Sleep amount and quality are important to maintain health, light exposure transported to the pineal gland via suprachiasmatic nucleus pineal pathway, and this affect melatonin synthesis. Melatonin exerts its action by receptors called MT1, MT2 that found in peripheral tissues including pancreas, which affect its endocrine function. In this study we investigate the effect of type of sleep disturbance on the histological structure and the expression of melatonin receptor (MTNR1B) in the pancreas. A sample of 45 adult healthy male rats had free access to water and feeding, divided into 3 groups (15 in each group): the control group had normal 24 h diurnal variation, group A subjected to interruption of sleep by light exposure for 2 h at three intervals, and group B subjected to a reduction in sleep duration by 7 h. This experiment continued for 14 days, animals were scarified by euthanasia by cervical dislocation, pancreatic tissue prepared for paraffin blocks and stained by H&E, and IHC for MTNR1B. Histomorhometric analysis done by image J (V 1.54), immunohistochemical assessment done by Aprioscope image analysis software 12.4.6.5003) mean total positivity of expression was selected, statistical analysis done by SSPS (25 V) and Tukeyꞌs test. Histological evaluation revealed changes in sleep disturbance groups including fat deposition, vascular dilatation, and apoptotic changes for group of cells within islets of Langerhans which showed significant reduction in their count in sleep disturbance groups compared to control, and non-significant change in their area across the groups, but significant reduction in area in sleep deprived group compared to sleep interruption. Immunohistochemical expression of MTNR1B showed it only expressed within the area of islets of Langerhans, with non-significant increase in expression in sleep disturbed groups, being more in sleep deprived group. This study showed that the pancreas is affected by sleep disturbance patterns, mainly its endocrine part (islets of Langerhans), with study expression of melatonin receptor within them. This may suggest a role of melatonin in maintaining pancreatic ꞵ cells.

The mammalian pineal gland maintains normal circadian rhythms and homeostasis by secreting melatonin. However, the lack of a single-cell-resolved regulatory map limits our understanding of how these neuroendocrine functions are orchestrated. Here, we constructed a multiomics atlas of the pineal gland from Macaca fascicularis by integrating snRNA-seq, snATAC-seq, and spatial transcriptomics. We identified pinealocytes as the predominant cell type, alongside six glial and vascular lineages. Chromatin accessibility analysis delineated cell-type-specific regions enriched for melatonin synthesis and phototransduction genes. Notably, we resolved a dual-layer regulatory architecture: While melatonin synthesis programs are robustly organized, circadian clock regulators exhibit a distinct, sparse spatial pattern. Coexpression networks further identified core modules and regulatory hubs-including CRX/OTX2, LHX4, and RORA-that integrate these circadian and light-responsive signals. Cell-cell communication analysis identified signaling axes, such as PTN-ALK/SDC2, RA-RORB, and NRG1-ERBB4, that potentially coordinate this spatial functional organization. Integrating genetic traits showed that sleep and neuropsychiatric risk variants preferentially map to these pineal regulatory modules. Specifically, sleep-associated loci converged on MEIS1-linked elements, while bipolar disorder-associated loci highlighted candidate genes of RDH12 and SDK2. Overall, this study reveals the cellular diversity and spatial regulatory logic of the primate pineal gland, providing a physiological foundation for investigating circadian and neuroendocrine regulation in healthy and disease models.

N-acetylserotonin protects against renal ischemia-reperfusion injury by exhibiting antioxidant, anti-inflammatory and antiapoptotic effects through regulation of Nrf2 and TLR4/NF-κB/iNOS expression.

A GATA transcription factor modulates melatonin production and drought resistance in Hypericum perforatum.

