Cardioprotective potential of a lanosteryl triterpene from Protorhus longifolia.

CONTEXT: The current rapid increase in the incidence of cardiovascular events indicates a need for the discovery of more effective cardioprotective agents. OBJECTIVE: This study evaluated the cardioprotective potential of a lanosteryl triterpene from Protorhus longifolia (Benrh.) Engl. stem bark. MATERIALS AND METHODS: Spectroscopic data analysis was used to confirm the structure of methyl-3ß-hydroxylanosta-9, 24-dien-21-oate (RA-3). The cardioprotective effect of RA-3 in isoproterenol-induced myocardial injury in hyperlipidemic rats was investigated. Rats were divided into the normal diet (ND) fed and high fat diet (HFD) fed groups. The HFD rats were further subdivided into three groups. The experimental group was orally administered with RA-3 (100 mg/kg) for 15 days. The rats were then injected with isoproterenol (85 mg/kg) to induce myocardial injury. At the end of the experiment, hearts and blood tissues were collected and used for histology and biochemical assays, respectively. RESULTS: RA-3 exhibited a cardioprotective effect as it minimized myocardial injury in HFD rats. Few lesions of acute hyaline degeneration and reduced fat deposition were observed in the heart tissue of the triterpene pretreated rats. Lactate dehydrogenase (LDH) activity was decreased in the blood of the RA-3 pretreated rats (44.1 mU/mL) compared to the untreated group (64.8 mU/mL). Increased glutathione (GSH) content and catalase (CAT) activity along with lower levels of malondialdehyde (MDA) in the triterpene pretreated animals (120.8 nmol/µL) than in the non-treated HFD fed rats (143.6 nmol/µL) were also observed. DISCUSSION AND CONCLUSION: The cardioprotective effect exhibited by RA-3 indicates its potential use in the management of cardiovascular diseases (CVD) and related health problems.

Hypermethylation at the CXCR5 gene locus limits trafficking potential of CD8+ T cells into B-cell follicles during HIV-1 infection.

CD8+ T cells play an important role in HIV control. However, in human lymph nodes (LNs), only a small subset of CD8+ T cells express CXCR5, the chemokine receptor required for cell migration into B-cell follicles, which are major sanctuaries for HIV persistence in individuals on therapy. Here, we investigate the impact of HIV infection on follicular CD8+ T cell (fCD8) frequencies, trafficking patterns, and CXCR5 regulation. We show that, although HIV infection results in a marginal increase in fCD8s in LNs, the majority of HIV-specific CD8+ T cells are CXCR5- (non-fCD8s) (P < .003). Mechanistic investigations using Assay for Transposase-Accessible Chromatin using sequencing showed that non-fCD8s have closed chromatin at the CXCR5 transcriptional start site (TSS). DNA bisulfite sequencing identified DNA hypermethylation at the CXCR5 TSS as the most probable cause of closed chromatin. Transcriptional factor footprint analysis revealed enrichment of transforming growth factors (TGFs) at the TSS of fCD8s. In vitro stimulation of non-fCD8s with recombinant TGF-ß resulted in a significant increase in CXCR5 expression (fCD8s). Thus, this study identifies TGF-ß signaling as a viable strategy for increasing fCD8 frequencies in follicular areas of the LN where they are needed to eliminate HIV-infected cells, with implications for HIV cure strategies.