{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:02:55Z","timestamp":1787022175973,"version":"build-2736575974"},"reference-count":97,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["ORF-2025-676"],"award-info":[{"award-number":["ORF-2025-676"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec039\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Paracetamol overdose causes severe hepatotoxicity.\n                      <jats:italic>Sonchus oleraceus<\/jats:italic>\n                      is traditionally used to treat liver disorders, but its potential against paracetamol-induced liver injury is unexplored. This work aimed to investigate the protective mechanisms of an\n                      <jats:italic>S. oleraceus<\/jats:italic>\n                      extract (SOEtOH) using\n                      <jats:italic>in vivo<\/jats:italic>\n                      , histological and biochemical assessments along with metabolomics profiling and\n                      <jats:italic>in silico<\/jats:italic>\n                      studies, including molecular docking and dynamic simulations (MD).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec040\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>\n                      SOEtOH was administered to rats with paracetamol-induced hepatotoxicity at 50, 100, and 200\u2009mg\/kg doses. Serum enzymes, hepatic antioxidants, and histopathology were evaluated. UPLC-MS characterized bioactive metabolites and molecular docking and assessed their anti-inflammatory potential. SOEtOH significantly restored serum ALT and AST toward normal levels in a dose-dependent manner. It also replenished depleted hepatic glutathione (up to 3.9-fold) and superoxide dismutase (up to 4.7-fold). Immunohistochemistry revealed SOEtOH progressively attenuated caspase-3 expression related to apoptosis. It also ameliorated characteristic histopathological alterations like necrosis, inflammation, and sinusoidal congestion. Thirty-two bioactive metabolites, including flavonoids, phenolic acids, and terpenes, were identified. Molecular docking revealed potent anti-inflammatory effects via JNK inhibition, with luteolin-\n                      <jats:italic>O<\/jats:italic>\n                      -dihexoside, isorhamnetin-\n                      <jats:italic>O<\/jats:italic>\n                      -hexoside, di-\n                      <jats:italic>O<\/jats:italic>\n                      -caffeoylquinic, and kaempferol-\n                      <jats:italic>O<\/jats:italic>\n                      -hexoside having the strongest binding affinities. MD simulations demonstrated that these compounds\u2019 complexes significantly contribute to JNK1 and JNK2\u2019s catalytic binding site.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec041\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This integrated study demonstrates that SOEtOH protects against paracetamol hepatotoxicity by mitigating oxidative stress and inhibiting pro-inflammatory\/apoptotic signaling. Our results reveal therapeutic lead compounds that may be further explored for clinical applications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0325782","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T13:40:28Z","timestamp":1750945228000},"page":"e0325782","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hepatoprotective action of Sonchus oleraceus against paracetamol-induced toxicity via Nrf2\/KEAP-1\/HO-1 pathway in relation to its metabolite fingerprint and in silico studies"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6100-6498","authenticated-orcid":true,"given":"Mohamed F.","family":"Abdelhameed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marawan A.","family":"El-Baset","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira R.","family":"Khattab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rehab F.","family":"Taher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"El-Saied","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa S.","family":"Abd Elkarim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed F.","family":"Essa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"El-Rashedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"Farag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Imagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3302-3623","authenticated-orcid":true,"given":"Abdelsamed I.","family":"Elshamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5903-6329","authenticated-orcid":true,"given":"Ahmed M.","family":"Abd-ElGawad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"issue":"3","key":"pone.0325782.ref001","article-title":"Interventions