Melatonin feeding changed the microbial diversity and metabolism of the broiler cecum.

To study the effect of melatonin supplementation on the gut microbes of broilers, 160 healthy 3-week-old Ross 308 broilers with similar body weights were selected and randomly divided into four groups (M0, M20, M40, and M80) supplemented with 0, 20, 40, or 80 mg/kg melatonin. The results showed that the abundance-based coverage estimator (ACE) index of cecum microorganisms was significantly lower in the M80 group. The dominant phyla of intestinal contents in the M0, M20, M40, and M80 groups were Bacteroidetes and Firmicutes. The M40 group showed an increase in the relative abundance of Bacteroidetes spp. in the intestine, while the relative abundance of Ruminococcus spp. in the intestine of the M20, M40, and M80 groups was significantly greater than that of the M0 group. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses revealed that the supplementation of melatonin increases the expression of genes related to cellular processes (cell motility, cell growth and death, and cellular community-eukaryotes), environmental information processing (membrane transport and signal transduction), and genetic information processing (transport and transcription), and Cluster of Orthologous Groups (COG) of proteins functional analyses revealed that the supplementation of melatonin resulted in a significant increase in cellular processes and signaling (cell motility, signal transduction mechanisms, intracellular trafficking, secretion, and vesicular transport), information storage and processing (RNA processing and modification, chromatin structure and dynamics, translation, ribosomal structure, and biogenesis), metabolism (energy production and conversion, lipid transportation and metabolism, inorganic ion transport and metabolism, secondary metabolite biosynthesis, transport, and catabolism), and poorly characterized (general function prediction only). In summary, supplementation of feed with melatonin can increase the diversity of intestinal microorganisms and the relative abundance of Bacteroides and Firmicutes in the cecum, improve digestive ability and nutrient absorption ability, and positively regulate the metabolic ability of broilers.

Melatonin Alleviates Osteoarthritis by Regulating NADPH Oxidase 4-Induced Ferroptosis and Mitigating Mitochondrial Dysfunction.

Recent evidence indicates that the damaged regions in osteoarthritis are accompanied by the accumulation of iron ions. Ferroptosis, as an iron-dependent form of cell death, holds significant implications in osteoarthritis. Melatonin, a natural product with strong scavenging abilities against reactive oxygen species and lipid peroxidation, plays a crucial role in the treatment of osteoarthritis. This study aims to demonstrate the existence of ferroptosis in osteoarthritis and explore the specific mechanism of melatonin in suppressing ferroptosis and alleviating osteoarthritis. Our findings reveal that melatonin reverses inflammation-induced oxidative stress and lipid peroxidation while promoting the expression of extracellular matrix components in chondrocytes, safeguarding the cells. Our research has revealed that NADPH oxidase 4 (NOX4) serves as a crucial molecule in the ferroptosis process of osteoarthritis. Specifically, NOX4 is located on mitochondria in chondrocytes, which can induce disorders in mitochondrial energy metabolism and dysfunction, thereby intensifying oxidative stress and lipid peroxidation. LC-MS analysis further uncovered that GRP78 is a downstream binding protein of NOX4. NOX4 induces ferroptosis by weakening GRP78's protective effect on GPX4 and reducing its expression. Melatonin can inhibit the upregulation of NOX4 on mitochondria and mitigate mitochondrial dysfunction, effectively suppressing ferroptosis and alleviating osteoarthritis. This suggests that melatonin therapy represents a promising new approach for the treatment of osteoarthritis.

Multi-class plant hormone HILIC-MS/MS analysis coupled with high-throughput phenotyping to investigate plant-environment interactions.

