Search

Because saliva melatonin levels are known to be approximately 30% of plasma melatonin levels,3 the saliva concentrations measured by RIA at 03:00 hours are consistent with the plasma levels in Figure 1, with daytime saliva melatonin levels below 3 pg/ml. In summary, measuring morning melatonin levels with plasma melatonin ELISA kits is a poor choice on two levels. GLO:8EA/01jan22:jpi12773-fig-0003.jpg PHOTO (COLOR): 3 Individual mean saliva melatonin levels from 10 papers that sampled saliva from at least 03:00 hours ( ) and from 24 papers that assayed melatonin in single morning time points. [Extracted from the article]

The melatonin system and circadian disruption have well‐established links with aggressive behaviors; however, the biological underpinnings have not been thoroughly investigated. Here, we aimed at examining the current knowledge regarding the neurobiological and psychopharmacological involvement of the melatonin system in aggressive/violent behaviors. To this end, we performed a systematic review on Embase and Pubmed/MEDLINE of preclinical and clinical evidence linking the melatonin system, melatonin, and melatoninergic drugs with aggressive/violent behaviors. Two blinded raters performed an independent screening of the relevant literature. Overall, this review included 38 papers distributed between clinical and preclinical models. Eleven papers specifically addressed the existing evidence in rodent models, five in fish models, and 21 in humans. The data indicate that depending on the species, model, and timing of administration, melatonin may exert a complex influence on aggressive/violent behaviors. Particularly, the apparent contrasting findings on the link between the melatonin system and aggression/violence (with either increased, no, or decreased effect) shown in preclinical models underscore the need for further research to develop more accurate and fruitful translational models. Likewise, the significant heterogeneity found in the results of clinical studies does not allow yet to draw any firm conclusion on the efficacy of melatonin or melatonergic drugs on aggressive/violent behaviors. However, findings in children and in traits associated with aggressive/violent behavior, including irritability and anger, are emerging and deserve empirical attention given the low toxicity of melatonin and melatonergic drugs. [ABSTRACT FROM AUTHOR]

Previous studies have reported inconsistent results about exogenous melatonin's sleep‐promoting effects. A possible explanation relies on the heterogeneity in administration schedule and dose, which might be accountable for differences in treatment efficacy. In this paper, we undertook a systematic review and meta‐analysis of double‐blind, randomized controlled trials performed on patients with insomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep‐related parameters. The standardized mean difference between treatment and placebo groups in terms of sleep onset latency and total sleep time were used as outcomes. Dose−response and meta‐regression models were estimated to explore how time of administration, dose, and other treatment‐related parameters might affect exogenous melatonin's efficacy. We included 26 randomized controlled trials published between 1987 and 2020, for a total of 1689 observations. Dose−response meta‐analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day. Meta‐regression models showed that insomnia status (β = 0.50, p < 0.001) and time between treatment administration and the sleep episode (β = −0.16, p = 0.023) were significant predictors of sleep onset latency, while the time of day (β = −0.086, p < 0.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timing of administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day), as compared to the exogenous melatonin schedule most used in clinical practice (2 mg 30 min before the desired bedtime), might optimize the efficacy of exogenous melatonin in promoting sleep. [ABSTRACT FROM AUTHOR]

The first monograph on the European hamster from the Strasbourg region dates back to 1765. By the 1930s, a long and continuous chronobiological research tradition was established for this species, starting with the works of Charles Kayser, who published between 1938 and 1971. Another early key researcher in this area was Bernhard Canguilhem with publications from 1966 to 1999. From the 1980s onwards, "the Pévets," Paul Pévet and his wife, Mireille Masson-Pévet, gave new energy to European hamster research. They broadened the research scope from basic hibernation research to mechanistic studies of circannual rhythms and from physiological aspects to molecular details. One main underlying question in their research was the role of melatonin. Thanks to their enthusiasm and vision, the European hamster is today one of the best - if not the best - studied circannual species. At least 73 parameters are described to cycle. Thirty-two of them have been shown to be driven by a circannual clock. Moreover, ground-breaking advances in our understanding of the mechanistic of hibernation, circannual clock functioning, and its entrainment were made. With most of this research being conducted in Strasbourg, Paul Pévet was instrumental in providing the necessary resources that made these innovative and unconventional long-term animal studies possible, contributing to fundamental research and, ultimately, to species conservation., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In vitro differentiation of stem cells into functional gametes remains of great interest in the biomedical field. Skin‐derived stem cells (SDSCs) are an adult stem cells that provides a wide range of clinical applications without inherent ethical restrictions. In this paper, porcine SDSCs were successfully differentiated into primordial germ cell‐like cells (PGCLCs) in conditioned media. The PGCLCs were characterized in terms of cell morphology, marker gene expression, and epigenetic properties. Furthermore, we also found that 25 μM melatonin (MLT) significantly increased the proliferation of the SDSC‐derived PGCLCs while acting through the MLT receptor type 1 (MT1). RNA‐seq results found the mitogen‐activated protein kinase (MAPK) signaling pathway was more active when PGCLCs were cultured with MLT. Moreover, the effect of MLT was attenuated by the use of S26131 (MT1 antagonist), crenolanib (platelet‐derived growth factor receptor inhibitor), U0126 (mitogen‐activated protein kinase kinase inhibitor), or CCG‐1423 (serum response factor transcription inhibitor), suggesting that MLT promotes the proliferation processes through the MAPK pathway. Taken together, this study highlights the role of MLT in promoting PGCLCs proliferation. Importantly, this study provides a suitable in vitro model for use in translational studies and could help to answer numerous remaining questions related to germ cell physiology. [ABSTRACT FROM AUTHOR]

In 1992, a paper reported that the melatonin content of the rat duodenum was 24 000 ± 2000 pg/g tissue (range: 4000–100 000 pg/g) while the pineal melatonin content was 580 000 ± 36 000 pg/g. The data has been used for the last 30 years to infer that the gut produces 400 hundred times more melatonin than the pineal gland and that it is the source of plasma melatonin during the daytime. No‐one has ever challenged the statement. In this review, evidence is summarised from the literature that pinealectomy eliminates melatonin from the circulation and that studies to the contrary have relied upon poorly validated immunoassays that overstate the levels. Similarly studies that have reported increases in plasma melatonin following tryptophan administration failed to account for cross reactivity of tryptophan and its metabolites in immunoassays. The most extraordinary observation from the literature is that in those studies that have measured melatonin in the gut since 1992, the tissue content is vastly lower than the original report, even when the methodology used could be overestimating the melatonin content due to cross reactivity. Using the more contemporary results we can calculate that rather than a 400:1 ratio of duodenum: pineal melatonin, a ratio of 0.05–0.19: 1 is likely. The gut is not a major extra‐pineal source of melatonin; indeed it may well not produce any. [ABSTRACT FROM AUTHOR]

