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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
Melatonin Regulates Rheumatoid Synovial Fibroblasts-Related Inflammation: Implications for Pathological Skeletal Muscle Treatment 褪黑激素调节类风湿滑膜成纤维细胞相关炎症:病理骨骼肌治疗的意义》。
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-24 DOI: 10.1111/jpi.13009
Chen-Ming Su, Chun-Hao Tsai, Hsien-Te Chen, Yi-Syuan Wu, Shun-Fa Yang, Chih-Hsin Tang

Melatonin has been reported to regulate circadian rhythms and have anti-inflammatory characteristics in various inflammatory autoimmune diseases, but its effects in diseases-associated muscle atrophy remain controversial. This study is aimed to determine the evidence of melatonin in rheumatoid arthritis (RA)-related pathological muscle atrophy. We used initially bioinformatics results to show that melatonin regulated significantly the correlation between pro-inflammation and myogenesis in RA synovial fibroblasts (RASF) and myoblasts. The conditioned medium (CM) from melatonin-treated RASF was incubated in myoblasts with growth medium and differentiated medium to investigate the markers of pro-inflammation, atrophy, and myogenesis. We found that melatonin regulated RASF CM-induced pathological muscle pro-inflammation and atrophy in myoblasts and differentiated myocytes through NF-κB signaling pathways. We also showed for the first time that miR-30c-1-3p is negatively regulated by three inflammatory cytokines in human RASF, which is associated with murine-differentiated myocytes. Importantly, oral administration with melatonin in a collagen-induced arthritis (CIA) mouse model also significantly improved arthritic swelling, hind limb grip strength as well as pathological muscle atrophy. In conclusion, our study is the first to demonstrate not only the underlying mechanism whereby melatonin decreases pro-inflammation in RA-induced pathological muscle atrophy but also increases myogenesis in myoblasts and differentiated myocytes.

据报道,褪黑素可调节昼夜节律,并在各种炎症性自身免疫疾病中具有抗炎特性,但其在疾病相关肌肉萎缩中的作用仍存在争议。本研究旨在确定褪黑激素在类风湿性关节炎(RA)相关病理性肌肉萎缩中的作用证据。我们利用生物信息学的初步研究结果表明,褪黑激素能显著调节类风湿性关节炎滑膜成纤维细胞(RASF)和成肌细胞的促炎和肌生成之间的相关性。将褪黑素处理过的RASF的条件培养基(CM)与肌母细胞的生长培养基和分化培养基一起培养,以研究促炎、萎缩和肌生成的标志物。我们发现,褪黑激素可通过 NF-κB 信号通路调控 RASF CM 在成肌细胞和分化肌细胞中诱导的病理性肌肉促炎和萎缩。我们还首次发现,在人类 RASF 中,miR-30c-1-3p 受三种炎症细胞因子的负向调节,这与小鼠分化的肌细胞有关。重要的是,在胶原诱导的关节炎(CIA)小鼠模型中口服褪黑素也能显著改善关节炎肿胀、后肢握力以及病理性肌肉萎缩。总之,我们的研究首次证明了褪黑激素不仅能减少RA诱导的病理性肌肉萎缩中的促炎作用,还能增加成肌细胞和分化肌细胞的肌生成的内在机制。
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引用次数: 0
Melatonin Attenuates Diabetic Retinopathy by Regulating EndMT of Retinal Vascular Endothelial Cells via Inhibiting the HDAC7/FOXO1/ZEB1 Axis 褪黑激素通过抑制 HDAC7/FOXO1/ZEB1 轴调节视网膜血管内皮细胞的内切酶抑制糖尿病视网膜病变
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-19 DOI: 10.1111/jpi.13008
Jiayi Ning, Minghong Pan, Hanyi Yang, Zhaoyang Wang, Xiaolan Wang, Kai Guo, Yingtong Feng, Tingke Xie, Yixuan Chen, Chengming Chen, Sida Liu, Yimeng Zhang, Yuanyong Wang, Xiaolong Yan, Jing Han

