Identification of the shared gene signatures between pulmonary fibrosis and pulmonary hypertension using bioinformatics analysis

Zhao et al., Frontiers in Immunology, doi:10.3389/fimmu.2023.1197752, Sep 2023
Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
Lower risk for mortality, ventilation, ICU, hospitalization, recovery, cases, and viral clearance.
No treatment is 100% effective. Protocols combine treatments.
6,300+ studies for 210+ treatments. c19early.org
Meta Analysis
In silico study identifying IGF1 as a shared gene between pulmonary fibrosis and hypertension that promotes inflammation, fibrosis, and cell proliferation when overactivated. Molecular docking analysis demonstrated ivermectin directly binds IGF1 through multiple binding modes. This suggests ivermectin may inhibit IGF1 signaling. Since uncontrolled inflammation and lung fibrosis are major issues in severe COVID-19, ivermectin's ability to bind IGF1 indicates it may be able to reduce IGF1-mediated inflammation and fibrosis. By binding and inhibiting IGF1, ivermectin could potentially attenuate damaging effects of hyperactive IGF1 signaling on lung tissues observed in critical COVID-19 cases. This proposed mechanism of action via IGF1 binding provides a rationale for how ivermectin could protect lungs against inflammatory damage in severe COVID-19.
74 preclinical studies support the efficacy of ivermectin for COVID-19:
34 in silico studies1-34
26 in vitro studies2,35-59
14 in vivo animal studies46,52,59-70
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N771, Dengue37,72,73, HIV-173, Simian virus 4074, Zika37,75,76, West Nile76, Yellow Fever77,78, Japanese encephalitis77, Chikungunya78, Semliki Forest virus78, Human papillomavirus57, Epstein-Barr57, BK Polyomavirus79, and Sindbis virus78.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins71,73,74,80, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing38, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination41,81, shows dose-dependent inhibition of wildtype and omicron variants36, exhibits dose-dependent inhibition of lung injury61,66, may inhibit SARS-CoV-2 via IMPase inhibition37, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation9, inhibits SARS-CoV-2 3CLpro54, may inhibit SARS-CoV-2 RdRp activity28, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages60, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation82, may interfere with SARS-CoV-2's immune evasion via ORF8 binding4, may inhibit SARS-CoV-2 by disrupting CD147 interaction83-86, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1959,87, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage8, may minimize SARS-CoV-2 induced cardiac damage40,48, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation88, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses1, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways35, increases Bifidobacteria which play a key role in the immune system89, has immunomodulatory51 and anti-inflammatory70,90 properties, and has an extensive and very positive safety profile91.
Important missing comments or errors? Let us know.
Zhao et al., 4 Sep 2023, peer-reviewed, 12 authors. Contact: wenhui5621006@126.com, pandyyuan@tongji.edu.cn, gongsugang@tongji.edu.cn.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
Identification of the shared gene signatures between pulmonary fibrosis and pulmonary hypertension using bioinformatics analysis
Hui Zhao, Lan Wang, Yi Yan, Qin-Hua Zhao, Jing He, Rong Jiang, Ci-Jun Luo, Hong-Ling Qiu, Yu-Qing Miao, Su-Gang Gong, Ping Yuan, Wen-Hui Wu
Frontiers in Immunology, doi:10.3389/fimmu.2023.1197752
Pulmonary fibrosis (PF) and pulmonary hypertension (PH) have common pathophysiological features, such as the significant remodeling of pulmonary parenchyma and vascular wall. There is no effective specific drug in clinical treatment for these two diseases, resulting in a worse prognosis and higher mortality. This study aimed to screen the common key genes and immune characteristics of PF and PH by means of bioinformatics to find new common therapeutic targets. Expression profiles are
Ethics statement The studies involving humans were approved by the Ethics Committee of Shanghai Pulmonary Hospital (numbers: K22-137Y). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Author contributions HZ, LW, and YY investigated the literature research, got the data, and analyzed the data. Q-HZ and JH wrote the article. RJ and C-JL modified the figures. H-LQ and Y-QM revised the article. W-HW, PY, and S-GG conceived the idea of the study, designed the steps of the study, and directed the data analysis. All authors contributed to the article and approved the submitted version. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1197752/ full#supplementary-material
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DOI record: { "DOI": "10.3389/fimmu.2023.1197752", "ISSN": [ "1664-3224" ], "URL": "http://dx.doi.org/10.3389/fimmu.2023.1197752", "abstract": "<jats:p>Pulmonary fibrosis (PF) and pulmonary hypertension (PH) have common pathophysiological features, such as the significant remodeling of pulmonary parenchyma and vascular wall. There is no effective specific drug in clinical treatment for these two diseases, resulting in a worse prognosis and higher mortality. This study aimed to screen the common key genes and immune characteristics of PF and PH by means of bioinformatics to find new common therapeutic targets. Expression profiles are downloaded from the Gene Expression Database. Weighted gene co-expression network analysis is used to identify the co-expression modules related to PF and PH. We used the ClueGO software to enrich and analyze the common genes in PF and PH and obtained the protein–protein interaction (PPI) network. Then, the differential genes were screened out in another cohort of PF and PH, and the shared genes were crossed. Finally, RT-PCR verification and immune infiltration analysis were performed on the intersection genes. In the result, the positive correlation module with the highest correlation between PF and PH was determined, and it was found that lymphocyte activation is a common feature of the pathophysiology of PF and PH. Eight common characteristic genes (<jats:italic>ACTR2, COL5A2, COL6A3, CYSLTR1, IGF1, RSPO3, SCARNA17</jats:italic> and <jats:italic>SEL1L</jats:italic>) were gained. Immune infiltration showed that compared with the control group, resting CD4 memory T cells were upregulated in PF and PH. Combining the results of crossing characteristic genes in ImmPort database and RT-PCR, the important gene <jats:italic>IGF1</jats:italic> was obtained. Knocking down <jats:italic>IGF1</jats:italic> could significantly reduce the proliferation and apoptosis resistance in pulmonary microvascular endothelial cells, pulmonary smooth muscle cells, and fibroblasts induced by hypoxia, platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor-β1 (TGF-β1), respectively. Our work identified the common biomarkers of PF and PH and provided a new candidate gene for the potential therapeutic targets of PF and PH in the future.</jats:p>", "alternative-id": [ "10.3389/fimmu.2023.1197752" ], "author": [ { "affiliation": [], "family": "Zhao", "given": "Hui", "sequence": "first" }, { "affiliation": [], "family": "Wang", "given": "Lan", "sequence": "additional" }, { "affiliation": [], "family": "Yan", "given": "Yi", "sequence": "additional" }, { "affiliation": [], "family": "Zhao", "given": "Qin-Hua", "sequence": "additional" }, { "affiliation": [], "family": "He", "given": "Jing", "sequence": "additional" }, { "affiliation": [], "family": "Jiang", "given": "Rong", "sequence": "additional" }, { "affiliation": [], "family": "Luo", "given": "Ci-Jun", "sequence": "additional" }, { "affiliation": [], "family": "Qiu", "given": "Hong-Ling", "sequence": "additional" }, { "affiliation": [], "family": "Miao", "given": "Yu-Qing", "sequence": "additional" }, { "affiliation": [], "family": "Gong", "given": "Su-Gang", "sequence": "additional" }, { "affiliation": [], "family": "Yuan", "given": "Ping", "sequence": "additional" }, { "affiliation": [], "family": "Wu", "given": "Wen-Hui", "sequence": "additional" } ], "container-title": "Frontiers in Immunology", "container-title-short": "Front. 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