Search Results (199)

Excess caloric intake and insufficient physical activity are the two major drivers underlying the global obesity and type 2 diabetes mellitus epidemics. However, circadian misalignment of caloric intake and physical activity, as commonly experienced by nightshift workers, can also have detrimental effects on body weight and glucose homeostasis. We have previously reported that combined restriction of eating and voluntary wheel running to the inactive phase (i.e., a rat model for circadian misalignment) shifted liver and muscle clock rhythms by ~12 h and prevented the reduction in the amplitude of the muscle clock oscillation otherwise induced by light-phase feeding. Here, we extended on these findings and investigated how a high-fat diet (HFD) affects body composition and liver and muscle clock gene rhythms in male Wistar rats while restricting both eating and exercise to either the inactive or active phase. To do this, we used four experimental conditions: sedentary controls with no wheel access on a non-obesogenic diet (NR), sedentary controls with no wheel access on an HFD (NR-H), and two experimental groups on an HFD with simultaneous access to a running wheel and HFD time-restricted to either the light phase (light-run-light-fed + HFD, LRLF-H) or the dark phase (dark-run-dark-fed + HFD. DRDF-H). Consumption of an HFD did not alter the daily running distance of the time-restricted groups but did increase the running intensity in the LRLF-H group compared to a previously published LRLF chow fed group. However, no such increase was observed for the DRDF-H group. LRLF-H ameliorated light phase-induced disturbances in the soleus clock more effectively than under chow conditions and had a protective effect against HFD-induced changes in liver clock gene expression. Together with (our) previously published results, these data suggest that eating healthy and being active at the wrong time of the day can be as detrimental as eating unhealthy and being active at the right time of the day. Full article

Circadian rhythms are intrinsic 24 h cycles that regulate metabolic processes across multiple tissues, with skeletal muscle emerging as a central node in this temporal network. Muscle clocks govern gene expression, fuel utilisation, mitochondrial function, and insulin sensitivity, thereby maintaining systemic energy homeostasis. However, circadian misalignment, whether due to behavioural disruption, nutrient excess, or metabolic disease, impairs these rhythms and contributes to insulin resistance, and the development of obesity, and type 2 diabetes mellitus. Notably, the muscle clock remains responsive to non-photic cues, particularly exercise, which can reset and amplify circadian rhythms even in metabolically impaired states. This work synthesises multi-level evidence from rodent models, human trials, and in vitro studies to elucidate the role of skeletal muscle clocks in circadian metabolic health. It explores how exercise entrains the muscle clock via molecular pathways involving AMPK, SIRT1, and PGC-1α, and highlights the time-of-day dependency of these effects. Emerging data demonstrate that optimally timed exercise enhances glucose uptake, mitochondrial biogenesis, and circadian gene expression more effectively than time-agnostic training, especially in individuals with metabolic dysfunction. Finally, findings are integrated from multi-omic approaches that have uncovered dynamic, time-dependent molecular signatures that underpin circadian regulation and its disruption in obesity. These technologies are uncovering biomarkers and signalling nodes that may inform personalised, temporally targeted interventions. By combining mechanistic insights with translational implications, this review positions skeletal muscle clocks as both regulators and therapeutic targets in metabolic disease. It offers a conceptual framework for chrono-exercise strategies and highlights the promise of multi-omics in developing precision chrono-medicine approaches aimed at restoring circadian alignment and improving metabolic health outcomes. Full article

