Search Results (92)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of type 2 diabetes and obesity, yet their actions extend beyond glycemic control and weight loss. This narrative review synthesizes current preclinical and clinical evidence examining the bidirectional relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and circadian biology. A structured literature search was conducted in PubMed using combinations of the terms ‘GLP-1,’ ‘circadian,’ ‘chronobiology,’ ‘sleep,’ ‘obesity,’ and ‘type 2 diabetes’ through January 2026. Accumulating evidence indicates that GLP-1 physiology is closely coupled to circadian timing systems and sleep–wake regulation. In this narrative review, we synthesize emerging data that reframe GLP-1RAs as chronometabolic modulators, acting at the intersection of metabolism, circadian biology, and sleep. We review circadian control of GLP-1 secretion by intestinal L-cells, emphasizing the role of core clock genes and the vulnerability of incretin rhythms to circadian misalignment from shift work, nocturnal light exposure, and sleep loss. We then examine GLP-1 receptor signaling within central and peripheral clock networks, including feedback effects on hypothalamic and hepatic circadian regulation. Emerging data suggest that GLP-1 signaling is under circadian regulation and may, in turn, influence central and peripheral clock systems. Comparative discussion of semaglutide, liraglutide, and tirzepatide highlights agent-specific pharmacokinetics and emerging clinical data linking GLP-1RA therapy to sleep outcomes, particularly obstructive sleep apnea. Finally, we outline translational opportunities for chronotherapy and precision medicine, positioning GLP-1RAs as integrative tools for metabolic and sleep-related disease rather than purely weight-centric therapies. We propose that GLP-1 receptor agonists may function as chronometabolic modulators, with potential implications for personalized chronopharmacological strategies in metabolic disease. Full article

Glioblastoma is the most common and aggressive brain tumour in adults, and despite ongoing efforts, effective treatment remains limited. Standard therapies often face challenges because of the tumour’s specific biology, its aggressive nature, and the presence of certain physiological barriers in the brain that impede chemotherapeutics from reaching their target. Emerging research in circadian biology highlights the role of the internal circadian clock in tumour progression and treatment response. Evidence suggests that aligning therapy to patients’ chronotypes could potentially improve treatment outcomes. At the same time, advances in nanotechnology—including functionalized nanoparticles for drug and/or gene delivery—show promising results while reducing side effects. Additionally, evolving and prominent artificial intelligence tools may significantly contribute to progress in the design of next-generation personalised therapies. This review provides a unique and integrative perspective by examining the hurdles in treating GB and exploring innovative strategies, such as the integration of nanotechnology into chronotherapy protocols, to enhance therapeutic efficacy. The Chronobiology–Nanotechnology combination could not only improve GB patients’ survival rates but also lead to a more effective and less toxic personalised approach, distinguishing this work from previous reviews. Full article

Background/Objectives: Combined chronotherapy (CCT), which combines repeated sleep deprivation and light therapy, is used in the clinical treatment of severe depression. Despite its potential to rapidly reduce depressive symptoms, CCT is infrequently used in clinical practice. We explored whether actigraphy-derived within-patient changes in physical activity, sleep parameters, and sleep–wake patterns prior to CCT can help identify those most likely to benefit from this treatment, supporting personalized mental health care. Methods: Actigraphy data from nine severely depressed patients were collected before, during, and after CCT. Data were assessed with a questionnaire on depressive symptoms (Inventory of Depressive Symptomatology—Self Report, IDS-SR) and actigraphy measures for sleep–wake patterns and physical activity: daily mean activity level, rhythm (intradaily variability (IV), interdaily stability (IS)), Midpoint of Sleep (MSF), time in bed, sleep efficiency (SE), and the fragmentation index (FI). Variables were compared before and after CCT by systematic visual inspection due to the small sample size. A prior set Minimal Clinically Important Difference (MCID) of a 30% change in IDS scores from before and the week after CCT was used to categorize patients as responders (n = 3) or nonresponders (n = 6) to CCT. Results: After CCT, for both responders and nonresponders, there was a notable decrease in IDS, IV and FI. Prior to CCT, responders, compared to nonresponders, were characterized with higher IDS, more time in bed and higher FI, while having lower SE. Conclusions: We concluded that actigraphy assessments during regular CCT are feasible and found preliminary evidence that patients with the most disrupted sleep–wake patterns prior to treatment may benefit most from CCT. Full article

