{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:30:12Z","timestamp":1776274212568,"version":"3.50.1"},"reference-count":106,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T00:00:00Z","timestamp":1686528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Psoriasis is a chronic skin disease that affects millions of people worldwide. In 2014, psoriasis was recognized by the World Health Organization (WHO) as a serious non-communicable disease. In this study, a systems biology approach was used to investigate the underlying pathogenic mechanism of psoriasis and identify the potential drug targets for therapeutic treatment. The study involved the construction of a candidate genome-wide genetic and epigenetic network (GWGEN) through big data mining, followed by the identification of real GWGENs of psoriatic and non-psoriatic using system identification and system order detection methods. Core GWGENs were extracted from real GWGENs using the Principal Network Projection (PNP) method, and the corresponding core signaling pathways were annotated using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Comparing core signaling pathways of psoriasis and non-psoriasis and their downstream cellular dysfunctions, STAT3, CEBPB, NF-\u03baB, and FOXO1 are identified as significant biomarkers of pathogenic mechanism and considered as drug targets for the therapeutic treatment of psoriasis. Then, a deep neural network (DNN)-based drug-target interaction (DTI) model was trained by the DTI dataset to predict candidate molecular drugs. By considering adequate regulatory ability, toxicity, and sensitivity as drug design specifications, Naringin, Butein, and Betulinic acid were selected from the candidate molecular drugs and combined into potential multi-molecule drugs for the treatment of psoriasis.<\/jats:p>","DOI":"10.3390\/ijms241210033","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T01:35:30Z","timestamp":1686620130000},"page":"10033","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Drug Target Identification and Drug Repurposing in Psoriasis through Systems Biology Approach, DNN-Based DTI Model and Genome-Wide Microarray Data"],"prefix":"10.3390","volume":"24","author":[{"given":"Yu-Ping","family":"Zhan","sequence":"first","affiliation":[{"name":"Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bor-Sen","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1038\/nature05663","article-title":"Pathogenesis and therapy of psoriasis","volume":"445","author":"Lowes","year":"2007","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1080\/13548500802512294","article-title":"The psychological sequelae of psoriasis: Results of a qualitative study","volume":"14","author":"Magin","year":"2009","journal-title":"Psychol. Health Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1111\/jdv.13854","article-title":"Venereology. A systematic review of worldwide epidemiology of psoriasis","volume":"31","author":"Michalek","year":"2017","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_4","unstructured":"World Health Organization (2016). World Health Organization Global Report on Psoriasis, World Health Organization."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1093\/hmg\/7.10.1537","article-title":"The genetics of psoriasis: A complex disorder of the skin and immune system","volume":"7","author":"Bhalerao","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rendon, A., and Sch\u00e4kel, K. (2019). Psoriasis pathogenesis and treatment. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061475"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/j.1529-8019.2010.01312.x","article-title":"Psoriasis: Depression, anxiety, smoking, and drinking habits","volume":"23","author":"Hayes","year":"2010","journal-title":"Dermatol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaad.2005.01.010","article-title":"Adverse effects of topical glucocorticosteroids","volume":"54","author":"Hengge","year":"2006","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_9","first-page":"173","article-title":"A clinical review of phototherapy for psoriasis","volume":"33","author":"Zhang","year":"2018","journal-title":"JAAD"},{"key":"ref_10","first-page":"1371","article-title":"Photocarcinogenesis and skin cancer prevention strategies","volume":"36","author":"Seebode","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1365-2230.1996.tb00142.x","article-title":"Methotrexate for psoriasis","volume":"21","author":"Boffa","year":"1996","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1111\/1346-8138.13860","article-title":"Switching of biologics in psoriasis: Reasons and results","volume":"44","author":"Honda","year":"2017","journal-title":"Br. J. Dermatol."