scholarly journals Network pharmacology-based mechanistic investigation of Jinshui Huanxian formula acing on idiopathic pulmonary fibrosis

2020 ◽  
Author(s):  
Tiantian Liu ◽  
Pengli Xu ◽  
Shuishui Qi ◽  
Shaorui Ke ◽  
Qin Hu ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Drug Targets ◽  
Target Genes ◽  
Receptor Protein ◽  
Disease Genes ◽  
Protein Kinase Activity ◽  
Mesenchymal Transition ◽  
Mechanistic Investigation

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease with high incidence rate, morbidity and mortality. Jinshui Huanxian formula (JHF) is an empirical formula for the pathogenesis of lung-kidney qi deficiency and phlegm-blood stasis in pulmonary fibrosis. The purpose of this study is to explore the pharmacological mechanism of JHF action in IPF therapy by network interaction analysis. Methods The main active components and corresponding target genes of JHF were predicted using various databases. Two sets of IPF disease genes were obtained from the DisGeNET database and GEO database. Two sets of drug targets for IPF treatment were collected and the overlapping genes between disease genes and drug targets were analyzed. The target genes of JHF were intersected with the differentially expressed genes of IPF to obtain the predicted targets of JHF acting on IPF. The functions and pathways of predicted targets acting on IPF were analyzed by using DAVID and KEGG pathway database. Finally, the resulting drug target mechanisms were validated in a rat model of pulmonary fibrosis. Results 494 active compounds and 1304 corresponding targets were screened. Intersection analysis showed that 4 genes were common genes of JHF targets, IPF disease genes and anti-IPF drugs in KEGG database, and these genes were targeted by several compounds of JHF respectively. 72 JHF targets were closely related with IPF, and were thus considered therapeutically relevant. The targets were screened and participated in the regulation of IPF through 18 pathways. The molecular functions of targets included regulation of oxidoreductase activity, kinase regulator activity, phosphotransferase activity and transmembrane receptor protein kinase activity. In vivo experiments showed that JHF could alleviate the degree of pulmonary fibrosis, including the decrease of collagen deposition and epithelial-mesenchymal transition. Conclusions This study explored the mechanisms of JHF from a systematic point of view, trying to identify the specific target pathways acing on IPF. Pharmacological network with in vivo validation explained the potential roles and mechanisms of JHF in IPF therapy.

scholarly journals Network Pharmacology-Based Mechanistic Investigation of Jinshui Huanxian Formula Acting on Idiopathic Pulmonary Fibrosis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Tiantian Liu ◽  
Pengli Xu ◽  
Shuishui Qi ◽  
Shaorui Ke ◽  
Qin Hu ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Drug Target ◽  
Target Genes ◽  
Receptor Protein ◽  
Protein Kinase Activity ◽  
Mesenchymal Transition ◽  
Mechanistic Investigation ◽  
Intersection Analysis

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease with high incidence, morbidity, and mortality rates. Jinshui Huanxian formula (JHF) is an empirical formula that targets the pathogenesis of lung-kidney qi deficiency and phlegm-blood stasis in pulmonary fibrosis (PF). The purpose of this study was to explore JHF’s potential pharmacological mechanisms in IPF therapy using network intersection analysis. JHF’s primary active components and corresponding target genes were predicted using various databases. Two sets of IPF disease genes were obtained from the DisGeNET and GEO databases and two sets of IPF drug targets were collected. The disease and drug target genes were analyzed. The JHF target genes that intersected with IPF’s differentially expressed genes were identified to predict JHF’s targets of action in IPF. The functions and pathways of predicted targets acting on IPF were analyzed using the DAVID and KEGG pathway databases. Finally, the resulting drug target mechanisms were validated in a rat model of PF. The initial analyses identified 494 active compounds and 1,304 corresponding targets for JHF. The intersection analysis revealed four common genes for the JHF targets, IPF disease, and anti-IPF drugs in the KEGG database. Furthermore, these genes were targeted by several JHF compounds. Seventy-two JHF targets were closely related to IPF, which suggests that they are therapeutically relevant. Target screening revealed that they regulate IPF through 18 pathways. The targets’ molecular functions included regulation of oxidoreductase activity, kinase regulator activity, phosphotransferase activity, and transmembrane receptor protein kinase activity. In vivo experiments showed that JHF alleviated the degree of PF, including decreases in collagen deposition and epithelial-mesenchymal transition. This study systematically explored JHF’s mechanisms to identify the specific target pathways involved in IPF. The generated pharmacological network, paired with in vivo validation, elucidates the potential roles and mechanisms of JHF in IPF therapy.

scholarly journals Potential function and molecular mechanism of circRNAs involved in idiopathic pulmonary fibrosis