Plant hormones are chemical signals governing almost every aspect of a plant's life cycle and responses to environmental cues. They are enmeshed within complex signaling networks that can only be deciphered by using broad-scale analytical methods to capture information about several plant hormone classes simultaneously. Methods used for this purpose are all based on reversed-phase (RP) liquid chromatography and mass spectrometric detection. Hydrophilic interaction chromatography (HILIC) is an alternative chromatographic method that performs well in analyses of biological samples. We therefore developed and validated a HILIC method for broad-scale plant hormone analysis including a rapid sample preparation procedure; moreover, derivatization or fractionation is not required. The method enables plant hormone screening focused on polar and moderately polar analytes including cytokinins, auxins, jasmonates, abscisic acid and its metabolites, salicylates, indoleamines (melatonin), and 1-aminocyclopropane-1-carboxylic acid (ACC), for a total of 45 analytes. Importantly, the major pitfalls of ACC analysis have been addressed. Furthermore, HILIC provides orthogonal selectivity to conventional RP methods and displays greater sensitivity, resulting in lower limits of quantification. However, it is less robust, so procedures to increase its reproducibility were established. The method's potential is demonstrated in a case study by employing an approach combining hormonal analysis with phenomics to examine responses of three Arabidopsis ecotypes toward three abiotic stress treatments: salinity, low nutrient availability, and their combination. The case study showcases the value of the simultaneous determination of several plant hormone classes coupled with phenomics data when unraveling processes involving complex cross-talk under diverse plant-environment interactions.

Melatonin attenuates affective disorders and cognitive deficits induced by perinatal exposure to a glyphosate-based herbicide via antioxidant pathway in adult male and female rats.

The massive use of herbicides, particularly glyphosate-based herbicides (GBHs), raises several worries, notably their neurotoxic effects. Several studies have explored the consequences of developmental exposure. Our work aims to determine the impact of maternal exposure to GBH on behavioral disorders and memory deficits, as well as the involvement of oxidative stress in the hippocampus and prefrontal cortex. In addition, our study explores the neuroprotective properties of melatonin in male and female offspring. Pregnant Wistar rats were injected with GBH 75 mg/kg during gestation and lactation. After weaning, the offspring were treated with melatonin (4 mg/kg) from postnatal days 30-58. Our results show that GBH increases anxiety-like behavior levels in offspring, as well as depression-like behavior. GBH also impairs working memory in progeny. While markers of oxidative stress show a disturbance in lipid peroxidation and catalase activity, with a more pronounced effect in females, on the other hand, melatonin considerably attenuated the neurotoxic impact observed in the offspring, with higher efficacy in females. The oxidative stress results confirm the antioxidant power of melatonin to counteract the damaging effects of exposure to environmental contaminants such as glyphosate-based pesticides. It will then be interesting to further our work to fully understand the sex-dependent effect of melatonin.

Late Bedtime and Altered Diurnal Axial Length Rhythms of the Eye.

PURPOSE: Affecting one-third of the population worldwide and increasing, the sight-threatening condition myopia is causing a significant socio-economic burden. To better understand its etiology, recent studies investigated the role of ocular and systemic rhythms, yet results are conflicting. Here we profiled 24-h variations of axial length of the eye and salivary melatonin concentration in young adults with and without myopia and explored the potential impacts of bedtime on these rhythms. METHODS: A total of 25 healthy young adults (age 25.0 ± 4.8 years, 13 females) completed this study, including 13 myopes (mean spherical equivalent refractive error -2.93 ± 1.46 diopters) and 12 non-myopes (0.14 ± 0.42 diopters). Saliva sample collection and axial length measurements were repeated for seven times over 24 h starting from 8 am. Information on sleep and chronotype was collected at first visit with the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. RESULTS: Significant diurnal rhythms of axial length and salivary melatonin concentration were identified in both refractive groups (both p < 0.001), with no myopia-related rhythm difference (interaction of measurement time-point × myopia, p = 0.9). Late bedtime was associated with altered rhythms (p = 0.009) and smaller diurnal change (p = 0.01) in axial length. Elevated melatonin levels were observed in myopes (p = 0.006) and in late sleepers (p = 0.017). CONCLUSIONS: These findings suggest that sleep/wake cycles may be involved in the regulation of axial length rhythms. Further research is needed to determine if there exists a causal relationship between the two.

Melatonin downregulates angiogenesis and lymphangiogenesis by regulating tumor-associated macrophages via NLRP3 inflammasomes in lung adenocarcinoma.

