Infectious Diseases Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Emergency Department, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang, Hebei, China.
Kaohsiung J Med Sci. 2024 Nov;40(11):1006-1019. doi: 10.1002/kjm2.12900. Epub 2024 Nov 1.
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（BBR）是一种被广泛认可的中药，因其具有有希望的抗炎作用而受到极大关注。核因子红细胞 2 相关因子 2（Nrf2）的激活可有效防止败血症引起的氧化应激和炎症反应引起的器官损伤。本研究探讨了 BBR 缓解败血症引起的急性胃损伤的潜力，特别关注其作用机制是否涉及 Nrf2 信号通路的激活。腹腔注射 BBR 后，小鼠采用盲肠结扎穿刺（CLP）法诱导败血症。在体外实验中，先用 BBR 预处理正常胃上皮细胞（GES-1），然后用脂多糖（LPS）处理。然后进行功能测定以评估细胞增殖和凋亡。为了验证 Nrf2 在细胞焦亡和炎症中的作用，用 Nrf2 的 siRNA（si-Nrf2）转染 LPS 处理的 GES-1 细胞。此外，给小鼠注射 Nrf2 抑制剂 ML385 以确认 BBR 在体内的保护作用。BBR 呈剂量依赖性减轻胃组织损伤，抑制炎症细胞因子释放，并降低 NLRP3、ASC 和 GSDMD-N 的表达。在体外，BBR 促进 GES-1 细胞增殖，抑制凋亡，并抑制 TNF-α、IL-18、IL-1β、NLRP3、ASC 和 GSDMD-N 的水平。进一步分析表明，敲低 Nrf2 逆转了 BBR 对 LPS 处理的 GES-1 细胞细胞焦亡的抑制作用。通过与 Keap1 结合，BBR 有效地阻止了 Nrf2 的泛素化和降解，最终促进其核转位。体内实验证实，ML385 逆转了 BBR 对细胞焦亡和炎症的保护作用。我们的研究表明，BBR 与 Keap1 相互作用激活胃上皮细胞中的 Keap1/Nrf2 信号通路，从而抑制败血症引起的急性胃损伤中的细胞焦亡和炎症。
