{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:47:42Z","timestamp":1785408462608,"version":"3.56.0"},"reference-count":43,"publisher":"Institute of Physiology of the Czech Academy of Sciences","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"abstract":"<jats:p>This study investigated how non-hepatic surgery and subsequent acute stress affect iron distribution, redox state, antioxidant defence, and inflammation-related gene expressions and iron metabolism in the liver of borderline hypertensive rats. We used air-jet stress as a model of acute psychological stress (3 sessions of 5 sec. air-jet) applied approximately 22 hours post-surgery (carotid artery and jugular vein cannulation). Both the surgery (Su) and post-surgical stress (Su+Str) increased corticosterone and reduced iron concentrations in plasma, while increasing remanent magnetisation (Mr) and coercivity (Hc) in whole blood. In the liver, Su and Su+Str reduced mRNA expressions of genes encoding NFR2 and GPX4 proteins (Nfe2l2 and Gpx4, respectively), and induced a significant increase in hepatic conjugated dienes, proinflammatory factors (Il1b) and iron-regulating genes mRNA (Hmox1, Fpn1, Fth1, Hamp, Tfr1), despite elevated Hmox1 and Sod1 mRNA expressions. In addition, hepatic Mr and Hc after Su and Su+Str were elevated, suggesting a qualitative change of iron-containing substances in circulation and liver tissue. In addition, in the Su+Str group, the elevated saturation magnetisation (Ms) is indicative of elevated total iron content. These findings suggest that a mild non-hepatic surgery may reduce hepatic mRNA expression of NRF2 and GPX4, which was associated with oxidative tissue damage accompanied by qualitative alterations in cellular iron, indicating a pro-ferroptotic state that, together with enhanced inflammation, may contribute to post-surgical liver injury. Additionally, the combination of surgery and acute post-surgical stress led to tissue iron accumulation, which may contribute to liver damage.<\/jats:p>","DOI":"10.33549\/physiolres.935716","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T20:05:59Z","timestamp":1768248359000},"page":"S271","source":"Crossref","is-referenced-by-count":1,"title":["Surgery and Acute Stress Decrease NRF2 mRNA Expression and Promote Iron Metabolism Alteration, Oxidative Stress, and Inflammatory Gene Expression in the Liver of Prehypertensive Rats"],"prefix":"10.33549","author":[{"given":"M","family":"Kluknavsky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Balis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Micurova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Skratek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Manka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Bernatova","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0380mmw63","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre of Experimental Medicine of the Slovak Academy of Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"ref0","doi-asserted-by":"crossref","unstructured":"1.\tIvascu R, Torsin LI, Hostiuc L, Nitipir C, Corneci D, Dutu M. The surgical stress response and anesthesia: a narrative review. J Clin Med 2024;13:3017. https:\/\/doi.org\/10.3390\/jcm13103017","DOI":"10.3390\/jcm13103017"},{"key":"ref1","doi-asserted-by":"crossref","unstructured":"2.\tWax DB, Porter SB, Lin HM, Hossain S, Reich DL. Association of preanesthesia hypertension with adverse outcomes. J Cardiothorac Vasc Anesth 2010;24:927-930. https:\/\/doi.org\/10.1053\/j.jvca.2010.06.022","DOI":"10.1053\/j.jvca.2010.06.022"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"3.