Melatonin

Abstract

Aging heightens susceptibility to ischemia-reperfusion (IR) injury, complicating liver transplantation, while the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome drives IR- and aging-induced inflammation. Although the effects of melatonin (MLT) on IR or aging have been studied separately, its impact on NLRP3 inflammasome activation in age- related IR injury remains unclear. This study investigates the impact of aging on hepatic IR injury, evaluating MLT therapeutic potential. for mitigating age-related damage. Aged and young male Wistar rats underwent 60 min of ischemia followed by 6-24 h of reperfusion. MLT (1 mg/100 g body weight) was injected 30 min before ischemia, 10 min before reperfusion, and 2 h after reperfusion. Liver injury, oxidative stress and inflammatory responses, and activation of the NLRP3 inflammasome pathway were evaluated. Aged livers exhibited exacerbated IR injury, marked by elevated transaminases levels, severe histopathological damage, increased oxidative stress and heightened inflammatory responses compared to young IR-injured rats. MLT treatment significantly alleviated liver injury, reducing oxidative stress and inflammatory markers expression. Aging-associated IR injury correlated with increased NLRP3 inflammasome activation and pyroptosis, evidenced by the upregulation of apoptosis-associated speck-like protein containing a CARD (ASC-1), caspase-1 cleavage, interleukin (IL)-1β maturation and increased Il18 and Gsdmd gene expression; while MLT treatment suppressed this activation, downregulating these markers in aged IR-injured livers. These findings highlight the efficacy of MLT in mitigating IR-induced liver damage in aged rats by inhibiting the NLRP3 inflammasome activation, supporting its potential as a therapeutic strategy for age-related liver dysfunction.

Abstract

People with autism spectrum disorders (ASD) show a relative suppression of the melatonergic pathway across CNS and systemic cells. The differential regulation of the mitochondrial melatonergic pathway may therefore be an important core aspect of ASD pathophysiology in all its manifestations. Recent data across diverse human cells show that the melatonergic pathway is powerfully regulated by interactions between signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), with the composition of the NF-κB dimer determining whether the melatonergic pathway is upregulated or downregulated. Diverse aspects of ASD pathoetiology and pathophysiology, including the aryl hydrocarbon receptor (AhR), microRNAs, suboptimal mitochondrial function, pro-inflammatory cytokines, glucocorticoid receptor, vagal nerve, and oxytocin, are all intimately linked to pineal and/or local melatonin regulation, indicating the relevance of the mitochondrial melatonergic pathway regulation in the pathoetiology and pathophysiology of ASD. This article reviews and integrates diverse aspects of ASD pathoetiology and pathophysiology, with implications for future research and treatment.

Abstract

Reaching term gestation requires a complex interplay between the uterus and hormonal signals regulating its contractile profile. Most pregnancy-associated hormones vary in their overall level of release throughout pregnancy, but also have a circadian release pattern, including progesterone, oxytocin, and melatonin. It remains poorly understood how the circadian release of hormones impacts uterine function. To determine how time-of-day, mouse strain, and melatonin proficiency were associated with the uterotonic efficacy of oxytocin, the primary hormone promoting uterine contractions, we used melatonin-deficient C57BL/6 and melatonin-proficient CBA/C57BL/6 (CBA/B6) female mice on gestation day 18. Through RNAscope, we found that oxytocin receptor (Oxtr) mRNA exhibited a time-of-day variation that differed between the uterine endometrium and myometrium. This uterine layer-specific, time-of-day difference in Oxtr was associated with a shift in phase of the molecular clock reporter PER2::Luciferase. A strain-specific effect of PER2::Luciferase rhythms were observed in the uterus, where CBA/B6 had a shorter PER2::Luciferase period than C57BL/6. In addition, CBA/B6 uteri had lower spontaneous uterine contraction force compared to C57BL/6. Despite the difference in spontaneous contractions and circadian period, the capacity of oxytocin to induce contractions varied by time-of-day, independent of mouse strain. Together, these findings reveal that uterine responsiveness to oxytocin is gated by circadian time, with Oxtr expression and uterine contractions showing diurnal variation. At the same time, mouse strain was associated with PER2::Luciferase period and baseline uterine contractility. These results underscore the relevance of circadian timing in uterine physiology and that strain differences impact basal uterine function.

