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Melatonin alleviates myocardial dysfunction through inhibition of endothelial-to-mesenchymal transition via the NF-κB pathway 褪黑素通过NF-κB途径抑制内皮细胞向间质转化,从而缓解心肌功能障碍。
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-15 DOI: 10.1111/jpi.12958
Ran Kim, Minsuk Kim, Seongtae Jeong, Sejin Kim, Hanbyeol Moon, Hojin Kim, Min Young Lee, Jongmin Kim, Hyung-Sik Kim, Murim Choi, Kunyoo Shin, Byeong-Wook Song, Woochul Chang

Endothelial-to-mesenchymal transition (EndMT) is a complex biological process of cellular transdifferentiation by which endothelial cells (ECs) lose their characteristics and acquire mesenchymal properties, leading to cardiovascular remodeling and complications in the adult cardiovascular diseases environment. Melatonin is involved in numerous physiological and pathological processes, including aging, and has anti-inflammatory and antioxidant activities. This molecule is an effective therapeutic candidate for preventing oxidative stress, regulating endothelial function, and maintaining the EndMT balance to provide cardiovascular protection. Although recent studies have documented improved cardiac function by melatonin, the mechanism of action of melatonin on EndMT remains unclear. The present study investigated the effects of melatonin on induced EndMT by transforming growth factor-β2/interleukin-1β in both in vivo and in vitro models. The results revealed that melatonin reduced the migratory ability and reactive oxygen species levels of the cells and ameliorated mitochondrial dysfunction in vitro. Our findings indicate that melatonin prevents endothelial dysfunction and inhibits EndMT by activating related pathways, including nuclear factor kappa B and Smad. We also demonstrated that this molecule plays a crucial role in restoring cardiac function by regulating the EndMT process in the ischemic myocardial condition, both in vessel organoids and myocardial infarction (MI) animal models. In conclusion, melatonin is a promising agent that attenuates EC dysfunction and ameliorates cardiac damage compromising the EndMT process after MI.

内皮细胞向间充质细胞转化(EndMT)是一个复杂的细胞转分化生物学过程,通过这一过程,内皮细胞(EC)失去其特性并获得间充质特性,从而导致心血管重塑和成人心血管疾病环境中的并发症。褪黑激素参与了包括衰老在内的许多生理和病理过程,并具有抗炎和抗氧化活性。该分子是预防氧化应激、调节内皮功能和维持内皮细胞间质平衡以保护心血管的有效候选疗法。虽然最近的研究证明褪黑素能改善心脏功能,但褪黑素对 EndMT 的作用机制仍不清楚。本研究在体内和体外模型中研究了褪黑激素对转化生长因子-β2/白细胞介素-1β诱导的内膜增生作用的影响。结果显示,褪黑素降低了细胞的迁移能力和活性氧水平,并改善了体外线粒体功能障碍。我们的研究结果表明,褪黑激素可通过激活相关途径(包括核因子卡巴B和Smad)来预防内皮功能障碍和抑制内膜移植。我们还证明,无论是在血管器官组织还是心肌梗塞(MI)动物模型中,这种分子都能通过调节缺血心肌的内膜移植过程,在恢复心脏功能方面发挥关键作用。总之,褪黑素是一种很有前景的药物,它能减轻心肌梗死后心肌细胞的功能障碍并改善损害内膜移植过程的心脏损伤。
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引用次数: 0
Rational modification of melatonin for broad-spectrum antifungal agents discovery 合理改造褪黑素以发现广谱抗真菌剂。
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-15 DOI: 10.1111/jpi.12960
Huanyu Cai, Renjian Li, Yu Chen, Ruiqing Bi, Xueru Fang, Peng Wu, Weilong Xu, Longzhu Bao, Zhu Liu, Jun Li, Guotian Li, Huailong Teng

