{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T17:35:39Z","timestamp":1786988139394,"version":"build-2736575974"},"reference-count":52,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273115"],"award-info":[{"award-number":["82273115"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015508","name":"Shandong Academy of Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015508","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pharmacology"],"published-print":{"date-parts":[[2025,9]]},"DOI":"10.1016\/j.ejphar.2025.177900","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T17:27:54Z","timestamp":1751563674000},"page":"177900","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"special_numbering":"C","title":["Novel mechanisms of metformin-induced vasorelaxation of mesenteric arterioles via endothelium-dependent hyperpolarization to treat murine colitis"],"prefix":"10.1016","volume":"1003","author":[{"given":"Luyun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejphar.2025.177900_bib1","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: identifying and developing new uses for existing drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"10.1016\/j.ejphar.2025.177900_bib2","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/S0016-5085(19)34333-1","article-title":"Quantitative measurement of regional colon blood flow in the normal and pathological human bowel","volume":"51","author":"Bacaner","year":"1966","journal-title":"Gastroenterology"},{"key":"10.1016\/j.ejphar.2025.177900_bib3","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1007\/s00125-008-1053-5","article-title":"Metformin and the intestine","volume":"51","author":"Bailey","year":"2008","journal-title":"Diabetologia"},{"key":"10.1016\/j.ejphar.2025.177900_bib4","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.1038\/s41467-021-23198-6","article-title":"Zinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle","volume":"12","author":"Betrie","year":"2021","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejphar.2025.177900_bib5","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/0895-7061(95)00356-8","article-title":"Vascular effects of metformin. Possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat","volume":"9","author":"Bhalla","year":"1996","journal-title":"Am. J. Hypertens."},{"key":"10.1016\/j.ejphar.2025.177900_bib6","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1053\/j.gastro.2014.08.033","article-title":"Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice","volume":"147","author":"Chassaing","year":"2014","journal-title":"Gastroenterology"},{"key":"10.1016\/j.ejphar.2025.177900_bib7","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.1002\/ejoc.202100245","article-title":"Addressing the target identification and accelerating the repositioning of anti-inflammatory\/anti-cancer organic compounds by computational approaches","volume":"2021","author":"Chini","year":"2021","journal-title":"Eur. J. Org Chem."},{"key":"10.1016\/j.ejphar.2025.177900_bib8","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1111\/apha.12805","article-title":"Nonlinear effects of potassium channel blockers on endothelium-dependent hyperpolarization","volume":"219","author":"Coleman","year":"2017","journal-title":"Acta Physiol."},{"key":"10.1016\/j.ejphar.2025.177900_bib9","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2021.684538","article-title":"Role of serosal TRPV4-Constituted SOCE mechanism in secretagogues-stimulated intestinal epithelial anion secretion","volume":"12","author":"Cui","year":"2021","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.ejphar.2025.177900_bib10","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1097\/FJC.0000000000000346","article-title":"Endothelium-dependent hyperpolarization and endothelial dysfunction","volume":"67","author":"F\u00e9l\u00e9tou","year":"2016","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"10.1016\/j.ejphar.2025.177900_bib11","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: from mechanisms of action to therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell Metab."},{"key":"10.1016\/j.ejphar.2025.177900_bib12","article-title":"Segmental regulation of intestinal motility by colitis and the adaptive immune system in the mouse ileum and Colon","author":"Gomez-Bris","year":"2024","journal-title":"Am. J. Pathol."},{"key":"10.1016\/j.ejphar.2025.177900_bib13","doi-asserted-by":"crossref","DOI":"10.3390\/ijms19010315","article-title":"Endothelium-dependent hyperpolarization (EDH) in hypertension: the role of endothelial ion channels","volume":"19","author":"Goto","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.ejphar.2025.177900_bib14","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/11534750-000000000-00000","article-title":"Clinical pharmacokinetics of metformin","volume":"50","author":"Graham","year":"2011","journal-title":"Clin. Pharmacokinet."},{"key":"10.1016\/j.ejphar.2025.177900_bib15","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2024.156037","article-title":"Paeoniae radix alba improved intestinal mucosal microcirculation disturbance by regulating lncRNA MALAT1\/HIF-1\u03b1 pathway in the treatment of ulcerative colitis","volume":"135","author":"Gu","year":"2024","journal-title":"Phytomedicine"},{"key":"10.1016\/j.ejphar.2025.177900_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.metabol.2021.154701","article-title":"Taurine treatment reverses protein malnutrition-induced endothelial dysfunction of the pancreatic vasculature: the role of hydrogen sulfide","volume":"116","author":"Guizoni","year":"2021","journal-title":"Metabolism"},{"key":"10.1016\/j.ejphar.2025.177900_bib17","article-title":"Nutrient-induced hyperosmosis evokes vasorelaxation via TRPV1-mediated endothelium-dependent hyperpolarization in healthy and colitis mice","author":"Guo","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.ejphar.2025.177900_bib18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1113\/jphysiol.1978.sp012179","article-title":"Mechanical properties of smooth muscle cells in the walls of arterial resistance vessels","volume":"275","author":"Halpern","year":"1978","journal-title":"J. Physiol."