{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:24:55Z","timestamp":1760059495410,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21mk0101216","JP22mk0101216","JP23mk0101216","21K12133"],"award-info":[{"award-number":["JP21mk0101216","JP22mk0101216","JP23mk0101216","21K12133"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP21mk0101216","JP22mk0101216","JP23mk0101216","21K12133"],"award-info":[{"award-number":["JP21mk0101216","JP22mk0101216","JP23mk0101216","21K12133"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>The coronavirus pathogenesis pathway, which consists of severe acute respiratory syndrome (SARS) coronavirus infection and signaling pathways, including the interferon pathway, the transforming growth factor beta pathway, the mitogen-activated protein kinase pathway, the apoptosis pathway, and the inflammation pathway, is activated upon coronaviral infection. An artificial intelligence approach based on machine learning was utilized to develop models with images of the coronavirus pathogenesis pathway to predict the activation states. Data on coronaviral infection held in a database were analyzed with Ingenuity Pathway Analysis (IPA), a network pathway analysis tool. Data related to SARS coronavirus 2 (SARS-CoV-2) were extracted from more than 100,000 analyses and datasets in the IPA database. A total of 27 analyses, including nine analyses of SARS-CoV-2-infected human-induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes and fibroblasts, and a total of 22 analyses of SARS-CoV-2-infected lung adenocarcinoma (LUAD), were identified as being related to \u201chuman\u201d and \u201cSARS coronavirus 2\u201d in the database. The coronavirus pathogenesis pathway was activated in SARS-CoV-2-infected iPSC-derived cells and LUAD cells. A prediction model was developed in Python 3.11 using images of the coronavirus pathogenesis pathway under different conditions. The prediction model of activation states of the coronavirus pathogenesis pathway may aid in treatment identification.<\/jats:p>","DOI":"10.3390\/cimb47060466","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T10:45:26Z","timestamp":1750157126000},"page":"466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Artificial Intelligence Approach in Machine Learning-Based Modeling and Networking of the Coronavirus Pathogenesis Pathway"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3706-0616","authenticated-orcid":false,"given":"Shihori","family":"Tanabe","sequence":"first","affiliation":[{"name":"Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki-ku, Kawasaki 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9616-7408","authenticated-orcid":false,"given":"Sabina","family":"Quader","sequence":"additional","affiliation":[{"name":"Innovation Centre of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, Kawasaki 210-0821, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuichi","family":"Ono","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1494-7716","authenticated-orcid":false,"given":"Hiroyoshi Y.","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3394-2147","authenticated-orcid":false,"given":"Akihisa","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Mechanical Systems Engineering, Graduate School of Systems Design Tokyo Metropolitan University, Hachioji 192-0397, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6150-6545","authenticated-orcid":false,"given":"Motohiro","family":"Kojima","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Kyoto Prefecture University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward J.","family":"Perkins","sequence":"additional","affiliation":[{"name":"US Army Engineer Research and Development Center, Vicksburg, MS 39180, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Horacio","family":"Cabral","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/CMR.00074-20","article-title":"Immunopathogenesis of Coronavirus-Induced Acute Respiratory Distress Syndrome (ARDS): Potential Infection-Associated Hemophagocytic Lymphohistiocytosis","volume":"34","author":"Quan","year":"2020","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kosyreva, A., Dzhalilova, D., Lokhonina, A., Vishnyakova, P., and Fatkhudinov, T. (2021). The Role of Macrophages in the Pathogenesis of SARS-CoV-2-Associated Acute Respiratory Distress Syndrome. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.682871"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1146\/annurev-micro-020518-115759","article-title":"Human Coronavirus: Host-Pathogen Interaction","volume":"73","author":"Fung","year":"2019","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bakadia, B.M., He, F., Souho, T., Lamboni, L., Ullah, M.W., Boni, B.O., Ahmed, A.A.Q., Mukole, B.M., and Yang, G. (2021). Prevention and treatment of COVID-19: Focus on interferons, chloroquine\/hydroxychloroquine, azithromycin, and vaccine. Biomed. Pharmacother., 133.","DOI":"10.1016\/j.biopha.2020.111008"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1159\/000533606","article-title":"TGF-\u03b21 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis","volume":"15","author":"Hejenkowska","year":"2023","journal-title":"J. Innate Immun."},{"key":"ref_6","first-page":"e32361","article-title":"Mitogen Activated Protein Kinase (MAPK) Activation, p53, and Autophagy Inhibition Characterize the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein Induced Neurotoxicity","volume":"14","author":"Kyriakopoulos","year":"2022","journal-title":"Cureus"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lokau, J., Garbers, Y., Vicente, M.M., Dittrich, A., Meltendorf, S., Lingel, H., M\u00fcnster-K\u00fchnel, A.K., Brunner-Weinzierl, M., and Garbers, C. (2024). Long-term increase in soluble interleukin-6 receptor levels in convalescents after mild COVID-19 infection. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1488745"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/VB-20-0014","article-title":"Aging- and gender-related modulation of RAAS: Potential implications in COVID-19 disease","volume":"3","author":"Monteonofrio","year":"2021","journal-title":"Vasc. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eabf7872","DOI":"10.1126\/scitranslmed.abf7872","article-title":"SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19","volume":"13","author":"Kang","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1056\/NEJMe2116493","article-title":"Receipt of mRNA Vaccine against COVID-19 and Myocarditis","volume":"385","author":"Caforio","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"30","DOI":"10.52793\/ACMR.2022.3(4)-41","article-title":"Relationship between COVID-19 vaccine and myocarditis","volume":"3","author":"Tanabe","year":"2022","journal-title":"Adv. Clin. Med. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sessa, F., Salerno, M., Esposito, M., Di Nunno, N., Zamboni, P., and Pomara, C. (2021). Autopsy Findings and Causality Relationship between Death and COVID-19 Vaccination: A Systematic Review. J. Clin. Med., 10.","DOI":"10.3390\/jcm10245876"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pomara, C., Sessa, F., Ciaccio, M., Dieli, F., Esposito, M., Giammanco, G.M., Garozzo, S.F., Giarratano, A., Prati, D., and Rappa, F. (2021). COVID-19 Vaccine and Death: Causality Algorithm According to the WHO Eligibility Diagnosis. Diagnostics, 11.","DOI":"10.3390\/diagnostics11060955"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/bph.16262","article-title":"Cardiac side effects of RNA-based SARS-CoV-2 vaccines: Hidden cardiotoxic effects of mRNA-1273 and BNT162b2 on ventricular myocyte function and structure","volume":"181","author":"Schreckenberg","year":"2024","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","unstructured":"WHO (2025, April 21). A Clinical Case Definition of Post COVID-19 Condition by a Delphi Consensus. Available online: https:\/\/www.who.int\/publications\/i\/item\/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Schneider, A., Hapfelmeier, A., Grei\u00dfel, A., Limbach, M., Schwarzl, G., Ebert, F., Huber, V., and Hayden, M.C. (2025). The implications of somatic symptom disorder on the impairment of daily life are greater in post-COVID syndrome than in asthma or COPD\u2014Results of a cross-sectional study in a rehabilitation clinic. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-96055-x"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e70123","DOI":"10.1002\/iid3.70123","article-title":"Regulatory T Cell Phenotype Related to Cytokine Expression Patterns in Post-COVID-19 Pulmonary Fibrosis and Idiopathic Pulmonary Fibrosis","volume":"13","author":"Gangi","year":"2025","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.2131\/fts.9.37","article-title":"Molecular network analysis of RNA viral infection pathway in diffuse- and intestinal-type gastric cancer","volume":"9","author":"Tanabe","year":"2022","journal-title":"Fundam. Toxicol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Tanabe, S., Quader, S., Ono, R., Cabral, H., Aoyagi, K., Hirose, A., Yokozaki, H., and Sasaki, H. (2021). Cell Cycle Regulation and DNA Damage Response Networks in Diffuse- and Intestinal-Type Gastric Cancer. Cancers, 