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  • RAV transcription factors are essential for disease resistance against cassava bacterial blight via activation of melatonin biosynthesis genes
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-11-19
    Yunxie Wei, Yanli Chang, Hongqiu Zeng, Guoyin Liu, Chaozu He, Haitao Shi

    This article is protected by copyright. All rights reserved.

    更新日期:2017-11-20
  • Melatonin improves the meiotic maturation of porcine oocytes by reducing endoplasmic reticulum stress during in vitro maturation
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-11-17
    Hyo-Jin Park, Jae-Young Park, Jin-Woo Kim, Seul-Gi Yang, Jae-Min Jung, Min-Ji Kim, Man-Jong Kang, Young Ho Cho, Gabbine Wee, Hee-Young Yang, Bong-Seok Song, Sun-Uk Kim, Deog-Bon Koo

    This article is protected by copyright. All rights reserved.

    更新日期:2017-11-17
  • Inhibiting MT2-TFE3-dependent autophagy enhances melatonin–induced apoptosis in tongue squamous cell carcinoma
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-11-17
    Tengfei Fan, Huifeng Pi, Min Li, Zhenhu Ren, Zhijing He, Feiya Zhu, Li Tian, Manyu Tu, Jia Xie, Mengyu Liu, Yuming Li, Miduo Tan, Gaoming Li, Weijia Qing, Russel J. Reiter, Zhengping Yu, Hanjiang Wu, Zhou Zhou

    This article is protected by copyright. All rights reserved.

    更新日期:2017-11-17
  • Neuroprotective effects of melatonin on amphetamine-induced dopaminergic fiber degeneration in the hippocampus of postnatal rats
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-11-17
    Tanawan Leeboonngam, Ratchadaporn Pramong, Kwankanit Sae-ung, Piyarat Govitrapong, Pansiri Phansuwan-Pujito

    This article is protected by copyright. All rights reserved.

    更新日期:2017-11-17
  • Melatonin and Serotonin: Mediators in the Symphony of Plant Morphogenesis
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-11-17
    Lauren A E Erland, Mukund R Shukla, Amritpal S Singh, Susan J Murch, Praveen K Saxena

    This article is protected by copyright. All rights reserved.

    更新日期:2017-11-17
  • Melatonin alleviates low PS I limited carbon assimilation under elevated CO2 and enhances the cold tolerance of offspring in chlorophyll b-deficient mutant wheat
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-11-17
    Xiangnan Li, Marian Brestic, Dun-Xian Tan, Marek Zivcak, Xiancan Zhu, Shengqun Liu, Fengbin Song, Russel J. Reiter, Fulai Liu

    This article is protected by copyright. All rights reserved.

    更新日期:2017-11-17
  • Melatonin alleviates adipose inflammation through elevating α-ketoglutarate and diverting adipose-derived exosomes to macrophages in mice
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-11-17
    Zhenjiang Liu, Lu Gan, Tiantian Zhang, Qian Ren, Chao Sun

    This article is protected by copyright. All rights reserved.

    更新日期:2017-11-17
  • Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-10-23
    Bharati Sinha, Qiaofeng Wu, Wei Li, Yanyang Tu, Ana C. Sirianni, Yanchun Chen, Jiying Jiang, Xinmu Zhang, Wu Chen, Shuanhu Zhou, Russel J. Reiter, Simon M. Manning, Nirav J. Patel, Ali M. Aziz-Sultan, Terrie E. Inder, Robert M. Friedlander, Jianfang Fu, Xin Wang

    The function of melatonin as a protective agent against newborn hypoxic-ischemic (H-I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 knockout mice following H-I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H-I brain injury, at least in part, by the restoration of MT1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.

    更新日期:2017-10-24
  • Effects of melatonin on fatty liver disease: The role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-10-23
    Hao Zhou, Wenjuan Du, Ye Li, Chen Shi, Nan Hu, Sai Ma, Weihu Wang, Jun Ren

    Mitochondrial dysfunction has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through poorly defined mechanisms. Melatonin supplementation has been found to protect liver function in diabetes and obesity. Here, we intensively explored the role and mechanism of melatonin in the development of NAFLD. We demonstrated that the onset of diet-induced NAFLD greatly caused NR4A1 upregulation in hepatocytes, leading to the activation of DNA-PKcs and p53. On the one hand, p53 aided Drp1 migration in the mitochondria and consequently drove mitochondrial fission. On the other hand, p53 repressed Bnip3 transcription and expression, resulting in mitophagy arrest. The excessive fission and deficient mitophagy dramatically mediated mitochondrial dysfunction, including extensive mPTP opening, reduction in mitochondrial potential, oxidative stress, calcium overload, mitochondrial respiratory collapse, and ATP shortage. However, genetic deletion of NR4A1 or DNA-PKcs could definitively reverse NAFLD progression and the mitochondrial dysfunction. Similarly, melatonin supplementation could robustly reduce the damage to liver and mitochondrial structure and function in NAFLD. Mechanistically, melatonin halted fission but recovered mitophagy via blockade of NR4A1/DNA-PKcs/p53 pathway, finally improving mitochondrial and liver function in the setting of NAFLD. Our results identify NR4A1/DNA-PKcs/p53 pathway as the novel molecular mechanism underlying the pathogenesis of NAFLD via regulation of Drp1-mediated mitochondrial fission and Bnip3-related mitophagy. Meanwhile, we also confirm that melatonin has the ability to cut off the NR4A1/DNA-PKcs/p53 pathway, which confers a protective advantage to hepatocytes and mitochondria. The manipulation of NR4A1/DNA-PKcs/p53 pathway by melatonin highlights a new entry point for treating NAFLD.

    更新日期:2017-10-23
  • Melatonin prevents endothelial cell pyroptosis via regulation of long noncoding RNA MEG3/miR-223/NLRP3 axis
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-10-11
    Yong Zhang, Xin Liu, Xue Bai, Yuan Lin, Zhange Li, Jiangbo Fu, Mingqi Li, Tong Zhao, Huan Yang, Ranchen Xu, Jiamin Li, Jin Ju, Benzhi Cai, Chaoqian Xu, Baofeng Yang

    This article is protected by copyright. All rights reserved.

    更新日期:2017-10-11
  • Melatonin improves the fertilization capacity and developmental ability of bovine oocytes by regulating cytoplasmic maturation events
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-10-11
    Xue-Ming Zhao, Na Wang, Hai-Sheng Hao, Chong-Yang Li, Ya-Han Zhao, Chang-Liang Yan, Hao-Yu Wang, Wei-Hua Du, Dong Wang, Yan Liu, Yun-Wei Pang, Hua-Bin Zhu

    Melatonin is a well-characterized antioxidant that has been successfully used to protect oocytes from reactive oxygen species during in vitro maturation (IVM), resulting in improved fertilization capacity and development ability. However, the mechanism via which melatonin improves oocyte fertilization capacity and development ability remains to be determined. Here, we studied the effects of melatonin on cytoplasmic maturation of bovine oocytes. In the present study, bovine oocytes were cultured in IVM medium supplemented with 0, 10–7, 10–9, and 10−11 mol/L melatonin, and the cytoplasmic maturation parameters of MII oocytes after IVM were investigated, including redistribution of organelles (mitochondria, cortical granules [CGs], and endoplasmic reticulum [ER]), intracellular glutathione (GSH) and ATP levels, expression of endogenous antioxidant genes (Cat, Sod1, and GPx), and fertilization-related events (IP3R1 distribution and expression of CD9 and Juno). Our results showed that melatonin significantly improved the cytoplasmic maturation of bovine oocytes by improving the normal distribution of organelles, increasing intracellular GSH and ATP levels, enhancing antioxidant gene expression levels, and modulating fertilization-related events, all of which resulted in increased fertilization capacity and developmental ability. Meanwhile, melatonin also increased the mRNA and protein expression levels of the Tet1 gene and decreased the Dnmt1 gene mRNA and protein levels in bovine oocytes, indicating that melatonin regulates the expression of the detected genes via demethylation. These findings shed insights into the potential mechanisms by which melatonin improves oocyte quality during IVM.