Pineal region tumors (PTs) represent extremely rare pathologies, characterized by highly heterogeneous histological patterns. Most of the available evidence for Gamma Knife radiosurgical (GKSR) treatment of PTs arises from multimodal regimens, including GKSR as an adjuvant modality or as a salvage treatment at recurrence. We aimed to gather existing evidence on the topic and analyze single‐patient‐level data to address the efficacy and safety of primary GKSR. This is a systematic review of the literature (PubMed, Embase, Cochrane, Science Direct) and pooled analysis of single‐patient‐level data. A total of 1054 original works were retrieved. After excluding duplicates and irrelevant works, we included 13 papers (n = 64 patients). An additional 12 patients were included from the authors' original series. A total of 76 patients reached the final analysis; 56.5% (n = 43) received a histological diagnosis. Confirmed lesions included pineocytoma WHO grade I (60.5%), pineocytoma WHO grade II (14%), pineoblastoma WHO IV (7%), pineal tumor with intermediate differentiation WHO II/III (4.7%), papillary tumor of pineal region WHO II/III (4.7%), germ cell tumor (2.3%), neurocytoma WHO I (2.3%), astrocytoma WHO II (2.3%) and WHO III (2.3%). Presumptive diagnoses were achieved in the remaining 43.5% (n = 33) of cases and comprised of pineocytoma (9%), germ cell tumor (6%), low‐grade glioma (6%), high‐grade glioma (3%), meningioma (3%) and undefined in 73%. The mean age at the time of GKSR was 38.7 years and the mean lesional volume was 4.2 ± 4 cc. All patients received GKSR with a mean marginal dose of 14.7 ± 2.1 Gy (50% isodose). At a median 36‐month follow‐up, local control was achieved in 80.3% of cases. Thirteen patients showed progression after a median time of 14 months. Overall mortality was 13.2%. The median OS was not reached for all included lesions, except high‐grade gliomas (8mo). The 3‐year OS was 100% for LGG and pineal tumors with intermediate differentiation, 91% for low‐grade pineal lesions, 66% for high‐grade pineal lesions, 60% for germ cell tumors (GCTs), 50% for HGG, and 82% for undetermined tumors. The 3‐year progression‐free survival (PFS) was 100% for LGG and pineal intermediate tumors, 86% for low‐grade pineal, 66% for high‐grade pineal, 33.3% for GCTs, and 0% for HGG. Median PFS was 5 months for HGG and 34 months for GCTs. The radionecrosis rate was 6%, and cystic degeneration was observed in 2%. Ataxia as a presenting symptom strongly predicted mortality (odds ratio [OR] 104, p =.02), while GCTs and HGG histology well predicted PD (OR: 13, p =.04). These results support the efficacy and safety of primary GKSR treatment of PTs. Further studies are needed to validate these results, which highlight the importance of the initial presumptive diagnosis for choosing the best therapeutic strategy. [ABSTRACT FROM AUTHOR]

The pineal gland hormone melatonin continues to be of considerable interest to biomedical researchers. Of particular interest is the pattern of secretion of melatonin in relation to sleep timing as well as its potential role in certain diseases. Measuring melatonin in biological fluids such as blood and saliva presents particular methodological challenges since the production and secretion of the hormone are known to be extremely low during the light phase in almost all situations. Active secretion only occurs around the time of lights out in a wide range of species. The challenge then is to develop practical high‐throughput assays that are sufficiently sensitive and accurate enough to detect levels of melatonin less than 1 pg/mL in biological fluids. Mass spectrometry assays have been developed that achieve the required sensitivity, but are really not practical or even widely available to most researchers. Melatonin radioimmunoassays and ELISA have been developed and are commercially available. But the quality of the results that are being published is very variable, partly not only because of poor experimental designs, but also because of poor assays. In this review, I discuss issues around the design of studies involving melatonin measurement. I then provide a critical assessment of 21 immunoassay kits marketed by 11 different companies with respect to validation, specificity and sensitivity. Technical managers of the companies were contacted in an attempt to obtain information not available online or in kit inserts. A search of the literature was also conducted to uncover papers that have reported the use of these assays, and where possible, both daytime and night‐time plasma or saliva melatonin concentrations were extracted and tabulated. The results of the evaluations are disturbing, with many kits lacking any validation studies or using inadequate validation methods. Few assays have been properly assessed for specificity, while others report cross‐reaction profiles that can be expected to result in over estimation of the melatonin levels. Some assays are not fit for purpose because they are not sensitive enough to determine plasma or saliva DLMO of 10 and 3 pg/mL, respectively. Finally, some assays produce unrealistically high daytime melatonin levels in humans and laboratory animals in the order of hundreds of pg/mL. In summary, this review provides a comprehensive and unique assessment of the current commercial melatonin immunoassays and their use in publications. It provides researchers new to the field with the information they need to design valid melatonin studies from both the perspective of experimental/clinical trial design and the best assay methodologies. It will also hopefully help journal editors and reviewers who may not be fully aware of the pitfalls of melatonin measurement make better informed decisions on publication acceptability. [ABSTRACT FROM AUTHOR]

The nocturnal surge of melatonin is the endocrine expression of the circadian system and is essential for organizing the timing of various endogenous processes. Previous works suggest that, in the beginning of a defense response, the increase in circulating tumor necrosis factor-α (TNF-α) leads to a transient block of nocturnal melatonin production and promotes a disruption of internal time organization. In the present paper, the concentration of melatonin and cytokines [TNF-α, interferon-γ (IFN-γ), interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12] in the colostrum (postdelivery day 3) and in the milk (postdelivery days 10, 15, 20 and 30) obtained at midday and midnight from mothers who gave birth by vaginal or cesarean section were compared. The nocturnal melatonin surge observed 3 days after vaginal delivery was absent after cesarean section. IL-12 presented no daily variation in either case, while daily variations in IFN-γ, IL-10, IL-4 and IL-5 were observed after vaginal delivery and cesarean section. On the other hand, the increase in TNF-α after cesarean section resulted in suppression of the nocturnal melatonin surge. Daily variation of IL-2 was only observed after recovery of the nocturnal melatonin surge, 30 days after cesarean section. The present paper supports the hypothesis of a cross-talk between the pineal gland and the immune system, which could represent a putative immune–pineal axis. [ABSTRACT FROM AUTHOR]

