Search Results (971)

Exercise medicine has traditionally focused on defining the optimal mode, intensity, duration, and frequency of physical activity required to improve health and performance. However, increasing evidence suggests that biological timing represents an additional and often overlooked determinant of exercise responsiveness. Circadian rhythms regulate numerous physiological processes relevant to exercise adaptation, including metabolism, mitochondrial function, protein turnover, and skeletal muscle function, while exercise itself is increasingly recognised as a potent non-photic zeitgeber capable of influencing circadian organisation. Rather than advocating a universally optimal time-of-day for exercise, this Perspective proposes “chrono-exercise medicine”, as a conceptual framework through which biological timing can be integrated into personalised exercise prescription. It discusses the emerging role of circadian phenotyping, skeletal muscle molecular clocks, and temporal multi-omic approaches for understanding interindividual variability in exercise responses. Together, with key methodological, translational, and clinical challenges that must be addressed to enable biologically informed exercise prescription. It is proposed that the future of precision medicine will depend not only on how exercise is prescribed, but also on when it is prescribed and to whom. Full article

Background/Objectives: Chronotype describes individual preferences regarding the timing of sleep, food intake, and other daily activities and is commonly evaluated using the Morningness–Eveningness Questionnaire (MEQ). Individuals with a morning chronotype generally prefer earlier sleep–wake schedules, whereas those with an evening chronotype exhibit delayed circadian timing and achieve peak alertness later in the day. Previous evidence has linked evening chronotype to an elevated risk of obesity and metabolic dysfunction; however, its association with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), particularly with hepatic steatosis and fibrosis, has not yet been fully elucidated. Methods: This cross-sectional study included 119 medication-naïve adults, predominantly with obesity (mean age 41.5 ± 11.9 years; 58 men, 49%), recruited at the Nutrition Center of the National Institute of Gastroenterology “Saverio de Bellis.” Hepatic steatosis (controlled attenuation parameter [CAP] > 275 dB/m) and liver fibrosis (liver stiffness > 8.2 kPa) were assessed by transient elastography (FibroScan). Results: Hepatic steatosis was detected in 62% of participants (n = 74), whereas fibrosis was identified in 15% (n = 18). When chronotype was analyzed as a continuous variable, no significant correlations were observed with either CAP (r = 0.017, p = 0.852) or liver stiffness measurements (r = −0.045, p = 0.629). Although these associations did not reach statistical significance, the corresponding confidence intervals remained compatible with small-to-moderate effect sizes, particularly for fibrosis, reflecting the limited number of participants with fibrotic disease. Conclusions: In this sample, chronotype was not significantly associated with FibroScan-derived measures of hepatic steatosis or fibrosis. Associations with selected metabolic and behavioral characteristics were identified, although these findings require confirmation in adequately powered longitudinal investigations. To our knowledge, only a limited number of studies have explored these relationships using objective FibroScan-derived measurements in medication-naïve individuals. Consequently, the present findings should be considered hypothesis-generating and warrant validation in larger prospective cohorts. Full article

Heat exposure is an increasingly important climate-related determinant of mental health, yet the biological mechanisms linking heat to psychiatric outcomes remain insufficiently integrated. This narrative review synthesizes evidence from climate medicine, thermoregulation, neuroscience, psychoneuroimmunology, sleep research, psychopharmacology, epidemiology, and psychiatry to examine how acute and chronic heat exposure may influence mental health. Heat acts as a multi-system biological stressor by challenging thermoregulation, increasing autonomic and cardiovascular strain, disrupting hydration, impairing sleep and circadian rhythms, activating stress-response systems, and contributing to neuroinflammation, oxidative stress, mitochondrial dysfunction, blood–brain barrier disruption, and neurotransmitter alterations. These pathways may interact with psychotropic medication exposure and impaired behavioral thermoregulation, particularly among people with severe mental illness, older adults, individuals receiving lithium, people with cognitive impairment, substance use disorders, outdoor workers, and those living in poorly cooled environments. Heat-related psychiatric vulnerability is therefore transdiagnostic but heterogeneous, with relevance to distress, depression, anxiety, mood instability, psychosis, substance-related crises, cognitive dysfunction, delirium, and suicide-related outcomes. The review also distinguishes pathways supported by stronger human evidence from mechanisms supported mainly by experimental, preclinical, severe-spectrum, or indirect evidence. It proposes an integrative biological model and an evidence-informed translational agenda focused on exposure assessment, biomarkers, sleep and circadian monitoring, medication safety, risk prediction, physiological adaptation, heat-mitigation strategies, heat-health action plans, and implementation-oriented evaluation. Full article

