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Int. J. Mol. Sci., Volume 15, Issue 5 (May 2014), Pages 7049-9172

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Open AccessArticle The Peroxisome Proliferator-Activated Receptor (PPAR) α Agonist Fenofibrate Suppresses Chemically Induced Lung Alveolar Proliferative Lesions in Male Obese Hyperlipidemic Mice
Int. J. Mol. Sci. 2014, 15(5), 9160-9172; https://doi.org/10.3390/ijms15059160
Received: 6 March 2014 / Revised: 7 May 2014 / Accepted: 12 May 2014 / Published: 22 May 2014
Cited by 4 | PDF Full-text (2622 KB) | HTML Full-text | XML Full-text
Abstract
Activation of peroxisome proliferator-activated receptor (PPAR) α disrupts growth-related activities in a variety of human cancers. This study was designed to determine whether fenofibrate, a PPARα agonist, can suppress 4-nitroquinoline 1-oxide (4-NQO)-induced proliferative lesions in the lung of obese hyperlipidemic mice. Male Tsumura
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Activation of peroxisome proliferator-activated receptor (PPAR) α disrupts growth-related activities in a variety of human cancers. This study was designed to determine whether fenofibrate, a PPARα agonist, can suppress 4-nitroquinoline 1-oxide (4-NQO)-induced proliferative lesions in the lung of obese hyperlipidemic mice. Male Tsumura Suzuki Obese Diabetic mice were subcutaneously injected with 4-NQO to induce lung proliferative lesions, including adenocarcinomas. They were then fed a diet containing 0.01% or 0.05% fenofibrate for 29 weeks, starting 1 week after 4-NQO administration. At week 30, the incidence and multiplicity (number of lesions/mouse) of pulmonary proliferative lesions were lower in mice treated with 4-NQO and both doses of fenofibrate compared with those in mice treated with 4-NQO alone. The incidence and multiplicity of lesions were significantly lower in mice treated with 4-NQO and 0.05% fenofibrate compared with those in mice treated with 4-NQO alone (p < 0.05). Both doses of fenofibrate significantly reduced the proliferative activity of the lesions in 4-NQO-treated mice (p < 0.05). Fenofibrate also significantly reduced the serum insulin and insulin-like growth factor (IGF)-1 levels, and decreased the immunohistochemical expression of IGF-1 receptor (IGF-1R), phosphorylated Akt, and phosphorylated Erk1/2 in lung adenocarcinomas. Our results indicate that fenofibrate can prevent the development of 4-NQO-induced proliferative lesions in the lung by modulating the insulin-IGF axis. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Open AccessArticle Functional Polymorphisms of the ABCG2 Gene Are Associated with Gout Disease in the Chinese Han Male Population
Int. J. Mol. Sci. 2014, 15(5), 9149-9159; https://doi.org/10.3390/ijms15059149
Received: 30 January 2014 / Revised: 23 April 2014 / Accepted: 12 May 2014 / Published: 22 May 2014
Cited by 14 | PDF Full-text (335 KB) | HTML Full-text | XML Full-text
Abstract
Background: Gout is a common type of arthritis that is characterized by hyperuricemia, tophi and joint inflammation. Genetic variations in the ABCG2 gene have been reported to influence serum uric acid levels and to participate in the pathogenesis of gout, but no further
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Background: Gout is a common type of arthritis that is characterized by hyperuricemia, tophi and joint inflammation. Genetic variations in the ABCG2 gene have been reported to influence serum uric acid levels and to participate in the pathogenesis of gout, but no further data have been reported in the Han Chinese population. Methods: Peripheral blood DNA was isolated from 352 male patients with gout and 350 gout-free normal male controls. High-resolution melting analysis and Sanger sequencing were performed to identify the genetic polymorphisms V12M, Q141K and Q126X in the ABCG2 gene. Genotype and haplotype analyses were utilized to determine the disease odds ratios (ORs). A prediction model for gout risk using ABCG2 protein function was established based on the genotype combination of Q126X and Q141K. Results: For Q141K, the A allele frequency was 49.6% in the gout