Melatonin is a well-known animal substance, which has recently been detected in plant tissues. However, there are only a few studies concerning its possible physiological role in plants. In this paper, we investigate the possible effect of melatonin on the regeneration of lateral and adventious roots in etiolated hypocotyls of Lupinus albus L. compared with the effect of indole-3-acetic acid. We performed this study by measuring both molecules in roots. Six-day-old derooted lupin hypocotyls immersed in several melatonin or indole-3-acetic acid concentrations were used to induce roots. A macro- and microscopic study of the histological origin of the adventitious and lateral roots was made, while melatonin and indole-3-acetic acid in the roots were quantified using liquid chromatography with fluorescence detection. The data show that both melatonin and indole-3-acetic acid induced the appearance of root primordia from pericicle cells, modifying the pattern of distribution of adventitious or lateral roots, the time-course, the number and length of adventitious roots, and the number of lateral roots. Melatonin and indole-3-acetic acid were detected and quantified in lupin primary roots, where both molecules were present in similar concentrations. The physiological effect of exogenous melatonin as root promoter was demonstrated, its action being similar to that of indole-3-acetic acid. [ABSTRACT FROM AUTHOR]

Loss of circadian rhythmicity fundamentally affects the neuroendocrine, immune, and autonomic system, similar to chronic stress and may play a central role in the development of stress-related disorders. Recent articles have focused on the role of sleep and circadian disruption in the pathophysiology of posttraumatic stress disorder ( PTSD), suggesting that chronodisruption plays a causal role in PTSD development. Direct and indirect human and animal PTSD research suggests circadian system-linked neuroendocrine, immune, metabolic and autonomic dysregulation, linking circadian misalignment to PTSD pathophysiology. Recent experimental findings also support a specific role of the fundamental synchronizing pineal hormone melatonin in mechanisms of sleep, cognition and memory, metabolism, pain, neuroimmunomodulation, stress endocrinology and physiology, circadian gene expression, oxidative stress and epigenetics, all processes affected in PTSD. In the current paper, we review available literature underpinning a potentially beneficiary role of an add-on melatonergic treatment in PTSD pathophysiology and PTSD-related symptoms. The literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications. We conclude that adjuvant melatonergic treatment could provide a potentially promising treatment strategy in the management of PTSD and especially PTSD-related syndromes and comorbidities. Rigorous preclinical and clinical studies are needed to validate this hypothesis. [ABSTRACT FROM AUTHOR]

In this paper, we analyze the biological relevance of melatonin in diabetogenesis. As has recently been demonstrated, melatonin decreases insulin secretion via specific melatonin receptor isoforms (MT1 and MT2) in the pancreatic β-cells. In addition, type 2 diabetic rats, as well as patients, exhibit decreased melatonin levels, whereas the levels in type 1 diabetic rats are increased. The latter effects were normalized by insulin substitution, which signifies that a specific receptor-mediated insulin-melatonin antagonism exists. These results are in agreement with several recent genome-wide association studies, which have identified a number of single nucleotide polymorphisms in the MTNR1B gene, encoding the MT2 receptor, that were closely associated with a higher prognostic risk of developing type 2 diabetes. We hypothesize that catecholamines, which decrease insulin levels and stimulate melatonin synthesis, control insulin-melatonin interactions. The present results support this assertion as we show that catecholamines are increased in type 1 but are diminished in type 2 diabetes. Another important line of inquiry involves the fact that melatonin protects the β-cells against functional overcharge and, consequently, hinders the development of type 2 diabetes. In this context, it is striking that at advanced ages, melatonin levels are reduced and the incidence of type 2 diabetes is increased. Thus, melatonin appears to have a protective biological role. Here, we strongly repudiate misconceptions, resulting from observations that melatonin reduces the plasma insulin level, that the blockage of melatonin receptors would be of benefit in the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Melatonin is an endogenous indoleamine, produced mainly by the pineal gland. Melatonin has been proven to have chronobiotic, antioxidant, antihypertensive , anxiolytic and sedative properties. There are also experimental and clinical data supporting an analgesic role of melatonin. In experimental studies, melatonin shows potent analgesic effects in a dose-dependent manner. In clinical studies, melatonin has been shown to have analgesic benefits in patients with chronic pain (fibromyalgia, irritable bowel syndrome, migraine). The physiologic mechanism underlying the analgesic actions of melatonin has not been clarified. The effects may be linked to Gi-coupled melatonin receptors, to Gi-coupled opioid μ-receptors or GABA-B receptors with unknown downstream changes with a consequential reduction in anxiety and pain. Also, the repeated administration of melatonin improves sleep and thereby may reduce anxiety, which leads to lower levels of pain. In this paper, we review the current evidence regarding the analgesic properties of melatonin in animals and humans with chronic pain. [ABSTRACT FROM AUTHOR]

Glaucoma is a frequent ophthalmologic condition leading to chronic progressive optic neuropathy, which can result in visual impairment and blindness. In addition, glaucoma is associated with a dysregulation of circadian rhythms, as well as with a high incidence of sleep disorders, depression, and anxiety. However, because of their high comorbidity in older age, these conditions have not received much scientific attention and are often undertreated. In the current paper, we review the available literature on the role of melatonergic mechanisms in glaucoma, regulation of circadian rhythms, and depression. The literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications. Recently, there has been evidence for a progressive loss of intrinsically photosensitive retinal ganglion cells (ipRGC) because of oxidative stress in glaucoma. As ipRGC are responsible for the photic transduction to the circadian system and subsequent melatonin secretion, and melatonin is involved in the pathophysiology of circadian desynchronization, sleep disorder, and depression, an impairment of photo-dependent melatonergic signaling may be a common pathway connecting glaucoma with these comorbidities. This fact, as well as the proven retinal neuroprotective role of melatonin, suggests that melatonergic drugs provide a potentially promising treatment strategy supplementing the management of intraocular pressure by pharmacological and surgical measures. Additionally, multidisciplinary treatment focusing on depression and normalization of circadian rhythms might be beneficial for glaucoma patients. Furthermore, glaucoma might be a useful model for studying the pathophysiological interactions between the melatonergic, circadian, and mood systems. [ABSTRACT FROM AUTHOR]

