Glutathione S-transferase T1 and M1 null genotypes and Parkinson's disease risk: evidence from an updated meta-analysis.

Glutathione S-transferase T1 and M1 (GSTT1 and GSTM1) have been reported to be associated with Parkinson's disease (PD). However, the results of these previous studies were inconsistent. The reported studies were conducted from 1990 to 2014 by searching PubMed. The total Odds Ratio and 95 % Confidence Interval were calculated and analyzed by Review Manager 5.1 and STATA 12. We also did subgroup analysis of ethnicity, publication year and sample size of total cases. Sensitivity analysis and publication bias were also done to evaluate the credibility of the results. A total of 3753 PD patients and 5636 controls from 19 case-control studies were identified. Overall, no association was observed (OR 1.01, 95 % CI 0.99-1.21, P = 0.07) between GSTM1 null genotype and PD. There was significant association in Caucasians when subgroup analysis of ethnicity was performed, and the same conclusion was observed in European and UK. And it was also in publication year of 1995-1999 and in sample size of total cases of <90 and 91-181. However, there was no significant association between GSTT1 null genotype and PD risk in this meta-analysis. Publication bias was negligible and the overall results were stable by sensitivity analysis. A slight increase of PD risk was detected in the meta-analysis of GSTM1 null genotype in subgroup analysis of ethnicity, publication year and sample size of total cases. However, short of statistical significance was detected for GSTT1 null genotype.

Degradation-Kinetics-Controllable and Tissue-Regeneration-Matchable Photocross-linked Alginate Hydrogels for Bone Repair.

Photocross-linked alginate hydrogels, due to their biodegradability, biocompatibility, strong control for gelling kinetics in space and time, and admirable adaptability for in situ polymerization with a minimally invasive approach in surgical procedures, have created great expectations in bone regeneration. However, hydrogels with suitable degradation kinetics that can match the tissue regeneration process have not been designed, which limits their further application in bone tissue engineering. Herein, we finely developed an oxidation strategy for alginate to obtain hydrogels with more suitable degradation rates and comprehensively explored their physical and biological performances in vitro and in vivo to further advance the clinical application for the hydrogels in bone repair. The physical properties of the gels can be tuned via tailoring the degree of alginate oxidation. In particular, in vivo degradation studies showed that the degradation rates of the gels were significantly increased by oxidizing alginate. The activity, proliferation, initial adhesion, and osteogenic differentiation of rat and rabbit bone marrow stromal cells (BMSCs) cultured with/in the hydrogels were explored, and the results demonstrated that the gels possessed excellent biocompatibility and that the encapsulated BMSCs were capable of osteogenic differentiation. Furthermore, in vivo implantation of rabbit BMSC-loaded gels into tibial plateau defects of rabbits demonstrated the feasibility of hydrogels with appropriate degradation rates for bone repair. This study indicated that hydrogels with increasingly controllable and matchable degradation kinetics and satisfactory bioproperties demonstrate great clinical potential in bone tissue engineering and regenerative medicine and could also provide references for drug/growth-factor delivery therapeutic strategies for diseases requiring specific drug/growth-factor durations of action.

Bio-functional strontium-containing photocrosslinked alginate hydrogels for promoting the osteogenic behaviors.

In recent years, photocrosslinked alginate hydrogel has been widely studied in bone tissue engineering, owing to its numerous advantages. However, there are still some shortcomings like insufficient mechanical strength and lack of bone induction. To compensate for these deficiencies, in this work, a novel doped strontium (Sr) photocrosslinked methacrylated alginate (Sr-PMA) hydrogel was developed. Photocrosslinked alginate hydrogel fabricated via crosslinking methacrylate-modified alginate under ultraviolet (UV) light was placed into strontium solutions to prepare Sr-PMA gel by chelating reaction. The chemical structures, swelling behaviors, degradation profiles, elastic moduli, Sr2+ ion release and surface morphology of the Sr-PMA hydrogel were characterized, and we found that physical properties of the gels can be tailored by varying concentration of Sr2+ ions. And MC3T3-E1 cell viability, proliferation and mineralization outside the hydrogel were also investigated. Further research on cell survival, multiplication, osteogenic differentiation of the cells encapsulated in Sr-PMA hydrogels were explored. In vitro studies of biological properties revealed that incorporation of Sr2+ into photocrosslinked alginate gels significantly improved osteogenic differentiation capabilities and mineralization via stimulating expression of osteogenesis related genes and proteins of the cells compared to strontium-free photocrosslinked alginate gels. The research demonstrates that the innovative Sr-PMA hydrogels possessing adjustable physical performances, excellent biocompatibility and osteogenic differentiation capabilities could be potentially applied to bone tissue engineering and regenerative medicine. Meanwhile, it also provides a reference for the modification of biological properties of biomaterials.

