中药新药与临床药理2025，Vol.36Issue(12)：2034-2043,10.DOI:10.19378/j.issn.1003-9783.2025.12.003
左归降糖舒心方对糖尿病动脉粥样硬化小鼠肠道黏膜屏障的影响及机制
Effect and Mechanism of Zuogui Jiangtang Shuxin Formula on the Intestinal Mucosal Barrier in Mice with Diabetic Atherosclerosis
摘要
Abstract
Objective To investigate the effect and mechanism of Zuogui Jiangtang Shuxin Formula(ZGJTSXF)on the intestinal mucosal barrier in mice with diabetic atherosclerosis.Methods After one week of acclimatization,male Apoe-/-mice were intraperitoneally injected with a low dose of streptozotocin(40 mg·kg-1)once daily for five consecutive days.After confirming fasting blood glucose levels＞11.1 mmol·L-1,the mice were continuously fed a high-fat diet for 12 weeks.Upon successful modeling,the mice were randomly divided into the model group,the metformin group(0.065 g·kg-1),the ZGJTSXF group(28.86 g·kg-1),and male C57BL/6 mice served as the blank control group with five mice per group.The treatment groups received the respective drugs by gavage(15 mL·kg-1),while the blank control and model groups received an equal volume of distilled water,once daily for 8 consecutive weeks.Serum levels of glucagon-like peptide-1(GLP-1),cholecystokinin(CCK),lipopolysaccharide(LPS),interleukin-18(IL-18),and interleukin-1β(IL-1β)were measured by ELISA.Pathological changes in the aorta and ileum were observed by hematoxylin-eosin(HE)staining.The number of goblet cells in ileal tissue was assessed by periodic acid-Schiff(PAS)staining.The mRNA expression levels of intestinal tight junction proteins Claudin-1,zonula occludens-1(ZO-1),and Occludin in the ileum were detected by RT-qPCR.The protein expression levels of NOD-like receptor thermal protein domain associated protein 3(NLRP3),IL-1β,and Gasdermin D-N-terminal fragment(GSDMD-N)in the ileum were measured by Western Blot.Results Compared with the blank control group,the model group showed significantly decreased serum levels of GLP-1 and CCK(P＜0.01),and significantly increased serum levels of LPS,IL-1β,and IL-18(P＜0.01).The aortic intima was thickened and structurally disordered,with an uneven inner wall and large atherosclerotic plaques protruding into the lumen.Under high magnification,cholesterol crystals within the plaques,disordered smooth muscle cell arrangement,subintimal foam cells,lipid accumulation,and inflammatory cell infiltration were observed.The structural integrity of the ileum was disrupted,with disordered arrangement of the intestinal mucosal epithelium,partial thickening and interruption of the lamina propria,and loose and broken intestinal villi.The ileal villus height and crypt depth were significantly reduced(P＜0.01).The number of PAS-positive cells in the ileum was significantly decreased(P＜0.01).The mRNA expression levels of Claudin-1,ZO-1,and Occludin in the ileum were significantly downregulated(P＜0.01).The protein expression levels of NLRP3,IL-1β,and GSDMD-N in the ileum were significantly increased(P＜0.01).Compared with the model group,the ZGJTSXF group and the metformin group showed significantly increased serum levels of GLP-1 and CCK(P＜0.01),and significantly decreased serum levels of LPS,IL-1β,and IL-18(P＜0.01).The degree of aortic lumen stenosis and plaque lesions was reduced,with a relatively smoother vascular wall,scattered atherosclerotic plaques,and varying degrees of improvement in lipid accumulation and inflammatory cell infiltration.Damage to the ileal mucosal epithelium was ameliorated,the ileal structure was relatively intact,intestinal villus density increased,and villus breakage was reduced.The ileal villus height and crypt depth were significantly increased(P＜0.05,P＜0.01).The number of PAS-positive cells in the ileum was significantly increased(P＜0.05,P＜0.01).The mRNA expression levels of Claudin-1,ZO-1,and Occludin in the ileum were significantly upregulated(P＜0.05,P＜0.01).The protein expression levels of NLRP3,IL-1β,and GSDMD-N in the ileum were significantly decreased(P＜0.05,P＜0.01).Conclusion ZGJTSXF can improve gastrointestinal hormone secretion,reduce inflammatory factor levels,and repair the intestinal mucosal barrier in mice with diabetic atherosclerosis.Its mechanism of action may be related to the regulation of the NLRP3 inflammasome signaling pathway and the inhibition of intestinal inflammatory factor expression.关键词
左归降糖舒心方/糖尿病动脉粥样硬化/肠道黏膜屏障/细胞焦亡/NLRP3炎症小体信号通路/炎症因子/小鼠Key words
Zuogui Jiangtang Shuxin Formula/diabetic atherosclerosis/intestinal mucosal barrier/pyroptosis/NLRP3 inflammasome signaling pathway/inflammatory factors/mice分类
医药卫生引用本文复制引用
杨金伟,周毅,肖凡,喻嵘..左归降糖舒心方对糖尿病动脉粥样硬化小鼠肠道黏膜屏障的影响及机制[J].中药新药与临床药理,2025,36(12):2034-2043,10.基金项目
国家自然科学基金项目(82205077) （82205077）
湖南省自然科学基金项目(2022JJ40315) （2022JJ40315）
湖南省教育厅资助科研项目(21B0390) （21B0390）
湖南省卫生健康委科研计划项目(D202303067601) （D202303067601）
中药粉体与创新药物省部共建国家重点实验室培育基地开放基金项目(21PTKF1016). （21PTKF1016）
