{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:46:32Z","timestamp":1760060792987,"version":"build-2065373602"},"reference-count":69,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"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>Acute mesenteric ischemia (AMI) is a life-threatening condition characterised by oxidative stress, inflammation, apoptosis, and necrosis of intestinal epithelial cells. Different drugs with vasoactive, antioxidant, and anti-inflammatory properties have been used to treat AMI. Levosimendan is a drug with proven anti-ischemic effects used in the management of acute congestive heart failure. This study evaluated the protective effects of levosimendan pretreatment on intestinal, as well as lung, heart, and kidney tissue in a rat model of mesenteric artery ischemia\/reperfusion (I\/R) injury. Male Wistar rats (N = 24) were divided into four groups: control, I\/R, levosimendan (LS) 1 mg\/kg i.p, and LS + I\/R (1 mg\/kg i.p. 30 min before injury). I\/R by itself caused elevation of oxidative markers (thyobarbituric acid reactive species (TBARS), hydrogen peroxide (H2O2), super oxide anjon radical (O2\u2212), and nitrogen dioxide (NO2\u2212)), induced inflammation (macrophage infiltration and Interleukin-6 (IL-6) production), and apoptosis (nuclear factor kappa light-chain enhancer of activated B cells (NF-\u03baB), cleaved caspase-3 (CC3), and terminal deoxy-nucleotidyl transferase (TdT)-mediated dUTP nick end labelling (TUNEL)). Levosimendan pretreatment significantly reduced oxidative stress markers and enhanced antioxidant defences (catalase (CAT), reduced glutathione (GSH), and superoxide dismutase (SOD)). Histological analysis revealed reduced mucosal damage and preserved goblet cells in intestinal tissue. Similar protective effects of levosimendan were observed in other organs such as lung, heart, and kidney. Immunohistochemistry showed reduced epithelial apoptosis and upregulation of antioxidant and anti-inflammatory proteins. These findings highlight levosimendan\u2019s ability to protect mesenteric I\/R tissue injury and multi-organ damage by suppressing oxidative stress, inflammation, and apoptosis, emphasising its therapeutic potential in clinical settings.<\/jats:p>","DOI":"10.3390\/ijms26189131","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T10:08:58Z","timestamp":1758276538000},"page":"9131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Levosimendan Pretreatment Attenuates Mesenteric Artery Ischemia\/Reperfusion Injury and Multi-Organ Damage in Rats"],"prefix":"10.3390","volume":"26","author":[{"given":"Zoran","family":"Matkovi\u0107","sequence":"first","affiliation":[{"name":"Department of Surgery, General Hospital \u201cSveti Apostol Luka\u201d, 74000 Doboj, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8433-7808","authenticated-orcid":false,"given":"Milica","family":"Gaji\u0107 Boji\u0107","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7649-186X","authenticated-orcid":false,"given":"Uglje\u0161a","family":"Mali\u010devi\u0107","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Pathophysiology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Krivoku\u0107a","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Pathophysiology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1790-0729","authenticated-orcid":false,"given":"Neboj\u0161a","family":"Mandi\u0107-Kova\u010devi\u0107","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Pharmacy, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4219-5806","authenticated-orcid":false,"given":"Sne\u017eana","family":"Uletilovi\u0107","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Medical Biochemistry and Chemistry, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3436-1694","authenticated-orcid":false,"given":"Ljiljana","family":"Amid\u017ei\u0107","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Human Genetics, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8245-1405","authenticated-orcid":false,"given":"Sanja","family":"Jovi\u010di\u0107","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Histology and Embryology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9441-7569","authenticated-orcid":false,"given":"Maja","family":"Barud\u017eija","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Histology and Embryology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9431-0736","authenticated-orcid":false,"given":"Milo\u0161 P.","family":"Stojiljkovi\u0107","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radoslav","family":"Gajanin","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Pathology, University Clinical Centre of the Republic of