Berberine safeguards sepsis-triggered acute gastric damage and inhibits pyroptosis in gastric epithelial cells via suppressing the ubiquitination and degradation of Nrf2.

Shu-Rui Xie, Yan-Jun Liu, Fen-Qiao Chen, Zhao Pan
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Abstract

Berberine (BBR), a widely recognized traditional Chinese medicine, has attracted considerable attention for its promising anti-inflammatory effects. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) effectively safeguards against organ damage stemming from sepsis-induced oxidative stress and inflammatory responses. This study examined the potential of BBR in alleviating sepsis-induced acute gastric injury, with a particular focus on elucidating whether its mechanism of action involves the activation of the Nrf2 signaling pathway. Following intraperitoneal injection of BBR, mice were subjected to the cecal ligation and puncture (CLP) method to induce sepsis. In vitro experiments involved pre-treating the normal gastric epithelial cells (GES-1) with BBR, followed by treatment with lipopolysaccharide (LPS). Functional assays were then performed to assess cell proliferation and apoptosis. To validate the role of Nrf2 in pyroptosis and inflammation, siRNA targeting Nrf2 (si-Nrf2) was transfected into LPS-treated GES-1 cells. Additionally, mice were administered the Nrf2 inhibitor ML385 to confirm the protective effects of BBR in vivo. BBR displayed a dose-dependent effect in mitigating gastric tissue damage, suppressing the release of inflammatory cytokines, and reducing the expression of NLRP3, ASC, and GSDMD-N. In vitro, BBR fostered GES-1 cell proliferation, hindered apoptosis, and suppressed the levels of TNF-α, IL-18, IL-1β, NLRP3, ASC, and GSDMD-N. Further analysis revealed that knocking down Nrf2 reversed BBR's inhibitory effect on pyroptosis in LPS-treated GES-1 cells. Through binding to Keap1, BBR efficiently prevented the ubiquitination and degradation of Nrf2, ultimately promoting its nuclear translocation. In vivo experiments confirmed that ML385 reversed the protective effect of BBR on pyroptosis and inflammation. Our research reveals that BBR interacts with Keap1 to activate the Keap1/Nrf2 signaling pathway in gastric epithelial cells, thereby suppressing pyroptosis and inflammation in sepsis-induced acute gastric injury.

小檗碱能保护败血症引发的急性胃损伤,并通过抑制 Nrf2 的泛素化和降解抑制胃上皮细胞的脓毒症。
小檗碱(BBR)是一种广受认可的传统中药,因其良好的抗炎效果而备受关注。激活核因子红细胞2相关因子2(Nrf2)可有效防止脓毒症诱发的氧化应激和炎症反应对器官造成的损伤。本研究探讨了 BBR 在减轻败血症诱发的急性胃损伤方面的潜力,尤其侧重于阐明其作用机制是否涉及 Nrf2 信号通路的激活。小鼠腹腔注射 BBR 后,采用盲肠结扎和穿刺(CLP)法诱导败血症。体外实验包括用 BBR 预处理正常胃上皮细胞(GES-1),然后用脂多糖(LPS)处理。然后进行功能测试,评估细胞增殖和凋亡情况。为了验证 Nrf2 在化脓和炎症中的作用,将靶向 Nrf2 的 siRNA(si-Nrf2)转染到 LPS 处理过的 GES-1 细胞中。此外,还给小鼠注射了 Nrf2 抑制剂 ML385,以证实 BBR 在体内的保护作用。BBR 在减轻胃组织损伤、抑制炎症细胞因子的释放以及减少 NLRP3、ASC 和 GSDMD-N 的表达方面显示出剂量依赖性效应。在体外,BBR促进了GES-1细胞增殖,阻碍了细胞凋亡,抑制了TNF-α、IL-18、IL-1β、NLRP3、ASC和GSDMD-N的水平。通过与 Keap1 结合,BBR 有效阻止了 Nrf2 的泛素化和降解,最终促进了其核转运。体内实验证实,ML385逆转了BBR对热蛋白沉积和炎症的保护作用。我们的研究揭示了BBR与Keap1相互作用,激活胃上皮细胞中的Keap1/Nrf2信号通路,从而抑制败血症诱导的急性胃损伤中的热蛋白沉积和炎症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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