{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:13:22Z","timestamp":1786119202521,"version":"build-2736575974"},"reference-count":93,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Guazuma ulmifolia<\/jats:italic>\n                      is traditionally used for liver disorders, but its protective mechanisms against heavy metal toxicity are poorly defined. This study evaluated the phytochemical profile and hepatoprotective mechanisms of\n                      <jats:italic>G. ulmifolia<\/jats:italic>\n                      butanol extract (Gul-BuOH) against cadmium-induced liver injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>\n                      Gul-BuOH was chemically profiled by UPLC-PDA-ESI\u2013qTOF-MS\/MS. Cadmium hepatotoxicity was induced in rats, followed by Gul-BuOH treatment (100 and 200 mg\/kg). Liver injury, oxidative stress, inflammation, gene expression (Let-7a, HOTAIR), histopathology, HO-1\/Sirt-1 immunoreactivity, and serum metabolomic changes were assessed. Chemical profiling led to the annotation of 42 compounds, including mainly flavonoids and phenolic acids, highlighting the rich phytochemical composition of\n                      <jats:italic>G. ulmifolia<\/jats:italic>\n                      . CdCl\n                      <jats:sub>2<\/jats:sub>\n                      exposure increased hepatic Cd accumulation and elevated ALT, AST, and ALP, reduced TAC, and increased NO and MDA. Gul-BuOH significantly reduced hepatic Cd levels by 2.6- and 3.2-fold, restored TAC by 38.3% and 83.2%, and decreased NO (56.3% and 63.4%) and MDA (45.4% and 54.6%) at 100 and 200 mg\/kg, respectively. Inflammatory markers NF-\u03baB-p and TNF-\u03b1 were markedly suppressed, while miRNA Let-7a was upregulated and lncRNA HOTAIR was downregulated. Histological and immunohistochemical analyses revealed near-complete restoration of hepatic architecture and normalization of HO-1 and Sirt-1 expression at the high dose. Serum metabolomics\u2019 OPLS-DA model performance indicators demonstrated strong reliability, with an R\n                      <jats:sup>2<\/jats:sup>\n                      Y (explained variance) of 0.991 and a Q\n                      <jats:sup>2<\/jats:sup>\n                      (predictive variance) of 0.988). The model identified 36 significantly altered metabolites that were largely normalized by Gul-BuOH, implicating linoleic acid metabolism, amino acid biosynthesis, and ascorbate-related pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Gul-BuOH affords dose-dependent protection against Cd-induced liver injury by modulating oxidative stress, inflammation, metal detoxification, and metabolic pathways, supporting the traditional use of G. ulmifolia and its potential as a multi-target hepatoprotective agent.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0355464","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T17:43:43Z","timestamp":1786038223000},"page":"e0355464","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Guazuma ulmifolia butanol extract protects against cadmium-induced hepatotoxicity via HO-1\/Sirt-1 activation, miRNA\u2013lncRNA modulation, and metabolic reprogramming"],"prefix":"10.1371","volume":"21","author":[{"given":"Osama Ahmed","family":"Elsabagh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelbaset M.","family":"Elgamal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba A.","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naglaa 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against cadmium toxicity in rats","volume":"9","author":"AF Abdel-Razik","year":"2016","journal-title":"Arabian J Chem"},{"key":"pone.0355464.ref003","doi-asserted-by":"crossref","DOI":"10.1016\/j.sciaf.2024.e02295","article-title":"Potentially toxic elements contamination and ecological risk assessment in surface sediments of Moulouya Estuary (Northeastern, Morocco)","volume":"25","author":"N Basraoui","year":"2024","journal-title":"Scientific African"},{"issue":"11","key":"pone.0355464.ref004","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.3390\/met11111714","article-title":"Cadmium recovery from spent Ni-Cd batteries: a brief review","volume":"11","author":"E Blumbergs","year":"2021","journal-title":"Metals"},{"issue":"1","key":"pone.0355464.ref005","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00204-024-03903-2","article-title":"Heavy