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Sample records for alters melatonin secretion

  1. Altered waveform of plasma nocturnal melatonin secretion in premenstrual depression.

    PubMed

    Parry, B L; Berga, S L; Kripke, D F; Klauber, M R; Laughlin, G A; Yen, S S; Gillin, J C

    1990-12-01

    The nocturnal secretion of plasma melatonin was determined under dim to dark conditions in eight patients with prospectively confirmed premenstrual syndrome and in eight age- and menstrual cycle phase-matched normal control subjects. Plasma samples for melatonin were collected every 30 minutes from 6 PM to 9 AM during the early follicular, late follicular, midluteal and late luteal phases of the menstrual cycle. Compared with normal controls, patients with premenstrual syndrome had an earlier (phase-advanced) offset of melatonin secretion, which contributed to a shorter secretion duration and a decreased area under the curve. No statistically significant differences were found between women with premenstrual syndrome and normal controls for melatonin onset or peak concentration, or for estradiol or progesterone levels. The data demonstrate that women with premenstrual syndrome have chronobiological abnormalities of melatonin secretion. The fact that these patients respond to treatments that affect circadian physiology, such as sleep deprivation and phototherapy, suggests that circadian abnormalities may contribute to the pathogenesis of premenstrual syndrome.

  2. Melatonin in Epilepsy: A New Mathematical Model of Diurnal Secretion

    PubMed Central

    Kijonka, Marek; Pęcka, Marcin; Sokół, Maria

    2016-01-01

    Purpose. The main objective of the study was to create a mathematical model that describes the melatonin circadian secretion and, then the functionality of the model was tested by a comparison of the melatonin secretions in children with and without epilepsy. Material and Methods. The patients were divided into the epilepsy group (EG, n = 52) and the comparison group (CG, n = 30). The melatonin level was assessed by a radioimmunoassay method. The diurnal melatonin secretion was described using a nonlinear least squares method. Spearman's rank correlation coefficient was chosen to estimate the dependence of the acquired data. The model reproduces blood concentration profiles and its parameters were statistically analyzed using the Mann-Whitney-Wilcoxon test and logistic regression. Results. The correlation analysis performed for the EG and CG groups showed moderate correlations between age and the melatonin secretion model parameters. Patients with epilepsy are characterized by an increased phase shift of melatonin release. PMID:27478439

  3. Melatonin in Epilepsy: A New Mathematical Model of Diurnal Secretion.

    PubMed

    Paprocka, Justyna; Kijonka, Marek; Pęcka, Marcin; Sokół, Maria

    2016-01-01

    Purpose. The main objective of the study was to create a mathematical model that describes the melatonin circadian secretion and, then the functionality of the model was tested by a comparison of the melatonin secretions in children with and without epilepsy. Material and Methods. The patients were divided into the epilepsy group (EG, n = 52) and the comparison group (CG, n = 30). The melatonin level was assessed by a radioimmunoassay method. The diurnal melatonin secretion was described using a nonlinear least squares method. Spearman's rank correlation coefficient was chosen to estimate the dependence of the acquired data. The model reproduces blood concentration profiles and its parameters were statistically analyzed using the Mann-Whitney-Wilcoxon test and logistic regression. Results. The correlation analysis performed for the EG and CG groups showed moderate correlations between age and the melatonin secretion model parameters. Patients with epilepsy are characterized by an increased phase shift of melatonin release. PMID:27478439

  4. Evidence for feedback control of pineal melatonin secretion.

    PubMed

    Bedrosian, Tracy A; Herring, Kamillya L; Walton, James C; Fonken, Laura K; Weil, Zachary M; Nelson, Randy J

    2013-05-10

    Melatonin is the principle hormonal product of the pineal gland. It is secreted with a robust daily rhythm, peaking near the middle of the night. During the daytime, concentrations remain very low, as exposure to light robustly suppresses its secretion. The regulation of melatonin by light is well-characterized, but an interesting feature of the daily melatonin rhythm is that its peak occurs near the middle of the night and then levels begin to drop hours before morning light exposure. The mechanism underlying the light-independent drop in melatonin during late night remains unspecified. Feedback control is one mechanism of hormone regulation, but no studies thus far have explored the possibility of such regulation in the pineal of white-footed mice (Peromyscus leucopus). The pineal gland and SCN express melatonin receptors, and melatonin regulates its own receptor density in the brain. We investigated the possibility of feedback control of melatonin by administering melatonin receptor antagonists to female white-footed mice and then measuring plasma melatonin concentrations. In the first experiment, we observed that luzindole, a dual MT1/MT2 receptor antagonist administered 1h after lights off, caused an increase in plasma melatonin both 1 and 2h later. In a second experiment, we did not observe a change in melatonin concentrations following injection of an antagonist specific for the MT2 subtype. These results suggest the possibility of feedback control of melatonin release, occurring preferentially through the MT1 receptor subtype. PMID:23528860

  5. Light exposure, melatonin secretion, and menstrual cycle parameters: an integrative review.

    PubMed

    Barron, Mary Lee

    2007-07-01

    Dysfunction in menstrual physiology has pronounced effects on quality of life, involving mood changes, body image, infertility, and pregnancy complications. Light exposure may affect menstrual cycles and symptoms through the influence of melatonin secretion. The purpose of this systematic review is to determine the current state of knowledge about the effects of light and melatonin secretion on menstrual phase and cycle alterations. A brief overview of the influence of melatonin on human physiology is included. There is evidence of a relationship between light exposure and melatonin secretion and irregular menstrual cycles, menstrual cycle symptoms, and disordered ovarian function. In women with a psychopathology such as bipolar disorder or an endocrinopathy such as polycystic ovary syndrome, there seems to be greater vulnerability to the influence of light-dark exposure. Research on the complex role of light-dark exposure in menstrual physiology has implications for treatment of menstrual-associated disorders.

  6. Central Interleukin-1β Suppresses the Nocturnal Secretion of Melatonin

    PubMed Central

    Herman, A. P.; Bochenek, J.; Król, K.; Krawczyńska, A.; Antushevich, H.; Pawlina, B.; Herman, A.; Romanowicz, K.; Tomaszewska-Zaremba, D.

    2016-01-01

    In vertebrates, numerous processes occur in a rhythmic manner. The hormonal signal reliably reflecting the environmental light conditions is melatonin. Nocturnal melatonin secretion patterns could be disturbed in pathophysiological states, including inflammation, Alzheimer's disease, and depression. All of these states share common elements in their aetiology, including the overexpression of interleukin- (IL-) 1β in the central nervous system. Therefore, the present study was designed to determine the effect of the central injection of exogenous IL-1β on melatonin release and on the expression of the enzymes of the melatonin biosynthetic pathway in the pineal gland of ewe. It was found that intracerebroventricular injections of IL-1β (50 µg/animal) suppressed (P < 0.05) nocturnal melatonin secretion in sheep regardless of the photoperiod. This may have resulted from decreased (P < 0.05) synthesis of the melatonin intermediate serotonin, which may have resulted, at least partially, from a reduced expression of tryptophan hydroxylase. IL-1β also inhibited (P < 0.05) the expression of the melatonin rhythm enzyme arylalkylamine-N-acetyltransferase and hydroxyindole-O-methyltransferase. However, the ability of IL-1β to affect the expression of these enzymes was dependent upon the photoperiod. Our study may shed new light on the role of central IL-1β in the aetiology of disruptions in melatonin secretion. PMID:27212805

  7. [Melatonin secretion in women of advanced reproductive age].

    PubMed

    Ermolenko, K S; Rapoport, S I; Solov'eva, A V

    2013-01-01

    The patient's age is a key factor determining success of in vitro fertilization. The ovarian reserve and oocyte quality are known to decrease with age. Much attention has been given recently to the role of epiphysis and its hormone, melatonin, in synchronization of daily and seasonal biorhythms in anti-stress protection and neuroregulation of reproductive processes. The aim of our work was to study melatonin levels in infertile women of reproductive age. We also measured sex hormones, anti-Mullerian hormone, FSH, and LH in blood and melatonin sulfate in urine at 8 points (RIA). Women of advanced reproductive age showed markedly reduced melatonin secretion due to functional disorders in the hypothalamic-pituitary-gonadal axis. Results of the study suggest the necessity of prescription of exogenous melatonin to the patients included in assisted reproduction programs for the improvement of their efficacy.

  8. Nocturnal melatonin secretion in multiple sclerosis patients with affective disorders.

    PubMed

    Sandyk, R; Awerbuch, G I

    1993-02-01

    The pineal gland has been implicated recently in the pathogenesis of multiple sclerosis (MS), a chronic demyelinating disease of CNS. Since nocturnal melatonin secretion is low in some groups of patients with mental depression, we predicted lower melatonin secretion in MS patients with history of affective illness compared to those without psychiatric disorders. To test this hypothesis, we studied single nocturnal plasma melatonin levels and the incidence of pineal calcification (PC) on CT scan in a cohort of 25 MS patients (4 men, 21 women; mean age = 39.4 years, SD = 9.3), 15 of whom had a history of coexisting psychiatric disorders with predominant affective symptomatology. Other factors that may be related to depression such as vitamin B12, folic acid, zinc, magnesium, and homocysteine, were also included in the analysis. Neither any of the metabolic factors surveyed nor the incidence of PC distinguished the psychiatric from the control group. However, the mean melatonin level in the psychiatric patients was significantly lower than in the control group. Since low melatonin secretion in patients with depression may be related to a phase-advance of the circadian oscillator regulating the offset of melatonin secretion, we propose that the depression of MS likewise may reflect the presence of dampened circadian oscillators. Furthermore, since exacerbation of motor symptoms in MS patients may be temporally related to worsening of depression, we propose that circadian phase lability may also underlie the relapsing-remitting course of the disease. Consequently, pharmacological agents such as lithium or bright light therapy, which have been shown to phase-delay circadian rhythms, might be effective in the treatment of affective symptoms in MS as well as preventing motor exacerbation and hastening a remission from an acute attack. PMID:8063528

  9. Acute melatonin treatment alters dendritic morphology and circadian clock gene expression in the hippocampus of Siberian hamsters.

    PubMed

    Ikeno, Tomoko; Nelson, Randy J

    2015-02-01

    In the hippocampus of Siberian hamsters, dendritic length and dendritic complexity increase in the CA1 region whereas dendritic spine density decreases in the dentate gyrus region at night. However, the underlying mechanism of the diurnal rhythmicity in hippocampal neuronal remodeling is unknown. In mammals, most daily rhythms in physiology and behaviors are regulated by a network of circadian clocks. The central clock, located in the hypothalamus, controls melatonin secretion at night and melatonin modifies peripheral clocks by altering expression of circadian clock genes. In this study, we examined the effects of acute melatonin treatment on the circadian clock system as well as on morphological changes of hippocampal neurons. Male Siberian hamsters were injected with melatonin in the afternoon; 4 h later, mRNA levels of hypothalamic and hippocampal circadian clock genes and hippocampal neuron dendritic morphology were assessed. In the hypothalamus, melatonin treatment did not alter Period1 and Bmal1 expression. However, melatonin treatment increased both Period1 and Bmal1 expression in the hippocampus, suggesting that melatonin affected molecular oscillations in the hippocampus. Melatonin treatment also induced rapid remodeling of hippocampal neurons; melatonin increased apical dendritic length and dendritic complexity in the CA1 region and reduced the dendritic spine density in the dentate gyrus region. These data suggest that structural changes in hippocampal neurons are regulated by a circadian clock and that melatonin functions as a nighttime signal to coordinate the diurnal rhythm in neuronal remodeling.

  10. Melatonin secretion and puberty in female lambs exposed to environmental electric and magnetic fields

    SciTech Connect

    Lee, J.M. Jr.; Stormshak, F.; Thompson, J.M.; Thinesen, P.; Painter, L.J.; Olenchek, E.G.; Hess, D.L.; Forbes, R.; Foster, D.L. )

    1993-10-01

    This study determined whether chronic exposure of female lambs to the electric and magnetic fields (EMF) of a high voltage transmission line can alter pineal secretion of melatonin and the normal occurrence of puberty. Twenty female Suffolk lambs were assigned randomly in equal numbers to a control and a treatment group. Treatment from 2 to 10 mo of age consisted of continuous exposure within the electrical environment of a 500-kV transmission line (mean electric field 6 kV/m, mean magnetic field 40 mG). Treated lambs were penned directly beneath the transmission line; control lambs were maintained in a pen of similar construction 229 m from the line where EMF were at ambient levels (mean electric field < 10 V/m, mean magnetic field < 0.3 mG). Melatonin was analyzed by RIA in serum of blood samples collected at 0.5-3-h intervals over eight 48-h periods. To assess attainment of puberty, serum concentrations of progesterone were determined by RIA from blood samples collected twice weekly beginning at 19 wk of age. Concentrations of circulating melatonin in control and treated lambs were low during daylight hours and increased during nighttime hours. The characteristic pattern of melatonin secretion during nighttime (amplitude, phase, and duration) did not differ between control and treatment groups. Age at puberty and number of subsequent estrous cycles also did not differ between groups. These data suggest that chronic exposure of developing female sheep to 60-Hz environmental EMF does not affect the mechanisms underlying the generation of the circadian pattern of melatonin secretion or the mechanisms involved in the onset of reproductive activity.

  11. Melatonin modulates secretion of growth hormone and prolactin by trout pituitary glands and cells in culture.

    PubMed

    Falcón, J; Besseau, L; Fazzari, D; Attia, J; Gaildrat, P; Beauchaud, M; Boeuf, G

    2003-10-01

    In Teleost fish, development, growth, and reproduction are influenced by the daily and seasonal variations of photoperiod and temperature. Early in vivo studies indicated the pineal gland mediates the effects of these external factors, most probably through the rhythmic production of melatonin. The present investigation was aimed at determining whether melatonin acts directly on the pituitary to control GH and prolactin (PRL) secretion in rainbow trout. We show that 2-[125I]-iodomelatonin, a melatonin analog, binds selectively to membrane preparations and tissue sections from trout pituitaries. The affinity was within the range of that found for the binding to brain microsomal preparations, but the number of binding sites was 20-fold less than in the brain. In culture, melatonin inhibited pituitary cAMP accumulation induced by forskolin, the adenyl cyclase stimulator. Forskolin also induced an increase in GH release, which was reduced in the presence of picomolar concentrations of melatonin. At higher concentrations, the effects of melatonin became stimulatory. In the absence of forskolin, melatonin induced a dose-dependent increase in GH release, and a dose-dependent decrease in PRL release. Melatonin effects were abolished upon addition of luzindole, a melatonin antagonist. Our results provide the first evidence that melatonin modulates GH and PRL secretion in Teleost fish pituitary. Melatonin effects on GH have never been reported in any vertebrate before. The effects result from a direct action of melatonin on pituitary cells. The complexity of the observed responses suggests several types of melatonin receptors might be involved.

  12. Melatonin

    PubMed Central

    Pévet, Paul

    2002-01-01

    Melatonin (MEL) is a hormone synthesized and secreted by the pineal gland deep within the brain in response to photoperiodic cues relayed from the retina via an endogenous circadian oscillator within the suprachiasmatic nucleus in the hypothalamus. The circadian rhythm of melatonin production and release, characterized by nocturnal activity and daytime quiescence, is an important temporal signal to the body structures that can read it. Melatonin acts through high-affinity receptors located centrally and in numerous peripheral organs. Different receptor subtypes have been cloned and characterized: MT1 and MT2 (transmembrane G-protein-coupled receptors), and MT3. However, their physiological role remains unelucidated, although livestock management applications already include the control of seasonal breeding and milk production. As for potential therapeutic applications, exogenous melatonin or a melatonin agonist and selective 5-hydroxytrypiamine receptor (5-HT2c) antagonist, eg, S 20098, can be used to manipulate circadian processes such as the sleep-vake cycle, which are frequently disrupted in many conditions, most notably seasonal affective disorder. PMID:22034091

  13. [Bulimia, bulimia-anorexia and nocturnal secretion of melatonin and cortisol].

    PubMed

    Parienti, V; Kennedy, S H; Brown, G M; Costa, D

    1988-01-01

    The authors compared nocturnal variations of melatonin (MT) and cortisol levels in subjects with bulimia (n = 12), 6 with a normal body weight and 6 with anorexia nervosa, as well as 6 control subjects. The hypothesis, formulated for anorexia nervosa, that a decrease of noradrenergic activity induces a decrease of pineal activity, therefore a decrease of melatonin secretion, was not confirmed by our study. Moreover, in subjects with bulimia in the absence of anorexia nervosa, no significant decrease of nocturnal melatonin secretion was reported. Significant differences were due to cortisol variations when comparing MTmax/Cmin ratios. Melatonin did not add any complementary biological cue for diagnostic assessment for subjects with eating disorder and depression. The results of this study suggest that melatonin does not appear to be a useful biological marker in bulimia.

  14. Melatonin secretion is impaired in women with preeclampsia and an abnormal circadian blood pressure rhythm.

    PubMed

    Bouchlariotou, Sofia; Liakopoulos, Vassilios; Giannopoulou, Myrto; Arampatzis, Spyridon; Eleftheriadis, Theodoros; Mertens, Peter R; Zintzaras, Elias; Messinis, Ioannis E; Stefanidis, Ioannis

    2014-08-01

    Non-dipping circadian blood pressure (BP) is a common finding in preeclampsia, accompanied by adverse outcomes. Melatonin plays pivotal role in biological circadian rhythms. This study investigated the relationship between melatonin secretion and circadian BP rhythm in preeclampsia. Cases were women with preeclampsia treated between January 2006 and June 2007 in the University Hospital of Larissa. Volunteers with normal pregnancy, matched for chronological and gestational age, served as controls. Twenty-four hour ambulatory BP monitoring was applied. Serum melatonin and urine 6-sulfatoxymelatonin levels were determined in day and night time samples by enzyme-linked immunoassays. Measurements were repeated 2 months after delivery. Thirty-one women with preeclampsia and 20 controls were included. Twenty-one of the 31 women with preeclampsia were non-dippers. Compared to normal pregnancy, in preeclampsia there were significantly lower night time melatonin (48.4 ± 24.7 vs. 85.4 ± 26.9 pg/mL, p<0.001) levels. Adjustment for circadian BP rhythm status ascribed this finding exclusively to non-dippers (p<0.01). Two months after delivery, in 11 of the 21 non-dippers both circadian BP and melatonin secretion rhythm reappeared. In contrast, in cases with retained non-dipping status (n=10) melatonin secretion rhythm remained impaired: daytime versus night time melatonin (33.5 ± 13.0 vs. 28.0 ± 13.8 pg/mL, p=0.386). Urinary 6-sulfatoxymelatonin levels were, overall, similar to serum melatonin. Circadian BP and melatonin secretion rhythm follow parallel course in preeclampsia, both during pregnancy and, at least 2 months after delivery. Our findings may be not sufficient to implicate a putative therapeutic effect of melatonin, however, they clearly emphasize that its involvement in the pathogenesis of a non-dipping BP in preeclampsia needs intensive further investigation.

  15. Daytime melatonin infusions induce sleep in pigeons without altering subsequent amounts of nocturnal sleep.

    PubMed

    Mintz, E M; Phillips, N H; Berger, R J

    1998-12-18

    Daily infusions of melatonin restore sleep suppressed by continuous bright light in pigeons. To test whether melatonin could also induce sleep in pigeons on a 12:12 h light-dark cycle (LD), pigeons received 12-h intravenous melatonin infusions during the day. Melatonin induced sleep during the day, increased EEG slow wave activity, and decreased body temperature and locomotor activity. None of these variables were altered during the night following infusions. The induction of extended daytime sleep by melatonin infusions indicates that melatonin is a principal factor in the regulation of sleep in pigeons.

  16. Melatonin in mood disorders.

    PubMed

    Srinivasan, Venkataramanujan; Smits, Marcel; Spence, Warren; Lowe, Alan D; Kayumov, Leonid; Pandi-Perumal, Seithikurippu R; Parry, Barbara; Cardinali, Daniel P

    2006-01-01

    The cyclic nature of depressive illness, the diurnal variations in its symptomatology and the existence of disturbed sleep-wake and core body temperature rhythms, all suggest that dysfunction of the circadian time keeping system may underlie the pathophysiology of depression. As a rhythm-regulating factor, the study of melatonin in various depressive illnesses has gained attention. Melatonin can be both a 'state marker' and a 'trait marker' of mood disorders. Measurement of melatonin either in saliva or plasma, or of its main metabolite 6-sulfatoxymelatonin in urine, have documented significant alterations in melatonin secretion in depressive patients during the acute phase of illness. Not only the levels but also the timing of melatonin secretion is altered in bipolar affective disorder and in patients with seasonal affective disorder (SAD). A phase delay of melatonin secretion takes place in SAD, as well as changes in the onset, duration and offset of melatonin secretion. Bright light treatment, that suppresses melatonin production, is effective in treating bipolar affective disorder and SAD, winter type. This review discusses the role of melatonin in the pathophysiology of bipolar disorder and SAD.

  17. Melatonin and its precursor, L-tryptophan: influence on pancreatic amylase secretion in vivo and in vitro.

    PubMed

    Jaworek, Jolanta; Nawrot, Katarzyna; Konturek, Stanisław J; Leja-Szpak, Anna; Thor, Piotr; Pawlik, Wiesław W

    2004-04-01

    Melatonin, considered as a main pineal product, may be also synthetized in the gastrointestinal tract from L-tryptophan. Melatonin has been recently shown to affect insulin release and its receptors have been characterized in the pancreas however, the effects of melatonin on the pancreatic enzyme secretion have not been examined. The aim of this study was to investigate the effects of melatonin or L-tryptophan on amylase secretion in vivo in anaesthetized rats with pancreato-biliary fistulas, and in vitro using isolated pancreatic acini. Melatonin (1, 5 or 25 mg/kg) or L-tryptophan (10, 50 or 250 mg/kg) given to the rats as a intraperitoneal (i.p.) bolus injection produced significant and dose-dependent increases in pancreatic amylase secretion under basal conditions or following stimulation of enzyme secretion by diversion of bile-pancreatic juice. This was accompanied by a dose-dependent rise in melatonin plasma level. Stimulation of pancreatic enzyme secretion caused by melatonin or L-tryptophan was completely abolished by vagotomy, deactivation of sensory nerves with capsaicin or pretreatment with CCK1 receptor antagonists (tarazepide or L-364,718). Pretreatment with luzindole, an antagonist of melatonin MT(2) receptor failed to affect melatonin- or L-tryptophan-induced amylase secretion. Administration of melatonin (1, 5 or 25 mg/kg i.p.) or L-tryptophan (10, 50 or 250 mg/kg i.p.) to the rats resulted in the dose-dependent increase of cholecystokinin (CCK) plasma immunoreactivity. Enzyme secretion from isolated pancreatic acini was not significantly affected by melatonin or L-tryptophan used at doses of 10(-8) -10(-5) M. We conclude that exogenous melatonin, as well as that produced endogenously from L-tryptophan, stimulates pancreatic enzyme secretion in vivo while increasing CCK release. Stimulatory effect of melatonin or L-tryptophan on the exocrine pancreas involves vagal sensory nerves and the CCK release by these substances.

  18. Melatonin

    MedlinePlus

    ... may be used in these pills: natural and synthetic (manmade). Natural melatonin is made from the pineal ... a virus so it is not recommended. The synthetic form of melatonin does not carry this risk. ...

  19. Decreased melatonin secretion in a phenotypically male 46,XX patient with classic 21-hydroxylase deficiency.

    PubMed

    Luboshitzky, R; Qupti, G; Shen-Orr, Z; Hardoff, R

    2000-01-01

    The possible role of gonadal steroids and gonadotropins in regulating melatonin secretion has been suggested in clinical syndromes of the hypothalamic-pituitary-gonadal axis. We describe the results of melatonin secretion in a 37-year old male patient who presented with azoospermia. The patient was an XX male, had classic simple virilizing form of 21-hydroxylase deficiency, which led to a masculine phenotype. He was ovariectomized at the age of three years and reared as a male. Melatonin production (aMT6s) was determined at baseline and during 12 months of replacement therapy. Results were compared with those obtained in age-matched male controls. Pretreatment aMT6s values were decreased (14.3 microg/24 h vs. 29.0+/-5.5 in controls). Dexamethasone replacement was associated with an increase in aMT6s values (19.3-20.9 microg/24 h). The addition of testosterone to dexamethasone replacement resulted in normalization of aMT6s (27.6-33.1 microg/24 h) and serum 17OH progesterone, testosterone and estradiol levels. The present data indicate that androgen excess due to 21 hydroxylase deficiency is associated with decreased melatonin secretion. These results support the hypothesis that sex steroids modulate melatonin secretion.

  20. Geomagnetic activity influences the melatonin secretion at latitude 70 degrees N.

    PubMed

    Weydahl, A; Sothern, R B; Cornélissen, G; Wetterberg, L

    2001-01-01

    Factors other than light may affect variations in melatonin, including disturbances in the geomagnetic field. Such a possibility was tested in Alta, Norway, located at latitude 70 degrees N, where the aurora borealis is a result of large changes in the horizontal component (H) of the geomagnetic field. Geomagnetic disturbances are felt more strongly closer to the pole than at lower latitudes. Also noteworthy in Alta is the fact that the sun does not rise above the horizon for several weeks during the winter. To examine whether changes in geomagnetic activity influence the secretion of melatonin, saliva was collected from 25 healthy subjects in Alta several times during the day-night and at different times of the year. Single cosinor analyses yielded individual estimates of.the circadian amplitude and MESOR of melatonin. A 3-hour mean value for the local geomagnetic activity index, K, was used for approximately the same 24-hour span. A circadian rhythm was found to characterize both melatonin and K, the peak in K (23:24) preceding that of melatonin (06:08). During the span of investigation, a circannual variation also characterized both variables. Correlation analyses suggest that changes in geomagnetic activity had to be of a certain magnitude to affect the circadian amplitude of melatonin. If large enough (> 80 nT/3 h), changes in geomagnetic activity also significantly decreased salivary melatonin concentration. PMID:11774869

  1. Spectral modulation of light wavelengths using optical filters: effect on melatonin secretion.

    PubMed

    Casper, Robert F; Rahman, Shadab

    2014-08-01

    Shiftwork has been identified as a risk factor for various medical problems, such as cancer, heart disease, metabolic disturbances, depression, and anxiety disorders, and as reviewed this month, adverse reproductive function. Shiftwork misaligns physiological rhythms with respect to each other and to external environmental rhythms such as the 24-hour light/dark cycle. Light is the strongest time cue for entraining circadian rhythms in mammals, and aberrant light exposure patterns during shiftwork is one of the key factors that induce circadian misalignment. We have recently demonstrated, in both animal and clinical models, that filtering short wavelengths (below 480 nm) from nocturnal lighting can attenuate alterations in hormone secretion (melatonin and glucocorticoids) and in central and peripheral clock gene expression induced by nighttime light exposure. We also demonstrated that the use of optical filters led to an improvement in mood and in cognitive performance under controlled laboratory conditions and during field-based shiftwork studies. Moreover, there was an increase in sleep duration and quality on nights immediately following night shifts. We believe it is likely that optical filters incorporated into glasses or as coverings for light bulbs could be used as a method to improve or prevent many of the medical problems associated with circadian misalignment and rotating shiftwork.

  2. Dietary melatonin alters uterine artery hemodynamics in pregnant holstein heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective was to examine uterine artery hemodynamics and maternal serum profiles in pregnant heifers supplemented with dietary melatonin (MEL) or no supplementation (CON). In addition, melatonin receptor–mediated responses in steroid metabolism were examined using a bovine endometrial epithelial...

  3. Circadian secretion of cortisol and melatonin in cluster headache during active cluster periods and remission.

    PubMed Central

    Waldenlind, E; Gustafsson, S A; Ekbom, K; Wetterberg, L

    1987-01-01

    The cyclic nature of cluster headache warranted a study of the 24-hour rhythms of serum cortisol and melatonin. They were both altered during cluster periods as compared with periods of remission and healthy controls. The 24-hour mean and maximal cortisol levels were higher and the timing of the cortisol minimum was delayed as compared to the same patients in remission. Although there was no relation between the cortisol and melatonin levels and headaches, the rise of cortisol following many attacks might in part represent an adaptive response to pain. The nocturnal melatonin maximum was lower during cluster periods than in remission. This finding, and the dysautonomic signs during attacks, may reflect a change of the vegetative tone in a hyposympathetic direction. Images PMID:3572435

  4. Melatonin implants do not alter estrogen feedback or advance puberty in gilts.

    PubMed

    Kennaway, D J; Hughes, P E; van Wettere, W H E J

    2015-05-01

    Puberty in pigs is often delayed during late summer and autumn, with long daylength the most likely cause. We hypothesised (1) that gilts born around the shortest day would have a later release from the negative feedback actions of estradiol than gilts born around the spring equinox and (2) melatonin treatment would result in an earlier release from estradiol negative feedback and advance the onset of puberty in gilts born around the spring equinox. We first determined the optimal number of estradiol implants required to monitor the release from estradiol negative feedback in ovariectomised gilts. Secondly we determined whether melatonin implants altered negative feedback in 4 cohorts of ovariectomised gilts born between the winter solstice and spring equinox, and in the following year whether melatonin altered the time of the first ovulation in 5 cohorts of intact gilts born between the winter solstice and spring equinox. Plasma LH and FSH increased between 126 and 210d of age (P<0.001) in each cohort (season), but there was no effect of cohort, melatonin treatment or interactions (P>0.05). Age at first detection of elevated plasma progesterone in untreated, intact gilts decreased across the 4 cohorts (P<0.05). Melatonin treatment of intact gilts failed to advance the age of puberty irrespective of their season of birth (P>0.05). In conclusion, while we confirmed that estradiol sensitivity is decreased as gilts age, we failed to demonstrate any effects of season or melatonin on estradiol feedback or melatonin on puberty. PMID:25618532

  5. Melatonin Alters the Mechanical and Thermal Hyperalgesia Induced by Orofacial Pain Model in Rats.

    PubMed

    Scarabelot, Vanessa Leal; Medeiros, Liciane Fernandes; de Oliveira, Carla; Adachi, Lauren Naomi Spezia; de Macedo, Isabel Cristina; Cioato, Stefania Giotti; de Freitas, Joice S; de Souza, Andressa; Quevedo, Alexandre; Caumo, Wolnei; Torres, Iraci Lucena da Silva

    2016-10-01

    Melatonin is a neuroendocrine hormone that presents a wide range of physiological functions including regulating circadian rhythms and sleep, enhancing immune function, sleep improvement, and antioxidant effects. In addition, melatonin has received special attention in pain treatment since it is effective and presents few adverse effects. In this study, we evaluated the effect of acute dose of melatonin upon hyperalgesia induced by complete Freund's adjuvant in a chronic orofacial pain model in Sprague-Dawley rats. Nociceptive behavior was assessed by facial Von Frey and the hot plate tests at baseline and thereafter 30, 60, and 120 min, 24 h, and 7 days after melatonin treatment. We demonstrated that acute melatonin administration alters mechanical and thermal hyperalgesia induced by an orofacial pain model (TMD), highlighting that the melatonin effect upon mechanical hyperalgesia remained until 7 days after its administration. Besides, we observed specific tissue profiles of neuroimmunomodulators linked to pain conditions and/or melatonin effect (brain-derived neurotrophic factor, nerve growth factor, and interleukins 6 and 10) in the brainstem levels, and its effects were state-dependent of the baseline of these animals. PMID:27378529

  6. [The circadian system in man: From the internal clock to melatonin secretion].

    PubMed

    Touitou, Y

    2016-09-01

    The internal or biological clock which is located in the suprachiasmatic nuclei of the anterior hypothalamus is controlled by clock genes and environmental factors which are able to synchronize the clock to 24h. Rhythm desynchronization (shiftwork and nightwork, transmeridian flights, aging, some psychiatric diseases, blindness, intake of some drugs…) occurs when the internal clock does no longer work in harmony with the astronomical time i.e. our watch. The circadian system consists of three major elements, which are the clock, the retinohypothalamic tract and melatonin which is secreted by the pineal gland and considered as the arrow of the clock. Both light and melatonin present a phase response curve useful for the treatment of sleep circadian disorders.

  7. Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance.

    PubMed

    Álvarez-Sánchez, Nuria; Cruz-Chamorro, Ivan; López-González, Antonio; Utrilla, José C; Fernández-Santos, José M; Martínez-López, Alicia; Lardone, Patricia J; Guerrero, Juan M; Carrillo-Vico, Antonio

    2015-11-01

    Experimental autoimmune encephalomyelitis (EAE), the experimental model for multiple sclerosis (MS), is triggered by myelin-specific Th1 and Th17 cells. The immunomodulatory activities of melatonin have been shown to be beneficial under several conditions in which the immune system is exacerbated. Here, we sought to elucidate the basis of the melatonin protective effect on EAE by characterizing the T effector/regulatory responses, particularly those of the memory cell subsets. Melatonin was tested for its effect on Th1, Th17 and T regulatory (Treg) cells in the lymph nodes and CNS of immunodominant peptide of myelin oligodendrocyte glycoprotein (pMOG)-immunized and EAE mice, respectively. The capacity of melatonin to ameliorate EAE as well as modifying both T cell response and effector/regulatory balance was surveyed. T cell memory subsets and CD44, a key activation marker involved in the EAE pathogenesis, were also examined. Melatonin protected from EAE by decreasing peripheral and central Th1/Th17 responses and enhancing both the Treg frequency and IL-10 synthesis in the CNS. Melatonin reduced the T effector memory population and its pro-inflammatory response and regulated CD44 expression, which was decreased in T effector cells and increased in Tregs. The alterations in the T cell subpopulations were associated with a reduced mononuclear infiltration (CD4 and CD11b cells) of the melatonin-treated mice CNS. For the first time, we report that melatonin protects against EAE by controlling peripheral and central T effector/regulatory responses, effects that might be partially mediated by CD44. This immunomodulatory effect on EAE suggests that melatonin may represent an effective treatment option for MS.

  8. Sleep Deprivation Aggravates Median Nerve Injury-Induced Neuropathic Pain and Enhances Microglial Activation by Suppressing Melatonin Secretion

    PubMed Central

    Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

    2014-01-01

    deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion. SLEEP 2014;37(9):1513-1523. PMID:25142572

  9. Interleukin-1 β Modulates Melatonin Secretion in Ovine Pineal Gland: Ex Vivo Study.

    PubMed

    Herman, A P; Bochenek, J; Skipor, J; Król, K; Krawczyńska, A; Antushevich, H; Pawlina, B; Marciniak, E; Tomaszewska-Zaremba, D

    2015-01-01

    The study was designed to determine the effect of proinflammatory cytokine, interleukin- (IL-) 1β, on melatonin release and expression enzymes essential for this hormone synthesis: arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT) in ovine pineal gland, taking into account the immune status of animals before sacrificing. Ewes were injected by lipopolysaccharide (LPS; 400 ng/kg) or saline, two hours after sunset during short day period (December). Animals were euthanized three hours after the injection. Next, the pineal glands were collected and divided into four explants. The explants were incubated with (1) medium 199 (control explants), (2) norepinephrine (NE; 10 µM), (3) IL-1β (75 pg/mL), or (4) NE + IL-1β. It was found that IL-1β abolished (P < 0.05) NE-induced increase in melatonin release. Treatment with IL-1β also reduced (P < 0.05) expression of AA-NAT enzyme compared to NE-treated explants. There was no effect of NE or IL-1β treatment on gene expression of HIOMT; however, the pineal fragments isolated from LPS-treated animals were characterized by elevated (P < 0.05) expression of HIOMT mRNA and protein compared to the explants from saline-treated ewes. Our study proves that IL-1β suppresses melatonin secretion and its action seems to be targeted on the reduction of pineal AA-NAT protein expression.

  10. Interleukin-1β Modulates Melatonin Secretion in Ovine Pineal Gland: Ex Vivo Study

    PubMed Central

    Herman, A. P.; Bochenek, J.; Skipor, J.; Król, K.; Krawczyńska, A.; Antushevich, H.; Pawlina, B.; Marciniak, E.; Tomaszewska-Zaremba, D.

    2015-01-01

    The study was designed to determine the effect of proinflammatory cytokine, interleukin- (IL-) 1β, on melatonin release and expression enzymes essential for this hormone synthesis: arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT) in ovine pineal gland, taking into account the immune status of animals before sacrificing. Ewes were injected by lipopolysaccharide (LPS; 400 ng/kg) or saline, two hours after sunset during short day period (December). Animals were euthanized three hours after the injection. Next, the pineal glands were collected and divided into four explants. The explants were incubated with (1) medium 199 (control explants), (2) norepinephrine (NE; 10 µM), (3) IL-1β (75 pg/mL), or (4) NE + IL-1β. It was found that IL-1β abolished (P < 0.05) NE-induced increase in melatonin release. Treatment with IL-1β also reduced (P < 0.05) expression of AA-NAT enzyme compared to NE-treated explants. There was no effect of NE or IL-1β treatment on gene expression of HIOMT; however, the pineal fragments isolated from LPS-treated animals were characterized by elevated (P < 0.05) expression of HIOMT mRNA and protein compared to the explants from saline-treated ewes. Our study proves that IL-1β suppresses melatonin secretion and its action seems to be targeted on the reduction of pineal AA-NAT protein expression. PMID:26339621

  11. Regulation of melatonin secretion in the pineal organ of the domestic duck--an in vitro study.

    PubMed

    Prusik, M; Lewczuk, B; Ziółkowska, N; Przybylska-Gornowicz, B

    2015-01-01

    The aim of study was to determine the mechanisms regulating melatonin secretion in the pineal organs of 1-day-old and 9-month-old domestic ducks. The pineals were cultured in a superfusion system under different light conditions. Additionally, some explants were treated with norepinephrine. The pineal glands of 1-day-old ducks released melatonin in a well-entrained, regular rhythm during incubation under a 12 hrs light:12 hrs dark cycle and adjusted their secretory activity to a reversed 12 hrs dark:12 hrs light cycle within 2 days. In contrast, the diurnal changes in melatonin secretion from the pineals of 9-month-old ducks were largely irregular and the adaptation to a reversed cycle lasted 3 days. The pineal organs of nestling and adult ducks incubated in a continuous light or darkness secreted melatonin in a circadian rhythm. The treatment with norepinephrine during photophases of a light-dark cycle resulted in: 1) a precise adjustment of melatonin secretion rhythm to the presence of this catecholamine in the culture medium, 2) a very high amplitude of the rhythm, 3) a rapid adaptation of the pineal secretory activity to a reversed light-dark cycle. The effects of norepinephrine were similar in the pineal organs of nestlings and adults. In conclusion, melatonin secretion in the duck pineal organ is controlled by three main mechanisms: the direct photoreception, the endogenous generator and the noradrenergic transmission. The efficiency of intra-pineal, photosensitivity-based regulatory mechanism is markedly lower in adult than in nestling individuals.

  12. Effect of constant-release implants of melatonin on seasonal cycles in reproduction, prolactin secretion and moulting in rams.

    PubMed

    Lincoln, G A; Ebling, F J

    1985-01-01

    Seasonal cycles in the size of the testes, blood plasma concentration of testosterone, FSH and prolactin, intensity of the sexual skin flush, timing of rutting behaviour and moulting of the body coat were recorded in Soay rams after s.c. implantation of melatonin contained in a Silastic envelope which increased the circulating blood levels of melatonin to 200-600 pg/ml for many months. Two groups of 8 adult rams were held under alternating periods of short days (8L:16D) and long days (16L:8D) to drive the seasonal cycles and the treatments with melatonin were initiated during the long or short days, and one group of 8 ram lambs was kept out of doors and given implants during the long days of summer (4 melatonin-implanted and 4 control (empty implants) rams per group). The treatments demonstrated that melatonin implants during exposure to long days resulted in a rapid 'switch on' of reproductive redevelopment similar to that produced by exposure to short days melatonin implants prevented the rams from showing the normal responses to changes in the prevailing photoperiod rendering them nonphotoperiodic; and long-term cyclic changes in testicular activity, prolactin secretion and other characteristics occurred in the melatonin-implanted rams; the pattern was similar to that previously observed in rams exposed to prolonged periods of short days. The overall results are consistent with the view that melatonin is the physiological hormone that relays the effects of changing photoperiod on reproduction and other seasonal features, and that continuous exogenous melatonin from an implant interferes with the normal 'signal' and produces an over-riding short-day response. PMID:3918164

  13. Rapid shift in sleep time and acrophase of melatonin secretion in short shift work schedule.

    PubMed

    Quera-Salva, M A; Defrance, R; Claustrat, B; De Lattre, J; Guilleminault, C

    1996-09-01

    Tolerance to shift work and adaptability to shifting schedules is an issue of growing importance in industrialized society. We studied 40 registered nurses, 20 on fixed day-shifts and 20 on fixed night-shifts, to assess whether workers with rapidly shifting schedules were able to adapt their melatonin secretion and sleep-wake cycles. The day-shift worked 5 days with 2 days off and the night-shift worked 3 nights with 2 off. All night-shift personnel acknowledged shifting back to daytime schedules on their days off. Sleep-wake was determined by sleep logs and actigraphy. To measure 6-sulfatoxymelatonin levels, urine was collected at 2-hour intervals on the last work day and on the last day off. Night-shift workers slept significantly more on days off. Napping on the job occurred in 9/20 night-shift workers (mean 114 minutes) between 3 and 6 a.m. The acrophase of 6-sulfatoxymelatonin in day-shift nurses occurred at similar times on workdays and off days. In night-shift nurses, the acrophase was about 7 a.m. on days off, but had a random distribution on workdays. Further analysis revealed two subgroups of night-shift nurses: six subjects (group A).demonstrated a rapid shift in melatonin secretion (acrophase at near 12 noon on work days and at near 7 a.m. on days off) while 14 nurses (group B) did not shift. Group A nurses slept more in the daytime on work days and their total sleep time was the same as day-shift nurses. Group A was slightly younger and was composed solely of women (there were nine women and five men in group B). Age may be a factor in the ability to adapt to rapidly shifting schedules.

  14. Review of Disrupted Sleep Patterns in Smith-Magenis Syndrome and Normal Melatonin Secretion in a Patient with an Atypical Interstitial 17p11.2 Deletion

    PubMed Central

    Boudreau, Eilis A.; Johnson, Kyle P.; Jackman, Angela R.; Blancato, Jan; Huizing, Marjan; Bendavid, Claude; Jones, MaryPat; Chandrasekharappa, Settara C.; Lewy, Alfred J.; Smith, Ann C. M.; Magenis, R. Ellen

    2009-01-01

    Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body’s signal for nighttime darkness. Published reports of 24-hour melatonin secretion patterns in two independent SMS cohorts (US & France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion (∼6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.1p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern. PMID:19530184

  15. In the Heat of the Night: Thermo-TRPV Channels in the Salmonid Pineal Photoreceptors and Modulation of Melatonin Secretion.

    PubMed

    Nisembaum, Laura Gabriela; Besseau, Laurence; Paulin, Charles-Hubert; Charpantier, Alice; Martin, Patrick; Magnanou, Elodie; Fuentès, Michael; Delgado, Maria-Jesus; Falcón, Jack

    2015-12-01

    Photoperiod plays an essential role in the synchronization of metabolism, physiology, and behavior to the cyclic variations of the environment. In vertebrates, information is relayed by the pineal cells and translated into the nocturnal production of melatonin. The duration of this signal corresponds to the duration of the night. In fish, the pinealocytes are true photoreceptors in which the amplitude of the nocturnal surge is modulated by temperature in a species-dependent manner. Thus, the daily and annual variations in the amplitude and duration of the nocturnal melatonin signal provide information on daily and calendar time. Both light and temperature act on the activity of the penultimate enzyme in the melatonin biosynthesis pathway, the arylalkylamine N-acetyltransferase (serotonin → N-acetylserotonin). Although the mechanisms of the light/dark regulation of melatonin secretion are quite well understood, those of temperature remain unelucidated. More generally, the mechanisms of thermoreception are unknown in ectotherms. Here we provide the first evidence that two thermotransient receptor potential (TRP) channels, TRPV1 and TRPV4, are expressed in the pineal photoreceptor cells of a teleost fish, in which they modulate melatonin secretion in vitro. The effects are temperature dependent, at least for TRPV1. Our data support the idea that the pineal of fish is involved in thermoregulation and that the pineal photoreceptors are also thermoreceptors. In other nervous and nonnervous tissues, TRPV1 and TRPV4 display a ubiquitous but quantitatively variable distribution. These results are a fundamental step in the elucidation of the mechanisms of temperature transduction in fish. PMID:26389691

  16. Seasonal Patterns of Melatonin, Cortisol, and Progesterone Secretion in Female Lambs Raised Beneath a 500-KV Transmission Line

    NASA Astrophysics Data System (ADS)

    Lee, Jack Monroe, Jr.

    There is ongoing controversy about the possibility of adverse biological effects from environmental exposures to electric and magnetic fields. These fields are produced by all electrical equipment and appliances including electrical transmission lines. The objective of this environmental science study was to investigate the possible effects of a high voltage transmission line on domestic sheep (Ovis aries L.), a species that can often be found near such lines. The study was primarily designed to determine whether a specific effect of electric and magnetic fields found in laboratory animals also occurs in livestock under natural environmental conditions. The effect is the ability of fields, at levels found in the environment, to significantly depress the normally high nocturnal concentrations of the pineal hormone-melatonin. Ten female Suffolk lambs were penned for 10 months directly beneath a 500-kV transmission line near Estacada, Oregon. Ten other lambs of the same type were penned in a control area away from the transmission line where electric and magnetic fields were at ambient levels. Serum melatonin was analyzed by radioimmunoassay (RIA) from 6618 blood samples collected at 0.5 to 3-hour intervals over eight 48-hour periods. Serum progesterone was analyzed by RIA from blood samples collected twice weekly. Serum cortisol was also assayed by RIA from the blood samples collected during the 48-hour samples. Results showed that lambs in both the control and line groups had the typical pattern of melatonin secretion consisting of low daytime and high nighttime serum concentrations. There were no statistically significant differences between groups in melatonin levels, or in the phase or duration of the nighttime melatonin elevation. Age at puberty and number of reproductive cycles also did not differ between groups. Serum cortisol showed a circadian rhythm with highest concentrations during the day. There were, however, no differences in cortisol concentrations

  17. Melatonin receptor activation regulates GnRH gene expression and secretion in GT1-7 GnRH neurons. Signal transduction mechanisms.

    PubMed

    Roy, Deboleena; Belsham, Denise D

    2002-01-01

    Melatonin plays a significant role in the control of the hypothalamic-pituitary-gonadal axis. Using the GT1-7 cell line, an in vitro model of GnRH-secreting neurons of the hypothalamus, we examined the potential signal transduction pathways activated by melatonin directly at the level of the GT1-7 neuron. We found that melatonin inhibits forskolin-stimulated adenosine 3'-, 5'-cyclic monophosphate accumulation in GT1-7 cells through an inhibitory G protein. Melatonin induced protein kinase C activity by 1.65-fold over basal levels, increased the phosphorylation of extracellular signal-regulated kinase 1 and 2 proteins, and activated c-fos and junB mRNA expression in GT1-7 cells. Using the protein kinase A inhibitor H-89, the protein kinase C inhibitor bisindolylmaleimide, and the mitogen-activated protein kinase kinase inhibitor PD98059, we found that the melatonin-mediated cyclical regulation of GnRH mRNA expression may involve the protein kinase C and the extracellular signal-regulated kinase 1 and 2 pathways, but not the protein kinase A pathway. We found that melatonin suppresses GnRH secretion by approximately 45% in the GT1-7 neurons. However, in the presence of the inhibitors H-89, bisindolylmaleimide, and PD98059 melatonin was unable to suppress GnRH secretion. These results provide insights into the potential signal transduction mechanisms involved in the control of GnRH gene expression and secretion by melatonin.

  18. Changes in melatonin secretion in tourists after rapid movement to another lighting zone without transition of time zone.

    PubMed

    Wieczorek, Joanna; Blazejczyk, Krzysztof; Morita, Takeshi

    2016-01-01

    Most of the research in the field of Chronobiology is focused on the problem of the circadian rhythms (CR) desynchronization. In travelers, it results mostly from the changes of surrounding: photoperiod, local climate conditions (radiation and thermal load) and behavior (e.g. type and place of tourism and activity level). Until now, it was not documented whether the changes in melatonin (MLT) secretion occur in effect of mid-distance transparallel travels (TpT), without complications arising due to time-zone transitions (e.g. jet-lag syndrome). To cope with this problem, a special field experiment was carried out. In the experiment, MLT characteristics were examined twice a year in real conditions through a group of young tourists (23-26 years old) at their place of habitual residence (Warsaw, Poland), and at their tourist destination (Tromso, Norway). Transition to circumpolar zone in summer has resulted in insignificant reduction in melatonin peak value (MPV) compared to preflight control (2 days before travel) and the melatonin peak time (MPT) was delayed. However, after traveling southward on the returning flight, MPV was lower compared to control and MPT was advanced. In winter, MPV was insignificantly higher in comparison to preflight control and MPT was almost unchanged. While changes in MPV do not depend on season, flight direction and day of stay after flight than MPT was differentiated seasonally and due to direction of flight. MPV and MPT were significantly modified by characteristics of individual light exposure during daytime and evening. The experiment showed also that in real conditions activity level is an important factor affected melatonin peak in tourists. In winter, greater daytime activity significantly influenced earlier MPT occurrence, both after northward and southward flights. PMID:26817496

  19. Melatonin and 6-methoxy-2-benzoxazolinone (6-MBOA) alter the response of the male Syrian hamster to natural photoperiod

    NASA Astrophysics Data System (ADS)

    Vaughan, M. K.; Little, J. C.; Powell, D. C.; Puig-Domingo, M.; Reiter, R. J.

    1988-06-01

    Adult male hamsters bearing either a blank beeswax, 6-methoxy-2-benzoxazolinone (6-MBOA), or melatonin pellet were exposed to 8 weeks (Oct. 6 Dec. 6) of natural autumn decreasing photoperiod (<11 h light) and temperature conditions (mean 10°C for last 4 weeks) or to a 14 h light/10 h dark (14L∶10D) photoperiod and controlled temperature (20°C). Melatonin but not 6-MBOA pellets partially prevented the combined effects of short photoperiod and cold temperatures on the testes and accessory organs. However, both 6-MBOA-and melatonin-treated hamsters maintained outdoors had significantly higher pituitary follicle stimulating hormone (FSH) values compared to their respective indoor-treated controls or to the animals kept outdoors and treated with a blank beeswax pellet. When one compares the various effects of 6-MBOA and melatonin (2 mg/month) on the reproductive system of the male hamster, 6-MBOA is not as effective as melatonin in altering reproductive responses to short photoperiod and cool temperatures at the dose administered.

  20. Beneficial effects of melatonin in a rat model of sporadic Alzheimer's disease.

    PubMed

    Rudnitskaya, Ekaterina A; Maksimova, Kseniya Yi; Muraleva, Natalia A; Logvinov, Sergey V; Yanshole, Lyudmila V; Kolosova, Nataliya G; Stefanova, Natalia A

    2015-06-01

    Melatonin synthesis is disordered in patients with Alzheimer's disease (AD). To determine the role of melatonin in the pathogenesis of AD, suitable animal models are needed. The OXYS rats are an experimental model of accelerated senescence that has also been proposed as a spontaneous rat model of AD-like pathology. In the present study, we demonstrate that disturbances in melatonin secretion occur in OXYS rats at 4 months of age. These disturbances occur simultaneously with manifestation of behavioral abnormalities against the background of neurodegeneration and alterations in hormonal status but before the signs of amyloid-β accumulation. We examined whether oral administration of melatonin could normalize the melatonin secretion and have beneficial effects on OXYS rats before progression to AD-like pathology. The results showed that melatonin treatment restored melatonin secretion in the pineal gland of OXYS rats as well as the serum levels of growth hormone and IGF-1, the level of BDNF in the hippocampus and the healthy state of hippocampal neurons. Additionally, melatonin treatment of OXYS rats prevented an increase in anxiety and the decline of locomotor activity, of exploratory activity, and of reference memory. Thus, melatonin may be involved in AD progression, whereas oral administration of melatonin could be a prophylactic strategy to prevent or slow down the progression of some features of AD pathology.

  1. Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics.

    PubMed

    Swanson, Garth R; Gorenz, Annika; Shaikh, Maliha; Desai, Vishal; Forsyth, Christopher; Fogg, Louis; Burgess, Helen J; Keshavarzian, Ali

    2015-06-15

    Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = -0.39, P = 0.03; urinary sucralose, r = -0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia. PMID:25907689

  2. Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics.

    PubMed

    Swanson, Garth R; Gorenz, Annika; Shaikh, Maliha; Desai, Vishal; Forsyth, Christopher; Fogg, Louis; Burgess, Helen J; Keshavarzian, Ali

    2015-06-15

    Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = -0.39, P = 0.03; urinary sucralose, r = -0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia.

  3. Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics

    PubMed Central

    Gorenz, Annika; Shaikh, Maliha; Desai, Vishal; Forsyth, Christopher; Fogg, Louis; Burgess, Helen J.; Keshavarzian, Ali

    2015-01-01

    Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = −0.39, P = 0.03; urinary sucralose, r = −0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia. PMID:25907689

  4. Melatonin treatment during early life interacts with restraint to alter neuronal morphology and provoke depressive-like responses

    PubMed Central

    Aubrecht, Taryn G.; Weil, Zachary M.; Nelson, Randy J.

    2014-01-01

    Stressors during early life induce anxiety- and depressive-like responses in adult rodents. Siberian hamsters (Phodopus sungorus) exposed to short days post-weaning also increase adult anxiety- and depressive-like behaviors. To test the hypothesis that melatonin and exposure to stressors early in life interact to alter adult affective responses, we administered melatonin either during the perinatal (gestational day 7 to postnatal day 14) or postnatal (day 15–56) periods and also exposed a subset of dams to restraint during gestation (1 h–2×/day for 4 days). During the final week of injections, depressive-like behaviors were assessed using the sucrose anhedonia and forced swim tests. Hamsters exposed to prenatal restraint and treated with melatonin only during the postnatal period increased depressive-like responses in the forced swim test relative to all other groups. Offspring from restrained dams increased the number of fecal boli produced during the forced swim test, an anxiety-like response. In the present study, prenatal restraint reduced CA1 dendritic branching overall and perinatal melatonin protected hamsters from this restraint-induced reduction. These results suggest that the photoperiodic conditions coincident with birth and early life stressors are important in the development of adult affective responses. PMID:24486255

  5. Melatonin treatment during early life interacts with restraint to alter neuronal morphology and provoke depressive-like responses.

    PubMed

    Aubrecht, Taryn G; Weil, Zachary M; Nelson, Randy J

    2014-04-15

    Stressors during early life induce anxiety- and depressive-like responses in adult rodents. Siberian hamsters (Phodopus sungorus) exposed to short days post-weaning also increase adult anxiety- and depressive-like behaviors. To test the hypothesis that melatonin and exposure to stressors early in life interact to alter adult affective responses, we administered melatonin either during the perinatal (gestational day 7 to postnatal day 14) or postnatal (day 15-56) periods and also exposed a subset of dams to restraint during gestation (1 h-2×/day for 4 days). During the final week of injections, depressive-like behaviors were assessed using the sucrose anhedonia and forced swim tests. Hamsters exposed to prenatal restraint and treated with melatonin only during the postnatal period increased depressive-like responses in the forced swim test relative to all other groups. Offspring from restrained dams increased the number of fecal boli produced during the forced swim test, an anxiety-like response. In the present study, prenatal restraint reduced CA1 dendritic branching overall and perinatal melatonin protected hamsters from this restraint-induced reduction. These results suggest that the photoperiodic conditions coincident with birth and early life stressors are important in the development of adult affective responses. PMID:24486255

  6. Effect of constant-release melatonin implants and prolonged exposure to a long day photoperiod on prolactin secretion and hair growth in mouflon (Ovis gmelini musimon).

    PubMed

    Santiago-Moreno, J; López-Sebastián, A; del Campo, A; González-Bulnes, A; Picazo, R; Gómez-Brunet, A

    2004-05-01

    The aims of this study were to examine whether mouflons exposed to constant long and short day photoperiods are able to exhibit an annual cycle of hair growth and moult, and prolactin (PRL) secretion. Mouflon ewes were assigned to three groups of treatment. Ewes were maintained, either under natural photoperiod (control, n = 9), or received a series of subcutaneous melatonin implants from December to April (n = 8), or were exposed to a constant long day photoperiod (16-h light:8-h dark; 16L:8D) during 18 months (n = 7). Blood was collected weekly to determine PRL concentrations, and hair samples were clipped weekly from the base of the neck to measure the length of predominant hair. Under constant long days and with melatonin implants, mouflons expressed an annual rhythm of PRL secretion, even though these treatments modified the times of rise or falling of PRL concentrations throughout the year. Hair growth initiation was almost coincident with the summer solstice in both control and melatonin-implanted mouflons but occurred two months earlier in long day hold mouflons (P < 0.001). Long day hold mouflons had a lower hair growth rate than control and melatonin-implanted mouflons (P < 0.001), and at the end of the experiment, a shorter hair length (3.4 +/- 0.24 cm; P < 0.01) than control (4.3 +/- 0.17 cm), and melatonin-implanted mouflons (4.2 +/- 0.12 cm). Our data support the conclusion that in mouflon, an endogenous circannual rhythm of PRL secretion exists, and that the seasonal cycle of hair growth and moult appears to depend, at least in part, on circulating levels of PRL. PMID:15063923

  7. Dietary intake of melatonin from tropical fruit altered urinary excretion of 6-sulfatoxymelatonin in healthy volunteers.

    PubMed

    Johns, Nutjaree Pratheepawanit; Johns, Jeffrey; Porasuphatana, Supatra; Plaimee, Preeyaporn; Sae-Teaw, Manit

    2013-01-30

    This study assessed the melatonin content of six tropical fruits and examined whether human consumption could contribute to dietary melatonin as measured by 6-sulfatoxymelatonin (aMT6-s, a marker of circulating melatonin in the body). Melatonin was extracted using methanol and analyzed by high-performance liquid chromatography. In a clinical crossover study, 30 healthy volunteers consumed selected fruits one at a time, with a 1week wash-out period between fruits, until completing all six fruits. Most fruits had moderate melatonin content. Significant increases in urine aMT6-s concentrations were seen after the consumption of pineapple (266%, p = 0.004), banana (180%, p = 0.001), and orange (47%, p = 0.007). The need to analyze melatonin both in fruit and as in vivo uptake was demonstrated. Further study is warranted regarding the clinical effect of fruit consumption in people with age-related melatonin reduction problems such as sleeplessness and illnesses involving oxidative damage.

  8. Investigation of the effects of magnetic field exposure on human melatonin. Interim report

    SciTech Connect

    Graham, C.; Cook, M.R.; Cohen, H.D.

    1994-08-01

    Several rodent studies have suggested that magnetic field exposure may alter the daily pattern of melatonin secretion. This study investigated melatonin levels in mean exposed overnight to magnetic fields of 10 mG and 200 mG. The study also assessed the potential effects of exposure on a number of performance and self-reported endpoints in the subjects. Investigation of this area is important, as altered diurnal melatonin cycles have been linked to a variety of endpoints, including reproductive outcome, neurobehavioral function, and carcinogenesis. The results of this investigation did not support the a priori hypothesis that exposure to 60-Hz magnetic fields of 10 mG and 200 mG alters nighttime melatonin levels in a population of adult males. However, the data suggested the possibility of differential sensitivity to magnetic fields based on an individual`s baseline melatonin level.

  9. Continuous light after a long-day treatment is equivalent to melatonin implants to stimulate testosterone secretion in Alpine male goats.

    PubMed

    Delgadillo, J A; Vélez, L I; Flores, J A

    2016-04-01

    In rams, artificial long days followed by continuous light stimulate testosterone secretion during the non-breeding season. The objective of this study was to determine whether artificial long days followed by continuous light could stimulate testosterone secretion in Alpine bucks as well as in those exposed to long days followed by a melatonin treatment. All bucks were kept in shaded open pens. Control males were exposed to natural photoperiod conditions (n=5). Males of the two experimental groups were exposed to 2.5 months of long days from 1 December (n=5 each). On 16 February, one group of males was exposed to 24 h of light per day until 30 June; the other group was exposed to natural variations of photoperiod and received two s.c. melatonin implants. Testicular weight was determined every 2 weeks, and the plasma testosterone concentrations once a week. In the control and the two photoperiodic-treated groups, a treatment×time interaction was detected for testicular weight and plasma testosterone concentrations (P<0.001). In control bucks, testicular weight increased from January and peaked in June, whereas in both photoperiodic-treated groups, this variable increased from January, but peaked in April, when the values were higher than in controls (P<0.05). In the control group, plasma testosterone concentrations remained low from January to June, whereas in both photoperiodic-treated groups, this variable remained low from January to March; thereafter, these levels increased in both photoperiodic-treated groups, and were higher than controls in April and May (P<0.05). We conclude that continuous light after a long-day treatment stimulate testosterone secretion in Alpine male goats during the non-breeding season as well as the long days followed by a melatonin treatment. Therefore, continuous light could replace the implants of melatonin. PMID:26527165

  10. Continuous light after a long-day treatment is equivalent to melatonin implants to stimulate testosterone secretion in Alpine male goats.

    PubMed

    Delgadillo, J A; Vélez, L I; Flores, J A

    2016-04-01

    In rams, artificial long days followed by continuous light stimulate testosterone secretion during the non-breeding season. The objective of this study was to determine whether artificial long days followed by continuous light could stimulate testosterone secretion in Alpine bucks as well as in those exposed to long days followed by a melatonin treatment. All bucks were kept in shaded open pens. Control males were exposed to natural photoperiod conditions (n=5). Males of the two experimental groups were exposed to 2.5 months of long days from 1 December (n=5 each). On 16 February, one group of males was exposed to 24 h of light per day until 30 June; the other group was exposed to natural variations of photoperiod and received two s.c. melatonin implants. Testicular weight was determined every 2 weeks, and the plasma testosterone concentrations once a week. In the control and the two photoperiodic-treated groups, a treatment×time interaction was detected for testicular weight and plasma testosterone concentrations (P<0.001). In control bucks, testicular weight increased from January and peaked in June, whereas in both photoperiodic-treated groups, this variable increased from January, but peaked in April, when the values were higher than in controls (P<0.05). In the control group, plasma testosterone concentrations remained low from January to June, whereas in both photoperiodic-treated groups, this variable remained low from January to March; thereafter, these levels increased in both photoperiodic-treated groups, and were higher than controls in April and May (P<0.05). We conclude that continuous light after a long-day treatment stimulate testosterone secretion in Alpine male goats during the non-breeding season as well as the long days followed by a melatonin treatment. Therefore, continuous light could replace the implants of melatonin.

  11. Melatonin in animal models

    PubMed Central

    Pévet, Paul

    2003-01-01

    Melatonin is a hormone synthesized and secreted during the night by the pineal gland. Its production is mainly driven by the Orcadian clock, which, in mammals, is situated in the suprachiasmatic nucleus of the hypothalamus. The melatonin production and release displays characteristic daily (nocturnal) and seasonal patterns (changes in duration proportional to the length of the night) of secretion. These rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes. In mammals, the role of melatonin in the control of seasonality is well documented, and the sites and mechanisms of action involved are beginning to be identified. The exact role of the hormone in the diurnal (Orcadian) timing system remains to be determined. However, exogenous melatonin has been shown to affect the circadian clock. The molecular and cellular mechanisms involved in this well-characterized “chronobiotic” effect have also begun to be characterized. The circadian clock itself appears to be an important site for the entrapment effect of melatonin and the presence of melatonin receptors appears to be a prerequisite. A better understanding of such “chronobiotic” effects of melatonin will allow clarification of the role of endogenous melatonin in circadian organization. PMID:22033558

  12. Alterations in Lipid Levels of Mitochondrial Membranes Induced by Amyloid-β: A Protective Role of Melatonin

    PubMed Central

    Rosales-Corral, Sergio A.; Lopez-Armas, Gabriela; Cruz-Ramos, Jose; Melnikov, Valery G.; Tan, Dun-Xian; Manchester, Lucien C.; Munoz, Ruben; Reiter, Russel J.

    2012-01-01

    Alzheimer pathogenesis involves mitochondrial dysfunction, which is closely related to amyloid-β (Aβ) generation, abnormal tau phosphorylation, oxidative stress, and apoptosis. Alterations in membranal components, including cholesterol and fatty acids, their characteristics, disposition, and distribution along the membranes, have been studied as evidence of cell membrane alterations in AD brain. The majority of these studies have been focused on the cytoplasmic membrane; meanwhile the mitochondrial membranes have been less explored. In this work, we studied lipids and mitochondrial membranes in vivo, following intracerebral injection of fibrillar amyloid-β (Aβ). The purpose was to determine how Aβ may be responsible for beginning of a vicious cycle where oxidative stress and alterations in cholesterol, lipids and fatty acids, feed back on each other to cause mitochondrial dysfunction. We observed changes in mitochondrial membrane lipids, and fatty acids, following intracerebral injection of fibrillar Aβ in aged Wistar rats. Melatonin, a well-known antioxidant and neuroimmunomodulator indoleamine, reversed some of these alterations and protected mitochondrial membranes from obvious damage. Additionally, melatonin increased the levels of linolenic and n-3 eicosapentaenoic acid, in the same site where amyloid β was injected, favoring an endogenous anti-inflammatory pathway. PMID:22666620

  13. Seasonal regulation of reproduction: altered role of melatonin under naturalistic conditions in hamsters.

    PubMed

    Butler, Matthew P; Turner, Kevin W; Park, Jin Ho; Schoomer, Elanor E; Zucker, Irving; Gorman, Michael R

    2010-09-22

    The seasonal reproductive cycle of photoperiodic rodents is conceptualized as a series of discrete melatonin-dependent neuroendocrine transitions. Least understood is the springtime restoration of responsiveness to winter-like melatonin signals (breaking of refractoriness) that enables animals to once again respond appropriately to winter photoperiods the following year. This has been posited to require many weeks of long days based on studies employing static photoperiods instead of the annual pattern of continually changing photoperiods under which these mechanisms evolved. Maintaining Siberian hamsters under simulated natural photoperiods, we demonstrate that winter refractoriness is broken within six weeks after the spring equinox. We then test whether a history of natural photoperiod exposure can eliminate the requirement for long-day melatonin signalling. Hamsters pinealectomized at the spring equinox and challenged 10 weeks later with winter melatonin infusions exhibited gonadal regression, indicating that refractoriness was broken. A photostimulatory effect on body weight is first observed in the last four weeks of winter. Thus, the seasonal transition to the summer photosensitive phenotype is triggered prior to the equinox without exposure to long days and is thereafter melatonin-independent. Distinctions between photoperiodic and circannual seasonal organization erode with the incorporation in the laboratory of ecologically relevant day length conditions. PMID:20444712

  14. Adrenergic activation of melatonin secretion in ovine pineal explants in short-term superfusion culture occurs via protein synthesis independent and dependent phenomena.

    PubMed

    Lewczuk, Bogdan; Ziółkowska, Natalia; Prusik, Magdalena; Przybylska-Gornowicz, Barbara

    2014-01-01

    The ovine pineal is generally considered as an interesting model for the study on adrenergic regulation of melatonin secretion due to some functional similarities with this gland in the human. The present investigations, performed in the superfusion culture of pineal explants, demonstrated that the norepinephrine-induced elevation of melatonin secretion in ovine pinealocytes comprised of two subsequent periods: a rapid increase phase and a slow increase phase. The first one included the quick rise in release of N-acetylserotonin and melatonin, occurring parallel to elevation of NE concentration in the medium surrounding explants. This rapid increase phase was not affected by inhibition of translation. The second, slow increase phase began after NE level had reached the maximum concentration in the culture medium and lasted about two hours. It was completely abolished by the treatment with translation inhibitors. The obtained results showed for the first time that the regulation of N-acetylserotonin synthesis in pinealocytes of some species like the sheep involves the on/off mechanism, which is completely independent of protein synthesis and works very fast. They provided strong evidence pointing to the need of revision of the current opinion that arylalkylamines N-acetyltransferase activity in pinealocytes is controlled exclusively by changes in enzyme abundance.

  15. Adrenergic Activation of Melatonin Secretion in Ovine Pineal Explants in Short-Term Superfusion Culture Occurs via Protein Synthesis Independent and Dependent Phenomena

    PubMed Central

    2014-01-01

    The ovine pineal is generally considered as an interesting model for the study on adrenergic regulation of melatonin secretion due to some functional similarities with this gland in the human. The present investigations, performed in the superfusion culture of pineal explants, demonstrated that the norepinephrine-induced elevation of melatonin secretion in ovine pinealocytes comprised of two subsequent periods: a rapid increase phase and a slow increase phase. The first one included the quick rise in release of N-acetylserotonin and melatonin, occurring parallel to elevation of NE concentration in the medium surrounding explants. This rapid increase phase was not affected by inhibition of translation. The second, slow increase phase began after NE level had reached the maximum concentration in the culture medium and lasted about two hours. It was completely abolished by the treatment with translation inhibitors. The obtained results showed for the first time that the regulation of N-acetylserotonin synthesis in pinealocytes of some species like the sheep involves the on/off mechanism, which is completely independent of protein synthesis and works very fast. They provided strong evidence pointing to the need of revision of the current opinion that arylalkylamines N-acetyltransferase activity in pinealocytes is controlled exclusively by changes in enzyme abundance. PMID:25133175

  16. Melatonin and human puberty: current perspectives.

    PubMed

    Cavallo, A

    1993-10-01

    Many studies of melatonin in human puberty are difficult to interpret in light of methodological considerations such as the use of single blood samples collected either during the day or at night; a small number of observations; the failure to include the temporal characteristics of melatonin secretion; the definition of puberty by the use of broad clinical features without use of hormonal markers of puberty; the lack of control for the actual duration and intensity of light exposure during the days preceding the study; and the cross sectional nature of most studies. The few studies that have examined the plasma melatonin rhythm in humans by multiple blood sampling overnight or over 24 hr suggest that normal pubertal development (as well as normal ovarian function) are not linked to alterations in the plasma melatonin profile. There is, however, some evidence to suggest that disorders of the hypothalamic-pituitary-gonadal axis (delayed puberty, precocious puberty, hypothalamic amenorrhea) may be linked to altered plasma melatonin profile, at least in some cases. These findings, taken together with strong evidence for the role of the pineal gland in the reproductive function of other vertebrate species, render unlikely the inference that the pineal gland has no role in the development and function of the human reproductive axis. Thus, one may speculate that a pineal-puberty relation does exist in humans and that the research techniques applied to date have been inadequate to uncover this relation.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Antioxidant properties of melatonin--an emerging mystery.

    PubMed

    Beyer, C E; Steketee, J D; Saphier, D

    1998-11-15

    Over three centuries ago, the French philosopher René Descartes described the pineal gland as "the seat of the soul." However, it was not until the late 1950s that the chemical identity and biosynthesis of melatonin, the principal hormone secreted by the pineal body, were revealed. Melatonin, named from the Greek melanos, meaning black, and tonos, meaning color, is a biogenic amine with structural similarities to serotonin. The mechanisms mediating the synthesis of melatonin are transcriptionally regulated by the photoperiodic environment. Once synthesized, the neurohormone is a biologic modulator of mood, sleep, sexual behavior, reproductive alterations, immunologic function, and circadian rhythms. Moreover, melatonin exerts its regulatory roles through high-affinity, pertussis toxin-sensitive, G-protein (or guanine nucleotide binding protein) coupled receptors that reside primarily in the eye, kidney, gastrointestinal tract, blood vessels, and brain. Additional evidence also indicates a role for melatonin in aging and age-related diseases, probably related to its efficient free radical scavenger (or antioxidant) activity. The potential clinical benefit of melatonin as an antioxidant is remarkable, suggesting that it may be of use in the treatment of many pathophysiological disease states including various cancers, hypertension, pulmonary diseases, and a variety of neurodegenerative diseases such as Alzheimer's disease. This review summarizes the biosynthesis of melatonin and its many endocrine and physiological functions, including its therapeutic potential in human disease states. Emphasis is placed on the recent speculations indicating that this pineal hormone serves as an endogenous antioxidant agent with proficient free radical scavenging activity.

  18. Effects of melatonin on water metabolism and renal function in male Syrian hamsters (Mesocricetus auratus).

    PubMed

    Richardson, B A; Studier, E H; Stallone, J N; Kennedy, C M

    1992-09-01

    The pineal indoleamine, melatonin, has been shown to influence many physiological systems within the mammalian body. Few studies, however, have examined the influence of melatonin on renal function. This study investigated the effects of melatonin on water metabolism and renal function. Young adult male Syrian hamsters were maintained on a long photoperiod (LD 14:10) in metabolic cages. The animals received daily (1700) injections of either control vehicle or 25 micrograms of melatonin for 85 consecutive days. Melatonin administration resulted in significant increases in water consumption and urine production. Water budgets were also significantly influenced by melatonin, as were urinary osmolality, urinary sodium, and potassium concentrations, but urinary calcium concentrations were essentially unaltered. When excretion rates for sodium, potassium, and calcium were calculated, no differences were observed between the vehicle control and melatonin-treated groups. Injections of melatonin also significantly decreased plasma antidiuretic hormone (ADH). These results demonstrate that afternoon injections of melatonin can alter renal function, which may involve direct (i.e., on ADH secretion and/or thirst mechanisms) or indirect (i.e., behavioral) effects. PMID:1453309

  19. Effects of melatonin on water metabolism and renal function in male Syrian hamsters (Mesocricetus auratus).

    PubMed

    Richardson, B A; Studier, E H; Stallone, J N; Kennedy, C M

    1992-09-01

    The pineal indoleamine, melatonin, has been shown to influence many physiological systems within the mammalian body. Few studies, however, have examined the influence of melatonin on renal function. This study investigated the effects of melatonin on water metabolism and renal function. Young adult male Syrian hamsters were maintained on a long photoperiod (LD 14:10) in metabolic cages. The animals received daily (1700) injections of either control vehicle or 25 micrograms of melatonin for 85 consecutive days. Melatonin administration resulted in significant increases in water consumption and urine production. Water budgets were also significantly influenced by melatonin, as were urinary osmolality, urinary sodium, and potassium concentrations, but urinary calcium concentrations were essentially unaltered. When excretion rates for sodium, potassium, and calcium were calculated, no differences were observed between the vehicle control and melatonin-treated groups. Injections of melatonin also significantly decreased plasma antidiuretic hormone (ADH). These results demonstrate that afternoon injections of melatonin can alter renal function, which may involve direct (i.e., on ADH secretion and/or thirst mechanisms) or indirect (i.e., behavioral) effects.

