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Oxidative-stress-induced neuronal injury is a major contributor to neurodegenerative diseases, underscoring the need for novel neuroprotective strategies. Natural products with antioxidant and mitochondrial-stabilizing properties are increasingly recognized as promising multi-target therapeutics. Show less

Obesity and depression are two of the most prevalent diseases with increasing trends worldwide; it has been some time since the first epidemiological associations were first described. Currently, there is abundant evidence showing the physiology and the molecular aspects that intersect the biology of both ailments. This narrative review aims to synthesize current evidence on the epidemiology and shared pathophysiology of obesity and major depressive disorder, emphasizing convergent inflammatory, neuroendocrine, metabolic, genetic, and gut-brain mechanisms. We aggregate evidence for a bidirectional relationship mediated by: (1) chronic low-grade inflammation (elevated CRP, IL-6, TNF-α; microglial activation); (2) HPA axis dysregulation (hyper/corticosteronemia, impaired feedback, altered CRH/ACTH signaling); (3) metabolic and neurotrophic signaling deficits (insulin and leptin resistance, dysregulated adipokines such as leptin/adiponectin, impaired BDNF and synaptic plasticity); (4) lipid-derived neurotoxicity and mitochondrial stress (saturated fatty acids, ceramides, oxidative stress); and (5) gut-brain axis perturbations (microbiota dysbiosis, increased intestinal permeability, LPS-driven endotoxemia, altered short-chain fatty acids and tryptophan-kynurenine metabolism). We highlight how these convergent pathways promote neuroinflammation and mood dysregulation in individuals with obesity and summarize clinical consequences for screening, integrated management, and targeted interventions that modulate immune, neuroendocrine, metabolic, and microbial processes. Finally, we outline priorities for identifying shared biomarkers and advancing personalized strategies via multi-omics and systems medicine to improve prevention, diagnosis, and treatment. Show less

The chronic unpredictable mild stress (CUMS) paradigm is a well-known preclinical model used to investigate the pathophysiology of stress-induced neuropsychiatric disorders. This review integrates recent findings to elucidate how chronic stress initiates a multifaceted cascade involving neuroendocrine dysregulation, metabolic dysfunction, immune activation and synaptic impairment. Persistent stimulation of hypothalamic-pituitary adrenal (HPA) axis results in hypercortisolaemia, insulin resistance and compromised neuroplasticity through dysregulated BDNF-TrkB signalling, oxidative stress and activation of inflammatory pathways. Compelling evidence highlights both the Gut brain axis (GBA) and epigenetic alterations as central to stress-induced neuropathology. Stress-mediated microbial dysbiosis and intestinal barrier disruption amplify central inflammation through altered tryptophan metabolism and immune neurotransmitter signalling. Simultaneously, epigenetic modification including DNA methylation, histone remodelling and microRNAs encodes transcriptional changes that results in behavioural and cognitive deficits. While, CUMS model offers strong face and predictive validity but its translational relevance is constrained by protocol validity and limited modelling of psychological stressors. Nonetheless, it remains instrumental for evaluating pharmacological and non-pharmacological interventions targeting inflammatory, neurotrophic and metabolic pathways. Future refinement should incorporate biomarker discovery and gene-environment interaction paradigms. In synthesizing these diverse mechanistic insights, this review underscores the value of the CUMS model in identifying system-level therapeutic targets and advancing translational research in stress-related brain disorder. Show less

Exercise and heat stress have been reported to independently provide benefits to brain health. We tested the hypothesis that 8 weeks of post-exercise local heating, passive local heating only, or exercise training only improves cognitive performance compared to a control group. Sixty young, healthy participants (n = 30 female, age: 23 [3] years) were randomised into one of four groups: control (CON), aerobic exercise (EX), local heating (HEAT), or combined heat and exercise (HEATEX). Participants completed supervised sessions three times per week for 8 weeks. Exercise sessions were completed at 70-75% of maximum heart rate on a cycle ergometer, and local heating sessions involved hot water immersion (42°C) of the feet (both 45 min duration). The HEATEX group performed both the EX and HEAT components sequentially in the same session (90 min total duration). Cognitive performance was measured at baseline and at the end of the 8-week intervention using the digit symbol substitution task (DSST) and the Stroop test. There was a main effect of time (P < 0.001) where DSST performance improved; however, there was no group effect (P = 0.089) or time by group interaction (P = 0.119). There was no effect of the interventions on Stroop cost (baseline: 90 [SD: 70] ms; post-intervention: 84 [SD: 70] ms; time by condition interaction P = 0.205). Similarly, there were no effects of the interventions on circulating plasma concentrations of brain-derived neurotrophic factor (interaction P = 0.189). Eight weeks of exercise training and/or local heating is not sufficient to improve cognitive performance in young, moderately fit individuals. Show less

Genetic polymorphisms play a crucial role in regulating the physiological mechanisms underlying athletic performance, including muscle structure, energy metabolism, and cognitive functions. In recent years, increasing attention has been directed toward genetic variants that may influence cognitive traits such as motivation, stress tolerance, and attention, which are critical for optimal athletic performance. The present study aimed to provide the first preliminary meta-analysis of the association between athlete status and specific candidate polymorphisms related to cognitive processes (COMT rs4680, BDNF rs6265, OPRM1 rs1799971, and APOE rs7412/rs429358). A total of 17 case-control studies meeting the inclusion criteria were retrieved from relevant databases and included in the analysis. Statistical evaluations were performed using random- and fixed-effects models with a 95% confidence interval. The results indicated a potential association between the COMT Val158Met polymorphism and athlete status in both the overall and power athlete subgroups (p < 0.05). In contrast, no significant associations were observed for BDNF rs6265, OPRM1 rs1799971, or APOE rs7412/rs429358. However, this finding is based on a small number of studies and must be interpreted as exploratory. While this preliminary meta-analysis highlights a significant evidence gap, it also underscores, due to methodological limitations, the need for further empirical studies to understand the potential role of these polymorphisms in athlete status. Show less

High-intensity exercise promotes visceral adipose tissue (VAT) breakdown in females via the hypothalamic ERα pathway, and exogenous lactate infusion combined with aerobic training (AT) mimics this effect. However, whether lactate administration can independently mediate hypothalamic plasticity and VAT catabolism as a standalone nutritional strategy remains unexplored. Firstly, using a two-factor design (Lactate × AT) in female SD rats, we showed that long-term exogenous lactate infusion independently induced co-expression of Estrogen receptor α (ERα) and Brain-derived neurotrophic factor (BDNF) in the ventromedial hypothalamus (VMH) and elevated local field potential spectral power in specific bands. These neural adaptations were accompanied by increased resting metabolic rate, enhanced fat oxidation, and enhanced lipolysis, thereby preventing excessive VAT accumulation induced by a high-fat diet. Furthermore, pharmacological inhibition confirmed that Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-α (PGC-1α) acts as a co-upstream signal of ERα and BDNF mediating this process. Our findings reveal that standalone lactate administration induces functional plasticity and metabolic reprogramming through the VMH PGC-1α-ERα pathway, independent of exercise, and effectively suppresses pathological VAT accumulation in female rats. This study identifies potential nutritional interventions and mechanistic targets for preventing female-centered obesity. Show less