Network-based identification genetic effect of SARS-CoV-2 infections to Idiopathic pulmonary fibrosis (IPF) patients

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is accountable for the cause of coronavirus disease (COVID-19) that causes a major threat to humanity. As the spread of the virus is probably getting out of control on every day, the epidemic is now crossing the most dreadful phase. Idiopathic pulmonary fibrosis (IPF) is a risk factor for COVID-19 as patients with long-term lung injuries are more likely to suffer in the severity of the infection. Transcriptomic analyses of SARS-CoV-2 infection and IPF patients in lung epithelium cell datasets were selected to identify the synergistic effect of SARS-CoV-2 to IPF patients. Common genes were identified to find shared pathways and drug targets for IPF patients with COVID-19 infections. Using several enterprising Bioinformatics tools, protein–protein interactions (PPIs) network was designed. Hub genes and essential modules were detected based on the PPIs network. TF-genes and miRNA interaction with common differentially expressed genes and the activity of TFs are also identified. Functional analysis was performed using gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway and found some shared associations that may cause the increased mortality of IPF patients for the SARS-CoV-2 infections. Drug molecules for the IPF were also suggested for the SARS-CoV-2 infections.

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Gene Expression Changes Associated with Nintedanib Treatment in Idiopathic Pulmonary Fibrosis Fibroblasts: A Next-Generation Sequencing and Bioinformatics Study

Journal of Clinical Medicine ◽

10.3390/jcm8030308 ◽

2019 ◽

Vol 8 (3) ◽

pp. 308 ◽

Cited By ~ 7

Author(s):

Chau-Chyun Sheu ◽

Wei-An Chang ◽

Ming-Ju Tsai ◽

Ssu-Hui Liao ◽

Inn-Wen Chong ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Next Generation Sequencing ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Protein Interactions ◽

Next Generation ◽

Protein Protein Interactions ◽

Bioinformatics Study ◽

Generation Sequencing

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease. Therapeutic options for IPF remain limited. Nintedanib, a tyrosine kinase inhibitor approved for IPF treatment, is known to inhibit fibroblasts proliferation, migration and transformation to myofibroblasts. However, how nintedanib changes gene regulations in IPF has never been systematically investigated. We conducted a next-generation sequencing and bioinformatics study to evaluate the changes of mRNA and miRNA profiles in IPF fibroblasts treated with 2 µM and 4 µM nintedanib, compared to those without treatment. We identified 157 upregulated and 151 downregulated genes and used STRING and DAVID databases for analysis of protein–protein interactions, biological pathways, and molecular functions. We found strong protein–protein interactions within these dysregulated genes, mostly involved in the pathways of cell cycle and mitotic cell cycle. We also discovered 13 potential miRNA–mRNA interactions associated with nintedanib treatment. After validation using miRDB, TargetScan, and RT-qPCR, we identified 4 downregulated genes (DDX11, E2F1, NPTX1, and PLXNA4) which might be repressed by the upregulated hsa-miR-486-3p. According to the proposed functions of DDX11, E2F1, and PLXNA4 reported in previous studies, these gene expression changes together might contribute to decreased proliferation of fibroblasts and decreased angiogenesis in the microenvironment of IPF. Our findings need further studies to confirm.

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Long-term nintedanib treatment in idiopathic pulmonary fibrosis (IPF): final data from INPULSIS-ON

10.1055/s-0039-1678102 ◽

2019 ◽

Author(s):

U Costabel ◽

B Crestani ◽

M Quaresma ◽

M Kaye ◽

T Ogura ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Final Data

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Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension

Thorax ◽

10.1136/thoraxjnl-2016-209701 ◽

2017 ◽

Vol 73 (6) ◽

pp. 581-583 ◽

Cited By ~ 21

Author(s):

Luca Richeldi ◽

Michael Kreuter ◽

Moisés Selman ◽

Bruno Crestani ◽

Anne-Marie Kirsten ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Term Treatment ◽

Adverse Event Profile ◽

Open Label ◽

Comparator Group ◽

Long Term Treatment ◽

Open Label Extension ◽

Rate Of Decline

The TOMORROW trial of nintedanib comprised a randomised, placebo-controlled, 52-week period followed by a further blinded treatment period and an open-label extension. We assessed outcomes across these periods in patients randomised to nintedanib 150 mg twice daily or placebo at the start of TOMORROW. The annual rate of decline in FVC was −125.4 mL/year (95% CI −168.1 to −82.7) in the nintedanib group and −189.7 mL/year (95% CI −229.8 to −149.6) in the comparator group. The adverse event profile of nintedanib remained consistent throughout the studies. These results support a benefit of nintedanib on slowing progression of idiopathic pulmonary fibrosis beyond 52 weeks.