Tumor-associated macrophages (TAMs), present within the tumor microenvironment (TME), strictly modulate tumor angiogenesis and lymphangiogenesis. Nevertheless, the associated signaling networks and candidate drug targets for these events remains to be elucidated. Given its antioxidative activities, we speculated that melatonin may reduce pyroptosis, and thereby modulate both angiogenesis and lymphangiogenesis. We revealed that a co-culture of A549 cells and THP-1 macrophages strongly enhanced expressions of the NLRP3 inflammasome axis members, and augmented angiogenesis and lymphangiogenesis. Next, we overexpressed NLRP3 in the A549 cells, and demonstrated that excess NLRP3 expression substantially upregulated VEGF and CXCL cytokine expressions, and enhanced lymphatic endothelial cells (LECs) tube formation. In contrast, NLRP3 inhibition produced the opposite effect. In addition, relative to controls, melatonin administration strongly inhibited the NLRP3 inflammasome axis, as well as angiogenesis and lymphangiogenesis in the co-culture system. Subsequent animal experiments using a Lewis Lung Carcinoma (LLC) subcutaneous tumor model in mice corroborate these findings. Melatonin treatment and NLRP3 knockdown significantly inhibit tumor growth and downregulate NLRP3 and IL-1ß expression in tumor tissues. Furthermore, melatonin downregulates the expression of angiogenic and lymphangiogenic markers in tumor tissues. Taken together, the evidence suggested that a THP-1 macrophage and A549 cell co-culture stimulates angiogenesis and lymphangiogenesis via the NLRP3 axis. Melatonin protected against the TAMs- and NLRP3 axis-associated promotion of the aforementioned events in vitro and in vivo. Hence, melatonin is a promising candidate for managing for tumor-related angiogenesis and lymphangiogenesis in lung adenocarcinoma.

Melatonin prevents the transgenerational toxicity of nanoplastics in zebrafish (Danio rerio).

As a novel pollutant, microplastic pollution has become a global environmental concern. Melatonin (MT) has a protective effect on the damage caused by pollutants. However, there is still a lack of research on the transgenerational toxicity of microplastics and the alleviation of microplastics toxicity by MT. In this study, the adult zebrafish was exposed to (0, 0.1 and 1 mg/L) polystyrene nanoplastics (PSNP) with or without (1 µM) MT for 14 days, and embryos (F1) were used for experiments. Our study found that long-term exposure of parents to 1 mg/L PSNP reduced fertilization rate and survival rate of offspring, increased the deformity rate and induced embryos to hatch in advance. The growth inhibition of offspring was related to the gene transcription of the growth hormone/insulin-like growth factor axis. Moreover, PSNP caused oxidative stress in offspring, damaged immune system, reduced antioxidant capacity and induced apoptosis. MT supplementation could effectively alleviate the developmental toxicity and oxidative damage of offspring, but the negative effects brought by PSNP could not be completely eliminated. Our research provided a new reference for the protective effect of MT on transgenerational toxicity induced by PSNP.

Melatonin enhances NK cell function in aged mice by increasing T-bet expression via the JAK3-STAT5 signaling pathway.

Natural killer (NK) cells are crucial innate immune cells that provide defense against viruses and tumors. However, aging is associated with alterations in NK cell composition and compromised cell functions. Melatonin, known for its anti-tumor effects, has been reported to improve NK cell function. However, the molecular mechanism underlying melatonin's effect on senescent NK cells remains unclear. In this study, we aimed to elucidate the mechanism by which melatonin enhances the function of senescent NK cells. Our findings revealed that melatonin significantly increased the number and function of NK cells in aging mice. The results suggest that melatonin enhances NK cell proliferation, degranulation, and IFN-γ secretion. Further investigations demonstrated that melatonin promotes NK cell maturation and activation, mainly via the JAK3/STAT5 signaling pathway, leading to increased expression of T-bet. These discoveries provide a theoretical basis for potential immunotherapy strategies based on melatonin-mediated modulation of NK cell function in aging individuals.

Melatonin Regulates Neuronal Synaptic Plasticity in the Supramammillary Nucleus and Attenuates Methamphetamine-Induced Conditioned Place Preference and Sensitization in Mice.