Srpska, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Academy of Sciences and Arts of the Republic of Srpska, 78000 Banja Luka, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergej","family":"Bolevich","sequence":"additional","affiliation":[{"name":"Department of Pathologic Physiology, First Moscow State Medical University \u201cI.M. Sechenov\u201d, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6643-1781","authenticated-orcid":false,"given":"Ranko","family":"\u0160krbi\u0107","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Academy of Sciences and Arts of the Republic of Srpska, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department of Pathologic Physiology, First Moscow State Medical University \u201cI.M. Sechenov\u201d, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13017-015-0041-6","article-title":"Importance of emergency open surgery in the treatment of acute mesenteric ischemia","volume":"26","author":"Duran","year":"2015","journal-title":"World J. Emerg. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3243","DOI":"10.3748\/wjg.v12.i20.3243","article-title":"Update in management of mesenteric ischemia","volume":"12","author":"Chang","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/bjs.4459","article-title":"Systematic review of survival after acute mesenteric ischaemia according to disease aetiology","volume":"91","author":"Schoots","year":"2004","journal-title":"Br. J. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1001\/archinte.164.10.1054","article-title":"Acute mesenteric ischemia: A clinical review","volume":"164","author":"Oldenburg","year":"2004","journal-title":"Arch. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1159\/000508739","article-title":"Acute Mesenteric Ischemia","volume":"36","author":"Khun","year":"2020","journal-title":"Visc. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s00068-016-0634-0","article-title":"ESTES guidelines: Acute mesenteric ischaemia","volume":"42","author":"Tilsed","year":"2016","journal-title":"Eur. J. Trauma Emerg. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/j.2040-4603.2017.tb00741.x","article-title":"Ischemia\/reperfusion","volume":"7","author":"Kalogeris","year":"2016","journal-title":"Compr. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.drudis.2018.05.034","article-title":"Mesenteric ischemia-reperfusion: An overview of preclinical drug strategies","volume":"23","author":"Bertoni","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15327","DOI":"10.3748\/wjg.v20.i41.15327","article-title":"Intestinal ischemia-reperfusion of macaques triggers a strong innate immune response","volume":"20","author":"Wu","year":"2014","journal-title":"World J. Gastroenterol."},{"doi-asserted-by":"crossref","unstructured":"Badripour, A., Behzadi, M., Hassanipour, A., Azar, P.R.S., Rahbar, A., Abbaslou, Z., Ehghaghi, E., Piranviseh, A., Khavandi, M.M., and Ahmadi-Tafti, S.M. (2022). Albendazole ameliorates inflammatory response in a rat model of acute mesenteric ischemia reperfusion injury. Biomed. Pharmacother., 153.","key":"ref_10","DOI":"10.1016\/j.biopha.2022.113320"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13017-022-00443-x","article-title":"Acute mesenteric ischemia: Updated guidelines of the World Society for Emergency Surgery","volume":"17","author":"Bala","year":"2022","journal-title":"World J. Emerg. Surg."},{"doi-asserted-by":"crossref","unstructured":"Soares, R.O.S., Losada, D.M., Jordani, M.C., Evora, P., and Castro-E-Silva, O. (2019). Ischemia\/Reperfusion injury. Revisited an overview of latest Pharmacological Strategies. Int. J. Mol. Sci., 20.","key":"ref_12","DOI":"10.3390\/ijms20205034"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1211\/0022357001773715","article-title":"Comparison of the vasorelaxant effect of cromacalli and a new inodilator, levosimendan, in the isolated human portal vein","volume":"52","author":"Pataricza","year":"2000","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/sj.bjp.0706781","article-title":"The levosimendan metabolite OR-1896 induces vasodilation by activating K(ATP) and BK(Ca) channels in isolated rat arterioles","volume":"148","author":"Erdei","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"325","DOI":"10.3109\/08941939.2013.806615","article-title":"The effect of levosimendan in rat mesenteric ischemia\/reperfusion injury","volume":"26","author":"Polat","year":"2013","journal-title":"J. Investig. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s44158-022-00074-3","article-title":"The effect of postreperfusion levosimendan in an experimental intestinal ischemia-reperfusion model","volume":"2","author":"Aygun","year":"2022","journal-title":"J. Anesth. Analg. Crit. Care"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"137613","DOI":"10.1097\/00003246-199309000-00023","article-title":"Reperfusion injury after intestinal ischemia","volume":"21","author":"Schoenberg","year":"1993","journal-title":"Crit. Care Med."