Background: The candidate therapeutic peptide TnP demonstrates broad, system-level regulatory capacity, revealed through integrated network analysis from transcriptomic data in zebrafish. Our study primarily identifies TnP as a multifaceted modulator of drug metabolism, wound healing, proteolytic activity, and pigmentation pathways. Results: Transcriptomic profiling of TnP-treated larvae following tail fin amputation revealed 558 differentially expressed genes (DEGs), categorized into four functional networks: (1) drug-metabolizing enzymes (cyp3a65, cyp1a) and transporters (SLC/ABC families), where TnP alters xenobiotic processing through Phase I/II modulation; (2) cellular trafficking and immune regulation, with upregulated myosin genes (myhb/mylz3) enhancing wound repair and tlr5-cdc42 signaling fine-tuning inflammation; (3) proteolytic cascades (c6ast4, prss1) coupled to autophagy (ulk1a, atg2a) and metabolic rewiring (g6pca.1-tg axis); and (4) melanogenesis-circadian networks (pmela/dct-fbxl3l) linked to ubiquitin-mediated protein turnover. Key findings highlight TnP’s unique coordination of rapid (protease activation) and sustained (metabolic adaptation) responses, enabled by short network path lengths (1.6–2.1 edges). Hub genes, such as nr1i2 (pxr), ppara, and bcl6aa/b, mediate crosstalk between these systems, while potential risks—including muscle hypercontractility (myhb overexpression) or cardiovascular effects (ace2-ppp3ccb)—underscore the need for targeted delivery. The zebrafish model validated TnP-conserved mechanisms with human relevance, particularly in drug metabolism and tissue repair. TnP’s ability to synchronize extracellular matrix remodeling, immune resolution, and metabolic homeostasis supports its development for the treatment of fibrosis, metabolic disorders, and inflammatory conditions. Conclusions: Future work should focus on optimizing tissue-specific delivery and assessing genetic variability to advance clinical translation. This system-level analysis positions TnP as a model example for next-generation multi-pathway therapeutics. Full article

Sleep deprivation impairs immune function, and melatonin has emerged as a key mediator in this process. This narrative review analyzes 50 studies published between 2000 and 2025 to determine the extent to which reduced melatonin synthesis contributes to immune dysregulation. Consistent sleep loss lowers melatonin levels, which correlates with elevated proinflammatory cytokines (e.g., IL-6 and TNF-α), increased oxidative stress, and reduced immune cell activity, including that of natural killer (NK) cells and CD4+ lymphocytes. Melatonin regulates immune pathways, including NF-κB signaling. It also supports mitochondrial health and helps maintain gut barrier integrity. These effects are particularly relevant in vulnerable populations, including older adults and shift workers. Experimental findings also highlight melatonin’s therapeutic potential in infections like SARS-CoV-2, where it modulates inflammatory responses and viral entry mechanisms. Despite the heterogeneity of study methodologies, a consistent correlation emerges between circadian disruption, melatonin suppression, and immune imbalance. These findings underscore melatonin’s dual role as a chronobiotic and immunomodulator. Addressing sleep loss and considering melatonin-based interventions may help restore immune homeostasis. More clinical trials are needed to determine the best dosing, long-term efficacy, and population-specific strategies for supplementation. Promoting healthy sleep is crucial for preventing chronic inflammation and diseases associated with immune dysfunction. Full article

Intermittent fasting (IF) is emerging as a heterogeneous neurometabolic intervention with the possibility of changing the course of neurodegenerative diseases. Through the modulation of the gut–brain axis (GBA), cellular bioenergetics (or metabolic) reprogramming, and involvement in preserved stress adaptation pathways, IF influences a range of physiological mechanisms, including mitobiogenesis, autophagy, circadian rhythm alignment, and neuroinflammation. This review critically synthesises current preclinical and early clinical evidence illustrating IF’s capability to supplement synaptic plasticity and integrity, reduce toxic proteins (proteotoxic) burden, and rehabilitate glial and immune homeostasis across models of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. The key players behind these effects are bioactive metabolites such as short-chain fatty acids (SCFA) and β-hydroxybutyrate (BHB), and molecular mediators such as brain-derived neurotrophic factor (BDNF). We feature the therapeutic pertinence of IF-induced changes in gut microbiota composition, immune response, and mitochondrial dynamics, and we discuss emerging approaches for merging IF into precision medicine frameworks. Crucial challenges include individual variability, protocol optimisation, safety in cognitively vulnerable populations, and the need for biomarker-guided, ethically grounded clinical trials. Finally, we propose IF as a scalable and flexible intervention that, when personalised and integrated with other modalities, may reframe neurodegeneration from a model of irreversible decline to one of modifiable resilience. Full article

