Search Results (265)

Obesity is a chronic inflammatory condition whose rising incidence has turned it into a global epidemic, a trend that also affects people living with inflammatory bowel diseases (IBD). Recent epidemiological data indicate that roughly 25 to 40% of patients with IBD are overweight and that 15 to 40% have obesity. Obesity can contribute to the pathogenesis of IBD and acts as a negative prognostic factor for disease course, response to pharmacological treatment, hospitalizations, post-surgical complications, and quality of life. Overall, the rate of adverse events related to the intestinal disease is higher in patients with obesity, and early data suggest that exposure to weight-loss interventions is associated with more favourable disease outcomes. The relationship between obesity and IBD is complex and involves systemic inflammation, increased production of proinflammatory cytokines, greater intestinal permeability, microbiota alterations, dietary patterns, and hormonal changes. Weight loss interventions, including lifestyle modification, pharmacological treatment, and bariatric surgery, appear to influence IBD-related outcomes, with growing attention to the emerging role of glucagon-like peptide-1 (GLP-1) receptor agonists. Several questions remain open and could guide future research, since a full understanding of the interplay between IBD and obesity is crucial for effective personalized treatment. Full article

Interindividual variability in psychotropic drug response contributes to treatment failure, adverse drug reactions, and repeated medication adjustments. Pharmacogenetics supports precision prescribing by identifying genetic variants associated with drug metabolism, efficacy, and tolerability, and evidence-based recommendations are available for several psychotropic medications. However, genotype predicts metabolic capacity rather than the enzyme activity actually expressed in vivo or the systemic drug exposure achieved at a given time. This narrative review examines phenoconversion, the mismatch between genotype-predicted and observed metabolic phenotype, and its implications for psychiatric pharmacotherapy. Drug–drug interactions, smoking, inflammation, physiological changes, and disease-related factors can modify drug-metabolizing enzyme activity or otherwise alter systemic drug exposure despite an unchanged genotype. We discuss how these influences can limit the applicability of genotype-based dosing recommendations and propose a dynamic framework integrating pharmacogenetic results with concomitant medications, clinical conditions, lifestyle factors, therapeutic drug monitoring, and longitudinal changes in patient status. This framework may also refine the assessment of treatment adequacy, because prescribed dose, duration, and adherence do not necessarily ensure adequate drug exposure. Future clinical decision-support systems should combine pharmacogenetic and longitudinal clinical data to enable more individualized and dynamically informed psychopharmacological treatment. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as systemic cardiometabolic disorders rather than isolated liver diseases. Cardiovascular disease (CVD) represents the leading cause of mortality in patients with MASLD/MASH, highlighting the need for therapeutic strategies that address both hepatic and cardiovascular risk. MASLD/MASH and CVD are connected through a network of interdependent mechanisms, including adipose tissue dysfunction, insulin resistance, altered insulin–glucagon signaling, atherogenic dyslipidemia, lipotoxicity, mitochondrial and endoplasmic reticulum stress, innate immune activation, chronic inflammation, endothelial dysfunction, thrombogenic signaling, and dysregulated hepatokine and adipokine pathways. These mechanisms provide potential therapeutic entry points across the liver–adipose tissue–vascular axis. Lifestyle modification and conventional cardiometabolic therapies remain foundational, while several pharmacological agents increasingly target specific components of this network. We summarize the mechanistic rationale and clinical evidence for emerging therapies, including glucagon-like peptide-1 receptor agonists, dual incretin agonists, fibroblast growth factor 21 analogs, thyroid hormone receptor-β agonists, peroxisome proliferator-activated receptor agonists, and agents targeting de novo lipogenesis. We further discuss why residual metabolic, inflammatory, and fibrogenic activity may limit monotherapy and how mechanism-based combination therapy could improve efficacy while mitigating treatment-related metabolic liabilities. Finally, we outline future priorities, including biomarker-guided patient selection, longitudinal noninvasive monitoring, integrated hepatic–cardiovascular trial endpoints, adaptive combination strategies, and development of therapies targeting immune, fibrogenic, and inter-organ signaling pathways. Full article