β-hydroxy-β-methylbutyrate (HMB), a bioactive metabolite of leucine, is widely recognized for its anabolic and anti-catabolic effects in skeletal muscle. However, the molecular mechanisms underlying these effects, particularly in relation to circadian regulation, remain incompletely understood. Here, we investigated the impact of HMB on dexamethasone-induced muscle atrophy in C2C12 myotubes, with a focus on anabolic signaling and circadian clock regulation. C2C12 myotubes were treated with HMB or HMB after dexamethasone-induced atrophy. HMB treatment significantly improved cell viability, surface area and fiber diameter by reducing expression of CBL-B, MuRF1 and Atrogin1, key mediators of muscle proteolysis, and increasing myogenin expression compared with atrophic conditions. While HMB did not activate AKT or mTOR, it robustly increased phosphorylation of P70S6K and S6 through a phospholipase D (PLD)-dependent mechanism. HMB restored disrupted circadian clock gene expression induced by dexamethasone, including normalization of expression patterns. HMB also enhanced circadian rhythmic amplitude and advanced phase timing, indicating improved clock robustness. These findings identify circadian regulation as a novel target of HMB action and demonstrate that HMB preserves muscle homeostasis through coordinated modulation of anabolic signaling and intrinsic circadian machinery. This study provides mechanistic insight into how HMB protects against muscle atrophy and highlights circadian regulation as an important contributor to skeletal muscle health. Full article

Background/Objectives: Despite existing guidelines on limiting screen time, children and adolescents are spending an increasing number of hours in front of digital devices. This increase raises concerns about long-term health consequences, particularly in the context of the growing prevalence in childhood overweight and obesity. The aim of this review is to present the current state of knowledge regarding the relationship between increased screen time and weight-related health outcomes in the pediatric population. It also highlights the need for health education targeting both children and parents, based primarily on developing skills to manage time spent in front of electronic screens. Methods: A narrative review of the literature was conducted in the MEDLINE (PubMed), Web of Science and Scopus databases, including studies published between 2015 and 2025. Results: Available evidence suggests that prolonged screen exposure may be associated with reduced physical activity, circadian rhythm disturbances, including sleep problems, increased stress levels, and adverse mental health outcomes. These factors may interact and reinforce one another, potentially contributing to a positive energy balance and an increased risk of overweight and obesity among young people. Conclusions: The evidence reviewed highlights the ongoing digitalisation of younger generations and the potential consequences of excessive screen use. The underlying mechanisms appear complex and multidirectional. However, methodological heterogeneity across studies underscores the need for well-designed longitudinal and intervention research. Full article

Human African trypanosomiasis (HAT) or sleeping sickness is a neglected tropical disease with a progressive central nervous system (CNS) involvement and marked sleep and circadian rhythm abnormalities. Even though this is a prominent feature of HAT, the connection between parasite neuroinvasion, neuroinflammation, circadian dysfunction, and neurological impairment is not fully understood. This narrative review aims to summarize the most up-to-date knowledge about sleep and circadian disturbance in HAT and proposes an integrated approach for the Trypanosome-Associated Sleep Disorder (TASD). The relevant literature was identified by searching major biomedical databases for HAT, sleep disorders, circadian rhythms, neuroinflammation, and CNS invasion. The review covers the steps by which the CNS becomes invaded, how the barriers are disrupted, how the CNS becomes activated by inflammatory responses, and how the hypothalamic and circadian regulatory networks are disrupted. The evidence suggests that excessive daytime sleepiness, fragmented nocturnal sleep, circadian misalignment, and neuropsychiatric manifestations are related to the activation of inflammatory cytokines, altered neurotransmitter signaling, activation of the kynurenine pathway, dysregulation of clock genes, and disruption of the suprachiasmatic nucleus. We also discuss TASD as a syndrome-like phenotype of CNS involvement and propose a three-stage model of sleep–wake dysfunction in HAT. The review unites these integral mechanisms in a single mechanistic framework to offer a unified understanding of the sleep pathology associated with HAT. There are still important gaps in our knowledge of biomarkers, disease staging, and irreversible neuronal damage, which indicate priorities for future research and better clinical management. Full article

