International Journal of Molecular Sciences

Editorial

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4 pages, 417 KiB

Open AccessEditorial

Non-Coding RNAs in Cancer: An Interview with Dr. Martin Pichler

by International Journal of Molecular Sciences Editorial Office

MDPI AG, Klybeckstrasse 64, CH-4057 Basel, Switzerland

Int. J. Mol. Sci. 2016, 17(4), 605; https://doi.org/10.3390/ijms17040605 - 21 Apr 2016

Cited by 1 | Viewed by 5818

Abstract

In this issue, we are pleased and honored to have an interview with Professor Martin Pichler, who is the Collection Editor for the International Journal of Molecular Sciences Topical Collection of “Regulation by Non-Coding RNAs” [1].[...] Full article

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

Research

Jump to: Editorial, Review, Other

12 pages, 6656 KiB

Open AccessArticle

Neutralization of Bacterial YoeB_Spn Toxicity and Enhanced Plant Growth in Arabidopsis thaliana via Co-Expression of the Toxin-Antitoxin Genes

by Fauziah Abu Bakar¹, Chew Chieng Yeo²

and Jennifer Ann Harikrishna^1,*

¹ Centre for Research in Biotechnology for Agriculture (CEBAR) and Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia

² Biomedical Research Centre, Faculty of Medicine, Universiti Sultan Zainal Abidin, Medical Campus, 21300 Kuala Terengganu, Malaysia

Int. J. Mol. Sci. 2016, 17(4), 321; https://doi.org/10.3390/ijms17040321 - 20 Apr 2016

Cited by 4 | Viewed by 5882

Abstract

Bacterial toxin-antitoxin (TA) systems have various cellular functions, including as part of the general stress response. The genome of the Gram-positive human pathogen Streptococcus pneumoniae harbors several putative TA systems, including yefM-yoeB_Spn, which is one of four systems that had been [...] Read more.

Bacterial toxin-antitoxin (TA) systems have various cellular functions, including as part of the general stress response. The genome of the Gram-positive human pathogen Streptococcus pneumoniae harbors several putative TA systems, including yefM-yoeB_Spn, which is one of four systems that had been demonstrated to be biologically functional. Overexpression of the yoeB_Spn toxin gene resulted in cell stasis and eventually cell death in its native host, as well as in Escherichia coli. Our previous work showed that induced expression of a yoeB_Spn toxin-Green Fluorescent Protein (GFP) fusion gene apparently triggered apoptosis and was lethal in the model plant, Arabidopsis thaliana. In this study, we investigated the effects of co-expression of the yefM_Spn antitoxin and yoeB_Spn toxin-GFP fusion in transgenic A. thaliana. When co-expressed in Arabidopsis, the YefM_Spn antitoxin was found to neutralize the toxicity of YoeB_Spn-GFP. Interestingly, the inducible expression of both yefM_Spn antitoxin and yoeB_Spn toxin-GFP fusion in transgenic hybrid Arabidopsis resulted in larger rosette leaves and taller plants with a higher number of inflorescence stems and increased silique production. To our knowledge, this is the first demonstration of a prokaryotic antitoxin neutralizing its cognate toxin in plant cells. Full article

(This article belongs to the Section Molecular Toxicology)

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11 pages, 2529 KiB

Open AccessArticle

Environmental Conditions Influence Induction of Key ABC-Transporter Genes Affecting Glyphosate Resistance Mechanism in Conyza canadensis

by Eleni Tani¹, Demosthenis Chachalis^2,*, Ilias S. Travlos³ and Dimitrios Bilalis³

¹ Laboratory of Plant Breeding, Department of Crop Science, Agricultural University of Athens, Iera Odos 75, 11855 Athens, Greece

² Laboratory of Weed Science, Benaki Phytopathological Institute, S. Delta 8, 14561 Athens, Greece

³ Laboratory of Agronomy, Department of Crop Science, Agricultural University of Athens, Iera Odos 75, 11855 Athens, Greece

Int. J. Mol. Sci. 2016, 17(4), 342; https://doi.org/10.3390/ijms17040342 - 20 Apr 2016

Cited by 22 | Viewed by 6498

Abstract

Conyza canadensis has been reported to be the most frequent weed species that evolved resistance to glyphosate in various parts of the world. The objective of the present study was to investigate the effect of environmental conditions (temperature and light) on the expression [...] Read more.

Conyza canadensis has been reported to be the most frequent weed species that evolved resistance to glyphosate in various parts of the world. The objective of the present study was to investigate the effect of environmental conditions (temperature and light) on the expression levels of the EPSPS gene and two major ABC-transporter genes (M10 and M11) on glyphosate susceptible (GS) and glyphosate resistant (GR) horseweed populations, collected from several regions across Greece. Real-time PCR was conducted to determine the expression level of the aforementioned genes when glyphosate was applied at normal (1×; 533 g·a.e.·ha⁻¹) and high rates (4×, 8×), measured at an early one day after treatment (DAT) and a later stage (four DAT) of expression. Plants were exposed to light or dark conditions, at three temperature regimes (8, 25, 35 °C). GR plants were made sensitive when exposed to 8 °C with light; those sensitized plants behaved biochemically (shikimate accumulation) and molecularly (expression of EPSPS and ABC-genes) like the GS plants. Results from the current study show the direct link between the environmental conditions and the induction level of the above key genes that likely affect the efficiency of the proposed mechanism of glyphosate resistance. Full article

(This article belongs to the Special Issue Effects of Herbicides and Heavy Metals to the Structure and Function of Plant Cells)

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13 pages, 3115 KiB

Open AccessArticle

pH-Responsive Hyaluronic Acid-Based Mixed Micelles for the Hepatoma-Targeting Delivery of Doxorubicin

by Jing-Liang Wu^*, Gui-Xiang Tian, Wen-Jing Yu, Guang-Tao Jia, Tong-Yi Sun and Zhi-Qin Gao^*

School of Bioscience and Technology, Weifang Medical University, Wei Fang 261053, Shandong, China

Int. J. Mol. Sci. 2016, 17(4), 364; https://doi.org/10.3390/ijms17040364 - 30 Mar 2016

Cited by 49 | Viewed by 9903

Abstract

The tumor targetability and stimulus responsivity of drug delivery systems are crucial in cancer diagnosis and treatment. In this study, hepatoma-targeting mixed micelles composed of a hyaluronic acid–glycyrrhetinic acid conjugate and a hyaluronic acid-l-histidine conjugate (HA–GA/HA–His) were prepared through ultrasonic dispersion. [...] Read more.

The tumor targetability and stimulus responsivity of drug delivery systems are crucial in cancer diagnosis and treatment. In this study, hepatoma-targeting mixed micelles composed of a hyaluronic acid–glycyrrhetinic acid conjugate and a hyaluronic acid-l-histidine conjugate (HA–GA/HA–His) were prepared through ultrasonic dispersion. The formation and characterization of the mixed micelles were confirmed via ¹H-NMR, particle size, and ζ potential measurements. The in vitro cellular uptake of the micelles was evaluated using human liver carcinoma (HepG2) cells. The antitumor effect of doxorubicin (DOX)-loaded micelles was investigated in vitro and in vivo. Results indicated that the DOX-loaded HA–GA/HA–His micelles showed a pH-dependent controlled release and were remarkably absorbed by HepG2 cells. Compared with free DOX, the DOX-loaded HA–GA/HA–His micelles showed a higher cytotoxicity to HepG2 cells. Moreover, the micelles effectively inhibited tumor growth in H22 cell-bearing mice. These results suggest that the HA–GA/HA–His mixed micelles are a good candidate for drug delivery in the prevention and treatment of hepatocarcinoma. Full article

(This article belongs to the Special Issue Drug Delivery and Antimicrobial Agents)

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13 pages, 2333 KiB

Open AccessArticle

RTN3 Regulates the Expression Level of Chemokine Receptor CXCR4 and is Required for Migration of Primordial Germ Cells

by Haitao Li, Rong Liang, Yanan Lu, Mengxia Wang and Zandong Li^*

State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China

Int. J. Mol. Sci. 2016, 17(4), 382; https://doi.org/10.3390/ijms17040382 - 8 Apr 2016

Cited by 25 | Viewed by 7068

Abstract

CXCR4 is a crucial chemokine receptor that plays key roles in primordial germ cell (PGC) homing. To further characterize the CXCR4-mediated migration of PGCs, we screened CXCR4-interacting proteins using yeast two-hybrid screening. We identified reticulon3 (RTN3), a member of the reticulon family, and [...] Read more.

CXCR4 is a crucial chemokine receptor that plays key roles in primordial germ cell (PGC) homing. To further characterize the CXCR4-mediated migration of PGCs, we screened CXCR4-interacting proteins using yeast two-hybrid screening. We identified reticulon3 (RTN3), a member of the reticulon family, and considered an apoptotic signal transducer, as able to interact directly with CXCR4. Furthermore, we discovered that the mRNA and protein expression levels of CXCR4 could be regulated by RTN3. We also found that RTN3 altered CXCR4 translocation and localization. Moreover, increasing the signaling of either CXCR4b or RTN3 produced similar PGC mislocalization phenotypes in zebrafish. These results suggested that RTN3 modulates PGC migration through interaction with, and regulation of, CXCR4. Full article

(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)

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14 pages, 8407 KiB

Open AccessArticle

Starvation after Cobalt-60 γ-Ray Radiation Enhances Metastasis in U251 Glioma Cells by Regulating the Transcription Factor SP1

by Tuo Zhao, Hailong Wang, Hong Ma, Hao Wang, Bo Chen and Yulin Deng^*

School of Life Science, Beijing Institute of Technology, Beijing 100081, China

Int. J. Mol. Sci. 2016, 17(4), 386; https://doi.org/10.3390/ijms17040386 - 5 Apr 2016

Cited by 9 | Viewed by 6069

Abstract

Radiation is of clinical importance during glioma therapy; however, vasculature damage is observed over the treatment course. This type of tissue damage might lead to starvation conditions, affecting tumor metastasis. To test this possibility, we compared starvation conditions in conjunction with radiation treatment [...] Read more.

Radiation is of clinical importance during glioma therapy; however, vasculature damage is observed over the treatment course. This type of tissue damage might lead to starvation conditions, affecting tumor metastasis. To test this possibility, we compared starvation conditions in conjunction with radiation treatment to monitor metastatic ability in the U251 glioma cell line. Transcriptome, western blot, and immunofluorescence analyses were used to measure the RNA and protein expression changes of the U251 cells after various treatments. We found that starvation combined with radiation treatment yielded the most significant expression changes in metastasis-related factors compared to that in the control groups. In addition, a metastasis assay was used to directly measure the metastatic ability of the treated cells, which confirmed that the U251 cells treated with starvation combined with radiation possessed the highest metastatic ability. Furthermore, bioinformatics analysis demonstrated that SP1 represented a common transcription factor associated with changes in metastasis-related factors. Blocking SP1 activity by an inhibitor suppressed the starvation-plus-radiation treatment-mediated enhancement of U251 cell metastasis. Our study provides the first evidence that starvation caused by radiation might play a significant role in enhancing the ability of the glioma cell line U251 to metastasize via regulation of the transcription factor SP1. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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17 pages, 431 KiB

Open AccessArticle

Identification of Serum Peptidome Signatures of Non-Small Cell Lung Cancer

by Agnieszka Klupczynska¹, Agata Swiatly¹, Joanna Hajduk¹, Jan Matysiak¹

, Wojciech Dyszkiewicz², Krystian Pawlak² and Zenon J. Kokot^1,*

¹ Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6 Street, 60-780 Poznan, Poland

² Department of Thoracic Surgery, Poznan University of Medical Sciences, Szamarzewskiego 62 Street, 60-569 Poznan, Poland

Int. J. Mol. Sci. 2016, 17(4), 410; https://doi.org/10.3390/ijms17040410 - 31 Mar 2016

Cited by 19 | Viewed by 6692

Abstract

Due to high mortality rates of lung cancer, there is a need for identification of new, clinically useful markers, which improve detection of this tumor in early stage of disease. In the current study, serum peptide profiling was evaluated as a diagnostic tool [...] Read more.

Due to high mortality rates of lung cancer, there is a need for identification of new, clinically useful markers, which improve detection of this tumor in early stage of disease. In the current study, serum peptide profiling was evaluated as a diagnostic tool for non-small cell lung cancer patients. The combination of the ZipTip technology with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for the analysis of peptide pattern of cancer patients (n = 153) and control subjects (n = 63) was presented for the first time. Based on the observed significant differences between cancer patients and control subjects, the classification model was created, which allowed for accurate group discrimination. The model turned out to be robust enough to discriminate a new validation set of samples with satisfactory sensitivity and specificity. Two peptides from the diagnostic pattern for non-small cell lung cancer (NSCLC) were identified as fragments of C3 and fibrinogen α chain. Since ELISA test did not confirm significant differences in the expression of complement component C3, further study will involve a quantitative approach to prove clinical utility of the other proteins from the proposed multi-peptide cancer signature. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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14 pages, 4136 KiB

Open AccessArticle

Intra-Articular Injection of Cross-Linked Hyaluronic Acid-Dexamethasone Hydrogel Attenuates Osteoarthritis: An Experimental Study in a Rat Model of Osteoarthritis

by Zhiwei Zhang^1,*

, Xiaochun Wei¹, Jizong Gao², Yu Zhao¹, Yamin Zhao², Li Guo¹, Chongwei Chen^1,3, Zhiqing Duan¹, Pengcui Li¹ and Lei Wei^1,3,*

¹ Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Department of Orthopedics, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Taiyuan 030001, China

² BioRegen Biomedical (Changzhou) Co. Ltd., 167-5 East East Road, Changzhou 213025, China

³ Department of Orthopedics, Warren Alpert Medical School of Brown University, Suite 402A, 1 Hoppin Street, Providence, RI 02903, USA

Int. J. Mol. Sci. 2016, 17(4), 411; https://doi.org/10.3390/ijms17040411 - 15 Apr 2016

Cited by 70 | Viewed by 12618

Abstract

Cross-linked hyaluronic acid hydrogel (cHA gel) and dexamethasone (Dex) have been used to treat knee osteoarthritis (OA) in clinical practice owing to their chondroprotective and anti-inflammatory effects, respectively. The aim of the present study was to compare the treatment effects of the cHA [...] Read more.

Cross-linked hyaluronic acid hydrogel (cHA gel) and dexamethasone (Dex) have been used to treat knee osteoarthritis (OA) in clinical practice owing to their chondroprotective and anti-inflammatory effects, respectively. The aim of the present study was to compare the treatment effects of the cHA gel pre-mixed with/without Dex in a surgery-induced osteoarthritis model in rats. Anterior cruciate ligament transection (ACLT) surgery was performed on the right knee of rats to induce OA. Male 2-month-old Sprague-Dawley rats were randomly divided into five groups (n = 10/per group): (1) ACLT + saline; (2) ACLT + cHA gel; (3) ACLT + cHA-Dex (0.2 mg/mL) gel; (4) ACLT + cHA-Dex (0.5 mg/mL) gel; (5) Sham + saline. Intra-joint injections were performed four weeks after ACLT in the right knee. All animals were euthanized at 12 weeks post-surgery. Cartilage damage and changes in the synovial membrane were assessed by micro X-ray, Indian ink articular surface staining, Safranin-O/Fast Green staining, immunohistochemistry, hematoxylin and eosin staining of the synovial membrane, and quantitative reverse transcription-polymerase chain reaction for changes in gene expression. Micro X-ray revealed that the knee joint treated with the cHA-Dex gel was wider than those treated with cHA gel alone or saline. The cHA-Dex gel group had less Indian ink staining (indicator of cartilage fibrillation) than the cHA gel or saline injection groups. Safranin-O/Fast Green staining indicated that increased proteoglycan staining and less cartilage damage were found in the cHA-Dex gel group compared with the cHA gel or saline injection groups. Quantification of histology findings from saline, cHA gel, cHA-Dex (0.2 mg/mL) gel, cHA-Dex (0.5 mg/mL) gel, and sham groups were 5.84 ± 0.29, 4.50 ± 0.87, 3.00 ± 1.00, 2.00 ± 0.48, and 0.30 ± 0.58 (p < 0.05), respectively. A strong staining of type II collagen was found in both the cHA-Dex gel groups compared with saline group or cHA alone group. Similar result was found for the mRNA level of aggrecan and opposite result for type X collagen. Hematoxylin and eosin staining in the synovial membrane showed less synovial lining cell layers and reduced inflammatory cell infiltration in cHA-Dex gel-treated animals compared with saline or cHA only groups. Altogether, cHA-Dex gel has better chondroprotective and anti-inflammatory effects in rat surgery-induced osteoarthritis than cHA alone. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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16 pages, 2659 KiB

Open AccessArticle

Comparative Analysis of Volatile Composition in Chinese Truffles via GC × GC/HR-TOF/MS and Electronic Nose

by Ning Zhang¹

, Haitao Chen^2,*, Baoguo Sun^3,*, Xueying Mao¹, Yuyu Zhang⁴ and Ying Zhou⁵

¹ College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China

² Beijing Laboratory for Food Quality and Safety, Beijing Technology and Business University (BTBU), Beijing 100048, China

³ Beijing Advanced Innovation Center for Food Nutrition and Human Health (BTBU), Beijing 100048, China

⁴ Beijing Key Laboratory of Flavor Chemistry, Beijing Technology and Business University (BTBU), Beijing 100048, China

⁵ Yunnan ZhuoYi Food Company LTD, Jiangchuan 650032, China

Int. J. Mol. Sci. 2016, 17(4), 412; https://doi.org/10.3390/ijms17040412 - 5 Apr 2016

Cited by 28 | Viewed by 7396

Abstract

To compare the volatile compounds of Chinese black truffle and white truffle from Yunnan province, this study presents the application of a direct solvent extraction/solvent-assisted flavor evaporation (DSE-SAFE) coupled with a comprehensive two-dimensional gas chromatography (GC × GC) high resolution time-of-flight mass spectrometry [...] Read more.

To compare the volatile compounds of Chinese black truffle and white truffle from Yunnan province, this study presents the application of a direct solvent extraction/solvent-assisted flavor evaporation (DSE-SAFE) coupled with a comprehensive two-dimensional gas chromatography (GC × GC) high resolution time-of-flight mass spectrometry (HR-TOF/MS) and an electronic nose. Both of the analytical methods could distinguish the aroma profile of the two samples. In terms of the overall profile of truffle samples in this research, more kinds of acids were detected via the method of DSE-SAFE. Besides, compounds identified in black truffle (BT), but not in white truffle (WT), or vice versa, and those detected in both samples at different levels were considered to play an important role in differentiating the two samples. According to the analysis of electronic nose, the two samples could be separated, as well. Full article

(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food)

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13 pages, 3619 KiB

Open AccessArticle

Exploring the Interaction Natures in Plutonyl (VI) Complexes with Topological Analyses of Electron Density

by Jiguang Du^1,*, Xiyuan Sun^2,† and Gang Jiang^3,†

¹ College of Physical Science and Technology, Sichuan University, Chengdu 610064, China

² College of Sciences, Sichuan Agricultural University, Ya′an 625014, China

³ Institutes of Atomic and Molecular Physics, Sichuan University, Chengdu 610065, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 414; https://doi.org/10.3390/ijms17040414 - 11 Apr 2016

Cited by 16 | Viewed by 6291

Abstract

The interaction natures between Pu and different ligands in several plutonyl (VI) complexes are investigated by performing topological analyses of electron density. The geometrical structures in both gaseous and aqueous phases are obtained with B3LYP functional, and are generally in agreement with available [...] Read more.

The interaction natures between Pu and different ligands in several plutonyl (VI) complexes are investigated by performing topological analyses of electron density. The geometrical structures in both gaseous and aqueous phases are obtained with B3LYP functional, and are generally in agreement with available theoretical and experimental results when combined with all-electron segmented all-electron relativistic contracted (SARC) basis set. The Pu–

O_{y l}

bond orders show significant linear dependence on bond length and the charge of oxygen atoms in plutonyl moiety. The closed-shell interactions were identified for Pu-Ligand bonds in most complexes with quantum theory of atoms in molecules (QTAIM) analyses. Meanwhile, we found that some Pu–Ligand bonds, like Pu–OH⁻, show weak covalent. The interactive nature of Pu–ligand bonds were revealed based on the interaction quantum atom (IQA) energy decomposition approach, and our results indicate that all Pu–Ligand interactions is dominated by the electrostatic attraction interaction as expected. Meanwhile it is also important to note that the quantum mechanical exchange-correlation contributions can not be ignored. By means of the non-covalent interaction (NCI) approach it has been found that some weak and repulsion interactions existed in plutonyl(VI) complexes, which can not be distinguished by QTAIM, can be successfully identified. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2016)

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11 pages, 7475 KiB

Open AccessArticle

The Retentive Strength of Cemented Zirconium Oxide Crowns after Dentin Pretreatment with Desensitizing Paste Containing 8% Arginine and Calcium Carbonate

by Raphael Pilo^*, Noga Harel, Joseph Nissan

and Shifra Levartovsky

Department of Oral Rehabilitation, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv 6997801, Israel

Int. J. Mol. Sci. 2016, 17(4), 426; https://doi.org/10.3390/ijms17040426 - 25 Mar 2016

Cited by 12 | Viewed by 6386

Abstract

The effect of dentin pretreatment with Desensitizing Paste containing 8% arginine and calcium carbonate on the retention of zirconium oxide (Y-TZP) crowns was tested. Forty molar teeth were mounted and prepared using a standardized protocol. Y-TZP crowns were produced using computer-aided design and [...] Read more.

The effect of dentin pretreatment with Desensitizing Paste containing 8% arginine and calcium carbonate on the retention of zirconium oxide (Y-TZP) crowns was tested. Forty molar teeth were mounted and prepared using a standardized protocol. Y-TZP crowns were produced using computer-aided design and computer-aided manufacturing (CAD-CAM) technology. The 40 prepared teeth were either pretreated with Desensitizing Paste or not pretreated. After two weeks, each group was subdivided into two groups, cemented with either Resin Modified Glass Ionomer Cement (RMGIC) or Self Adhesive Resin Cement (SARC)). Prior to cementation, the surface areas of the prepared teeth were measured. After aging, the cemented crown-tooth assemblies were tested for retentive strength using a universal testing machine. The debonded surfaces of the teeth and crowns were examined microscopically at 10× magnification. Pretreating the dentin surfaces with Desensitizing Paste prior to cementation did not affect the retention of the Y-TZP crowns. The retentive values for RMGIC (3.04 ± 0.77 MPa) were significantly higher than those for SARC (2.28 ± 0.58 MPa). The predominant failure modes for the RMGIC and SARC were adhesive cement-dentin and adhesive cement-crown, respectively. An 8.0% arginine and calcium carbonate in-office desensitizing paste can be safely used to reduce post-cementation sensitivity without reducing the retentive strength of Y-TZP crowns. Full article

(This article belongs to the Special Issue Molecular Research on Dental Materials and Biomaterials)

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11 pages, 3479 KiB

Open AccessArticle

Monocyte Subsets and Related Chemokines in Carotid Artery Stenosis and Ischemic Stroke

by Gerrit M. Grosse¹, Walter J. Schulz-Schaeffer², Omke E. Teebken³, Ramona Schuppner¹, Meike Dirks¹, Hans Worthmann¹, Ralf Lichtinghagen⁴, Gerrit Maye⁵, Florian P. Limbourg^5,† and Karin Weissenborn^1,6,*,†

¹ Department of Neurology, Hannover Medical School, 30625 Hannover, Germany

² Department of Neuropathology, University Medical Center Göttingen, 37099 Göttingen, Germany

³ Department of Vascular Surgery, Klinikum Peine, 31226 Peine, Germany

⁴ Department of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany

⁵ Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany

⁶ Center for Systems Neuroscience (ZSN), 30559 Hannover, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 433; https://doi.org/10.3390/ijms17040433 - 23 Mar 2016

Cited by 25 | Viewed by 6301

Abstract

Carotid stenosis (CS) is an important cause of ischemic stroke. However, reliable markers for the purpose of identification of high-risk, so-called vulnerable carotid plaques, are still lacking. Monocyte subsets are crucial players in atherosclerosis and might also contribute to plaque rupture. In this [...] Read more.

Carotid stenosis (CS) is an important cause of ischemic stroke. However, reliable markers for the purpose of identification of high-risk, so-called vulnerable carotid plaques, are still lacking. Monocyte subsets are crucial players in atherosclerosis and might also contribute to plaque rupture. In this study we, therefore, aimed to investigate the potential role of monocyte subsets and associated chemokines as clinical biomarkers for vulnerability of CS. Patients with symptomatic and asymptomatic CS (n = 21), patients with cardioembolic ischemic strokes (n = 11), and controls without any cardiovascular disorder (n = 11) were examined. Cardiovascular risk was quantified using the Essen Stroke Risk Score (ESRS). Monocyte subsets in peripheral blood were measured by quantitative flow cytometry. Plaque specimens were histologically analyzed. Furthermore, plasma levels of monocyte chemotactic protein 1 (MCP-1) and fractalkine were measured. Intermediate monocytes (Mon2) were significantly elevated in symptomatic and asymptomatic CS-patients compared to controls. Mon2 counts positively correlated with the ESRS. Moreover, stroke patients showed an elevation of Mon2 compared to controls, independent of the ESRS. MCP-1 levels were significantly higher in patients with symptomatic than in those with asymptomatic CS. Several histological criteria significantly differed between symptomatic and asymptomatic plaques. However, there was no association of monocyte subsets or chemokines with histological features of plaque vulnerability. Due to the multifactorial influence on monocyte subsets, the usability as clinical markers for plaque vulnerability seems to be limited. However, monocyte subsets may be critically involved in the pathology of CS. Full article

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

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9 pages, 214 KiB

Open AccessArticle

Screening for Neurocognitive Impairment in HIV-Infected Individuals at First Contact after HIV Diagnosis: The Experience of a Large Clinical Center in Northern Italy

by Emanuele Focà^*

, Paola Magro, Davide Motta, Silvia Compostella, Salvatore Casari, Andrea Bonito, Nigritella Brianese, Alice Ferraresi, Paola Rodari, Maria Chiara Pezzoli, Eugenia Quiros-Roldan

and Francesco Castelli

Department of Infectious and Tropical Diseases, University of Brescia and Brescia Spedali Civili General Hospital, Piazzale Spedali Civili 1, 25123 Brescia, Italy

Int. J. Mol. Sci. 2016, 17(4), 434; https://doi.org/10.3390/ijms17040434 - 24 Mar 2016

Cited by 25 | Viewed by 5558

Abstract

Neurocognitive disorders are emerging, probably underestimated, complications in HIV-infected people. The aim of the study was to assess neurocognitive profiles of newly detected HIV-infected patients. We performed an observational retrospective single-cohort study. Illiterates and patients with neurologic symptoms or previous psychiatric diagnosis were [...] Read more.

Neurocognitive disorders are emerging, probably underestimated, complications in HIV-infected people. The aim of the study was to assess neurocognitive profiles of newly detected HIV-infected patients. We performed an observational retrospective single-cohort study. Illiterates and patients with neurologic symptoms or previous psychiatric diagnosis were excluded. Neuropsychological profiles were assessed using a validated battery of neuropsychological tests. We included 206 patients; with males representing the majority of them (85%). Risk factors for HIV acquisition were unprotected sexual intercourse (homo/bisexual in 39.8% and heterosexual in 60.2%). Thirty-nine patients (18.9%) were previous injection drug users, while 41 (19.9%) were alcohol abusers. Mean education was 11.1 years (SD—standard deviation—3.7). A high prevalence of HIV-associated neurocognitive disorders (HAND, 47.1%) was present in HIV-infected patients: particularly, asymptomatic neurocognitive impairment (ANI) was found in 30.6%, mild neurocognitive disorder (MND) in 15% and HIV-associated dementia (HAD) in 1.5%. Male gender, low degree of education, AIDS diagnosis and gepatitis B virus (HBV) co-infection were factors independently associated with HAND in a multivariable logistic regression model. Our data suggest that patient-specific factors and AIDS diagnosis have a certain kind of impact in HAND occurrence. A complete neuropsychological screening must be recommended in all patients at HIV-infection diagnosis. Full article

(This article belongs to the Special Issue Infectious Diseases: Pathophysiology, Diagnostics, Therapies, and Prevention)

14 pages, 2834 KiB

Open AccessArticle

Knock-Down of Endogenous Bornavirus-Like Nucleoprotein 1 Inhibits Cell Growth and Induces Apoptosis in Human Oligodendroglia Cells

by Peng He^1,2,3,†, Lin Sun^2,3,4,†, Dan Zhu^2,3,4,†, Hong Zhang^2,3, Liang Zhang^2,3, Yujie Guo^2,3, Siwen Liu^2,3, Jingjing Zhou^2,3, Xiaoyan Xu^2,3 and Peng Xie^1,2,3,4,*

¹ Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, China

² Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016, China

³ Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016, China

⁴ Department of Neurology, the First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 435; https://doi.org/10.3390/ijms17040435 - 24 Mar 2016

Cited by 22 | Viewed by 6881

Abstract

Endogenous bornavirus-like nucleoprotein elements (EBLNs) have been discovered in the genomes of various animals including humans, whose functions have been seldom studied. To explore the biological functions of human EBLNs, we constructed a lentiviral vector expressing a short-hairpin RNA [...] Read more.

Endogenous bornavirus-like nucleoprotein elements (EBLNs) have been discovered in the genomes of various animals including humans, whose functions have been seldom studied. To explore the biological functions of human EBLNs, we constructed a lentiviral vector expressing a short-hairpin RNA against human EBLN1, which successfully inhibited EBLN1 expression by above 80% in infected human oligodendroglia cells (OL cells). We found that EBLN1 silencing suppressed cell proliferation, induced G2/M phase arrest, and promoted apoptosis in OL cells. Gene expression profiling demonstrated that 1067 genes were up-regulated, and 2004 were down-regulated after EBLN1 silencing. The top 10 most upregulated genes were PI3, RND3, BLZF1, SOD2, EPGN, SBSN, INSIG1, OSMR, CREB3L2, and MSMO1, and the top 10 most-downregulated genes were KRTAP2-4, FLRT2, DIDO1, FAT4, ESCO2, ZNF804A, SUV420H1, ZC3H4, YAE1D1, and NCOA5. Pathway analysis revealed that these differentially expressed genes were mainly involved in pathways related to the cell cycle, the mitogen-activated protein kinase pathway, p53 signaling, and apoptosis. The gene expression profiles were validated by using quantitative reverse transcription polymerase chain reaction (RT-PCR) for detecting these 20 most-changed genes. Three genes closely related to glioma, RND3, OSMR, and CREB3L2, were significantly upregulated and might be the key factors in EBLN1 regulating the proliferation and apoptosis of OL cells. This study provides evidence that EBLN1 plays a key role in regulating cell life and death, thereby opening several avenues of investigation regarding EBLN1 in the future. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 2593 KiB

Open AccessArticle

Mechanical and IL-1β Responsive miR-365 Contributes to Osteoarthritis Development by Targeting Histone Deacetylase 4

by Xu Yang^1,†, Yingjie Guan^2,†, Shaoqi Tian¹, Yuanhe Wang¹, Kang Sun^1,* and Qian Chen²

¹ Department of Orthopedics, the Affiliated Hospital of Qingdao University, 1677 Wutaishan Rd, Qingdao 266000, China

² Cell and Molecular Biology Laboratory, Department of Orthopedics, Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI 02903, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 436; https://doi.org/10.3390/ijms17040436 - 23 Mar 2016

Cited by 86 | Viewed by 7298

Abstract

Mechanical stress plays an important role in the initiation and progression of osteoarthritis. Studies show that excessive mechanical stress can directly damage the cartilage extracellular matrix and shift the balance in chondrocytes to favor catabolic activity over anabolism. However, the underlying mechanism remains [...] Read more.

Mechanical stress plays an important role in the initiation and progression of osteoarthritis. Studies show that excessive mechanical stress can directly damage the cartilage extracellular matrix and shift the balance in chondrocytes to favor catabolic activity over anabolism. However, the underlying mechanism remains unknown. MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis pathogenesis. We have found that mechanical loading up-regulated microRNA miR-365 in growth plate chondrocytes, which promotes chondrocyte differentiation. Here, we explored the role of the mechanical responsive microRNA miR-365 in pathogenesis of osteoarthritis (OA). We found that miR-365 was up-regulated by cyclic loading and IL-1β stimulation in articular chondrocytes through a mechanism that involved the transcription factor NF-κB. miR-365 expressed significant higher level in rat anterior cruciate ligament (ACL) surgery induced OA cartilage as well as human OA cartilage from primary OA patients and traumatic OA Patients. Overexpression of miR-365 in chondrocytes increases gene expression of matrix degrading enzyme matrix metallopeptidase 13 (MMP13) and collagen type X (Col X). The increase in miR-365 expression in OA cartilage and in response to IL-1 may contribute to the abnormal gene expression pattern characteristic of OA. Inhibition of miR-365 down-regulated IL-1β induced MMP13 and Col X gene expression. We further showed histone deacetylase 4 (HDAC4) is a direct target of miR-365, which mediates mechanical stress and inflammation in OA pathogenesis. Thus, miR-365 is a critical regulator of mechanical stress and pro-inflammatory responses, which contributes cartilage catabolism. Manipulation of the expression of miR-365 in articular chondrocytes by miR-365 inhibitor may be a potent therapeutic target for the prevention and treatment of osteoarthritis. Full article

(This article belongs to the Special Issue Apoptotic Chondrocytes and Osteoarthritis)

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13 pages, 3832 KiB

Open AccessArticle

Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer

by Xiaolei Li^1,2,†, Qianhui Zhang^3,†, Kai Fan⁴, Baiyan Li⁵, Huifeng Li⁶, Hanping Qi³, Jing Guo³, Yonggang Cao^3,* and Hongli Sun^3,*

¹ Department of Pathology, Harbin Medical University-Daqing, Daqing 163319, China

² Department of Scientific Research, Third Affiliated Hospital of Guizhou Medical University, Duyun 558000, China

³ Department of Pharmacology, Harbin Medical University-Daqing, Daqing 163319, China

⁴ Department of Pathophysiology, Harbin Medical University-Daqing, Daqing 163319, China

⁵ Department of Pharmacology, Harbin Medical University, Harbin 150081, China

⁶ Department of Pathology, Daqing General Hospital Group Oilfield General Hospital, Daqing 163319, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 437; https://doi.org/10.3390/ijms17040437 - 24 Mar 2016

Cited by 62 | Viewed by 7359

Abstract

(1) Background: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca²⁺-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance [...] Read more.

(1) Background: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca²⁺-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance and biological functions of TRPV3 in non-small cell lung cancer (NSCLC); (2) Methods: Immunohistochemistry was used to detect the expression of TRPV3 in NSCLC tissues and adjacent noncancerous lung tissues. Western blot was used to detect the protein expressions of TRPV3, CaMKII, p-CaMKII, CyclinA, CyclinD, CyclinE1, CDK2, CDK4, and P27. Small interfering RNA was used to deplete TRPV3 expression. A laser scanning confocal microscope was used to measure intracellular calcium concentration ([Ca²⁺]_i). Flow cytometry was used to analyze cell cycle; (3) Results: TRPV3 was overexpressed in 65 of 96 (67.7%) human lung cancer cases and correlated with differentiation (p = 0.001) and TNM stage (p = 0.004). Importantly, TRPV3 expression was associated with short overall survival. In addition, blocking or knockdown of TRPV3 could inhibit lung cancer cell proliferation. Moreover, TRPV3 inhibition could decrease [Ca²⁺]_i of lung cancer cells and arrest cell cycle at the G1/S boundary. Further results revealed that TRPV3 inhibition decreased expressions of p-CaMKII, CyclinA, CyclinD1, CyclinE, and increased P27 level; (4) Conclusions: Our findings demonstrate that TRPV3 was overexpressed in NSCLC and correlated with lung cancer progression. TRPV3 activation could promote proliferation of lung cancer cells. TRPV3 might serve as a potential companion drug target in NSCLC. Full article

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

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15 pages, 3976 KiB

Open AccessArticle

TOR Pathway-Mediated Juvenile Hormone Synthesis Regulates Nutrient-Dependent Female Reproduction in Nilaparvata lugens (Stål)

by Kai Lu^1,2, Xia Chen¹, Wen-Ting Liu¹ and Qiang Zhou^2,*

¹ College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China

² State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

Int. J. Mol. Sci. 2016, 17(4), 438; https://doi.org/10.3390/ijms17040438 - 28 Mar 2016

Cited by 60 | Viewed by 7895

Abstract

The “target of rapamycin” (TOR) nutritional signaling pathway and juvenile hormone (JH) regulation of vitellogenesis has been known for a long time. However, the interplay between these two pathways regulating vitellogenin (Vg) expression remains obscure. Here, we first demonstrated the key role of [...] Read more.

The “target of rapamycin” (TOR) nutritional signaling pathway and juvenile hormone (JH) regulation of vitellogenesis has been known for a long time. However, the interplay between these two pathways regulating vitellogenin (Vg) expression remains obscure. Here, we first demonstrated the key role of amino acids (AAs) in activation of Vg synthesis and egg development in Nilaparvata lugens using chemically defined artificial diets. AAs induced the expression of TOR and S6K (S6 kinase), whereas RNAi-mediated silencing of these two TOR pathway genes and rapamycin application strongly inhibited the AAs-induced Vg synthesis. Furthermore, knockdown of Rheb (Ras homologue enriched in brain), TOR, S6K and application of rapamycin resulted in a dramatic reduction in the mRNA levels of jmtN (juvenile hormone acid methyltransferase, JHAMT). Application of JH III on the RNAi (Rheb and TOR) and rapamycin-treated females partially rescued the Vg expression. Conversely, knockdown of either jmtN or met (methoprene-tolerant, JH receptor) and application of JH III had no effects on mRNA levels of Rheb, TOR and S6K and phosphorylation of S6K. In summary, our results demonstrate that the TOR pathway induces JH biosynthesis that in turn regulates AAs-mediated Vg synthesis in N. lugens. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 1253 KiB

Open AccessArticle

The Role of Ultrahigh Resolution Fourier Transform Mass Spectrometry (FT-MS) in Astrobiology-Related Research: Analysis of Meteorites and Tholins

by Árpád Somogyi^1,*, Roland Thissen², Francois-Régis Orthous-Daunay² and Véronique Vuitton²

¹ Campus Chemical Instrument Center, Mass Spectrometry and Proteomics Laboratory, Ohio State University, Columbus, OH 43210, USA

² Université Grenoble Alpes, CNRS, IPAG, Grenoble F-38000, France

Int. J. Mol. Sci. 2016, 17(4), 439; https://doi.org/10.3390/ijms17040439 - 24 Mar 2016

Cited by 18 | Viewed by 7238

Abstract

It is an important but also a challenging analytical problem to understand the chemical composition and structure of prebiotic organic matter that is present in extraterrestrial materials. Its formation, evolution and content in the building blocks (“seeds”) for more complex molecules, such as [...] Read more.

It is an important but also a challenging analytical problem to understand the chemical composition and structure of prebiotic organic matter that is present in extraterrestrial materials. Its formation, evolution and content in the building blocks (“seeds”) for more complex molecules, such as proteins and DNA, are key questions in the field of exobiology. Ultrahigh resolution mass spectrometry is one of the best analytical techniques that can be applied because it provides reliable information on the chemical composition and structure of individual components of complex organic mixtures. Prebiotic organic material is delivered to Earth by meteorites or generated in laboratories in simulation (model) experiments that mimic space or atmospheric conditions. Recent representative examples for ultrahigh resolution mass spectrometry studies using Fourier-transform (FT) mass spectrometers such as Orbitrap and ion cyclotron resonance (ICR) mass spectrometers are shown and discussed in the present article, including: (i) the analysis of organic matter of meteorites; (ii) modeling atmospheric processes in ICR cells; and (iii) the structural analysis of laboratory made tholins that might be present in the atmosphere and surface of Saturn’s largest moon, Titan. Full article

(This article belongs to the Special Issue Fourier Transform Mass Spectrometry in Molecular Sciences)

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13 pages, 3189 KiB

Open AccessArticle

Molecular Characterization of MaCCS, a Novel Copper Chaperone Gene Involved in Abiotic and Hormonal Stress Responses in Musa acuminata cv. Tianbaojiao

by Xin Feng, Fanglan Chen, Weihua Liu, Min Kyaw Thu, Zihao Zhang, Yukun Chen

, Chunzhen Cheng, Yuling Lin, Tianchi Wang and Zhongxiong Lai^*

Institute of Horticultural Biotechnology, Fujian Agriculture and Forestry University, Fuzhou 350002, China

Int. J. Mol. Sci. 2016, 17(4), 441; https://doi.org/10.3390/ijms17040441 - 24 Mar 2016

Cited by 20 | Viewed by 5468

Abstract

Copper/zinc superoxide dismutases (Cu/ZnSODs) play important roles in improving banana resistance to adverse conditions, but their activities depend on the copper chaperone for superoxide dismutase (CCS) delivering copper to them. However, little is known about CCS in monocots and under stress conditions. Here, [...] Read more.

Copper/zinc superoxide dismutases (Cu/ZnSODs) play important roles in improving banana resistance to adverse conditions, but their activities depend on the copper chaperone for superoxide dismutase (CCS) delivering copper to them. However, little is known about CCS in monocots and under stress conditions. Here, a novel CCS gene (MaCCS) was obtained from a banana using reverse transcription PCR and rapid-amplification of cDNA ends (RACE) PCR. Sequence analyses showed that MaCCS has typical CCS domains and a conserved gene structure like other plant CCSs. Alternative transcription start sites (ATSSs) and alternative polyadenylation contribute to the mRNA diversity of MaCCS. ATSSs in MaCCS resulted in one open reading frame containing two in-frame start codons to form two protein versions, which is supported by the MaCCS subcellular localization of in both cytosol and chloroplasts. Furthermore, MaCCS promoter was found to contain many cis-elements associated with abiotic and hormonal responses. Quantitative real-time PCR analysis showed that MaCCS was expressed in all tested tissues (leaves, pseudostems and roots). In addition, MaCCS expression was significantly induced by light, heat, drought, abscisic acid and indole-3-acetic acid, but inhibited by relatively high concentrations of CuSO₄ and under cold treatment, which suggests that MaCCS is involved in abiotic and hormonal responses. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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21 pages, 9440 KiB

Open AccessArticle

The Protective Role of Carbon Monoxide (CO) Produced by Heme Oxygenases and Derived from the CO-Releasing Molecule CORM-2 in the Pathogenesis of Stress-Induced Gastric Lesions: Evidence for Non-Involvement of Nitric Oxide (NO)

by Katarzyna Magierowska¹, Marcin Magierowski^1,*

, Marcin Surmiak^1,2, Juliusz Adamski³, Agnieszka Irena Mazur-Bialy⁴

, Robert Pajdo¹, Zbigniew Sliwowski¹, Slawomir Kwiecien¹ and Tomasz Brzozowski¹

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

² Division of Molecular Biology and Clinical Genetics, Department of Medicine, Jagiellonian University Medical College, 31-006 Cracow, Poland

³ Department of Forensic Toxicology, Institute of Forensic Research, 31-033 Cracow, Poland

⁴ Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-531 Cracow, Poland

Int. J. Mol. Sci. 2016, 17(4), 442; https://doi.org/10.3390/ijms17040442 - 24 Mar 2016

Cited by 38 | Viewed by 7868

Abstract

Carbon monoxide (CO) produced by heme oxygenase (HO)-1 and HO-2 or released from the CO-donor, tricarbonyldichlororuthenium (II) dimer (CORM-2) causes vasodilation, with unknown efficacy against stress-induced gastric lesions. We studied whether pretreatment with CORM-2 (0.1–10 mg/kg oral gavage (i.g.)), RuCl₃ (1 mg/kg [...] Read more.

Carbon monoxide (CO) produced by heme oxygenase (HO)-1 and HO-2 or released from the CO-donor, tricarbonyldichlororuthenium (II) dimer (CORM-2) causes vasodilation, with unknown efficacy against stress-induced gastric lesions. We studied whether pretreatment with CORM-2 (0.1–10 mg/kg oral gavage (i.g.)), RuCl₃ (1 mg/kg i.g.), zinc protoporphyrin IX (ZnPP) (10 mg/kg intraperitoneally (i.p.)), hemin (1–10 mg/kg i.g.) and CORM-2 (1 mg/kg i.g.) combined with N^G-nitro-l-arginine (l-NNA, 20 mg/kg i.p.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 mg/kg i.p.), indomethacin (5 mg/kg i.p.), SC-560 (5 mg/kg i.g.), and celecoxib (10 mg/kg i.g.) affects gastric lesions following 3.5 h of water immersion and restraint stress (WRS). Gastric blood flow (GBF), the number of gastric lesions and gastric CO and nitric oxide (NO) contents, blood carboxyhemoglobin (COHb) level and the gastric expression of HO-1, HO-2, hypoxia inducible factor 1α (HIF-1α), tumor necrosis factor α (TNF-α), cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) were determined. CORM-2 (1 mg/kg i.g.) and hemin (10 mg/kg i.g.) significantly decreased WRS lesions while increasing GBF, however, RuCl₃ was ineffective. The impact of CORM-2 was reversed by ZnPP, ODQ, indomethacin, SC-560 and celecoxib, but not by l-NNA. CORM-2 decreased NO and increased HO-1 expression and CO and COHb content, downregulated HIF-1α, as well as WRS-elevated COX-2 and iNOS mRNAs. Gastroprotection by CORM-2 and HO depends upon CO’s hyperemic and anti-inflammatory properties, but is independent of NO. Full article

(This article belongs to the Special Issue Metalloproteins)

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15 pages, 6718 KiB

Open AccessArticle

The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages

by Paola Maroni¹, Paola Bendinelli², Massimo Resnati³, Emanuela Matteucci², Enrico Milan³ and Maria Alfonsina Desiderio^2,*

¹ Istituto Ortopedico Galeazzi, Scientific Institute for Research, Hospitalization and Health Care (IRCCS), Milano 20161, Italy

² Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Milano 20133, Italy

³ San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milano 20133, Italy

Int. J. Mol. Sci. 2016, 17(4), 443; https://doi.org/10.3390/ijms17040443 - 25 Mar 2016

Cited by 14 | Viewed by 5983

Abstract

Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and [...] Read more.

Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)

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18 pages, 2684 KiB

Open AccessArticle

Targeted Disruption of Melanin Biosynthesis Genes in the Human Pathogenic Fungus Lomentospora prolificans and Its Consequences for Pathogen Survival

by Ayat Al-Laaeiby^1,2, Michael J. Kershaw¹, Tina J. Penn¹ and Christopher R. Thornton^1,*

¹ Biosciences, College of Life and Environmental Sciences, University of Exeter, Stocker Road, Exeter EX4 4QD, UK

² Cell and Biotechnology Research Unit, College of Science, University of Basrah, Basrah 61004, Iraq

Int. J. Mol. Sci. 2016, 17(4), 444; https://doi.org/10.3390/ijms17040444 - 24 Mar 2016

Cited by 25 | Viewed by 7113

Abstract

The dematiaceous (melanised) fungus Lomentospora (Scedosporium) prolificans is a life-threatening opportunistic pathogen of immunocompromised humans, resistant to anti-fungal drugs. Melanin has been shown to protect human pathogenic fungi against antifungal drugs, oxidative killing and environmental stresses. To determine the protective role [...] Read more.

The dematiaceous (melanised) fungus Lomentospora (Scedosporium) prolificans is a life-threatening opportunistic pathogen of immunocompromised humans, resistant to anti-fungal drugs. Melanin has been shown to protect human pathogenic fungi against antifungal drugs, oxidative killing and environmental stresses. To determine the protective role of melanin in L. prolificans to oxidative killing (H₂O₂), UV radiation and the polyene anti-fungal drug amphotericin B, targeted gene disruption was used to generate mutants of the pathogen lacking the dihydroxynaphthalene (DHN)-melanin biosynthetic enzymes polyketide synthase (PKS1), tetrahydroxynapthalene reductase (4HNR) and scytalone dehydratase (SCD1). Infectious propagules (spores) of the wild-type strain 3.1 were black/brown, whereas spores of the PKS-deficient mutant ΔLppks1::hph were white. Complementation of the albino mutant ΔLppks1::hph restored the black-brown spore pigmentation, while the 4HNR-deficient mutant ΔLp4hnr::hph and SCD-deficient mutant ΔLpscd1::hph both produced orange-yellow spores. The mutants ΔLppks1::hph and ΔLp4hnr::hph showed significant reductions in spore survival following H₂O₂ treatment, while spores of ΔLpscd1::hph and the ΔLppks1::hph complemented strain ΔLppks1::hph:PKS showed spore survivals similar to strain 3.1. Spores of the mutants ΔLp4hnr::hph and ΔLpscd1::hph and complemented strain ΔLppks1::hph:PKS showed spore survivals similar to 3.1 following exposure to UV radiation, but survival of ΔLppks1::hph spores was significantly reduced compared to the wild-type strain. Strain 3.1 and mutants ΔLp4hnr::hph and ΔLppks1::hph:PKS were resistant to amphotericin B while, paradoxically, the PKS1- and SCD1-deficient mutants showed significant increases in growth in the presence of the antifungal drug. Taken together, these results show that while melanin plays a protective role in the survival of the pathogen to oxidative killing and UV radiation, melanin does not contribute to its resistance to amphotericin B. Full article

(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)

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17 pages, 2714 KiB

Open AccessArticle

Species Identification of Bovine, Ovine and Porcine Type 1 Collagen; Comparing Peptide Mass Fingerprinting and LC-Based Proteomics Methods

by Mike Buckley

Manchester Institute of Biotechnology, the University of Manchester, Manchester, M1 7DN, UK

Int. J. Mol. Sci. 2016, 17(4), 445; https://doi.org/10.3390/ijms17040445 - 24 Mar 2016

Cited by 65 | Viewed by 10478

Abstract

Collagen is one of the most ubiquitous proteins in the animal kingdom and the dominant protein in extracellular tissues such as bone, skin and other connective tissues in which it acts primarily as a supporting scaffold. It has been widely investigated scientifically, not [...] Read more.