SlSNAT1-dependent melatonin synthesis enhances tomato cold tolerance by promoting SlNCED1-mediated ABA accumulation, thereby strengthening antioxidant capacity, maintaining photosynthesis, and reducing ROS-induced membrane damage under cold stress. Cold stress limits greenhouse tomato growth by suppressing photosynthesis, promoting reactive oxygen species (ROS) accumulation, and disrupting membrane integrity, which ultimately reduces yield. Melatonin (MT) enhances plant stress tolerance, but its role in regulating cold adaptation in tomato remains unclear. Here, we used CRISPR/Cas9-generated SlSNAT1 mutants and VIGS-mediated SlNCED1-silenced plants to test how MT influences abscisic acid (ABA) biosynthesis and cold tolerance. The SlSNAT1 mutation markedly reduced endogenous MT, decreased the expression of ABA biosynthetic genes (SlNCED1/2), and increased the expression of ABA catabolic genes (SlCYP707A1/2), thereby weakening cold-induced ABA accumulation. Accordingly, the mutants showed higher membrane permeability and ROS levels, together with lower photosynthetic efficiency and reduced antioxidant enzyme activity under cold stress. SlNCED1 silencing further reduced ABA accumulation and antioxidant capacity. By contrast, exogenous MT partly restored ABA content, antioxidant enzyme activity, and photosynthetic performance, thereby alleviating cold injury. Correlation analysis showed that ABA content was positively associated with antioxidant activity, photosynthetic traits, and osmotic regulators, but negatively associated with ROS levels and membrane damage. MT synthesis mediated by SlSNAT1 promotes ABA accumulation, at least in part, by enhancing SlNCED1 expression. These findings clarify a mechanism underlying MT-ABA cross talk during cold stress and suggest a potential strategy to enhance cold tolerance in greenhouse tomato.

Major depressive disorder (MDD) ranks among the leading causes of disability worldwide. Current treatments often yield suboptimal outcomes, largely due to an incomplete understanding of its underlying pathology. There is, therefore, a pressing need to identify novel core pathological targets. Iron serves as an essential cofactor for several key enzymes in tryptophan (Trp) metabolism, playing a central role in its regulatory pathways. Iron deficiency (ID) can profoundly disrupt Trp metabolic homeostasis in both the peripheral and central nervous systems. This review synthesizes preclinical and clinical evidence to elucidate how ID drives the pathogenesis of MDD through the following interconnected mechanisms: (1) Impairing the activity of tryptophan hydroxylase (TPH), thereby reducing the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin; (2) Skewing the kynurenine pathway (KP) flux toward neurotoxic metabolites via the “dysfunctional activation” of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO); (3) Disrupting gut microbiota-mediated indole metabolism, compromising intestinal barrier integrity, and amplifying neuroinflammatory responses. These metabolic disturbances collectively contribute to a vicious pathological cycle involving neurochemical imbalance, a neurotoxic microenvironment, peripheral-central inflammatory crosstalk, and ferroptosis-mediated neuronal damage, ultimately entrenching the depressive phenotype. Furthermore, this review outlines multidimensional therapeutic strategies targeting the iron-Trp metabolic axis for depression. In conclusion, we propose that the iron-Trp metabolic axis represents a promising cross-diagnostic target for MDD, offering new theoretical insights and practical avenues for its precision treatment.

Circadian disruption represents a global health issue associated with cardiometabolic diseases, sleep disturbances, and mood disorders, driven by a pathophysiological network including clock gene dysregulation and impaired melatonin synthesis. Vitamin D exerts pleiotropic effects on metabolic regulation, immune function, neurotransmission, and possibly circadian synchronization. Emerging evidence suggests that vitamin D and its hydroxyderivatives modulate clock gene expression, influence transcriptional regulators such as retinoic acid receptor-related orphan receptors and REV-ERBs, and interact with melatonin synthesis and signaling. Vitamin D deficiency has been associated with metabolic syndrome, impaired sleep quality, and depression. Although interventional studies yield heterogeneous results, higher vitamin D status may confer protective metabolic and neurobehavioral effects. This review summarizes current evidence on the role of vitamin D in circadian disruption and evaluates its potential therapeutic relevance in circadian-metabolic dysregulation.