This paper represents an essential aspect of recent investigations into the functional and clinical implications of insulin-melatonin interrelationships. The aim of the study was to analyze whether melatonin reduces insulin secretion in an animal in a manner comparable to the pattern observed in previous in vitro experiments; to this end, we used two models: Wistar and type 2-diabetic Goto-Kakizaki (GK) rats. Thirty-two Wistar and 32 GK rats were divided into two subgroups of 16 rats each; each subgroup was treated either with or without melatonin. The daily administration of melatonin, starting in 8- wk-old rats, was adjusted to 2.5 mg/kg body weight. Melatonin was given daily during the dark period for 12 hr. After 9 wk of treatment, the rats were sacrificed in the middle of the dark period. Melatonin administration strongly enhanced the plasma melatonin level and diminished the expression of pancreatic melatonin receptor-mRNA, whereas the expression of pineal AA-NAT and HIOMT was unchanged. Furthermore, the experiments showed in agreement with recent in vitro results of pancreatic islets that plasma insulin levels were diminished after melatonin treatment. However, the pineal insulin receptor expression was increased after melatonin administration. The pancreatic expression of glucagon, GLUT2, and glucokinase was decreased in GK rats, whereas the glucose levels, as well as the parameters of glucose sensing, GLUT2-mRNA, and glucokinase-mRNA, were unchanged after melatonin administration in both Wistar and GK rats. In summary, the results show that melatonin administration decreases plasma insulin levels in vivo and, furthermore, that an insulin-melatonin antagonism exists. [ABSTRACT FROM AUTHOR]

Serotonin N-acetyltransferase (AANAT) catalyzes the conversion of serotonin to N-acetylserotonin, which is the immediate precursor for formation of melatonin. Although it is known that AANAT is degraded via the proteasomal proteolysis, detailed mechanisms are not defined. In this paper, we tested the in vivo role of proteasome inhibition on AANAT activity and melatonin release and examined the amino acid residues in AANAT that contribute to the proteasome degradation. We have shown that inhibition of proteasome activities in vivo in the intact pineal gland fails to prevent the light-induced suppression of melatonin secretion. Furthermore, in cell lines stably expressing AANAT, inhibition of proteasomal proteolysis, which resulted in a large accumulation of AANAT protein, similarly failed to increase AANAT enzyme activity proportional to the amount of proteins accumulated. Site-directed mutagenesis analysis of AANAT revealed that the AANAT degradation is independent of lysine and the two surface cysteine residues. Deletion analysis of N-terminus identified the second amino acid leucine (L2) as the key residue that contributes to the proteasomal proteolysis of AANAT protein. These results suggest that rat AANAT protein is degraded via the N-end rule pathway of proteasomal proteolysis and the leucine at the N-terminus appears to be the key residue recognized by N-end rule pathway. [ABSTRACT FROM AUTHOR]

Endothelial cells produce NO by activation of constitutive nitric oxide synthase (NOS) and transcription of inducible NOS (iNOS). We have previously shown that melatonin, in the nanomolar range, inhibits activation of constitutive NOS, and in the present paper, we evaluated whether it could interfere with the expression of iNOS, which is activated by lipopolysaccharide (LPS), a major component of gram-negative bacteria cell walls. Primary cultures of rat endothelial cells were loaded with fluorescent probe for NO detection. Nuclear factor kappa B (NF-κB) translocation in endothelial cells elicited by LPS was measured by electromobility shift assay, and the vasodilation of aortic rings was accessed by recording isometric contraction. Melatonin in a micromolar but not in a nanomolar range inhibits the NO production induced by LPS. This effect is not dependent on the activation of G protein-coupled melatonin receptors. The nuclear NF-κB translocation is a process necessary for iNOS transcription, and melatonin also inhibits its translocation. LPS induced vasodilation only in endothelium-intact aortic rings, and melatonin (10 μm) inhibits the vasodilation. Here, we show that concentrations compatible with nocturnal melatonin surge (nm) did not interfere with the activity of iNOS. Considering that micromolar melatonin concentrations could be locally achieved through production by activated immune competent cells, extra-pineal melatonin could have a protective effect against tissue injury. We propose that melatonin blocked the LPS-induced vasodilation by inhibiting the NF-κB pathway. Finally, we propose that the effect of melatonin on vascular reactivity is one of the mechanisms that underlies the protective effect of this indolamine against LPS. [ABSTRACT FROM AUTHOR]

Melatonin, an indole mainly synthesized in the pineal gland during the dark phase, plays a role as an endogenous antioxidant and an anticancer agent in many tumors. Melatonin, at pharmacological concentrations, inhibits cell growth and induces neuroendocrine differentiation in prostate cancer cells. Classically it has been considered that melatonin enters freely into most of cells by passive diffusion through the cell membrane; however, there are few studies examining how melatonin is taken up by cancer cells. The aim of the present paper was to study the uptake of melatonin into human androgen-dependent LNCaP and androgen-independent PC-3 prostate cancer cells. Increased concentrations of melatonin induced a rapid and transitory rise in intracellular melatonin content in both cell types, with a peak of maximal content at 6 hr after melatonin addition, following a rhythmic uptake; melatonin was found in both cytoplasm and nuclear fractions. Inhibition of protein or RNA synthesis partially blocked melatonin uptake in both cell lines. Interestingly, melatonin pulse incubation led to a higher uptake after four cycles of pulse incubation. Neither extracellular Ca2+/K+ alterations nor the presence of bovine serum albumin or charcoal-stripped serum modified the profile of melatonin uptake. On the contrary, chemical binding of melatonin to BSA totally prevented melatonin from entering into cells. The present data support the hypothesis that a facilitated diffusion or an active process rather than simple passive diffusion through the cell membrane is the major mechanism in melatonin uptake by prostate cancer cells and it accounts for its intracellular concentration (350 nm–3.3 μm), which is related to its anti-tumor actions. [ABSTRACT FROM AUTHOR]

Control of the acute phase of Trypanosoma cruzi infection is critically dependent on cytokine-mediated macrophage activation to intracellular killing, natural killer (NK) cells, CD4+ T cells, CD8+ T cells and B cells. Cell-mediated immunity in T. cruzi infection is also modulated by cytokines, but in addition to parasite-specific responses, autoimmunity can be also triggered. Importantly, cytokines may also play a role in the cell-mediated immunity of infected subjects. Here we studied the role of cytokines in the regulation of innate and adaptive immunity during the acute phase of T. cruzi infection in Wistar rats. Melatonin is an effective regulator of the immune system. Macrophages and T lymphocytes, which have melatonin receptors, are target cells for the immunomodulatory function of melatonin. In this paper melatonin was orally given via two protocols: prior to and concomitant with infection. Both treatments were highly effective against T. cruzi with enhanced action for the concomitant treatment. The data suggest an up-regulation of the TH-1 immune response as all analyzed parameters, interleukin (IL)-4, IL-10, transforming growth factor-β1 and splenocyte proliferation, displayed reduced levels as compared with the untreated counterparts. However, the direct effects of melatonin on immune cells have not been fully investigated during T. cruzi infection. We conclude that in light of the current results, melatonin exerted important therapeutic benefits through its immune regulatory effects. [ABSTRACT FROM AUTHOR]