Collagen is one of the most ubiquitous proteins in the animal kingdom and the dominant protein in extracellular tissues such as bone, skin and other connective tissues in which it acts primarily as a supporting scaffold. It has been widely investigated scientifically, not only as a biomedical material for regenerative medicine, but also for its role as a food source for both humans and livestock. Due to the long-term stability of collagen, as well as its abundance in bone, it has been proposed as a source of biomarkers for species identification not only for heat- and pressure-rendered animal feed but also in ancient archaeological and palaeontological specimens, typically carried out by peptide mass fingerprinting (PMF) as well as in-depth liquid chromatography (LC)-based tandem mass spectrometric methods. Through the analysis of the three most common domesticates species, cow, sheep, and pig, this research investigates the advantages of each approach over the other, investigating sites of sequence variation with known functional properties of the collagen molecule. Results indicate that the previously identified species biomarkers through PMF analysis are not among the most variable type 1 collagen peptides present in these tissues, the latter of which can be detected by LC-based methods. However, it is clear that the highly repetitive sequence motif of collagen throughout the molecule, combined with the variability of the sites and relative abundance levels of hydroxylation, can result in high scoring false positive peptide matches using these LC-based methods. Additionally, the greater alpha 2(I) chain sequence variation, in comparison to the alpha 1(I) chain, did not appear to be specific to any particular functional properties, implying that intra-chain functional constraints on sequence variation are not as great as inter-chain constraints. However, although some of the most variable peptides were only observed in LC-based methods, until the range of publicly available collagen sequences improves, the simplicity of the PMF approach and suitable range of peptide sequence variation observed makes it the ideal method for initial taxonomic identification prior to further analysis by LC-based methods only when required. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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11 pages, 2100 KiB

Open AccessArticle

Structure of the PLP-Form of the Human Kynurenine Aminotransferase II in a Novel Spacegroup at 1.83 Å Resolution

by Alireza Nematollahi¹, Guanchen Sun¹, Stephen J. Harrop², Jane R. Hanrahan³ and W. Bret Church^1,*

¹ Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia

² MX Beamlines, Australian Synchrotron, 800 Blackburn Road, Clayton, VIC 3168, Australia

³ Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia

Int. J. Mol. Sci. 2016, 17(4), 446; https://doi.org/10.3390/ijms17040446 - 25 Mar 2016

Cited by 15 | Viewed by 5957

Abstract

Kynurenine aminotransferase II (KAT-II) is a 47 kDa pyridoxal phosphate (PLP)-dependent enzyme, active as a homodimer, which catalyses the transamination of the amino acids kynurenine (KYN) and 3-hydroxykynurenine (3-HK) in the tryptophan pathway, and is responsible for producing metabolites that lead to kynurenic [...] Read more.

Kynurenine aminotransferase II (KAT-II) is a 47 kDa pyridoxal phosphate (PLP)-dependent enzyme, active as a homodimer, which catalyses the transamination of the amino acids kynurenine (KYN) and 3-hydroxykynurenine (3-HK) in the tryptophan pathway, and is responsible for producing metabolites that lead to kynurenic acid (KYNA), which is implicated in several neurological diseases such as schizophrenia. In order to fully describe the role of KAT-II in the pathobiology of schizophrenia and other brain disorders, the crystal structure of full-length PLP-form hKAT-II was determined at 1.83 Å resolution, the highest available. The electron density of the active site reveals an aldimine linkage between PLP and Lys263, as well as the active site residues, which characterize the fold-type I PLP-dependent enzymes. Full article

(This article belongs to the Section Biochemistry)

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20 pages, 9881 KiB

Open AccessArticle

Fragment Screening of Human Aquaporin 1

by Janet To and Jaume Torres^*

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore

Int. J. Mol. Sci. 2016, 17(4), 449; https://doi.org/10.3390/ijms17040449 - 25 Mar 2016

Cited by 3 | Viewed by 6348

Abstract

Aquaporins (AQPs) are membrane proteins that enable water transport across cellular plasma membranes in response to osmotic gradients. Phenotypic analyses have revealed important physiological roles for AQPs, and the potential for AQP water channel modulators in various disease states has been proposed. For [...] Read more.

Aquaporins (AQPs) are membrane proteins that enable water transport across cellular plasma membranes in response to osmotic gradients. Phenotypic analyses have revealed important physiological roles for AQPs, and the potential for AQP water channel modulators in various disease states has been proposed. For example, AQP1 is overexpressed in tumor microvessels, and this correlates with higher metastatic potential and aggressiveness of the malignancy. Chemical modulators would help in identifying the precise contribution of water channel activity in these disease states. These inhibitors would also be important therapeutically, e.g., in anti-cancer treatment. This perceived importance contrasts with the lack of success of high-throughput screens (HTS) to identify effective and specific inhibitors of aquaporins. In this paper, we have screened a library of 1500 “fragments”, i.e., smaller than molecules used in HTS, against human aquaporin (hAQP1) using a thermal shift assay and surface plasmon resonance. Although these fragments may not inhibit their protein target, they bound to and stabilized hAQP1 (sub mM binding affinities (K_D), with an temperature of aggregation shift ΔT_agg of +4 to +50 °C) in a concentration-dependent fashion. Chemically expanded versions of these fragments should follow the determination of their binding site on the aquaporin surface. Full article

(This article belongs to the Special Issue Aquaporin)

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8 pages, 211 KiB

Open AccessArticle

Asymmetric Dimethylarginine versus Proton Pump Inhibitors Usage in Patients with Stable Coronary Artery Disease: A Cross-Sectional Study

by Olga Kruszelnicka^1,*, Jolanta Świerszcz², Jacek Bednarek³, Bernadeta Chyrchel², Andrzej Surdacki^2,† and Jadwiga Nessler^1,†

¹ Department of Coronary Artery Disease and Heart Failure, Jagiellonian University Medical College and John Paul II Hospital, 80 Prądnicka, 31-202 Cracow, Poland

² Second Department of Cardiology, Jagiellonian University Medical College and University Hospital, 17 Kopernika, 31-501 Cracow, Poland

³ Department of Electrocardiology, John Paul II Hospital, 80 Prądnicka, 31-202 Cracow, Poland

^† Joint senior authors on this work.

Int. J. Mol. Sci. 2016, 17(4), 454; https://doi.org/10.3390/ijms17040454 - 15 Apr 2016

Cited by 10 | Viewed by 4794

Abstract

A recent experimental study suggested that proton pump inhibitors (PPI), widely used to prevent gastroduodenal complications of dual antiplatelet therapy, may increase the accumulation of the endogenous nitric oxide synthesis antagonist asymmetric dimethylarginine (ADMA), an adverse outcome predictor. Our aim was to assess [...] Read more.

A recent experimental study suggested that proton pump inhibitors (PPI), widely used to prevent gastroduodenal complications of dual antiplatelet therapy, may increase the accumulation of the endogenous nitric oxide synthesis antagonist asymmetric dimethylarginine (ADMA), an adverse outcome predictor. Our aim was to assess the effect of PPI usage on circulating ADMA in coronary artery disease (CAD). Plasma ADMA levels were compared according to PPI use for ≥1 month prior to admission in 128 previously described non-diabetic men with stable CAD who were free of heart failure or other coexistent diseases. Patients on PPI tended to be older and with insignificantly lower estimated glomerular filtration rate (GFR). PPI use was not associated with any effect on plasma ADMA (0.51 ± 0.11 (SD) vs. 0.50 ± 0.10 µmol/L for those with PPI (n = 53) and without PPI (n = 75), respectively; p = 0.7). Additionally, plasma ADMA did not differ between PPI users and non-users stratified by a history of current smoking, CAD severity or extent. The adjustment for patients’ age and GFR did not substantially change the results. Thus, PPI usage does not appear to affect circulating ADMA in non-diabetic men with stable CAD. Whether novel mechanisms of adverse PPI effects on the vasculature can be translated into clinical conditions, requires further studies. Full article

(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging 2016)

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12 pages, 2057 KiB

Open AccessArticle

Liver Fibrosis in HCV Monoinfected and HIV/HCV Coinfected Patients: Dysregulation of Matrix Metalloproteinases (MMPs) and Their Tissue Inhibitors TIMPs and Effect of HCV Protease Inhibitors

by Tiziana Latronico¹, Claudia Mascia², Ilaria Pati¹, Paola Zuccala², Fabio Mengoni², Raffaella Marocco³, Tiziana Tieghi^2,3, Valeria Belvisi^2,3, Miriam Lichtner^2,3, Vincenzo Vullo², Claudio Maria Mastroianni^2,3,*

and Grazia Maria Liuzzi¹

¹ Department of Biosciences, Biotechnologies and Biopharmaceutics, Aldo Moro University, Bari 70126, Italy

² Department of Public Health and Infectious Diseases, Sapienza University, Rome 00185, Italy

³ Infectious Diseases Unit, Sapienza University, Polo Pontino, Latina 04100, Italy

Int. J. Mol. Sci. 2016, 17(4), 455; https://doi.org/10.3390/ijms17040455 - 26 Mar 2016

Cited by 41 | Viewed by 6150

Abstract

An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to liver fibrosis in patients with hepatitis C (HCV) infection. We measured the circulating levels of different MMPs and TIMPs in HCV monoinfected and HIV/HCV coinfected patients and evaluated [...] Read more.

An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to liver fibrosis in patients with hepatitis C (HCV) infection. We measured the circulating levels of different MMPs and TIMPs in HCV monoinfected and HIV/HCV coinfected patients and evaluated the potential for anti-HCV therapy to modulate MMP and TIMP levels in HCV subjects. We analyzed 83 plasma samples from 16 HCV monoinfected patients undergoing dual or triple anti-HCV therapy, 15 HIV/HCV coinfected patients with undetectable HIV load, and 10 healthy donors (HD). Levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, TIMP-1, and TIMP-2 were measured by a SearchLight Multiplex Immunoassay Kit. MMP-2 and MMP-9 were the highest expressed MMPs among all the analyzed samples and their levels significantly increased in HCV monoinfected and HIV/HCV coinfected subjects compared to HD. TIMP-1 levels were significantly higher in HCV and HIV/HCV subjects compared to HD and were correlated with liver stiffness. These findings raise the possibility of using circulating TIMP-1 as a non-invasive marker of liver fibrosis in HCV infection. A longitudinal study demonstrated that MMP-9 levels significantly decreased (40% reduction from baseline) in patients receiving dual as well as triple direct-acting antivirals (DAA) anti-HCV therapy, which had no effect on MMP-2, TIMP-1, and TIMP-2. As the dysregulation of MMP-2 and MMP-9 may reflect inflammatory processes in the liver, the decrease of MMP-9 following HCV protease inhibitor treatment suggests a positive effect on the reduction of liver inflammation. Full article

(This article belongs to the Special Issue Infectious Diseases: Pathophysiology, Diagnostics, Therapies, and Prevention)

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11 pages, 553 KiB

Open AccessArticle

Additive Effect of Non-Alcoholic Fatty Liver Disease on Metabolic Syndrome-Related Endothelial Dysfunction in Hypertensive Patients

by Maria Perticone¹, Antonio Cimellaro², Raffaele Maio³, Benedetto Caroleo³, Angela Sciacqua², Giorgio Sesti²

and Francesco Perticone^2,*

¹ Department of Experimental and Clinical Medicine, University Magna Græcia, Catanzaro 88100, Italy

² Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro 88100, Italy

³ Unit of Cardiovascular Diseases, Azienda Ospedaliera Mater Domini, Catanzaro 88100, Italy

Int. J. Mol. Sci. 2016, 17(4), 456; https://doi.org/10.3390/ijms17040456 - 26 Mar 2016

Cited by 26 | Viewed by 6588

Abstract

Metabolic syndrome (MS) is characterized by an increased risk of incident diabetes and cardiovascular (CV) events, identifying insulin resistance (IR) and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD) is bidirectionally linked with MS as a consequence of metabolic and [...] Read more.

Metabolic syndrome (MS) is characterized by an increased risk of incident diabetes and cardiovascular (CV) events, identifying insulin resistance (IR) and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD) is bidirectionally linked with MS as a consequence of metabolic and inflammatory abnormalities. We addressed the question if the evolution in NAFLD might worsen endothelium-dependent vasodilating response in MS hypertensives. We recruited 272 Caucasian newly-diagnosed never-treated hypertensive outpatients divided into three groups according to the presence/absence of MS alone or in combination with NAFLD. MS and NAFLD were defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and non-invasive fatty liver index, respectively. We determined IR by using the homeostasis model assessment (HOMA) index. Vascular function, as forearm blood flow (FBF), was determined through strain-gauge plethysmography after intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside. MS+NAFLD+ group showed worse metabolic, inflammatory and vascular profiles compared with MS−NAFLD− and MS+NAFLD−. HOMA resulted in being the strongest predictor of FBF both in the MS+NAFLD− and in the MS+NAFLD+ groups, accounting for 20.5% and 33.2% of its variation, respectively. In conclusion, we demonstrated that MS+NAFLD+ hypertensives show a worse endothelium-dependent vasodilation compared with MS+NAFLD−, allowing for consideration of NAFLD as an early marker of endothelial dysfunction in hypertensives. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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13 pages, 7863 KiB

Open AccessArticle

Meta-Analysis on Associations of RGS1 and IL12A Polymorphisms with Celiac Disease Risk

by Cong-Cong Guo^1,†, Man Wang^1,†, Feng-Di Cao², Wei-Huang Huang¹, Di Xiao¹, Xing-Guang Ye¹, Mei-Ling Ou¹, Na Zhang¹, Bao-Huan Zhang¹, Yang Liu¹, Guang Yang^3,4,* and Chun-Xia Jing^1,4,*

¹ Department of Epidemiology, School of Medicine, Jinan University, Guangzhou 510632, China

² Department of Stomatology of the First Affiliated Hospital of Jinan University, Guangzhou 510632, China

³ Department of Parasitology, School of Medicine, Jinan University, Guangzhou 510632, China

⁴ Key Laboratory of Environmental Exposure and Health in Guangzhou, Jinan University, Guangzhou 510632, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 457; https://doi.org/10.3390/ijms17040457 - 30 Mar 2016

Cited by 12 | Viewed by 5609

Abstract

The pathogenesis of celiac disease (CD) has been related to polymorphisms in the regulator of G-protein signaling 1 (RGS1) and interleukin-12 A (IL12A) genes, but the existing findings are inconsistent. Our aim is to investigate the associations of two single-nucleotide polymorphisms (SNPs) (rs2816316 [...] Read more.

The pathogenesis of celiac disease (CD) has been related to polymorphisms in the regulator of G-protein signaling 1 (RGS1) and interleukin-12 A (IL12A) genes, but the existing findings are inconsistent. Our aim is to investigate the associations of two single-nucleotide polymorphisms (SNPs) (rs2816316 in RGS1 and rs17810546 in IL12A) with CD risk using meta-analysis. We searched PubMed and Web of Science on RGS1 rs2816316 and IL12A rs17810546 with CD risk. Odds ratio (OR) and 95% confidence interval (CI) of each SNP were estimated. All statistical analyses were performed on Stata 12.0. A total of seven studies were retrieved and analyzed. The available data indicated the minor allele C of rs2816316 was negatively associated with CD (C vs. A: OR = 0.77, 95% CI = 0.74–0.80), and a positive association was found for the minor allele G of rs17810546 (G vs. A: OR = 1.37, 95% CI = 1.31–1.43). The co-dominant model of genotype effect confirmed the significant associations between RGS1 rs2816316/IL12A rs17810546 and CD. No evidence of publication bias was observed. Our meta-analysis supports the associations of RGS1 and IL12A with CD and strongly calls for further studies to better understand the roles of RGS1 and IL12A in the pathogenesis of CD. Full article

(This article belongs to the Section Biochemistry)

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9 pages, 885 KiB

Open AccessArticle

Apolipoprotein A1-Unique Peptide as a Diagnostic Biomarker for Acute Ischemic Stroke

by Xu Zhao¹, Yue Yu¹, Wenlong Xu², Lei Dong², Yuan Wang¹, Bing Gao¹, Guangyu Li^2,* and Wentao Zhang^1,*

¹ School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China

² Department of Neurosurgery, First Affiliated Hospital of China Medical University, Shenyang 110001, China

Int. J. Mol. Sci. 2016, 17(4), 458; https://doi.org/10.3390/ijms17040458 - 28 Mar 2016

Cited by 34 | Viewed by 5376

Abstract

Clinically-informative biomarkers of ischemic stroke are needed for rapid diagnosis and timely treatment. In the present study, APOA1 unique peptide (APOA1-UP), a novel peptide biomarker, was identified and quantified by multiple reaction monitoring (MRM) using labeled reference peptide (LRP). Serum samples of 94 [...] Read more.

Clinically-informative biomarkers of ischemic stroke are needed for rapid diagnosis and timely treatment. In the present study, APOA1 unique peptide (APOA1-UP), a novel peptide biomarker, was identified and quantified by multiple reaction monitoring (MRM) using labeled reference peptide (LRP). Serum samples of 94 patients in the ischemic stroke group and 37 patients in the non-stroke group were analyzed for the levels of total APOA1-UP, low density lipoprotein cholesterol (LDL-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and total cholesterol (TC). Median ratio of total APOA1-UP/LRP was 2.14 (interquartile range, 0.40) in the non-stroke group and 1.32 (0.44) in the ischemic stroke group (p < 0.0001). The serum level of total APOA1-UP was independently correlated with the presence of ischemic stroke by multivariate logistic regression analysis (p < 0.0001). From the receiver operating characteristic (ROC) curve, the area under the curve (AUC) was 0.9750 and the optimal cutoff value of the serum APOA1-UP level was 1.80, which yielded a sensitivity of 90.63% and a specificity of 97.14%. The diagnostic efficiency of HDL-C was lower, with an AUC of 0.7488. Therefore, the serum level of APOA1-UP is a diagnostic biomarker candidate for ischemic stroke in the early stage. Full article

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

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11 pages, 1788 KiB

Open AccessArticle

Aripiprazole and Haloperidol Activate GSK3β-Dependent Signalling Pathway Differentially in Various Brain Regions of Rats

by Bo Pan^1,2

, Xu-Feng Huang^1,2 and Chao Deng^1,2,*

¹ Illawarra Health and Medical Research Institute, Wollongong 2522, Australia

² School of Medicine, University of Wollongong, Wollongong 2522, Australia

Int. J. Mol. Sci. 2016, 17(4), 459; https://doi.org/10.3390/ijms17040459 - 28 Mar 2016

Cited by 18 | Viewed by 5865

Abstract

Aripiprazole, a dopamine D₂ receptor (D₂R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects [...] Read more.

Aripiprazole, a dopamine D₂ receptor (D₂R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3β-dependent signalling pathways in the prefrontal cortex (PFC), nucleus accumbens (NAc), and caudate putamen (CPu), in comparison with haloperidol (a D₂R antagonist) and bifeprunox (a D₂R partial agonist). Rats were orally administrated aripiprazole (0.75 mg/kg), bifeprunox (0.8 mg/kg), haloperidol (0.1 mg/kg) or vehicle three times per day for one week. The levels of protein kinase B (Akt), p-Akt, GSK3β, p-GSK3β, dishevelled (Dvl)-3, and β-catenin were measured by Western Blots. Aripiprazole increased GSK3β phosphorylation in the PFC and NAc, respectively, while haloperidol elevated it in the NAc only. However, Akt activity was not changed by any of these drugs. Additionally, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3 and β-catenin in the NAc. The present study suggests that activation of GSK3β phosphorylation in the PFC and NAc may be involved in the clinical profile of aripiprazole; additionally, aripiprazole can increase GSK3β phosphorylation via the Dvl-GSK3β-β-catenin signalling pathway in the NAc, probably due to its relatively low intrinsic activity at D₂Rs. Full article

(This article belongs to the Special Issue Antipsychotics)

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14 pages, 774 KiB

Open AccessArticle

Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients

by Yoon-Kyum Shin^1,2 and Sung-Rae Cho^1,2,3,4,*

¹ Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, Korea

² Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea

³ Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul 03722, Korea

⁴ Yonsei Stem Cell Research Center, Avison Biomedical Research Center, Seoul 03722, Korea

Int. J. Mol. Sci. 2016, 17(4), 463; https://doi.org/10.3390/ijms17040463 - 30 Mar 2016

Cited by 21 | Viewed by 8221

Abstract

Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a [...] Read more.

Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a pilot study, 3 patients were treated with EPO and G-CSF for 5 consecutive days, with follow-up on day 30. In an exploratory double-blind study, 6 patients were allocated to treatment with either EPO+G-CSF or placebo. Treatment was applied once a day for 5 days per month over 3 months. Participants were followed up for 6 months. To substantiate safety, vital signs, adverse events, and hematological values were measured on days 0, 5, and 30 in each cycle and on day 180. Functional outcomes were determined on day 0 and 180. In the laboratory measurements, EPO+G-CSF combination therapy significantly elevated erythropoietin, CD34⁺ hematopoietic stem cells, white blood cells, and neutrophils on day 5 of each cycle. There were no observations of serious adverse events. In the functional outcomes, the grip power of the dominant hand was increased in the EPO+G-CSF treatment group. In conclusion, this exploratory study suggests a novel strategy of EPO+G-CSF combination therapy for stroke patients. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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11 pages, 2516 KiB

Open AccessArticle

Two ω-3 FADs Are Associated with Peach Fruit Volatile Formation

by Jiao-Jiao Wang¹, Hong-Ru Liu¹, Jie Gao¹, Yu-Ji Huang², Bo Zhang^1,*

and Kun-Song Chen¹

¹ Zhejiang Provincial Key Laboratory of Horticultural Plant Integrative Biology/Laboratory of Fruit Quality Biology, Zhejiang University, Hangzhou 310058, China

² College of Horticulture, Fujian Agriculture and Forestry University, Fuzhou 350002, China

Int. J. Mol. Sci. 2016, 17(4), 464; https://doi.org/10.3390/ijms17040464 - 29 Mar 2016

Cited by 40 | Viewed by 5652

Abstract

Aroma-related volatiles, together with sugars and acids, play an important role in determining fruit flavor quality. Characteristic volatiles of peach fruit are mainly derived from fatty acids such as linoleic acid (18:2) and linolenic acid (18:3). In the present study, six genes encoding [...] Read more.

Aroma-related volatiles, together with sugars and acids, play an important role in determining fruit flavor quality. Characteristic volatiles of peach fruit are mainly derived from fatty acids such as linoleic acid (18:2) and linolenic acid (18:3). In the present study, six genes encoding fatty acid desaturases (FAD) were cloned, including two ω-6 FAD genes (PpFAD2, PpFAD6) and four ω-3 FAD genes (PpFAD3-1, PpFAD3-2, PpFAD7 and PpFAD8). Heterologous expression of peach FADs in tobacco plants showed that PpFAD3-1, and PpFAD3-2 significantly reduced contents of 18:2, and accumulated significant higher levels of 18:3. In the case of volatiles, transgenic plants produced lower concentrations of hexanal and higher levels of (E)-2-hexenal. Consequently, the ratio of the (E)-2-hexenal and hexanal was about 5- and 3-fold higher than that of wild type (WT) in PpFAD3-1 and PpFAD3-2 transformants, respectively. No significant changes in volatile profiles were observed in transgenic plants overexpressing the four other peach FAD genes. Real-time quantitative polymerase chain reaction (qPCR) analysis showed that ripe fruit had high PpFAD3-1 and low PpFAD3-2 transcript levels. In contrast, high PpFAD3-2 and low PpFAD3-1 transcript levels were observed in young fruit. These results indicate a temporal regulation of these two ω-3 FADs during development and ripening, influencing peach fruit volatile formation. Full article

(This article belongs to the Section Molecular Plant Sciences)

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19 pages, 3903 KiB

Open AccessArticle

Anti-Apoptotic and Pro-Survival Effect of Alpinate Oxyphyllae Fructus (AOF) in a d-Galactose-Induced Aging Heart

by Yung-Ming Chang^1,2,3, Hen-Hong Chang^4,5,6, Wei-Wen Kuo⁷, Hung-Jen Lin^5,6, Yu-Lan Yeh^8,9

, Vijaya Padma Viswanadha¹⁰, Chin-Chuan Tsai^1,2, Ray-Jade Chen¹¹, Hsin-Nung Chang¹² and Chih-Yang Huang^12,13,14,*

¹ The School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung 84001, Taiwan

² Chinese Medicine Department, E-DA Hospital, Kaohsiung 82445, Taiwan

³ 1PT Biotechnology Co., Ltd., Taichung 433, Taiwan

⁴ Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung 40402, Taiwan

⁵ Departments of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan

⁶ School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan

⁷ Department of Biological Science and Technology, China Medical University, Taichung 40447, Taiwan

⁸ Department of pathology, Changhua Christian Hospital, Changhua 50506, Taiwan

⁹ Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 35665, Taiwan

¹⁰ Department of Biotechnology, Bharathiar University, Coimbatore 641046, India

¹¹ Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan

¹² Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan

¹³ School of Chinese Medicine, China Medical University, Taichung 40447, Taiwan

¹⁴ Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan

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Int. J. Mol. Sci. 2016, 17(4), 466; https://doi.org/10.3390/ijms17040466 - 29 Mar 2016

Cited by 48 | Viewed by 7956

Abstract

Aging, a natural biological/physiological phenomenon, is accelerated by reactive oxygen species (ROS) accumulation and identified by a progressive decrease in physiological function. Several studies have shown a positive relationship between aging and chronic heart failure (HF). Cardiac apoptosis was found in age-related diseases. [...] Read more.

Aging, a natural biological/physiological phenomenon, is accelerated by reactive oxygen species (ROS) accumulation and identified by a progressive decrease in physiological function. Several studies have shown a positive relationship between aging and chronic heart failure (HF). Cardiac apoptosis was found in age-related diseases. We used a traditional Chinese medicine, Alpinate Oxyphyllae Fructus (AOF), to evaluate its effect on cardiac anti-apoptosis and pro-survival. Male eight-week-old Sprague–Dawley (SD) rats were segregated into five groups: normal control group (NC), d-Galactose-Induced aging group (Aging), and AOF of 50 (AL (AOF low)), 100 (AM (AOF medium)), 150 (AH (AOF high)) mg/kg/day. After eight weeks, hearts were measured by an Hematoxylin–Eosin (H&E) stain, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-assays and Western blotting. The experimental results show that the cardiomyocyte apoptotic pathway protein expression increased in the d-Galactose-Induced aging groups, with dose-dependent inhibition in the AOF treatment group (AL, AM, and AH). Moreover, the expression of the pro-survival p-Akt (protein kinase B (Akt)), Bcl-2 (B-cell lymphoma 2), anti-apoptotic protein (Bcl-xL) protein decreased significantly in the d-Galactose-induced aging group, with increased performance in the AOF treatment group with levels of p-IGFIR and p-PI3K (Phosphatidylinositol-3′ kinase (PI3K)) to increase by dosage and compensatory performance. On the other hand, the protein of the Sirtuin 1 (SIRT1) pathway expression decreased in the aging groups and showed improvement in the AOF treatment group. Our results suggest that AOF strongly works against ROS-induced aging heart problems. Full article

(This article belongs to the Section Biochemistry)

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11 pages, 1851 KiB

Open AccessArticle

Restricted Gene Flow for Gadus macrocephalus from Yellow Sea Based on Microsatellite Markers: Geographic Block of Tsushima Current

by Na Song¹, Ming Liu¹, Takashi Yanagimoto², Yasunori Sakurai³, Zhi-Qiang Han⁴ and Tian-Xiang Gao^4,*

¹ Fisheries College, Ocean University of China, Qingdao 266003, China

² National Research Institute of Fisheries Science, Fisheries Research Agency, Yokohama 220-6115, Japan

³ Graduate School of Fisheries Sciences, Hokkaido University, Hokkaido 041-8611, Japan

⁴ Fishery College, Zhejiang Ocean University, Zhoushan 316022, China

Int. J. Mol. Sci. 2016, 17(4), 467; https://doi.org/10.3390/ijms17040467 - 29 Mar 2016

Cited by 8 | Viewed by 6412

Abstract

The Pacific cod Gadus macrocephalus is a demersal, economically important fish in the family Gadidae. Population genetic differentiation of Pacific cod was examined across its northwestern Pacific range by screening variation of eight microsatellite loci in the present study. All four populations exhibited [...] Read more.

The Pacific cod Gadus macrocephalus is a demersal, economically important fish in the family Gadidae. Population genetic differentiation of Pacific cod was examined across its northwestern Pacific range by screening variation of eight microsatellite loci in the present study. All four populations exhibited high genetic diversity. Pairwise fixation index (F_st) suggested a moderate to high level of genetic differentiation among populations. Population of the Yellow Sea (YS) showed higher genetic difference compared to the other three populations based on the results of pairwise F_st, three-dimensional factorial correspondence analysis (3D-FCA) and STRUCTURE, which implied restricted gene flow among them. Wilcoxon signed rank tests suggested no significant heterozygosity excess and no recent genetic bottleneck events were detected. Microsatellite DNA is an effective molecular marker for detecting the phylogeographic pattern of Pacific cod, and these Pacific cod populations should be three management units. Full article

(This article belongs to the Special Issue Fish Molecular Biology)

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17 pages, 2809 KiB

Open AccessArticle

Redox Proteomic Profiling of Specifically Carbonylated Proteins in the Serum of Triple Transgenic Alzheimer’s Disease Mice

by Liming Shen¹, Youjiao Chen¹, Aochu Yang¹, Cheng Chen¹, Liping Liao¹, Shuiming Li², Ming Ying¹, Jing Tian¹, Qiong Liu^1,* and Jiazuan Ni¹

¹ Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Science, Shenzhen University, Shenzhen 518060, China

² Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Science, Shenzhen University, Shenzhen 518060, China

Int. J. Mol. Sci. 2016, 17(4), 469; https://doi.org/10.3390/ijms17040469 - 12 Apr 2016

Cited by 21 | Viewed by 7881

Abstract

Oxidative stress is a key event in the onset and progression of neurodegenerative diseases, including Alzheimer’s disease (AD). To investigate the role of oxidative stress in AD and to search for potential biomarkers in peripheral blood, serums were collected in this study from [...] Read more.

Oxidative stress is a key event in the onset and progression of neurodegenerative diseases, including Alzheimer’s disease (AD). To investigate the role of oxidative stress in AD and to search for potential biomarkers in peripheral blood, serums were collected in this study from the 3-, 6-, and 12-month-old triple transgenic AD mice (3×Tg-AD mice) and the age- and sex-matched non-transgenic (non-Tg) littermates. The serum oxidized proteins were quantified by slot-blot analysis and enzyme-linked immunosorbent assay (ELISA) to investigate the total levels of serum protein carbonyl groups. Western blotting, in conjunction with two-dimensional gel electrophoresis (2D-Oxyblot), was employed to identify and quantify the specifically-carbonylated proteins in the serum of 3×Tg-AD mice. The results showed that the levels of serum protein carbonyls were increased in the three month old 3×Tg-AD mice compared with the non-Tg control mice, whereas no significant differences were observed in the six and 12 months old AD mice, suggesting that oxidative stress is an early event in AD progression. With the application of 2D-Oxyblot analysis, (immunoglobin) Ig gamma-2B chain C region (IGH-3), Ig lambda-2 chain C region (IGLC2), Ig kappa chain C region (IGKC), and Ig kappa chain V-V region HP R16.7 were identified as significantly oxidized proteins compared with the control. Among them IGH-3 and IGKC were validated via immunoprecipitation and Western blot analysis. Identification of oxidized proteins in the serums of 3×Tg-AD mice can not only reveal potential roles of those proteins in the pathogenesis of AD but also provide potential biomarkers of AD at the early stage. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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15 pages, 11159 KiB

Open AccessArticle

GL-1196 Suppresses the Proliferation and Invasion of Gastric Cancer Cells via Targeting PAK4 and Inhibiting PAK4-Mediated Signaling Pathways

by Jian Zhang¹, Hong-Yan Zhang¹, Jian Wang², Liang-Hao You¹, Rui-Zhi Zhou¹, Dong-Mei Zhao², Mao-Sheng Cheng² and Feng Li^1,*

¹ Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China

² Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China

Int. J. Mol. Sci. 2016, 17(4), 470; https://doi.org/10.3390/ijms17040470 - 11 Apr 2016

Cited by 19 | Viewed by 7150 | Correction

Abstract

Gastric cancer, which is the most common malignant gastrointestinal tumor, has jumped to the third leading cause of cancer-related mortality worldwide. It is of great importance to identify novel and potent drugs for gastric cancer treatment. P21-activated kinase 4 (PAK4) has emerged as [...] Read more.

Gastric cancer, which is the most common malignant gastrointestinal tumor, has jumped to the third leading cause of cancer-related mortality worldwide. It is of great importance to identify novel and potent drugs for gastric cancer treatment. P21-activated kinase 4 (PAK4) has emerged as an attractive target for the development of anticancer drugs in consideration of its vital functions in tumorigenesis and progression. In this paper, we reported that GL-1196, as a small molecular compound, effectively suppressed the proliferation of human gastric cancer cells through downregulation of PAK4/c-Src/EGFR/cyclinD1 pathway and CDK4/6 expression. Moreover, GL-1196 prominently inhibited the invasion of human gastric cancer cells in parallel with blockage of the PAK4/LIMK1/cofilin pathway. Interestingly, GL-1196 also inhibited the formation of filopodia and induced cell elongation in SGC7901 and BGC823 cells. Taken together, these results provided novel insights into the potential therapeutic strategy for gastric cancer. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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16 pages, 3147 KiB

Open AccessArticle

The Expression Profile of Complement Components in Podocytes

by Xuejuan Li, Fangrui Ding, Xiaoyan Zhang, Baihong Li and Jie Ding^*

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China

Int. J. Mol. Sci. 2016, 17(4), 471; https://doi.org/10.3390/ijms17040471 - 30 Mar 2016

Cited by 41 | Viewed by 7532

Abstract

Podocytes are critical for maintaining the glomerular filtration barrier and are injured in many renal diseases, especially proteinuric kidney diseases. Recently, reports suggested that podocytes are among the renal cells that synthesize complement components that mediate glomerular diseases. Nevertheless, the profile and extent [...] Read more.

Podocytes are critical for maintaining the glomerular filtration barrier and are injured in many renal diseases, especially proteinuric kidney diseases. Recently, reports suggested that podocytes are among the renal cells that synthesize complement components that mediate glomerular diseases. Nevertheless, the profile and extent of complement component expression in podocytes remain unclear. This study examined the expression profile of complement in podocytes under physiological conditions and in abnormal podocytes induced by multiple stimuli. In total, 23/32 complement component components were detected in podocyte by conventional RT-PCR. Both primary cultured podocytes and immortalized podocytes expressed the complement factors C1q, C1r, C2, C3, C7, MASP, CFI, DAF, CD59, C4bp, CD46, Protein S, CR2, C1qR, C3aR, C5aR, and Crry (17/32), whereas C4, CFB, CFD, C5, C6, C8, C9, MBL1, and MBL2 (9/32) complement factors were not expressed. C3, Crry, and C1q-binding protein were detected by tandem mass spectrometry. Podocyte complement gene expression was affected by several factors (puromycin aminonucleoside (PAN), angiotensin II (Ang II), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β)). Representative complement components were detected using fluorescence confocal microscopy. In conclusion, primary podocytes express various complement components at the mRNA and protein levels. The complement gene expressions were affected by several podocyte injury factors. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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14 pages, 1231 KiB

Open AccessArticle

Multiplex Immunoassay of Plasma Cytokine Levels in Men with Alcoholism and the Relationship to Psychiatric Assessments

by Ann M. Manzardo^*

, Albert B. Poje

, Elizabeth C. Penick and Merlin G. Butler

Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, MO 64101, USA

Int. J. Mol. Sci. 2016, 17(4), 472; https://doi.org/10.3390/ijms17040472 - 29 Mar 2016

Cited by 26 | Viewed by 7583

Abstract

Chronic alcohol use alters adaptive immunity and cytokine activity influencing immunological and hormone responses, inflammation, and wound healing. Brain cytokine disturbances may impact neurological function, mood, cognition and traits related to alcoholism including impulsiveness. We examined the relationship between plasma cytokine levels and [...] Read more.

Chronic alcohol use alters adaptive immunity and cytokine activity influencing immunological and hormone responses, inflammation, and wound healing. Brain cytokine disturbances may impact neurological function, mood, cognition and traits related to alcoholism including impulsiveness. We examined the relationship between plasma cytokine levels and self-rated psychiatric symptoms in 40 adult males (mean age 51 ± 6 years; range 33–58 years) with current alcohol dependence and 30 control males (mean age 48 ± 6 years; range 40–58 years) with no history of alcoholism using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Log-transformed cytokine levels were analyzed for their relationship with the Symptom Checklist-90R (SCL-90R), Barratt Impulsivity Scales (BIS) and Alcoholism Severity Scale (ASS). Inflammatory cytokines (interferon γ-induced protein-10 (IP-10); monocyte chemoattractant protein-1 (MCP1); regulated on activation, normal T cell expressed and secreted (RANTES)) were significantly elevated in alcoholism compared to controls while bone marrow-derived hematopoietic cytokines and chemokines (granulocyte-colony stimulating factor (GCSF); soluble CD40 ligand (sCD40L); growth-related oncogene (GRO)) were significantly reduced. GRO and RANTES levels were positively correlated with BIS scales; and macrophage-derived chemokine (MDC) levels were positively correlated with SCL-90R scale scores (p < 0.05). Elevated inflammatory mediators in alcoholism may influence brain function leading to increased impulsiveness and/or phobia. The novel association between RANTES and GRO and impulsivity phenotype in alcoholism should be further investigated in alcoholism and psychiatric conditions with core impulsivity and anxiety phenotypes lending support for therapeutic intervention. Full article

(This article belongs to the Special Issue Alcoholism: Molecular Mechanisms and Treatment Strategies)

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8 pages, 1049 KiB

Open AccessCommunication

Fluorescence-Lifetime Imaging Microscopy for Visualization of Quantum Dots’ Endocytic Pathway

by Leona Damalakiene¹, Vitalijus Karabanovas^2,3,*

, Saulius Bagdonas¹ and Ricardas Rotomskis^1,2

¹ Biophotonics Group of Laser Research Center, Faculty of Physics, Vilnius University, Sauletekio 9, b. 3, Vilnius LT-10222, Lithuania

² Biomedical Physics Laboratory, National Cancer Institute, P. Baublio 3b, Vilnius LT-08406, Lithuania

³ Department of Chemistry and Bioengineering, Vilnius Gediminas Technical University, Vilnius LT-10223, Lithuania

Int. J. Mol. Sci. 2016, 17(4), 473; https://doi.org/10.3390/ijms17040473 - 30 Mar 2016

Cited by 19 | Viewed by 6834

Abstract

Accumulation of carboxylated polyethylene glycol (PEG) CdSe/ZnSquantum dots (QDs) has been monitored in living fibroblasts using confocal microscopy for fluorescence intensity and fluorescence-lifetime imaging (FLIM). The wide range of mean photoluminescence (PL) lifetime values was observed for the intracellular QDs in different intracellular [...] Read more.

Accumulation of carboxylated polyethylene glycol (PEG) CdSe/ZnSquantum dots (QDs) has been monitored in living fibroblasts using confocal microscopy for fluorescence intensity and fluorescence-lifetime imaging (FLIM). The wide range of mean photoluminescence (PL) lifetime values was observed for the intracellular QDs in different intracellular microenvironment, which revealed structural heterogeneity of endosomes and enabled the distinguishing among endosomes of different maturity. Full article

(This article belongs to the Special Issue Inorganic Nanostructures in Biological Systems)

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15 pages, 1812 KiB

Open AccessArticle

Thymoquinone Modulates Blood Coagulation in Vitro via Its Effects on Inflammatory and Coagulation Pathways

by Vandhana Muralidharan-Chari

, Jaehan Kim, Ahlam Abuawad, Mubeena Naeem, Huadong Cui and Shaker A. Mousa^*

The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rennselaer, NY 12144, USA

Int. J. Mol. Sci. 2016, 17(4), 474; https://doi.org/10.3390/ijms17040474 - 30 Mar 2016

Cited by 22 | Viewed by 8940

Abstract

Thymoquinone (THQ) is a major component of black seeds. Given that both THQ and black seeds exhibit anti-cancer and anti-inflammatory activities, we hypothesized that THQ will affect cancer-associated thrombosis (CAT), which is primarily triggered by tissue factor (TF) and inflammation. The effect of [...] Read more.

Thymoquinone (THQ) is a major component of black seeds. Given that both THQ and black seeds exhibit anti-cancer and anti-inflammatory activities, we hypothesized that THQ will affect cancer-associated thrombosis (CAT), which is primarily triggered by tissue factor (TF) and inflammation. The effect of both black seed-extracted and purchased (“pure”) THQ on normal blood coagulation was tested with in vitro thromboelastography (TEG) and activated partial thromboplastin time (aPTT) coagulation assays. The effect of pure THQ on CAT was tested with aPTT assay using pancreatic cancer cell lines that are either positive or negative for TF, and with TEG assay using lipopolysaccharide as an inflammatory trigger. Additionally, the direct effect of THQ on the inactivation of factors IIa and Xa was assessed. Since TNF-α facilitates crosstalk between inflammation and thrombosis by triggering the NF-κB pathway, we tested THQ’s ability to interfere with this communication with a luciferase assay. Both extracted and pure THQ had minimal effects on normal blood coagulation. Pure THQ reversed CAT initiated by both TF and inflammation to basal levels (p < 0.001). Mechanistically, while THQ had minimal to no effect on factor IIa and Xa inactivation, it strongly reduced the effects of TNF-α on NF-κB elements (p < 0.001). THQ has a minimal effect on basal coagulation and can reverse CAT in vitro, possibly by interfering with the crosstalk between inflammation and coagulation. This study suggests the utility of THQ as a preventative anticoagulant and/or as a supplement to existing chemotherapies and anticoagulant therapies. Full article

(This article belongs to the Special Issue The Mechanism of Action of Food Components in Disease Prevention)

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17 pages, 1836 KiB

Open AccessArticle

Combining miRNA and mRNA Expression Profiles in Wilms Tumor Subtypes

by Nicole Ludwig^1,*, Tamara V. Werner¹, Christina Backes², Patrick Trampert³, Manfred Gessler⁴, Andreas Keller², Hans-Peter Lenhof³, Norbert Graf⁵

and Eckart Meese¹

¹ Department of Human Genetics, Saarland University, 66421 Homburg/Saar, Germany

² Chair for Clinical Bioinformatics, Building E2.1, 66123 Saarbruecken, Germany

³ Center for Bioinformatics, Saarland University, Building E.1.1, 66041 Saarbruecken, Germany

⁴ Developmental Biochemistry, Biocenter, and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, 97074 Wuerzburg, Germany

⁵ Department of Pediatric Oncology and Hematology, Medical School, Saarland University, 66421 Homburg, Germany

Int. J. Mol. Sci. 2016, 17(4), 475; https://doi.org/10.3390/ijms17040475 - 30 Mar 2016

Cited by 46 | Viewed by 7897

Abstract

Wilms tumor (WT) is the most common childhood renal cancer. Recent findings of mutations in microRNA (miRNA) processing proteins suggest a pivotal role of miRNAs in WT genesis. We performed miRNA expression profiling of 36 WTs of different subtypes and four normal kidney [...] Read more.

Wilms tumor (WT) is the most common childhood renal cancer. Recent findings of mutations in microRNA (miRNA) processing proteins suggest a pivotal role of miRNAs in WT genesis. We performed miRNA expression profiling of 36 WTs of different subtypes and four normal kidney tissues using microarrays. Additionally, we determined the gene expression profile of 28 of these tumors to identify potentially correlated target genes and affected pathways. We identified 85 miRNAs and 2107 messenger RNAs (mRNA) differentially expressed in blastemal WT, and 266 miRNAs and 1267 mRNAs differentially expressed in regressive subtype. The hierarchical clustering of the samples, using either the miRNA or mRNA profile, showed the clear separation of WT from normal kidney samples, but the miRNA pattern yielded better separation of WT subtypes. A correlation analysis of the deregulated miRNA and mRNAs identified 13,026 miRNA/mRNA pairs with inversely correlated expression, of which 2844 are potential interactions of miRNA and their predicted mRNA targets. We found significant upregulation of miRNAs-183, -301a/b and -335 for the blastemal subtype, and miRNAs-181b, -223 and -630 for the regressive subtype. We found marked deregulation of miRNAs regulating epithelial to mesenchymal transition, especially in the blastemal subtype, and miRNAs influencing chemosensitivity, especially in regressive subtypes. Further research is needed to assess the influence of preoperative chemotherapy and tumor infiltrating lymphocytes on the miRNA and mRNA patterns in WT. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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14 pages, 3271 KiB

Open AccessArticle

Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells

by Ji-Sun Jung¹, Young-Ho Ahn¹

, Byung-In Moon² and Hee-Sun Kim^1,*

¹ Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul 07985, Korea

² Department of Surgery, Ewha Womans University Medical School, Seoul 07985, Korea

Int. J. Mol. Sci. 2016, 17(4), 477; https://doi.org/10.3390/ijms17040477 - 31 Mar 2016

Cited by 17 | Viewed by 7578

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which play a pivotal role in invasion, migration, and angiogenesis of glioma. Therefore, controlling MMPs is potentially an important therapeutic strategy for glioma. In the present study, we found that exogenous cell-permeable short-chain C2 [...] Read more.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which play a pivotal role in invasion, migration, and angiogenesis of glioma. Therefore, controlling MMPs is potentially an important therapeutic strategy for glioma. In the present study, we found that exogenous cell-permeable short-chain C2 ceramide inhibits phorbol myristate acetate (PMA)-induced MMP-1, -3, and -9 gene expressions in U87MG and U373MG human astroglioma cells. In addition, C2 ceramide inhibited the protein secretion and enzymatic activities of MMP-1, -3, and -9. The Matrigel invasion assay and wound healing assay showed that C2 ceramide suppresses the in vitro invasion and migration of glioma cells, which appears to be involved in strong inhibition of MMPs by C2 ceramide. Subsequent mechanistic studies revealed that C2 ceramide inhibits PMA-induced mitogen-activated protein kinase (MAPK) phosphorylation and nuclear factor (NF)-κB/activator protein (AP)-1 DNA binding activities. Furthermore, C2 ceramide significantly inhibited PMA-induced reactive oxygen species (ROS) production and NADPH oxidase 4 (NOX4) expression, and inhibition of ROS by diphenylene iodonium (DPI, NADPH oxidase inhibitor) mimicked the effects of C2 ceramide on MMP expression and NF-κB/AP-1 via inhibition of p38 MAPK. The results suggest C2 ceramide inhibits MMP expression and glioma invasion, at least partly, by modulating ROS-p38 MAPK signaling axis and other MAPK signaling pathways. Full article

(This article belongs to the Special Issue Metalloproteins)

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15 pages, 1965 KiB

Open AccessArticle

Different Serum Free Fatty Acid Profiles in NAFLD Subjects and Healthy Controls after Oral Fat Load

by Roberto Gambino^*, Elisabetta Bugianesi, Chiara Rosso

, Lavinia Mezzabotta, Silvia Pinach, Natalina Alemanno, Francesca Saba and Maurizio Cassader

Department of Medical Sciences, University of Turin, C.so Dogliotti 14, 10126 Torino, Italy

Int. J. Mol. Sci. 2016, 17(4), 479; https://doi.org/10.3390/ijms17040479 - 31 Mar 2016

Cited by 90 | Viewed by 10391

Abstract

Background: Free fatty acid (FFA) metabolism can impact on metabolic conditions, such as obesity and nonalcoholic fatty liver disease (NAFLD). This work studied the increase in total FFA shown in NAFLD subjects to possibly characterize which fatty acids significantly accounted for the whole [...] Read more.

Background: Free fatty acid (FFA) metabolism can impact on metabolic conditions, such as obesity and nonalcoholic fatty liver disease (NAFLD). This work studied the increase in total FFA shown in NAFLD subjects to possibly characterize which fatty acids significantly accounted for the whole increase. Methods: 21 patients with NAFLD were selected according to specified criteria. The control group consisted of nine healthy subjects. All subjects underwent an oral standard fat load. Triglycerides; cholesterol; FFA; glucose and insulin were measured every 2 h with the determination of fatty acid composition of FFA. Results: higher serum FFA levels in NAFLD subjects are mainly due to levels of oleic, palmitic and linoleic acids at different times. Significant increases were shown for docosahexaenoic acid, linolenic acid, eicosatrienoic acid, and arachidonic acid, although this was just on one occasion. In the postprandial phase, homeostatic model assessment HOMA index positively correlated with the ω3/ω6 ratio in NAFLD patients. Conclusions: the higher serum levels of FFA in NAFLD subjects are mainly due to levels of oleic and palmitic acids which are the most abundant circulating free fatty acids. This is almost exactly corresponded with significant increases in linoleic acid. An imbalance in the n-3/n-6 fatty acids ratio could modulate postprandial responses with more pronounced effects in insulin-resistant subjects, such as NAFLD patients. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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12 pages, 6702 KiB

Open AccessArticle

High Salt Diet Affects Renal Sodium Excretion and ERRα Expression

by Dan Wang, Yang Wang, Fu-Qiang Liu

, Zu-Yi Yuan and Jian-Jun Mu^*

Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Key Laboratory of Molecular Cardiology, No. 277 Yanta West Road, Xi’an 710061, China

Int. J. Mol. Sci. 2016, 17(4), 480; https://doi.org/10.3390/ijms17040480 - 1 Apr 2016

Cited by 15 | Viewed by 6202

Abstract

Kidneys regulate the balance of water and sodium and therefore are related to blood pressure. It is unclear whether estrogen-related receptor α (ERRα), an orphan nuclear receptor and transcription factor highly expressed in kidneys, affects the reabsorption of water and sodium. The aim [...] Read more.

Kidneys regulate the balance of water and sodium and therefore are related to blood pressure. It is unclear whether estrogen-related receptor α (ERRα), an orphan nuclear receptor and transcription factor highly expressed in kidneys, affects the reabsorption of water and sodium. The aim of this study was to determine whether changes in the expressions of ERRα, Na⁺/K⁺-ATPase and epithelial sodium channel (ENaC) proteins affected the reabsorption of water and sodium in kidneys of Dahl salt-sensitive (DS) rats. SS.13BN rats, 98% homologous to the DS rats, were used as a normotensive control group. The 24 h urinary sodium excretion of the DS and SS.13BN rats increased after the 6-week high salt diet intervention, while sodium excretion was increased in DS rats with daidzein (agonist of ERRα) treatment. ERRα expression was decreased, while β- and γ-ENaC mRNA expressions were increased upon high sodium diet treatment in the DS rats. In the chromatin immunoprecipitation (CHIP) assay, positive PCR signals were obtained in samples treated with anti-ERRα antibody. The transcriptional activity of ERRα was decreased upon high salt diet intervention. ERRα reduced the expressions of β- and γ-ENaC by binding to the ENaC promoter, thereby increased Na+ reabsorption. Therefore, ERRα might be one of the factors causing salt-sensitive hypertension. Full article

(This article belongs to the Special Issue Molecular Research on Hypertension)

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23 pages, 3243 KiB

Open AccessArticle

Gastrointestinal Endogenous Protein-Derived Bioactive Peptides: An in Vitro Study of Their Gut Modulatory Potential

by Lakshmi A. Dave^1,2, Maria Hayes², Leticia Mora³, Carlos A. Montoya¹, Paul J. Moughan¹ and Shane M. Rutherfurd^1,*

¹ The Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand

² Teagasc, The Irish Agricultural and Food Development Authority, Food BioSciences Department, Ashtown, Dublin 15, Ireland

³ Instituto de Agroquı́mica y Tecnologı́a de Alimentos (CSIC), Avenida Agustín Escardino 7, 46980 Paterna, Valencia 46002, Spain

Int. J. Mol. Sci. 2016, 17(4), 482; https://doi.org/10.3390/ijms17040482 - 1 Apr 2016

Cited by 18 | Viewed by 6163

Abstract

A recently proposed paradigm suggests that, like their dietary counterparts, digestion of gastrointestinal endogenous proteins (GEP) may also produce bioactive peptides. With an aim to test this hypothesis, in vitro digests of four GEP namely; trypsin (TRYP), lysozyme (LYS), mucin (MUC), serum albumin [...] Read more.

