穿心莲
纤维化
穿心莲内酯
医学
蛋白激酶B
肾
PI3K/AKT/mTOR通路
癌症研究
药理学
细胞凋亡
炎症
坏死
化学
病理
内科学
生物化学
替代医学
作者
Zhenzhen Guan,Yaming Wang,Haiwei Xu,Yake Wang,Di Wu,Zhizi Zhang,Zihan Liu,Ning Shang,Di Zhang,Jing Sun,Xinyi He,Yingxue Li,Lina Zhu,Zhentao Liu,Mingliang Zhang,Zhihao Xu,Zhe Song,Gui‐Fu Dai
标识
DOI:10.1016/j.intimp.2022.109201
摘要
Tubulointerstitial fibrosis (TIF) is a prominent pathological manifestation for the progression of almost all chronic kidney diseases (CKDs) to end-stage renal failure. However, there exist few efficient therapies to cure TIF. Our recent results showed that (8R, 12S)-isoandrographolide (ISA), a diterpenoid lactone ingredient of traditional Chinese herbal Andrographis paniculata (Burm.f.) Nees, exhibited anti-pulmonary fibrosis in silica-induced mice. Herein, we investigated the therapeutic effect of ISA on TIF, using mice subjected to unilateral ureteral obstruction (UUO) and human kidney proximal tubular epithelial (HK-2) cells treated with transforming growth factor-β1 (TGF-β1) or tumor necrosis factor-α (TNF-α). The pathological changes and collagen deposition results displayed that ISA administration significantly attenuated inflammatory response, ameliorated TIF, and protected the kidney injury. Interestingly, ISA revealed much lower cytotoxicity on HK-2 cells, but exhibited stronger inhibitory effect on tubular epithelial mesenchymal transformation (EMT) and inflammation, as compared to andrographolide (AD), the major ingredient of A. paniculata extract that has been reported to ameliorate TIF in diabetic nephropathy mice. It was further clarified that the amelioration of TIF by ISA was associated with suppressing the aberrant activation of AKT/GSK-3β/β-catenin pathway through network pharmacology analysis and experimental validation. Taken together, these findings indicate that ISA is a promising lead compound for development of anti-TIF, and even broad-spectrum anti-fibrotic drugs.
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