2020 ◽  
Author(s):  
Fangwei Li ◽  
Hong Wang ◽  
Hongyan Tao ◽  
Fanqi Wu ◽  
Dan Wang ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Molecular Mechanism ◽  
Target Genes ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Differentially Expressed ◽  
Circular Rnas

Abstract Background: Recent studies have found a regulatory role of circular RNAs (circRNAs) in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the function and underlying molecular mechanism of circRNAs involved in IPF are uncertain and incomplete. This study aimed to further provide some critical information for the circRNA function in IPF using bioinformatic analysis. Methods: We searched in the NCBI (National Center for Biotechnology Information) Gene Expression Omnibus (GEO) database to find the circRNA expression profiles of human IPF. The microarray data GSE102660 was obtained and differentially expressed circRNAs were identified through R software. Results: 6 significantly up-regulated and 13 significantly down-regulated circRNAs were identified involved in the pathogenesis of IPF. The binding sites of miRNAs for each differentially expressed circRNA were also predicted and circRNA-miRNA-mRNA networks were constructed for the most up-regulated hsa_circ_0004099 and down-regulated hsa_circ_0029633. In addition, GO and KEGG enrichment analysis revealed the molecular function and enriched pathways of the target genes of circRNAs in IPF.Conclusion: These findings suggest that candidate circRNAs might serve an important role in the pathogenesis of IPF. Therefore, these circRNAs might be potential biomarkers for diagnosis and promising targets for treatment of IPF, which still need further verification in vivo and in vitro.

scholarly journals microRNA-186 in extracellular vesicles from bone marrow mesenchymal stem cells alleviates idiopathic pulmonary fibrosis via interaction with SOX4 and DKK1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Zhou ◽  
Yang Lin ◽  
Xiuhua Kang ◽  
Zhicheng Liu ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Extracellular Vesicles ◽  
Luciferase Assay ◽  
Therapeutic Effects ◽  
Loss Of Function ◽  
Fibroblast Activation ◽  
Promising Therapeutic Approach

Abstract Background Previous reports have identified that human bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) with their cargo microRNAs (miRNAs) are a promising therapeutic approach for the treatment of idiopathic pulmonary fibrosis (IPF). Therefore, we explored whether delivery of microRNA-186 (miR-186), a downregulated miRNA in IPF, by BMSC EVs could interfere with the progression of IPF in a murine model. Methods In a co-culture system, we assessed whether BMSC-EVs modulated the activation of fibroblasts. We established a mouse model of PF to evaluate the in vivo therapeutic effects of BMSC-EVs and determined miR-186 expression in BMSC-EVs by polymerase chain reaction. Using a loss-of-function approach, we examined how miR-186 delivered by BMSC-EVs affected fibroblasts. The putative relationship between miR-186 and SRY-related HMG box transcription factor 4 (SOX4) was tested using luciferase assay. Next, we investigated whether EV-miR-186 affected fibroblast activation and PF by targeting SOX4 and its downstream gene, Dickkopf-1 (DKK1). Results BMSC-EVs suppressed lung fibroblast activation and delayed IPF progression in mice. miR-186 was downregulated in IPF but enriched in the BMSC-EVs. miR-186 delivered by BMSC-EVs could suppress fibroblast activation. Furthermore, miR-186 reduced the expression of SOX4, a target gene of miR-186, and hence suppressed the expression of DKK1. Finally, EV-delivered miR-186 impaired fibroblast activation and alleviated PF via downregulation of SOX4 and DKK1. Conclusion In conclusion, miR-186 delivered by BMSC-EVs suppressed SOX4 and DKK1 expression, thereby blocking fibroblast activation and ameliorating IPF, thus presenting a novel therapeutic target for IPF.

scholarly journals Overlapping effects of miR-21 inhibition and drugs for idiopathic pulmonary fibrosis in the post-myocardial infarction setting

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
A Aimo ◽  
O Iborra Egea ◽  
C Passino ◽  
M Emdin
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Protein Interactions ◽  
Target Genes ◽  
Cardiac Fibrosis ◽  
Biological Significance ◽  
Oral Drugs ◽  
Network Analyses ◽  
Funding Sources ◽  
And Migration