metals: toxicity and human health effects","volume":"99","author":"K Jomova","year":"2025","journal-title":"Arch 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Ethnopharmacol"},{"key":"pone.0355464.ref017","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.sajb.2016.08.003","article-title":"Phenolic composition and antioxidant, anticholinesterase and antibiotic-modulating antifungal activities of Guazuma ulmifolia Lam. (Malvaceae) ethanol extract","volume":"110","author":"SM Morais","year":"2017","journal-title":"South African J Botany"},{"issue":"1","key":"pone.0355464.ref018","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.jep.2008.01.015","article-title":"Hypotensive and vasorelaxant effects of the procyanidin fraction from Guazuma ulmifolia bark in normotensive and hypertensive rats","volume":"117","author":"GA Magos","year":"2008","journal-title":"J Ethnopharmacol"},{"issue":"2","key":"pone.0355464.ref019","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jep.2008.04.007","article-title":"The anti-diabetic properties of Guazuma ulmifolia Lam are mediated by the stimulation of glucose uptake in normal and diabetic adipocytes without inducing adipogenesis","volume":"118","author":"AJ Alonso-Castro","year":"2008","journal-title":"J Ethnopharmacol"},{"issue":"2","key":"pone.0355464.ref020","doi-asserted-by":"crossref","DOI":"10.13005\/bpj\/2446","article-title":"Hypocholesterolemia effect of guazuma ulmifolia lamk on rats model hyperlipidemic and liver histopathological picture","volume":"15","author":"ES Em Sutrisna","year":"2022","journal-title":"Biomed Pharmacol J"},{"key":"pone.0355464.ref021","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/B978-0-323-99661-7.00003-5","article-title":"Paradigms in miRNA biogenesis pathways","volume-title":"MicroRNA in human infectious diseases","author":"M Panda","year":"2024"},{"issue":"5","key":"pone.0355464.ref022","doi-asserted-by":"crossref","first-page":"471","DOI":"10.3748\/wjg.v30.i5.471","article-title":"Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a clinically relevant mouse model","volume":"30","author":"H Hua","year":"2024","journal-title":"World J Gastroenterol"},{"issue":"1","key":"pone.0355464.ref023","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.ncrna.2016.11.002","article-title":"Long non-coding RNAs: Mechanism of action and functional utility","volume":"1","author":"SA Bhat","year":"2016","journal-title":"Noncoding RNA Res"},{"issue":"0","key":"pone.0355464.ref024","doi-asserted-by":"crossref","first-page":"0","DOI":"10.21608\/ejbo.2024.257350.2624","article-title":"Molecular techniques to ascertain the genetic strategies in some Malvaceae s.l. Species","volume":"0","author":"GE El-Badan","year":"2024","journal-title":"Egypt J Bot"},{"key":"pone.0355464.ref025","doi-asserted-by":"crossref","first-page":"121041","DOI":"10.1016\/j.jep.2025.121041","article-title":"Metabolomic insights into anti-inflammatory, antipyretic, and antinociceptive properties of Ilex paraguariensis: a UPLC-MS\/MS analysis of phytochemicals and metabolic pathways","volume":"358","author":"NM Ammar","year":"2026","journal-title":"J Ethnopharmacol"},{"key":"pone.0355464.ref026","doi-asserted-by":"crossref","first-page":"103237","DOI":"10.1016\/j.tice.2025.103237","article-title":"Bioactive-rich Mangifera indica leaf extracts alleviate inflammation, pain, and fever via suppression of pro-inflammatory cytokines and activation of Nrf2 pathways","volume":"99","author":"MM Elghonemy","year":"2026","journal-title":"Tissue Cell"},{"key":"pone.0355464.ref027","doi-asserted-by":"crossref","first-page":"117770","DOI":"10.1016\/j.lfs.2020.117770","article-title":"Hepatoprotective effect of atorvastatin on Cadmium chloride induced hepatotoxicity in rats","volume":"254","author":"Z Goodarzi","year":"2020","journal-title":"Life Sci"},{"key":"pone.0355464.ref028","volume-title":"American Public Health Association, American Water Works Association, Water Environment Federation, eds., Standard methods for the examination of water and wastewater, American Public Health Association, Washington, DC","author":"L Bridgewater","year":"2017"},{"issue":"5","key":"pone.0355464.ref029","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1136\/jcp.54.5.356","article-title":"Method for the