  20. Regulation of aldosterone secretion during altered sodium intake.

    PubMed

    Aguilera, G; Catt, K J

    1983-07-01

    The interactions of the renin-angiotensin system with other factors in the regulation of aldosterone secretion were analyzed during altered sodium in the rat. During sodium restriction, the rise in aldosterone one secretion was accompanied by trophic changes in the adrenal glomerulosa zone including increased angiotensin II receptors and enzymes of early and late steps in the aldosterone biosynthetic pathway. All these effects of sodium restriction were reproduced by infusion of angiotensin II, and could be prevented by administration of the converting enzyme inhibitor, SQ 14,225. These findings indicate that the adrenal secretory and trophic responses to sodium restriction are mediated by angiotensin II. In hypophysectomized rats, the basal activities of the enzymes of the early aldosterone biosynthetic pathway were reduced, contributing to the blunted aldosterone responsiveness to sodium deficiency. However, sodium restriction for 6 days significantly increased adrenal glomerulosa angiotensin II receptors and enzymes of the early and late aldosterone biosynthetic pathway, indicating that the pituitary gland is not necessary for the adrenal effects of angiotensin II. In contrast to the prominent glomerulotropic actions of angiotensin II in rats on normal or low sodium intake, infusion of angiotensin II during high sodium intake did not increase blood aldosterone, angiotensin II receptors, or 18-hydroxylase activity, indicating that the trophic actions of the octapeptide are determined by the state of sodium balance. In recent studies, other factors including potassium, dopamine and somatostatin have been shown to potentiate or inhibit the actions of angiotensin II on the adrenal gland. The ability of such factors to influence the effects of angiotensin II could serve as a protective mechanism to modulate aldosterone responses to angiotensin II when elevations in the circulating level of the peptide occur in the absence of sodium deficiency.

  1. Melatonin and sleep in humans.

    PubMed

    Dawson, D; Encel, N

    1993-08-01

    Early studies on the physiological effects of melatonin typically reported hypnotic 'side-effects'. Later studies, specifically addressing this action, failed to reliably replicate hypnotic effects using standard polysomnography. This difference may be related to differences in the basic physiological action of melatonin compared with more conventional hypnotics. It is suggested that melatonin exerts a hypnotic effect through thermoregulatory mechanisms. By lowering core body temperature, melatonin reduces arousal and increases sleep-propensity. Thus, in humans, one role of melatonin is to transduce the light-dark cycle and define a window-of-opportunity in which sleep-propensity is enhanced. As such, melatonin is likely to be an effective hypnotic agent for sleep disruption associated with elevated temperature due to low circulating melatonin levels. The combined circadian and hypnotic effects of melatonin suggest a synergistic action in the treatment of sleep disorders related to the inappropriate timing of sleep and wakefulness. Adjuvant melatonin may also improve sleep disruption caused by drugs known to alter normal melatonin production (e.g., beta-blockers and benzodiazepines). If melatonin is to be developed as a successful clinical treatment, differences between the pharmacological profile following exogenous administration and the normal endogenous rhythm should be minimized. Continued development as a useful clinical tool requires control of both the amplitude and duration of the exogenous melatonin pulse. There is a need to develop novel drug delivery systems that can reliably produce a square-wave pulse of melatonin at physiological levels for 8-10 hr duration.

  2. Seasonal Patterns of Melatonin, Cortisol, and Progesterone Secretion in Female Lambs Raised Beneath a 500-kV Transmission Line.

    SciTech Connect

    Lee, Jack M.

    1992-06-01

    Although several kinds of biological effects of electric and magnetic fields have been reported from laboratory studies, few have been independently replicated. When this study was being planned, the suppression of nighttime melatonin in rodents was thought to represent one of the strongest known effects of these fields. The effect had been replicated by a single laboratory for 60-Hz electric fields, and by multiple laboratories for d-c magnetic fields. The primary objective of this study was to determine whether the effect of electric and magnetic fields on melatonin would also occur in sheep exposed to a high voltage transmission line. The specific hypothesis tested by this experiment was as follows: The electrical environment produced by a 60-Hz, 500-kV transmission line causes a depression in nocturnal melatonin in chronically exposed female lambs. This may mimic effects of pinealectomy or constant long-day photoperiods, thus delaying the onset of reproductive cycles. Results of the study do not provide evidence to support the hypothesis. Melatonin concentrations in the sheep exposed to the transmission line showed the normal pattern of low daytime and high nighttime serum levels. As compared to the control group, there were no statistically significant group differences in the mean amplitude, phase, or duration of the nighttime melatonin elevation.

  3. Evidence of melatonin secretion in cetaceans: plasma concentration and extrapineal HIOMT-like presence in the bottlenose dolphin Tursiops truncatus.

    PubMed

    Panin, Mattìa; Gabai, Gianfranco; Ballarin, Cristina; Peruffo, Antonella; Cozzi, Bruno

    2012-06-01

    The pineal gland is generally believed to be absent in cetaceans, although few and subsequently unconfirmed reports described the organ in some species. The recent description of a complete and photographed pineal body in a bottlenose dolphin (Tursiops truncatus) prompted us to examine a series of 29 brains of the same species, but no gland was found. We then decided to investigate if the main product of the gland, melatonin, was nevertheless produced and present in the plasma of this species. We collected plasma and serum samples from a series of captive bottlenose dolphins for a period of 7 months spanning from winter to summer and we determined the indoleamine concentration by radio-immunoassay (RIA). The results demonstrated for the first time a quantitative assessment of melatonin production in the blood of a cetacean. Melatonin levels were comparable to those of terrestrial mammals (5.15-27.74 pg/ml daylight concentration), with indications of both seasonal and daily variation although the presence of a circadian rhythm remains uncertain. Immunohistochemical analyses using as a marker hydroxyindole-O-methyl-transferase (HIOMT, the key enzyme involved in the biosynthesis of the hormone), suggested extrapineal melatonin production by the retina, the Harderian gland and the gut. The enzyme was unequivocally localized in all the three tissues, and, specifically, ganglion cells in the retina showed a very strong HIOMT-immunoreactivity. Our results suggest that further research might reveal unexplored aspects of melatonin production in cetaceans and deserves special attention and further efforts. PMID:22554922

  4. Melatonin modulates M4-type ganglion-cell photoreceptors.

    PubMed

    Pack, W; Hill, D D; Wong, K Y

    2015-09-10

    In the retina, melatonin is secreted at night by rod/cone photoreceptors and serves as a dark-adaptive signal. Melatonin receptors have been found in many retinal neurons including melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting it could modulate the physiology of these inner retinal photoreceptors. Here, we investigated whether melatonin modulates the alpha-like M4-type ipRGCs, which are believed to mediate image-forming vision as well as non-image-forming photoresponses. Applying melatonin during daytime (when endogenous melatonin secretion is low) caused whole-cell-recorded M4 cells' rod/cone-driven depolarizing photoresponses to become broader and larger, whereas the associated elevation in spike rate was reduced. Melanopsin-based light responses were not affected significantly. Nighttime application of the melatonin receptor antagonist luzindole also altered M4 cells' rod/cone-driven light responses but in the opposite ways: the duration and amplitude of the graded depolarization were reduced, whereas the accompanying spiking increase was enhanced. These luzindole-induced changes confirmed that M4 cells are modulated by endogenous melatonin. Melatonin could induce the above effects by acting directly on M4 cells because immunohistochemistry detected MT1 receptors in these cells, although it could also act presynaptically. Interestingly, the daytime and nighttime recordings showed significant differences in resting membrane potential, spontaneous spike rate and rod/cone-driven light responses, suggesting that M4 cells are under circadian control. This is the first report of a circadian variation in ipRGCs' resting properties and synaptic input, and of melatoninergic modulation of ipRGCs. PMID:26141846

  5. Melatonin and male reproduction.

    PubMed

    Li, Chunjin; Zhou, Xu

    2015-06-15

    Melatonin is a neurohormone secreted by the pineal gland whose concentrations in the body are regulated by both the dark-light and seasonal cycles. The reproductive function of seasonal breeding animals is clearly influenced by the circadian variation in melatonin levels. Moreover, a growing body of evidence indicates that melatonin has important effects in the reproduction of some non-seasonal breeding animals. In males, melatonin affects reproductive regulation in three main ways. First, it regulates the secretion of two key neurohormones, GnRH and LH. Second, it regulates testosterone synthesis and testicular maturation. Third, as a potent free radical scavenger that is both lipophilic and hydrophilic, it prevents testicular damage caused by environmental toxins or inflammation. This review summarizes the existing data on the possible biological roles of melatonin in male reproduction. Overall, the literature data indicate that melatonin affects the secretion of both gonadotropins and testosterone while also improving sperm quality. This implies that it has important effects on the regulation of testicular development and male reproduction.

  6. Melatonin: the dark force.

    PubMed

    Bergstrom, W H; Hakanson, D O

    1998-01-01

    Although the pineal gland was described 2,300 years ago, its functions remained obscure and productive research was limited until 1958, when Lerner and associates defined melatonin. In 1965 Wurtman and Axelrod advanced the "melatonin hypothesis," according to which the pineal gland acts as a transducer responding to changes in circumambient light by changing its rates of melatonin output. Sites and mechanisms of melatonin action are still poorly understood. Two consistent effects are the induction of sleep and an antigonadotropic influence on reproductive structure and behavior. The former is demonstrable and clinically useful in human subjects; the latter has been shown in birds, rodents, and sheep. Alteration of skin color by the contraction of melanophores was effected by pineal extracts before the discovery of melatonin. This phenomenon, seen in reptiles, amphibians, and fish, has received little recent attention. Areas of greater interest and potential importance include the antimitotic effects of melatonin on some types of tumor cells in culture and the apparent in vivo protection of immunocompetent lymphocytes during chronic stress, which reduces the functional capacity of lymphocytes in control rodents. Clinical application of the antimitotic and immunosupportive properties of melatonin seems likely in the near future. Unfortunately, this innocent molecule has been touted in two recent books and many advertisements as an aphrodisiac, rejuvenator, protector against disease, and general wonder-worker. Because interest in melatonin is high, all physicians can expect questions and may have use for the information provided in this review.

  7. Melatonin and female reproduction.

    PubMed

    Tamura, Hiroshi; Takasaki, Akihisa; Taketani, Toshiaki; Tanabe, Manabu; Lee, Lifa; Tamura, Isao; Maekawa, Ryo; Aasada, Hiromi; Yamagata, Yoshiaki; Sugino, Norihiro

    2014-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) is secreted during the dark hours at night by the pineal gland. After entering the circulation, melatonin acts as an endocrine factor and a chemical messenger of light and darkness. It regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It also affects the brain, immune, gastrointestinal, cardiovascular, renal, bone and endocrine functions and acts as an oncostatic and anti-aging molecule. Many of melatonin's actions are mediated through interactions with specific membrane-bound receptors expressed not only in the central nervous system, but also in peripheral tissues. Melatonin also acts through non-receptor-mediated mechanisms, for example serving as a scavenger for reactive oxygen species and reactive nitrogen species. At both physiological and pharmacological concentrations, melatonin attenuates and counteracts oxidative stress and regulates cellular metabolism. Growing scientific evidence of reproductive physiology supports the role of melatonin in human reproduction. This review was conducted to investigate the effects of melatonin on female reproduction and to summarize our findings in this field.

  8. Experiments on the effects of a continuous 16.7 Hz magnetic field on melatonin secretion, core body temperature, and heart rates in humans.

    PubMed

    Griefahn, B; Künemund, C; Blaszkewicz, M; Golka, K; Mehnert, P; Degen, G

    2001-12-01

    The present study investigated the hypothesis that a strong extremely low frequency magnetic field partially suppresses the synthesis of melatonin and subsequently elevates the core body temperature. Seven healthy young men (16-22 years) took part in a control and in an exposure session. Three men experienced first the control and then the exposure session, four men experienced the sessions in reverse order. Control sessions were performed as constant routines, where the participants spent 24 hour periods continuously in bed while air temperature was 18 degrees C, illumination less than 30 lux, and the sound pressure level 50 dBA. The exposure sessions differed from that protocol only between 6 pm and 2 am when a strong extremely low frequency magnetic field was continuously applied (16.7 Hz, 0.2 mT). Assuming that the participants were unable to perceive the field consciously, they were blind against the actual condition. Salivary melatonin levels were determined hourly; body core temperatures and heart rates were registered continuously throughout. Neither of these parameters revealed alterations that can be related to the influence of the magnetic field. The present results, taken together with other investigations using that particular field, lead to the hypothesis that the effects most likely, occur, only after repetitive exposures to intermittent fields.

  9. The foetal pig pineal gland is richly innervated by nerve fibres containing catecholamine-synthesizing enzymes, neuropeptide Y (NPY) and C-terminal flanking peptide of NPY, but it does not secrete melatonin.

    PubMed

    Bulc, Michał; Lewczuk, Bogdan; Prusik, Magdalena; Całka, Jarosław

    2013-05-01

    Innervation of the mammalian pineal gland during prenatal development is poorly recognized. Therefore, immunofluorescence studies of the pineals of 70- and 90-day-old foetuses of the domestic pig were performed using antibodies against tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DβH), neuropeptide Y (NPY) and C-terminal flanking peptide of NPY (CPON). The investigated glands were supplied by numerous nerve fibres containing TH and DβH. The density of these fibres was higher in the distal and middle parts of the gland than in the proximal one. NPY and CPON were identified in the majority of DβH-positive fibres as well as in a small population of DβH-negative fibres localized mainly in the proximal part of the pineal. The immunoreactive fibres were more numerous in 90-day-old foetuses than in 70-day-old ones. The effect of norepinephrine on melatonin secretion by the foetal pineals in the short-term organ culture was studied to determine the role of DβH-positive fibres during prenatal life. For the same purpose melatonin was measured in the blood in the umbilical cords and in the jugular vein of the mother. The pineals of both groups of foetuses did not secrete melatonin in the organ culture, independently of the presence or absence of norepinephrine in the medium. Melatonin concentrations in the blood in the umbilical cords of foetuses from the same litter and in the jugular vein of their mother were similar. The presence of adrenergic nerve fibres in the pig pineal during gestation does not seem to be associated with the control of melatonin secretion.

  10. Exogenous melatonin reproduces the effects of short day lengths on hippocampal function in male white-footed mice, Peromyscus leucopus.

    PubMed

    Walton, J C; Chen, Z; Travers, J B; Nelson, R J

    2013-09-17

    Photoperiodism is a biological phenomenon, common among organisms living outside of the tropics, by which environmental day length is used to ascertain the time of year to engage in seasonally-appropriate adaptations. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive winter responses to short day lengths mediated by the extended duration of nightly melatonin secretion. Exposure to short days alters hippocampal dendritic morphology, impairs spatial learning and memory, and impairs hippocampal long-term potentiation (LTP). To determine the role of melatonin in these photoperiod-induced alterations of behavioral, neuroanatomical, and neurophysiological processes in this species, we implanted male mice subcutaneously with melatonin or empty Silastic capsules and exposed them to long or short day lengths. After 10 weeks, mice were assessed for hippocampal LTP, tested for spatial learning and memory in the Barnes maze, and morphometric analysis of neurons in the hippocampus using Golgi staining. Extending the duration of melatonin exposure, by short-day exposure or via melatonin implants, impaired both Schaffer collateral LTP in the CA1 region of the hippocampus and spatial learning and memory, and altered neuronal morphology in all hippocampal regions. The current results demonstrate that chronic melatonin implants reproduce the effects of short days on the hippocampus and implicate melatonin signaling as a critical factor in day-length-induced changes in the structure and function of the hippocampus in a photoperiodic rodent. PMID:23806713

  11. Exogenous Melatonin Reproduces the Effects of Short Day Lengths on Hippocampal Function in Male White-Footed Mice, Peromyscus leucopus

    PubMed Central

    Walton, James C.; Chen, Zhixiong; Travers, Joseph B.; Nelson, Randy J.

    2013-01-01

    Photoperiodism is a biological phenomenon, common among organisms living outside of the tropics, by which environmental day length is used to ascertain time of year to engage in seasonally-appropriate adaptations. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive winter responses to short day lengths mediated by the extended duration of nightly melatonin secretion. Exposure to short days alters hippocampal dendritic morphology, impairs spatial learning and memory, and impairs hippocampal long term potentiation (LTP). To determine the role of melatonin in these photoperiod-induced alterations of behavioral, neuroanatomical, and neurophysiological processes in this species, we implanted male mice subcutaneously with melatonin or empty Silastic capsules and exposed them to long or short day lengths. After ten weeks, mice were assessed for hippocampal LTP, tested for spatial learning and memory in the Barnes maze, and morphometric analysis of neurons in the hippocampus using Golgi staining. Extending the duration of melatonin exposure, by short day exposure or via melatonin implants, impaired both Schaffer collateral LTP in the CA1 region of the hippocampus and spatial learning and memory, and altered neuronal morphology in all hippocampal regions. The current results demonstrate that chronic melatonin implants reproduce the effects of short days on the hippocampus and implicate melatonin signaling as a critical factor in day-length induced changes in the structure and function of the hippocampus in a photoperiodic rodent. PMID:23806713

  12. Exogenous melatonin reproduces the effects of short day lengths on hippocampal function in male white-footed mice, Peromyscus leucopus.

    PubMed

    Walton, J C; Chen, Z; Travers, J B; Nelson, R J

    2013-09-17

    Photoperiodism is a biological phenomenon, common among organisms living outside of the tropics, by which environmental day length is used to ascertain the time of year to engage in seasonally-appropriate adaptations. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive winter responses to short day lengths mediated by the extended duration of nightly melatonin secretion. Exposure to short days alters hippocampal dendritic morphology, impairs spatial learning and memory, and impairs hippocampal long-term potentiation (LTP). To determine the role of melatonin in these photoperiod-induced alterations of behavioral, neuroanatomical, and neurophysiological processes in this species, we implanted male mice subcutaneously with melatonin or empty Silastic capsules and exposed them to long or short day lengths. After 10 weeks, mice were assessed for hippocampal LTP, tested for spatial learning and memory in the Barnes maze, and morphometric analysis of neurons in the hippocampus using Golgi staining. Extending the duration of melatonin exposure, by short-day exposure or via melatonin implants, impaired both Schaffer collateral LTP in the CA1 region of the hippocampus and spatial learning and memory, and altered neuronal morphology in all hippocampal regions. The current results demonstrate that chronic melatonin implants reproduce the effects of short days on the hippocampus and implicate melatonin signaling as a critical factor in day-length-induced changes in the structure and function of the hippocampus in a photoperiodic rodent.

  13. Melatonin Receptor Genes in Vertebrates

    PubMed Central

    Li, Di Yan; Smith, David Glenn; Hardeland, Rüdiger; Yang, Ming Yao; Xu, Huai Liang; Zhang, Long; Yin, Hua Dong; Zhu, Qing

    2013-01-01

    Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor. PMID:23712359

  14. Effects of placing micro-implants of melatonin in the pars tuberalis, pars distalis and the lateral septum of the forebrain on the secretion of FSH and prolactin, and testicular size in rams.

    PubMed

    Lincoln, G A

    1994-08-01

    administration of melatonin in the PT, but not in the PD or septum, affected the photoperiodically induced cycle in the secretion of FSH and prolactin. In the PT group there was no significant change in the plasma concentrations of FSH during the treatment with melatonin, but there was a significant (P < 0.001, ANOVA) decrease in the levels of FSH after the treatment associated with premature regression of the testes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7931000

  15. [Biological potentiality of melatonin].

    PubMed

    Muñoz Barragán, Luciano

    2002-01-01

    The pineal gland is an epithalamic structure whose mission is to integrate incoming environmental information with other types of information deriving from the inner milieu itself of the organism, releasing melatonin, a substance able to elicit responses in the central nervous and endocrine systems. Secreted rhythmically during the scotophase, melatonin is involved in reproductive mechanisms, in cyclically developing nosological. Processes, and in the genesis or maintenance of cerebral biorhythms. Owing to its ability to uptake free radicals produced by cell metabolism, it is a potent antioxidant agent that is able to delay cellular ageing and inhibit cellular proliferation in both experimental and spontaneous tumours. PMID:12812036

  16. Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells

    SciTech Connect

    Raza, Haider John, Annie; Brown, Eric M.; Benedict, Sheela; Kambal, Amr

    2008-01-15

    Cellular oxidative stress and alterations in redox metabolisms have been implicated in the etiology and pathology of many diseases including cancer. Antioxidant treatments have been proven beneficial in controlling these diseases. We have recently shown that 4-hydroxynonenal (4-HNE), a by-product of lipid peroxidation, induces oxidative stress in PC12 cells by compromising the mitochondrial redox metabolism. In this study, we have further investigated the deleterious effects of 4-HNE on mitochondrial respiratory functions and apoptosis using the same cell line. In addition, we have also compared the effects of two antioxidants, curcumin and melatonin, used as chemopreventive agents, on mitochondrial redox metabolism and respiratory functions in these cells. 4-HNE treatment has been shown to cause a reduction in glutathione (GSH) pool, an increase in reactive oxygen species (ROS), protein carbonylation and apoptosis. A marked inhibition in the activities of the mitochondrial respiratory enzymes, cytochrome c oxidase and aconitase was observed after 4-HNE treatment. Increased nuclear translocation of NF-kB/p65 protein was also observed after 4-HNE treatment. Curcumin and melatonin treatments, on the other hand, maintained the mitochondrial redox and respiratory functions without a marked effect on ROS production and cell viability. These results suggest that 4-HNE-induced cytotoxicity may be associated, at least in part, with the altered mitochondrial redox and respiratory functions. The alterations in mitochondrial energy metabolism and redox functions may therefore be critical in determining the difference between cell death and survival.

  17. Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells.

    PubMed

    Raza, Haider; John, Annie; Brown, Eric M; Benedict, Sheela; Kambal, Amr

    2008-01-15

    Cellular oxidative stress and alterations in redox metabolisms have been implicated in the etiology and pathology of many diseases including cancer. Antioxidant treatments have been proven beneficial in controlling these diseases. We have recently shown that 4-hydroxynonenal (4-HNE), a by-product of lipid peroxidation, induces oxidative stress in PC12 cells by compromising the mitochondrial redox metabolism. In this study, we have further investigated the deleterious effects of 4-HNE on mitochondrial respiratory functions and apoptosis using the same cell line. In addition, we have also compared the effects of two antioxidants, curcumin and melatonin, used as chemopreventive agents, on mitochondrial redox metabolism and respiratory functions in these cells. 4-HNE treatment has been shown to cause a reduction in glutathione (GSH) pool, an increase in reactive oxygen species (ROS), protein carbonylation and apoptosis. A marked inhibition in the activities of the mitochondrial respiratory enzymes, cytochrome c oxidase and aconitase was observed after 4-HNE treatment. Increased nuclear translocation of NF-kB/p65 protein was also observed after 4-HNE treatment. Curcumin and melatonin treatments, on the other hand, maintained the mitochondrial redox and respiratory functions without a marked effect on ROS production and cell viability. These results suggest that 4-HNE-induced cytotoxicity may be associated, at least in part, with the altered mitochondrial redox and respiratory functions. The alterations in mitochondrial energy metabolism and redox functions may therefore be critical in determining the difference between cell death and survival. PMID:17935746

  18. Melatonin as a proconvulsive hormone in humans.

    PubMed

    Sandyk, R; Tsagas, N; Anninos, P A

    1992-03-01

    The pineal gland and melatonin exert a major influence in the control of brain electrical activity and have been shown to be involved in seizure and sleep mechanisms. Since pinealectomy has been reported to result in seizures in experimental animals, it is assumed that melatonin has anticonvulsant properties. Indeed, limited studies in humans with temporal lobe epilepsy indicate that melatonin attenuates seizure activity. In the present communication we present evidence, based on magnetoencephalographic (MEG) brain measurements, that melatonin may exert proconvulsive activity in humans as well. The proconvulsive properties of melatonin may explain several phenomena associated with epilepsy such as the increased occurrence of seizures at night when melatonin plasma levels are 5 to 8-fold higher than during the day and the observed exacerbation of seizures premenstrually and during pregnancy as well as the attenuation of seizures in the menopause. Furthermore, our findings suggest that anticonvulsants which decrease melatonin secretion, such as the benzodiazepines, may exert their antiepileptic activity by attenuating nocturnal melatonin secretion. Finally, we propose that patients with nocturnal epilepsy or those experiencing exacerbation of seizures premenstrually may benefit from the administration of agents which block the secretion or action of melatonin. PMID:1342024

  19. Altered Myokine Secretion Is an Intrinsic Property of Skeletal Muscle in Type 2 Diabetes

    PubMed Central

    Ciaraldi, Theodore P.; Ryan, Alexander J.; Mudaliar, Sunder R.; Henry, Robert R.

    2016-01-01

    Skeletal muscle secretes factors, termed myokines. We employed differentiated human skeletal muscle cells (hSMC) cultured from Type 2 diabetic (T2D) and non-diabetic (ND) subjects to investigate the impact of T2D on myokine secretion. Following 24 hours of culture concentrations of selected myokines were determined to range over 4 orders of magnitude. T2D hSMC released increased amounts of IL6, IL8, IL15, TNFa, Growth Related Oncogene (GRO)a, monocyte chemotactic protein (MCP)-1, and follistatin compared to ND myotubes. T2D and ND hSMC secreted similar levels of IL1ß and vascular endothelial growth factor (VEGF). Treatment with the inflammatory agents lipopolysaccharide (LPS) or palmitate augmented the secretion of many myokines including: GROa, IL6, IL8, IL15, and TNFa, but did not consistently alter the protein content and/or phosphorylation of IkBa, p44/42 MAPK, p38 MAPK, c-Jun N-terminal kinase (JNK) and NF-kB, nor lead to consistent changes in basal and insulin-stimulated glucose uptake or free fatty acid oxidation. Conversely, treatment with pioglitazone or oleate resulted in modest reductions in the secretion of several myokines. Our results demonstrate that altered secretion of a number of myokines is an intrinsic property of skeletal muscle in T2D, suggesting a putative role of myokines in the response of skeletal muscle to T2D. PMID:27453994

  20. Melatonin, environmental light, and breast cancer.

    PubMed

    Srinivasan, V; Spence, D W; Pandi-Perumal, S R; Trakht, I; Esquifino, A I; Cardinali, D P; Maestroni, G J

    2008-04-01

    Although many factors have been suggested as causes for breast cancer, the increased incidence of the disease seen in women working in night shifts led to the hypothesis that the suppression of melatonin by light or melatonin deficiency plays a major role in cancer development. Studies on the 7,12-dimethylbenz[a]anthracene and N-methyl-N-nitrosourea experimental models of human breast cancer indicate that melatonin is effective in reducing cancer development. In vitro studies in MCF-7 human breast cancer cell line have shown that melatonin exerts its anticarcinogenic actions through a variety of mechanisms, and that it is most effective in estrogen receptor (ER) alpha-positive breast cancer cells. Melatonin suppresses ER gene, modulates several estrogen dependent regulatory proteins and pro-oncogenes, inhibits cell proliferation, and impairs the metastatic capacity of MCF-7 human breast cancer cells. The anticarcinogenic action on MCF-7 cells has been demonstrated at the physiological concentrations of melatonin attained at night, suggesting thereby that melatonin acts like an endogenous antiestrogen. Melatonin also decreases the formation of estrogens from androgens via aromatase inhibition. Circulating melatonin levels are abnormally low in ER-positive breast cancer patients thereby supporting the melatonin hypothesis for breast cancer in shift working women. It has been postulated that enhanced endogenous melatonin secretion is responsible for the beneficial effects of meditation as a form of psychosocial intervention that helps breast cancer patients.

  1. Changes in plasma melatonin levels and pineal organ melatonin synthesis following acclimation of rainbow trout (Oncorhynchus mykiss) to different water salinities.

    PubMed

    López-Patiño, Marcos A; Rodríguez-Illamola, Arnau; Gesto, Manuel; Soengas, José L; Míguez, Jesús M

    2011-03-15

    Melatonin has been suggested to play a role in fish osmoregulation, and in salmonids has been related to the timing of adaptive mechanisms during smolting. It has been described that acclimation to different environmental salinities alters levels of circulating melatonin in a number of fish species, including rainbow trout. However, nothing is known regarding salinity effects on melatonin synthesis in the pineal organ, which is the main source of rhythmically produced and secreted melatonin in blood. In the present study we have evaluated, in rainbow trout, the effects of acclimation to different salinities on day and night plasma melatonin values and pineal organ melatonin synthesis. Groups of freshwater (FW)-adapted rainbow trout were placed in tanks with four different levels of water salinity (FW, 6, 12, 18 p.p.t.; parts per thousand) and maintained for 6 h or 5 days. Melatonin content in plasma and pineal organs, as well as the pineal content of serotonin (5-HT) and its main oxidative metabolite (5-hydroxyindole-3-acetic acid; 5-HIAA) were measured by high performance liquid chromatography. In addition, day-night changes in pineal organ arylalkylamine N-acetyltransferase (AANAT2) activity and aanat2 gene expression were studied. Plasma osmolalities were found to be higher in rainbow trout exposed to all salinity levels compared with the control FW groups. A salinity-dependent increase in melatonin content was found in both plasma and pineal organs. This effect was observed during the night, and was related to an increase in aanat2 mRNA abundance and AANAT2 enzyme activity, both of which also occurred during the day. Also, the levels of indoles (5-HT, 5-HIAA) in the pineal organ were negatively affected by increasing water salinity, which seems to be related to the higher recruitment of 5-HT as a substrate for the increased melatonin synthesis. A stimulatory effect of salinity on pineal aanat2 mRNA expression was also identified. These results indicate that

  2. Constant light induces alterations in melatonin levels, food intake, feed efficiency, visceral adiposity, and circadian rhythms in rats.

    PubMed

    Wideman, Cyrilla H; Murphy, Helen M

    2009-10-01

    Melatonin levels, metabolic parameters, circadian rhythm activity patterns, and behavior were observed in rats subjected to a 12-h/12-h light/dark cycle (LD) compared to animals exposed to continuous dark (DD) or continuous light (LL). LD and DD animals were similar in melatonin levels, food intake, relative food intake, feed efficiency, water intake, circadian activity levels, and behavior. LL animals had lower melatonin levels in the subjective dark compared to LD and DD animals. Food intake, relative food intake, and water intake values were lower and feed efficiency was more positive in LL animals compared to LD and DD animals. In addition, LL animals exhibited greater visceral adiposity than the other two groups. The circadian rhythmicity of activity became free-running in LL animals and there was a decrease in overall activity. Notable behavioral changes in LL animals were an increase in irritability and excitability. Results indicate that a decrease in melatonin levels and concomitant changes in metabolism, circadian rhythms, and behavior are consequences of exposure to constant light. PMID:19761654

  3. Treatment with melatonin after status epilepticus attenuates seizure activity and neuronal damage but does not prevent the disturbance in diurnal rhythms and behavioral alterations in spontaneously hypertensive rats in kainate model of temporal lobe epilepsy.

    PubMed

    Petkova, Zlatina; Tchekalarova, Jana; Pechlivanova, Daniela; Moyanova, Slavianka; Kortenska, Lidia; Mitreva, Rumiana; Popov, Deyan; Markova, Petya; Lozanov, Valentin; Atanasova, Dimitrina; Lazarov, Nikolai; Stoynev, Alexander

    2014-02-01

    Melatonin is involved in the control of circadian and seasonal rhythmicity, possesses potent antioxidant activity, and exerts a neuroprotective and anticonvulsant effect. Spontaneously hypertensive rats (SHRs) are widely accepted as an experimental model of essential hypertension with hyperactivity, deficient sustained attention, and alterations in circadian autonomic profiles. The purpose of the present study was to determine whether melatonin treatment during epileptogenesis can prevent the deleterious consequences of status epilepticus (SE) in SHRs in the kainate (KA) model of temporal lobe of epilepsy (TLE). Spontaneous recurrent seizures (SRSs) were EEG- and video-recorded during and after the treatment protocol. Melatonin (10mg/kg diluted in drinking water, 8weeks) increased the seizure-latent period, decreased the frequency of SRSs, and attenuated the circadian rhythm of seizure activity in SHRs. However, melatonin was unable to affect the disturbed diurnal rhythms and behavioral changes associated with epilepsy, including the decreased anxiety level, depression, and impaired spatial memory. Melatonin reduced neuronal damage specifically in the CA1 area of the hippocampus and piriform cortex and decreased hippocampal serotonin (5-HT) levels both in control and epileptic SHRs. Although long-term melatonin treatment after SE shows a potential to attenuate seizure activity and neuronal loss, it is unable to restore epilepsy-associated behavioral abnormalities in SHRs. PMID:24440891

  4. Treatment with melatonin after status epilepticus attenuates seizure activity and neuronal damage but does not prevent the disturbance in diurnal rhythms and behavioral alterations in spontaneously hypertensive rats in kainate model of temporal lobe epilepsy.

    PubMed

    Petkova, Zlatina; Tchekalarova, Jana; Pechlivanova, Daniela; Moyanova, Slavianka; Kortenska, Lidia; Mitreva, Rumiana; Popov, Deyan; Markova, Petya; Lozanov, Valentin; Atanasova, Dimitrina; Lazarov, Nikolai; Stoynev, Alexander

    2014-02-01

    Melatonin is involved in the control of circadian and seasonal rhythmicity, possesses potent antioxidant activity, and exerts a neuroprotective and anticonvulsant effect. Spontaneously hypertensive rats (SHRs) are widely accepted as an experimental model of essential hypertension with hyperactivity, deficient sustained attention, and alterations in circadian autonomic profiles. The purpose of the present study was to determine whether melatonin treatment during epileptogenesis can prevent the deleterious consequences of status epilepticus (SE) in SHRs in the kainate (KA) model of temporal lobe of epilepsy (TLE). Spontaneous recurrent seizures (SRSs) were EEG- and video-recorded during and after the treatment protocol. Melatonin (10mg/kg diluted in drinking water, 8weeks) increased the seizure-latent period, decreased the frequency of SRSs, and attenuated the circadian rhythm of seizure activity in SHRs. However, melatonin was unable to affect the disturbed diurnal rhythms and behavioral changes associated with epilepsy, including the decreased anxiety level, depression, and impaired spatial memory. Melatonin reduced neuronal damage specifically in the CA1 area of the hippocampus and piriform cortex and decreased hippocampal serotonin (5-HT) levels both in control and epileptic SHRs. Although long-term melatonin treatment after SE shows a potential to attenuate seizure activity and neuronal loss, it is unable to restore epilepsy-associated behavioral abnormalities in SHRs.

  5. Gastric bypass alters both glucose-dependent and glucose-independent regulation of islet hormone secretion

    PubMed Central

    Salehi, Marzieh; Woods, Stephen C.; D’Alessio, David A.

    2015-01-01

    Aims Roux-en-Y gastric bypass surgery (GB) is characterized by accentuated, but short-lived postprandial elevations of blood glucose and insulin. This profile has been attributed to effects of relative hyperglycemia to directly stimulate β-cells and an augmented incretin effect. We hypothesized additional glucose-independent stimulation of insulin secretion in GB subjects. Methods Fifteen subjects with prior GB, and six matched obese non-surgical controls, and seven lean individuals were recruited. Islet hormones were measured before and after meal ingestion during hyperinsulinemic hypoglycemic clamps to minimize the direct effects of glycemia and glucose-dependent gastrointestinal hormones on insulin secretion. Results The GB subjects had less suppression of fasting β-cell secretion during the insulin clamp compared to controls. In addition, meal-induced insulin secretion increased in the GB subjects but not controls during fixed sub-basal glycemia. In contrast the glucagon responses to hypoglycemia and meal ingestion were lower in the GB subjects than controls. Conclusions Among subjects with GB the response of insulin and glucagon secretion to decreasing blood glucose is blunted, but meal-induced insulin secretion is stimulated even at fixed systemic sub-basal glycemia. These findings indicate that following GB islet hormone secretion is altered as a result of factors beyond circulatory glucose levels. PMID:26316298

  6. Melatonin, endocrine pancreas and diabetes.

    PubMed

    Peschke, Elmar

    2008-01-01

    Melatonin influences insulin secretion both in vivo and in vitro. (i) The effects are MT(1)-and MT(2)-receptor-mediated. (ii) They are specific, high-affinity, pertussis-toxin-sensitive, G(i)-protein-coupled, leading to inhibition of the cAMP-pathway and decrease of insulin release. [Correction added after online publication 4 December 2007: in the preceding sentence, 'increase of insulin release' was changed to 'decrease of insulin release'.] Furthermore, melatonin inhibits the cGMP-pathway, possibly mediated by MT(2) receptors. In this way, melatonin likely inhibits insulin release. A third system, the IP(3)-pathway, is mediated by G(q)-proteins, phospholipase C and IP(3), which mobilize Ca(2+) from intracellular stores, with a resultant increase in insulin. (iii) Insulin secretion in vivo, as well as from isolated islets, exhibits a circadian rhythm. This rhythm, which is apparently generated within the islets, is influenced by melatonin, which induces a phase shift in insulin secretion. (iv) Observation of the circadian expression of clock genes in the pancreas could possibly be an indication of the generation of circadian rhythms in the pancreatic islets themselves. (v) Melatonin influences diabetes and associated metabolic disturbances. The diabetogens, alloxan and streptozotocin, lead to selective destruction of beta-cells through their accumulation in these cells, where they induce the generation of ROS. Beta-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. Results suggest that melatonin in pharmacological doses provides protection against ROS. (vi) Finally, melatonin levels in plasma, as well as the arylalkylamine-N-acetyltransferase (AANAT) activity, are lower in diabetic than in nondiabetic rats and humans. In contrast, in the pineal gland, the AANAT mRNA is increased and the insulin receptor mRNA is decreased, which indicates a close interrelationship between insulin and melatonin. PMID:18078445

  7. Chronobiology of Melatonin beyond the Feedback to the Suprachiasmatic Nucleus—Consequences to Melatonin Dysfunction

    PubMed Central

    Hardeland, Rüdiger

    2013-01-01

    The mammalian circadian system is composed of numerous oscillators, which gradually differ with regard to their dependence on the pacemaker, the suprachiasmatic nucleus (SCN). Actions of melatonin on extra-SCN oscillators represent an emerging field. Melatonin receptors are widely expressed in numerous peripheral and central nervous tissues. Therefore, the circadian rhythm of circulating, pineal-derived melatonin can have profound consequences for the temporal organization of almost all organs, without necessarily involving the melatonin feedback to the suprachiasmatic nucleus. Experiments with melatonin-deficient mouse strains, pinealectomized animals and melatonin receptor knockouts, as well as phase-shifting experiments with explants, reveal a chronobiological role of melatonin in various tissues. In addition to directly steering melatonin-regulated gene expression, the pineal hormone is required for the rhythmic expression of circadian oscillator genes in peripheral organs and to enhance the coupling of parallel oscillators within the same tissue. It exerts additional effects by modulating the secretion of other hormones. The importance of melatonin for numerous organs is underlined by the association of various diseases with gene polymorphisms concerning melatonin receptors and the melatonin biosynthetic pathway. The possibilities and limits of melatonergic treatment are discussed with regard to reductions of melatonin during aging and in various diseases. PMID:23481642

  8. Testicular and somatic growth in Siberian hamsters depend on the melatonin-free interval between twice daily melatonin signals.

    PubMed

    Freeman, D A; Larkin, J E; Seliby, L

    2002-03-01

    In Siberian hamsters, day length is encoded by the duration of the nocturnal melatonin signal; short and long melatonin signals over the course of several weeks stimulate and inhibit somatic and gonadal development, respectively, in prepubertal males. We sought to determine whether juvenile male Siberian hamsters respond to multiple melatonin signals each day and the manner in which the sequence of melatonin signals and the duration of the melatonin-free interval between signals affects development. Twenty-one day old male Siberian hamsters, gestated and maintained in a short-day photoperiod of 10 h light/day (10 L), were transferred to constant light to suppress endogenous melatonin secretion and received s.c. infusions of melatonin or saline for 12 days. Hamsters infused with saline retained small testes, whereas one short melatonin infusion each day resulted in significant testicular growth. Other hamsters were provided with two melatonin signals each day, one long (9 h) and one short (4 or 5 h); the order in which these signals was administered and the duration of the melatonin-free interval after each signal varied between groups. In asymmetrical melatonin infusions, the first and second daily infusions were followed by 3-h and 7-h melatonin-free intervals, respectively, whereas in symmetrical infusions, each melatonin signal was followed by a 5-h melatonin-free interval. In the asymmetrical sequence, the melatonin signal that immediately preceded the longer melatonin-free interval determined the rate gonadal growth. Equal melatonin-free intervals after each of the long and short daily melatonin infusions produced intermediate increases in gonadal and somatic development. The hypothalamic-pituitary-gonadal axis of Siberian hamsters can respond to multiple melatonin signals each day, with the rate of testicular growth determined primarily by the duration of the melatonin-free interval following each infusion.

  9. Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome

    PubMed Central

    Potocki, L.; Glaze, D.; Tan, D.; Park, S.; Kashork, C.; Shaffer, L.; Reiter, R.; Lupski, J.

    2000-01-01

    abnormalities in the circadian rhythm of melatonin and altered sleep patterns could be secondary to aberrations in the production, secretion, distribution, or metabolism of melatonin; however, a direct role for COPS3 could not be established.


Keywords: melatonin; circadian rhythms; Smith-Magenis syndrome; COPS3 PMID:10851253

  10. Diel changes in plasma melatonin and corticosterone concentrations in tropical Nazca boobies (Sula granti) in relation to moon phase and age.

    PubMed

    Tarlow, Elisa M; Hau, Michaela; Anderson, David J; Wikelski, Martin

    2003-10-01

    We investigated the effects of moon phases and age on diel rhythms of plasma melatonin and corticosterone in free-living Nazca boobies (Sula granti) on the Galápagos Islands, Ecuador. Melatonin and corticosterone secretion are regulated by the circadian system and the two hormones play a role in the control of locomotor activity and foraging, which can be influenced by moon phases. These seabirds have a long life span and in many vertebrates circadian function deteriorates with age. The functioning of the circadian system under different environmental conditions and changes related to age are poorly understood and hardly studied in wild birds. Nazca boobies had generally low plasma melatonin concentrations but showed a diel variation with higher concentrations at 00:00 and 16:00h. The diel variations in melatonin concentrations disappeared during full moon, suggesting that natural light levels at night can suppress melatonin secretion in Nazca boobies. Maximal melatonin concentrations tended to decline in older birds (10-19 years). Birds showed a clear diel variation in basal plasma corticosterone with a peak in the early morning, before the active period begins, and low concentrations throughout the day. As with melatonin, there were no diel variations in corticosterone at full moon, which may be due to different activity patterns in response to food availability or changes in the circadian system. While other studies have found a relationship between corticosterone and melatonin, we found no such correlation in Nazca boobies. The lunar cycle appears to affect the hormone titers of Nazca boobies both directly and indirectly. First, melatonin rhythms can be directly affected by the light intensity associated with full moon. Second, prey availability may change foraging patterns and can therefore indirectly alter corticosterone secretion in Nazca boobies.

  11. Altered folate metabolism modifies cell proliferation and progesterone secretion in human placental choriocarcinoma JEG-3 cells.

    PubMed

    Moussa, Carolyne; Ross, Nikia; Jolette, Philippe; MacFarlane, Amanda J

    2015-09-28

    Folate is an essential B vitamin required for de novo purine and thymidylate synthesis, and for the remethylation of homocysteine to form methionine. Folate deficiency has been associated with placenta-related pregnancy complications, as have SNP in genes of the folate-dependent enzymes, methionine synthase (MTR) and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). We aimed to determine the effect of altered folate metabolism on placental cell proliferation, viability and invasive capacity and on progesterone and human chorionic gonadotropin (hCG) secretion. Human placental choriocarcinoma (JEG-3) cells cultured in low folic acid (FA) (2 nM) demonstrated 13% (P<0.001) and 26% (P<0.001) lower proliferation, 5.5% (P=0.025) and 7.5% (P=0.004) lower invasion capacity, and 5 to 7.5% (P=0.004-0.025) lower viability compared with control (20 nM) or supplemented (100 nM) cells, respectively. FA concentration had no effect on progesterone or hCG secretion. Small interfering RNA (siRNA) knockdown of MTR gene and protein expression resulted in 17.7% (P<0.0001) lower proliferation and 61% (P=0.014) higher progesterone secretion, but had no effect on cell invasion and hCG secretion. siRNA knockdown of MTHFD1 gene expression in the absence of detectable changes in protein expression resulted in 10.3% (P=0.001) lower cell proliferation, but had no effect on cell invasion and progesterone or hCG secretion. Our data indicate that impaired folate metabolism can result in lower trophoblast proliferation, and could alter viability, invasion capacity and progesterone secretion, which may explain in part the observed associations between folate and placenta-related complications.

  12. Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients

    PubMed Central

    Artemiou, Panagiotis; Bilecova-Rabajdova, Miroslava; Sabol, Frantisek; Torok, Pavol; Kolarcik, Peter; Kolesar, Adrian

    2015-01-01

    Introduction Post-cardiac surgery delirium is a severe complication. The circadian rhythm of melatonin secretion has been shown to be altered postoperatively. Aim of the study It was hypothesized that restoring normal sleeping patterns with a substance that is capable of resynchronizing circadian rhythm such as exogenous administration of melatonin may possibly reduce the incidence of postoperative delirium. Material and methods This paper represents a prospective clinical observational study. Two consecutive groups of 250 consecutive patients took part in the study. Group A was the control group and group B was the melatonin group. In group B, the patients received prophylactic melatonin treatment. The main objectives were to observe the incidence of delirium, to identify any predictors of delirium, and to compare the two groups based on the delirium incidence. Results The incidence of delirium was 8.4% in the melatonin group vs. 20.8% in the control group (p = 0.001). Predictors of delirium in the melatonin group were age (p = 0.001) and higher EuroSCORE II value (p = 0.001). In multivariate analysis, age and EuroSCORE II value (p = 0.014) were predictors of postoperative delirium. Comparing the groups, the main predictors of delirium were age (p = 0.001), EuroSCORE II value (p = 0.001), cardio-pulmonary bypass (CPB) time (p = 0.001), aortic cross-clamping (ACC) time (p = 0.008), sufentanil dose (p = 0.001) and mechanical ventilation (p = 0.033). Conclusions Administration of melatonin significantly decreases the incidence of postoperative delirium after cardiac surgery. Prophylactic treatment with melatonin should be considered in every patient scheduled for cardiac surgery. PMID:26336494

  13. Melatonin: Nature's most versatile biological signal?

    PubMed

    Pandi-Perumal, S R; Srinivasan, V; Maestroni, G J M; Cardinali, D P; Poeggeler, B; Hardeland, R

    2006-07-01

    Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or

  14. TRIBUTYLTIN ALTERS SECRETION OF INTERLEUKIN 1 BETA FROM HUMAN IMMUNE CELLS

    PubMed Central

    Brown, Shyretha; Whalen, Margaret

    2014-01-01

    Tributyltin (TBT) has been used as a biocide in industrial applications such as wood preservation, antifouling paint, and antifungal agents. Due to its many uses, it contaminates the environment and has been found in human blood samples. Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine that promotes cell growth, tissue repair, and immune response regulation. Produced predominately by both monocytes and macrophages, IL-1β appears to increase the invasiveness of certain tumors. This study shows that TBT modifies the secretion of IL-1β from increasingly reconstituted preparations of human immune cells. IL-1β secretion was examined after 24h, 48h, or 6 day exposures to TBT in highly enriched human NK cells, monocyte-depleted (MD) peripheral blood mononuclear cells (MD-PBMCs), PBMCs, granulocytes, and a preparation combining both PBMCs and granulocytes (PBMCs+granulocytes). TBT altered IL-1β secretion from all of the cells preparations. The 200 nM concentration of TBT normally blocked the secretion of IL-1β, while lower concentrations (usually 5-50 nM) elevated secretion of IL-1β. Examination of the signaling pathway(s) responsible for the elevated secretion of IL-1β were carried out in MD-PBMCs. Pathways examined were IL-1β processing (Caspase-1), mitogen-activated protein kinases (MAPKs), and nuclear factor kappa B (NFκB). Results indicated that MAPK pathways (p44/42 and p38) appear to be the targets of TBT that lead to increased IL-1β secretion from immune cells. These results from human immune cells show IL-1β dysregulation by TBT is occurring ex vivo. Thus, potential for in vivo effects on pro-inflammatory cytokine levels may possibly be a consequence of TBT exposures. PMID:25382723

  15. Pharmacology and function of melatonin receptors

    SciTech Connect

    Dubocovich, M.L.

    1988-09-01

    The hormone melatonin is secreted primarily from the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone, through an action in the brain, appears to be involved in the regulation of various neural and endocrine processes that are cued by the daily change in photoperiod. This article reviews the pharmacological characteristics and function of melatonin receptors in the central nervous system, and the role of melatonin in mediating physiological functions in mammals. Melatonin and melatonin agonists, at picomolar concentrations, inhibit the release of dopamine from retina through activation of a site that is pharmacologically different from a serotonin receptor. These inhibitory effects are antagonized by the novel melatonin receptor antagonist luzindole (N-0774), which suggests that melatonin activates a presynaptic melatonin receptor. In chicken and rabbit retina, the pharmacological characteristics of the presynaptic melatonin receptor and the site labeled by 2-(125I)iodomelatonin are identical. It is proposed that 2-(125I)iodomelatonin binding sites (e.g., chicken brain) that possess the pharmacological characteristics of the retinal melatonin receptor site (order of affinities: 2-iodomelatonin greater than 6-chloromelatonin greater than or equal to melatonin greater than or equal to 6,7-di-chloro-2-methylmelatonin greater than 6-hydroxymelatonin greater than or equal to 6-methoxymelatonin greater than N-acetyltryptamine greater than or equal to luzindole greater than N-acetyl-5-hydroxytryptamine greater than 5-methoxytryptamine much greater than 5-hydroxytryptamine) be classified as ML-1 (melatonin 1). The 2-(125I)iodomelatonin binding site of hamster brain membranes possesses different binding and pharmacological characteristics from the retinal melatonin receptor site and should be classified as ML-2. 64 references.

  16. Posttranscriptional regulation of pineal melatonin synthesis in Octodon degus.

    PubMed

    Lee, Soo Jung; Liu, Tiecheng; Chattoraj, Asamanja; Zhang, Samantha L; Wang, Lijun; Lee, Theresa M; Wang, Michael M; Borjigin, Jimo

    2009-08-01

    Small laboratory animals have provided significant information about melatonin regulation, yet most of these organisms are nocturnal and regulate melatonin synthesis by mechanisms that diverge from those of humans. For example, in all rodents examined, melatonin secretion occurs with a time lag of several hours after the onset of darkness; in addition, arylalkylamine N-acetyltransferase (AANAT), the key enzyme in melatonin synthesis, displays dynamic transcriptional activation specifically at night in all rodents studied to date. In ungulates and primates including humans, on the other hand, melatonin secretion occurs immediately during the early night and is controlled by circadian posttranscriptional regulation of AANAT. We hypothesize that the diurnal Octodon degus (an Hystricognath rodent) could serve as an improved experimental model for studies of human melatonin regulation. To test this, we monitored melatonin production in degus using pineal microdialysis and characterized the regulation of melatonin synthesis by analyzing degu Aanat. Degu pineal melatonin rises with little latency at night, as in ungulates and primates. In addition, degu Aanat mRNA expression displays no detectable diurnal variation, suggesting that, like ungulates and primates, melatonin in this species is regulated by a posttranscriptional mechanism. Compared with AANAT from all rodents examined to date, the predicted amino acid sequence of degu AANAT is phylogenetically more closely related to ungulate and primate AANAT. These data suggest that Octodon degus may provide an ideal model system for laboratory investigation of mechanisms of melatonin synthesis and secretion in diurnal mammals.

  17. Genetic Deletion of MT1 Melatonin Receptors Alters Spontaneous Behavioral Rhythms in Male and Female C57BL/6 Mice

    PubMed Central

    Adamah-Biassi, E.B.; Hudson, R.L.; Dubocovich, M.L.

    2015-01-01

    Behaviors vary over the 24 hr. light/dark cycle and these temporal patterns reflect in part modulation by circadian neural circuits and hormones, such as melatonin. The goal of this study was to investigate if MT1 melatonin receptors are involved in behavioral regulation by comparing male and female C57 wild type (WT) mice with C57 mice that had a genetic deletion of the MT1 receptor (MT1KO). A comprehensive array of fifteen distinct spontaneous behaviors was recorded continuously in the homecage over multiple days using the HomeCageScan system. Behaviors assessed were activity-like (i.e. come down, hang, jump, walk), exploration-like (i.e. dig, groom, rear up, sniff, stretch), resting-like (i.e. awake, remain low, rest, twitch) and ingestion-like (i.e. drink, eat). Phenotypic array and temporal distribution analysis revealed distinct behavioral rhythms that differed between WT and MT1KO mice. The rhythms were consistent from day to day in males and varied with the estrous cycle in females. We also studied the role of MT1 receptors on depressive and anxiety-like behaviors. Genetic deletion of MT1 receptors increased immobility time in the forced swim test and decreased the number of marbles buried in the marble burying test in both male and female C57 mice. We conclude that MT1 melatonin receptors are involved in neural pathways modulating diurnal rhythms of spontaneous behavior in the homecage as well as pathways regulating depressive and anxiolytic-like behaviors. PMID:25200199

  18. [The influence of melatonin on human reproduction].

    PubMed

    Boczek-Leszczyk, Emilia; Juszczak, Marlena

    2007-08-01

    This paper reviews the possible participation of melatonin in the process of human reproduction. The results of several studies have shown the clear correlation between melatonin and gonadotropins and/or sexual steroids, which suggest that melatonin may be involved in the sexual maturation, ovulation or menopause. Decreased secretion of melatonin which coexists with increased fertility in the summer is specific for women living on the north hemisphere. Moreover, abnormal levels of melatonin in the blood are associated with several disorders of the hypothalamus-pituitary-gonads axis activity, i.e., precocious or delayed pubertas, hypogonadotrophic or hypergonadotrophic hypogonadism or amenorrhoea. Melatonin binding sites have been demonstrated in the central nervous system (mainly in the pars dystalis of the pituitary and hypothalamic suprachiasmatic nucleus) as well as in the reproductive organs, e.g., human granulosa cells, prostate and spermatozoa. Melatonin can, therefore, influence the gonadal function indirectly--via its effect on gonadotropin-releasing hormone and/or gonadotropins secretion. It may also act directly; several data show that melatonin can be synthesized in gonads. PMID:18044344

  19. [The influence of melatonin on human reproduction].

    PubMed

    Boczek-Leszczyk, Emilia; Juszczak, Marlena

    2007-08-01

    This paper reviews the possible participation of melatonin in the process of human reproduction. The results of several studies have shown the clear correlation between melatonin and gonadotropins and/or sexual steroids, which suggest that melatonin may be involved in the sexual maturation, ovulation or menopause. Decreased secretion of melatonin which coexists with increased fertility in the summer is specific for women living on the north hemisphere. Moreover, abnormal levels of melatonin in the blood are associated with several disorders of the hypothalamus-pituitary-gonads axis activity, i.e., precocious or delayed pubertas, hypogonadotrophic or hypergonadotrophic hypogonadism or amenorrhoea. Melatonin binding sites have been demonstrated in the central nervous system (mainly in the pars dystalis of the pituitary and hypothalamic suprachiasmatic nucleus) as well as in the reproductive organs, e.g., human granulosa cells, prostate and spermatozoa. Melatonin can, therefore, influence the gonadal function indirectly--via its effect on gonadotropin-releasing hormone and/or gonadotropins secretion. It may also act directly; several data show that melatonin can be synthesized in gonads.

  20. Long noncoding RNA H19 mediates melatonin inhibition of premature senescence of c-kit(+) cardiac progenitor cells by promoting miR-675.

    PubMed

    Cai, Benzhi; Ma, Wenya; Bi, Chongwei; Yang, Fan; Zhang, Lai; Han, Zhenbo; Huang, Qi; Ding, Fengzhi; Li, Yuan; Yan, Gege; Pan, Zhenwei; Yang, Baofeng; Lu, Yanjie

    2016-08-01

    Melatonin, a hormone secreted by the pineal gland, possesses multiple biological activities such as antitumor, antioxidant, and anti-ischemia. C-kit(+) cardiac progenitor cells (CPCs) have emerged as a promising tool for the treatment of heart diseases. However, the senescence of CPCs due to pathological stimuli leads to the decline of CPCs' functions and regenerative potential. This study was conducted to demonstrate whether melatonin antagonizes the senescence of CPCs in response to oxidative stress. Here, we found that the melatonin treatment markedly inhibited the senescent characteristics of CPCs after exposed to sublethal concentration of H2 O2 , including the increase in senescence-associated β-galactosidase (SA-β-gal)-positive CPCs, senescence-associated heterochromatin loci (SAHF), secretory IL-6 level, and the upregulation of p53 and p21 proteins. Senescence-associated proliferation reduction was also attenuated by melatonin in CPCs. Luzindole, the melatonin membrane receptor blocker, may block the melatonin-mediated suppression of premature senescence in CPCs. Interestingly, we found that long noncoding RNA H19 and its derived miR-675 were downregulated by H2 O2 in CPCs, but melatonin treatment could counter this alteration. Furthermore, knockdown of H19 or miR-675 blocked antisenescence actions of melatonin on H2 O2 -treated CPCs. It was further verified that H19-derived miR-675 targeted at the 3'UTR of USP10, which resulted in the downregulation of p53 and p21 proteins. In summary, melatonin antagonized premature senescence of CPCs via H19/miR-675/USP10 pathway, which provides new insights into pharmacological actions and potential applications of melatonin on the senescence of CPCs.

  1. A Review of Melatonin, Its Receptors and Drugs

    PubMed Central

    Emet, Mucahit; Ozcan, Halil; Ozel, Lutfu; Yayla, Muhammed; Halici, Zekai; Hacimuftuoglu, Ahmet

    2016-01-01

    After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activity-regulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/RORα: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future. PMID:27551178

  2. A Review of Melatonin, Its Receptors and Drugs.

    PubMed

    Emet, Mucahit; Ozcan, Halil; Ozel, Lutfu; Yayla, Muhammed; Halici, Zekai; Hacimuftuoglu, Ahmet

    2016-06-01

    After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activity-regulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/RORα: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future. PMID:27551178

  3. Antepartum depression severity is increased during seasonally longer nights: Relationship to melatonin and cortisol timing and quantity

    PubMed Central

    Meliska, Charles J.; Martínez, Luis F.; López, Ana M.; Sorenson, Diane L.; Nowakowski, Sara; Kripke, Daniel F.; Elliott, Jeffrey; Parry, Barbara L.

    2014-01-01

    Current research suggests that mood varies from season to season in some individuals, in conjunction with light-modulated alterations in chronobiologic indices like melatonin and cortisol. The primary aim of this study was to evaluate the effects of seasonal variations in darkness on mood in depressed antepartum women, and to determine the relationship of seasonal mood variations to contemporaneous blood melatonin and cortisol measures; a secondary aim was to evaluate the influence of seasonal factors on measures of melancholic versus atypical depressive symptoms. We obtained measures of mood and overnight concentrations of plasma melatonin and serum cortisol in 19 depressed patients (DP) and 12 healthy control (HC) antepartum women, during on-going seasonal variations in daylight/darkness, in a cross-sectional design. Analyses of variance showed that in DP, but not HC, Hamilton Depression Rating Scale (HRSD) scores were significantly higher in women tested during seasonally longer vs. shorter nights. This exacerbation of depressive symptoms occurred when the dim light melatonin onset, the melatonin synthesis offset and the time of maximum cortisol secretion (acrophase) were phase-advanced (temporally shifted earlier), and melatonin quantity was reduced, in DP but not HC. Serum cortisol increased across gestational weeks in both the HC and DP groups, which did not differ significantly in cortisol concentration. Nevertheless, serum cortisol concentration correlated positively with HRSD score in DP but not HC; notably, HC showed neither significant mood changes nor altered melatonin and cortisol timing or quantity in association with seasonal variations. These findings suggest that depression severity during pregnancy may become elevated in association with seasonally-related phase-advances in melatonin and cortisol timing and reduced melatonin quantity that occur in DP, but not HC. Thus, women who experience antepartum depression may be more susceptible than their

  4. Therapeutic potential of melatonin in oral medicine and periodontology.

    PubMed

    Najeeb, Shariq; Khurshid, Zohaib; Zohaib, Sana; Zafar, Muhammad Sohail

    2016-08-01

    Melatonin (N-acetyl-5-methoxy tryptamine) is a substance secreted by multiple organs in vertebrates. In addition to playing a part in the circadian cycle of the body, melatonin is known to have antioxidant, antiinflammatory, and antioncotic effects on human tissues. Oral cavity is affected by a number of conditions such as periodontitis, mucositis, cancers, and cytotoxicity from various drugs or biomaterials. Research has suggested that melatonin is effective in treating the aforementioned pathologies. Furthermore, melatonin has been observed to enhance osseointegration and bone regeneration. The aim of this review is to critically analyze and summarize the research focusing on the potential of melatonin in the field of oral medicine. Topical administration of melatonin has a positive effect on periodontal health and osseointegration. Furthermore, melatonin is particularly effective in improving the periodontal parameters of diabetic patients with periodontitis. Melatonin exerts a regenerative effect on periodontal bone and may be incorporated into of periodontal scaffolds. The cytotoxic effect of various drugs and dental materials may be countered by the antioxidant properties of melatonin. Topical administration of melatonin promotes the healing of tooth extraction sockets and may also impede the progression of oral cancer. Although, there are a number of current and potential applications of melatonin, further long term clinical and animal studies are needed to assess its efficacy. Moreover, the role of melatonin supplements in the management of periodontitis should also be assessed. PMID:27523451

  5. Hypokalemia decreases testosterone production in male mice by altering luteinizing hormone secretion.

    PubMed

    Sánchez-Capelo, A; Castells, M T; Cremades, A; Peñafiel, R

    1996-09-01

    Potassium deficiency produced by feeding mice a low potassium diet caused a marked decrease in plasma and testicular testosterone concentrations and a concomitant fall in the weight of seminal vesicles and in renal ornithine decarboxylase activity. All of these parameters were rapidly restored when potassium supply was normalized. Immunocytochemical analysis of gonadotropes and plasma LH values suggested that the pulsatile liberation of LH by the pituitary was impaired in the potassium-deficient male mice. Because the synthesis of testosterone in the potassium-deficient mice was stimulated by exogenous LH, hCG, or GnRH, one can conclude that alteration of the transcellular potassium gradient could affect the regulation of the hypothalamo-hypophyseal-testicular axis by affecting the pulsatile release of GnRH. Our results showing that the stimulation of LH secretion after castration was similar in control and potassium-deficient male mice suggest that a testicular factor(s) different from testosterone could be implicated in the abnormal regulation of LH secretion in potassium-deficient mice. We conclude that plasma potassium concentration is an important factor in the regulation of gonadotropin secretion and testicular functions. PMID:8756540

  6. Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans

    PubMed Central

    Rajaratnam, Shantha M W; Middleton, Benita; Stone, Barbara M; Arendt, Josephine; Dijk, Derk-Jan

    2004-01-01

    The rhythm of plasma melatonin originating from the pineal gland and driven by the circadian pacemaker located in the suprachiasmatic nucleus is closely associated with the circadian (approximately 24 h) variation in sleep propensity and sleep spindle activity in humans. We investigated the contribution of melatonin to variation in sleep propensity, structure, duration and EEG activity in a protocol in which sleep was scheduled to begin during the biological day, i.e. when endogenous melatonin concentrations are low. The two 14 day trials were conducted in an environmental scheduling facility. Each trial included two circadian phase assessments, baseline sleep and nine 16 h sleep opportunities (16.00–08.00 h) in near darkness. Eight healthy male volunteers (24.4 ± 4.4 years) without sleep complaints were recruited, and melatonin (1.5 mg) or placebo was administered at the start of the first eight 16 h sleep opportunities. During melatonin treatment, sleep in the first 8 h of the 16 h sleep opportunities was increased by 2 h. Sleep per 16 h was not significantly different and approached asymptotic values of 8.7 h in both conditions. The percentage of rapid eye movement (REM) sleep was not affected by melatonin, but the percentage of stage 2 sleep and sleep spindle activity increased, and the percentage of stage 3 sleep decreased. During the washout night, the melatonin-induced advance in sleep timing persisted, but was smaller than on the preceding treatment night and was consistent with the advance in the endogenous melatonin rhythm. These data demonstrate robust, direct sleep-facilitating and circadian effects of melatonin without concomitant changes in sleep duration, and support the use of melatonin in the treatment of sleep disorders in which the circadian melatonin rhythm is delayed relative to desired sleep time. PMID:15459246

  7. Helical packing of needles from functionally altered Shigella type III secretion systems.

    PubMed

    Cordes, Frank S; Daniell, Sarah; Kenjale, Roma; Saurya, Saroj; Picking, Wendy L; Picking, William D; Booy, Frank; Lea, Susan M; Blocker, Ariel

    2005-11-25

    Gram-negative bacteria commonly interact with eukaryotic host cells using type III secretion systems (TTSSs or secretons), which comprise cytoplasmic, transmembrane and extracellular domains. The extracellular domain is a hollow needle-like structure protruding 60 nm beyond the bacterial surface. The TTSS is activated to transfer bacterial proteins directly into a host cell only upon physical contact with the target cell. We showed previously that the monomer of the Shigella flexneri needle, MxiH, assembles into a helical structure with parameters similar to those defining the architecture of the extracellular components of bacterial flagella. By analogy with flagella, which are known to exist in different helical states, we proposed that changes in the helical packing of the needle might be used to sense host cell contact. Here, we show that, on the contrary, mutations within MxiH that lock the TTSS into altered secretion states do not detectably alter the helical packing of needles. This implies that either: (1) host cell contact is signalled through the TTSS via helical changes in the needle that are significantly smaller than those linked to structural changes in the flagellar filament and therefore too small to be detected by our analysis methods or (2) that signal transduction in this system occurs via a novel molecular mechanism. PMID:16243352

  8. A low-protein diet during pregnancy alters glucose metabolism and insulin secretion.

    PubMed

    Souza, Denise de Fátima I; Ignácio-Souza, Letícia M; Reis, Sílvia Regina de L; Reis, Marise Auxiliadora de B; Stoppiglia, Luiz Fabrizio; Carneiro, Everardo Magalhães; Boschero, Antonio Carlos; Arantes, Vanessa Cristina; Latorraca, Márcia Queiroz

    2012-03-01

    In pancreatic islets, glucose metabolism is a key process for insulin secretion, and pregnancy requires an increase in insulin secretion to compensate for the typical insulin resistance at the end of this period. Because a low-protein diet decreases insulin secretion, this type of diet could impair glucose homeostasis, leading to gestational diabetes. In pancreatic islets, we investigated GLUT2, glucokinase and hexokinase expression patterns as well as glucose uptake, utilization and oxidation rates. Adult control non-pregnant (CNP) and control pregnant (CP) rats were fed a normal protein diet (17%), whereas low-protein non-pregnant (LPNP) and low-protein pregnant (LPP) rats were fed a low-protein diet (6%) from days 1 to 15 of pregnancy. The insulin secretion in 2.8 mmol l(-1) of glucose was higher in islets from LPP rats than that in islets from CP, CNP and LPNP rats. Maximal insulin release was obtained at 8.3 and 16.7 mmol l(-1) of glucose in LPP and CP groups, respectively. The glucose dose-response curve from LPNP group was shifted to the right in relation to the CNP group. In the CP group, the concentration-response curve to glucose was shifted to the left compared with the CNP group. The LPP groups exhibited an "inverted U-shape" dose-response curve. The alterations in the GLUT2, glucokinase and hexokinase expression patterns neither impaired glucose metabolism nor correlated with glucose islet sensitivity, suggesting that β-cell sensitivity to glucose requires secondary events other than the observed metabolic/molecular events. PMID:22034157

  9. Rotating wall vessel exposure alters protein secretion and global gene expression in Staphylococcus aureus

    NASA Astrophysics Data System (ADS)

    Rosado, Helena; O'Neill, Alex J.; Blake, Katy L.; Walther, Meik; Long, Paul F.; Hinds, Jason; Taylor, Peter W.

    2012-04-01

    Staphylococcus aureus is routinely recovered from air and surface samples taken aboard the International Space Station (ISS) and poses a health threat to crew. As bacteria respond to the low shear forces engendered by continuous rotation conditions in a Rotating Wall Vessel (RWV) and the reduced gravitational field of near-Earth flight by altering gene expression, we examined the effect of low-shear RWV growth on protein secretion and gene expression by three S. aureus isolates. When cultured under 1 g, the total amount of protein secreted by these strains varied up to fourfold; under continuous rotation conditions, protein secretion by all three strains was significantly reduced. Concentrations of individual proteins were differentially reduced and no evidence was found for increased lysis. These data suggest that growth under continuous rotation conditions reduces synthesis or secretion of proteins. A limited number of changes in gene expression under continuous rotation conditions were noted: in all isolates vraX, a gene encoding a polypeptide associated with cell wall stress, was down-regulated. A vraX deletion mutant of S. aureus SH1000 was constructed: no differences were found between SH1000 and ΔvraX with respect to colony phenotype, viability, protein export, antibiotic susceptibility, vancomycin kill kinetics, susceptibility to cold or heat and gene modulation. An ab initio protein-ligand docking simulation suggests a major binding site for β-lactam drugs such as imipenem. If such changes to the bacterial phenotype occur during spaceflight, they will compromise the capacity of staphylococci to cause systemic infection and to circumvent antibacterial chemotherapy.

  10. Do plasma melatonin concentrations decline with age?

    NASA Technical Reports Server (NTRS)

    Zeitzer, J. M.; Daniels, J. E.; Duffy, J. F.; Klerman, E. B.; Shanahan, T. L.; Dijk, D. J.; Czeisler, C. A.

    1999-01-01

    PURPOSE: Numerous reports that secretion of the putative sleep-promoting hormone melatonin declines with age have led to suggestions that melatonin replacement therapy be used to treat sleep problems in older patients. We sought to reassess whether the endogenous circadian rhythm of plasma melatonin concentration changes with age in healthy drug-free adults. METHODS: We analyzed the amplitude of plasma melatonin profiles during a constant routine in 34 healthy drug-free older subjects (20 women and 14 men, aged 65 to 81 years) and compared them with 98 healthy drug-free young men (aged 18 to 30 years). RESULTS: We could detect no significant difference between a healthy and drug-free group of older men and women as compared to one of young men in the endogenous circadian amplitude of the plasma melatonin rhythm, as described by mean 24-hour average melatonin concentration (70 pmol/liter vs 73 pmol/liter, P = 0.97), or the duration (9.3 hours vs 9.1 hours, P = 0.43), mean (162 pmol/liter vs 161 pmol/liter, P = 0.63), or integrated area (85,800 pmol x min/liter vs 86,700 pmol x min/liter, P = 0.66) of the nocturnal peak of plasma melatonin. CONCLUSION: These results do not support the hypothesis that reduction of plasma melatonin concentration is a general characteristic of healthy aging. Should melatonin replacement therapy or melatonin supplementation prove to be clinically useful, we recommend that an assessment of endogenous melatonin be carried out before such treatment is used in older patients.

  11. Bidirectional effect of electromagnetic fields on ketanserin-induced yawning in patients with multiple sclerosis: the role of melatonin.

    PubMed

    Sandyk, R

    1996-03-01

    5-HT2 receptors regulate sleep including yawning behavior. Ritanserin, a selective 5-HT2A receptor antagonist, increases the duration of slow wave in rats and humans. This effect is more pronounced during the light period when melatonin plasma levels are low; melatonin inhibits the sleep effects of ritanserin. These findings indicate that melatonin co-determines the effects of ritanserin on sleep. In a cohort of multiple sclerosis (MS) patients ketanserin, a selective 5-HT2A receptor antagonist, induces recurrent yawning particularly when administered in daytime. The frequency of yawning induced by the drug was modified by AC pulsed picotesla flux electromagnetic fields (EMFs) which affect melatonin secretion. Two MS patients are presented in whom the frequency of ketanserin-induced yawning was altered in opposite directions by these EMFs. The first patient, a 50 year old woman with a remitting-relapsing course, developed recurrent yawning and sleepiness after administration of ketanserin (10 mg, PO). Yawning was decreased dramatically during application of EMFs but was unaffected by a placebo EMFs treatment. The second patient, a 35 year old man with a chronic progressive course, manifested a single and brief yawn after administration of an equal dose of ketanserin. Yawning was increased dramatically during application of EMFs while remaining unchanged during a placebo EMFs treatment. These observations demonstrate a bidirectional effect of picotesla flux EMFs on ketanserin-induced yawning which may be related to differences in daytime melatonin plasma levels among MS patients. If validated by estimations of melatonin plasma levels in a larger cohort of patients the information derived from the effects of picotesla EMFs on ketanserin-induced yawning could be used to: (a) assess pineal melatonin functions in patients with MS; (b) indicate differences in pineal functions between male and female MS patients; and (c) indicate a relationship between plasma melatonin

  12. Mood disorders, circadian rhythms, melatonin and melatonin agonists.

    PubMed

    Quera Salva, M A; Hartley, S

    2012-01-01

    Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.

  13. Role of melatonin in embryo fetal development

    PubMed Central

    Voiculescu, SE; Zygouropoulos, N; Zahiu, CD; Zagrean, AM

    2014-01-01

    Melatonin is an indoleamine produced by the pineal gland and secreted in a circadian manner. In the past few decades, research over this topic has been enhanced. Melatonin has many important roles in the human physiology: regulator of the circadian rhythms, sleep inducer, antioxidant, anticarcinogenic. This paper reviews the involvement of melatonin in embryo fetal development. The pineal gland develops completely postpartum, so both the embryo and the fetus are dependent on the maternal melatonin provided transplacentally. Melatonin appears to be involved in the normal outcome of pregnancy beginning with the oocyte quality and finishing with the parturition. Its pregnancy night-time concentrations increase after 24 weeks of gestation, with significantly high levels after 32 weeks. Melatonin receptors are widespread in the embryo and fetus since early stages. There is solid evidence that melatonin is neuroprotective and has a positive effect on the outcome of the compromised pregnancies. In addition, chronodisruption leads to a reproductive dysfunction. Thus, the influence of melatonin on the developing human fetus may not be limited to the entertaining of circadian rhythmicity, but further studies are needed. PMID:25713608

  14. Role of melatonin in embryo fetal development.

    PubMed

    Voiculescu, S E; Zygouropoulos, N; Zahiu, C D; Zagrean, A M

    2014-01-01

    Melatonin is an indoleamine produced by the pineal gland and secreted in a circadian manner. In the past few decades, research over this topic has been enhanced. Melatonin has many important roles in the human physiology: regulator of the circadian rhythms, sleep inducer, antioxidant, anticarcinogenic. This paper reviews the involvement of melatonin in embryo fetal development. The pineal gland develops completely postpartum, so both the embryo and the fetus are dependent on the maternal melatonin provided transplacentally. Melatonin appears to be involved in the normal outcome of pregnancy beginning with the oocyte quality and finishing with the parturition. Its pregnancy night-time concentrations increase after 24 weeks of gestation, with significantly high levels after 32 weeks. Melatonin receptors are widespread in the embryo and fetus since early stages. There is solid evidence that melatonin is neuroprotective and has a positive effect on the outcome of the compromised pregnancies. In addition, chronodisruption leads to a reproductive dysfunction. Thus, the influence of melatonin on the developing human fetus may not be limited to the entertaining of circadian rhythmicity, but further studies are needed.

  15. Melatonin and human skin aging

    PubMed Central

    Kleszczynski, Konrad; Fischer, Tobias W.