A recently proposed paradigm suggests that, like their dietary counterparts, digestion of gastrointestinal endogenous proteins (GEP) may also produce bioactive peptides. With an aim to test this hypothesis, in vitro digests of four GEP namely; trypsin (TRYP), lysozyme (LYS), mucin (MUC), serum albumin (SA) and a dietary protein chicken albumin (CA) were screened for their angiotensin-I converting (ACE-I), renin, platelet-activating factor-acetylhydrolase (PAF-AH) and dipeptidyl peptidase-IV inhibitory (DPP-IV) and antioxidant potential following simulated in vitro gastrointestinal digestion. Further, the resultant small intestinal digests were enriched to obtain peptides between 3–10 kDa in size. All in vitro digests of the four GEP were found to inhibit ACE-I compared to the positive control captopril when assayed at a concentration of 1 mg/mL, while the LYS < 3-kDa permeate fraction inhibited renin by 40% (±1.79%). The LYS < 10-kDa fraction inhibited PAF-AH by 39% (±4.34%), and the SA < 3-kDa fraction inhibited DPP-IV by 45% (±1.24%). The MUC < 3-kDa fraction had an ABTS-inhibition antioxidant activity of 150 (±24.79) µM trolox equivalent and the LYS < 10-kDa fraction inhibited 2,2-Diphenyl-1-picrylhydrazyl (DPPH) by 54% (±1.62%). Moreover, over 190 peptide-sequences were identified from the bioactive GEP fractions. The findings of the present study indicate that GEP are a significant source of bioactive peptides which may influence gut function. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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14 pages, 2763 KiB

Open AccessArticle

Mesenchymal Stem Cells Ameliorated Glucolipotoxicity in HUVECs through TSG-6

by Xingxing An¹, Lan Li¹, Younan Chen^1,2, Ai Luo³, Zuyao Ni⁴, Jingping Liu¹, Yujia Yuan¹, Meimei Shi¹, Bo Chen¹, Dan Long¹, Jingqiu Cheng^1,* and Yanrong Lu^1,*

¹ Key Laboratory of Transplant Engineering and Immunology, Ministry of Health; West China Hospital, Sichuan University, Chengdu 610041, China

² School of Biomedical Sciences, CHIRI Biosciences, Curtin University, GPO Box U1987, Perth, WA 6845, Australia

³ Sichuan Neo-Life Stem Cell Biotech Inc. Chengdu 610041, China

⁴ Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada

Int. J. Mol. Sci. 2016, 17(4), 483; https://doi.org/10.3390/ijms17040483 - 1 Apr 2016

Cited by 20 | Viewed by 7255

Abstract

Glucolipotoxicity is one of the critical causal factors of diabetic complications. Whether mesenchymal stem cells (MSCs) have effects on glucolipotoxicity in human umbilical vein endothelial cells (HUVECs) and mechanisms involved are unclear. Thirty mM glucose plus 100 μM palmitic acid was used to [...] Read more.

Glucolipotoxicity is one of the critical causal factors of diabetic complications. Whether mesenchymal stem cells (MSCs) have effects on glucolipotoxicity in human umbilical vein endothelial cells (HUVECs) and mechanisms involved are unclear. Thirty mM glucose plus 100 μM palmitic acid was used to induce glucolipotoxicity in HUVECs. MSCs and HUVECs were co-cultured at the ratio of 1:5 via Transwell system. The mRNA expressions of inflammatory factors were detected by RT-qPCR. The productions of reactive oxygen species (ROS), cell cycle and apoptosis were analyzed by flow cytometry. The tumor necrosis factor-α stimulated protein 6 (TSG-6) was knockdown in MSCs by RNA interference. High glucose and palmitic acid remarkably impaired cell viability and tube formation capacity, as well as increased the mRNA expression of inflammatory factors, ROS levels, and cell apoptosis in HUVECs. MSC co-cultivation ameliorated these detrimental effects in HUVECs, but no effect on ROS production. Moreover, TSG-6 was dramatically up-regulated by high glucose and fatty acid stimulation in both MSCs and HUVECs. TSG-6 knockdown partially abolished the protection mediated by MSCs. MSCs had protective effects on high glucose and palmitic acid induced glucolipotoxicity in HUVECs, and TSG-6 secreted by MSCs was likely to play an important role in this process. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)

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9 pages, 215 KiB

Open AccessArticle

KRAS G12V Mutation Detection by Droplet Digital PCR in Circulating Cell-Free DNA of Colorectal Cancer Patients

by Susana Olmedillas López^1,*

, Dolores C. García-Olmo², Mariano García-Arranz^1,3, Héctor Guadalajara^3,4, Carlos Pastor⁵ and Damián García-Olmo^1,3,5

¹ Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid 28040, Spain

² Experimental Research Unit, General University Hospital of Albacete, Albacete 02006, Spain

³ Department of Surgery, School of Medicine, Autónoma University of Madrid, Madrid 28029, Spain

⁴ Department of General Surgery, General Hospital of Villalba, Madrid 28400, Spain

⁵ Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain

Int. J. Mol. Sci. 2016, 17(4), 484; https://doi.org/10.3390/ijms17040484 - 1 Apr 2016

Cited by 45 | Viewed by 9363

Abstract

KRAS mutations are responsible for resistance to anti-epidermal growth factor receptor (EGFR) therapy in colorectal cancer patients. These mutations sometimes appear once treatment has started. Detection of KRAS mutations in circulating cell-free DNA in plasma (“liquid biopsy”) by droplet digital PCR (ddPCR) has [...] Read more.

KRAS mutations are responsible for resistance to anti-epidermal growth factor receptor (EGFR) therapy in colorectal cancer patients. These mutations sometimes appear once treatment has started. Detection of KRAS mutations in circulating cell-free DNA in plasma (“liquid biopsy”) by droplet digital PCR (ddPCR) has emerged as a very sensitive and promising alternative to serial biopsies for disease monitoring. In this study, KRAS G12V mutation was analyzed by ddPCR in plasma DNA from 10 colorectal cancer patients and compared to six healthy donors. The percentage of KRAS G12V mutation relative to wild-type sequences in tumor-derived DNA was also determined. KRAS G12V mutation circulating in plasma was detected in 9 of 10 colorectal cancer patients whose tumors were also mutated. Colorectal cancer patients had 35.62 copies of mutated KRAS/mL plasma, whereas in healthy controls only residual copies were found (0.62 copies/mL, p = 0.0066). Interestingly, patients with metastatic disease showed a significantly higher number of mutant copies than M0 patients (126.25 versus 9.37 copies/mL, p = 0.0286). Wild-type KRAS was also significantly elevated in colorectal cancer patients compared to healthy controls (7718.8 versus 481.25 copies/mL, p = 0.0002). In conclusion, KRAS G12V mutation is detectable in plasma of colorectal cancer patients by ddPCR and could be used as a non-invasive biomarker. Full article

(This article belongs to the Special Issue Circulating Tumor Cells)

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13 pages, 1032 KiB

Open AccessArticle

Do Variants in GSTs Modify the Association between Traffic Air Pollution and Asthma in Adolescence?

by Gayan Bowatte¹

, Caroline J. Lodge^1,2, Adrian J. Lowe^1,2, Bircan Erbas³, Martine Dennekamp⁴, Guy B. Marks^5,6, Jennifer Perret¹, Jennie Hui⁷, Matthias Wjst⁸, Lyle C. Gurrin¹, Katrina J. Allen^2,9, Michael J. Abramson⁴

, Melanie C. Matheson^1,† and Shyamali C. Dharmage^1,2,*,†

¹ Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population & Global Health, the University of Melbourne, Melbourne, VIC 3053, Australia

² Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia

³ School of Psychology & Public Health, Department of Public Health, Latrobe University, Melbourne, VIC 3086, Australia

⁴ School of Public Health & Preventive Medicine, Monash University, The Alfred, Melbourne, VIC 3004, Australia

⁵ Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW 2037, Australia

⁶ South Western Sydney Clinical School, University of New South Wales, Sydney, NSW 2052, Australia

⁷ Busselton Population Medical Research Institute, Perth WA 6009, Australia

⁸ Molecular Genetics of Lung Diseases, Comprehensive Pneumology Center, Helmholtz Zentrum, Muenchen 81377, Germany

⁹ Department of Allergy and Immunology, Royal Children’s Hospital, Parkville, VIC 3052, Australia

^† These authors equally contributed to this work.

Int. J. Mol. Sci. 2016, 17(4), 485; https://doi.org/10.3390/ijms17040485 - 1 Apr 2016

Cited by 24 | Viewed by 7271

Abstract

Polymorphisms in genes involved in the oxidative stress response may partially explain the documented heterogeneous associations between traffic-related air pollution (TRAP) exposure and asthma and allergies in children. We investigated whether the GSTT1, GSTM1 and GSTP1 gene polymorphisms modified the associations between [...] Read more.

Polymorphisms in genes involved in the oxidative stress response may partially explain the documented heterogeneous associations between traffic-related air pollution (TRAP) exposure and asthma and allergies in children. We investigated whether the GSTT1, GSTM1 and GSTP1 gene polymorphisms modified the associations between TRAP exposure during the first year of life and asthma, wheeze and hay fever in adolescence. We used a birth cohort of 620 high risk infants from the Melbourne Atopy Cohort Study. TRAP exposure during the first year of life was defined as the cumulative length of major roads within 150 m of each participant’s residence during the first year of life. Wheeze, asthma and hay fever were measured at ages 12 (n = 370) and 18 (n = 434) years. The associations and interactions with glutathione S-transferases (GST s) were investigated using regression models. Overall, there was no relationship between TRAP exposure during the first year of life and current asthma, wheeze and hay fever at ages 12 or 18 years. However, in GSTT1 null carriers, every 100 m increase in cumulative lengths of major road exposure during the first year of life was associated with a 2.31-fold increased risk of wheeze and a 2.15-fold increased risk of asthma at 12 years. TRAP is associated with some respiratory outcomes in carriers of genetic polymorphisms in oxidative stress metabolism genes. Full article

(This article belongs to the Special Issue Molecular Research on Global Climate Change and Atmospheric Pollution)

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10 pages, 448 KiB

Open AccessArticle

The Impact of Specific Viruses on Clinical Outcome in Children Presenting with Acute Heart Failure

by Maria Giulia Gagliardi^1,*, Alessandra Fierabracci²

, Mara Pilati¹, Marcello Chinali¹, Carlo Bassano³, Francesca Saura⁴, Isabella Giovannoni⁵ and Paola Francalanci⁵

¹ Medical and Surgical Department of Cardiology, Children’s Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy

² Immuno-Infectivology and Clinical Trials Area, Children’s Hospital Bambino Gesù, Viale S. Paolo 15, 00146 Rome, Italy

³ Operative Unit and Chair of Cardiac Surgery, Tor Vergata University, Viale Oxford 81, 00133 Rome, Italy

⁴ Department of Laboratory Medicine, Children’s Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy

⁵ Department of Pathology, Children’s Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy

Int. J. Mol. Sci. 2016, 17(4), 486; https://doi.org/10.3390/ijms17040486 - 1 Apr 2016

Cited by 16 | Viewed by 5489

Abstract

The presence and type of viral genomes have been suggested as the main etiology for inflammatory dilated cardiomyopathy. Information on the clinical implication of this finding in a large population of children is lacking. We evaluated the prevalence, type, and clinical impact of [...] Read more.

The presence and type of viral genomes have been suggested as the main etiology for inflammatory dilated cardiomyopathy. Information on the clinical implication of this finding in a large population of children is lacking. We evaluated the prevalence, type, and clinical impact of specific viral genomes in endomyocardial biopsies (EMB) collected between 2001 and 2013 among 63 children admitted to our hospital for acute heart failure (median age 2.8 years). Viral genome was searched by polymerase chain reaction (PCR). Patients underwent a complete two-dimensional echocardiographic examination at hospital admission and at discharge and were followed-up for 10 years. Twenty-seven adverse events (7 deaths and 20 cardiac transplantations) occurred during the follow-up. Viral genome was amplified in 19/63 biopsies (35%); PVB19 was the most commonly isolated virus. Presence of specific viral genome was associated with a significant recovery in ejection fraction, compared to patients without viral evidence (p < 0.05). In Cox-regression analysis, higher survival rate was related to virus-positive biopsies (p < 0.05). When comparing long-term prognosis among different viral groups, a trend towards better prognosis was observed in the presence of isolated Parvovirus B19 (PVB19) (p = 0.07). In our series, presence of a virus-positive EMB (mainly PVB19) was associated with improvement over time in cardiac function and better long-term prognosis. Full article

(This article belongs to the Special Issue Infectious Diseases: Pathophysiology, Diagnostics, Therapies, and Prevention)

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12 pages, 1999 KiB

Open AccessArticle

Optical Absorption Spectra and Electronic Properties of Symmetric and Asymmetric Squaraine Dyes for Use in DSSC Solar Cells: DFT and TD-DFT Studies

by Reda M. El-Shishtawy^1,*, Shaaban A. Elroby^1,2,*

, Abdullah M. Asiri¹ and Klaus Müllen³

¹ Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah B.O. 208203, Saudi Arabia

² Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 6251, Egypt

³ Max-Planck Institute for Polymer Research, Ackermannweg 10, Mainz 55128, Germany

Int. J. Mol. Sci. 2016, 17(4), 487; https://doi.org/10.3390/ijms17040487 - 1 Apr 2016

Cited by 35 | Viewed by 9048

Abstract

The electronic absorption spectra, ground-state geometries and electronic structures of symmetric and asymmetric squaraine dyes (SQD1–SQD4) were investigated using density functional theory (DFT) and time-dependent (TD-DFT) density functional theory at the B3LYP/6-311++G** level. The calculated ground-state geometries reveal pronounced conjugation in these dyes. [...] Read more.

The electronic absorption spectra, ground-state geometries and electronic structures of symmetric and asymmetric squaraine dyes (SQD1–SQD4) were investigated using density functional theory (DFT) and time-dependent (TD-DFT) density functional theory at the B3LYP/6-311++G** level. The calculated ground-state geometries reveal pronounced conjugation in these dyes. Long-range corrected time dependent density functionals Perdew, Burke and Ernzerhof (PBE, PBE1PBE (PBE0)), and the exchange functional of Tao, Perdew, Staroverov, and Scuseria (TPSSh) with 6-311++G** basis set were employed to examine optical absorption properties. In an extensive comparison between the optical data and DFT benchmark calculations, the BEP functional with 6-311++G** basis set was found to be the most appropriate in describing the electronic absorption spectra. The calculated energy values of lowest unoccupied molecular orbitals (LUMO) were 3.41, 3.19, 3.38 and 3.23 eV for SQD1, SQD2, SQD3, and SQD4, respectively. These values lie above the LUMO energy (−4.26 eV) of the conduction band of TiO₂ nanoparticles indicating possible electron injection from the excited dyes to the conduction band of the TiO₂ in dye-sensitized solar cells (DSSCs). Also, aromaticity computation for these dyes are in good agreement with the data obtained optically and geometrically with SQD4 as the highest aromatic structure. Based on the optimized molecular geometries, relative positions of the frontier orbitals, and the absorption maxima, we propose that these dyes are suitable components of photovoltaic DSSC devices. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2016)

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15 pages, 1410 KiB

Open AccessArticle

RORC2 Genetic Variants and Serum Levels in Patients with Rheumatoid Arthritis

by Agnieszka Paradowska-Gorycka^1,*, Barbara Stypinska¹, Andrzej Pawlik²

, Katarzyna Romanowska-Prochnicka³, Ewa Haladyj³, Malgorzata Manczak⁴ and Marzena Olesinska³

¹ Department of Biochemistry and Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland

² Department of Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland

³ Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland

⁴ Department of Epidemiology and Health Promotion, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland

Int. J. Mol. Sci. 2016, 17(4), 488; https://doi.org/10.3390/ijms17040488 - 1 Apr 2016

Cited by 3 | Viewed by 6179

Abstract

Background: In the present study, we aimed to evaluate whether polymorphisms within the RORc2 gene are involved in the risk and severity of rheumatoid arthritis (RA). Methods: 591 RA patients and 341 healthy individuals were examined for RORc2 gene polymorphisms. Serum retinoic acid [...] Read more.

Background: In the present study, we aimed to evaluate whether polymorphisms within the RORc2 gene are involved in the risk and severity of rheumatoid arthritis (RA). Methods: 591 RA patients and 341 healthy individuals were examined for RORc2 gene polymorphisms. Serum retinoic acid receptor-related orphan receptor C (RORc) levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: The rs9826 A/G, rs12045886 T/C and rs9017 G/A RORc2 gene SNPs show no significant differences in the proportion of cases and control. Overall, rs9826 and rs9017 were in high linkage disequilibrium (LD) with D’ = 0.952 and r² = 0.874, except rs9826 and rs12045886; and rs12045886 and rs9017 in weak LD. The genotype–phenotype analysis showed a significant association between RORc2 rs9826 A/G and rs9017 G/A single nucleotide polymorphisms (SNPs) and median of C-reactive protein (CRP). Serum RORc levels was higher in RA patients with rs9826AA, rs12045886TT and -TC, and rs9017AA genotypes compared to healthy subjects with the same genotypes (p = 0.02, p = 0.04 and p = 0.01, respectively). Moreover, the median of RORc protein level was higher in RA patients with number of swollen joints bigger then 3 (p = 0.04) and with Health Assessment Questionnaires (HAQ) score bigger then 1.5 (0.049). Conclusions: Current findings indicated that the RORc2 genetic polymorphism and the RORc2 protein level may be associated with severity of RA in the Polish population. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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15 pages, 3994 KiB

Open AccessArticle

Individual Assessment of Brain Tissue Changes in MS and the Effect of Focal Lesions on Short-Term Focal Atrophy Development in MS: A Voxel-Guided Morphometry Study

by Jan Fox¹, Matthias Kraemer², Thorsten Schormann³, Andreas Dabringhaus⁴, Jochen Hirsch⁵, Philipp Eisele¹, Kristina Szabo¹, Christel Weiss⁶, Michael Amann⁷, Katrin Weier⁸, Yvonne Naegelin⁸, Ludwig Kappos⁸ and Achim Gass^1,*

¹ Universitätsmedizin Mannheim, Department of Neurology, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany

² Hospital zum Heiligen Geist, Department for Early Rehabilitation, Kempen 47906, Germany

³ Institute for Anatomy, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, Düsseldorf 40001, Germany

⁴ Deutsches Institut für Medizinische Dokumentation und Information, Waisenhausgasse 36-38a, Köln 50676, Germany

⁵ Fraunhofer MEVIS, Institut für Bildgestützte Medizin, Universitätsallee 29, Bremen 28359, Germany

⁶ Department of Biometry and Statistics, Medical Faculty Mannheim, Ruprecht-Karls University Heidelberg, Mannheim 68167, Germany

⁷ MIAC, Basel, Universitätsspital Basel, Mittlere Strasse 83, Basel 4056, Switzerland

⁸ Neurology, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel, Petersgraben 4, Basel 4052, Switzerland

Int. J. Mol. Sci. 2016, 17(4), 489; https://doi.org/10.3390/ijms17040489 - 1 Apr 2016

Cited by 15 | Viewed by 6768

Abstract

We performed voxel-guided morphometry (VGM) investigating the mechanisms of brain atrophy in multiple sclerosis (MS) related to focal lesions. VGM maps detect regional brain changes when comparing 2 time points on high resolution T1-weighted (T1w) magnetic resonace imaging (MRI). Two T1w MR datasets [...] Read more.

We performed voxel-guided morphometry (VGM) investigating the mechanisms of brain atrophy in multiple sclerosis (MS) related to focal lesions. VGM maps detect regional brain changes when comparing 2 time points on high resolution T1-weighted (T1w) magnetic resonace imaging (MRI). Two T1w MR datasets from 92 relapsing-remitting MS patients obtained 12 months apart were analysed with VGM. New lesions and volume changes of focal MS lesions as well as in the surrounding tissue were identified by visual inspection on colour coded VGM maps. Lesions were dichotomized in active and inactive lesions. Active lesions, defined by either new lesions (NL) (volume increase > 5% in VGM), chronic enlarging lesions (CEL) (pre-existent T1w lesions with volume increase > 5%), or chronic shrinking lesions (CSL) (pre-existent T1w lesions with volume reduction > 5%) in VGM, were accompanied by tissue shrinkage in surrounding and/or functionally related regions. Volume loss within the corpus callosum was highly correlated with the number of lesions in its close proximity. Volume loss in the lateral geniculate nucleus was correlated with lesions along the optic radiation. VGM analysis provides strong evidence that all active lesion types (NL, CEL, and CSL) contribute to brain volume reduction in the vicinity of lesions and/or in anatomically and functionally related areas of the brain. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis)

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15 pages, 1416 KiB

Open AccessArticle

Pegylated Trastuzumab Fragments Acquire an Increased in Vivo Stability but Show a Largely Reduced Affinity for the Target Antigen

by Fabio Selis^1,*,†

, Giuseppina Focà^2,3,†, Annamaria Sandomenico^2,3,*

, Carla Marra¹, Concetta Di Mauro⁴, Gloria Saccani Jotti⁵, Silvia Scaramuzza¹, Annalisa Politano¹, Riccardo Sanna¹, Menotti Ruvo^2,3 and Giancarlo Tonon¹

¹ Bioker srl-Multimedica Group, c/o Institute of Genetics and Biophysics, National Research Council (CNR-IGB) via P. Castellino 111, 80131 Napoli, Italy

² Institute of Biostructure and Bioimaging, National Research Council (IBB-CNR), via Mezzocannone 16, 80134 Napoli, Italy

³ Centro Interuniversitario di Ricerca sui Peptidi Bioattivi (CIRPeB), University of Naples Federico II, via Mezzocannone 16, 80134 Napoli, Italy

⁴ Department of Clinical Medicine and Surgery, University of Naples Federico II, 80134 Napoli, Italy

⁵ Department of Biomedical, Biotechnological and Translational Science (S.Bi.Bi.T.), Università di Parma, 43126 Parma, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 491; https://doi.org/10.3390/ijms17040491 - 1 Apr 2016

Cited by 32 | Viewed by 8624

Abstract

PEGylation of biomolecules is a major approach to increase blood stream half-life, stability and solubility of biotherapeutics and to reduce their immunogenicity, aggregation potential and unspecific interactions with other proteins and tissues. Antibodies have generally long half-lives due to high molecular mass and [...] Read more.

PEGylation of biomolecules is a major approach to increase blood stream half-life, stability and solubility of biotherapeutics and to reduce their immunogenicity, aggregation potential and unspecific interactions with other proteins and tissues. Antibodies have generally long half-lives due to high molecular mass and stability toward proteases, however their size lowers to some extent their potential because of a reduced ability to penetrate tissues, especially those of tumor origin. Fab or otherwise engineered smaller fragments are an alternative but are less stable and are much less well retained in circulation. We have here investigated the effects of various PEGylations on the binding properties and in vivo half-life of Fab fragments derived from the enzymatic splitting of Trastuzumab. We find that PEGylation increases the half-life of the molecules but also strongly affects the ability to recognize the target antigen in a way that is dependent on the extent and position of the chemical modification. Data thus support the concept that polyethylene glycol (PEG) conjugation on Trastuzumab Fabs increases half-life but reduces their affinity and this is a fine balance, which must be carefully considered for the design of strategies based on the use of antibody fragments. Full article

(This article belongs to the Special Issue Molecule- and Cell-Targeted Drug Design and Screening and Identification of Natural Product)

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13 pages, 1722 KiB

Open AccessArticle

MicroRNA-15b Modulates Molecular Mediators of Blood Induced Arthropathy in Hemophilia Mice

by Dwaipayan Sen¹ and Giridhara R. Jayandharan^1,2,*

¹ Department of Hematology, Christian Medical College, 632004 Vellore, India

² Department of Biological Sciences and Bioengineering, Indian Institute of Technology, 208016 Kanpur, India

Int. J. Mol. Sci. 2016, 17(4), 492; https://doi.org/10.3390/ijms17040492 - 8 Apr 2016

Cited by 14 | Viewed by 5654

Abstract

The development of arthropathy is a major co-morbidity in patients with hemophilia. The present study was designed to study the role of a microRNA biomarker (miR-15b) in the development of joint disease. To investigate the expression profile of miR-15b during the development of [...] Read more.

The development of arthropathy is a major co-morbidity in patients with hemophilia. The present study was designed to study the role of a microRNA biomarker (miR-15b) in the development of joint disease. To investigate the expression profile of miR-15b during the development of arthropathy, we first isolated and studied small RNA from the acute and chronic hemarthrosis model of hemophilia A mice. We observed that miR-15b was consistently repressed (~1- to 4-fold) from the onset of joint bleeding (1, 3, 7 and 24 h) until six bleeding episodes (up to 90 days). To test if reconstitution of miR-15b modulates biomarkers of joint damage in a chronic hemarthrosis model, we administered an adeno-associated virus (AAV) 5-miR-15b vector intra-articularly alone or in combination with systemic administration of AAV2-factor VIII. miR-15b overexpression downregulated markers of angiogenesis and hypoxia (vascular epithelial growth factor α (VEGF-α) and hypoxia inducing factor 2α (HIF-2α), ~70% and ~34%, respectively) in the affected joints. In addition, the co-administration of miR-15b and factor VIII vectors reduced the levels of the chondrodegenerative matrix-metalloproteinases (MMPs) 1, 3, 9 and 14 (~14% to 60%) in the injured joints. These data demonstrate for the first time the role of a miR-15b in the development of hemophilic arthropathy and has implications in development of miR based therapies for joint disease. Full article

(This article belongs to the Special Issue MicroRNA in Various Disease States as Biomarkers)

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13 pages, 3896 KiB

Open AccessArticle

Bacterial Expression and Kinetic Analysis of Carboxylesterase 001D from Helicoverpa armigera

by Yongqiang Li¹, Jianwei Liu², Mei Lu¹, Zhiqing Ma¹

, Chongling Cai¹, Yonghong Wang^1,* and Xing Zhang¹

¹ Research and Development Centre of Biorational Pesticides, Northwest Agriculture and Forestry University, Yangling 712100, China

² Commonwealth Scientific and Industrial Research Organisation Land & Water Flagship, Canberra, ACT 2601, Australia

Int. J. Mol. Sci. 2016, 17(4), 493; https://doi.org/10.3390/ijms17040493 - 2 Apr 2016

Cited by 20 | Viewed by 6955

Abstract

Carboxylesterasesare an important class of detoxification enzymes involved in insecticide resistance in insects. A subgroup of Helicoverpa armigera esterases, known as Clade 001, was implicated in organophosphate and pyrethroid insecticide resistance due to their overabundance in resistant strains. In this work, a novel [...] Read more.

Carboxylesterasesare an important class of detoxification enzymes involved in insecticide resistance in insects. A subgroup of Helicoverpa armigera esterases, known as Clade 001, was implicated in organophosphate and pyrethroid insecticide resistance due to their overabundance in resistant strains. In this work, a novel carboxylesterasegene 001D of H. armigera from China was cloned, which has an open reading frame of 1665 nucleotides encoding 554 amino acid residues. We used a series of fusion proteins to successfully express carboxylesterase 001D in Escherichia coli. Three different fusion proteins were generated and tested. The enzyme kinetic assay towards 1-naphthyl acetate showed all three purified fusion proteins are active with a Kcat between 0.35 and 2.29 s⁻¹, and a Km between 7.61 and 19.72 μM. The HPLC assay showed all three purified fusion proteins had low but measurable hydrolase activity towards β-cypermethrin and fenvalerate insecticides (specific activities ranging from 0.13 to 0.67 μM·min⁻¹·(μM⁻¹·protein)). The enzyme was stable up to 40 °C and at pH 6.0–11.0. The results imply that carboxylesterase 001D is involved in detoxification, and this moderate insecticide hydrolysis may suggest that overexpression of the gene to enhance insecticide sequestration is necessary to allow carboxylesterases to confer resistance to these insecticides in H. armigera. Full article

(This article belongs to the Collection Computational, Structural and Spectroscopic Studies of Enzyme Mechanisms, Inhibition and Dynamics)

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12 pages, 1445 KiB

Open AccessArticle

Wnt9A Induction Linked to Suppression of Human Colorectal Cancer Cell Proliferation

by Irshad Ali^1,*, Bani Medegan² and Donald P. Braun³

¹ Senior Research Associate, Translational Research Laboratory, Cancer Treatment Centers of America^®, 2520 Elisha Avenue, Zion, IL 60099, USA

² Research Associate, Translational Research Laboratory, Cancer Treatment Centers of America^®, 2520 Elisha Avenue, Zion, IL 60099, USA

³ VP Translational Research and Chief Science Officer, Cancer Treatment Centers of America^®, 2610 Sheridan Rd., Zion, IL 60099, USA

Int. J. Mol. Sci. 2016, 17(4), 495; https://doi.org/10.3390/ijms17040495 - 2 Apr 2016

Cited by 20 | Viewed by 7898

Abstract

Most studies of Wnt signaling in malignant tissues have focused on the canonical Wnt pathway (CWP) due to its role in stimulating cellular proliferation. The role of the non-canonical Wnt pathway (NCWP) in tissues with dysregulated Wnt signaling is not fully understood. Understanding [...] Read more.

Most studies of Wnt signaling in malignant tissues have focused on the canonical Wnt pathway (CWP) due to its role in stimulating cellular proliferation. The role of the non-canonical Wnt pathway (NCWP) in tissues with dysregulated Wnt signaling is not fully understood. Understanding NCWP’s role is important since these opposing pathways act in concert to maintain homeostasis in healthy tissues. Our preliminary studies demonstrated that LiCl inhibited proliferation of primary cells derived from colorectal cancer (CRC). Since LiCl stimulates cell proliferation in normal tissues and NCWP suppresses it, the present study was designed to investigate the impact of NCWP components in LiCl-mediated effects. LiCl-mediated inhibition of CRC cell proliferation (p < 0.001) and increased apoptosis (p < 0.01) coincided with 23-fold increase (p < 0.025) in the expression of the NCWP ligand, Wnt9A. LiCl also suppressed β-catenin mRNA (p < 0.03), total β-catenin protein (p < 0.025) and the active form of β-catenin. LiCl-mediated inhibition of CRC cell proliferation was partially reversed by IWP-2, and Wnt9A antibody. Recombinant Wnt9A protein emulated LiCl effects by suppressing β-catenin protein (p < 0.001), inhibiting proliferation (p < 0.001) and increasing apoptosis (p < 0.03). This is the first study to demonstrate induction of a NCWP ligand, Wnt9A as part of a mechanism for LiCl-mediated suppression of CRC cell proliferation. Full article

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

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11 pages, 682 KiB

Open AccessArticle

Characterization of Virulence Properties of Aeromonas veronii Isolated from Diseased Gibel Carp (Carassius gibelio)

by Jingjing Sun^1,2, Xiaojun Zhang^1,*, Xiaojian Gao^1,2, Qun Jiang¹, Yi Wen³ and Li Lin^4,*

¹ College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China

² College of Ocean, Huaihai Institute of Technology, Lianyungang 222005, China

³ Bren School of Environmental Science and Management, University of California, Santa Barbara, CA 93106, USA

⁴ Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China

Int. J. Mol. Sci. 2016, 17(4), 496; https://doi.org/10.3390/ijms17040496 - 1 Apr 2016

Cited by 83 | Viewed by 8214

Abstract

Aeromonas veronii is a kind of opportunistic pathogen to fish and humans, significantly impending aquaculture production. Recently, we isolated two A. veronii strains, named GYC1 and GYC2, from diseased Gibel carp (Carassius gibelio) in China. Based on gyrB (DNA gyrase [...] Read more.

Aeromonas veronii is a kind of opportunistic pathogen to fish and humans, significantly impending aquaculture production. Recently, we isolated two A. veronii strains, named GYC1 and GYC2, from diseased Gibel carp (Carassius gibelio) in China. Based on gyrB (DNA gyrase B subunit) genes of GYC1 and GYC2, the constructed phylogenetic tree showed that the two strains were clustered with A. veronii. Sixteen virulence genes related to the pathogenicity of Aeromonas spp. were subjected to PCR assay. The genes of ompAI, ompAII, lafA, act, aer, fla, gcaT and acg were detected in the two strains, while genes of hly, ahp, lip, ast and alt were not detected. Additionally, genes eprCAI, ela and exu were only detected in the strain GYC1. Furthermore, the results of extracellular enzyme analysis revealed that the two isolates can produce hemolysin, caseinase, esterase, amylase and lecithinase, which were closely related to the pathogenicity of the two strains. However, the results showed that there was no gelatinase activity in either strain. According to the antibiotic resistant assay, the two strains were sensitive to cephalosporins and aminoglycosides, while they were resistant to penicillins and quinolones. Through this study, the virulence characteristics, including virulence genes and extracellular enzymes, the pathogenicity of A. veronii was clarified, enhancing the understanding about this pathogenic bacterium and providing the theoretical basis in disease control. Full article

(This article belongs to the Special Issue Fish Molecular Biology)

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14 pages, 3087 KiB

Open AccessArticle

Triptolide Modulates TREM-1 Signal Pathway to Inhibit the Inflammatory Response in Rheumatoid Arthritis

by Danping Fan^1,†, Xiaojuan He^1,2,†, Yanqin Bian³, Qingqing Guo^1,4, Kang Zheng¹, Yukun Zhao^1,3, Cheng Lu¹

, Baoqin Liu⁵, Xuegong Xu^5,*, Ge Zhang^2,*

and Aiping Lu^1,2,3,*

¹ Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China

² Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, Hong Kong, China

³ E-Institute of Chinese Traditional Internal Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

⁴ School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China

⁵ Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou 450002, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 498; https://doi.org/10.3390/ijms17040498 - 2 Apr 2016

Cited by 93 | Viewed by 9283

Abstract

Triptolide (TP), an active component isolated from Tripterygiumwilfordii Hook F, has therapeutic potential against rheumatoid arthritis (RA). However, the underlying molecular mechanism has not been fully elucidated. The aim of this study is to investigate the mechanisms of TP acting on RA [...] Read more.

Triptolide (TP), an active component isolated from Tripterygiumwilfordii Hook F, has therapeutic potential against rheumatoid arthritis (RA). However, the underlying molecular mechanism has not been fully elucidated. The aim of this study is to investigate the mechanisms of TP acting on RA by combining bioinformatics analysis with experiment validation. The human protein targets of TP and the human genes of RA were found in the PubChem database and NCBI, respectively. These two dataset were then imported into Ingenuity Pathway Analysis (IPA) software online, and then the molecular network of TP on RA could be set up and analyzed. After that, both in vitro and in vivo experiments were done to further verify the prediction. The results indicated that the main canonical signal pathways of TP protein targets networks were mainly centered on cytokine and cellular immune signaling, and triggering receptors expressed on myeloid cells (TREM)-1 signaling was searched to be the top one shared signaling pathway and involved in the cytokine and cellular immune signaling. Further in vitro experiments indicated that TP not only remarkably lowered the levels of TREM-1 and DNAX-associated protein (DAP)12, but also significantly suppressed the activation of janus activating kinase (JAK)2 and signal transducers and activators of transcription (STAT)3. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in lipopolysaccharides (LPS)-stimulated U937 cells also decreased after treatment with TP. Furthermore, TREM-1 knockdown was able to interfere with the inhibition effects of TP on these cytokines production. In vivo experiments showed that TP not only significantly inhibited the TREM-1 mRNA and DAP12 mRNA expression, and activation of JAK2 and STAT3 in ankle of rats with collagen-induced arthritis (CIA), but also remarkably decreased production of TNF-α, IL-1β and IL-6 in serum and joint. These findings demonstrated that TP could modulate the TREM1 signal pathway to inhibit the inflammatory response in RA. Full article

(This article belongs to the Special Issue Molecule- and Cell-Targeted Drug Design and Screening and Identification of Natural Product)

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23 pages, 4923 KiB

Open AccessArticle

Comparative Small RNA Analysis of Pollen Development in Autotetraploid and Diploid Rice

by Xiang Li^†, Muhammad Qasim Shahid^†

, Jinwen Wu

, Lan Wang, Xiangdong Liu^*

and Yonggen Lu^*

¹ State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou 510642, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 499; https://doi.org/10.3390/ijms17040499 - 12 Apr 2016

Cited by 105 | Viewed by 10354

Abstract

MicroRNAs (miRNAs) play key roles in plant reproduction. However, knowledge on microRNAome analysis in autotetraploid rice is rather limited. Here, high-throughput sequencing technology was employed to analyze miRNAomes during pollen development in diploid and polyploid rice. A total of 172 differentially expressed miRNAs [...] Read more.

MicroRNAs (miRNAs) play key roles in plant reproduction. However, knowledge on microRNAome analysis in autotetraploid rice is rather limited. Here, high-throughput sequencing technology was employed to analyze miRNAomes during pollen development in diploid and polyploid rice. A total of 172 differentially expressed miRNAs (DEM) were detected in autotetraploid rice compared to its diploid counterpart, and 57 miRNAs were specifically expressed in autotetraploid rice. Of the 172 DEM, 115 and 61 miRNAs exhibited up- and down-regulation, respectively. Gene Ontology analysis on the targets of up-regulated DEM showed that they were enriched in transport and membrane in pre-meiotic interphase, reproduction in meiosis, and nucleotide binding in single microspore stage. osa-miR5788 and osa-miR1432-5p_R+1 were up-regulated in meiosis and their targets revealed interaction with the meiosis-related genes, suggesting that they may involve in the genes regulation associated with the chromosome behavior. Abundant 24 nt siRNAs associated with transposable elements were found in autotetraploid rice during pollen development; however, they significantly declined in diploid rice, suggesting that 24 nt siRNAs may play a role in pollen development. These findings provide a foundation for understanding the effect of polyploidy on small RNA expression patterns during pollen development that cause pollen sterility in autotetraploid rice. Full article

(This article belongs to the Special Issue Plant Molecular Biology)

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10 pages, 595 KiB

Open AccessArticle

Association between Pre-Transplant Serum Malondialdehyde Levels and Survival One Year after Liver Transplantation for Hepatocellular Carcinoma

by Leonardo Lorente^1,*

, Sergio T. Rodriguez², Pablo Sanz³, Pedro Abreu-González⁴

, Dácil Díaz⁵, Antonia M. Moreno⁵, Elisa Borja⁵, María M. Martín², Alejandro Jiménez⁶ and Manuel A. Barrera³

¹ Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, Santa Cruz de Tenerife 38320, Spain

² Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Crta Rosario s/n, Santa Cruz Tenerife 38010, Spain

³ Department of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Crta Rosario s/n, Santa Cruz Tenerife 38010, Spain

⁴ Department of Physiology, Faculty of Medicine, University of the La Laguna, Ofra, s/n, La Laguna, Santa Cruz de Tenerife 38320, Spain

⁵ Department of Digestive, Hospital Universitario Nuestra Señora de Candelaria, Crta Rosario s/n, Santa Cruz Tenerife 38010, Spain

⁶ Research Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, Santa Cruz de Tenerife 38320, Spain

Int. J. Mol. Sci. 2016, 17(4), 500; https://doi.org/10.3390/ijms17040500 - 5 Apr 2016

Cited by 31 | Viewed by 5406

Abstract

Previous studies have found higher levels of serum malondialdehyde (MDA) in hepatocellular carcinoma (HCC) patients compared to healthy controls and higher MDA concentrations in tumoral tissue of HCC patients than in non-tumoral tissue. However, the association between pre-transplant serum levels of MDA and [...] Read more.

Previous studies have found higher levels of serum malondialdehyde (MDA) in hepatocellular carcinoma (HCC) patients compared to healthy controls and higher MDA concentrations in tumoral tissue of HCC patients than in non-tumoral tissue. However, the association between pre-transplant serum levels of MDA and survival in HCC patients after liver transplantation (LT) has not been described, and the aim of the present study was to determine whether such an association exists. In this observational study we measured serum MDA levels in 127 patients before LT. We found higher pre-LT serum MDA levels in 15 non-surviving than in 112 surviving patients one year after LT (p = 0.02). Exact binary logistic regression analysis revealed that pre-LT serum levels of MDA over 3.37 nmol/mL were associated with mortality after one year of LT (Odds ratio = 5.38; 95% confidence interval (CI) = from 1.580 to infinite; p = 0.007) adjusting for age of the deceased donor. The main finding of our study was that there is an association between serum MDA levels before LT for HCC and 1-year survival after LT. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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12 pages, 418 KiB

Open AccessArticle

Genome-Wide Mapping of Growth-Related Quantitative Trait Loci in Orange-Spotted Grouper (Epinephelus coioides) Using Double Digest Restriction-Site Associated DNA Sequencing (ddRADseq)

by Hui Yu^1,2,†, Xinxin You^2,3,†, Jia Li^1,2, Hankui Liu², Zining Meng³, Ling Xiao³, Haifa Zhang⁴, Hao-Ran Lin^3,5,*, Yong Zhang^3,4,5,* and Qiong Shi^1,2,6,*

¹ BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China

² Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, State Key Laboratory of Agricultural Genomics, BGI, Shenzhen 518083, China

³ State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China

⁴ Marine Fisheries Development Center of Guangdong Province, Huizhou 510610, China

⁵ South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Guangzhou 510275, China

⁶ College of Life Sciences, Shenzhen University, Shenzhen 518060, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 501; https://doi.org/10.3390/ijms17040501 - 6 Apr 2016

Cited by 33 | Viewed by 7254

Abstract

Mapping of quantitative trait loci (QTL) is essential for the discovery of genetic structures that related to complex quantitative traits. In this study, we identified 264,072 raw SNPs (single-nucleotide polymorphisms) by double digest restriction site associated DNA sequencing (ddRADseq), and utilized 3029 of [...] Read more.

Mapping of quantitative trait loci (QTL) is essential for the discovery of genetic structures that related to complex quantitative traits. In this study, we identified 264,072 raw SNPs (single-nucleotide polymorphisms) by double digest restriction site associated DNA sequencing (ddRADseq), and utilized 3029 of these SNPs to construct a genetic linkage map in orange-spotted grouper (Epinephelus coioides) using a regression mapping algorithm. The genetic map contained 24 linkage groups (LGs) spanning a total genetic distance of 1231.98 cM. Twenty-seven significant growth-related QTLs were identified. Furthermore, we identified 17 genes (fez2, alg3, ece2, arvcf, sla27a4, sgk223, camk2, prrc2b, mchr1, sardh, pappa, syk, tert, wdrcp91, ftz-f1, mate1 and notch1) including three (tert, ftz-f1 and notch1) that have been reported to be involved in fish growth. To summarize, we mapped growth-related QTLs in the orange-spotted grouper. These QTLs will be useful in marker-assisted selection (MAS) efforts to improve growth-related traits in this economically important fish. Full article

(This article belongs to the Special Issue Fish Molecular Biology)

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15 pages, 6184 KiB

Open AccessArticle

Regulation of Adipogenesis by Quinine through the ERK/S6 Pathway

by Xiaomin Ning^†, Jingjing He^†, Xin’e Shi and Gongshe Yang^*

¹ Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest Agriculture and Forestry University, Yangling 712100, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 504; https://doi.org/10.3390/ijms17040504 - 13 Apr 2016

Cited by 22 | Viewed by 6766

Abstract

Quinine is a bitter tasting compound that is involved in the regulation of body weight as demonstrated in in vivo animal models and in vitro models of the adipogenic system. Arguments exist over the positive or negative roles of quinine in both in [...] Read more.

Quinine is a bitter tasting compound that is involved in the regulation of body weight as demonstrated in in vivo animal models and in vitro models of the adipogenic system. Arguments exist over the positive or negative roles of quinine in both in vivo animal models and in vitro cell models, which motivates us to further investigate the functions of quinine in the in vitro adipogenic system. To clarify the regulatory functions of quinine in adipogenesis, mouse primary preadipocytes were induced for differentiation with quinine supplementation. The results showed that quinine enhanced adipogenesis in a dose dependent manner without affecting lipolysis. The pro-adipogenic effect of quinine was specific, as other bitter tasting agonists had no effect on adipogenesis. Moreover, the pro-adipogenic effect of quinine was mediated by activation of ERK/S6 (extracellular-signal-regulated kinase/Ribosomal protein S6) signaling. Knockdown of bitter taste receptor T2R106 (taste receptor, type 2, member 106) impaired the pro-adipogenic effect of quinine and suppressed the activation of ERK/S6 signaling. Taken together, quinine stimulates adipogenesis through ERK/S6 signaling, which at least partly functions via T2R106. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

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14 pages, 1640 KiB

Open AccessArticle

Expression of Castor LPAT2 Enhances Ricinoleic Acid Content at the sn-2 Position of Triacylglycerols in Lesquerella Seed

by Grace Q. Chen^1,*,†, Harrie Van Erp^2,3,†, Jose Martin-Moreno³, Kumiko Johnson¹, Eva Morales¹, John Browse², Peter J. Eastmond³

and Jiann-Tsyh Lin¹

¹ Western Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, 800 Buchanan St., Albany, CA 94710, USA

² Institute of Biological Chemistry, Washington State University, Pullman, Washington, DC 99164, USA

³ Department of Plant Biology and Crop Science, Rothamsted Research, Harpenden, Hertfordshire AL5 2JQ, UK

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 507; https://doi.org/10.3390/ijms17040507 - 6 Apr 2016

Cited by 44 | Viewed by 8167

Abstract

Lesquerella is a potential industrial oilseed crop that makes hydroxy fatty acid (HFA). Unlike castor its seeds are not poisonous but accumulate lesquerolic acid mostly at the sn-1 and sn-3 positions of triacylglycerol (TAG), whereas castor contains ricinoleic acid (18:1OH) at [...] Read more.

Lesquerella is a potential industrial oilseed crop that makes hydroxy fatty acid (HFA). Unlike castor its seeds are not poisonous but accumulate lesquerolic acid mostly at the sn-1 and sn-3 positions of triacylglycerol (TAG), whereas castor contains ricinoleic acid (18:1OH) at all three positions. To investigate whether lesquerella can be engineered to accumulate HFAs in the sn-2 position, multiple transgenic lines were made that express castor lysophosphatidic acid acyltransferase 2 (RcLPAT2) in the seed. RcLPAT2 increased 18:1OH at the sn-2 position of TAGs from 2% to 14%–17%, which resulted in an increase of tri-HFA-TAGs from 5% to 13%–14%. Our result is the first example of using a LPAT to increase ricinoleic acid at the sn-2 position of seed TAG. This work provides insights to the mechanism of HFA-containing TAG assembly in lesquerella and directs future research to optimize this plant for HFA production. Full article

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

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13 pages, 2592 KiB

Open AccessArticle

UPLC-MS/MS-Based Profiling of Eicosanoids in RAW264.7 Cells Treated with Lipopolysaccharide

by Jae Won Lee^1,†

, Hyuck Jun Mok^2,†, Dae-Young Lee¹

, Seung Cheol Park², Myeong Soon Ban¹, Jehun Choi¹, Chun Geon Park¹, Young-Sup Ahn¹, Kwang Pyo Kim^2,* and Hyung Don Kim^1,3,*

¹ Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong 369-873, Korea

² Department of Applied Chemistry, The Institute of Natural Science, College of Applied Science, Kyung Hee University, Yongin 446-701, Korea

³ Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 361-763, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 508; https://doi.org/10.3390/ijms17040508 - 6 Apr 2016

Cited by 20 | Viewed by 7194

Abstract

While both the pro- and anti-inflammatory effects of several eicosanoids have been widely studied, the degree of inflammation in cells that results from various eicosanoids has yet to be comprehensively studied. The objective of this study was to assess the effect of lipopolysaccharide [...] Read more.

While both the pro- and anti-inflammatory effects of several eicosanoids have been widely studied, the degree of inflammation in cells that results from various eicosanoids has yet to be comprehensively studied. The objective of this study was to assess the effect of lipopolysaccharide (LPS) treatment on eicosanoid content in RAW264.7 cells. An Ultra performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)-based profiling method was used to analyze the eicosanoid contents of RAW264.7 cells treated with different LPS concentrations. The profiling data were subjected to statistical analyses, such as principal component analysis (PCA) and hierarchical clustering analysis. LPS treatment increased nitric oxide production and secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, in a concentration-dependent manner. In total, 79 eicosanoids were identified in the cells. RAW264.7 cells treated with different LPS concentrations were well differentiated in the PCA score plot. A heatmap was used to identify the eicosanoids that were up- or down-regulated according to the degree of inflammation and LPS concentration. Thirty-nine eicosanoids were upregulated and seven were down-regulated by LPS treatment in a concentration-dependent manner. Our novel UPLC-MS/MS technique can profile eicosanoids, and can evaluate the correlations between inflammation and eicosanoid metabolism. Full article

(This article belongs to the Section Biochemistry)

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20 pages, 5334 KiB

Open AccessArticle

Power Frequency Magnetic Fields Affect the p38 MAPK-Mediated Regulation of NB69 Cell Proliferation Implication of Free Radicals

by María Antonia Martínez^1,*, Alejandro Úbeda¹, Jorge Moreno² and María Ángeles Trillo¹

¹ Servicio de Investigación-BEM, University Hospital Ramón y Cajal-IRYCIS, 28034 Madrid, Spain

² Departamento de Ingeniería Eléctrica, Electrónica y de Automatización y Física Aplicada, Technical School of Engineering and Industrial Design (ETSID), UPM, 28012 Madrid, Spain

Int. J. Mol. Sci. 2016, 17(4), 510; https://doi.org/10.3390/ijms17040510 - 6 Apr 2016

Cited by 22 | Viewed by 7022

Abstract

The proliferative response of the neuroblastoma line NB69 to a 100 µT, 50 Hz magnetic field (MF) has been shown mediated by activation of the MAPK-ERK1/2 pathway. This work investigates the MF effect on the cell cycle of NB69, the participation of p38 [...] Read more.