measurement of antioxidant activity in human fluids","volume":"54","author":"D Koracevic","year":"2001","journal-title":"J Clin Pathol"},{"issue":"2","key":"pone.0355464.ref030","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"H Ohkawa","year":"1979","journal-title":"Anal Biochem"},{"key":"pone.0355464.ref031","first-page":"123","article-title":"The determination of nitrite in water","volume":"1","author":"H Montgomery","year":"1971","journal-title":"Analyst"},{"issue":"11","key":"pone.0355464.ref032","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1136\/jcp.25.11.940","article-title":"Standardization of clinical enzyme assays: a reference method for aspartate and alanine transaminases","volume":"25","author":"JH Wilkinson","year":"1972","journal-title":"J Clin Pathol"},{"issue":"250","key":"pone.0355464.ref033","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1136\/adc.46.250.842","article-title":"Normal ranges and diagnostic value of serum 5\u2019nucleotidase and alkaline phosphatase activities in infancy","volume":"46","author":"A Belfield","year":"1971","journal-title":"Arch Dis Child"},{"issue":"5","key":"pone.0355464.ref034","doi-asserted-by":"crossref","DOI":"10.1002\/fsn3.70314","article-title":"Amaranthus spinosus Linn. Extract as an Innovative Strategy to Regulate Biomarkers for Ovarian Hyperthecosis via Circular RNA (hsa\u2010circ\u20100001577): Evidence From Biochemical, Metabolomics, Histological, and Phytochemical Profiling","volume":"13","author":"NM Ammar","year":"2025","journal-title":"Food Science & Nutrition"},{"issue":"11","key":"pone.0355464.ref035","doi-asserted-by":"crossref","first-page":"15495","DOI":"10.1007\/s00210-025-04191-y","article-title":"Unveiling the pharmacological mechanisms of Spirulina platensis in rheumatoid arthritis rats through the integration of serum metabolomics, pathways analysis, and experimental validation","volume":"398","author":"DS Ghallab","year":"2025","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"pone.0355464.ref036","doi-asserted-by":"crossref","first-page":"117784","DOI":"10.1016\/j.jep.2024.117784","article-title":"Metabolomic insights into the therapeutic mechanisms of costus (Saussurea costus (Falc.) Lipsch.) root extract in propylthiouracil-induced hypothyroidism rat model","volume":"324","author":"HM Dawood","year":"2024","journal-title":"J Ethnopharmacol"},{"key":"pone.0355464.ref037","doi-asserted-by":"crossref","first-page":"116504","DOI":"10.1016\/j.bcp.2024.116504","article-title":"Unveiling the protective potential of mirabegron against thioacetamide-induced hepatic encephalopathy in rats: Insights into cAMP\/PPAR-\u03b3\/p-ERK1\/2\/p S536 NF-\u03baB p 65 and p-CREB\/BDNF\/TrkB in parallel with oxidative and apoptotic trajectories","volume":"229","author":"NF Hassan","year":"2024","journal-title":"Biochem Pharmacol"},{"key":"pone.0355464.ref038","doi-asserted-by":"crossref","first-page":"107511","DOI":"10.1016\/j.micpath.2025.107511","article-title":"In vitro and in vivo attenuation of Salmonella resistance using a novel synthesized chloramphenicol magnesium Nano-complex","volume":"203","author":"FM Mosallam","year":"2025","journal-title":"Microb Pathog"},{"issue":"6","key":"pone.0355464.ref039","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0325782","article-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","volume":"20","author":"MF Abdelhameed","year":"2025","journal-title":"PLoS One"},{"key":"pone.0355464.ref040","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.enzmictec.2016.02.003","article-title":"Methylation of flavonoids: Chemical structures, bioactivities, progress and perspectives for biotechnological production","volume":"86","author":"N Koirala","year":"2016","journal-title":"Enzyme Microb Technol"},{"issue":"3","key":"pone.0355464.ref041","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s11101-015-9426-0","article-title":"Methoxylated flavones: occurrence, importance, biosynthesis","volume":"15","author":"A Berim","year":"2015","journal-title":"Phytochem Rev"},{"issue":"9","key":"pone.0355464.ref042","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.jasms.2004.06.003","article-title":"Determination of the glycosylation site of flavonoid monoglucosides by metal complexation and tandem mass spectrometry","volume":"15","author":"BD Davis","year":"2004","journal-title":"J