Journal of Pineal Research最新文献

{"title":"Melatonin suppression by light involves different retinal photoreceptors in young and older adults","authors":"Raymond P. Najjar,&nbsp;Abhishek S. Prayag,&nbsp;Claude Gronfier","doi":"10.1111/jpi.12930","DOIUrl":"10.1111/jpi.12930","url":null,"abstract":"<p>Age-related sleep and circadian rhythm disturbances may be due to altered nonvisual photoreception. Here, we investigated the temporal dynamics of light-induced melatonin suppression in young and older individuals. In a within-subject design study, young and older participants were exposed for 60 min (0030-0130 at night) to nine narrow-band lights (range: 420−620 nm). Plasma melatonin suppression was calculated at 15, 30, 45, and 60 min time intervals. Individual spectral sensitivity of melatonin suppression and photoreceptor contribution were predicted for each interval and age group. In young participants, melanopsin solely drove melatonin suppression at all time intervals, with a peak sensitivity at 485.3 nm established only after 15 min of light exposure. Conversely, in older participants, spectral light-driven melatonin suppression was best explained by a more complex model combining melanopsin, S-cone, and M-cone functions, with a stable peak (~500 nm) at 30, 45, and 60 min of light exposure. Aging is associated with a distinct photoreceptor contribution to melatonin suppression by light. While in young adults melanopsin-only photoreception is a reliable predictor of melatonin suppression, in older individuals this process is jointly driven by melanopsin, S-cone, and M-cone functions. These findings offer new prospects for customizing light therapy for older individuals.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12930","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139397947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin facts: Lack of evidence that melatonin is a radical scavenger in living systems","authors":"Jean A. Boutin,&nbsp;Maxime Liberelle,&nbsp;Saïd Yous,&nbsp;Gilles Ferry,&nbsp;Françoise Nepveu","doi":"10.1111/jpi.12926","DOIUrl":"10.1111/jpi.12926","url":null,"abstract":"<p>Melatonin is a small natural compound, so called a neuro-hormone that is synthesized mainly in pineal gland in animals. Its main role is to master the clock of the body, under the surveillance of light. In other words, it transfers the information concerning night and day to the peripheral organs which, without it, could not “know” which part of the circadian rhythm the body is in. Besides its main circadian and circannual rhythms mastering, melatonin is reported to be a radical scavenger and/or an antioxidant. Because radical scavengers are chemical species able to neutralize highly reactive and toxic species such as reactive oxygen species, one would like to transfer this property to living system, despite impossibilities already largely reported in the literature. In the present commentary, we refresh the memory of the readers with this notion of radical scavenger, and review the possible evidence that melatonin could be an in vivo radical scavenger, while we only marginally discuss here the fact that melatonin is a molecular antioxidant, a feature that merits a review on its own. We conclude four things: (i) the evidence that melatonin is a scavenger in acellular systems is overwhelming and could not be doubted; (ii) the transposition of this property in living (animal) systems is (a) theoretically impossible and (b) not proven in any system reported in the literature where most of the time, the delay of the action of melatonin is over several hours, thus signing a probable induction of cellular enzymatic antioxidant defenses; (iii) this last fact needs a confirmation through the discovery of a nuclear factor—a key relay in induction processes—that binds melatonin and is activated by it and (iv) we also gather the very important description of the radical scavenging capacity of melatonin in acellular systems that is now proven and shared by many other double bond-bearing molecules. We finally discussed briefly on the reason—scientific or else—that led this description, and the consequences of this claim, in research, in physiology, in pathology, but most disturbingly in therapeutics where a vast amount of money, hope, and patient <i>bien-être</i> are at stake.