Low concentrations (nanomolar) of melatonin had been previously shown to inhibit cell proliferation in several cancer cell lines as well as in experimental animal models. Additionally, cell growth inhibition and differentiation of prostate cancer cell lines by high concentrations (micromolar to millimolar) of melatonin have been recently reported. In the present paper, we show the induction of apoptosis by high doses of melatonin in the human neuroblastoma cell line SK-N-MC. We found accumulation of cells in the G2/M cell cycle phase and induction of cellular death, measured as lactate dehydrogenase (LDH) released into the culture medium, under millimolar concentration of melatonin. Apoptosis was evaluated using 4,6-diamidino-2-phenylindole staining, DNA gel electrophoresis, electron microscopy, and annexin V binding. Apoptosis progressed through the classical pathway, which involves caspase-3 activation. Cell death was dose and time-dependent; the lowest effective concentration of melatonin was 100 μm. Treatment with 1 mm melatonin for 6 days induced cell death in 75% of the cells. This novel finding shows that a nontoxic natural indoleamine may be potential therapy for some types of human neuroblastomas. [ABSTRACT FROM AUTHOR]

A large number of data show that melatonin has immunomodulatory properties and is produced by immunocompetent cells; also, some evidence suggests a ‘feedback’ of the activated immune system on the pineal gland. In this paper, we studied immune–pineal interactions in colostrum obtained from healthy puerperae and mothers with mastitis taking into account that, (a) melatonin levels in milk reflects pineal activity and (b) colostrum quiescent mononuclear and polymorphonuclear phagocytes from healthy mothers in culture are adequate for evaluating the ability of immunocompetent cells to produce melatonin. Here we compared the diurnal and nocturnal melatonin levels in colostrum from healthy puerperae and mothers with mastitis; this is a unique noninvasive model for determining pineal activity in the proinflammatory phase of a defense response. In addition, we determined the ‘in vitro’ production of melatonin by colostrum immunocompetent cells stimulated by enteropathogenic Escherichia coli or zymosan. Suppression of nocturnal melatonin rise in mothers with mastitis was highly correlated with increased tumor necrosis factor- α (TNF- α) secretion. This result, interpreted taking into account the presence of the transcription factor nuclear factor kappa B in pineal gland, suggest that the proinflammatory cytokine can inhibit nocturnal pineal melatonin production. On the other hand, stimulated, but not quiescent, immunocompetent cells secreted in the colostrum produced melatonin in vitro. In addition, this production ceases after bacteria killing. These results suggest that during the response to an injury the production of melatonin can be transiently shifted from an endocrine (pineal) to a paracrine (immunocompetent cells) source. [ABSTRACT FROM AUTHOR]

The main structures involved in the circadian system in mammals are the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN contain multiple autonomous single-cell circadian oscillators that are coupled among themselves, generating a single rhythm. However, under determined circumstances, the oscillators may uncouple and generate several rhythmic patterns. Rats exposed to an artificially established 22-h light–dark cycle (T22) express two stable circadian rhythms in their motor activity that reflect the separate activities of two groups of oscillators in the morphologically well-defined ventrolateral and dorsomedial SCN subdivisions. In the experiments described in this paper, we studied the effect of melatonin and diazepam (DZP) administration in drinking water on the dissociated components of rat motor activity exposed to T22, to deduce the possible mechanism of these drugs on the circadian system. In order to suppress the endogenous circadian rhythm of melatonin, in some of the rats the pineal gland or the superior cervical ganglia were removed. The results show that melatonin or DZP treatment increased the manifestation of the light-dependent component to the detriment of the manifestation of the non-light-dependent component and that melatonin, but not DZP, shortens the period of the non-light-dependent component. These findings suggest that both DZP and melatonin favor entrainment to external light, and that melatonin could also act on the SCN, producing changes in the period of the circadian cycle. [ABSTRACT FROM AUTHOR]

The effects of melatonin in mammalian cells are exerted via specific receptors or are related to its free radical scavenging activity. It has previously been reported that melatonin inhibits insulin secretion in the pancreatic islets of the rat and in rat insulinoma INS1 cells via Gi-protein-coupled MT1 receptors and the cyclic adenosine 3′,5′-monophosphate pathway. However, the inositol-1,4,5-trisphosphate (IP3) pathway is involved in the insulin secretory response as well, and the melatonin signal may play a part in its regulation. This paper addresses the involvement of the second messengers IP3 and intracellular Ca2+ ([Ca2+]i) in the signalling cascade of melatonin in the rat insulinoma INS1 cell, a model for the pancreatic β-cell. For this purpose melatonin at concentrations ranging from 1 to 100 nmol/L, carbachol and the nonselective melatonin receptor antagonist luzindole were used to stimulate INS1 cell batches, followed by an IP3-mass assay and Ca2+ imaging. Molecular biological studies relating to the mRNA of IP3 receptor (IP3R) subtypes and their relative abundance in INS1 cells showed expression of IP3R-1, IP3R-2 and IP3R-3 mRNA. In conclusion, we found that in rat insulinoma INS1 cells there is a dose-dependent stimulation of IP3 release by melatonin, which is accompanied by a likewise transient increase in [Ca2+]i concentrations. The melatonin effect observed mimics carbachol action. It can be abolished by 30 μmol/L luzindole and is sustained in Ca2+-free medium, suggesting a mechanism that includes the depletion of Ca2+ from intracellular stores. [ABSTRACT FROM AUTHOR]

In chronically inflamed animals, adrenal hormones exert a positive control on the secretion of melatonin by the pineal gland. In this paper, the mechanism of corticosterone as a modulator of melatonin andN-acetylserotonin (NAS) was determined. Rat pineal glands in culture, stimulated for 5 hr with noradrenaline (10 nm), were previously incubated with corticosterone (1.0 nm–1.0 μm) for 48 hr in the presence or absence of the glucocorticoid receptor (GR) antagonist, mifepristone (1.0 μm), the proteasome inhibitor,N-acetyl-leucinyl-leucinyl-norleucinal-H (ALLN, 12.5 μm) or the antagonist of the nuclear factor kappa B (NFκB), pyrrolidinedithiocarbamate (PDTC, 12.5 μm). Corticosterone potentiated noradrenaline-induced melatonin and NAS production in a bell-shaped manner. The increase in NAS (12.9 ± 2.7, n = 6 versus 34.3 ± 8.3 ng per pineal) and melatonin (16.3 ± 2.0, n = 6 versus 44.3 ± 12.9 ng per pineal) content induced by 1 μmcorticosterone was blocked by mifepristone, and mimicked by ALLN and PDTC. The presence of GRs was shown by [3H]-dexamethasone binding (0.30 ± 0.09 pmol/mg protein) and corticosterone inhibition of NFκB nuclear translocation was demonstrated by electromobility shift assay. Therefore, corticosterone potentiates noradrenaline-induced melatonin and NAS production through GR inhibition of NFκB nuclear translocation. To the best of our knowledge, this is the first time that this relevant pathway for passive and acquired immune response is shown to modulate melatonin production in pineal gland. [ABSTRACT FROM AUTHOR]