Abstract

In vitro oocyte maturation (IVM) is a pivotal process influencing the success of embryo production in laboratory and clinical settings. However, oxidative stress (OS) often compromises oocyte quality during IVM. Antioxidants such as melatonin and epigallocatechin-3-gallate (EGCG) are known to mitigate OS by neutralizing reactive oxygen species (ROS) and bolstering antioxidant defenses. Despite extensive studies on their individual effects, the synergistic impact of melatonin and EGCG remains underexplored. Utilizing a mouse model, this study evaluated their combined effect on oocyte maturation, focusing on nuclear and cytoplasmic development, intracellular ROS, glutathione (GSH) levels, and subsequent embryonic competence. The results demonstrated that melatonin and EGCG significantly enhanced the polar body extrusion rate (p < 0.05), with the combination group achieving the highest rate of 91.96%. Cumulus expansion was observed to improve across all treated groups, with the combination treatment showing the highest cumulus expansion index (CEI) of 3.06. Furthermore, the combination treatment significantly reduced ROS levels and increased GSH content, indicating enhanced antioxidant capacity (p < 0.01). Embryonic development outcomes, including cleavage and blastocyst rates, were markedly higher in the combination group at 75.23% and 53.97%, respectively, demonstrating superior developmental potential (p < 0.01). These findings suggest that the melatonin-EGCG combination offers a novel and effective strategy to combat oxidative damage during IVM, thereby improving oocyte quality and embryonic development potential in mice.

Abstract

Obesity is a major contributor to kidney injury, in part through circadian rhythms disruption and oxidative stress. Melatonin, a circadian clock regulator, has been proposed as a protective agent against metabolic and renal complications. We investigated the effects of chronic melatonin supplementation on kidney injury and circadian regulation in a rat obesity model. We hypothesized that melatonin administration ameliorates kidney injury induced by a high-calorie diet. Male Wistar rats were fed a normal or hypercaloric diet for six weeks, followed by seven weeks of vehicle or melatonin treatment (30 mg/kg/day in drinking water); biometric parameters and renal injury were assessed. Obese rats exhibited increased visceral adiposity, elevated resistin, renal hypertrophy, fibrosis, tubular degeneration, and glomerular injury, accompanied by higher KIM-1 levels. Melatonin attenuated renal fibrosis, reduced KIM-1, TGFβ, and TNFR1 levels, improved proximal tubule and glomerular damage, and lowered adipose TNF-α levels in the obese groups. In lean controls, melatonin increased nuclear BMAL1 levels, while in obese rats this effect was blunted; of note, BMAL1 accumulated in distal tubular cytoplasm in both melatonin-treated groups. These findings suggest that melatonin mitigates obesity-induced renal pathology through anti-fibrotic inflammation-related mechanisms, while also revealing a novel link between circadian disruption and kidney injury. Our results support melatonin as a therapeutic agent for obesity-related renal disease.

Abstract

The pineal gland is an organ that undergoes significant degeneration with age, and these degenerative changes lead to numerous physiological alterations. This study investigated age-related molecular changes and Alzheimer's disease (AD)-associated pathology in the human pineal gland using histopathological analyses. This study collected a total of 54 human pineal gland specimens. Of these, 47 were categorised into five age groups: 0-20, 21-40, 41-60, 61-80, and 81-100 years. A further 7 cases with confirmed AD-related neuropathological changes were assigned to the AD group, while matched to 7 controls. Our findings revealed that pineal calcification was initiated as early as age 3, with progressive accumulation of calcification and accompanying cellular loss during the ageing process. A remarkable degree of sexual dimorphism was observed: female-predominant patterns included lipofuscin deposition and pineal cysts, whereas male-predominant characteristics included glial fibrillary acidic protein (GFAP) immunoreactivity and connective tissue expression. Significantly, phosphorylated Tau (P-Tau) and amyloid-beta (Aβ) have recently been detected within the pineal gland. Aβ deposition was positively correlated with age and was markedly elevated in individuals with AD. Furthermore, individuals with AD exhibited marked pineal cellular depletion compared with controls, alongside elevated GFAP expression. Cerebro-spinal fluid analysis further revealed significantly reduced melatonin levels in the AD cohort. Overall, this study systematically elucidated the multidimensional pathological features of the pineal gland during ageing and AD progression, and these findings may open new avenues for mechanistic exploration and precision medicine in AD.

