HMGB1蛋白在病毒感染致病机制中的作用研究进展

高迁移率族蛋白1(HMGB1)是一种高度保守的核蛋白,广泛存在于哺乳动物细胞内,在核内参与核小体的构建与稳定以及基因的转录,核外参与介导炎症反应。近年多项研究表明,HMGB1参与了多种病毒(SARS、HIV、HPV、HSV等)感染的致病过程,本文就其研究进展作一综述。     

HMGB1在角膜损伤和修复中的作用研究进展

角膜是眼部抵御外来病原微生物侵入的重要屏障,其完整性与眼部健康密切相关。角膜发生损伤后,其自身会进行修复和重新上皮化,该过程常伴随炎症反应及炎症介质的释放。适度的炎症反应可促进损伤修复,而过度炎症反应会伴有大量炎症介质的释放,加剧角膜损伤。高迁移率族蛋白1 (high mobility group box 1, HMGB1)是参与角膜组织损伤和修复过程的常见炎症介质之一,过度表达的HMGB1可加剧角膜修复过程中的瘢痕化,导致角膜透明度降低,对疾病的转归产生负面影响。因此,干扰HMGB1有望成为治疗角膜损伤的新方式。本文从HMGB1的结构与功能、HMGB1在角膜损伤及修复中的作用、HMGB1的调控及其在角膜疾病中的应用三个方面进行回顾和总结。     

HMGB1在抗肿瘤免疫发生中的作用

高迁移率族蛋白B1(high mobility group box 1, HMGB1)是一种广泛分布于哺乳动物细胞的高度保守的核蛋白。HMGB1对肿瘤的发生发展具有一定的影响,能够通过多种信号分子途径来促进肿瘤的增殖、迁移和侵袭等。随着相关研究的不断深入,人们发现,HMGB1与免疫细胞抗肿瘤作用的发挥也有密切联系。因此,HMGB1有望成为肿瘤免疫治疗的重要靶点之一。然而,HMGB1生物学功能复杂,对肿瘤免疫的影响作用也不单一。为了更好地将HMGB1应用于肿瘤治疗,本文就HMGB1在抗肿瘤免疫发生中的作用及其机制的研究进展作一综述。     

高迁移率族蛋白B1在炎症性疾病中的研究进展

高迁移率族蛋白B1(high mobility group box 1 protein,HMGB1)是广泛存在于真核细胞核内的非组蛋白染色体结合蛋白,因其在聚丙烯酰胺凝胶电泳(PAGE)中迁移速度快而得名。近年来的研究表明,HMGB1作为一种重要的晚期炎症介质,在多种急慢性炎症中均有表达。本文就高迁移率族蛋白B1的结构、释放、致炎作用、与炎症性疾病的关系以及炎症时对高迁移率族蛋白B1的干预措施等方面研究近况做一综述。     

HMGB1与冠心病关系的研究进展

高迁移率族蛋白B1(high mobility group box1protein,HMGB1)是一种高度保守的核内非组蛋白,可由致病因素引发细胞被动释放或损伤、凋亡和坏死细胞主动分泌而产生。HMGB1可以在真核细胞坏死过程中被释放到细胞外。越来越多的研究证明,HMGB1是一种重要的潜在炎性介质,通过与其特异性受体结合而发挥着重要的炎症细胞因子作用。近年来研究表明,HMGB1通过参与炎症过程而影响动脉粥样硬化斑块的进展。因此,HMGB1可能是机体冠状动脉炎性疾病的重要靶点。本文对HMGB1及其作用机制进行综述,为心血管疾病的预防和治疗提供文献依据。     

晚期炎症介质-高迁移率族蛋白B-1

高迁移率族蛋白-1(HMGB-1)是一类广泛存在于真核细胞内的非组核蛋白,是由肿瘤坏死因子(TNF-a)刺激巨噬细胞分泌。HMGB-1全身性炎症反应失控性发展是致使组织损伤和器官衰竭的根本原因,在脓毒症HMGB-1升高程度与感染严重性呈正相关。HMGB-1是炎症晚期重要介质,抑制HMGB-1能够预防内毒素和细菌攻击所致MODS,改善严重脓毒症的预后。尽管对HMGB-1防治作用的确切机制与应用效果尚待深入探讨,但HMGB-1为临床干预脓毒症提供了较宽的时间窗。     

HMGB1在缺血-再灌注损伤中的作用机制研究进展

高迁移率族蛋白B1(high mobility group protein B1,HMGB1)是一类核内非组蛋白,人HMGB1含有215个氨基酸残基,定位于人染色体13q12,它在核内主要参与维持核小体的结构、识别和结合DNA、调控DNA的复制转录等.HMGB1主要通过两种途径释放到细胞外,与Toll样受体、晚期糖基化终产物受体等受体相互作用激活核因子κB、有丝分裂原激活蛋白激酶p38信号通路,释放炎症介质参与缺血-再灌注损伤的发生发展.对HMGB1作用的生物学基础的深入研究,将提供治疗缺血-再灌注损伤的新靶点.     

