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Melatonin Ameliorates Cadmium-Induced Liver Fibrosis Via Modulating Gut Microbiota and Bile Acid Metabolism 褪黑素通过调节肠道微生物群和胆汁酸代谢改善镉诱导的肝纤维化
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-18 DOI: 10.1111/jpi.70005
Xianjiao Liu, Weili Kang, Jinyan Li, Xin Li, Peng Yang, Mengdie Shi, Zhongyu Wang, Yanyan Wang, Andrea Del Pilar Abreo Medina, Dandan Liu, Fenxia Zhu, Hong Shen, Kehe Huang, Xingxiang Chen, Yunhuan Liu

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.

镉(Cd)是一种广泛存在的环境污染物,对人体健康具有很高的毒性。研究表明,褪黑素可改善镉引起的肝损伤。然而,其作用机制尚未阐明。本研究旨在探讨褪黑素对镉诱导的肝损伤和肝纤维化的影响。研究采用 16S rRNA 基因测序和基于质谱的代谢组学相结合的方法,探讨肠道微生物组及其代谢物的变化对褪黑素在 Cd 诱导的小鼠肝损伤和肝纤维化中的调控作用。此外,还采用了非吸收性抗生素、粪便微生物群移植(FMT)计划和肠道特异性褪黑素X受体(FXR)基因敲除小鼠来探讨褪黑素(MT)对镉处理小鼠肝损伤和肝纤维化的机制。褪黑素能明显改善镉暴露小鼠的肝脏炎症、胆管增生、肝损伤和肝纤维化,并明显降低肝脏胆汁酸水平。MT 治疗重塑了肠道微生物群,改善了肠道屏障功能,减少了肠道衍生脂多糖(LPS)的产生。MT能明显降低肠道中被称为FXR拮抗剂的tauro-β-muricholic acid的水平。值得注意的是,MT能显著激活肠道FXR信号传导,从而抑制肝脏胆汁酸的合成,减轻接触镉的小鼠的肝脏炎症。然而,MT 并不能改善 Cd 诱导的 Abx 治疗小鼠肝损伤和肝纤维化。相反,MT 对 FMT 小鼠因 Cd 引起的肝损伤和肝纤维化仍有保护作用。有趣的是,MT未能逆转Cd暴露的肠上皮细胞特异性FXR基因敲除小鼠的肝损伤和纤维化,这表明肠道FXR信号介导了MT治疗的保护作用。MT通过重塑肠道菌群、激活肠道FXR介导的对肝脏胆汁酸合成的抑制以及减少小鼠的LPS渗漏来改善Cd诱导的肝损伤和肝纤维化。
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引用次数: 0
Timing Matters: Late, but Not Early, Exercise Training Ameliorates MASLD in Part by Modulating the Gut-Liver Axis in Mice 时机很重要:晚期而非早期的运动训练可部分通过调节小鼠的肠道-肝脏轴来改善 MASLD。
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-13 DOI: 10.1111/jpi.70003
Artemiy Kovynev, Zhixiong Ying, Sen Zhang, Emanuele Olgiati, Joost M. Lambooij, Clara Visentin, Bruno Guigas, Quinten R. Ducarmon, Patrick C. N. Rensen, Milena Schönke

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; L-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 Akkermansia, Lachnospiraceae, and Rikenella. 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.