patients and 30.9% in the controls (OR 2.20, 95% confidence interval (CI): 1.77–2.74, p = 8.99 × 10−13). Regarding Q126X, the T allele frequency was 4.7% in the gout patients and 1.7% in the controls (OR 2.91, 95% CI: 1.49–5.68, p = 1.57 × 10−3). The A allele frequency for V12M was lower (18.3%) in the gout patients than in the controls (29%) (OR 0.55, 95% CI 0.43–0.71, p = 2.55 × 10−6). In the order of V12M, Q126X and Q141K, the GCA and GTC haplotypes indicated increased disease risk (OR = 2.30 and 2.71, respectively). Patients with mild to severe ABCG2 dysfunction accounted for 78.4% of gout cases. Conclusion: The ABCG2 126X and 141K alleles are associated with an increased risk of gout, whereas 12M has a protective effect on gout susceptibility in the Han Chinese population. ABCG2 dysfunction can be used to evaluate gout risk. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Open AccessArticle Aerobic Degradation of Trichloroethylene by Co-Metabolism Using Phenol and Gasoline as Growth Substrates
Int. J. Mol. Sci. 2014, 15(5), 9134-9148; https://doi.org/10.3390/ijms15059134
Received: 29 January 2014 / Revised: 24 April 2014 / Accepted: 4 May 2014 / Published: 22 May 2014
Cited by 7 | PDF Full-text (366 KB) | HTML Full-text | XML Full-text
Abstract
Trichloroethylene (TCE) is a common groundwater contaminant of toxic and carcinogenic concern. Aerobic co-metabolic processes are the predominant pathways for TCE complete degradation. In this study, Pseudomonas fluorescens was studied as the active microorganism to degrade TCE under aerobic condition by co-metabolic degradation
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Trichloroethylene (TCE) is a common groundwater contaminant of toxic and carcinogenic concern. Aerobic co-metabolic processes are the predominant pathways for TCE complete degradation. In this study, Pseudomonas fluorescens was studied as the active microorganism to degrade TCE under aerobic condition by co-metabolic degradation using phenol and gasoline as growth substrates. Operating conditions influencing TCE degradation efficiency were optimized. TCE co-metabolic degradation rate reached the maximum of 80% under the optimized conditions of degradation time of 3 days, initial OD600 of microorganism culture of 0.14 (1.26 × 107 cell/mL), initial phenol concentration of 100 mg/L, initial TCE concentration of 0.1 mg/L, pH of 6.0, and salinity of 0.1%. The modified transformation capacity and transformation yield were 20 μg (TCE)/mg (biomass) and 5.1 μg (TCE)/mg (phenol), respectively. Addition of nutrient broth promoted TCE degradation with phenol as growth substrate. It was revealed that catechol 1,2-dioxygenase played an important role in TCE co-metabolism. The dechlorination of TCE was complete, and less chlorinated products were not detected at the end of the experiment. TCE could also be co-metabolized in the presence of gasoline; however, the degradation rate was not high (28%). When phenol was introduced into the system of TCE and gasoline, TCE and gasoline could be removed at substantial rates (up to 59% and 69%, respectively). This study provides a promising approach for the removal of combined pollution of TCE and gasoline. Full article
(This article belongs to the Special Issue Biodegradability of Materials)
Open AccessReview Brain Metastasis-Initiating Cells: Survival of the Fittest
Int. J. Mol. Sci. 2014, 15(5), 9117-9133; https://doi.org/10.3390/ijms15059117
Received: 15 April 2014 / Revised: 12 May 2014 / Accepted: 13 May 2014 / Published: 22 May 2014
Cited by 11 | PDF Full-text (548 KB) | HTML Full-text | XML Full-text
Abstract
Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only
