Pineal Hormone Melatonin Research Articles

Melatonin-independent Photoperiodic Entrainment of the Circannual TSH Rhythm in the Pars Tuberalis of the European Hamster.

Adaptation of biological rhythms to a seasonal environment in circannual mammals is achieved via the synchronization of intrinsic circannual rhythms to the external year by photoperiod. In mammals, the photoperiodic information is integrated to seasonal physiology via the pineal hormone melatonin regulation of pars tuberalis (PT) TSHβ expression and its downstream control of hypothalamic dio2 gene expression. In the circannual European hamster, however, photoperiodic entrainment of the circannual clock is possible in pinealectomized animals. The present study explores whether the TSHβ expression in the PT and the downstream hypothalamic pathways are regulated by photoperiod in European hamsters in the absence of melatonin. All animals were kept on an accelerated photoperiodic regime, which compressed the natural year to a 6-month cycle. Sham-operated European hamsters and half of the pinealectomized European hamsters entrained their annual cycle in reproduction, body weight, and activity pattern to this cycle, whereas the other half of the pinealectomized animals followed only each second cycle. In all animals, PT TSHβ and hypothalamic dio2 expressions were higher in hamsters displaying a summer physiological state than in those in winter state. Moreover, in agreement with their seasonal state, reproductive animals (summer state) showed higher expression of rfrp and lower expression of kiss1-genes encoding central regulators of the reproductive axis-than those animals in reproductive quiescence (winter state), indicating the hypothalamic integration of the photoperiodic signal even in pinealectomized animals. The appropriate occurrence of a well-characterized activity pattern indicative of a so-called sensitive phase to short photoperiod suggested that the SCN constructs the melatonin-independent photoperiodic message. This message is sufficient to entrain the circannual rhythm in TSHβ expression in the PT and the downstream hypothalamic neuroendocrine pathway through a yet unknown pathway. These results reinforce the hypothesis that the PT is the site for the integration of circannual and photoperiodic information.

MORPHOFUNCTIONAL CHANGES IN KIDNEYS OF RATS WITH GENTAMICIN-INDUCED ACUTE KIDNEY INJURY AND USE OF MELATONIN

Aminoglycosides are effective antibiotics, but their accumulation in kidney cortex causes nephrotoxic effects in 20-30% of patients, which significantly limits their use. For this reason, search for the new therapies aimed at prevention of gentamicin-induced acute kidney injury (AKI) is highly relevant. Thus, the objective of our research was to study the functional and histopathological changes in kidneys of rats with gentamicin-induced AKI, and estimate the renoprotective potential of pineal hormone melatonin, which possesses antioxidant, anti-inflammatory and immunomodulatory effects. The study was conducted on 24 non-linear male rats. Gentamicin-induced AKI was modeled by daily administration of 4% gentamicin sulphate (80 mg/kg) for 6 days. Melatonin (Sigma Aldrich, USA) was injected daily at a dose of 5 mg/kg. Functional state of kidneys was assessed by diuresis, creatinine clearance, urine protein excretion, fractional excretion of sodium, and plasma potassium level. Documentation of the pathological processes was performed by the computer morphometry of objects in histological preparations. Statistical analysis of the data was performed using SPSS 17.0 software. Administration of gentamicin resulted in a significant impairment of renal function of experimental animals. A decrease in creatinine clearance by 3.1 times along with a reduction of diuresis by 1.9 times, and an increase in plasma creatinine concentration by 2.6 times was observed. There also was an increase in urine protein level by 5.2 times, an elevation of fractional sodium excretion and a reduction of plasma potassium level. Use of melatonin caused a significant improvement of renal function comparing to model pathology group. Functional disturbances were accompanied with the significant histopathological changes in kidney tissue: necrosis of the 27±5.2% epithelial cells of proximal tubules with the signs of hydropic vacuolization (7±2.1%) or reversible hydropic swelling (76±1.5%) in the rest of cells; swelling or deformation of some glomeruli. In the medulla tubular lumen were dilated and partially filled with hyaline casts, tubular cells had signs of dystrophy. Use of melatonin contributed to the restraint of the histopathological changes, confirmed by the decrease of the prevalence and severity of tubular necrosis (1.2%), dystrophy (64±2.3%), and injury of glomeruli. Obtained results verify the significant nephroprotective effect of pineal hormone melatonin, providing a background for the further in-depth study of its renal effects as well as its prospects as a nephroprotector.