代谢功能障碍相关性脂肪性肝病(MASLD)影响着全球 20 亿人,目前大多可通过运动训练等生活方式干预来治疗。然而,目前还不清楚运动的积极作用是否仅限于独特的昼夜节律窗口。因此,我们旨在研究运动训练的时间是否会对 MASLD 的发展产生不同程度的调节作用。给20周大的雄性APOE*3-Leiden.CETP小鼠喂食高脂肪-高胆固醇饮食以诱发MASLD,并在12周内每周5次、每次1小时的跑步机训练,训练时间可以是暗相的早期(ZT13;E-RUN)或晚期(ZT22;L-RUN),而相应的静坐组(E-SED和L-SED)则不进行训练。晚期而非早期运动训练降低了 MASLD 评分、体重、脂肪量和肝脏甘油三酯,同时肠道微生物群的组成也发生了改变。具体来说,只有晚期运动训练才会增加产生短链脂肪酸的细菌科和属的数量,如Akkermansia、Lachnospiraceae和Rikenella。为了评估肠道微生物群在训练诱导效应中的作用,研究重复了训练小鼠(仅 ZT22,RUN)或久坐小鼠(SED)作为久坐受体小鼠的粪便供体(RUN FMT 和 SED FMT)。与 SED FMT 相比,粪便微生物群移植降低了 RUN FMT 的肝脏重量和血浆甘油三酯,并有降低 MASLD 评分和肝脏甘油三酯的趋势。在这个临床前模型中,运动训练的时机是对MASLD产生积极影响的关键因素,而后期运动的影响部分是通过肠肝轴介导的。
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引用次数: 0
Melatonin Protects Against Cocaine-Induced Blood−Brain Barrier Dysfunction and Cognitive Impairment by Regulating miR-320a-Dependent GLUT1 Expression 褪黑激素通过调节依赖于 miR-320a 的 GLUT1 表达,防止可卡因诱发的血脑屏障功能障碍和认知障碍
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-13 DOI: 10.1111/jpi.70002
Jia-Yi Wei, Hui Liu, Yuan Li, Dan Zhao, Bo Wang, Hui-Jie Wang, Li Wang, Kang-Ji Wang, Jin-Li Yue, Hong-Yan Zhang, Tian-Yue Li, Yi-Jue Miao, Kai-Li Wang, Pai-Ge Tong, Zhuo Zhang, Ze-Ye Li, Zheng Shi, Jia-Yuan Yao, Dong-Xin Liu, Wen-Gang Fang, Bo Li, De-Shu Shang, Yuan Lyu, Hong-Zan Sun, Wei-Dong Zhao, Yu-Hua Chen

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.

滥用可卡因与血脑屏障(BBB)功能障碍密切相关,但可卡因破坏 BBB 的确切机制仍不清楚。在这项研究中,我们发现可卡因治疗会降低脑微血管内皮细胞中葡萄糖转运体1(GLUT1)的表达,而葡萄糖转运体1是可卡因诱导脑葡萄糖摄取、血脑屏障渗漏和认知障碍的关键因素。从机理上讲,我们的研究结果表明,可卡因会上调 miR-320a,而 miR-320a 又会通过 beta 2 肾上腺素能受体(ADRB2)抑制 GLUT1 的表达。值得注意的是,向脑部微血管内皮细胞注射编码全长 GLUT1 的腺相关病毒或 miR-320a 抑制剂能显著缓解可卡因诱导的 BBB 渗漏和认知障碍。此外,我们还发现褪黑激素(一种众所周知的神经保护激素)能减轻可卡因诱导的 BBB 破坏和认知障碍。褪黑激素的这种保护作用是通过 MT1 受体介导的 cAMP/PKA/CREB 信号通路抑制,上调脑内皮细胞中依赖 miR-320a 的 GLUT1 表达。总之,我们的研究结果表明,可卡因会下调脑微血管 GLUT1,导致 BBB 功能障碍,并强调褪黑激素是治疗可卡因相关并发症的潜在治疗药物。
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引用次数: 0
Disruption of Melatonin Signaling Leads to Lipids Accumulation in the Liver of Melatonin Proficient Mice 褪黑激素信号的中断导致褪黑激素熟练小鼠肝脏中的脂质堆积
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-13 DOI: 10.1111/jpi.70007
Varunika Goyal, Gianluca Tosini

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.