},{"key":"10.1016\/j.ejphar.2025.177900_bib19","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-11430-7","article-title":"Metformin improves endothelial function and reduces blood pressure in diabetic spontaneously hypertensive rats independent from glycemia control: Comparison to vildagliptin","volume":"7","author":"Hamidi Shishavan","year":"2017","journal-title":"Sci. Rep."},{"key":"10.1016\/j.ejphar.2025.177900_bib20","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1097\/01.MIB.0000160772.78951.61","article-title":"The vasculature and inflammatory bowel disease: contribution to pathogenesis and clinical pathology","volume":"11","author":"Hatoum","year":"2005","journal-title":"Inflamm. Bowel Dis."},{"key":"10.1016\/j.ejphar.2025.177900_bib21","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/S0016-5085(03)00699-1","article-title":"Acquired microvascular dysfunction in inflammatory bowel disease: loss of nitric oxide-mediated vasodilation","volume":"125","author":"Hatoum","year":"2003","journal-title":"Gastroenterology"},{"key":"10.1016\/j.ejphar.2025.177900_bib22","doi-asserted-by":"crossref","first-page":"H1791","DOI":"10.1152\/ajpheart.00552.2003","article-title":"The vascular contribution in the pathogenesis of inflammatory bowel disease","volume":"285","author":"Hatoum","year":"2003","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"10.1016\/j.ejphar.2025.177900_bib23","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1111\/bph.14762","article-title":"Endothelial TRPV4 channels modulate vascular tone by Ca(2+) -induced Ca(2+) release at inositol 1,4,5-trisphosphate receptors","volume":"176","author":"Heathcote","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.ejphar.2025.177900_bib24","doi-asserted-by":"crossref","DOI":"10.3390\/ijms23031264","article-title":"Metformin and insulin resistance: a review of the underlying mechanisms behind changes in GLUT4-Mediated glucose transport","volume":"23","author":"Herman","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.ejphar.2025.177900_bib25","doi-asserted-by":"crossref","DOI":"10.1002\/eji.202249866","article-title":"Emerging roles of host and microbial bioactive lipids in inflammatory bowel diseases","author":"Kayama","year":"2023","journal-title":"Eur. J. Immunol."},{"key":"10.1016\/j.ejphar.2025.177900_bib26","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1093\/ecco-jcc\/jjy045","article-title":"Gut barrier Dysfunction-A primary defect in twins with Crohn's disease predominantly caused by genetic predisposition","volume":"12","author":"Keita A","year":"2018","journal-title":"J Crohns Colitis"},{"key":"10.1016\/j.ejphar.2025.177900_bib27","article-title":"Metformin affects Gut Microbiota composition and diversity associated with Amelioration of Dextran Sulfate Sodium-Induced colitis in mice","volume":"12","author":"Liu","year":"2021","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.ejphar.2025.177900_bib28","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.3748\/wjg.v20.i13.3507","article-title":"Glucose intolerance and diabetes mellitus in ulcerative colitis: pathogenetic and therapeutic implications","volume":"20","author":"Maconi","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"10.1016\/j.ejphar.2025.177900_bib29","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1038\/ncomms3192","article-title":"Metformin improves healthspan and lifespan in mice","volume":"4","author":"Martin-Montalvo","year":"2013","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejphar.2025.177900_bib30","doi-asserted-by":"crossref","first-page":"740","DOI":"10.7326\/M15-2650","article-title":"Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis","volume":"164","author":"Maruthur","year":"2016","journal-title":"Ann. Intern. Med."},{"key":"10.1016\/j.ejphar.2025.177900_bib31","doi-asserted-by":"crossref","first-page":"H1165","DOI":"10.1152\/ajpheart.00486.2008","article-title":"Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes","volume":"295","author":"Matsumoto","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"10.1016\/j.ejphar.2025.177900_bib32","doi-asserted-by":"crossref","DOI":"10.1155\/2015\/628157","article-title":"Intestinal permeability in inflammatory bowel disease: pathogenesis, clinical evaluation, and therapy of Leaky Gut","volume":"2015","author":"Michielan","year":"2015","journal-title":"Mediators Inflamm"},{"key":"10.1016\/j.ejphar.2025.177900_bib33","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2021.114850","article-title":"Differential contribution of renal cytochrome P450 enzymes to kidney endothelial dysfunction and vascular oxidative stress in obesity","volume":"195","author":"Mu\u00f1oz","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"10.1016\/j.ejphar.2025.177900_bib34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.coph.2019.03.005","article-title":"Agonist-evoked endothelial Ca2+ signalling microdomains","volume":"45","author":"Murphy","year":"2019","journal-title":"Curr. Opin. Pharmacol."},{"key":"10.1016\/j.ejphar.2025.177900_bib35","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1152\/physrev.00020.2014","article-title":"Store-operated calcium channels","volume":"95","author":"Prakriya","year":"2015","journal-title":"Physiol. Rev."