},{"key":"ref_18","first-page":"156","article-title":"Beneficial Pharmacological effects of Levosimendan on Antioxidant status of Acute Inflammation Induced in Paw of rat: Involvement in Inflammatory Mediators","volume":"112","author":"Karakus","year":"2013","journal-title":"BCPT"},{"key":"ref_19","first-page":"38","article-title":"Effect of Concentrated Apple Extract on Experimental Colitis Induced by Acetic Acid","volume":"6","author":"Pastrelo","year":"2017","journal-title":"Int. J. Mol. Cell. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"212","DOI":"10.21037\/atm-22-483","article-title":"Levosimendan protects from sepsis-inducing cardiac dysfunction by suppressing inflammation, oxidative stress and regulating cardiac mitophagy via the PINK-1-Parkin pathway in mice","volume":"10","author":"Shi","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.24976\/Discov.Med.202436186.135","article-title":"Levosimendan Ameliorates Hypoxia-Induced Brain Injury in Rats by Modulating PTEN\/Akt Signaling Pathway-Mediated Ferroptosis","volume":"36","author":"Meng","year":"2024","journal-title":"Discov. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1172\/JCI42917","article-title":"PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice","volume":"121","author":"Qiu","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_23","first-page":"G749","article-title":"Contributions of ischemia and reperfusion to mucosal lesion formation","volume":"250","author":"Parks","year":"1986","journal-title":"Am. J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00423-010-0727-x","article-title":"Intestinal ishemia\/reperfusion: Microcirculatory pathology and functional consequences","volume":"396","author":"Wolmar","year":"2011","journal-title":"Langenbeck\u2019s Arch. Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104431","DOI":"10.1016\/j.cdnut.2024.104431","article-title":"Glucosae- Stimulated mucus secretion by Goblet cells Mitigates Intestinal Barrier dysfunction in a rat model of Mesenteric Ischemia\/ reperfusion Injury","volume":"8","author":"Guo","year":"2024","journal-title":"Curr. Dev. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1136\/gutjnl-2011-301956","article-title":"Ischaemia-induced mucus barrier loss and bacterial penetration are rapidly counteracted by increased goblet cell secretory activity in human and rat colon","volume":"62","author":"Grootjans","year":"2013","journal-title":"Gut"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"232","DOI":"10.4161\/gmic.23866","article-title":"Goblet cell compound exocytosis in the defense against bacterial invasion in the colon exposed to ischemia-reperfusion","volume":"4","author":"Grootjans","year":"2013","journal-title":"Gut Microbes"},{"doi-asserted-by":"crossref","unstructured":"Shimada, M., Koyama, Y., Kobayashi, Y., Matsumoto, Y., Kobayashi, H., and Shimada, S. (2024). Si-based agent alleviated small bowel ischemia-reperfusion injury through antioxidant effects. Sci. Rep., 14.","key":"ref_28","DOI":"10.1038\/s41598-024-54542-7"},{"doi-asserted-by":"crossref","unstructured":"Agoston, D.V. (2017). How to translate time? The temporal aspect of human and rodent biology. Front. Neurol., 8.","key":"ref_29","DOI":"10.3389\/fneur.2017.00092"},{"key":"ref_30","first-page":"1731","article-title":"Transcription factors Nrf2 and NF-\u03baB contribute to inflammation and apoptosis induced by intestinal ischemia-reperfusion in mice","volume":"40","author":"Meng","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2182930","DOI":"10.1080\/08941939.2023.2182930","article-title":"The Effect of Antioxidant Astaxanthin on Intestinal Ischemia Reperfusion Damage in Rats","volume":"36","author":"Yilmaz","year":"2023","journal-title":"J. Investig. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13678","DOI":"10.18632\/oncotarget.14624","article-title":"Down-regulation of toll-like receptor 4 alleviates intestinal ischemia reperfusion injury and acute lung injury in mice","volume":"8","author":"Zhu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_33","first-page":"1783","article-title":"Upregulation of antioxidant nuclear factor erythroid 2-related factor 2 and its dependent genes associated with enhancing renal ischemic preconditioning renoprotection using levosimendan and cilostazol in an ischemia\/reperfusion rat model","volume":"17","author":"Tawfik","year":"2021","journal-title":"Arch. Med. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e508","DOI":"10.1097\/CCM.0000000000001269","article-title":"Anti-Inflammatory Profile of Levosimendan in Cecal Ligation-Induced Septic Mice and in Lipopolysaccharide-Stimulated Macrophages","volume":"43","author":"Wang","year":"2015","journal-title":"Crit. Care Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"20","DOI":"10.2174\/157489011794578482","article-title":"The protective effects of levosimendan on ischemia\/reperfusion injury and apoptosis","volume":"6","author":"Scheiermann","year":"2011","journal-title":"Recent Pat. Cardiovasc. Drug Discov."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1053\/j.jvca.2009.08.003","article-title":"Levosimendan attenuates reperfusion injury in an isolated perfused rat heart model","volume":"24","author":"Ozturk","year":"2010","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_37","first-page":"1353","article-title":"Protective effects elicited by levosimendan against liver ischemia\/reperfusion injury in anesthetized rats","volume":"19","author":"Grossini","year":"2013","journal-title":"Liver Transplant."},{"key":"ref_38","first-page":"485","article-title":"Cell-specific Activation of the Nrf2 Antioxidant Pathway Increases Mucosal Inflammation in Acute but Not in Chronic Colitis","volume":"11","author":"Gerstgrasser","year":"2017","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1146\/annurev-pharmtox-010818-021856","article-title":"Modulating NRF2 in Disease: Timing Is Everything","volume":"59","author":"Dodson","year":"2019","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1074\/jbc.M113.490920","article-title":"Modulation of nuclear factor E2-related factor-2 (Nrf2) activation by the stress response gene immediate early response-3 (IER3) in colonic epithelial cells: A novel mechanism of cellular adaption to inflammatory stress","volume":"289","author":"Stachel","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1104\/pp.19.00405","article-title":"Malondialdehyde: Facts and Artifacts","volume":"180","author":"Morales","year":"2019","journal-title":"Plant Physiol."},{"doi-asserted-by":"crossref","unstructured":"Ucar, B.I., Ucar, G., Saha, S., Buttari, B., Profumo, E., and Saso, L. (2021). Pharmacological Protection against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway. Antioxidants, 10.","key":"ref_42","DOI":"10.3390\/antiox10060823"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8081","DOI":"10.3748\/wjg.v21.i26.8081","article-title":"Ischemic preconditioning ameliorates intestinal injury induced by ischemia-reperfusion in rats","volume":"21","author":"Ji","year":"2015","journal-title":"World J. Gastroenterol."},{"doi-asserted-by":"crossref","unstructured":"O\u2019Rourke, S.A., Shanley, L.C., and Dunne, A. (2024). The Nrf2-HO-1 system and inflammaging. Front. Immunol., 15.","key":"ref_44","DOI":"10.3389\/fimmu.2024.1457010"},{"doi-asserted-by":"crossref","unstructured":"Gao, W., Guo, L., Yang, Y., Wang, Y., Xia, S., Gong, H., Zhang, B.K., and Yan, M. (2022). Dissecting the Crosstalk Between Nrf2 and NF-\u03baB Response Pathways in Drug-Induced Toxicity. Front. Cell Dev. Biol., 9.","key":"ref_45","DOI":"10.3389\/fcell.2021.809952"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"113429","DOI":"10.1016\/j.phytochem.2022.113429","article-title":"Antioxidant and anti-inflammation effects of dietary phytochemicals: The Nrf2\/NF-\u03baB signalling pathway and upstream factors of Nrf2","volume":"204","author":"Wu","year":"2022","journal-title":"Phytochemistry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bbadis.2016.11.005","article-title":"Nrf2 signaling pathway: Pivotal roles in inflammation","volume":"1863","author":"Ahmed","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"365","DOI":"10.7326\/0003-4819-149-5-200809020-00028","article-title":"Use of levosimendan for cardiogenic shock in patients with apical ballooning syndrome","volume":"149","author":"Vitale","year":"2008","journal-title":"Ann. Intern. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1097\/FJC.0b013e31819c9a17","article-title":"Effects of levosimendan on energy balance: Preclinical and clinical evidence","volume":"53","author":"Nieminen","year":"2009","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0014-2999(01)01350-4","article-title":"Levosimendan is an opener of mitochondrial K(ATP) channels","volume":"428","author":"Kopustinskiene","year":"2001","journal-title":"Eur. J. Pharmacol."