Inhibition of SIRT2 by Targeting GSK3ß-Mediated Phosphorylation Alleviates SIRT2 Toxicity in SH-SY5Y Cells.

Sirtuin 2 (SIRT2) is thought to be important in the pathogenesis of Parkinson's disease (PD), and the inhibition of SIRT2 rescues α-synuclein toxicity in a cellular model of PD. Recent studies have focused on identifying inhibitors of SIRT2, but little is known about the processes that directly regulate its function. GSK3ß is a serine/threonine protein kinase that affects a wide range of biological functions, and it is localized in Lewy bodies (LBs). Therefore, we investigated whether SIRT2 is regulated by GSK3ß and enhances cell death in PD. In the present study, Western blot showed that total SIRT2 levels did not change noticeably in a cellular model of PD but that SIRT2 phosphorylation was increased, and GSK3ß activity was elevated. In addition, mass spectrometry (MS) studies indicated that SIRT2 was phosphorylated by GSK3ß at three specific sites. Phospho- or dephospho-mimicking studies demonstrated that this postmodification (phosphorylation) increased SIRT2 toxicity in SH-SY5Y cells. Collectively, our findings identify a posttranslational mechanism that controls SIRT2 function in PD and provide evidence for a novel regulatory pathway involving GSK3ß, SIRT2, and α-synuclein.

Exploring HIV prevention strategies among street-based female sex workers in Chongqing, China.

BACKGROUND: Commercial sex plays an increasingly important role in China's growing HIV and sexually transmitted infection (STI) epidemics. In China, street-based sex workers (SSWs) are a subgroup of female sex workers with a particularly high risk of HIV/STI infections but are neglected in responses to HIV. This study assesses changes in HIV voluntary counseling and testing (VCT) utilization and high-risk sexual behaviors following a three-month HIV preventive intervention among SSWs in Chongqing, China. METHODS: A three-month intervention was conducted by a team of peer educators, outreach workers from community-based organizations and health professionals. It mainly included distribution of free pamphlets and condoms and delivery of onsite and clinic-based VCT. Cross-sectional surveys were conducted prior to (n = 100) and immediately following (n = 112) the intervention to assess its impact. In-depth interviews were conducted among 12 SSWs after the intervention to further explore potential barriers to HIV prevention. RESULTS: The intervention significantly increased SSWs' participation in VCT (from 2.0%-15.2%, P < 0.001). Despite participants' improved HIV-related knowledge level (from 24.0%-73.2%, P < 0.001), there were minimal changes in the levels of condom use with clients. Qualitative research revealed that fear of police arrest and stigma were the main barriers to VCT utilization. Low condom use was associated with family financial constraints, inadequate power in condom negotiation, low awareness and misconceptions of HIV infection risks. CONCLUSION: HIV intervention improved VCT utilization and knowledge but we did not observe an increase in condom use after this short intervention. SSWs faced substantial economic, social and environmental barriers to VCT utilization and condom use.

miR-124 represses ROCK1 expression to promote neurite elongation through activation of the PI3K/Akt signal pathway.

Recent studies have demonstrated an important role for miR-124, the most abundant and well-conserved brain-specific microRNA(miRNA), in promoting neurite outgrowth and elongation during neuronal differentiation. This miRNA's target genes and the mechanisms that execute this role remain unclear. In this study, we identified ROCK1, a small GTPase Rho kinase, as a direct target of miR-124 for regulating neurite elongation. miR-124 significantly inhibited ROCK1 expression in M17 cells. Inhibiting ROCK1 promoted neurite elongation, and the overexpression of ROCK1 strongly repressed the neurite elongation-enhancing effect of miR-124 in M17 cells. We determined that Akt functions as a novel ROCK1 downstream effector in regulating neurite outgrowth and elongation.

[Effects of peroxisome proliferator-activated receptors γ on the expression of insulin receptor substrate-4 gene in rat cortical neurons and mouse brain].

OBJECTIVE: To investigate the effect of peroxisome proliferator-activated receptors γ (PPARγ) on insulin receptor substrate-4 (IRS-4) gene expression in the brain. METHODS: Primarily cultured cortical neurons from E17-18 Sprague Dawley rats, after 1 week of plating, were exposed to 10 µmol/L PPARγ agonist rosiglitazone for 0, 1, 4 or 24 h. Adult C57BL/6J mice or conditional brain PPARγ knock-out mice (B-PPARγ-KO, BKO) received an intraperitoneal injection of rosiglitazone in 10% DMSO at 12 mg/kg or injection of the same volume of saline containing 10% DMSO. The effect of rosiglitazone on the survival of the neurons was examined by MTT assay. The expression of IRS-4 mRNA was analyzed by real-time quantitative PCR. RESULTS: The survival of the cortical neurons showed no significant difference between the agonist groups and the control group. The expression of IRS-4 mRNA was significantly up-regulated in the cortical tissues and neurons of the agonist groups compared with the control groups (P<0.05), but in BKO mice without treatment, IRS-4 mRNA expression was significantly down-regulated (P<0.05). CONCLUSION: PPARγ can enhance the expression of IRS-4 mRNA in the brain.

Tumor necrosis factor-α gene polymorphisms and risk of oral cancer: evidence from a meta-analysis.

