Inflammatory protein signatures in individuals with obesity and metabolic syndrome.

There is variability in the metabolic health status among individuals presenting with obesity; some may be metabolically healthy, while others may have developed the metabolic syndrome, a cluster including insulin resistance, hypertension, dyslipidemia, and increased risk of cardiovascular disease and type 2 diabetes. The mechanisms contributing to this metabolic heterogeneity are not fully understood. To address this question, plasma samples from 48 individuals with BMI ≥ 35 kg/m2 were examined (27 with and 21 without metabolic syndrome). Fasting plasma samples were subjected to Olink proteomics analysis for 184 cardiometabolic and inflammation-enriched proteins. Data analysis showed a clear differentiation between the two groups with distinct plasma protein expression profiles. Twenty-four proteins were differentially expressed (DEPs) between the two groups. Pathways related to immune cell migration, leukocyte chemotaxis, chemokine signaling, mucosal inflammatory response, tissue repair and remodeling were enriched in the group with metabolic syndrome. Functional analysis of DEPs revealed upregulation of 15 immunological pathways. The study identifies some of the pathways that are altered and reflect metabolic health in individuals with obesity. This provides valuable insights into some of the underlying mechanisms and can lead to identification of therapeutic targets to improve metabolic health in individuals with obesity.

Antioxidative Stress Metabolic Pathways in Moderately Active Individuals.

Physical activity (PA) is known to have beneficial effects on health, primarily through its antioxidative stress properties. However, the specific metabolic pathways that underlie these effects are not fully understood. This study aimed to investigate the metabolic pathways that are involved in the protective effects of moderate PA in non-obese and healthy individuals. Data on 305 young, non-obese participants were obtained from the Qatar Biobank. The participants were classified as active or sedentary based on their self-reported PA levels. Plasma metabolomics data were collected and analyzed to identify differences in metabolic pathways between the two groups. The results showed that active participants had increased activation of antioxidative, stress-related pathways, including lysoplasmalogen, plasmalogen, phosphatidylcholine, vitamin A, and glutathione. Additionally, there were significant associations between glutathione metabolites and certain clinical traits, including bilirubin, uric acid, hemoglobin, and iron. This study provides new insights into the metabolic pathways that are involved in the protective effects of moderate PA in non-obese and healthy individuals. The findings may have implications for the development of new therapeutic strategies that target these pathways.

The Metabolic Switch of Physical Activity in Non-Obese Insulin Resistant Individuals.

Healthy non-obese insulin resistant (IR) individuals are at higher risk of metabolic syndrome. The metabolic signature of the increased risk was previously determined. Physical activity can lower the risk of insulin resistance, but the underlying metabolic pathways remain to be determined. In this study, the common and unique metabolic signatures of insulin sensitive (IS) and IR individuals in active and sedentary individuals were determined. Data from 305 young, aged 20-30, non-obese participants from Qatar biobank, were analyzed. The homeostatic model assessment of insulin resistance (HOMA-IR) and physical activity questionnaires were utilized to classify participants into four groups: Active Insulin Sensitive (ISA, n = 30), Active Insulin Resistant (IRA, n = 20), Sedentary Insulin Sensitive (ISS, n = 21) and Sedentary Insulin Resistant (SIR, n = 23). Differences in the levels of 1000 metabolites between insulin sensitive and insulin resistant individuals in both active and sedentary groups were compared using orthogonal partial least square discriminate analysis (OPLS-DA) and linear models. The study indicated significant differences in fatty acids between individuals with insulin sensitivity and insulin resistance who engaged in physical activity, including monohydroxy, dicarboxylate, medium and long chain, mono and polyunsaturated fatty acids. On the other hand, the sedentary group showed changes in carbohydrates, specifically glucose and pyruvate. Both groups exhibited alterations in 1-carboxyethylphenylalanine. The study revealed different metabolic signature in insulin resistant individuals depending on their physical activity status. Specifically, the active group showed changes in lipid metabolism, while the sedentary group showed alterations in glucose metabolism. These metabolic discrepancies demonstrate the beneficial impact of moderate physical activity on high risk insulin resistant healthy non-obese individuals by flipping their metabolic pathways from glucose based to fat based, ultimately leading to improved health outcomes. The results of this study carry significant implications for the prevention and treatment of metabolic syndrome in non-obese individuals.

Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction.