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12926","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139037223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fate of melatonin orally administered in preterm newborns: Antioxidant performance and basis for neuroprotection","authors":"Francesca Garofoli,&nbsp;Valentina Franco,&nbsp;Patrizia Accorsi,&nbsp;Riccardo Albertini,&nbsp;Micol Angelini,&nbsp;Carlo Asteggiano,&nbsp;Salvatore Aversa,&nbsp;Elena Ballante,&nbsp;Renato Borgatti,&nbsp;Raffaella F. Cabini,&nbsp;Camilla Caporali,&nbsp;Luisa Chiapparini,&nbsp;Sara Cociglio,&nbsp;Elisa Fazzi,&nbsp;Stefania Longo,&nbsp;Laura Malerba,&nbsp;Valeria Materia,&nbsp;Laura Mazzocchi,&nbsp;Cecilia Naboni,&nbsp;Michela Palmisani,&nbsp;Anna Pichiecchio,&nbsp;Lorenzo Pinelli,&nbsp;Camilla Pisoni,&nbsp;Lorenzo Preda,&nbsp;Alice Riboli,&nbsp;Francesco M. Risso,&nbsp;Vittoria Rizzo,&nbsp;Elisa Rognone,&nbsp;Anna M. Simoncelli,&nbsp;Paola Villani,&nbsp;Chryssoula Tzialla,&nbsp;Stefano Ghirardello,&nbsp;Simona Orcesi","doi":"10.1111/jpi.12932","DOIUrl":"10.1111/jpi.12932","url":null,"abstract":"<p>Preterm infants cannot counteract excessive reactive oxygen species (ROS) production due to preterm birth, leading to an excess of lipid peroxidation with malondialdehyde (MDA) production, capable of contributing to brain damage. Melatonin (ME), an endogenous brain hormone, and its metabolites, act as a free radical scavenger against ROS. Unfortunately, preterms have an impaired antioxidant system, resulting in the inability to produce and release ME. This prospective, multicenter, parallel groups, randomized, double-blind, placebo-controlled trial aimed to assess: (i) the endogenous production of ME in very preterm infants (gestational age ≤ 29 + 6 WE, 28 infants in the ME and 26 in the placebo group); (ii) the exogenous hormone availability and its metabolization to the main metabolite, 6-OH-ME after 15 days of ME oral treatment; (iii) difference of MDA plasma concentration, as peroxidation marker, after treatment. Blood was collected before the first administration (T1) and after 15 days of administration (T2). ME and 6-OH-ME were detected by liquid chromatography tandem mass spectrometry, MDA was measured by liquid chromatograph with fluorescence detection. ME and 6-OH-ME were not detectable in the placebo group at any study time-point. ME was absent in the active group at T1. In contrast, after oral administration, ME and 6-OH-ME resulted highly detectable and the difference between concentrations T2 versus T1 was statistically significant, as well as the difference between treated and placebo groups at T2. MDA levels seemed stable during the 15 days of treatment in both groups. Nevertheless, a trend in the percentage of neonates with reduced MDA concentration at T2/T1 was 48.1% in the ME group versus 38.5% in the placebo group. We demonstrated that very preterm infants are not able to produce endogenous detectable plasma levels of ME during their first days of life. Still, following ME oral administration, appreciable amounts of ME and 6-OH-ME were available. The trend of MDA reduction in the active group requires further clinical trials to fix the dosage, the length of ME therapy and to identify more appropriate indexes to demonstrate, at biological and clinical levels, the antioxidant activity and consequent neuroprotectant potential of ME in very preterm newborns.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12932","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138794335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An independent comparison of the Novolytix salivary melatonin radioimmunoassay with the new Novolytix salivary melatonin enzyme-linked immunosorbent assay","authors":"Helen J. Burgess,&nbsp;David Kagan,&nbsp;Muneer Rizvydeen,&nbsp;Leslie M. Swanson,&nbsp;Hyungjin M. Kim","doi":"10.1111/jpi.12933","DOIUrl":"10.1111/jpi.12933","url":null,"abstract":"<p>The dim light melatonin onset (DLMO) is the current gold standard biomarker of the timing of the central circadian clock in humans and is often assessed from saliva samples. To date, only one commercially available salivary melatonin assay is considered accurate at the low daytime levels required to accurately detect the DLMO (Novolytix RIA RK-DSM2). The aim of this study was to conduct the first independent evaluation of a newly improved enzyme-linked immunosorbent