HMGB1在脑缺血再灌注损伤过程中的作用及其相关抑制剂的研究进展

高迁移率族蛋白1 (high mobility group box-1, HMGB1)是一种含有215个氨基酸残基的核蛋白,几乎存在于所有真核细胞中,参与调节染色体结构、基因转录、DNA复制和修复等多项生理过程,在生长发育过程中发挥着重要作用。越来越多的研究结果显示,HMGB1通过多种途径参与细胞凋亡、自噬和炎症反应等多种病理生理过程,从而诱导脑缺血再灌注(cerebral ischemia-reperfusion, CIR)损伤。此外,目前发现存在多种物质能靶向抑制HMGB1的表达,进而发挥抗炎、抗细胞凋亡和抗氧化损伤等作用,但具体作用机制仍需更加深入的研究。进一步挖掘和探索HMGB1在CIR损伤中的具体作用及其相关抑制剂将为CIR损伤的临床治疗提供新的潜在候选策略和思路。因此,本文就HMGB1在CIR损伤过程中的作用及其相关抑制剂的研究进展作一简要综述。     

小鼠HMGB1启动子荧光素酶报告基因的构建及功能鉴定

利用PCR技术扩增小鼠高迁移率族蛋白1(HMGB1)基因启动子序列,构建小鼠HMGB1启动子荧光素酶报告基因pGL3-basic-HMGB1.经PCR、酶切及测序鉴定后,用脂质体法将pGL3-basic-HMGB1转入巨噬细胞264.7中,并应用萤光素酶测定系统检测其活性.检测结果显示pGL3-basic-HMGB1具有启动子活性.小鼠HMGB1启动子荧光素酶报告基因pGL3-basic-HMGB1的成功构建,为进一步研究HMGB1提供基本材料.     

HMGB1对大鼠糖尿病足溃疡炎症的影响及机制分析

目的:分析高迁移率族蛋白1(High mobility group protein 1,HMGB1)对大鼠糖尿病足溃疡炎症的影响及机制。方法:经腹腔注射链脲佐菌素建立糖尿病大鼠模型,并在大鼠的双后足背部做一3 mm×7 mm的全层矩形皮肤缺损,接种质控菌株。将建模成功的大鼠随机分成:模型组(等量生理盐水)、低剂量组(12.5μg·kg~(-1)·d~(-1))、中剂量组(25μg·kg~(-1)·d~(-1))和高剂量组(50μg·kg~(-1)·d~(-1)),每组6只,每天单次腹腔注射,连续给药14 d。另取6只大鼠作为空白组(等量生理盐水)。于规定时间对各组大鼠创面愈合率、微血管密度(Microvascular density,MVD)、组织中血管内皮生长因子(Vascular endothelial growth factor,VEGF)、CD45、Toll样受体4(Toll like receptor 4,TLR4)、核因子κB (Nuclear factor kappa-B,NF-κB)、白介素-1β(Interleukin-1β,IL-1β)、白介素-6 (Interleukin-6,IL-6)、IL-8(Interleukin-8,IL-8)和肿瘤坏死因子-α(Tumor necrosis factor-α,TNF-α)m RNA或蛋白表达量进行检测。结果:与对照组相比,模型组大鼠创面治愈率和微血管密度均较低,VEGF、CD45、TLR4、NF-κB、IL-1β、IL-6、IL-8和TNF-αm RNA或蛋白表达量均较高(P0.05)。与模型组相比,三个剂量组大鼠创面治愈率和微血管密度均明显降低(P0.05),VEGF、CD45、TLR4、NF-κB、IL-1β、IL-6、IL-8和TNF-αm RNA或蛋白表达量均较高(P0.05)。且随着HMGB1注射剂量增大,创面愈合率、血管生成明显减少(P 0.05),炎症因子表达量显著升高(P 0.05)。结论:HMGB1对大鼠糖尿病足溃疡炎症有促进作用,机制可能与HMGB1/TLR4/NF-κB信号通路相关。     

