Analysis of molecular mechanism of Chinese medicine Jinhong decoction (JHD) in synergistically treating sepsis and COVID-19 based on network pharmacology

Jinghan Fan; Yang Yang; Fan Zhang; Xiaowei Wu; Jiajun Li; Li Liang; Qi Tang; Bo Yan; Jiancheng Zhang; Xuming Pan; Guangjun Jin; Changlong Wei; Pingping Han; Yuzhou He

Jinghan Fan, Yang Yang, Fan Zhang, Xiaowei Wu, Jiajun Li, Li Liang, Qi Tang, Bo Yan, Jiancheng Zhang, Xuming Pan, Guangjun Jin, Changlong Wei, Pingping Han, Yuzhou He

PLOS One, doi:10.1371/journal.pone.0339457

Sepsis and COVID-19 are the two mutually-reinforcing risk factors, whose interaction drastically increases mortality rate. Jinhong decoction (JHD) as a Chinese medicine exhibits clinical efficacy against them, but related action mechanism remains to be explored. To this end, using network pharmacology, this study screened active ingredients of JHD and their targets from TCMSP, HERB, PubChem and SwissTargetPrediction databases as well as the targets for these two diseases from DisGeNET, OMIM, Drugbank, TTD, and GeneCards. By intersecting drug and disease targets, we identified common targets and constructed a drug-ingredient-target network. GO and KEGG enrichment analyses revealed key target-related signaling pathways, and transcriptomics analysis further validated tissue distribution of these targets and their expressions. Our identified six key target genes (AKT1, MMP9, ICAM1, TLR4, BCL2, and HIF1A) were mainly involved in the regulations of immunometabolism, inflammation, and cell survival in both diseases. Functional enrichment analysis indicated that JHD displayed synergistic efficacy against both diseases by simultaneously modulating HIF-1, TNF, and NF-κB signaling pathways. Tissue distribution analyses of these 6 key target genes revealed that CD33 + myeloid cells, fetal lung cells, and bronchial epithelial cells might play an important role in treating both diseases. Overall, this study demonstrates that JHD treats sepsis and COVID-19 through a multi-ingredient, multi-target, and multi-pathway inter-related mechanism, exhibiting a great application potential.

References

Atwa, El-Ghafar, Hassanein, Mahdi, Sayed et al., Candesartan Attenuates Cisplatin-Induced Lung Injury by Modulating Oxidative Stress, Inflammation, and TLR-4/NF-κB, JAK1/STAT3, and Nrf2/HO-1 Signaling, Pharmaceuticals, doi:10.3390/ph15101222

Bao, Wang, Liu, Zhang, Zhang, Jinhong decoction protects sepsis-associated acute lung injury by reducing intestinal bacterial translocation and improving gut microbial homeostasis, Front Pharmacol, doi:10.3389/fphar.2023.1079482

Chen, Wang, Liu, Gao, Meng et al., Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-κB and MAPK signaling, Pharmacol Res, doi:10.1016/j.phrs.2022.106473

Dell'annunziata, Folliero, Palma, Crudele, Finamore et al., Anthraquinone Rhein Exhibits Antibacterial Activity against Staphylococcus aureus, Applied Sciences, doi:10.3390/app12178691

Deng, Chen, Wu, Su, Xu et al., Exploring the anti-inflammatory and immune regulatory effects of Taohe Chengqi decoction in sepsis-induced lung injury, J Ethnopharmacol, doi:10.1016/j.jep.2024.118404

Ekins, Nikolsky, Nikolskaya, Techniques: application of systems biology to absorption, distribution, metabolism, excretion and toxicity, Trends Pharmacol Sci, doi:10.1016/j.tips.2005.02.006

Fang, Dong, Liu, Guo, Zhao et al., HERB: a high-throughput experiment-and reference-guided database of traditional Chinese medicine, Nucleic Acids Res, doi:10.1093/nar/gkaa1063

Fang, Wu, Zhang, Zhou, Zhang et al., Inflammatory indices reflect distinct pathogenic cellular programs driving sepsis progression: The role of mmp9 protein macromolecules, Int J Biol Macromol, doi:10.1016/j.ijbiomac.2025.143024

Gao, Peng, Tang, Deng, Wang et al., Anti-Inflammatory Effects of Camellia fascicularis Polyphenols via Attenuation of NF-κB and MAPK Pathways in LPS-Induced THP-1 Macrophages, J Inflamm Res, doi:10.2147/JIR.S349981

Gassen, Bajaj, Emanuel, Dethloff, Chua, SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals, Nat Commun, doi:10.1038/s41467-021-24007-w

Gfeller, Grosdidier, Wirth, Michielin, Zoete, SwissTargetPrediction: a web server for target prediction of bioactive small molecules, Nucleic Acids Res, doi:10.1093/nar/gku293

Ghanem, Essayli, Kotaich, Zein, Sahebkar et al., Phenotypic switch of vascular smooth muscle cells in COVID-19: Role of cholesterol, calcium, and phosphate, J Cell Physiol, doi:10.1002/jcp.31424

Gong, Fox, Boutros, Prediction of early breast cancer patient survival using ensembles of hypoxia signatures, Cold Spring Harbor Laboratory, doi:10.1101/181289