Abstract

Neonatal hypoxic-ischemic brain damage (HIBD) is a leading cause of neurological dysfunction and long-term disability in newborns. Lactate accumulation and metabolic disturbances after brain injury inhibit neurogenesis, while the restorative capacity of endogenous neural stem cells (NSCs) is essential for neural reconstruction. Melatonin (Mel) alleviates neonatal brain injury, but its effects on NSCs proliferation and migration remain unclear, and the visualization methods for dynamic monitoring of metabolic changes are inadequate. In this study, a neonatal rat model of HIBD was established, and multimodal MRI combined with histological techniques was employed to evaluate the effects of Mel on NSCs regeneration and metabolic conditions in the hippocampal dentate gyrus. Using these techniques, the potential neuroprotective effects of Mel via the JAK2/STAT3 pathway were investigated. Multimodal MRI revealed that Mel increased cerebral blood flow and oxygen saturation, reduced lactate levels, improved brain metabolic microenvironment, and alleviated brain damage caused by HIBD. EdU/Nestin and EdU/DCX staining revealed that Mel promoted the proliferation and migration of endogenous NSCs, thereby enhancing neurogenesis. In addition, the use of a JAK2 inhibitor (WP1066) and agonist (C-A1) verified that Mel exerted its protective effects by down-regulating the JAK2/STAT3 pathway. Morris water maze further confirmed that Mel improved spatial learning and memory function in neonatal rats with HIBD. Multimodal MRI offers a visual basis for monitoring metabolic changes and therapeutic effects, while Mel enhances neurogenesis and mitigates brain injury through inhibition of the JAK2/STAT3 pathway, thus providing a theoretical basis for the clinical application of Mel in HIBD in neonates.

Abstract

Chronic stress-induced sleep disorders are characterized by disrupted sleep architecture and a significant reduction in slow-wave sleep (SWS). These disorders represent a major public health challenge and are mechanistically linked to the hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. This study employed a translational research paradigm-including zebrafish screening, a chronic unpredictable mild stress (CUMS) mouse model, and an eight-week randomized, placebo-controlled human trial-to evaluate the efficacy of a combination of walnut peptide and theanine (WPT). Treatment with WPT reduced waking activity and duration in pentylenetetrazole (PTZ)-induced zebrafish. In CUMS mice, the combination significantly improved sleep architecture by restoring the duration of SWS and enhanced sleep quality by increasing delta wave power density. Mechanistically, the intervention corrected hypothalamic-pituitary-adrenal (HPA) axis hyperactivity by lowering elevated serum corticosterone (CORT) levels. Furthermore, it modulated central neurotransmitters, notably reversing stress-induced deficits by increasing the levels of the inhibitory neurotransmitter GABA and tryptophan, a key precursor for serotonin and melatonin. In the human trial, the WPT restored sleep duration and improved subjective sleep quality scores (assessed by the Pittsburgh Sleep Quality Index, PSQI). In conclusion, this translational study provides robust evidence that the WPT effectively improves chronic stress-induced sleep disorders in zebrafish and mice, and improves sleep disturbances in adults (PSQI ≥ 7) by regulating HPA axis function and restoring the duration and quality of SWS. This makes it a highly promising nutritional intervention strategy.

Abstract

To investigate the mechanism of chronic intermittent hypoxia on gastric injury in rats and the intervening effect and possible mechanism of melatonin.

Abstract

Melatonin has demonstrated beneficial effects in regulating inflammatory processes in various tissues, but its role in mare uterine physiology remains unclear.

Abstract

p-Synephrine (p-Syn), a natural alkaloid isolated from Citrus aurantium L., promotes fat oxidation and is therefore widely used as a weight loss dietary supplement. It was recently reported to exert a potent antidepressant effect. However, its molecular targets remain undefined. Gastrodin (Gas), extracted from Gastrodia elata Blume, exerts antidepressant effects by targeting Melatonin Receptor 1A (MT1).

