炎症和肥胖

近来研究表明：脂肪和巨噬细胞之间存在惊人的相似之处。这个结论引发人们猜测：炎症反应也许是连接肥胖和糖尿病的桥梁。     

Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKε

Arenaviruses perturb innate antiviral defense by blocking induction of type I interferon (IFN) production. Accordingly, the arenavirus nucleoprotein (NP) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (IRF3) in response to virus infection. Here, we sought to identify cellular factors involved in innate antiviral signaling targeted by arenavirus NP. Consistent with previous studies, infection with the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) prevented phosphorylation of IRF3 in response to infection with Sendai virus, a strong inducer of the retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS) pathway of innate antiviral signaling. Using a combination of coimmunoprecipitation and confocal microscopy, we found that LCMV NP associates with the IκB kinase (IKK)-related kinase IKKε but that, rather unexpectedly, LCMV NP did not bind to the closely related TANK-binding kinase 1 (TBK-1). The NP-IKKε interaction was highly conserved among arenaviruses from different clades. In LCMV-infected cells, IKKε colocalized with NP but not with MAVS located on the outer membrane of mitochondria. LCMV NP bound the kinase domain (KD) of IKKε (IKBKE) and blocked its autocatalytic activity and its ability to phosphorylate IRF3, without undergoing phosphorylation. Together, our data identify IKKε as a novel target of arenavirus NP. Engagement of NP seems to sequester IKKε in an inactive complex. Considering the important functions of IKKε in innate antiviral immunity and other cellular processes, the NP-IKKε interaction likely plays a crucial role in arenavirus-host interaction.     

连接肥胖和糖尿病的激素——抵抗素

2型糖尿病的发生主要是因为组织对胰岛素抵抗的缘故,往往与肥胖症相伴随,肥胖引起胰岛素抵抗的确切机制尚不清楚。抵抗素（resistin)是新近发现的一种由脂肪细胞分泌的激素,其作用是对抗胰岛素,使血糖水平升高,脂肪细胞增生繁殖而致肥胖,是糖尿病和肥胖症研究领域的突破性进展。抵抗素的发现对于糖尿病的治疗具有重要的指导意义。     

肥胖与慢性炎症

肥胖及其相关的代谢类疾病严重影响人类的健康,而肥胖诱导的慢性炎症是胰岛素抵抗和代谢综合症发病的关键因素.脂肪组织慢性炎症发生的机制及其与代谢综合症的关系已经成为全球瞩目的研究热点.慢性炎症的特征主要包括脂肪组织中促炎细胞因子表达量增加,抗炎细胞因子表达量降低以及大量巨噬细胞浸润.鉴于肥胖及其相关代谢综合症对人类健康的巨大危害,现对慢性炎症的发生机制,肥胖和慢性炎症之间的关系,脂肪组织炎症中巨噬细胞浸润以及和信号传导通路进行综述.     

肥胖与慢性炎症的研究进展

肥胖常伴随着一系列代谢综合征的发生,肥胖引起的慢性炎症因为与各种代谢综合征的密切联系而成为目前的研究热点。慢性炎症的发生很复杂,涉及多个组织、器官和系统,并且炎症的发生会反过来影响组织的功能。目前针对慢性炎症发生机制的研究结果显示脂肪因子和免疫系统、内质网应激、细胞自噬作用以及内毒素的作用等形成的信号网络参与了慢性炎症的触发和发展。本文就慢性炎症与肥胖关联的几种可能发生机制的最新研究进展作一简要综述。     

Development of a High-Throughput Assay for Identifying Inhibitors of TBK1 and IKKε

IKKε and TBK1 are noncanonical IKK family members which regulate inflammatory signaling pathways and also play important roles in oncogenesis. However, few inhibitors of these kinases have been identified. While the substrate specificity of IKKε has recently been described, the substrate specificity of TBK1 is unknown, hindering the development of high-throughput screening technologies for inhibitor identification. Here, we describe the optimal substrate phosphorylation motif for TBK1, and show that it is identical to the phosphorylation motif previously described for IKKε. This information enabled the design of an optimal TBK1/IKKε substrate peptide amenable to high-throughput screening and we assayed a 6,006 compound library that included 4,727 kinase-focused compounds to discover in vitro inhibitors of TBK1 and IKKε. 227 compounds in this library inhibited TBK1 at a concentration of 10 μM, while 57 compounds inhibited IKKε. Together, these data describe a new high-throughput screening assay which will facilitate the discovery of small molecule TBK1/IKKε inhibitors possessing therapeutic potential for both inflammatory diseases and cancer.     