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Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only months. Despite the high rate of BM-associated mortality, very little research is conducted in this area. Lack of research and staggeringly low patient survival is indicative that a novel approach to BMs and their treatment is needed. The ability of a small subset of primary tumor cells to produce macrometastases is reminiscent of brain tumor-initiating cells (BTICs) or cancer stem cells (CSCs) hypothesized to form primary brain tumors. BTICs are considered stem cell-like due to their self-renewal and differentiation properties. Similar to the subset of cells forming metastases, BTICs are most often a rare subpopulation. Based on the functional definition of a TIC, cells capable of forming a BM could be considered to be brain metastasis-initiating cells (BMICs). These putative BMICs would not only have the ability to initiate tumor growth in a secondary niche, but also the machinery to escape the primary tumor, migrate through the circulation, and invade the neural niche. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
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Open AccessArticle Chemical Characterization and Antitumor Activities of Polysaccharide Extracted from Ganoderma lucidum
Int. J. Mol. Sci. 2014, 15(5), 9103-9116; https://doi.org/10.3390/ijms15059103
Received: 19 March 2014 / Revised: 1 May 2014 / Accepted: 4 May 2014 / Published: 22 May 2014
Cited by 18 | PDF Full-text (2188 KB) | HTML Full-text | XML Full-text
Abstract
Ganoderma lucidum polysaccharide (GLP) is a biologically active substance reported to possess anti-tumor ability. Nonetheless, the mechanisms of GLP-stimulated apoptosis are still unclear. This study aims to determine the inhibitory and apoptosis-inducing effects of GLP on HCT-116 cells. We found that GLP reduced
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Ganoderma lucidum polysaccharide (GLP) is a biologically active substance reported to possess anti-tumor ability. Nonetheless, the mechanisms of GLP-stimulated apoptosis are still unclear. This study aims to determine the inhibitory and apoptosis-inducing effects of GLP on HCT-116 cells. We found that GLP reduced cell viability on HCT-116 cells in a time- and dose-dependent manner, which in turn, induced cell apoptosis. The observed apoptosis was characterized by morphological changes, DNA fragmentation, mitochondrial membrane potential decrease, S phase population increase, and caspase-3 and -9 activation. Furthermore, inhibition of c-Jun N-terminal kinase (JNK) by SP600125 led to a dramatic decrease of the GLP-induced apoptosis. Western blot analysis unveiled that GLP up-regulated the expression of Bax/Bcl-2, caspase-3 and poly (ADP-ribose) polymerase (PARP). These results demonstrate that apoptosis stimulated by GLP in human colorectal cancer cells is associated with activation of mitochondrial and mitogen-activated protein kinase (MAPK) pathways. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Open AccessArticle Green Conversion of Agroindustrial Wastes into Chitin and Chitosan by Rhizopus arrhizus and Cunninghamella elegans Strains
Int. J. Mol. Sci. 2014, 15(5), 9082-9102; https://doi.org/10.3390/ijms15059082
Received: 12 January 2014 / Revised: 31 March 2014 / Accepted: 25 April 2014 / Published: 21 May 2014
Cited by 9 | PDF Full-text (1067 KB) | HTML Full-text | XML Full-text
Abstract
This article sets out a method for producing chitin and chitosan by Cunninghamella elegans and Rhizopus arrhizus strains using a green metabolic conversion of agroindustrial wastes (corn steep liquor and molasses). The physicochemical characteristics of the biopolymers and antimicrobial activity are described. Chitin
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This article sets out a method for producing chitin and chitosan by Cunninghamella elegans and Rhizopus arrhizus strains using a green metabolic conversion of agroindustrial wastes (corn steep liquor and molasses). The physicochemical characteristics of the biopolymers and antimicrobial activity are described. Chitin and chitosan were extracted by alkali-acid treatment, and characterized by infrared spectroscopy, viscosity and X-ray diffraction. The effectiveness of chitosan from C. elegans and R. arrhizus in inhibiting the growth of Listeria monocytogenes, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella enterica, Escherichia coli and Yersinia enterocolitica were evaluated by determining the minimum inhibitory concentrations (MIC) and the minimum bactericidal concentrations (MBC). The highest production of