Melatonin, an indolic neuromodulator with putative oncostatic and proposed anti-inflammatory properties, primarily demonstrated in preclinical models, is produced at extrapineal sites—most notably in the gut. Its canonical actions are mediated by high-affinity GPCRs (MT1/MT2) and by NQO2, a cytosolic enzyme with a melatonin-binding site (historically termed “MT3”). A growing body of work highlights a bidirectional interaction between the gut microbiota and host melatonin. We integrated two lines of work: (i) three clinical cohorts—cardiac arrhythmias (n = 111; 46–75 y), epilepsy (n = 77; 20–59 y), and stage III–IV solid cancers (25–79 y)—profiled with stool 16S rRNA sequencing, SCFA measurements, and circulating melatonin/urinary 6-sulfatoxymelatonin and (ii) an age-spanning cognitive cohort with melatonin phenotyping, microbiome analyses, and exploratory immune/metabolite readouts, including a novel observation of melatonin binding on bacterial membranes. Across all three disease cohorts, we observed moderate-to-severe dysbiosis, with reduced alpha-diversity and shifted beta-structure. The core dysbiosis implicated tryptophan-active taxa (Bacteroides/Clostridiales proteolysis and indolic conversions) and depletion of SCFA-forward commensals (e.g., Faecalibacterium, Blautia, Akkermansia, and several Lactobacillus/Bifidobacterium spp.). Synthesised literature indicates that typical human gut commensals rarely secrete measurable melatonin in vitro; rather, their metabolites (SCFAs, lactate, and tryptophan derivatives) regulate host enterochromaffin serotonin/melatonin production. In arrhythmia models, dysbiosis, bile-acid remodelling, and autonomic/inflammatory tone align with melatonin-sensitive antiarrhythmic effects. Epilepsy exhibits circadian seizure patterns and tryptophan–metabolite signatures, with modest and heterogeneous responses to add-on melatonin. Cancer cohorts show broader dysbiosis consistent with melatonin’s oncostatic actions. In the cognitive cohort, the absence of dysbiosis tracked with preserved learning across ages, and exploratory immunohistochemistry suggested melatonin-binding sites on bacterial membranes in ~15–17% of samples. A unifying microbiota–tryptophan–melatonin axis plausibly integrates circadian, electrophysiologic, and immune–oncologic phenotypes. Practical levers include fiber-rich diets (to drive SCFAs), light hygiene, and time-aware therapy, with indication-specific use of melatonin. Our conclusions regarding microbiota–melatonin crosstalk rely primarily on local paracrine effects within the gut mucosa (where melatonin concentrations are 10–400× plasma levels), whereas systemic chronotherapy conclusions depend on circulating melatonin amplitude and phase. This original research article presents primary data from four prospectively enrolled clinical cohorts (total n = 577). Full article

Cardiometabolic diseases, including hypertension, type 2 diabetes, dyslipidemia, and obesity, along with their cardiovascular complications, remain leading causes of morbidity and mortality worldwide, imposing significant public health, economic, and societal burdens. Conventional pharmacological therapies often show limited efficacy and increased adverse effects because they do not account for the body’s intrinsic circadian rhythms, which regulate organ function, drug absorption, and metabolism. Chronopharmacology, which aligns treatment timing with these biological rhythms, offers a strategy to enhance therapeutic outcomes. This review presents a comprehensive analysis of chronopharmacology principles applied to cardiometabolic disease management, integrating molecular, physiological, and clinical perspectives. It examines how core clock genes and tissue-specific circadian patterns influence drug action and absorption and summarizes evidence-based time-optimized interventions for hypertension, diabetes, dyslipidemia, obesity, and multimorbid patients. Furthermore, the review highlights emerging innovations, including artificial intelligence-guided dosing, circadian-biomarker-informed therapy selection, and wearable digital devices for real-time monitoring of biological rhythms. By synthesizing mechanistic and clinical insights, circadian-aligned treatment strategies are shown to improve drug efficacy, reduce adverse effects, and support the development of precision, rhythm-based therapeutics, offering a practical framework for personalized cardiometabolic disease care. Full article

