{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:02:56Z","timestamp":1784822576391,"version":"3.55.0"},"reference-count":54,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T00:00:00Z","timestamp":1683936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Health Industry Development Institute","award":["HF20C0212"],"award-info":[{"award-number":["HF20C0212"]}]},{"name":"Korea Health Industry Development Institute","award":["HF21C0061"],"award-info":[{"award-number":["HF21C0061"]}]},{"DOI":"10.13039\/501100003710","name":"Ministry of Health &amp; Welfare, Republic of Korea","doi-asserted-by":"publisher","award":["HF20C0212"],"award-info":[{"award-number":["HF20C0212"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Ministry of Health &amp; Welfare, Republic of Korea","doi-asserted-by":"publisher","award":["HF21C0061"],"award-info":[{"award-number":["HF21C0061"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) is a global health problem that is closely associated with obesity and metabolic syndrome. Spatholobi caulis (SC) is a herbal medicine with potential hepatoprotective effects; however, its active compounds and underlying mechanisms have not been fully explored. In this study, we combined a multiscale network-level approach with experimental validation to investigate SC\u2019s antioxidant properties and their impact on NAFLD. Data collection and network construction were performed, and active compounds and key mechanisms were identified through multi-scale network analysis. Validation was conducted using in vitro steatotic hepatocyte models and in vivo high-fat diet-induced NAFLD models. Our findings revealed that SC treatment improved NAFLD by modulating multiple proteins and signaling pathways, including AMPK signaling pathways. Subsequent experiments showed that SC treatment reduced lipid accumulation and oxidative stress. We also validated SC\u2019s effects on AMPK and its crosstalk pathways, emphasizing their role in hepatoprotection. We predicted procyanidin B2 to be an active compound of SC and validated it using a lipogenesis in vitro model. Histological and biochemical analyses confirmed that SC ameliorated liver steatosis and inflammation in mice. This study presents SC\u2019s potential use in NAFLD treatment and introduces a novel approach for identifying and validating active compounds in herbal medicine.<\/jats:p>","DOI":"10.3390\/antiox12051097","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T02:02:11Z","timestamp":1684116131000},"page":"1097","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Unraveling the Antioxidant Capacity of Spatholobi caulis in Nonalcoholic Fatty Liver Disease: A Multiscale Network Approach Integrated with Experimental Validation"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8884-7940","authenticated-orcid":false,"given":"Su-Jin","family":"Bae","sequence":"first","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won-Yung","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seon-Been","family":"Bak","sequence":"additional","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3323-7106","authenticated-orcid":false,"given":"Young-Woo","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea"},{"name":"Department of Computer Science and Engineering, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41575-019-0145-7","article-title":"From NASH to HCC: Current concepts and future challenges","volume":"16","author":"Anstee","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lee, S.K., Yoon, D.W., Lee, S.W., Kim, J.Y., Kim, J.K., and Shin, C. (2015). Non-alcoholic fatty liver disease among sasang constitutional types: A population-based study in Korea. BMC Complement. Altern. Med., 15.","DOI":"10.1186\/s12906-015-0925-8"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1146\/annurev-biochem-061516-045037","article-title":"Oxidative stress","volume":"86","author":"Sies","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nasc\u00e8, A., Gariani, K., Jornayvaz, F.R., and Szanto, I. (2022). NADPH oxidases connecting fatty liver disease, insulin resistance and type 2 diabetes: Current knowledge and therapeutic outlook. Antioxidants, 11.","DOI":"10.3390\/antiox11061131"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1089\/ars.2013.5619","article-title":"Role of NADPH oxidases in liver fibrosis","volume":"20","author":"Paik","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.redox.2015.07.005","article-title":"Role of NADPH oxidases in the redox biology of liver fibrosis","volume":"6","author":"Fabregat","year":"2015","journal-title":"Redox Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1007\/s12035-017-0652-x","article-title":"Protective effects of Spatholobi caulis extract on neuronal damage and focal ischemic stroke\/reperfusion injury","volume":"55","author":"Park","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/ptr.1226","article-title":"Effects of the ethyl acetate fraction of Spatholobi caulis on tumour cell aggregation and migration","volume":"17","author":"Kang","year":"2003","journal-title":"Phytother. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jep.2016.10.075","article-title":"Spatholobi caulis extracts promote angiogenesis in HUVECs in vitro and in zebrafish embryos in vivo via up-regulation of VEGFRs","volume":"200","author":"Zhou","year":"2017","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"153285","DOI":"10.1016\/j.phymed.2020.153285","article-title":"Spatholobi caulis dispensing granule reduces deep vein thrombus burden through antiinflammation via SIRT1 and Nrf2","volume":"77","author":"Tang","year":"2020","journal-title":"Phytomedicine"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhang, C., Liu, J., He, X., Sheng, Y., Yang, C., Li, H., Xu, J., Xu, W., and Huang, K. (2019). Caulis spatholobi ameliorates obesity through activating brown adipose tissue and modulating the composition of gut microbiota. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205150"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bae, S.-J., Bak, S.B., and Kim, Y.W. (2022). Coordination of AMPK and YAP by Spatholobi caulis and Procyanidin B2 Provides Antioxidant Effects In Vitro and In Vivo. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213730"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e180","DOI":"10.1111\/liv.12523","article-title":"Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non-alcoholic steatohepatitis (NASH)?","volume":"34","author":"Tariq","year":"2014","journal-title":"Liver Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: The next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lee, W.Y., Lee, C.Y., Kim, Y.S., and Kim, C.E. (2019). The methodological trends of traditional herbal medicine employing network pharmacology. Biomolecules, 9.","DOI":"10.3390\/biom9080362"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lee, D.H., Lee, W.Y., Jung, K.W., Kwon, Y.S., Kim, D.Y., Hwang, G.S., Kim, C.E., Lee, S.L., and Kang, K.S. (2019). The inhibitory effect of cordycepin on the proliferation of MCF-7 breast cancer cells, and its mechanism: An investigation using network pharmacology-based analysis. Biomolecules, 9.","DOI":"10.3390\/biom9090407"},{"key":"ref_18","first-page":"4697","article-title":"A network pharmacology approach to investigate the pharmacological effects of Guizhi Fuling Wan on uterine fibroids","volume":"14","author":"Zeng","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.freeradbiomed.2023.02.016","article-title":"Integrative approach to uncover antioxidant properties of Bupleuri Radix and its active compounds: Multiscale interactome-level analysis with experimental validation","volume":"199","author":"Bak","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1038\/s41467-021-21770-8","article-title":"Identification of disease treatment mechanisms through the multiscale interactome","volume":"12","author":"Ruiz","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_21","first-page":"49","article-title":"The analysis of traditional korean medicine\u2019s information circumstance and the future plan of OASIS","volume":"31","author":"Yea","year":"2010","journal-title":"J. Korean Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1093\/nar\/gkp1014","article-title":"Update of TTD: Therapeutic Target Database","volume":"38","author":"Zhu","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1093\/nar\/gkm795","article-title":"STITCH: Interaction networks of chemicals and proteins","volume":"36","author":"Kuhn","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.chembiol.2019.05.004","article-title":"A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling","volume":"26","author":"Huang","year":"2019","journal-title":"Cell Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.neuron.2019.05.002","article-title":"SynGO: An evidence-based, expert-curated knowledge base for the synapse","volume":"103","author":"Koopmans","year":"2019","journal-title":"Neuron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1021\/acs.jproteome.8b00702","article-title":"Cytoscape StringApp: Network analysis and visualization of proteomics data","volume":"18","author":"Doncheva","year":"2018","journal-title":"J. Proteome Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107526","DOI":"10.1016\/j.intimp.2021.107526","article-title":"Protein network exploration prioritizes targets for modulating neuroinflammation in Parkinson\u2019s disease","volume":"95","author":"Bonte","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1053\/j.gastro.2008.03.002","article-title":"Cellular and molecular mechanisms of liver injury","volume":"134","author":"Malhi","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_30","first-page":"1624","article-title":"Signal transductions and nonalcoholic fatty liver: A mini-review","volume":"7","author":"Zeng","year":"2014","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41575-021-00571-w","article-title":"Hippo signalling in the liver: Role in development, regeneration and disease","volume":"19","author":"Russell","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Phung, H.M., Lee, H., Lee, S., Jang, D., Kim, C.-E., Kang, K.S., Seo, C.-S., and Choi, Y.