{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T06:59:58Z","timestamp":1771484398881,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T00:00:00Z","timestamp":1663891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH-NIDDK","award":["P30 DK079337"],"award-info":[{"award-number":["P30 DK079337"]}]},{"name":"NIH-NIDDK","award":["R01 DK059600"],"award-info":[{"award-number":["R01 DK059600"]}]},{"name":"NIH-NIDDK","award":["R01 DK118932"],"award-info":[{"award-number":["R01 DK118932"]}]},{"name":"NIH-NIDDK","award":["T32 DK116672"],"award-info":[{"award-number":["T32 DK116672"]}]},{"name":"Alabama Drug Discovery Alliance","award":["P30 DK079337"],"award-info":[{"award-number":["P30 DK079337"]}]},{"name":"Alabama Drug Discovery Alliance","award":["R01 DK059600"],"award-info":[{"award-number":["R01 DK059600"]}]},{"name":"Alabama Drug Discovery Alliance","award":["R01 DK118932"],"award-info":[{"award-number":["R01 DK118932"]}]},{"name":"Alabama Drug Discovery Alliance","award":["T32 DK116672"],"award-info":[{"award-number":["T32 DK116672"]}]},{"name":"PRIME","award":["P30 DK079337"],"award-info":[{"award-number":["P30 DK079337"]}]},{"name":"PRIME","award":["R01 DK059600"],"award-info":[{"award-number":["R01 DK059600"]}]},{"name":"PRIME","award":["R01 DK118932"],"award-info":[{"award-number":["R01 DK118932"]}]},{"name":"PRIME","award":["T32 DK116672"],"award-info":[{"award-number":["T32 DK116672"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase \u00bd level. We identified small-molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and yet-undefined effects of the enzyme system. Through cell-based, high-throughput screens for induction of HO-1 driven by the human HO-1 promoter\/enhancer, we identified two novel small molecules and broxaldine (an FDA-approved drug) for further consideration as candidate compounds exhibiting an Emax \u226570% of 5 \u00b5M hemin and EC50 &lt;10 \u00b5M. RNA sequencing identified shared binding motifs to NRF2, a transcription factor known to regulate antioxidant genes, including HMOX1. In vitro, the cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of a candidate compound induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small-molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI.<\/jats:p>","DOI":"10.3390\/antiox11101888","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T21:14:28Z","timestamp":1664140468000},"page":"1888","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of Cytoprotective Small-Molecule Inducers of Heme-Oxygenase-1"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5089-7176","authenticated-orcid":false,"given":"Gelare","family":"Ghajar-Rahimi","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA"},{"name":"Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA"},{"name":"Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amie M.","family":"Traylor","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA"},{"name":"Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bini","family":"Mathew","sequence":"additional","affiliation":[{"name":"Southern Research, Birmingham, AL 35205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James R.","family":"Bostwick","sequence":"additional","affiliation":[{"name":"Southern Research, Birmingham, AL 35205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N Miranda","family":"Nebane","sequence":"additional","affiliation":[{"name":"Southern Research, Birmingham, AL 35205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna A.","family":"Zmijewska","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA"},{"name":"Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie K.","family":"Esman","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA"},{"name":"Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saakshi","family":"Thukral","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA"},{"name":"Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Zhai","sequence":"additional","affiliation":[{"name":"Southern Research, Birmingham, AL 35205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijaya","family":"Sambandam","sequence":"additional","affiliation":[{"name":"Southern Research, Birmingham, AL 35205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita M.","family":"Cowell","sequence":"additional","affiliation":[{"name":"Southern Research, Birmingham, AL 35205, USA"},{"name":"Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark J.","family":"Suto","sequence":"additional","affiliation":[{"name":"Southern Research, Birmingham, AL 35205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James F.","family":"George","sequence":"additional","affiliation":[{"name":"Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA"},{"name":"Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corinne E.","family":"Augelli-Szafran","sequence":"additional","affiliation":[{"name":"Southern Research, Birmingham, AL 35205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anupam","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA"},{"name":"Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA"},{"name":"Department of Veterans Affairs, Birmingham, AL 35233, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1681\/ASN.V115965","article-title":"Renal response to tissue injury: Lessons from heme oxygenase-1 GeneAblation and expression","volume":"11","author":"Agarwal","year":"2000","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/sj.ki.5001565","article-title":"Heme oxygenase-1: A provenance for cytoprotective pathways in the kidney and other tissues","volume":"70","author":"Nath","year":"2006","journal-title":"Kidney Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1097\/01.mnh.0000437613.88158.d3","article-title":"Heme oxygenase-1 and