Obesity has become a major global public health concern, with prevalence rates rising dramatically over the past several decades and affecting more than one billion people worldwide. The increasing burden of obesity has been largely driven by sedentary lifestyles and the consumption of energy-dense, nutrient-poor diets, although its etiology is multifactorial, involving complex interactions among genetic, metabolic, endocrine, and environmental factors. Beyond excess adiposity, obesity is closely associated with numerous chronic diseases, including cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), hypertension, cancer, and chronic inflammatory disorders. Emerging evidence indicates that oxidative stress plays a pivotal role in the pathogenesis of obesity and its related metabolic complications. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are generated during normal cellular metabolism, serve important physiological functions in cell signaling and redox regulation. However, excessive production of these reactive species or impairment of endogenous antioxidant defense systems disrupts redox homeostasis, leading to oxidative damage to lipids, proteins, and nucleic acids. Such alterations contribute to cellular dysfunction, chronic inflammation, and disease progression. In this context, dietary antioxidants have attracted considerable attention due to their ability to neutralize free radicals, inhibit lipid peroxidation, and restore redox balance. Natural antioxidants derived from fruits, vegetables, and other plant-based foods may act individually or synergistically to enhance cellular defense mechanisms against oxidative stress. Furthermore, growing evidence suggests that antioxidant-rich dietary patterns may offer protective effects against obesity-associated metabolic disturbances and chronic diseases. However, clinical benefits of isolated antioxidant supplementation remain inconsistent and appear to depend on dose, bioavailability, baseline redox status, disease stage, and the preservation of physiological redox signaling. Understanding the molecular mechanisms underlying antioxidant-mediated regulation of redox homeostasis may facilitate the development of nutritional strategies for obesity prevention and management, while contributing to the reduction in oxidative stress and obesity-related disease burden and the promotion of long-term health. Full article

Diet and lifestyle are modifiable determinants of oxidative balance through their influence on exposure to antioxidant and pro-oxidant factors. The oxidative balance score (OBS) is a composite index that reflects the balance between these exposures, with higher scores indicating a predominance of antioxidant factors. In this exploratory pilot study, we examined three OBSs (nutrient-, food-, and lifestyle-based), as well as their combined versions (nutrient–lifestyle and food–lifestyle), across clinical subgroups and evaluated their associations with biomarkers of oxidative stress, inflammation, lipid metabolism, and liver-related biomarkers. A total of 44 older adults were enrolled and stratified into three subgroups (16 healthy, 14 hypercholesterolemia, and 14 post–myocardial infarction). Each participant completed a questionnaire, a 3-day food record, and underwent blood sampling. OBSs were calculated based on 15 nutrients, nine food groups, and two lifestyle components. Correlations and multiple linear regression analyses were performed to examine associations between OBSs and the following biomarkers: plasma total antioxidant capacity (TEAC and FRAP), C-reactive protein (CRP), HDL cholesterol, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The nutrient–lifestyle OBS (OBSN-L) was significantly associated with lower ALT and AST (adjusted ALT β = −1.06; p = 0.048; AST β = −0.54; p = 0.034). A similar association was observed for the nutrient OBS (OBSN) (adjusted AST β = −0.64; p = 0.022). No significant associations were observed for TEAC, FRAP, or CRP. Neither the OBSF nor the OBSF-L was associated with any circulating biomarkers. Higher nutrient-based OBSs, with or without lifestyle integration, were independently associated with lower liver transaminase levels in older adults with varying levels of cardiovascular risk. OBSs may help to capture dietary and lifestyle patterns associated with liver-related biomarkers. These exploratory findings warrant confirmation in larger, prospective studies. Full article

Circadian rhythm disruption (CRD)-related intestinal inflammation is a significant cause of gastrointestinal disorders. Although the benefits of physical exercise have been investigated, its preventive and therapeutic roles in CRD-related intestinal inflammation remain ambiguous. Given the critical role of gut microbiota in regulating intestinal homeostasis and the inflammatory response to external stimuli, we hypothesized that gut microbiota could mediate the anti-inflammatory efficacy of physical exercise on intestinal inflammation. Initially, a two-sample bidirectional Mendelian randomization (MR) was conducted on the causality between physical exercise, intestinal inflammation, and gut microbiota. Subsequently, the preventive efficacy was evaluated in a CRD mouse model. Next, a potential anti-inflammatory mechanism was explored through transcriptomic sequencing, 16S rRNA sequencing, and fecal metabolome analysis. The results of the MR suggested alleviated intestinal inflammation from gut microbiota modulated by physical exercise. Ameliorated intestinal injury and inflammation were observed in exercising CRD mice, which was dampened by oral chenodeoxycholic acid (CDCA) administration. Then, comprehensive analysis indicated that the benefit of physical exercise may be associated with enhanced intestinal clock gene expression and the genus Prevotella. Our findings indicate the potential for the effects of physical exercise to be relevant to reduced CDCA; they also emphasize the benefits of undertaking adequate physical activity in maintaining a healthy condition within a modern lifestyle that involves various risk factors. Full article