-K. (2020). Analysis and anticancer effects of active compounds from Spatholobi caulis in human breast cancer cells. Processes, 8.","DOI":"10.3390\/pr8091193"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jpba.2014.09.006","article-title":"Simultaneous determination of 16 phenolic constituents in Spatholobi caulis by high performance liquid chromatography\/electrospray ionization triple quadrupole mass spectrometry","volume":"102","author":"Zhang","year":"2015","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1002\/cbin.10915","article-title":"Mechanisms of AMPK in the maintenance of ATP balance during energy metabolism","volume":"42","author":"Ke","year":"2018","journal-title":"Cell Biol. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nrm3311","article-title":"AMPK: A nutrient and energy sensor that maintains energy homeostasis","volume":"13","author":"Hardie","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","first-page":"E730","article-title":"Treatment of nonalcoholic fatty liver disease: Role of AMPK","volume":"311","author":"Smith","year":"2016","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"108306","DOI":"10.1016\/j.intimp.2021.108306","article-title":"Liensinine alleviates high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) through suppressing oxidative stress and inflammation via regulating TAK1\/AMPK signaling","volume":"104","author":"Liang","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/s41569-018-0063-3","article-title":"The Hippo pathway in the heart: Pivotal roles in development, disease, and regeneration","volume":"15","author":"Wang","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.ceb.2008.10.001","article-title":"The Hippo\u2013YAP pathway: New connections between regulation of organ size and cancer","volume":"20","author":"Zhao","year":"2008","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.molmed.2015.01.003","article-title":"Disease implications of the Hippo\/YAP pathway","volume":"21","author":"Plouffe","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.devcel.2020.06.025","article-title":"Integration of Hippo-YAP signaling with metabolism","volume":"54","author":"Ibar","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.devcel.2022.02.004","article-title":"YAP regulates an SGK1\/mTORC1\/SREBP-dependent lipogenic program to support proliferation and tissue growth","volume":"57","author":"Vaidyanathan","year":"2022","journal-title":"Dev. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/ncb3111","article-title":"Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway","volume":"17","author":"Mo","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/j.freeradbiomed.2005.05.024","article-title":"Procyanidin B2 has anti-and pro-oxidant effects on metal-mediated DNA damage","volume":"39","author":"Sakano","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.imbio.2018.07.001","article-title":"Procyanidin B2 protects rats from paraquat-induced acute lung injury by inhibiting NLRP3 inflammasome activation","volume":"223","author":"Jiang","year":"2018","journal-title":"Immunobiology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/cbin.11229","article-title":"The protective effects of grape seed procyanidin B2 against asporin mediates glycated low-density lipoprotein induced-cardiomyocyte apoptosis and fibrosis","volume":"44","author":"Li","year":"2020","journal-title":"Cell Biol. Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1002\/mnfr.201500181","article-title":"Procyanidin B2 attenuates neurological deficits and blood\u2013brain barrier disruption in a rat model of cerebral ischemia","volume":"59","author":"Wu","year":"2015","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4109","DOI":"10.2147\/OTT.S195615","article-title":"Grape seed procyanidin B2 promotes the autophagy and apoptosis in colorectal cancer cells via regulating PI3K\/Akt signaling pathway","volume":"12","author":"Zhang","year":"2019","journal-title":"Onco. Targets Ther."},{"key":"ref_50","first-page":"15638","article-title":"Protection of procyanidin B2 on mitochondrial dynamics in sepsis associated acute kidney injury via promoting Nrf2 nuclear translocation","volume":"12","author":"Liu","year":"2020","journal-title":"Aging (Albany N. Y.)"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1039\/C5FO01062D","article-title":"Grape seed procyanidin B2 protects podocytes from high glucose-induced mitochondrial dysfunction and apoptosis via the AMPK-SIRT1-PGC-1\u03b1 axis in vitro","volume":"7","author":"Cai","year":"2016","journal-title":"Food Funct."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"955","DOI":"10.3748\/wjg.v25.i8.955","article-title":"Procyanidin B2 protects against diet-induced obesity and non-alcoholic fatty liver disease via the modulation of the gut microbiota in rabbits","volume":"25","author":"Xing","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.freeradbiomed.2018.08.024","article-title":"Procyanidin B2 ameliorates free fatty acids-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state","volume":"126","author":"Su","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"104285","DOI":"10.1016\/j.jff.2020.104285","article-title":"Procyanidin B2 prevents dyslipidemia via modulation of gut microbiome and related metabolites in high-fat diet fed mice","volume":"75","author":"Xiao","year":"2020","journal-title":"J. Funct. 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