Methamphetamine (METH) is an addictive drug that threatens human health. The supramammillary nucleus (SuM) and its neural circuits play key roles in the regulation of spatial memory retrieval, and hippocampal contextual or social memory. Melatonin (MLT), a pineal hormone, can regulate hypothalamic-neurohypophysial activity. Our previous study showed that MLT attenuates METH-induced locomotor sensitization. However, whether MLT regulates SuM function and participates in METH-induced contextual memory retrieval remains unclear. Using a mouse model of METH-conditioned place preference (CPP) and sensitization, we found that METH activated c-Fos expression and elevated calcium (Ca²âº) levels in SuM neurons. Chemogenetic inhibition of SuM attenuates CPP and sensitization. Pretreatment with MLT decreased c-Fos expression and Ca2+ levels in the SuM and reversed METH-induced addictive behavior, effects that were blocked with the selective MT2 receptors antagonist 4P-PDOT and the MT1 receptors antagonist S26131. Furthermore, MLT reduced SuM synaptic plasticity, glutamate (Glu) release, and neuronal oscillations caused by METH, which were blocked by 4P-PDOT. In conclusion, our data revealed that MLT regulates neuronal synaptic plasticity in the SuM, likely through the MLT receptors (MTs), and plays a role in modulating METH-addictive behavior.

Effect of melatonin as a therapeutic strategy against intrauterine growth restriction: a mini-review of current state.

Intrauterine growth restriction (IUGR) or intrauterine growth retardation is a condition that the fetus does not grow as expected. And the biometric profile does not match with the age of fetus. This condition is associated with increased mortality and morbidity of the neonates along with increased risk of cardiovascular, lung, and central nervous system damage. Despite close monitoring of high-risk mothers and the development of new therapeutic approaches, the optimal outcome has not been achieved yet that it indicates the importance of investigations on new therapeutic approaches. Melatonin (MLT) is a neurohormone mainly produced by the pineal gland and has a wide range of effects on different organs due to the broad dispersion of its receptors. Moreover, melatonin is produced by the placenta and also its receptors have been found on the surface of this organ. Not only studies showed the importance of this neurohormone on growth and development of fetus but also they proved its highly anti-oxidant properties. As in IUGR the oxidative stress and inflammation increased melatonin could counteract these changes and improved organ's function. In this study, we found that use of MLT could be a good clinical approach for the treatment of IUGR as its high anti-oxidant activity and vasodilation could dampen the mechanisms lead to the IUGR development.

Transcriptome analysis reveals the promoting effects of exogenous melatonin on the selenium uptake in grape under selenium stress.

Introduction: Exogenous melatonin (MT) can promote horticultural crops growth under stress conditions. Methods: In this study, the effects of exogenous MT on the accumulation of selenium (Se) in grape were studied under Se stress. Results and discussion: Under Se stress, exogenous MT increased the biomass, content of photosynthetic pigments and antioxidant enzyme activity of grapevines. Compared with Se treatment, MT increased the root biomass, shoot biomass, chlorophyll a content, chlorophyll b content, carotenoids, superoxide dismutase activity, and peroxidase activity by 18.11%, 7.71%, 25.70%, 25.00%, 25.93%, 5.73%, and 9.41%, respectively. Additionally, MT increased the contents of gibberellin, auxin, and MT in grapevines under Se stress, while it decreased the content of abscisic acid. MT increased the contents of total Se, organic Se and inorganic Se in grapevines. Compared with Se treatment, MT increased the contents of total Se in the roots and shoots by 48.82% and 135.66%, respectively. A transcriptome sequencing analysis revealed that MT primarily regulated the cellular, metabolic, and bioregulatory processes of grapevine under Se stress, and the differentially expressed genes (DEGs) were primarily enriched in pathways, such as aminoacyl-tRNA biosynthesis, spliceosome, and flavonoid biosynthesis. These involved nine DEGs and nine metabolic pathways in total. Moreover, a field experiment showed that MT increased the content of Se in grapes and improved their quality. Therefore, MT can alleviate the stress of Se in grapevines and promote their growth and the accumulation of Se.

The Bidirectional Relationship Between Sleep Disturbance and Functional Dyspepsia: A Systematic Review to Understand Mechanisms and Implications on Management.