Metformin and melatonin inhibit DMBA-induced mammary tumorigenesis in rats fed a high-fat diet.

The data from in-vitro and in-vivo studies show that both peroral antidiabetic metformin (MF) and pineal hormone melatonin (MT) inhibit the growth of many cancers, including breast cancer. However, most in-vivo studies used standard-type diet with low fat content. Therefore, in this study, we evaluated the chemopreventive effect of MF and MT in an in-vivo model of breast cancer in rats on a high-fat diet (10% of total fat). Mammary carcinogenesis was induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats. Chemoprevention with MF (administered in a diet, 0.2%) and MT (administered in tap water, 20 mg/l) was induced 20 days before the carcinogen administration through the termination of the experiment (14 weeks after carcinogen administration). Tumor growth parameters were analyzed together with histopathological examination and immunohistochemical detection of KI67 (proliferation marker), caspase-3, BAX, BCL-2 (apoptosis markers), and CD24 and CD44 (cancer stem cell markers) in mammary tumor samples. The combination of chemopreventive agents decreased tumor incidence by 29%. Cumulative tumor volume was lower in all groups treated with chemoprevention. Histopathology did not show significant changes in high-grade/low-grade tumor ratio. Immunohistochemistry showed increased expression of BAX in the combination group, and caspase-3 expression increased in both MT and combination groups. MT, and particularly the MF and MT combination, inhibited DMBA-induced mammary tumor growth in rats by apoptosis stimulation in cancer cells. Our results indicate that MT supplements in patients treated with MF may have a considerable effect on the incidence of breast cancer.

How to Monitor the Neuroimmune Biological Response in Patients Affected by Immune Alteration-Related Systemic Diseases.

The clinical management of patients affected by systemic diseases, including cancer and autoimmune diseases, is generally founded on the evaluation of the only markers related to the single disease rather than the biological immuno-inflammatory response of patients, despite the fundamental role of cytokine network in the pathogenesis of cancer and autoimmunity is well known. Cancer progression has appeared to be associated with a progressive decline in the blood levels of the main antitumor cytokines, including IL-2 and IL-12, in association with an increase in those of inflammatory cytokines, including IL-6, TNF-alpha, and IL-1-beta, and immunosuppressive cytokines, namely TGF-beta and IL-10. On the other hand, the severity of the autoimmune diseases has been proven to be greater in the presence of high blood levels of IL-17, TNF-alpha, IL-6, IL-1-beta, IFN-gamma, and IL-18, in association with low levels of TGF-beta and IL-10. However, because of excessive cost and complexity of analyzing the data regarding the secretion of the single cytokines, the relation between lymphocyte-induced immune activation and monocyte-macrophage-mediated immunosuppression has been recently proven to be expressed by the simple lymphocyte-to-monocyte ratio (LMR). The evidence of low LMR values has appeared to correlate with a poor prognosis in cancer and with a disease control in the autoimmune diseases. Moreover, since the in vivo immunoinflammatory response is physiologically under a neuroendocrine modulation, for the evaluation of patient biological response it would be necessary to investigate the function of at least the two main neuroendocrine structures involved in the neuroendocrine modulation of the immune responses, consisting of the hypothalamic-pituitary-adrenal axis and the pineal gland, since the lack of physiological circadian rhythm of cortisol and pineal hormone melatonin has appeared to be associated with a worse prognosis in the human systemic diseases.

Melatonin exerts an inhibitory effect on insulin gene transcription via MTNR1B and the downstream Raf‑1/ERK signaling pathway.

