{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:47:06Z","timestamp":1790934426463,"version":"4.1.0"},"reference-count":118,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T00:00:00Z","timestamp":1615334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until cell death. The critical event in such a series of harmful events in the cell is the unwanted accumulation of fatty acids that leads to lipotoxicity. Lipid analysis provides additional insight into the pathogenesis of ischemia\/reperfusion (I\/R) disorders and reveals new targets for drug action. The profile of changes in the composition of fatty acids in the cell, as well as the time course of these changes, indicate both the mechanism of damage and new therapeutic possibilities. A therapeutic approach to reperfusion lipotoxicity involves attenuation of fatty acids overload, i.e., their transport to adipose tissue and\/or inhibition of the adverse effects of fatty acids on cell damage and death. The latter option involves using PPAR agonists and drugs that modulate the transport of fatty acids via carnitine into the interior of the mitochondria or the redirection of long-chain fatty acids to peroxisomes.<\/jats:p>","DOI":"10.3390\/ijms22062798","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T13:27:20Z","timestamp":1615382840000},"page":"2798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia\u2014Reperfusion Injury"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8869-9976","authenticated-orcid":false,"given":"Zoran","family":"Todorovi\u0107","sequence":"first","affiliation":[{"name":"School of Medicine, University of Belgrade, 11129 Belgrade, Serbia"},{"name":"University Medical Centre \u201cBe\u017eanijska kosa\u201d, 11080 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4406-8376","authenticated-orcid":false,"given":"Sini\u0161a","family":"\u0110ura\u0161evi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0706-3800","authenticated-orcid":false,"given":"Maja","family":"Stojkovi\u0107","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9540-4961","authenticated-orcid":false,"given":"Ilijana","family":"Grigorov","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of Republic of Serbia, 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, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0333-333X","authenticated-orcid":false,"given":"Neboj\u0161a","family":"Jasni\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1403-4688","authenticated-orcid":false,"given":"Tomislav","family":"Tosti","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelica Bjeki\u0107","family":"Macut","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Belgrade, 11129 Belgrade, Serbia"},{"name":"University Medical Centre \u201cBe\u017eanijska kosa\u201d, 11080 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Thiemermann","sequence":"additional","affiliation":[{"name":"Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"\u0110or\u0111evi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3727\/105221617X15042750874156","article-title":"Hepatic Ischemia\/Reperfusion: Mechanisms of Tissue Injury, Repair, and Regeneration","volume":"17","author":"Konishi","year":"2017","journal-title":"Gene Expr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1159\/000489241","article-title":"Current Mechanistic Concepts in Ischemia and Reperfusion Injury","volume":"46","author":"Wu","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41419-020-2298-2","article-title":"Ferroptosis: Past, present and future","volume":"11","author":"Li","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"RA161","DOI":"10.12659\/MSM.883533","article-title":"The Na+\/Ca2+ exchanger in cardiac ischemia\/reperfusion injury","volume":"18","author":"Chen","year":"2012","journal-title":"Med. Sci. Monit."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Shoda, W., Nomura, N., Ando, F., Tagashira, H., Iwamoto, T., Ohta, A., Isobe, K., Mori, T., Susa, K., and Sohara, E. (2020). Sodium-calcium exchanger 1 is the key molecule for urinary potassium excretion against acute hyperkalemia. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0235360"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3748\/wjg.v25.i3.287","article-title":"Roles of Na+\/Ca2+ exchanger 1 in digestive system physiology and pathophysiology","volume":"25","author":"Liao","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1254\/jphs.FP0060911","article-title":"Involvement of the Na+\/Ca2+ exchanger in ouabain-induced inotropy and arrhythmogenesis in guinea-pig myocardium as revealed by SEA0400","volume":"103","author":"Tanaka","year":"2007","journal-title":"J. Pharmacol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1161\/01.CIR.0000095274.72486.94","article-title":"Dynamic regulation of sodium\/calcium exchange function in human heart failure","volume":"108","author":"Weber","year":"2003","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12816","DOI":"10.1073\/pnas.1904005116","article-title":"Persistence of the permeability transition pore in human mitochondria devoid of an assembled ATP synthase","volume":"116","author":"Carroll","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3389\/fphys.2015.00093","article-title":"Oxidative stress-mediated HMGB1 biology","volume":"6","author":"Yu","year":"2015","journal-title":"Front. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Durasevic, S., Stojkovic, M., Bogdanovic, L., Pavlovic, S., Borkovic-Mitic, S., Grigorov, I., Bogojevic, D., Jasnic, N., Tosti, T., and Durovic, S. (2019). The Effects of Meldonium on the Renal Acute Ischemia\/Reperfusion Injury in Rats. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225747"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/s41598-020-80011-y","article-title":"The effects of meldonium on the acute ischemia\/reperfusion liver injury in rats","volume":"11","author":"Durasevic","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7266","DOI":"10.3390\/molecules15107266","article-title":"The Nrf2 system as a potential target for the development of indirect antioxidants","volume":"15","author":"Jung","year":"2010","journal-title":"Molecules"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1093\/ndt\/gft091","article-title":"Renohepatic crosstalk: Does acute kidney injury cause liver dysfunction?","volume":"28","author":"Lane","year":"2013","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"302","DOI":"10.3389\/fonc.2014.00302","article-title":"The mitochondrial permeability transition pore and cancer: Molecular mechanisms involved in cell death","volume":"4","author":"Bonora","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14681","DOI":"10.1073\/pnas.95.25.14681","article-title":"Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria","volume":"95","author":"Narita","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1242\/dmm.016741","article-title":"The challenge of translating ischemic conditioning from animal models to humans: The role of comorbidities","volume":"7","author":"McCafferty","year":"2014","journal-title":"Dis. Model. Mech."},{"key":"ref_18","unstructured":"Injac, R., Karljikovi\u0107-Raji\u0107, K., and \u0160trukelj, B. (2009). The influence of drugs on biochemical markers of ischemia-reperfusion injury. The Analysis of Pharmacologically Active Compounds in Biomolecules in Real Samples, Transworld Research Network."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00210-007-0183-5","article-title":"Novel pharmacological approaches to the treatment of renal ischemia-reperfusion injury: A comprehensive review","volume":"376","author":"Chatterjee","year":"2007","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Todorovic, Z., Medic, B., Basta-Jovanovic, G., Radojevic Skodric, S., Stojanovic, R., Rovcanin, B., and Prostran, M. (2014). Acute pretreatment with chloroquine attenuates renal I\/R injury in rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092673"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e005092","DOI":"10.1161\/JAHA.116.005092","article-title":"Inhibition of IkappaB Kinase at 24 Hours After Acute Kidney Injury Improves Recovery of Renal Function and Attenuates Fibrosis","volume":"6","author":"Johnson","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1254\/jphs.SC0070374","article-title":"Acute protective effects of simvastatin in the rat model of renal ischemia-reperfusion injury: It is never too late for the pretreatment","volume":"107","author":"Todorovic","year":"2008","journal-title":"J. Pharmacol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Griffiths, W., and Wang, Y. (2020). Chapter 1: Lipidomics Basics. Lipidomics: Current and Emerging Techniques, Royal Society of Chemistry.","DOI":"10.1039\/9781788013109"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1007\/s00216-019-02241-y","article-title":"Lipidomics from sample preparation to data analysis: A primer","volume":"412","author":"Zullig","year":"2020","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.plipres.2014.06.001","article-title":"Systems biology strategies to study lipidomes in health and disease","volume":"55","author":"Hyotylainen","year":"2014","journal-title":"Prog. Lipid Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3389\/fmed.2015.00052","article-title":"Alteration of Fatty Acid Oxidation in Tubular Epithelial Cells: From Acute Kidney Injury to Renal Fibrogenesis","volume":"2","author":"Simon","year":"2015","journal-title":"Front. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"F1714","DOI":"10.1152\/ajprenal.00322.2018","article-title":"What we need to know about lipid-associated injury in case of renal ischemia-reperfusion","volume":"315","author":"Erpicum","year":"2018","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1111\/j.1523-1755.2005.00325.x","article-title":"Triglyceride accumulation in injured renal tubular cells: Alterations in both synthetic and catabolic pathways","volume":"67","author":"Johnson","year":"2005","journal-title":"Kidney Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13018","DOI":"10.1073\/pnas.95.22.13018","article-title":"Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis","volume":"95","author":"Cases","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Shu, H., Peng, Y., Hang, W., Nie, J., Zhou, N., and Wang, D.W. (2020). The role of CD36 in cardiovascular disease. Cardiovasc. Res., cvaa319.","DOI":"10.1093\/cvr\/cvaa319"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.mam.2012.07.010","article-title":"SLC27 fatty acid transport proteins","volume":"34","author":"Anderson","year":"2013","journal-title":"Mol. Aspects Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1039\/C6MD00043F","article-title":"Fatty Acid Transport Proteins: Targeting FATP2 as a Gatekeeper Involved in the Transport of Exogenous Fatty Acids","volume":"7","author":"Black","year":"2016","journal-title":"Medchemcomm"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrd2589","article-title":"Fatty acid-binding proteins: Role in metabolic diseases and potential as drug targets","volume":"7","author":"Furuhashi","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/1479-7364-5-3-170","article-title":"The human fatty acid-binding protein family: Evolutionary divergences and functions","volume":"5","author":"Smathers","year":"2011","journal-title":"Hum. Genom."