International Journal of Molecular Sciences

18 pages, 3056 KiB

Open AccessArticle

Impact of the β-Lactam Resistance Modifier (−)-Epicatechin Gallate on the Non-Random Distribution of Phospholipids across the Cytoplasmic Membrane of Staphylococcus aureus

by Helena Rosado¹, Robert D. Turner², Simon J. Foster² and Peter W. Taylor^1,*

¹ School of Pharmacy, University College London, London WC1N 1AX, UK

² Krebs Institute, University of Sheffield, Western Bank, Sheffield S10 2TN, UK

Int. J. Mol. Sci. 2015, 16(8), 16710-16727; https://doi.org/10.3390/ijms160816710 - 23 Jul 2015

Cited by 16 | Viewed by 7289

Abstract

The polyphenol (−)-epicatechin gallate (ECg) inserts into the cytoplasmic membrane (CM) of methicillin-resistant Staphylococcus aureus (MRSA) and reversibly abrogates resistance to β-lactam antibiotics. ECg elicits an increase in MRSA cell size and induces thickened cell walls. As ECg partially delocalizes penicillin-binding protein PBP2 [...] Read more.

The polyphenol (−)-epicatechin gallate (ECg) inserts into the cytoplasmic membrane (CM) of methicillin-resistant Staphylococcus aureus (MRSA) and reversibly abrogates resistance to β-lactam antibiotics. ECg elicits an increase in MRSA cell size and induces thickened cell walls. As ECg partially delocalizes penicillin-binding protein PBP2 from the septal division site, reduces PBP2 and PBP2a complexation and induces CM remodelling, we examined the impact of ECg membrane intercalation on phospholipid distribution across the CM and determined if ECg affects the equatorial, orthogonal mode of division. The major phospholipids of the staphylococcal CM, lysylphosphatidylglycerol (LPG), phosphatidylglycerol (PG), and cardiolipin (CL), were distributed in highly asymmetric fashion; 95%–97% of LPG was associated with the inner leaflet whereas PG (~90%) and CL (~80%) were found predominantly in the outer leaflet. ECg elicited small, significant changes in LPG distribution. Atomic force microscopy established that ECg-exposed cells divided in similar fashion to control bacteria, with a thickened band of encircling peptidoglycan representing the most recent plane of cell division, less distinct ribs indicative of previous sites of orthogonal division and concentric rings and “knobbles” representing stages of peptidoglycan remodelling during the cell cycle. Preservation of staphylococcal membrane lipid asymmetry and mode of division in sequential orthogonal planes appear key features of ECg-induced stress. Full article

(This article belongs to the Special Issue Phenolics and Polyphenolics 2015)

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12 pages, 1231 KiB

Open AccessArticle

Identification of New Potential Interaction Partners for Human Cytoplasmic Copper Chaperone Atox1: Roles in Gene Regulation?

by Helena Öhrvik¹ and Pernilla Wittung-Stafshede^2,*

¹ Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala 751 23, Sweden

² Department of Chemistry, Umeå University, Umeå 901 87, Sweden

Int. J. Mol. Sci. 2015, 16(8), 16728-16739; https://doi.org/10.3390/ijms160816728 - 23 Jul 2015

Cited by 29 | Viewed by 7691

Abstract

The human copper (Cu) chaperone Atox1 delivers Cu to P_1B type ATPases in the Golgi network, for incorporation into essential Cu-dependent enzymes. Atox1 homologs are found in most organisms; it is a 68-residue ferredoxin-fold protein that binds Cu in a conserved surface-exposed [...] Read more.

The human copper (Cu) chaperone Atox1 delivers Cu to P_1B type ATPases in the Golgi network, for incorporation into essential Cu-dependent enzymes. Atox1 homologs are found in most organisms; it is a 68-residue ferredoxin-fold protein that binds Cu in a conserved surface-exposed Cys-X-X-Cys (CXXC) motif. In addition to its well-documented cytoplasmic chaperone function, in 2008 Atox1 was suggested to have functionality in the nucleus. To identify new interactions partners of Atox1, we performed a yeast two-hybrid screen with a large human placenta library of cDNA fragments using Atox1 as bait. Among 98 million fragments investigated, 25 proteins were found to be confident interaction partners. Nine of these were uncharacterized proteins, and the remaining 16 proteins were analyzed by bioinformatics with respect to cell localization, tissue distribution, function, sequence motifs, three-dimensional structures and interaction networks. Several of the hits were eukaryotic-specific proteins interacting with DNA or RNA implying that Atox1 may act as a modulator of gene regulation. Notably, because many of the identified proteins contain CXXC motifs, similarly to the Cu transport reactions, interactions between these and Atox1 may be mediated by Cu. Full article

(This article belongs to the Special Issue Metalloproteins)

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10 pages, 872 KiB

Open AccessArticle

Diurnal Expression of the Per2 Gene and Protein in the Lateral Habenular Nucleus

by Zhigong Zhao, Haiyan Xu, Yongmao Liu, Li Mu, Jinyu Xiao and Hua Zhao^*

Department of Physiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China

Int. J. Mol. Sci. 2015, 16(8), 16740-16749; https://doi.org/10.3390/ijms160816740 - 23 Jul 2015

Cited by 18 | Viewed by 7170

Abstract

The suprachiasmatic nucleus plays an important role in generating circadian rhythms in mammals. The lateral habenular nucleus (LHb) is closely linked to this structure. Interestingly, the LHb shows a rhythmic firing rate in vivo and in vitro, and sustained oscillation of rhythmic [...] Read more.

The suprachiasmatic nucleus plays an important role in generating circadian rhythms in mammals. The lateral habenular nucleus (LHb) is closely linked to this structure. Interestingly, the LHb shows a rhythmic firing rate in vivo and in vitro, and sustained oscillation of rhythmic genes in vitro. However, under the in vivo condition, whether rhythmic gene expression in the LHb has circadian rhythms remains unknown. In this study, we examined LHb tissue in rats to determine Period2 (Per2) gene and protein expression at six zeitgeber time points (ZT2, ZT6, ZT10, ZT14, ZT18, and ZT22) in a 12-h light and 12-h dark (LD) environment. We found that in the LD environment, Per2 gene expression and PER2 protein levels in the LHb were higher in the day and lower in the night, showing periodic oscillation, with a peak at ZT10 and a trough at ZT22 (Per2 mRNA) and ZT18 (PER2 protein). We conclude that Per2 expression and PER2 protein levels in the LHb have rhythmic oscillation in vivo. This study provides a basis for further study on the role of the LHb in the circadian rhythm system. Full article

(This article belongs to the Special Issue The Pathophysiology of Neuropsychiatric Disorders and New Therapeutic Targets)

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13 pages, 5391 KiB

Open AccessArticle

Characterization of a Type 1 Metallothionein Gene from the Stresses-Tolerant Plant Ziziphus jujuba

by Mingxia Yang^1,2,†, Fan Zhang^3,†, Fan Wang⁴, Zhigang Dong², Qiufen Cao^1,5,* and Mingchang Chen^1,6

¹ The Institute of Loess Plateau, Shanxi University, Taiyuan 030006, China

² Pomology Institute of Shanxi Academy of Agricultural Sciences, Taigu 030815, China

³ Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China

⁴ Jinguo Museum of Shanxi Province, Linfen 043400, China

⁵ Biotechnology Research Center of Shanxi Academy of Agricultural Sciences, Taiyuan 030031, China

⁶ Department of Agriculture Shanxi Province, Taiyuan 030002, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 16750-16762; https://doi.org/10.3390/ijms160816750 - 23 Jul 2015

Cited by 41 | Viewed by 7143

Abstract

Plant metallothioneins (MTs) are a family of low molecular weight, cysteine-rich, and metal-binding proteins, which play an important role in the detoxification of heavy metal ions, osmotic stresses, and hormone treatment. Sequence analysis revealed that the open-reading frame (ORF) of ZjMT was 225 [...] Read more.

Plant metallothioneins (MTs) are a family of low molecular weight, cysteine-rich, and metal-binding proteins, which play an important role in the detoxification of heavy metal ions, osmotic stresses, and hormone treatment. Sequence analysis revealed that the open-reading frame (ORF) of ZjMT was 225 bp, which encodes a protein composed of 75 amino acid residues with a calculated molecular mass of 7.376 kDa and a predicated isoelectric point (pI) of 4.83. ZjMT belongs to the type I MT, which consists of two highly conserved cysteine-rich terminal domains linked by a cysteine free region. Our studies showed that ZjMT was primarily localized in the cytoplasm and the nucleus of cells and ZjMT expression was up-regulated by NaCl, CdCl₂ and polyethylene glycol (PEG) treatments. Constitutive expression of ZjMT in wild type Arabidopsis plants enhanced their tolerance to NaCl stress during the germination stage. Compared with the wild type, transgenic plants accumulate more Cd²⁺ in root, but less in leaf, suggesting that ZjMT may have a function in Cd²⁺ retension in roots and, therefore, decrease the toxicity of Cd²⁺. 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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15 pages, 992 KiB

Open AccessReview

Get to Understand More from Single-Cells: Current Studies of Microfluidic-Based Techniques for Single-Cell Analysis

by Shih-Jie Lo and Da-Jeng Yao^*

Institute of Nanoengineering and Microsystem, National Tsing Hua University, Hsinchu 300, Taiwan

Int. J. Mol. Sci. 2015, 16(8), 16763-16777; https://doi.org/10.3390/ijms160816763 - 23 Jul 2015

Cited by 26 | Viewed by 11474

Abstract

This review describes the microfluidic techniques developed for the analysis of a single cell. The characteristics of microfluidic (e.g., little sample amount required, high-throughput performance) make this tool suitable to answer and to solve biological questions of interest about a single cell. This [...] Read more.

This review describes the microfluidic techniques developed for the analysis of a single cell. The characteristics of microfluidic (e.g., little sample amount required, high-throughput performance) make this tool suitable to answer and to solve biological questions of interest about a single cell. This review aims to introduce microfluidic related techniques for the isolation, trapping and manipulation of a single cell. The major approaches for detection in single-cell analysis are introduced; the applications of single-cell analysis are then summarized. The review concludes with discussions of the future directions and opportunities of microfluidic systems applied in analysis of a single cell. Full article

(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)

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14 pages, 3225 KiB

Open AccessArticle

Effects of the Bradyrhizobium japonicum waaL (rfaL) Gene on Hydrophobicity, Motility, Stress Tolerance, and Symbiotic Relationship with Soybeans

by Jun-Gu Noh^1,†, Han-Eul Jeon^1,†, Jae-Seong So¹ and Woo-Suk Chang^2,3,*

¹ Department of Biological Engineering, Inha University, Incheon 402-751, Korea

² Department of Biology, University of Texas, Arlington, TX 76019, USA

³ Division of Biotechnology, College of Environmental and Bioresource Sciences, Chonbuk National University, Iksan 570-752, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 16778-16791; https://doi.org/10.3390/ijms160816778 - 23 Jul 2015

Cited by 21 | Viewed by 7266

Abstract

We cloned and sequenced the waaL (rfaL) gene from Bradyrhizobium japonicum, which infects soybean and forms nitrogen-fixing nodules on soybean roots. waaL has been extensively studied in the lipopolysaccharide (LPS) biosynthesis of enteric bacteria, but little is known about its [...] Read more.

We cloned and sequenced the waaL (rfaL) gene from Bradyrhizobium japonicum, which infects soybean and forms nitrogen-fixing nodules on soybean roots. waaL has been extensively studied in the lipopolysaccharide (LPS) biosynthesis of enteric bacteria, but little is known about its function in (brady)rhizobial LPS architecture. To characterize its role as O-antigen ligase in the LPS biosynthesis pathway, we constructed a waaL knock-out mutant and its complemented strain named JS015 and CS015, respectively. LPS analysis showed that an LPS structure of JS015 is deficient in O-antigen as compared to that of the wild type and complemented strain CS015, suggesting that WaaL ligates the O-antigen to lipid A-core oligosaccharide to form a complete LPS. JS015 also revealed increased cell surface hydrophobicity, but it showed decreased motility in soft agar plates. In addition to the alteration in cell surface properties, disruption of the waaL gene caused increased sensitivity of JS015 to hydrogen peroxide, osmotic pressure, and novobiocin. Specifically, plant tests revealed that JS015 failed to nodulate the host plant soybean, indicating that the rhizobial waaL gene is responsible for the establishment of a symbiotic relationship between soybean and B. japonicum. Full article

(This article belongs to the Special Issue Plant Microbe Interaction)

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14 pages, 697 KiB

Open AccessArticle

Human Leukocyte Antigen Class II Alleles Are Associated with Hepatitis C Virus Natural Susceptibility in the Chinese Population

by Ming Yue¹, Ke Xu², Meng-Ping Wu³, Ya-Ping Han¹, Peng Huang³, Zhi-Hang Peng³, Jie Wang⁴, Jing Su³, Rong-Bin Yu³, Jun Li^1,* and Yun Zhang^3,5,*

¹ Department of Infectious Diseases, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China

² Department of Acute Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing 210009, China

³ Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China

⁴ School of Nursing, Nanjing Medical University, Nanjing 211166, China

⁵ Institute of Epidemiology and Microbiology, Huadong Research Institute for Medicine and Biotechnics, Nanjing 210002, China

Int. J. Mol. Sci. 2015, 16(8), 16792-16805; https://doi.org/10.3390/ijms160816792 - 23 Jul 2015

Cited by 9 | Viewed by 5289

Abstract

Human leukocyte antigen (HLA) class II molecule influences host antigen presentation and anti-viral immune response. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) within HLA class II gene were associated with different clinical outcomes of hepatitis C virus [...] Read more.

Human leukocyte antigen (HLA) class II molecule influences host antigen presentation and anti-viral immune response. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) within HLA class II gene were associated with different clinical outcomes of hepatitis C virus (HCV) infection. Three HLA class II SNPs (rs3077, rs2395309 and rs2856718) were genotyped by TaqMan assay among Chinese population, including 350 persistent HCV infection patients, 194 spontaneous viral clearance subjects and 973 HCV-uninfected control subjects. After logistic regression analysis, the results indicated that the rs2856718 TC genotype was significantly associated with the protective effect of the HCV natural susceptibility (adjusted OR: 0.712, 95% CI: 0.554–0.914) when compared with reference TT genotype, and this remained significant after false discovery rate (FDR) correction (p = 0.024). Moreover, the protective effect of rs2856718 was observed in dominant genetic models (adjusted OR: 0.726, 95% CI: 0.574–0.920), and this remained significant after FDR correction (p = 0.024). In stratified analysis, a significant decreased risk was found in rs2856718C allele in the male subgroup (adjusted OR: 0.778, 95% CI: 0.627–0.966) and hemodialysis subgroup (adjusted OR: 0.713, 95% CI: 0.552–0.921). Our results indicated that the genetic variations of rs2856718 within the HLA-DQ gene are associated with the natural susceptibility to HCV infection among the Chinese population. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

10 pages, 1196 KiB

Open AccessArticle

Novel Radiolytic Rotenone Derivative, Rotenoisin B with Potent Anti-Carcinogenic Activity in Hepatic Cancer Cells

by Srilatha Badaboina^1,†, Hyoung-Woo Bai^1,†, Yun Hee Na^1,2, Chul-Hong Park^1,3, Tae Hoon Kim⁴, Tae-Hoon Lee^2,5

and Byung Yeoup Chung^1,*

¹ Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185, Korea

² Interdisciplinary Graduate Program in Molecular Medicine, Chonnam National University, Gwangju 501-746, Korea

³ School of Biological Sciences and Biotechnology, Chonnam National University, Gwangju 500-757, Korea

⁴ Department of Food Science and Biotechnology, Daegu University, Gyeongsan-si, 712-714, Korea

⁵ Department of Biochemistry, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 16806-16815; https://doi.org/10.3390/ijms160816806 - 24 Jul 2015

Cited by 22 | Viewed by 6479

Abstract

Rotenone, isolated from roots of derris plant, has been shown to possess various biological activities, which lead to attempting to develop a potent drug against several diseases. However, recent studies have demonstrated that rotenone has the potential to induce several adverse effects such [...] Read more.

Rotenone, isolated from roots of derris plant, has been shown to possess various biological activities, which lead to attempting to develop a potent drug against several diseases. However, recent studies have demonstrated that rotenone has the potential to induce several adverse effects such as a neurodegenerative disease. Radiolytic transformation of the rotenone with gamma-irradiation created a new product, named rotenoisin B. The present work was designed to investigate the anticancer activity of rotenoisin B with low toxicity and its molecular mechanism in hepatic cancer cells compared to a parent compound, rotenone. Our results showed rotenoisin B inhibited hepatic cancer cells’ proliferation in a dose dependent manner and increased in apoptotic cells. Interestingly, rotenoisin B showed low toxic effects on normal cells compared to rotenone. Mitochondrial transmembrane potential has been decreased, which leads to cytochrome c release. Down regulation of anti-apoptotic Bcl-2 levels as well as the up regulation of proapoptotic Bax levels were observed. The cleaved PARP (poly ADP-ribose polymerase) level increased as well. Moreover, phosphorylation of extracellular signal regulated kinase (ERK) and p38 slightly up regulated and intracellular reactive oxygen species (ROS) increased as well as cell cycle arrest predominantly at the G₂/M phase observed. These results suggest that rotenoisin B might be a potent anticancer candidate similar to rotenone in hepatic cancer cells with low toxicity to normal cells even at high concentrations compared to rotenone. Full article

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

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17 pages, 1366 KiB

Open AccessArticle

Differential DNA Methylation in Relation to Age and Health Risks of Obesity

by María Luisa Mansego¹, Fermín I. Milagro¹

, María Ángeles Zulet^1,2

, María J. Moreno-Aliaga^1,2 and José Alfredo Martínez^1,2,*

¹ CIBERobn, Fisiopatología de la Obesidad y la Nutrición, Institute of Health Carlos III, Madrid, Spain and Department of Nutrition, Food Science and Physiology, Nutrition Research Center, University of Navarra, Pamplona 31008, Spain

² Navarra Institute for Health Research (IdiSNA), Pamplona 31008, Spain

Int. J. Mol. Sci. 2015, 16(8), 16816-16832; https://doi.org/10.3390/ijms160816816 - 24 Jul 2015

Cited by 43 | Viewed by 8768

Abstract

The aim of this study was to evaluate whether genome-wide levels of DNA methylation are associated with age and the health risks of obesity (HRO); defined according to BMI categories as “Low HRO” (overweight and class 1 obesity) versus “High HRO” (class 2 [...] Read more.

The aim of this study was to evaluate whether genome-wide levels of DNA methylation are associated with age and the health risks of obesity (HRO); defined according to BMI categories as “Low HRO” (overweight and class 1 obesity) versus “High HRO” (class 2 and class 3 obesity). Anthropometric measurements were assessed in a subsample of 48 volunteers from the Metabolic Syndrome Reduction in Navarra (RESMENA) study and 24 women from another independent study, Effects of Lipoic Acid and Eicosapentaenoic Acid in Human Obesity (OBEPALIP study). In the pooled population; the methylation levels of 55 CpG sites were significantly associated with age after Benjamini-Hochberg correction. In addition, DNA methylation of three CpG sites located in ELOVL2; HOXC4 and PI4KB were further negatively associated with their mRNA levels. Although no differentially methylated CpG sites were identified in relation to HRO after multiple testing correction; several nominally significant CpG sites were identified in genes related to insulin signaling; energy and lipid metabolism. Moreover, statistically significant associations between BMI or mRNA levels and two HRO-related CpG sites located in GPR133 and ITGB5 are reported. As a conclusion, these findings from two Spanish cohorts add knowledge about the important role of DNA methylation in the age-related regulation of gene expression. In addition; a relevant influence of age on DNA methylation in white blood cells was found, as well as, on a trend level, novel associations between DNA methylation and obesity. Full article

(This article belongs to the Special Issue Gene-Nutrient Interactions)

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15 pages, 929 KiB

Open AccessReview

The miR-200 Family: Versatile Players in Epithelial Ovarian Cancer

by Goda G. Muralidhar and Maria V. Barbolina^*

Department of Biopharmaceutical Sciences, University of Illinois at Chicago, 833 S Wood Street, 335 College of Pharmacy Building, Chicago, IL 60612, USA

Int. J. Mol. Sci. 2015, 16(8), 16833-16847; https://doi.org/10.3390/ijms160816833 - 24 Jul 2015

Cited by 67 | Viewed by 9036

Abstract

The role of microRNAs (miRNAs or miRs) in the pathology of epithelial ovarian cancer (EOC) has been extensively studied. Many miRNAs differentially expressed in EOC as compared to normal controls have been identified, prompting further inquiry into their role in the disease. miRNAs [...] Read more.

The role of microRNAs (miRNAs or miRs) in the pathology of epithelial ovarian cancer (EOC) has been extensively studied. Many miRNAs differentially expressed in EOC as compared to normal controls have been identified, prompting further inquiry into their role in the disease. miRNAs belonging to the miR-200 family have repeatedly surfaced over multiple profiling studies. In this review, we attempt to consolidate the data from different studies and highlight mechanisms by which these miRNAs influence progression of metastasis and chemo-resistance in EOC. Full article

(This article belongs to the Special Issue RNA Interference)

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32 pages, 1029 KiB

Open AccessReview

Therapeutic Hypothermia in Spinal Cord Injury: The Status of Its Use and Open Questions

by Jiaqiong Wang^1,*,† and Damien D. Pearse^{1,2,3,4,*,†}

¹ The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, the Lois Pope Life Center, Locator code (R-48), PO BOX 016960, Miami, FL 33136, USA

² The Department of Neurological Surgery, University of Miami Miller School of Medicine, the Lois Pope Life Center, Locator code (R-48), PO BOX 016960, Miami, FL 33136, USA

³ The Neuroscience Program, University of Miami Miller School of Medicine, the Lois Pope Life Center, Locator code (R-48), PO BOX 016960, Miami, FL 33136, USA

⁴ The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, the Lois Pope Life Center, Locator code (R-48), PO BOX 016960, Miami, FL 33136, USA

^† These authors contributed equally to the work.

Int. J. Mol. Sci. 2015, 16(8), 16848-16879; https://doi.org/10.3390/ijms160816848 - 24 Jul 2015

Cited by 62 | Viewed by 9581

Abstract

Spinal cord injury (SCI) is a major health problem and is associated with a diversity of neurological symptoms. Pathophysiologically, dysfunction after SCI results from the culmination of tissue damage produced both by the primary insult and a range of secondary injury mechanisms. The [...] Read more.

Spinal cord injury (SCI) is a major health problem and is associated with a diversity of neurological symptoms. Pathophysiologically, dysfunction after SCI results from the culmination of tissue damage produced both by the primary insult and a range of secondary injury mechanisms. The application of hypothermia has been demonstrated to be neuroprotective after SCI in both experimental and human studies. The myriad of protective mechanisms of hypothermia include the slowing down of metabolism, decreasing free radical generation, inhibiting excitotoxicity and apoptosis, ameliorating inflammation, preserving the blood spinal cord barrier, inhibiting astrogliosis, promoting angiogenesis, as well as decreasing axonal damage and encouraging neurogenesis. Hypothermia has also been combined with other interventions, such as antioxidants, anesthetics, alkalinization and cell transplantation for additional benefit. Although a large body of work has reported on the effectiveness of hypothermia as a neuroprotective approach after SCI and its application has been translated to the clinic, a number of questions still remain regarding its use, including the identification of hypothermia’s therapeutic window, optimal duration and the most appropriate rewarming rate. In addition, it is necessary to investigate the neuroprotective effect of combining therapeutic hypothermia with other treatment strategies for putative synergies, particularly those involving neurorepair. Full article

(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)

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17 pages, 4366 KiB

Open AccessArticle

Murine K_2P5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K_2P3.1- and K_V1.3-Dependent Mechanisms

by Stefan Bittner^1,*, Nicole Bobak², Majella-Sophie Hofmann¹, Michael K. Schuhmann³, Tobias Ruck¹, Kerstin Göbel¹

, Wolfgang Brück⁴, Heinz Wiendl¹ and Sven G. Meuth^1,5

¹ Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, Münster 48149, Germany

² LabEx ICST, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS and Université de Nice-Sophia Antipolis, Valbonne 06560, France

³ Department of Neurology, University of Würzburg, Würzburg 97070, Germany

⁴ Department of Neuropathology, University Medical Center, Georg August University, Göttingen 37073, Germany

⁵ Department of Physiology I-Neuropathophysiology, University of Münster, Münster 48149, Germany

Int. J. Mol. Sci. 2015, 16(8), 16880-16896; https://doi.org/10.3390/ijms160816880 - 24 Jul 2015

Cited by 5 | Viewed by 6480

Abstract

Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K_2P5.1 (TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T [...] Read more.

Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K_2P5.1 (TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K_2P5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K_2P5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K_2P5.1 knockout (K_2P5.1⁻^/⁻) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K_2P5.1⁻^/⁻ mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K_2P3.1 and K_V1.3 seems to counterbalance the deletion of K_2P5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K_2P5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K_2P5.1-targeting drugs. Full article

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

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23 pages, 2043 KiB

Open AccessReview

Technologies for Single-Cell Isolation

by Andre Gross^1,2,†, Jonas Schoendube^1,2,†, Stefan Zimmermann^1,†, Maximilian Steeb¹, Roland Zengerle^1,3,4 and Peter Koltay^1,2,*

¹ Laboratory for MEMS Applications, IMTEK–Department of Microsystems Engineering, University of Freiburg, Georges-Koehler-Allee 103, Freiburg 79110, Germany

² Cytena GmbH, Georges-Koehler-Allee 103, Freiburg 79110, Germany

³ Hahn-Schickard, Georges-Koehler-Allee 103, Freiburg 79110, Germany

⁴ BIOSS–Centre for Biological Signalling Studies, University of Freiburg, Freiburg 79110, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 16897-16919; https://doi.org/10.3390/ijms160816897 - 24 Jul 2015

Cited by 382 | Viewed by 40330

Abstract

The handling of single cells is of great importance in applications such as cell line development or single-cell analysis, e.g., for cancer research or for emerging diagnostic methods. This review provides an overview of technologies that are currently used or in development to [...] Read more.

The handling of single cells is of great importance in applications such as cell line development or single-cell analysis, e.g., for cancer research or for emerging diagnostic methods. This review provides an overview of technologies that are currently used or in development to isolate single cells for subsequent single-cell analysis. Data from a dedicated online market survey conducted to identify the most relevant technologies, presented here for the first time, shows that FACS (fluorescence activated cell sorting) respectively Flow cytometry (33% usage), laser microdissection (17%), manual cell picking (17%), random seeding/dilution (15%), and microfluidics/lab-on-a-chip devices (12%) are currently the most frequently used technologies. These most prominent technologies are described in detail and key performance factors are discussed. The survey data indicates a further increasing interest in single-cell isolation tools for the coming years. Additionally, a worldwide patent search was performed to screen for emerging technologies that might become relevant in the future. In total 179 patents were found, out of which 25 were evaluated by screening the title and abstract to be relevant to the field. Full article

(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)

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33 pages, 764 KiB

Open AccessReview

Autonomic Dysregulation in Multiple Sclerosis

by Alexandra Pintér^1,2,*,†, Domonkos Cseh^1,†, Adrienn Sárközi¹, Ben M. Illigens³ and Timo Siepmann^2,4,5,*,†

¹ Institute of Human Physiology and Clinical Experimental Research, Faculty of Medicine, Semmelweis University, Budapest 1085, Hungary

² Center for Clinical Research and Management Education, Division of Health Care Sciences, Dresden International University, Dresden 01067, Germany

³ Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

⁴ Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany

⁵ Department of Psychotherapy and Psychosomatic Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 16920-16952; https://doi.org/10.3390/ijms160816920 - 24 Jul 2015

Cited by 41 | Viewed by 15087

Abstract

Multiple sclerosis (MS) is a chronic, progressive central neurological disease characterized by inflammation and demyelination. In patients with MS, dysregulation of the autonomic nervous system may present with various clinical symptoms including sweating abnormalities, urinary dysfunction, orthostatic dysregulation, gastrointestinal symptoms, and sexual dysfunction. [...] Read more.

Multiple sclerosis (MS) is a chronic, progressive central neurological disease characterized by inflammation and demyelination. In patients with MS, dysregulation of the autonomic nervous system may present with various clinical symptoms including sweating abnormalities, urinary dysfunction, orthostatic dysregulation, gastrointestinal symptoms, and sexual dysfunction. These autonomic disturbances reduce the quality of life of affected patients and constitute a clinical challenge to the physician due to variability of clinical presentation and inconsistent data on diagnosis and treatment. Early diagnosis and initiation of individualized interdisciplinary and multimodal strategies is beneficial in the management of autonomic dysfunction in MS. This review summarizes the current literature on the most prevalent aspects of autonomic dysfunction in MS and provides reference to underlying pathophysiological mechanisms as well as means of diagnosis and treatment. Full article

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

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13 pages, 1946 KiB

Open AccessArticle

MicroRNA Profiling of B Cell Subsets from Systemic Lupus Erythematosus Patients Reveals Promising Novel Biomarkers

by Isabelle Duroux-Richard^1,2,*, Jimena Cuenca^3,4, Clara Ponsolles^1,2, Alejandro Badilla Piñeiro³, Fernando Gonzalez³, Christine Roubert⁵, Roser Areny⁶, Rosa Chea⁷, Jacqueline Pefaur⁷, Yves-Marie Pers^1,2,8, Fernando E. Figueroa³, Christian Jorgensen^1,2,8, Maroun Khoury^3,4,† and Florence Apparailly^1,2,8,†

¹ INSERM, U1183, Institute of Regenerative Medicine and Biotherapy, University Hospital Saint Eloi, Montpellier 34295, France

² University of Montpellier, Montpellier 34090, France

³ Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago 7620001, Chile

⁴ Cells for Cells, Santiago 7620001, Chile

⁵ Exploratory Unit, Sanofi R & D, Montpellier 34184, France

⁶ Hospital Félix Bulnes, Santiago 7510021, Chile

⁷ Hospital Barros Luco, Santiago 8900085, Chile

⁸ Clinical Department for Osteoarticular Diseases, University Hospital Lapeyronie, Montpellier 34295, France

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 16953-16965; https://doi.org/10.3390/ijms160816953 - 27 Jul 2015

Cited by 37 | Viewed by 7544

Abstract

MicroRNAs control the differentiation and function of B cells, which are considered key elements in the pathogenesis of systemic lupus erythematosus (SLE). However, a common micro(mi)RNA signature has not emerged since published data includes patients of variable ethnic background, type of disease, and [...] Read more.

MicroRNAs control the differentiation and function of B cells, which are considered key elements in the pathogenesis of systemic lupus erythematosus (SLE). However, a common micro(mi)RNA signature has not emerged since published data includes patients of variable ethnic background, type of disease, and organ involvement, as well as heterogeneous cell populations. Here, we aimed at identifying a miRNA signature of purified B cells from renal and non-renal severe SLE patients of Latin American background, a population known to express severe disease. Genome-wide miRNA expression analyses were performed on naive and memory B cells and revealed two categories of miRNA signatures. The first signature represents B cell subset-specific miRNAs deregulated in SLE: 11 and six miRNAs discriminating naive and memory B cells of SLE patients from healthy controls (HC), respectively. Whether the miRNA was up or down-regulated in memory B cells as compared with naive B cells in HC, this difference was abolished in SLE patients, and vice versa. The second signature identifies six miRNAs associated with specific pathologic features affecting renal outcome, providing a further understanding for SLE pathogenesis. Overall, the present work provided promising biomarkers in molecular diagnostics for disease severity as well as potential new targets for therapeutic intervention in SLE. Full article

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

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15 pages, 3047 KiB

Open AccessArticle

Molecular Characterization of Bovine SMO Gene and Effects of Its Genetic Variations on Body Size Traits in Qinchuan Cattle (Bos taurus)

by Ya-Ran Zhang^1,†, Lin-Sheng Gui^1,†, Yao-Kun Li¹, Bi-Jie Jiang¹, Hong-Cheng Wang¹, Ying-Ying Zhang¹ and Lin-Sen Zan^1,2,*

¹ College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China

² National Beef Cattle Improvement Center of Northwest A&F University, Yangling 712100, Shaanxi, China

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2015, 16(8), 16966-16980; https://doi.org/10.3390/ijms160816966 - 27 Jul 2015

Cited by 6 | Viewed by 5502

Abstract

Smoothened (Smo)-mediated Hedgehog (Hh) signaling pathway governs the patterning, morphogenesis and growth of many different regions within animal body plans. This study evaluated the effects of genetic variations of the bovine SMO gene on economically important body size traits in Chinese Qinchuan cattle. [...] Read more.

Smoothened (Smo)-mediated Hedgehog (Hh) signaling pathway governs the patterning, morphogenesis and growth of many different regions within animal body plans. This study evaluated the effects of genetic variations of the bovine SMO gene on economically important body size traits in Chinese Qinchuan cattle. Altogether, eight single nucleotide polymorphisms (SNPs: 1–8) were identified and genotyped via direct sequencing covering most of the coding region and 3ʹUTR of the bovine SMO gene. Both the p.698Ser.>Ser. synonymous mutation resulted from SNP1 and the p.700Ser.>Pro. non-synonymous mutation caused by SNP2 mapped to the intracellular C-terminal tail of bovine Smo protein; the other six SNPs were non-coding variants located in the 3ʹUTR. The linkage disequilibrium was analyzed, and five haplotypes were discovered in 520 Qinchuan cattle. Association analyses showed that SNP2, SNP3/5, SNP4 and SNP6/7 were significantly associated with some body size traits (p < 0.05) except SNP1/8 (p > 0.05). Meanwhile, cattle with wild-type combined haplotype Hap1/Hap1 had significantly (p < 0.05) greater body length than those with Hap2/Hap2. Our results indicate that variations in the SMO gene could affect body size traits of Qinchuan cattle, and the wild-type haplotype Hap1 together with the wild-type alleles of these detected SNPs in the SMO gene could be used to breed cattle with superior body size traits. Therefore, our results could be helpful for marker-assisted selection in beef cattle breeding programs. Full article

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

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24 pages, 974 KiB

Open AccessReview

Evaluating the Oxidative Stress in Inflammation: Role of Melatonin

by Aroha Sánchez^1,†, Ana Cristina Calpena^1,†

and Beatriz Clares^2,*,†

¹ Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Barcelona, Joan XXIII Avenue, Barcelona 08028, Spain

² Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Campus of Cartuja Street, Granada 18071, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 16981-17004; https://doi.org/10.3390/ijms160816981 - 27 Jul 2015

Cited by 124 | Viewed by 15174

Abstract

Oxygen is used by eukaryotic cells for metabolic transformations and energy production in mitochondria. Under physiological conditions, there is a constant endogenous production of intermediates of reactive oxygen (ROI) and nitrogen species (RNI) that interact as signaling molecules in physiological mechanisms. When these [...] Read more.

Oxygen is used by eukaryotic cells for metabolic transformations and energy production in mitochondria. Under physiological conditions, there is a constant endogenous production of intermediates of reactive oxygen (ROI) and nitrogen species (RNI) that interact as signaling molecules in physiological mechanisms. When these species are not eliminated by antioxidants or are produced in excess, oxidative stress arises. Oxidative stress can damage proteins, lipids, DNA, and organelles. It is a process directly linked to inflammation; in fact, inflammatory cells secrete a large number of cytokines and chemokines responsible for the production of ROI and RNI in phagocytic and nonphagocytic cells through the activation of protein kinases signaling. Currently, there is a wide variety of diseases capable of producing inflammatory manifestations. While, in the short term, most of these diseases are not fatal they have a major impact on life quality. Since there is a direct relationship between chronic inflammation and many emerging disorders like cancer, oral diseases, kidney diseases, fibromyalgia, gastrointestinal chronic diseases or rheumatics diseases, the aim of this review is to describe the use and role of melatonin, a hormone secreted by the pineal gland, that works directly and indirectly as a free radical scavenger, like a potent antioxidant. Full article

(This article belongs to the Special Issue Antioxidant 2.0——Redox Modulation by Food and Drugs)

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13 pages, 788 KiB

Open AccessArticle

The Role of CzcRS Two-Component Systems in the Heavy Metal Resistance of Pseudomonas putida X4

by Pulin Liu¹

, Xi Chen¹, Qiaoyun Huang^1,2,* and Wenli Chen^1,*

¹ State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China

² Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River), Ministry of Agriculture, College of Resources and Environment, Huazhong Agricultural University, Wuhan 430070, China

Int. J. Mol. Sci. 2015, 16(8), 17005-17017; https://doi.org/10.3390/ijms160817005 - 27 Jul 2015

Cited by 20 | Viewed by 5832

Abstract

The role of different czcRS genes in metal resistance and the cross-link between czcRS and czcCBA in Pseudomonas putida X4 were studied to advance understanding of the mechanisms by which P. putida copes with metal stress. Similar to P. putida KT2440, two complete [...] Read more.

The role of different czcRS genes in metal resistance and the cross-link between czcRS and czcCBA in Pseudomonas putida X4 were studied to advance understanding of the mechanisms by which P. putida copes with metal stress. Similar to P. putida KT2440, two complete czcRS1 and czcRS2 two-component systems, as well as a czcR3 without the corresponding sensing component were amplified in P. putida X4. The histidine kinase genes czcS1 and czcS2 were inactivated and fused to lacZ by homologous recombination. The lacZ fusion assay revealed that Cd²⁺ and Zn²⁺ caused a decrease in the transcription of czcRS1, whereas Cd²⁺ treatment enhanced the transcription of czcRS2. The mutation of different czcRSs showed that all czcRSs are necessary to facilitate full metal resistance in P. putida X4. A putative gene just downstream of czcR3 is related to metal ion resistance, and its transcription was activated by Zn²⁺. Data from quantitative real-time polymerase chain reaction (qRT-PCR) strongly suggested that czcRSs regulate the expression of czcCBA, and a cross-link exists between different czcRSs. Full article

(This article belongs to the Special Issue Microbial Metabolism of Toxic Organic Pollutants and Transformation of Metals/Metalloids and Ecotoxicity Assessment)

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11 pages, 1213 KiB

Open AccessArticle

miR-198 Represses the Proliferation of HaCaT Cells by Targeting Cyclin D2

by Jian Wang¹, Guorong Dan¹, Tao Shangguan¹, Han Hao², Ran Tang², Kaige Peng¹, Jiqing Zhao¹, Huiqin Sun¹ and Zhongmin Zou^1,*

¹ Institute of Toxicology, School of Preventive Medicine, the Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China

² The 17th Student Battalion, School of Preventive Medicine, the Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China

Int. J. Mol. Sci. 2015, 16(8), 17018-17028; https://doi.org/10.3390/ijms160817018 - 27 Jul 2015

Cited by 22 | Viewed by 7531

Abstract

Background: MiR-198 has been considered as an inhibitor of cell proliferation, invasion, migration and a promoter of apoptosis in most cancer cells, while its effect on non-cancer cells is poorly understood. Methods: The effect of miR-198 transfection on HaCaT cell proliferation was firstly [...] Read more.

Background: MiR-198 has been considered as an inhibitor of cell proliferation, invasion, migration and a promoter of apoptosis in most cancer cells, while its effect on non-cancer cells is poorly understood. Methods: The effect of miR-198 transfection on HaCaT cell proliferation was firstly detected using Cell Count Kit-8 and the cell cycle progression was analyzed by flow cytometry. Using bioinformatics analyses and luciferase assay, a new target of miR-198 was searched and identified. Then, the effect of the new target gene of miR-198 on cell proliferation and cell cycle was also detected. Results: Here we showed that miR-198 directly bound to the 3′-UTR of CCND2 mRNA, which was a key regulator in cell cycle progression. Overexpressed miR-198 repressed CCND2 expression at mRNA and protein levels and subsequently led to cell proliferation inhibition and cell cycle arrest in the G1 phase. Transfection ofSiCCND2 in HaCaT cells showed similar inhibitory effects on cell proliferation and cell cycle progression. Conclusion: In conclusion, we have identified that miR-198 inhibited HaCaT cell proliferation by directly targeting CCND2. Full article

(This article belongs to the Special Issue Molecular Machinery of Cell Growth Regulation)

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19 pages, 893 KiB

Open AccessReview

Ethanol versus Phytochemicals in Wine: Oral Cancer Risk in a Light Drinking Perspective

by Elena M. Varoni^1,*,†

, Giovanni Lodi¹ and Marcello Iriti^2,*,†

¹ Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, via Beldiletto 1/3, 20142 Milan, Italy

² Dipartimento di Scienze Agrarie e Ambientali, Università degli Studi di Milano, via G. Celoria 2, 20122 Milan, Italy

^† These authors contributed equally to the work.

Int. J. Mol. Sci. 2015, 16(8), 17029-17047; https://doi.org/10.3390/ijms160817029 - 27 Jul 2015

Cited by 27 | Viewed by 8963

Abstract

This narrative review aims to summarize the current controversy on the balance between ethanol and phytochemicals in wine, focusing on light drinking and oral cancer. Extensive literature search included PUBMED and EMBASE databases to identify in human studies and systematic reviews (up to [...] Read more.

This narrative review aims to summarize the current controversy on the balance between ethanol and phytochemicals in wine, focusing on light drinking and oral cancer. Extensive literature search included PUBMED and EMBASE databases to identify in human studies and systematic reviews (up to March 2015), which contributed to elucidate this issue. Independently from the type of beverage, meta-analyses considering light drinking (≤1 drinks/day or ≤12.5 g/day of ethanol) reported relative risks (RR) for oral, oro-pharyngeal, or upper aero-digestive tract cancers, ranging from 1.0 to 1.3. One meta-analysis measured the overall wine-specific RR, which corresponded to 2.1. Although little evidence exists on light wine intake, phytochemicals seem not to affect oral cancer risk, being probably present below the effective dosages and/or due to their low bioavailability. As expected, the risk of oral cancer, even in light drinking conditions, increases when associated with smoking habit and high-risk genotypes of alcohol and aldehyde dehydrogenases. Full article

(This article belongs to the Special Issue Molecular Research in Plant Secondary Metabolism 2015)

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40 pages, 1082 KiB

Open AccessReview

Milk—A Nutrient System of Mammalian Evolution Promoting mTORC1-Dependent Translation

by Bodo C. Melnik

Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Osnabrück D-49090, Germany

Int. J. Mol. Sci. 2015, 16(8), 17048-17087; https://doi.org/10.3390/ijms160817048 - 27 Jul 2015

Cited by 92 | Viewed by 27733

Abstract

Based on own translational research of the biochemical and hormonal effects of cow’s milk consumption in humans, this review presents milk as a signaling system of mammalian evolution that activates the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the pivotal regulator [...] Read more.

Based on own translational research of the biochemical and hormonal effects of cow’s milk consumption in humans, this review presents milk as a signaling system of mammalian evolution that activates the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the pivotal regulator of translation. Milk, a mammary gland-derived secretory product, is required for species-specific gene-nutrient interactions that promote appropriate growth and development of the newborn mammal. This signaling system is highly conserved and tightly controlled by the lactation genome. Milk is sufficient to activate mTORC1, the crucial regulator of protein, lipid, and nucleotide synthesis orchestrating anabolism, cell growth and proliferation. To fulfill its mTORC1-activating function, milk delivers four key metabolic messengers: (1) essential branched-chain amino acids (BCAAs); (2) glutamine; (3) palmitic acid; and (4) bioactive exosomal microRNAs, which in a synergistical fashion promote mTORC1-dependent translation. In all mammals except Neolithic humans, postnatal activation of mTORC1 by milk intake is restricted to the postnatal lactation period. It is of critical concern that persistent hyperactivation of mTORC1 is associated with aging and the development of age-related disorders such as obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. Persistent mTORC1 activation promotes endoplasmic reticulum (ER) stress and drives an aimless quasi-program, which promotes aging and age-related diseases. Full article

(This article belongs to the Special Issue Gene-Nutrient Interactions)

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13 pages, 2217 KiB

Open AccessArticle

The Photoprotective Effect of S-Methylmethionine Sulfonium in Skin

by Won-Serk Kim¹, Hyun-Min Seo¹, Wang-Kyun Kim², Joon-Seok Choi³, Ikyon Kim² and Jong-Hyuk Sung^2,*

¹ Department of Dermatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Korea

² College of Pharmacy, Yonsei University, Incheon 406-840, Korea

³ College of Pharmacy, Catholic University of Daegu, Gyeongbuk 712-702, Korea

Int. J. Mol. Sci. 2015, 16(8), 17088-17100; https://doi.org/10.3390/ijms160817088 - 28 Jul 2015

Cited by 15 | Viewed by 7057

Abstract

S-Methylmethionine sulfonium (SMMS) was reported to have wound-healing effects; we therefore have investigated the photoprotective effect of SMMS in the present study. SMMS increased the viability of keratinocyte progenitor cells (KPCs) and human dermal fibroblasts (hDFs) following ultraviolet B (UVB) irradiation, and [...] Read more.

S-Methylmethionine sulfonium (SMMS) was reported to have wound-healing effects; we therefore have investigated the photoprotective effect of SMMS in the present study. SMMS increased the viability of keratinocyte progenitor cells (KPCs) and human dermal fibroblasts (hDFs) following ultraviolet B (UVB) irradiation, and reduced the UVB-induced apoptosis in these cells. SMMS increased the phosphorylation of extracellular signal-regulated kinases (ERK), and the inhibitor of the mitogen-activated protein kinase pathway significantly decreased the SMMS-induced viability of KPCs and hDFs. In addition, SMMS attenuated the UVB-induced reactive oxygen species (ROS) generation in KPCs and hDFs. SMMS induced the collagen synthesis and reduced the matrix metalloproteinase-1 expression in UVB-irradiated hDFs. In animal studies, application of 5% and 10% SMMS before and after UVB-irradiation significantly decreased the UVB-induced erythema index and depletion of Langerhans cells. In summary, SMMS protects KPCs and hDFs from UVB irradiation, and reduces UVB-induced skin erythema and immune suppression. Therefore, SMMS can be used as a cosmetic raw material, and protect skin from UVB. Full article

(This article belongs to the Section Biochemistry)

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59 pages, 5263 KiB

Open AccessReview

Opportunities for Bio-Based Solvents Created as Petrochemical and Fuel Products Transition towards Renewable Resources

by James H. Clark^*, Thomas J. Farmer

, Andrew J. Hunt and James Sherwood

Green Chemistry Centre of Excellence, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK

Int. J. Mol. Sci. 2015, 16(8), 17101-17159; https://doi.org/10.3390/ijms160817101 - 28 Jul 2015

Cited by 211 | Viewed by 29707

Abstract

The global bio-based chemical market is growing in size and importance. Bio-based solvents such as glycerol and 2-methyltetrahydrofuran are often discussed as important introductions to the conventional repertoire of solvents. However adoption of new innovations by industry is typically slow. Therefore it might [...] Read more.

