• The Korean Journal of Physiology and Pharmacology
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• v.14 no.6
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• pp.365-369
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• 2010

In this study, we examined whether melatonin promotes apoptotic cell death via p53 in prostate LNCaP cells. Melatonin treatment significantly curtailed the growth of LNCaP cells in a dose- and time-dependent manner. Melatonin treatment (0 to 3 mM) induced the fragmentation of poly(ADP-ribose) polymerase (PARP) and activation of caspase-3, caspase-8, and caspase-9. Moreover, melatonin markedly activated Bax expression and decreased Bcl-2 expression in dose increments. To investigate p53 and p21 expression, LNCaP cells were treated with 0 to 3 mM melatonin. Melatonin increased the expressions of p53, p21, and p27. Treatment with mitogen-activated protein kinase (MAPK) inhibitors, PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor), confirmed that the melatonin-induced apoptosis was p21-dependent, but ERK-independent. With the co-treatment of PD98059 and melatonin, the expression of p-p53, p21, and MDM2 did not decrease. These effects were opposite to the expression of p-p53, p21, and MDM2 observed with SP600125 and SB202190 treatments. Together, these results suggest that p53-dependent induction of JNK/p38 MAPK directly participates in apoptosis induced by melatonin.

• Archives of Plastic Surgery
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• v.32 no.6
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• pp.683-688
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• 2005

The ischemia-reperfusion injury of the skeletal muscles is caused by generation of reactive oxygen during ischemia and reperfusion. Melatonin or N-Acetyl-5-methoxy- tryptamine is suggested to have antioxidant effects in several tissues. In present study, we examined the protective effect of melatonin in a rat hind limb ischemia-reperfusion injury. Dimethyl-sulfoxide(DMSO) was also tested for comparison. Ischemia was induced for 4 hours by vascular clamping and followed by 1 hour or 24 hours of reperfusion. Muscle injury was evaluated in 4 groups such as single laparotomy group(control), ischemia-reperfusion group, DMSO group, melatonin group. Eedema ratio and malondialdehyde(MDA) of muscle tissue and serum level of creatine kinase(CK), were measeured at the end of reperfusion. DMSO and melatonin group showed significant amelioration of edema and serum CK compared with ischemia-reperfusion group. The decreasing effect was more prominent in melatonin group. The muscle tissue MDA concentration is significantly lower in melatonin group than in ischemia-reperfusion group. The results show that melatonin prevents and improves ischemia-reperfusion injury more effectively in a rat hind limb than DMSO dose. Thus, clinically the melatonin may be used for a beneficial treatment of such injuries

• Korean Journal of Veterinary Research
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• v.45 no.4
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• pp.553-562
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• 2005

Melatonin, the principal hormone of the vertebral pineal gland, participates in the regulation of cardiovascular system in vitro and in vivo. Lithium inhibits both inositol polyphosphate phosphatase (IPPase) and inositol monophosphatase (IMPase), which are involved in a wide range of signal transduction pathways. The aim of the present study was to assess the effect of lithium on endothelial-dependent relaxation to melatonin and on the melatonin-induced inhibition of contraction by phenylephrine (PE) in isolated rat aorta. Melatonin induced a concentration-dependent relaxation in PE-precontracted in endothelium-intact (+E) aortic rings. Melatonin inhibited a PE-induced sustained contraction in +E aortic rings. These effects of melatonin on relaxation and contractile responses were inhibited by pretreatment with lithium. In PE-precontracted +E aortic rings, the melatonin-induced vasorelaxations and the inhibitory effects of melatonin on maximal contractions were inhibited by endothelium removal or by pretreatment with L-$N^G$-nitro-arginine (L-NNA), 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (ODQ) and nifedipine and verapamil, but not by tetrabutylammonium, clotrimazole and glibenclamide, However, in endothelium-denuded (-E) aortic rings and in the presence of L-NNA and ODQ in +E aortic rings, the melatonin-induced residual relaxations and the melatonin-induced residual contractile responses to PE were not affected by lithium. It is concluded that the inositol phosphate pathway may be involved in endothelial-dependent relaxation induced by melatonin.

• The Korean Journal of Physiology and Pharmacology
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• v.12 no.2
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• pp.37-41
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• 2008

Melatonin has been reported to protect neurons from a variety of neurotoxicity. However, the underlying mechanism by which melatonin exerts its neuroprotective property has not yet been clearly understood. We previously demonstrated that melatonin protected kainic acid-induced neuronal cell death in mouse hippocampus, accompanied by sustained activation of Akt, a critical mediator of neuronal survival. To further elucidate the neuroprotective action of melatonin, we examined in the present study the causal mechanism how Akt signaling pathway is regulated by melatonin in a rat primary astrocyte culture model. Melatonin resulted in increased astrocytic Akt phosphorylation, which was significantly decreased with wortmannin, a specific inhibitor of PI3K, suggesting that activation of Akt by melatonin is mediated through the PI3K-Akt signaling pathway. Furthermore, increased Akt activation was also significantly decreased with luzindole, a non-selective melatonin receptor antagonist. As downstream signaling pathway of Akt activation, increased levels of CREB phoshorylation and GDNF expression were observed, which were also attenuated with wortmannin and luzindole. These results strongly suggest that melatonin exerts its neuroprotective property in astrocytes through the activation of plasma membrane receptors and then PI3K-Akt signaling pathway.