The proliferative response of the neuroblastoma line NB69 to a 100 µT, 50 Hz magnetic field (MF) has been shown mediated by activation of the MAPK-ERK1/2 pathway. This work investigates the MF effect on the cell cycle of NB69, the participation of p38 and c-Jun N-terminal (JNK) kinases in the field-induced proliferative response and the potential involvement of reactive oxygen species (ROS) in the activation of the MAPK-ERK1/2 and -p38 signaling pathways. NB69 cultures were exposed to the 100 µT MF, either intermittently for 24, 42 or 63 h, or continuously for periods of 15 to 120 min, in the presence or absence of p38 or JNK inhibitors: SB203580 and SP600125, respectively. Antioxidant N-acetylcysteine (NAC) was used as ROS scavenger. Field exposure induced transient activation of p38, JNK and ERK1/2. The MF proliferative effect, which was mediated by changes in the cell cycle, was blocked by the p38 inhibitor, but not by the JNK inhibitor. NAC blocked the field effects on cell proliferation and p38 activation, but not those on ERK1/2 activation. The MF-induced proliferative effects are exerted through sequential upregulation of MAPK-p38 and -ERK1/2 activation, and they are likely mediated by a ROS-dependent activation of p38. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 5722 KiB

Open AccessArticle

The Effects of Different Purifying Methods on the Chemical Properties, in Vitro Anti-Tumor and Immunomodulatory Activities of Abrus cantoniensis Polysaccharide Fractions

by Shaowei Wu¹, Xiong Fu^1,*, Margaret A. Brennan², Charles S. Brennan^1,2,*

and Chen Chun¹

¹ College of Light Industry and Food Sciences, South China University of Technology, Guangzhou 510640, China

² Centre for Food Research and Innovation, Lincoln University, Lincoln 7648, New Zealand

Int. J. Mol. Sci. 2016, 17(4), 511; https://doi.org/10.3390/ijms17040511 - 6 Apr 2016

Cited by 33 | Viewed by 7729

Abstract

Abrus cantoniensis (Hance) is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, [...] Read more.

Abrus cantoniensis (Hance) is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, AP-ACl-2, AP-ACl-3, AP-H and AP-L). Fourier-transform infrared spectroscopy (FT-IR) and gas chromatography (GC) were used to characterize these Abrus polysaccharides fractions (APF). In vitro anti-tumor and immunomodulatory activities were also investigated and compared using the rank-sum ratio (RSR) method. Results demonstrated significant differences in the structure and bioactivities among APF, which were associated to the process used for their purification. Among the APF, AP-ACl-3 yield was 613.5 mg/kg of product and consisted of rhamnose (9.8%), arabinose (8.9%), fructose (3.0%), galactose (9.9%), glucose (4.3%), galacturonic acid (3.0%) and glucuronic acid (61.1%) with a molecular weight of 4.4 × 10⁴ Da. Furthermore, AP-ACl-3 exhibited considerable bioactivities significantly preventing the migration of MCF-7 cells and stimulating lymphocyte proliferation along with nitric oxide (NO) production of peritoneal macrophages. AP-ACl-3 could be explored as a novel potential anti-tumor and immunomodulatory agent. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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14 pages, 965 KiB

Open AccessArticle

SAAFEC: Predicting the Effect of Single Point Mutations on Protein Folding Free Energy Using a Knowledge-Modified MM/PBSA Approach

by Ivan Getov^†, Marharyta Petukh^† and Emil Alexov^*

¹ Computational Biophysics and Bioinformatics, Physics Department, Clemson University, Clemson, SC 29634, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 512; https://doi.org/10.3390/ijms17040512 - 7 Apr 2016

Cited by 77 | Viewed by 7350

Abstract

Folding free energy is an important biophysical characteristic of proteins that reflects the overall stability of the 3D structure of macromolecules. Changes in the amino acid sequence, naturally occurring or made in vitro, may affect the stability of the corresponding protein and [...] Read more.

Folding free energy is an important biophysical characteristic of proteins that reflects the overall stability of the 3D structure of macromolecules. Changes in the amino acid sequence, naturally occurring or made in vitro, may affect the stability of the corresponding protein and thus could be associated with disease. Several approaches that predict the changes of the folding free energy caused by mutations have been proposed, but there is no method that is clearly superior to the others. The optimal goal is not only to accurately predict the folding free energy changes, but also to characterize the structural changes induced by mutations and the physical nature of the predicted folding free energy changes. Here we report a new method to predict the Single Amino Acid Folding free Energy Changes (SAAFEC) based on a knowledge-modified Molecular Mechanics Poisson-Boltzmann (MM/PBSA) approach. The method is comprised of two main components: a MM/PBSA component and a set of knowledge based terms delivered from a statistical study of the biophysical characteristics of proteins. The predictor utilizes a multiple linear regression model with weighted coefficients of various terms optimized against a set of experimental data. The aforementioned approach yields a correlation coefficient of 0.65 when benchmarked against 983 cases from 42 proteins in the ProTherm database. Availability: the webserver can be accessed via http://compbio.clemson.edu/SAAFEC/. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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20 pages, 3854 KiB

Open AccessArticle

Analysis of Protein Composition and Bioactivity of Neoponera villosa Venom (Hymenoptera: Formicidae)

by Wallace Felipe Blohem Pessoa¹

, Ludimilla Carvalho Cerqueira Silva¹, Leila De Oliveira Dias¹, Jacques Hubert Charles Delabie²

, Helena Costa¹

and Carla Cristina Romano^1,*

¹ State University of Santa Cruz (UESC)—Center of Biotechnology and Genetics (CBG), Ilhéus, Bahia 45662-900, Brazil

² Myrmecology Laboratory of the Cocoa Research Center—CEPEC, Executive Committee of the Cocoa Crop (CEPLAC), Ilhéus, Bahia 45660-000, Brazil

Int. J. Mol. Sci. 2016, 17(4), 513; https://doi.org/10.3390/ijms17040513 - 21 Apr 2016

Cited by 15 | Viewed by 6410

Abstract

Ants cause a series of accidents involving humans. Such accidents generate different reactions in the body, ranging from a mild irritation at the bite site to anaphylactic shock, and these reactions depend on the mechanism of action of the venom. The study of [...] Read more.

Ants cause a series of accidents involving humans. Such accidents generate different reactions in the body, ranging from a mild irritation at the bite site to anaphylactic shock, and these reactions depend on the mechanism of action of the venom. The study of animal venom is a science known as venomics. Through venomics, the composition of the venom of several ant species has already been characterized and their biological activities described. Thus, the aim of this study was to evaluate the protein composition and biological activities (hemolytic and immunostimulatory) of the venom of Neoponera villosa (N. villosa), an ant widely distributed in South America. The protein composition was evaluated by proteomic techniques, such as two-dimensional electrophoresis. To assess the biological activity, hemolysis assay was carried out and cytokines were quantified after exposure of macrophages to the venom. The venom of N. villosa has a profile composed of 145 proteins, including structural and metabolic components (e.g., tubulin and ATPase), allergenic and immunomodulatory proteins (arginine kinase and heat shock proteins (HSPs)), protective proteins of venom (superoxide dismutase (SOD) and catalase) and tissue degradation proteins (hyaluronidase and phospholipase A2). The venom was able to induce hemolysis in human erythrocytes and also induced release of both pro-inflammatory cytokines, as the anti-inflammatory cytokine release by murine macrophages. These results allow better understanding of the composition and complexity of N. villosa venom in the human body, as well as the possible mechanisms of action after the bite. Full article

(This article belongs to the Section Biochemistry)

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22 pages, 3203 KiB

Open AccessArticle

Modeling of the Reaction Mechanism of Enzymatic Radical C–C Coupling by Benzylsuccinate Synthase

by Maciej Szaleniec^1,*

and Johann Heider²

¹ Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Kraków 30-239, Poland

² Laboratory of Microbial Biochemistry, and LOEWE-Center for Synthetic Microbiology, Philipps-University of Marburg, Marburg 35043, Germany

Int. J. Mol. Sci. 2016, 17(4), 514; https://doi.org/10.3390/ijms17040514 - 7 Apr 2016

Cited by 15 | Viewed by 7100

Abstract

Molecular modeling techniques and density functional theory calculations were performed to study the mechanism of enzymatic radical C–C coupling catalyzed by benzylsuccinate synthase (BSS). BSS has been identified as a glycyl radical enzyme that catalyzes the enantiospecific fumarate addition to toluene initiating its [...] Read more.

Molecular modeling techniques and density functional theory calculations were performed to study the mechanism of enzymatic radical C–C coupling catalyzed by benzylsuccinate synthase (BSS). BSS has been identified as a glycyl radical enzyme that catalyzes the enantiospecific fumarate addition to toluene initiating its anaerobic metabolism in the denitrifying bacterium Thauera aromatica, and this reaction represents the general mechanism of toluene degradation in all known anaerobic degraders. In this work docking calculations, classical molecular dynamics (MD) simulations, and DFT+D2 cluster modeling was employed to address the following questions: (i) What mechanistic details of the BSS reaction yield the most probable molecular model? (ii) What is the molecular basis of enantiospecificity of BSS? (iii) Is the proposed mechanism consistent with experimental observations, such as an inversion of the stereochemistry of the benzylic protons, syn addition of toluene to fumarate, exclusive production of (R)-benzylsuccinate as a product and a kinetic isotope effect (KIE) ranging between 2 and 4? The quantum mechanics (QM) modeling confirms that the previously proposed hypothetical mechanism is the most probable among several variants considered, although C–H activation and not C–C coupling turns out to be the rate limiting step. The enantiospecificity of the enzyme seems to be enforced by a thermodynamic preference for binding of fumarate in the pro(R) orientation and reverse preference of benzyl radical attack on fumarate in pro(S) pathway which results with prohibitively high energy barrier of the radical quenching. Finally, the proposed mechanism agrees with most of the experimental observations, although the calculated intrinsic KIE from the model (6.5) is still higher than the experimentally observed values (4.0) which suggests that both C–H activation and radical quenching may jointly be involved in the kinetic control of the reaction. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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15 pages, 4021 KiB

Open AccessArticle

Autophagic Cell Death and Apoptosis Jointly Mediate Cisatracurium Besylate-Induced Cell Injury

by Haixia Zhuang^1,†, Weili Tian^2,†, Wen Li^2,†, Xingli Zhang^2,†, Jingjing Wang¹, Yue Yang¹, Xin Liu¹, Zhengyuan Xia³, Du Feng^2,4,* and Liangqing Zhang^1,*

¹ Department of Anesthesiology, Guangdong Medical University, Zhanjiang 524001, China

² Guangdong Key Laboratory of Age-Related Cardiac-Cerebral Vascular Disease, Institute of Neurology, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China

³ Anesthesiology Research Laboratory, Department of Anesthesiology, University of Hong Kong, Hong Kong, China

⁴ The Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Medical School, Boston, MA 02115, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 515; https://doi.org/10.3390/ijms17040515 - 6 Apr 2016

Cited by 7 | Viewed by 7793

Abstract

Cisatracurium besylate is an ideal non-depolarizing muscle relaxant which is widely used in clinical application. However, some studies have suggested that cisatracurium besylate can affect cell proliferation. Moreover, its specific mechanism of action remains unclear. Here, we found that the number of GFP-LC3 [...] Read more.

Cisatracurium besylate is an ideal non-depolarizing muscle relaxant which is widely used in clinical application. However, some studies have suggested that cisatracurium besylate can affect cell proliferation. Moreover, its specific mechanism of action remains unclear. Here, we found that the number of GFP-LC3 (green fluoresent protein-light chain 3) positive autophagosomes and the rate of mitochondria fracture both increased significantly in drug-treated GFP-LC3 and MitoDsRed stable HeLa cells. Moreover, cisatracurium promoted the co-localization of LC3 and mitochondria and induced formation of autolysosomes. Levels of mitochondrial proteins decreased, which were reversed by the lysosome inhibitor Bafinomycin A1. Similar results with evidence of dose-dependent effects were found in both HeLa and Human Umbilical Vein Endothelial Cells (HUVECs). Cisatracurium lowered HUVEC viability to 0.16 (OD490) at 100 µM and to 0.05 (OD490) after 48 h in vitro; it increased the cell death rate to 56% at 100 µM and to 60% after 24 h in a concentration- and time-dependent manner (p < 0.01). Cell proliferation decreased significantly by four fold in Atg5 WT (wildtype) MEF (mouse embryonic fibroblast) (p < 0.01) but was unaffected in Atg5 KO (Knockout) MEF, even upon treatment with a high dose of cisatracurium. Cisatracurium induced significant increase in cell death of wild-type MEFs even in the presence of the apoptosis inhibitor zVAD. Thus, we conclude that activation of both the autophagic cell death and cell apoptosis pathways contributes to cisatracurium-mediated cell injury. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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10 pages, 1196 KiB

Open AccessArticle

Intervention of Grape Seed Proanthocyanidin Extract on the Subchronic Immune Injury in Mice Induced by Aflatoxin B1

by Miao Long^†

, Yi Zhang^†, Peng Li, Shu-Hua Yang, Wen-Kui Zhang, Jian-Xin Han, Yuan Wang and Jian-Bin He^*

¹ Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2016, 17(4), 516; https://doi.org/10.3390/ijms17040516 - 8 Apr 2016

Cited by 57 | Viewed by 7378

Abstract

The aim was to investigate the prevention of grape seed proanthocyanidin extract (GSPE) on the subchronic immune injury induced by aflatoxin B1 (AFB1) and the possible ameliorating effect of GSPE in mice. The subchronic AFB1-induced immune injury mice model was set up with [...] Read more.

The aim was to investigate the prevention of grape seed proanthocyanidin extract (GSPE) on the subchronic immune injury induced by aflatoxin B1 (AFB1) and the possible ameliorating effect of GSPE in mice. The subchronic AFB1-induced immune injury mice model was set up with the continuous administration of 100 μg/kg body weight (BW) AFB1 for six weeks by intragastric administration. Then, intervention with different doses (50 and 100 mg/kg BW) of GSPE was conducted on mice to analyze the changes of body weight, immune organ index, antioxidant capability of spleen, serum immunoglobulin content, and the expression levels of inflammatory cytokines. The prevention of GSPE on the immune injury induced by AFB1 was studied. The GSPE could relieve the AFB1-induced reduction of body weight gain and the atrophy of the immune organ. The malondialdehyde (MDA) level of the spleen in the AFB1 model group significantly increased, but levels of catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-P_X), and superoxide dismutase (SOD) significantly decreased. The GSPE could significantly inhibit the oxidative stress injury of the spleen induced by AFB1. AFB1 exposure could not significantly change the contents of IgA, IgG, or IgM. AFB1 significantly improved the expression of interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Additionally, GSPE could decrease the expression of these four proinflammatory factors to different degrees and inhibit the inflammatory reaction of mice. The results suggest that GSPE alleviates AFB1-induced oxidative stress and significantly improves the immune injury of mice induced by AFB1. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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22 pages, 1583 KiB

Open AccessArticle

MicroRNAs in Hyperglycemia Induced Endothelial Cell Dysfunction

by Maskomani Silambarasan¹, Jun Rong Tan¹, Dwi Setyowati Karolina¹, Arunmozhiarasi Armugam¹, Charanjit Kaur² and Kandiah Jeyaseelan^1,3,*

¹ Department of Biochemistry, NUS Medicine, National University of Singapore, Singapore 117596, Singapore

² Department of Anatomy, NUS Medicine, National University of Singapore, Singapore 117594, Singapore

³ Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Clayton VIC 3800, Australia

Int. J. Mol. Sci. 2016, 17(4), 518; https://doi.org/10.3390/ijms17040518 - 7 Apr 2016

Cited by 71 | Viewed by 9101

Abstract

Hyperglycemia is closely associated with prediabetes and Type 2 Diabetes Mellitus. Hyperglycemia increases the risk of vascular complications such as diabetic retinopathy, diabetic nephropathy, peripheral vascular disease and cerebro/cardiovascular diseases. Under hyperglycemic conditions, the endothelial cells become dysfunctional. In this study, we investigated [...] Read more.

Hyperglycemia is closely associated with prediabetes and Type 2 Diabetes Mellitus. Hyperglycemia increases the risk of vascular complications such as diabetic retinopathy, diabetic nephropathy, peripheral vascular disease and cerebro/cardiovascular diseases. Under hyperglycemic conditions, the endothelial cells become dysfunctional. In this study, we investigated the miRNA expression changes in human umbilical vein endothelial cells exposed to different glucose concentrations (5, 10, 25 and 40 mM glucose) and at various time intervals (6, 12, 24 and 48 h). miRNA microarray analyses showed that there is a correlation between hyperglycemia induced endothelial dysfunction and miRNA expression. In silico pathways analyses on the altered miRNA expression showed that the majority of the affected biological pathways appeared to be associated to endothelial cell dysfunction and apoptosis. We found the expression of ten miRNAs (miR-26a-5p, -26b-5p, 29b-3p, -29c-3p, -125b-1-3p, -130b-3p, -140-5p, -192-5p, -221-3p and -320a) to increase gradually with increasing concentration of glucose. These miRNAs were also found to be involved in endothelial dysfunction. At least seven of them, miR-29b-3p, -29c-3p, -125b-1-3p, -130b-3p, -221-3p, -320a and -192-5p, can be correlated to endothelial cell apoptosis. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

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13 pages, 1856 KiB

Open AccessArticle

MMP9 Rs3918242 Polymorphism Affects Tachycardia-Induced MMP9 Expression in Cultured Atrial-Derived Myocytes but Is Not a Risk Factor for Atrial Fibrillation among the Taiwanese

by Fu-Chih Hsiao¹, Yung-Hsin Yeh¹, Wei-Jan Chen¹, Yi-Hsin Chan¹, Chi-Tai Kuo¹, Chun-Li Wang¹, Chi-Jen Chang¹, Hsin-Yi Tsai¹, Feng-Chun Tsai^2,*,† and Lung-An Hsu^1,*,†

¹ Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 5, Fu-Shin Road, Kwei-Shan, Taoyuan 33305, Taiwan

² Division of Cardiac Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 521; https://doi.org/10.3390/ijms17040521 - 7 Apr 2016

Cited by 6 | Viewed by 6179

Abstract

Matrix metalloproteinase (MMP) plays an important role in the pathogenesis of atrial fibrillation (AF). The MMP9 promoter has a functional polymorphism rs3918242 that can regulate the level of gene transcription. This study recruited 200 AF patients and 240 controls. The MMP9 rs3918242 was [...] Read more.

Matrix metalloproteinase (MMP) plays an important role in the pathogenesis of atrial fibrillation (AF). The MMP9 promoter has a functional polymorphism rs3918242 that can regulate the level of gene transcription. This study recruited 200 AF patients and 240 controls. The MMP9 rs3918242 was examined by polymerase chain reactions. HL-1 atrial myocytes were cultured and electrically stimulated. Right atrial appendages were obtained from six patients with AF and three controls with sinus rhythm undergoing open heart surgery. The MMP9 expression and activity were determined using immunohistochemical analysis and gelatin zymography, respectively. Rapid pacing induces MMP9 secretion from HL-1 myocytes in a time- and dose-dependent manner. The responsiveness of MMP9 transcriptional activity to tachypacing was significantly enhanced by rs3918242. The expression of MMP9 was increased in fibrillating atrial tissue than in sinus rhythm. However, the distribution of rs3918242 genotypes and allele frequencies did not significantly differ between the control and AF groups. HL-1 myocyte may secrete MMP9 in response to rapid pacing, and the secretion could be modulated by rs3918242. Although the MMP9 expression of human atrial myocyte is associated with AF, our study did not support the association of susceptibility to AF among Taiwanese subjects with the MMP9 rs3918242 polymorphism. Full article

(This article belongs to the Special Issue Metalloproteins)

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16 pages, 3481 KiB

Open AccessArticle

Interleukin-17A Differentially Induces Inflammatory and Metabolic Gene Expression in the Adipose Tissues of Lean and Obese Mice

by Yine Qu^1,2, Qiuyang Zhang¹, Siqi Ma², Sen Liu¹, Zhiquan Chen^1,3, Zhongfu Mo^1,4 and Zongbing You^1,5,6,7,8,*

¹ Department of Structural and Cellular Biology, Tulane University, New Orleans, LA 70112, USA

² Department of Histology and Embryology, School of Basic Medicine of North China University of Science and Technology, Tangshan 063000, China

³ Department of Thoracic Surgery, Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China

⁴ Department of Obstetrics and Gynecology, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang 050000, China

⁵ Department of Orthopaedic Surgery, Tulane University, New Orleans, LA 70112, USA

⁶ Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University, New Orleans, LA 70112, USA

⁷ Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University, New Orleans, LA 70112, USA

⁸ Tulane Center for Aging, Tulane University, New Orleans, LA 70112, USA

Int. J. Mol. Sci. 2016, 17(4), 522; https://doi.org/10.3390/ijms17040522 - 7 Apr 2016

Cited by 25 | Viewed by 8992

Abstract

The functions of interleukin-17A (IL-17A) in adipose tissues and adipocytes have not been well understood. In the present study, male mice were fed with a regular diet (n = 6, lean mice) or a high-fat diet (n = 6, obese mice) [...] Read more.

The functions of interleukin-17A (IL-17A) in adipose tissues and adipocytes have not been well understood. In the present study, male mice were fed with a regular diet (n = 6, lean mice) or a high-fat diet (n = 6, obese mice) for 30 weeks. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were analyzed for IL-17A levels. SAT and VAT were treated with IL-17A and analyzed for inflammatory and metabolic gene expression. Mouse 3T3-L1 pre-adipocytes were differentiated into adipocytes, followed with IL-17A treatment and analysis for inflammatory and metabolic gene expression. We found that IL-17A levels were higher in obese SAT than lean SAT; the basal expression of inflammatory and metabolic genes was different between SAT and VAT and between lean and obese adipose tissues. IL-17A differentially induced expression of inflammatory and metabolic genes, such as tumor necrosis factor α, Il-6, Il-1β, leptin, and glucose transporter 4, in adipose tissues of lean and obese mice. IL-17A also differentially induced expression of inflammatory and metabolic genes in pre-adipocytes and adipocytes, and IL-17A selectively activated signaling pathways in adipose tissues and adipocytes. These findings suggest that IL-17A differentially induces inflammatory and metabolic gene expression in the adipose tissues of lean and obese mice. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

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17 pages, 6222 KiB

Open AccessArticle

Placental Expression Patterns of Galectin-1, Galectin-2, Galectin-3 and Galectin-13 in Cases of Intrauterine Growth Restriction (IUGR)

by Stefan Hutter¹, Julia Knabl¹, Ulrich Andergassen¹, Simone Hofmann¹, Christina Kuhn¹, Sven Mahner¹, Petra Arck² and Udo Jeschke^1,*

¹ Department of Gynecology and Obstetrics, Ludwig Maximilians University of Munich, Maistraße 11, 80337 Munich, Germany

² Department of Gynecology and Obstetrics, University of Hamburg, Martinistr. 52, 20246 Hamburg, Germany

Int. J. Mol. Sci. 2016, 17(4), 523; https://doi.org/10.3390/ijms17040523 - 7 Apr 2016

Cited by 33 | Viewed by 6657

Abstract

Galectins (gal) are members of the mammalian β-galactoside-binding proteins and recognize Galβ1-4GlcNAc and Galβ1-4GalNac (Thomsen-Friedenreich antigen (TF)) sequences of several cell surface oligosaccharides. In this study, gal-1, -2, -3 and -13 were investigated systematically in the trophoblast and decidua compartment of intrauterine growth [...] Read more.

Galectins (gal) are members of the mammalian β-galactoside-binding proteins and recognize Galβ1-4GlcNAc and Galβ1-4GalNac (Thomsen-Friedenreich antigen (TF)) sequences of several cell surface oligosaccharides. In this study, gal-1, -2, -3 and -13 were investigated systematically in the trophoblast and decidua compartment of intrauterine growth restriction (IUGR) placentas and normal third trimester control placentas and stratified by fetal gender and gestational age. Within this study, 29 third trimester placentas after delivery were analyzed. Fetal gender was equally divided within both groups, and immunohistochemical staining was analyzed according to fetal gender and gestational age. Double immune-fluorescence with trophoblast-specific markers was used to identify galectin-expressing cells at the feto-maternal interface in the decidua. Gal-3 was significantly downregulated only in the extravillous trophoblast of IUGR placentas. In contrast, expressions of gal-2 and gal-13 were downregulated in both villous and extravillous trophoblast cells of IUGR placentas. In addition, gal-2 and gal-13 showed a highly correlated expression scheme in the placenta. There are significant gender-specific expression patterns for single prototype galectins with downregulation of gal-2 and gal-13 of male gender placentas in cases of IUGR. Gal-3 as the chimera type galectin shows only little gender-specific differences in expression, which disappear in IUGR cases. Full article

(This article belongs to the Special Issue Glycan–Receptor Interaction)

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12 pages, 216 KiB

Open AccessArticle

Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis

by Kun-Ming Rau^1,2, Han-Ku Chen³, Li-Yen Shiu^4,5, Tsai-Ling Chao⁶, Yi-Ping Lo⁴, Chin-Chou Wang^2,7, Meng-Chih Lin^2,7

and Chao-Cheng Huang^2,8,*

¹ Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung 833, Taiwan

² Chang Gung Memorial Hospital, Kaohsiung, Taiwan and Chang Gung University College of Medicine, Tao-Yuan 333, Taiwan

³ Department of Pathology, Yuan’s General Hospital, Kaohsiung 802, Taiwan

⁴ Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan

⁵ Department of Medical Research, Cell Therapy and Research Center, E-Da Hospital, I-shou University, Kaohsiung 840, Taiwan

⁶ Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan

⁷ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan

⁸ Biobank and Tissue Bank and Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan

Int. J. Mol. Sci. 2016, 17(4), 524; https://doi.org/10.3390/ijms17040524 - 7 Apr 2016

Cited by 27 | Viewed by 5561

Abstract

Mutations on epidermal growth factor receptor (EGFR) of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR [...] Read more.

Mutations on epidermal growth factor receptor (EGFR) of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-specific real-time polymerase chain reaction to analyze K-ras mutation. Forty-nine paired tissues with both primary adenocarcinoma of lung and matched brain metastasis were collected. Thirteen patients (26.5%) were discordant for the status of EGFR between primary and metastatic sites. K-ras gene could be checked in paired specimens from 33 patients, thirteen patients (39.6%) were discordant for the status of K-ras. In primary lung adenocarcinoma, there were 14 patients of mutant EGFR had mutant K-ras synchronously. This study revealed that the status of EGFR mutation in lung adenocarcinomas is relatively consistent between primary and metastatic sites compared to K-ras mutation. However, there are still a few cases of adenocarcinoma of lung showing discordance for the status of EGFR mutation. Repeated analysis of EGFR mutation is highly recommended if tissue from metastatic or recurrent site is available for the evaluation of target therapy. Full article

(This article belongs to the Special Issue Brain Metastasis 2016)

15 pages, 412 KiB

Open AccessArticle

Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

by David Ramírez

and Julio Caballero^*

Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca. 2 Norte 685, Casilla 721, Talca, Chile

Int. J. Mol. Sci. 2016, 17(4), 525; https://doi.org/10.3390/ijms17040525 - 20 Apr 2016

Cited by 134 | Viewed by 10660

Abstract

Molecular docking is a computational chemistry method which has become essential for the rational drug design process. In this context, it has had great impact as a successful tool for the study of ligand–receptor interaction modes, and for the exploration of large chemical [...] Read more.

Molecular docking is a computational chemistry method which has become essential for the rational drug design process. In this context, it has had great impact as a successful tool for the study of ligand–receptor interaction modes, and for the exploration of large chemical datasets through virtual screening experiments. Despite their unquestionable merits, docking methods are not reliable for predicting binding energies due to the simple scoring functions they use. However, comparisons between two or three complexes using the predicted binding energies as a criterion are commonly found in the literature. In the present work we tested how wise is it to trust the docking energies when two complexes between a target protein and enantiomer pairs are compared. For this purpose, a ligand library composed by 141 enantiomeric pairs was used, including compounds with biological activities reported against seven protein targets. Docking results using the software Glide (considering extra precision (XP), standard precision (SP), and high-throughput virtual screening (HTVS) modes) and AutoDock Vina were compared with the reported biological activities using a classification scheme. Our test failed for all modes and targets, demonstrating that an accurate prediction when binding energies of enantiomers are compared using docking may be due to chance. We also compared pairs of compounds with different molecular weights and found the same results. Full article

(This article belongs to the Special Issue Big Data Analysis and QSAR/QSPR Research in Chemistry, Bio-Medical, and Network Sciences)

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13 pages, 3670 KiB

Open AccessArticle

Melatonin Suppresses Autophagy Induced by Clinostat in Preosteoblast MC3T3-E1 Cells

by Yeong-Min Yoo¹

, Tae-Young Han² and Han Sung Kim^1,*

¹ Yonsei-Fraunhofer Medical Device Laboratory, Department of Biomedical Engineering, Yonsei University, Wonju, 26493 Gangwon-do, Korea

² Fraunhofer Institute IKTS-MD, Maria-Reiche-Str.2, 01109 Dresden, Germany

Int. J. Mol. Sci. 2016, 17(4), 526; https://doi.org/10.3390/ijms17040526 - 8 Apr 2016

Cited by 38 | Viewed by 8056

Abstract

Microgravity exposure can cause cardiovascular and immune disorders, muscle atrophy, osteoporosis, and loss of blood and plasma volume. A clinostat device is an effective ground-based tool for simulating microgravity. This study investigated how melatonin suppresses autophagy caused by simulated microgravity in preosteoblast MC3T3-E1 [...] Read more.

Microgravity exposure can cause cardiovascular and immune disorders, muscle atrophy, osteoporosis, and loss of blood and plasma volume. A clinostat device is an effective ground-based tool for simulating microgravity. This study investigated how melatonin suppresses autophagy caused by simulated microgravity in preosteoblast MC3T3-E1 cells. In preosteoblast MC3T3-E1 cells, clinostat rotation induced a significant time-dependent increase in the levels of the autophagosomal marker microtubule-associated protein light chain (LC3), suggesting that autophagy is induced by clinostat rotation in these cells. Melatonin treatment (100, 200 nM) significantly attenuated the clinostat-induced increases in LC3 II protein, and immunofluorescence staining revealed decreased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2), indicating a decrease in autophagosomes. The levels of phosphorylation of mammalian target of rapamycin (p-mTOR) (Ser2448), phosphorylation of extracellular signal-regulated kinase (p-ERK), and phosphorylation of serine-threonine protein kinase (p-Akt) (Ser473) were significantly reduced by clinostat rotation. However, their expression levels were significantly recovered by melatonin treatment. Also, expression of the Bcl-2, truncated Bid, Cu/Zn- superoxide dismutase (SOD), and Mn-SOD proteins were significantly increased by melatonin treatment, whereas levels of Bax and catalase were decreased. The endoplasmic reticulum (ER) stress marker GRP78/BiP, IRE1α, and p-PERK proteins were significantly reduced by melatonin treatment. Treatment with the competitive melatonin receptor antagonist luzindole blocked melatonin-induced decreases in LC3 II levels. These results demonstrate that melatonin suppresses clinostat-induced autophagy through increasing the phosphorylation of the ERK/Akt/mTOR proteins. Consequently, melatonin appears to be a potential therapeutic agent for regulating microgravity-related bone loss or osteoporosis. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 1889 KiB

Open AccessArticle

Bavachin from Psoralea corylifolia Improves Insulin-Dependent Glucose Uptake through Insulin Signaling and AMPK Activation in 3T3-L1 Adipocytes

by Hyejin Lee¹, Hua Li¹, Minsoo Noh² and Jae-Ha Ryu^1,*

¹ College of Pharmacy and Research Center for Cell Fate Control, Sookmyung Women’s University, 52 Hyochangwongil, Yongsan-gu, Seoul 140-742, Korea

² Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-Gu, Seoul 151-742, Korea

Int. J. Mol. Sci. 2016, 17(4), 527; https://doi.org/10.3390/ijms17040527 - 8 Apr 2016

Cited by 46 | Viewed by 8821

Abstract

The fruit of Psoralea corylifolia L. (Fabaceae) (PC), known as “Bo-Gol-Zhee” in Korea has been used as traditional medicine. Ethanol and aqueous extracts of PC have an anti-hyperglycemic effect by increasing plasma insulin levels and decreasing blood glucose and total plasma [...] Read more.

The fruit of Psoralea corylifolia L. (Fabaceae) (PC), known as “Bo-Gol-Zhee” in Korea has been used as traditional medicine. Ethanol and aqueous extracts of PC have an anti-hyperglycemic effect by increasing plasma insulin levels and decreasing blood glucose and total plasma cholesterol levels in type 2 diabetic rats. In this study, we purified six compounds from PC and investigated their anti-diabetic effect. Among the purified compounds, bavachin most potently accumulated lipids during adipocyte differentiation. Intracellular lipid accumulation was measured by Oil Red-O (ORO) cell staining to investigate the effect of compounds on adipogenesis. Consistently, bavachin activated gene expression of adipogenic transcriptional factors, proliferator-activated receptorγ (PPARγ) and CCAAT/enhancer binding protein-α (C/EBPα). Bavachin also increased adiponectin expression and secretion in adipocytes. Moreover, bavachin increased insulin-induced glucose uptake by differentiated adipocytes and myoblasts. In differentiated adipocytes, we found that bavachin enhanced glucose uptake via glucose transporter 4 (GLUT4) translocation by activating the Akt and 5′AMP-activated protein kinase (AMPK) pathway in the presence or absence of insulin. These results suggest that bavachin from Psoralea corylifolia might have therapeutic potential for type 2 diabetes by activating insulin signaling pathways. Full article

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

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20 pages, 4863 KiB

Open AccessArticle

Pathways Regulating Spheroid Formation of Human Follicular Thyroid Cancer Cells under Simulated Microgravity Conditions: A Genetic Approach

by Stefan Riwaldt¹, Johann Bauer^2,*, Markus Wehland¹, Lasse Slumstrup³, Sascha Kopp¹, Elisabeth Warnke¹, Anita Dittrich³, Nils E. Magnusson⁴, Jessica Pietsch¹, Thomas J. Corydon³

, Manfred Infanger¹ and Daniela Grimm^1,3

¹ Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke University Clinic, Leipziger Str. 44, 39120 Magdeburg, Germany

² Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany

³ Institute of Biomedicine, Aarhus University, Wilhelm Meyers Allé 4, 8000 Aarhus C, Denmark

⁴ Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, 8000 Aarhus C, Denmark

Int. J. Mol. Sci. 2016, 17(4), 528; https://doi.org/10.3390/ijms17040528 - 8 Apr 2016

Cited by 42 | Viewed by 9180

Abstract

Microgravity induces three-dimensional (3D) growth in numerous cell types. Despite substantial efforts to clarify the underlying mechanisms for spheroid formation, the precise molecular pathways are still not known. The principal aim of this paper is to compare static 1g-control cells with [...] Read more.

Microgravity induces three-dimensional (3D) growth in numerous cell types. Despite substantial efforts to clarify the underlying mechanisms for spheroid formation, the precise molecular pathways are still not known. The principal aim of this paper is to compare static 1g-control cells with spheroid forming (MCS) and spheroid non-forming (AD) thyroid cancer cells cultured in the same flask under simulated microgravity conditions. We investigated the morphology and gene expression patterns in human follicular thyroid cancer cells (UCLA RO82-W-1 cell line) after a 24 h-exposure on the Random Positioning Machine (RPM) and focused on 3D growth signaling processes. After 24 h, spheroid formation was observed in RPM-cultures together with alterations in the F-actin cytoskeleton. qPCR indicated more changes in gene expression in MCS than in AD cells. Of the 24 genes analyzed VEGFA, VEGFD, MSN, and MMP3 were upregulated in MCS compared to 1g-controls, whereas ACTB, ACTA2, KRT8, TUBB, EZR, RDX, PRKCA, CAV1, MMP9, PAI1, CTGF, MCP1 were downregulated. A pathway analysis revealed that the upregulated genes code for proteins, which promote 3D growth (angiogenesis) and prevent excessive accumulation of extracellular proteins, while genes coding for structural proteins are downregulated. Pathways regulating the strength/rigidity of cytoskeletal proteins, the amount of extracellular proteins, and 3D growth may be involved in MCS formation. Full article

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

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18 pages, 3840 KiB

Open AccessArticle

Anti-Inflammatory and Cytoprotective Effects of TMC-256C1 from Marine-Derived Fungus Aspergillus sp. SF-6354 via up-Regulation of Heme Oxygenase-1 in Murine Hippocampal and Microglial Cell Lines

by Dong-Cheol Kim¹, Kwang-Ho Cho¹, Wonmin Ko¹, Chi-Su Yoon¹, Jae Hak Sohn², Joung Han Yim³, Youn-Chul Kim¹ and Hyuncheol Oh^1,*

¹ Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea

² College of Medical and Life Sciences, Silla University, Busan 46958, Korea

³ Korea Polar Research Institute, KORDI, Yeonsu-gu, Incheon 21990, Korea

Int. J. Mol. Sci. 2016, 17(4), 529; https://doi.org/10.3390/ijms17040529 - 8 Apr 2016

Cited by 17 | Viewed by 7769

Abstract

In the course of searching for bioactive secondary metabolites from marine fungi, TMC-256C1 was isolated from an ethyl acetate extract of the marine-derived fungus Aspergillus sp. SF6354. TMC-256C1 displayed anti-neuroinflammatory effect in BV2 microglial cells induced by lipopolysaccharides (LPS) as well as neuroprotective [...] Read more.

In the course of searching for bioactive secondary metabolites from marine fungi, TMC-256C1 was isolated from an ethyl acetate extract of the marine-derived fungus Aspergillus sp. SF6354. TMC-256C1 displayed anti-neuroinflammatory effect in BV2 microglial cells induced by lipopolysaccharides (LPS) as well as neuroprotective effect against glutamate-stimulated neurotoxicity in mouse hippocampal HT22 cells. TMC-256C1 was shown to develop a cellular resistance to oxidative damage caused by glutamate-induced cytotoxicity and reactive oxygen species (ROS) generation in HT22 cells, and suppress the inflammation process in LPS-stimulated BV2 cells. Furthermore, the neuroprotective and anti-neuroinflammatory activities of TMC-256C1 were associated with upregulated expression of heme oxygenase (HO)-1 and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) in HT22 and BV2 cells. We also found that TMC-256C1 activated p38 mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in HT22 and BV2 cells. These results demonstrated that TMC-256C1 activates HO-1 protein expression, probably by increasing nuclear Nrf2 levels via the activation of the p38 MAPK and PI3K/Akt pathways. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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19 pages, 2982 KiB

Open AccessArticle

Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells

by Juan Liu¹, Yujing Zhang², Aichun Liu^3,*, Jinghua Wang¹, Lianqiao Li³, Xi Chen¹, Xinyu Gao¹, Yanming Xue¹, Xiaomin Zhang¹ and Yao Liu¹

¹ Department of Hematology, Harbin Medical University Second Hospital, Harbin 150086, China

² Department of Pediatrics, Harbin Medical University Second Hospital, Harbin 150086, China

³ Department of Hematology and Lymphology, Harbin Medical University Cancer Hospital, Harbin 150086, China

Int. J. Mol. Sci. 2016, 17(4), 531; https://doi.org/10.3390/ijms17040531 - 8 Apr 2016

Cited by 52 | Viewed by 10380

Abstract

Although dasatinib is effective in most imatinib mesylate (IMT)-resistant chronic myeloid leukemia (CML) patients, the underlying mechanism of its effectiveness in eliminating imatinib-resistant cells is only partially understood. This study investigated the effects of dasatinib on signaling mechanisms driving-resistance in imatinib-resistant CML cell [...] Read more.

Although dasatinib is effective in most imatinib mesylate (IMT)-resistant chronic myeloid leukemia (CML) patients, the underlying mechanism of its effectiveness in eliminating imatinib-resistant cells is only partially understood. This study investigated the effects of dasatinib on signaling mechanisms driving-resistance in imatinib-resistant CML cell line K562 (K562R^IMT). Compared with K562 control cells, exsomal release, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling and autophagic activity were increased significantly in K562R^IMT cells and mTOR-independent beclin-1/Vps34 signaling was shown to be involved in exosomal release in these cells. We found that Notch1 activation-mediated reduction of phosphatase and tensin homolog (PTEN) was responsible for the increased Akt/mTOR activities in K562R^IMT cells and treatment with Notch1 γ-secretase inhibitor prevented activation of Akt/mTOR. In addition, suppression of mTOR activity by rapamycin decreased the level of activity of p70S6K, induced upregulation of p53 and caspase 3, and led to increase of apoptosis in K562R^IMT cells. Inhibition of autophagy by spautin-1 or beclin-1 knockdown decreased exosomal release, but did not affect apoptosis in K562R^IMT cells. In summary, in K562R^IMT cells dasatinib promoted apoptosis through downregulation of Akt/mTOR activities, while preventing exosomal release and inhibiting autophagy by downregulating expression of beclin-1 and Vps34. Our findings reveal distinct dasatinib-induced mechanisms of apoptotic response and exosomal release in imatinib-resistant CML cells. Full article

(This article belongs to the Section Biochemistry)

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9 pages, 1165 KiB

Open AccessArticle

Fast Conversion of Ionic Liquids and Poly(Ionic Liquid)s into Porous Nitrogen-Doped Carbons in Air

by Yongjun Men¹, Martina Ambrogi¹, Baohang Han² and Jiayin Yuan^1,*

¹ Department of Colloid Chemistry, Max Planck Institute of Colloids and Interfaces, Potsdam D–14476, Germany

² National Center for Nanoscience and Technology, Beijing 100190, China

Int. J. Mol. Sci. 2016, 17(4), 532; https://doi.org/10.3390/ijms17040532 - 8 Apr 2016

Cited by 10 | Viewed by 7565

Abstract

Ionic liquids and poly(ionic liquid)s have been successfully converted into nitrogen-doped porous carbons with tunable surface area up to 1200 m²/g at high temperatures in air. Compared to conventional carbonization process conducted under inert gas to produce nitrogen-doped carbons, the new [...] Read more.

Ionic liquids and poly(ionic liquid)s have been successfully converted into nitrogen-doped porous carbons with tunable surface area up to 1200 m²/g at high temperatures in air. Compared to conventional carbonization process conducted under inert gas to produce nitrogen-doped carbons, the new production method was completed in a rather shorter time without noble gas protection. Full article

(This article belongs to the Special Issue Ionic Liquids 2016 and Selected Papers from ILMAT III)

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12 pages, 2084 KiB

Open AccessArticle

Programming Effects of Prenatal Glucocorticoid Exposure with a Postnatal High-Fat Diet in Diabetes Mellitus

by Jiunn-Ming Sheen^1,†, Chih-Sung Hsieh^2,3,†, You-Lin Tain¹

, Shih-Wen Li¹, Hong-Ren Yu¹, Chih-Cheng Chen¹, Miao-Meng Tiao¹

, Yu-Chieh Chen^1,* and Li-Tung Huang^1,*

¹ Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung 833, Taiwan

² Department of Medical Administration, Pu-Li Christian Hospital, Pu-Li, Nantou 545, Taiwan

³ Department of Applied Chemistry, National Chi-Nan University, Pu-Li, Nantou 545, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 533; https://doi.org/10.3390/ijms17040533 - 8 Apr 2016

Cited by 21 | Viewed by 6148

Abstract

Increasing evidence has shown that many chronic diseases originate from early life, even before birth, through what are termed as fetal programming effects. Glucocorticoids are frequently used prenatally to accelerate the maturation of the lungs of premature infants. High-fat diets are associated with [...] Read more.

Increasing evidence has shown that many chronic diseases originate from early life, even before birth, through what are termed as fetal programming effects. Glucocorticoids are frequently used prenatally to accelerate the maturation of the lungs of premature infants. High-fat diets are associated with insulin resistance, but the effects of prenatal glucocorticoid exposure plus a postnatal high-fat diet in diabetes mellitus remain unclear. We administered pregnant Sprague-Dawley rats’ intraperitoneal dexamethasone (0.1 mg/kg body weight) or vehicle at gestational days 14–20. Male offspring were administered a normal or high-fat diet starting from weaning. We assessed the effects of prenatal steroid exposure plus postnatal high-fat diet on the liver, pancreas, muscle and fat at postnatal day 120. At 15 and 30 min, sugar levels were higher in the dexamethasone plus high-fat diet (DHF) group than the vehicle plus high-fat diet (VHF) group in the intraperitoneal glucose tolerance test (IPGTT). Serum insulin levels at 15, 30 and 60 min were significantly higher in the VHF group than in the vehicle and normal diet group. Liver insulin receptor and adenosine monophosphate-activated protein kinase mRNA expressions and protein levels were lower in the DHF group. Insulin receptor and insulin receptor substrate-1 mRNA expressions were lower in the epididymal adipose tissue in the VHF and DHF groups. “Programming” of liver or epididymal adipose tissue resulted from prenatal events. Prenatal steroid exposure worsened insulin resistance in animals fed a high-fat diet. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

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14 pages, 2814 KiB

Open AccessArticle

Pancreatic Transdifferentiation and Glucose-Regulated Production of Human Insulin in the H4IIE Rat Liver Cell Line

by Binhai Ren¹, Chang Tao¹, Margaret Anne Swan², Nichole Joachim², Rosetta Martiniello-Wilks¹, Najah T. Nassif¹

, Bronwyn A. O’Brien¹ and Ann M. Simpson^1,*

¹ School of Life Sciences and Centre for Health Technologies, University of Technology Sydney, P.O. Box 123, Broadway, 2007 Sydney, NSW, Australia

² School of Medical Sciences (Anatomy & Histology) and Bosch Institute, University of Sydney, 2006 Sydney, NSW, Australia

Int. J. Mol. Sci. 2016, 17(4), 534; https://doi.org/10.3390/ijms17040534 - 8 Apr 2016

Cited by 4 | Viewed by 7289

Abstract

Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat [...] Read more.

Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat NeuroD1 gene alone, or the human insulin gene and rat NeuroD1 genes together, to the rat liver cell line, H4IIE, to determine if storage of insulin and pancreatic transdifferentiation occurred. Stable clones were selected and expanded into cell lines: H4IIEins (insulin gene alone), H4IIE/ND (NeuroD1 gene alone), and H4IIEins/ND (insulin and NeuroD1 genes). The H4IIEins cells did not store insulin; however, H4IIE/ND and H4IIEins/ND cells stored 65.5 ± 5.6 and 1475.4 ± 171.8 pmol/insulin/5 × 10⁶ cells, respectively. Additionally, several β cell transcription factors and pancreatic hormones were expressed in both H4IIE/ND and H4IIEins/ND cells. Electron microscopy revealed insulin storage vesicles in the H4IIE/ND and H4IIEins/ND cell lines. Regulated secretion of insulin to glucose (0–20 mmol/L) was seen in the H4IIEins/ND cell line. The H4IIEins/ND cells were transplanted into diabetic immunoincompetent mice, resulting in normalization of blood glucose. This data shows that the expression of NeuroD1 and insulin in liver cells may be a useful strategy for inducing islet neogenesis and reversing diabetes. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

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15 pages, 4949 KiB

Open AccessArticle

Inhibition of IFN-γ-Induced Nitric Oxide Dependent Antimycobacterial Activity by miR-155 and C/EBPβ

by Yongwei Qin^1,2, Qinglan Wang¹, Youlang Zhou³, Yinong Duan² and Qian Gao^1,*

¹ Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

² Department of Pathogen and Immunology, Medical College, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu, China

³ Hand Surgery Research Center, Department of Hand Surgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong 226001, Jiangsu, China

Int. J. Mol. Sci. 2016, 17(4), 535; https://doi.org/10.3390/ijms17040535 - 8 Apr 2016

Cited by 30 | Viewed by 7266

Abstract

miR-155 (microRNA-155) is an important non-coding RNA in regulating host crucial biological regulators. However, its regulatory function in mycobacterium infection remains unclear. Our study demonstrates that miR-155 expression is significantly increased in macrophages after Mycobacterium marinum (M.m) infection. Transfection with anti-miR-155 [...] Read more.

miR-155 (microRNA-155) is an important non-coding RNA in regulating host crucial biological regulators. However, its regulatory function in mycobacterium infection remains unclear. Our study demonstrates that miR-155 expression is significantly increased in macrophages after Mycobacterium marinum (M.m) infection. Transfection with anti-miR-155 enhances nitric oxide (NO) synthesis and decreases the mycobacterium burden, and vice versa, in interferon γ (IFN-γ) activated macrophages. More importantly, miR-155 can directly bind to the 3′UTR of CCAAT/enhancer binding protein β (C/EBPβ), a positive transcriptional regulator of nitric oxide synthase (NOS2), and regulate C/EBPβ expression negatively. Knockdown of C/EBPβ inhibit the production of nitric oxide synthase and promoted mycobacterium survival. Collectively, these data suggest that M.m-induced upregulation of miR-155 downregulated the expression of C/EBPβ, thus decreasing the production of NO and promoting mycobacterium survival, which may provide an insight into the function of miRNA in subverting the host innate immune response by using mycobacterium for its own profit. Understanding how miRNAs partly regulate microbicidal mechanisms may represent an attractive way to control tuberculosis infectious. Full article

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

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15 pages, 2231 KiB

Open AccessArticle

Structural Investigation for Optimization of Anthranilic Acid Derivatives as Partial FXR Agonists by in Silico Approaches

by Meimei Chen^1,*, Xuemei Yang¹, Xinmei Lai¹, Jie Kang¹, Huijuan Gan¹ and Yuxing Gao²

¹ College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China

² College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China

Int. J. Mol. Sci. 2016, 17(4), 536; https://doi.org/10.3390/ijms17040536 - 8 Apr 2016

Cited by 15 | Viewed by 6166

Abstract

In this paper, a three level in silico approach was applied to investigate some important structural and physicochemical aspects of a series of anthranilic acid derivatives (AAD) newly identified as potent partial farnesoid X receptor (FXR) agonists. Initially, both two and three-dimensional quantitative [...] Read more.