The pineal hormone melatonin influences the secretion of insulin by pancreatic islets via the G‑protein‑coupled melatoninreceptors1 and2 that are expressed in pancreatic β‑cells. Genome‑wide association studies indicate that melatonin receptor 1B(MTNR1B) single nucleotide polymorphisms are tightly associated with type 2 diabetes mellitus(T2DM). However, the underlying mechanism is unclear. Raf‑1 serves a critical role in the mitogen‑activated protein kinase(MAPK) pathways in β‑cell survival and proliferation and, therefore, may be involved in the mechanism by which melatonin impacts on T2DM through MTNR1B. In the present study, the mRNA expression of the two mouse insulin genes Ins1 and Ins2 was investigated in MIN6 cells treated with different concentrations of melatonin, and insulin secretion was detected under the same conditions. Following the overexpression or silencing of MTNR1B, the activities of components of the MAPK signaling pathway, including Raf‑1 and ERK, were evaluated. The impact of MTNR1B knockdown on the melatonin‑regulated insulin gene expression and insulin secretion were also investigated. The results demonstrated that exogenous melatonin inhibited the expression of insulin mRNA in the MIN6 cells. Insulin secretion by the MIN6 cells, however, was not affected by melatonin. The MAPK signaling pathway was inhibited in MIN6 cells by treatment with melatonin or the overexpression of MTNR1B. The knockdown of MTNR1B totally attenuated the regulating effect of melatonin on insulin gene expression. Additionally, the inductive effect of melatonin on the expression of insulin mRNA was attenuated when the activities of Raf‑1 or ERK were blocked using the chemical inhibitors GW5074 and U0126, respectively. It may be concluded that melatonin exerts an inhibitory effect on insulin transcription via MTNR1B and the downstream MAPK signaling pathway.

Melatonin Modulates Thyroid Hormones and Splenocytes Proliferation Through Mediation of Its MT1 and MT2 Receptors in Hyperthyroid Mice

Hyperthyroidism is characterized by an increased metabolic rate with the alteration of immune activity. The pineal hormone melatonin regulates various physiological activities through sensitization of MT1 and MT2 membrane receptors in mammals. In the present study we have evaluated the involvement of MT1 and MT2 receptors in melatonin mediated modulation of thyroid hormones and splenocyte proliferation in experimentally induced hyperthyroidic mice. The l-thyroxine treatment induced the hyperthyroidism in mice evidenced with hypersecretion of T3 and T4 hormones from thyroid gland. Hyperthyroidic state increased the TSH hormone level which might be inducing hyper activity in thyroid gland. Exogenous melatonin suppressed the thyroid hormones level as well as TSH level in circulation. The l-thyroxine treatment increased the splenocyte proliferation and showed synergic effects along with melatonin. l-thyroxine treated mice alone or along with melatonin treatment showed differential expression pattern of MT1 and MT2 receptors protein in thyroid and spleen tissues. It seems that melatonin regulates thyroid hormones and splenocyte proliferation through activation of MT1 and MT2 receptors.

Качество жизни женщин с климактерическим синдромом в перименопаузе при лечении гормоном эпифиза мелатонином

Качество жизни женщин с климактерическим синдромом в перименопаузе при лечении гормоном эпифиза мелатонином

Local Actions of Melatonin in Somatic Cells of the Testis

The pineal hormone melatonin regulates testicular function through the hypothalamic-adenohypophyseal axis. In addition, direct actions of melatonin in somatic cells of the testis have been described. Melatonin acts as a local modulator of the endocrine activity in Leydig cells. In Sertoli cells, melatonin influences cellular growth, proliferation, energy metabolism and the oxidation state, and consequently may regulate spermatogenesis. These data pinpoint melatonin as a key player in the regulation of testicular physiology (i.e., steroidogenesis, spermatogenesis) mostly in seasonal breeders. In patients with idiopathic infertility, melatonin exerts anti-proliferative and anti-inflammatory effects on testicular macrophages, and provides protective effects against oxidative stress in testicular mast cells. Consequently, melatonin is also involved in the modulation of inflammatory and oxidant/anti-oxidant states in testicular pathology. Overall, the literature data indicate that melatonin has important effects on testicular function and male reproduction.