Glutathione is an abundant intracellular low-molecular-weight thiol that contributes importantly to cellular redox homeostasis. Besides its well-established role in the antioxidant defense of the cell, glutathione regulates mitochondrial function, metabolism of toxicants, protein thiol oxidation/reduction, redox signaling, and immunity. Disturbances in glutathione metabolism have been shown to play a role in various diseases; however, it has become clear that changes in glutathione metabolism are a part of a complex, multifactorial process. In this review, we summarize current knowledge of the molecular mechanisms governing glutathione synthesis, recycling, compartmentalization, and biological functions, with particular emphasis on redox signaling, the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway, and reversible protein S-glutathionylation. We further examine how disturbances in glutathione homeostasis interact with mitochondrial dysfunction, chronic inflammation, metabolic stress, and impaired cellular signaling in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, Wilson’s disease, type 2 diabetes, and nonalcoholic fatty liver disease. We also evaluate current translational interventions targeting restoration of glutathione balance through glutathione supplementation, precursor supplementation, pharmacological modulation of endogenous antioxidant mechanisms, dietary interventions, and changes in lifestyle. Despite the fact that many interventions have been promising at the mechanistic and experimental level, there are still insufficient clinical data because of the problems associated with glutathione availability, tissue specificity, disease variability, and a lack of sufficiently powered clinical trials. The conclusion of this review is that glutathione should not be viewed as a universal therapeutic target; instead, glutathione should be perceived as an important factor contributing to cellular resilience and able to help other disease-specific interventions. Future progress in glutathione-based interventions will likely depend on integrating redox biomarkers, patient stratification, and precision medicine strategies to identify individuals most likely to benefit from targeted modulation of glutathione homeostasis. Full article

Background/Objectives: Dietary inflammation may influence cardiometabolic health, yet the gut mycobiome and bacterial–fungal interactions remain unclear. Building upon our earlier findings and data from the TALENTs trial (Targeting Aging and Longevity with Exogenous Nucleotides) baseline data, we explored gut fungal profiles and bacterial–fungal co-occurrence patterns in relation to the Dietary Inflammatory Index (DII) and Life’s Essential 8 (LE8) in older adults. Methods: We enrolled 301 community residents aged 60–70 years, with 285 providing qualified fungal internal transcribed spacer (ITS) sequencing data. DII scores were derived from 3-day dietary records to reflect dietary inflammatory risk, and LE8 (integrating health behaviors including physical activity and metabolic health factors including BMI, blood lipids, blood pressure, and blood glucose) was used to assess cardiovascular health; LE8_non-diet was applied as a sensitivity measure. Fungal diversity, genus-level taxa, ecological guilds, and bacterial–fungal associations were analyzed using diversity indices, ZINB/Hurdle models, bootstrap, E-values, DIABLO analysis, and network construction. Results: DII showed an inverse correlation with LE8_non-diet (r = −0.130, p = 0.024). Fungal alpha and beta diversity did not differ significantly across DII-defined groups. Conversely, better cardiovascular status was linked to higher fungal richness, with significantly elevated Chao1 and ACE indices in the high-CVH group (both p < 0.05). Additionally, integrated ZINB, Hurdle, and stability analyses jointly pinpointed four candidate fungal genera that correlated with both DII and LE8. Both ZINB and DIABLO analyses consistently indicated that antagonistic interactions dominated gut bacterial–fungal associations (89.9% vs. 63.8% of negative associations, respectively), with DIABLO further revealing synchronized community-level co-variation between the two kingdoms (r = 0.325, p < 0.01). FUNGuild prediction further revealed saprotrophic guilds enriched in the high-CVH group and host-associated guilds in the low-CVH group, with similar patterns across DII-defined groups. Conclusions: This cross-sectional study reveals gut mycobiome profiles and potential bacterial–fungal co-occurrence patterns among older adults stratified by dietary inflammatory potential and cardiovascular health status, generating testable hypotheses for subsequent nutritional and metabolic research integrating lifestyle behaviors and functional health outcomes. Full article