    2012-01-01

    Like the whole organism, skin follows the process of aging during life-time. Additional to internal factors, several environmental factors, such as solar radiation, considerably contribute to this process. While fundamental mechanisms regarding skin aging are known, new aspects of anti-aging agents such as melatonin are introduced. Melatonin is a hormone produced in the glandula pinealis that follows a circadian light-dependent rhythm of secretion. It has been experimentally implicated in skin functions such as hair cycling and fur pigmentation, and melatonin receptors are expressed in many skin cell types including normal and malignant keratinocytes, melanocytes and fibroblasts. It possesses a wide range of endocrine properties as well as strong antioxidative activity. Regarding UV-induced solar damage, melatonin distinctly counteracts massive generation of reactive oxygen species, mitochondrial and DNA damage. Thus, there is considerable evidence for melatonin to be an effective anti-skin aging compound, and its various properties in this context are described in this review. PMID:23467217

  16. Melatonin and Pancreatic Islets: Interrelationships between Melatonin, Insulin and Glucagon

    PubMed Central

    Peschke, Elmar; Bähr, Ina; Mühlbauer, Eckhard

    2013-01-01

    The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin–insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes. PMID:23535335

  17. Melatonin reduces obesity and restores adipokine patterns and metabolism in obese (ob/ob) mice.

    PubMed

    Favero, Gaia; Stacchiotti, Alessandra; Castrezzati, Stefania; Bonomini, Francesca; Albanese, Massimo; Rezzani, Rita; Rodella, Luigi Fabrizio

    2015-10-01

    The increasing incidence of obesity, leading to metabolic complications, is now recognized as a major public health problem. The adipocytes are not merely energy-storing cells, but they play crucial roles in the development of the so-called metabolic syndrome due to the adipocyte-derived bioactive factors such as adipokines, cytokines, and growth factors. The dysregulated production and secretion of adipokines seen in obesity is linked to the pathogenesis of the metabolic disease processes. In this study, we hypothesized that dietary melatonin administration would support an anti-inflammatory response and play an important role in energy metabolism in subcutaneous and visceral adipose tissues of obese mice and so may counteract some of the disruptive effects of obesity. Lean and obese mice (ob/ob) received melatonin or vehicle in drinking water for 8 weeks. Thereafter, they were evaluated for morphologic alteration, inflammatory cell infiltration, and the adipokine patterns in visceral and subcutaneous white fat depots. In obese mice treated with vehicle, we observed a significant increase in fat depots, inflammation, and a dysregulation of the adipokine network. In particular, we measured a significant reduction of adiponectin and an increase of tumor necrosis factor α, resistin, and visfatin in adipose tissue deposits. These changes were partially reversed when melatonin was supplemented to obese mice. Melatonin supplementation by regulating inflammatory infiltration ameliorates obesity-induced adipokine alteration, whereas melatonin administration in lean mice was unaffected. Thus, it is likely that melatonin would be provided in supplement form to control some of the disruptive effects on the basis of obesity pathogenic process.

  18. Failure of ethanol metabolites to alter gonadotropin secretion or luteinizing hormone synthesis in vitro.

    PubMed

    Uddin, S; Kirsteins, L; LaPaglia, N; Emanuele, N V; Lawrence, A M; Kelley, M R; Emanuele, M A

    1995-08-01

    The impact of ethanol on the male reproductive axis are multiple and varied, with both gonadal and control hypothalamic-pituitary pertubations being reported. There appears to be a discrepancy, however, between the in vivo and in vitro effects of ethanol on hypothalamic luteinizing hormones releasing hormone (LHRH) and the pituitary gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH). While in vivo data suggests a decrease in LHRH release after EtOH, in vitro studies find no effect on secretion. Similarly, in vivo acute EtOH profoundly diminishes LH synthesis and secretion, while in vitro impaired release with no alteration in the transcription of beta LH has been found. A potential exploration for these discrept results could be the in vivo metabolism of EtOH into acetaldehyde and acetate, or the subsequent formation of salsolinol, a product of acetate combining with dopamine. To test this possibility, a series of in vitro experiments were conducted exposing dispensed anterior pituitary cells from male rats to different doses of acetaldehyde, acetate or salsolinol for varying amounts of time for which gonadotropin secretion and beta LH mRNA levels were assessed. The results demonstrated no effect of either acetaldehyde or acetate on basal or LHRH stimulated LH release, FSH release or steady-state beta LH mRNA levels. These data suggest that the metabolites of EtOH, which occur in vivo but not in vitro, are not responsible for the discrepant gonadotropin changes reported between the in vivo and in vitro setting. Other potential mechanisms to explain this phenomenon include differences in the molarity of EtOH, hyperprolactinemia and suprapituitary influences including hypothalamic LHRH, catecholamines, excitatory amino acids, substance P and beta endorphin.

  19. Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism

    PubMed Central

    Jansen, S. W.; Akintola, A. A.; Roelfsema, F.; van der Spoel, E.; Cobbaert, C. M.; Ballieux, B. E.; Egri, P.; Kvarta-Papp, Z.; Gereben, B.; Fekete, C.; Slagboom, P. E.; van der Grond, J.; Demeneix, B. A.; Pijl, H.; Westendorp, R. G. J.; van Heemst, D.

    2015-01-01

    Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism. PMID:26089239

  20. Human melatonin during continuous magnetic field exposure

    SciTech Connect

    Graham, C.; Cook, M.R.; Riffle, D.W.

    1997-05-01

    This report describes the third in a series of double-blind, laboratory-based studies that were aimed at determining the effects of nocturnal exposure to power frequency magnetic fields on blood levels of melatonin in human volunteers. The two earlier studies evaluated effects on melatonin of intermittent exposure to 60 Hz circularly polarized magnetic fields at 10 and 200 mG. No overall effects on melatonin levels were found. In the present study, men were exposed continuously rather than intermittently through the night to the same 200 mG magnetic field condition that was used previously; again, no overall effects on melatonin levels were found. The authors conclude that the intermittent and continuous exposure conditions used in the laboratory to date are not effective in altering nocturnal blood levels of melatonin in human volunteers.

  1. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    PubMed

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways. PMID:26530153

  2. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    PubMed

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways.

  3. Differences between circadian and ultradian organization of cortisol and melatonin rhythms during activity and rest.

    PubMed

    Rivest, R W; Schulz, P; Lustenberger, S; Sizonenko, P C

    1989-04-01

    We compared the cortisol and melatonin circadian and ultradian rhythms in normal men using two approaches: 1) the men were exposed successively to two conditions, one normal and a second chosen to alter differently each of the hormones, i.e. complete bedrest for 34 h (supine, fasting, and under dim light), and 2) analyses of the rhythms using a combination of curve smoothing for the description of the 24-h rhythm, and peak detection and spectral analysis for the measurement of periodic phenomena. Blood was sampled every 30 min from 0700-0700 h. A diurnal rhythm was detected for both hormones, with different underlying frequencies. Plasma cortisol had an ultradian rhythm of 8 h. From 0000-0800 h (night) and 0830-1600 h (early day), the pulsatile activity and baseline values of cortisol were high, while from 1630-2400 h (late day), these variables were low. During complete bedrest, pulsatile activity and baseline values were even higher during the night period, and the nocturnal peak of cortisol, usually present between 0300-1000 h, was split in two, with an early peak at 0000-0400 h. There were two specific events during the day associated with synchronous, high amplitude pulses: awakening and eating at noon. No such pulses occurred at suppertime or when the men fasted. Melatonin secretion was organized around a 5.5-h period. In the rest condition, plasma melatonin values were higher during the night. The 24-h rhythms of cortisol and melatonin were temporally related. Plasma melatonin began to rise when plasma cortisol was at its lowest, it peaked when cortisol began to rise, and it began to decrease when cortisol reached its peak, with a 5-h phase delay between plasma cortisol and melatonin rise at night. In summary, melatonin and cortisol rhythms have different ultradian frequencies, suggesting an intrinsic difference in the mechanisms controlling their secretion. In addition, their responses to restricted physical activity in an environment with dim light were

  4. Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours

    PubMed Central

    Söderquist, Fanny; Janson, Eva Tiensuu; Rasmusson, Annica J.; Ali, Abir; Stridsberg, Mats; Cunningham, Janet L.

    2016-01-01

    Background/Aims Small intestinal neuroendocrine tumours (SI-NETs) are derived from enterochromaffin cells. After demonstrating melatonin in enterochromaffin cells, we hypothesized that SI-NETs may express and secrete melatonin, which may have an impact on clinical factors and treatment response. Methods Tumour tissue from 26 patients with SI-NETs, representing paired sections of primary tumour and metastasis, were immunohistochemically stained for melatonin and its receptors, MT1 and MT2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT1 and MT2 in tumour cells were compared to other tumour markers and clinical parameters. Melatonin was measured at two time points in fasting morning plasma from 43 patients with SI-NETs. Results Melatonin IR was found in all SI-NETS. Melatonin IR intensity in primary tumours correlated inversely to proliferation index (p = 0.022) and patients reported less diarrhoea when melatonin IR was high (p = 0.012). MT1 IR was low or absent in tumours. MT2 expression was medium to high in primary tumours and generally reduced in metastases (p = 0.007). Plasma-melatonin ranged from 4.5 to 220.0 pg/L. Higher levels were associated with nausea at both time points (p = 0.027 and p = 0.006) and flush at the second sampling. In cases with disease stabilization or remission (n = 34), circulating melatonin levels were reduced in the second sample (p = 0.038). Conclusion Immunoreactive melatonin is present in SI-NETs. Circulating levels of melatonin in patients with SI-NETs are reduced after treatment. Our results are congruent with recent understanding of melatonin’s endocrine and paracrine functions and SI-NETs may provide a model for further studies of melatonin function. PMID:27736994

  5. Clinical aspects of melatonin.

    PubMed

    Reiter, Russel J; Korkmaz, Ahmet

    2008-11-01

    Melatonin is produced in the human pineal gland, particularly at night, with the circadian rhythm of blood melatonin levels closely paralleling its production within the pineal gland. Light exposure at night, or rapid transmeridian travel severely compromises the circadian production of melatonin. The disturbed melatonin rhythm contributes to jet lag and sleep inefficiency, both of which are improved by melatonin administration. Melatonin is also a highly effective direct free radical scavenger and antioxidant. In this capacity, melatonin reduces experimental cataractogenesis, traumatic injury to the spinal cord and brain, and protects against oxidative damage to neurons and glia in models of stroke, Parkinsonism, and Alzheimer's disease. Additionally, melatonin and its metabolites are highly effective in protecting against ionizing radiation. Finally, melatonin may be a treatment for hypertension. Melatonin's high efficacy, its high safety profile, and its virtual lack of toxicity make it of interest in clinical medicine. PMID:18997997

  6. Melatonin: a "Higgs boson" in human reproduction.

    PubMed

    Dragojevic Dikic, Svetlana; Jovanovic, Ana Mitrovic; Dikic, Srdjan; Jovanovic, Tomislav; Jurisic, Aleksandar; Dobrosavljevic, Aleksandar

    2015-02-01

    As the Higgs boson could be a key to unlocking mysteries regarding our Universe, melatonin, a somewhat mysterious substance secreted by the pineal gland primarily at night, might be a crucial factor in regulating numerous processes in human reproduction. Melatonin is a powerful antioxidant which has an essential role in controlling several physiological reactions, as well as biological rhythms throughout human reproductive life. Melatonin, which is referred to as a hormone, but also as an autocoid, a chronobiotic, a hypnotic, an immunomodulator and a biological modifier, plays a crucial part in establishing homeostatic, neurohumoral balance and circadian rhythm in the body through synergic actions with other hormones and neuropeptides. This paper aims to analyze the effects of melatonin on the reproductive function, as well as to shed light on immunological and oncostatic properties of one of the most powerful hormones.

  7. Potency of Melatonin in Living Beings

    PubMed Central

    Choi, Donchan

    2013-01-01

    Living beings are surrounded by various changes exhibiting periodical rhythms in environment. The environmental changes are imprinted in organisms in various pattern. The phenomena are believed to match the external signal with organisms in order to increase their survival rate. The signals are categorized into circadian, seasonal, and annual cycles. Among the cycles, the circadian rhythm is regarded as the most important factor because its periodicity is in harmony with the levels of melatonin secreted from pineal gland. Melatonin is produced by the absence of light and its presence displays darkness. Melatonin plays various roles in creatures. Therefore, this review is to introduce the diverse potential ability of melatonin in manifold aspects in living organism. PMID:25949131

  8. Neurobiology, Pathophysiology, and Treatment of Melatonin Deficiency and Dysfunction

    PubMed Central

    Hardeland, Rüdiger

    2012-01-01

    Melatonin is a highly pleiotropic signaling molecule, which is released as a hormone of the pineal gland predominantly during night. Melatonin secretion decreases during aging. Reduced melatonin levels are also observed in various diseases, such as types of dementia, some mood disorders, severe pain, cancer, and diabetes type 2. Melatonin dysfunction is frequently related to deviations in amplitudes, phasing, and coupling of circadian rhythms. Gene polymorphisms of melatonin receptors and circadian oscillator proteins bear risks for several of the diseases mentioned. A common symptom of insufficient melatonin signaling is sleep disturbances. It is necessary to distinguish between symptoms that are curable by short melatonergic actions and others that require extended actions during night. Melatonin immediate release is already effective, at moderate doses, for reducing difficulties of falling asleep or improving symptoms associated with poorly coupled circadian rhythms, including seasonal affective and bipolar disorders. For purposes of a replacement therapy based on longer-lasting melatonergic actions, melatonin prolonged release and synthetic agonists have been developed. Therapies with melatonin or synthetic melatonergic drugs have to consider that these agents do not only act on the SCN, but also on numerous organs and cells in which melatonin receptors are also expressed. PMID:22629173

  9. The effect of age and pre-light melatonin concentration on the melatonin sensitivity to dim light.

    PubMed

    Nathan, P J; Burrows, G D; Norman, T R

    1999-05-01

    The hormone melatonin is secreted at night from the pineal gland, with light being a potent inhibitor of its secretion. Age related decreases in plasma melatonin concentrations have indicated that this may be related to pineal calcification with aging. Recently, it was shown that the melatonin sensitivity to light may be a biological marker of bipolar disorder. However, on average, patients were older than the control group in most studies, and it is not known if age has an effect on the melatonin suppression by light. To test this hypothesis, the present study investigated the effect of age on the melatonin sensitivity to dim light (200 lux). Participants were grouped into three age groups. On the testing night, they were placed in a dark room from 21.00 h to 02.30 h. Light exposure was for an hour from midnight to 01.00 h. Blood samples were collected at regular intervals for measurement of plasma melatonin. No significant differences were found in the percentage suppression of melatonin within the age groups defined in the present study (P > 0.5). No correlation was also found between age and percentage suppression of melatonin (r2 = 0.007; P > 0.1). Our results suggest that the melatonin suppression by light (200 lux) is not affected by age. PMID:10435774

  10. Melatonin, energy metabolism, and obesity: a review.

    PubMed

    Cipolla-Neto, J; Amaral, F G; Afeche, S C; Tan, D X; Reiter, R J

    2014-05-01

    Melatonin is an old and ubiquitous molecule in nature showing multiple mechanisms of action and functions in practically every living organism. In mammals, pineal melatonin functions as a hormone and a chronobiotic, playing a major role in the regulation of the circadian temporal internal order. The anti-obesogen and the weight-reducing effects of melatonin depend on several mechanisms and actions. Experimental evidence demonstrates that melatonin is necessary for the proper synthesis, secretion, and action of insulin. Melatonin acts by regulating GLUT4 expression and/or triggering, via its G-protein-coupled membrane receptors, the phosphorylation of the insulin receptor and its intracellular substrates mobilizing the insulin-signaling pathway. Melatonin is a powerful chronobiotic being responsible, in part, by the daily distribution of metabolic processes so that the activity/feeding phase of the day is associated with high insulin sensitivity, and the rest/fasting is synchronized to the insulin-resistant metabolic phase of the day. Furthermore, melatonin is responsible for the establishment of an adequate energy balance mainly by regulating energy flow to and from the stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue. The reduction in melatonin production, as during aging, shift-work or illuminated environments during the night, induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian disorganization characterizing a state of chronodisruption leading to obesity. The available evidence supports the suggestion that melatonin replacement therapy might contribute to restore a more healthy state of the organism.

  11. Melatonin regulation of biliary functions

    PubMed Central

    Glaser, Shannon; Han, Yuyan; Francis, Heather

    2014-01-01

    The intrahepatic biliary epithelium is a three-dimensional tubular system lined by cholangiocytes, epithelial cells that in addition to modify ductal bile are also the targets of vanishing bile duct syndromes (i.e., cholangiopathies) such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) that are characterized by the damage/proliferation of cholangiocytes. Cholangiocyte proliferation is critical for the maintenance of the biliary mass and secretory function during the pathogenesis of cholangiopathies. Proliferating cholangiocytes serve as a neuroendocrine compartment during the progression of cholangiopathies, and as such secrete and respond to hormones, neurotransmitters and neuropeptides contributing to the autocrine and paracrine pathways that regulate biliary homeostasis. The focus of this review is to summarize the recent findings related to the role of melatonin in the modulation of biliary functions and liver damage in response to a number of insults. We first provide a general background on the general function of cholangiocytes including their anatomic characteristics, their innervation and vascularization as well the role of these cells on secretory and proliferation events. After a background on the synthesis and regulation of melatonin and its role on the maintenance of circadian rhythm, we will describe the specific effects of melatonin on biliary functions and liver damage. After a summary of the topics discussed, we provide a paragraph on the future perspectives related to melatonin and liver functions. PMID:24696836

  12. High membrane permeability for melatonin.

    PubMed

    Yu, Haijie; Dickson, Eamonn J; Jung, Seung-Ryoung; Koh, Duk-Su; Hille, Bertil

    2016-01-01

    The pineal gland, an endocrine organ in the brain, synthesizes and secretes the circulating night hormone melatonin throughout the night. The literature states that this hormone is secreted by simple diffusion across the pinealocyte plasma membrane, but a direct quantitative measurement of membrane permeability has not been made. Experiments were designed to compare the cell membrane permeability to three indoleamines: melatonin and its precursors N-acetylserotonin (NAS) and serotonin (5-HT). The three experimental approaches were (1) to measure the concentration of effluxing indoleamines amperometrically in the bath while cells were being dialyzed internally by a patch pipette, (2) to measure the rise of intracellular indoleamine fluorescence as the compound was perfused in the bath, and (3) to measure the rate of quenching of intracellular fura-2 dye fluorescence as indoleamines were perfused in the bath. These measures showed that permeabilities of melatonin and NAS are high (both are uncharged molecules), whereas that for 5-HT (mostly charged) is much lower. Comparisons were made with predictions of solubility-diffusion theory and compounds of known permeability, and a diffusion model was made to simulate all of the measurements. In short, extracellular melatonin equilibrates with the cytoplasm in 3.5 s, has a membrane permeability of ∼1.7 µm/s, and could not be retained in secretory vesicles. Thus, it and NAS will be "secreted" from pineal cells by membrane diffusion. Circumstances are suggested when 5-HT and possibly catecholamines may also appear in the extracellular space passively by membrane diffusion. PMID:26712850

  13. Expression and cellular localizaion of melatonin-synthesizing enzymes in rat and human salivary glands.

    PubMed

    Shimozuma, Masashi; Tokuyama, Reiko; Tatehara, Seiko; Umeki, Hirochika; Ide, Shinji; Mishima, Kenji; Saito, Ichiro; Satomura, Kazuhito

    2011-04-01

    Melatonin, discovered in 1958, is secreted by the pineal gland primarily during the night. Its secretion is controlled by the light/dark cycle of the environment. Melatonin is also produced in and secreted by various extrapineal organs, tissues and cells and its synthesizing enzyme arylalkylamine N-acetyltransferase (AANAT) is expressed in various extrapineal organs, tissues and cells. Recently, it was reported that melatonin is present in saliva, but it is not certain where melatonin was synthesized and whether it was secreted into saliva and what function it may have in saliva. The present study was performed to investigate where melatonin was synthesized and whether it was secreted by salivary glands into saliva. We performed immunohistochemical analysis of the expression of AANAT in rat parotid, submandibular and sublingual glands and the expression of both AANAT and hydroxyindole-O-methyltransferase (HIOMT) in human submandibular glands. We evaluated the expression of AANAT and HIOMT mRNA in rat submandibular glands by quantitative reverse transcription-polymerase chain reaction. As a result, we observed expression of AANAT in epithelial cells of striated ducts in rat salivary glands and expression of AANAT, HIOMT and melatonin in epithelial cells of striated ducts in human submandibular glands. In addition, we also confirmed the expression of the most potent melatonin receptor, melatonin 1a receptor, in rat buccal mucosa. Our findings suggest that melatonin might be produced and secreted by salivary glands directly into saliva and that it might play some physiological role in the oral cavity.

  14. Pharmacological doses of melatonin induce alterations in mitochondrial mass and potential, bcl-2 levels and K+ currents in UVB-exposed U937 cells.

    PubMed

    Canonico, Barbara; Luchetti, Francesca; Ambrogini, Patrizia; Arcangeletti, Marcella; Betti, Michele; Cesarini, Erica; Lattanzi, Davide; Ciuffoli, Stefano; Palma, Fulvio; Cuppini, Riccardo; Papa, Stefano

    2013-03-01

    Apoptosis is observed in 'actively' dying cells after the exposure to cell stressors such as ultraviolet light irradiation. Since melatonin has been proposed to act under stressful conditions as cell protection factor, in this study we examined the potential of this molecule when used at pharmacological concentrations to control mitochondrial damage and apoptotic signalling of UVB irradiated U937 human leukaemic cells. Moreover, the effect of melatonin treatment on electrophysiological properties and membrane K(+) currents of irradiated U937 cells was investigated as functional aspects relevant to the anti-apoptotic role of melatonin. The general effect is associated with the restoration of mass, number and membrane potential of mitochondria, with a lower caspase activation and bcl-2 upregulation. In the presence of the caspase inhibitor ZVAD-Fmk, melatonin seems to drive UVB stressed cells to follow the mitochondrial intrinsic pathway, interfering just at the mitochondrial level. Moreover, treatment with melatonin, as well as ZVAD-Fmk, prevented the K(+) current reduction observed late following the UVB insult application, by sparing cells from death; this result also indicates that the decrease of K(+) leakage currents could represent a functional feature of apoptotic process in UV-exposed U937 cells.

  15. Examination of the melatonin hypothesis in women exposed at night to EMF or bright light.

    PubMed Central

    Graham, C; Cook, M R; Gerkovich, M M; Sastre, A

    2001-01-01

    It has been hypothesized that the increased incidence of breast cancer in industrial societies is related to greater exposure to power-frequency electric and magnetic fields (EMF) and/or the presence of high levels of light at night (LAN). EMF and LAN are said to reduce circulating levels of the hormone melatonin which, in turn, allows estrogen levels to rise and stimulate the turnover of breast epithelial stem cells and increase the risk for malignant transformation. Three laboratory-based studies, in which a total of 53 healthy young women were exposed at night to EMF or to LAN under controlled exposure conditions, were performed to determine whether such exposures reduce melatonin and are associated with further alterations in estrogen. All-night exposure to industrial-strength magnetic fields (60 Hz, 28.3 microT) had no effect on the blood levels of melatonin or estradiol. In contrast, nocturnal melatonin levels were profoundly suppressed, and the time of peak concentration was significantly delayed in women exposed to LAN, regardless of whether they were in the follicular or luteal phase of the menstrual cycle. These changes, however, were not associated with alterations in point-for-point matching measures of estradiol. Women who chronically secrete high or low amounts of melatonin each night (area-under-curve range: 86-1,296 pg/mL) also did not differ in their blood levels of estradiol. Taken together, these results are consistent with a growing body of evidence which generally suggests that environmental EMF exposure has little or no effect on the parameters measured in this report. PMID:11401762

  16. Melatonin and clinical application.

    PubMed

    Wetterberg, L

    1999-01-01

    A review of the different publications dealing with melatonin in humans shows that this field has been very active in the last few years. Normative melatonin values have been defined. Various relationships between melatonin and other traits have been studied, such as sleep, circadian rhythm, surgical stress and anaesthesia. Age-related melatonin studies and melatonin during depression and other psychiatric disorders have been reviewed. Finally, some studies have been performed to use melatonin as a medication for sleep disturbance in depression, for jet-lag and as a skin protector for ultraviolet light. PMID:10420439

  17. Melatonin regulates proteomic changes during leaf senescence in Malus hupehensis.

    PubMed

    Wang, Ping; Sun, Xun; Xie, Yinpeng; Li, Mingjun; Chen, Wei; Zhang, Sheng; Liang, Dong; Ma, Fengwang

    2014-10-01

    Despite the relationship between melatonin and aging, the overall changes and regulation of proteome profiling by long-term melatonin exposure during leaf senescence is not well understood. In this study, leaf senescence in Malus hupehensis plants was delayed when exogenous melatonin was regularly applied to the roots for 2 months compared with natural leaf senescence. Proteins of samples 0 and 50 day for both treatments were extracted and labeled with TMT regents before being examined via NanoLC-MS/MS. The proteomics data showed that 622 and 309 proteins were altered by senescence and melatonin, respectively. Our GO analysis by Blast2GO revealed that most of the altered proteins that are involved in major metabolic processes exhibited hydrolase activity and were mainly located in the plastids. These proteins were classified into several senescence-related functional categories, including degradation of macromolecules, redox and stress responses, transport, photosynthesis, development, and other regulatory proteins. We found that melatonin treatment led to the downregulation of proteins that are normally upregulated during senescence. The melatonin-related delay in senescence might have occurred due to the altering of proteins involved in processes associated with senescence. And as well, there are many unknown regulatory proteins possibly being involved in the melatonin's function. This study is the first to demonstrate changes at the proteome level in response to exogenous melatonin in plants. Our findings provide a set of informative and fundamental data about the role of melatonin in apple leaf senescence.

  18. Does the impairment of the hypothalamic-pituitary-gonadal axis in anorexia nervosa depend on increased sensitivity to endogenous melatonin?

    PubMed

    Pawlikowski, M; Zarzycki, J

    1999-02-01

    The authors hypothesize that the impairment of hypothalamic-pituitary-gonadal axis in patients suffering from anorexia nervosa depends (at least in part) on the increased sensitivity to endogenous melatonin. The hypothesis is based mainly on the following facts: (1) melatonin is well known to exert an inhibitory effect on gonadotropin secretion; (2) melatonin binding is increased in brains of fasted rats; (3) undernutrition dramatically increases the inhibitory effect of exogenous melatonin on gonadotropin-releasing hormone-induced gonadotropin secretion in female rats; (4) the administration of propranolol in girls suffering from anorexia nervosa diminishes the nocturnal peak of melatonin and, in parallel, restores the gonadotropin response to gonadotropin-releasing hormone.

  19. Seasonal changes in serum melatonin in women with previous breast cancer.

    PubMed Central

    Holdaway, I. M.; Mason, B. H.; Gibbs, E. E.; Rajasoorya, C.; Hopkins, K. D.

    1991-01-01

    A seasonal variation in the month of initial detection of breast cancer has been previously observed in pre-menopausal women, and it has been proposed that this may be due to cyclic changes in tumour growth mediated by the effects of melatonin on ovarian function. To investigate this possibility serum melatonin concentrations have been measured every 2 h for 24 h at the summer and winter solstice in 20 pre-menopausal women with previous breast cancer and nine controls. Twelve women had detected their tumour in winter and eight in summer. Overall melatonin secretion assessed by either amplitude of the nocturnal melatonin pulse or the area under the 24 h melatonin curve (AUC) was not different between breast cancer women or controls. However, the amplitude and AUC fell in winter in breast cancer patients (summer to winter 93.6 to 77.5 pg ml-1, P less than 0.002 and 743 to 634 AUC units, P less than 0.005 for amplitude and AUC respectively), whereas the winter minus summer values were significantly positive in controls compared with cancer patients. The abnormal fall in winter values in the women with previous breast cancer was confined to the group of women who had been winter detectors (mean summer to winter levels 94.9 to 72.6 pg ml-1, P less than 0.01 and 775 to 637 AUC units, P less than 0.05 for amplitude and AUC respectively) whereas there was no significant seasonal alteration in these measurements in summer detectors. The acrophase of the nocturnal pulse of serum melatonin was significantly advanced in both groups of women with previous breast cancer (change in acrophase winter to summer from 0210 h to 0140 h in summer detectors, P less than 0.01, 0330 h to 0210 h in winter detectors, P less than 0.05) with a similar although nonsignificant trend in control women. The abnormal reduction of serum melatonin seen in wintertime in winter detectors of breast cancer could promote tumour growth at this season and so contribute to the decreased survival previously

  20. [Alteration of thyroid hormone secretion after long-term exposure to low doses of endocrine disruptor DDT].

    PubMed

    Iaglova, N V; Iaglov, V V

    2014-01-01

    Endocrine disruptors are exogenous substances that exhibit hormone-like action and consequently disrupt homeostatic action of endogenous hormones. DDT is the most common disruptor. The objective was to evaluate changes in thyroid hormone secretion after long-term exposure to low doses of DDT. The experiment was performed on male Wistar rats. The rats were given DDT at doses of 1.89±0.86 мg/kg/day and 7.77±0.17 мg/kg/day for 6 and 10 weeks. Dose dependent increase of serum total thyroxine, total triiodthyronine, and thyroid peroxidase was revealed after 6 weeks exposure. After 10 weeks free thyroxine secretion was reduced. Such alterations of the thyroid status are typical for iodine deficient goiter. The data obtained indicate that the main mechanism of DDT action includes disruption of thyroxine secretion by thyrocytes, but not inhibition of deiodinase activity and decrease of blood thyroid binding proteins. PMID:25552505

  1. [Alteration of thyroid hormone secretion after long-term exposure to low doses of endocrine disruptor DDT].

    PubMed

    Iaglova, N V; Iaglov, V V

    2014-01-01

    Endocrine disruptors are exogenous substances that exhibit hormone-like action and consequently disrupt homeostatic action of endogenous hormones. DDT is the most common disruptor. The objective was to evaluate changes in thyroid hormone secretion after long-term exposure to low doses of DDT. The experiment was performed on male Wistar rats. The rats were given DDT at doses of 1.89±0.86 мg/kg/day and 7.77±0.17 мg/kg/day for 6 and 10 weeks. Dose dependent increase of serum total thyroxine, total triiodthyronine, and thyroid peroxidase was revealed after 6 weeks exposure. After 10 weeks free thyroxine secretion was reduced. Such alterations of the thyroid status are typical for iodine deficient goiter. The data obtained indicate that the main mechanism of DDT action includes disruption of thyroxine secretion by thyrocytes, but not inhibition of deiodinase activity and decrease of blood thyroid binding proteins.

  2. [Melatonin: a new wonder drug?].

    PubMed

    Wirz-Justice, A

    1996-10-15

    Melatonin, the hormone of the pineal gland is secreted during the night. It provides temporal information on diurnal and seasonal variation to the brain and the body. It is not a "classical" sleeping pill, and it should not be taken as such. The sole sufficiently investigated indication in humans is the treatment of certain sleep disorders from the group of sleep-wake-rhythm disturbances. These manifest themselves by sleep time of the day, i.e. in shift workers, after flights across time zones and in some blind and aged persons. None of the other promises, i.e. that melatonin conserves youth, prolong life, heals cancer or is a free radicals scavenger, have been confirmed by clinical studies. PMID:8966432

  3. [Melatonin: a new wonder drug?].

    PubMed

    Wirz-Justice, A

    1996-10-15

    Melatonin, the hormone of the pineal gland is secreted during the night. It provides temporal information on diurnal and seasonal variation to the brain and the body. It is not a "classical" sleeping pill, and it should not be taken as such. The sole sufficiently investigated indication in humans is the treatment of certain sleep disorders from the group of sleep-wake-rhythm disturbances. These manifest themselves by sleep time of the day, i.e. in shift workers, after flights across time zones and in some blind and aged persons. None of the other promises, i.e. that melatonin conserves youth, prolong life, heals cancer or is a free radicals scavenger, have been confirmed by clinical studies.

  4. Roles of Melatonin in Fetal Programming in Compromised Pregnancies

    PubMed Central

    Chen, Yu-Chieh; Sheen, Jiunn-Ming; Tiao, Miao-Meng; Tain, You-Lin; Huang, Li-Tung

    2013-01-01

    Compromised pregnancies such as those associated with gestational diabetes mellitus, intrauterine growth retardation, preeclampsia, maternal undernutrition, and maternal stress may negatively affect fetal development. Such pregnancies may induce oxidative stress to the fetus and alter fetal development through the epigenetic process that may affect development at a later stage. Melatonin is an oxidant scavenger that reverses oxidative stress during the prenatal period. Moreover, the role of melatonin in epigenetic modifications in the field of developmental programming has been studied extensively. Here, we describe the physiological function of melatonin in pregnancy and discuss the roles of melatonin in fetal programming in compromised pregnancies, focusing on its involvement in redox and epigenetic mechanisms. PMID:23466884

  5. High membrane permeability for melatonin

    PubMed Central

    Yu, Haijie; Dickson, Eamonn J.; Jung, Seung-Ryoung; Koh, Duk-Su

    2016-01-01

    The pineal gland, an endocrine organ in the brain, synthesizes and secretes the circulating night hormone melatonin throughout the night. The literature states that this hormone is secreted by simple diffusion across the pinealocyte plasma membrane, but a direct quantitative measurement of membrane permeability has not been made. Experiments were designed to compare the cell membrane permeability to three indoleamines: melatonin and its precursors N-acetylserotonin (NAS) and serotonin (5-HT). The three experimental approaches were (1) to measure the concentration of effluxing indoleamines amperometrically in the bath while cells were being dialyzed internally by a patch pipette, (2) to measure the rise of intracellular indoleamine fluorescence as the compound was perfused in the bath, and (3) to measure the rate of quenching of intracellular fura-2 dye fluorescence as indoleamines were perfused in the bath. These measures showed that permeabilities of melatonin and NAS are high (both are uncharged molecules), whereas that for 5-HT (mostly charged) is much lower. Comparisons were made with predictions of solubility-diffusion theory and compounds of known permeability, and a diffusion model was made to simulate all of the measurements. In short, extracellular melatonin equilibrates with the cytoplasm in 3.5 s, has a membrane permeability of ∼1.7 µm/s, and could not be retained in secretory vesicles. Thus, it and NAS will be “secreted” from pineal cells by membrane diffusion. Circumstances are suggested when 5-HT and possibly catecholamines may also appear in the extracellular space passively by membrane diffusion. PMID:26712850

  6. Absence of an increase in the duration of the circadian melatonin secretory episode in totally blind human subjects

    NASA Technical Reports Server (NTRS)

    Klerman, E. B.; Zeitzer, J. M.; Duffy, J. F.; Khalsa, S. B.; Czeisler, C. A.

    2001-01-01

    The daily rhythm of melatonin influences multiple physiological measures, including sleep tendency, circadian rhythms, and reproductive function in seasonally breeding mammals. The biological signal for photoperiodic changes in seasonally breeding mammals is a change in the duration of melatonin secretion, which in a natural environment reflects the different durations of daylight across the year, with longer nights leading to a longer duration of melatonin secretion. These seasonal changes in the duration of melatonin secretion do not simply reflect the known acute suppression of melatonin secretion by ocular light exposure, but also represent long-term changes in the endogenous nocturnal melatonin episode that persist in constant conditions. As the eyes of totally blind individuals do not transmit ocular light information, we hypothesized that the duration of the melatonin secretory episode in blind subjects would be longer than those in sighted individuals, who are exposed to light for all their waking hours in an urban environment. We assessed the melatonin secretory profile during constant posture, dim light conditions in 17 blind and 157 sighted adults, all of whom were healthy and using no prescription or nonprescription medications. The duration of melatonin secretion was not significantly different between blind and sighted individuals. Healthy blind individuals after years without ocular light exposure do not have a longer duration of melatonin secretion than healthy sighted individuals.

  7. Melatonin attenuates methamphetamine-induced inhibition of neurogenesis in the adult mouse hippocampus: An in vivo study.

    PubMed

    Singhakumar, Rachen; Boontem, Parichart; Ekthuwapranee, Kasima; Sotthibundhu, Areechun; Mukda, Sujira; Chetsawang, Banthit; Govitrapong, Piyarat

    2015-10-01

    Methamphetamine (METH), a highly addictive psychostimulant drug, is known to exert neurotoxic effects to the dopaminergic neural system. Long-term METH administration impairs brain functions such as cognition, learning and memory. Newly born neurons in the dentate gyrus of the hippocampus play an important role in spatial learning and memory. Previous in vitro studies have shown that METH inhibits cell proliferation and neurogenesis in the hippocampus. On the other hand, melatonin, a major indole secreted by the pineal gland, enhances neurogenesis in both the subventricular zone and dentate gyrus. In this study, adult C57BL/6 mice were used to study the beneficial effects of melatonin on METH-induced alterations in neurogenesis and post-synaptic proteins related to learning and memory functions in the hippocampus. The results showed that METH caused a decrease in neuronal phenotypes as determined by the expressions of nestin, doublecortin (DCX) and beta-III tubulin while causing an increase in glial fibrillary acidic protein (GFAP) expression. Moreover, METH inhibited mitogen-activated protein kinase (MAPK) signaling activity and altered expression of the N-methyl-d-aspartate (NMDA) receptor subunits NR2A and NR2B as well as calcium/calmodulin-dependent protein kinase II (CaMKII). These effects could be attenuated by melatonin pretreatment. In conclusion, melatonin prevented the METH-induced reduction in neurogenesis, increase in astrogliogenesis and alteration of NMDA receptor subunit expression. These findings may indicate the beneficial effects of melatonin on the impairment of learning and memory caused by METH.

  8. Anti-inflammatory effects of melatonin in multiple sclerosis.

    PubMed

    Farez, Mauricio F; Calandri, Ismael L; Correale, Jorge; Quintana, Francisco J

    2016-10-01

    Melatonin is a hormone with complex roles in the pathogenesis of autoimmune disorders. Over the years, it has become clear that melatonin may exacerbate some autoimmune conditions, whereas it alleviates others such as multiple sclerosis. Multiple sclerosis is an autoimmune disorder characterized by a dysregulated immune response directed against the central nervous system. Indeed, the balance between pathogenic CD4(+) T cells secreting IFN-γ (TH 1) or IL-17 (TH 17); and FoxP3(+) regulatory T cells and IL-10(+) type 1 regulatory T cells (Tr1 cells) is thought to play an important role in disease activity. Recent evidence suggests that melatonin ameliorates multiple sclerosis by controlling the balance between effector and regulatory cells, suggesting that melatonin-triggered signaling pathways are potential targets for therapeutic intervention. Here, we review the available data on the effects of melatonin on immune processes relevant for MS and discuss its therapeutic potential. PMID:27561251

  9. A melatonin-independent seasonal timer induces neuroendocrine refractoriness to short day lengths.

    PubMed

    Butler, Matthew P; Turner, Kevin W; Zucker, Irving

    2008-06-01

    The duration of nocturnal pineal melatonin secretion transduces effects of day length (DL) on the neuroendocrine axis of photoperiodic rodents. Long DLs support reproduction, and short DLs induce testicular regression, followed several months later by spontaneous recrudescence; gonadal regrowth is thought to reflect development of tissue refractoriness to melatonin. In most photoperiodic species, pinealectomy does not diminish reproductive competence in long DLs. Turkish hamsters (Mesocricetus brandti) deviate from this norm: elimination of melatonin secretion in long-day males by pinealectomy or constant light treatment induces testicular regression and subsequently recrudescence; the time course of these gonadal transitions is similar to that observed in males transferred from long to short DLs. In the present study, long-day Turkish hamsters that underwent testicular regression and recrudescence in constant light subsequently were completely unresponsive to the antigonadal effects of short DLs. Other hamsters that manifested testicular regression and recrudescence in short DLs were unresponsive to the antigonadal effects of pinealectomy or constant light. Long-term suppression of melatonin secretion induces a physiological state in Turkish hamsters similar or identical to the neuroendocrine refractoriness produced by short-day melatonin signals (i.e., neural refractoriness to melatonin develops in the absence of circulating melatonin secretion). A melatonin-independent interval timer, which would remain operative in the absence of melatonin during hibernation, may determine the onset of testicular recrudescence in the spring. In this respect, Turkish hamsters differ from most other photoperiodic rodents.

  10. Proteins altered by elevated levels of palmitate or glucose implicated in impaired glucose-stimulated insulin secretion

    PubMed Central

    Sol, E-ri M; Hovsepyan, Meri; Bergsten, Peter

    2009-01-01

    Background Development of type 2 diabetes mellitus (T2DM) is characterized by aberrant insulin secretory patterns, where elevated insulin levels at non-stimulatory basal conditions and reduced hormonal levels at stimulatory conditions are major components. To delineate mechanisms responsible for these alterations we cultured INS-1E cells for 48 hours at 20 mM glucose in absence or presence of 0.5 mM palmitate, when stimulatory secretion of insulin was reduced or basal secretion was elevated, respectively. Results After culture, cells were protein profiled by SELDI-TOF-MS and 2D-PAGE. Differentially expressed proteins were discovered and identified by peptide mass fingerprinting. Complimentary protein profiles were obtained by the two approaches with SELDI-TOF-MS being more efficient in separating proteins in the low molecular range and 2D-PAGE in the high molecular range. Identified proteins included alpha glucosidase, calmodulin, gars, glucose-6-phosphate dehydrogenase, heterogenous nuclear ribonucleoprotein A3, lon peptidase, nicotineamide adenine dinucleotide hydrogen (NADH) dehydrogenase, phosphoglycerate kinase, proteasome p45, rab2, pyruvate kinase and t-complex protein. The observed glucose-induced differential protein expression pattern indicates enhanced glucose metabolism, defense against reactive oxygen species, enhanced protein translation, folding and degradation and decreased insulin granular formation and trafficking. Palmitate-induced changes could be related to altered exocytosis. Conclusion The identified altered proteins indicate mechanism important for altered β-cell function in T2DM. PMID:19607692

  11. Ethanol-induced alterations in the posttranslational processing, but not secretion of luteinizing hormone-releasing hormone in vitro.

    PubMed

    Uddin, S; Wilson, T; Emanuele, M A; Williams, D; Kelley, M R; Emanuele, N

    1996-05-01

    The effects of ethanol (EtOH) on the male hypothalamic pituitary reproductive axis are multiple and varied. Although direct gonadal toxicity has been reported, hypothalamic-pituitary perturbations have also been noted. The difficulty of sampling the hypothalamus has made direct investigation of EtOH-induced alterations on luteinizing hormone-releasing hormone (LHRH) fraught with interpretation problems. To circumvent this, we have conducted a series of experiments exploring the effect of 200 mg% EtOH in vitro on GT1-7 cells, a newly developed LHRH secreting neural cell line. Cell lines were treated with EtOH-containing or EtOH-free media for 2, 6, 24, or 48 hr. EtOH caused no significant change in LHRH secretion at any time point, although there was a trend to increased secretion after 2 hr EtOH exposure when compared with control. Significantly increased total (i.e., cellular plus secreted) pro-LHRH coupled with significantly reduced cellular LHRH after 6 hr only of EtOH exposure suggested that EtOH caused a transient decrease in processing from bioinactive pro-LHRH to bioactive LHRH. However, even at this time point, LHRH secretion from these EtOH-exposed cells was no different than from control cells. Steady-state LHRH mRNA levels were not changed by EtOH at any time point. These findings are concordant with previous in vitro data using hypothalamic tissue that has similarly demonstrated no effect of EtOH on LHRH secretion. Taken together with the in vivo demonstration that EtOH reduces hypothalamic-pituitary portal blood levels of LHRH, these data indicate that EtOH exerts its effect either at an extrahypothalamic locus and/or on non-LHRH-producing cells within the hypothalamus.

  12. Astrocyte-Secreted Factors Selectively Alter Neural Stem and Progenitor Cell Proliferation in the Fragile X Mouse

    PubMed Central

    Sourial, Mary; Doering, Laurie C.

    2016-01-01

    An increasing body of evidence indicates that astrocytes contribute to the governance and fine tuning of stem and progenitor cell production during brain development. The effect of astrocyte function in cell production in neurodevelopmental disorders is unknown. We used the Neural Colony Forming Cell assay to determine the effect of astrocyte conditioned media (ACM) on the generation of neurospheres originating from either progenitor cells or functional stem cells in the knock out (KO) Fragile X mouse model. ACM from both normal and Fmr1-KO mice generated higher percentages of smaller neurospheres indicative of restricted proliferation of the progenitor cell population in Fmr1-KO brains. Wild type (WT) neurospheres, but not KO neurospheres, showed enhanced responses to ACM from the Fmr1-KO mice. In particular, Fmr1-KO ACM increased the percentage of large neurospheres generated, representative of spheres produced from neural stem cells. We also used 2D DIGE to initiate identification of the astrocyte-secreted proteins with differential expression between Fmr1-KO and WT cortices and hippocampi. The results further support the critical role of astrocytes in governing neural cell production in brain development and point to significant alterations in neural cell proliferation due to astrocyte secreted factors from the Fragile X brain. Highlights: • We studied the proliferation of neural stem and progenitor cells in Fragile X. • We examined the role of astrocyte-secreted factors in neural precursor cell biology. • Astrocyte-secreted factors with differential expression in Fragile X identified. PMID:27242437

  13. Nocturnal plasma melatonin and alpha-melanocyte stimulating hormone levels during exacerbation of multiple sclerosis.

    PubMed

    Sandyk, R; Awerbuch, G I

    1992-01-01

    The pineal gland has been implicated recently in the pathogenesis of multiple sclerosis (MS). To investigate this hypothesis further, we studied nocturnal plasma melatonin levels and the presence or absence of pineal calcification (PC) on CT scan in a cohort of 25 patients (5 men, 20 women; mean age: 41.1 years; SD = 11.1; range: 27-72) who were admitted to a hospital Neurology service for exacerbation of symptoms. Plasma alpha-melanocyte stimulating hormone (alpha-MSH) estimations were included in the study since there is evidence for a feedback inhibition between alpha-MSH and melatonin secretion. Abnormal melatonin levels were found in 13 patients (52.0%), 11 of whom had nocturnal levels which were below the daytime values (i.e., < 25 pg/ml). Although melatonin levels were unrelated to the patient's age and sex, there was a positive correlation with age of onset of symptoms (p < .0001) and an inverse correlation with the duration of illness (p < .05). PC was noted in 24 of 25 patients (96%) underscoring the pathogenetic relationship between MS and the pineal gland. Alpha-MSH levels were undetectable in 15 patients (60.0%), low in two patients (8.0%), normal in seven patients (28.0%), and elevated in one patient (4.0%). Collectively, abnormal alpha-MSH levels were found in over 70% of patients. These findings support the hypothesis that MS may be associated with pineal failure and suggest, furthermore, that alterations in the secretion of alpha-MSH also occur during exacerbation of symptoms. The relevance of these findings to the pathogenesis of MS are discussed. PMID:1305632

  14. The flavonoid myricetin reduces nocturnal melatonin levels in the blood through the inhibition of serotonin N-acetyltransferase.

    PubMed

    Shin, Jae-Cheon; Jung, Hoe-Yune; Harikishore, Amaravadhi; Kwon, Oh-Deog; Yoon, Ho Sup; Kim, Kyong-Tai; Choi, Bo-Hwa

    2013-10-18

    Melatonin is secreted during the hours of darkness and is thought to influence the circadian and seasonal timing of a variety of physiological processes. AANAT, which is expressed in the pineal gland, retina, and various other tissues, catalyzes the conversion of serotonin to N-acetylserotonin and is the rate-limiting enzyme in the biosynthetic pathway of melatonin. The compounds that modulate the activity of AANAT can be used to treat patients with circadian rhythm disorders that are associated with specific circadian rhythm alterations, such as shift work disorder. In the present study, we screened modulators of AANAT activity from the water extracts of medicinal plants. Among the 267 tested medicinal plant extracts, Myricae Cortex (Myrica rubra), Perillae Herba (Perilla sikokiana), and Eriobotryae Folium (Eriobotrya japonica) showed potent inhibition of AANAT activity. Myricetin (5,7,3',4',5'-pentahydroxyflavonol), a main component of the Myricae Cortex, strongly inhibited the activity of AANAT and probably block the access to the substrate by docking to the catalytic residues that are important for AANAT activity. Myricetin significantly decreased the nocturnal serum melatonin levels in rats. In addition, the locomotor activity of rats treated with myricetin decreased during the nighttime and slightly increased throughout the day. These results suggest that myricetin could be used as a therapy to increase nighttime alertness by changing the circadian rhythm of serum melatonin and locomotor activity.

  15. Influence of altered CSF solute composition on parotid salivary secretion in goats.

    PubMed

    Olsson, K

    1976-06-01

    Infusions of hypertonic NaCl solution into the CSF of the lateral cerebral ventricle of the goat caused a marked reduction in parotid salivary flow concomitant with a rise in salivary [Na+]. Corresponding infusions of iso- or hypertonic glucose and glycerol solutions affected salivary secretion in the opposite direction. The possibility is discussed that a periventricular sodium-sensitive mechanism, which is of importance in the central control of fluid balance, also may participate in the regulation of parotid secretion in the goat. This interpretation of the results is to some extent obscured by the observation of a high incidence of intermittent rumination during the intraventricular infusions of glucose and glycerol solution.

  16. Melatonin for sleep problems in children with neurodevelopmental disorders.

    PubMed

    2015-10-01

    Children with neurodevelopmental disorders are at risk of sleep problems, typically difficulty getting to sleep, sleep/wake rhythm disturbances and reduced duration of sleep (insomnia). This may be associated with abnormally timed or inadequate secretion of melatonin, a naturally-occurring hormone involved in coordinating the body's sleep-wake cycle. Previously, we reviewed the use of a melatonin product licensed for primary insomnia in adults aged over 55 years. Here we review off-label and unlicensed use of melatonin in children with attention-deficit hyperactivity disorder (ADHD) or autism spectrum disorder or related neurodevelopmental disorders. PMID:26471270

  17. Role of melatonin in upper gastrointestinal tract.

    PubMed

    Konturek, S J; Konturek, P C; Brzozowski, T; Bubenik, G A

    2007-12-01

    Melatonin, an indole formed enzymatically from L-tryptophan, is the most versatile and ubiquitous hormone molecule produced not only in all animals but also in some plants. This review focuses on the role of melatonin in upper portion of gastrointestinal tract (GIT), including oral cavity, esophagus, stomach and duodenum, where this indole is generated and released into the GIT lumen and into the portal circulation to be uptaken, metabolized by liver and released with bile into the duodenum. The biosynthetic steps of melatonin with two major rate limiting enzymes, arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT), transforming tryptophan to melatonin, originally identified in pinealocytes have been also detected in entero-endocrine (EE) cells of GIT wall, where this indole may act via endocrine, paracrine and/or luminal pathway through G-protein coupled receptors. Melatonin in GIT was shown to be generated in about 500 times larger amounts than it is produced in pineal gland. The production of melatonin by pineal gland shows circadian rhythm with high night-time peak, especially at younger age, followed by the fall during the day-light time. As a highly lipophilic substance, melatonin reaches all body cells within minutes, to serve as a convenient circadian timing signal for alteration of numerous body functions.. Following pinealectomy, the light/dark cycle of plasma melatonin levels disappears, while its day-time blood concentrations are attenuated but sustained mainly due to its release from the GIT. After oral application of tryptophan, the plasma melatonin increases in dose-dependent manner both in intact and pinealectomized animals, indicating that extrapineal sources such as GIT rather than pineal gland are the major producers of this indole. In the upper portion of GIT, melatonin exhibits a wide spectrum of activities such as circadian entrainment, free radicals scavenging activity, protection of mucosa against

  18. Use of anesthesia dramatically alters the oral glucose tolerance and insulin secretion in C57Bl/6 mice.

    PubMed

    Windeløv, Johanne A; Pedersen, Jens; Holst, Jens J

    2016-06-01

    Evaluation of the impact of anesthesia on oral glucose tolerance in mice. Anesthesia is often used when performing OGTT in mice to avoid the stress of gavage and blood sampling, although anesthesia may influence gastrointestinal motility, blood glucose, and plasma insulin dynamics. C57Bl/6 mice were anesthetized using the following commonly used regimens: (1) hypnorm/midazolam repetitive or single injection; (2) ketamine/xylazine; (3) isoflurane; (4) pentobarbital; and (5) A saline injected, nonanesthetized group. Oral glucose was administered at time 0 min and blood glucose measured in the time frame -15 to +150 min. Plasma insulin concentration was measured at time 0 and 20 min. All four anesthetic regimens resulted in impaired glucose tolerance compared to saline/no anesthesia. (1) hypnorm/midazolam increased insulin concentrations and caused an altered glucose tolerance; (2) ketamine/xylazine lowered insulin responses and resulted in severe hyperglycemia throughout the experiment; (3) isoflurane did not only alter the insulin secretion but also resulted in severe hyperglycemia; (4) pentobarbital resulted in both increased insulin secretion and impaired glucose tolerance. All four anesthetic regimens altered the oral glucose tolerance, and we conclude that anesthesia should not be used when performing metabolic studies in mice. PMID:27255361

  19. Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma: its synthesis is reduced favoring cholangiocarcinoma growth.

    PubMed

    Han, Yuyan; Demorrow, Sharon; Invernizzi, Pietro; Jing, Qing; Glaser, Shannon; Renzi, Anastasia; Meng, Fanyin; Venter, Julie; Bernuzzi, Francesca; White, Mellanie; Francis, Heather; Lleo, Ana; Marzioni, Marco; Onori, Paolo; Alvaro, Domenico; Torzilli, Guido; Gaudio, Eugenio; Alpini, Gianfranco

    2011-10-01

    Cholangiocarcinoma (CCA) is a devastating biliary cancer. Melatonin is synthesized in the pineal gland and peripheral organs from serotonin by two enzymes, serotonin N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT). Cholangiocytes secrete neuroendocrine factors, including serotonin-regulating CCA growth by autocrine mechanisms. Melatonin exerts its effects by interaction with melatonin receptor type 1A/1B (MT1/MT2) receptors. We propose that 1) in CCA, there is decreased expression of AANAT and ASMT and secretion of melatonin, changes that stimulate CCA growth; and 2) in vitro overexpression of AANAT decreases CCA growth. We evaluated the 1) expression of AANAT, ASMT, melatonin, and MT1/MT2 in human nonmalignant and CCA lines and control and CCA biopsy samples; 2) melatonin levels in nonmalignant and CCA lines, and bile and serum from controls and patients with intrahepatic CCA; 3) effect of melatonin on the growth and expression of AANAT/ASMT and MT1/MT2 in CCA lines implanted into nude mice; and 4) effect of AANAT overexpression on the proliferation, apoptosis, and expression of MT1/MT2 in Mz-ChA-1 cells. The expression of AANAT, ASMT, and melatonin decreased, whereas MT1/MT2 expression increased in CCA lines and biopsy samples. Melatonin secretion decreased in the supernatant of CCA lines and bile of CCA patients. Melatonin decreased xenograft CCA tumor growth in nude mice by increased AANAT/ASMT and melatonin, along with reduced MT1/MT2 expression. Overexpression of AANAT in Mz-ChA-1 cells inhibited proliferation and MT1/MT2 expression and increased apoptosis. There is dysregulation of the AANAT/ASMT/melatoninmelatonin receptor axis in CCA, which inhibited melatonin secretion and subsequently enhanced CCA growth.

  20. Melatonin and pituitary-gonadal function in disorders of eating behavior.

    PubMed

    Ferrari, E; Foppa, S; Bossolo, P A; Comis, S; Esposti, G; Licini, V; Fraschini, F; Brambilla, F

    1989-01-01

    In order to study the possible relationships between melatonin secretion and pituitary-gonadal function, the circadian rhythm of plasma melatonin, the basal levels of estradiol-17beta and testosterone and the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response to luteinizing hormone-releasing hormone (LH-RH) stimulation were evaluated in normally cycling healthy women and in two groups of women with menstrual dysfunctions related to eating disorders (19 patients with anorexia nervosa and 16 with primary obesity). The circadian rhythm of plasma melatonin reached statistical significance in anorectic patients but not in obese patients. The mean 24 h melatonin level was significantly higher in anorectic than in obese patients and in control subjects. However, both groups of patients shared some abnormalities of melatonin circadian pattern, such as increased ratio between day and night melatonin levels, abnormal secretory peaks during the light hours and great interindividual variability for timing, amplitude, and duration of melatonin nocturnal peak. A selective impairment of LH secretion was observed in both anorectic and obese patients. By considering together the two groups of patients and controls, a linear inverse correlation between the circadian mesor of plasma melatonin and the basal and LH-RH stimulated LH levels was found. The persistence of a certain melatonin secretion during the light hours in both anorectic and obese patients could play an inhibitory role on the pituitary gonadal function in these subjects.

  1. Melatonin has multiorgan effects.

    PubMed

    Opie, Lionel H; Lecour, Sandrine

    2016-10-01

    Melatonin, widely used to counter transatlantic travel jet lag and insomnia, is synthesized in the suprachiasmatic nucleus of the anterior pituitary gland. Its release into the circulation is stimulated by the onset of darkness, followed by a progressive decrease in blood levels with the onset of dawn. Melatonin administration can maintain the quality of sleep and help to counteract age-induced cognitive decline. Melatonin can also limit the severity of a variety of cardiovascular and cerebrovascular diseases, diabetes, and cancer. PMID:27533945

  2. Melatonin, But not auxin, affects postnatal reproductive development in the marsh rice rat (Oryzomys palustris).

    PubMed

    Edmonds, Kent E

    2013-06-01

    Melatonin and the plant hormone auxin (indole-3-acetic acid) have some structural similarity and, may thus exert comparable physiological effects on reproduction and growth. To test this possibility, I examined the effects of melatonin and auxin administration on reproductive and non-reproductive organ development in an animal model, the marsh rice rat Oryzomys palustris. Juvenile males housed under 14L:10D conditions were injected daily for four weeks with saline, melatonin, auxin, or melatonin and auxin, and the development of the testes and other organs was assessed. Melatonin alone significantly inhibited the development of the testes, seminal vesicles, Harderian glands, and overall somatic growth, but not the spleen. Auxin did not affect any endpoint measured. When melatonin was administered simultaneously with auxin, the melatonin effects dominated in suppressing reproduction and growth. The administration of melatonin or auxin in the drinking water produced results similar to the effects of melatonin and auxin injections reported herein. Lastly, both melatonin and auxin in the drinking water failed to alter any short photoperiod-induced reproductive inhibition. These data suggest that structural similarities between melatonin and auxin do not result in similar postnatal effects on reproductive and non-reproductive organ development on a long photoperiod and further suggest that melatonin and auxin do not operate through a common physiological mechanism.

  3. Evidence of melatonin synthesis in the ram reproductive tract.

    PubMed

    Gonzalez-Arto, M; Hamilton, T R dos S; Gallego, M; Gaspar-Torrubia, E; Aguilar, D; Serrano-Blesa, E; Abecia, J A; Pérez-Pé, R; Muiño-Blanco, T; Cebrián-Pérez, J A; Casao, A

    2016-01-01

    Melatonin is a ubiquitous molecule found in a wide range of fluids, one of them being ram seminal plasma, in which it can reach higher concentrations than those found in blood, suggesting an extrapineal secretion by the reproductive tract. In order to identify the source of the melatonin found in ram seminal plasma, we first tried to determine whether the melatonin levels were maintained during the day. For this purpose, melatonin concentrations were measured in seminal plasma obtained from first ejaculates of six rams at 6:00 a.m. in total darkness, at 10:00 a.m. and at 14:00 p.m. The melatonin concentration was higher (p < 0.05) in ejaculates collected at 6:00 a.m. than at 10:00 and 14:00. There was no statistical difference between the latter. To further corroborate an extrapineal secretion of melatonin, the presence of the two key enzymes involved in melatonin synthesis, arylalkylamine-N-acetyltransferase (AANAT) and N-acetylserotonin-O-methyltransferase (ASMT) was analyzed by RT-PCR, q-PCR and Western-blot in ram testes, epididymis, and accessory glands. The RT-PCR showed the presence of the m-RNA codifying both AANAT and ASTM in all the tissues under study, but the q-PCR and Western-blot revealed that gene expression of these enzymes was significantly higher in the testis (p < 0.05). Immunohistochemistry confirmed the presence of AANAT and ASMT in the testis and revealed that they were found in the Leydig cells, spermatocytes, and spermatids. Also, measurable levels of melatonin were found in testicular tissue and the tail of the epididymis. In conclusion, our study indicates that the testes are one of the likely sources of the high levels of melatonin found in ram seminal plasma, at least during the day. PMID:26742835

  4. Evidence of melatonin synthesis in the ram reproductive tract.

    PubMed

    Gonzalez-Arto, M; Hamilton, T R dos S; Gallego, M; Gaspar-Torrubia, E; Aguilar, D; Serrano-Blesa, E; Abecia, J A; Pérez-Pé, R; Muiño-Blanco, T; Cebrián-Pérez, J A; Casao, A

    2016-01-01

    Melatonin is a ubiquitous molecule found in a wide range of fluids, one of them being ram seminal plasma, in which it can reach higher concentrations than those found in blood, suggesting an extrapineal secretion by the reproductive tract. In order to identify the source of the melatonin found in ram seminal plasma, we first tried to determine whether the melatonin levels were maintained during the day. For this purpose, melatonin concentrations were measured in seminal plasma obtained from first ejaculates of six rams at 6:00 a.m. in total darkness, at 10:00 a.m. and at 14:00 p.m. The melatonin concentration was higher (p < 0.05) in ejaculates collected at 6:00 a.m. than at 10:00 and 14:00. There was no statistical difference between the latter. To further corroborate an extrapineal secretion of melatonin, the presence of the two key enzymes involved in melatonin synthesis, arylalkylamine-N-acetyltransferase (AANAT) and N-acetylserotonin-O-methyltransferase (ASMT) was analyzed by RT-PCR, q-PCR and Western-blot in ram testes, epididymis, and accessory glands. The RT-PCR showed the presence of the m-RNA codifying both AANAT and ASTM in all the tissues under study, but the q-PCR and Western-blot revealed that gene expression of these enzymes was significantly higher in the testis (p < 0.05). Immunohistochemistry confirmed the presence of AANAT and ASMT in the testis and revealed that they were found in the Leydig cells, spermatocytes, and spermatids. Also, measurable levels of melatonin were found in testicular tissue and the tail of the epididymis. In conclusion, our study indicates that the testes are one of the likely sources of the high levels of melatonin found in ram seminal plasma, at least during the day.

  5. Melatonin-induced protein synthesis in the rat parotid gland.

    PubMed

    Cevik-Aras, H; Godoy, T; Ekstrom, J

    2011-02-01

    Melatonin occurs in large amounts in the intestinal mucosa and is released during a meal. Recent studies of ours reveal that exogenous melatonin evokes the in vivo secretion of protein and amylase from the rat parotid gland. The aim of the present study was to investigate the effect of melatonin on the protein synthesis of the parotid gland of pentobarbitone-anaesthetised rats as estimated by the rate of incorporation of [³H]leucine into trichloroacetic acid-insoluble material of the gland. Compared with the parotid protein synthesis (set at 100%) of those rats exposed to an intravenous infusion of melatonin (25 mg/kg during 1 hour), under muscarinic and α- and β-adrenoceptor blockade, the synthesis in the corresponding glands of saline-treated control rats was less (by 25%). The synthesis was also less when the melatonin administration was combined with the melatonin 2-preferring receptor antagonist luzindole (24%), the non-selective nitric oxide synthase inhibitor L-NAME (18%) and the neuronal nitric oxide synthase inhibitor N-PLA (21%). Almost all the melatonin receptor-mediated effect was due to nitric oxide generation via the activity of neuronal type nitric oxide synthase. The present findings lend further weight to the idea that salivary glandular activity associated with food intake is hormonally influenced and they also suggest clinical implications for melatonin in the treatment of xerostomia. Since melatonin is known to exert anti-inflammatory actions in the oral cavity, the stimulatory effect of melatonin may include the synthesis of proteins of importance for the oral defence.

  6. Melatonin and farm animals: endogenous rhythms and exogenous applications.

    PubMed

    Paterson, A M; Foldes, A

    1994-05-01

    Studies on farm animals have contributed significantly to our increased understanding of basic melatonin-related physiological mechanisms, as well as to the regulation of reproduction and pelage in individual domestic species. This review concentrates on recent work on the role of melatonin in the regulation of porcine reproduction, cervine endocrine, and behavioral cycles and wool and cashmere production which has added to this knowledge base. Early studies of the domestic pig indicated that melatonin secretion in this species differed markedly from that in other domestic and laboratory animals. There is now clear evidence that this is not the case and that the domestic pig uses a circadian rhythm of melatonin release for the transduction of photoperiodic information. Apparent inconsistencies among reports may be due, in part, to differences in the conditions under which the experiments were performed and to the assay systems employed to measure circulating melatonin, the concentrations of which are much lower than in other domestic species. Appropriately administered exogenous melatonin advances the onset of puberty in gilts, and may prove to be effective in overcoming seasonal infertility in female pigs. Appropriately timed melatonin and/or photoperiod treatments, administered to ruminants in utero, influence the reproductive physiology of the offspring, indicating that even in species which don't develop an endogenous melatonin rhythm till some weeks postnatally, awareness of photoenvironment, presumably via maternal melatonin, predates birth. Pre- or early postnatal melatonin-related treatments also influence the development/cycle frequency of pelage. Areas requiring further investigation include the hormonal/growth factors involved, reasons for the transient nature of the effects in sheep and goats, and the reason for similar effects on pelage of augmenting or inactivating melatonin. Aspects of endogenous melatonin rhythms in farm species which require

  7. TNF-α alters the inflammatory secretion profile of human first trimester placenta.

    PubMed

    Siwetz, Monika; Blaschitz, Astrid; El-Heliebi, Amin; Hiden, Ursula; Desoye, Gernot; Huppertz, Berthold; Gauster, Martin

    2016-04-01

    Implantation and subsequent placental development depend on a well-orchestrated interaction between fetal and maternal tissues, involving a fine balanced synergistic cross-talk of inflammatory and immune-modulating factors. Tumor necrosis factor (TNF)-α has been increasingly recognized as pivotal factor for successful pregnancy, although high maternal TNF-α levels are associated with a number of adverse pregnancy conditions including gestational hypertension and gestational diabetes mellitus. This study describes effects of exogenously applied TNF-α, mimicking increased maternal TNF-α levels, on the secretion profile of inflammation associated factors in human first trimester villous placenta. Conditioned culture media from first trimester villous placental explants were analyzed by inflammation antibody arrays and ELISA after 48 h culture in the presence or absence of TNF-α. Inflammation antibody arrays identified interleukin (IL)-6, IL-8, chemokine (C-C motif) ligand 2 (CCL2), CCL4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most abundantly secreted inflammation-associated factors under basal culture conditions. In the presence of TNF-α, secretion of GM-CSF, CCL5, and IL-10 increased, whereas IL-4 and macrophage CSF levels decreased compared with controls. ELISA analysis verified antibody arrays by showing significantly increased synthesis and release of GM-CSF and CCL5 by placental explants in response to TNF-α. Immunohistochemistry localized GM-CSF in the villous trophoblast compartment, whereas CCL5 was detected in maternal platelets adhering to perivillous fibrin deposits on the villous surface. mRNA-based in situ padlock probe approach localized GM-CSF and CCL5 transcripts in the villous trophoblast layer and the villous stroma. Results from this study suggest that the inflammatory secretion profile of human first trimester placenta shifts towards increased levels of GM-CSF, CCL5, and IL10 in response to elevated maternal

  8. Melatonin modulates the fetal cardiovascular defense response to acute hypoxia.

    PubMed

    Thakor, Avnesh S; Allison, Beth J; Niu, Youguo; Botting, Kimberley J; Serón-Ferré, Maria; Herrera, Emilio A; Giussani, Dino A

    2015-08-01

    Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability.

  9. Differential gene expression profile and altered cytokine secretion of thyroid cancer cells in space.

    PubMed

    Ma, Xiao; Pietsch, Jessica; Wehland, Markus; Schulz, Herbert; Saar, Katrin; Hübner, Norbert; Bauer, Johann; Braun, Markus; Schwarzwälder, Achim; Segerer, Jürgen; Birlem, Maria; Horn, Astrid; Hemmersbach, Ruth; Waßer, Kai; Grosse, Jirka; Infanger, Manfred; Grimm, Daniela

    2014-02-01

    This study focuses on the effects of short-term [22 s, parabolic flight campaign (PFC)] and long-term (10 d, Shenzhou 8 space mission) real microgravity on changes in cytokine secretion and gene expression patterns in poorly differentiated thyroid cancer cells. FTC-133 cells were cultured in space and on a random positioning machine (RPM) for 10 d, to evaluate differences between real and simulated microgravity. Multianalyte profiling was used to evaluate 128 secreted cytokines. Microarray analysis revealed 63 significantly regulated transcripts after 22 s of microgravity during a PFC and 2881 after 10 d on the RPM or in space. Genes in several biological processes, including apoptosis (n=182), cytoskeleton (n=80), adhesion/extracellular matrix (n=98), proliferation (n=184), stress response (n=268), migration (n=63), angiogenesis (n=39), and signal transduction (n=429), were differentially expressed. Genes and proteins involved in the regulation of cancer cell proliferation and metastasis, such as IL6, IL8, IL15, OPN, VEGFA, VEGFD, FGF17, MMP2, MMP3, TIMP1, PRKAA, and PRKACA, were similarly regulated under RPM and spaceflight conditions. The resulting effect was mostly antiproliferative. Gene expression during the PFC was often regulated in the opposite direction. In summary, microgravity is an invaluable tool for exploring new targets in anticancer therapy and can be simulated in some aspects in ground-based facilities.

  10. Systemic alteration of cell-surface and secreted glycoprotein expression in malignant breast cancer cell lines.

    PubMed

    Timpe, Leslie C; Yen, Roger; Haste, Nicole V; Litsakos-Cheung, Christina; Yen, Ten-Yang; Macher, Bruce A

    2013-11-01

    Breast cancer cell lines express fewer transmembrane and secreted glycoproteins than nonmalignant ones. The objective of these experiments was to characterize the changes in the expression of several hundred glycoproteins quantitatively. Secreted and cell-surface glycoproteins were isolated using a glycoprotein capture protocol and then identified by tandem mass spectrometry. Glycoproteins expressed by a group of cell lines originating from malignant tumors of the breast were compared with those expressed by a nonmalignant set. The average number of spectral counts (proportional to relative protein abundance) and the total number of glycopeptides in the malignant samples were reduced to about two-thirds of the level in the nonmalignant samples. Most glycoproteins were expressed at a different level in the malignant samples, with nearly as many increasing as decreasing. The glycoproteins with reduced expression accounted for a larger change in spectral counts, and hence for the net loss of spectral counts in the malignant lines. Similar results were found when the glycoproteins were studied via identified glycosylation sites only, or through identified sites together with non-glycopeptides. The overall reduction is largely due to the loss of integrins, laminins and other proteins that form or interact with the basement membrane.

  11. Melatonin: a multitasking molecule.

    PubMed

    Reiter, Russel J; Tan, Dun-Xian; Fuentes-Broto, Lorena

    2010-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) has revealed itself as an ubiquitously distributed and functionally diverse molecule. The mechanisms that control its synthesis within the pineal gland have been well characterized and the retinal and biological clock processes that modulate the circadian production of melatonin in the pineal gland are rapidly being unravelled. A feature that characterizes melatonin is the variety of mechanisms it employs to modulate the physiology and molecular biology of cells. While many of these actions are mediated by well-characterized, G-protein coupled melatonin receptors in cellular membranes, other actions of the indole seem to involve its interaction with orphan nuclear receptors and with molecules, for example calmodulin, in the cytosol. Additionally, by virtue of its ability to detoxify free radicals and related oxygen derivatives, melatonin influences the molecular physiology of cells via receptor-independent means. These uncommonly complex processes often make it difficult to determine specifically how melatonin functions to exert its obvious actions. What is apparent, however, is that the actions of melatonin contribute to improved cellular and organismal physiology. In view of this and its virtual absence of toxicity, melatonin may well find applications in both human and veterinary medicine.

  12. Expression of melatonin (MT1, MT2) and melatonin-related receptors in the adult rat testes and during development.

    PubMed

    Izzo, Gaia; Francesco, Aniello; Ferrara, Diana; Campitiello, Maria Rosaria; Serino, Ismene; Minucci, Sergio; d'Istria, Michela

    2010-08-01

    It is well known that melatonin provokes reproductive alterations in response to changes in hours of daylight in seasonally breeding mammals, exerting a regulatory role at different levels of the hypothalamic-pituitary-gonadal axis. Although it has also been demonstrated that melatonin may affect testicular activity in vertebrates, until now, very few data support the hypothesis of a local action of melatonin in the male gonads. The aim of this study was to investigate whether MT1, MT2 melatonin receptors and the H9 melatonin-related receptor, are expressed in the adult rat testes and during development. A semi-quantitative RT-PCR method was used to analyse the expression of MT1, MT2 and H9 receptors mRNAs in several rat tissues, mainly focusing on testes during development and adult life. Our results provide molecular evidences of the presence of both MT1 and, for the first time, MT2 melatonin receptors as well as of the H9 melatonin-related receptor in the examined tissues, including adult testes. During development MT1 and MT2 transcripts are expressed at lower levels in testes of rats from 1 day to 1 week of age, lightly increased at 2 weeks of age and remained permanently expressed throughout development until 6 months. These data strongly support the hypothesis that melatonin acts directly in male vertebrate gonads suggesting that rat testes may be a suitable model to verify the role of indolamine in vertebrate testicular activity.

  13. Biological rhythms and melatonin in mood disorders and their treatments.

    PubMed

    Lanfumey, Laurence; Mongeau, Raymond; Hamon, Michel

    2013-05-01

    Affective disorders such as major depression, bipolar disorders and seasonal affective disorders have been described as alterations of various neuronal systems. In addition to the classical monoaminergic hypotheses that have been long proposed to explain the pathophysiology of these disorders, a strong association between circadian rhythms and mood regulation has been suggested in the light of several clinical and preclinical findings. In this review, we summarize the different hypotheses on pathophysiology mechanisms underlying depressive disorders and put a special emphasis on the alterations of melatonin secretion and associated changes in biological rhythms that characterize mood disorders. Causal relationships between alterations in circadian rhythms and mood disorders are strongly supported by the antidepressant efficacy of innovative pharmacological treatments aimed at resynchronizing endogenous rhythms in depressed patients. Genetic, epigenetic and environmental factors generating desynchronization between endogenous biological rhythms and exogenous rhythms driven by environmental and societal constraints are very probably involved in the vulnerability to mood disorders. Further investigations of the molecular/cellular bases of the relationships between stress axis dysfunctions, endogenous biological rhythm dysregulations and associated functional and anatomical brain alterations should allow important progress in the knowledge of pathophysiological mechanisms of affective disorders and the downstream development of innovative, more effective and better tolerated, therapies.