\tEgan BM, Stevens-Fabry S. Prehypertension-prevalence, health risks, and management strategies. Nat Rev Cardiol 2015;12:289-300. https:\/\/doi.org\/10.1038\/nrcardio.2015.17","DOI":"10.1038\/nrcardio.2015.17"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"4.\tKluknavsky M, Balis P, Skratek M, Manka J, Bernatova I. (-)-Epicatechin reduces the blood pressure of young borderline hypertensive rats during the post-treatment period. Antioxidants 2020;9:96. https:\/\/doi.org\/10.3390\/antiox9020096","DOI":"10.3390\/antiox9020096"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"5.\t\u0160arenac O, Lozi\u0107 M, Drakuli\u0107 S, Baji\u0107 D, Paton JF, Murphy D, et al. Autonomic mechanisms underpinning the stress response in borderline hypertensive rats. Exp Physiol 2011;96:574-589. https:\/\/doi.org\/10.1113\/expphysiol.2010.055970","DOI":"10.1113\/expphysiol.2010.055970"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"6.\tZhao M, Chen J, Wang W, Wang L, Ma L, Shen H, et al. Psychological stress induces hypoferremia through the IL-6-hepcidin axis in rats. Biochem Biophys Res Commun 2008;373:90-93. https:\/\/doi.org\/10.1016\/j.bbrc.2008.05.166","DOI":"10.1016\/j.bbrc.2008.05.166"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"7.\tLi Y, Zheng Y, Qian J, Chen X, Shen Z, Tao L, et al. Preventive effects of zinc against psychological stress-induced iron dyshomeostasis, erythropoiesis inhibition, and oxidative stress status in rats. Biol Trace Elem Res 2012;147:285-291. https:\/\/doi.org\/10.1007\/s12011-011-9319-z","DOI":"10.1007\/s12011-011-9319-z"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"8.\tKasahara E, Nakamura A, Morimoto K, Ito S, Hori M, Sekiyama A. Social defeat stress impairs systemic iron metabolism by activating the hepcidin-ferroportin axis. FASEB Bioadv 2024;6:263-275. https:\/\/doi.org\/10.1096\/fba.2024-00071","DOI":"10.1096\/fba.2024-00071"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"9.\tHortov\u00e1-Kohoutkov\u00e1 M, Skot\u00e1kov\u00e1 M, Onyango IG, Slez\u00e1kov\u00e1 M, Panovsk\u00fd R, Opat\u0159il L, et al. Hepcidin and ferritin levels as markers of immune cell activation during septic shock, severe COVID-19 and sterile inflammation. Front Immunol 2023;14:1110540. https:\/\/doi.org\/10.3389\/fimmu.2023.1110540","DOI":"10.3389\/fimmu.2023.1110540"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"10.\tPiagnerelli M, Cotton F, Herpain A, Rapotec A, Chatti R, Gulbis B, et al. Time course of iron metabolism in critically ill patients. Acta Clin Belg 2013;68:22-27. https:\/\/doi.org\/10.2143\/ACB.68.1.2062715","DOI":"10.2143\/ACB.68.1.2062715"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"11.\tPagani A, Nai A, Silvestri L, Camaschella C. Hepcidin and anemia: a tight relationship. Front Physiol 2019;10:1294. https:\/\/doi.org\/10.3389\/fphys.2019.01294","DOI":"10.3389\/fphys.2019.01294"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"12.\tGensluckner S, Wernly B, Datz C, Aigner E. Iron, oxidative stress, and metabolic dysfunction-associated steatotic liver disease. Antioxidants 2024;13:208. https:\/\/doi.org\/10.3390\/antiox13020208","DOI":"10.3390\/antiox13020208"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"13.\tVnukov V, Gutsenko O, Milyutina N, Kornienko I, Ananyan A, Plotnikov A, et al. SkQ1 regulates expression of Nrf2, ARE-controlled genes encoding antioxidant enzymes, and their activity in cerebral cortex under oxidative stress. Biochemistry (Mosc) 2017;82:942-952. https:\/\/doi.org\/10.1134\/S0006297917080090","DOI":"10.1134\/S0006297917080090"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"14.