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Abstract The hormonal decline during menopause increases women's risk of chronic diseases. D-limonene, a monoterpene found in the human diet, possesses biological properties related to hypolipemic, antioxidant, anti-inflammatory, and gut microbiota-modulating activities, primarily observed in preclinical studies. Postprandial responses include physiological adaptations to the stress of a nutrient surplus, providing an opportunity to assess metabolic resilience, being a suitable strategy for exploring post-menopause-associated metabolic alterations. Here, we investigated the effects of D-limonene supplementation (2 g/day) on postprandial metabolism in postmenopausal women (n = 9) challenged with a standardized mixed meal in a 3-week single-arm clinical study. Our findings revealed that D-limonene did not induce marked differences in postprandial responses to the dietary challenge. The supplementation with D-limonene induced no alterations in serum lipid/lipoprotein profile or glycemia/insulinemia. D-limonene supplementation did not affect the transient postprandial inflammatory response regarding changes in gene expression of peripheral blood mononuclear cells (PBMC) and circulating inflammatory markers. Nevertheless, D-limonene reduced postprandial levels of lithocholic acid, a gut microbiota-derived bile acid, and regulated the plasma concentrations of selected amino acids, carbohydrate metabolism-derived metabolites, and organic acids. In conclusion, our data do not support the claim that short-term D-limonene supplementation beneficially affects the postprandial metabolism of postmenopausal women. Graphical Abstract

Food intake triggers extensive changes in the blood metabolome. The kinetics of these changes depend on meal composition and on intrinsic, health-related characteristics of each individual, making the assessment of changes in the postprandial metabolome an opportunity to assess someone's metabolic status. To enable the usage of dietary challenges as diagnostic tools, profound knowledge about changes that occur in the postprandial period in healthy individuals is needed. In this study, we characterize the time-resolved changes in plasma levels of 634 metabolites in response to an oral glucose tolerance test (OGTT), an oral lipid tolerance test (OLTT), and a mixed meal (SLD) in healthy young males (n = 15). Metabolite levels for samples taken at different time points (20 per individual) during the challenges were available from targeted (132 metabolites) and non-targeted (502 metabolites) metabolomics. Almost half of the profiled metabolites (n = 308) showed a significant change in at least one challenge, thereof 111 metabolites responded exclusively to one particular challenge. Examples include azelate, which is linked to ω-oxidation and increased only in OLTT, and a fibrinogen cleavage peptide that has been linked to a higher risk of cardiovascular events in diabetes patients and increased only in OGTT, making its postprandial dynamics a potential target for risk management. A pool of 89 metabolites changed their plasma levels during all three challenges and represents the core postprandial response to food intake regardless of macronutrient composition. We used fuzzy c-means clustering to group these metabolites into eight clusters based on commonalities of their dynamic response patterns, with each cluster following one of four primary response patterns: (i) “decrease-increase” (valley-like) with fatty acids and acylcarnitines indicating the suppression of lipolysis, (ii) “increase-decrease” (mountain-like) including a cluster of conjugated bile acids and the glucose/insulin cluster, (iii) “steady decrease” with metabolites reflecting a carryover from meals prior to the study, and (iv) “mixed” decreasing after the glucose challenge and increasing otherwise. Despite the small number of subjects, the diversity of the challenges and the wealth of metabolomic data make this study an important step toward the characterization of postprandial responses and the identification of markers of metabolic processes regulated by food intake.

Abstract We propose herein a mathematical model to predict the COVID-19 evolution and evaluate the impact of governmental decisions on this evolution, attempting to explain the long duration of the pandemic in the 26 Brazilian states and their capitals well as in the Federative Unit. The prediction was performed based on the growth rate of new cases in a stable period, and the graphics plotted with the significant governmental decisions to evaluate the impact on the epidemic curve in each Brazilian state and city. Analysis of the predicted new cases was correlated with the total number of hospitalizations and deaths related to COVID-19. Because Brazil is a vast country, with high heterogeneity and complexity of the regional/local characteristics and governmental authorities among Brazilian states and cities, we individually predicted the epidemic curve based on a specific stable period with reduced or minimal interference on the growth rate of new cases. We found good accuracy, mainly in a short period (weeks). The most critical governmental decisions had a significant temporal impact on pandemic curve growth. A good relationship was found between the predicted number of new cases and the total number of inpatients and deaths related to COVID-19. In summary, we demonstrated that interventional and preventive measures directly and significantly impact the COVID-19 pandemic using a simple mathematical model. This model can easily be applied, helping, and directing health and governmental authorities to make further decisions to combat the pandemic.