Huang, Zhang, Zhou, Chen, PPAR gamma and PGC-1alpha activators protect against diabetic nephropathy by suppressing the inflammation and NF-kappaB activation, Nephrology, doi:10.1111/nep.14381

Kim, Chen, Cheng, Gindulyte, He et al., PubChem 2019 update: improved access to chemical data, Nucleic Acids Res, doi:10.1093/nar/gky1033

Langston, Rossi, Yang, Ohley, Perez et al., Omics of endothelial cell dysfunction in sepsis, Vasc Biol, doi:10.1530/VB-22-0003

Lee, Ha, Shin, Jeong, Jeon et al., Spiraea prunifolia var. simpliciflora Attenuates Oxidative Stress and Inflammatory Responses in a Murine Model of Lipopolysaccharide-Induced Acute Lung Injury and TNF-α-Stimulated NCI-H292 Cells, Antioxidants

Lewis, Chan, Pinheiro, Armitage-Chan, Garden, The immunopathology of sepsis: pathogen recognition, systemic inflammation, the compensatory anti-inflammatory response, and regulatory T cells, J Vet Intern Med, doi:10.1111/j.1939-1676.2012.00905.x

Li, Jia, Yang, Wu, Peng et al., Sepsis-associated encephalopathy: Mechanisms, Diagnosis, and Treatments update, Int J Biol Sci, doi:10.7150/ijbs.102234

Liang, Liu, Guo, Li, Niu et al., Jinhong decoction ameliorates injury in septic mice without disrupting the equilibrium of gut microbiota, J Pharm Biomed Anal, doi:10.1016/j.jpba.2024.116404

Liu, Aulin, Kossen, Cathalina, Bremmer et al., A system pharmacology Boolean network model for the TLR4-mediated inflammatory response in early sepsis, J Pharmacokinet Pharmacodyn, doi:10.1007/s10928-022-09828-6

Liu, Liu, Fan, Chen, Xu, Network Pharmacology Bridges Traditional Application and Modern Development of Traditional Chinese Medicine, Chinese Herbal Medicines, doi:10.1016/s1674-6384(15)60014-4

Lu, Liu, Dong, Su, Zhou, Discovering common pathogenetic processes between COVID-19 and sepsis by bioinformatics and system biology approach, Front Immunol, doi:10.3389/fimmu.2022.975848

Luo, Qin, Zhang, Ren, Fang et al., Anthraquinones from the Aerial Parts of Rubia cordifolia with Their NO Inhibitory and Antibacterial Activities, Molecules, doi:10.3390/molecules27051730

Luo, Yao, Chen, Sun, An examination of the LPS-TLR4 immune response through the analysis of molecular structures and protein-protein interactions, Cell Commun Signal, doi:10.1186/s12964-025-02149-4

Lévy, Wiedemann, Hejblum, Durand, Lefebvre et al., CD177, a specific marker of neutrophil activation, is associated with coronavirus disease 2019 severity and death, iScience, doi:10.1016/j.isci.2021.102711

Majumder, Minko, Recent Developments on Therapeutic and Diagnostic Approaches for COVID-19, AAPS J, doi:10.1208/s12248-020-00532-2

Mi, Xia, Bian, The influence of ICAM1 rs5498 on diabetes mellitus risk: evidence from a meta-analysis, Inflamm Res, doi:10.1007/s00011-019-01220-4

Otasek, Morris, Bouças, Pico, Demchak, Cytoscape Automation: empowering workflow-based network analysis, Genome Biol, doi:10.1186/s13059-019-1758-4

Peter, Sandeep, Rao, Kalpana, Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19, Front Pharmacol, doi:10.3389/fphar.2020.583777

Pouraminaei, Mirzaiey, Khoshdel, Hajizadeh, Mahmoodi et al., The effect of Cressa Cretica hydroalcoholic extract on apoptosis and the expression of Bcl2, Bax and P53 genes in hepatoma cell line HepG2, Gene Reports, doi:10.1016/j.genrep.2020.100692

Qiao, Yin, Zheng, Li, Feng, Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications, Cell Commun Signal, doi:10.1186/s12964-024-01620-y

Ren, Deng, Li, Liu, Li, Possible pharmacological targets and mechanisms of sivelestat in protecting acute lung injury, Comput Biol Med, doi:10.1016/j.compbiomed.2024.108080

Ru, Li, Wang, Zhou, Li et al., TCMSP: a database of systems pharmacology for drug discovery from herbal medicines, J Cheminform, doi:10.1186/1758-2946-6-13

Sharma, Prateeksha, Singh, Singh, Rao et al., Nanocurcumin Potently Inhibits SARS-CoV-2 Spike Protein-Induced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial Cells, ACS Appl Bio Mater, doi:10.1021/acsabm.1c00874

Sherman, Panzade, Imamichi, DAVID Ortholog: an integrative tool to enhance functional analysis through orthologs, Bioinformatics, doi:10.1093/bioinformatics/btae615

Stelzer, Rosen, Plaschkes, Zimmerman, Twik et al., The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses, Curr Protoc Bioinformatics, doi:10.1002/cpbi.5