\tTian X, Li Y, Lei L, Feng X, Xin H, Chen H, et al. The tf\/Nrf2\/GSTP1 pathway is involved in stress\u2010induced hepatocellular injury through ferroptosis. J Cell Mol Med 2024;28:e18494. https:\/\/doi.org\/10.1111\/jcmm.18494","DOI":"10.1111\/jcmm.18494"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"15.\tBehuliak M, Pint\u00e9rov\u00e1 M, Bencze M, Petrov\u00e1 M, L\u00ed\u0161kov\u00e1 S, Karen P, et al. Ca2+ sensitization and Ca2+ entry in the control of blood pressure and adrenergic vasoconstriction in conscious Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens 2013;31:2025-2035. https:\/\/doi.org\/10.1097\/HJH.0b013e328362adb3","DOI":"10.1097\/HJH.0b013e328362adb3"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"16.\tL\u00ed\u0161kov\u00e1 S, Bali\u0161 P, Mi\u010durov\u00e1 A, Kluknavsk\u00fd M, Okuliarov\u00e1 M, Puzserov\u00e1 A, et al. Effect of iron oxide nanoparticles on vascular function and nitric oxide production in acute stress-exposed rats. Physiol Res 2020;69:1067. https:\/\/doi.org\/10.33549\/physiolres.934567","DOI":"10.33549\/physiolres.934567"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"17.\tSong H, Zhang S, Sun X, Liu J, Wu Y, Guo W, et al. Distinct iron deposition profiles of liver zones in various models with iron homeostasis disorders. Adv Sci 2018;5:1800866. https:\/\/doi.org\/10.1002\/advs.201800866","DOI":"10.1002\/advs.201800866"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"18.\tPuzserova A, Slezak P, Balis P, Bernatova I. Long-term social stress induces nitric oxide-independent endothelial dysfunction in normotensive rats. Stress 2013;16:331-339. https:\/\/doi.org\/10.3109\/10253890.2012.725116","DOI":"10.3109\/10253890.2012.725116"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"19.\t\u0160kr\u00e1tek M, Dvure\u010denskij A, Kluknavsk\u00fd M, Barta A, Bali\u0161 P, Mi\u010durov\u00e1 A, et al. Sensitive SQUID bio-magnetometry for determination and differentiation of biogenic iron and iron oxide nanoparticles in biological samples. Nanomaterials 2020;10:1993. https:\/\/doi.org\/10.3390\/nano10101993","DOI":"10.3390\/nano10101993"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"20.\tKluknavsky M, Micurova A, Cebova M, \u015eaman E, Cacanyiova S, Bernatova I. MLN-4760 induces oxidative stress without blood pressure and behavioural alterations in SHRs: roles of Nfe2l2 gene, nitric oxide and hydrogen sulfide. Antioxidants 2022;11:2385. https:\/\/doi.org\/10.3390\/antiox11122385","DOI":"10.3390\/antiox11122385"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"21.\tD\u00edaz-Mu\u00f1oz M, V\u00e1zquez-Mart\u00ednez O, B\u00e1ez-Ruiz A, Mart\u00ednez-Cabrera G, Soto-Abraham MV, \u00c1vila-Casado MC, et al. Daytime food restriction alters liver glycogen, triacylglycerols, and cell size: a histochemical, morphometric, and ultrastructural study. Comp Hepatol 2010;9:5. https:\/\/doi.org\/10.1186\/1476-5926-9-5","DOI":"10.1186\/1476-5926-9-5"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"22.\tLarkin LM, Horwitz BA, McDonald RB. Effect of cold on serum substrate and glycogen concentration in young and old Fischer 344 rats. Exp Gerontol 1992;27:179-190. https:\/\/doi.org\/10.1016\/0531-5565(92)90042-X","DOI":"10.1016\/0531-5565(92)90042-X"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"23.