通过褪黑激素受体 1 型(MT1)和 2 型(MT2)发出的褪黑激素信号在调节多种生理功能方面发挥着重要作用。对啮齿类动物和人类的研究表明,褪黑激素信号的中断可能会影响葡萄糖代谢、胰岛素敏感性和瘦素水平。不断积累的实验证据还表明,在啮齿动物体内施用外源性褪黑激素对血脂水平有好处。然而,褪黑激素信号调节血脂的分子机制仍不清楚。此外,大多数针对小鼠的研究都是在褪黑素缺乏的小鼠体内以超生理剂量施用外源性褪黑素进行的。因此,这些研究的结果可能会受到这两个因素的很大影响。在本研究中,我们利用褪黑激素缺陷小鼠(C3H-f+/f+)报告了褪黑激素信号清除对肝脏生物学和转录组的影响。我们的数据表明,MT1 或 MT2 信号的缺失会导致血脂谱的破坏和肝脏中脂类沉积的增加。在缺乏 MT1 的小鼠中,这些影响比 MT2 更明显。从三种基因型肝脏的 RNA-seq 中获得的基因表达谱显示,去除 MT1 会影响 4255 个基因(即 40.6%)的转录。相反,移除 MT2 会影响 1864 个转录本(即 17.2%)的转录。最后,我们发现了一组参与脂质生物学的 13 个基因,当褪黑激素信号中断时,这些基因可能在肝脏中脂质的积累中发挥关键作用。总之,我们的研究表明,褪黑激素信号传导是肝脏生理和代谢的重要调节因子。我们的研究还表明,去除 MT1 信号比去除 MT2 更有害。
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引用次数: 0
Heat Treatment of Saliva to Reduce Infectious Disease Contamination Does Not Impact the Analysis of Melatonin by Radioimmunoassay. 为减少传染病污染而对唾液进行热处理不会影响通过放射免疫分析法分析褪黑素。
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-01 DOI: 10.1111/jpi.70009
Mark D Salkeld, David J Kennaway

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 (p < 0.0001) and the slope of the Deming regression analysis close to 1.0 (Y = 1.04X + 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 (p < 0.0001), however melatonin concentrations were consistently overestimated when compared to the untreated controls with Deming regression slope of Y = 1.26X + 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.

唾液中褪黑激素水平的测定是评估人类中枢昼夜节律时钟时间的关键方法之一,无论是在研究还是在临床环境中都是如此。唾液中的褪黑激素水平通常是在实验室环境中通过 RIA 或酶联免疫吸附试验测定的,而严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)的出现给唾液样本中褪黑激素的常规安全评估带来了严峻挑战。然而,生物液体中的 SARS-CoV-2 可在至少 55-60°C 的温度下暴露 30 分钟而失活,因此本研究的目的是评估使用 Novolytix 放射免疫分析仪 (RK-DSM2) 对唾液样本进行预处理加热步骤以测定褪黑激素的有效性。解冻根据暗光褪黑素起始采样方案收集的 40 份存档唾液样本,并将其等分到三个相同的组中--对照组(无预处理)、56°C 检测前热处理组(30 分钟)和 70°C 检测前热处理组(30 分钟)。检测前加热至 56°C 30 分钟的样本中褪黑激素浓度与未处理的对照组接近,两组样本之间的皮尔逊相关系数为 0.99(p<0.05)。
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引用次数: 0
From Seasonality to Species Conservation: Chronobiological Research on European Hamsters in Strasbourg, France 从季节性到物种保护:法国斯特拉斯堡欧洲仓鼠的时间生物学研究
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-16 DOI: 10.1111/jpi.13012
Stefanie Monecke

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.

关于斯特拉斯堡地区欧洲仓鼠的第一部专著可追溯到 1765 年。到 20 世纪 30 年代,从 Charles Kayser 在 1938 年至 1971 年期间发表的著作开始,该物种的时间生物学研究传统已经形成。Bernhard Canguilhem 是这一领域的另一位早期重要研究者,他在 1966 年至 1999 年期间发表了大量著作。从 20 世纪 80 年代起,"佩韦夫妇",即保罗-佩韦(Paul Pévet)和他的妻子米勒-马松-佩韦(Mireille Masson-Pévet),为欧洲仓鼠研究注入了新的活力。他们扩大了研究范围,从基础冬眠研究到循环节律的机理研究,从生理方面到分子细节。他们研究的一个主要基本问题是褪黑激素的作用。由于他们的热情和远见卓识,欧洲仓鼠如今已成为研究得最好(如果不是最好的话)的周期性物种之一。至少有 73 个参数被描述为周期。其中 32 个参数已被证明由周期时钟驱动。此外,我们对冬眠的机理、环流钟的功能及其夹带的理解也取得了突破性进展。这项研究大部分是在斯特拉斯堡进行的,保罗-贝韦在提供必要资源方面发挥了重要作用,使这些创新和非常规的长期动物研究成为可能,为基础研究做出了贡献,并最终为物种保护做出了贡献。
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引用次数: 0
RETRACTION: Effects of Melatonin on Fatty Liver Disease: The Role of NR4A1/DNA-Pkcs/P53 Pathway, Mitochondrial Fission, and Mitophagy 返回:褪黑素对脂肪肝的影响:NR4A1/DNA-Pkcs/P53通路、线粒体分裂和丝裂吞噬的作用
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-16 DOI: 10.1111/jpi.70001

RETRACTION: 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,” Journal of Pineal Research 64, no. 1 (2018): e12450, https://doi.org/10.1111/jpi.12450.