In this paper, a three level in silico approach was applied to investigate some important structural and physicochemical aspects of a series of anthranilic acid derivatives (AAD) newly identified as potent partial farnesoid X receptor (FXR) agonists. Initially, both two and three-dimensional quantitative structure activity relationship (2D- and 3D-QSAR) studies were performed based on such AAD by a stepwise technology combined with multiple linear regression and comparative molecular field analysis. The obtained 2D-QSAR model gave a high predictive ability (R²_train = 0.935, R²_test = 0.902, Q²_LOO = 0.899). It also uncovered that number of rotatable single bonds (b_rotN), relative negative partial charges (RPC⁻), oprea's lead-like (opr_leadlike), subdivided van der Waal’s surface area (SlogP_VSA2) and accessible surface area (ASA) were important features in defining activity. Additionally, the derived3D-QSAR model presented a higher predictive ability (R²_train = 0.944, R²_test = 0.892, Q²_LOO = 0.802). Meanwhile, the derived contour maps from the 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving FXR agonist activity. Finally, nine newly designed AAD with higher predicted EC₅₀ values than the known template compound were docked into the FXR active site. The excellent molecular binding patterns of these molecules also suggested that they can be robust and potent partial FXR agonists in agreement with the QSAR results. Overall, these derived models may help to identify and design novel AAD with better FXR agonist activity. Full article

(This article belongs to the Special Issue Big Data Analysis and QSAR/QSPR Research in Chemistry, Bio-Medical, and Network Sciences)

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16 pages, 4082 KiB

Open AccessArticle

A Proteomic Approach for the Identification of Up-Regulated Proteins Involved in the Metabolic Process of the Leiomyoma

by Blendi Ura¹, Federica Scrimin¹, Giorgio Arrigoni^2,3, Cinzia Franchin^2,3, Lorenzo Monasta^1,*

and Giuseppe Ricci^1,4

¹ Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, Trieste 34137, Italy

² Department of Biomedical Sciences, University of Padova, Padova 35121, Italy

³ Proteomics Center, Padova University, Padova 35129, Italy

⁴ Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste 34149, Italy

Int. J. Mol. Sci. 2016, 17(4), 540; https://doi.org/10.3390/ijms17040540 - 9 Apr 2016

Cited by 12 | Viewed by 6557

Abstract

Uterine leiomyoma is the most common benign smooth muscle cell tumor of the uterus. Proteomics is a powerful tool for the analysis of complex mixtures of proteins. In our study, we focused on proteins that were upregulated in the leiomyoma compared to the [...] Read more.

Uterine leiomyoma is the most common benign smooth muscle cell tumor of the uterus. Proteomics is a powerful tool for the analysis of complex mixtures of proteins. In our study, we focused on proteins that were upregulated in the leiomyoma compared to the myometrium. Paired samples of eight leiomyomas and adjacent myometrium were obtained and submitted to two-dimensional gel electrophoresis (2-DE) and mass spectrometry for protein identification and to Western blotting for 2-DE data validation. The comparison between the patterns revealed 24 significantly upregulated (p < 0.05) protein spots, 12 of which were found to be associated with the metabolic processes of the leiomyoma and not with the normal myometrium. The overexpression of seven proteins involved in the metabolic processes of the leiomyoma was further validated by Western blotting and 2D Western blotting. Four of these proteins have never been associated with the leiomyoma before. The 2-DE approach coupled with mass spectrometry, which is among the methods of choice for comparative proteomic studies, identified a number of proteins overexpressed in the leiomyoma and involved in several biological processes, including metabolic processes. A better understanding of the mechanism underlying the overexpression of these proteins may be important for therapeutic purposes. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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12 pages, 3082 KiB

Open AccessArticle

Deficiency of Senescence Marker Protein 30 Exacerbates Cardiac Injury after Ischemia/Reperfusion

by Shinpei Kadowaki¹, Tetsuro Shishido^1,*, Toshiki Sasaki¹, Takayuki Sugai¹, Taro Narumi¹, Yuki Honda¹, Yoichiro Otaki¹, Daisuke Kinoshita¹, Tetsuya Takahashi¹, Satoshi Nishiyama¹, Hiroki Takahashi¹, Takanori Arimoto¹, Takuya Miyamoto¹, Tetsu Watanabe¹, Akihiko Ishigami², Yasuchika Takeishi³

and Isao Kubota¹

¹ Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 iidanihi, Yamagata 990-9585, Japan

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

³ Department of Cardiology and Hematology, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan

Int. J. Mol. Sci. 2016, 17(4), 542; https://doi.org/10.3390/ijms17040542 - 11 Apr 2016

Cited by 11 | Viewed by 6428

Abstract

Early myocardial reperfusion is an effective therapy but ischemia/reperfusion (I/R) causes lethal myocardial injury. The aging heart was reported to show greater cardiac damage after I/R injury than that observed in young hearts. Senescence marker protein 30 (SMP30), whose expression decreases with age, [...] Read more.

Early myocardial reperfusion is an effective therapy but ischemia/reperfusion (I/R) causes lethal myocardial injury. The aging heart was reported to show greater cardiac damage after I/R injury than that observed in young hearts. Senescence marker protein 30 (SMP30), whose expression decreases with age, plays a role in reducing oxidative stress and apoptosis. However, the impact of SMP30 on myocardial I/R injury remains to be determined. In this study, the left anterior descending coronary artery was occluded for 30 min, followed by reperfusion in wild-type (WT) and SMP30 knockout (KO) mice. After I/R, cardiomyocyte apoptosis and the ratio of infarct area/area at risk were higher, left ventricular fractional shortening was lower, and reactive oxygen species (ROS) generation was enhanced in SMP30 KO mice. Moreover, the previously increased phosphorylation of GSK-3β and Akt was lower in SMP30 KO mice than in WT mice. In cardiomyocytes, silencing of SMP30 expression attenuated Akt and GSK-3β phosphorylation, and increased Bax to Bcl-2 ratio and cardiomyocyte apoptosis induced by hydrogen peroxide. These results suggested that SMP30 deficiency augments myocardial I/R injury through ROS generation and attenuation of Akt activation. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 2819 KiB

Open AccessArticle

The Long Intron 1 of Growth Hormone Gene from Reeves’ Turtle (Chinemys reevesii) Correlates with Negatively Regulated GH Expression in Four Cell Lines

by Wen-Sheng Liu^{1,2,3,4,*,†}, Jing-E Ma^1,2,3,†

, Wei-Xia Li^1,2,3, Jin-Ge Zhang^1,2,3, Juan Wang^1,2,3, Qing-Hua Nie^1,2,3

, Feng-Fang Qiu^1,2,3, Mei-Xia Fang^1,2,3, Fang Zeng^1,2,3, Xing Wang^1,2,3, Xi-Ran Lin^1,2,3, Li Zhang^1,2,3, Shao-Hao Chen^1,2,3 and Xi-Quan Zhang^1,2,3,*

¹ Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China

² Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510642, China

³ Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou 510642, China

⁴ College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 543; https://doi.org/10.3390/ijms17040543 - 12 Apr 2016

Cited by 7 | Viewed by 5413

Abstract

Turtles grow slowly and have a long lifespan. Ultrastructural studies of the pituitary gland in Reeves’ turtle (Chinemys reevesii) have revealed that the species possesses a higher nucleoplasmic ratio and fewer secretory granules in growth hormone (GH) cells than other animal [...] Read more.

Turtles grow slowly and have a long lifespan. Ultrastructural studies of the pituitary gland in Reeves’ turtle (Chinemys reevesii) have revealed that the species possesses a higher nucleoplasmic ratio and fewer secretory granules in growth hormone (GH) cells than other animal species in summer and winter. C. reevesii GH gene was cloned and species-specific similarities and differences were investigated. The full GH gene sequence in C. reevesii contains 8517 base pairs (bp), comprising five exons and four introns. Intron 1 was found to be much longer in C. reevesii than in other species. The coding sequence (CDS) of the turtle’s GH gene, with and without the inclusion of intron 1, was transfected into four cell lines, including DF-1 chicken embryo fibroblasts, Chinese hamster ovary (CHO) cells, human embryonic kidney 293FT cells, and GH4C1 rat pituitary cells; the turtle growth hormone (tGH) gene mRNA and protein expression levels decreased significantly in the intron-containing CDS in these cell lines, compared with that of the corresponding intronless CDS. Thus, the long intron 1 of GH gene in Reeves’ turtle might correlate with downregulated gene expression. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 2888 KiB

Open AccessArticle

Comparison of Topical Hemostatic Agents in a Swine Model of Extremity Arterial Hemorrhage: BloodSTOP iX Battle Matrix vs. QuikClot Combat Gauze

by Huixi Li¹, Lin Wang¹, Amjad Alwaal¹

, Yung-Chin Lee¹, Amanda Reed-Maldonado¹, Taylor A. Spangler², Lia Banie¹, Reginald B. O’Hara³ and Guiting Lin^1,*

¹ Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA

² VDx Veterinary Diagnostics, Davis, CA 95616, USA

³ Department of Aeromedical Research, U.S. Air Force School of Aerospace Medicine, Wright-Patterson Air Force Base, Dayton, OH 45433, USA

Int. J. Mol. Sci. 2016, 17(4), 545; https://doi.org/10.3390/ijms17040545 - 12 Apr 2016

Cited by 22 | Viewed by 10447

Abstract

BloodSTOP iX Battle Matrix (BM) and QuikClot Combat Gauze (CG) have both been used to treat traumatic bleeding. The purpose of this study was to examine the efficacy and initial safety of both products in a swine extremity arterial hemorrhage model, which mimics [...] Read more.

BloodSTOP iX Battle Matrix (BM) and QuikClot Combat Gauze (CG) have both been used to treat traumatic bleeding. The purpose of this study was to examine the efficacy and initial safety of both products in a swine extremity arterial hemorrhage model, which mimics combat injury. Swine (37.13 ± 0.56 kg, N_BM = 11, N_CG = 9) were anesthetized and splenectomized. We then isolated the femoral arteries and performed a 6 mm arteriotomy. After 45 s of free bleeding, either BM or CG was applied. Fluid resuscitation was provided to maintain a mean arterial pressure of 65 mmHg. Animals were observed for three hours or until death. Fluoroscopic angiography and wound stability challenge tests were performed on survivors. Tissue samples were collected for histologic examination. Stable hemostasis was achieved in 11/11 BM and 5/9 CG subjects, with recovery of mean arterial pressure and animal survival for three hours (p < 0.05, Odds Ratio (OR) = 18.82 (0.85–415.3)). Time to stable hemostasis was shorter for the BM-treated group (4.8 ± 2.5 min vs. 58 ± 20.1 min; Median = 2, Interquartile Range (IQR) = 0 min vs. Median = 60, IQR = 120 min; p < 0.05) and experienced longer total stable hemostasis (175.2 ± 2.5 min vs. 92.4 ± 29.9 min; Median = 178, IQR = 0 min vs. Median = 120, IQR = 178 min; p < 0.05). Post-treatment blood loss was lower with BM (9.5 ± 2.4 mL/kg, Median = 10.52, IQR = 13.63 mL/kg) compared to CG (29.9 ± 9.9 mL/kg, Median = 29.38, IQR = 62.44 mL/kg) (p = 0.2875). Standard BM products weighed less compared to CG (6.9 ± 0.03 g vs. 20.2 ± 0.4 g) (p < 0.05) and absorbed less blood (3.4 ± 0.8 g vs. 41.9 ± 12.3 g) (p < 0.05). Fluoroscopic angiography showed recanalization in 5/11 (BM) and 0/5 (CG) surviving animals (p = 0.07, OR = 9.3 (0.41–208.8)). The wound stability challenge test resulted in wound re-bleeding in 1/11 (BM) and 5/5 (CG) surviving animals (p < 0.05, OR = 0.013 (0.00045–0.375)). Histologic evidence indicated no wound site, distal limb or major organ damage in either group. BM is more effective and portable in treating arterial hemorrhage compared to CG. There was no histologic evidence of further damage in either group. Full article

(This article belongs to the Special Issue Vascular Biology and Therapeutics)

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10 pages, 1587 KiB

Open AccessArticle

A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent

by Eun Ju Oh¹, Jong Il Park¹, Ji Eun Lee¹, Cheol Hwan Myung¹, Su Yeon Kim², Sung Eun Chang^2,*

and Jae Sung Hwang^1,*

¹ Department of Genetic Engineering, Graduate School of Biotechnology, Kyung Hee University, Yongin 446-701, Korea

² Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong Songpa-gu, Seoul 138-736, Korea

Int. J. Mol. Sci. 2016, 17(4), 546; https://doi.org/10.3390/ijms17040546 - 12 Apr 2016

Cited by 18 | Viewed by 7857

Abstract

BW723C86, a serotonin receptor 2B agonist, has been investigated as a potential therapeutic for various conditions such as anxiety, hyperphagia and hypertension. However, the functional role of BW723C86 against melanogenesis remains unclear. In this study, we investigate the effect of serotonin receptor 2B [...] Read more.

BW723C86, a serotonin receptor 2B agonist, has been investigated as a potential therapeutic for various conditions such as anxiety, hyperphagia and hypertension. However, the functional role of BW723C86 against melanogenesis remains unclear. In this study, we investigate the effect of serotonin receptor 2B (5-HTR2B) agonist on melanogenesis and elucidate the mechanism involved. BW723C86 reduced melanin synthesis and intracellular tyrosinase activity in melan-A cells and normal human melanocytes. The expression of melanogenesis-related proteins (tyrosinase, TRP-1 and TRP-2) and microphthalmia-associated transcription factor (MITF) in melan-A cells decreased after BW723C86 treatment. The promoter activity of MITF was also reduced by BW723C86 treatment. The reduced level of MITF was associated with inhibition of protein kinase A (PKA) and cAMP response element-binding protein (CREB) activation by BW723C86 treatment. These results suggest that the serotonin agonist BW723C86 could be a potential therapeutic agent for skin hyperpigmentation disorders. Full article

(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)

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11 pages, 871 KiB

Open AccessArticle

SAAMBE: Webserver to Predict the Charge of Binding Free Energy Caused by Amino Acids Mutations

by Marharyta Petukh^1,†, Luogeng Dai^1,2,† and Emil Alexov^1,*

¹ Computational Biophysics and Bioinformatics, Physics Department, Clemson University, Clemson, SC 29634, USA

² Department of Computer Sciences, Clemson University, Clemson, SC 29634, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 547; https://doi.org/10.3390/ijms17040547 - 12 Apr 2016

Cited by 62 | Viewed by 6364

Abstract

Predicting the effect of amino acid substitutions on protein–protein affinity (typically evaluated via the change of protein binding free energy) is important for both understanding the disease-causing mechanism of missense mutations and guiding protein engineering. In addition, researchers are also interested in understanding [...] Read more.

Predicting the effect of amino acid substitutions on protein–protein affinity (typically evaluated via the change of protein binding free energy) is important for both understanding the disease-causing mechanism of missense mutations and guiding protein engineering. In addition, researchers are also interested in understanding which energy components are mostly affected by the mutation and how the mutation affects the overall structure of the corresponding protein. Here we report a webserver, the Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) webserver, which addresses the demand for tools for predicting the change of protein binding free energy. SAAMBE is an easy to use webserver, which only requires that a coordinate file be inputted and the user is provided with various, but easy to navigate, options. The user specifies the mutation position, wild type residue and type of mutation to be made. The server predicts the binding free energy change, the changes of the corresponding energy components and provides the energy minimized 3D structure of the wild type and mutant proteins for download. The SAAMBE protocol performance was tested by benchmarking the predictions against over 1300 experimentally determined changes of binding free energy and a Pearson correlation coefficient of 0.62 was obtained. How the predictions can be used for discriminating disease-causing from harmless mutations is discussed. The webserver can be accessed via http://compbio.clemson.edu/saambe_webserver/. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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15 pages, 2646 KiB

Open AccessArticle

The Molecular Epidemiology and Evolutionary Dynamics of Influenza B Virus in Two Italian Regions during 2010–2015: The Experience of Sicily and Liguria

by Fabio Tramuto^1,2,*

, Andrea Orsi^3,4, Carmelo Massimo Maida¹

, Claudio Costantino¹

, Cecilia Trucchi³, Cristiano Alicino³, Francesco Vitale^1,2 and Filippo Ansaldi^3,4

¹ Department of Health Promotion Sciences and Mother-Child Care “G. D’Alessandro”—Hygiene Section, University of Palermo, Palermo 90127, Italy

² Clinical Epidemiology Unit, University Hospital “Paolo Giaccone”, Palermo 90127, Italy

³ Department of Health Sciences, University of Genoa, Genoa 16132, Italy

⁴ Hygiene Unit, IRCCS University Hospital “San Martino”—IST National Institute for Cancer Research, Genoa 16132, Italy

Int. J. Mol. Sci. 2016, 17(4), 549; https://doi.org/10.3390/ijms17040549 - 13 Apr 2016

Cited by 24 | Viewed by 5963

Abstract

Molecular epidemiology of influenza B virus remained poorly studied in Italy, despite representing a major contributor to seasonal epidemics. This study aimed to reconstruct the phylogenetic relationships and genetic diversity of the hemagglutinin gene sequences of 197 influenza B strains circulating in both [...] Read more.

Molecular epidemiology of influenza B virus remained poorly studied in Italy, despite representing a major contributor to seasonal epidemics. This study aimed to reconstruct the phylogenetic relationships and genetic diversity of the hemagglutinin gene sequences of 197 influenza B strains circulating in both Southern (Sicily) and Northern (Liguria) Italy between 2010 and 2015. Upper respiratory tract specimens of patients displaying symptoms of influenza-like illness were screened by real-time RT-PCR assay for the presence of influenza B virus. PCR-positive influenza B samples were further analyzed by sequencing. Neighbor-joining phylogenetic trees were constructed and the amino-acid alignments were analyzed. Phylogenetic analysis showed clusters in B/Victoria clade 1A/1B (n = 29, 14.7%), and B/Yamagata clades 2 (n = 112, 56.8%) and 3 (n = 56, 28.4%). Both influenza B lineages were found to co-circulate during the study period, although a lineage swap from B/Victoria to B/Yamagata occurred in Italy between January 2011 and January 2013. The most represented amino-acid substitutions were N116K in the 120-loop (83.9% of B/Yamagata clade 3 strains) and I146V in the 150-loop (89.6% of B/Victoria clade 1 strains). D197N in 190-helix was found in almost all viruses collected. Our findings provide further evidence to support the adoption of quadrivalent influenza vaccines in our country. Full article

(This article belongs to the Special Issue Infectious Diseases: Pathophysiology, Diagnostics, Therapies, and Prevention)

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11 pages, 1015 KiB

Open AccessArticle

The Isolation of DNA by Polycharged Magnetic Particles: An Analysis of the Interaction by Zeta Potential and Particle Size

by Yazan Haddad^1,2

, Kledi Xhaxhiu^2,3, Pavel Kopel^1,2

, David Hynek^1,2, Ondrej Zitka^1,2 and Vojtech Adam^1,2,*

¹ Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic

² Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno, Czech Republic

³ Department of Chemistry, Faculty of Natural Sciences, University of Tirana, Blv. Zog I, No. 2/1, 1001 Tirana, Albania

Int. J. Mol. Sci. 2016, 17(4), 550; https://doi.org/10.3390/ijms17040550 - 20 Apr 2016

Cited by 24 | Viewed by 10398

Abstract

Magnetic isolation of biological targets is in major demand in the biotechnology industry today. This study considers the interaction of four surface-modified magnetic micro- and nanoparticles with selected DNA fragments. Different surface modifications of nanomaghemite precursors were investigated: MAN37 (silica-coated), MAN127 (polyvinylpyrrolidone-coated), MAN158 [...] Read more.

Magnetic isolation of biological targets is in major demand in the biotechnology industry today. This study considers the interaction of four surface-modified magnetic micro- and nanoparticles with selected DNA fragments. Different surface modifications of nanomaghemite precursors were investigated: MAN37 (silica-coated), MAN127 (polyvinylpyrrolidone-coated), MAN158 (phosphate-coated), and MAN164 (tripolyphosphate-coated). All particles were positive polycharged agglomerated monodispersed systems. Mean particle sizes were 0.48, 2.97, 2.93, and 3.67 μm for MAN37, MAN127, MAN164, and MAN158, respectively. DNA fragments exhibited negative zeta potential of −0.22 mV under binding conditions (high ionic strength, low pH, and dehydration). A decrease in zeta potential of particles upon exposure to DNA was observed with exception of MAN158 particles. The measured particle size of MAN164 particles increased by nearly twofold upon exposure to DNA. Quantitative PCR isolation of DNA with a high retrieval rate was observed by magnetic particles MAN127 and MAN164. Interaction between polycharged magnetic particles and DNA is mediated by various binding mechanisms such as hydrophobic and electrostatic interactions. Future development of DNA isolation technology requires an understanding of the physical and biochemical conditions of this process. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles)

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19 pages, 3692 KiB

Open AccessArticle

Insights into the Antimicrobial Mechanism of Action of Human RNase6: Structural Determinants for Bacterial Cell Agglutination and Membrane Permeation

by David Pulido^*,†,‡, Javier Arranz-Trullén^†, Guillem Prats-Ejarque, Diego Velázquez, Marc Torrent^§, Mohammed Moussaoui and Ester Boix^*

¹ Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, E-08193 Cerdanyola del Vallès, Spain

^† These authors contributed equally to this work.

^‡ Present address: Department of Life Sciences, Imperial College London, South Kensington Campus London, SW7 2AZ London, UK

^§ Present address: Microbiology Department, Hospital del Valle Hebron, 08035 Barcelona, Spain

Int. J. Mol. Sci. 2016, 17(4), 552; https://doi.org/10.3390/ijms17040552 - 13 Apr 2016

Cited by 46 | Viewed by 6661

Abstract

Human Ribonuclease 6 is a secreted protein belonging to the ribonuclease A (RNaseA) superfamily, a vertebrate specific family suggested to arise with an ancestral host defense role. Tissue distribution analysis revealed its expression in innate cell types, showing abundance in monocytes and neutrophils. [...] Read more.

Human Ribonuclease 6 is a secreted protein belonging to the ribonuclease A (RNaseA) superfamily, a vertebrate specific family suggested to arise with an ancestral host defense role. Tissue distribution analysis revealed its expression in innate cell types, showing abundance in monocytes and neutrophils. Recent evidence of induction of the protein expression by bacterial infection suggested an antipathogen function in vivo. In our laboratory, the antimicrobial properties of the protein have been evaluated against Gram-negative and Gram-positive species and its mechanism of action was characterized using a membrane model. Interestingly, our results indicate that RNase6, as previously reported for RNase3, is able to specifically agglutinate Gram-negative bacteria as a main trait of its antimicrobial activity. Moreover, a side by side comparative analysis with the RN6(1–45) derived peptide highlights that the antimicrobial activity is mostly retained at the protein N-terminus. Further work by site directed mutagenesis and structural analysis has identified two residues involved in the protein antimicrobial action (Trp1 and Ile13) that are essential for the cell agglutination properties. This is the first structure-functional characterization of RNase6 antimicrobial properties, supporting its contribution to the infection focus clearance. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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10 pages, 2113 KiB

Open AccessArticle

RETRACTED: 6-Pyrazolylpurine as an Artificial Nucleobase for Metal-Mediated Base Pairing in DNA Duplexes

by J. Christian Léon¹, Indranil Sinha^1,2 and Jens Müller^1,2,*

¹ Institut für Anorganische und Analytische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 30, 48149 Münster, Germany

² NRW Graduate School of Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 30, 48149 Münster, Germany

Int. J. Mol. Sci. 2016, 17(4), 554; https://doi.org/10.3390/ijms17040554 - 14 Apr 2016

Cited by 9 | Viewed by 6467 | Retraction

Abstract

The artificial nucleobase 6-pyrazol-1-yl-purine (6PP) has been investigated with respect to its usability in metal-mediated base pairing. As was shown by temperature-dependent UV spectroscopy, 6PP may form weakly stabilizing 6PP–Ag(I)–6PP homo base pairs. Interestingly, 6PP can be used to selectively recognize a complementary [...] Read more.

The artificial nucleobase 6-pyrazol-1-yl-purine (6PP) has been investigated with respect to its usability in metal-mediated base pairing. As was shown by temperature-dependent UV spectroscopy, 6PP may form weakly stabilizing 6PP–Ag(I)–6PP homo base pairs. Interestingly, 6PP can be used to selectively recognize a complementary pyrimidine nucleobase. The addition of Ag(I) to a DNA duplex comprising a central 6PP:C mispair (C = cytosine) leads to a slight destabilization of the duplex. In contrast, a stabilizing 6PP–Ag(I)–T base pair is formed with a complementary thymine (T) residue. It is interesting to note that 6PP is capable of differentiating between the pyrimidine moieties despite the fact that it is not as sterically crowded as 6-(3,5-dimethylpyrazol-1-yl)purine, an artificial nucleobase that had previously been suggested for the recognition of nucleic acid sequences via the formation of a metal-mediated base pair. Hence, the additional methyl groups of 6-(3,5-dimethylpyrazol-1-yl)purine may not be required for the specific recognition of the complementary nucleobase. Full article

(This article belongs to the Special Issue Applied Bioinorganic Chemistry and Selected Papers from 13th ISABC)

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12 pages, 3150 KiB

Open AccessArticle

Linear and Branched PEIs (Polyethylenimines) and Their Property Space

by Claudiu N. Lungu¹

, Mircea V. Diudea¹, Mihai V. Putz^2,3,* and Ireneusz P. Grudziński⁴

¹ Department of Chemistry, Faculty of Chemistry and Chemical Engineering, Babes-Bolyai University, 400028 Cluj, Romania

² Laboratory of Structural and Computational Physical-Chemistry for Nanosciences and QSAR, Biology-Chemistry Department, Faculty of Chemistry, Biology, Geography, West University of Timisoara, Str. Pestalozzi No. 16, 300115 Timisoara, Romania

³ Laboratory of Renewable Energies-Photovoltaics, R&D National Institute for Electrochemistry and Condensed Matter, Dr. A. Paunescu Podeanu Str. No. 144, RO-300569 Timisoara, Romania

⁴ Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland

Int. J. Mol. Sci. 2016, 17(4), 555; https://doi.org/10.3390/ijms17040555 - 13 Apr 2016

Cited by 66 | Viewed by 8866

Abstract

A chemical property space defines the adaptability of a molecule to changing conditions and its interaction with other molecular systems determining a pharmacological response. Within a congeneric molecular series (compounds with the same derivatization algorithm and thus the same brute formula) the chemical [...] Read more.

A chemical property space defines the adaptability of a molecule to changing conditions and its interaction with other molecular systems determining a pharmacological response. Within a congeneric molecular series (compounds with the same derivatization algorithm and thus the same brute formula) the chemical properties vary in a monotonic manner, i.e., congeneric compounds share the same chemical property space. The chemical property space is a key component in molecular design, where some building blocks are functionalized, i.e., derivatized, and eventually self-assembled in more complex systems, such as enzyme-ligand systems, of which (physico-chemical) properties/bioactivity may be predicted by QSPR/QSAR (quantitative structure-property/activity relationship) studies. The system structure is determined by the binding type (temporal/permanent; electrostatic/covalent) and is reflected in its local electronic (and/or magnetic) properties. Such nano-systems play the role of molecular devices, important in nano-medicine. In the present article, the behavior of polyethylenimine (PEI) macromolecules (linear LPEI and branched BPEI, respectively) with respect to the glucose oxidase enzyme GOx is described in terms of their (interacting) energy, geometry and topology, in an attempt to find the best shape and size of PEIs to be useful for a chosen (nanochemistry) purpose. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2016)

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13 pages, 7544 KiB

Open AccessArticle

Prediction of Toxin Genes from Chinese Yellow Catfish Based on Transcriptomic and Proteomic Sequencing

by Bing Xie^1,2,†

, Xiaofeng Li^1,†, Zhilong Lin^2,†, Zhiqiang Ruan³, Min Wang³, Jie Liu², Ting Tong², Jia Li³, Yu Huang³, Bo Wen^2,*, Ying Sun^1,2,* and Qiong Shi^2,3,4,*

¹ Section on Marine biobank, China National Genebank, Shenzhen 518083, China

² BGI-Shenzhen, Shenzhen 518083, China

³ Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, Shenzhen 518083, China

⁴ Center for Marine Research, College of Life Sciences, Shenzhen University, Shenzhen 518060, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 556; https://doi.org/10.3390/ijms17040556 - 13 Apr 2016

Cited by 16 | Viewed by 7194

Abstract

Fish venom remains a virtually untapped resource. There are so few fish toxin sequences for reference, which increases the difficulty to study toxins from venomous fish and to develop efficient and fast methods to dig out toxin genes or proteins. Here, we utilized [...] Read more.

Fish venom remains a virtually untapped resource. There are so few fish toxin sequences for reference, which increases the difficulty to study toxins from venomous fish and to develop efficient and fast methods to dig out toxin genes or proteins. Here, we utilized Chinese yellow catfish (Pelteobagrus fulvidraco) as our research object, since it is a representative species in Siluriformes with its venom glands embedded in the pectoral and dorsal fins. In this study, we set up an in-house toxin database and a novel toxin-discovering protocol to dig out precise toxin genes by combination of transcriptomic and proteomic sequencing. Finally, we obtained 15 putative toxin proteins distributed in five groups, namely Veficolin, Ink toxin, Adamalysin, Za2G and CRISP toxin. It seems that we have developed a novel bioinformatics method, through which we could identify toxin proteins with high confidence. Meanwhile, these toxins can also be useful for comparative studies in other fish and development of potential drugs. Full article

(This article belongs to the Special Issue Fish Molecular Biology)

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21 pages, 6979 KiB

Open AccessArticle

Genome Sequence of the Fish Pathogen Yersinia ruckeri SC09 Provides Insights into Niche Adaptation and Pathogenic Mechanism

by Tao Liu^1,†, Kai-Yu Wang^1,2,*,†, Jun Wang^1,†, De-Fang Chen³, Xiao-Li Huang³, Ping Ouyang¹, Yi Geng¹, Yang He¹, Yi Zhou^2,3 and Jie Min¹

¹ Department of Basic Veterinary, Veterinary Medicine College, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611134, Sichuan, China

² Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611134, Sichuan, China

³ Department of Aquaculture, College of Animal Science & Technology, Sichuan Agricultural University, Chengdu 611134, Sichuan, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 557; https://doi.org/10.3390/ijms17040557 - 14 Apr 2016

Cited by 37 | Viewed by 8103

Abstract

Yersinia ruckeri is the etiologic agent of enteric red mouth disease (ERM), a severe fish disease prevailing in worldwide aquaculture industries. Here we report for the first time the complete genome of Y. ruckeri (Yersinia ruckeri) SC09, a highly virulent strain [...] Read more.

Yersinia ruckeri is the etiologic agent of enteric red mouth disease (ERM), a severe fish disease prevailing in worldwide aquaculture industries. Here we report for the first time the complete genome of Y. ruckeri (Yersinia ruckeri) SC09, a highly virulent strain isolated from Ictalurus punctatus with severe septicemia. SC09 possesses a single chromosome of 3,923,491 base pairs, which contains 3651 predicted protein coding sequences (CDS), 19 rRNA genes, and 79 tRNA genes. Among the CDS, we have identified a Ysa locus containing genes encoding all the components of a type III secretion system (T3SS). Comparative analysis suggest that SC09-Ysa share extensive similarity in sequence, gene content, and gene arrangement with Salmonella enterica pathogenicity island 1 (SPI1) and chromosome-encoded T3SS from Yersinia enterocolitica biotype 1B. Furthermore, phylogenetic analysis shown that SC09-Ysa and SPI1-T3SS belong on the same branch of the phylogenetic tree. These results suggest that SC09-Ysa and SPI1-T3SS appear to mediate biological function to adapt to specific hosts with a similar niche, and both of them are likely to facilitate the development of an intracellular niche. In addition, our analysis also indicated that a substantial part of the SC09 genome might contribute to adaption in the intestinal microenvironment, including a number of proteins associated with aerobic or anaerobic respiration, signal transduction, and various stress reactions. Genomic analysis of the bacterium offered insights into the pathogenic mechanism associated with intracellular infection and intestinal survivability, which constitutes an important first step in understanding the pathogenesis of Y. ruckeri. Full article

(This article belongs to the Special Issue Fish Molecular Biology)

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14 pages, 1922 KiB

Open AccessCommunication

Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells

by Yushuang Ding¹, Hongge Wang², Jiajing Niu², Manyu Luo³, Yangmei Gou², Lining Miao³, Zhihua Zou^2,*

and Ying Cheng^1,4,*

¹ Department of Radiotherapy, the Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China

² School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun 130012, China

³ Department of Nephrology, the Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China

⁴ Department of Thoracic Oncology, Jilin Provincial Cancer Hospital, 1018 Huguang Street, Changchun 130012, China

Int. J. Mol. Sci. 2016, 17(4), 558; https://doi.org/10.3390/ijms17040558 - 14 Apr 2016

Cited by 97 | Viewed by 8871

Abstract

Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells [...] Read more.

Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells via induction of oxidative stress, though they target both cancer and normal cells. Recently, alantolactone (ATL), a natural sesquiterpene lactone, has been shown to induce apoptosis by increasing ROS levels specifically in cancer cells; however, the molecular mechanisms linking ROS overproduction to apoptosis remain unclear. Here we show that the ATL-induced ROS overload in human SW480 and SW1116 colorectal cancer cells was followed by a prominent accumulation of cellular oxidized guanine (8-oxoG) and immediate increase in the number of DNA strand breaks, indicating that increased ROS resulted in extensive oxidative DNA damage. Consequently, the G₁/S-CDK suppresser CDKN1B (p21) and pro-apoptotic proteins Bax and activated caspase-3 were upregulated, while anti-apoptotic Bcl-2 was downregulated, which were followed by cell cycle arrest at G₁ and marked apoptosis in ATL-treated cancer but not non-cancer cells. These results suggest that the ATL-induced ROS overload triggers cell death through induction of massive oxidative DNA damage and subsequent activation of the intrinsic apoptosis pathway. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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13 pages, 1182 KiB

Open AccessArticle

Characterization of miR-206 Promoter and Its Association with Birthweight in Chicken

by Xinzheng Jia^1,2, Huiran Lin^1,2, Bahareldin Ali Abdalla^1,2 and Qinghua Nie^1,2,*

¹ Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China

² Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou 510642, China

Int. J. Mol. Sci. 2016, 17(4), 559; https://doi.org/10.3390/ijms17040559 - 14 Apr 2016

Cited by 17 | Viewed by 5856

Abstract

miRNAs have been widely investigated in terms of cell proliferation and differentiation. However, little is known about their effects on bird growth. Here we characterized the promoter of miR-206 in chicken and found that the preferable promoter was located in 1200 bp upstream [...] Read more.

miRNAs have been widely investigated in terms of cell proliferation and differentiation. However, little is known about their effects on bird growth. Here we characterized the promoter of miR-206 in chicken and found that the preferable promoter was located in 1200 bp upstream of pri-miR-206. In this region, many key transcription factors, including MyoD, c-Myb, CEBPα/β, AP-4, RAP1, Brn2, GATA-1/2/3, E47, Sn, upstream stimulatory factor (USF) and CdxA, were predicted to bind and interact with miR-206 promoter. Overexpression of MyoD sharply increased miR-206 expression in both fibroblast and myoblast cells, and also the regulation in the myoblast cells was much stronger, indicating that miR-206 was regulated by MyoD combined with other muscle specific transcriptional factors. Aiming to further investigate the relationship between miR-206 mutation and transcriptional expression, total of 23 SNPs were identified in the two distinct bird lines by sequencing. Interestingly, the motif bound by MyoD was individually destroyed by G-to-C mutation located at 419 bp upstream of miR-206 precursor. Co-transfecting MyoD and miR-206 promoter in DF-1 cells, the luciferase activity of promoter containing homozygous GG types was significantly higher than CC ones (p < 0.05). Thus, this mutation caused low expression of miR-206. Consistently, eight variants including G-419C mutation exhibited a great effect on birthweight through maker-trait association analysis in F2 population (p < 0.05). Additionally, the regulation of miR-206 on embryo muscle mass mainly by increasing MyoG and muscle creatine kinase (MCK) expression (p < 0.05) with little change in MyoD, TMEM8C and myosin heavy chain (MHC). In conclusion, our findings provide a novel mutation destroying the promoter activity of miR-206 in birds and shed new light to understand the regulation mechanism of miR-206 on the embryonic muscle growth. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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13 pages, 3328 KiB

Open AccessArticle

Development and Characterization of a Humanized Anti-HER2 Antibody HuA21 with Potent Anti-Tumor Properties in Breast Cancer Cells

by Ruilin Li^1,2,3, Siyi Hu^4,5, Yan Chang¹, Zhihui Zhang⁶, Zhao Zha^4,6, Hui Huang⁵, Guodong Shen⁴, Jing Liu^4,6, Lihua Song^1,2,* and Wei Wei^1,2,*

¹ Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China

² Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei 230032, China

³ Department of Pharmacy, the Third Affiliated Hospital of Anhui Medical University, Hefei 230032, China

⁴ School of Life Science, University of Science and Technology of China, Hefei 230026, China

⁵ Anke Biotechnology Co., Ltd., Hefei 230088, China

⁶ Hefei Hanke Mab Biotechnology Co., Ltd., Hefei 230088, China

Int. J. Mol. Sci. 2016, 17(4), 563; https://doi.org/10.3390/ijms17040563 - 15 Apr 2016

Cited by 9 | Viewed by 7376

Abstract

Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor [...] Read more.

Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor activity of the novel engineered monoclonal antibody humanized chA21 (HuA21) that targets HER2 on the basis of chA21, and we describe the underlying mechanisms. Our results reveal that HuA21 markedly inhibits the proliferation and migration of HER2-overexpressing breast cancer cells and causes enhanced antibody-dependent cell-mediated cytotoxicity potency against HER2-overexpressing tumor cells. In particular, HuA21, but not trastuzumab (Tra), markedly suppresses growth and enhances the internalization of the antibody in Tra-resistant BT-474 breast cancer cells. These characteristics are highly associated with the intrinsic ability of HuA21 to down-regulate HER2 activation and inhibit the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) signaling pathways. Furthermore, the combination of HuA21 with Tra synergistically enhances the anti-tumor effects in vitro and in vivo and inhibits HER2 activation and the ERK1/2 and Akt signaling pathways. Altogether, our results suggest that HuA21 may represent a unique anti-HER2 antibody with potential as a therapeutic candidate alone or in combination with other anti-HER2 reagents in cancer therapy. Full article

(This article belongs to the Special Issue Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy)

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6 pages, 963 KiB

Open AccessCommunication

miRTargetLink—miRNAs, Genes and Interaction Networks

by Maarten Hamberg¹, Christina Backes¹, Tobias Fehlmann¹, Martin Hart², Benjamin Meder³, Eckart Meese² and Andreas Keller^1,*

¹ Chair for Clinical Bioinformatics, Saarland University, Saarbrücken D-66041, Germany

² Department of Human Genetics, Saarland University, Homburg D-66421, Germany

³ Internal Medicine, Heidelberg University, Heidelberg D-69120, Germany

Int. J. Mol. Sci. 2016, 17(4), 564; https://doi.org/10.3390/ijms17040564 - 14 Apr 2016

Cited by 96 | Viewed by 10462

Abstract

Information on miRNA targeting genes is growing rapidly. For high-throughput experiments, but also for targeted analyses of few genes or miRNAs, easy analysis with concise representation of results facilitates the work of life scientists. We developed miRTargetLink, a tool for automating respective analysis [...] Read more.

Information on miRNA targeting genes is growing rapidly. For high-throughput experiments, but also for targeted analyses of few genes or miRNAs, easy analysis with concise representation of results facilitates the work of life scientists. We developed miRTargetLink, a tool for automating respective analysis procedures that are frequently applied. Input of the web-based solution is either a single gene or single miRNA, but also sets of genes or miRNAs, can be entered. Validated and predicted targets are extracted from databases and an interaction network is presented. Users can select whether predicted targets, experimentally validated targets with strong or weak evidence, or combinations of those are considered. Central genes or miRNAs are highlighted and users can navigate through the network interactively. To discover the most relevant biochemical processes influenced by the target network, gene set analysis and miRNA set analysis are integrated. As a showcase for miRTargetLink, we analyze targets of five cardiac miRNAs. miRTargetLink is freely available without restrictions at www.ccb.uni-saarland.de/mirtargetlink. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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14 pages, 2038 KiB

Open AccessArticle

Profilings of MicroRNAs in the Liver of Common Carp (Cyprinus carpio) Infected with Flavobacterium columnare

by Lijuan Zhao^1,2,3,4, Hong Lu^1,2,3, Qinglei Meng^1,2,3, Jinfu Wang^1,2,3, Weimin Wang⁴, Ling Yang^1,2,3,* and Li Lin^4,5,*

¹ Shandong Freshwater Fisheries Research Institute, Jinan 250013, China

² Shandong Provincial Key Laboratory of Freshwater Genetics and Breeding, Jinan 250013, China

³ Shandong Provincial Freshwater Aquatic Products Quality Inspection Center, Jinan 250013, China

⁴ Key Lab of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan 430070, China

⁵ Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China

Int. J. Mol. Sci. 2016, 17(4), 566; https://doi.org/10.3390/ijms17040566 - 15 Apr 2016

Cited by 40 | Viewed by 6271

Abstract

MicroRNAs (miRNAs) play important roles in regulation of many biological processes in eukaryotes, including pathogen infection and host interactions. Flavobacterium columnare (FC) infection can cause great economic loss of common carp (Cyprinus carpio) which is one of the most important cultured [...] Read more.

MicroRNAs (miRNAs) play important roles in regulation of many biological processes in eukaryotes, including pathogen infection and host interactions. Flavobacterium columnare (FC) infection can cause great economic loss of common carp (Cyprinus carpio) which is one of the most important cultured fish in the world. However, miRNAs in response to FC infection in common carp has not been characterized. To identify specific miRNAs involved in common carp infected with FC, we performed microRNA sequencing using livers of common carp infected with and without FC. A total of 698 miRNAs were identified, including 142 which were identified and deposited in the miRbase database (Available online: http://www.mirbase.org/) and 556 had only predicted miRNAs. Among the deposited miRNAs, eight miRNAs were first identified in common carp. Thirty of the 698 miRNAs were differentially expressed miRNAs (DIE-miRNAs) between the FC infected and control samples. From the DIE-miRNAs, seven were selected randomly and their expression profiles were confirmed to be consistent with the microRNA sequencing results using RT-PCR and qRT-PCR. In addition, a total of 27,363 target genes of the 30 DIE-miRNAs were predicted. The target genes were enriched in five Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including focal adhesion, extracellular matrix (ECM)-receptor interaction, erythroblastic leukemia viral oncogene homolog (ErbB) signaling pathway, regulation of actin cytoskeleton, and adherent junction. The miRNA expression profile of the liver of common carp infected with FC will pave the way for the development of effective strategies to fight against FC infection. Full article

(This article belongs to the Special Issue Fish Molecular Biology)

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12 pages, 1254 KiB

Open AccessArticle

Changes in Air CO₂ Concentration Differentially Alter Transcript Levels of NtAQP1 and NtPIP2;1 Aquaporin Genes in Tobacco Leaves

by Francesca Secchi^*, Andrea Schubert and Claudio Lovisolo

Dipartimento di Scienze Agrarie, Forestali e Alimentari (DISAFA), ULF Colture arboree e Fisiologia Vegetale, Largo Paolo Braccini 2, 10095 Grugliasco (TO), Italy

Int. J. Mol. Sci. 2016, 17(4), 567; https://doi.org/10.3390/ijms17040567 - 14 Apr 2016

Cited by 10 | Viewed by 5763

Abstract

The aquaporin specific control on water versus carbon pathways in leaves is pivotal in controlling gas exchange and leaf hydraulics. We investigated whether Nicotiana tabacum aquaporin 1 (NtAQP1) and Nicotiana tabacum plasma membrane intrinsic protein 2;1 (NtPIP2;1) gene expression [...] Read more.

The aquaporin specific control on water versus carbon pathways in leaves is pivotal in controlling gas exchange and leaf hydraulics. We investigated whether Nicotiana tabacum aquaporin 1 (NtAQP1) and Nicotiana tabacum plasma membrane intrinsic protein 2;1 (NtPIP2;1) gene expression varies in tobacco leaves subjected to treatments with different CO₂ concentrations (ranging from 0 to 800 ppm), inducing changes in photosynthesis, stomatal regulation and water evaporation from the leaf. Changes in air CO₂ concentration ([CO₂]) affected net photosynthesis (Pn) and leaf substomatal [CO₂] (Ci). Pn was slightly negative at 0 ppm air CO₂; it was one-third that of ambient controls at 200 ppm, and not different from controls at 800 ppm. Leaves fed with 800 ppm [CO₂] showed one-third reduced stomatal conductance (g_s) and transpiration (E), and their g_s was in turn slightly lower than in 200 ppm– and in 0 ppm–treated leaves. The 800 ppm air [CO₂] strongly impaired both NtAQP1 and NtPIP2;1 gene expression, whereas 0 ppm air [CO₂], a concentration below any in vivo possible conditions and specifically chosen to maximize the gene expression alteration, increased only the NtAQP1 transcript level. We propose that NtAQP1 expression, an aquaporin devoted to CO₂ transport, positively responds to CO₂ scarcity in the air in the whole range 0–800 ppm. On the contrary, expression of NtPIP2;1, an aquaporin not devoted to CO₂ transport, is related to water balance in the leaf, and changes in parallel with g_s. These observations fit in a model where upregulation of leaf aquaporins is activated at low Ci, while downregulation occurs when high Ci saturates photosynthesis and causes stomatal closure. Full article

(This article belongs to the Special Issue Gene–Environment Interactions)

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16 pages, 1048 KiB

Open AccessArticle

Prognostic Value of MicroRNAs in Preoperative Treated Rectal Cancer

by Azadeh Azizian¹, Ingo Epping¹, Frank Kramer², Peter Jo¹, Markus Bernhardt¹, Julia Kitz³, Gabriela Salinas⁴, Hendrik A. Wolff⁵, Marian Grade¹, Tim Beißbarth², B. Michael Ghadimi¹ and Jochen Gaedcke^1,*

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

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

³ Department of Pathology, University Medical Center Göttingen, Robert-Koch-Str. 40, Göttingen 37075, Germany

⁴ Department of Developmental Biochemistry, University of Göttingen, Göttingen 37075, Germany

⁵ Medical Practice Radiotherapy München, Burgstraße 7, München 80331, Germany

Int. J. Mol. Sci. 2016, 17(4), 568; https://doi.org/10.3390/ijms17040568 - 15 Apr 2016

Cited by 18 | Viewed by 6873

Abstract

Background: Patients with locally advanced rectal cancer are treated with preoperative chemoradiotherapy followed by surgical resection. Despite similar clinical parameters (uT2-3, uN+) and standard therapy, patients’ prognoses differ widely. A possible prediction of prognosis through microRNAs as biomarkers out of treatment-naïve biopsies would [...] Read more.

Background: Patients with locally advanced rectal cancer are treated with preoperative chemoradiotherapy followed by surgical resection. Despite similar clinical parameters (uT2-3, uN+) and standard therapy, patients’ prognoses differ widely. A possible prediction of prognosis through microRNAs as biomarkers out of treatment-naïve biopsies would allow individualized therapy options. Methods: Microarray analysis of 45 microdissected preoperative biopsies from patients with rectal cancer was performed to identify potential microRNAs to predict overall survival, disease-free survival, cancer-specific survival, distant-metastasis-free survival, tumor regression grade, or nodal stage. Quantitative real-time polymerase chain reaction (qPCR) was performed on an independent set of 147 rectal cancer patients to validate relevant miRNAs. Results: In the microarray screen, 14 microRNAs were significantly correlated to overall survival. Five microRNAs were included from previous work. Finally, 19 miRNAs were evaluated by qPCR. miR-515-5p, miR-573, miR-579 and miR-802 demonstrated significant correlation with overall survival and cancer-specific survival (p < 0.05). miR-573 was also significantly correlated with the tumor regression grade after preoperative chemoradiotherapy. miR-133b showed a significant correlation with distant-metastasis-free survival. miR-146b expression levels showed a significant correlation with nodal stage. Conclusion: Specific microRNAs can be used as biomarkers to predict prognosis of patients with rectal cancer and possibly stratify patients’ therapy if validated in a prospective study. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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11 pages, 1440 KiB

Open AccessArticle

Downregulation of Plasma miR-215 in Chronic Myeloid Leukemia Patients with Successful Discontinuation of Imatinib

by Kazuma Ohyashiki^1,2,*

, Tomohiro Umezu²

, Seiichiro Katagiri¹

, Chiaki Kobayashi², Kenko Azuma³, Tetsuzo Tauchi¹, Seiichi Okabe¹, Yutaka Fukuoka⁴ and Junko H. Ohyashiki³

¹ Department of Hematology, Tokyo Medical University, Tokyo 160-0023, Japan

² Department of Molecular Science, Tokyo Medical University, Tokyo 160-0023, Japan

³ Department of Molecular Oncology, Institute of Medical Science, Tokyo Medical University, Tokyo 160-0023, Japan

⁴ Department of Electrical Engineering, Kogakuin University, Tokyo 163-8677, Japan

Int. J. Mol. Sci. 2016, 17(4), 570; https://doi.org/10.3390/ijms17040570 - 15 Apr 2016

Cited by 37 | Viewed by 6620

Abstract

Approximately 40% of chronic myeloid leukemia (CML) patients who discontinue imatinib (IM) therapy maintain undetectable minimal residual disease (UMRD) for more than one year (stopping IM (STOP-IM)). To determine a possible biomarker for STOP-IM CML, we examined plasma miRNA expression in CML patients [...] Read more.

Approximately 40% of chronic myeloid leukemia (CML) patients who discontinue imatinib (IM) therapy maintain undetectable minimal residual disease (UMRD) for more than one year (stopping IM (STOP-IM)). To determine a possible biomarker for STOP-IM CML, we examined plasma miRNA expression in CML patients who were able to discontinue IM. We first screened candidate miRNAs in unselected STOP-IM patients, who had sustained UMRD after discontinuing IM for more than six months, in comparison with healthy volunteers, by using a TaqMan low-density array for plasma or exosomes. Exosomal miR-215 and plasma miR-215 were downregulated in the STOP-IM group compared to the control, indicating that the biological relevance of the plasma miR-215 level is equivalent to that of the exosomal level. Next, we performed real-time quantitative RT-PCR in 20 STOP-IM patients, 32 patients with UMRD on continued IM therapy (IM group) and 28 healthy volunteers. The plasma miRNA-215 level was significantly downregulated in the STOP-IM group (p < 0.0001); we determined the cut-off level and divided the IM group patients into two groups according to whether the plasma miR-215 was downregulated or not. The IM group patients with a low plasma miR-215 level had a significantly higher total IM intake, compared to the patients with elevated miR-215 levels (p = 0.0229). Functional annotation of miR-215 target genes estimated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatic tools involved cell cycle, mitosis, DNA repair and cell cycle checkpoint. Our study suggests a possible role of miR-215 in successful IM discontinuation. Full article

(This article belongs to the Special Issue MicroRNA in Various Disease States as Biomarkers)

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13 pages, 1384 KiB

Open AccessArticle

Significance of Matrix Metalloproteinase 9 Expression as Supporting Marker to Cytokeratin 19 mRNA in Sentinel Lymph Nodes in Breast Cancer Patients

by Marek Murawski¹, Marta Woźniak², Kamila Duś-Szachniewicz², Paweł Kołodziej³, Marta Rzeszutko² and Piotr Ziółkowski^2,3,*

¹ Department of Gynecology and Obstetrics, Wrocław Medical University, Chałubińskiego 3, 50-368 Wrocław, Poland

² Department of Pathology, Wrocław Medical University, Marcinkowskiego 1, 50-368 Wrocław, Poland

³ Division of Pathology, Sokołowski Hospital Wałbrzych, Sokołowskiego 4, 58-309 Wałbrzych, Poland

Int. J. Mol. Sci. 2016, 17(4), 571; https://doi.org/10.3390/ijms17040571 - 21 Apr 2016

Cited by 3 | Viewed by 5869

Abstract

One-step nucleic acid amplification (OSNA) detects and quantifies, with the use of a polymerase chain reaction, the presence of cytokeratin 19 mRNA in sentinel lymph nodes. The main advantage of the OSNA assay is the avoidance of second surgery in case of positive [...] Read more.