\tBoshuizen M, Binnekade JM, Nota B, van de Groep K, Cremer OL, Tuinman PR, et al. Iron metabolism in critically ill patients developing anemia of inflammation: a case control study. Ann Intensive Care 2018;8:56. https:\/\/doi.org\/10.1186\/s13613-018-0407-5","DOI":"10.1186\/s13613-018-0407-5"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"24.\tCherry-Bukowiec JR, Engoren M, Wiktor A, Raghavendran K, Napolitano LM. Hepcidin and anemia in surgical critical care: a prospective cohort study. Crit Care Med 2018;46(6):e567-74. https:\/\/doi.org\/10.1097\/CCM.0000000000003089","DOI":"10.1097\/CCM.0000000000003089"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"25.\tStoffel NU, Lazrak M, Bellitir S, El Mir N, El Hamdouchi A, Barkat A, et al. The opposing effects of acute inflammation and iron deficiency anemia on serum hepcidin and iron absorption in young women. Haematologica 2019;104:1143. https:\/\/doi.org\/10.3324\/haematol.2018.208645","DOI":"10.3324\/haematol.2018.208645"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"26.\tTandara L, Salamuni\u0107 I. Iron metabolism: current facts and future directions. Biochem Med (Zagreb) 2012;22:311-28. https:\/\/doi.org\/10.11613\/BM.2012.034","DOI":"10.11613\/BM.2012.034"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"27.\tGrassi-Schultheiss P, Heller F, Dobson J. Analysis of magnetic material in the human heart, spleen and liver. Biometals 1997;10:351-355. https:\/\/doi.org\/10.1023\/A:1018340920329","DOI":"10.1023\/A:1018340920329"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"28.\tEverett J, Brooks J, Lermyte F, O'Connor PB, Sadler PJ, Dobson J, et al. Iron stored in ferritin is chemically reduced in the presence of aggregating A\u03b2(1-42). Sci Rep 2020;10:10332. https:\/\/doi.org\/10.1038\/s41598-020-67117-z","DOI":"10.1038\/s41598-020-67117-z"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"29.\tGong K, Liang K, Li H, Luo H, Chen Y, Yin K, et al. Oxidative ferritin destruction: a key mechanism of iron overload in acetaminophen-induced hepatocyte ferroptosis. Int J Mol Sci 2025;26:7585. https:\/\/doi.org\/10.3390\/ijms26157585","DOI":"10.3390\/ijms26157585"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"30.\tShivaswamy V, Ramakrishna Kurup C, Ramasarma T. Ferrous-iron induces lipid peroxidation with little damage to energy transduction in mitochondria. Mol Cell Biochem 1993;120:141-149. https:\/\/doi.org\/10.1007\/BF00926087","DOI":"10.1007\/BF00926087"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"31.\tLiu Y, Li F, Zhang L, Wu J, Wang Y, Yu H. Taurine alleviates lipopolysaccharide-induced liver injury by anti-inflammation and antioxidants in rats. Mol Med Rep 2017;16:6512-6517. https:\/\/doi.org\/10.3892\/mmr.2017.7414","DOI":"10.3892\/mmr.2017.7414"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"32.\tMalik IA, Naz N, Sheikh N, Khan S, Moriconi F, Blaschke M, et al. Comparison of changes in gene expression of transferrin receptor-1 and other iron-regulatory proteins in rat liver and brain during acute-phase response. Cell Tissue Res 2011;344:299-312. https:\/\/doi.org\/10.1007\/s00441-011-1152-3","DOI":"10.1007\/s00441-011-1152-3"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"33.\tChristiansen H, Sheikh N, Saile B, Reuter F, Rave-Frank M, Hermann RM, et al. X-irradiation in rat liver: consequent upregulation of hepcidin and downregulation of hemojuvelin and ferroportin-1 gene expression. Radiology 2007;242:189-197. https:\/\/doi.org\/10.1148\/radiol.2421060083","DOI":"10.1148\/radiol.2421060083"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"34.