The global bio-based chemical market is growing in size and importance. Bio-based solvents such as glycerol and 2-methyltetrahydrofuran are often discussed as important introductions to the conventional repertoire of solvents. However adoption of new innovations by industry is typically slow. Therefore it might be anticipated that neoteric solvent systems (e.g., ionic liquids) will remain niche, while renewable routes to historically established solvents will continue to grow in importance. This review discusses bio-based solvents from the perspective of their production, identifying suitable feedstocks, platform molecules, and relevant product streams for the sustainable manufacturing of conventional solvents. Full article

(This article belongs to the Special Issue Green Chemistry and the Biorefinery)

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21 pages, 796 KiB

Open AccessReview

Recent Breakthroughs in the Antioxidant and Anti-Inflammatory Effects of Morella and Myrica Species

by Bruno J. C. Silva^1,†, Ana M. L. Seca^1,2,†

, Maria Do Carmo Barreto^1,3 and Diana C. G. A. Pinto^2,*,†

¹ Department of Technological Science and Development, University of Azores, Ponta Delgada 9501-801, Portugal

² Department of Chemistry & Química Orgânica Produtos Naturais and Agroalimentares, University of Aveiro, Aveiro 3810-193, Portugal

³ Centro Investigação Recursos Naturais, University of Azores, Ponta Delgada 9501-801, Portugal

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17160-17180; https://doi.org/10.3390/ijms160817160 - 28 Jul 2015

Cited by 30 | Viewed by 11002

Abstract

Oxidative stress is one of the risk factors for the development of several chronic diseases, such as diabetes, cancer, cardiovascular and neurodegenerative diseases. Antioxidants are therefore highly sought and can be seen as a type of preventive medicine against several diseases. Myrica and [...] Read more.

Oxidative stress is one of the risk factors for the development of several chronic diseases, such as diabetes, cancer, cardiovascular and neurodegenerative diseases. Antioxidants are therefore highly sought and can be seen as a type of preventive medicine against several diseases. Myrica and Morella genus (Myricaceae) are taxonomically very close and their species are trees or shrubs with edible fruits that exhibit relevant uses in traditional medicine, for instance in Chinese or Japanese folk medicine they are used to treat diarrhea, digestive problems, headache, burns and skin diseases. Nearly 36 compounds were isolated from different morphological parts of Myrica and/or Morella species and their antioxidant and anti-inflammatory activities evaluated. Thirteen of these compounds exhibit greater effects than the positive controls used. Adenodimerin A was the most active compound reported (in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay EC₅₀= 7.9 ± 0.3 µM). These results are just one aspect of the antioxidant and anti-inflammatory evaluations reported regarding Myrica and Morella species, so a comprehensive overview on the current status, highlighting the antioxidant health promoting effect of these species, their key antioxidant compounds as well as the compounds with protective effects against oxidative stress related diseases such as inflammation, is relevant. Full article

(This article belongs to the Special Issue Antioxidant 2.0——Redox Modulation by Food and Drugs)

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12 pages, 1019 KiB

Open AccessArticle

Prognostic Value of Preoperative Serum Levels of Periostin (PN) in Early Breast Cancer (BCa)

by Pier Vitale Nuzzo^1,2, Alessandra Rubagotti^1,2, Francesca Argellati¹, Antonio Di Meglio^1,2, Elisa Zanardi^1,2, Linda Zinoli¹, Paola Comite³, Michele Mussap³ and Francesco Boccardo^1,2,*

¹ Academic Unit of Medical Oncology, IRCCS San Martino University Hospital—IST National Cancer Research Institute, Largo Rosanna Benzi 10, 16132 Genoa, Italy

² Department of Medicine, School of Medicine, University of Genoa, Largo Rosanna Benzi 10, 16132 Genoa, Italy

³ Department of Laboratory Medicine, IRCCS San Martino University Hospital—IST National Cancer Research Institute Largo Rosanna Benzi 10, 16132 Genoa, Italy

Int. J. Mol. Sci. 2015, 16(8), 17181-17192; https://doi.org/10.3390/ijms160817181 - 28 Jul 2015

Cited by 26 | Viewed by 6474

Abstract

PN is a secreted cell adhesion protein critical for carcinogenesis. Elevated serum levels of PN have been implicated as playing an important role in different types of cancer, and a few reports suggest a potential role as a prognostic marker. We evaluated the [...] Read more.

PN is a secreted cell adhesion protein critical for carcinogenesis. Elevated serum levels of PN have been implicated as playing an important role in different types of cancer, and a few reports suggest a potential role as a prognostic marker. We evaluated the prognostic significance of preoperative serum PN concentration in patients with BCa receiving curative surgery. Enzyme-Linked Immunosorbent Assay (ELISA) was performed to determine the preoperative serum PN level in 182 patients. The correlations between serum PN concentration with clinical pathological features and PN expression in primary tumor samples were analyzed. The prognostic impact of serum PN levels with all-cause and BCa-specific mortality was also investigated. Appropriate statistics were used. Elevated serum PN levels were significantly associated with patient age (p = 0.005), adjuvant systemic therapy (p = 0.04) and progesterone receptor (PgR) status (p = 0.02). No correlation between PN preoperative serum levels and other clinical-pathological parameters, including either the epithelial or the stromal PN expression of primary tumor or the combination of the two, was found. Similarly, no association between serum PN levels and either all-cause or BCa-specific mortality was found. However, subgroup analysis revealed a correlation between higher PN serum levels and all-cause mortality in patients with node-negative disease (p = 0.05) and in those with a low PgR expression (p = 0.03). Higher levels of serum PN were also found to correlate with BCa-specific mortality in the subgroup of patients who did not receive any adjuvant systemic therapy (p = 0.04). Our findings suggest that PN was detectable in the serum of early BCa patients before surgery and increased base-line serum levels predicted worse long-term survival outcomes in specific subgroups of patients. Full article

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

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38 pages, 1858 KiB

Open AccessReview

Protein Folding and Mechanisms of Proteostasis

by José Fernando Díaz-Villanueva, Raúl Díaz-Molina

and Victor García-González^*

Facultad de Medicina, Universidad Autónoma de Baja California, Mexicali, Baja California 21000, México

Int. J. Mol. Sci. 2015, 16(8), 17193-17230; https://doi.org/10.3390/ijms160817193 - 28 Jul 2015

Cited by 262 | Viewed by 24531

Abstract

Highly sophisticated mechanisms that modulate protein structure and function, which involve synthesis and degradation, have evolved to maintain cellular homeostasis. Perturbations in these mechanisms can lead to protein dysfunction as well as deleterious cell processes. Therefore in recent years the etiology of a [...] Read more.

Highly sophisticated mechanisms that modulate protein structure and function, which involve synthesis and degradation, have evolved to maintain cellular homeostasis. Perturbations in these mechanisms can lead to protein dysfunction as well as deleterious cell processes. Therefore in recent years the etiology of a great number of diseases has been attributed to failures in mechanisms that modulate protein structure. Interconnections among metabolic and cell signaling pathways are critical for homeostasis to converge on mechanisms associated with protein folding as well as for the preservation of the native structure of proteins. For instance, imbalances in secretory protein synthesis pathways lead to a condition known as endoplasmic reticulum (ER) stress which elicits the adaptive unfolded protein response (UPR). Therefore, taking this into consideration, a key part of this paper is developed around the protein folding phenomenon, and cellular mechanisms which support this pivotal condition. We provide an overview of chaperone protein function, UPR via, spatial compartmentalization of protein folding, proteasome role, autophagy, as well as the intertwining between these processes. Several diseases are known to have a molecular etiology in the malfunction of mechanisms responsible for protein folding and in the shielding of native structure, phenomena which ultimately lead to misfolded protein accumulation. This review centers on our current knowledge about pathways that modulate protein folding, and cell responses involved in protein homeostasis. Full article

(This article belongs to the Special Issue Protein Folding)

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14 pages, 2586 KiB

Open AccessArticle

Mapping of Powdery Mildew Resistance Gene pmCH89 in a Putative Wheat-Thinopyrum intermedium Introgression Line

by Liyuan Hou¹, Xiaojun Zhang^2,3, Xin Li^2,3, Juqing Jia⁴, Huizhen Yang², Haixian Zhan^2,3, Linyi Qiao^2,3, Huijuan Guo^2,3 and Zhijian Chang^2,3,*

¹ College of Life Science, Shanxi University, Taiyuan 030006, Shanxi, China

² Institute of Crop Science, Shanxi Academy of Agricultural Sciences, Taiyuan 030031, Shanxi, China

³ Key Laboratory for Crop Gene Resources and Germplasm Enhancement on the Loess Plateau, Ministry of Agriculture, Taiyuan 030031, Shanxi, China

⁴ College of Agronomy, Shanxi Agricultural University, Taigu 030801, Shanxi, China

Int. J. Mol. Sci. 2015, 16(8), 17231-17244; https://doi.org/10.3390/ijms160817231 - 28 Jul 2015

Cited by 8 | Viewed by 6595

Abstract

Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally serious disease adversely affecting wheat production. The Bgt-resistant wheat breeding line CH09W89 was derived after backcrossing a Bgt resistant wheat-Thinopyrum intermedium partial amphiploid TAI7045 with susceptible [...] Read more.

Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally serious disease adversely affecting wheat production. The Bgt-resistant wheat breeding line CH09W89 was derived after backcrossing a Bgt resistant wheat-Thinopyrum intermedium partial amphiploid TAI7045 with susceptible wheat cultivars. At the seedling stage, CH09W89 exhibited immunity or high resistance to Bgt pathotypes E09, E20, E21, E23, E26, Bg1, and Bg2, similar to its donor line TAI7045 and Th. intermedium. No Th. intermedium chromatin was detected based on genomic in situ hybridization of mitotic chromosomes. To determine the mode of inheritance of the Bgt resistance and the chromosomal location of the resistance gene, CH09W89 was crossed with two susceptible wheat cultivars. The results of the genetic analysis showed that the adult resistance to Bgt E09 in CH09W89 was controlled by a single recessive gene, which was tentatively designated as pmCH89. Two polymorphic SSR markers, Xwmc310 and Xwmc125, were linked to the resistance gene with genetic distances 3.1 and 2.7 cM, respectively. Using the Chinese Spring aneuploid and deletion lines, the resistance gene and its linked markers were assigned to chromosome arm 4BL in the bin 0.68–0.78. Due to its unique position on chromosome 4BL, pmCH89 appears to be a new locus for resistance to powdery mildew. These results will be of benefit for improving powdery mildew resistance in wheat breeding programs. Full article

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

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28 pages, 953 KiB

Open AccessReview

Advances in the Study of the Antiatherogenic Function and Novel Therapies for HDL

by Peiqiu Cao¹, Haitao Pan¹, Tiancun Xiao^2,3, Ting Zhou³, Jiao Guo^1,* and Zhengquan Su^1,*

¹ Key Research Center of Liver Regulation for Hyperlipemia SATCM/Class III, Laboratory of Metabolism SATCM, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China

² Inorganic Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QR, UK

³ Guangzhou Boxabio Ltd., D-106 Guangzhou International Business Incubator, Guangzhou 510530, China

Int. J. Mol. Sci. 2015, 16(8), 17245-17272; https://doi.org/10.3390/ijms160817245 - 28 Jul 2015

Cited by 12 | Viewed by 8412

Abstract

The hypothesis that raising high-density lipoprotein cholesterol (HDL-C) levels could improve the risk for cardiovascular disease (CVD) is facing challenges. There is multitudinous clear clinical evidence that the latest failures of HDL-C-raising drugs show no clear association with risks for CVD. At the [...] Read more.

The hypothesis that raising high-density lipoprotein cholesterol (HDL-C) levels could improve the risk for cardiovascular disease (CVD) is facing challenges. There is multitudinous clear clinical evidence that the latest failures of HDL-C-raising drugs show no clear association with risks for CVD. At the genetic level, recent research indicates that steady-state HDL-C concentrations may provide limited information regarding the potential antiatherogenic functions of HDL. It is evident that the newer strategies may replace therapeutic approaches to simply raise plasma HDL-C levels. There is an urgent need to identify an efficient biomarker that accurately predicts the increased risk of atherosclerosis (AS) in patients and that may be used for exploring newer therapeutic targets. Studies from recent decades show that the composition, structure and function of circulating HDL are closely associated with high cardiovascular risk. A vast amount of data demonstrates that the most important mechanism through which HDL antagonizes AS involves the reverse cholesterol transport (RCT) process. Clinical trials of drugs that specifically target HDL have so far proven disappointing, so it is necessary to carry out review on the HDL therapeutics. Full article

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

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16 pages, 2060 KiB

Open AccessArticle

Fenarimol, a Pyrimidine-Type Fungicide, Inhibits Brassinosteroid Biosynthesis

by Keimei Oh^1,*, Tadashi Matsumoto^1,2, Ayumi Yamagami³, Tomoki Hoshi¹, Takeshi Nakano^3,4 and Yuko Yoshizawa¹

¹ Department of Biotechnology, Faculty of Bioresource Sciences, Akita Prefectural University, 241-438, Shimoshinjo Nakano, Akita 010-0195, Japan

² National Agricultural Research Center, National Agriculture and Food Research Organization, 3-1-1 Kannondai, Tsukuba, Ibaraki 305-8666, Japan

³ Gene Discovery Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan

⁴ CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

Int. J. Mol. Sci. 2015, 16(8), 17273-17288; https://doi.org/10.3390/ijms160817273 - 29 Jul 2015

Cited by 19 | Viewed by 8856

Abstract

The plant steroid hormone brassinosteroids (BRs) are important signal mediators that regulate broad aspects of plant growth and development. With the discovery of brassinoazole (Brz), the first specific inhibitor of BR biosynthesis, several triazole-type BR biosynthesis inhibitors have been developed. In this article, [...] Read more.

The plant steroid hormone brassinosteroids (BRs) are important signal mediators that regulate broad aspects of plant growth and development. With the discovery of brassinoazole (Brz), the first specific inhibitor of BR biosynthesis, several triazole-type BR biosynthesis inhibitors have been developed. In this article, we report that fenarimol (FM), a pyrimidine-type fungicide, exhibits potent inhibitory activity against BR biosynthesis. FM induces dwarfism and the open cotyledon phenotype of Arabidopsis seedlings in the dark. The IC₅₀ value for FM to inhibit stem elongation of Arabidopsis seedlings grown in the dark was approximately 1.8 ± 0.2 μM. FM-induced dwarfism of Arabidopsis seedlings could be restored by brassinolide (BL) but not by gibberellin (GA). Assessment of the target site of FM in BR biosynthesis by feeding BR biosynthesis intermediates indicated that FM interferes with the side chain hydroxylation of BR biosynthesis from campestanol to teasterone. Determination of the binding affinity of FM to purified recombinant CYP90D1 indicated that FM induced a typical type II binding spectrum with a K_d value of approximately 0.79 μM. Quantitative real-time PCR analysis of the expression level of the BR responsive gene in Arabidopsis seedlings indicated that FM induces the BR deficiency in Arabidopsis. Full article

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

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14 pages, 1227 KiB

Open AccessArticle

Combined Spectroscopic and Calorimetric Studies to Reveal Absorption Mechanisms and Conformational Changes of Protein on Nanoporous Biomaterials

by Saharnaz Ahmadi¹, Maryam Farokhi², Parisa Padidar³ and Mojtaba Falahati^3,*

¹ Department of Biology, Science and Research Branch, Islamic Azad University, Tehran P. O. Box: 1477893855, Iran

² Department of Nanotechnology and Advanced materials, Materials and Energy Research Center, Tehran P. O. Box: 31787316, Iran

³ Department of Nanotechnology, Faculty of Advance Science and Technology, Islamic Azad University of Pharmaceutical Sciences (IAUPS), Tehran P. O. Box: 193956466, Iran

Int. J. Mol. Sci. 2015, 16(8), 17289-17302; https://doi.org/10.3390/ijms160817289 - 29 Jul 2015

Cited by 8 | Viewed by 6246

Abstract

In this study the effect of surface modification of mesoporous silica nanoparticles (MSNs) on its adsorption capacities and protein stability after immobilization of beta-lactoglobulin B (BLG-B) was investigated. For this purpose, non-functionalized (KIT-6) and aminopropyl-functionalized cubic Ia3d mesoporous silica ([n-PrNH₂ [...] Read more.

In this study the effect of surface modification of mesoporous silica nanoparticles (MSNs) on its adsorption capacities and protein stability after immobilization of beta-lactoglobulin B (BLG-B) was investigated. For this purpose, non-functionalized (KIT-6) and aminopropyl-functionalized cubic Ia3d mesoporous silica ([n-PrNH₂-KIT-6]) nanoparticles were used as nanoporous supports. Aminopropyl-functionalized mesoporous nanoparticles exhibited more potential candidates for BLG-B adsorption and minimum BLG leaching than non-functionalized nanoparticles. It was observed that the amount of adsorbed BLG is dependent on the initial BLG concentration for both KIT-6 and [n-PrNH₂-KIT-6] mesoporous nanoparticles. Also larger amounts of BLG-B on KIT-6 was immobilized upon raising the temperature of the medium from 4 to 55 °C while such increase was undetectable in the case of immobilization of BLG-B on the [n-PrNH₂-KIT-6]. At temperatures above 55 °C the amounts of adsorbed BLG on both studied nanomaterials decreased significantly. By Differential scanning calorimetry or DSC analysis the heterogeneity of the protein solution and increase in Tm may indicate that immobilization of BLG-B onto the modified KIT-6 results in higher thermal stability compared to unmodified one. The obtained results provide several crucial factors in determining the mechanism(s) of protein adsorption and stability on the nanostructured solid supports and the development of engineered nano-biomaterials for controlled drug-delivery systems and biomimetic interfaces for the immobilization of living cells. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 5450 KiB

Open AccessArticle

Distribution of ADAT-Dependent Codons in the Human Transcriptome

by Àlbert Rafels-Ybern¹, Camille Stephan-Otto Attolini¹ and Lluís Ribas De Pouplana^1,2,*

¹ Institute for Research in Biomedicine (IRB), Parc Cientific de Barcelona, C/Baldiri Reixac 10, 08028 Bacelona, Spain

² Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain

Int. J. Mol. Sci. 2015, 16(8), 17303-17314; https://doi.org/10.3390/ijms160817303 - 29 Jul 2015

Cited by 20 | Viewed by 6976

Abstract

Nucleotide modifications in the anticodons of transfer RNAs (tRNA) play a central role in translation efficiency, fidelity, and regulation of translation, but, for most of these modifications, the details of their function remain unknown. The heterodimeric adenosine deaminases acting on tRNAs (ADAT2-ADAT3, or [...] Read more.

Nucleotide modifications in the anticodons of transfer RNAs (tRNA) play a central role in translation efficiency, fidelity, and regulation of translation, but, for most of these modifications, the details of their function remain unknown. The heterodimeric adenosine deaminases acting on tRNAs (ADAT2-ADAT3, or ADAT) are enzymes present in eukaryotes that convert adenine (A) to inosine (I) in the first anticodon base (position 34) by hydrolytic deamination. To explore the influence of ADAT activity on mammalian translation, we have characterized the human transcriptome and proteome in terms of frequency and distribution of ADAT-related codons. Eight different tRNAs can be modified by ADAT and, once modified, these tRNAs will recognize NNC, NNU and NNA codons, but not NNG codons. We find that transcripts coding for proteins highly enriched in these eight amino acids (ADAT-aa) are specifically enriched in NNC, NNU and NNA codons. We also show that the proteins most enriched in ADAT-aa are composed preferentially of threonine, alanine, proline, and serine (TAPS). We propose that the enrichment in ADAT-codons in these proteins is due to the similarities in the codons that correspond to TAPS. Full article

(This article belongs to the Special Issue Functions of Transfer RNAs)

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16 pages, 997 KiB

Open AccessArticle

DeepCNF-D: Predicting Protein Order/Disorder Regions by Weighted Deep Convolutional Neural Fields

by Sheng Wang^1,2,*,†, Shunyan Weng^3,†, Jianzhu Ma² and Qingming Tang²

¹ Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA

² Toyota Technological Institute at Chicago, Chicago, IL 60637, USA

³ MoE Key Laboratory of Developmental Genetics and Neuropsychiatric Diseases, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17315-17330; https://doi.org/10.3390/ijms160817315 - 29 Jul 2015

Cited by 60 | Viewed by 8305

Abstract

Intrinsically disordered proteins or protein regions are involved in key biological processes including regulation of transcription, signal transduction, and alternative splicing. Accurately predicting order/disorder regions ab initio from the protein sequence is a prerequisite step for further analysis of functions and mechanisms for [...] Read more.

Intrinsically disordered proteins or protein regions are involved in key biological processes including regulation of transcription, signal transduction, and alternative splicing. Accurately predicting order/disorder regions ab initio from the protein sequence is a prerequisite step for further analysis of functions and mechanisms for these disordered regions. This work presents a learning method, weighted DeepCNF (Deep Convolutional Neural Fields), to improve the accuracy of order/disorder prediction by exploiting the long-range sequential information and the interdependency between adjacent order/disorder labels and by assigning different weights for each label during training and prediction to solve the label imbalance issue. Evaluated by the CASP9 and CASP10 targets, our method obtains 0.855 and 0.898 AUC values, which are higher than the state-of-the-art single ab initio predictors. Full article

(This article belongs to the Special Issue In-Silico Prediction and Characterization of Intrinsic Disorder in Proteins)

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13 pages, 662 KiB

Open AccessReview

Infections and Systemic Lupus Erythematosus: Binding or Sparring Partners?

by Donato Rigante¹ and Susanna Esposito^2,*

¹ Institute of Pediatrics, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, 00168 Rome, 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. 2015, 16(8), 17331-17343; https://doi.org/10.3390/ijms160817331 - 29 Jul 2015

Cited by 64 | Viewed by 9114

Abstract

Extensive work on experimental animal models clearly demonstrates that infectious agents can break immunological tolerance to self-antigens and induce autoimmune disorders, mainly systemic lupus erythematosus (SLE). The establishment of a causative link between infections and autoimmunity has been largely studied in a host [...] Read more.

Extensive work on experimental animal models clearly demonstrates that infectious agents can break immunological tolerance to self-antigens and induce autoimmune disorders, mainly systemic lupus erythematosus (SLE). The establishment of a causative link between infections and autoimmunity has been largely studied in a host of clinical studies, proving the role of infectious agents in the induction, as well as in the progression or exacerbation of SLE. However, we are far from a plain understanding of microbial-host interactions in the pathogenesis of SLE. Much serological, molecular and geoepidemiological evidence supports the relationship of different environmental infectious triggers in the inception of SLE-related autoimmune phenomena with adjuvant effects. The promotion of autoimmune responses through bystander activation or epitope spreading via multiple inflammatory pathways has been confirmed in animal models. Different viruses have been implicated in SLE pathogenesis, particularly Epstein-Barr virus, but also parvovirus B19, cytomegalovirus and retroviruses. SLE patients usually have an impaired immune response towards Epstein-Barr virus and dysregulation of the viral latency period. Furthermore, the accumulation of endogenous retroviral products might trigger the production of interferon and anti-DNA antibodies. In addition, protozoan infections might even protect from autoimmune processes and rescind an ongoing B cell activation. Herein, we discuss which type of infections induce, exacerbate or inhibit autoimmune disorders and analyze the principal infection-induced immunological mechanisms influencing the development of SLE. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in the Pathogenesis of Systemic Lupus Erythematosus)

24 pages, 5044 KiB

Open AccessArticle

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Pathway Is Induced by Mechanical Load and Reduces the Activity of Hedgehog Signaling in Chondrogenic Micromass Cell Cultures

by Tamás Juhász^1,*

, Eszter Szentléleky¹, Csilla Szűcs Somogyi¹, Roland Takács¹

, Nóra Dobrosi¹, Máté Engler¹, Andrea Tamás², Dóra Reglődi² and Róza Zákány¹

¹ Department of Anatomy, Histology and Embryology, University of Debrecen, Medical and Health Science Centre, Nagyerdei krt. 98, H-4032 Debrecen, Hungary

² Department of Anatomy, MTA-PTE "Lendület" PACAP Research Team, University of Pécs, Medical School, Szigeti út 12, H-7624 Pécs, Hungary

Int. J. Mol. Sci. 2015, 16(8), 17344-17367; https://doi.org/10.3390/ijms160817344 - 29 Jul 2015

Cited by 21 | Viewed by 7792

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurohormone exerting protective function during various stress conditions either in mature or developing tissues. Previously we proved the presence of PACAP signaling elements in chicken limb bud-derived chondrogenic cells in micromass cell cultures. Since no [...] Read more.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurohormone exerting protective function during various stress conditions either in mature or developing tissues. Previously we proved the presence of PACAP signaling elements in chicken limb bud-derived chondrogenic cells in micromass cell cultures. Since no data can be found if PACAP signaling is playing any role during mechanical stress in any tissues, we aimed to investigate its contribution in mechanotransduction during chondrogenesis. Expressions of the mRNAs of PACAP and its major receptor, PAC1 increased, while that of other receptors, VPAC1, VPAC2 decreased upon mechanical stimulus. Mechanical load enhanced the expression of collagen type X, a marker of hypertrophic differentiation of chondrocytes and PACAP addition attenuated this elevation. Moreover, exogenous PACAP also prevented the mechanical load evoked activation of hedgehog signaling: protein levels of Sonic and Indian Hedgehogs and Gli1 transcription factor were lowered while expressions of Gli2 and Gli3 were elevated by PACAP application during mechanical load. Our results suggest that mechanical load activates PACAP signaling and exogenous PACAP acts against the hypertrophy inducing effect of mechanical load. Full article

(This article belongs to the Special Issue Molecular Machinery of Cell Growth Regulation)

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26 pages, 1273 KiB

Open AccessReview

Direct Reprogramming—The Future of Cardiac Regeneration?

by Stefanie A. Doppler^1,*, Marcus-André Deutsch¹, Rüdiger Lange^1,2 and Markus Krane^1,2

¹ Division of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich 80636, Germany

² DZHK (German Center for Cardiovascular Research)—Partner Site Munich Heart Alliance, Munich 80802, Germany

Int. J. Mol. Sci. 2015, 16(8), 17368-17393; https://doi.org/10.3390/ijms160817368 - 29 Jul 2015

Cited by 23 | Viewed by 9387

Abstract

Today, the only available curative therapy for end stage congestive heart failure (CHF) is heart transplantation. This therapeutic option is strongly limited by declining numbers of available donor hearts and by restricted long-term performance of the transplanted graft. The disastrous prognosis for CHF [...] Read more.

Today, the only available curative therapy for end stage congestive heart failure (CHF) is heart transplantation. This therapeutic option is strongly limited by declining numbers of available donor hearts and by restricted long-term performance of the transplanted graft. The disastrous prognosis for CHF with its restricted therapeutic options has led scientists to develop different concepts of alternative regenerative treatment strategies including stem cell transplantation or stimulating cell proliferation of different cardiac cell types in situ. However, first clinical trials with overall inconsistent results were not encouraging, particularly in terms of functional outcome. Among other approaches, very promising ongoing pre-clinical research focuses on direct lineage conversion of scar fibroblasts into functional myocardium, termed “direct reprogramming” or “transdifferentiation.” This review seeks to summarize strategies for direct cardiac reprogramming including the application of different sets of transcription factors, microRNAs, and small molecules for an efficient generation of cardiomyogenic cells for regenerative purposes. Full article

(This article belongs to the Special Issue Artificial Organs)

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28 pages, 785 KiB

Open AccessReview

Treatment Strategies that Enhance the Efficacy and Selectivity of Mitochondria-Targeted Anticancer Agents

by Josephine S. Modica-Napolitano^1,* and Volkmar Weissig²

¹ Department of Biology, Merrimack College, North Andover, MA 01845, USA

² Department of Pharmaceutical Sciences, Midwestern University, College of Pharmacy, Glendale, AZ 85308, USA

Int. J. Mol. Sci. 2015, 16(8), 17394-17421; https://doi.org/10.3390/ijms160817394 - 29 Jul 2015

Cited by 73 | Viewed by 8836

Abstract

Nearly a century has passed since Otto Warburg first observed high rates of aerobic glycolysis in a variety of tumor cell types and suggested that this phenomenon might be due to an impaired mitochondrial respiratory capacity in these cells. Subsequently, much has been [...] Read more.

Nearly a century has passed since Otto Warburg first observed high rates of aerobic glycolysis in a variety of tumor cell types and suggested that this phenomenon might be due to an impaired mitochondrial respiratory capacity in these cells. Subsequently, much has been written about the role of mitochondria in the initiation and/or progression of various forms of cancer, and the possibility of exploiting differences in mitochondrial structure and function between normal and malignant cells as targets for cancer chemotherapy. A number of mitochondria-targeted compounds have shown efficacy in selective cancer cell killing in pre-clinical and early clinical testing, including those that induce mitochondria permeability transition and apoptosis, metabolic inhibitors, and ROS regulators. To date, however, none has exhibited the standards for high selectivity and efficacy and low toxicity necessary to progress beyond phase III clinical trials and be used as a viable, single modality treatment option for human cancers. This review explores alternative treatment strategies that have been shown to enhance the efficacy and selectivity of mitochondria-targeted anticancer agents in vitro and in vivo, and may yet fulfill the clinical promise of exploiting the mitochondrion as a target for cancer chemotherapy. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)

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23 pages, 1245 KiB

Open AccessArticle

Combination of Aβ Secretion and Oxidative Stress in an Alzheimer-Like Cell Line Leads to the Over-Expression of the Nucleotide Excision Repair Proteins DDB2 and XPC

by Anne Forestier, Thierry Douki, Viviana De Rosa, David Béal and Walid Rachidi^*

Laboratoire Lésions des Acides Nucléiques, Université Joseph Fourier-Grenoble 1/CEA/Institut Nanoscience et Cryogénie/SCIB, UMR-E3, Grenoble, France

Int. J. Mol. Sci. 2015, 16(8), 17422-17444; https://doi.org/10.3390/ijms160817422 - 30 Jul 2015

Cited by 15 | Viewed by 6580

Abstract

Repair of oxidative DNA damage, particularly Base Excision Repair (BER), impairment is often associated with Alzheimer’s disease pathology. Here, we aimed at investigating the complete Nucleotide Excision Repair (NER), a DNA repair pathway involved in the removal of bulky DNA adducts, status in [...] Read more.

Repair of oxidative DNA damage, particularly Base Excision Repair (BER), impairment is often associated with Alzheimer’s disease pathology. Here, we aimed at investigating the complete Nucleotide Excision Repair (NER), a DNA repair pathway involved in the removal of bulky DNA adducts, status in an Alzheimer-like cell line. The level of DNA damage was quantified using mass spectrometry, NER gene expression was assessed by qPCR, and the NER protein activity was analysed through a modified version of the COMET assay. Interestingly, we found that in the presence of the Amyloid β peptide (Aβ), NER factors were upregulated at the mRNA level and that NER capacities were also specifically increased following oxidative stress. Surprisingly, NER capacities were not differentially improved following a typical NER-triggering of ultraviolet C (UVC) stress. Oxidative stress generates a differential and specific DNA damage response in the presence of Aβ. We hypothesized that the release of NER components such as DNA damage binding protein 2 (DDB2) and Xeroderma Pigmentosum complementation group C protein (XPC) following oxidative stress might putatively involve their apoptotic role rather than DNA repair function. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology)

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11 pages, 650 KiB

Open AccessArticle

Effects of Surface-Deacetylated Chitin Nanofibers in an Experimental Model of Hypercholesterolemia

by Kazuo Azuma^1,*, Tomone Nagae², Takeshi Nagai³, Hironori Izawa², Minoru Morimoto⁴, Yusuke Murahata¹, Tomohiro Osaki¹, Takeshi Tsuka¹, Tomohiro Imagawa¹, Norihiko Ito¹, Yoshiharu Okamoto¹, Hiroyuki Saimoto² and Shinsuke Ifuku^2,*

¹ Department of Clinical Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680-8533, Japan

² Graduate School of Engineering, Tottori University, Tottori 680-8552, Japan

³ Japan Food Research Laboratories, Tama 206-0025, Japan

⁴ Division of Instrumental Analysis, Research Center for Bioscience and Technology, Tottori University, Tottori 680-8550, Japan

Int. J. Mol. Sci. 2015, 16(8), 17445-17455; https://doi.org/10.3390/ijms160817445 - 30 Jul 2015

Cited by 23 | Viewed by 6432

Abstract

This study evaluated the effects of oral administration of surface-deacetylated chitin nanofibers (SDACNFs) on hypercholesterolemia using an experimental model. All rats were fed a high cholesterol diet with 1% w/w cholesterol and 0.5% w/w cholic acid for 28 days. [...] Read more.

This study evaluated the effects of oral administration of surface-deacetylated chitin nanofibers (SDACNFs) on hypercholesterolemia using an experimental model. All rats were fed a high cholesterol diet with 1% w/w cholesterol and 0.5% w/w cholic acid for 28 days. Rats were divided equally into four groups: the control group was administered 0.05% acetic acid dissolved in tap water, and the SDACNF, chitosan (CS), and cellulose nanofiber (CLNF) groups were administered 0.1% CNF, CS, or CLNF dissolved in the tap water, respectively, during the experimental period. Changes in body weight, intake of food and water, and organ weight were measured. Serum blood chemistry and histopathological examination of the liver were performed. Administration of SDACNF did not affect body weight change, food and water intake, or organ weights. Administration of SDACNF and CS decreased the diet-induced increase in serum total cholesterol, chylomicron, very-low-density lipoprotein, and phospholipid levels on day 14. Moreover, oral administration of SDACNFs suppressed the increase of alanine transaminase levels on day 29 and suppressed vacuolar degeneration and accumulation of lipid droplets in liver tissue. These data indicate that SDACNF has potential as a functional food for patients with hypercholesterolemia. Full article

(This article belongs to the Special Issue Chitins 2015)

13 pages, 683 KiB

Open AccessArticle

A Single Nucleotide Polymorphism near the CYP17A1 Gene Is Associated with Left Ventricular Mass in Hypertensive Patients under Pharmacotherapy

by Matthias Huber^1,*, Susanne Lezius², Rona Reibis³, Andras Treszl², Dorota Kujawinska¹, Stefanie Jakob¹, Karl Wegscheider², Heinz Völler^4,5 and Reinhold Kreutz¹

¹ Institute of Clinical Pharmacology and Toxicology, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany

² Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

³ Cardiological Outpatient Clinic Am Park Sanssouci, 14469 Potsdam, Germany

⁴ Klinik am See, Rehabilitation Center for Cardiovascular Diseases, 15562 Rüdersdorf, Germany

⁵ Center of Rehabilitation Research, University of Potsdam, 14469 Potsdam, Germany

Int. J. Mol. Sci. 2015, 16(8), 17456-17468; https://doi.org/10.3390/ijms160817456 - 30 Jul 2015

Cited by 11 | Viewed by 7113

Abstract

Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular [...] Read more.

Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular mass. Notably, genome wide association studies supported the role of this enzyme in BP control. Against this background, we investigated associations between single nucleotide polymorphisms (SNPs) in or nearby the CYP17A1 gene with BP and left ventricular mass in patients with arterial hypertension and associated cardiovascular organ damage treated according to guidelines. Patients (n = 1007, mean age 58.0 ± 9.8 years, 83% men) with arterial hypertension and cardiac left ventricular ejection fraction (LVEF) ≥40% were enrolled in the study. Cardiac parameters of left ventricular mass, geometry and function were determined by echocardiography. The cohort comprised patients with coronary heart disease (n = 823; 81.7%) and myocardial infarction (n = 545; 54.1%) with a mean LVEF of 59.9% ± 9.3%. The mean left ventricular mass index (LVMI) was 52.1 ± 21.2 g/m^2.7 and 485 (48.2%) patients had left ventricular hypertrophy. There was no significant association of any investigated SNP (rs619824, rs743572, rs1004467, rs11191548, rs17115100) with mean 24 h systolic or diastolic BP. However, carriers of the rs11191548 C allele demonstrated a 7% increase in LVMI (95% CI: 1%–12%, p = 0.017) compared to non-carriers. The CYP17A1 polymorphism rs11191548 demonstrated a significant association with LVMI in patients with arterial hypertension and preserved LVEF. Thus, CYP17A1 may contribute to cardiac hypertrophy in this clinical condition. Full article

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

13 pages, 859 KiB

Open AccessArticle

Interleukin-17A Gene Expression in Morbidly Obese Women

by Fernando Zapata-Gonzalez^1,†, Teresa Auguet^1,2,†, Gemma Aragonès¹, Esther Guiu-Jurado¹, Alba Berlanga¹, Salomé Martinez³, Andreu Martí², Fátima Sabench⁴, Mercé Hernandez⁴, Carmen Aguilar¹, Joan Josep Sirvent³, Rosa Jorba⁵, Daniel Del Castillo⁴ and Cristóbal Richart^1,2,*

¹ Grup de Recerca GEMMAIR (AGAUR)—Medicina Aplicada, Departament de Medicina i Cirurgia, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain

² Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007 Tarragona, Spain

³ Servei Anatomia Patològica, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007 Tarragona, Spain

⁴ Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, IISPV, Universitat Rovira i Virgili (URV), Avinguda Doctor Josep Laporte, 2, 43204 Tarragona, Spain

⁵ Servei de Cirurgia, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007 Tarragona, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17469-17481; https://doi.org/10.3390/ijms160817469 - 30 Jul 2015

Cited by 26 | Viewed by 6419

Abstract

Data from recent studies conducted in rodent models and humans suggest that interleukin-17A (IL-17A) plays a role in the induction of inflammation in adipose tissue during obesity. The aim of this study was to assess the gene expression of IL-17A in adipose tissue [...] Read more.

Data from recent studies conducted in rodent models and humans suggest that interleukin-17A (IL-17A) plays a role in the induction of inflammation in adipose tissue during obesity. The aim of this study was to assess the gene expression of IL-17A in adipose tissue of morbidly obese patients. We used RT-PCR to evaluate the expression of IL-17A and several adipo/cytokines in the visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of 10 normal-weight control women (BMI < 25 kg/m²) and 30 morbidly obese women (MO, BMI > 40 kg/m²). We measured serum levels of IL-17A and adipo/cytokines in MO and normal weight women. IL-17A expression was significantly higher in VAT than in SAT in MO patients (p = 0.0127). It was very low in normal-weight controls in both VAT and SAT tissues. We found positive correlations between IL-17A and IL-6, lipocalin-2 and resistin in VAT of MO patients. The circulating level of IL-17A was higher in the normal-weight group than the MO patients (p = 0.032), and it was significantly related to adiponectin and TNFRII levels. In conclusion, IL-17A expression in VAT is increased in morbidly obese women, which suggests a link between obesity and innate immunity in low-grade chronic inflammation in morbidly obese women. Full article

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

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12 pages, 1506 KiB

Open AccessArticle

Development of Ophiocordyceps sinensis through Plant-Mediated Interkingdom Host Colonization

by Wei Lei^1,2, Guren Zhang², Qingyun Peng² and Xin Liu^2,*

¹ Laboratory of Cardiovascular Diseases, Guangdong Medical College, Zhanjiang 524001, China

² Food and Health Engineering Research Center of State Education Ministry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

Int. J. Mol. Sci. 2015, 16(8), 17482-17493; https://doi.org/10.3390/ijms160817482 - 30 Jul 2015

Cited by 24 | Viewed by 6616

Abstract

Ophiocordyceps sinensis is a well-known entomogenous and medicinal fungus. After its anamorphs parasitize the larvae of the genus Thitarodes, fruit-bodies may form to be used as medicine. However, its developmental mechanisms remain unknown. The distribution of O. sinensis was determined in different [...] Read more.

Ophiocordyceps sinensis is a well-known entomogenous and medicinal fungus. After its anamorphs parasitize the larvae of the genus Thitarodes, fruit-bodies may form to be used as medicine. However, its developmental mechanisms remain unknown. The distribution of O. sinensis was determined in different tissues of the Thitarodes larvae and the dominant plant species using real-time quantitative polymerase chain reaction (qPCR) and fluorescence in situ hybridization (FISH) technique, respectively. We found that more fungal material was located in plants than in larvae, especially in Ranunculus tanguticus. A considerable amount was detected in larval intestinal-wall and plant roots. It is suggested that plants are the potential hosts of O. sinensis, which modifies our understanding of the life cycle of O. sinensis and indicates that the phytophagous larvae may become infected as they feed. Our research may contribute to the study of systematic evolution and population ecology of O. sinensis, elucidate its developmental mechanism and promote sustainable harvesting. Full article

(This article belongs to the Special Issue Plant Microbe Interaction)

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20 pages, 918 KiB

Open AccessReview

Molecular Mechanisms to Control Post-Transplantation Hepatitis B Recurrence

by Akinobu Takaki^1,*, Tetsuya Yasunaka¹ and Takahito Yagi²

¹ Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan

² Department of Gastroenterological Surgery Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan

Int. J. Mol. Sci. 2015, 16(8), 17494-17513; https://doi.org/10.3390/ijms160817494 - 30 Jul 2015

Cited by 8 | Viewed by 7079

Abstract

Hepatitis B often progresses to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). Although newer nucleos(t)ide analogues result in >90% viral and hepatitis activity control, severely decompensated patients still need OLT because of drug-resistant virus, acute exacerbation, or hepatocellular carcinoma. Acute hepatitis B [...] Read more.

Hepatitis B often progresses to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). Although newer nucleos(t)ide analogues result in >90% viral and hepatitis activity control, severely decompensated patients still need OLT because of drug-resistant virus, acute exacerbation, or hepatocellular carcinoma. Acute hepatitis B is also an indication for OLT, because it can progress to fatal acute liver failure. After OLT, the hepatitis B recurrence rate is >80% without prevention, while >90% of transplant recipients are clinically controlled with combined hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogue treatment. However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost; therefore, several treatment protocols with low-dose HBIG, combined with nucleos(t)ide analogues, have been investigated. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using an HBV envelope (HBs) antigen vaccine. Patients who are not HBV carriers, such as those with acutely infected liver failure, are good candidates for vaccination. For chronic HBV carrier liver cirrhosis patients, a successful vaccine response can only be achieved in selected patients, such as those treated with experimentally reduced immunosuppression protocols. The present protocol for post-OLT HBV control and the future prospects of newer treatment strategies are reviewed. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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21 pages, 1355 KiB

Open AccessReview

Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine

by Vittorio Simeon^1,*,†, Katia Todoerti^1,†, Francesco La Rocca¹

, Antonella Caivano¹, Stefania Trino¹, Marta Lionetti², Luca Agnelli²

, Luciana De Luca¹

, Ilaria Laurenzana¹, Antonino Neri² and Pellegrino Musto³

¹ Laboratory of Pre-Clinical and Translational Research, Reference Cancer Center of Basilicata, Scientific Institute of Hospitalization and Treatment, Rionero in Vulture 85028, Italy

² Department of Clinical Sciences and Community Health, University of Milan and Hematology, Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan 20122, Italy

³ Scientific Direction, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture 85028, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17514-17534; https://doi.org/10.3390/ijms160817514 - 30 Jul 2015

Cited by 22 | Viewed by 8132

Abstract

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last [...] Read more.

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL). Full article

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

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11 pages, 1015 KiB

Open AccessArticle

Features in the Lipid Status of Two Generations of Fingerlings (0+) of Atlantic Salmon (Salmo salar L.) Inhabiting the Arenga River (Kola Peninsula)

by Nina N. Nemova^1,†, Svetlana A. Murzina^1,*, Zinaida A. Nefedova^1,† and Alexey E. Veselov^2,†

¹ Environmental Biochemistry Lab, Institute of Biology, Karelian Research Centre of the Russian Academy of Sciences, Pushkinskaya st., 11, 185910 Petrozavodsk, Russia

² Fish and Aquatic Invertebrate Ecology Lab, Institute of Biology, Karelian Research Centre of the Russian Academy of Sciences, Pushkinskaya st., 11, 185910 Petrozavodsk, Russia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17535-17545; https://doi.org/10.3390/ijms160817535 - 30 Jul 2015

Cited by 4 | Viewed by 4015

Abstract

The present research focused on determining the lipid status of salmon fingerlings (0+) in early development after dispersal form groups of spawning nests in biotopes of different hydrological conditions. The revealed qualitative and quantitative differences in the levels of phospholipids and fatty acids [...] Read more.

The present research focused on determining the lipid status of salmon fingerlings (0+) in early development after dispersal form groups of spawning nests in biotopes of different hydrological conditions. The revealed qualitative and quantitative differences in the levels of phospholipids and fatty acids among two generations of Atlantic salmon fingerlings (0+) living in different biotopes of the Arenga River (a tributary of the Varzuga River) may be associated with the peculiarities of their genetically determined processes of the biosynthesis and modification of individual lipid classes and trophoecological factors (food spectrum, quality and availability of food objects, and hydrological regime). The research was organized to observe the dynamics of these developmental changes from ages 0+ to 2+. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 1192 KiB

Open AccessArticle

Economic Assessment of Supercritical CO₂ Extraction of Waxes as Part of a Maize Stover Biorefinery

by Thomas M. Attard, Con Robert McElroy and Andrew J. Hunt^*

Department of Chemistry, University of York, Heslington, York YO10 5DD, UK

Int. J. Mol. Sci. 2015, 16(8), 17546-17564; https://doi.org/10.3390/ijms160817546 - 31 Jul 2015

Cited by 57 | Viewed by 8588

Abstract

To date limited work has focused on assessing the economic viability of scCO₂ extraction to obtain waxes as part of a biorefinery. This work estimates the economic costs for wax extraction from maize stover. The cost of manufacture (COM) for [...] Read more.

