脂噬在动脉粥样硬化中的作用及中医药干预研究进展

动脉粥样硬化(As)是一种多因素共同作用的慢性炎症性血管病变。脂质蓄积是As发生的关键病理因素之一,其通过触发血管内炎症细胞浸润、内皮细胞损伤、泡沫细胞形成、血管平滑肌细胞增殖及迁移等多个病理环节,最终导致As斑块形成。脂噬作为一种选择性的自噬进程,通过溶酶体介导选择性降解细胞内储存中性脂质的细胞器脂滴,减少脂质沉积,从而维持细胞稳态,成为As研究的新靶点。本文对细胞脂噬功能在As中的作用的研究进展及相关中医药治疗进行讨论,旨在从脂噬角度为中医药防治As提供可行性思路。     

ncRNA调控细胞程序性死亡影响动脉粥样硬化的研究进展

动脉粥样硬化(As)是许多心血管疾病(CVD)的发病基础,巨噬细胞、平滑肌细胞和内皮细胞是参与As病变的主要细胞,诸多研究证实上述细胞程序性死亡(PCD)可影响As的发生发展,调控上述PCD可能成为防治As的关键。近年来许多研究发现非编码RNA(ncRNA)通过调控相关因子参与PCD,如凋亡、自噬、焦亡、坏死性凋亡、铁死亡和铜死亡等。该文对ncRNA通过调控PCD影响As的机制展开讨论,为As的治疗提供新思路。     

内皮细胞,平滑肌细胞,血小板和动脉粥样硬化

十余年前,美国病理学家Ross提出了动脉粥样硬化(As)发生的损伤反应学说.该学说指出,包括脂质、血小板损伤因子在内的多种因素所致的动脉内皮损伤是As发生的始动环节。其后在血小板促生长因子(PDGF)等作用下,动脉中膜的平滑肌细胞(SMC)迁移到内膜增殖、分泌,加之SMC内外脂质沉积,形成了As斑块。继而Ross又提出,应该重视对与As发生密切相关的三种细胞成份—内皮细胞(EC)、SMC和血小板的研究。内膜损伤是As发生的始动环节。目前已发现二百多种易致内膜损伤的危险因子。     

巨噬细胞自噬在动脉粥样硬化中作用的研究进展

动脉粥样硬化(As)所致心脑血管疾病在全球的罹患率及致死率名居前列,严重威胁人类健康。血脂紊乱和氧化炎症等状态使血管内膜下巨噬细胞对胆固醇的多进少出,导致胞内积聚大量脂滴(LDs),演变为泡沫细胞,成为As斑块形成的中心环节。自噬是细胞一种保护性物质降解途径,基础性自噬有利于细胞的物质代谢平衡,但自噬缺陷或异常则使细胞清除能力下降,引发代谢应激、氧化、炎症及细胞死亡等,与As斑块发生发展密切相关。本文就巨噬细胞自噬在胆固醇代谢、炎症、氧化应激、凋亡等方面的作用作一综述。     

动脉粥样硬化血管壁的Warburg效应

动脉粥样硬化(As)是一种以动脉血管壁脂质沉积为病理特征的慢性炎症性疾病。致As因素所诱导的血管壁慢性炎症在该疾病的病理进程中起着重要作用。单核细胞/巨噬细胞的能量代谢重新编程与As的发生发展密切相关。Warburg效应是细胞能量代谢的重要方式,该效应可能参与As的某些病理过程,如血管平滑肌增殖、内皮细胞功能障碍和炎症等。本文就As血管壁的Warburg效应进行综述。     

调节性T细胞在动脉粥样硬化发生机制中作用的研究进展

动脉粥样硬化(As)是动脉血管壁的一种慢性炎症性病变,相关免疫机制参与其发生、发展过程。调节性T细胞(Treg)是一种具有独特免疫调节功能的T淋巴细胞亚群,大量证据表明,Treg的数量变化和功能障碍与As的发病机制密切相关。文章简要阐述Treg在As发展中的作用机制,并介绍了Treg作为一种新型药物治疗靶点在预防和治疗As中的最新研究进展,以期对动脉粥样硬化性疾病的发生与防治提供新思路。     

