{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T17:13:27Z","timestamp":1771953207922,"version":"3.50.1"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2017,7,20]],"date-time":"2017-07-20T00:00:00Z","timestamp":1500508800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,7,20]],"date-time":"2017-07-20T00:00:00Z","timestamp":1500508800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:p>Toxin\u2010induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti\u2010inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the <jats:sc>d<\/jats:sc>\u2010galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase\u2013mediated deoxyuridine triphosphate nick end\u2010labeling (TUNEL)\u2010positive cells and mortality compared with vehicle\u2010injected controls. VLX103 decreased GalN\/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN\/TNF. In GalN\/LPS\u2010treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c\u2010Jun N\u2010terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN\/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol\u2010induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL\u2010positive cells. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: VLX103 effectively decreases toxin\u2010induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (H<jats:sc>epatology<\/jats:sc> 2017;66:922\u2013935).<\/jats:p>","DOI":"10.1002\/hep.29244","type":"journal-article","created":{"date-parts":[[2017,5,3]],"date-time":"2017-05-03T23:32:43Z","timestamp":1493854363000},"page":"922-935","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":18,"title":["Pentamidine blocks hepatotoxic injury in mice"],"prefix":"10.1097","volume":"66","author":[{"given":"Enpeng","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Medicine and the Marion Bessin Liver Research Center,Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghulam","family":"Ilyas","sequence":"additional","affiliation":[{"name":"Department of Medicine and the Marion Bessin Liver Research Center,Albert Einstein College of Medicine,Bronx,NY"},{"name":"Division of Digestive Diseases,Department of Medicine, Emory University School of 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