从“一气周流”论述细胞焦亡与代谢综合征血管内皮损伤的相关性

“一气周流”是中医经典理论,其核心思想认为中气（脾胃之气）是整个气机运转的枢纽。脾胃虚弱,肝气郁结,水谷精微运化疏泄失常,日久痰浊瘀血内生,积聚于血管,引起代谢综合征血管内皮损伤。临床及实验研究均证实健脾疏肝方剂柴芪汤对代谢综合征及相关血管内皮损伤具有较好改善作用。细胞焦亡是一种促炎性程序性细胞死亡方式,在血管内皮炎症反应中具有重要作用,这一过程类似于中医“痰瘀浊毒”的积聚。基于“一气周流”理论探讨细胞焦亡与代谢综合征血管内皮损伤的机制,为中医经典理论和中医药防治代谢综合征血管并发症提供理论依据。     

NOD样受体蛋白1炎性小体在创伤性中枢神经损伤中的作用

NOD样受体蛋白1（NOD-like receptor protein 1,NLRP1）炎性小体在人体固有免疫反应中发挥着重要作用,可促进半胱氨酸蛋白水解酶（cysteinyl aspartate specific proteinases,Caspases）的活化,进一步激活白介素-18和白介素-1β,同时介导细胞焦亡,NLRP1炎性小体在创伤性中枢神经损伤中发挥着作用,本文就NLRP1炎性小体的结构、NLRP1炎性小体在创伤性中枢神经损伤中的激活以及以NLRP1炎性小体为靶点的治疗等方面进行了综述。     

Innate immune inflammatory cell death: PANoptosis and PANoptosomes in host defense and disease

Regulated cell death (RCD) triggered by innate immune activation is an important strategy for host survival during pathogen invasion and perturbations of cellular homeostasis. There are two main categories of RCD, including nonlytic and lytic pathways. Apoptosis is the most well-characterized nonlytic RCD, and the inflammatory pyroptosis and necroptosis pathways are among the best known lytic forms. While these were historically viewed as independent RCD pathways, extensive evidence of cross-talk among their molecular components created a knowledge gap in our mechanistic understanding of RCD and innate immune pathway components, which led to the identification of PANoptosis. PANoptosis is a unique innate immune inflammatory RCD pathway that is regulated by PANoptosome complexes upon sensing pathogens, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) or the cytokines produced downstream. Cytosolic innate immune sensors and regulators, such as ZBP1, AIM2 and RIPK1, promote the assembly of PANoptosomes to drive PANoptosis. In this review, we discuss the molecular components of the known PANoptosomes and highlight the mechanisms of PANoptosome assembly, activation and regulation identified to date. We also discuss how PANoptosomes and mutations in PANoptosome components are linked to diseases. Given the impact of RCD, and PANoptosis specifically, across the disease spectrum, improved understanding of PANoptosomes and their regulation will be critical for identifying new therapeutic targets and strategies.     

Pyroptosis-induced inflammation and tissue damage

Pyroptosis is a programmed necrotic cell death executed by gasdermins, a family of pore-forming proteins. The cleavage of gasdermins by specific proteases enables their pore-forming activity. The activation of the prototype member of the gasdermin family, gasdermin D (GSDMD), is linked to innate immune monitoring by inflammasomes. Additional gasdermins such as GSDMA, GSDMB, GSDMC, and GSDME are activated by inflammasome-independent mechanisms. Pyroptosis is emerging as a key host defense strategy against pathogens. However, excessive pyroptosis causes cytokine storm and detrimental inflammation leading to tissue damage and organ dysfunction. Consequently, dysregulated pyroptotic responses contribute to the pathogenesis of various diseases, including sepsis, atherosclerosis, acute respiratory distress syndrome, and neurodegenerative disorders. This review will discuss the inflammatory consequences of pyroptosis and the mechanisms of pyroptosis-induced tissue damage and disease pathogenesis.     

Pyroptosis: A road to next-generation cancer immunotherapy

The goal of cancer immunotherapy is to clear tumor cells by activating antitumor immunity, especially by mobilizing tumor-reactive CD8⁺T cells. Pyroptosis, programmed lytic cell death mediated by gasdermin (GSDM), results in the release of cellular antigens, damage-associated molecular patterns (DAMPs) and cytokines. Therefore, pyroptotic tumor cell-derived tumor antigens and DAMPs not only reverse immunosuppression of the tumor microenvironment (TME) but also enhance tumor antigen presentation by dendritic cells, leading to robust antitumor immunity. Exploring nanoparticles and other approaches to spatiotemporally control tumor pyroptosis by regulating gasdermin expression and activation is promising for next-generation immunotherapy.     