Am Soc Mass Spectrom"},{"issue":"1","key":"pone.0355464.ref043","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":"F Cuyckens","year":"2004","journal-title":"J Mass Spectrom"},{"issue":"1","key":"pone.0355464.ref044","doi-asserted-by":"crossref","first-page":"16210","DOI":"10.1038\/s41598-019-52736-y","article-title":"Isorhamnetin Alleviates Steatosis and Fibrosis in Mice with Nonalcoholic Steatohepatitis","volume":"9","author":"M Ganbold","year":"2019","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0355464.ref045","first-page":"679","volume":"12","author":"J Sun","year":"2007","journal-title":"Screening Non-colored Phenolics in Red Wines using Liquid Chromatography\/Ultraviolet and Mass Spectrometry\/Mass Spectrometry Libraries"},{"key":"pone.0355464.ref046","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.ejphar.2013.02.059","article-title":"The procyanidin trimer C1 induces macrophage activation via NF-\u03baB and MAPK pathways, leading to Th1 polarization in murine splenocytes","volume":"714","author":"N-Y Sung","year":"2013","journal-title":"Eur J Pharmacol"},{"key":"pone.0355464.ref047","doi-asserted-by":"crossref","first-page":"100800","DOI":"10.1016\/j.fbio.2020.100800","article-title":"Mass spectrometry-based metabolites profiling of nutrients and anti-nutrients in major legume sprouts","volume":"39","author":"MA Farag","year":"2021","journal-title":"Food Bioscience"},{"issue":"15","key":"pone.0355464.ref048","first-page":"2456","article-title":"Flavone C-Glycosides from Dianthus superbus L","volume":"17","author":"M Chu","year":"2025","journal-title":"Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) via Multi-Pathway Regulations"},{"key":"pone.0355464.ref049","doi-asserted-by":"crossref","first-page":"113804","DOI":"10.1016\/j.jpba.2020.113804","article-title":"Metabolite pro\ufb01les of Pulicaria crispa and P. incisa in relation to their in-vitro\/ in-vivo antioxidant activity and hepatoprotective effect: A comparative mass spectrometry-based metabolomics","volume":"194","author":"OA El-Sabagh","year":"2021","journal-title":"J Pharm Biomed Anal"},{"key":"pone.0355464.ref050","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.phytochem.2013.07.003","article-title":"Metabolomics driven analysis of artichoke leaf and its commercial products via UHPLC-q-TOF-MS and chemometrics","volume":"95","author":"MA Farag","year":"2013","journal-title":"Phytochemistry"},{"issue":"7","key":"pone.0355464.ref051","doi-asserted-by":"crossref","first-page":"760","DOI":"10.3390\/antiox14070760","article-title":"Regulatory Mechanisms of Phenolic Acids in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Review","volume":"14","author":"S Zhang","year":"2025","journal-title":"Antioxidants (Basel)"},{"key":"pone.0355464.ref052","doi-asserted-by":"crossref","first-page":"125857","DOI":"10.1016\/j.foodchem.2019.125857","article-title":"Mutamba (Guazuma ulmifolia Lam.) fruit as a novel source of dietary fibre and phenolic compounds","volume":"310","author":"GA Pereira","year":"2020","journal-title":"Food Chem"},{"key":"pone.0355464.ref053","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkab1062","article-title":"HMDB 5.0: the Human Metabolome Database for 2022","volume":"50","author":"DS Wishart","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"16","key":"pone.0355464.ref054","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.3390\/molecules29163760","article-title":"Identification of Fatty Acids, Amides and Cinnamic Acid Derivatives in Supercritical-CO2 Extracts of Cinnamomum tamala Leaves Using UPLC-Q-TOF-MSE Combined with Chemometrics","volume":"29","author":"H Lohani","year":"2024","journal-title":"Molecules"},{"issue":"4","key":"pone.0355464.ref055","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1007\/s12011-024-04307-0","article-title":"Unveiling the Hub Genes Involved in Cadmium-Induced Hepatotoxicity","volume":"203","author":"B Yang","year":"2025","journal-title":"Biol Trace Elem Res"},{"issue":"3","key":"pone.0355464.ref056","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1007\/s12011-025-04761-4","article-title":"Protective Role of Purslane Supplementation Against Cadmium-Induced Renal and Gill Toxicity in Nile Tilapia: Insights into Antioxidant Defense and Ion 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