Abstract

Between 50% and 80% of children diagnosed with Autism Spectrum Disorder (ASD) are estimated to experience sleep disturbances, highlighting the importance of exploring the role of the circadian clock in ASD development. Previous studies have identified a potential link between Bmal1 deficiency and ASD in mouse models. In this study, we first characterise the expression patterns of circadian proteins. Subsequent behavioural tests and western blot analyses revealed that mice exposed to valproic acid (VPA) displayed autistic-like behaviours, along with altered circadian protein expression and disruption in Wnt signalling protein levels. Further studies showed that Bmal1 knockout exacerbates these behavioural changes and further impaired Wnt signalling and downstream protein expression in VPA-exposed mice. Notably, treatment with the circadian biomarker melatonin reversed Wnt downregulation and improved the behaviour deficit in VPA-exposed mice. The therapeutic effect of melatonin appears to be mediated by its regulation of the Wnt/β-catenin signalling pathway, which is linked to Bmal1-mediated circadian dysfunction. Together, our findings provide experimental evidence supporting the role of circadian dysregulation in ASD pathogenesis, highlight the therapeutic potential of melatonin in VPA-exposed mice, and suggest that Bmal1 may act as a co-activator in the Wnt-β-catenin signalling pathway.

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation and emphysema and is induced primarily by cigarette smoke (CS) exposure. Emerging evidence suggests that alveolar macrophage (AM) pyroptosis contributes to COPD pathogenesis; however, the underlying mechanisms are incompletely understood. Moreover, although melatonin is known to have therapeutic potential for COPD, whether the regulation of AM pyroptosis contributes to its therapeutic effects remains unclear. Here, we investigated the mechanism by which AM pyroptosis participates in COPD airway inflammation and the effect of melatonin in CS-induced COPD model mice and cigarette smoke extract (CSE)-stimulated MH-S cells. Our in vivo experiments revealed that melatonin treatment improved lung function and alleviated emphysema and airway inflammation in COPD mice. Additionally, elevated AM pyroptosis and increased NLRP3 inflammasome activation were observed in COPD mice, and both of these changes were mitigated by melatonin treatment. Further in vitro experiments demonstrated that melatonin inhibited NLRP3 inflammasome activation in MH-S cells. Importantly, melatonin also suppressed CSE-induced pyroptosis, as evidenced by improved membrane integrity (lower proportion of PI-positive cells and reduced LDH release), decreased levels of IL-1β and IL-18, and downregulated GSDMD-N expression. Notably, the NLRP3 inhibitor MCC950 reversed CSE-induced inflammation and pyroptosis, and the protective effect of melatonin was offset by treatment with the NLRP3 antagonist nigericin. Taken together, our results suggest that melatonin alleviates airway inflammation in COPD possibly by inhibiting NLRP3-mediated pyroptosis in AMs, thereby implicating AM pyroptosis in the pathogenesis of COPD and highlighting melatonin's potential as a therapeutic candidate.

Abstract

Intervertebral disc degeneration (IVDD), a primary cause of chronic low back pain, involves extracellular matrix (ECM) degradation and nucleus pulposus cell apoptosis. While traditionally linked to mechanical stress, inflammation, oxidative stress, and metabolic dysfunction, emerging evidence positions circadian clock disruption as the central hub integrating these factors. Under physiological conditions, the core clock genes BMAL1/CLOCK regulate ECM homeostasis.