  14. Melatonin and Ischemic Stroke: Mechanistic Roles and Action

    PubMed Central

    Andrabi, Syed Suhail; Parvez, Suhel; Tabassum, Heena

    2015-01-01

    Stroke is one of the most devastating neurological disabilities and brain's vulnerability towards it proves to be fatal and socio-economic loss of millions of people worldwide. Ischemic stroke remains at the center stage of it, because of its prevalence amongst the several other types attacking the brain. The various cascades of events that have been associated with stroke involve oxidative stress, excitotoxicity, mitochondrial dysfunction, upregulation of Ca2+ level, and so forth. Melatonin is a neurohormone secreted by pineal and extra pineal tissues responsible for various physiological processes like sleep and mood behaviour. Melatonin has been implicated in various neurological diseases because of its antioxidative, antiapoptotic, and anti-inflammatory properties. We have previously reviewed the neuroprotective effect of melatonin in various models of brain injury like traumatic brain injury and spinal cord injury. In this review, we have put together the various causes and consequence of stroke and protective role of melatonin in ischemic stroke. PMID:26435711

  15. Melatonin-synthesizing enzymes and melatonin receptor in rat thyroid cells.

    PubMed

    García-Marín, Rocío; de Miguel, Manuel; Fernández-Santos, José María; Carrillo-Vico, Antonio; Utrilla, José Carmelo; Morillo-Bernal, Jesús; Díaz-Parrado, Eduardo; Rodríguez-Prieto, Ismael; Guerrero, Juan Miguel; Martín-Lacave, Inés

    2012-11-01

    Melatonin is an indoleamine with a wide spectrum of biological activities other than transmitting photoperiod information, including antioxidant, oncostatic, anti-aging and immunomodulatory properties. Although melatonin is synthesized mainly in the pineal gland, other tissues have the same capacity. In the present study, we examined whether two key enzymes in melatonin biosynthesis, arylalkylamine Nacetyltransferase (AANAT) and hydroxyindole-O-methyltransferase (HIOMT) and its receptor MT₁ are expressed in the two endocrine thyroid cells of the rat, follicular cells and C cells. Reverse transcriptase polymerase chain reaction analyses demonstrated that both AANAT and HIOMT mRNAs are expressed in the rat thyroid C-cells, and MT₁ expression has been detected in C cells and follicular cells. Immunofluorescence revealed that AANAT protein is localized in C-cell cytoplasm, and MT₁ protein in both cell populations. These findings demonstrate that the rat thyroid expresses AANAT, HIOMT, and its receptor MT₁, showing that C cells are the main melatonin-synthesizing sites in the thyroid. This local C-cell-secreted melatonin may protect follicular cells from the oxidative stress inherent to the thyroid gland, and could also have paracrine and autocrine functions.

  16. Meal induced gut hormone secretion is altered in aerobically trained compared to sedentary young healthy males.

    PubMed

    Lund, Michael Taulo; Taudorf, Lærke; Hartmann, Bolette; Helge, Jørn Wulff; Holst, Jens Juel; Dela, Flemming

    2013-11-01

    Postprandial insulin release is lower in healthy aerobically trained (T) compared to untrained (UT) individuals. This may be mediated by a lower release of the two incretin hormones [glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] in T. The aim of this study was to assess and compare gut hormone response and satiety changes after a liquid meal intake in young, healthy T and UT males. Postprandial gut hormone release and subjective feelings of hunger, satiety, fullness and prospective food consumption were assessed before and frequently for the following 3 h after a 200 ml liquid meal (1,260 kJ and 27, 41 and 32 energy % as protein, carbohydrates and fat, respectively) in ten T and ten UT young, healthy male subjects. The insulin and GIP responses were markedly lower in T than UT and correlated during the first 30 min after the liquid meal. Baseline GLP-1 concentration was higher in T versus UT, but the response in the following 3 h after a liquid meal was similar in T and UT. Satiety measures did not differ between groups throughout the test. It is possible that in aerobically T subjects, a lower GIP release is partly responsible for a lower postprandial incretin stimulated insulin secretion.

  17. Antiangiogenic effects of melatonin in endothelial cell cultures.

    PubMed

    Alvarez-García, Virginia; González, Alicia; Alonso-González, Carolina; Martínez-Campa, Carlos; Cos, Samuel

    2013-05-01

    Endothelial cells represent one of the critical cellular elements in tumor microenvironment playing a crucial role in the growth and progression of cancer through controlling angiogenesis. Vascular endothelial growth factor (VEGF) produced from tumor cells is essential for the expansion of breast cancer and may function in both paracrine and autocrine manners to promote proliferation, growth, survival and migration of endothelial cells. Since melatonin regulates tumor microenvironment by decreasing the secretion of VEGF by malignant epithelial cells and also regulates VEGF expression in human breast cancer cells, the aim of the present study was to investigate the anti-angiogenic activity of melatonin against the pro-angiogenic effects of breast cancer cells. In this work, we demonstrate that melatonin strongly inhibited the proliferation as well as invasion/migration of human umbilical vein endothelial cells (HUVECs). Melatonin disrupted tube formation and counteracted the VEGF-stimulated tubular network formation by HUVEC. In addition, conditioned media collected from human breast cancer cells were angiogenically active and stimulated tubule length formation and this effect was significantly counteracted by the addition of anti-VEGF or melatonin. Melatonin also disintegrated preformed capillary network. All these findings demonstrate that melatonin may play a role in the paracrine interactions that take place between malignant epithelial cells and proximal endothelial cells. Melatonin could be important in reducing endothelial cell proliferation, invasion, migration and tube formation, through a downregulatory action on VEGF. Taken together, our findings suggest that melatonin could potentially be beneficial as an antiangiogenic agent in breast cancer with possible future clinical applications. PMID:23473980

  18. Melatonin and Oral Cavity

    PubMed Central

    Cengiz, Murat İnanç; Cengiz, Seda; Wang, Hom-Lay

    2012-01-01

    While initially the oral cavity was considered to be mainly a source of various bacteria, their toxins and antigens, recent studies showed that it may also be a location of oxidative stress and periodontal inflammation. Accordingly, this paper focuses on the involvement of melatonin in oxidative stress diseases of oral cavity as well as on potential therapeutic implications of melatonin in dental disorders. Melatonin has immunomodulatory and antioxidant activities, stimulates the proliferation of collagen and osseous tissue, and acts as a protector against cellular degeneration associated with aging and toxin exposure. Arising out of its antioxidant actions, melatonin protects against inflammatory processes and cellular damage caused by the toxic derivates of oxygen. As a result of these actions, melatonin may be useful as a coadjuvant in the treatment of certain conditions of the oral cavity. However, the most important effect of melatonin seems to result from its potent antioxidant, immunomodulatory, protective, and anticancer properties. Thus, melatonin could be used therapeutically for instance, locally, in the oral cavity damage of mechanical, bacterial, fungal, or viral origin, in postsurgical wounds caused by tooth extractions and other oral surgeries. Additionally, it can help bone formation in various autoimmunological disorders such as Sjorgen syndrome, in periodontal diseases, in toxic effects of dental materials, in dental implants, and in oral cancers. PMID:22792106

  19. Melatonin, the Hormone of Darkness: From Sleep Promotion to Ebola Treatment

    PubMed Central

    Masters, Alina; Pandi-Perumal, Seithikurippu R; Seixas, Azizi; Girardin, Jean-Louis; McFarlane, Samy I.

    2015-01-01

    Melatonin is a hormone secreted by the enigmatic pineal gland in response to darkness, hence the name hormone of darkness. It has generated a great deal of interest as a therapeutic modality for various diseases particularly sleep disorders. This pleiotropic molecule has anti-inflammatory, antioxidant and anticoagulopathic properties in addition to its endothelial protective effects. In this article we discuss melatonin secretion and mechanisms of action as well as therapeutic rationale. We also highlight the potential utility of melatonin in the deadly modern-day Ebola epidemic. PMID:25705578

  20. Hypernatremia-induced vasopressin secretion is not altered in TRPV1-/- rats.

    PubMed

    Tucker, Andrew Blake; Stocker, Sean D

    2016-09-01

    Changes in osmolality or extracellular NaCl concentrations are detected by specialized neurons in the hypothalamus to increase vasopressin (VP) and stimulate thirst. Recent in vitro evidence suggests this process is mediated by an NH2-terminal variant of the transient receptor potential vanilloid type 1 (TRPV1) channel expressed by osmosensitive neurons of the lamina terminalis and vasopressinergic neurons of the supraoptic nucleus. The present study tested this hypothesis in vivo by analysis of plasma VP levels during acute hypernatremia in awake control and TRPV1(-/-) rats. TRPV1(-/-) rats were produced by a Zinc-finger-nuclease 2-bp deletion in exon 13. Intravenous injection of the TRPV1 agonist capsaicin produced hypotension and bradycardia in control rats, but this response was absent in TRPV1(-/-) rats. Infusion of 2 M NaCl (1 ml/h iv) increased plasma osmolality, electrolytes, and VP levels in both control and TRPV1(-/-) rats. However, plasma VP levels did not differ between strains at any time. Furthermore, a linear regression between plasma VP versus osmolality revealed a significant correlation in both control and TRPV1(-/-) rats, but the slope of the regression lines was not attenuated in TRPV1(-/-) versus control rats. Hypotension produced by intravenous injection of minoxidil decreased blood pressure and increased plasma VP levels similarly in both groups. Finally, both treatments stimulated thirst; however, cumulative water intakes in response to hypernatremia or hypotension were not different between control and TRPV1(-/-) rats. These findings suggest that TRPV1 channels are not necessary for VP secretion and thirst stimulated by hypernatremia. PMID:27335281

  1. Effect of L-NAME-induced hypertension on melatonin receptors and melatonin levels in the pineal gland and the peripheral organs of rats.

    PubMed

    Benova, Miroslava; Herichova, Iveta; Stebelova, Katarina; Paulis, Ludovit; Krajcirovicova, Kristina; Simko, Fedor; Zeman, Michal

    2009-04-01

    Melatonin plays a role in blood pressure (BP) control. The aim of this study was to determine whether melatonin concentrations and melatonin receptor levels are altered in L-NAME-treated, NO-deficient hypertensive rats. Two groups of male adult Wistar rats were investigated: rats (n=36) treated with NO-synthase inhibitor L-NAME (40 mg kg(-1)) and age-matched controls (n=36). BP was measured weekly by tail-cuff plethysmography. After 4 weeks, L-NAME administration increased BP (178+/-1 vs. control 118+/-1 mm Hg). At the end of treatment, rats were killed in regular 4 h intervals over a 24-h period. Melatonin concentrations in the plasma, pineal gland, heart and kidney and melatonin receptor (MT(1)) density in the aorta were determined. A significant daily rhythm of melatonin concentrations was found in the blood, pineal gland, kidney and heart of both control and hypertensive rats. Peak nighttime pineal melatonin concentrations were higher in L-NAME-treated rats than in controls (3.38+/-0.48 vs. 1.75+/-0.33 ng per pineal gland). No differences between both groups were found in melatonin concentrations in blood, kidney and heart or in the MT(1) receptor density in the aorta. Our results suggest that L-NAME treatment enhances melatonin production in the pineal gland, potentially by decreasing an inhibitory effect of NO on melatonin production in the pineal gland. However, the enhanced pineal melatonin formation was insufficient to increase melatonin concentrations in circulation, heart and kidney of L-NAME-treated rats, indicating an increased use of melatonin in hypertensive animals.

  2. Melatonin Alleviates Liver Apoptosis in Bile Duct Ligation Young Rats

    PubMed Central

    Sheen, Jiunn-Ming; Chen, Yu-Chieh; Hsu, Mei-Hsin; Tain, You-Lin; Huang, Ying-Hsien; Tiao, Mao-Meng; Li, Shih-Wen; Huang, Li-Tung

    2016-01-01

    Bile duct ligation (BDL)-treated rats display cholestasis and liver damages. The potential protective activity of melatonin in young BDL rats in terms of apoptosis, mitochondrial function, and endoplasmic reticulum (ER) homeostasis has not yet been evaluated. Three groups of young male Sprague-Dawley rats were used: one group received laparotomy (Sham), a second group received BDL for two weeks (BDL), and a third group received BDL and intraperitoneal melatonin (100 mg/day) for two weeks (BDL + M). BDL group rats showed liver apoptosis, increased pro-inflamamtory mediators, caspases alterations, anti-apoptotic factors changes, and dysfunction of ER homeostasis. Melatonin effectively reversed apoptosis, mainly through intrinsic pathway and reversed ER stress. In addition, in vitro study showed melatonin exerted its effect mainly through the melatonin 2 receptor (MT2) in HepG2 cells. In conclusion, BDL in young rats caused liver apoptosis. Melatonin rescued the apoptotic changes via the intrinsic pathway, and possibly through the MT2 receptor. Melatonin also reversed ER stress induced by BDL. PMID:27556445

  3. Melatonin Alleviates Liver Apoptosis in Bile Duct Ligation Young Rats.

    PubMed

    Sheen, Jiunn-Ming; Chen, Yu-Chieh; Hsu, Mei-Hsin; Tain, You-Lin; Huang, Ying-Hsien; Tiao, Mao-Meng; Li, Shih-Wen; Huang, Li-Tung

    2016-01-01

    Bile duct ligation (BDL)-treated rats display cholestasis and liver damages. The potential protective activity of melatonin in young BDL rats in terms of apoptosis, mitochondrial function, and endoplasmic reticulum (ER) homeostasis has not yet been evaluated. Three groups of young male Sprague-Dawley rats were used: one group received laparotomy (Sham), a second group received BDL for two weeks (BDL), and a third group received BDL and intraperitoneal melatonin (100 mg/day) for two weeks (BDL + M). BDL group rats showed liver apoptosis, increased pro-inflamamtory mediators, caspases alterations, anti-apoptotic factors changes, and dysfunction of ER homeostasis. Melatonin effectively reversed apoptosis, mainly through intrinsic pathway and reversed ER stress. In addition, in vitro study showed melatonin exerted its effect mainly through the melatonin 2 receptor (MT2) in HepG2 cells. In conclusion, BDL in young rats caused liver apoptosis. Melatonin rescued the apoptotic changes via the intrinsic pathway, and possibly through the MT2 receptor. Melatonin also reversed ER stress induced by BDL. PMID:27556445

  4. Arabidopsis Transcriptome Analysis Reveals Key Roles of Melatonin in Plant Defense Systems

    PubMed Central

    Weeda, Sarah; Zhang, Na; Zhao, Xiaolei; Ndip, Grace; Guo, Yangdong; Buck, Gregory A.; Fu, Conggui; Ren, Shuxin

    2014-01-01

    Melatonin is a ubiquitous molecule and exists across kingdoms including plant species. Studies on melatonin in plants have mainly focused on its physiological influence on growth and development, and on its biosynthesis. Much less attention has been drawn to its affect on genome-wide gene expression. To comprehensively investigate the role(s) of melatonin at the genomics level, we utilized mRNA-seq technology to analyze Arabidopsis plants subjected to a 16-hour 100 pM (low) and 1 mM (high) melatonin treatment. The expression profiles were analyzed to identify differentially expressed genes. 100 pM melatonin treatment significantly affected the expression of only 81 genes with 51 down-regulated and 30 up-regulated. However, 1 mM melatonin significantly altered 1308 genes with 566 up-regulated and 742 down-regulated. Not all genes altered by low melatonin were affected by high melatonin, indicating different roles of melatonin in regulation of plant growth and development under low and high concentrations. Furthermore, a large number of genes altered by melatonin were involved in plant stress defense. Transcript levels for many stress receptors, kinases, and stress-associated calcium signals were up-regulated. The majority of transcription factors identified were also involved in plant stress defense. Additionally, most identified genes in ABA, ET, SA and JA pathways were up-regulated, while genes pertaining to auxin responses and signaling, peroxidases, and those associated with cell wall synthesis and modifications were mostly down-regulated. Our results indicate critical roles of melatonin in plant defense against various environmental stresses, and provide a framework for functional analysis of genes in melatonin-mediated signaling pathways. PMID:24682084

  5. Arabidopsis transcriptome analysis reveals key roles of melatonin in plant defense systems.

    PubMed

    Weeda, Sarah; Zhang, Na; Zhao, Xiaolei; Ndip, Grace; Guo, Yangdong; Buck, Gregory A; Fu, Conggui; Ren, Shuxin

    2014-01-01

    Melatonin is a ubiquitous molecule and exists across kingdoms including plant species. Studies on melatonin in plants have mainly focused on its physiological influence on growth and development, and on its biosynthesis. Much less attention has been drawn to its affect on genome-wide gene expression. To comprehensively investigate the role(s) of melatonin at the genomics level, we utilized mRNA-seq technology to analyze Arabidopsis plants subjected to a 16-hour 100 pM (low) and 1 mM (high) melatonin treatment. The expression profiles were analyzed to identify differentially expressed genes. 100 pM melatonin treatment significantly affected the expression of only 81 genes with 51 down-regulated and 30 up-regulated. However, 1 mM melatonin significantly altered 1308 genes with 566 up-regulated and 742 down-regulated. Not all genes altered by low melatonin were affected by high melatonin, indicating different roles of melatonin in regulation of plant growth and development under low and high concentrations. Furthermore, a large number of genes altered by melatonin were involved in plant stress defense. Transcript levels for many stress receptors, kinases, and stress-associated calcium signals were up-regulated. The majority of transcription factors identified were also involved in plant stress defense. Additionally, most identified genes in ABA, ET, SA and JA pathways were up-regulated, while genes pertaining to auxin responses and signaling, peroxidases, and those associated with cell wall synthesis and modifications were mostly down-regulated. Our results indicate critical roles of melatonin in plant defense against various environmental stresses, and provide a framework for functional analysis of genes in melatonin-mediated signaling pathways.

  6. Phenotypic and functional alteration of CD4+ T cells after antigen stimulation. Resolution of two populations of memory T cells that both secrete interleukin 4

    PubMed Central

    1989-01-01

    Phenotypic and functional alteration of murine CD4+ T cells after antigenic stimulation was studied using two anti-T cell mAbs recently described that define four distinct T cell subsets. Activation of T cells resulted in the permanent loss of 3G11 expression. However, two phenotypically distinct memory T cell populations were established depending on the system used; whereas those for anti-KLH antibody response were enriched in the fraction expression 6C10 (Fr. III), memory T cells for the allogeneic MLR lacked such expression (Fr. IV). Furthermore, successive stimulation with antigen in vitro resulted in secretion of IL-4 without detectable IL-2. This alteration of phenotype and interleukin secretion was also demonstrable when starting with 3G11+6C10- cells (Fr. I), the fraction that secretes IL-2 exclusively upon activation. PMID:2525174

  7. THE ESTROGENIC AND ANTIANDROGENIC PESTICIDE METHOXYCHLOR ALTERS THE REPRODUCTIVE TRACT AND BEHAVIOR WITHOUT AFFECTING PITUITARY SIZE OR LH AND PROLACTIN SECRETION IN MALE RATS

    EPA Science Inventory

    The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats.

    Gray LE Jr, Ostby J, Cooper RL, Kelce WR.

    Endocrinology Branch, United States Environment...

  8. Effect of melatonin on kidney cold ischemic preservation injury

    PubMed Central

    Aslaner, Arif; Gunal, Omer; Turgut, Hamdi Taner; Celik, Erdal; Yildirim, Umran; Demirci, Rojbin Karakoyun; Gunduz, Umut Riza; Calis, Hasan; Dogan, Sami

    2013-01-01

    Melatonin is a potent free radical scavenger of reactive oxygen species, nitric oxide synthase inhibitor and a well-known antioxidant secreted from pineal gland. This hormone has been reported to protect tissue from oxidative damage. In this study, we aim to investigate the effect of melatonin on kidney cold ischemia time when added to preservation solution. Thirty male Wistar albino rats were divided equally into three groups; Ringer Lactate (RL) solution, University of Wisconsin (UW) solution with and without melatonin. The serum Lactate Dehydrogenase (LDH) activities of the preservation solutions at 2nd, 24th, 36th, and 48th hours were determined. Tissue malondialdehyde (MDA) levels were also measured and a histological examination was performed at 48th hour. Melatonin that added to preservation solution prevented enzyme elevation and decreased lipid peroxidation in preservation solution when compared to the control group (p<0.05). The histological examination revealed that UW solution containing melatonin significantly prevented the kidney from pathological injury (p<0.05). Melatonin added to preservation solutions such as UW solution seemed to protect the tissue preserved effectively from cold ischemic injury for up to 48 hour. PMID:24179573

  9. Potent therapeutic effect of melatonin on aging skin in pinealectomized rats.

    PubMed

    Eşrefoğlu, Mukaddes; Seyhan, Muammer; Gül, Mehmet; Parlakpinar, Hakan; Batçioğlu, Kadir; Uyumlu, Burçin

    2005-10-01

    It is generally agreed that one of the major contributors to skin aging is reactive oxygen species. As organisms reach advanced age, free radical generation increases and the activity of tissue antioxidant enzyme system decreases. Melatonin is an antioxidant and free radical scavenger. The present study was first aimed to determine the morphometric and biochemical changes caused by long-term pinealectomy in order to investigate the role of melatonin as skin architecture. Secondly, the effect of exogenous melatonin administration on these changes was determined. Rats were pinealectomized or sham operated (control) for 6 months. Half of the pinealectomized rats were treated with 4 mg/kg melatonin during the last month of the experiment. Pinealectomy resulted in important morphometric and biochemical changes in the back, abdominal and thoracic skin. The thickness of epidermis and dermis and the number of dermal papillae and hair follicles were reduced. Melatonin administration to pinealectomized rats significantly improved these alterations in all body areas (P < 0.005). On the contrary, in pinealectomized rats the levels of antioxidant enzymes, catalase and glutathione peroxidase were decreased. Melatonin restored the levels of these enzymes. The pinealectomy-induced increases in lipid peroxidation in the abdominal and thoracic skin were significantly reduced by melatonin treatment (P < 0.005 and 0.01 respectively). These results suggest that melatonin is highly efficient anti-aging factor and, as melatonin levels decrease with age, melatonin treatment may reduce age-related skin changes. PMID:16150102

  10. Advances in the Research of Melatonin in Autism Spectrum Disorders: Literature Review and New Perspectives

    PubMed Central

    Tordjman, Sylvie; Najjar, Imen; Bellissant, Eric; Anderson, George M.; Barburoth, Marianne; Cohen, David; Jaafari, Nemat; Schischmanoff, Olivier; Fagard, Rémi; Lagdas, Enas; Kermarrec, Solenn; Ribardiere, Sophie; Botbol, Michel; Fougerou, Claire; Bronsard, Guillaume; Vernay-Leconte, Julie

    2013-01-01

    Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests. PMID:24129182

  11. Nocturnal Melatonin Profiles in Patients with Delayed Sleep-Wake Phase Disorder and Control Sleepers.

    PubMed

    Micic, Gorica; Lovato, Nicole; Gradisar, Michael; Burgess, Helen J; Ferguson, Sally A; Kennaway, David J; Lack, Leon

    2015-10-01

    A significant delay in the timing of endogenous circadian rhythms has been associated with delayed sleep phase disorder (DSPD). More recently, other mechanisms have also been proposed to account for this disorder. To further explore the etiology of DSPD, the present study compared nocturnal melatonin profiles of 26 DSPD patients (18 males, 8 females; age, 21.73 ± 4.98 years) and 17 normally timed good sleepers (10 males, 7 females; age, 23.82 ± 5.23 years) in a time-free, dim-light (<10 lux) laboratory environment. A 30-h modified constant routine with alternating 20-min sleep opportunities and 40 min of enforced wakefulness was used to measure the endogenous melatonin circadian rhythm. Salivary melatonin was sampled half-hourly from 1820 h to 0020 h and then hourly from 0120 h to 1620 h. DSPD patients had significantly later timed melatonin profiles that were delayed by approximately 3 h compared to normal sleepers, and there were no notable differences in the relative duration of secretion between groups. However, melatonin secretion between dim-light melatonin onset (DLMO) and acrophase was less prominent in DSPD patients compared to good sleepers, who showed a more acute initial surge of melatonin following the DLMO. Although the regulatory role of melatonin is unknown, abnormal melatonin profiles have been linked to psychiatric and neurological disorders (e.g., major depression, obsessive compulsive disorder, Parkinson disease). These results therefore suggest that in addition to a delayed endogenous circadian rhythm, a diminished initial surge of melatonin secretion following DLMO may contribute to the etiology of DSPD.

  12. Melatonin protects skin keratinocyte from hydrogen peroxide-mediated cell death via the SIRT1 pathway

    PubMed Central

    Lee, Ju-Hee; Moon, Ji-Hong; Nazim, Uddin MD.; Lee, You-Jin; Seol, Jae-Won; Eo, Seong-Kug; Lee, John-Hwa; Park, Sang-Youel

    2016-01-01

    Melatonin (N-acetyl-5-methoxytryptamine), which is primarily synthesized in and secreted from the pineal gland, plays a pivotal role in cell proliferation as well as in the regulation of cell metastasis and cell survival in a diverse range of cells. The aim of this study is to investigate protection effect of melatonin on H2O2-induced cell damage and the mechanisms of melatonin in human keratinocytes. Hydrogen peroxide dose-dependently induced cell damages in human keratinocytes and co-treatment of melatonin protected the keratinocytes against H2O2-induced cell damage. Melatonin treatment activated the autophagy flux signals, which were identified by the decreased levels of p62 protein. Inhibition of autophagy flux via an autophagy inhibitor and ATG5 siRNA technique blocked the protective effects of melatonin against H2O2-induced cell death in human keratinocytes. And we found the inhibition of sirt1 using sirtinol and sirt1 siRNA reversed the protective effects of melatonin and induces the autophagy process in H2O2-treated cells. This is the first report demonstrating that autophagy flux activated by melatonin protects human keratinocytes through sirt1 pathway against hydrogen peroxide-induced damages. And this study also suggest that melatonin could potentially be utilized as a therapeutic agent in skin disease. PMID:26918354

  13. Maternal melatonin treatment influences rates of neonatal development of meadow vole pups.

    PubMed

    Lee, T M; Spears, N; Tuthill, C R; Zucker, I

    1989-03-01

    Meadow vole dams, housed in a 14L:10D photoperiod were injected daily 3 h before onset of darkness with 10 micrograms melatonin. Treatment during gestation or lactation produced offspring that exhibited altered somatic, testicular, and pelage growth. Gestational melatonin treatment decreased preweaning weight gain, delayed testicular development, and increased pelage growth in offspring, whereas melatonin treatment during lactation increased pelage depth at weaning and increased post-weaning somatic growth. These results suggest that pre- and postnatal maternal melatonin secretory patterns influence postnatal development of photosensitive traits in offspring. PMID:2667649

  14. Anorexigenic effects of miglitol in concert with the alterations of gut hormone secretion and gastric emptying in healthy subjects.

    PubMed

    Kaku, H; Tajiri, Y; Yamada, K

    2012-04-01

    Although the α-glucosidase inhibitor miglitol (MG) has been reported to have anorexigenic effects, the mechanism remains to be elucidated. The objective of this study was to explore the effects of MG on appetite in relation to concomitant changes in postprandial gut hormone levels. This randomized open-label crossover study included 20 healthy volunteers. The effects of 50 mg MG on glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin levels were assessed in conjunction with a simultaneous determination of appetite scores using visual analogue scales (VAS) over 3 h after the ingestion of a 592 kcal test cookie. Additionally, the gastric emptying rate (GER) was measured using breath ¹³CO₂ appearance in 10 subjects. 12 subjects were administered 50 mg MG thrice a day for 1 week, and alterations of the gut hormone levels and the VAS scores for appetite were evaluated. MG pre-administration resulted in a significant enhancement of GLP-1 and PYY responses induced by the cookie ingestion. Following MG administration, ghrelin level declined at 1 h, with a persistent suppression during the postprandial phase in contrast to the restoration to the basal level without MG. Furthermore, MG pre-administration suppressed appetite and maintained satiety evaluated using a VAS rating with concomitant inhibition of GER after cookie ingestion. One-week administration of MG did not influence either gut hormone levels before a meal or VAS rating during a whole day. These observations suggest that MG exerts an anorexigenic effects with concomitant alterations of gut hormone secretions and gastric emptying after meal ingestion. PMID:22351480

  15. Analysis Method and Experimental Conditions Affect Computed Circadian Phase from Melatonin Data

    PubMed Central

    Klerman, Hadassa; St. Hilaire, Melissa A.; Kronauer, Richard E.; Gooley, Joshua J.; Gronfier, Claude; Hull, Joseph T.; Lockley, Steven W.; Santhi, Nayantara; Wang, Wei; Klerman, Elizabeth B.

    2012-01-01

    Accurate determination of circadian phase is necessary for research and clinical purposes because of the influence of the master circadian pacemaker on multiple physiologic functions. Melatonin is presently the most accurate marker of the activity of the human circadian pacemaker. Current methods of analyzing the plasma melatonin rhythm can be grouped into three categories: curve-fitting, threshold-based and physiologically-based linear differential equations. To determine which method provides the most accurate assessment of circadian phase, we compared the ability to fit the data and the variability of phase estimates for seventeen different markers of melatonin phase derived from these methodological categories. We used data from three experimental conditions under which circadian rhythms - and therefore calculated melatonin phase - were expected to remain constant or progress uniformly. Melatonin profiles from older subjects and subjects with lower melatonin amplitude were less likely to be fit by all analysis methods. When circadian drift over multiple study days was algebraically removed, there were no significant differences between analysis methods of melatonin onsets (P = 0.57), but there were significant differences between those of melatonin offsets (P<0.0001). For a subset of phase assessment methods, we also examined the effects of data loss on variability of phase estimates by systematically removing data in 2-hour segments. Data loss near onset of melatonin secretion differentially affected phase estimates from the methods, with some methods incorrectly assigning phases too early while other methods assigning phases too late; missing data at other times did not affect analyses of the melatonin profile. We conclude that melatonin data set characteristics, including amplitude and completeness of data collection, differentially affect the results depending on the melatonin analysis method used. PMID:22511928

  16. Tributyltin (TBT) and Dibutyltin (DBT) Alter Secretion of Tumor Necrosis Factor Alpha (TNFα) from Human Natural Killer (NK) Cells and a Mixture of T cells and NK Cells

    PubMed Central

    Hurt, Kelsi; Hurd-Brown, Tasia; Whalen, Margaret

    2012-01-01

    Butyltins (BTs) have been in widespread use. Tributyltin (TBT) has been used as a biocide in a variety of applications and is found in human blood samples. Dibutyltin (DBT) has been used as a stabilizer in polyvinyl chloride plastics and as a de-worming agent in poultry. DBT, like TBT, is found in human blood. Human natural killer (NK) cells are the earliest defense against tumors and viral infections and secrete the cytokine tumor necrosis factor (TNF) alpha (α). TNFα is an important regulator of adaptive and innate immune responses. TNFα promotes inflammation and an association between malignant transformation and inflammation has been established. Previously, we have shown that TBT and DBT were able to interfere with the ability of NK cells to lyse tumor target cells. Here we show that BTs alter cytokine secretion by NK cells as well as a mixture of T and NK lymphocytes (T/NK cells). We examined 24 h, 48 h, and 6 day exposures to TBT (200- 2.5 nM) and DBT (5- 0.05 µM) on TNFα secretion by highly enriched human NK cells and T/NK cells. The results indicate that TBT (200 - 2.5 nM) decreased TNFα secretion from NK cells. In the T/NK cells 200 nM TBT decreased secretion while 100-5 nM TBT increased secretion of TNFα. NK cells or T/NK cells exposed to higher concentrations of DBT showed decreased TNFα secretion while lower concentrations showed increased secretion. The effects of BTs on TNFα secretion are seen at concentrations present in human blood. PMID:23047847

  17. Secreted herpes simplex virus-2 glycoprotein G alters thermal pain sensitivity by modifying NGF effects on TRPV1.

    PubMed

    Cabrera, Jorge Rubén; Viejo-Borbolla, Abel; Alcamí, Antonio; Wandosell, Francisco

    2016-01-01

    Genital herpes is a painful disease frequently caused by the neurotropic pathogen herpes simplex virus type 2 (HSV-2). We have recently shown that HSV-2-secreted glycoprotein G (SgG2) interacts with and modulates the activity of the neurotrophin nerve growth factor (NGF). This interaction modifies the response of the NGF receptor TrkA, increasing NGF-dependent axonal growth. NGF is not only an axonal growth modulator but also an important mediator of pain and inflammation regulating the amount, localization, and activation of the thermal pain receptor transient receptor potential vanilloid 1 (TRPV1). In this work, we addressed whether SgG2 could contribute to HSV-2-induced pain. Injection of SgG2 in the mouse hindpaw produced a rapid and transient increase in thermal pain sensitivity. At the molecular level, this acute increase in thermal pain induced by SgG2 injection was dependent on differential NGF-induced phosphorylation and in changes in the amount of TrkA and TRPV1 in the dermis. These results suggest that SgG2 alters thermal pain sensitivity by modulating TRPV1 receptor. PMID:27576911

  18. Secreted herpes simplex virus-2 glycoprotein G alters thermal pain sensitivity by modifying NGF effects on TRPV1.

    PubMed

    Cabrera, Jorge Rubén; Viejo-Borbolla, Abel; Alcamí, Antonio; Wandosell, Francisco

    2016-08-30

    Genital herpes is a painful disease frequently caused by the neurotropic pathogen herpes simplex virus type 2 (HSV-2). We have recently shown that HSV-2-secreted glycoprotein G (SgG2) interacts with and modulates the activity of the neurotrophin nerve growth factor (NGF). This interaction modifies the response of the NGF receptor TrkA, increasing NGF-dependent axonal growth. NGF is not only an axonal growth modulator but also an important mediator of pain and inflammation regulating the amount, localization, and activation of the thermal pain receptor transient receptor potential vanilloid 1 (TRPV1). In this work, we addressed whether SgG2 could contribute to HSV-2-induced pain. Injection of SgG2 in the mouse hindpaw produced a rapid and transient increase in thermal pain sensitivity. At the molecular level, this acute increase in thermal pain induced by SgG2 injection was dependent on differential NGF-induced phosphorylation and in changes in the amount of TrkA and TRPV1 in the dermis. These results suggest that SgG2 alters thermal pain sensitivity by modulating TRPV1 receptor.

  19. Twice Daily Melatonin Peaks in Siberian but not Syrian Hamsters under 24 h Light:Dark:Light:Dark Cycles

    PubMed Central

    Raiewski, Evan E.; Elliott, Jeffrey A.; Evans, Jennifer A.; Glickman, Gena L.; Gorman, Michael R.

    2016-01-01

    The daily pattern of blood borne melatonin varies seasonally under the control of a multi-oscillator circadian pacemaker. Here we examine patterns of melatonin secretion and locomotor activity in Siberian and Syrian hamsters entrained to bimodal LDLD8:4:8:4 and LD20:4 lighting schedules that facilitate novel temporal arrangements of component circadian oscillators. Under LDLD, both species robustly bifurcated wheel-running activity in distinct day scotophase (DS) and night scotophase (NS) bouts. Siberian hamsters displayed significant melatonin increases during each scotophase in LDLD, and in the single daily scotophase of LD20:4. The bimodal melatonin secretion pattern persisted in acutely extended 16 h scotophases. Syrian hamsters, in contrast, showed no significant increases in plasma melatonin during either scotophase of LDLD8:4:8:4 or in LD20:4. In this species, detectable levels were observed only when the day scotophase of LDLD was acutely extended to yield 16 h of darkness. Established species differences in the phase lag of nocturnal melatonin secretion relative to activity onset may underlie the above contrast: In non-bifurcated entrainment to 24 h LD cycles, Siberian hamsters show increased melatonin secretion within ~ 2 h after activity onset, whereas in Syrian hamsters, detectable melatonin secretion phase lags activity onset and the L/D transition by at least 4 h. The present results provide new evidence indicating multi-oscillator regulation of the waveform of melatonin secretion, specifically, the circadian control of the onset, offset, and duration of nocturnal secretion. PMID:23003567

  20. Twice daily melatonin peaks in Siberian but not Syrian hamsters under 24 h light:dark:light:dark cycles.

    PubMed

    Raiewski, Evan E; Elliott, Jeffrey A; Evans, Jennifer A; Glickman, Gena L; Gorman, Michael R

    2012-11-01

    The daily pattern of blood-borne melatonin varies seasonally under the control of a multi-oscillator circadian pacemaker. Here we examine patterns of melatonin secretion and locomotor activity in Siberian and Syrian hamsters entrained to bimodal LDLD8:4:8:4 and LD20:4 lighting schedules that facilitate novel temporal arrangements of component circadian oscillators. Under LDLD, both species robustly bifurcated wheel-running activity in distinct day scotophase (DS) and night scotophase (NS) bouts. Siberian hamsters displayed significant melatonin increases during each scotophase in LDLD, and in the single daily scotophase of LD20:4. The bimodal melatonin secretion pattern persisted in acutely extended 16 h scotophases. Syrian hamsters, in contrast, showed no significant increases in plasma melatonin during either scotophase of LDLD8:4:8:4 or in LD20:4. In this species, detectable levels were observed only when the DS of LDLD was acutely extended to yield 16 h of darkness. Established species differences in the phase lag of nocturnal melatonin secretion relative to activity onset may underlie the above contrast: In non-bifurcated entrainment to 24 h LD cycles, Siberian hamsters show increased melatonin secretion within ≈ 2 h after activity onset, whereas in Syrian hamsters, detectable melatonin secretion phase lags activity onset and the L/D transition by at least 4 h. The present results provide new evidence indicating multi-oscillator regulation of the waveform of melatonin secretion, specifically, the circadian control of the onset, offset and duration of nocturnal secretion.

  1. Duration of melatonin regulates seasonal plasticity in subtropical Indian weaver bird, Ploceus philippinus.

    PubMed

    Surbhi; Kumari, Yatinesh; Rani, Sangeeta; Tsutsui, Kazuyoshi; Kumar, Vinod

    2015-09-01

    Day length regulates seasonal plasticity connected with reproduction in birds. Rhythmic pineal melatonin secretion is a reliable indicator of the night length, hence day length. Removal of rhythmic melatonin secretion by exposure to constant bright light (LLbright) or by pinealectomy renders several species of songbirds including Indian weaver bird (Ploceus philippinus) arrhythmic. Present study investigated whether rhythmic melatonin is involved in the regulation of key reproductive neuropeptides (GnRH I and GnIH) and reproduction linked neural changes, viz. song control nuclei, in Indian weaver birds. Two experiments were performed using birds in an arrhythmic condition with low (under LLbright) or no (in the absence of pineal gland) endogenous melatonin. In experiment I, three groups of birds (n=5 each) entrained to 12L:12D were exposed to LLbright (25lux) for two weeks. Beginning on day 15 of LLbright, a control group received vehicle for 16h and two treatment groups were given melatonin in drinking water for 8h or 16h. In experiment II, one group of sham-operated and three groups of pinealectomized birds (n=5 each) entrained to 12L:12D were exposed to constant dim light (LLdim, 0.5lux). Beginning on day 15 of LLdim, three groups received similar treatment as in experiment I. Birds were perfused after thirty cycles of the melatonin treatment, and brain sections were immunohistochemically double-labeled for GnRH I and GnIH or Nissl stained. Activity was recorded throughout the experiments, while body mass and testes were measured at the beginning and end of the experiment. Birds were synchronized with melatonin cycles and measured the duration of melatonin as "night". Pinealectomized birds that received 16h of melatonin had significantly higher GnIH-ir cells than those received 8h melatonin; there was no difference in the GnRH I immunoreactivity between two treatment groups however. Intact birds that received long duration melatonin cycles exhibited small song

  2. Klebsiella pneumoniae O antigen loss alters the outer membrane protein composition and the selective packaging of proteins into secreted outer membrane vesicles.

    PubMed

    Cahill, Bethaney K; Seeley, Kent W; Gutel, Dedra; Ellis, Terri N

    2015-11-01

    Klebsiella pneumoniae is a nosocomial pathogen which naturally secretes lipopolysaccharide (LPS) and cell envelope associated proteins into the environment through the production of outer membrane vesicles (OMVs). The loss of the LPS O antigen has been demonstrated in other bacterial species to significantly alter the composition of OMVs. Therefore, this study aimed to comprehensively analyze the impact of O antigen loss on the sub-proteomes of both the outer membrane and secreted OMVs from K. pneumoniae. As determined by LC-MS/MS, OMVs were highly enriched with outer membrane proteins involved in cell wall, membrane, and envelope biogenesis as compared to the source cellular outer membrane. Deletion of wbbO, the enzyme responsible for O antigen attachment to LPS, decreased but did not eliminate this enrichment effect. Additionally, loss of O antigen resulted in OMVs with increased numbers of proteins involved in post-translational modification, protein turnover, and chaperones as compared to secreted vesicles from the wild type. This alteration of OMV composition may be a compensatory mechanism to deal with envelope stress. This comprehensive analysis confirms the highly distinct protein composition of OMVs as compared to their source membrane, and provides evidence for a selective sorting mechanism that involves LPS polysaccharides. These data support the hypothesis that modifications to LPS alters both the mechanics of protein sorting and the contents of secreted OMVs and significantly impacts the protein composition of the outer membrane.

  3. Advancement of reproductive activity, seasonal reduction in prolactin secretion and seasonal pelage changes in pubertal red deer hinds (Cervus elaphus) subjected to artificially shortened daily photoperiod or daily melatonin treatments.

    PubMed

    Webster, J R; Barrell, G K

    1985-01-01

    Prepubertal red deer hinds were subjected to shortened daily photoperiod (8 h light per day, N = 3) or a daily (afternoon) melatonin injection (N = 4) for 83 days starting on 8 January, 2 weeks after the summer solstice. Compared with control hinds (N = 3) these treatments caused premature moulting of summer pelage, reduced serum prolactin concentrations to barely detectable levels about 34 days earlier than usual and advanced the date of mating. Calves were born earlier (P less than 0.005) in the hinds exposed to a shortened photoperiod (12 November +/- 1.7 days) and melatonin treatment (11 November +/- 3.2 days) than in control hinds (13 December +/- 7.9 days). Serum progesterone levels recorded before the first detected oestrus indicated that silent ovulations had occurred in many of the hinds (6 of 10) in this experiment. This study demonstrated the role of shortened daily photoperiod in red deer and indicated that the effects of reduced photoperiod observed were mediated by melatonin. PMID:3968657

  4. Melatonin elicits protein kinase C-mediated calcium response in immortalized GT1-7 GnRH neurons.

    PubMed

    Kelestimur, Haluk; Ozcan, Mete; Kacar, Emine; Alcin, Ergul; Yılmaz, Bayram; Ayar, Ahmet

    2012-01-30

    Melatonin is suggested to have effects on hypothalamic-pituitary-gonadal (HPG) axis. The pulsatile pattern of GnRH release, which results in the intermittent release of gonadotropic hormones from the pituitary, has a critical importance for reproductive function but the factors responsible from this release pattern are not known. Calcium is a second messenger involved in hormone release. Therefore, investigation of the effects of melatonin on intracellular free calcium levels ([Ca(2+)](i)) would provide critical information on hormone release in immortalized GnRH neurons. The pattern of melatonin-induced intracellular calcium signaling was investigated by fluorescence calcium imaging using the immortalized GnRH-secreting GT1-7 hypothalamic neurons. Melatonin caused a significant increase in [Ca(2+)](i,) which was greatly blocked by luzindole, a melatonin antagonist, or attenuated by pre-treatment with protein kinase C inhibitor. This study suggests that melatonin seems to have a direct effect on GnRH neurons.

  5. Effect of melatonin on total food intake and macronutrient choice in rats.

    PubMed

    Angers, K; Haddad, N; Selmaoui, B; Thibault, L

    2003-10-01

    Melatonin, a hormone secreted in a rhythmic manner over 24 h mainly by the pineal gland, is used to alleviate the symptoms of jetlag and treat sleeping problems. The objective of the present study was to examine the effects of a 7-h phase-shift from the natural peak of melatonin secretion on total food intake and macronutrient selection. Forty-eight adult Wistar rats of both sexes were divided in three dietary groups, each group offered a simultaneous and different choice of a carbohydrate- and a protein-rich diet. Macronutrient intakes following intraperitoneal administration of four doses of melatonin (3000, 6000, 10000 and 15000 pg/ml blood) at dark onset were examined. Melatonin increased short- (4 h postinjection) and long-term (12 h postinjection) nocturnal total food intake in both male and female rats, mainly with the two highest doses. This effect of melatonin was mainly due to a short-term increase of intake across all carbohydrate-rich diet preparations (dextrin/cornstarch, cornstarch, and sucrose/cornstarch) and across genders. This consistent effect of melatonin on the intake of carbohydrate-rich diets with contrasting sensory attributes rules out the possibility that melatonin acts on sensorymotor pathways, thus suggesting that melatonin's effect on food intake is controlled by the carbohydrate content of the diet. In contrast, melatonin could be affecting some sensory or motor processes peculiar to the ingestion of protein since it increased protein-rich diet intake inconsistently across the various preparations (casein, soy isolate, and egg protein) as well as genders. This evidence supports the view that melatonin acts as a time indicator, reinforcing the animals with a "night cue", and favors predominant carbohydrate intake normally occurring at the beginning of the activity period.

  6. Altered secretion of selected arachidonic acid metabolites during subclinical endometritis relative to estrous cycle stage and grade of fibrosis in mares.

    PubMed

    Gajos, Katarzyna; Kozdrowski, Roland; Nowak, Marcin; Siemieniuch, Marta J

    2015-08-01

    Mares that fail to become pregnant after repeated breeding, without showing typical signs of clinical endometritis, should be suspected of subclinical endometritis (SE). Contact with infectious agents results in altered synthesis and secretion of inflammatory mediators, including cytokines and arachidonic acid metabolites, and disturbs endometrial functional balance. To address the hypothesis that SE affects the immune endocrine status of the equine endometrium, spontaneous secretion of prostaglandin E(2) (PGE(2)), prostaglandin F(2α) (PGF(2α)), 6-keto-PGF(1α )(a metabolite of prostacyclin I(2)), leukotriene B(4) (LTB(4)), and leukotriene C(4) (LTC(4)) was examined. In addition, secretion of these factors was examined relative to the grade of inflammation, fibrosis, and estrous cycle stage. Eighty-two warmblood mares, of known breeding history, were enrolled in this study. On the basis of histopathologic assessment, mares were classified as suffering from first-grade SE, second-grade SE, or being healthy. The grade of fibrosis and the infiltration of endometrial tissue with polymorphonuclear leukocytes were examined by routine hematoxylin-eosin staining. In mares suffering from SE, the secretion profiles of PGE(2), 6-keto-PGF(1α), LTB(4), and LTC(4) were changed compared to mares that did not suffer from endometritis. The secretion of PGE(2) and 6-keto-PGF1α was increased, whereas that of LTB(4) and LTC(4) was decreased. Secretion of 6-keto-PGF(1α) was increased in first- and second-grade SE (P < 0.01). The concentration of PGI(2) metabolite was increased only in inflamed endometrium, independently of the inflammation grade, but was not affected by fibrosis. Prostaglandin E(2) secretion was increased in second-grade SE (P < 0.05). The secretion of LTB(4) decreased in both first- and second-grade SE (P < 0.05), whereas secretion of LTC(4) was decreased only in second-grade SE (P < 0.05). Fibrosis did not change the secretion profile of PGE(2), PGF(2α), and 6

  7. Experimental and clinical aspects of melatonin and clock genes in diabetes.

    PubMed

    Peschke, Elmar; Bähr, Ina; Mühlbauer, Eckhard

    2015-08-01

    The pineal hormone melatonin influences insulin secretion, as well as glucagon and somatostatin secretion, both in vivo and in vitro. These effects are mediated by two specific, high-affinity, seven transmembrane, pertussis toxin-sensitive, Gi-protein-coupled melatonin receptors, MT1 and MT2. Both isoforms are expressed in the β-cells, α-cells as well as δ-cells of the pancreatic islets of Langerhans and are involved in the modulation of insulin secretion, leading to inhibition of the adenylate cyclase-dependent cyclic adenosine monophosphate as well as cyclic guanosine monophosphate formation in pancreatic β-cells by inhibiting the soluble guanylate cyclase, probably via MT2 receptors. In this way, melatonin also likely inhibits insulin secretion, whereas using the inositol triphosphate pathway after previous blocking of Gi-proteins by pertussis toxin, melatonin increases insulin secretion. Desynchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genomewide association studies pinpointing variances of the MT2 receptor as a risk factor for this rapidly spreading metabolic disturbance. As melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. Observations of the circadian expression of clock genes (Clock, Bmal1, Per1,2,3, and Cry1,2) in pancreatic islets, as well as in INS1 rat insulinoma cells, may indicate that circadian rhythms are generated in the β-cells themselves. The circadian secretion of insulin from pancreatic islets is clock-driven. Disruption of circadian rhythms and clock function leads to metabolic disturbances, for example, type 2 diabetes. The study of melatonin-insulin interactions in diabetic rat models has revealed an inverse relationship between these two hormones. Both type 2 diabetic rats and patients exhibit decreased melatonin levels and slightly increased

  8. Acutely administered melatonin decreases somatostatin-binding sites and the inhibitory effect of somatostatin on adenylyl cyclase activity in the rat hippocampus.

    PubMed

    Izquierdo-Claros, Rosa María; Boyano-Adánez Md, María del Carmen; Arilla-Ferreiro, Eduardo

    2004-03-01

    Melatonin is known to increase neuronal activity in the hippocampus, an effect contrary to that of somatostatin (somatotropin release-inhibiting factor, SRIF). Thus, the aim of this study was to investigate whether the somatostatinergic system is implicated in the mechanism of action of melatonin in the rat hippocampus. One group of rats was injected a single dose of melatonin [25 microg/kg subcutaneously (s.c.)] or saline containing ethanol (0.5%, s.c.) and killed 5 hr later. Melatonin significantly decreased the SRIF-like immunoreactivity levels and induced a significant decrease in the density of SRIF receptors as well as in the dissociation constant (Kd). SRIF-mediated inhibition of basal and forskolin-stimulated adenylyl cyclase activity was markedly decreased in hippocampal membranes from melatonin-treated rats. The functional activity of Gi proteins was similar in hippocampal membranes from melatonin-treated and control rats. Western blot analyses revealed that melatonin administration did not alter Gialpha1 or Gialpha2 levels. To determine if the changes observed were related to melatonin-induced activation of central melatonin receptors, a melatonin receptor antagonist, luzindole, was administered prior to melatonin injection. Pretreatment with luzindole (10 mg/kg, s.c.) did not alter the melatonin-induced effects on the above-mentioned parameters and luzindole, alone, had no observable effect. The present results demonstrate that melatonin decreases the activity of the SRIF receptor-effector system in the rat hippocampus, an effect which is apparently not mediated by melatonin receptors. As SRIF exerts an opposite effect to that of melatonin on hippocampal neuronal activity, it is possible that the SRIFergic system could be implicated in the mechanism of action of melatonin in the rat.

  9. Placental melatonin system is present throughout pregnancy and regulates villous trophoblast differentiation.

    PubMed

    Soliman, Ahmed; Lacasse, Andrée-Anne; Lanoix, Dave; Sagrillo-Fagundes, Lucas; Boulard, Véronique; Vaillancourt, Cathy

    2015-08-01

    Melatonin is highly produced in the placenta where it protects against molecular damage and cellular dysfunction arising from hypoxia/re-oxygenation-induced oxidative stress as observed in primary cultures of syncytiotrophoblast. However, little is known about melatonin and its receptors in the human placenta throughout pregnancy and their role in villous trophoblast development. The purpose of this study was to determine melatonin-synthesizing enzymes, arylalkylamine N-acetyltransferase (AANAT) and hydroxyindole O-methyltransferase (HIOMT), and melatonin receptors (MT1 and MT2) expression throughout pregnancy as well as the role of melatonin and its receptors in villous trophoblast syncytialization. Our data show that the melatonin generating system is expressed throughout pregnancy (from week 7 to term) in placental tissues. AANAT and HIOMT show maximal expression at the 3rd trimester of pregnancy. MT1 receptor expression is maximal at the 1st trimester compared to the 2nd and 3rd trimesters, while MT2 receptor expression does not change significantly during pregnancy. Moreover, during primary villous cytotrophoblast syncytialization, MT1 receptor expression increases, while MT2 receptor expression decreases. Treatment of primary villous cytotrophoblast with an increasing concentration of melatonin (10 pM-1 mM) increases the fusion index (syncytium formation; 21% augmentation at 1 mM melatonin vs. vehicle) and β-hCG secretion (121% augmentation at 1 mM melatonin vs. vehicle). This effect of melatonin appears to be mediated via its MT1 and MT2 receptors. In sum, melatonin machinery (synthetizing enzymes and receptors) is expressed in human placenta throughout pregnancy and promotes syncytium formation, suggesting an essential role of this indolamine in placental function and pregnancy well-being.

  10. The role of melatonin in anaesthesia and critical care.

    PubMed

    Kurdi, Madhuri S; Patel, Tushar

    2013-03-01

    Melatonin is a neurohormone secreted by the pineal gland. It is widely present in both plant and animal sources. In several countries, it is sold over the counter as tablets and as food supplement or additive. Currently, it is most often used to prevent jet lag and to induce sleep. It has been and is being used in several clinical trials with different therapeutic approaches. It has sedative, analgesic, anti-inflammatory, anti-oxidative and chronobiotic effects. In the present review, the potential therapeutic benefits of melatonin in anaesthesia and critical care are presented. This article aims to review the physiological properties of melatonin and how these could prove useful for several clinical applications in perioperative management, critical care and pain medicine. The topic was handsearched from textbooks and journals and electronically from PubMed, and Google scholar using text words.

  11. Chronic melatonin administration mitigates behavioral dysfunction induced by γ-irradiation.

    PubMed

    Haridas, Seenu; Kumar, Mayank; Manda, Kailash

    2012-11-01

    Melatonin, a 'hormone of darkness,' has been reported to play a role in a wide variety of physiological responses including reproduction, circadian homeostasis, sleep, retinal neuromodulation, and vasomotor responses. Our recent studies reported a prophylactic effect of exogenous melatonin against radiation-induced neurocognitive changes. However, there is no reported evidence for a mitigating effect of chronic melatonin administration against radiation-induced behavioral alterations. In the present study, C57BL/6 mice were given either whole day chronic melatonin administration (CMA) or chronic night-time melatonin administration (CNMA) by a low dose of melatonin in drinking water for a period of 2 weeks and 1 month following exposure to 6 Gy of γ-radiation. Various behavioral endpoints, such as locomotor activities, gross behavioral traits, basal anxiety level, and depressive tendencies were scored at different time points. Radiation exposure significantly impaired gross behavioral traits as observed in the open field exploratory paradigms and forced swim test. Both the CMA and CNMA significantly ameliorated the radiation-induced changes in exploratory tendencies, risk-taking behavior and gross behavior traits, such as rearing and grooming. Melatonin administration afforded anxiolytic function against radiation in terms of center exploration tendencies. The radiation-induced augmentation of immobility time in the forced swim test, indices of depression-like behavior was also inhibited by chronic melatonin administration. The results demonstrated the mitigating effect of chronic melatonin administration on radiation-induced affective disorders in mice. PMID:23026539

  12. A direct influence of moonlight intensity on changes in melatonin production by cultured pineal glands of the golden rabbitfish, Siganus guttatus.

    PubMed

    Takemura, Akihiro; Ueda, Satomi; Hiyakawa, Nanae; Nikaido, Yoshiaki

    2006-04-01

    Rabbitfish are a restricted lunar-synchronized spawner that spawns around a species-specific lunar phase. It is not known how the fish perceive changes in cues from the moon. One possible explanation is that rabbitfish utilize changes in moonlight intensity to establish synchrony. The purpose of the present study was to examine whether or not the pineal gland of the golden rabbitfish can directly perceive changes in moonlight intensity. Isolated pineal glands were statically cultured under natural or artificial light conditions and melatonin secreted into the culture medium was measured using a time-resolved fluoroimmunoassay. Under an artificial light/dark cycle, melatonin secretion significantly increased during the dark phase. Under continuous light conditions, melatonin secretion was suppressed, while culture under continuous dark conditions seemed to duplicate melatonin secretion corresponding to the light/dark cycle in which the fish were acclimated. When cultured pineal glands were kept under natural light conditions on the dates of the full and the new moon, small amounts of melatonin were secreted at night. Moreover, exposure of cultured pineal glands to artificial and natural light conditions resulted in a significant decrease of melatonin secretion within 2 hr. These results suggest that the isolated pineal gland of golden rabbitfish responds to environmental light cycles and that 'brightness' of the night moon has an influence on melatonin secretion from the isolated pineal gland.

  13. Continuous Melatonin Attenuates the Regressing Activities of Short Photoperiod in Male Golden Hamsters

    PubMed Central

    Choi, Donchan

    2013-01-01

    Golden hamsters reproduce in a limited time of a year. Their sexual activities are active in summer but inactive in winter during which day length does not exceed night time and environmental conditions are severe to them. The reproductive activities are determined by the length of light in a day (photoperiod). Melatonin is synthesized and secreted only at night time from the pineal gland. Duration of elevated melatonin is longer in winter than summer, resulting in gonadal regression. The present study aimed at the influences of continuous melatonin treatments impinging on the gonadal function in male golden hamsters. Animals received empty or melatonin-filled capsules for 10 weeks. They were divided into long photoperiod (LP) and short photoperiod (SP). All the animals maintained in LP (either empty or melatonin-filled capsules) showed large testes, implying that melatonin had no effects on testicular functions. Animals housed in SP displayed completely regressed testes. But animals kept in SP and implanted with melatonin capsules exhibited blockage of full regression by SP. These results suggest that constant release of melatonin prohibits the regressing influence of SP. PMID:25949127

  14. Effects of moonlight exposure on plasma melatonin rhythms in the seagrass rabbitfish, Siganus canaliculatus.

    PubMed

    Rahman, Md Saydur; Kim, Byung-Ho; Takemura, Akihiro; Park, Chang-Bum; Lee, Young-Don

    2004-08-01

    Influences of light-dark (LD) cycle and moonlight exposure on plasma melatonin rhythms in the seagrass rabbitfish, Siganus canaliculatus, a lunar synchronized spawner, were determined by time-resolved fluoroimmunoassay (TR-FIA). When the fish were exposed to a natural LD (12:12) cycle, plasma melatonin levels exhibited a clear daily rhythm, with higher levels at midnight and lower levels during the day. These rhythms were not evident under either constant light (LL) or constant dark (DD) conditions. Plasma melatonin levels under LL condition were low and high under DD condition. These results indicate that plasma melatonin rhythms are driven by LD cycle in this species. When the fish were exposed to the 4 lunar phases, plasma melatonin levels around the new moon were significantly higher than during the first quarter moon and the full moon. Exposure to experimental new moon and full moon conditions caused significant increases and decreases of plasma melatonin levels, respectively. The synchronous rhythmicity of melatonin levels in the plasma support the hypothesis that the seagrass rabbitfish perceives moonlight intensity and responds with secretion of melatonin into the bloodstream.

  15. Effect of mobile usage on serum melatonin levels among medical students.

    PubMed

    Shrivastava, Abha; Saxena, Yogesh

    2014-01-01

    Exposure to extremely low frequency (ELF) electromagnetic radiations from mobile phones may affect the circadian rhythm of melatonin in mobile users. The study was designed with objective to evaluate the influence of mobile phone on circadian rhythm of melatonin and to find the association if any between the hours of mobile usage with serum melatonin levels. All the volunteers medical students using mobiles for > 2 hrs/day were included in high users group and volunteers who used mobile for ≤ 2 hrs where included in low users group. Both high and low users volunteers were sampled three times in the same day (Morning-3-4 am, Noon 1-2 pm, Evening-5-6 pm) for estimation of serum melatonin levels: Comparsion of sernum melatonin levels in high users and low users were done by Mann Whitney "U" Test. Reduced morning melatonin levels (3-4 am) was observed in high users (> 2 hrs/day) i.e high users had a disturbed melatonin circadian rhythm.There was a negative correlation between melatonin secretion and hours of mobile usages.

  16. Melatonin improves spermatogonial stem cells transplantation efficiency in azoospermic mice

    PubMed Central

    Gholami, Mohammadreza; Saki, Ghasem; Hemadi, Masoud; Khodadadi, Ali; Mohammadi-asl, Javad

    2014-01-01

    Objective(s): Transplantation quality improvement and reduction of cellular damage are important goals that are now considered by researchers. Melatonin is secreted from the pineal gland and some organs such as testes. According to beneficial effects of melatonin (such as its antioxidant and antiapoptotic properties), researchers have proposed that the use of melatonin may improve transplantation quality. The aim of this study was to investigate the effects of melatonin on the spermatogonial stem cells transplantation in the azoospermic mice. Materials and Methods: The testes of the BALB/c mice pups (6-day-old) after vitrified-thawed, were digested with enzymes (collagenase, DNaseΙ, trypsin-EDTA) to disperse the cells. The SSCs, type A, were isolated from the rest of testicular cells by MACS. Spermatogonial stem cells were labeled with PKH26 fluorescent kit. Labeled spermatogonial stem cells were transplanted into the testes of infertile mice (busulfan 40 mg/kg). The mice died two months after transplantation and the efficiency of spermatogenesis was investigated. TNP2 and hematoxyline-eosin staining were used to detect the efficiency of cell transplantation. Results: TNP2 were detected in the samples that received melatonin and spermatogonial stem cells transplantation, simultaneously. TNP2 was not detectable in the transplant recipient mice that received placebo for 10 weeks (control group). According to hematoxyline-eosin staining, melatonin improved structure of testes. Conclusion: Administration of melatonin (20 mg/kg) simultaneously with transplantation of spermatogonial stem cells in azoospermia mouse testis increases the efficiency of transplantation and improves structural properties of the testes tissue. PMID:24711891

  17. Melatonin in Glycyrrhiza uralensis: response of plant roots to spectral quality of light and UV-B radiation.

    PubMed

    Afreen, F; Zobayed, S M A; Kozai, T

    2006-09-01

    Melatonin (N-acetyl-5-methoxytryptamine) is known to be synthesized and secreted by the pineal gland in vertebrates. Evidence for the occurrence of melatonin in the roots of Glycyrrhiza uralensis plants and the response of this plant to the spectral quality of light including red, blue and white light (control) and UV-B radiation (280-315 nm) for the synthesis of melatonin were investigated. Melatonin was extracted and quantified in seed, root, leaf and stem tissues and results revealed that the root tissues contained the highest concentration of melatonin; melatonin concentrations also increased with plant development. After 3 months of growth under red, blue and white fluorescent lamps, the melatonin concentrations were highest in red light exposed plants and varied depending on the wavelength of light spectrum in the following order red > blue > or = white light. Interestingly, in a more mature plant (6 months) melatonin concentration was increased considerably; the increments in concentration were X4, X5 and X3 in 6-month-old red, blue and white light exposed (control) plants, respectively. The difference in melatonin concentrations between blue and white light exposed (control) plants was not significant. The concentration of melatonin quantified in the root tissues was highest in the plants exposed to high intensity UV-B radiation for 3 days followed by low intensity UV-B radiation for 15 days. The reduction of melatonin under longer periods of UV-B exposure indicates that melatonin synthesis may be related to the integrated (intensity and duration) value of UV-B irradiation. Melatonin in G. uralensis plant is presumably for protection against oxidative damage caused as a response to UV irradiation.

  18. Alleviation of cold damage to photosystem II and metabolisms by melatonin in Bermudagrass

    PubMed Central

    Fan, Jibiao; Hu, Zhengrong; Xie, Yan; Chan, Zhulong; Chen, Ke; Amombo, Erick; Chen, Liang; Fu, Jinmin

    2015-01-01

    As a typical warm-season grass, Bermudagrass [Cynodon dactylon (L).Pers.] is widely applied in turf systems and animal husbandry. However, cold temperature is a key factor limiting resource utilization for Bermudagrass. Therefore, it is relevant to study the mechanisms by which Burmudagrass responds to cold. Melatonin is a crucial animal and plant hormone that is responsible for plant abiotic stress responses. The objective of this study was to investigate the role of melatonin in cold stress response of Bermudagrass. Wild Bermudagrass pre-treated with 100 μM melatonin was subjected to different cold stress treatments (−5°C for 8 h with or without cold acclimation). The results showed lower malondialdehyde (MDA) and electrolyte leakage (EL) values, higher levels of chlorophyll, and greater superoxide dismutase and peroxidase activities after melatonin treatment than those in non-melatonin treatment under cold stress. Analysis of chlorophyll a revealed that the chlorophyll fluorescence transient (OJIP) curves were higher after treatment with melatonin than that of non-melatonin treated plants under cold stress. The values of photosynthetic fluorescence parameters increased after treatment with melatonin under cold stress. The analysis of metabolism showed alterations in 46 metabolites in cold-stressed plants after melatonin treatment. Among the measured metabolites, five sugars (arabinose, mannose, glucopyranose, maltose, and turanose) and one organic acid (propanoic acid) were significantly increased. However, valine and threonic acid contents were reduced in melatonin-treated plants. In summary, melatonin maintained cell membrane stability, increased antioxidant enzymes activities, improved the process of photosystem II, and induced alterations in Bermudagrass metabolism under cold stress. PMID:26579171

  19. Secretion of Sparfloxacin from the Human Intestinal Caco-2 Cell Line Is Altered by P-Glycoprotein Inhibitors

    PubMed Central

    Cormet-Boyaka, Estelle; Huneau, Jean-François; Mordrelle, Agnès; Boyaka, Prosper N.; Carbon, Claude; Rubinstein, Ethan; Tomé, Daniel

    1998-01-01

    The mechanism of intestinal secretion of the difluorinated quinolone sparfloxacin was investigated with the epithelial cell line Caco-2 and was compared to that of the P-glycoprotein (P-gp) substrate vinblastine. The P-gp inhibitors verapamil and progesterone significantly increased the epithelial cell accumulation of both vinblastine and sparfloxacin. This increase is likely to result from an inhibition of drug secretion since both vinblastine uptake and sparfloxacin uptake are known to proceed through a passive transmembrane diffusion. The unidirectional fluxes across cell monlayers grown on permeable filters indicated that a net secretion of sparfloxacin and vinblastine occurred across Caco-2 cells. These secretions were significantly inhibited by the MDR-reversing agent verapamil. We conclude that the P-gp is likely to be involved in the intestinal elimination of the difluorinated quinolone sparfloxacin. PMID:9756763

  20. Melatonin: Buffering the Immune System

    PubMed Central

    Carrillo-Vico, Antonio; Lardone, Patricia J.; Álvarez-Sánchez, Nuria; Rodríguez-Rodríguez, Ana; Guerrero, Juan M.

    2013-01-01

    Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed. PMID:23609496

  1. Calcium-signaling components in rat insulinoma β-cells (INS-1) and pancreatic islets are differentially influenced by melatonin.

    PubMed

    Bazwinsky-Wutschke, Ivonne; Mühlbauer, Eckhard; Albrecht, Elke; Peschke, Elmar

    2014-05-01

    The pineal secretory product melatonin exerts its influence on the insulin secretion of pancreatic islets by different signaling pathways. The purpose of this study was to analyze the impact of melatonin on calcium-signaling components under different conditions. In a transfected INS-1 cell line overexpressing the human MT2 receptor (hMT2-INS-1), melatonin treatment induced even stronger depressive effects on calcium/calmodulin-dependent kinase 2d and IV (Camk2d, CamkIV) transcripts during 3-isobutyl-1-methylxanthine (IBMX) treatment than in normal INS-1 cells, indicating a crucial influence of melatonin receptor density on transcript-level regulation. In addition, melatonin induced a significant downregulation of calmodulin (Calm1) in IBMX-treated hMT2-INS-1 cells. Long-term administration of melatonin alone reduced CamkIV transcript levels in INS-1 cells; however, transcript levels of Camk2d remained unchanged. The release of insulin was diminished under long-term melatonin treatment. The impact of melatonin also involved reductions in CAMK2D protein during IBMX or forskolin treatments in INS-1 cells, as measured by an enzyme-linked immunosorbent assay, indicating a functional significance of transcriptional changes in pancreatic islets. Furthermore, analysis of melatonin receptor knockout mice showed that the transcript levels of Camk2d, CamkIV, and Calm1 were differentially influenced according to the melatonin receptor subtype deleted. In conclusion, this study provides evidence that melatonin has different impacts on the regulation of Calm1 and Camk. These calcium-signaling components are known as participants in the calcium/calmodulin pathway, which plays an important functional role in the modulation of the β-cell signaling pathways leading to insulin secretion.

  2. Response of plasma prorenin and active renin to chronic and acute alterations of renin secretion in normal humans. Studies using a direct immunoradiometric assay.

    PubMed Central

    Toffelmire, E B; Slater, K; Corvol, P; Menard, J; Schambelan, M

    1989-01-01

    We employed a novel immunoradiometric assay to measure plasma levels of active renin and prorenin in physiologic and pharmacologic studies designed to characterize renin biosynthesis and processing in response to both chronic and acute stimuli of renin secretion in normal human subjects. Stimulation of renin secretion with prolonged dietary sodium restriction or amiloride resulted in marked increases in the plasma levels of prorenin, active renin, and plasma renin activity (PRA); suppression of renin secretion with indomethacin resulted in parallel decreases in prorenin, active renin, and PRA. In contrast, acute stimulation with upright activity or administration of an angiotensin-converting enzyme inhibitor, which increased active renin and PRA from 2- to 15-fold, had no effect on prorenin levels. Based on studies in cultured human juxtaglomerular tumor cells, it has been proposed that prorenin is secreted constitutively whereas active renin is stored in and released from secretory granules through a regulated pathway. Our studies are consistent with such a model: the parallel changes in active renin and prorenin with experimental maneuvers of long duration suggest that both the constitutive and regulated pathways are altered under these conditions. The increase in active renin levels in the absence of a change in prorenin that occurs in response to acute stimuli presumably represents the release of preformed active enzyme that is stored in secretory granules. PMID:2643635

  3. The benefits of four weeks of melatonin treatment on circadian patterns in resistance-trained athletes.

    PubMed

    Leonardo-Mendonça, Roberto C; Martinez-Nicolas, Antonio; de Teresa Galván, Carlos; Ocaña-Wilhelmi, Javier; Rusanova, Iryna; Guerra-Hernández, Eduardo; Escames, Germaine; Acuña-Castroviejo, Darío

    2015-01-01

    Exercise can induce circadian phase shifts depending on the duration, intensity and frequency. These modifications are of special meaning in athletes during training and competition. Melatonin, which is produced by the pineal gland in a circadian manner, behaves as an endogenous rhythms synchronizer, and it is used as a supplement to promote resynchronization of altered circadian rhythms. In this study, we tested the effect of melatonin administration on the circadian system in athletes. Two groups of athletes were treated with 100 mg day(-1) of melatonin or placebo 30 min before bed for four weeks. Daily rhythm of salivary melatonin was measured before and after melatonin administration. Moreover, circadian variables, including wrist temperature (WT), motor activity and body position rhythmicity, were recorded during seven days before and seven days after melatonin or placebo treatment with the aid of specific sensors placed in the wrist and arm of each athlete. Before treatment, the athletes showed a phase-shift delay of the melatonin circadian rhythm, with an acrophase at 05:00 h. Exercise induced a phase advance of the melatonin rhythm, restoring its acrophase accordingly to the chronotype of the athletes. Melatonin, but not placebo treatment, changed daily waveforms of WT, activity and position. These changes included a one-hour phase advance in the WT rhythm before bedtime, with a longer nocturnal steady state and a smaller reduction when arising at morning than the placebo group. Melatonin, but not placebo, also reduced the nocturnal activity and the activity and position during lunch/nap time. Together, these data reflect the beneficial effect of melatonin to modulate the circadian components of the sleep-wake cycle, improving sleep efficiency. PMID:26361788

  4. Melatonin induces gene-specific effects on rhythmic mRNA expression in the pars tuberalis of the Siberian hamster (Phodopus sungorus).

    PubMed

    Wagner, Gabriela C; Johnston, Jonathan D; Tournier, Benjamin B; Ebling, Francis J P; Hazlerigg, David G

    2007-01-01

    In mammals, circadian and photoperiodic information is encoded in the pineal melatonin signal. The pars tuberalis (PT) of the pituitary is a melatonin target tissue, which transduces photoperiodic changes and drives seasonal changes in prolactin secretion from distal lactotroph cells. Measurement of photoperiodic time in the PT is believed to occur through melatonin dependent changes in clock gene expression, although it is unclear whether the PT should be considered a melatonin sensitive peripheral oscillator. We tested this hypothesis in the Siberian hamster (Phodopus sungorus) firstly by investigating the effects of melatonin injection, and secondly by determining whether temporal variation in gene expression within the PT persists in the absence of a rhythmic melatonin signal. Hamsters preconditioned to long days were treated with melatonin during the late light phase, to advance the timing of the nocturnal melatonin peak, or placed in constant light for one 24 h cycle, thereby suppressing endogenous melatonin secretion. Gene expression in the PT was measured by in situ hybridization. We show that melatonin rapidly induces cry1 mRNA expression without the need for a prolonged melatonin-free interval, acutely inhibits mt1 expression, advances the timing of peak rev-erb alpha expression and modulates per1 expression. With the exception of cry1, these genes continue to show temporal changes in expression over a first cycle in the absence of a melatonin signal. Our data are consistent with the hypothesis that the hamster PT contains a damped endogenous circadian oscillator, which requires a rhythmic melatonin signal for long-term synchronization.

  5. Melatonin-mediated insulin synthesis during endoplasmic reticulum stress involves HuD expression in rat insulinoma INS-1E cells.

    PubMed

    Yoo, Yeong-Min

    2013-09-01

    In this study, we investigated how melatonin mediates insulin synthesis through endoplasmic reticulum (ER) via HuD expression in rat insulinoma INS-1E cells. Under ER stress condition (thapsigargin with/without melatonin, tunicamycin with/without melatonin), phosphorylation of AMP-activated protein kinase (p-AMPK) was significantly increased when compared with only with/without melatonin (control/melatonin). Insulin receptor substrate (IRS) two protein was significantly reduced under conditions of ER stress when compared with control/melatonin, but no expression of IRS1 protein was observed. In thapsigargin treatment, melatonin (10, 50 μm) increased IRS2 protein expression in a dose-dependent manner. p-Akt (Ser473) expression significantly decreased under ER stress condition prior to control/melatonin. Melatonin (10, 50 μm) significantly reduced nuclear and cellular p85α expressions in a dose-dependent manner when compared with only thapsigargin or tunicamycin. These results indicate the activation of the aforementioned expressions under regulation of the pathway, AMPK → IRS2 → Akt/PKB → PI3K (p85α). However, mammalian target of rapamycin and raptor protein, mTORC1, was found to be independent of the ER stress response. In thapsigargin treatment, melatonin increased nuclear mammalian RNA-binding protein (HuD) expression and reduced cellular HuD expression and subsequently resulted in a decrease in cellular insulin level and rise in insulin secretion in a dose-dependent manner. In tunicamycin treatment, HuD and insulin proteins showed similar expression tendencies. These results indicate that ER stress/melatonin, especially thapsigargin/melatonin, increased nuclear HuD expression and subsequently resulted in a decrease in intracellular biosynthesis; it is hypothesized that extracellular secretion of insulin may be regulated by melatonin.

