{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T02:55:23Z","timestamp":1768272923395,"version":"3.49.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T00:00:00Z","timestamp":1647129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2019R1A2C1003200"],"award-info":[{"award-number":["2019R1A2C1003200"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","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":"Korea Health Industry Development Institute","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":["Molecules"],"abstract":"<jats:p>Natural products and medicinal herbs have been used to treat various human diseases by regulating cellular functions and metabolic pathways. Angelica gigas NAKAI (AG) helps regulate pathological processes in some medical fields, including gastroenterology, gynecology, and neuropsychiatry. Although some papers have reported its diverse indications, the effects of AG against arachidonic acid (AA)+ iron and carbon tetrachloride (CCl4) have not been reported. In HepG2 cells, AA+ iron induced cellular apoptosis and mitochondrial damage, as assessed by mitochondrial membrane permeability (MMP) and the expression of apoptosis-related proteins. On the other hand, AG markedly inhibited these detrimental phenomena and reactive oxygen species (ROS) production induced by AA+ iron. AG activated the liver kinase B1 (LKB1)-dependent AMP-activated protein kinase (AMPK), which affected oxidative stress in the cells. Moreover, AG also regulated the expression of yes-associated protein (YAP) signaling as mediated by the AMPK pathways. In mice, an oral treatment of AG protected against liver toxicity induced by CCl4, as indicated by the plasma and histochemical parameters. Among the compounds in AG, decursin had antioxidant activity and affected the AMPK pathway. In conclusion, AG has antioxidant effects in vivo and in vitro, indicating that natural products such as AG could be potential candidate for the nutraceuticals to treat various disorders by regulating mitochondrial dysfunction and cellular metabolic pathways.<\/jats:p>","DOI":"10.3390\/molecules27061858","type":"journal-article","created":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T22:29:43Z","timestamp":1647210583000},"page":"1858","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Angelica gigas NAKAI and Its Active Compound, Decursin, Inhibit Cellular Injury as an Antioxidant by the Regulation of AMP-Activated Protein Kinase and YAP Signaling"],"prefix":"10.3390","volume":"27","author":[{"given":"Yu-Rim","family":"Song","sequence":"first","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6054-7679","authenticated-orcid":false,"given":"Boyun","family":"Jang","sequence":"additional","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7398-538X","authenticated-orcid":false,"given":"Sung-Min","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8884-7940","authenticated-orcid":false,"given":"Su-Jin","family":"Bae","sequence":"additional","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seon-Been","family":"Bak","sequence":"additional","affiliation":[{"name":"School of Korean Medicine, Dongguk University, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/j.freeradbiomed.2010.09.006","article-title":"Oxidative stress, inflammation, and cancer: How are they linked?","volume":"49","author":"Reuter","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.canlet.2016.03.042","article-title":"Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals","volume":"387","author":"Prasad","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/978-981-15-7360-6_20","article-title":"Molecular mechanisms of nonalcoholic fatty liver disease (NAFLD)\/Nonalcoholic Steatohepatitis (NASH)","volume":"1261","author":"Ota","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_4","first-page":"568","article-title":"Non-alcoholic fatty liver disease--new view","volume":"24","author":"Lawniczak","year":"2008","journal-title":"Pol. Merkur. Lekarski"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sztolsztener, K., Chabowski, A., Harasim-Symbor, E., Bielawiec, P., and Konstantynowicz-Nowicka, K. (2020). Arachidonic acid as an early indicator of inflammation during non-alcoholic fatty liver disease development. Biomolecules, 10.","DOI":"10.3390\/biom10081133"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/978-3-319-48382-5_19","article-title":"Non-alcoholic fatty liver disease","volume":"960","author":"Engin","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.freeradbiomed.2013.08.174","article-title":"Free radical biology for medicine: Learning from nonalcoholic fatty liver disease","volume":"65","author":"Serviddio","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"513","DOI":"10.3109\/02656736.2014.971446","article-title":"Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review","volume":"30","author":"Slimen","year":"2014","journal-title":"Int. J. Hyperth."