In recent years, bile acids (BA) have received great interest due to their pleiotropic biological activity and the presence of plasma membrane-bound and nuclear receptors. Moreover, BA in blood have been identified by metabolite screening approaches as biomarkers that are associated with various diseases and even with a human longevity phenotype. With the growing interest in the microbiota contribution to the health-disease trajectory, BA that undergo deconjugation and other modifications by bacteria in the large intestine have become a prime target as a microbiome diversity modifier. We here profiled BA by a quantitative and a semiquantitative approach in 15 healthy and phenotypically very similar young individuals for over a 36-h fasting period, an oral glucose tolerance test (OGTT), and an oral lipid tolerance test (OLTT). We demonstrate a remarkable heterogeneity of the responses and describe the different dynamics of the plasma changes that likely originate from different routes by which BA enters the peripheral blood, and that may represent a direct secretion from the liver into the blood and a route that reaches the blood as a spill-over after passing from the gallbladder through the intestine and the portal system. We discuss the finding that an individual transport process involved in the passage of BA could be a critical determinant in the kinetics of plasma appearance and the overall phenotypic variability found.

Insulin secretion following ingestion of a carbohydrate load affects a multitude of metabolic pathways that simultaneously change direction and quantity of interorgan fluxes of sugars, lipids and amino acids. In the present study, we aimed at identifying markers associated with differential responses to an OGTT a population of healthy adults. By use of three metabolite profiling platforms, we assessed these postprandial responses of a total of 202 metabolites in plasma of 72 healthy volunteers undergoing comprehensive phenotyping and of which half enrolled into a weight-loss program over a three-month period. A standard oral glucose tolerance test (OGTT) served as dietary challenge test to identify changes in postprandial metabolite profiles. Despite classified as healthy according to WHO criteria, two discrete clusters (A and B) were identified based on the postprandial glucose profiles with a balanced distribution of volunteers based on gender and other measures. Cluster A individuals displayed 26% higher postprandial glucose levels, delayed glucose clearance and increased fasting plasma concentrations of more than 20 known biomarkers of insulin resistance and diabetes previously identified in large cohort studies. The volunteers identified by canonical postprandial responses that form cluster A may be called pre-pre-diabetics and defined as “at risk” for development of insulin resistance. Moreover, postprandial changes in selected fatty acids and complex lipids, bile acids, amino acids, acylcarnitines and sugars like mannose revealed marked differences in the responses seen in cluster A and cluster B individuals that sustained over the entire challenge test period of 240 min. Almost all metabolites, including glucose and insulin, returned to baseline values at the end of the test (at 240 min), except a variety of amino acids and here those that have been linked to diabetes development. Analysis of the corresponding metabolite profile in a fasting blood sample may therefore allow for early identification of these subjects at risk for insulin resistance without the need to undergo an OGTT.

Metabolic switching has been raised as an important phenomenon to be studied in relation to xenobiotic metabolites, since the dose of the exposure determines the formation of metabolites and their bioactivity. Limonene is a monoterpene mostly found in citrus fruits with health activity, and its phase II metabolites and activity are still not clear. The aim of this work was to evaluate the effects of D-limonene in the development of diet-induced obesity in mice and to investigate metabolites that could be generated in a study assessing different doses of supplementation. Animals were induced to obesity and supplemented with 0.1% or 0.8% D-limonene added to the feed. Limonene phase I and II metabolites were identified in liver and urine by LC-ESI-qToF-MS/MS. To the best of our knowledge, in this study three new phase I metabolites and ten different phase II metabolites were first attributed to D-limonene. Supplementation with 0.1% D-limonene was associated with lower weight gain and a trend to lower accumulation of adipose tissue deposits. The metabolites limonene-8,9-diol, perillic acid and perillic acid-8,9-diol should be explored in future research as anti-obesogenic agents as they were the metabolites most abundant in the urine of mice that received 0.1% D-limonene in their feed.