Functional dyspepsia (FD) is a prevalent chronic digestive disorder that significantly impacts patients' quality of life. Sleep disturbance (SD) is common among FD patients, yet the relationship between SD and FD remains poorly characterized. This systematic review explores the bidirectional relationship between FD and SD, investigating underlying mechanisms and implications for management. A rigorous and comprehensive systematic search was conducted across PubMed, PubMed Central (PMC), Google Scholar, Cochrane Library, and ScienceDirect using select keywords related to SD and FD. Only studies published in English from the past 10 years that met inclusion and exclusion criteria were included. Quality assessment tools specific to study types were employed to minimize bias. After applying inclusion and exclusion criteria and quality assessments, the review encompassed 30 studies. The key findings reveal that FD is frequently associated with SD, with a significant proportion of FD patients reporting poor sleep quality. The mechanisms linking SD and FD are complex, involving the circadian rhythm, visceral hypersensitivity, immune responses, and psychological factors. Nonpharmacological treatments like cognitive behavioral therapy (CBT), acupuncture, and pharmacological neuromodulators have shown promise in managing FD and SD, offering hope for improved patient outcomes. SD and FD share a significant bidirectional relationship, influenced by a complex interplay of physiological, psychological, and lifestyle factors. Addressing SD in FD patients may improve overall symptom management. Further research is crucial, as it should focus on isolating specific SD causes and their direct impacts on FD and other functional gastrointestinal disorders (FGIDs), opening up new avenues for understanding and treatment.

Melatonin inhibits bovine viral diarrhea virus replication by ER stress-mediated NF-κB signal pathway and autophagy in MDBK cells.

Bovine viral diarrhea-mucosal disease (BVD-MD) is a contagious disease in cattle, caused by the bovine viral diarrhea virus (BVDV). This virus continues to spread globally, exerting pressure on both public health and the economy. Despite its impact, there are currently no effective drugs for treating BVDV. This study utilized Madin-Darby bovine kidney (MDBK) cells as a model to investigate the antiviral effects of melatonin against Bovine Viral Diarrhea Virus (BVDV) and its connection with endoplasmic reticulum (ER) stress. Our results show that melatonin can suppress BVDV proliferation in MDBK cells by modulating the endoplasmic reticulum (ER) stress-mediated NF-κB pathway and autophagy. Specifically, melatonin alleviated ER stress, inhibited the activation of IκBα and p65, regulated autophagy, and reduced the expression levels of pro-inflammatory cytokines. Further, when we treated BVDV-infected cells with the ER stress inducer thapsigargin, it led to significant activation of the NF-κB pathway and autophagy. Conversely, treating the cells with the ER stress inhibitor 4-phenylbutyric acid reversed these effects. These findings suggest that melatonin exerts its antiviral effects primarily through the PERK-eIF2α-ATF4 of ER stress-mediated NF-κB pathway and autophagy. Overall, our study underscores the potential of melatonin as an effective protective and therapeutic option against BVDV, offering insights into its anti-infective mechanisms.

Assessing the Effect of Exogenous Melatonin on Orthodontic Tooth Movement.

OBJECTIVE: To examine the effect of orthodontic tooth movement on experimental Wistar rats by synthesizing melatonin formulation for administration and conducting serological analysis of alkaline phosphatase (ALP) and melatonin, along with histological evaluation and immunohistochemistry analysis of ALP and interleukin-6 (IL-6) in both control and experimental groups. METHODOLOGY: Nine male Wistar rats were randomly divided into negative (n = 3), positive control (n = 3), and experimental groups (n = 3). Endogenous melatonin levels (pg/mL) were assessed, and an orthodontic force of 10 cN was applied to positive control and experimental groups using a ligature wire. The experimental group received a daily dose of 10 mg/kg melatonin via intraperitoneal injection. After eight weeks, blood samples and radiographs were collected, and mandible sections were prepared for histopathological and immunohistochemical evaluation. RESULTS: The radiographic evaluation shows minimal orthodontically induced tooth movement in comparison to the positive control group. In serological analysis, ALP was found to be increased in rats under the melatonin group. And, in the immunohistochemical evaluation, ALP was found to be increased in the melatonin group, whereas IL-6 was found to be decreased in the same (P = 0.027). CONCLUSIONS: The study elucidates that the administration of exogenous melatonin during orthodontic tooth movement in Wistar rats induces bone formation and inhibits resorption, eventually decelerating the process of orthodontic tooth movement. Our study emphasizes melatonin's dualistic role in stimulating bone production and suppressing resorption, offering potential therapeutic clinical implications in orthodontics.

