Association Between Alcohol Consumption and Blood Pressure Levels Among HIV Sero-Positive and Sero-Negative Cohorts: A Secondary Analysis of the Vukuzazzi Study.

BACKGROUND: The effect of hypertension is aggravated by lifestyle factors such as alcohol consumption. This study sought to determine the association between alcohol consumption and the level of blood pressures among HIV seronegative and seropositive cohorts. METHODS: This secondary analysis was performed on a cross-sectional survey data of 17 922 participants during the period between 2018 and 2020. A questionnaire was used to obtain participants' alcohol consumption history, which was categorized into non-alcohol consumers, non-heavy alcohol consumers, and heavy alcohol consumers. A linear regression model was used to establish relationships among participants with raised blood pressure (BP ≥ 140/90 mmHg). RESULTS: Out of the total participants, 3553 (19.82%) were hypertensives. Almost 13% of the hypertensives (n = 458; 12.89%) were undiagnosed, and 12.44 % (442) had uncontrolled hypertension. About 14.52% of the hypertensives (3553) were not on any antihypertensive medication. Male non-consumers of alcohol had the highest systolic and diastolic BP; uncontrolled systolic BP (165.53 ± 20.87 mmHg), uncontrolled diastolic BP (102.28 ± 19.21mmHg). Adjusted for covariates, moderate alcohol consumption was associated with HTN among participants who were HIV seropositive [unadjusted (RR = 1.772, P = .006, 95% CI (1.178-2.665)], [RR = 1.772, P = .005, 95% CI (1.187-2.64)]. [unadjusted RR = 1.876, P = .036, 95% CI (1.043-3.378)], adjusted RR = 1.876, P = .041, 95% CI (1.024-3.437). Both moderate and heavy alcohol consumption were significantly related to hypertension among HIV sero-negative [unadjusted model, moderate consumption RR = 1.534 P = .003, 95% CI (1.152-2.044)], [adjusted model, moderate alcohol consumption RR = 1.535, P = .006, 95% CI (1.132-2.080)], [unadjusted model, heavy alcohol consumption, RR = 2.480, P = .030, 95% CI (1.091-5.638)], [adjusted model RR = 2.480, P = .034, 95% CI (1.072-5.738)]. CONCLUSION: Alcohol consumption is significantly related to increase BP regardless of HIV infection.

A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway.

BAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also control several signaling processes including proteostasis, apoptosis, and transcription. The largest isoform, BAG1L, controls the activity of the androgen receptor (AR) and is upregulated in prostate cancer. Here, we show that BAG1L regulates AR dynamics in the nucleus and its ablation attenuates AR target gene expression especially those involved in oxidative stress and metabolism. We show that a small molecule, A4B17, that targets the BAG domain downregulates AR target genes similar to a complete BAG1L knockout and upregulates the expression of oxidative stress-induced genes involved in cell death. Furthermore, A4B17 outperformed the clinically approved antagonist enzalutamide in inhibiting cell proliferation and prostate tumor development in a mouse xenograft model. BAG1 inhibitors therefore offer unique opportunities for antagonizing AR action and prostate cancer growth.

Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer.

Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.