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3892\/etm.2021.9612","article-title":"FABP4 alleviates endoplasmic reticulum stress-mediated ischemia-reperfusion injury in PC12 cells via regulation of PPARgamma","volume":"21","author":"Yang","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"917","DOI":"10.3389\/fphar.2018.00917","article-title":"Pharmacological Inhibition of Fatty Acid-Binding Protein 4 (FABP4) Protects Against Rhabdomyolysis-Induced Acute Kidney Injury","volume":"9","author":"Huang","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.jhep.2015.05.030","article-title":"Fatty acid binding protein-4 (FABP4) is a hypoxia inducible gene that sensitizes mice to liver ischemia\/reperfusion injury","volume":"63","author":"Hu","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41577-019-0240-6","article-title":"Efferocytosis in health and disease","volume":"20","author":"Doran","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1111\/j.1439-0396.2007.00752.x","article-title":"Liver lipid metabolism","volume":"92","author":"Nguyen","year":"2008","journal-title":"J. Anim. Physiol. Anim. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Johnston, M.R., and Sobhi, H.F. (2017). Advances in Fatty Acid Analysis for Clinical Investigation and Diagnosis using GC\/MS Methodology. J. Biochem. Analyt. Stud., 3.","DOI":"10.16966\/2576-5833.111"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"S61","DOI":"10.1016\/j.freeradbiomed.2017.04.214","article-title":"P 129\u2014Alteration of phospholipidome profile in the heart of an animal model of acute myocardial infarction","volume":"108","author":"Melo","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4149","DOI":"10.3892\/mmr.2015.3908","article-title":"Analysis of polyunsaturated fatty acids and the omega-6 inflammatory pathway in hepatic ischemia\/re-perfusion injury","volume":"12","author":"Kirac","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"E314","DOI":"10.1007\/BF02854902","article-title":"Lipids and lipidomics in brain injury and diseases","volume":"8","author":"Adibhatla","year":"2006","journal-title":"AAPS J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100151","DOI":"10.1074\/jbc.RA120.016565","article-title":"An imbalanced ratio between PC(16:0\/16:0) and LPC(16:0) revealed by lipidomics supports the role of the Lands\u2019 cycle in ischemic brain injury","volume":"296","author":"Zheng","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_45","first-page":"2155179019897002","article-title":"Critical Shifts in Cerebral White Matter Lipid Profiles After Ischemic\u2013Reperfusion Brain Injury in Fetal Sheep as Demonstrated by the Positive Ion Mode MALDI-Mass Spectrometry","volume":"12","author":"Gallucci","year":"2020","journal-title":"Cell Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"12120","DOI":"10.1038\/s41598-020-68995-z","article-title":"IL-10 attenuates OxPCs-mediated lipid metabolic responses in ischemia reperfusion injury","volume":"10","author":"Bagchi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.12659\/MSM.908732","article-title":"Lipid Biomarkers in Acute Myocardial Infarction Before and After Percutaneous Coronary Intervention by Lipidomics Analysis","volume":"24","author":"Feng","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s003950170057","article-title":"Production and metabolism of ceramide in normal and ischemic-reperfused myocardium of rats","volume":"96","author":"Zhang","year":"2001","journal-title":"Basic Res. Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3646725","DOI":"10.1155\/2018\/3646725","article-title":"Ceramide and Ischemia\/Reperfusion Injury","volume":"2018","author":"He","year":"2018","journal-title":"J. Lipids"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5076","DOI":"10.3390\/ijms16035076","article-title":"Ceramide-induced apoptosis in renal tubular cells: A role of mitochondria and sphingosine-1-phoshate","volume":"16","author":"Ueda","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.plipres.2017.03.001","article-title":"Lipids in exosomes: Current knowledge and the way forward","volume":"66","author":"Skotland","year":"2017","journal-title":"Prog. Lipid Res."},{"key":"ref_52","unstructured":"Watson, R.R., and Preedy, V.R. (2019). Chapter 27\u2014Cadmium and Fullerenes in Liver Diseases. Dietary Interventions in Liver Disease, Elsevier Academic Press."