• Journal of Veterinary Science
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• v.22 no.4
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• pp.54.1-54.13
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• 2021

Background: Hypoxia causes oxidative stress and affects cardiovascular function and the programming of cardiovascular disease. Melatonin promotes antioxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione peroxidase, and catalase. Objectives: This study aims to investigate the correlation between melatonin and hypoxia induction in cardiomyocytes differentiation. Methods: Mouse embryonic stem cells (mESCs) were induced to myocardial differentiation. To demonstrate the influence of melatonin under hypoxia, mESC was pretreated with melatonin and then cultured in hypoxic condition. The cardiac beating ratio of the mESC-derived cardiomyocytes, mRNA and protein expression levels were investigated. Results: Under hypoxic condition, the mRNA expression of cardiac-lineage markers (Brachyury, Tbx20, and cTn1) and melatonin receptor (Mtnr1a) was reduced. The mRNA expression of cTn1 and the beating ratio of mESCs increased when melatonin was treated simultaneously with hypoxia, compared to when only exposed to hypoxia. Hypoxia-inducible factor (HIF)-1α protein decreased with melatonin treatment under hypoxia, and Mtnr1a mRNA expression increased. When the cells were exposed to hypoxia with melatonin treatment, the protein expressions of phospho-extracellular signal-related kinase (p-ERK) and Bcl-2-associated X proteins (Bax) decreased, however, the levels of phospho-protein kinase B (p-Akt), phosphatidylinositol 3-kinase (PI3K), B-cell lymphoma 2 (Bcl-2) proteins, and antioxidant enzymes including Cu/Zn-SOD, Mn-SOD, and catalase were increased. Competitive melatonin receptor antagonist luzindole blocked the melatonin-induced effects. Conclusions: This study demonstrates that hypoxia inhibits cardiomyocytes differentiation and melatonin partially mitigates the adverse effect of hypoxia in myocardial differentiation by regulating apoptosis and oxidative stress through the p-AKT and PI3K pathway.

• Journal of Photoscience
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• v.9 no.2
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• pp.249-251
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• 2002

The avian pineal as well as the retina has been known to contain several types of photoreceptors with different visual pigments such as rhodopsin, iodopsin and the pineal specific opsin, pinopsin. These organs are also known to have circadian clock to regulate melatonin production. Exposure of animals to light causes a decline of the melatonin level and the phase shifts of melatonin rhythms in the pineal and retina. Therefore, the circadian clock system of these organs seem to consist of three elements, i.e., light input, oscillator and melatonin output systems. In birds, it was suggested that rhodopsin might be involved in the entrainment of pineal melatonin rhythms from the action spectrum experiment for controlling NAT activity rhythms. However, there are much more pinopsin-immunoreactive (Pino-IR) cells than rhodopsin (Rho-IR) and iodopsin (Iodo-IR) cells in the avian pineal. We found that Pino-IR cells appeared earlier embryonic stages than Rho-IR and Iodo-IR cells. So, we tried to identify the visual pigments involved in the circadian melatonin rhythms in the pineal and retina. Organ cultured pineals were exposed to monochromatic light to find out which opsin participates in regulation of melatonin rhythms. The action spectra showed a peak at 475nm, suggesting that pinopsin is the major photopigment to regulate melatonin production in birds.

• Sleep Medicine and Psychophysiology
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• v.22 no.1
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• pp.5-10
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• 2015

The secretion of melatonin exhibits a circadian rhythm entrained with the sleep-wake cycle. An alteration of this secretory rhythm has been found in various psychiatric disorders. This review summarizes the regulation of melatonin and its relationship to the circadian rhythm, major depressive disorder, bipolar disorder, seasonal affective disorder, Alzheimer's disease and autism. The review also looks at the effect of melatonin and melatonin agonist on sleep and symptoms of depression, bipolar disorder and seasonal affective disorder. In Alzheimer's disease, the circadian rhythm alterations are associated with the change of melatonin levels and melatonin receptors. It has been reported that melatonin and melatonin synthetic enzyme levels decrease in autism spectrum disorder.

