• The Korean Journal of Physiology and Pharmacology
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• 제14권6호
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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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• 제32권6호
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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

• 대한수의학회지
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• 제45권4호
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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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• 제12권2호
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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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• 제22권4호
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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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• 제9권2호
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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.

• 수면정신생리
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• 제22권1호
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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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• 제22권1호
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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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• 제55권9호
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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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• 제28권2호
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• pp.83-87
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• 2004

본 연구는 돼지의 난포란을 체외에서 성숙, 수정시킨 체외수정란의 체외배양 체계를 확립하고 그 기작을 규명하기 위하여 체외배양액에 항산화제인 melatonin의 첨가 및 melatonin과 sodium nitroprusside(SNP)의 첨가배양이 체외수정란의 체외발육에 미치는 영향을 검토하고자 실시하였다. NCSU 23 배양액에 melatonin을 0, 1, 5 및 10nM을 첨가하여 체외배양을 실시한 결과, 배반포기까지 발육율은 17.8%, 26.1%, 20.0% 및 16.3%로서 melatonin 1nM 첨가구가 여타구에 비해 통계적으로 유의하게 높은 성적을 나타냈으며(P<0.05), 상실배기 이상 발육 성적에서도 melatonin 1 nM 첨가구가 39.1%로서 대조구 33.3%, 5 nM 첨가구의 33.3% 및 10 nM 첨가구의 27.9%보다 높은 발육율을 나타냈다(P<0.05). NCSU 23 배양액에 SNP를 0, 50 및 100 $\muM을 첨가하여 체외 배양한 결과, 상실배 이상 발육성적은 각각 41.9%, 25.6% 및 28.4%로서 SNP 첨가구가 대조구보다 유의적으로 낮은 성적을 나타내었다(P<0.05). NCSU 23 배양액에 대조구, SNP 50 $\muM, SNP 50 $\muM에 melatonin 1, 5 및 10nM을 혼합첨가하여 체외 발육율을 조사한 결과, 배반포기 발육율은 각각 2.5%, 1.2%, 9.9%, 5.1% 및 3.7%로서 SNP 50$\mu$M + Mel. 1nM 첨가구가 여타구 보다 높은 성적을 나타냈으며, 상실배기 이상 체외 발육율은 31.3%, 34.1%, 39.5%, 29.4% 및 39.5%로서 SNP 50 $\mu M + Mel. 1 nM 첨가구와 SNP 50 $\muM + Mel. 10 nM 첨가구가 여타구보다 높은 발육율을 나타냈다. 모든 처리구에서 배반포까지 발육된 체외수정란의 세포수는 커다란 차이가 인정되지 않았다.