Circadian rhythms govern cellular metabolism, redox balance, and endocrine signaling in numerous tissues. However, chronic disturbance of these biological rhythms, mediated by modern lifestyle factors including shift work, sleep irregularity, and prolonged light exposure, has been increasingly associated with oxidative stress, metabolic dysregulation, and the pathogenesis of chronic diseases. This review discusses recent mechanistic advances that link circadian misalignment with tissue-specific metabolic reprogramming and impaired proteostasis, focusing on metabolic inflammation and associated pathologies. Emerging work reveals a close interdependence between the circadian clock and proteasome-mediated protein turnover and highlights this interplay’s importance in maintaining redox homeostasis. Furthermore, circadian modulation of the activity of the inflammasome complex is suggested to represent an important, but largely unexplored, risk factor in the pathobiology of both malignancy and metabolic syndrome. Recently, researchers have proposed them as novel endocrine regulators of systemic energy balance and inflammation, with a focus on their circadian regulation. In addition, the emerging domains of chrono-epigenetics and tissue-specific programming of the clock pathways may serve to usher in novel therapies through precision medicine. Moving ahead, circadian-based therapeutic approaches, including time-restricted feeding, chronopharmacology, and metabolic rewiring, have high potential for re-establishing physiological domain homeostasis linked to metabolic inflammation pathologies. Elucidating this reciprocal relationship between circadian biology and cellular stress pathways may one day facilitate the generation of precise interventions aiming to alleviate the health burden associated with circadian disruption. Full article

Background: Frozen shoulder (FS) is a common musculoskeletal condition with significant socioeconomic impact. Despite its prevalence, the condition lacks a definitive understanding and universally effective treatment approach. Objective: To evaluate the effects of an intervention combining manual therapy, conventional exercises, and strategies to improve sleep quality and circadian rhythm on recovery and biomarkers in patients with FS. Methods: A single-blind, randomized, controlled trial was conducted with 34 participants divided into control and experimental groups (n = 17 each). Both groups received manual therapy and conventional exercises, while the experimental group (EG) also received sleep and circadian rhythm optimization instructions. Biomarkers (fasting glucose, insulin, Homeostasis Model Assessment of Insulin Resistance (HOMA) index, leptin, triglycerides, total cholesterol, HDL cholesterol, uric acid, CRP, IL-1β, IL-6, IL-17, IL-10, IL-33, HMGB1, and TNF-α) and functional outcomes (SPADI, ROM, and PSQI) were assessed pre- and post-intervention. Results: After six weeks, the EG showed significant improvements in IL-10 levels (mean change: 2.5 pg/mL vs. 0.5 pg/mL in the control group (CG), p = 0.03), IL-6 reduction (−1.8 pg/mL vs. −0.4 pg/mL, p = 0.02), and HOMA index (−0.8 vs. −0.2, p = 0.04). ROM improved by 20 degrees in the EG versus 10 degrees in the CG (p = 0.01), SPADI scores decreased by 25 points versus 15 points (p = 0.03), and PSQI improved by 4 points compared to 2 points (p = 0.05). Conclusion: The integration of sleep quality and circadian rhythm optimization into conventional rehabilitation significantly enhances recovery, particularly IL-10 modulation, but these did not translate into superior clinical improvements within the study period. Further long-term studies are needed to confirm whether early biological effects lead to sustained functional recovery in FS patients. Full article

Bisphenol A (BPA) is a widespread environmental endocrine disruptor with significant neurodevelopmental and behavioral risks. The present study explored the role of the circadian clock protein NR1D1 in mediating BPA-induced anxiety-like behavior and brain inflammation early in life. Zebrafish embryos exposed to BPA exhibited anxiety-like behavior characterized by altered motor activity patterns. Notably, BPA exposure suppressed the expression of the circadian clock gene nr1d1, accompanied by increased transcriptional and protein levels of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α. These changes created a pro-inflammatory microenvironment that disrupted dopamine system homeostasis, contributing to the observed behavioral abnormalities. Activation of NR1D1 using GSK effectively reversed BPA-induced inflammatory responses and restored normal dopamine levels and behavioral phenotypes. These findings highlight NR1D1 as a critical regulator linking circadian rhythm disruption, neuroinflammation, and dopaminergic dysfunction to anxiety-like behavior. This study provides novel insights into the mechanisms underlying BPA-induced neurotoxicity and identifies NR1D1 as a potential therapeutic target for mitigating the adverse effects of early-life BPA exposure. Full article

