. A [...] Read more.

Helicases and translocases use the energy of nucleoside triphosphate binding and hydrolysis to unwind/resolve structured nucleic acids or move along a single-stranded or double-stranded polynucleotide chain, respectively. These molecular motors facilitate a variety of transactions including replication, DNA repair, recombination, and transcription. A key partner of eukaryotic DNA helicases/translocases is the single-stranded DNA binding protein Replication Protein A (RPA). Biochemical, genetic, and cell biological assays have demonstrated that RPA interacts with these human molecular motors physically and functionally, and their association is enriched in cells undergoing replication stress. The roles of DNA helicases/translocases are orchestrated with RPA in pathways of nucleic acid metabolism. RPA stimulates helicase-catalyzed DNA unwinding, enlists translocases to sites of action, and modulates their activities in DNA repair, fork remodeling, checkpoint activation, and telomere maintenance. The dynamic interplay between DNA helicases/translocases and RPA is just beginning to be understood at the molecular and cellular levels, and there is still much to be learned, which may inform potential therapeutic strategies. Full article

(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)

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13 pages, 943 KiB

Open AccessReview

Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

by Tzu-Ting Huang^1,2

, Jung-Chen Su^3,4, Chun-Yu Liu^1,2,5,*, Chung-Wai Shiau^3,* and Kuen-Feng Chen^6,7,*

¹ Comprehensive Breast Health Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan

² Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan

³ Institute of Biopharmaceutical Sciences, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei 112, Taiwan

⁴ Faculty of Pharmacy, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei 112, Taiwan

⁵ School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei 112, Taiwan

⁶ Department of Medical Research, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan

⁷ National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan

Int. J. Mol. Sci. 2017, 18(6), 1234; https://doi.org/10.3390/ijms18061234 - 8 Jun 2017

Cited by 50 | Viewed by 13766

Abstract

The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we [...] Read more.

The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p-STAT3 signaling and combined strategies that were/are discovered in our and our colleagues’ laboratories. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)

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12 pages, 1880 KiB

Open AccessArticle

Micro-Electromechanical Affinity Sensor for the Monitoring of Glucose in Bioprocess Media

by Lorenz Theuer^1,†, Micha Lehmann¹, Stefan Junne¹, Peter Neubauer^1,* and Mario Birkholz²

¹ Chair of Bioprocess Engineering, Department of Biotechnology, Technical University Berlin, ACK24, Ackerstr. 76, 13355 Berlin, Germany

² IHP, Im Technologiepark 25, 15236 Frankfurt (Oder), Germany

^† Present address: RISE Acreo, Box 787, SE-60117 Norrköping, Sweden.

Int. J. Mol. Sci. 2017, 18(6), 1235; https://doi.org/10.3390/ijms18061235 - 8 Jun 2017

Cited by 10 | Viewed by 5382

Abstract

An affinity-viscometry-based micro-sensor probe for continuous glucose monitoring was investigated with respect to its suitability for bioprocesses. The sensor operates with glucose and dextran competing as binding partner for concanavalin A, while the viscosity of the assay scales with glucose concentration. Changes in [...] Read more.

An affinity-viscometry-based micro-sensor probe for continuous glucose monitoring was investigated with respect to its suitability for bioprocesses. The sensor operates with glucose and dextran competing as binding partner for concanavalin A, while the viscosity of the assay scales with glucose concentration. Changes in viscosity are determined with a micro-electromechanical system (MEMS) in the measurement cavity of the sensor probe. The study aimed to elucidate the interactions between the assay and a typical phosphate buffered bacterial cultivation medium. It turned out that contact with the medium resulted in a significant long-lasting drift of the assay’s viscosity at zero glucose concentration. Adding glucose to the medium lowers the drift by a factor of eight. The c_glc values measured off-line with the glucose sensor for monitoring of a bacterial cultivation were similar to the measurements with an enzymatic assay with a difference of less than ±0.15 g·L⁻¹. We propose that lectin agglomeration, the electro-viscous effect, and constitutional changes of concanavalin A due to exchanges of the incorporated metal ions may account for the observed viscosity increase. The study has demonstrated the potential of the MEMS sensor to determine sensitive viscosity changes within very small sample volumes, which could be of interest for various biotechnological applications. Full article

(This article belongs to the Special Issue Biomolecular Engineering and Bioelectronics)

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14 pages, 762 KiB

Open AccessReview

The Roles of Long Non-Protein-Coding RNAs in Osteo-Adipogenic Lineage Commitment

by Hirotaka Yoshioka and Yuji Yoshiko^*

Department of Calcified Tissue Biology, Hiroshima University Institute of Biomedical and Health Sciences, 734-8553 Hiroshima, Japan

Int. J. Mol. Sci. 2017, 18(6), 1236; https://doi.org/10.3390/ijms18061236 - 9 Jun 2017

Cited by 24 | Viewed by 5674

Abstract

Osteoblasts and adipocytes share a common mesenchymal progenitor in the bone marrow. This implies that a reciprocal relationship exists between osteogenic and adipogenic differentiation. Further, cells of osteoblast lineage transdifferentiate into adipocytes under some circumstances. Dysregulation of osteo-adipogenic fate-determination leads to bone diseases [...] Read more.

Osteoblasts and adipocytes share a common mesenchymal progenitor in the bone marrow. This implies that a reciprocal relationship exists between osteogenic and adipogenic differentiation. Further, cells of osteoblast lineage transdifferentiate into adipocytes under some circumstances. Dysregulation of osteo-adipogenic fate-determination leads to bone diseases such as osteoporosis, accompanied by an increase in bone marrow adipose tissue. Thus, the fine-tuning of osteo-adipogenesis is necessary for bone homeostasis. Osteo-adipogenic progression is governed by a complex crosstalk of extrinsic signals, transcription factors, and epigenetic factors. Long non-protein-coding RNAs (lncRNAs) act in part as epigenetic regulators in a broad range of biological activities, such as chromatin organization, transcriptional regulation, post-translational modifications, and histone modification. In this review, we highlight the roles of epigenetic regulators, particularly lncRNAs, in the osteo-adipogenic lineage commitment of bone marrow mesenchymal stem cells and the adipogenic transdifferentiation of osteoblasts. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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20 pages, 604 KiB

Open AccessReview

The Functions of Metamorphic Metallothioneins in Zinc and Copper Metabolism

by Artur Krężel¹

and Wolfgang Maret^2,*

¹ Department of Chemical Biology, Faculty of Biotechnology, University of Wrocław, Joliot-Curie 14a, 50-383 Wrocław, Poland

² Division of Diabetes and Nutritional Sciences, Department of Biochemistry, Faculty of Life Sciences and Medicine, King’s College London, 150 Stamford Street, London SE1 9NH, UK

Int. J. Mol. Sci. 2017, 18(6), 1237; https://doi.org/10.3390/ijms18061237 - 9 Jun 2017

Cited by 242 | Viewed by 12501

Abstract

Recent discoveries in zinc biology provide a new platform for discussing the primary physiological functions of mammalian metallothioneins (MTs) and their exquisite zinc-dependent regulation. It is now understood that the control of cellular zinc homeostasis includes buffering of Zn²⁺ ions at picomolar [...] Read more.

Recent discoveries in zinc biology provide a new platform for discussing the primary physiological functions of mammalian metallothioneins (MTs) and their exquisite zinc-dependent regulation. It is now understood that the control of cellular zinc homeostasis includes buffering of Zn²⁺ ions at picomolar concentrations, extensive subcellular re-distribution of Zn²⁺, the loading of exocytotic vesicles with zinc species, and the control of Zn²⁺ ion signalling. In parallel, characteristic features of human MTs became known: their graded affinities for Zn²⁺ and the redox activity of their thiolate coordination environments. Unlike the single species that structural models of mammalian MTs describe with a set of seven divalent or eight to twelve monovalent metal ions, MTs are metamorphic. In vivo, they exist as many species differing in redox state and load with different metal ions. The functions of mammalian MTs should no longer be considered elusive or enigmatic because it is now evident that the reactivity and coordination dynamics of MTs with Zn²⁺ and Cu⁺ match the biological requirements for controlling—binding and delivering—these cellular metal ions, thus completing a 60-year search for their functions. MT represents a unique biological principle for buffering the most competitive essential metal ions Zn²⁺ and Cu⁺. How this knowledge translates to the function of other families of MTs awaits further insights into the specifics of how their properties relate to zinc and copper metabolism in other organisms. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

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6 pages, 1659 KiB

Open AccessBrief Report

Syk Activity Is Dispensable for Platelet GP1b-IX-V Signaling

by Rachit Badolia^1,2, John C. Kostyak^1,2, Carol Dangelmaier^1,2 and Satya P. Kunapuli^1,2,3,*

¹ Department of Physiology, Temple University, Room 414 MRB, 3420 N. Broad Street, Philadelphia, PA 19140, USA

² Sol Sherry Thrombosis Research Center, Temple University, Room 414 MRB, 3420 N. Broad Street, Philadelphia, PA 19140, USA

³ Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA

Int. J. Mol. Sci. 2017, 18(6), 1238; https://doi.org/10.3390/ijms18061238 - 9 Jun 2017

Cited by 8 | Viewed by 5411

Abstract

The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. [...] Read more.

The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. However, there have been conflicting reports regarding the role of Syk in GP1b signaling. In this study, we sought to resolve these conflicting reports and clarify the role of Syk in VWF-induced platelet activation. The inhibition of Syk with the selective Syk inhibitors, OXSI-2 and PRT-060318, did not inhibit VWF-induced platelet adhesion, agglutination, aggregation, or secretion. In contrast, platelets stimulated with the Glycoprotein VI (GPVI) agonist, collagen-related peptide (CRP), failed to cause any aggregation or secretion in presence of the Syk inhibitors. Furthermore, GP1b-induced platelet signaling was unaffected in the presence of Syk inhibitors, but GPVI-induced signaling was abolished under similar conditions. Thus, we conclude that Syk kinase activity does not play any functional role downstream of GP1b-mediated platelet activation. Full article

(This article belongs to the Special Issue Mechanisms of Platelet Thrombus Formation)

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11 pages, 671 KiB

Open AccessReview

Genomic Insight into the Role of lncRNAs in Cancer Susceptibility

by Ping Gao and Gong-Hong Wei^*

Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90014, Finland

Int. J. Mol. Sci. 2017, 18(6), 1239; https://doi.org/10.3390/ijms18061239 - 9 Jun 2017

Cited by 80 | Viewed by 6780

Abstract

With the development of advanced genomic methods, a large amount of long non-coding RNAs (lncRNAs) have been found to be important for cancer initiation and progression. Given that most of the genome-wide association study (GWAS)-identiﬁed cancer risk SNPs are located in the noncoding [...] Read more.

With the development of advanced genomic methods, a large amount of long non-coding RNAs (lncRNAs) have been found to be important for cancer initiation and progression. Given that most of the genome-wide association study (GWAS)-identiﬁed cancer risk SNPs are located in the noncoding region, the expression and function of lncRNAs are more likely to be affected by the SNPs. The SNPs may affect the expression of lncRNAs directly through disrupting the binding of transcription factors or indirectly by affecting the expression of regulatory factors. Moreover, SNPs may disrupt the interaction between lncRNAs and other RNAs orproteins. Unveiling the relationship of lncRNA, protein-coding genes, transcription factors and miRNAs from the angle of genomics will improve the accuracy of disease prediction and help ﬁnd new therapeutic targets. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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11 pages, 356 KiB

Open AccessArticle

Right- vs. Left-Sided Metastatic Colorectal Cancer: Differences in Tumor Biology and Bevacizumab Efficacy

by Paola Ulivi¹, Emanuela Scarpi^2,*

, Elisa Chiadini¹, Giorgia Marisi¹, Martina Valgiusti³, Laura Capelli¹, Andrea Casadei Gardini³, Manlio Monti³, Silvia Ruscelli³, Giovanni Luca Frassineti³, Daniele Calistri¹

, Dino Amadori³ and Alessandro Passardi³

¹ Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via P. Maroncelli 40, 47014 Meldola, Italy

² Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via P. Maroncelli 40, 47014 Meldola, Italy

³ Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via P. Maroncelli 40, 47014 Meldola, Italy

Int. J. Mol. Sci. 2017, 18(6), 1240; https://doi.org/10.3390/ijms18061240 - 9 Jun 2017

Cited by 43 | Viewed by 6411

Abstract

There is evidence of a different response to treatment with regard to the primary tumor localization (right-sided or left-sided) in patients with metastatic colorectal cancer (mCRC). We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the [...] Read more.

There is evidence of a different response to treatment with regard to the primary tumor localization (right-sided or left-sided) in patients with metastatic colorectal cancer (mCRC). We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the 370 patients with metastatic colorectal cancer enrolled onto the phase III prospective multicenter “Italian Trial in Advanced Colorectal Cancer (ITACa)”, randomized to receive first-line chemotherapy (CT) or CT plus bevacizumab (CT + B). RAS and BRAF mutations; baseline expression levels of circulating vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX2), ephrin type-B receptor 4 (EPHB4), hypoxia-inducible factor 1-alpha (HIF-1α), lactate dehydrogenase (LDH), and high-sensitivity C reactive protein (hs-CRP); and inflammatory indexes such as the neutrophil-to-lymphocyte ratio, platelet-lymphocyte rate and systemic immune-inflammation index were evaluated. Patients with right-sided tumors showed a longer median progression-free survival in the CT + B arm than in the CT group (12.6 vs. 9.0 months, respectively, p = 0.017). Baseline inflammatory indexes were significantly higher in left-sided tumors, whereas eNOS and EPHB4 expression was significantly higher and BRAF mutation more frequent in right-sided tumors. Our data suggest a greater efficacy of the CT + B combination in right-sided mCRC, which might be attributable to the lower inflammatory status and higher expression of pro-angiogenic factors that appear to characterize these tumors. Full article

(This article belongs to the Special Issue Latest Advances in Colorectal Cancer Research: Molecular Mechanisms and Therapies)

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13 pages, 6146 KiB

Open AccessArticle

The Implication of Substance P in the Development of Tendinopathy: A Case Control Study

by Soo-Hong Han^1,†, Wonchul Choi^1,†

, Jiye Song², Jaehee Kim¹, Seungyong Lee¹, Youngrak Choi¹, Seong-Eun Byun¹, Taekeun Ahn¹

, Heejung Ahn³, Catherine Ding⁴, Lloyd Baik⁴, Spencer Ward⁴, Kang Ting⁴ and Soonchul Lee^1,*

¹ Department of Orthopedic Surgery, CHA Bundang Medical Center, CHA University, Gyeonggi-do 13496, Korea

² Institute for Clinical Research, Department of Orthopedic Surgery, CHA Bundang Medical Center, CHA University, Gyeonggi-do 13496, Korea

³ Department of Pathology, CHA Bundang Medical Center, CHA University School of Medicine, Gyeonggi-do 13496, Korea

⁴ Division of Growth and Development and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA 90095, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1241; https://doi.org/10.3390/ijms18061241 - 9 Jun 2017

Cited by 15 | Viewed by 5576

Abstract

It was reported that substance P had beneficial effects in the healing of acute tendon injury. However, the relationship between substance P and degenerative tendinopathy development remains unclear. The purpose of this study was to determine the role of substance P in the [...] Read more.

It was reported that substance P had beneficial effects in the healing of acute tendon injury. However, the relationship between substance P and degenerative tendinopathy development remains unclear. The purpose of this study was to determine the role of substance P in the pathogenesis of tendinopathy. Healthy and tendinopathy tendon were harvested from human and tenocytes were cultured individually. The expression levels of genes associated with tendinopathy were compared. Next, substance P was exogenously administered to the healthy tenocyte and the effect was evaluated. The results showed that tendinopathy tenocytes had higher levels of COL3A1, MMP1, COX2, SCX, ACTA2, and substance P gene expression compared to healthy tenocytes. Next, substance P treatment on the healthy tenocyte displayed similar changes to that of the tendinopathy tenocytes. These differences between the two groups were also determined by Western blot. Additionally, cells with substance P had the tendinopathy change morphologically although cellular proliferation was significantly higher compared to that of the control group. In conclusion, substance P enhanced cellular proliferation, but concomitantly increased immature collagen (type 3 collagen). Substance P plays a crucial role in tendinopathy development and could be a future therapeutic target for treatment. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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18 pages, 831 KiB

Open AccessReview

Legume Lectins: Proteins with Diverse Applications

by Irlanda Lagarda-Diaz¹, Ana Maria Guzman-Partida² and Luz Vazquez-Moreno^2,*

¹ CONACyT-Universidad de Sonora, Blvd. Luis Encinas y Rosales, Hermosillo, Sonora 83000, Mexico

² Coordinacion de Ciencia de los Alimentos, Centro de Investigacion en Alimentacion y Desarrollo, A.C., Apartado Postal 1735, Hermosillo, Sonora 83304, Mexico

Int. J. Mol. Sci. 2017, 18(6), 1242; https://doi.org/10.3390/ijms18061242 - 12 Jun 2017

Cited by 146 | Viewed by 17190

Abstract

Lectins are a diverse class of proteins distributed extensively in nature. Among these proteins; legume lectins display a variety of interesting features including antimicrobial; insecticidal and antitumor activities. Because lectins recognize and bind to specific glycoconjugates present on the surface of cells and [...] Read more.

Lectins are a diverse class of proteins distributed extensively in nature. Among these proteins; legume lectins display a variety of interesting features including antimicrobial; insecticidal and antitumor activities. Because lectins recognize and bind to specific glycoconjugates present on the surface of cells and intracellular structures; they can serve as potential target molecules for developing practical applications in the fields of food; agriculture; health and pharmaceutical research. This review presents the current knowledge of the main structural characteristics of legume lectins and the relationship of structure to the exhibited specificities; provides an overview of their particular antimicrobial; insecticidal and antitumor biological activities and describes possible applications based on the pattern of recognized glyco-targets. Full article

(This article belongs to the Special Issue Plant Lectins: From Model Species to Crop Plants)

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21 pages, 4033 KiB

Open AccessReview

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System

by Yung-Tsu Cho

, Che-Wen Yang and Chia-Yu Chu^*

Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan

Int. J. Mol. Sci. 2017, 18(6), 1243; https://doi.org/10.3390/ijms18061243 - 9 Jun 2017

Cited by 200 | Viewed by 36652

Abstract

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. [...] Read more.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. Reactivation of human herpesviruses (HHV), especially HHV-6, is the hallmark of the disease. Anti-viral immune responses intertwined with drug hypersensitivity make the disease more complicated and protracted. In recent years, emerging studies have outlined the disease more clearly, though several important questions remain unresolved. In this review, we provide an overview of DRESS syndrome, including clinical presentations, histopathological features, pathomechanisms, and treatments. Full article

(This article belongs to the Special Issue Drug Hypersensitivity)

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31 pages, 9734 KiB

Open AccessReview

Lignin from Micro- to Nanosize: Production Methods

by Stefan Beisl^*

, Angela Miltner

and Anton Friedl

Institute of Chemical, Environmental and Biological Engineering, TU Wien, 1060 Vienna, Austria

Int. J. Mol. Sci. 2017, 18(6), 1244; https://doi.org/10.3390/ijms18061244 - 10 Jun 2017

Cited by 194 | Viewed by 16908

Abstract

Lignin is the second most abundant biopolymer after cellulose. It has long been obtained as a by-product of cellulose production in pulp and paper production, but had rather low added-value applications. A changing paper market and the emergence of biorefinery projects should generate [...] Read more.

Lignin is the second most abundant biopolymer after cellulose. It has long been obtained as a by-product of cellulose production in pulp and paper production, but had rather low added-value applications. A changing paper market and the emergence of biorefinery projects should generate vast amounts of lignin with the potential of value addition. Nanomaterials offer unique properties and the preparation of lignin nanoparticles and other nanostructures has therefore gained interest as a promising technique to obtain value-added lignin products. Due to lignin’s high structural and chemical heterogeneity, methods must be adapted to these different types. This review focuses on the ability of different formation methods to cope with the huge variety of lignin types and points out which particle characteristics can be achieved by which method. The current research’s main focus is on pH and solvent-shifting methods where the latter can yield solid and hollow particles. Solvent shifting also showed the capability to cope with different lignin types and solvents and antisolvents, respectively. However, process conditions have to be adapted to every type of lignin and reduction of solvent demand or the integration in a biorefinery process chain must be focused. Full article

(This article belongs to the Special Issue The Lignin Challenge: Exploring Innovative Applications)

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10 pages, 1014 KiB

Open AccessCommunication

Transcriptional Responses in the Murine Spleen after Toxoplasma gondii Infection: Inflammasome and Mucus-Associated Genes

by Eva B. Znalesniak¹, Ting Fu^1,†, Franz Salm^1,†, Ulrike Händel² and Werner Hoffmann^1,*

¹ Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany

² Institute of Medical Microbiology and Hygiene, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1245; https://doi.org/10.3390/ijms18061245 - 10 Jun 2017

Cited by 21 | Viewed by 5922

Abstract

The spleen plays an important role in coordinating both adaptive and innate immune responses. Here, the transcriptional response to T. gondii infection in the murine spleen was characterized concerning inflammasome sensors (two different models: seven days after oral or four weeks after intraperitoneal [...] Read more.

The spleen plays an important role in coordinating both adaptive and innate immune responses. Here, the transcriptional response to T. gondii infection in the murine spleen was characterized concerning inflammasome sensors (two different models: seven days after oral or four weeks after intraperitoneal infection). Additionally, Tff1^KO and Tff3^KO mice were investigated because TFF genes are often upregulated during inflammation. The expression of the pattern-recognition receptors Nlrp3, Nlrp12, and Nlrp1a was significantly increased after infection. This increase was diminished in Tff1^KO and Tff3^KO mice pointing towards a positive regulation of the inflammatory response by Tff1 and Tff3. Furthermore, the transcription of Tff1 (encoding a motogenic lectin) and other secretory genes was analyzed, i.e., gastrokines (Gkn), IgG Fc binding protein (Fcgbp), and the mucin Muc2. The corresponding gene products belong to an interactome protecting mucous epithelia. Tff1 was significantly induced after infection, which might increase the motility of immune cells. In contrast, Gkn3, Fcgbp, and Muc2 were downregulated seven days after oral infection; whereas four weeks after i.p. infection only Gkn3 remained downregulated. This might be an indication that Gkn3, Fcgbp, and Muc2 are involved in the transient disruption of the splenic architecture and its reorganization, which is characteristic after T. gondii infection. Full article

(This article belongs to the Special Issue Spleen: Crossroad between Immune System, Metabolic Asset and Endocrine Function)

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13 pages, 1898 KiB

Open AccessArticle

Effect of Light- and Dark-Germination on the Phenolic Biosynthesis, Phytochemical Profiles, and Antioxidant Activities in Sweet Corn (Zea mays L.) Sprouts

by Nan Xiang¹, Xinbo Guo^1,*

, Fengyuan Liu¹, Quan Li¹, Jianguang Hu^2,3 and Charles Stephen Brennan^1,4,*

¹ School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China

² Crop Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China

³ Key Laboratory of Crops Genetics Improvement of Guangdong Province, Guangzhou 510640, China

⁴ Department of Wine, Food and Molecular Bioscience, Lincoln University, Canterbury 7647, New Zealand

Int. J. Mol. Sci. 2017, 18(6), 1246; https://doi.org/10.3390/ijms18061246 - 10 Jun 2017

Cited by 53 | Viewed by 7669

Abstract

Sweet corn is one of the most widely planted crops in China. Sprouting of grains is a new processes to increase the nutritional value of grain products. The present study explores the effects of light on the nutritional quality of sweet corn sprouts. [...] Read more.

Sweet corn is one of the most widely planted crops in China. Sprouting of grains is a new processes to increase the nutritional value of grain products. The present study explores the effects of light on the nutritional quality of sweet corn sprouts. Gene expression of phenolic biosynthesis, phytochemical profiles and antioxidant activity were studied. Two treatments (light and dark) were selected and the morphological structure of sweet corn sprouts, as well as their biochemical composition were investigated to determine the effects of light on the regulation of genes responsible for nutritional compounds. Transcription analyses for three key-encoding genes in the biosynthesis of the precursors of phenolic were studied. Results revealed a negative regulation in the expression of _ZmPAL with total phenolic content (TPC) in the light group. TPC and total flavonoid content (TFC) increased during germination and this was correlated with an increase in antioxidant activity (r = 0.95 and 1.0). The findings illustrate that the nutritional value of sweet corn for the consumer can be improved through germination to the euphylla stage. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2017)

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15 pages, 1190 KiB

Open AccessReview

Flavonoids, Thyroid Iodide Uptake and Thyroid Cancer—A Review

by Carlos F. L. Gonçalves¹, Mariana L. De Freitas² and Andrea C. F. Ferreira^3,4,*

¹ Carlos Frederico Lima Gonçalves, Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil

² Mariana Lopes de Freitas, Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil

³ Andrea Claudia Freitas Ferreira, Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil

⁴ NUMPEX, Campus Duque de Caxias, Universidade Federal do Rio de Janeiro, Duque de Caxias, 25245-390 Rio de Janeiro, Brazil

Int. J. Mol. Sci. 2017, 18(6), 1247; https://doi.org/10.3390/ijms18061247 - 12 Jun 2017

Cited by 50 | Viewed by 13008

Abstract

Thyroid cancer is the most common malignant tumor of the endocrine system and the incidence has been increasing in recent years. In a great part of the differentiated carcinomas, thyrocytes are capable of uptaking iodide. In these cases, the main therapeutic approach includes [...] Read more.

