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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 ENDOCRINOLOGY & METABOLISM 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 ENDOCRINOLOGY & METABOLISM 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 ENDOCRINOLOGY & METABOLISM 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 ENDOCRINOLOGY & METABOLISM 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 ENDOCRINOLOGY & METABOLISM 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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引用次数: 0
Investigating the safety profiles of exogenous melatonin and associated adverse events: A pharmacovigilance study using WHO-VigiBase 调查外源性褪黑素的安全性概况及相关不良事件:利用 WHO-VigiBase 进行药物警戒研究。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-03-25 DOI: 10.1111/jpi.12949
Minyoung Ha, Dongwon Yoon, Chae-Young Lee, Mose Lee, Young-Wook Kim, Jung-Min Lee, Ju-Young Shin

Melatonin, a pineal hormone that modulates circadian rhythms, sleep, and neurotransmitters, is widely used to treat sleep disorders. However, there are limited studies on the safety of melatonin. Therefore, we aimed to present the overall patterns of adverse events (AEs) following melatonin administration and identify potential safety signals associated with melatonin. Using VigiBase, a global individual case safety report (ICSRs) database managed by the World Health Organization (WHO), we conducted a retrospective, observational, pharmacovigilance study of melatonin between January 1996 and September 2022. Disproportionality analysis was conducted using two comparator settings: all other drugs and other sleep medications. We used multivariable logistic regression to estimate reporting odds ratios (RORs) with 95% confidence intervals (CIs) to compare the frequencies of AEs reporting between melatonin and each comparator setting. Furthermore, we assessed adverse events of special interests (AESIs) that could potentially be associated with melatonin. Signals were identified when the following criteria were met: cases ≥3, x2 ≥ 4, IC025 ≥ 0, and the lower end of the 95% CI of ROR > 2. These signals were then compared with the AE information on the drug labels provided by regulatory bodies. A total of 35 479 AE reports associated with melatonin were identified, with a higher proportion of reports from females (57.1%) and individuals aged 45–64 years (20.8%). We identified 21 AEs that were commonly detected as safety signals in the disproportionality analyses, including tic, educational problems, disturbance in social behavior, body temperature fluctuation, and growth retardation. In AESI analyses, accidents and injuries (adjusted ROR 2.97; 95% CI, 2.80–3.16), fall (2.24; 2.12–2.37), nightmare (4.90; 4.37–5.49), and abnormal dreams (3.68; 3.19–4.25) were detected as a signal of melatonin when compared to all other drugs, whereas those signals were not detected when compared to other sleep medications. In this pharmacovigilance study, exogenous melatonin showed safety profiles comparable to other sleep medications. However, several unexpected potential safety signals were identified, underscoring the need for further investigation at the population level.

褪黑素是一种松果体激素,可调节昼夜节律、睡眠和神经递质,被广泛用于治疗睡眠障碍。然而,有关褪黑素安全性的研究却很有限。因此,我们旨在介绍服用褪黑素后不良事件(AEs)的总体模式,并识别与褪黑素相关的潜在安全信号。我们利用世界卫生组织(WHO)管理的全球个体病例安全报告(ICSRs)数据库 VigiBase,对 1996 年 1 月至 2022 年 9 月期间的褪黑素进行了一项回顾性、观察性药物警戒研究。我们使用两种参照物进行了比例失调分析:所有其他药物和其他睡眠药物。我们使用多变量逻辑回归法估算了报告几率比(RORs)和 95% 置信区间(CIs),以比较褪黑素和每种参照物之间的 AE 报告频率。此外,我们还评估了可能与褪黑素有关的特殊利益不良事件(AESIs)。当符合以下标准时,我们将确定信号:病例数≥3、x2≥4、IC025≥0、ROR 的 95% CI 下限 > 2。然后将这些信号与监管机构提供的药物标签上的 AE 信息进行比较。共发现了 35 479 份与褪黑素相关的 AE 报告,其中女性(57.1%)和 45-64 岁人群(20.8%)的报告比例较高。在比例失调分析中,我们发现了 21 种作为安全信号的常见 AE,包括抽搐、教育问题、社交行为障碍、体温波动和生长迟缓。在AESI分析中,与所有其他药物相比,褪黑素可检测到意外伤害(调整后ROR为2.97;95% CI为2.80-3.16)、跌倒(2.24;2.12-2.37)、噩梦(4.90;4.37-5.49)和异常梦境(3.68;3.19-4.25)信号,而与其他睡眠药物相比,则未检测到这些信号。在这项药物警戒研究中,外源性褪黑素的安全性与其他睡眠药物相当。不过,也发现了几个意想不到的潜在安全信号,这表明有必要在人群层面开展进一步调查。
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引用次数: 0
Melatonin MT1 receptors regulate the Sirt1/Nrf2/Ho-1/Gpx4 pathway to prevent α-synuclein-induced ferroptosis in Parkinson's disease 褪黑素MT1受体调节Sirt1/Nrf2/Ho-1/Gpx4通路,以防止帕金森病中α-突触核蛋白诱导的铁突变。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-03-15 DOI: 10.1111/jpi.12948
Qian-Kun Lv, Kang-Xin Tao, Xiao-Yu Yao, Meng-Zhu Pang, Bing-Er Cao, Chun-Feng Liu, Fen Wang