OBJECTIVES: To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19) METHODS: This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. RESULTS: The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. CONCLUSIONS: Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.

Abstract Background A number of computational tools for metabolism prediction have been developed over the last 20 years to predict the structures of small molecules undergoing biological transformation or environmental degradation. These tools were largely developed to facilitate absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies, although there is now a growing interest in using such tools to facilitate metabolomics and exposomics studies. However, their use and widespread adoption is still hampered by several factors, including their limited scope, breath of coverage, availability, and performance. Results To address these limitations, we have developed BioTransformer, a freely available software package for accurate, rapid, and comprehensive in silico metabolism prediction and compound identification. BioTransformer combines a machine learning approach with a knowledge-based approach to predict small molecule metabolism in human tissues (e.g. liver tissue), the human gut as well as the environment (soil and water microbiota), via its metabolism prediction tool. A comprehensive evaluation of BioTransformer showed that it was able to outperform two state-of-the-art commercially available tools (Meteor Nexus and ADMET Predictor), with precision and recall values up to 7 times better than those obtained for Meteor Nexus or ADMET Predictor on the same sets of pharmaceuticals, pesticides, phytochemicals or endobiotics under similar or identical constraints. Furthermore BioTransformer was able to reproduce 100% of the transformations and metabolites predicted by the EAWAG pathway prediction system. Using mass spectrometry data obtained from a rat experimental study with epicatechin supplementation, BioTransformer was also able to correctly identify 39 previously reported epicatechin metabolites via its metabolism identification tool, and suggest 28 potential metabolites, 17 of which matched nine monoisotopic masses for which no evidence of a previous report could be found. Conclusion BioTransformer can be used as an open access command-line tool, or a software library. It is freely available at https://bitbucket.org/djoumbou/biotransformerjar/. Moreover, it is also freely available as an open access RESTful application at www.biotransformer.ca, which allows users to manually or programmatically submit queries, and retrieve metabolism predictions or compound identification data.

Roux-en-Y gastric bypass (RYGB) is an effective method to achieve sustained weight loss, but the mechanisms responsible for RYGB effects have not yet been fully characterized. In this study, we profiled the concentrations of 143 lipid metabolites in dry blood spots (DBS) of RYGB patients. DBS from obese patients (BMI range 35–44 kg/m2) were collected 7 days before, 15 and 90 days after the surgery. LC-MS/MS was used to quantify acylcarnitines, phosphatidylcholines, sphingomyelins and bile acids. RYGB caused a rapid increase in acylcarnitine levels that proved to be only transient, contrasting with the sustained decrease in phosphatidylcholines and increase of sphingomyelins and bile acids. A PLS-DA analysis revealed a 3-component model (R2 = 0.9, Q2 = 0.74) with key metabolites responsible for the overall metabolite differences. These included the BCAA-derived acylcarnitines and sphingomyelins with 16 and 18 carbons. We found important correlations between the levels of BCAA-derived acylcarnitines and specific sphingomyelins with plasma cholesterol and triacylglycerol concentrations. Along with the marked weight loss and clinical improvements, RYGB induced specific alterations in plasma acylcarnitines, bile acid and phospholipid levels. This calls for more studies on RYGB effects aiming to elucidate the metabolic adaptations that follow this procedure.