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.5604\/17322693.1224259","article-title":"Endogenous mechanisms of reactive oxygen species (ROS) generation","volume":"70","author":"Sarniak","year":"2016","journal-title":"Postepy Hig. Med. Dosw."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.redox.2015.09.005","article-title":"Thierry Soldati, reactive oxygen species and mitochondria: A nexus of cellular homeostasis","volume":"6","author":"Dunn","year":"2015","journal-title":"Redox Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1159\/000485089","article-title":"Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species","volume":"44","author":"He","year":"2017","journal-title":"Cell Physiol. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1016\/j.freeradbiomed.2009.07.018","article-title":"Efficacy of sauchinone as a novel AMPK-activating lignan for preventing iron-induced oxidative stress and liver injury","volume":"47","author":"Kim","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Napolitano, G., Fasciolo, G., Meo, S.D., and Venditti, P. (2019). Vitamin E supplementation and mitochondria in experimental and functional hyperthyroidism: A mini-review. Nutrients, 11.","DOI":"10.3390\/nu11122900"},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1248\/cpb.c15-00081","article-title":"Quantitative analysis of marker compounds in Angelica gigas, Angelica sinensis, and Angelica acutiloba by HPLC\/DAD","volume":"63","author":"Jeong","year":"2015","journal-title":"Chem. Pharm. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1248\/bpb.b12-00046","article-title":"Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas","volume":"35","author":"Mahat","year":"2012","journal-title":"Biol. Pharm. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1142\/S0192415X16500919","article-title":"Angelica gigas Ameliorates Hyperglycemia and Hepatic Steatosis in C57BL\/KsJ-db\/db Mice via Activation of AMP-Activated Protein Kinase Signaling Pathway","volume":"44","author":"Bae","year":"2016","journal-title":"Am. J. Chin. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s10068-019-00698-2","article-title":"Pilot-scale subcritical-water extraction of nodakenin and decursin from Angelica gigas Nakai","volume":"29","author":"Ko","year":"2019","journal-title":"Food Sci. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jang, E.J., Kim, S.C., Lee, J.H., Lee, J.R., Kim, I.K., Baek, S.Y., and Kim, Y.W. (2018). Fucoxanthin, the constituent of Laminaria japonica, triggers AMPK-mediated cytoprotection and autophagy in hepatocytes under oxidative stress. BMC Complement. Altern. Med., 18.","DOI":"10.1186\/s12906-018-2164-2"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1080\/13880209.2020.1750658","article-title":"Emodin in Rheum undulatum inhibits oxidative stress in the liver via AMPK with Hippo\/Yap signalling pathway","volume":"58","author":"Lee","year":"2020","journal-title":"Pharm. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.cbi.2015.06.024","article-title":"Oxyresveratrol abrogates oxidative stress by activating ERK-Nrf2 pathway in the liver","volume":"245","author":"Choi","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"108889","DOI":"10.1016\/j.cbi.2019.108889","article-title":"Rifampicin activates AMPK and alleviates oxidative stress in the liver as mediated with Nrf2 signaling","volume":"315","author":"Lee","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kim, S.J., Ko, S.M., Choi, E.J., Ham, S.H., Kwon, Y.D., Lee, Y.B., and Cho, H.Y. (2018). Simultaneous determination of decursin, decursinol angelate, nodakenin, and decursinol of angelica gigas nakai in human plasma by UHPLC-MS\/MS: Application to pharmacokinetic study. Molecules, 23.","DOI":"10.3390\/molecules23051019"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41392-020-00443-w","article-title":"Metabolism pathways of arachidonic acids: Mechanisms and potential therapeutic targets","volume":"6","author":"Wang","year":"2021","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.bbalip.2006.03.014","article-title":"Oxidative stress and arachidonic acid mobilization","volume":"1761","author":"Balboa","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/S1089-3261(02)00004-1","article-title":"Iron overload disorders","volume":"6","author":"Turlin","year":"2002","journal-title":"Clin. Liver Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1056\/NEJMp048363","article-title":"Orchestration of iron homeostasis","volume":"352","author":"Fleming","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/BF00144626","article-title":"Hepatic iron deposition in human disease and animal models","volume":"9","author":"Halliday","year":"1996","journal-title":"Biometals"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1161\/01.CIR.103.19.2395","article-title":"Increased release of arachidonic acid and eicosanoids in iron-overloaded cardiomyocytes","volume":"103","author":"Mattera","year":"2001","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3109\/10715769609149047","article-title":"The mechanism of iron (III) stimulation of lipid peroxidation","volume":"25","author":"Tadolini","year":"1996","journal-title":"Free Radic. Res."