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.

返回: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," Journal of Pineal Research 64, no. 1 (2018): e12450, https://doi.org/10.1111/jpi.12450.The 上述文章于2017年10月5日在线发表于Wiley Online Library(wileyonlinelibrary.com),经期刊主编Gianluca Tosini和John Wiley and Sons Ltd.同意,已撤回其更正(https://doi.org/10.1111/jpi.12946)。在对第三方就DNA-PKcsfl/fl小鼠模型生成的科学完整性以及图4 A和J、图5E-G和图7A和E中数据的可靠性提出的其他问题进行调查后,双方同意撤稿。资深通讯作者所在的研究所表示,该研究不是在他们的大学进行的。鉴于所发现问题的严重程度,编辑对所提供的数据失去了信心,文章的结论也不再可靠。第一作者不同意撤稿,其他作者均未做出回应。
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引用次数: 0
Melatonin Inhibits ET-1 Production to Break Crosstalk Between Prostate Cancer and Bone Cells: Implication for Osteoblastic Bone Metastasis Treatment 褪黑激素抑制 ET-1 生成,打破前列腺癌与骨细胞之间的串联:对成骨细胞骨转移治疗的启示
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-16 DOI: 10.1111/jpi.70000
Liang-Wei Lin, Tien-Huang Lin, Sanskruti Swain, Jen-Kai Fang, Jeng-Hung Guo, Shun-Fa Yang, Chih-Hsin Tang

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.

骨转移是晚期前列腺癌(PCa)患者死亡的主要原因。PCa 往往会扩散到骨骼,并获得骨样表型,导致成骨细胞性骨转移。遗憾的是,目前尚无有效的治疗方法。不过,调节昼夜节律的褪黑激素已被发现具有抗肿瘤特性。褪黑素是否能有效治疗PCa骨转移,目前尚未确定。我们的研究结果表明,褪黑激素能抑制成骨细胞PCa细胞中内皮素-1(ET-1)的产生,从而抑制成骨细胞的分化。临床结果表明,与非转移性PCa患者相比,骨转移PCa患者的ET-1水平更高。此外,褪黑激素诱导的 miR-let-7f-5p 可抑制 ET-1 促进的成骨细胞分化。褪黑激素还能抑制成骨细胞PCa细胞的仿骨特性。重要的是,在胫骨内注射 PCa 转移模型中,褪黑激素抑制了 ET-1 的产生和成骨细胞的分化,从而降低了成骨性 PCa 肿瘤的生长。综上所述,褪黑素通过上调miR-let-7f-5p减少ET-1的产生,从而抑制成骨性PCa调控的成骨细胞生成,同时抑制成骨性PCa的仿骨特性。褪黑素疗法可能是治疗成骨细胞性PCa骨转移的一种很有前景的方法。
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引用次数: 0
Melatonin, Melatonin Receptors and Sleep: Moving Beyond Traditional Views 褪黑激素、褪黑激素受体与睡眠:超越传统观点
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-14 DOI: 10.1111/jpi.13011
Stefano Comai, Gabriella Gobbi

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.