biomass (24.60 g/L), chitin (83.20 mg/g) and chitosan (49.31 mg/g) was obtained by R. arrhizus. Chitin and chitosan from both fungi showed a similar degree of deacetylation, respectively of 25% and 82%, crystallinity indices of 33.80% and 32.80% for chitin, and 20.30% and 17.80% for chitosan. Both chitin and chitosan presented similar viscosimetry of 3.79–3.40 cP and low molecular weight of 5.08 × 103 and 4.68 × 103 g/mol. They both showed identical MIC and MBC for all bacteria assayed. These results suggest that: agricultural wastes can be produced in an environmentally friendly way; chitin and chitosan can be produced economically; and that chitosan has antimicrobial potential against pathogenic bacteria. Full article
(This article belongs to the Section Green Chemistry)
Open AccessArticle A pH and Redox Dual Responsive 4-Arm Poly(ethylene glycol)-block-poly(disulfide histamine) Copolymer for Non-Viral Gene Transfection in Vitro and in Vivo
Int. J. Mol. Sci. 2014, 15(5), 9067-9081; https://doi.org/10.3390/ijms15059067
Received: 28 January 2014 / Revised: 6 May 2014 / Accepted: 12 May 2014 / Published: 21 May 2014
Cited by 12 | PDF Full-text (2224 KB) | HTML Full-text | XML Full-text
Abstract
A novel 4-arm poly(ethylene glycol)-b-poly(disulfide histamine) copolymer was synthesized by Michael addition reaction of poly(ethylene glycol) (PEG) vinyl sulfone and amine-capped poly(disulfide histamine) oligomer, being denoted as 4-arm PEG-SSPHIS. This copolymer was able to condense DNA into nanoscale polyplexes (<200 nm in average
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A novel 4-arm poly(ethylene glycol)-b-poly(disulfide histamine) copolymer was synthesized by Michael addition reaction of poly(ethylene glycol) (PEG) vinyl sulfone and amine-capped poly(disulfide histamine) oligomer, being denoted as 4-arm PEG-SSPHIS. This copolymer was able to condense DNA into nanoscale polyplexes (<200 nm in average diameter) with almost neutral surface charge (+(5–10) mV). Besides, these polyplexes were colloidal stable within 4 h in HEPES buffer saline at pH 7.4 (physiological environment), but rapidly dissociated to liberate DNA in the presence of 10 mM glutathione (intracellular reducing environment). The polyplexes also revealed pH-responsive surface charges which markedly increased with reducing pH values from 7.4–6.3 (tumor microenvironment). In vitro transfection experiments showed that polyplexes of 4-arm PEG-SSPHIS were capable of exerting enhanced transfection efficacy in MCF-7 and HepG2 cancer cells under acidic conditions (pH 6.3–7.0). Moreover, intravenous administration of the polyplexes to nude mice bearing HepG2-tumor yielded high transgene expression largely in tumor rather other normal organs. Importantly, this copolymer and its polyplexes had low cytotoxicity against the cells in vitro and caused no death of the mice. The results of this study indicate that 4-arm PEG-SSPHIS has high potential as a dual responsive gene delivery vector for cancer gene therapy. Full article
(This article belongs to the Special Issue Biodegradable Materials)
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Open AccessArticle Detection of a Specific Biomarker for Epstein-Barr Virus Using a Polymer-Based Genosensor
Int. J. Mol. Sci. 2014, 15(5), 9051-9066; https://doi.org/10.3390/ijms15059051
Received: 31 July 2013 / Revised: 4 May 2014 / Accepted: 7 May 2014 / Published: 21 May 2014
Cited by 9 | PDF Full-text (868 KB) | HTML Full-text | XML Full-text
Abstract
This paper describes methodology for direct and indirect detections of a specific oligonucleotide for Epstein-Barr virus (EBV) using electrochemical techniques. The sequence of oligonucleotide probe (EBV1) revealed a high sequence identity (100%) with the EBV genome. For the development of the genosensor, EBV1