for paracetamol (acetaminophen) overdoses. Protocol for a cochrane review","author":"J Brok","year":"2001","journal-title":"Cochrane Database Syst Rev"},{"issue":"18","key":"pone.0325782.ref002","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1016\/0006-2952(81)90576-1","article-title":"Drug-induced lipid peroxidation in mice--I. Modulation by monooxygenase activity, glutathione and selenium status","volume":"30","author":"A Wendel","year":"1981","journal-title":"Biochem Pharmacol"},{"issue":"28","key":"pone.0325782.ref003","doi-asserted-by":"crossref","first-page":"17940","DOI":"10.1074\/jbc.273.28.17940","article-title":"Identification of the hepatic protein targets of reactive metabolites of acetaminophen in vivo in mice using two-dimensional gel electrophoresis and mass spectrometry","volume":"273","author":"Y Qiu","year":"1998","journal-title":"J Biol Chem"},{"issue":"9","key":"pone.0325782.ref004","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.4254\/wjh.v13.i9.1143","article-title":"Drug-induced liver injury and COVID-19: a review for clinical practice","volume":"13","author":"GX Ortiz","year":"2021","journal-title":"World J Hepatol"},{"key":"pone.0325782.ref005","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.redox.2016.10.001","article-title":"Oxidative stress during acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential","volume":"10","author":"K Du","year":"2016","journal-title":"Redox Biol"},{"issue":"2","key":"pone.0325782.ref006","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1093\/toxsci\/kfw158","article-title":"Editor\u2019s highlight: metformin protects against acetaminophen hepatotoxicity by attenuation of mitochondrial oxidant stress and dysfunction","volume":"154","author":"K Du","year":"2016","journal-title":"Toxicol Sci"},{"issue":"2","key":"pone.0325782.ref007","doi-asserted-by":"crossref","first-page":"202","DOI":"10.34172\/jhp.2023.21","article-title":"Apigenin role against thioacetamide-triggered liver fibrosis: deciphering the PPAR\u03b3\/TGF-\u03b21\/NF-\u03baB and the HIF\/FAK\/AKT pathways","volume":"12","author":"RF Abdel-Rahman","year":"2023","journal-title":"J Herbmed Pharmacol"},{"issue":"1","key":"pone.0325782.ref008","first-page":"4181656","article-title":"Chemical composition and nutritional value of three Sonchus species","volume":"2022","author":"GX de Paula Filho","year":"2022","journal-title":"Int J Food Sci"},{"issue":"2","key":"pone.0325782.ref009","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0306-3623(94)00194-R","article-title":"Preventive and curative effects of Artemisia absinthium on acetaminophen and CCl4-induced hepatotoxicity","volume":"26","author":"AUH Gilani","year":"1995","journal-title":"Gen Pharmacol Vasc S"},{"key":"pone.0325782.ref010","doi-asserted-by":"crossref","first-page":"5562849","DOI":"10.1155\/2022\/5562849","article-title":"Green fabrication of silver nanoparticles using euphorbia serpens kunth aqueous extract, their characterization, and investigation of its in vitro antioxidative, antimicrobial, insecticidal, and cytotoxic activities","volume":"2022","author":"N Ahmad","year":"2022","journal-title":"Biomed Res Int"},{"issue":"3","key":"pone.0325782.ref011","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.37285\/ijpsn.2017.10.3.7","article-title":"Evaluation of hemolytic and anti-hemolytic activity of the aerial parts of Sonchus oleraceus extracts","volume":"10","author":"J Dima","year":"2017","journal-title":"IJPSN"},{"issue":"12","key":"pone.0325782.ref012","first-page":"1712","article-title":"Chemical composition, antioxidant, and cytotoxic activity of essential oils in the above-ground parts of sonchus oleraceus L","volume":"13","author":"AE-NG El Gendy","year":"2024","journal-title":"Plants (Basel)"},{"issue":"1","key":"pone.0325782.ref013","doi-asserted-by":"crossref","first-page":"77","DOI":"10.2991\/efood.k.191018.002","article-title":"Phenolic extract from Sonchus oleraceus L. protects diabetes\u2010related liver injury in rats through TLR4\/NF\u2010\u03baB signaling pathway","volume":"1","author":"L Chen","year":"2020","journal-title":"eFood"},{"issue":"1","key":"pone.0325782.ref014","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1080\/13880209.2017.1280514","article-title":"The anti-inflammatory effect of Sonchus oleraceus aqueous extract on lipopolysaccharide stimulated RAW 264.7 cells and mice","volume":"55","author":"Q Li","year":"2017","journal-title":"Pharm Biol"},{"issue":"2","key":"pone.0325782.ref015","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.jep.2009.04.037","article-title":"Evaluation