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Risk of progression of idiopathic pulmonary fibrosis to connective tissue disease: a long-term observational study in 527 patients

Clinical Rheumatology ◽

10.1007/s10067-021-05659-x ◽

2021 ◽

Author(s):

Byeongzu Ghang ◽

So Hye Nam ◽

Jungsun Lee ◽

Doo-Ho Lim ◽

Soo Min Ahn ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Connective Tissue ◽

Pulmonary Fibrosis ◽

Observational Study ◽

Connective Tissue Disease ◽

Risk Of Progression

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Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows

Methods in Molecular Biology - Proteomics for Drug Discovery ◽

10.1007/978-1-4939-7201-2_15 ◽

2017 ◽

pp. 221-236 ◽

Cited By ~ 11

Author(s):

Alexander Goncearenco ◽

Minghui Li ◽

Franco L. Simonetti ◽

Benjamin A. Shoemaker ◽

Anna R. Panchenko

Keyword(s):

Cancer Therapy ◽

Protein Interactions ◽

In Silico ◽

Drug Targets ◽

Protein Protein Interactions ◽

Anti Cancer

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Long-term Effectiveness of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis Is Independent of Baseline Forced Vital Capacity

CHEST Journal ◽

10.1016/j.chest.2016.08.552 ◽

2016 ◽

Vol 150 (4) ◽

pp. 538A ◽

Cited By ~ 1

Author(s):

Paul Noble ◽

Carlo Albera ◽

Klaus-Uwe Kirchgaessler ◽

Frank Gilberg ◽

Ute Petzinger ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Forced Vital Capacity ◽

Vital Capacity

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

European Heart Journal ◽

10.1093/eurheartj/ehab724.1313 ◽

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.

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Tianlongkechuanling Inhibits Pulmonary Fibrosis Through Down-Regulation of Arginase-Ornithine Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.661129 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peng Wang ◽

Yuanyuan Shi ◽

Yadong Li ◽

Lili Zhang ◽

Sihao Qu ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Protein Interactions ◽

Smooth Muscle Actin ◽

Collagen Deposition ◽

Protein Protein Interactions ◽

Down Regulation ◽

Kegg Pathways ◽

Ppi Networks ◽

Tandem Mass Tag ◽

Pathway Expression

Background: Pulmonary Fibrosis (PF) is an interstitial lung disease characterized by excessive accumulation of extracellular matrix in the lungs, which disrupts the structure and gas exchange of the alveoli. There are only two approved therapies for PF, nintedanib (Nib) and pirfenidone. Therefore, the use of Chinese medicine for PF is attracting attention. Tianlongkechuanling (TL) is an effective Chinese formula that has been applied clinically to alleviate PF, which can enhance lung function and quality of life.Purpose: The potential effects and specific mechanisms of TL have not been fully explored, yet. In the present study, proteomics was performed to explore the therapeutic protein targets of TL on Bleomycin (BLM)-induced Pulmonary Fibrosis.Method: BLM-induced PF mice models were established. Hematoxylineosin staining and Masson staining were used to analyze histopathological changes and collagen deposition. To screen the differential proteins expression between the Control, BLM, BLM + TL and BLM + Nib (BLM + nintedanib) groups, quantitative proteomics was performed using tandem mass tag (TMT) labeling with nanoLC-MS/MS [nano liquid chromatographymass spectrometry]). Changes in the profiles of the expressed proteins were analyzed using the bioinformatics tools Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein–protein interactions (PPI) were established by STRING. Expressions of α-smooth muscle actin (α-SMA), Collagen I (Col1a1), Fibronectin (Fn1) and enzymes in arginase-ornithine pathway were detected by Western blot or RT-PCR.Result: TL treatments significantly ameliorated BLM-induced collagen deposition in lung tissues. Moreover, TL can inhibit the protein expressions of α-SMA and the mRNA expressions of Col1a1 and Fn1. Using TMT technology, we observed 253 differentially expressed proteins related to PPI networks and involved different KEGG pathways. Arginase-ornithine pathway is highly significant. The expression of arginase1 (Arg1), carbamoyltransferase (OTC), carbamoy-phosphate synthase (CPS1), argininosuccinate synthase (ASS1), ornithine aminotransferase (OAT) argininosuccinate lyase (ASL) and inducible nitric oxide synthase (iNOS) was significantly decreased after TL treatments.Conclusion: Administration of TL in BLM-induced mice resulted in decreasing pulmonary fibrosis. Our findings propose that the down regulation of arginase-ornithine pathway expression with the reduction of arginase biosynthesis is a central mechanism and potential treatment for pulmonary fibrosis with the prevention of TL.

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