| 1. |
- Chaste, Pauline, et al.
(författare)
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Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders.
- 2011
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Ingår i: Journal of Pineal Research. - 0742-3098 .- 1600-079X. ; 51:4, s. 394-399
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Tidskriftsartikel (refereegranskat)abstract
- Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.
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| 2. |
- Gomez-Pinilla, Pedro J, et al.
(författare)
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Melatonin restores impaired contractility in aged guinea pig urinary bladder
- 2008
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Ingår i: Journal of Pineal Research. - : Blackwell Publishing Ltd. - 1600-079X .- 0742-3098. ; 44:4, s. 416-425
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Tidskriftsartikel (refereegranskat)abstract
- Urinary bladder disturbances are frequent in the elderly population but the responsible mechanisms are poorly understood. This study evaluates the effects of aging on detrusor myogenic contractile responses and the impact of melatonin treatment. The contractility of bladder strips from adult, aged and melatonin-treated guinea pigs was evaluated by isometric tension recordings. Cytoplasmatic calcium concentration ([Ca2+](i)) was estimated by epifluorescence microscopy of fura-2-loaded isolated detrusor smooth muscle cells, and the levels of protein expression and phosphorylation were quantitated by Western blotting. Aging impairs the contractile response of detrusor strips to cholinergic and purinergic agonists and to membrane depolarization. The impaired contractility correlates with increased [Ca2+](i) in response to the stimuli, suggesting a reduced Ca(2+)sensitivity. Indeed, the agonist-induced contractions in adult strips were sensitive to blockade with Y27362, an inhibitor of Rho kinase (ROCK) and GF109203X, an inhibitor of protein kinase C (PKC), but these inhibitors had negligible effects in aged strips. The reduced Ca2+ sensitivity in aged tissues correlated with lower levels of RhoA, ROCK, PKC and the two effectors CPI-17 and MYPT1, and with the absence of CPI-17 and MYPT1 phosphorylation in response to agonists. Interestingly, melatonin treatment restored impaired contractility via normalization of Ca2+ handling and Ca2+ sensitizations pathways. Moreover, the indoleamine restored age-induced changes in oxidative stress and mitochondrial polarity. These results suggest that melatonin might be a novel therapeutic tool to palliate aging-related urinary bladder contractile impairment.
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| 3. |
- Marqueze, Elaine C., et al.
(författare)
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Exogenous melatonin decreases circadian misalignment and body weight among early types
- 2021
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Ingår i: Journal of Pineal Research. - : Wiley. - 0742-3098 .- 1600-079X. ; 71:2
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Tidskriftsartikel (refereegranskat)abstract
- Shift workers experience chronic circadian misalignment, which can manifest itself in reduced melatonin production, and has been associated with metabolic disorders. In addition, chronotype modulates the effect of night shift work, with early types presenting greater circadian misalignment when working night shift as compared to late types. Melatonin supplementation has shown positive results reducing weight gain in animal models, but the effect of exogenous melatonin in humans on body weight in the context of shift work remains inconsistent. The aim of this study was thus to evaluate the effects of exogenous melatonin on circadian misalignment and body weight among overweight night shift workers, according to chronotype, under real-life conditions. We conducted a double-blind, randomized, placebo-controlled, crossover trial where melatonin (3 mg) or placebo was administered on non-night shift nights for 12 weeks in 27 female nurses (37.1 yo, +/- 5.9 yo; BMI 29.9 kg/m(2), +/- 3.3 kg/m(2)). Melatonin (or placebo) was only taken on nights when the participants did not work night shifts, that is, on nights when they slept (between night shifts and on days off). Composite Phase Deviations (CPD) of actigraphy-based mid-sleep timing were calculated to measure circadian misalignment. The analyses were performed for the whole group and by chronotype. We found approximately 20% reduction in circadian misalignment after exogenous melatonin administration considering all chronotypes. Moreover, melatonin supplementation in those who presented high circadian misalignment, as observed in early chronotypes, reduced body weight, BMI, waist circumference, and hip circumference, without any change in the participants' calorie intake or physical activity levels.
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| 4. |
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| 5. |
- Pierozan, Paula, et al.