To date limited work has focused on assessing the economic viability of scCO₂ extraction to obtain waxes as part of a biorefinery. This work estimates the economic costs for wax extraction from maize stover. The cost of manufacture (COM) for maize stover wax extraction was found to be €88.89 per kg of wax, with the fixed capital investment (FCI) and utility costs (C_UT) contributing significantly to the COM. However, this value is based solely on scCO₂ extraction of waxes and does not take into account the downstream processing of the biomass following extraction. The cost of extracting wax from maize stover can be reduced by utilizing pelletized leaves and combusting the residual biomass to generate electricity. This would lead to an overall cost of €10.87 per kg of wax (based on 27% combustion efficiency for electricity generation) and €4.56 per kg of wax (based on 43% combustion efficiency for electricity generation). A sensitivity analysis study showed that utility costs (cost of electricity) had the greatest effect on the COM. Full article

(This article belongs to the Special Issue Green Chemistry and the Biorefinery)

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24 pages, 1660 KiB

Open AccessReview

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

by Ahmed Abdelhak¹, Andreas Junker², Johannes Brettschneider¹, Jan Kassubek¹

, Albert C. Ludolph¹, Markus Otto¹ and Hayrettin Tumani^1,*

¹ Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081 Ulm, Germany

² Institute of Neuropathology, University Hospital Göttingen, Robert-Koch-Str 40, 37075 Göttingen, Germany

Int. J. Mol. Sci. 2015, 16(8), 17565-17588; https://doi.org/10.3390/ijms160817565 - 31 Jul 2015

Cited by 25 | Viewed by 13710

Abstract

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and [...] Read more.

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs. Full article

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

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22 pages, 1049 KiB

Open AccessReview

Progress and Prospects of Anti-HBV Gene Therapy Development

by Mohube B. Maepa, Ilke Roelofse, Abdullah Ely and Patrick Arbuthnot^*

Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, Health Sciences Faculty, University of the Witwatersrand, Wits 2050, South Africa

Int. J. Mol. Sci. 2015, 16(8), 17589-17610; https://doi.org/10.3390/ijms160817589 - 31 Jul 2015

Cited by 35 | Viewed by 11988

Abstract

Despite the availability of an effective vaccine against hepatitis B virus (HBV), chronic infection with the virus remains a major global health concern. Current drugs against HBV infection are limited by emergence of resistance and rarely achieve complete viral clearance. This has prompted [...] Read more.

Despite the availability of an effective vaccine against hepatitis B virus (HBV), chronic infection with the virus remains a major global health concern. Current drugs against HBV infection are limited by emergence of resistance and rarely achieve complete viral clearance. This has prompted vigorous research on developing better drugs against chronic HBV infection. Advances in understanding the life cycle of HBV and improvements in gene-disabling technologies have been impressive. This has led to development of better HBV infection models and discovery of new drug candidates. Ideally, a regimen against chronic HBV infection should completely eliminate all viral replicative intermediates, especially covalently closed circular DNA (cccDNA). For the past few decades, nucleic acid-based therapy has emerged as an attractive alternative that may result in complete clearance of HBV in infected patients. Several genetic anti-HBV strategies have been developed. The most studied approaches include the use of antisense oligonucleotides, ribozymes, RNA interference effectors and gene editing tools. This review will summarize recent developments and progress made in the use of gene therapy against HBV. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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26 pages, 8651 KiB

Open AccessArticle

RNase L Cleavage Products Promote Switch from Autophagy to Apoptosis by Caspase-Mediated Cleavage of Beclin-1

by Mohammad Adnan Siddiqui, Sushovita Mukherjee, Praveen Manivannan and Krishnamurthy Malathi^*

Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA

Int. J. Mol. Sci. 2015, 16(8), 17611-17636; https://doi.org/10.3390/ijms160817611 - 31 Jul 2015

Cited by 51 | Viewed by 11871

Abstract

Autophagy and apoptosis share regulatory molecules enabling crosstalk in pathways that affect cellular homeostasis including response to viral infections and survival of tumor cells. Ribonuclease L (RNase L) is an antiviral endonuclease that is activated in virus-infected cells and cleaves viral and cellular [...] Read more.

Autophagy and apoptosis share regulatory molecules enabling crosstalk in pathways that affect cellular homeostasis including response to viral infections and survival of tumor cells. Ribonuclease L (RNase L) is an antiviral endonuclease that is activated in virus-infected cells and cleaves viral and cellular single-stranded RNAs to produce small double-stranded RNAs with roles in amplifying host responses. Activation of RNase L induces autophagy and apoptosis in many cell types. However, the mechanism by which RNase L mediates crosstalk between these two pathways remains unclear. Here we show that small dsRNAs produced by RNase L promote a switch from autophagy to apoptosis by caspase-mediated cleavage of Beclin-1, terminating autophagy. The caspase 3-cleaved C-terminal fragment of Beclin-1 enhances apoptosis by translocating to the mitochondria along with proapoptotic protein, Bax, and inducing release of cytochrome C to the cytosol. Cleavage of Beclin-1 determines switch to apoptosis since expression of caspase-resistant Beclin-1 inhibits apoptosis and sustains autophagy. Moreover, inhibiting RNase L-induced autophagy promotes cell death and inhibiting apoptosis prolongs autophagy in a cross-inhibitory mechanism. Our results demonstrate a novel role of RNase L generated small RNAs in cross-talk between autophagy and apoptosis that impacts the fate of cells during viral infections and cancer. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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18 pages, 1644 KiB

Open AccessArticle

Validation of FRET Assay for the Screening of Growth Inhibitors of Escherichia coli Reveals Elongasome Assembly Dynamics

by René Van der Ploeg, Spyridon Theodoros Goudelis and Tanneke Den Blaauwen^*

Bacterial Cell Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherland

Int. J. Mol. Sci. 2015, 16(8), 17637-17654; https://doi.org/10.3390/ijms160817637 - 31 Jul 2015

Cited by 21 | Viewed by 7442

Abstract

The increase in antibiotic resistant bacteria demands the development of new antibiotics against preferably new targets. The common approach is to test compounds for their ability to kill bacteria or to design molecules that inhibit essential protein activities in vitro. In the [...] Read more.

The increase in antibiotic resistant bacteria demands the development of new antibiotics against preferably new targets. The common approach is to test compounds for their ability to kill bacteria or to design molecules that inhibit essential protein activities in vitro. In the first case, the mode of action of the drug is unknown and in the second case, it is not known whether the compound will pass the impermeable barrier of the bacterial envelope. We developed an assay that detects the target of a compound, as well as its ability to pass the membrane(s) simultaneously. The Escherichia coli cytoskeletal protein MreB recruits protein complexes (elongasomes) that are essential for cell envelope growth. An in cell Förster Resonance Energy Transfer (FRET) assay was developed to detect the interaction between MreB molecules and between MreB and the elongasome proteins RodZ, RodA and PBP2. Inhibition of the polymerization of MreB by S-(3,4-dichlorobenzyl) isothiourea (A22) or of the activity of PBP2 by mecilinam resulted in loss or reduction of all measured interactions. This suggests that the interactions between the elongasome proteins are governed by a combination of weak affinities and substrate availability. This validated in cell FRET assay can be used to screen for cell envelope growth inhibitors. Full article

(This article belongs to the Special Issue Förster Resonance Energy Transfer (FRET) 2015)

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13 pages, 1288 KiB

Open AccessArticle

High Expression of LAMP3 Is a Novel Biomarker of Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma

by Xiaoyu Liao^†, Yuanbin Chen^†, Deqing Liu, Fangfang Li, Xizhao Li and Weihua Jia^*

¹ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17655-17667; https://doi.org/10.3390/ijms160817655 - 31 Jul 2015

Cited by 33 | Viewed by 5843

Abstract

Lysosomal-associated membrane protein 3 (LAMP3), identified as a molecular marker of mature dendritic cells, is one of the LAMP family members. Its expression was induced by hypoxia, and was associated with hypoxia mediated metastasis in breast and cervical cancers. However, epithelial expression of [...] Read more.

Lysosomal-associated membrane protein 3 (LAMP3), identified as a molecular marker of mature dendritic cells, is one of the LAMP family members. Its expression was induced by hypoxia, and was associated with hypoxia mediated metastasis in breast and cervical cancers. However, epithelial expression of LAMP3 and its prognostic value in esophageal squamous cell carcinoma (ESCC) is still unknown. In the current study, mRNA expression of LAMP3 in 157 ESCC tissues and 50 adjacent normal tissues was detected by quantitative real-time PCR (qRT-PCR). LAMP3 protein expression in 46 paired cancerous and normal tissues was detected by immunohistochemistry (IHC). Then, DNA copy number was examined to observe its potential correlation with mRNA expression. The results showed that both mRNA and protein expression level of LAMP3 was significantly higher in cancerous tissues compared with normal controls (p < 0.001). LAMP3 DNA copy number was amplified in 70% of ESCC tissues and positive correlated with mRNA expression (p = 0.037). Furthermore, patients with higher LAMP3 expression had worse overall survival (HR = 1.90, 95% CI = 1.17–3.09, p = 0.010) and disease-free survival (HR = 1.80, 95% CI = 1.18–2.74, p = 0.006). In conclusion, our results suggest that epithelial LAMP3 expression is an independent prognostic biomarker for ESCC. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 1989 KiB

Open AccessArticle

Unveiling the Mode of Action of Two Antibacterial Tanshinone Derivatives

by Dongdong Wang, Wuxia Zhang, Tingting Wang, Na Li, Haibo Mu, Jiwen Zhang and Jinyou Duan^*

College of Science, Northwest A&F University, Yangling 712100, Shaanxi, China

Int. J. Mol. Sci. 2015, 16(8), 17668-17681; https://doi.org/10.3390/ijms160817668 - 31 Jul 2015

Cited by 43 | Viewed by 7384

Abstract

In this study, 2-(N-pyrrolidine-alkyl) tanshinones bearing pyrrolidine groups were synthesized and the antibacterial mechanism was explored. These derivatives selectively elicited antibacterial activity against Gram-positive bacteria. Moreover, their antibacterial activities were time-, concentration-dependent and persistent. It appeared that Fenton-mediated hydroxyl radicals were [...] Read more.

In this study, 2-(N-pyrrolidine-alkyl) tanshinones bearing pyrrolidine groups were synthesized and the antibacterial mechanism was explored. These derivatives selectively elicited antibacterial activity against Gram-positive bacteria. Moreover, their antibacterial activities were time-, concentration-dependent and persistent. It appeared that Fenton-mediated hydroxyl radicals were involved, and the disruption of cell membranes was observed. This study indicates that 2-(N-pyrrolidine-alkyl) tanshinones might be potential candidates as antibacterial agents. Full article

(This article belongs to the Section Materials Science)

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14 pages, 1462 KiB

Open AccessArticle

MiR-30b Is Involved in the Homocysteine-Induced Apoptosis in Human Coronary Artery Endothelial Cells by Regulating the Expression of Caspase 3

by Feng Li^1,†, Qi Chen^1,†, Xiaowei Song¹, Lei Zhou² and Jianliang Zhang^1,*

¹ Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China

² Department of Cadre Recuperation, Navy Medical Service Sanatorium, Hangzhou 310002, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17682-17695; https://doi.org/10.3390/ijms160817682 - 31 Jul 2015

Cited by 32 | Viewed by 6952

Abstract

Homocysteine (Hcy) is an independent risk factor for a variety of cardiovascular diseases, such as coronary heart disease, hypertension, stroke, etc. There is a close relationship between the vascular endothelial cell apoptosis and these diseases. Recent studies have shown homocysteine can induce [...] Read more.

Homocysteine (Hcy) is an independent risk factor for a variety of cardiovascular diseases, such as coronary heart disease, hypertension, stroke, etc. There is a close relationship between the vascular endothelial cell apoptosis and these diseases. Recent studies have shown homocysteine can induce apoptosis in endothelial cells, which may be an important mechanism for the development of theses cardiovascular diseases. Although there are several reports about how the Hcy induces apoptosis in endothelial cells, the exact mechanism is not fully understood. MicroRNAs are small, non-coding RNA. Previous studies have shown that there is a close relationship between several microRNAs and cell apoptosis. However, there are no studies about the role of microRNAs in Hcy-induced apoptosis in endothelial cells so far. In this study, we constructed the model of homocysteine-induced apoptosis in human coronary artery endothelial cells (HCAECs) and found miR-30b was significantly down-regulated by 1 mmol/L Hcy. In addition, overexpression of miR-30b can improve the Hcy-induced apoptosis in HCAECs by downregulating caspase-3 expression. Therefore, miR-30b may play an important role in Hcy-induced apoptosis in endothelial cells. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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23 pages, 1013 KiB

Open AccessArticle

Evaluation of Antioxidant, Antidiabetic and Anticholinesterase Activities of Smallanthus sonchifolius Landraces and Correlation with Their Phytochemical Profiles

by Daniela Russo^1,*, Patrícia Valentão²

, Paula B. Andrade²

, Eloy C. Fernandez³ and Luigi Milella^1,*

¹ Department of Science, Basilicata University, 85100 Potenza, Italy

² Rede de Química e Tecnologia/Laboratório Associado para a Química Verde (REQUIMTE/LAQV), Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal

³ Department of Crop Sciences and Agroforestry, Faculty of Tropical AgriSciences, Czech University of Life Sciences, 165 21 Prague, Czech Republic

Int. J. Mol. Sci. 2015, 16(8), 17696-17718; https://doi.org/10.3390/ijms160817696 - 31 Jul 2015

Cited by 107 | Viewed by 11492

Abstract

The present study aimed to investigate the phytochemical profile of leaf methanol extracts of fourteen Smallanthus sonchifolius (yacon) landraces and their antioxidant, anticholinesterase and antidiabetic activities that could lead to the finding of more effective agents for the treatment and management of Alzheimer’s [...] Read more.

The present study aimed to investigate the phytochemical profile of leaf methanol extracts of fourteen Smallanthus sonchifolius (yacon) landraces and their antioxidant, anticholinesterase and antidiabetic activities that could lead to the finding of more effective agents for the treatment and management of Alzheimer’s disease and diabetes. For this purpose, antioxidant activity was assessed using different tests: ferric reducing ability power (FRAP), 2,2-diphenyl-1-picryl hydrazyl (DPPH), nitric oxide (˙NO) and superoxide (O₂˙⁻) scavenging and lipid peroxidation inhibition assays. Anticholinesterase activity was investigated by quantifying the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, whereas antidiabetic activity was investigated by α-amylase and α-glucosidase inhibition tests. To understand the contribution of metabolites, phytochemical screening was also performed by high performance liquid chromatography-diode array detector (HPLC-DAD) system. Among all, methanol extract of PER09, PER04 and ECU44 landraces exhibited the highest relative antioxidant capacity index (RACI). ECU44 was found to be rich in 4,5-di-O-caffeoylquinic acid (CQA) and 3,5-di-O-CQA and displayed a good α-amylase and α-glucosidase inhibition, showing the lowest IC₅₀ values. Flavonoids, instead, seem to be involved in the AChE and BChE inhibition. The results of this study revealed that the bioactive compound content differences could be determinant for the medicinal properties of this plant especially for antioxidant and antidiabetic activities. Full article

(This article belongs to the Special Issue Phenolics and Polyphenolics 2015)

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15 pages, 2539 KiB

Open AccessArticle

Colloidal Stability & Conformational Changes in β-Lactoglobulin: Unfolding to Self-Assembly

by Steven Blake, Samiul Amin^*, Wei Qi, Madhabi Majumdar and E. Neil Lewis

Malvern Instruments, 7221 Lee Deforest Drive, Suite 300, Columbia, MD 21046, USA

Int. J. Mol. Sci. 2015, 16(8), 17719-17733; https://doi.org/10.3390/ijms160817719 - 3 Aug 2015

Cited by 12 | Viewed by 7579

Abstract

A detailed understanding of the mechanism of unfolding, aggregation, and associated rheological changes is developed in this study for β-Lactoglobulin at different pH values through concomitant measurements utilizing dynamic light scattering (DLS), optical microrheology, Raman spectroscopy, and differential scanning calorimetry (DSC). The diffusion [...] Read more.

A detailed understanding of the mechanism of unfolding, aggregation, and associated rheological changes is developed in this study for β-Lactoglobulin at different pH values through concomitant measurements utilizing dynamic light scattering (DLS), optical microrheology, Raman spectroscopy, and differential scanning calorimetry (DSC). The diffusion interaction parameter k_D emerges as an accurate predictor of colloidal stability for this protein consistent with observed aggregation trends and rheology. Drastic aggregation and gelation were observed at pH 5.5. Under this condition, the protein’s secondary and tertiary structures changed simultaneously. At higher pH (7.0 and 8.5), oligomerizaton with no gel formation occurred. For these solutions, tertiary structure and secondary structure transitions were sequential. The low frequency Raman data, which is a good indicator of hydrogen bonding and structuring in water, has been shown to exhibit a strong correlation with the rheological evolution with temperature. This study has, for the first time, demonstrated that this low frequency Raman data, in conjunction with the DSC endotherm, can be been utilized to deconvolve protein unfolding and aggregation/gelation. These findings can have important implications for the development of protein-based biotherapeutics, where the formulation viscosity, aggregation, and stability strongly affects efficacy or in foods where protein structuring is critical for functional and sensory performance. Full article

(This article belongs to the Special Issue Protein Folding)

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12 pages, 2243 KiB

Open AccessArticle

BAMBI Promotes C2C12 Myogenic Differentiation by Enhancing Wnt/β-Catenin Signaling

by Qiangling Zhang, Xin-E Shi, Chengchuang Song, Shiduo Sun, Gongshe Yang

and Xiao Li^*

Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China

Int. J. Mol. Sci. 2015, 16(8), 17734-17745; https://doi.org/10.3390/ijms160817734 - 3 Aug 2015

Cited by 30 | Viewed by 9403

Abstract

Bone morphogenic protein and activin membrane-bound inhibitor (BAMBI) is regarded as an essential regulator of cell proliferation and differentiation that represses transforming growth factor-β and enhances Wnt/β-catenin signaling in various cell types. However, its role in skeletal muscle remains largely unknown. [...] Read more.

Bone morphogenic protein and activin membrane-bound inhibitor (BAMBI) is regarded as an essential regulator of cell proliferation and differentiation that represses transforming growth factor-β and enhances Wnt/β-catenin signaling in various cell types. However, its role in skeletal muscle remains largely unknown. In the current study, we found that the expression level of BAMBI peaked in the early differentiation phase of the C2C12 rodent myoblast cell line. Knockdown of BAMBI via siRNA inhibited C2C12 differentiation, indicated by repressed MyoD, MyoG, and MyHC expression as well as reductions in the differentiation and fusion indices. BAMBI knockdown reduced the activity of Wnt/β-catenin signaling, as characterized by the decreased nuclear translocation of β-catenin and the lowered transcription of Axin2, which is a well-documented target gene of the Wnt/β-catenin signaling pathway. Furthermore, treatment with LiCl, an activator of Wnt/β-catenin signaling, rescued the reduction in C2C12 differentiation caused by BAMBI siRNA. Taken together, our data suggest that BAMBI is required for normal C2C12 differentiation, and that its role in myogenesis is mediated by the Wnt/β-catenin pathway. Full article

(This article belongs to the Special Issue Molecular Machinery of Cell Growth Regulation)

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17 pages, 1108 KiB

Open AccessReview

Hepatitis B Virus Infection, MicroRNAs and Liver Disease

by Neelakshi Sarkar and Runu Chakravarty^*

ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata-700010, India

Int. J. Mol. Sci. 2015, 16(8), 17746-17762; https://doi.org/10.3390/ijms160817746 - 3 Aug 2015

Cited by 43 | Viewed by 8133

Abstract

Hepatitis B virus (HBV) attacks the liver and can cause both acute as well as chronic liver diseases which might lead to liver cirrhosis and hepatocellular carcinoma. Regardless of the availability of a vaccine and numerous treatment options, HBV is a major cause [...] Read more.

Hepatitis B virus (HBV) attacks the liver and can cause both acute as well as chronic liver diseases which might lead to liver cirrhosis and hepatocellular carcinoma. Regardless of the availability of a vaccine and numerous treatment options, HBV is a major cause of morbidity and mortality across the world. Recently,microRNAs (miRNAs) have emerged as important modulators of gene function. Studies on the role of miRNA in the regulation of hepatitis B virus gene expression have been the focus of modern antiviral research. miRNAs can regulate viral replication and pathogenesis in a number of different ways, which includefacilitation, direct or indirect inhibition, activation of immune response, epigenetic modulation, etc. Nevertheless, these mechanisms can appropriately be used with a diagnosticand/or therapeutic approach. The present review is an attempt to classify specific miRNAs that are reported to be associated with various aspects of hepatitis B biology, in order to precisely present the participation of individual miRNAs in multiple aspects relating to HBV. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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16 pages, 880 KiB

Open AccessReview

Mitochondrial Mechanisms in Septic Cardiomyopathy

by María Cecilia Cimolai^1,2, Silvia Alvarez², Christoph Bode¹ and Heiko Bugger^1,*

¹ Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Str. 55, 79106 Freiburg, Germany

² Institute of Biochemistry and Molecular Medicine, School of Pharmacy and Biochemistry, University of Buenos Aires-National Scientific and Technical Research Council (UBA-CONICET), Junín 956, C1113AAD Buenos Aires, Argentina

Int. J. Mol. Sci. 2015, 16(8), 17763-17778; https://doi.org/10.3390/ijms160817763 - 3 Aug 2015

Cited by 132 | Viewed by 13331

Abstract

Sepsis is the manifestation of the immune and inflammatory response to infection that may ultimately result in multi organ failure. Despite the therapeutic strategies that have been used up to now, sepsis and septic shock remain a leading cause of death in critically [...] Read more.

Sepsis is the manifestation of the immune and inflammatory response to infection that may ultimately result in multi organ failure. Despite the therapeutic strategies that have been used up to now, sepsis and septic shock remain a leading cause of death in critically ill patients. Myocardial dysfunction is a well-described complication of severe sepsis, also referred to as septic cardiomyopathy, which may progress to right and left ventricular pump failure. Many substances and mechanisms seem to be involved in myocardial dysfunction in sepsis, including toxins, cytokines, nitric oxide, complement activation, apoptosis and energy metabolic derangements. Nevertheless, the precise underlying molecular mechanisms as well as their significance in the pathogenesis of septic cardiomyopathy remain incompletely understood. A well-investigated abnormality in septic cardiomyopathy is mitochondrial dysfunction, which likely contributes to cardiac dysfunction by causing myocardial energy depletion. A number of mechanisms have been proposed to cause mitochondrial dysfunction in septic cardiomyopathy, although it remains controversially discussed whether some mechanisms impair mitochondrial function or serve to restore mitochondrial function. The purpose of this review is to discuss mitochondrial mechanisms that may causally contribute to mitochondrial dysfunction and/or may represent adaptive responses to mitochondrial dysfunction in septic cardiomyopathy. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)

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19 pages, 5186 KiB

Open AccessArticle

Ovine Hair Follicle Stem Cells Derived from Single Vibrissae Reconstitute Haired Skin

by Huishan Zhang¹, Shoubing Zhang², Huashan Zhao^1,3, Jingqiao Qiao¹, Shuang Liu¹, Zhili Deng^1,3, Xiaohua Lei¹, Lina Ning¹, Yujing Cao¹, Yong Zhao⁴ and Enkui Duan^1,*

¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

² Department of Histology & Embryology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China

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

⁴ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

Int. J. Mol. Sci. 2015, 16(8), 17779-17797; https://doi.org/10.3390/ijms160817779 - 3 Aug 2015

Cited by 13 | Viewed by 8376

Abstract

Hair follicle stem cells (HFSCs) possess fascinating self-renewal capacity and multipotency, which play important roles in mammalian hair growth and skin wound repair. Although HFSCs from other mammalian species have been obtained, the characteristics of ovine HFSCs, as well as the methods to [...] Read more.

Hair follicle stem cells (HFSCs) possess fascinating self-renewal capacity and multipotency, which play important roles in mammalian hair growth and skin wound repair. Although HFSCs from other mammalian species have been obtained, the characteristics of ovine HFSCs, as well as the methods to isolate them have not been well addressed. Here, we report an efficient strategy to obtain multipotent ovine HFSCs. Through microdissection and organ culture, we obtained keratinocytes that grew from the bulge area of vibrissa hair follicles, and even abundant keratinocytes were harvested from a single hair follicle. These bulge-derived keratinocytes are highly positive for Krt15, Krt14, Tp63, Krt19 and Itga6; in addition to their strong proliferation abilities in vitro, these keratinocytes formed new epidermis, hair follicles and sebaceous glands in skin reconstitution experiments, showing that these are HFSCs from the bulge outer root sheath. Taken together, we developed an efficient in vitro system to enrich ovine HFSCs, providing enough HFSCs for the investigations about the ovine hair cycle, aiming to promote wool production in the future. Full article

(This article belongs to the Special Issue Molecular Research of Epidermal Stem Cells 2015)

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14 pages, 1652 KiB

Open AccessArticle

2,6-Bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)pyridine and Its Benzene Analog as Nonmetallic Cleaving Agents of RNA Phosphodiester Linkages

by Luigi Lain, Salla Lahdenpohja, Harri Lönnberg

and Tuomas Lönnberg^*

Department of Chemistry, University of Turku, Vatselankatu 2, FIN-20014 Turku, Finland

Int. J. Mol. Sci. 2015, 16(8), 17798-17811; https://doi.org/10.3390/ijms160817798 - 3 Aug 2015

Cited by 4 | Viewed by 5550

Abstract

2,6-Bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)pyridine (11a) and 1,3-bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)benzene (11b) have been shown to accelerate at 50 mmol·L⁻¹ concentration both the cleavage and mutual isomerization of uridylyl-3′,5′-uridine and uridylyl-2′,5′-uridine by up to two orders of magnitude. The catalytically active ionic forms are the [...] Read more.

2,6-Bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)pyridine (11a) and 1,3-bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)benzene (11b) have been shown to accelerate at 50 mmol·L⁻¹ concentration both the cleavage and mutual isomerization of uridylyl-3′,5′-uridine and uridylyl-2′,5′-uridine by up to two orders of magnitude. The catalytically active ionic forms are the tri- (in the case of 11b) tetra- and pentacations. The pyridine nitrogen is not critical for efficient catalysis, since the activity of 11b is even slightly higher than that of 11a. On the other hand, protonation of the pyridine nitrogen still makes 11a approximately four times more efficient as a catalyst, but only for the cleavage reaction. Interestingly, the respective reactions of adenylyl-3′,5′-adenosine were not accelerated, suggesting that the catalysis is base moiety selective. Full article

(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)

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14 pages, 689 KiB

Open AccessArticle

Composition, Cytotoxic and Antimicrobial Activities of Satureja intermedia C.A.Mey Essential Oil

by Javad Sharifi-Rad^1,2

, Mehdi Sharifi-Rad³

, Seyedeh Mahsan Hoseini-Alfatemi^4,*, Marcello Iriti^5,*

, Majid Sharifi-Rad⁶

and Marzieh Sharifi-Rad⁷

¹ Zabol Medicinal Plants Research Center, Zabol University of Medical Sciences, Zabol 61615-585, Iran

² Department of Pharmacognosy, Faculty of Pharmacy, Zabol University of Medical Sciences, Zabol 61615-585, Iran

³ Department of Medical Parasitology, Zabol University of Medical Sciences, Zabol 61663-335, Iran

⁴ Pediatric Infections Research Center, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran 15468-15514, Iran

⁵ Department of Agricultural and Environmental Sciences, Milan State University, via G. Celoria 2, Milan 20133, Italy

⁶ Department of Range and Watershed Management, Faculty of Natural Resources, University of Zabol, Zabol 98615-538, Iran

⁷ Department of Chemistry, Faculty of Science, University of Zabol, Zabol 98615-538, Iran

Int. J. Mol. Sci. 2015, 16(8), 17812-17825; https://doi.org/10.3390/ijms160817812 - 3 Aug 2015

Cited by 60 | Viewed by 7590

Abstract

In this study, the essential oil (EO) constituents from the aerial parts of Satureja intermedia C.A.Mey were detected by GC and GC/MS. The antimicrobial activity of EO on oral pathogens and its cytotoxicity to human cancer cells were determined by the microbroth dilution [...] Read more.

In this study, the essential oil (EO) constituents from the aerial parts of Satureja intermedia C.A.Mey were detected by GC and GC/MS. The antimicrobial activity of EO on oral pathogens and its cytotoxicity to human cancer cells were determined by the microbroth dilution method and the crystal violet staining method, respectively. Thirty-nine compounds were identified and the main EO constituents were γ-terpinene (37.1%), thymol (30.2%), p-cymene (16.2%), limonene (3.9%), α-terpinene (3.3%), myrcene (2.5%), germacrene B (1.4%), elemicine (1.1%) and carvacrol (0.5%). The S. intermedia EO showed a concentration-dependent decrease in viability of Hep-G2 (hepatocellular carcinoma) and MCF-7 (breast adenocarcinoma) human cancer cell lines (p < 0.05). Antimicrobial screening of S. intermedia EO demonstrated slight antibacterial and antifungal activities against Streptococcus mutants, S. salivarius, Enterococcus faecalis, Staphylococcus aureus, Candida albicans and C. glabrata. Further preclinical studies are needed to assess the efficacy and safety of S. intermedia EO as a new promising anticancer agent. Full article

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

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12 pages, 1033 KiB

Open AccessArticle

Renal Transcriptome Analysis of Programmed Hypertension Induced by Maternal Nutritional Insults

by You-Lin Tain^1,2,*

, Chien-Ning Hsu^3,4

, Julie Y. H. Chan² and Li-Tung Huang^1,5

¹ Departments of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

² Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

³ Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan

⁴ School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan

⁵ Department of Traditional Chinese Medicine, Chang Gung University, Linkow 244, Taiwan

Int. J. Mol. Sci. 2015, 16(8), 17826-17837; https://doi.org/10.3390/ijms160817826 - 3 Aug 2015

Cited by 45 | Viewed by 6456

Abstract

Maternal nutrition can affect development, leading to long-term effects on the health of offspring. The most common outcome is programmed hypertension. We examined whether alterations in renal transcriptome are responsible for generating programmed hypertension among four different models using next-generation RNA sequencing (NGS) [...] Read more.

Maternal nutrition can affect development, leading to long-term effects on the health of offspring. The most common outcome is programmed hypertension. We examined whether alterations in renal transcriptome are responsible for generating programmed hypertension among four different models using next-generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received 50% caloric restriction (CR), intraperitoneal injection of 45 mg/kg streptozotocin, 60% high-fructose (HF) diet, or 1% NaCl in drinking water to conduct CR, diabetes, HF, or high-salt models, respectively. All four models induced programmed hypertension in adult male offspring. We observed 16 shared genes in a two-week-old kidney among four different models. The identified differential expressed genes (DEGs) that are related to the regulation of blood pressure included Adrb3, Alb, Apoe, Calca, Kng1, Adm2, Guca2b, Hba2, Hba-a2, and Ppara. The peroxisome proliferator-activated receptor (PPAR) signaling pathway and glutathione metabolism pathway were shared by the CR, diabetes, and HF models. Conclusively, a variety of maternal nutritional insults induced the same phenotype—programmed hypertension with differential alterations of renal transcriptome in adult male offspring. The roles of DEGs identified by the NGS in this study deserve further clarification to develop ideal maternal dietary interventions and thus spare the next generations from the burden of hypertension. Full article

(This article belongs to the Special Issue Nutrigenetics and Nutrigenomics)

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19 pages, 3041 KiB

Open AccessCommunication

Direct Injection of CRISPR/Cas9-Related mRNA into Cytoplasm of Parthenogenetically Activated Porcine Oocytes Causes Frequent Mosaicism for Indel Mutations

by Masahiro Sato^1,*,†

, Miyu Koriyama^2,†, Satoshi Watanabe³, Masato Ohtsuka⁴

, Takayuki Sakurai⁵, Emi Inada⁶, Issei Saitoh⁷, Shingo Nakamura⁸

and Kazuchika Miyoshi²

¹ Section of Gene Expression Regulation, Frontier Science Research Center, Kagoshima University, Kagoshima 890-8544, Japan

² Laboratory of Animal Reproduction, Faculty of Agriculture, Kagoshima University, Kagoshima 890-0065, Japan

³ Animal Genome Research Unit, Division of Animal Science, National Institute of Agrobiological Sciences, Ibaraki 305-8602, Japan

⁴ Division of Basic Molecular Science and Molecular Medicine, School of Medicine, Tokai University, Kanagawa 259-1193, Japan

⁵ Department of Cardiovascular Research, Graduate school of Medicine, Shinshu University, Nagano 390-8621, Japan

⁶ Department of Pediatric Dentistry, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan

⁷ Division of Pediatric Dentistry, Department of Oral Health Sciences, Course for Oral Life Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan

⁸ Division of Biomedical Engineering, National Defense Medical College Research Institute, Saitama 359-8513, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17838-17856; https://doi.org/10.3390/ijms160817838 - 3 Aug 2015

Cited by 53 | Viewed by 11938

Abstract

Some reports demonstrated successful genome editing in pigs by one-step zygote microinjection of mRNA of CRISPR/Cas9-related components. Given the relatively long gestation periods and the high cost of housing, the establishment of a single blastocyst-based assay for rapid optimization of the above system [...] Read more.

Some reports demonstrated successful genome editing in pigs by one-step zygote microinjection of mRNA of CRISPR/Cas9-related components. Given the relatively long gestation periods and the high cost of housing, the establishment of a single blastocyst-based assay for rapid optimization of the above system is required. As a proof-of-concept, we attempted to disrupt a gene (GGTA1) encoding the α-1,3-galactosyltransferase that synthesizes the α-Gal epitope using parthenogenetically activated porcine oocytes. The lack of α-Gal epitope expression can be monitored by staining with fluorescently labeled isolectin BS-I-B₄ (IB4), which binds specifically to the α-Gal epitope. When oocytes were injected with guide RNA specific to GGTA1 together with enhanced green fluorescent protein (EGFP) and human Cas9 mRNAs, 65% (24/37) of the developing blastocysts exhibited green fluorescence, although almost all (96%, 23/24) showed a mosaic fluorescent pattern. Staining with IB4 revealed that the green fluorescent area often had a reduced binding activity to IB4. Of the 16 samples tested, six (five fluorescent and one non-fluorescent blastocysts) had indel mutations, suggesting a correlation between EGFP expression and mutation induction. Furthermore, it is suggested that zygote microinjection of mRNAs might lead to the production of piglets with cells harboring various mutation types. Full article

(This article belongs to the Special Issue Genome Editing)

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13 pages, 7072 KiB

Open AccessArticle

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

by Zejun Liu^1,2, Heguo Cai¹, Xinpeng Zheng¹, Bing Zhang^3,* and Chun Xia^1,*

¹ Department of Sports Medicine & Joint Surgery, Zhongshan Hospital, Xiamen University, Xiamen 361004, China

² The People's Hospital, Hubei University of Medicine, Shiyan 442000, China

³ Medical School, Xiamen University, Xiamen 361102, China

Int. J. Mol. Sci. 2015, 16(8), 17857-17869; https://doi.org/10.3390/ijms160817857 - 4 Aug 2015

Cited by 25 | Viewed by 6355

Abstract

The issue of whether ERK activation determines matrix synthesis or degradation in osteoarthritis (OA) pathogenesis currently remains controversial. Our previous study shows that PLCγ1 and mTOR are involved in the matrix metabolism of OA cartilage. Investigating the interplays of PLCγ1, mTOR and ERK [...] Read more.

The issue of whether ERK activation determines matrix synthesis or degradation in osteoarthritis (OA) pathogenesis currently remains controversial. Our previous study shows that PLCγ1 and mTOR are involved in the matrix metabolism of OA cartilage. Investigating the interplays of PLCγ1, mTOR and ERK in matrix degradation of OA will facilitate future attempts to manipulate ERK in OA prevention and therapy. Here, cultured human normal chondrocytes and OA chondrocytes were treated with different inhibitors or transfected with expression vectors, respectively. The levels of ERK, p-ERK, PLCγ1, p-PLCγ1, mTOR, p-mTOR and MMP-13 were then evaluated by Western blotting analysis. The results manifested that the expression level of ERK in human OA chondrocytes was lower than that in human normal articular chondrocytes, and the up-regulation of ERK could promote matrix synthesis, including the decrease in MMP-13 level and the increase in Aggrecan level in human OA chondrocytes. Furthermore, the PLCγ1/ERK axis and a mutual inhibition of mTOR and ERK were observed in human OA chondrocytes. Interestingly, activated ERK had no inhibitory effect on MMP-13 expression in PLCγ1-transformed OA chondrocytes. Combined with our previous study, the non-effective state of ERK activation by PLCγ1 on MMP-13 may be partly attributed to the inhibition of the PLCγ1/mTOR axis on the PLCγ1/ERK axis. Therefore, the study indicates that the mutual inhibition of ERK and mTOR is involved in PLCγ1-mediated MMP-13 expression in human OA chondrocytes, with important implication for the understanding of OA pathogenesis as well as for its prevention and therapy. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 1613 KiB

Open AccessArticle

A Pilot Study of the Photoprotective Effects of Strawberry-Based Cosmetic Formulations on Human Dermal Fibroblasts

by Massimiliano Gasparrini¹

, Tamara Yuliett Forbes-Hernandez^1,2

, Sadia Afrin¹

, José Miguel Alvarez-Suarez^1,3, Ana M. Gonzàlez-Paramàs⁴

, Celestino Santos-Buelga⁴

, Stefano Bompadre⁵, José Luis Quiles⁶

, Bruno Mezzetti⁷

and Francesca Giampieri^1,*

¹ Department of Clinical Sciences, Faculty of Medicine, Polytechnic University of Marche, Ancona 60131, Italy

² Area de Nutrición y Salud, Universidad Internacional Iberoamericana (UNINI), Campeche 24040, Mexico

³ Facultad de Ciencias de la Salud, Universidad Nacional de Chimborazo, Riobamba 060150, Ecuador

⁴ Grupo de Investigación en Polifenoles (GIP-USAL), Faculty of Pharmacy, Salamanca University, Campus Miguel de Unamuno, Salamanca E37007, Spain

⁵ Dipartimento di Scienze Biomediche e Sanità Pubblica, Facoltà di Medicina, Università Politecnica delle Marche Via Ranieri 65, Ancona 60131, Italy

⁶ Department of Physiology, Institute of Nutrition and Food Technology "José Mataix", Biomedical Research Centre, University of Granada, Granada 18071, Spain

⁷ Dipartimento di Scienze Agrarie, Alimentari e Ambientali, Università Politecnica delle Marche, Ancona 60131, Italy

Int. J. Mol. Sci. 2015, 16(8), 17870-17884; https://doi.org/10.3390/ijms160817870 - 4 Aug 2015

Cited by 26 | Viewed by 8214

Abstract

Strawberry polyphenols have been extensively studied over the last two decades for their beneficial properties. Recently, their possible use in ameliorating skin conditions has also been proposed; however, their role in preventing UVA-induced damage in cosmetic formulation has not yet been investigated. Skin [...] Read more.

Strawberry polyphenols have been extensively studied over the last two decades for their beneficial properties. Recently, their possible use in ameliorating skin conditions has also been proposed; however, their role in preventing UVA-induced damage in cosmetic formulation has not yet been investigated. Skin is constantly exposed to several environmental stressors, such as UVA radiation, that induce oxidative stress, inflammation and cell death via the production of reactive oxygen species (ROS). In the present study, we assessed the potential photoprotective capacity of different strawberry-based formulations, enriched with nanoparticles of Coenzyme Q₁₀ and with sun protection factor 10 (SPF10), in human dermal fibroblasts (HuDe) exposed to UVA radiation. We confirmed that strawberries are a very rich source of polyphenols, anthocyanins and vitamins, and possess high total antioxidant capacity. We also showed that strawberry extracts (25 μg/mL–1 mg/mL) exert a noticeable photoprotection in HuDe, increasing cell viability in a dose-dependent way, and that these effects are potentiated by the presence of CoQ_10red (100 μg/mL). We have demonstrated for the first time that the topical use of strawberry extract may provide good photoprotection, even if more in-depth studies are strongly encouraged in order to evaluate the cellular and molecular effects of strawberry protection. Full article

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

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24 pages, 2421 KiB

Open AccessArticle

Involvement of Ethylene in the Latex Metabolism and Tapping Panel Dryness of Hevea brasiliensis

by Riza-Arief Putranto^1,2,†, Eva Herlinawati^3,†, Maryannick Rio¹, Julie Leclercq¹, Piyanuch Piyatrakul^1,4, Eric Gohet⁵, Christine Sanier¹, Fetrina Oktavia³, Julien Pirrello¹, Kuswanhadi^6,* and Pascal Montoro^1,*

¹ Centre International de Recherche Agronomique pour le Développement, Unité Mixte de Recherche Amélioration Génétique & Adaptation des Plantes Méditerranéennes et Tropicales, F-34398 Montpellier, France

² Indonesian Research Institute for Biotechnology and Bioindustry, Bogor 16128, Indonesia

³ Indonesia Rubber Research Institute, Sembawa Research Centre, Palembang 30001, Indonesia

⁴ Rubber Research Institute of Thailand, Chatuchak, Bangkok 10900, Thailand

⁵ Centre International de Recherche Agronomique pour le Développement, Unité de Recherche Performance des Systèmes de Culture des Plantes Pérennes, F-34398 Montpellier, France

⁶ Indonesia Rubber Research Institute, Bogor 16151, Indonesia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17885-17908; https://doi.org/10.3390/ijms160817885 - 4 Aug 2015

Cited by 55 | Viewed by 11867

Abstract

Ethephon, an ethylene releaser, is used to stimulate latex production in Hevea brasiliensis. Ethylene induces many functions in latex cells including the production of reactive oxygen species (ROS). The accumulation of ROS is responsible for the coagulation of rubber particles in latex [...] Read more.

Ethephon, an ethylene releaser, is used to stimulate latex production in Hevea brasiliensis. Ethylene induces many functions in latex cells including the production of reactive oxygen species (ROS). The accumulation of ROS is responsible for the coagulation of rubber particles in latex cells, resulting in the partial or complete stoppage of latex flow. This study set out to assess biochemical and histological changes as well as changes in gene expression in latex and phloem tissues from trees grown under various harvesting systems. The Tapping Panel Dryness (TPD) susceptibility of Hevea clones was found to be related to some biochemical parameters, such as low sucrose and high inorganic phosphorus contents. A high tapping frequency and ethephon stimulation induced early TPD occurrence in a high latex metabolism clone and late occurrence in a low latex metabolism clone. TPD-affected trees had smaller number of laticifer vessels compared to healthy trees, suggesting a modification of cambial activity. The differential transcript abundance was observed for twenty-seven candidate genes related to TPD occurrence in latex and phloem tissues for ROS-scavenging, ethylene biosynthesis and signalling genes. The predicted function for some Ethylene Response Factor genes suggested that these candidate genes should play an important role in regulating susceptibility to TPD. Full article

(This article belongs to the Special Issue Abiotic Stress and Gene Networks in Plants)

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24 pages, 2615 KiB

Open AccessArticle

Membrane Affinity of Platensimycin and Its Dialkylamine Analogs

by Ian Rowe^1,2,†, Min Guo^2,†, Anthony Yasmann^1,†, Abigail Cember³, Herman O. Sintim² and Sergei Sukharev^1,4,*

¹ Department of Biology, University of Maryland, College Park, MD 20742, USA

² Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA

³ Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA

⁴ Maryland Biophysics Program, University of Maryland, College Park, MD 20742, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17909-17932; https://doi.org/10.3390/ijms160817909 - 4 Aug 2015

Cited by 6 | Viewed by 6068

Abstract

Membrane permeability is a desired property in drug design, but there have been difficulties in quantifying the direct drug partitioning into native membranes. Platensimycin (PL) is a new promising antibiotic whose biosynthetic production is costly. Six dialkylamine analogs of PL were synthesized with [...] Read more.

Membrane permeability is a desired property in drug design, but there have been difficulties in quantifying the direct drug partitioning into native membranes. Platensimycin (PL) is a new promising antibiotic whose biosynthetic production is costly. Six dialkylamine analogs of PL were synthesized with identical pharmacophores but different side chains; five of them were found inactive. To address the possibility that their activity is limited by the permeation step, we calculated polarity, measured surface activity and the ability to insert into the phospholipid monolayers. The partitioning of PL and the analogs into the cytoplasmic membrane of E. coli was assessed by activation curve shifts of a re-engineered mechanosensitive channel, MscS, in patch-clamp experiments. Despite predicted differences in polarity, the affinities to lipid monolayers and native membranes were comparable for most of the analogs. For PL and the di-myrtenyl analog QD-11, both carrying bulky sidechains, the affinity for the native membrane was lower than for monolayers (half-membranes), signifying that intercalation must overcome the lateral pressure of the bilayer. We conclude that the biological activity among the studied PL analogs is unlikely to be limited by their membrane permeability. We also discuss the capacity of endogenous tension-activated channels to detect asymmetric partitioning of exogenous substances into the native bacterial membrane and the different contributions to the thermodynamic force which drives permeation. Full article

(This article belongs to the Special Issue Membrane Protein Based Biosensors)

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19 pages, 2875 KiB

Open AccessArticle

Conformational Motions and Functionally Key Residues for Vitamin B12 Transporter BtuCD–BtuF Revealed by Elastic Network Model with a Function-Related Internal Coordinate

by Ji-Guo Su^1,*, Xiao Zhang¹, Shu-Xin Zhao¹, Xing-Yuan Li¹, Yan-Xue Hou¹, Yi-Dong Wu¹, Jian-Zhuo Zhu¹ and Hai-Long An^2,*

¹ College of Science, Yanshan University, Qinhuangdao 066004, China

² Key Laboratory of Molecular Biophysics, Institute of Biophysics, Hebei University of Technology, Tianjin 300130, China

Int. J. Mol. Sci. 2015, 16(8), 17933-17951; https://doi.org/10.3390/ijms160817933 - 4 Aug 2015

Cited by 5 | Viewed by 4702

Abstract

BtuCD–BtuF from Escherichia coli is a binding protein-dependent adenosine triphosphate (ATP)-binding cassette (ABC) transporter system that uses the energy of ATP hydrolysis to transmit vitamin B12 across cellular membranes. Experimental studies have showed that during the transport cycle, the transporter undergoes conformational transitions [...] Read more.