},{"key":"ref_13","first-page":"1239","article-title":"Principles of early drug discovery","volume":"162","author":"Hughes","year":"2011","journal-title":"Br. J. Dermatol."},{"key":"ref_14","first-page":"151","article-title":"The importance of clinical trials in drug development","volume":"8","author":"Akhondzadeh","year":"2016","journal-title":"Avicenna J. Med. Biotechnol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13722-015-0024-7","article-title":"Designer drugs 2015: Assessment and management","volume":"10","author":"Weaver","year":"2015","journal-title":"Addict. Sci. Clin. Pract."},{"key":"ref_16","first-page":"100041","article-title":"Repurposing approved therapeutics for new indication: Addressing unmet needs in psoriasis treatment","volume":"2","author":"Jain","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ting, C.-T., and Chen, B.-S. (2022). Repurposing Multiple-Molecule Drugs for COVID-19-Associated Acute Respiratory Distress Syndrome and Non-Viral Acute Respiratory Distress Syndrome via a Systems Biology Approach and a DNN-DTI Model Based on Five Drug Design Specifications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073649"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"405","DOI":"10.3390\/stresses2040029","article-title":"Multiple-Molecule Drug Repositioning for Disrupting Progression of SARS-CoV-2 Infection by Utilizing the Systems Biology Method through Host-Pathogen-Interactive Time Profile Data and DNN-Based DTI Model with Drug Design Specifications","volume":"2","author":"Wang","year":"2022","journal-title":"Stresses"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Yeh, S.-J., Chung, Y.-C., and Chen, B.-S. (2022). Investigating the Role of Obesity in Prostate Cancer and Identifying Biomarkers for Drug Discovery: Systems Biology and Deep Learning Approaches. Molecules, 27.","DOI":"10.3390\/molecules27030900"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yeh, S.-J., Lin, J.-F., and Chen, B.-S. (2021). Multiple-molecule drug design based on systems biology approaches and deep neural network to mitigate human skin aging. Molecules, 26.","DOI":"10.3390\/molecules26113178"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/BF02294361","article-title":"Model selection and Akaike\u2019s information criterion (AIC): The general theory and its analytical extensions","volume":"52","author":"Bozdogan","year":"1987","journal-title":"Psychometrika"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6367","DOI":"10.1073\/pnas.86.16.6367","article-title":"Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes","volume":"86","author":"Grossman","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s12026-013-8481-0","article-title":"JAK\/STAT\/PKC\u03b4 molecular pathways in synovial fluid T lymphocytes reflect the in vivo T helper-17 expansion in psoriatic arthritis","volume":"58","author":"Fiocco","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s40265-020-01261-8","article-title":"JAK inhibitors for treatment of psoriasis: Focus on selective TYK2 inhibitors","volume":"80","author":"Nogueira","year":"2020","journal-title":"Drugs"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1172\/JCI0215650","article-title":"What does Stat3 do?","volume":"109","author":"Levy","year":"2002","journal-title":"J. Clin. Investig"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"933","DOI":"10.2174\/1381612003400182","article-title":"Inhibitors of tyrosine kinases in the treatment of psoriasis","volume":"6","author":"Klein","year":"2000","journal-title":"Curr. Pharm. Des."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.jdermsci.2010.03.023","article-title":"Vascular endothelial growth factor (VEGF) in the pathogenesis of psoriasis\u2014A possible target for novel therapies?","volume":"58","author":"Canavese","year":"2010","journal-title":"J. Dermatol. Sci"},{"key":"ref_28","first-page":"247","article-title":"VEGF involvement in psoriasis","volume":"88","author":"Marina","year":"2015","journal-title":"Clujul Med. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1046\/j.1365-4362.2003.01821.x","article-title":"Examination of Bcl-2, Bcl-X and bax protein expression in psoriasis","volume":"42","author":"Erkek","year":"2003","journal-title":"Int. J. Dermatol."