    更新日期:2017-10-11
  • Dynamin-related protein 1-mediated mitochondrial fission contributes to post-traumatic cardiac dysfunction in rats and the protective effect of melatonin
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-10-11
    Mingge Ding, Jiao Ning, Na Feng, Zeyang Li, Zhenhua Liu, Yuanbo Wang, Yueming Wang, Xing Li, Cong Huo, Xin Jia, Rong Xu, Feng Fu, Xiaoming Wang, Jianming Pei

    Mechanical trauma (MT) causes myocardial injury and cardiac dysfunction. However, the underlying mechanism remains largely unclear. This study investigated the role of mitochondrial dynamics in post-traumatic cardiac dysfunction and the protective effects of melatonin. Adult male Sprague Dawley rats were subjected to 5-minute rotations (200 revolutions at a rate of 40 rpm) to induce MT model. Melatonin was administrated intraperitoneally 5 minute after MT. Mitochondrial morphology, myocardial injury, and cardiac function were determined in vivo. There was smaller size of mitochondria and increased number of mitochondria per μm2 in the hearts after MT when the secondary myocardial injury was induced. Melatonin treatment at the dose of 30 mg/kg reduced serine 616 phosphorylation of Drp1 and inhibited mitochondrial Drp1 translocation and mitochondrial fission in the hearts of rats subjected to MT, which contributed to the reduction of myocardial injury and the improvement of cardiac function. In vitro, H9c2 cells cultured in 20% traumatic plasma (TP) for 12 hour showed enhanced mitochondrial fission, mitochondrial membrane potential (∆Ψm) loss, mitochondrial cytochrome c release, and decreased mitochondrial complex I-IV activities. Pretreatment with melatonin (100 μmol/L) efficiently inhibited TP-induced mitochondrial fission, ∆Ψm loss, cytochrome c release, and improved mitochondrial function. Melatonin's protective effects were attributed to its role in suppressing plasma TNF-α overproduction, which was responsible for Drp1-mediated mitochondrial fission. Taken together, our results demonstrate for the first time that abnormal mitochondrial dynamics is involved in post-traumatic cardiac dysfunction. Melatonin has significant pharmacological potential in protecting against MT-induced cardiac dysfunction by preventing excessive mitochondrial fission.

    更新日期:2017-10-11
  • Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission and mitophagy
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-10-05
    Hao Zhou, Wenjuan Du, Ye Li, Chen Shi, Nan Hu, Sai Ma, Weihu Wang, Jun Ren

    This article is protected by copyright. All rights reserved.

    更新日期:2017-10-05
  • Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-09-22
    Helen F. Galley, Barry McCormick, Kirsten L. Wilson, Damon A. Lowes, Lesley Colvin, Carole Torsney

    Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction in mitochondrial membrane potential and metabolic rate, independent of concentration (20-100 μmol/L). Mitochondrial volume was increased dose-dependently by paclitaxel (200% increase at 100 μmol/L). These effects were prevented by co-treatment with 1 μmol/L melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co-exposure to 1 μmol/L melatonin of either the breast cancer cell line MCF-7 or the ovarian carcinoma cell line A2780. In a rat model of paclitaxel-induced painful peripheral neuropathy, pretreatment with oral melatonin (5/10/50 mg/kg), given as a daily bolus dose, was protective, dose-dependently limiting development of mechanical hypersensitivity (19/43/47% difference from paclitaxel control, respectively). Melatonin (10 mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel-induced elevated 8-isoprostane F2α levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel-induced reduction in C-fibre activity-dependent slowing (by 64%). Notably, melatonin limited the development of mechanical hypersensitivity in both male and female animals (by 50/41%, respectively), and an additive effect was found when melatonin was given with the current treatment, duloxetine (75/62% difference, respectively). Melatonin is therefore a potential treatment to limit the development of painful neuropathy resulting from chemotherapy treatment.

    更新日期:2017-10-04
  • Melatonin alleviates weanling stress in mice: involvement of intestinal microbiota
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-09-05
    Wenkai Ren, Peng Wang, Jiameng Yan, Gang Liu, Benhua Zeng, Tarique Hussain, Can Peng, Jie Yin, Bie Tan, Tiejun Li, Hong Wei, Guoqiang Zhu, Russel J. Reiter, Yulong Yin

    Melatonin influences intestinal microbiota, and the pathogenesis of various diseases. This study was conducted to explore whether melatonin alleviates weanling stress through intestinal microbiota in a weanling mouse model. Melatonin supplementation in weanling mice (provided in the drinking water at a dosage of 0.2mg/ml for 2 weeks) significantly improved body weight gain (1.4±0.03 g/day in melatonin group vs. 1.2±0.06 g/day in control group) and intestinal morphology [i.e., villus length (258.1±12.2 um in melatonin group vs. 219.5±5.5 um in control group), crypt depth (105.9±0.2 um in melatonin group vs. 119.3±3.6 um in control group) and villus to crypt ratio (2.5±0.03 in melatonin group vs. 1.8±0.06 in control group)], but had little effect on the proliferation or apoptosis of intestinal cells, the numbers of Paneth cells and goblet cells, as well as the expression of makers related to enterocytes (sucrase) and endocrine cells (chromogranin A and peptide YY) in the ileum. Melatonin supplementation had little effect on serum levels of amino acids or stress-related parameters (e.g., SOD, TNF-α, and angiotensin I). 16S rRNA sequencing suggested that melatonin supplementation increased the richness indices of intestinal microbiota (observed species, Chao 1 and ACE), and shaped the composition of intestinal microbiota [e.g., increase in the abundance of Lactobacillus (19±3% in melatonin group vs. 6±2% in control group)], which was demonstrated using an ex vivo proliferation assay and colonic loop proliferation assay. Melatonin supplementation also significantly influenced the metabolism of intestinal microbiota, such as amino acids metabolism and drug metabolism. More importantly, in antibiotic-treated weanling mice and germ-free weanling mice, melatonin failed to affect body weight gain or intestinal morphology. Melatonin significantly reduced (by about 60%) the bacterial load of enterotoxigenic Escherichia coli (ETEC)-infected weanling mice, but had little effect on ETEC load in antibiotic-pretreated animals. In conclusion, melatonin affects body weight gain, intestinal morphology, and intestinal ETEC infection through intestinal microbiota in weanling mice. The findings highlight the importance of intestinal microbiota in mediating the various physiological functions of melatonin in the host.

    更新日期:2017-09-06
  • Melatonin improves the fertilization capacity and developmental ability of bovine oocytes by regulating cytoplasmic maturation events
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-08-22
    Xue-Ming Zhao, Na Wang, Hai-Sheng Hao, Chong-Yang Li, Ya-Han Zhao, Chang-Liang Yan, Hao-Yu Wang, Wei-Hua Du, Dong Wang, Yan Liu, Yun-Wei Pang, Hua-Bin Zhu

    Melatonin is a well-characterized antioxidant that has been successfully used to protect oocytes from reactive oxygen species during in vitro maturation (IVM), resulting in improved fertilization capacity and development ability. However, the mechanism via which melatonin improves oocyte fertilization capacity and development ability remains to be determined. Here, we studied the effects of melatonin on cytoplasmic maturation of bovine oocytes. In the present study, bovine oocytes were cultured in IVM medium supplemented with 0, 10–7, 10–9, and 10-11 M melatonin, and the cytoplasmic maturation parameters of MII oocytes after IVM were investigated, including redistribution of organelles (mitochondria, cortical granules [CGs], and endoplasmic reticulum [ER]), intracellular glutathione (GSH) and ATP levels, expression of endogenous antioxidant genes (Cat, Sod1, and GPx), and fertilization-related events (IP3R1 distribution and expression of CD9 and Juno). Our results showed that melatonin significantly improved the cytoplasmic maturation of bovine oocytes by improving the normal distribution of organelles, increasing intracellular GSH and ATP levels, enhancing antioxidant gene expression levels, and modulating fertilization-related events, all of which resulted in increased fertilization capacity and developmental ability. Meanwhile, melatonin also increased the mRNA and protein expression levels of the Tet1 gene and decreased the Dnmt1 gene mRNA and protein levels in bovine oocytes, indicating that melatonin regulates the expression of the detected genes via demethylation. These findings shed insights into the potential mechanisms by which melatonin improves oocyte quality during IVM.