The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

High-mobility group box 1 (HMGB1) protein is a highly abundant protein that can promote the pathogenesis of inflammatory and autoimmune diseases once it is in an extracellular location. This translocation can occur with immune cell activation as well as cell death, with the conditions for release associated with the expression of different isoforms. These isoforms result from post-translational modifications, with the redox states of three cysteines at positions 23, 45 and 106 critical for activity. Depending on the redox states of these residues, HMGB1 can induce cytokine production via toll-like receptor 4 (TLR4) or promote chemotaxis by binding the chemokine CXCL12 for stimulation via CXCR4. Fully oxidized HMGB1 is inactive. During the course of inflammatory disease, HMGB1 can therefore play a dynamic role depending on its redox state. As a mechanism to generate alarmins, cell death is an important source of HMGB1, although each major cell death form (necrosis, apoptosis, pyroptosis and NETosis) can lead to different isoforms of HMGB1 and variable levels of association of HMGB1 with nucleosomes. The association of HMGB1 with nucleosomes may contribute to the pathogenesis of systemic lupus erythematosus by producing nuclear material whose immunological properties are enhanced by the presence of an alarmin. Since HMGB1 levels in blood or tissue are elevated in many inflammatory and autoimmune diseases, this molecule can serve as a unique biomarker as well as represent a target of novel therapies to block its various activities.     

血清HMGB1、AT和炎性因子在急性创伤患者中表达水平及其与血栓形成的相关性分析

摘要 目的：分析血清高迁移率族蛋白B1（HMGB1）、抗凝血酶（AT）和炎性因子在急性创伤患者中表达水平及其与血栓形成的相关性。方法：将2020年1月～2022年12月本院收治的90例急性创伤患者纳入观察组,记录其血栓形成率,另将同期在本院进行体检的50例健康体检者纳入对照组,分别检测观察组、对照组及有无血栓形成患者的血清HMGB1、AT和炎性因子[白介素-6（IL-6）、白介素-10（IL-10）、白介素-1β（IL-1β）]水平;采用双变量Spearman相关性法检验血清HMGB1、AT和炎性因子与血栓形成的相关性;建立多因素Logistic模型分析影响急性创伤患者血栓形成的独立危险因素;分析血清HMGB1、AT和炎性因子在急性创伤患者血栓形成中的预测效能。结果：与对照组比较,观察组血清HMGB1、IL-6、IL-10、IL-1β水平较高,血清AT水平较低（P＜0.05）。与无血栓组比较,血栓组血清HMGB1、IL-6、IL-10、IL-1β水平较高,血清AT水平较低（P＜0.05）。急性创伤患者血栓形成与血清HMGB1、IL-6、IL-10、IL-1β呈正相关性,与血清AT呈负相关性（P＜0.05）。多因素Logistic分析结果显示,血清HMGB1、AT、IL-6、IL-10、IL-1β均是导致急性创伤患者血栓形成的独立危险因素（P＜0.05）。血清HMGB1、AT、HMGB1+AT+炎性因子对急性创伤患者血栓形成的预测值较高,AUC值分别为0.868、0.857、0.912;血清IL-6、IL-10、IL-1β对急性创伤患者血栓形成的预测值一般,AUC值分别为0.761、0.758、0.784、0.767。结论：血清HMGB1、AT和炎性因子与急性创伤及其血栓形成均存在一定关联,可根据其指标水平变化评估并预测急性创伤患者的损伤情况和血栓形成风险。     

高迁移率族蛋白1在脓毒症血管内皮细胞激活过程中的作用

血管内皮细胞激活是脓毒症病理生理过程的中心环节。活化的血管内皮细胞为炎症介质的聚集和迁移提供了重要的场所,是放大炎症反应的前提条件。高迁移率族蛋白1（high-mobility group box protein1,HMGB1）是脓毒症晚期致死性的促炎介质,维持并延长了脓毒症病理过程。HMGBl通过晚期糖基化终产物受体（advanced glycation end products receptor,RAGE）对血管内皮细胞有重要的激活作用。     

人HMGB1分子的克隆、重组蛋白表达与生物学活性

采用RT-PCR,从重症肝炎病人外周血单个核细胞（peripheral blood mononuclear cells PBMCs）的mRNA中扩增高迁移率族蛋白1（high mobility group box－1 protein,HMGB1）基因,构建重组表达质粒pGEX4T-1-HMGB1,转化入大肠杆菌,测序证实其序列与基因数据库中HMGB1基因(NM_002128)一致。诱导表达的融合蛋白GST-HMGB1,用Glutathione Sepharose 4B亲和层析纯化,经Thrombin酶切得到HMGB1。结果显示：经Western-blotting检测,GST-HMGB1 和HMGB1均具有免疫活性; ELISA和MTT检测发现,两者均能刺激RAW264.7细胞产生大量TNF-α,明显刺激HeLa细胞增殖。GST-HMGB1具有良好的生物学活性,为今后的研究打下了基础。     