High-altitude environments pose significant risks for insomnia development, which severely compromises both physiological health and occupational performance. To elucidate the mechanisms underlying altitude-induced sleep disruption and establish a validated animal model for therapeutic intervention development, we exposed Sprague-Dawley rats to hypobaric hypoxia (5500 m altitude equivalent: 308 mmHg, 20.37% O₂, PiO₂ 8.0 kPa) for 7 days. We employed continuous wireless telemetry to monitor EEG/EMG signals, with concurrent analysis of physiological parameters, blood biochemistry, histopathology, transcriptomics, and protein expression. Quantitative analyses demonstrated decreased caloric intake, transient body mass reduction, and immune-metabolic disturbances. While total sleep duration showed no significant variation, sleep architecture displayed elevated wakefulness periods, reduced active wakefulness, a decreasing trend of slow-wave sleep (SWS), and increased paradoxical sleep (PS) accompanied by attenuated circadian oscillations. The duration of SWS episodes was significantly shortened, indicating a sleep homeostasis imbalance that peaked on day 3. Biochemical profiling revealed reduced levels of antioxidant enzymes, elevated pro-inflammatory cytokines, and hypothalamic–pituitary–adrenal axis activation. Transcriptomic analyses identified the critical involvement of serotonergic/glutamatergic synaptic regulation, lipid metabolism, IL-17 signaling, and cortisol synthesis pathways. Western blot analyses confirmed OX2R upregulation, 5-HT1AR downregulation, and circadian gene dysregulation. Our findings demonstrate that hypobaric hypoxia induces sleep disruption via coordinated mechanisms involving oxidative stress, inflammatory activation, HPA axis hyperactivity, neurotransmitter imbalance, and circadian clock dysfunction, providing a robust preclinical model for mechanistic exploration and therapeutic target identification. Full article

Sleep deprivation is a prevalent issue that disrupts the circadian rhythm of estrogen, particularly estradiol, thereby significantly affecting women’s skin health and appearance. These disruptions can impair skin barrier functionality and decrease dermal collagen synthesis. In this study, our results demonstrate that topical taurine supplementation promotes the expression of tight junction (TJ)-related proteins and enhances collagen production, effectively restoring skin homeostasis in sleep-deprived female mice. Mechanistically, taurine upregulates the expression of TMEM38B, a gene encoding the TRIC-B trimeric cation channel, resulting in increased intracellular calcium ion levels. This, in turn, promotes the upregulation of TJ-related proteins, such as ZO-1, occludin, and claudin-11 in epidermal cells, while also enhancing the expression of type III collagen in fibroblasts, thus restoring skin homeostasis. These findings suggest that taurine may serve as an alternative to estradiol, effectively improving skin homeostasis disrupted by sleep deprivation while mitigating the potential risks associated with exogenous estrogen supplementation. Collectively, these results provide preliminary insights into the protective mechanisms of taurine against sleep deprivation-induced skin impairments and establish a foundation for its potential application in treating skin conditions related to estrogen imbalances, such as skin aging in menopausal women. Full article

The biological clock is crucial for controlling the circadian rhythm of the human body and maintaining the stable cyclic changes of various human life activities. Cardiovascular disease has become one of the primary problems affecting human life and health in today’s society. Cardiovascular disease exhibits distinct circadian rhythms, with the core clock gene protein Brain and muscle ARNT-like protein 1 (BMAL1) playing critical roles in both physiological cardiac function and pathological processes. BMAL1 regulates myocardial gene expression, maintains normal structures, and stabilizes circadian rhythms to preserve cardiac homeostasis. In the pathological state of myocardial ischemia, BMAL1 ameliorates myocardial ischemic injury by regulating intrinsic mechanisms such as oxidative stress response, energy metabolism, immune-inflammatory response, and apoptosis and autophagy in cardiomyocytes. This review systematically examines BMAL1’s involvement in myocardial ischemic injury through the circadian regulation of cardiac function. We analyze its multidimensional impacts on oxidative stress, energy metabolism, immune-inflammatory responses, apoptosis, and autophagy, highlighting the biological significance of this clock gene in ischemic pathophysiology. Full article

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone associated with the regulation of biological rhythms. The indoleamine is secreted by the pineal gland during the night, following a circadian rhythm. The highest plasmatic levels are reached during the night, whereas the lowest levels are achieved during the day. In addition to the pineal gland, other organs and tissues also produce melatonin, like, for example, the retina, Harderian glands, gut, ovaries, testes, skin, leukocytes, or bone marrow. The list of organs is extensive, including the cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, carotid body, placenta, and endometrium. At all these locations, the availability of melatonin is intended for local use. Interestingly, a decline of the circadian amplitude of the melatonin secretion occurs in old subjects in comparison to that found in younger subjects. Moreover, genetic and environmental factors are the primary causes of diseases, and oxidative stress is a key contributor to most pathologies. Numerous studies exist that show interesting effects of melatonin in different models of disease. Impairment in its secretion might have deleterious consequences for cellular physiology. In this regard, melatonin is a natural compound that is a carrier of a not yet completely known potential that deserves consideration. Thus, melatonin has emerged as a helpful ally that could be considered as a guard with powerful tools to orchestrate homeostasis in the body, majorly based on its antioxidant effects. In this review, we provide an overview of the widespread actions of melatonin against diseases preferentially affecting the elderly. Full article