of the antinociceptive activity of extracts of Sonchus oleraceus L. in mice","volume":"124","author":"FC Vilela","year":"2009","journal-title":"J Ethnopharmacol"},{"issue":"3","key":"pone.0325782.ref016","doi-asserted-by":"crossref","first-page":"4548","DOI":"10.3390\/molecules20034548","article-title":"Anti-ageing effects of Sonchus oleraceus L. (p\u016bh\u0101) leaf extracts on H2O2-induced cell senescence","volume":"20","author":"ZQ Ou","year":"2015","journal-title":"Molecules"},{"key":"pone.0325782.ref017","first-page":"1","article-title":"Algerian Sonchus oleraceus L.: a comparison of different extraction solvent on phytochemical composition, antioxidant properties and anti-cholinesterase activity","author":"F Aissani","year":"2022","journal-title":"Adv Tradit Med"},{"key":"pone.0325782.ref018","first-page":"7","article-title":"Healing effects of formulations with extract of Sonchus oleraceus","volume":"46","author":"I dos Anjos Nonato","year":"2018","journal-title":"Acta Sci Vet"},{"issue":"8","key":"pone.0325782.ref019","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nrc2694","article-title":"Signal integration by JNK and p38 MAPK pathways in cancer development","volume":"9","author":"EF Wagner","year":"2009","journal-title":"Nat Rev 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OA"},{"issue":"1","key":"pone.0325782.ref023","doi-asserted-by":"crossref","DOI":"10.1002\/ddr.70038","article-title":"Bioinformatics exploration of the therapeutic potential of lotus seed compounds in multiple sclerosis: a network analysis of c-jun pathway","volume":"86","author":"R Rushendran","year":"2025","journal-title":"Drug Dev Res"},{"key":"pone.0325782.ref024","doi-asserted-by":"crossref","first-page":"9572803","DOI":"10.1155\/2018\/9572803","article-title":"Nephroprotective effect of sonchus oleraceus extract against kidney injury induced by ischemia-reperfusion in wistar rats","volume":"2018","author":"L Torres-Gonz\u00e1lez","year":"2018","journal-title":"Oxid Med Cell Longev"},{"issue":"1","key":"pone.0325782.ref025","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12906-023-03931-y","article-title":"Hepatoprotective effect of methanol extract of Agave americana leaves on paracetamol induced hepatotoxicity in Wistar albino rats","volume":"23","author":"KD Ayenew","year":"2023","journal-title":"BMC Complement Med Ther"},{"issue":"11","key":"pone.0325782.ref026","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.14202\/vetworld.2019.1682-1688","article-title":"Histopathological changes of acetaminophen-induced liver injury and subsequent liver regeneration in BALB\/C and ICR mice","volume":"12","author":"F Muhammad-Azam","year":"2019","journal-title":"Vet World"},{"issue":"1","key":"pone.0325782.ref027","doi-asserted-by":"crossref","first-page":"19779","DOI":"10.1038\/s41598-019-56320-2","article-title":"Assessment of the hepatoprotective effect of developed lipid-polymer hybrid nanoparticles (LPHNPs) encapsulating naturally extracted \u03b2-sitosterol against CCl4 induced hepatotoxicity in rats","volume":"9","author":"EM Abdou","year":"2019","journal-title":"Scientific Reports"},{"issue":"6","key":"pone.0325782.ref028","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.3390\/antiox12061263","article-title":"Metabolites profiling and bioassays reveal Bassia indica ethanol extract protective effect against stomach ulcers development via HMGB1\/TLR-4\/NF-\u03baB pathway","volume":"12","author":"ZA El-Gendy","year":"2023","journal-title":"Antioxidants"},{"issue":"7","key":"pone.0325782.ref029","doi-asserted-by":"crossref","first-page":"786","DOI":"10.3390\/metabo13070786","article-title":"Protective action mechanisms of launaea mucronata extract and its nano-formulation against nephrotoxicity in rats as revealed via biochemical, histopathological, and UPLC-QTOF-MS\/MS analyses","volume":"13","author":"AA El-Fadaly","year":"2023","journal-title":"Metabolites"},{"issue":"2","key":"pone.0325782.ref030","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1080\/07391102.2023.2222828","article-title":"Computational investigation of four isoquinoline alkaloids against polycystic ovarian syndrome","volume":"42","author":"MK Moka","year":"2024","journal-title":"J Biomol Struct Dyn"},{"key":"pone.0325782.ref031","first-page":"37","article-title":"Molecular dynamics simulations: advances and applications","volume":"8","author":"A Hospital","year":"2015","journal-title":"Adv Appl Bioinform Chem"},{"issue":"10","key":"pone.0325782.ref032","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1021\/acs.jcim.8b00462","article-title":"GPU-accelerated