TGF-β1-induced EMT activation via both Smad-dependent and MAPK signaling pathways in Cu-induced pulmonary fibrosis

Background: Coronavirus Disease 2019 (COVID-19) is still a relevant global problem. Although some patients have recovered from COVID-19, the sequalae to the SARS-CoV-2 infection may include pulmonary fibrosis, which may contribute to considerable economic burden and health-care challenges. Convalescent Chinese Prescription (CCP) has been widely used during the COVID-19 recovery period for patients who were at high risk of pulmonary fibrosis and is recommended by the Diagnosis and Treatment Protocol for COVID-19 (Trial Version sixth, seventh). However, its underlying mechanism is still unclear.Methods: In this study, an integrated pharmacology approach was implemented, which involved evaluation of absorption, distribution, metabolism and excretion of CCP, data mining of the disease targets, protein-protein interaction (PPI) network construction, and analysis, enrichment analysis, and molecular docking simulation, to predict the bioactive components, potential targets, and molecular mechanism of CCP for pulmonary fibrosis associated with SARS-CoV-2 infection.Results: The active compound of CCP and the candidate targets, including pulmonary fibrosis targets, were obtained through database mining. The Drug-Disease network was constructed. Sixty-five key targets were identified by topological analysis. The findings of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation suggested that the VEGF, Toll-like 4 receptor, MAPK signaling pathway, and TGF-β1 signaling pathways may be involved in pulmonary fibrosis. In the molecular docking analyses, VEGF, TNF-α, IL-6, MMP9 exhibited good binding activity. Findings from our study indicated that CCP could inhibit the expression of VEGF, TNF-α, IL-6, MMP9, TGF-β1 via the VEGF, Toll-like 4 receptor, MAPK, and TGF-β1 signaling pathways.Conclusion: Potential mechanisms involved in CCP treatment for COVID-19 pulmonary fibrosis associated with SARS-CoV-2 infection involves multiple components and multiple target points as well as multiple pathways. These findings may offer a profile for further investigations of the anti-fibrotic mechanism of CCP.

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Diosmetin prevents TGF-β1-induced epithelial-mesenchymal transition via ROS/MAPK signaling pathways

Life Sciences ◽

10.1016/j.lfs.2016.04.023 ◽

2016 ◽

Vol 153 ◽

pp. 1-8 ◽

Cited By ~ 27

Author(s):

Ai Ge ◽

Yuan Ma ◽

Ya-Nan Liu ◽

Ye-Shan Li ◽

Hao Gu ◽

...

Keyword(s):

Signaling Pathways ◽

Epithelial Mesenchymal Transition ◽

Mapk Signaling ◽

Mesenchymal Transition ◽

Mapk Signaling Pathways ◽

Tgf Β1

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Isorhamnetin Inhibits Liver Fibrosis by Reducing Autophagy and Inhibiting Extracellular Matrix Formation via the TGF-β1/Smad3 and TGF-β1/p38 MAPK Pathways

Mediators of Inflammation ◽

10.1155/2019/6175091 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Ning Liu ◽

Jiao Feng ◽

Xiya Lu ◽

Zhilu Yao ◽

Qing Liu ◽

...

Keyword(s):

Extracellular Matrix ◽

Liver Fibrosis ◽

Signaling Pathways ◽

P38 Mapk ◽

Transforming Growth Factor ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Duct Ligation ◽

Mapk Signaling Pathways ◽

Tgf Β1

Objective. Liver fibrosis is a consequence of wound-healing responses to chronic liver insult and may progress to liver cirrhosis if not controlled. This study investigated the protection against liver fibrosis by isorhamnetin. Methods. Mouse models of hepatic fibrosis were established by intraperitoneal injection of carbon tetrachloride (CCl4) or bile duct ligation (BDL). Isorhamnetin 10 or 30 mg/kg was administered by gavage 5 days per week for 8 weeks in the CCl4 model and for 2 weeks in the BDL model. Protein and mRNA expressions were assayed by western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction. Results. Isorhamnetin significantly inhibited liver fibrosis in both models, inhibiting hepatic stellate cell (HSC) activation, extracellular matrix (ECM) deposition, and autophagy. The effects were associated with downregulation of transforming growth factor β1 (TGF-β1) mediation of Smad3 and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Conclusion. Isorhamnetin protected against liver fibrosis by reducing ECM formation and autophagy via inhibition of TGF-β1-mediated Smad3 and p38 MAPK signaling pathways.

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Differential Activation of MAPK Signaling Pathways by TGF-β1 Forms the Molecular Mechanism Behind Its Dose-Dependent Bidirectional Effects on Hematopoiesis

Stem Cells and Development ◽

10.1089/154732804773099236 ◽

2004 ◽

Vol 13 (1) ◽

pp. 27-38 ◽

Cited By ~ 29

Author(s):

V.P. Kale

Keyword(s):

Signaling Pathways ◽

Molecular Mechanism ◽

Mapk Signaling ◽

Differential Activation ◽

Dose Dependent ◽

Mapk Signaling Pathways ◽

Tgf Β1 ◽

Bidirectional Effects

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Salidroside Ameliorates Renal Interstitial Fibrosis by Inhibiting the TLR4/NF-κB and MAPK Signaling Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms20051103 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1103 ◽

Cited By ~ 8

Author(s):

Rui Li ◽

Yujuan Guo ◽

Yiming Zhang ◽

Xue Zhang ◽

Lingpeng Zhu ◽

...

Keyword(s):

Signaling Pathways ◽

Inflammatory Cytokines ◽

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Mapk Signaling ◽

Renal Interstitial Fibrosis ◽

Mapk Signaling Pathways ◽

Tgf Β1

Salidroside (Sal) is an active ingredient that is isolated from Rhodiola rosea, which has been reported to have anti-inflammatory activities and a renal protective effect. However, the role of Sal on renal fibrosis has not yet been elucidated. Here, the purpose of the current study is to test the protective effects of Sal against renal interstitial fibrosis (RIF), and to explore the underlying mechanisms using both in vivo and in vitro models. In this study, we establish the unilateral ureteric obstruction (UUO) or folic acid (FA)-induced mice renal interstitial fibrosis in vivo and the transforming growth factor (TGF)-β1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro. The levels of kidney functional parameters and inflammatory cytokines in serum are examined. The degree of renal damage and fibrosis is determined by histological assessment. Immunohistochemistry and western blotting are used to determine the mechanisms of Sal against RIF. Our results show that treatment with Sal can ameliorate tubular injury and deposition of the extracellular matrix (ECM) components (including collagen Ш and collagen I). Furthermore, Sal administration significantly suppresses epithelial-mesenchymal transition (EMT), as evidenced by a decreased expression of α-SMA, vimentin, TGF-β1, snail, slug, and a largely restored expression of E-cadherin. Additionally, Sal also reduces the levels of serum biochemical markers (serum creatinine, Scr; blood urea nitrogen, BUN; and uric acid, UA) and decreases the release of inflammatory cytokines (IL-1β, IL-6, TNF-α). Further study revealed that the effect of Sal on renal interstitial fibrosis is associated with the lower expression of TLR4, p-IκBα, p-NF-κB and mitogen-activated protein kinases (MAPK), both in vivo and in vitro. In conclusion, Sal treatment improves kidney function, ameliorates the deposition of the ECM components and relieves the protein levels of EMT markers in mouse kidneys and HK-2 cells. Furthermore, Sal treatment significantly decreases the release of inflammatory cytokines and inhibits the TLR4/NF-κB and MAPK signaling pathways. Collectively, these results suggest that the administration of Sal could be a novel therapeutic strategy in treating renal fibrosis.

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