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This paper describes methodology for direct and indirect detections of a specific oligonucleotide for Epstein-Barr virus (EBV) using electrochemical techniques. The sequence of oligonucleotide probe (EBV1) revealed a high sequence identity (100%) with the EBV genome. For the development of the genosensor, EBV1 was grafted to the platform sensitized with poly(4-aminothiophenol). After that, the hybridization reaction was carried out with the complementary target (EBV2) on the modified electrode surface using ethidium bromide as DNA intercalator. The oxidation peak currents of ethidium bromide increased linearly with the values of the concentration of the complementary sequences in the range from 3.78 to 756 µmol·L−1. In nonstringent experimental conditions, this genosensor can detect 17.32 nmol·L−1 (three independent experiments) of oligonucleotide target, discriminating between complementary and non-complementary oligonucleotides, as well as differentiating one-base mismatch, as required for detection of genetic diseases caused by point mutations. The biosensor also displayed high specificity to the EBV target with elimination of interference from mix (alanine, glucose, uric acid, ascorbic acid, bovine serum albumin (BSA), glutamate and glycine) and good stability (120 days). In addition, it was possible to observe differences between hybridized and non-hybridized surfaces through atomic force microscopy. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Open AccessArticle Over-Expression of Catalase in Myeloid Cells Confers Acute Protection Following Myocardial Infarction
Int. J. Mol. Sci. 2014, 15(5), 9036-9050; https://doi.org/10.3390/ijms15059036
Received: 17 April 2014 / Revised: 12 May 2014 / Accepted: 14 May 2014 / Published: 21 May 2014
Cited by 4 | PDF Full-text (1048 KB) | HTML Full-text | XML Full-text
Abstract
Cardiovascular disease is the leading cause of death in the United States and new treatment options are greatly needed. Oxidative stress is increased following myocardial infarction and levels of antioxidants decrease, causing imbalance that leads to dysfunction. Therapy involving catalase, the endogenous scavenger
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Cardiovascular disease is the leading cause of death in the United States and new treatment options are greatly needed. Oxidative stress is increased following myocardial infarction and levels of antioxidants decrease, causing imbalance that leads to dysfunction. Therapy involving catalase, the endogenous scavenger of hydrogen peroxide (H2O2), has been met with mixed results. When over-expressed in cardiomyocytes from birth, catalase improves function following injury. When expressed in the same cells in an inducible manner, catalase showed a time-dependent response with no acute benefit, but a chronic benefit due to altered remodeling. In myeloid cells, catalase over-expression reduced angiogenesis during hindlimb ischemia and prevented monocyte migration. In the present study, due to the large inflammatory response following infarction, we examined myeloid-specific catalase over-expression on post-infarct healing. We found a significant increase in catalase levels following infarction that led to a decrease in H2O2 levels, leading to improved acute function. This increase in function could be attributed to reduced infarct size and improved angiogenesis. Despite these initial improvements, there was no improvement in chronic function, likely due to increased fibrosis. These data combined with what has been previously shown underscore the need for temporal, cell-specific catalase delivery as a potential therapeutic option. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease 2015)
Open AccessArticle Mangiferin Facilitates Islet Regeneration and β-Cell Proliferation through Upregulation of Cell Cycle and β-Cell Regeneration Regulators
Int. J. Mol. Sci. 2014, 15(5), 9016-9035; https://doi.org/10.3390/ijms15059016
Received: 16 January 2014 / Revised: 21 April 2014 / Accepted: 24 April 2014 / Published: 20 May 2014
Cited by 12 | PDF Full-text (3835 KB) | HTML Full-text | XML Full-text
Abstract
Mangiferin, a xanthonoid found in plants including mangoes and iris unguicularis, was suggested in previous studies to have anti-hyperglycemic function, though the underlying mechanisms are largely unknown. This study was designed to determine the therapeutic effect of mangiferin by the regeneration of β-cells
[...] Read more.
