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- Title
Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages.
- Authors
Rosario-Rodríguez, Lester J.; Cantres-Rosario, Yadira M.; Carrasquillo-Carrión, Kelvin; Rodríguez-De Jesús, Ana E.; Cartagena-Isern, Luz J.; García-Requena, Luis A.; Roche-Lima, Abiel; Meléndez, Loyda M.
- 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.
- Subjects
OXIDATIVE stress; PROTEOMICS; EXOCYTOSIS; CANNABINOID receptors; CATHEPSIN B; HIV-positive persons
- Publication
International Journal of Molecular Sciences, 2024, Vol 25, Issue 6, p3246
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms25063246