不要低估血管平滑肌细胞在动脉粥样硬化斑块形成中的作用

血管内皮细胞、平滑肌细胞(SMC)和巨噬细胞共同参与动脉粥样硬化(As)斑块形成。近年研究表明,SMC来源的细胞占As斑块中细胞总数的70%以上。As斑块中的SMC通过自分泌细胞因子促进自身的增殖、迁移和炎症反应,通过旁分泌激活单核/巨噬细胞并将其募集到As损伤部位,同时通过其细胞膜表面表达的脂蛋白受体摄取脂质形成泡沫细胞。SMC在As斑块形成中扮演十分重要的角色,应进一步深化对SMC在As发生发展中的作用及作用机制的研究。     

环状RNA与动脉粥样硬化的相关性及中药调控研究进展

环状RNA是一种新兴的非编码RNA,与动脉粥样硬化(As)的脂质沉积、炎症反应、细胞凋亡、增殖和修复等过程密切相关,影响As的发生发展。传统中药在防治As中具有重要的学术价值,其调控机制尚未得到全面总结。文章对环状RNA与As中的脂质沉积、炎症反应和巨噬细胞的联系进行了综述,总结回顾环状RNA与As相关性及中药调控研究进展。     

NLRP3炎症小体在动脉粥样硬化中的作用机制和靶向炎症治疗的研究进展

动脉粥样硬化(As)是由一系列复杂因素引起的病理过程,包括内皮功能障碍、动脉血管壁中脂质沉积、巨噬细胞浸润、平滑肌细胞功能失调、泡沫细胞形成等,炎症反应在这一过程中发挥了重要的作用。NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症小体是炎症细胞的传导器,其激活后介导炎症反应,激活下游的白细胞介素18、白细胞介素1β,从而参与As的发生和发展。因此,针对NLRP3炎症小体和下游炎症因子的特异性抑制剂是目前临床药物研究的潜在靶点,有望成为治疗As的一种新的治疗措施。文章对NLRP3炎症小体的结构和激活机制及与As的关系进行了讨论,同时对靶向NLRP3炎症小体和下游炎症因子的药物进行了介绍。     

miR-145在动脉粥样硬化发展中的作用

动脉粥样硬化(As)是一种由炎症、固有免疫以及脂质浸润等多种因素参与的综合性病变。mi RNA是一类长度约18~24 nt的具有调节功能的非编码RNA,是基因转录后水平的重要调控者,能够调节细胞内的反应与功能。研究表明,mi RNA参与了多种血管疾病的进程,如在As的各个阶段中均有mi RNA的功能异常,其中,mi R-145能够通过调节下游多种靶基因表达,从而影响细胞的增殖、迁移以及细胞表型转变,在As的发生、发展中起着重要作用。     

NLRP3炎性体在心肌病和心律失常中的作用及研究进展

NLRP3炎性体是先天免疫反应的参与者，通过相关激活信号来触发炎症。NLRP3炎性体在心肌细胞和心脏成纤维细胞中表达，通过水解含半胱氨酸的天冬氨酸蛋白水解酶(caspase-1)前体生成caspase-1促使白介素（IL）-1β、IL-18的成熟和释放而导致细胞焦亡，其浸润影响到心肌病和心律失常等心血管疾病的发生发展过程。在这篇综述中，我们介绍了NLRP3炎性体在心肌病和心律失常中的作用及相关机制，对探索针对NLRP3炎症体在此类疾病中的治疗方案有重要意义。     

The interplay between the gut microbiota and NLRP3 activation affects the severity of acute pancreatitis in mice