Numerous studies have been conducted regarding association between TNF-α and oral cancer risk, but the results remain controversial. The present meta-analysis is performed to acquire a more precise estimation of relationships. Databases of Pubmed, the Cochrane library and the China National Knowledge Internet (CNKI) were retrieved until August 10, 2013. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated with fixed- or random-effect models. The heterogeneity assumption was assessed by I-squared test. Among the eight included case-control studies, all were focused on TNF-α-308G>A and four also concerned the TNF-α-238G>A polymorphism. It was found that oral cancer risk were significant decreased with the TNF-α-308G>A polymorphism in the additive genetic model (GG vs. AA, OR=0.19, 95% CI: [0.04, 1.00], P=0.05, I2=68.9%) and the dominant genetic model (GG+GA vs. AA, OR=0.22, 95% CI: [0.06, 0.82], P=0.03, I2=52.4%); however, no significant association was observed in allele contrast (G vs. A, OR=0.70, 95% CI: [0.23, 2.16], P=0.54, I2=95.9%) and recessive genetic models (GG vs. GA+AA, OR=0.72, 95% CI: [0.33, 1.57], P=0.41, I2=93.1%). For the TNF-α-238G>A polymorphism, significant associations with oral cancer risk were found in the allele contrast (G vs. A, OR=2.75, 95% CI: [1.25, 6.04], P=0.01, I2=0.0%) and recessive genetic models (GG vs. GA+AA, OR=2.23, 95%CI: [1.18, 4.23], P=0.01, I2=0.0%). Conclusively, this meta-analysis indicates that TNF-α polymorphisms may contribute to the risk of oral cancer. Allele G and the GG+GA genotype of TNF-α- 308G>A may decrease the risk of oral cancer, while allele G and the GG genotype of TNF-α-238G>A may cause an increase.

Association between tumor necrosis factor alpha-238G/a polymorphism and tuberculosis susceptibility: a meta-analysis study.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) plays a key role in the containment of tuberculosis. The relationship between the TNF -238G/A polymorphism and tuberculosis susceptibility remains inconclusive. A comprehensive meta-analysis was made to provide a more precise estimate of the relationship between them. METHODS: Multiple search strategies were used. A fixed effect model was takentook to estimate pooled OR with 95% confidence interval (CI) for the association between the TNF -238G/A polymorphism and tuberculosis susceptibility. The Chi-squared-based Q-test and I-squaredI2 statistic were calculated to examine heterogeneity. Begg's funnel plot and Egger's test were used to assess publication bias. RESULTS: 9 case-control studies were included in this meta-analysis. No significant heterogeneity was demonstrated, and no obvious publication bias was detected among the included studies. The meta-analysis indicated that there was no significant association between the TNF -238G/A polymorphism and tuberculosis susceptibility (GA+AA versus GG model: OR=1.005, 95% CI: 0.765-1.319; A versus G model: OR=1.000, 95% CI: 0.769-1.300). In the subgroup analyses by ethnicity, types of TB and human immunodeficiency virus (HIV) status, no significant association were identified. CONCLUSIONS: The meta-analysis involving 2723 subjects did not detect any association between the TNF -238G/A polymorphism and tuberculosis susceptibility.

Awareness and knowledge of schistosomiasis infection and prevention in the "Three Gorges Dam" reservoir area: a cross-sectional study on local residents and health personnel.

BACKGROUND: Schistosomiasis is a severe public health problem in China. It has been predicted that the ecological changes caused by the "Three Gorges Dam", the world's largest hydropower project, could potentially aggravate the spread of schistosomiasis in the area. This study focused on investigating (a) local residents' knowledge on the potential risks of schistosomiasis and (b) the capability of local health personnel in preventing schistosomiasis. MATERIALS AND METHODS: A quantitative survey combined with qualitative interviews was conducted in three counties of the reservoir area during November and December 2008. A total of 1386 inhabitants and 180 local health personals participated in questionnaire survey; 18 inhabitants, 21 health professionals, and 8 local government officials were interviewed. RESULTS: Of the surveyed inhabitants, 66.3% had no access to safe drinking water; 47.9% had water-contact regularly through farming or swimming; 58.7% did not have hygienic toilets; and only 13.7% used methane for energy. Besides, only 3.8% of the inhabitants had knowledge scores higher than 6 points within the range 0-10. Educational level, occupation and income were significant predictors of knowledge score (P<0.05). Only about 5% of the inhabitants had some knowledge on schistosomiasis. Among health professionals surveyed, 6.7% had college or higher education; 26.7% had prior schistosomiasis control experience; 75.6% did not receive any relevant training in the past year; and only 52.2% had basic knowledge of schistosomiasis. The logistic regression analysis identified occupation and time at work as significant factors to their knowledge level (P<0.05). Moreover, the surveillance work was often severely hindered by a shortage of funding, and challenged by monitoring of migrant population. There were very limited training opportunities for the health workers, and almost no health education for inhabitants, if any, neither efficient nor effective. CONCLUSION: Although there were multiple risks for potential Schistosoma japonicum infections in the study area, the knowledge level on schistosomiasis and surveillance was relatively low both in local residents and health personnel. Thus, more health education and professional training are urgently required to local residents and health personnel, respectively. By considering limited activities in surveillance and health education been implemented, a strategy plan on intervention to ensure a stronger inter-sectoral cooperation is recommended in order to reduce schistosomiasis transmission risks in this area.