Thyroid cancer is the most common malignant tumor of the endocrine system and the incidence has been increasing in recent years. In a great part of the differentiated carcinomas, thyrocytes are capable of uptaking iodide. In these cases, the main therapeutic approach includes thyroidectomy followed by ablative therapy with radioiodine. However, in part of the patients, the capacity to concentrate iodide is lost due to down-regulation of the sodium-iodide symporter (NIS), the protein responsible for transporting iodide into the thyrocytes. Thus, therapy with radioiodide becomes ineffective, limiting therapeutic options and reducing the life expectancy of the patient. Excessive ingestion of some flavonoids has been associated with thyroid dysfunction and goiter. Nevertheless, studies have shown that some flavonoids can be beneficial for thyroid cancer, by reducing cell proliferation and increasing cell death, besides increasing NIS mRNA levels and iodide uptake. Recent data show that the flavonoids apingenin and rutin are capable of increasing NIS function and expression in vivo. Herein we review literature data regarding the effect of flavonoids on thyroid cancer, besides the effect of these compounds on the expression and function of the sodium-iodide symporter. We will also discuss the possibility of using flavonoids as adjuvants for therapy of thyroid cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food 2017)

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20 pages, 897 KiB

Open AccessReview

Personalized Medicine: New Perspectives for the Diagnosis and the Treatment of Renal Diseases

by Anna Gluba-Brzózka^1,*

, Beata Franczyk², Robert Olszewski³, Maciej Banach⁴ and Jacek Rysz²

¹ Department of Nephrology, Hypertension and Family Medicine, WAM Teaching Hospital, Lodz 90-549, Poland

² Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz 90-549, Poland

³ Department of Ultrasound, Institute of Fundamental Technological Research, Polish Academy of Sciences (IPPT PAN), Warsaw 02-106, Poland

⁴ Department of Hypertension, Medical University of Lodz, Lodz 90-549, Poland

Int. J. Mol. Sci. 2017, 18(6), 1248; https://doi.org/10.3390/ijms18061248 - 10 Jun 2017

Cited by 5 | Viewed by 5965

Abstract

The prevalence of renal diseases is rising and reaching 5–15% of the adult population. Renal damage is associated with disturbances of body homeostasis and the loss of equilibrium between exogenous and endogenous elements including drugs and metabolites. Studies indicate that renal diseases are [...] Read more.

The prevalence of renal diseases is rising and reaching 5–15% of the adult population. Renal damage is associated with disturbances of body homeostasis and the loss of equilibrium between exogenous and endogenous elements including drugs and metabolites. Studies indicate that renal diseases are influenced not only by environmental but also by genetic factors. In some cases the disease is caused by mutation in a single gene and at that time severity depends on the presence of one or two mutated alleles. In other cases, renal disease is associated with the presence of alteration within a gene or genes, but environmental factors are also necessary for the development of disease. Therefore, it seems that the analysis of genetic aspects should be a natural component of clinical and experimental studies. The goal of personalized medicine is to determine the right drug, for the right patient, at the right time. Whole-genome examinations may help to change the approach to the disease and the patient resulting in the creation of “personalized medicine” with new diagnostic and treatment strategies designed on the basis of genetic background of each individual. The identification of high-risk patients in pharmacogenomics analyses will help to avoid many unwarranted side effects while optimizing treatment efficacy for individual patients. Personalized therapies for kidney diseases are still at the preliminary stage mainly due to high costs of such analyses and the complex nature of human genome. This review will focus on several areas of interest: renal disease pathogenesis, diagnosis, treatment, rate of progression and the prediction of prognosis. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease 2017)

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24 pages, 3094 KiB

Open AccessReview

Emerging Role of the Spleen in the Pharmacokinetics of Monoclonal Antibodies, Nanoparticles and Exosomes

by Mauro Cataldi^1,2,*

, Chiara Vigliotti¹, Teresa Mosca², MariaRosaria Cammarota¹ and Domenico Capone²

¹ Division of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, Federico II University of Naples, 80131 Naples, Italy

² Section of Clinical Pharmacology, Integrated Care Department of Clinical Neurosciences, Anesthesiology and Drug-Use, Federico II University Hospital, 80131 Naples, Italy

Int. J. Mol. Sci. 2017, 18(6), 1249; https://doi.org/10.3390/ijms18061249 - 10 Jun 2017

Cited by 217 | Viewed by 21857

Abstract

After being absorbed, drugs distribute in the body in part to reach target tissues, in part to be disposed in tissues where they do not exert clinically-relevant effects. Therapeutically-relevant effects are usually terminated by drug metabolism and/or elimination. The role that has been [...] Read more.

After being absorbed, drugs distribute in the body in part to reach target tissues, in part to be disposed in tissues where they do not exert clinically-relevant effects. Therapeutically-relevant effects are usually terminated by drug metabolism and/or elimination. The role that has been traditionally ascribed to the spleen in these fundamental pharmacokinetic processes was definitely marginal. However, due to its high blood flow and to the characteristics of its microcirculation, this organ would be expected to be significantly exposed to large, new generation drugs that can hardly penetrate in other tissues with tight endothelial barriers. In the present review, we examine the involvement of the spleen in the disposition of monoclonal antibodies, nanoparticles and exosomes and the possible implications for their therapeutic efficacy and toxicity. The data that we will review lead to the conclusion that a new role is emerging for the spleen in the pharmacokinetics of new generation drugs, hence suggesting that this small, neglected organ will certainly deserve stronger attention by pharmacologists in the future. Full article

(This article belongs to the Special Issue Spleen: Crossroad between Immune System, Metabolic Asset and Endocrine Function)

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12 pages, 1607 KiB

Open AccessArticle

Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

by Tabito Kino¹

, Tomoaki Ishigami^1,*, Tsumugi Murata¹, Hiroshi Doi¹, Rie Nakashima-Sasaki¹, Lin Chen¹, Michiko Sugiyama¹, Kengo Azushima^1,2

, Hiromichi Wakui¹, Shintaro Minegishi¹ and Kouichi Tamura¹

¹ Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan

² Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore

Int. J. Mol. Sci. 2017, 18(6), 1250; https://doi.org/10.3390/ijms18061250 - 11 Jun 2017

Cited by 9 | Viewed by 9960

Abstract

The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN [...] Read more.

The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake. We found that EPL failed to reduce blood pressure in KO mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression analyses of laser-captured specimens in ASDN suggested the presence of non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 KO mice suggest that enhanced ENaC gene expression is critically involved in salt-sensitive hypertension under certain conditions of specific enzyme isoforms for their ubiquitination. Full article

(This article belongs to the Special Issue Selected Papers from the Renin–Angiotensin–Aldosterone System (RAAS)2016: Official Satellite of ISH2016, from September 23 to 24 in Tokyo, Japan)

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14 pages, 2420 KiB

Open AccessArticle

AA-NAT, MT1 and MT2 Correlates with Cancer Stem-Like Cell Markers in Colorectal Cancer: Study of the Influence of Stage and p53 Status of Tumors

by Jorge Casado^1,†, Almudena Iñigo-Chaves^2,†, Sergio M. Jiménez-Ruiz¹, Sandra Ríos-Arrabal^1,3, Ángel Carazo-Gallego¹, Cristina González-Puga⁴, María Isabel Núñez^1,3, Ángeles Ruíz-Extremera^1,5,6

, Javier Salmerón^1,2,5 and Josefa León^1,2,5,*

¹ Biosanitary Research Institute, ibs.Granada, 18012 Granada, Spain

² Clinical Management Unit of Digestive Disease, San Cecilio University Hospital, 18012 Granada, Spain

³ Department of Radiology and Physical Medicine, University of Granada, 18012 Granada, Spain

⁴ General Surgery Unit, San Cecilio University Hospital, 18012 Granada, Spain

⁵ Ciber of Hepatic and Digestive Diseases (CIBERehd), Biosanitary Research Institute, ibs.Granada, 18012 Granada, Spain

⁶ Pediatric Unit, Granada University and San Cecilio University Hospital, 18012 Granada, Spain

^† These authors contribute equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1251; https://doi.org/10.3390/ijms18061251 - 11 Jun 2017

Cited by 17 | Viewed by 5360

Abstract

The characterization of colon cancer stem cells (CSCs) may help to develop novel diagnostic and therapeutic procedures. p53 loss increases the pool of CSCs in colorectal cancer (CRC). Recent reports suggest that the oncostatic effects of melatonin could be related to its ability [...] Read more.

The characterization of colon cancer stem cells (CSCs) may help to develop novel diagnostic and therapeutic procedures. p53 loss increases the pool of CSCs in colorectal cancer (CRC). Recent reports suggest that the oncostatic effects of melatonin could be related to its ability to kill CSCs. Although there are no data linking the loss of p53 function and melatonin synthesis or signaling in cancer, melatonin does activate the p53 tumor-suppressor pathway in this disease. In this work, we analyze whether the expression of melatonin synthesis and signaling genes are related to the expression of CSC markers and the implication of p53 status in samples from patients with CRC. Arylalkylamine N-acetyltransferase (AA-NAT), MT1, and MT2 expression decreased in tumor samples versus normal mucosa samples in mutated p53 (mtp53) tumors versus those with wild-type p53 (wtp53). Further, AA-NAT and MT2 expression were lower in advanced stages of the disease in wtp53 tumors. On the contrary, CD44 and CD66c expression was higher in tumor versus normal mucosa in wtp53 tumors. Additionally, CD44 expression was higher in advanced stages of the disease regardless of the p53 status. Patients with CD44_highCD66c_high and wtp53 tumors in advanced stages showed low expression of AA-NAT and MT2 in wtp53 tumors. These results could indicate a possible interaction of these pathways in CRC. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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17 pages, 3947 KiB

Open AccessArticle

Friction-Induced Mitochondrial Dysregulation Contributes to Joint Deterioration in Prg4 Knockout Mice

by Kimberly A. Waller¹, Ling X. Zhang² and Gregory D. Jay^2,3,4,*

¹ Department of Orthopedics, Warren Alpert School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA

² Department of Emergency Medicine, Warren Alpert School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA

³ School of Engineering, Brown University, Providence, RI 02912, USA

⁴ Department of Emergency Medicine, Rhode Island Hospital, Coro West, 1 Hoppin Street, Suite 106, Providence, RI 02903, USA

Int. J. Mol. Sci. 2017, 18(6), 1252; https://doi.org/10.3390/ijms18061252 - 11 Jun 2017

Cited by 30 | Viewed by 6707

Abstract

Deficiency of PRG4 (lubricin), the boundary lubricant in mammalian joints, contributes to increased joint friction accompanied by superficial and upper intermediate zone chondrocyte caspase-3 activation, as shown in lubricin-null (Prg4^−/−) mice. Caspase-3 activity appears to be reversible [...] Read more.

Deficiency of PRG4 (lubricin), the boundary lubricant in mammalian joints, contributes to increased joint friction accompanied by superficial and upper intermediate zone chondrocyte caspase-3 activation, as shown in lubricin-null (Prg4^−/−) mice. Caspase-3 activity appears to be reversible upon the restitution of Prg4 either endogenously in vivo, in a gene trap mouse, or as an applied lubricant in vitro. In this study we show that intra-articular injection of human PRG4 in vivo in Prg4^−/− mice prevented caspase-3 activation in superficial zone chondrocytes and was associated with a modest decrease in whole joint friction measured ex vivo using a joint pendulum method. Non-lubricated Prg4^−/− mouse cartilage shows caspase cascade activation caused by mitochondrial dysregulation, and significantly higher levels of peroxynitrite (ONOO⁻ and ⁻OH) and superoxide (O⁻₂) compared to Prg4^+/+ and Prg4^+/− cartilage. Enzymatic activity levels of caspase 8 across Prg4 mutant mice were not significantly different, indicating no extrinsic apoptosis pathway activation. Western blots showed caspase-3 and 9 activation in Prg4^−/− tissue extracts, and the appearance of nitrosylated Cys163 in the active cleft of caspase-3 which inhibits its enzymatic activity. These findings are relevant to patients at risk for arthrosis, from camptodactyl-arthropathy-coxa vara-pericarditis (CACP) syndrome and transient lubricin insufficiency due to trauma and inflammation. Full article

(This article belongs to the Special Issue Apoptotic Chondrocytes and Osteoarthritis)

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18 pages, 2424 KiB

Open AccessArticle

Experimental Autoimmune Encephalomyelitis (EAE)-Induced Elevated Expression of the E1 Isoform of Methyl CpG Binding Protein 2 (MeCP2E1): Implications in Multiple Sclerosis (MS)-Induced Neurological Disability and Associated Myelin Damage

by Tina Khorshid Ahmad¹, Ting Zhou¹, Khaled AlTaweel¹, Claudia Cortes¹, Ryan Lillico¹

, Ted Martin Lakowski¹, Kiana Gozda¹ and Michael Peter Namaka^1,2,3,4,*

¹ College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, MB R3E 0T5, Canada

² College of Pharmacy, Third Military Medical University, Chongqing 400038, China

³ Department of Medical Rehabilitation, College of Medicine, Faculty of Health Sciences, Winnipeg, MB R3E 0T6, Canada

⁴ Department of Internal Medicine, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3A 1R9, Canada

Int. J. Mol. Sci. 2017, 18(6), 1254; https://doi.org/10.3390/ijms18061254 - 12 Jun 2017

Cited by 9 | Viewed by 7586

Abstract

Multiple sclerosis (MS) is a chronic neurological disease characterized by the destruction of central nervous system (CNS) myelin. At present, there is no cure for MS due to the inability to repair damaged myelin. Although the neurotrophin brain derived neurotrophic factor (BDNF) has [...] Read more.

Multiple sclerosis (MS) is a chronic neurological disease characterized by the destruction of central nervous system (CNS) myelin. At present, there is no cure for MS due to the inability to repair damaged myelin. Although the neurotrophin brain derived neurotrophic factor (BDNF) has a beneficial role in myelin repair, these effects may be hampered by the over-expression of a transcriptional repressor isoform of methyl CpG binding protein 2 (MeCP2) called MeCP2E1. We hypothesize that following experimental autoimmune encephalomyelitis (EAE)-induced myelin damage, the immune system induction of the pathogenic MeCP2E1 isoform hampers the myelin repair process by repressing BDNF expression. Using an EAE model of MS, we identify the temporal gene and protein expression changes of MeCP2E1, MeCP2E2 and BDNF. The expression changes of these key biological targets were then correlated with the temporal changes in neurological disability scores (NDS) over the entire disease course. Our results indicate that MeCP2E1 mRNA levels are elevated in EAE animals relative to naïve control (NC) and active control (AC) animals during all time points of disease progression. Our results suggest that the EAE-induced elevations in MeCP2E1 expression contribute to the repressed BDNF production in the spinal cord (SC). The sub-optimal levels of BDNF result in sustained NDS and associated myelin damage throughout the entire disease course. Conversely, we observed no significant differences in the expression patterns displayed for the MeCP2E2 isoform amongst our experimental groups. However, our results demonstrate that baseline protein expression ratios between the MeCP2E1 versus MeCP2E2 isoforms in the SC are higher than those identified within the dorsal root ganglia (DRG). Thus, the DRG represents a more conducive environment than that of the SC for BDNF production and transport to the CNS to assist in myelin repair. Henceforth, the sub-optimal BDNF levels we report in the SC may arise from the elevated MeCP2E1 vs. MeCP2E2 ratio in the SC that creates a more hostile environment thereby preventing local BDNF production. At the level of transcript, we demonstrate that EAE-induces the pathological enhanced expression of MeCP2E1 that contributes to enhanced NDS during the entire disease course. Thus, the pathological induction of the MeCP2E1 isoform contributes to the disruption of the normal homeostatic signaling equilibrium network that exists between cytokines, neurotrophins and chemokines that regulate the myelin repair process by repressing BDNF. Our research suggests that the elevated ratio of MeCP2E1 relative to MeCP2E2 may be a useful diagnostic marker that clinicians can utilize to determine the degree of neurological disability with associated myelin damage. The elevated MeCP2E1 vs. MeCP2E2 ratios (E1/E2) in the SC prevent BDNF from reaching optimal levels required for myelin repair. Thus, the lower E1/E2 ratios in the DRG, allow the DRG to serve as a weak secondary compensatory mechanism for enhanced production and delivery of BDNF to the SC to try to assist in myelin repair. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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9 pages, 427 KiB

Open AccessArticle

Association of miR-938G>A Polymorphisms with Primary Ovarian Insufficiency (POI)-Related Gene Expression

by Sung Hwan Cho^1,†, Eun Hee Ahn^2,†

, Hui Jeong An¹, Ji Hyang Kim², Jung Jae Ko¹, Young Ran Kim², Woo Sik Lee³ and Nam Keun Kim^1,*

¹ Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, Korea

² Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea

³ Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul 06135, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1255; https://doi.org/10.3390/ijms18061255 - 12 Jun 2017

Cited by 19 | Viewed by 5278

Abstract

MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to investigate whether polymorphisms in miR-938 are associated with the risk of primary ovarian insufficiency (POI) and POI-related target gene regulation. We identified the miR-938G>A polymorphisms [...] Read more.

MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to investigate whether polymorphisms in miR-938 are associated with the risk of primary ovarian insufficiency (POI) and POI-related target gene regulation. We identified the miR-938G>A polymorphisms within the seed sequence of mature miRNA and aligned the seed sequence with the 3′ untranslated region (UTR) of the gonadotropin-releasing hormone receptor (GnRHR) mRNA, a miR-938 target gene. We found that the binding of miR-938 to the 3′-UTR of GnRHR mRNA was significantly different between normal and variant alleles. Our data suggests that the dysregulation of miR-938G>A influences the binding to GnRHR and that miR-938G>A polymorphisms might contribute to regulation of POI-related target genes. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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13 pages, 2173 KiB

Open AccessArticle

Molecular Cloning and Functional Characterization of a Hexokinase from the Oriental River Prawn Macrobrachium nipponense in Response to Hypoxia

by Shengming Sun¹

, Fujun Xuan², Hongtuo Fu^1,*, Jian Zhu^1,* and Xianping Ge¹

¹ Key Laboratory of Genetic Breeding and Aquaculture Biology of Freshwater Fishes, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China

² Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, Yancheng Teachers University, Yancheng 224051, China

Int. J. Mol. Sci. 2017, 18(6), 1256; https://doi.org/10.3390/ijms18061256 - 13 Jun 2017

Cited by 20 | Viewed by 5143

Abstract

Metabolic adjustment to hypoxia in Macrobrachium nipponense (oriental river prawn) implies a shift to anaerobic metabolism. Hexokinase (HK) is a key glycolytic enzyme in prawns. The involvement of HK in the hypoxia inducible factors (HIFs) pathway is unclear in prawns. In this study, [...] Read more.

Metabolic adjustment to hypoxia in Macrobrachium nipponense (oriental river prawn) implies a shift to anaerobic metabolism. Hexokinase (HK) is a key glycolytic enzyme in prawns. The involvement of HK in the hypoxia inducible factors (HIFs) pathway is unclear in prawns. In this study, the full-length cDNA for HK (MnHK) was obtained from M. nipponense, and its properties were characterized. The full-length cDNA (2385 bp) with an open reading frame of 1350 bp, encoded a 450-amino acid protein. MnHK contained highly conserved amino acids in the glucose, glucose-6-phosphate, ATP, and Mg⁺² binding sites. Quantitative real-time reverse transcription PCR assays revealed the tissue-specific expression pattern of MnHK, with abundant expression in the muscle, and gills. Kinetic studies validated the hexokinase activity of recombinant HK. Silencing of HIF-1α or HIF-1β subunit genes blocked the induction of HK and its enzyme activities during hypoxia in muscles. The results suggested that MnHK is a key factor that increases the anaerobic rate, and is probably involved in the HIF-1 pathway related to highly active metabolism during hypoxia. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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24 pages, 926 KiB

Open AccessReview

Wound-Healing Studies in Cornea and Skin: Parallels, Differences and Opportunities

by Anne Bukowiecki^1,2, Deniz Hos^1,3, Claus Cursiefen^1,3 and Sabine A. Eming^2,3,4,*

¹ Department of Ophthalmology, University Hospital of Cologne, 50937 Cologne, Germany

² Department of Dermatology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany

³ Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany

⁴ Excellence Cluster: Cellular Stress Responses in Aging-associated Diseases, CECAD, University of Cologne, 50931 Cologne, Germany

Int. J. Mol. Sci. 2017, 18(6), 1257; https://doi.org/10.3390/ijms18061257 - 12 Jun 2017

Cited by 153 | Viewed by 16387

Abstract

The cornea and the skin are both organs that provide the outer barrier of the body. Both tissues have developed intrinsic mechanisms that protect the organism from a wide range of external threats, but at the same time also enable rapid restoration of [...] Read more.

The cornea and the skin are both organs that provide the outer barrier of the body. Both tissues have developed intrinsic mechanisms that protect the organism from a wide range of external threats, but at the same time also enable rapid restoration of tissue integrity and organ-specific function. The easy accessibility makes the skin an attractive model system to study tissue damage and repair. Findings from skin research have contributed to unravelling novel fundamental principles in regenerative biology and the repair of other epithelial-mesenchymal tissues, such as the cornea. Following barrier disruption, the influx of inflammatory cells, myofibroblast differentiation, extracellular matrix synthesis and scar formation present parallel repair mechanisms in cornea and skin wound healing. Yet, capillary sprouting, while pivotal in proper skin wound healing, is a process that is rather associated with pathological repair of the cornea. Understanding the parallels and differences of the cellular and molecular networks that coordinate the wound healing response in skin and cornea are likely of mutual importance for both organs with regard to the development of regenerative therapies and understanding of the disease pathologies that affect epithelial-mesenchymal interactions. Here, we review the principal events in corneal wound healing and the mechanisms to restore corneal transparency and barrier function. We also refer to skin repair mechanisms and their potential implications for regenerative processes in the cornea. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration)

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13 pages, 1543 KiB

Open AccessPerspective

Deconstructing Signaling Pathways in Cancer for Optimizing Cancer Combination Therapies

by Ryuji Yamaguchi^1,*

and Guy Perkins²

¹ Department of Anesthesia, Kansai Medical University, Hirakata, Osaka 573-1010, Japan

² National Center for Microscopy and Imaging Research, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA

Int. J. Mol. Sci. 2017, 18(6), 1258; https://doi.org/10.3390/ijms18061258 - 12 Jun 2017

Cited by 4 | Viewed by 8019

Abstract

A single cancer cell left behind after surgery and/or chemotherapy could cause a recurrence of cancer. It is our belief that the failure of chemotherapies is the failure to induce apoptosis in all cancer cells. Given the extraordinary heterogeneity of cancer, it is [...] Read more.

A single cancer cell left behind after surgery and/or chemotherapy could cause a recurrence of cancer. It is our belief that the failure of chemotherapies is the failure to induce apoptosis in all cancer cells. Given the extraordinary heterogeneity of cancer, it is very difficult to eliminate all cancer cells with a single agent targeting a particular gene product. Furthermore, combinations of any two or three agents exhibiting some proven efficacy on a particular cancer type have not fared better, often compounding adverse effects without evidence of expected synergistic effects. Thus, it is imperative that a way be found to select candidates that when combined, will (1) synergize, making the combination therapy greater than the sum of its parts, and (2) target all the cancer cells in a patient. In this article, we discuss our experience and relation to current evidence in the cancer treatment literature in which, by deconstructing signaling networks, we have identified a lynchpin that connects the growth signals present in cancer with mitochondria-dependent apoptotic pathways. By targeting this lynchpin, we have added a key component to a combination therapy that sensitizes cancer cells for apoptosis. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)

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13 pages, 5428 KiB

Open AccessArticle

Gibberellic Acid Signaling Is Required to Induce Flowering of Chrysanthemums Grown under Both Short and Long Days

by Bin Dong, Ye Deng, Haibin Wang, Ri Gao, Githeng’u K. Stephen, Sumei Chen, Jiafu Jiang^* and Fadi Chen^*

College of Horticulture, Nanjing Agricultural University, Key Laboratory of Landscape Agriculture, Ministry of Agriculture, Nanjing 210095, China

Int. J. Mol. Sci. 2017, 18(6), 1259; https://doi.org/10.3390/ijms18061259 - 12 Jun 2017

Cited by 43 | Viewed by 8383

Abstract

Flower bud formation and flowering in chrysanthemums occur under short day conditions (SD), but the molecular basis for the switch to reproductive growth is less well understood than in model plants. Here, a spontaneous mutant able to flower under long days is described. [...] Read more.