    更新日期:2017-09-06
  • Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-08-22
    Helen F. Galley, Barry McCormick, Kirsten L. Wilson, Damon A. Lowes, Lesley Colvin, Carole Torsney

    Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction of mitochondrial membrane potential and metabolic rate, independent of concentration (20-100μM). Mitochondrial volume was increased dose-dependently by paclitaxel (200% increase at 100μM). These effects were prevented by co-treatment with 1μM melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co-exposure to 1μM melatonin of either the breast cancer cell line MCF-7, or the ovarian carcinoma cell line A2780. In a rat model of paclitaxel-induced painful peripheral neuropathy, pre-treatment with oral melatonin (5/10/50mg/kg), given as a daily bolus dose, was protective, dose-dependently limiting development of mechanical hypersensitivity (19/43/47% difference from paclitaxel control, respectively). Melatonin (10mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel-induced elevated 8-isoprostane F2α levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel-induced reduction of C fibre activity-dependent slowing (by 64%). Notably melatonin limited the development of mechanical hypersensitivity in both male and female animals (by 50/41%, respectively) and an additive effect was found when melatonin was given with the current treatment, duloxetine (75/62% difference, respectively). Melatonin is therefore a potential treatment to limit the development of painful neuropathy resulting from chemotherapy treatment.

    更新日期:2017-09-06
  • Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-08-10
    Bharati Sinha, Qiaofeng Wu, Wei Li, Yanyang Tu, Ana C. Sirianni, Yanchun Chen, Jiying Jiang, Xinmu Zhang, Shuanhu Zhou, Wu Chen, Russel J. Reiter, Simon Manning, Nirav J. Patel, Ali M. Aziz-Sultan, Terri E. Inder, Robert M. Friedlander, Jianfang Fu, Xin Wang

    The function of melatonin as a protective agent against newborn hypoxic-ischemic (H-I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases is still evolving. The present study was designed to investigate whether expression of MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 knockout mice following H-I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H-I brain injury, at least in part, by the restoration of MT1 receptors, the inhibition of mitochondrial cell death pathways, and the suppression of astrocytic and microglial activation.

    更新日期:2017-09-06
  • Maternal administration of melatonin exerts short- and long-term neuroprotective effects on the offspring from lipopolysaccharide-treated mice
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-09-06
    Ana Paula Domínguez Rubio, Fernando Correa, Julieta Aisemberg, Damián Dorfman, María Victoria Bariani, Ruth Estela Rosenstein, María Zorrilla Zubilete, Ana María Franchi

    Preterm birth is a major contributor to early and delayed physical and cognitive impairment. Epidemiological and experimental data indicate that maternal infections are a significant and preventable cause of preterm birth. Recently, melatonin has been suggested to exert neuroprotective effects in several models of brain injury. Here, we sought to investigate whether the administration of melatonin is able to prevent lipopolysaccharide (LPS)-induced fetal brain damage in a model of LPS-induced preterm labor. For this purpose, 15-day pregnant BALB/c mice received intraperitoneally 2 doses of LPS or vehicle: the first one at 10:00 hours (0.26 mg/kg) and the second at 13:00 hours (0.52 mg/kg). On day 14 of pregnancy, a group of mice was subcutaneously implanted with a pellet of 25 mg melatonin. This experimental protocol resulted in 100% of preterm birth and pup death in the LPS group and a 50% of term birth and pup survival in the melatonin + LPS group. In the absence of melatonin, fetuses from LPS-treated mothers showed histological signs of brain damage, microglial/macrophage activation, and higher levels of IL-1β, inducible nitric oxide synthase (NOS), and neuronal NOS mRNAs as well as increased histone acetyltransferase activity and histone H3 hyperacetylation. In contrast, antenatal administration of melatonin prevented LPS-induced fetal brain damage. Moreover, when behavioral traits were analyzed in the offspring from control, melatonin, and melatonin + LPS, no significant differences were found, suggesting that melatonin prevented LPS-induced long-term neurodevelopmental impairments. Collectively, our results suggest that melatonin could be a new therapeutic tool to prevent fetal brain damage and its long-term consequences induced by maternal inflammation.

    更新日期:2017-09-06
  • Melatonin ameliorates hypoglycemic stress-induced brain endothelial tight junction injury by inhibiting protein nitration of TP53-induced glycolysis and apoptosis regulator
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-09-06
    Cheng-kun Wang, Muhammad Masood Ahmed, Quan Jiang, Nan-nan Lu, Chao Tan, Yin-ping Gao, Qaisar Mahmood, Dan-yang Chen, Kohji Fukunaga, Mei Li, Zhong Chen, Christopher S. Wilcox, Ying-mei Lu, Zheng-hong Qin, Feng Han

    Severe hypoglycemia has a detrimental impact on the cerebrovasculature, but the molecular events that lead to the disruption of the integrity of the tight junctions remain unclear. Here, we report that the microvessel integrity was dramatically compromised (59.41% of wild-type mice) in TP53-induced glycolysis and apoptosis regulator (TIGAR) transgenic mice stressed by hypoglycemia. Melatonin, a potent antioxidant, protects against hypoglycemic stress-induced brain endothelial tight junction injury in the dosage of 400 nmol/L in vitro. FRET (fluorescence resonance energy transfer) imaging data of endothelial cells stressed by low glucose revealed that TIGAR couples with calmodulin to promote TIGAR tyrosine nitration. A tyrosine 92 mutation interferes with the TIGAR-dependent NADPH generation (55.60% decreased) and abolishes its protective effect on tight junctions in human brain microvascular endothelial cells. We further demonstrate that the low-glucose-induced disruption of occludin and Caludin5 as well as activation of autophagy was abrogated by melatonin-mediated blockade of nitrosative stress in vitro. Collectively, we provide information on the detailed molecular mechanisms for the protective actions of melatonin on brain endothelial tight junctions and suggest that this indole has translational potential for severe hypoglycemia-induced neurovascular damage.

    更新日期:2017-09-06
  • Cadmium-induced melatonin synthesis in rice requires light, hydrogen peroxide, and nitric oxide: Key regulatory roles for tryptophan decarboxylase and caffeic acid O-methyltransferase
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-09-06
    Kyungjin Lee, Geun-Hee Choi, Kyoungwhan Back

    In plants, melatonin production is induced by stimuli such as cold and drought, and cadmium (Cd) is the best elicitor of melatonin production in rice. However, the mechanism by which Cd induces melatonin synthesis in plants remains unknown. We challenged rice seedlings with Cd under different light conditions and found that continuous light produced the highest levels of melatonin, while continuous dark failed to induce melatonin production. Transcriptional and translational induction of tryptophan decarboxylase contributed to the light induction of melatonin during Cd treatment, whereas the protein level of light-induced caffeic acid O-methyltransferase (COMT) was decreased by Cd treatment. In analogy, COMT enzyme activity was inhibited in vitro by Cd in a dose-dependent manner. Notably, the Cd-induced melatonin synthesis was significantly impaired by treatment with either an H2O2 production inhibitor (DPI) or an NO scavenger (cPTIO). The combination of both inhibitors almost completely abolished Cd-induced melatonin synthesis, suggesting an absolute requirement for H2O2 and NO. However, neither serotonin nor N-acetylserotonin (NAS) was induced by H2O2 alone. In contrast, NO significantly induced serotonin production but not NAS or melatonin production. This indicated that serotonin did not enter chloroplasts, where serotonin N-acetyltransferase (SNAT) is constitutively expressed. This suggests that chloroplastidic SNAT expression prevents increased melatonin production after exposure to stress, ultimately leading to the maintenance of a steady-state melatonin level inside cells.