Heat shock proteins of the HSP70 family and their BAG co-chaperones regulate responses to oxidative stress, inflammation, apoptosis, and ischemia, all central to coronary artery disease (CAD) pathogenesis. The contribution of genetic variants within HSP70-family and BAG co-chaperone genes to CAD susceptibility remains unclear. Thus, we sought to evaluate associations of HSP70- and BAG-related SNPs with CAD risk and to characterize their potential regulatory effects using comprehensive bioinformatic analyses. A case–control cohort of 834 CAD patients and 1328 controls of Russian ethnicity was genotyped for 13 SNPs. Associations with CAD susceptibility and traits were tested using log-additive regression with adaptive permutation. Loci underwent functional annotation. The C allele of BAG1 rs706121 was associated with increased CAD risk overall (OR = 1.24, p_perm = 0.019), in males (OR = 1.39, p_perm = 0.002), and in smokers (OR = 1.39, p_perm = 0.020). BAG3 rs196329 was associated with lower risk in males (A allele: OR = 0.82, p_perm = 0.040), whereas HSPA6 rs753856 was associated with reduced risk in physically active individuals (G allele: OR = 0.61, p_perm = 0.008). Additional associations involved clinical or biochemical traits. Functional annotation identified potential regulatory effects, including eQTL associations, overlap with histone marks, and allele-dependent changes in transcription factor binding. HSP70 and BAG variants may contribute to CAD susceptibility and support sex- and lifestyle-informed risk assessment. Full article

Metabolic syndrome (MetS) is a complex metabolic disorder that includes central fat accumulation and insulin resistance, abnormal lipid levels, high blood pressure, and ongoing mild inflammation as its main symptoms. The global rise in metabolic syndrome parallels the increasing prevalence of male infertility, suggesting a potential association between metabolic health and reproductive function. Male fertility suffers from obesity, which represents a major element of metabolic syndrome because it disrupts hormonal balance, raises scrotal temperatures, and causes oxidative damage and HPG axis malfunction. Excess body fat functions as an endocrine system that induces the body to produce pro-inflammatory cytokines, which include tumor necrosis factor-α and interleukin-6, and various other inflammatory substances that result in ongoing body-wide inflammation. The state of inflammation leads to damaged spermatogenesis, which results in lower testosterone production and impaired semen quality that includes changes in sperm concentration, motility, morphology, and DNA integrity. The combination of insulin resistance and metabolic disturbances that occur in MetS leads to oxidative stress and mitochondrial dysfunction, which harms male reproductive abilities in testicular tissue. Recent research shows that adipokines and endocrine disruptors, together with epigenetic modifications, function as mediators that establish the connection between metabolic syndrome and male infertility. The development of targeted therapeutic strategies and lifestyle interventions requires researchers to study how obesity and chronic inflammation interact with each other to create reproductive dysfunction. This review defines the pathophysiological mechanisms that connect metabolic syndrome to male infertility by focusing on how obesity-related inflammation affects male reproductive health. Full article

Cardiovascular disease (CVD) is the result of a complex interaction between genetic, lifestyle, and environmental factors, which may vary over the course of life. Traditional risk factors do not explain all patients’ risks; thus, the research of additional biomarkers to refine cardiovascular risk prediction has attracted considerable interest in recent years. Genetic factors, as well as air pollution exposure, among nontraditional factors, have been found to be critical determinants of CV risk. Accordingly, this narrative review aims to provide a comprehensive summary of the literature (PubMed) on the combined effects of air pollution and genetic susceptibility on CVD risk. Although different limitations and pitfalls are still to be solved, available evidence suggests that genetic variants (especially genes related to detoxification and inflammation) are involved in the association between air pollution exposure and CV adverse events. Thus, this research area could provide further knowledge of the etiology of CVD, offering new tools for targeted prevention and treatment of more susceptible subjects from a more personalized medicine point of view. Full article