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"F1334","DOI":"10.1152\/ajprenal.00431.2011","article-title":"Acute unilateral ischemic renal injury induces progressive renal inflammation, lipid accumulation, histone modification, and \u201cend-stage\u201d kidney disease","volume":"301","author":"Zager","year":"2011","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/j.1523-1755.2005.00061.x","article-title":"Renal tubular triglyercide accumulation following endotoxic, toxic, and ischemic injury","volume":"67","author":"Zager","year":"2005","journal-title":"Kidney Int."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1194\/jlr.R066597","article-title":"Oxidative stress and lipotoxicity","volume":"57","author":"Hauck","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nchembio727","article-title":"Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors","volume":"1","author":"Kagan","year":"2005","journal-title":"Nat. Chem. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1007\/s12272-020-01273-8","article-title":"Emerging roles of ferroptosis in liver pathophysiology","volume":"43","author":"Kim","year":"2020","journal-title":"Arch. Pharm. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nchembio.2079","article-title":"Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis","volume":"12","author":"Shimada","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1254\/jphs.SCE06002X","article-title":"Single-dose intravenous simvastatin treatment attenuates renal injury in an experimental model of ischemia-reperfusion in the rat","volume":"102","author":"Nesic","year":"2006","journal-title":"J. Pharmacol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1475-2891-13-17","article-title":"Peroxisome proliferator-activated receptors and their ligands: Nutritional and clinical implications\u2014A review","volume":"13","year":"2014","journal-title":"Nutr. J."},{"key":"ref_62","first-page":"BR532","article-title":"Agonists of peroxisome-proliferator activated receptor-alpha (clofibrate and WY14643) reduce renal ischemia\/reperfusion injury in the rat","volume":"8","author":"Sivarajah","year":"2002","journal-title":"Med. Sci. Monit."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.lfs.2018.05.009","article-title":"Polyacetylene glycoside attenuates ischemic kidney injury by co-inhibiting inflammation, mitochondria dysfunction and lipotoxicity","volume":"204","author":"Zhou","year":"2018","journal-title":"Life Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.bbalip.2010.11.002","article-title":"PPARbeta\/delta activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells","volume":"1811","author":"Palomer","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/2197-425X-1-9","article-title":"Effects of the PPAR-beta\/delta agonist GW0742 during resuscitated porcine septic shock","volume":"1","author":"Wepler","year":"2013","journal-title":"Intensive Care Med. Exp."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.freeradbiomed.2010.10.710","article-title":"Peroxisome proliferator-activated receptor beta\/delta agonism protects the kidney against ischemia\/reperfusion injury in diabetic rats","volume":"50","author":"Collino","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1164\/rccm.201002-0240OC","article-title":"Protective role of peroxisome proliferator-activated receptor-beta\/delta in septic shock","volume":"182","author":"Kapoor","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1159\/000072088","article-title":"Agonists of peroxisome-proliferator activated receptor-gamma reduce renal ischemia\/reperfusion injury","volume":"23","author":"Sivarajah","year":"2003","journal-title":"Am. J. Nephrol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1046\/j.1523-1755.2002.00212.x","article-title":"Propionyl-L-carnitine prevents renal function deterioration due to ischemia\/reperfusion","volume":"61","author":"Mister","year":"2002","journal-title":"Kidney Int."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/j.1527-3458.2005.tb00267.x","article-title":"Mildronate: An antiischemic drug for neurological indications","volume":"11","author":"Sjakste","year":"2005","journal-title":"CNS Drug Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5765","DOI":"10.1113\/JP274415","article-title":"Muscle carnitine availability plays a central role in regulating fuel metabolism in the rodent","volume":"595","author":"Porter","year":"2017","journal-title":"J. Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.phrs.2016.01.019","article-title":"Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity","volume":"113","author":"Dambrova","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"20130446","DOI":"10.1098\/rstb.2013.0446","article-title":"How to deal with oxygen radicals stemming from mitochondrial fatty acid oxidation","volume":"369","author":"Speijer","year":"2014","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.freeradbiomed.2008.04.029","article-title":"Fatty acids as modulators of the cellular production of reactive oxygen species","volume":"45","author":"Schonfeld","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1194\/jlr.R067629","article-title":"Short- and medium-chain fatty acids in energy metabolism: The cellular perspective","volume":"57","author":"Schonfeld","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5748","DOI":"10.1074\/jbc.M109.026203","article-title":"Electron transport chain-dependent and -independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation","volume":"285","author":"Seifert","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_77","first-page":"2397847320915143","article-title":"Meldonium: Pharmacological, toxicological, and analytical aspects","volume":"4","author":"Berlato","year":"2020","journal-title":"Toxicol. Res. Appl."