    更新日期:2017-09-06
  • Melatonin reduces inflammatory response in peripheral T helper lymphocytes from relapsing-remitting multiple sclerosis patients
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-09-06
    Nuria Álvarez-Sánchez, Ivan Cruz-Chamorro, María Díaz-Sánchez, Helia Sarmiento-Soto, Pablo Medrano-Campillo, Alicia Martínez-López, Patricia J. Lardone, Juan M. Guerrero, Antonio Carrillo-Vico

    Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system in which the immune system plays a central role. In particular, effector populations such as T helper (Th) 1, Th9, Th17, and Th22 cells are involved in disease development, whereas T regulatory cells (Tregs) are associated with the resolution of the disease. Melatonin levels are impaired in patients with MS, and exogenous melatonin ameliorates the disease in MS animal models by modulating the Th1/Th17/Treg responses and also improves quality of life and several symptoms in patients with MS. However, no study has examined melatonin's effect on T cells from relapsing-remitting MS (RR-MS) patients. Therefore, the objectives of the present study were to evaluate the effects of the in vitro administration of melatonin to peripheral blood mononuclear cells (PBMCs) from 64 RR-MS patients and 64 sex- and age-matched healthy subjects on Th1, Th9, Th17, Th22, and Treg responses and to analyze the expression of the melatonin effector/receptor system in these cells. Melatonin decreased Th1 and Th22 responses in patients, whereas it did not affect the Th17 and Treg subsets. Melatonin also promoted skewing toward a more protective cytokine microenvironment, as shown by an increased anti-inflammatory/Th1 ratio. Furthermore, for the first time, we describe the overexpression of the melatonin effector/receptor system in PBMCs from patients with MS; this alteration might be relevant to the disease because acetylserotonin O-methyltransferase expression significantly correlates with disease progression and T effector/regulatory responses in patients. Therefore, our data suggest that melatonin may be an effective treatment for MS.

    更新日期:2017-09-06
  • Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-08-21
    Hao Zhou, Dandan Li, Pingjun Zhu, Shunying Hu, Nan Hu, Sai Ma, Ying Zhang, Tianwen Han, Jun Ren, Feng Cao, Yundai Chen

    Platelet activation is a major (patho-) physiological mechanism that underlies ischemia/reperfusion (I/R) injury. In this study, we explored the molecular signals for platelet hyperactivity and investigated the beneficial effects of melatonin on platelet reactivity in response to I/R injury. After reperfusion, peroxisome proliferator-activated receptor γ (PPARγ) was progressively downregulated in patients with acute myocardial infarction undergoing coronary artery bypass grafting (CABG) surgery and in mice with I/R injury model. Loss of PPARγ was closely associated with FUN14 domain containing 1 (FUNDC1) dephosphorylation and mitophagy activation, leading to increased mitochondrial electron transport chain complex (ETC.) activity, enhanced mitochondrial respiratory function, and elevated ATP production. The improved mitochondrial function strongly contributed to platelet aggregation, spreading, expression of P-selectin, and final formation of micro-thromboses, eventually resulting in myocardial dysfunction and microvascular structural destruction. However, melatonin powerfully suppressed platelet activation via restoration of the PPARγ content in platelets, which subsequently blocked FUNDC1-required mitophagy, mitochondrial energy production, platelet hyperactivity, and cardiac I/R injury. In contrast, genetic ablation of PPARγ in platelet abolished the beneficial effects of melatonin on mitophagy, mitochondrial ATP supply, and platelet activation. Our results lay the foundation for the molecular mechanism of platelet activation in response to I/R injury and highlight that the manipulation of the PPARγ/FUNDC1/mitophagy pathway by melatonin could be a novel strategy for cardioprotection in the setting of cardiac I/R injury.

    更新日期:2017-09-06
  • Melatonin protects against the pathological cardiac hypertrophy induced by transverse aortic constriction through activating PGC-1β: In vivo and in vitro studies
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-08-16
    Mengen Zhai, Zhenhua Liu, Bin Zhang, Lin Jing, Buying Li, Kaifeng Li, Xiuju Chen, Meng Zhang, Bo Yu, Kai Ren, Yang Yang, Wei Yi, Jian Yang, Jincheng Liu, Dinghua Yi, Hongliang Liang, Zhenxiao Jin, Russel J. Reiter, Weixun Duan, Shiqiang Yu

    Melatonin, a circadian molecule secreted by the pineal gland, confers a protective role against cardiac hypertrophy induced by hyperthyroidism, chronic hypoxia, and isoproterenol. However, its role against pressure overload-induced cardiac hypertrophy and the underlying mechanisms remains elusive. In this study, we investigated the pharmacological effects of melatonin on pathological cardiac hypertrophy induced by transverse aortic constriction (TAC). Male C57BL/6 mice underwent TAC or sham surgery at day 0 and were then treated with melatonin (20 mg/kg/day, via drinking water) for 4 or 8 weeks. The 8-week survival rate following TAC surgery was significantly increased by melatonin. Melatonin treatment for 8 weeks markedly ameliorated cardiac hypertrophy. Compared with the TAC group, melatonin treatment for both 4 and 8 weeks reduced pulmonary congestion, upregulated the expression level of α-myosin heavy chain, downregulated the expression level of β-myosin heavy chain and atrial natriuretic peptide, and attenuated the degree of cardiac fibrosis. In addition, melatonin treatment slowed the deterioration of cardiac contractile function caused by pressure overload. These effects of melatonin were accompanied by a significant upregulation in the expression of peroxisome proliferator-activated receptor-gamma co-activator-1 beta (PGC-1β) and the inhibition of oxidative stress. In vitro studies showed that melatonin also protects against angiotensin II-induced cardiomyocyte hypertrophy and oxidative stress, which were largely abolished by knocking down the expression of PGC-1β using small interfering RNA. In summary, our results demonstrate that melatonin protects against pathological cardiac hypertrophy induced by pressure overload through activating PGC-1β.

    更新日期:2017-09-06
  • Melatonin inhibits nucleus pulposus (NP) cell proliferation and extracellular matrix (ECM) remodeling via the melatonin membrane receptors mediated PI3K-Akt pathway
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-08-16
    Zheng Li, Xingye Li, Chong Chen, Matthew T. V. Chan, William Ka Kei Wu, Jianxiong Shen

    Pinealectomy in vertebrates accelerated intervertebral disk degeneration (IDD). However, the potential mechanisms, particularly melatonin's role, are still to be clarified. In this study, for first time, melatonin membrane receptors of MT1 and MT2 were found to be present in the human intervertebral disk tissues and nucleus pulposus (NP) cells, respectively. Melatonin treatment significantly inhibited NP cell proliferation in dose-dependent manner. Accordingly, melatonin down-regulated gene expression of cyclin D1, PCNA, matrix metallopeptidase-3, and matrix metallopeptidase-9 and upregulated gene expression of collagen type II alpha 1 chain and aggrecan in NP cells. These effects of melatonin were blocked by luzindole, a nonspecific melatonin membrane receptor antagonist. Signaling pathway analysis indicated that in the intervertebral disk tissues and NP cells, melatonin acted on MT1/2 and subsequently reduced phosphorylation of phosphoinositide 3-kinase p85 regulatory subunit, phosphoinositide-dependent kinase-1, and Akt. The results indicate that melatonin is a crucial regulator of NP cell function and plays a vital role in prevention of IDD.

