Journal of Pineal Research最新文献

{"title":"Protective Activity of Melatonin Combinations and Melatonin-Based Hybrid Molecules in Neurodegenerative Diseases","authors":"Francesca Galvani,&nbsp;Mariarosaria Cammarota,&nbsp;Federica Vacondio,&nbsp;Silvia Rivara,&nbsp;Francesca Boscia","doi":"10.1111/jpi.70008","DOIUrl":"https://doi.org/10.1111/jpi.70008","url":null,"abstract":"<p>The identification of protective agents for the treatment of neurodegenerative diseases is the mainstay therapeutic goal to modify the disease course and arrest the irreversible disability progression. Pharmacological therapies synergistically targeting multiple pathogenic pathways, including oxidative stress, mitochondrial dysfunction, and inflammation, are prime candidates for neuroprotection. Combination or synergistic therapy with melatonin, whose decline correlates with altered sleep/wake cycle and impaired glymphatic “waste clearance” system in neurodegenerative diseases, has a great therapeutic potential to treat inflammatory neurodegenerative states. Despite the protective outcomes observed in preclinical studies, mild or poor outcomes were observed in clinical settings, suggesting that melatonin combinations promoting synergistic actions at appropriate doses might be more suitable to treat multifactorial neurodegenerative disorders. In this review, we first summarize the key melatonin actions and pathways contributing to cell protection and its therapeutic implication in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We remark the major controversies in the field, mostly generated by the lack of a common consensus for the optimal dosing, molecular targets, and toxicity. Then, we review the literature investigating the efficacy of melatonin combinations with approved or investigational neuroprotective agents and of melatonin-containing hybrid molecules, both in vitro and in animal models of AD, PD, and MS, as well as the efficacy of add-on melatonin in clinical settings. We highlight the rationale for such melatonin combinations with a focus on the comparison with single-agent treatment and on the assays in which an additive or a synergistic effect has been achieved. We conclude that a better characterization of the mechanisms underlying such melatonin synergistic actions under neuroinflammation at appropriate doses needs to be tackled to advance successful clinical translation of neuroprotective melatonin combination therapies or melatonin-based hybrid molecules.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 8","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708051","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":"Heat Treatment of Saliva to Reduce Infectious Disease Contamination Does Not Impact the Analysis of Melatonin by Radioimmunoassay","authors":"Mark D. Salkeld,&nbsp;David J. Kennaway","doi":"10.1111/jpi.70009","DOIUrl":"10.1111/jpi.70009","url":null,"abstract":"<div>\u0000 \u0000 <p>The determination of melatonin levels in saliva represents one of the key methods for assessing the timing of the central circadian clock in humans, both in research and clinical settings. Melatonin levels in saliva are typically determined in a laboratory setting by RIA or enzyme-linked immunosorbent assay and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presented a serious challenge to the routine, safe assessment of melatonin in saliva samples. However, SARS-CoV-2 present in biological fluids can be inactivated by exposure to temperatures of at least 55–60°C for 30 min and the aim of this study was to assess the validity of applying a pretreatment heating step to saliva samples being prepared for melatonin determination using the Novolytix Radioimmunoassay (RK-DSM2). 40 archived saliva samples collected under a Dim Light Melatonin Onset sampling protocol were thawed and aliquoted into three identical groups—Controls (no pretreatment), 56°C pre-assay heat-treatment (30 min), and 70°C pre-assay heat-treatment (30 min). Melatonin concentrations in samples that were heated to 56°C for 30 min before assaying showed close agreement with the untreated controls, with the Pearson's correlation coefficient between the two sets of samples of 0.99 (<i>p</i> &lt; 0.0001) and the slope of the Deming regression analysis close to 1.0 (<i>Y</i> = 1.04<i>X</i> + 0.168). When saliva samples were pretreated to 70°C for 30 min before assaying, the subsequent melatonin determinations were still strongly correlated with the untreated controls (Pearsons correlation coefficient = 0.97 (<i>p</i> &lt; 0.0001), however melatonin concentrations were consistently overestimated when compared to the untreated controls with Deming regression slope of <i>Y</i> = 1.26<i>X</i> + 0.241. These results indicate that a 56°C pretreatment step is suitable for inclusion in standard operating protocols for melatonin determinations using the Novolytix RIA, as a way of effectively minimizing the potential for accidental pathogen exposure while handling saliva samples.