assay (ELISA; Novolytix MLTN-96) and compare it with the recommended radioimmunoassay (RIA)—both in terms of melatonin concentrations and derived DLMOs. Twenty participants (15 females, 18–59 years old) provided saliva samples every 30 min in dim light starting 6 h before their habitual bedtime, yielding a total of 260 saliva samples. Both the RIA and ELISA yielded daytime melatonin concentrations &lt;2 pg/mL, indicating adequate accuracy to detect the DLMO. The melatonin concentrations from the two assays were highly correlated (<i>r</i> = .94, <i>p</i> &lt; .001), although the RIA yielded lower levels of melatonin concentration than the ELISA, on average by 0.70 pg/mL (<i>p</i> = .006). Seventeen DLMOs were calculated from the melatonin profiles and the DLMOs from both assays were not statistically different (<i>p</i> = .36) and were highly correlated (<i>r</i> = .97, <i>p</i> &lt; .001). Two DLMOs derived from the RIA occurred more than 30 min earlier than the DLMO derived from the ELISA. These results indicate that the new Novolytix ELISA is an appropriate assay to use if the Novolytix RIA is not feasible or available.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12933","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138794333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved","authors":"Daniel P. Cardinali","doi":"10.1111/jpi.12931","DOIUrl":"10.1111/jpi.12931","url":null,"abstract":"<p>Because the chronobiotic and cytoprotective molecule melatonin diminishes with age, its involvement in postmenopausal and senescence pathology has been considered since long. One relevant melatonin target site in aging individuals is bone where melatonin chronobiotic effects mediated by MT1 and MT2 receptors are demonstrable. Precursors of bone cells located in bone marrow are exposed to high quantities of melatonin and the possibility arises that melatonin acts a cytoprotective compound via an autacoid effect. Proteins that are incorporated into the bone matrix, like procollagen type I c-peptide, augment after melatonin exposure. Melatonin augments osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts. Osteoclasts are target cells for melatonin as they degrade bone partly by generating free radicals. Osteoclast activity and bone resorption are impaired via the free radical scavenger properties of melatonin. The administration of melatonin in chronobiotic doses (less than 10 mg daily) is commonly used in clinical studies on melatonin effect on bone. However, human equivalent doses allometrically derived from animal studies are in the 1–1.5 mg/kg/day range for a 75 kg human adult, a dose rarely used clinically. In view of the absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers, further investigation is needed to determine whether high melatonin doses have higher therapeutic efficacy in preventing bone loss.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12931","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138574347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin improves cholestatic liver disease via the gut-liver axis","authors":"Xianjiao Liu,&nbsp;Jinyan Li,&nbsp;Mengdie Shi,&nbsp;Jun Fu,&nbsp;Yubo Wang,&nbsp;Weili Kang,&nbsp;Jinyan Liu,&nbsp;Fenxia Zhu,&nbsp;Kehe Huang,&nbsp;Xingxiang Chen,&nbsp;Yunhuan Liu","doi":"10.1111/jpi.12929","DOIUrl":"10.1111/jpi.12929","url":null,"abstract":"<p>Cholestatic liver disease is characterized by disturbances in the intestinal microbiota and excessive accumulation of toxic bile acids (BA) in the liver. Melatonin (MT) can improve liver diseases. However, the underlying mechanism remains unclear. This study aimed to explore the mechanism of MT on hepatic BA synthesis, liver injury, and fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed and <i>Mdr2</i>^{<i>–/–</i>} mice. MT significantly improved hepatic injury and fibrosis with a significant decrease in hepatic BA accumulation in DDC-fed and <i>Mdr2</i>^{<i>–/–</i>} mice. MT reprogramed gut microbiota and augmented fecal bile salt hydrolase activity, which was related to increasing intestinal BA deconjugation and fecal BA excretion in both DDC-fed and <i>Mdr2</i>^{<i>–/–</i>} mice. MT significantly activated the intestinal farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF-15) axis and subsequently inhibited hepatic BA synthesis in DDC-fed and <i>Mdr2</i>^{<i>–/–</i>} mice. MT failed to improve DDC-induced liver fibrosis and BA synthesis in antibiotic-treated mice. Furthermore, MT provided protection against DDC-induced liver injury and fibrosis in fecal microbiota transplantation mice. MT did not decrease liver injury and fibrosis in DDC-fed intestinal epithelial cell-specific FXR knockout mice, suggesting that the intestinal FXR mediated the anti-fibrosis effect of MT. In conclusion, MT ameliorates cholestatic liver diseases by remodeling gut microbiota and activating intestinal FXR/FGF-15 axis-mediated inhibition of hepatic BA synthesis and promotion of BA excretion in mice.