  6. Seasonal serum concentrations of melatonin in cycling and noncycling mares.

    PubMed

    Diekman, M A; Braun, W; Peter, D; Cook, D

    2002-11-01

    To determine whether secretory patterns of melatonin change throughout the seasons in mares, blood samples were drawn byvenipuncture from nine mares at noon and midnight for five successive days at monthly intervals from August through July at the University of Missouri in Columbia, MO. In addition, during September, December, March, and June, blood samples were drawn from indwelling catheters at 2-h intervals for 48 or 72 h. Mares were predominantly Quarter Horses weighing approximately 450 kg and ranged from 3 to 12 yr of age. Mares were housed in outdoor paddocks with three-sided run-in sheds for shelter. During the noon and midnight bleeding period, mares were placed in a larger open-sided barn with outside runs. Mares remained outdoors with the barn being used as a shelter in the event of inclement weather. All lights in the shed were converted to red light. Often, moonlight provided enough illumination to collect blood samples. Mares were returned to their normal paddock after each sampling period. For analysis of data, a mare was considered to be cycling if serum concentrations of progesterone were greater than 1 ng/ mL. For a mare to be classified as exhibiting a nocturnal rise of melatonin, serum concentrations of melatonin had to be at least two times greater at midnight than at noon. By month, a relationship did not exist (chi2; P > 0.05) among mares that were exhibiting estrous cycles and exhibiting nocturnal rises of melatonin. Likewise, examination of serum profiles of melatonin taken at 2-h intervals for 48 h revealed considerable variation among mares throughout the seasons. A nocturnal rise in serum melatonin was observed only in June (P < 0.02). In March and December, serum melatonin was greater in cycling mares than noncycling mares, but the elevation was not associated with light-dark periods (P < 0.01). Two of the mares exhibited estrous cycles throughout the seasons but melatonin secretion in these two mares were similar to that observed in

  7. Mutual effects of melatonin and activin on induction of aldosterone production by human adrenocortical cells.

    PubMed

    Hara, Takayuki; Otsuka, Fumio; Tsukamoto-Yamauchi, Naoko; Inagaki, Kenichi; Hosoya, Takeshi; Nakamura, Eri; Terasaka, Tomohiro; Komatsubara, Motoshi; Makino, Hirofumi

    2015-08-01

    Melatonin has been reported to suppress adrenocorticotropin (ACTH) secretion in the anterior pituitary and cortisol production in the adrenal by different mechanisms. However, the effect of melatonin on aldosterone production has remained unknown. In this study, we investigated the role of melatonin in the regulation of aldosterone production using human adrenocortical H295R cells by focusing on the activin system expressed in the adrenal. Melatonin receptor MT1 mRNA and protein were expressed in H295R cells and the expression levels of MT1 were increased by activin treatment. Activin increased ACTH-induced, but not angiotensin II (Ang II)-induced, aldosterone production. Melatonin alone did not affect basal synthesis of either aldosterone or cortisol. However, melatonin effectively enhanced aldosterone production induced by co-treatment with ACTH and activin, although melatonin had no effect on aldosterone production induced by Ang II in combination with activin. These changes in steroidogenesis became apparent when the steroid production was evaluated by the ratio of aldosterone/cortisol. Melatonin also enhanced dibutyryl-AMP-induced aldosterone/cortisol levels in the presence of activin, suggesting a functional link to the cAMP-PKA pathway for induction of aldosterone production by melatonin and activin. In accordance with the data for steroids, ACTH-induced, but not Ang II-induced, cAMP synthesis was also amplified by co-treatment with melatonin and activin. Furthermore, the ratio of ACTH-induced mRNA level of CYP11B2 compared with that of CYP17 was amplified in the condition of treatment with both melatonin and activin. In addition, melatonin increased expression of the activin type-I receptor ALK-4 but suppressed expression of inhibitory Smads6/7, leading to the enhancement of Smad2 phosphorylation. Collectively, the results showed that melatonin facilitated aldosterone production induced by ACTH and activin via the cAMP-PKA pathway. The results also

  8. Melatonin promotes ripening and improves quality of tomato fruit during postharvest life.

    PubMed

    Sun, Qianqian; Zhang, Na; Wang, Jinfang; Zhang, Haijun; Li, Dianbo; Shi, Jin; Li, Ren; Weeda, Sarah; Zhao, Bing; Ren, Shuxin; Guo, Yang-Dong

    2015-02-01

    In this study, the effect of melatonin on the postharvest ripening and quality improvement of tomato fruit was carried out. The tomatoes were immersed in exogenous melatonin for 2h, and then the related physiological indicators and the expression of genes during post-harvest life were evaluated. Compared with control check (CK), the 50 µM melatonin treatment significantly increased lycopene levels by 5.8-fold. Meanwhile, the key genes involved in fruit colour development, including phytoene synthase1 (PSY1) and carotenoid isomerase (CRTISO), showed a 2-fold increase in expression levels. The rate of water loss from tomato fruit also increased 8.3%, and the expression of aquaporin genes, such as SlPIP12Q, SlPIPQ, SlPIP21Q, and SlPIP22, was up-regulated 2- to 3-fold under 50 µM melatonin treatment. In addition, 50 µM melatonin treatment enhanced fruit softening, increased water-soluble pectin by 22.5%, and decreased protopectin by 19.5%. The expression of the cell wall modifying proteins polygalacturonase (PG), pectin esterase1 (PE1), β-galactosidase (TBG4), and expansin1 (Exp1) was up-regulated under 50 µM melatonin treatment. Melatonin increased ethylene production by 27.1%, accelerated the climacteric phase, and influenced the ethylene signalling pathway. Alteration of ethylene production correlated with altered 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS4) expression. The expression of ethylene signal transduction-related genes such as NR, SlETR4, SlEIL1, SlEIL3, and SlERF2, was enhanced by 50 µM melatonin. The effect of melatonin on ethylene biosynthesis, ethylene perception, and ethylene signalling may contribute to fruit ripening and quality improvement in tomato. This research may promote the application of melatonin on postharvest ripening and quality improvement of tomato fruit as well as other horticultural productions in the future.

  9. Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders.

    PubMed

    Williams, Wilbur P Trey; McLin, Dewey E; Dressman, Marlene A; Neubauer, David N

    2016-09-01

    Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs.

  10. Melatonin effect on rat body weight regulation in response to high-fat diet at middle age.

    PubMed

    Puchalski, Stephaney S; Green, Jill N; Rasmussen, Dennis D

    2003-07-01

    We previously demonstrated that daily melatonin administration to middle-aged rats to restore youthful plasma melatonin levels also decreased body weight, visceral fat, plasma leptin, and plasma insulin to more youthful levels, without detectable changes in consumption of chow diet. We now evaluate: (a) whether melatonin alters consumption of a more precisely quantifiable liquid diet similar in high-fat content to the typical American diet; (b) differences between melatonin-induced endocrine responses in the fasted vs fed state; and (c) time course of these responses. Ten-month-old male Sprague- Dawley rats received liquid diet containing either 0.2 micro g/mL melatonin (MELATONIN) or vehicle (CONTROL) (n = 14/treatment); the diet was available throughout each night, but was removed for the final 10 h of each daytime. MELATONIN rats gained 4% body weight during the first 2 wk and then stabilized, whereas CONTROL rats continued to gain for an additional week, achieving 8% gain (p < 0.05 vs MELATONIN). During the first 3 wk, afternoon tail-blood leptin, but not insulin, levels decreased in melatonin-treated rats (p < 0.05 vs CONTROL). After 8 wk, half of the rats were killed at the midpoint of the dark period (NIGHT; fed) and half at the end of the light period (DAYTIME; fasted). NIGHT but not DAYTIME plasma leptin levels were decreased in MELATONIN rats, whereas DAYTIME but not NIGHT plasma insulin levels were decreased (p < 0.05 vs CONTROL). Melatonin treatment did not alter cumulative food consumption. Thus, melatonin decreased weight gain in response to high-fat diet, decreased plasma leptin levels within 3 wk-before decreasing plasma insulin-and exerted these metabolic effects independent of total food consumption.

  11. Melatonin and Parkinson's disease.

    PubMed

    Mayo, Juan C; Sainz, Rosa M; Tan, Dun-Xian; Antolín, Isaac; Rodríguez, Carmen; Reiter, Russel J

    2005-07-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is characterized by a progressive loss of dopamine in the substantia nigra and striatum. However, over 70% of dopaminergic neuronal death occurs before the first symptoms appear, which makes either early diagnosis or effective treatments extremely difficult. Only symptomatic therapies have been used, including levodopa (l-dopa), to restore dopamine content; however, the use of l-dopa leads to some long-term pro-oxidant damage. In addition to a few specific mutations, oxidative stress and generation of free radicals from both mitochondrial impairment and dopamine metabolism are considered to play critical roles in PD etiology. Thus, the use of antioxidants as an important co-treatment with traditional therapies for PD has been suggested. Melatonin, or N-acetyl-5-methoxy-tryptamine, an indole mainly produced in the pineal gland, has been shown to have potent endogenous antioxidant actions. Because neurodegenerative disorders are mainly caused by oxidative damage, melatonin has been tested successfully in both in vivo and in vitro models of PD. The present review provides an up-to-date account of the findings and mechanisms involved in neuroprotection of melatonin in PD.

  12. The anti-tumor activity of pineal melatonin and cancer enhancing life styles in industrialized societies.

    PubMed

    Bartsch, Christian; Bartsch, Hella

    2006-05-01

    This review discusses the potential role of the anti-tumor activity of pineal melatonin for the aetiology and prevention of cancers related to life-styles in industrialized societies, e.g. frequent long-distance flights as well as chronic night shift work leading to circadian disturbances of neuroendocrine parameters including melatonin. Experimental studies show that melatonin controls not only the growth of well-differentiated cancers, but also possesses anti-carcinogenic properties. Therefore, it is plausible that disturbances of circadian melatonin rhythmicity could be functionally involved in elevated cancer risks among aircrew members and nurses frequently working on night shifts. Due to the suppression of melatonin by light it can be assumed that too much artificial light at night could, at least in part, be responsible for generally increasing rates of e.g. breast cancer in industrialized countries. It is discussed under which conditions a transient substitutional therapy with melatonin could be justified or which forms of living could help to physiologically foster melatonin secretion to optimise control over cancerous growth and development.

  13. Melatonin prevents neural tube defects in the offspring of diabetic pregnancy.

    PubMed

    Liu, Shangming; Guo, Yuji; Yuan, Qiuhuan; Pan, Yan; Wang, Liyan; Liu, Qian; Wang, Fuwu; Wang, Jingjing; Hao, Aijun

    2015-11-01

    Melatonin, an endogenous neurohormone secreted by the pineal gland, has a variety of physiological functions and neuroprotective effects. However, its protective role on the neural tube defects (NTDs) was not very clear. The aim of this study was to investigate the effects of melatonin on the incidence of NTDs (including anencephaly, encephalocele, and spina bifida) of offspring from diabetic pregnant mice as well as its underlying mechanisms. Pregnant mice were given 10 mg/kg melatonin by daily i.p. injection from embryonic day (E) 0.5 until being killed on E11.5. Here, we showed that melatonin decreased the NTDs (especially exencephaly) rate of embryos exposed to maternal diabetes. Melatonin stimulated proliferation of neural stem cells (NSCs) under hyperglycemic condition through the extracellular regulated protein kinases (ERK) pathway. Furthermore, as a direct free radical scavenger, melatonin decreased apoptosis of NSCs exposed to hyperglycemia. In the light of these findings, it suggests that melatonin supplementation may play an important role in the prevention of neural malformations in diabetic pregnancy. PMID:26475080

  14. Melatonin Signaling Controls the Daily Rhythm in Blood Glucose Levels Independent of Peripheral Clocks.

    PubMed

    Owino, Sharon; Contreras-Alcantara, Susana; Baba, Kenkichi; Tosini, Gianluca

    2016-01-01

    Melatonin is rhythmically secreted by both the pineal gland and retina in a circadian fashion, with its peak synthesis occurring during the night. Once synthesized, melatonin exerts its effects by binding to two specific G-protein coupled receptors-melatonin receptor type 1(MT1) and melatonin receptor type 2(MT2). Recent studies suggest the involvement of MT1 and MT2 in the regulation of glucose homeostasis; however the ability of melatonin signaling to impart timing cues on glucose metabolism remains poorly understood. Here we report that the removal of MT1 or MT2 in mice abolishes the daily rhythm in blood glucose levels. Interestingly, removal of melatonin receptors produced small effects on the rhythmic expression patterns of clock genes within skeletal muscle, liver, and adipose tissue. Taken together, our data suggest that the loss of the daily rhythm in blood glucose observed in MT1(-/-) and MT2(-/-) mice does not occur as a consequence of 'disrupted' clocks within insulin sensitive tissues. Finally our results highlight a diurnal contribution of melatonin receptor signaling in the daily regulation of blood glucose levels.

  15. Insulin modulates norepinephrine-mediated melatonin synthesis in cultured rat pineal gland.

    PubMed

    Garcia, Rodrigo Antonio Peliciari; Afeche, Solange Castro; Scialfa, Julieta Helena; do Amaral, Fernanda Gaspar; dos Santos, Sabrina Heloísa José; Lima, Fabio Bessa; Young, Martin Elliot; Cipolla-Neto, José

    2008-01-01

    The mammalian pineal gland synthesizes melatonin in a circadian manner, peaking during the dark phase. This synthesis is primarily regulated by sympathetic innervations via noradrenergic fibers, but is also modulated by many peptidergic and hormonal systems. A growing number of studies reveal a complex role for melatonin in influencing various physiological processes, including modulation of insulin secretion and action. In contrast, a role for insulin as a modulator of melatonin synthesis has not been investigated previously. The aim of the current study was to determine whether insulin modulates norepinephrine (NE)-mediated melatonin synthesis. The results demonstrate that insulin (10(- 8)M) potentiated norepinephrine-mediated melatonin synthesis and tryptophan hydroxylase (TPOH) activity in ex vivo incubated pineal glands. When ex vivo incubated pineal glands were synchronized (12h NE-stimulation, followed by 12h incubation in the absence of NE), insulin potentiated NE-mediated melatonin synthesis and arylalkylamine-N-acetyltransferase (AANAT) activity. Insulin did not affect the activity of hydroxyindole-O-methyltranferase (HIOMT), nor the gene expression of tpoh, aanat, or hiomt, under any of the conditions investigated. We conclude that insulin potentiates NE-mediated melatonin synthesis in cultured rat pineal gland, potentially through post-transcriptional events.

  16. Melatonin, light and chronobiological disorders.

    PubMed

    Lewy, A J; Sack, R L; Singer, C M

    1985-01-01

    Human plasma melatonin concentrations can be measured accurately and sensitively by gas chromatography-negative chemical ionization mass spectrometry. With this assay, we have shown that: in rats and in humans, plasma melatonin is exclusively derived from the pineal gland; propranolol and clonidine reduce melatonin levels in human; some blind people appear to have free-running melatonin secretory circadian rhythms; bright light can acutely suppress human melatonin production according to a linear fluence-response relationship; manic-depressive patients appear to be supersensitive to light, even when they are well; melatonin levels are greater in manic patients than in depressed patients; in experiments to test the clock-gate model and the hypothesized phase-response curve, two different effects of light appear to present in humans: an acute suppressant effect (mainly in the evening during long photoperiods) and an entrainment effect (particularly during the morning but also in the evening). When blood is sampled for measuring melatonin levels as a marker for circadian phase position, bright light should be avoided after 5 p.m. (the dim light melatonin onset). Bright-light exposure in the morning appears to advance circadian rhythms, whereas bright-light exposure in the evening appears to delay them. Once a patient has been 'phase typed' (phase-advanced vs. phase-delayed), predictions can be made about whether morning or evening light would be more effective in treating the sleep or mood disorder. PMID:3836816

  17. Inter-relationships of the chronobiotic, melatonin, with leptin and adiponectin: implications for obesity.

    PubMed

    Szewczyk-Golec, Karolina; Woźniak, Alina; Reiter, Russel J

    2015-10-01

    Obesity and its medical complications represent a significant problem throughout the world. In recent decades, mechanisms underlying the progression of obesity have been intensively examined. The involvement of both the behavioral aspects, such as calorie-rich diet, low physical activity and sleep deprivation, and the intrinsic factors, including adipose tissue deregulation, chronic inflammation, oxidative stress, and chronodisruption, has been identified. The circadian disturbances of the adipose tissue endocrine function have been correlated with obesity. Leptin and adiponectin are adipokines strongly associated with glucose and lipid metabolism and with energy balance. Their synthesis and secretion display circadian rhythms that are disturbed in the obese state. Hyperleptinemia resulting in leptin resistance, and hypo-adiponectinemia have been linked to the pathophysiology of the obesity-related disorders. A deficiency of melatonin, one of the consequences of sleep deprivation, has also been demonstrated to correlate with obesity. Melatonin is a pineal secretory product involved in numerous actions, such as regulation of internal biological clocks and energy metabolism, and it functions as an antioxidant and as an anti-inflammatory agent. There exists a substantial amount of evidence supporting the beneficial effects of melatonin supplementation on obesity and its complications. In the current review, the results of studies related to the interactions between melatonin, and both leptin and adiponectin are discussed. Despite the existence of some inconsistencies, melatonin has been found to normalize the expression and secretion patterns of both adipokines. These results support the concept of melatonin as a potential therapeutic agent for obesity and related disorders.

  18. Genetic, temporal and developmental differences between melatonin rhythm generating systems in the teleost fish pineal organ and retina.

    PubMed

    Falcón, J; Gothilf, Y; Coon, S L; Boeuf, G; Klein, D C

    2003-04-01

    Complete melatonin rhythm generating systems, including photodetector, circadian clock and melatonin synthesis machinery, are located within individual photoreceptor cells in two sites in Teleost fish: the pineal organ and retina. In both, light regulates daily variations in melatonin secretion by controlling the activity of arylalkylamine N-acetyltransferase (AANAT). However, in each species examined to date, marked differences exist between the two organs which may involve the genes encoding the photopigments, genes encoding AANAT, the times of day at which AANAT activity and melatonin production peak and the developmental schedule. We review the fish pineal and retinal melatonin rhythm generating systems and consider the evolutional pressures and other factors which led to these differences.

  19. Impact of maternal melatonin suppression on forced swim and tail suspension behavioral despair tests in adult offspring

    PubMed Central

    Voiculescu, SE; Rosca, AE; Zeca, V; Zagrean, L; Zagrean, AM

    2015-01-01

    Melatonin is an essential hormone, which regulates circadian rhythms and has antioxidative and anticarcinogenic effects. As melatonin secretion is suppressed by light, this effect was examined on the offspring of the Wistar rat females exposed to continuous light (500 lux) during the second half of the pregnancy (day 12 to 21). Control rats were kept under a 12:12 light-dark cycle. The resulted male offspring have been behaviorally assessed for depression after postnatal day 60 by using Forced Swim Test (FST) and Tail Suspension Test (TST). Animals resulted from the melatonin deprived pregnancies have developed an abnormal response in the TST, but a normal FST behavior. Also, TST active movement was different in the melatonin suppression group compared to the control group. These findings suggest that intrauterine melatonin deprivation might be linked to the depressive like behavior in adult male offspring. PMID:25866579

  20. Melatonin enhances DNA repair capacity possibly by affecting genes involved in DNA damage responsive pathways

    PubMed Central

    2013-01-01

    Background Melatonin, a hormone-like substance involved in the regulation of the circadian rhythm, has been demonstrated to protect cells against oxidative DNA damage and to inhibit tumorigenesis. Results In the current study, we investigated the effect of melatonin on DNA strand breaks using the alkaline DNA comet assay in breast cancer (MCF-7) and colon cancer (HCT-15) cell lines. Our results demonstrated that cells pretreated with melatonin had significantly shorter Olive tail moments compared to non-melatonin treated cells upon mutagen (methyl methanesulfonate, MMS) exposure, indicating an increased DNA repair capacity after melatonin treatment. We further examined the genome-wide gene expression in melatonin pretreated MCF-7 cells upon carcinogen exposure and detected altered expression of many genes involved in multiple DNA damage responsive pathways. Genes exhibiting altered expression were further analyzed for functional interrelatedness using network- and pathway-based bioinformatics analysis. The top functional network was defined as having relevance for “DNA Replication, Recombination, and Repair, Gene Expression, [and] Cancer”. Conclusions These findings suggest that melatonin may enhance DNA repair capacity by affecting several key genes involved in DNA damage responsive pathways. PMID:23294620

  1. Critical time delay of the pineal melatonin rhythm in humans due to weak electromagnetic exposure.

    PubMed

    Halgamuge, Malka N

    2013-08-01

    Electromagnetic fields (EMFs) can increase free radicals, activate the stress response and alter enzyme reactions. Intracellular signalling is mediated by free radicals and enzyme kinetics is affected by radical pair recombination rates. The magnetic field component of an external EMF can delay the "recombination rate" of free radical pairs. Magnetic fields thus increase radical life-times in biological systems. Although measured in nanoseconds, this extra time increases the potential to do more damage. Melatonin regulates the body's sleep-wake cycle or circadian rhythm. The World Health Organization (WHO) has confirmed that prolonged alterations in sleep patterns suppress the body's ability to make melatonin. Considerable cancer rates have been attributed to the reduction of melatonin production as a result of jet lag and night shift work. In this study, changes in circadian rhythm and melatonin concentration are observed due to the external perturbation of chemical reaction rates. We further analyze the pineal melatonin rhythm and investigate the critical time delay or maturation time of radical pair recombination rates, exploring the impact of the mRNA degradation rate on the critical time delay. The results show that significant melatonin interruption and changes to the circadian rhythm occur due to the perturbation of chemical reaction rates, as also reported in previous studies. The results also show the influence of the mRNA degradation rate on the circadian rhythm's critical time delay or maturation time. The results support the hypothesis that exposure to weak EMFs via melatonin disruption can adversely affect human health.

  2. Static and extremely low frequency electromagnetic field exposure: reported effects on the circadian production of melatonin.

    PubMed

    Reiter, R J

    1993-04-01

    -visible electromagnetic fields influence the melatonin forming ability of the pineal gland remain unknown; however, the retinas in particular have been theorized to serve as magnetoreceptors with the altered melatonin cycle being a consequence of a disturbance in the neural biological clock, i.e., the suprachiasmatic nuclei (SCN) of the hypothalamus, which generates the circadian melatonin rhythm. The disturbances in pineal melatonin production induced by either light exposure or non-visible electromagnetic field exposure at night appear to be the same but whether the underlying mechanisms are similar remains unknown. PMID:8098713

  3. Developmental effect of light deprivation on synaptic plasticity of rats’ hippocampus: implications for melatonin

    PubMed Central

    Talaei, Sayyed Alireza; Azami, Abolfazl; Salami, Mahmoud

    2016-01-01

    Objective(s): There are few reports have demonstrated the effect of a change-in-light experience on the structure and function of hippocampus. A change-in-light experience also affects the circadian pattern of melatonin secretion. This study aimed to investigate developmental effect of exogenous melatonin on synaptic plasticity of hippocampus of light deprived rats. Materials and Methods: The effects of intracerebroventricular (ICV) injection of 2μg/5μl melatonin was evaluated on the basic and tetanized field excitatory post-synaptic potentials (fEPSPs) recorded in the hippocampal CA3-CA1 pathway of normal light-reared (LR) and dark-reared (DR) rats at 2, 4, and 6 weeks of age. Using RT-PCR and western blotting, developmental changes in the expression of melatonin receptors, MT1 and MT2, in the hippocampus were also evaluated. Results: The amplitude of basic responses decreased across age in the LR rats. While light deprivation increased the amplitude of baseline fEPSPs, it decreased the degree of potentiation in post-tetanus responses. Melatonin injection also increased the amplitude of fEPSPs and suppressed the induction of long-term potentiation in both LR and DR rats. The expression of melatonin receptors increased in the hippocampus during brain development, and dark rearing reversed the expression patterns of both receptors. Conclusion: Although melatonin changed basic and tetanized responses of CA1 neurons across age during critical period of brain development, the pattern of its effects did not match the expression pattern of melatonin receptors in the hippocampus. Thus, the effects of melatonin on hippocampal neuronal responses may be exerted through other ways, like intercellular molecules and nuclear hormone receptors. PMID:27746873

  4. Seasonal variations in the nycthemeral rhythm of plasma melatonin in the camel (Camelus dromedarius).

    PubMed

    El Allali, K; Achaaban, M R; Vivien-Roels, B; Bothorel, B; Tligui, N S; Pévet, P

    2005-09-01

    Seasonal changes in the pattern of plasma melatonin were investigated in two groups of camels (Camelus dromedarius): 11 adult and six young camels. Animals were subjected to the outdoor conditions of a desert environment. Blood samples were taken at regular intervals of about 3 hr (added to particular samples at 1 hr before then 30 min and 1 hr after sunset, and 1 hr before and 1 hr after sunrise) for 24 hr at both solstices and equinoxes of the year. The plasma melatonin levels steeply increased soon after sunset and remained elevated throughout all the night. Then, melatonin concentrations progressively declined shortly before sunrise and returned to daytime basal levels 1 hr later. There was no seasonal variation in the amplitude or in the offset of the melatonin peak or in the daytime basal levels. The onset of the nocturnal peak was delayed by 2 hr in June at the summer solstice (P < 0.05), which can be related to the changes in night length between the two solstices. A significant effect of age was observed in all seasons. Melatonin levels were higher in the young camel group (fall equinox: P < 0.001; spring equinox: P < 0.01; winter solstice: P < 0.01; summer solstice: P < 0.05). The pattern of melatonin secretion in the camel showed a significant seasonal variation parallel to the photoperiodic changes of the year. The observed decline of melatonin levels during an extra-light pulse in the middle of the night indicates the light control of melatonin synthesis. It is not yet known if, in this low latitude desert region, the seasonal breeding period of the camel is cued by the photoperiod. The data obtained, however, clearly demonstrate that the camel has the capacity to follow and to integrate photoperiodic changes through melatonin changes. PMID:16098088

  5. Prospective Study on Salivary Evening Melatonin and Sleep before and after Pinealectomy in Humans.

    PubMed

    Slawik, Helen; Stoffel, Michael; Riedl, Lina; Veselý, Zdenko; Behr, Michael; Lehmberg, Jens; Pohl, Corina; Meyer, Bernhard; Wiegand, Michael; Krieg, Sandro M

    2016-02-01

    Melatonin is secreted systemically from the pineal gland maximally at night but is also produced locally in many tissues. Its chronobiological function is mainly exerted by pineal melatonin. It is a feedback regulator of the main circadian pacemaker in the hypothalamic suprachiasmatic nuclei and of many peripheral oscillators. Although exogenous melatonin is approved for circadian rhythm sleep disorders and old-age insomnia, research on endogenous melatonin in humans is hindered by the great interindividual variability of its amount and circadian rhythm. Single case studies on pinealectomized patients report on disrupted but also hypersomnic sleep. This is the first systematic prospective report on sleep with respect to pinealectomy due to pinealocytoma World Health Organization grade I without chemo- or radiotherapy. Before and after pinealectomy, 8 patients completed questionnaires on sleep quality and circadian rhythm (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Morningness-Eveningness Questionnaire), 2 nights of polysomnography, salivary evening melatonin profiles, and qualitative assessment of 2 weeks of actigraphy and sleep logs. Six patients were assessed retrospectively up to 4 years after pinealectomy. Before pinealectomy, all but 1 patient showed an evening melatonin rise typical for indifferent chronotypes. After pinealectomy, evening saliva melatonin was markedly diminished, mostly below the detection limit of the assay (0.09 pg/mL). No systematic change in subjective sleep quality or standard measures of polysomnography was found. Mean pre- and postoperative sleep efficiency was 94% and 95%, and mean sleep-onset latency was 21 and 17 min, respectively. Sleep-wake rhythm during normal daily life did not change. Retrospective patients had a reduced sleep efficiency (90%) and more stage changes, although this was not significantly different from prospective patients. In conclusion, melatonin does seem to have a modulatory, not a

  6. Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced IL-6 secretion

    PubMed Central

    Shehu Shey, Muki; Randhawa, April Kaur; Bowmaker, Mark; Smith, Elizabeth; Jens Scriba, Thomas; de Kock, Marwou; Mahomed, Hassan; Hussey, Gregory; Richard Hawn, Thomas; Albert Hanekom, Willem

    2010-01-01

    Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens. The influence of human TLR6 polymorphisms on susceptibility to infection is only partially understood. Most microbes contain lipopeptides recognized by TLR2/1 or TLR2/6 heterodimers. Our aim was to determine whether single nucleotide polymorphisms (SNPs) in TLR6 are associated with altered immune responses to lipopeptides and whole mycobacteria. We sequenced the TLR6 coding region in 100 healthy South African adults to assess genetic variation and determined associations between polymorphisms and lipopeptide- and mycobacteria-induced IL-6 production in whole blood. We found 2 polymorphisms, C745T and G1083C that were associated with altered IL-6 secretion. G1083C was associated with altered IL-6 levels in response to lipopeptides, Mycobacterium tuberculosis lysate (Mtb, P = 0.018) and BCG (P = 0.039). The 745T allele was also associated with lower NF-κB signaling in response to di-acylated lipopeptide, PAM2 (P = 0.019) or Mtb (P = 0.026) in a HEK293 cell line reconstitution assay, compared with the 745C allele. We conclude that TLR6 polymorphisms may be associated with altered lipopeptide-induced cytokine responses and recognition of Mtb. These studies provide new insight into the role of TLR6 variation and the innate immune response to human infection. PMID:20445564

  7. Melatonin-Producing Endophytic Bacteria from Grapevine Roots Promote the Abiotic Stress-Induced Production of Endogenous Melatonin in Their Hosts

    PubMed Central

    Jiao, Jian; Ma, Yaner; Chen, Sha; Liu, Chonghuai; Song, Yuyang; Qin, Yi; Yuan, Chunlong; Liu, Yanlin

    2016-01-01

    Endophytes form symbiotic relationships with plants and constitute an important source of phytohormones and bioactive secondary metabolites for their hosts. To date, most studies of endophytes have focused on the influence of these microorganisms on plant growth and physiology and their role in plant defenses against biotic and abiotic stressors; however, to the best of our knowledge, the ability of endophytes to produce melatonin has not been reported. In the present study, we isolated and identified root-dwelling bacteria from three grapevine varieties and found that, when cultured under laboratory conditions, some of the bacteria strains secreted melatonin and tryptophan-ethyl ester. The endophytic bacterium Bacillus amyloliquefaciens SB-9 exhibited the highest level of in vitro melatonin secretion and also produced three intermediates of the melatonin biosynthesis pathway: 5-hydroxytryptophan, serotonin, and N-acetylserotonin. After B. amyloliquefaciens SB-9 colonization, the plantlets exhibited increased plant growth. Additionally, we found that, in grapevine plantlets exposed to salt or drought stress, colonization by B. amyloliquefaciens SB-9 increased the upregulation of melatonin synthesis, as well as that of its intermediates, but reduced the upregulation of grapevine tryptophan decarboxylase genes (VvTDCs) and a serotonin N-acetyltransferase gene (VvSNAT) transcription, when compared to the un-inoculated control. Colonization by B. amyloliquefaciens SB-9 was also able to counteract the adverse effects of salt- and drought-induced stress by reducing the production of malondialdehyde and reactive oxygen species (H2O2 and O2-) in roots. Therefore, our findings demonstrate the occurrence of melatonin biosynthesis in endophytic bacteria and provide evidence for a novel form of communication between beneficial endophytes and host plants via melatonin. PMID:27708652

  8. Melatonin Inhibits CXCL10 and MMP-1 Production in IL-1β-Stimulated Human Periodontal Ligament Cells.

    PubMed

    Hosokawa, Ikuko; Hosokawa, Yoshitaka; Shindo, Satoru; Ozaki, Kazumi; Matsuo, Takashi

    2016-08-01

    Melatonin is a hormone that is mainly secreted by the pineal gland and exhibits a wide spectrum of activities, including antioxidant functions. Melatonin has been detected in gingival crevicular fluid. However, the role of melatonin in periodontal tissue is still uncertain. The aim of this study was to examine the effects of melatonin on inflammatory mediator expression in human periodontal ligament cells (HPDLC). Interleukin (IL)-1β induced CXC chemokine ligand (CXCL)10, matrix metalloproteinase (MMP)-1, and tissue inhibitors of metalloproteinase (TIMP)-1 production in HPDLC. Melatonin decreased CXCL10 and MMP-1 production and increased TIMP-1 production in IL-1β-stimulated HPDLC. Western blot analysis showed that melatonin inhibited p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK) phosphorylation, and IkB-α degradation and phosphorylation in IL-1β-stimulated HPDLC. These results suggest that melatonin might inhibit Th1 cell migration by reducing CXCL10 production. Moreover, melatonin might inhibit soft tissue destruction by decreasing MMP-1 production in periodontal lesions. PMID:27271323

  9. Melatonin Inhibits CXCL10 and MMP-1 Production in IL-1β-Stimulated Human Periodontal Ligament Cells.

    PubMed

    Hosokawa, Ikuko; Hosokawa, Yoshitaka; Shindo, Satoru; Ozaki, Kazumi; Matsuo, Takashi

    2016-08-01

    Melatonin is a hormone that is mainly secreted by the pineal gland and exhibits a wide spectrum of activities, including antioxidant functions. Melatonin has been detected in gingival crevicular fluid. However, the role of melatonin in periodontal tissue is still uncertain. The aim of this study was to examine the effects of melatonin on inflammatory mediator expression in human periodontal ligament cells (HPDLC). Interleukin (IL)-1β induced CXC chemokine ligand (CXCL)10, matrix metalloproteinase (MMP)-1, and tissue inhibitors of metalloproteinase (TIMP)-1 production in HPDLC. Melatonin decreased CXCL10 and MMP-1 production and increased TIMP-1 production in IL-1β-stimulated HPDLC. Western blot analysis showed that melatonin inhibited p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK) phosphorylation, and IkB-α degradation and phosphorylation in IL-1β-stimulated HPDLC. These results suggest that melatonin might inhibit Th1 cell migration by reducing CXCL10 production. Moreover, melatonin might inhibit soft tissue destruction by decreasing MMP-1 production in periodontal lesions.

  10. Melatonin involvement in oxidative processes.

    PubMed

    Ianăş, O; Olinescu, R; Bădescu, I

    1991-01-01

    The fact that the pineal gland, by its melatonin (MT) production, responds to environmental light variations (the day-night cycle), being also a modulator of the body adaptation to these conditions, may lead to the assumption of its involvement in the body oxidative processes. The redox capacity of melatonin was followed-up in vitro by the chemiluminescence phenomenon. The system generating chemiluminescence as well as free radicals was made up of luminol and H2O2. Incubation of melatonin in doses of 0.08-0.5 microM/ml with the generating system showed that in doses under 0.25 microM/ml melatonin has a pro-oxidative effect while in doses above this value it has an antioxidative effect. The diagram of the results shows the answer specific to a modulator. The study of the correlation between the dose of melatonin with highest pro-oxidative properties and the various peroxide concentrations in the generating system showed that melatonin gets antioxidative properties with the increase in peroxide concentrations (less than 8 mM/ml). In the presence of a hypothalamic homogenate, which is a stimulant of the chemiluminescence-generating system (PXI = 16), melatonin has a dose-dependent antioxidative effect. Similar results were also obtained by adding tryptophan--a free radicals acceptor (PXI = 0.1) and the substrate in melatonin synthesis to the reaction medium. Melatonin in low concentrations (greater than 0.1 microM/ml) has an antioxidative effect while in higher doses it has a dose-dependent pro-oxidative effect.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1821072

  11. Mutant Copper-Zinc Superoxide Dismutase (SOD1) Induces Protein Secretion Pathway Alterations and Exosome Release in Astrocytes

    PubMed Central

    Basso, Manuela; Pozzi, Silvia; Tortarolo, Massimo; Fiordaliso, Fabio; Bisighini, Cinzia; Pasetto, Laura; Spaltro, Gabriella; Lidonnici, Dario; Gensano, Francesco; Battaglia, Elisa; Bendotti, Caterina; Bonetto, Valentina

    2013-01-01

    Amyotrophic lateral sclerosis is the most common motor neuron disease and is still incurable. The mechanisms leading to the selective motor neuron vulnerability are still not known. The interplay between motor neurons and astrocytes is crucial in the outcome of the disease. We show that mutant copper-zinc superoxide dismutase (SOD1) overexpression in primary astrocyte cultures is associated with decreased levels of proteins involved in secretory pathways. This is linked to a general reduction of total secreted proteins, except for specific enrichment in a number of proteins in the media, such as mutant SOD1 and valosin-containing protein (VCP)/p97. Because there was also an increase in exosome release, we can deduce that astrocytes expressing mutant SOD1 activate unconventional secretory pathways, possibly as a protective mechanism. This may help limit the formation of intracellular aggregates and overcome mutant SOD1 toxicity. We also found that astrocyte-derived exosomes efficiently transfer mutant SOD1 to spinal neurons and induce selective motor neuron death. We conclude that the expression of mutant SOD1 has a substantial impact on astrocyte protein secretion pathways, contributing to motor neuron pathology and disease spread. PMID:23592792

  12. Hepatoprotective actions of melatonin: Possible mediation by melatonin receptors

    PubMed Central

    Mathes, Alexander M

    2010-01-01

    Melatonin, the hormone of darkness and messenger of the photoperiod, is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone’s intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo, and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis, hemorrhagic shock, ischemia/reperfusion, and in numerous models of toxic liver injury. Melatonin’s influence on hepatic antioxidant enzymes and other potentially relevant pathways, such as nitric oxide signaling, hepatic cytokine and heat shock protein expression, are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection, this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy. PMID:21182223

  13. Novel Staphylococcus aureus Secreted Protein Alters Keratinocyte Proliferation and Elicits a Proinflammatory Response In Vitro and In Vivo.

    PubMed

    Merriman, Joseph A; Klingelhutz, Aloysius J; Diekema, Daniel J; Leung, Donald Y M; Schlievert, Patrick M

    2015-08-11

    Staphylococcus aureus is a leading cause of surgical site infections that results in increased hospital stays due to the development of chronic wounds. Little is known about factors involved in S. aureus' ability to prevent wounds from healing. We discovered a novel secreted protein produced by a surgical site isolate of S. aureus that prevents keratinocyte proliferation. The protein has a molecular weight of 15.7 kDa and an isoelectric point of 8.9. The cloned and purified protein has cytotoxic and proinflammatory properties, as shown in vitro and in vivo. Potent biological effects on keratinocytes and rabbit skin suggest that this protein may play an important role in preventing re-epithelialization. Its lack of homology to known exotoxins suggests that this protein is novel, and this observation is likely to open a new field of research in S. aureus exotoxins. Due to its cytotoxic activities, we call this new protein ε-cytotoxin. PMID:26177220

  14. Leptin modulates norepinephrine-mediated melatonin synthesis in cultured rat pineal gland.

    PubMed

    Peliciari-Garcia, Rodrigo Antonio; Andrade-Silva, Jéssica; Cipolla-Neto, José; Carvalho, Carla Roberta de Oliveira

    2013-01-01

    Pineal melatonin synthesis can be modulated by many peptides, including insulin. Because melatonin appears to alter leptin synthesis, in this work we aimed to investigate whether leptin would have a role on norepinephrine- (NE-)mediated melatonin synthesis in cultured rat pineal glands. According to our data, cultured rat pineal glands express leptin receptor isoform b (Ob-Rb). Pineal expression of Ob-Rb mRNA was also observed in vivo. Administration of leptin (1 nM) associated with NE ( 1 µM) reduced melatonin content as well as arylalkylamine-N-acetyl transferase (AANAT) activity and expression in cultured pineal glands. Leptin treatment per se induced the expression of STAT3 in cultured pineal glands, but STAT3 does not participate in the leptin modulation of NE-mediated pineal melatonin synthesis. In addition, the expression of inducible cAMP early repressor (ICER) was further induced by leptin challenge when associated with NE. In conclusion, leptin inhibition of pineal melatonin synthesis appears to be mediated by a reduction in AANAT activity and expression as well as by increased expression of Icer mRNA. Peptidergic signaling within the pineal gland appears to be one of the most important signals which modulates melatonin synthesis; leptin, as a member of this system, is not an exception.

  15. GnRH Episodic Secretion Is Altered by Pharmacological Blockade of Gap Junctions: Possible Involvement of Glial Cells.

    PubMed

    Pinet-Charvet, Caroline; Geller, Sarah; Desroziers, Elodie; Ottogalli, Monique; Lomet, Didier; Georgelin, Christine; Tillet, Yves; Franceschini, Isabelle; Vaudin, Pascal; Duittoz, Anne

    2016-01-01

    Episodic release of GnRH is essential for reproductive function. In vitro studies have established that this episodic release is an endogenous property of GnRH neurons and that GnRH secretory pulses are associated with synchronization of GnRH neuron activity. The cellular mechanisms by which GnRH neurons synchronize remain largely unknown. There is no clear evidence of physical coupling of GnRH neurons through gap junctions to explain episodic synchronization. However, coupling of glial cells through gap junctions has been shown to regulate neuron activity in their microenvironment. The present study investigated whether glial cell communication through gap junctions plays a role in GnRH neuron activity and secretion in the mouse. Our findings show that Glial Fibrillary Acidic Protein-expressing glial cells located in the median eminence in close vicinity to GnRH fibers expressed Gja1 encoding connexin-43. To study the impact of glial-gap junction coupling on GnRH neuron activity, an in vitro model of primary cultures from mouse embryo nasal placodes was used. In this model, GnRH neurons possess a glial microenvironment and were able to release GnRH in an episodic manner. Our findings show that in vitro glial cells forming the microenvironment of GnRH neurons expressed connexin-43 and displayed functional gap junctions. Pharmacological blockade of the gap junctions with 50 μM 18-α-glycyrrhetinic acid decreased GnRH secretion by reducing pulse frequency and amplitude, suppressed neuronal synchronization and drastically reduced spontaneous electrical activity, all these effects were reversed upon 18-α-glycyrrhetinic acid washout.

  16. The rat oocyte synthesises melatonin.

    PubMed

    Sakaguchi, Kenichiro; Itoh, Masanori T; Takahashi, Noriyuki; Tarumi, Wataru; Ishizuka, Bunpei

    2013-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine originally identified in the pineal gland, where it is synthesised enzymatically from serotonin (5-hydroxytryptamine) by the sequential action of arylalkylamine N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT; also known as hydroxyindole O-methyltransferase). Melatonin directly affects ovarian functions and previous studies have suggested that melatonin is synthesised in the ovary. In the present study, we examined whether AANAT and ASMT are expressed in the adult rat ovary. Reverse transcription-polymerase chain reaction analyses demonstrated that both AANAT and ASMT mRNAs are expressed in the ovary. Western blotting for AANAT protein showed that the ovary, like the pineal gland, contains this enzymatic protein with a molecular mass of 24kDa. Immunohistochemistry revealed that the AANAT protein is localised to the oocyte, corpus luteum and medulla, including mast cells. AANAT protein was found in oocytes at all stages of follicular development, and its levels in oocytes increased progressively throughout follicular development. Furthermore, isolated oocytes metabolised exogenous serotonin to melatonin. These findings demonstrate that melatonin is synthesised from serotonin in oocytes. Melatonin synthesised in the oocyte may be implicated in its own growth or maturation, for example, by acting as a calmodulin antagonist or an antioxidant.

  17. Nocturnal melatonin levels decode daily light environment and reflect seasonal states in night-migratory blackheaded bunting (Emberiza melanocephala).

    PubMed

    Malik, Shalie; Singh, Jyoti; Trivedi, Amit Kumar; Singh, Sudhi; Rani, Sangeeta; Kumar, Vinod

    2015-05-01

    We proposed two perhaps overlapping hypotheses. Hypothesis 1 examined whether daily light information was transduced by a change in the pattern of daily melatonin secretion. Hypothesis 2 tested whether the melatonin amplitude peak was contingent upon seasonal states. To test these hypotheses, we performed three experiments on night migratory blackheaded buntings (Emberiza melanocephala). The first two experiments measured plasma melatonin levels in buntings exposed to light-dark (LD) cycles, with white and/or blue (450 nm) and red (640 nm) light periods differing by about 10-12 fold in the level of illuminance. In birds exposed to a 12 h day (white light) at 0.66 W m(-2) (dim) and 7.85 W m(-2) (bright) light intensities (experiment 1), night melatonin levels were significantly affected by the end of 8-week exposure in the dim, not bright, day with buntings showing a bimodal nocturnal melatonin peak. Similarly, in birds on 13 h days in white, blue and red light periods at 0.028 W m(-2) (dim) and 0.28 (bright) W m(-2) intensities (experiment 2), mid night melatonin levels were significantly higher in red than in the blue or white light periods after 4.5 weeks of exposure. The third experiment measured plasma melatonin levels in buntings that were held under natural light conditions (NDL, 27°N; experiment 3A), or exposed to LD cycles (experiment 3B). There were slightly more elevated melatonin levels early at night during the spring (photosensitive) than during the autumn (photorefractory) migration season, without a difference in nocturnal melatonin peak between these two times providing almost similar light hours. Similarly, there was no difference in mid night melatonin levels between photosensitive and photorefractory buntings subjected to a skeleton photoperiod (1L : 11D : 1L : 11D), although melatonin levels were higher in the first than in the second 11 h dark phase in photosensitive birds. Overall, these results show that (i) nocturnal melatonin

  18. Nocturnal melatonin levels decode daily light environment and reflect seasonal states in night-migratory blackheaded bunting (Emberiza melanocephala).

    PubMed

    Malik, Shalie; Singh, Jyoti; Trivedi, Amit Kumar; Singh, Sudhi; Rani, Sangeeta; Kumar, Vinod

    2015-05-01

    We proposed two perhaps overlapping hypotheses. Hypothesis 1 examined whether daily light information was transduced by a change in the pattern of daily melatonin secretion. Hypothesis 2 tested whether the melatonin amplitude peak was contingent upon seasonal states. To test these hypotheses, we performed three experiments on night migratory blackheaded buntings (Emberiza melanocephala). The first two experiments measured plasma melatonin levels in buntings exposed to light-dark (LD) cycles, with white and/or blue (450 nm) and red (640 nm) light periods differing by about 10-12 fold in the level of illuminance. In birds exposed to a 12 h day (white light) at 0.66 W m(-2) (dim) and 7.85 W m(-2) (bright) light intensities (experiment 1), night melatonin levels were significantly affected by the end of 8-week exposure in the dim, not bright, day with buntings showing a bimodal nocturnal melatonin peak. Similarly, in birds on 13 h days in white, blue and red light periods at 0.028 W m(-2) (dim) and 0.28 (bright) W m(-2) intensities (experiment 2), mid night melatonin levels were significantly higher in red than in the blue or white light periods after 4.5 weeks of exposure. The third experiment measured plasma melatonin levels in buntings that were held under natural light conditions (NDL, 27°N; experiment 3A), or exposed to LD cycles (experiment 3B). There were slightly more elevated melatonin levels early at night during the spring (photosensitive) than during the autumn (photorefractory) migration season, without a difference in nocturnal melatonin peak between these two times providing almost similar light hours. Similarly, there was no difference in mid night melatonin levels between photosensitive and photorefractory buntings subjected to a skeleton photoperiod (1L : 11D : 1L : 11D), although melatonin levels were higher in the first than in the second 11 h dark phase in photosensitive birds. Overall, these results show that (i) nocturnal melatonin

  19. Pathophysiologic changes in IA-2/IA-2β null mice are secondary to alterations in the secretion of hormones and neurotransmitters.

    PubMed

    Cai, Tao; Notkins, Abner L

    2016-02-01

    IA-2 and IA-2β are transmembrane proteins of dense-core vesicles (DCV). The deletion of these proteins results in a reduction in the number of DCV and the secretion of hormones and neurotransmitters. As a result, this leads to a variety of pathophysiologic changes. The purpose of this review is to describe these changes, which are characterized by glucose intolerance, female infertility, behavior and learning abnormalities and alterations in the diurnal circadian rhythms of blood pressure, heart rate, spontaneous physical activity and body temperature. These findings show that the deletion of IA-2 and IA-2β results in multiple pathophysiologic changes and represents a unique in vivo model for studying the effect of hormone and neurotransmitter reduction on known and still unrecognized targets.

  20. Nocturnal headache associated with melatonin deficiency due to a pineal gland cyst.

    PubMed

    Karadaş, Omer; Ipekdal, Ilker H; Ulaş, Umit H; Odabaşi, Zeki

    2012-02-01

    The cyclic nature of some of headache disorders is closely related to melatonin, which is secreted by the pineal gland. We report a 29-year-old male patient with a 2.5-year history of headaches that woke him in the middle of the night. These headaches were pulsatile and continued until sunrise. During these attacks he also suffered from allodynia over the scalp, bilateral conjunctival hyperemia, and nervousness. His brain MRI showed a 5mm by 4mm neuroepithelial cyst in the pineal gland. The peak plasma melatonin level that was measured at 2 am was 28 pg/mL. The patient underwent oral melatonin treatment (6 mg/day). After 1 month he experienced a 70% reduction in his symptoms. When the melatonin dosage was increased to 10mg/day he became headache-free, and 5 months after the treatment began, had no complaints. His 5-month follow-up plasma melatonin level at 2 am was 61 pg/mL. To our knowledge this is the first report of a patient with nocturnal headache associated with a low level of melatonin due to a neuroepithelial cyst in the pineal gland.

  1. Melatonin, immunity and cost of reproductive state in male European starlings.

    PubMed

    Bentley, G E; Demas, G E; Nelson, R J; Ball, G F

    1998-07-01

    The effects of reproductive condition and exogenous melatonin on immune function were investigated in castrated European starlings, Sturnus vulgaris. Photorefractory and photostimulated starlings exposed to long days were implanted with melatonin or with blank capsules. Photostimulated starlings with blank capsules exhibited reduced splenocyte proliferation in response to the T-cell mitogen, concanavalin A, compared with the other long-day birds. Exogenous melatonin prevented the suppression of immune function by photostimulation. Photorefractory starlings, with or without melatonin implants, exhibited enhanced immune function compared with photostimulated starlings implanted with blanks. This enhancement was not mediated by endogenous melatonin, but appeared to be related to changes in reproductive state. In addition to the traditional costs of reproduction in birds (e.g. raising of young), there may be a cost of the reproductive state of starlings (i.e. whether they are photorefractory or photostimulated). These data are, we believe, the first to indicate a direct effect of reproductive state on immune function that is independent of both photoperiod (i.e., changes in the duration of melatonin secretion) and gonadal steroids.

  2. Melatonin, immunity and cost of reproductive state in male European starlings.

    PubMed Central

    Bentley, G E; Demas, G E; Nelson, R J; Ball, G F

    1998-01-01

    The effects of reproductive condition and exogenous melatonin on immune function were investigated in castrated European starlings, Sturnus vulgaris. Photorefractory and photostimulated starlings exposed to long days were implanted with melatonin or with blank capsules. Photostimulated starlings with blank capsules exhibited reduced splenocyte proliferation in response to the T-cell mitogen, concanavalin A, compared with the other long-day birds. Exogenous melatonin prevented the suppression of immune function by photostimulation. Photorefractory starlings, with or without melatonin implants, exhibited enhanced immune function compared with photostimulated starlings implanted with blanks. This enhancement was not mediated by endogenous melatonin, but appeared to be related to changes in reproductive state. In addition to the traditional costs of reproduction in birds (e.g. raising of young), there may be a cost of the reproductive state of starlings (i.e. whether they are photorefractory or photostimulated). These data are, we believe, the first to indicate a direct effect of reproductive state on immune function that is independent of both photoperiod (i.e., changes in the duration of melatonin secretion) and gonadal steroids. PMID:9699312

  3. Salivary melatonin and cortisol and occupational injuries among Italian hospital workers.

    PubMed

    Valent, Francesca; Mariuz, Marika; Liva, Giulia; Verri, Sara; Arlandini, Sara; Vivoli, Roberto

    2016-10-01

    Stress, circadian patterns, and sleep-related factors may have a role on occupational injuries. We investigated the association between occupational injuries among the workers of an Italian hospital and their secretion of salivary melatonin and cortisol. We used a case-control study design. 27 injured cases and 31 non-injured controls provided 5 salivary samples every 60 min from 9 pm to 1 am. Melatonin and cortisol concentrations were measured, and the Dim Light Melatonin Onset (DLMO) derived using two fixed thresholds (1 and 3 pg/mL). The associations between injury, melatonin, cortisol, and DLMO were assessed through univariate and multivariate analyses. Non-injured controls had higher melatonin (median 2.28 pg/mL) and lower cortisol concentrations (0.71 ng/mL), as well as earlier DLMO times (9:00 pm with the 1 pg/mL melatonin cutoff) than cases (1.01 pg/mL, 1.14 ng/mL and 9:12 pm, respectively), although only few results were statistically significant. Measuring these hormones might be helpful to characterize the risk of injury among hospital workers.

  4. Clinical Aspects of Melatonin Intervention in Alzheimer’s Disease Progression

    PubMed Central

    Cardinali, Daniel P; Furio, Analía M; Brusco, Luis I

    2010-01-01

    Melatonin secretion decreases in Alzheimer´s disease (AD) and this decrease has been postulated as responsible for the circadian disorganization, decrease in sleep efficiency and impaired cognitive function seen in those patients. Half of severely ill AD patients develop chronobiological day-night rhythm disturbances like an agitated behavior during the evening hours (so-called “sundowning”). Melatonin replacement has been shown effective to treat sundowning and other sleep wake disorders in AD patients. The antioxidant, mitochondrial and antiamyloidogenic effects of melatonin indicate its potentiality to interfere with the onset of the disease. This is of particularly importance in mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. The aim of this manuscript was to assess published evidence of the efficacy of melatonin to treat AD and MCI patients. PubMed was searched using Entrez for articles including clinical trials and published up to 15 January 2010. Search terms were “Alzheimer” and “melatonin”. Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. The analysis of published evidence made it possible to postulate melatonin as a useful ad-on therapeutic tool in MCI. In the case of AD, larger randomized controlled trials are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) before melatonin´s use can be advocated. PMID:21358972

  5. Light-induced melatonin suppression at night after exposure to different wavelength composition of morning light.

    PubMed

    Kozaki, Tomoaki; Kubokawa, Ayaka; Taketomi, Ryunosuke; Hatae, Keisuke

    2016-03-11

    Bright nocturnal light has been shown to suppress melatonin secretion. However, bright light exposure during the day might reduce light-induced melatonin suppression at night. The human circadian system is sensitive to short wavelength light. This study evaluated the preventive effect of different wavelengths of daytime light on light-induced melatonin suppression at night. Twelve male subjects were exposed to various light conditions (dim, white, and bluish white light) between the hours of 09:00 and 10:30 (daytime light conditions). They were then exposed to light (300lx) again between 01:00 and 02:30 (night-time light exposure). Subjects provided saliva samples before (00:55) and after night-time light exposure (02:30). A two-tailed paired t-test yielded significant decrements in melatonin concentrations after night-time light exposure under daytime dim and white light conditions. No significant differences were found in melatonin concentrations between pre- and post-night-time light exposure with bluish-white light. Present findings suggest that daytime blue light exposure has an acute preventive impact on light-induced melatonin suppression in individuals with a general life rhythm (sleep/wake schedule). These findings may be useful for implementing artificial light environments for humans in, for example, hospitals and underground shopping malls to reduce health risks.

  6. Light-induced melatonin suppression at night after exposure to different wavelength composition of morning light.

    PubMed

    Kozaki, Tomoaki; Kubokawa, Ayaka; Taketomi, Ryunosuke; Hatae, Keisuke

    2016-03-11

    Bright nocturnal light has been shown to suppress melatonin secretion. However, bright light exposure during the day might reduce light-induced melatonin suppression at night. The human circadian system is sensitive to short wavelength light. This study evaluated the preventive effect of different wavelengths of daytime light on light-induced melatonin suppression at night. Twelve male subjects were exposed to various light conditions (dim, white, and bluish white light) between the hours of 09:00 and 10:30 (daytime light conditions). They were then exposed to light (300lx) again between 01:00 and 02:30 (night-time light exposure). Subjects provided saliva samples before (00:55) and after night-time light exposure (02:30). A two-tailed paired t-test yielded significant decrements in melatonin concentrations after night-time light exposure under daytime dim and white light conditions. No significant differences were found in melatonin concentrations between pre- and post-night-time light exposure with bluish-white light. Present findings suggest that daytime blue light exposure has an acute preventive impact on light-induced melatonin suppression in individuals with a general life rhythm (sleep/wake schedule). These findings may be useful for implementing artificial light environments for humans in, for example, hospitals and underground shopping malls to reduce health risks. PMID:26777427

  7. Augmented expression and secretion of adipose-derived pigment epithelium-derived factor does not alter local angiogenesis or contribute to the development of systemic metabolic derangements.

    PubMed

    Lakeland, Thomas V; Borg, Melissa L; Matzaris, Maria; Abdelkader, Amany; Evans, Roger G; Watt, Matthew J

    2014-06-15

    Impaired coupling of adipose tissue expansion and vascularization is proposed to lead to adipocyte hypoxia and inflammation, which in turn contributes to systemic metabolic derangements. Pigment epithelium-derived factor (PEDF) is a powerful antiangiogenic factor that is secreted by adipocytes, elevated in obesity, and implicated in the development of insulin resistance. We explored the angiogenic and metabolic role of adipose-derived PEDF through in vivo studies of mice with overexpression of PEDF in adipocytes (PEDF-aP2). PEDF expression in white adipocytes and PEDF secretion from adipose tissue was increased in transgenic mice, but circulating levels of PEDF were not increased. Overexpression of PEDF did not alter vascularization, the partial pressure of O2, cellular hypoxia, or gene expression of inflammatory markers in adipose tissue. Energy expenditure and metabolic substrate utilization, body mass, and adiposity were not altered in PEDF-aP2 mice. Whole body glycemic control was normal as assessed by glucose and insulin tolerance tests, and adipocyte-specific glucose uptake was unaffected by PEDF overexpression. Adipocyte lipolysis was increased in PEDF-aP2 mice and associated with increased adipose triglyceride lipase and decreased perilipin 1 expression. Experiments conducted in mice rendered obese by high-fat feeding showed no differences between PEDF-aP2 and wild-type mice for body mass, adiposity, whole body energy expenditure, glucose tolerance, or adipose tissue oxygenation. Together, these data indicate that adipocyte-generated PEDF enhances lipolysis but question the role of PEDF as a major antiangiogenic or proinflammatory mediator in adipose tissue in vivo.

  8. Calcium, calcification, and melatonin biosynthesis in the human pineal gland: a postmortem study into age-related factors.

    PubMed

    Schmid, H A; Requintina, P J; Oxenkrug, G F; Sturner, W

    1994-05-01

    It is believed that pineal calcification may be age-associated and that the well-demonstrated age-related decline in melatonin biosynthesis may be an expression of an alteration in calcium homeostasis in the pinealocyte. Prior correlations of melatonin to calcium deposition and age were made on the basis of radiological or semiquantitative analysis. In this postmortem study of 33 subjects (age range 3 months to 65 years) calcium deposits measured by atomic absorption spectrometry correlated positively with age in day and night samples (day: r = 0.56, P < 0.05; night: r = 0.818, P < 0.001). Nighttime (2200 h to 0800 h) pineal melatonin content (HPLC fluorometry) was higher than daytime melatonin levels (nighttime 3.80 +/- 0.3 vs. daytime 0.85 +/- 0.4 ng/mg protein). Nighttime calcium levels in the supernatant correlated negatively with melatonin content (r = -0.59, P < 0.05). PMID:7807371

  9. The hockey-stick method to estimate evening dim light melatonin onset (DLMO) in humans.

    PubMed

    Danilenko, Konstantin V; Verevkin, Evgeniy G; Antyufeev, Viktor S; Wirz-Justice, Anna; Cajochen, Christian

    2014-04-01

    The onset of melatonin secretion in the evening is the most reliable and most widely used index of circadian timing in humans. Saliva (or plasma) is usually sampled every 0.5-1 hours under dim-light conditions in the evening 5-6 hours before usual bedtime to assess the dim-light melatonin onset (DLMO). For many years, attempts have been made to find a reliable objective determination of melatonin onset time either by fixed or dynamic threshold approaches. The here-developed hockey-stick algorithm, used as an interactive computer-based approach, fits the evening melatonin profile by a piecewise linear-parabolic function represented as a straight line switching to the branch of a parabola. The switch point is considered to reliably estimate melatonin rise time. We applied the hockey-stick method to 109 half-hourly melatonin profiles to assess the DLMOs and compared these estimates to visual ratings from three experts in the field. The DLMOs of 103 profiles were considered to be clearly quantifiable. The hockey-stick DLMO estimates were on average 4 minutes earlier than the experts' estimates, with a range of -27 to +13 minutes; in 47% of the cases the difference fell within ±5 minutes, in 98% within -20 to +13 minutes. The raters' and hockey-stick estimates showed poor accordance with DLMOs defined by threshold methods. Thus, the hockey-stick algorithm is a reliable objective method to estimate melatonin rise time, which does not depend on a threshold value and is free from errors arising from differences in subjective circadian phase estimates. The method is available as a computerized program that can be easily used in research settings and clinical practice either for salivary or plasma melatonin values.

  10. Plasma melatonin and urinary 6-hydroxymelatonin levels in patients with pulmonary tuberculosis.

    PubMed

    Ozkan, Esin; Yaman, Halil; Cakir, Erdinc; Deniz, Omer; Oztosun, Muzaffer; Gumus, Seyfettin; Akgul, Emin Ozgur; Agilli, Mehmet; Cayci, Tuncer; Kurt, Yasemin Gulcan; Aydin, Ibrahim; Arslan, Yakup; Ilhan, Nevin; Ilhan, Necip; Erbil, Mehmet Kemal

    2012-08-01

    Tuberculosis (TB) is the second most frequent cause of death in the world, after AIDS. Delay in diagnosing TB is an important worldwide problem. It seriously threatens public health. Cell-mediated immune responses play an important role in the pathogenesis of TB infection. The course of Mycobacterium tuberculosis (MTb) infection is regulated by two distinct T cell cytokine patterns. Melatonin is a biomolecule (mainly secreted by the pineal gland) with free radical scavenging, antioxidant and immunoregulatory properties. Melatonin has both its direct and indirect immunomodulatory effects on the immune system. In this study, we measured plasma melatonin and urine 6-hydroxy melatonin sulphate (6-HMS) concentrations in patients with newly diagnosed TB for the purpose of investigating whether there was a relationship between their levels and MTb infection. Thirty-one newly diagnosed patients presenting with active TB and 31 healthy subjects as the control group were included in this study. Blood and 24-h urine samples were collected from all individuals. Plasma melatonin levels and urine 6-HMS were measured. Our results show that in patients with TB, mean melatonin and 6-HMS concentrations were significantly lower than in the control subjects (p = 0.037, p < 0.001, respectively). We believe that the treatment of TB patients with melatonin might result in a wide range of health benefits including improved quality of life and reduced severity of infection in these patients. Supplementation with melatonin may be considered as an adjunctive therapy to classic treatment of pulmonary TB, especially during the acute phase of infection.

  11. Melatonin protects against oxidative stress caused by delta-aminolevulinic acid: implications for cancer reduction.

    PubMed

    Karbownik, Małgorzata; Reiter, Russel J

    2002-01-01

    delta-Aminolevulinic acid (ALA) is a precursor of haem. The increased concentration of ALA is typically related to acute intermittent porphyria, hereditary tyrosinemia, and lead poisoning. delta-Aminolevulinic acid produced in excess accumulates in a number of organs, causes oxidative damage, and often leads to cancer. Melatonin (N-acetyl-5-methoxytryptamine) is a well-known antioxidant, free radical scavenger, and exhibits anticarcinogenic properties. It protects DNA, lipids, and proteins from oxidative damage. The protective effects of melatonin against ALA-induced oxidation of guanine bases, lipid peroxidation, and alterations in membrane fluidity in several organs have been documented. There is an inverse relationship between melatonin and ALA concentrations in both experimental and clinical conditions of porphyria. The marked efficacy of melatonin in protecting against ALA-related oxidative stress, its oncostatic properties, and low toxicity constitute reasons to consider the use of this indoleamine as a co-treatment in patients suffering from disturbances related to ALA accumulation.

  12. Melatonin modifies the rhythm of protein synthesis.

    PubMed

    Brodsky, V Y; Dubovaya, N D; Zvezdina, T K; Fateeva, V I; Mal'chenko, L A

    2010-07-01

    Melatonin (5 nM) added to medium with primary hepatocyte cultures shifted the phase of circahoralian rhythm of protein synthesis and hence, can be a factor synchronizing fluctuations in protein synthesis and rhythm organizer in the hepatocyte population. Blockade of melatonin receptors with luzindole (20 nM) arrested rhythm organization of protein synthesis by melatonin. Prospects of studying biochemical mechanisms of protein synthesis rhythm organization with other drugs (calcium agonists, similarly to melatonin) are discussed.

  13. Mitochondrial and metabolic dysfunction in renal convoluted tubules of obese mice: protective role of melatonin.

    PubMed

    Stacchiotti, Alessandra; Favero, Gaia; Giugno, Lorena; Lavazza, Antonio; Reiter, Russel J; Rodella, Luigi Fabrizio; Rezzani, Rita

    2014-01-01

    Obesity is a common and complex health problem, which impacts crucial organs; it is also considered an independent risk factor for chronic kidney disease. Few studies have analyzed the consequence of obesity in the renal proximal convoluted tubules, which are the major tubules involved in reabsorptive processes. For optimal performance of the kidney, energy is primarily provided by mitochondria. Melatonin, an indoleamine and antioxidant, has been identified in mitochondria, and there is considerable evidence regarding its essential role in the prevention of oxidative mitochondrial damage. In this study we evaluated the mechanism(s) of mitochondrial alterations in an animal model of obesity (ob/ob mice) and describe the beneficial effects of melatonin treatment on mitochondrial morphology and dynamics as influenced by mitofusin-2 and the intrinsic apoptotic cascade. Melatonin dissolved in 1% ethanol was added to the drinking water from postnatal week 5-13; the calculated dose of melatonin intake was 100 mg/kg body weight/day. Compared to control mice, obesity-related morphological alterations were apparent in the proximal tubules which contained round mitochondria with irregular, short cristae and cells with elevated apoptotic index. Melatonin supplementation in obese mice changed mitochondria shape and cristae organization of proximal tubules, enhanced mitofusin-2 expression, which in turn modulated the progression of the mitochondria-driven intrinsic apoptotic pathway. These changes possibly aid in reducing renal failure. The melatonin-mediated changes indicate its potential protective use against renal morphological damage and dysfunction associated with obesity and metabolic disease.

  14. Early maternal undernutrition programs increased feed intake, altered glucose metabolism and insulin secretion, and liver function in aged female offspring

    PubMed Central

    George, Lindsey A.; Zhang, Liren; Tuersunjiang, Nuermaimaiti; Ma, Yan; Long, Nathan M.; Uthlaut, Adam B.; Smith, Derek T.; Nathanielsz, Peter W.

    2012-01-01

    Insulin resistance and obesity are components of the metabolic syndrome that includes development of cardiovascular disease and diabetes with advancing age. The thrifty phenotype hypothesis suggests that offspring of poorly nourished mothers are predisposed to the various components of the metabolic syndrome due to adaptations made during fetal development. We assessed the effects of maternal nutrient restriction in early gestation on feeding behavior, insulin and glucose dynamics, body composition, and liver function in aged female offspring of ewes fed either a nutrient-restricted [NR 50% National Research Council (NRC) recommendations] or control (C: 100% NRC) diet from 28 to 78 days of gestation, after which both groups were fed at 100% of NRC from day 79 to lambing and through lactation. Female lambs born to NR and C dams were reared as a single group from weaning, and thereafter, they were fed 100% NRC recommendations until assigned to this study at 6 yr of age. These female offspring were evaluated by a frequently sampled intravenous glucose tolerance test, followed by dual-energy X-ray absorptiometry for body composition analysis prior to and after ad libitum feeding of a highly palatable pelleted diet for 11 wk with automated monitoring of feed intake (GrowSafe Systems). Aged female offspring born to NR ewes demonstrated greater and more rapid feed intake, greater body weight gain, and efficiency of gain, lower insulin sensitivity, higher insulin secretion, and greater hepatic lipid and glycogen content than offspring from C ewes. These data confirm an increased metabolic “thriftiness” of offspring born to NR mothers, which continues into advanced age, possibly predisposing these offspring to metabolic disease. PMID:22277936

  15. Early maternal undernutrition programs increased feed intake, altered glucose metabolism and insulin secretion, and liver function in aged female offspring.

    PubMed

    George, Lindsey A; Zhang, Liren; Tuersunjiang, Nuermaimaiti; Ma, Yan; Long, Nathan M; Uthlaut, Adam B; Smith, Derek T; Nathanielsz, Peter W; Ford, Stephen P

    2012-04-01

    Insulin resistance and obesity are components of the metabolic syndrome that includes development of cardiovascular disease and diabetes with advancing age. The thrifty phenotype hypothesis suggests that offspring of poorly nourished mothers are predisposed to the various components of the metabolic syndrome due to adaptations made during fetal development. We assessed the effects of maternal nutrient restriction in early gestation on feeding behavior, insulin and glucose dynamics, body composition, and liver function in aged female offspring of ewes fed either a nutrient-restricted [NR 50% National Research Council (NRC) recommendations] or control (C: 100% NRC) diet from 28 to 78 days of gestation, after which both groups were fed at 100% of NRC from day 79 to lambing and through lactation. Female lambs born to NR and C dams were reared as a single group from weaning, and thereafter, they were fed 100% NRC recommendations until assigned to this study at 6 yr of age. These female offspring were evaluated by a frequently sampled intravenous glucose tolerance test, followed by dual-energy X-ray absorptiometry for body composition analysis prior to and after ad libitum feeding of a highly palatable pelleted diet for 11 wk with automated monitoring of feed intake (GrowSafe Systems). Aged female offspring born to NR ewes demonstrated greater and more rapid feed intake, greater body weight gain, and efficiency of gain, lower insulin sensitivity, higher insulin secretion, and greater hepatic lipid and glycogen content than offspring from C ewes. These data confirm an increased metabolic "thriftiness" of offspring born to NR mothers, which continues into advanced age, possibly predisposing these offspring to metabolic disease. PMID:22277936

  16. Electric power, melatonin, and breast cancer

    SciTech Connect

    Stevens, R.G.

    1987-08-01

    In this paper, the epidemiology of breast cancer will be discussed, followed by a brief description of the effect of electric fields on melatonin and the relation of melatonin to mammary cancer in rats. Finally, there will be a consideration of factors such as alcohol that affect melatonin and their relation to breast cancer risk. 55 refs.

  17. Lead (Pb) alters the norepinephrine-induced secretion of luteinizing hormone releasing hormone from the median eminence of adult male rats in vitro

    SciTech Connect

    Bratton, G.R.; Hiney, J.K.; Dees, W.L. )

    1994-01-01

    In the present study, the authors evaluated the in vitro effects of lead (Pb) on basal and stimulated luteinizing hormone releasing hormone (LHRH) and Prostaglandin E[sub 2] (PGE[sub 2]) secretion. Median eminences (ME) were removed from brains of adult male rats and preincubated for 15 minutes in Krebs-Ringer bicarbonate glucose buffer in an atmosphere of 95% O[sub 2]-5% CO[sub 2]. These media were discarded and all MEs were subjected to one of the following experiments. In Experiment 1, all MEs were incubated for 30 minutes in medium only. These media were collected and replaced with medium only (controls) or with medium containing Pb doses ranging from 5 to 20 [mu]M. After this 60-minute incubation, media were collected, then replaced with new medium containing 60 [mu]M norepinephrine (NE), or NE plus each dose of Pb, then incubated for a final 30-minute period. Experiment 2 was conducted as above, except PGE[sub 2] (2.8 [mu]M) replaced the NE. In both experiments, the amounts of LHRH released was measured by RIA. In experiment 3, NE was again used for the challenge; however, this time, the amount of PGE[sub 2] released was measured by RIA. Results indicate that Pb did not alter basal LHRH release, but compared with controls, significantly blocked NE-induced LHRH release in a dose-related manner. Conversely, Pb had no effect on the PGE[sub 2]-induced release of LHRH. Additionally, Pb did not alter basal PGE[sub 2] release; however, it significantly blocked the NE-induced release of PGE[sub 2]. Since NE-induced LHRH release is mediated by PGE[sub 2], these results support the hypothesis that Pb is capable of altering the hypothalamus and suggest that this effect is due, at least in part, to the diminished PGE[sub 2] synthesis/release within the ME, resulting in diminished LHRH secretion.

  18. Amyloid β peptide directly impairs pineal gland melatonin synthesis and melatonin receptor signaling through the ERK pathway.

    PubMed

    Cecon, Erika; Chen, Min; Marçola, Marina; Fernandes, Pedro A C; Jockers, Ralf; Markus, Regina P

    2015-06-01

    Melatonin is the hormone produced by the pineal gland known to regulate physiologic rhythms and to display immunomodulatory and neuroprotective properties. It has been reported that Alzheimer disease patients show impaired melatonin production and altered expression of the 2 G protein-coupled melatonin receptors (MTRs), MT₁ and MT₂, but the underlying mechanisms are not known. Here we evaluated whether this dysfunction of the melatonergic system is directly caused by amyloid β peptides (Aβ(1-40) and Aβ(1-42)). Aβ treatment of rat pineal glands elicited an inflammatory response within the gland, evidenced by the up-regulation of 52 inflammatory genes, and decreased the production of melatonin up to 75% compared to vehicle-treated glands. Blocking NF-κB activity prevented this effect. Exposure of HEK293 cells stably expressing recombinant MT₁ or MT₂ receptors to Aβ lead to a 40% reduction in [(125)I]iodomelatonin binding to MT₁. ERK1/2 activation triggered by MTRs, but not by the β₂-adrenergic receptor, was markedly impaired by Aβ in HEK293 transfected cells, as well as in primary rat endothelial cells expressing endogenous MTRs. Our data reveal the melatonergic system as a new target of Aβ, opening new perspectives to Alzheimer disease diagnosis and therapeutic intervention.

  19. Variability of plasma melatonin level in pony mares (Equus caballus), comparison with the hybrid: mules and with jennies (Equus asinus).

    PubMed

    Guillaume, Daniel; Zarazaga, Luiz A; Malpaux, Benoît; Chemineau, Philippe

    2006-01-01

    In long-day breeders like horses, the length of nocturnal melatonin secretion is the main messenger of photoperiod. Previous studies have shown that the nocturnal jugular melatonin concentration is lower in horses, than in mules but is unknown in donkeys. The aim of this study was to estimate the inter-animal variability of plasma melatonin concentration in domestic mares and to compare this concentration with those observed in domestic jennies and in their hybrid mules. In the autumn, blood samples were collected at 22 h, 23 h, 0 h and 1 h during 2 nights at 3 weeks intervals, in 110 pony mares, 10 jennies and 6 mules maintained under natural photoperiod. Melatonin was assayed by a validated RIA method. The statistical analysis of the measures was done with a specific unbalanced analysis of variance model. The effect of species and individuals (nested under species) was highly significant. The mean melatonin concentration was 24 pg.mL(-1) in mares and was significantly lower than in jennies and in mules which were 90 pg.mL(-1) and 169 pg.mL(-1) respectively. The melatonin plasma concentration was higher in jennies than in mares. These results suggest that the melatonin concentration is genetically determined.