Abstract

Skin pigmentation by the endogenous pigment melanin is a highly coordinated process in which hormones play a crucial role. They are synthesized not only in classical endocrine organs but also in the skin itself, which acts as an independent endocrine organ. Among the endocrine target structures of the skin, the melanocortin 1 receptor (MC1R) is of particular importance. Via its high expression and tonic activity in melanocytes, as well as by binding to natural melanocortins such as α‑melanocyte-stimulating hormone (α-MSH), being generated in the skin following ultraviolet (UV) light irradiation, MC1R crucially contributes to the different skin phototypes. Gene mutations of MC1R resulting in defective cyclic adenosine monophosphate (cAMP)-mediated signalling can lead to a shift of the eumelanin/pheomelanin ratio towards the pro-oxidant, yellowish-orange pheomelanin. In patients with Addison's disease and associated syndromes, ectopic proopiomelanocortin syndrome and primary adrenal cortex insufficiency elevated melanocortin levels result in increased melanin content of the skin. Two synthetic melanocortins, afamelanotide (NDP-α-MSH) and setmelanotide, are currently approved in Germany. By targeting MC1R directly (afamelanotide) or as a bystander effect (setmelanotide), both agents increase the skin melanin content. Non-licenced synthetic melanocortins, on the other hand, are used as lifestyle products in an unregulated manner. Additional hormones regulating melanogenesis and skin pigmentation include estrogens, thyroid hormones, insulin, insulin-like growth-factor‑1 and melatonin. They are of physiological and clinical relevance during pregnancy and in patients with melasma and vitiligo. Autoimmune thyroid disorders and diabetes are associated with non-segmental vitiligo. Melatonin appears to have a lightening effect on skin pigmentation by melanin.

Abstract

Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and high recurrence rates, contributing to poor prognoses of TNBC patients. However, the lack of appropriate molecular targets limits the effectiveness of current antineoplastic therapies. Therefore, effective therapeutic strategies are urgently needed. Melatonin (N-acetyl-5-methoxytryptamine) has shown a broad spectrum of anticancer activities, but its potential for treating TNBC remains elusive. In this study, we discovered that melatonin suppressed the growth and invasiveness of TNBC cells through downregulating glycolytic capacity in association with inhibition of Yes-associated protein 1 (YAP1) signaling. Notably, melatonin suppressed expression of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme participated in nicotinamide adenine dinucleotide (NAD) turnover and contributes to protein poly(ADP)-ribosylation (PARylation). As a result, melatonin potentiated DNA damage and elevated apoptosis. Furthermore, it is found that melatonin suppressed NAMPT expression via inhibition of YAP1. Moreover, downregulation of glycolysis decreased protein PARylation levels and increased DNA damage accumulation, suggesting that melatonin suppresses the crosstalk between glycolysis and DNA repair signaling. Combined treatment with melatonin and Olaparib, an inhibitor of the major conductor of protein PARylation, poly(ADP-ribose) polymerase (PARP), showed additive inhibitory effects on breast cancer proliferation compared to their single treatment. These findings demonstrated that melatonin may be a promising agent for targeting YAP1-mediated glycolysis and DNA repair in breast cancer for enhancing the therapeutic efficacy of Olaparib in TNBC patients.

Abstract

This study investigated the association between nighttime noise control and melatonin secretion alongside bone repair-related factors in patients with osteoporotic vertebral compression fractures.

Abstract

This study investigates the impact of sleep restriction (SR) on flap viability and its underlying mechanisms. It reveals that SR triggers clock rhythmic ferroptosis, which leads to impaired skin barrier function and increased flap necrosis.

Abstract

Heat stress represents a critical environmental and occupational hazard that impairs male reproductive capacity across mammalian species, including humans. It primarily exerts its deleterious effects by inducing oxidative stress and apoptosis in testicular Leydig cells, ultimately disrupting testosterone biosynthesis. In this study, primary Leydig cells (PLCs) were subjected to heat stress, which significantly elevated intracellular ROS, MDA, and XO levels while reducing TAC and SOD activities, leading to increased apoptosis. Pretreatment with 0.1 μM melatonin effectively restored redox homeostasis, lowering ROS, MDA, and XO and enhancing TAC and SOD, thereby markedly decreasing apoptotic cell death. Mechanistic studies showed that melatonin increased NRF2 expression, and NQO1 levels, while decreasing KEAP1, and reversed heat-induced upregulation of Bax and γH2AX and downregulation of Bcl-2. In vivo, melatonin-treated mice exhibited preservation of 3β-HSD-positive Leydig cell number, reduced seminiferous tubule vacuolization, normalized serum testosterone levels, and restoration of STAR, CYP11A1, and 3β-HSD protein expression. These findings demonstrate that melatonin alleviates heat stress-induced oxidative injury and apoptosis via activation of the KEAP1-NRF2 pathway and thereby protects Leydig cell function and testosterone production.