Associations between dietary folate intake and risks of esophageal, gastric and pancreatic cancers: an overall and dose-response meta-analysis.

There are still some controversies on the association between dietary folate intake and the risk of upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers. Hence, a comprehensive meta-analysis on all available literatures was performed to clarify the relationship between dietary folate intake and risks of upper gastrointestinal cancers. An electric search was performed up to December 12th, 2016 within the PubMed, MEDLINE AND EMBASE databases. Ultimately, a total of 46 studies which evaluated the association between folate intake and risks of upper gastrointestinal cancers were included. According to the data from included studies, the pooled results showed significant association between folate intake and esophageal (OR = 0.545, 95%CI = 0.432-0.658), gastric (OR=0.762, 95%CI=0.648-0.876) and pancreatic (OR=0.731, 95%CI=0.555-0.907) cancers. Linearity dose-response analysis indicated that with 100µg/day increment in dietary folate intake, the risk of esophageal, gastric and pancreatic cancers would decrease by 9%, 1.5% and 6%, respectively. These findings indicated that higher level of dietary folate intake could help for preventing upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers.

MicroRNA­187 is an independent prognostic factor in lung cancer and promotes lung cancer cell invasion via targeting of PTRF.

MicroRNAs (miRNAs) are involved in the progression of different types of cancers giving new hope for cancer treatment. The role and regulatory mechanism of microRNA­187 (miR­187) are largely unknown. In the present study, 74 patients with non­small cell lung cancer (NSCLC) were selected. Tumor tissues and matched normal tissues were collected for determining the expression level of miR­187. Cell research was performed to detect the function of miR­187. The expression level was measured and miR­187 was found to be overexpressed in the NSCLC cell lines and tissues. Overexpression of miR­187 promoted cell proliferation in the A549 and H1650 cell lines. Moreover, overexpression of miR­187 also promoted cell migration and invasion. Polymerase I and transcript release factor (PTRF) was identified as a target of miR­187. Overexpression of miR­187 suppressed the expression of PTRF. Knockdown of PTRF promoted lung cancer cell invasion, and overexpression of PTRF had a negative effect on lung cancer cell invasion. The PTRF messenger RNA (mRNA) levels in cancer tissues were significantly lower than those in their adjacent normal lung tissues as determined by real­time PCR (RT­PCR). The expression of the PTRF protein was significantly weaker than that in the adjacent normal lung tissues using immunohistochemical staining. The findings revealed that miR­187 promotes cell growth and invasion by targeting PTRF and miR­187 may be a new prognostic factor for NSCLC.

Cisplatin-mediated cytotoxicity through inducing CYP4A 11 expression in human renal tubular epithelial cells.

Cisplatin (CP) is a major antineoplastic drug for the treatment of solid tumors, but it has dose-dependent renal tubular toxicity. Previous studies have shown that induction of cytochrome P450 (CYP) by CP may play a role in the renal injury of CP. The aim of this study was to investigate the relationship between CP-induced toxicity and CYP4A11 expression in human renal tubular epithelial cells (HK-2). 20-Hydroxyeicosatetraenoic acid (20-HETE) is a CYP4A11 metabolite of arachidonic acid that plays an important role in renal injury. The activity of lactate dehydrogenase (LDH) was determined by spectrophotometer. CYP4A11 expression was analyzed by immunocytochemistry. CYP4A11 mRNA and protein expression were evaluated by RT-PCR and Western blot analyses. Results showed that 20-HETE (1, 10, 50 µM), a CYP4A11 metabolite of arachidonic acid, significantly increased lactate dehydrogenase (LDH) release in these cells. When CP (10(-4) M) and 20-HETE (1, 10, 50 µM) were co-applied to these cells, CP-induced LDH release was significantly exaggerated by 20-HETE. Furthermore, clofibrate, a CYP4A inducer, also increased LDH release in CP-treated cells. In contrast, the CYP4A inhibitor N-Hydrocy-N'-(-4-butyl-2-methylphenyl) formamidine (HET-0016) decreased LDH release in CP-treated cells. Immunocytochemical analysis showed that CYP4A11expression was much stronger in CP-(10(-4) M) treated cells than that in clofibrate-treated cells. Further RT-PCR and Western blot analyses demonstrated that CYP4A11 mRNA and protein expression were significantly up-regulated in CP- (10(-4) M) treated cells compared to the clofibrate group. The findings of this study indicate that CP is a potent inducer of CYP4A11, and it exerts its toxic functions via the induction of CYP4A11 and 20-HETE generation.