\tNaz N, Malik IA, Sheikh N, Ahmad S, Khan S, Blaschke M, et al. Ferroportin-1 is a 'nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins. Lab Invest 2012;92:842-856. https:\/\/doi.org\/10.1038\/labinvest.2012.52","DOI":"10.1038\/labinvest.2012.52"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"35.\tStockwell BR, Angeli JPF, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017;171:273-285. https:\/\/doi.org\/10.1016\/j.cell.2017.09.021","DOI":"10.1016\/j.cell.2017.09.021"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"36.\tChen HJC, Yip T, Lee JK, Juliani J, Sernia C, Hill AF, et al. Restraint stress alters expression of glucocorticoid bioavailability mediators, suppresses Nrf2, and promotes oxidative stress in liver tissue. Antioxidants 2020;9:853. https:\/\/doi.org\/10.3390\/antiox9090853","DOI":"10.3390\/antiox9090853"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"37.\tGe M, Yao W, Wang Y, Yuan D, Chi X, Luo G, et al. Propofol alleviates liver oxidative stress via activating Nrf2 pathway. J Surg Res 2015;196:373-381. https:\/\/doi.org\/10.1016\/j.jss.2015.03.016","DOI":"10.1016\/j.jss.2015.03.016"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"38.\tKwak MK, Itoh K, Yamamoto M, Kensler TW. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the Nrf2 promoter. Mol Cell Biol 2002;22:2883-2892. https:\/\/doi.org\/10.1128\/MCB.22.9.2883-2892.2002","DOI":"10.1128\/MCB.22.9.2883-2892.2002"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"39.\tChang CK, Llanes S, Schumer W. Effect of dexamethasone on NF-\u03baB activation, tumor necrosis factor formation, and glucose dyshomeostasis in septic rats. J Surg Res 1997;72:141-145. https:\/\/doi.org\/10.1006\/jsre.1997.5173","DOI":"10.1006\/jsre.1997.5173"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"40.\tGonz\u00e1lez MV, Jim\u00e9nez B, Berciano MT, Gonz\u00e1lez-Sancho JM, Caelles C, Lafarga M, et al. Glucocorticoids antagonize AP-1 by inhibiting the activation\/phosphorylation of JNK without affecting its subcellular distribution. J Cell Biol 2000;150:1199-1208. https:\/\/doi.org\/10.1083\/jcb.150.5.1199","DOI":"10.1083\/jcb.150.5.1199"},{"key":"ref40","doi-asserted-by":"crossref","unstructured":"41.\tSheikh N, Batusic DS, Dudas J, Tron K, Neubauer K, Saile B, et al. Hepcidin and hemojuvelin gene expression in rat liver damage: in vivo and in vitro studies. Am J Physiol Gastrointest Liver Physiol 2006;291:G482-G490. https:\/\/doi.org\/10.1152\/ajpgi.00586.2005","DOI":"10.1152\/ajpgi.00586.2005"},{"key":"ref41","doi-asserted-by":"crossref","unstructured":"42. Spiers JG, Steiger N, Khadka A, Juliani J, Hill AF, Lavidis NA, et al. Repeated acute stress modulates hepatic inflammation and markers of macrophage polarisation in the rat. Biochimie 2021;180:30-42. https:\/\/doi.org\/10.1016\/j.biochi.2020.10.014","DOI":"10.1016\/j.biochi.2020.10.014"},{"key":"ref42","doi-asserted-by":"crossref","unstructured":"43. Gong P, Cederbaum AI. Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1. Hepatology 2006;43:144-153. https:\/\/doi.org\/10.1002\/hep.21004","DOI":"10.1002\/hep.21004"}],"container-title":["Physiological Research"],"original-title":[],"deposited":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T20:06:04Z","timestamp":1768248364000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.biomed.cas.cz\/physiolres\/pdf\/2025\/74_S271.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,31]]},"references-count":43,"URL":"https:\/\/doi.org\/10.33549\/physiolres.935716","relation":{},"ISSN":["0862-8408","1802-9973"],"issn-type":[{"value":"0862-8408","type":"print"},{"value":"1802-9973","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,31]]}}}