acute kidney injury","volume":"23","author":"Nath","year":"2014","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1681\/ASN.2010030238","article-title":"Heme oxygenase-1 inhibits renal tubular macroautophagy in acute kidney injury","volume":"21","author":"Bolisetty","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.1681\/ASN.2014080770","article-title":"Heme Oxygenase-1 Regulates Myeloid Cell Trafficking in AKI","volume":"26","author":"Hull","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Stec, D.E., and Hinds, T.D. (2020). Natural Product Heme Oxygenase Inducers as Treatment for Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249493"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2009.04.007","article-title":"Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease","volume":"47","author":"Morse","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1089\/ars.2016.6659","article-title":"Heme Oxygenase-1 in Kidney Health and Disease","volume":"25","author":"Lever","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1046\/j.1523-1755.2001.00471.x","article-title":"Heme protein-induced chronic renal inflammation: Suppressive effect of induced heme oxygenase-1","volume":"59","author":"Nath","year":"2001","journal-title":"Kidney Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1046\/j.1523-1755.2000.00101.x","article-title":"Renal response to repetitive exposure to heme proteins: Chronic injury induced by an acute insult","volume":"57","author":"Nath","year":"2000","journal-title":"Kidney Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.2215\/CJN.00710113","article-title":"Acute Kidney Injury Advisory Group of the American Society of Nephrology: World incidence of AKI: A meta-analysis","volume":"8","author":"Susantitaphong","year":"2013","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16476","DOI":"10.1074\/jbc.M109.058586","article-title":"Sp1 regulates chromatin looping between an intronic enhancer and distal promoter of the human heme oxygenase-1 gene in renal cells","volume":"285","author":"Deshane","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"F515","DOI":"10.1152\/ajprenal.00137.2003","article-title":"An internal enhancer regulates heme- and cadmium-mediated induction of human heme oxygenase-1","volume":"285","author":"Sikorski","year":"2003","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6875","DOI":"10.1074\/jbc.M608456200","article-title":"JunB and JunD regulate human heme oxygenase-1 gene expression in renal epithelial cells","volume":"282","author":"Hock","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"F385","DOI":"10.1152\/ajprenal.00335.2015","article-title":"Proximal tubule-targeted heme oxygenase-1 in cisplatin-induced acute kidney injury","volume":"310","author":"Bolisetty","year":"2016","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e125503","DOI":"10.1172\/jci.insight.125503","article-title":"Resident macrophages reprogram toward a developmental state after acute kidney injury","volume":"4","author":"Lever","year":"2019","journal-title":"JCI Insight"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1126\/science.1105136","article-title":"The ENCODE (ENCyclopedia Of DNA Elements) Project","volume":"306","author":"Consortium","year":"2004","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Consortium, E.P. (2011). A user\u2019s guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol., 9.","DOI":"10.1371\/journal.pbio.1001046"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1093\/bioinformatics\/btq466","article-title":"ChEA: Transcription factor regulation inferred from integrating genome-wide ChIP-X experiments","volume":"26","author":"Lachmann","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R., and Ma\u2019ayan, A. (2013). Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-128"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e90","DOI":"10.1002\/cpz1.90","article-title":"Gene Set Knowledge Discovery with Enrichr","volume":"1","author":"Xie","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_24","first-page":"2515","article-title":"Tetrazolium-based assays for cellular viability: A critical examination of selected parameters affecting formazan production","volume":"51","author":"Vistica","year":"1991","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4423","DOI":"10.1172\/JCI67867","article-title":"Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury","volume":"123","author":"Zarjou","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1172\/JCI115847","article-title":"Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat","volume":"90","author":"Nath","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1007\/s00018-016-2223-0","article-title":"Role of Nrf2\/HO-1 system in development, oxidative stress response and diseases: An evolutionarily conserved mechanism","volume":"73","author":"Loboda","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"F726","DOI":"10.1152\/ajprenal.2000.278.5.F726","article-title":"Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis","volume":"278","author":"Shiraishi","year":"2000","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1038\/ki.1995.414","article-title":"Induction of heme oxygenase in toxic renal injury: A protective role in cisplatin nephrotoxicity in the rat","volume":"48","author":"Agarwal","year":"1995","journal-title":"Kidney Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1046\/j.1523-1755.1998.00731.x","article-title":"Intracellular targets in heme protein-induced renal injury","volume":"53","author":"Nath","year":"1998","journal-title":"Kidney Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1046\/j.1523-1755.2001.01000.x","article-title":"Cytoprotective role of heme oxygenase (HO)-1 in