Flower bud formation and flowering in chrysanthemums occur under short day conditions (SD), but the molecular basis for the switch to reproductive growth is less well understood than in model plants. Here, a spontaneous mutant able to flower under long days is described. In an attempt to reveal the pathway(s) involved in the formation of flower buds under contrasting daylengths, transcriptome sequencing was carried out in plants grown both under SD and long day conditions (LD). A number of differentially transcribed genes involved in the various known flowering pathways were identified. Both circadian clock genes and Chrysanthemum FLOWERING LOCUS T Like3 (CmFTL3) were up-regulated under SD, thereby inducing floral bud formation and flowering. The gibberellin (GA) signaling pathway-related genes Gibberellin 20-oxidase (GA20ox) and Gibberellin receptor (GID1) were up-regulated in the mutant under LD, while the catabolic genes Gibberellin 2-oxidase (GA2ox) and GA-INSENSITIVE (GAI) were down-regulated, thereby inducing the transcription of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) and LEAFY (LFY). The GA content of the leaf was higher in the mutant than in the wild type (WT) under LD and SD, and the mutant has more branching than WT plants under LD or SD. When treated with GA, the mutant flowered earlier under both SD and LD relative to WT, but there was no detectable phenotype difference between the two lines. The indication was that the photoperiod pathway majorly regulates flower bud formation and flowering time in chrysanthemums under SD. The GA signaling pathway only plays a subsidiary role for flowering. However, the GA signaling pathway predominated for flowering under LD. Full article

(This article belongs to the Section Molecular Plant Sciences)

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29 pages, 328 KiB

Open AccessReview

The Therapeutic Potential of Anti-Inflammatory Exerkines in the Treatment of Atherosclerosis

by Megan Yu^1,*, Sheng-Feng Tsai² and Yu-Min Kuo^2,3

¹ Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA

² Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan

³ Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan 70101, Taiwan

Int. J. Mol. Sci. 2017, 18(6), 1260; https://doi.org/10.3390/ijms18061260 - 13 Jun 2017

Cited by 35 | Viewed by 8075

Abstract

Although many cardiovascular (CVD) medications, such as antithrombotics, statins, and antihypertensives, have been identified to treat atherosclerosis, at most, many of these therapeutic agents only delay its progression. A growing body of evidence suggests physical exercise could be implemented as a non-pharmacologic treatment [...] Read more.

Although many cardiovascular (CVD) medications, such as antithrombotics, statins, and antihypertensives, have been identified to treat atherosclerosis, at most, many of these therapeutic agents only delay its progression. A growing body of evidence suggests physical exercise could be implemented as a non-pharmacologic treatment due to its pro-metabolic, multisystemic, and anti-inflammatory benefits. Specifically, it has been discovered that certain anti-inflammatory peptides, metabolites, and RNA species (collectively termed “exerkines”) are released in response to exercise that could facilitate these benefits and could serve as potential therapeutic targets for atherosclerosis. However, much of the relationship between exercise and these exerkines remains unanswered, and there are several challenges in the discovery and validation of these exerkines. This review primarily highlights major anti-inflammatory exerkines that could serve as potential therapeutic targets for atherosclerosis. To provide some context and comparison for the therapeutic potential of exerkines, the anti-inflammatory, multisystemic benefits of exercise, the basic mechanisms of atherosclerosis, and the limited efficacies of current anti-inflammatory therapeutics for atherosclerosis are briefly summarized. Finally, key challenges and future directions for exploiting these exerkines in the treatment of atherosclerosis are discussed. Full article

(This article belongs to the Section Biochemistry)

11 pages, 913 KiB

Open AccessArticle

Enhanced Osteogenic Differentiation in Zoledronate-Treated Osteoporotic Patients

by Luca Dalle Carbonare¹

, Monica Mottes²

, Giovanni Malerba²

, Antonio Mori^1,2, Martina Zaninotto³, Mario Plebani³, Alessandra Dellantonio¹ and Maria Teresa Valenti^1,*

¹ Department of Medicine, Internal Medicine, Section D, University of Verona, Piazzale Scuro, 10, 37134 Verona, Italy

² Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Piazzale Scuro, 10, 37134 Verona, Italy

³ Department of Laboratory Medicine Azienda Ospedaliera, University of Padova Via Giustiniani, 2, 35128 Padova, Italy

Int. J. Mol. Sci. 2017, 18(6), 1261; https://doi.org/10.3390/ijms18061261 - 13 Jun 2017

Cited by 23 | Viewed by 4590

Abstract

Bisphosphonates are well known inhibitors of osteoclast activity and thus may be employed to influence osteoblast activity. The present study was designed to evaluate the in vivo effects of zoledronic acid (ZA) on the proliferation and osteoblastic commitment of mesenchymal stem cells (MSC) [...] Read more.

Bisphosphonates are well known inhibitors of osteoclast activity and thus may be employed to influence osteoblast activity. The present study was designed to evaluate the in vivo effects of zoledronic acid (ZA) on the proliferation and osteoblastic commitment of mesenchymal stem cells (MSC) in osteoporotic patients. We studied 22 postmenopausal osteoporotic patients. Densitometric, biochemical, cellular and molecular data were collected before as well as after 6 and 12 months of ZA treatment. Peripheral blood MSC-like cells were quantified by colony-forming unit fibroblastic assay; their osteogenic differentiation potential was evaluated after 3 and 7 days of induction, respectively. Circulating MSCs showed significantly increased expression levels of osteoblastic marker genes such as Runt-related transcription factor 2 (RUNX2), and Osteonectin (SPARC) during the 12 months of monitoring time. Lumbar bone mineral density (BMD) variation and SPARC gene expression correlated positively. Bone turnover marker levels were significantly lowered after ZA treatment; the effect was more pronounced for C terminal telopeptide (CTX) than for Procollagen Type 1 N-Terminal Propeptide (P1NP) and bone alkaline phosphatase (bALP). Our findings suggest a discrete anabolic activity supported by osteogenic commitment of MSCs, consequent to ZA treatment. We confirm its anabolic effects in vivo on osteogenic precursors. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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13 pages, 2342 KiB

Open AccessArticle

Amphotericin B, an Anti-Fungal Medication, Directly Increases the Cytotoxicity of NK Cells

by Nayoung Kim^1,2, Ji-Wan Choi^2,3, Hye-Ran Park³, Inki Kim^1,2 and Hun Sik Kim^2,3,4,*

¹ Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea

² Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea

³ Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea

⁴ Department of Microbiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea

Int. J. Mol. Sci. 2017, 18(6), 1262; https://doi.org/10.3390/ijms18061262 - 13 Jun 2017

Cited by 11 | Viewed by 5289

Abstract

Immunomodulatory drugs (IMiDs) present one example of immunomodulatory agents that improve cancer immunotherapy. Based on the cytotoxic activity of natural killer (NK) cells against cancer cells, a high throughput screening method for the identification of novel immunomodulatory molecules with the potential to stimulate [...] Read more.

Immunomodulatory drugs (IMiDs) present one example of immunomodulatory agents that improve cancer immunotherapy. Based on the cytotoxic activity of natural killer (NK) cells against cancer cells, a high throughput screening method for the identification of novel immunomodulatory molecules with the potential to stimulate NK cell cytotoxicity against cancer cells was designed and tested using an approved drug library. Among the primary hit compounds, the anti-fungal drug amphotericin B (AMP-B) increased the cytotoxicity of NK cell line and human primary NK cells in a direct manner. The increase in NK cell activity was related to increased formation of NK-target cell conjugates and the subsequent granule polarization toward target cells. The results of the present study indicate that AMP-B could serve a dual function as an anti-fungal and immunomodulatory drug. Full article

(This article belongs to the Special Issue Natural Killer (NK) Cells)

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10 pages, 1102 KiB

Open AccessArticle

Expression of Salivary miR-203a-3p Was Related with Oral Health-Related Quality of Life in Healthy Volunteers

by Terumasa Kobayashi¹, Takaaki Tomofuji^2,*, Tatsuya Machida¹, Toshiki Yoneda¹, Daisuke Ekuni¹

, Tetsuji Azuma¹, Takayuki Maruyama³, Akiko Hirose² and Manabu Morita¹

¹ Department of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan

² Department of Community Oral Health, Asahi University of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan

³ Center of Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan

Int. J. Mol. Sci. 2017, 18(6), 1263; https://doi.org/10.3390/ijms18061263 - 13 Jun 2017

Cited by 8 | Viewed by 4261

Abstract

Oral health-related quality of life (OHRQoL) is a multidimensional construct that involves subjective evaluation of an individual’s oral health. Although it is difficult to evaluate OHRQoL biologically, recently, it has been reported that circulating microRNAs (miRNAs) in several body fluids could reflect various [...] Read more.

Oral health-related quality of life (OHRQoL) is a multidimensional construct that involves subjective evaluation of an individual’s oral health. Although it is difficult to evaluate OHRQoL biologically, recently, it has been reported that circulating microRNAs (miRNAs) in several body fluids could reflect various health conditions. The aim of this pilot study was to investigate whether salivary miRNAs expression differs according to OHRQoL in healthy volunteers. Forty-six volunteers (median age, 23.0 years) were recruited, and their OHRQoL was assessed using the Japanese version of the Oral Health Impact Profile (OHIP-J). Then, we compared salivary microRNA profiles of the high-OHRQoL group (≤25th percentile score of OHIP-J) and the low-OHRQoL group (≥75th percentile score of OHIP-J) using the polymerase chain reaction (PCR) array and the quantitative real-time PCR. There were no significant differences between the two groups in terms of oral health status. In the PCR array, miR-203a-3p and miR-30b-5p were significantly more expressed in the low-OHRQoL group (p < 0.05). Quantitative real-time PCR assay also showed that miR-203a-3p was more highly expressed in the low-OHRQoL group than in the high-OHRQoL group (p < 0.05). These observations suggest that expression of salivary miR-203a-3p was related with OHRQoL in healthy volunteers. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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14 pages, 2951 KiB

Open AccessArticle

Quantification of Bone Fatty Acid Metabolism and Its Regulation by Adipocyte Lipoprotein Lipase

by Alexander Bartelt^1,2,*,†, Till Koehne^3,4, Klaus Tödter¹, Rudolph Reimer⁵, Brigitte Müller^1,2, Friederike Behler-Janbeck^1,2, Joerg Heeren¹, Ludger Scheja¹ and Andreas Niemeier^1,2,*

¹ Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

² Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

³ Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

⁴ Department of Orthodontotics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

⁵ Electronmicroscopy and Micro-Technology, Heinrich-Pette-Institut for Experimental Virology, Martinistr. 52, 20246 Hamburg, Germany

^† Current address: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Harvard University, 665 Huntington Avenue, Boston, MA 02115, USA.

Int. J. Mol. Sci. 2017, 18(6), 1264; https://doi.org/10.3390/ijms18061264 - 13 Jun 2017

Cited by 42 | Viewed by 7559

Abstract

Adipocytes are master regulators of energy homeostasis. Although the contributions of classical brown and white adipose tissue (BAT and WAT, respectively) to glucose and fatty acid metabolism are well characterized, the metabolic role of adipocytes in bone marrow remains largely unclear. Here, we [...] Read more.

Adipocytes are master regulators of energy homeostasis. Although the contributions of classical brown and white adipose tissue (BAT and WAT, respectively) to glucose and fatty acid metabolism are well characterized, the metabolic role of adipocytes in bone marrow remains largely unclear. Here, we quantify bone fatty acid metabolism and its contribution to systemic nutrient handling in mice. Whereas in parts of the skeleton the specific amount of nutrients taken-up from the circulation was lower than in other metabolically active tissues such as BAT or liver, the overall contribution of the skeleton as a whole organ was remarkable, placing it among the top organs involved in systemic glucose as well as fatty acid clearance. We show that there are considerable site-specific variations in bone marrow fatty acid composition throughout the skeleton and that, especially in the tibia, marrow fatty acid profiles resemble classical BAT and WAT. Using a mouse model lacking lipoprotein lipase (LPL), a master regulator of plasma lipid turnover specifically in adipocytes, we show that impaired fatty acid flux leads to reduced amounts of dietary essential fatty acids while there was a profound increase in de novo produced fatty acids in both bone marrow and cortical bone. Notably, these changes in fatty acid profiles were not associated with any gross skeletal phenotype. These results identify LPL as an important regulator of fatty acid transport to skeletal compartments and demonstrate an intricate functional link between systemic and skeletal fatty acid and glucose metabolism. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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14 pages, 1469 KiB

Open AccessArticle

Predicting Outcome and Therapy Response in mCRC Patients Using an Indirect Method for CTCs Detection by a Multigene Expression Panel: A Multicentric Prospective Validation Study

by Yolanda Vidal Insua¹, Juan De la Cámara², Elena Brozos Vázquez¹, Ana Fernández³, Francisca Vázquez Rivera¹, Mª José Villanueva Silva⁴, Jorge Barbazán¹, Laura Muinelo-Romay^1,5

, Sonia Candamio Folgar¹, Alicia Abalo^1,5, Rafael López-López¹, Miguel Abal¹ and Lorena Alonso-Alconada^1,*

¹ Translational Medical Oncology, Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela, SERGAS Group, CIBERONC, Trav. Choupana s/n, 15706 Santiago de Compostela, Spain

² Arquitecto Macide Hospital, SERGAS Group, Av. Residencia s/n, 15405 Ferrol, Spain

³ University Hospital of Ourense, SERGAS Group, Ramon Puga 54, 32005 Ourense, Spain

⁴ University Hospital of Vigo, SERGAS Group, Pizarro 22, 36204 Vigo, Spain

⁵ Liquid Biopsy Analysis Unit, Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela, SERGAS Group, CIBERONC, Trav. Choupana s/n, 15706 Santiago de Compostela, Spain

Int. J. Mol. Sci. 2017, 18(6), 1265; https://doi.org/10.3390/ijms18061265 - 13 Jun 2017

Cited by 16 | Viewed by 4717

Abstract

Colorectal cancer (CRC) is one of the major causes of cancer-related deaths. Early detection of tumor relapse is crucial for determining the most appropriate therapeutic management. In clinical practice, computed tomography (CT) is routinely used, but small tumor changes are difficult to visualize, [...] Read more.

Colorectal cancer (CRC) is one of the major causes of cancer-related deaths. Early detection of tumor relapse is crucial for determining the most appropriate therapeutic management. In clinical practice, computed tomography (CT) is routinely used, but small tumor changes are difficult to visualize, and reliable blood-based prognostic and monitoring biomarkers are urgently needed. The aim of this study was to prospectively validate a gene expression panel (composed of GAPDH, VIL1, CLU, TIMP1, TLN1, LOXL3 and ZEB2) for detecting circulating tumor cells (CTCs) as prognostic and predictive tool in blood samples from 94 metastatic CRC (mCRC) patients. Patients with higher gene panel expression before treatment had a reduced progression-free survival (PFS) and overall-survival (OS) rates compared with patients with low expression (p = 0.003 and p ≤ 0.001, respectively). Patients with increased expression of CTCs markers during treatment presented PFS and OS times of 8.95 and 11.74 months, respectively, compared with 14.41 and 24.7 for patients presenting decreased expression (PFS; p = 0.020; OS; p ≤ 0.001). Patients classified as non-responders by CTCs with treatment, but classified as responders by CT scan, showed significantly shorter survival times (PFS: 8.53 vs. 11.70; OS: 10.37 vs. 24.13; months). In conclusion, our CTCs detection panel demonstrated efficacy for early treatment response assessment in mCRC patients, and with increased reliability compared to CT scan. Full article

(This article belongs to the Special Issue Latest Advances in Colorectal Cancer Research: Molecular Mechanisms and Therapies)

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10 pages, 371 KiB

Open AccessArticle

Hypoxia Inducible Factor-2 Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS)

by Annika Dötsch^1,*, Lewin Eisele², Miriam Rabeling¹, Katharina Rump^1,3, Kai Walstein¹, Alexandra Bick¹, Linda Cox¹, Andrea Engler¹, Hagen S. Bachmann³, Karl-Heinz Jöckel², Michael Adamzik^1,4, Jürgen Peters¹ and Simon T. Schäfer^1,5

¹ Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Hufelandstraße 55, D-45122 Essen, Germany

² Institut für Medizinische Informatik, Biometrie und Epidemiologie, D-45122 Essen, Germany

³ Institut für Pharmakogenetik, Universitätsklinikum Essen and Universität Duisburg-Essen, D-45122 Essen, Germany

⁴ Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie; Universitätsklinikum, Knappschaftskrankenhaus Bochum and Ruhruniversität Bochum, In der Schornau 23-25, D-44892 Bochum, Germany

⁵ Klinik für Anaesthesiologie, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, D-81377 München, Germany

Int. J. Mol. Sci. 2017, 18(6), 1266; https://doi.org/10.3390/ijms18061266 - 14 Jun 2017

Cited by 12 | Viewed by 5423

Abstract

Hypoxia-inducible-factor-2α (HIF-2α) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902) are [...] Read more.

Hypoxia-inducible-factor-2α (HIF-2α) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902) are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs’ prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2α or PHD2 genes are (1) common, and (2) independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay) and HIF-2α-polymorphism (restriction digest + agarose-gel visualization), and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2α CC-carriers (CG: 0.38%; GG: 0%), 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%; CC: 78.8%), and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%; CC: 52.4%). PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09–10.22; p = 0.034) within 30-days, whereas the other SNPs had no significant impact (p = ns). The homozygous HIF-2α GG-genotype was not present in our Caucasian ARDS cohort; however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS. Full article

(This article belongs to the Special Issue Sepsis)

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9 pages, 1384 KiB

Open AccessArticle

Centrosomal Protein 70 Is a Mediator of Paclitaxel Sensitivity

by Xingjuan Shi^1,*, Yujue Wang¹, Xiaoou Sun², Chan Wang¹, Peng Jiang¹, Yu Zhang¹, Qinghai Huang¹, Xiangdong Liu¹, Dengwen Li³, Jun Zhou^3,4 and Min Liu^4,*

¹ Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing 210096, China

² School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China

³ State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China

⁴ Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan 250014, China

Int. J. Mol. Sci. 2017, 18(6), 1267; https://doi.org/10.3390/ijms18061267 - 20 Jun 2017

Cited by 7 | Viewed by 4600

Abstract

Centrosome aberrations have been implicated in the development and progression of breast cancer. Our previous worked show that centrosomal protein 70 (Cep70) regulates breast cancer growth and metastasis. However, it remains elusive whether Cep70 is implicated in the sensitivity of the anti-microtubule drug [...] Read more.

Centrosome aberrations have been implicated in the development and progression of breast cancer. Our previous worked show that centrosomal protein 70 (Cep70) regulates breast cancer growth and metastasis. However, it remains elusive whether Cep70 is implicated in the sensitivity of the anti-microtubule drug paclitaxel in breast cancer. Here we provide evidence that Cep70 is a mediator of paclitaxel sensitivity in breast cancer. Cell proliferation assays show that Cep70 expression correlates with paclitaxel sensitivity in breast cancer cell lines. In addition, paclitaxel sensitivity varies when altering Cep70 expression level. Mechanistic studies reveal that Cep70 interacts with tubulin, and promotes the ability of paclitaxel to stimulate microtubule assembly. These data demonstrate that Cep70 mediates paclitaxel sensitivity in breast cancer. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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13 pages, 2849 KiB

Open AccessArticle

An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities

by Shintaro Minegishi¹, Tomoaki Ishigami^1,*, Hisho Kawamura¹, Tabito Kino¹

, Lin Chen¹, Rie Nakashima-Sasaki¹, Hiroshi Doi¹, Kengo Azushima¹

, Hiromichi Wakui¹, Yumi Chiba² and Kouichi Tamura¹

¹ Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan

² Department of Nursing, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan

Int. J. Mol. Sci. 2017, 18(6), 1268; https://doi.org/10.3390/ijms18061268 - 14 Jun 2017

Cited by 12 | Viewed by 5842

Abstract

We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha [...] Read more.

We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene encodes the α subunit of the human cardiac voltage-gated sodium channel (I Na), and the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene encodes rapidly activating delayed rectifier K channels (I Kr). Both ion channels have also been shown to bind to Nedd4-2 via a conserved Proline-Tyrosine (PY) motif in C-terminal with subsequent ubiquitination and degradation by proteasome. Therefore, loss of Nedd4-2 C2 isoform might be involved in electrophysiological impairment under various conditions. We demonstrate here that Nedd4-2 C2 isoform causes cardiac conduction change in resting condition as well as proarrhythmic change after acute myocardial infarction (MI). The Nedd4-2 C2 knockout (KO) mice showed bradycardia, prolonged QRS, QT intervals, and suppressed PR interval in resting condition. In addition, enhancement of T peak/T end interval was found in mice with surgical ligation of the distal left coronary artery. Morphological analyses based on both ultrasonography of the living heart, as well as histopathological findings revealed that Nedd4-2 C2 KO mice show no significant structural changes from wild-type littermates under resting conditions. These results suggested that Nedd4-2 with C2 domain might play an important role in cardio-renal syndrome through post-transcriptional modification of both ENaC and cardiac ion channels, which are critical for kidney and heart functions. Full article

(This article belongs to the Special Issue Selected Papers from the Renin–Angiotensin–Aldosterone System (RAAS)2016: Official Satellite of ISH2016, from September 23 to 24 in Tokyo, Japan)

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15 pages, 2786 KiB

Open AccessArticle

CRISPR/Cas9-Mediated Correction of the FANCD1 Gene in Primary Patient Cells

by Karolina Skvarova Kramarzova^1,2, Mark J. Osborn^1,3,4,5,*, Beau R. Webber¹

, Anthony P. DeFeo¹, Amber N. McElroy¹, Chong Jai Kim⁶ and Jakub Tolar^1,3,5

¹ Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA

² Childhood Leukemia Investigation Prague (CLIP), Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague 15006, Czech Republic

³ Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA

⁴ Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA

⁵ Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN 55455, USA

⁶ Asan Institute for Life Sciences, Asan Medical Center, Asan-Minnesota Institute for Innovating Transplantation, Seoul 138-736, Korea

Int. J. Mol. Sci. 2017, 18(6), 1269; https://doi.org/10.3390/ijms18061269 - 14 Jun 2017

Cited by 28 | Viewed by 8363

Abstract

Fanconi anemia (FA) is an inherited condition characterized by impaired DNA repair, physical anomalies, bone marrow failure, and increased incidence of malignancy. Gene editing holds great potential to precisely correct the underlying genetic cause such that gene expression remains under the endogenous control [...] Read more.

Fanconi anemia (FA) is an inherited condition characterized by impaired DNA repair, physical anomalies, bone marrow failure, and increased incidence of malignancy. Gene editing holds great potential to precisely correct the underlying genetic cause such that gene expression remains under the endogenous control mechanisms. This has been accomplished to date only in transformed cells or their reprogrammed induced pluripotent stem cell counterparts; however, it has not yet been reported in primary patient cells. Here we show the ability to correct a mutation in Fanconi anemia D1 (FANCD1) primary patient fibroblasts. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system was employed to target and correct a FANCD1 gene deletion. Homologous recombination using an oligonucleotide donor was achieved and a pure population of modified cells was obtained by using inhibitors of poly adenosine diphosphate-ribose polymerase (poly ADP-ribose polymerase). FANCD1 function was restored and we did not observe any promiscuous cutting of the CRISPR/Cas9 at off target sites. This consideration is crucial in the context of the pre-malignant FA phenotype. Altogether we show the ability to correct a patient mutation in primary FANCD1 cells in a precise manner. These proof of principle studies support expanded application of gene editing for FA. Full article

(This article belongs to the Special Issue Genome Editing 2018)

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22 pages, 7092 KiB

Open AccessArticle

Terpenoids from Platostoma rotundifolium (Briq.) A. J. Paton Alter the Expression of Quorum Sensing-Related Virulence Factors and the Formation of Biofilm in Pseudomonas aeruginosa PAO1

by Tsiry Rasamiravaka^1,5,*,†, Jérémie Ngezahayo^2,3,*,†

, Laurent Pottier², Sofia Oliveira Ribeiro², Florence Souard^2,6,7, Léonard Hari³, Caroline Stévigny², Mondher El Jaziri¹ and Pierre Duez^2,4

¹ Laboratory of Plant Biotechnology, Université Libre de Bruxelles, rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium

² Laboratoire de Pharmacognosie, Bromatologie et Nutrition Humaine, Faculté de Pharmacie, Université Libre de Bruxelles, CP 205/09, Boulevard du Triomphe, 1050 Bruxelles, Belgium

³ Centre de Recherche Universitaire en Pharmacopée et Médecine Traditionnelle (CRUPHAMET), Faculté des Sciences, Université du Burundi, BP 2700 Bujumbura, Burundi

⁴ Unit of Therapeutic Chemistry and Pharmacognosy, Université de Mons (UMONS), Bâtiment VI, Chemin du Champ de Mars 25, 7000 Mons, Belgium

⁵ Laboratoire de Biotechnologie et Microbiologie, Département de Biochimie Fondamentale et Appliquée, Faculté des Sciences, Université d’Antananarivo (UA), BP 906, Antananarivo 101, Madagascar

⁶ Département de Pharmacochimie Moléculaire, Université Grenoble Alpes, 38000 Grenoble, France

⁷ Département de Pharmacochimie Moléculaire, Centre National de Recherche Scientifique, 38000 Grenoble, France

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1270; https://doi.org/10.3390/ijms18061270 - 14 Jun 2017

Cited by 27 | Viewed by 6077

Abstract

Platostoma rotundifolium (Briq.) A. J. Paton aerial parts are widely used in Burundi traditional medicine to treat infectious diseases. In order to investigate their probable antibacterial activities, crude extracts from P. rotundifolium were assessed for their bactericidal and anti-virulence properties against an opportunistic [...] Read more.