In this study, we addressed the functional significance of co-operative DNA binding of the cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) in an experimental murine model of acute myocardial infarction (MI). STAT1 knock-in mice expressing a phenylalanine-to-alanine substitution at position 77 in the STAT1 amino-terminal domain were examined for the early clinical effects produced by ligation of the left anterior descending coronary artery (LAD), an established model for MI. The F77A mutation has been previously reported to disrupt amino-terminal interactions between adjacent STAT1 dimers resulting in impaired tetramerization and defective co-operative binding on DNA, while leaving other protein functions unaffected. Our results demonstrate that a loss of STAT1 tetramer stabilization improves survival of adult male mice and ameliorates left ventricular dysfunction in female mice, as determined echocardiographically by an increased ejection fraction and a reduced left intra-ventricular diameter. We found that the ratio of STAT3 to STAT1 protein level was higher in the infarcted tissue in knock-in mice as compared to wild-type (WT) mice, which was accompanied by an enhanced infiltration of immune cells in the infarcted area, as determined by histology. Additionally, RNA sequencing of the infarcted tissue 24 h after LAD ligation revealed an upregulation of inflammatory genes in the knock-in mice, as compared to their WT littermates. Concomitantly, genes involved in oxidative phosphorylation and other metabolic pathways showed a significantly more pronounced downregulation in the infarcted tissue from STAT1F77A/F77A mice than in WT animals. Based on these results, we propose that dysfunctional STAT1 signalling owing to a lack of oligomerisation results in a compensatory increase in STAT3 expression and promotes early infiltration of immune cells in the infarcted area, which has beneficial effects on left ventricular remodelling in early MI following LAD ligation.

Complement C5a and Clinical Markers as Predictors of COVID-19 Disease Severity and Mortality in a Multi-Ethnic Population.

Coronavirus disease-2019 (COVID-19) was declared as a pandemic by WHO in March 2020. SARS-CoV-2 causes a wide range of illness from asymptomatic to life-threatening. There is an essential need to identify biomarkers to predict disease severity and mortality during the earlier stages of the disease, aiding treatment and allocation of resources to improve survival. The aim of this study was to identify at the time of SARS-COV-2 infection patients at high risk of developing severe disease associated with low survival using blood parameters, including inflammation and coagulation mediators, vital signs, and pre-existing comorbidities. This cohort included 89 multi-ethnic COVID-19 patients recruited between July 14th and October 20th 2020 in Doha, Qatar. According to clinical severity, patients were grouped into severe (n=33), mild (n=33) and asymptomatic (n=23). Common routine tests such as complete blood count (CBC), glucose, electrolytes, liver and kidney function parameters and markers of inflammation, thrombosis and endothelial dysfunction including complement component split product C5a, Interleukin-6, ferritin and C-reactive protein were measured at the time COVID-19 infection was confirmed. Correlation tests suggest that C5a is a predictive marker of disease severity and mortality, in addition to 40 biological and physiological parameters that were found statistically significant between survivors and non-survivors. Survival analysis showed that high C5a levels, hypoalbuminemia, lymphopenia, elevated procalcitonin, neutrophilic leukocytosis, acute anemia along with increased acute kidney and hepatocellular injury markers were associated with a higher risk of death in COVID-19 patients. Altogether, we created a prognostic classification model, the CAL model (C5a, Albumin, and Lymphocyte count) to predict severity with significant accuracy. Stratification of patients using the CAL model could help in the identification of patients likely to develop severe symptoms in advance so that treatments can be targeted accordingly.

SnoRNAs and miRNAs Networks Underlying COVID-19 Disease Severity.

There is a lack of predictive markers for early and rapid identification of disease progression in COVID-19 patients. Our study aims at identifying microRNAs (miRNAs)/small nucleolar RNAs (snoRNAs) as potential biomarkers of COVID-19 severity. Using differential expression analysis of microarray data (n = 29), we identified hsa-miR-1246, ACA40, hsa-miR-4532, hsa-miR-145-5p, and ACA18 as the top five differentially expressed transcripts in severe versus asymptomatic, and ACA40, hsa-miR-3609, ENSG00000212378 (SNORD78), hsa-miR-1231, hsa-miR-885-3p as the most significant five in severe versus mild cases. Moreover, we found that white blood cell (WBC) count, absolute neutrophil count (ANC), neutrophil (%), lymphocyte (%), red blood cell (RBC) count, hemoglobin, hematocrit, D-Dimer, and albumin are significantly correlated with the identified differentially expressed miRNAs and snoRNAs. We report a unique miRNA and snoRNA profile that is associated with a higher risk of severity in a cohort of SARS-CoV-2 infected patients. Altogether, we present a differential expression analysis of COVID-19-associated microRNA (miRNA)/small nucleolar RNA (snoRNA) signature, highlighting their importance in SARS-CoV-2 infection.