BtuCD–BtuF from Escherichia coli is a binding protein-dependent adenosine triphosphate (ATP)-binding cassette (ABC) transporter system that uses the energy of ATP hydrolysis to transmit vitamin B12 across cellular membranes. Experimental studies have showed that during the transport cycle, the transporter undergoes conformational transitions between the “inward-facing” and “outward-facing” states, which results in the open–closed motions of the cytoplasmic gate of the transport channel. The opening–closing of the channel gate play critical roles for the function of the transporter, which enables the substrate vitamin B12 to be translocated into the cell. In the present work, the extent of opening of the cytoplasmic gate was chosen as a function-related internal coordinate. Then the mean-square fluctuation of the internal coordinate, as well as the cross-correlation between the displacement of the internal coordinate and the movement of each residue in the protein, were calculated based on the normal mode analysis of the elastic network model to analyze the function-related motions encoded in the structure of the system. In addition, the key residues important for the functional motions of the transporter were predicted by using a perturbation method. In order to facilitate the calculations, the internal coordinate was introduced as one of the axes of the coordinate space and the conventional Cartesian coordinate space was transformed into the internal/Cartesian space with linear approximation. All the calculations were carried out in this internal/Cartesian space. Our method can successfully identify the functional motions and key residues for the transporter BtuCD–BtuF, which are well consistent with the experimental observations. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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23 pages, 705 KiB

Open AccessReview

Combined Screening for Early Detection of Pre-Eclampsia

by Hee Jin Park^†

, Sung Shin Shim^*,† and Dong Hyun Cha

¹ Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul 135-081, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17952-17974; https://doi.org/10.3390/ijms160817952 - 4 Aug 2015

Cited by 58 | Viewed by 9506

Abstract

Although the precise pathophysiology of pre-eclampsia remains unknown, this condition continues to be a major cause of maternal and fetal mortality. Early prediction of pre-eclampsia would allow for timely initiation of preventive therapy. A combination of biophysical and biochemical markers are superior to [...] Read more.

Although the precise pathophysiology of pre-eclampsia remains unknown, this condition continues to be a major cause of maternal and fetal mortality. Early prediction of pre-eclampsia would allow for timely initiation of preventive therapy. A combination of biophysical and biochemical markers are superior to other tests for early prediction of the development of pre-eclampsia. Apart from the use of parameters in first-trimester aneuploidy screening, cell-free fetal DNA quantification is emerging as a promising marker for prediction of pre-eclampsia. This article reviews the current research of the most important strategies for prediction of pre-eclampsia, including the use of maternal risk factors, mean maternal arterial pressure, ultrasound parameters, and biomarkers. Full article

(This article belongs to the Special Issue Prediction, Diagnostics and Prevention of Pregnancy Complications)

24 pages, 727 KiB

Open AccessReview

Effect of Heavy Metals in Plants of the Genus Brassica

by Miguel P. Mourato^*, Inês N. Moreira, Inês Leitão, Filipa R. Pinto

, Joana R. Sales and Luisa Louro Martins

LEAF—Linking Landscape, Environment, Agriculture and Food, Instituto Superior de Agronomia, Universidade de Lisboa, 1349-017 Lisboa, Portugal

Int. J. Mol. Sci. 2015, 16(8), 17975-17998; https://doi.org/10.3390/ijms160817975 - 4 Aug 2015

Cited by 213 | Viewed by 16090

Abstract

Several species from the Brassica genus are very important agricultural crops in different parts of the world and are also known to be heavy metal accumulators. There have been a large number of studies regarding the tolerance, uptake and defense mechanism in several [...] Read more.

Several species from the Brassica genus are very important agricultural crops in different parts of the world and are also known to be heavy metal accumulators. There have been a large number of studies regarding the tolerance, uptake and defense mechanism in several of these species, notably Brassica juncea and B. napus, against the stress induced by heavy metals. Numerous studies have also been published about the capacity of these species to be used for phytoremediation purposes but with mixed results. This review will focus on the latest developments in the study of the uptake capacity, oxidative damage and biochemical and physiological tolerance and defense mechanisms to heavy metal toxicity on six economically important species: B. juncea, B. napus, B. oleracea, B. carinata, B. rapa and B. nigra. Full article

(This article belongs to the Special Issue Abiotic Stress and Gene Networks in Plants)

19 pages, 2945 KiB

Open AccessArticle

Experimental and Theoretical Investigations on the Supermolecular Structure of Isoliquiritigenin and 6-O-α-D-Maltosyl-β-cyclodextrin Inclusion Complex

by Bin Li^1,†, Benguo Liu^1,†, Jiaqi Li¹, Huizhi Xiao², Junyi Wang¹ and Guizhao Liang^2,*

¹ School of Food Science, Henan Institute of Science and Technology, Xinxiang 453003, China

² Key Laboratory of Biorheological Science and Technology, Ministry of Education, School of Bioengineering, Chongqing University, Chongqing 400044, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 17999-18017; https://doi.org/10.3390/ijms160817999 - 4 Aug 2015

Cited by 29 | Viewed by 6500

Abstract

Isoliquiritigenin (ILTG) possesses many pharmacological properties. However, its poor solubility and stability in water hinders its wide applications. The solubility of bioactive compounds can often be enhanced through preparation and delivery of various cyclodextrin (CD) inclusion complexes. The 6-O-α-D-maltosyl-β-CD [...] Read more.

Isoliquiritigenin (ILTG) possesses many pharmacological properties. However, its poor solubility and stability in water hinders its wide applications. The solubility of bioactive compounds can often be enhanced through preparation and delivery of various cyclodextrin (CD) inclusion complexes. The 6-O-α-D-maltosyl-β-CD (G₂-β-CD), as one of the newest developments of CDs, has high aqueous solubility and low toxicity, especially stable inclusion characteristics with bioactive compounds. In this work, we for the first time construct and characterize the supermolecular structure of ILTG/G₂-β-CD by scanning electron microscopy (SEM), ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffractometry (XRD). The solubility of ILTG in water at 25 °C rises from 0.003 to 0.717 mg/mL by the encapsulation with G₂-β-CD. Our experimental observations on the presence of the ILTG/G₂-β-CD inclusion complex are further supported by the ONIOM(our Own N-layer Integrated Orbital molecular Mechanics)-based QM/MM (Quantum Mechanics/Molecular Mechanics) calculations, typically substantiating these supermolecular characteristics, such as detailed structural assignments, preferred binding orientations, selectivity, solvent effects, interaction energies and forces of the ILTG/G₂-β-CD inclusion complex. Our results have elucidated how ILTG interacts with G₂-β-CD, demonstrating the primary host-guest interactions between ILTG and G₂-β-CD, characterized by hydrogen bonds, hydrophobic interactions, electrostatic forces, and conformational effects, are favored for the formation of the ILTG/G₂-β-CD inclusion. Full article

(This article belongs to the Special Issue Solution Chemical Kinetics)

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15 pages, 2755 KiB

Open AccessArticle

Stromal Cell-Derived Factor-1α Plays a Crucial Role Based on Neuroprotective Role in Neonatal Brain Injury in Rats

by Miki Mori, Keiichi Matsubara^*, Yuko Matsubara, Yuka Uchikura, Hisashi Hashimoto^†, Toru Fujioka^† and Takashi Matsumoto^†

¹ Department of Obstetrics and Gynecology, Ehime University School of Medicine, Toon, Ehime 791-0295, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 18018-18032; https://doi.org/10.3390/ijms160818018 - 5 Aug 2015

Cited by 11 | Viewed by 5990

Abstract

Owing to progress in perinatal medicine, the survival of preterm newborns has markedly increased. However, the incidence of cerebral palsy has risen in association with increased preterm birth. Cerebral palsy is largely caused by cerebral hypoxic ischemia (HI), for which there are no [...] Read more.

Owing to progress in perinatal medicine, the survival of preterm newborns has markedly increased. However, the incidence of cerebral palsy has risen in association with increased preterm birth. Cerebral palsy is largely caused by cerebral hypoxic ischemia (HI), for which there are no effective medical treatments. We evaluated the effects of stromal cell-derived factor-1α (SDF-1α) on neonatal brain damage in rats. Left common carotid (LCC) arteries of seven-day-old Wistar rat pups were ligated, and animals were exposed to hypoxic gas to cause cerebral HI. Behavioral tests revealed that the memory and spatial perception abilities were disturbed in HI animals, and that SDF-1α treatment improved these cognitive functions. Motor coordination was also impaired after HI but was unimproved by SDF-1α treatment. SDF-1α reduced intracranial inflammation and induced cerebral remyelination, as indicated by the immunohistochemistry results. These data suggest that SDF-1α specifically influences spatial perception abilities in neonatal HI encephalopathy. Full article

(This article belongs to the Special Issue The Immune System and Inflammation in Cerebral Ischemia)

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21 pages, 1082 KiB

Open AccessReview

Hepatitis C in Special Patient Cohorts: New Opportunities in Decompensated Liver Cirrhosis, End-Stage Renal Disease and Transplant Medicine

by Anna Hüsing, Iyad Kabar, Hartmut H. Schmidt^* and Hauke S. Heinzow

Department of Transplant Medicine, University Hospital Muenster, 48149 Münster, Germany

Int. J. Mol. Sci. 2015, 16(8), 18033-18053; https://doi.org/10.3390/ijms160818033 - 5 Aug 2015

Cited by 11 | Viewed by 9014

Abstract

Worldwide, hepatitis C virus (HCV) is a common infection. Due to new antiviral approaches and the approval of direct-acting antiviral agents (DAA), HCV therapy has become more comfortable. Nevertheless, there are special patient groups, in whom treatment of HCV is still challenging. Due [...] Read more.

Worldwide, hepatitis C virus (HCV) is a common infection. Due to new antiviral approaches and the approval of direct-acting antiviral agents (DAA), HCV therapy has become more comfortable. Nevertheless, there are special patient groups, in whom treatment of HCV is still challenging. Due to only few data available, tolerability and efficacy of DAAs in special patient cohorts still remain unclear. Such special patient cohorts comprise HCV in patients with decompensated liver disease (Child-Pugh Class B or C), patients with chronic kidney disease, and patients on waiting lists to renal/liver transplantation or those with HCV recurrence after liver transplantation. HCV infection in these patient cohorts has been shown to be associated with increased morbidity and mortality and may lead to reduced graft survival after transplantation. Successful eradication of HCV results in a better outcome concerning liver-related complications and in a better clinical outcome of these patients. In this review, we analyze available data and results from recently published literature and provide an overview of current recommendations of HCV-therapy regimen in these special patient cohorts. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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23 pages, 1359 KiB

Open AccessReview

Genes and Pathways Involved in Adult Onset Disorders Featuring Muscle Mitochondrial DNA Instability

by Naghia Ahmed, Dario Ronchi^* and Giacomo Pietro Comi^*

Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, via Francesco Sforza 35, Milan 20122, Italy

Int. J. Mol. Sci. 2015, 16(8), 18054-18076; https://doi.org/10.3390/ijms160818054 - 5 Aug 2015

Cited by 26 | Viewed by 9620

Abstract

Replication and maintenance of mtDNA entirely relies on a set of proteins encoded by the nuclear genome, which include members of the core replicative machinery, proteins involved in the homeostasis of mitochondrial dNTPs pools or deputed to the control of mitochondrial dynamics and [...] Read more.

Replication and maintenance of mtDNA entirely relies on a set of proteins encoded by the nuclear genome, which include members of the core replicative machinery, proteins involved in the homeostasis of mitochondrial dNTPs pools or deputed to the control of mitochondrial dynamics and morphology. Mutations in their coding genes have been observed in familial and sporadic forms of pediatric and adult-onset clinical phenotypes featuring mtDNA instability. The list of defects involved in these disorders has recently expanded, including mutations in the exo-/endo-nuclease flap-processing proteins MGME1 and DNA2, supporting the notion that an enzymatic DNA repair system actively takes place in mitochondria. The results obtained in the last few years acknowledge the contribution of next-generation sequencing methods in the identification of new disease loci in small groups of patients and even single probands. Although heterogeneous, these genes can be conveniently classified according to the pathway to which they belong. The definition of the molecular and biochemical features of these pathways might be helpful for fundamental knowledge of these disorders, to accelerate genetic diagnosis of patients and the development of rational therapies. In this review, we discuss the molecular findings disclosed in adult patients with muscle pathology hallmarked by mtDNA instability. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)

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19 pages, 1350 KiB

Open AccessArticle

miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients

by Katharina Troppan^1,*, Kerstin Wenzl¹, Martin Pichler^2,3, Beata Pursche¹, Daniela Schwarzenbacher³, Julia Feichtinger^4,5, Gerhard G. Thallinger^4,5

, Christine Beham-Schmid⁶, Peter Neumeister^1,† and Alexander Deutsch^1,†

¹ Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria

² Department of Experimental Therapeutics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

³ Division of Oncology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria

⁴ Bioinformatics, Institute for Knowledge Discovery, Graz University of Technology, 8010 Graz, Austria

⁵ Omics Center Graz, BioTechMed Graz, 8010 Graz, Austria

⁶ Department of Pathology, Medical University Graz, 8036 Graz, Austria

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 18077-18095; https://doi.org/10.3390/ijms160818077 - 5 Aug 2015

Cited by 57 | Viewed by 6815

Abstract

Micro-RNAs (miRNAs) are short non-coding single-stranded RNA molecules regulating gene expression at the post-transcriptional level. miRNAs are involved in cell development, differentiation, apoptosis, and proliferation. miRNAs can either function as tumor suppressor genes or oncogenes in various important pathways. The expression of specific [...] Read more.

Micro-RNAs (miRNAs) are short non-coding single-stranded RNA molecules regulating gene expression at the post-transcriptional level. miRNAs are involved in cell development, differentiation, apoptosis, and proliferation. miRNAs can either function as tumor suppressor genes or oncogenes in various important pathways. The expression of specific miRNAs has been identified to correlate with tumor prognosis. For miRNA expression analysis real-time PCR on 81 samples was performed, including 63 diffuse large B-cell lymphoma (DLBCL, 15 of germinal center B-cell like subtype, 17 non germinal center B-cell, 23 transformed, and eight unclassified) and 18 controls, including nine peripheral B-cells, 5 germinal-center B-cells, four lymphadenitis samples, and 4 lymphoma cell lines (RI-1, SUDHL4, Karpas, U2932). Expression levels of a panel of 11 miRNAs that have been previously involved in other types of cancer (miR-15b_2, miR-16_1*, miR-16_2, miR-16_2*, miR-27a, miR-27a*, miR-98-1, miR-103a, miR-185, miR-199a, and miR-497) were measured and correlated with clinical data. Furthermore, cell lines, lacking miR-199a and miR-497 expression, were electroporated with the two respective miRNAs and treated with standard immunochemotherapy routinely used in patients with DLBCL, followed by functional analyses including cell count and apoptosis assays. Seven miRNAs (miR-16_1*, miR-16_2*, miR-27a, miR-103, miR-185, miR-199, and miR-497) were statistically significantly up-regulated in DLBCL compared to normal germinal cells. However, high expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Full article

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

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15 pages, 3445 KiB

Open AccessArticle

Assessing Transformations of Algal Organic Matter in the Long-Term: Impacts of Humification-Like Processes

by Maud Leloup^*, Virginie Pallier, Rudy Nicolau and Geneviève Feuillade-Cathalifaud^*

EA 4330 Groupement de Recherche Eau, Sol, Environnement (GRESE), Ecole Nationale Supérieure d\'Ingénieurs de Limoges (ENSIL), University of Limoges, Parc d'ESTER Technopôle, 16 rue Atlantis, Limoges Cedex F-87068, France

Int. J. Mol. Sci. 2015, 16(8), 18096-18110; https://doi.org/10.3390/ijms160818096 - 5 Aug 2015

Cited by 14 | Viewed by 5657

Abstract

Algae and cyanobacteria are important contributors to the natural organic matter (NOM) of eutrophic water resources. The objective of this work is to increase knowledge on the modifications of algal organic matter (AOM) properties in the long term to anticipate blooms footprint in [...] Read more.

Algae and cyanobacteria are important contributors to the natural organic matter (NOM) of eutrophic water resources. The objective of this work is to increase knowledge on the modifications of algal organic matter (AOM) properties in the long term to anticipate blooms footprint in such aquatic environments. The production of AOM from an alga (Euglena gracilis) and a cyanobacteria (Microcystis aeruginosa) was followed up and characterized during the stationary phase and after one year and four months of cultivation, in batch experiments. Specific UV absorbance (SUVA) index, organic matter fractionation according to hydrophobicity and apparent molecular weight were combined to assess the evolution of AOM. A comparison between humic substances (HS) mainly derived from allochthonous origins and AOM characteristics was performed to hypothesize impacts of AOM transformation processes on the water quality of eutrophic water resources. Each AOM fraction underwent a specific evolution pattern, depending on its composition. Impacts of humification-like processes were predominant over release of biopolymers due to cells decay and led to an increase in the hydrophobic compounds part and molecular weights over time. However, the hydrophilic fraction remained the major fraction whatever the growth stage. Organic compounds generated by maturation of these precursors corresponded to large and aliphatic structures. Full article

(This article belongs to the Special Issue Microalgal Biotechnology)

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18 pages, 1674 KiB

Open AccessArticle

UV Differentially Induces Oxidative Stress, DNA Damage and Apoptosis in BCR-ABL1-Positive Cells Sensitive and Resistant to Imatinib

by Ewelina Synowiec¹, Grazyna Hoser², Katarzyna Wojcik¹, Elzbieta Pawlowska³, Tomasz Skorski⁴ and Janusz Błasiak^1,*

¹ Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland

² Department of Clinical Cytobiology, Medical Center for Postgraduate Education, Marymoncka 99, 01-813 Warsaw, Poland

³ Department of Orthodontics, Medical University of Lodz, Pomorska 251, 92-216 Lodz, Poland

⁴ Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA 19140, USA

Int. J. Mol. Sci. 2015, 16(8), 18111-18128; https://doi.org/10.3390/ijms160818111 - 5 Aug 2015

Cited by 16 | Viewed by 6615

Abstract

Chronic myeloid leukemia (CML) cells express the active BCR-ABL1 protein, which has been targeted by imatinib in CML therapy, but resistance to this drug is an emerging problem. BCR-ABL1 induces endogenous oxidative stress promoting genomic instability and imatinib resistance. In the present work, [...] Read more.

Chronic myeloid leukemia (CML) cells express the active BCR-ABL1 protein, which has been targeted by imatinib in CML therapy, but resistance to this drug is an emerging problem. BCR-ABL1 induces endogenous oxidative stress promoting genomic instability and imatinib resistance. In the present work, we investigated the extent of oxidative stress, DNA damage, apoptosis and expression of apoptosis-related genes in BCR-ABL1 cells sensitive and resistant to imatinib. The resistance resulted either from the Y253H mutation in the BCR-ABL1 gene or incubation in increasing concentrations of imatinib (AR). UV irradiation at a dose rate of 0.12 J/(m²·s) induced more DNA damage detected by the T4 pyrimidine dimers glycosylase and hOGG1, recognizing oxidative modifications to DNA bases in imatinib-resistant than -sensitive cells. The resistant cells displayed also higher susceptibility to UV-induced apoptosis. These cells had lower native mitochondrial membrane potential than imatinib-sensitive cells, but UV-irradiation reversed that relationship. We observed a significant lowering of the expression of the succinate dehydrogenase (SDHB) gene, encoding a component of the complex II of the mitochondrial respiratory chain, which is involved in apoptosis sensing. Although detailed mechanism of imatinib resistance in AR cells in unknown, we detected the presence of the Y253H mutation in a fraction of these cells. In conclusion, imatinib-resistant cells may display a different extent of genome instability than their imatinib-sensitive counterparts, which may follow their different reactions to both endogenous and exogenous DNA-damaging factors, including DNA repair and apoptosis. Full article

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

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20 pages, 811 KiB

Open AccessReview

Neurological and Epigenetic Implications of Nutritional Deficiencies on Psychopathology: Conceptualization and Review of Evidence

by Jianghong Liu^*

, Sophie R. Zhao and Teresa Reyes

School of Nursing, University of Pennsylvania, 418 Curie Blvd., Philadelphia, PA 19104, USA

Int. J. Mol. Sci. 2015, 16(8), 18129-18148; https://doi.org/10.3390/ijms160818129 - 5 Aug 2015

Cited by 16 | Viewed by 10493

Abstract

In recent years, a role for epigenetic modifications in the pathophysiology of disease has received significant attention. Many studies are now beginning to explore the gene–environment interactions, which may mediate early-life exposure to risk factors, such as nutritional deficiencies and later development of [...] Read more.

In recent years, a role for epigenetic modifications in the pathophysiology of disease has received significant attention. Many studies are now beginning to explore the gene–environment interactions, which may mediate early-life exposure to risk factors, such as nutritional deficiencies and later development of behavioral problems in children and adults. In this paper, we review the current literature on the role of epigenetics in the development of psychopathology, with a specific focus on the potential for epigenetic modifications to link nutrition and brain development. We propose a conceptual framework whereby epigenetic modifications (e.g., DNA methylation) mediate the link between micro- and macro-nutrient deficiency early in life and brain dysfunction (e.g., structural aberration, neurotransmitter perturbation), which has been linked to development of behavior problems later on in life. Full article

(This article belongs to the Special Issue Gene-Nutrient Interactions)

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36 pages, 2717 KiB

Open AccessReview

A Review of Cell Adhesion Studies for Biomedical and Biological Applications

by Amelia Ahmad Khalili¹ and Mohd Ridzuan Ahmad^1,2,*

¹ Department of Control and Mechatronic Engineering, Faculty of Electrical Engineering, Universiti Teknologi Malaysia, Johor 81310, Malaysia

² Institute of Ibnu Sina, Universiti Teknologi Malaysia, Johor 81310, Malaysia

Int. J. Mol. Sci. 2015, 16(8), 18149-18184; https://doi.org/10.3390/ijms160818149 - 5 Aug 2015

Cited by 781 | Viewed by 39862

Abstract

Cell adhesion is essential in cell communication and regulation, and is of fundamental importance in the development and maintenance of tissues. The mechanical interactions between a cell and its extracellular matrix (ECM) can influence and control cell behavior and function. The essential function [...] Read more.

Cell adhesion is essential in cell communication and regulation, and is of fundamental importance in the development and maintenance of tissues. The mechanical interactions between a cell and its extracellular matrix (ECM) can influence and control cell behavior and function. The essential function of cell adhesion has created tremendous interests in developing methods for measuring and studying cell adhesion properties. The study of cell adhesion could be categorized into cell adhesion attachment and detachment events. The study of cell adhesion has been widely explored via both events for many important purposes in cellular biology, biomedical, and engineering fields. Cell adhesion attachment and detachment events could be further grouped into the cell population and single cell approach. Various techniques to measure cell adhesion have been applied to many fields of study in order to gain understanding of cell signaling pathways, biomaterial studies for implantable sensors, artificial bone and tooth replacement, the development of tissue-on-a-chip and organ-on-a-chip in tissue engineering, the effects of biochemical treatments and environmental stimuli to the cell adhesion, the potential of drug treatments, cancer metastasis study, and the determination of the adhesion properties of normal and cancerous cells. This review discussed the overview of the available methods to study cell adhesion through attachment and detachment events. Full article

(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)

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39 pages, 2037 KiB

Open AccessReview

Exploiting the Pleiotropic Antioxidant Effects of Established Drugs in Cardiovascular Disease

by Sebastian Steven^1,2,†, Thomas Münzel^1,†

and Andreas Daiber^1,*,†

¹ Medical Clinic, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany

² Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 18185-18223; https://doi.org/10.3390/ijms160818185 - 5 Aug 2015

Cited by 60 | Viewed by 12172

Abstract

Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources [...] Read more.

Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antioxidant defense systems might be more promising. Since basic research demonstrated the contribution of different inflammatory cells to vascular oxidative stress and clinical trials identified chronic inflammatory disorders as risk factors for cardiovascular events, atherosclerosis and cardiovascular disease are closely associated with inflammation. Therefore, modulation of the inflammatory response is a new and promising approach in the therapy of cardiovascular disease. Classical anti-inflammatory therapeutic compounds, but also established drugs with pleiotropic immunomodulatory abilities, demonstrated protective effects in various models of cardiovascular disease. However, results from ongoing clinical trials are needed to further evaluate the value of immunomodulation for the treatment of cardiovascular disease. Full article

(This article belongs to the Special Issue Antioxidant 2.0——Redox Modulation by Food and Drugs)

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28 pages, 2630 KiB

Open AccessReview

Mitochondria Retrograde Signaling and the UPR^mt: Where Are We in Mammals?

by Thierry Arnould^1,*

, Sébastien Michel^1,2 and Patricia Renard¹

¹ Laboratory of Biochemistry and Cell Biology (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, 5000 Namur, Belgium

² Department of Physiology, University of Lausanne, Rue du Bugnon 7, CH-1005 Lausanne, Switzerland

Int. J. Mol. Sci. 2015, 16(8), 18224-18251; https://doi.org/10.3390/ijms160818224 - 6 Aug 2015

Cited by 119 | Viewed by 21518

Abstract

Mitochondrial unfolded protein response is a form of retrograde signaling that contributes to ensuring the maintenance of quality control of mitochondria, allowing functional integrity of the mitochondrial proteome. When misfolded proteins or unassembled complexes accumulate beyond the folding capacity, it leads to alteration [...] Read more.

Mitochondrial unfolded protein response is a form of retrograde signaling that contributes to ensuring the maintenance of quality control of mitochondria, allowing functional integrity of the mitochondrial proteome. When misfolded proteins or unassembled complexes accumulate beyond the folding capacity, it leads to alteration of proteostasis, damages, and organelle/cell dysfunction. Extensively studied for the ER, it was recently reported that this kind of signaling for mitochondrion would also be able to communicate with the nucleus in response to impaired proteostasis. The mitochondrial unfolded protein response (UPR^mt) is activated in response to different types and levels of stress, especially in conditions where unfolded or misfolded mitochondrial proteins accumulate and aggregate. A specific UPR^mt could thus be initiated to boost folding and degradation capacity in response to unfolded and aggregated protein accumulation. Although first described in mammals, the UPR^mt was mainly studied in Caenorhabditis elegans, and accumulating evidence suggests that mechanisms triggered in response to a UPR^mt might be different in C. elegans and mammals. In this review, we discuss and integrate recent data from the literature to address whether the UPR^mt is relevant to mitochondrial homeostasis in mammals and to analyze the putative role of integrated stress response (ISR) activation in response to the inhibition of mtDNA expression and/or accumulation of mitochondrial mis/unfolded proteins. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)

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18 pages, 2189 KiB

Open AccessArticle

The Histone Deacetylase Inhibitor BML-210 Influences Gene and Protein Expression in Human Promyelocytic Leukemia NB4 Cells via Epigenetic Reprogramming

by Veronika Borutinskaitė and Rūta Navakauskienė^*

Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Mokslininkų 12, Vilnius LT 08662, Lithuania

Int. J. Mol. Sci. 2015, 16(8), 18252-18269; https://doi.org/10.3390/ijms160818252 - 6 Aug 2015

Cited by 8 | Viewed by 5769

Abstract

Today, cancer is understood as an epigenetic as well as genetic disease. The main epigenetic hallmarks of the cancer cell are DNA methylation and histone modifications. Proteins such as histone deacetylases (HDACs) that cause modifications of histones and other proteins can be targets [...] Read more.

Today, cancer is understood as an epigenetic as well as genetic disease. The main epigenetic hallmarks of the cancer cell are DNA methylation and histone modifications. Proteins such as histone deacetylases (HDACs) that cause modifications of histones and other proteins can be targets for novel anticancer agents. Recently, interest in compounds that can inhibit HDACs increased, and now there are many HDACs inhibitors (HDACIs) available with different chemical structures, biological and biochemical properties; hopefully some of them will succeed, probably in combination with other agents, in cancer therapies. In our study we focused on the novel HDACI–BML-210. We found that BML-210 (N-phenyl-Nʹ-(2-Aminophenyl)hexamethylenediamide) inhibits the growth of NB4 cells in dose- and time-dependent manner. In this study we also examined how expression and activity of HDACs are affected after leukemia cell treatment with BML-210. Using a mass spectrometry method we identified proteins that changed expression after treatment with BML-210. We prepared RT-PCR analysis of these genes and the results correlated with proteomic data. Based on these and other findings from our group, we suggest that HDACIs, like BML-210, can be promising anticancer agents in promyelocytic leukemia treatment. Full article

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

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13 pages, 766 KiB

Open AccessReview

Kynurenines and Multiple Sclerosis: The Dialogue between the Immune System and the Central Nervous System

by Cecilia Rajda¹, Zsófia Majláth¹, Dániel Pukoli^1,2 and László Vécsei^1,3,*

¹ Department of Neurology, University of Szeged, Szeged H-6725, Hungary

² Department of Neurology, Markhot Ferenc County Hospital, Eger H-3300, Hungary

³ MTA-SZTE Neuroscience Research Group, Szeged H-6725, Hungary

Int. J. Mol. Sci. 2015, 16(8), 18270-18282; https://doi.org/10.3390/ijms160818270 - 6 Aug 2015

Cited by 35 | Viewed by 8766

Abstract

Multiple sclerosis is an inflammatory disease of the central nervous system, in which axonal transection takes place in parallel with acute inflammation to various, individual extents. The importance of the kynurenine pathway in the physiological functions and pathological processes of the nervous system [...] Read more.

Multiple sclerosis is an inflammatory disease of the central nervous system, in which axonal transection takes place in parallel with acute inflammation to various, individual extents. The importance of the kynurenine pathway in the physiological functions and pathological processes of the nervous system has been extensively investigated, but it has additionally been implicated as having a regulatory function in the immune system. Alterations in the kynurenine pathway have been described in both preclinical and clinical investigations of multiple sclerosis. These observations led to the identification of potential therapeutic targets in multiple sclerosis, such as synthetic tryptophan analogs, endogenous tryptophan metabolites (e.g., cinnabarinic acid), structural analogs (laquinimod, teriflunomid, leflunomid and tranilast), indoleamine-2,3-dioxygenase inhibitors (1MT and berberine) and kynurenine-3-monooxygenase inhibitors (nicotinylalanine and Ro 61-8048). The kynurenine pathway is a promising novel target via which to influence the immune system and to achieve neuroprotection, and further research is therefore needed with the aim of developing novel drugs for the treatment of multiple sclerosis and other autoimmune diseases. Full article

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

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10 pages, 4027 KiB

Open AccessCommunication

Microwave-Induced Chemotoxicity of Polydopamine-Coated Magnetic Nanocubes

by Khachatur Julfakyan¹, Yevhen Fatieiev¹, Shahad Alsaiari¹, Lin Deng¹, Alaa Ezzeddine¹

, Dingyuan Zhang^1,2, Vincent M. Rotello³ and Niveen M. Khashab^1,*

¹ Smart Hybrid Materials (SHMs) Laboratory, Advanced Membranes and Porous Materials Center, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia

² Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

³ Department of Chemistry, University of Massachusetts Amherst, Amherst, MA 01003, USA

Int. J. Mol. Sci. 2015, 16(8), 18283-18292; https://doi.org/10.3390/ijms160818283 - 6 Aug 2015

Cited by 1 | Viewed by 5963

Abstract

Polydopamine-coated FeCo nanocubes (PDFCs) were successfully synthesized and tested under microwave irradiation of 2.45 GHz frequency and 0.86 W/cm² power. These particles were found to be non-toxic in the absence of irradiation, but gained significant toxicity upon irradiation. Interestingly, no increase in [...] Read more.

Polydopamine-coated FeCo nanocubes (PDFCs) were successfully synthesized and tested under microwave irradiation of 2.45 GHz frequency and 0.86 W/cm² power. These particles were found to be non-toxic in the absence of irradiation, but gained significant toxicity upon irradiation. Interestingly, no increase in relative heating rate was observed when the PDFCs were irradiated in solution, eliminating nanoparticle (NP)-induced thermal ablation as the source of toxicity. Based on these studies, we propose that microwave-induced redox processes generate the observed toxicity. Full article

(This article belongs to the Special Issue Developmental and Reproductive Toxicity of Iron Oxide Nanoparticles)

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19 pages, 3047 KiB

Open AccessArticle

Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats

by Tristan J. King^1,2, Tetyana Shandala¹, Alice M. Lee¹, Bruce K. Foster³, Ke-Ming Chen⁴, Peter R. Howe^5,6

and Cory J. Xian^1,*

¹ Sansom Institute for Health Research, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA 5001, Australia

² Department of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5001, Australia

³ Department of Orthopaedic Surgery, Women's and Children's Hospital, North Adelaide, SA 5006, Australia

⁴ Institute of Orthopaedics, Lanzhou General Hospital, Lanzhou Command of Chinese People's Liberation Army, Lanzhou 730050, China

⁵ Nutritional Physiology Research Centre, School of Health Sciences, University of South Australia, Adelaide, SA 5001, Australia

⁶ Clinical Nutrition Research Centre, University of Newcastle, Callaghan, NSW 2308, Australia

Int. J. Mol. Sci. 2015, 16(8), 18293-18311; https://doi.org/10.3390/ijms160818293 - 6 Aug 2015

Cited by 29 | Viewed by 7462

Abstract

Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of [...] Read more.

Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage. Full article

(This article belongs to the Special Issue Phenolics and Polyphenolics 2015)

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16 pages, 1322 KiB

Open AccessArticle

A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA)

by Andrea Luchetti¹, Silvia Anna Ciafrè^1,*

, Michela Murdocca¹, Arianna Malgieri¹, Andrea Masotti², Massimo Sanchez³, Maria Giulia Farace¹, Giuseppe Novelli¹

and Federica Sangiuolo¹

¹ Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy

² Gene Expression-Microarrays Laboratory, Bambino Gesù Children's Hospital-IRCCS Polo di Ricerca-V.le di San Paolo 15, 00146 Rome, Italy

³ Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy

Int. J. Mol. Sci. 2015, 16(8), 18312-18327; https://doi.org/10.3390/ijms160818312 - 6 Aug 2015

Cited by 22 | Viewed by 7263

Abstract

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis [...] Read more.

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA. Full article

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

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20 pages, 849 KiB

Open AccessReview

Chitosan in Molecularly-Imprinted Polymers: Current and Future Prospects

by Long Xu^1,†, Yun-An Huang^1,†, Qiu-Jin Zhu^1,2,* and Chun Ye¹

¹ School of Liquor & Food Engineering, Guizhou University, Guiyang 550025, China

² Key Laboratory of Agricultural & Animal Products Store and Processing of Guizhou Province, Guiyang 550025, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 18328-18347; https://doi.org/10.3390/ijms160818328 - 7 Aug 2015

Cited by 113 | Viewed by 13650

Abstract

Chitosan is widely used in molecular imprinting technology (MIT) as a functional monomer or supporting matrix because of its low cost and high contents of amino and hydroxyl functional groups. The various excellent properties of chitosan, which include nontoxicity, biodegradability, biocompatibility, and attractive [...] Read more.

Chitosan is widely used in molecular imprinting technology (MIT) as a functional monomer or supporting matrix because of its low cost and high contents of amino and hydroxyl functional groups. The various excellent properties of chitosan, which include nontoxicity, biodegradability, biocompatibility, and attractive physical and mechanical performances, make chitosan a promising alternative to conventional functional monomers. Recently, chitosan molecularly-imprinted polymers have gained considerable attention and showed significant potential in many fields, such as curbing environmental pollution, medicine, protein separation and identification, and chiral-compound separation. These extensive applications are due to the polymers’ desired selectivity, physical robustness, and thermal stability, as well as their low cost and easy preparation. Cross-linkers, which fix the functional groups of chitosan around imprinted molecules, play an important role in chitosan molecularly-imprinted polymers. This review summarizes the important cross-linkers of chitosan molecularly-imprinted polymers and illustrates the cross-linking mechanism of chitosan and cross-linkers based on the two glucosamine units. Finally, some significant attempts to further develop the application of chitosan in MIT are proposed. Full article

(This article belongs to the Special Issue Chitins 2015)

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20 pages, 1359 KiB

Open AccessReview

Overview of Nrf2 as Therapeutic Target in Epilepsy

by Liliana Carmona-Aparicio^1,*, Claudia Pérez-Cruz², Cecilia Zavala-Tecuapetla³, Leticia Granados-Rojas¹, Liliana Rivera-Espinosa⁴, Hortencia Montesinos-Correa⁵, Jacqueline Hernández-Damián⁶, José Pedraza-Chaverri⁶, Aristides III Sampieri⁷, Elvia Coballase-Urrutia¹ and Noemí Cárdenas-Rodríguez^1,*

¹ Laboratory of Neurochemistry (Neurosciences), National Institute of Pediatrics, D.F. 04530, Mexico

² Laboratory of Neuroplasticity and Neurodegeneration, Cinvestav, D.F. 07360, Mexico

³ Laboratory of Physiology of the Reticular Formation, National Institute of Neurology and Neurosurgery-MVS, D.F. 14269, Mexico

⁴ Laboratory of Pharmacology, National Institute of Pediatrics, D.F. 04530, Mexico

⁵ Service of Endocrinology, National Institute of Pediatrics, D.F. 04530, Mexico

⁶ Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, D.F. 04150, Mexico

⁷ Department of Comparative Biology, Faculty of Sciences, National Autonomous University of Mexico, D.F. 04150, Mexico

Int. J. Mol. Sci. 2015, 16(8), 18348-18367; https://doi.org/10.3390/ijms160818348 - 7 Aug 2015

Cited by 61 | Viewed by 11177

Abstract

Oxidative stress is a biochemical state of imbalance in the production of reactive oxygen and nitrogen species and antioxidant defenses. It is involved in the physiopathology of degenerative and chronic neuronal disorders, such as epilepsy. Experimental evidence in humans and animals support the [...] Read more.

Oxidative stress is a biochemical state of imbalance in the production of reactive oxygen and nitrogen species and antioxidant defenses. It is involved in the physiopathology of degenerative and chronic neuronal disorders, such as epilepsy. Experimental evidence in humans and animals support the involvement of oxidative stress before and after seizures. In the past few years, research has increasingly focused on the molecular pathways of this process, such as that involving transcription factor nuclear factor E2-related factor 2 (Nrf2), which plays a central role in the regulation of antioxidant response elements (ARE) and modulates cellular redox status. The aim of this review is to present experimental evidence on the role of Nrf2 in this neurological disorder and to further determine the therapeutic impact of Nrf2 in epilepsy. Full article

(This article belongs to the Special Issue The Pathophysiology of Neuropsychiatric Disorders and New Therapeutic Targets)

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16 pages, 3180 KiB

Open AccessArticle

The Essential Role of Vitellogenin Receptor in Ovary Development and Vitellogenin Uptake in Bactrocera dorsalis (Hendel)

by Lin Cong^1,2, Wen-Jia Yang^1,3, Xuan-Zhao Jiang¹, Jin-Zhi Niu¹, Guang-Mao Shen¹, Chun Ran² and Jin-Jun Wang^1,*

¹ Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China

² Citrus Research Institute, Southwest University, Chongqing 400712, China

³ College of Biology and Environmental Engineering, Guiyang University, Guiyang 550005, China

Int. J. Mol. Sci. 2015, 16(8), 18368-18383; https://doi.org/10.3390/ijms160818368 - 7 Aug 2015

Cited by 54 | Viewed by 8228

Abstract

The vitellogenin receptor (VgR) functions as an essential component in uptaking and transporting vitellogenin (Vg) in female adults, which is involved in ovary development and oviposition. This study aimed to clarify the molecular characteristics and function of VgR in the oriental fruit fly [...] Read more.

The vitellogenin receptor (VgR) functions as an essential component in uptaking and transporting vitellogenin (Vg) in female adults, which is involved in ovary development and oviposition. This study aimed to clarify the molecular characteristics and function of VgR in the oriental fruit fly Bactrocera dorsalis (Hendel). Here, we identified the full-length of BdVgR (GenBank Accession No. JX469118), encoding a 1925 residue (aa) protein with a 214.72 kDa molecular mass and several typical motifs of low-density lipoprotein receptor superfamily (LDLR). Phylogenic analysis suggested that BdVgR was evolutionary conserved with other Dipteran VgRs. The expression of BdVgR was exclusively detected in the ovaries rather than head, thorax or other tissues. The developmental expression patterns showed that the signal of BdVgR was detectable in very beginning of adult stage, and positively correlated with the growth rate of ovaries and the expression levels of its ligands. In addition, we also demonstrated that the expression level of BdVgR, and ovary development were significantly suppressed after being injected with BdVgR-targeted dsRNA. Together, all of these results indicated that BdVgR was critical for yolk protein absorption and ovary maturation in B. dorsalis, playing a vital role in female reproduction. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 2369 KiB

Open AccessArticle

Hesperidin, A Popular Antioxidant Inhibits Melanogenesis via Erk1/2 Mediated MITF Degradation

by Heun Joo Lee¹, Woo Jin Lee², Sung Eun Chang^2,*

and Ga-Young Lee^1,*

¹ Department of Dermatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Pyeong-dong, Jongno-gu, Seoul 110-746, 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. 2015, 16(8), 18384-18395; https://doi.org/10.3390/ijms160818384 - 7 Aug 2015

Cited by 84 | Viewed by 11873

Abstract

Regulation of melanogenesis has been the focus of treatment for hyperpigmentary skin disorders. Although hesperidin is one of the most well-known, naturally occurring flavonoids with antioxidant and anti-inflammatory effect, its anti-melanogenic effect is not known. The present study aims to determine the anti-melanogenic [...] Read more.

Regulation of melanogenesis has been the focus of treatment for hyperpigmentary skin disorders. Although hesperidin is one of the most well-known, naturally occurring flavonoids with antioxidant and anti-inflammatory effect, its anti-melanogenic effect is not known. The present study aims to determine the anti-melanogenic effect of hespiridin as well as its underlying molecular mechanisms. Melanin contents were measured in normal human melanocytes and B16F10 melanoma cells. Protein and mRNA levels of tyrosinase, microphthalmia-associated transcription factor (MITF), tyrosinase related protein-1 (TRP-1) and TRP-2 were determined. Melanogenesis-regulating signals were examined. In results, hesperidin strongly inhibited melanin synthesis and tyrosinase activity. Hesperidin decreased tyrosinase, TRP-1, and TRP-2 protein expression but increased phospho-extracellular signal-regulated kinase 1/2 (p-Erk1/2) expression. Specific inhibitor of Erk1/2 or proteasome inhibitor reversed the inhibition of melanogenesis induced by hesperidin. Taken together, hesperidin, a popular antioxidant, stimulated Erk1/2 phosphorylation which subsequently degraded MITF which resulted in suppression of melanogenic enzymes and melanin synthesis. Full article

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

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16 pages, 778 KiB

Open AccessArticle

Permeability Study of Polyphenols Derived from a Phenolic-Enriched Hibiscus sabdariffa Extract by UHPLC-ESI-UHR-Qq-TOF-MS

by Isabel Borrás-Linares^1,2,†, María Herranz-López^3,†

, Enrique Barrajón-Catalán³

, David Arráez-Román^1,2,*

, Isabel Gonzálezlvarez⁴

, Marival Bermejo⁴, Alberto Fernández Gutiérrez^1,2, Vicente Micol^3,‡,§

and Antonio Segura-Carretero^1,2,‡

¹ Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Avda Fuentenueva s/n, 18071 Granada, Spain

² Research and Development Functional Food Centre, Health Science Technological Park, Avda Conocimiento s/n, 18016 Granada, Spain

³ Instituto de Biología Molecular y Celular (IBMC), Miguel Hernández University, Elche, 03202 Alicante, Spain

⁴ Pharmacokinetics and Pharmaceutical Technology Area, Engineering Department, Universidad Miguel Hernández, San Juan de Alicante, 03550 Alicante, Spain

^† These authors contributed equally to this work.

^‡ These authors share co-senior authorship.

^§ CIBER (CB12/03/30038, Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud Carlos III).

Int. J. Mol. Sci. 2015, 16(8), 18396-18411; https://doi.org/10.3390/ijms160818396 - 7 Aug 2015

Cited by 32 | Viewed by 9711

Abstract

Previous findings on the capacity of Hibiscus sabdariffa (HS) polyphenols to ameliorate metabolic disturbances justify the necessity of studies oriented to find the potential metabolites responsible for such an effect. The present study examined the intestinal epithelial membrane permeability of polyphenols present in [...] Read more.

