Peroxisome proliferator-activated receptor-gamma: potential molecular therapeutic target for HIV-1-associated brain inflammation
Bibliographic record
Abstract
Despite the use of combination antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated brain inflammation. Primary cellular targets of HIV-1 in the brain are macrophages, microglia, and to a certain extent astrocytes which in response to infection release inflammatory markers, viral proteins [i.e., glycoprotein 120 (gp120)] and exhibit impaired glutamate uptake. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Compelling evidence suggests that PPARγ exerts anti-inflammatory properties in neurological disorders. The goal of this study was to examine the role of PPARγ in the context of HIV-1 ADA gp120-induced inflammation in vitro, in primary cultures of rat astrocytes and microglia, and in vivo, in a rodent model of HIV-1 ADA gp120-associated brain inflammation. Primary mixed cultures of rat astrocytes and microglia were treated with PPARγ agonists (rosiglitazone or pioglitazone) and exposed to HIV-1 ADA gp120. Inflammatory cytokines and indicator of oxidative stress response (TNFα, IL-1β, iNOS) were measured using qPCR, and glutamate transporter (GLT-1) was quantified by immunoblotting. In vivo, rats were administered an intracerebroventricular injection of HIV-1 ADA gp120 and an intraperitoneal injection of PPARγ agonist (rosiglitazone) or co-administration with PPARγ antagonist (GW9662). qPCR and immunoblotting analyses were applied to measure inflammatory markers, GLT-1 and PPARγ. In primary mixed cultures of rat astrocytes and microglia, HIV-1 ADA gp120 exposure resulted in a significant elevation of inflammatory markers and a decrease in GLT-1 expression which were significantly attenuated with rosiglitazone or pioglitazone treatment. Similarly, in vivo, treatment with rosiglitazone reversed the gp120-mediated inflammatory response and downregulation of GLT-1. Furthermore, we demonstrated that the anti-inflammatory effects of PPARγ agonist rosiglitazone were mediated through inhibition of NF-κB. Our data demonstrate that gp120 can induce an inflammatory response and decrease expression of GLT-1 in the brain in vitro and in vivo. We have also successfully shown that these effects can be reversed by treatment with PPARγ agonists, rosiglitazone or pioglitazone. Together our data suggest that targeting PPARγ signaling may provide an option for preventing/treating HIV-associated brain inflammation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".