Szklarczyk, Gable, Lyon, Junge, Wyder et al., STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets, Nucleic Acids Res, doi:10.1093/nar/gky1131

Tao, Xu, Wang, Li, Wang et al., Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease, J Ethnopharmacol, doi:10.1016/j.jep.2012.09.051

Tian, Liu, Li, Zhao, Shereen et al., HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19, Signal Transduct Target Ther, doi:10.1038/s41392-021-00726-w

Tong, Ding, Liu, Li, Liu et al., Classification of subtypes and identification of dysregulated genes in sepsis, Front Cell Infect Microbiol, doi:10.3389/fcimb.2023.1226159

Vazquez-Armendariz, Tata, Recent advances in lung organoid development and applications in disease modeling, J Clin Invest, doi:10.1172/JCI170500

Venet, Schilling, Cazalis, Demaret, Poujol et al., Modulation of LILRB2 protein and mRNA expressions in septic shock patients and after ex vivo lipopolysaccharide stimulation, Hum Immunol, doi:10.1016/j.humimm.2017.03.010

Wang, Chen, Chen, Yan, Liu, Discovery of the key active compounds in Citri Reticulatae Pericarpium (Citrus reticulata "Chachi") and their therapeutic potential for the treatment of COVID-19 based on comparative metabolomics and network pharmacology, Front Pharmacol, doi:10.3389/fphar.2022.1048926

Wang, Wang, Guo, Liao, Chai et al., In silico high-throughput screening system for AKT1 activators with therapeutic applications in sepsis acute lung injury, Front Cell Infect Microbiol, doi:10.3389/fcimb.2022.1050497

Wen, The effective substances study and clinical observation of Jinhong decoction in the treatment of sepsis

Wu, He, Liu, Xu, Chen et al., Mechanisms of JinHong Formula on treating sepsis explored by randomized controlled trial combined with network pharmacology, J Ethnopharmacol, doi:10.1016/j.jep.2022.116040

Wu, Tsueng, Afrasiabi, Su, BioGPS: building your own mash-up of gene annotations and expression profiles, Nucleic Acids Res, doi:10.1093/nar/gkv1104

Xia, Xun, Lu, Lu, Yang et al., Network pharmacology and molecular docking analyses on Lianhua Qingwen capsule indicate Akt1 is a potential target to treat and prevent COVID-19, Cell Prolif, doi:10.1111/cpr.12949

Xie, Zhang, Dong, Zhang, MicroRNA-146a improves sepsis-induced cardiomyopathy by regulating the TLR-4/NF-κB signaling pathway, Exp Ther Med, doi:10.3892/etm.2019.7657

Xu, Zhang, Huang, Li, Yu et al., A novel chemometric method for the prediction of human oral bioavailability, Int J Mol Sci, doi:10.3390/ijms13066964

Yuki, Koutsogiannaki, Pattern recognition receptors as therapeutic targets for bacterial, viral and fungal sepsis, Int Immunopharmacol, doi:10.1016/j.intimp.2021.107909

Zhai, Liu, Zhang, Chen, Wang et al., Network pharmacology: a crucial approach in traditional Chinese medicine research, Chin Med, doi:10.1186/s13020-024-01056-z

Zhang, Guo, Zhang, Xu, Liu et al., Huashibaidu formula attenuates sepsis-induced acute lung injury via suppressing cytokine storm: Implications for treatment of COVID-19, Phytomedicine, doi:10.1016/j.phymed.2022.154549

Zhang, Yao, Yang, Wang, Du, PI3K/Akt and HIF-1 signaling pathway in hypoxia-ischemia (Review), Mol Med Rep, doi:10.3892/mmr.2018.9375

Zhang, Zhang, Zhou, Wang, Wang et al., Network pharmacology: towards the artificial intelligence-based precision traditional Chinese medicine, Brief Bioinform, doi:10.1093/bib/bbad518

Zhou, Ma, Yu, Chen, Zhang et al., Formula Improves Glucocorticoid Resistance of Chronic Obstructive Pulmonary Disease via Downregulating the PI3K-Akt Signaling Pathway and Promoting GRα Expression, Evid Based Complement Alternat Med, doi:10.1155/2023/4359616