Platostoma rotundifolium (Briq.) A. J. Paton aerial parts are widely used in Burundi traditional medicine to treat infectious diseases. In order to investigate their probable antibacterial activities, crude extracts from P. rotundifolium were assessed for their bactericidal and anti-virulence properties against an opportunistic bacterial model, Pseudomonas aeruginosa PAO1. Whereas none of the tested extracts exert bacteriostatic and/or bactericidal proprieties, the ethyl acetate and dichloromethane extracts exhibit anti-virulence properties against Pseudomonas aeruginosa PAO1 characterized by an alteration in quorum sensing gene expression and biofilm formation without affecting bacterial viability. Bioguided fractionation of the ethyl acetate extract led to the isolation of major anti-virulence compounds that were identified from nuclear magnetic resonance and high-resolution molecular spectroscopy spectra as cassipourol, β-sitosterol and α-amyrin. Globally, cassipourol and β-sitosterol inhibit quorum sensing-regulated and -regulatory genes expression in las and rhl systems without affecting the global regulators gacA and vfr, whereas α-amyrin had no effect on the expression of these genes. These terpenoids disrupt the formation of biofilms at concentrations down to 12.5, 50 and 50 µM for cassipourol, β-sitosterol and α-amyrin, respectively. Moreover, these terpenoids reduce the production of total exopolysaccharides and promote flagella-dependent motilities (swimming and swarming). The isolated terpenoids exert a wide range of inhibition processes, suggesting a complex mechanism of action targeting P. aeruginosa virulence mechanisms which support the wide anti-infectious use of this plant species in traditional Burundian medicine. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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12 pages, 2476 KiB

Open AccessArticle

Lipid Storage and Autophagy in Melanoma Cancer Cells

by Claudia Giampietri^1,*

, Simonetta Petrungaro¹

, Martina Cordella², Claudio Tabolacci²

, Luana Tomaipitinca¹, Antonio Facchiano³, Adriana Eramo², Antonio Filippini¹

, Francesco Facchiano^2,† and Elio Ziparo^1,†

¹ Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome 00161, Italy

² Department of Oncology and Molecular Medicine Istituto Superiore di Sanità, ISS, Rome 00161, Italy

³ Istituto Dermopatico dell’Immacolata IDI-IRCCS, Rome 00167, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1271; https://doi.org/10.3390/ijms18061271 - 15 Jun 2017

Cited by 41 | Viewed by 6349

Abstract

Cancer stem cells (CSC) represent a key cellular subpopulation controlling biological features such as cancer progression in all cancer types. By using melanospheres established from human melanoma patients, we compared less differentiated melanosphere-derived CSC to differentiating melanosphere-derived cells. Increased lipid uptake was found [...] Read more.

Cancer stem cells (CSC) represent a key cellular subpopulation controlling biological features such as cancer progression in all cancer types. By using melanospheres established from human melanoma patients, we compared less differentiated melanosphere-derived CSC to differentiating melanosphere-derived cells. Increased lipid uptake was found in melanosphere-derived CSC vs. differentiating melanosphere-derived cells, paralleled by strong expression of lipogenic factors Sterol Regulatory Element-Binding Protein-1 (SREBP-1) and Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ). An inverse relation between lipid-storing phenotype and autophagy was also found, since microtubule-associated protein 1A/1B-Light Chain 3 (LC3) lipidation is reduced in melanosphere-derived CSC. To investigate upstream autophagy regulators, Phospho-AMP activated Protein Kinase (P-AMPK) and Phospho-mammalian Target of Rapamycin (P-mTOR) were analyzed; lower P-AMPK and higher P-mTOR expression in melanosphere-derived CSC were found, thus explaining, at least in part, their lower autophagic activity. In addition, co-localization of LC3-stained autophagosome spots and perilipin-stained lipid droplets was demonstrated mainly in differentiating melanosphere-derived cells, further supporting the role of autophagy in lipid droplets clearance. The present manuscript demonstrates an inverse relationship between lipid-storing phenotype and melanoma stem cells differentiation, providing novel indications involving autophagy in melanoma stem cells biology. Full article

(This article belongs to the Special Issue Stem Cell Research)

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12 pages, 241 KiB

Open AccessReview

Osteoblast Role in Rheumatic Diseases

by Addolorata Corrado, Nicola Maruotti and Francesco Paolo Cantatore^*

Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia Medical School, 71122 Foggia, Italy

Int. J. Mol. Sci. 2017, 18(6), 1272; https://doi.org/10.3390/ijms18061272 - 15 Jun 2017

Cited by 43 | Viewed by 6009

Abstract

Alterations in osteoblast growth, differentiation and activity play a role in the pathogenesis of several rheumatic diseases, such as rheumatoid arthritis, spondyloarthritides, osteoarthritis, and osteoporosis. In fact, in these rheumatic diseases, abnormal activity of Wnt signaling, receptor activator of nuclear factor-κB (RANK)-RANK ligand [...] Read more.

Alterations in osteoblast growth, differentiation and activity play a role in the pathogenesis of several rheumatic diseases, such as rheumatoid arthritis, spondyloarthritides, osteoarthritis, and osteoporosis. In fact, in these rheumatic diseases, abnormal activity of Wnt signaling, receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) signaling, bone morphogenetic proteins (BMPs) pathway and other mechanisms have been described in osteoblasts. This review article is focused on current knowledge on the role of osteoblast dysregulation occurring in rheumatic diseases. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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9 pages, 712 KiB

Open AccessReview

Hormesis and Defense of Infectious Disease

by Sebastian Weis^1,2,3,*, Ignacio Rubio⁴, Kristin Ludwig⁴, Cynthia Weigel^1,5 and Elisa Jentho¹

¹ Department of Anesthesiology and Intensive Care Medicine, University Hospital Jena, Jena 07747, Germany

² Center for Infectious Diseases and Infection Control, University Hospital Jena, Jena 07747, Germany

³ Center for Sepsis Control and Care, University Hospital Jena, Jena 07747, Germany

⁴ Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, Jena 07745, Germany

⁵ Fritz Lipmann Institute, Leibniz Institute on Aging, Jena 07745, Germany

Int. J. Mol. Sci. 2017, 18(6), 1273; https://doi.org/10.3390/ijms18061273 - 15 Jun 2017

Cited by 23 | Viewed by 6626

Abstract

Infectious diseases are a global health burden and remain associated with high social and economic impact. Treatment of affected patients largely relies on antimicrobial agents that act by directly targeting microbial replication. Despite the utility of host specific therapies having been assessed in [...] Read more.

Infectious diseases are a global health burden and remain associated with high social and economic impact. Treatment of affected patients largely relies on antimicrobial agents that act by directly targeting microbial replication. Despite the utility of host specific therapies having been assessed in previous clinical trials, such as targeting the immune response via modulating the cytokine release in sepsis, results have largely been frustrating and did not lead to the introduction of new therapeutic tools. In this article, we will discuss current evidence arguing that, by applying the concept of hormesis, already approved pharmacological agents could be used therapeutically to increase survival of patients with infectious disease via improving disease tolerance, a defense mechanism that decreases the extent of infection-associated tissue damage without directly targeting pathogenic microorganisms. Full article

(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)

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21 pages, 3841 KiB

Open AccessArticle

Autocrine Human Growth Hormone Promotes Invasive and Cancer Stem Cell-Like Behavior of Hepatocellular Carcinoma Cells by STAT3 Dependent Inhibition of CLAUDIN-1 Expression

by Yi-Jun Chen^1,†, Ming-Liang You^1,†, Qing-Yun Chong^1,†, Vijay Pandey¹, Qiu-Shi Zhuang¹, Dong-Xu Liu², Lan Ma³, Tao Zhu^4,5 and Peter E. Lobie^1,3,*

¹ Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 119077, Singapore

² School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 1010, New Zealand

³ Tsinghua Berkeley Shenzhen Institute (TBSI), Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China

⁴ Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230026, China

⁵ The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230022, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1274; https://doi.org/10.3390/ijms18061274 - 15 Jun 2017

Cited by 41 | Viewed by 8592

Abstract

Despite progress in diagnosis and treatment of hepatocellular carcinoma (HCC), the clinical outcome is still unsatisfactory. Increased expression of human growth hormone (hGH) in HCC has been reported and is associated with poor survival outcome in HCC patients. Herein, we investigated the mechanism [...] Read more.

Despite progress in diagnosis and treatment of hepatocellular carcinoma (HCC), the clinical outcome is still unsatisfactory. Increased expression of human growth hormone (hGH) in HCC has been reported and is associated with poor survival outcome in HCC patients. Herein, we investigated the mechanism of the oncogenic effects of hGH in HCC cell lines. In vitro functional assays demonstrated that forced expression of hGH in these HCC cell lines promoted cell proliferation, cell survival, anchorage-independent growth, cell migration, and invasion, as previously reported. In addition, forced expression of hGH promoted cancer stem cell (CSC)-like properties of HCC cells. The increased invasive and CSC-like properties of HCC cells with forced expression of hGH were mediated by inhibition of the expression of the tight junction component CLAUDIN-1. Consistently, depletion of CLAUDIN-1 expression increased the invasive and CSC-like properties of HCC cell lines. Moreover, forced expression of CLAUDIN-1 abrogated the acquired invasive and CSC-like properties of HCC cell lines with forced expression of hGH. We further demonstrated that forced expression of hGH inhibited CLAUDIN-1 expression in HCC cell lines via signal transducer and activator of transcription 3 (STAT3) mediated inhibition of CLAUDIN-1 transcription. Hence, we have elucidated a novel hGH-STAT3-CLAUDIN-1 axis responsible for invasive and CSC-like properties in HCC. Inhibition of hGH should be considered as a therapeutic option to hinder progression and relapse of HCC. Full article

(This article belongs to the Special Issue Growth Hormone: Therapeutic Possibilities)

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21 pages, 3137 KiB

Open AccessArticle

Globular Adiponectin Inhibits Lipopolysaccharide-Primed Inflammasomes Activation in Macrophages via Autophagy Induction: The Critical Role of AMPK Signaling

by Mi Jin Kim¹, Eun Hye Kim¹, Nirmala TiliJa Pun¹, Jae-Hoon Chang¹, Jung-Ae Kim¹

, Jee-Heon Jeong¹, Dong Young Choi¹, Sang-Hyun Kim² and Pil-Hoon Park^1,*

¹ College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea

² Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Korea

Int. J. Mol. Sci. 2017, 18(6), 1275; https://doi.org/10.3390/ijms18061275 - 15 Jun 2017

Cited by 45 | Viewed by 9456

Abstract

The inflammasome acts as a key platform for the activation of pro-inflammatory cytokines. Adiponectin exhibits potent anti-inflammatory properties. However, the effect of adiponectin on the modulation of the inflammasome has not been explored. Herein, we show that globular adiponectin (gAcrp) suppressed lipopolysaccharide (LPS)-primed [...] Read more.

The inflammasome acts as a key platform for the activation of pro-inflammatory cytokines. Adiponectin exhibits potent anti-inflammatory properties. However, the effect of adiponectin on the modulation of the inflammasome has not been explored. Herein, we show that globular adiponectin (gAcrp) suppressed lipopolysaccharide (LPS)-primed inflammasomes activation in murine peritoneal macrophages judged by prevention of interleukin-1β (IL-1β) maturation, caspase-1 activation, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, and pyroptotic cell death. Interestingly, pretreatment with 3-methyl adenine, a pharmacological inhibitor of autophagy, abrogated the suppressive effects of gAcrp on IL-1β secretion and caspase-1 activation, indicating the crucial role of autophagy induction in gAcrp-modulation of the inflammasome activation. In addition, inhibition of 5′Adenosine monophaspahate (AMP)-activated protein kinase (AMPK) signaling abolished suppressive effect of gAcrp on inflammasomes activation. Furthermore, autophagy induction or inhibition of the inflammasome activation by gAcrp was not observed in macrophages deficient in AMPK. Taken together, these results indicate that adiponectin inhibits LPS-primed inflammasomes activation in macrophages via autophagy induction and AMPK signaling-dependent mechanisms. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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14 pages, 1088 KiB

Open AccessReview

PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue

by Marco Spadaccini^1,†, Silvia D’Alessio^1,2,†, Laurent Peyrin-Biroulet³ and Silvio Danese^1,4,*

¹ Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Milan 20089, Italy

² Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan 20129, Italy

³ Department of Hepato-Gastroenterology and Inserm U954, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy 54500, France

⁴ Department of Biomedical Sciences, Humanitas University, Milan 20089, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1276; https://doi.org/10.3390/ijms18061276 - 15 Jun 2017

Cited by 61 | Viewed by 15944

Abstract

Background. In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological [...] Read more.

Background. In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological drugs, a significant proportion of patients is unaffected by or lose their response to these compounds, along with increased risks of infections and malignancies. For these reasons there is an urgent need to look for new pharmacological targets. The novel Phosphodiesterase 4 (PDE4) inhibitors have been recently introduced as new modulators of intracellular signals and gene transcription for the treatment of IBD. Aim. To discuss and describe the state of the art of this new class of compounds in the IBD field, with particular attention to apremilast. Methods. Published articles selected from PubMed were comprehensively reviewed, with key words including apremilast, inflammatory disease, IBD, psoriasis, psoriatic arthritis, pathogenesis, therapies, and treatment. Results. PDE4 inhibitors generate elevated intracellular levels of cyclic Adenosine Monophosphate (cAMP), that consequently down-regulate the release of pro-inflammatory cytokines in the mucosa of IBD patients. The newly developed apremilast is one of these drugs and has already been approved for the treatment of dermatologic/rheumatologic inflammatory conditions; studies in psoriasis and psoriatic arthritis have in fact demonstrated its clinical activity. However, no clinical trials have yet been published on the use of apremilast in IBD. Conclusion. In light of the similarity of pro-inflammatory signaling pathways across the gut, the skin, and joints, apremilast is likely supposed to show its efficacy also in IBD. Full article

(This article belongs to the Special Issue Dissecting Mechanisms of Action of Biologics in Inflammatory Bowel Diseases)

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17 pages, 2347 KiB

Open AccessArticle

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

by Stephanie Trend¹

, Anderson P. Jones¹

, Sian Geldenhuys¹, Scott N. Byrne^2,3, Marzena J. Fabis-Pedrini⁴, David Nolan^5,6, David R. Booth³, William M. Carroll⁴, Robyn M. Lucas⁷

, Allan G. Kermode^4,6 and Prue H. Hart^1,*

¹ Telethon Kids Institute, University of Western Australia, Perth, WA 6008, Australia

² Cellular Photoimmunology Group, Infectious Diseases & Immunology, Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia

³ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2006, Australia

⁴ Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, University of Western Australia, Sir Charles Gairdner Hospital, Perth, WA 6009, Australia

⁵ Immunology Department, Royal Perth Hospital, Perth, WA 6000, Australia

⁶ Institute for Immunology and Infectious Disease, Murdoch University, Perth, WA 6150, Australia

⁷ National Centre for Epidemiology & Population Health, Research School of Population Health, Australian National University, Canberra, ACT 0200, Australia

Int. J. Mol. Sci. 2017, 18(6), 1277; https://doi.org/10.3390/ijms18061277 - 15 Jun 2017

Cited by 8 | Viewed by 6205

Abstract

It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC). This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches [...] Read more.

It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC). This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches early in disease. Peripheral blood mononuclear cells (PBMCs) were collected from 18 people with CIS, 19 HC and 13 individuals with other demyelinating conditions (ODC) including multiple sclerosis (MS). Individuals with CIS separated into two groups, namely those with early (≤14 days post-diagnostic magnetic resonance imaging (MRI); n = 6) and late (≥27 days; n = 12) blood sampling. Transitional B cells were increased in the blood of CIS patients independently of when blood was taken. However, there were two time-dependent effects found in the late CIS group relative to HC, including decreased CD56bright NK cells, which correlated significantly with time since MRI, and increased CD141+ myeloid dendritic cell (mDC2) frequencies. Higher CD1c+ B cells and lower non-classical monocyte frequencies were characteristic of more recent demyelinating disease activity (ODC and early CIS). Analysing cell populations by time since symptoms (subjective) and diagnostic MRI (objective) may contribute to understanding CIS. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2017)

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14 pages, 1430 KiB

Open AccessArticle

Development of Biopolymer Composite Films Using a Microfluidization Technique for Carboxymethylcellulose and Apple Skin Particles

by Inyoung Choi¹, Yoonjee Chang², So-Hyang Shin³, Eunmi Joo¹, Hyun Ju Song¹, Haeyoung Eom¹ and Jaejoon Han^1,4,*

¹ Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea

² Institute of Control Agents for Microorganisms, Korea University, Seoul 02841, Korea

³ Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 16419, Korea

⁴ Department of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea

Int. J. Mol. Sci. 2017, 18(6), 1278; https://doi.org/10.3390/ijms18061278 - 15 Jun 2017

Cited by 31 | Viewed by 5674

Abstract

Biopolymer films based on apple skin powder (ASP) and carboxymethylcellulose (CMC) were developed with the addition of apple skin extract (ASE) and tartaric acid (TA). ASP/CMC composite films were prepared by mixing CMC with ASP solution using a microfluidization technique to reduce particle [...] Read more.

Biopolymer films based on apple skin powder (ASP) and carboxymethylcellulose (CMC) were developed with the addition of apple skin extract (ASE) and tartaric acid (TA). ASP/CMC composite films were prepared by mixing CMC with ASP solution using a microfluidization technique to reduce particle size. Then, various concentrations of ASE and TA were incorporated into the film solution as an antioxidant and an antimicrobial agent, respectively. Fourier transform infrared (FTIR), optical, mechanical, water barrier, and solubility properties of the developed films were then evaluated to determine the effects of ASE and TA on physicochemical properties. The films were also analyzed for antioxidant effect on 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity and antimicrobial activities against Listeria monocytogenes, Staphylococcus aureus, Salmonella enterica, and Shigella flexneri. From the results, the ASP/CMC film containing ASE and TA was revealed to enhance the mechanical, water barrier, and solubility properties. Moreover, it showed the additional antioxidant and antimicrobial properties for application as an active packaging film. Full article

(This article belongs to the Special Issue Biodegradable Materials 2017)

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11 pages, 614 KiB

Open AccessReview

Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors

by Cynthia I. Chude

and Ravi K. Amaravadi^*

Department of Medicine and Abramson Cancer Center, University of Pennsylvania, 852 BRB, 421 Curie Blvd, Philadelphia, PA 19104, USA

Int. J. Mol. Sci. 2017, 18(6), 1279; https://doi.org/10.3390/ijms18061279 - 16 Jun 2017

Cited by 310 | Viewed by 13429

Abstract

Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer [...] Read more.

Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer therapies. Hydroxychloroquine (HCQ) is the only clinically-approved autophagy inhibitor, and this systematic review focuses on HCQ use in cancer clinical trials. Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage. This has provided the base for multiple ongoing clinical trials involving HCQ alone and in combination with other treatments. However, due to its potency, there is still a need for more potent and specific autophagy inhibitors. There are multiple autophagy inhibitors in the pre-clinical stage at various stages of development. Additional studies on the mechanism of HCQ and other autophagy inhibitors are still required to answer questions surrounding how these agents will eventually be used in the clinic. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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14 pages, 4802 KiB

Open AccessArticle

GPE Promotes the Proliferation and Migration of Mouse Embryonic Neural Stem Cells and Their Progeny In Vitro

by Cristina Almengló^1,2

, Pablo Devesa², Jesús Devesa^3,*

and Víctor M. Arce¹

¹ Department of Physiology, University of Santiago de Compostela, Santiago de Compostela 15710, Spain

² Research and Development, Medical Center Foltra, Teo 15886, Spain

³ Scientific Direction, Medical Center Foltra, Teo 15886, Spain

Int. J. Mol. Sci. 2017, 18(6), 1280; https://doi.org/10.3390/ijms18061280 - 16 Jun 2017

Cited by 13 | Viewed by 5684

Abstract

This study was designed to investigate a possible role of the N-terminal tripeptide of insulin-like growth factor-1 (IGF-I), Gly-Pro-Glu (GPE), physiologically generated in neurons following IGF-I-specific cleavage, in promoting neural regeneration after an injury. Primary cultures of mouse neural stem cells (NSCs), obtained [...] Read more.

This study was designed to investigate a possible role of the N-terminal tripeptide of insulin-like growth factor-1 (IGF-I), Gly-Pro-Glu (GPE), physiologically generated in neurons following IGF-I-specific cleavage, in promoting neural regeneration after an injury. Primary cultures of mouse neural stem cells (NSCs), obtained from 13.5 Days post-conception (dpc) mouse embryos, were challenged with either GPE, growth hormone (GH), or GPE + GH and the effects on cell proliferation, migration, and survival were evaluated both under basal conditions and in response to a wound healing assay. The cellular pathways activated by GPE were also investigated by using specific chemical inhibitors. The results of the study indicate that GPE treatment promotes the proliferation and the migration of neural stem cells in vitro through a mechanism that involves the activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase PI3K-Akt pathways. Intriguingly, both GPE effects and the signaling pathways activated were similar to those observed after GH treatment. Based upon the results obtained from this study, GPE, as well as GH, may be useful in promoting neural protection and/or regeneration after an injury. Full article

(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment 2017)

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28 pages, 2719 KiB

Open AccessArticle

A Panel of MicroRNAs as Diagnostic Biomarkers for the Identification of Prostate Cancer

by Rhonda Daniel^1,†, Qianni Wu^1,†, Vernell Williams², Gene Clark¹, Georgi Guruli³ and Zendra Zehner^1,*

¹ Department of Biochemistry and Molecular Biology, VCU Medical Center and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0614, USA

² Molecular Diagnostic Laboratory, Department of Pathology, VCU Health System, Virginia Commonwealth University, Richmond, VA 23298-0248, USA

³ Division of Urology, VCU Medical Center and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0037, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1281; https://doi.org/10.3390/ijms18061281 - 16 Jun 2017

Cited by 60 | Viewed by 7787

Abstract

Prostate cancer is the most common non-cutaneous cancer among men; yet, current diagnostic methods are insufficient, and more reliable diagnostic markers need to be developed. One answer that can bridge this gap may lie in microRNAs. These small RNA molecules impact protein expression [...] Read more.