Foi avaliado o perfil dos ácidos graxos da gordura intramuscular do Longissimus dorsi de vacas de descarte mestiças, da segunda (G2 - 3/4Charolês (C) 1/4Nelore (N) e 3/4NC) e da terceira geração (G3 - 5/8CN e 5/8NC) de cruzamento rotativo Charolês - Nelore, terminadas em confinamento e abatidas com 465, 507 ou 566kg. Os animais apresentaram, na média, no início do confinamento, 8,5 anos, 388,6kg e 2,35 pontos de escore da condição corporal. A dieta alimentar, relação volumoso:concentrado de 48:52, continha 12,5% de proteína bruta e 2,99Mcal de energia digestível por kg de matéria seca. Os ácidos graxos saturados C14:0 (merístico) e C16:0 (palmítico) reduziram as suas participações em 19 e 10%, respectivamente, com o aumento do peso de abate de 465 para 566kg, mesmo comportamento observado para o C 18:0 (esteárico). Houve menor representação dos ácidos saturados em detrimento aos insaturados com o incremento do peso de abate, sendo a associação negativa (r=-0,61; PThe Longissimus dorsi marbling fatty acid profile of crossbred cull cows, from the second (G2- 3/4Charolais (C) Nellore (N) and 3/4NC) and third (G3 - 5/8CN and 5/8NC) generation of Charolais - Nellore rotational crossbreeding, feedlot finished and slaughtered with 465, 507 and 566 kg were evaluate. At the beginning of the experiment the average age, weight and body condition were, respectively, 8.5 years, 388.6kg and 2.35 points. The diet, with 48:52 roughage:concentrate ratio, contained 12.5% crude protein and 2.99Mcal of digestible energy per kg of dry matter. The fatty acids saturated C14:0 (myristic) and C16:0 (palmitic) reduce the his participations in 19 and 10%, respectively, with the amplification of the weight of slaughter of 465 about to 566kg, even behavior observer about to the C18:0 (stearic). There was minor representation of the acids saturated detriment insaturad with the increase of the weight of slaughter, being the association negative (r=-0.61; P=.01) among the marbling and the fraction of fat saturated on fat intramuscular of the muscle Longissimus dorsi. The meat from the culls 3/4NC presented major fraction from the fatty acids palmitic and palmitic-oleico. These was reduction of the participation of the fatty acid pentadecanoic and palmitic-oleico, and increase of the fraction of the fatty acid stearic from G2 about to G3. The increase of the weight of culls cows appease a profile of fatty acid from fat intramuscular of the Longissimus dorsi beneficial on the health human reducing the participation of fatty acids hipercolesterolemics and increase the hipocolesterolemics. The culls cows 3/4Charolês 1/4Nelore they presented high fraction of fatty acid palmitic and palmitic-oleico, while the 5/8Charolês 3/8Nelore presented demonstrate high concentration of stearic. Animals from third generation of the Charolais - Nellore rotational crossbreeding, presented meat with low concentration of the fatty acid palmitic-oleico and high of stearic.

Foram avaliados o perfil dos ácidos graxos da gordura intramuscular e a qualidade da carne de vacas de descarte terminadas em confinamento recebendo dietas sem ou com monensina sódica (200mg animal-1 dia-1). A dieta continha 12,5% de proteína bruta e 2,99Mcal de energia digestível kg-1 de matéria seca, composta de 48% de volumoso (silagem de milho) e 52% de concentrado. A presença de monensina não teve efeito significativo sobre a cor, a textura e o marmoreio, apresentando valores médios de 3,55; 3,29 e 6,38 pontos, respectivamente. Quanto às características sensoriais, a carne dos animais alimentados com monensina demonstra ser menos palatável (PThe marbling fatty acid profile and the meat quality of cull cows feedlot finished receiving diets without or with sodic monensin (200mg animal-1 day-1) were evaluated. The diet contained 12.5% of crude protein and 2.99 Mcal of digestible energy kg-1 of dry matter, composed of 48% of roughage (corn silage) and 52% of concentrate. The monensin presence didn’t have significant effect on the color, texture and marbling, presenting medium values of 3.55, 3.29 and 6.38 points, respectively. Concerning the sensorial characteristics, the meat of the animals fed with monensin it demonstrated to be less palatable (P