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Meldonium is an anti-ischemic and anti-inflammatory agent which negatively interferes with lipid metabolism by shifting energy production from fatty acid oxidation to glycolysis, as a less oxygen-demanding pathway. Thus, we investigated the effects of a four-week meldonium pre-treatment on faecal-induced sepsis in Sprague-Dawley male rats. Surprisingly, under septic conditions, meldonium increased animal mortality rate compared with the meldonium non-treated group. However, analysis of the tissue oxidative status did not provide support for the detrimental effects of meldonium, nor did the analysis of the tissue inflammatory status showing anti-inflammatory, anti-apoptotic, and anti-necrotic effects of meldonium. After performing tissue lipidomic analysis, we concluded that the potential cause of the meldonium harmful effect is to be found in the overall decreased lipid metabolism. The present study underlines the importance of uninterrupted energy production in sepsis, closely drawing attention to the possible harmful effects of lipid-mobilization impairment caused by certain therapeutics. This could lead to the much-needed revision of the existing guidelines in the clinical treatment of sepsis while paving the way for discovering new therapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms22189698","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T02:41:07Z","timestamp":1631068867000},"page":"9698","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Effects of a Meldonium Pre-Treatment on the Course of the Faecal-Induced Sepsis in Rats"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4406-8376","authenticated-orcid":false,"given":"Sini\u0161a","family":"\u0110ura\u0161evi\u0107","sequence":"first","affiliation":[{"name":"Faculty of Biology, University of Belgrade, 11000 Belgrade, 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Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2022-2447","authenticated-orcid":false,"given":"Sa\u0161a","family":"\u0110urovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of General and Physical Chemistry, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofija","family":"Glumac","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5651-7178","authenticated-orcid":false,"given":"Sla\u0111an","family":"Pavlovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, 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