Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the “gut-bone” axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.
骨质疏松症(OP)是一个严重的全球性健康问题,对生产力和人类寿命有重大影响。肠道微生物群失调已被证实与骨质疏松症的进展密切相关。褪黑素(MLT)是一种重要的内源性激素,可调节骨代谢、维持骨平衡并改善骨质疏松症的进展。多项研究表明,褪黑激素参与调节肠道微生物群和肠道屏障功能。然而,肠道微生物群衍生的 MLT 对 OP 的积极影响仍不清楚。在这里,我们发现 OP 会导致肠道色氨酸紊乱并减少肠道微生物群衍生的 MLT 的产生,而服用 MLT 可减轻 OP 相关的临床症状并逆转肠道微生物群失调,包括肠道微生物群的多样性、许多益生菌(如 Allobaculum 和 Parasutterella)的相对丰度以及肠道菌群的代谢功能(如氨基酸代谢、核苷酸代谢和能量代谢)。值得注意的是,MLT 能明显增加短链脂肪酸的产生,减少三甲胺 N-氧化物相关代谢物的产生。重要的是,MLT 可以调节 M1/M2 巨噬细胞的动态平衡,降低血清中促炎细胞因子的水平,并恢复肠道屏障功能。综上所述,我们的研究结果强调了肠道微生物衍生的 MLT 通过与 SCFA 代谢相关的 "肠-骨 "轴在 OP 进展中的重要作用,这可能为开发 MLT 作为治疗 OP 的药物提供了新的见解。
{"title":"Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism","authors":"Yueqi Chen, Chuan Yang, Zihan Deng, Tingwen Xiang, Qingrong Ni, Jianzhong Xu, Dong Sun, Fei Luo","doi":"10.1111/jpi.12954","DOIUrl":"https://doi.org/10.1111/jpi.12954","url":null,"abstract":"<p>Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as <i>Allobaculum</i> and <i>Parasutterella</i>, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the “gut-bone” axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553080","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}
Identifying the target cells of a hormone is a key step in understanding its function. Once the molecular nature of the receptors for a hormone has been established, researchers can use several techniques to detect these receptors. Here I will review the different tools used over the years to localize melatonin receptors and the problems associated with each of these techniques. The radioligand 2-[125I] iodomelatonin was the first tool to allow localization of melatonin receptors on tissue sections. Once the MT1 and MT2 receptors were cloned, in situ hybridization could be used to detect the messenger RNA for these receptors. The deduced amino acid sequences for MT1 and MT2 receptors allowed the production of peptide immunogens to generate antibodies against the MT1 and MT2 receptors. Finally, transgenic reporters driven by the promoter elements of the MT1 and MT2 genes have been used to map the expression of MT1 and MT2 in the brain and the retina. Several issues have complicated the localization of melatonin receptors and the characterization of melatonin target cells over the last three decades. Melatonin receptors are expressed at low levels, leading to sensitivity issues for their detection. The second problem are specificity issues with antibodies directed against the MT1 and MT2 melatonin receptors. These receptors are G protein-coupled receptors and many antibodies directed against such receptors have been shown to present similar problems concerning their specificity. Despite these specificity problems which start to be seriously addressed by recent studies, antibodies will be important tools in the future to identify and phenotype melatonin target cells. However, we will have to be more stringent than previously when establishing their specificity. The results obtained by these antibodies will have to be confronted and be coherent with results obtained by other techniques.