DOI record: { "DOI": "10.1371/journal.pone.0339457", "ISSN": [ "1932-6203" ], "URL": "http://dx.doi.org/10.1371/journal.pone.0339457", "abstract": "\n Sepsis and COVID-19 are the two mutually-reinforcing risk factors, whose interaction drastically increases mortality rate. Jinhong decoction (JHD) as a Chinese medicine exhibits clinical efficacy against them, but related action mechanism remains to be explored. To this end, using network pharmacology, this study screened active ingredients of JHD and their targets from TCMSP, HERB, PubChem and SwissTargetPrediction databases as well as the targets for these two diseases from DisGeNET, OMIM, Drugbank, TTD, and GeneCards. By intersecting drug and disease targets, we identified common targets and constructed a drug-ingredient-target network. GO and KEGG enrichment analyses revealed key target-related signaling pathways, and transcriptomics analysis further validated tissue distribution of these targets and their expressions. Our identified six key target genes (\n AKT1\n ,\n MMP9\n ,\n ICAM1\n ,\n TLR4\n ,\n BCL2\n , and\n HIF1A\n ) were mainly involved in the regulations of immunometabolism, inflammation, and cell survival in both diseases. Functional enrichment analysis indicated that JHD displayed synergistic efficacy against both diseases by simultaneously modulating HIF-1, TNF, and NF-κB signaling pathways. Tissue distribution analyses of these 6 key target genes revealed that CD33 + myeloid cells, fetal lung cells, and bronchial epithelial cells might play an important role in treating both diseases. Overall, this study demonstrates that JHD treats sepsis and COVID-19 through a multi-ingredient, multi-target, and multi-pathway inter-related mechanism, exhibiting a great application potential.\n ", "author": [ { "ORCID": "https://orcid.org/0009-0004-3659-7424", "affiliation": [], "authenticated-orcid": true, "family": "Fan", "given": "Jinghan", "sequence": "first" }, { "affiliation": [], "family": "Yang", "given": "Yang", "sequence": "additional" }, { "affiliation": [], "family": "Zhang", "given": "Fan", "sequence": "additional" }, { "affiliation": [], "family": "Wu", "given": "Xiaowei", "sequence": "additional" }, { "affiliation": [], "family": "Li", "given": "Jiajun", "sequence": "additional" }, { "affiliation": [], "family": "Liang", "given": "Li", "sequence": "additional" }, { "affiliation": [], "family": "Tang", "given": "Qi", "sequence": "additional" }, { "affiliation": [], "family": "Yan", "given": "Bo", "sequence": "additional" }, { "affiliation": [], "family": "Zhang", "given": "Jiancheng", "sequence": "additional" }, { "affiliation": [], "family": "Pan", "given": "Xuming", "sequence": "additional" }, { "affiliation": [], "family": "Jin", "given": "Guangjun", "sequence": "additional" }, { "affiliation": [], "family": "Wei", "given": "Changlong", "sequence": "additional" }, { "affiliation": [], "family": "Han", "given": "Pingping", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-9441-4188", "affiliation": [], "authenticated-orcid": true, "family": "He", "given": "Yuzhou", "sequence": "additional" } ], "container-title": "PLOS One", "container-title-short": "PLoS One", "content-domain": { "crossmark-restriction": false, "domain": [ "www.plosone.org" ] }, "created": { "date-parts": [ [ 2025, 12, 18 ] ], "date-time": "2025-12-18T18:38:47Z", "timestamp": 1766083127000 }, "deposited": { "date-parts": [ [ 2025, 12, 18 ] ], "date-time": "2025-12-18T18:38:56Z", "timestamp": 1766083136000 }, "editor": [ { "affiliation": [], "family": "Ahmad", "given": "Ashfaq", "sequence": "first" } ], "funder": [ { "DOI": "10.13039/501100017594", "award": [ "2025C02188" ], "award-info": [ { "award-number": [ "2025C02188" ] } ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/501100017594", "id-type": "DOI" } ], "name": "Medical Science and Technology Project of Zhejiang Province" }, { "DOI": "10.13039/501100012175", "award": [ "No. GZY-ZJ-KJ-24070" ], "award-info": [ { "award-number": [ "No. GZY-ZJ-KJ-24070" ] } ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/501100012175", "id-type": "DOI" } ], "name": "Zhejiang Traditional Chinese Medicine Administration" }, { "DOI": "10.13039/501100017531", "award": [ "2022KY234" ], "award-info": [ { "award-number": [ "2022KY234" ] } ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/501100017531", "id-type": "DOI" } ], "name": "Medical and Health Research Project of Zhejiang Province" }, { "award": [ "2025JKZKTS65" ], "award-info": [ { "award-number": [ "2025JKZKTS65" ] } ], "name": "the Research Project of Zhejiang Chinese Medical University" } ], "indexed": { "date-parts": [ [ 2025, 12, 18 ] ], "date-time": "2025-12-18T18:55:47Z", "timestamp": 1766084147991, "version": "3.48.0" }, "is-referenced-by-count": 0, "issue": "12", "issued": { "date-parts": [ [ 2025, 12, 18 ] ] }, "journal-issue": { "issue": "12", "published-online": { "date-parts": [ [ 2025, 12, 18 ] ] } }, "language": "en", "license": [ { "URL": "http://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 12, 18 ] ], "date-time": "2025-12-18T00:00:00Z", "timestamp": 1766016000000 } } ], "link": [ { "URL": "https://dx.plos.org/10.1371/journal.pone.0339457", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "340", "original-title": [], "page": "e0339457", "prefix": "10.1371", "published": { "date-parts": [ [ 2025, 12, 18 ] ] }, "published-online": { "date-parts": [ [ 2025, 12, 18 ] ] }, "publisher": "Public Library of Science (PLoS)", "reference": [ { "DOI": "10.3389/fimmu.2022.975848", "article-title": "Discovering common pathogenetic processes between COVID-19 and sepsis by bioinformatics and system biology approach", "author": "L Lu", "doi-asserted-by": "crossref", "first-page": "975848", "journal-title": "Front Immunol", "key": "pone.0339457.ref001", "volume": "13", "year": "2022" }, { "DOI": "10.1111/j.1939-1676.2012.00905.x", "article-title": "The immunopathology of sepsis: pathogen recognition, systemic inflammation, the compensatory anti-inflammatory response, and regulatory T cells", "author": "DH Lewis", "doi-asserted-by": "crossref", "first-page": "457", "issue": "3", "journal-title": "J Vet Intern Med", "key": "pone.0339457.ref002", "volume": "26", "year": "2012" }, { "DOI": "10.3389/fphar.2023.1079482", "article-title": "Jinhong decoction protects sepsis-associated acute lung injury by reducing intestinal bacterial translocation and improving gut microbial homeostasis", "author": "K Bao", "doi-asserted-by": "crossref", "first-page": "1079482", "journal-title": "Front Pharmacol", "key": "pone.0339457.ref003", "volume": "14", "year": "2023" }, { "DOI": "10.1016/j.jep.2022.116040", "article-title": "Mechanisms of JinHong Formula on treating sepsis explored by randomized controlled trial combined with network pharmacology", "author": "X Wu", "doi-asserted-by": "crossref", "first-page": "116040", "journal-title": "J Ethnopharmacol", "key": "pone.0339457.ref004", "volume": "305", "year": "2023" }, { "DOI": "10.1016/S1674-6384(15)60014-4", "article-title": "Network Pharmacology Bridges Traditional Application and Modern Development of Traditional Chinese Medicine", "author": "C Liu", "doi-asserted-by": "crossref", "first-page": "3", "issue": "1", "journal-title": "Chinese Herbal Medicines", "key": "pone.0339457.ref005", "volume": "7", "year": "2015" }, { "DOI": "10.1186/s13020-024-01056-z", "article-title": "Network pharmacology: a crucial approach in traditional Chinese medicine research", "author": "Y Zhai", "doi-asserted-by": "crossref", "first-page": "8", "issue": "1", "journal-title": "Chin Med", "key": "pone.0339457.ref006", "volume": "20", "year": "2025" }, { "DOI": "10.1093/bib/bbad518", "article-title": "Network pharmacology: towards the artificial intelligence-based precision traditional Chinese medicine", "author": "P Zhang", "doi-asserted-by": "crossref", "issue": "1", "journal-title": "Brief Bioinform", "key": "pone.0339457.ref007", "volume": "25", "year": "2023" }, { "DOI": "10.1016/j.phrs.2022.106473", "article-title": "Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-κB and MAPK signaling", "author": "X-S Chen", "doi-asserted-by": "crossref", "first-page": "106473", "journal-title": "Pharmacol Res", "key": "pone.0339457.ref008", "volume": "185", "year": "2022" }, { "DOI": "10.2147/JIR.S349981", "article-title": "Anti-Inflammatory Effects of Camellia fascicularis Polyphenols via Attenuation of NF-κB and MAPK Pathways in LPS-Induced THP-1 Macrophages", "author": "M Gao", "doi-asserted-by": "crossref", "first-page": "851", "journal-title": "J Inflamm Res", "key": "pone.0339457.ref009", "volume": "15", "year": "2022" }, { "DOI": "10.3389/fphar.2020.583777", "article-title": "Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19", "author": "AE Peter", "doi-asserted-by": "crossref", "first-page": "583777", "journal-title": "Front Pharmacol", "key": "pone.0339457.ref010", "volume": "11", "year": "2021" }, { "author": "Z Wen", "key": "pone.0339457.ref011", "year": "2021" }, { "DOI": "10.7150/ijbs.102234", "article-title": "Sepsis-associated encephalopathy: Mechanisms, Diagnosis, and Treatments update", "author": "J Li", "doi-asserted-by": "crossref", "first-page": "3214", "issue": "7", "journal-title": "Int J Biol Sci", "key": "pone.0339457.ref012", "volume": "21", "year": "2025" }, { "DOI": "10.1016/j.intimp.2021.107909", "article-title": "Pattern recognition receptors as therapeutic targets for bacterial, viral and fungal sepsis", "author": "K Yuki", "doi-asserted-by": "crossref", "first-page": "107909", "journal-title": "Int Immunopharmacol", "key": "pone.0339457.ref013", "volume": "98", "year": "2021" }, { "DOI": "10.1208/s12248-020-00532-2", "article-title": "Recent Developments on Therapeutic and Diagnostic