Abstract

Major depressive disorder (MDD) is a major public health issue worldwide. It not only causes an increased socio-economic burden, but also negatively affects personal lives. It has been shown that depression leads to impairments in synaptic plasticity, such as impaired long-term potentiation (LTP) in the prefrontal cortex (PFC). A recent study reported that administration of agomelatine, a melatonin receptor agonist and 5-hydroxytryptamine (5-HT) 2C antagonist, which may be involved in synaptic functions, for 1 week has a rapid antidepressive effect. Moreover, the mechanism of Glycogen synthase kinase 3β (GSK3β), regulated by signal transducer and activator of transcription 3 (STAT3), may play an important role in the synapse-related pathological mechanisms of depression. Hence, we used chronic social defeat stress (CSDS) as an animal model of depression, to investigate whether synaptic plasticity impairment in depression, improved by agomelatine, is mediated through the STAT3 mechanism. The results showed that depressive-like behaviors were reversed after 1 week of agomelatine treatment. Moreover, the impairment of LTP and alteration of spine density were reversed by agomelatine in the PFC. We further applied AG490, an inhibitor of STAT3, to demonstrate that the therapeutic mechanism of agomelatine improves synaptic plasticity through STAT3-regulated phosphorylation of GSK3β. Taken together, these results demonstrated that STAT3-regulated downstream molecules are potential therapeutic targets for the rapid action of antidepressants.

Abstract

Type 2 diabetes (T2D) is a heterogeneous metabolic disorder. Recent cluster-based classifications offer insights into distinct pathophysiological subtypes. The objective of the study is to investigate the association of genetic variants in T2D-related genes with defined T2D clusters. We analyzed 678 single nucleotide polymorphisms (SNPs) from ten genes (CDKAL1, CDKN2A, CDKN2B, HHEX, KCNQ1, MTNR1B, PAX4, SLC30A8, TCF7L2, and UBE2E2) in 471 T2D patients classified into four clusters: Severe Insulin-Deficient Diabetes (SIDD), Mild Obesity-related Diabetes (MOD), Mild Age-related Diabetes (MARD), and Metabolic Syndrome-related Diabetes (MSD). Genotyping was performed using the Axiom PDMRAv2 array. Following Hardy-Weinberg Equilibrium filtering, 376 SNPs were analysed. The association between T2D clusters and SNPs was assessed by multinomial logistic regression. Nineteen SNPs showed significant differences in genotypic frequencies among clusters (p < 0.05). Eight SNPs (rs61875103 in TCF7L2; rs12576156, rs2283220, rs2074197, and rs163165 KCNQ1; rs4710943, rs9368248, and rs6456379 in CDKAL1) significantly associated with cluster assignment. Cluster-specific effects were most notable in SIDD and MOD subgroups. Our findings support genetic heterogeneity of TCF7L2, KCNQ1, and CDKAL1 in T2D clusters and underscore the potential for genetically informed precision therapy strategies.

Abstract

Melatonin (MLT) is a potentially effective therapeutic agent for mitigating brain injury under various pathological conditions. However, the molecular mechanisms of its ability to ameliorate diabetic cognitive dysfunction (DCD) require further elucidation. In this study, we demonstrated that MLT administration improved the learning and memory deficits in type 2 diabetes mellitus (T2DM) mice, concurrently attenuated acyl-CoA synthetase long-chain family member 4 (ACSL4) - dependent ferroptosis in diabetic brain tissue and neuronal cells exposed to high glucose/palmitic acid (HG + PA), as indicated by reduced lipid peroxidation, elevated GSH and SOD levels, increased GPX4 levels, and downregulated ACSL4 expression. Furthermore, MLT reversed nuclear receptor coactivator 4 (NCOA4) -mediated ferritinophagy in vivo and in vitro. This opinion was demonstrated by decreased intracellular ROS and Fe2+ levels, reduced NCOA4 expression, and increased Ferritin levels. Mechanistic investigations revealed that MLT directly binds to stimulator of interferon genes (STING) and suppresses its expression and activation, as determined by surface plasmon resonance, molecular docking, and cellular thermal shift assays. Consequently, MLT treatment disrupted the subsequent recruitment of NCOA4 and ACSL4 to STING. Pharmacological activation or genetic overexpression of STING attenuated the inhibitory effect of MLT on ferroptosis and ferritinophagy. In contrast, STING silencing had the opposite effects under the aforementioned conditions. Our findings revealed that melatonin exerts dual regulatory mechanisms, inhibiting ACSL4-dependent ferroptosis and suppressing NCOA4 axis-mediated ferritinophagy through directly targeting STING, thereby ameliorating diabetic cognitive dysfunction.