Natural products, known for their environmental safety, are regarded as a significant basis for the modification and advancement of fungicides. Melatonin, as a low-cost natural indole, exhibits diverse biological functions, including antifungal activity. However, its potential as an antifungal agent has not been fully explored. In this study, a series of melatonin derivatives targeting the mitogen-activated protein kinase (Mps1) protein of fungal pathogens were synthesized based on properties of melatonin, among which the trifluoromethyl-substituted derivative Mt-23 exhibited antifungal activity against seven plant pathogenic fungi, and effectively reduced the severity of crop diseases, including rice blast, Fusarium head blight of wheat and gray mold of tomato. In particular, its EC50 (5.4 µM) against the rice blast fungus Magnaporthe oryzae is only one-fourth that of isoprothiolane (22 µM), a commercial fungicide. Comparative analyzes revealed that Mt-23 simultaneously targets the conserved protein kinase Mps1 and lipid protein Cap20. Surface plasmon resonance assays showed that Mt-23 directly binds to Mps1 and Cap20. In this study, we provide a strategy for developing antifungal agents by modifying melatonin, and the resultant melatonin derivative Mt-23 is a commercially valuable, eco-friendly and broad-spectrum antifungal agent to combat crop disease.

天然产品以其环境安全性而闻名,被认为是改良和改进杀真菌剂的重要基础。褪黑素作为一种低成本的天然吲哚,具有多种生物功能,包括抗真菌活性。然而,它作为抗真菌剂的潜力尚未得到充分挖掘。本研究根据褪黑素的特性,合成了一系列靶向真菌病原体丝裂原活化蛋白激酶(Mps1)蛋白的褪黑素衍生物,其中三氟甲基取代衍生物 Mt-23 对七种植物病原真菌具有抗真菌活性,能有效减轻稻瘟病、小麦镰刀菌头枯病和番茄灰霉病等作物病害的严重程度。特别是它对稻瘟病菌 Magnaporthe oryzae 的半数有效浓度(5.4 µM)仅为商用杀菌剂异丙硫环(22 µM)的四分之一。比较分析表明,Mt-23 同时以保守的蛋白激酶 Mps1 和脂质蛋白 Cap20 为靶标。表面等离子共振试验表明,Mt-23 可直接与 Mps1 和 Cap20 结合。在这项研究中,我们提供了一种通过修饰褪黑素来开发抗真菌剂的策略,由此产生的褪黑素衍生物 Mt-23 是一种具有商业价值、环保且广谱的抗真菌剂,可用于防治作物病害。
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引用次数: 0
Melatonin ameliorates 10-hydroxycamptothecin-induced oxidative stress and apoptosis via autophagy-regulated p62/Keap1/Nrf2 pathway in mouse testicular cells 褪黑素通过自噬调节的p62/Keap1/Nrf2途径改善小鼠睾丸细胞中10-羟基喜树碱诱导的氧化应激和细胞凋亡。
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-13 DOI: 10.1111/jpi.12959
Jinmei Cheng, Junjie Xu, Yimin Gu, Yueming Wang, Jianyu Wang, Fei Sun

10-Hydroxycamptothecin (HCPT) is a widely used clinical anticancer drug but has a significant side effect profile. Melatonin has a beneficial impact on the chemotherapy of different cancer cells and reproductive processes, but the effect and underlying molecular mechanism of melatonin's involvement in the HCPT-induced side effects in cells, especially in the testicular cells, are poorly understood. In this study, we found that melatonin therapy significantly restored HCPT-induced testicular cell damage and did not affect the antitumor effect of HCPT. Further analysis found that melatonin therapy suppressed HCPT-induced DNA damage associated with ataxia-telangiectasia mutated- and Rad3-related and CHK1 phosphorylation levels in the testis. Changes in apoptosis-associated protein levels (Bax, Bcl-2, p53, and Cleaved caspase-3) and in reactive oxygen species-associated proteins (Nrf2 and Keap1) and index (malondialdehyde and glutathione) suggested that melatonin treatment relieved HCPT-induced cell apoptosis and oxidative damage, respectively. Mechanistically, melatonin-activated autophagy proteins (ATG7, Beclin1, and LC3bII/I) may induce p62-dependent autophagy to degrade Keap1, eliciting Nrf2 from Keap1-Nrf2 interaction to promote antioxidant enzyme expression such as HO-1, which would salvage HCPT-induced ROS production and mitochondrial dysfunction. Collectively, this study reveals that melatonin therapy may protect testicular cells from HCPT-induced damage via the activation of autophagy, which alleviates oxidative stress, mitochondrial dysfunction, and cell apoptosis.

