{"doi":"10.1093/rpsppr/rqad013","title":"LP342, a novel histone deacetylase inhibitor, decreases nitro-oxidative stress, mitochondrial dysfunction and hepatic ischaemia/reperfusion injury in mice","abstract":"Abstract Objectives Some histone deacetylase (HDAC) isoforms contribute to ischaemia/reperfusion (IR) injury (IRI). Here, we examined whether LP342, the lead candidate of a new generation of hydrazide-based HDAC inhibitors (HDACi), decreases hepatic IRI. Methods IR was induced by clamping blood vessels to ~70% of the livers of mice for 1 h. Key findings At 6 h after reperfusion, ALT markedly increased, and wide-spread necrosis, leukocyte infiltration, and apoptosis occurred. LP342 treatment (1 mg/kg, ip) at 20 h or 1 h before ischaemia markedly decreased IRI whereas LP342 treatment upon reperfusion was marginally protective. Nitro-oxidative stress, c-Jun-N-terminal kinase (JNK) activation, and mitochondrial dysfunction contribute to IRI. 4-Hydroxynonenal, 3-nitrotyrosine, inducible nitric oxide synthase (iNOS), JNK activation and Sab binding increased markedly after IR, which LP342 blunted. LP342 also induced thioredoxin-1 expression before and after IR. LP342 also decreased mitochondrial depolarisation as detected by intravital microscopy at 2 h after IR. Lastly, LP342 increased acetylation of both histone-3 (class I HDAC substrate) and NFκB p65 but not tubulin (class II HDAC substrate) before and after IR. Conclusions This novel HDACi protects against IRI most likely by epigenetic upregulation of antioxidant proteins and post-translational modifications of NFκB thus inhibiting iNOS expression and inflammatory responses.","journal":"RPS Pharmacy and Pharmacology Reports","year":2023,"id":361968,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9633,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":594232,"name":"Yasodha Krishnasamy","orcid":null,"position":1,"is_corresponding":false},{"id":333548,"name":"Li Li","orcid":"0000-0002-7720-6731","position":2,"is_corresponding":false},{"id":342793,"name":"John J. Lemasters","orcid":"0000-0002-7627-6295","position":3,"is_corresponding":false},{"id":70878,"name":"C. James Chou","orcid":"0000-0001-6808-9089","position":4,"is_corresponding":false},{"id":593497,"name":"Zhi Zhong","orcid":"0000-0002-2377-0070","position":5,"is_corresponding":false},{"id":853810,"name":"Devadoss J. Samuvel","orcid":null,"position":0,"is_corresponding":true}],"reference_count":119,"raw_metadata":null,"created_at":"2026-07-19T01:14:15.063476Z","pmid":"37092117","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":[]}