The circadian rhythm is an internal timing system formed by the body’s adaptation to the Earth’s rotation, which helps maintain homeostasis by regulating physiological, metabolic, and behavioral activities. The gut microbiota (GM), the largest microbial ecosystem in the human body, exhibits a bidirectional regulatory relationship with the host circadian clock. Emerging evidence indicates that circadian rhythm disruption (CRD) is linked to disturbances in the diurnal oscillations and compositional balance of the GM, accompanied by reduced short-chain fatty acid levels, increased lipopolysaccharide leakage, and altered tryptophan metabolism. These microbial abnormalities may be involved in anxiety-like behaviors through three major pathways: neuroendocrine (hyperactivation of the HPA axis), immune (microglia-mediated neuroinflammation), and neurotransmitter (imbalance of the serotonergic and dopaminergic systems). Conversely, microbial metabolites such as butyrate and secondary bile acids may reciprocally regulate peripheral clock gene expression, forming a complex “circadian rhythm–GM–anxiety” interaction network. This review summarizes the molecular basis of circadian–GM interactions, potential GM-mediated mechanisms linking CRD with anxiety, and emerging intervention strategies including chrononutrition (time-restricted feeding, sequential nutrient intake), microbiota-targeted therapies (probiotics/prebiotics, fecal microbiota transplantation), and light therapy and melatonin supplementation. Future directions should focus on cell-specific mechanisms using single-cell and spatial transcriptomics, developing personalized interventions that integrate chronotype and microbiome profiling, and conducting large-scale randomized controlled trials to facilitate clinical translation. This review provides a framework for understanding the integrative role of circadian biology and gut microbiota in anxiety and may help develop precision intervention paradigms. Full article

Introduction: The widespread use of digital devices has significantly increased screen time among children and adolescents, raising concerns about its effects on dietary behaviors and health outcomes. This narrative review aimed to examine the relationship between screen exposure, unhealthy eating behaviors, and associated physical and mental health risks in pediatric populations. Methods: A narrative review of the literature was conducted using PubMed, Scopus, and Web of Science databases, with the final search updated on 30 April 2026. Studies involving individuals aged 0–18 years were included if they investigated screen time, dietary behaviors, obesity, cardiometabolic risk, sleep, or mental health outcomes. Observational studies, interventional studies, systematic reviews, and meta-analyses were considered. Findings were synthesized qualitatively according to pre-specified thematic domains, with greater interpretive weight given to systematic reviews, meta-analyses, randomized trials, longitudinal cohorts, and large population-based studies. Results: Excessive screen time was consistently associated with unhealthy eating behaviors, including increased snacking, mindless eating, breakfast skipping, and higher consumption of ultra-processed and energy-dense foods. Digital food marketing and exposure to food advertising may influence children’s food preferences and intake. High screen exposure was also associated with sedentary behavior, sleep disturbances, circadian dysregulation, and altered appetite-related hormones such as leptin and ghrelin. These pathways may contribute to, or be consistent with, obesity, insulin resistance, dyslipidemia, hypertension, and metabolic syndrome, although most evidence remains observational. Moreover, excessive screen use was associated with anxiety, depression, emotional eating, binge-eating behaviors, and body image dissatisfaction, particularly among adolescents. Conclusions: Screen time may represent a modifiable behavioral and environmental correlate of dietary habits, metabolic health, and psychological wellbeing in children and adolescents. Prevention strategies should focus not only on reducing screen duration but also on improving the quality and context of media use through family-based interventions, school programs, digital literacy, promotion of physical activity, and regulation of digital food marketing. Further longitudinal and interventional studies are needed to clarify causal relationships and develop effective prevention strategies. Full article

Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-β, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type–specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies. Full article

