Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation

Accumulating evidences showed metformin and berberine, well‐known glucose‐lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes. Glucose output was measured in primary hepatocytes. Compound C and adenoviruses expressing dominant negative AMP‐activated protein kinase (AMPK) α1/2 were exploited to inactivate AMPK pathway. Cellular NAD⁺/NADH ratio was assayed to evaluate energy transforming and redox state. Rotenone ameliorated hyperglycaemia and insulin resistance in db/db mice. It induced glucose consumption and glycolysis and reduced hepatic glucose output. Rotenone also activated AMPK. Furthermore, it remained effective with AMPK inactivation. The enhanced glycolysis and repressed gluconeogenesis correlated with a reduction in cellular NAD⁺/NADH ratio, which resulted from complex I suppression. Amobarbital, another representative complex I inhibitor, stimulated glucose consumption and decreased hepatic glucose output in vitro, too. Similar changes were observed while expression of NDUFA13, a subunit of complex I, was knocked down with gene silencing. These findings reveal mitochondrial complex I emerges as a key drug target for diabetes treatment. Inhibition of complex I improves glucose homoeostasis via non‐AMPK pathway, which may relate to the suppression of the cellular NAD⁺/NADH ratio.     

广东本地及移民学龄儿童饮食结构和肠道菌群差异分析

[目的]探究广东本地及移民学龄儿童的饮食结构及肠道菌群分布的差异.[方法]以广东深圳为采样点,随机抽样选取48名广东本地儿童和34名移民儿童,进行膳食问卷调查和晨便采集.采用Mann-Whitney U test分析本地及移民儿童饮食因子摄入频率的差异,并使用Illumina Miseq高通量测序技术对儿童的肠道菌群进...     

Synthesis,receptor binding studies,optical spectroscopic and in silico structural characterization of morphiceptin analogs with cis‐4‐amino‐L‐proline residues

Three novel morphiceptin analogs, in which Pro in position 2 and/or 4 was replaced by cis‐4‐aminoproline connected with the preceding amino acid through the primary amino group, were synthesized. The opioid receptor affinities, functional assay results, enzymatic degradation studies and experimental and in silico structural analysis of such analogs are presented. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.     

Adeno-associated viruses (AAV)

Recombinant adeno-associated virus derived vectors (rAAV) a thought to be a most promising candidates for gene therapy applications. Their nonpathogenic nature as well as the encouraging capability to infect both proliferating and non proliferating cells are advantages for gene therapy applications. Here, we summarize the potential mechanisms responsible for AAV maintenance and site-specific integration to human genome. The role of Rep proteins, inverted terminal repeats and p5 promotor sequences for chromosomal incorporation of AAV are discussed. Making the site-specific integrative recombinant AAV vectors for gene therapy seems to be closely dependent on the development of viral vectorology.     

The variation of 15 autosomal microsatellite DNA loci in five indigenous populations of South Siberia

The allele frequencies of 15 autosomal STR loci (D3S1358, vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317, D7S820, D16S539, D2S1338, D8S1179, D21S11, D18S51, and D19S433) included into the AmpFlSTR SGM Plus and AmpFlSTR Profiler Plus kits (Applied Biosystems, United States) were determined for five indigenous populations of South Siberia: Buryats, Altaians, Tofalars, Sojots, and Khakassians (N = 261). No significant differences in allele frequencies were found between the populations. The combined power of discrimination of the STR loci was determined for every population.     

克山病是一种“心肌线粒体病(Mitochondrial Cardiomyopathy)”

亚急克病人心肌线粒体内膜电子传递链的琥珀酸氧化酶系,琥珀酸脱氢酶和细胞色素氧化酶活性明显低于对照。H~ -ATP酶的活性及其对寡霉素的敏感性都明显下降。ATP能量化后线粒体膜电位的变化也比对照明显降低。膜脂流动性低于对照。亚急克病人心肌线粒体内观察到较多的电子致密无定形物质,经电镜X射线微区等方法分析,认为这些物质不是Ca_3(PO_4)_2,而可能是一种蛋白质凝聚物。此外,心肌线粒体的硒含量远低于对照,而Ca含量明显高于对照。上述结果都反映亚急克病人心肌线粒体明显损伤。根据克山病患者心肌细胞线粒体结构与功能方面呈现的如此广泛与明显的异常,可将克山病称为“心肌线粒体病(Mitochondrial Cardiomyopathy)”。     

IGFBP‐4 enhances VEGF‐induced angiogenesis in a mouse model of myocardial infarction

Vascular endothelial growth factor (VEGF) is a well‐known angiogenic factor, however its ability in promoting therapeutic angiogenesis following myocardial infarction (MI) is limited. Here, we aimed to investigate whether dual treatment with insulin‐like growth factor binding protein‐4 (IGFBP‐4), an agent that protects against early oxidative damage, can be effective in enhancing the therapeutic effect of VEGF following MI. Combined treatment with IGFBP‐4 enhanced VEGF‐induced angiogenesis and prevented cell damage via enhancing the expression of a key angiogenic factor angiopoietin‐1. Dual treatment with the two agents synergistically decreased cardiac fibrosis markers collagen‐I and collagen‐III following MI. Importantly, while the protective action of IGFBP‐4 occurs at an early stage of ischemic injury, the action of VEGF occurs at a later stage, at the onset angiogenesis. Our findings demonstrate that VEGF treatment alone is often not enough to protect against oxidative stress and promote post‐ischemic angiogenesis, whereas the combined treatment with IGFBP4 and VEGF can utilize the dual roles of these agents to effectively protect against ischemic and oxidative injury, and promote angiogenesis. These findings provide important insights into the roles of these agents in the clinical setting, and suggest new strategies in the treatment of ischemic heart disease.