Mechanism of action of a novel IDO1 inhibitor and icartin combination on diabetic nephropathy based on intestinal flora combined with metabolomics
- VernacularTitle:基于肠道菌群结合代谢组学探讨新型IDO1抑制剂与淫羊藿苷元组合物对糖尿病肾病的作用机制
- Author:
Meng LI
1
;
De-yu CUI
;
Yi-fan LIU
;
Yan XU
;
Meng-meng SHEN
;
Xiao-yan LU
;
Jing-chun YAO
Author Information
- Publication Type:Journal Article
- Keywords: diabetic nephropathy; intestinal flora; metabolomics; IDO-1 inhibitors; Icartin; oxidative stress
- From: Chinese Pharmacological Bulletin 2025;41(3):528-537
- CountryChina
- Language:Chinese
- Abstract: Aim To study the protective effect of a combination of IDO-1 inhibitor(3-047)with Icartin(Y003)at a mass ratio of 1∶1.6 on diabetic nephrop-athy in db/db mice and its mechanism of action.Methods After 24 weeks of treatment in db/db mice,on the basis of pharmacodynamic evaluation,16S rD-NA gene sequencing combined with untargeted metabo-lomics was used to further investigate the mechanism of improvement of diabetic nephropathy from the perspec-tive of the"microbial-intestinal-nephrotic"axis by the combination of 3-047 and Y003.Results Compared with the control group,mice in the model group showed significantly higher levels of FBG,Scr,BUN,TC,TG,LDL-C,lower levels of HDL-C(P＜0.05),significantly increased urinary albumin excretion rate,thickening of the glomerular basement membrane and dilatation of the tunica albuginea,aggravation of oxida-tive stress damage,lower abundance,structural and functional disorders of the intestinal flora.The combi-nation of 3-047 and Y003 could improve the above conditions to different degrees,significantly increase the relative abundance of Alloprevotella,Alistipes and Dubosiella,and decrease the relative abundance of Ligilactobacillus,Dubosiella and Lactococcus.A total of 11 biomarkers with significant differences were screened by metabolomics and enriched to the pathways of alanine,tyrosine and tryptophan biosynthesis,and unsaturated fatty acid biosynthesis.Conclusions The combination of 3-047 and Y003 could improve the dis-orders of glucose-lipid metabolism,reduce the structur-al and functional damage of renal tissues,and alleviate oxidative stress by regulating the intestinal flora and re-lated amino acid metabolism,and thus achieve a pro-tective effect on mice with diabetic nephropathy,dem-onstrating that the intestinal flora and the related me-tabolites are potential targets for the treatment of dia-betic nephropathy.