The anti-parallel dimer binding interface in STAT3 transcription factor is required for the inactivation of cytokine-mediated signal transduction.

Signal transducer and activator of transcription 3 (STAT3) gain-of-function mutations have been widely reported in patients with tumors and haematological malignancies. However, the molecular mechanisms of these pathogenic mutations remain largely uninvestigated. In this study, we have extensively characterized two STAT3 missense mutations, namely a valine-to-alanine exchange in the amino-terminal region (V77A) and a phenylalanine-to-alanine substitution (F174A) in the coiled-coil domain. The two mutants displayed elevated levels of tyrosine phosphorylation, premature nuclear accumulation, and differential transcriptional responses following stimulation of cells with interleukin-6 and interferon-É£. In line with their hyper-phosphorylated status, a greater fraction of V77A and F174A proteins was bound to DNA on high-affinity binding sites termed sis-inducible elements (SIE) as compared to the wild-type (WT) protein. Unexpectedly, these STAT3 variants displayed similar kinetics using in vitro kinase and dephosphorylation assays performed with recombinant Janus kinase 2 (JAK2) and Tc45 phosphatase, respectively. This indicates that the two mutations neither affected the susceptibility of STAT3 to the enzymatic activity of the inactivating tyrosine phosphatase nor to the activating kinase. However, experiments triggering intracellular dephosphorylation by the addition of the tyrosine-kinase inhibitor staurosporine to cytokine-pretreated cells showed that the two mutants partially resisted dephosphorylation. From these data, we propose that the F174A missense mutation hinders the exchange from a parallel to an anti-parallel dimer conformation, thereby increasing the ratio of tyrosine-phosphorylated molecules bound to DNA and enhancing gene-dependent transcription. Our data point to the physiological importance of the anti-parallel dimer conformation in the inactivation of the cytokine-induced STAT3 signalling pathway.

Relationship between serum 25-hydroxyvitamin D and red blood cell indices in German adolescents.

Since the impact of vitamin D on red blood cell formation has not been well studied, we aimed at assessing the putative link between serum 25-hydroxyvitamin D (25[OH]D) concentrations and hematological markers of erythropoiesis in a large cohort of German adolescents aged 11 to 17 years. In total, 5066 participants from the population-based, nationally representative KiGGS study (Kinder- und Jugendgesundheitssurvey, German Health Interview and Examination Survey for Children and Adolescents) were grouped into either tertiles or clinically accepted cutoff levels for serum 25(OH)D. Results demonstrated significant and inverse correlations between 25(OH)D levels and several hematological parameters including hemoglobin concentration (r = - 0.04, p = 0.003), mean corpuscular hemoglobin (r = - 0.11, p < 0.001), red blood cell count (r = - 0.04, p = 0.002), and soluble transferrin receptor (r = - 0.1, p < 0.001), whereas, in contrast, serum 25(OH)D was positively correlated to the mean corpuscular volume of erythrocytes (r = 0.08, p < 0.001). Multinomial regression models adjusted for clinically relevant confounders confirmed statistically significant differences between the two strata of 25(OH)D groups with respect to red blood cell markers (hemoglobin concentration, red blood cell count, mean corpuscular volume, and corpuscular hemoglobin, as well as iron and soluble transferrin receptor). CONCLUSIONS: The link between serum 25(OH)D and several important hematological parameters may point to an inhibitory role of vitamin D in the regulation of erythropoiesis in adolescents. What is Known: • The physiological effects of vitamin D on calcium homeostasis and bone metabolism have been established. • However, much less is known about the impact of circulating vitamin D on erythropoiesis. What is New: • Data from the KiGGS study in German adolescents demonstrated significant associations between serum vitamin D concentrations and red blood cell indices. • Further studies should be conducted to decipher the underlying mechanisms of vitamin D on erythropoiesis.