10-羟基喜树碱(HCPT)是一种广泛应用于临床的抗癌药物,但具有明显的副作用。褪黑素对不同癌细胞的化疗和生殖过程都有益处,但褪黑素参与 HCPT 诱导的细胞副作用,尤其是睾丸细胞副作用的影响和潜在分子机制却鲜为人知。在这项研究中,我们发现褪黑素疗法能明显恢复 HCPT 诱导的睾丸细胞损伤,并且不影响 HCPT 的抗肿瘤效果。进一步的分析发现,褪黑激素疗法抑制了 HCPT 诱导的 DNA 损伤,与共济失调-特朗吉特氏症突变相关,并抑制了睾丸中 Rad3 相关和 CHK1 磷酸化水平。细胞凋亡相关蛋白水平(Bax、Bcl-2、p53和裂解的caspase-3)以及活性氧相关蛋白(Nrf2和Keap1)和指标(丙二醛和谷胱甘肽)的变化表明,褪黑素治疗分别缓解了HCPT诱导的细胞凋亡和氧化损伤。从机理上讲,褪黑素激活的自噬蛋白(ATG7、Beclin1和LC3bII/I)可能诱导p62依赖性自噬降解Keap1,从Keap1-Nrf2相互作用中激发Nrf2促进HO-1等抗氧化酶的表达,从而挽救HCPT诱导的ROS产生和线粒体功能障碍。总之,本研究揭示了褪黑素疗法可通过激活自噬保护睾丸细胞免受HCPT诱导的损伤,从而缓解氧化应激、线粒体功能障碍和细胞凋亡。
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引用次数: 0
Circadian desynchrony and glucose metabolism 昼夜节律不同步与葡萄糖代谢
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-02 DOI: 10.1111/jpi.12956
Esther M. Speksnijder, Peter H. Bisschop, Sarah E. Siegelaar, Dirk Jan Stenvers, Andries Kalsbeek

The circadian timing system controls glucose metabolism in a time-of-day dependent manner. In mammals, the circadian timing system consists of the main central clock in the bilateral suprachiasmatic nucleus (SCN) of the anterior hypothalamus and subordinate clocks in peripheral tissues. The oscillations produced by these different clocks with a period of approximately 24-h are generated by the transcriptional-translational feedback loops of a set of core clock genes. Glucose homeostasis is one of the daily rhythms controlled by this circadian timing system. The central pacemaker in the SCN controls glucose homeostasis through its neural projections to hypothalamic hubs that are in control of feeding behavior and energy metabolism. Using hormones such as adrenal glucocorticoids and melatonin and the autonomic nervous system, the SCN modulates critical processes such as glucose production and insulin sensitivity. Peripheral clocks in tissues, such as the liver, muscle, and adipose tissue serve to enhance and sustain these SCN signals. In the optimal situation all these clocks are synchronized and aligned with behavior and the environmental light/dark cycle. A negative impact on glucose metabolism becomes apparent when the internal timing system becomes disturbed, also known as circadian desynchrony or circadian misalignment. Circadian desynchrony may occur at several levels, as the mistiming of light exposure or sleep will especially affect the central clock, whereas mistiming of food intake or physical activity will especially involve the peripheral clocks. In this review, we will summarize the literature investigating the impact of circadian desynchrony on glucose metabolism and how it may result in the development of insulin resistance. In addition, we will discuss potential strategies aimed at reinstating circadian synchrony to improve insulin sensitivity and contribute to the prevention of type 2 diabetes.

