Targeting TGR5 Ameliorates Pulmonary Fibrosis by Regulating TGF-β1 Associated Signaling Pathways

2020 ◽  
Author(s):  
Xueqing Liu ◽  
Bi Chen ◽  
Lifang Zhao ◽  
Wenjie You ◽  
Fangfang Wang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Tgf Β1

scholarly journals Potential Mechanism Prediction of Herbal Medicine for Pulmonary Fibrosis Associated with SARS-CoV-2 Infection Based on Network Analysis and Molecular Docking

2021 ◽  
Vol 12 ◽  
Author(s):  
De Jin ◽  
Xuedong An ◽  
Yuqing Zhang ◽  
Shenghui Zhao ◽  
Liyun Duan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Topological Analysis ◽  
Recovery Period ◽  
Treatment Protocol ◽  
Docking Simulation ◽  
Mapk Signaling ◽  
Tnf Α ◽  
Tgf Β1

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.

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

2021 ◽  
Vol 11 ◽  
Author(s):  
Fan Yang ◽  
Zhen-feng Hou ◽  
Hao-yue Zhu ◽  
Xiao-xuan Chen ◽  
Wan-yang Li ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Gene Expression Omnibus ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Collagen Remodeling ◽  
Gsk 3Β ◽  
Tgf Β1

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-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-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.

Costunolide inhibits pulmonary fibrosis via regulating NF-kB and TGF-β1/Smad2/Nrf2-NOX4 signaling pathways

2019 ◽  
Vol 510 (2) ◽  
pp. 329-333 ◽  
Author(s):  
Bin Liu ◽  
Yumei Rong ◽  
Dan Sun ◽  
Wuwei Li ◽  
Hong Chen ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Tgf Β1

scholarly journals Azithromycin Attenuates Bleomycin-Induced Pulmonary Fibrosis Partly by Inhibiting the Expression of LOX and LOXL-2

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiang Tong ◽  
Shijie Zhang ◽  
Dongguang Wang ◽  
Li Zhang ◽  
Jizheng Huang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Lung Tissue ◽  
Type I Collagen ◽  
Lysyl Oxidase ◽  
Specific Inhibitor ◽  
Lung Fibroblasts ◽  
Type I ◽  
Primary Mouse ◽  
Tgf Β1

Pulmonary fibrosis (PF) is a chronic and progressive process of tissue repair. Azithromycin (AZM) may be beneficial for the treatment of PF because AZM has anti-inflammatory and immune regulatory roles and inhibits remodeling, but the mechanism is not entirely clear. In this study, we established a mouse PF model induced by bleomycin (BLM) and primary mouse lung fibroblasts stimulated by transforming growth factor (TGF)-β1 to explore the possible mechanisms of AZM in PF. Results showed that AZM reduces mortality and lung inflammation and attenuates BLM-induced PF in mice. AZM effectively reduced the expression of α-smooth muscle actin (SMA) and type I collagen. Meanwhile, expression of lysyl oxidase (LOX) and lysyl oxidase-like protein (LOXL)-2 in the lung tissue of mice after AZM treatment was significantly lower than in the BLM group. In addition, this study found that AZM significantly inhibits the TGF-β1/Smad and JNK/c-Jun signaling pathways in vivo, and expression of a-SMA, type I collagen, LOX and LOXL-2 in the lung tissue of mice treated with AZM was significantly lower than that in the BLM group. In vitro, AZM also effectively inhibited type I collagen, LOX, LOXL-2 and JNK-c-Jun signaling pathways in TGF-β1-stimulated primary mouse fibroblasts, and this effect was similar to that of a JNK-specific inhibitor (SP600125). In conclusion, AZM effectively attenuated BLM-induced PF in mice, which may play a role by partially inhibiting the JNK/c-Jun and TGF-β1/Smad signaling pathways and reducing production of LOX and LOXL2.

scholarly journals COVID-19: Immunohistochemical Analysis of TGF-β Signaling Pathways in Pulmonary Fibrosis