Background/Objectives: Juvenile myoclonic epilepsy (JME) is characterized by seizures clustering in the early morning hours, reflecting circadian modulation of cortical excitability. To the best of our knowledge, circadian rest–activity rhythms have not previously been objectively characterized in adolescents with JME, a gap that may be relevant to understanding seizure timing in this population. This study aimed to characterize circadian rest–activity rhythms and sleep parameters in adolescents with JME compared to healthy controls (HCs) and to explore whether chronotype relates to the strength of circadian rhythm. Methods: This pilot case–control study analyzed data from 11 adolescents with JME and 10 age- and sex-matched HCs who underwent 14-day continuous wrist actigraphy. Non-parametric circadian rhythm analysis (NPCRA) and cosinor analysis were conducted, and conventional sleep–wake parameters and night-to-night variability were derived. Subjective data from the Morningness–Eveningness Questionnaire (MEQ), the Pittsburgh Sleep Quality Index, a modified Epworth Sleepiness Scale, and the Pediatric Sleep Questionnaire were included. Between-group comparisons used the Mann–Whitney U test with an effect size of r. Results: Patients showed significantly lower interdaily stability (p = 0.002, r = 0.692), higher intradaily variability (p = 0.022, r = 0.500), reduced peak daytime activity (p = 0.002, r = 0.672), and attenuated cosinor (p = 0.013, r = 0.544) and mesor (p = 0.001, r = 0.754) amplitude, all with large effect sizes. Night-to-night variability was significantly greater for sleep efficiency (p = 0.010, r = 0.561), the fragmentation index (p = 0.003, r = 0.653), and mean sleep-bout duration (p = 0.020, r = 0.509). The MEQ score correlated positively with cosinor amplitude (rho = 0.679, p = 0.022) and peak daytime activity (rho = 0.615, p = 0.044). No significant group differences were found in conventional sleep–wake parameters. Given the exploratory nature of this pilot study, no correction for multiple comparisons was applied, and these findings should be considered hypothesis-generating. Conclusions: This pilot study provides preliminary evidence of circadian rest–activity rhythm disruption in a small and clinically heterogeneous adolescent cohort, with large effect sizes in JME, despite preserved conventional sleep parameters, underscoring the potential value of NPCRA-based actigraphy monitoring in this population and the need for replication in larger cohorts. Full article

Background/Objectives: Circadian disruption resulting from factors such as jet lag, shift work, or aging leads to exaggerated inflammatory responses and increased disease susceptibility. However, the core dynamical mechanism by which circadian disruption exacerbates innate immune responses remains poorly understood. Methods: We develop an integrated mathematical model coupling the mammalian circadian clock with antigen-induced innate immune responses, incorporating key regulatory interactions including glucocorticoid modulation and pro-inflammatory positive feedback loops. Results: The model successfully recapitulates experimental data regarding homeostatic immune circadian oscillations and time-dependent gating of acute inflammatory responses. Dynamic analyses reveal that the circadian clock exerts its gating function by modulating the bistable characteristics within pro-inflammatory positive feedback loops. Circadian disruption, simulated as jet lag or age-related reduction in clock gene amplitude, reshapes this bistable landscape and prolongs residence duration in the pathological hyperinflammatory state. Conclusions: This shift not only amplifies acute cytokine bursts but also sustains exaggerated inflammatory activity, providing a mechanistic explanation for acute tissue injury and chronic low-grade inflammation (inflammaging) under these circadian disruption scenarios. Full article

Background: Competitive sports represent a powerful physiological and psychological stressor capable of modulating neuroendocrine and immune pathways. Water polo, characterized by intense intermittent exertion and frequent physical contact, provides a unique model to investigate competition-related stress biology. Methods: Sixteen male Italian Serie C water polo players were enrolled in the study. Using a within-subject design, saliva samples were collected under controlled circadian conditions. Salivary biomarkers, including cortisol, IgA, and cytokines, were assessed both before and after training sessions and competitive matches. Results: Both training and competition elicited POST-session increases in salivary cortisol and cytokines, alongside reductions in IgA. However, competition produced significantly higher anticipatory and POST-session cortisol concentrations. A larger POST-session decreases in IgA compared with training was observed. Cytokine concentrations increased from PRE- to POST-session in both conditions, with significantly greater induction during competition across the panel. During training, selected cytokines showed positive within-session correlations with cortisol, indicating coordinated hypothalamic–pituitary–adrenal–immune activation under lower psychosocial load. These associations were attenuated and less consistent during competition. Conclusions: Official competition amplifies endocrine and immune responses beyond those observed during match-like training in elite water polo players, despite comparable physical demands. Altered cytokine–cortisol coupling under competitive conditions suggests modulation of neuroendocrine–immune integration by psychosocial stress. Combined salivary profiling of cortisol, cytokines, and IgA represents a feasible, non-invasive approach for monitoring psychophysiological load in elite aquatic team sports. Full article