{"title":"Thirty-seven years of MT1 and MT2 melatonin receptor localization in the brain: Past and future challenges","authors":"Paul Klosen","doi":"10.1111/jpi.12955","DOIUrl":"https://doi.org/10.1111/jpi.12955","url":null,"abstract":"<p>Identifying the target cells of a hormone is a key step in understanding its function. Once the molecular nature of the receptors for a hormone has been established, researchers can use several techniques to detect these receptors. Here I will review the different tools used over the years to localize melatonin receptors and the problems associated with each of these techniques. The radioligand 2-[<sup>125</sup>I] iodomelatonin was the first tool to allow localization of melatonin receptors on tissue sections. Once the MT1 and MT2 receptors were cloned, in situ hybridization could be used to detect the messenger RNA for these receptors. The deduced amino acid sequences for MT1 and MT2 receptors allowed the production of peptide immunogens to generate antibodies against the MT1 and MT2 receptors. Finally, transgenic reporters driven by the promoter elements of the <i>MT1</i> and <i>MT2</i> genes have been used to map the expression of MT1 and MT2 in the brain and the retina. Several issues have complicated the localization of melatonin receptors and the characterization of melatonin target cells over the last three decades. Melatonin receptors are expressed at low levels, leading to sensitivity issues for their detection. The second problem are specificity issues with antibodies directed against the MT1 and MT2 melatonin receptors. These receptors are G protein-coupled receptors and many antibodies directed against such receptors have been shown to present similar problems concerning their specificity. Despite these specificity problems which start to be seriously addressed by recent studies, antibodies will be important tools in the future to identify and phenotype melatonin target cells. However, we will have to be more stringent than previously when establishing their specificity. The results obtained by these antibodies will have to be confronted and be coherent with results obtained by other techniques.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12955","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140546810","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}
Melatonin (5-methoxy-N-acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT1 and MT2 receptors are the best-characterized. They are members of the G protein-coupled receptor superfamily, preferentially coupling to Gi/o proteins but also to other G proteins in a cell-context-depending manner. In this review, experts on melatonin receptors will summarize the current state of the field. We briefly report on the discovery and classification of melatonin receptors, then focus on the molecular structure of human MT1 and MT2 receptors and highlight the importance of molecular simulations to identify new ligands and to understand the structural dynamics of these receptors. We then describe the state-of-the-art of the intracellular signaling pathways activated by melatonin receptors and their complexes. Brief statements on the molecular toolbox available for melatonin receptor studies and future perspectives will round-up this review.
{"title":"Melatonin receptor structure and signaling","authors":"Hiroyuki H. Okamoto, Erika Cecon, Osamu Nureki, Silvia Rivara, Ralf Jockers","doi":"10.1111/jpi.12952","DOIUrl":"https://doi.org/10.1111/jpi.12952","url":null,"abstract":"<p>Melatonin (5-methoxy-<i>N</i>-acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT<sub>1</sub> and MT<sub>2</sub> receptors are the best-characterized. They are members of the G protein-coupled receptor superfamily, preferentially coupling to G<sub>i/o</sub> proteins but also to other G proteins in a cell-context-depending manner. In this review, experts on melatonin receptors will summarize the current state of the field. We briefly report on the discovery and classification of melatonin receptors, then focus on the molecular structure of human MT<sub>1</sub> and MT<sub>2</sub> receptors and highlight the importance of molecular simulations to identify new ligands and to understand the structural dynamics of these receptors. We then describe the state-of-the-art of the intracellular signaling pathways activated by melatonin receptors and their complexes. Brief statements on the molecular toolbox available for melatonin receptor studies and future perspectives will round-up this review.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12952","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140537773","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}
Marie Paule Felder-Schmittbuhl, David Hicks, Christophe P. Ribelayaga, Gianluca Tosini
Melatonin is an important player in the regulation of many physiological functions within the body and in the retina. Melatonin synthesis in the retina primarily occurs during the night and its levels are low during the day. Retinal melatonin is primarily synthesized by the photoreceptors, but whether the synthesis occurs in the rods and/or cones is still unclear. Melatonin exerts its influence by binding to G protein-coupled receptors named melatonin receptor type 1 (MT1) and type 2 (MT2). MT1 and MT2 receptors activate a wide variety of signaling pathways and both receptors are present in the vertebrate photoreceptors where they may form MT1/MT2 heteromers (MT1/2h). Studies in rodents have shown that melatonin signaling plays an important role in the regulation of retinal dopamine levels, rod/cone coupling as well as the photopic and scotopic electroretinogram. In addition, melatonin may play an important role in protecting photoreceptors from oxidative stress and can protect photoreceptors from apoptosis. Critically, melatonin signaling is involved in the modulation of photoreceptor viability during aging and other studies have implicated melatonin in the pathogenesis of age-related macular degeneration. Hence melatonin may represent a useful tool in the fight to protect photoreceptors—and other retinal cells—against degeneration due to aging or diseases.