Tracking insomnia seasonal variations through consumption of hypnotics

IntroductionLight-stimulated release of melanopsin suppresses the nocturnal production of melatonin and is sending signals to multiple brain areas, including hypothalamic suprachiasmatic nuclei and thus controlling the release of the pineal hormone melatonin and therefore control the circadian rhythm. Consumption of sedatives and hypnotics was used as an indirect measure of seasonal variations in sleep disturbances among inpatients at University Psychiatric Hospital Vrapče.MethodsRetrograde record analysis was performed from 1st January to 31st December 2012 on commonly used hypnotics and sedatives: zolpidem, nitrazepam, flurazepam, and midazolam.ResultsThe lowest consumption of hypnotics was recorded in the months of November, August and September while the highest consumption was recorded in January, December and March which can be seen in Fig. 1. Although there were differences in the monthly prescription of hypnotics, when it comes to seasonal patterns, there are no statistically significant differences.ConclusionsThere is no significant difference between the consumption of hypnotics in the observed seasons although the consumption of hypnotics is higher in the months with shorter daylight. This study attempted to correlate exposure to light and insomnia through the prescription of hypnotics and it is possible there are other important variables not included in this study.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Sleep, Melatonin, and the Menopausal Transition: What Are the Links?

The pineal hormone Melatonin plays an important role in the regulation of the circadian sleep/wake cycle, mood, and perhaps immune functions, carcinogensis and reproduction. The human circadian rhythm of melatonin release from the pineal gland is tightly synchronized with the habitual hours of sleep. Peri- and postmenopausal women often complain of difficulties initiating and/or maintaining sleep, with frequent nocturnal and early morning awakenings. In this review we discuss the pathophysiology of melatonin function as it relates to sleep disorders in menopausal women, highlighting the potential use of exogenous melatonin during the menopausal transition and beyond.

The psychoneuroendocrine-immunotherapy of cancer: Historical evolution and clinical results.

The prognosis of the neoplastic diseases depends not only on the biogenetic characteristics of cancer cells but also on the immunological response of patients, which may influence the biological features of cancer cells themselves as well as the angiogenic processes. Moreover, the immune system in vivo is under a physiological psychoneuroendocrine (PNE) regulation, mainly mediated by the brain opioid system and the pineal gland. In more detail, the anticancer immunity is stimulated by the pineal hormone melatonin (MLT) and inhibited by the opioid system, namely, through a mu-opioid receptor. Several alterations involving the pineal endocrine function and the opioid system have been described in cancer patients, which could play a role in tumor progression itself. Therefore, the pharmacological correction of cancer progression-related anomalies could contribute to control cancer diffusion, namely, the pineal endocrine deficiency and the hyperactivity of brain opioid system. In fact, the administration of pharmacological doses of the only MLT has already been proven to prolong the 1-year survival in untreatable metastatic cancer patients. Better results may be achieved by associating other pineal indoles to MLT, mu-opioid antagonists, cannabinoids, beta-carbolines. Moreover, these neuroendocrine combinations may be successfully associated with antitumor cytokines, such as interleukin (IL)-2 and IL-12, as a PNE-immune cancer therapy as well as with antitumor plants as PNE-phytotherapy of cancer in an attempt to propose possible anticancer treatments also to patients with disseminated cancer and untreatable according to the standard oncology.