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S1050-1738(02)00175-5","article-title":"Mildronate: Cardioprotective Action through Carnitine-Lowering Effect","volume":"12","author":"Dambrova","year":"2002","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/cbf.1719","article-title":"Correction of glycaemia and GLUT1 level by mildronate in rat streptozotocin diabetes mellitus model","volume":"29","author":"Sokolovska","year":"2011","journal-title":"Cell Biochem. Funct."},{"key":"ref_80","first-page":"93","article-title":"Pharmacokinetic analysis of the cardioprotective effect of 3-(2,2, 2-trimethylhydrazinium) propionate in mice: Inhibition of carnitine transport in kidney","volume":"289","author":"Kuwajima","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"35","DOI":"10.18565\/cardio.2015.8.35-42","article-title":"Effects of Meldonium in Early Postmyocardial Infarction Period","volume":"55","author":"Nechaeva","year":"2015","journal-title":"Kardiologiia"},{"key":"ref_82","first-page":"39","article-title":"The use of mildronate in combined therapy of postinfarction chronic heart failure in patients with type 2 diabetes mellitus","volume":"85","author":"Statsenko","year":"2007","journal-title":"Klin. Med."},{"key":"ref_83","first-page":"10","article-title":"Effect of mildronate on life quality of patients with chronic heart failure","volume":"71","author":"Nedoshivin","year":"1999","journal-title":"Ter. Arkh."},{"key":"ref_84","unstructured":"Kuka, J. (2011). The Regulation of Carnitine System for Cardioprotection, R\u012bga Stradi\u0146\u0161 University."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.lfs.2008.08.008","article-title":"Mildronate decreases carnitine availability and up-regulates glucose uptake and related gene expression in the mouse heart","volume":"83","author":"Liepinsh","year":"2008","journal-title":"Life Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1177\/1074248411419502","article-title":"The cardioprotective effect of mildronate is diminished after co-treatment with L-carnitine","volume":"17","author":"Kuka","year":"2012","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1097\/01.fjc.0000250077.07702.23","article-title":"Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction","volume":"48","author":"Liepinsh","year":"2006","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1248\/bpb.23.770","article-title":"Effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on tissue carnitine and lipid levels in rats","volume":"23","author":"Hayashi","year":"2000","journal-title":"Biol. Pharm. Bull."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1111\/j.1476-5381.2009.00319.x","article-title":"Protective effects of mildronate in an experimental model of type 2 diabetes in Goto-Kakizaki rats","volume":"157","author":"Liepinsh","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"301","DOI":"10.3390\/medicina49070047","article-title":"Mildronate and its neuroregulatory mechanisms: Targeting the mitochondria, neuroinflammation, and protein expression","volume":"49","author":"Klusa","year":"2013","journal-title":"Medicina"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3390\/medicina47100079","article-title":"Mildronate as a regulator of protein expression in a rat model of Parkinson\u2019s disease","volume":"47","author":"Isajevs","year":"2011","journal-title":"Medicina"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4465","DOI":"10.3390\/ijms11114465","article-title":"Neuroprotective properties of mildronate, a small molecule, in a rat model of Parkinson\u2019s disease","volume":"11","author":"Klusa","year":"2010","journal-title":"Int. J. Mol. Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.neulet.2009.12.055","article-title":"Neuroprotective properties of mildronate, a mitochondria-targeted small molecule","volume":"470","author":"Pupure","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"525","DOI":"10.3390\/medicina48100077","article-title":"Search for stroke-protecting agents in endothelin-1-induced ischemic stroke model in rats","volume":"48","author":"Rumaks","year":"2012","journal-title":"Medicina"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"490","DOI":"10.18097\/PBMC20115705490","article-title":"The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rat streptozotocin-induced diabetes mellitus model","volume":"57","author":"Sokolovska","year":"2011","journal-title":"Biomed. Khim."