Post-synthetic acetylation of HMGB1 protein modulates its interactions with supercoiled DNA

High mobility group box (HMGB) proteins 1 and 2 are abundant non-histone nuclear proteins that regulate chromatin structure because of their structure-specific binding to DNA. Here, we have investigated how the post-synthetic acetylation of HMGB1 affects its interaction with negatively supercoiled DNA by employing monoacetylated at Lys2 protein, isolated from butyrate-treated cells. Our data reveal that this modification enhances three reaction parameters: binding affinity, supercoiling activity and capacity to protect the supercoiled DNA from relaxation by topoisomerase I. We show that monoacetylation at Lys2 mimics the effect of acidic tail removal but to a lesser extent thus demonstrating that in vivo acetylated HMGB1 is capable of modulating its interaction with negatively supercoiled DNA.     

Regulation of HMGB1 release by inflammasomes

High mobility group box 1 (HMGB1) is an evolutionarily conserved non-histone chromatin-binding protein. During infection or injury, activated immune cells and damaged cells release HMGB1 into the extracellular space, where HMGB1 functions as a proinflammatory mediator and contributes importantly to the pathogenesis of infl ammatory diseases. Recent studies reveal that inflammasomes, intracellular protein complexes, critically regulate HMGB1 release from activated immune cells in response to a variety of exogenous and endogenous danger signals. Double stranded RNA dependent kinase (PKR), an intracellular danger-sensing molecule, physically interacts with inflammasome components and is important for inflammasome activation and HMGB1 release. Together, these studies not only unravel novel mechanisms of HMGB1 release during infl ammation, but also provide potential therapeutic targets to treat HMGB1-related infl ammatory diseases.     

弹性成像定量分析对自身免疫性肝病的诊断价值

目的:自身免疫性肝病的发病机理至今尚未明确,与多种疾病之间存在着联系,临床诊断具有一定的难度。本研究利用超声弹性成像技术定量分析自身免疫性肝病的病理特征,探讨该技术的诊断价值,为自身免疫性疾病的治疗提供诊断依据。方法:选取我院2011年3月-2013年6月收治的自身免疫性肝病患者182例,随机分为观察组和对照组。观察组98例患者采用弹性成像定量分析的方法进行诊断,对照组84例则采用常规病理学诊断。观察并比较两组患者的诊断准确率及诊断耗时。结果:观察组检出94例,诊断率为95.92%;对照组检出81例,诊断率为96.43%,两组诊断准确率比较无明显差异(P0.05)。观察组平均诊断耗时为5.6 h;对照组平均诊断耗时为11.6 h,观察组诊断时间比对照组短,差异具有统计学意义(P0.05)。结论:弹性成像定量分析对自身免疫性肝病的诊断准确率与病理活检诊断具有较好的一致性,且诊断耗时短、患者依从性好,值得在临床中进一步推广应用以辅助病理诊断,避免误诊或漏诊现象发生。     

HMGB1-dependent and -independent autophagy

HMGB1 (high mobility group box 1) is a multifunctional, ubiquitous protein located inside and outside cells that plays a critical role in various physiological and pathological processes including cell development, differentiation, inflammation, immunity, metastasis, metabolism, and death. Increasing evidence demonstrates that HMGB1-dependent autophagy promotes chemotherapy resistance, sustains tumor metabolism requirements and T cell survival, prevents polyglutamine aggregates and excitotoxicity, and protects against endotoxemia, bacterial infection, and ischemia-reperfusion injury in vitro or in vivo. In contrast, HMGB1 may not be required for autophagy in some organs such as the liver and heart. Understanding HMGB1-dependent and -independent autophagy in more detail will provide insight into the integrated stress response and guide HMGB1-based therapeutic intervention.     

HMGB1-dependent and -independent autophagy

HMGB1 (high mobility group box 1) is a multifunctional, ubiquitous protein located inside and outside cells that plays a critical role in various physiological and pathological processes including cell development, differentiation, inflammation, immunity, metastasis, metabolism, and death. Increasing evidence demonstrates that HMGB1-dependent autophagy promotes chemotherapy resistance, sustains tumor metabolism requirements and T cell survival, prevents polyglutamine aggregates and excitotoxicity, and protects against endotoxemia, bacterial infection, and ischemia-reperfusion injury in vitro or in vivo. In contrast, HMGB1 may not be required for autophagy in some organs such as the liver and heart. Understanding HMGB1-dependent and -independent autophagy in more detail will provide insight into the integrated stress response and guide HMGB1-based therapeutic intervention.