{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:46:46Z","timestamp":1791812806447,"version":"4.3.4"},"reference-count":65,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100014786","name":"Northern Border University","doi-asserted-by":"publisher","award":["NBU\u2010CRP\u20102026\u20102510"],"award-info":[{"award-number":["NBU\u2010CRP\u20102026\u20102510"]}],"id":[{"id":"10.13039\/501100014786","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environmental Toxicology"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The present study investigated the hepatoprotective effects of hesperidin (HES) encapsulated in chitosan nanoparticles (HES\u2010CNPs) against Malathion (MAL)\u2010induced liver toxicity in rats. Ninety male Wistar rats were randomly divided into six groups: a control group, groups treated with HES (100\u2009mg\/kg BW) or HES\u2010CNPs (100\u2009mg\/kg BW), a MAL\u2010exposed group (27\u2009mg\/kg BW), and two combination groups receiving MAL (27\u2009mg\/kg BW) together with either HES or HES\u2010CNPs (100\u2009mg\/kg BW) for four consecutive weeks. MAL administration induced profound biochemical and molecular alterations in rats. It significantly reduced serum total protein and its fractions, while elevating hepatic enzyme activities, bilirubin, cholesterol, and triglycerides (TGs). Oxidative stress was evident by decreased activities of antioxidant enzymes (CAT, SOD, GPx), reduced glutathione levels, and increased malondialdehyde and reactive oxygen species (ROS). At the molecular level, MAL exposure upregulated proapoptotic genes (p53, Bax, caspase\u20103, caspase\u20109) and inflammatory markers (TNF\u2010\u03b1, NF\u2010\u03baB), while down\u2010regulating the antiapoptotic gene Bcl\u20102 and the cytoprotective gene Nrf2. Exposure to MAL significantly increased hepatic DNA oxidative damage, as indicated by elevated 8\u2010hydroxy\u20102\u2032\u2010deoxyguanosine (8\u2010OHdG) levels and DNA fragmentation. Treatment with HES\u2010CNPs provided significantly greater protection than crude HES (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). These hepatoprotective effects were evidenced by normalization of liver function biomarkers and lipid profile, restoration of antioxidant enzyme activities and glutathione levels, reduction of lipid peroxidation, suppression of proinflammatory and proapoptotic markers, upregulation of Nrf2 and Bcl\u20102, attenuation of DNA oxidative damage (8\u2010OHdG) and fragmentation, and marked improvement of hepatic histoarchitectural and ultrastructural integrity. HES demonstrated strong binding affinity toward key proteins involved in oxidative stress, apoptosis, and inflammatory pathways, as revealed by in silico studies. In conclusion, HES\u2010CNPs demonstrated improved hepatoprotection against MAL toxicity through the activation of the Nrf2\/HO\u20101 antioxidant pathway and the inhibition of NF\u2010\u03baB\/p53\u2010mediated inflammation and apoptosis.\n                  <\/jats:p>","DOI":"10.1002\/tox.70082","type":"journal-article","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T05:23:36Z","timestamp":1774070616000},"page":"1459-1477","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hesperidin\u2010Loaded Chitosan Nanoparticles Restore Hepatic Homeostasis by Targeting Nrf2\/\n                    <scp>HO<\/scp>\n                    \u20101 and\n                    <scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    \/p53 Signaling in Malathion\u2010Exposed Rats"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7444-2499","authenticated-orcid":false,"given":"Ekramy M.","family":"Elmorsy","sequence":"first","affiliation":[{"name":"Center for Health Research, Northern Border University  Arar Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayat B.","family":"Al\u2010Ghafari","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Experimental Biochemistry Unit King Fahd Medical Research Center, King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda A.","family":"Al Doghaither","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesam","family":"Nofal","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences Northern Border University  Arar Kingdom of Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed M.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine Zagazig University  Zagazig Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayman R.","family":"Baiuomy","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine Taif University  Taif Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaymaa H. E.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine Benha University  Benha Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8518-7641","authenticated-orcid":false,"given":"Eman M.","family":"Embaby","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Veterinary Medicine Mansoura University  Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.5114\/ceh.2019.87637"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.912625"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3605"},{"issue":"2","key":"e_1_2_11_5_1","first-page":"215","article-title":"A Review on Biodegradation of Toxic Organophosphate Compounds","volume":"2","author":"Ahmadizad Firozjaei S. A.","year":"2015","journal-title":"Journal of Applied Biotechnology Reports"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23094523"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.5897\/AJPP11.226"},{"issue":"1","key":"e_1_2_11_8_1","first-page":"95","article-title":"Hesperidin Alleviates Malathion\u2010Induced Nephrotoxicity in Rats: Impact on Oxidative Damage, Inflammation, Pyroptosis and Apoptosis","volume":"45","author":"Saati A. A.","year":"2025","journal-title":"Bulletin of Egyptian Society for Physiological Sciences"},{"issue":"1","key":"e_1_2_11_9_1","first-page":"56","article-title":"Histomorphometric