益肾健脾泻浊中药对慢性肾脏病妊娠大鼠肾脏NLRP3/caspase-1/IL-1β信号通路及细胞焦亡的影响＊

目的 观察益肾健脾泻浊中药对慢性肾脏病妊娠大鼠肾脏NLRP3/caspase-1/IL-1β信号通路及细胞焦亡的影响。方法 将雌性Wistar大鼠随机分为6组，分别为对照组（Sham）、对照组 + 妊娠组（SP）、单侧输尿管结扎组（UUO）、UUO + 妊娠组（UP）、UUO + 妊娠 + 益肾健脾泻浊中药组（TCM）、UUO + 妊娠 + 依普利酮组（EPL）。UUO各组采用结扎单侧输尿管的方法复制慢性肾病模型，治疗组分别给予依普利酮100 mg?（kg?天）^-1和益肾健脾泻浊方3.11 g?（kg?天）^-1治疗。8周后妊娠各组大鼠按动情周期与雄鼠合笼，妊娠第19天处死母鼠。检测各组肾功能，醛固酮含量，采用SABC法及Western blot法检测核因子κB（Nuclear factor-kappa B，NF-κB）、核苷酸结合寡聚结构域样受体蛋白3 NOD［nucleotide-binding oligomerization domain-like receptor protein 3，NLRP3］、天冬氨酸特异性半胱氨酸蛋白1［Caspase-1］、白介素1β（Interleukine-1 beta，IL-1β）的表达，TUNEL法检测肾细胞DNA损伤情况。结果 与UUO组比较，UP组血清肌酐（Scr）、血尿素氮（BUN）和24 h尿蛋白及醛固酮含量较Sham组显著升高（P < 0.05），治疗后，两给药组Scr、BUN、24 h尿蛋白、醛固酮显著降低（P < 0.05）。与Sham组比较，SP组大鼠肾组织NF-κB、NLRP3、Caspase-1、IL-1β表达明显升高（P < 0.05），TUNEL阳性细胞少量增加（P < 0.05）。NLRP3炎症小体主要表达于浸润巨噬细胞及肾小管上皮细胞；Caspase-1和IL-1β主要表达于肾小管上皮细胞胞浆；TUNEL阳性细胞主要见于远端小管上皮细胞。与UUO组比较，UP组大鼠肾组织NF-κB、NLRP3、Pro-caspase-1、Caspase-1、Pro-IL-1β、IL-1β指标表达也明显升高（P < 0.05），TUNEL阳性细胞明显增多（P < 0.05）。与UP组比较，EPL、TCM组大鼠肾组织上述指标表达明显降低（P < 0.05），TUNEL阳性细胞明显减少（P < 0.05）。两个给药组间各项指标无明显差异。结论 益肾健脾泻浊方及依普利酮可缓解慢性肾病妊娠大鼠肾脏炎症损伤，下调肾脏NLRP3炎症小体信号通路分子表达，从而抑制细胞焦亡，减轻肾脏炎症损伤。     

恩格列净通过抑制细胞焦亡改善糖尿病小鼠肾脏损伤

目的研究恩格列净(empagliflozin)对db/db小鼠肾脏损伤的保护作用及其潜在作用机制。方法db/db小鼠随机分为糖尿病肾病组(db/db组)和恩格列净治疗组(Empa组,恩格列净10 mg·kg-1·d-1灌胃),C57BL/6J小鼠作为正常对照组。干预3个月,检测血清生化、炎症因子等指标;病理染色观察肾脏病理学改变;检测细胞焦亡相关分子NLRP3、Cleaved Caspase-1、GSDMD的蛋白表达水平。结果与db/db组相比,Empa组空腹血糖、HbA1C、血脂、血清IL-1β、IL-18及ACR明显降低(均P<0.05),病理染色显示Empa组肾小球固缩、肾间质纤维化明显改善,Empa组肾脏组织NLRP3、Cleaved Caspase-1、GSDMD蛋白表达下调(P<0.05)。结论恩格列净可能通过抑制NLRP3/Caspase-1/GSDMD细胞焦亡信号通路而改善糖尿病小鼠肾脏损伤。     

Circular RNA PPP1CC promotes Porphyromonas gingivalis-lipopolysaccharide-induced pyroptosis of vascular smooth muscle cells by activating the HMGB1/TLR9/AIM2 pathway

ObjectivePorphyromonas gingivalis (Pg) plays a critical role in the occurrence and development of atherosclerosis. Lipopolysaccharide from Pg (Pg-LPS) could lead to pyroptosis of vascular smooth muscle cells (VSMCs) and induce instability of atherosclerotic plaque. Therefore, pyroptosis of VSMCs could promote the process of atherosclerosis. However, the exact mechanism of Pg-LPS-induced pyroptosis of VSMCs is unclear.MethodsWe determined pyroptosis and expression of interleukin (IL)-1β and IL-18 in VSMCs using 4′,6-diamidino-2-phenylindole staining and ELISA after stimulation by Pg-LPS. We established a knockdown plasmid containing the circular (circ)RNA PPP1CC and transfected it into VSMCs. Luciferase assays were performed to reveal the association between microRNAs miR-103a-3p and miR-107 and circRNA PPP1CC.ResultsStimulation of Pg-LPS led to pyroptosis of VSMCs. Knockdown of circRNA PPP1CC relieved the Pg-LPS-induced pyroptosis of VSMCs and suppressed the expression of HMGB1, TLR9, AIM2, and cleaved caspase-1. Luciferase assays showed that PPP1CC directly targeted and competitively adsorbed miR-103a-3p and miR-107, weakening the inhibitory effect of these microRNAs on the expression of HMGB1.ConclusionKnockdown of circRNA PPP1CC relieved Pg-LPS-induced pyroptosis of VSMCs. Pyroptosis of VSMCs appears to promote atherosclerosis and may represent a novel therapeutic target for its treatment.     

Caspase‐11: The driving factor for noncanonical inflammasomes

Inflammasomes are large multiprotein platforms that mediate the processing of caspase‐1, which in turn promotes the maturation and release of IL‐1β and IL‐18 in response to microbial and danger signals. While the canonical pathway of inflammasome activation has been known for some time, a novel mechanism of noncanonical inflammasome activation mediated by caspase‐11 was more recently identified. This pathway engages caspase‐11 to trigger both caspase‐1‐dependent and ‐independent production of the inflammatory cytokines IL‐1β, IL‐18, and IL‐1α, as well as to promote pyroptosis, a form of genetically programmed cell death that is associated with the release of such cytokines. In this review, we gather together studies on both the mechanisms and implications of caspase‐11‐mediated noncanonical inflammasome activation, and discuss the emerging importance of this pathway in regulating host defense against intracellular bacterial pathogens.