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.pbb.2013.03.012","article-title":"Mildronate enhances learning\/memory and changes hippocampal protein expression in trained rats","volume":"106","author":"Klusa","year":"2013","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1136\/bjsports-2016-096357","article-title":"Story behind meldonium-from pharmacology to performance enhancement: A narrative review","volume":"51","author":"Schobersberger","year":"2017","journal-title":"Br. J. Sports Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bbr.2011.03.027","article-title":"Mildronate treatment improves functional recovery following middle cerebral artery occlusion in rats","volume":"222","author":"Svalbe","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ejphar.2013.12.006","article-title":"Mildronate, the inhibitor of L-carnitine transport, induces brain mitochondrial uncoupling and protects against anoxia-reoxygenation","volume":"723","author":"Makrecka","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.gene.2013.10.017","article-title":"L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders","volume":"533","author":"Ribas","year":"2014","journal-title":"Gene"},{"key":"ref_101","first-page":"32","article-title":"Antioxidant activity of mildronate and L-carnitine in the treatment of patients with cerebrovascular diseases","volume":"66","author":"Suslina","year":"2003","journal-title":"Eksp. Klin. Farmakol."},{"key":"ref_102","first-page":"77","article-title":"The efficacy of the mildronate treatment of patients with ischemic stroke","volume":"7","author":"Vinichuk","year":"1991","journal-title":"Vrach. Delo"},{"key":"ref_103","first-page":"98","article-title":"Use of mildronate for the treatment of patients with circulatory encephalopathy against a background of stenosis of major arteries of the head","volume":"5\u20136","author":"Dziak","year":"2003","journal-title":"Lik. Sprava"},{"key":"ref_104","first-page":"78","article-title":"Condition of the higher brain functions in patients with dyscirculatory encephalopathy treated with mildronate","volume":"2","author":"Abeuov","year":"2004","journal-title":"Meditsina"},{"key":"ref_105","first-page":"33","article-title":"Significance of mildronate for improvement of results of early rehabilitation results of neurological patients","volume":"12","author":"Vetra","year":"1999","journal-title":"Latv. Arstu Zurnals"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"131","DOI":"10.26641\/2307-0404.2018.2.133951","article-title":"Meldonium and neuroprotection. Theory, experiment and clinical practice","volume":"23","author":"Muslin","year":"2018","journal-title":"Med. Perspekt."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Soares, R.O.S., Losada, D.M., Jordani, M.C., Evora, P., and Castro, E.S.O. (2019). Ischemia\/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205034"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1111\/ajt.12187","article-title":"Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers","volume":"13","author":"Karimian","year":"2013","journal-title":"Am. J. Transplant."},{"key":"ref_109","first-page":"554","article-title":"Liver Regeneration-Related Cytokine Profiles in Donors and Recipients Before and After Living-Donor Liver Transplant","volume":"16","author":"Fingas","year":"2018","journal-title":"Exp. Clin. Transplant."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1002\/bjs.9035","article-title":"Systematic review and meta-analysis of the effect of perioperative steroids on ischaemia-reperfusion injury and surgical stress response in patients undergoing liver resection","volume":"100","author":"Orci","year":"2013","journal-title":"Br. J. Surg."},{"key":"ref_111","first-page":"432","article-title":"Effects of N-Acetylcysteine Addition to University of Wisconsin Solution on the Rate of Ischemia-Reperfusion Injury in Adult Orthotopic Liver Transplant","volume":"15","author":"Aliakbarian","year":"2017","journal-title":"Exp. Clin. Transplant."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"476","DOI":"10.2119\/2008-00034.Klune","article-title":"HMGB1: Endogenous danger signaling","volume":"14","author":"Klune","year":"2008","journal-title":"Mol. Med."},{"key":"ref_113","first-page":"1194","article-title":"Adenovirus-mediated bcl-2 gene transfer inhibits renal ischemia\/reperfusion induced tubular oxidative stress and apoptosis","volume":"5","author":"Chien","year":"2005","journal-title":"Am. J. Transplant."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1046\/j.1471-4159.2003.01756.x","article-title":"Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity","volume":"85","author":"Zhao","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Zahedi, K., Barone, S., and Soleimani, M. (2019). Polyamine Catabolism in Acute Kidney. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms20194790"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1742-7843.2009.00461.x","article-title":"Effects of long-term mildronate treatment on cardiac and liver functions in rats","volume":"105","author":"Liepinsh","year":"2009","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1089\/ars.2017.7342","article-title":"Transcriptional Regulation by Nrf2","volume":"29","author":"Tonelli","year":"2018","journal-title":"Antioxid. Redox Signal."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/2798\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:33:24Z","timestamp":1760160804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/2798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,10]]},"references-count":118,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22062798"],"URL":"https:\/\/doi.org\/10.3390\/ijms22062798","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,10]]}}}