human kidney with various renal diseases","volume":"60","author":"Morimoto","year":"2001","journal-title":"Kidney Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1681\/ASN.2011121147","article-title":"Plasma and urinary heme oxygenase-1 in AKI","volume":"23","author":"Zager","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/pr.2015.44","article-title":"Genetic Polymorphisms of Heme-oxygenase 1 (HO-1) may Impact on Acute Kidney Injury, Bronchopulmonary Dysplasia and Mortality in Premature Infants","volume":"77","author":"Askenazi","year":"2015","journal-title":"Pediatr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1111\/j.1600-6143.2004.00420.x","article-title":"Fundamental role for HO-1 in the self-protection of renal allografts","volume":"4","author":"Baan","year":"2004","journal-title":"Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1681\/ASN.2016010038","article-title":"Length Polymorphisms in Heme Oxygenase-1 and AKI after Cardiac Surgery","volume":"27","author":"Leaf","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.bbrc.2007.05.207","article-title":"Erythropoietin induces heme oxygenase-1 expression and attenuates oxidative stress","volume":"359","author":"Katavetin","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1097\/01.shk.0000091205.08003.fd","article-title":"Delayed administration of alpha-melanocyte-stimulating hormone or combined therapy with BAY 11-7085 protects against gut ischemia-reperfusion injury","volume":"20","author":"Zou","year":"2003","journal-title":"Shock"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.4049\/jimmunol.174.4.2297","article-title":"In vitro and in vivo induction of heme oxygenase 1 in mouse macrophages following melanocortin receptor activation","volume":"174","author":"Lam","year":"2005","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/nm0302-240","article-title":"Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice","volume":"8","author":"Lee","year":"2002","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1172\/JCI23056","article-title":"Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury","volume":"115","author":"Mori","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"613249","DOI":"10.1155\/2015\/613249","article-title":"Carbon Monoxide Inhibits Tenascin-C Mediated Inflammation via IL-10 Expression in a Septic Mouse Model","volume":"2015","author":"Uddin","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/74680","article-title":"Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway","volume":"6","author":"Otterbein","year":"2000","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1111\/j.0954-6820.1978.tb14903.x","article-title":"Transitory renal failure following rapid administration of a relatively large amount of hematin in a patient with acute intermittent porphyria in clinical remission","volume":"203","author":"Dhar","year":"1978","journal-title":"Acta Med. Scand."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1016\/j.freeradbiomed.2005.11.020","article-title":"Carbon monoxide, oxidative stress, and mitochondrial permeability pore transition","volume":"40","author":"Piantadosi","year":"2006","journal-title":"Free Radic. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"F425","DOI":"10.1152\/ajprenal.00297.2003","article-title":"The story so far: Molecular regulation of the heme oxygenase-1 gene in renal injury","volume":"286","author":"Sikorski","year":"2004","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5933","DOI":"10.1128\/MCB.25.14.5933-5946.2005","article-title":"Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1","volume":"25","author":"Yang","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Yang, C.C., Hsiao, L.D., Wang, C.Y., Lin, W.N., Shih, Y.F., Chen, Y.W., Cho, R.L., Tseng, H.C., and Yang, C.M. (2022). HO-1 Upregulation by Kaempferol via ROS-Dependent Nrf2-ARE Cascade Attenuates Lipopolysaccharide-Mediated Intercellular Cell Adhesion Molecule-1 Expression in Human Pulmonary Alveolar Epithelial Cells. Antioxidants, 11.","DOI":"10.3390\/antiox11040782"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1042\/BJ20090339","article-title":"Human haem oxygenase-1 induction by nitro-linoleic acid is mediated by cAMP, AP-1 and E-box response element interactions","volume":"422","author":"Wright","year":"2009","journal-title":"Biochem. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7","DOI":"10.15430\/JCP.2022.27.1.7","article-title":"Non-canonical vs. Canonical Functions of Heme Oxygenase-1 in Cancer","volume":"27","author":"Jagadeesh","year":"2022","journal-title":"J. Cancer Prev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s00134-009-1723-x","article-title":"Histopathology of septic shock induced acute kidney injury: Apoptosis and leukocytic infiltration","volume":"36","author":"Lerolle","year":"2010","journal-title":"Intensiv. Care Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1186\/s13054-018-2287-3","article-title":"Kidney histopathology in lethal human sepsis","volume":"22","author":"Aslan","year":"2018","journal-title":"Crit. Care"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1681\/ASN.2010050484","article-title":"Sepsis and acute kidney injury","volume":"22","author":"Zarjou","year":"2011","journal-title":"J. Am. Soc. Nephrol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/10\/1888\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:38:26Z","timestamp":1760143106000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/10\/1888"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,23]]},"references-count":52,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["antiox11101888"],"URL":"https:\/\/doi.org\/10.3390\/antiox11101888","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,23]]}}}