2021 ◽  
Vol 23 (1) ◽  
pp. 168
Author(s):  
Caroline Busatta Vaz de Vaz de Paula ◽  
Seigo Nagashima ◽  
Vanessa Liberalesso ◽  
Mariana Collete ◽  
Felipe Paes Gomes da da Silva ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Diffuse Alveolar Damage ◽  
Life Quality ◽  
Immunohistochemical Analysis ◽  
Tissue Expression ◽  
Control Group ◽  
Caveolin 1 ◽  
Injury Control ◽  
Tgf Β1

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-β is intimately involved in the fibrogenic process. When activated, TGF-β promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-β1 tissue expression) involved in the TGF-β1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-β1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-β pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-β inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.

scholarly journals TGF-β1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways

2007 ◽  
Vol 293 (3) ◽  
pp. L790-L799 ◽  
Author(s):  
Mickey M. Martin ◽  
Jessica A. Buckenberger ◽  
Jinmai Jiang ◽  
Geraldine E. Malana ◽  
Daren L. Knoell ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Lung Fibroblasts ◽  
Pi3k Signaling ◽  
R Gene ◽  
Ang Ii ◽  
Tgf Β1

Both angiotensin II (ANG II) and transforming growth factor-β1 (TGF-β1) are thought to be involved in mediating pulmonary fibrosis. Interactions between the renin-angiotensin system (RAS) and TGF-β1 have been well documented, with most studies describing the effect of ANG II on TGF-β1 expression. However, recent gene expression profiling experiments demonstrated that the angiotensin II type 1 receptor (AT1R) gene was a novel TGF-β1 target in human adult lung fibroblasts. In this report, we show that TGF-β1 augments human AT1R (hAT1R) steady-state mRNA and protein levels in a dose- and time-dependent manner in primary human fetal pulmonary fibroblasts (hPFBs). Nuclear run-on experiments demonstrate that TGF-β1 transcriptionally activates the hAT1R gene and does not influence hAT1R mRNA stability. Pharmacological inhibitors and specific siRNA knockdown experiments demonstrate that the TGF-β1 type 1 receptor (TβRI/ALK5), Smad2/3, and Smad4 are essential for TGF-β1-stimulated hAT1R expression. Additional pharmacological inhibitor and small interference RNA experiments also demonstrated that p38 MAPK, JNK, and phosphatidylinositol 3-kinase (PI3K) signaling pathways are also involved in the TGF-β1-stimulated increase in hAT1R density. Together, our results suggest an important role for cross talk among Smad, p38 MAPK, JNK, and PI3K pathways in mediating the augmented expression of hAT1R following TGF-β1 treatment in hPFB. This study supports the hypothesis that a self-potentiating loop exists between the RAS and the TGF-β1 signaling pathways and suggests that ANG II and TGF-β1 may cooperate in the pathogenesis of pulmonary fibrosis. The synergy between these systems may require that both pathways be simultaneously inhibited to treat fibrotic lung disease.

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

2021 ◽  
Vol 418 ◽  
pp. 115500
Author(s):  
Hongrui Guo ◽  
Zhijie Jian ◽  
Huan Liu ◽  
Hengmin Cui ◽  
Huidan Deng ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Mapk Signaling ◽  
Mapk Signaling Pathways ◽  
Tgf Β1

scholarly journals Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3β/β-catenin and TGF-β1/Smad2/3 signaling pathways

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Qun Lv ◽  
Jianjun Wang ◽  
Changqing Xu ◽  
Xuqing Huang ◽  
Zhaoyang Ruan ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Gsk 3Β ◽  
Tgf Β1

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

scholarly journals Urolithin A attenuates renal fibrosis by inhibiting TGF-β1/Smad and MAPK signaling pathways

2021 ◽  
Vol 83 ◽  
pp. 104547
Author(s):  
Zhenzhen Cheng ◽  
Jingjing Tu ◽  
Hongpan Zhang ◽  
Yi zhang ◽  
Benhong Zhou
Keyword(s):  
Signaling Pathways ◽  
Renal Fibrosis ◽  
Mapk Signaling ◽  
Urolithin A ◽  
Mapk Signaling Pathways ◽  
Tgf Β1
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