ABSTRACT

Early dysbiosis of the gut microbiota is associated with the severity of acute pancreatitis (AP), although the underlying mechanism is unclear. Here, we investigated the role of crosstalk between NLRP3 and the gut microbiota in the development of AP utilizing gut microbiota deficient mice, as well as NLRP3 knockout (KO) mouse models. Pancreatic damage and systemic inflammation were improved in antibiotic-treated (Abx) and germ-free (GF) mice, accompanied by weakened activity of the intestinal NLRP3 inflammasome. Interestingly, fecal microbiota transplantation (FMT) reactivated the intestinal NLRP3 inflammasome and exacerbated the disease in Abx and GF mice. Although the gut barrier in GF and Abx mice was disrupted, gut microbiota deficiency ameliorated the severity of AP, probably due to the reduction in bacterial translocation from the gut to the pancreas. The composition of the gut microbiota was significantly different between NLRP3 KO mice and wild-type (WT) mice at baseline, and there were alterations in response to the induction of AP. While a dramatic shift in the gut microbiota with overgrowth of Escherichia-Shigella was observed in WT mice suffering from AP, there was no significant change in NLRP3 KO mice with or without AP, suggesting that NLRP3 deficiency counteracts AP-induced microbial disturbance. With a strengthened gut barrier and decreased systemic inflammation, NLRP3 KO mice showed less severe AP, as revealed by reduced pancreatic neutrophilic infiltration and necrosis. Taken together, these results identified the bidirectional modulation between the gut microbiota and NLRP3 in the progression of AP, which suggests the interplay of the host and microbiome during AP.     

Inflammatory bowel diseases and inflammasome

Inflammatory bowel disease (IBD), the most important entities being ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory conditions that result from chronic dysregulation of the mucosal immune system in the intestinal tract. Although the precise pathogenesis of IBD is still incompletely understood, increased levels of proinflammatory cytokines, including interleukin (IL)-1b, IL-18 and tumor necrosis factor-a, are detected in active IBD and correlate with the severity of inflammation, indicating that these cytokines may play a key role in the development of IBD. Recently, the intracellular nucleotide-binding oligomerization domain-like receptor (NLR) family members, including NLRP1, NLRP3, NLRC4 and NLRP6, are emerging as important regulators of intestinal homeostasis. Together, one of those aforementioned molecules or the DNA sensor absent in melanoma 2 (AIM2), apoptosis-associated speck-like protein containing 'a caspase recruitment domain (CARD)' (ASC) and caspase-1 form a large (> 700 kDa) multi-protein complex called the inflammasome. Stimulation with specific microbial and endogenous molecules triggers inflammasome assembly and caspase-1 activation. Activated caspase-1 leads to the secretion of proinflammatory cytokines, including IL-1b and IL-18, and the promotion of pyroptosis, a form of phagocyte cell death induced by bacterial pathogens, in an inflamed tissue. Therefore, inflammasomes are assumed to mediate host defense against microbial pathogens and gut homeostasis, so that their dysregulation might contribute to IBD pathogenesis. This review focuses on recent advances of the role of NLRP3 inflammasome signaling in IBD pathogenesis. Improving knowledge of the inflammasome could provide insights into potential therapeutic targets for patients with IBD.     

Gut Microbiota Dysbiosis Induced by a High-Fat Diet Increases Susceptibility to Atrial Fibrillation