The Palliative Curative Treatment of Untreatable Metastatic Solid Tumor Patients by a Psycho-Neuroendocrino-Immunophytotherapic (PNEIF) Regimen with Natural Anticancer Agents

Several natural agents, including both human endogenous neuroendocrine substances, namely the pineal hormones, and plants, mainly Aloe, Myrrh and Magnolia, have been proven to exert anticancer activities, due to antiproliferative and immunomodulating properties. On this basis, a study was planned in an attempt to evaluate the therapeutic efficacy of a psychoneuroendocrinoimmun-phytotherapic (PNEIF) regimen with pineal hormones and antitumor plants in a group of untreatable metastatic solid tumor patients, for whom no treatment other than the palliative therapy was available, because of lack of response to previous chemotherapies, poor clinical status or personal refusal of chemotherapy, and with a life expectancy less than 1 year. The pineal hormone melatonin (MLT) and 5-methoxytryptamine (5-MTT) were given orally at 100 mg/day in the dark period and at 5 mg in the light period of the day, respectively, in association with Aloe and Myrrh mixture at 10 ml thrice/day, Magnolia cortex at 500 mg twice/day and Bowellia at 1000 mg/day in patients with brain metastases. A complete response (CR) and partial response (PR) were achieved in 2 and in 8 patients. Then, an objective tumor regression was obtained in 10/132 (8%) patients. A stable disease (SD) was found in 61 patients, then a disease control (DC), consisting of CR plus PR plus SD, was achieved in 71/132 (54%) patients, whereas the remaining patients had a progressive disease (PD). A survival longer than 1 year was seen in 63/132 (48%) patients, and the percent of 2 and 3-year survival obtained in patients with response or SD was significantly longer than that found in patients with PD. The treatment was well tolerated and no relevant biological toxicity occurred. This preliminary study would demonstrate that a PNEIF combination with natural anticancer agents may prolong the survival time in patients, for whom no standard therapy was available other than the only palliative therapy, and with an expected survival less than 1 year.

Melatonin and Metformin Diminish Oxidative Stress in Heart Tissue in a Rat Model of High Fat Diet and Mammary Carcinogenesis.

The aim of this study was to determine the effects of long-term administration of the oral antidiabetic metformin or the pineal hormone melatonin, and a combination thereof, in preventing oxidative stress in the heart tissue of female Sprague-Dawley rats with mammary tumors induced by N-methyl-N-nitrosourea (NMU) (50mg/kg) given on the 42nd postnatal day. Metformin and melatonin were administered 12days before and 16weeks after the carcinogen. During the experiment, all animals were fed a high fat diet (10% total fat, 2.5% from lard, and 7.5% from palm oil). The findings are that mammary carcinogenesis generated oxidative stress. Reactive oxygen species (ROS) content, estimated from thiobarbituric acid reactive substances (TBARS), oxidatively modified protein content (aldehyde and ketone derivatives), and the activity of the antioxidant enzymes superoxide dismutase, glutathione reductase, and glutathione peroxidase were all augmented. Metformin caused a decrease in oxidative stress in the heart, accompanied by a decrease in diene conjugates, the elimination of ROS (stable total antioxidant status), and the activation of catalase and glutathione reductase. Melatonin caused an increase in total antioxidant status and a substantial reduction in ROS as estimated from aldehyde and ketone derivatives, lipid peroxidation at the initial (diene conjugates) and terminal stages (TBARS), and increased catalase and glutathione peroxidase activities. Metformin and melatonin combined reversed the effects of NMU on oxidative stress. In conclusion, melatonin reduces the level of oxidative stress in the heart tissue, caused by NMU carcinogenesis and a high fat diet, significantly stronger than metformin.

Waiting for the Sun: the circannual programme of reindeer is delayed by the recurrence of rhythmical melatonin secretion after the arctic night.

At temperate latitudes, the annual cycle of day length synchronizes circannual rhythms, and, in mammals, this is mediated via nocturnal production of the pineal hormone melatonin, proportional to the length of the night. Here, we studied circannual synchronization in an arctic species, the reindeer (Rangifer tarandus tarandus), which ceases to produce a rhythmic melatonin signal when it is exposed to extended periods of continuous midwinter darkness and continuous midsummer light. Using food intake, antler growth and moult as endpoints, we demonstrate that when animals living at 70°N are transferred from natural photoperiods in late autumn to either continuous light or continuous darkness, they undergo a conspicuous acceleration of the circannual programme. We conclude that rhythmical melatonin secretion, recommencing when the Sun reappears late in January, is required for proper timing of spring physiological responses, through a delaying effect on the circannual programme set in motion during the preceding autumn.