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 8","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674484","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":"Melatonin Ameliorates Cadmium-Induced Liver Fibrosis Via Modulating Gut Microbiota and Bile Acid Metabolism","authors":"Xianjiao Liu,&nbsp;Weili Kang,&nbsp;Jinyan Li,&nbsp;Xin Li,&nbsp;Peng Yang,&nbsp;Mengdie Shi,&nbsp;Zhongyu Wang,&nbsp;Yanyan Wang,&nbsp;Andrea Del Pilar Abreo Medina,&nbsp;Dandan Liu,&nbsp;Fenxia Zhu,&nbsp;Hong Shen,&nbsp;Kehe Huang,&nbsp;Xingxiang Chen,&nbsp;Yunhuan Liu","doi":"10.1111/jpi.70005","DOIUrl":"10.1111/jpi.70005","url":null,"abstract":"<div>\u0000 \u0000 <p>Cadmium (Cd) is a widespread environmental contaminant with high toxicity to human health. Melatonin has been shown to improve Cd-induced liver damage. However, its mechanism has not yet been elucidated. In this study, we aimed to investigate the effects of melatonin on Cd-induced liver damage and fibrosis. A combination of 16S rRNA gene sequencing and mass spectrometry-based metabolomics was adopted to investigate changes in the gut microbiome and its metabolites on the regulation of melatonin in Cd-induced liver injury and fibrosis of mice. Further, nonabsorbable antibiotics, a fecal microbiota transplantation (FMT) program and intestine-specific farnesoid X receptor (FXR) knockout mice were employed to explore the mechanism of melatonin (MT) on liver injury and fibrosis in Cd treated mice. MT significantly improved hepatic inflammation, bile duct hyperplasia, liver damage, and liver fibrosis, with a notable decrease in liver bile acid levels in Cd-exposed mice. MT treatment remodeled the gut microbiota, improved gut barrier function, and reduced the production of gut-derived lipopolysaccharide (LPS). MT significantly decreased the intestinal tauro-β-muricholic acid levels, which are known as FXR antagonists. Notably, MT prominently activated the intestinal FXR signaling, subsequently inhibiting liver bile acid synthesis and decreasing hepatic inflammation in Cd-exposed mice. However, MT could not ameliorate Cd-induced liver damage and fibrosis in Abx-treated mice. Conversely, MT still exerted a protective effect on Cd-induced liver damage and fibrosis in FMT mice. Interestingly, MT failed to reverse liver damage and fibrosis in Cd-exposed intestinal epithelial cell-specific FXR gene knockout mice, indicating that intestinal FXR signaling mediated the protective effect of MT treatment. MT improves Cd-induced liver damage and fibrosis through reshaping the intestinal flora, activating the intestinal FXR-mediated suppression of liver bile acid synthesis and reducing LPS leakage in mice.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 8","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646362","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":"Timing Matters: Late, but Not Early, Exercise Training Ameliorates MASLD in Part by Modulating the Gut-Liver Axis in Mice","authors":"Artemiy Kovynev,&nbsp;Zhixiong Ying,&nbsp;Sen Zhang,&nbsp;Emanuele Olgiati,&nbsp;Joost M. Lambooij,&nbsp;Clara Visentin,&nbsp;Bruno Guigas,&nbsp;Quinten R. Ducarmon,&nbsp;Patrick C. N. Rensen,&nbsp;Milena Schönke","doi":"10.1111/jpi.70003","DOIUrl":"10.1111/jpi.70003","url":null,"abstract":"<p>Metabolic dysfunction-associated steatotic liver disease (MASLD) affects two billion people worldwide and is currently mostly treatable via lifestyle interventions, such as exercise training. However, it is unclear whether the positive effects of exercise are restricted to unique circadian windows. We therefore aimed to study whether the timing of exercise training differentially modulates MASLD development. Twenty weeks old male APOE*3-Leiden.CETP mice were fed a high fat-high cholesterol diet to induce MASLD and treadmill-trained for 1 h five times per week for 12 weeks either early (ZT13; E-RUN) or late (ZT22; <span>L</span>-RUN) in the dark phase while corresponding sedentary groups (E-SED and L-SED) did not. Late, but not early exercise training decreased the MASLD