Diabetic retinopathy (DR) is characterized as a microvascular disease. Nonproliferative diabetic retinopathy (NPDR) presents with alterations in retinal blood flow and vascular permeability, thickening of the basement membrane, loss of pericytes, and formation of acellular capillaries. Endothelial–mesenchymal transition (EndMT) of retinal microvessels may play a critical role in advancing NPDR. Melatonin, a hormone primarily secreted by the pineal gland, is a promising therapeutic for DR. This study explored the EndMT in retinal microvessels of NPDR and its related mechanisms. The effect of melatonin on the retina of diabetic rats was evaluated by electroretinogram (ERG) and histopathologic slide staining. Furthermore, the effect of melatonin on human retinal microvascular endothelial cells (HRMECs) was detected by EdU incorporation assay, scratch assay, transwell assay, and tube formation test. Techniques such as RNA-sequencing, overexpression or knockdown of target genes, extraction of cytoplasmic and nuclear protein, co-immunoprecipitation (co-IP), and multiplex immunofluorescence facilitated the exploration of the mechanisms involved. Our findings reveal, for the first time, that melatonin attenuates diabetic retinopathy by regulating EndMT of retinal vascular endothelial cells via inhibiting the HDAC7/FOXO1/ZEB1 axis. Collectively, these results suggest that melatonin holds potential as a therapeutic strategy to reduce retinal vascular damage and protect vision in NPDR.

糖尿病视网膜病变(DR)是一种微血管疾病。非增殖性糖尿病视网膜病变(NPDR)表现为视网膜血流和血管通透性的改变、基底膜增厚、周细胞丢失以及无细胞毛细血管的形成。视网膜微血管的内皮-间质转化(EndMT)可能在促进 NPDR 的发展中起着至关重要的作用。褪黑激素是一种主要由松果体分泌的激素,是一种很有前景的 DR 治疗药物。本研究探讨了 NPDR 视网膜微血管的 EndMT 及其相关机制。通过视网膜电图(ERG)和组织病理学切片染色评估了褪黑素对糖尿病大鼠视网膜的影响。此外,褪黑素对人视网膜微血管内皮细胞(HRMECs)的影响还通过EdU掺入试验、划痕试验、transwell试验和成管试验进行了检测。RNA测序、过表达或敲除靶基因、提取细胞质和细胞核蛋白、共免疫沉淀(co-IP)和多重免疫荧光等技术促进了对相关机制的探索。我们的研究结果首次揭示了褪黑激素通过抑制 HDAC7/FOXO1/ZEB1 轴来调节视网膜血管内皮细胞的 EndMT,从而减轻糖尿病视网膜病变。总之,这些结果表明,褪黑激素有可能作为一种治疗策略,减少NPDR患者的视网膜血管损伤并保护视力。
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引用次数: 0
Melatonin Prevents Thioacetamide–Induced Gut Leakiness and Liver Fibrosis Through the Gut–Liver Axis via Modulating Sirt1-Related Deacetylation of Gut Junctional Complex and Hepatic Proteins 褪黑素通过调节与 Sirt1 相关的肠道连接复合体和肝脏蛋白质的去乙酰化,防止硫代乙酰胺诱发的肠道渗漏和肝纤维化
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-13 DOI: 10.1111/jpi.13007
Wiramon Rungratanawanich, Karli Rae LeFort, Young-Eun Cho, Xiaoling Li, Byoung-Joon Song

Intestinal barrier dysfunction with high serum endotoxin is common in patients with liver fibrosis, but the mechanisms underlying liver fibrosis remain unclear. Melatonin is a well-recognized antioxidant and an anti-inflammatory agent that benefits multiple organs. However, the beneficial effects of melatonin on gut leakiness–associated liver fibrosis have not been systemically studied. Here, we investigated the protective mechanisms of melatonin against thioacetamide (TAA)–induced gut barrier dysfunction and hepatic fibrosis by focusing on posttranslational protein modifications through the gut–liver axis. Our results showed that gut leakiness markers, including decreased gut tight/adherens junction proteins (TJ/AJs) with increased intestinal deformation, apoptosis, and serum endotoxin, were observed early at 1 week after TAA exposure. Liver injury, apoptosis, and fibrosis were prominent at 2 and 4 weeks. Mechanistically, we found that gut TJ/AJs were hyper-acetylated, followed by ubiquitin-dependent proteolysis, leading to their degradation and gut leakiness. Gut dysbiosis, hepatic protein hyper-acetylation, and SIRT1 downregulation were also observed. Consistently, intestinal Sirt1 deficiency greatly enhanced protein hyper-acetylation, gut leakiness, endotoxemia, and liver fibrosis. Pretreatment with melatonin prevented or improved all these changes in both the gut and liver. Furthermore, melatonin blunted protein acetylation and injury in TAA–exposed T84 human intestinal and AML12 mouse liver cells. Overall, this study demonstrated novel mechanisms by which melatonin prevents gut leakiness and liver fibrosis through the gut–liver axis by attenuating the acetylation of intestinal and hepatic proteins. Thus, melatonin consumption can become a potentially safe supplement for liver fibrosis patients by preventing protein hyper-acetylation and gut leakiness.

