{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T03:13:17Z","timestamp":1778728397840,"version":"3.51.4"},"reference-count":42,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100004242","name":"Princess Nourah Bint Abdulrahman University","doi-asserted-by":"publisher","award":["PNURSP2026R211"],"award-info":[{"award-number":["PNURSP2026R211"]}],"id":[{"id":"10.13039\/501100004242","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007446","name":"King Khalid University","doi-asserted-by":"publisher","award":["1\/95\/46"],"award-info":[{"award-number":["1\/95\/46"]}],"id":[{"id":"10.13039\/501100007446","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Tissue and Cell"],"published-print":{"date-parts":[[2026,8]]},"DOI":"10.1016\/j.tice.2026.103425","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T16:22:49Z","timestamp":1772209369000},"page":"103425","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["Metformin is associated with the suppression of the TNF-\u03b1\/iNOS\/TIMP-1 axis-mediated liver injury and fibrosis secondary to diabetes"],"prefix":"10.1016","volume":"101","author":[{"given":"Hind","family":"Zafrah","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saif A.","family":"Alqahtani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fahaid","family":"Al-Hashem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5773-1160","authenticated-orcid":false,"given":"Bahjat","family":"Al-Ani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nourah M.","family":"Alzamil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.tice.2026.103425_bib1","doi-asserted-by":"crossref","first-page":"39403","DOI":"10.1074\/jbc.M504140200","article-title":"Nitric oxide induces TIMP-1 expression by activating the transforming growth factor beta-Smad signaling pathway","volume":"280","author":"Akool El","year":"2005","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tice.2026.103425_bib2","doi-asserted-by":"crossref","first-page":"9328","DOI":"10.1002\/jcp.27616","article-title":"Metformin inhibits mTOR-HIF-1\u03b1 axis and profibrogenic and inflammatory biomarkers in thioacetamide-induced hepatic tissue alterations","volume":"234","author":"Al-Hashem","year":"2019","journal-title":"J. Cell Physiol."},{"key":"10.1016\/j.tice.2026.103425_bib3","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1080\/01913123.2024.2440479","article-title":"Metformin ameliorates diabetes-induced hepatic ultrastructural damage and the immune biomarker CD86 and inflammation in rats","volume":"49","author":"Alshahrani","year":"2025","journal-title":"Ultrastruct. Pathol."},{"key":"10.1016\/j.tice.2026.103425_bib4","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/labinvest.2015.67","article-title":"The role of iNOS in cholesterol-induced liver fibrosis","volume":"95","author":"Anavi","year":"2015","journal-title":"Lab Invest"},{"key":"10.1016\/j.tice.2026.103425_bib5","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1111\/joim.12289","article-title":"Family history of type 2 diabetes increases the risk of both obesity and its complications: is type 2 diabetes a disease of inappropriate lipid storage?","volume":"277","author":"Cederberg","year":"2015","journal-title":"J. Intern. Med."},{"key":"10.1016\/j.tice.2026.103425_bib6","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22010463","article-title":"The association between hepatic encephalopathy and diabetic encephalopathy: the brain-liver axis","volume":"22","author":"Cheon","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.tice.2026.103425_bib7","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1124\/jpet.106.119214","article-title":"Inhaled CD86 antisense oligonucleotide suppresses pulmonary inflammation and airway hyper-responsiveness in allergic mice","volume":"321","author":"Crosby","year":"2007","journal-title":"J. Pharm. Exp. Ther."},{"key":"10.1016\/j.tice.2026.103425_bib8","doi-asserted-by":"crossref","first-page":"527","DOI":"10.3897\/pharmacia.69.e83067","article-title":"Nitric oxide-mediated effects of L-ornithine-L-aspartate in acute toxic liver injury","volume":"69","author":"Datsko","year":"2022","journal-title":"Pharmacia"},{"issue":"7","key":"10.1016\/j.tice.2026.103425_bib9","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.3390\/diagnostics12071762","article-title":"MiR-155 dysregulation is associated with the augmentation of ROS\/p53 axis of fibrosis in thioacetamide-induced hepatotoxicity and is protected by resveratrol","volume":"12","author":"Dawood","year":"2022","journal-title":"Diagnostics (Basel)"},{"issue":"5","key":"10.1016\/j.tice.2026.103425_bib10","doi-asserted-by":"crossref","first-page":"984","DOI":"10.3390\/biomedicines10050984","article-title":"Metformin protects against diabetic cardiomyopathy: an association between desmin-sarcomere injury and the iNOS\/mTOR\/TIMP-1 fibrosis