score, body weight, fat mass, and liver triglycerides, accompanied by an altered composition of the gut microbiota. Specifically, only late exercise training increased the abundance of short-chain fatty acid-producing bacterial families and genera, such as <i>Akkermansia, Lachnospiraceae</i>, and <i>Rikenella</i>. To assess the role of the gut microbiota in training-induced effects, the study was repeated and trained (ZT22 only, RUN) or sedentary mice (SED) served as fecal donors for sedentary recipient mice (RUN FMT and SED FMT). Fecal microbiota transplantation reduced liver weight and plasma triglycerides in RUN FMT compared to SED FMT and tended to lower the MASLD score and liver triglycerides. Timing of exercise training is a critical factor for the positive effect on MASLD in this preclinical model, and the effect of late exercise is partially mediated via the gut-liver axis.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 8","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613146","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 Protects Against Cocaine-Induced Blood−Brain Barrier Dysfunction and Cognitive Impairment by Regulating miR-320a-Dependent GLUT1 Expression","authors":"Jia-Yi Wei,&nbsp;Hui Liu,&nbsp;Yuan Li,&nbsp;Dan Zhao,&nbsp;Bo Wang,&nbsp;Hui-Jie Wang,&nbsp;Li Wang,&nbsp;Kang-Ji Wang,&nbsp;Jin-Li Yue,&nbsp;Hong-Yan Zhang,&nbsp;Tian-Yue Li,&nbsp;Yi-Jue Miao,&nbsp;Kai-Li Wang,&nbsp;Pai-Ge Tong,&nbsp;Zhuo Zhang,&nbsp;Ze-Ye Li,&nbsp;Zheng Shi,&nbsp;Jia-Yuan Yao,&nbsp;Dong-Xin Liu,&nbsp;Wen-Gang Fang,&nbsp;Bo Li,&nbsp;De-Shu Shang,&nbsp;Yuan Lyu,&nbsp;Hong-Zan Sun,&nbsp;Wei-Dong Zhao,&nbsp;Yu-Hua Chen","doi":"10.1111/jpi.70002","DOIUrl":"10.1111/jpi.70002","url":null,"abstract":"<div>\u0000 \u0000 <p>Cocaine abuse has been strongly linked to blood−brain barrier (BBB) dysfunction, though the exact mechanism by which cocaine disrupts the BBB remains unclear. In this study, we found that cocaine treatment reduces the expression of glucose transporter 1 (GLUT1) in brain microvascular endothelial cells, a key factor in cocaine-induced brain glucose uptake, BBB leakage, and cognitive impairment. Mechanistically, our results show that cocaine upregulates miR-320a, which in turn suppresses GLUT1 expression via the beta 2-adrenergic receptor (ADRB2). Notably, the administration of adeno-associated viruses encoding full-length GLUT1 or miR-320a inhibitors to the brain microvascular endothelium significantly mitigated cocaine-induced BBB leakage and cognitive deficits. Additionally, we discovered that melatonin, a well-known neuroprotective hormone, alleviates cocaine-induced BBB disruption and cognitive impairment. This protective effect of melatonin was mediated through the upregulation of miR-320a-dependent GLUT1 expression in brain endothelial cells via MT₁ receptor-mediated inhibition of the cAMP/PKA/CREB signaling pathway. In conclusion, our findings demonstrate that cocaine downregulates brain microvascular GLUT1, leading to BBB dysfunction, and highlight melatonin as a potential therapeutic agent for treating cocaine-related complications.</p></div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 8","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613145","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":"Disruption of Melatonin Signaling Leads to Lipids Accumulation in the Liver of Melatonin Proficient Mice","authors":"Varunika Goyal,&nbsp;Gianluca Tosini","doi":"10.1111/jpi.70007","DOIUrl":"10.1111/jpi.70007","url":null,"abstract":"<div>\u0000 \u0000 <p>Melatonin signaling via melatonin receptor type 1 (MT₁) and type 2 (MT₂) plays an important role in the regulation of several physiological functions. Studies in rodents and humans have demonstrated that disruption of melatonin signaling may affect glucose metabolism, insulin sensitivity, and leptin levels. Accumulating experimental evidence also indicates that in rodents the administration of exogenous melatonin has a beneficial effect on the blood lipid levels. However, the molecular mechanism by which melatonin signaling may regulate lipids is still unclear. In addition, most of the studies with mice have been performed in melatonin-deficient mice by administering exogenous melatonin at supraphysiological doses. Hence the results of these studies may be greatly affected by these two factors. In this study, we report the effects of melatonin signaling removal on the liver biology and transcriptome using melatonin-proficient mice (C3H-f^+/f+) in which MT₁ or MT₂ have been