肝纤维化患者常伴有肠屏障功能障碍和高血清内毒素,但肝纤维化的内在机制仍不清楚。褪黑素是一种公认的抗氧化剂和抗炎剂,对多个器官有益。然而,褪黑激素对肠道渗漏相关肝纤维化的有益作用尚未得到系统研究。在这里,我们研究了褪黑素对硫代乙酰胺(TAA)诱导的肠道屏障功能障碍和肝纤维化的保护机制,重点是通过肠道-肝脏轴的翻译后蛋白质修饰。我们的研究结果表明,在暴露于硫代乙酰胺1周后的早期就观察到了肠道渗漏标记物,包括肠道紧密/粘连接头蛋白(TJ/AJs)减少,肠道变形、细胞凋亡和血清内毒素增加。肝损伤、细胞凋亡和纤维化在 2 周和 4 周时更为突出。从机理上讲,我们发现肠道 TJ/AJs 被过度乙酰化,随后泛素依赖性蛋白水解,导致其降解和肠道渗漏。同时还观察到肠道菌群失调、肝脏蛋白质高乙酰化和 SIRT1 下调。一致的是,肠道 Sirt1 缺乏会大大增强蛋白质高乙酰化、肠道渗漏、内毒素血症和肝纤维化。褪黑激素的预处理可防止或改善肠道和肝脏的所有这些变化。此外,褪黑素还能减弱暴露于 TAA 的 T84 人肠道细胞和 AML12 小鼠肝细胞中的蛋白质乙酰化和损伤。总之,这项研究证明了褪黑素通过肠肝轴减轻肠道和肝脏蛋白质乙酰化防止肠道渗漏和肝纤维化的新机制。因此,服用褪黑素可以防止蛋白质高乙酰化和肠道渗漏,从而成为肝纤维化患者的一种潜在安全补充剂。
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引用次数: 0
Melatonin Alleviates Osteoarthritis by Regulating NADPH Oxidase 4–Induced Ferroptosis and Mitigating Mitochondrial Dysfunction 褪黑激素通过调节 NADPH 氧化酶 4 诱导的铁氧化作用和减轻线粒体功能障碍缓解骨关节炎。
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-04 DOI: 10.1111/jpi.12992
Qi Wang, Beijie Qi, Shi Shi, Weihao Jiang, Dejian Li, Xinhua Jiang, Chengqing Yi

Recent evidence indicates that the damaged regions in osteoarthritis are accompanied by the accumulation of iron ions. Ferroptosis, as an iron-dependent form of cell death, holds significant implications in osteoarthritis. Melatonin, a natural product with strong scavenging abilities against reactive oxygen species and lipid peroxidation, plays a crucial role in the treatment of osteoarthritis. This study aims to demonstrate the existence of ferroptosis in osteoarthritis and explore the specific mechanism of melatonin in suppressing ferroptosis and alleviating osteoarthritis. Our findings reveal that melatonin reverses inflammation-induced oxidative stress and lipid peroxidation while promoting the expression of extracellular matrix components in chondrocytes, safeguarding the cells. Our research has revealed that NADPH oxidase 4 (NOX4) serves as a crucial molecule in the ferroptosis process of osteoarthritis. Specifically, NOX4 is located on mitochondria in chondrocytes, which can induce disorders in mitochondrial energy metabolism and dysfunction, thereby intensifying oxidative stress and lipid peroxidation. LC-MS analysis further uncovered that GRP78 is a downstream binding protein of NOX4. NOX4 induces ferroptosis by weakening GRP78's protective effect on GPX4 and reducing its expression. Melatonin can inhibit the upregulation of NOX4 on mitochondria and mitigate mitochondrial dysfunction, effectively suppressing ferroptosis and alleviating osteoarthritis. This suggests that melatonin therapy represents a promising new approach for the treatment of osteoarthritis.