    更新日期:2017-09-06
  • Melatonin impedes Tet1-dependent mGluR5 promoter demethylation to relieve pain
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-08-16
    Ming-Chun Hsieh, Yu-Cheng Ho, Cheng-Yuan Lai, Dylan Chou, Hsueh-Hsiao Wang, Gin-Den Chen, Tzer-Bin Lin, Hsien-Yu Peng

    Melatonin (N-acetyl-5-methoxytryptamine)/MT2 receptor-dependent epigenetic modification represents a novel pathway in the treatment of neuropathic pain. Because spinal ten-eleven translocation methylcytosine dioxygenase 1 (Tet1)-dependent epigenetic demethylation has recently been linked to pain hypersensitivity, we hypothesized that melatonin/MT2-dependent analgesia involves spinal Tet1-dependent demethylation. Here, we showed that spinal Tet1 gene transfer by intrathecal delivery of Tet1-encoding vectors to naïve rats produced profound and long-lasting nociceptive hypersensitivity. In addition, enhanced Tet1 expression, Tet1-metabotropic glutamate receptor subtype 5 (mGluR5) promoter coupling, demethylation at the mGluR5 promoter, and mGluR5 expression in dorsal horn neurons were observed. Rats subjected to spinal nerve ligation and intraplantar complete Freund's adjuvant injection displayed tactile allodynia and behavioral hyperalgesia associated with similar changes in the dorsal horn. Notably, intrathecal melatonin injection reversed the protein expression, protein-promoter coupling, promoter demethylation, and pain hypersensitivity induced by Tet1 gene transfer, spinal nerve ligation, and intraplantar complete Freund's adjuvant injection. All the effects caused by melatonin were blocked by pretreatment with a MT2 receptor-selective antagonist. In conclusion, melatonin relieves pain by impeding Tet1-dependent demethylation of mGluR5 in dorsal horn neurons through the MT2 receptor. Our findings link melatonin/MT2 signaling to Tet1-dependent epigenetic demethylation of nociceptive genes for the first time and suggest melatonin as a promising therapy for the treatment of pain.

    更新日期:2017-09-06
  • Rapid modulation of the silent information regulator 1 by melatonin after hypoxia-ischemia in the neonatal rat brain
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-08-07
    Silvia Carloni, Giulia Riparini, Giuseppe Buonocore, Walter Balduini

    Increasing evidence indicates that melatonin possesses protective effects toward different kinds of damage in various organs, including the brain. In a neonatal model of hypoxia-ischemia (HI), melatonin was neuroprotective and preserved the expression of the silent information regulator 1 (SIRT1) 24 hours after the insult. This study aimed to gain more insight into the role of SIRT1 in the protective effect of melatonin after HI by studying the early (1 hour) modulation of SIRT1 and its downstream targets, and the consequences on necrosis, apoptosis, autophagy, and glial cell activation. We found that melatonin administered 5 minutes after the ischemic insult significantly reduced necrotic cell death assessed 1 hour after its administration. In parallel, we found a reduced activation of the early phases of intrinsic apoptosis, detected by reduced BAX translocation to the mitochondria and preservation of the mitochondrial expression of cytochrome C, indicating a reduced outer mitochondrial membrane permeabilization in the melatonin-treated ischemic animals. These effects were concomitant to increased expression and activity of SIRT1, reduced expression and acetylation of p53, and increased autophagy activation. Melatonin also reduced HI-induced glial cells activation. SIRT1 was expressed in neurons after HI and melatonin but not in reactive glial cells expressing GFAP. Colocalization between SIRT1 and GFAP was found in some cells in control conditions. In summary, our results provide more insight into the connection between SIRT1 and melatonin in neuroprotection. The possibility that melatonin-induced SIRT1 activity might contribute to differentiate neuronal progenitor cells during the neurodegenerative process needs to be further investigated.

    更新日期:2017-09-06
  • Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27Kip1 promoter in primordial follicles
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-07-18
    Hoon Jang, Younghwa Na, Kwonho Hong, Sangho Lee, Sohyeon Moon, Minha Cho, Miseon Park, Ok-Hee Lee, Eun Mi Chang, Dong Ryul Lee, Jung Jae Ko, Woo Sik Lee, Youngsok Choi

    Premature ovarian failure during chemotherapy is a serious problem for young women with cancer. To preserve the fertility of these patients, approaches to prevent chemotherapy-induced ovarian failure are needed. In a previous study, we reported that melatonin treatment prevents the depletion of the dormant follicle pool via repression of the simultaneous activation of dormant primordial follicles by cisplatin. However, melatonin's protective effect was only partial and thus insufficient. In this study, we found that the hormone ghrelin enhances the protective effect of melatonin against cisplatin-induced ovarian failure in mouse model. Co-administration of melatonin and ghrelin more effectively prevented cisplatin-induced follicle disruption. Simultaneous treatment with melatonin and ghrelin almost restored the number of primordial follicles and the corpus luteum in cisplatin-treated ovaries, compared with single administration. We found melatonin and ghrelin receptors on the cell membrane of premature oocytes of primordial follicles. In addition, melatonin and ghrelin co-administration inhibited the cisplatin-induced phosphorylation of PTEN and FOXO3a that induces cytoplasmic translocation of FOXO3a. Inhibition of FOXO3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO3a for the p27Kip1 promoter in primordial follicles. Co-administration of melatonin and ghrelin in cisplatin-treated ovaries restored the expression of p27Kip1, which is critical for retention of the dormant status of primordial follicles. In conclusion, these findings suggest that melatonin and ghrelin co-administration is suitable for use as a fertoprotective adjuvant therapy during cisplatin chemotherapy in young female cancer patients.

    更新日期:2017-09-06
  • Melatonin reduces endoplasmic reticulum stress and corneal dystrophy-associated TGFBIp through activation of endoplasmic reticulum-associated protein degradation
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-07-18
    Seung-il Choi, Eunhee Lee, Begum Akuzum, Jang Bin Jeong, Yong-Sun Maeng, Tae-im Kim, Eung Kweon Kim

    Endoplasmic reticulum (ER) stress is emerging as a factor for the pathogenesis of granular corneal dystrophy type 2 (GCD2). This study was designed to investigate the molecular mechanisms underlying the protective effects of melatonin on ER stress in GCD2. Our results showed that GCD2 corneal fibroblasts were more susceptible to ER stress-induced death than were wild-type cells. Melatonin significantly inhibited GCD2 corneal cell death, caspase-3 activation, and poly (ADP-ribose) polymerase 1 cleavage caused by the ER stress inducer, tunicamycin. Under ER stress, melatonin significantly suppressed the induction of immunoglobulin heavy-chain-binding protein (BiP) and activation of inositol-requiring enzyme 1α (IRE1α), and their downstream target, alternative splicing of X-box binding protein 1(XBP1). Notably, the reduction in BiP and IRE1α by melatonin was suppressed by the ubiquitin-proteasome inhibitor, MG132, but not by the autophagy inhibitor, bafilomycin A1, indicating involvement of the ER-associated protein degradation (ERAD) system. Melatonin treatment reduced the levels of transforming growth factor-β-induced protein (TGFBIp) significantly, and this reduction was suppressed by MG132. We also found reduced mRNA expression of the ERAD system components HRD1 and SEL1L, and a reduced level of SEL1L protein in GCD2 cells. Interestingly, melatonin treatments enhanced SEL1L levels and suppressed the inhibition of SEL1L N-glycosylation caused by tunicamycin. In conclusion, this study provides new insights into the mechanisms by which melatonin confers its protective actions during ER stress. The results also indicate that melatonin might have potential as a therapeutic agent for ER stress-related diseases including GCD2.

    更新日期:2017-09-06
  • Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-07-18
    Longsen Han, Haichao Wang, Ling Li, Xiaoyan Li, Juan Ge, Russel J. Reiter, Qiang Wang

    Maternal obesity in humans is associated with poor outcomes across the reproductive spectrum. Emerging evidence indicates that these defects are likely attributed to factors within the oocyte. Although various molecules and pathways may contribute to impaired oocyte quality, prevention of fertility issues associated with maternal obesity is a challenge. Using mice fed a high-fat diet (HFD) as an obesity model, we document spindle disorganization, chromosome misalignment, and elevated reactive oxygen species (ROS) levels in oocytes from obese mice. Oral administration of melatonin to HFD mice not only reduces ROS generation, but also prevents spindle/chromosome anomalies in oocytes, consequently promoting the developmental potential of early embryos. Consistent with this finding, we find that melatonin supplement during in vitro maturation also markedly attenuates oxidative stress and meiotic defects in HFD oocytes. Finally, by performing morpholino knockdown and acetylation-mimetic mutant overexpression assays, we reveal that melatonin ameliorates maternal obesity-induced defective phenotypes in oocytes through the SIRT3-SOD2-dependent mechanism. In sum, our data uncover the marked beneficial effects of melatonin on oocyte quality from obese females; this opens a new area for optimizing culture system as well as fertility management.