  20. Urinary Excretion of Melatonin and Association with Breast Cancer: Meta-Analysis and Review of the Literature

    PubMed Central

    Basler, Michelle; Jetter, Alexander; Fink, Daniel; Seifert, Burkhardt; Kullak-Ublick, Gerd A.; Trojan, Andreas

    2014-01-01

    Summary Background Melatonin is an endocrine hormone secreted by the pineal gland during night hours that provides several biological functions in the circadian rhythm of humans. Due to anti-estrogenic properties, melatonin is considered to exhibit a protective role against the development of breast cancer (BC). Moreover, disruption of melatonin production through environmental influences, such as night work, is assumed to be a risk factor for BC. Materials and Methods We reviewed recent findings concerning biological effects of melatonin on BC and conducted a meta-analysis to evaluate the association between melatonin and BC incidence. In random and fixed effects statistical models, concentrations (tertiles, quartiles) of the primary urinary metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s), were tested for the assumption that women with the highest values would exhibit a lower risk of BC. Results Statistical analysis of data from 5 prospective case-control studies indicates an inverse association between BC risk and the highest levels of urinary aMT6s. This effect seems to be influenced by lag intervals between aMT6s collection and the occurrence of BC, timing and methods of urine sampling, as well as genetic and environmental factors. Conclusion On the basis of the results of our meta-analysis, melatonin is likely to affect BC occurrence in women. However, methodological dissonances may require further studies. PMID:25177260

  1. Neuroendocrinology of melatonin in reproduction: recent developments.

    PubMed

    Pang, S F; Li, L; Ayre, E A; Pang, C S; Lee, P P; Xu, R K; Chow, P H; Yu, Z H; Shiu, S Y

    1998-06-01

    The circadian melatonin rhythm with high levels in the dark period is important for the synchronization of reproductive response to appropriate environmental conditions in animals. The target sites of melatonin action on reproductive functions remain to be clarified. Using autoradiography (ARG) and radioreceptor binding assays with 2[125I]iodomelatonin, a melatonin agonist, as the radioligand, studies on the sites of melatonin action have increased significantly in the last ten years. The recent cloning of melatonin receptor subtypes also allowed the characterization of receptor(s) to the molecular level. Earlier reports have documented that the hypothalamic-pituitary axis plays a vital role in the regulation of reproduction by melatonin. This is supported in part by the demonstration of melatonin receptors in the suprachiasmatic nuclei (SCN) in the brain and pars tuberalis (PT) in the pituitary. However, the nature of SCN and PT involvement in the reproductive action of melatonin remains unknown. In addition to the hypothalamus and pituitary, the two classical sites of melatonin action, other targets have been identified. The recent demonstration of 2[125I]iodomelatonin binding sites or melatonin receptors in the testis, epididymis, vas deferens, prostate, ovary and mammary gland suggest the concept of multiple sites of melatonin action on the reproductive system. The presence of melatonin receptors in the said tissues is consistent with earlier reports of direct melatonin actions on different levels of the reproductive system. This multiple levels of melatonin action, from the hypothalamus, pituitary, gonads to other reproductive tissues form a robust system of photoperiodic control in animal reproduction. This would guarantee successful gestation and delivery of the offspring at a time with optimum food availability and ultimately favourable for the survival of species. Molecular and cellular studies of melatonin signaling system(s), its regulation and effects

  2. Prenatal melatonin exposure affects luteinizing hormone and hypothalamic and striatal neuropeptide Y in the male rat offspring.

    PubMed

    Díaz, E; Debeljuk, L; Arce, A; Esquifino, A; Díaz, B

    2000-10-13

    The present study examines the influence of prenatal melatonin on the hypothalamic and striatal neuropeptide Y (NPY) concentrations as well as on luteinizing hormone (LH) levels. Male rat offspring of control and melatonin treated mother rats were studied at different ages of the sexual development: infantile, prepubertal, pubertal and adult ages. Hypothalamic NPY levels were much higher during the juvenile than throughout the infantile period. After prenatal melatonin treatment significantly higher values since day 15 up to 35, also at 60 days of age were found, as compared with controls. Striatal NPY levels were lower than in hypothalamus. Again, NPY in the striatum from offspring of melatonin treated mother rats showed significantly higher values than the respective controls at most of the ages studied. However, prenatal melatonin exerted an inhibitory influence upon LH secretion pattern, since decreased concentrations up to 25 days of age and delayed peak values at pubertal age were observed. The present study also suggest that the effect of NPY upon LH secretion is related to sexual development, since NPY exerted opposite effect in infantile than in pubertal period and melatonin administration during intrauterine life prevented this effect.

  3. A role of melatonin in neuroectodermal-mesodermal interactions: the hair follicle synthesizes melatonin and expresses functional melatonin receptors.

    PubMed

    Kobayashi, Hiromi; Kromminga, Arno; Dunlop, Thomas W; Tychsen, Birte; Conrad, Franziska; Suzuki, Naoto; Memezawa, Ai; Bettermann, Albrecht; Aiba, Setsuya; Carlberg, Carsten; Paus, Ralf

    2005-10-01

    Since mammalian skin expresses the enzymatic apparatus for melatonin synthesis, it may be an extrapineal site of melatonin synthesis. However, evidence is still lacking that this is really the case in situ. Here, we demonstrate melatonin-like immunoreactivity (IR) in the outer root sheath (ORS) of mouse and human hair follicles (HFs), which corresponds to melatonin, as shown by radioimmunoassay and liquid chromatography/tandem mass spectrometry (LC/MS/MS). The melatonin concentration in organ-cultured mouse skin, mouse vibrissae follicles, and human scalp HFs far exceeds the respective melatonin serum level and is significantly increased ex vivo by stimulation with norepinephrine (NE), the key stimulus for pineal melatonin synthesis. By real-time PCR, transcripts for the melatonin membrane receptor MT2 and for the nuclear mediator of melatonin signaling, retinoid orphan receptor alpha (ROR)alpha, are detectable in murine back skin. Transcript levels for these receptors fluctuate in a hair cycle-dependent manner, and are maximal during apoptosis-driven HF regression (catagen). Melatonin may play a role in hair cycle regulation, since its receptors (MT2 and RORalpha) are expressed in murine skin in a hair cycle-dependent manner, and because it inhibits keratinocyte apoptosis and down-regulates ERalpha expression. Therefore, the HF is both, a prominent extrapineal melatonin source, and an important peripheral melatonin target tissue. Regulated intrafollicular melatonin synthesis and signaling may play a previously unrecognized role in the endogenous controls of hair growth, for example, by modulating keratinocyte apoptosis during catagen and by desensitizing the HF to estrogen signaling. As a prototypic neuroectodermal-mesodermal interaction model, the HF can be exploited for dissecting the obscure role of melatonin in such interactions in peripheral tissues. PMID:16030176

  4. Usefulness of Endoscopic Imaging to Visualize Regional Alterations in Acid Secretion of Noncancerous Gastric Mucosa after Helicobacter pylori Eradication

    PubMed Central

    Iijima, Katsunori; Abe, Yasuhiko; Koike, Tomoyuki; Takahashi, Yasushi; Ara, Nobuyuki; Shimosegawa, Tooru

    2016-01-01

    Purpose Endoscopic diagnosis of gastric cancer (GC) that emerges after eradication of Helicobacter pylori may be affected by unique morphological changes. Using comprehensive endoscopic imaging, which can reveal biological alterations in gastric mucosa after eradication, previous studies demonstrated that Congo red chromoendoscopy (CRE) might clearly show an acid non-secretory area (ANA) with malignant potential, while autofluorescence imaging (AFI) without drug injection or dyeing may achieve early detection or prediction of GC. We aimed to determine whether AFI might be an alternative to CRE for identification of high-risk areas of gastric carcinogenesis after eradication. Materials and Methods We included 27 sequential patients with metachronous GC detected during endoscopic surveillance for a mean of 82.8 months after curative endoscopic resection for primary GC and eradication. After their H. pylori infection status was evaluated by clinical interviews and 13C-urea breath tests, the consistency in the extension of corpus atrophy (e.g., open-type or closed-type atrophy) between AFI and CRE was investigated as a primary endpoint. Results Inconsistencies in atrophic extension between AFI and CRE were observed in 6 of 27 patients, although CRE revealed all GC cases in the ANA. Interobserver and intraobserver agreements in the evaluation of atrophic extension by AFI were significantly less than those for CRE. Conclusions We demonstrated that AFI findings might be less reliable for the evaluation of gastric mucosa with malignant potential after eradication than CRE findings. Therefore, special attention should be paid when we clinically evaluate AFI findings of background gastric mucosa after eradication (University Hospital Medical Information Network Center registration number: UMIN000020849). PMID:27752392

  5. A test of the coincidence and duration models of melatonin action in Siberian hamsters: the effects of 1-hr melatonin infusions on testicular development in intact and pinealectomized prepubertal Phodopus sungorus.

    PubMed

    Gündüz, B; Stetson, M H

    2001-03-01

    The pineal hormone melatonin is known to play an important role in mediating photoperiodic messages to the reproductive system in seasonal breeding animals. Our goal was to test, in a single experimental paradigm, two hypotheses that have been forwarded to describe how the circadian rhythm of pineal melatonin transmits photoperiodic information to the reproductive system: 1) induction, i.e., a short-day effect, occurs when secreted melatonin and a circadian rhythm of sensitivity to melatonin coincide in time; 2) induction occurs following exposure to elevated circulating melatonin levels for a prescribed duration. In order to determine the relative validity of these hypotheses, we investigated the testicular maturation response to 1-hr daily infusions of 10, 25, and 50 ng of melatonin in pinealectomized intact and prepubertal Siberian hamsters (Phodopus sungorus). Animals received, beginning on day 15 of life, programmed subcutaneous infusions of melatonin or vehicle at one of five time points (19:00-20:00, 20:00-21:00, 21:00-22:00, 24:00-01:00, and 03:00-04:00 hr) for 15 days. In animals gestated and raised in a long photoperiod (LD16:8 = 16L, where L is the duration of light in hours, and D that of dark), melatonin infusion right after lights off (20:00-21:00 hr) significantly retarded gonadal maturation; this dose was ineffective at other times tested. Doses of 10 and 25 ng melatonin were ineffective at all time points. Identical results were obtained in prepubertal hamsters gestated in a short photoperiod (LD10:14 = 10L) and raised in 16L; these results were independent of the presence or absence of the pineal gland. In animals gestated and raised in 10L, melatonin infusions failed to suppress testicular development beyond that induced by the photoperiod; testicular development was maximally suppressed in all groups. The results of these investigations are best explained under the experimental conditions employed here: 1) the photoperiodic gonadal response in

  6. Seasonal variations of melatonin in ram seminal plasma are correlated to those of testosterone and antioxidant enzymes

    PubMed Central

    2010-01-01

    Background Some breeds of sheep are highly seasonal in terms of reproductive capability, and these changes are regulated by photoperiod and melatonin secretion. These changes affect the reproductive performance of rams, impairing semen quality and modifying hormonal profiles. Also, the antioxidant defence systems seem to be modulated by melatonin secretion, and shows seasonal variations. The aim of this study was to investigate the presence of melatonin and testosterone in ram seminal plasma and their variations between the breeding and non-breeding seasons. In addition, we analyzed the possible correlations between these hormones and the antioxidant enzyme defence system activity. Methods Seminal plasma from nine Rasa Aragonesa rams were collected for one year, and their levels of melatonin, testosterone, superoxide dismutase (SOD), glutathione reductase (GRD), glutathione peroxidase (GPX) and catalase (CAT) were measured. Results All samples presented measurable quantities of hormones and antioxidant enzymes. Both hormones showed monthly variations, with a decrease after the winter solstice and a rise after the summer solstice that reached the maximum levels in October-November, and a marked seasonal variation (P < 0.01) with higher levels in the breeding season. The yearly pattern of GRD and catalase was close to that of melatonin, and GRD showed a significant seasonal variation (P < 0.01) with a higher activity during the breeding season. Linear regression analysis between the studied hormones and antioxidant enzymes showed a significant correlation between melatonin and testosterone, GRD, SOD and catalase. Conclusions These results show the presence of melatonin and testosterone in ram seminal plasma, and that both hormones have seasonal variations, and support the idea that seasonal variations of fertility in the ram involve interplay between melatonin and the antioxidant defence system. PMID:20540737

  7. Melatonin regulation of antioxidant enzyme gene expression.

    PubMed

    Mayo, J C; Sainz, R M; Antoli, I; Herrera, F; Martin, V; Rodriguez, C

    2002-10-01

    Antioxidant enzymes (AOEs) are part of the primary cellular defense against free radicals induced by toxins and/or spontaneously formed in cells. Melatonin (MLT) has received much attention in recent years due to its direct free radical scavenging and antioxidant properties. In the present work we report that MLT, at physiological serum concentrations (1 nM), increases the mRNA of both superoxide dismutases (SODs) and glutathione peroxidase (GPx) in two neuronal cell lines. The MLT effect on both SODs and GPx mRNA was mediated by a de novo synthesized protein. MLT alters mRNA stability for Cu-Zn SOD and GPx. Experiments with a short time treatment (pulse action) of MLT suggest that the regulation of AOE gene expression is likely to be receptor mediated, because 1-h treatment with MLT results in the same response as a 24-h treatment.

  8. Glucose‐based microbial production of the hormone melatonin in yeast Saccharomyces cerevisiae

    PubMed Central

    Germann, Susanne M.; Baallal Jacobsen, Simo A.; Schneider, Konstantin; Harrison, Scott J.; Jensen, Niels B.; Chen, Xiao; Stahlhut, Steen G.; Borodina, Irina; Luo, Hao; Zhu, Jiangfeng; Maury, Jérôme

    2016-01-01

    Abstract Melatonin is a natural mammalian hormone that plays an important role in regulating the circadian cycle in humans. It is a clinically effective drug exhibiting positive effects as a sleep aid and a powerful antioxidant used as a dietary supplement. Commercial melatonin production is predominantly performed by complex chemical synthesis. In this study, we demonstrate microbial production of melatonin and related compounds, such as serotonin and N‐acetylserotonin. We generated Saccharomyces cerevisiae strains that comprise heterologous genes encoding one or more variants of an L‐tryptophan hydroxylase, a 5‐hydroxy‐L‐tryptophan decarboxylase, a serotonin acetyltransferase, an acetylserotonin O‐methyltransferase, and means for providing the cofactor tetrahydrobiopterin via heterologous biosynthesis and recycling pathways. We thereby achieved de novo melatonin biosynthesis from glucose. We furthermore accomplished increased product titers by altering expression levels of selected pathway enzymes and boosting co‐factor supply. The final yeast strain produced melatonin at a titer of 14.50 ± 0.57 mg L−1 in a 76h fermentation using simulated fed‐batch medium with glucose as sole carbon source. Our study lays the basis for further developing a yeast cell factory for biological production of melatonin. PMID:26710256

  9. Melatonin treatment in old mice enables a more youthful response to LPS in the brain.

    PubMed Central

    Perreau, V.M.; Bondy, S.C.; Cotman, C.W.; Sharman, K.G.; Sharman, E.H.

    2007-01-01

    Melatonin modulates the expression of a number of genes related to inflammation and immunity. Declining levels of melatonin with age may thus relate to some of the changes in immune function that occur with age. mRNA expression levels in murine CNS were measured using oligonucleotide microarrays in order to determine whether a dietary melatonin supplement may modify age-related changes in the response to an inflammatory challenge. CB6F1 male mice were fed 40ppm melatonin for 9 weeks prior to sacrifice at 26.5 months of age, and compared with age-matched untreated controls and 4.5-month-old controls. A subset of both young and old animals was injected i.p. with lipopolysaccharide (LPS). After 3 hours, total RNA was extracted from whole brain (excluding brain stem and cerebellum), and individual samples were hybridized to Affymetrix Mouse 430-2.0 arrays. Data were analyzed in Dchip and GeneSpring. Melatonin treatment markedly altered the response in gene expression of older animals subjected to an LPS challenge. These changes in general, caused the response to more closely resemble that of young animals subjected to the same LPS challenge. Thus melatonin treatment effects a major shift in the response of the CNS to an inflammatory challenge, causing a transition to a more youthful mRNA expression profile. PMID:17070935

  10. Protective effects of melatonin against caustic esophageal burn injury in rats.

    PubMed

    Larios-Arceo, F; Ortiz, G G; Huerta, M; Leal-Cortés, C; Saldaña, J A; Bitzer-Quintero, O K; Rodríguez-Reynoso, S

    2008-09-01

    Caustic ingestion is one of the most life-threatening events in the pediatric age group, which requires the immediate management and subsequent treatment of its most significant complication, i.e. alterations in esophageal structure. We investigated whether melatonin could reduce the esophageal burn damage induced by sodium hydroxide. It was assumed that melatonin could be effective because of its function as a direct free radical scavenger, its antioxidative actions and its ability to diminish tissue hydroxyproline (HP) levels. Esophageal burns were induced in male rats by the administration of 10% sodium hydroxide. Lipid peroxidation (LPO) products were then measured at the following times: 0, 1, 6, 24, 48 and 72 hr after treatment. Tissue HP concentrations in the injured area were assessed at 14 days after the administration of sodium hydroxide. The groups received either systemic melatonin or normal saline. There were two, non-ischemic, sham control groups treated with or without melatonin. LPO products, malondialdehyde (MDA) and 4-hydroxyalkenal (4-HDA), increased immediately after the administration of sodium hydroxide; this indicates the participation of free radicals in the development of damage. Melatonin diminished the oxidative response and the amount of HP in the late phase of the lesion. Melatonin reduced oxidative damage in the early phase of the esophageal burns induced by sodium hydroxide.

  11. Testicular response to melatonin or suprachiasmatic nuclei ablation in the spotted skunk.

    PubMed

    Berria, M; DeSantis, M; Mead, R A

    1990-07-01

    Testes of the Western spotted skunk enlarge and regress seasonally. The pineal hormone, melatonin, may be important in timing this seasonal reproductive activity. Likewise, the suprachiasmatic nuclei (SCN) have been implicated as possible neural regulators of pineal and reproductive events. These experiments were conducted to determine whether ablation of the SCN or constant administration of melatonin alters timing of the seasonal pattern of testicular regression and recrudescence. Male skunks (n = 24) were treated as follows: six received two empty Silastic capsules, six received two melatonin-filled Silastic capsules, six received sham lesions to the SCN, and six received lesions to the SCN (SCNx). All skunks were exposed to a natural photoperiod and had regressed testes at the onset of the experiment. Four of six males from the SCNx group had an average of 94 +/- 11.3% of these nuclei destroyed. Sham SCNx, animals with less than 40% of the SCN ablated, and males with empty capsules did not have fully enlarged testes until October. SCNx and melatonin-treated skunks exhibited a hastening of testicular recrudescence with maximal testis size being reached in June. Skunks with lesions to the SCN maintained enlarged testes for 5 months while all other groups exhibited rapid regression after attaining maximal testis size. Testicular regression occurred from July through October in animals receiving continuous melatonin, while controls exhibited recrudescence during this same period. Our data suggest that the SCN, melatonin, and thus the pineal gland, play a role in regulating the seasonal testicular cycle of the spotted skunk.

  12. Glucose-based microbial production of the hormone melatonin in yeast Saccharomyces cerevisiae.

    PubMed

    Germann, Susanne M; Baallal Jacobsen, Simo A; Schneider, Konstantin; Harrison, Scott J; Jensen, Niels B; Chen, Xiao; Stahlhut, Steen G; Borodina, Irina; Luo, Hao; Zhu, Jiangfeng; Maury, Jérôme; Forster, Jochen

    2016-05-01

    Melatonin is a natural mammalian hormone that plays an important role in regulating the circadian cycle in humans. It is a clinically effective drug exhibiting positive effects as a sleep aid and a powerful antioxidant used as a dietary supplement. Commercial melatonin production is predominantly performed by complex chemical synthesis. In this study, we demonstrate microbial production of melatonin and related compounds, such as serotonin and N-acetylserotonin. We generated Saccharomyces cerevisiae strains that comprise heterologous genes encoding one or more variants of an L-tryptophan hydroxylase, a 5-hydroxy-L-tryptophan decarboxylase, a serotonin acetyltransferase, an acetylserotonin O-methyltransferase, and means for providing the cofactor tetrahydrobiopterin via heterologous biosynthesis and recycling pathways. We thereby achieved de novo melatonin biosynthesis from glucose. We furthermore accomplished increased product titers by altering expression levels of selected pathway enzymes and boosting co-factor supply. The final yeast strain produced melatonin at a titer of 14.50 ± 0.57 mg L(-1) in a 76h fermentation using simulated fed-batch medium with glucose as sole carbon source. Our study lays the basis for further developing a yeast cell factory for biological production of melatonin.

  13. Melatonin Anticancer Effects: Review

    PubMed Central

    Di Bella, Giuseppe; Mascia, Fabrizio; Gualano, Luciano; Di Bella, Luigi

    2013-01-01

    Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet aggregation, leukocyte formula regulation and hemoglobin synthesis. Its significant atoxic, apoptotic, oncostatic, angiogenetic, differentiating and antiproliferative properties against all solid and liquid tumors have also been documented. Thanks, in fact, to its considerable functional versatility, MLT can exert both direct and indirect anticancer effects in factorial synergy with other differentiating, antiproliferative, immunomodulating and trophic molecules that form part of the anticancer treatment formulated by Luigi Di Bella (Di Bella Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin D3, prolactin inhibitors, chondroitin-sulfate). The interaction between MLT and the DBM molecules counters the multiple processes that characterize the neoplastic phenotype (induction, promotion, progression and/or dissemination, tumoral mutation). All these particular characteristics suggest the use of MLT in oncological diseases. PMID:23348932

  14. Melatonin regulating the expression of miRNAs involved in hair follicle cycle of cashmere goats skin.

    PubMed

    Fu, Shaoyin; Zhao, Hongli; Zheng, Zhuqing; Li, Jinquan; Zhang, Wenguang

    2014-12-01

    Melatonin and microRNAs (miRNAs) play important roles in regulating hair follicle development. However, the effect of melatonin on the expression pattern of miRNAs in skin and follicle of cashmere goats remain largely undefined. To explore the mechanism of melatonin affecting cashmere growth mediated by miRNAs, the effect of melatonin implants administered in Nei Mongol cashmere goats was assessed. In the experiment, five yearling does were implanted with melatonin, with the remaining other five females as control group. The expression of six candidate miRNAs was quantified by reverse transcription-real time polymerase chain reaction (RT-qPCR). The results indicated that melatonin significantly altered the expression pattern of miRNAs. Except for let-7a, the expression levels of miR-203, miR-205, miR-96, miR-183 and miR-199a occur three transitions during a cashmere cycle; melatonin changed the co-expression pattern of miRNAs. The correlation coefficient between miRNAs is 0.87-0.99 in control group(P<0.01). Compared with the control group, the correlation coefficient between some miRNAs (let-7a and miR-96, miR-199a, miR-205;miR-203 and miR-96, miR-199a; miR-96 and miR-183; miR-183 and miR-199a) was significantly weakened in melatonin group. Melatonin might induce second growth of cashmere mediated by down-regulating the expression level of some miRNAs in June in melatonin implanted group. PMID:25487268

  15. Stress inhibition of melatonin synthesis in the pineal organ of rainbow trout (Oncorhynchus mykiss) is mediated by cortisol.

    PubMed

    López-Patiño, Marcos A; Gesto, Manuel; Conde-Sieira, Marta; Soengas, José L; Míguez, Jesús M

    2014-04-15

    Cortisol has been suggested to mediate the effect of stress on pineal melatonin synthesis in fish. Therefore, we aimed to determine how pineal melatonin synthesis is affected by exposing rainbow trout to different stressors, such as hypoxia, chasing and high stocking density. In addition, to test the hypothesis that cortisol is a mediator of such stress-induced effects, a set of animals were intraperitoneally implanted with coconut oil alone or containing cortisol (50 mg kg(-1) body mass) and sampled 5 or 48 h post-injection at midday and midnight. The specificity of such effect was also assessed in cultured pineal organs exposed to cortisol alone or with the general glucocorticoid receptor antagonist, mifepristone (RU486). Stress (in particular chasing and high stocking density) affected the patterns of plasma and pineal organ melatonin content during both day and night, with the greatest reduction occurring at night. The decrease in nocturnal melatonin levels in the pineal organ of stressed fish was accompanied by increased serotonin content and decreased AANAT2 enzymatic activity and mRNA abundance. Similar effects on pineal melatonin synthesis to those elicited by stress were observed in trout implanted with cortisol for either 5 or 48 h. These data indicate that stress negatively influences the synthesis of melatonin in the pineal organ, thus attenuating the day-night variations of circulating melatonin. The effect might be mediated by increased cortisol, which binds to trout pineal organ-specific glucocorticoid receptors to modulate melatonin rhythms. Our results in cultured pineal organs support this. Considering the role of melatonin in the synchronization of daily and annual rhythms, the results suggest that stress-induced alterations in melatonin synthesis could affect the availability of fish to integrate rhythmic environmental information.

  16. Protective effect of melatonin against zonisamide-induced reproductive disorders in male rats

    PubMed Central

    Abdu, Faiza

    2013-01-01

    Introduction Zonisamide (ZNS) is a modern antiepileptic drug (AED) that is distinguished from other AEDs by its unique structure and broad mechanistic profile. The pineal hormone melatonin is involved in the regulation of reproductive function, including the timing of the luteinizing hormone (LH) surge. The aim of the present work was to study the protective effect of melatonin against the potential suppression impact of ZNS on reproductive activity. Material and methods Ninety adult albino male rats were allocated to several groups treated with melatonin (10 mg/kg BW), ZNS (10, 20 and 50 mg/kg BW) and 10 mg/kg of melatonin plus ZNS (10, 20 or 50 mg/kg BW, respectively). Reproductive hormones (testosterone, LH and follicle-stimulating hormone (FSH)) levels were measured in animal serum. Sperm abnormalities and DNA fragmentation in testis tissues as well as expression alteration of several reproductive-related genes were analyzed. Results The results revealed that ZNS decreased the levels of serum free testosterone, LH, and FSH and expression of their encoding genes in male rats. In addition, ZNS treatment increased the sperm abnormalities and DNA fragmentation and inducible nitric oxide synthase (iNOS) in testis tissues as well as GABA level in liver tissues. However, melatonin supplementation inhibited the negative symptoms of ZNS in which it increased the levels of reproductive hormones and expression of their encoding genes in the ZNS-treated rats. Moreover, melatonin decreased the sperm abnormalities, DNA fragmentation, iNOS activity and GABA level in ZNS-treated rats. Conclusions The data obtained in this study suggest that melatonin administration confers protection against toxicity inflicted by ZNS, and support the contention that melatonin protection is achieved by its ability as a scavenger for free radicals generated by ZNS. PMID:26170862

  17. The effect of melatonin on acetylsalicylic acid-induced kidney and testis damage.

    PubMed

    Altintas, R; Polat, A; Parlakpinar, H; Vardi, N; Beytur, A; Oguz, F; Sagir, M; Yildiz, A; Duran, Z R

    2014-04-01

    The aim of this study was to evaluate the acute effect of high-dose acetylsalicylic acid (ASA) on kidney and testis, and the potential protective and therapeutic effects of melatonin on ASA-related pathology. A total of 40 rats were randomly divided into the following 5 groups (n = 8): group 1: control, not given any drug; group 2: only 200 mg/kg ASA was given; group 3: 5 mg/kg melatonin was given 45 min before administering 200 mg/kg ASA; group 4: 5 mg/kg melatonin was given 45 min after administering 200 mg/kg ASA; and group 5: only 5 mg/kg melatonin was given. The histopathological changes and the biochemical findings; such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), reduced glutathione (GSH), and blood urea nitrogen (BUN) as well as serum creatinine (Cr) levels were evaluated. ASA significantly increased MDA levels in both kidney and testis, whereas it significantly decreased the values of SOD, CAT, GPX, and GSH in kidney and CAT levels in testis. Melatonin significantly decreased MDA levels in kidney and ameliorated it in testis, whereas it caused elevation in the levels of antioxidants. BUN and Cr levels were higher after ASA, whereas these levels were diminished after melatonin administration. The improvement obtained by melatonin on ASA-induced histological alterations was more prominent when it was used after ASA in kidney and before ASA in testis. In this study, we demonstrated the beneficial effect of melatonin on high-dose ASA-related pathology of kidney and testis for the first time.

  18. 'Melatonin isomer' in wine is not an isomer of the melatonin but tryptophan-ethylester.

    PubMed

    Gardana, Claudio; Iriti, Marcello; Stuknytė, Milda; De Noni, Ivano; Simonetti, Paolo

    2014-11-01

    Melatonin is a neurohormone, chronobiotic, and antioxidant compound found in wine and deriving directly from grapes and/or synthesized by yeast during alcoholic fermentation. In addition, a melatonin isomer has been detected in different foods, wine among them. The special interest for melatonin isomer related to the fact that it was found in greater quantities than melatonin and probably shares some of its biological properties. Despite this, its chemical structure has not yet been defined; although some researchers hypothesize, it could be melatonin with the ethylacetamide group shifted into position N1. Thus, the aim of our study was to identify the structures of the melatonin isomer. For this purpose, melatonin and melatonin isomer in Syrah wine were separated chromatographically by a sub-2 μm particle column and detected by tandem mass spectrometry. The sample was then purified and concentrated by solid-phase extraction, hydrolyzed with alkali or esterase, and substrates and products quantified by UPLC-MS/MS. Moreover, melatonin, melatonin isomer, and their product ions were evaluated by high-resolution mass spectrometry. The amount of melatonin isomer and melatonin in the wine was 84 ± 4 and 3 ± 0 ng/mL, respectively. In the solutions, containing diluted alkali or esterase, melatonin isomer was hydrolyzed in about 8 min. Correspondingly, tryptophan was detected, and its amount increased and reached the maximum concentration in about 8 min. Melatonin concentration was not affected by diluted alkali or esterase. The fragmentation pattern of melatonin isomer was different from that of melatonin but comparable to that of tryptophan-ethylester. Finally, the so-called melatonin isomer identity was verified by cochromatography with authentic standard of tryptophan-ethylester.

  19. Neuroprotective effect of melatonin in experimentally induced hypobaric hypoxia.

    PubMed

    Vornicescu, Corina; Boşca, Bianca; Crişan, Doiniţa; Yacoob, Sumaya; Stan, Nora; Filip, Adriana; Şovrea, Alina

    2013-01-01

    Melatonin (MEL) is an endogenous neurohormone with many biological functions, including a powerful antioxidant effect. The aim of the present study was to determine whether MEL protects the brain tissue from the oxidative stress induced by hypobaric hypoxia (HH) in vivo. This study was performed on Wistar rats randomly assigned in four groups, according to the pressure conditions and treatment: Group 1: normoxia and placebo; Group 2: HH and placebo; Group 3: normoxia and MEL; and Group 4: HH and MEL. The following aspects were evaluated: cognitive function (space reference and memory), oxidative stress parameters - serum and brain malondialdehyde (MDA) and reduced glutathione (GSH) levels -, and brain tissue macroscopic and microscopic morphological changes. Exposure to oxidative stress results in cognitive dysfunctions and biochemical alterations: significant increase of MDA and reduction of GSH in both serum and brain tissue. The most important morphological changes were observed in Group 2: increased cellularity, loss of pericellular haloes, shrunken neurons with scanty cytoplasm and hyperchromatic, pyknotic or absent nuclei; reactive gliosis, edema and blood-brain barrier alterations could also be observed in some areas. MEL treatment significantly diminished all these effects. Our results suggest that melatonin is a neuroprotective antioxidant both in normoxia and hypobaric hypoxia that can prevent and counteract the deleterious effects of oxidative stress (neuronal death, reactive astrogliosis, memory impairment and cognitive dysfunctions). Dietary supplements containing melatonin might be useful neuroprotective agents for the therapy of hypoxia-induced consequences. PMID:24399008

  20. Melatonin reduces migratory restlessness in Sylvia warblers during autumnal migration

    PubMed Central

    2013-01-01

    Introduction A remarkable aspect of bird migration is its nocturnality, particularly common in Passeriformes. The switch in activity from purely diurnal to also nocturnal is evident even in caged birds that during migratory periods develop an intense nocturnal restlessness, termed Zugunruhe. The mechanisms that control this major change in activity are mostly unknown. Previous work with Sylvia warblers suggested an involvement of melatonin, a hormone associated with day-night cycles in most vertebrates. In a recent study we found no effects of melatonin administration on Zugunruhe during spring migration. However, previous studies indicated that the response to melatonin manipulation could differ between spring and autumn migration, which are in fact separate life history stages. Here we tested whether a non-invasive treatment with melatonin can alter Zugunruhe in wild garden warblers S. borin and blackcaps S. atricapilla subject to temporary captivity at an autumnal stopover site. Food availability in the cage (yes/no) was added as a second factor because previous work showed that it enhanced Zugunruhe. Results The melatonin treatment significantly decreased the amount of Zugunruhe, while the availability of food only tended to increase the amount of Zugunruhe. Fuel deposits also had a strong effect on the amount of nocturnal activity: lean birds with a fat score of 1 showed significantly less Zugunruhe than fatter birds. The change in body mass during the time spent in the recording cage depended on food availability, but not on any of the other factors. Conclusions This study shows that the migratory programme of two Sylvia warblers can be manipulated by administration of exogenous melatonin and confirms that this hormone is involved in the control of migratory behaviour. To our knowledge, this is one of the first demonstrations that the autumn migratory programme can be altered by hormonal manipulation in migrating birds. The comparison with a similar study

  1. Prospects of the clinical utilization of melatonin.

    PubMed

    Bubenik, G A; Blask, D E; Brown, G M; Maestroni, G J; Pang, S F; Reiter, R J; Viswanathan, M; Zisapel, N

    1998-01-01

    This review summarizes the present knowledge on melatonin in several areas on physiology and discusses various prospects of its clinical utilization. Ever increasing evidence indicates that melatonin has an immuno-hematopoietic role. In animal studies, melatonin provided protection against gram-negative septic shock, prevented stress-induced immunodepression, and restored immune function after a hemorrhagic shock. In human studies, melatonin amplified the antitumoral activity of interleukin-2. Melatonin has been proven as a powerful cytostatic drug in vitro as well as in vivo. In the human clinical field, melatonin appears to be a promising agent either as a diagnostic or prognostic marker of neoplastic diseases or as a compound used either alone or in combination with the standard cancer treatment. Utilization of melatonin for treatment of rhythm disorders, such as those manifested in jet lag, shift work or blindness, is one of the oldest and the most successful clinical application of this chemical. Low doses of melatonin applied in controlled-release preparation were very effective in improving the sleep latency, increasing the sleep efficiency and rising sleep quality scores in elderly, melatonin-deficient insomniacs. In the cardiovascular system, melatonin seems to regulate the tone of cerebral arteries; melatonin receptors in vascular beds appear to participate in the regulation of body temperature. Heat loss may be the principal mechanism in the initiation of sleepiness caused by melatonin. The role of melatonin in the development of migraine headaches is at present uncertain but more research could result in new ways of treatment. Melatonin is the major messenger of light-dependent periodicity, implicated in the seasonal reproduction of animals and pubertal development in humans. Multiple receptor sites detected in brain and gonadal tissues of birds and mammals of both sexes indicate that melatonin exerts a direct effect on the vertebrate reproductive

  2. Melatonin promotes ripening and improves quality of tomato fruit during postharvest life

    PubMed Central

    Sun, Qianqian; Zhang, Na; Wang, Jinfang; Zhang, Haijun; Li, Dianbo; Shi, Jin; Li, Ren; Weeda, Sarah; Zhao, Bing; Ren, Shuxin; Guo, Yang-Dong

    2015-01-01

    In this study, the effect of melatonin on the postharvest ripening and quality improvement of tomato fruit was carried out. The tomatoes were immersed in exogenous melatonin for 2h, and then the related physiological indicators and the expression of genes during post-harvest life were evaluated. Compared with control check (CK), the 50 µM melatonin treatment significantly increased lycopene levels by 5.8-fold. Meanwhile, the key genes involved in fruit colour development, including phytoene synthase1 (PSY1) and carotenoid isomerase (CRTISO), showed a 2-fold increase in expression levels. The rate of water loss from tomato fruit also increased 8.3%, and the expression of aquaporin genes, such as SlPIP12Q, SlPIPQ, SlPIP21Q, and SlPIP22, was up-regulated 2- to 3-fold under 50 µM melatonin treatment. In addition, 50 µM melatonin treatment enhanced fruit softening, increased water-soluble pectin by 22.5%, and decreased protopectin by 19.5%. The expression of the cell wall modifying proteins polygalacturonase (PG), pectin esterase1 (PE1), β-galactosidase (TBG4), and expansin1 (Exp1) was up-regulated under 50 µM melatonin treatment. Melatonin increased ethylene production by 27.1%, accelerated the climacteric phase, and influenced the ethylene signalling pathway. Alteration of ethylene production correlated with altered 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS4) expression. The expression of ethylene signal transduction-related genes such as NR, SlETR4, SlEIL1, SlEIL3, and SlERF2, was enhanced by 50 µM melatonin. The effect of melatonin on ethylene biosynthesis, ethylene perception, and ethylene signalling may contribute to fruit ripening and quality improvement in tomato. This research may promote the application of melatonin on postharvest ripening and quality improvement of tomato fruit as well as other horticultural productions in the future. PMID:25147270

  3. Melatonin: a universal time messenger.

    PubMed

    Erren, Thomas C; Reiter, Russel J

    2015-01-01

    Temporal organization plays a key role in humans, and presumably all species on Earth. A core building block of the chronobiological architecture is the master clock, located in the suprachi asmatic nuclei [SCN], which organizes "when" things happen in sub-cellular biochemistry, cells, organs and organisms, including humans. Conceptually, time messenging should follow a 5 step-cascade. While abundant evidence suggests how steps 1 through 4 work, step 5 of "how is central time information transmitted througout the body?" awaits elucidation. Step 1: Light provides information on environmental (external) time; Step 2: Ocular interfaces between light and biological (internal) time are intrinsically photosensitive retinal ganglion cells [ipRGS] and rods and cones; Step 3: Via the retinohypothalamic tract external time information reaches the light-dependent master clock in the brain, viz the SCN; Step 4: The SCN translate environmental time information into biological time and distribute this information to numerous brain structures via a melanopsin-based network. Step 5: Melatonin, we propose, transmits, or is a messenger of, internal time information to all parts of the body to allow temporal organization which is orchestrated by the SCN. Key reasons why we expect melatonin to have such role include: First, melatonin, as the chemical expression of darkness, is centrally involved in time- and timing-related processes such as encoding clock and calendar information in the brain; Second, melatonin travels throughout the body without limits and is thus a ubiquitous molecule. The chemial conservation of melatonin in all tested species could make this molecule a candidate for a universal time messenger, possibly constituting a legacy of an all-embracing evolutionary history.

  4. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension.

    PubMed

    Repová-Bednárová, K; Aziriová, S; Hrenák, J; Krajčírovičová, K; Adamcová, M; Paulis, L; Simko, F

    2013-01-01

    Chronic continuous light exposure leads to melatonin deficiency along with complex neurohumoral activation resulting in hypertension development in rats. The aim of this study was to show, whether continuous light induces fibrotic rebuilding of the aorta and whether the treatment with melatonin or angiotensin converting enzyme inhibitor captopril can prevent these potential alterations. In a six-week experiment, 3-month-old Wistar rats were divided into 4 groups (ten per group): controls, rats exposed to continuous light, exposed to continuous light plus treated with captopril (100 mg/kg/24 h) and exposed to continuous light plus treated with melatonin (10 mg/kg/24 h). Systolic blood pressure (SBP) and collagen type I and III in the media of thoracic aorta were measured. Continuous light induced hypertension and fibrotic rebuilding of the aorta in terms of enhancement of collagen I and III concentration in the aortic media. Both captopril and melatonin prevented SBP rise and reduced collagen III concentration in the aorta. However, only melatonin reduced collagen I and the sum of collagen I and III in the aortic tissue. We conclude that in continuous light-induced hypertension, administration of melatonin, along with SBP reduction, decreases collagen I and III concentration in the aorta. It is suggested that antifibrotic effect of melatonin may reduce the stiffness of the aorta and small arteries and beneficially influence the nature of the pulse wave and peripheral vascular resistance.

  5. Protective actions of melatonin and growth hormone on the aged cardiovascular system.

    PubMed

    Paredes, Sergio D; Forman, Katherine A; García, Cruz; Vara, Elena; Escames, Germaine; Tresguerres, Jesús A F

    2014-05-01

    Epidemiological studies indicate that certain aspects of lifestyle and genetics act as risk factors for a variety of cardiovascular disorders, including coronary disease, hypertension, heart failure and stroke. Aging, however, appears to be the major contributor for morbidity and mortality of the impaired cardiovascular system. Growth hormone (GH) and melatonin seem to prevent cardiac aging, as they contribute to the recovery of several physiological parameters affected by age. These hormones exhibit antioxidant properties and decrease oxidative stress and apoptosis. This paper summarizes a set of studies related to the potential role that therapy with GH and melatonin may play in the protection of the altered cardiac function due to aging, with a focus on experiments performed in our laboratory using the senescence-accelerated mouse as an aging model. In general, we observed significantly increased inflammation, oxidative stress and apoptosis markers in hearts from senescence-accelerated prone 10-month-old animals compared to 2-month-old controls, while anti-inflammatory and antiapoptotic markers as well as endothelial nitric oxide synthase were decreased. Senescence-accelerated resistant animals showed no significant changes with age. GH or melatonin treatment prevented the age-dependent cardiac alterations observed in the senescence-accelerated prone group. Combined administration of GH plus melatonin reduced the age-related changes in senescence-accelerated prone hearts in an additive fashion that was different to that displayed when administered alone. GH and melatonin may be potential agents for counteracting oxidative stress, apoptosis and inflammation in the aging heart.

  6. Melatonin in human preovulatory follicular fluid

    NASA Technical Reports Server (NTRS)

    Brzezinski, Amnon; Seibel, Machelle M.; Lynch, Harry J.; Deng, Mei-Hua; Wurtman, Richard J.

    1987-01-01

    Melatonin, the major hormone of the pineal gland, has antigonadotrophic activity in many mammals and may also be involved in human reproduction. Melatonin suppresses steroidogenesis by ovarian granulosa and luteal cells in vitro. To determine if melatonin is present in the human ovary, preovulatory follicular fluids (n = 32) from 15 women were assayed for melatonin by RIA after solvent extraction. The fluids were obtained by laparoscopy or sonographically controlled follicular puncture from infertile women undergoing in vitro fertilization and embryo transfer. All patients had received clomiphene citrate, human menopausal gonadotropin, and hCG to stimulate follicle formation. Blood samples were obtained by venipuncture 30 rain or less after follicular aspiration. All of the follicular fluids contained melatonim, in concentrations substantially higher than those in the corresponding serum. A positive correlation was found between follicular fluid and serum melatonin levels in each woman; these observations indicate that preovulatory follicles contain substantial amounts of melatonin that may affect ovarian steroidogenesis.

  7. Ultradian oscillation in expression of four melatonin receptor subtype genes in the pineal gland of the grass puffer, a semilunar-synchronized spawner, under constant darkness.

    PubMed

    Ikegami, Taro; Maruyama, Yusuke; Doi, Hiroyuki; Hattori, Atsuhiko; Ando, Hironori

    2015-01-01

    Melatonin receptor gene expression as well as melatonin synthesis and secretion activities were examined in the pineal gland of the grass puffer, which exhibits unique lunar/tidal cycle-synchronized mass spawing: spawning occurs before high tide on the day of spring tide during spawing season. Melatonin synthesizing activity was assessed by the abundance of arylalkylamine N-acetyltransferase 2 (AANAT2) mRNA. The amount of aanat2 mRNA was low during light phase and initiated to increase after the light was turned off. The secretion of melatonin from primary pineal organ culture was stimulated after the light was turned off and ceased immediately after the light was turned on. The expression levels of four melatonin receptor subtype genes (mel 1a 1.4, mel 1a 1.7, mel1b, and mel1c) showed synchronous variations, and the levels tended to be high during the dark phase under light/dark conditions. These results suggest that the action of melatonin on the pineal gland is highly dependent on light and photoperiod, possibly with stronger action during night time. Under constant darkness, the expression of four melatonin receptor subtype genes showed unique ultradian oscillations with the period of 14.0-15.4 h, suggesting the presence of a circatidal oscillator in the pineal gland. The present results indicate that melatonin may serve local chronobiological functions in the pineal gland. These cyclic expressions of melatonin receptor genes in the pineal gland may be important in the control of the lunar/tidal cycle-synchronized mass spawning in the grass puffer.

  8. Ultradian oscillation in expression of four melatonin receptor subtype genes in the pineal gland of the grass puffer, a semilunar-synchronized spawner, under constant darkness

    PubMed Central

    Ikegami, Taro; Maruyama, Yusuke; Doi, Hiroyuki; Hattori, Atsuhiko; Ando, Hironori

    2015-01-01

    Melatonin receptor gene expression as well as melatonin synthesis and secretion activities were examined in the pineal gland of the grass puffer, which exhibits unique lunar/tidal cycle-synchronized mass spawing: spawning occurs before high tide on the day of spring tide during spawing season. Melatonin synthesizing activity was assessed by the abundance of arylalkylamine N-acetyltransferase 2 (AANAT2) mRNA. The amount of aanat2 mRNA was low during light phase and initiated to increase after the light was turned off. The secretion of melatonin from primary pineal organ culture was stimulated after the light was turned off and ceased immediately after the light was turned on. The expression levels of four melatonin receptor subtype genes (mel1a1.4, mel1a1.7, mel1b, and mel1c) showed synchronous variations, and the levels tended to be high during the dark phase under light/dark conditions. These results suggest that the action of melatonin on the pineal gland is highly dependent on light and photoperiod, possibly with stronger action during night time. Under constant darkness, the expression of four melatonin receptor subtype genes showed unique ultradian oscillations with the period of 14.0–15.4 h, suggesting the presence of a circatidal oscillator in the pineal gland. The present results indicate that melatonin may serve local chronobiological functions in the pineal gland. These cyclic expressions of melatonin receptor genes in the pineal gland may be important in the control of the lunar/tidal cycle-synchronized mass spawning in the grass puffer. PMID:25688184

  9. Therapeutic potential of melatonin and its analogs in Parkinson’s disease: focus on sleep and neuroprotection

    PubMed Central

    Srinivasan, Venkatramanujam; Cardinali, Daniel P.; Srinivasan, Uddanapalli S.; Kaur, Charanjit; Brown, Gregory M.; Spence, D. Warren; Hardeland, Rüdiger; Pandi-Perumal, Seithikurippu R.

    2011-01-01

    Sleep disorders constitute major nonmotor features of Parkinson’s disease (PD) that have a substantial effect on patients’ quality of life and can be related to the progression of the neurodegenerative disease. They can also serve as preclinical markers for PD, as it is the case for rapid eye movement (REM)-associated sleep behavior disorder (RBD). Although the etiology of sleep disorders in PD remains undefined, the assessment of the components of the circadian system, including melatonin secretion, could give therapeutically valuable insight on their pathophysiopathology. Melatonin is a regulator of the sleep/wake cycle and also acts as an effective antioxidant and mitochondrial function protector. A reduction in the expression of melatonin MT1 and MT2 receptors has been documented in the substantia nigra of PD patients. The efficacy of melatonin for preventing neuronal cell death and for ameliorating PD symptoms has been demonstrated in animal models of PD employing neurotoxins. A small number of controlled trials indicate that melatonin is useful in treating disturbed sleep in PD, in particular RBD. Whether melatonin and the recently developed melatonergic agents (ramelteon, tasimelteon, agomelatine) have therapeutic potential in PD is also discussed. PMID:22010042

  10. [Melatonin in dermatology. Experimental and clinical aspects].

    PubMed

    Fischer, T; Wigger-Alberti, W; Elsner, P

    1999-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) is a hormone with multiple functions in humans, produced by the pineal gland and stimulated by beta-adrenergic receptors. Serum melatonin levels exhibit a circadian rhythm with low levels during the day, rise in the evening and maximum levels at night between 2 and 4 a.m. Melatonin participates in the regulation of several physiological processes such as seasonal biological rhythm, daily sleep induction, aging and modulation of immunobiological defence reactions. Furthermore, melatonin has a highly lipophilic molecular structure facilitating penetration of cell membranes and serving as an extra- and intracellular free radical scavenger. Melatonin seems to quench mainly hydroxyl radicals, the most damaging of all free radicals. Melatonin may play a role in the etiology and treatment of several dermatoses e.g. atopic eczema, psoriasis and malignant melanoma. The influence of melatonin on hair growth is another aspect. Topical application of melatonin inhibits the development of UV-erythema. Penetration through skin after topical application and oral bioavailability auxit further investigations on the pharmacokinetic and pharmacodynamic actions of melatonin. PMID:10068925

  11. Nonpineal melatonin in the alligator (Alligator mississippiensis).

    PubMed

    Roth, J J; Gern, W A; Roth, E C; Ralph, C L; Jacobson, E

    1980-10-31

    All living and most fossil representatives of the reptilian subclass Archosauria lack pineal bodies. Arrhythmic, low-level, nonpineal melatonin is present, however, in the blood of Alligator mississippiensis. Although pineal bodies have been implicated in circadian phenomena, these results suggest that arrhytmic melatonin in alligators may not be involved incircadian events and indicate that the pineal is not the only source of the hormone melatonin. The evolutionary loss of the pineal in Archosauria occurred during the Mesozoic, and era noted for its seasonal stability. Arrhythmic melatonin titers inalligators and pineal loss in alligators and other archosaurs may be related to Mesozoic seasonal stability.

  12. Melatonin receptors: Current status, facts, and hypothesis

    SciTech Connect

    Stankov, B.; Reiter, R.J. )

    1990-01-01

    Great progress has been made in the identification of melatonin binding sites, commonly identified as melatonin receptors by many authors, in recent years. The bulk of these studies have investigated the sites using either autoradiographic and biochemical techniques with the majority of the experiments being done on the rat, Djungarian and Syrian hamster, and sheep, although human tissue has also been employed. Many of the studies have identified melatonin binding in the central nervous system with either tritium- or iodine-labelled ligands. The latter ligand seems to provide the most reproducible and consistent data. Of the central neural tissues examined, the suprachiasmatic nuclei are most frequently mentioned as a location for melatonin binding sites although binding seems to be widespread in the brain. The other tissue that has been prominently mentioned as a site for melatonin binding is the pars tuberalis of the anterior pituitary gland. There may be time-dependent variations in melatonin binding densities in both neural and pituitary gland tissue. Very few attempts have been made to identify melatonin binding outside of the central nervous system despite the widespread actions of melatonin. Preliminary experiments have been carried out on the intracellular second messengers which mediate the actions of melatonin.

  13. The effects of extremely low-frequency magnetic fields on melatonin and cortisol, two marker rhythms of the circadian system

    PubMed Central

    Touitou, Yvan; Selmaoui, Brahim

    2012-01-01

    In the past 30 years the concern that daily exposure to extremely low-frequency magnetic fields (ELF-EMF) (1 to 300 Hz) might be harmful to human health (cancer, neurobehavioral disturbances, etc) has been the object of debate, and has become a public health concern. This has resulted in the classification of ELF-EMF into category 2B, ie, agents that are “possibly carcinogenic to humans” by the International Agency for Research on Cancer. Since melatonin, a neurohormone secreted by the pineal gland, has been shown to possess oncostatic properties, a “melatonin hypothesis” has been raised, stating that exposure to EMF might decrease melatonin production and therefore might promote the development of breast cancer in humans. Data from the literature reviewed here are contradictory. In addition, we have demonstrated a lack of effect of ELF-EMF on melatonin secretion in humans exposed to EMF (up to 20 years' exposure) which rebuts the melatonin hypothesis. Currently, the debate concerns the effects of ELF-EMF on the risk of childhood leukemia in children chronically exposed to more than 0.4 μT. Further research is thus needed to obtain more definite answers regarding the potential deleterious effects of ELF-EMF. PMID:23393415

  14. The effects of extremely low-frequency magnetic fields on melatonin and cortisol, two marker rhythms of the circadian system.

    PubMed

    Touitou, Yvan; Selmaoui, Brahim

    2012-12-01

    In the past 30 years the concern that daily exposure to extremely low-frequency magnetic fields (ELF-EMF) (1 to 300 Hz) might be harmful to human health (cancer, neurobehavioral disturbances, etc) has been the object of debate, and has become a public health concern. This has resulted in the classification of ELF-EMF into category 2B, ie, agents that are "possibly carcinogenic to humans" by the International Agency for Research on Cancer. Since melatonin, a neurohormone secreted by the pineal gland, has been shown to possess oncostatic properties, a "melatonin hypothesis" has been raised, stating that exposure to EMF might decrease melatonin production and therefore might promote the development of breast cancer in humans. Data from the literature reviewed here are contradictory. In addition, we have demonstrated a lack of effect of ELF-EMF on melatonin secretion in humans exposed to EMF (up to 20 years' exposure) which rebuts the melatonin hypothesis. Currently, the debate concerns the effects of ELF-EMF on the risk of childhood leukemia in children chronically exposed to more than 0.4 μT. Further research is thus needed to obtain more definite answers regarding the potential deleterious effects of ELF-EMF.

  15. Melatonin-Mediated Intracellular Insulin during 2-Deoxy-d-glucose Treatment Is Reduced through Autophagy and EDC3 Protein in Insulinoma INS-1E Cells

    PubMed Central

    Kim, Han Sung; Han, Tae-Young

    2016-01-01

    2-DG triggers glucose deprivation without altering other nutrients or metabolic pathways and then activates autophagy via activation of AMPK and endoplasmic reticulum (ER) stress. We investigated whether 2-DG reduced intracellular insulin increased by melatonin via autophagy/EDC3 in insulinoma INS-1E cells. p-AMPK and GRP78/BiP level were significantly increased by 2-DG in the presence/absence of melatonin, but IRE1α level was reduced in 2-DG treatment. Levels of p85α, p110, p-Akt (Ser473, Thr308), and p-mTOR (Ser2481) were also significantly reduced by 2-DG in the presence/absence of melatonin. Mn-SOD increased with 2-DG plus melatonin compared to groups treated with/without melatonin alone. Bcl-2 was decreased and Bax increased with 2-DG plus melatonin. LC3II level increased with 2-DG treatment in the presence/absence of melatonin. Intracellular insulin production increased in melatonin plus 2-DG but reduced in treatment with 2-DG with/without melatonin. EDC3 was increased by 2-DG in the presence/absence of melatonin. Rapamycin, an mTOR inhibitor, increased GRP78/BiP and EDC3 levels in a dose-dependent manner and subsequently resulted in a decrease in intracellular production of insulin. These results suggest that melatonin-mediated insulin synthesis during 2-DG treatment involves autophagy and EDC3 protein in rat insulinoma INS-1E cells and subsequently results in a decrease in intracellular production of insulin. PMID:27493704

  16. Effects of damage to the suprachiasmatic area of the anterior hypothalamus on the daily melatonin and cortisol rhythms in the rhesus monkey

    SciTech Connect

    Reppert, S.M.; Perlow, M.J.; Ungerleider, L.G.; Mishkin, M.; Tamarkin, L.; Orloff, D.G.; Hoffman, H.J.; Klein, D.C.

    1981-12-01

    The effects of lesions of the suprachiasmatic nucleus (SCN) on the circadian rhythms in melatonin and cortisol were examined in the rhesus monkey. The concentrations of the two hormones were monitored in cerebrospinal fluid (CSF) withdrawn from two sham-operated animals, two animals with complete bilateral SCN lesions, and two animals with partial SCN damage at 4 and 8 months after surgery. In the sham-operated animals, as in the intact animal, the daily melatonin rhythm was entrained to the daily light-dark cycle, was suppressed in constant light, and persisted in constant darkness. In contrast, neither animal with complete SCN ablation exhibited a daily pattern of CSF melatonin in diurnal lighting at 4 months after surgery nor were their melatonin levels at constant low values. Furthermore, CSF melatonin concentrations were not suppressed in either animal by constant light. Surprisingly, at 8 months after surgery, spectral analysis revealed a 24-hr component to the melatonin patterns for each animal with complete SCN ablation in both diurnal lighting and constant darkness. The two animals with partial SCN damage exhibited a daily melatonin rhythm in diurnal lighting, but constant light did not suppress CSF melatonin concentrations consistently. Daily rhythms persisted in both for a 6 1/2-d period of study in constant darkness. In contrast to the alterations in the melatonin rhythm after SCN damage, there was no apparent effect of either partial or complete SCN ablation on the daily CSF cortisol rhythm. These data indicate that, in the rhesus monkey, the SCN is important for the generation, photic entrainment, and photic suppression of the melatonin rhythm. However, circadian oscillators located outside of the SCN region may control the normal daily cortisol rhythm and perhaps the melatonin rhythm in the absence of the SCN.

  17. Melatonin-Mediated Intracellular Insulin during 2-Deoxy-d-glucose Treatment Is Reduced through Autophagy and EDC3 Protein in Insulinoma INS-1E Cells.

    PubMed

    Kim, Han Sung; Han, Tae-Young; Yoo, Yeong-Min

    2016-01-01

    2-DG triggers glucose deprivation without altering other nutrients or metabolic pathways and then activates autophagy via activation of AMPK and endoplasmic reticulum (ER) stress. We investigated whether 2-DG reduced intracellular insulin increased by melatonin via autophagy/EDC3 in insulinoma INS-1E cells. p-AMPK and GRP78/BiP level were significantly increased by 2-DG in the presence/absence of melatonin, but IRE1α level was reduced in 2-DG treatment. Levels of p85α, p110, p-Akt (Ser473, Thr308), and p-mTOR (Ser2481) were also significantly reduced by 2-DG in the presence/absence of melatonin. Mn-SOD increased with 2-DG plus melatonin compared to groups treated with/without melatonin alone. Bcl-2 was decreased and Bax increased with 2-DG plus melatonin. LC3II level increased with 2-DG treatment in the presence/absence of melatonin. Intracellular insulin production increased in melatonin plus 2-DG but reduced in treatment with 2-DG with/without melatonin. EDC3 was increased by 2-DG in the presence/absence of melatonin. Rapamycin, an mTOR inhibitor, increased GRP78/BiP and EDC3 levels in a dose-dependent manner and subsequently resulted in a decrease in intracellular production of insulin. These results suggest that melatonin-mediated insulin synthesis during 2-DG treatment involves autophagy and EDC3 protein in rat insulinoma INS-1E cells and subsequently results in a decrease in intracellular production of insulin. PMID:27493704

  18. Increased L-CPT-1 activity and altered gene expression in pancreatic islets of malnourished adult rats: a possible relationship between elevated free fatty acid levels and impaired insulin secretion.

    PubMed

    de Barros Reis, Marise Auxiliadora; Arantes, Vanessa Cristina; Cunha, Daniel Andrade; Latorraca, Márcia Queiroz; Toyama, Marcos Hikari; Carneiro, Everardo Magalhães; Boschero, Antonio Carlos

    2008-02-01

    Intrauterine growth restriction is associated with chronically elevated levels of serum fatty acids and reduced glucose-stimulated insulin secretion. Lipid metabolism in pancreatic beta cells is critical for the regulation of insulin secretion, and the chronic exposure to fatty acids results in higher palmitate oxidation rates and an altered insulin response to glucose. Using a rat model of isocaloric protein restriction, we examined whether pre- and postnatal protein malnutrition influences the properties of pancreatic islet carnitine palmitoyltransferase-1 (liver isoform, L-CPT-1), a rate-limiting enzyme that regulates fatty acid oxidation in mitochondria. The activity of L-CPT-1 in pancreatic islets increased in the low protein (LP), although the L-CPT-1 mRNA levels were unaffected by malnutrition. The susceptibility of enzyme to inhibition by malonyl-CoA was unaltered and the content of malonyl-CoA was reduced in LP cells. Because the mitochondrial oxidation of fatty acids is related to the altered expression of a number of genes encoding proteins involved in insulin secretion, the levels of expression of insulin and GLUT-2 mRNA were assessed. A reduced expression of both genes was observed in malnourished rats. These results provide further evidence that increased L-CPT-1 activity and changes in gene expression in pancreatic islets may be involved in the reduced insulin secretion seen in malnourished rats. PMID:17531461

  19. MT1 melatonin receptors mediate somatic, behavioral, and reproductive neuroendocrine responses to photoperiod and melatonin in Siberian hamsters (Phodopus sungorus).

    PubMed

    Prendergast, Brian J

    2010-02-01

    Environmental day length drives nocturnal pineal melatonin secretion, which in turn generates or entrains seasonal cycles of physiology, reproduction, and behavior. In mammals, melatonin (MEL) binds to a number of receptor subtypes including high-affinity (MT1 and MT2) and low-affinity (MT3, nuclear orphan receptors) binding sites, which are distributed throughout the central nervous system and periphery. The MEL receptors that mediate photoperiodic reproductive and behavioral responses to MEL have not been identified in a reproductively photoperiodic species. Here I tested the hypothesis that MT1 receptors are necessary and sufficient to engage photoperiodic responses by challenging male Siberian hamsters (Phodopus sungorus), a species that does not express functional MT2 receptors, with ramelteon (RAM), a specific MT1/MT2 receptor agonist. In hamsters housed in a long-day photoperiod, late-afternoon RAM treatment inhibited gonadotropin secretion, induced gonadal regression, and suppressed food intake and body mass, mimicking effects of MEL. In addition, chronic (24 h/d) RAM infusions were sufficient to obscure endogenous MEL signaling, and these treatments attenuated gonadal regression in short days. Together, the outcomes indicate that signaling at the MT1 receptor is sufficient and necessary to mediate the effects of photoperiod-driven changes in MEL on behavior and reproductive function in a reproductively photoperiodic mammal.

  20. A review of the melatonin functions in zebrafish physiology.

    PubMed

    Lima-Cabello, Elena; Díaz-Casado, María E; Guerrero, Jose A; Otalora, Beatriz B; Escames, Germaine; López, Luis C; Reiter, Russel J; Acuña-Castroviejo, Darío

    2014-08-01

    Melatonin is part of the evolutionary conserved highly functional network in vertebrates. It plays a central role in the adaptative behavior of the animal to the environment, including entrainment of daily and annual physiological rhythms, reproductive behavior, food intake, locomotor activity, growth, and breeding performance. In zebrafish, apart from its synchronizing capabilities, melatonin seems to have a major role in multiple physiological processes. Extensive knowledge of its genome and the identification of a series of genes with the same functions as those in humans, the relative ease of obtaining mutants, and the similarities between zebrafish and human pathologies make it an excellent experimental model organism of human diseases. Moreover, it is a common experimental species because of easy handling, breeding, and developmental control. Among other pathophysiologies, zebrafish are now used in studies of neurodegeneration and neurological diseases, endocrine diseases, behavior, muscular dystrophies, developmental alterations, circadian rhythms, and drugs screening. The purpose of this review was to update the current knowledge on the synthesis and biological functions of melatonin in zebrafish, keeping in mind its relevance not only in the physiology of the animal, but also in pathophysiological conditions.

  1. [MELATONIN CONCENTRATION IN THE BLOOD OF VITILIGO PATIENTS WITH STRESS IN ANAMNESIS].

    PubMed

    Tsiskarishvili, N I; Katsitadze, A; Tsiskarishvili, N V; Tsiskarishvil, Ts; Chitanava, L

    2016-05-01

    In recent years, despite some progress in the study of vitiligo many aspects of pathogenesis and treatment of this dermatosis remain unsolved or are highly controversial. It is believed that progression of disease is associated with a genetic predisposition, autoimmune processes and oxidative stress, but the concrete role of stress on the processes having place in the organism of vitiligo patients so far is not investigated. As we know, epiphysis is the main regulator of adaptation of the individual to the environment. An important product of secretion of the pineal gland is the hormone melatonin - a universal regulator of vital functions and biorhythms of the body. Psychoses, neuroses, depression, immunopathology are aspects of disturbances in circadian, seasonal and annual rhythms of the synthesis of this hormone. Clinical and experimental studies indicate that the hormone melatonin, which is one of the links in a stress defense mechanism of the body, has antioxidant and immunomodulatory properties. The purpose of this study was to determine plasma level of melatonin in the blood of vitiligo patients (with stress in anamnesis), depending on the clinical form and duration of the disease. 41 patients with vitiligo (16 with segmental and 25 with non-segmental form) with stress in anamnesis and duration of disease from several months to 20 years were under observation. The level of melatonin in the blood plasma was determined by ELISA (IBL - international - reagent), the results were expressed in units of pg/ml. According to the results of our study, 8 patients with segmental vitiligo had the normal level of plasma melatonin concentration (in the range of 20.2-31.1 pg/ml), in 2 cases - the level was near the norm (19.2 pg/ml). In the group of patients with non-segmental vitiligo, the level of melatonin was below the norm (12.5 pg/ml) and in 2 cases, the content of melatonin was very low - 4.05 pg / ml. Correlation analysis of melatonin levels with duration of disease

  2. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson’s disease

    PubMed Central

    Videnovic, Aleksandar; Noble, Charleston; Reid, Kathryn J.; Peng, Jie; Turek, Fred W.; Marconi, Angelica; Rademaker, Alfred W.; Simuni, Tanya; Zadikoff, Cindy; Zee, Phyllis C.

    2014-01-01

    Importance Diurnal fluctuations of motor and non-motor symptoms and high prevalence of sleep/wake disturbances in Parkinson’s disease (PD) suggest a role of the circadian system in the modulation of these symptoms. Yet, surprisingly little is known regarding circadian function in PD, and whether circadian dysfunction is involved in the development of sleep/wake disturbances in PD. Objective The objective of this study was to determine the relationship between the timing and amplitude of the 24-hour melatonin rhythm, a marker of endogenous circadian rhythmicity, with self-reported sleep quality, the severity of daytime sleepiness and disease metrics. Design A cross-sectional study, (2009–2012). Setting PD and Movement Disorders Center, Northwestern University, Chicago. Participants Twenty PD patients on stable dopaminergic therapy and 15 age-matched controls underwent blood sampling for the measurement of serum melatonin levels at 30-minute intervals for 24 hours under modified constant routine conditions. Main Outcome Measure(s) Clinical and demographic data, self-reported measures of sleep quality (Pittsburgh Sleep Quality Index (PSQI)) and daytime sleepiness (Epworth Sleepiness Scale (ESS)), circadian markers of the melatonin rhythm, including the amplitude, area-under-the-curve (AUC), and phase of the 24-hour rhythm. Results Participants with PD had a blunted circadian rhythms of melatonin secretion compared to controls; both the amplitude of the melatonin rhythm and the 24-hour AUC for circulating melatonin levels were significantly lower in PD participants compared with controls (p<0.001). Markers of circadian phase were not significantly different between the two groups. Among PD participants, those with excessive daytime sleepiness (ESS score ≥10) had a significantly lower amplitude of the melatonin rhythm and the 24-hour melatonin AUC compared with PD participants without excessive sleepiness (p=0.001). Disease duration, UPDRS scores, levodopa

  3. Effects of intrauterine growth restriction on sleep and the cardiovascular system: The use of melatonin as a potential therapy?

    PubMed

    Yiallourou, Stephanie R; Wallace, Euan M; Miller, Suzanne L; Horne, Rosemary S C

    2016-04-01

    Intrauterine growth restriction (IUGR) complicates 5-10% of pregnancies and is associated with increased risk of preterm birth, mortality and neurodevelopmental delay. The development of sleep and cardiovascular control are closely coupled and IUGR is known to alter this development. In the long-term, IUGR is associated with altered sleep and an increased risk of hypertension in adulthood. Melatonin plays an important role in the sleep-wake cycle. Experimental animal studies have shown that melatonin therapy has neuroprotective and cardioprotective effects in the IUGR fetus. Consequently, clinical trials are currently underway to assess the short and long term effects of antenatal melatonin therapy in IUGR pregnancies. Given melatonin's role in sleep regulation, this hormone could affect the developing infants' sleep-wake cycle and cardiovascular function after birth. In this review, we will 1) examine the role of melatonin as a therapy for IUGR pregnancies and the potential implications on sleep and the cardiovascular system; 2) examine the development of sleep-wake cycle in fetal and neonatal life; 3) discuss the development of cardiovascular control during sleep; 4) discuss the effect of IUGR on sleep and the cardiovascular system and 5) discuss the future implications of melatonin therapy in IUGR pregnancies.

  4. Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans

    PubMed Central

    Chamberlain, Kyle; Smith, Kurt A.; Khalsa, Sat Bir S.; Rajaratnam, Shantha M. W.; Van Reen, Eliza; Zeitzer, Jamie M.; Czeisler, Charles A.; Lockley, Steven W.

    2011-01-01

    Context: Millions of individuals habitually expose themselves to room light in the hours before bedtime, yet the effects of this behavior on melatonin signaling are not well recognized. Objective: We tested the hypothesis that exposure to room light in the late evening suppresses the onset of melatonin synthesis and shortens the duration of melatonin production. Design: In a retrospective analysis, we compared daily melatonin profiles in individuals living in room light (<200 lux) vs. dim light (<3 lux). Patients: Healthy volunteers (n = 116, 18–30 yr) were recruited from the general population to participate in one of two studies. Setting: Participants lived in a General Clinical Research Center for at least five consecutive days. Intervention: Individuals were exposed to room light or dim light in the 8 h preceding bedtime. Outcome Measures: Melatonin duration, onset and offset, suppression, and phase angle of entrainment were determined. Results: Compared with dim light, exposure to room light before bedtime suppressed melatonin, resulting in a later melatonin onset in 99.0% of individuals and shortening melatonin duration by about 90 min. Also, exposure to room light during the usual hours of sleep suppressed melatonin by greater than 50% in most (85%) trials. Conclusions: These findings indicate that room light exerts a profound suppressive effect on melatonin levels and shortens the body's internal representation of night duration. Hence, chronically exposing oneself to electrical lighting in the late evening disrupts melatonin signaling and could therefore potentially impact sleep, thermoregulation, blood pressure, and glucose homeostasis. PMID:21193540

  5. Melatonin inhibits paraquat-induced cell death in bovine preimplantation embryos.

    PubMed

    Pang, Yun-Wei; Sun, Ye-Qing; Sun, Wei-Jun; Du, Wei-Hua; Hao, Hai-Sheng; Zhao, Shan-Jiang; Zhu, Hua-Bin

    2016-03-01

    Preimplantation embryos are sensitive to oxidative stress-induced damage that can be caused by reactive oxygen species (ROS) originating from normal embryonic metabolism and/or the external surroundings. Paraquat (PQ), a commonly used pesticide and potent ROS generator, can induce embryotoxicity. The present study aimed to investigate the effects of melatonin on PQ-induced damage during embryonic development in bovine preimplantation embryos. PQ treatment significantly reduced the ability of bovine embryos to develop to the blastocyst stage, and the addition of melatonin markedly reversed the developmental failure caused by PQ (20.9% versus 14.3%). Apoptotic assay showed that melatonin pretreatment did not change the total cell number in blastocysts, but the incidence of apoptotic nuclei and the release of cytochrome c were significantly decreased. Using real-time quantitative polymerase chain reaction analysis, we found that melatonin pre-incubation significantly altered the expression levels of genes associated with redox signaling, particularly by attenuating the transcript level of Txnip and reinforcing the expression of Trx. Furthermore, melatonin pretreatment significantly reduced the expression of the pro-apoptotic caspase-3 and Bax, while the expression of the anti-apoptotic Bcl-2 and XIAP was unaffected. Western blot analysis showed that melatonin protected bovine embryos from PQ-induced damage in a p38-dependent manner, but extracellular signal-regulated kinase (ERK) and c-JUN N-terminal kinase (JNK) did not appear to be involved. Together, these results identify an underlying mechanism by which melatonin enhances the developmental potential of bovine preimplantation embryos under oxidative stress conditions.

  6. Melatonin improves experimental colitis with sleep deprivation

    PubMed Central

    PARK, YOUNG-SOOK; CHUNG, SOOK-HEE; LEE, SEONG-KYU; KIM, JA-HYUN; KIM, JUN-BONG; KIM, TAE-KYUN; KIM, DONG-SHIN; BAIK, HAING-WOON

    2015-01-01

    Sleep deprivation (SD) is an epidemic phenomenon in modern countries, and its harmful effects are well known. SD acts as an aggravating factor in inflammatory bowel disease. Melatonin is a sleep-related neurohormone, also known to have antioxidant and anti-inflammatory effects in the gastrointestinal tract; however, the effects of melatonin on colitis have been poorly characterized. Thus, in this study, we assessed the measurable effects of SD on experimental colitis and the protective effects of melatonin. For this purpose, male imprinting control region (ICR) mice (n=24) were used; the mice were divided into 4 experimental groups as follows: the control, colitis, colitis with SD and colitis with SD and melatonin groups. Colitis was induced by the administration of 5% dextran sulfate sodium (DSS) in the drinking water for 6 days. The mice were sleep-deprived for 3 days. Changes in body weight, histological analyses of colon tissues and the expression levels of pro-inflammatory cytokines and genes were evaluated. SD aggravated inflammation and these effects were reversed by melatonin in the mice with colitis. In addition, weight loss in the mice with colitis with SD was significantly reduced by the injection of melatonin. Treatment with melatonin led to high survival rates in the mice, in spite of colitis with SD. The levels of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-17, interferon-γ and tumor necrosis factor-α, in the serum of mice were significantly increased by SD and reduced by melatonin treatment. The melatonin-treated group showed a histological improvement of inflammation. Upon gene analysis, the expression of the inflammatory genes, protein kinase Cζ (PKCζ) and calmodulin 3 (CALM3), was increased by SD, and the levels decreased following treatment with melatonin. The expression levels of the apoptosis-related inducible nitric oxide synthase (iNOS) and wingless-type MMTV integration site family, member 5A (Wnt5a) genes was

  7. The Melatonin Receptor Agonist Ramelteon Effectively Treats Insomnia and Behavioral Symptoms in Autistic Disorder

    PubMed Central

    Oka, Yasunori

    2014-01-01

    Children with autism spectrum disorders (ASD), including autistic disorder, frequently suffer from comorbid sleep problems. An altered melatonin rhythm is considered to underlie the impairment in sleep onset and maintenance in ASD. We report three cases with autistic disorder in whom nocturnal symptoms improved with ramelteon, a selective melatonin receptor agonist. Insomnia and behavior, assessed using the Clinical Global Impression-Improvement Scale, improved in two cases with 2 mg ramelteon and in the third case with 8 mg ramelteon. Our findings demonstrate that ramelteon is effective not only for insomnia, but for behavioral problems as well, in patients with autistic disorder. PMID:24955274

  8. Daily differential expression of melatonin-related genes and clock genes in rat cumulus-oocyte complex: changes after pinealectomy.

