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.     

Pyroptosis and its role in cancer

Programmed cell death (PCD) is mediated by specific genes that encode signals. It can balance cell survival and death. Pyroptosis is a type of inflammatory, caspase-dependent PCD mediated by gasdermin proteins, which function in pore formation, cell expansion, and plasma membrane rupture, followed by the release of intracellular contents. Pyroptosis is mediated by caspase-1/3/4/5/11 and is primarily divided into the classical pathway, which is dependent on caspase-1, and the non-classical pathway, which is dependent on caspase-4/5/11. Inflammasomes play a vital role in these processes. The various components of the pyroptosis pathway are related to the occurrence, invasion, and metastasis of tumors. Research on pyroptosis has revealed new options for tumor treatment. This article summarizes the recent research progress on the molecular mechanism of pyroptosis, the relationship between the various components of the pyroptosis pathway and cancer, and the applications and prospects of pyroptosis in anticancer therapy.     

焦亡及其与头颈部肿瘤关系的研究进展

细胞程序性死亡是指细胞依赖于某些特定的基因编码信号或活动的死亡方式。细胞凋亡、自噬、胀亡、焦亡等均属于细胞程序性死亡。其中,焦亡是一种依赖含半胱氨酸的天冬氨酸蛋白水解酶（caspase）的细胞程序性死亡方式。近年来,国内外相关研究发现,焦亡与炎性疾病、自身免疫性疾病及肿瘤均有关系。充分了解焦亡发生的机制及其与肿瘤的关系,对肿瘤的治疗具有一定的指导意义。本文针对焦亡的相关机制及焦亡与头颈部肿瘤的相关研究进展进行综述。     

Research progresses of molecular mechanism of pyroptosis and its related diseases

Pyroptosis is a newly discovered untypical form of programmed cell death by inflammatory response, which is dependent on the classic pathway of Caspase-1 and the non-canonical pathway of Caspase-11 in mice or orthologue Caspase-4/-5 in Humans. It has been found that the Gasdermin family of protein is a key molecule in the formation of membrane pores of pyroptosis. After being cleaved by inflammatory caspases, it releases a N-terminal fragment with perforating activity to trigger pyroptosis. That pyroptosis is closely related to the occurrence and development of certain diseases. Now, the molecular mechanism of pyroptosis and pyroptosis-related diseases are reviewed.     

Inflammasome activation by NLRP1 and NLRC4 in patients with coronary stenosis

Objective and designWe performed an experimental, analytical and prospective study to evaluate the systemic activation of inflammasome in atherosclerosis’ patients, in order to shed light into responsible mechanisms for plaque formation.SubjectsWe included sixty individuals distributed into 3 groups: 2 groups based on the report from the angiography (severe lesions - SL and primary lesions - PL) and 1 group enclosing healthy individuals (HC).MethodsThe expression assays of inflammasome genes NLRP1, NLRC4, CASP-1 and IL-1β were performed using Real Time qPCR, with specific Taqman Assays. IL-1β serum levels were analysed by commercial kit. Were applied the Shapiro-Wilk and Student’s T-test as statistical tests. Statistical significance was set to p ≤ 0.05.ResultsUpregulation of NLRP1 (+3.47 FC, p = 0.0001), NLRC4 (+7.06 FC, p = 6.792 × 10⁻⁰⁹) and IL-1β (+2.43 FC, p = 0.005) was observed in all atherosclerosis patients when compared to HC. According to stenosis severity, patients with primary lesions showed upregulation of inflammasome genes NLRP1 (+2.87 FC, p = 0.0008), NLRC4 (+6.34 FC, p = 4.134 × 10^-07) and IL-1β (+3.39 FC, p = 0.0012) with respect to the HC group. No statistical difference was found in IL-1β serum levels according the assessed groups.ConclusionsInflammasome activation in atherosclerosis’s patients can be systemic altered and may be triggered by NLRP1 and NLRC4 receptors. IL-1β gene expression was identified in our study as an important systemic detectable marker of plaque severity.     

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、...     

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。     

细胞焦亡对肝癌发生发展的影响及中医药的干预作用

细胞焦亡是一种新发现的程序性细胞死亡方式,在肝癌中发挥着关键作用。故拟基于细胞焦亡的分子机制及其在肝癌发病机制中的作用进行深入分析,并结合中医药在调节焦亡肝癌发展过程中的作用进行探讨,以期为临床提供新的治疗思路。