Dehydroepiandrosterone promotes pulmonary artery relaxation by NADPH oxidation-elicited subunit dimerization of protein kinase G 1α

The activity of glucose-6-phosphate dehydrogenase (G6PD) controls a vascular smooth muscle relaxing mechanism promoted by the oxidation of cytosolic NADPH, which has been associated with activation of the 1α form of protein kinase G (PKG-1α) by a thiol oxidation-elicited subunit dimerization. This PKG-1α-activation mechanism appears to contribute to responses of isolated endothelium-removed bovine pulmonary arteries (BPA) elicited by peroxide, cytosolic NADPH oxidation resulting from G6PD inhibition, and hypoxia. Dehydroepiandrosterone (DHEA) is a steroid hormone with pulmonary vasodilator activity, which has beneficial effects in treating pulmonary hypertension. Because multiple mechanisms have been suggested for the vascular effects of DHEA and one of the known actions of DHEA is inhibiting G6PD, we investigated whether it promoted relaxation associated with NADPH oxidation, PKG-1α dimerization, and PKG activation detected by increased vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Relaxation of BPA to DHEA under aerobic or hypoxic conditions was associated with NADPH oxidation, PKG-1α dimerization, and increased VASP phosphorylation. The vasodilator activity of DHEA was markedly attenuated in pulmonary arteries and aorta from a PKG knockin mouse containing a serine in place of a cysteine involved in PKG dimerization. DHEA promoted increased PKG dimerization in lungs from wild-type mice, which was not detected in the PKG knockin mouse model. Thus PKG-1α dimerization is a major contributing factor to the vasodilator actions of DHEA and perhaps its beneficial effects in treating pulmonary hypertension

Low Neuroactive Steroids Identifies a Biological Subtype of Depression in Adults with Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy

AbstractBackgroundThe prevalence and mortality risk of depression in people with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. In the current study, we aimed to identify plasma metabolites associated with depressive symptoms in people with HIV receiving ART.MethodsThis is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores. Plasma metabolite profiling was performed in 2 independent cohorts (total n = 99) using liquid and gas chromatography and tandem mass spectrometry.ResultsParticipants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate [DHEA-S], androstenediols, and pregnenolone sulfate) compared with those without depressive symptoms. The cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (P &amp;lt; .01) because of low DHEA-S levels, whereas cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios (adjusted odds ratio, 2.5 per 1-unit increase in z score; 95% confidence interval, 1.3–4.7), independent of age and sex. The kynurenine-to-tryptophan ratio showed no significant associations.ConclusionsThese findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiological mechanisms of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting.</jats:sec

Low Neuroactive Steroids Identifies a Biological Subtype of Depression in Adults with Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy.

BackgroundThe prevalence and mortality risk of depression in people with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. In the current study, we aimed to identify plasma metabolites associated with depressive symptoms in people with HIV receiving ART.MethodsThis is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores. Plasma metabolite profiling was performed in 2 independent cohorts (total n = 99) using liquid and gas chromatography and tandem mass spectrometry.ResultsParticipants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate [DHEA-S], androstenediols, and pregnenolone sulfate) compared with those without depressive symptoms. The cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (P &lt; .01) because of low DHEA-S levels, whereas cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios (adjusted odds ratio, 2.5 per 1-unit increase in z score; 95% confidence interval, 1.3-4.7), independent of age and sex. The kynurenine-to-tryptophan ratio showed no significant associations.ConclusionsThese findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiological mechanisms of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting

Circadian rhythm reprogramming during lung inflammation

Circadian rhythms are known to regulate immune responses in healthy animals, but it is unclear whether they persist during acute illnesses where clock gene expression is disrupted by systemic inflammation. Here, we use a genome-wide approach to investigate circadian gene and metabolite expression in the lungs of endotoxemic mice and find that novel cellular and molecular circadian rhythms are elicited in this setting. The endotoxin-specific circadian program exhibits unique features, including a divergent group of rhythmic genes and metabolites compared to the basal state and a distinct periodicity and phase distribution. At the cellular level endotoxin treatment also alters circadian rhythms of leukocyte counts within the lung in a bmal1-dependent manner, such that granulocytes rather than lymphocytes become the dominant oscillating cell type. Our results show that inflammation produces a complex reorganization of cellular and molecular circadian rhythms that are relevant to early events in lung injury