Mangiferin, a xanthonoid found in plants including mangoes and iris unguicularis, was suggested in previous studies to have anti-hyperglycemic function, though the underlying mechanisms are largely unknown. This study was designed to determine the therapeutic effect of mangiferin by the regeneration of β-cells in mice following 70% partial pancreatectomy (PPx), and to explore the mechanisms of mangiferin-induced β-cell proliferation. For this purpose, adult C57BL/6J mice after 7–14 days post-PPx, or a sham operation were subjected to mangiferin (30 and 90 mg/kg body weight) or control solvent injection. Mangiferin-treated mice exhibited an improved glycemia and glucose tolerance, increased serum insulin levels, enhanced β-cell hyperplasia, elevated β-cell proliferation and reduced β-cell apoptosis. Further dissection at the molecular level showed several key regulators of cell cycle, such as cyclin D1, D2 and cyclin-dependent kinase 4 (Cdk4) were significantly up-regulated in mangiferin-treated mice. In addition, critical genes related to β-cell regeneration, such as pancreatic and duodenal homeobox 1 (PDX-1), neurogenin 3 (Ngn3), glucose transporter 2 (GLUT-2), Forkhead box protein O1 (Foxo-1), and glucokinase (GCK), were found to be promoted by mangiferin at both the mRNA and protein expression level. Thus, mangiferin administration markedly facilitates β-cell proliferation and islet regeneration, likely by regulating essential genes in the cell cycle and the process of islet regeneration. These effects therefore suggest that mangiferin bears a therapeutic potential in preventing and/or treating the diabetes. Full article
(This article belongs to the Special Issue Nutritional Control of Metabolism)
Open AccessArticle Effect of a Novel Quaternary Ammonium Methacrylate Polymer (QAMP) on Adhesion and Antibacterial Properties of Dental Adhesives
Int. J. Mol. Sci. 2014, 15(5), 8998-9015; https://doi.org/10.3390/ijms15058998
Received: 3 March 2014 / Revised: 14 April 2014 / Accepted: 16 April 2014 / Published: 20 May 2014
Cited by 8 | PDF Full-text (988 KB) | HTML Full-text | XML Full-text
Abstract
This study investigated the resin–dentin bond strength (μTBS), degree of conversion (DC), and antibacterial potential of an innovative adhesive system containing a quaternary ammonium methacrylate polymer (QAMP) using in situ and in vitro assays. Forty-two human third molars were flattened until the dentin
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This study investigated the resin–dentin bond strength (μTBS), degree of conversion (DC), and antibacterial potential of an innovative adhesive system containing a quaternary ammonium methacrylate polymer (QAMP) using in situ and in vitro assays. Forty-two human third molars were flattened until the dentin was exposed and were randomly distributed into three groups of self-etching adhesive systems: Clearfil™ SE Bond containing 5% QAMP (experimental group), Clearfil™ Protect Bond (positive control) and Clearfil™ SE Bond (negative control). After light curing, three 1 mm-increments of composite resin were bonded to each dentin surface. A total of thirty of these bonded teeth (10 teeth per group) was sectioned to obtain stick-shaped specimens and tested under tensile stress immediately, and after 6 and 12 months of storage in distilled water. Twelve bonded teeth (4 teeth per group) were longitudinally sectioned in a mesio-to-distal direction to obtain resin-bonded dentin slabs. In situ DC was evaluated by micro-Raman spectroscopy. In vitro DC of thin films of each adhesive system was measured using Fourier transform infrared spectroscopy. In vitro susceptibility tests of these three adhesive systems were performed by the minimum inhibitory/minimum bactericidal concentration (MIC/MBC) assays against Streptococcus mutans, Lactobacillus casei, and Actinomyces naeslundii. No statistically significant difference in μTBS was observed between Clearfil™ SE Bond containing 5% QAMP and Clearfil™ SE Bond (p > 0.05) immediately, and after 6 and 12 months of water storage. However Clearfil™ Protect Bond showed a significant reduction of