BackgroundObesity is a significant risk factor for atrial fibrillation (AF), and the gut microbiota is closely related to obesity-induced diseases. However, whether the gut microbiota is involved in regulating obesity-induced AF has not been studied. This study investigated whether gut microbiota dysbiosis affects obesity-related AF.MethodsFecal microbes derived from normal diet (ND)-fed and high-fat diet (HD)-fed mice were transplanted into those fed normally. Morphologic, biochemical, functional, histologic, electrophysiological studies, molecular analysis, 16S rRNA gene amplicon sequencing, and RNA-sequencing were performed.ResultsTransplantation of the HD gut microbes in ND-maintained (THD) mice led to a significant increase in the susceptibility to AF. Gut microbiota analysis showed a significant increase in Desulfovibrionaceae, which generated metabolic endotoxemia in THD mice. Transplantation with HD microbes also resulted in significantly increased levels of circulating lipopolysaccharide (LPS), significant disruption in the histologic architecture of the intestinal tissue, and significantly increased proinflammatory cytokines in the left atrium, indicating that atrial inflammation likely contributed to AF susceptibility. RNA-sequencing showed that the THD group had enhanced activation of ferroptosis and TLR4/NF-κB/NLRP3 inflammasome signalling pathway. Inhibiting the ferroptosis or NLRP3 inflammasome signalling pathway significantly improved atrial fibrosis and reduced susceptibility to obesity-related gut dysbiosis-induced AF.ConclusionsThis study provides evidence showing an original causal role of gut microbiota dysbiosis in the pathogenesis of obesity-related AF, which showed elevated LPS and dysregulation of atrial pathologic remodelling by activating ferroptosis and the TLR4/NF-κB/NLRP3 inflammasome signalling pathway.     

中国动脉粥样硬化近三年基础研究进展

动脉粥样硬化(As)是一种与心血管疾病密切相关的病理过程,严重威胁人类健康。近三年来,中国学者主要致力于As模型的构建,聚焦铁死亡、焦亡、自噬、肠道微生物菌群、外泌体、氧化应激、低剪切应力、非编码RNA与As的关系,并进行了大量深入的研究工作。广泛而深入的基础研究为As防治策略的选择和药物的研发提供新的思路,以期实现临床转化。文章就近三年来中国学者围绕上述领域对As开展的基础研究作一综述。     

核苷酸结合寡聚化结构域样受体蛋白3炎性小体抑制剂

NLRP3炎性小体是由核苷酸结合寡聚化结构域(nucleotide-binding oligomerization domain,NOD)样受体蛋白3(Nod-like receptor protein3,NLRP3)、凋亡相关斑点样蛋白(apoptosis associated speck-like protein containing CARD,ASC)及无活性的半胱氨酸天冬氨酸蛋白酶1(cysteine-requiring asparate protease-1,caspase-1)前体组成的复合体。已有多项实验研究证实NLRP3炎性小体的活化是各种危险因素激活机体炎症反应的关键环节,NLRP3炎性小体参与到了多种疾病的发生发展过程中,如2型糖尿病、冠状动脉粥样硬化、痛风、NLRP3相关自身炎症性疾病、阿尔兹海默病、炎性肠病等。研发靶向调控NLRP3炎性小体的药物为治疗此类炎症代谢性疾病提供了新的思路。本文对近年来NLRP3炎性小体抑制剂的研究进展进行综述。     

IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation

Pathogenic infections and tissue injuries trigger the assembly of inflammasomes, cytosolic protein complexes that activate caspase-1, leading to cleavage of pro-IL-1β and pro-IL-18 and to pyroptosis, a proinflammatory cell death program. Although microbial recognition by Toll-like receptors (TLRs) is known to induce the synthesis of the major caspase-1 substrate pro-IL-1β, the role of TLRs has been considered limited to up-regulation of the inflammasome components. During infection with a virulent microbe, TLRs and nucleotide-binding oligomerization domain-like receptors (NLRs) are likely activated simultaneously. To examine the requirements and outcomes of combined activation, we stimulated TLRs and a specific NLR, nucleotide binding and oligomerization, leucine-rich repeat, pyrin domain-containing 3 (NLRP3), simultaneously and discovered that such activation triggers rapid caspase-1 cleavage, leading to secretion of presynthesized inflammatory molecules and pyroptosis. This acute caspase-1 activation is independent of new protein synthesis and depends on the TLR-signaling molecule IL-1 receptor-associated kinase (IRAK-1) and its kinase activity. Importantly, Listeria monocytogenes induces NLRP3-dependent rapid caspase-1 activation and pyroptosis, both of which are compromised in IRAK-1–deficient macrophages. Our results reveal that simultaneous sensing of microbial ligands and virulence factors by TLRs and NLRP3, respectively, leads to a rapid TLR- and IRAK-1–dependent assembly of the NLRP3 inflammasome complex, and that such activation is important for release of alarmins, pyroptosis, and early IFN-γ production by memory CD8 T cells, all of which could be critical for early host defense.Toll-like receptors (TLRs) recognize conserved molecules from pathogens and initiate signaling that activates NF-κB, MAP kinases, and IFN response factor proteins (1, 2). This signaling induces proinflammatory cytokines, chemokines, adhesion molecules, and inflammasome components, all of which facilitate effector responses (1, 2). A second family of receptors, nucleotide-binding oligomerization domain-like like receptors (NLRs), reside in the cytosol and are activated in response to either microbial ligands that gain access to the cytosol or virulence factors, such as bacterial toxins (3, 4).Activation of NLRs leads to assembly of an inflammasome complex, leading to activation and cleavage of cysteine protease, caspase-1, which in turns cleaves IL-1β and IL-18, leading to their secretion (5). The widely studied nucleotide binding and oligomerization, leucine-rich repeat, pyrin domain-containing 3 (NLRP3) inflammasome, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and procaspase-1, undergoes assembly in response to stimulation by various stimuli, including ATP, nigericin, maitotoxin, uric acid crystals, silica, asbestos, and such pathogens as Staphylococcus aureus, Streptococcus pyogenes, Listeria monocytogenes, and Salmonella typhimurium (6).Inflammasome-mediated caspase-1 activation promotes inflammation and host defense by two principal avenues: secretion of mature cytokines (IL-1β and IL-18) and activation of pyroptosis (7), a proinflammatory cell death pathway that eliminates the infected cell and removes the niche for intracellular microbial replication (8). The current understanding of the biology of IL-1β synthesis and secretion holds that the TLR signaling pathway induces synthesis and accumulation of pro-IL-1β in the cytosol, and inflammasome ligands cause assembly of the respective inflammasome complexes, leading to cleavage of pro-IL-1β by active caspase-1. The role of TLR signaling is thus considered limited to synthesis of the substrates or up-regulation of levels of the components of the inflammasome complexes themselves.In the present study, we investigated whether TLRs play a direct role in activation of the NLRP3 inflammosome and discovered that there are at least two phases of NLRP3 inflammasome activation. The early phase, acute inflammasome activation, is independent of new protein synthesis, depends on simultaneous activation of TLRs and NLRP3, and is directly regulated by TLR signaling via the TLR-signaling molecule IL-1 receptor-associated kinase (IRAK-1). The late phase, involving priming-dependent activation of the NLRP3 inflammasome, occurs independent of direct participation of IRAK-1. We also found that the acute IRAK-1–dependent NLRP3 inflammasome activation pathway is critical for pyroptosis and secretion of inflammatory proteins presynthesized by the cell. Our findings provide evidence supporting a direct link between TLR signaling and NLRP3 inflammasome activation and ascribe a unique function to IRAK-1 in early innate responses.     

NLRP3炎性小体与心血管疾病的研究进展

炎性小体(inflammasome)是一种多蛋白复合物,主要由识别炎症的胞浆型模式识别受体(PRRs)、接头蛋白凋亡相关斑点样蛋白(ASC)和效应蛋白前半胱天冬酶-1(pro-caspase-1)三部分组成。炎性小体的激活过程中最主要的步骤是白细胞介素-1β(IL-1β)和白细胞介素-18(IL-18)等炎性因子的成熟和释放,从而引起炎症反应。在心血管疾病中,有关核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎性小体的研究最为广泛。诸多研究表明,心血管疾病的危险因素同样可以激活NLRP3炎性小体进而促进疾病的发展。本文就近年来对NLRP3炎性小体在动脉粥样硬化、心肌梗死、高血压等心血管疾病中的形成、激活及相关治疗等方面进行综述。