Prostate cancer is the most common non-cutaneous cancer among men; yet, current diagnostic methods are insufficient, and more reliable diagnostic markers need to be developed. One answer that can bridge this gap may lie in microRNAs. These small RNA molecules impact protein expression at the translational level, regulating important cellular pathways, the dysregulation of which can exert tumorigenic effects contributing to cancer. In this study, high throughput sequencing of small RNAs extracted from blood from 28 prostate cancer patients at initial stages of diagnosis and prior to treatment was used to identify microRNAs that could be utilized as diagnostic biomarkers for prostate cancer compared to 12 healthy controls. In addition, a group of four microRNAs (miR-1468-3p, miR-146a-5p, miR-1538 and miR-197-3p) was identified as normalization standards for subsequent qRT-PCR confirmation. qRT-PCR analysis corroborated microRNA sequencing results for the seven top dysregulated microRNAs. The abundance of four microRNAs (miR-127-3p, miR-204-5p, miR-329-3p and miR-487b-3p) was upregulated in blood, whereas the levels of three microRNAs (miR-32-5p, miR-20a-5p and miR-454-3p) were downregulated. Data analysis of the receiver operating curves for these selected microRNAs exhibited a better correlation with prostate cancer than PSA (prostate-specific antigen), the current gold standard for prostate cancer detection. In summary, a panel of seven microRNAs is proposed, many of which have prostate-specific targets, which may represent a significant improvement over current testing methods. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)

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11 pages, 2795 KiB

Open AccessArticle

Acute Effect of Metformin on Postprandial Hypertriglyceridemia through Delayed Gastric Emptying

by Daisuke Sato¹, Katsutaro Morino^1,*

, Fumiyuki Nakagawa^1,2, Koichiro Murata¹, Osamu Sekine¹, Fumiaki Beppu³, Naohiro Gotoh³, Satoshi Ugi¹ and Hiroshi Maegawa¹

¹ Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Seta-Otsu 520-2192, Shiga, Japan

² Nishiwaki Laboratory, Cimic Biopharma Corporation, Nishiwaki 677-0032, Hyogo, Japan

³ Department of Food Science and Technology, Tokyo University of Marine Science and Technology, Minato-ku 108-8477, Tokyo, Japan

Int. J. Mol. Sci. 2017, 18(6), 1282; https://doi.org/10.3390/ijms18061282 - 16 Jun 2017

Cited by 16 | Viewed by 6552

Abstract

Postprandial hypertriglyceridemia is a potential target for cardiovascular disease prevention in patients with diabetic dyslipidemia. Metformin has been reported to reduce plasma triglyceride concentrations in the postprandial states. However, little is known about the mechanisms underlying the triglyceride-lowering effect of metformin. Here, we [...] Read more.

Postprandial hypertriglyceridemia is a potential target for cardiovascular disease prevention in patients with diabetic dyslipidemia. Metformin has been reported to reduce plasma triglyceride concentrations in the postprandial states. However, little is known about the mechanisms underlying the triglyceride-lowering effect of metformin. Here, we examined the effects of metformin on lipid metabolism after olive oil-loading in 129S mice fed a high fat diet for three weeks. Metformin administration (250 mg/kg) for one week decreased postprandial plasma triglycerides. Pre-administration (250 mg/kg) of metformin resulted in a stronger triglyceride-lowering effect (approximately 45% lower area under the curve) than post-administration. A single administration (250 mg/kg) of metformin lowered plasma postprandial triglycerides comparably to administration for one week, suggesting an acute effect of metformin on postprandial hypertriglyceridemia. To explore whole body lipid metabolism after fat-loading, stomach size, fat absorption in the intestine, and fat oxidation (¹³C/¹²C ratio in expired CO₂ after administration of glyceryl-1-¹³C tripalmitate) were measured with and without metformin (250 mg/kg) pre-treatment. In metformin-treated mice, larger stomach size, lower fat oxidation, and no change in lipid absorption were observed. In conclusion, metformin administration before fat loading reduced postprandial hypertriglyceridemia, most likely by delaying gastric emptying. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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62 pages, 439 KiB

Open AccessReview

Antibacterial and Antifungal Activities of Spices

by Qing Liu¹, Xiao Meng¹, Ya Li¹

, Cai-Ning Zhao¹, Guo-Yi Tang¹ and Hua-Bin Li^1,2,*

¹ Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China

² South China Sea Bioresource Exploitation and Utilization Collaborative Innovation Center, Sun Yat-sen University, Guangzhou 510006, China

Int. J. Mol. Sci. 2017, 18(6), 1283; https://doi.org/10.3390/ijms18061283 - 16 Jun 2017

Cited by 342 | Viewed by 39184

Abstract

Infectious diseases caused by pathogens and food poisoning caused by spoilage microorganisms are threatening human health all over the world. The efficacies of some antimicrobial agents, which are currently used to extend shelf-life and increase the safety of food products in food industry [...] Read more.

Infectious diseases caused by pathogens and food poisoning caused by spoilage microorganisms are threatening human health all over the world. The efficacies of some antimicrobial agents, which are currently used to extend shelf-life and increase the safety of food products in food industry and to inhibit disease-causing microorganisms in medicine, have been weakened by microbial resistance. Therefore, new antimicrobial agents that could overcome this resistance need to be discovered. Many spices—such as clove, oregano, thyme, cinnamon, and cumin—possessed significant antibacterial and antifungal activities against food spoilage bacteria like Bacillus subtilis and Pseudomonas fluorescens, pathogens like Staphylococcus aureus and Vibrio parahaemolyticus, harmful fungi like Aspergillus flavus, even antibiotic resistant microorganisms such as methicillin resistant Staphylococcus aureus. Therefore, spices have a great potential to be developed as new and safe antimicrobial agents. This review summarizes scientific studies on the antibacterial and antifungal activities of several spices and their derivatives. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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10 pages, 3503 KiB

Open AccessReview

p53 Expression as a Diagnostic Biomarker in Ulcerative Colitis-Associated Cancer

by Kazuhiro Kobayashi¹

, Hiroyuki Tomita^2,*

, Masahito Shimizu³, Takuji Tanaka⁴, Natsuko Suzui¹, Tatsuhiko Miyazaki¹ and Akira Hara^1,2

¹ Pathology Division, Gifu University Hospital, Gifu 501-1194, Japan

² Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan

³ Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan

⁴ Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1. Kashima-tyo, Gifu 500-8513, Japan

Int. J. Mol. Sci. 2017, 18(6), 1284; https://doi.org/10.3390/ijms18061284 - 16 Jun 2017

Cited by 50 | Viewed by 8279

Abstract

Ulcerative colitis (UC) is defined as an idiopathic inflammatory disorder primarily involving the mucosa and submucosa of the colon. UC-associated colon cancers (also known as colitic cancers) develop through the inflammation–dysplasia sequence, which is a major problem affecting the prognosis of patients with [...] Read more.

Ulcerative colitis (UC) is defined as an idiopathic inflammatory disorder primarily involving the mucosa and submucosa of the colon. UC-associated colon cancers (also known as colitic cancers) develop through the inflammation–dysplasia sequence, which is a major problem affecting the prognosis of patients with UC. It is therefore very important to detect malignancy from UC at an early stage. As precancerous lesions arising in UC, there are pathological adenomatous changes, basal cell changes, in situ anaplasia, clear cell changes, and pan-cellular change. It is considered that the mutation of the p53 gene plays a crucial role, and the protein expression of p53 in dysplastic crypts may serve as a good biomarker in the early stages of UC-associated colon carcinogenesis. Immunohistochemistry for p53 is a very valuable diagnostic tool in UC-associated colon cancers. However, protein expression of p53 is not always universal, and additional methods may be required to assess p53 status in UC-associated colon cancers. Full article

(This article belongs to the Special Issue Inflammation and Cancer)

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10 pages, 200 KiB

Open AccessReview

The Ability of Extracellular Vesicles to Induce a Pro-Inflammatory Host Response

by Maike E. Van Hezel^1,2, Rienk Nieuwland³, Robin Van Bruggen² and Nicole P. Juffermans^1,*

¹ Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Amsterdam 1012 WP, The Netherlands

² Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam 1006 AD, The Netherlands

³ Laboratory of Experimental Clinical Chemistry, Vesicle Observation Centre, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands

Int. J. Mol. Sci. 2017, 18(6), 1285; https://doi.org/10.3390/ijms18061285 - 16 Jun 2017

Cited by 60 | Viewed by 5561

Abstract

Extracellular vesicles (EVs) can modulate the host immune response, executing both pro- and anti-inflammatory effects. As EVs increasingly gain attention as potential carriers for targeted gene and drug delivery, knowledge on the effects of EVs on the host immune response is important. This [...] Read more.

Extracellular vesicles (EVs) can modulate the host immune response, executing both pro- and anti-inflammatory effects. As EVs increasingly gain attention as potential carriers for targeted gene and drug delivery, knowledge on the effects of EVs on the host immune response is important. This review will focus on the ability of EVs to trigger a pro-inflammatory host response by activating target cells. The overall view is that EVs can augment an inflammatory response, thereby potentially contributing to organ injury. This pro-inflammatory potential of EVs may hamper its use for therapeutic drug delivery. Whether removal of EVs as a means to reduce a pro-inflammatory or pro-coagulant response during hyper-inflammatory conditions is beneficial remains to be determined. Prior to any proposed therapeutic application, there is a need for further studies on the role of EVs in physiology and pathophysiology using improved detection and characterization methods to elucidate the roles of EVs in inflammatory conditions. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

11 pages, 1118 KiB

Open AccessArticle

Determination of Sulfonamide Residues in Food by Capillary Zone Electrophoresis with On-Line Chemiluminescence Detection Based on an Ag(III) Complex

by Tingting Dai, Jie Duan, Xinghua Li, Xiangdong Xu, Hongmei Shi^* and Weijun Kang^*

School of public Health, Hebei Medical University, Shijiazhuang 050017, China

Int. J. Mol. Sci. 2017, 18(6), 1286; https://doi.org/10.3390/ijms18061286 - 16 Jun 2017

Cited by 40 | Viewed by 4822

Abstract

The presence of sulfonamide (SA) residues in foods is largely due to the raising of animals with sulfonamide antibiotics added or polluted feedstuff. In this paper, a sensitive method was developed for the determination of the residues of three sulfonamides in animal-derived food; [...] Read more.

The presence of sulfonamide (SA) residues in foods is largely due to the raising of animals with sulfonamide antibiotics added or polluted feedstuff. In this paper, a sensitive method was developed for the determination of the residues of three sulfonamides in animal-derived food; the SAs include sulfadimidine (SDD), sulfadiazine (SDZ), and sulfathiazole (STZ). The method is based on capillary zone electrophoresis (CE) with online chemiluminescence (CL) detection, using an Ag(III) complex as an oxidant. These SAs have an inhibiting effect on the Ag(III)–luminol CL reaction. The electrophoretic buffer is 12.0 mM sodium borate. Under a set of optimized conditions, the linear ranges for the detections were found to be 10.0–200 µg·mL⁻¹ for SDD and SDZ, and 2.0–50.0 µg·mL⁻¹ for STZ. The detection limits were 2.75, 3.14, and 0.65 µg·mL⁻¹ for SDD, SDZ, and STZ, respectively. Relative standard deviations (RSD) for the peak heights were between 2.1% and 2.8% (n = 7). The proposed method was used in the analysis of the SAs in samples from pork meat, chicken meat, and milk, showing satisfactory detection results. A reaction mechanism was also proposed for the Ag(III)–luminol–SA CL reactions. The method has potential applications for the monitoring of residue levels of the three SAs in food, providing food safety data. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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15 pages, 957 KiB

Open AccessReview

The Therapeutic Benefit of Bacterial Membrane Vesicles

by Natalie J. Bitto¹ and Maria Kaparakis-Liaskos^1,2,*

¹ Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Melbourne, Victoria 3086, Australia

² Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Melbourne, Victoria 3068, Australia

Int. J. Mol. Sci. 2017, 18(6), 1287; https://doi.org/10.3390/ijms18061287 - 16 Jun 2017

Cited by 109 | Viewed by 13330

Abstract

The therapeutic potential of extracellular vesicles from eukaryotes has gained strong interest in recent years. However, research into the therapeutic application of their bacterial counterparts, known as bacterial membrane vesicles, is only just beginning to be appreciated. Membrane vesicles (MVs) from both Gram-positive [...] Read more.

The therapeutic potential of extracellular vesicles from eukaryotes has gained strong interest in recent years. However, research into the therapeutic application of their bacterial counterparts, known as bacterial membrane vesicles, is only just beginning to be appreciated. Membrane vesicles (MVs) from both Gram-positive and Gram-negative bacteria offer significant advantages in therapeutic development, including large-scale, cost effective production and ease of molecular manipulation to display foreign antigens. The nanoparticle size of MVs enables their dissemination through numerous tissue types, and their natural immunogenicity and self-adjuvanting capability can be harnessed to induce both cell-mediated and humoral immunity in vaccine design. Moreover, the ability to target MVs to specific tissues through the display of surface receptors raises their potential use as targeted MV-based anti-cancer therapy. This review discusses recent advances in MV research with particular emphasis on exciting new possibilities for the application of MVs in therapeutic design. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

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20 pages, 1299 KiB

Open AccessReview

Proteomic High Affinity Zn²⁺ Trafficking: Where Does Metallothionein Fit in?

by David H. Petering^* and Afsana Mahim

Department of Chemistry and Biochemistry, University of Wisconsin–Milwaukee, Milwaukee, WI 53217, USA

Int. J. Mol. Sci. 2017, 18(6), 1289; https://doi.org/10.3390/ijms18061289 - 17 Jun 2017

Cited by 30 | Viewed by 7399

Abstract

The cellular constitution of Zn-proteins and Zn-dependent signaling depend on the capacity of Zn²⁺ to find specific binding sites in the face of a plethora of other high affinity ligands. The most prominent of these is metallothionein (MT). It serves as a [...] Read more.

The cellular constitution of Zn-proteins and Zn-dependent signaling depend on the capacity of Zn²⁺ to find specific binding sites in the face of a plethora of other high affinity ligands. The most prominent of these is metallothionein (MT). It serves as a storage site for Zn²⁺ under various conditions, and has chemical properties that support a dynamic role for MT in zinc trafficking. Consistent with these characteristics, changing the availability of zinc for cells and tissues causes rapid alteration of zinc bound to MT. Nevertheless, zinc trafficking occurs in metallothionein-null animals and cells, hypothetically making use of proteomic binding sites to mediate the intracellular movements of zinc. Like metallothionein, the proteome contains a large concentration of proteins that strongly coordinate zinc. In this environment, free Zn²⁺ may be of little significance. Instead, this review sets forth the basis for the hypothesis that components of the proteome and MT jointly provide the platform for zinc trafficking. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

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14 pages, 420 KiB

Open AccessReview

Propolis Diterpenes as a Remarkable Bio-Source for Drug Discovery Development: A Review

by Noushin Aminimoghadamfarouj and Alireza Nematollahi^*

Faculty of Pharmacy A15, The University of Sydney, Sydney NSW 2006, Australia

Int. J. Mol. Sci. 2017, 18(6), 1290; https://doi.org/10.3390/ijms18061290 - 17 Jun 2017

Cited by 46 | Viewed by 7217

Abstract

Propolis is one of the complex, but valuable, bio-sources for discovering therapeutic compounds. Diterpenes are organic compounds composed of four isoprene units and are known for their biological and pharmacological characteristics, such as antibacterial, anticancer, and anti-inflammatory activities. Recently, advancements have been made [...] Read more.

Propolis is one of the complex, but valuable, bio-sources for discovering therapeutic compounds. Diterpenes are organic compounds composed of four isoprene units and are known for their biological and pharmacological characteristics, such as antibacterial, anticancer, and anti-inflammatory activities. Recently, advancements have been made in the development of antibacterial and anticancer leads from propolis-isolated diterpenes, and scrutiny of these compounds is being pursued. Thus, this review covers the progress in this arena, with a focus on the chemistry and biological activities of propolis diterpenes. It is anticipated that important information, in a comprehensive and concise manner, will be delivered here for better understanding of natural product drug discovery research. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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15 pages, 4531 KiB

Open AccessArticle

Optimization of Polyplex Formation between DNA Oligonucleotide and Poly(ʟ-Lysine): Experimental Study and Modeling Approach

by Tudor Vasiliu¹, Corneliu Cojocaru², Alexandru Rotaru¹, Gabriela Pricope¹, Mariana Pinteala¹ and Lilia Clima^1,*

¹ Center of Advanced Research in Bionanocojugates and biopolymers, “Petru Poni” Institute of Macromolecular Chemistry, Iasi, Romania Aleea Grigore Ghica Voda 41A, 70487 Iasi, Romania

² Department of Inorganic Polymers, “Petru Poni” Institute of Macromolecular Chemistry, Iasi, Romania Aleea Grigore Ghica Voda 41A, 70487 Iasi, Romania

Int. J. Mol. Sci. 2017, 18(6), 1291; https://doi.org/10.3390/ijms18061291 - 17 Jun 2017

Cited by 26 | Viewed by 5073

Abstract

The polyplexes formed by nucleic acids and polycations have received a great attention owing to their potential application in gene therapy. In our study, we report experimental results and modeling outcomes regarding the optimization of polyplex formation between the double-stranded DNA (dsDNA) and [...] Read more.

The polyplexes formed by nucleic acids and polycations have received a great attention owing to their potential application in gene therapy. In our study, we report experimental results and modeling outcomes regarding the optimization of polyplex formation between the double-stranded DNA (dsDNA) and poly(ʟ-Lysine) (PLL). The quantification of the binding efficiency during polyplex formation was performed by processing of the images captured from the gel electrophoresis assays. The design of experiments (DoE) and response surface methodology (RSM) were employed to investigate the coupling effect of key factors (pH and N/P ratio) affecting the binding efficiency. According to the experimental observations and response surface analysis, the N/P ratio showed a major influence on binding efficiency compared to pH. Model-based optimization calculations along with the experimental confirmation runs unveiled the maximal binding efficiency (99.4%) achieved at pH 5.4 and N/P ratio 125. To support the experimental data and reveal insights of molecular mechanism responsible for the polyplex formation between dsDNA and PLL, molecular dynamics simulations were performed at pH 5.4 and 7.4. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 617 KiB

Open AccessReview

Differentiated Thyroid Cancer—Treatment: State of the Art

by Benedikt Schmidbauer^†, Karin Menhart^†, Dirk Hellwig

and Jirka Grosse^*

¹ Department of Nuclear Medicine, University of Regensburg, 93053 Regensburg, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1292; https://doi.org/10.3390/ijms18061292 - 17 Jun 2017

Cited by 150 | Viewed by 24375

Abstract

Differentiated thyroid cancer (DTC) is a rare malignant disease, although its incidence has increased over the last few decades. It derives from follicular thyroid cells. Generally speaking, the prognosis is excellent. If treatment according to the current guidelines is given, cases of recurrence [...] Read more.

Differentiated thyroid cancer (DTC) is a rare malignant disease, although its incidence has increased over the last few decades. It derives from follicular thyroid cells. Generally speaking, the prognosis is excellent. If treatment according to the current guidelines is given, cases of recurrence or persistence are rare. DTC requires special expertise by the treating physician. In recent years, new therapeutic options for these patients have become available. For this article we performed a systematic literature review with special focus on the guidelines of the American Thyroid Association, the European Association of Nuclear Medicine, and the German Society of Nuclear Medicine. For DTC, surgery and radioiodine therapy followed by levothyroxine substitution remain the established therapeutic procedures. Even metastasized tumors can be cured this way. However, in rare cases of radioiodine-refractory tumors, additional options are to be discussed. These include strict suppression of thyroid-stimulating hormone (also known as thyrotropin, TSH) and external local radiotherapy. Systemic cytostatic chemotherapy does not play a significant role. Recently, multikinase or tyrosine kinase inhibitors have been approved for the treatment of radioiodine-refractory DTC. Although a benefit for overall survival has not been shown yet, these new drugs can slow down tumor progression. However, they are frequently associated with severe side effects and should be reserved for patients with threatening symptoms only. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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16 pages, 5520 KiB

Open AccessArticle

Interactions between a Heparin Trisaccharide Library and FGF-1 Analyzed by NMR Methods

by María José García-Jiménez¹, Sergio Gil-Caballero¹, Ángeles Canales², Jesús Jiménez-Barbero^3,4,5, José L. De Paz¹ and Pedro M. Nieto^1,*

¹ Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de La Cartuja, CSIC and Universidad de Sevilla, Américo Vespucio, 49, 41092 Sevilla, Spain

² Complutense University of Madrid, Fac CC Quim, Department Quim Organ 1, Avd Complutense S/N, E-28040 Madrid, Spain

³ CIC bioGUNE, Bizkaia Technology Park, Building 801A, 48170 Derio, Spain

⁴ Basque Foundation for Science, Maria Diaz de Haro 13, 48009 Bilbao, Spain

⁵ Department of Organic Chemistry II, Faculty of Science and Technology, University of the Basque Country, 48940 Leioa, Bizkaia, Spain

Int. J. Mol. Sci. 2017, 18(6), 1293; https://doi.org/10.3390/ijms18061293 - 17 Jun 2017

Cited by 12 | Viewed by 5598

Abstract

FGF-1 is a potent mitogen that, by interacting simultaneously with Heparan Sulfate Glycosaminoglycan HSGAG and the extracellular domains of its membrane receptor (FGFR), generates an intracellular signal that finally leads to cell division. The overall structure of the ternary complex Heparin:FGF-1:FGFR has been [...] Read more.

FGF-1 is a potent mitogen that, by interacting simultaneously with Heparan Sulfate Glycosaminoglycan HSGAG and the extracellular domains of its membrane receptor (FGFR), generates an intracellular signal that finally leads to cell division. The overall structure of the ternary complex Heparin:FGF-1:FGFR has been finally elucidated after some controversy and the interactions within the ternary complex have been deeply described. However, since the structure of the ternary complex was described, not much attention has been given to the molecular basis of the interaction between FGF-1 and the HSGAG. It is known that within the complex, the carbohydrate maintains the same helical structure of free heparin that leads to sulfate groups directed towards opposite directions along the molecular axis. The precise role of single individual interactions remains unclear, as sliding and/or rotating of the saccharide along the binding pocket are possibilities difficult to discard. The HSGAG binding pocket can be subdivided into two regions, the main one can accommodate a trisaccharide, while the other binds a disaccharide. We have studied and analyzed the interaction between FGF-1 and a library of trisaccharides by STD-NMR and selective longitudinal relaxation rates. The library of trisaccharides corresponds to the heparin backbone and it has been designed to interact with the main subsite of the protein. Full article

(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)

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11 pages, 208 KiB

Open AccessReview

by Edmund J. Miller^1,2,3

and Helena M. Linge^1,4,*

¹ The Center for Heart and Lung Research, The Feinstein Institute for Medical Research Manhasset, New York, NY 11030, USA

² The Elmezzi Graduate School of Molecular Medicine, Manhasset, New York, NY 11030, USA

³ Hofstra Northwell School of Medicine, Hempstead, New York, NY 11549, USA

⁴ Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, 221 00 Lund, Sweden

Int. J. Mol. Sci. 2017, 18(6), 1294; https://doi.org/10.3390/ijms18061294 - 17 Jun 2017

Cited by 21 | Viewed by 5144

Abstract

This review examines the current status of knowledge of sepsis and pneumonia in the elderly population and how the dynamics of the pulmonary challenge affects outcome and consequences. Led by an unprecedented shift in demographics, where a larger proportion of the population will [...] Read more.

This review examines the current status of knowledge of sepsis and pneumonia in the elderly population and how the dynamics of the pulmonary challenge affects outcome and consequences. Led by an unprecedented shift in demographics, where a larger proportion of the population will reach an older age, clinical and experimental research shows that aging is associated with certain pulmonary changes, but it is during infectious insult of the lungs, as in the case of pneumonia, that the age-related differences in responsiveness and endurance become obvious and lead to a worse outcome than in the younger population. This review points to the neutrophil, and the endothelium as important players in understanding age-associated changes in responsiveness to infectious challenge of the lung. It also addresses how the immunological set-point influences injury-repair phases, remote organ damage and how intake of drugs may alter the state of responsiveness in the users. Further, it points out the importance of considering age as a factor in inclusion criteria in clinical trials, in vitro/ex vivo experimental designs and overall interpretation of results. Full article

(This article belongs to the Special Issue Immunology of Aging)

19 pages, 1247 KiB

Open AccessReview

EGFR and EGFRvIII Promote Angiogenesis and Cell Invasion in Glioblastoma: Combination Therapies for an Effective Treatment

by Stefanie Keller¹ and Mirko H. H. Schmidt^1,2,3,*

¹ Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Mainz Neuroscience Network (rmn2), Johannes Gutenberg University, School of Medicine, 55131 Mainz, Germany

² German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, 55131 Mainz, Germany

³ German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

Int. J. Mol. Sci. 2017, 18(6), 1295; https://doi.org/10.3390/ijms18061295 - 18 Jun 2017

Cited by 100 | Viewed by 10872

Abstract

Epidermal growth factor receptor (EGFR) and the mutant EGFRvIII are major focal points in current concepts of targeted cancer therapy for glioblastoma multiforme (GBM), the most malignant primary brain tumor. The receptors participate in the key processes of tumor cell invasion and tumor-related [...] Read more.