axis","volume":"10","author":"Dawood","year":"2022","journal-title":"Biomedicines"},{"issue":"7","key":"10.1016\/j.tice.2026.103425_bib11","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.3390\/biomedicines10071644","article-title":"Metformin Is associated with the inhibition of renal artery AT1R\/ET-1\/iNOS axis in a rat model of diabetic nephropathy with suppression of inflammation and oxidative stress and kidney injury","volume":"10","author":"Dawood","year":"2022","journal-title":"Biomedicines"},{"key":"10.1016\/j.tice.2026.103425_bib12","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1002\/hep.23280","article-title":"Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications","volume":"51","author":"Fabbrini","year":"2010","journal-title":"Hepatology"},{"key":"10.1016\/j.tice.2026.103425_bib13","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.coph.2020.10.016","article-title":"The role of the liver in the modulation of glucose and insulin in non alcoholic fatty liver disease and type 2 diabetes","volume":"55","author":"Guerra","year":"2020","journal-title":"Curr. Opin. Pharm."},{"key":"10.1016\/j.tice.2026.103425_bib14","article-title":"Metformin alleviates steatohepatitis in diet-induced obese mice in a SIRT1-dependent way","volume":"12","author":"Guo","year":"2021","journal-title":"Front Pharm."},{"key":"10.1016\/j.tice.2026.103425_bib15","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1080\/01913123.2018.1551258","article-title":"Insulin protects against hepatocyte ultrastructural damage induced by type 1 diabetes mellitus in rats","volume":"42","author":"Haidara","year":"2018","journal-title":"Ultra Pathol."},{"key":"10.1016\/j.tice.2026.103425_bib16","doi-asserted-by":"crossref","first-page":"771","DOI":"10.5551\/jat.RV17023","article-title":"Pathophysiology of diabetic dyslipidemia","volume":"25","author":"Hirano","year":"2018","journal-title":"J. Atheroscler. Thromb."},{"key":"10.1016\/j.tice.2026.103425_bib17","doi-asserted-by":"crossref","first-page":"319","DOI":"10.3350\/cmh.2015.21.4.319","article-title":"Nitric oxide in liver fibrosis: the role of inducible nitric oxide synthase","volume":"21","author":"Iwakiri","year":"2015","journal-title":"Clin. Mol. Hepatol."},{"key":"10.1016\/j.tice.2026.103425_bib18","article-title":"Advances in the regulation of inflammatory mediators in nitric oxide synthase: implications for disease modulation and therapeutic approaches","volume":"26","author":"Kim","year":"2025","journal-title":"Int J. Mol. Sci."},{"key":"10.1016\/j.tice.2026.103425_bib19","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1056\/NEJMoa012512","article-title":"Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin","volume":"346","author":"Knowler","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.tice.2026.103425_bib20","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/35007508","article-title":"Obesity as a medical problem","volume":"404","author":"Kopelman","year":"2000","journal-title":"Nature"},{"key":"10.1016\/j.tice.2026.103425_bib21","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1172\/JCI88881","article-title":"Liver inflammation and fibrosis","volume":"127","author":"Koyama","year":"2017","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.tice.2026.103425_bib22","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4093\/dmj.2021.0280","article-title":"Insulin resistance: from mechanisms to therapeutic strategies","volume":"46","author":"Lee","year":"2022","journal-title":"Diabetes Metab. J."},{"key":"10.1016\/j.tice.2026.103425_bib23","doi-asserted-by":"crossref","first-page":"8377","DOI":"10.3748\/wjg.v20.i26.8377","article-title":"Non-alcoholic fatty liver disease and diabetes: from physiopathological interplay to diagnosis and treatment","volume":"20","author":"Leite","year":"2014","journal-title":"World J. Gastroenterol."},{"issue":"19","key":"10.1016\/j.tice.2026.103425_bib24","doi-asserted-by":"crossref","first-page":"3001","DOI":"10.3390\/cells11193001","article-title":"Macrophages, chronic inflammation, and insulin resistance","volume":"11","author":"Li","year":"2022","journal-title":"Cells"},{"key":"10.1016\/j.tice.2026.103425_bib25","doi-asserted-by":"crossref","first-page":"399","DOI":"10.2337\/dc20-1997","article-title":"Advanced liver fibrosis is common in patients with type 2 diabetes followed in the outpatient setting: the need for systematic screening","volume":"44","author":"Lomonaco","year":"2021","journal-title":"Diabetes Care"},{"key":"10.1016\/j.tice.2026.103425_bib26","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/482027a","article-title":"Public health: the toxic truth about sugar","volume":"482","author":"Lustig","year":"2012","journal-title":"Nature"},{"key":"10.1016\/j.tice.2026.103425_bib27","doi-asserted-by":"crossref","DOI":"10.3390\/ijms24021074","article-title":"Glycogen-endoplasmic reticulum connection in the liver","volume":"24","author":"Mandl","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.tice.2026.103425_bib28","doi-asserted-by":"crossref","first-page":"175","DOI":"10.31989\/ffhd.v8i3.423","article-title":"Metformin inhibits expression of the proinflammatory biomarker inducible nitric oxide synthase in hepatocytes","volume":"8","author":"Nakatake","year":"2018","journal-title":"Funct. Foods Health Dis."