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Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-?1/Smad3 and Wnt/?-Catenin Signaling Pathways.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-?1/Smad3 and Wnt/?-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-?R1, Smad3, Wnt3a, and GSK-3? through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3?, and ?-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.

SUBMITTER: Yang F

PROVIDER: S-EPMC7878558 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-β1/Smad3 and Wnt/β-Catenin Signaling Pathways.

Yang Fan F Hou Zhen-Feng ZF Zhu Hao-Yue HY Chen Xiao-Xuan XX Li Wan-Yang WY Cao Ren-Shuang RS Li Yu-Xuan YX Chen Ru R Zhang Wei W

Frontiers in pharmacology 20210129

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from <i>Rehmannia glutinosa</i>, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF ...[more]

PMID: 33584272

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Project description:BackgroundBuyang Huanwu Decoction (BHD) is a classical Chinese Medicine formula empirically used for diabetic nephropathy (DN). However, its therapeutic efficacies and the underlying mechanisms remain obscure. In our study, we aim to evaluate the renoprotective effect of BHD on a streptozotocin (STZ)-induced diabetic nephropathy mouse model and explore the potential underlying mechanism in mouse mesangial cells (MCs) treated with high glucose in vitro, followed by screening the active compounds in BHD.MethodsMice were received 50 mg/kg streptozotocin (STZ) or citrate buffer intraperitoneally for 5 consecutive days. BHD was intragastrically administrated for 12 weeks starting from week 4 after the diabetes induction. The quality control and quantitative analysis of BHD were studied by high-performance liquid chromatography (HPLC). Renal function was evaluated by urinary albumin excretion (UAE) using ELISA. The mesangial matrix expansion and renal fibrosis were measured using periodic acid-schiff (PAS) staining and Masson Trichrome staining. Mouse mesangial cells (MCs) were employed to study molecular mechanisms.ResultsWe found that the impaired renal function in diabetic nephropathy was significantly restored by BHD, as indicated by the decreased UAE without affecting the blood glucose level. Consistently, BHD markedly alleviated STZ-induced diabetic glomerulosclerosis and tubulointerstitial injury as shown by PAS staining, accompanied by a reduction of renal inflammation and fibrosis. Mechanistically, BHD inhibited the activation of TGF-β1/Smad3 and NF-κB signaling in diabetic nephropathy while suppressing Arkadia expression and restoring renal Smad7. We further found that calycosin-7-glucoside (CG) was one of the active compounds from BHD, which significantly suppressed high glucose-induced inflammation and fibrosis by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways in mesangial cells.ConclusionBHD could attenuate renal fibrosis and inflammation in STZ-induced diabetic kidneys via inhibiting TGF-β1/Smad3 and NF-κB signaling while suppressing the Arkadia and restoring renal Smad7. CG could be one of the active compounds in BHD to suppress renal inflammation and fibrosis in diabetic nephropathy.

Dataset Information

Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-?1/Smad3 and Wnt/?-Catenin Signaling Pathways.

Publications

Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-β1/Smad3 and Wnt/β-Catenin Signaling Pathways.

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