• Archives of Pharmacal Research
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• v.22 no.1
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• pp.35-43
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• 1999

Overstimulation of both kainate (KA) and N-methyl-D-aspartate (NMDA) receptors has been reported to induce excitatoxicity which can be characterized by neuronal damage and formation of reactive oxygen free radicals. Neuroprotective effect of melatonin against KA-induced excitotoxicity have been documented in vitro and in vivo. It is, however, not clear whether melationin is also neuroportective against excitotoxicity mediated by NMDA receptors. In the present work, we tested the in vivo protective effects of striatally infused melatonin against the oxidative stress and neuronal damage induced by the injection of KA and NMDA receptors into the rat striatum. Melatonin implants consisting of 22-gauge stainless-steel cannule with melatonin fused inside the tip were placed bilaterally in the rat brain one week prior to intrastriatal injection of glutamate receptor subtype agonists. Melatonin showed protective effects against the elevation of lipid peroxidation induced by either KA or NMDA and recovered Cu, Zn-superoxide dismutase activities reduced by both KA and NMDA into the control level. Melatonin also clearly blocked both KA- and NMDA-receptor mediated neuronal damage assessed by the determination of choline acetyltransferase activity in striatal monogenages and by microscopic observation of rat brain section stained with cresyl violet. The protective effects of melatonin are comparable to those of DNQX and MK801 which are the KA- and NMDA-receptor antagonist, respectively. It is suggested that melatonin could protect against striatal oxidative damages mediated by glutamate receptors, both non-NMDA and NMDA receptors.

• BMB Reports
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• v.55 no.9
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• pp.459-464
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• 2022

Various mechanisms have been suggested to explain the chemopreventive and tumor-inhibitory effects of melatonin. Despite the growing evidence supporting melatonin-induced mitochondrial dysfunction, it remains largely unknown how this phenomenon modulates metabolic reprogramming in cancer cells. The aim of our study was to identify the mechanism underlying the anti-proliferative and apoptotic effects of melatonin, which is known to inhibit glycolysis. We analyzed the time-dependent effects of melatonin on mitochondrial respiration and glycolysis in liver cancer cells. The results showed that from a cell bioenergetic point of view, melatonin caused an acute reduction in mitochondrial respiration, however, increased reactive oxygen species production, thereby inhibiting mTORC1 activity from an early stage post-treatment without affecting glycolysis. Nevertheless, administration of melatonin for a longer time reduced expression of c-Myc protein, thereby suppressing glycolysis via downregulation of HK2 and LDHA. The data presented herein suggest that melatonin suppresses mitochondrial respiration and glycolysis simultaneously in HCC cells, leading to anti-cancer effects. Thus, melatonin can be used as an adjuvant agent for therapy of liver cancer.

• Reproductive and Developmental Biology
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• v.28 no.2
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• pp.83-87
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• 2004

The objective of this study was performed to establish the in vitro culture system of porcine in vitro maturation and in vitro fertilization(IVM/IVF) embryo. These studies was to determine the effects of melatonin, nitric oxide donor(SNP), and the combination effects of SNP and melatonin in porcine IVM/IVF embryos. In routine porcine IVM/IVF procedure, oocytes were cultured for 40∼44h incubation, and the zygotes were cultured for 40∼44h in NCSU 23 medium. Then 2 to 8 cell embryos were removed cumulus cell and were allotted randomly to NCSU 23 containing different concentration of melatonin, SNP and SNP plus melatonin in 5% $O_2$, 5% $CO_2$ and 90% $N_2$ at 38.5$^{\circ}C$. Cell numbers of blastocyst were also counted using double fluorescence stain method. In NCSU 23 medium treated with melatonin 0, 1, 5 and 10 nM, the developmental rate of morula plus blastocysts were 33.3%, 39.1%, 33.3% and 27.9%, respectivly. This result show that the developmental rate of morula and blascytocys treated with 1 nM melatonin was higher than in any other groups(P<0.05). The developmental rates of morula plus blastocysts were 41.9% in 0 uM SNP, 25.6% in 50 uM and 28.4% in 100 uM, respectively. The developmental rate of morula plus blastocysts were decreased treated with SNP in NCSU 23. In combined effects of SNP plus melatonin (0, SNP 50 uM, SNP 50 uM plus melatonin 1 nM, SNP 50 uM plus melatonin 5 nM and SNP 50 uM plus melatonin 10 nM), the developmental rates beyond morula stage of porcine embryos were 31.3%, 34.1%, 39.5%, 29.4% and 39.5%, respectively. The addition of SNP 50 uM plus maltonin 1 nM, developmental rates of blastocyst was higher rate than in any other groups. Cell numbers of blastocyst in NCSU 23 treated with melatonin 0, 1, 5 and 10 nM were 41.0, 42.6, 39.6 and 33.0, respectively. In combined effects of SNP plus melatonin (0, SNP 50 uM, SNP 50 uM plus melatonin 1 nM , SNP 50 uM plus melatonin 5 nM and SNP 50 uM plus melatonin 10 nM), cell numbers of developed blastocyst were 36.3, 34.6, 39.0, 39.9 and 39.0, respectively. These result show that the cell numbers of blastocyst treated with 0, 1 and 5 nM melatonin were higher than in 10 nM group(P<0.05), but cell numbers of blatocyst produced by SNP plus melatonin were not significantly difference in all experimental groups.