},{"key":"10.1016\/j.ejphar.2025.177900_bib36","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/S2213-8587(13)70152-9","article-title":"Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial","volume":"2","author":"Preiss","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"10.1016\/j.ejphar.2025.177900_bib37","doi-asserted-by":"crossref","DOI":"10.3390\/molecules25051154","article-title":"Repositioning natural products in drug discovery","volume":"25","author":"Rastelli","year":"2020","journal-title":"Molecules"},{"key":"10.1016\/j.ejphar.2025.177900_bib38","article-title":"Etrasimod corticosteroid-free efficacy, impact of concomitant corticosteroids on efficacy and safety, and corticosteroid-sparing effect in UC: analyses of the ELEVATE UC clinical programme","author":"Sands","year":"2024","journal-title":"J Crohns Colitis"},{"key":"10.1016\/j.ejphar.2025.177900_bib39","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/bcpt.13377","article-title":"Nitric oxide and endothelium-dependent hyperpolarization mediated by hydrogen peroxide in health and disease","volume":"127","author":"Shimokawa","year":"2020","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"10.1016\/j.ejphar.2025.177900_bib40","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1097\/00005344-199611000-00014","article-title":"The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation","volume":"28","author":"Shimokawa","year":"1996","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"10.1016\/j.ejphar.2025.177900_bib41","doi-asserted-by":"crossref","DOI":"10.1096\/fj.202100831RR","article-title":"Metformin ameliorates chronic colitis in a mouse model by regulating interferon-\u03b3-producing lamina propria CD4(+) T cells through AMPK activation","volume":"36","author":"Takahara","year":"2022","journal-title":"Faseb j"},{"key":"10.1016\/j.ejphar.2025.177900_bib42","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/BF02934083","article-title":"Assessment of blood flow in the small intestine by laser doppler flowmetry: comparison of healthy small intestine and small intestine in Crohn's disease","volume":"32","author":"Tateishi","year":"1997","journal-title":"J. Gastroenterol."},{"key":"10.1016\/j.ejphar.2025.177900_bib43","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2211933120","article-title":"Metformin acts in the gut and induces gut-liver crosstalk","volume":"120","author":"Tobar","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.ejphar.2025.177900_bib44","doi-asserted-by":"crossref","DOI":"10.1016\/j.metabol.2022.155223","article-title":"Metformin: is it a drug for all reasons and diseases?","volume":"133","author":"Triggle","year":"2022","journal-title":"Metabolism"},{"key":"10.1016\/j.ejphar.2025.177900_bib45","article-title":"Peripheral artery disease mediating the effect of metabolic syndrome related diseases on lower limb ulcers: mendelian randomization analysis","volume":"15","author":"Wang","year":"2024","journal-title":"Front. Endocrinol."},{"key":"10.1016\/j.ejphar.2025.177900_bib46","article-title":"Metformin ameliorates chronic colitis-related intestinal fibrosis via inhibiting TGF-\u03b21\/Smad3 signaling","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.ejphar.2025.177900_bib47","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.02242","article-title":"Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis","volume":"3","author":"Wheaton","year":"2014","journal-title":"eLife"},{"key":"10.1016\/j.ejphar.2025.177900_bib48","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaut.2023.103062","article-title":"Gut microbiome, metabolome, host immunity associated with inflammatory bowel disease and intervention of fecal microbiota transplantation","author":"Wu","year":"2023","journal-title":"J. Autoimmun."},{"key":"10.1016\/j.ejphar.2025.177900_bib49","doi-asserted-by":"crossref","first-page":"5149","DOI":"10.1038\/s41598-024-55869-x","article-title":"Type 2 diabetes and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study","volume":"14","author":"Xu","year":"2024","journal-title":"Sci. Rep."},{"key":"10.1016\/j.ejphar.2025.177900_bib50","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.jare.2021.11.001","article-title":"Beneficial effect of capsaicin via TRPV4\/EDH signals on mesenteric arterioles of normal and colitis mice","volume":"39","author":"Zhang","year":"2022","journal-title":"J. Adv. Res."},{"key":"10.1016\/j.ejphar.2025.177900_bib51","article-title":"Elucidating novel mechanism of action of spiperone for drug repurposing to prevent and treat murine colitis and sepsis","volume":"361","author":"Zhang","year":"2024","journal-title":"Life Sci."},{"key":"10.1016\/j.ejphar.2025.177900_bib52","article-title":"Cyclopiazonic acid-induced Ca2+ Store depletion initiates endothelium-dependent hyperpolarization-mediated vasorelaxation of mesenteric arteries in healthy and colitis mice","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Physiol."}],"container-title":["European Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0014299925006545?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0014299925006545?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T04:31:56Z","timestamp":1762144316000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0014299925006545"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":52,"alternative-id":["S0014299925006545"],"URL":"https:\/\/doi.org\/10.1016\/j.ejphar.2025.177900","relation":{},"ISSN":["0014-2999"],"issn-type":[{"value":"0014-2999","type":"print"}],"subject":[],"published":{"date-parts":[[2025,9]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Novel mechanisms of metformin-induced vasorelaxation of mesenteric arterioles via endothelium-dependent hyperpolarization to treat murine colitis","name":"articletitle","label":"Article Title"},{"value":"European Journal of Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejphar.2025.177900","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"177900"}}