Melatonin alleviates apple replant disease by regulating the endophytic microbiome of roots and phloridzin accumulation.

Melatonin administration is an environmentally effective strategy to mitigate apple replant disease (ARD), but its mechanism of action is unknown. This study investigated the protective effect of melatonin on ARD and the underlying mechanism. In field experiments, melatonin significantly reduced phloridzin levels in apple roots and rhizosphere soil. A correlation analysis indicated that a potential antagonistic interaction between melatonin and phloridzin was crucial for improving soil physicochemical properties, increasing the diversity of endophytic bacterial communities in roots of apple seedlings, and promoting mineral element absorption by the plants. Melatonin also reduced the abundance of Fusarium in roots. The ability of melatonin to reduce phloridzin levels both in soil and in plants was also demonstrated in a pot experiment. Azovibrio were specifically recruited in response to melatonin and their abundance was negatively correlated with phloridzin levels. Fusarium species that have a negative impact on plant growth were also inhibited by melatonin. Our results show that melatonin improves the rhizosphere environment as well as the structure of the endophytic microbiota community, by reducing phloridzin levels in rhizosphere soil and roots. These regulatory effects of melatonin support its use to improve the physiological state of plants under ARD conditions and thereby overcome the barriers of perennial cropping systems.

Investigating the efficacy of melatonin, topical sodium citrate, and multivitamin with zinc as a potential treatment for postinfectious loss of smell.

OBJECTIVES: Upper respiratory tract infections, including COVID-19, are associated with olfactory dysfunction and there is a need for novel therapeutic approaches. The aim of study was evaluating the effectiveness of adding melatonin, multivitamin and sodium citrate to olfactory training for the treatment of olfactory loss caused by COVID-19. METHODS: We evaluated olfactory function using University of Pennsylvania Smell Identification Test (UPSIT ®) scores and self-reported patient outcomes in post-infectious smell loss cases. We investigated the effectiveness involved olfactory training combined with sodium citrate, melatonin, and multivitamin supplements with zinc over a three-month period compared to an olfactory training alone. RESULTS: A total of 66 patients were included, with 33 in each group. There was no significant difference in the proportion of participants who showed improvement in UPSIT scores between the groups (OR = 1.43, 95% CI 0.43-4.8, p =  0.56). Both groups showed improvement in average test scores, but there were no significant differences in self-reported olfactory ability or discomfort with olfactory loss. Qualitative symptoms, such as parosmia and phantosmia, were reported by a similar proportion in both groups before and after the treatment (p =  0.11, p =  1, respectively). CONCLUSIONS: Olfactory training alone and olfactory training with associated with melatonin, multivitamins and topical sodium citrate did not show significant differences in improving olfactory function in post-COVID-19 patients.

The Bioenergetics of Traumatic Brain Injury and its Long-Term Impact for Brain Plasticity and Function.

Mitochondria provide the energy to keep cells alive and functioning and they have the capacity to influence highly complex molecular events. Mitochondria are essential to maintain cellular energy homeostasis that determines the course of neurological disorders, including traumatic brain injury (TBI). Various aspects of mitochondria metabolism such as autophagy can have long-term consequences for brain function and plasticity. In turn, mitochondria bioenergetics can impinge on molecular events associated with epigenetic modifications of DNA, which can extend cellular memory for a long time. Mitochondrial dysfunction leads to pathological manifestations such as oxidative stress, inflammation, and calcium imbalance that threaten brain plasticity and function. Hence, targeting mitochondrial function may have great potential to lessen the outcomes of TBI.

A mathematical model of melatonin synthesis and interactions with the circadian clock.