    更新日期:2017-09-06
  • Plant mitochondria synthesize melatonin and enhance the tolerance of plants to drought stress
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-07-17
    Lin Wang, Chao Feng, Xiaodong Zheng, Yan Guo, Fangfang Zhou, Dongqian Shan, Xuan Liu, Jin Kong

    Synthesis of melatonin in mitochondria was reported in animals. However, there is no report on whether plant mitochondria also produce melatonin. Herein, we show that plant mitochondria are a major site for melatonin synthesis. In an in vitro study, isolated apple mitochondria had the capacity to generate melatonin. Subcellular localization analysis documented that an apple SNAT isoform, MzSNAT5, was localized in the mitochondria of both Arabidopsis protoplasts and apple callus cells. The kinetic analysis revealed that the recombinant MzSNAT5 protein exhibited high enzymatic activity to catalyze serotonin to N-acetylserotonin with the Km and Vmax of 55 μmol/L and 0.909 pmol/min/mg protein at 35°C, respectively; this pathway functioned over a wide range of temperatures from 5 to 75°C. In an in vivo study, MzSNAT5 was drought inducible. The transgenic Arabidopsis ectopically expressing MzSNAT5 elevated the melatonin level and, hence, enhanced drought tolerance. The mechanistic study indicated that the ectopically expressing MzSNAT5 allows plant mitochondria to increase melatonin synthesis. As a potent free radical scavenger, melatonin reduces the oxidative stress caused by the elevated reactive oxygen species which are generated under drought stress in plants. Our findings provide evidence that engineered melatonin-enriched plants exhibit enhanced oxidative tolerance.

    更新日期:2017-09-06
  • Melatonin delays photoreceptor degeneration in a mouse model of autosomal recessive retinitis pigmentosa
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-06-20
    Xiao-Jian Xu, Shu-Min Wang, Ying Jin, Yun-Tao Hu, Kang Feng, Zhi-Zhong Ma

    Retinitis pigmentosa (RP) comprises a group of incurable inherited retinal degenerations. Targeting common processes, instead of mutation-specific treatment, has proven to be an innovative strategy to combat debilitating retinal degeneration. Growing evidence indicates that melatonin possesses a potent activity against neurodegenerative disorders by mitigating cell damage associated with apoptosis and inflammation. Given the pleiotropic role of melatonin in central nervous system, the aim of the present study was to investigate whether melatonin would afford protection against retinal degeneration in autosomal recessive RP (arRP). Rd10, a well-characterized murine model of human arRP, received daily intraperitoneal injection of melatonin (15 mg/kg) between postnatal day (P) 13 and P30. Retinas treated with melatonin or vehicle were harvested for analysis at P30 and P45, respectively. The findings showed that melatonin could dampen the photoreceptors death and delay consequent retinal degeneration. We also observed that melatonin weakened the expression of glial fibrillary acidic protein (GFAP) in Müller cells. Additionally, melatonin could alleviate retinal inflammatory response visualized by IBA1 staining, which was further corroborated by downregulation of inflammation-related genes, such as tumor necrosis factor alpha (Tnf-α), chemokine (C-C motif) ligand 2 (Ccl2), and chemokine (C-X-C motif) ligand 10 (Cxcl10). These data revealed that melatonin could ameliorate retinal degeneration through potentially attenuating apoptosis, reactive gliosis, and microglial activation in rd10 mice. Moreover, these results suggest melatonin as a promising agent improving photoreceptors survival in human RP.

    更新日期:2017-09-06
  • Melatonin protects bone marrow mesenchymal stem cells against iron overload-induced aberrant differentiation and senescence
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-06-20
    Fan Yang, Lei Yang, Yuan Li, Gege Yan, Chao Feng, Tianyi Liu, Rui Gong, Ye Yuan, Ning Wang, Elina Idiiatullina, Timur Bikkuzin, Valentin Pavlov, Yang Li, Chaorun Dong, Dawei Wang, Yang Cao, Zhenbo Han, Lai Zhang, Qi Huang, Fengzhi Ding, Zhengang Bi, Benzhi Cai

    Bone marrow mesenchymal stem cells (BMSCs) are an expandable population of stem cells which can differentiate into osteoblasts, chondrocytes and adipocytes. Dysfunction of BMSCs in response to pathological stimuli contributes to bone diseases. Melatonin, a hormone secreted from pineal gland, has been proved to be an important mediator in bone formation and mineralization. The aim of this study was to investigate whether melatonin protected against iron overload-induced dysfunction of BMSCs and its underlying mechanisms. Here, we found that iron overload induced by ferric ammonium citrate (FAC) caused irregularly morphological changes and markedly reduced the viability in BMSCs. Consistently, osteogenic differentiation of BMSCs was significantly inhibited by iron overload, but melatonin treatment rescued osteogenic differentiation of BMSCs. Furthermore, exposure to FAC led to the senescence in BMSCs, which was attenuated by melatonin as well. Meanwhile, melatonin was able to counter the reduction in cell proliferation by iron overload in BMSCs. In addition, protective effects of melatonin on iron overload-induced dysfunction of BMSCs were abolished by its inhibitor luzindole. Also, melatonin protected BMSCs against iron overload-induced ROS accumulation and membrane potential depolarization. Further study uncovered that melatonin inhibited the upregulation of p53, ERK and p38 protein expressions in BMSCs with iron overload. Collectively, melatonin plays a protective role in iron overload-induced osteogenic differentiation dysfunction and senescence through blocking ROS accumulation and p53/ERK/p38 activation.

    更新日期:2017-09-06
  • Melatonin influences the sonic hedgehog signaling pathway in porcine cumulus oocyte complexes
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-06-09
    Sanghoon Lee, Jun-Xue Jin, Anukul Taweechaipaisankul, Geon A. Kim, Curie Ahn, Byeong Chun Lee

    Melatonin, which is synthesized in the pineal gland and peripheral reproductive organs, has antioxidant properties and regulates physiological processes. It is well known that melatonin affects in vitro maturation (IVM) of oocytes and embryonic development in many species. However, beneficial effects of melatonin on IVM have been explained mainly by indirect antioxidant effects and little information is available on the underlying mechanism by which melatonin directly acts on porcine cumulus oocyte complexes (COCs). Sonic hedgehog (Shh) signaling is important for follicle development, oocyte maturation, and embryo development, and there may be a relationship between melatonin and Shh signaling. To examine this, we designed three groups: (i) control, (ii) melatonin (10−9 mol/L), and (iii) melatonin with cyclopamine (2 μmol/L; Shh signaling inhibitor). The aim of this study was to investigate the effects of these agents on cumulus expansion, oocyte maturation, embryo development after parthenogenetic activation (PA), gene expression in cumulus cells, oocytes and blastocysts, and protein expression in COCs. Melatonin significantly increased the proportion of COCs exhibiting complete cumulus expansion (degree 4), PA blastocyst formation rates, and total cell numbers, which were inhibited by addition of cyclopamine. Simultaneously, the expression of cumulus expansion-related genes (Ptgs1, Ptgs2, and Has2) and Shh signaling-related genes (Shh, Pthc1, Smo, and Gli1) and proteins (Ptch1, Smo, and Gli1) in cumulus cells was upregulated in the melatonin-treated group, and these effects were also inhibited by cyclopamine. In conclusion, our results suggest that Shh signaling mediates effects of melatonin to improve porcine cumulus expansion and subsequent embryo development.