genetically ablated. Our data indicate that the absence of MT₁ or MT₂ signaling leads to disruption of the blood lipids profile and an increase in lipids deposition in the liver. These effects were more pronounced in the mice lacking MT₁ than MT₂. The gene expression profiles obtained with RNA-seq from the livers of the three genotypes revealed that removal of MT₁ affected the transcription of 4255 genes (i.e., 40.6%). Conversely, the removal of MT₂ affected the transcription of 1864 transcripts (i.e., 17.2%). Finally, we identified a group of 13 genes involved in lipids biology that may play a key role in the accumulation of lipids in the liver when melatonin signaling is disrupted. In conclusion, our study indicates that melatonin signaling is an important modulator of liver physiology and metabolism. Our study also indicated that the removal of MT₁ signaling is more deleterious than MT₂ removal.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 8","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613142","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":"From Seasonality to Species Conservation: Chronobiological Research on European Hamsters in Strasbourg, France","authors":"Stefanie Monecke","doi":"10.1111/jpi.13012","DOIUrl":"https://doi.org/10.1111/jpi.13012","url":null,"abstract":"<p>The first monograph on the European hamster from the Strasbourg region dates back to 1765. By the 1930s, a long and continuous chronobiological research tradition was established for this species, starting with the works of Charles Kayser, who published between 1938 and 1971. Another early key researcher in this area was Bernhard Canguilhem with publications from 1966 to 1999. From the 1980s onwards, “the Pévets,” Paul Pévet and his wife, Mireille Masson-Pévet, gave new energy to European hamster research. They broadened the research scope from basic hibernation research to mechanistic studies of circannual rhythms and from physiological aspects to molecular details. One main underlying question in their research was the role of melatonin. Thanks to their enthusiasm and vision, the European hamster is today one of the best – if not the best – studied circannual species. At least 73 parameters are described to cycle. Thirty-two of them have been shown to be driven by a circannual clock. Moreover, ground-breaking advances in our understanding of the mechanistic of hibernation, circannual clock functioning, and its entrainment were made. With most of this research being conducted in Strasbourg, Paul Pévet was instrumental in providing the necessary resources that made these innovative and unconventional long-term animal studies possible, contributing to fundamental research and, ultimately, to species conservation.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 7","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.13012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447762","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":"RETRACTION: Effects of Melatonin on Fatty Liver Disease: The Role of NR4A1/DNA-Pkcs/P53 Pathway, Mitochondrial Fission, and Mitophagy","authors":"","doi":"10.1111/jpi.70001","DOIUrl":"https://doi.org/10.1111/jpi.70001","url":null,"abstract":"<p><b>RETRACTION:</b> H. Zhou, W. Du, Y. Li, C. Shi, N. Hu, S. Ma, W. Wang, and J. Ren, “Effects of Melatonin on Fatty Liver Disease: The Role of NR4A1/DNA-Pkcs/P53 Pathway, Mitochondrial Fission, and Mitophagy,” <i>Journal of Pineal Research</i> 64, no. 1 (2018): e12450, https://doi.org/10.1111/jpi.12450.</p><p>The above article, published online on 05 October 2017, in Wiley Online Library (wileyonlinelibrary.com) and its correction (https://doi.org/10.1111/jpi.12946) have been retracted by agreement between the journal Editor-in-Chief, Gianluca Tosini, and John Wiley and Sons Ltd. The retraction has been agreed upon following an investigation into additional concerns raised by a third party regarding the scientific integrity of the generation of DNA-PKcsfl/fl mouse model and the reliability of the data presented in Figure 4 A and J, Figure 5E-G and Figure 7A and E. The original raw data was not available upon request from the authors. The senior corresponding author's institute stated that the study was not conducted at their university. Given the extent of the identified issues, the editors have lost confidence in the data presented and the article's conclusions can no longer be considered reliable. The first author disagrees with the retraction, and all other authors remained unresponsive.