Previous findings on the capacity of Hibiscus sabdariffa (HS) polyphenols to ameliorate metabolic disturbances justify the necessity of studies oriented to find the potential metabolites responsible for such an effect. The present study examined the intestinal epithelial membrane permeability of polyphenols present in a phenolic-enriched Hibiscus sabdariffa extract (PEHS), free and encapsulated, using the Caco-2 cell line. Additionally, selected polyphenols (quercetin, quercetin-3-glucoside, quercetin-3-glucuronide, and N-feruloyltyramine) were also studied in the same absorption model. The powerful analytical platform used ultra-high-performance liquid chromatography coupled with ultra-high-resolution quadrupole time-of-flight mass spectrometry (UHPLC-ESI-UHR-Qq-TOF-MS), and enabled the characterization of seven new compounds in PEHS. In the permeation study, only a few compounds were able to cross the cell monolayer and the permeability was lower when the extract was in an encapsulated form. Pure compounds showed a moderate absorption in all cases. Nevertheless, these preliminary results may need further research to understand the complete absorption mechanism of Hibiscus polyphenols. Full article

(This article belongs to the Special Issue Phenolics and Polyphenolics 2015)

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27 pages, 3987 KiB

Open AccessArticle

Polymodal Transient Receptor Potential Vanilloid (TRPV) Ion Channels in Chondrogenic Cells

by Csilla Szűcs Somogyi^1,*, Csaba Matta^1,2, Zsofia Foldvari¹, Tamás Juhász¹

, Éva Katona¹, Ádám Roland Takács¹, Tibor Hajdú¹, Nóra Dobrosi¹, Pál Gergely³ and Róza Zákány^1,*

¹ Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary

² Department of Veterinary Preclinical Sciences, School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK

³ Cell Biology and Signalling Research Group of the Hungarian Academy of Sciences, Department of Medical Chemistry, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary

Int. J. Mol. Sci. 2015, 16(8), 18412-18438; https://doi.org/10.3390/ijms160818412 - 7 Aug 2015

Cited by 32 | Viewed by 9760

Abstract

Mature and developing chondrocytes exist in a microenvironment where mechanical load, changes of temperature, osmolarity and acidic pH may influence cellular metabolism. Polymodal Transient Receptor Potential Vanilloid (TRPV) receptors are environmental sensors mediating responses through activation of linked intracellular signalling pathways. In chondrogenic [...] Read more.

Mature and developing chondrocytes exist in a microenvironment where mechanical load, changes of temperature, osmolarity and acidic pH may influence cellular metabolism. Polymodal Transient Receptor Potential Vanilloid (TRPV) receptors are environmental sensors mediating responses through activation of linked intracellular signalling pathways. In chondrogenic high density cultures established from limb buds of chicken and mouse embryos, we identified TRPV1, TRPV2, TRPV3, TRPV4 and TRPV6 mRNA expression with RT-PCR. In both cultures, a switch in the expression pattern of TRPVs was observed during cartilage formation. The inhibition of TRPVs with the non-selective calcium channel blocker ruthenium red diminished chondrogenesis and caused significant inhibition of proliferation. Incubating cell cultures at 41 °C elevated the expression of TRPV1, and increased cartilage matrix production. When chondrogenic cells were exposed to mechanical load at the time of their differentiation into matrix producing chondrocytes, we detected increased mRNA levels of TRPV3. Our results demonstrate that developing chondrocytes express a full palette of TRPV channels and the switch in the expression pattern suggests differentiation stage-dependent roles of TRPVs during cartilage formation. As TRPV1 and TRPV3 expression was altered by thermal and mechanical stimuli, respectively, these are candidate channels that contribute to the transduction of environmental stimuli in chondrogenic cells. Full article

(This article belongs to the Special Issue Molecular Machinery of Cell Growth Regulation)

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15 pages, 697 KiB

Open AccessArticle

Identification of Hydroxyanthraquinones as Novel Inhibitors of Hepatitis C Virus NS3 Helicase

by Atsushi Furuta^1,2, Masayoshi Tsubuki³, Miduki Endoh³, Tatsuki Miyamoto^1,2, Junichi Tanaka⁴, Kazi Abdus Salam^5,†, Nobuyoshi Akimitsu⁵, Hidenori Tani⁶, Atsuya Yamashita⁷, Kohji Moriishi⁷

, Masamichi Nakakoshi⁸, Yuji Sekiguchi², Satoshi Tsuneda^1,*

and Naohiro Noda^1,2,*

¹ Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan

² Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan

³ Institute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

⁴ Department of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan

⁵ Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

⁶ Environmental Measurement Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 16-1 Onogawa, Tsukuba, Ibaraki 305-8569, Japan

⁷ Department of Microbiology, Division of Medicine, Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan

⁸ Department of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan

^† Current address: Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA

Int. J. Mol. Sci. 2015, 16(8), 18439-18453; https://doi.org/10.3390/ijms160818439 - 7 Aug 2015

Cited by 23 | Viewed by 7362

Abstract

Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. [...] Read more.

Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. Some anthracyclines are known to be NS3 helicase inhibitors and have a hydroxyanthraquinone moiety in their structures; mitoxantrone, a hydroxyanthraquinone analogue, is also known to inhibit NS3 helicase. Therefore, we hypothesized that the hydroxyanthraquinone moiety alone could also inhibit NS3 helicase. Here, we performed a structure–activity relationship study on a series of hydroxyanthraquinones by using a fluorescence-based helicase assay. Hydroxyanthraquinones inhibited NS3 helicase with IC₅₀ values in the micromolar range. The inhibitory activity varied depending on the number and position of the phenolic hydroxyl groups, and among different hydroxyanthraquinones examined, 1,4,5,8-tetrahydroxyanthraquinone strongly inhibited NS3 helicase with an IC₅₀ value of 6 µM. Furthermore, hypericin and sennidin A, which both have two hydroxyanthraquinone-like moieties, were found to exert even stronger inhibition with IC₅₀ values of 3 and 0.8 µM, respectively. These results indicate that the hydroxyanthraquinone moiety can inhibit NS3 helicase and suggest that several key chemical structures are important for the inhibition. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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20 pages, 450 KiB

Open AccessReview

Novel Electrocardiographic Patterns for the Prediction of Hypertensive Disorders of Pregnancy—From Pathophysiology to Practical Implications

by Fabio Angeli^1,*

, Enrica Angeli² and Paolo Verdecchia³

¹ Division of Cardiology and Cardiovascular Pathophysiology, Hospital "S.M. della Misericordia", Perugia 06100, Italy

² Department of Obstetrics and Gynecology, Hospital "San Giovanni Battista", Foligno 06034, Italy

³ Department of Internal medicine, Hospital of Assisi, Assisi 06081, Italy

Int. J. Mol. Sci. 2015, 16(8), 18454-18473; https://doi.org/10.3390/ijms160818454 - 7 Aug 2015

Cited by 18 | Viewed by 12981

Abstract

Hypertensive disorders of pregnancy are a major cause of poor outcome, including placental abruption, organ failure, cerebrovascular accident and disseminated intravascular coagulation. These disorders are associated with increased fetal risk of intrauterine growth restriction, intrauterine death and prematurity. Electrocardiography (ECG) recently emerged as [...] Read more.

Hypertensive disorders of pregnancy are a major cause of poor outcome, including placental abruption, organ failure, cerebrovascular accident and disseminated intravascular coagulation. These disorders are associated with increased fetal risk of intrauterine growth restriction, intrauterine death and prematurity. Electrocardiography (ECG) recently emerged as a useful tool to evaluate cardiovascular complications during pregnancy. Specifically, left atrial abnormalities detected by standard ECG are associated with a fourfold increased risk of developing hypertensive disorders during pregnancy. The mechanisms linking left atrial abnormality on ECG with hypertensive disorders are still elusive. Several mechanisms, possibly reflected by abnormal left atrial activation on ECG, has been suggested. These include increased reactivity to angiotensin II and up-regulation of angiotensin type 1 receptors, with activation of autoantibodies targeting these receptors. Full article

(This article belongs to the Special Issue Prediction, Diagnostics and Prevention of Pregnancy Complications)

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33 pages, 1352 KiB

Open AccessReview

Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands

by Zdzisław Chilmonczyk^1,2,*, Andrzej Jacek Bojarski³, Andrzej Pilc³ and Ingebrigt Sylte⁴

¹ National Medicines Institute, Chełmska 30/34, 00-725 Warszawa, Poland

² Institute of Nursing and Health Sciences, University of Rzeszów, W. Kopisto 2A, 35-310 Rzeszów, Poland

³ Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland

⁴ Faculty of Health Sciences, University of Tromsø—The Arctic University of Norway, No-9037 Tromsø, Norway

Int. J. Mol. Sci. 2015, 16(8), 18474-18506; https://doi.org/10.3390/ijms160818474 - 7 Aug 2015

Cited by 78 | Viewed by 16468

Abstract

Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. [...] Read more.

Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT_1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT_1A agonists could form a new class of antidepressant drugs, and mixed 5-HT_1A receptor ligands/serotonin transporter (SERT) inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT_1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT_1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT_1A receptor cooperates with other signal transduction systems (like the 5-HT_1B or 5-HT_2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT_1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies. Full article

(This article belongs to the Special Issue The Pathophysiology of Neuropsychiatric Disorders and New Therapeutic Targets)

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15 pages, 4472 KiB

Open AccessArticle

Differentiation Effects of Platelet-Rich Plasma Concentrations on Synovial Fluid Mesenchymal Stem Cells from Pigs Cultivated in Alginate Complex Hydrogel

by Hao-Che Tang^1,2,†, Wei-Chuan Chen^3,†, Chih-Wei Chiang³, Lei-Yen Chen⁴, Yu-Ching Chang⁵ and Chih-Hwa Chen^3,6,*

¹ Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Keelung 204, Taiwan

² College of Medicine, Chang Gung University, Taoyuan 333, Taiwan

³ Bone and Joint Research Center, Department of Orthopedics and Traumatology, Taipei Medical University Hospital, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

⁴ Spine Department, Lin-Sun Hospital, Taichung 403, Taiwan

⁵ Division of Pediatric General Medicine, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan

⁶ Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 18507-18521; https://doi.org/10.3390/ijms160818507 - 7 Aug 2015

Cited by 21 | Viewed by 6988

Abstract

This article studied the effects of platelet-rich plasma (PRP) on the potential of synovial fluid mesenchymal stem cells (SF-MSCs) to differentiate. The PRP and SF-MSCs were obtained from the blood and knees of pigs, respectively. The identification of SF-MSCs and their ability to [...] Read more.

This article studied the effects of platelet-rich plasma (PRP) on the potential of synovial fluid mesenchymal stem cells (SF-MSCs) to differentiate. The PRP and SF-MSCs were obtained from the blood and knees of pigs, respectively. The identification of SF-MSCs and their ability to differentiate were studied by histological and surface epitopes, respectively. The SF-MSCs can undergo trilineage mesenchymal differentiation under osteogenic, chondrogenic, and adipocyte induction. The effects of various PRP concentrations (0%, 20% and 50% PRP) on differentiation were evaluated using the SF-MSCs-alginate system, such as gene expression and DNA proliferation. A 50% PRP concentration yielded better differentiation than the 20% PRP concentration. PRP favored the chondrogenesis of SF-MSCs over their osteogenesis in a manner that depended on the ratios of type II collagen/type I collagen and aggrecan/osteopontin. Eventually, PRP promoted the proliferation of SF-MSCs and induced chondrogenic differentiation of SF-MSCs in vitro. Both PRP and SF-MSCs could be feasibly used in regenerative medicine and orthopedic surgeries. Full article

(This article belongs to the Special Issue Biomaterials for Tissue Engineering)

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22 pages, 1456 KiB

Open AccessArticle

Comparison of Soybean Transformation Efficiency and Plant Factors Affecting Transformation during the Agrobacterium Infection Process

by Yuying Jia, Xingdong Yao, Mingzhe Zhao, Qiang Zhao, Yanli Du, Cuimei Yu^* and Futi Xie^*

Soybean Research Institute, Shenyang Agricultural University, Shenyang 110866, China

Int. J. Mol. Sci. 2015, 16(8), 18522-18543; https://doi.org/10.3390/ijms160818522 - 7 Aug 2015

Cited by 27 | Viewed by 10616

Abstract

The susceptibility of soybean genotype to Agrobacterium infection is a key factor for the high level of genetic transformation efficiency. The objective of this study is to evaluate the plant factors related to transformation in cotyledonary nodes during the Agrobacterium infection process. This [...] Read more.

The susceptibility of soybean genotype to Agrobacterium infection is a key factor for the high level of genetic transformation efficiency. The objective of this study is to evaluate the plant factors related to transformation in cotyledonary nodes during the Agrobacterium infection process. This study selected three genotypes (Williams 82, Shennong 9 and Bert) with high transformation efficiency, which presented better susceptibility to Agrobacterium infection, and three low transformation efficiency genotypes (General, Liaodou 16 and Kottman), which showed a relatively weak susceptibility. Gibberellin (GA) levels and soybean GA20ox2 and CYP707A2 transcripts of high-efficiency genotypes increased and were higher than those of low-efficiency genotypes; however, the opposite performance was shown in abscisic acid (ABA). Higher zeatin riboside (ZR) content and DNA quantity, and relatively higher expression of soybean IPT5, CYCD3 and CYCA3 were obtained in high-efficiency genotypes. High-efficiency genotypes had low methyl jasmonate (MeJA) content, polyphenol oxidase (PPO) and peroxidase (POD) activity, and relatively lower expression of soybean OPR3, PPO1 and PRX71. GA and ZR were positive plant factors for Agrobacterium-mediated soybean transformation by facilitating germination and growth, and increasing the number of cells in DNA synthesis cycle, respectively; MeJA, PPO, POD and ABA were negative plant factors by inducing defence reactions and repressing germination and growth, respectively. Full article

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

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20 pages, 2788 KiB

Open AccessArticle

SCM-198 Ameliorates Cognitive Deficits, Promotes Neuronal Survival and Enhances CREB/BDNF/TrkB Signaling without Affecting Aβ Burden in AβPP/PS1 Mice

by Zhen-Yi Hong, Shuang-Shuang Yu, Zhi-Jun Wang and Yi-Zhun Zhu^*

Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China

Int. J. Mol. Sci. 2015, 16(8), 18544-18563; https://doi.org/10.3390/ijms160818544 - 7 Aug 2015

Cited by 31 | Viewed by 7283

Abstract

SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson’s disease and Alzheimer’s disease (AD). In this study, we demonstrated for the first time that 3-month oral [...] Read more.

SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson’s disease and Alzheimer’s disease (AD). In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-β protein precursor and presenilin-1(AβPP/PS1) double-transgenic mice without affecting amyloid-β (Aβ) burden. In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 1988 KiB

Open AccessArticle

Wnt3a Promotes the Vasculogenic Mimicry Formation of Colon Cancer via Wnt/β-Catenin Signaling

by Lisha Qi^1,2,3,†, Wangzhao Song^1,2,3,†, Zhiyong Liu^1,2,3, Xiulan Zhao⁴, Wenfeng Cao^1,2,3,* and Baocun Sun^1,2,3,4,*

¹ Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China

² The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China

³ National Clinical Research Center for Cancer, Tianjin 300060, China

⁴ Department of Pathology, Tianjin Medical University, Tianjin 300070, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 18564-18579; https://doi.org/10.3390/ijms160818564 - 10 Aug 2015

Cited by 62 | Viewed by 8612

Abstract

Our previous study provided evidence that non-canonical Wnt signaling is involved in regulating vasculogenic mimicry (VM) formation. However, the functions of canonical Wnt signaling in VM formation have not yet been explored. In this study, we found the presence of VM was related [...] Read more.

Our previous study provided evidence that non-canonical Wnt signaling is involved in regulating vasculogenic mimicry (VM) formation. However, the functions of canonical Wnt signaling in VM formation have not yet been explored. In this study, we found the presence of VM was related to colon cancer histological differentiation (p < 0.001), the clinical stage (p < 0.001), and presence of metastasis and recurrence (p < 0.001). VM-positive colon cancer samples showed increased Wnt3a expression (p < 0.001) and β-catenin nuclear expression (p < 0.001) compared with the VM-negative samples. In vitro, over-regulated Wnt3a expression in HT29 colon cancer cells promoted the capacity to form tube-like structures in the three-dimensional (3-D) culture together with increased expression of endothelial phenotype-associated proteins such as VEGFR2 and VE-cadherin. The mouse xenograft model showed that Wnt3a-overexpressing cells grew into larger tumor masses and formed more VM than the control cells. In addition, the Wnt/β-catenin signaling antagonist Dickkopf-1(Dkk1) can reverse the capacity to form tube-like structures and can decrease the expressions of VEGFR2 and VE-cadherin in Wnt3a-overexpressing cells. Taken together, our results suggest that Wnt/β-catenin signaling is involved in VM formation in colon cancer and might contribute to the development of more accurate treatment modalities aimed at VM. Full article

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

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21 pages, 2111 KiB

Open AccessReview

Evaluation and Management of Neurogenic Bladder: What Is New in China?

by Limin Liao^1,2,3,4

¹ Department of Urology, China Rehabilitation Research Center, Beijing 100068, China

² Department of Urology, Capital Medical University, Beijing 100069, China

³ Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing 100068, China

⁴ Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing 100068, China

Int. J. Mol. Sci. 2015, 16(8), 18580-18600; https://doi.org/10.3390/ijms160818580 - 10 Aug 2015

Cited by 49 | Viewed by 12873

Abstract

Neurogenic bladder (NB) or neurogenic lower urinary tract dysfunction (NLUTD), a dysfunction of the urinary bladder and urethra due to disease of the central nervous system or peripheral nerves, is a major global medical and social problem. Numerous nervous system abnormalities, such as: [...] Read more.

Neurogenic bladder (NB) or neurogenic lower urinary tract dysfunction (NLUTD), a dysfunction of the urinary bladder and urethra due to disease of the central nervous system or peripheral nerves, is a major global medical and social problem. Numerous nervous system abnormalities, such as: stroke, Alzheimer’s and Parkinson’s diseases, traumatic spinal cord injury, spinal cord tumors, congenital spina bifida, and diabetes, can cause NB/NLUTD. There are two major types of bladder control problems associated with NB/NLUTD: the bladder becomes either overactive or underactive depending on the nature, level, and extent of nerve damage. This review specifically focuses on the diagnosis and management of NB/NLUTD in China as well as on recent efforts to treat this disease. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2022)

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27 pages, 777 KiB

Open AccessReview

Role of Pharmacogenetics in Hematopoietic Stem Cell Transplantation Outcome in Children

by Raffaella Franca^1,*, Gabriele Stocco², Diego Favretto¹, Nagua Giurici¹, Giuliana Decorti² and Marco Rabusin¹

¹ Institute for Maternal and Child Health (I.R.C.C.S.) Burlo Garofolo, UO Pediatric Hemato-Oncology, Trieste 34137, Italy

² Department of Life Sciences, University of Trieste, Trieste 34127, Italy

Int. J. Mol. Sci. 2015, 16(8), 18601-18627; https://doi.org/10.3390/ijms160818601 - 10 Aug 2015

Cited by 8 | Viewed by 6379

Abstract

Hematopoietic stem cell transplantation (HSCT) is an established therapeutic procedure for several congenital and acquired disorders, both malignant and nonmalignant. Despite the great improvements in HSCT clinical practices over the last few decades, complications, such as graft vs. host disease (GVHD) and sinusoidal [...] Read more.

Hematopoietic stem cell transplantation (HSCT) is an established therapeutic procedure for several congenital and acquired disorders, both malignant and nonmalignant. Despite the great improvements in HSCT clinical practices over the last few decades, complications, such as graft vs. host disease (GVHD) and sinusoidal obstructive syndrome (SOS), are still largely unpredictable and remain the major causes of morbidity and mortality. Both donor and patient genetic background might influence the success of bone marrow transplantation and could at least partially explain the inter-individual variability in HSCT outcome. This review summarizes some of the recent studies on candidate gene polymorphisms in HSCT, with particular reference to pediatric cohorts. The interest is especially focused on pharmacogenetic variants affecting myeloablative and immunosuppressive drugs, although genetic traits involved in SOS susceptibility and transplant-related mortality are also reviewed. Full article

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

14 pages, 2630 KiB

Open AccessArticle

ALS-Linked P56S-VAPB Mutation Impairs the Formation of Multinuclear Myotube in C2C12 Cells

by Yukako Tokutake¹, Keita Yamada², Masaki Ohata², Yoshihito Obayashi², Megumi Tsuchiya² and Shinichi Yonekura^1,2,3,*

¹ Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 399-4598, Japan

² Graduate School of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 399-4598, Japan

³ Department of Interdisciplinary Genome Sciences and Cell Metabolism, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 399-4598, Japan

Int. J. Mol. Sci. 2015, 16(8), 18628-18641; https://doi.org/10.3390/ijms160818628 - 10 Aug 2015

Cited by 19 | Viewed by 7848

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that affects upper and lower motor neurons. Since motor neurons target skeletal muscles, the maintenance system of muscles is disturbed in ALS; however, the mechanism by which this occurs is unknown. In the [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that affects upper and lower motor neurons. Since motor neurons target skeletal muscles, the maintenance system of muscles is disturbed in ALS; however, the mechanism by which this occurs is unknown. In the present study, we investigated the effects of ALS-associated P56S-vesicle-associated membrane protein-associated protein B (VAPB) (P56S-VAPB) on the IRE1-XBP1 pathway, which is involved in the unfolded protein response (UPR) of the mouse myoblast cell line (C2C12 cells). Experiments with C2C12 cells transfected with wild-type wt-VAPB and P56S-VAPB expression vectors showed reduced myotube formation and aberrant myonuclear position in cells expressing P56S-VAPB. Activity of the IRE1-XBP1 pathway in the cells visualized with the ERAI system revealed that the pathway was disrupted in cells expressing P56S-VAPB, whereas the IRE1-XBP1 pathway activity was enhanced in the differentiation process of normal C2C12 cells. These results suggest that disruption of the IRE1-XBP1 pathway is a cause for the reduced myotube formation in P56S-VAPB-expressing cells. The expression level of the VAPB protein has been reported to be reduced in the neurons of patients with ALS. Therefore, it is expected that the IRE1-XBP1 pathway is also impaired in muscle tissues of patients with ALS, which causes a disturbance in the muscle maintenance system. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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22 pages, 780 KiB

Open AccessReview

Bioactive Compounds of Blueberries: Post-Harvest Factors Influencing the Nutritional Value of Products

by Anna Michalska^1,2,† and Grzegorz Łysiak^3,*,†

¹ Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Division of Food Science, Str. Tuwima 10, Olsztyn 10-748, Poland

² Institute of Agricultural Engineering, Wrocław University of Environmental and Life Sciences, Str. Chelmonskiego 37a, Wroclaw 51-630, Poland

³ Department of Pomology, Poznan University of Life Sciences, Str. Dąbrowskiego 159, Poznań 60-594, Poland

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 18642-18663; https://doi.org/10.3390/ijms160818642 - 10 Aug 2015

Cited by 177 | Viewed by 21762

Abstract

Blueberries, besides having commonly-recognized taste properties, are also a valuable source of health-promoting bioactive compounds. For several decades, blueberries have gained in popularity all over the world, and recent years have seen not only an increase in fresh consumption, but also in the [...] Read more.

Blueberries, besides having commonly-recognized taste properties, are also a valuable source of health-promoting bioactive compounds. For several decades, blueberries have gained in popularity all over the world, and recent years have seen not only an increase in fresh consumption, but also in the importance of blueberries for the processing industry. Blueberry processing mostly consists of freezing and juicing. Recently, more attention has been drawn to dewatering and drying, which are promising areas for developing novel blueberry products. Processing affects each biologically-active compound in a different way, and it is still unknown what changes those compounds undergo at the molecular level after the application of different processing technologies. This work presents the most recent state of knowledge about the pre-treatment and processing methods applied to blueberries and their influence on the content of biologically-active compounds. The presentation of methods is preceded by a brief overview of the characteristics of the blueberry species, a description of the chemical composition of the fruit and a short note about the main growing areas, production volumes and the management of fruit crops. Full article

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

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19 pages, 2529 KiB

Open AccessArticle

Changes of the Cytoplasmic Proteome in Response to Alcoholic Hepatotoxicity in Rats

by Dong Hwan Kim^1,2,†, Eun-Mi Lee^2,3,†, Sun-Hee Do⁴, Da-Hee Jeong² and Kyu-Shik Jeong^2,3,*

¹ College of Interdisciplinary & Creative Studies, Konyang University, Nonsan 320-711, Korea

² College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Korea

³ Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu 702-701, Korea

⁴ College of Veterinary Medicine, Konkuk University, Seoul 143-701, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 18664-18682; https://doi.org/10.3390/ijms160818664 - 10 Aug 2015

Cited by 8 | Viewed by 6181

Abstract

Proteomic analyses have already been used in a number of hepatological studies and provide important information. However, few reports have focused on changes in the cytoplasmic proteome. The present study therefore aimed to evaluate changes in cytoplasmic proteome of rats in response to [...] Read more.

Proteomic analyses have already been used in a number of hepatological studies and provide important information. However, few reports have focused on changes in the cytoplasmic proteome. The present study therefore aimed to evaluate changes in cytoplasmic proteome of rats in response to alcoholic hepatotoxicity. Rats were fed a Liber-DeCarli liquid diet containing ethanol for four weeks. Cytoplasmic proteins except mitochondrial proteins from the livers of these animals were investigated using two-dimensional gel electrophoresis and mass spectrometry. Alcohol induced a decrease in body weight gain and an increase in alanine transaminase (ALT), cholesterol, and phospholipid levels. Histopathological observations revealed hepatic damage characterized by necrosis and fatty change in alcohol-treated group at week 2, which continues until week 4. Our proteomic analysis revealed that 25 proteins were differentially expressed in the ethanol-fed group. Of these, 12 cytoplasmic proteins are being reported for the first time. Taken together, our results provide further insights into the disease mechanism and therapeutic information of alcoholic liver disease. Full article

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

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31 pages, 777 KiB

Open AccessReview

Scanning for Therapeutic Targets within the Cytokine Network of Idiopathic Inflammatory Myopathies

by Boel De Paepe^1,*

and Jana Zschüntzsch²

¹ Neuromuscular Reference Center, Laboratory for Neuropathology, 10K12E, Ghent University Hospital, 9000 Ghent, Belgium

² Department of Neurology, University Medical Centre, Göttingen University, 37075 Göttingen, Germany

Int. J. Mol. Sci. 2015, 16(8), 18683-18713; https://doi.org/10.3390/ijms160818683 - 11 Aug 2015

Cited by 26 | Viewed by 7355

Abstract

The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many [...] Read more.

The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNFα, LTβ, BAFF), Interferons (IFNα/β/γ), Interleukins (IL-1/6/12/15/18/23) and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21). Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNFα treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNFα agents to treat other diseases, pointing to the complex effects of TNFα neutralization. Treatment with anti-IFNα has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction. Full article

(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)

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18 pages, 3167 KiB

Open AccessArticle

Formation of Chlorotriophenoxy Radicals from Complete Series Reactions of Chlorotriophenols with H and OH Radicals

by Fei Xu, Xiangli Shi, Qingzhu Zhang^* and Wenxing Wang

Environment Research Institute, Shandong University, Jinan 250100, China

Int. J. Mol. Sci. 2015, 16(8), 18714-18731; https://doi.org/10.3390/ijms160818714 - 11 Aug 2015

Cited by 11 | Viewed by 5590

Abstract

The chlorothiophenoxy radicals (CTPRs) are key intermediate species in the formation of polychlorinated dibenzothiophenes/thianthrenes (PCDT/TAs). In this work, the formation of CTPRs from the complete series reactions of 19 chlorothiophenol (CTP) congeners with H and OH radicals were investigated theoretically by using the [...] Read more.

The chlorothiophenoxy radicals (CTPRs) are key intermediate species in the formation of polychlorinated dibenzothiophenes/thianthrenes (PCDT/TAs). In this work, the formation of CTPRs from the complete series reactions of 19 chlorothiophenol (CTP) congeners with H and OH radicals were investigated theoretically by using the density functional theory (DFT) method. The profiles of the potential energy surface were constructed at the MPWB1K/6-311+G(3df,2p)//MPWB1K/6-31+G(d,p) level. The rate constants were evaluated by the canonical variational transition-state (CVT) theory with the small curvature tunneling (SCT) contribution at 600–1200 K. The present study indicates that the structural parameters, thermal data, and rate constants as well as the formation potential of CTPRs from CTPs are strongly dominated by the chlorine substitution at the ortho-position of CTPs. Comparison with the study of formation of chlorophenoxy radicals (CPRs) from chlorophenols (CPs) clearly shows that the thiophenoxyl-hydrogen abstraction from CTPs by H is more efficient than the phenoxyl-hydrogen abstraction from CPs by H, whereas the thiophenoxyl-hydrogen abstraction from CTPs by OH is less impactful than the phenoxyl-hydrogen abstraction from CPs by OH. Reactions of CTPs with H can occur more readily than that of CTPs with OH, which is opposite to the reactivity comparison of CPs with H and OH. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2015)

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9 pages, 979 KiB

Open AccessReview

LincRNA-p21: Implications in Human Diseases

by Sai-Sai Tang^1,2,3, Bi-Ying Zheng⁴ and Xing-Dong Xiong^1,2,3,5,*

¹ Institute of Aging Research, Guangdong Medical University, Dongguan 523808, China

² Institute of Biochemistry & Molecular Biology, Guangdong Medical University, Zhanjiang 524023, China

³ Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan 523808, China

⁴ Institute of Laboratory Medicine, Guangdong Medical University, Dongguan 523808, China

⁵ Department of Pharmacology and the Penn State Hershey Cancer Institute, Milton S. Hershey Medical Center, the Pennsylvania State University College of Medicine, Hershey, PA 17033, USA

Int. J. Mol. Sci. 2015, 16(8), 18732-18740; https://doi.org/10.3390/ijms160818732 - 11 Aug 2015

Cited by 62 | Viewed by 9264

Abstract

Long noncoding RNAs (lncRNAs), which lack significant protein-coding capacity, regulate various biological processes through diverse and as yet poorly understood molecular mechanisms. However, a number of studies in the past few years have documented important functions for lncRNAs in human diseases. Among these [...] Read more.

Long noncoding RNAs (lncRNAs), which lack significant protein-coding capacity, regulate various biological processes through diverse and as yet poorly understood molecular mechanisms. However, a number of studies in the past few years have documented important functions for lncRNAs in human diseases. Among these lncRNAs, lincRNA-p21 has been proposed to be a novel regulator of cell proliferation, apoptosis and DNA damage response, and involved in the initiation and progression of human diseases. In this review, we summarize the current knowledge of lincRNA-p21, mainly focus on the known biological functions and its underlying mechanisms. Moreover, we highlight the growing body of evidences for the importance of lincRNA-p21 in diverse human diseases, which indicate lincRNA-p21 as a potential diagnostic marker and/or a valuable therapeutic target for these diseases. Full article

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

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11 pages, 1681 KiB

Open AccessTechnical Note

In Vitro Expansion of CAG, CAA, and Mixed CAG/CAA Repeats

by Grzegorz Figura, Edyta Koscianska

and Wlodzimierz J. Krzyzosiak^*

Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Str., 61-704 Poznan, Poland

Int. J. Mol. Sci. 2015, 16(8), 18741-18751; https://doi.org/10.3390/ijms160818741 - 11 Aug 2015

Cited by 14 | Viewed by 5862

Abstract

Polyglutamine diseases, including Huntington’s disease and a number of spinocerebellar ataxias, are caused by expanded CAG repeats that are located in translated sequences of individual, functionally-unrelated genes. Only mutant proteins containing polyglutamine expansions have long been thought to be pathogenic, but recent evidence [...] Read more.

Polyglutamine diseases, including Huntington’s disease and a number of spinocerebellar ataxias, are caused by expanded CAG repeats that are located in translated sequences of individual, functionally-unrelated genes. Only mutant proteins containing polyglutamine expansions have long been thought to be pathogenic, but recent evidence has implicated mutant transcripts containing long CAG repeats in pathogenic processes. The presence of two pathogenic factors prompted us to attempt to distinguish the effects triggered by mutant protein from those caused by mutant RNA in cellular models of polyglutamine diseases. We used the SLIP (Synthesis of Long Iterative Polynucleotide) method to generate plasmids expressing long CAG repeats (forming a hairpin structure), CAA-interrupted CAG repeats (forming multiple unstable hairpins) or pure CAA repeats (not forming any secondary structure). We successfully modified the original SLIP protocol to generate repeats of desired length starting from constructs containing short repeat tracts. We demonstrated that the SLIP method is a time- and cost-effective approach to manipulate the lengths of expanded repeat sequences. Full article

(This article belongs to the Section Biochemistry)

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26 pages, 2443 KiB

Open AccessArticle

Comparative Analysis of the Brassica napus Root and Leaf Transcript Profiling in Response to Drought Stress

by Chunqing Liu¹, Xuekun Zhang², Ka Zhang¹, Hong An¹, Kaining Hu¹, Jing Wen¹, Jinxiong Shen¹, Chaozhi Ma¹, Bin Yi^1,*, Jinxing Tu¹ and Tingdong Fu¹

¹ National Key Laboratory of Crop Genetic Improvement, National Center of Rapeseed Improvement in Wuhan, Huazhong Agricultural University, Wuhan 430070, China

² Key Laboratory of Oil Crop Biology and Genetic Breeding of the Ministry of Agriculture, Oil Crops Research Institute, Chinese Academy of Agriculture Sciences, Wuhan 430062, China

Int. J. Mol. Sci. 2015, 16(8), 18752-18777; https://doi.org/10.3390/ijms160818752 - 11 Aug 2015

Cited by 46 | Viewed by 11373

Abstract

Drought stress is one of the major abiotic factors affecting Brassica napus (B. napus) productivity. In order to identify genes of potential importance to drought stress and obtain a deeper understanding of the molecular mechanisms regarding the responses of B. napus [...] Read more.

Drought stress is one of the major abiotic factors affecting Brassica napus (B. napus) productivity. In order to identify genes of potential importance to drought stress and obtain a deeper understanding of the molecular mechanisms regarding the responses of B. napus to dehydration stress, we performed large-scale transcriptome sequencing of B. napus plants under dehydration stress using the Illumina sequencing technology. In this work, a relatively drought tolerant B. napus line, Q2, identified in our previous study, was used. Four cDNA libraries constructed from mRNAs of control and dehydration-treated root and leaf were sequenced by Illumina technology. A total of 6018 and 5377 differentially expressed genes (DEGs) were identified in root and leaf. In addition, 1745 genes exhibited a coordinated expression profile between the two tissues under drought stress, 1289 (approximately 74%) of which showed an inverse relationship, demonstrating different regulation patterns between the root and leaf. The gene ontology (GO) enrichment test indicated that up-regulated genes in root were mostly involved in “stimulus” “stress” biological process, and activated genes in leaf mainly functioned in “cell” “cell part” components. Furthermore, a comparative network related to plant hormone signal transduction and AREB/ABF, AP2/EREBP, NAC, WRKY and MYC/MYB transcription factors (TFs) provided a view of different stress tolerance mechanisms between root and leaf. Some of the DEGs identified may be candidates for future research aimed at detecting drought-responsive genes and will be useful for understanding the molecular mechanisms of drought tolerance in root and leaf of B. napus. Full article

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

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18 pages, 1416 KiB

Open AccessReview

New Immunosuppressive Therapies in Uveitis Treatment

by Salvador Mérida¹, Elena Palacios², Amparo Navea^1,2 and Francisco Bosch-Morell^1,2,*

¹ Instituto de Ciencias Biomédicas, Universidad CEU Cardenal Herrera, Valencia 46113, Spain

² Oftalmología Médica, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, Valencia 46020, Spain

Int. J. Mol. Sci. 2015, 16(8), 18778-18795; https://doi.org/10.3390/ijms160818778 - 11 Aug 2015

Cited by 34 | Viewed by 15216

Abstract

Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments [...] Read more.

Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines. Full article

(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)

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16 pages, 1981 KiB

Open AccessArticle

Influence of Pre-Freezing Temperature on the Corneal Endothelial Cytocompatibility and Cell Delivery Performance of Porous Hyaluronic Acid Hydrogel Carriers

by Jui-Yang Lai^1,2,3,4

¹ Institute of Biochemical and Biomedical Engineering, Chang Gung University, Taoyuan 33302, Taiwan

² Biomedical Engineering Research Center, Chang Gung University, Taoyuan 33302, Taiwan

³ Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan

⁴ Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan

Int. J. Mol. Sci. 2015, 16(8), 18796-18811; https://doi.org/10.3390/ijms160818796 - 11 Aug 2015

Cited by 14 | Viewed by 5867

Abstract

The development of porous hyaluronic acid (HA) hydrogels for corneal endothelial tissue engineering is attractive because they can be used as functional cell delivery carriers to help in the reconstruction of damaged areas. The purpose of this study was to investigate the corneal [...] Read more.

The development of porous hyaluronic acid (HA) hydrogels for corneal endothelial tissue engineering is attractive because they can be used as functional cell delivery carriers to help in the reconstruction of damaged areas. The purpose of this study was to investigate the corneal endothelial cytocompatibility and cell delivery performance of porous HA hydrogel biomaterials fabricated at different pre-freezing temperatures. As compared to their counterparts prepared at −80 °C, the HA samples fabricated at higher pre-freezing temperature (i.e., 0 °C) exhibited a larger pore size and higher porosity, thereby leading to lower resistance to glucose permeation. Live/dead assays and gene expression analyses showed that the restricted porous structure of HA carriers decreases the viability and ionic pump function of cultured corneal endothelial cells (CECs). The results also indicated that the porous hydrogel biomaterials fabricated at high pre-freezing temperature seem to be more compatible with rabbit CECs. In an animal model of corneal endothelial dysfunction, the wounded rabbit corneas receiving bioengineered CEC sheets and restricted porous-structured HA carriers demonstrated poor tissue reconstruction. The therapeutic efficacy of cell sheet transplants can be improved by using carrier materials prepared at high pre-freezing temperature. Our findings suggest that the cryogenic operation temperature-mediated pore microstructure of HA carriers plays an important role in corneal endothelial cytocompatibility and cell delivery performance. Full article

(This article belongs to the Special Issue Biomaterials for Tissue Engineering)

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13 pages, 777 KiB

Open AccessArticle

Quantitative Structure-Activity Relationships Study on the Rate Constants of Polychlorinated Dibenzo-p-Dioxins with OH Radical

by Chuansong Qi¹, Chenxi Zhang^2,3 and Xiaomin Sun^2,*

¹ College of Chemical Engineering, Beijing Institute of Petrochemical Technology, Beijing 102617, China

² Environment Research Institute, Shandong University, Jinan 250100, China

³ Department of Resources and Environment, Binzhou University, Binzhou 256600, China

Int. J. Mol. Sci. 2015, 16(8), 18812-18824; https://doi.org/10.3390/ijms160818812 - 12 Aug 2015

Cited by 3 | Viewed by 4241

Abstract

The OH-initiated reaction rate constants (k_OH) are of great importance to measure atmospheric behaviors of polychlorinated dibenzo-p-dioxins (PCDDs) in the environment. The rate constants of 75 PCDDs with the OH radical at 298.15 K have been calculated using [...] Read more.

The OH-initiated reaction rate constants (k_OH) are of great importance to measure atmospheric behaviors of polychlorinated dibenzo-p-dioxins (PCDDs) in the environment. The rate constants of 75 PCDDs with the OH radical at 298.15 K have been calculated using high level molecular orbital theory, and the rate constants (k_α, k_β, k_γ and k_OH) were further analyzed by the quantitative structure-activity relationships (QSAR) study. According to the QSAR models, the relations between rate constants and the numbers and positions of Cl atoms, the energy of the highest occupied molecular orbital (E_HOMO), the energy of the lowest unoccupied molecular orbital (E_LUMO), the difference ΔE_HOMO-LUMO between E_HOMO and E_LUMO, and the dipole of oxidizing agents (D) were discussed. It was found that E_HOMO is the main factor in the k_OH. The number of Cl atoms is more effective than the number of relative position of these Cl atoms in the k_OH. The k_OH decreases with the increase of the substitute number of Cl atoms. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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11 pages, 2397 KiB

Open AccessArticle

Osteoclast Differentiation Is Impaired in a Subgroup of SLE Patients and Correlates Inversely with Mycophenolate Mofetil Treatment

by Barbara G. Fürnrohr^1,2,*,†, Benjamin Rhodes^3,4, Luis E. Munoz¹, Katrin Weiß^1,5, Tim J. Vyse⁴ and Georg Schett¹

¹ Department of Internal Medicine 3 and Institute for Clinical Immunology, Ulmenweg 18, University of Erlangen-Nuremberg, 91054 Erlangen, Germany

² Division of Genetic Epidemiology and Division of Biological Chemistry, Innrain 80/IV, Medical University Innsbruck, 6020 Innsbruck, Austria

³ Department of Rheumatology, University Hospitals Birmingham NHS foundation trust, Edgbaston, B15 2GW Birmingham, UK

⁴ Division of Genetics and Molecular Medicine and Division of Immunology, Infection and Inflammatory Disease, King's College London, Great Maze Pond, SE1 9RT London, UK

⁵ Division of Molecular Immunology of the Department of Internal Medicine 3, Ulmenweg 18, University of Erlangen-Nuremberg, 91054 Erlangen, Germany

^† Present address: Division of Biological Chemistry, Innrain 80/IV, Medical University Innsbruck, 6020 Innsbruck, Austria

Int. J. Mol. Sci. 2015, 16(8), 18825-18835; https://doi.org/10.3390/ijms160818825 - 12 Aug 2015

Cited by 8 | Viewed by 6080

Abstract

Osteoporosis can arise in systemic lupus erythematosus (SLE) patients secondary to medication and/or chronic inflammation. To analyze if patients with SLE have phenotypically-impaired osteoclastogenesis, we differentiated ex vivo monocytes from 72 SLE patients and 15 healthy individuals into osteoclasts followed by TRAP staining [...] Read more.

Osteoporosis can arise in systemic lupus erythematosus (SLE) patients secondary to medication and/or chronic inflammation. To analyze if patients with SLE have phenotypically-impaired osteoclastogenesis, we differentiated ex vivo monocytes from 72 SLE patients and 15 healthy individuals into osteoclasts followed by TRAP staining and counting. We identified a subgroup of SLE patients (45%) with a significantly impaired osteoclast differentiation, relative to the other SLE patients or healthy individuals (OR 11.2; 95% CI 1.4–89.9). A review of medication indicated that patients with osteoclast counts equal to healthy donors were significantly more likely to be treated with mycophenolate mofetil (MMF) compared to patients with impaired osteoclastogenesis. We analyzed expression of RANKL and the MMF target genes IMPDH1 and IMPDH2 in osteoclasts by qPCR, but detected no difference. Since MMF might influence interferon-α (IFNα) and -γ (IFNγ) we measured serum IFNα and IFNγ levels. Patients with very low osteoclast counts also had comparably higher IFNα serum levels than patients with normal osteoclast counts. We conclude that in vitro osteoclastogenesis is impaired in a subgroup of SLE patients. This correlates inversely with MMF treatment and high IFNα serum levels. Further observational study will be required to determine whether this translates into a clinically meaningful effect. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in the Pathogenesis of Systemic Lupus Erythematosus)

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29 pages, 3630 KiB

Open AccessReview

From Genome to Structure and Back Again: A Family Portrait of the Transcarbamylases

by Dashuang Shi^1,2,*

, Norma M. Allewell^3,4 and Mendel Tuchman^1,2

¹ Center for Genetic Medicine Research, Children's National Medical Center, the George Washington University, Washington, DC 20010, USA

² Department of Integrative Systems Biology, Children's National Medical Center, the George Washington University, Washington, DC 20010, USA

³ Department of Cell Biology and Molecular Genetics, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, MD 20742, USA

⁴ Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, MD 20742, USA

Int. J. Mol. Sci. 2015, 16(8), 18836-18864; https://doi.org/10.3390/ijms160818836 - 12 Aug 2015

Cited by 19 | Viewed by 8635

Abstract

Enzymes in the transcarbamylase family catalyze the transfer of a carbamyl group from carbamyl phosphate (CP) to an amino group of a second substrate. The two best-characterized members, aspartate transcarbamylase (ATCase) and ornithine transcarbamylase (OTCase), are present in most organisms from bacteria to [...] Read more.

Enzymes in the transcarbamylase family catalyze the transfer of a carbamyl group from carbamyl phosphate (CP) to an amino group of a second substrate. The two best-characterized members, aspartate transcarbamylase (ATCase) and ornithine transcarbamylase (OTCase), are present in most organisms from bacteria to humans. Recently, structures of four new transcarbamylase members, N-acetyl-l-ornithine transcarbamylase (AOTCase), N-succinyl-l-ornithine transcarbamylase (SOTCase), ygeW encoded transcarbamylase (YTCase) and putrescine transcarbamylase (PTCase) have also been determined. Crystal structures of these enzymes have shown that they have a common overall fold with a trimer as their basic biological unit. The monomer structures share a common CP binding site in their N-terminal domain, but have different second substrate binding sites in their C-terminal domain. The discovery of three new transcarbamylases, l-2,3-diaminopropionate transcarbamylase (DPTCase), l-2,4-diaminobutyrate transcarbamylase (DBTCase) and ureidoglycine transcarbamylase (UGTCase), demonstrates that our knowledge and understanding of the spectrum of the transcarbamylase family is still incomplete. In this review, we summarize studies on the structures and function of transcarbamylases demonstrating how structural information helps to define biological function and how small structural differences govern enzyme specificity. Such information is important for correctly annotating transcarbamylase sequences in the genome databases and for identifying new members of the transcarbamylase family. Full article

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

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13 pages, 1024 KiB

Open AccessArticle

Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease

by Kyle Farmer¹, Catherine A. Smith¹, Shawn Hayley^1,* and Jeffrey Smith²

¹ Carleton University Department of Neuroscience, 1125 Colonel By Drive, Life Sciences Research Building, Ottawa, ON K1S 5B6, Canada

² Carleton University Department of Chemistry and Institute of Biochemistry, 1125 Colonel By Drive, Steacie Building, Ottawa, ON K1S 5B6, Canada

Int. J. Mol. Sci. 2015, 16(8), 18865-18877; https://doi.org/10.3390/ijms160818865 - 12 Aug 2015

Cited by 69 | Viewed by 8231

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent [...] Read more.

Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. However, information regarding the lipid alterations in animal models of PD is lacking. In this study, we utilized high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) and novel HPLC solvent methodology to profile phosphatidylcholines and sphingolipids within the substantia nigra. The ipsilateral substantia nigra pars compacta was collected from rats 21 days after an infusion of 6-hydroxydopamine (6-OHDA), or vehicle into the anterior dorsal striatum. We identified 115 lipid species from their mass/charge ratio using the LMAPS Lipid MS Predict Database. Of these, 19 lipid species (from phosphatidylcholine and lysophosphotidylcholine lipid classes) were significantly altered by 6-OHDA, with most being down-regulated. The two lipid species that were up-regulated were LPC (16:0) and LPC (18:1), which are important for neuroinflammatory signalling. These findings provide a first step in the characterization of lipid changes in early stages of PD-like pathology and could provide novel targets for early interventions in PD. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology)

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16 pages, 822 KiB

Open AccessReview

Detecting Antigen-Specific T Cell Responses: From Bulk Populations to Single Cells

by Chansavath Phetsouphanh^1,*, John James Zaunders^1,2 and Anthony Dominic Kelleher^1,2

¹ Kirby Institute, University of New South Wales, 2031 Sydney, Australia

² Centre for Applied Medical Research, St. Vincent’s Hospital, 2010 Sydney, Australia

Int. J. Mol. Sci. 2015, 16(8), 18878-18893; https://doi.org/10.3390/ijms160818878 - 12 Aug 2015

Cited by 31 | Viewed by 10160

Abstract

A new generation of sensitive T cell-based assays facilitates the direct quantitation and characterization of antigen-specific T cell responses. Single-cell analyses have focused on measuring the quality and breadth of a response. Accumulating data from these studies demonstrate that there is considerable, previously-unrecognized, [...] Read more.

A new generation of sensitive T cell-based assays facilitates the direct quantitation and characterization of antigen-specific T cell responses. Single-cell analyses have focused on measuring the quality and breadth of a response. Accumulating data from these studies demonstrate that there is considerable, previously-unrecognized, heterogeneity. Standard assays, such as the ICS, are often insufficient for characterization of rare subsets of cells. Enhanced flow cytometry with imaging capabilities enables the determination of cell morphology, as well as the spatial localization of the protein molecules within a single cell. Advances in both microfluidics and digital PCR have improved the efficiency of single-cell sorting and allowed multiplexed gene detection at the single-cell level. Delving further into the transcriptome of single-cells using RNA-seq is likely to reveal the fine-specificity of cellular events such as alternative splicing (i.e., splice variants) and allele-specific expression, and will also define the roles of new genes. Finally, detailed analysis of clonally related antigen-specific T cells using single-cell TCR RNA-seq will provide information on pathways of differentiation of memory T cells. With these state of the art technologies the transcriptomics and genomics of Ag-specific T cells can be more definitively elucidated. Full article

(This article belongs to the Special Issue Single Cell Analysis in Biotechnology and Systems Biology)

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29 pages, 1150 KiB

Open AccessReview

Cardiovascular Disease Modeling Using Patient-Specific Induced Pluripotent Stem Cells

by Atsushi Tanaka¹, Shinsuke Yuasa^2,*, Koichi Node¹ and Keiichi Fukuda²

¹ Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan

² Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan

Int. J. Mol. Sci. 2015, 16(8), 18894-18922; https://doi.org/10.3390/ijms160818894 - 12 Aug 2015

Cited by 38 | Viewed by 15582

Abstract

The generation of induced pluripotent stem cells (iPSCs) has opened up a new scientific frontier in medicine. This technology has made it possible to obtain pluripotent stem cells from individuals with genetic disorders. Because iPSCs carry the identical genetic anomalies related to those [...] Read more.

The generation of induced pluripotent stem cells (iPSCs) has opened up a new scientific frontier in medicine. This technology has made it possible to obtain pluripotent stem cells from individuals with genetic disorders. Because iPSCs carry the identical genetic anomalies related to those disorders, iPSCs are an ideal platform for medical research. The pathophysiological cellular phenotypes of genetically heritable heart diseases such as arrhythmias and cardiomyopathies, have been modeled on cell culture dishes using disease-specific iPSC-derived cardiomyocytes. These model systems can potentially provide new insights into disease mechanisms and drug discoveries. This review focuses on recent progress in cardiovascular disease modeling using iPSCs, and discusses problems and future perspectives concerning their use. 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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15 pages, 872 KiB

Open AccessArticle

Nutritional Characterization and Phenolic Profiling of Moringa oleifera Leaves Grown in Chad, Sahrawi Refugee Camps, and Haiti

by Alessandro Leone^1,2,*

, Giovanni Fiorillo^1,2,†, Franca Criscuoli^1,2,†, Stefano Ravasenghi^1,2,†, Laura Santagostini³, Gelsomina Fico^4,5, Angela Spadafranca^1,2, Alberto Battezzati^1,2, Alberto Schiraldi², Federica Pozzi^6,†, Sara Di Lello^7,†, Sandro Filippini^8,† and Simona Bertoli^1,2

¹ International Center for the Assessment of Nutritional Status (ICANS), University of Milan, Via Sandro Botticelli 21, 20133 Milan, Italy

² Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, Italy

³ Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milan, Italy

⁴ Department of Pharmaceutical Sciences (DISFARM), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy

⁵ Botanic Garden G.E. Ghirardi, Department of Pharmaceutical Sciences (DISFARM), University of Milan, Via Religione 25, 25088 Toscolano Maderno, Italy

⁶ AVSI Foundation, Via Legnone, 20158 Milan, Italy

⁷ Movimento Africa 70, Via Missori 14, 20900 Monza, Italy

⁸ ACRA Foundation, Via Lazzaretto 3, 20124 Milan, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 18923-18937; https://doi.org/10.3390/ijms160818923 - 12 Aug 2015

Cited by 153 | Viewed by 14728

Abstract

Moringa oleifera is a plant that grows in tropical and subtropical areas of the world. Its leaves are rich of nutrients and bioactive compounds. However, several differences are reported in the literature. In this article we performed a nutritional characterization and a phenolic [...] Read more.

Moringa oleifera is a plant that grows in tropical and subtropical areas of the world. Its leaves are rich of nutrients and bioactive compounds. However, several differences are reported in the literature. In this article we performed a nutritional characterization and a phenolic profiling of M. oleifera leaves grown in Chad, Sahrawi refugee camps, and Haiti. In addition, we investigated the presence of salicylic and ferulic acids, two phenolic acids with pharmacological activity, whose presence in M. oleifera leaves has been scarcely investigated so far. Several differences were observed among the samples. Nevertheless, the leaves were rich in protein, minerals, and β-carotene. Quercetin and kaempferol glycosides were the main phenolic compounds identified in the methanolic extracts. Finally, salicylic and ferulic acids were found in a concentration range of 0.14–0.33 and 6.61–9.69 mg/100 g, respectively. In conclusion, we observed some differences in terms of nutrients and phenolic compounds in M. oleifera leaves grown in different countries. Nevertheless, these leaves are a good and economical source of nutrients for tropical and sub-tropical countries. Furthermore, M. oleifera leaves are a source of flavonoids and phenolic acids, among which salicylic and ferulic acids, and therefore they could be used as nutraceutical and functional ingredients. Full article

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

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18 pages, 2238 KiB

Open AccessArticle

Protective Effects of Hong Shan Capsule against Lethal Total-Body Irradiation-Induced Damage in Wistar Rats

by Jianzhong Li^1,*, Jing Xu^1,2, Weiheng Xu¹, Yang Qi¹, Yiming Lu¹, Lei Qiu¹, Zhenlin Hu¹, Zhiyong Chu³, Yifeng Chai¹ and Junping Zhang^1,*

¹ School of Pharmacy, Second Military Medical University, Shanghai 200433, China

² Department of Pharmacy, East Hospital, Dongji University, Shanghai 200085, China

³ Department of Preventive Medicine, Naval Medical Research Institute, Shanghai 200433, China

Int. J. Mol. Sci. 2015, 16(8), 18938-18955; https://doi.org/10.3390/ijms160818938 - 12 Aug 2015

Cited by 15 | Viewed by 5395

Abstract

Hong Shan Capsule (HSC), a crude drug of 11 medicinal herbs, was used in clinical practice for the treatment of radiation injuries in China. In this study, we investigated its protection in rats against acute lethal total-body irradiation (TBI). Pre-administration of HSC reduced [...] Read more.

Hong Shan Capsule (HSC), a crude drug of 11 medicinal herbs, was used in clinical practice for the treatment of radiation injuries in China. In this study, we investigated its protection in rats against acute lethal total-body irradiation (TBI). Pre-administration of HSC reduced the radiation sickness characteristics, while increasing the 30-day survival of the irradiated rats. Administration of HSC also reduced the radiation sickness characteristics and increased the 30-day survival of mice after exposure to lethal TBI. Ultrastructural observation illustrated that the pretreatment of rats with HSC significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed the dramatic effect of HSC on alterations of gene expression caused by lethal TBI. Pretreatment with HSC prevented differential expression of 66% (1398 genes) of 2126 genes differentially expressed in response to TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway. Our analysis indicated that the pretreatment of rats with HSC modulated these pathways induced by lethal TBI, such as multiple MAPK pathways, suggesting that pretreatment with HSC might provide protective effects on lethal TBI mainly or partially through the modulation of these pathways. Our data suggest that HSC has the potential to be used as an effective therapeutic or radio-protective agent to minimize irradiation damage. Full article

(This article belongs to the Section Biochemistry)

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20 pages, 7308 KiB

Open AccessArticle

A Natural Triterpene Derivative from Euphorbia kansui Inhibits Cell Proliferation and Induces Apoptosis against Rat Intestinal Epithelioid Cell Line in Vitro

by Fangfang Cheng¹, Yanjing Yang², Li Zhang^1,*

, Yudan Cao¹, Weifeng Yao¹, Yuping Tang^1,*

and Anwei Ding¹

¹ Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China

² Medicament Department, Zhangjiagang Hospital of Traditional Chinese Medicine, Suzhou 215600, China

Int. J. Mol. Sci. 2015, 16(8), 18956-18975; https://doi.org/10.3390/ijms160818956 - 12 Aug 2015

Cited by 31 | Viewed by 7374

Abstract

Kansenone is a triterpene from the root of the traditional Chinese medicine, Euphorbia kansui. However, kansenone exerts serious toxicity, but the exact mechanism was not clear. In this work, the effects of kansenone on cell proliferation, cell cycle, cell damage, and cell [...] Read more.

Kansenone is a triterpene from the root of the traditional Chinese medicine, Euphorbia kansui. However, kansenone exerts serious toxicity, but the exact mechanism was not clear. In this work, the effects of kansenone on cell proliferation, cell cycle, cell damage, and cell apoptosis were investigated. The suppression of cell proliferation was assessed via the colorimetric MTT assay, and cell morphology was visualized via inverted microscopy after IEC-6 cells were incubated with different concentrations of kansenone. Reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA) content were detected for evaluating cell damage. RNase/propidium iodide (PI) labeling for evaluation of cell cycle distribution was performed by flow cytometry analysis. Annexin V-fluorescein isothiocyanate (FITC)/PI and Hoechst 33342/Annexin V-FITC/PI staining assay for cell apoptosis detection were performed using confocal laser scanning microscopy and high content screening. Moreover, apoptosis induction was further confirmed by transmission electron microscope (TEM) and JC-1 mitochondrial membrane potential, western blot and RT-PCR analysis. The results demonstrated that kansenone exerted high cytotoxicity, induced cell arrest at G0/G1 phase, and caused mitochondria damage. In addition, kansenone could up-regulate the apoptotic proteins Bax, AIF, Apaf-1, cytochrome c, caspase-3, caspase-9, caspase-8, FasR, FasL, NF-κB, and TNFR1 mRNA expression levels, and down-regulate the anti-apoptotic Bcl-2 family proteins, revealing that kansenone induces apoptosis through both the death receptor and mitochondrial pathways. Full article

(This article belongs to the Section Molecular Toxicology)

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33 pages, 2270 KiB

Open AccessReview

Physiological and Molecular Aspects of Tolerance to Environmental Constraints in Grain and Forage Legumes

by Adnane Bargaz^1,*, Mainassara Zaman-Allah²

, Mohamed Farissi³

, Mohamed Lazali⁴, Jean-Jacques Drevon⁵, Rim T. Maougal⁶ and Carlsson Georg¹

¹ Department of Biosystems and Technology, Swedish University of Agricultural Sciences, Box 103, SE-23053 Alnarp, Sweden

² International Maize and Wheat Improvement Center (CIMMYT), Southern Africa Regional Office, MP163 Harare, Zimbabwe

³ Polyvalent Laboratory for Research & Development, Polydisciplinary Faculty, Sultan Moulay Sliman University, 23000 Beni-Mellal, Morocco

⁴ Faculté des Sciences de la Nature et de la Vie & des Sciences de la Terre, Université de Khemis Miliana, 44225 Ain Defla, Algeria

⁵ Unité mixte de recherche, Écologie Fonctionnelle & Biogéochimie des Sols et Agroécosystèmes, Institut National de la Recherche Agronomique, 34060 Montpellier, France

⁶ Laboratoire de génétique Biochimie et biotechnologies végétales Faculté des Sciences de la Nature et de la Vie, Université des frères Mentouri, 25017 Constantine, Algeria

Int. J. Mol. Sci. 2015, 16(8), 18976-19008; https://doi.org/10.3390/ijms160818976 - 13 Aug 2015

Cited by 43 | Viewed by 8198

Abstract

Despite the agronomical and environmental advantages of the cultivation of legumes, their production is limited by various environmental constraints such as water or nutrient limitation, frost or heat stress and soil salinity, which may be the result of pedoclimatic conditions, intensive use of [...] Read more.

Despite the agronomical and environmental advantages of the cultivation of legumes, their production is limited by various environmental constraints such as water or nutrient limitation, frost or heat stress and soil salinity, which may be the result of pedoclimatic conditions, intensive use of agricultural lands, decline in soil fertility and environmental degradation. The development of more sustainable agroecosystems that are resilient to environmental constraints will therefore require better understanding of the key mechanisms underlying plant tolerance to abiotic constraints. This review provides highlights of legume tolerance to abiotic constraints with a focus on soil nutrient deficiencies, drought, and salinity. More specifically, recent advances in the physiological and molecular levels of the adaptation of grain and forage legumes to abiotic constraints are discussed. Such adaptation involves complex multigene controlled-traits which also involve multiple sub-traits that are likely regulated under the control of a number of candidate genes. This multi-genetic control of tolerance traits might also be multifunctional, with extended action in response to a number of abiotic constraints. Thus, concrete efforts are required to breed for multifunctional candidate genes in order to boost plant stability under various abiotic constraints. Full article

(This article belongs to the Special Issue Abiotic Stress and Gene Networks in Plants)

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18 pages, 1277 KiB

Open AccessReview

by Ignacio Herraiz¹, Elisa Simón¹, Paula Isabel Gómez-Arriaga¹, José Manuel Martínez-Moratalla¹, Antonio García-Burguillo¹, Elena Ana López Jiménez² and Alberto Galindo^1,*

¹ Fetal Medicine Unit-Maternal and Child Health and Development Network (SAMID), Department of Obstetrics and Gynaecology, Hospital Universitario "12 de Octubre", Universidad Complutense de Madrid, 28041 Madrid, Spain

² Department of Clinical Biochemistry, Hospital Universitario "12 de Octubre", Universidad Complutense de Madrid, 28041 Madrid, Spain

Int. J. Mol. Sci. 2015, 16(8), 19009-19026; https://doi.org/10.3390/ijms160819009 - 13 Aug 2015

Cited by 91 | Viewed by 12014

Abstract

Placental dysfunction is involved in a group of obstetrical conditions including preeclampsia, intrauterine growth restriction, and placental abruption. Their timely and accurate recognition is often a challenge since diagnostic criteria are still based on nonspecific signs and symptoms. The discovering of the role [...] Read more.

Placental dysfunction is involved in a group of obstetrical conditions including preeclampsia, intrauterine growth restriction, and placental abruption. Their timely and accurate recognition is often a challenge since diagnostic criteria are still based on nonspecific signs and symptoms. The discovering of the role of angiogenic-related factors (sFlt-1/PlGF) in the underlying pathophysiology of placental dysfunction, taking into account that angiogenesis-related biomarkers are not specific to any particular placental insufficiency-related disease, has marked an important step for improving their early diagnosis and prognosis assessment. However, sFlt-1/PlGF has not been yet established as a part of most guidelines. We will review the current evidence on the clinical utility of sFlt-1/PlGF and propose a new protocol for its clinical integration. Full article

(This article belongs to the Special Issue Prediction, Diagnostics and Prevention of Pregnancy Complications)

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13 pages, 1501 KiB

Open AccessArticle

Human Dermal Stem/Progenitor Cell-Derived Conditioned Medium Improves Senescent Human Dermal Fibroblasts

by Ji-Yong Jung^†, Joong Hyun Shim^†, Hyun Choi, Tae Ryong Lee^* and Dong Wook Shin^*

¹ Amorepacific Corporation R&D Center, 314-1 Bora-dong, Giheung-gu, Yongin-si, Geyonggi-do 446729, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19027-19039; https://doi.org/10.3390/ijms160819027 - 13 Aug 2015

Cited by 11 | Viewed by 7319

Abstract

Adult skin stem cells are recognized as potential therapeutics to rejuvenate aged skin. We previously demonstrated that human dermal stem/progenitor cells (hDSPCs) with multipotent capacity could be enriched from human dermal fibroblasts using collagen type IV. However, the effects of hDSPCs on cellular [...] Read more.

Adult skin stem cells are recognized as potential therapeutics to rejuvenate aged skin. We previously demonstrated that human dermal stem/progenitor cells (hDSPCs) with multipotent capacity could be enriched from human dermal fibroblasts using collagen type IV. However, the effects of hDSPCs on cellular senescence remain to be elucidated. In the present study, we investigated whether conditioned medium (CM) collected from hDSPC cultures (hDSPC-CM) exhibits beneficial effects on senescent fibroblasts. We found that hDSPC-CM promoted proliferation and decreased the expression level of senescence-associated β-galactosidase in senescent fibroblasts. In addition, p53 phosphorylation and p21 expression were significantly reduced in senescent fibroblasts treated with hDSPC-CM. hDSPC-CM restored the expression levels of collagen type I, collagen type III, and tissue inhibitor of metalloproteinase, and antagonized the increase of matrix metalloproteinase 1 expression. Finally, we demonstrated that hDSPC-CM significantly reduced reactive oxygen species levels by specifically up-regulating the expression level of superoxide dismutase 2. Taken together, these data suggest that hDSPC-CM can be applied as a potential therapeutic agent for improving human aged skin. Full article

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

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15 pages, 760 KiB

Open AccessReview

Disorder Prediction Methods, Their Applicability to Different Protein Targets and Their Usefulness for Guiding Experimental Studies

by Jennifer D. Atkins¹, Samuel Y. Boateng¹, Thomas Sorensen² and Liam J. McGuffin^1,*

¹ School of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6AS, UK

² Diamond Light Source Ltd., Diamond House, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0DE, UK

Int. J. Mol. Sci. 2015, 16(8), 19040-19054; https://doi.org/10.3390/ijms160819040 - 13 Aug 2015

Cited by 56 | Viewed by 7473

Abstract

The role and function of a given protein is dependent on its structure. In recent years, however, numerous studies have highlighted the importance of unstructured, or disordered regions in governing a protein’s function. Disordered proteins have been found to play important roles in [...] Read more.

The role and function of a given protein is dependent on its structure. In recent years, however, numerous studies have highlighted the importance of unstructured, or disordered regions in governing a protein’s function. Disordered proteins have been found to play important roles in pivotal cellular functions, such as DNA binding and signalling cascades. Studying proteins with extended disordered regions is often problematic as they can be challenging to express, purify and crystallise. This means that interpretable experimental data on protein disorder is hard to generate. As a result, predictive computational tools have been developed with the aim of predicting the level and location of disorder within a protein. Currently, over 60 prediction servers exist, utilizing different methods for classifying disorder and different training sets. Here we review several good performing, publicly available prediction methods, comparing their application and discussing how disorder prediction servers can be used to aid the experimental solution of protein structure. The use of disorder prediction methods allows us to adopt a more targeted approach to experimental studies by accurately identifying the boundaries of ordered protein domains so that they may be investigated separately, thereby increasing the likelihood of their successful experimental solution. Full article

(This article belongs to the Special Issue In-Silico Prediction and Characterization of Intrinsic Disorder in Proteins)

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31 pages, 1128 KiB

Open AccessReview

Current Understanding of the Interplay between Phytohormones and Photosynthesis under Environmental Stress

by Mayank Anand Gururani^*

, Tapan Kumar Mohanta and Hanhong Bae^*

School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbook 712-749, Korea

Int. J. Mol. Sci. 2015, 16(8), 19055-19085; https://doi.org/10.3390/ijms160819055 - 13 Aug 2015

Cited by 121 | Viewed by 10280

Abstract

Abiotic stress accounts for huge crop losses every year across the globe. In plants, the photosynthetic machinery gets severely damaged at various levels due to adverse environmental conditions. Moreover, the reactive oxygen species (ROS) generated as a result of stress further promote the [...] Read more.

Abiotic stress accounts for huge crop losses every year across the globe. In plants, the photosynthetic machinery gets severely damaged at various levels due to adverse environmental conditions. Moreover, the reactive oxygen species (ROS) generated as a result of stress further promote the photosynthetic damage by inhibiting the repair system of photosystem II. Earlier studies have suggested that phytohormones are not only required for plant growth and development, but they also play a pivotal role in regulating plants’ responses to different abiotic stress conditions. Although, phytohormones have been studied in great detail in the past, their influence on the photosynthetic machinery under abiotic stress has not been studied. One of the major factors that limits researchers fromelucidating the precise roles of phytohormones is the highly complex nature of hormonal crosstalk in plants. Another factor that needs to be elucidated is the method used for assessing photosynthetic damage in plants that are subjected to abiotic stress. Here, we review the current understanding on the role of phytohormones in the photosynthetic machinery under various abiotic stress conditions and discuss the potential areas for further research. Full article

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

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10 pages, 1098 KiB

Open AccessArticle

Fumaric Acid Esters Do Not Reduce Inflammatory NF-κB/p65 Nuclear Translocation, ICAM-1 Expression and T-Cell Adhesiveness of Human Brain Microvascular Endothelial Cells

by Axel Haarmann, Mathias Nehen, Annika Deiß and Mathias Buttmann^*

Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, Würzburg 97080, Germany

Int. J. Mol. Sci. 2015, 16(8), 19086-19095; https://doi.org/10.3390/ijms160819086 - 13 Aug 2015

Cited by 13 | Viewed by 7053

Abstract

Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated [...] Read more.

Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 µM blocked the IL-1β-induced nuclear translocation of NF-κB/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1β-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1β-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells. Full article

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

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15 pages, 3844 KiB

Open AccessArticle

Lead Poisoning Disturbs Oligodendrocytes Differentiation Involved in Decreased Expression of NCX3 Inducing Intracellular Calcium Overload

by Teng Ma^1,2, Xiyan Wu¹, Qiyan Cai¹, Yun Wang¹, Lan Xiao¹, Yanping Tian^1,*

and Hongli Li^1,*

¹ Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China

² Battalion 7 of Cadet Brigade, Third Military Medical University, Chongqing 400038, China

Int. J. Mol. Sci. 2015, 16(8), 19096-19110; https://doi.org/10.3390/ijms160819096 - 13 Aug 2015

Cited by 22 | Viewed by 5943

Abstract

Lead (Pb) poisoning has always been a serious health concern, as it permanently damages the central nervous system. Chronic Pb accumulation in the human body disturbs oligodendrocytes (OLs) differentiation, resulting in dysmyelination, but the molecular mechanism remains unknown. In this study, Pb at [...] Read more.

Lead (Pb) poisoning has always been a serious health concern, as it permanently damages the central nervous system. Chronic Pb accumulation in the human body disturbs oligodendrocytes (OLs) differentiation, resulting in dysmyelination, but the molecular mechanism remains unknown. In this study, Pb at 1 μM inhibits OLs precursor cells (OPCs) differentiation via decreasing the expression of Olig 2, CNPase proteins in vitro. Moreover, Pb treatment inhibits the sodium/calcium exchanger 3 (NCX3) mRNA expression, one of the major means of calcium (Ca²⁺) extrusion at the plasma membrane during OPCs differentiation. Also addition of KB-R7943, NCX3 inhibitor, to simulate Pb toxicity, resulted in decreased myelin basic protein (MBP) expression and cell branching. Ca²⁺ response trace with Pb and KB-R7943 treatment did not drop down in the same recovery time as the control, which elevated intracellular Ca²⁺ concentration reducing MBP expression. In contrast, over-expression of NCX3 in Pb exposed OPCs displayed significant increase MBP fluorescence signal in positive regions and CNPase expression, which recovered OPCs differentiation to counterbalance Pb toxicity. In conclusion, Pb exposure disturbs OLs differentiation via affecting the function of NCX3 by inducing intracellular calcium overload. Full article

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

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19 pages, 2474 KiB

Open AccessReview

Route and Regulation of Zinc, Cadmium, and Iron Transport in Rice Plants (Oryza sativa L.) during Vegetative Growth and Grain Filling: Metal Transporters, Metal Speciation, Grain Cd Reduction and Zn and Fe Biofortification

by Tadakatsu Yoneyama^1,*, Satoru Ishikawa² and Shu Fujimaki³

¹ Department of Applied Biological Chemistry, The University of Tokyo, Tokyo 113-8657, Japan

² Soil Environment Division, National Institute for Agro-Environmental Sciences, Tsukuba, Ibaraki 305-8604, Japan

³ Quantum, Beam Science Center, Japan Atomic Energy Agency, Takasaki, Gunma 370-1292, Japan

Int. J. Mol. Sci. 2015, 16(8), 19111-19129; https://doi.org/10.3390/ijms160819111 - 13 Aug 2015

Cited by 149 | Viewed by 18063

Abstract

Zinc (Zn) and iron (Fe) are essential but are sometimes deficient in humans, while cadmium (Cd) is toxic if it accumulates in the liver and kidneys at high levels. All three are contained in the grains of rice, a staple cereal. Zn and [...] Read more.

Zinc (Zn) and iron (Fe) are essential but are sometimes deficient in humans, while cadmium (Cd) is toxic if it accumulates in the liver and kidneys at high levels. All three are contained in the grains of rice, a staple cereal. Zn and Fe concentrations in rice grains harvested under different levels of soil/hydroponic metals are known to change only within a small range, while Cd concentrations show greater changes. To clarify the mechanisms underlying such different metal contents, we synthesized information on the routes of metal transport and accumulation in rice plants by examining metal speciation, metal transporters, and the xylem-to-phloem transport system. At grain-filling, Zn and Cd ascending in xylem sap are transferred to the phloem by the xylem-to-phloem transport system operating at stem nodes. Grain Fe is largely derived from the leaves by remobilization. Zn and Fe concentrations in phloem-sap and grains are regulated within a small range, while Cd concentrations vary depending on xylem supply. Transgenic techniques to increase concentrations of the metal chelators (nicotianamine, 2′-deoxymugineic acid) are useful in increasing grain Zn and Fe concentrations. The elimination of OsNRAMP5 Cd-uptake transporter and the enhancement of root cell vacuolar Cd sequestration reduce uptake and root-to-shoot transport, respectively, resulting in a reduction of grain Cd accumulation. Full article

(This article belongs to the Special Issue Regulation of Plant Mineral Nutrition: Transport, Sensing and Signalling)

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23 pages, 1283 KiB

Open AccessArticle

Synthesis and in Vitro Antifungal Activity against Botrytis cinerea of Geranylated Phenols and Their Phenyl Acetate Derivatives

by María I. Chávez^1,†, Mauricio Soto^1,†, Lautaro Taborga^1,†

, Katy Díaz¹, Andrés F. Olea², Camila Bay³, Hugo Peña-Cortés⁴ and Luis Espinoza^1,*

¹ Departamento de Química, Universidad Técnica Federico Santa María, Valparaíso 2340000, Chile

² Instituto de Ciencias Químicas Aplicadas, Facultad de Ingeniería, Universidad Autónoma de Chile, Santiago 8910339, Chile

³ Facultad de Ingeniería, Universidad de Chile, Santiago 8370448, Chile

⁴ Facultad de Medicina, Hontaneda 2664, Universidad de Valparaíso, Valparaíso 2340000, Chile

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19130-19152; https://doi.org/10.3390/ijms160819130 - 14 Aug 2015

Cited by 10 | Viewed by 6774

Abstract

The inhibitory effects on the mycelial growth of plant pathogen Botritys cinerea have been evaluated for a series of geranylphenols substituted with one, two and three methoxy groups in the aromatic ring. The results show that the antifungal activity depends on the structure [...] Read more.

The inhibitory effects on the mycelial growth of plant pathogen Botritys cinerea have been evaluated for a series of geranylphenols substituted with one, two and three methoxy groups in the aromatic ring. The results show that the antifungal activity depends on the structure of the geranylphenols, increasing from 40% to 90% by increasing the number of methoxy groups. On the other hand, the acetylation of the –OH group induces a change of activity that depends on the number of methoxy groups. The biological activity of digeranyl derivatives is lower than that exhibited by the respective monogeranyl compound. All tested geranylphenols have been synthesized by direct coupling of geraniol and the respective phenol. The effect of solvent on yields and product distribution is discussed. For monomethoxyphenols the reaction gives better yields when acetonitrile is used as a solvent and AgNO₃ is used as a secondary catalyst. However, for di- and trimethoxyphenols the reaction proceeds only in dioxane. Full article

(This article belongs to the Section Green Chemistry)

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17 pages, 1914 KiB

Open AccessReview

Current Status on Stem Cells and Cancers of the Gastric Epithelium

by Werner Hoffmann

Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany

Int. J. Mol. Sci. 2015, 16(8), 19153-19169; https://doi.org/10.3390/ijms160819153 - 14 Aug 2015

Cited by 35 | Viewed by 12754

Abstract

Gastric cancer is still a leading cause of cancer-related mortality worldwide in spite of declining incidence. Gastric cancers are, essentially, adenocarcinomas and one of the strongest risk factors is still infection with Helicobacter pylori. Within the last years, it became clear that [...] Read more.

Gastric cancer is still a leading cause of cancer-related mortality worldwide in spite of declining incidence. Gastric cancers are, essentially, adenocarcinomas and one of the strongest risk factors is still infection with Helicobacter pylori. Within the last years, it became clear that gastric self-renewal and carcinogenesis are intimately linked, particularly during chronic inflammatory conditions. Generally, gastric cancer is now regarded as a disease resulting from dysregulated differentiation of stem and progenitor cells, mainly due to an inflammatory environment. However, the situation in the stomach is rather complex, consisting of two types of gastric units which show bidirectional self-renewal from an unexpectedly large variety of progenitor/stem cell populations. As in many other tumors, cancer stem cells have also been characterized for gastric cancer. This review focuses on the various gastric epithelial stem cells, how they contribute to self-renewal and which routes are known to gastric adenocarcinomas, including their stem cells. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Regeneration and Tissue Repair)

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14 pages, 2075 KiB

Open AccessArticle

Cdc42-Interacting Protein 4 Represses E-Cadherin Expression by Promoting β-Catenin Translocation to the Nucleus in Murine Renal Tubular Epithelial Cells

by Chuou Xu, Qiaodan Zhou, Lili Liu, Ping Liu, Guangchang Pei, Rui Zeng, Min Han and Gang Xu^*

Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China

Int. J. Mol. Sci. 2015, 16(8), 19170-19183; https://doi.org/10.3390/ijms160819170 - 14 Aug 2015

Cited by 9 | Viewed by 6405

Abstract

Renal fibrosis is an inevitable outcome of end-stage chronic kidney disease. During this process, epithelial cells lose E-cadherin expression. β-Catenin may act as a mediator by accumulation and translocation to the nucleus. Studies have suggested that CIP4, a Cdc42 effector protein, is associated [...] Read more.

Renal fibrosis is an inevitable outcome of end-stage chronic kidney disease. During this process, epithelial cells lose E-cadherin expression. β-Catenin may act as a mediator by accumulation and translocation to the nucleus. Studies have suggested that CIP4, a Cdc42 effector protein, is associated with β-catenin. However, whether CIP4 contributes to E-cadherin loss in epithelial cells by regulating β-catenin translocation is unclear. In this study, we investigated the involvement of CIP4 in β-catenin translocation. Expression of CIP4 was upregulated in renal tissues of 5/6 nephrectomized rats and mainly distributed in renal tubular epithelia. In TGF-β1-treated NRK-52E cells, upregulation of CIP4 expression was accompanied by reduced expression of E-cadherin. CIP4 overexpression promoted the translocation of β-catenin to the nucleus, which was accompanied by reduced expression of E-cadherin even without TGF-β1 stimulation. In contrast, CIP4 depletion by using siRNA inhibited the translocation of β-catenin to the nucleus and reversed the decrease in expression of E-cadherin. The interaction between CIP4 and β-catenin was detected. We also show that β-catenin depletion could restore the expression of E-cadherin that was suppressed by CIP4 overexpression. In conclusion, these results suggest that CIP4 overexpression represses E-cadherin expression by promoting β-catenin translocation to the nucleus. Full article

(This article belongs to the Section Biochemistry)

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11 pages, 1488 KiB

Open AccessArticle

Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

by Alwin M. Hartman^1,†, Milon Mondal^1,†, Nedyalka Radeva², Gerhard Klebe² and Anna K. H. Hirsch^1,*

¹ Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands

² Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19184-19194; https://doi.org/10.3390/ijms160819184 - 14 Aug 2015

Cited by 14 | Viewed by 7328

Abstract

Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer’s disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, [...] Read more.

Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer’s disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, for the design, preparation and biochemical evaluation of a new series of inhibitors of endothiapepsin. Here, we have optimized a hit, identified by de novo structure-based drug design (SBDD) and DCC, by using structure-based design approaches focusing on the optimization of an amide–π interaction. Biochemical results are in agreement with SBDD. These results will provide useful insights for future structure-based optimization of inhibitors for the real drug targets as well as insights into molecular recognition. Full article

(This article belongs to the Special Issue Supramolecular Interactions)

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30 pages, 1071 KiB

Open AccessReview

Gene Networks Involved in Hormonal Control of Root Development in Arabidopsis thaliana: A Framework for Studying Its Disturbance by Metal Stress

by Stefanie De Smet^*, Ann Cuypers, Jaco Vangronsveld

and Tony Remans

Centre for Environmental Sciences, Environmental Biology, Hasselt University, Agoralaan Gebouw D, 3590 Diepenbeek, Belgium

Int. J. Mol. Sci. 2015, 16(8), 19195-19224; https://doi.org/10.3390/ijms160819195 - 14 Aug 2015

Cited by 59 | Viewed by 26891

Abstract

Plant survival under abiotic stress conditions requires morphological and physiological adaptations. Adverse soil conditions directly affect root development, although the underlying mechanisms remain largely to be discovered. Plant hormones regulate normal root growth and mediate root morphological responses to abiotic stress. Hormone synthesis, [...] Read more.

Plant survival under abiotic stress conditions requires morphological and physiological adaptations. Adverse soil conditions directly affect root development, although the underlying mechanisms remain largely to be discovered. Plant hormones regulate normal root growth and mediate root morphological responses to abiotic stress. Hormone synthesis, signal transduction, perception and cross-talk create a complex network in which metal stress can interfere, resulting in root growth alterations. We focus on Arabidopsis thaliana, for which gene networks in root development have been intensively studied, and supply essential terminology of anatomy and growth of roots. Knowledge of gene networks, mechanisms and interactions related to the role of plant hormones is reviewed. Most knowledge has been generated for auxin, the best-studied hormone with a pronounced primary role in root development. Furthermore, cytokinins, gibberellins, abscisic acid, ethylene, jasmonic acid, strigolactones, brassinosteroids and salicylic acid are discussed. Interactions between hormones that are of potential importance for root growth are described. This creates a framework that can be used for investigating the impact of abiotic stress factors on molecular mechanisms related to plant hormones, with the limited knowledge of the effects of the metals cadmium, copper and zinc on plant hormones and root development included as case example. Full article

(This article belongs to the Special Issue Abiotic Stress and Gene Networks in Plants)

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23 pages, 960 KiB

Open AccessReview

The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes

by Leilei Zhong^1,†, Xiaobin Huang^1,2,†, Marcel Karperien¹

and Janine N. Post^1,*

¹ Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands

² School of Life Sciences, Chongqing University, Chongqing 400030, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19225-19247; https://doi.org/10.3390/ijms160819225 - 14 Aug 2015

Cited by 109 | Viewed by 13247

Abstract

Hypertrophic differentiation of chondrocytes is a main barrier in application of mesenchymal stem cells (MSCs) for cartilage repair. In addition, hypertrophy occurs occasionally in osteoarthritis (OA). Here we provide a comprehensive review on recent literature describing signal pathways in the hypertrophy of MSCs-derived [...] Read more.

Hypertrophic differentiation of chondrocytes is a main barrier in application of mesenchymal stem cells (MSCs) for cartilage repair. In addition, hypertrophy occurs occasionally in osteoarthritis (OA). Here we provide a comprehensive review on recent literature describing signal pathways in the hypertrophy of MSCs-derived in vitro differentiated chondrocytes and chondrocytes, with an emphasis on the crosstalk between these pathways. Insight into the exact regulation of hypertrophy by the signaling network is necessary for the efficient application of MSCs for articular cartilage repair and for developing novel strategies for curing OA. We focus on articles describing the role of the main signaling pathways in regulating chondrocyte hypertrophy-like changes. Most studies report hypertrophic differentiation in chondrogenesis of MSCs, in both human OA and experimental OA. Chondrocyte hypertrophy is not under the strict control of a single pathway but appears to be regulated by an intricately regulated network of multiple signaling pathways, such as WNT, Bone morphogenetic protein (BMP)/Transforming growth factor-β (TGFβ), Parathyroid hormone-related peptide (PTHrP), Indian hedgehog (IHH), Fibroblast growth factor (FGF), Insulin like growth factor (IGF) and Hypoxia-inducible factor (HIF). This comprehensive review describes how this intricate signaling network influences tissue-engineering applications of MSCs in articular cartilage (AC) repair, and improves understanding of the disease stages and cellular responses within an OA articular joint. Full article

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

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43 pages, 2854 KiB

Open AccessReview

Disease Resistance Gene Analogs (RGAs) in Plants

by Manoj Kumar Sekhwal^1,†, Pingchuan Li^1,†, Irene Lam¹, Xiue Wang², Sylvie Cloutier³ and Frank M. You^1,4,*

¹ Cereal Research Centre, Agriculture and Agri-Food Canada, Morden, MB R6M 1Y5, Canada

² National Key Laboratory of Crop Genetics and Germplasm Enhancement, Cytogenetics Institute, Nanjing Agricultural University, Nanjing 210095, China

³ Eastern Cereal and Oilseed Research Centre, Agriculture and Agri-Food Canada, Ottawa, ON K1A 0C6, Canada

⁴ Plant Science Department, University of Manitoba, Winnipeg, MB R3T 2N6, Canada

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19248-19290; https://doi.org/10.3390/ijms160819248 - 14 Aug 2015

Cited by 234 | Viewed by 22850

Abstract

Plants have developed effective mechanisms to recognize and respond to infections caused by pathogens. Plant resistance gene analogs (RGAs), as resistance (R) gene candidates, have conserved domains and motifs that play specific roles in pathogens’ resistance. Well-known RGAs are nucleotide binding [...] Read more.

Plants have developed effective mechanisms to recognize and respond to infections caused by pathogens. Plant resistance gene analogs (RGAs), as resistance (R) gene candidates, have conserved domains and motifs that play specific roles in pathogens’ resistance. Well-known RGAs are nucleotide binding site leucine rich repeats, receptor like kinases, and receptor like proteins. Others include pentatricopeptide repeats and apoplastic peroxidases. RGAs can be detected using bioinformatics tools based on their conserved structural features. Thousands of RGAs have been identified from sequenced plant genomes. High-density genome-wide RGA genetic maps are useful for designing diagnostic markers and identifying quantitative trait loci (QTL) or markers associated with plant disease resistance. This review focuses on recent advances in structures and mechanisms of RGAs, and their identification from sequenced genomes using bioinformatics tools. Applications in enhancing fine mapping and cloning of plant disease resistance genes are also discussed. Full article

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

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17 pages, 1446 KiB

Open AccessArticle

Tangential Flow Ultrafiltration Allows Purification and Concentration of Lauric Acid-/Albumin-Coated Particles for Improved Magnetic Treatment

by Jan Zaloga^1,†, Marcus Stapf^2,†, Johannes Nowak³, Marina Pöttler¹, Ralf P. Friedrich¹, Rainer Tietze¹, Stefan Lyer¹, Geoffrey Lee⁴, Stefan Odenbach³, Ingrid Hilger²

and Christoph Alexiou^1,*

¹ Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius Stiftungsprofessur for Nanomedicine, University Hospital Erlangen, 91054 Erlangen, Germany

² Institute for Diagnostic and Interventional Radiology, University Hospital Jena, 07747 Jena, Germany

³ Chair of Magnetofluiddynamics, Measuring and Automation Technology, Technische Universität Dresden, 01069 Dresden, Germany

⁴ Division of Pharmaceutics, Friedrich Alexander University Erlangen-Nuremberg, 91058 Erlangen, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19291-19307; https://doi.org/10.3390/ijms160819291 - 14 Aug 2015

Cited by 29 | Viewed by 8102

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) are frequently used for drug targeting, hyperthermia and other biomedical purposes. Recently, we have reported the synthesis of lauric acid-/albumin-coated iron oxide nanoparticles SEON^LA-BSA, which were synthesized using excess albumin. For optimization of magnetic treatment applications, [...] Read more.

Superparamagnetic iron oxide nanoparticles (SPIONs) are frequently used for drug targeting, hyperthermia and other biomedical purposes. Recently, we have reported the synthesis of lauric acid-/albumin-coated iron oxide nanoparticles SEON^LA-BSA, which were synthesized using excess albumin. For optimization of magnetic treatment applications, SPION suspensions need to be purified of excess surfactant and concentrated. Conventional methods for the purification and concentration of such ferrofluids often involve high shear stress and low purification rates for macromolecules, like albumin. In this work, removal of albumin by low shear stress tangential ultrafiltration and its influence on SEON^LA-BSA particles was studied. Hydrodynamic size, surface properties and, consequently, colloidal stability of the nanoparticles remained unchanged by filtration or concentration up to four-fold (v/v). Thereby, the saturation magnetization of the suspension can be increased from 446.5 A/m up to 1667.9 A/m. In vitro analysis revealed that cellular uptake of SEON^LA-BSAchanged only marginally. The specific absorption rate (SAR) was not greatly affected by concentration. In contrast, the maximum temperature T_max in magnetic hyperthermia is greatly enhanced from 44.4 °C up to 64.9 °C by the concentration of the particles up to 16.9 mg/mL total iron. Taken together, tangential ultrafiltration is feasible for purifying and concentrating complex hybrid coated SPION suspensions without negatively influencing specific particle characteristics. This enhances their potential for magnetic treatment. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2015)

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18 pages, 1950 KiB

Open AccessArticle

Overexpressing Ferredoxins in Chlamydomonas reinhardtii Increase Starch and Oil Yields and Enhance Electric Power Production in a Photo Microbial Fuel Cell

by Li-Fen Huang^*, Ji-Yu Lin, Kui-You Pan, Chun-Kai Huang and Ying-Kai Chu

Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320, Taiwan

Int. J. Mol. Sci. 2015, 16(8), 19308-19325; https://doi.org/10.3390/ijms160819308 - 14 Aug 2015

Cited by 34 | Viewed by 7843

Abstract

Ferredoxins (FDX) are final electron carrier proteins in the plant photosynthetic pathway, and function as major electron donors in diverse redox-driven metabolic pathways. We previously showed that overexpression of a major constitutively expressed ferredoxin gene PETF in Chlamydomonas decreased the reactive oxygen species [...] Read more.

Ferredoxins (FDX) are final electron carrier proteins in the plant photosynthetic pathway, and function as major electron donors in diverse redox-driven metabolic pathways. We previously showed that overexpression of a major constitutively expressed ferredoxin gene PETF in Chlamydomonas decreased the reactive oxygen species (ROS) level and enhanced tolerance to heat stress. In addition to PETF, an endogenous anaerobic induced FDX5 was overexpressed in transgenic Chlamydomonas lines here to address the possible functions of FDX5. All the independent FDX transgenic lines showed decreased cellular ROS levels and enhanced tolerance to heat and salt stresses. The transgenic Chlamydomonas lines accumulated more starch than the wild-type line and this effect increased almost three-fold in conditions of nitrogen depletion. Furthermore, the lipid content was higher in the transgenic lines than in the wild-type line, both with and without nitrogen depletion. Two FDX-overexpressing Chlamydomonas lines were assessed in a photo microbial fuel cell (PMFC); power density production by the transgenic lines was higher than that of the wild-type cells. These findings suggest that overexpression of either PETF or FDX5 can confer tolerance against heat and salt stresses, increase starch and oil production, and raise electric power density in a PMFC. Full article

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

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21 pages, 1170 KiB

Open AccessArticle

Identification of Proteins Modulated in the Date Palm Stem Infested with Red Palm Weevil (Rhynchophorus ferrugineus Oliv.) Using Two Dimensional Differential Gel Electrophoresis and Mass Spectrometry

by Khawaja Ghulam Rasool^1,2,*, Muhammad Altaf Khan³, Abdulrahman Saad Aldawood¹, Muhammad Tufail^1,2, Muhammad Mukhtar^4,* and Makio Takeda²

¹ Department of Plant Protection, College of Food and Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia

² Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan

³ Department of Plant Production, College of Food and Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia

⁴ Department of Biotechnology, American University of Ras Al Khaimah, Ras Al Khaimah 10021, United Arab Emirates

Int. J. Mol. Sci. 2015, 16(8), 19326-19346; https://doi.org/10.3390/ijms160819326 - 17 Aug 2015

Cited by 21 | Viewed by 8360

Abstract

A state of the art proteomic methodology using Matrix Assisted Laser Desorption/Ionization-Time of Flight (MALDI TOF) has been employed to characterize peptides modulated in the date palm stem subsequent to infestation with red palm weevil (RPW). Our analyses revealed 32 differentially expressed peptides [...] Read more.

