{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:28:21Z","timestamp":1760059701686,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hungarian National Research, Development and Innovation Office (NKFI)","award":["ADVANCED 149858","SZTE\/SZGYA-5S864","5S774","5S775","7820"],"award-info":[{"award-number":["ADVANCED 149858","SZTE\/SZGYA-5S864","5S774","5S775","7820"]}]},{"name":"Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged","award":["ADVANCED 149858","SZTE\/SZGYA-5S864","5S774","5S775","7820"],"award-info":[{"award-number":["ADVANCED 149858","SZTE\/SZGYA-5S864","5S774","5S775","7820"]}]},{"name":"University of Szeged Open Access Fund","award":["ADVANCED 149858","SZTE\/SZGYA-5S864","5S774","5S775","7820"],"award-info":[{"award-number":["ADVANCED 149858","SZTE\/SZGYA-5S864","5S774","5S775","7820"]}]},{"name":"National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation","award":["ADVANCED 149858","SZTE\/SZGYA-5S864","5S774","5S775","7820"],"award-info":[{"award-number":["ADVANCED 149858","SZTE\/SZGYA-5S864","5S774","5S775","7820"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>This study aimed to characterize the time-dependent effects of methane (CH4) inhalation, initiated at defined intervals following sepsis onset, on organ function, systemic oxygen utilization, and mitochondrial respiration in a rodent model. Adult rats were subjected to abdominal sepsis or sham operation. Septic animals were assigned to groups receiving 2.2% CH4 in normoxic air at specific post-insult phases (early: 3\u20136 h; intermediate: 16\u201319 h; late: 19\u201322 h), while a control group remained untreated. At 24 h, organ function was evaluated using a Rat-Specific Organ Failure Assessment (ROFA) score, along with measurements of plasma myeloperoxidase (MPO) activity, Complex I\u2013II-linked oxidative phosphorylation in renal and cerebellar tissues, systemic oxygen extraction, and global tissue perfusion (pCO2-gap). Sepsis induced significant organ dysfunction, impaired hemodynamics, reduced oxygen utilization, and decreased mitochondrial respiration. CH4 inhalation improved survival when administered early, restored cerebellar mitochondrial respiration during the intermediate phase, and in the late phase reduced ROFA scores and MPO levels, while attenuating mitochondrial dysfunction in renal and cerebellar tissues. All CH4-treated groups demonstrated improved renal function and enhanced tissue oxygenation. Targeted CH4 inhalation during sepsis confers protective effects by preserving mitochondrial function, reducing inflammation, and improving oxygen dynamics, suggesting promising therapeutic potential.<\/jats:p>","DOI":"10.3390\/antiox14070814","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T06:46:12Z","timestamp":1751438772000},"page":"814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Time Matters: Methane Inhalation Mitigates Mitochondrial and Organ Dysfunction in Advanced Experimental Sepsis"],"prefix":"10.3390","volume":"14","author":[{"given":"Levente Frigyes","family":"Gul\u00e1csi","sequence":"first","affiliation":[{"name":"Institute of Surgical Research, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Attila","family":"Rutai","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5477-9572","authenticated-orcid":false,"given":"L\u00e1szl\u00f3","family":"Juh\u00e1sz","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00e1lint L\u00e1szl\u00f3","family":"Czak\u00f3","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3139-0235","authenticated-orcid":false,"given":"Andrea","family":"Szab\u00f3","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mih\u00e1ly","family":"Boros","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f3zsef","family":"Kaszaki","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4368-1275","authenticated-orcid":false,"given":"Marietta Zita","family":"Poles","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Szabolcs P\u00e9ter","family":"Tall\u00f3sy","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1186\/cc3753","article-title":"The microcirculation is the motor of sepsis","volume":"9","author":"Ince","year":"2005","journal-title":"Crit. Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"66","DOI":"10.4161\/viru.26907","article-title":"The role of mitochondrial dysfunction in sepsis-induced multi-organ failure","volume":"5","author":"Singer","year":"2014","journal-title":"Virulence"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"139","DOI":"10.5492\/wjccm.v12.i3.139","article-title":"Sepsis-induced mitochondrial dysfunction: A narrative review","volume":"12","author":"Nedel","year":"2023","journal-title":"World J. Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/BF01709751","article-title":"The SOFA (Sepsis-Related Organ Failure Assessment) score to describe organ dysfunction\/failure","volume":"22","author":"Vincent","year":"1996","journal-title":"Intensive Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.brainres.2015.04.062","article-title":"Sepsis-induced brain mitochondrial dysfunction is associated with altered mitochondrial Src and PTP1B levels","volume":"1620","author":"Lyu","year":"2015","journal-title":"Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.ccc.2020.11.010","article-title":"Sepsis-associated acute kidney injury","volume":"37","author":"Gomez","year":"2021","journal-title":"Crit. Care Clin."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhang, X., Agborbesong, E., and Li, X. (2021). The role of mitochondria in acute kidney injury and chronic kidney disease and its therapeutic potential. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222011253"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s13054-020-02950-2","article-title":"Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019: Results from a systematic review and meta-analysis","volume":"24","author":"Bauer","year":"2020","journal-title":"Crit. Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1097\/CCM.0000000000005017","article-title":"Current trends in sepsis-related mortality in the United States","volume":"49","author":"Prest","year":"2021","journal-title":"Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1093\/bja\/aev163","article-title":"Microcirculatory dysfunction and resuscitation: Why, when, and how","volume":"115","author":"Moore","year":"2015","journal-title":"Br. J. Anaesth."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/sur.2017.278","article-title":"Sepsis 2018: Definitions and guideline changes","volume":"19","author":"Napolitano","year":"2018","journal-title":"Surg. Infect."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Boros, M., and Keppler, F. (2019). Methane production and bioactivity \u2212 A link to oxido-reductive stress. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01244"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Juh\u00e1sz, L., Tall\u00f3sy, S.P., N\u00e1szai, A., Varga, G., \u00c9rces, D., and Boros, M. (2022). Bioactivity of inhaled CH4 and interactions with other biological gases. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.824749"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1912746","DOI":"10.1155\/2018\/1912746","article-title":"Methane medicine: A rising star gas with powerful anti-inflammation, antioxidant, and antiapoptosis properties","volume":"2018","author":"Jia","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4756846","DOI":"10.1155\/2018\/4756846","article-title":"Methane-rich saline ameliorates sepsis-induced acute kidney injury through anti-inflammation, antioxidative, and antiapoptosis effects by regulating endoplasmic reticulum stress","volume":"2018","author":"Jia","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e163","DOI":"10.1097\/SHK.0000000000001310","article-title":"Methane-rich saline protects against sepsis-induced liver damage by regulating the PPAR-\u03b3\/NF-\u03baB signaling pathway","volume":"52","author":"Li","year":"2019","journal-title":"Shock"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1097\/SHK.0000000000002586","article-title":"Methane administration during oxygenation mitigates acute kidney injury in a pig model of 24-h veno-venous extracorporeal membrane oxygenation","volume":"63","author":"Vida","year":"2025","journal-title":"Shock"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tall\u00f3sy, S.P., Poles, M.Z., Rutai, A., Fejes, R., Juh\u00e1sz, L., Buri\u00e1n, K., S\u00f3ki, J., Szab\u00f3, A., Boros, M., and Kaszaki, J. (2021). The microbial composition of the initial insult can predict the prognosis of experimental sepsis. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-02129-x"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/SHK.0000000000001212","article-title":"Minimum quality threshold in pre-clinical sepsis studies (MQTIPSS): An international expert consensus initiative for improvement of animal modeling in sepsis","volume":"50","author":"Osuchowski","year":"2018","journal-title":"Shock"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Juh\u00e1sz, L., Rutai, A., Fejes, R., Tall\u00f3sy, S.P., Poles, M.Z., Szab\u00f3, A., Szatm\u00e1ri, I., F\u00fcl\u00f6p, F., V\u00e9csei, L., and Boros, M. (2020). Divergent effects of the N-methyl-D-aspartate receptor antagonist kynurenic acid and the synthetic analog SZR-72 on microcirculatory and mitochondrial dysfunction in experimental sepsis. Front. Med., 7.","DOI":"10.3389\/fmed.2020.566582"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1159\/000179155","article-title":"Measurement of neutrophil content in brain and lung tissue by a modified myeloperoxidase assay","volume":"16","author":"Kuebler","year":"1996","journal-title":"Int. J. Microcirc. Clin. Exp."