(författare)
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The environmental neurotoxin beta-N-methylamino-L-alanine inhibits melatonin synthesis in primary pinealocytes and a rat model
- 2018
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Ingår i: Journal of Pineal Research. - : WILEY. - 0742-3098 .- 1600-079X. ; 65:1
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Tidskriftsartikel (refereegranskat)abstract
- The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is a glutamate receptor agonist that can induce oxidative stress and has been implicated as a possible risk factor for neurodegenerative disease. Detection of BMAA in mussels, crustaceans, and fish illustrates that the sources of human exposure to this toxin are more abundant than previously anticipated. The aim of this study was to determine uptake of BMAA in the pineal gland and subsequent effects on melatonin production in primary pinealocyte cultures and a rat model. Autoradiographic imaging of 10-day-old male rats revealed a high and selective uptake in the pineal gland at 30minutes to 24hours after C-14-L-BMAA administration (0.68mg/kg). Primary pinealocyte cultures exposed to 0.05-3mmol/L BMAA showed a 57%-93% decrease in melatonin synthesis in vitro. Both the metabotropic glutamate receptor 3 (mGluR3) antagonist Ly341495 and the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate prevented the decrease in melatonin secretion, suggesting that BMAA inhibits melatonin synthesis by mGluR3 activation and PKC inhibition. Serum analysis revealed a 45% decrease in melatonin concentration in neonatal rats assessed 2weeks after BMAA administration (460mg/kg) and confirmed an inhibition of melatonin synthesis in vivo. Given that melatonin is a most important neuroprotective molecule in the brain, the etiology of BMAA-induced neurodegeneration may include mechanisms beyond direct excitotoxicity and oxidative stress.
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| 6. |
- Sjöblom, Markus, et al.
(författare)
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Melatonin in the duodenal lumen is a potent stimulant of mucosal bicarbonate secretion
- 2003
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Ingår i: Journal of Pineal Research. - 0742-3098 .- 1600-079X. ; 34:4, s. 288-293
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Tidskriftsartikel (refereegranskat)abstract
- Melatonin, originating from intestinal enterochromaffin cells, mediates vagal and sympathetic neural stimulation of the HCO secretion by the duodenal mucosa. This alkaline secretion is considered the first line of mucosal defense against hydrochloric acid discharged from the stomach. We have studied whether luminally applied melatonin stimulates the protective secretion and whether a melatonin pathway is involved in acid-induced stimulation of the secretion. Rats were anaesthetized (Inactin(R)) and a 12-mm segment of proximal duodenum with an intact blood supply was cannulated in situ . Mucosal HCO secretion (pH-stat) and the mean arterial blood pressure were continuously recorded. Luminal melatonin at a concentration of 1.0 mu m increased (P < 0.05) the secretion from 7.20 +/- 1.35 to 13.20 +/- 1.51 mu Eq/cm/hr. The MT2 selective antagonist luzindole (600 nmol/kg, i.v.) had no effect on basal HCO secretion, but inhibited (P < 0.05) secretion stimulated by luminal melatonin. Hexamethonium (10 mg/kg i.v. followed by continuous i.v. infusion at a rate of 10 mg/kg/hr), abolishes neurally mediated rises in secretion and also inhibited (P < 0.05) the stimulation by luminal melatonin. Exposure of the lumen to acid containing perfusate (pH 2.0) for 5 min increased (P < 0.05) the HCO secretion from 5.85 +/- 0.82 to 12.35 +/- 1.51 mu Eq/cm/hr, and luzindole significantly inhibited (P < 0.05) this rise in secretion. The study thus demonstrates that luminal melatonin is a potent stimulant of duodenal HCO secretion and, furthermore, strongly suggests melatonin as an important mediator of acid-induced secretion.
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| 7. |
- Sommansson, Anna, et al.
(författare)
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Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivo
- 2013
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Ingår i: Journal of Pineal Research. - : Wiley. - 0742-3098 .- 1600-079X. ; 54:3, s. 282-291
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal epithelial intercellular tight junctions (TJs) provide a rate-limiting barrier restricting passive transepithelial movement of solutes. TJs are highly dynamic areas, and their permeability is changed in response to various stimuli. Defects in the intestinal epithelial TJ barrier may contribute to intestinal inflammation or leaky gut. The gastrointestinal tract may be the largest extrapineal source of endogenous melatonin. Melatonin released from the duodenal mucosa is a potent stimulant of duodenal mucosal bicarbonate secretion (DBS). The aim of this study was to elucidate the role of melatonin in regulating duodenal mucosal barrier functions, including mucosal permeability, DBS, net fluid flux, and duodenal motor activity, in the living animal. Rats were anesthetized with thiobarbiturate, and a ~30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. Melatonin and the selective melatonin receptor antagonist luzindole were perfused luminally or given intravenously. Effects on permeability (blood-to-lumen clearance of (51) Cr-EDTA), DBS, mucosal net fluid flux, and duodenal motility were monitored. Luminal melatonin caused a rapid decrease in paracellular permeability and an increase in DBS, but had no effect on duodenal motor activity or net fluid flux. Luzindole did not influence any of the basal parameters studied, but significantly inhibited the effects of melatonin. The nonselective and noncompetitive nicotinic acetylcholine receptor antagonist mecamylamine abolished the effect of melatonin on duodenal permeability and reduced that on DBS. In conclusion, these findings provide evidence that melatonin significantly decreases duodenal mucosal paracellular permeability and increases DBS. The data support the important role of melatonin in the neurohumoral regulation of duodenal mucosal barrier.