The pineal hormone melatonin exhibits immunomodulatory activity well documented in mammals and birds. The mechanism of melatonin action within the immune system is, however, poorly understood. In mammalian immune cells in vitro, melatonin acts mainly as an antiapoptotic, oncostatic and antiproliferative agent, and these effects are exertedviaspecific receptors or are related to its free radical scavenging activity. In previous studies we have found that in short-term chicken splenocyte cultures in vitro melatonin stimulated basil proliferation and inhibited that stimulated with phytohemagglutinin, a T-cell mitogen. This paper is devoted to the involvement of membrane receptors, previously characterised by us as MT2 (Mel1b) and Mel1c subtypes, in the above mentioned melatonin effects in chicken splenocyte cultures. For this purpose, in present study a nonselective melatonin receptor antagonist, luzindole, and the selective MT2 blocker, 4P-PDOT, were used. The effect of melatonin on second messengers, cyclic adenosine-3′,5′-monophosphate (cAMP) and inositol-1,4,5-trisphosphate (IP3), involved in the regulation of proliferation, was examined. We have found that the stimulation of proliferation occursviaMel1c receptor and is associated with the changes in intracellular second messengers concentration: a decrease in cAMP and an increase in IP3. In contrast, in mitogen-activated splenocytes, melatonin-induced inhibition of proliferation is mediated by MT2 receptors and is related to cAMP accumulation, as well as a decrease in IP3. In conclusion, we have demonstrated that the stimulatory and inhibitory effect of melatonin on chicken splenocytes in vitro, dependent on the magnitude of cell stimulation, resulted from two different subtypes of membrane receptors. [ABSTRACT FROM AUTHOR]

Seasonal and circadian changes have been observed in dietary selection and feeding behavior of fish. It is known that the light–dark cycle is the principal mediator of the production of pineal-derived melatonin in fish, and also that the digestive tract synthesizes and secretes melatonin and indeed is the principal extrapineal source of this secretor product, suggesting that melatonin could be involved in the processes of feeding and/or digestion. Fish are capable of regulating their energy intake from separate sources of macronutrients, but the mechanisms of this selection process are unknown. In the present paper, we explored the effect of melatonin administered orally to European sea bass on their selection of encapsulated macronutrients. Melatonin doses of 0.1, 0.5, and 2.5 mg/kg body weight were administered in gelatin capsules. The voluntarily ingested melatonin was absorbed into the fish's plasma, 45 min after the administration reaching a level depending on the dose that was up to 26 times greater than the controls with the highest dose of melatonin. The indole produced a dose-dependent inhibition of total food intake of 9, 26, and 34%, respectively, and also modified the pattern of macronutrient selection. Carbohydrate intake was significantly reduced (by 17, 33, and 42% for the three doses, respectively), but the observed reductions in fat and protein intake were not statistically significant. On the contrary, fat percentage significantly increased for the highest dose, but no changes were observed in the protein or carbohydrate percentages for any of the melatonin doses. In conclusion, orally administered melatonin affected both the amount of food consumed and the pattern of macronutrients selected. This is the first evidence for the existence of neurohumoral mediators involved in the selection of macronutrients in fish. [ABSTRACT FROM AUTHOR]

Alzheimer's disease, among other pathological features, is characterized by an over-accumulation of amyloid-β peptide, metal ions, and oxidative stress proteins in the brain. Amyloid-β aggregated peptides with bound metal ions may initiate free radical generation with consequent protein and lipid oxidation, reactive oxygen species formation and eventually neuronal death. Melatonin is able to dramatically reduce the free radical formation which follows the interaction between transition metal ions and amyloid-β . This paper reports the scavenging effect of melatonin of reactants generated by amyloid peptides in combination with some metal ions. [ABSTRACT FROM AUTHOR]

Food allergy affects more than 500 million people in the world, and its prevalence is increasing at an alarming rate causing serious public health concerns; however, prevention and treatment methods are still under investigation and are relatively scarce so far. Insights on pathophysiology reveal a complex interplay of the immune cells (e.g., DCs, T cells, and B cells) resulting in allergy or tolerance. Studies have shown that melatonin metabolisms are altered in patients with allergic diseases, suggesting that melatonin might impact allergic diseases. Notably, melatonin can orchestrate the differentiation and function of immune cells. Additionally, the disease severities of many allergic diseases and the function of the immune system exhibit circadian rhythmicity. Therefore, melatonin, a rhythm regulator, may also act indirectly on the immune system through the circadian clock to regulate food allergies. Herein, we reviewed the impacts of melatonin on food allergy and its underlying regulatory mechanisms, providing a theoretical reference for melatonin as effective means of prevention and treatment for food allergy in the future. [ABSTRACT FROM AUTHOR]

The accelerated pace of life at present time has resulted in tremendous alterations in living patterns. Changes in diet and eating patterns, in particular, coupled with irregular light–dark (LD) cycles will further induce circadian misalignment and lead to disease. Emerging data has highlighted the regulatory effects of diet and eating patterns on the host‐microbe interactions with the circadian clock (CC), immunity, and metabolism. Herein, we studied how LD cycles regulate the homeostatic crosstalk among the gut microbiome (GM), hypothalamic and hepatic CC oscillations, and immunity and metabolism using multiomics approaches. Our data demonstrated that central CC oscillations lost rhythmicity under irregular LD cycles, but LD cycles had minimal effects on diurnal expression of peripheral CC genes in the liver including Bmal1. We further demonstrated that the GM could regulate hepatic circadian rhythms under irregular LD cycles, the candidate bacteria including Limosilactobacillus, Actinomyces, Veillonella, Prevotella, Campylobacter, Faecalibacterium, Kingella, and Clostridia vadinBB60 et al. A comparative transcriptomic study of innate immune genes indicated that different LD cycles had varying effects on immune functions, while irregular LD cycles had greater impacts on hepatic innate immune functions than those in the hypothalamus. Extreme LD cycle alterations (LD0/24 and LD24/0) had worse impacts than slight alterations (LD8/16 and LD16/8), and led to gut dysbiosis in mice receiving antibiotics. Metabolome data also demonstrated that hepatic tryptophan metabolism mediated the homeostatic crosstalk among GM‐liver–brain axis in response to different LD cycles. These research findings highlighted that GM could regulate immune and metabolic disorders induced by circadian dysregulation. Further, the data provided potential targets for developing probiotics for individuals with circadian disruption such as shift workers. [ABSTRACT FROM AUTHOR]

