Abstract：
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.
OBJECTIVE: 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.
CONCLUSIONS: 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.
OBJECTIVE: 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.
CONCLUSIONS: 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.
摘要：
背景：溃疡性结肠炎（UC）是一种慢性，缺乏有效治疗靶点和根治药物的非特异性炎症性肠病。氧连素(OBB),一种新的肠道菌群引起的小檗碱氧化代谢产物（BBR），已经显示出不同的药理特性。
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大鼠通过TNBS的温和灌肠建立。灌胃给药7天后处死大鼠。重量的减少,疾病活动指数，评估宏观和组织学结肠改变。通过ELISA对分子机制进行了进一步的研究，qRT-PCR,免疫组织化学，或蛋白质印迹。
结果：OBB治疗可显着降低体重减轻，宏观分数，和结肠重量/长度比，以及减轻结肠炎大鼠结肠病理性恶化和MPO活力，达到优于BBR的保护效果。此外,OBB通过促进IL-13和IL-4的产生，降低TNF-α的含量来调节促炎因子和抗炎因子之间的不平衡，IL-2、IL-8和IL-22。此外，OBB预处理通过增强抗氧化防御基因表达显着改善氧化应激(包括HO-1，GCLM，GCLC,和NQO-1），从而增加SOD和GSH，并降低MDA和ROS活性。此外，OBB显著抑制NF-κBp65的易位和IκBα的磷酸化,促进HO-1表达，Keap1降解和Nrf2核易位。
结论：本研究首次表明OBB对TNBS引起的大鼠结肠炎具有优于BBR的治疗效果。OBB的保护作用可能与调节Keap1/Nrf2/NF-κB介导的炎症反应和氧化应激密切相关。这些证据强调了OBB作为改善结肠炎的潜在候选者的潜力。
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大鼠通过TNBS的温和灌肠建立。灌胃给药7天后处死大鼠。重量的减少,疾病活动指数，评估宏观和组织学结肠改变。通过ELISA对分子机制进行了进一步的研究，qRT-PCR,免疫组织化学，或蛋白质印迹。
结果：OBB治疗可显着降低体重减轻，宏观分数，和结肠重量/长度比，以及减轻结肠炎大鼠结肠病理性恶化和MPO活力，达到优于BBR的保护效果。此外,OBB通过促进IL-13和IL-4的产生，降低TNF-α的含量来调节促炎因子和抗炎因子之间的不平衡，IL-2、IL-8和IL-22。此外，OBB预处理通过增强抗氧化防御基因表达显着改善氧化应激(包括HO-1，GCLM，GCLC,和NQO-1），从而增加SOD和GSH，并降低MDA和ROS活性。此外，OBB显著抑制NF-κBp65的易位和IκBα的磷酸化,促进HO-1表达，Keap1降解和Nrf2核易位。
结论：本研究首次表明OBB对TNBS引起的大鼠结肠炎具有优于BBR的治疗效果。OBB的保护作用可能与调节Keap1/Nrf2/NF-κB介导的炎症反应和氧化应激密切相关。这些证据强调了OBB作为改善结肠炎的潜在候选者的潜力。