One-step nucleic acid amplification (OSNA) detects and quantifies, with the use of a polymerase chain reaction, the presence of cytokeratin 19 mRNA in sentinel lymph nodes. The main advantage of the OSNA assay is the avoidance of second surgery in case of positive sentinel lymph node diagnosis. The objective of this study was to evaluate the significance of matrix metalloproteinase 9 expression by immunohistochemistry as supporting marker to cytokeratin 19 mRNA in sentinel lymph nodes in breast cancer patients and to relate this expression with clinicopathological data. This study was conducted on fresh sentinel lymph nodes obtained from 40 patients with tumors classified as carcinoma of no special type. The presence of metastatic cells in the slices of lymph nodes was evaluated by immunohistochemistry using antibodies for CK19 and MMP-9. Expression of CK19 and MMP-9 in lymph nodes was also confirmed by means of Western blot analysis. Results indicated that the strongest correlation with CK19 mRNA was displayed by MMP-9, CK19 (by immunohistochemistry, IHC), and nodal metastases (p < 0.001). Higher histological grading also positively correlated with CK19 mRNA, however that correlation was less significant. Since MMP-9 shows very strong correlation with CK19 mRNA in breast carcinoma of no special type metastases, expression of MMP-9 in sentinel lymph nodes should be considered as useful method whenever OSNA analysis is not available. Full article

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

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10 pages, 9099 KiB

Open AccessArticle

Physical Characteristics of the Leaves and Latex of Papaya Plants Infected with the Papaya meleira Virus

by Anuar Magaña-Álvarez^1,2, Jean Carlos Vencioneck Dutra¹, Tarcio Carneiro¹, Daisy Pérez-Brito^2,*, Raúl Tapia-Tussell², Jose Aires Ventura^1,3, Inocencio Higuera-Ciapara⁴, Patricia Machado Bueno Fernandes¹ and Antonio Alberto Ribeiro Fernandes¹

¹ Núcleo de Biotecnologia, Universidade Federal do Espírito Santo, Av. Marechal Campos 1468, Vitória, Espírito Santo 29040-090, Brazil

² Laboratorio GeMBio, Centro de Investigación Científica de Yucatán A.C., Calle 43 # 130, Col. Chuburná de Hidalgo, Mérida, Yucatán 97200, Mexico

³ Instituto Capixaba de Pesquisa, Assistência Técnica e Extensão Rural, R. Afonso Sarlo 160, Vitória, Espírito Santo 29052-010, Brazil

⁴ Unidad de Tecnología de Alimentos, Centro de Investigación y Asistencia Tecnológica y Diseño del Estado de Jalisco A.C., Ave. Normalistas # 800, Col. Colinas de la Norma, Guadalajara, Jalisco 44270, Mexico

Int. J. Mol. Sci. 2016, 17(4), 574; https://doi.org/10.3390/ijms17040574 - 15 Apr 2016

Cited by 4 | Viewed by 6832

Abstract

Sticky disease, which is caused by Papaya meleira virus (PMeV), is a significant papaya disease in Brazil and Mexico, where it has caused severe economic losses, and it seems to have spread to Central and South America. Studies assessing the pathogen-host interaction at [...] Read more.

Sticky disease, which is caused by Papaya meleira virus (PMeV), is a significant papaya disease in Brazil and Mexico, where it has caused severe economic losses, and it seems to have spread to Central and South America. Studies assessing the pathogen-host interaction at the nano-histological level are needed to better understand the mechanisms that underlie natural resistance. In this study, the topography and mechanical properties of the leaf midribs and latex of healthy and PMeV-infected papaya plants were observed by atomic force microscopy and scanning electron microscopy. Healthy plants displayed a smooth surface with practically no roughness of the leaf midribs and the latex and a higher adhesion force than infected plants. PMeV promotes changes in the leaf midribs and latex, making them more fragile and susceptible to breakage. These changes, which are associated with increased water uptake and internal pressure in laticifers, causes cell disruption that leads to spontaneous exudation of the latex and facilitates the spread of PMeV to other laticifers. These results provide new insights into the papaya-PMeV interaction that could be helpful for controlling papaya sticky disease. Full article

(This article belongs to the Special Issue Plant Molecular Biology)

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11 pages, 4620 KiB

Open AccessArticle

Hybrid Macro-Porous Titanium Ornamented by Degradable 3D Gel/nHA Micro-Scaffolds for Bone Tissue Regeneration

by Bo Yin¹, Pei Ma^1,2, Jun Chen¹, Hai Wang¹, Gui Wu¹, Bo Li¹, Qiang Li¹, Zhifeng Huang¹, Guixing Qiu¹ and Zhihong Wu^1,3,4,*

¹ Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China

² Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

³ Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China

⁴ Beijing Key Laboratory for Genetic Research of Bone and Joint Disease, No. 1 Shuaifuyuan, Beijing 100730, China

Int. J. Mol. Sci. 2016, 17(4), 575; https://doi.org/10.3390/ijms17040575 - 15 Apr 2016

Cited by 19 | Viewed by 6796

Abstract

Porous titanium is a kind of promising material for bone substitution, while its bio-inert property results in demand of modifications to improve the osteointegration capacity. In this study, gelatin (Gel) and nano-hydroxyapatite (nHA) were used to construct 3D micro-scaffolds in the pores of [...] Read more.

Porous titanium is a kind of promising material for bone substitution, while its bio-inert property results in demand of modifications to improve the osteointegration capacity. In this study, gelatin (Gel) and nano-hydroxyapatite (nHA) were used to construct 3D micro-scaffolds in the pores of porous titanium in the ratios of Gel:nHA = 1:0, Gel:nHA = 1:1, and Gel:nHA = 1:3, respectively. Cell attachment and proliferation, and gene and protein expression levels of osteogenic markers were evaluated in MC3T3-E1 cells, followed by bone regeneration assessment in a rabbit radius defect model. All hybrid scaffolds with different composition ratio were found to have significant promotional effects in cell adhesion, proliferation and differentiation, in which the group with Gel:nHA = 1:1 showed the best performance in vitro, as well as the most bone regeneration volume in vivo. This 3D micro-scaffolds modification may be an innovative method for porous titanium ornamentation and shows potential application values in clinic. Full article

(This article belongs to the Section Materials Science)

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12 pages, 1844 KiB

Open AccessArticle

Titanium Dioxide Particle Type and Concentration Influence the Inflammatory Response in Caco-2 Cells

by Saeko Tada-Oikawa^1,2, Gaku Ichihara³, Hitomi Fukatsu¹, Yuka Shimanuki¹, Natsuki Tanaka¹, Eri Watanabe³, Yuka Suzuki^2,†, Masahiko Murakami², Kiyora Izuoka², Jie Chang^2,‡, Wenting Wu^2,§, Yoshiji Yamada⁴

and Sahoko Ichihara^2,4,*

¹ Department of Human Nutrition, School of Life Studies, Sugiyama Jogakuen University, Nagoya 464-8662, Japan

² Graduate School of Regional Innovation Studies, Mie University, Tsu 514-8507, Japan

³ Department of Occupational and Environmental Health, Tokyo Univeristy of Science, Noda 278-8510, Japan

⁴ Department of Human Genomics, Life Scinece Research Center, Mie University, Tsu 514-8507, Japan

^† Present address: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

^‡ Present address: School of Public Health, Medical College of Soochow University, Suzhou 215006, China

^§ Present address: Toray International (China), Shanghai 200040, China

Int. J. Mol. Sci. 2016, 17(4), 576; https://doi.org/10.3390/ijms17040576 - 16 Apr 2016

Cited by 54 | Viewed by 7865

Abstract

Titanium dioxide (TiO₂) nanoparticles are widely used in cosmetics, sunscreens, biomedicine, and food products. When used as a food additive, TiO₂ nanoparticles are used in significant amounts as white food-coloring agents. However, the effects of TiO₂ nanoparticles on the [...] Read more.

Titanium dioxide (TiO₂) nanoparticles are widely used in cosmetics, sunscreens, biomedicine, and food products. When used as a food additive, TiO₂ nanoparticles are used in significant amounts as white food-coloring agents. However, the effects of TiO₂ nanoparticles on the gastrointestinal tract remain unclear. The present study was designed to determine the effects of five TiO₂ particles of different crystal structures and sizes in human epithelial colorectal adenocarcinoma (Caco-2) cells and THP-1 monocyte-derived macrophages. Twenty-four-hour exposure to anatase (primary particle size: 50 and 100 nm) and rutile (50 nm) TiO₂ particles reduced cellular viability in a dose-dependent manner in THP-1 macrophages, but in not Caco-2 cells. However, 72-h exposure of Caco-2 cells to anatase (50 nm) TiO₂ particles reduced cellular viability in a dose-dependent manner. The highest dose (50 µg/mL) of anatase (100 nm), rutile (50 nm), and P25 TiO₂ particles also reduced cellular viability in Caco-2 cells. The production of reactive oxygen species tended to increase in both types of cells, irrespective of the type of TiO₂ particle. Exposure of THP-1 macrophages to 50 µg/mL of anatase (50 nm) TiO₂ particles increased interleukin (IL)-1β expression level, and exposure of Caco-2 cells to 50 µg/mL of anatase (50 nm) TiO₂ particles also increased IL-8 expression. The results indicated that anatase TiO₂ nanoparticles induced inflammatory responses compared with other TiO₂ particles. Further studies are required to determine the in vivo relevance of these findings to avoid the hazards of ingested particles. Full article

(This article belongs to the Special Issue Cellular Toxicity of Nanoparticles)

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15 pages, 4779 KiB

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Up-Regulation of PAI-1 and Down-Regulation of uPA Are Involved in Suppression of Invasiveness and Motility of Hepatocellular Carcinoma Cells by a Natural Compound Berberine

by Xuanbin Wang^1,2, Ning Wang³, Hongliang Li^1,2, Ming Liu^1,2, Fengjun Cao¹, Xianjun Yu¹, Jingxuan Zhang¹, Yan Tan¹, Longchao Xiang^1,2 and Yibin Feng^3,*

¹ Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Mid-Road, Shiyan 442000, China

² Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, 30 South Renmin Road, Shiyan 442000, China

³ School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China

Int. J. Mol. Sci. 2016, 17(4), 577; https://doi.org/10.3390/ijms17040577 - 16 Apr 2016

Cited by 40 | Viewed by 7922

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death and its prognosis remains poor due to the high risk of tumor recurrence and metastasis. Berberine (BBR) is a natural compound derived from some medicinal plants, and accumulating evidence has shown its [...] Read more.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death and its prognosis remains poor due to the high risk of tumor recurrence and metastasis. Berberine (BBR) is a natural compound derived from some medicinal plants, and accumulating evidence has shown its potent anti-tumor activity with diverse action on tumor cells, including inducing cancer cell death and blocking cell cycle and migration. Molecular targets of berberine involved in its inhibitory effect on the invasiveness remains not yet clear. In this study, we identified that berberine exhibits a potent inhibition on the invasion and migration of HCC cells. This was accompanied by a dose-dependent down-regulation of expression of Cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9 in berberine-treated HCC cells. Furthermore, berberine inactivated p38 and Erk1/2 signaling pathway in HCC cells. Primarily, this may be attributed to the up-regulation of plasminogen activator inhibitor-1 (PAI-1), a tumor suppressor that can antagonize uPA receptor and down-regulation of uPA. Blockade of uPA receptor-associated pathways leads to reduced invasiveness and motility of berberine-treated HCC cells. In conclusion, our findings identified for the first time that inactivation of uPA receptor by up-regulation of PAI-1 and down-regulation of uPA is involved in the inhibitory effect of berberine on HCC cell invasion and migration. Full article

(This article belongs to the Special Issue Plant-Derived Pharmaceuticals by Molecular Farming 2016)

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9 pages, 360 KiB

Open AccessArticle

Biodiesel Production from Chlorella protothecoides Oil by Microwave-Assisted Transesterification

by Mustafa Ömer Gülyurt, Didem Özçimen^* and Benan İnan

Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yıldız Technical University, Davutpasa Campus, 34220 Istanbul, Turkey

Int. J. Mol. Sci. 2016, 17(4), 579; https://doi.org/10.3390/ijms17040579 - 22 Apr 2016

Cited by 32 | Viewed by 6338

Abstract

In this study, biodiesel production from microalgal oil by microwave-assisted transesterification was carried out to investigate its efficiency. Transesterification reactions were performed by using Chlorella protothecoides oil as feedstock, methanol, and potassium hydroxide as the catalyst. Methanol:oil ratio, reaction time and catalyst:oil ratio [...] Read more.

In this study, biodiesel production from microalgal oil by microwave-assisted transesterification was carried out to investigate its efficiency. Transesterification reactions were performed by using Chlorella protothecoides oil as feedstock, methanol, and potassium hydroxide as the catalyst. Methanol:oil ratio, reaction time and catalyst:oil ratio were investigated as process parameters affected methyl ester yield. 9:1 methanol/oil molar ratio, 1.5% KOH catalyst/oil ratio and 10 min were optimum values for the highest fatty acid methyl ester yield. Full article

(This article belongs to the Special Issue Algae Based Bio-Renewable Energy for Sustainability)

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14 pages, 2910 KiB

Open AccessArticle

Exogenous R-Spondin1 Induces Precocious Telogen-to-Anagen Transition in Mouse Hair Follicles

by Na Li^1,2,†, Shu Liu^1,†, Hui-Shan Zhang¹, Zhi-Li Deng¹, Hua-Shan Zhao¹, Qian Zhao³, Xiao-Hua Lei¹, Li-Na Ning¹, Yu-Jing Cao¹, Hai-Bin Wang¹, Shuang Liu^1,* and En-Kui Duan^1,*

¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

² University of Chinese Academy of Sciences, Beijing 100049, China

³ State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 582; https://doi.org/10.3390/ijms17040582 - 20 Apr 2016

Cited by 25 | Viewed by 9336

Abstract

R-spondin proteins are novel Wnt/β-catenin agonists, which signal through their receptors leucine-rich repeat-containing G-protein coupled receptor (LGR) 4/5/6 and substantially enhance Wnt/β-catenin activity. R-spondins are reported to function in embryonic development. They also play important roles in stem cell functions in adult tissues, [...] Read more.

R-spondin proteins are novel Wnt/β-catenin agonists, which signal through their receptors leucine-rich repeat-containing G-protein coupled receptor (LGR) 4/5/6 and substantially enhance Wnt/β-catenin activity. R-spondins are reported to function in embryonic development. They also play important roles in stem cell functions in adult tissues, such as the intestine and mammary glands, which largely rely on Wnt/β-catenin signaling. However, in the skin epithelium and hair follicles, the information about R-spondins is deficient, although the expressions and functions of their receptors, LGR4/5/6, have already been studied in detail. In the present study, highly-enriched expression of the R-spondin family genes (Rspo1/2/3/4) in the hair follicle dermal papilla is revealed. Expression of Rspo1 in the dermal papilla is specifically and prominently upregulated before anagen entry, and exogenous recombinant R-spondin1 protein injection in mid-telogen leads to precocious anagen entry. Moreover, R-spondin1 activates Wnt/β-catenin signaling in cultured bulge stem cells in vitro, changing their fate determination without altering the cell proliferation. Our pioneering study uncovers a role of R-spondin1 in the activation of cultured hair follicle stem cells and the regulation of hair cycle progression, shedding new light on the governance of Wnt/β-catenin signaling in skin biology and providing helpful clues for future treatment of hair follicle disorders. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 3393 KiB

Open AccessArticle

In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System

by Fanny Knöspel¹, Frank Jacobs², Nora Freyer¹, Georg Damm³

, An De Bondt², Ilse Van den Wyngaert², Jan Snoeys², Mario Monshouwer², Marco Richter¹, Nadja Strahl¹, Daniel Seehofer³ and Katrin Zeilinger^1,*

¹ Bioreactor Group, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany

² Janssen Research & Development, Beerse 2340, Belgium

³ Department for General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany

Int. J. Mol. Sci. 2016, 17(4), 584; https://doi.org/10.3390/ijms17040584 - 16 Apr 2016

Cited by 24 | Viewed by 8409

Abstract

Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the [...] Read more.

Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro. Full article

(This article belongs to the Section Molecular Toxicology)

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15 pages, 1731 KiB

Open AccessArticle

Chromosome 9p21 and ABCA1 Genetic Variants and Their Interactions on Coronary Heart Disease and Ischemic Stroke in a Chinese Han Population

by Xiao-Li Cao^1,2, Rui-Xing Yin^1,*, Feng Huang¹, Jin-Zhen Wu¹ and Wu-Xian Chen¹

¹ Department of Cardiology, Institute of Cardiovascular Diseases, the First Affiliated Hospital, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, China

² Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, China

Int. J. Mol. Sci. 2016, 17(4), 586; https://doi.org/10.3390/ijms17040586 - 18 Apr 2016

Cited by 35 | Viewed by 6972

Abstract

The single nucleotide polymorphisms (SNPs) related to both coronary heart disease (CHD) and ischemic stroke (IS) in Chinese individuals have not been identified definitely. This study was developed to evaluate the genetic susceptibility to CHD and IS on the chromosome 9p21 and the [...] Read more.

The single nucleotide polymorphisms (SNPs) related to both coronary heart disease (CHD) and ischemic stroke (IS) in Chinese individuals have not been identified definitely. This study was developed to evaluate the genetic susceptibility to CHD and IS on the chromosome 9p21 and the adenosine triphosphate (ATP)-binding cassette transporter A1 genes (ABCA1) in a Chinese Han population. Genotypes of the rs1333040, rs1333042, rs4977574, rs2066715 and rs2740483 SNPs were determined in 1134 unrelated patients (CHD, 565 and IS, 569) and 541 controls. The frequencies of the rs4977574 genotypes and alleles between CHD and control groups, and the rs2740483 genotypes and alleles between IS and control groups were different (p = 0.006–0.001). The subjects with rs1333042GG genotype and the carriers of the rs4977574G allele were associated with increased risk of CHD. The carriers of the rs4977574G allele were associated with increased risk of IS. However, the carriers of the rs2740483C allele had lower risk of IS than the non-carriers of the rs2740483C allele after controlling for potential confounders. The rs4977574GG-age (>60 year) interaction increased the risk of CHD (p = 0.022), whereas the rs2740483CG/CC-body mass index (>24 kg/m²) interaction decreased the risk of IS (p = 0.035). The interactions of rs1333040-rs1333042 on the risk of CHD and IS were relatively strong, whereas the interactions of rs1333040-rs1333042-rs2066715 and rs1333040-rs1333042-rs2066715-rs2740483 on the risk of CHD, and rs1333040-rs1333042-rs4977574 and rs1333040-rs1333042-rs4977574-rs2740483 on the risk of IS were relatively weak. These findings suggest that some common variants on the chromosome 9p21 and ABCA1 and their interactions may significantly modify the risk of CHD and IS independent of effects on serum lipid levels. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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22 pages, 11186 KiB

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Overexpression of the Transcription Factors GmSHN1 and GmSHN9 Differentially Regulates Wax and Cutin Biosynthesis, Alters Cuticle Properties, and Changes Leaf Phenotypes in Arabidopsis

by Yangyang Xu^1,2, Hanying Wu¹, Mingming Zhao^1,2, Wang Wu^1,2, Yinong Xu¹ and Dan Gu^1,*

¹ Key Laboratory of Photobiology, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China

² College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China

Int. J. Mol. Sci. 2016, 17(4), 587; https://doi.org/10.3390/ijms17040587 - 21 Apr 2016

Cited by 30 | Viewed by 8657

Abstract

SHINE (SHN/WIN) clade proteins, transcription factors of the plant-specific APETALA 2/ethylene-responsive element binding factor (AP2/ERF) family, have been proven to be involved in wax and cutin biosynthesis. Glycine max is an important economic crop, but its molecular mechanism of wax biosynthesis is rarely [...] Read more.

SHINE (SHN/WIN) clade proteins, transcription factors of the plant-specific APETALA 2/ethylene-responsive element binding factor (AP2/ERF) family, have been proven to be involved in wax and cutin biosynthesis. Glycine max is an important economic crop, but its molecular mechanism of wax biosynthesis is rarely characterized. In this study, 10 homologs of Arabidopsis SHN genes were identified from soybean. These homologs were different in gene structures and organ expression patterns. Constitutive expression of each of the soybean SHN genes in Arabidopsis led to different leaf phenotypes, as well as different levels of glossiness on leaf surfaces. Overexpression of GmSHN1 and GmSHN9 in Arabidopsis exhibited 7.8-fold and 9.9-fold up-regulation of leaf cuticle wax productions, respectively. C31 and C29 alkanes contributed most to the increased wax contents. Total cutin contents of leaves were increased 11.4-fold in GmSHN1 overexpressors and 5.7-fold in GmSHN9 overexpressors, mainly through increasing C16:0 di-OH and dioic acids. GmSHN1 and GmSHN9 also altered leaf cuticle membrane ultrastructure and increased water loss rate in transgenic Arabidopsis plants. Transcript levels of many wax and cutin biosynthesis and leaf development related genes were altered in GmSHN1 and GmSHN9 overexpressors. Overall, these results suggest that GmSHN1 and GmSHN9 may differentially regulate the leaf development process as well as wax and cutin biosynthesis. Full article

(This article belongs to the Special Issue Molecular Research in Plant Secondary Metabolism 2015)

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11 pages, 489 KiB

Open AccessArticle

Hepatoprotective Limonoids from Andiroba (Carapa guianensis)

by Kiyofumi Ninomiya^1,2, Seiya Miyazawa¹, Kaiten Ozeki¹, Natsuko Matsuo¹, Osamu Muraoka^1,2,3, Takashi Kikuchi⁴, Takeshi Yamada⁴

, Reiko Tanaka^4,* and Toshio Morikawa^1,2,*

¹ Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan

² Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan

³ Laboratory of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan

⁴ Laboratory of Medicinal Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan

Int. J. Mol. Sci. 2016, 17(4), 591; https://doi.org/10.3390/ijms17040591 - 19 Apr 2016

Cited by 22 | Viewed by 5925

Abstract

Three gedunin-type limonoids, gedunin (1), 6α-acetoxygedunin (2), and 7-deacetoxy-7-oxogedunin (3), which were isolated from the seed and flower oils of andiroba (Carapa guianensis Aublet, Meliaceae), exhibited hepatoprotective effects at doses of 25 mg/kg, p.o. against d [...] Read more.

Three gedunin-type limonoids, gedunin (1), 6α-acetoxygedunin (2), and 7-deacetoxy-7-oxogedunin (3), which were isolated from the seed and flower oils of andiroba (Carapa guianensis Aublet, Meliaceae), exhibited hepatoprotective effects at doses of 25 mg/kg, p.o. against d-galactosamine (d-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. To characterize the mechanisms of action of 1–3 and clarify the structural requirements for their hepatoprotective effects, 17 related limonoids (1–17) isolated from the seed and/or flower oils of C. guianensis were examined in in vitro studies assessing their effects on (i) d-GalN-induced cytotoxicity in primary cultured mouse hepatocytes, (ii) LPS-induced nitric oxide (NO) production in mouse peritoneal macrophages, and (iii) tumor necrosis factor-α (TNF-α)-induced cytotoxicity in L929 cells. The mechanisms of action of 1–3 are likely to involve the inhibition of LPS-induced macrophage activation and reduced sensitivity of hepatocytes to TNF-α; however, these compounds did not decrease the cytotoxicity caused by d-GalN. In addition, the structural requirements of limonoids (1–17) for inhibition of LPS-induced NO production in mouse peritoneal macrophages and TNF-α-induced cytotoxicity in L929 cells were evaluated. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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9 pages, 2579 KiB

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The Prognostic Role of STEAP1 Expression Determined via Immunohistochemistry Staining in Predicting Prognosis of Primary Colorectal Cancer: A Survival Analysis

by Ching-Hsiao Lee¹, Sung-Lang Chen^2,3, Wen-Wei Sung^1,2,4,5, Hung-Wen Lai^6,7, Ming-Ju Hsieh^5,8,9, Hsu-Heng Yen^2,10

, Tzu-Cheng Su¹¹, Yu-Hu Chiou⁵, Chia-Yu Chen¹¹, Cheng-Yu Lin¹¹, Mei-Ling Chen^11,* and Chih-Jung Chen^1,2,11,*

¹ Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan

² School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan

³ Department of Urology, Chung Shan Medical University Hospital, Taichung 402, Taiwan

⁴ Department of Medical Education, Chung Shan Medical University Hospital, Taichung 402, Taiwan

⁵ Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan

⁶ Department of Surgery, Changhua Christian Hospital, Changhua 500, Taiwan

⁷ School of Medicine, National Yang Ming University, Taipei 112, Taiwan

⁸ Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan

⁹ School of Optometry, Chung Shan Medical University, Taichung 402, Taiwan

¹⁰ Department of Gastroenterology, Changhua Christian Hospital, Changhua 500, Taiwan

¹¹ Department of Surgical Pathology, Changhua Christian Hospital, Changhua 500, Taiwan

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Int. J. Mol. Sci. 2016, 17(4), 592; https://doi.org/10.3390/ijms17040592 - 19 Apr 2016

Cited by 20 | Viewed by 6440

Abstract

STEAP1 (six transmembrane epithelial antigen of the prostate 1) is a transmembrane protein that functions as a potential channel or transporter protein. It is overexpressed in certain cancers and is viewed as a promising therapeutic target. However, the prognostic role of STEAP1 is [...] Read more.

STEAP1 (six transmembrane epithelial antigen of the prostate 1) is a transmembrane protein that functions as a potential channel or transporter protein. It is overexpressed in certain cancers and is viewed as a promising therapeutic target. However, the prognostic role of STEAP1 is still controversial, and no role for STEAP1 has yet been indicated in colorectal cancer. The aim of this study was to investigate the possible association of STEAP1 expression with colorectal cancer prognosis. STEAP1 expression was analyzed by immunohistochemical staining of a tissue array of 165 cancer specimens from primary colorectal cancer patients. The mean and medium follow-up times after surgery were 5.1 and 3.9 years, respectively. A total of 139 patients died during the 13 years of follow-up in the survey period. The prognostic value of STEAP1 with respect to overall survival was analyzed by Kaplan-Meier analysis and Cox proportional hazard models. In total, 164 samples displayed detectable STEAP1 expression in the cytoplasm and membrane. Low STEAP1 expression was correlated with poor overall survival (five-year survival: 33.7% vs. 57.0%, low expression vs. high expression, p = 0.020). Accordingly, multivariate analysis identified low STEAP1 expression as an independent risk factor (hazard ratio = 1.500, p = 0.018), especially in elderly patients or those with late stage cancers, late T values, and early N values. We suggest that analysis of STEAP1 expression by immunohistochemical staining could serve as an independent prognostic marker for colorectal patients. This finding should be validated by other investigative groups. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment 2016)

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14 pages, 7894 KiB

Open AccessArticle

Development of a Three-Dimensional (3D) Printed Biodegradable Cage to Convert Morselized Corticocancellous Bone Chips into a Structured Cortical Bone Graft

by Ying-Chao Chou^1,2, Demei Lee¹, Tzu-Min Chang¹, Yung-Heng Hsu^1,2, Yi-Hsun Yu^1,2, Shih-Jung Liu^1,2,* and Steve Wen-Neng Ueng²

¹ Department of Mechanical Engineering, Chang Gung University, Taoyuan 33302, Taiwan

² Department of Orthopedics, Chang Gung Memorial Hospital, Taoyuan 33375, Taiwan

Int. J. Mol. Sci. 2016, 17(4), 595; https://doi.org/10.3390/ijms17040595 - 20 Apr 2016

Cited by 25 | Viewed by 8258

Abstract

This study aimed to develop a new biodegradable polymeric cage to convert corticocancellous bone chips into a structured strut graft for treating segmental bone defects. A total of 24 adult New Zealand white rabbits underwent a left femoral segmental bone defect creation. Twelve [...] Read more.

This study aimed to develop a new biodegradable polymeric cage to convert corticocancellous bone chips into a structured strut graft for treating segmental bone defects. A total of 24 adult New Zealand white rabbits underwent a left femoral segmental bone defect creation. Twelve rabbits in group A underwent three-dimensional (3D) printed cage insertion, corticocancellous chips implantation, and Kirschner-wire (K-wire) fixation, while the other 12 rabbits in group B received bone chips implantation and K-wire fixation only. All rabbits received a one-week activity assessment and the initial image study at postoperative 1 week. The final image study was repeated at postoperative 12 or 24 weeks before the rabbit scarification procedure on schedule. After the animals were sacrificed, both femurs of all the rabbits were prepared for leg length ratios and 3-point bending tests. The rabbits in group A showed an increase of activities during the first week postoperatively and decreased anterior cortical disruptions in the postoperative image assessments. Additionally, higher leg length ratios and 3-point bending strengths demonstrated improved final bony ingrowths within the bone defects for rabbits in group A. In conclusion, through this bone graft converting technique, orthopedic surgeons can treat segmental bone defects by using bone chips but with imitate characters of structured cortical bone graft. Full article

(This article belongs to the Special Issue Molecular Research on Dental Materials and Biomaterials)

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14 pages, 1878 KiB

Open AccessArticle

Tetrabromidocuprates(II)—Synthesis, Structure and EPR

by André Zabel¹, Alette Winter², Alexandra Kelling¹, Uwe Schilde¹ and Peter Strauch^1,*

¹ Institute of Chemistry, University of Potsdam, Karl-Liebknechtstr.-Str. 24-25, Potsdam D-14476, Germany

² Engineering Education Research Group, Hamburg University of Technology (TUHH), Am Schwarzberg-Campus 3 (E), Hamburg D-21073, Germany

Int. J. Mol. Sci. 2016, 17(4), 596; https://doi.org/10.3390/ijms17040596 - 20 Apr 2016

Cited by 9 | Viewed by 7204

Abstract

Metal-containing ionic liquids (ILs) are of interest for a variety of technical applications, e.g., particle synthesis and materials with magnetic or thermochromic properties. In this paper we report the synthesis of, and two structures for, some new tetrabromidocuprates(II) with several “onium” cations in [...] Read more.

Metal-containing ionic liquids (ILs) are of interest for a variety of technical applications, e.g., particle synthesis and materials with magnetic or thermochromic properties. In this paper we report the synthesis of, and two structures for, some new tetrabromidocuprates(II) with several “onium” cations in comparison to the results of electron paramagnetic resonance (EPR) spectroscopic analyses. The sterically demanding cations were used to separate the paramagnetic Cu(II) ions for EPR measurements. The EPR hyperfine structure in the spectra of these new compounds is not resolved, due to the line broadening resulting from magnetic exchange between the still-incomplete separated paramagnetic Cu(II) centres. For the majority of compounds, the principal g values (g_‖ and g_⊥) of the tensors could be determined and information on the structural changes in the [CuBr₄]²⁻ anions can be obtained. The complexes have high potential, e.g., as ionic liquids, as precursors for the synthesis of copper bromide particles, as catalytically active or paramagnetic ionic liquids. Full article

(This article belongs to the Special Issue Ionic Liquids 2016 and Selected Papers from ILMAT III)

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10 pages, 1762 KiB

Open AccessCommunication

Active and Repressive Chromatin-Associated Proteome after MPA Treatment and the Role of Midkine in Epithelial Monolayer Permeability

by Niamat Khan^1,2, Christof Lenz^1,3

, Lutz Binder¹, Dasaradha Venkata Krishna Pantakani¹ and Abdul R. Asif^1,*

¹ Institute for Clinical Chemistry/UMG-Laboratories, University Medical Center, Robert-Koch-Str. 40, 37075 Göttingen, Germany

² Department of Biotechnology & Genetic Engineering, Kohat University of Science and Technology, Kohat 26000, Khyber Pakhtunkhwa, Pakistan

³ Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany

Int. J. Mol. Sci. 2016, 17(4), 597; https://doi.org/10.3390/ijms17040597 - 20 Apr 2016

Cited by 4 | Viewed by 7062

Abstract

Mycophenolic acid (MPA) is prescribed to maintain allografts in organ-transplanted patients. However, gastrointestinal (GI) complications, particularly diarrhea, are frequently observed as a side effect following MPA therapy. We recently reported that MPA altered the tight junction (TJ)-mediated barrier function in a Caco-2 cell [...] Read more.

Mycophenolic acid (MPA) is prescribed to maintain allografts in organ-transplanted patients. However, gastrointestinal (GI) complications, particularly diarrhea, are frequently observed as a side effect following MPA therapy. We recently reported that MPA altered the tight junction (TJ)-mediated barrier function in a Caco-2 cell monolayer model system. This study investigates whether MPA induces epigenetic changes which lead to GI complications, especially diarrhea. Methods: We employed a Chromatin Immunoprecipitation-O-Proteomics (ChIP-O-Proteomics) approach to identify proteins associated with active (H3K4me3) as well as repressive (H3K27me3) chromatin histone modifications in MPA-treated cells, and further characterized the role of midkine, a H3K4me3-associated protein, in the context of epithelial monolayer permeability. Results: We identified a total of 333 and 306 proteins associated with active and repressive histone modification marks, respectively. Among them, 241 proteins were common both in active and repressive chromatin, 92 proteins were associated exclusively with the active histone modification mark, while 65 proteins remained specific to repressive chromatin. Our results show that 45 proteins which bind to the active and seven proteins which bind to the repressive chromatin region exhibited significantly altered abundance in MPA-treated cells as compared to DMSO control cells. A number of novel proteins whose function is not known in bowel barrier regulation were among the identified proteins, including midkine. Our functional integrity assays on the Caco-2 cell monolayer showed that the inhibition of midkine expression prior to MPA treatment could completely block the MPA-mediated increase in barrier permeability. Conclusions: The ChIP-O-Proteomics approach delivered a number of novel proteins with potential implications in MPA toxicity. Consequently, it can be proposed that midkine inhibition could be a potent therapeutic approach to prevent the MPA-mediated increase in TJ permeability and leak flux diarrhea in organ transplant patients. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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28 pages, 9584 KiB

Open AccessArticle

In Silico Structure and Sequence Analysis of Bacterial Porins and Specific Diffusion Channels for Hydrophilic Molecules: Conservation, Multimericity and Multifunctionality

by Hilde S. Vollan^1,2, Tone Tannæs¹

, Gert Vriend³ and Geir Bukholm^2,4,*

¹ Department of Clinical Molecular Biology (EpiGen), Division of Medicine, Akershus University Hospital and University of Oslo, PO box 28, N-1478 Lørenskog, Norway

² Norwegian Institute of Public Health, Box 4404 Nydalen, N-0403 Oslo, Norway

³ Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands

⁴ Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Pb 5003, N-1430 Ås, Norway

Int. J. Mol. Sci. 2016, 17(4), 599; https://doi.org/10.3390/ijms17040599 - 21 Apr 2016

Cited by 17 | Viewed by 11014

Abstract

Diffusion channels are involved in the selective uptake of nutrients and form the largest outer membrane protein (OMP) family in Gram-negative bacteria. Differences in pore size and amino acid composition contribute to the specificity. Structure-based multiple sequence alignments shed light on the structure-function [...] Read more.

Diffusion channels are involved in the selective uptake of nutrients and form the largest outer membrane protein (OMP) family in Gram-negative bacteria. Differences in pore size and amino acid composition contribute to the specificity. Structure-based multiple sequence alignments shed light on the structure-function relations for all eight subclasses. Entropy-variability analysis results are correlated to known structural and functional aspects, such as structural integrity, multimericity, specificity and biological niche adaptation. The high mutation rate in their surface-exposed loops is likely an important mechanism for host immune system evasion. Multiple sequence alignments for each subclass revealed conserved residue positions that are involved in substrate recognition and specificity. An analysis of monomeric protein channels revealed particular sequence patterns of amino acids that were observed in other classes at multimeric interfaces. This adds to the emerging evidence that all members of the family exist in a multimeric state. Our findings are important for understanding the role of members of this family in a wide range of bacterial processes, including bacterial food uptake, survival and adaptation mechanisms. Full article

(This article belongs to the Section Biochemistry)

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18 pages, 3487 KiB

Open AccessArticle

A Reverse-Genetics Mutational Analysis of the Barley HvDWARF Gene Results in Identification of a Series of Alleles and Mutants with Short Stature of Various Degree and Disturbance in BR Biosynthesis Allowing a New Insight into the Process

by Damian Gruszka^1,*

, Malgorzata Gorniak¹, Ewelina Glodowska¹, Ewa Wierus¹, Jana Oklestkova²

, Anna Janeczko³, Miroslaw Maluszynski¹ and Iwona Szarejko¹

¹ Department of Genetics, Faculty of Biology and Environment Protection, University of Silesia, Jagiellonska 28, 40-032 Katowice, Poland

² Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University, and Institute of Experimental Botany, Academy of Sciences of the Czech Republic, CZ–783 71 Olomouc, Czech Republic

³ Institute of Plant Physiology, Polish Academy of Sciences, Niezapominajek 21, 30-239 Krakow, Poland

Int. J. Mol. Sci. 2016, 17(4), 600; https://doi.org/10.3390/ijms17040600 - 22 Apr 2016

Cited by 22 | Viewed by 6646

Abstract

Brassinosteroids (BRs) are plant steroid hormones, regulating a broad range of physiological processes. The largest amount of data related with BR biosynthesis has been gathered in Arabidopsis thaliana, however understanding of this process is far less elucidated in monocot crops. Up to [...] Read more.

Brassinosteroids (BRs) are plant steroid hormones, regulating a broad range of physiological processes. The largest amount of data related with BR biosynthesis has been gathered in Arabidopsis thaliana, however understanding of this process is far less elucidated in monocot crops. Up to now, only four barley genes implicated in BR biosynthesis have been identified. Two of them, HvDWARF and HvBRD, encode BR-6-oxidases catalyzing biosynthesis of castasterone, but their relation is not yet understood. In the present study, the identification of the HvDWARF genomic sequence, its mutational and functional analysis and characterization of new mutants are reported. Various types of mutations located in different positions within functional domains were identified and characterized. Analysis of their impact on phenotype of the mutants was performed. The identified homozygous mutants show reduced height of various degree and disrupted skotomorphogenesis. Mutational analysis of the HvDWARF gene with the “reverse genetics” approach allowed for its detailed functional analysis at the level of protein functional domains. The HvDWARF gene function and mutants’ phenotypes were also validated by measurement of endogenous BR concentration. These results allowed a new insight into the BR biosynthesis in barley. Full article

(This article belongs to the Section Molecular Plant Sciences)

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10 pages, 2950 KiB

Open AccessArticle

Characterization of Stripe Rust Resistance Genes in the Wheat Cultivar Chuanmai45

by Ennian Yang^1,*, Guangrong Li², Liping Li¹, Zhenyu Zhang³, Wuyun Yang¹, Yunliang Peng³, Yongqing Zhu⁴, Zujun Yang² and Garry M. Rosewarne^1,5,6

¹ Crop Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 610066, China

² School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China

³ Institute of Plant Protection, Sichuan Academy of Agricultural Sciences, Chengdu 610066, China

⁴ Institute of Agro Products Processing Science and Technology, Sichuan Academy of Agricultural Sciences, Chengdu 610066, China

⁵ International Maize and Wheat Improvement Centre (CIMMYT), Apdo. Postal 6-6-41, Mexico 06600, D.F., Mexico

⁶ Department of Environment and Primary Industries, 110 Natimuk Rd, Horsham, Victoria 3401, Australia

Int. J. Mol. Sci. 2016, 17(4), 601; https://doi.org/10.3390/ijms17040601 - 21 Apr 2016

Cited by 22 | Viewed by 6616

Abstract

The objective of this research was to characterize the high level of resistance to stripe that has been observed in the released wheat cultivar, Chuanmai45. A combination of classic genetic analysis, molecular and cytogenetic methods were used to characterize resistance in an F [...] Read more.

The objective of this research was to characterize the high level of resistance to stripe that has been observed in the released wheat cultivar, Chuanmai45. A combination of classic genetic analysis, molecular and cytogenetic methods were used to characterize resistance in an F₂ population derived from Chuanmai45 and the susceptible Chuanmai42. Inheritance of resistance was shown to be conferred by two genes in Chuanmai45. Fluorescence in situ hybridization (FISH) was used along with segregation studies to show that one gene was located on a 1RS.1BL translocation. Molecular markers were employed to show that the other locus was located on chromosome 4B. The defeated gene, Yr24/26, on chromosome 1BL was present in the susceptible parent and lines that recombined this gene with the 1RS.1BL translocation were identified. The germplasm, loci, and associated markers identified in this study will be useful for application in breeding programs utilizing marker-assisted selection. Full article

(This article belongs to the Special Issue Plant Innate Immunity)

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14 pages, 3193 KiB

Open AccessArticle

The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential

by Kun-Chun Chiang^1,*,†, Ta-Sen Yeh^2,†, Shin-Cheh Chen², Jong-Hwei S. Pang³, Chun-Nan Yeh², Jun-Te Hsu², Li-Wei Chen⁴, Sheng-Fong Kuo⁵, Masashi Takano⁶, Atsushi Kittaka⁶, Tai C. Chen⁷, Chi-Chin Sun⁸ and Horng-Heng Juang^9,10,*

¹ General Surgery Department and Zebrafish Center, Chang Gung Memorial Hospital, Chang Gung University, Keelung 20401, Taiwan

² General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 20401, Taiwan

³ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 20401, Taiwan

⁴ Department of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Keelung 20401, Taiwan

⁵ Department of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chang Gung University, Keelung 20401, Taiwan

⁶ Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo 13228, Japan

⁷ Endocrine Core Lab, Boston University School of Medicine, Boston, MA 02118, USA

⁸ Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University, Keelung 20401, Taiwan

⁹ Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan 20401, Taiwan

¹⁰ Urology Department, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 20401, Taiwan

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2016, 17(4), 606; https://doi.org/10.3390/ijms17040606 - 21 Apr 2016

Cited by 26 | Viewed by 7492

Abstract

Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃), the newly-synthesized 1α,25(OH) [...] Read more.

Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃), the newly-synthesized 1α,25(OH)₂D₃ analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH)₂D₃ and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH)₂D₃ and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH)₂D₃ induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin) and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition) process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH)₂D₃ and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9) activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH)₂D₃ and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

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13 pages, 5758 KiB

Open AccessArticle

Mmu-miR-1894-3p Inhibits Cell Proliferation and Migration of Breast Cancer Cells by Targeting Trim46

by Li Zhang¹, Xiaoying Li¹, Wei Dong¹, Caixian Sun¹, Deyu Guo^2,* and Lianfeng Zhang^1,*

¹ Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China

² Laboratory of Animal Sciences, Xuanwu Hospital of Capital Medical University, Beijing 100053, China

Int. J. Mol. Sci. 2016, 17(4), 609; https://doi.org/10.3390/ijms17040609 - 22 Apr 2016

Cited by 29 | Viewed by 11531

Abstract

Breast cancer is the second leading cause of cancer death in women and the presence of metastasis significantly decreases survival. MicroRNAs are involved in tumor progression and the metastatic spreading of breast cancer. Here, we reported that a microRNA, mmu-miR-1894, significantly decreased the [...] Read more.

Breast cancer is the second leading cause of cancer death in women and the presence of metastasis significantly decreases survival. MicroRNAs are involved in tumor progression and the metastatic spreading of breast cancer. Here, we reported that a microRNA, mmu-miR-1894, significantly decreased the lung metastasis of 4TO7 mouse breast cancer cells by 86.7% in mouse models. Mmu-miR-1894-3p was the functional mature form of miR-1894 and significantly decreased the lung metastasis of 4TO7 cells by 90.8% in mouse models. A dual-luciferase reporter assay indicated that mmu-miR-1894-3p directly targeted the tripartite motif containing 46 (Trim46) 3′-untranslated region (UTR) and downregulated the expression of Trim46 in 4TO7 cells. Consistent with the effect of mmu-miR-1894-3p, knockdown of Trim46 inhibited the experimental lung metastasis of 4TO7 cells. Moreover, knockdown of human Trim46 also prohibited the cell proliferation, migration and wound healing of MBA-MD-231 human breast cancer cells. These results suggested that the effect of knockdown of Trim46 alone was sufficient to recapitulate the effect of mmu-miR-1894 on the metastasis of the breast cancer cells in mouse and that Trim46 was involved in the proliferation and migration of mouse and human breast cancer cells. Full article

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

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14 pages, 6010 KiB

Open AccessArticle

Smad3 Sensitizes Hepatocelluar Carcinoma Cells to Cisplatin by Repressing Phosphorylation of AKT

by Hong-Hao Zhou, Lin Chen, Hui-Fang Liang, Guang-Zhen Li, Bi-Xiang Zhang^* and Xiao-Ping Chen^*

Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China

Int. J. Mol. Sci. 2016, 17(4), 610; https://doi.org/10.3390/ijms17040610 - 22 Apr 2016

Cited by 21 | Viewed by 6359

Abstract

Background: Heptocelluar carcinoma (HCC) is insensitive to chemotherapy due to limited bioavailability and acquired drug resistance. Smad3 plays dual roles by inhibiting cell growth initially and promoting the progression of advanced tumors in HCC. However, the role of smad3 in chemosensitivity of HCC [...] Read more.

Background: Heptocelluar carcinoma (HCC) is insensitive to chemotherapy due to limited bioavailability and acquired drug resistance. Smad3 plays dual roles by inhibiting cell growth initially and promoting the progression of advanced tumors in HCC. However, the role of smad3 in chemosensitivity of HCC remains elusive. Methods: The role of smad3 in chemosensitivity of HCC was measured by cell viability, apoptosis, plate colony formation assays and xenograft tumor models. Non-smad signaling was detected by Western blotting to search for the underlying mechanisms. Results: Smad3 enhanced the chemosensitivity of HCC cells to cisplatin. Smad3 upregulated p21^Waf1/Cip1 and downregulated c-myc and bcl2 with the treatment of cisplatin. Moreover, overexpression of smad3 repressed the phosphorylation of AKT, and vice versa. Inhibition of PI3K/AKT pathway by LY294002 restored chemosensitivity of smad3-deficiency cells to cisplatin in HCC. Conclusion: Smad3 sensitizes HCC cells to the effects of cisplatin by repressing phosphorylation of AKT and combination of inhibitor of AKT pathway and conventional chemotherapy may be a potential way to solve drug resistance in HCC. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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15 pages, 6281 KiB

Open AccessArticle

The AaDREB1 Transcription Factor from the Cold-Tolerant Plant Adonis amurensis Enhances Abiotic Stress Tolerance in Transgenic Plant

by Jun-Mei Zong^†, Xiao-Wei Li^†, Yuan-Hang Zhou, Fa-Wei Wang, Nan Wang, Yuan-Yuan Dong, Yan-Xi Yuan, Huan Chen, Xiu-Ming Liu, Na Yao and Hai-Yan Li^*

¹ College of Life Sciences, Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun 130118, Jilin, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 611; https://doi.org/10.3390/ijms17040611 - 22 Apr 2016

Cited by 38 | Viewed by 6684

Abstract

Dehydration-responsive element binding (DREB) transcription factors (TFs) play important roles in the regulation of plant resistance to environmental stresses and can specifically bind to dehydration-responsive element/C-repeat element (DRE/CRT) proteins (G/ACCGAC) and activate expression of many stress-inducible genes. Here, we cloned and characterized a [...] Read more.

Dehydration-responsive element binding (DREB) transcription factors (TFs) play important roles in the regulation of plant resistance to environmental stresses and can specifically bind to dehydration-responsive element/C-repeat element (DRE/CRT) proteins (G/ACCGAC) and activate expression of many stress-inducible genes. Here, we cloned and characterized a novel gene (AaDREB1) encoding the DREB1 transcription factor from the cold-tolerant plant Adonis amurensis. Quantitative real-time (qRT)-PCR results indicated that AaDREB1 expression was induced by salt, drought, cold stress, and abscisic acid application. A yeast one-hybrid assay demonstrated that AaDREB1 encodes a transcription activator and specifically binds to DRE/CRT. Furthermore, transgenic Arabidopsis and rice harboring AaDREB1 showed enhanced tolerance to salt, drought, and low temperature. These results indicated that AaDREB1 might be useful in genetic engineering to improve plant stress tolerance. Full article

(This article belongs to the Special Issue Gene–Environment Interactions)

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15 pages, 3468 KiB

Open AccessArticle

Unfractionated Heparin Promotes Osteoclast Formation in Vitro by Inhibiting Osteoprotegerin Activity

by Binghan Li^1,2,3,4, Dan Lu⁵, Yuqing Chen^1,2,3,4, Minghui Zhao^1,2,3,4 and Li Zuo^1,2,3,4,*

¹ Renal Division, Peking University First Hospital, No. 8 Xishiku Street, Xi Cheng District, Beijing 100034, China

² Peking University Institute of Nephrology, Beijing 100034, China

³ Key Laboratory of Renal Disease, Ministry of Health, Beijing 100034, China

⁴ Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing 100034, China

⁵ Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xi Cheng District, Beijing 100034, China

Int. J. Mol. Sci. 2016, 17(4), 613; https://doi.org/10.3390/ijms17040613 - 22 Apr 2016

Cited by 22 | Viewed by 6596

Abstract

Heparin has been proven to enhance bone resorption and induce bone loss. Since osteoclasts play a pivotal role in bone resorption, the effect of heparin on osteoclastogenesis needs to be clarified. Since osteocytes are the key modulator during osteoclastogenesis, we evaluated heparin’s effect [...] Read more.