Amlodipine prevents adriamycin-induced toxicity in cultured rat mesangial cells by up-regulation of Smad6, Smad7 expression.

Extensive studies have demonstrated that transforming growth factor-beta (TGF-ß) plays an important role in the progression of renal diseases. A central component of TGF-ß is the TGF-ß family-specific Smad signal transduction pathway. TGF-ß signals through Smad2, 4 to mediate renal fibrosis, whereas induction of Smad6, 7 inhibits renal fibrosis and inflammation. Amlodipine is the most frequently used antihypertensive drug among dihydropyridines. It is beneficial to the kidney and is widely used in treating kidney diseases. The aim of this study was to investigate effects of amlodipine on adriamycin-induced changes of lactate dehydrogenase (LDH) and expression of Smad6, 7 in rat mesangial cells. Results showed that amlodipine (10(-8) to 10(-5)mol/l) significantly decreased LDH activity in rat mesangial cells when given in combination with TGF-ß1 (P<0.01); amlodipine (10(-7), 10(-6)mol/l) significantly increased Smad6, 7 mRNA and protein expression in cells treated with adriamycin and TGF-ß1 (P<0.01). In conclusion, amlodipine protects against adriamycin-induced toxicity in rat mesangial cells by up-regulation of Smad6, 7 expressions.

Ligustrazine inhibits lipopolysaccharide-induced proliferation by affecting P27, Bcl-2 expression in rat mesangial cells.

Ligustrazine has a renoprotective effect against nephritis. In the present study, we investigated the roles of ligustrazine on lipopolysaccharide-induced changes of proliferation, cell cycle in cultured rat mesangial cells. 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay revealed that rat mesangial cells treated with lipopolysaccharide (10mg/l) underwent significant proliferation compared with control group. This effect was significantly inhibited by ligustrazine (400 to 2500 mg/l). Flow cytometric analysis revealed that cells treated with lipopolysaccharide showed significant reduction in the ratio of G0/G1 phase and significant elevation in the ratio of S+G2/M phase. The changes of cell cycle induced by lipopolysaccharide were reversed by ligustrazine. In addition, lipopolysaccharide suppressed P27 protein expression was significantly increased by ligustrazine (100, 500, 2500 mg/l). Moreover, rat mesangial cells treated with lipopolysaccharide showed scanty apoptosis with up-regulation of Bcl-2expression, while Bax protein expression was not changed. Ligustrazine (100, 500, 2500 mg/l) significantly reversed lipopolysaccharide-induced up-regulation of Bcl-2 protein and increased apoptotic cell death. In summary, ligustrazine displayed a significant inhibiting effect on lipopolysaccharide-induced proliferation through increasing P27 and decreasing Bcl-2 protein expression in rat mesangial cells.

Differential roles of dihydropyridine calcium antagonist nifedipine, nitrendipine and amlodipine on gentamicin-induced renal tubular toxicity in rats.

In the present study, we investigated the antioxidative potencies of dihydropyridine calcium antagonists prototype nifedipine, the second generation drug nitrendipine, and the long acting, third generation drug amlodipine on gentamicin-induced renal tubular toxicity in Sprague-Dawley rats. In addition, we analyzed the relationship between renal tubular cell apoptosis and the antioxidative properties of these dihydropyridine calcium antagonists. Results showed that treatment with gentamicin alone caused significant changes in the levels of urinary protein, urinary N-acetyl-beta-d-glucosaminidase, serum creatinine, and blood urea nitrogen. Nifedipine and amlodipine effectively reversed the effect of gentamicin on these parameters. In contrast, nitrendipine either had no effect or worsened gentamicin-induced changes in the levels of urinary protein, urinary N-acetyl-beta-d-glucosaminidase, serum creatinine, and blood urea nitrogen. Furthermore, gentamicin treatment caused significant increases in the levels of malondialdehyde, nitric oxide, nitric oxide synthase and significant decreases in the levels of reduced glutathione, glutathione-S-transferase, and superoxide dismutase in kidney tissues. These effects were dramatically reduced by nifedipine and amlodipine but not affected by nitrendipine. In addition to the biochemical changes, histopathological studies showed that gentamicin caused structural damages in the kidneys; renal tubular cell apoptosis, a decrease in Bcl-2 expression and an increase in Bax expression were observed in all rats treated with gentamicin, nifedipine and amlodipine effectively reversed the effect of gentamicin while nitrendipine worsened them. In conclusion, this study clearly indicated that nifedipine and amlodipine protected against gentamicin-induced nephrotoxicity while nitrendipine had little effect, or even worsened.