In vertebrates, arylalkylamine N‐acetyltransferase (AANAT; EC 2.3.1.87) is the time‐keeping and key regulatory enzyme in melatonin (Mel) biosynthesis. AANAT is present in the pineal gland, retina, and other regions where it is controlled by light, cyclic adenosine monophosphate (cAMP) levels, and the molecular clock. AANAT converts serotonin to N‐acetyl serotonin (NAS) and the last enzyme in the pathway, hydroxy‐o‐methyltransferase (HIOMT), forms Mel by NAS methylation. We have previously shown that AANAT is expressed in chicken retinal ganglion cells (RGCs) during daytime at the level of mRNA and enzyme activity. Here we investigated the presence of AANAT protein and mRNA throughout development in the chicken embryonic retina as well as AANAT expression, phosphorylation, and its sub‐cellular localization in primary cultures of retinal neurons from E10 embryonic retinas exposed to blue light (BL) and controls kept in the dark (D). From embryonic days 7–10 (E7‐10) AANAT mRNA and protein were visualized mainly concentrated in the forming ganglion cell layer (GCL), while from E17 through postnatal days, expression was detectable all through the different retinal cell layers. At postnatal day 10 (PN10) when animals were subjected to a 12:12 h LD cycle, AANAT was mainly expressed in the GCL and inner nuclear layer cells at noon (Zeitgeber Time (ZT 6)) and in the photoreceptor cell layer at night (ZT 21). Primary cultures of retinal neurons exhibited an induction of AANAT protein when cells were exposed to BL for 1 h as compared with D controls. After BL exposure, AANAT showed a significant change in intracellular localization from the cytoplasm to the nucleus in the BL condition, remaining in the nucleus 1–2 h in the D after BL stimulation. BL induction of nuclear AANAT was substantially inhibited when cultures were treated with the protein synthesis inhibitor cycloheximide (CHD). Furthermore, the phosphorylated form of the enzyme (pAANAT) increased after BL in nuclear fractions obtained from primary cultures as compared with D controls. Finally, the knockdown of AANAT by sh‐RNA in primary cultures affected cell viability regardless of the light condition. AANAT knockdown also affected the redox balance, sh‐AANAT treated cultures showing higher levels of reactive oxygen species (ROS) than in the sh‐control. Our results support the idea that AANAT is a BL‐sensing enzyme in the inner retina of diurnal vertebrates, undergoing phosphorylation and nuclear importation in response to BL stimulation. Moreover, it can be inferred that AANAT plays a novel role in nuclear function, cell viability, and, likely, through redox balance regulation. [ABSTRACT FROM AUTHOR]

In Figure S2F, the incorrect image was placed in the migration experiment of the PGC1A group of the Caki-1 cell. Melatonin/PGC1A/UCP1 promotes tumor slimming and represses tumor progression by initiating autophagy and lipid browning. [Extracted from the article]

Due to time zones, sun time and local time rarely match. The difference between local and sun time, which we designate by Solar Jet Lag (SoJL), depends on location within a time zone and can range from zero to several hours. Daylight saving time (DST) simply adds 1 h to SoJL, independently of the location. We hypothesised that the impact of DST is particularly problematic in patients with delayed sleep‐wake phase disorder (DSWPD), worsening their sleep debt. DSWPD is characterised by a chronic misalignment between the internal and social timing, reflected by an inability to fall asleep and wake‐up at conventional or socially acceptable times. We analysed the clinical records of 162 DSWPD patients from a sleep medicine centre in Lisbon, Portugal (GMTzone), and separated them into two groups: the ones diagnosed across DST or across Standard Time (ST). We included 82 patients (54.9% male; age: median [Q1, Q3] 34.5 [25.0, 45.3]; range 16–92; 54 in DST and 28 in ST) who had Dim Light Melatonin Onset (DLMO) measured as a marker for the circadian phase and sleep timing (onset, SO, mid‐point, MS and end, SE) self‐reported separately for work‐ and work‐free days. Differences between ST and DST were compared using Mann–Whitney or Student's t‐tests. On a weekly average, patients in DST slept less (difference between medians of 37 min. p <.01), mainly due to sleep on workdays (SDw,p <.01), which also correlated with SoJL (rsp =.38, p <.01). While the time from DLMO to SO was similar in those in ST or those in DST, the time from DLMO to SE was significantly shorter for those in DST. The average duration between DLMO and sleep end was close to 10.5 h in ST, the biological night length described in the literature. Our results favour perennial ST and suggest assigning time‐zones close to sun time to prevent social jetlag and sleep deprivation. [ABSTRACT FROM AUTHOR]

Although ramelteon has been examined as a relatively new therapeutic option for delirium prevention, current evidence to evaluate its efficacy is limited. We conducted an updated meta‐analysis and examine the reliability of existing evidence regarding the effect of ramelteon on delirium prevention in hospitalized patients. Seven major electronic databases were systematically searched to identify randomized controlled trials examining the efficacy of ramelteon in delirium prevention. Data were pooled using a frequentist‐restricted maximum‐likelihood random‐effects model. A trial sequential analysis was performed using relative risk reduction thresholds of 50%. The primary outcome was the incidence of delirium (reported as odds ratio with 95% confidence intervals). The secondary outcomes were the days of delirium, all‐cause mortality, and all‐cause discontinuation. Of 187 potentially eligible studies identified, 8 placebo‐controlled randomized controlled trials (n = 587) were included. This updated meta‐analysis showed that ramelteon was associated with lower odds of delirium occurrence than placebo (0.50; 0.29−0.86; I2 = 17.48%). In trial sequential analysis, the effect of ramelteon across the superiority boundary when using a relative risk reduction threshold ranging from 40% to 60%. In subgroup analyses, ramelteon compared with placebo was associated with lower odds of delirium occurrence in the elderly group (k = 5; 0.28; 0.09−0.85; I2 = 27.93%) and multiple dosage group (k = 5; 0.34; 0.14−0.82; I2 = 44.24%) but not in the non‐elderly and non‐multiple dosage groups. When considering surgical patients and medical patients separately, ramelteon showed a trend in the treatment of delirium prevention in both groups, while these findings were not statistically significant. No significant between‐group differences were found in the secondary outcomes. The current meta‐analysis provides updated and reliable evidence that ramelteon, in comparison with placebo, reduces the risk of delirium among hospitalized patients. [ABSTRACT FROM AUTHOR]

