{"doi":"10.1016/j.redox.2023.103022","title":"The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury","abstract":"PURPOSE: Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells. EXPERIMENTAL DESIGN: Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI. RESULTS: Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI. CONCLUSIONS: Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation.","journal":"Redox Biology","year":2024,"id":421231,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9632,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":393435,"name":"Casey Pulliam","orcid":"0000-0002-1509-894X","position":1,"is_corresponding":false},{"id":343250,"name":"Ann Tomanek‐Chalkley","orcid":null,"position":2,"is_corresponding":false},{"id":948435,"name":"Prerna Rastogi","orcid":"0000-0001-9682-6365","position":3,"is_corresponding":false},{"id":49075,"name":"Hsiang Wen","orcid":null,"position":4,"is_corresponding":false},{"id":626037,"name":"Sanjana Dayal","orcid":"0000-0001-6156-2996","position":5,"is_corresponding":false},{"id":375947,"name":"Benjamin R. Griffin","orcid":"0000-0001-8599-5462","position":6,"is_corresponding":false},{"id":371821,"name":"Diana Zepeda‐Orozco","orcid":"0000-0003-0671-4453","position":7,"is_corresponding":false},{"id":407927,"name":"Amy L. Sindler","orcid":null,"position":8,"is_corresponding":false},{"id":382791,"name":"Carryn M. Anderson","orcid":"0000-0001-5036-8389","position":9,"is_corresponding":false},{"id":1214067,"name":"Robert C. Beardsley","orcid":null,"position":10,"is_corresponding":false},{"id":646169,"name":"Eugene P. Kennedy","orcid":"0009-0008-7418-3774","position":11,"is_corresponding":false},{"id":297605,"name":"Douglas R. Spitz","orcid":"0000-0002-1254-8765","position":12,"is_corresponding":false},{"id":393437,"name":"Bryan G. Allen","orcid":"0000-0002-4893-7105","position":13,"is_corresponding":false},{"id":297594,"name":"Kranti A. Mapuskar","orcid":"0000-0002-7311-7184","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T01:57:36.298171Z","pmid":"38215546","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}