μTBS after 12 months of storage (p = 0.039). In addition, QAMP provided no significant change in DC after incorporating into Clearfil™ SE Bond (p > 0.05). Clearfil™ SE Bond containing 5% QAMP demonstrated MIC/MBC values similar to the positive control against L. casei and A. naeslundii and higher than the negative control for all evaluated bacterial strains. The use of QAMP in an adhesive system demonstrated effective bond strength, a suitable degree of conversion, and adequate antibacterial effects against oral bacteria, and may be useful as a new approach to provide long-lasting results for dental adhesives. Full article
(This article belongs to the Special Issue Antimicrobial Polymers)
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Open AccessArticle Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model
Int. J. Mol. Sci. 2014, 15(5), 8979-8997; https://doi.org/10.3390/ijms15058979
Received: 7 April 2014 / Revised: 5 May 2014 / Accepted: 13 May 2014 / Published: 20 May 2014
Cited by 11 | PDF Full-text (2146 KB) | HTML Full-text | XML Full-text
Abstract
Cyclosporin A (CsA), a calcineurin inhibitor, remain the cornerstone of immunosuppressive regimens, regardless of nephrotoxicity, which depends on the duration of drug exposure. The mechanisms and biomarkers underlying the transition from CsA-induced renal dysfunction to nephrotoxicity deserve better elucidation, and would help clinical
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Cyclosporin A (CsA), a calcineurin inhibitor, remain the cornerstone of immunosuppressive regimens, regardless of nephrotoxicity, which depends on the duration of drug exposure. The mechanisms and biomarkers underlying the transition from CsA-induced renal dysfunction to nephrotoxicity deserve better elucidation, and would help clinical decisions. This study aimed to clarify these issues, using a rat model of short- and long-term CsA (5 mg/kg bw/day) treatments (3 and 9 weeks, respectively). Renal function was assessed on serum and urine; kidney tissue was used for histopathological characterization and gene and/or protein expression of markers of proliferation, fibrosis and inflammation. In the short-term, creatinine and blood urea nitrogen (BUN) levels increased and clearances decreased, accompanied by glomerular filtration rate (GFR) reduction, but without kidney lesions; at that stage, CsA exposure induced proliferating cell nuclear antigen (PCNA), transforming growth factor beta 1 (TGF-β1), factor nuclear kappa B (NF-κβ) and Tumor Protein P53 (TP53) kidney mRNA up-regulation. In the long-term treatment, renal dysfunction data was accompanied by glomerular and tubulointerstitial lesions, with remarkable kidney mRNA up-regulation of the mammalian target of rapamycin (mTOR) and the antigen identified by monoclonal antibody Ki-67 (Mki67), accompanied by mTOR protein overexpression. Transition from CsA-induced renal dysfunction to nephrotoxicity is accompanied by modification of molecular mechanisms and biomarkers, being mTOR one of the key players for kidney lesion evolution, thus suggesting, by mean of molecular evidences, that early CsA replacement by mTOR inhibitors is indeed the better therapeutic choice to prevent chronic allograft nephropathy. Full article
(This article belongs to the Special Issue Renal Toxicology—Epidemiology and Mechanisms)
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Open AccessArticle Genes and Gene Networks Involved in Sodium Fluoride-Elicited Cell Death Accompanying Endoplasmic Reticulum Stress in Oral Epithelial Cells
Int. J. Mol. Sci. 2014, 15(5), 8959-8978; https://doi.org/10.3390/ijms15058959
Received: 13 February 2014 / Revised: 5 May 2014 / Accepted: 13 May 2014 / Published: 20 May 2014
Cited by 8 | PDF Full-text (2549 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Here, to understand the molecular mechanisms underlying cell death induced by sodium fluoride (NaF), we analyzed gene expression patterns in rat oral epithelial ROE2 cells exposed to NaF using global-scale microarrays and bioinformatics tools. A relatively high concentration of NaF (2 mM) induced
[...] Read more.