A state of the art proteomic methodology using Matrix Assisted Laser Desorption/Ionization-Time of Flight (MALDI TOF) has been employed to characterize peptides modulated in the date palm stem subsequent to infestation with red palm weevil (RPW). Our analyses revealed 32 differentially expressed peptides associated with RPW infestation in date palm stem. To identify RPW infestation associated peptides (I), artificially wounded plants (W) were used as additional control beside uninfested plants, a conventional control (C). A constant unique pattern of differential expression in infested (I), wounded (W) stem samples compared to control (C) was observed. The upregulated proteins showed relative fold intensity in order of I > W and downregulated spots trend as W > I, a quite interesting pattern. This study also reveals that artificially wounding of date palm stem affects almost the same proteins as infestation; however, relative intensity is quite lower than in infested samples both in up and downregulated spots. All 32 differentially expressed spots were subjected to MALDI-TOF analysis for their identification and we were able to match 21 proteins in the already existing databases. Relatively significant modulated expression pattern of a number of peptides in infested plants predicts the possibility of developing a quick and reliable molecular methodology for detecting plants infested with date palm. Full article

(This article belongs to the Special Issue Plant Proteomic Research)

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22 pages, 2385 KiB

Open AccessArticle

GC–MS-Based Metabonomic Profiling Displayed Differing Effects of Borna Disease Virus Natural Strain Hu-H1 and Laboratory Strain V Infection in Rat Cortical Neurons

by Siwen Liu^1,2,3,†, Liv Bode^2,†, Lujun Zhang^1,2,3,†, Peng He^2,3,†, Rongzhong Huang⁴, Lin Sun^2,3,5, Shigang Chen^2,3, Hong Zhang^2,3, Yujie Guo^2,3,5, Jingjing Zhou^2,3, Yuying Fu^2,3, Dan Zhu⁵ and Peng Xie^1,2,3,5,*

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

² Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016, China

³ Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016, China

⁴ Department of Rehabilitation, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China

⁵ Department of Neurology, the First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19347-19368; https://doi.org/10.3390/ijms160819347 - 17 Aug 2015

Cited by 17 | Viewed by 5990

Abstract

Borna disease virus (BDV) persists in the central nervous systems of a wide variety of vertebrates and causes behavioral disorders. Previous studies have revealed that metabolic perturbations are associated with BDV infection. However, the pathophysiological effects of different viral strains remain largely unknown. [...] Read more.

Borna disease virus (BDV) persists in the central nervous systems of a wide variety of vertebrates and causes behavioral disorders. Previous studies have revealed that metabolic perturbations are associated with BDV infection. However, the pathophysiological effects of different viral strains remain largely unknown. Rat cortical neurons infected with human strain BDV Hu-H1, laboratory BDV Strain V, and non-infected control (CON) cells were cultured in vitro. At day 12 post-infection, a gas chromatography coupled with mass spectrometry (GC–MS) metabonomic approach was used to differentiate the metabonomic profiles of 35 independent intracellular samples from Hu-H1-infected cells (n = 12), Strain V-infected cells (n = 12), and CON cells (n = 11). Partial least squares discriminant analysis (PLS-DA) was performed to demonstrate discrimination between the three groups. Further statistical testing determined which individual metabolites displayed significant differences between groups. PLS-DA demonstrated that the whole metabolic pattern enabled statistical discrimination between groups. We identified 31 differential metabolites in the Hu-H1 and CON groups (21 decreased and 10 increased in Hu-H1 relative to CON), 35 differential metabolites in the Strain V and CON groups (30 decreased and 5 increased in Strain V relative to CON), and 21 differential metabolites in the Hu-H1 and Strain V groups (8 decreased and 13 increased in Hu-H1 relative to Strain V). Comparative metabonomic profiling revealed divergent perturbations in key energy and amino acid metabolites between natural strain Hu-H1 and laboratory Strain V of BDV. The two BDV strains differentially alter metabolic pathways of rat cortical neurons in vitro. Their systematic classification provides a valuable template for improved BDV strain definition in future studies. Full article

(This article belongs to the Section Biochemistry)

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18 pages, 5371 KiB

Open AccessArticle

DNA Targeting Sequence Improves Magnetic Nanoparticle-Based Plasmid DNA Transfection Efficiency in Model Neurons

by Matthew M. Vernon¹, David A. Dean² and Jon Dobson^1,3,4,*

¹ Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA

² School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA

³ Department of Materials Science and Engineering, University of Florida, Gainesville, FL 32603, USA

⁴ Institute for Cell Engineering & Regenerative Medicine (ICERM), University of Florida, Gainesville, FL 32611, USA

Int. J. Mol. Sci. 2015, 16(8), 19369-19386; https://doi.org/10.3390/ijms160819369 - 17 Aug 2015

Cited by 14 | Viewed by 8980

Abstract

Efficient non-viral plasmid DNA transfection of most stem cells, progenitor cells and primary cell lines currently presents an obstacle for many applications within gene therapy research. From a standpoint of efficiency and cell viability, magnetic nanoparticle-based DNA transfection is a promising gene vectoring [...] Read more.

Efficient non-viral plasmid DNA transfection of most stem cells, progenitor cells and primary cell lines currently presents an obstacle for many applications within gene therapy research. From a standpoint of efficiency and cell viability, magnetic nanoparticle-based DNA transfection is a promising gene vectoring technique because it has demonstrated rapid and improved transfection outcomes when compared to alternative non-viral methods. Recently, our research group introduced oscillating magnet arrays that resulted in further improvements to this novel plasmid DNA (pDNA) vectoring technology. Continued improvements to nanomagnetic transfection techniques have focused primarily on magnetic nanoparticle (MNP) functionalization and transfection parameter optimization: cell confluence, growth media, serum starvation, magnet oscillation parameters, etc. Noting that none of these parameters can assist in the nuclear translocation of delivered pDNA following MNP-pDNA complex dissociation in the cell’s cytoplasm, inclusion of a cassette feature for pDNA nuclear translocation is theoretically justified. In this study incorporation of a DNA targeting sequence (DTS) feature in the transfecting plasmid improved transfection efficiency in model neurons, presumably from increased nuclear translocation. This observation became most apparent when comparing the response of the dividing SH-SY5Y precursor cell to the non-dividing and differentiated SH-SY5Y neuroblastoma cells. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2015)

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14 pages, 2598 KiB

Open AccessArticle

15,16-Dihydrotanshinone I from the Functional Food Salvia miltiorrhiza Exhibits Anticancer Activity in Human HL-60 Leukemia Cells: in Vitro and in Vivo Studies

by Jun-Jen Liu¹, Hsueh-Hsia Wu¹, Tzu-Ho Chen¹, Wan Leung^2,* and Yu-Chih Liang^1,3,*

¹ School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, No. 250 Wuxing St., Taipei 11031, Taiwan

² Department of Radiology and Nuclear Medicine, Yuan’s General Hospital, No. 162 Cheng Kung 1st Road, Kaohsiung 80249, Taiwan

³ Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, No. 252 Wuxing St., Taipei 11031, Taiwan

Int. J. Mol. Sci. 2015, 16(8), 19387-19400; https://doi.org/10.3390/ijms160819387 - 17 Aug 2015

Cited by 39 | Viewed by 7056

Abstract

15,16-Dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge which is a functional food in Asia. In this study, we investigated the apoptotic effect of DHTS on the human acute myeloid leukemia (AML) type III HL-60 cell line. We found that treatment with [...] Read more.

15,16-Dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge which is a functional food in Asia. In this study, we investigated the apoptotic effect of DHTS on the human acute myeloid leukemia (AML) type III HL-60 cell line. We found that treatment with 1.5 μg/mL DHTS increased proapoptotic Bax and Bad protein expressions and activated caspases-3, -8, and -9, thus leading to poly ADP ribose polymerase (PARP) cleavage and resulting in cell apoptosis. DHTS induced sustained c-Jun N-terminal kinase (JNK) phosphorylation and Fas ligand (FasL) expression. The anti-Fas blocking antibody reversed the DHTS-induced cell death, and the JNK-specific inhibitor, SP600125, inhibited DHTS-induced caspase-3, -8, -9, and PARP cleavage. In a xenograft nude mice model, 25 mg/kg DHTS showed a great effect in attenuating HL-60 tumor growth. Taken together, these results suggest that DHTS can induce HL-60 cell apoptosis in vitro and inhibit HL-60 cell growth in vivo; the underlying mechanisms might be mediated through activation of the JNK and FasL signal pathways. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals in Functional Foods for Cancer Prevention)

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18 pages, 1322 KiB

Open AccessArticle

Methyl Sartortuoate Inhibits Colon Cancer Cell Growth by Inducing Apoptosis and G2/M-Phase Arrest

by Qiusheng Lan^1,†, Shoufeng Li^2,†, Wei Lai¹, Heyang Xu¹, Yang Zhang¹, Yujie Zeng¹, Wenjian Lan^3,* and Zhonghua Chu^1,*

¹ Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China

² Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou 350000, China

³ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19401-19418; https://doi.org/10.3390/ijms160819401 - 17 Aug 2015

Cited by 10 | Viewed by 6588

Abstract

The potential anti-neoplastic activity of terpenoids is of continued interest. In this study, we investigate whether methyl sartortuoate, a terpenoid isolated from soft coral, induced cell cycle arrest and apoptosis in a human colon cancer cell line. Culture studies found that methyl sartortuoate [...] Read more.

The potential anti-neoplastic activity of terpenoids is of continued interest. In this study, we investigate whether methyl sartortuoate, a terpenoid isolated from soft coral, induced cell cycle arrest and apoptosis in a human colon cancer cell line. Culture studies found that methyl sartortuoate inhibited colon cancer cell (LoVo and RKO) growth and caused apoptotic death in a concentration- and time-dependent manner, by activation of caspase-8, caspase-9, caspase-3, p53 and Bax, and inactivation of B-cell lymphoma 2 (Bcl-2) apoptosis regulating proteins. Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways. Methyl sartortuoate also up-regulated phospho-JNK and phospho-p38 expression levels. This resulted in cell cycle arrest at the G2-M phase and apoptosis in LoVo and RKO cells. Treatment with the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 prevented methyl sartortuoate-induced apoptosis in LoVo cells. Moreover, methyl sartortuoate also prevented neoplasm growth in NOD-SCID nude mice inoculated with LoVo cells. Taken together, these findings suggest that methyl sartortuoate is capable of leading to activation of caspase-8, -9, -3, increasing p53 and Bax/Bcl-2 ratio apoptosis through MAPK-dependent apoptosis and results in G2-M phase arrest in LoVo and RKO cells. Thus, methyl sartortuoate may be a promising anticancer candidate. Full article

(This article belongs to the Special Issue Molecular Machinery of Cell Growth Regulation)

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14 pages, 2446 KiB

Open AccessArticle

Lentiviral-Mediated Short Hairpin RNA Knockdown of MTDHInhibits Cell Growth and Induces Apoptosis by Regulatingthe PTEN/AKT Pathway in Hepatocellular Carcinoma

by Wen-Fang Li¹, Qin Ou², Hang Dai¹ and Chang-An Liu^1,3,*

¹ Department of Hepatibiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

² Department of Cancer Research Center, Hubei Medical University, Shiyan 442000, China

³ State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, Shiyan 442000, China

Int. J. Mol. Sci. 2015, 16(8), 19419-19432; https://doi.org/10.3390/ijms160819419 - 17 Aug 2015

Cited by 32 | Viewed by 5938

Abstract

The activation of oncogenes and the loss of tumor suppressor genes are believed toplay critical roles in the pathogenesis of human hepatocellular carcinoma (HCC). Metaherin (MTDH), also called astrocyte elevated gene-1 (AEG-1), is frequently amplified in a variety of cancers, but the roles [...] Read more.

The activation of oncogenes and the loss of tumor suppressor genes are believed toplay critical roles in the pathogenesis of human hepatocellular carcinoma (HCC). Metaherin (MTDH), also called astrocyte elevated gene-1 (AEG-1), is frequently amplified in a variety of cancers, but the roles of MTDH with regard to growth and apoptosis in HCC have not yet been studied. In the present study, we first analyzed the expression of MTDH in HCC samples. We found that MTDH protein levels are higher in most HCC cancerous tissues compared with their matched adjacent non-tumor tissues. Additionally, the MTDH mRNA was also higher in HCC tissues compared to their matched adjacent non-tumor tissues. Knockdown of the endogenous MTDH using small interfering RNA further showed that deficiency of MTDH suppressed cell growth and caused apoptosis in HCC cells. Knockdown MTDH promoted PTEN and p53 expression in HCC cells and inhibited AKT phosphorylation. Knockdown MTDH also inhibited tumor growth in vivo. All these results indicated that MTDH protein levels in most HCC tissues are higher than non-tumor tissues, and knockdown of MTDH inhibited growth and induced apoptosis in HCC cells through the activation of PTEN. Therefore, MTDH might be an effective targeted therapy gene for HCC. Full article

(This article belongs to the Special Issue Molecular Machinery of Cell Growth Regulation)

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14 pages, 961 KiB

Open AccessArticle

Molecular and Functional Characterization of Thioredoxin 1from Korean Rose Bitterling (Rhodeus uyekii)

by Julan Kim, Ji Young Moon, Woo-Jin Kim, Dong-Gyun Kim, Bo-Hye Nam, Young-Ok Kim, Jung Youn Park, Cheul Min An and Hee Jeong Kong^*

Biotechnology Research Division, National Fisheries Research and Development Institute, Busan 619-705, Korea

Int. J. Mol. Sci. 2015, 16(8), 19433-19446; https://doi.org/10.3390/ijms160819433 - 17 Aug 2015

Cited by 10 | Viewed by 5850

Abstract

Thioredoxin is a multifunctional antioxidant enzyme that belongs to the reductase family. In this study, we cloned and characterized thioredoxin 1 cDNA from the Korean rose bitterling Rhodeus uyekii (RuTrx). The full-length RuTrx cDNA consists of 674 bp with a 324 nt open [...] Read more.

Thioredoxin is a multifunctional antioxidant enzyme that belongs to the reductase family. In this study, we cloned and characterized thioredoxin 1 cDNA from the Korean rose bitterling Rhodeus uyekii (RuTrx). The full-length RuTrx cDNA consists of 674 bp with a 324 nt open reading frame (ORF) encoding a 107 aa protein. The deduced RuTrx amino acid sequence indicated a characteristic redox active site, ³¹WCGPC³⁵. Pairwise alignment revealed RuTrx amino acid identity (55.1%–83.2%) with orthologs from various species of mammalia, amphibia, fish and bird. Phylogenetic analysis was conducted to determine the evolutionary position of RuTrx. Expression analysis showed that RuTrx transcripts were present in all of the tissues examined, and was high in the hepatopancreas of R. uyekii. During early development, the expression of RuTrx transcripts was increased. Recombinant RuTrx protein (rRuTrx) was tested for its capacity to serve as an antioxidant enzyme using a metal-catalyzed oxidation (MCO) system. The ability of rRuTrx to protect against supercoiled DNA cleavage due to oxidative nicking increased in a dose-dependent manner. In Raw264.7 cells, Dihydroethidium (DHE) staining for ROS production indicated the antioxidant activity of rRuTrx. Together, these findings suggest that RuTrx may play a role in maintaining the redox state balance in Korean rose bitterling R. uyekii. Full article

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

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11 pages, 830 KiB

Open AccessCommunication

Pyrosequencing-Based Assays for Rapid Detection of HER2 and HER3 Mutations in Clinical Samples Uncover an E332E Mutation Affecting HER3 in Retroperitoneal Leiomyosarcoma

by Paula González-Alonso^1,†, Cristina Chamizo^1,†, Víctor Moreno², Juan Madoz-Gúrpide¹, Nerea Carvajal¹, Lina Daoud¹, Sandra Zazo¹, Ester Martín-Aparicio¹, Ion Cristóbal²

, Raúl Rincón¹, Jesús García-Foncillas² and Federico Rojo^1,*

¹ Group of Cancer Biomarkers, Pathology Department, Health Research Institute Fundación Jiménez Díaz (IIS-FJD, UAM), Avda. Reyes Católicos 2, 28040 Madrid, Spain

² Translational Oncology Division, Oncohealth Institute, Fundación Jiménez Díaz Hospital, Avda. Reyes Católicos 2, 28040 Madrid, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19447-19457; https://doi.org/10.3390/ijms160819447 - 17 Aug 2015

Cited by 3 | Viewed by 7552

Abstract

Mutations in Human Epidermal Growth Factor Receptors (HER) are associated with poor prognosis of several types of solid tumors. Although HER-mutation detection methods are currently available, such as Next-Generation Sequencing (NGS), alternative pyrosequencing allow the rapid characterization of specific mutations. We developed specific [...] Read more.

Mutations in Human Epidermal Growth Factor Receptors (HER) are associated with poor prognosis of several types of solid tumors. Although HER-mutation detection methods are currently available, such as Next-Generation Sequencing (NGS), alternative pyrosequencing allow the rapid characterization of specific mutations. We developed specific PCR-based pyrosequencing assays for identification of most prevalent HER2 and HER3 mutations, including S310F/Y, R678Q, L755M/P/S/W, V777A/L/M, 774-776 insertion, and V842I mutations in HER2, as well as M91I, V104M/L, D297N/V/Y, and E332E/K mutations in HER3. We tested 85 Formalin Fixed and Paraffin Embbeded (FFPE) samples and we detected three HER2-V842I mutations in colorectal carcinoma (CRC), ovarian carcinoma, and pancreatic carcinoma patients, respectively, and a HER2-L755M mutation in a CRC specimen. We also determined the presence of a HER3-E332K mutation in an urothelial carcinoma sample, and two HER3-D297Y mutations, in both gastric adenocarcinoma and CRC specimens. The D297Y mutation was previously detected in breast and gastric tumors, but not in CRC. Moreover, we found a not-previously-described HER3-E332E synonymous mutation in a retroperitoneal leiomyosarcoma patient. The pyrosequencing assays presented here allow the detection and characterization of specific HER2 and HER3 mutations. These pyrosequencing assays might be implemented in routine diagnosis for molecular characterization of HER2/HER3 receptors as an alternative to complex NGS approaches. Full article

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

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19 pages, 1973 KiB

Open AccessReview

Mitochondrial and Ubiquitin Proteasome System Dysfunction in Ageing and Disease: Two Sides of the Same Coin?

by Jaime M. Ross^*, Lars Olson and Giuseppe Coppotelli^*

Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm 171 77, Sweden

Int. J. Mol. Sci. 2015, 16(8), 19458-19476; https://doi.org/10.3390/ijms160819458 - 17 Aug 2015

Cited by 93 | Viewed by 12883

Abstract

Mitochondrial dysfunction and impairment of the ubiquitin proteasome system have been described as two hallmarks of the ageing process. Additionally, both systems have been implicated in the etiopathogenesis of many age-related diseases, particularly neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. Interestingly, these [...] Read more.

Mitochondrial dysfunction and impairment of the ubiquitin proteasome system have been described as two hallmarks of the ageing process. Additionally, both systems have been implicated in the etiopathogenesis of many age-related diseases, particularly neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. Interestingly, these two systems are closely interconnected, with the ubiquitin proteasome system maintaining mitochondrial homeostasis by regulating organelle dynamics, the proteome, and mitophagy, and mitochondrial dysfunction impairing cellular protein homeostasis by oxidative damage. Here, we review the current literature and argue that the interplay of the two systems should be considered in order to better understand the cellular dysfunction observed in ageing and age-related diseases. Such an approach may provide valuable insights into molecular mechanisms underlying the ageing process, and further discovery of treatments to counteract ageing and its associated diseases. Furthermore, we provide a hypothetical model for the heterogeneity described among individuals during ageing. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)

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13 pages, 5112 KiB

Open AccessArticle

Plasma-Derived Fibronectin Stimulates Chondrogenic Differentiation of Human Subchondral Cortico-Spongious Progenitor Cells in Late-Stage Osteoarthritis

by Chao Jiang^†, Pei Ma^†, Bupeng Ma, Zhihong Wu, Guixing Qiu, Xinlin Su, Zenan Xia, Zixing Ye and Yipeng Wang^*

¹ Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19477-19489; https://doi.org/10.3390/ijms160819477 - 18 Aug 2015

Cited by 7 | Viewed by 6512

Abstract

Migration and chondrogenesis of human subchondral cortico-spongious progenitor cells (SPCs) are the key steps in the repair of microfracture-induced articular cartilage defects. The aim of this study was to evaluate the effect of human plasma-derived fibronectin (Fn) on the chondrogenic differentiation of SPCs, [...] Read more.

Migration and chondrogenesis of human subchondral cortico-spongious progenitor cells (SPCs) are the key steps in the repair of microfracture-induced articular cartilage defects. The aim of this study was to evaluate the effect of human plasma-derived fibronectin (Fn) on the chondrogenic differentiation of SPCs, which was isolated from subchondrol cortico-spongious bone of late-stage osteoarthritis (OA) patients. SPCs were isolated and cultured for three passages. Stem cell surface antigens of SPCs were analyzed by flow cytometry. The osteogenic, chondrogenic and adipogenic differentiation potential were detected by histological staining. The chondrogenesis potential of SPCs with or without stimulation of either Fn or BMP-2 were studied by immunochemical staining and gene expression analysis. Cells isolated from subchondral bone presented to be positive for CD44, CD73, CD90, and CD166, and showed high capacity of osteogenic, adipogenic and chondrogenic differentiation, which suggested this cell population to be MSC-like cells. Stimulating with Fn increased the expression of SOX-9, aggrecan, collagen II while decreased the formation of collagen I by immunochemical staining. Gene expression analysis showed similar results. These results suggest that plasma-derived Fn can increase the chondrogenic differentiation of SPCs isolated from late-stage OA and improve cartilage repair after microfracture. Full article

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

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18 pages, 1549 KiB

Open AccessArticle

How Common Is Disorder? Occurrence of Disordered Residues in Four Domains of Life

by Mikhail Yu. Lobanov and Oxana V. Galzitskaya^*

Institute of Protein Research, Russian Academy of Sciences, Pushchino 142290, Moscow Region, Russia

Int. J. Mol. Sci. 2015, 16(8), 19490-19507; https://doi.org/10.3390/ijms160819490 - 18 Aug 2015

Cited by 22 | Viewed by 5551

Abstract

Disordered regions play important roles in protein adaptation to challenging environmental conditions. Flexible and disordered residues have the highest propensities to alter the protein packing. Therefore, identification of disordered/flexible regions is important for structural and functional analysis of proteins. We used the IsUnstruct [...] Read more.

Disordered regions play important roles in protein adaptation to challenging environmental conditions. Flexible and disordered residues have the highest propensities to alter the protein packing. Therefore, identification of disordered/flexible regions is important for structural and functional analysis of proteins. We used the IsUnstruct program to predict the ordered or disordered status of residues in 122 proteomes, including 97 eukaryotic and 25 large bacterial proteomes larger than 2,500,000 residues. We found that bacterial and eukaryotic proteomes contain comparable fraction of disordered residues, which was 0.31 in the bacterial and 0.38 in the eukaryotic proteomes. Additional analysis of the total of 1540 bacterial proteomes of various sizes yielded a smaller fraction of disordered residues, which was only 0.26. Together, the results showed that the larger is the size of the proteome, the larger is the fraction of the disordered residues. A continuous dependence of the fraction of disordered residues on the size of the proteome is observed for four domains of life: Eukaryota, Bacteria, Archaea, and Viruses. Furthermore, our analysis of 122 proteomes showed that the fraction of disordered residues increased with increasing the length of homo-repeats for polar, charged, and small residues, and decreased for hydrophobic residues. The maximal fraction of disordered residues was obtained for proteins containing lysine and arginine homo-repeats. The minimal fraction was found in valine and leucine homo-repeats. For 15-residue long homo-repeats these values were 0.2 (for Val and Leu) and 0.7 (for Lys and Arg). Full article

(This article belongs to the Special Issue In-Silico Prediction and Characterization of Intrinsic Disorder in Proteins)

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10 pages, 1135 KiB

Open AccessArticle

Terpenoids from the Octocoral Sinularia gaweli

by Wun-Jie Lin^1,2,†, Tung-Ying Wu^3,†, Tzu-Rong Su^4,5, Zhi-Hong Wen⁶

, Jih-Jung Chen⁷, Lee-Shing Fang⁸, Yang-Chang Wu^3,9,10,11,* and Ping-Jyun Sung^1,2,3,6,11,*

¹ Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, Taiwan

² National Museum of Marine Biology & Aquarium, Pingtung 944, Taiwan

³ Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan

⁴ Department of Beauty Science, Meiho University, Pingtung 912, Taiwan

⁵ Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Pingtung 928, Taiwan

⁶ Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 804, Taiwan

⁷ Graduate Institute of Pharmaceutical Technology & Department of Pharmacy, Tajen University, Pingtung 907, Taiwan

⁸ Department of Sport, Health and Leisure, Cheng Shiu University, Kaohsiung 833, Taiwan

⁹ School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan

¹⁰ Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan

¹¹ Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2015, 16(8), 19508-19517; https://doi.org/10.3390/ijms160819508 - 18 Aug 2015

Cited by 9 | Viewed by 5733

Abstract

Two eudesmane sesquiterpenoids, verticillatol (1) and 5α-acetoxy-4(14)-eudesmene-1β-ol (2) and two cembrane diterpenoids, (–)-leptodiol acetate (3) and sinulacembranolide A (4) were isolated from the octocoral Sinularia gaweli and compounds 2–4 are new isolates. The [...] Read more.

Two eudesmane sesquiterpenoids, verticillatol (1) and 5α-acetoxy-4(14)-eudesmene-1β-ol (2) and two cembrane diterpenoids, (–)-leptodiol acetate (3) and sinulacembranolide A (4) were isolated from the octocoral Sinularia gaweli and compounds 2–4 are new isolates. The structures of new terpenoids 2–4 were elucidated by spectroscopic methods and by comparison the spectral data with those of known analogues. Terpenoid 4 was found to inhibit the accumulation of the pro-inflammatory inducible nitric oxide synthase (iNOS) protein of the lipopolysaccharide (LPS)-stimulated RAW264.7 marcophage cells. Full article

(This article belongs to the Special Issue Bioactivity of Marine Natural Products)

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19 pages, 1468 KiB

Open AccessReview

Intracellular Delivery of Molecular Cargo Using Cell-Penetrating Peptides and the Combination Strategies

by Hua Li^1,2, Tung Yu Tsui^2,* and Wenxue Ma^3,*

¹ Department of Basic Medical Science, Huzhou University School of Medicine, Huzhou 313000, China

² Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

³ Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0820, USA

Int. J. Mol. Sci. 2015, 16(8), 19518-19536; https://doi.org/10.3390/ijms160819518 - 18 Aug 2015

Cited by 53 | Viewed by 11710

Abstract

Cell-penetrating peptides (CPPs) can cross cellular membranes in a non-toxic fashion, improving the intracellular delivery of various molecular cargos such as nanoparticles, small molecules and plasmid DNA. Because CPPs provide a safe, efficient, and non-invasive mode of transport for various cargos into cells, [...] Read more.

Cell-penetrating peptides (CPPs) can cross cellular membranes in a non-toxic fashion, improving the intracellular delivery of various molecular cargos such as nanoparticles, small molecules and plasmid DNA. Because CPPs provide a safe, efficient, and non-invasive mode of transport for various cargos into cells, they have been developed as vectors for the delivery of genetic and biologic products in recent years. Most common CPPs are positively charged peptides. While delivering negatively charged molecules (e.g., nucleic acids) to target cells, the internalization efficiency of CPPs is reduced and inhibited because the cationic charges on the CPPs are neutralized through the covering of CPPs by cargos on the structure. Even under these circumstances, the CPPs can still be non-covalently complexed with the negatively charged molecules. To address this issue, combination strategies of CPPs with other typical carriers provide a promising and novel delivery system. This review summarizes the latest research work in using CPPs combined with molecular cargos including liposomes, polymers, cationic peptides, nanoparticles, adeno-associated virus (AAV) and calcium for the delivery of genetic products, especially for small interfering RNA (siRNA). This combination strategy remedies the reduced internalization efficiency caused by neutralization. Full article

(This article belongs to the Special Issue Cell-Penetrating Peptides)

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16 pages, 1061 KiB

Open AccessReview

Therapeutic Strategies and New Intervention Points in Chronic Hepatitis Delta Virus Infection

by Zhimin Guo¹ and Thomas King^2,*

¹ Huron Peak Ave., Superior, CO 80027, USA

² Allevagen, LLC, 4105 Perry St., Denver, CO 80212, USA

Int. J. Mol. Sci. 2015, 16(8), 19537-19552; https://doi.org/10.3390/ijms160819537 - 18 Aug 2015

Cited by 6 | Viewed by 7976

Abstract

Chronic hepatitis delta virus infection (CHD) is a condition arising from super-infection of hepatitis B virus (HBV)-infected patients, resulting in a more rapid advance in liver pathology and hepatocellular carcinoma than is observed for HBV mono-infection. Although hepatitis delta virus (HDV) is structurally [...] Read more.

Chronic hepatitis delta virus infection (CHD) is a condition arising from super-infection of hepatitis B virus (HBV)-infected patients, resulting in a more rapid advance in liver pathology and hepatocellular carcinoma than is observed for HBV mono-infection. Although hepatitis delta virus (HDV) is structurally simple, its life cycle involves the complex participation of host enzymes, HBV-derived surface antigen (HBsAg), and HDV-auto-ribozyme and hepatitis delta antigen (HDAg) activities. Unsatisfactory clinical trial results with interferon-based therapies are motivating researchers to adjust and redirect the approach to CHD drug development. This new effort will likely require additional structural and functional studies of the viral and cellular/host components involved in the HDV replication cycle. This review highlights recent work aimed at new drug interventions for CHD, with interpretation of key pre-clinical- and clinical trial outcomes and a discussion of promising new technological approaches to antiviral drug design. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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49 pages, 4364 KiB

Open AccessArticle

Double Variational Binding—(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands

by Mihai V. Putz^1,*, Nicoleta A. Dudaș¹ and Adriana Isvoran^2,*

¹ Laboratory of Structural and Computational Physical-Chemistry for Nanosciences and QSAR, Biology-Chemistry Department, West University of Timisoara, Str. Pestalozzi No. 16, 300115 Timisoara, Romania

² Environmental Advanced Researches Laboratories, Biology-Chemistry Department, West University of Timisoara, Str. Pestalozzi No. 16, 300115 Timisoara, Romania

Int. J. Mol. Sci. 2015, 16(8), 19553-19601; https://doi.org/10.3390/ijms160819553 - 18 Aug 2015

Cited by 8 | Viewed by 8151

Abstract

Variational quantitative binding–conformational analysis for a series of anti-HIV pyrimidine-based ligands is advanced at the individual molecular level. This was achieved by employing ligand-receptor docking algorithms for each molecule in the 1,3-disubstituted uracil derivative series that was studied. Such computational algorithms were employed [...] Read more.

Variational quantitative binding–conformational analysis for a series of anti-HIV pyrimidine-based ligands is advanced at the individual molecular level. This was achieved by employing ligand-receptor docking algorithms for each molecule in the 1,3-disubstituted uracil derivative series that was studied. Such computational algorithms were employed for analyzing both genuine molecular cases and their simplified molecular input line entry system (SMILES) transformations, which were created via the controlled breaking of chemical bonds, so as to generate the longest SMILES molecular chain (LoSMoC) and Branching SMILES (BraS) conformations. The study identified the most active anti-HIV molecules, and analyzed their special and relevant bonding fragments (chemical alerts), and the recorded energetic and geometric docking results (i.e., binding and affinity energies, and the surface area and volume of bonding, respectively). Clear computational evidence was also produced concerning the ligand-receptor pocket binding efficacies of the LoSMoc and BraS conformation types, thus confirming their earlier presence (as suggested by variational quantitative structure-activity relationship, variational-QSAR) as active intermediates for the molecule-to-cell transduction process. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2015)

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10 pages, 455 KiB

Open AccessReview

Genetic Polymorphisms of Glutathione-Related Enzymes (GSTM1, GSTT1, and GSTP1) and Schizophrenia Risk: A Meta-Analysis

by Su Kang Kim^1,†, Sang Wook Kang^1,†, Joo-Ho Chung¹

, Hae Jeong Park¹, Kyu Bong Cho² and Min-Su Park^3,*

¹ Kohwang Medical Research Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea

² Department of Biomedical Laboratory Science, College of Health Sciences, Shinhan University, Gyeonggi 480-701, Korea

³ Department of Surgery, School of Medicine, Kyung Hee University, Seoul 130-702, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19602-19611; https://doi.org/10.3390/ijms160819602 - 19 Aug 2015

Cited by 27 | Viewed by 6268

Abstract

The association between polymorphisms of glutathione-related enzyme (GST) genes and the risk of schizophrenia has been investigated in many published studies. However, their results were inconclusive. Therefore, we performed a meta-analysis to explore the association between the GSTM1, GSTT1, and GSTP1 [...] Read more.

The association between polymorphisms of glutathione-related enzyme (GST) genes and the risk of schizophrenia has been investigated in many published studies. However, their results were inconclusive. Therefore, we performed a meta-analysis to explore the association between the GSTM1, GSTT1, and GSTP1 polymorphisms and the risk of schizophrenia. Twelve case-control studies were included in this meta-analysis. The odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Our meta-analysis results revealed that GSTM1, GSTT1, and GSTP1 polymorphisms were not related to risk of schizophrenia (p > 0.05 in each model). Further analyses based on ethnicity, GSTM polymorphism showed weak association with schizophrenia in East Asian population (OR = 1.314, 95% CI = 1.025–1.684, p = 0.031). In conclusion, our meta-analysis indicated the GSTM1 polymorphism may be the only genetic risk factor for schizophrenia in East Asian population. However, more meta-analysis with a larger sample size were needed to provide more precise evidence. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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19 pages, 5080 KiB

Open AccessArticle

Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer

by Filippo Lococo¹, Massimiliano Paci¹, Cristian Rapicetta¹, Teresa Rossi², Valentina Sancisi², Luca Braglia³, Silvio Cavuto³, Alessandra Bisagni⁴, Italia Bongarzone⁵, Douglas M. Noonan^6,7, Adriana Albini^2,* and Sally Maramotti²

¹ Thoracic Surgery Unit, Department of Cardiology, Thoracic and Vascular Surgery, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia 42123, Italy

² Laboratory of Translational Research, Research and Statistic Infrastructure, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia 42123, Italy

³ Clinical Trials and Statistics Unit, Department of Infrastructure Research and Statistics, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia 42123, Italy

⁴ Pathology Unit, Department of Oncology and Advanced Technologies, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia 42123, Italy

⁵ Proteomics Laboratory, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, Italy

⁶ Department of Biotechnology and Life Sciences, University of Insubria, Varese 21100, Italy

⁷ Scientific and Technology Park, IRCCS MultiMedica, Milan 20138, Italy

Int. J. Mol. Sci. 2015, 16(8), 19612-19630; https://doi.org/10.3390/ijms160819612 - 19 Aug 2015

Cited by 22 | Viewed by 7083

Abstract

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While [...] Read more.

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies. Full article

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

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14 pages, 2711 KiB

Open AccessReview

Structural Features of the ATP-Binding Cassette (ABC) Transporter ABCA3

by Alessandro Paolini^†, Antonella Baldassarre^†, Ilaria Del Gaudio and Andrea Masotti^*

¹ Bambino Gesù Children's Hospital-IRCCS, Gene Expression-Microarrays Laboratory, Viale di San Paolo 15, 00146 Rome, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19631-19644; https://doi.org/10.3390/ijms160819631 - 19 Aug 2015

Cited by 27 | Viewed by 11597

Abstract

In this review we reported and discussed the structural features of the ATP-Binding Cassette (ABC) transporter ABCA3 and how the use of bioinformatics tools could help researchers to obtain a reliable structural model of this important transporter. In fact, a model of ABCA3 [...] Read more.

In this review we reported and discussed the structural features of the ATP-Binding Cassette (ABC) transporter ABCA3 and how the use of bioinformatics tools could help researchers to obtain a reliable structural model of this important transporter. In fact, a model of ABCA3 is still lacking and no crystallographic structures (of the transporter or of its orthologues) are available. With the advent of next generation sequencing, many disease-causing mutations have been discovered and many more will be found in the future. In the last few years, ABCA3 mutations have been reported to have important pediatric implications. Thus, clinicians need a reliable structure to locate relevant mutations of this transporter and make genotype/phenotype correlations of patients affected by ABCA3-related diseases. In conclusion, we strongly believe that the model preliminarily generated by these novel bioinformatics tools could be the starting point to obtain more refined models of the ABCA3 transporter. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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12 pages, 1050 KiB

Open AccessArticle

Engineering of Self-Assembled Fibronectin Matrix Protein and Its Effects on Mesenchymal Stem Cells

by Ye-Rang Yun^1,2, Le B. Hang Pham³, Yie-Ri Yoo³, Sujin Lee³, Hae-Won Kim^1,2,4,* and Jun-Hyeog Jang^3,*

¹ Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 330-714, Korea

² Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, Korea

³ Department of Biochemistry, Inha University School of Medicine, Incheon 400-712, Korea

⁴ Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan 330-714, Korea

Int. J. Mol. Sci. 2015, 16(8), 19645-19656; https://doi.org/10.3390/ijms160819645 - 19 Aug 2015

Cited by 10 | Viewed by 6118

Abstract

Fibronectin (FN) contributes to cell adhesion, proliferation, and differentiation in various cell types. To enhance the activity of fibronectin at the sites of focal adhesion, we engineered a novel recombinant fibronectin (FNIII10) fragment connected to the peptide amphiphile sequence (PA), LLLLLLCCCGGDS. In this [...] Read more.

Fibronectin (FN) contributes to cell adhesion, proliferation, and differentiation in various cell types. To enhance the activity of fibronectin at the sites of focal adhesion, we engineered a novel recombinant fibronectin (FNIII10) fragment connected to the peptide amphiphile sequence (PA), LLLLLLCCCGGDS. In this study, the effects of FNIII10-PA on rat mesenchymal stem cells (rMSCs) were compared with those of FNIII10. FNIII10-PA showed the prominent protein adhesion activity. In addition, FNIII10-PA showed a significantly higher effect on adhesion, proliferation, and differentiation of rMSCs than FNIII10. Taken together, the FNIII10-containing self-assembled sequence enhanced rMSCs adhesion, proliferation, and differentiation. Full article

(This article belongs to the Special Issue Protein Engineering)

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14 pages, 1011 KiB

Open AccessReview

The Incremental Induction of Neuroprotective Properties by Multiple Therapeutic Strategies for Primary and Secondary Neural Injury

by Seunghoon Lee^1,2,3,†, Sookyoung Park^3,4,†, Jinyoung Won^2,3,5, Sang-Rae Lee⁶, Kyu-Tae Chang⁶ and Yonggeun Hong^1,2,3,5,*

¹ Department of Physical Therapy, College of Biomedical Science & Engineering, Inje University, Gimhae 50834, Korea

² Biohealth Products Research Center (BPRC), Inje University, Gimhae 50834, Korea

³ Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae 50834, Korea

⁴ Department of Physical Therapy, College of Life Sciences, Kyungnam University, Changwon 51767, Korea

⁵ Department of Rehabilitation Science, Graduate School of Inje University, Gimhae 50834, Korea

⁶ National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang 28116, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19657-19670; https://doi.org/10.3390/ijms160819657 - 19 Aug 2015

Cited by 15 | Viewed by 6244

Abstract

Neural diseases including injury by endogenous factors, traumatic brain injury, and degenerative neural injury are eventually due to reactive oxygen species (ROS). Thus ROS generation in neural tissues is a hallmark feature of numerous forms of neural diseases. Neural degeneration and the neural [...] Read more.

Neural diseases including injury by endogenous factors, traumatic brain injury, and degenerative neural injury are eventually due to reactive oxygen species (ROS). Thus ROS generation in neural tissues is a hallmark feature of numerous forms of neural diseases. Neural degeneration and the neural damage process is complex, involving a vast array of tissue structure, transcriptional/translational, electrochemical, metabolic, and functional events within the intact neighbors surrounding injured neural tissues. During aging, multiple changes involving physical, chemical, and biochemical processes occur from the molecular to the morphological levels in neural tissues. Among many recommended therapeutic candidates, melatonin also plays a role in protecting the nervous system from anti-inflammation and efficiently safeguards neuronal cells via antioxidants and other endogenous/exogenous beneficial factors. Therefore, given the wide range of mechanisms responsible for neuronal damage, multi-action drugs or therapies for the treatment of neural injury that make use of two or more agents and target several pathways may have greater efficacy in promoting functional recovery than a single therapy alone. Full article

(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)

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27 pages, 3636 KiB

Open AccessReview

Spatial Regulation of Root Growth: Placing the Plant TOR Pathway in a Developmental Perspective

by Adam Barrada^1,2,3, Marie-Hélène Montané^1,2,3, Christophe Robaglia^1,2,3 and Benoît Menand^1,2,3,*

¹ Laboratoire de Génétique et Biophysique des Plantes, Aix-Marseille Université, Marseille F-13009, France

² Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche Biologie Végétale & Microbiologie Environnementales, Marseille F-13009, France

³ Commissariat à l’énergie Atomique et aux Energies Alternatives (CEA), Institut de Biologie Environnementale et Biotechnologie (IBEB), Marseille, F-13009, France

Int. J. Mol. Sci. 2015, 16(8), 19671-19697; https://doi.org/10.3390/ijms160819671 - 19 Aug 2015

Cited by 44 | Viewed by 14038

Abstract

Plant cells contain specialized structures, such as a cell wall and a large vacuole, which play a major role in cell growth. Roots follow an organized pattern of development, making them the organs of choice for studying the spatio-temporal regulation of cell proliferation [...] Read more.

Plant cells contain specialized structures, such as a cell wall and a large vacuole, which play a major role in cell growth. Roots follow an organized pattern of development, making them the organs of choice for studying the spatio-temporal regulation of cell proliferation and growth in plants. During root growth, cells originate from the initials surrounding the quiescent center, proliferate in the division zone of the meristem, and then increase in length in the elongation zone, reaching their final size and differentiation stage in the mature zone. Phytohormones, especially auxins and cytokinins, control the dynamic balance between cell division and differentiation and therefore organ size. Plant growth is also regulated by metabolites and nutrients, such as the sugars produced by photosynthesis or nitrate assimilated from the soil. Recent literature has shown that the conserved eukaryotic TOR (target of rapamycin) kinase pathway plays an important role in orchestrating plant growth. We will summarize how the regulation of cell proliferation and cell expansion by phytohormones are at the heart of root growth and then discuss recent data indicating that the TOR pathway integrates hormonal and nutritive signals to orchestrate root growth. Full article

(This article belongs to the Special Issue Molecular Machinery of Cell Growth Regulation)

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15 pages, 391 KiB

Open AccessReview

Hepatocellular Carcinoma in Patients with a Sustained Response to Anti-Hepatitis C Therapy

by Roberta D'Ambrosio^*, Cristina Della Corte and Massimo Colombo

Division of Gastroenterology and Hepatology, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan 20122, Italy

Int. J. Mol. Sci. 2015, 16(8), 19698-19712; https://doi.org/10.3390/ijms160819698 - 19 Aug 2015

Cited by 54 | Viewed by 6527

Abstract

Hepatocellular carcinoma (HCC) is a common, life-threatening complication of longstanding infection with the hepatitis C virus (HCV), likely a consequence of the direct oncogenic activity of the virus cooperating with liver cell inflammation in transforming the liver into a mitogenic and mutagenic environment. [...] Read more.

Hepatocellular carcinoma (HCC) is a common, life-threatening complication of longstanding infection with the hepatitis C virus (HCV), likely a consequence of the direct oncogenic activity of the virus cooperating with liver cell inflammation in transforming the liver into a mitogenic and mutagenic environment. The achievement of a sustained virological response (SVR) to interferon-based therapies has been shown to benefit the course of hepatitis C in terms of reduced rates of liver-related complications and mortality from all causes. Interestingly, while achievement of an SVR is associated with a negligible risk of developing clinical decompensation over the years, the risk of HCC is not fully abrogated following HCV clearance, but it remains the dominant complication in all SVR populations. The factors accounting for such a residual risk of HCC in SVR patients are not fully understood, yet the persistence of the subverted architecture of the liver, diabetes and alcohol abuse are likely culprits. In the end, the risk of developing an HCC in SVR patients is attenuated by 75% compared to non-responders or untreated patients, whereas responders who develop an HCC may be stratified in different categories of HCC risk by a score based on the same demographic and liver disease-based variables, such as those that predict liver cancer in viremic patients. All in all, this prevents full understanding of those factors that drive HCC risk once HCV has been eradicated. Here, we critically review current understanding of HCC in SVR patients focusing on factors that predict residual risk of HCC among these patients and providing a glimpse of the expected benefits of new anti-HCV regimens based on direct antiviral agents. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

15 pages, 790 KiB

Open AccessArticle

Inhibitory Effects of Amorphigenin on the Mitochondrial Complex I of Culex pipiens pallens Coquillett (Diptera: Culicidae)

by Mingshan Ji^†, Yaping Liang^†, Zumin Gu and Xiuwei Li^*

¹ Department of Pesticide Science, College of Plant Protection, Shenyang Agricultural University, Shenyang 110866, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19713-19727; https://doi.org/10.3390/ijms160819713 - 20 Aug 2015

Cited by 6 | Viewed by 5398

Abstract

Previous studies in our laboratory found that the extract from seeds of Amorpha fruticosa in the Leguminosae family had lethal effects against mosquito larvae, and an insecticidal compound amorphigenin was isolated. In this study, the inhibitory effects of amorphigenin against the mitochondrial complex [...] Read more.