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138476366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypnotic effects of melatonin depend on the environmental lighting conditions in the rat","authors":"Yumeng Wang,&nbsp;Tom Deboer","doi":"10.1111/jpi.12928","DOIUrl":"10.1111/jpi.12928","url":null,"abstract":"<p>Acute effects of exogenous melatonin have been widely reported to promote sleep or induce drowsiness in human. However, testing of the hypnotic effects of melatonin in nocturnal rodents has yielded contradictory results. The latter may be associated with differences in concentration, lighting conditions, time of administration of melatonin, and possibly the type of analysis. In this study, electroencephalogram (EEG) and electromyogram were recorded in pigmented male Brown Norway rats under both light-dark (LD) and constant dark (DD) conditions. Melatonin was administered intraperitoneally at a moderate dose of 3 mg/kg, at either 1 h after lights on under LD condition or 1 h after the activity offset under DD condition. The dosage is known to be able to entrain nocturnal rodents in DD conditions, but does not change sleep in rodents in LD. Only the rats under DD conditions showed a significant reduction in nonrapid eye movement (NREM) sleep latency, while the NREM sleep power spectrum remained unaffected. Under LD condition, melatonin did not alter NREM and rapid eye movement (REM) sleep latency, and had only minor effects on the NREM sleep EEG. Regardless of lighting conditions, melatonin administration resulted in less, but longer episodes for all vigilance states suggesting increased vigilance state consolidation. In the discussion, we compare our results with a summary of previously published data concerning the hypnotic effects of melatonin in polysomnographic/EEG-confirmed sleep in humans and nocturnal rodents. In conclusion, the hypnotic effect of exogenous melatonin in nocturnal rodents not only depends on the time of day, and concentration, but is also influenced by the lighting conditions. Regardless of inducing sleep or not, melatonin may consolidate sleep and through that enhance sleep quality.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12928","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138456700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-species single-cell landscape of vertebrate pineal gland","authors":"Jihong Zheng,&nbsp;Wenqi Song,&nbsp;Yihang Zhou,&nbsp;Xuan Li,&nbsp;Meng Wang,&nbsp;Chao Zhang","doi":"10.1111/jpi.12927","DOIUrl":"10.1111/jpi.12927","url":null,"abstract":"<p>The pineal gland has evolved from a photoreceptive organ in fish to a neuroendocrine organ in mammals. This study integrated multiple daytime single-cell RNA-seq datasets from the pineal glands of zebrafish, rats, and monkeys, providing a detailed examination of the evolutionary transition at single-cell resolution. We identified key factors responsible for the anatomical and functional transformation of the pineal gland. We retrieved and integrated daytime single-cell transcriptomic datasets from the pineal glands of zebrafish, rats, and monkeys, resulting in a total of 22 431 cells after rigorous quality filtering. Comparative analysis was then conducted to elucidate the evolution of pineal cells, their photosensitivity, their role in melatonin production, and the signaling processes within the glands of these species. Our analysis identified distinct cellular compositions of the pineal gland in zebrafish, rats, and monkeys. Zebrafish photoreceptors exhibited comprehensive phototransduction gene expression, while specific genes, including transducin (<i>Gngt1</i>, <i>Gnb3</i>, and <i>Gngt2</i>) and phosducin (<i>Pdc</i>), were consistently present in mammalian