{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T20:47:10Z","timestamp":1781556430868,"version":"3.54.5"},"reference-count":51,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T00:00:00Z","timestamp":1694736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s NextGenerationEU economic recovery package via the National Recovery and Resilience Plan of the Republic of Bulgaria","award":["BG-RRP-2.004-0004-C01"],"award-info":[{"award-number":["BG-RRP-2.004-0004-C01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oxidative stress is a common phenomenon of many liver disorders; it both affects patient survival and directly influences the applicability, effectiveness, and toxicity of drugs. In the pursuit of reliable natural remedies for hepatoprotection, this study reports on the complete phytochemical characterization, antioxidant, and hepatoprotective activities of the Prenanthes purpurea methanol-aqueous extract in an in vitro model of diclofenac-induced liver injury (DILI). An ultra high-performance liquid chromatography\u2013high-resolution mass spectrometry analysis (UHPLC-HRMS) was conducted, delineating more than 100 secondary metabolites for the first time in the species, including a series of phenolic acid-hexosides, acylquinic, acylhydroxyquinic and acyltartaric acids, and flavonoids. Quinic acid, chlorogenic, 3,5-dicaffeoylquinic and 5-feruloylhydroxyquinic acid, caffeoyltartaric and cichoric acids, eryodictiol-O-hexuronide, and luteolin O-hexuronide dominated the phytochemical profile and most likely contributed to the observed hepatoprotective activity of the studied P. purpurea leaf extract. The potency and molecular basis of cellular protection were investigated in parallel with pure caffeoylquinic acids in a series of pretreatment experiments that verified the antiapoptotic and antioxidant properties of the natural products.<\/jats:p>","DOI":"10.3390\/ijms241814148","type":"journal-article","created":{"date-parts":[[2023,9,17]],"date-time":"2023-09-17T06:12:21Z","timestamp":1694931141000},"page":"14148","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Phytochemical Profiling, In Vitro Antioxidant, and Hepatoprotective Activity of Prenanthes purpurea L. and Caffeoylquinic Acids in Diclofenac-Induced Hepatotoxicity on HEP-G2 Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5763-0730","authenticated-orcid":false,"given":"Rositsa","family":"Mihaylova","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1254-2419","authenticated-orcid":false,"given":"Reneta","family":"Gevrenova","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Stefanova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1952-9903","authenticated-orcid":false,"given":"Dimitrina","family":"Zheleva-Dimitrova","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9938-6542","authenticated-orcid":false,"given":"Vessela","family":"Balabanova","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6548-7823","authenticated-orcid":false,"given":"G\u00f6khan","family":"Zengin","sequence":"additional","affiliation":[{"name":"Physiology and Biochemistry Research Laboratory, Department of Biology, Science Faculty, Selcuk University, Konya 42130, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4860-9053","authenticated-orcid":false,"given":"Rumyana","family":"Simeonova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2841-7089","authenticated-orcid":false,"given":"Georgi","family":"Momekov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,15]]},"reference":[{"key":"ref_1","first-page":"1135","article-title":"Review article: Drug hepatotoxicity: Aliment","volume":"25","author":"Chang","year":"2007","journal-title":"Pharmacol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bj\u00f6rnsson, E. (2016). Hepatotoxicity by Drugs: The Most Common Implicated Agents. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17020224"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1517\/14740338.3.6.519","article-title":"Diclofenac-induced liver injury: A paradigm of idiosyncratic drug toxicity","volume":"3","author":"Aithal","year":"2004","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"187","DOI":"10.5604\/01.3001.0010.8633","article-title":"Recent Advances in Hepatotoxicity of Non Steroidal Anti-Inflammatory Drugs","volume":"17","author":"Meunier","year":"2018","journal-title":"Ann. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5651","DOI":"10.3748\/wjg.v16.i45.5651","article-title":"Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage?","volume":"16","author":"Bessone","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_6","unstructured":"Daly, A.K. (2017). Comprehensive Medicinal Chemistry III, Elsevier."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1093\/qjmed\/hcg138","article-title":"Hepatocellular Damage from Non-Steroidal Anti-Inflammatory Drugs","volume":"96","author":"Dargan","year":"2003","journal-title":"QJM Int. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"32608","DOI":"10.1021\/acsomega.0c04942","article-title":"Development of Novel Diclofenac Analogs Designed to Avoid Metabolic Activation and Hepatocyte Toxicity","volume":"5","author":"Tateishi","year":"2020","journal-title":"ACS Omega"},{"key":"ref_9","unstructured":"Hacker, M. (2009). Pharmacology, Elsevier."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"64","DOI":"10.2174\/1872312812666180913120736","article-title":"Formation of a Toxic Quinoneimine Metabolite from Diclofenac: A Quantum Chemical Study","volume":"13","author":"Ramesh","year":"2019","journal-title":"Drug Metab. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101751","DOI":"10.1016\/j.redox.2020.101751","article-title":"Diclofenac impairs autophagic flux via oxidative stress and lysosomal dysfunction: Implications for hepatotoxicity","volume":"37","author":"Jung","year":"2020","journal-title":"Redox Biol."},{"key":"ref_12","first-page":"21","article-title":"Topical Diclofenac-Induced Hepatotoxicity","volume":"13","author":"Delungahawatta","year":"2023","journal-title":"J. Community Hosp. Intern. Med. Perspect."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107763","DOI":"10.18632\/oncotarget.21201","article-title":"The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury","volume":"8","author":"Selvaraj","year":"2017","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s43066-023-00248-w","article-title":"Promising hepatoprotective agents from the natural sources: A study of scientific evidence","volume":"13","author":"Pandey","year":"2023","journal-title":"Egypt. Liver J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.3389\/fphar.2019.01482","article-title":"Drug-Induced Liver Injury: Biomarkers, Requirements, Candidates, and Validation","volume":"10","author":"Meunier","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Khan, M.A., Ahmad, W., Ahmad, M., and Nisar, M. (2017). Hepatoprotective effect of the solvent extracts of Viola canescens Wall. ex. Roxb. against CCl4 induced toxicity through antioxidant and membrane stabilizing activity. BMC Complement. Altern. Med., 17.","DOI":"10.1186\/s12906-016-1537-7"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Machado, I.F., Miranda, R.G., Dorta, D.J., Rolo, A.P., and Palmeira, C.M. (2023). Targeting Oxidative Stress with Polyphenols to Fight Liver Diseases. Antioxidants, 12.","DOI":"10.3390\/antiox12061212"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.toxicon.2023.107177","article-title":"Hepatoprotective effects of chlorogenic acid on mice exposed to aflatoxin B1: Modulation of oxidative stress and inflammation","volume":"231","author":"Cheng","year":"2023","journal-title":"Toxicon"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zheleva-Dimitrova, D., Simeonova, R., Kondeva-Burdina, M., Savov, Y., Balabanova, V., Zengin, G., Petrova, A., and Gevrenova, R. (2023). Antioxidant and Hepatoprotective Potential of Echinops ritro L. Extracts on Induced Oxidative Stress In Vitro\/In Vivo. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24129999"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s006060200010","article-title":"Chemosystematic investigations on phenolics from flowerheads of Central European taxa of Hieracium sensu lato (Asteraceae)","volume":"231","author":"Zidorn","year":"2002","journal-title":"Plant Syst. Evol."},{"key":"ref_21","unstructured":"Bobrov, E.G., and Tzvelev, N.N. (1964). Flora of the USSR, Publishing House of the USSR Academy of Sciences."