},{"key":"ref_31","first-page":"742","article-title":"Synergistic toxicity of iron and arachidonic acid in HepG2 cells overexpressing CYP2E1","volume":"60","author":"Caro","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1124\/mol.108.051128","article-title":"Inhibition of arachidonic acid and iron-induced mitochondrial dysfunction and apoptosis by oltipraz and novel 1,2-dithiole-3-thione congeners","volume":"75","author":"Shin","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cbi.2005.12.009","article-title":"Free radicals, metals and antioxidants in oxidative stress-induced cancer","volume":"160","author":"Valko","year":"2006","journal-title":"Chem. Biol. Interact."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12279","DOI":"10.1074\/jbc.REV120.011356","article-title":"From overnutrition to liver injury: AMP-activated protein kinase in nonalcoholic fatty liver diseases","volume":"295","author":"Zhao","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.tem.2017.05.004","article-title":"AMPK as a Therapeutic Target for Treating Metabolic Diseases","volume":"28","author":"Day","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13045-020-00949-4","article-title":"The MAPK and AMPK signalings: Interplay and implication in targeted cancer therapy","volume":"13","author":"Yuan","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1042\/BJ20090613","article-title":"AMPK alpha1 regulates the antioxidant status of vascular endothelial cells","volume":"421","author":"Colombo","year":"2009","journal-title":"Biochem. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.bcp.2013.05.007","article-title":"Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease","volume":"86","author":"Sid","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1042\/bst0301064","article-title":"Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase","volume":"30","author":"Hardie","year":"2002","journal-title":"Biochem. Soc. Trans."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6054","DOI":"10.1002\/jcp.27258","article-title":"Glucagon attenuates lipid accumulation in cow hepatocytes through AMPK signaling pathway activation","volume":"234","author":"Li","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1002\/hep.23860","article-title":"Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis","volume":"52","author":"Woodhoo","year":"2010","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yun, U.J., Bae, S.J., Song, Y.R., and Kim, Y.W. (2022). A Critical YAP in Malignancy of HCC Is Regulated by Evodiamine. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031855"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.cbi.2010.01.029","article-title":"Synergistic hepatotoxicity of N, N-dimethylformamide with carbon tetrachloride in association with endoplasmic reticulum stress","volume":"184","author":"Kim","year":"2010","journal-title":"Chem. Biol. Interact."},{"key":"ref_45","first-page":"5390","article-title":"Potential roles of AMP-activated protein kinase in liver regeneration in mice with acute liver injury","volume":"17","author":"Huang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1159\/000157141","article-title":"Mechanisms of carbon tetrachloride hepatotoxicity","volume":"8","author":"Clawson","year":"1989","journal-title":"Pathol. Immunopathol. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0748-5514(85)90026-1","article-title":"Pathological mechanisms in carbon tetrachloride hepatotoxicity","volume":"1","author":"Brattin","year":"1985","journal-title":"J. Free Radic. Biol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Naji, K.M., Al-Shaibani, E.S., Alhadi, F.A., Al-Soudi, S.A., and D\u2019Souza, M.R. (2017). Hepatoprotective and antioxidant effects of single clove garlic against CCl4-induced hepatic damage in rabbits. BMC Complement. Altern. Med., 17.","DOI":"10.1186\/s12906-017-1916-8"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Sahreen, S., Khan, M.R., and Khan, R.A. (2011). Hepatoprotective effects of methanol extract of Carissa opaca leaves on CCl4-induced damage in rat. BMC Complement. Altern. Med., 11.","DOI":"10.1186\/1472-6882-11-48"},{"key":"ref_50","first-page":"649","article-title":"Mechanism of carbon tetrachloride-induced hepatotoxicity. Hepatocellular damage by reactive carbon tetrachloride metabolites","volume":"56","author":"Boll","year":"2001","journal-title":"Z. Nat. C. J. Biosci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/6\/1858\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:35:45Z","timestamp":1760135745000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/6\/1858"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,13]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["molecules27061858"],"URL":"https:\/\/doi.org\/10.3390\/molecules27061858","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,13]]}}}