The dramatic shift in human behavior from hunter-gatherer to modern lifestyles has led to a systematic disruption of the human circadian cycle. Contributors include night-shift work, jet lag, and less intuitive but widespread factors, such as exposure to artificial light at night and irregular eating schedules. Circadian disruption is classified as a Group 2A carcinogen by the International Agency for Research on Cancer (IARC). Hepatocellular carcinoma (HCC) is the third most deadly cancer worldwide, with a rising prevalence in Western countries, largely driven by increasing rates of obesity and steatotic liver disease-associated hepatocarcinogenesis. Emerging evidence suggests that circadian disruption plays a significant role in HCC pathogenesis. Several genes involved in metabolism, cell survival, and immunosurveillance are under the control of circadian rhythms. Experimental preclinical data and epidemiological studies have indicated a strong association between circadian disruption and HCC development. Moreover, molecular signatures related to circadian regulation appear to accurately predict the prognosis of patients with HCC. The concept of chronotherapy is also gaining interest, with studies suggesting improved immunotherapy effectiveness when immune checkpoint inhibitors are administered in the morning. This review summarizes the current literature on the impact of circadian disruption on HCC pathogenesis, prognosis, and treatment. Full article

Colorectal cancer (CRC) is a life-threatening malignancy, but our understanding of its pathogenic mechanisms remains incomplete—posing a major constraint on the development of effective therapeutic strategies. The transcription-translation feedback loop of clock genes (e.g., BMAL1, CLOCK, PER1/2/3, and CRY1/2) provides a promising novel avenue for deciphering the initiation and progression of CRC. Mounting evidence indicates that core circadian clock genes play pivotal roles in CRC oncogenesis by orchestrating the regulation of the cell cycle, epithelial–mesenchymal transition (EMT), metabolic reprogramming, and the tumor microenvironment. This review systematically summarizes the expression patterns and mechanistic roles of core clock genes in CRC, while elucidating their molecular underpinnings in tumor progression via key signaling cascades (e.g., Wnt/β-catenin and c-Myc/p21 pathways). We emphasize the associations between circadian disruption and CRC—including diagnostic markers, prognostic assessment, and chemosensitivity—and provide an in-depth discussion of chronotherapeutic strategies and their translational potential. Finally, we identify unaddressed scientific questions and propose future research directions to facilitate the development of novel targeted therapies for CRC. Full article

Melatonin, a key regulator of the circadian rhythm, exerts strong antioxidant effects by scavenging reactive oxygen species (ROS) and modulating enzymatic redox balance. Xanthine oxidoreductase (XOR), a molybdenum- and iron–sulfur-containing enzyme, catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid—the final steps of purine catabolism—serving as an important enzymatic source of ROS under physiological conditions. XOR exists in three interconvertible isoforms: xanthine dehydrogenase (XDH), which uses NAD⁺ as an electron acceptor; xanthine oxidase (XO), which transfers electrons to oxygen, producing superoxide and hydrogen peroxide; and an intermediate form (XDO) that reflects the redox-dependent interconversion between the two. This study aimed to evaluate temporal and sex-dependent variations in XOR isoforms and their relationship with melatonin levels in healthy individuals. Sixty-six volunteers (33 women aged 24–38 and 33 men aged 24–44) were examined. Blood samples were collected at 02:00, 08:00, 14:00, and 20:00. Serum melatonin was measured using ELISA, and XOR isoform activities were determined spectrophotometrically. Melatonin exhibited a precise 24 h rhythm with a nocturnal peak at 02:00 (~98 pg/mL) and a daytime nadir at 14:00 (~9 pg/mL). XO activity varied significantly (p < 0.01), showing an inverse correlation with melatonin in men (ρ = −0.52, p = 0.006), while XDO activity correlated positively with melatonin in women at 14:00 (ρ = 0.48, p = 0.01). These findings indicate sex-specific and time-dependent regulation of XOR isoforms, suggesting that redox homeostasis is modulated differently in men and women throughout the day. Understanding these dynamics may refine the interpretation of oxidative stress biomarkers and help optimize diagnostic and chronotherapeutic approaches in redox-related disorders. Full article

Daily rhythms define physical, mental, and behavioral changes that the body experiences over a 24 h cycle. The light–dark cycle plays a crucial role in regulating daily rhythms, but other factors such as food intake, stress, and physical activity also affect them. Cortisol secretion exhibits one of the largest endocrine amplitudes, with an early morning peak and late-evening nadir driven by the suprachiasmatic nucleus and hypothalamus–pituitary–adrenal axis, representing the most robust endocrine output of the circadian system. Beyond photic cues, feeding is a potent non-photic zeitgeber that entrains peripheral oscillators and dynamically shapes cortisol secretion. This narrative review aims to explore the effect of feeding in modulating cortisol secretion. The misalignment of the daily cortisol-secretion rhythm, with blunted cortisol awakening response and elevated evening levels, leads to metabolic syndrome, psychiatric disorders, shift work, and jet lag. In endogenous hypercortisolism, the loss of rhythmicity rather than absolute exposure best predicts risk. Therefore, we discuss practical nutritional tools as opportunities to partially restore rhythmic hypothalamus–pituitary–adrenal axis physiology. Full article