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| 8. |
- Xue, Pei, et al.
(författare)
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No association between a common type 2 diabetes risk gene variant in the melatonin receptor gene (MTNR1B) and mortality among type 2 diabetes patients
- 2022
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Ingår i: Journal of Pineal Research. - : John Wiley & Sons. - 0742-3098 .- 1600-079X. ; 72:2
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Tidskriftsartikel (refereegranskat)abstract
- The minor G risk allele in the common melatonin receptor gene (MTNR1B, rs10830963) has been associated with an increased risk of myocardial infarction among patients with type 2 diabetes (T2D). Furthermore, activating the melatonin receptor 1B through melatonin has been shown to promote cell proliferation, which could be hypothesized to increase cancer risk. Cardiovascular disease (CVD) and cancer are common causes of death among T2D patients. Using data from 14,736 T2D patients who participated in the UK Biobank investigation, we hypothesized an additive effect of the G risk allele on all-cause mortality, CVD mortality, and cancer mortality. As shown by Cox regression adjusted for confounders such as age, glucose-lowering medication, and socioeconomic status, no significant trend between the number of G risk alleles and mortality outcomes was found during the follow-up period of 11.1 years. Our negative findings do not speak against the role of this gene variant in the development of T2D, as repeatedly shown by previous large-scale studies. Instead, they may suggest that rs10830963 is less relevant for T2D patients' survival.
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| 9. |
- Nagorny, Cecilia, et al.
(författare)
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Distribution of melatonin receptors in murine pancreatic islets.
- 2011
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Ingår i: Journal of Pineal Research. - 1600-079X. ; 50, s. 412-417
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Tidskriftsartikel (refereegranskat)abstract
- Melatonin has multiple receptor-dependent and receptor-independent functions. At the cell membrane, melatonin interacts with its receptors MT1 and MT2, which are expressed in numerous tissues. Genome-wide association studies have recently shown that the MTNR1B/MT2 receptor may be involved in the pathogenesis of type 2 diabetes mellitus. In line with these findings, expression of melatonin receptors has been shown in mouse, rat, and human pancreatic islets. MT1 and MT2 are G-protein-coupled receptors and are proposed to exert inhibitory effects on insulin secretion. Here, we show by immunocytochemistry that these membrane melatonin receptors have distinct locations in the mouse islet. MT1 is expressed in α-cells while MT2 is located to the β-cells. These findings help to unravel the complex machinery underlying melatonin's role in the regulation of islet function.
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| 10. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Melatonin-evoked in vivo secretion of protein and amylase from the parotid gland of the anaesthetised rat.
- 2008
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Ingår i: Journal of pineal research. - 1600-079X. ; 45:4, s. 413-21
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Tidskriftsartikel (refereegranskat)abstract
- The intravenous infusion of melatonin (5 and 25 mg/kg over 10 min) evoked a dose-dependent output of protein and amylase but no overt fluid secretion from the parotid gland of the pentobarbitone-anaesthetised rat, as revealed by increased concentrations of protein and amylase activity in a subsequent wash-out flow of saliva in response to an intravenous bolus injection of methacholine (5 microg/kg) 10 min later. The secretory responses to melatonin occurred in the presence of alpha- and beta-adrenoceptor antagonists. They were not affected by the cholecystokinin A-receptor antagonist, lorglumide, and they were reproduced in eviscerated animals acutely subjected to postganglionic sympathetic and parasympathetic denervation of the gland. The responses to melatonin were partially dependent on nitric oxide generation, through the activity of nitric oxide synthase of the neuronal type. Immunoblotting showed both melatonin receptors of type 1 and type 2 to be expressed in parotid gland tissue. The relative specific melatonin 2-receptor antagonist luzindole prevented the expected secretory effects of melatonin. The results favour a direct action by melatonin on melatonin receptors of parotid secretory cells and suggest a potential physiological role for melatonin in the regulation of salivary glandular activities.
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