青蒿素类化合物与肥胖诱导的代谢性炎症

青蒿素类化合物是治疗疟疾的首选药物,具有高效、速效、低毒和安全的特点。近三十年来,大量研究结果证明青蒿素类化合物具有抗炎和免疫调节功能;这些研究主要集中于自身免疫性疾病,如类风湿性关节炎、全身性红斑狼疮、哮喘病和过敏反应等。最新研究表明,青蒿素类化合物可通过促进白色脂肪棕色化和增强棕色脂肪功能,起到预防肥胖的作用。作为肥胖过程中免疫细胞和炎症状况变化显著的脂肪组织,青蒿素类化合物是否参与其中的免疫炎症调节以及在该过程中发挥的潜在作用有待进一步实验的验证。本文对已有的青蒿素类化合物在抗炎和免疫调节方面的报道进行总结,并对青蒿素类化合物在改善肥胖诱导代谢性炎症方面的潜在应用进行展望。     

IKKα的研究进展

IκB激酶(IKK复合体)是NF-κB信号转导途径成员之一,包括3个亚基:催化亚基IKKα、IKKβ和调节亚基IKKγ。无刺激时,NF-κB与抑制蛋白IκB家族的一个成员结合,或者与无活性前体(如p100)结合而以无活性形式存在。在外界信号如TNF-α或淋巴毒素β等刺激下,经过复杂的信号转导,IKK复合体被激活,导致IκB和(或)p100发生磷酸化,结果NF-κB被释放出来,进入细胞核内激活靶基因。最新研究发现在TNF-α刺激下,IKKα可直接进入细胞核内,通过催化组蛋白H3磷酸化进而激活特定NF-κB应答基因的表达。IKKα是首次发现的信号转导途径中直接进入细胞核内调节基因表达的上游成分,为NF-κB信号转导途径的研究开辟了新的道路。     

肥胖、炎症与认知功能的相关性研究进展

肥胖与多种疾病的发生密切相关且严重影响人类健康,而肥胖者机体的长期慢性炎症可能导致认知功能障碍。肥胖、炎症与认知功能障碍发生的关系复杂且尚未得到全面确切的阐述。研究普遍认为,肥胖能够促进机体多种炎性因子的分泌,并通过炎性因子诱发肥胖相关并发症,或调节炎症信号通路、激活神经细胞、引发神经炎症等途径,继而影响脑部功能,导致认知障碍。本文就现有研究对肥胖、炎症和认知功能的相关性作简要综述。     

从岩石圈到生物圈 岩溶,连接无机和有机世界的桥梁

正附存在碳酸盐岩中是碳,是地球最大的碳库,其碳量达6.0×108亿吨,占地球总碳量的99.5%,是海洋和陆地植被碳库的1562倍和3.0×104倍。在地球演化的历史长河中,古老的硅酸盐岩风化消耗大气CO_2,在生物作用下,将地球大气CO_2转化为有机碳和无机碳,其转化的结果是,地球大气CO_2浓度由原始大气的25%降低到现代大气的0.03%。而根据化     

肠道菌群介导肥胖结肠癌患者的炎症和肠道通透性改变的机制研究

目的研究肠道菌群介导肥胖结肠癌患者的炎症和肠道通透性改变的机制研究。方法收集患有(OB-CRC)和没有肥胖症(L-CRC)的肠癌患者粪便样本,肥胖健康对照组(L-HC)的粪便样本作为对照。16S rRNA测序分析各组的种群数量和种类。酶联免疫吸附测定法测定患者血清人连蛋白、IL-10和IL-1β的水平。LC-MS(ESI-MS)检测氧化三甲胺的血清浓度。结果肥胖的存在并没有引起CRC患者肠道细菌多样性和丰富度的显著变化。然而,OB-CRC患者表现出特定的肠道微生物群,其特征是产生丁酸盐的细菌减少和机会致病菌过多。促炎细胞因子IL-1β水平明显升高,有害的细菌代谢物TMAO,以及这些病人的肠道通透性明显增加。结论肥胖相关的肠道菌群可能在结肠癌的炎症反应和改变肠道通透性的发展中起到关键作用,这为临床采用新的结肠癌预防诊断工具提供了新的理论依据。     

