Integrative Molecular Structure Elucidation and Construction of an Extended Metabolic Pathway Associated with an Ancient Innate Immune Response in COVID-19 Patients.

We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antiviral activities. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed a characteristic spin-system motif, indicating the presence of an extended panel of urinary metabolites during the acute viral replication phase. Mass spectrometry additionally enabled the characterization and quantification of the most abundant serum metabolites, showing the potential diagnostic value of the compounds for viral infections. In total, we unveiled ten nucleoside (cytosine- and uracil-based) analogue structures, eight of which were previously unknown in humans allowing us to propose a new extended viperin pathway for the innate production of antiviral compounds. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ, and IL-10, suggest an association with the viperin enzyme contributing to an ancient endogenous innate immune defense mechanism against viral infection.

Characterizing the plasma metabolome during 14 days of live-high, train-low simulated altitude: A metabolomic approach.

NEW FINDINGS: What is the central question of this study? Does 14 days of live-high, train-low simulated altitude alter an individual's metabolomic/metabolic profile? What is the main finding and its importance? This study demonstrated that ∼200 h of moderate simulated altitude exposure resulted in greater variance in measured metabolites between subject than within subject, which indicates individual variability during the adaptive phase to altitude exposure. In addition, metabolomics results indicate that altitude alters multiple metabolic pathways, and the time course of these pathways is different over 14 days of altitude exposure. These findings support previous literature and provide new information on the acute adaptation response to altitude. ABSTRACT: The purpose of this study was to determine the influence of 14 days of normobaric hypoxic simulated altitude exposure at 3000 m on the human plasma metabolomic profile. For 14 days, 10 well-trained endurance runners (six men and four women; 29 ± 7 years of age) lived at 3000 m simulated altitude, accumulating 196.4 ± 25.6 h of hypoxic exposure, and trained at ∼600 m. Resting plasma samples were collected at baseline and on days 3 and 14 of altitude exposure and stored at -80°C. Plasma samples were analysed using liquid chromatography-high-resolution mass spectrometry to construct a metabolite profile of altitude exposure. Mass spectrometry of plasma identified 36 metabolites, of which eight were statistically significant (false discovery rate probability 0.1) from baseline to either day 3 or day 14. Specifically, changes in plasma metabolites relating to amino acid metabolism (tyrosine and proline), glycolysis (adenosine) and purine metabolism (adenosine) were observed during altitude exposure. Principal component canonical variate analysis showed significant discrimination between group means (P < 0.05), with canonical variate 1 describing a non-linear recovery trajectory from baseline to day 3 and then back to baseline by day 14. Conversely, canonical variate 2 described a weaker non-recovery trajectory and increase from baseline to day 3, with a further increase from day 3 to 14. The present study demonstrates that metabolomics can be a useful tool to monitor metabolic changes associated with altitude exposure. Furthermore, it is apparent that altitude exposure alters multiple metabolic pathways, and the time course of these changes is different over 14 days of altitude exposure.

Effect of exercise on acute postprandial glucose concentrations and interleukin-6 responses in sedentary and overweight males.

This study examined the effect of 2 forms of exercise on glucose tolerance and the concurrent changes in markers associated with the interleukin (IL)-6 pathways. Fifteen sedentary, overweight males (29.0 ± 3.1 kg/m2) completed 2 separate, 3-day trials in randomised and counterbalanced order. An oral glucose tolerance test (OGTT; 75 g) was performed at the same time on each day of the trial. Day 2 of each trial consisted of a single 30-min workload-matched bout of either high-intensity intermittent exercise (HIIE; alternating 100% and 50% of peak oxygen uptake) or continuous moderate-intensity exercise (CME; 60 % of peak oxygen uptake) completed 1 h prior to the OGTT. Venous blood samples were collected before, immediately after, 1 h after, and 25 h after exercise for measurement of insulin, C-peptide, IL-6, and the soluble IL-6 receptors (sIL-6R; soluble glycoprotein 130 (sgp130)). Glucose area under the curve (AUC) was calculated from capillary blood samples collected throughout the OGTT. Exercise resulted in a modest (4.4%; p = 0.003) decrease in the glucose AUC when compared with the pre-exercise AUC; however, no differences were observed between exercise conditions (p = 0.65). IL-6 was elevated immediately after and 1 h after exercise, whilst sgp130 and sIL-6R concentrations were reduced immediately after exercise. In summary, exercise was effective in reducing glucose AUC, which was attributed to improvements that took place between 60 and 120 min into the OGTT, and was in parallel with an increased ratio of IL-6 to sIL-6R, which accords with an increased activation via the "classical" IL-6 signalling pathway. Our findings suggest that acute HIIE did not improve glycaemic response when compared with CME.