    更新日期:2017-09-06
  • The role of melatonin in the neurodevelopmental etiology of schizophrenia: A study in human olfactory neuronal precursors
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-06-09
    Tania Galván-Arrieta, Citlali Trueta, Montserrat G. Cercós, Marcela Valdés-Tovar, Salvador Alarcón, Julian Oikawa, Horacio Zamudio-Meza, Gloria Benítez-King

    Dim light exposure of the mother during pregnancy has been proposed as one of the environmental factors that affect the fetal brain development in schizophrenia. Melatonin circulating levels are regulated by the environmental light/dark cycle. This hormone stimulates neuronal differentiation in the adult brain. However, little is known about its role in the fetal human brain development. Olfactory neuronal precursors (ONPs) are useful for studying the physiopathology of neuropsychiatric diseases because they mimic all the stages of neurodevelopment in culture. Here, we first characterized whether melatonin stimulates neuronal differentiation in cloned ONPs obtained from a healthy control subject (HCS). Then, melatonin effects were evaluated in primary cultures of ONPs derived from a patient diagnosed with schizophrenia (SZ) and an age- and gender-matched HCS. Axonal formation was evidenced morphologically by tau immunostaining and by GSK3β phosphorylated state. Potassium-evoked secretion was assessed as a functional feature of differentiated neurons. As well, we report the expression of MT1/2 receptors in human ONPs for the first time. Melatonin stimulated axonal formation and ramification in cloned ONPs through a receptor-mediated mechanism and enhanced the amount and velocity of axonal and somatic secretion. SZ ONPs displayed reduced axogenesis associated with lower levels of pGSK3β and less expression of melatonergic receptors regarding the HCS ONPs. Melatonin counteracted this reduction in SZ cells. Altogether, our results show that melatonin signaling is crucial for functional differentiation of human ONPs, strongly suggesting that a deficit of this indoleamine may lead to an impaired neurodevelopment which has been associated with the etiology of schizophrenia.

    更新日期:2017-09-06
  • Issue Information
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-08-02

    None

    更新日期:2017-09-06
  • The role and therapeutic potential of melatonin in age-related ocular diseases
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-07-18
    Almudena Crooke, Fernando Huete-Toral, Basilio Colligris, Jesús Pintor

    The eye is continuously exposed to solar UV radiation and pollutants, making it prone to oxidative attacks. In fact, oxidative damage is a major cause of age-related ocular diseases including cataract, glaucoma, age-related macular degeneration, and diabetic retinopathy. As the nature of lens cells, trabecular meshwork cells, retinal ganglion cells, retinal pigment epithelial cells, and photoreceptors is postmitotic, autophagy plays a critical role in their cellular homeostasis. In age-related ocular diseases, this process is impaired, and thus, oxidative damage becomes irreversible. Other conditions such as low-grade chronic inflammation and angiogenesis also contribute to the development of retinal diseases (glaucoma, age-related macular degeneration and diabetic retinopathy). As melatonin is known to have remarkable qualities such as antioxidant/antinitridergic, mitochondrial protector, autophagy modulator, anti-inflammatory, and anti-angiogenic, it can represent a powerful tool to counteract all these diseases. The present review analyzes the role and therapeutic potential of melatonin in age-related ocular diseases, focusing on nitro-oxidative stress, autophagy, inflammation, and angiogenesis mechanisms.

    更新日期:2017-09-06
  • Melatonin enhances neural stem cell differentiation and engraftment by increasing mitochondrial function
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-05-18
    Miguel Mendivil-Perez, Viviana Soto-Mercado, Ana Guerra-Librero, Beatriz I. Fernandez-Gil, Javier Florido, Ying-Qiang Shen, Miguel A. Tejada, Vivian Capilla-Gonzalez, Iryna Rusanova, José M. Garcia-Verdugo, Darío Acuña-Castroviejo, Luis Carlos López, Carlos Velez-Pardo, Marlene Jimenez-Del-Rio, José M. Ferrer, Germaine Escames

    Neural stem cells (NSCs) are regarded as a promising therapeutic approach to protecting and restoring damaged neurons in neurodegenerative diseases (NDs) such as Parkinson's disease and Alzheimer's disease (PD and AD, respectively). However, new research suggests that NSC differentiation is required to make this strategy effective. Several studies have demonstrated that melatonin increases mature neuronal markers, which reflects NSC differentiation into neurons. Nevertheless, the possible involvement of mitochondria in the effects of melatonin during NSC differentiation has not yet been fully established. We therefore tested the impact of melatonin on NSC proliferation and differentiation in an attempt to determine whether these actions depend on modulating mitochondrial activity. We measured proliferation and differentiation markers, mitochondrial structural and functional parameters as well as oxidative stress indicators and also evaluated cell transplant engraftment. This enabled us to show that melatonin (25 μM) induces NSC differentiation into oligodendrocytes and neurons. These effects depend on increased mitochondrial mass/DNA/complexes, mitochondrial respiration, and membrane potential as well as ATP synthesis in NSCs. It is also interesting to note that melatonin prevented oxidative stress caused by high levels of mitochondrial activity. Finally, we found that melatonin enriches NSC engraftment in the ND mouse model following transplantation. We concluded that a combined therapy involving transplantation of NSCs pretreated with pharmacological doses of melatonin could efficiently restore neuronal cell populations in PD and AD mouse models depending on mitochondrial activity promotion.

    更新日期:2017-09-06
  • Melatonin successfully rescues hippocampal bioenergetics and improves cognitive function following drug intoxication by promoting Nrf2-ARE signaling activity
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-05-25
    Li-You Chen, Ting-Yi Renn, Wen-Chieh Liao, Fu-Der Mai, Ying-Jui Ho, George Hsiao, Ai-Wei Lee, Hung-Ming Chang

    Prolonged exposure to gamma-hydroxybutyric acid (GHB) would cause drug intoxication in which impaired cognitive function results from enhanced hippocampal oxidative stress may serve as a major symptom in this deficiency. Considering melatonin possesses significant anti-oxidative efficacy, this study aimed to determine whether melatonin would successfully promote the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) signaling, depress oxidative stress, and rescue hippocampal bioenergetics and cognitive function following drug intoxication injury. Adolescent rats subjected to 10 days of GHB were received melatonin at doses of either 10 or 100 mg/kg. Time-of-flight secondary ion mass spectrometry, biochemical assay, quantitative histochemistry, [14C]-2-deoxyglucose analysis, together with Morris water maze were employed to detect the molecular signaling, oxidative status, bioenergetic level, as well as the cognitive performances, respectively. Results indicated that in GHB-intoxicated rats, enhanced oxidative stress, increased cholesterol level, and decreased anti-oxidative enzymes activities were detected in hippocampal regions. Intense oxidative stress paralleled well with reduced bioenergetics and poor performance in behavioral testing. However, in rats treated with melatonin following GHB intoxication, all above parameters and cognitive function were gradually returned to nearly normal levels. Melatonin also remarkably promoted the translocation of Nrf2 from cytoplasm to nucleus in a dose-dependent manner, thereby increased the Nrf2-ARE signaling-related downstream anti-oxidative enzymes activities. As melatonin effectively rescues hippocampal bioenergetics through depressing the oxidative stress by promoting Nrf2-ARE molecular machinery, this study thus highlights for the first time that clinical use of melatonin may serve as a therapeutic strategy to improve the cognitive function in unsuspecting victims suffered from GHB intoxication injury.

    更新日期:2017-09-06
  • Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-06-09
    Mingming Zhang, Jie Lin, Shanjie Wang, Zheng Cheng, Jianqiang Hu, Tingting Wang, Wanrong Man, Tao Yin, Wenyi Guo, Erhe Gao, Russel J. Reiter, Haichang Wang, Dongdong Sun

    This study investigated the effects of melatonin on diabetic cardiomyopathy (DCM) and determined the underlying mechanisms. Echocardiography indicated that melatonin notably mitigated the adverse left ventricle remodeling and alleviated cardiac dysfunction in DCM. The mechanisms were attributed to increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin inhibited Mst1 phosphorylation and promoted Sirt3 expression in DCM. These results indicated that melatonin may exert its effects through Mst1/Sirt3 signaling. To verify this hypothesis, a DCM model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1−/−) mice was constructed. As expected, melatonin increased autophagy, reduced apoptosis and improved mitochondrial biogenesis in Mst1 Tg mice subjected to DCM injury, while it had no effects on Mst1−/− mice. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe the mechanisms involved. Melatonin administration promoted autophagic flux as demonstrated by elevated LC3-II and lowered p62 expression in the presence of bafilomycin A1. The results suggest that melatonin alleviates cardiac remodeling and dysfunction in DCM by upregulating autophagy, limiting apoptosis, and modulating mitochondrial integrity and biogenesis. The mechanisms are associated with Mst1/Sirt3 signaling.