昼夜节律定时系统以依赖时间的方式控制葡萄糖代谢。在哺乳动物中,昼夜节律计时系统由下丘脑前部双侧簇上核(SCN)中的主要中央时钟和外周组织中的从属时钟组成。这些不同时钟产生的周期约为 24 小时的振荡是由一组核心时钟基因的转录-翻译反馈回路产生的。葡萄糖稳态是这种昼夜节律定时系统控制的日节律之一。SCN 中的中央起搏器通过向下丘脑中枢的神经投射来控制葡萄糖平衡,而下丘脑中枢则控制着进食行为和能量代谢。利用肾上腺糖皮质激素和褪黑激素等激素以及自主神经系统,SCN 可调节葡萄糖生成和胰岛素敏感性等关键过程。肝脏、肌肉和脂肪组织等组织中的外周时钟可增强和维持这些 SCN 信号。在最佳状态下,所有这些时钟都与行为和环境的光/暗周期同步和一致。当内部计时系统受到干扰时,对葡萄糖代谢的负面影响就会显现出来,这也被称为昼夜节律不同步或昼夜节律失调。昼夜节律不同步可能发生在多个层面,因为光照或睡眠的时间错配尤其会影响中枢时钟,而食物摄入或体力活动的时间错配则尤其涉及外周时钟。在这篇综述中,我们将总结研究昼夜节律不同步对糖代谢的影响以及如何导致胰岛素抵抗的文献。此外,我们还将讨论旨在恢复昼夜节律同步以改善胰岛素敏感性并有助于预防 2 型糖尿病的潜在策略。
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引用次数: 0
Industrial and academic approaches to the search for alternative melatonin receptor ligands: An historical survey 寻找替代褪黑激素受体配体的工业和学术方法:历史回顾
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-29 DOI: 10.1111/jpi.12953
Annalida Bedini, Jean A. Boutin, Céline Legros, Darius P. Zlotos, Gilberto Spadoni

The search for melatonin receptor agonists formed the main part of melatonin medicinal chemistry programs for the last three decades. In this short review, we summarize the two main aspects of these programs: the development of all the necessary tools to characterize the newly synthesized ligands at the two melatonin receptors MT1 and MT2, and the medicinal chemist's approaches to find chemically diverse ligands at these receptors. Both strategies are described. It turns out that the main source of tools were industrial laboratories, while the medicinal chemistry was mainly carried out in academia. Such complete accounts are interesting, as they delineate the spirits in which the teams were working demonstrating their strength and innovative character. Most of the programs were focused on nonselective agonists and few of them reached the market. In contrast, discovery of MT1-selective agonists and melatonergic antagonists with proven in vivo activity and MT1 or MT2-selectivity is still in its infancy, despite the considerable interest that subtype selective compounds may bring in the domain, as the physiological respective roles of the two subtypes of melatonin receptors, is still poorly understood. Poly-pharmacology applications and multitarget ligands have also been considered.

寻找褪黑素受体激动剂是过去三十年来褪黑素药物化学项目的主要内容。在这篇简短的综述中,我们总结了这些计划的两个主要方面:开发所有必要的工具来表征新合成的褪黑激素受体 MT1 和 MT2 配体,以及药物化学家寻找这些受体的化学多样性配体的方法。本文介绍了这两种策略。事实证明,工具的主要来源是工业实验室,而药物化学主要在学术界进行。这些完整的描述非常有趣,因为它们勾勒出了各团队的工作精神,展示了他们的实力和创新特点。大多数项目都集中在非选择性激动剂上,进入市场的产品寥寥无几。相比之下,MT1 选择性激动剂和褪黑素能拮抗剂的发现仍处于起步阶段,尽管亚型选择性化合物可能会给该领域带来相当大的兴趣,但由于人们对褪黑素受体两个亚型各自的生理作用仍知之甚少,因此这些药物已被证实具有体内活性和 MT1 或 MT2 选择性。此外,还考虑了多药理应用和多靶点配体。
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引用次数: 0
Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism 肠道微生物产生的色氨酸代谢物褪黑激素通过调节 SCFA 和 TMAO 代谢改善骨质疏松症
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-15 DOI: 10.1111/jpi.12954
Yueqi Chen, Chuan Yang, Zihan Deng, Tingwen Xiang, Qingrong Ni, Jianzhong Xu, Dong Sun, Fei Luo

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。
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引用次数: 0
Thirty-seven years of MT1 and MT2 melatonin receptor localization in the brain: Past and future challenges 脑内 MT1 和 MT2 褪黑激素受体定位 37 年:过去和未来的挑战
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-12 DOI: 10.1111/jpi.12955
Paul Klosen

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.