褪黑激素在调节人体和视网膜的许多生理功能方面发挥着重要作用。视网膜中褪黑激素的合成主要发生在夜间,白天含量较低。视网膜上的褪黑激素主要由感光细胞合成,但合成是否发生在视杆细胞和/或视锥细胞尚不清楚。褪黑激素通过与名为褪黑激素受体 1 型(MT1)和 2 型(MT2)的 G 蛋白偶联受体结合来施加影响。MT1和MT2受体可激活多种信号通路,这两种受体都存在于脊椎动物的感光器中,它们可形成MT1/MT2异构体(MT1/2h)。对啮齿类动物的研究表明,褪黑激素信号在调节视网膜多巴胺水平、视杆细胞/视锥细胞耦合以及视网膜光电图和散光光电图方面发挥着重要作用。此外,褪黑激素在保护光感受器免受氧化应激和防止光感受器凋亡方面也发挥着重要作用。重要的是,褪黑激素信号在衰老过程中参与调节光感受器的活力,其他研究也表明褪黑激素与老年性黄斑变性的发病机制有关。因此,褪黑激素可能是保护光感受器和其他视网膜细胞免受衰老或疾病引起的退化的有效工具。
{"title":"Melatonin in the mammalian retina: Synthesis, mechanisms of action and neuroprotection","authors":"Marie Paule Felder-Schmittbuhl, David Hicks, Christophe P. Ribelayaga, Gianluca Tosini","doi":"10.1111/jpi.12951","DOIUrl":"https://doi.org/10.1111/jpi.12951","url":null,"abstract":"<p>Melatonin is an important player in the regulation of many physiological functions within the body and in the retina. Melatonin synthesis in the retina primarily occurs during the night and its levels are low during the day. Retinal melatonin is primarily synthesized by the photoreceptors, but whether the synthesis occurs in the rods and/or cones is still unclear. Melatonin exerts its influence by binding to G protein-coupled receptors named melatonin receptor type 1 (MT<sub>1</sub>) and type 2 (MT<sub>2</sub>). MT<sub>1</sub> and MT<sub>2</sub> receptors activate a wide variety of signaling pathways and both receptors are present in the vertebrate photoreceptors where they may form MT<sub>1</sub>/MT<sub>2</sub> heteromers (MT<sub>1/2h</sub>). Studies in rodents have shown that melatonin signaling plays an important role in the regulation of retinal dopamine levels, rod/cone coupling as well as the photopic and scotopic electroretinogram. In addition, melatonin may play an important role in protecting photoreceptors from oxidative stress and can protect photoreceptors from apoptosis. Critically, melatonin signaling is involved in the modulation of photoreceptor viability during aging and other studies have implicated melatonin in the pathogenesis of age-related macular degeneration. Hence melatonin may represent a useful tool in the fight to protect photoreceptors—and other retinal cells—against degeneration due to aging or diseases.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12951","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140345586","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}
Homeobox genes encode transcription factors that are widely known to control developmental processes. This is also the case in the pineal gland, a neuroendocrine brain structure devoted to nighttime synthesis of the hormone melatonin. Thus, in accordance with high prenatal gene expression, knockout studies have identified a specific set of homeobox genes that are essential for development of the pineal gland. However, as a special feature of the pineal gland, homeobox gene expression persists into adulthood, and gene product abundance exhibits 24 h circadian rhythms. Recent lines of evidence show that some homeobox genes even control expression of enzymes catalyzing melatonin synthesis. We here review current knowledge of homeobox genes in the rodent pineal gland and suggest a model for dual functions of homeobox gene-encoded transcription factors in developmental and circadian mature neuroendocrine function.
{"title":"Homeobox gene-encoded transcription factors in development and mature circadian function of the rodent pineal gland","authors":"Martin F. Rath","doi":"10.1111/jpi.12950","DOIUrl":"https://doi.org/10.1111/jpi.12950","url":null,"abstract":"<p>Homeobox genes encode transcription factors that are widely known to control developmental processes. This is also the case in the pineal gland, a neuroendocrine brain structure devoted to nighttime synthesis of the hormone melatonin. Thus, in accordance with high prenatal gene expression, knockout studies have identified a specific set of homeobox genes that are essential for development of the pineal gland. However, as a special feature of the pineal gland, homeobox gene expression persists into adulthood, and gene product abundance exhibits 24 h circadian rhythms. Recent lines of evidence show that some homeobox genes even control expression of enzymes catalyzing melatonin synthesis. We here review current knowledge of homeobox genes in the rodent pineal gland and suggest a model for dual functions of homeobox gene-encoded transcription factors in developmental and circadian mature neuroendocrine function.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12950","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140333215","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}