pinealocytes. We found transcriptional similarities between the pineal gland and retina, underscoring shared evolutionary and functional pathways. Zebrafish displayed unique light-responsive circadian gene activity compared to rats and monkeys. Key ligand-receptor interactions were identified, especially involving <i>MDK</i> and <i>PTN</i>, influencing melatonin synthesis across species. Furthermore, we observed species-specific GPCR (G protein-coupled receptors) expressions related to melatonin synthesis and their alignment with retinal expressions. Our findings also highlighted specific transcription factors (TFs) and regulatory networks associated with pineal gland evolution and function. Our study provides a detailed analysis of the pineal gland's evolution from fish to mammals. We identified key transcriptional changes and controls that highlight the gland's functional diversity. Notably, we found significant ligand-receptor interactions influencing melatonin synthesis and demonstrated parallels between pineal and retinal expressions. These insights enhance our understanding of the pineal gland's role in phototransduction, melatonin production, and circadian rhythms in vertebrates.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138450553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-10-induced STAT3/NF-κB crosstalk modulates pineal and extra-pineal melatonin synthesis","authors":"Marlina O. Córdoba-Moreno,&nbsp;Gabriela Christine Santos,&nbsp;Sandra M. Muxel,&nbsp;Débora dos Santos-Silva,&nbsp;Caroline L. Quiles,&nbsp;Kassiano D. S. Sousa,&nbsp;Regina P. Markus,&nbsp;Pedro Augusto C. M. Fernandes","doi":"10.1111/jpi.12923","DOIUrl":"10.1111/jpi.12923","url":null,"abstract":"<p>Immune-pineal axis activation is part of the assembly of immune responses. Proinflammatory cytokines inhibit the pineal synthesis of melatonin while inducing it in macrophages by mechanisms dependent on nuclear factor-κB (NF-κB) activation. Cytokines activating the Janus kinase/signal transducer and activator of transcription (STAT) pathways, such as interferon-gamma (IFN-γ) and interleukin-10 (IL-10), modulate melatonin synthesis in the pineal, bone marrow (BM), and spleen. The stimulatory effect of IFN-γ upon the pineal gland depends on STAT1/NF-κB interaction, but the mechanisms controlling IL-10 effects on melatonin synthesis remain unclear. Here, we evaluated the role of STAT3 and NF-κB activation by IL-10 upon the melatonin synthesis of rats' pineal gland, BM, spleen, and peritoneal cells. The results show that IL-10-induced interaction of (p)STAT3 with specific NF-κB dimmers leads to different cell effects. IL-10 increases the pineal's acetylserotonin O-methyltransferase (ASMT), <i>N</i>-acetylserotonin, and melatonin content via nuclear translocation of NF-κB/STAT3. In BM, the nuclear translocation of STAT3/p65-NF-κB complexes increases ASMT expression and melatonin content. Increased pSTAT3/p65-NF-κB nuclear translocation in the spleen enhances phosphorylated serotonin <i>N</i>-acetyltransferase ((p)SNAT) expression and melatonin content. Conversely, in peritoneal cells, IL-10 leads to NF-κB p50/p50 inhibitory dimmer nuclear translocation, decreasing (p)SNAT expression and melatonin content. In conclusion, IL-10's effects on melatonin production depend on the NF-κB subunits interacting with (p)STAT3. Thus, variations of IL-10 levels and downstream pathways during immune responses might be critical regulatory factors adjusting pineal and extra-pineal synthesis of melatonin.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138289884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The MT1 receptor as the target of ramelteon neuroprotection in ischemic stroke","authors":"Xinmu Zhang,&nbsp;Bin Peng,&nbsp;Shenqi Zhang,&nbsp;Jian Wang,&nbsp;Xiong Yuan,&nbsp;Sharon Peled,&nbsp;Wu Chen,&nbsp;Jinyin Ding,&nbsp;Wei Li,&nbsp;Andrew Zhang,&nbsp;Qiaofeng Wu,&nbsp;Irina G. Stavrovskaya,&nbsp;Chengliang Luo,&nbsp;Bharati Sinha,&nbsp;Yanyang Tu,&nbsp;Xiaojing Yuan,&nbsp;Mingchang Li,&nbsp;Shuqing Liu,&nbsp;Jianfang Fu,&nbsp;Ali Aziz-Sultan,&nbsp;Bruce S. Kristal,&nbsp;Gil Alterovitz,&nbsp;Rose Du,&nbsp;Shuanhu Zhou,&nbsp;Xin Wang","doi":"10.1111/jpi.12925","DOIUrl":"10.1111/jpi.12925","url":null,"abstract":"<p>Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138175059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}