Impact of Moderate Physical Activity on Inflammatory Markers and Telomere Length in Sedentary and Moderately Active Individuals with Varied Insulin Sensitivity

Introduction: Physical activity-associated immune response plays a crucial role in the aging process. This study aimed to determine the impact of short-term moderate physical activity on cytokine levels, oxidative stress markers, and telomere length in lean/ overweight young subjects. Methods: Fasting blood samples were collected from 368 participants at Qatar Biobank. Based on their homeostatic model assessment of insulin resistance (HOMA-IR), participants were categorized as insulin sensitive (IS) or insulin resistant (IR). Subsequently, they were divided into four groups: sedentary IS (n = 90), sedentary IR (n = 90), moderately active IS (n = 94), and moderately active IR (n = 94). Moderate physical activity was defined as walking at least two days per week for more than 150 minutes, as determined by physical activity questionnaires. Serum samples were analyzed for circulating inflammatory cytokines (IL-1β, IL-1RA, IL-6, IL-10, IL-22, MCP-1/CCL2, TNF-α), as well as antioxidant enzyme levels (SOD and catalase). Telomere lengths were measured in the respective DNA samples. Results: Moderately active IR participants exhibited significantly lower SOD activity, while catalase activity did not show significant differences. Moderately active IS participants had higher IL-6 and IL-10 levels compared to sedentary IS participants, with no significant differences observed in the IR counterparts. Telomere length did not significantly differ between the physically active and sedentary groups. Conclusion: This study highlights the potential anti-inflammatory and anti-oxidative stress effects of moderate physical activity in individuals with insulin sensitivity and insulin resistance. However, no significant changes in telomere length were observed, suggesting a complex relationship between physical activity and the aging process. Further research is needed to fully understand the underlying mechanisms and optimize the balance between anti-inflammation and anti-oxidation through exercise and lifestyle adjustments.</p

Metabolic Signature of Leukocyte Telomere Length in Elite Male Soccer Players

Introduction: Biological aging is associated with changes in the metabolic pathways. Leukocyte telomere length (LTL) is a predictive marker of biological aging; however, the underlying metabolic pathways remain largely unknown. The aim of this study was to investigate the metabolic alterations and identify the metabolic predictors of LTL in elite male soccer players. Methods: Levels of 837 blood metabolites and LTL were measured in 126 young elite male soccer players who tested negative for doping abuse at anti-doping laboratory in Italy. Multivariate analysis using orthogonal partial least squares (OPLS), univariate linear models and enrichment analyses were conducted to identify metabolites and metabolic pathways associated with LTL. Generalized linear model followed by receiver operating characteristic (ROC) analysis were conducted to identify top metabolites predictive of LTL. Results: Sixty-seven metabolites and seven metabolic pathways showed significant associations with LTL. Among enriched pathways, lysophospholipids, benzoate metabolites, and glycine/serine/threonine metabolites were elevated with longer LTL. Conversely, monoacylglycerols, sphingolipid metabolites, long chain fatty acids and polyunsaturated fatty acids were enriched with shorter telomeres. ROC analysis revealed eight metabolites that best predict LTL, including glutamine, N-acetylglutamine, xanthine, beta-sitosterol, N2-acetyllysine, stearoyl-arachidonoyl-glycerol (18:0/20:4), N-acetylserine and 3-7-dimethylurate with AUC of 0.75 (0.64–0.87, p &lt; 0.0001). Conclusion: This study characterized the metabolic activity in relation to telomere length in elite soccer players. Investigating the functional relevance of these associations could provide a better understanding of exercise physiology and pathophysiology of elite athletes.</p

Molecular regulators of exercise-mediated insulin sensitivity in non-obese individuals

Insulin resistance is a significant contributor to the development of type 2 diabetes (T2D) and is associated with obesity, physical inactivity, and low maximal oxygen uptake. While intense and prolonged exercise may have negative effects, physical activity can have a positive influence on cellular metabolism and the immune system. Moderate exercise has been shown to reduce oxidative stress and improve antioxidant status, whereas intense exercise can increase oxidative stress in the short term. The impact of exercise on pro-inflammatory cytokine production is complex and varies depending on intensity and duration. Exercise can also counteract the harmful effects of ageing and inflamm-ageing. This review aims to examine the molecular pathways altered by exercise in non-obese individuals at higher risk of developing T2D, including glucose utilization, lipid metabolism, mitochondrial function, inflammation and oxidative stress, with the potential to improve insulin sensitivity. The focus is on understanding the potential benefits of exercise for improving insulin sensitivity and providing insights for future targeted interventions before onset of disease

Comparing the Metabolic Profiles Associated with Fitness Status between Insulin-Sensitive and Insulin-Resistant Non-Obese Individuals