A major obstacle to the development of effective medications for bipolar disorder (BD) is the incomplete understanding of BD pathophysiology, as therapeutics that target the causal mechanisms underpinning BD are more likely to fully address symptoms and prevent recurrence of the disease. Converging evidence suggests that reduced melatonin secretion and function (hypomelatoninaemia) may play a key role in the pathophysiology of BD; however, this relationship has not yet been fully characterised. Increased sensitivity of light-induced melatonin suppression and alterations in synthesis, receptor activity, and metabolism of melatonin may contribute to hypomelatoninaemia in BD. Hypomelatoninaemia may also functionally amplify hypercortisolaemia and sleep disturbance that are common in the disorder (and vice versa), and contribute to oxidative stress, heightened inflammation, and dopaminergic dysfunction in BD. Furthermore, melatonin shows promise as a potential therapeutic agent for BD. Here, we review the preclinical and clinical data addressing the relationships between hypomelatoninaemia, hypercortisolaemia, sleep disturbance, oxidative stress, inflammation, and hyperdopaminergia in BD.

Transcriptomic and phenotypic analysis of maize with CRISPR/Cas9-mediated targeted mutagenesis of melatonin synthesis genes under drought stress.

UHPLC-MS/MS, transcriptomic, and genomic analyses unravel the molecular mechanism on melatonin biosynthesis in Tartary buckwheat sprouts.

The human brain consumes approximately 20% of total energy production despite comprising only 2% of body mass, rendering neurons particularly vulnerable to oxidative damage. Modern indoor lifestyles have dramatically reduced exposure to near-infrared (NIR) radiation, a component of sunlight that penetrates biological tissues. Concurrently, age-related declines in both pineal melatonin production and mitochondrial function have been implicated in the pathogenesis of neurodegenerative diseases. Additionally, aging is associated with declining availability of glutathione precursors, particularly glycine and cysteine, which may limit endogenous antioxidant responses even when enzymatic capacity is preserved. This hypothesis paper synthesizes evidence from photobiomodulation (PBM) research, mitochondrial biology, and melatonin biochemistry to propose a mechanistic framework whereby NIR radiation activates mitochondrial melatonin synthesis, potentially triggering an antioxidant cascade that may confer neuroprotection. The framework explicitly incorporates the requirement for adequate glutathione precursor substrate availability as a potential rate-limiting factor. A targeted narrative synthesis informed the development of the proposed mechanistic framework. Peer-reviewed publications were identified through searches of PubMed, Web of Science, and Google Scholar (1990-2025) using terms related to PBM, mitochondrial melatonin, glutathione metabolism, and neuroprotection. Studies were selected based on relevance to the proposed framework, with emphasis on mechanistic studies, randomized controlled trials, and systematic reviews. Priority was given to publications from 2020 to 2025, while seminal foundational studies were retained regardless of publication date. Evidence supporting each component of the proposed cascade was categorized by strength to maintain transparency regarding the distinction between established findings and untested hypotheses. The proposed NIR-mitochondrial melatonin-glutathione cascade represents a biologically plausible mechanism for endogenous neuroprotection, contingent upon adequate substrate availability. While substantial evidence supports individual components, the integrated hypothesis requires rigorous experimental validation. Concurrent attention to glutathione precursor status through glycine and N-acetylcysteine (NAC) supplementation may be necessary to realize the full therapeutic potential of this approach.

In defending against pathogens, plants deploy diverse secondary metabolites and signaling molecules. Among these, melatonin orchestrates plant growth and development, modulates stress responses, and regulates intracellular redox homeostasis and signaling. However, the mechanisms of melatonin in plant-pathogen interaction are rarely reported. Using Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) as model bacteria, we designed a two-step high-throughput screening strategy to screen the plant natural product library and the bacterial mutant library. This study reveals that melatonin is perceived by a bacterial receptor histidine kinase CpxA, which subsequently modulates bacterial virulence. In detail, bacterial CpxA senses melatonin through Glu48 and Thr51 sites located in the periplasmic sensor region. Thus, melatonin inhibits autophosphorylation of CpxA and decreases transphosphorylation of the response regulator CpxR. The DNA-binding capacity of CpxR to promoters of type III secretion system (T3SS) genes is weakened by reduced phosphorylation cascade of CpxA/R, inhibiting bacterial T3SS genes expression and virulence. We also showed that increasing melatonin synthesis in plants can enhance disease resistance and sustain crop productivity. This study illustrates a previously unknown mechanism by which plants disarm the pathogenicity of bacteria, as well as provide effective molecular targets for crop genetic improvement and biopesticides development.

