[2,6-二甲氧基-1,4-苯醌通过抑制NLRP3炎性小体激活减轻葡聚糖硫酸钠诱导的小鼠溃疡性结肠炎]
[2,6-dimethoxy-1,4-benzoquinone alleviates dextran sulfate sodium-induced ulcerative colitis in mice by suppressing NLRP3 inflammasome activation].
作者信息
Liu Chenfei, Zhang Wei, Zeng Yao, Liang Yan, Wang Mengting, Zhang Mingfang, Li Xinyuan, Wang Fengchao, Yang Yanqing
机构信息
Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China.
Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, China.
出版信息
Nan Fang Yi Ke Da Xue Xue Bao. 2025 Aug 20;45(8):1654-1662. doi: 10.12122/j.issn.1673-4254.2025.08.10.
OBJECTIVES
To investigate the therapeutic mechanism of 2,6-dimethoxy-1,4-benzoquinone (DMQ) for alleviating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice.
METHODS
Eighteen male C57BL/6J mice were equally randomized into control group, DSS group and DMQ treatment group. In DSS and DMQ groups, the mice were treated with DSS in drinking water to induce UC, and received intraperitoneal injections of sterile PBS or DMQ (20 mg/kg) during modeling. The changes in body weight, disease activity index (DAI), colon length, spleen weight, and colon histological scores of the mice were examined, and the percentages of Th17 and IFN-γ CD8 T cells in the mesenteric lymph nodes and spleen were analyzed using flow cytometry. The expressions of tight junction proteins (Occludin and ZO-1), proteins associated with inflammasome activation (caspase-1 and p20), IL-1β and TNF-α in the colon tissues were detected using Western blotting or ELISA. In the cell experiment, mouse bone marrow-derived macrophages (BMDMs) primed with lipopolysaccharide (LPS) were treated with DMQ, followed by stmulation with nigericin to activate the classical NLRP3 inflammasome pathway. In cultured human peripheral blood mononuclear cells (PBMCs) treated with either LPS alone or LPS plus nigericin, the effects of DMQ on inflammasome activation, pyroptosis, and cytokine release were evaluated Western blotting, ELISA, and flow cytometry.
RESULTS
In DSS-treated mice, DMQ treatment significantly alleviated DSS-induced body weight loss, colon shortening, spleen enlargement, and colon inflammation. The DMQ-treated mice showed significantly reduced percentages of Th17 cells and IFN-γ CD8 T cells in the mesenteric lymph nodes and spleen, with increased occludin and ZO-1 expressions and decreased caspase-1 expression in the colon tissue. DMQ obviously inhibited classical NLRP3 inflammasome activation in mouse BMDMs and both the classical and alternative pathways of NLRP3 activation in human PBMCs, causing also suppression of caspase-1-dependent pyroptosis.
CONCLUSIONS
DMQ ameliorates DSS-induced UC in mice by inhibiting NLRP3 inflammasome activation.
目的
探讨2,6 - 二甲氧基 - 1,4 - 苯醌（DMQ）缓解葡聚糖硫酸钠（DSS）诱导的小鼠溃疡性结肠炎（UC）的治疗机制。
方法
将18只雄性C57BL/6J小鼠随机分为对照组、DSS组和DMQ治疗组，每组6只。DSS组和DMQ组小鼠通过饮用含DSS的水诱导UC，并在造模期间腹腔注射无菌PBS或DMQ（20 mg/kg）。检测小鼠体重、疾病活动指数（DAI）、结肠长度、脾脏重量和结肠组织学评分的变化，并用流式细胞术分析肠系膜淋巴结和脾脏中Th17细胞和IFN-γ CD8 T细胞的百分比。采用蛋白质免疫印迹法或酶联免疫吸附测定（ELISA）检测结肠组织中紧密连接蛋白（闭合蛋白和紧密连接蛋白1）、与炎性小体激活相关的蛋白（半胱天冬酶 - 1和p20）、白细胞介素 - 1β和肿瘤坏死因子 - α的表达。在细胞实验中，用脂多糖（LPS）预处理的小鼠骨髓来源巨噬细胞（BMDM）用DMQ处理，然后用尼日利亚菌素刺激以激活经典的NLRP3炎性小体途径。在用LPS单独处理或LPS加尼日利亚菌素处理的培养的人外周血单个核细胞（PBMC）中，通过蛋白质免疫印迹法、ELISA和流式细胞术评估DMQ对炎性小体激活、细胞焦亡和细胞因子释放的影响。
结果
在DSS处理的小鼠中，DMQ治疗显著减轻了DSS诱导的体重减轻、结肠缩短、脾脏肿大和结肠炎症。DMQ处理的小鼠肠系膜淋巴结和脾脏中Th17细胞和IFN-γ CD8 T细胞的百分比显著降低，结肠组织中闭合蛋白和紧密连接蛋白1的表达增加，半胱天冬酶 - 1的表达降低。DMQ明显抑制小鼠BMDM中经典的NLRP3炎性小体激活以及人PBMC中NLRP3激活的经典和替代途径，还导致半胱天冬酶 - 1依赖性细胞焦亡受到抑制。
结论
DMQ通过抑制NLRP3炎性小体激活改善DSS诱导的小鼠UC。
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