Neuronal membrane capacitance (Cm) has traditionally been viewed as a static biophysical property determined solely by the geometric and dielectric characteristics of the lipid bilayer. Recent discoveries have fundamentally challenged this perspective, revealing that Cm exhibits robust circadian oscillations that profoundly influence neural computation and behavior. These rhythmic fluctuations in membrane capacitance are orchestrated by intrinsic cellular clocks through coordinated regulation of molecular processes including transcriptional control of membrane proteins, lipid metabolism, ion channel trafficking, and glial-mediated extracellular matrix remodeling. The dynamic modulation of Cm directly impacts the membrane time constant (τm = RmCm), thereby altering synaptic integration windows, action potential dynamics, and network synchronization across the 24 h cycle. At the computational level, circadian Cm oscillations enable neurons to shift between temporal summation and coincidence detection modes, optimizing information processing according to behavioral demands throughout the day–night cycle. These biophysical rhythms influence critical aspects of cognition including memory consolidation, attention, working memory, and sensory processing. Disruptions in normal Cm rhythmicity are increasingly implicated in neuropsychiatric and neurodegenerative disorders, including depression, schizophrenia, Alzheimer’s disease, and epilepsy, where altered membrane dynamics compromise neural circuit stability and information transfer. The integration of circadian biophysics with chronomedicine offers promising therapeutic avenues, including chronotherapeutic strategies that target membrane properties, personalized interventions based on individual chronotypes, and environmental modifications that restore healthy biophysical rhythms. This review synthesizes evidence from molecular chronobiology, cellular electrophysiology, and systems neuroscience to establish circadian Cm regulation as a fundamental mechanism linking molecular timekeeping to neural computation and behavior. Full article

Background: Breast cancer remains a major global health threat to women. While current therapies exist, their limitations necessitate novel strategies. Melatonin, an endogenous circadian regulator, has shown anti-tumor potential, but its mechanisms from a circadian perspective require further exploration. Methods: The anti-tumor effects of melatonin were evaluated through cell proliferation, colony formation, and apoptosis assays. Through data analysis and experimental verification at the RNA and protein levels, the regulatory effect of it on the core clock gene BMAL1 was studied. The role of BMAL1 in mediating melatonin’s suppression of glucose metabolism was assessed by measuring glucose uptake and lactate production. Downstream effector molecules of BMAL1 were identified through molecular interaction and transcriptional regulation analyses. Results: Melatonin significantly inhibited breast cancer cell proliferation and colony formation and induced apoptosis. Mechanistically, it upregulates the core clock gene BMAL1, which suppresses glucose metabolism. ALDH3A1 was identified as a key downstream target of BMAL1, defining a novel “melatonin-BMAL1-ALDH3A1” axis. In vivo studies confirmed that this axis effectively inhibits tumor growth without apparent toxicity, and SR8278 also shows a synergistic effect when used in combination with melatonin. Conclusions: Our findings elucidate the role of the “melatonin-BMAL1-ALDH3A1” axis in combating breast cancer, offering a new direction for treatment and laying the groundwork for developing precision chronotherapy-based combination regimens. Full article

The bidirectional relationship between obstructive sleep apnea (OSA) and type 2 diabetes mellitus (T2DM) represents a critical intersection in metabolic medicine. Therefore, the present review examines the most recent data regarding molecular mechanisms linking OSA and T2DM, analyzing key biomarkers including hypoxia-inducible factors (HIF 1α), inflammatory mediators, adipokines, microRNAs, hormones, and neuropeptides that serve as both diagnostic indicators and potential therapeutic targets. Key molecular findings from the scientific literature report elevated HIF-1α promoting insulin resistance, decreased SIRT1 levels, dysregulated microRNA-181a and microRNA-199a, increased inflammatory cytokines (TNF-α, IL-6, CRP), and altered adipokine profiles with reduced adiponectin and elevated leptin and resistin. Current clinical evidence reveals significant therapeutic potential for modern antidiabetic medications in the management of OSA. GLP-1 receptor agonists, particularly tirzepatide, received FDA approval as the first medication for moderate-to-severe OSA in obese adults, showing a 55–63% AHI reduction. SGLT2 inhibitors also demonstrate promising results through weight loss and cardiovascular protection mechanisms. This integrated approach represents the evolution toward comprehensive OSA management beyond traditional mechanical ventilation strategies. Future research should focus on developing personalized treatment algorithms based on individual molecular biomarker profiles, investigating combination therapies, and exploring novel targets, including chronotherapy agents. Full article