ABSTRACT Pineal melatonin is a potent synchronizer within the circadian system. Certain extra-pineal tissues also synthesize melatonin, including the gastrointestinal organs, whose melatonin contents can exceed that of pineal severalfold. Considering the role of pineal melatonin as a general synchronizer, we investigated whether the intestinal melatonin could serve a similar role in the local organization of the metabolic events, as a core element of the Food-Entrainable Oscillator (FEO). To be considered so, the intestinal secretory activity should meet some requirements: it should have self-sustained rhythmicity, that should also be synchronized to but not depend on feeding. To test this, we analyzed the circadian expression of the rate-limiting enzyme of melatonin synthesis, AANAT, in the intestine of rats. We found that AANAT expression varies along the intestine and shows a clear circadian pattern only in the proximal (duodenal) and distal (colonic) edges. The circadian variation in duodenum was abolished by fasting, implying that this activity is not self-sustained but reactive to feeding. The colon had the highest AANAT expression that was also rhythmic, but the phase of this rhythm was not synchronized to feeding. We propose that intestinal melatonin derives from different populations of secreting cells, but none of these populations meets the criteria for a pacemaker underlying the FEO.

Introduction: Age-related macular degeneration (AMD) is a degenerative retinal disorder leading to central vision loss. This study investigates the association between AMD and sleep quality and sleep duration. Methods: Our team examined a variety of published literature, such as case series, clinical trials, and economic studies. These studies were retrieved from the online databases of peer-reviewed literature, CINHAL, EMBASE, and MEDLINE, as well as literature that was published, but not peer reviewed. We used the statistical analysis software STATA 15.0 to assess for any overall relationships between AMD and sleep quality, sleep duration, or both. Results: Nine articles, with a total of 4,502 subjects, were used to conduct the meta-analysis. There were significantly higher Pittsburgh Sleep Quality Index (PSQI) scores (greater than 5) among AMD patients: effect size (ES) = 0.52, 95%; confidence interval (CI): (0.38, 0.65). These scores indicate that individuals with AMD often have higher PSQI scores, suggesting poorer sleep quality. Furthermore, the meta-analysis showed significantly higher rates of insomnia among AMD patients: ES = 0.02, 95%; CI: (0.01, 0.03). The effect of AMD on sleep time was nonsignificant: ES = 0.04, 95%; CI: (–0.17, 0.25). The odds ratio for sleep time over 8 hr was also not significant among patients with AMD: ES = 0.99, 95%; CI: (0.64, 1.52). Discussion: The findings highlight a significant association between AMD and poor sleep quality, evidenced by higher PSQI scores and increased rates of insomnia among AMD patients. The disruptions in sleep are likely due to the psychological stress associated with vision loss related to AMD, as well as potential disruptions in melatonin synthesis and circadian rhythms. Implications for Practitioners: These results emphasize the need for targeted interventions, such as cognitive-behavioral therapy and melatonin supplementation, to improve sleep quality in this population. Additional studies are needed to elucidate the underlying mechanisms of sleep disturbances in AMD and to assess the efficacy of these treatments.

Melatonin, the pineal gland hormone, is produced in various extrapineal tissues as well, and its reduction has been reported in sporadic Alzheimer's disease (AD). The exact reason for tissue melatonin synthesis, despite the pineal source of melatonin, is not well understood, although the melatonin decline in the biological fluids of AD patients is a reasonable justification for melatonin therapy in cognitive impairment. However, the effectiveness of melatonin administration in AD patients was insignificant. Additionally, there is evidence of alterations in local melatonin synthesis in pathological situations, and little is known regarding its physiological or pathological modulators. Recently, the decline in the hippocampal enzyme of melatonin synthesis has been reported in amyloid-β neurotoxicity. It has been shown that reduced hippocampal melatonin synthesis by siRNA has been associated with cognitive decline. This review has included AD studies that noticed the impacts of melatonin prescription on memory and cognitive function in both animal research and randomized controlled trials, while also reviewing the available data regarding the alterations in brain tissue melatonin synthesis. This review highlights the role of brain (extrapineal) tissue melatonin synthesis in cognitive function in AD pathophysiology. Understanding the induction pattern of extrapineal melatonin synthesis, dosing optimization of exogenous administration, noting gender-specific differences, and clarifying microbiota-melatonin interactions point toward new approaches that may enhance the effectiveness of melatonin-based interventions for preventing or delaying AD progression.