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons and aggregation of α-synuclein (α-syn). Ferroptosis, a form of cell death induced by iron accumulation and lipid peroxidation, is involved in the pathogenesis of PD. It is unknown whether melatonin receptor 1 (MT1) modulates α-syn and ferroptosis in PD. Here, we used α-syn preformed fibrils (PFFs) to induce PD models in vivo and in vitro. In PD mice, α-syn aggregation led to increased iron deposition and ferroptosis. MT1 knockout exacerbated these changes and resulted in more DA neuronal loss and severe motor impairment. MT1 knockout also suppressed the Sirt1/Nrf2/Ho1/Gpx4 pathway, reducing resistance to ferroptosis, and inhibited expression of ferritin Fth1, leading to more release of ferrous ions. In vitro experiments confirmed these findings. Knockdown of MT1 enhanced α-syn PFF-induced intracellular α-syn aggregation and suppressed expression of the Sirt1/Nrf2/Ho1/Gpx4 pathway and Fth1 protein, thereby aggravating ferroptosis. Conversely, overexpression of MT1 reversed these effects. Our findings reveal a novel mechanism by which MT1 activation prevents α-syn-induced ferroptosis in PD, highlighting the neuroprotective role of MT1 in PD.

帕金森病(PD)是一种神经退行性疾病,以多巴胺能(DA)神经元的丧失和α-突触核蛋白(α-syn)的聚集为特征。铁变态反应是一种由铁积累和脂质过氧化诱导的细胞死亡形式,与帕金森病的发病机制有关。目前尚不清楚褪黑激素受体1(MT1)是否会调节α-syn和铁突变在帕金森病中的作用。在这里,我们利用α-syn预成纤维(PFFs)诱导体内和体外的帕金森病模型。在帕金森病小鼠中,α-syn的聚集导致铁沉积和铁变态反应增加。MT1基因敲除会加剧这些变化,导致更多的DA神经元缺失和严重的运动障碍。MT1基因敲除还抑制了Sirt1/Nrf2/Ho1/Gpx4通路,降低了对铁沉积的抵抗力,并抑制了铁蛋白Fth1的表达,导致更多的亚铁离子释放。体外实验证实了这些发现。敲除MT1会增强α-syn PFF诱导的细胞内α-syn聚集,抑制Sirt1/Nrf2/Ho1/Gpx4通路和Fth1蛋白的表达,从而加剧铁蛋白沉积。相反,过量表达 MT1 则会逆转这些影响。我们的研究结果揭示了一种新的机制,即MT1活化可防止α-syn诱导的帕金森病铁变态反应,突出了MT1在帕金森病中的神经保护作用。
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引用次数: 0
Correction to “Effects of melatonin on fatty liver disease: The role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy” 褪黑素对脂肪肝的影响:NR4A1/DNA-PKcs/p53通路、线粒体分裂和有丝分裂的作用"。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-02-29 DOI: 10.1111/jpi.12946

Zhou H, Du W, Li Y, et al. Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res. 2018;64:e12450. https://doi.org/10.1111/jpi.12450

Upon the publication of the article, the authors have discovered inaccuracies in one representative Oil Red image presented in Figure 2A. Specifically, errors occurred during the figure assembly process, resulting in the inclusion of the wrong representative image for the LFD+WT group in Figure 2A. It is important to emphasize that these corrections do not compromise the scientific integrity of the study's conclusions. The authors unanimously support this corrigendum and sincerely apologize for any inconvenience caused by this oversight. The accurate images, obtained during the original experimental procedures, are provided below.

Zhou H, Du W, Li Y, et al. 褪黑激素对脂肪肝的影响:NR4A1/DNA-PKcs/p53通路、线粒体裂变和有丝分裂的作用。J Pineal Res. 2018;64:e12450。 https://doi.org/10.1111/jpi.12450Upon 文章发表后,作者发现图 2A 中的一张代表性油红图像存在不准确之处。具体来说,在图组装过程中出现了错误,导致图 2A 中 LFD+WT 组的代表图像被错误地纳入。需要强调的是,这些更正不会影响研究结论的科学完整性。作者一致支持这一更正,并对这一疏忽造成的不便表示诚挚的歉意。以下是在原始实验过程中获得的准确图像。
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引用次数: 0
Melatonin inhibits the stemness of head and neck squamous cell carcinoma by modulating HA synthesis via the FOSL1/HAS3 axis 褪黑激素通过FOSL1/HAS3轴调节HA合成,从而抑制头颈部鳞状细胞癌的干细胞性
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-02-25 DOI: 10.1111/jpi.12940
Xinyue Luo, Jingjing Wang, Yang Chen, Xiaocheng Zhou, Zhe Shao, Ke Liu, Zhengjun Shang