Heparin has been proven to enhance bone resorption and induce bone loss. Since osteoclasts play a pivotal role in bone resorption, the effect of heparin on osteoclastogenesis needs to be clarified. Since osteocytes are the key modulator during osteoclastogenesis, we evaluated heparin’s effect on osteoclastogenesis in vitro by co-culturing an osteocyte cell line (MLO-Y4) and pre-osteoclasts (RAW264.7). In this co-culture system, heparin enhanced osteoclastogenesis and osteoclastic bone resorption while having no influence on the production of RANKL (receptor activator of NFκB ligand), M-CSF (macrophage colony-stimulating factor), and OPG (osteoprotegerin), which are three main regulatory factors derived from osteocytes. According to previous studies, heparin could bind specifically to OPG and inhibit its activity, so we hypothesized that this might be a possible mechanism of heparin activity. To test this hypothesis, osteoclastogenesis was induced using recombinant RANKL or MLO-Y4 supernatant. We found that heparin has no effect on RANKL-induced osteoclastogenesis (contains no OPG). However, after incubation with OPG, the capacity of MLO-Y4 supernatant for supporting osteoclast formation was increased. This effect disappeared after OPG was neutralized and reappeared after OPG was replenished. These results strongly suggest that heparin promotes osteocyte-modulated osteoclastogenesis in vitro, at least partially, through inhibiting OPG activity. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 7501 KiB

Open AccessArticle

Epigenetic Modulation of Human Induced Pluripotent Stem Cell Differentiation to Oligodendrocytes

by Panagiotis Douvaras¹, Tomasz Rusielewicz¹, Kwi Hye Kim², Jeffery D. Haines², Patrizia Casaccia^2,* and Valentina Fossati^1,*

¹ The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA

² Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

Int. J. Mol. Sci. 2016, 17(4), 614; https://doi.org/10.3390/ijms17040614 - 22 Apr 2016

Cited by 25 | Viewed by 9444

Abstract

Pluripotent stem cells provide an invaluable tool for generating human, disease-relevant cells. Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system, characterized by myelin damage. Oligodendrocytes are the myelinating cells of the central nervous system (CNS); they differentiate from progenitor [...] Read more.

Pluripotent stem cells provide an invaluable tool for generating human, disease-relevant cells. Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system, characterized by myelin damage. Oligodendrocytes are the myelinating cells of the central nervous system (CNS); they differentiate from progenitor cells, and their membranes ensheath axons, providing trophic support and allowing fast conduction velocity. The current understanding of oligodendrocyte biology was founded by rodent studies, where the establishment of repressive epigenetic marks on histone proteins, followed by activation of myelin genes, leads to lineage progression. To assess whether this epigenetic regulation is conserved across species, we differentiated human embryonic and induced pluripotent stem cells to oligodendrocytes and asked whether similar histone marks and relative enzymatic activities could be detected. The transcriptional levels of enzymes responsible for methylation and acetylation of histone marks were analyzed during oligodendrocyte differentiation, and the post-translational modifications on histones were detected using immunofluorescence. These studies showed that also in human cells, differentiation along the oligodendrocyte lineage is characterized by the acquisition of multiple repressive histone marks, including deacetylation of lysine residues on histone H3 and trimethylation of residues K9 and K27. These data suggest that the epigenetic modulation of oligodendrocyte identity is highly conserved across species. Full article

(This article belongs to the Special Issue Pluripotent Stem Cell Technology for Disease Modeling, Drug Discovery and Regenerative Medicine)

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14 pages, 3402 KiB

Open AccessArticle

Piperlongumine Suppresses Proliferation of Human Oral Squamous Cell Carcinoma through Cell Cycle Arrest, Apoptosis and Senescence

by San-Yuan Chen^1,2,†, Geng-Hung Liu^2,†, Wen-Ying Chao³, Chung-Sheng Shi⁴, Ching-Yen Lin⁵, Yun-Ping Lim⁶, Chieh-Hsiang Lu⁷, Peng-Yeh Lai²

, Hau-Ren Chen^2,* and Ying-Ray Lee^3,5,*

¹ Department of Chinese Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 600, Taiwan

² Department of Life Science, National Chung Cheng University, Chiayi 621, Taiwan

³ Department of Nursing, Min-Hwei Junior College of Health Care Management, Tainan City 736, Taiwan

⁴ Graduate Institute of Clinical Medical Sciences, Chang Gung University, Chiayi 613, Taiwan

⁵ Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 600, Taiwan

⁶ Department of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan

⁷ Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 600, Taiwan

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2016, 17(4), 616; https://doi.org/10.3390/ijms17040616 - 23 Apr 2016

Cited by 37 | Viewed by 7173

Abstract

Oral squamous cell carcinoma (OSCC), an aggressive cancer originating in the oral cavity, is one of the leading causes of cancer deaths in males worldwide. This study investigated the antitumor activity and mechanisms of piperlongumine (PL), a natural compound isolated from Piper longum [...] Read more.

Oral squamous cell carcinoma (OSCC), an aggressive cancer originating in the oral cavity, is one of the leading causes of cancer deaths in males worldwide. This study investigated the antitumor activity and mechanisms of piperlongumine (PL), a natural compound isolated from Piper longum L., in human OSCC cells. The effects of PL on cell proliferation, the cell cycle, apoptosis, senescence and reactive oxygen species (ROS) levels in human OSCC cells were investigated. PL effectively inhibited cell growth, caused cell cycle arrest and induced apoptosis and senescence in OSCC cells. Moreover, PL-mediated anti-human OSCC behavior was inhibited by an ROS scavenger N-acetyl-l-cysteine (NAC) treatment, suggesting that regulation of ROS was involved in the mechanism of the anticancer activity of PL. These findings suggest that PL suppresses tumor growth by regulating the cell cycle and inducing apoptosis and senescence and is a potential chemotherapy agent for human OSCC cells. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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21 pages, 1861 KiB

Open AccessReview

Nucleotide Excision Repair and Vitamin D—Relevance for Skin Cancer Therapy

by Elzbieta Pawlowska¹, Daniel Wysokinski² and Janusz Blasiak^2,*

¹ Department of Orthodontics, Medical University of Lodz, 92-216 Lodz, Poland

² Department of Molecular Genetics, University of Lodz, 90-236 Lodz, Poland

Int. J. Mol. Sci. 2016, 17(4), 372; https://doi.org/10.3390/ijms17040372 - 6 Apr 2016

Cited by 27 | Viewed by 9975

Abstract

Ultraviolet (UV) radiation is involved in almost all skin cancer cases, but on the other hand, it stimulates the production of pre-vitamin D3, whose active metabolite, 1,25-dihydroxyvitamin D3 (1,25VD3), plays important physiological functions on binding with its receptor (vitamin D receptor, VDR). UV-induced [...] Read more.

Ultraviolet (UV) radiation is involved in almost all skin cancer cases, but on the other hand, it stimulates the production of pre-vitamin D3, whose active metabolite, 1,25-dihydroxyvitamin D3 (1,25VD3), plays important physiological functions on binding with its receptor (vitamin D receptor, VDR). UV-induced DNA damages in the form of cyclobutane pyrimidine dimers or (6-4)-pyrimidine-pyrimidone photoproducts are frequently found in skin cancer and its precursors. Therefore, removing these lesions is essential for the prevention of skin cancer. As UV-induced DNA damages are repaired by nucleotide excision repair (NER), the interaction of 1,25VD3 with NER components can be important for skin cancer transformation. Several studies show that 1,25VD3 protects DNA against damage induced by UV, but the exact mechanism of this protection is not completely clear. 1,25VD3 was also shown to affect cell cycle regulation and apoptosis in several signaling pathways, so it can be considered as a potential modulator of the cellular DNA damage response, which is crucial for mutagenesis and cancer transformation. 1,25VD3 was shown to affect DNA repair and potentially NER through decreasing nitrosylation of DNA repair enzymes by NO overproduction by UV, but other mechanisms of the interaction between 1,25VD3 and NER machinery also are suggested. Therefore, the array of NER gene functioning could be analyzed and an appropriate amount of 1.25VD3 could be recommended to decrease UV-induced DNA damage important for skin cancer transformation. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

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20 pages, 451 KiB

Open AccessReview

Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy

by Harinder Gill, Anskar Y. H. Leung and Yok-Lam Kwong^*

Department of Medicine, Queen Mary Hospital, Hong Kong, China

Int. J. Mol. Sci. 2016, 17(4), 440; https://doi.org/10.3390/ijms17040440 - 24 Mar 2016

Cited by 50 | Viewed by 11278

Abstract

Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematopoietic stem cell disorders characterized by cytopenia, ineffective hematopoiesis, and progression to secondary acute myeloid leukemia in high-risk cases. Conventional prognostication relies on clinicopathological parameters supplemented by cytogenetic information. However, recent studies have shown [...] Read more.

Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematopoietic stem cell disorders characterized by cytopenia, ineffective hematopoiesis, and progression to secondary acute myeloid leukemia in high-risk cases. Conventional prognostication relies on clinicopathological parameters supplemented by cytogenetic information. However, recent studies have shown that genetic aberrations also have critical impacts on treatment outcome. Moreover, these genetic alterations may themselves be a target for treatment. The mutation landscape in MDS is shaped by gene aberrations involved in DNA methylation (TET2, DNMT3A, IDH1/2), histone modification (ASXL1, EZH2), the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1/2), transcription (RUNX1, TP53, BCOR, PHF6, NCOR, CEBPA, GATA2), tyrosine kinase receptor signaling (JAK2, MPL, FLT3, GNAS, KIT), RAS pathways (KRAS, NRAS, CBL, NF1, PTPN11), DNA repair (ATM, BRCC3, DLRE1C, FANCL), and cohesion complexes (STAG2, CTCF, SMC1A, RAD21). A detailed understanding of the pathogenetic mechanisms leading to transformation is critical for designing single-agent or combinatorial approaches in target therapy of MDS. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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29 pages, 1504 KiB

Open AccessReview

Gut Microbiota and Lifestyle Interventions in NAFLD

by David Houghton^1,*, Christopher J. Stewart²

, Christopher P. Day^1,3 and Michael Trenell^1,*

¹ Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE4 6BE, UK

² Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA

³ Liver Unit, Newcastle upon Tyne Hospitals NHS Trust, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK

Int. J. Mol. Sci. 2016, 17(4), 447; https://doi.org/10.3390/ijms17040447 - 25 Mar 2016

Cited by 88 | Viewed by 18566

Abstract

The human digestive system harbors a diverse and complex community of microorganisms that work in a symbiotic fashion with the host, contributing to metabolism, immune response and intestinal architecture. However, disruption of a stable and diverse community, termed “dysbiosis”, has been shown to [...] Read more.

The human digestive system harbors a diverse and complex community of microorganisms that work in a symbiotic fashion with the host, contributing to metabolism, immune response and intestinal architecture. However, disruption of a stable and diverse community, termed “dysbiosis”, has been shown to have a profound impact upon health and disease. Emerging data demonstrate dysbiosis of the gut microbiota to be linked with non-alcoholic fatty liver disease (NAFLD). Although the exact mechanism(s) remain unknown, inflammation, damage to the intestinal membrane, and translocation of bacteria have all been suggested. Lifestyle intervention is undoubtedly effective at improving NAFLD, however, not all patients respond to these in the same manner. Furthermore, studies investigating the effects of lifestyle interventions on the gut microbiota in NAFLD patients are lacking. A deeper understanding of how different aspects of lifestyle (diet/nutrition/exercise) affect the host–microbiome interaction may allow for a more tailored approach to lifestyle intervention. With gut microbiota representing a key element of personalized medicine and nutrition, we review the effects of lifestyle interventions (diet and physical activity/exercise) on gut microbiota and how this impacts upon NAFLD prognosis. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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16 pages, 245 KiB

Open AccessReview

Recurrent Fever in Children

by Sofia Torreggiani¹, Giovanni Filocamo¹ and Susanna Esposito^2,*

¹ Pediatric Medium Intensive Care Unit, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

² Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

Int. J. Mol. Sci. 2016, 17(4), 448; https://doi.org/10.3390/ijms17040448 - 25 Mar 2016

Cited by 19 | Viewed by 13124

Abstract

Children presenting with recurrent fever may represent a diagnostic challenge. After excluding the most common etiologies, which include the consecutive occurrence of independent uncomplicated infections, a wide range of possible causes are considered. This article summarizes infectious and noninfectious causes of recurrent fever [...] Read more.

Children presenting with recurrent fever may represent a diagnostic challenge. After excluding the most common etiologies, which include the consecutive occurrence of independent uncomplicated infections, a wide range of possible causes are considered. This article summarizes infectious and noninfectious causes of recurrent fever in pediatric patients. We highlight that, when investigating recurrent fever, it is important to consider age at onset, family history, duration of febrile episodes, length of interval between episodes, associated symptoms and response to treatment. Additionally, information regarding travel history and exposure to animals is helpful, especially with regard to infections. With the exclusion of repeated independent uncomplicated infections, many infective causes of recurrent fever are relatively rare in Western countries; therefore, clinicians should be attuned to suggestive case history data. It is important to rule out the possibility of an infectious process or a malignancy, in particular, if steroid therapy is being considered. After excluding an infectious or neoplastic etiology, immune-mediated and autoinflammatory diseases should be taken into consideration. Together with case history data, a careful physical exam during and between febrile episodes may give useful clues and guide laboratory investigations. However, despite a thorough evaluation, a recurrent fever may remain unexplained. A watchful follow-up is thus mandatory because new signs and symptoms may appear over time. Full article

(This article belongs to the Special Issue Infectious Diseases: Pathophysiology, Diagnostics, Therapies, and Prevention)

12 pages, 666 KiB

Open AccessReview

Nutritional Signaling via Free Fatty Acid Receptors

by Junki Miyamoto¹, Sae Hasegawa¹, Mayu Kasubuchi¹, Atsuhiko Ichimura², Akira Nakajima¹ and Ikuo Kimura^1,*

¹ Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-0057, Japan

² Department of Biological Chemistry, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto 606-8501, Japan

Int. J. Mol. Sci. 2016, 17(4), 450; https://doi.org/10.3390/ijms17040450 - 25 Mar 2016

Cited by 182 | Viewed by 14417

Abstract

Excess energy is stored primarily as triglycerides, which are mobilized when demand for energy arises. Dysfunction of energy balance by excess food intake leads to metabolic diseases, such as obesity and diabetes. Free fatty acids (FFAs) provided by dietary fat are not only [...] Read more.

Excess energy is stored primarily as triglycerides, which are mobilized when demand for energy arises. Dysfunction of energy balance by excess food intake leads to metabolic diseases, such as obesity and diabetes. Free fatty acids (FFAs) provided by dietary fat are not only important nutrients, but also contribute key physiological functions via FFA receptor (FFAR)-mediated signaling molecules, which depend on FFAs’ carbon chain length and the ligand specificity of the receptors. Functional analyses have revealed that FFARs are critical for metabolic functions, such as peptide hormone secretion and inflammation, and contribute to energy homeostasis. In particular, recent studies have shown that the administration of selective agonists of G protein-coupled receptor (GPR) 40 and GPR120 improved glucose metabolism and systemic metabolic disorders. Furthermore, the anti-inflammation and energy metabolism effects of short chain FAs have been linked to the activation of GPR41 and GPR43. In this review, we summarize recent progress in research on FFAs and their physiological roles in the regulation of energy metabolism. Full article

(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)

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14 pages, 3400 KiB

Open AccessReview

Epigenetic Modifications in Essential Hypertension

by Ingrid A. Wise and Fadi J. Charchar^*

Faculty of Science & Technology, Federation University Australia, University Drive, Mount Helen, VIC 3350, Australia

Int. J. Mol. Sci. 2016, 17(4), 451; https://doi.org/10.3390/ijms17040451 - 25 Mar 2016

Cited by 96 | Viewed by 15188

Abstract

Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world’s leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as [...] Read more.

Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world’s leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH. Indeed, a complex and interactive genetic and environmental system exists to determine an individual’s risk of EH. Epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. Epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including EH. Epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic Mendelian inheritance. This review concentrates on epigenetic modifications to DNA structure, including the influence of non-coding RNAs on hypertension development. Full article

(This article belongs to the Special Issue Molecular Research on Hypertension)

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13 pages, 912 KiB

Open AccessReview

Role of Non-Coding RNAs in the Transgenerational Epigenetic Transmission of the Effects of Reprotoxicants

by Eduardo Larriba

and Jesús Del Mazo^*

Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, Madrid 28040, Spain

Int. J. Mol. Sci. 2016, 17(4), 452; https://doi.org/10.3390/ijms17040452 - 25 Mar 2016

Cited by 38 | Viewed by 11032

Abstract

Non-coding RNAs (ncRNAs) are regulatory elements of gene expression and chromatin structure. Both long and small ncRNAs can also act as inductors and targets of epigenetic programs. Epigenetic patterns can be transmitted from one cell to the daughter cell, but, importantly, also through [...] Read more.

Non-coding RNAs (ncRNAs) are regulatory elements of gene expression and chromatin structure. Both long and small ncRNAs can also act as inductors and targets of epigenetic programs. Epigenetic patterns can be transmitted from one cell to the daughter cell, but, importantly, also through generations. Diversity of ncRNAs is emerging with new and surprising roles. Functional interactions among ncRNAs and between specific ncRNAs and structural elements of the chromatin are drawing a complex landscape. In this scenario, epigenetic changes induced by environmental stressors, including reprotoxicants, can explain some transgenerationally-transmitted phenotypes in non-Mendelian ways. In this review, we analyze mechanisms of action of reprotoxicants upon different types of ncRNAs and epigenetic modifications causing transgenerationally transmitted characters through germ cells but affecting germ cells and reproductive systems. A functional model of epigenetic mechanisms of transgenerational transmission ncRNAs-mediated is also proposed. Full article

(This article belongs to the Special Issue The Molecular Mechanisms of Toxicant/Toxin-Induced Diseases and Their Chemoprevention)

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26 pages, 9953 KiB

Open AccessReview

Infrared Irradiation: Toward Green Chemistry, a Review

by René Escobedo¹

, René Miranda¹ and Joel Martínez^2,*

¹ Department of Chemistry, Faculty of Superior Studies Cuautitlan, Campus 1, Autonomous National University of Mexico, Cuautitlan Izcalli, State of Mexico 54740, Mexico

² Chemistry Science Faculty, Sciences and Engineering Postgrade, Autonomous University of San Luis, San Luis Potosi, State of San Luis Potosí 78210, Mexico

Int. J. Mol. Sci. 2016, 17(4), 453; https://doi.org/10.3390/ijms17040453 - 26 Mar 2016

Cited by 58 | Viewed by 8483

Abstract

This review provides a comprehensive overview of where infrared irradiation has been employed, mainly as regards activating green mode for natural products extractions, as well as to favor a reaction, highlighting its actual importance. It is also underlined that infrared irradiation heating has [...] Read more.

This review provides a comprehensive overview of where infrared irradiation has been employed, mainly as regards activating green mode for natural products extractions, as well as to favor a reaction, highlighting its actual importance. It is also underlined that infrared irradiation heating has been around for a long time; however, only in the last eighteen years have many of its advantages been applied to satisfy a wide range of chemical processes, natural products extractions, and for the promotion of many kinds of reactions. In addition, it is brought to light that near infrared irradiation is more efficient than middle and far infrared irradiations, being easily controllable and with the quality of a fast responding heat source. Thus, the main objective of this review is to offer infrared irradiation as an alternative clean energy source to activate reactions, in addition to favor the selective extraction of natural products, all of which is within the Green Chemistry protocol. Some recent results from our laboratory are also included. Full article

(This article belongs to the Section Green Chemistry)

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13 pages, 216 KiB

Open AccessReview

NAFLD and Increased Aortic Stiffness: Parallel or Common Physiopathological Mechanisms?

by Cristiane A. Villela-Nogueira, Nathalie C. Leite, Claudia R. L. Cardoso and Gil F. Salles^*

Department of Internal Medicine, Medical School and University Hospital Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rua Croton 72, Rio de Janeiro 22750-240, Brazil

Int. J. Mol. Sci. 2016, 17(4), 460; https://doi.org/10.3390/ijms17040460 - 20 Apr 2016

Cited by 40 | Viewed by 7067

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide. Liver inflammation and fibrosis related to NAFLD contribute to disease progression and increasing liver-related mortality and morbidity. Increasing data suggest that NAFLD may be linked to atherosclerotic vascular [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide. Liver inflammation and fibrosis related to NAFLD contribute to disease progression and increasing liver-related mortality and morbidity. Increasing data suggest that NAFLD may be linked to atherosclerotic vascular disease independent of other established cardiovascular risk factors. Central arterial stiffness has been recognized as a measure of cumulative cardiovascular risk marker load, and the measure of carotid-femoral pulse wave velocity (cf-PWV) is regarded as the gold standard assessment of aortic stiffness. It has been shown that increased aortic stiffness predicts cardiovascular morbidity and mortality in several clinical settings, including type 2 diabetes mellitus, a well-known condition associated with advanced stages of NAFLD. Furthermore, recently-published studies reported a strong association between NAFLD and increased arterial stiffness, suggesting a possible link in the pathogenesis of atherosclerosis and NAFLD. We sought to review the published data on the associations between NAFLD and aortic stiffness, in order to better understand the interplay between these two conditions and identify possible common physiopathological mechanisms. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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16 pages, 570 KiB

Open AccessReview

Linking Pesticide Exposure with Pediatric Leukemia: Potential Underlying Mechanisms

by Antonio F. Hernández^1,* and Pablo Menéndez^2,3,*

¹ Department of Legal Medicine and Toxicology, University of Granada School of Medicine, Granada 18016, Spain

² Department of Biomedicine, Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Barcelona 08036, Spain

³ Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain

Int. J. Mol. Sci. 2016, 17(4), 461; https://doi.org/10.3390/ijms17040461 - 29 Mar 2016

Cited by 69 | Viewed by 9729

Abstract

Leukemia is the most common cancer in children, representing 30% of all childhood cancers. The disease arises from recurrent genetic insults that block differentiation of hematopoietic stem and/or progenitor cells (HSPCs) and drives uncontrolled proliferation and survival of the differentiation-blocked clone. Pediatric leukemia [...] Read more.

Leukemia is the most common cancer in children, representing 30% of all childhood cancers. The disease arises from recurrent genetic insults that block differentiation of hematopoietic stem and/or progenitor cells (HSPCs) and drives uncontrolled proliferation and survival of the differentiation-blocked clone. Pediatric leukemia is phenotypically and genetically heterogeneous with an obscure etiology. The interaction between genetic factors and environmental agents represents a potential etiological driver. Although information is limited, the principal toxic mechanisms of potential leukemogenic agents (e.g., etoposide, benzene metabolites, bioflavonoids and some pesticides) include topoisomerase II inhibition and/or excessive generation of free radicals, which may induce DNA single- and double-strand breaks (DNA-DSBs) in early HSPCs. Chromosomal rearrangements (duplications, deletions and translocations) may occur if these lesions are not properly repaired. The initiating hit usually occurs in utero and commonly leads to the expression of oncogenic fusion proteins. Subsequent cooperating hits define the disease latency and occur after birth and may be of a genetic, epigenetic or immune nature (i.e., delayed infection-mediated immune deregulation). Here, we review the available experimental and epidemiological evidence linking pesticide exposure to infant and childhood leukemia and provide a mechanistic basis to support the association, focusing on early initiating molecular events. Full article

(This article belongs to the Special Issue The Molecular Mechanisms of Toxicant/Toxin-Induced Diseases and Their Chemoprevention)

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11 pages, 1056 KiB

Open AccessReview

Mechanism of Sleep Disturbance in Children with Atopic Dermatitis and the Role of the Circadian Rhythm and Melatonin

by Yung-Sen Chang^1,2,3 and Bor-Luen Chiang^2,4,*

¹ Department of Pediatrics, Taipei City Hospital Renai Branch, Taipei 106, Taiwan

² Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan

³ School of Medicine, National Yang-Ming University, Taipei 112, Taiwan

⁴ Department of Medical Research, National Taiwan University Hospital, Taipei 100, Taiwan

Int. J. Mol. Sci. 2016, 17(4), 462; https://doi.org/10.3390/ijms17040462 - 29 Mar 2016

Cited by 83 | Viewed by 16543

Abstract

Sleep disturbance is common in children with atopic dermatitis (AD). It is a major factor leading to impaired quality of life in these patients and could have negative effects on neurocognitive function and behavior. However, the pathophysiology of sleep disturbance in children with [...] Read more.

Sleep disturbance is common in children with atopic dermatitis (AD). It is a major factor leading to impaired quality of life in these patients and could have negative effects on neurocognitive function and behavior. However, the pathophysiology of sleep disturbance in children with AD is poorly understood, and there is no consensus on how to manage sleep problems in these patients. Pruritus and scratching could lead to sleep disruption but is unlikely the sole etiology. The circadian rhythm of cytokines, the immune system, and skin physiology such as transcutaneous water loss and skin blood flow might also play a role. Recent studies have suggested that melatonin could also be involved due to its multiple effects on sleep, immunomodulation, and anti-oxidant ability. Environmental factors should also be considered. In this review, we summarize the current understanding of the pathophysiology of sleep disturbance in children with AD, and discuss possible therapeutic implications. Full article

(This article belongs to the Special Issue Sleep, Circadian Rhythm and Skin)

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37 pages, 1441 KiB

Open AccessReview

Hepatoprotective Effects of Chinese Medicinal Herbs: A Focus on Anti-Inflammatory and Anti-Oxidative Activities

by Puiyan Lam¹

, Fan Cheung¹, Hor Yue Tan¹, Ning Wang¹, Man Fung Yuen²

and Yibin Feng^1,*

¹ School of Chinese Medicine, The University of Hong Kong, Hong Kong, China

² Division of Gastroenterology and Hepatology, Queen Mary Hospital and Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Int. J. Mol. Sci. 2016, 17(4), 465; https://doi.org/10.3390/ijms17040465 - 29 Mar 2016

Cited by 132 | Viewed by 15101

Abstract

The liver is intimately connected to inflammation, which is the innate defense system of the body for removing harmful stimuli and participates in the hepatic wound-healing response. Sustained inflammation and the corresponding regenerative wound-healing response can induce the development of fibrosis, cirrhosis and [...] Read more.

The liver is intimately connected to inflammation, which is the innate defense system of the body for removing harmful stimuli and participates in the hepatic wound-healing response. Sustained inflammation and the corresponding regenerative wound-healing response can induce the development of fibrosis, cirrhosis and eventually hepatocellular carcinoma. Oxidative stress is associated with the activation of inflammatory pathways, while chronic inflammation is found associated with some human cancers. Inflammation and cancer may be connected by the effect of the inflammation-fibrosis-cancer (IFC) axis. Chinese medicinal herbs display abilities in protecting the liver compared to conventional therapies, as many herbal medicines have been shown as effective anti-inflammatory and anti-oxidative agents. We review the relationship between oxidative stress and inflammation, the development of hepatic diseases, and the hepatoprotective effects of Chinese medicinal herbs via anti-inflammatory and anti-oxidative mechanisms. Moreover, several Chinese medicinal herbs and composite formulae, which have been commonly used for preventing and treating hepatic diseases, including Andrographis Herba, Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, Lycii Fructus, Coptidis Rhizoma, curcumin, xiao-cha-hu-tang and shi-quan-da-bu-tang, were selected for reviewing their hepatoprotective effects with focus on their anti-oxidative and ant-inflammatory activities. This review aims to provide new insight into how Chinese medicinal herbs work in therapeutic strategies for liver diseases. Full article

(This article belongs to the Section Biochemistry)

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46 pages, 379 KiB

Open AccessReview

The Honolulu Liver Disease Cluster at the Medical Center: Its Mysteries and Challenges

by Rolf Teschke^* and Axel Eickhoff

Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany

Int. J. Mol. Sci. 2016, 17(4), 476; https://doi.org/10.3390/ijms17040476 - 31 Mar 2016

Cited by 28 | Viewed by 7211

Abstract

In 2013, physicians at the Honolulu Queen’s Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was [...] Read more.

In 2013, physicians at the Honolulu Queen’s Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was the cause of this mysterious cluster. Subsequent reexamination, however, has revealed that this QMC cohort is heterogeneous and not a cluster with a single agent causing a single disease. It is heterogeneous because patients used multiple DS’s and drugs and because patients appeared to have suffered from multiple liver diseases: liver cirrhosis, liver failure by acetaminophen, hepatotoxicity by non-steroidal antiinflammatory drugs (NSAIDs), resolving acute viral hepatitis by hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella zoster virus (VZV), and suspected hepatitis E virus (HEV). Failing to exclude these confounders and to consider more viable diagnoses, the QMC physicians may have missed specific treatment options in some of their patients. The QMC physicians unjustifiably upgraded their Roussel Uclaf Causality Assessment Method (RUCAM) causality scores so that all patients would appear to be “probable” for OEP. However, subsequent RUCAM reassessments by our group demonstrated a lack of causality for OEP in the evaluated QMC cases. The QMC’s questionable approaches explain the extraordinary accumulation of suspected OEP cases at the QMC in Hawaii as single place, whereas similar cohorts were not published by any larger US liver center, substantiating that the problem is with the QMC. In this review article, we present and discuss new case data and critically evaluate upcoming developments of problematic regulatory assessments by the US Centers for Disease Control and Prevention (CDC), the Hawaii Department of Health (HDOH), and the Food and Drug Administration (FDA), as based on invalid QMC conclusions, clarifying now also basic facts and facilitating constructive discussions. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

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11 pages, 217 KiB

Open AccessReview

Novel Insights into the Role of Long Noncoding RNA in Ocular Diseases

by Fang Li^†, Xuyang Wen^†, He Zhang^* and Xianqun Fan^*

¹ Department of Ophthalmology, Ninth People’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200025, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 478; https://doi.org/10.3390/ijms17040478 - 31 Mar 2016

Cited by 64 | Viewed by 9951

Abstract

Recent advances have suggested that long noncoding RNAs (lncRNAs) are differentially expressed in ocular tissues and play a critical role in the pathogenesis of different types of eye diseases. Here, we summarize the functions and mechanisms of known aberrantly-expressed lncRNAs and present a [...] Read more.

Recent advances have suggested that long noncoding RNAs (lncRNAs) are differentially expressed in ocular tissues and play a critical role in the pathogenesis of different types of eye diseases. Here, we summarize the functions and mechanisms of known aberrantly-expressed lncRNAs and present a brief overview of relevant reports about lncRNAs in such ocular diseases as glaucoma, proliferative vitreoretinopathy (PVR), diabeticretinopathy (DR), and ocular tumors. We intend to highlight comprehensive studies that provide detailed data about the mechanisms of lncRNAs, their applications as diagnostic or prognostic biomarkers, and their potential therapeutic targets. Although our understanding of lncRNAs is still in its infancy, these examples may provide helpful insights into the methods by which lncRNAs interfere with ocular diseases. Full article

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

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20 pages, 544 KiB

Open AccessReview

Diet, Microbiota, Obesity, and NAFLD: A Dangerous Quartet

by Mariana Verdelho Machado^1,2 and Helena Cortez-Pinto^1,2,*

¹ Departamento de Gastrenterologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte (CHLN), 1649-035 Lisbon, Portugal

² Laboratório de Nutrição, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Alameda da Universidade, 1649-004 Lisboa, Portugal

Int. J. Mol. Sci. 2016, 17(4), 481; https://doi.org/10.3390/ijms17040481 - 1 Apr 2016

Cited by 105 | Viewed by 14546

Abstract

Recently, the importance of the gut-liver-adipose tissue axis has become evident. Nonalcoholic fatty liver disease (NAFLD) is the hepatic disease of a systemic metabolic disorder that radiates from energy-surplus induced adiposopathy. The gut microbiota has tremendous influences in our whole-body metabolism, and is [...] Read more.

Recently, the importance of the gut-liver-adipose tissue axis has become evident. Nonalcoholic fatty liver disease (NAFLD) is the hepatic disease of a systemic metabolic disorder that radiates from energy-surplus induced adiposopathy. The gut microbiota has tremendous influences in our whole-body metabolism, and is crucial for our well-being and health. Microorganisms precede humans in more than 400 million years and our guest flora evolved with us in order to help us face aggressor microorganisms, to help us maximize the energy that can be extracted from nutrients, and to produce essential nutrients/vitamins that we are not equipped to produce. However, our gut microbiota can be disturbed, dysbiota, and become itself a source of stress and injury. Dysbiota may adversely impact metabolism and immune responses favoring obesity and obesity-related disorders such as insulin resistance/diabetes mellitus and NAFLD. In this review, we will summarize the latest evidence of the role of microbiota/dysbiota in diet-induced obesity and NAFLD, as well as the potential therapeutic role of targeting the microbiota in this set. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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11 pages, 208 KiB

Open AccessReview

Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome after Liver Transplant

by Stefano Gitto and Erica Villa^*

Department of Gastroenterology, Azienda Ospedaliero-Universitaria and University of Modena and Reggio Emilia, Via del Pozzo 1, 41124 Modena, Italy

Int. J. Mol. Sci. 2016, 17(4), 490; https://doi.org/10.3390/ijms17040490 - 2 Apr 2016

Cited by 32 | Viewed by 9702

Abstract

Liver transplant is the unique curative therapy for patients with acute liver failure or end-stage liver disease, with or without hepatocellular carcinoma. Increase of body weight, onset of insulin resistance and drug-induced alterations of metabolism are reported in liver transplant recipients. In this [...] Read more.

Liver transplant is the unique curative therapy for patients with acute liver failure or end-stage liver disease, with or without hepatocellular carcinoma. Increase of body weight, onset of insulin resistance and drug-induced alterations of metabolism are reported in liver transplant recipients. In this context, post-transplant diabetes mellitus, hyperlipidemia, and arterial hypertension can be often diagnosed. Multifactorial illnesses occurring in the post-transplant period represent significant causes of morbidity and mortality. This is especially true for metabolic syndrome. Non-alcoholic steatosis and steatohepatitis are hepatic manifestations of metabolic syndrome and after liver transplant both recurrent and de novo steatosis can be found. Usually, post-transplant steatosis shows an indolent outcome with few cases of fibrosis progression. However, in the post-transplant setting, both metabolic syndrome and steatosis might play a key role in the stratification of morbidity and mortality risk, being commonly associated with cardiovascular disease. The single components of metabolic syndrome can be treated with targeted drugs while lifestyle intervention is the only reasonable therapeutic approach for transplant patients with non-alcoholic steatosis or steatohepatitis. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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14 pages, 212 KiB

Open AccessReview

Diagnosing Lung Cancers through Examination of Micro-RNA Biomarkers in Blood, Plasma, Serum and Sputum: A Review and Summary of Current Literature

by Jennifer Gyoba^1,*,†, Shubham Shan^1,†, Wilson Roa² and Eric L. R. Bédard^1,*

¹ Division of Thoracic Surgery, University of Alberta, Edmonton, AB T6G 2R3, Canada

² Department of Oncology, University of Alberta, Edmonton, AB T6G 2R3, Canada

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 494; https://doi.org/10.3390/ijms17040494 - 1 Apr 2016

Cited by 58 | Viewed by 7411

Abstract

Lung cancer is the leading cause of cancer related morbidity and mortality worldwide. Currently, the vast majority of lung cancers are diagnosed at a late stage, when patients become symptomatic leading to dismal, less than 15% five-year survival rates. Evidence has demonstrated that [...] Read more.

Lung cancer is the leading cause of cancer related morbidity and mortality worldwide. Currently, the vast majority of lung cancers are diagnosed at a late stage, when patients become symptomatic leading to dismal, less than 15% five-year survival rates. Evidence has demonstrated that screening computed tomography scans can be used to detect lung cancer, but these scans have high false positive rates. Therefore, there is a continued need for the development of minimally-invasive methods to screen the high risk population and diagnose lung cancer at an earlier, curable stage. One such promising area is the use micro-RNAs. These are short, non-coding RNA molecules that have been shown in previous research to be dysregulated in cancers. This review will focus on the potential use of miRNA levels in various biological fluids (whole blood, plasma, serum, and sputum) and demonstrate their potential utility as screening and diagnostic biomarkers for lung cancer. Current research will be analyzed and compared, and future directions in establishing the use of miRNAs for detecting lung cancer will be discussed. Full article

(This article belongs to the Special Issue MicroRNA in Various Disease States as Biomarkers)

17 pages, 836 KiB

Open AccessReview

Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review

by Brandon P. Lucke-Wold^1,†

, Aric F. Logsdon^2,†, Branavan Manoranjan³, Ryan C. Turner¹

, Evan McConnell⁴

, George Edward Vates⁴, Jason D. Huber², Charles L. Rosen¹ and J. Marc Simard^5,*

¹ Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV 26505, USA

² Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV 26505, USA

³ McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8S 4K1, Canada

⁴ Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY 14642, USA

⁵ Departments of Neurosurgery, Pathology, and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA

^† Denotes Equal Contribution for First Author.

Int. J. Mol. Sci. 2016, 17(4), 497; https://doi.org/10.3390/ijms17040497 - 2 Apr 2016

Cited by 252 | Viewed by 24041

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes including vasospasm, cognitive decline, and even death. Currently, treatment options are limited for this potentially life threatening injury. Recent evidence suggests that neuroinflammation plays a critical role in injury expansion and brain damage. Red [...] Read more.

Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes including vasospasm, cognitive decline, and even death. Currently, treatment options are limited for this potentially life threatening injury. Recent evidence suggests that neuroinflammation plays a critical role in injury expansion and brain damage. Red blood cell breakdown products can lead to the release of inflammatory cytokines that trigger vasospasm and tissue injury. Preclinical models have been used successfully to improve understanding about neuroinflammation following aneurysmal rupture. The focus of this review is to provide an overview of how neuroinflammation relates to secondary outcomes such as vasospasm after aneurysmal rupture and to critically discuss pharmaceutical agents that warrant further investigation for the treatment of subarachnoid hemorrhage. We provide a concise overview of the neuroinflammatory pathways that are upregulated following aneurysmal rupture and how these pathways correlate to long-term outcomes. Treatment of aneurysm rupture is limited and few pharmaceutical drugs are available. Through improved understanding of biochemical mechanisms of injury, novel treatment solutions are being developed that target neuroinflammation. In the final sections of this review, we highlight a few of these novel treatment approaches and emphasize why targeting neuroinflammation following aneurysmal subarachnoid hemorrhage may improve patient care. We encourage ongoing research into the pathophysiology of aneurysmal subarachnoid hemorrhage, especially in regards to neuroinflammatory cascades and the translation to randomized clinical trials. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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31 pages, 1107 KiB

Open AccessReview

MicroRNA and Heart Failure

by Lee Lee Wong^1,†, Juan Wang^1,†, Oi Wah Liew¹

, Arthur Mark Richards^1,2,3 and Yei-Tsung Chen^1,*

¹ Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, #08-01, MD6 Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore

² Cardiac Department, National University Health System, Tower Block Level 9, 1E Kent Ridge Road, Singapore 119228, Singapore

³ Christchurch Heart Institute, Department of Medicine, University of Otago, PO Box 4345, Christchurch 8014, New Zealand

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 502; https://doi.org/10.3390/ijms17040502 - 6 Apr 2016

Cited by 109 | Viewed by 12170

Abstract

Heart failure (HF) imposes significant economic and public health burdens upon modern society. It is known that disturbances in neurohormonal status play an important role in the pathogenesis of HF. Therapeutics that antagonize selected neurohormonal pathways, specifically the renin-angiotensin-aldosterone and sympathetic nervous systems, [...] Read more.

Heart failure (HF) imposes significant economic and public health burdens upon modern society. It is known that disturbances in neurohormonal status play an important role in the pathogenesis of HF. Therapeutics that antagonize selected neurohormonal pathways, specifically the renin-angiotensin-aldosterone and sympathetic nervous systems, have significantly improved patient outcomes in HF. Nevertheless, mortality remains high with about 50% of HF patients dying within five years of diagnosis thus mandating ongoing efforts to improve HF management. The discovery of short noncoding microRNAs (miRNAs) and our increasing understanding of their functions, has presented potential therapeutic applications in complex diseases, including HF. Results from several genome-wide miRNA studies have identified miRNAs differentially expressed in HF cohorts suggesting their possible involvement in the pathogenesis of HF and their potential as both biomarkers and as therapeutic targets. Unravelling the functional relevance of miRNAs within pathogenic pathways is a major challenge in cardiovascular research. In this article, we provide an overview of the role of miRNAs in the cardiovascular system. We highlight several HF-related miRNAs reported from selected cohorts and review their putative roles in neurohormonal signaling. Full article

(This article belongs to the Special Issue MicroRNA in Various Disease States as Biomarkers)

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11 pages, 401 KiB

Open AccessReview

Diabetes Mellitus Induces Alzheimer’s Disease Pathology: Histopathological Evidence from Animal Models

by Nobuyuki Kimura

Section of Cell Biology and Pathology, Department of Alzheimer’s Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology (NCGG), Gengo 35, Moriika, Obu, Aichi 474-8511, Japan

Int. J. Mol. Sci. 2016, 17(4), 503; https://doi.org/10.3390/ijms17040503 - 5 Apr 2016

Cited by 102 | Viewed by 14541

Abstract

Alzheimer’s disease (AD) is the major causative disease of dementia and is characterized pathologically by the accumulation of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain. Although genetic studies show that β-amyloid protein (Aβ), the major component of SPs, is the [...] Read more.

Alzheimer’s disease (AD) is the major causative disease of dementia and is characterized pathologically by the accumulation of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain. Although genetic studies show that β-amyloid protein (Aβ), the major component of SPs, is the key factor underlying AD pathogenesis, it remains unclear why advanced age often leads to AD. Interestingly, several epidemiological and clinical studies show that type II diabetes mellitus (DM) patients are more likely to exhibit increased susceptibility to AD. Moreover, growing evidence suggests that there are several connections between the neuropathology that underlies AD and DM, and there is evidence that the experimental induction of DM can cause cognitive dysfunction, even in rodent animal models. This mini-review summarizes histopathological evidence that DM induces AD pathology in animal models and discusses the possibility that aberrant insulin signaling is a key factor in the induction of AD pathology. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

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10 pages, 766 KiB

Open AccessReview

The Role of Docosahexaenoic Acid (DHA) in the Control of Obesity and Metabolic Derangements in Breast Cancer

by Alessio Molfino^1,*, Maria Ida Amabile^1,2

, Massimo Monti², Stefano Arcieri², Filippo Rossi Fanelli¹ and Maurizio Muscaritoli¹

¹ Department of Clinical Medicine, Sapienza University of Rome, viale dell’Università 37, 00185 Rome, Italy

² Department of Surgical Sciences, Sapienza University of Rome, viale Regina Margherita 324, 00161 Rome, Italy

Int. J. Mol. Sci. 2016, 17(4), 505; https://doi.org/10.3390/ijms17040505 - 5 Apr 2016

Cited by 23 | Viewed by 9355

Abstract

Obesity represents a major under-recognized preventable risk factor for cancer development and recurrence, including breast cancer (BC). Healthy diet and correct lifestyle play crucial role for the treatment of obesity and for the prevention of BC. Obesity is significantly prevalent in western countries [...] Read more.

Obesity represents a major under-recognized preventable risk factor for cancer development and recurrence, including breast cancer (BC). Healthy diet and correct lifestyle play crucial role for the treatment of obesity and for the prevention of BC. Obesity is significantly prevalent in western countries and it contributes to almost 50% of BC in older women. Mechanisms underlying obesity, such as inflammation and insulin resistance, are also involved in BC development. Fatty acids are among the most extensively studied dietary factors, whose changes appear to be closely related with BC risk. Alterations of specific ω-3 polyunsaturated fatty acids (PUFAs), particularly low basal docosahexaenoic acid (DHA) levels, appear to be important in increasing cancer risk and its relapse, influencing its progression and prognosis and affecting the response to treatments. On the other hand, DHA supplementation increases the response to anticancer therapies and reduces the undesired side effects of anticancer therapies. Experimental and clinical evidence shows that higher fish consumption or intake of DHA reduces BC cell growth and its relapse risk. Controversy exists on the potential anticancer effects of marine ω-3 PUFAs and especially DHA, and larger clinical trials appear mandatory to clarify these aspects. The present review article is aimed at exploring the capacity of DHA in controlling obesity-related inflammation and in reducing insulin resistance in BC development, progression, and response to therapies. Full article

(This article belongs to the Special Issue The Mechanism of Action of Food Components in Disease Prevention)

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21 pages, 1144 KiB

Open AccessReview

Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma

by Atik Badshah Shaikh^1,†

, Fangfei Li^1,†, Min Li^1,2,†, Bing He^1,†, Xiaojuan He¹, Guofen Chen³, Baosheng Guo¹, Defang Li¹, Feng Jiang¹, Lei Dang¹, Shaowei Zheng⁴, Chao Liang¹, Jin Liu¹, Cheng Lu¹

, Biao Liu¹, Jun Lu¹, Luyao Wang¹, Aiping Lu^1,* and Ge Zhang^1,*

¹ Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China

² Department of Orthopaedic Surgery, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China

³ Orthopaedic Surgery Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

⁴ Department of Orthopaedic Surgery, the First Hospital of Huizhou, Huizhou 516000, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 506; https://doi.org/10.3390/ijms17040506 - 6 Apr 2016

Cited by 112 | Viewed by 11062

Abstract

Osteosarcoma (OS) is a bone cancer mostly occurring in pediatric population. Current treatment regime of surgery and intensive chemotherapy could cure about 60%–75% patients with primary osteosarcoma, however only 15% to 30% can be cured when pulmonary metastasis or relapse has taken place. [...] Read more.

Osteosarcoma (OS) is a bone cancer mostly occurring in pediatric population. Current treatment regime of surgery and intensive chemotherapy could cure about 60%–75% patients with primary osteosarcoma, however only 15% to 30% can be cured when pulmonary metastasis or relapse has taken place. Hence, novel precise OS-targeting therapies are being developed with the hope of addressing this issue. This review summarizes the current development of molecular mechanisms and targets for osteosarcoma. Therapies that target these mechanisms with updated information on clinical trials are also reviewed. Meanwhile, we further discuss novel therapeutic targets and OS-targeting drug delivery systems. In conclusion, a full insight in OS pathogenesis and OS-targeting strategies would help us explore novel targeted therapies for metastatic osteosarcoma. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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22 pages, 1045 KiB

Open AccessReview

Cytotoxicity of Nanoparticles Contained in Food on Intestinal Cells and the Gut Microbiota

by Esther E. Fröhlich¹

and Eleonore Fröhlich^2,*

¹ Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, Graz A-8010, Austria

² Center for Medical Research, Medical University of Graz, Stiftingtalstr. 24, Graz A-8010, Austria

Int. J. Mol. Sci. 2016, 17(4), 509; https://doi.org/10.3390/ijms17040509 - 6 Apr 2016

Cited by 195 | Viewed by 17821

Abstract

Toxicity of nanoparticles (NPs) upon oral exposure has been studied in animals using physiological changes, behavior, histology, and blood analysis for evaluation. The effects recorded include the combination of the action on cells of the exposed animal and the reaction of the microorganisms [...] Read more.

Toxicity of nanoparticles (NPs) upon oral exposure has been studied in animals using physiological changes, behavior, histology, and blood analysis for evaluation. The effects recorded include the combination of the action on cells of the exposed animal and the reaction of the microorganisms that populate the external and internal surfaces of the body. The importance of these microorganisms, collectively termed as microbiota, for the health of the host has been widely recognized. They may also influence toxicity of NPs but these effects are difficult to differentiate from toxicity on cells of the gastrointestinal tract. To estimate the likelihood of preferential damage of the microbiota by NPs the relative sensitivity of enterocytes and bacteria was compared. For this comparison NPs with antimicrobial action present in consumer products were chosen. The comparison of cytotoxicity with Escherichia coli as representative for intestinal bacteria and on gastrointestinal cells revealed that silver NPs damaged bacteria at lower concentrations than enterocytes, while the opposite was true for zinc oxide NPs. These results indicate that silver NPs may cause adverse effects by selectively affecting the gut microbiota. Fecal transplantation from NP-exposed animals to unexposed ones offers the possibility to verify this hypothesis. Full article

(This article belongs to the Special Issue Cellular Toxicity of Nanoparticles)

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12 pages, 1116 KiB

Open AccessReview

Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression

by Lilly Y. W. Bourguignon

San Francisco Veterans Affairs Medical Center, Department of Medicine, University of California at San Francisco & Endocrine Unit (111N2), 4150 Clement Street, San Francisco, CA 94121, USA

Int. J. Mol. Sci. 2016, 17(4), 517; https://doi.org/10.3390/ijms17040517 - 7 Apr 2016

Cited by 28 | Viewed by 5939

Abstract

Solid tumor invasion, metastasis and therapeutic drug resistance are the common causes for serious morbidity and cancer recurrence in patients. A number of research studies have searched for malignancy-related biomarkers and drug targets that are closely linked to tumor cell properties. One of [...] Read more.

Solid tumor invasion, metastasis and therapeutic drug resistance are the common causes for serious morbidity and cancer recurrence in patients. A number of research studies have searched for malignancy-related biomarkers and drug targets that are closely linked to tumor cell properties. One of the candidates is matrix hyaluronan (HA), which is known as one of the major extracellular matrix (ECM) components. HA serves as a physiological ligand for surface CD44 molecule and also functions as a bio-regulator. The binding of HA to CD44 has been shown to stimulate concomitant activation of a number of oncogenic pathways and abnormal cellular processes in cancer cells and cancer stem cells (CSCs). MicroRNAs (miRNAs) belong to a class of small RNAs containing ~20–25 nucleotides and are known to promote aberrant cellular functions in cancer cells. In this article, I have focused on the role of HA interaction with CD44 and several important signaling molecules in the regulation of unique miRNAs (e.g., miR-21, miR-302 and miR-10b) and their downstream targets leading to multiple tumor cell-specific functions (e.g., tumor cell growth, drug resistance and metastasis) and cancer progression. This new knowledge could provide the groundwork necessary for establishing new tumor markers and developing important, novel drugs targeted against HA/CD44-associated tumor progression, which can be utilized in the therapeutic treatment of metastatic cancer patients. Full article

(This article belongs to the Special Issue MicroRNA in Various Disease States as Biomarkers)

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25 pages, 7592 KiB

Open AccessReview

Challenging Density Functional Theory Calculations with Hemes and Porphyrins

by Sam P. De Visser^1,*

and Martin J. Stillman^2,*

¹ Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, the University of Manchester, 131 Princess Street, Manchester M1 7DN, UK

² Department of Chemistry, The University of Western Ontario, London, ON N6A 5B7, Canada

Int. J. Mol. Sci. 2016, 17(4), 519; https://doi.org/10.3390/ijms17040519 - 7 Apr 2016

Cited by 28 | Viewed by 10439

Abstract

In this paper we review recent advances in computational chemistry and specifically focus on the chemical description of heme proteins and synthetic porphyrins that act as both mimics of natural processes and technological uses. These are challenging biochemical systems involved in electron transfer [...] Read more.