Alterations in Hepatic Tissue From Malathion\u2010Induced Toxicity: An Experimental Animal Study","volume":"10","author":"Channar S. P.","year":"2021","journal-title":"Journal of Islamabad Medical & Dental College"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12906-025-04918-7"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25245980"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7342"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-025-01310-w"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1553992"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.169"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612826666201127122313"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2022.01.052"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox13060727"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10030435"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28135209"},{"key":"e_1_2_11_21_1","article-title":"New Insights Into Therapeutic Applications and Nanoformulation Approaches of Hesperidin: An Updated Review","volume":"10","author":"Bansal K.","year":"2024","journal-title":"Pharmacological Research"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15020211"},{"key":"e_1_2_11_23_1","first-page":"305","volume-title":"Lipid Based Nanocarriers for Drug Delivery","author":"Varma A. K.","year":"2024"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph17080999"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/polym15040793"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1080\/1828051X.2024.2445768"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/1708172"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.592238"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/2288892"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2009.11.044"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fenvs.2022.860359"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.14218\/JCTH.2023.00446"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu14122387"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e38937"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2021-0283-OA"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom13081262"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/tox.20390"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2007.08.047"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11356-015-5014-5"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxrep.2017.12.021"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.4103\/JAPTR.JAPTR_298_24"},{"issue":"7","key":"e_1_2_11_43_1","first-page":"929","article-title":"The Ameliorative Effects of Hesperidin in Rats Developed Hepatotoxicity With Deltamethrin","volume":"28","author":"Karabekir S. C.","year":"2025","journal-title":"Iranian Journal of Basic Medical Sciences"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.09.014"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.2298\/SARH1404257R"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2006.08.008"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2008.07.005"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.010884"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41935-019-0142-6"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.4103\/jphi.JPHI_7_19"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1080\/21691401.2018.1559175"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40199-020-00344-x"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370220903671"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13197-014-1704-0"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0935-9"},{"issue":"1","key":"e_1_2_11_56_1","first-page":"33","article-title":"Hesperidin Mitigates Doxorubicin\u2010Induced Hepatic Toxicity in Rats, Targeting JAK\u2010STAT Signaling Pathway","volume":"33","author":"Khodir S. A.","year":"2025","journal-title":"Mansoura Journal of Forensic Medicine and Clinical Toxicology"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008656"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.07.004"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-4431.2008.00363.x"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.985363"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408398.2020.1863907"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.3390\/polym15132953"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.carbpol.2020.116075"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11051-011-0715-2"},{"issue":"1","key":"e_1_2_11_65_1","first-page":"49","article-title":"Malathion and Malaoxon Environmental Levels Used for Exposure Assessment and Risk Characterization of Aerial Applications to Residential Areas of Southern California, 1989\u20101990","volume":"4","author":"Bradman M.","year":"1994","journal-title":"Journal of Exposure Analysis and Environmental Epidemiology"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pestbp.2015.07.006"}],"container-title":["Environmental Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/tox.70082","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/tox.70082","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/tox.70082","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:07:09Z","timestamp":1791810429000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/tox.70082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":65,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1002\/tox.70082"],"URL":"https:\/\/doi.org\/10.1002\/tox.70082","archive":["Portico"],"relation":{},"ISSN":["1520-4081","1522-7278"],"issn-type":[{"value":"1520-4081","type":"print"},{"value":"1522-7278","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,20]]},"assertion":[{"value":"2025-11-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}