},{"key":"ref_22","unstructured":"POWO (2023, August 16). Plants of the World Online. Facilitated by the Royal Botanic Gardens, Kew. Published on the Internet. Available online: http:\/\/www.plantsoftheworldonline.org\/."},{"key":"ref_23","unstructured":"Stojanov, N., Stefanov, B., and Kitanov, B. (1967). Flora Republicae Bulgaricae, Part II, Nauka i Izkustvo."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13127-011-0064-0","article-title":"Molecular and phytochemical systematics of the subtribe Hypochaeridinae (Asteraceae, Cichorieae)","volume":"12","author":"Enke","year":"2012","journal-title":"Org. Divers. Evol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.bse.2005.07.018","article-title":"Occurrence of equisetumpyrone and other phenolics in Leontodon crispus","volume":"34","author":"Zidorn","year":"2006","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1016\/j.phytochem.2008.06.013","article-title":"Sesquiterpene lactones and their precursors as chemosystematic markers in the tribe Cichorieae of the Asteraceae","volume":"69","author":"Zidorn","year":"2008","journal-title":"Phytochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.bse.2009.09.006","article-title":"Flavonoids as chemosystematic markers in the tribe Cichorieae of the Asteraceae","volume":"38","author":"Sareedenchai","year":"2010","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_28","unstructured":"Funk, V.A., Susanna, A., Stuessy, T., and Bayer, R. (2009). Systematics, Evolution and Biogeography of Compositae, International Association for Plant Taxonomy (IAPT)."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"841","DOI":"10.2298\/JSC101210072P","article-title":"A new trisaccharide derivative from Prenanthes purpurea","volume":"76","author":"Posch","year":"2011","journal-title":"J. Serbian Chem. Soc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1248\/cpb.35.1969","article-title":"Studies on sesquiterpene glycosides from Prenanthes acerifolia","volume":"35","author":"Myiase","year":"1987","journal-title":"BENTH Chem. Pharm. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"88","DOI":"10.7324\/JAPS.2014.401016","article-title":"Evaluation of Anti-Bacterial, Analgesic and Anti-Inflammatory activities of Oncocalyxone A isolated from Prenanthes sarmentosus","volume":"4","author":"Ilayaraja","year":"2014","journal-title":"J. Appl. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"112268","DOI":"10.1016\/j.fct.2021.112268","article-title":". Tanacetum vulgare L. (Tansy) as an effective bioresource with promising pharmacological effects from natural arsenal","volume":"153","author":"Ak","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"112817","DOI":"10.1016\/j.indcrop.2020.112817","article-title":"Integrated phytochemistry, bio-functional potential and multivariate analysis of Tanacetum macrophyllum (Waldst. & Kit.) Sch.Bip. and Telekia speciosa (Schreb.) Baumg. (Asteraceae)","volume":"155","author":"Gevrenova","year":"2020","journal-title":"Ind. Crop. Prod."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gevrenova, R., Zengin, G., Sinan, K.I., Y\u0131ld\u0131ztugay, E., Zheleva-Dimitrova, D., Picot-Allain, C., Mahomoodally, M.F., Imran, M., and Dall\u2019Acqua, S. (2021). UHPLC-MS Characterization and Biological Insights of Different Solvent Extracts of Two Achillea Species (A. aleppica and A. santolinoides) from Turkey. Antioxidants, 10.","DOI":"10.3390\/antiox10081180"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gevrenova, R., Zengin, G., Sinan, K.I., Zheleva-Dimitrova, D., Balabanova, V., Kolmayer, M., Voynikov, Y., and Joubert, O. (2022). An In-Depth Study of Metabolite Profile and Biological Potential of Tanacetum balsamita L. (Costmary). Plants, 12.","DOI":"10.3390\/plants12010022"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s11306-007-0082-2","article-title":"Proposed minimum reporting standards for chemical analysis: Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI)","volume":"3","author":"Sumner","year":"2007","journal-title":"Metabolomics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.jphotobiol.2018.10.025","article-title":"Efficient discrimination