Previous studies in our laboratory found that the extract from seeds of Amorpha fruticosa in the Leguminosae family had lethal effects against mosquito larvae, and an insecticidal compound amorphigenin was isolated. In this study, the inhibitory effects of amorphigenin against the mitochondrial complex I of Culex pipiens pallens (Diptera: Culicidae) were investigated and compared with that of rotenone. The results showed that amorphigenin and rotenone can decrease the mitochondrial complex I activity both in vivo and in vitro as the in vivo IC₅₀ values (the inhibitor concentrations leading to 50% of the enzyme activity lost) were determined to be 2.4329 and 2.5232 μmol/L, respectively, while the in vitro IC₅₀ values were 2.8592 and 3.1375 μmol/L, respectively. Both amorphigenin and rotenone were shown to be reversible and mixed-I type inhibitors of the mitochondrial complex I of Cx. pipiens pallens, indicating that amorphigenin and rotenone inhibited the enzyme activity not only by binding with the free enzyme but also with the enzyme-substrate complex, and the values of K_I and K_IS for amorphigenin were determined to be 20.58 and 87.55 μM, respectively, while the values for rotenone were 14.04 and 69.23 μM, respectively. Full article

(This article belongs to the Section Biochemistry)

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24 pages, 5799 KiB

Open AccessArticle

Genome-Wide Identification and Expression Analyses of Aquaporin Gene Family during Development and Abiotic Stress in Banana

by Wei Hu^1,†, Xiaowan Hou^1,†, Chao Huang^2,†, Yan Yan¹, Weiwei Tie¹, Zehong Ding¹, Yunxie Wei¹, Juhua Liu¹, Hongxia Miao¹, Zhiwei Lu¹, Meiying Li¹, Biyu Xu^1,* and Zhiqiang Jin^3,*

¹ Key Laboratory of Biology and Genetic Resources of Tropical Crops, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, Hainan, China

² College of Life Science and Technology, Huazhong University of Science & Technology (HUST), Wuhan 430074, Hubei, China

³ Key Laboratory of Genetic Improvement of Bananas, Hainan Province, Haikou Experimental Station, Chinese Academy of Tropical Agricultural Sciences, Haikou 570102, Hainan, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19728-19751; https://doi.org/10.3390/ijms160819728 - 20 Aug 2015

Cited by 71 | Viewed by 10166

Abstract

Aquaporins (AQPs) function to selectively control the flow of water and other small molecules through biological membranes, playing crucial roles in various biological processes. However, little information is available on the AQP gene family in bananas. In this study, we identified 47 banana [...] Read more.

Aquaporins (AQPs) function to selectively control the flow of water and other small molecules through biological membranes, playing crucial roles in various biological processes. However, little information is available on the AQP gene family in bananas. In this study, we identified 47 banana AQP genes based on the banana genome sequence. Evolutionary analysis of AQPs from banana, Arabidopsis, poplar, and rice indicated that banana AQPs (MaAQPs) were clustered into four subfamilies. Conserved motif analysis showed that all banana AQPs contained the typical AQP-like or major intrinsic protein (MIP) domain. Gene structure analysis suggested the majority of MaAQPs had two to four introns with a highly specific number and length for each subfamily. Expression analysis of MaAQP genes during fruit development and postharvest ripening showed that some MaAQP genes exhibited high expression levels during these stages, indicating the involvement of MaAQP genes in banana fruit development and ripening. Additionally, some MaAQP genes showed strong induction after stress treatment and therefore, may represent potential candidates for improving banana resistance to abiotic stress. Taken together, this study identified some excellent tissue-specific, fruit development- and ripening-dependent, and abiotic stress-responsive candidate MaAQP genes, which could lay a solid foundation for genetic improvement of banana cultivars. Full article

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

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17 pages, 4989 KiB

Open AccessArticle

Polymer/Iron Oxide Nanoparticle Composites—A Straight Forward and Scalable Synthesis Approach

by Jens Sommertune¹, Abhilash Sugunan¹, Anwar Ahniyaz¹, Rebecca Stjernberg Bejhed², Anna Sarwe³, Christer Johansson³, Christoph Balceris⁴, Frank Ludwig⁴, Oliver Posth⁵ and Andrea Fornara^1,*

¹ SP, Technical Research Institute of Sweden, Box 5607, SE-114 86 Stockholm, Sweden

² Department of Engineering Sciences, Solid State Physics, Uppsala University, SE-751 21 Uppsala, Sweden

³ Acreo Swedish ICT AB, Box 53071, SE-400 14 Göteborg, Sweden

⁴ Institute of Electrical Measurement and Fundamental Electrical Engineering, TU Braunschweig, D-38106 Braunschweig, Germany

⁵ Physikalisch-Technische Bundesanstalt, 10587 Berlin, Germany

Int. J. Mol. Sci. 2015, 16(8), 19752-19768; https://doi.org/10.3390/ijms160819752 - 20 Aug 2015

Cited by 24 | Viewed by 8259

Abstract

Magnetic nanoparticle systems can be divided into single-core nanoparticles (with only one magnetic core per particle) and magnetic multi-core nanoparticles (with several magnetic cores per particle). Here, we report multi-core nanoparticle synthesis based on a controlled precipitation process within a well-defined oil in [...] Read more.

Magnetic nanoparticle systems can be divided into single-core nanoparticles (with only one magnetic core per particle) and magnetic multi-core nanoparticles (with several magnetic cores per particle). Here, we report multi-core nanoparticle synthesis based on a controlled precipitation process within a well-defined oil in water emulsion to trap the superparamagnetic iron oxide nanoparticles (SPION) in a range of polymer matrices of choice, such as poly(styrene), poly(lactid acid), poly(methyl methacrylate), and poly(caprolactone). Multi-core particles were obtained within the Z-average size range of 130 to 340 nm. With the aim to combine the fast room temperature magnetic relaxation of small individual cores with high magnetization of the ensemble of SPIONs, we used small (<10 nm) core nanoparticles. The performed synthesis is highly flexible with respect to the choice of polymer and SPION loading and gives rise to multi-core particles with interesting magnetic properties and magnetic resonance imaging (MRI) contrast efficacy. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2015)

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11 pages, 842 KiB

Open AccessArticle

Magnetic Nanoparticle Arrays Self-Assembled on Perpendicular Magnetic Recording Media

by Abdul Rahman Mohtasebzadeh¹, Longfei Ye^1,2 and Thomas M. Crawford^1,*

¹ Smart State Center for Experimental Nanoscale Physics, Department of Physics and Astronomy, University of South Carolina, Columbia, SC 29208, USA

² MagAssemble, Irmo, SC 29063, USA

Int. J. Mol. Sci. 2015, 16(8), 19769-19779; https://doi.org/10.3390/ijms160819769 - 20 Aug 2015

Cited by 16 | Viewed by 6146

Abstract

We study magnetic-field directed self-assembly of magnetic nanoparticles onto templates recorded on perpendicular magnetic recording media, and quantify feature width and height as a function of assembly time. Feature widths are determined from Scanning Electron Microscope (SEM) images, while heights are obtained with [...] Read more.

We study magnetic-field directed self-assembly of magnetic nanoparticles onto templates recorded on perpendicular magnetic recording media, and quantify feature width and height as a function of assembly time. Feature widths are determined from Scanning Electron Microscope (SEM) images, while heights are obtained with Atomic Force Microscopy (AFM). For short assembly times, widths were ~150 nm, while heights were ~14 nm, a single nanoparticle on average with a 10:1 aspect ratio. For long assembly times, widths approach 550 nm, while the average height grows to 3 nanoparticles, ~35 nm; a 16:1 aspect ratio. We perform magnetometry on these self-assembled structures and observe the slope of the magnetic moment vs. field curve increases with time. This increase suggests magnetic nanoparticle interactions evolve from nanoparticle–nanoparticle interactions to cluster–cluster interactions as opposed to feature–feature interactions. We suggest the aspect ratio increase occurs because the magnetic field gradients are strongest near the transitions between recorded regions in perpendicular media. If these gradients can be optimized for assembly, strong potential exists for using perpendicular recording templates to assemble complex heterogeneous materials. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2015)

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16 pages, 5788 KiB

Open AccessArticle

Endoplasmic Reticulum Stress Cooperates in Zearalenone-Induced Cell Death of RAW 264.7 Macrophages

by Fenglei Chen^1,†, Qian Li^1,†, Zhe Zhang¹

, Pengfei Lin¹, Lanjie Lei², Aihua Wang² and Yaping Jin^1,*

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

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

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19780-19795; https://doi.org/10.3390/ijms160819780 - 20 Aug 2015

Cited by 50 | Viewed by 10032

Abstract

Zearalenone (ZEA) is a fungal mycotoxin that causes cell apoptosis and necrosis. However, little is known about the molecular mechanisms of ZEA toxicity. The objective of this study was to explore the effects of ZEA on the proliferation and apoptosis of RAW 264.7 [...] Read more.

Zearalenone (ZEA) is a fungal mycotoxin that causes cell apoptosis and necrosis. However, little is known about the molecular mechanisms of ZEA toxicity. The objective of this study was to explore the effects of ZEA on the proliferation and apoptosis of RAW 264.7 macrophages and to uncover the signaling pathway underlying the cytotoxicity of ZEA in RAW 264.7 macrophages. This study demonstrates that the endoplasmic reticulum (ER) stress pathway cooperated in ZEA-induced cell death of the RAW 264.7 macrophages. Our results show that ZEA treatment reduced the viability of RAW 264.7 macrophages in a dose- and time-dependent manner as shown by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay (MTT) and flow cytometry assay. Western blots analysis revealed that ZEA increased the expression of glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP), two ER stress-related marker genes. Furthermore, treating the cells with the ER stress inhibitors 4-phenylbutyrate (4-PBA) or knocking down CHOP, using lentivirus encoded short hairpin interfering RNAs (shRNAs), significantly diminished the ZEA-induced increases in GRP78 and CHOP, and cell death. In summary, our results suggest that ZEA induces the apoptosis and necrosis of RAW 264.7 macrophages in a dose- and time-dependent manner via the ER stress pathway in which the activation of CHOP plays a critical role. Full article

(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress)

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16 pages, 705 KiB

Open AccessArticle

Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration

by Francesco Parmeggiani^1,*, Ciro Costagliola²

, Francesco Semeraro³, Mario R Romano⁴, Michele Rinaldi⁵, Carla Enrica Gallenga¹

, Maria Luisa Serino⁶, Carlo Incorvaia¹, Sergio D’Angelo¹, Katia De Nadai¹, Roberto Dell’Omo², Andrea Russo³, Donato Gemmati⁶

and Paolo Perri¹

¹ Eye Clinic, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Via Aldo Moro 8, 44124 Cona-Ferrara, Italy

² Eye Clinic, Department of Health Sciences, University of Molise, Via Francesco de Sanctis 1, 86100 Campobasso, Italy

³ Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy

⁴ Eye Clinic, Department of Neuroscience, Reproductive and Odonto-Stomatological Sciences, “Federico II” University of Naples, Via Pansini 5, 80131 Napoli, Italy

⁵ Department of Ophthalmology, Second University of Naples, Via Pansini 5, 80131 Napoli, Italy

⁶ Center of Hemostasis and Thrombosis, Department of Medical Sciences, University of Ferrara, Corso Giovecca 203, 44121 Ferrara, Italy

Int. J. Mol. Sci. 2015, 16(8), 19796-19811; https://doi.org/10.3390/ijms160819796 - 20 Aug 2015

Cited by 7 | Viewed by 5867

Abstract

Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic [...] Read more.

Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic therapy with verteporfin (PDT-V) is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985) has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1) total number of photodynamic treatments; and (2) change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype) received a higher number of photodynamic treatments than patients without it (GG wild-type genotype) (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively). Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively). The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of both anti-thrombophilic effects due to FXIII-A G185T variant and photo-thrombotic action of PDT-V toward CNV provides several clues about the rationale of this intriguing pharmacogenetic correlation. Further investigations are warranted to outline the appropriate paradigm for guiding PDT-V utilization in the course of the combined therapeutic protocol for neovascular macular degeneration. Full article

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

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24 pages, 2835 KiB

Open AccessArticle

In Silico Analysis of Correlations between Protein Disorder and Post-Translational Modifications in Algae

by Atsushi Kurotani and Tetsuya Sakurai^*

RIKEN Center for Sustainable Resource Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan

Int. J. Mol. Sci. 2015, 16(8), 19812-19835; https://doi.org/10.3390/ijms160819812 - 20 Aug 2015

Cited by 21 | Viewed by 6717

Abstract

Recent proteome analyses have reported that intrinsically disordered regions (IDRs) of proteins play important roles in biological processes. In higher plants whose genomes have been sequenced, the correlation between IDRs and post-translational modifications (PTMs) has been reported. The genomes of various eukaryotic algae [...] Read more.

Recent proteome analyses have reported that intrinsically disordered regions (IDRs) of proteins play important roles in biological processes. In higher plants whose genomes have been sequenced, the correlation between IDRs and post-translational modifications (PTMs) has been reported. The genomes of various eukaryotic algae as common ancestors of plants have also been sequenced. However, no analysis of the relationship to protein properties such as structure and PTMs in algae has been reported. Here, we describe correlations between IDR content and the number of PTM sites for phosphorylation, glycosylation, and ubiquitination, and between IDR content and regions rich in proline, glutamic acid, serine, and threonine (PEST) and transmembrane helices in the sequences of 20 algae proteomes. Phosphorylation, O-glycosylation, ubiquitination, and PEST preferentially occurred in disordered regions. In contrast, transmembrane helices were favored in ordered regions. N-glycosylation tended to occur in ordered regions in most of the studied algae; however, it correlated positively with disordered protein content in diatoms. Additionally, we observed that disordered protein content and the number of PTM sites were significantly increased in the species-specific protein clusters compared to common protein clusters among the algae. Moreover, there were specific relationships between IDRs and PTMs among the algae from different groups. Full article

(This article belongs to the Special Issue In-Silico Prediction and Characterization of Intrinsic Disorder in Proteins)

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15 pages, 1319 KiB

Open AccessReview

Mitochondrial Transcription Factor A and Mitochondrial Genome as Molecular Targets for Cisplatin-Based Cancer Chemotherapy

by Kimitoshi Kohno^1,*, Ke-Yong Wang², Mayu Takahashi³, Tomoko Kurita⁴, Yoichiro Yoshida⁵, Masakazu Hirakawa⁶, Yoshikazu Harada⁷, Akihiro Kuma⁸, Hiroto Izumi⁹ and Shinji Matsumoto¹

¹ Asahi Matsumoto Hospital, Kokuramimami-ku Tsuda, Kitakyushu-shi 800-0242, Japan

² Shared-Use Research Center, University of Occupational and Environmental Health School of Medicine, Yahatanishi-ku, Kitakyushu-shi 807-8555, Japan

³ Department of Neurosurgery, University of Occupational and Environmental Health School of Medicine, Yahatanishi-ku, Kitakyushu-shi 807-8555, Japan

⁴ Department of Gynecology, University of Occupational and Environmental Health School of Medicine, Yahatanishi-ku, Kitakyushu-shi 807-8555, Japan

⁵ Department of Gastroenterological Surgery, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan

⁶ Department of Radiology, Beppu Hospital, Kyushu University, Beppu 874-0838, Japan

⁷ Department of Pathology and Cell Biology, University of Occupational and Environmental Health School of Medicine, Yahatanishi-ku, Kitakyushu-shi 807-8555, Japan

⁸ Second Department of Internal Medicine, University of Occupational and Environmental Health School of Medicine, Yahatanishi-ku, Kitakyushu-shi 807-8555, Japan

⁹ Department of Occupational Pneumology, Institute of Industrial Ecological Science, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu-shi 807-8555, Japan

Int. J. Mol. Sci. 2015, 16(8), 19836-19850; https://doi.org/10.3390/ijms160819836 - 20 Aug 2015

Cited by 29 | Viewed by 10280

Abstract

Mitochondria are important cellular organelles that function as control centers of the energy supply for highly proliferative cancer cells and regulate apoptosis after cancer chemotherapy. Cisplatin is one of the most important chemotherapeutic agents and a key drug in therapeutic regimens for a [...] Read more.

Mitochondria are important cellular organelles that function as control centers of the energy supply for highly proliferative cancer cells and regulate apoptosis after cancer chemotherapy. Cisplatin is one of the most important chemotherapeutic agents and a key drug in therapeutic regimens for a broad range of solid tumors. Cisplatin may directly interact with mitochondria, which can induce apoptosis. The direct interactions between cisplatin and mitochondria may account for our understanding of the clinical activity of cisplatin and development of resistance. However, the basis for the roles of mitochondria under treatment with chemotherapy is poorly understood. In this review, we present novel aspects regarding the unique characteristics of the mitochondrial genome in relation to the use of platinum-based chemotherapy and describe our recent work demonstrating the importance of the mitochondrial transcription factor A (mtTFA) expression in cancer cells. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)

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17 pages, 2257 KiB

Open AccessArticle

Curcumol Inhibits Growth and Induces Apoptosis of Colorectal Cancer LoVo Cell Line via IGF-1R and p38 MAPK Pathway

by Juan Wang^1,2,†, Fengxiang Huang^1,†, Zhun Bai³, Bixia Chi², Jiacai Wu² and Xu Chen^1,*

¹ College of Pharmacy, Guilin Medical University, Guilin 541004, China

² Research Center for Science, Guilin Medical University, Guilin 541004, China

³ Intensive Care Unit, Zhuzhou Central Hospital, Zhuzhou 412007, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19851-19867; https://doi.org/10.3390/ijms160819851 - 20 Aug 2015

Cited by 69 | Viewed by 10010

Abstract

Curcumol, isolated from the traditional medical plant Rhizoma Curcumae, is the bioactive component of Zedoary oil, whose potential anti-tumor effect has attracted considerable attention in recent years. Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its [...] Read more.

Curcumol, isolated from the traditional medical plant Rhizoma Curcumae, is the bioactive component of Zedoary oil, whose potential anti-tumor effect has attracted considerable attention in recent years. Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its anti-cancer effect in colorectal cancer LoVo cells still remains unclear. In the present study, we found that curcumol showed growth inhibition and induced apoptosis of LoVo cells in a dose- and time-dependent manner. The occurrence of its proliferation inhibition and apoptosis came with suppression of IGF-1R expression, and then increased the phosphorylation of p38 mitogen activated protein kinase (MAPK), which might result in a cascade response by inhibiting the CREB survival pathway and finally triggered Bax/Bcl-2 and poly(ADP-ribose) polymerase 1 (PARP-1) apoptosis signals. Moreover, curcumol inhibited colorectal cancer in xenograft models of nude mice. Immunohistochemical and Western blot analysis revealed that curcumol could decrease the expression of ki-67, Bcl-2 as well as CREB1, and increase the expression of Bax and the phosphorylation of p38, which were consistent with our in vitro study. Overall, our in vitro and in vivo data confirmed the anti-cancer activity of curcumol, which was related to a significant inhibition of IGF-1R and activation of p38 MAPKs, indicating that curcumol may be a potential anti-tumor agent for colorectal carcinoma therapy. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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18 pages, 503 KiB

Open AccessArticle

Accurate Ab Initio and Template-Based Prediction of Short Intrinsically-Disordered Regions by Bidirectional Recurrent Neural Networks Trained on Large-Scale Datasets

by Viola Volpato^1,2, Badr Alshomrani^1,2 and Gianluca Pollastri^1,2,*

¹ School of Computer Science, University College Dublin, Belfield, Dublin 4, Ireland

² Adaptive and Complex Systems Laboratory, University College Dublin, Belfield, Dublin 4, Ireland

Int. J. Mol. Sci. 2015, 16(8), 19868-19885; https://doi.org/10.3390/ijms160819868 - 21 Aug 2015

Cited by 1 | Viewed by 5979

Abstract

Intrinsically-disordered regions lack a well-defined 3D structure, but play key roles in determining the function of many proteins. Although predictors of disorder have been shown to achieve relatively high rates of correct classification of these segments, improvements over the the years have been [...] Read more.

Intrinsically-disordered regions lack a well-defined 3D structure, but play key roles in determining the function of many proteins. Although predictors of disorder have been shown to achieve relatively high rates of correct classification of these segments, improvements over the the years have been slow, and accurate methods are needed that are capable of accommodating the ever-increasing amount of structurally-determined protein sequences to try to boost predictive performances. In this paper, we propose a predictor for short disordered regions based on bidirectional recurrent neural networks and tested by rigorous five-fold cross-validation on a large, non-redundant dataset collected from MobiDB, a new comprehensive source of protein disorder annotations. The system exploits sequence and structural information in the forms of frequency profiles, predicted secondary structure and solvent accessibility and direct disorder annotations from homologous protein structures (templates) deposited in the Protein Data Bank. The contributions of sequence, structure and homology information result in large improvements in predictive accuracy. Additionally, the large scale of the training set leads to low false positive rates, making our systems a robust and efficient way to address high-throughput disorder prediction. Full article

(This article belongs to the Special Issue In-Silico Prediction and Characterization of Intrinsic Disorder in Proteins)

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34 pages, 1310 KiB

Open AccessReview

Regulatory Roles of Non-Coding RNAs in Colorectal Cancer

by Jun Wang^†, Yong-Xi Song^†, Bin Ma, Jia-Jun Wang, Jing-Xu Sun, Xiao-Wan Chen, Jun-Hua Zhao, Yu-Chong Yang and Zhen-Ning Wang^*

¹ Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang 110001, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19886-19919; https://doi.org/10.3390/ijms160819886 - 21 Aug 2015

Cited by 69 | Viewed by 9417

Abstract

Non-coding RNAs (ncRNAs) have recently gained attention because of their involvement in different biological processes. An increasing number of studies have demonstrated that mutations or abnormal expression of ncRNAs are closely associated with various diseases including cancer. The present review is a comprehensive [...] Read more.

Non-coding RNAs (ncRNAs) have recently gained attention because of their involvement in different biological processes. An increasing number of studies have demonstrated that mutations or abnormal expression of ncRNAs are closely associated with various diseases including cancer. The present review is a comprehensive examination of the aberrant regulation of ncRNAs in colorectal cancer (CRC) and a summary of the current findings on ncRNAs, including long ncRNAs, microRNAs, small interfering RNAs, small nucleolar RNAs, small nuclear RNAs, Piwi-interacting RNAs, and circular RNAs. These ncRNAs might become novel biomarkers and targets as well as potential therapeutic tools for the treatment of CRC in the near future and this review may provide important clues for further research on CRC and for the selection of effective therapeutic targets. Full article

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

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16 pages, 21991 KiB

Open AccessArticle

Selection and Characterization of Single Chain Antibody Fragments Specific for Hsp90 as a Potential Cancer Targeting Molecule

by Edyta Petters¹, Aleksandra Sokolowska-Wedzina¹ and Jacek Otlewski^1,2,*

¹ Faculty of Biotechnology, Department of Protein Engineering, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland

² Wroclaw Research Centre EIT+, Stablowicka 147, 54-066 Wroclaw, Poland

Int. J. Mol. Sci. 2015, 16(8), 19920-19935; https://doi.org/10.3390/ijms160819920 - 21 Aug 2015

Cited by 4 | Viewed by 7245

Abstract

Heat shock proteins play an essential role in facilitating malignant transformation and they have been recognized as important factors in human cancers. One of the key elements of the molecular chaperones machinery is Hsp90 and it has recently become a target for anticancer [...] Read more.

Heat shock proteins play an essential role in facilitating malignant transformation and they have been recognized as important factors in human cancers. One of the key elements of the molecular chaperones machinery is Hsp90 and it has recently become a target for anticancer therapeutic approaches. The potential and importance of Hsp90-directed agents becomes apparent when one realizes that disruption of Hsp90 function may influence over 200 oncogenic client proteins. Here, we described the selection and characterization of Hsp90-specific antibody fragments from commercially available Tomlinson I and J phage display libraries. The affinities of Hsp90-binding scFv variants were measured using SPR method. Then, based on the best clone selected, we performed the affinity maturation procedure and obtained valuable Hsp90-specific clones. The selected binders were expressed and applied for immunostaining, ELISA and SPR analysis using model cancer cell lines. All performed experiments confirmed the ability of selected antibodies to interact with the Hsp90. Therefore, the presented Hsp90-specific scFv, might be a starting point for the development of a novel antibody-based strategy targeting cancer. Full article

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

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24 pages, 5926 KiB

Open AccessReview

Resolving Intra- and Inter-Molecular Structure with Non-Contact Atomic Force Microscopy

by Samuel Paul Jarvis

School of Physics & Astronomy, University of Nottingham, Nottingham NG7 2RD, UK

Int. J. Mol. Sci. 2015, 16(8), 19936-19959; https://doi.org/10.3390/ijms160819936 - 21 Aug 2015

Cited by 37 | Viewed by 13208

Abstract

A major challenge in molecular investigations at surfaces has been to image individual molecules, and the assemblies they form, with single-bond resolution. Scanning probe microscopy, with its exceptionally high resolution, is ideally suited to this goal. With the introduction of methods exploiting molecularly-terminated [...] Read more.

A major challenge in molecular investigations at surfaces has been to image individual molecules, and the assemblies they form, with single-bond resolution. Scanning probe microscopy, with its exceptionally high resolution, is ideally suited to this goal. With the introduction of methods exploiting molecularly-terminated tips, where the apex of the probe is, for example, terminated with a single CO, Xe or H2 molecule, scanning probe methods can now achieve higher resolution than ever before. In this review, some of the landmark results related to attaining intramolecular resolution with non-contact atomic force microscopy (NC-AFM) are summarised before focussing on recent reports probing molecular assemblies where apparent intermolecular features have been observed. Several groups have now highlighted the critical role that flexure in the tip-sample junction plays in producing the exceptionally sharp images of both intra- and apparent inter-molecular structure. In the latter case, the features have been identified as imaging artefacts, rather than real intermolecular bonds. This review discusses the potential for NC-AFM to provide exceptional resolution of supramolecular assemblies stabilised via a variety of intermolecular forces and highlights the potential challenges and pitfalls involved in interpreting bonding interactions. Full article

(This article belongs to the Special Issue Supramolecular Interactions)

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18 pages, 1119 KiB

Open AccessArticle

Inhibition of NF-κB in Tumor Cells Exacerbates Immune Cell Activation Following Photodynamic Therapy

by Mans Broekgaarden¹, Milan Kos^1,†, Freek A. Jurg^1,†, Adriaan A. Van Beek², Thomas M. Van Gulik¹ and Michal Heger^1,*

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

² Department of Cell Biology and Immunology, Wageningen University, 6709 PG Wageningen, The Netherlands

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 19960-19977; https://doi.org/10.3390/ijms160819960 - 21 Aug 2015

Cited by 22 | Viewed by 7726

Abstract

Although photodynamic therapy (PDT) yields very good outcomes in numerous types of superficial solid cancers, some tumors respond suboptimally to PDT. Novel treatment strategies are therefore needed to enhance the efficacy in these therapy-resistant tumors. One of these strategies is to combine PDT [...] Read more.

Although photodynamic therapy (PDT) yields very good outcomes in numerous types of superficial solid cancers, some tumors respond suboptimally to PDT. Novel treatment strategies are therefore needed to enhance the efficacy in these therapy-resistant tumors. One of these strategies is to combine PDT with inhibitors of PDT-induced survival pathways. In this respect, the transcription factor nuclear factor κB (NF-κB) has been identified as a potential pharmacological target, albeit inhibition of NF-κB may concurrently dampen the subsequent anti-tumor immune response required for complete tumor eradication and abscopal effects. In contrast to these postulations, this study demonstrated that siRNA knockdown of NF-κB in murine breast carcinoma (EMT-6) cells increased survival signaling in these cells and exacerbated the inflammatory response in murine RAW 264.7 macrophages. These results suggest a pro-death and immunosuppressive role of NF-κB in PDT-treated cells that concurs with a hyperstimulated immune response in innate immune cells. Full article

(This article belongs to the Special Issue Advances in Photodynamic Therapy)

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11 pages, 899 KiB

Open AccessArticle

Atherosclerotic Calcification Detection: A Comparative Study of Carotid Ultrasound and Cone Beam CT

by Fisnik Jashari¹, Pranvera Ibrahimi^1,*, Elias Johansson^1,2, Jan Ahlqvist³, Conny Arnerlöv⁴, Maria Garoff³, Eva Levring Jäghagen³, Per Wester¹ and Michael Y. Henein¹

¹ Department of Public Health and Clinical Medicine, Umeå University, 90187 Umeå, Sweden

² Department of Pharmacology and Clinical Neuroscience, Umeå University, 90187 Umeå, Sweden

³ Department of Odontology, Umeå University, 90187 Umeå, Sweden

⁴ Department of Surgical and Perioperative Sciences, Umeå University, 90187 Umeå, Sweden

Int. J. Mol. Sci. 2015, 16(8), 19978-19988; https://doi.org/10.3390/ijms160819978 - 21 Aug 2015

Cited by 21 | Viewed by 6918

Abstract

Background and Aim: Arterial calcification is often detected on ultrasound examination but its diagnostic accuracy is not well validated. The aim of this study was to determine the accuracy of carotid ultrasound B mode findings in detecting atherosclerotic calcification quantified by cone beam [...] Read more.

Background and Aim: Arterial calcification is often detected on ultrasound examination but its diagnostic accuracy is not well validated. The aim of this study was to determine the accuracy of carotid ultrasound B mode findings in detecting atherosclerotic calcification quantified by cone beam computed tomography (CBCT). Methods: We analyzed 94 carotid arteries, from 88 patients (mean age 70 ± 7 years, 33% females), who underwent pre-endarterectomy ultrasound examination. Plaques with high echogenic nodules and posterior shadowing were considered calcified. After surgery, the excised plaques were examined using CBCT, from which the calcification volume (mm3) was calculated. In cases with multiple calcifications the largest calcification nodule volume was used to represent the plaque. Carotid artery calcification by the two imaging techniques was compared using conventional correlations. Results: Carotid ultrasound was highly accurate in detecting the presence of calcification; with a sensitivity of 88.2%. Based on the quartile ranges of calcification volumes measured by CBCT we have divided plaque calcification into four groups: <8; 8–35; 36–70 and >70 mm3. Calcification volumes ≥8 were accurately detectable by ultrasound with a sensitivity of 96%. Of the 21 plaques with <8 mm3 calcification volume; only 13 were detected by ultrasound; resulting in a sensitivity of 62%. There was no difference in the volume of calcification between symptomatic and asymptomatic patients. Conclusion: Carotid ultrasound is highly accurate in detecting the presence of calcified atherosclerotic lesions of volume ≥8 mm3; but less accurate in detecting smaller volume calcified plaques. Further development of ultrasound techniques should allow better detection of early arterial calcification. Full article

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

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12 pages, 669 KiB

Open AccessReview

Docosahexaenoic Acid Levels in Blood and Metabolic Syndrome in Obese Children: Is There a Link?

by Carlotta Lassandro¹, Giuseppe Banderali¹, Giovanni Radaelli¹, Elisa Borghi²

, Francesca Moretti¹ and Elvira Verduci^1,*

¹ Department of Pediatrics, San Paolo Hospital, Department of Health Science, University of Milan, I-20142 Milan, Italy

² Microbiology Unit, Department of Health Sciences, University of Milan, I-20142 Milan, Italy

Int. J. Mol. Sci. 2015, 16(8), 19989-20000; https://doi.org/10.3390/ijms160819989 - 21 Aug 2015

Cited by 8 | Viewed by 6295

Abstract

Prevalence of metabolic syndrome is increasing in the pediatric population. Considering the different existing criteria to define metabolic syndrome, the use of the International Diabetes Federation (IDF) criteria has been suggested in children. Docosahexaenoic acid (DHA) has been associated with beneficial effects on [...] Read more.

Prevalence of metabolic syndrome is increasing in the pediatric population. Considering the different existing criteria to define metabolic syndrome, the use of the International Diabetes Federation (IDF) criteria has been suggested in children. Docosahexaenoic acid (DHA) has been associated with beneficial effects on health. The evidence about the relationship of DHA status in blood and components of the metabolic syndrome is unclear. This review discusses the possible association between DHA content in plasma and erythrocytes and components of the metabolic syndrome included in the IDF criteria (obesity, alteration of glucose metabolism, blood lipid profile, and blood pressure) and non-alcoholic fatty liver disease in obese children. The current evidence is inconsistent and no definitive conclusion can be drawn in the pediatric population. Well-designed longitudinal and powered trials need to clarify the possible association between blood DHA status and metabolic syndrome. Full article

(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Diseases)

19 pages, 2938 KiB

Open AccessArticle

Exploiting Size-Dependent Drag and Magnetic Forces for Size-Specific Separation of Magnetic Nanoparticles

by Hunter B. Rogers¹, Tareq Anani¹, Young Suk Choi¹, Ronald J. Beyers² and Allan E. David^1,*

¹ Department of Chemical Engineering, Auburn University, 212 Ross Hall, Auburn, AL 36849, USA

² Auburn University MRI Research Center, Auburn, AL 36849, USA

Int. J. Mol. Sci. 2015, 16(8), 20001-20019; https://doi.org/10.3390/ijms160820001 - 21 Aug 2015

Cited by 12 | Viewed by 6742

Abstract

Realizing the full potential of magnetic nanoparticles (MNPs) in nanomedicinerequires the optimization of their physical and chemical properties. Elucidation of the effectsof these properties on clinical diagnostic or therapeutic properties, however, requires thesynthesis or purification of homogenous samples, which has proved to be [...] Read more.

Realizing the full potential of magnetic nanoparticles (MNPs) in nanomedicinerequires the optimization of their physical and chemical properties. Elucidation of the effectsof these properties on clinical diagnostic or therapeutic properties, however, requires thesynthesis or purification of homogenous samples, which has proved to be difficult. Whileinitial simulations indicated that size-selective separation could be achieved by flowingmagnetic nanoparticles through a magnetic field, subsequent in vitro experiments wereunable to reproduce the predicted results. Magnetic field-flow fractionation, however, wasfound to be an effective method for the separation of polydisperse suspensions of iron oxidenanoparticles with diameters greater than 20 nm. While similar methods have been used toseparate magnetic nanoparticles before, no previous work has been done with magneticnanoparticles between 20 and 200 nm. Both transmission electron microscopy (TEM) anddynamic light scattering (DLS) analysis were used to confirm the size of the MNPs. Furtherdevelopment of this work could lead to MNPs with the narrow size distributions necessary fortheir in vitro and in vivo optimization. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2015)

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13 pages, 2571 KiB

Open AccessArticle

Over-Expression of Porcine Myostatin Missense Mutant Leads to A Gender Difference in Skeletal Muscle Growth between Transgenic Male and Female Mice

by Dezun Ma¹, Pengfei Gao¹, Lili Qian², Qingqing Wang¹, Chunbo Cai², Shengwang Jiang¹, Gaojun Xiao¹ and Wentao Cui^1,*

¹ State Key Laboratory for Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China

² College of Biological Sciences, China Agricultural University, Beijing 100193, China

Int. J. Mol. Sci. 2015, 16(8), 20020-20032; https://doi.org/10.3390/ijms160820020 - 24 Aug 2015

Cited by 8 | Viewed by 7104

Abstract

Myostatin, a transforming growth factor-β family member, is a negative regulator of skeletal muscle development and growth. Piedmontese cattle breeds have a missense mutation, which results in a cysteine to tyrosine substitution in the mature myostatin protein (C313Y). This loss-of-function mutation in myostatin [...] Read more.

Myostatin, a transforming growth factor-β family member, is a negative regulator of skeletal muscle development and growth. Piedmontese cattle breeds have a missense mutation, which results in a cysteine to tyrosine substitution in the mature myostatin protein (C313Y). This loss-of-function mutation in myostatin results in a double-muscled phenotype in cattle. Myostatin propeptide is an inhibitor of myostatin activity and is considered a potential agent to stimulate muscle growth in livestock. In this study, we generated transgenic mice overexpressing porcine myostatin missense mutant (pmMS), C313Y, and wild-type porcine myostatin propeptide (ppMS), respectively, to examine their effects on muscle growth in mice. Enhanced muscle growth was observed in both pmMS and ppMS transgenic female mice and also in ppMS transgenic male mice. However, there was no enhanced muscle growth observed in pmMS transgenic male mice. To explore why there is such a big difference in muscle growth between pmMS and ppMS transgenic male mice, the expression level of androgen receptor (AR) mutant AR45 was measured by Western blot. Results indicated that AR45 expression significantly increased in pmMS transgenic male mice while it decreased dramatically in ppMS transgenic male mice. Our data demonstrate that both pmMS and ppMS act as myostatin inhibitors in the regulation of muscle growth, but the effect of pmMS in male mice is reversed by an increased AR45 expression. These results provide useful insight and basic theory to future studies on improving pork quality by genetically manipulating myostatin expression or by regulating myostatin activity. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 1978 KiB

Open AccessArticle

Extraction of Peptidoglycan from L. paracasei subp. Paracasei X12 and Its Preliminary Mechanisms of Inducing Immunogenic Cell Death in HT-29 Cells

by Pei-Jun Tian^1,†, Bao-Long Li^2,†, Yu-Juan Shan^1,*, Jin-Na Zhang³, Jing-Yu Chen¹, Min Yu² and Lan-Wei Zhang^1,*

¹ School of Food Science and Engineering, Harbin Institute of Technology, No. 73 Huanghe Road, Harbin 150000, China

² Center of Safety and Evaluation of Drugs, Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Harbin 150000, China

³ School of Municipal and Environmental Engineering, Harbin Institute of Technology, No. 73 Huanghe Road, Harbin 150000, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 20033-20049; https://doi.org/10.3390/ijms160820033 - 24 Aug 2015

Cited by 37 | Viewed by 7911

Abstract

L. paracasei subp. paracasei X12 was previously isolated from a Chinese traditional fermented cheese with anticancer activities and probiotic potential. Herein, the integral peptidoglycan (X12-PG) was extracted by a modified trichloroacetic acid (TCA) method. X12-PG contained the four representative amino acids Asp, Glu, [...] Read more.

L. paracasei subp. paracasei X12 was previously isolated from a Chinese traditional fermented cheese with anticancer activities and probiotic potential. Herein, the integral peptidoglycan (X12-PG) was extracted by a modified trichloroacetic acid (TCA) method. X12-PG contained the four representative amino acids Asp, Glu, Ala and Lys, and displayed the similar lysozyme sensitivity, UV-visible scanning spectrum and molecular weight as the peptidoglycan standard. X12-PG could induce the production of apoptotic bodies observed by transmission electron microscopy (TEM). X12-PG could significantly induced the translocation of calreticulin (CRT) and the release of high mobility group box 1 protein (HMGB1), the two notable hallmarks of immunogenic cell death (ICD), with the endoplastic reticulum (ER) damaged and subsequently intracellular [Ca²⁺] elevated. Our findings implied that X12-PG could induce the ICD of HT-29 cells through targeting at the ER. The present results may enlighten the prospect of probiotics in the prevention of colon cancer. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 2393 KiB

Open AccessArticle

Development of a New Monomer for the Synthesis of Intrinsic Antimicrobial Polymers with Enhanced Material Properties

by Florian Brodkorb^1,*,†, Björn Fischer^1,†, Katrin Kalbfleisch^1,†, Oliver Robers^1,†, Carina Braun², Sophia Dohlen², Judith Kreyenschmidt², Reinhard Lorenz¹ and Martin Kreyenschmidt¹

¹ Institute of Construction and Functional Materials, University of Applied Sciences Münster, Stegerwaldstraße 39, 48565 Steinfurt, Germany

² Institute of Animal Science, University Bonn, Katzenburgweg 7-9, 53113 Bonn, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 20050-20066; https://doi.org/10.3390/ijms160820050 - 24 Aug 2015

Cited by 5 | Viewed by 7456

Abstract

The use of biocidal compounds in polymers is steadily increasing because it is one solution to the need for safety and hygiene. It is possible to incorporate an antimicrobial moiety to a polymer. These polymers are referred to as intrinsic antimicrobial. The biocidal [...] Read more.

The use of biocidal compounds in polymers is steadily increasing because it is one solution to the need for safety and hygiene. It is possible to incorporate an antimicrobial moiety to a polymer. These polymers are referred to as intrinsic antimicrobial. The biocidal action results from contact of the polymer to the microorganisms, with no release of active molecules. This is particularly important in critical fields like food technology, medicine and ventilation technology, where migration or leaching is crucial and undesirable. The isomers N-(1,1-dimethylethyl)-4-ethenyl-benzenamine and N-(1,1-dimethyl-ethyl)-3-ethenyl-benzenamine (TBAMS) are novel (Co-)Monomers for intrinsic anti-microbial polymers. The secondary amines were prepared and polymerized to the corresponding water insoluble polymer. The antimicrobial activity was analyzed by the test method JIS Z 2801:2000. Investigations revealed a high antimicrobial activity against Staphylococcus aureus and Escherichia coli with a reduction level of >4.5 log₁₀ units. Furthermore, scanning electron microscopy (SEM) of E. coli. in contact with the polymer indicates a bactericidal action which is caused by disruption of the bacteria cell membranes, leading to lysis of the cells. Full article

(This article belongs to the Special Issue Antimicrobial Polymers 2016)

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15 pages, 718 KiB

Open AccessArticle

Variants of MicroRNA Genes: Gender-Specific Associations with Multiple Sclerosis Risk and Severity

by Ivan Kiselev^1,*,†, Vitalina Bashinskaya^1,2,†, Olga Kulakova^1,2, Natalia Baulina¹, Ekaterina Popova³, Alexey Boyko³ and Olga Favorova^1,2

¹ Dep. of Molecular Biology and Medical biotechnology, Pirogov Russian National Research Medical University, Moscow 117997, Russia

² Lab. of Functional Genomics of Cardiovascular Diseases, Russian Cardiology Research and Production Complex, Moscow 121552, Russia

³ Dep. of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University, Moscow 117997, Russia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 20067-20081; https://doi.org/10.3390/ijms160820067 - 24 Aug 2015

Cited by 35 | Viewed by 7245

Abstract

Multiple sclerosis (MS) is an autoimmune neuro-inflammatory disease arising from complex interactions of genetic, epigenetic, and environmental factors. Variations in genes of some microRNAs—key post-transcriptional regulators of many genes—can influence microRNAs expression/function and contribute to MS via expression changes of protein-coding target mRNA [...] Read more.

Multiple sclerosis (MS) is an autoimmune neuro-inflammatory disease arising from complex interactions of genetic, epigenetic, and environmental factors. Variations in genes of some microRNAs—key post-transcriptional regulators of many genes—can influence microRNAs expression/function and contribute to MS via expression changes of protein-coding target mRNA genes. We performed an association study of polymorphous variants of MIR146A rs2910164, MIR196A2 rs11614913, MIR499A rs3746444 MIR223 rs1044165 and their combinations with MS risk and severity. 561 unrelated patients with bout-onset MS and 441 healthy volunteers were enrolled in the study. We observed associations of MS risk with allele MIR223*T and combination (MIR223*T + MIR146A*G/G) carriage in the entire groups and in women at Bonferroni-corrected significance level (p_corr < 0.05). Besides, MIR146A*G/G association with MS was observed in women with nominal significance (p_f = 0.025). No MS associations were found in men. A more severe MS course (MSSS value > 3.5) was associated with the carriage of MIR499A*C/T and, less reliably, of MIR499A*C (p_corr = 0.006 and p_corr = 0.024, respectively) and with the carriage of combinations (MIR499A*C/T + MIR196A2*C) and (MIR499A*C + MIR196A2*C) (p_corr = 0.00078 and p_corr = 0.0059, respectively). These associations also showed gender specificity, as they were not significant in men and substantially reinforced in women. The strongest association with MS severity was observed in women for combination (MIR499A*C/T + MIR196A2*C): p_corr = 4.43 × 10⁻⁶ and OR = 3.23 (CI: 1.99–5.26). Full article

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

13 pages, 856 KiB

Open AccessArticle

A Futile Redox Cycle Involving Neuroglobin Observed at Physiological Temperature

by Anyang Liu^† and Thomas Brittain^*,†

¹ School of Biological Sciences, University of Auckland, Auckland 1142, New Zealand

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2015, 16(8), 20082-20094; https://doi.org/10.3390/ijms160820082 - 24 Aug 2015

Cited by 6 | Viewed by 4715

Abstract

Previous studies identifying the potential anti-apoptotic role of neuroglobin raise the question as to how cells might employ neuroglobin to avoid the apoptotic impact of acute hypoxia whilst also avoiding chronic enhancement of tumour formation. We show that under likely physiological conditions neuroglobin [...] Read more.

Previous studies identifying the potential anti-apoptotic role of neuroglobin raise the question as to how cells might employ neuroglobin to avoid the apoptotic impact of acute hypoxia whilst also avoiding chronic enhancement of tumour formation. We show that under likely physiological conditions neuroglobin can take part in a futile redox cycle. Determination of the rate constants for each of the steps in the cycle allows us to mathematically model the steady state concentration of the active anti-apoptotic ferrous form of neuroglobin under various conditions. Under likely normal physiological conditions neuroglobin is shown to be present in the ferrous state at approximately 30% of its total cellular concentration. Under hypoxic conditions this rapidly rises to approximately 80%. Temporal analysis of this model indicates that the transition from low concentrations to high concentration of ferrous neuroglobin occurs on the seconds time scale. These findings indicate a potential control model for the anti-apoptotic activity of neuroglobin, under likely physiological conditions, whereby, in normoxic conditions, the anti-apoptotic activity of neuroglobin is maintained at a low level, whilst immediately a transition occurs to a hypoxic situation, as might arise during stroke, the anti-apoptotic activity is drastically increased. In this way the cell avoids unwanted increased oncogenic potential under normal conditions, but the rapid activation of neuroglobin provides anti-apoptotic protection in times of acute hypoxia. Full article

(This article belongs to the Section Biochemistry)

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Int. J. Mol. Sci., Volume 16, Issue 8 (August 2015) – 181 articles , Pages 16710-20099

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