Epidermal growth factor receptor (EGFR) and the mutant EGFRvIII are major focal points in current concepts of targeted cancer therapy for glioblastoma multiforme (GBM), the most malignant primary brain tumor. The receptors participate in the key processes of tumor cell invasion and tumor-related angiogenesis and their upregulation correlates with the poor prognosis of glioma patients. Glioma cell invasion and increased angiogenesis share mechanisms of the degradation of the extracellular matrix (ECM) through upregulation of ECM-degrading proteases as well as the activation of aberrant signaling pathways. This review describes the role of EGFR and EGFRvIII in those mechanisms which might offer new combined therapeutic approaches targeting EGFR or EGFRvIII together with drug treatments against proteases of the ECM or downstream signaling to increase the inhibitory effects of mono-therapies. Full article

(This article belongs to the Special Issue Glioma Cell Invasion)

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26 pages, 1978 KiB

Open AccessReview

Cutaneous Manifestations of Human and Murine Leishmaniasis

by Breanna M. Scorza¹, Edgar M. Carvalho^2,3 and Mary E. Wilson^1,4,5,6,*

¹ Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA

² Instituto de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, 40296-710, Brazil

³ Federal University of Bahia, Hospital Universitário Prof. Edgard Santos, Salvador, BA, Brazil

⁴ Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA

⁵ Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA

⁶ Veterans’ Affairs Medical Center, Iowa City, IA 52242, USA

Int. J. Mol. Sci. 2017, 18(6), 1296; https://doi.org/10.3390/ijms18061296 - 18 Jun 2017

Cited by 179 | Viewed by 22406

Abstract

The leishmaniases are diseases caused by pathogenic protozoan parasites of the genus Leishmania. Infections are initiated when a sand fly vector inoculates Leishmania parasites into the skin of a mammalian host. Leishmania causes a spectrum of inflammatory cutaneous disease manifestations. The type of [...] Read more.

The leishmaniases are diseases caused by pathogenic protozoan parasites of the genus Leishmania. Infections are initiated when a sand fly vector inoculates Leishmania parasites into the skin of a mammalian host. Leishmania causes a spectrum of inflammatory cutaneous disease manifestations. The type of cutaneous pathology is determined in part by the infecting Leishmania species, but also by a combination of inflammatory and anti-inflammatory host immune response factors resulting in different clinical outcomes. This review discusses the distinct cutaneous syndromes described in humans, and current knowledge of the inflammatory responses associated with divergent cutaneous pathologic responses to different Leishmania species. The contribution of key hematopoietic cells in experimental cutaneous leishmaniasis in mouse models are also reviewed and compared with those observed during human infection. We hypothesize that local skin events influence the ensuing adaptive immune response to Leishmania spp. infections, and that the balance between inflammatory and regulatory factors induced by infection are critical for determining cutaneous pathology and outcome of infection. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions 2017)

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25 pages, 1537 KiB

Open AccessReview

Autophagic Mechanism in Anti-Cancer Immunity: Its Pros and Cons for Cancer Therapy

by Ying-Ying Li^1,2, Lynn G. Feun², Angkana Thongkum³, Chiao-Hui Tu⁴, Shu-Mei Chen⁴, Medhi Wangpaichitr^5,6

, Chunjing Wu⁶, Macus T. Kuo⁷ and Niramol Savaraj^1,6,*

¹ Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA

² Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA

³ Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Thailand Chulabhorn Graduate Institute, Laksi, Bangkok 10210, Thailand

⁴ Department of Neurosurgery, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan

⁵ Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA

⁶ Division of Hematology and Oncology, Miami Veterans Affairs Healthcare System, Miami, FL 33125, USA

⁷ Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

Int. J. Mol. Sci. 2017, 18(6), 1297; https://doi.org/10.3390/ijms18061297 - 19 Jun 2017

Cited by 30 | Viewed by 8107

Abstract

Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress. It has been appreciated that autophagy acts as a double-edge sword to decide the fate of cancer cells upon stress factors, molecular subtypes, [...] Read more.

Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress. It has been appreciated that autophagy acts as a double-edge sword to decide the fate of cancer cells upon stress factors, molecular subtypes, and microenvironmental conditions. Currently, the majority of evidence support that autophagy in cancer cells is a vital mechanism bringing on resistance to current and prospective treatments, yet whether autophagy affects the anticancer immune response remains unclear and controversial. Accumulated studies have demonstrated that triggering autophagy is able to facilitate anticancer immunity due to an increase in immunogenicity, whereas other studies suggested that autophagy is likely to disarm anticancer immunity mediated by cytotoxic T cells and nature killer (NK) cells. Hence, this contradiction needs to be elucidated. In this review, we discuss the role of autophagy in cancer cells per se and in cancer microenvironment as well as its dual regulatory roles in immune surveillance through modulating presentation of tumor antigens, development of immune cells, and expression of immune checkpoints. We further focus on emerging roles of autophagy induced by current treatments and its impact on anticancer immune response, and illustrate the pros and cons of utilizing autophagy in cancer immunotherapy based on preclinical references. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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14 pages, 1884 KiB

Open AccessArticle

Using Coexpression Protein Interaction Network Analysis to Identify Mechanisms of Danshensu Affecting Patients with Coronary Heart Disease

by Mengqi Huo, Zhixin Wang, Dongxue Wu, Yanling Zhang^* and Yanjiang Qiao^*

Key Laboratory of Traditional Chinese Medicine Information Engineer of State Administration of Traditional Chinese Medicine; School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China

Int. J. Mol. Sci. 2017, 18(6), 1298; https://doi.org/10.3390/ijms18061298 - 19 Jun 2017

Cited by 28 | Viewed by 4970

Abstract

Salvia miltiorrhiza, known as Danshen, has attracted worldwide interest for its substantial effects on coronary heart disease (CHD). Danshensu (DSS) is one of the main active ingredients of Danshen on CHD. Although it has been proven to have a good clinical effect [...] Read more.

Salvia miltiorrhiza, known as Danshen, has attracted worldwide interest for its substantial effects on coronary heart disease (CHD). Danshensu (DSS) is one of the main active ingredients of Danshen on CHD. Although it has been proven to have a good clinical effect on CHD, the action mechanisms remain elusive. In the current study, a coexpression network-based approach was used to illustrate the beneficial properties of DSS in the context of CHD. By integrating the gene expression profile data and protein-protein interactions (PPIs) data, two coexpression protein interaction networks (CePIN) in a CHD state (CHD CePIN) and a non-CHD state (non-CHD CePIN) were generated. Then, shared nodes and unique nodes in CHD CePIN were attained by conducting a comparison between CHD CePIN and non-CHD CePIN. By calculating the topological parameters of each shared node and unique node in the networks, and comparing the differentially expressed genes, target proteins involved in disease regulation were attained. Then, Gene Ontology (GO) enrichment was utilized to identify biological processes associated to target proteins. Consequently, it turned out that the treatment of CHD with DSS may be partly attributed to the regulation of immunization and blood circulation. Also, it indicated that sodium/hydrogen exchanger 3 (SLC9A3), Prostaglandin G/H synthase 2 (PTGS2), Oxidized low-density lipoprotein receptor 1 (OLR1), and fibrinogen gamma chain (FGG) may be potential therapeutic targets for CHD. In summary, this study provided a novel coexpression protein interaction network approach to provide an explanation of the mechanisms of DSS on CHD and identify key proteins which maybe the potential therapeutic targets for CHD. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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15 pages, 3141 KiB

Open AccessArticle

Gene Expression Profiling Reveals Potential Players of Left-Right Asymmetry in Female Chicken Gonads

by Zhiyi Wan^1,†, Yanan Lu^1,†, Lei Rui¹, Xiaoxue Yu¹

, Fang Yang², Chengfang Tu³ and Zandong Li^1,*

¹ State key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China

² College of Life Sciences, Peking University, Beijing 100871, China

³ Annoroad Gene Technology Co., Ltd., Beijing 100176, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1299; https://doi.org/10.3390/ijms18061299 - 20 Jun 2017

Cited by 12 | Viewed by 5633

Abstract

Most female birds develop only a left ovary, whereas males develop bilateral testes. The mechanism underlying this process is still not completely understood. Here, we provide a comprehensive transcriptional analysis of female chicken gonads and identify novel candidate side-biased genes. RNA-Seq analysis was [...] Read more.

Most female birds develop only a left ovary, whereas males develop bilateral testes. The mechanism underlying this process is still not completely understood. Here, we provide a comprehensive transcriptional analysis of female chicken gonads and identify novel candidate side-biased genes. RNA-Seq analysis was carried out on total RNA harvested from the left and right gonads on embryonic day 6 (E6), E12, and post-hatching day 1 (D1). By comparing the gene expression profiles between the left and right gonads, 347 differentially expressed genes (DEGs) were obtained on E6, 3730 were obtained on E12, and 2787 were obtained on D1. Side-specific genes were primarily derived from the autosome rather than the sex chromosome. Gene ontology and pathway analysis showed that the DEGs were most enriched in the Piwi-interactiing RNA (piRNA) metabolic process, germ plasm, chromatoid body, P granule, neuroactive ligand-receptor interaction, microbial metabolism in diverse environments, and methane metabolism. A total of 111 DEGs, five gene ontology (GO) terms, and three pathways were significantly different between the left and right gonads among all the development stages. We also present the gene number and the percentage within eight development-dependent expression patterns of DEGs in the left and right gonads of female chicken. Full article

(This article belongs to the Section Biochemistry)

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8 pages, 1638 KiB

Open AccessArticle

Knockout of Murine Mamld1 Impairs Testicular Growth and Daily Sperm Production but Permits Normal Postnatal Androgen Production and Fertility

by Mami Miyado¹, Kaoru Yoshida²

, Kenji Miyado³

, Momori Katsumi^1,4, Kazuki Saito^1,5, Shigeru Nakamura^1,6, Tsutomu Ogata^1,7 and Maki Fukami^1,*

¹ Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan

² Faculty of Biomedical Engineering, Toin University of Yokohama, Yokohama 225-8502, Japan

³ Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan

⁴ Department of NCCHD Child Health and Development, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

⁵ Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

⁶ Department of Pediatric Urology, Jichi Medical University, Children’s Medical Center Tochigi, Tochigi 329-0498, Japan

⁷ Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan

Int. J. Mol. Sci. 2017, 18(6), 1300; https://doi.org/10.3390/ijms18061300 - 19 Jun 2017

Cited by 13 | Viewed by 5525

Abstract

MAMLD1 has been implicated in testicular function in both human and mouse fetuses. Although three patients with MAMLD1 mutations were reported to have hypergonadotropic hypogonadism in their teens, the functional significance of MAMLD1 in the postnatal testis remains unclear. Here, we analyzed the [...] Read more.

MAMLD1 has been implicated in testicular function in both human and mouse fetuses. Although three patients with MAMLD1 mutations were reported to have hypergonadotropic hypogonadism in their teens, the functional significance of MAMLD1 in the postnatal testis remains unclear. Here, we analyzed the phenotype of Mamld1 knockout (KO) male mice at reproductive ages. The reproductive organs of KO male mice were morphologically unremarkable, except for relatively small testes. Seminiferous tubule size and number of proliferating spermatogonia/spermatocytes were reduced in the KO testis. Daily sperm production of KO mice was mildly attenuated, whereas total sperm counts in epididymal semen remained normal. Sperm motility and morphology, as well as androgen levels in serum and testicular tissues and the number of pups born from cross-mated wildtype (WT) female mice, were comparable between WT and KO male mice. These results indicate that MAMLD1 contributes to the maintenance of postnatal testicular growth and daily sperm production but is dispensable for androgen biosynthesis and fertility. MAMLD1 likely plays supporting roles in multiple and continuous steps of male reproduction. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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9 pages, 1412 KiB

Open AccessArticle

Epidermal Growth Factor Enhances Cellular Uptake of Polystyrene Nanoparticles by Clathrin-Mediated Endocytosis

by Le Thi Minh Phuc^1,2

and Akiyoshi Taniguchi^1,2,*

¹ Cellular Functional Nanomaterials Group, Research Center for Functional Materials, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan

² Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan

Int. J. Mol. Sci. 2017, 18(6), 1301; https://doi.org/10.3390/ijms18061301 - 19 Jun 2017

Cited by 25 | Viewed by 6102

Abstract

The interaction between nanoparticles and cells has been studied extensively, but most research has focused on the effect of various nanoparticle characteristics, such as size, morphology, and surface charge, on the cellular uptake of nanoparticles. In contrast, there have been very few studies [...] Read more.

The interaction between nanoparticles and cells has been studied extensively, but most research has focused on the effect of various nanoparticle characteristics, such as size, morphology, and surface charge, on the cellular uptake of nanoparticles. In contrast, there have been very few studies to assess the influence of cellular factors, such as growth factor responses, on the cellular uptake efficiency of nanoparticles. The aim of this study was to clarify the effects of epidermal growth factor (EGF) on the uptake efficiency of polystyrene nanoparticles (PS NPs) by A431 cells, a human carcinoma epithelial cell line. The results showed that EGF enhanced the uptake efficiency of A431 cells for PS NPs. In addition, inhibition and localization studies of PS NPs and EGF receptors (EGFRs) indicated that cellular uptake of PS NPs is related to the binding of EGF–EGFR complex and PS NPs. Different pathways are used to enter the cells depending on the presence or absence of EGF. In the presence of EGF, cellular uptake of PS NPs is via clathrin-mediated endocytosis, whereas, in the absence of EGF, uptake of PS NPs does not involve clathrin-mediated endocytosis. Our findings indicate that EGF enhances cellular uptake of PS NPs by clathrin-mediated endocytosis. This result could be important for developing safe nanoparticles and their safe use in medical applications. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety)

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15 pages, 1766 KiB

Open AccessArticle

Suppression of Ghrelin Exacerbates HFCS-Induced Adiposity and Insulin Resistance

by Xiaojun Ma^1,2,†, Ligen Lin^2,3,†

, Jing Yue^2,4,†, Chia-Shan Wu⁵, Cathy A. Guo⁵, Ruitao Wang⁶, Kai-Jiang Yu⁶, Sridevi Devaraj⁷, Peter Murano⁵, Zheng Chen⁸ and Yuxiang Sun^2,5,*

¹ Department of Internal Medicine, Zhengzhou University, Zhengzhou 450052, China

² Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA

³ State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau 999078, China

⁴ Department of Reproductive Medicine, Huazhong Science and Technology University, Wuhan 430030, China

⁵ Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA

⁶ Department of Internal Medicine, Harbin Medical University, Harbin 150081, China

⁷ Department of Pathology and Immunology, Baylor College of Medicine; Houston, TX 77030, USA

⁸ Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX 77030, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1302; https://doi.org/10.3390/ijms18061302 - 19 Jun 2017

Cited by 25 | Viewed by 7057

Abstract

High fructose corn syrup (HFCS) is widely used as sweetener in processed foods and soft drinks in the United States, largely substituting sucrose (SUC). The orexigenic hormone ghrelin promotes obesity and insulin resistance; ghrelin responds differently to HFCS and SUC ingestion. Here we [...] Read more.

High fructose corn syrup (HFCS) is widely used as sweetener in processed foods and soft drinks in the United States, largely substituting sucrose (SUC). The orexigenic hormone ghrelin promotes obesity and insulin resistance; ghrelin responds differently to HFCS and SUC ingestion. Here we investigated the roles of ghrelin in HFCS- and SUC-induced adiposity and insulin resistance. To mimic soft drinks, 10-week-old male wild-type (WT) and ghrelin knockout (Ghrelin^−/−) mice were subjected to ad lib. regular chow diet supplemented with either water (RD), 8% HFCS (HFCS), or 10% sucrose (SUC). We found that SUC-feeding induced more robust increases in body weight and body fat than HFCS-feeding. Comparing to SUC-fed mice, HFCS-fed mice showed lower body weight but higher circulating glucose and insulin levels. Interestingly, we also found that ghrelin deletion exacerbates HFCS-induced adiposity and inflammation in adipose tissues, as well as whole-body insulin resistance. Our findings suggest that HFCS and SUC have differential effects on lipid metabolism: while sucrose promotes obesogenesis, HFCS primarily enhances inflammation and insulin resistance, and ghrelin confers protective effects for these metabolic dysfunctions. Full article

(This article belongs to the Special Issue Gene-Diet Interactions in Chronic Diseases)

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17 pages, 20655 KiB

Open AccessArticle

The Arabidopsis GPR1 Gene Negatively Affects Pollen Germination, Pollen Tube Growth, and Gametophyte Senescence

by Xiao Yang

, Qinying Zhang, Kun Zhao

, Qiong Luo, Shuguang Bao, Huabin Liu and Shuzhen Men^*

Department of Plant Biology and Ecology, College of Life Sciences, Nankai University, Tianjin 300071, China

Int. J. Mol. Sci. 2017, 18(6), 1303; https://doi.org/10.3390/ijms18061303 - 21 Jun 2017

Cited by 16 | Viewed by 9446

Abstract

Genes essential for gametophyte development and fertilization have been identified and studied in detail; however, genes that fine-tune these processes are largely unknown. Here, we characterized an unknown Arabidopsis gene, GTP-BINDING PROTEIN RELATED1 (GPR1). GPR1 is specifically expressed in ovule, pollen, [...] Read more.

Genes essential for gametophyte development and fertilization have been identified and studied in detail; however, genes that fine-tune these processes are largely unknown. Here, we characterized an unknown Arabidopsis gene, GTP-BINDING PROTEIN RELATED1 (GPR1). GPR1 is specifically expressed in ovule, pollen, and pollen tube. Enhanced green fluorescent protein-tagged GPR1 localizes to both nucleus and cytoplasm, and it also presents in punctate and ring-like structures. gpr1 mutants exhibit no defect in gametogenesis and seed setting, except that their pollen grains are pale in color. Scanning electron microscopy analyses revealed a normal patterned but thinner exine on gpr1 pollen surface. This may explain why gpr1 pollen grains are pale. We next examined whether GPR1 mutation affects post gametogenesis processes including pollen germination, pollen tube growth, and ovule senescence. We found that gpr1 pollen grains germinated earlier, and their pollen tubes elongated faster. Emasculation assay revealed that unfertilized gpr1 pistil expressed the senescence marker P_BFN1:GUS (GUS: a reporter gene that encodes β-glucuronidase) one-day earlier than the wild type pistil. Consistently, ovules and pollen grains of gpr1 mutants showed lower viability than those of the wild type at 4 to 5 days post anthesis. Together, these data suggest that GPR1 functions as a negative regulator of pollen germination, pollen tube growth, and gametophyte senescence to fine-tune the fertilization process. Full article

(This article belongs to the Section Molecular Plant Sciences)

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14 pages, 777 KiB

Open AccessArticle

Serum Biomarkers for Discrimination between Hepatitis C-Related Arthropathy and Early Rheumatoid Arthritis

by Isabela Siloşi¹

, Lidia Boldeanu^2,3

, Viorel Biciuşcă⁴

, Maria Bogdan⁵

, Carmen Avramescu²

, Citto Taisescu⁴

, Vlad Padureanu⁴

, Mihail Virgil Boldeanu^1,3,*

, Anica Dricu⁶ and Cristian Adrian Siloşi⁷

¹ Department of Immunology-Laboratory of Immunology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, Craiova 200349, Romania

² Department of Microbiology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, Craiova 200690, Romania

³ Medico Science SRL-Stem Cell Bank Unit, 1B Brazda lui Novac Street, Craiova 200690, Romania

⁴ Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, Craiova 200690, Romania

⁵ Department of Pharmacology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, Craiova 200349, Romania

⁶ Department of Functional Sciences, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, Craiova 200690, Romania

⁷ Department of Surgery, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, Craiova 200349, Romania

Int. J. Mol. Sci. 2017, 18(6), 1304; https://doi.org/10.3390/ijms18061304 - 19 Jun 2017

Cited by 16 | Viewed by 4392

Abstract

In the present study, we aimed to estimate the concentrations of cytokines (interleukin 6, IL-6, tumor necrosis factor-α, TNF-α) and auto-antibodies (rheumatoid factor IgM isotype, IgM-RF, antinuclear auto-antibodies, ANA, anti–cyclic citrullinated peptide antibodies IgG isotype, IgG anti-CCP3.1, anti-cardiolipin IgG isotype, IgG anti-aCL) in [...] Read more.

In the present study, we aimed to estimate the concentrations of cytokines (interleukin 6, IL-6, tumor necrosis factor-α, TNF-α) and auto-antibodies (rheumatoid factor IgM isotype, IgM-RF, antinuclear auto-antibodies, ANA, anti–cyclic citrullinated peptide antibodies IgG isotype, IgG anti-CCP3.1, anti-cardiolipin IgG isotype, IgG anti-aCL) in serum of patients with eRA (early rheumatoid arthritis) and HCVrA (hepatitis C virus-related arthropathy) and to assess the utility of IL-6, TNF-α together with IgG anti-CCP and IgM-RF in distinguishing between patients with true eRA and HCVrA, in the idea of using them as differential immunomarkers. Serum samples were collected from 54 patients (30 diagnosed with eRA-subgroup 1 and 24 with HCVrA-subgroup 2) and from 28 healthy control persons. For the evaluation of serum concentrations of studied cytokines and auto-antibodies, we used immunoenzimatique techniques. The serum concentrations of both proinflammatory cytokines were statistically significantly higher in patients of subgroup 1 and subgroup 2, compared to the control group (p < 0.0001). Our study showed statistically significant differences of the mean concentrations only for ANA and IgG anti-CCP between subgroup 1 and subgroup 2. We also observed that IL-6 and TNF-α better correlated with auto-antibodies in subgroup 1 than in subgroup 2. In both subgroups of patients, ROC curves indicated that IL-6 and TNF-α have a higher diagnostic utility as markers of disease. In conclusion, we can say that, due to high sensitivity for diagnostic accuracy, determination of serum concentrations of IL-6 and TNF-α, possibly in combination with auto-antibodies, could be useful in the diagnosis and distinguishing between patients with true eRA and HCV patients with articular manifestation and may prove useful in the monitoring of the disease course. Full article

(This article belongs to the Special Issue Hepatitis Virus Infection and Research)

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8 pages, 178 KiB

Open AccessReview

The Role of HCG in Implantation: A Mini-Review of Molecular and Clinical Evidence

by Antonis Makrigiannakis^1,*,†, Thomas Vrekoussis^2,†, Emmanouel Zoumakis³, Sophia N. Kalantaridou⁴ and Udo Jeschke⁵

¹ Department of Obstetrics and Gynecology, Medical School, University of Crete, Heraklion 71003, Greece

² Department of Obstetrics and Gynecology, Medical School, University of Ioannina, Ioannina 45110, Greece

³ Department of Pediatrics, Medical School, University of Athens, Athens 11527, Greece

⁴ Second Department of Obstetrics and Gynecology, Medical School, University of Athens, Athens 11528, Greece

⁵ Departments of Obstetrics and Gynecology, Medical School, Ludwig-Maximilians University of Munich, Campus Innenstadt & Campus Grosshadern, Munich 80337, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1305; https://doi.org/10.3390/ijms18061305 - 19 Jun 2017

Cited by 57 | Viewed by 9222

Abstract

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, [...] Read more.

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes. Full article

(This article belongs to the Special Issue hCG—An Endocrine, Regulator of Gestation and Cancer)

10 pages, 643 KiB

Open AccessReview

Fortifying Horticultural Crops with Essential Amino Acids: A Review

by Guoping Wang¹, Mengyun Xu¹, Wenyi Wang^1,2,* and Gad Galili^2,*

¹ College of Horticulture, South China Agricultural University, Guangzhou 510642, China

² Department of Plant Science, Weizmann Institute of Science, Rehovot 76100, Israel

Int. J. Mol. Sci. 2017, 18(6), 1306; https://doi.org/10.3390/ijms18061306 - 19 Jun 2017

Cited by 40 | Viewed by 8602

Abstract

To feed the world′s growing population, increasing the yield of crops is not the only important factor, improving crop quality is also important, and it presents a significant challenge. Among the important crops, horticultural crops (particularly fruits and vegetables) provide numerous health compounds, [...] Read more.

To feed the world′s growing population, increasing the yield of crops is not the only important factor, improving crop quality is also important, and it presents a significant challenge. Among the important crops, horticultural crops (particularly fruits and vegetables) provide numerous health compounds, such as vitamins, antioxidants, and amino acids. Essential amino acids are those that cannot be produced by the organism and, therefore, must be obtained from diet, particularly from meat, eggs, and milk, as well as a variety of plants. Extensive efforts have been devoted to increasing the levels of essential amino acids in plants. Yet, these efforts have been met with very little success due to the limited genetic resources for plant breeding and because high essential amino acid content is generally accompanied by limited plant growth. With a deep understanding of the biosynthetic pathways of essential amino acids and their interactions with the regulatory networks in plants, it should be possible to use genetic engineering to improve the essential amino acid content of horticultural plants, rendering these plants more nutritionally favorable crops. In the present report, we describe the recent advances in the enhancement of essential amino acids in horticultural plants and possible future directions towards their bio-fortification. Full article

(This article belongs to the Section Molecular Plant Sciences)

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11 pages, 13186 KiB

Open AccessArticle

Candida albicans Impairments Induced by Peppermint and Clove Oils at Sub-Inhibitory Concentrations

by Katarzyna Rajkowska^1,*

, Anna Otlewska¹, Alina Kunicka-Styczyńska¹

and Agnieszka Krajewska²

¹ Institute of Fermentation Technology and Microbiology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Lodz 90-924, Poland

² Institute of General Food Chemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Lodz 90-924, Poland

Int. J. Mol. Sci. 2017, 18(6), 1307; https://doi.org/10.3390/ijms18061307 - 19 Jun 2017

Cited by 30 | Viewed by 9123

Abstract

Members of Candida species cause significant health problems, inducing various types of superficial and deep-seated mycoses in humans. In order to prevent from Candida sp. development, essential oils are more and more frequently applied, due to their antifungal activity, low toxicity if used [...] Read more.