Background: Obesity is a major independent risk factor for atrial fibrillation (AF), contributing to adverse outcomes and complicating rhythm control. While lifestyle modification is recommended, catheter ablation remains central to management. Conventional thermal ablation techniques often yield suboptimal results in obese patients due to anatomical and biophysical challenges. Pulsed field ablation (PFA), a novel non-thermal modality, may overcome these limitations. Methods: A systematic search of PubMed, Scopus, and Embase identified observational cohort studies (2017–2026) evaluating PFA outcomes in obese AF patients or across BMI categories. Four cohort studies met the inclusion criteria. Results: Findings on AF recurrence were heterogeneous. Recurrence rates appeared lower with PFA compared to radiofrequency ablation (RFA), though differences were not statistically significant. In a PFA-only study, freedom from arrhythmia recurrence did not vary across BMI categories. Compared with cryoballoon ablation (CBA), one matched-cohort study demonstrated significantly higher one-year freedom from AF with PFA-PVI, whereas another reported no difference. Left atrial epicardial adipose tissue (LA EAT) emerged as the only independent predictor of recurrence in PFA patients, suggesting electrical field perturbation by fat tissue. Radiation exposure was lower with PFA than CBA, while fluoroscopy time and periprocedural complications were comparable across groups. Conclusions: Current observational evidence suggests that PFA may be a feasible and safe option for AF ablation in overweight and obese patients, with outcomes comparable to conventional ablation techniques. However, comparative efficacy and long-term safety remain uncertain. Obesity-related adipose hypertrophy, systemic inflammation, and atrial remodeling may alter electric field distribution, contributing to variable recurrence outcomes. Larger prospective and randomized trials are warranted to define the long-term role of PFA in this high-risk population. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the hepatic manifestation of systemic metabolic dysfunction and has emerged as one of the leading causes of chronic liver disease worldwide. Its pathogenesis is complex and multifactorial, involving insulin resistance, altered lipid metabolism, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation. Beyond these classical mechanisms, growing evidence highlights the central role of modifiable lifestyle-related factors, including chronic positive energy balance, high intake of fructose and saturated fats, ultra-processed foods, physical inactivity, sleep disruption, and environmental exposures such as endocrine-disrupting chemicals and air pollution, which have been associated with the activation of lipogenic and proinflammatory pathways in preclinical and observational studies. Conversely, protective dietary patterns, particularly the Mediterranean diet, together with regular physical activity, exert hepatoprotective metabolic and anti-inflammatory effects. An extensive literature search was conducted across the PubMed, Scopus, Cochrane Library, and Embase databases, covering publications through June 2026. The review was conducted following the SANRA recommendations for narrative reviews. The inclusion criteria encompassed clinical trials, systematic reviews, meta-analyses, and international clinical practice guidelines. This review provides an integrated framework by linking in a single interpretative model the classical pathogenic pathways with emerging dietary, behavioral, and environmental determinants and with systemic interorgan communication networks involving hepatokines, adipokines, and myokines. Understanding MASLD as a multisystemic metabolic disease driven by multiple determinants has critical implications for the development of targeted preventive and therapeutic strategies aimed at reducing its global burden and prevalence. Full article

Over the last few decades, survival among patients with lung cancer (LC) has progressively improved due to major advances in treatment strategies, particularly the introduction of immunotherapy and targeted therapies, as well as the increased detection of early-stage disease resulting from the widespread use of chest computed tomography (CT). Although the reduction in mortality, frequently achieved through effective control of the primary disease, represents a major therapeutic success, it also raises new clinical challenges, including the long-term management of cancer remission or disease stability and the competing risk of adverse outcomes related to comorbidities and treatment-related toxicities. Among these, cardiovascular (CV) complications have emerged as particularly relevant because of their frequency and prognostic impact. Within the framework of a holistic long-term management approach, increasing attention should be directed toward non-pharmacological interventions targeting lifestyle factors, particularly nutrition and physical exercise, whose role remains underestimated. These interventions may modulate chronic inflammation and immune responses, which are key drivers influencing both the effectiveness of novel anticancer therapies and the progression of cardiovascular complications. Patients with LC frequently present malnutrition and unfavorable lifestyle patterns associated with substantial physical and psychological stress, factors that may negatively affect treatment outcomes and overall prognosis. This narrative review examines the emerging role of targeted nutritional strategies and structured physical exercise as integral components of supportive care in LC, with a specific focus on their impact on cardiac metabolism, CV risk, and response to anticancer therapies, including immunotherapy. Full article

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with marked clinical heterogeneity and a multifactorial pathogenesis. Environmental and lifestyle factors, including obesity, tobacco exposure, microbiome dysbiosis, dietary patterns, and plastic-associated endocrine disruptors, have all been linked to HS risk or disease severity. However, these exposures alone do not fully explain why only some individuals develop HS, why age at onset and severity vary substantially, or why disease occurs in patients without major identifiable environmental burden. In parallel, genetic studies have demonstrated that inherited susceptibility is a central component of HS pathogenesis. Rare loss-of-function variants in γ-secretase complex genes cause a small subset of familial, autosomal dominant HS, while genome-wide association studies have shown that population-level risk implicates pathways involved in epithelial differentiation, follicular biology, immune signaling, and cutaneous inflammation. Recent work further suggests that common and rare genetic risk may converge on shared biological mechanisms, including γ-secretase-related signaling. While nature vs. nurture arguments dichotomize genetic constitution and environmental exposures, current evidence supports a model in which genetic susceptibility interacts with environmental exposures to shape HS risk, clinical expression, and disease progression. In this review, we examine the evidence supporting both exposomic and genomic contributions to HS and argue that the disease is best understood as arising from their intersection rather than from either domain alone. Full article