最近的证据表明,骨关节炎的受损区域伴随着铁离子的积累。铁变态反应是一种依赖于铁的细胞死亡形式,在骨关节炎中具有重要意义。褪黑素是一种天然产物,具有很强的清除活性氧和脂质过氧化的能力,在骨关节炎的治疗中起着至关重要的作用。本研究旨在证明骨关节炎中存在铁变态反应,并探索褪黑素抑制铁变态反应、缓解骨关节炎的具体机制。我们的研究结果表明,褪黑素能逆转炎症诱导的氧化应激和脂质过氧化反应,同时促进软骨细胞细胞外基质成分的表达,保护细胞。我们的研究发现,NADPH 氧化酶 4(NOX4)是骨关节炎铁氧化过程中的一个关键分子。具体来说,NOX4 位于软骨细胞的线粒体上,可诱导线粒体能量代谢紊乱和功能障碍,从而加剧氧化应激和脂质过氧化。LC-MS分析进一步发现,GRP78是NOX4的下游结合蛋白。NOX4 通过削弱 GRP78 对 GPX4 的保护作用并减少其表达,从而诱导铁变态反应。褪黑素可抑制线粒体上NOX4的上调,缓解线粒体功能障碍,有效抑制铁变态反应,缓解骨关节炎。这表明,褪黑素疗法是治疗骨关节炎的一种很有前景的新方法。
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引用次数: 0
Melatonin Regulates Neuronal Synaptic Plasticity in the Supramammillary Nucleus and Attenuates Methamphetamine-Induced Conditioned Place Preference and Sensitization in Mice 褪黑素调节小鼠颌上核的神经元突触可塑性并减弱甲基苯丙胺诱导的条件性位置偏好和敏感性
IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-02 DOI: 10.1111/jpi.13006
Qingyu Ren, Weikai Han, Yanan Yue, Yaqi Tang, Qingwei Yue, Stefano Comai, Jinhao Sun

Methamphetamine (METH) is an addictive drug that threatens human health. The supramammillary nucleus (SuM) and its neural circuits play key roles in the regulation of spatial memory retrieval, and hippocampal contextual or social memory. Melatonin (MLT), a pineal hormone, can regulate hypothalamic-neurohypophysial activity. Our previous study showed that MLT attenuates METH-induced locomotor sensitization. However, whether MLT regulates SuM function and participates in METH-induced contextual memory retrieval remains unclear. Using a mouse model of METH-conditioned place preference (CPP) and sensitization, we found that METH activated c-Fos expression and elevated calcium (Ca²⁺) levels in SuM neurons. Chemogenetic inhibition of SuM attenuates CPP and sensitization. Pretreatment with MLT decreased c-Fos expression and Ca2+ levels in the SuM and reversed METH-induced addictive behavior, effects that were blocked with the selective MT2 receptors antagonist 4P-PDOT and the MT1 receptors antagonist S26131. Furthermore, MLT reduced SuM synaptic plasticity, glutamate (Glu) release, and neuronal oscillations caused by METH, which were blocked by 4P-PDOT. In conclusion, our data revealed that MLT regulates neuronal synaptic plasticity in the SuM, likely through the MLT receptors (MTs), and plays a role in modulating METH-addictive behavior.

甲基苯丙胺(METH)是一种威胁人类健康的成瘾性药物。绒毛上核(SuM)及其神经回路在调节空间记忆检索和海马情境记忆或社会记忆方面发挥着关键作用。褪黑激素(MLT)是一种松果体激素,可调节下丘脑-神经-生理活动。我们之前的研究表明,MLT 可减轻 METH 诱导的运动敏感性。然而,MLT 是否调节 SuM 功能并参与 METH 诱导的情境记忆检索仍不清楚。利用小鼠的 METH 条件性位置偏好(CPP)和致敏模型,我们发现 METH 会激活 SuM 神经元中 c-Fos 的表达并升高钙(Ca²⁺)水平。对SuM的化学抑制可减轻CPP和致敏作用。MLT预处理可降低SuM中c-Fos的表达和Ca2+的水平,并逆转METH诱导的成瘾行为,这些效应被选择性MT2受体拮抗剂4P-PDOT和MT1受体拮抗剂S26131所阻断。此外,MLT 还能降低 METH 引起的 SuM 突触可塑性、谷氨酸(Glu)释放和神经元振荡,4P-PDOT 也能阻断这些作用。总之,我们的数据揭示了 MLT 可能通过 MLT 受体(MTs)调节 SuM 中神经元突触的可塑性,并在调节 METH 上瘾行为中发挥作用。
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引用次数: 0
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Journal of Pineal Research
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