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 7","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447761","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 Inhibits ET-1 Production to Break Crosstalk Between Prostate Cancer and Bone Cells: Implication for Osteoblastic Bone Metastasis Treatment","authors":"Liang-Wei Lin,&nbsp;Tien-Huang Lin,&nbsp;Sanskruti Swain,&nbsp;Jen-Kai Fang,&nbsp;Jeng-Hung Guo,&nbsp;Shun-Fa Yang,&nbsp;Chih-Hsin Tang","doi":"10.1111/jpi.70000","DOIUrl":"https://doi.org/10.1111/jpi.70000","url":null,"abstract":"<div>\u0000 \u0000 <p>Bone metastasis is the primary cause of death among patients with advanced prostate cancer (PCa). PCa tends to spread to bones and acquire the bone-like phenotype, causing osteoblastic bone metastasis. Unfortunately, there is no effective treatment for this condition. However, melatonin, which regulates our circadian rhythm, has been found to have anti-tumor properties. It has yet to be established whether it is effective in treating osteoblastic PCa metastasis. Our findings show that melatonin inhibits the production of endothelin-1 (ET-1) in osteoblastic PCa cells, suppressing osteoblast differentiation. Clinical results indicate that bone metastatic PCa patients have higher levels of ET-1 compared to nonmetastatic PCa patients. Furthermore, melatonin-induced miR-let-7f-5p inhibits ET-1-promoted osteoblast differentiation in osteoblastic PCa. Melatonin also suppresses the property of osteomimicry in osteoblastic PCa cells. Importantly, in the intratibia injection PCa metastasis model, melatonin decreased osteoblastic PCa tumor growth, inhibiting ET-1 production and osteoblast differentiation in vivo. Taken together, melatonin inhibits osteoblastic PCa-regulated osteoblastogenesis by reducing ET-1 production through upregulation of miR-let-7f-5p, while suppressing the property of osteomimicry in osteoblastic PCa. Melatonin therapy could be a promising approach to treating bone metastasis in osteoblastic PCa.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 7","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447763","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":"Melatonin, Melatonin Receptors and Sleep: Moving Beyond Traditional Views","authors":"Stefano Comai,&nbsp;Gabriella Gobbi","doi":"10.1111/jpi.13011","DOIUrl":"https://doi.org/10.1111/jpi.13011","url":null,"abstract":"<p>Sleep, constituting approximately one-third of the human lifespan, is a crucial physiological process essential for physical and mental well-being. Normal sleep consists of an orderly progression through wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep, all of which are tightly regulated. Melatonin, often referred to as the “hormone of sleep,” plays a pivotal role as a regulator of the sleep/wake cycle and exerts its effects through high-affinity G-protein coupled receptors known as MT1 and MT2. Selective modulation of these receptors presents a promising therapeutic avenue for sleep disorders. This review examines research on the multifaceted role of melatonin in sleep regulation, focusing on selective ligands targeting MT1 and MT2 receptors, as well as studies involving MT1 and MT2 knockout mice. Contrary to common beliefs, growing evidence suggests that melatonin, through MT1 and MT2 receptors, might not only influence circadian aspects of sleep but likely, also modulate the homeostatic process of sleep and sleep architecture, or could be the molecule linking the homeostatic and circadian regulation of sleep. Furthermore, the distinct brain localization of MT1 and MT2 receptors, with MT1 receptors primarily regulating REM sleep and MT2 receptors regulating NREM sleep, is discussed. Collectively, sleep regulation extends beyond the circulating levels and circadian peak of melatonin; it also critically involves the expression, molecular activation, and regulatory functions of MT1 and MT2 receptors across various brain regions and nuclei involved in the regulation of sleep. This research underscores the importance of ongoing investigation into the selective roles of MT1 and MT2 receptors in sleep. Such research efforts are expected to pave the way for the development of targeted MT1 or MT2 receptors ligands, thereby optimizing therapeutic interventions for sleep disorders.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 7","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.13011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435646","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}