A BSTRACT Sleep is a vital physiological process essential for maintaining overall health, supporting cellular repair, immune regulation, and cognitive functions. Sleep disruptions are associated with adverse health outcomes, including cardiovascular diseases, metabolic disorders, and impaired mental health. Sleep regulation is orchestrated by the circadian rhythm and homeostatic sleep drive, with melatonin—a neurohormone secreted by the pineal gland—playing a pivotal role in modulating these processes. Melatonin synthesis follows a biochemical pathway, converting serotonin to melatonin through key enzymes, AANAT and HIOMT, under circadian control. The suprachiasmatic nucleus (SCN) governs its secretion via light-responsive pathways, with light exposure inhibiting and darkness stimulating melatonin production. Acting through MT1 and MT2 receptors in the SCN and other brain regions, melatonin facilitates sleep onset, circadian rhythm alignment, and sleep maintenance while exerting antioxidant, anti-inflammatory, and chronobiotic effects. Exogenous melatonin has emerged as a therapeutic agent for managing sleep disorders, such as circadian rhythm sleep-wake disorders, jet lag, and insomnia. Its chronobiotic properties enable circadian phase-shifting, aligning sleep-wake cycles with environmental cues. Despite its growing use, questions remain regarding optimal dosing and long-term safety. This review delves into the physiology of melatonin, its synthesis, regulation, and mechanisms of action in sleep regulation. It also examines its therapeutic potential, highlighting gaps in research and paving the way for future studies on melatonin’s broader implications in health and disease.

Saline-alkali stress severely restricts the growth and cultivation of blue honeysuckle (Lonicera caerulea L.). Exogenous melatonin (MT) regulates plant stress resistance, but its alleviation mechanism in this species remains unclear. This study analyzed the effects of 0, 25, 100, and 200 µmol/L MT on blue honeysuckle seedlings under saline-alkali stress. Results showed 100 µmol/L MT exerted the optimal effect: it mitigated photoinhibition by increasing PSII’s maximum photochemical efficiency (Fv/Fm) and optimizing light energy distribution; enhanced antioxidant defense via upregulating SOD, POD, and CAT activities while reducing MDA content; regulated proline and soluble sugar accumulation to maintain osmotic balance; and activated stress response networks by upregulating NAC/WRKY transcription factors and auxin/ABA-related genes, as well as SNAT/ASMT pathway genes for endogenous MT synthesis. Notably, 200 µmol/L MT induced inhibitory effects via oxidative feedback. In conclusion, 100 µmol/L exogenous MT significantly improves blue honeysuckle’s saline-alkali tolerance through synergistic regulation of photosynthetic stability, antioxidant defense, and transcriptional reprogramming, providing a theoretical basis for saline-alkali land cultivation and MT agricultural application.

The dim-light melatonin onset (DLMO) is a commonly used circadian marker indicating the start time of evening melatonin synthesis in humans. Several quantitative techniques have been developed to determine DLMO from melatonin time series, including fixed- or variable-threshold techniques and the hockey-stick method developed by Danilenko et al (2014). Here, we introduce dlmoR, an open-source (MIT License) implementation of the hockey-stick method written in R. Our clean-room implementation follows the original algorithm description, supported by iterative validation against the existing binary executable. We benchmarked dlmoR on 112 melatonin time series data sets from two independent studies and found high agreement with the reference implementation: mean discrepancies were min for the Heinrichs and Spitschan (2025) data set and min for the Blume et al. (2024) data set, with circular correlation coefficients of 0.964 and 0.986, respectively. Paired t-tests () indicated no systematic difference or bias between methods. Beyond reproducing the hockey-stick algorithm, dlmoR adds capabilities absent from the original executable, including interactive visual diagnostics and bootstrapped confidence intervals, offering qualitative and quantitative views of estimation uncertainty. It supports programmatic, reproducible analysis of melatonin profiles, including batch processing and parameter manipulation. Leveraging this flexibility, we evaluated the sensitivity of the hockey-stick algorithm to controlled changes in sampling schedules, threshold levels, data completeness, and noise. Moderate changes, such as small timing jitter, limited data loss, or modest threshold shifts, kept estimates stable within ±10 min, whereas pronounced alterations to sampling schedules, large multi-point deletions, or substantial threshold changes delayed estimates by over 40 min or prevented estimation. This analysis reveals fundamental limitations in the algorithm's internal mechanics, particularly in how it identifies the onset window and models the melatonin rise, and underscores the need for new uncertainty-aware approaches to DLMO estimation.

