Nigakinone 通过调节胆汁酸谱和 FXR/NLRP3 信号通路减轻 DSS 诱导的实验性结肠炎,Phytotherapy Research

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Nigakinone 通过调节胆汁酸谱和 FXR/NLRP3 信号通路减轻 DSS 诱导的实验性结肠炎
Phytotherapy Research ( IF 6.1 ) Pub Date : 2022-08-23 , DOI: 10.1002/ptr.7588
Fangle Liu _{1,

2} , Yufeng Yao ₁ , Qian Wang ₁ , Fengxue Zhang ₂ , Meiqi Wang ₁ , Chenchen Zhu ₁ , Chaozhan Lin ₁

Affiliation

胆汁酸 (BA) 代谢紊乱与溃疡性结肠炎 (UC) 发病机制的相关性如今已得到认识。法尼醇 X 受体 (FXR) 是 BA 稳态和炎症的控制器，是 UC 治疗的一个有前途的目标。Nigakinone 对结肠炎具有潜在的治疗作用。在此，我们研究了 nigakinone 在葡聚糖硫酸钠 (DSS) 诱导的结肠炎动物中的抗 UC 作用和机制。测量了参与核苷酸结合寡聚化结构域、富含亮氨酸重复序列和含吡啶结构域 3 (NLRP3) 信号通路的相关靶点。BA 靶向代谢组学用于揭示尼加酮对结肠炎 BA 谱的调节作用，同时确定了 FXR 的表达及其涉及 BA 肠肝循环的介导靶点。通过分子对接、双荧光素酶报告基因® (DLR™) 测定、FXR 沉默细胞和 FXR 基因敲除小鼠研究了 FXR 在尼加酮治疗结肠炎中的关键作用。结果表明，nigakinone 减轻了 DSS 诱导的结肠炎症状，包括 NLRP3 激活引起的过度炎症反应，以及肠粘膜屏障的损伤。Nigakinone 通过控制 FXR 介导的胆固醇羟化酶和转运蛋白来调节 BA 疾病，然后减少结肠中的 BA 积累。分子对接和 DLR™ 分析表明 FXR 可能是尼加酮的靶标。体外包括 NLRP3 激活引起的过度炎症反应，以及肠粘膜屏障的损伤。Nigakinone 通过控制 FXR 介导的胆固醇羟化酶和转运蛋白来调节 BA 疾病，然后减少结肠中的 BA 积累。分子对接和 DLR™ 分析表明 FXR 可能是尼加酮的靶标。体外包括 NLRP3 激活引起的过度炎症反应，以及肠粘膜屏障的损伤。Nigakinone 通过控制 FXR 介导的胆固醇羟化酶和转运蛋白来调节 BA 疾病，然后减少结肠中的 BA 积累。分子对接和 DLR™ 分析表明 FXR 可能是尼加酮的靶标。体外, nigakinone 通过 FXR 激活和炎症细胞因子的抑制来抑制 BA 诱导的炎症和细胞损伤。然而，nigakinone 对结肠炎的改善作用被体内或体外 FXR 敲除或沉默所抑制。总之，nigakinone 通过调节 BA 谱和 FXR/NLRP3 信号通路改善实验性结肠炎。

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Nigakinone alleviates DSS-induced experimental colitis via regulating bile acid profile and FXR/NLRP3 signaling pathways

The correlation of bile acid (BA) metabolism disorder with the pathogenesis of ulcerative colitis (UC) is realized nowadays. Farnesoid X receptor (FXR), a controller for BA homeostasis and inflammation, is a promising target for UC therapy. Nigakinone has potential therapeutic effects on colitis. Herein, we investigated the anti-UC effects and mechanism of nigakinone in colitic animals induced by dextran sulfate sodium (DSS). The related targets involved in the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) signaling pathway were measured. BA-targeted metabolomics was employed to reveal the regulatory effects of nigakinone on BA profile in colitis, while expressions of FXR and its mediated targets referring to BA enterohepatic circulation were determined. The critical role of FXR in the treatment of nigakinone for colitis was studied via molecule-docking, dual-luciferase reporter® (DLR™) assays, FXR silencing cells, and FXR knockout mice. Results showed nigakinone attenuated DSS-induced colitis symptoms, including excessive inflammatory response by NLRP3 activation, and injury of the intestinal mucosal barrier. Nigakinone regulated BA disorders by controlling cholesterol hydroxylase and transporters mediated by FXR, then decreased BA accumulation in colon. Molecular-docking and DLR™ assays indicated FXR might be a target of nigakinone. In vitro, nigakinone restrained BA-induced inflammation and cell damage via FXR activation and inhibition of inflammatory cytokines. However, ameliorating effects of nigakinone on colitis were suppressed by FXR knockout or silencing in vivo or in vitro. Taken together, nigakinone ameliorated experimental colitis via regulating BA profile and FXR/NLRP3 signaling pathway.

更新日期：2022-08-23

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