Role of the Pineal Hormone Melatonin in Delaying the Ageing Process

Role of the Pineal Hormone Melatonin in Delaying the Ageing Process

Clinical Utility of Melatonin in Fibromyalgia Diagnosis

Fibromyalgia syndrome (FMS) is a chronic disease with an unknown etiology, which is characterized by reduced pain threshold (hyperallgesia) & pain with normally innocuous stimuli (allodynia).This diffuse pain is often disease associated with wide range of other symptoms including fatigue, sleep disturbance, stiffness& more.FMS often occur concomitantly with other rheumatologic disease such as rheumatoid arthritis(RA), systemic lupus erthymatosus(SLE). The pineal hormone melatonin (MT) exerts a variety of effects on the immune system. MT activates immune cells and enhances inflammatory cytokine and nitric oxide production.Methods: We were studied 75 subjects, 55 of subjects were FMS patients defined by the American Colleague of Rheumatology (ACR 2010) criteria. Patients' mean age was 32.5 ± 13.9 years. They were classified into two groups: Group I of 25 primary FMS patients . Group II of 30 secondary FMS patients with other rheumatologic disease such as RA, SLE. Twenty age and sex matched healthy individuals were included in the study as a control group.Results:Mean Melatonin titers were significantly reduced (p<0.0001) in primary FMs patients compared to the controls (21.32vs. 30.9 pg/ml), but they were significantly elevated (p<0.0001) in secondary FMS compared to controls (138.1vs.30.9 pg/ml). Our data imposed that, in 1ry FMS there were negative correlations of MT titers with tender points (r=-0.848**,p<0.0001), sleep disturbance(r=-0.963**, p< 0.0001**), Fatigue (r= -0.972**, p<0.001**), WPI (r= -0,953 **, p<0.0001) and SS (r=-0.901**, p< 0.0001). Conclusions:In primary FMS patients melatonin level is lower than melatonin level in control, but MT level is high in secondary FMS patients. There was a negative correlation between MT with tender points, sleep disturbance, fatigue, SS & WPI. But there was a positive correlation between MT & cognitive symptoms.

Chronomedicine and type 2 diabetes: shining some light on melatonin.

In mammals, the circadian timing system drives rhythms of physiology and behaviour, including the daily rhythms of feeding and activity. The timing system coordinates temporal variation in the biochemical landscape with changes in nutrient intake in order to optimise energy balance and maintain metabolic homeostasis. Circadian disruption (e.g. as a result of shift work or jet lag) can disturb this continuity and increase the risk of cardiometabolic disease. Obesity and metabolic disease can also disturb the timing and amplitude of the clock in multiple organ systems, further exacerbating disease progression. As our understanding of the synergy between the timing system and metabolism has grown, an interest has emerged in the development of novel clock-targeting pharmaceuticals or nutraceuticals for the treatment of metabolic dysfunction. Recently, the pineal hormone melatonin has received some attention as a potential chronotherapeutic drug for metabolic disease. Melatonin is well known for its sleep-promoting effects and putative activity as a chronobiotic drug, stimulating coordination of biochemical oscillations through targeting the internal timing system. Melatonin affects the insulin secretory activity of the pancreatic beta cell, hepatic glucose metabolism and insulin sensitivity. Individuals with type 2 diabetes mellitus have lower night-time serum melatonin levels and increased risk of comorbid sleep disturbances compared with healthy individuals. Further, reduced melatonin levels, and mutations and/or genetic polymorphisms of the melatonin receptors are associated with an increased risk of developing type 2 diabetes. Herein we review our understanding of molecular clock control of glucose homeostasis, detail the influence of circadian disruption on glucose metabolism in critical peripheral tissues, explore the contribution of melatonin signalling to the aetiology of type 2 diabetes, and discuss the pros and cons of melatonin chronopharmacotherapy in disease management.

