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细胞焦亡(pyroptoysis)是由活化的caspase-1触发的一种特殊的细胞程序性死亡。肾脏细胞焦亡在肾损伤中发挥着重要的作用。GSDMD切割焦亡关键蛋白caspase-1引起下游炎性反应因子IL-18,IL-1β的成熟和释放引起肾脏炎性反应和细胞焦亡发生。本文从NLRP3激活导致肾脏炎性反应、GSDMD裂解引发细胞焦亡等角度,阐释NLRP3-caspase-1-GSDMD介导的细胞焦亡在肾脏炎性反应中的作用。 相似文献
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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. 相似文献
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刘岳衡 《国际病理科学与临床杂志》2016,(7):1006-1011
细胞焦亡(Pyroptosis)是一种以促炎性为特点的细胞程序性死亡方式,分为依赖半胱氨酸蛋白酶-1(Caspase-1)的经典细胞焦亡途径和依赖半胱氨酸蛋白酶-4/5/11(Caspase-4/5/11)的非经典细胞焦亡途径。研究表明细胞焦亡广泛参与到多种疾病的发生发展中。最近研究人员发现GSDMD和Pannexin-1可能是介导细胞焦亡的关键物质,但具体机制和相互关系仍有待进一步深入研究。 相似文献
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基于细胞焦亡探讨中医药干预肿瘤炎性微环境的新机制 总被引:1,自引:0,他引:1
细胞焦亡是一种能产生炎性反应并引发细胞膜破裂、溶解的新型死亡方式。该死亡方式依赖于半胱氨酸蛋白酶家族1的启动,以致炎性反应小体在病原体的反应下聚集,从而发生焦性细胞死亡。焦亡的细胞在形态学、生物学、基因学特征上与传统的细胞死亡方式均有明显的不同。细胞焦亡已被发现参与多种人类疾病进程,而在肿瘤发生发展中扮演的角色也引起高度关注。因此,细胞焦亡发生机制及传导通路的研究,将为肿瘤的防治提供重要的治疗策略。本文基于细胞焦亡的生物学特征和信号传导通路,以及焦亡与传统细胞死亡方式的区别,结合中医药在肿瘤中应用特点,为探索中医药治疗肿瘤的新策略提供了理论依据。 相似文献
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目的 探究黄芩素对急性肺损伤(acute lung injure,ALI)小鼠的治疗作用以及对NOD样受体热蛋白结构域3(NOD-like receptor family pyrin domain containing 3,NLRP3)/半胱氨酸天冬氨酸蛋白酶-1(cystein-asparate protease-1,Caspase-1)/消皮素D(gasdermin D,GSDMD)焦亡通路的调控作用。方法 60只雄性C57BL/6小鼠随机分为对照组、模型组、Caspase-1抑制剂VX-765(30 mg/kg)组和黄芩素低、中、高剂量(10、20、40 mg/kg)组,每组10只。除对照组外,其余各组ip脂多糖(lipopolysaccharide,LPS,15 mg/kg),分别于造模前24 h和造模0.5 h后给予黄芩素或VX-765(30 mg/kg)干预。造模24 h后,检测小鼠肺湿干质量比以评价肺肿胀;苏木素-伊红(HE)染色法检测肺组织病理变化;透射电子显微镜观察肺组织中巨噬细胞损伤情况;ELISA法检测小鼠血清和肺泡灌洗液中白细胞介素-1β(interleukin-1β,IL-1β)、IL-6、IL-18、IL-1α和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)水平;采用Western blotting检测肺组织NLRP3、凋亡相关的斑点样蛋白(apoptosis-associated speck-like protein containing CARD,ASC)、cleaved Caspase-1、pro Caspase-1、GSDMD-N以及GSDMD蛋白表达。人源单核细胞白血病THP-1细胞加入100 nmol/L佛波酯诱导24 h,贴壁后随机分为对照组、模型组、VX-765(500 nmol/L)组和黄芩素低、中、高剂量(3、10、30 μmol/L)组,除对照组外,采用1 μg/mL LPS联合5 mmol/L三磷酸腺苷(adenosine triphosphate,ATP)刺激THP-1细胞建立细胞炎症模型,给予黄芩素或VX-765干预,采用CCK-8法检测细胞活力;ELISA法检测上清液中IL-1β、IL-18和IL-1α水平;LDH试剂盒检测上清液中乳酸脱氢酶(lactate dehydrogenase,LDH)活力;免疫荧光评估NLRP3炎症小体组装情况;采用膜联蛋白-V-PE(Annexin-V-PE)/7-氨基放线菌素(7-aminoactinomycin,7-AAD)试剂盒评价细胞焦亡情况;Western blotting检测细胞NLRP3/Caspase-1/GSDMD通路相关蛋白表达。结果 在ALI小鼠模型中,与模型组比较,VX-765组和黄芩素组小鼠肺肿胀程度明显减轻(P<0.01),肺组织损伤评分显著降低(P<0.01),肺组织中巨噬细胞炎性病变得到缓解,血清及肺泡灌洗液中IL-6、IL-1β、TNF-α、IL-18、IL-1α水平明显降低(P<0.05、0.01),肺组织NLRP3、ASC、cleaved Caspase-1、pro Caspase-1、GSDMD-N以及GSDMD蛋白表达水平均显著降低(P<0.05、0.01)。在细胞炎症模型中,与模型组比较,VX-765组和黄芩素组THP-1细胞IL-1β、IL-18、IL-1α分泌量显著降低(P<0.01),NLRP3/Caspase-1/GSDMD通路相关蛋白表达水平明显降低(P<0.05、0.01),NLRP3炎症小体组装明显被抑制(P<0.05、0.01),LDH释放量及细胞焦亡率显著降低(P<0.01)。结论 黄芩素通过抑制NLRP3/Caspase-1/GSDMD通路介导的细胞焦亡,从而改善LPS诱导的小鼠ALI。 相似文献