of natural stereoisomers of chicoric acid, an HIV-1 integrase inhibitor","volume":"189","author":"Nobela","year":"2018","journal-title":"J. Photochem. Photobiol. B"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zheleva-Dimitrova, D., Petrova, A., Zengin, G., Sinan, K.I., Balabanova, V., Joubert, O., Zidorn, C., Voynikov, Y., Simeonova, R., and Gevrenova, R. (2023). Metabolite profiling and bioactivity of Cicerbita alpina (L.) Wallr. (Asteraceae, Cichorieae). Plants, 12.","DOI":"10.3390\/plants12051009"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jms.585","article-title":"Mass spectrometry in the structural analysis of flavonoids","volume":"39","author":"Cuyckens","year":"2004","journal-title":"J. Mass Spectrom."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Bohm, B.A., and Stuessy, T.F. (2001). Flavonoids of the Sunflower Family (Asteraceae), Springer.","DOI":"10.1007\/978-3-7091-6181-4"},{"key":"ref_42","first-page":"181","article-title":"Caffeoyl Derivatives: Major Antioxidant Compounds of Some Wild Herbs of the Asteraceae Family","volume":"02","author":"Fraisse","year":"2011","journal-title":"Food Nutr. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"952943","DOI":"10.1155\/2014\/952943","article-title":"A Review on Protocatechuic Acid and Its Pharmacological Potential","volume":"2014","author":"Kakkar","year":"2014","journal-title":"ISRN Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.biopha.2018.09.069","article-title":"Syringic acid (SA)\u2014A Review of Its Occurrence, Biosynthesis, Pharmacological and Industrial Importance","volume":"108","author":"Srinivasulu","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1080\/1028415X.2017.1354543","article-title":"Pharmacological effects of protocatechuic acid and its therapeutic potential in neurodegenerative diseases: Review on the basis of in vitro and in vivo studies in rodents and humans","volume":"22","author":"Krzysztoforska","year":"2019","journal-title":"Nutr. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"200","DOI":"10.22270\/jddt.v11i2-S.4823","article-title":"A Review of the Pharmacological Characteristics of Vanillic Acid","volume":"11","author":"Ingole","year":"2021","journal-title":"J. Drug Deliv. Ther."},{"key":"ref_47","first-page":"4162","article-title":"Research progress on pharmacological effects of p-coumaric acid","volume":"24","author":"Guan","year":"2018","journal-title":"Chin. Tradit. Herb. Drugs"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Rojas-Gonz\u00e1lez, A., Figueroa-Hern\u00e1ndez, C.Y., Gonz\u00e1lez-Rios, O., Su\u00e1rez-Quiroz, M.L., Gonz\u00e1lez-Amaro, R.M., Hern\u00e1ndez-Estrada, Z.J., and Rayas-Duarte, P. (2022). Coffee Chlorogenic Acids Incorporation for Bioactivity Enhancement of Foods: A Review. Molecules, 27.","DOI":"10.3390\/molecules27113400"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s13765-016-0195-2","article-title":"Antioxidant and cognitive-enhancing activities of Arctium lappa L. roots in A\u03b21-42-induced mouse model","volume":"59","author":"Kwon","year":"2016","journal-title":"Appl. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.sajb.2020.10.022","article-title":"Investigation of the anti-inflammatory and antioxidant activities of luteolin, kaempferol, apigenin and quercetin","volume":"137","author":"Tian","year":"2021","journal-title":"S. Afr. J. Bot."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"481","DOI":"10.4314\/ajtcam.v11i2.37","article-title":"Investigation of Antioxidant Potentials of Solvent Extracts from Different Anatomical Parts of Asphodeline Anatolica E. Tuzlaci: An Endemic Plant to Turkey","volume":"11","author":"Zengin","year":"2014","journal-title":"Afr. J. Tradit. Complement. Altern. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14148\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:51:45Z","timestamp":1760129505000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14148"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,15]]},"references-count":51,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241814148"],"URL":"https:\/\/doi.org\/10.3390\/ijms241814148","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,15]]}}}