Approaches for COVID-19", "author": "J Majumder", "doi-asserted-by": "crossref", "first-page": "14", "issue": "1", "journal-title": "AAPS J", "key": "pone.0339457.ref014", "volume": "23", "year": "2021" }, { "DOI": "10.1016/j.ijbiomac.2025.143024", "article-title": "Inflammatory indices reflect distinct pathogenic cellular programs driving sepsis progression: The role of mmp9 protein macromolecules", "author": "B Fang", "doi-asserted-by": "crossref", "first-page": "143024", "journal-title": "Int J Biol Macromol", "key": "pone.0339457.ref015", "volume": "309", "year": "2025" }, { "DOI": "10.1186/1758-2946-6-13", "article-title": "TCMSP: a database of systems pharmacology for drug discovery from herbal medicines", "author": "J Ru", "doi-asserted-by": "crossref", "first-page": "13", "journal-title": "J Cheminform", "key": "pone.0339457.ref016", "volume": "6", "year": "2014" }, { "DOI": "10.1016/j.tips.2005.02.006", "article-title": "Techniques: application of systems biology to absorption, distribution, metabolism, excretion and toxicity", "author": "S Ekins", "doi-asserted-by": "crossref", "first-page": "202", "issue": "4", "journal-title": "Trends Pharmacol Sci", "key": "pone.0339457.ref017", "volume": "26", "year": "2005" }, { "DOI": "10.3390/ijms13066964", "article-title": "A novel chemometric method for the prediction of human oral bioavailability", "author": "X Xu", "doi-asserted-by": "crossref", "first-page": "6964", "issue": "6", "journal-title": "Int J Mol Sci", "key": "pone.0339457.ref018", "volume": "13", "year": "2012" }, { "DOI": "10.1016/j.jep.2012.09.051", "article-title": "Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease", "author": "W Tao", "doi-asserted-by": "crossref", "first-page": "1", "issue": "1", "journal-title": "J Ethnopharmacol", "key": "pone.0339457.ref019", "volume": "145", "year": "2013" }, { "DOI": "10.1093/nar/gkaa1063", "article-title": "HERB: a high-throughput experiment- and reference-guided database of traditional Chinese medicine", "author": "S Fang", "doi-asserted-by": "crossref", "journal-title": "Nucleic Acids Res", "key": "pone.0339457.ref020", "volume": "49", "year": "2021" }, { "article-title": "PubChem 2019 update: improved access to chemical data", "author": "S Kim", "journal-title": "Nucleic Acids Res", "key": "pone.0339457.ref021", "volume": "47", "year": "2019" }, { "DOI": "10.1093/nar/gku293", "article-title": "SwissTargetPrediction: a web server for target prediction of bioactive small molecules", "author": "D Gfeller", "doi-asserted-by": "crossref", "journal-title": "Nucleic Acids Res", "key": "pone.0339457.ref022", "volume": "42", "year": "2014" }, { "DOI": "10.1002/cpbi.5", "article-title": "The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses", "author": "G Stelzer", "doi-asserted-by": "crossref", "journal-title": "Curr Protoc Bioinformatics", "key": "pone.0339457.ref023", "volume": "54", "year": "2016" }, { "DOI": "10.1093/nar/gky1131", "article-title": "STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets", "author": "D Szklarczyk", "doi-asserted-by": "crossref", "journal-title": "Nucleic Acids Res", "key": "pone.0339457.ref024", "volume": "47", "year": "2019" }, { "DOI": "10.1186/s13059-019-1758-4", "article-title": "Cytoscape Automation: empowering workflow-based network analysis", "author": "D Otasek", "doi-asserted-by": "crossref", "first-page": "185", "issue": "1", "journal-title": "Genome Biol", "key": "pone.0339457.ref025", "volume": "20", "year": "2019" }, { "DOI": "10.1093/bioinformatics/btae615", "article-title": "DAVID Ortholog: an integrative tool to enhance functional analysis through orthologs", "author": "BT Sherman", "doi-asserted-by": "crossref", "issue": "10", "journal-title": "Bioinformatics", "key": "pone.0339457.ref026", "volume": "40", "year": "2024" }, { "author": "IY Gong", "journal-title": "Prediction of early breast cancer patient survival using ensembles of hypoxia signatures", "key": "pone.0339457.ref027", "year": "2017" }, { "article-title": "BioGPS: building your own mash-up of gene annotations and expression profiles", "author": "C Wu", "journal-title": "Nucleic Acids Res", "key": "pone.0339457.ref028", "volume": "44", "year": "2016" }, { "DOI": "10.3389/fcimb.2023.1226159", "article-title": "Classification of subtypes and identification of dysregulated genes in sepsis", "author": "R Tong", "doi-asserted-by": "crossref", "first-page": "1226159", "journal-title": "Front Cell Infect Microbiol", "key": "pone.0339457.ref029", "volume": "13", "year": "2023" }, { "DOI": "10.1016/j.humimm.2017.03.010", "article-title": "Modulation of LILRB2 protein and mRNA expressions in septic shock patients and after ex vivo lipopolysaccharide stimulation", "author": "F Venet", "doi-asserted-by": "crossref", "first-page": "441", "journal-title": "Hum Immunol", "key": "pone.0339457.ref030", "volume": "78", "year": "2017" }, { "DOI": "10.1016/j.isci.2021.102711", "article-title": "CD177, a