Background: Although there has been an improvement in the survival rates of patients following heart transplantation, many complications, such as hypertension, continue to develop. The aim of the study was to assess the 24-hour blood pressure profile and hypertension treatment among patients after heart transplantation and comparison to the control group. Methods: A retrospective data analysis included 26 male patients post-heart transplantation and 39 male patients in the control group. During a routine visit, the following data were collected: 24-hour blood pressure monitoring, laboratory tests, and medical history. Results: Hypertension was diagnosed in 76.9% of heart transplant recipients (HTXr) and in 56.4% of the control group (Cx). During the night-time rest period, diastolic blood pressure values ≥ 70 mmHg were observed in 76.9% of HTXr (vs. 33.33% Cx, p = 0.001). The average daytime systolic/diastolic blood pressure did not differ significantly between the groups. It was also observed that the groups differed in circadian blood pressure (Chi²ML = 15.87, p < 0.001), as there were significantly more reverse dippers in HTXr than in the control group (30.8% (8) vs. 10.3% (4)). The same proportions were also noted in HTXr and the control group in terms of isolated nocturnal hypertension. Conclusions: Heart transplant recipients require a tailored approach to hypertension management, including a variety of medications and appropriate chronotherapy. Full article

Skeletal muscle plays vital roles in locomotion, metabolic regulation and endocrine signalling. Critically, it undergoes structural and functional decline with age, leading to a progressive loss of muscle mass and strength (sarcopenia) and contributing to a systemic loss of tissue resilience to stressors of multiple tissue systems (frailty). Emerging evidence implicates misalignments in both the circadian molecular clock and redox homeostasis as major drivers of age-related skeletal muscle deterioration. The circadian molecular clock, through core clock components such as BMAL1 and CLOCK, orchestrates rhythmic gene, protein and myokine expression impacting diurnal regulation of skeletal muscle structure and metabolism, mitochondrial function, antioxidant defence, extracellular matrix organisation and systemic inter-tissue communication. In parallel, the master redox regulator, NRF2, maintains cellular antioxidant defence, tissue stress resistance and mitochondrial health. Disruption of either system impairs skeletal muscle contractility, metabolism, and regenerative capacity as well as systemic homeostasis. Notably, NRF2-mediated redox signalling is clock-regulated and, in turn, affects circadian clock regulation. Both systems are responsive to external cues such as exercise and hormones, yet studies do not consistently include circadian timing or biological sex as key methodological variables. Given that circadian regulation shifts with age and differs between sexes, aligning exercise interventions with one’s own chronotype may enhance health benefits, reduce adverse side effects, and overcome anabolic resistance with ageing. This review highlights the essential interplay between circadian and redox systems in skeletal muscle homeostasis and systemic health and argues for incorporating personalised chrono-redox approaches and sex-specific considerations into future experimental research and clinical studies, aiming to improve functional outcomes in age-related sarcopenia and broader age-related metabolic and musculoskeletal conditions. Full article

Background/Objectives: Wolfram syndrome is a rare neurodegenerative disorder primarily known for its multisystemic manifestations. Although classically associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, emerging evidence suggests a consistent pattern of executive dysfunction in many affected individuals. Methods: Based on findings from a scoping review and results obtained through the Dysexecutive Questionnaire in a Spanish patient cohort, we propose that WFS1 gene mutations—via chronic endoplasmic reticulum stress—disrupt serotonergic and cholinergic neurotransmission, leading to impairments in planning, inhibition, and emotional regulation. Results: Importantly, recent studies have highlighted the interplay between WFS1-related molecular dysfunction and circadian regulation. Given the role of the endoplasmic reticulum and mitochondrial signaling in circadian homeostasis, and the frequent sleep disturbances observed in patients with Wolfram syndrome, we hypothesize that circadian dysregulation may contribute to the neurobehavioral phenotype. Conclusions: This essay explores neuropsychological foundations of executive dysfunction in WS, and frames the current evidence as hypothesis-generating rather than causal; executive difficulties may be a salient clinical feature and merit consideration in routine care. Furthermore, the potential involvement of circadian mechanisms opens new avenues for future research and therapeutic approaches. Because circadian disruption is linked to psychiatric symptoms and fatigue, emphasizing diurnal patterns, sleep–wake timing, and chronotype may guide circadian-informed assessment. Full article