摘要
炎症性肠病(inflammatory bowel disease,IBD)以慢性复发性肠道炎症为特征,包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn’s disease,CD)。IBD已成为全球性的医疗保健问题。临床上尚缺乏有效治疗药物。本研究聚焦于UC模型,旨在寻找新的治疗策略。前期研究发现,五味子甲素(schisandrin A,SchA)体外具有抗炎作用,并促进法尼醇X受体(farnesoid X receptor,FXR)的转录活性。FXR反向调控NF-κB的转录活性,在调节炎症反应中具有重要作用。因此,本研究主要探讨SchA对UC的保护作用及其通过FXR信号通路调控的机制。在RAW264.7细胞上评价SchA对炎症因子mRNA水平的影响。用双荧光素酶报告基因实验验证SchA与FXR靶向关系。动物实验遵循上海中医药大学动物伦理委员会规定(批准号:PZSHUTCM2304250005)。野生型或FXR敲除的C57BL/6小鼠自由饮用3%右旋葡聚糖硫酸钠(dextran sodium sulfate,DSS)7天诱导小鼠急性UC,并灌胃给药SchA连续7天。实验期间每日监测小鼠体重及粪便情况。采用RT-qPCR方法检测结肠组织炎症因子、FXR靶基因的mRNA水平。结果显示:体外SchA抑制脂多糖(lipopolysaccharide,LPS)诱导的炎症因子mRNA水平的增加。同时,SchA可以增加FXR的转录活性。在野生型小鼠中,SchA能明显改善急性UC小鼠的体重下降、结肠缩短、稀便和便血;SchA显著降低结肠组织中促炎因子基因的表达、增加FXR靶基因的表达。在FXR敲除小鼠中,SchA对小鼠急性UC的缓解作用消失。综上,SchA可通过FXR信号通路降低肠道炎症,缓解DSS诱导的小鼠急性UC,提示五味子木脂素类化合物可能是IBD药物开发的先导化合物。
Inflammatory bowel disease(IBD)is characterized by chronic relapsing intestinal inflammation and encompasses ulcerative colitis(UC)and Crohn's disease(CD).IBD has emerged as a global healthcare problem.Clinically efficacious therapeutic agents are deficient.This study concentrates on models of ulcerative colitis with the objective of discovering novel therapeutic strategies.Previous investigations have established that schisandrin A demonstrates anti-inflammatory effects in vitro,concurrently enhancing the transcriptional activity of farnesoid X receptor(FXR).FXR inversely modulates the transcriptional activity of NF-κB,which has an important role in regulating inflammatory responses.Consequently,the current study was to explore the safeguarding influence of schisandrin A on ulcerative colitis and delineate the mechanism by which it regulates this effect through the FXR signaling pathway.The effect of schisandrin A on the mRNA levels of inflammatory factors was evaluated in RAW264.7 cells.The dual luciferase reporter gene assay was used to verify the relationship between schisandrin A and FXR targeting.The animal experiments were performed in accordance with the regulations of the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine(approval No.PZSHUTCM2304250005).Acute ulcerative colitis was induced in wild-type or FXR knockout C57BL/6 mice by drinking 3%dextran sodium sulfate(DSS)for 7 days,and schisandrin A was administered via gavage for a continuous treatment period of 7 days.The body weight and faecal were monitored daily.The mRNA levels of inflammatory factors in colon tissue and FXR target genes were measured by RT-qPCR.The findings revealed that schisandrin A,in vitro,impeded the lipopolysaccharide(LPS)-induced elevation in mRNA levels of inflammatory factors and schisandrin A could augment transcriptional activity of FXR.In wild-type mice,schisandrin A significantly improved weight loss,colon shortening,loose stools and blood in stools in mice with acute ulcerative colitis,and schisandrin A significantly reduced the expression of pro-inflammatory factors genes and significantly increased the expression of FXR target genes in colon tissues.In FXR knockout mice,the administration of schisandrin A failed to yield ameliorative effect on acute ulcerative colitis in mice.In conclusion,schisandrin A can reduce intestinal inflammation through the FXR signaling pathway to alleviate acute ulcerative colitis in mice.Implications arise that Schisandra lignans could serve as lead compounds for drug development aimed at inflammatory bowel disease.
作者
蒋嘉瑞
董跨
金玉春
杨心茹
罗亦轩
徐书扬
王汛江
谷丽华
石燕红
杨莉
王峥涛
王旭
丁丽丽
JIANG Jia-rui;DONG Kua;JIN Yu-chun;YANG Xin-ru;LUO Yi-xuan;XU Shu-yang;WANG Xun-jiang;GU Li-hua;SHI Yan-hong;YANG Li;WANG Zheng-tao;WANG Xu;DING Li-li(The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines,Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Shanghai R&D Center for Standardization of Traditional Chinese Medicines,Shanghai 201203,China;Department of Breast Surgery,the Obstetrics and Gynecology Hospital of Fudan University,Shanghai 200011,China)
出处
《药学学报》
CAS
CSCD
北大核心
2024年第5期1261-1270,共10页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(82122074,82274165,82204406,82130115,81920108033)。
关键词
五味子甲素
结肠炎
葡聚糖硫酸钠
法尼醇X受体
抗炎
schisandrin A
colitis
dextran sodium sulfate
farnesoid X receptor
anti-inflammatory