Members of Candida species cause significant health problems, inducing various types of superficial and deep-seated mycoses in humans. In order to prevent from Candida sp. development, essential oils are more and more frequently applied, due to their antifungal activity, low toxicity if used appropriately, and biodegrability. The aim of the study was to characterize the early alterations in Candida albicans metabolic properties in relation to proteins and chromosomal DNA profiles, after treatment with peppermint and clove oils at sub-inhibitory concentrations. The yeasts were affected by the oils even at a concentration of 0.0075% v/v, which resulted in changes in colony morphotypes and metabolic activities. Peppermint and clove oils at concentrations ranging from 0.015× MIC (minimal inhibitory concentration) to 0.5× MIC values substantially affected the enzymatic abilities of C. albicans, and these changes were primarily associated with the loss or decrease of activity of all 9 enzymes detected in the untreated yeast. Moreover, 29% isolates showed additional activity of N-acetyl-β-glucosaminidase and 14% isolates—α-fucosidase in comparison to the yeast grown without essential oils addition. In response to essential oils at 0.25–0.5× MIC, extensive changes in C. albicans whole-cell protein profiles were noted. However, the yeast biochemical profiles were intact with the sole exception of the isolate treated with clove oil at 0.5× MIC. The alterations were not attributed to gross chromosomal rearrangements in C. albicans karyotype. The predominantly observed decrease in protein fractions and the yeast enzymatic activity after treatment with the oils should be considered as a phenotypic response of C. albicans to the essential oils at their sub-inhibitory concentrations and may lead to the reduction of this yeast pathogenicity. Full article

(This article belongs to the Special Issue Effective Mechanisms of Plant Bioactive Essential Fats and Oils)

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2 pages, 166 KiB

Open AccessLetter

Letter to the Editor: “Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy”

by Chiara Nicolazzo

, Cristina Raimondi, Flavia Loreni, Paola Gazzaniga and Angela Gradilone^*

Circulating Tumor Cells Unit, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 324, 00161 Rome, Italy

Int. J. Mol. Sci. 2017, 18(6), 1308; https://doi.org/10.3390/ijms18061308 - 19 Jun 2017

Viewed by 3646

Abstract

To the Editor, We read with great interest the article “Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy” published by Coco, S. et al. in International Journal [...] Read more.

To the Editor, We read with great interest the article “Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy” published by Coco, S. et al. in International Journal of Molecular Sciences on 11 May 2017 [1].[...] Full article

2 pages, 134 KiB

Open AccessReply

Reply to the Letter to the Editor by C. Nicolazzo et al.: “Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy”

by Angela Alama^*

, Simona Coco

, Irene Vanni and Francesco Grossi

Lung Cancer Unit, IRCCS AOU San Martino—IST Istituto Nazionale per la Ricerca sul Cancro, L.go R. Benzi 10, 16132 Genova, Italy

Int. J. Mol. Sci. 2017, 18(6), 1309; https://doi.org/10.3390/ijms18061309 - 19 Jun 2017

Cited by 1 | Viewed by 3502

Abstract

Reply: Thank you for the valuable comments. We agree with the concern that distinguishing genuine circulating tumor cells (CTCs) from other circulating cells by morphology may be questionable.[...] Full article

27 pages, 359 KiB

Open AccessReview

Microbiota, Inflammation and Colorectal Cancer

by Cécily Lucas, Nicolas Barnich

and Hang Thi Thu Nguyen^*

M2iSH, UMR 1071 Inserm, University of Clermont Auvergne, INRA USC 2018, Clermont-Ferrand 63001, France

Int. J. Mol. Sci. 2017, 18(6), 1310; https://doi.org/10.3390/ijms18061310 - 20 Jun 2017

Cited by 257 | Viewed by 16661

Abstract

Colorectal cancer, the fourth leading cause of cancer-related death worldwide, is a multifactorial disease involving genetic, environmental and lifestyle risk factors. In addition, increased evidence has established a role for the intestinal microbiota in the development of colorectal cancer. Indeed, changes in the [...] Read more.

Colorectal cancer, the fourth leading cause of cancer-related death worldwide, is a multifactorial disease involving genetic, environmental and lifestyle risk factors. In addition, increased evidence has established a role for the intestinal microbiota in the development of colorectal cancer. Indeed, changes in the intestinal microbiota composition in colorectal cancer patients compared to control subjects have been reported. Several bacterial species have been shown to exhibit the pro-inflammatory and pro-carcinogenic properties, which could consequently have an impact on colorectal carcinogenesis. This review will summarize the current knowledge about the potential links between the intestinal microbiota and colorectal cancer, with a focus on the pro-carcinogenic properties of bacterial microbiota such as induction of inflammation, the biosynthesis of genotoxins that interfere with cell cycle regulation and the production of toxic metabolites. Finally, we will describe the potential therapeutic strategies based on intestinal microbiota manipulation for colorectal cancer treatment. Full article

(This article belongs to the Special Issue Inflammation and Cancer)

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13 pages, 657 KiB

Open AccessArticle

Sexually Transmitted Infections: A Novel Screening Strategy for Improving Women’s Health in Vulnerable Populations

by Elena R. Frati¹

, Ester Fasoli¹, Marianna Martinelli¹

, Daniela Colzani¹, Silvia Bianchi¹, Luciana Carnelli², Antonella Amendola^1,3,4, Pierfranco Olivani⁵ and Elisabetta Tanzi^1,3,4,*

¹ Department of Biomedical Sciences for Health, University of Milan, Via C. Pascal 36, 20133 Milan, Italy

² Lega Italiana per la Lotta contro i Tumori (LILT), Section of Milan, Viale Molise 5, 20137 Milan, Italy

³ Coordinated Research Center “EpiSoMI”, University of Milan, Via C. Pascal 36, 20133 Milan, Italy

⁴ CIRI-IV, Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16100 Genoa, Italy

⁵ NAGA Centre, Associazione Volontaria di Assistenza Socio-Sanitaria e per i Diritti di Cittadini Stranieri, Rom e Sinti, Via L. L. Zamenhof 7/A, 20136 Milan, Italy

Int. J. Mol. Sci. 2017, 18(6), 1311; https://doi.org/10.3390/ijms18061311 - 20 Jun 2017

Cited by 18 | Viewed by 5764

Abstract

Background: Migrant women are one of the most vulnerable population to health problems and well-being. This study aimed at implementing a counseling and preventive strategy for sexually transmitted infections (STIs) in undocumented migrant women in Milan, Italy. Methods: Women (ages 18–65) were enrolled [...] Read more.

Background: Migrant women are one of the most vulnerable population to health problems and well-being. This study aimed at implementing a counseling and preventive strategy for sexually transmitted infections (STIs) in undocumented migrant women in Milan, Italy. Methods: Women (ages 18–65) were enrolled at the NAGA Centre (2012–2013) and asked for a urine sample in order to carry out molecular detection of Human papillomavirus (HPV), Chlamydia trachomatis (Ct), Trichomonas vaginalis (Tv), Neisseria gonorrhoeae (Ng)-DNA. Socio-demographic and sexual behavior information were collected. All HPV/Ct+ women were offered Pap tests and/or were prescribed antibiotic treatment. Results: 537/757 women participated in the study (acceptability rate: 70.9%). Most of the women were from Latin America (45.6%) and Eastern Europe (30.7%); >60% of them had stable partners, did not use contraception and had had at least one pregnancy. The prevalence rates of HPV, Ct, Tv and Ng infections were 24.2%, 7.8%, 4.8% and 0%, respectively. In all, 43.2% of the positive women agreed to undergo a gynecological examination and accepted suitable treatment. Conclusions: This study shows an overall high prevalence of STIs in undocumented migrant women in Milan. The screening strategy based on counseling and urine testing contributed to the successfully high acceptability rate. More appropriate health services that adequately address all aspects of women’s health are required. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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10 pages, 1168 KiB

Open AccessArticle

Synthesis and Biodegradation of Poly(l-lactide-co-β-propiolactone)

by Yuushou Nakayama^1,*

, Kazuki Aihara¹, Zhengguo Cai²

, Takeshi Shiono^1,*

and Chikara Tsutsumi³

¹ Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, Higashi-Hiroshima 739-8527, Japan

² State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Material Science and Engineering, Donghua University, Shanghai 201620, China

³ Department of Applied Chemistry and Biotechnology, Niihama National College of Technology, Niihama 792-8580, Japan

Int. J. Mol. Sci. 2017, 18(6), 1312; https://doi.org/10.3390/ijms18061312 - 20 Jun 2017

Cited by 14 | Viewed by 6210

Abstract

Although the copolymerizations of l-lactide (LA) with seven- or six-membered ring lactones have been extensively studied, the copolymerizations of LA with four-membered ring lactones have scarcely been reported. In this work, we studied the copolymerization of LA with β-propiolactone (PL) and the [...] Read more.

Although the copolymerizations of l-lactide (LA) with seven- or six-membered ring lactones have been extensively studied, the copolymerizations of LA with four-membered ring lactones have scarcely been reported. In this work, we studied the copolymerization of LA with β-propiolactone (PL) and the properties of the obtained copolymers. The copolymerization of LA with PL was carried out using trifluoromethanesulfonic acid as a catalyst and methanol as an initiator to produce poly(LA-co-PL) with M_n of ~50,000 and PL-content of 6–67 mol %. The T_g values of the copolymers were rapidly lowered with increasing PL-contents. The T_m and ΔH_m of the copolymers gradually decreased with increasing PL-contents, indicating their decreased crystallinity. Biodegradation test of the copolymers in compost demonstrated their improved biodegradability in comparison with the homopolymer of LA. Full article

(This article belongs to the Special Issue Biodegradable Materials 2017)

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10 pages, 1032 KiB

Open AccessReview

Soluble (Pro)renin Receptor and Obstructive Sleep Apnea Syndrome: Oxidative Stress in Brain?

by Kazuhiro Takahashi^1,*

, Koji Ohba¹, Kazuki Tajima¹, Tsuguo Nishijima² and Shigeru Sakurai²

¹ Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan

² Division of Behavioral Sleep Medicine, Iwate Medical University School of Medicine, Morioka, Iwate 020-0850, Japan

Int. J. Mol. Sci. 2017, 18(6), 1313; https://doi.org/10.3390/ijms18061313 - 20 Jun 2017

Cited by 14 | Viewed by 6345

Abstract

(Pro)renin receptor ((P)RR) is a multi-functional molecule that is related to both the renin-angiotensin system (RAS) and vacuolar H⁺-ATPase (v-ATPase), an ATP-dependent multi-subunit proton pump. Soluble (P)RR (s(P)RR), which consists of the extracellular domain of (P)RR, is present in blood and [...] Read more.

(Pro)renin receptor ((P)RR) is a multi-functional molecule that is related to both the renin-angiotensin system (RAS) and vacuolar H⁺-ATPase (v-ATPase), an ATP-dependent multi-subunit proton pump. Soluble (P)RR (s(P)RR), which consists of the extracellular domain of (P)RR, is present in blood and urine. Elevated plasma s(P)RR concentrations are reported in patients with chronic kidney disease and pregnant women with hypertension or diabetes mellitus. In addition, we have shown that plasma s(P)RR concentrations are elevated in patients with obstructive sleep apnea syndrome (OSAS). Interestingly, the levels are elevated in parallel with the severity of OSAS, but are not related to the presence of hypertension or the status of the circulating RAS in OSAS. It is known that v-ATPase activity protects cells from endogenous oxidative stress, and loss of v-ATPase activity results in chronic oxidative stress. We hypothesize that hypoxia and subsequent oxidative stress, perhaps in the brain, may be one of the factors that elevate plasma s(P)RR levels in OSAS. Full article

(This article belongs to the Special Issue Selected Papers from the Renin–Angiotensin–Aldosterone System (RAAS)2016: Official Satellite of ISH2016, from September 23 to 24 in Tokyo, Japan)

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15 pages, 913 KiB

Open AccessReview

Melatonin as a Novel Interventional Candidate for Fragile X Syndrome with Autism Spectrum Disorder in Humans

by Jinyoung Won^1,2,3,†, Yunho Jin^1,2,3,†, Jeonghyun Choi^1,2,3, Sookyoung Park^2,3,4, Tae Ho Lee⁵, Sang-Rae Lee⁶, Kyu-Tae Chang^6,* and Yonggeun Hong^1,2,3,4,*

¹ Department of Rehabilitation Science, Graduate School of Inje University, Gimhae 50834, Korea

² Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae 50834, Korea

³ Biohealth Products Research Center (BPRC), Inje University, Gimhae 50834, Korea

⁴ Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University, Gimhae 50834, Korea

⁵ Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

⁶ National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang 28116, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1314; https://doi.org/10.3390/ijms18061314 - 20 Jun 2017

Cited by 20 | Viewed by 9622

Abstract

Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD). FXS with ASD results from the loss of fragile X mental retardation (fmr) gene products, including fragile X mental retardation protein (FMRP), which triggers a variety [...] Read more.

Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD). FXS with ASD results from the loss of fragile X mental retardation (fmr) gene products, including fragile X mental retardation protein (FMRP), which triggers a variety of physiological and behavioral abnormalities. This disorder is also correlated with clock components underlying behavioral circadian rhythms and, thus, a mutation of the fmr gene can result in disturbed sleep patterns and altered circadian rhythms. As a result, FXS with ASD individuals may experience dysregulation of melatonin synthesis and alterations in melatonin-dependent signaling pathways that can impair vigilance, learning, and memory abilities, and may be linked to autistic behaviors such as abnormal anxiety responses. Although a wide variety of possible causes, symptoms, and clinical features of ASD have been studied, the correlation between altered circadian rhythms and FXS with ASD has yet to be extensively investigated. Recent studies have highlighted the impact of melatonin on the nervous, immune, and metabolic systems and, even though the utilization of melatonin for sleep dysfunctions in ASD has been considered in clinical research, future studies should investigate its neuroprotective role during the developmental period in individuals with ASD. Thus, the present review focuses on the regulatory circuits involved in the dysregulation of melatonin and disruptions in the circadian system in individuals with FXS with ASD. Additionally, the neuroprotective effects of melatonin intervention therapies, including improvements in neuroplasticity and physical capabilities, are discussed and the molecular mechanisms underlying this disorder are reviewed. The authors suggest that melatonin may be a useful treatment for FXS with ASD in terms of alleviating the adverse effects of variations in the circadian rhythm. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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10 pages, 1093 KiB

Open AccessReview

The Role of Hemoproteins: Hemoglobin, Myoglobin and Neuroglobin in Endogenous Thiosulfate Production Processes

by Anna Bilska-Wilkosz^*

, Małgorzata Iciek, Magdalena Górny and Danuta Kowalczyk-Pachel

Chair of Medical Biochemistry, Jagiellonian University Collegium Medicum ,7 Kopernika Street, Kraków 31-034, Poland

Int. J. Mol. Sci. 2017, 18(6), 1315; https://doi.org/10.3390/ijms18061315 - 20 Jun 2017

Cited by 28 | Viewed by 8644

Abstract

Thiosulfate formation and biodegradation processes link aerobic and anaerobic metabolism of cysteine. In these reactions, sulfite formed from thiosulfate is oxidized to sulfate while hydrogen sulfide is transformed into thiosulfate. These processes occurring mostly in mitochondria are described as a canonical hydrogen sulfide [...] Read more.

Thiosulfate formation and biodegradation processes link aerobic and anaerobic metabolism of cysteine. In these reactions, sulfite formed from thiosulfate is oxidized to sulfate while hydrogen sulfide is transformed into thiosulfate. These processes occurring mostly in mitochondria are described as a canonical hydrogen sulfide oxidation pathway. In this review, we discuss the current state of knowledge on the interactions between hydrogen sulfide and hemoglobin, myoglobin and neuroglobin and postulate that thiosulfate is a metabolically important product of this processes. Hydrogen sulfide oxidation by ferric hemoglobin, myoglobin and neuroglobin has been defined as a non-canonical hydrogen sulfide oxidation pathway. Until recently, it appeared that the goal of thiosulfate production was to delay irreversible oxidation of hydrogen sulfide to sulfate excreted in urine; while thiosulfate itself was only an intermediate, transient metabolite on the hydrogen sulfide oxidation pathway. In the light of data presented in this paper, it seems that thiosulfate is a molecule that plays a prominent role in the human body. Thus, we hope that all these findings will encourage further studies on the role of hemoproteins in the formation of this undoubtedly fascinating molecule and on the mechanisms responsible for its biological activity in the human body. Full article

(This article belongs to the Special Issue Metalloproteins 2017)

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17 pages, 2972 KiB

Open AccessReview

Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches

by Leticia De las Vecillas Sánchez^1,2, Leila A. Alenazy^1,3,4, Marlene Garcia-Neuer¹ and Mariana C. Castells^1,*

¹ Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA

² Department of Allergy, Marqués de Valdecilla University Hospital-IDIVAL, 39011 Santander, Spain

³ Department of Medicine, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia

⁴ Master of Medical Sciences in Immunology Program, Harvard Medical School, Boston, MA 02115, USA

Int. J. Mol. Sci. 2017, 18(6), 1316; https://doi.org/10.3390/ijms18061316 - 20 Jun 2017

Cited by 112 | Viewed by 16428

Abstract

Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross [...] Read more.

Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross reactivity with environmental allergens. Avoidance of the offending allergenic drug may impact disease management, quality of life, and life expectancy. Precision medicine provides new tools for the understanding and management of hypersensitivity reactions (HSRs), as well as a personalized treatment approach for IgE (Immunoglobuline E) and non-IgE mediated HSRs with drug desensitization (DS). DS induces a temporary hyporesponsive state by incremental escalation of sub-optimal doses of the offending drug. In vitro models have shown evidence that IgE desensitization is an antigen-specific process which blocks calcium flux, impacts antigen/IgE/FcεRI complex internalization and prevents the acute and late phase reactions as well as mast cell mediator release. Through a “bench to bedside” approach, in vitro desensitization models help elucidate the molecular pathways involved in DS, providing new insights to improved desensitization protocols for all patients. The aim of this review is to summarize up to date information on the drug HSRs, the IgE mediated mechanisms of desensitization, and their clinical applications. Full article

(This article belongs to the Special Issue Drug Hypersensitivity)

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16 pages, 2068 KiB

Open AccessArticle

The Protease Inhibitor CI2c Gene Induced by Bird Cherry-Oat Aphid in Barley Inhibits Green Peach Aphid Fecundity in Transgenic Arabidopsis

by Aleksandra Losvik^†, Lisa Beste^†, Sara Mehrabi and Lisbeth Jonsson^*

¹ Department of Ecology, Environment and Plant Sciences, Stockholm University, 106 91 Stockholm, Sweden

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1317; https://doi.org/10.3390/ijms18061317 - 20 Jun 2017

Cited by 14 | Viewed by 5350

Abstract

Aphids are phloem feeders that cause large damage globally as pest insects. They induce a variety of responses in the host plant, but not much is known about which responses are promoting or inhibiting aphid performance. Here, we investigated whether one of the [...] Read more.

Aphids are phloem feeders that cause large damage globally as pest insects. They induce a variety of responses in the host plant, but not much is known about which responses are promoting or inhibiting aphid performance. Here, we investigated whether one of the responses induced in barley by the cereal aphid, bird cherry-oat aphid (Rhopalosiphum padi L.) affects aphid performance in the model plant Arabidopsis thaliana L. A barley cDNA encoding the protease inhibitor CI2c was expressed in A. thaliana and aphid performance was studied using the generalist green peach aphid (Myzus persicae Sulzer). There were no consistent effects on aphid settling or preference or on parameters of life span and long-term fecundity. However, short-term tests with apterous adult aphids showed lower fecundity on three of the transgenic lines, as compared to on control plants. This effect was transient, observed on days 5 to 7, but not later. The results suggest that the protease inhibitor is taken up from the tissue during probing and weakly inhibits fecundity by an unknown mechanism. The study shows that a protease inhibitor induced in barley by an essentially monocot specialist aphid can inhibit a generalist aphid in transgenic Arabidopsis. Full article

(This article belongs to the Special Issue Plant Defense Genes Against Biotic Stresses)

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18 pages, 3030 KiB

Open AccessArticle

Fluorescence Analysis of Vitamin D Receptor Status of Circulating Tumor Cells (CTCS) in Breast Cancer: From Cell Models to Metastatic Patients

by Xi Zhang¹, Simone Hofmann¹, Brigitte Rack¹, Nadia Harbeck¹, Udo Jeschke¹

and Sophie Sixou^1,2,*

¹ Department of Obstetrics and Gynaecology, Breast Center, Ludwig-Maximilians University of Munich (LMU), Maistrasse 11, Munich 80337, Germany

² Faculty of Pharmacy, University Paul Sabatier Toulouse III, Toulouse cedex 09 31062, France

Int. J. Mol. Sci. 2017, 18(6), 1318; https://doi.org/10.3390/ijms18061318 - 20 Jun 2017

Cited by 11 | Viewed by 7436

Abstract

The Vitamin D receptor (VDR) expressed in normal breast tissue and breast tumors has been suggested as a new prognostic biomarker in breast cancer (BC). Besides, increasing evidence supports the view that the detection of circulating tumor cells (CTCs) predicts outcome in early [...] Read more.

The Vitamin D receptor (VDR) expressed in normal breast tissue and breast tumors has been suggested as a new prognostic biomarker in breast cancer (BC). Besides, increasing evidence supports the view that the detection of circulating tumor cells (CTCs) predicts outcome in early and metastatic BC. Consequently, an evaluation of VDR expression in the CTCs of BC patients may allow optimization of their treatment. As an attempt to profile and subtype the CTCs of metastatic patients, we established an innovative fluorescence technique using nine BC cell lines to visualize, define, and compare their individual VDR status. Afterwards, we tested the CTC presence and VDR expression in blood samples (cytospins) collected from 23 metastatic BC patients. The results demonstrated major differences in the VDR levels among the nine cell lines, and VDR positive CTCs were detected in 46% of CTC-positive patients, with a total of 42 CTCs individually analyzed. Due to the limited number of patients in this study, no correlation between VDR expression and BC subtype classification (according to estrogen receptor (ER), progesterone receptor (PR) and HER2) could be determined, but our data support the view that VDR evaluation is a potential new prognostic biomarker to help in the optimization of therapy management for BC patients. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects and Therapeutic Uses)

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17 pages, 656 KiB

Open AccessReview

The Intersection of NGF/TrkA Signaling and Amyloid Precursor Protein Processing in Alzheimer’s Disease Neuropathology

by Nadia Canu^1,2,†, Giuseppina Amadoro^3,†, Viviana Triaca^2,†, Valentina Latina³, Valentina Sposato⁴, Veronica Corsetti⁴, Cinzia Severini², Maria Teresa Ciotti² and Pietro Calissano^4,*

¹ Department of System Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00137 Rome, Italy

² Institute of Cellular Biology and Neurobiology, National Council of Research Rome, Via del Fosso del Fiorano 64, 00143 Rome, Italy

³ Institute of Translational Pharmacology, National Research Council (CNR) Rome, Via Fosso del Cavaliere 100, 00133 Rome, Italy

⁴ European Brain Research Institute Rome, Via del Fosso del Fiorano 64, 00143 Rome, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1319; https://doi.org/10.3390/ijms18061319 - 20 Jun 2017

Cited by 56 | Viewed by 11790

Abstract

Dysfunction of nerve growth factor (NGF) and its high-affinity Tropomyosin receptor kinase A (TrkA) receptor has been suggested to contribute to the selective degeneration of basal forebrain cholinergic neurons (BFCN) associated with the progressive cognitive decline in Alzheimer's disease (AD). The aim of [...] Read more.