Circadian rhythms are molecular oscillations governed by transcriptional–translational feedback loops (TTFLs) operating in nearly all cell types and are fundamental to physiological homeostasis. Key circadian regulators, such as circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), period (PER), and cryptochrome (CRY) gene families, regulate intracellular metabolism, oxidative balance, mitochondrial function, and synaptic plasticity. Circadian disruption is known as a central contributor to the molecular pathophysiology of neurodegenerative disorders. Disease-specific disruptions in clock gene expression and melatoninergic signaling are known as potential early-stage molecular biomarkers. Melatonin, a neurohormone secreted by the pineal gland, modulates clock gene expression, mitochondrial stability, and inflammatory responses. It also regulates epigenetic and metabolic processes through nuclear receptors and metabolic regulators involved in circadian and cellular stress pathways, thereby exerting neuroprotective effects and maintaining neuronal integrity. This review provides recent findings from the past five years, highlighting how circadian dysregulation mediates key molecular and cellular disturbances and the translational potential of circadian-based therapies in neurodegenerative diseases. Full article

Melatonin is an indolamine derived from tryptophan, which is highly conserved throughout evolution, including in zebrafish, where it controls important cellular processes, such as circadian rhythms, oxidative stress, inflammation, and mitochondrial homeostasis. These functions of melatonin and its synthesis route are quite similar to those in humans. One of the most important enzymes in melatonin synthesis is acetylserotonin O-methyltransferase (ASMT), the rate-limiting enzyme, which catalyzes its final step. Due to genome duplication, zebrafish has two genes for this enzyme, asmt1 and asmt2. These genes show differential expression; asmt1 is primarily expressed in the retina and the pineal gland, and asmt2 is expressed in peripheral tissues, indicating different functions. Therefore, the aim of this work was to develop a mutant model for each asmt gene and to analyze their phenotypic effects in zebrafish. The results showed that the loss of 80% of the asmt2 gene affected melatonin concentration and consequently disrupted the sleep/wake rhythm in larvae, decreasing by 50% the distance traveled. In contrast, the loss of asmt1 had a greater influence on the physical condition of adults, as locomotor activity decreased by 50%, and 75% showed malformations. These data reveal distinct functional roles of melatonin depending on their site of production that may affect the development of zebrafish. Full article

Periodontitis is a chronic inflammatory disease characterized by the destruction of tooth-supporting structures, influenced by immune system dysregulation, oxidative stress, and imbalances in bone metabolism. Given its multifactorial pathogenesis, bioactive compounds such as vitamin D, melatonin, and omega-3 fatty acids have emerged as potential adjuncts to periodontal therapy due to their immunomodulatory, anti-inflammatory, and antioxidative properties. This narrative review explores the role of these three supplements in periodontal health, their potential in synergistic effects, and existing research gaps, providing a foundation for future studies on their clinical applications. Vitamin D is essential for calcium homeostasis, bone remodeling, and immune function. It modulates both innate and adaptive immune responses, enhancing antimicrobial peptide production and reducing inflammatory cytokine expression. Omega-3 fatty acids reduce the production of pro-inflammatory eicosanoids while promoting the synthesis of pro-resolving lipid mediators, contributing to bone preservation and immune balance. Melatonin, known for its antioxidant and osteogenic properties, supports bone remodeling by stimulating osteoblast proliferation and inhibiting osteoclast activity, while also regulating circadian rhythms, which may influence oral health. Although these bioactive compounds show promising effects in preclinical and clinical studies, significant knowledge gaps remain regarding optimal dosages, long-term efficacy, combined use, and standardized treatment protocols. Further clinical trials are necessary to elucidate their therapeutic value in periodontal disease management, especially those focused on their potential synergistic mechanisms. Understanding their synergistic mechanisms may open new avenues for adjunctive strategies in periodontal therapy. Full article