Circadian clocks are endogenous timing systems that coordinate plant physiology, metabolism, development, and stress responses with daily and seasonal environmental cycles. In crops, circadian and photoperiodic pathways influence agronomically important traits including photosynthesis, carbon allocation, flowering time, growth, stress resilience, and nutritional quality. Although flowering time and photoperiod response pathways have long been indirectly exploited during domestication and breeding, the broader potential of circadian regulation for crop improvement and time-sensitive management remains only partially developed. This review examines the role of plant circadian clocks in crop productivity, with emphasis on molecular mechanisms, crop-specific clock-associated loci, breeding strategies, and chrono-agricultural applications. We summarize conserved and divergent features of the plant clock, including transcriptional repression and activation modules, environmental entrainment, and post-transcriptional regulatory layers. We then discuss how circadian regulation shapes productivity traits and highlight examples from rice, wheat, barley, maize, soybean, sorghum, tomato, and other crops. These examples show that agricultural adaptation often involves fine-tuning or rewiring circadian and photoperiodic outputs rather than maintaining a universal optimal clock state. Finally, we evaluate chrono-agriculture as an emerging framework for aligning management practices with biological timing. While controlled-environment agriculture and high-value horticultural systems are currently the most practical settings for testing chrono-agricultural strategies, open-field applications require careful consideration of environmental variability, sensor limitations, labour, machinery logistics, economic feasibility, and multi-environment validation. Integrating circadian biology with crop genetics, phenotyping, modelling, and agronomy may provide new opportunities to improve productivity, resilience, resource-use efficiency, and quality traits in sustainable agricultural systems. Full article

Stroke remains one of the leading causes of long-term disability and death worldwide. Growing evidence suggests that both stroke onset and severity exhibit strong circadian patterns. This blood–brain interface (BBI), which regulates bidirectional communication between the peripheral circulation and the central nervous system, plays a critical role in cerebrovascular injury. Aging further exacerbates these processes by dampening the molecular clock function and increasing inflammatory activation. In this review, we examine the circadian regulation of the BBI, aging, and its implications in stroke vulnerability. Understanding how circadian biology modulates neurovascular function may reveal novel therapeutic targets and time-of-day-dependent approaches for stroke prevention and treatment. Full article

The pineal gland regulates circadian physiology through the periodic production of melatonin (MLT). In addition to its established role as a chronobiotic agent, MLT regulates redox homeostasis and mitochondrial physiology. Mitochondria and redox-active molecules, particularly reactive oxygen species (ROS), play essential roles in reproduction, including gamete physiology, fertilization, and early embryonic development. Although excessive oxidative stress (OS) impairs fertility, controlled ROS signaling is necessary for normal reproductive function. This comprehensive review synthesizes current evidence regarding MLT as a key intermediary linking circadian signaling with mitochondrial physiology and redox homeostasis. We discuss molecular pathways through which MLT regulates mitochondrial function, including activation of the Nrf2 signaling pathway, modulation of mitochondrial permeability transition, regulation of electron transport chain (ETC) efficiency, and apoptotic signaling. Furthermore, this study investigates MLT’s ability to scavenge free radicals and activate antioxidant defense mechanisms. Moreover, we review novel findings regarding the effects of MLT in experimental animals and humans, assisted reproductive technologies (ART) such as in vitro fertilization (IVF), and consider the translational significance of the hormone as an enhancer of fertility. We also highlight gaps in the literature, including methodological inconsistencies, supraphysiologic doses, and insufficient data from large human cohorts. Lastly, we discuss an integrative model whereby MLT may function as an important regulator of mitochondrial redox balance, with potential implications for reproductive physiology and reproductive outcomes, and propose new avenues for investigation. Full article