},{"issue":"8","key":"10.1016\/j.tice.2026.103425_bib29","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1210\/jc.2010-2415","article-title":"Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients","volume":"96","author":"Nkontchou","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"10.1016\/j.tice.2026.103425_bib30","article-title":"Risk of liver fibrosis in patients with prediabetes and diabetes mellitus","volume":"17","author":"Park","year":"2022","journal-title":"PLoS One"},{"key":"10.1016\/j.tice.2026.103425_bib31","doi-asserted-by":"crossref","first-page":"26","DOI":"10.2337\/dci23-0085","article-title":"Economic costs of diabetes in the U.S. in 2022","volume":"47","author":"Parker","year":"2024","journal-title":"Diabetes Care"},{"key":"10.1016\/j.tice.2026.103425_bib32","doi-asserted-by":"crossref","first-page":"827","DOI":"10.5009\/gnl20367","article-title":"Effects of metformin on hepatic steatosis in adults with nonalcoholic fatty liver disease and diabetes: insights from the cellular to patient levels","volume":"15","author":"Pinyopornpanish","year":"2021","journal-title":"Gut Liver"},{"key":"10.1016\/j.tice.2026.103425_bib33","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1053\/meta.2000.17721","article-title":"A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat","volume":"49","author":"Reed","year":"2000","journal-title":"Metabolism"},{"key":"10.1016\/j.tice.2026.103425_bib34","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1177\/1747493018778713","article-title":"Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke","volume":"13","author":"Sacks","year":"2018","journal-title":"Int. J. Stroke"},{"key":"10.1016\/j.tice.2026.103425_bib35","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0153289","article-title":"Investigating the role of TNF-\u03b1 and IFN-\u03b3 activation on the dynamics of iNOS gene expression in LPS stimulated macrophages","volume":"11","author":"Salim","year":"2016","journal-title":"PLoS One"},{"key":"10.1016\/j.tice.2026.103425_bib36","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S1074-7613(03)00171-7","article-title":"TNF\/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection","volume":"19","author":"Serbina","year":"2003","journal-title":"Immunity"},{"key":"10.1016\/j.tice.2026.103425_bib37","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1172\/JCI29069","article-title":"Inflammation and insulin resistance","volume":"116","author":"Shoelson","year":"2006","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.tice.2026.103425_bib38","doi-asserted-by":"crossref","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"10.1016\/j.tice.2026.103425_bib39","doi-asserted-by":"crossref","first-page":"3024","DOI":"10.1111\/febs.15877","article-title":"Liver macrophages and inflammation in physiology and physiopathology of non-alcoholic fatty liver disease","volume":"289","author":"Thibaut","year":"2022","journal-title":"Febs J."},{"key":"10.1016\/j.tice.2026.103425_bib40","doi-asserted-by":"crossref","first-page":"734","DOI":"10.2337\/dc06-1539","article-title":"Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease","volume":"30","author":"Tolman","year":"2007","journal-title":"Diabetes Care"},{"key":"10.1016\/j.tice.2026.103425_bib41","article-title":"Type 2 diabetes complications are associated with liver fibrosis independent of hemoglobin A1c","volume":"28","author":"Trivedi","year":"2023","journal-title":"Ann. Hepatol."},{"key":"10.1016\/j.tice.2026.103425_bib42","doi-asserted-by":"crossref","first-page":"12292","DOI":"10.1038\/s41598-017-12548-4","article-title":"Increased liver AGEs induce hepatic injury mediated through an OST48 pathway","volume":"7","author":"Zhuang","year":"2017","journal-title":"Sci. Rep."}],"container-title":["Tissue and Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0040816626001175?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0040816626001175?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T02:53:48Z","timestamp":1778727228000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0040816626001175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":42,"alternative-id":["S0040816626001175"],"URL":"https:\/\/doi.org\/10.1016\/j.tice.2026.103425","relation":{},"ISSN":["0040-8166"],"issn-type":[{"value":"0040-8166","type":"print"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Metformin is associated with the suppression of the TNF-\u03b1\/iNOS\/TIMP-1 axis-mediated liver injury and fibrosis secondary to diabetes","name":"articletitle","label":"Article Title"},{"value":"Tissue and Cell","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.tice.2026.103425","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"103425"}}