Abstract

Society needs alternatives to painful, expensive, and cumbersome injections for diseases like diabetes. Franko et al. developed cells that sense melatonin to deliver glucagon-like peptide-1 (GLP-1) therapy during sleep. This circadian-synchronized approach restored normal blood sugar in diabetic mice, advancing the field of smart cells for patient-centered circadian medicine.

Abstract

Circadian rhythms are endogenous 24-h oscillations in physiological processes, with their regulation dependent on a molecular network comprising the core clock genes (CLOCK, BMAL1, PER, CRY) and other key clock genes (NR1D1/2, RORs). Research indicates that circadian rhythm disruption is a significant risk factor for immune dysregulation, while maintaining circadian rhythm balance may offer new therapeutic avenues for autoimmune diseases. This review systematically examines the regulatory mechanisms of the circadian clock genes in innate immunity, adaptive immunity (particularly Th17 cell differentiation and function), and inflammatory responses. By elucidating their molecular interactions, it clarifies the pivotal role of these clock genes in autoimmune diseases. Additionally, we have summarized research progress on small molecule modulators targeting clock genes, as well as non-pharmacological interventions such as sleep regulation, intermittent fasting (IF)/time-restricted feeding (TRF), and melatonin supplementation.In summary, this review aims to elucidate the role of clock genes in immune regulation and inflammatory responses, emphasizing their potential as therapeutic targets for autoimmune diseases.

Abstract

Mistimed eating disrupts the circadian rhythm of hepatic metabolism, thereby increasing the risk of fatty liver disease. Responding to nutrient status and light cues respectively, insulin and melatonin coordinately regulate hepatic lipid homeostasis and circadian clock oscillation. However, whether non-active phase eating-induced hepatic lipid accumulation involves altered rhythmic interactions between insulin and melatonin remains unclear. This study employed a porcine model to investigate the effects of eating time on hepatic lipid metabolism through a 3-month comparative trial of daytime-restricted feeding (DRF) versus nighttime-restricted feeding (NRF). Compared to DRF, NRF promoted hepatic lipogenesis and reversed the circadian rhythm of circulating insulin, synchronizing it with melatonin. To determine whether the temporal coordination of insulin and melatonin regulates hepatic lipid metabolism, we administered these hormones to immortalized porcine hepatocytes either synchronously (SYN) or alternately (ALT) at 12-h intervals for 72 h. The results showed that SYN increased intracellular triglyceride (TG) accumulation in hepatocytes, enhanced mitochondrial fission, reduced mitochondrial membrane potential and ATP production during circadian time 0-12 phase, while upregulating the core clock gene BMAL1 levels in this stage. Overall, this study demonstrated that nighttime eating in diurnal animals induces an imbalance in BMAL1-mediated hepatic mitochondrial fission and fusion by synchronizing the circadian rhythms of insulin and melatonin, promoting triglyceride accumulation through impaired metabolic efficiency. Our findings establish a mechanistic link between mistimed eating and hepatic steatosis from the perspective of hormone rhythms regulated by food and light, offering new insights for chrononutrition-based interventions in metabolic diseases.

Abstract

Pro-inflammatory macrophage function is linked to an increase in mitochondrial fission. Melatonin has a positive impact on atherosclerosis and has a significant effect on the control of mitochondrial fission and fusion. Nevertheless, it is still unclear how melatonin contributes to slowing the advancement of atherosclerosis.

