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.

Blood pressure interactions with the DASH dietary pattern, sodium, and potassium: The International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP).

BACKGROUND: Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet enhances potassium intake and reduces sodium intake and blood pressure (BP), but the underlying metabolic pathways are unclear. OBJECTIVES: Among free-living populations, we delineated metabolic signatures associated with the DASH diet adherence, 24-hour urinary sodium and potassium excretions, and the potential metabolic pathways involved. METHODS: We used 24-hour urinary metabolic profiling by proton nuclear magnetic resonance spectroscopy to characterize the metabolic signatures associated with the DASH dietary pattern score (DASH score) and 24-hour excretion of sodium and potassium among participants in the United States (n = 2164) and United Kingdom (n = 496) enrolled in the International Study of Macro- and Micronutrients and Blood Pressure (INTERMAP). Multiple linear regression and cross-tabulation analyses were used to investigate the DASH-BP relation and its modulation by sodium and potassium. Potential pathways associated with DASH adherence, sodium and potassium excretion, and BP were identified using mediation analyses and metabolic reaction networks. RESULTS: Adherence to the DASH diet was associated with urinary potassium excretion (correlation coefficient, r = 0.42; P < 0.0001). In multivariable regression analyses, a 5-point higher DASH score (range, 7 to 35) was associated with a lower systolic BP by 1.35 mmHg (95% CI, -1.95 to -0.80 mmHg; P = 1.2 × 10-5); control of the model for potassium but not sodium attenuated the DASH-BP relation. Two common metabolites (hippurate and citrate) mediated the potassium-BP and DASH-BP relationships, while 5 metabolites (succinate, alanine, S-methyl cysteine sulfoxide, 4-hydroxyhippurate, and phenylacetylglutamine) were found to be specific to the DASH-BP relation. CONCLUSIONS: Greater adherence to the DASH diet is associated with lower BP and higher potassium intake across levels of sodium intake. The DASH diet recommends greater intake of fruits, vegetables, and other potassium-rich foods that may replace sodium-rich processed foods and thereby influence BP through overlapping metabolic pathways. Possible DASH-specific pathways are speculated but confirmation requires further study. INTERMAP is registered as NCT00005271 at www.clinicaltrials.gov.

Characterization of metabolic responses to healthy diets and association with blood pressure: application to the Optimal Macronutrient Intake Trial for Heart Health (OmniHeart), a randomized controlled study.

Background: Interindividual variation in the response to diet is common, but the underlying mechanism for such variation is unclear. Objective: The objective of this study was to use a metabolic profiling approach to identify a panel of urinary metabolites representing individuals demonstrating typical (homogeneous) metabolic responses to healthy diets, and subsequently to define the association of these metabolites with improvement of risk factors for cardiovascular diseases (CVDs). Design: 24-h urine samples from 158 participants with pre-hypertension and stage 1 hypertension, collected at baseline and following the consumption of a carbohydrate-rich, a protein-rich, and a monounsaturated fat-rich healthy diet (6 wk/diet) in a randomized, crossover study, were analyzed by proton (1H) nuclear magnetic resonance (NMR) spectroscopy. Urinary metabolite profiles were interrogated to identify typical and variable responses to each diet. We quantified the differences in absolute excretion of metabolites, distinguishing between dietary comparisons within the typical response groups, and established their associations with CVD risk factors using linear regression. Results: Globally all 3 diets induced a similar pattern of change in the urinary metabolic profiles for the majority of participants (60.1%). Diet-dependent metabolic variation was not significantly associated with total cholesterol or low-density lipoprotein (LDL) cholesterol concentration. However, blood pressure (BP) was found to be significantly associated with 6 urinary metabolites reflecting dietary intake [proline-betaine (inverse), carnitine (direct)], gut microbial co-metabolites [hippurate (direct), 4-cresyl sulfate (inverse), phenylacetylglutamine (inverse)], and tryptophan metabolism [N-methyl-2-pyridone-5-carboxamide (inverse)]. A dampened clinical response was observed in some individuals with variable metabolic responses, which could be attributed to nonadherence to diet (≤25.3%), variation in gut microbiome activity (7.6%), or a combination of both (7.0%). Conclusions: These data indicate interindividual variations in BP in response to dietary change and highlight the potential influence of the gut microbiome in mediating this relation. This approach provides a framework for stratification of individuals undergoing dietary management. The original OmniHeart intervention study and the metabolomics study were registered at www.clinicaltrials.gov as NCT00051350 and NCT03369535, respectively.

Medicine-related services in community pharmacy: public preferences for pharmacy attributes and promotional methods and comparison with pharmacists' perceptions.

BACKGROUND: Public awareness of pharmacy services designed to support the use of medicines is low, yet little is known about how the public view promotion of these services, or their preferences for the attributes of pharmacies from which they would like to receive them. OBJECTIVE: To compare the public's preferred attributes of pharmacies and methods for promoting medicine-related services with community pharmacists' perceptions of their customers' views. METHODS: Parallel surveys were conducted in South East England, using a street survey for the general public and a postal survey for community pharmacists. RESULTS: Response rates were as follows: public 47.2% (1,000/2,012) and pharmacists 40.8% (341/836). Pharmacists' perceptions of customer preferences for using the same pharmacy, independent ownership, and personal knowledge of the pharmacist were higher than actual public preferences. More pharmacists than public respondents also believed that approachability and previous good service would be important. The public's desires for long opening hours and for a pharmacy with a good relationship with their doctor's surgery were higher than pharmacists believed. The majority of the public prefer not to interrupt a pharmacist who is busy in the dispensary, which was not perceived by pharmacists as a factor. Pharmacists' perceptions aligned more with the preferences of regular medicine users and frequent pharmacy users. Both groups viewed direct recommendation as the most effective approach for promoting pharmacy services, particularly by doctors and pharmacy staff. Pharmacists' expectations of the effectiveness of posters and mass media methods were much higher than those of the public. CONCLUSION: Pharmacists and pharmacy owners must ensure good relationships with local medical practices to enable them to maximize opportunities for using the promotional methods judged most effective in encouraging the use of medicine-related services. Staff must be approachable and enable access to pharmacists, ensuring that perceptions of pharmacist busyness are not a deterrent.