In this paper we review recent advances in computational chemistry and specifically focus on the chemical description of heme proteins and synthetic porphyrins that act as both mimics of natural processes and technological uses. These are challenging biochemical systems involved in electron transfer as well as biocatalysis processes. In recent years computational tools have improved considerably and now can reproduce experimental spectroscopic and reactivity studies within a reasonable error margin (several kcal·mol⁻¹). This paper gives recent examples from our groups, where we investigated heme and synthetic metal-porphyrin systems. The four case studies highlight how computational modelling can correctly reproduce experimental product distributions, predicted reactivity trends and guide interpretation of electronic structures of complex systems. The case studies focus on the calculations of a variety of spectroscopic features of porphyrins and show how computational modelling gives important insight that explains the experimental spectra and can lead to the design of porphyrins with tuned properties. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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21 pages, 1145 KiB

Open AccessReview

Bird Integumentary Melanins: Biosynthesis, Forms, Function and Evolution

by Ismael Galván¹ and Francisco Solano^2,*

¹ Department of Evolutionary Ecology, Doñana Biological Station—CSIC, 41092 Sevilla, Spain

² Department of Biochemistry and Molecular Biology B & Immunology, School of Medicine and IMIB, University of Murcia, 30100 Murcia, Spain

Int. J. Mol. Sci. 2016, 17(4), 520; https://doi.org/10.3390/ijms17040520 - 8 Apr 2016

Cited by 115 | Viewed by 14640

Abstract

Melanins are the ubiquitous pigments distributed in nature. They are one of the main pigments responsible for colors in living cells. Birds are among the most diverse animals regarding melanin-based coloration, especially in the plumage, although they also pigment bare parts of the [...] Read more.

Melanins are the ubiquitous pigments distributed in nature. They are one of the main pigments responsible for colors in living cells. Birds are among the most diverse animals regarding melanin-based coloration, especially in the plumage, although they also pigment bare parts of the integument. This review is devoted to the main characteristics of bird melanins, including updated views of the formation and nature of melanin granules, whose interest has been raised in the last years for inferring the color of extinct birds and non-avian theropod dinosaurs using resistant fossil feathers. The molecular structure of the two main types of melanin, eumelanin and pheomelanin, and the environmental and genetic factors that regulate avian melanogenesis are also presented, establishing the main relationship between them. Finally, the special functions of melanin in bird feathers are also discussed, emphasizing the aspects more closely related to these animals, such as honest signaling, and the factors that may drive the evolution of pheomelanin and pheomelanin-based color traits, an issue for which birds have been pioneer study models. Full article

(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)

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25 pages, 2093 KiB

Open AccessReview

Induced Pluripotent Stem Cell Therapies for Cervical Spinal Cord Injury

by Vanessa M. Doulames and Giles W. Plant^*

Stanford Partnership for Spinal Cord Injury and Repair, Department of Neurosurgery, Stanford University School of Medicine, 265 Campus Drive Stanford, California, CA 94305, USA

Int. J. Mol. Sci. 2016, 17(4), 530; https://doi.org/10.3390/ijms17040530 - 9 Apr 2016

Cited by 41 | Viewed by 23055

Abstract

Cervical-level injuries account for the majority of presented spinal cord injuries (SCIs) to date. Despite the increase in survival rates due to emergency medicine improvements, overall quality of life remains poor, with patients facing variable deficits in respiratory and motor function. Therapies aiming [...] Read more.

Cervical-level injuries account for the majority of presented spinal cord injuries (SCIs) to date. Despite the increase in survival rates due to emergency medicine improvements, overall quality of life remains poor, with patients facing variable deficits in respiratory and motor function. Therapies aiming to ameliorate symptoms and restore function, even partially, are urgently needed. Current therapeutic avenues in SCI seek to increase regenerative capacities through trophic and immunomodulatory factors, provide scaffolding to bridge the lesion site and promote regeneration of native axons, and to replace SCI-lost neurons and glia via intraspinal transplantation. Induced pluripotent stem cells (iPSCs) are a clinically viable means to accomplish this; they have no major ethical barriers, sources can be patient-matched and collected using non-invasive methods. In addition, the patient’s own cells can be used to establish a starter population capable of producing multiple cell types. To date, there is only a limited pool of research examining iPSC-derived transplants in SCI—even less research that is specific to cervical injury. The purpose of the review herein is to explore both preclinical and clinical recent advances in iPSC therapies with a detailed focus on cervical spinal cord injury. Full article

(This article belongs to the Special Issue Pluripotent Stem Cell Technology for Disease Modeling, Drug Discovery and Regenerative Medicine)

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23 pages, 287 KiB

Open AccessReview

Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

by Miren García-Cortés^1,2,†

, Mercedes Robles-Díaz^1,2,*,†, Aida Ortega-Alonso¹, Inmaculada Medina-Caliz¹ and Raul J. Andrade^1,2

¹ Servicio de Farmacología Clíınica and Unidad de Gestión Clínica (UGC) de Gastroenterología y Hepatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga (UMA), 29010 Málaga, Spain

² Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 537; https://doi.org/10.3390/ijms17040537 - 9 Apr 2016

Cited by 113 | Viewed by 22920

Abstract

Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are [...] Read more.

Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

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25 pages, 2298 KiB

Open AccessReview

Pathogens Use and Abuse MicroRNAs to Deceive the Immune System

by Thomas B. Flór and Bianca Blom^*

Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, The Netherlands

Int. J. Mol. Sci. 2016, 17(4), 538; https://doi.org/10.3390/ijms17040538 - 9 Apr 2016

Cited by 15 | Viewed by 6796

Abstract

Emerging evidence has demonstrated that microRNAs (miRs) play a role in the survival and amplification of viruses, bacteria and other pathogens. There are various ways in which pathogens can benefit from miR-directed alterations in protein translation and signal transduction. Members of the herpesviridae [...] Read more.

Emerging evidence has demonstrated that microRNAs (miRs) play a role in the survival and amplification of viruses, bacteria and other pathogens. There are various ways in which pathogens can benefit from miR-directed alterations in protein translation and signal transduction. Members of the herpesviridae family have previously been shown to encode multiple miRs, while the production of miRs by viruses like HIV-1 remained controversial. Recently, novel techniques have facilitated the elucidation of true miR targets by establishing miR-argonaute association and the subsequent interactions with their cognate cellular mRNAs. This, in combination with miR reporter assays, has generated physiologically relevant evidence that miRs from the herpesviridae family have the potential to downregulate multiple cellular targets, which are involved in immune activation, cytokine signaling and apoptosis. In addition, viruses and bacteria have also been linked to the induction of host cellular miRs, which have the capacity to mitigate immune activation, cytokine signaling and apoptosis. Interfering with miR expression may be clinically relevant. In the case of hepatitis C infection, the cellular miR-122 is already targeted therapeutically. This not only exemplifies how important miRs can be for the survival of specific viruses, but it also delineates the potential to use miRs as drug targets. In this paper we will review the latest reports on viruses and bacteria that abuse miR regulation for their benefit, which may be of interest in the development of miR-directed therapies. Full article

(This article belongs to the Special Issue MicroRNA in Various Disease States as Biomarkers)

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10 pages, 208 KiB

Open AccessReview

Infectious Discitis and Spondylodiscitis in Children

by Nicola Principi and Susanna Esposito^*

Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

Int. J. Mol. Sci. 2016, 17(4), 539; https://doi.org/10.3390/ijms17040539 - 9 Apr 2016

Cited by 76 | Viewed by 11878

Abstract

In children, infectious discitis (D) and infectious spondylodiscitis (SD) are rare diseases that can cause significant clinical problems, including spinal deformities and segmental instabilities. Moreover, when the infection spreads into the spinal channel, D and SD can cause devastating neurologic complications. Early diagnosis [...] Read more.

In children, infectious discitis (D) and infectious spondylodiscitis (SD) are rare diseases that can cause significant clinical problems, including spinal deformities and segmental instabilities. Moreover, when the infection spreads into the spinal channel, D and SD can cause devastating neurologic complications. Early diagnosis and treatment may reduce these risks. The main aim of this paper is to discuss recent concepts regarding the epidemiology, microbiology, clinical presentation, diagnosis, and treatment of pediatric D and SD. It is highlighted that particular attention must be paid to the identification of the causative infectious agent and its sensitivity to antibiotics, remembering that traditional culture frequently leads to negative results and modern molecular methods can significantly increase the detection rate. Several different bacterial pathogens can cause D and SD, and, in some cases, particularly those due to Staphylococcus aureus, Kingella kingae, Mycobacterium tuberculosis, Brucella spp., the appropriate choice of drug is critical to achieve cure. Full article

(This article belongs to the Special Issue Infectious Diseases: Pathophysiology, Diagnostics, Therapies, and Prevention)

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14 pages, 232 KiB

Open AccessReview

Fidelity in Animal Modeling: Prerequisite for a Mechanistic Research Front Relevant to the Inflammatory Incompetence of Acute Pediatric Malnutrition

by Bill Woodward

Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada

Int. J. Mol. Sci. 2016, 17(4), 541; https://doi.org/10.3390/ijms17040541 - 11 Apr 2016

Cited by 3 | Viewed by 7100

Abstract

Inflammatory incompetence is characteristic of acute pediatric protein-energy malnutrition, but its underlying mechanisms remain obscure. Perhaps substantially because the research front lacks the driving force of a scholarly unifying hypothesis, it is adrift and research activity is declining. A body of animal-based research [...] Read more.

Inflammatory incompetence is characteristic of acute pediatric protein-energy malnutrition, but its underlying mechanisms remain obscure. Perhaps substantially because the research front lacks the driving force of a scholarly unifying hypothesis, it is adrift and research activity is declining. A body of animal-based research points to a unifying paradigm, the Tolerance Model, with some potential to offer coherence and a mechanistic impetus to the field. However, reasonable skepticism prevails regarding the relevance of animal models of acute pediatric malnutrition; consequently, the fundamental contributions of the animal-based component of this research front are largely overlooked. Design-related modifications to improve the relevance of animal modeling in this research front include, most notably, prioritizing essential features of pediatric malnutrition pathology rather than dietary minutiae specific to infants and children, selecting windows of experimental animal development that correspond to targeted stages of pediatric immunological ontogeny, and controlling for ontogeny-related confounders. In addition, important opportunities are presented by newer tools including the immunologically humanized mouse and outbred stocks exhibiting a magnitude of genetic heterogeneity comparable to that of human populations. Sound animal modeling is within our grasp to stimulate and support a mechanistic research front relevant to the immunological problems that accompany acute pediatric malnutrition. Full article

(This article belongs to the Collection Feature Annual Reviews in Molecular Sciences)

9 pages, 402 KiB

Open AccessReview

Campylobacter jejuni Fatal Sepsis in a Patient with Non-Hodgkin’s Lymphoma: Case Report and Literature Review of a Difficult Diagnosis

by Maria Teresa Gallo^1,†, Enea Gino Di Domenico^1,*,†

, Luigi Toma²

, Francesco Marchesi³, Lorella Pelagalli⁴, Nicola Manghisi¹, Fiorentina Ascenzioni⁵, Grazia Prignano¹, Andrea Mengarelli³ and Fabrizio Ensoli¹

¹ Department of Clinical Pathology and Microbiology, San Gallicano Institute, IRCCS, Rome 00144, Italy

² Department of Infectious Disease, San Gallicano Institute, IRCCS, Rome 00144, Italy

³ Department of Hematology, Regina Elena National Cancer Institute IRCCS, Rome 00144, Italy

⁴ Intensive Care Medicine, Regina Elena National Cancer Institute IRCCS, Rome 00144, Italy

⁵ Department of Biology and Biotechnology “Charles Darwin”, University of Rome Sapienza, Rome 00185, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 544; https://doi.org/10.3390/ijms17040544 - 12 Apr 2016

Cited by 11 | Viewed by 6728

Abstract

Campylobacter jejuni (C. jejuni) bacteremia is difficult to diagnose in individuals with hematological disorders undergoing chemotherapy. The cause can be attributed to the rarity of this infection, to the variable clinical presentation, and to the partial overlapping symptoms underlying the disease. [...] Read more.

Campylobacter jejuni (C. jejuni) bacteremia is difficult to diagnose in individuals with hematological disorders undergoing chemotherapy. The cause can be attributed to the rarity of this infection, to the variable clinical presentation, and to the partial overlapping symptoms underlying the disease. Here, we report a case of a fatal sepsis caused by C. jejuni in a 76-year-old Caucasian man with non-Hodgkin’s lymphoma. After chemotherapeutic treatment, the patient experienced fever associated with severe neutropenia and thrombocytopenia without hemodynamic instability, abdominal pain, and diarrhea. The slow growth of C. jejuni in the blood culture systems and the difficulty in identifying it with conventional biochemical phenotyping methods contributed to the delay of administering a targeted antimicrobial treatment, leading to a fatal outcome. Early recognition and timely intervention are critical for the successful management of C. jejuni infection. Symptoms may be difficult to recognize in immunocompromised patients undergoing chemotherapy. Thus, it is important to increase physician awareness regarding the clinical manifestations of C. jejuni to improve therapeutic efficacy. Moreover, the use of more aggressive empirical antimicrobial treatments with aminoglycosides and/or carbapenems should be considered in immunosuppressed patients, in comparison to those currently indicated in the guidelines for cancer-related infections supporting the use of cephalosporins as monotherapy. Full article

(This article belongs to the Special Issue Infectious Diseases: Pathophysiology, Diagnostics, Therapies, and Prevention)

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15 pages, 605 KiB

Open AccessReview

Role of Serum Uric Acid and Ferritin in the Development and Progression of NAFLD

by Rosa Lombardi, Giuseppina Pisano and Silvia Fargion^*

Department of Pathophysiology and Transplantation, IRCCS “Ca’ Granda” IRCCS Foundation, Poiliclinico Hospital, University of Milan, Centro delle Malattie Metaboliche del Fegato, Milan 20122, Italy

Int. J. Mol. Sci. 2016, 17(4), 548; https://doi.org/10.3390/ijms17040548 - 12 Apr 2016

Cited by 82 | Viewed by 11302

Abstract

Nonalcoholic fatty liver disease (NAFLD), tightly linked to the metabolic syndrome (MS), has emerged as a leading cause of chronic liver disease worldwide. Since it is potentially progressive towards non-alcoholic steatohepatitis (NASH) and hepatic fibrosis, up to cirrhosis and its associated complications, the [...] Read more.

Nonalcoholic fatty liver disease (NAFLD), tightly linked to the metabolic syndrome (MS), has emerged as a leading cause of chronic liver disease worldwide. Since it is potentially progressive towards non-alcoholic steatohepatitis (NASH) and hepatic fibrosis, up to cirrhosis and its associated complications, the need for predictive factors of NAFLD and of its advanced forms is mandatory. Despite the current “gold standard” for the assessment of liver damage in NAFLD being liver biopsy, in recent years, several non-invasive tools have been designed as alternatives to histology, of which fibroscan seems the most promising. Among the different serum markers considered, serum uric acid (SUA) and ferritin have emerged as possible predictors of severity of liver damage in NAFLD. In fact, as widely described in this review, they share common pathogenetic pathways and are both associated with hepatic steatosis and MS, thus suggesting a likely synergistic action. Nevertheless, the power of these serum markers seems to be too low if considered alone, suggesting that they should be included in a wider perspective together with other metabolic and biochemical parameters in order to predict liver damage. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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20 pages, 636 KiB

Open AccessReview

Is There Room for Second-Generation Antipsychotics in the Pharmacotherapy of Panic Disorder? A Systematic Review Based on PRISMA Guidelines

by Giampaolo Perna^1,2,3,*, Alciati Alessandra¹, Balletta Raffaele¹, Mingotto Elisa¹, Diaferia Giuseppina¹, Cavedini Paolo¹, Nobile Maria^1,4 and Caldirola Daniela¹

¹ Department of Clinical Neurosciences, Hermanas Hospitalarias, Villa San Benedetto Menni Hospital, FoRiPsi, via Roma 16, Albese con Cassano, 22032 Como, Italy

² Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 Maastricht, The Netherlands

³ Department of Psychiatry and Behavioral Sciences, Leonard Miller School of Medicine, Miami University, Miami, FL 33136, USA

⁴ Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, 23842 Lecco, Italy

Int. J. Mol. Sci. 2016, 17(4), 551; https://doi.org/10.3390/ijms17040551 - 13 Apr 2016

Cited by 12 | Viewed by 7378

Abstract

A role for second-generation antipsychotics (SGAs) in the treatment of panic disorders (PD) has been proposed, but the actual usefulness of SGAs in this disorder is unclear. According to the PRISMA guidelines, we undertook an updated systematic review of all of the studies [...] Read more.

A role for second-generation antipsychotics (SGAs) in the treatment of panic disorders (PD) has been proposed, but the actual usefulness of SGAs in this disorder is unclear. According to the PRISMA guidelines, we undertook an updated systematic review of all of the studies that have examined, in randomized controlled trials, the efficacy and tolerability of SGAs (as either monotherapy or augmentation) in the treatment of PD, with or without other comorbid psychiatric disorders. Studies until 31 December 2015 were identified through PubMed, PsycINFO, Embase, Cochrane Library and Clinical trials.gov. Among 210 studies, five were included (two involving patients with a principal diagnosis of PD and three involving patients with bipolar disorder with comorbid PD or generalized anxiety disorder). All were eight-week trials and involved treatments with quetiapine extended release, risperidone and ziprasidone. Overall, a general lack of efficacy of SGAs on panic symptoms was observed. Some preliminary indications of the antipanic effectiveness of risperidone are insufficient to support its use in PD, primarily due to major limitations of the study. However, several methodological limitations may have negatively affected all of these studies, decreasing the validity of the results and making it difficult to draw reliable conclusions. Except for ziprasidone, SGAs were well tolerated in these short-term trials. Full article

(This article belongs to the Special Issue Antipsychotics)

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25 pages, 8057 KiB

Open AccessReview

Beyond the Niche: Myelodysplastic Syndrome Topobiology in the Laboratory and in the Clinic

by Eugenia Flores-Figueroa^1,*

and Dita Gratzinger^2,*

¹ Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Avenida Cuauhtémoc 330, Colonia Doctores, c.p. 06720 Mexico City, Mexico

² Department of Pathology, Stanford University School of Medicine 300 Pasteur Dr., L235, Stanford, CA 94305, USA

Int. J. Mol. Sci. 2016, 17(4), 553; https://doi.org/10.3390/ijms17040553 - 13 Apr 2016

Cited by 10 | Viewed by 8143

Abstract

We review the murine and human microenvironment and hematopoietic stem cell niche in the context of intact bone marrow architecture in man and mouse, both in normal and in myelodysplastic syndrome marrow. We propose that the complexity of the hematopoietic stem cell niche [...] Read more.

We review the murine and human microenvironment and hematopoietic stem cell niche in the context of intact bone marrow architecture in man and mouse, both in normal and in myelodysplastic syndrome marrow. We propose that the complexity of the hematopoietic stem cell niche can usefully be approached in the context of its topobiology, and we provide a model that incorporates in vitro and in vivo models as well as in situ findings from intact human marrow to explain the changes seen in myelodysplastic syndrome patients. We highlight the clinical application of the study of the bone marrow microenvironment and its topobiology in myelodysplastic syndromes. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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12 pages, 793 KiB

Open AccessReview

RNase 7 in Cutaneous Defense

by Franziska Rademacher^†, Maren Simanski^† and Jürgen Harder^*

¹ Department of Dermatology, University of Kiel, 24105 Kiel, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 560; https://doi.org/10.3390/ijms17040560 - 14 Apr 2016

Cited by 34 | Viewed by 7085

Abstract

RNase 7 belongs to the RNase A superfamily and exhibits a broad spectrum of antimicrobial activity against various microorganisms. RNase 7 is expressed in human skin, and expression in keratinocytes can be induced by cytokines and microbes. These properties suggest that RNase 7 [...] Read more.

RNase 7 belongs to the RNase A superfamily and exhibits a broad spectrum of antimicrobial activity against various microorganisms. RNase 7 is expressed in human skin, and expression in keratinocytes can be induced by cytokines and microbes. These properties suggest that RNase 7 participates in innate cutaneous defense. In this review, we provide an overview about the role of RNase 7 in cutaneous defense with focus on the molecular mechanism of the antimicrobial activity of RNase 7, the regulation of RNase 7 expression, and the role of RNase 7 in skin diseases. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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22 pages, 3579 KiB

Open AccessReview

Linkers Having a Crucial Role in Antibody–Drug Conjugates

by Jun Lu^1,2,†, Feng Jiang^1,2,3,†, Aiping Lu^1,2,* and Ge Zhang^1,2,*

¹ Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China

² Institute of Integrated Bioinfomedicine & Translational Science, Hong Kong Baptist University Shenzhen Research Institute and Continuing Education, Shenzhen 518000, China

³ Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology, Haimen 226100, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 561; https://doi.org/10.3390/ijms17040561 - 14 Apr 2016

Cited by 233 | Viewed by 21769

Abstract

Antibody–drug conjugates (ADCs) comprised of a desirable monoclonal antibody, an active cytotoxic drug and an appropriate linker are considered to be an innovative therapeutic approach for targeted treatment of various types of tumors and cancers, enhancing the therapeutic parameter of the cytotoxic drug [...] Read more.

Antibody–drug conjugates (ADCs) comprised of a desirable monoclonal antibody, an active cytotoxic drug and an appropriate linker are considered to be an innovative therapeutic approach for targeted treatment of various types of tumors and cancers, enhancing the therapeutic parameter of the cytotoxic drug and reducing the possibility of systemic cytotoxicity. An appropriate linker between the antibody and the cytotoxic drug provides a specific bridge, and thus helps the antibody to selectively deliver the cytotoxic drug to tumor cells and accurately releases the cytotoxic drug at tumor sites. In addition to conjugation, the linkers maintain ADCs’ stability during the preparation and storage stages of the ADCs and during the systemic circulation period. The design of linkers for ADCs is a challenge in terms of extracellular stability and intracellular release, and intracellular circumstances, such as the acid environment, the reducing environment and cathepsin, are considered as the catalysts to activate the triggers for initiating the cleavage of ADCs. This review discusses the linkers used in the clinical and marketing stages for ADCs and details the fracture modes of the linkers for the further development of ADCs. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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15 pages, 510 KiB

Open AccessReview

NAFLD and Chronic Kidney Disease

by Morgan Marcuccilli^1,* and Michel Chonchol^2,*

¹ Division of Renal Diseases and Hypertension, University of Colorado Hospital, Aurora, CO 80045, USA

² Division of Renal Diseases and Hypertension, University of Colorado Denver, 13199 East Montview Boulevard, Suite 495, Aurora, CO 80045, USA

Int. J. Mol. Sci. 2016, 17(4), 562; https://doi.org/10.3390/ijms17040562 - 14 Apr 2016

Cited by 160 | Viewed by 21505

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries and it is now considered a risk factor for cardiovascular disease. Evidence linking NAFLD to the development and progression of chronic kidney disease (CKD) is emerging [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries and it is now considered a risk factor for cardiovascular disease. Evidence linking NAFLD to the development and progression of chronic kidney disease (CKD) is emerging as a popular area of scientific interest. The rise in simultaneous liver-kidney transplantation as well as the significant cost associated with the presence of chronic kidney disease in the NAFLD population make this entity a worthwhile target for screening and therapeutic intervention. While several cross-sectional and case control studies have been published to substantiate these theories, very little data exists on the underlying cause of NAFLD and CKD. In this review, we will discuss the most recent publications on the diagnosis of NAFLD as well new evidence regarding the pathophysiology of NAFLD and CKD as an inflammatory disorder. These mechanisms include the role of obesity, the renin-angiotensin system, and dysregulation of fructose metabolism and lipogenesis in the development of both disorders. Further investigation of these pathways may lead to novel therapies that aim to target the NAFLD and CKD. However, more prospective studies that include information on both renal and liver histology will be necessary in order to understand the relationship between these diseases. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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10 pages, 672 KiB

Open AccessReview

The Role of Galectin-3 in the Kidneys

by Szu-Chia Chen^1,2,3,4

and Po-Lin Kuo^1,5,*

¹ Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

² Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan

³ Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan

⁴ Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

⁵ Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung 804, Taiwan

Int. J. Mol. Sci. 2016, 17(4), 565; https://doi.org/10.3390/ijms17040565 - 14 Apr 2016

Cited by 102 | Viewed by 11223

Abstract

Galectin-3 is a 32- to 35-kDa member of the galectin family of b-galactoside-binding lectins, which is characterized by a carbohydrate recognition domain. Through its carbohydrate-binding function, it regulates cell growth, differentiation, and inflammation. It also plays a complex, context-dependent role in the kidneys. [...] Read more.

Galectin-3 is a 32- to 35-kDa member of the galectin family of b-galactoside-binding lectins, which is characterized by a carbohydrate recognition domain. Through its carbohydrate-binding function, it regulates cell growth, differentiation, and inflammation. It also plays a complex, context-dependent role in the kidneys. During development, it promotes nephrogenesis and is strongly expressed in the ureteric bud and its derivatives. An increase in the concentration of galectin-3 has been reported to be associated with fibrosis of the kidneys. Elevated levels of plasma galectin-3 are also associated with increased risks of rapid renal function decline, incident chronic kidney disease, and progressive renal impairment, and also with cardiovascular end points, infection, and all-cause mortality in patients with renal function impairment. This review discusses a general survey on galectin-3 expressions in nephrogenesis, kidney injury animal models, clinical renal diseases, renal transplantation and the potential role of galectin-3 for treatment in kidney disease. Full article

(This article belongs to the Special Issue Glycan–Receptor Interaction)

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32 pages, 6236 KiB

Open AccessReview

Molecular Mechanisms of the Anti-Obesity and Anti-Diabetic Properties of Flavonoids

by Mohammed Kawser Hossain, Ahmed Abdal Dayem

, Jihae Han, Yingfu Yin

, Kyeongseok Kim, Subbroto Kumar Saha

, Gwang-Mo Yang, Hye Yeon Choi and Ssang-Goo Cho^*

Department of Animal Biotechnology, Animal Resources Research Center, Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Gwangjin-gu, Seoul 05029, Korea

Int. J. Mol. Sci. 2016, 17(4), 569; https://doi.org/10.3390/ijms17040569 - 15 Apr 2016

Cited by 391 | Viewed by 28714

Abstract

Obesity and diabetes are the most prevailing health concerns worldwide and their incidence is increasing at a high rate, resulting in enormous social costs. Obesity is a complex disease commonly accompanied by insulin resistance and increases in oxidative stress and inflammatory marker expression, [...] Read more.

Obesity and diabetes are the most prevailing health concerns worldwide and their incidence is increasing at a high rate, resulting in enormous social costs. Obesity is a complex disease commonly accompanied by insulin resistance and increases in oxidative stress and inflammatory marker expression, leading to augmented fat mass in the body. Diabetes mellitus (DM) is a metabolic disorder characterized by the destruction of pancreatic β cells or diminished insulin secretion and action insulin. Obesity causes the development of metabolic disorders such as DM, hypertension, cardiovascular diseases, and inflammation-based pathologies. Flavonoids are the secondary metabolites of plants and have 15-carbon skeleton structures containing two phenyl rings and a heterocyclic ring. More than 5000 naturally occurring flavonoids have been reported from various plants and have been found to possess many beneficial effects with advantages over chemical treatments. A number of studies have demonstrated the potential health benefits of natural flavonoids in treating obesity and DM, and show increased bioavailability and action on multiple molecular targets. This review summarizes the current progress in our understanding of the anti-obesity and anti-diabetic potential of natural flavonoids and their molecular mechanisms for preventing and/or treating obesity and diabetes. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

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26 pages, 283 KiB

Open AccessReview

In Search of New Therapeutic Targets in Obesity Treatment: Sirtuins

by Alina Kurylowicz

Department of Human Epigenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland

Int. J. Mol. Sci. 2016, 17(4), 572; https://doi.org/10.3390/ijms17040572 - 19 Apr 2016

Cited by 43 | Viewed by 7887

Abstract

Most of the available non-invasive medical therapies for obesity are non-efficient in a long-term evaluation; therefore there is a constant need for new methods of treatment. Research on calorie restriction has led to the discovery of sirtuins (silent information regulators, SIRTs), enzymes regulating [...] Read more.

Most of the available non-invasive medical therapies for obesity are non-efficient in a long-term evaluation; therefore there is a constant need for new methods of treatment. Research on calorie restriction has led to the discovery of sirtuins (silent information regulators, SIRTs), enzymes regulating different cellular pathways that may constitute potential targets in the treatment of obesity. This review paper presents the role of SIRTs in the regulation of glucose and lipid metabolism as well as in the differentiation of adipocytes. How disturbances of SIRTs’ expression and activity may lead to the development of obesity and related complications is discussed. A special emphasis is placed on polymorphisms in genes encoding SIRTs and their possible association with susceptibility to obesity and metabolic complications, as well as on data regarding altered expression of SIRTs in human obesity. Finally, the therapeutic potential of SIRTs-targeted strategies in the treatment of obesity and related disorders is discussed. Full article

(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)

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17 pages, 705 KiB

Open AccessReview

Current Insights into Long Non-Coding RNAs in Renal Cell Carcinoma

by Maximilian Seles¹, Georg C. Hutterer^1,*, Tobias Kiesslich^2,3, Karl Pummer¹, Ioana Berindan-Neagoe^4,5,6

, Samantha Perakis⁷, Daniela Schwarzenbacher⁸, Michael Stotz⁸, Armin Gerger^8,9 and Martin Pichler^4,8

¹ Department of Urology, Medical University of Graz, A-8036 Graz, Austria

² Department of Internal Medicine I, Salzburger Landeskliniken (SALK), Paracelsus Medical University, A-5020 Salzburg, Austria

³ Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, A-5020 Salzburg, Austria

⁴ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA

⁵ Research Center of Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania

⁶ Department of Experimental Pathology, The Oncology Institute Ion Chiricuta, 400015 Cluj-Napoca, Romania

⁷ Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria

⁸ Division of Oncology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria

⁹ Center for Biomarker Research in Medicine, Medical University of Graz, A-8036 Graz, Austria

Int. J. Mol. Sci. 2016, 17(4), 573; https://doi.org/10.3390/ijms17040573 - 15 Apr 2016

Cited by 74 | Viewed by 7571

Abstract

Renal cell carcinoma (RCC) represents a deadly disease with rising mortality despite intensive therapeutic efforts. It comprises several subtypes in terms of distinct histopathological features and different clinical presentations. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts in the genome which vary in expression [...] Read more.

Renal cell carcinoma (RCC) represents a deadly disease with rising mortality despite intensive therapeutic efforts. It comprises several subtypes in terms of distinct histopathological features and different clinical presentations. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts in the genome which vary in expression levels and length and perform diverse functions. They are involved in the inititation, evolution and progression of primary cancer, as well as in the development and spread of metastases. Recently, several lncRNAs were described in RCC. This review emphasises the rising importance of lncRNAs in RCC. Moreover, it provides an outlook on their therapeutic potential in the future. Full article

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

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22 pages, 1455 KiB

Open AccessReview

Modulating Composition and Metabolic Activity of the Gut Microbiota in IBD Patients

by Mario Matijašić^1,*, Tomislav Meštrović², Mihaela Perić¹, Hana Čipčić Paljetak¹, Marina Panek¹, Darija Vranešić Bender³, Dina Ljubas Kelečić³, Željko Krznarić^3,4,5

and Donatella Verbanac¹

¹ Center for Translational and Clinical Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia

² Clinical Microbiology and Parasitology Unit, Polyclinic "Dr. Zora Profozić", Bosutska 19, 10000 Zagreb, Croatia

³ Department of Internal Medicine, Division of Clinical Nutrition, Clinical Hospital Centre Zagreb, 10000 Zagreb, Croatia

⁴ Department of Internal Medicine, Division of Gastroenterology and Hepatology, Clinical Hospital Centre Zagreb, 10000 Zagreb, Croatia

⁵ Department of Internal Medicine, University of Zagreb School of Medicine, 10000 Zagreb, Croatia

Int. J. Mol. Sci. 2016, 17(4), 578; https://doi.org/10.3390/ijms17040578 - 19 Apr 2016

Cited by 66 | Viewed by 11003

Abstract

The healthy intestine represents a remarkable interface where sterile host tissues come in contact with gut microbiota, in a balanced state of homeostasis. The imbalance of gut homeostasis is associated with the onset of many severe pathological conditions, such as inflammatory bowel disease [...] Read more.

The healthy intestine represents a remarkable interface where sterile host tissues come in contact with gut microbiota, in a balanced state of homeostasis. The imbalance of gut homeostasis is associated with the onset of many severe pathological conditions, such as inflammatory bowel disease (IBD), a chronic gastrointestinal disorder increasing in incidence and severely influencing affected individuals. Despite the recent development of next generation sequencing and bioinformatics, the current scientific knowledge of specific triggers and diagnostic markers to improve interventional approaches in IBD is still scarce. In this review we present and discuss currently available and emerging therapeutic options in modulating composition and metabolic activity of gut microbiota in patients affected by IBD. Therapeutic approaches at the microbiota level, such as dietary interventions alone or with probiotics, prebiotics and synbiotics, administration of antibiotics, performing fecal microbiota transplantation (FMT) and the use of nematodes, all represent a promising opportunities towards establishing and maintaining of well-being as well as improving underlying IBD symptoms. Full article

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

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30 pages, 1941 KiB

Open AccessReview

Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

by Flaminia Pantano^1,†, Roberta Tittarelli^1,†, Giulio Mannocchi¹, Simona Zaami¹, Serafino Ricci¹, Raffaele Giorgetti², Daniela Terranova¹, Francesco P. Busardò^1,* and Enrico Marinelli¹

¹ Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy

² Section of Legal Medicine, Università Politecnica delle Marche, 60121 Ancona, Italy

^† Authors contributed equally to the manuscript.

Int. J. Mol. Sci. 2016, 17(4), 580; https://doi.org/10.3390/ijms17040580 - 16 Apr 2016

Cited by 80 | Viewed by 22799

Abstract

The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, [...] Read more.

The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

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19 pages, 519 KiB

Open AccessReview

Proteomic and Microscopic Strategies towards the Analysis of the Cytoskeletal Networks in Major Neuropsychiatric Disorders

by Joëlle V. F. Coumans^1,*, Suresh K. A. Palanisamy², Jim McFarlane²

and Pierre D. J. Moens²

¹ School of Rural Medicine, University of New England, Armidale, NSW 2351, Australia

² Center for Bioactive Discovery in Health and Aging, School of Science and Technology, University of New England, Armidale, NSW 2351, Australia

Int. J. Mol. Sci. 2016, 17(4), 581; https://doi.org/10.3390/ijms17040581 - 20 Apr 2016

Cited by 8 | Viewed by 9772

Abstract

Mental health disorders have become worldwide health priorities. It is estimated that in the next 20 years they will account for a 16 trillion United State dollars (US$) loss. Up to now, the underlying pathophysiology of psychiatric disorders remains elusive. Altered cytoskeleton proteins [...] Read more.

Mental health disorders have become worldwide health priorities. It is estimated that in the next 20 years they will account for a 16 trillion United State dollars (US$) loss. Up to now, the underlying pathophysiology of psychiatric disorders remains elusive. Altered cytoskeleton proteins expression that may influence the assembly, organization and maintenance of cytoskeletal integrity has been reported in major depressive disorders, schizophrenia and to some extent bipolar disorders. The use of quantitative proteomics, dynamic microscopy and super-resolution microscopy to investigate disease-specific protein signatures holds great promise to improve our understanding of these disorders. In this review, we present the currently available quantitative proteomic approaches use in neurology, gel-based, stable isotope-labelling and label-free methodologies and evaluate their strengths and limitations. We also reported on enrichment/subfractionation methods that target the cytoskeleton associated proteins and discuss the need of alternative methods for further characterization of the neurocytoskeletal proteome. Finally, we present live cell imaging approaches and emerging dynamic microscopy technology that will provide the tools necessary to investigate protein interactions and their dynamics in the whole cells. While these areas of research are still in their infancy, they offer huge potential towards the understanding of the neuronal network stability and its modification across neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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11 pages, 993 KiB

Open AccessReview

The Development of Sugar-Based Anti-Melanogenic Agents

by Bum-Ho Bin¹

, Sung Tae Kim¹, Jinhyuk Bhin², Tae Ryong Lee^1,* and Eun-Gyung Cho^1,*

¹ AmorePacific Corporation Research & Deveolopment Center, Yongin, Gyeonggi-do 446-729, Korea

² Department of Chemical Engineering, POSTECH, Pohang 790-784, Korea

Int. J. Mol. Sci. 2016, 17(4), 583; https://doi.org/10.3390/ijms17040583 - 16 Apr 2016

Cited by 28 | Viewed by 8467

Abstract

The regulation of melanin production is important for managing skin darkness and hyperpigmentary disorders. Numerous anti-melanogenic agents that target tyrosinase activity/stability, melanosome maturation/transfer, or melanogenesis-related signaling pathways have been developed. As a rate-limiting enzyme in melanogenesis, tyrosinase has been the most attractive target, [...] Read more.

The regulation of melanin production is important for managing skin darkness and hyperpigmentary disorders. Numerous anti-melanogenic agents that target tyrosinase activity/stability, melanosome maturation/transfer, or melanogenesis-related signaling pathways have been developed. As a rate-limiting enzyme in melanogenesis, tyrosinase has been the most attractive target, but tyrosinase-targeted treatments still pose serious potential risks, indicating the necessity of developing lower-risk anti-melanogenic agents. Sugars are ubiquitous natural compounds found in humans and other organisms. Here, we review the recent advances in research on the roles of sugars and sugar-related agents in melanogenesis and in the development of sugar-based anti-melanogenic agents. The proposed mechanisms of action of these agents include: (a) (natural sugars) disturbing proper melanosome maturation by inducing osmotic stress and inhibiting the PI3 kinase pathway and (b) (sugar derivatives) inhibiting tyrosinase maturation by blocking N-glycosylation. Finally, we propose an alternative strategy for developing anti-melanogenic sugars that theoretically reduce melanosomal pH by inhibiting a sucrose transporter and reduce tyrosinase activity by inhibiting copper incorporation into an active site. These studies provide evidence of the utility of sugar-based anti-melanogenic agents in managing skin darkness and curing pigmentary disorders and suggest a future direction for the development of physiologically favorable anti-melanogenic agents. Full article

(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)

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20 pages, 1617 KiB

Open AccessReview

Phytochemical and Pharmacological Profiles of Three Fagopyrum Buckwheats

by Rui Jing^1,†, Hua-Qiang Li^1,†, Chang-Ling Hu², Yi-Ping Jiang¹, Lu-Ping Qin¹ and Cheng-Jian Zheng^1,*

¹ Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

² Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 589; https://doi.org/10.3390/ijms17040589 - 19 Apr 2016

Cited by 106 | Viewed by 10676

Abstract

The genus Fagopyrum (Polygonaceae), currently comprising 15 species of plants, includes three important buckwheat species: Fagopyrum esculentum (F. esculentum) Moench. (common buckwheat), Fagopyrum tataricum (F. tataricum) (L.) Gaertn. (tartary buckwheat) and Fagopyrum dibotrys (F. dibotrys) (D. Don) [...] Read more.

The genus Fagopyrum (Polygonaceae), currently comprising 15 species of plants, includes three important buckwheat species: Fagopyrum esculentum (F. esculentum) Moench. (common buckwheat), Fagopyrum tataricum (F. tataricum) (L.) Gaertn. (tartary buckwheat) and Fagopyrum dibotrys (F. dibotrys) (D. Don) Hara. (perennial buckwheat), which have been well explored due to their long tradition of both edible and medicinal use. This review aimed to present an up-to-date and comprehensive analysis of the phytochemistry and pharmacology of the three Fagopyrum buckwheats. In addition, the scope for future research was also discussed. All available references included in this paper were compiled from major databases, such as MEDLINE, Pubmed, Scholar, Elsevier, Springer, Wiley and CNKI. A total of 106 compounds isolated from three Fagopyrum buckwheats can be mainly divided into six classes: flavonoids, phenolics, fagopyritols, triterpenoids, steroids and fatty acids. Flavonoids and phenolic compounds were considered to be the major active components. Considerable pharmacological experiments both in vitro and in vivo have validated that Fagopyrum buckwheats possess antitumor, anti-oxidant, anti-inflammatory, hepatoprotective, anti-diabetic activities, etc. All reported data lead us to conclude that Fagopyrum buckwheats have convincing medicinal potential. However, further research is needed to explore its bioactive constituents, the relationship to their structural activities and the molecular mechanisms of action. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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10 pages, 685 KiB

Open AccessReview

Matrilin-3 Role in Cartilage Development and Osteoarthritis

by Manjunatha S. Muttigi^1,2

, Inbo Han³

, Hun-Kuk Park⁴, Hansoo Park^1,* and Soo-Hong Lee^2,*

¹ School of Integrative Engineering, Chung-Ang University, Seoul 06911, Korea

² Department of Biomedical Science, CHA University, Seongnam-Si 13488, Korea

³ Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Korea

⁴ Department of Biomedical Engineering, Collage of Medicine, Kyung Hee University, Seoul 02447, Korea

Int. J. Mol. Sci. 2016, 17(4), 590; https://doi.org/10.3390/ijms17040590 - 20 Apr 2016

Cited by 33 | Viewed by 7788

Abstract

The extracellular matrix (ECM) of cartilage performs essential functions in differentiation and chondroprogenitor cell maintenance during development and regeneration. Here, we discuss the vital role of matrilin-3, an ECM protein involved in cartilage development and potential osteoarthritis pathomechanisms. As an adaptor protein, matrilin-3 [...] Read more.

The extracellular matrix (ECM) of cartilage performs essential functions in differentiation and chondroprogenitor cell maintenance during development and regeneration. Here, we discuss the vital role of matrilin-3, an ECM protein involved in cartilage development and potential osteoarthritis pathomechanisms. As an adaptor protein, matrilin-3 binds to collagen IX to form a filamentous network around cells. Matrilin-3 is an essential component during cartilage development and ossification. In addition, it interacts directly or indirectly with transforming growth factor β (TGF-β), and bone morphogenetic protein 2 (BMP2) eventually regulates chondrocyte proliferation and hypertrophic differentiation. Interestingly, matrilin-3 increases interleukin receptor antagonists (IL-Ra) in chondrocytes, suggesting its role in the suppression of IL-1β-mediated inflammatory action. Matrilin-3 downregulates the expression of matrix-degrading enzymes, such as a disintegrin metalloproteinase with thrombospondin motifs 4 (ADAMTS4) and ADAMTS5, matrix metalloproteinase 13 (MMP13), and collagen X, a hypertrophy marker during development and inflammatory conditions. Matrilin-3 essentially enhances collagen II and aggrecan expression, which are required to maintain the tensile strength and elasticity of cartilage, respectively. Interestingly, despite these attributes, matrilin-3 induces osteoarthritis-associated markers in chondrocytes in a concentration-dependent manner. Existing data provide insights into the critical role of matrilin-3 in inflammation, matrix degradation, and matrix formation in cartilage development and osteoarthritis. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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12 pages, 1427 KiB

Open AccessReview

Soluble Epidermal Growth Factor Receptors (sEGFRs) in Cancer: Biological Aspects and Clinical Relevance

by Sally Maramotti^1,*, Massimiliano Paci², Gloria Manzotti¹

, Cristian Rapicetta², Mila Gugnoni¹, Carla Galeone², Alfredo Cesario³ and Filippo Lococo^2,*

¹ Laboratory of Translational Research, Research and Statistic Infrastructure, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia 42123, Italy

² Thoracic Surgery Unit, Department of Cardiology, Thoracic and Vascular Surgery, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia 42123, Italy

³ Head, Systems Medicine, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia 42123, Italy

Int. J. Mol. Sci. 2016, 17(4), 593; https://doi.org/10.3390/ijms17040593 - 19 Apr 2016

Cited by 39 | Viewed by 8562

Abstract

The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, [...] Read more.

The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, accordingly, may be useful in establishing the potential risk of cancer, defining differential diagnosis and prognosis, predicting the response to treatment, and monitoring the disease progression. The existence of circulating soluble growth factor receptors (sGFRs) deriving from their membrane counterparts has stimulated the interest of researchers to investigate the use of such molecules as potential cancer biomarkers. But what are the origins of circulating sGFRs? Are they naturally occurring molecules or tumor-derived products? Among these, the epidermal growth factor receptor (EGFR) is a cell-surface molecule significantly involved in cancer development and progression; it can be processed into biological active soluble isoforms (sEGFR). We have carried out an extensive review of the currently available literature on the sEGFRs and their mechanisms of regulation and biological function, with the intent to clarify the role of these molecules in cancer (and other pathological conditions) and, on the basis of the retrieved evidences, speculate about their potential use in the clinical setting. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment 2016)

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22 pages, 1571 KiB

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Rationale and Methodology of Reprogramming for Generation of Induced Pluripotent Stem Cells and Induced Neural Progenitor Cells

by Zuojun Tian^1,2,3, Fuzheng Guo³, Sangita Biswas^2,3,* and Wenbin Deng^2,3,*

¹ Department of Neurology, the Institute of Guangzhou Respiratory Disease, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China

² Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA

³ Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA

Int. J. Mol. Sci. 2016, 17(4), 594; https://doi.org/10.3390/ijms17040594 - 20 Apr 2016

Cited by 7 | Viewed by 10051

Abstract

Great progress has been made regarding the capabilities to modify somatic cell fate ever since the technology for generation of induced pluripotent stem cells (iPSCs) was discovered in 2006. Later, induced neural progenitor cells (iNPCs) were generated from mouse and human cells, bypassing [...] Read more.

Great progress has been made regarding the capabilities to modify somatic cell fate ever since the technology for generation of induced pluripotent stem cells (iPSCs) was discovered in 2006. Later, induced neural progenitor cells (iNPCs) were generated from mouse and human cells, bypassing some of the concerns and risks of using iPSCs in neuroscience applications. To overcome the limitation of viral vector induced reprogramming, bioactive small molecules (SM) have been explored to enhance the efficiency of reprogramming or even replace transcription factors (TFs), making the reprogrammed cells more amenable to clinical application. The chemical induced reprogramming process is a simple process from a technical perspective, but the choice of SM at each step is vital during the procedure. The mechanisms underlying cell transdifferentiation are still poorly understood, although, several experimental data and insights have indicated the rationale of cell reprogramming. The process begins with the forced expression of specific TFs or activation/inhibition of cell signaling pathways by bioactive chemicals in defined culture condition, which initiates the further reactivation of endogenous gene program and an optimal stoichiometric expression of the endogenous pluri- or multi-potency genes, and finally leads to the birth of reprogrammed cells such as iPSCs and iNPCs. In this review, we first outline the rationale and discuss the methodology of iPSCs and iNPCs in a stepwise manner; and then we also discuss the chemical-based reprogramming of iPSCs and iNPCs. Full article

(This article belongs to the Special Issue Pluripotent Stem Cell Technology for Disease Modeling, Drug Discovery and Regenerative Medicine)

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14 pages, 1009 KiB

Open AccessReview

Amniotic Fluid Stem Cells: A Novel Source for Modeling of Human Genetic Diseases

by Ivana Antonucci^1,2, Martina Provenzano¹, Melissa Rodrigues¹, Andrea Pantalone³, Vincenzo Salini³, Patrizia Ballerini¹, Cesar V. Borlongan⁴ and Liborio Stuppia^1,2,*

¹ Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, G. d’Annunzio University, Chieti-Pescara, Via dei Vestini 31, 66013 Chieti, Italy

² Ce.S.I-Met, G. d’Annunzio University, Chieti-Pescara, Via Colle dell’Ara n.1, 66100 Chieti, Italy

³ Department of Medicine and Aging, G. d’Annunzio University, Chieti-Pescara Via dei Vestini 31, 66013 Chieti, Italy

⁴ Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, FL 33612, USA

Int. J. Mol. Sci. 2016, 17(4), 607; https://doi.org/10.3390/ijms17040607 - 22 Apr 2016

Cited by 18 | Viewed by 9307

Abstract

In recent years, great interest has been devoted to the use of Induced Pluripotent Stem cells (iPS) for modeling of human genetic diseases, due to the possibility of reprogramming somatic cells of affected patients into pluripotent cells, enabling differentiation into several cell types, [...] Read more.

In recent years, great interest has been devoted to the use of Induced Pluripotent Stem cells (iPS) for modeling of human genetic diseases, due to the possibility of reprogramming somatic cells of affected patients into pluripotent cells, enabling differentiation into several cell types, and allowing investigations into the molecular mechanisms of the disease. However, the protocol of iPS generation still suffers from technical limitations, showing low efficiency, being expensive and time consuming. Amniotic Fluid Stem cells (AFS) represent a potential alternative novel source of stem cells for modeling of human genetic diseases. In fact, by means of prenatal diagnosis, a number of fetuses affected by chromosomal or Mendelian diseases can be identified, and the amniotic fluid collected for genetic testing can be used, after diagnosis, for the isolation, culture and differentiation of AFS cells. This can provide a useful stem cell model for the investigation of the molecular basis of the diagnosed disease without the necessity of producing iPS, since AFS cells show some features of pluripotency and are able to differentiate in cells derived from all three germ layers “in vitro”. In this article, we describe the potential benefits provided by using AFS cells in the modeling of human genetic diseases. Full article

(This article belongs to the Special Issue Pluripotent Stem Cell Technology for Disease Modeling, Drug Discovery and Regenerative Medicine)

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1 pages, 147 KiB

Open AccessCorrection

Correction: Li, G., et al. A Novel Ligustrazine Derivative T-VA Prevents Neurotoxicity in Differentiated PC12 Cells and Protects the Brain against Ischemia Injury in MCAO Rats. Int. J. Mol. Sci. 2015, 16, 21759–21774

by Guoliang Li^1,†, Yufei Tian^1,†, Yuzhong Zhang², Ying Hong¹, Yingzhi Hao¹, Chunxiao Chen², Penglong Wang^1,*

and Haimin Lei^1,*

¹ School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China

² Department of Pathology, Beijing University of Chinese Medicine, Beijing 100029, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(4), 468; https://doi.org/10.3390/ijms17040468 - 29 Mar 2016

Viewed by 3638

Abstract

The authors wish to change the first author’s name “Guoling Li” to “Guoliang Li” on the Page of their paper published in the International Journal of Molecular Sciences [1]. [...]
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1 pages, 144 KiB

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Kai, M. Roles of RNA-Binding Proteins in DNA Damage Response. Int. J. Mol. Sci. 2016, 17, 310

by Mihoko Kai

Department of Radiation Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD 21231, USA

Int. J. Mol. Sci. 2016, 17(4), 604; https://doi.org/10.3390/ijms17040604 - 21 Apr 2016

Cited by 41 | Viewed by 4276

Abstract

The author would like to insert the citation after the following sentence, “These RBPs are detected on laser trackswithin one minute after laser irradiation, and are excluded from the laser tracks shortly (within 10–15 min, depending on conditions of laser irradiation) [1]”, in [...] Read more.

The author would like to insert the citation after the following sentence, “These RBPs are detected on laser trackswithin one minute after laser irradiation, and are excluded from the laser tracks shortly (within 10–15 min, depending on conditions of laser irradiation) [1]”, in the paper published in the International Journal of Molecular Sciences [2].[...] Full article

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