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Wenjuan Rui Sheng Li Hong Xiao Ming Xiao Jingping Shi 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2020,23(11):762
BackgroundInflammasome-induced neuroinflammation is a major pathogenic mechanism underlying the degeneration of nigral dopaminergic neurons in Parkinson’s disease (PD). Baicalein is a flavonoid isolated from the traditional Chinese medicinal herbal Scutellaria baicalensis Georgi with known anti-inflammatory and neuroprotective efficacy in models of neurodegenerative diseases, including PD. However, its effects on inflammasome-induced neuroinflammation during PD remain unclear.MethodsWe used N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like pathology in mice. Behavioral assessments including the pole test, rotarod test, and open field test were conducted to evaluate the effects of baicalein on MPTP-induced motor dysfunction. The efficacies of baicalein against MPTP-induced dopaminergic neuron loss and glial cell activation in the substantia nigra compact were examined by immunohistochemistry, effects on proinflammatory cytokines by quantitative real-time PCR and enzyme-linked immunosorbent assay, and effects on inflammasome pathway activation by immunoblotting and flow cytometry.ResultsAdministration of baicalein reversed MPTP-induced motor dysfunction, loss of dopaminergic neurons, and pro-inflammatory cytokine elevation. Baicalein also inhibited NLRP3 and caspase-1 activation and suppressed gasdermin D-dependent pyroptosis. Additionally, baicalein inhibited the activation and proliferation of disease-associated proinflammatory microglia.ConclusionsThese findings suggest that baicalein can reverse MPTP-induced neuroinflammation in mice by suppressing NLRP3/caspase-1/gasdermin D pathway. Our study provides potential insight into the use of baicalein in PD therapy. 相似文献
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目的:探究五味子丙素(SchC)对脂多糖(LPS)诱导心肌细胞HL-1炎症反应与细胞焦亡的影响。方法:培养小鼠心肌细胞HL-1,将其分为空白对照组、模型组(LPS)、LPS+SchC组。SchC预处理1 h后,分别以LPS刺激24 h或48 h,ELISA法提取细胞培养液上清液,检测细胞因子IL-1β、HMGB1和TNF-α的分泌,MTT法收集细胞检测细胞活力,Western Blot检测cleaved-Caspase1、GSDMD-N和NLRP3的表达;将HL-1细胞分为空白对照组、模型组(LPS)、LPS+siGSDMD(GSDMD siRNA)组、LPS+siGSDMD+SchC组,给药预处理1 h后,LPS刺激24 h,收集细胞培养液上清液,ELISA法检测IL-1β的分泌,MTT法检测细胞活力。结果:与LPS组比较,LPS+SchC组细胞活力得到改善(P<0.05),IL-1β、HMGB1和TNF-α的分泌均显著降低(P<0.05);Western Blot结果表明,与LPS组比较,LPS+SchC组的cleaved-Caspase1、GSDMD-N段和NLRP3蛋白水平显著降低(P<0.05);ELISA和MTT结果表明,与LPS组比较,LPS+siGSDMD组IL-1β的分泌显著降低(P<0.05)且细胞活力显著得到改善(P<0.01),然而LPS+siGSDMD组与LPS+siGSDMD+SchC组的IL-1β分泌水平和细胞活力并无显著性差异。结论:五味子丙素能有效缓解LPS诱导HL-1的炎症反应和细胞焦亡。 相似文献
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