Hyaluronic acid (HA) is a glycosaminoglycan and the main component of the extracellular matrix (ECM), which has been reported to interact with its receptor CD44 to play critical roles in the self-renewal and maintenance of cancer stem cells (CSCs) of multiple malignancies. Melatonin is a neuroendocrine hormone with pleiotropic antitumor properties. However, whether melatonin could regulate HA accumulation in the ECM to modulate the stemness of head and neck squamous cell carcinoma (HNSCC) remains unknown. In this study, we found that melatonin suppressed CSC-related markers, such as CD44, of HNSCC cells and decreased the tumor-initiating frequency of CSCs in vivo. In addition, melatonin modulated HA synthesis of HNSCC cells by downregulating the expression of hyaluronan synthase 3 (HAS3). Further study showed that the Fos-like 1 (FOSL1)/HAS3 axis mediated the inhibitory effects of melatonin on HA accumulation and stemness of HNSCC in a receptor-independent manner. Taken together, melatonin modulated HA synthesis through the FOSL1/HAS3 axis to inhibit the stemness of HNSCC cells, which elucidates the effect of melatonin on the ECM and provides a novel perspective on melatonin in HNSCC treatment.

透明质酸(HA)是一种糖胺聚糖,也是细胞外基质(ECM)的主要成分,有报道称透明质酸与其受体CD44相互作用,在多种恶性肿瘤的癌症干细胞(CSC)自我更新和维持过程中发挥关键作用。褪黑激素是一种神经内分泌激素,具有多种抗肿瘤特性。然而,褪黑激素是否能调节头颈部鳞状细胞癌(HNSCC)ECM中的HA积累以调节其干性仍是未知数。在这项研究中,我们发现褪黑激素抑制了HNSCC细胞的CD44等CSC相关标记物,并降低了体内CSC的肿瘤诱发频率。此外,褪黑素还通过下调透明质酸合成酶3(HAS3)的表达来调节HNSCC细胞的HA合成。进一步的研究表明,Fos样1(FOSL1)/HAS3轴以受体无关的方式介导了褪黑激素对HNSCC的HA积累和干性的抑制作用。综上所述,褪黑素通过FOSL1/HAS3轴调节HA合成以抑制HNSCC细胞的干性,这阐明了褪黑素对ECM的影响,并为褪黑素治疗HNSCC提供了一个新的视角。
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引用次数: 0
Melatonin is a potential novel analgesic agent for osteoarthritis: Evidence from cohort studies in humans and preclinical research in rats 褪黑素是一种潜在的新型骨关节炎镇痛剂:来自人类队列研究和大鼠临床前研究的证据。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-02-13 DOI: 10.1111/jpi.12945
Hui Li, Bin Zhou, Jing Wu, Yuqing Zhang, Weiya Zhang, Michael Doherty, Xinjia Deng, Ning Wang, Dongxing Xie, Yilun Wang, Hui Xie, Changjun Li, Jie Wei, Guanghua Lei, Chao Zeng

Melatonin exhibits potential for pain relief and long-term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox-proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community-based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30–0.73) during the follow-up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation.

褪黑素具有缓解疼痛的潜力和长期安全性。我们研究了口服褪黑素对骨关节炎(OA)的镇痛效果,并调查了其潜在机制。我们利用英国初级保健数据库中的数据,对患有 OA 的患者进行了一项队列研究,分别使用量子回归模型和 Cox 比例危险模型,比较了褪黑素启动者和催眠药苯二氮卓类药物(即活性比较药)启动者的口服镇痛处方数量和膝关节/髋关节置换风险。为了阐明因果关系,我们研究了褪黑素对疼痛行为的影响,并探讨了在单碘乙酸大鼠 OA 模型中可能作为褪黑素潜在调节剂的几种代谢物。利用另一项基于社区的队列研究(即湘雅 OA 研究)的数据,我们验证了关键血清代谢物与有症状膝关节 OA 事件之间的关联。与苯二氮卓类催眠药队列(n = 8135)相比,褪黑素队列(n = 813)的后续口服镇痛药处方明显较少(第50百分位数:5 vs. 7,第75百分位数:19 vs. 29,第99百分位数:140 vs. 162),并且在随访期间进行膝关节/髋关节置换的风险较低(危险比 = 0.47,95% Cl:0.30-0.73)。在大鼠身上,口服褪黑素可减轻疼痛行为并提高血清中甘氨酸的水平。在人类(n = 760)中,基线血清甘氨酸水平与发生无症状膝关节退行性关节炎的风险成反比。总之,我们的研究结果表明,口服褪黑素具有治疗 OA 疼痛的巨大潜力。甘氨酸在其镇痛机制中的潜在作用值得进一步研究。
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Journal of Pineal Research
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