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911.
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913.
Siwen Dong Yujin Shi Xiaojing Dong Xia Xiao Jianli Qi Lili Ren Zichun Xiang Zhuo Zhou Jianwei Wang Xiaobo Lei 《The Journal of biological chemistry》2022,298(5)
Pyroptosis is an inflammatory form of programmed cell death that is executed by the gasdermin (GSDM)-N domain of GSDM family proteins, which form pores in the plasma membrane. Although pyroptosis acts as a host defense against invasive pathogen infection, its role in the pathogenesis of enterovirus 71 (EV71) infection is unclear. In the current study, we found that EV71 infection induces cleavage of GSDM E (GSDME) by using western blotting analysis, an essential step in the switch from caspase-3-mediated apoptosis to pyroptosis. We show that this cleavage is independent of the 3C and 2A proteases of EV71. However, caspase-3 activation is essential for this cleavage, as GSDME could not be cleaved in caspase-3-KO cells upon EV71 infection. Further analyses showed that EV71 infection induced pyroptosis in WT cells but not in caspase-3/GSDME double-KO cells. Importantly, GSDME is required to induce severe disease during EV71 infection, as GSDME deficiency in mice was shown to alleviate pathological symptoms. In conclusion, our results reveal that GSDME is important for the pathogenesis of EV71 via mediating initiation of pyroptosis. 相似文献
914.
The purpose of many microarray studies is to find the association between gene expression and sample characteristics such as treatment type or sample phenotype. There has been a surge of efforts developing different methods for delineating the association. Aside from the high dimensionality of microarray data, one well recognized challenge is the fact that genes could be complicatedly inter-related, thus making many statistical methods inappropriate to use directly on the expression data. Multivariate methods such as principal component analysis (PCA) and clustering are often used as a part of the effort to capture the gene correlation, and the derived components or clusters are used to describe the association between gene expression and sample phenotype. We propose a method for patient population dichotomization using maximally selected test statistics in combination with the PCA method, which shows favorable results. The proposed method is compared with a currently well-recognized method. 相似文献
915.
随着同步辐射光源(尤其是目前快速发展的第四代同步辐射光源)技术的进步,可用于实验的辐射通量越来越高,实验样品(特别是蛋白质等生物大分子样品)受到的辐照损伤也越来越严重。在全球现有的同步辐射装置上,蛋白质等生物大分子溶液专用小角X射线散射(SAXS)实验站的光子通量基本上都在1013cps量级。在如此高的通量下,蛋白质等生物大分子溶液样品在实验测量中受到的辐照损伤极其严重。如果没有有效的辐照防护措施,蛋白质溶液样品在毫秒级辐照时间内便会辐照损伤,导致不能获取有效的实验数据。辐照损伤严重制约了SAXS实验技术在蛋白质溶液样品方面的应用。因而,认识蛋白质溶液样品辐照损伤的产生机理、影响因素、判断标准,以及有效降低辐照损伤程度、延缓辐照损伤产生时间的方法,对于蛋白质等生物大分子溶液的散射实验具有重要的指导意义。本文在简要概述生物大分子溶液样品辐照损伤产生机理、影响因素、辐照剂量等基本概念的基础上,重点综述了同步辐射SAXS实验中辐照损伤的判断标准和防护措施。此外,本文还对比了各种防护措施的优缺点,讨论了在建HEPS新光源中SAXS束线可用的散射数据采集时间,指出辐照损伤防护剂是有价值的研究方向... 相似文献
916.
Amino acid starvation‐induced LDLR trafficking accelerates lipoprotein endocytosis and LDL clearance
Ye Chen Xiao Wu Jing Zhang Guopin Pan Xiaoyun Wang Xiaosun Guo Jianli Wang Xiaopei Cui Haiqing Gao Mei Cheng Jingwen Yang Cheng Zhang Fan Jiang 《EMBO reports》2022,23(3)
Mammalian cells utilize Akt‐dependent signaling to deploy intracellular Glut4 toward cell surface to facilitate glucose uptake. Low‐density lipoprotein receptor (LDLR) is the cargo receptor mediating endocytosis of apolipoprotein B‐containing lipoproteins. However, signaling‐controlled regulation of intracellular LDLR trafficking remains elusive. Here, we describe a unique amino acid stress response, which directs the deployment of intracellular LDLRs, causing enhanced LDL endocytosis, likely via Ca2+ and calcium/calmodulin‐dependent protein kinase II‐mediated signalings. This response is independent of induction of autophagy. Amino acid stress‐induced increase in LDL uptake in vitro is comparable to that by pravastatin. In vivo, acute AAS challenge for up to 72 h enhanced the rate of hepatic LDL uptake without changing the total expression level of LDLR. Reducing dietary amino acids by 50% for 2 to 4 weeks ameliorated high fat diet‐induced hypercholesterolemia in heterozygous LDLR‐deficient mice, with reductions in both LDL and VLDL fractions. We suggest that identification of signaling‐controlled regulation of intracellular LDLR trafficking has advanced our understanding of the LDLR biology, and may benefit future development of additional therapeutic strategies for treating hypercholesterolemia. 相似文献
917.
