HDAC6 promotes sepsis development by impairing PHB1-mediated mitochondrial respiratory chain function.

OBJECTIVE: This study was aimed at investigating the regulation of mitochondrial function by histone deacetylase 6 (HDAC6) and the role of HDAC6 in the development and progression of sepsis. RESULTS: HDAC6 downregulated PHB1 and subsequently promoted the development of CLP-induced sepsis. Inhibition of HDAC6 significantly attenuated CLP-induced sepsis through inhibition of mitochondrial dysfunction and reduced oxidant production, thus protecting the rats from oxidative injury. CONCLUSIONS: In this sepsis model, HDAC6 inhibits the expression and function of PHB1 and alters the function of the mitochondrial respiratory chain mediated by PHB1, thus enhancing the production of oxidants and increasing oxidative stress and thereby leading to severe oxidative injury in multiple organs. METHODS: The expression of HDAC6 and prohibitin 1 (PHB1) in humans and in a rat model of sepsis was measured by quantitative reverse-transcription PCR and western blotting. Sepsis induction by cecal ligation and puncture (CLP) was confirmed by histological analysis. Concentrations of different sepsis markers were measured by an enzyme-linked immunosorbent assay, and mitochondrial function was assessed via the mitochondrial respiratory control rate.

Interaction of type 2 diabetes mellitus with chromosome 9p21 rs10757274 polymorphism on the risk of myocardial infarction: a case-control study in Chinese population.

BACKGROUND: Myocardial infarction (MI) is a serious complication of Coronary Artery Disease (CAD). Previous studies have identified genetic variants on chromosome 9p21 and 6p24 that are associated with CAD, but further studies need to be conducted to investigate whether these genetic variants are associated with the pathogenesis of MI. We therefore performed this study to assess the association between the risk of MI and SNP rs10757274 on chromosome 9p21 and SNP rs6903956 on chromosome 6p24, and to explore the gene-environment interactions in a Chinese population. METHODS: A hospital-based case-control study, consisting of 502 MI patients and 308 controls, was conducted in a Chinese population. Demographic, behavioral information and clinical characteristics were collected, and genotyping of the two SNPs was performed using single base primer extension genotyping technology. The unconditional logistic regression (ULR) method was adopted to assess the association of the two SNPs with MI risk. Both generalized multifactor dimensionality reduction (GMDR) and ULR methods were applied to explore the effect of gene-environment interactions on the risk of MI. RESULTS: After adjusting for covariates, it was observed that SNP rs10757274 on chromosome 9p21 was significantly associated with MI. Compared with subjects carrying the AA genotype, subjects carrying the GA or GG genotypes had a higher MI risk (ORa = 1.52, 95% CI:1.06-2.19, pa = 0.0227; ORa = 2.40, 95% CI:1.51-3.81, pa = 0.0002, respectively). Furthermore, a two-factor gene-environment interaction model of CDKN2A/B (rs10757274) and type 2 diabetes mellitus (T2DM) was identified to be the best model by GMDR (p = 0.0107), with a maximum prediction accuracy of 59.18%, and a maximum Cross-validation Consistency of 10/10. By using the ULR method, additive interaction analysis found that the combined effect resulted in T2DM-positive subjects with genotype GG/GA having an MI risk 4.38 times that of T2DM-negative subjects with genotype AA (ORadd = 4.38, 95% CI:2.56-7.47, padd < 0.0001). CONCLUSIONS: These results show that gene polymorphism of CDKN2A/B (rs10757274) is associated with MI risk in a Chinese population. Furthermore, T2DM is likely to have an interaction with CDKN2A/B (rs10757274) that contributes to the risk of MI.

Association analysis of common genetic variations in MUC5AC gene with the risk of non-cardia gastric cancer in a Chinese population.

Several lines of evidence suggest that genetic variation in MUC5AC gene might contribute to the risk of gastric cancer. We conducted a case-control study to evaluate the relationship between common genetic variations in MUC5AC gene and non-cardia gastric cancer using an LD-based tagSNP approach in Baotou, north-western China. We genotyped 12 tagSNPs by TaqMan method among 288 cases with non-cardia gastric cancer and 281 normal controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for non-cardia gastric cancer risk in association with alleles, genotypes and haplotypes. We observed that the frequencies of rs3793964 C allele and rs11040869 A allele were significantly lower in cases than in controls. Meanwhile, minor allele homozygotes of rs3793964 and rs11040869 were significantly associated with a decreased risk of non-cardia gastric cancer when compared with their major allele homozygotes. Furthermore, a statistically significantly protective effect of rs885454 genotypes on non-cardia gastric cancer was also observed (for CT vs. CC: OR=0.581, 95%CI=0.408-0.829; for CT/TT vs. CC: OR=0.623, 95%CI=0.451-0.884). Our results indicated that some common genetic variations in the MUC5AC gene might have effects on the risk of non-cardia gastric cancer in our studied population.

Common genetic variations in the MUC5AC gene are not related to helicobacter pylori serologic status.

Several lines of evidence suggest that MUC5AC genetic polymorphisms might confer susceptibility to H. pylori infection and therefore gastric cancer risk. We here assessed the association of common polymorphisms in the MUC5AC gene with H. pylori seroprevalence using an LD-based tagSNP approach in a north-western Chinese Han population. A total of 12 tagSNPs were successfully genotyped among 281 unrelated ethnic Han Chinese who had no cancer history, and no identifiable gastric disease or genetic disease. No significant association between any alleles, genotypes or haplotypes and H. pylori seroprevalence was observed. Our results suggest that common genetic variations in MUC5AC gene might not make a major contribution to the risk of H. pylori infection.

miR395 is involved in detoxification of cadmium in Brassica napus.

The toxic metal cadmium (Cd) constitutes one of the major inorganic contaminants in environments. microRNAs (miRNAs) are a class of endogenous non-coding small RNAs. miR395 is conserved and regulates sulfate assimilation and distribution in higher plants, but whether it is involved in detoxification of Cd in plants has not been described. In this study, transgenic rapeseed (Brassica napus) over-expressing miR395 was identified under Cd stress. miR395-over-expressing plants showed a lower degree of Cd-induced oxidative stress than wild type. By contrast, chlorophyll, glutathione and non-protein thiols contents were higher in the transformants than wild type. Determination of growth response showed that 35S::MIR395 plants accumulated higher levels of biomass and sulfur than wild type under Cd exposure. miR395 transgenic plants had higher levels of Cd in plants, particularly at the high supply of Cd in the medium, but they tended to repress Cd translocation from roots to shoots. Simultaneously, expression of metal-tolerance genes such as BnPCS1, BnHO1 and Sultr1;1 was up-regulated under Cd stress, and the expression of the genes was more pronounced in 35S::MIR395 plants than in wild type. These results suggest that miR395 would be involved in detoxification of Cd in B. napus.