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.freeradbiomed.2018.03.024","article-title":"Reduction of nitrosative stress by CH4: Neuroprotection through xanthine oxidoreductase inhibition in a rat model of mesenteric ischemia-reperfusion","volume":"120","author":"Poles","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhang, X., Li, N., Shao, H., Meng, Y., Wang, L., Wu, Q., Yao, Y., Li, J., Bian, J., and Zhang, Y. (2016). Methane limits LPS-induced NF-\u03baB\/MAPKs signal in macrophages and suppresses immune response in mice by enhancing PI3K\/AKT\/GSK-3\u03b2-mediated IL-10 expression. Sci. Rep., 6.","DOI":"10.1038\/srep29359"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"148000","DOI":"10.1016\/j.brainres.2022.148000","article-title":"Methane-rich saline protects against sepsis-associated cognitive deficits in mice","volume":"1791","author":"Wang","year":"2022","journal-title":"Brain Res."},{"key":"ref_26","first-page":"844580","article-title":"The use of methylene blue in adult patients with septic shock: A systematic review and meta-analysis","volume":"75","author":"Ng","year":"2025","journal-title":"Braz. J. Anesthesiol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Alissa, A., Alrashed, M.A., Alshaya, A.I., Al Sulaiman, K., and Alharbi, S. (2024). Reevaluating vitamin C in sepsis and septic shock: A potential benefit in severe cases?. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1476242"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"349","DOI":"10.5492\/wjccm.v11.i6.349","article-title":"Current role of high dose vitamin C in sepsis management: A concise review","volume":"11","author":"Juneja","year":"2022","journal-title":"World J. Crit. Care Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1097\/CCM.0b013e31823dae05","article-title":"The anti-inflammatory effects of CH4","volume":"40","author":"Boros","year":"2012","journal-title":"Crit. Care Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.bbabio.2017.02.009","article-title":"NO control of mitochondrial function in normal and transformed cells","volume":"1858","author":"Tengan","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhang, B., Tian, X., Li, G., Zhao, H., Wang, X., Yin, Y., Yu, J., and Meng, C. (2021). Methane inhalation protects against lung ischemia-reperfusion injury in rats by regulating pulmonary surfactant via the Nrf2 pathway. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.615974"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1042\/bj3070433","article-title":"Methane-induced haemolysis of human erythrocytes","volume":"307","author":"Batliwala","year":"1995","journal-title":"Biochem. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1016\/j.bbamem.2016.04.016","article-title":"The cellular membrane as a mediator for small molecule interaction with membrane proteins","volume":"1858","author":"Mayne","year":"2016","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s12640-020-00270-5","article-title":"Sepsis and cerebral dysfunction: BBB damage, neuroinflammation, oxidative stress, apoptosis and autophagy as key mediators and the potential therapeutic approaches","volume":"39","author":"Gu","year":"2021","journal-title":"Neurotox. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1042\/CS20220549","article-title":"Neurochemical effects of sepsis on the brain","volume":"137","author":"Barichello","year":"2023","journal-title":"Clin. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.freeradbiomed.2016.12.014","article-title":"Methane ameliorates spinal cord ischemia-reperfusion injury in rats: Antioxidant, anti-inflammatory and anti-apoptotic activity mediated by Nrf2 activation","volume":"103","author":"Wang","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","first-page":"5030","article-title":"Mitochondrial mechanisms of sepsis-induced organ failure","volume":"13","author":"Exline","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/nrneph.2017.107","article-title":"Mitochondrial energetics in the kidney","volume":"13","author":"Bhargava","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s40635-025-00732-0","article-title":"Renal mitochondria response to sepsis: A sequential biopsy evaluation of experimental porcine model","volume":"13","author":"Chvojka","year":"2025","journal-title":"Intensive Care Med. Exp."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1016\/j.celrep.2015.02.034","article-title":"Tetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research","volume":"10","author":"Moullan","year":"2015","journal-title":"Cell Rep."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/7\/814\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:02:13Z","timestamp":1760032933000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/7\/814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,1]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["antiox14070814"],"URL":"https:\/\/doi.org\/10.3390\/antiox14070814","relation":{},"ISSN":["2076-3921"],"issn-type":[{"type":"electronic","value":"2076-3921"}],"subject":[],"published":{"date-parts":[[2025,7,1]]}}}