脂肪细胞特性及其在肥胖相关炎症中的作用

在肥胖症中,脂肪组织中低度慢性炎症的积累可导致脂肪组织功能障碍和全身能量代谢失衡。低度全身炎症可能与一些代谢紊乱或心血管疾病和其他慢性疾病的恶化有关。脂肪细胞具有复杂的生物学特性,能够选择性地激活不同的代谢途径以响应环境刺激。研究表明,脂肪细胞在适当的刺激下可以容易地分化和去分化,从而根据代谢需要将自身转化成不同的表型。虽然其潜在的机制尚未完全明了,但脂肪细胞大小的增加和在过量喂养下不能储存甘油三酯对代谢功能失调至关重要,并表现为以炎症和凋亡途径激活及促炎脂肪因子分泌为特征。在肥胖症中,脂肪因子分泌的改变、脂肪细胞失衡和脂肪酸释放到循环系统中,有助于维持免疫细胞的激活和浸润到组织器官。最近研究发现,脂肪细胞还参与调节与肥胖炎症相关的巨噬细胞、中性粒细胞和调节性T细胞等免疫细胞的活性。了解脂肪细胞调节途径和去分化过程可能有助于研究抑制肥胖相关炎症和相关代谢紊乱的新策略。     

肿瘤防治新靶向:炎症和微生物

近年来,炎症逐渐成为相关肿瘤发生不可忽视的重要因素。研究发现:炎症诱导肿瘤的发生主要通路为NF-κB–IL6–STAT3途径,同时微生物和炎症介导的肿瘤发生之间也存在一定的联系。这些研究为癌症的治疗提供了新的理论基础,文章中阐述了NF-κB–IL6–STAT3通路在炎症诱导肿瘤发生中的重要作用以及引起相关炎症的微生物活动,提出了肿瘤治疗的新方向。     

大学生创新性实验——连接教学与科研的桥梁

我系以"国家大学生创新性实验计划"为契机,根据已有的工作基础,结合教育部与西安交通大学的计划,建立了以"大学生创新性实验计划"为核心的阶梯式培养体系。从"开放实验日""开放实验项目""校级大学生创新性实验项目"到"国家大学生创新性实验计划"渐次递进,以激发学生的学习兴趣和原动力,并培养学生的动手和创新能力,为《生物化学》与《分子生物学》教学与科学研究之间架起一座桥梁。     

Evasion of Antiviral Immunity through Sequestering of TBK1/IKKε/IRF3 into Viral Inclusion Bodies

Cells are equipped with pattern recognition receptors (PRRs) such as the Toll-like and RIG-I-like receptors that mount innate defenses against viruses. However, viruses have evolved multiple strategies to evade or thwart host antiviral responses. Viral inclusion bodies (IBs), which are accumulated aggregates of viral proteins, are commonly formed during the replication of some viruses in infected cells, but their role in viral immune evasion has rarely been explored. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging febrile illness caused by a novel phlebovirus in the Bunyaviridae. The SFTS viral nonstructural protein NSs can suppress host beta interferon (IFN-β) responses. NSs can form IBs in infected and transfected cells. Through interaction with tank-binding kinase 1 (TBK1), viral NSs was able to sequester the IKK complex, including IKKε and IRF3, into IBs, although NSs did not interact with IKKε or IRF3 directly. When cells were infected with influenza A virus, IRF3 was phosphorylated and active phosphorylated IRF3 (p-IRF3) was translocated into the nucleus. In the presence of NSs, IRF3 could still be phosphorylated, but p-IRF3 was trapped in cytoplasmic IBs, resulting in reduced IFN-β induction and enhanced viral replication. Sequestration of the IKK complex and active IRF3 into viral IBs through the interaction of NSs and TBK1 is a novel mechanism for viral evasion of innate immunity.     

S-亚硝基化与肥胖诱导炎症下的内质网应激障碍

<正>炎症与内质网应激(ERS)之间在多种疾病中存在密切联系,然而慢性炎症是否参与对未折叠蛋白反应(UPR)及内质网稳态的调控及其具体机制尚不清楚。最近,来自哈佛大学、哥伦比亚大学及清华大学的联合研究团队发表在《科学》(Science)杂志上的文章发现,肥胖诱导的慢性炎症可以上调肝脏中UPR反应关键因子肌醇依赖酶1(IRE1α)的亚硝基化,进而导致X盒结合蛋白1(XBP1)剪切降低引起糖代谢紊乱等功能障碍。