Oxyberberine ameliorates TNBS-induced colitis in rats through suppressing inflammation and oxidative stress via Keap1/Nrf2/NF-κB signaling pathways,Phytomedicine

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Oxyberberine ameliorates TNBS-induced colitis in rats through suppressing inflammation and oxidative stress via Keap1/Nrf2/NF-κB signaling pathways
Phytomedicine ( IF 6.7 ) Pub Date : 2023-05-23 , DOI: 10.1016/j.phymed.2023.154899
Cailan Li ₁ , Meigui Liu ₂ , Li Deng ₃ , Dandan Luo ₄ , Runfang Ma ₂ , Qiang Lu ₂

Affiliation

Background

Ulcerative colitis (UC) is a chronic, unspecific inflammatory bowel disorder lacking effective therapeutic targets and radical drugs. Oxyberberine (OBB), a novel intestinal flora-elicited oxidative metabolite of berberine (BBR), has been revealed to exhibit diverse pharmacological properties.

Purpose

In this follow-up study, we attempted to shed light on the possible therapeutic effect and latent mechanism of OBB on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-evoked UC in rats.

Methods

UC rats were established via a gentle enema of TNBS. Rats were sacrificed after intragastric administration of drugs for seven days. The weight reduction, disease activity index, macroscopic and histological colonic alterations were assessed. Further investigation on molecular mechanisms was conducted by ELISA, qRT-PCR, immunohistochemistry, or Western blot.

Results

OBB treatment remarkably decreased the weight loss, macroscopic scores, and colonal weight/length ratio, as well as mitigated the colonic pathological deterioration and MPO vitality in colitis rats, achieving a superior protective effect to BBR. Additionally, OBB modulated the disequilibrium between pro- and anti-inflammatory factors by promoting the production of IL-13 and IL-4, and lowering the contents of TNF-α, IL-2, IL-8, and IL-22. Furthermore, OBB pretreatment dramatically ameliorated oxidative stress via enhancing antioxidant defense genes expressions (including HO-1, GCLM, GCLC, and NQO-1), thereby increasing SOD and GSH, and decreasing MDA and ROS activities. Furthermore, OBB strikingly restrained the translocation of NF-κB p65 and phosphorylation of IκBα, promoted HO-1 expression, Keap1 degradation and Nrf2 nuclear translocation.

Conclusion

The study firstly indicated that OBB had a superior therapeutic effect than BBR against TNBS-elicited colitis in rats. The protective effect of OBB might be closely related to the modulation of Keap1/Nrf2/NF-κB-mediated inflammatory response and oxidant stress. The evidences highlight the potentiality of OBB as a prospective candidate for the amelioration of colitis.

中文翻译：

氧小檗碱通过 Keap1/Nrf2/NF-κB 信号通路抑制炎症和氧化应激，从而改善 TNBS 诱导的大鼠结肠炎

背景

溃疡性结肠炎 (UC) 是一种慢性、非特异性炎症性肠病，缺乏有效的治疗靶点和根治性药物。氧小檗碱 (OBB) 是一种新型肠道菌群引发的小檗碱 (BBR) 氧化代谢物，已被证明具有多种药理学特性。

目的

在这项后续研究中，我们试图阐明 OBB 对 2, 4, 6-三硝基苯磺酸 (TNBS) 诱发的大鼠 UC 的可能治疗作用和潜在机制。

方法

UC 大鼠是通过温和的 TNBS 灌肠建立的。大鼠灌胃给药7天后处死。评估了体重减轻、疾病活动指数、宏观和组织学结肠改变。通过 ELISA、qRT-PCR、免疫组织化学或蛋白质印迹对分子机制进行了进一步研究。

结果

OBB治疗显着降低了结肠炎大鼠的体重减轻、宏观评分和结肠重量/长度比，并减轻了结肠病理恶化和MPO活力，对BBR具有更好的保护作用。此外，OBB 通过促进 IL-13 和 IL-4 的产生以及降低 TNF-α、IL-2、IL-8 和 IL-22 的含量来调节促炎因子和抗炎因子之间的不平衡。此外，OBB 预处理通过增强抗氧化防御基因表达（包括HO-1、GCLM、GCLC和NQO-1）显着改善氧化应激)，从而增加 SOD 和 GSH，降低 MDA 和 ROS 活性。此外，OBB 显着抑制了 NF-κB p65 的易位和 IκBα 的磷酸化，促进了 HO-1 表达、Keap1 降解和 Nrf2 核易位。