13.","DOI":"10.20944\/preprints202110.0198.v1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3390\/onco3010002","article-title":"Regulation of Epithelial\u2013Mesenchymal Transition Pathway and Artificial Intelligence-Based Modeling for Pathway Activity Prediction","volume":"3","author":"Tanabe","year":"2023","journal-title":"Onco"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hoagland, D.A., Clarke, D.J.B., M\u00f8ller, R., Han, Y., Yang, L., Wojciechowicz, M.L., Lachmann, A., Oguntuyo, K.Y., Stevens, C., and Lee, B. (2020). Modulating the transcriptional landscape of SARS-CoV-2 as an effective method for developing antiviral compounds. bioRxiv.","DOI":"10.1101\/2020.07.12.199687"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yoshikawa, T., Hill, T.E., Yoshikawa, N., Popov, V.L., Galindo, C.L., Garner, H.R., Peters, C.J., and Tseng, C.-T. (2010). Dynamic Innate Immune Responses of Human Bronchial Epithelial Cells to Severe Acute Respiratory Syndrome-Associated Coronavirus Infection. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008729"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.cell.2020.04.026","article-title":"Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19","volume":"181","author":"Liu","year":"2020","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Daamen, A.R., Bachali, P., Owen, K.A., Kingsmore, K.M., Hubbard, E.L., Labonte, A.C., Robl, R., Shrotri, S., Grammer, A.C., and Lipsky, P.E. (2021). Comprehensive transcriptomic analysis of COVID-19 blood, lung, and airway. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-86002-x"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Bermejo, J.A., Kang, S., Rockwood, S.J., Simoneau, C.R., Joy, D.A., Ramadoss, G.N., Silva, A.C., Flanigan, W.R., Li, H., and Nakamura, K. (2020). SARS-CoV-2 infection of human iPSC-derived cardiac cells predicts novel cytopathic features in hearts of COVID-19 patients. bioRxiv.","DOI":"10.1101\/2020.08.25.265561"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tanabe, S., Quader, S., Cabral, H., Perkins, E.J., Yokozaki, H., and Sasaki, H. (2024). Master Regulators of Causal Networks in Intestinal- and Diffuse-Type Gastric Cancer and the Relation to the RNA Virus Infection Pathway. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202407.0200.v1"},{"key":"ref_29","unstructured":"Shimizu, H. (2023). Machine Learning in Python: Machine Learning of Life Science Data, Yodosha. Jikken Igaku Bessatsu Python De Jissen Seimeikagaku data no Kikaigakushu."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5359","DOI":"10.1038\/s41467-023-41146-4","article-title":"Interpreting biologically informed neural networks for enhanced proteomic biomarker discovery and pathway analysis","volume":"14","author":"Hartman","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"D672","DOI":"10.1093\/nar\/gkae909","article-title":"KEGG: Biological systems database as a model of the real world","volume":"53","author":"Kanehisa","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1007\/s40265-020-01389-7","article-title":"Decitabine\/Cedazuridine: First Approval","volume":"80","author":"Dhillon","year":"2020","journal-title":"Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"113098","DOI":"10.1016\/j.celrep.2023.113098","article-title":"Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment","volume":"42","author":"Yabushita","year":"2023","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41392-021-00497-4","article-title":"Therapeutic potential of C1632 by inhibition of SARS-CoV-2 replication and viral-induced inflammation through upregulating let-7","volume":"6","author":"Xie","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cell.2009.10.014","article-title":"An epigenetic switch involving NF-\u03baB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation","volume":"139","author":"Iliopoulos","year":"2009","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/rmv.2141","article-title":"Interleukin-6 in COVID-19: A systematic review and meta-analysis","volume":"30","author":"Coomes","year":"2020","journal-title":"Rev. Med. Virol."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/6\/466\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:53:44Z","timestamp":1760032424000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/6\/466"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,17]]},"references-count":36,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["cimb47060466"],"URL":"https:\/\/doi.org\/10.3390\/cimb47060466","relation":{},"ISSN":["1467-3045"],"issn-type":[{"type":"electronic","value":"1467-3045"}],"subject":[],"published":{"date-parts":[[2025,6,17]]}}}