Pineal volume and evening melatonin in young people with affective disorders.

Affective disorders in young people have been associated with disruptions in circadian rhythms, including abnormalities in secretion of the pineal hormone melatonin. Previous research reports relationships between pineal gland volumes, melatonin secretion, and sleep-wake cycles, but the relationship between these factors has not been explored in affective disorders. This study aimed to characterize these factors and explore associations with mood symptoms and functioning in a sample of young people with affective disorders. Pineal volume from magnetic resonance imaging and melatonin assay from evening dim-light saliva collection were evaluated in 50 individuals (15-30years old; 72% female) with bipolar, depressive, or anxiety disorders. Actigraphy monitoring was also conducted for approximately two weeks to derive sleep-wake measures. Pineal volume was associated with melatonin secretion across the evening, replicating previous findings in psychiatrically healthy individuals. Pineal volume was smaller in participants in which melatonin onset was not detected. Timing of melatonin secretion was related to sleep timing, but amount of melatonin and pineal volume were not related to any sleep-wake measures. A shorter phase angle between onset of melatonin secretion and sleep onset was associated with longer total sleep time. Lower melatonin levels were associated with poorer social and occupational functioning. Although pineal volume is not directly related to sleep disturbances or symptoms, melatonin may influence both sleep-wake cycles and functioning in the early stages of affective disorder. Causal links remain to be established, however, treatments that target circadian rhythms may be useful in improving functioning in young people with affective disorders.

Dose dependent sun protective effect of topical melatonin: A randomized, placebo-controlled, double-blind study

BackgroundUltraviolet radiation (UVR) by sunlight results in an increasing number of skin conditions. Earlier studies have suggested a protective effect of topical treatment with the pineal hormone melatonin. However, this protective effect has never been evaluated in natural sunlight, and the optimal dosing has not been clarified. ObjectiveThe aim of this study was to investigate the sun protective effect of topical treatment with three different doses of melatonin (0.5%, 2.5%, 12.5%) against erythema induced by natural sunlight. MethodThe study was a randomized, placebo-controlled, double-blind study in healthy volunteers. Twenty-three healthy volunteers, 8 male and 15 female, were enrolled. The protective effect of three different doses of melatonin cream (0.5%, 2.5%, 12.5%) against erythema induced by natural sunlight was tested. All participants had their backs exposed to sun from 1:22 PM to 2:02 PM local time and UV-index was 9. Primary outcome was reduction in erythema evaluated by chromatography after sun exposure, when treated with topical melatonin cream (0.5%, 2.5%, 12.5%) versus placebo and no treatment. The erythema reaction was evaluated with chromatography and visual scoring at baseline, one, four, eight and 24h after exposure. ResultsSignificant difference in erythema formation was found between areas treated with melatonin cream 12.5% and areas receiving placebo or no treatment (repeated measures ANOVA p=0.001). No differences were found between placebo and the 0.5% and 2.5% concentrations. ConclusionApplication of melatonin cream 12.5% protects against natural sunlight induced erythema.

The melatonin-sensitive circadian clock of the enteric bacterium Enterobacter aerogenes

Circadian clocks are fundamental properties of all eukaryotic organisms and at least some prokaryotic organisms. Recent studies in our laboratory have shown that the gastrointestinal system contains a circadian clock that controls many, if not all, aspects of gastrointestinal function. We now report that at least one species of intestinal bacteria, Enterobacter aerogenes, responds to the pineal and gastrointestinal hormone melatonin by an increase in swarming activity. This swarming behavior is expressed rhythmically, with a period of approximately 24 hrs. Transformation of E. aerogenes to express luciferase with a MotA promoter reveals circadian patterns of bioluminescence that are synchronized by melatonin and whose periods are temperature compensated from 26°C to 40°C. Bioinformatics suggest similarities between the E. aerogenes and cyanobacterial clocks, suggesting the circadian clock may have evolved very early in the evolution of life. They also point to a coordination of host circadian clocks with those residing in the microbiota themselves.