(1) Background: Young non-obese insulin-resistant (IR) individuals could be at risk of developing metabolic diseases including type 2 diabetes mellitus. The protective effect of physical activity in this apparently healthy group is expected but not well characterized. In this study, clinically relevant metabolic profiles were determined and compared among active and sedentary insulin-sensitive (IS) and IR young non-obese individuals. (2) Methods: Data obtained from Qatar Biobank for 2110 young (20-30 years old) non-obese (BMI ≤ 30) healthy participants were divided into four groups, insulin-sensitive active (ISA, 30.7%), insulin-sensitive sedentary (ISS, 21.4%), insulin-resistant active (IRA, 20%), and insulin-resistant sedentary (IRS, 23.3%), using the homeostatic model assessment of insulin resistance (HOMA-IR) and physical activity questionnaires. The effect of physical activity on 66 clinically relevant biochemical tests was compared among the four groups using linear models. (3) Results: Overall, non-obese IR participants had significantly ( ≤ 0.001) worse vital signs, blood sugar profiles, inflammatory markers, liver function, lipid profiles, and vitamin D levels than their IS counterparts. Physical activity was positively associated with left handgrip ( ≤ 0.01) and levels of creatine kinase ( ≤ 0.001) and creatine kinase-2 ( ≤ 0.001) in both IS and IR subjects. Furthermore, physical activity was positively associated with levels of creatinine ( ≤ 0.01) and total vitamin D ( = 0.006) in the IR group and AST ( = 0.001), folate ( = 0.001), and hematocrit ( = 0.007) in the IS group. Conversely, physical inactivity was negatively associated with the white blood cell count ( = 0.001) and an absolute number of lymphocytes ( = 0.003) in the IR subjects and with triglycerides ( = 0.005) and GGT-2 ( ≤ 0.001) in the IS counterparts. (4) Conclusions: An independent effect of moderate physical activity was observed in non-obese apparently healthy individuals a with different HOMA-IR index. The effect was marked by an improved health profile including higher vitamin D and lower inflammatory markers in IRA compared to IRS, and a higher oxygen carrying capacity and lipid profile in ISA compared to the ISS counterparts.QatarUniversity grant number IRCC-2022-467 (M.A.E.,M.S.,A.A.)

Structural dynamics in the evolution of a bilobed protein scaffold

Novel biophysical tools allow the structural dynamics of proteins and the regulation of such dynamics by binding partners to be explored in unprecedented detail. Although this has provided critical insights into protein function, the means by which structural dynamics direct protein evolution remain poorly understood. Here, we investigated how proteins with a bilobed structure, composed of two related domains from the periplasmic-binding protein–like II domain family, have undergone divergent evolution, leading to adaptation of their structural dynamics. We performed a structural analysis on ∼600 bilobed proteins with a common primordial structural core, which we complemented with biophysical studies to explore the structural dynamics of selected examples by single-molecule Förster resonance energy transfer and Hydrogen–Deuterium exchange mass spectrometry. We show that evolutionary modifications of the structural core, largely at its termini, enable distinct structural dynamics, allowing the diversification of these proteins into transcription factors, enzymes, and extracytoplasmic transport-related proteins. Structural embellishments of the core created interdomain interactions that stabilized structural states, reshaping the active site geometry, and ultimately altered substrate specificity. Our findings reveal an as-yet-unrecognized mechanism for the emergence of functional promiscuity during long periods of evolution and are applicable to a large number of domain architectures

ANCHOR: a web server and database for analysis of protein–protein interaction binding pockets for drug discovery

ANCHOR is a web-based tool whose aim is to facilitate the analysis of protein–protein interfaces with regard to its suitability for small molecule drug design. To this end, ANCHOR exploits the so-called anchor residues, i.e. amino acid side-chains deeply buried at protein–protein interfaces, to indicate possible druggable pockets to be targeted by small molecules. For a given protein–protein complex submitted by the user, ANCHOR calculates the change in solvent accessible surface area (ΔSASA) upon binding for each side-chain, along with an estimate of its contribution to the binding free energy. A Jmol-based tool allows the user to interactively visualize selected anchor residues in their pockets as well as the stereochemical properties of the surrounding region such as hydrogen bonding. ANCHOR includes a Protein Data Bank (PDB) wide database of pre-computed anchor residues from more than 30 000 PDB entries with at least two protein chains. The user can query according to amino acids, buried area (SASA), energy or keywords related to indication areas, e.g. oncogene or diabetes. This database provides a resource to rapidly assess protein–protein interactions for the suitability of small molecules or fragments with bioisostere anchor analogues as possible compounds for pharmaceutical intervention. ANCHOR web server and database are freely available at http://structure.pitt.edu/anchor

Designing Focused Chemical Libraries Enriched in Protein-Protein Interaction Inhibitors using Machine-Learning Methods

Protein-protein interactions (PPIs) may represent one of the next major classes of therapeutic targets. So far, only a minute fraction of the estimated 650,000 PPIs that comprise the human interactome are known with a tiny number of complexes being drugged. Such intricate biological systems cannot be cost-efficiently tackled using conventional high-throughput screening methods. Rather, time has come for designing new strategies that will maximize the chance for hit identification through a rationalization of the PPI inhibitor chemical space and the design of PPI-focused compound libraries (global or target-specific). Here, we train machine-learning-based models, mainly decision trees, using a dataset of known PPI inhibitors and of regular drugs in order to determine a global physico-chemical profile for putative PPI inhibitors. This statistical analysis unravels two important molecular descriptors for PPI inhibitors characterizing specific molecular shapes and the presence of a privileged number of aromatic bonds. The best model has been transposed into a computer program, PPI-HitProfiler, that can output from any drug-like compound collection a focused chemical library enriched in putative PPI inhibitors. Our PPI inhibitor profiler is challenged on the experimental screening results of 11 different PPIs among which the p53/MDM2 interaction screened within our own CDithem platform, that in addition to the validation of our concept led to the identification of 4 novel p53/MDM2 inhibitors. Collectively, our tool shows a robust behavior on the 11 experimental datasets by correctly profiling 70% of the experimentally identified hits while removing 52% of the inactive compounds from the initial compound collections. We strongly believe that this new tool can be used as a global PPI inhibitor profiler prior to screening assays to reduce the size of the compound collections to be experimentally screened while keeping most of the true PPI inhibitors. PPI-HitProfiler is freely available on request from our CDithem platform website, www.CDithem.com

Facile Synthesis of N-Substituted Benzimidazoles

A particularly mild and efficient one-pot synthesis of N-substituted benzimidazole derivatives was developed. 2-Fluoro-5-nitrophenylisocyanide reacts with a diverse set of primary amines to afford the respective products in moderate to very good yield (35-95%; 20 examples)