    PubMed

    Coelho, L A; Peres, R; Amaral, F G; Reiter, R J; Cipolla-Neto, J

    2015-05-01

    This study investigated the maturational stage (immature and mature ovaries) differences of mRNA expression of melatonin-forming enzymes (Aanat and Asmt), melatonin membrane receptors (Mt1 and Mt2) and putative nuclear (Rorα) receptors, and clock genes (Clock, Bmal1, Per1, Per2, Cry1, Cry2) in cumulus-oocyte complexes (COC) from weaning Wistar rats. We also examined the effects of pinealectomy and of melatonin pharmacological replacement on the daily expression of these genes in COC. qRT-PCR analysis revealed that in oocytes, the mRNA expression of Asmt, Mt2, Clock, Bmal1, Per2, and Cry1 were higher (P < 0.05) in immature ovaries than in the mature ones. In cumulus cells, the same pattern of mRNA expression for Asmt, Aanat, Rorα, Clock, Per1, Cry1, and Cry2 genes was observed. In oocytes, pinealectomy altered the daily mRNA expression profiles of Asmt, Mt1, Mt2, Clock, Per1, Cry1, and Cry2 genes. In cumulus cells, removal of the pineal altered the mRNA expression profiles of Mt1, Mt2, Rorα, Aanat, Asmt, Clock, Bmal1, Per2, Cry1, and Cry2 genes. Melatonin treatment partially or completely re-established the daily mRNA expression profiles of most genes studied. The mRNA expression of melatonin-related genes and clock genes in rat COC varies with the maturational stage of the meiotic cellular cycle in addition to the hour of the day. This suggests that melatonin might act differentially in accordance with the maturational stage of cumulus/oocyte complex. In addition, it seems that circulating pineal melatonin is very important in the design of the daily profile of mRNA expression of COC clock genes and genes related to melatonin synthesis and action.

  9. Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations.

    PubMed

    la Fleur, S E; Kalsbeek, A; Wortel, J; van der Vliet, J; Buijs, R M

    2001-12-01

    The effects of melatonin on glucose metabolism are far from understood. In rats, the biological clock generates a 24-h rhythm in plasma glucose concentrations, with declining concentrations in the dark period. We hypothesized that, in the rat, melatonin enhances the dark signal of the biological clock, decreasing glucose concentrations in the dark period. We measured 24-h rhythms of plasma concentrations of glucose and insulin in pinealectomized rats fed ad libitum and subjected to a scheduled feeding regimen with six meals equally distributed over the light/dark cycle and compared them with previous data of intact rats. Pinealectomy dampened the amplitude of the 24-h rhythm in plasma glucose concentrations in rats fed ad libitum, and abolished it completely in rats subjected to the scheduled feeding regimen, while plasma insulin concentrations did not change under both conditions. Pinealectomy abolished the nocturnal decline in plasma glucose concentrations irrespective of whether rats were fed ad libitum or subjected to the scheduled feeding regimen. Melatonin replacement restored 24-h mean plasma glucose concentrations in pinealectomized rats that were subjected to the scheduled feeding regimen but, interestingly, it did not restore the 24-h rhythm. Melatonin treatment also resulted in higher meal-induced insulin responses, probably mediated via an increased sensitivity of the beta-cells. Taken together, our data demonstrate that the pineal hormone, melatonin, influences both glucose metabolism and insulin secretion from the pancreatic beta-cell. The present study also demonstrates that removal of the pineal gland cannot be compensated by mimicking plasma melatonin concentrations only.

  10. Genetic deletion of MT₁/MT₂ melatonin receptors enhances murine cognitive and motor performance.

    PubMed

    O'Neal-Moffitt, G; Pilli, J; Kumar, S S; Olcese, J

    2014-09-26

    Melatonin, an indoleamine hormone secreted into circulation at night primarily by the brain's pineal gland, has been shown to have a wide variety of actions on the development and physiology of neurons in the CNS. Acting via two G-protein-coupled membrane receptors (MT1 and MT2), melatonin modulates neurogenesis, synaptic functions, neuronal cytoskeleton and gene expression. In the present studies, we sought to characterize the behavior and neuronal biology of transgenic mice lacking both of these melatonin receptors as a way to understand the hormone's receptor versus non-receptor-mediated actions in CNS-dependent activities, such as learning and memory, anxiety, general motor performance and circadian rhythmicity. Assessment of these behaviors was complemented by molecular analyses of gene expression in the brain. Our results demonstrate mild behavioral hyperactivity and a lengthened circadian period of free-running motor activity in melatonin receptor-deficient mice as compared to receptor-intact control mice beginning at an early age. Significant improvement in cognitive performance was found using the Barnes Maze and the Y-Maze. No behavioral changes in anxiety levels were found. Electrophysiological measures in hippocampal slices revealed a clear enhancement of long-term potentiation in mice lacking melatonin receptors with no significant differences in paired-pulse facilitation. Quantitative analysis of brain protein expression levels of phosphoCREB and phosphoERK1/2 and key markers of synaptic activity (synapsin, glutamate receptor 1, spinophilin, and glutamic acid decarboxylase 1) revealed significant differences between the double-knockout and wild-type animals, consistent with the behavioral findings. Thus, genetic deletion of melatonin receptors produces mice with enhanced cognitive and motor performance, supporting the view that these receptors play an important role in neurobehavioral development.

  11. Melatonin as a Signaling Molecule for Metabolism Regulation in Response to Hypoxia in the Crab Neohelice granulata

    PubMed Central

    Maciel, Fábio Everton; Geihs, Márcio Alberto; Cruz, Bruno Pinto; Vargas, Marcelo Alves; Allodi, Silvana; Marins, Luis Fernando; Nery, Luiz Eduardo Maia

    2014-01-01

    Melatonin has been identified in a variety of crustacean species, but its function is not as well understood as in vertebrates. The present study investigates whether melatonin has an effect on crustacean hyperglycemic hormone (CHH) gene expression, oxygen consumption (VO2) and circulating glucose and lactate levels, in response to different dissolved-oxygen concentrations, in the crab Neohelice granulata, as well as whether these possible effects are eyestalk- or receptor-dependent. Melatonin decreased CHH expression in crabs exposed for 45 min to 6 (2, 200 or 20,000 pmol·crab−1) or 2 mgO2·L−1 (200 pmol·crab−1). Since luzindole (200 nmol·crab−1) did not significantly (p > 0.05) alter the melatonin effect, its action does not seem to be mediated by vertebrate-typical MT1 and MT2 receptors. Melatonin (200 pmol·crab−1) increased the levels of glucose and lactate in crabs exposed to 6 mgO2·L−1, and luzindole (200 nmol·crab−1) decreased this effect, indicating that melatonin receptors are involved in hyperglycemia and lactemia. Melatonin showed no effect on VO2. Interestingly, in vitro incubation of eyestalk ganglia for 45 min at 0.7 mgO2·L−1 significantly (p < 0.05) increased melatonin production in this organ. In addition, injections of melatonin significantly increased the levels of circulating melatonin in crabs exposed for 45 min to 6 (200 or 20,000 pmol·crab−1), 2 (200 and 20,000 pmol·crab−1) and 0.7 (200 or 20,000 pmol·crab−1) mgO2·L−1. Therefore, melatonin seems to have an effect on the metabolism of N. granulata. This molecule inhibited the gene expression of CHH and caused an eyestalk- and receptor-dependent hyperglycemia, which suggests that melatonin may have a signaling role in metabolic regulation in this crab. PMID:25486055

  12. Melatonin as a signaling molecule for metabolism regulation in response to hypoxia in the crab Neohelice granulata.

    PubMed

    Maciel, Fábio Everton; Geihs, Márcio Alberto; Cruz, Bruno Pinto; Vargas, Marcelo Alves; Allodi, Silvana; Marins, Luis Fernando; Nery, Luiz Eduardo Maia

    2014-12-04

    Melatonin has been identified in a variety of crustacean species, but its function is not as well understood as in vertebrates. The present study investigates whether melatonin has an effect on crustacean hyperglycemic hormone (CHH) gene expression, oxygen consumption (VO2) and circulating glucose and lactate levels, in response to different dissolved-oxygen concentrations, in the crab Neohelice granulata, as well as whether these possible effects are eyestalk- or receptor-dependent. Melatonin decreased CHH expression in crabs exposed for 45 min to 6 (2, 200 or 20,000 pmol·crab-1) or 2 mgO2·L-1 (200 pmol·crab-1). Since luzindole (200 nmol·crab-1) did not significantly (p > 0.05) alter the melatonin effect, its action does not seem to be mediated by vertebrate-typical MT1 and MT2 receptors. Melatonin (200 pmol·crab-1) increased the levels of glucose and lactate in crabs exposed to 6 mgO2·L-1, and luzindole (200 nmol·crab-1) decreased this effect, indicating that melatonin receptors are involved in hyperglycemia and lactemia. Melatonin showed no effect on VO2. Interestingly, in vitro incubation of eyestalk ganglia for 45 min at 0.7 mgO2·L-1 significantly (p < 0.05) increased melatonin production in this organ. In addition, injections of melatonin significantly increased the levels of circulating melatonin in crabs exposed for 45 min to 6 (200 or 20,000 pmol·crab-1), 2 (200 and 20,000 pmol·crab-1) and 0.7 (200 or 20,000 pmol·crab-1) mgO2·L-1. Therefore, melatonin seems to have an effect on the metabolism of N. granulata. This molecule inhibited the gene expression of CHH and caused an eyestalk- and receptor-dependent hyperglycemia, which suggests that melatonin may have a signaling role in metabolic regulation in this crab.

  13. Melatonin in Antinociception: Its Therapeutic Applications

    PubMed Central

    Srinivasan, Venkatramanujam; Lauterbach, Edward C; Ho, Khek Yu; Acuña-Castroviejo, Dario; Zakaria, Rahimah; Brzezinski, Amnon

    2012-01-01

    The intensity of pain sensation exhibits marked day and night variations. Since the intensity of pain perception is low during dark hours of the night when melatonin levels are high, this hormone has been implicated as one of the prime antinociceptive substances. A number of studies have examined the antinociceptive role of melatonin in acute, inflammatory and neuropathic pain animal models. It has been demonstrated that melatonin exerts antinociceptive actions by acting at both spinal cord and supraspinal levels. The mechanism of antinociceptive actions of melatonin involves opioid, benzodiazepine, α1- and α2-adrenergic, serotonergic and cholinergic receptors. Most importantly however, the involvement of MT1/MT2 melatonergic receptors in the spinal cord has been well documented as an antinociceptive mechanism in a number of animal models of pain perception. Exogenous melatonin has been used effectively in the management of pain in medical conditions such as fibromyalgia, irritable bowel syndrome and migraine and cluster headache. Melatonin has been tried during surgical operating conditions and has been shown to enhance both preoperative and post-operative analgesia. The present review discusses the available evidence indicating that melatonin, acting through MT1/MT2 melatonin receptors, plays an important role in the pathophysiological mechanism of pain. PMID:23204986

  14. Melatonin, light therapy, and jet lag.

    PubMed

    Lathrop, N J; Lentz, M

    2001-01-01

    If you enter the words jet lag into your Internet search engine, multiple sites come up. Jet lag is a term common to all travelers, but what is it? The medication melatonin, available in most convenience stores, is marketed as a sleep agent or treatment for jet lag, but is it safe? Is it a sleeping pill? How is light therapy related to melatonin?

  15. Melatonin as an Antioxidant for Stroke Neuroprotection.

    PubMed

    Watson, Nate; Diamandis, Theo; Gonzales-Portillo, Chiara; Reyes, Stephanny; Borlongan, Cesar V

    2016-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from the pineal gland that has a wide range of clinical applications. While melatonin was originally assessed as a hormone specializing in regulation of the normal circadian rhythm in mammals, it now has been shown to be an effective free radical scavenger and antioxidant. Current research has focused on central nervous system (CNS) disorders, stroke in particular, for potential melatonin-based therapeutics. As of now, the realm of potential therapy regimens is focused on three main treatments: exogenously delivered melatonin, pineal gland grafting, and melatonin-mediated stem cell therapy. All therapies contain both costs and benefits, and current research is still focused on finding the best treatment plan. While comprehensive research has been conducted, more research regarding the safety of such therapies is needed in order to transition into the clinical level of testing. Antioxidants such as traditional Chinese medicine, (-)-epigallocatechin-3-gallate (EGCG), and lavender oil, which have been used for thousands of years as treatment, are now gaining recognition as effective melatonin treatment alternatives. This review will further discuss relevant studies assessing melatonin-based therapeutics and provide evidence of other natural melatonin treatment alternatives for the treatment of stroke. PMID:26497887

  16. Effect of Melatonin and Cholesterol on the Structure of DOPC and DPPC Membranes

    SciTech Connect

    Drolle, E; Kucerka, Norbert; Hoopes, M I; Choi, Y; Katsaras, John; Karttunen, M; Leonenko, Z

    2013-01-01

    The cell membrane plays an important role in the molecular mechanism of amyloid toxicity associated with Alzheimer's disease. The membrane's chemical composition and the incorporation of small molecules, such as melatonin and cholesterol, can alter its structure and physical properties, thereby affecting its interaction with amyloid peptides. Both melatonin and cholesterol have been recently linked to amyloid toxicity. Melatonin has been shown to have a protective role against amyloid toxicity. However, the underlying molecular mechanism of this protection is still not well understood, and cholesterol's role remains controversial. We used small-angle neutron diffraction (SAND) from oriented lipid multi-layers, small-angle neutron scattering (SANS) from unilamellar vesicles experiments andMolecular Dynamics (MD) simulations to elucidate non-specific interactions of melatonin and cholesterol with 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dipalmitoyl-snglycero-3-phosphocholine (DPPC) model membranes. We conclude that melatonin decreases the thickness of both model membranes by disordering the lipid hydrocarbon chains, thus increasing membrane fluidity. This result is in stark contrast to the much accepted ordering effect induced by cholesterol, which causes membranes to thicken.

  17. Melatonin and hypothalamic-pituitary-gonadal axis.

    PubMed

    Shi, L; Li, N; Bo, L; Xu, Z

    2013-01-01

    Melatonin (N-acetyl-5-methoxy-tryptamine), a principal product of the pineal gland, is produced mainly during the dark phase of the circadian cycle. This hormone plays a crucial role in the regulation of circadian and seasonal changes in various aspects of physiology and neuroendocrine functions. In mammals, melatonin can influence sexual maturation and reproductive functions via activation of its receptors and binding sites in the hypothalamic-pituitary-gonadal (HPG) axis. This review summarizes current knowledge of melatonin on the hypothalamus, pituitary gland, and gonads. We also review recent progress in clinical applications of melatonin or potentials of using melatonin, as a reducer of oxidative stress, to improve reproductive functions for the diseases such as women infertility.

  18. [The influence of melatonin on hair physiology].

    PubMed

    Fischer, T W

    2009-12-01

    Melatonin, the pineal gland hormone and a strong antioxidant, has long been known, particularly in animal-experiment based research and the wool-producing industry, to be a potent regulatory neuroendocrine substance in relation to hair growth, hair color and hair cycle, depending on light periods, seasonal rhythms, environmental factors and reproductive rhythms. Nevertheless, the biological mechanisms of this extremely versatile hormone, especially with regard to human hair follicles, are not fully understood. In recent years, however, essential knowledge has been gained on the melatoninergic system of the skin, melatonin levels in keratinocytes and hair follicles, extrapineal intrafollicular melatonin synthesis and noradrenalin-induced increase in synthesis, as well as hair cycle-dependent expression of the membrane-bound melatonin receptor MT2 and the nuclear receptor RORalpha. Functional data on the growth of human hair both in vitro and in vivo show that melatonin might play an essential role in hair physiology. PMID:19957072

  19. Mechanisms of isoproterenol-induced cardiac mitochondrial damage: protective actions of melatonin.

    PubMed

    Mukherjee, Debasri; Ghosh, Arnab K; Dutta, Mousumi; Mitra, Elina; Mallick, Sanjaya; Saha, Bhaskar; Reiter, Russel J; Bandyopadhyay, Debasish

    2015-04-01

    Mitochondrial dysfunction due to oxidative damage is the key feature of several diseases. We have earlier reported mitochondrial damage resulting from the generation of oxidative stress as a major pathophysiological effect of isoproterenol (ISO)-induced myocardial ischemia in rats. That melatonin is an antioxidant that ameliorates oxidative stress in experimental animals as well as in humans is well established. We previously demonstrated that melatonin provides cardioprotection against ISO-induced myocardial injury as a result of its antioxidant properties. The mechanism of ISO-induced cardiac mitochondrial damage and protection by melatonin, however, remains to be elucidated in vitro. In this study, we provide evidence that ISO causes dysfunction of isolated goat heart mitochondria. Incubation of cardiac mitochondria with increasing concentrations of ISO decreased mitochondrial succinate dehydrogenase (SDH) activity, which plays a pivotal role in mitochondrial bioenergetics, as well as altered the activities of other key enzymes of the Kreb's cycle and the respiratory chain. Co-incubation of ISO-challenged mitochondria with melatonin prevented the alterations in enzyme activity. That these changes in mitochondrial energy metabolism were due to the perpetration of oxidative stress by ISO was evident from the increased levels of lipid peroxidation and decreased reduced glutathione/oxidized glutathione ratio. ISO-induced oxidative stress also altered mitochondrial redox potential and brought about changes in the activity of the antioxidant enzymes manganese superoxide dismutase and glutathione peroxidase, eventually leading to alterations in total ATPase activity and membrane potential. Melatonin ameliorated these changes likely through its antioxidant abilities suggesting a possible mechanism of cardioprotection by this indole against ISO-induced myocardial injury. PMID:25652673

  20. The daily melatonin pattern in Djungarian hamsters depends on the circadian phenotype.

    PubMed

    Schöttner, Konrad; Simonneaux, Valérie; Vuillez, Patrick; Steinlechner, Stephan; Pévet, Paul; Weinert, Dietmar

    2011-12-01

    Djungarian hamsters (Phodopus sungorus) bred at the Institute of Halle reveal three different circadian phenotypes. The wild type (WT) shows normal locomotor activity patterns, whereas in hamsters of the DAO (delayed activity onset) type, the activity onset is continuously delayed. Since the activity offset in those hamsters remains coupled to "light-on," the activity time becomes compressed. Hamsters of the AR (arrhythmic) type are episodically active throughout the 24 h. Previous studies showed that a disturbed interaction of the circadian system with the light-dark (LD) cycle contributes to the phenomenon observed in DAO hamsters. To gain better insight into the underlying mechanisms, the authors investigated the daily melatonin rhythm, as it is a reliable marker of the circadian clock. Hamsters were kept individually under standardized laboratory conditions (LD 14:10, T=22°C±2°C, food and water ad libitum). WT, DAO (with exactly 5 h delay of activity onset), and AR hamsters were used for pineal melatonin and urinary 6-sulfatoxymelatonin (aMT6s) measurement. Pineal melatonin content was determined at 3 time points: 4 h after "light-off" [D+4], 1 h before "light-on" [L-1], and 1h after "light-on" [L+1]). The 24-h profile of melatonin secretion was investigated by transferring the animals to metabolic cages for 27?h to collect urine at 3-h intervals for aMT6s analysis. WT hamsters showed high pineal melatonin content during the dark time (D+4, L-1), which significantly decreased at the beginning of the light period (L+1). In contrast, DAO hamsters displayed low melatonin levels during the part of the dark period when animals were still resting (D+4). At the end of the dark period (L-1), melatonin content increased significantly and declined again when light was switched on (L+1). AR hamsters showed low melatonin levels, comparable to daytime values, at all 3 time points. The results were confirmed by aMT6s data. WT hamsters showed a marked circadian pattern of

  1. Melatonin synergizes with citalopram to induce antidepressant-like behavior and to promote hippocampal neurogenesis in adult mice.

    PubMed

    Ramírez-Rodríguez, Gerardo; Vega-Rivera, Nelly Maritza; Oikawa-Sala, Julián; Gómez-Sánchez, Ariadna; Ortiz-López, Leonardo; Estrada-Camarena, Erika

    2014-05-01

    Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here, we found decreased immobility behavior in mice treated with melatonin (<14-33%) and citalopram (<17-30%). Additionally, the MLTCITAL combination also decreased immobility (<22-35%) in comparison with control mice, reflecting an antidepressant-like effect after 14 days of treatment. Moreover, MLTCITAL decreased plasma corticosterone levels (≤13%) and increased cell proliferation (>29%), survival (>39%), and the absolute number of -associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant-like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.

  2. Melatonin Regulates Somatotrope and Lactotrope Function Through Common and Distinct Signaling Pathways in Cultured Primary Pituitary Cells From Female Primates

    PubMed Central

    Ibáñez-Costa, Alejandro; Córdoba-Chacón, José; Gahete, Manuel D.; Kineman, Rhonda D.; Castaño, Justo P.

    2015-01-01

    Melatonin (MT) is secreted by the pineal gland and exhibits a striking circadian rhythm in its release. Depending on the species studied, some pituitary hormones also display marked circadian/seasonal patterns and rhythms of secretion. However, the precise relationship between MT and pituitary function remains controversial, and studies focusing on the direct role of MT in normal pituitary cells are limited to nonprimate species. Here, adult normal primate (baboons) primary pituitary cell cultures were used to determine the direct impact of MT on the functioning of all pituitary cell types from the pars distalis. MT increased GH and prolactin (PRL) expression/release in a dose- and time-dependent fashion, a response that was blocked by somatostatin. However, MT did not significantly affect ACTH, FSH, LH, or TSH expression/release. MT did not alter GHRH- or ghrelin-induced GH and/or PRL secretions, suggesting that MT may activate similar signaling pathways as ghrelin/GHRH. The effects of MT on GH/PRL release, which are likely mediated through MT1 receptor, involve both common (adenylyl cyclase/protein kinase A/extracellular calcium-channels) and distinct (phospholipase C/intracellular calcium-channels) signaling pathways. Actions of MT on pituitary cells also included regulation of the expression of other key components for the control of somatotrope/lactotrope function (GHRH, ghrelin, and somatostatin receptors). These results show, for the first time in a primate model, that MT directly regulates somatotrope/lactotrope function, thereby lending support to the notion that the actions of MT on these cells might substantially contribute to the define daily patterns of GH and PRL observed in primates and perhaps in humans. PMID:25545385

  3. Melatonin Signal Transduction Pathways Require E-Box-Mediated Transcription of Per1 and Per2 to Reset the SCN Clock at Dusk

    PubMed Central

    Kandalepas, Patty C.; Mitchell, Jennifer W.; Gillette, Martha U.

    2016-01-01

    Melatonin is released from the pineal gland into the circulatory system at night in the absence of light, acting as “hormone of darkness” to the brain and body. Melatonin also can regulate circadian phasing of the suprachiasmatic nucleus (SCN). During the day-to-night transition, melatonin exposure advances intrinsic SCN neural activity rhythms via the melatonin type-2 (MT2) receptor and downstream activation of protein kinase C (PKC). The effects of melatonin on SCN phasing have not been linked to daily changes in the expression of core genes that constitute the molecular framework of the circadian clock. Using real-time RT-PCR, we found that melatonin induces an increase in the expression of two clock genes, Period 1 (Per1) and Period 2 (Per2). This effect occurs at CT 10, when melatonin advances SCN phase, but not at CT 6, when it does not. Using anti-sense oligodeoxynucleotides (α ODNs) to Per 1 and Per 2, as well as to E-box enhancer sequences in the promoters of these genes, we show that their specific induction is necessary for the phase-altering effects of melatonin on SCN neural activity rhythms in the rat. These effects of melatonin on Per1 and Per2 were mediated by PKC. This is unlike day-active non-photic signals that reset the SCN clock by non-PCK signal transduction mechanisms and by decreasing Per1 expression. Rather, this finding extends roles for Per1 and Per2, which are critical to photic phase-resetting, to a nonphotic zeitgeber, melatonin, and suggest that the regulation of these clock gene transcripts is required for clock resetting by diverse regulatory cues. PMID:27362940

  4. Induction of ecdysteroidogenesis, methyl farnesoate synthesis and expression of ecdysteroid receptor and retinoid X receptor in the hepatopancreas and ovary of the giant mud crab, Scylla serrata by melatonin.

    PubMed

    Girish, B P; Swetha, Ch; Reddy, P Sreenivasula

    2015-01-01

    Melatonin, a chronobiotic molecule, is known to modulate several physiological functions in crustaceans including reproduction, molting and glucose homeostasis. In our earlier studies (Sainath and Reddy, 2010a), we observed hyperglycemia in crabs after melatonin administration and concluded that melatonin is another crustacean hyperglycemic hormone. In the current study, we have further examined the role of melatonin in regulating the levels of methyl farnesoate and ecdysteroid in the giant mud crab Scylla serrata and determined that melatonin indeed is a reproductive hormone. Further, we have determined partial nucleotide sequences of retinoid X receptor (RXR) and ecdysone receptor (EcR) in S. serrata and also studied the effect of melatonin on expression of these genes. Cloned RXR and EcR possess high sequence similarity with other Brachyuran genes. Administration of melatonin elevated circulatory methyl farnesoate (MF) and ecdysteroid levels in crabs. Since MF and ecdysteroid act through RXR and EcR respectively and these receptors are involved in the regulation of reproduction in crustaceans, we measured the expression levels of RXR and EcR in hepatopancreas and ovary after melatonin administration. The expression levels of both RXR and EcR increased significantly in the hepatopancreas and ovary of melatonin injected crabs when compared to the controls. In vitro culture of mandibular organ (MO) and Y-organ (YO) in the presence of melatonin resulted in a significant increase in the secretion of methyl farnesoate and ecdysteroid respectively. From the above studies it is clear that melatonin stimulates YO and MO, resulting in increased synthesis of ecdysteroids and methyl farnesoate, and thereby inducing reproduction in S. serrata.

  5. Melatonin 4 mg as prophylactic therapy for primary headaches: a pilot study

    PubMed Central

    Bougea, Anastasia; Spantideas, Nikolaos; Lyras, Vasilis; Avramidis, Theodoros; Thomaidis, Thomas

    2016-01-01

    Summary There is growing evidence that headaches are connected to melatonin secretion. Our aim was to assess the potential effectiveness of melatonin for primary headache prevention. Forty-nine patients (37 with migraine and 12 with chronic tension-type headache, TTH) were prescribed oral melatonin, 4 mg, 30 minutes before bedtime for six months. Forty-one (83.6%) of the 49 patients completed the study, while eight dropped out for personal reasons. A statistically significant reduction in headache frequency was found between baseline and final follow-up after six months of treatment (p=0.033 for TTH patients and p<0.001 for migraineurs). The Headache Impact Test score was significantly reduced in both groups of headache patients (p=0.002 and p<0.001, respectively). At baseline, melatonin levels, measured both during a headache attack and a pain-free period, did not differ between patients with TTH and migraineurs (p=0.539 and p=0.693, respectively), and no statistically significant differences in Hamilton Depression Rating Scale scores were found between the two groups. This pilot study shows promising results, in terms of headache frequency reduction and daily quality of life improvement, in both groups. PMID:27027892

  6. The effects of photoperiod and melatonin on serum prolactin levels of mink during the autumn molt.

    PubMed

    Rose, J; Stormshak, F; Oldfield, J; Adair, J

    1985-01-01

    An experiment was conducted to determine the effects of a reduced daily photoperiod and exogenous melatonin on serum prolactin levels of mink during the autumn molt and growth of the winter pelage. During the last week of June, adult standard dark female mink (Mustela vision) were exposed to natural changes in daylength (controls), a reduced photoperiod of 6 h light: 18 h dark (6L:18D) or exposure to natural changes in daylength and treated with melatonin (10 mg) in a Silastic implant inserted subcutaneously over the scapular area. Beginning July 2, and continuing through October 22, blood samples were collected at nine biweekly intervals, and serum prolactin concentrations were quantified by a heterologous double antibody radioimmunoassay. Both reduced photoperiod and exogenous melatonin caused serum prolactin levels to decline rapidly after mid-July, resulting in concentrations that were significantly lower than those of controls 6 to 8 wk earlier. These data suggest that growth of the winter pelage of mink is strongly associated with declining prolactin levels. It appears that part of the photoperiodic-induced effects on fur growth of the mink are mediated through melatonin and its effects on prolactin synthesis and/or secretion. PMID:3831298

  7. Absence of detectable melatonin and preservation of cortisol and thyrotropin rhythms in tetraplegia

    NASA Technical Reports Server (NTRS)

    Zeitzer, J. M.; Ayas, N. T.; Shea, S. A.; Brown, R.; Czeisler, C. A.

    2000-01-01

    The human circadian timing system regulates the temporal organization of several endocrine functions, including the production of melatonin (via a neural pathway that includes the spinal cord), TSH, and cortisol. In traumatic spinal cord injury, afferent and efferent circuits that influence the basal production of these hormones may be disrupted. We studied five subjects with chronic spinal cord injury (three tetraplegic and two paraplegic, all neurologically complete injuries) under stringent conditions in which the underlying circadian rhythmicity of these hormones could be examined. Melatonin production was absent in the three tetraplegic subjects with injury to their lower cervical spinal cord and was of normal amplitude and timing in the two paraplegic subjects with injury to their upper thoracic spinal cord. The amplitude and the timing of TSH and cortisol rhythms were robust in the paraplegics and in the tetraplegics. Our results indicate that neurologically complete cervical spinal injury results in the complete loss of pineal melatonin production and that neither the loss of melatonin nor the loss of spinal afferent information disrupts the rhythmicity of cortisol or TSH secretion.

  8. Role of Melatonin in Traumatic Brain Injury and Spinal Cord Injury

    PubMed Central

    Naseem, Mehar; Parvez, Suhel

    2014-01-01

    Brain and spinal cord are implicated in incidences of two of the most severe injuries of central nervous system (CNS). Traumatic brain injury (TBI) is a devastating neurological deficit involving primary and secondary injury cascades. The primary and secondary mechanisms include complex consequences of activation of proinflammatory cytokines, cerebral edema, upregulation of NF-κβ, disruption of blood-brain barrier (BBB), and oxidative stress. Spinal cord injury (SCI) includes primary and secondary injury cascades. Primary injury leads to secondary injury in which generation of free radicals and oxidative or nitrative damage play an important pathophysiological role. The indoleamine melatonin is a hormone secreted or synthesized by pineal gland in the brain which helps to regulate sleep and wake cycle. Melatonin has been shown to be a versatile hormone having antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties. It has a special characteristic of crossing BBB. Melatonin has neuroprotective role in the injured part of the CNS after TBI and SCI. A number of studies have successfully shown its therapeutic value as a neuroprotective agent in the treatment of neurodegenerative diseases. Here in this review we have compiled the literature supporting consequences of CNS injuries, TBI and SCI, and the protective role of melatonin in it. PMID:25587567

  9. Reduced peak, but no diurnal variation, in thrombin generation upon melatonin supplementation in tetraplegia. A randomised, placebo-controlled study.

    PubMed

    Iversen, Per Ole; Dahm, Anders; Skretting, Grethe; Mowinckel, Marie-Christine; Stranda, Annicke; Østerud, Bjarne; Sandset, Per Morten; Kostovski, Emil

    2015-11-01

    Tetraplegic patients have increased risk of venous thrombosis despite anti-thrombotic prophylaxis. Moreover, they have blunted plasma variations in melatonin and altered diurnal variation of several haemostatic markers, compared with able-bodied. However, whether healthy individuals and tetraplegic patients, with or without melatonin, display abnormalities in thrombin generation during a 24-hour (h) cycle, is unknown. We therefore used the Calibrated Automated Thrombogram (CAT) assay to examine diurnal variations and the possible role of melatonin in thrombin generation. Six men with long-standing complete tetraplegia were included in a randomised placebo-controlled cross-over study with melatonin supplementation (2 mg, 4 consecutive nights), whereas six healthy, able-bodied men served as controls. Ten plasma samples were collected frequently during a 24-h awake/sleep cycle. No significant diurnal variation of any of the measured CAT indices was detected in the three study groups. Whereas endogenous thrombin potential (ETP) was independent (p > 0.05) of whether the tetraplegic men received melatonin or placebo, melatonin decreased (p = 0.005) peak values in tetraplegia compared with those given placebo. Able-bodied men had lower (p = 0.019) ETP and Lag-Time (p = 0.018) compared with tetraplegics receiving placebo. Neither the Time-to-Peak nor the Start-Tail was affected (p > 0.05) by melatonin in tetraplegia. In conclusion, indices of thrombin generation are not subjected to diurnal variation in healthy able-bodied or tetraplegia, but peak thrombin generation is reduced in tetraplegic men receiving oral melatonin. PMID:26202881

  10. Melatonin in Alzheimer’s Disease

    PubMed Central

    Lin, Li; Huang, Qiong-Xia; Yang, Shu-Sheng; Chu, Jiang; Wang, Jian-Zhi; Tian, Qing

    2013-01-01

    Alzheimer’s disease (AD), an age-related neurodegenerative disorder with progressive cognition deficit, is characterized by extracellular senile plaques (SP) of aggregated β-amyloid (Aβ) and intracellular neurofibrillary tangles, mainly containing the hyperphosphorylated microtubule-associated protein tau. Multiple factors contribute to the etiology of AD in terms of initiation and progression. Melatonin is an endogenously produced hormone in the brain and decreases during aging and in patients with AD. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning and slows down the progression of cognitive impairment in AD patients. Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties. It not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ. Our studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting the cholinergic system and in anti-inflammation. The aim of this review is to stimulate interest in melatonin as a potentially useful agent in the prevention and treatment of AD. PMID:23857055

  11. Melatonin influence in ovary transplantation: systematic review.

    PubMed

    Shiroma, M E; Botelho, N M; Damous, L L; Baracat, E C; Soares-Jr, J M

    2016-01-01

    Melatonin is an indolamine produced by the pineal gland and it can exert a potent antioxidant effect. Its free radical scavenger properties have been used to advantage in different organ transplants in animal experiments. Several concentrations and administration pathways have been tested and melatonin has shown encouraging beneficial results in many transplants of organs such as the liver, lungs, heart, pancreas, and kidneys. The objective of the present study was to review the scientific literature regarding the use of melatonin in ovary transplantation. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was carried out using the Cochrane and Pubmed databases and employing the terms 'melatonin' AND 'ovary' AND 'transplantation.' After analysis, 5 articles were extracted addressing melatonin use in ovary transplants and involving 503 animals. Melatonin enhanced various graft aspects like morphology, apoptosis, immunological reaction, revascularization, oxidative stress, and survival rate. Melatonin's antioxidative and antiapoptotic properties seemingly produce positive effects on ovarian graft activity. Despite the promising results, further studies in humans need to be conducted to consolidate its use, as ovary transplantation for fertility preservation is gradually being moved from the experimental stage to a clinical setting. PMID:27287621

  12. Functions of melatonin in plants: a review.

    PubMed

    Arnao, Marino B; Hernández-Ruiz, Josefa

    2015-09-01

    The number of studies on melatonin in plants has increased significantly in recent years. This molecule, with a large set of functions in animals, has also shown great potential in plant physiology. This review outlines the main functions of melatonin in the physiology of higher plants. Its role as antistress agent against abiotic stressors, such as drought, salinity, low and high ambient temperatures, UV radiation and toxic chemicals, is analyzed. The latest data on their role in plant-pathogen interactions are also discussed. Both abiotic and biotic stresses produce a significant increase in endogenous melatonin levels, indicating its possible role as effector in these situations. The existence of endogenous circadian rhythms in melatonin levels has been demonstrated in some species, and the data, although limited, suggest a central role of this molecule in the day/night cycles in plants. Finally, another aspect that has led to a large volume of research is the involvement of melatonin in aspects of plant development regulation. Although its role as a plant hormone is still far of from being fully established, its involvement in processes such as growth, rhizogenesis, and photosynthesis seems evident. The multiple changes in gene expression caused by melatonin point to its role as a multiregulatory molecule capable of coordinating many aspects of plant development. This last aspect, together with its role as an alleviating-stressor agent, suggests that melatonin is an excellent prospect for crop improvement.

  13. Melatonin in human preovulatory follicular fluid

    NASA Technical Reports Server (NTRS)

    Brzezinski, Amnon; Seibel, Machelle M.; Lynch, Harry J.; Deng, Mei-Hua; Wurtman, Richard J.

    1987-01-01

    Melatonin, the major hormone of the pineal gland, has antigonadotrophic activity in many mammals and may also be involved in human reproduction. Melatonin suppresses steroidogenesis by ovarian granulosa and luteal cells in vitro. To determine if melatonin is present in the human ovary, preovulatory follicular fluids (n = 32) from 15 women were assayed for melatonin by RIA after solvent extraction. The fluids were obtained by laparoscopy or sonographically controlled follicular puncture from infertile women undergoing in vitro fertilization and embryo transfer. All patients had received clomiphene citrate, human menopausal gonadotropin, and hCG to stimulate follicle formation. Blood samples were obtained by venipuncture 30 min or less after follicular aspiration. All of the follicular fluids contained melatonin, in concentrations (35.6 plus or minus 4.8 (plus or minus SEM) pg/mL) substantially higher than those in the corresponding serum (10.0 plus or minus 1.4 pg/mL). A positive correlation was found between follicular fluid and serum melatonin levels in each woman (r = 0.770; P less than 0.001). These observations indicate that preovulatory follicles contain substantial amounts of melatonin that may affect ovarian steroidogenesis.

  14. Mitochondria-targeted drugs enhance Nlrp3 inflammasome-dependent IL-1β secretion in association with alterations on cellular redox and energy status

    PubMed Central

    Jabaut, Joshua; Ather, Jennifer L.; Taracanova, Alexandra; Poynter, Matthew E.; Ckless, Karina

    2013-01-01

    The Nlrp3 inflammasome is activated in response to an array of environmental and endogenous molecules leading to caspase-1-dependent IL-1β processing and secretion by myeloid cells. Several identified Nlrp3 inflammasome activators also trigger reactive oxygen species (ROS) production. However, the initial concept that NADPH oxidases are the primary source of ROS production during inflammasome activation is becoming less accepted. Therefore, the importance of mitochondrial-derived ROS has been recently explored. In this study, we explore the impact of mitochondria dysfunction and ROS production on Nlrp3 inflammasome stimulation and IL-1β secretion induced by serum amyloid A (SAA) in primary mouse peritoneal macrophages. To induce mitochondrial dysfunction, we utilized antimycin A, which blocks electron flow at complex III, and carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), a mitochondrial oxidative phosphorylation uncoupler. We also utilized a superoxide dismutase (SOD) mimetic, MnTBAP, which targets the mitochondria, as well as the broad spectrum antioxidants DPI (diphenyleneiodonium chloride) and ebselen. Our findings demonstrate that SAA alone induces mitochondrial ROS in a time-dependent manner. We observed that MnTBAP and ebselen blocked IL-1β secretion caused by SAA only when added prior to stimulation, and DPI augmented IL-1β secretion. Surprisingly, these effects were not directly related to intracellular or mitochondrial ROS levels. We also found that mitochondrial-targeted drugs increased IL-1β secretion regardless of their impact on mitochondrial function and ROS levels, suggesting that mitochondrial ROS-dependent and -independent mechanisms play a role in the Nlrp3 inflammasome - IL-1β secretion axis in SAA-stimulated cells. Finally, we found that FCCP significantly sustained the association of the Nlrp3 inflammasome complex, which could explain the most robust effect among the drugs tested in enhancing IL-1β secretion in SAA

  15. Photoperiodic regulation of circulating leukocytes in juvenile Siberian hamsters: mediation by melatonin and testosterone.

    PubMed

    Prendergast, Brian J; Hotchkiss, Andrew K; Nelson, Randy J

    2003-12-01

    The reproductive system of Siberian hamsters (Phodopus sungorus) undergoes rapid phenotypic responses to changes in day length that occur around the time of weaning. The present experiments tested whether the immune system of Siberian hamsters is similarly photoperiodic early in life and whether photoperiodic changes in melatonin or gonadal hormone secretions mediate any such responses to day length. Circulating blood leukocyte concentrations (WBC) were measured in juvenile male Siberian hamsters that were gestated in long-days (LD), transferred to short-days (SD) on the day of birth, and subsequently either remained in SD or were transferred from SD to LD at 18 days of age (day 18). WBC values were comparable between LD and SD hamsters on day 18. Between day 18 and day 32, SD hamsters exhibited a 3-fold increase in WBC, whereas LD hamsters failed to undergo a significant increase in WBC during this interval. WBC of LD hamsters was significantly lower than that of SD hamsters on day 25 and on day 32. In LD housed males, peripheral injections of melatonin delivered so as to extend the nocturnal duration of elevated endogenous melatonin secretion (i.e., provided in late afternoon) on days 18-31 increased WBC as measured on day 32. Peripubertal (day 17) gonadectomy abolished the immunosuppressive effect of LD exposure on WBC, and treatment with silastic implants containing testosterone suppressed WBC independent of photoperiod treatment. These data indicate that juvenile Siberian hamsters are immunologically responsive to photoperiod and that the leukocyte responses to day length are the result of melatonin-mediated effects of photoperiod on testicular hormone secretion.

  16. Roles of melatonin in abiotic stress resistance in plants.

    PubMed

    Zhang, Na; Sun, Qianqian; Zhang, Haijun; Cao, Yunyun; Weeda, Sarah; Ren, Shuxin; Guo, Yang-Dong

    2015-02-01

    In recent years melatonin has emerged as a research highlight in plant studies. Melatonin has different functions in many aspects of plant growth and development. The most frequently mentioned functions of melatonin are related to abiotic stresses such as drought, radiation, extreme temperature, and chemical stresses. This review mainly focuses on the regulatory effects of melatonin when plants face harsh environmental conditions. Evidence indicates that environmental stress can increase the level of endogenous melatonin in plants. Overexpression of the melatonin biosynthetic genes elevates melatonin levels in transgenic plants. The transgenic plants show enhanced tolerance to abiotic stresses. Exogenously applied melatonin can also improve the ability of plants to tolerate abiotic stresses. The mechanisms by which melatonin alleviates abiotic stresses are discussed.

  17. Melatonin attenuates Leishmania (L.) amazonensis infection by modulating arginine metabolism.

    PubMed

    Laranjeira-Silva, Maria Fernanda; Zampieri, Ricardo A; Muxel, Sandra M; Floeter-Winter, Lucile Maria; Markus, Regina P

    2015-11-01

    Acute inflammatory responses induced by bacteria or fungi block nocturnal melatonin synthesis by rodent pineal glands. Here, we show Leishmania infection does not impair daily melatonin rhythm in hamsters. Remarkably, the attenuated parasite burden and lesion progression in hamsters infected at nighttime was impaired by blockage of melatonin receptors with luzindole, whereas melatonin treatment during the light phase attenuated Leishmania infection. In vitro studies corroborated in vivo observations. Melatonin treatment reduced macrophage expression of Cat-2b, Cat1, and ArgI, genes involved in arginine uptake and polyamine synthesis. Indeed, melatonin reduced macrophage arginine uptake by 40%. Putrescine supplementation reverted the attenuation of infectivity by melatonin indicating that its effect was due to the arrest of parasite replication. This study shows that the Leishmania/host interaction varies in a circadian manner according to nocturnal melatonin pineal synthesis. Our results provide new data regarding Leishmania infectiveness and show new approaches for applying agonists of melatonin receptors in Leishmaniasis therapy.

  18. Melatonin: an Inhibitor of Breast Cancer

    PubMed Central

    Hill, Steven M.; Belancio, Victoria P.; Dauchy, Robert T.; Xiang, Shulin; Brimer, Samantha; Mao, Lulu; Hauch, Adam; Lundberg, Peter W.; Summers, Whitney; Yuan, Lin; Frasch, Tripp; Blask, David E.

    2015-01-01

    This review discusses recent work on melatonin-mediated circadian regulation and metabolic and molecular signaling mechanisms involved in human breast cancer growth and associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin, via the MT1 receptor, suppresses ERα mRNA expression and ERα transcriptional activity. As well, melatonin regulates the transactivation of other members of the nuclear receptor super-family, estrogen metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (Warburg effect), and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways including inhibition of p38 MAPK and repression of epithelial-to-mesenchymal transition. Studies demonstrate that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models indicate that LEN induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer to drive breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms underpinning the epidemiologic demonstration of elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LEN. PMID:25876649

  19. Melatonin: an inhibitor of breast cancer.

    PubMed

    Hill, Steven M; Belancio, Victoria P; Dauchy, Robert T; Xiang, Shulin; Brimer, Samantha; Mao, Lulu; Hauch, Adam; Lundberg, Peter W; Summers, Whitney; Yuan, Lin; Frasch, Tripp; Blask, David E

    2015-06-01

    The present review discusses recent work on melatonin-mediated circadian regulation, the metabolic and molecular signaling mechanisms that are involved in human breast cancer growth, and the associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin suppresses ERα mRNA expression and ERα transcriptional activity via the MT1 receptor. Melatonin also regulates the transactivation of other members of the nuclear receptor superfamily, estrogen-metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (the Warburg effect) and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type-specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways, including inhibition of p38 MAPK and repression of epithelial-mesenchymal transition (EMT). Studies have demonstrated that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models has indicated that LEN-induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer and drives breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms that underpin the epidemiologic demonstration of elevated breast cancer risk in night-shift workers and other individuals who are increasingly exposed to LEN. PMID:25876649

  20. Melatonin Treatment in Children with Developmental Disabilities.

    PubMed

    Schwichtenberg, A J; Malow, Beth A

    2015-06-01

    Melatonin is commonly recommended to treat sleep problems in children with developmental disabilities. However, few studies document the efficacy and safety of melatonin in these populations. This article reviews recent studies of melatonin efficacy in developmental disabilities. Overall, short treatment trials were associated with a significant decrease in sleep onset latency time for each of the disorders reviewed, with 1 notable exception-tuberous sclerosis. Reported side effects were uncommon and mild. Across disorders, additional research is needed to draw disability-specific conclusions. However, studies to date provide positive support for future trials that include larger groups of children with specific disabilities/syndromes. PMID:26055866

  1. Exposure to di(n-butyl)phthalate and benzo(a)pyrene alters IL-1{beta} secretion and subset expression of testicular macrophages, resulting in decreased testosterone production in rats

    SciTech Connect

    Zheng Shanjun; Tian Huaijun; Cao Jia; Gao Yuqi

    2010-10-01

    Di(n-butyl)phthalate (DBP) and benzo(a)pyrene (BaP) are environmental endocrine disruptors that are potentially hazardous to humans. These chemicals affect testicular macrophage immuno-endocrine function and testosterone production. However, the underlying mechanisms for these effects are not fully understood. It is well known that interleukin-1 beta (IL-1{beta}), which is secreted by testicular macrophages, plays a trigger role in regulating Leydig cell steroidogenesis. The purpose of this study was to reveal the effects of co-exposure to DBP and BaP on testicular macrophage subset expression, IL-1{beta} secretion and testosterone production. Adult male Sprague-Dawley rats were randomly divided into seven groups; two groups received DBP plus BaP (DBP + BaP: 50 + 1 or 250 + 5 mg/kg/day) four groups received DBP or BaP alone (DBP: 50 or 250 mg/kg/day; BaP: 1 or 5 mg/kg/day), and one group received vehicle alone (control). After co-exposure for 90 days, the relative expression of macrophage subsets and their functions changed. ED2{sup +} testicular macrophages (reactive with a differentiation-related antigen present on the resident macrophages) were activated and IL-1{beta} secretion was enhanced. DBP and BaP acted additively, as demonstrated by greater IL-1{beta} secretion relative to each compound alone. These observations suggest that exposure to DBP plus BaP exerted greater suppression on testosterone production compared with each compound alone. The altered balance in the subsets of testicular macrophages and the enhanced ability of resident testicular macrophages to secrete IL-1{beta}, resulted in enhanced production of IL-1{beta} as a potent steroidogenesis repressor. This may represent an important mechanism by which DBP and BaP repress steroidogenesis.

  2. Different neural melatonin-target tissues are critical for encoding and retrieving day length information in Siberian hamsters.

    PubMed

    Teubner, B J W; Freeman, D A

    2007-02-01

    Siberian hamsters exhibit several seasonal rhythms in physiology and behaviour, including reproduction, energy balance, body mass, and pelage colouration. Unambiguous long- and short day lengths stimulate and inhibit reproduction, respectively. Whether gonadal growth or regression occurs in an intermediate day length (e.g. 14 h L : 10 h D; 14L), depends on whether the antecedent day lengths were shorter (10L) or longer (16L). Variations in day length are encoded by the duration of nocturnal pineal melatonin secretion, which is decoded at several neural melatonin target tissues to control testicular structure and function. We assessed participation of three such structures in the acquisition and retrieval of day length information. Elimination of melatonin signalling to the nucleus reuniens (NRe), but not to the suprachiasmatic nucleus (SCN) or paraventricular thalamus (PVt), interfered with the acquisition of a long day reproductive response, whereas the obscuring of melatonin signals to the SCN and the NRe, but not to the PVt, interfered with the photoperiod history response. The SCN and NRe contribute in different ways to the melatonin-based system that mediates seasonal rhythms in male reproduction.

  3. Melatonin and Its Agonist Ramelteon in Alzheimer's Disease: Possible Therapeutic Value

    PubMed Central

    Srinivasan, Venkatramanujam; Kaur, Charanjit; Pandi-Perumal, Seithikurippu; Brown, Gregory M.; Cardinali, Daniel P.

    2011-01-01

    Alzheimer's disease (AD) is an age-associated neurodegenerative disease characterized by the progressive loss of cognitive function, loss of memory and insomnia, and abnormal behavioral signs and symptoms. Among the various theories that have been put forth to explain the pathophysiology of AD, the oxidative stress induced by amyloid β-protein (Aβ) deposition has received great attention. Studies undertaken on postmortem brain samples of AD patients have consistently shown extensive lipid, protein, and DNA oxidation. Presence of abnormal tau protein, mitochondrial dysfunction, and protein hyperphosphorylation all have been demonstrated in neural tissues of AD patients. Moreover, AD patients exhibit severe sleep/wake disturbances and insomnia and these are associated with more rapid cognitive decline and memory impairment. On this basis, the successful management of AD patients requires an ideal drug that besides antagonizing Aβ-induced neurotoxicity could also correct the disturbed sleep-wake rhythm and improve sleep quality. Melatonin is an effective chronobiotic agent and has significant neuroprotective properties preventing Aβ-induced neurotoxic effects in a number of animal experimental models. Since melatonin levels in AD patients are greatly reduced, melatonin replacement has the potential value to be used as a therapeutic agent for treating AD, particularly at the early phases of the disease and especially in those in whom the relevant melatonin receptors are intact. As sleep deprivation has been shown to produce oxidative damage, impaired mitochondrial function, neurodegenerative inflammation, and altered proteosomal processing with abnormal activation of enzymes, treatment of sleep disturbances may be a priority for arresting the progression of AD. In this context the newly introduced melatonin agonist ramelteon can be of much therapeutic value because of its highly selective action on melatonin MT1/MT2 receptors in promoting sleep. PMID:21197086

  4. The diurnal profile of melatonin during delirium in elderly patients--preliminary results.

    PubMed

    Piotrowicz, Karolina; Klich-Rączka, Alicja; Pac, Agnieszka; Zdzienicka, Anna; Grodzicki, Tomasz

    2015-12-01

    Delirium is an acute-onset syndrome that exacerbates patients' condition and significantly increases consequential morbidity and mortality. There is no comprehensive, cellular and tissue-level, pathophysiological theory. The melatonin hormone imbalance has been shown to be linked to circadian rhythms, sleep-wake cycle disturbances, and delirium incidence. There has been relatively little research about melatonin in delirium, and there has been no such study done in the group of elderly patients of a general medicine ward yet. The aim of our study was to compare melatonin hormone concentration in relation to the presence of delirium in elderly patients hospitalized in the general medicine ward. Blood samples were collected four times a day for two days (at 12:00, 18:00, 00:00 and 6:00), on the day when delirium was diagnosed and 72 h after the delirium resolution. Delirium was diagnosed with the Confusion Assessment Method and the criteria of the Diagnostic and Statistic Manual of Mental Disorders, 4th Revision. The mean age of 30 patients (73.3% women) was 86.5 ± 5.2 years. Delirium was diagnosed most often on the second and third day of hospitalization. A lot of predisposing and precipitating factors for delirium were identified. There was a significant difference in the melatonin hormone concentration measurement at 12:00 when patients had acute delirium and after its resolution [18.5 (13.8, 27.5) vs 12.9 (9.8, 17.8), p<0.01]. Different patterns of the melatonin hormone concentration were shown in analyses in the subgroups defined according to the patients' diagnosis of dementia. We found that the delirium recovery was, in fact, associated with the alteration of the daily profile of melatonin.

  5. Human melatonin in magnetic fields: Second study. Final report

    SciTech Connect

    Graham, C.; Cook, M.R.; Cohen, H.D.

    1995-11-01

    Melatonin (MLT) is a hormone secreted primarily at night by the pineal gland in the brain. A number of studies suggest it is part of the body`s natural defenses against cancer. This hormone is reported to stimulate immune function and has been implicated in the control of cell proliferation, the growth of transplanted tumors, and the promotion and/or co-promotion of mammary tumors. MLT also plays a key role in the regulation of reproductive hormones implicated in a number of carcinogenic processes. Studies with rodents, although not always consistent, suggest that nocturnal MLT levels may be suppressed by electric or magnetic field (EMF) exposure. This relationship has been proposed as a possible biological mechanism to account for epidemiological reports linking chronic EMF exposure and increased cancer risk. Research was needed to determine if a similar suppression of MLT occurs when humans are exposed to magnetic fields at night.

  6. Pineal melatonin is a circadian time-giver for leptin rhythm in Syrian hamsters

    PubMed Central

    Chakir, Ibtissam; Dumont, Stéphanie; Pévet, Paul; Ouarour, Ali; Challet, Etienne; Vuillez, Patrick

    2015-01-01

    Nocturnal secretion of melatonin from the pineal gland may affect central and peripheral timing, in addition to its well-known involvement in the control of seasonal physiology. The Syrian hamster is a photoperiodic species, which displays gonadal atrophy and increased adiposity when adapted to short (winter-like) photoperiods. Here we investigated whether pineal melatonin secreted at night can impact daily rhythmicity of metabolic hormones and glucose in that seasonal species. For that purpose, daily variations of plasma leptin, cortisol, insulin and glucose were analyzed in pinealectomized hamsters, as compared to sham-operated controls kept under very long (16 h light/08 h dark) or short photoperiods (08 h light/16 h dark). Daily rhythms of leptin under both long and short photoperiods were blunted by pinealectomy. Furthermore, the phase of cortisol rhythm under a short photoperiod was advanced by 5.6 h after pinealectomy. Neither plasma insulin, nor blood glucose displays robust daily rhythmicity, even in sham-operated hamsters. Pinealectomy, however, totally reversed the decreased levels of insulin under short days and the photoperiodic variations in mean levels of blood glucose (i.e., reduction and increase in long and short days, respectively). Together, these findings in Syrian hamsters show that circulating melatonin at night drives the daily rhythmicity of plasma leptin, participates in the phase control of cortisol rhythm and modulates glucose homeostasis according to photoperiod-dependent metabolic state. PMID:26074760

  7. Effects of melatonin implants on winter fur growth and testicular recrudescence in adult male raccoon dogs (Nyctereutes procyonoides).

    PubMed

    Xiao, Y; Forsberg, M; Laitinen, J T; Valtonen, M

    1996-04-01

    The effects of melatonin implants were investigated on winter fur growth, monitored by counting growing and mature hairs per bundle and testicular recrudescence, judged by testis width, score count of spermatogenesis, and serum testosterone in the adult male raccoon dogs. Melatonin administration in July highly elevated melatonin concentrations in serum and urine and induced an earlier decrease in prolactin secretion (August in the treated group vs September in the control group), winter fur growth (July-beginning of November in the treated group vs. August-end of November in the control group) and testicular recrudescence (October in the treated group vs. November in the control group). In the control animals, urinary excretion of melatonin between 1500-0900 hr increased during autumn followed by a rapid fall in winter. The increase from July (1.8 +/- 0.4 ng) to August (3.9 +/- 0.5 ng) and the subsequent unchanged levels until October coincided with the period of winter fur growth. The further increase in November (6.5 +/- 1.2 ng) coincided with the significant elevation in both testis width and score count of spermatogenesis. These results suggest a role of the increase in endogenous melatonin secretion during autumn in the growth of winter fur and testicular recrudescence in this species under natural conditions. Relatively high serum concentrations of prolactin were shown in two animals, one in the control group and another in the treated group. However, the parameters for testis and winter fur growth in the two cases were similar to those in the remainder of the animals. Thereby, the role of prolactin in the winter fur growth and the initiation of testicular recrudescence, if it is truly involved, is manifested through its decreasing secretion rather than the actual blood concentrations. PMID:8797182

  8. Photic and circadian regulation of retinal melatonin in mammals

    NASA Technical Reports Server (NTRS)

    Tosini, G.; Fukuhara, C.

    2003-01-01

    Several studies have established that melatonin synthesis occurs in the retina of vertebrates, including mammals. In mammals, a subpopulation of photoreceptors (probably the cones) synthesize melatonin. Melatonin synthesis in the retina is elevated at night and reduced during the day in a fashion similar to events in the pineal gland. Both the MT1 and MT2 melatonin receptors are present in the retina and retinal melatonin does not contribute to circulating levels, suggesting that retinal melatonin acts locally as a neurohormone and/or neuromodulator. Melatonin synthesis in the retina of mammals is under the control of a circadian oscillator, and circadian rhythms in melatonin synthesis and/or release have been described for several species of mammals. These rhythms are present in vivo, persist in vitro, are entrained by light and are temperature compensated. The cloning of the gene responsible for the synthesis of the enzyme arylalkylamine N-acetyltransferase (the key enzyme in the melatonin biosynthetic pathway) has allowed studies of the molecular mechanisms responsible for the generation of retinal melatonin rhythmicity. The present review focuses on the cellular and molecular mechanisms that regulate melatonin synthesis. In particular, we discuss how the photic environment and the circadian clock interact in determining melatonin levels, in addition to the role that melatonin plays in retinal physiology.

  9. Color indirect effects on melatonin regulation

    NASA Astrophysics Data System (ADS)

    Mian, Tian; Liu, Timon C.; Li, Yan

    2002-04-01

    Color indirect effect (CIE) is referred to as the physiological and psychological effects of color resulting from color vision. In previous papers, we have studied CIE from the viewpoints of the integrated western and Chinese traditional medicine, put forward the color-autonomic- nervous-subsystem model (CAM), and provided its time-theory foundation. In this paper, we applied it to study light effects on melatonin regulation in humans, and suggested that it is CIE that mediates light effects on melatonin suppression.

  10. Melatonin, light therapy, and jet lag.

    PubMed

    Lathrop, N J; Lentz, M

    2001-01-01

    If you enter the words jet lag into your Internet search engine, multiple sites come up. Jet lag is a term common to all travelers, but what is it? The medication melatonin, available in most convenience stores, is marketed as a sleep agent or treatment for jet lag, but is it safe? Is it a sleeping pill? How is light therapy related to melatonin? PMID:11552110

  11. Differences between Brahman and Holstein cows in heat-shock induced alterations of protein synthesis and secretion by oviducts and uterine endometrium.

    PubMed

    Malayer, J R; Hansen, P J

    1990-01-01

    Our objectives were to test differences in protein synthesis and secretion by cultured oviducts and endometrium from Brahman and Holstein cows and the response of those tissues to in vitro heat shock. Explants of oviductal tissue obtained at estrus from Holstein (n = 5) and Brahman (n = 6) cows were cultured at a homeothermic (39 degrees C) or heat shock (43 degrees C) temperature. At 6 h, cultures were pulse-chase labeled (2 h, L[4,5-3H]leucine; 2 h, L-leucine). Endometrial explants were cultured similarly except that pulse labeling was performed for the first 0 to 15, 0 to 30, 30 to 60 and 60 to 90 min following onset of heat shock. A temperature of 43 degrees C increased secretion of nondialyzable 3H-labeled macromolecules by both oviducts of Brahmans but depressed secretion by the oviduct ipsilateral to the side of ovulation of Holsteins. For both breeds, 43 degrees C decreased incorporation of [3H]leucine into trichloroacetic acid (TCA)-precipitable radioactivity in oviducts from the ipsilateral side. Secretion of 3H-labeled macromolecules by pulse-labeled endometrial explants increased at 43 degrees C. Heat shock caused an immediate increase in TCA-precipitable radioactivity in tissue during pulse labeling for Holstein tissues. Incorporation was decreased at 43 degrees C in tissue from Brahmans in the first 30 min and increased thereafter. Incorporation of [3H]thymidine by endometrial explants from Brahmans was increased at 43 degrees C, whereas it was suppressed at 43 degrees C in explants from Holstein cows. Heat shock proteins of 72,000 and 90,000 molecular weight were present in endometrial tissues. A major secretory product of endometrium had a molecular weight of 57,500 for Brahmans and a lower molecular weight (55,600) for Holsteins. PMID:2303398

  12. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor

    NASA Technical Reports Server (NTRS)

    Brainard, G. C.; Hanifin, J. P.; Greeson, J. M.; Byrne, B.; Glickman, G.; Gerner, E.; Rollag, M. D.

    2001-01-01

    The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 +/- 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects' pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R(2) = 0.81-0.95). The action spectrum constructed from these data fit an opsin template (R(2) = 0.91), which identifies 446-477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.

  13. Loss of Response to Melatonin Treatment Is Associated with Slow Melatonin Metabolism

    ERIC Educational Resources Information Center

    Braam, W.; van Geijlswijk, I.; Keijzer, Henry; Smits, Marcel G.; Didden, Robert; Curfs, Leopold M. G.

    2010-01-01

    Background: In some of our patients with intellectual disability (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment, while the good response returned only after considerable dose reduction. The cause for this loss of response to melatonin is yet unknown. We hypothesise that this…

  14. Prostaglandin F2 alpha-induced calcium transient in ovine large luteal cells: II. Modulation of the transient and resting cytosolic free calcium alters progesterone secretion.

    PubMed

    Wegner, J A; Martinez-Zaguilan, R; Gillies, R J; Hoyer, P B

    1991-02-01

    A previous study demonstrated that prostaglandin F2 alpha (PGF2 alpha) stimulates a transient increase in cytosolic free Ca2+ levels [( Ca2+]i) in ovine large luteal cells. In the present study, the magnitude of the PGF2 alpha (0.5 microM)-induced calcium transient in Hanks' medium (87 +/- 2 nM increase above resting levels) was reduced (P less than 0.05) but not completely eliminated in fura-2 loaded large luteal cells incubated in Ca2(+)-free or phosphate- and carbonate-free medium (10 +/- 1 nM, 32 +/- 6 nM, above resting levels; respectively). Preincubation for 2 min with 1 mM LaCl3 (calcium antagonist) eliminated the PGF2 alpha-induced calcium transient. The inhibitory effect of PGF2 alpha on secretion of progesterone was reduced in Ca2(+)-free medium or medium plus LaCl3. Resting [Ca2+]i levels and basal secretion of progesterone were both reduced (P less than 0.05) in large cells incubated in Ca2(+)-free medium (27 +/- 4 nM; 70 +/- 6% control, respectively) or with 5 microM 5,5'-dimethyl bis-(O-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid (40 +/- 2 nM; 49 +/- 1% control; respectively). In addition, secretion of progesterone was inhibited (P less than 0.05) by conditions that increased (P less than 0.05) [Ca2+]i; that is LaCl3 ([Ca2+]i, 120 +/- 17 nM; progesterone, 82 +/- 8% control) and PGF2 alpha ([Ca2+]i, 102 +/- 10 nM; progesterone, 82 +/- 3% control). In small luteal cells, resting [Ca2+]i levels and secretion of progesterone were reduced by incubation in Ca2(+)-free Hanks ([Ca2+]i, 28 +/- 2 nM; progesterone, 71 +/- 6% control), however, neither LaCl3 nor PGF2 alpha increased [Ca2+]i levels or inhibited secretion of progesterone. The findings presented here provide evidence that extracellular as well as intracellular calcium contribute to the PGF2 alpha-induced [Ca2+]i transient in large cells. Furthermore, whereas an adequate level of [Ca2+]i is required to support progesterone production in both small and large cells, optimal progesterone production in

  15. Like melatonin, agomelatine (S20098) increases the amplitude of oscillations of two clock outputs: melatonin and temperature rhythms.

    PubMed

    Castanho, Amélie; Bothorel, Béatrice; Seguin, Laure; Mocaër, Elisabeth; Pévet, Paul

    2014-04-01

    Depression and biological rhythms disturbances are strongly associated. Agomelatine is an antidepressant with melatoninergic MT1-MT2 agonist and serotoninergic 5-HT2c antagonist properties. Both melatonin and 5-HT are known to modulate circadian rhythmicity controlled by the endogenous clock located in the suprachiasmatic nuclei (SCN). The aim of the present study was to compare the effect of an acute injection of agomelatine (Ago), melatonin (MLT) or an antagonist 5-HT2c (S32006), on the rhythms of two robust clock outputs: the pineal MLT secretion and the body temperature rhythm (Tc). Daily endogenous MLT profiles were measured using transpineal microdialysis over 4 consecutive days in rats maintained on a 12 h light/12 h dark cycle. Simultaneously, Tc was recorded. The drugs were injected subcutaneously at three doses (1, 2.5 or 5 mg/kg) at the onset of darkness. Both Ago and MLT, at the dose of 2.5 mg/kg, increased the amplitude of the peak of MLT secretion and this effect was observed 2 d after injection. Moreover, both drugs induced a dose-dependent advance of the rhythm onset which resulted in lengthening of the MLT peak. S32006 had no effect on the rhythm of MLT. Ago, MLT and S32006 increased the amplitude of the rhythm of Tc. These data suggest a central action of Ago, directly on the SCN, via melatoninergic receptors responsible for both the increased amplitude of MLT rhythm and the phase advance. The increase in the amplitude of the body temperature could involve both MLT agonist and/or 5-HT2c antagonist properties of Ago.

  16. Identification of melatonin in Trichoderma spp. and detection of melatonin content under controlled-stress growth conditions from T. asperellum.

    PubMed

    Liu, Tong; Zhao, Fengzhou; Liu, Zhen; Zuo, Yuhu; Hou, Jumei; Wang, Yanjie

    2016-07-01

    T. koningii, T. harzianum, T. asperellum, T. longibrachiatum, and T. viride were analyzed using liquid chromatography-tandem mass spectrometry to determine whether melatonin is present. Results showed that there were abundant amounts of endogenous melatonin in five Trichoderma species, but no melatonin was found in any of the culture filtrates. T. asperellum had the highest amount of melatonin (27.588 ± 0.326 μg g(-1) dry mass), followed by T. koningii, T. harzianum, T. longibrachiatum, and T. viride. The endogenous melatonin content of T. asperellum in controlled-stress growth conditions was also detected. The data showed that chemical stressors (CdCl2 , CuSO4 , and H2 O2 ) provoked an increase in endogenous melatonin levels. CdCl2 had the highest stimulatory effect on melatonin production, as the product reached reaching up to three times the melatonin content of the control. NaCl stimulated a decrease of melatonin. Acidic conditions (pH 3 and pH 5) as well as slightly alkaline conditions (pH 9) resulted in an increase in the melatonin content, whereas pH11 resulted in a significant decrease in the melatonin content, only 12.276 ± 0.205 μg g(-1) dry mass. The current study is first to report melatonin content and the change of melatonin content under different stress situations in Trichoderma spp. PMID:26367376

  17. Melatonin: the dawning of a treatment for fibrosis?

    PubMed

    Hu, Wei; Ma, Zhiqiang; Jiang, Shuai; Fan, Chongxi; Deng, Chao; Yan, Xiaolong; Di, Shouyin; Lv, Jianjun; Reiter, Russel J; Yang, Yang

    2016-03-01

    Fibrosis is a common occurrence following organ injury and failure. To date, there is no effective treatment for this condition. Melatonin targets numerous molecular pathways, a consequence of its antioxidant and anti-inflammatory actions that reduce excessive fibrosis. Herein, we review the multiple protective effects of melatonin against fibrosis. There exist four major phases of the fibrogenic response including primary injury to the organ, activation of effector cells, the elaboration of extracellular matrix (ECM) and dynamic deposition. Melatonin regulates each of these phases. Additionally, melatonin reduces fibrosis levels in numerous organs. Melatonin exhibits its anti-fibrosis effects in heart, liver, lung, kidney, and other organs. In addition, adhesions which occur following surgical procedures are also inhibited by melatonin. The information reviewed here should be significant to understanding the protective role of melatonin against fibrosis, contribute to the design of further experimental studies related to melatonin and the fibrotic response and shed light on a potential treatment for fibrosis.

  18. Melatonin modulates intercellular communication among cultured chick astrocytes.

    PubMed

    Peters, Jennifer L; Cassone, Vincent M; Zoran, Mark J

    2005-01-01

    Melatonin, a pineal neurohormone, mediates circadian and seasonal processes in birds and mammals. Diencephalic astrocytes are sites of action, at least in birds, since they express melatonin receptors and melatonin affects their metabolism. We tested whether astrocytic calcium waves are also modulated by melatonin. Calcium waves, which we found to be regulated in cultured chick glial cells by an IP(3)-dependent mechanism, were potentiated by physiological concentrations of melatonin. Melatonin also increased resting calcium levels and reduced gap junctional coupling among astrocytes, at concentrations that facilitated calcium waves. These modulatory effects were diminished by melatonin receptor blockade and pertussis toxin (PTX). Thus, melatonin induced a functional shift in the mode of intercellular communication, between junctional coupling and calcium waves, among glial cells. We suggest a mechanism where neuroglial physiology, involving GTP-binding protein signaling pathways, links rhythmic circadian outputs to pervasive neurobehavioral states. PMID:15621008

  19. Putative melatonin receptors in a human biological clock

    SciTech Connect

    Reppert, S.M.; Weaver, D.R.; Rivkees, S.A.; Stopa, E.G.

    1988-10-07

    In vitro autoradiography with /sup 125/I-labeled melatonin was used to examine melatonin binding sites in human hypothalamus. Specific /sup 125/I-labeled melatonin binding was localized to the suprachiasmatic nuclei, the site of a putative biological clock, and was not apparent in other hypothalamic regions. Specific /sup 125/I-labeled melatonin binding was consistently found in the suprachiasmatic nuclei of hypothalami from adults and fetuses. Densitometric analysis of competition experiments with varying concentrations of melatonin showed monophasic competition curves, with comparable half-maximal inhibition values for the suprachiasmatic nuclei of adults (150 picomolar) and fetuses (110 picomolar). Micromolar concentrations of the melatonin agonist 6-chloromelatonin completely inhibited specific /sup 125/I-labeled melatonin binding, whereas the same concentrations of serotonin and norepinephrine caused only a partial reduction in specific binding. The results suggest that putative melatonin receptors are located in a human biological clock.

  20. A pilot double-blind randomised placebo-controlled dose–response trial assessing the effects of melatonin on infertility treatment (MIART): study protocol

    PubMed Central

    Fernando, Shavi; Osianlis, Tiki; Vollenhoven, Beverley; Wallace, Euan; Rombauts, Luk

    2014-01-01

    Introduction High levels of oxidative stress can have considerable impact on the outcomes of in vitro fertilisation (IVF). Recent studies have reported that melatonin, a neurohormone secreted from the pineal gland in response to darkness, has significant antioxidative capabilities which may protect against the oxidative stress of infertility treatment on gametes and embryos. Early studies of oral melatonin (3–4 mg/day) in IVF have suggested favourable outcomes. However, most trials were poorly designed and none have addressed the optimum dose of melatonin. We present a proposal for a pilot double-blind randomised placebo-controlled dose–response trial aimed to determine whether oral melatonin supplementation during ovarian stimulation can improve the outcomes of assisted reproductive technology. Methods and analyses We will recruit 160 infertile women into one of four groups: placebo (n=40); melatonin 2 mg twice per day (n=40); melatonin 4 mg twice per day (n=40) and melatonin 8 mg twice per day (n=40). The primary outcome will be clinical pregnancy rate. Secondary clinical outcomes include oocyte number/quality, embryo number/quality and fertilisation rate. We will also measure serum melatonin and the oxidative stress marker, 8-hydroxy-2′-deoxyguanosine at baseline and after treatment and levels of these in follicular fluid at egg pick-up. We will investigate follicular blood flow with Doppler ultrasound, patient sleepiness scores and pregnancy complications, comparing outcomes between groups. This protocol has been designed in accordance with the SPIRIT 2013 Guidelines. Ethics and dissemination Ethical approval has been obtained from Monash Health HREC (Ref: 13402B), Monash University HREC (Ref: CF14/523-2014000181) and Monash Surgical Private Hospital HREC (Ref: 14107). Data analysis, interpretation and conclusions will be presented at national and international conferences and published in peer-reviewed journals. Trial registration number ACTRN

  1. Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney.

    PubMed

    Mias, Céline; Trouche, Elodie; Seguelas, Marie-Hélène; Calcagno, Fabien; Dignat-George, Françoise; Sabatier, Florence; Piercecchi-Marti, Marie-Dominique; Daniel, Laurent; Bianchi, Pascale; Calise, Denis; Bourin, Philippe; Parini, Angelo; Cussac, Daniel

    2008-07-01

    Bone marrow mesenchymal stem cells (MSCs) have shown great potential in cell therapy of solid organs. Approaches to improving the ability of grafted MSCs to survive and secrete paracrine factors represent one of the challenges for the further development of this novel therapy. In the present study, we designed a strategy of ex vivo pretreatment with the pineal hormone melatonin to improve survival, paracrine activity, and efficiency of MSCs. Using a rat model of acute renal failure, we showed that melatonin pretreatment strongly increased survival of MSCs after intraparenchymal injection. This effect was concomitant with overstimulation of angiogenesis, proliferation of renal cells, and accelerated recovery of renal function. To gain insight into the mechanisms involved in the effects observed in vivo, melatonin was tested in vitro on cultured MSCs. Our results show that through stimulation of specific melatonin receptors, melatonin induced an overexpression of the antioxidant enzyme catalase and superoxide dismutase-1 and increased the resistance of MSCs to hydrogen peroxide-dependent apoptosis. Compared with untreated cells, MSCs incubated with melatonin displayed a higher expression of basic fibroblast growth factor and hepatocyte growth factor. In addition, conditioned culture media from melatonin-treated MSCs stimulated tube formation by endothelial progenitor cells and proliferation of proximal tubule cells in culture. In conclusion, our results show that melatonin behaves as a preconditioning agent increasing survival, paracrine activity, and efficiency of MSCs. The use of this molecule for pretreatment of stem cells may represent a novel and safe approach to improving the beneficial effects of cell therapy of solid organs.

  2. Prophylactic treatment with melatonin after status epilepticus: effects on epileptogenesis, neuronal damage, and behavioral changes in a kainate model of temporal lobe epilepsy.

    PubMed

    Tchekalarova, Jana; Petkova, Zlatina; Pechlivanova, Daniela; Moyanova, Slavianka; Kortenska, Lidia; Mitreva, Rumiana; Lozanov, Valentin; Atanasova, Dimitrina; Lazarov, Nikolai; Stoynev, Alexander

    2013-04-01

    Melatonin is a potent antioxidant which showed anticonvulsant activities both in experimental and clinical studies. In the present study, we examined the effect of melatonin treatment (10mg/kg/day, diluted in drinking water, 8 weeks) during epileptogenesis on the consequences of a kainate (KA)-induced status epilepticus (SE) in rats. Melatonin increased the latency in the appearance of spontaneous recurrent seizures (SRSs) and decreased their frequency only during the treatment period. The behavioral alterations associated with hyperactivity, depression-like behavior during the light phase, and deficits in hippocampus-dependent working memory were positively affected by melatonin treatment in rats with epilepsy. Melatonin reduced the neuronal damage in the CA1 area of the hippocampus and piriform cortex and recovered the decrease of hippocampal serotonin (5-HT) level in rats with epilepsy. Taken together, long-term melatonin treatment after SE was unable to suppress the development of epileptogenesis. However, it showed a potential in reducing some of the deleterious alterations that develop during the chronic epileptic state in a diurnal phase-dependent mode. PMID:23435277

  3. Prophylactic treatment with melatonin after status epilepticus: effects on epileptogenesis, neuronal damage, and behavioral changes in a kainate model of temporal lobe epilepsy.

