{"doi":"10.3390/ijms25063246","title":"Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages","abstract":"HIV-associated neurocognitive disorders (HAND) affect 15–55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain tissues of women with HAND. Increased CATB release from HIV-infected MDM leads to neurotoxicity, and their secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, CATB secretion, and neurotoxicity from HIV-infected MDM, but the mechanisms are not entirely understood. We hypothesized that HIV-1 infection upregulates the expression of proteins associated with oxidative stress and that a CB2R agonist could reverse these effects. MDM were isolated from healthy women donors (n = 3), infected with HIV-1ADA, and treated with JWH-133. After 13 days post-infection, cell lysates were labeled by Tandem Mass Tag (TMT) and analyzed by LC/MS/MS quantitative proteomics bioinformatics. While HIV-1 infection upregulated CATB, NF-κB signaling, Nrf2-mediated oxidative stress response, and lysosomal exocytosis, JWH-133 treatment downregulated the expression of the proteins involved in these pathways. Our results suggest that JWH-133 is a potential alternative therapy against HIV-induced neurotoxicity and warrant in vivo studies to test its potential against HAND.","journal":"International Journal of Molecular Sciences","year":2024,"id":434963,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"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":749613,"name":"Yadira M. Cantres-Rosario","orcid":"0000-0002-5794-9298","position":1,"is_corresponding":false},{"id":967820,"name":"Kelvin Carrasquillo","orcid":"0000-0001-7224-2349","position":2,"is_corresponding":false},{"id":1242140,"name":"Ana E. Rodríguez-De Jesús","orcid":null,"position":3,"is_corresponding":false},{"id":946801,"name":"Luz J. Cartagena-Isern","orcid":null,"position":4,"is_corresponding":false},{"id":946800,"name":"Luis A. García-Requena","orcid":null,"position":5,"is_corresponding":false},{"id":325122,"name":"Abiel Roche-Lima","orcid":"0000-0003-2246-6744","position":6,"is_corresponding":false},{"id":364788,"name":"Loyda M. Meléndez","orcid":"0000-0003-2571-8206","position":7,"is_corresponding":false},{"id":946363,"name":"Lester J. Rosario-Rodríguez","orcid":"0000-0003-1004-152X","position":0,"is_corresponding":true}],"reference_count":102,"raw_metadata":null,"created_at":"2026-07-19T01:59:58.582186Z","pmid":"38542221","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":[]}