},{"doi-asserted-by":"crossref","unstructured":"Adam, M., Meyer, S., Knors, H., Klinke, A., Radunski, U.K., Rudolph, T.K., Rudolph, V., Spin, J.M., Tsao, P.S., and Costard-J\u00e4ckle, A. (2015). Levosimendan shows anti-inflammatory effects and reduces the bioavailability of MPO in patients with severe heart failure. Sci. Rep., 5.","key":"ref_51","DOI":"10.1038\/srep09704"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1159\/000455950","article-title":"Levosimendan pretreatment inhibits myocardial apoptosis in pigs after coronary microembolization","volume":"41","author":"Wang","year":"2017","journal-title":"Cell Physiol. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1093\/bja\/aen367","article-title":"Pretreatment with levosimendan improves outcomes in patients undergoing coronary artery bypass graft surgery","volume":"102","author":"Tritapepe","year":"2009","journal-title":"Br. J. Anaesth."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.acthis.2008.09.010","article-title":"Effects of levosimendan and dobutamine on experimental acute lung injury in rats","volume":"111","author":"Vatansever","year":"2009","journal-title":"Acta Histochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.jss.2007.08.002","article-title":"Protective effects of levosimendan and iloprost on lung injury induced by limb ischemia-reperfusion: A rabbit model","volume":"147","author":"Yasa","year":"2008","journal-title":"J. Surg. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"577","DOI":"10.5606\/tgkdc.dergisi.2012.110","article-title":"Protective effects of cilostazol and levosimendan on lung injury induced by lower limb ischemia-reperfusion","volume":"20","author":"Aybek","year":"2012","journal-title":"Turk. J. Thorac. Cardiovasc. Surg."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"C22","DOI":"10.1093\/eurheartj\/sux002","article-title":"Pharmacological approaches to cardio-renal syndrome: The role of the inodilator levosimendan","volume":"19","author":"Fedele","year":"2017","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"F1453","DOI":"10.1152\/ajprenal.00485.2005","article-title":"Levosimendan protects against experimental endotoxemic acute renal failure","volume":"290","author":"Zager","year":"2006","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/0022-1759(80)90340-3","article-title":"A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture","volume":"38","author":"Pick","year":"1980","journal-title":"J. Immunol. Methods"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0003-2697(82)90118-X","article-title":"Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids","volume":"126","author":"Green","year":"1982","journal-title":"Anal. Biochem."},{"unstructured":"Greenwald, R.A. (1985). Nitroblue-tetrazolium reduction. Handbook of Methods for Oxygen Radical Research, CRC Press. [1st ed.].","key":"ref_61"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem."},{"unstructured":"Beutler, E. (1984). Red Cell Metabolism: A Manual of Biochemical Methods, Grune and Stratton. [3rd ed.].","key":"ref_63"},{"unstructured":"Beutler, E. (1982). Manual of Biochemical Methods, Grune and Stratton. [2nd ed.].","key":"ref_64"},{"key":"ref_65","first-page":"882","article-title":"Improved method for the determination of blood glutathione","volume":"61","author":"Beutler","year":"1963","journal-title":"J. Lab. Clin. Med."},{"doi-asserted-by":"crossref","unstructured":"Bajic, Z., Sobot, T., Amidzic, L., Vojinovic, N., Jovicic, S., Gajic Bojic, M., Djuric, D.M., Stojiljkovic, M.P., Bolevich, S., and Skrbic, R. (2024). Liraglutide Protects Cardiomyocytes against Isoprenaline-Induced Apoptosis in Experimental Takotsubo Syndrome. Biomedicines, 12.","key":"ref_66","DOI":"10.3390\/biomedicines12061207"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.colsurfb.2007.01.005","article-title":"Tissue-protective effects of fullerenol C60(OH)24 and amifostine in irradiated rats","volume":"58","year":"2007","journal-title":"Colloids. Surf. B Biointerfaces"},{"doi-asserted-by":"crossref","unstructured":"Ja\u0107evi\u0107, V., Nepovimova, E., and Ku\u010da, K. (2019). Acute Toxic Injuries of Rat\u2019s Visceral Tissues Induced by Different Oximes. Sci. Rep., 9.","key":"ref_68","DOI":"10.1038\/s41598-019-52768-4"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1007\/s00134-010-1811-y","article-title":"The Chiu\/Park scale for grading intestinal ischemia-reperfusion: If it ain\u2019t broke don\u2019t fix it!","volume":"36","author":"Oltean","year":"2010","journal-title":"Intensive Care Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9131\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:48:41Z","timestamp":1760035721000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,18]]},"references-count":69,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26189131"],"URL":"https:\/\/doi.org\/10.3390\/ijms26189131","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,9,18]]}}}