Abstract

Abnormal deposition of β-amyloid (Aβ) is a significant pathological feature of neurodegenerative diseases, particularly Alzheimer's disease (AD). The glymphatic system (GS) plays a crucial role in Aβ clearance. Various rhythmic activities of the organism dynamically influence Aβ clearance by modulating GS function. In this paper, we systematically review the mechanisms linking cardiovascular rhythms, respiratory rhythms, neural rhythms, circadian rhythms, and exercise patterns to Aβ clearance via the GS. Cardiovascular rhythms affect cerebral perfusion pressure and vascular pulsation to regulate GS transport efficiency; respiratory rhythms modulate intracranial pressure and cerebrospinal fluid (CSF) circulation through thoracic pressure variations; neural rhythms (including delta waves during non-rapid eye movement (NREM) sleep and neurovascular coupling) synchronize neuro-glial-vascular interactions to enhance GS clearance. Circadian rhythms coordinate these primary rhythms by regulating melatonin levels and cerebral blood flow, while exercise patterns adjust GS function via aquaporin-4 (AQP4) polarization. Additionally, we elaborate on the cascade effect of AD resulting from rhythmic dysregulation. A thorough understanding of how rhythmic activities impact Aβ clearance by the GS may offer new perspectives and potential intervention strategies for the prevention and treatment of AD through the concept of "synchronized multiple rhythms"-a novel framework that integrates multi-rhythm synergy. Clinically, this work provides a theoretical basis for developing targeted interventions, such as personalized exercise timing regimens, respiratory rhythm training, and closed-loop neurovascular feedback devices, to restore GS function in AD patients.

Abstract

Melatonin, the pineal gland hormone, is produced in several extra-pineal tissues. The arylalkylamine N-acetyltransferase (AANAT) enzyme activity determines the overall rate of tissue melatonin synthesis. A decline in AANAT enzyme activity during acute amyloid-β (Aβ) neurotoxicity and reduced melatonin levels in Alzheimer's patients have been reported. These findings raise the question of whether brain melatonin synthesis is altered during cognitive decline. We investigated whether cognitive impairment induced by Aβ administration could affect the activation status of AANAT, a key hippocampal enzyme of melatonin synthesis. Male Wistar rats received intra-cerebroventricular Aβ injection. Two weeks after Aβ administration, the neuroinflammation was assessed by interleukin-1 (IL-1β) immunohistochemical staining. Hippocampal long-term potentiation (LTP) was evaluated using the technique of local field recording. The cognitive function was assessed using the Morris water maze behavioral test.The hippocampal AANAT activation status was assessed by Western blotting, and HPLC was used for melatonin level analysis. Aβ-induced spatial memory and LTP impairments were confirmed by increased escape latencies and alterations in the fEPSP slope. The Aβ provided a neuroinflammatory context, demonstrated by increased in the IL-1𝛽 staining. These alterations were accompanied by a reduction in the activation status of AANAT, as indicated by the p-AANAT/total AANAT ratio, in both the electrophysiology and behavioral experimental groups.These data suggest that the local activation status of AANAT may be contributed in the cognitive function of the hippocampus in a rodent model of cognitive decline induced by Aβ administration.

Abstract

To investigate the protein expression levels of circadian clock genes in pituitary adenomas (PAs) using the immunohistochemical staining method.

Abstract

Acute kidney injury (AKI) caused by renal ischemia-reperfusion injury (RIRI) is primarily a mitochondrial disorder characterized by disrupted dynamics, impaired biogenesis, and defective quality control. Excessive DRP1-mediated fission, suppression of the AMPK-SIRT-PGC-1α axis, and failure of the PINK1-Parkin mitophagy system converge to drive tubular dysfunction and ferroptosis. Here, we integrate recent insights into a "mitochondrial reprogramming" framework encompassing three axes-dynamic remodeling, metabolic renewal, and proteostatic reinforcement. Therapeutic strategies targeting these axes, such as DRP1 inhibition, AMPK-SIRT-PGC-1α activation, and reinforcement of mitophagy and MAM integrity by agents like melatonin, puerarin, or Schisandrin B, have shown promise in restoring mitochondrial resilience. Furthermore, mitochondrial biomarkers and imaging tools (mtDNA, mitochondrial peptides, [18F]BCPP-EF PET) may enable phenotype-guided interventions. This review outlines the "RIRI-Mitochondria-AKI-CKD continuum," emphasizing that mitochondrial maladaptation bridges acute injury and chronic fibrosis, highlighting mitochondria as precision therapeutic targets in AKI.