    PubMed

    Tchekalarova, Jana; Petkova, Zlatina; Pechlivanova, Daniela; Moyanova, Slavianka; Kortenska, Lidia; Mitreva, Rumiana; Lozanov, Valentin; Atanasova, Dimitrina; Lazarov, Nikolai; Stoynev, Alexander

    2013-04-01

    Melatonin is a potent antioxidant which showed anticonvulsant activities both in experimental and clinical studies. In the present study, we examined the effect of melatonin treatment (10mg/kg/day, diluted in drinking water, 8 weeks) during epileptogenesis on the consequences of a kainate (KA)-induced status epilepticus (SE) in rats. Melatonin increased the latency in the appearance of spontaneous recurrent seizures (SRSs) and decreased their frequency only during the treatment period. The behavioral alterations associated with hyperactivity, depression-like behavior during the light phase, and deficits in hippocampus-dependent working memory were positively affected by melatonin treatment in rats with epilepsy. Melatonin reduced the neuronal damage in the CA1 area of the hippocampus and piriform cortex and recovered the decrease of hippocampal serotonin (5-HT) level in rats with epilepsy. Taken together, long-term melatonin treatment after SE was unable to suppress the development of epileptogenesis. However, it showed a potential in reducing some of the deleterious alterations that develop during the chronic epileptic state in a diurnal phase-dependent mode.

  4. Exogenous melatonin administration modifies cutaneous vasoconstrictor response to whole body skin cooling in humans.

    PubMed

    Aoki, Ken; Zhao, Kun; Yamazaki, Fumio; Sone, Ryoko; Alvarez, Guy E; Kosiba, Wojciech A; Johnson, John M

    2008-03-01

    Humans and other diurnal species experience a fall in internal temperature (T(int)) at night, accompanied by increased melatonin and altered thermoregulatory control of skin blood flow (SkBF). Also, exogenous melatonin induces a fall in T(int), an increase in distal skin temperatures and altered control of the cutaneous active vasodilator system, suggesting an effect of melatonin on the control of SkBF. To test whether exogenous melatonin also affects the more tonically active vasoconstrictor system in glabrous and nonglabrous skin during cooling, healthy males (n = 9) underwent afternoon sessions of whole body skin temperature (T(sk)) cooling (water-perfused suits) after oral melatonin (Mel; 3 mg) or placebo (Cont). Cutaneous vascular conductance (CVC) was calculated from SkBF (laser Doppler flowmetry) and non-invasive blood pressure. Baseline T(int) was lower in Mel than in Cont (P < 0.01). During progressive reduction of T(sk) from 35 degrees C to 32 degrees C, forearm CVC was first significantly reduced at T(sk) of 34.33 +/- 0.01 degrees C (P < 0.05) in Cont. In contrast, CVC in Mel was not significantly reduced until T(sk) reached 33.33 +/- 0.01 degrees C (P < 0.01). The decrease in forearm CVC in Mel was significantly less than in Cont at T(sk) of 32.66 +/- 0.01 degrees C and lower (P < 0.05). In Mel, palmar CVC was significantly higher than in Cont above T(sk) of 33.33 +/- 0.01 degrees C, but not below. Thus exogenous melatonin blunts reflex vasoconstriction in nonglabrous skin and shifts vasoconstrictor system control to lower T(int). It provokes vasodilation in glabrous skin but does not suppress the sensitivity to falling T(sk). These findings suggest that by affecting the vasoconstrictor system, melatonin has a causal role in the nocturnal changes in body temperature and its control.

  5. [Behavior of rats kept under conditions of a shifted light/dark regimen and receiving melatonin].

    PubMed

    Pertsov, S S

    2005-07-01

    We studied the effect of shift in the natural light/dark regimen (desynchronosis) and treatment with melatonin on behavioral characteristics of rats with different activity in the open-field test. Experiments were performed on 172 Wistar rats kept under conditions of the natural or shifted light/dark regimen. Some animals were intraperitoneally treated with 1 ml physiological saline or melatonin in doses of 1 and 2 mg/kg, while others did not receive the injections. Desynchronosis altered the normal rhythm of locomotor activity and abolished the differences between daytime and nighttime activity rats not receiving the injections. The influence of melatonin on locomotor activity of rats maintained under normal or shifted light/dark conditions depended on its dose, time of treatment, and initial behavioral characteristics of animals. Our results indicate that the use of melatonin for treatment of disturbances produced by a shift in the light/dark conditions should be performed taking into account individual behavioral characteristics of the organism.

  6. Oncostatic-Cytoprotective Effect of Melatonin and Other Bioactive Molecules: A Common Target in Mitochondrial Respiration

    PubMed Central

    Pacini, Nicola; Borziani, Fabio

    2016-01-01

    For several years, oncostatic and antiproliferative properties, as well as thoses of cell death induction through 5-methoxy-N-acetiltryptamine or melatonin treatment, have been known. Paradoxically, its remarkable scavenger, cytoprotective and anti-apoptotic characteristics in neurodegeneration models, such as Alzheimer’s disease and Parkinson’s disease are known too. Analogous results have been confirmed by a large literature to be associated to the use of many other bioactive molecules such as resveratrol, tocopherol derivatives or vitamin E and others. It is interesting to note that the two opposite situations, namely the neoplastic pathology and the neurodegeneration, are characterized by deep alterations of the metabolome, of mitochondrial function and of oxygen consumption, so that the oncostatic and cytoprotective action can find a potential rationalization because of the different metabolic and mitochondrial situations, and in the effect that these molecules exercise on the mitochondrial function. In this review we discuss historical and general aspects of melatonin, relations between cancers and the metabolome and between neurodegeneration and the metabolome, and the possible effects of melatonin and of other bioactive molecules on metabolic and mitochondrial dynamics. Finally, we suggest a common general mechanism as responsible for the oncostatic/cytoprotective effect of melatonin and of other molecules examined. PMID:26959015

  7. Role of MT1 Melatonin Receptors in Methamphetamine-induced Locomotor Sensitization in C57BL/6 Mice

    PubMed Central

    Hutchinson, Anthony J.; Ma, Jason; Liu, Jiabei; Hudson, Randall L.; Dubocovich, Margarita L.

    2015-01-01

    RATIONALE Melatonin modifies physiological and behavioral responses to psychostimulants, with the MT1 and MT2 melatonin receptors specifically implicated in facilitating methamphetamine-induced sensitization in melatonin-proficient mice. OBJECTIVE To assess differences in locomotor sensitization after a single dose of methamphetamine in low melatonin-expressing C57BL/6 wild-type and MT1KO mice, and comparing with melatonin-expressing C3H/HeN mice. METHODS Mice received a vehicle or methamphetamine (1.2 mg/kg, i.p.) pretreatment (Day 1) during the light (ZT5–9) or dark (ZT 19–21) periods in novel test arenas. Locomotor sensitization was assessed by methamphetamine challenge after an eight-day (Day 9) abstinence. TH protein expression was evaluated by immunofluorescence and Western blot analysis. RESULTS Methamphetamine pretreatment induced statistically significant locomotor sensitization upon challenge after eight-day abstinence in C3H and C57 wild-type mice during the light period. The magnitude of sensitization in C57 mice was diminished in the dark period and completely abrogated in MT1 receptor knockout (MT1KO) mice. No differences were observed in tyrosine hydroxylase immunoreactivity in the mesolimbic dopamine system. Additional exposures to the test arenas after methamphetamine pretreatment (Nights 2–6) enhanced sensitization. CONCLUSIONS Deletion of the MT1 melatonin receptor abolishes sensitization induced by a single METH pretreatment. The magnitude of sensitization is also altered by time of day and contextual cues. We conclude that the MT1 melatonin receptor is emerging as a novel target of therapeutic intervention for drug abuse disorders. PMID:23934259

  8. Melatonin as a selective estrogen enzyme modulator.

    PubMed

    Cos, S; González, A; Martínez-Campa, C; Mediavilla, M D; Alonso-González, C; Sánchez-Barceló, E J

    2008-12-01

    Melatonin exerts oncostatic effects on different kinds of tumors, especially on hormone-dependent breast cancer. The general conclusion is that melatonin, in vivo, reduces the incidence and growth of chemically-induced mammary tumors in rodents, and, in vitro, inhibits the proliferation and invasiveness of human breast cancer cells. Both studies support the hypothesis that melatonin inhibits the growth of breast cancer by interacting with estrogen-signaling pathways through three different mechanisms: (a) the indirect neuroendocrine mechanism which includes the melatonin down-regulation of the hypothalamic-pituitary-reproductive axis and the consequent reduction of circulating levels of gonadal estrogens, (b) direct melatonin actions at tumor cell level by interacting with the activation of the estrogen receptor, thus behaving as a selective estrogen receptor modulator (SERM), and (c) the regulation of the enzymes involved in the biosynthesis of estrogens in peripheral tissues, thus behaving as a selective estrogen enzyme modulator (SEEM). As melatonin reduces the activity and expression of aromatase, sulfatase and 17beta-hydroxysteroid dehydrogenase and increases the activity and expression of estrogen sulfotransferase, it may protect mammary tissue from excessive estrogenic effects. Thus, a single molecule has both SERM and SEEM properties, one of the main objectives desired for the breast antitumoral drugs. Since the inhibition of enzymes involved in the biosynthesis of estrogens is currently one of the first therapeutic strategies used against the growth of breast cancer, melatonin modulation of different enzymes involved in the synthesis of steroid hormones makes, collectively, this indolamine an interesting anticancer drug in the prevention and treatment of estrogen-dependent mammary tumors.

  9. The effects of supplemental melatonin administration on the healing of bone defects in streptozotocin-induced diabetic rats

    PubMed Central

    YILDIRIMTURK, Senem; BATU, Sule; ALATLI, Canan; OLGAC, Vakur; FIRAT, Deniz; SIRIN, Yigit

    2016-01-01

    ABSTRACT Diabetes mellitus (DM) causes an increased production of free radicals that can impair bone healing. Melatonin is a hormone secreted mainly by the pineal gland, which participates in the neutralization process of free radicals. Objective The aim of this study was to investigate histologic and biochemical effects of supplemental melatonin administration on bone healing and antioxidant defense mechanism in diabetic rats. Material and Methods Eighty-six Sprague-Dawley male rats were used in this study. Diabetes mellitus was induced by intraperitoneal (i.p.) administration of 65 mg/kg streptozotocin (STZ). Surgical bone defects were prepared in the tibia of each animal. Diabetic animals and those in control groups were treated either with daily melatonin (250 μg/animal/day/i.p.) diluted in ethanol, only ethanol, or sterile saline solution. Rats were humanely killed at the 10th and 30th postoperative days. Plasma levels of Advanced Oxidation Protein Products (AOPP), Malondialdehyde (MDA), and Superoxide Dismutase (SOD) were measured. The number of osteoblasts, blood vessels and the area of new mineralized tissue formation were calculated in histologic sections. Results At the 10th day, DM+MEL (rats receiving both STZ and melatonin) group had significantly higher number of osteoblasts and blood vessels as well as larger new mineralized tissue surfaces (p<0.05 for each) when compared with DM group. At the 30th day, DM group treated with melatonin had significantly lower levels of AOPP and MDA than those of DM group (p<0.05). Conclusion Melatonin administration in STZ induced diabetic rats reduced oxidative stress related biomarkers and showed beneficial effects on bone healing at short term. PMID:27383705

  10. Permeabilized myocardial fibers as model to detect mitochondrial dysfunction during sepsis and melatonin effects without disruption of mitochondrial network.

    PubMed

    Doerrier, Carolina; García, José A; Volt, Huayqui; Díaz-Casado, María E; Luna-Sánchez, Marta; Fernández-Gil, Beatriz; Escames, Germaine; López, Luis C; Acuña-Castroviejo, Darío

    2016-03-01

    Analysis of mitochondrial function is crucial to understand their involvement in a given disease. High-resolution respirometry of permeabilized myocardial fibers in septic mice allows the evaluation of the bioenergetic system, maintaining mitochondrial ultrastructure and intracellular interactions, which are critical for an adequate functionality. OXPHOS and electron transport system (ETS) capacities were assessed using different substrate combinations. Our findings show a severe septic-dependent impairment in OXPHOS and ETS capacities with mitochondrial uncoupling at early and late phases of sepsis. Moreover, sepsis triggers complex III (CIII)-linked alterations in supercomplexes structure, and loss of mitochondrial density. In these conditions, melatonin administration to septic mice prevented sepsis-dependent mitochondrial injury in mitochondrial respiration. Likewise, melatonin improved cytochrome b content and ameliorated the assembly of CIII in supercomplexes. These results support the use of permeabilized fibers to identify properly the respiratory deficits and specific melatonin effects in sepsis. PMID:26748191

  11. Protective effect of melatonin against propoxur-induced oxidative stress and suppression of humoral immune response in rats.

    PubMed

    Suke, Sanvidhan G; Kumar, Achint; Ahmed, Rafat S; Chakraborti, Ayanabha; Tripathi, A K; Mediratta, P K; Banerjee, B D

    2006-04-01

    Effect of melatonin in attenuation of propoxur induced oxidative stress and suppression of humoral immune response was studied in rats. Oral administration of propoxur (10 mg/kg) increased lipid peroxidation in serum after 28 days treatment. Superoxide dismutase, catalase and glutathione were also altered following propoxur exposure. In addition propoxur exposure markedly suppressed humoral immune response as assessed by antibody titre and plaque forming cell assay. Simultaneous treatment with melatonin (5 mg/kg, ip) markedly attenuated the effect of propoxur on (a) lipid peroxidation, (b) oxidative stress parameters and (c) immunotoxicity. Results have been discussed in the light of possible immunopotentiating and antioxidant effects of melatonin to understand the influence of oxidative stress on propoxur induced immunomodulation.

  12. Permeabilized myocardial fibers as model to detect mitochondrial dysfunction during sepsis and melatonin effects without disruption of mitochondrial network.

    PubMed

    Doerrier, Carolina; García, José A; Volt, Huayqui; Díaz-Casado, María E; Luna-Sánchez, Marta; Fernández-Gil, Beatriz; Escames, Germaine; López, Luis C; Acuña-Castroviejo, Darío

    2016-03-01

    Analysis of mitochondrial function is crucial to understand their involvement in a given disease. High-resolution respirometry of permeabilized myocardial fibers in septic mice allows the evaluation of the bioenergetic system, maintaining mitochondrial ultrastructure and intracellular interactions, which are critical for an adequate functionality. OXPHOS and electron transport system (ETS) capacities were assessed using different substrate combinations. Our findings show a severe septic-dependent impairment in OXPHOS and ETS capacities with mitochondrial uncoupling at early and late phases of sepsis. Moreover, sepsis triggers complex III (CIII)-linked alterations in supercomplexes structure, and loss of mitochondrial density. In these conditions, melatonin administration to septic mice prevented sepsis-dependent mitochondrial injury in mitochondrial respiration. Likewise, melatonin improved cytochrome b content and ameliorated the assembly of CIII in supercomplexes. These results support the use of permeabilized fibers to identify properly the respiratory deficits and specific melatonin effects in sepsis.

  13. Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer.

    PubMed

    Dauchy, Robert T; Xiang, Shulin; Mao, Lulu; Brimer, Samantha; Wren, Melissa A; Yuan, Lin; Anbalagan, Muralidharan; Hauch, Adam; Frasch, Tripp; Rowan, Brian G; Blask, David E; Hill, Steven M

    2014-08-01

    Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to antiestrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of estrogen receptor (ERα(+)) MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speed the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characteristics were not observed in animals in which the circadian melatonin rhythm was not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen. PMID:25062775

  14. A new concept for melatonin deficit: on pineal calcification and melatonin excretion.

    PubMed

    Kunz, D; Schmitz, S; Mahlberg, R; Mohr, A; Stöter, C; Wolf, K J; Herrmann, W M

    1999-12-01

    Even though exogenous melatonin has proven to influence sleep and circadian parameters, low endogenous melatonin is not related to sleep disturbances, nor does it predict response to melatonin replacement therapy. In this manuscript, we present a new concept towards a definition of a melatonin deficit. The purpose of the study was to introduce a marker for an intra-individual decrease in melatonin production. Therefore, we developed a method to quantify the degree of pineal calcification (DOC) using cranial computed tomography. Combining pineal DOC with the organs's size, we estimated the uncalcified pineal gland volume. This estimation was positively and significantly associated with 6-sulfatoxymelatonin (aMT6s), collected over 24 hours in urine, in 26 subjects. Data yielded evidence that the decline in aMT6s excretion with age can be sufficiently explained by an increased pineal calcification. These results suggest that DOC might be useful as an indicator of an intra-individual, decreased capability of the pineal gland to produce melatonin. DOC might prove to be a response-marker for melatonin replacement therapy and a vulnerability marker of the circadian timing system. PMID:10633482

  15. Beneficial effects of melatonin on in vitro bovine embryonic development are mediated by melatonin receptor 1.

    PubMed

    Wang, Feng; Tian, XiuZhi; Zhang, Lu; Gao, Chao; He, ChangJiu; Fu, Yao; Ji, PengYun; Li, Yu; Li, Ning; Liu, GuoShi

    2014-04-01

    In the current study, a fundamental question, that is, the mechanisms related to the beneficial effects of melatonin on mammalian embryonic development, was addressed. To examine the potential beneficial effects of melatonin on bovine embryonic development, different concentrations of melatonin (10(-11), 10(-9), 10(-7), 10(-5), 10(-3) M) were incubated with fertilized embryos. Melatonin in the range of 10(-11) to 10(-5) M significantly promoted embryonic development both in early culture medium (CR1aa +3 mg/mL BSA) and in later culture medium (CR1aa + 6%FBS). The most effective concentrations applied in the current studies were 10(-9) and 10(-7) M. Using quantitative real-time PCR with immunofluorescence and Western blot assays, the expression of melatonin receptor MT1 and MT2 genes was identified in bovine embryos. Further studies indicate that the beneficial effects of melatonin on bovine embryo development were mediated by the MT1 receptor. This is based on the facts that luzindole, a nonselective MT1 and MT2 antagonist, blocked the effect on melatonin-induced embryo development, while 4-P-PDOT, a selective MT2 antagonist, had little effect. Mechanistic explorations uncovered that melatonin application during bovine embryonic development significantly up-regulated the expression of antioxidative (Gpx4, SOD1, bcl-2) and developmentally important genes (SLC2A1, DNMT1A, and DSC2) while down-regulating expression of pro-apoptotic genes (P53, BAX, and Caspase-3). The results obtained from the current studies provide new information regarding the mechanisms by which melatonin promotes bovine embryonic development under both in vitro and in vivo conditions.

  16. Gut Melatonin in Vertebrates: Chronobiology and Physiology

    PubMed Central

    Mukherjee, Sourav; Maitra, Saumen Kumar

    2015-01-01

    Melatonin, following discovery in the bovine pineal gland, has been detected in several extra-pineal sources including gastrointestinal tract or gut. Arylalkylamine N-acetyltransferase (AANAT) is the key regulator of its biosynthesis. Melatonin in pineal is rhythmically produced with a nocturnal peak in synchronization with environmental light–dark cycle. A recent study on carp reported first that melatonin levels and intensity of a ~23 kDa AANAT protein in each gut segment also exhibit significant daily variations but, unlike pineal, show a peak at midday in all seasons. Extensive experimental studies ruled out direct role of light–dark conditions in determining temporal pattern of gut melatoninergic system in carp, and opened up possible role of environmental non-photic cue(s) as its synchronizer. Based on mammalian findings, physiological significance of gut-derived melatonin also appears unique because its actions at local levels sharing paracrine and/or autocrine functions have been emphasized. The purpose of this mini review is to summarize the existing data on the chronobiology and physiology of gut melatonin and to emphasize their relation with the same hormone derived in the pineal in vertebrates including fish. PMID:26257705

  17. The protective effect of melatonin against brain oxidative stress and hyperlocomotion in a rat model of mania induced by ouabain.

    PubMed

    Souza, Leandro C; Wilhelm, Ethel Antunes; Bortolatto, Cristiani Folharini; Nogueira, Cristina Wayne; Boeira, Silvana P; Jesse, Cristiano R

    2014-09-01

    This study was designed to investigate the protective effect of melatonin in a preclinical animal model of mania induced by ouabain (OUA). Male Wistar rats were pretreated with melatonin (5 or 20mg/kg; intraperitoneal, i.p.) for seven days or with the mood stabilizer lithium chloride (positive control) (45 mg/kg, per oral, p.o.). One day after the last dose, animals received an intracerebroventricular (i.c.v.) injection of OUA (5μl, 10(-5)M), a Na(+)K(+)ATPase-inhibiting compound. Locomotor activity was assessed in the open-field test (OFT). The levels of reactive species (RS), protein carbonyl (PC) and non-protein thiols (NPSH), as well as the activities of the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured in the cerebral cortex and hippocampus of rats. OUA markedly increased the locomotor activity in the OFT, and the pretreatment with melatonin or lithium chloride prevented this effect. Melatonin treatment (similar to lithium) was also effective in preventing the following alterations elicited by OUA: increase of RS and PC levels; depletion of NPSH levels; increase of SOD activity; and inhibition of CAT and GPx activities. Moreover, we found that brain oxidative stress and behavioural alterations elicited by OUA were significantly correlated. Our study showed that Melatonin, similarly to lithium, protected against OUA-induced brain oxidative stress and hyperlocomotion in rats. Thus, our findings reinforce the notion that oxidative stress may play an important role in the manic-like behavioural. Therefore, we indicate that melatonin has antimanic-like action, suggesting a potential role for this substance in the pharmacological management of Bipolar disorder.

  18. Expression of melatonin receptors in arteries involved in thermoregulation

    SciTech Connect

    Viswanathan, M.; Laitinen, J.T.; Saavedra, J.M. )

    1990-08-01

    Melatonin binding sites were localized and characterized in the vasculature of the rat by using the melatonin analogue 2-(125I)iodomelatonin (125I-melatonin) and quantitative in vitro autoradiography. The expression of these sites was restricted to the caudal artery and to the arteries that form the circle of Willis at the base of the brain. The arterial 125I-melatonin binding was stable, saturable, and reversible. Saturation studies revealed that the binding represented a single class of high-affinity binding sites with a dissociation constant (Kd) of 3.4 x 10(-11) M in the anterior cerebral artery and 1.05 x 10(-10) M in the caudal artery. The binding capacities (Bmax) in these arteries were 19 and 15 fmol/mg of protein, respectively. The relative order of potency of indoles for inhibition of 125I-melatonin binding at these sites was typical of a melatonin receptor: 2-iodomelatonin greater than melatonin greater than N-acetylserotonin much much greater than 5-hydroxytryptamine. Norepinephrine-induced contraction of the caudal artery in vitro was significantly prolonged and potentiated by melatonin in a concentration-dependent manner, suggesting that these arterial binding sites are functional melatonin receptors. Neither primary steps in smooth muscle contraction (inositol phospholipid hydrolysis) nor relaxation (adenylate cyclase activation) were affected by melatonin. Melatonin, through its action on the tone of these arteries, may cause circulatory adjustments in these arteries, which are believed to be involved in thermoregulation.

  19. The Protective Effects of Exogenous Melatonin on Nicotine-induced Changes in Mouse Ovarian Follicles

    PubMed Central

    Mohammadghasemi, Fahimeh; Jahromi, Sina Khajeh; Hajizadeh, Hadi; Homafar, Mohammad Amin; Saadat, Nazanin

    2012-01-01

    Background Nicotine exposure causes impaired fertility and ovarian dysfunction. The aim of this study was to investigate the possible protective role of melatonin, which is known as an antioxidant agent on altered ovarian functions upon nicotine exposure. Methods A total of 32 female adult NMRI mice were divided randomly into four groups (n = 8). The control group received vehicle, while group 2 received nicotine (40 µg/kg) for 15 days and group 3 melatonin (10 mg/kg) for 5 days. Group 4 received both nicotine (40 µg/kg) and melatonin (10 mg/kg) for the same periods. All animals were treated intraperitoneally. After autopsy on the 16th day, histopathological and morphometrical examinations were performed and serum estradiol concentrations were measured. The data were analyzed using ANOVA and Tukey post hoc test. A value of p < 0.05 was considered significant. Results Nicotine significantly reduced the number of pre-antral and antral follicles, as well as estradiol concentration compared to the control group (p < 0.05). However, the decrease in the number of primordial follicles was not significant in the nicotine treated group. A significant increase in the atretic follicles were observed in group 2 compared to the control group (p < 0.05). Moreover, melatonin caused a marked normalization in the number of ovarian follicles and estradiol levels in group 4 compared to group 2. Conclusion The results from this study suggest that melatonin may have a protective effect against nicotine-induced ovarian changes on the number of different stages of follicle growth. PMID:23926539

  20. Guanine nucleotide-binding protein regulation of melatonin receptors in lizard brain

    SciTech Connect

    Rivkees, S.A.; Carlson, L.L.; Reppert, S.M. )

    1989-05-01

    Melatonin receptors were identified and characterized in crude membrane preparations from lizard brain by using {sup 125}I-labeled melatonin ({sup 125}I-Mel), a potent melatonin agonist. {sup 125}I-Mel binding sites were saturable; Scatchard analysis revealed high-affinity and lower affinity binding sites, with apparent K{sub d} of 2.3 {plus minus} 1.0 {times} 10{sup {minus}11} M and 2.06 {plus minus} 0.43 {times} 10{sup {minus}10} M, respectively. Binding was reversible and inhibited by melatonin and closely related analogs but not by serotonin or norepinephrine. Treatment of crude membranes with the nonhydrolyzable GTP analog guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)), significantly reduced the number of high-affinity receptors and increased the dissociation rate of {sup 125}I-Mel from its receptor. Furthermore, GTP({gamma}S) treatment of ligand-receptor complexes solubilized by Triton X-100 also led to a rapid dissociation of {sup 125}I-Mel from solubilized ligand-receptor complexes. Gel filtration chromatography of solubilized ligand-receptor complexes revealed two major peaks of radioactivity corresponding to M{sub r} > 400,000 and M{sub r} ca. 110,000. This elution profile was markedly altered by pretreatment with GTP({gamma}S) before solubilization; only the M{sub r} 110,000 peak was present in GTP({gamma}S)-pretreated membranes. The results strongly suggest that {sup 125}I-mel binding sites in lizard brain are melatonin receptors, with agonist-promoted guanine nucleotide-binding protein (G protein) coupling and that the apparent molecular size of receptors uncoupled from G proteins is about 110,000.

  1. Melatonin membrane receptors in peripheral tissues: Distribution and functions

    PubMed Central

    Slominski, Radomir M.; Reiter, Russel J.; Schlabritz-Loutsevitch, Natalia; Ostrom, Rennolds S.; Slominski, Andrzej T.

    2012-01-01

    Many of melatonin’s actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes. PMID:22245784

  2. Melatonin enhances vertical bone augmentation in rat calvaria secluded spaces

    PubMed Central

    Shino, Hiromichi; Hasuike, Akira; Arai, Yoshinori; Honda, Masaki; Isokawa, Keitaro

    2016-01-01

    Background Melatonin has many roles, including bone remodeling and osseointegration of dental implants. The topical application of melatonin facilitated bone regeneration in bone defects. We evaluated the effects of topical application of melatonin on vertical bone augmentation in rat calvaria secluded spaces. Material and Methods In total, 12 male Fischer rats were used and two plastic caps were fixed in the calvarium. One plastic cap was filled with melatonin powder and the other was left empty. Results Newly generated bone at bone defects and within the plastic caps was evaluated using micro-CT and histological sections. New bone regeneration within the plastic cap was increased significantly in the melatonin versus the control group. Conclusions Melatonin promoted vertical bone regeneration in rat calvaria in the secluded space within the plastic cap. Key words:Melatonin, bone regeneration, bone defects, secluded space, rat calvarium. PMID:26595835

  3. Evaluating the Oxidative Stress in Inflammation: Role of Melatonin

    PubMed Central

    Sánchez, Aroha; Calpena, Ana Cristina; Clares, Beatriz

    2015-01-01

    Oxygen is used by eukaryotic cells for metabolic transformations and energy production in mitochondria. Under physiological conditions, there is a constant endogenous production of intermediates of reactive oxygen (ROI) and nitrogen species (RNI) that interact as signaling molecules in physiological mechanisms. When these species are not eliminated by antioxidants or are produced in excess, oxidative stress arises. Oxidative stress can damage proteins, lipids, DNA, and organelles. It is a process directly linked to inflammation; in fact, inflammatory cells secrete a large number of cytokines and chemokines responsible for the production of ROI and RNI in phagocytic and nonphagocytic cells through the activation of protein kinases signaling. Currently, there is a wide variety of diseases capable of producing inflammatory manifestations. While, in the short term, most of these diseases are not fatal they have a major impact on life quality. Since there is a direct relationship between chronic inflammation and many emerging disorders like cancer, oral diseases, kidney diseases, fibromyalgia, gastrointestinal chronic diseases or rheumatics diseases, the aim of this review is to describe the use and role of melatonin, a hormone secreted by the pineal gland, that works directly and indirectly as a free radical scavenger, like a potent antioxidant. PMID:26225957

  4. Sleep-wake Cycle Assessment in Type 2 Diabetes and Salivary Melatonin Correlates

    NASA Astrophysics Data System (ADS)

    Cavalcanti, Paula Regina Aguiar

    The aim of this study was to analyze the sleep-wake cycle of T2DM subjects and compare it to healthy controls using the nonparametric approach and to assess the changes in the circadian and homeostatic control of the sleep-wake cycle in type 2 diabetic (T2DM) and correlate it with melatonin concentration. The sample consisted of 21 subjects with diagnosis of T2DM for more than a year and 21 healthy controls matched for gender and age. Subjects were assessed using the Beck's Depression Inventory (BDI), the Apnea Risk Evaluation System (ARES), hemoglobin A1c (HbA1c), actigraphy and melatonin levels. The findings revealed that T2DM subjects demonstrate lower IS (p=.03), higher IV (p=.046) and lower rhythm amplitude (p=.02) when compared to healthy controls. Mean melatonin concentrations collected at bed time were significantly lower in the diabetic subjects than that of controls (11.7+/-7.27 pg/ml vs. 24.13+/-10.80pg/ml; p<.01). Actigraphic analysis during the wake phase demonstrated that diabetic subjects showed lower levels of activity (p=.02). Additionally, there was a significant difference decrease in sleep duration (p=.03), efficiency (p=.02); and higher activity counts during the sleep phase (p=.02) in the diabetic group. Sleep efficiency was significantly correlated with melatonin collected two hours before bed time (rho=.61; p=.047). Additionally, there were significant inverse relationships between melatonin collected at two hours before bed time and latency (rho=-.87; p=.001), wake after sleep onset (rho=-.69; p=.02) and nocturnal activity (rho=-.67; p=.03). Latency was inversely correlated with melatonin collected at bed time (rho=-.69; p=.02). These findings suggest that T2DM presents disturbances in the homeostatic and circadian drives, mainly characterized by less consistency across days of the daily circadian signal, higher rhythm fragmentation and lower rhythm amplitude. In addition to the lower melatonin levels, the decrease in the amplitude of the

  5. Melatonin and its precursors scavenge nitric oxide

    SciTech Connect

    Noda, Y.; Mori, A.; Liburdy, R.; Packer, L.

    1998-12-01

    Nitric oxide (NO) scavenging activity of melatonin, N-acetyl-5-hydroxytryptamine, serotonin, 5-hydroxytryptophan and L-tryptophan was examined by the Griess reaction using flow injection analysis. 1-Hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene(NOC-7) was used as NO generator. The Griess reagent stoichiometrically reacts with NO2-, which was converted by a cadmium-copper reduction column from the stable end products of NO oxidation. Except for tryptophan, all the compounds examined scavenged NO in a dose-dependent manner. Melatonin, which has a methoxy group in the 5-position and an acetyl side chain, exhibited the most potent scavenging activity among the compounds tested. Serotonin, N-acetyl-5-hydroxytryptamine, and 5-hydroxytryptophan, respectively, showed moderate scavenging activity compared to melatonin. Tryptophan, which has neither a methoxy nor a hydroxyl group in the 5-position, exhibited the least NO scavenging activity.

  6. Melatonin: Bone Metabolism in Oral Cavity

    PubMed Central

    López-Martínez, Fanny; Olivares Ponce, Patricia N.; Guerra Rodríguez, Miriam; Martínez Pedraza, Ricardo

    2012-01-01

    Throughout life, bone tissue undergoes a continuous process of resorption and formation. Melatonin, with its antioxidant properties and its ability to detoxify free radicals, as suggested by Conconi et al. (2000) may interfere in the osteoclast function and thereby inhibit bone resorption, as suggested by Schroeder et al. (1981). Inhibition of bone resorption may be enhanced by a reaction of indoleamine in osteoclastogenesis. That it has been observed melatonin, at pharmacological doses, decrease bone mass resorption by suppressing through down regulation of the RANK-L, as suggested by Penarrocha Diago et al. (2005) and Steflik et al. (1994). These data point an osteogenic effect towards that may be of melatonin of clinical importance, as it could be used as a therapeutic agent in situations in which would be advantageous bone formation, such as in the treatment of fractures or osteoporosis or their use as, a bioactive surface on implant as suggested by Lissoni et al. (1991). PMID:22927853

  7. Melatonin receptors: latest insights from mouse models

    PubMed Central

    Tosini, Gianluca; Owino, Sharon; Guillame, Jean-Luc; Jockers, Ralf

    2014-01-01

    Summary Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications towards type 2 diabetes development, visual functions, sleep disturbances and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. PMID:24903552

  8. Circadian rhythms of photorefractory siberian hamsters remain responsive to melatonin.

    PubMed

    Butler, Matthew P; Paul, Matthew J; Turner, Kevin W; Park, Jin Ho; Driscoll, Joseph R; Kriegsfeld, Lance J; Zucker, Irving

    2008-04-01

    Short day lengths increase the duration of nocturnal melatonin (Mel) secretion, which induces the winter phenotype in Siberian hamsters. After several months of continued exposure to short days, hamsters spontaneously revert to the spring-summer phenotype. This transition has been attributed to the development of refractoriness of Mel-binding tissues, including the suprachiasmatic nucleus (SCN), to long-duration Mel signals. The SCN of Siberian hamsters is required for the seasonal response to winter-like Mel signals, and becomes refractory to previously effective long-duration Mel signals restricted to this area. Acute Mel treatment phase shifts circadian locomotor rhythms of photosensitive Siberian hamsters, presumably by affecting circadian oscillators in the SCN. We tested whether seasonal refractoriness of the SCN to long-duration Mel signals also renders the circadian system of Siberian hamsters unresponsive to Mel. Males manifesting free-running circadian rhythms in constant dim red light were injected with Mel or vehicle for 5 days on a 23.5-h T-cycle beginning at circadian time 10. Mel injections caused significantly larger phase advances in activity onset than did the saline vehicle, but the magnitude of phase shifts to Mel did not differ between photorefractory and photosensitive hamsters. Similarly, when entrained to a 16-h light/8-h dark photocycle, photorefractory and photosensitive hamsters did not differ in their response to Mel injected 4 h before the onset of the dark phase. Activity onset in Mel-injected hamsters was masked by light but was revealed to be significantly earlier than in vehicle-injected hamsters upon transfer to constant dim red light. The acute effects of melatonin on circadian behavioral rhythms are preserved in photorefractory hamsters.

  9. Melatonin: an ancient molecule that makes oxygen metabolically tolerable.

    PubMed

    Manchester, Lucien C; Coto-Montes, Ana; Boga, Jose Antonio; Andersen, Lars Peter H; Zhou, Zhou; Galano, Annia; Vriend, Jerry; Tan, Dun-Xian; Reiter, Russel J

    2015-11-01

    Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary as photosynthesis is associated with the generation of toxic-free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple nonsulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its

  10. MT(1) melatonin receptor overexpression enhances the growth suppressive effect of melatonin in human breast cancer cells.

    PubMed

    Yuan, Lin; Collins, April R; Dai, Jun; Dubocovich, Margarita L; Hill, Steven M

    2002-06-28

    Melatonin inhibits the proliferation of estrogen receptor alpha (ERalpha)-positive (MCF-7), but not ERalpha-negative (MDA-MB-231) breast cancer cells. Here, we assessed the effect of MT(1) melatonin receptor stable overexpression in MCF-7 and MDA-MB-231 breast cancer cells on the growth-suppressive effects of melatonin. Parental and vector-transfected MCF-7 cells demonstrated a modest, but significant, growth-suppressive response to melatonin; however, melatonin treatment of MT(1)-transfected MCF-7 cells resulted in significantly enhanced growth-suppression. This response was blocked by an MT1/MT2 melatonin receptor antagonist. Interestingly, MT(1)-overexpression did not induce a melatonin-sensitive phenotype in melatonin-insensitive MDA-MB-231 cells. Finally, Northern blot analysis demonstrated an enhanced inhibition of ERalpha mRNA expression and an enhanced induction of pancreatic spasmolytic polypeptide (pS2) by melatonin in MT(1)-transfected MCF-7 cells relative to vector-transfected MCF-7 cells. These data suggest the involvement of the MT(1) melatonin receptor in mediation of melatonin effects on growth-suppression and gene-modulation in breast cancer cells.

  11. EEG and ocular correlates of circadian melatonin phase and human performance decrements during sleep loss

    NASA Technical Reports Server (NTRS)

    Cajochen, C.; Khalsa, S. B.; Wyatt, J. K.; Czeisler, C. A.; Dijk, D. J.

    1999-01-01

    The aim of this study was to quantify the associations between slow eye movements (SEMs), eye blink rate, waking electroencephalogram (EEG) power density, neurobehavioral performance, and the circadian rhythm of plasma melatonin in a cohort of 10 healthy men during up to 32 h of sustained wakefulness. The time course of neurobehavioral performance was characterized by fairly stable levels throughout the first 16 h of wakefulness followed by deterioration during the phase of melatonin secretion. This deterioration was closely associated with an increase in SEMs. Frontal low-frequency EEG activity (1-7 Hz) exhibited a prominent increase with time awake and little circadian modulation. EEG alpha activity exhibited circadian modulation. The dynamics of SEMs and EEG activity were phase locked to changes in neurobehavioral performance and lagged the plasma melatonin rhythm. The data indicate that frontal areas of the brain are more susceptible to sleep loss than occipital areas. Frontal EEG activity and ocular parameters may be used to monitor and predict changes in neurobehavioral performance associated with sleep loss and circadian misalignment.

  12. Tumor suppression in mice lacking GABARAP, an Atg8/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death

    PubMed Central

    Salah, F S; Ebbinghaus, M; Muley, V Y; Zhou, Z; Al-Saadi, K R D; Pacyna-Gengelbach, M; O'Sullivan, G A; Betz, H; König, R; Wang, Z-Q; Bräuer, R; Petersen, I

    2016-01-01

    GABARAP belongs to an evolutionary highly conserved gene family that has a fundamental role in autophagy. There is ample evidence for a crosstalk between autophagy and apoptosis as well as the immune response. However, the molecular details for these interactions are not fully characterized. Here, we report that the ablation of murine GABARAP, a member of the Atg8/LC3 family that is central to autophagosome formation, suppresses the incidence of tumor formation mediated by the carcinogen DMBA and results in an enhancement of the immune response through increased secretion of IL-1β, IL-6, IL-2 and IFN-γ from stimulated macrophages and lymphocytes. In contrast, TGF-β1 was significantly reduced in the serum of these knockout mice. Further, DMBA treatment of these GABARAP knockout mice reduced the cellularity of the spleen and the growth of mammary glands through the induction of apoptosis. Gene expression profiling of mammary glands revealed significantly elevated levels of Xaf1, an apoptotic inducer and tumor-suppressor gene, in knockout mice. Furthermore, DMBA treatment triggered the upregulation of pro-apoptotic (Bid, Apaf1, Bax), cell death (Tnfrsf10b, Ripk1) and cell cycle inhibitor (Cdkn1a, Cdkn2c) genes in the mammary glands. Finally, tumor growth of B16 melanoma cells after subcutaneous inoculation was inhibited in GABARAP-deficient mice. Together, these data provide strong evidence for the involvement of GABARAP in tumorigenesis in vivo by delaying cell death and its associated immune-related response. PMID:27124579

  13. Tumor suppression in mice lacking GABARAP, an Atg8/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death.

    PubMed

    Salah, F S; Ebbinghaus, M; Muley, V Y; Zhou, Z; Al-Saadi, K R D; Pacyna-Gengelbach, M; O'Sullivan, G A; Betz, H; König, R; Wang, Z-Q; Bräuer, R; Petersen, I

    2016-01-01

    GABARAP belongs to an evolutionary highly conserved gene family that has a fundamental role in autophagy. There is ample evidence for a crosstalk between autophagy and apoptosis as well as the immune response. However, the molecular details for these interactions are not fully characterized. Here, we report that the ablation of murine GABARAP, a member of the Atg8/LC3 family that is central to autophagosome formation, suppresses the incidence of tumor formation mediated by the carcinogen DMBA and results in an enhancement of the immune response through increased secretion of IL-1β, IL-6, IL-2 and IFN-γ from stimulated macrophages and lymphocytes. In contrast, TGF-β1 was significantly reduced in the serum of these knockout mice. Further, DMBA treatment of these GABARAP knockout mice reduced the cellularity of the spleen and the growth of mammary glands through the induction of apoptosis. Gene expression profiling of mammary glands revealed significantly elevated levels of Xaf1, an apoptotic inducer and tumor-suppressor gene, in knockout mice. Furthermore, DMBA treatment triggered the upregulation of pro-apoptotic (Bid, Apaf1, Bax), cell death (Tnfrsf10b, Ripk1) and cell cycle inhibitor (Cdkn1a, Cdkn2c) genes in the mammary glands. Finally, tumor growth of B16 melanoma cells after subcutaneous inoculation was inhibited in GABARAP-deficient mice. Together, these data provide strong evidence for the involvement of GABARAP in tumorigenesis in vivo by delaying cell death and its associated immune-related response. PMID:27124579

  14. Enhanced secretion of glucosyltransferase by changes in potassium ion concentrations is accompanied by an altered pattern of membrane fatty acids in Streptococcus salivarius.

    PubMed Central

    Markevics, L J; Jacques, N A

    1985-01-01

    Growth of Streptococcus salivarius ATCC 25975 in a Na+-based medium containing 1 to 50 mM K+ enhanced extracellular glucosyltransferase production by 3.7-fold over the level of enzyme found in a K+-based medium containing 184 mM K+. Enzyme synthesis and secretion were further enhanced in a nonlinear manner with respect to the concentration of K+ in the medium when cells were cultured from an inoculum grown in the presence of 1 mM K+. This concentration of K+ was the minimum required to maintain a near-maximum growth rate for S. salivarius in medium where K+ was limited. A maximum sevenfold stimulation of glucosyltransferase production occurred at 18 mM K+ under these conditions. Analysis of the total membrane lipids showed that the composition of octadecanoic acid increased with decreasing K+ concentration essentially at the expense of the octadecenoic acid moiety. Extracellular glucosyltransferase production was found to be directly related to the ratio of these two fatty acids. Similar confirmatory results over a greater range of enzyme production were obtained with nonproliferating cell suspensions. PMID:3156125

  15. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats.

    PubMed

    Chaudagar, K K; Viczenczova, C; Szeiffova Bacova, B; Egan Benova, T; Barancik, M; Tribulova, N

    2016-09-19

    We aimed to explore the effects of melatonin and n-3 polyunsaturated fatty acids (PUFA) supplementation on plasma and aortic nitric oxide (NO) levels in isoproterenol (Iso) affected spontaneously hypertensive (SHR) and Wistar rats. Untreated control rats were compared with Iso injected (118 mg/kg, s.c.) rats, and Iso injected plus supplemented with melatonin (10 mg/kg, p.o.) or PUFA (1.68 g/kg, p.o.) for two months. Plasma and aortic basal, L-NAME inhibited, adrenaline and acetylcholine stimulated NO were determined using Griess method. Plasma NO levels were lower in SHR versus Wistar rats. Iso decreased NO in Wistar while not in SHR. PUFA but not melatonin intake of Iso treated SHR increased plasma NO along with a decrease in systolic blood pressure. Basal aortic NO level was higher in SHR than Wistar rats and not altered by Iso. Intake of melatonin increased but PUFA decreased basal NO levels in Wistar+Iso and did not affect in SHR+Iso rats. Acetylcholine and adrenaline induced aortic NO release was significantly increased in Wistar+Iso but not SHR+Iso group. Melatonin intake increased Ach induced aortic NO in Wistar+Iso and SHR+Iso groups, whereas there was no effect of PUFA intake. Findings suggest that PUFA modulates plasma and melatonin aortic NO levels of isoproterenol affected rats in a strain-dependent manner. PMID:27643932

  16. Melatonin pathway genes and breast cancer risk among Chinese women.

    PubMed

    Deming, Sandra L; Lu, Wei; Beeghly-Fadiel, Alicia; Zheng, Ying; Cai, Qiuyin; Long, Jirong; Shu, Xiao Ou; Gao, Yu-Tang; Zheng, Wei

    2012-04-01

    Previous studies suggest that melatonin may act on cancer growth through a variety of mechanisms, most notably by direct anti-proliferative effects on breast cancer cells and via interactions with the estrogen pathway. Three genes are largely responsible for mediating the downstream effects of melatonin: melatonin receptors 1a and 1b (MTNR1a and MTNR1b), and arylalkylamine N-acetyltransferase (AANAT). It is hypothesized that genetic variation in these genes may lead to altered protein production or function. To address this question, we conducted a comprehensive evaluation of the association between common single nucleotide polymorphisms (SNPs) in the MTNR1a, MTNR1b, and AANAT genes and breast cancer risk among 2,073 cases and 2,083 controls, using a two-stage analysis of genome-wide association data among women of the Shanghai Breast Cancer Study. Results demonstrate two SNPs were consistently associated with breast cancer risk across both study stages. Compared with MTNR1b rs10765576 major allele carriers (GG or GA), a decreased risk of breast cancer was associated with the AA genotype (OR = 0.78, 95% CI = 0.62-0.97, P = 0.0281). Although no overall association was seen in the combined analysis, the effect of MTNR1a rs7665392 was found to vary by menopausal status (P-value for interaction = 0.001). Premenopausal women with the GG genotype were at increased risk for breast cancer compared with major allele carriers (TT or TG) (OR = 1.57, 95% CI = 1.07-2.31, P = 0.020), while postmenopausal women were at decreased risk (OR = 0.58, 95% 0.36-0.95, P = 0.030). No significant breast cancer associations were found for variants in the AANAT gene. These results suggest that common genetic variation in the MTNR1a and 1b genes may contribute to breast cancer susceptibility, and that associations may vary by menopausal status. Given that multiple variants in high linkage disequilibrium with MTNR1b rs76653292 have been associated with altered function or expression of insulin

  17. A label-free differential proteomics analysis reveals the effect of melatonin on promoting fruit ripening and anthocyanin accumulation upon postharvest in tomato.

    PubMed

    Sun, Qianqian; Zhang, Na; Wang, Jinfang; Cao, Yunyun; Li, Xingsheng; Zhang, Haijun; Zhang, Lei; Tan, Dun-Xian; Guo, Yang-Dong

    2016-09-01

    To better understand the function of melatonin in tomato fruit ripening and quality improvement, a label-free quantitation method was used to investigate the proteins that differ between the control (CK) and 50 μm melatonin treatment (M50) fruits. Proteomics data identified 241 proteins that were significantly influenced by melatonin. These proteins were involved in several ripening-related pathways, including cell wall metabolism, oxidative phosphorylation, carbohydrate, and fatty acid metabolism. Moreover, the application of exogenous melatonin increased eight proteins that are related to anthocyanin accumulation during fruit ripening. Additionally, the affected protein levels correlated with the corresponding gene transcript levels. Further, the total anthocyanin content from M50 increased by 52%, 48%, and 50% at 5, 8, and 13 DAT (day after melatonin treatment), respectively. The melatonin-mediated promotion of fruit ripening and quality might be due to the altered proteins involved in processes associated with ripening. In this work, we indicated that a senescence-related protein was downregulated in the M50 fruit, while a cell apoptosis inhibitor (API5) protein was upregulated. In addition, peroxidases (POD9, POD12, peroxidase p7-like) and catalase (CAT3) significantly increased in the M50 fruits. Based on the previous studies and our data, we inferred that melatonin might be positively related to fruit ripening but negatively related to fruit senescence. This research provides insights into the physiological and molecular mechanisms underlying melatonin-mediated fruit ripening as well as the anthocyanin formation process in tomato fruit at the protein concentration level, and we reveal possible candidates for regulation of anthocyanin formation during fruit ripening.

  18. Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis.

    PubMed

    Surendran, Kameswaran; Schiavi, Susan; Hruska, Keith A

    2005-08-01

    beta-Catenin functions as a transducer of Wnt signals to the nucleus, where it interacts with the T cell factor (TCF) family of DNA binding proteins to regulate gene expression. On the basis of the genes regulated by beta-catenin and TCF in various biologic settings, two predicted functions of beta-catenin/TCF-dependent transcription are to mediate the loss of epithelial polarity and to promote fibroblast activities, such as the increased synthesis of fibronectin during chronic renal disease. These predictions were tested by determination of the expression and function of an inhibitor of Wnt signaling, secreted frizzled-related protein 4 (sFRP4), during renal tubular epithelial injury initiated by unilateral ureteral obstruction (UUO). Despite increased sFRP4 gene expression in perivascular regions of injured kidneys, total sFRP4 protein levels decreased after injury. The decreased sFRP4 protein levels after UUO accompanied increased Wnt-dependent beta-catenin signaling in tubular epithelial and interstitial cells, along with increased expression of markers of fibrosis. Administration of recombinant sFRP4 protein caused a reduction in tubular epithelial beta-catenin signaling and suppressed the progression of renal fibrosis, as evidenced by a partial maintenance of E-cadherin mRNA expression and a reduction in the amount of fibronectin and alpha-smooth muscle actin proteins. Furthermore, recombinant sFRP4 reduced the number of myofibroblasts, a central mediator of fibrosis. It is concluded that beta-catenin signaling is activated in tubular epithelial and interstitial cells after renal injury, and recombinant sFRP4 can interfere with epithelial de-differentiation and with fibroblast differentiation and function during progression of renal fibrosis.

  19. Giardia duodenalis stimulates partial maturation of bovine dendritic cells associated with altered cytokine secretion and induction of T-cell proliferation.

    PubMed

    Grit, G H; Devriendt, B; Van Coppernolle, S; Geurden, T; Hope, J; Vercruysse, J; Cox, E; Geldhof, P; Claerebout, E

    2014-04-01

    Giardia duodenalis is an important intestinal parasite in animals and humans. The role of dendritic cells (DC) in the initiation of the immune response against G. duodenalis is poorly documented. The aim of this study was to test the hypothesis that G. duodenalis interferes with bovine DC function. Therefore, the effect of trophozoites and excretion/secretion products on bovine monocyte-derived dendritic cells (MoDC) was investigated. We assessed MoDC maturation and cytokine production of G. duodenalis-stimulated MoDC and the ability of these MoDC to take up antigen and induce lymphocyte proliferation. Little or no upregulation of maturation markers CD40 and CD80 was measured, but MHCII expression was increased after stimulation with low parasite concentrations. A dose-dependent decrease in ovalbumin uptake was observed in G. duodenalis-stimulated MoDC. In addition, stimulated MoDC induced proliferation of CD3(-) , γδ-T-cells and TCRαβ(+) CD4(+) and CD8(+) T-cells. Increased transcription of TGF-β was shown in CD4(+) T cells, and increased TNF-α, TGF-β, IL-10 and IL-4 were seen in γδ-T-cells. We found no evidence that G. duodenalis has a regulatory or inhibitory effect on bovine MoDC. MoDC stimulated with G. duodenalis are functionally active and able to induce proliferation of T cells that produce both pro- and anti-inflammatory cytokines.

  20. Protection against 1,2-di-methylhydrazine-induced systemic oxidative stress and altered brain neurotransmitter status by probiotic Escherichia coli CFR 16 secreting pyrroloquinoline quinone.

    PubMed

    Pandey, Sumeet; Singh, Ashish; Chaudhari, Nirja; Nampoothiri, Laxmipriya P; Kumar, G Naresh

    2015-05-01

    Exposure to environmental pollutant 1,2-dimethylhydrazine (DMH) is attributed to systemic oxidative stress and is known to cause neurotropic effect by altering brain neurotransmitter status. Probiotics are opted as natural therapeutic against oxidative stress and also have the ability to modulate gut-brain axis. Pyrroloquinoline quinone (PQQ) is water-soluble, heat-stable antioxidant molecule. Aim of the present study was to evaluate the antioxidant efficacy of PQQ-producing probiotic E. coli CFR 16 on DMH-induced systemic oxidative damage and altered neurotransmitter status in rat brain. Adult virgin Charles Forster rats (200-250 g) were given DMH dose (25 mg/kg body weight, s.c.) for 8 weeks. Blood lipid peroxidation levels exhibited a marked increase while antioxidant enzyme activities of superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase and glutathione peroxidase were found to be reduced in DMH-treated rats. Likewise, brain serotonin and norepinephrine levels displayed a significant decrease, whereas epinephrine levels demonstrated a marked increase in brain of these rats. PQQ-producing E. coli CFR 16 supplementation reduced systemic oxidative stress and also restored brain neurotransmitter status. However, E. coli CFR 16 did not show any effect on these parameters. In contrast, E. coli CFR 16:: vgb-gfp and E. coli CFR 16:: vgb-gfp vector exhibited some degree of protection again oxidative stress but they were not able to modulate neurotransmitter levels. In conclusion, continuous and sustained release of PQQ by probiotic E. coli in rat intestine ameliorates systemic oxidative stress and restored brain neurotransmitter levels.

  1. Renal melatonin excretion in sheep is enhanced by water diuresis.

    PubMed

    Valtonen, M; Laitinen, J T; Eriksson, L

    1993-09-01

    Diurnal variation in blood melatonin levels and renal melatonin excretion was monitored in five ewes by blood sampling and quantitative urine collection at 2-h intervals. A typical secretory pattern of melatonin was seen both in blood and urine levels and in the renal excretion of melatonin. Serum melatonin levels increased from daytime values of approximately 200 pmol/l to a mean of 800 pmol/l during darkness. Urine flow rate and urine osmolality did not show any clear diurnal rhythm. To examine whether urine flow rate affects renal melatonin excretion at night, urine was collected in three consecutive 30-min fractions, and blood was sampled in the middle of each urine collection period when the sheep were in normal water balance or after hydration. Hydration increased urine flow rate over sixfold and decreased urine osmolality well below plasma osmolality. Glomerular filtration rate, measured as creatinine clearance, did not change. Serum melatonin concentrations did not differ between hydrated and non-hydrated sheep. However, urinary melatonin excretion was 1.1 +/- 0.3 (S.E.M.) pmol/min at midnight in normal water balance, and significantly higher (2.6 +/- 0.4 pmol/min) in the hydrated state. In this study, the validity of urinary melatonin determinations as an indicator of pineal function was confirmed in normal water balance. In addition, our results suggest that a high tubular fluid load during diuresis increases urinary melatonin excretion because of decreased tubular reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Melatonin attenuates postharvest physiological deterioration of cassava storage roots.

    PubMed

    Ma, Qiuxiang; Zhang, Ting; Zhang, Peng; Wang, Zhen-Yu

    2016-05-01

    Melatonin reportedly increases abiotic and biotic stress tolerance in plants, but information on its in vivo effects during postharvest physiological deterioration (PPD) in cassava is limited. In this study, we investigated the effect of melatonin in regulating cassava PPD. Treatment with 500 mg/L melatonin significantly delayed cassava PPD and reduced the accumulation of hydrogen peroxide (H2O2) while increasing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR), but not ascorbate peroxidase (APX). Transcript analysis further showed that expression of copper/zinc SOD (MeCu/ZnSOD), MeCAT1, glutathione peroxidase (MeGPX), peroxidase 3 (MePX3), and glutathione S-transferases (MeGST) was higher in cassava roots sliced treated with 500 mg/L melatonin than in those not exposed to exogenous melatonin. These data demonstrate that melatonin delays cassava PPD by directly or indirectly maintaining homoeostasis of cellular reactive oxygen species (ROS). We also found that accumulation of endogenous melatonin and the transcript levels of melatonin biosynthesis genes changed dynamically during the PPD process. This finding suggested that endogenous melatonin acts as a signal modulator for maintaining cassava PPD progression and that manipulation of melatonin biosynthesis genes through genetic engineering might prevent cassava root deterioration. PMID:26989849

  3. Several antioxidant pathways are involved in astrocyte protection by melatonin.

    PubMed

    Martín, Vanesa; Sainz, Rosa M; Antolín, Isaac; Mayo, Juan C; Herrera, Federico; Rodríguez, Carmen

    2002-11-01

    Neuroprotection provided by melatonin has been shown to be more relevant in vivo than in neuronal cultures. Given the role of astrocytes in neuronal support and protection, studies were initiated to elucidate the possible protective effect of the antioxidant melatonin against oxidative stress in these cells. Both low and high concentrations of melatonin were able to protect astrocytes with even higher efficiency than the known antioxidant glutathione (GSH). The mechanisms involved may be different for high (1 mm) and low (100 nm) concentrations of the indole. The GSH cycling appeared not to be involved in the protection at high doses. High doses of melatonin neither influenced GSH levels nor gene expression for the several antioxidant enzymes studied; thus, melatonin's protective effect was likely because of its free radical scavenging action in this case. However, melatonin concentrations in the nanomolar range require the presence of GSH to be effective. No increase in GSH synthesis was found, but low doses of melatonin increased gene expression and activity of glutathione peroxidase. As this enzyme requires GSH as substrate to be active, this may be the reason why the effect of this melatonin concentration is GSH dependent. In vivo, melatonin levels exhibit a wide range of concentrations with much lower levels in the blood and significantly higher concentrations in other body fluids and within cells. Thus, melatonin may normally function as an indirect and direct antioxidant in vivo.

  4. Melatonin attenuates postharvest physiological deterioration of cassava storage roots.

    PubMed

    Ma, Qiuxiang; Zhang, Ting; Zhang, Peng; Wang, Zhen-Yu

    2016-05-01

    Melatonin reportedly increases abiotic and biotic stress tolerance in plants, but information on its in vivo effects during postharvest physiological deterioration (PPD) in cassava is limited. In this study, we investigated the effect of melatonin in regulating cassava PPD. Treatment with 500 mg/L melatonin significantly delayed cassava PPD and reduced the accumulation of hydrogen peroxide (H2O2) while increasing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR), but not ascorbate peroxidase (APX). Transcript analysis further showed that expression of copper/zinc SOD (MeCu/ZnSOD), MeCAT1, glutathione peroxidase (MeGPX), peroxidase 3 (MePX3), and glutathione S-transferases (MeGST) was higher in cassava roots sliced treated with 500 mg/L melatonin than in those not exposed to exogenous melatonin. These data demonstrate that melatonin delays cassava PPD by directly or indirectly maintaining homoeostasis of cellular reactive oxygen species (ROS). We also found that accumulation of endogenous melatonin and the transcript levels of melatonin biosynthesis genes changed dynamically during the PPD process. This finding suggested that endogenous melatonin acts as a signal modulator for maintaining cassava PPD progression and that manipulation of melatonin biosynthesis genes through genetic engineering might prevent cassava root deterioration.

  5. Neurobiological effects of melatonin as related to cancer.

    PubMed

    Hoang, Ba X; Shaw, David G; Pham, Phuong T; Levine, Stephen A

    2007-12-01

    Melatonin is a neurohormone naturally found in humans. Melatonin plays a role in maintaining sleep-wake rhythms; supplementation may help to regulate sleep disturbance that occur with jet lag, rotating shift-work and depression. Preliminary study of melatonin has shown potential for use in the treatment of epilepsy, tinnitus, migraine and neurodegenerative diseases. The latest publication in the Journal of Pineal Research by Edward Mills and colleagues has shown a compelling role of melatonin for the treatment of cancer. Melatonin's consistent relationship with cancer has been shown in many studies assessing links between shift work and cancer rates. High levels of melatonin have been linked to slower cancer progression. How melatonin affects cancer remains largely unclear. Although previous studies suggest different possible mechanisms, many of them are far distant from the primary physiological role of melatonin as a neurohormone. Conflicting studies are found on the role of melatonin in neurodegenerative diseases and cancer. In this article, we try to build and substantiate a neurobiological concept for the anticancer effects of melatonin. PMID:18090123

  6. Predominance of 2-hydroxymelatonin over melatonin in plants.

    PubMed

    Byeon, Yeong; Tan, Dun-Xian; Reiter, Russel J; Back, Kyoungwhan

    2015-11-01

    The cloning of the gene encoding melatonin 2-hydroxylase (M2H), which is responsible for the synthesis of 2-hydroxymelatonin, has expanded the study of melatonin metabolism in plants. Kinetic analysis of M2H enzymatic activity demonstrated that the catalytic efficiency of M2H is much higher than those of other melatonin biosynthetic enzymes such as serotonin N-acetyltransferase (SNAT) and N-acetylserotonin O-methyltransferase (ASMT), suggesting that melatonin metabolism is rapid in plants. To test this prediction, we selected 24 plant species belonging to 16 families and quantified the levels of melatonin and 2-hydroxymelatonin using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The melatonin levels in most of the species were <1 ng/g fresh weight (FW), while those in leaves from radish and feverfew were 3.5 and 3.3 ng/g FW, respectively. In contrast, the average levels of 2-hydroxymelatonin were much higher at 6.2 ng/g FW. The average ratio of 2-hydroxymelatonin to melatonin in plants was approximately 368:1, indicating that the accumulation of 2-hydroxymelatonin predominates over that of melatonin. These data were consistent with previous results on the kinetics of the corresponding enzymes, as well as with in vivo melatonin conversion data. Among several melatonin metabolites in plants, the most abundant metabolite was found to be 2-hydroxymelatonin (99%) followed by 4-hydroxymelatonin (0.05%), but 6-hydroxymelatonin was not detected in rice seedlings.

  7. Alcoholic fermentation induces melatonin synthesis in orange juice.

    PubMed

    Fernández-Pachón, M S; Medina, S; Herrero-Martín, G; Cerrillo, I; Berná, G; Escudero-López, B; Ferreres, F; Martín, F; García-Parrilla, M C; Gil-Izquierdo, A

    2014-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) is a molecule implicated in multiple biological functions. Its level decreases with age, and the intake of foods rich in melatonin has been considered an exogenous source of this important agent. Orange is a natural source of melatonin. Melatonin synthesis occurs during alcoholic fermentation of grapes, malt and pomegranate. The amino acid tryptophan is the precursor of all 5-methoxytryptamines. Indeed, melatonin appears in a shorter time in wines when tryptophan is added before fermentation. The aim of the study was to measure melatonin content during alcoholic fermentation of orange juice and to evaluate the role of the precursor tryptophan. Identification and quantification of melatonin during the alcoholic fermentation of orange juice was carried out by UHPLC-QqQ-MS/MS. Melatonin significantly increased throughout fermentation from day 0 (3.15 ng/mL) until day 15 (21.80 ng/mL) reaching larger amounts with respect to other foods. Melatonin isomer was also analysed, but its content remained stable ranging from 11.59 to 14.18 ng/mL. The enhancement of melatonin occurred mainly in the soluble fraction. Tryptophan levels significantly dropped from 13.80 mg/L (day 0) up to 3.19 mg/L (day 15) during fermentation. Melatonin was inversely and significantly correlated with tryptophan (r = 0.907). Therefore, the enhancement in melatonin could be due to both the occurrence of tryptophan and the new synthesis by yeast. In summary, the enhancement of melatonin in novel fermented orange beverage would improve the health benefits of orange juice by increasing this bioactive compound.

  8. Twenty-four-hour patterns of pineal melatonin and pituitary and plasma prolactin in male rats under 'natural' and artificial lighting conditions.

    PubMed

    Laakso, M L; Porkka-Heiskanen, T; Alila, A; Peder, M; Johansson, G

    1988-09-01

    Natural lighting differs from usual artificial lighting mainly as follows: it has larger spectral composition, fluctuations of intensity during the day, higher intensity levels during the night (moonlight, starlight), and gradual changes of illuminance at dawn and dusk. The present experiment was performed in order to study whether these features of lighting affect the 24-hour patterns of melatonin and prolactin in male rats. The rats were kept 7 days in 'natural' lighting (sunlight through windows) or in artificial lighting (cool white fluorescent lamps) of similar periodicities (13/11 h light/dark). The samples were collected at 3-hour intervals during a 24-hour period. Pineal melatonin contents, pituitary prolactin contents, and plasma prolactin concentrations were measured radioimmunologically. The nocturnal pineal melatonin contents were higher and the daytime contents lower in natural than in artificial lighting conditions. A corresponding 'strengthening of rhythm' of prolactin was found in natural lighting. A reason for the higher amplitude variation of melatonin in the natural lighting conditions may be the gradual changes of illuminance at dawn and dusk. The different pituitary and plasma prolactin patterns of the rats kept in the two lighting conditions might partly be explained by a stimulatory effect of melatonin on the production and secretion of prolactin, but other regulatory factors had to be involved, too.

  9. Effects of lights of different color temperature on the nocturnal changes in core temperature and melatonin in humans.

    PubMed

    Morita, T; Tokura, H

    1996-09-01

    A variety of types of artificial illumination has recently become available, differing in the quality of illumination and range of color temperature. In our previous studies we found that in subjects with normal color vision the nocturnal fall in core temperature and the increase of urinary melatonin excretion were suppressed by bright blue or green light, but not by bright red or dim lights. The aim of our present study was to examine from the view point of chronobiology whether the lights of different color temperature often used in everyday life may affect core temperature and urinary melatonin secretion differently. Experiments were carried out on five subjects with normal color vision. They were exposed for 5 hr (from 21:00 h to 2:00 h) to two kinds of bright (1000 lx) light of different color temperature (6500 K, 3000 K) with dim (50 lx) light as a control; after exposure they slept in darkness. Our main results were as follows: The light with a high color temperature of 6500 K more strongly suppressed the nocturnal fall of the core temperature and the nocturnal increase of melatonin secretion than the light with a low color temperature of 3000 K. This difference was particularly evident for core temperature during the sleep period following experimental illumination.

  10. Fundamental Issues of Melatonin-Mediated Stress Signaling in Plants

    PubMed Central

    Shi, Haitao; Chen, Keli; Wei, Yunxie; He, Chaozu

    2016-01-01

    As a widely known hormone in animals, melatonin (N-acetyl-5-methoxytryptamine) has been more and more popular research topic in various aspects of plants. To summarize the these recent advances, this review focuses on the regulatory effects of melatonin in plant response to multiple abiotic stresses including salt, drought, cold, heat and oxidative stresses and biotic stress such as pathogen infection. We highlight the changes of endogenous melatonin levels under stress conditions, and the extensive metabolome, transcriptome, and proteome reprogramming by exogenous melatonin application. Moreover, melatonin-mediated stress signaling and underlying mechanism in plants are extensively discussed. Much more is needed to further study in detail the mechanisms of melatonin-mediated stress signaling in plants. PMID:27512404

  11. Melatonin Signaling Controls Circadian Swimming Behavior in Marine Zooplankton

    PubMed Central

    Tosches, Maria Antonietta; Bucher, Daniel; Vopalensky, Pavel; Arendt, Detlev

    2014-01-01

    Summary Melatonin, the “hormone of darkness,” is a key regulator of vertebrate circadian physiology and behavior. Despite its ubiquitous presence in Metazoa, the function of melatonin signaling outside vertebrates is poorly understood. Here, we investigate the effect of melatonin signaling on circadian swimming behavior in a zooplankton model, the marine annelid Platynereis dumerilii. We find that melatonin is produced in brain photoreceptors with a vertebrate-type opsin-based phototransduction cascade and a light-entrained clock. Melatonin released at night induces rhythmic burst firing of cholinergic neurons that innervate locomotor-ciliated cells. This establishes a nocturnal behavioral state by modulating the length and the frequency of ciliary arrests. Based on our findings, we propose that melatonin signaling plays a role in the circadian control of ciliary swimming to adjust the vertical position of zooplankton in response to ambient light. PMID:25259919

  12. Fundamental Issues of Melatonin-Mediated Stress Signaling in Plants.

    PubMed

    Shi, Haitao; Chen, Keli; Wei, Yunxie; He, Chaozu

    2016-01-01

    As a widely known hormone in animals, melatonin (N-acetyl-5-methoxytryptamine) has been more and more popular research topic in various aspects of plants. To summarize the these recent advances, this review focuses on the regulatory effects of melatonin in plant response to multiple abiotic stresses including salt, drought, cold, heat and oxidative stresses and biotic stress such as pathogen infection. We highlight the changes of endogenous melatonin levels under stress conditions, and the extensive metabolome, transcriptome, and proteome reprogramming by exogenous melatonin application. Moreover, melatonin-mediated stress signaling and underlying mechanism in plants are extensively discussed. Much more is needed to further study in detail the mechanisms of melatonin-mediated stress signaling in plants. PMID:27512404

  13. Melatonin concentrations in the sudden infant death syndrome

    NASA Technical Reports Server (NTRS)

    Sturner, W. Q.; Lynch, H. J.; Deng, M. H.; Gleason, R. E.; Wurtman, R. J.

    1990-01-01

    The melatonin levels in various body fluids of the sudden infant death syndrome (SIDS) infants are compared with those of infants of comparable age who died of other causes to examine a possible relationship between pineal function and SIDS. After adjusting for age differences, cerebrospinal fluid melatonin levels are found to be significantly lower in the SIDS infants. It is suggested that diminished melatonin production may be characteristic of SIDS and could represent an impairment in the maturation of physiologic circadian organization.

  14. Effects of exposure to intermittent versus continuous red light on human circadian rhythms, melatonin suppression, and pupillary constriction.

    PubMed

    Ho Mien, Ivan; Chua, Eric Chern-Pin; Lau, Pauline; Tan, Luuan-Chin; Lee, Ivan Tian-Guang; Yeo, Sing-Chen; Tan, Sara Shuhui; Gooley, Joshua J

    2014-01-01

    Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21-28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm(-2) s(-1)), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light.

  15. Effects of Exposure to Intermittent versus Continuous Red Light on Human Circadian Rhythms, Melatonin Suppression, and Pupillary Constriction

    PubMed Central

    Ho Mien, Ivan; Chua, Eric Chern-Pin; Lau, Pauline; Tan, Luuan-Chin; Lee, Ivan Tian-Guang; Yeo, Sing-Chen; Tan, Sara Shuhui; Gooley, Joshua J.

    2014-01-01

    Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21–28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm−2 s−1), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light. PMID:24797245

  16. Effects of exposure to intermittent versus continuous red light on human circadian rhythms, melatonin suppression, and pupillary constriction.

    PubMed

    Ho Mien, Ivan; Chua, Eric Chern-Pin; Lau, Pauline; Tan, Luuan-Chin; Lee, Ivan Tian-Guang; Yeo, Sing-Chen; Tan, Sara Shuhui; Gooley, Joshua J

    2014-01-01

    Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21-28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm(-2) s(-1)), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light. PMID:24797245

  17. Melatonin for the treatment of irritable bowel syndrome.

    PubMed

    Siah, Kewin Tien Ho; Wong, Reuben Kong Min; Ho, Khek Yu

    2014-03-14

    Irritable bowel syndrome (IBS) is a common disorder characterized by recurrent abdominal pain or discomfort, in combination with disturbed bowel habits in the absence of identifiable organic cause. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone produced by the pineal gland and also large number by enterochromaffin cells of the digestive mucosa. Melatonin plays an important part in gastrointestinal physiology which includes regulation of gastrointestinal motility, local anti-inflammatory reaction as well as moderation of visceral sensation. Melatonin is commonly given orally. It is categorized by the United States Food and Drug Administration as a dietary supplement. Melatonin treatment has an extremely wide margin of safety though it may cause minor adverse effects, such as headache, rash and nightmares. Melatonin was touted as a potential effective candidate for IBS treatment. Putative role of melatonin in IBS treatment include analgesic effects, regulator of gastrointestinal motility and sensation to sleep promoter. Placebo-controlled studies in melatonin suffered from heterogeneity in methodology. Most studies utilized 3 mg at bedtime as the standard dose of trial. However, all studies had consistently showed improvement in abdominal pain, some showed improvement in quality of life of IBS patients. Melatonin is a relatively safe drug that possesses potential in treating IBS. Future studies should focus on melatonin effect on gut mobility as well as its central nervous system effect to elucidate its role in IBS patients.

  18. GIRK Channels Mediate the Nonphotic Effects of Exogenous Melatonin

    PubMed Central

    Hablitz, Lauren M.; Molzof, Hylton E.; Abrahamsson, Kathryn E.; Cooper, Joanna M.; Prosser, Rebecca A.

    2015-01-01

    Melatonin supplementation has been used as a therapeutic agent for several diseases, yet little is known about the underlying mechanisms by which melatonin synchronizes circadian rhythms. G-protein signaling plays a large role in melatonin-induced phase shifts of locomotor behavior and melatonin receptors activate G-protein-coupled inwardly rectifying potassium (GIRK) channels in Xenopus oocytes. The present study tested the hypothesis that melatonin influences circadian phase and electrical activity within the central clock in the suprachiasmatic nucleus (SCN) through GIRK channel activation. Unlike wild-type littermates, GIRK2 knock-out (KO) mice failed to phase advance wheel-running behavior in response to 3 d subcutaneous injections of melatonin in the late day. Moreover, in vitro phase resetting of the SCN circadian clock by melatonin was blocked by coadministration of a GIRK channel antagonist tertiapin-q (TPQ). Loose-patch electrophysiological recordings of SCN neurons revealed a significant reduction in the average action potential rate in response to melatonin. This effect was lost in SCN slices treated with TPQ and SCN slices from GIRK2 KO mice. The melatonin-induced suppression of firing rate corresponded with an increased inward current that was blocked by TPQ. Finally, application of ramelteon, a potent melatonin receptor agonist, significantly decreased firing rate and increased inward current within SCN neurons in a GIRK-dependent manner. These results are the first to show that GIRK channels are necessary for the effects of melatonin and ramelteon within the SCN. This study suggests that GIRK channels may be an alternative therapeutic target for diseases with evidence of circadian disruption, including aberrant melatonin signaling. SIGNIFICANCE STATEMENT Despite the widespread use of melatonin supplementation for the treatment of sleep disruption and other neurological diseases such as epilepsy and depression, no studies have elucidated the

  19. Melatonin for the treatment of irritable bowel syndrome.

    PubMed

    Siah, Kewin Tien Ho; Wong, Reuben Kong Min; Ho, Khek Yu

    2014-03-14

    Irritable bowel syndrome (IBS) is a common disorder characterized by recurrent abdominal pain or discomfort, in combination with disturbed bowel habits in the absence of identifiable organic cause. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone produced by the pineal gland and also large number by enterochromaffin cells of the digestive mucosa. Melatonin plays an important part in gastrointestinal physiology which includes regulation of gastrointestinal motility, local anti-inflammatory reaction as well as moderation of visceral sensation. Melatonin