A new mathematical model of melatonin synthesis in pineal cells is created and connected to a slightly modified previously created model of the circadian clock in the suprachiasmatic nucleus (SCN). The SCN influences the production of melatonin by upregulating two key enzymes in the pineal. The melatonin produced enters the blood and the cerebrospinal fluid and thus the SCN, influencing the circadian clock. We show that the model of melatonin synthesis corresponds well with extant experimental data and responds similarly to clinical experiments on bright light in the middle of the night. Melatonin is widely used to treat jet lag and sleep disorders. We show how the feedback from the pineal to the SCN causes phase resetting of the circadian clock. Melatonin doses early in the evening advance the clock and doses late at night delay the clock with a dead zone in between where the phase of the clock doesn't change.

Visual input regulates melanophore differentiation.

Introduction: Developmental processes continue in organisms in which sensory systems have reached functional maturity, however, little research has focused on the influence of sensory input on cell and tissue development. Here, we explored the influence of visual system activity on the development of skin melanophores in Xenopus laevis. Methods: Melanophore number was measured in X. laevis larvae after the manipulation of visual input through eye removal (enucleation) and/or incubation on a white or black substrate at the time when the visual system becomes functional (stage 40). To determine the developmental process impacted by visual input, migration, proliferation and differentiation of melanophores was assessed. Finally, the role of melatonin in driving melanophore differentiation was explored. Results: Enucleating, or maintaining stage 40 larvae on a black background, results in a pronounced increase in melanophore number in the perioptic region within 24 h. Time lapse analysis revealed that in enucleated larvae new melanophores appear through gradual increase in pigmentation, suggesting unpigmented cells in the perioptic region differentiate into mature melanophores upon reduced visual input. In support, we observed increased expression of melanization genes tyr, tyrp1, and pmel in the perioptic region of enucleated or black background-reared larvae. Conversely, maintaining larvae in full light suppresses melanophore differentiation. Interestingly, an extra-pineal melatonin signal was found to be sufficient and necessary to promote the transition to differentiated melanophores. Discussion: In this study, we found that at the time when the visual system becomes functional, X. laevis larvae possess a population of undifferentiated melanophores that can respond rapidly to changes in the external light environment by undergoing differentiation. Thus, we propose a novel mechanism of environmental influence where external sensory signals influence cell differentiation in a manner that would favor survival.

Melatonin modulates TLR4/MyD88/NF-κB signaling pathway to ameliorate cognitive impairment in sleep-deprived rats.

Sleep deprivation (SD) is commonplace in today's fast-paced society. SD is a severe public health problem globally since it may cause cognitive decline and even neurodegenerative disorders like Alzheimer's disease. Melatonin (MT) is a natural chemical secreted by the pineal gland with neuroprotective effects. The purpose of this study was to investigate the protective effect and mechanism of MT on chronic sleep deprivation-induced cognitive impairment. A 3-week modified multi-platform method was used to create the SD rat model. The Morris water maze test (MWM), Tissue staining (including Hematoxylin and Eosin (H & E) staining, Nissl staining, and immunofluorescence), Western blot, Enzyme-linked immunosorbent assay (ELISA), and Quantitative real-time polymerase chain reaction (qPCR) were used to investigate the protective effect and mechanism of MT in ameliorating cognitive impairment in SD rats. The results showed that MT (50 and 100 mg/kg) significantly improved cognitive function in rats, as evidenced by a shortening of escape latency and increased time of crossing the platform and time spent in the quadrant. Additionally, MT therapy alleviated hippocampus neurodegeneration and neuronal loss while lowering levels of pathogenic factors (LPS) and inflammatory indicators (IL-1ß, IL-6, TNF-α, iNOS, and COX2). Furthermore, MT treatment reversed the high expression of Aß42 and Iba1 as well as the low expression of ZO-1 and occludin, and inhibited the SD-induced TLR4/MyD88/NF-κB signaling pathway. In summary, MT ameliorated spatial recognition and learning memory dysfunction in SD rats by reducing neuroinflammation and increasing neuroprotection while inhibiting the TLR4/MyD88/NF-κB signaling pathway. Our study supports the use of MT as an alternate treatment for SD with cognitive impairment.