To determine whether IV melatonin therapy improves redox status and inflammatory responses in surgical patients with severe sepsis, a unicenter, phase II double‐blind, randomized, placebo‐controlled trial was carried out. The study included patients with severe sepsis marked by infectious systemic inflammatory response syndrome (SIRS), associated with organ dysfunction, hypoperfusion or hypotension requiring surgical intervention. IV melatonin at a daily dose of 60 mg, which was dissolved in 500 ml of 5% dextrose serum, was continuously administered to the patients for over 30 min starting on the day of the diagnoses during a 5‐day period. A total of 14 patients received a placebo treatment and 15 melatonin doses. Redox status decreased in melatonin‐treated patients during the 5 days of treatment as compared to the placebo‐treated patients. Procalcitonin performed better in the melatonin group, whose neutrophil to lymphocyte ratio was also significantly reduced, resulting in an improved evolution of the disease. Moreover, hospital stays decreased by 19.60% from 26.64 days for the placebo group to 21.42 days for the melatonin group. The placebo group recorded five mortalities, as compared to three for the melatonin group. IV melatonin administration improved the course of the disease in surgical patients with severe sepsis, with no side effects. Additional studies with higher doses of melatonin and a long duration of therapy need to be carried out to assess its clinical use. [ABSTRACT FROM AUTHOR]

There is a need to develop therapies for neonatal encephalopathy (NE) in low- and middle-income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation-amplified hypoxia-ischaemia (IA-HI) in the newborn piglet. The IA-HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N-acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA-HI by carotid artery occlusion and reduction in FiO 2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 μg/kg bolus + 1 μg/kg/h over 12 h). At 1 h after IA-HI, piglets were randomised to HI-saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15-30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI-saline, melatonin was associated with a reduction of 0.197 log 10 units (95% CrI [-0.366, -0.028], Pr (sup) 98.8%) in basal-ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [-0.676, 0.164], Pr (sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI-saline (Pr (sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr (sup) 95.4%). Compared to HI-saline, melatonin was associated with increased NeuN+ cell density (Pr (sup) 99.3%) across five of eight regions and reduction in TUNEL-positive cell death (Pr (sup) 89.7%). This study supports the translation of melatonin to early-phase clinical trials. Melatonin is protective following IA-HI where HT is not effective. These data guide the design of future dose-escalation studies in the next phase of the translational pipeline., (© 2024 The Author(s). Journal of Pineal Research published by John Wiley & Sons Ltd.)

Melatonin is a low‐cost natural small indole molecule with versatile biological functions. However, melatonin's fungicidal potential has not been fully exploited, and the mechanism remains elusive. Here, we report that melatonin broadly inhibited 13 plant pathogens. In the rice blast fungal pathogen Magnaporthe oryzae, melatonin inhibited fungal growth, formation of infection‐specific structures named appressoria, and plant infection, reducing disease severity. Melatonin entered fungal cells efficiently and colocalized with the critical mitogen‐activated protein kinase named Mps1, suppressing phosphorylation of Mps1. Melatonin's affinity for Mps1 via two hydrogen bonds was demonstrated using surface plasmon resonance and chemical modifications. To improve melatonin's efficiency, we obtained 20 melatonin derivatives. Tert‐butyloxycarbonyl melatonin showed a 25‐fold increase in fungicidal activities, demonstrating the feasibility of chemical modifications in melatonin modification. Our study demonstrated the broad‐spectrum fungicidal effect of melatonin by suppressing Mps1 as one of the targets. Through further systematic modifications, developing an eco‐friendly melatonin derivative of commercial values for agricultural applications appears promising. [ABSTRACT FROM AUTHOR]

The increasing number of people living with human immunodeficiency virus, HIV, (PLWH) have an elevated incidence of risk for noncommunicable comorbidities, the aetiology of which remains incompletely understood. While sleep disturbances are often reported in PLWH, it is unknown to what extent they relate to changes in the circadian and/or sleep homeostatic processes. We studied the relationship between sleep characteristics, circadian phase, and HIV status in older adults from the HAALSI (Health and Ageing in Africa: a Longitudinal Study of an INDEPTH Community in South Africa) subsample of the Agincourt Health and Demographic Surveillance System in South Africa (n = 187, 36 human immunodeficiency virus positive [HIV+], age: 66.7 ± 11.5 years, range 45—93 years), where HIV prevalence is high and (in contrast to the global north) does not associate significantly with potentially confounding behavioural differences. In participants with valid actigraphy data (n = 172), regression analyses adjusted for age and sex indicated that HIV+ participants had slightly later sleep onset (β =.16, p =.039), earlier sleep offset times (β = −.16, p =.049) and shorter total sleep times (β = −.20, p =.009) compared to the HIV negative (HIV−) participants. In a subset of participants (n = 51, 11 HIV+), we observed a later dim light melatonin onset (DLMO) in HIV+ (21:16 ± 01:47) than in HIV− (20:06 ± 00:58) participants (p =.006). This substantial difference remained when adjusted for age and sex (β = 1.21; p =.006). In 36 participants (6 HIV+) with DLMO and actigraphy data, median phase angle of entrainment was −6 min in the HIV+ group and +1 h 25 min in the HIV− group. DLMO time correlated with sleep offset (ρ = 0.47, p =.005) but not sleep onset (ρ = −0.086, p =.623). Collectively, our data suggest that the sleep phase occurred earlier than what would be biologically optimal among the HIV+ participants. This is the first report of a mistimed circadian phase in PLWH, which has important potential implications for their health and well‐being, especially given the well‐established relationships between circadian asynchrony and sleep deprivation with poorer health outcomes. [ABSTRACT FROM AUTHOR]

N‐Acetylserotonin (NAS) is an intermediate in the melatonin biosynthetic pathway. We investigated the anti‐inflammatory activity of NAS by focusing on its chemical feature oxidizable to an electrophile. NAS was readily oxidized by reaction with HOCl, an oxidant produced in the inflammatory state. HOCl‐reacted NAS (Oxi‐NAS), but not NAS, activated the anti‐inflammatory nuclear factor erythroid 2‐related factor 2 (Nrf2)‐heme oxygenase (HO)‐1 pathway in cells. Chromatographic and mass analyses demonstrated that Oxi‐NAS was the iminoquinone form of NAS and could react with N‐acetylcysteine possessing a nucleophilic thiol to form a covalent adduct. Oxi‐NAS bound to Kelch‐like ECH‐associated protein 1, resulting in Nrf2 dissociation. Moreover, rectally administered NAS increased the levels of nuclear Nrf2 and HO‐1 proteins in the inflamed colon of rats. Simultaneously, NAS was converted to Oxi‐NAS in the inflamed colon. Rectal NAS mitigated colonic damage and inflammation. The anticolitic effects were significantly compromised by the coadministration of an HO‐1 inhibitor. [ABSTRACT FROM AUTHOR]