Although the effect of genetic background on obesity-related phenotypes is well established, the main objective of this study is to determine the phenotypic responses to cafeteria diet (CAF) of two genetically distinct inbred rat strains and give insight into the molecular mechanisms that might be underlying. Lewis (LEW) and Wistar–Kyoto (WKY) rats were fed with either a standard or a CAF diet. The effects of the diet and the strain in the body weight gain, food intake, respiratory quotient, biochemical parameters in plasma as well as in the expression of genes that regulate leptin signalling were determined. Whereas CAF diet promoted weight gain in LEW and WKY rats, as consequence of increased energy intake, metabolic management of this energy surplus was significantly affected by genetic background. LEW and WKY showed a different metabolic profile, LEW rats showed hyperglycaemia, hypertriglyceridemia and high FFA levels, ketogenesis, high adiposity index and inflammation, but WKY did not. Leptin signalling, and specifically the LepRb-mediated regulation of STAT3 activation and Socs3 gene expression in the hypothalamus were inversely modulated by the CAF diet in LEW (upregulated) and WKY rats (downregulated). In the present study, we show evidence of gene-environment interactions in obesity exerted by differential phenotypic responses to CAF diet between LEW and WKY rats. Specifically, we found the leptin-signalling pathway as a divergent point between the strain-specific adaptations to diet.
The underlying mechanisms explaining the differential course of SARS-CoV-2 infection and the potential clinical consequences after COVID-19 resolution have not been fully elucidated. As a dysregulated mitochondrial activity could impair the immune response, we explored long-lasting changes in mitochondrial functionality, circulating cytokine levels, and metabolomic profiles of infected individuals after symptoms resolution, to evaluate whether a complete recovery could be achieved. Results of this pilot study evidenced that different parameters of aerobic respiration in lymphocytes of individuals recuperated from a severe course lagged behind those shown upon mild COVID-19 recovery, in basal conditions and after simulated reinfection, and they also showed altered glycolytic capacity. The severe groups showed trends to enhanced superoxide production in parallel to lower OPA1-S levels. Unbalance of pivotal mitochondrial fusion (MFN2, OPA1) and fission (DRP1, FIS1) proteins was detected, suggesting a disruption in mitochondrial dynamics, as well as a lack of structural integrity in the electron transport chain. In serum, altered cytokine levels of IL-1β, IFN-α2, and IL-27 persisted long after clinical recovery, and growing amounts of the latter after severe infection correlated with lower basal and maximal respiration, ATP production, and glycolytic capacity. Finally, a trend for higher circulating levels of 3-hydroxybutyrate was found in individuals recovered after severe compared to mild course. In summary, long after acute infection, mitochondrial and metabolic changes seem to differ in a situation of full recovery after mild infection versus the one evolving from severe infection.
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The data included here support the research article "Circulating endothelial microparticles are elevated in bicuspid aortic valve (BAV) disease and related to aortic dilation" (Alegret et al., 2016 [1]) where circulating levels of platelet endothelial cell adhesion molecule (PECAM(+)) endothelial microparticles (EMPs) were identified as a biological variable related to aortic dilation in patients with BAV disease. The data presented in this article are composed by four tables and one figure containing the clinical and echocardiographic characteristics of the patients (Alegret et al., 2016 [1]) included in this study, and summarize the results of multivariate linear analyses. Furthermore, is also included a figure showing a representative flow cytometry dot plots and histograms used in PECAM(+) EMPs quantification is also included.
Scope Macrophage stimulation with bacterial LPS triggers inflammasome activation, resulting in pro‐inflammatory IL‐1β cytokine maturation and secretion. IL‐1β underlies the pathologies of many diseases, including type‐2 diabetes. Thus, the modulation of the inflammatory response through bioactive food compounds, such as procyanidins, is a powerful tool to promote homeostasis. Methods and results To determine the role of procyanidin B 2 in inflammasome activation, LPS‐primed THP‐1‐macrophages were supplemented with or without procyanidin B 2 . Western blot analysis of COX 2 , iNOS, p65, NLRP3 and IL‐1β was performed followed by p65 supershift assay, in vivo caspase‐1 activation assay and NO, IL‐1β and IL‐6 determination. Procyanidin B 2 mediated inhibition of inflammasome activation includes the inactivation of the NF‐κB signalling pathway, the first stage required for the transcription of inflammasome precursors, through the inhibition of p65 nuclear expression and DNA binding, resulting in the transcriptional repression of target genes, such as COX 2 , iNOS and production of IL‐6 and NO. Furthermore, procyanidin B 2 decreases NLRP3 and pro‐IL‐1β cytoplasmic pools, limiting components of inflammasome activation and impeding inflammasome assembly and caspase‐1 activation, and finally secretion of active IL‐1β. Conclusion This study provides the first evidence that procyanidin B 2 inhibits inflammasome activation and IL‐1β secretion during LPS‐induced acute inflammation in human macrophages.
Metabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed. Only TSH (p=0.009) and ferritin (p=0.031) showed significant differences between euthyroid and LT4-treated patients in the ward, and TSH (p=0.044) and FT4 (p=0.012) in the ICU. Accordingly, severity and mortality were similar in euthyroid and LT4-treated patients. On the other hand, FT3 was negatively related to age (p=0.012), independently of sex and body mass index in hospitalized COVID-19 patients. Patients with low FT3 and older age showed a worse prognosis and higher levels of the COVID-19 severity markers IL-6 and IL-10 than patients with high FT3. IL-6 negatively correlated with FT3 (p=0.023) independently of age, body mass index and sex, whereas IL-10 positively associated with age (p=0.035) independently of FT3, body mass index and sex. A metabolomic cluster of 6 parameters defined low FT3 ward patients. Two parameters, esterified cholesterol (p=4.1x10 -4 ) and small HDL particles (p=6.0x10 -5 ) correlated with FT3 independently of age, body mass index and sex, whereas 3-hydroxybutyrate (p=0.010), acetone (p=0.076), creatinine (p=0.017) and high-density-lipoprotein (HDL) diameter (p=8.3x10 -3 ) were associated to FT3 and also to age, with p-values of 0.030, 0.026, 0.017 and 8.3x10 -3 , respectively. In conclusion, no significant differences in FT3, cytokines, and metabolomic profile, or in severity and outcome of COVID-19, were found during hospitalization between euthyroid patients and hypothyroid patients treated with LT4. In addition, FT3 and age negatively correlate in COVID-19 patients and parameters that predict poor prognosis were associated with low FT3, and/or with age. A metabolomic cluster indicative of a high ketogenic profile defines non-critical hospitalized patients with low FT3 levels.