Abstract Background Intracoronary infusion of a specific miR-21 inhibitor after reperfused MI has been reported to reduce cardiac fibrosis and hypertrophy and improve cardiac function in pigs. Possible drawbacks of anti-miR-21 therapy are the high costs of this therapy, and the need for intracoronary administration, preferably some days after reperfusion. Oral drugs with anti-fibrotic actions could have similar effects than anti-miR-21, while overcoming the limitations of anti-miR-21. We tested this hypothesis by examining the two oral drugs approved for idiopathic pulmonary fibrosis (nintedanib and pirfenidone). Methods We identified the regulatory profile of miR-21, which included 588 target genes. Only 99 of these interactions were supported by information from reporter gene assays. The biological significance of these 99 targets was evaluated through over-representation analysis, and 13 genes were identified as potentially related to cardiovascular diseases. We retrieved all known targets and main downstream interactions of nintedanib and pirfenidone from Drugbank. Finally, we cross-validated these datasets by using neural network analyses to search for protein-protein interactions, focusing on those shared by miR-21 inhibition, nintedanib and pirfenidone. Results Nintedanib and anti-miR21 had many targets in common, which could indicate an overlap in their corresponding mechanisms of action. The proto-oncogene SRC, which participates in gene transcription, immune response, apoptosis and migration, emerged as the leading signaling effector. By blocking SRC expression and many downstream effectors of SRC, as well as platelet-derived growth factor, nintedanib could decreased miR-21 expression. The molecular effects of nintedanib include inhibition of inflammation, fibrosis and angiogenesis, and then ultimately a relief from I/R injury, in a similar fashion than anti-miR-21. Contrary to nintedanib, no overlap between the effects of pirfenidone and anti-miR-21 was found. Conclusion Because of the remarkably strong overlapping with the targets of miR-21, there is a stronger rationale to assess nintedanib than pirfenidone as a cardioprotective therapy. If confirmed by experimental evidence, nintedanib could enter the stage of clinical trials to assess its efficacy in human patients with STEMI. Funding Acknowledgement Type of funding sources: None.

scholarly journals Airway Basal Cells show a dedifferentiated KRT17highPhenotype and promote Fibrosis in Idiopathic Pulmonary Fibrosis

2020 ◽  
Author(s):  
Benedikt Jaeger ◽  
Jonas Christian Schupp ◽  
Linda Plappert ◽  
Oliver Terwolbeck ◽  
Gian Kayser ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
De Novo ◽  
3D Culture ◽  
Xenograft Model ◽  
Basal Cells ◽  
Matrix Deposition ◽  
Mouse Xenograft Model

ABSTRACTIdiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. In this study we focus on the profibrotic properties of airway basal cells (ABC) obtained from patients with IPF (IPF-ABC). Single cell RNA sequencing of bronchial brushes revealed extensive reprogramming of IPF-ABC towards a KRT17high PTENlow dedifferentiated cell type. In the 3D organoid model, compared to ABC obtained from healthy volunteers, IPF-ABC give rise to more bronchospheres, de novo bronchial structures resembling lung developmental processes, induce fibroblast proliferation and extracellular matrix deposition in co-culture. Intratracheal application of IPF-ABC into minimally injured lungs of Rag2-/- or NRG mice causes severe fibrosis, remodeling of the alveolar compartment, and formation of honeycomb cyst-like structures. Connectivity MAP analysis of scRNA seq of bronchial brushings suggested that gene expression changes in IPF-ABC can be reversed by SRC inhibition. After demonstrating enhanced SRC expression and activity in these cells, and in IPF lungs, we tested the effects of saracatinib, a potent SRC inhibitor previously studied in humans. We demonstrated that saracatinib modified in-vitro and in-vivo the profibrotic changes observed in our 3D culture system and novel mouse xenograft model.

scholarly journals Protective Effect of Remdesivir Against Pulmonary Fibrosis in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaohe Li ◽  
Rui Liu ◽  
Yunyao Cui ◽  
Jingjing Liang ◽  
Zhun Bi ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Antiviral Drug ◽  
Alveolar Epithelial Cells ◽  
Lung Damage ◽  
Lung Fibroblasts ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Tgf Β1

Pulmonary fibrosis is a known sequela of severe or persistent lung damage. Existing clinical, imaging and autopsy studies have shown that the lungs exhibit a pathological pulmonary fibrosis phenotype after infection with coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pulmonary fibrosis may be one of the most serious sequelae associated with coronavirus disease 2019 (COVID-19). In this study, we aimed to examine the preventative effects of the antiviral drug remdesivir on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of remdesivir on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of remdesivir in lung fibroblasts and alveolar epithelial cells in vitro. The preventive remdesivir treatment was started on the day of bleomycin installation, and the results showed that remdesivir significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro experiments showed that remdesivir dose-dependently suppressed TGF-β1-induced lung fibroblast activation and improved TGF-β1-induced alveolar epithelial to mesenchymal transition. Our results indicate that remdesivir can preventatively alleviate the severity of pulmonary fibrosis and provide some reference for the prevention of pulmonary fibrosis in patients with COVID-19.

scholarly journals TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis

2017 ◽  
Vol 24 (11) ◽  
pp. 565-578 ◽  
Author(s):  
Hongqiang Wang ◽  
Rui Zhou ◽  
Li Sun ◽  
Jianling Xia ◽  
Xuchun Yang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Topoisomerase I ◽  
Target Genes ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Migration And Invasion ◽  
Glucose Transporter 1 ◽  
Mesenchymal Transition

Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo. Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression.

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