RESUMO
Neurological complications of AIDS (NeuroAIDS) include primary HIV-associated neurocognitive disorder (HAND). OAS3 is an enzyme belonging to the 2', 5' oligoadenylate synthase family induced by type I interferons and involved in the degradation of both viral and endogenous RNA. Here, we used microarray datasets from NCBI of brain samples of non-demented HIV-negative controls (NDC), HIV, deceased patients with HAND and encephalitis (HIVE) (treated and untreated with antiretroviral therapy, ART), and with HAND without HIVE. The HAND/HIVE patients were stratified according to the OAS3 gene expression. The genes positively and negatively correlated to the OAS3 gene expression were used to perform a genomic deconvolution analysis using neuroimmune signatures (NIS) belonging to sixteen signatures. Expression analysis revealed significantly higher OAS3 expression in HAND/HIVE and HAND/HIVE/ART compared with NDC. OAS3 expressed an excellent diagnostic ability to discriminate NDC from HAND/HIVE, HAND from HAND/HIVE, HAND from HAND/HIVE/ART, and HIV from HAND/HIVE. Noteworthy, OAS3 expression levels in the brains of HAND/HIVE patients were positively correlated with viral load in both peripheral blood and cerebrospinal fluid (CSF). Furthermore, deconvolution analysis revealed that the genes positively correlated to OAS3 expression were associated with inflammatory signatures. Neuronal activation profiles were significantly activated by the genes negatively correlated to OAS3 expression levels. Moreover, gene ontology analysis performed on genes characterizing the microglia signature highlighted an immune response as a main biological process. According to our results, genes positively correlated to OAS3 gene expression in the brains of HAND/HIVE patients are associated with inflammatory transcriptomic signatures and likely worse cognitive impairment.
Assuntos
Infecções por HIV , HIV , Humanos , HIV/genética , HIV/metabolismo , Transcriptoma , Infecções por HIV/complicações , Encéfalo/metabolismo , Transtornos Neurocognitivos/complicações , Transtornos Neurocognitivos/metabolismo , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismoRESUMO
We have previously shown that amylin has a protective effect upon the damaged rat gastric mucosa via a cytokine-mediated mechanism. Here, the effects of amylin on the proapoptotic cytokine TNF-related-apoptosis-inducing-ligand (TRAIL) were tested in the rat gastric mucosa damaged by reserpine administration in vivo. Intraperitoneal administration of reserpine in adult male Sprague-Dawley rats resulted in increased TRAIL expression in the gastric mucosa. Immunohistochemistry showed that the TRAIL death-receptor 5 (DR5) was constitutively expressed by the mucosa cells. Western blot showed that pretreatment of reserpine-treated rats with amylin was associated with attenuated expression of TRAIL. In the same samples, we also investigated about TRAIL-related signaling and observed that activation of caspases-8 and -3 occurs in parallel to increased TRAIL expression in rats treated with reserpine. Similarly to the latter, activation of caspases was attenuated in rats pretreated with amylin. Treatment with reserpine was associated with increased expression of the proapoptotic protein Bax, whereas that of the antiapoptotic protein Bcl-2 was significantly decreased. Amylin prevented the effects of reserpine on these genes. Reserpine sets into motion mechanisms of apoptosis in the rat gastric mucosa, which appear mediated, at least in part, by TRAIL. In addition, TRAIL downstream signaling is activated along with subversion of gene expression related to apoptosis. Amylin was able to prevent detrimental effects of reserpine. Finally, amylin and related molecules may be envisioned as protective agent in gastric mucosa damage.