Soil salinization poses a serious threat to plant development and represents a major obstacle to the sustainable production of crops worldwide. Melatonin (MT) contributes prominently to plant tolerance against abiotic environments. However, the molecular basis of transcriptional regulation underlying melatonin accumulation in tomato under saline-alkali stress is still largely unknown. Herein, we identify SlNAC2, a NAC transcription factor in tomato induced by saline-alkali stress, which suppresses the key melatonin biosynthetic genes SlCOMT2 and SlSNAT, while activating SlCV, a gene linked to reactive oxygen species (ROS) accumulation and programmed cell death. These regulatory effects reduce MT levels and promote excessive ROS production, ultimately altering the plant's tolerance to saline-alkali stress. Silencing of SlNAC2 through the RNA interference method significantly improves saline-alkali tolerance in tomato, while its constitutive overexpression shows increased susceptibility to saline-alkali stress. Further evidence reveals that under saline-alkali conditions, SlNAC2 directly targets cis-elements of SlCOMT2 and SlSNAT promoters, suppressing their transcription and consequently reducing melatonin levels, whereas simultaneously binding to the SlCV promoter to activate its expression, ultimately leading to ROS accumulation. Moreover, comprehensive protein interaction analyses confirmed that SlNAC2 physically associates with SlDREB2, a DREB-type transcription factor involved in salt stress response. Through its interaction with SlNAC2, SlDREB2 partially attenuates its repression of SlCOMT2 and SlSNAT, thereby increasing melatonin accumulation and ROS scavenging, ultimately enhancing tomato's resilience to saline-alkali stress conditions. Collectively, our findings reveal a SlNAC2-SlDREB2 regulatory module that finely tunes melatonin synthesis and ROS levels to regulate tomato's response to saline-alkali stress, providing new strategies for developing stress-resilient tomato varieties.

ABSTRACTCircadian rhythm alignment depends on environmental light detection via opsins. Pinopsin, originally identified in the pineal organ of birds and later in amphibian pineal complex and eyes, may play a role in this process, though its function has not been genetically tested. Evolutionary analysis suggests pinopsin was independently lost in several vertebrate lineages, including mammals (Synapsida), some reptiles (e.g. snakes and crocodiles), and teleost fish, but retained in birds, turtles, lizards, and non‐teleost Actinopterygii. We conducted a detailed genomic search of the pinopsin gene across 95 amphibian species and assessed its function in Xenopus laevis tadpoles using CRISPR/Cas9‐mediated knockout. Our survey indicates that pinopsin is highly conserved in salamanders and most anurans, but absent in many caecilians (Gymnophiona), which have a fossorial lifestyle with limited light exposure. To investigate its biological role, we generated X. laevis F0 pinopsin knockout tadpoles and evaluated two light‐sensitive responses: (1) day/night melatonin fluctuations inferred from skin pigmentation changes, and (2) locomotor activity over a 24‐h photoperiod. We show these responses depend only on pineal light sensitivity and are independent of eye sensitivity at developmental stage 46/47. Our findings reveal: (1) Pinopsin is co‐expressed with Aanat, a key enzyme in melatonin synthesis; (2) knockout tadpoles show paler skin during the light phase, suggesting pinopsin suppresses melatonin production in daylight; and (3) reduced daytime locomotor activity in F0 mutants, consistent with melatonin‐induced lethargy. Overall, pinopsin emerges as a critical opsin for light‐regulated circadian‐associated behavior in Xenopus, with likely conserved roles across amphibians (anurans and salamanders in general) and other non‐mammalian vertebrates, including birds, turtles, and lizards.