Jun Feng Lu Meng Qing Zhu Bao Cai Xie Xiao Chen Shi Huan Liu Rui Xin Zhang Bo Xia Jiang Wei Wu 《PLoS biology》2022,20(2)
Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15’s anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15’s specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight in rodents and nonhuman primates. This study reveals that the small molecule Camptothecin induces endogenous GDF15, suppressing food intake and reducing body weight in obese mice, suggesting a promising candidate for anti-obesity treatment. 相似文献
918.
Multiple evidence shows that metformin serves as a potential agent for Colorectal Cancer (CRC) treatment, while its molecular mechanisms still require detailed investigation. Here, we revealed that metformin specifically suppressed the proliferation of CRC cells by causing G1/S arrest, and INHBA is a potential target for metformin to play an anti-proliferation effect in CRC. We verified the oncogene role of INHBA by knocking down and overexpressing INHBA in CRC cells. Silencing INHBA abrogated the cell growth, while overexpression INHBA promotes the proliferation of CRC cells. As an oncogene, INHBA was aberrant overexpression in CRC tissues and closely related to the poor prognosis of CRC patients. In mechanism, INHBA is an important ligand of TGF-β signaling and metformin blocked the activation of TGF-β signaling by targeting INHBA, and then down-regulated the activity of PI3K/Akt pathway, leading to the reduction of cyclinD1 and cell cycle arrest. Together, these findings indicate that metformin down-regulates the expression of INHBA, then attenuating TGF-β/PI3K/Akt signaling transduction, thus inhibiting the proliferation of CRC. Our study elucidated a novel molecular mechanism for the anti-proliferation effect of metformin, providing a theoretical basis for the application of metformin in CRC therapy.Subject terms: Colorectal cancer, Cell growth, Target identification 相似文献
919.
Yaoqing Wang Xiao Zhang Haoya Yao Xiaocui Chen Lin Shang Ping Li Xiaojuan Cui Jia Zeng 《The Journal of biological chemistry》2022,298(3)
Diabetes normally causes lipid accumulation and oxidative stress in the kidneys, which plays a critical role in the onset of diabetic nephropathy; however, the mechanism by which dysregulated fatty acid metabolism increases lipid and reactive oxygen species (ROS) formation in the diabetic kidney is not clear. As succinate is remarkably increased in the diabetic kidney, and accumulation of succinate suppresses mitochondrial fatty acid oxidation and increases ROS formation, we hypothesized that succinate might play a role in inducing lipid and ROS accumulation in the diabetic kidney. Here we demonstrate a novel mechanism by which diabetes induces lipid and ROS accumulation in the kidney of diabetic animals. We show that enhanced oxidation of dicarboxylic acids by peroxisomes leads to lipid and ROS accumulation in the kidney of diabetic mice via the metabolite succinate. Furthermore, specific suppression of peroxisomal β-oxidation improved diabetes-induced nephropathy by reducing succinate generation and attenuating lipid and ROS accumulation in the kidneys of the diabetic mice. We suggest that peroxisome-generated succinate acts as a pathological molecule inducing lipid and ROS accumulation in kidney, and that specifically targeting peroxisomal β-oxidation might be an effective strategy in treating diabetic nephropathy and related metabolic disorders. 相似文献
920.
生态位分化是解释物种共存的重要理论。Schonenr认为空间维度对生态位差异形成的影响程度最高,营养维度次之,时间维度则最后被启动。为验证这一假说,我们于2018年12月至2019年11月,在浙江清凉峰国家级自然保护区龙塘山区域采用公里网格法布设52台红外相机,对同域分布且食性相似的黑麂和小麂种群进行监测,计算平均拍摄率,分析不同季节黑麂和小麂对不同植被类型、海拔、坡位、水源距离的选择差异,并运用核密度估计法分析二者日活动节律及重叠程度。结果显示,(1)黑麂和小麂对空间生态位的选择出现分化:黑麂偏好针阔混交林,主要栖息于1 301~1 500 m的高海拔地区,回避下坡位和谷地,在距离水源较近的区域内活动频繁;小麂则偏好落叶阔叶林,主要栖息于901~1 100 m的中海拔地区,偏好中坡位,回避谷地,对水源距离没有明显的选择倾向。(2)黑麂和小麂均为晨昏性活动的昼行性动物,二者全年日活动节律重叠程度较高(Δ4=0.86),仅冬季较低(Δ1=0.65)。上述结果支持Schonenr的假说:首先,空间维度对物种生态位分化的影响大于时间维度,龙塘山区域黑麂和小麂主要通过选择不同的栖息地来增加空间... 相似文献