Modulation of Human Hydrogen Sulfide Metabolism by Micronutrients, Preliminary Data

Background: Hydrogen sulfide (H2S) is a pivotal gasotransmitter networking with nitric oxide (NO) and carbon monoxide (CO) to regulate basic homeostatic functions. It is released by the alternative pathways of transulfuration by the enzymes Cystathionine Beta Synthase (CBS) and Cystathionine Gamma Lyase (CSE), and by Cysteine AminoTransferase (CAT)/ 3-Mercaptopyruvate Sulfur Transferase (3MPST). A non-enzymatic, intravascular release is also in place. We retrospectively investigated the possibility to modulate the endogenous H2S release and signaling in humans by a dietary manipulation with supplemented micronutrients (L-cystine, Taurine and pyridoxal 5-phopsphate/P5P). Methods: Patients referring for antiaging purposes underwent a 10-day supplementation. Blood was collected at baseline and after treatment and the metabolome was investigated by mass spectrometry to monitor the changes in the metabolites reporting on H2S metabolism and related pathways. Results: Data were available from 6 middle aged subjects (2 women). Micronutrients increased 3-mercaptopyruvate ( P = .03), reporting on the activity of CAT that provides the substrate for H2S release within mitochondria by 3MPST, decreased lanthionine ( P = .024), reporting the release of H2S from CBS, and had no significant effect of H2S release from CSE. This is compatible with a homeostatic balancing. We also recorded a strong increase of reporters of H2S-induced pathways including 5-MethylTHF ( P = .001) and SAME ( P = .022), reporting on methylation capacity, and of BH4 ( P = .021) and BH2 ( P = .028) reporting on nitric oxide metabolism. These activations may be explained by the concomitant induction of non-enzymatic release of H2S. Conclusions: Although the current evidences are weak and will need to be confirmed, the effect of micronutrients was compatible with an increase of the H2S endogenous release and signaling within the control of homeostatic mechanisms, further endorsing the role of feeding in health and disease. These effects might result in a H2S boosting effect in case of defective activity of pathologic origin, which should be checked in duly designed clinical trials.

EXPRESS: Metabolic Endophenotype Associated with Right Ventricular Glucose Uptake in Pulmonary Hypertension

Alterations in metabolism and bioenergetics are hypothesized in the mechanisms leading to pulmonary vascular remodeling and heart failure in pulmonary hypertension (PH). To test this, we performed metabolomic analyses on 30 PH individuals and 12 controls. Furthermore, using 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), we dichotomized PH patients into metabolic phenotypes of high and low right ventricle (RV) glucose uptake and followed them longitudinally. In support of metabolic alterations in PH and its progression, the high RV glucose group had higher RVSP (p < 0.001), worse RV function as measured by RV fractional area change and peak global longitudinal strain (both p < 0.05) and may be associated with poorer outcomes (33% death or transplantation in the high glucose RV uptake group compared to 7% in the low RV glucose uptake group at 5 years follow up, log-ranked p = 0.07). Pathway enrichment analysis identified key metabolic pathways including fructose catabolism, arginine-nitric oxide metabolism, tricarboxylic acid (TCA) cycle, and ketones metabolism. Integrative human protein-protein interactome network analysis of metabolomic and transcriptomic data identified key pathobiological pathways: arginine biosynthesis, TCA cycle, purine metabolism, hypoxia-inducible factor 1 and apelin signaling. These findings identify a PH metabolomic endophenotype, and for the first time link this to disease severity and outcomes.

Prevalence of IGFBP3, NOS3 and TCF7L2 polymorphisms and their association with hypertension: a population-based study with Brazilian women of African descent

Objective African ancestry seems to be a risk factor for hypertension; however, few genetic studies have addressed this issue. This study aimed to investigate the prevalence of polymorphisms NOS3; rs1799983, IGFBP3; rs11977526 and TCF7L2; rs7903146 in Brazilian women of African descent and their association with hypertension. Results The prevalences of the less frequent genotypes were 26.5% TT genotype of NOS3; rs1799983, 16.7% AA genotype of IGFBP3; rs11977526, and 18.3% TT genotype of TCF7L2; rs7903146. For these conditions, the prevalence of hypertension and PR (adjusted) relatively to the ancestral genotype were, respectively: 52.0% vs 24.5% (PR = 1.54; p < 0.001), 62.0% vs 24.1% (PR = 1.59; p < 0.001), and 38.9% vs 27.9% (PR = 0.86; p = 0.166). Associations with hypertension were statistically significant, except for the TCF7L2; rs7903146 polymorphism, after adjusted analysis. Brazilian Afro-descendant women with the TT genotype for the NOS3 gene and the AA genotype for the IGFBP3 gene are more susceptible to hypertension. The understanding of underlying mechanisms involving the pathogenesis of hypertension can motivate research for the development of new therapeutic targets related to nitric oxide metabolism and the management of oxidative stress.

Ocular growth and metabolomics are dependent upon the spectral content of ambient white light

Myopia results from an excessive axial growth of the eye, causing abnormal projection of remote images in front of the retina. Without adequate interventions, myopia is forecasted to affect 50% of the world population by 2050. Exposure to outdoor light plays a critical role in preventing myopia in children, possibly through the brightness and blue-shifted spectral composition of sunlight, which lacks in artificial indoor lighting. Here, we evaluated the impact of moderate levels of ambient standard white (SW: 233.1 lux, 3900 K) and blue-enriched white (BEW: 223.8 lux, 9700 K) lights on ocular growth and metabolomics in a chicken-model of form-deprivation myopia. Compared to SW light, BEW light decreased aberrant ocular axial elongation and accelerated recovery from form-deprivation. Furthermore, the metabolomic profiles in the vitreous and retinas of recovering form-deprived eyes were distinct from control eyes and were dependent on the spectral content of ambient light. For instance, exposure to BEW light was associated with deep lipid remodeling and metabolic changes related to energy production, cell proliferation, collagen turnover and nitric oxide metabolism. This study provides new insight on light-dependent modulations in ocular growth and metabolomics. If replicable in humans, our findings open new potential avenues for spectrally-tailored light-therapy strategies for myopia.