睡眠约占人类寿命的三分之一,是身心健康必不可少的重要生理过程。正常的睡眠由清醒、非快速眼动(NREM)睡眠和快速眼动(REM)睡眠有序地进行,所有这些睡眠过程都受到严格的调节。褪黑激素通常被称为 "睡眠激素",它在睡眠/觉醒周期的调节中起着关键作用,并通过称为 MT1 和 MT2 的高亲和性 G 蛋白偶联受体发挥其作用。对这些受体的选择性调节是治疗睡眠障碍的一条很有前景的途径。这篇综述探讨了褪黑素在睡眠调节中的多方面作用,重点是针对MT1和MT2受体的选择性配体,以及涉及MT1和MT2基因敲除小鼠的研究。与一般观点相反,越来越多的证据表明,褪黑激素通过MT1和MT2受体不仅可能影响睡眠的昼夜节律,还可能调节睡眠的平衡过程和睡眠结构,或者说,褪黑激素可能是连接睡眠的平衡调节和昼夜节律调节的分子。此外,还讨论了 MT1 和 MT2 受体在大脑中的不同定位,MT1 受体主要调节快速眼动睡眠,而 MT2 受体则调节非快速眼动睡眠。总之,睡眠调控不仅仅局限于褪黑激素的循环水平和昼夜节律峰值;它还关键地涉及 MT1 和 MT2 受体在参与睡眠调控的各个脑区和核团中的表达、分子激活和调控功能。这项研究强调了持续调查 MT1 和 MT2 受体在睡眠中的选择性作用的重要性。这些研究工作有望为开发有针对性的MT1或MT2受体配体铺平道路,从而优化对睡眠障碍的治疗干预。
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引用次数: 0
Differential Effects of Light and Dark Phase Modifications on Jet Lag Adaptability in Mice 明暗相位变化对小鼠时差适应性的不同影响
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-14 DOI: 10.1111/jpi.13010
Changxiao Ma, Haonan Li, Bingyi Shen, Huiwen Zheng, Yunfei Chen, Lihong Chen, Guangrui Yang

In chronobiology, shifting light/dark cycles is a common method to disrupt circadian rhythms. While the direction and magnitude of a phase shift (e.g., +6 denoting a 6-h advanced shift) dictate the temporal change before and after the shift, little attention has been paid to the duration and relative proportion of daytime and nighttime during the shift, leading to a critical, unexamined variable in circadian research. In this study, we introduce the concepts of “L-shift” (longer light phase on the shift day) and “D-shift” (longer dark phase), and investigate how these variations impact the adaptability of mice to jet lag. By examining multiple phase shifts (12L vs. 12D, +6L vs. +6D, −6L vs. −6D), we demonstrate that L-shifts not only facilitate faster adaptation but also significantly reduce the severity of sepsis in a jet lag-sensitive lipopolysaccharide-induced sepsis model. Further investigations with additional phase shifts at 1-h intervals (+8 to +11) reinforced the enhanced fitness of mice under L-shifts. Mechanistically, L-shifts were found to increase sleep duration, thereby improving circadian entrainment, with sleep deprivation nullifying the adaptability differences between lighting protocols. These findings underscore a previously unrecognized factor in circadian biology and suggest that optimizing lighting protocols could profoundly improve adaptability to circadian disruptions. This research opens new avenues for enhancing therapeutic strategies and refining experimental designs in the field of chronobiology.

在时间生物学中,改变光/暗周期是扰乱昼夜节律的常用方法。虽然相位变换的方向和幅度(例如,+6 表示提前 6 小时换班)决定了换班前后的时间变化,但人们很少关注换班期间白天和黑夜的持续时间和相对比例,这导致昼夜节律研究中出现了一个关键的、尚未研究的变量。在这项研究中,我们引入了 "L-shift"(换班日较长的光照阶段)和 "D-shift"(较长的黑暗阶段)的概念,并研究了这些变化如何影响小鼠对时差的适应性。通过研究多种相位变换(12L 与 12D、+6L 与 +6D、-6L 与 -6D),我们证明了在对时差敏感的脂多糖诱导败血症模型中,L 移位不仅能促进更快的适应,还能显著降低败血症的严重程度。通过对间隔 1 小时(+8 至 +11)的额外相位移动进行进一步研究,证实了小鼠在 L 型移动下的适应能力得到了增强。从机理上讲,L-班制能延长睡眠时间,从而改善昼夜节律的协调,而剥夺睡眠则会使不同照明方案之间的适应性差异失效。这些发现强调了昼夜节律生物学中一个以前未被发现的因素,并表明优化照明方案可以显著提高对昼夜节律紊乱的适应性。这项研究为改进治疗策略和完善昼夜生物学领域的实验设计开辟了新途径。
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引用次数: 0
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Journal of Pineal Research
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