molecular dynamics and free energy methods in amber18: performance enhancements and new features","volume":"58","author":"T-S Lee","year":"2018","journal-title":"J Chem Inf Model"},{"issue":"2","key":"pone.0325782.ref033","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jmgm.2005.12.005","article-title":"Automatic atom type and bond type perception in molecular mechanical calculations","volume":"25","author":"J Wang","year":"2006","journal-title":"J Mol Graph Model"},{"issue":"8","key":"pone.0325782.ref034","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"HJC Berendsen","year":"1984","journal-title":"J Chem Phys"},{"issue":"7","key":"pone.0325782.ref035","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data","volume":"9","author":"DR Roe","year":"2013","journal-title":"J Chem Theory Comput"},{"issue":"13","key":"pone.0325782.ref036","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera--a visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"J Comput Chem"},{"issue":"5","key":"pone.0325782.ref037","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1021\/ci500161d","article-title":"OriginPro 9.1: scientific data analysis and graphing software-software review","volume":"54","author":"E Seifert","year":"2014","journal-title":"J Chem Inf Model"},{"issue":"10","key":"pone.0325782.ref038","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1021\/ci4002475","article-title":"MMGBSA as a tool to understand the binding affinities of filamin-peptide interactions","volume":"53","author":"M Ylilauri","year":"2013","journal-title":"J Chem Inf Model"},{"issue":"1","key":"pone.0325782.ref039","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ci100275a","article-title":"Assessing the performance of the MM\/PBSA and MM\/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations","volume":"51","author":"T Hou","year":"2011","journal-title":"J Chem Inf Model"},{"issue":"1","key":"pone.0325782.ref040","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1021\/ci300425v","article-title":"MM\/GBSA binding energy prediction on the PDBbind data set: successes, failures, and directions for further improvement","volume":"53","author":"PA Greenidge","year":"2013","journal-title":"J Chem Inf Model"},{"key":"pone.0325782.ref041","doi-asserted-by":"crossref","DOI":"10.1201\/9781003220817","volume-title":"Food and lifestyle in health and disease","author":"C Pham-Huy","year":"2022"},{"issue":"23","key":"pone.0325782.ref042","doi-asserted-by":"crossref","first-page":"14903","DOI":"10.3390\/ijms232314903","article-title":"A discovery-based metabolomic approach using UPLC-Q-TOF-MS\/MS reveals potential antimalarial compounds present in artemisia annua L","volume":"23","author":"H Shi","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"7","key":"pone.0325782.ref043","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.3390\/molecules26071902","article-title":"Evaluation of antioxidant and enzyme inhibition properties of croton hirtus l\u2019h\u00e9r. extracts obtained with different solvents","volume":"26","author":"S Dall\u2019Acqua","year":"2021","journal-title":"Molecules"},{"issue":"1","key":"pone.0325782.ref044","doi-asserted-by":"crossref","first-page":"4966","DOI":"10.1038\/s41598-022-08479-4","article-title":"Metabolomics-based profiling of 4 avocado varieties using HPLC-MS\/MS and GC\/MS and evaluation of their antidiabetic activity","volume":"12","author":"IY Younis","year":"2022","journal-title":"Sci Rep"},{"issue":"4","key":"pone.0325782.ref045","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1016\/j.foodchem.2012.07.083","article-title":"Simultaneous determination of anthocyanins, coumarins and phenolic acids in fruits, kernels and liqueur of Prunus mahaleb L","volume":"135","author":"F Ieri","year":"2012","journal-title":"Food Chem"},{"issue":"5","key":"pone.0325782.ref046","doi-asserted-by":"crossref","first-page":"819","DOI":"10.3390\/antiox11050819","article-title":"Metabolic profiling, chemical composition, antioxidant capacity, and in vivo hepato- and nephroprotective effects of sonchus cornutus in mice exposed to cisplatin","volume":"11","author":"SS Elhady","year":"2022","journal-title":"Antioxidants (Basel)"},{"key":"pone.0325782.ref047","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.sajb.2021.03.010","article-title":"Tapping into the realm of underutilised green leafy vegetables: Using LC-IT-Tof-MS based methods to explore phytochemical richness of Sonchus oleraceus (L.) L.","volume":"145","author":"O Nobela","year":"2022","journal-title":"S Afr J