Previous studies show that astragaloside IV (ASIV) has anti-renal fibrosis effects. However, its mechanism remains elusive. In this study, we investigated the anti-fibrosis mechanisms of ASIV on chronic kidney disease (CKD) in vivo and in vitro. A CKD model was induced in rats with adenine (200 mg/kg/d, i.g.), and an in vitro renal fibrosis model was induced in human kidney-2 (HK-2) cells treated with TGF-β1. We revealed that ASIV significantly alleviated renal fibrosis by suppressing the expressions of epithelial–mesenchymal transition (EMT)-related proteins, including fibronectin, vimentin, and alpha-smooth muscle actin (α-SMA), and G2/M arrest-related proteins, including phosphorylated p53 (p-p53), p21, phosphorylated histone H3 (p-H3), and Ki67 in both of the in vivo and in vitro models. Transcriptomic analysis and subsequent validation showed that ASIV rescued ALDH2 expression and inhibited AKT/mTOR-mediated autophagy. Furthermore, in ALDH2-knockdown HK-2 cells, ASIV failed to inhibit AKT/mTOR-mediated autophagy and could not blunt EMT and G2/M arrest. In addition, we further demonstrated that rapamycin, an autophagy inducer, reversed the treatment of ASIV by promoting autophagy in TGF-β1-treated HK-2 cells. A dual-luciferase report assay indicated that ASIV enhanced the transcriptional activity of the ALDH2 promoter. In addition, a further molecular docking analysis showed the potential interaction of ALDH2 and ASIV. Collectively, our data indicate that ALDH2-mediated autophagy may be a novel target in treating renal fibrosis in CKD models, and ASIV may be an effective targeted drug for ALDH2, which illuminate a new insight into the treatment of renal fibrosis and provide new evidence of pharmacology to elucidate the anti-fibrosis mechanism of ASIV in treating renal fibrosis.
Background Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder often accompanied by chronic low-grade inflammation. Western medicine often causes negative side effects, such as premature ovarian failure. Therefore, this study evaluates the efficacy of modified Guishen pill (MGP) in ameliorating letrozole-induced PCOS in rats. Methods Six-week-old specific-pathogen free (SPF) female Sprague-Dawley rats were randomly divided into a blank group (Blank), model group (Model), positive group (Diane-35, 0.2 mg/kg BW), high dose MGP group (H.MGP, 23.96 g/kg BW), medium dose MGP group (M.MGP, 11.98 g/kg BW), and low dose MGP group (L.MGP, 5.99 g/kg BW). After 4 weeks of treatment, plasma, ovaries, and fecal samples were collected from the rats for analysis. Results MGP treatment improved ovarian function by improving estrous cycle, ovarian morphology, and endocrine functions in letrozole-induced PCOS rats. MGP alleviated inflammation by reducing macrophage infiltration and inhibiting the activation of NF-κB and MAPK pathways in the ovaries of letrozole-induced PCOS rats. 16S rDNA sequencing of the intestinal microbiome indicated that MGP regulated gut microbiota structure and restored gut microbiota dysbiosis. MGP significantly increased the relative abundance of bifidobacteria at the order, family, and genus levels. Moreover, correlation analysis showed that gut microbiota were correlated with the host phenotype of letrozole-induced PCOS rats. Conclusion MGP treatment could ameliorate letrozole-induced PCOS by improving ovarian function, reducing inflammation, and regulating the gut microbiota.
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