确定激素的靶细胞是了解其功能的关键一步。一旦确定了激素受体的分子性质,研究人员就可以使用多种技术来检测这些受体。在此,我将回顾多年来用于定位褪黑激素受体的不同工具,以及与每种技术相关的问题。放射性配体 2-[125I]碘褪黑激素是第一种在组织切片上定位褪黑激素受体的工具。一旦克隆出 MT1 和 MT2 受体,就可以使用原位杂交技术检测这些受体的信使 RNA。推导出 MT1 和 MT2 受体的氨基酸序列后,就可以生产多肽免疫原,产生针对 MT1 和 MT2 受体的抗体。最后,由 MT1 和 MT2 基因启动子元件驱动的转基因报告基因被用来绘制 MT1 和 MT2 在大脑和视网膜中的表达图。过去三十年来,有几个问题使褪黑激素受体的定位和褪黑激素靶细胞的特征描述变得复杂。褪黑激素受体的表达水平较低,导致检测灵敏度问题。第二个问题是针对 MT1 和 MT2 褪黑激素受体的抗体的特异性问题。这些受体是 G 蛋白偶联受体,许多针对此类受体的抗体都存在类似的特异性问题。尽管最近的研究开始认真解决这些特异性问题,但抗体仍将是未来识别褪黑激素靶细胞并对其进行表型的重要工具。不过,在确定其特异性时,我们必须比以前更加严格。这些抗体获得的结果必须与其他技术获得的结果相一致。
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引用次数: 0
Melatonin receptor structure and signaling 褪黑素受体的结构和信号传导
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-08 DOI: 10.1111/jpi.12952
Hiroyuki H. Okamoto, Erika Cecon, Osamu Nureki, Silvia Rivara, Ralf Jockers

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.

褪黑素(5-甲氧基-N-乙酰色胺)与膜受体的结合具有高亲和力和特异性。不同物种存在多种受体亚型,其中以哺乳动物的 MT1 和 MT2 受体最为典型。它们是G蛋白偶联受体超家族的成员,优先与Gi/o蛋白偶联,但也会根据细胞环境与其他G蛋白偶联。在本综述中,褪黑激素受体方面的专家将总结该领域的现状。我们将简要报告褪黑激素受体的发现和分类,然后重点介绍人类 MT1 和 MT2 受体的分子结构,并强调分子模拟在确定新配体和了解这些受体的结构动态方面的重要性。然后,我们介绍了由褪黑激素受体及其复合物激活的细胞内信号通路的最新进展。关于可用于褪黑激素受体研究的分子工具箱和未来展望的简要说明将为本综述画上圆满句号。
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引用次数: 0
Melatonin in the mammalian retina: Synthesis, mechanisms of action and neuroprotection 哺乳动物视网膜中的褪黑激素:合成、作用机制和神经保护
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-04 DOI: 10.1111/jpi.12951
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。
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引用次数: 0
Homeobox gene-encoded transcription factors in development and mature circadian function of the rodent pineal gland 啮齿动物松果体发育和成熟昼夜节律功能中的同源框基因编码转录因子
IF 10.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-01 DOI: 10.1111/jpi.12950
Martin F. Rath

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.

众所周知,Homeobox 基因编码的转录因子可控制发育过程。松果体也是如此,它是一种脑神经内分泌结构,专门负责在夜间合成荷尔蒙褪黑激素。因此,根据产前基因的高表达,基因敲除研究发现了一组特定的同源染色体基因,它们对松果体的发育至关重要。然而,作为松果体的一个特殊特征,homeobox 基因的表达一直持续到成年期,而且基因产物的丰度呈现 24 小时昼夜节律。最近的证据表明,一些同源染色体基因甚至能控制催化褪黑激素合成的酶的表达。在此,我们回顾了目前对啮齿动物松果体中同源框基因的了解,并提出了一个模型,说明同源框基因编码的转录因子在发育和昼夜节律成熟的神经内分泌功能中具有双重功能。
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Journal of Pineal Research
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