},{"key":"ref_30","first-page":"1079","article-title":"Discordant expression of Bcl-x and Bcl-2 by keratinocytes in vitro and psoriatic keratinocytes in vivo","volume":"146","author":"Johnson","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_31","first-page":"54","article-title":"STAT3 and NF-\u03baB are common targets for kaempferol-mediated attenuation of COX-2 expression in IL-6-induced macrophages and carrageenan-induced mouse paw edema","volume":"12","author":"Basu","year":"2017","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1111\/j.1468-3083.2010.03966.x","article-title":"Venereology. Insulin-like growth factor-1 in psoriatic plaques treated with PUVA and methotrexate","volume":"25","author":"Amin","year":"2011","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.steroids.2007.12.028","article-title":"MNAR plays an important role in ERa activation of Src\/MAPK and PI3K\/Akt signaling pathways","volume":"73","author":"Cheskis","year":"2008","journal-title":"Steroids"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s00403-018-1879-8","article-title":"The role of PI3K\/AKT\/FOXO signaling in psoriasis","volume":"311","author":"Zhang","year":"2019","journal-title":"Arch. Dermatol. Res."},{"key":"ref_35","first-page":"2327","article-title":"Identification of key pathways and genes in psoriasis via gene microarray analysis","volume":"13","author":"Chen","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1111\/ijd.12476","article-title":"Comparisons of gene expression in normal, lesional, and non-lesional psoriatic skin using DNA microarray techniques","volume":"53","author":"Xie","year":"2014","journal-title":"Int. J. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.it.2021.02.002","article-title":"Bcl6-mediated transcriptional regulation of follicular helper T cells (TFH)","volume":"42","author":"Choi","year":"2021","journal-title":"Trends Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1126\/science.1176676","article-title":"Bcl6 mediates the development of T follicular helper cells","volume":"325","author":"Nurieva","year":"2009","journal-title":"Science."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.molimm.2022.11.015","article-title":"Single-cell atlas reveals a high selection of IgA1-or IgG1-expressing plasma cells in patients with psoriasis","volume":"153","author":"Liu","year":"2023","journal-title":"Mol. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jdermsci.2012.11.002","article-title":"NF-\u03baB: An essential transcription factor in psoriasis","volume":"69","author":"Goldminz","year":"2013","journal-title":"J. Dermatol. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1600-0560.2007.00841.x","article-title":"Evaluation of survivin and NF-\u03baB in psoriasis, an immunohistochemical study","volume":"35","author":"Abdou","year":"2008","journal-title":"J. Cutan. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s00109-015-1338-3","article-title":"Isoliquiritigenin prevents the progression of psoriasis-like symptoms by inhibiting NF-\u03baB and proinflammatory cytokines","volume":"94","author":"Wu","year":"2016","journal-title":"J. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6783","DOI":"10.1096\/fj.201800354","article-title":"Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte-derived chemokine expression and neutrophil infiltration","volume":"32","author":"Lin","year":"2018","journal-title":"FASEB J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.advms.2015.07.011","article-title":"CXCL10 in psoriasis","volume":"60","author":"Ferrari","year":"2015","journal-title":"Adv. Med. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/jid.2012.194","article-title":"The emerging role of IL-17 in the pathogenesis of psoriasis: Preclinical and clinical findings","volume":"133","author":"Martin","year":"2013","journal-title":"J. Invest. Dermatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.immuni.2012.04.010","article-title":"The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury","volume":"37","author":"Lai","year":"2012","journal-title":"Immunity"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1021\/acschembio.8b00260","article-title":"Small molecule and pooled CRISPR screens investigating IL17 signaling identify BRD2 as a novel contributor to keratinocyte inflammatory responses","volume":"14","author":"Slivka","year":"2019","journal-title":"ACS Chem. Biol"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"24138","DOI":"10.1074\/jbc.M604597200","article-title":"Identification of common transcriptional regulatory elements in interleukin-17 target genes","volume":"281","author":"Shen","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/bjd.21232","article-title":"miR-378a regulates keratinocyte responsiveness to interleukin-17A in psoriasis","volume":"187","author":"Xia","year":"2022","journal-title":"Br. J. Dermatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5130","DOI":"10.1073\/pnas.72.12.5130","article-title":"Increased