specific marker of neutrophil activation, is associated with coronavirus disease 2019 severity and death", "author": "Y Lévy", "doi-asserted-by": "crossref", "first-page": "102711", "issue": "7", "journal-title": "iScience", "key": "pone.0339457.ref031", "volume": "24", "year": "2021" }, { "DOI": "10.1016/j.jpba.2024.116404", "article-title": "Jinhong decoction ameliorates injury in septic mice without disrupting the equilibrium of gut microbiota", "author": "T Liang", "doi-asserted-by": "crossref", "first-page": "116404", "journal-title": "J Pharm Biomed Anal", "key": "pone.0339457.ref032", "volume": "251", "year": "2024" }, { "DOI": "10.3390/app12178691", "article-title": "Anthraquinone Rhein Exhibits Antibacterial Activity against Staphylococcus aureus", "author": "F Dell’Annunziata", "doi-asserted-by": "crossref", "first-page": "8691", "issue": "17", "journal-title": "Applied Sciences", "key": "pone.0339457.ref033", "volume": "12", "year": "2022" }, { "DOI": "10.3390/molecules27051730", "article-title": "Anthraquinones from the Aerial Parts of Rubia cordifolia with Their NO Inhibitory and Antibacterial Activities", "author": "H Luo", "doi-asserted-by": "crossref", "first-page": "1730", "issue": "5", "journal-title": "Molecules", "key": "pone.0339457.ref034", "volume": "27", "year": "2022" }, { "article-title": "MicroRNA-146a improves sepsis-induced cardiomyopathy by regulating the TLR-4/NF-κB signaling pathway", "author": "J Xie", "first-page": "779", "issue": "1", "journal-title": "Exp Ther Med", "key": "pone.0339457.ref035", "volume": "18", "year": "2019" }, { "DOI": "10.3390/antiox9030198", "article-title": "Spiraea prunifolia var. simpliciflora Attenuates Oxidative Stress and Inflammatory Responses in a Murine Model of Lipopolysaccharide-Induced Acute Lung Injury and TNF-α-Stimulated NCI-H292 Cells", "author": "B-W Lee", "doi-asserted-by": "crossref", "first-page": "198", "issue": "3", "journal-title": "Antioxidants (Basel)", "key": "pone.0339457.ref036", "volume": "9", "year": "2020" }, { "DOI": "10.3390/ph15101222", "article-title": "Candesartan Attenuates Cisplatin-Induced Lung Injury by Modulating Oxidative Stress, Inflammation, and TLR-4/NF-κB, JAK1/STAT3, and Nrf2/HO-1 Signaling", "author": "AM Atwa", "doi-asserted-by": "crossref", "first-page": "1222", "issue": "10", "journal-title": "Pharmaceuticals (Basel)", "key": "pone.0339457.ref037", "volume": "15", "year": "2022" }, { "DOI": "10.1111/nep.14381", "article-title": "PPAR gamma and PGC-1alpha activators protect against diabetic nephropathy by suppressing the inflammation and NF-kappaB activation", "author": "S Huang", "doi-asserted-by": "crossref", "first-page": "858", "issue": "12", "journal-title": "Nephrology (Carlton)", "key": "pone.0339457.ref038", "volume": "29", "year": "2024" }, { "DOI": "10.1016/j.genrep.2020.100692", "article-title": "The effect of Cressa Cretica hydroalcoholic extract on apoptosis and the expression of Bcl2, Bax and P53 genes in hepatoma cell line HepG2", "author": "M Pouraminaei", "doi-asserted-by": "crossref", "first-page": "100692", "journal-title": "Gene Reports", "key": "pone.0339457.ref039", "volume": "20", "year": "2020" }, { "DOI": "10.1016/j.jep.2024.118404", "article-title": "Exploring the anti-inflammatory and immune regulatory effects of Taohe Chengqi decoction in sepsis-induced lung injury", "author": "M Deng", "doi-asserted-by": "crossref", "first-page": "118404", "journal-title": "J Ethnopharmacol", "key": "pone.0339457.ref040", "volume": "333", "year": "2024" }, { "DOI": "10.1007/s00011-019-01220-4", "article-title": "The influence of ICAM1 rs5498 on diabetes mellitus risk: evidence from a meta-analysis", "author": "W Mi", "doi-asserted-by": "crossref", "first-page": "275", "issue": "4", "journal-title": "Inflamm Res", "key": "pone.0339457.ref041", "volume": "68", "year": "2019" }, { "DOI": "10.1186/s12964-024-01620-y", "article-title": "Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications", "author": "X Qiao", "doi-asserted-by": "crossref", "first-page": "241", "issue": "1", "journal-title": "Cell Commun Signal", "key": "pone.0339457.ref042", "volume": "22", "year": "2024" }, { "DOI": "10.1016/j.compbiomed.2024.108080", "article-title": "Possible pharmacological targets and mechanisms of sivelestat in protecting acute lung injury", "author": "J Ren", "doi-asserted-by": "crossref", "first-page": "108080", "journal-title": "Comput Biol Med", "key": "pone.0339457.ref043", "volume": "170", "year": "2024" }, { "DOI": "10.1186/s12964-025-02149-4", "article-title": "An examination of the LPS-TLR4 immune response through the analysis of molecular structures and protein-protein interactions", "author": "R Luo", "doi-asserted-by": "crossref", "first-page": "142", "issue": "1", "journal-title": "Cell Commun