{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T08:31:35Z","timestamp":1783758695521,"version":"3.55.0"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["Code 001"],"award-info":[{"award-number":["Code 001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Instituto Nacional de Ci\u00eancia e Tecnologia em Entomologia Molecular - CNPq","award":["465678\/2014-9"],"award-info":[{"award-number":["465678\/2014-9"]}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2009\/09892-6"],"award-info":[{"award-number":["2009\/09892-6"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2016\/11523-2"],"award-info":[{"award-number":["2016\/11523-2"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"name":"N\u00facleo de Pesquisa em Mol\u00e9culas Bioativas de Artr\u00f3podes Vetores","award":["12.1.17661.1.7"],"award-info":[{"award-number":["12.1.17661.1.7"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Acetaminophen (<jats:italic>N<\/jats:italic>-acetyl-<jats:italic>p<\/jats:italic>-aminophenol, APAP) overdose is the most common cause of drug-induced liver injury (DILI). Although the primary hepatic damage is induced by APAP-derived toxic intermediates resulting from cytochrome P450 metabolism, immune components also play an important role in DILI pathophysiology.<jats:italic>Aedes aegypti<\/jats:italic>saliva is a source of bioactive molecules with<jats:italic>in vitro<\/jats:italic>anti-inflammatory and immunomodulatory activities. However, evidences on the therapeutic use of<jats:italic>Ae<\/jats:italic>.<jats:italic>aegypti<\/jats:italic>salivary preparations in animal models of relevant clinical conditions are still scarce. Thus, the present study was designed to evaluate the protective role of<jats:italic>Ae<\/jats:italic>.<jats:italic>aegypti<\/jats:italic>saliva in a murine model of APAP-induced DILI. C57BL\/6 mice were exposed to<jats:italic>Ae<\/jats:italic>.<jats:italic>aegypti<\/jats:italic>bites 2 hours after APAP overdose. Biochemical and immunological parameters were evaluated in blood and liver samples at different time points after APAP administration. Exposure to<jats:italic>Ae<\/jats:italic>.<jats:italic>aegypti<\/jats:italic>saliva attenuated liver damage, as demonstrated by reduced hepatic necrosis and serum levels of alanine aminotransferase in APAP-overdosed mice. The levels of hepatic CYP2E1, the major enzyme responsible for the bioactivation of APAP, were not changed in<jats:italic>Ae<\/jats:italic>.<jats:italic>aegypti<\/jats:italic>exposed animals, suggesting no effects in the generation of hepatotoxic metabolites. On the other hand, mice treated with<jats:italic>Ae<\/jats:italic>.<jats:italic>aegypti<\/jats:italic>saliva following APAP overdose presented lower serum concentration of TNF-\u03b1, IL-6, IL-1\u03b2 and IL-10, as well as reduced frequency of inflammatory cell populations in the liver, such as NKT cells, macrophages and dendritic cells. These findings show that<jats:italic>Ae<\/jats:italic>.<jats:italic>aegypti<\/jats:italic>saliva has bioactive molecules with therapeutic properties and may represent a prospective source of new compounds in the management of DILI-associated inflammatory disorders and, perhaps, many other inflammatory\/autoimmune diseases.<\/jats:p>","DOI":"10.1371\/journal.pone.0245788","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T23:15:54Z","timestamp":1612826154000},"page":"e0245788","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Aedes aegypti mosquito saliva ameliorates acetaminophen-induced liver injury in mice"],"prefix":"10.1371","volume":"16","author":[{"given":"Josiane B.","family":"Assis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Cogliati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliane","family":"Esteves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margareth L.","family":"Capurro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise M.","family":"Fonseca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1859-4973","authenticated-orcid":true,"given":"Anderson","family":"S\u00e1-Nunes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,8]]},"reference":[{"key":"pone.0245788.ref001","first-page":"74","article-title":"An Update on Treatment of Drug-Induced Liver Injury","volume":"2","author":"C Giordano","year":"2014","journal-title":"J Clin Transl Hepatol"},{"key":"pone.0245788.ref002","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1002\/pds.3906","article-title":"Trends in rates of acetaminophen-related adverse events in the United States","volume":"25","author":"JM Major","year":"2016","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"pone.0245788.ref003","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1136\/bmj.2.5512.497","article-title":"Acute Liver Necrosis Following Overdose of Paracetamol","volume":"2","author":"DGD Davidson","year":"1966","journal-title":"Br Med J"},{"key":"pone.0245788.ref004","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1136\/pgmj.54.632.400","article-title":"The spectrum of paracetamol (acetaminophen) overdose: Clinical and epidemiological studies","volume":"54","author":"AN Hamlyn","year":"1978","journal-title":"Postgrad Med J"},{"key":"pone.0245788.ref005","doi-asserted-by":"crossref","first-page":"93","DOI":"10.2165\/00003088-198207020-00001","article-title":"Clinical Pharmacokinetics of Paracetamol","volume":"7","author":"JAH Forrest","year":"1982","journal-title":"Clin Pharmacokinet"},{"key":"pone.0245788.ref006","doi-asserted-by":"crossref","first-page":"12063","DOI":"10.1074\/jbc.271.20.12063","article-title":"Role of CYP2E1 in the hepatotoxicity of acetaminophen","volume":"271","author":"SST Lee","year":"1996","journal-title":"J Biol Chem"},{"key":"pone.0245788.ref007","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1067\/mcp.2000.104736","article-title":"Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation","volume":"67","author":"PT Manyike","year":"2000","journal-title":"Clin Pharmacol Ther"},{"key":"pone.0245788.ref008","doi-asserted-by":"crossref","first-page":"227","DOI":"10.2165\/00002018-200528030-00004","article-title":"Tolerability of paracetamol","volume":"28","author":"GG Graham","year":"2005","journal-title":"Drug Saf"},{"key":"pone.0245788.ref009","first-page":"211","article-title":"Acetaminophen-induced hepatic necrosis. 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