Bot"},{"key":"pone.0325782.ref048","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.foodres.2018.11.003","article-title":"UPLC-MS metabolome based classification of Lupinus and Lens seeds: A prospect for phyto-equivalency of its different accessions","volume":"115","author":"MA Farag","year":"2019","journal-title":"Food Res Int"},{"key":"pone.0325782.ref049","doi-asserted-by":"crossref","first-page":"130739","DOI":"10.1016\/j.foodchem.2021.130739","article-title":"Authentication of saffron spice accessions from its common substitutes via a multiplex approach of UV\/VIS fingerprints and UPLC\/MS using molecular networking and chemometrics","volume":"367","author":"NM Hegazi","year":"2022","journal-title":"Food Chem"},{"key":"pone.0325782.ref050","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.indcrop.2018.10.017","article-title":"LC\u2013MS\/MS-based chemometric analysis of phytochemical diversity in 13 Ficus spp. (Moraceae): correlation to their in vitro antimicrobial and in silico quorum sensing inhibitory activities","volume":"126","author":"SS Elhawary","year":"2018","journal-title":"Ind Crops Prod"},{"key":"pone.0325782.ref051","doi-asserted-by":"crossref","first-page":"136677","DOI":"10.1016\/j.foodchem.2023.136677","article-title":"Detailed metabolite profiling and in vitro studies of Urospermum picroides as a potential functional food","volume":"427","author":"FR Saber","year":"2023","journal-title":"Food Chem"},{"key":"pone.0325782.ref052","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.sajb.2023.06.037","article-title":"Biochemometric approach to reveal Terminalia bentzoe cytotoxic effect against HepG2 cells in relation to its different organs and extraction solvents as analysed via UPLC-MS","volume":"159","author":"N Rummun","year":"2023","journal-title":"S Afr J Bot"},{"key":"pone.0325782.ref053","doi-asserted-by":"crossref","first-page":"133948","DOI":"10.1016\/j.foodchem.2022.133948","article-title":"Dissection of Moringa oleifera leaf metabolome in context of its different extracts, origin and in relationship to its biological effects as analysed using molecular networking and chemometrics","volume":"399","author":"ZT Abdel Shakour","year":"2023","journal-title":"Food Chem"},{"issue":"4","key":"pone.0325782.ref054","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.3390\/molecules26041000","article-title":"Chemical profile of launaea nudicaulis ethanolic extract and its antidiabetic effect in streptozotocin-induced rats","volume":"26","author":"SA El-Newary","year":"2021","journal-title":"Molecules"},{"key":"pone.0325782.ref055","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jpba.2016.03.037","article-title":"Anti-acetylcholinesterase potential and metabolome classification of 4 Ocimum species as determined via UPLC\/qTOF\/MS and chemometric tools","volume":"125","author":"MA Farag","year":"2016","journal-title":"J Pharm Biomed Anal"},{"issue":"1","key":"pone.0325782.ref056","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/s41598-022-27119-5","article-title":"Comparative metabolic profiling of olive leaf extracts from twelve different cultivars collected in both fruiting and flowering seasons","volume":"13","author":"EM Kabbash","year":"2023","journal-title":"Sci Rep"},{"key":"pone.0325782.ref057","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.biochi.2019.09.011","article-title":"Protocatechuic acid exhibits hepatoprotective, vasculoprotective, antioxidant and insulin-like effects in dexamethasone-induced insulin-resistant rats","volume":"167","author":"YA 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glycosides rich fraction from Egyptian Vicia calcarata Desf. against CCl4-induced liver damage in rats","volume":"28","author":"ANB Singab","year":"2005","journal-title":"Arch Pharm Res"},{"issue":"6","key":"pone.0325782.ref061","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1002\/rcm.3423","article-title":"Liquid chromatography\/triple quadrupole tandem mass spectrometry with multiple reaction monitoring for optimal selection of transitions to evaluate nutraceuticals from olive-tree materials","volume":"22","author":"RJ Luj\u00e1n","year":"2008","journal-title":"Rapid Commun Mass Spectrom"},{"issue":"4","key":"pone.0325782.ref062","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1093\/chromsci\/bmz006","article-title":"Comparative metabolite profiling of four citrus peel cultivars via ultra-performance liquid chromatography coupled with quadrupole-time-of-flight-mass spectrometry and multivariate data analyses","volume":"57","author":"NM 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