Dysfunction of nerve growth factor (NGF) and its high-affinity Tropomyosin receptor kinase A (TrkA) receptor has been suggested to contribute to the selective degeneration of basal forebrain cholinergic neurons (BFCN) associated with the progressive cognitive decline in Alzheimer's disease (AD). The aim of this review is to describe our progress in elucidating the molecular mechanisms underlying the dynamic interplay between NGF/TrkA signaling and amyloid precursor protein (APP) metabolism within the context of AD neuropathology. This is mainly based on the finding that TrkA receptor binding to APP depends on a minimal stretch of ~20 amino acids located in the juxtamembrane/extracellular domain of APP that carries the α- and β-secretase cleavage sites. Here, we provide evidence that: (i) NGF could be one of the “routing” proteins responsible for modulating the metabolism of APP from amyloidogenic towards non-amyloidogenic processing via binding to the TrkA receptor; (ii) the loss of NGF/TrkA signaling could be linked to sporadic AD contributing to the classical hallmarks of the neuropathology, such as synaptic loss, β-amyloid peptide (Aβ) deposition and tau abnormalities. These findings will hopefully help to design therapeutic strategies for AD treatment aimed at preserving cholinergic function and anti-amyloidogenic activity of the physiological NGF/TrkA pathway in the septo-hippocampal system. Full article

(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)

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14 pages, 3249 KiB

Open AccessArticle

Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis

by Jun Hee Lee¹, Yeo Min Yoon² and Sang Hun Lee^2,3,*

¹ Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA

² Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 336-745, Korea

³ Departments of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 330-930, Korea

Int. J. Mol. Sci. 2017, 18(6), 1320; https://doi.org/10.3390/ijms18061320 - 21 Jun 2017

Cited by 126 | Viewed by 8221

Abstract

Mesenchymal stem cells (MSC) are ideal materials for stem cell-based therapy. As MSCs reside in hypoxic microenvironments (low oxygen tension of 1% to 7%), several studies have focused on the beneficial effects of hypoxic preconditioning on MSC survival; however, the mechanisms underlying such [...] Read more.

Mesenchymal stem cells (MSC) are ideal materials for stem cell-based therapy. As MSCs reside in hypoxic microenvironments (low oxygen tension of 1% to 7%), several studies have focused on the beneficial effects of hypoxic preconditioning on MSC survival; however, the mechanisms underlying such effects remain unclear. This study aimed to uncover the potential mechanism involving 78-kDa glucose-regulated protein (GRP78) to explain the enhanced MSC bioactivity and survival in hindlimb ischemia. Under hypoxia (2% O₂), the expression of GRP78 was significantly increased via hypoxia-inducible factor (HIF)-1α. Hypoxia-induced GRP78 promoted the proliferation and migration potential of MSCs through the HIF-1α-GRP78-Akt signal axis. In a murine hind-limb ischemia model, hypoxic preconditioning enhanced the survival and proliferation of transplanted MSCs through suppression of the cell death signal pathway and augmentation of angiogenic cytokine secretion. These effects were regulated by GRP78. Our findings indicate that hypoxic preconditioning promotes survival, proliferation, and angiogenic cytokine secretion of MSCs via the HIF-1α-GRP78-Akt signal pathway, suggesting that hypoxia-preconditioned MSCs might provide a therapeutic strategy for MSC-based therapies and that GRP78 represents a potential target for the development of functional MSCs. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 1108 KiB

Open AccessReview

Adiponectin, a Therapeutic Target for Obesity, Diabetes, and Endothelial Dysfunction

by Arunkumar E. Achari and Sushil K. Jain^*

Department of Pediatrics, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103, USA

Int. J. Mol. Sci. 2017, 18(6), 1321; https://doi.org/10.3390/ijms18061321 - 21 Jun 2017

Cited by 945 | Viewed by 44711

Abstract

Adiponectin is the most abundant peptide secreted by adipocytes, whose reduction plays a central role in obesity-related diseases, including insulin resistance/type 2 diabetes and cardiovascular disease. In addition to adipocytes, other cell types, such as skeletal and cardiac myocytes and endothelial cells, can [...] Read more.

Adiponectin is the most abundant peptide secreted by adipocytes, whose reduction plays a central role in obesity-related diseases, including insulin resistance/type 2 diabetes and cardiovascular disease. In addition to adipocytes, other cell types, such as skeletal and cardiac myocytes and endothelial cells, can also produce this adipocytokine. Adiponectin effects are mediated by adiponectin receptors, which occur as two isoforms (AdipoR1 and AdipoR2). Adiponectin has direct actions in liver, skeletal muscle, and the vasculature.Adiponectin exists in the circulation as varying molecular weight forms, produced by multimerization. Several endoplasmic reticulum ER-associated proteins, including ER oxidoreductase 1-α (Ero1-α), ER resident protein 44 (ERp44), disulfide-bond A oxidoreductase-like protein (DsbA-L), and glucose-regulated protein 94 (GPR94), have recently been found to be involved in the assembly and secretion of higher-order adiponectin complexes. Recent data indicate that the high-molecular weight (HMW) complexes have the predominant action in metabolic tissues. Studies have shown that adiponectin administration in humans and rodents has insulin-sensitizing, anti-atherogenic, and anti-inflammatory effects, and, in certain settings, also decreases body weight. Therefore, adiponectin replacement therapy in humans may suggest potential versatile therapeutic targets in the treatment of obesity, insulin resistance/type 2 diabetes, and atherosclerosis. The current knowledge on regulation and function of adiponectin in obesity, insulin resistance, and cardiovascular disease is summarized in this review. Full article

(This article belongs to the Special Issue Adipokines)

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14 pages, 3252 KiB

Open AccessArticle

Identification and Validation of Reference Genes for Seashore Paspalum Response to Abiotic Stresses

by Yu Liu¹, Jun Liu¹, Lei Xu¹, Hui Lai¹, Yu Chen^1,*, Zhimin Yang¹ and Bingru Huang^2,*

¹ College of Agro-grassland Science, Nanjing Agricultural University, Nanjing 210095, China

² Department of Plant Biology and Pathology, Rutgers University, New Brunswick, NJ 08901, USA

Int. J. Mol. Sci. 2017, 18(6), 1322; https://doi.org/10.3390/ijms18061322 - 21 Jun 2017

Cited by 41 | Viewed by 5181

Abstract

Seashore paspalum (Paspalum vaginatum) is among the most salt- and cadmium-tolerant warm-season perennial grass species widely used as turf or forage. The objective of this study was to select stable reference genes for quantitative real-time polymerase chain reaction (qRT-PCR) analysis of [...] Read more.

Seashore paspalum (Paspalum vaginatum) is among the most salt- and cadmium-tolerant warm-season perennial grass species widely used as turf or forage. The objective of this study was to select stable reference genes for quantitative real-time polymerase chain reaction (qRT-PCR) analysis of seashore paspalum in response to four abiotic stresses. The stability of 12 potential reference genes was evaluated by four programs (geNorm, NormFinder, BestKeeper, and RefFinder). U2AF combined with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) showed stable expression in Cd-treated leaves and cold-treated roots. U2AF and FBOX were the most stable reference genes in Cd-treated roots and cold-treated leaves. In Polyethylene Glycol (PEG)- or salt-treated roots, the reference gene U2AF paired with either ACT or CYP were stable. SAND and CACS exhibited the most stability in salt-treated leaves, and combining UPL, PP2A, and EF1a was most suitable for PEG-treated leaves. The stability of U2AF and instability of UPL and TUB was validated by analyzing the expression levels of four target genes (MT2a, VP1, PIP1, and Cor413), and were shown to be capable of detecting subtle changes in expression levels of the target genes in seashore paspalum. This study demonstrated that FBOX, U2AF, and PP2A could be used in future molecular studies that aim to understand the mechanisms of abiotic stress tolerance in seashore paspalum. Full article

(This article belongs to the Section Molecular Plant Sciences)

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17 pages, 2271 KiB

Open AccessArticle

Diverse Regulation of Vitamin D Receptor Gene Expression by 1,25-Dihydroxyvitamin D and ATRA in Murine and Human Blood Cells at Early Stages of Their Differentiation

by Sylwia Janik^1,†, Urszula Nowak^2,†, Agnieszka Łaszkiewicz¹, Anastasiia Satyr², Michał Majkowski¹, Aleksandra Marchwicka², Łukasz Śnieżewski¹, Klaudia Berkowska², Marian Gabryś³, Małgorzata Cebrat¹ and Ewa Marcinkowska^2,*

¹ Laboratory of Molecular and Cellular Immunology, Department of Tumor Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Science, Weigla 12, 53-114 Wrocław, Poland

² Laboratory of Protein Biochemistry, Faculty of Biotechnology, University of Wrocław, Joliot-Curie 14a, 50-383 Wrocław, Poland

³ First Department of Obstetrics and Gynecology, Wrocław Medical University, Chałubińskiego 3, 50-368 Wrocław, Poland

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(6), 1323; https://doi.org/10.3390/ijms18061323 - 21 Jun 2017

Cited by 17 | Viewed by 8871

Abstract

Vitamin D receptor (VDR) is present in multiple blood cells, and the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is essential for the proper functioning of the immune system. The role of retinoic acid receptor α (RARα) in hematopoiesis is very important, [...] Read more.

Vitamin D receptor (VDR) is present in multiple blood cells, and the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is essential for the proper functioning of the immune system. The role of retinoic acid receptor α (RARα) in hematopoiesis is very important, as the fusion of RARα gene with PML gene initiates acute promyelocytic leukemia where differentiation of the myeloid lineage is blocked, followed by an uncontrolled proliferation of leukemic blasts. RARα takes part in regulation of VDR transcription, and unliganded RARα acts as a transcriptional repressor to VDR gene in acute myeloid leukemia (AML) cells. This is why we decided to examine the effects of the combination of 1,25D and all-trans-retinoic acid (ATRA) on VDR gene expression in normal human and murine blood cells at various steps of their development. We tested the expression of VDR and regulation of this gene in response to 1,25D or ATRA, as well as transcriptional activities of nuclear receptors VDR and RARs in human and murine blood cells. We discovered that regulation of VDR expression in humans is different from in mice. In human blood cells at early stages of their differentiation ATRA, but not 1,25D, upregulates the expression of VDR. In contrast, in murine blood cells 1,25D, but not ATRA, upregulates the expression of VDR. VDR and RAR receptors are present and transcriptionally active in blood cells of both species, especially at early steps of blood development. Full article

(This article belongs to the Special Issue The Biology and Treatment of Myeloid Leukaemias)

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12 pages, 875 KiB

Open AccessReview

Immune Checkpoints as a Target for Colorectal Cancer Treatment

by Alessandro Passardi¹

, Matteo Canale², Martina Valgiusti¹ and Paola Ulivi^2,*

¹ Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy

² Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy

Int. J. Mol. Sci. 2017, 18(6), 1324; https://doi.org/10.3390/ijms18061324 - 21 Jun 2017

Cited by 120 | Viewed by 11321

Abstract

Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, [...] Read more.

Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies. We present an updated review of the biological background and clinical development of immune checkpoint inhibitors in colorectal cancer (CRC). Early trial results on PD1 and PD-L1 blockade appear promising, especially in CRC patients with microsatellite instability (MSI). Clinical trials are ongoing to confirm these preliminary results, evaluate combination strategies and identify biomarkers to predict which patients are most likely to benefit from, or show resistance to, the effects of checkpoint inhibition. Full article

(This article belongs to the Special Issue Latest Advances in Colorectal Cancer Research: Molecular Mechanisms and Therapies)

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15 pages, 1794 KiB

Open AccessReview

New Insights in Thyroid Cancer and p53 Family Proteins

by Livia Manzella^1,*, Stefania Stella¹, Maria Stella Pennisi¹, Elena Tirrò¹

, Michele Massimino¹, Chiara Romano¹, Adriana Puma¹, Martina Tavarelli² and Paolo Vigneri¹

¹ Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy

² Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi Nesima Medical Center, University of Catania, 95122 Catania, Italy

Int. J. Mol. Sci. 2017, 18(6), 1325; https://doi.org/10.3390/ijms18061325 - 21 Jun 2017

Cited by 75 | Viewed by 9870

Abstract

Thyroid cancers are common endocrine malignancies that comprise tumors with different clinical and histological features. Indeed, papillary and follicular thyroid cancers are slow-growing, well-differentiated tumors, whereas anaplastic thyroid cancers are undifferentiated neoplasias that behave much more aggressively. Well-differentiated thyroid carcinomas are efficiently cured [...] Read more.

Thyroid cancers are common endocrine malignancies that comprise tumors with different clinical and histological features. Indeed, papillary and follicular thyroid cancers are slow-growing, well-differentiated tumors, whereas anaplastic thyroid cancers are undifferentiated neoplasias that behave much more aggressively. Well-differentiated thyroid carcinomas are efficiently cured by surgery and radioiodine, unlike undifferentiated tumors that fail to uptake radioactive iodine and are usually resistant to chemotherapy. Therefore, novel and more effective therapies for these aggressive neoplasias are urgently needed. Whereas most genetic events underlying the pathogenesis of well-differentiated thyroid cancers have been identified, the molecular mechanisms that generate undifferentiated thyroid carcinomas are still unclear. To date, one of the best-characterized genetic alterations leading to the development of poorly differentiated thyroid tumors is the loss of the p53 tumor suppressor gene. In addition, the existence of a complex network among p53 family members (p63 and p73) and their interactions with other factors that promote thyroid cancer progression has been well documented. In this review, we provide an update on the current knowledge of the role of p53 family proteins in thyroid cancer and their possible use as a therapeutic target for the treatment of the most aggressive variants of this disease. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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17 pages, 1099 KiB

Open AccessArticle

Adolescent Exposure to the Synthetic Cannabinoid WIN 55212-2 Modifies Cocaine Withdrawal Symptoms in Adult Mice

by María A. Aguilar^*

, Juan Carlos Ledesma^*, Marta Rodríguez-Arias, Carles Penalva, Carmen Manzanedo, José Miñarro and M. Carmen Arenas

Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibáñez 21, 46010 Valencia, Spain

Int. J. Mol. Sci. 2017, 18(6), 1326; https://doi.org/10.3390/ijms18061326 - 21 Jun 2017

Cited by 15 | Viewed by 7070

Abstract

Chronic cannabinoid consumption is an increasingly common behavior among teenagers and has been shown to cause long-lasting neurobehavioral alterations. Besides, it has been demonstrated that cocaine addiction in adulthood is highly correlated with cannabis abuse during adolescence. Cocaine consumption and subsequent abstinence from [...] Read more.

Chronic cannabinoid consumption is an increasingly common behavior among teenagers and has been shown to cause long-lasting neurobehavioral alterations. Besides, it has been demonstrated that cocaine addiction in adulthood is highly correlated with cannabis abuse during adolescence. Cocaine consumption and subsequent abstinence from it can cause psychiatric symptoms, such as psychosis, cognitive impairment, anxiety, and depression. The aim of the present research was to study the consequences of adolescent exposure to cannabis on the psychiatric-like effects promoted by cocaine withdrawal in adult mice. We pre-treated juvenile mice with the cannabinoid CB1 receptor agonist WIN 55212-2 (WIN) and then subjected them to a chronic cocaine treatment during adulthood. Following these treatments, animals were tested under cocaine withdrawal in the following paradigms: pre-pulse inhibition, object recognition, elevated plus maze, and tail suspension. The long-term psychotic-like actions induced by WIN were not modified after cocaine cessation. Moreover, the memory impairments induced by cocaine withdrawal were not altered by previous adolescent WIN intake. However, WIN pre-treatment prevented the anxiogenic effects observed after cocaine abstinence, and led to greater depressive-like symptoms following cocaine removal in adulthood. This study is the first to show the long-lasting behavioral consequences of juvenile exposure to WIN on cocaine withdrawal in adult mice. Full article

(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)

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30 pages, 1313 KiB

Open AccessReview

Fucaceae: A Source of Bioactive Phlorotannins

by Marcelo D. Catarino

, Artur M. S. Silva

and Susana M. Cardoso^*

Department of Chemistry & Organic Chemistry, Natural Products and Food Stuffs Research Unit (QOPNA), University of Aveiro, Aveiro 3810-193, Portugal

Int. J. Mol. Sci. 2017, 18(6), 1327; https://doi.org/10.3390/ijms18061327 - 21 Jun 2017

Cited by 122 | Viewed by 10055

Abstract

Fucaceae is the most dominant algae family along the intertidal areas of the Northern Hemisphere shorelines, being part of human customs for centuries with applications as a food source either for humans or animals, in agriculture and as remedies in folk medicine. These [...] Read more.

Fucaceae is the most dominant algae family along the intertidal areas of the Northern Hemisphere shorelines, being part of human customs for centuries with applications as a food source either for humans or animals, in agriculture and as remedies in folk medicine. These macroalgae are endowed with several phytochemicals of great industrial interest from which phlorotannins, a class of marine-exclusive polyphenols, have gathered much attention during the last few years due to their numerous possible therapeutic properties. These compounds are very abundant in brown seaweeds such as Fucaceae and have been demonstrated to possess numerous health-promoting properties, including antioxidant effects through scavenging of reactive oxygen species (ROS) or enhancement of intracellular antioxidant defenses, antidiabetic properties through their acarbose-like activity, stimulation of adipocytes glucose uptake and protection of β-pancreatic cells against high-glucose oxidative stress; anti-inflammatory effects through inhibition of several pro-inflammatory mediators; antitumor properties by activation of apoptosis on cancerous cells and metastasis inhibition, among others. These multiple health properties render phlorotannins great potential for application in numerous therapeutical approaches. This review addresses the major contribution of phlototannins for the biological effects that have been described for seaweeds from Fucaceae. In addition, the bioavailability of this group of phenolic compounds is discussed. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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14 pages, 3932 KiB

Open AccessReview

dIvergEnt: How IgE Axis Contributes to the Continuum of Allergic Asthma and Anti-IgE Therapies

by Óscar Palomares¹, Silvia Sánchez-Ramón^2,3

, Ignacio Dávila⁴, Luis Prieto⁵, Luis Pérez de Llano⁶, Marta Lleonart⁷, Christian Domingo^8,* and Antonio Nieto⁹

¹ Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, 28040 Madrid, Spain

² Department of Clinical Immunology and Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, 28040 Madrid, Spain

³ Department of Microbiology I, Complutense University School of Medicine, 28040 Madrid, Spain

⁴ Allergy Service, University Hospital of Salamanca and Institute for Biomedical Research of Salamanca (IBSAL), Biomedical and Diagnosis Science Department, Salamanca University School of Medicine, 37008 Salamanca, Spain

⁵ Department of Allergy and Immunology, University of Valencia and Dr. Peset University Hospital, 46017 Valencia, Spain

⁶ Neumology Service, Hospital Universitario Lucus Augusti, 27003 Lugo, Spain

⁷ Novartis Farmacéutica, 08013 Barcelona, Spain

⁸ Pulmonary Service, Corporació Sanitària Parc Taulí, Department of Medicine, Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain

⁹ Pediatric Pulmonology & Allergy Unit, Children’s Hospital La Fe, 46026 Valencia, Spain

Int. J. Mol. Sci. 2017, 18(6), 1328; https://doi.org/10.3390/ijms18061328 - 21 Jun 2017

Cited by 61 | Viewed by 10773

Abstract

Asthma is an airway disease characterised by chronic inflammation with intermittent or permanent symptoms including wheezing, shortness of breath, chest tightness, and cough, which vary in terms of their occurrence, frequency, and intensity. The most common associated feature in the airways of patients [...] Read more.

Asthma is an airway disease characterised by chronic inflammation with intermittent or permanent symptoms including wheezing, shortness of breath, chest tightness, and cough, which vary in terms of their occurrence, frequency, and intensity. The most common associated feature in the airways of patients with asthma is airway inflammation. In recent decades, efforts have been made to characterise the heterogeneous clinical nature of asthma. The interest in improving the definitions of asthma phenotypes and endotypes is growing, although these classifications do not always correlate with prognosis nor are always appropriate therapeutic approaches. Attempts have been made to identify the most relevant molecular and cellular biomarkers underlying the immunopathophysiological mechanisms of the disease. For almost 50 years, immunoglobulin E (IgE) has been identified as a central factor in allergic asthma, due to its allergen-specific nature. Many of the mechanisms of the inflammatory cascade underlying allergic asthma have already been elucidated, and IgE has been shown to play a fundamental role in the triggering, development, and chronicity of the inflammatory responses within the disease. Blocking IgE with monoclonal antibodies such as omalizumab have demonstrated their efficacy, effectiveness, and safety in treating allergic asthma. A better understanding of the multiple contributions of IgE to the inflammatory continuum of asthma could contribute to the development of novel therapeutic strategies for the disease. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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16 pages, 2109 KiB

Open AccessArticle

Development of a High-Density SNP-Based Linkage Map and Detection of QTL for β-Glucans, Protein Content, Grain Yield per Spike and Heading Time in Durum Wheat

by Ilaria Marcotuli¹

, Agata Gadaleta^1,*, Giacomo Mangini²

, Antonio Massimo Signorile², Silvana Addolorata Zacheo², Antonio Blanco², Rosanna Simeone² and Pasqualina Colasuonno¹

¹ Department of Agricultural and Environmental Science, University of Bari “Aldo Moro”, Via G. Amendola 165/A, 70126 Bari, Italy

² Department of Soil, Plant and Food Sciences, Section of Genetic and Plant Breeding, University of Bari “Aldo Moro”, Via G. Amendola 165/A, 70126 Bari, Italy

Int. J. Mol. Sci. 2017, 18(6), 1329; https://doi.org/10.3390/ijms18061329 - 21 Jun 2017

Cited by 57 | Viewed by 7212

Abstract

High-density genetic linkage maps of crop species are particularly useful in detecting qualitative and quantitative trait loci for important agronomic traits and in improving the power of classical approaches to identify candidate genes. The aim of this study was to develop a high-density [...] Read more.

High-density genetic linkage maps of crop species are particularly useful in detecting qualitative and quantitative trait loci for important agronomic traits and in improving the power of classical approaches to identify candidate genes. The aim of this study was to develop a high-density genetic linkage map in a durum wheat recombinant inbred lines population (RIL) derived from two elite wheat cultivars and to identify, characterize and correlate Quantitative Trait Loci (QTL) for β-glucan, protein content, grain yield per spike and heading time. A dense map constructed by genotyping the RIL population with the wheat 90K iSelect array included 5444 single nucleotide polymorphism (SNP) markers distributed in 36 linkage groups. Data for β-glucan and protein content, grain yield per spike and heading time were obtained from replicated trials conducted at two locations in southern Italy. A total of 19 QTL were detected in different chromosome regions. In particular, three QTL for β-glucan content were detected on chromosomes 2A and 2B (two loci); eight QTL controlling grain protein content were detected on chromosomes 1B, 2B, 3B (two loci), 4A, 5A, 7A and 7B; seven QTL for grain yield per spike were identified on chromosomes 1A, 2B, 3A (two loci), 3B (two loci) and 6B; and one marker-trait association was detected on chromosome 2A for heading time. The last was co-located with a β-glucan QTL, and the two QTL appeared to be negatively correlated. A genome scan for genomic regions controlling the traits and SNP annotated sequences identified five putative candidate genes involved in different biosynthesis pathways (β-glucosidase, GLU1a; APETALA2, TaAP2; gigantea 3, TaGI3; 14-3-3 protein, Ta14A; and photoperiod sensitivity, Ppd-A1). This study provides additional information on QTL for important agronomic traits that could be useful for marker-assisted breeding to obtain new genotypes with commercial and nutritional relevance. Full article

(This article belongs to the Special Issue Glucan: New Perspectives on Biochemistry and Application)

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14 pages, 663 KiB

Open AccessReview

PD-1/PD-L1 Blockade Therapy for Tumors with Downregulated MHC Class I Expression

by Michal Šmahel

Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, Průmyslová 595, 25250 Vestec, Czech Republic

Int. J. Mol. Sci. 2017, 18(6), 1331; https://doi.org/10.3390/ijms18061331 - 21 Jun 2017

Cited by 64 | Viewed by 15338

Abstract

The therapy of different advanced-stage malignancies with monoclonal antibodies blocking programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling has had an impressive long-lasting effect in a portion of patients, but in most cases, this therapy was not successful, or a secondary [...] Read more.

The therapy of different advanced-stage malignancies with monoclonal antibodies blocking programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling has had an impressive long-lasting effect in a portion of patients, but in most cases, this therapy was not successful, or a secondary resistance developed. To enhance its efficacy in treated patients, predictive biomarkers are searched for and various combination treatments are intensively investigated. As the downregulation of major histocompatibility complex (MHC) class I molecules is one of the most frequent mechanisms of tumor escape from the host’s immunity, it should be considered in PD-1/PD-L1 checkpoint inhibition. The potential for the use of a PD-1/PD-L1 blockade in the treatment of tumors with aberrant MHC class I expression is discussed, and some strategies of combination therapy are suggested. Full article

(This article belongs to the Special Issue Targeting Immune Checkpoints and Immunotherapy)

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Int. J. Mol. Sci., Volume 18, Issue 6 (June 2017) – 228 articles

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