Here, to understand the molecular mechanisms underlying cell death induced by sodium fluoride (NaF), we analyzed gene expression patterns in rat oral epithelial ROE2 cells exposed to NaF using global-scale microarrays and bioinformatics tools. A relatively high concentration of NaF (2 mM) induced cell death concomitant with decreases in mitochondrial membrane potential, chromatin condensation and caspase-3 activation. Using 980 probe sets, we identified 432 up-regulated and 548 down-regulated genes, that were differentially expressed by >2.5-fold in the cells treated with 2 mM of NaF and categorized them into 4 groups by K-means clustering. Ingenuity® pathway analysis revealed several gene networks from gene clusters. The gene networks Up-I and Up-II included many up-regulated genes that were mainly associated with the biological function of induction or prevention of cell death, respectively, such as Atf3, Ddit3 and Fos (for Up-I) and Atf4 and Hspa5 (for Up-II). Interestingly, knockdown of Ddit3 and Hspa5 significantly increased and decreased the number of viable cells, respectively. Moreover, several endoplasmic reticulum (ER) stress-related genes including, Ddit3, Atf4 and Hapa5, were observed in these gene networks. These findings will provide further insight into the molecular mechanisms of NaF-induced cell death accompanying ER stress in oral epithelial cells. Full article
(This article belongs to the Section Molecular Toxicology)
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Open AccessArticle Synthesis and Bioactivity of 5-Substituted-2-furoyl Diacylhydazide Derivatives with Aliphatic Chain
Int. J. Mol. Sci. 2014, 15(5), 8941-8958; https://doi.org/10.3390/ijms15058941
Received: 24 March 2014 / Revised: 2 May 2014 / Accepted: 5 May 2014 / Published: 20 May 2014
Cited by 6 | PDF Full-text (384 KB) | HTML Full-text | XML Full-text
Abstract
A series of 5-substituted-2-furoyl diacylhydazide derivatives with aliphatic chain were designed and synthesized. Their structures were characterized by IR, 1H NMR, elemental analysis, and X-ray single crystal diffraction. The anti-tumor bioassay revealed that some title compounds exhibited promising activity against the selected
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A series of 5-substituted-2-furoyl diacylhydazide derivatives with aliphatic chain were designed and synthesized. Their structures were characterized by IR, 1H NMR, elemental analysis, and X-ray single crystal diffraction. The anti-tumor bioassay revealed that some title compounds exhibited promising activity against the selected cancer cell lines, especially against the human promyelocytic leukemic cells (HL-60). Their fungicidal tests indicated that most of the title compounds showed significant anti-fungal activity. The preliminary structure-activity relationship showed that the aliphatic chain length and differences in the R2 group had obvious effects on the anti-tumor and anti-fungal activities. The bioassay results demonstrated that the title compounds hold great promise as novel lead compounds for further drug discovery. Full article
(This article belongs to the Section Materials Science)
Open AccessArticle Tagging SNPs in the MTHFR Gene and Risk of Ischemic Stroke in a Chinese Population
Int. J. Mol. Sci. 2014, 15(5), 8931-8940; https://doi.org/10.3390/ijms15058931
Received: 10 March 2014 / Revised: 7 May 2014 / Accepted: 8 May 2014 / Published: 20 May 2014
Cited by 18 | PDF Full-text (219 KB) | HTML Full-text | XML Full-text
Abstract
Stroke is currently the leading cause of functional impairments worldwide. Folate supplementation is inversely associated with risk of ischemic stroke. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism. The aim of this study is to examine whether genetic variants in
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Stroke is currently the leading cause of functional impairments worldwide. Folate supplementation is inversely associated with risk of ischemic stroke. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism. The aim of this study is to examine whether genetic variants in MTHFR gene are associated with the risk of ischemic stroke and fasting total serum homocysteine (tHcy) level. We genotyped nine tag SNPs in the MTHFR gene in a case-control study, including 543 ischemic stroke cases and 655 healthy controls in China. We found that subjects with the rs1801133 TT genotype and rs1801131 CC genotype had significant increased risks of ischemic stroke (adjusted odds ratio (OR) = 1.82, 95% confidence interval (CI): 1.27–2.61, p = 0.004; adjusted OR = 1.99, 95% CI: 1.12–3.56, p = 0.01) compared with subjects with the major alleles. Haplotype analysis also found that carriers of the MTHFR CTTCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had a significant reduced risk of ischemic stroke (adjusted OR = 0.53, 95% CI: 0.35–0.82) compared with those with the CTTTGA haplotype. Besides, the MTHFR rs1801133 and rs9651118 were significantly associated with serum levels of tHcy in healthy controls (p < 0.0001 and p = 0.02). These findings suggest that variants in the MTHFR gene may influence the risk of ischemic stroke and serum tHcy. Full article
(This article belongs to the collection Human Single Nucleotide Polymorphisms and Disease Diagnostics)
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