    更新日期:2017-09-06
  • Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-06-20
    Mengen Zhai, Buying Li, Weixun Duan, Lin Jing, Bin Zhang, Meng Zhang, Liming Yu, Zhenhua Liu, Bo Yu, Kai Ren, Erhe Gao, Yang Yang, Hongliang Liang, Zhenxiao Jin, Shiqiang Yu

    Sirtuins are a family of highly evolutionarily conserved nicotinamide adenine nucleotide-dependent histone deacetylases. Sirtuin-3 (SIRT3) is a member of the sirtuin family that is localized primarily to the mitochondria and protects against oxidative stress-related diseases, including myocardial ischemia/reperfusion (MI/R) injury. Melatonin has a favorable effect in ameliorating MI/R injury. We hypothesized that melatonin protects against MI/R injury by activating the SIRT3 signaling pathway. In this study, mice were pretreated with or without a selective SIRT3 inhibitor and then subjected to MI/R operation. Melatonin was administered intraperitoneally (20 mg/kg) 10 minutes before reperfusion. Melatonin treatment improved postischemic cardiac contractile function, decreased infarct size, diminished lactate dehydrogenase release, reduced the apoptotic index, and ameliorated oxidative damage. Notably, MI/R induced a significant decrease in myocardial SIRT3 expression and activity, whereas the melatonin treatment upregulated SIRT3 expression and activity, and thus decreased the acetylation of superoxide dismutase 2 (SOD2). In addition, melatonin increased Bcl-2 expression and decreased Bax, Caspase-3, and cleaved Caspase-3 levels in response to MI/R. However, the cardioprotective effects of melatonin were largely abolished by the selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP), suggesting that SIRT3 plays an essential role in mediating the cardioprotective effects of melatonin. In vitro studies confirmed that melatonin also protected H9c2 cells against simulated ischemia/reperfusion injury (SIR) by attenuating oxidative stress and apoptosis, while SIRT3-targeted siRNA diminished these effects. Taken together, our results demonstrate for the first time that melatonin treatment ameliorates MI/R injury by reducing oxidative stress and apoptosis via activating the SIRT3 signaling pathway.

    更新日期:2017-09-06
  • Melatonin inhibits neuronal dysfunction-associated with neuroinflammation by atopic psychological stress in NC/Nga atopic-like mouse models
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-06-09
    Gunhyuk Park, Seung Hoon Lee, Dal-Seok Oh, Yong-ung Kim

    Atopic dermatitis (AD), also known as atopic eczema, is chronic pruritic skin disease. AD can increase psychological stress as well, increasing glucocorticoid release and exacerbating the associated symptoms. Chronic glucocorticoid elevation disturbs neuroendocrine signaling and can induce neuroinflammation, neurotoxicity, and cognitive impairment; however, it is unclear whether AD-related psychological stress elevates glucocorticoids enough to cause neuronal damage. Therefore, we assessed the effects of AD-induced stress in a mouse AD model. AD-related psychological stress increased astroglial and microglial activation, neuroinflammatory cytokine expression, and markers of neuronal loss. Notably, melatonin administration inhibited the development of skin lesions, scratching behavior, and serum IgE levels in the model mice, and additionally caused a significant reduction in corticotropin-releasing hormone responsiveness, and a significant reduction in neuronal damage. Finally, we produced similar results in a corticosterone-induced AD-like skin model. This is the first study to demonstrate that AD-related psychological stress increases neuroendocrine dysfunction, exacerbates neuroinflammation, and potentially accelerates other neurodegenerative disease states.

    更新日期:2017-09-06
  • Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-06-20
    Kunal Sharan, Kirsty Lewis, Takahisa Furukawa, Vijay K. Yadav

    Tryptophan, an essential amino acid through a series of enzymatic reactions gives rise to various metabolites, viz. serotonin and melatonin, that regulate distinct biological functions. We show here that tryptophan metabolism in the pineal gland favors bone mass accrual through production of melatonin, a pineal-derived neurohormone. Pineal gland-specific deletion of Tph1, the enzyme that catalyzes the first step in the melatonin biosynthesis lead to a decrease in melatonin levels and a low bone mass due to an isolated decrease in bone formation while bone resorption parameters remained unaffected. Skeletal analysis of the mice deficient in MT1 or MT2 melatonin receptors showed a low bone mass in MT2−/− mice while MT1−/− mice had a normal bone mass compared to the WT mice. This low bone mass in the MT2−/− mice was due to an isolated decrease in osteoblast numbers and bone formation. In vitro assays of the osteoblast cultures derived from the MT1−/− and MT2−/− mice showed a cell intrinsic defect in the proliferation, differentiation and mineralization abilities of MT2−/− osteoblasts compared to WT counterparts, and the mutant cells did not respond to melatonin addition. Finally, we demonstrate that daily oral administration of melatonin can increase bone accrual during growth and can cure ovariectomy-induced structural and functional degeneration of bone by specifically increasing bone formation. By identifying pineal-derived melatonin as a regulator of bone mass through MT2 receptors, this study expands the role played by tryptophan derivatives in the regulation of bone mass and underscores its therapeutic relevance in postmenopausal osteoporosis.

    更新日期:2017-09-06
  • Enhancement of high glucose-induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2/Akt/NF-κB pathway
    J. Pineal. Res. (IF 10.391) Pub Date : 2017-07-17
    Xaykham Onphachanh, Hyun Jik Lee, Jae Ryong Lim, Young Hyun Jung, Jun Sung Kim, Chang Woo Chae, Sei-Jung Lee, Amr Ahmed Gabr, Ho Jae Han

    Hyperglycemia is a representative hallmark and risk factor for diabetes mellitus (DM) and is closely linked to DM-associated neuronal cell death. Previous investigators reported on a genome-wide association study and showed relationships between DM and melatonin receptor (MT), highlighting the role of MT signaling by assessing melatonin in DM. However, the role of MT signaling in DM pathogenesis is unclear. Therefore, we investigated the role of mitophagy regulators in high glucose-induced neuronal cell death and the effect of melatonin against high glucose-induced mitophagy regulators in neuronal cells. In our results, high glucose significantly increased PTEN-induced putative kinase 1 (PINK1) and LC-3B expressions; as well it decreased cytochrome c oxidase subunit 4 expression and Mitotracker™ fluorescence intensity. Silencing of PINK1 induced mitochondrial reactive oxygen species (ROS) accumulation and mitochondrial membrane potential impairment, increased expressions of cleaved caspases, and increased the number of annexin V-positive cells. In addition, high glucose-stimulated melatonin receptor 1B (MTNR1B) mRNA and PINK1 expressions were reversed by ROS scavenger N-acetyl cysteine pretreatment. Upregulation of PINK1 expression in neuronal cells is suppressed by pretreatment with MT2 receptor-specific inhibitor 4-P-PDOT. We further showed melatonin stimulated Akt phosphorylation, which was followed by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation. Silencing of PINK1 expression abolished melatonin-regulated mitochondrial ROS production, cleaved caspase-3 and caspase-9 expressions, and the number of annexin V-positive cells. In conclusion, we have demonstrated the melatonin stimulates PINK1 expression via an MT2/Akt/NF-κB pathway, and such stimulation is important for the prevention of neuronal cell apoptosis under high glucose conditions.

    更新日期:2017-09-06
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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