concentrations of nonesterified arachidonic acid, 12L-hydroxy-5, 8, 10, 14-eicosatetraenoic acid, prostaglandin E2, and prostaglandin F2alpha in epidermis of psoriasis","volume":"72","author":"Hamberg","year":"1975","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","first-page":"28","article-title":"Prostaglandin E2 induces vasodilation and pruritus, but no protein extravasation in atopic dermatitis and controls","volume":"47","author":"Neisius","year":"2002","journal-title":"J. Invest. Dermatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/S0140-6736(96)04328-0","article-title":"Pathophysiology of itching","volume":"348","author":"Greaves","year":"1996","journal-title":"Lancet"},{"key":"ref_53","first-page":"264","article-title":"TNF-alpha and apoptosis: Implications for the pathogenesis and treatment of psoriasis","volume":"1","author":"Victor","year":"2002","journal-title":"J. Drugs Dermatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.4049\/jimmunol.175.4.2721","article-title":"TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques","volume":"175","author":"Gottlieb","year":"2005","journal-title":"J. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cytogfr.2014.10.009","article-title":"An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17","volume":"26","author":"Grine","year":"2015","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/nrm3683","article-title":"Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death","volume":"14","author":"Ofengeim","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1365-2133.2004.06304.x","article-title":"The mitogen-activated protein kinases p38 and ERK1\/2 are increased in lesional psoriatic skin","volume":"152","author":"Johansen","year":"2005","journal-title":"Br. J. Dermatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.yexmp.2007.05.002","article-title":"Expression and localization of the activated mitogen-activated protein kinase in lesional psoriatic skin","volume":"83","author":"Yu","year":"2007","journal-title":"Exp. Mol. Pathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/j.1346-8138.2009.00696.x","article-title":"Differential expression of phosphorylated extracellular signal-regulated kinase 1\/2, phosphorylated p38 mitogen-activated protein kinase and nuclear factor-\u03baB p105\/p50 in chronic inflammatory skin diseases","volume":"36","author":"Wang","year":"2009","journal-title":"Br. J. Dermatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/S0923-1811(02)00064-6","article-title":"Extracellular regulated kinase and c-Jun N-terminal kinase are activated in psoriatic involved epidermis","volume":"30","author":"Takahashi","year":"2002","journal-title":"J. Dermatol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1007\/s13238-011-1113-3","article-title":"c-Jun, at the crossroad of the signaling network","volume":"2","author":"Meng","year":"2011","journal-title":"Protein Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0092-8674(02)01084-X","article-title":"Identification of a Wnt\/Dvl\/\u03b2-catenin\u2192 Pitx2 pathway mediating cell-type-specific proliferation during development","volume":"111","author":"Kioussi","year":"2002","journal-title":"Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"245","DOI":"10.21037\/atm.2018.04.09","article-title":"Molecular mechanisms of mechanotransduction in psoriasis","volume":"6","author":"Malakou","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1038\/jid.2010.67","article-title":"Evidence for altered Wnt signaling in psoriatic skin","volume":"130","author":"Gudjonsson","year":"2010","journal-title":"J. Invest. Dermatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A next generation connectivity map: L1000 platform and the first 1,000,000 profiles","volume":"171","author":"Subramanian","year":"2017","journal-title":"Cell"},{"key":"ref_66","first-page":"37","article-title":"Uncovering cancer gene regulation by accurate regulatory network inference from uninformative data","volume":"6","author":"Hillerton","year":"2020","journal-title":"NPJ 2D Mater. Appl."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s43018-019-0018-6","article-title":"Discovering the anticancer potential of non-oncology drugs by systematic viability profiling","volume":"1","author":"Corsello","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"W5","DOI":"10.1093\/nar\/gkab255","article-title":"ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties","volume":"49","author":"Xiong","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/med.10053","article-title":"Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection","volume":"24","author":"Cichewicz","year":"2004","journal-title":"Med. Res. Rev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1002\/med.20156","article-title":"Recent developments in anti-inflammatory natural products","volume":"29","author":"Gautam","year":"2009","journal-title":"Med. Res. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cbi.2012.01.002","article-title":"The anti-fibrotic effect of betulinic acid is mediated through the inhibition of NF-\u03baB nuclear protein translocation","volume":"195","author":"Wan","year":"2012","journal-title":"Chem. Biol. Interact"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/cbic.201100652","article-title":"The natural product betulinic acid inhibits C\/EBP family transcription factors","volume":"13","author":"Hollis","year":"2012","journal-title":"ChemBioChem"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4481","DOI":"10.1111\/bph.13233","article-title":"Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF-\u03ba B-and MAPK-ERK 1\/2-mediated COX-2 expression","volume":"172","author":"Lin","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/j.fct.2004.03.012","article-title":"Extract from Rhus verniciflua Stokes is capable of inhibiting the growth of human lymphoma cells","volume":"42","author":"Lee","year":"2004","journal-title":"Food Chem. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.bbrc.2004.08.063","article-title":"Inhibition of lipopolysaccharide-induced expression of inducible nitric oxide synthase by butein in RAW 264.7 cells","volume":"323","author":"Lee","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1124\/mol.108.052548","article-title":"Butein suppresses constitutive and inducible signal transducer and activator of transcription (STAT) 3 activation and STAT3-regulated gene products through the induction of a protein tyrosine phosphatase SHP-1","volume":"75","author":"Pandey","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"495","DOI":"10.5483\/BMBRep.2015.48.9.259","article-title":"Butein, a tetrahydroxychalcone, suppresses pro-inflammatory responses in HaCaT keratinocytes","volume":"48","author":"Seo","year":"2015","journal-title":"BMB Rep"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ejphar.2014.05.031","article-title":"Inhibition of adipocyte inflammation and macrophage chemotaxis by butein","volume":"738","author":"Wang","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"8809","DOI":"10.1021\/jf300669s","article-title":"Citrus flavanones: What is their role in cardiovascular protection?","volume":"60","author":"Chanet","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6185","DOI":"10.1021\/jf8006568","article-title":"Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity","volume":"56","author":"Castillo","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"121471","DOI":"10.1016\/j.lfs.2023.121471","article-title":"Naringin protects mice from D-galactose-induced lung aging and mitochondrial dysfunction: Implication of SIRT1 pathways","volume":"324","author":"Salama","year":"2023","journal-title":"Life Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.3892\/mmr.2012.1072","article-title":"Naringin inhibits chemokine production in an LPS-induced RAW 264.7 macrophage cell line","volume":"6","author":"Liu","year":"2012","journal-title":"Mol. Med. Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.foodres.2009.04.016","article-title":"Anti-inflammatory activity of naringin and the biosynthesised naringenin by naringinase immobilized in microstructured materials in a model of DSS-induced colitis in mice","volume":"42","author":"Amaro","year":"2009","journal-title":"Food Res. Int."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Deenonpoe, R., Prayong, P., Thippamom, N., Meephansan, J., and Na-Bangchang, K. (2019). Anti-inflammatory effect of naringin and sericin combination on human peripheral blood mononuclear cells (hPBMCs) from patient with psoriasis. BMC Complement Altern. Med., 19.","DOI":"10.1186\/s12906-019-2535-3"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3389\/fgene.2020.00117","article-title":"Investigation of the genome-wide genetic and epigenetic networks for drug discovery based on systems biology approaches in colorectal cancer","volume":"11","author":"Yeh","year":"2020","journal-title":"Front. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"D449","DOI":"10.1093\/nar\/gkh086","article-title":"The database of interacting proteins: 2004 update","volume":"32","author":"Salwinski","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"D358","DOI":"10.1093\/nar\/gkt1115","article-title":"The MIntAct project\u2014IntAct as a common curation platform for 11 molecular interaction databases","volume":"42","author":"Orchard","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"D535","DOI":"10.1093\/nar\/gkj109","article-title":"BioGRID: A general repository for interaction datasets","volume":"34","author":"Stark","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0014-5793(01)03293-8","article-title":"MINT: A Molecular INTeraction database","volume":"513","author":"Zanzoni","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_90","first-page":"405","article-title":"HTRIdb: An open-access database for experimentally verified human transcriptional regulation interactions","volume":"13","author":"Bovolenta","year":"2012","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1093\/bioinformatics\/btn439","article-title":"ITFP: An integrated platform of mammalian transcription factors","volume":"24","author":"Zheng","year":"2008","journal-title":"Bioinformatics"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1093\/nar\/28.1.316","article-title":"TRANSFAC: An integrated system for gene expression regulation","volume":"28","author":"Wingender","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Friard, O., Re, A., Taverna, D., De Bortoli, M., and Cor\u00e1, D. (2010). CircuitsDB: A database of mixed microRNA\/transcription factor feed-forward regulatory circuits in human and mouse. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-435"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e05005","DOI":"10.7554\/eLife.05005","article-title":"Predicting effective microRNA target sites in mammalian mRNAs","volume":"4","author":"Agarwal","year":"2015","journal-title":"elife"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"D92","DOI":"10.1093\/nar\/gkt1248","article-title":"starBase v2. 0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein\u2013RNA interaction networks from large-scale CLIP-Seq data","volume":"42","author":"Li","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"635","DOI":"10.3390\/cells2040635","article-title":"Systems biology as an integrated platform for bioinformatics, systems synthetic biology, and systems metabolic engineering","volume":"2","author":"Chen","year":"2013","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Chang, S., Wang, L.H.-C., and Chen, B.-S. (2020). Investigating core signaling pathways of hepatitis b virus pathogenesis for biomarkers identification and drug discovery via systems biology and deep learning method. Biomedicines, 8.","DOI":"10.3390\/biomedicines8090320"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"D684","DOI":"10.1093\/nar\/gkm795","article-title":"STITCH: Interaction networks of chemicals and proteins","volume":"36","author":"Kuhn","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_99","first-page":"1478","article-title":"Bioinformatics and Drug Design Group at NUS","volume":"10","author":"Chen","year":"2006","journal-title":"APBN"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"D506","DOI":"10.1093\/nar\/gky1049","article-title":"UniProt: A worldwide hub of protein knowledge","volume":"47","author":"research","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"D1035","DOI":"10.1093\/nar\/gkq1126","article-title":"DrugBank 3.0: A comprehensive resource for \u2018omics\u2019 research on drugs","volume":"39","author":"Knox","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"D1202","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem substance and compound databases","volume":"44","author":"Kim","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13321-018-0270-2","article-title":"PyBioMed: A python library for various molecular representations of chemicals, proteins and DNAs and their interactions","volume":"10","author":"Dong","year":"2018","journal-title":"J. Cheminform."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Chang, S., Chen, J.-Y., Chuang, Y.-J., and Chen, B.-S. (2020). Systems Approach to Pathogenic Mechanism of Type 2 Diabetes and Drug Discovery Design Based on Deep Learning and Drug Design Specifications. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010166"},{"key":"ref_106","unstructured":"Hecht-Nielsen, R. (1992). Neural Networks for Perception, Elsevier."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/10033\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:53:25Z","timestamp":1760126005000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/10033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,12]]},"references-count":106,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms241210033"],"URL":"https:\/\/doi.org\/10.3390\/ijms241210033","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,12]]}}}