坏死性下垂
溃疡性结肠炎
裂谷1
结肠炎
奶油
癌症研究
化学
细胞生物学
医学
生物
程序性细胞死亡
细胞凋亡
内科学
生物化学
转录因子
基因
疾病
作者
Chunxiao Liu,Hui Wang,Lu Han,Yifan Zhu,S'iakste Ni,Jingke Zhi,Xiping Yang,Zhi Jiang,Tian Sheng,Huanqiu Li,Qinghua Hu
标识
DOI:10.1038/s41467-024-46365-x
摘要
Abstract Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y 14 R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y 14 R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y 14 R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y 14 R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y 14 R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1 , inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y 14 R antagonist HDL-16 , which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y 14 R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.
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