Signal", "key": "pone.0339457.ref044", "volume": "23", "year": "2025" }, { "DOI": "10.1007/s10928-022-09828-6", "article-title": "A system pharmacology Boolean network model for the TLR4-mediated inflammatory response in early sepsis", "author": "F Liu", "doi-asserted-by": "crossref", "first-page": "645", "issue": "6", "journal-title": "J Pharmacokinet Pharmacodyn", "key": "pone.0339457.ref045", "volume": "49", "year": "2022" }, { "DOI": "10.1016/j.phymed.2022.154549", "article-title": "Huashibaidu formula attenuates sepsis-induced acute lung injury via suppressing cytokine storm: Implications for treatment of COVID-19", "author": "F Zhang", "doi-asserted-by": "crossref", "first-page": "154549", "journal-title": "Phytomedicine", "key": "pone.0339457.ref046", "volume": "109", "year": "2023" }, { "DOI": "10.1155/2023/4359616", "article-title": "Tiao-Bu-Fei-Shen Formula Improves Glucocorticoid Resistance of Chronic Obstructive Pulmonary Disease via Downregulating the PI3K-Akt Signaling Pathway and Promoting GRα Expression", "author": "P Zhou", "doi-asserted-by": "crossref", "first-page": "4359616", "journal-title": "Evid Based Complement Alternat Med", "key": "pone.0339457.ref047", "volume": "2023", "year": "2023" }, { "DOI": "10.3389/fphar.2022.1048926", "article-title": "Discovery of the key active compounds in Citri Reticulatae Pericarpium (Citrus reticulata “Chachi”) and their therapeutic potential for the treatment of COVID-19 based on comparative metabolomics and network pharmacology", "author": "F Wang", "doi-asserted-by": "crossref", "first-page": "1048926", "journal-title": "Front Pharmacol", "key": "pone.0339457.ref048", "volume": "13", "year": "2022" }, { "DOI": "10.3389/fcimb.2022.1050497", "article-title": "In silico high-throughput screening system for AKT1 activators with therapeutic applications in sepsis acute lung injury", "author": "Z Wang", "doi-asserted-by": "crossref", "first-page": "1050497", "journal-title": "Front Cell Infect Microbiol", "key": "pone.0339457.ref049", "volume": "12", "year": "2022" }, { "article-title": "Network pharmacology and molecular docking analyses on Lianhua Qingwen capsule indicate Akt1 is a potential target to treat and prevent COVID-19", "author": "Q-D Xia", "issue": "12", "journal-title": "Cell Prolif", "key": "pone.0339457.ref050", "volume": "53", "year": "2020" }, { "article-title": "PI3K/Akt and HIF‑1 signaling pathway in hypoxia‑ischemia (Review)", "author": "Z Zhang", "first-page": "3547", "issue": "4", "journal-title": "Mol Med Rep", "key": "pone.0339457.ref051", "volume": "18", "year": "2018" }, { "DOI": "10.1038/s41392-021-00726-w", "article-title": "HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19", "author": "M Tian", "doi-asserted-by": "crossref", "first-page": "308", "issue": "1", "journal-title": "Signal Transduct Target Ther", "key": "pone.0339457.ref052", "volume": "6", "year": "2021" }, { "DOI": "10.1021/acsabm.1c00874", "article-title": "Nanocurcumin Potently Inhibits SARS-CoV-2 Spike Protein-Induced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial Cells", "author": "Prateeksha", "doi-asserted-by": "crossref", "first-page": "483", "issue": "2", "journal-title": "ACS Appl Bio Mater", "key": "pone.0339457.ref053", "volume": "5", "year": "2022" }, { "article-title": "Omics of endothelial cell dysfunction in sepsis", "author": "JC Langston", "issue": "1", "journal-title": "Vasc Biol", "key": "pone.0339457.ref054", "volume": "4", "year": "2022" }, { "DOI": "10.1002/jcp.31424", "article-title": "Phenotypic switch of vascular smooth muscle cells in COVID-19: Role of cholesterol, calcium, and phosphate", "author": "L Ghanem", "doi-asserted-by": "crossref", "issue": "12", "journal-title": "J Cell Physiol", "key": "pone.0339457.ref055", "volume": "239", "year": "2024" }, { "DOI": "10.1038/s41467-021-24007-w", "article-title": "SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals", "author": "NC Gassen", "doi-asserted-by": "crossref", "first-page": "3818", "issue": "1", "journal-title": "Nat Commun", "key": "pone.0339457.ref056", "volume": "12", "year": "2021" }, { "DOI": "10.1172/JCI170500", "article-title": "Recent advances in lung organoid development and applications in disease modeling", "author": "AI Vazquez-Armendariz", "doi-asserted-by": "crossref", "issue": "22", "journal-title": "J Clin Invest", "key": "pone.0339457.ref057", "volume": "133", "year": "2023" } ], "reference-count": 57, "references-count": 57, "relation": {}, "resource": { "primary": { "URL": "https://dx.plos.org/10.1371/journal.pone.0339457" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Analysis of molecular mechanism of Chinese medicine Jinhong decoction (JHD) in synergistically treating sepsis and COVID-19 based on network pharmacology", "type": "journal-article", "update-policy": "https://doi.org/10.1371/journal.pone.corrections_policy", "volume": "20" }