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Correction to “Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways” 更正为 "褪黑素通过 PPARγ/FUNDC1/mitophagy 途径抑制血小板活化和功能,防止心脏缺血/再灌注损伤"。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-27 DOI: 10.1111/jpi.12947

Zhou H, Li D, Zhu P, et al. Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways. J. Pineal Res. 2017;63:e12438. https://doi.org/10.1111/jpi.12438

An incorrect version of the Ctrl+IR+GW group was inadvertently included in Figure 2A,I and Figure 4F of the published article. Please find the corrected figures below. It is important to note that these corrections do not affect the conclusions drawn from this study.

We apologize for this error.

Zhou H, Li D, Zhu P, et al. Melatonin inhibes platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways.J. Pineal Res. 2017;63:e12438。https://doi.org/10.1111/jpi.12438An,发表文章的图2A,I和图4F中不慎包含了Ctrl+IR+GW组的错误版本。更正后的图如下。需要注意的是,这些更正并不影响本研究得出的结论。
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引用次数: 0
Circadian light/dark cycle reversal exacerbates the progression of chronic kidney disease in mice 昼夜节律光/暗周期逆转会加剧小鼠慢性肾脏病的进展。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-27 DOI: 10.1111/jpi.12964
Jiayang Zhang, Lejia Qiu, Zhaiyi Liu, Jiaxin Liu, Bo Yu, Chengcheng Liu, Baoyin Ren, Jiaqi Zhang, Shuyao Li, Youfei Guan, Feng Zheng, Guangrui Yang, Lihong Chen

Circadian disruption such as shift work, jet lag, has gradually become a global health issue and is closely associated with various metabolic disorders. The influence and mechanism of circadian disruption on renal injury in chronic kidney disease (CKD) remains inadequately understood. Here, we evaluated the impact of environmental light disruption on the progression of chronic renal injury in CKD mice. By using two abnormal light exposure models to induce circadian disruption, we found that circadian disruption induced by weekly light/dark cycle reversal (LDDL) significantly exacerbated renal dysfunction, accelerated renal injury, and promoted renal fibrosis in mice with 5/6 nephrectomy and unilateral ureteral obstruction (UUO). Mechanistically, RNA-seq analysis revealed significant immune and metabolic disorder in the LDDL-conditioned CKD kidneys. Consistently, renal content of ATP was decreased and ROS production was increased in the kidney tissues of the LDDL-challenged CKD mice. Untargeted metabolomics revealed a significant buildup of lipids in the kidney affected by LDDL. Notably, the level of β-NMN, a crucial intermediate in the NAD+ pathway, was found to be particularly reduced. Moreover, we demonstrated that both β-NMN and melatonin administration could significantly rescue the light-disruption associated kidney dysfunction. In conclusion, environmental circadian disruption may exacerbate chronic kidney injury by facilitating inflammatory responses and disturbing metabolic homeostasis. β-NMN and melatonin treatments may hold potential as promising approaches for preventing and treating light-disruption associated CKD.

昼夜节律紊乱,如轮班工作、时差,已逐渐成为一个全球性的健康问题,并与各种代谢紊乱密切相关。昼夜节律紊乱对慢性肾脏病(CKD)肾损伤的影响和机制仍未得到充分了解。在这里,我们评估了环境光干扰对慢性肾脏病小鼠慢性肾损伤进展的影响。通过使用两种异常光照模型来诱导昼夜节律紊乱,我们发现每周光/暗周期逆转(LDDL)诱导的昼夜节律紊乱会显著加重5/6肾切除术和单侧输尿管梗阻(UUO)小鼠的肾功能障碍、加速肾损伤并促进肾纤维化。从机理上讲,RNA-seq分析表明,LDDL调节的CKD肾脏存在明显的免疫和代谢紊乱。LDDL挑战CKD小鼠肾脏组织中ATP含量减少,ROS产生增加。非靶向代谢组学显示,受 LDDL 影响的肾脏中脂类物质明显增多。值得注意的是,我们发现 NAD+ 通路中的重要中间体 β-NMN 的水平尤其降低。此外,我们还证明,服用β-NMN和褪黑激素可显著缓解与光干扰相关的肾功能障碍。总之,环境昼夜节律紊乱可能会通过促进炎症反应和扰乱代谢平衡而加剧慢性肾损伤。β-NMN和褪黑激素治疗可能是预防和治疗与光干扰相关的慢性肾脏病的有效方法。
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引用次数: 0
Melatonin restores hepatic lipid metabolic homeostasis disrupted by blue light at night in high-fat diet-fed mice 褪黑素可恢复高脂饮食小鼠夜间被蓝光破坏的肝脏脂质代谢平衡。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-23 DOI: 10.1111/jpi.12963
Qingyun Guan, Zixu Wang, Jing Cao, Yulan Dong, Shusheng Tang, Yaoxing Chen

Artificial light at night (ALAN) is an emerging environmental pollutant that threatens public health. Recently, ALAN has been identified as a risk factor for obesity; however, the role of ALAN and its light wavelength in hepatic lipid metabolic homeostasis remains undetermined. We showed that chronic dim (~5 lx) ALAN (dLAN) exposure significantly promoted hepatic lipid accumulation in obese or diabetic mice, with the most severe effect of blue light and little effect of green or red light. These metabolic phenotypes were attributed to blue rather than green or red dLAN interfering with hepatic lipid metabolism, especially lipogenesis and lipolysis. Further studies found that blue dLAN disrupted hepatic lipogenesis and lipolysis processes by inhibiting hepatic REV-ERBs. Mechanistically, feeding behavior mediated the regulation of dLAN on hepatic REV-ERBs. In addition, different effects of light wavelengths at night on liver REV-ERBs depended on the activation of the corticosterone (CORT)/glucocorticoid receptor (GR) axis. Blue dLAN could activate the CORT/GR axis significantly while other wavelengths could not. Notably, we demonstrated that exogenous melatonin could effectively inhibit hepatic lipid accumulation and restore the hepatic GR/REV-ERBs axis disrupted by blue dLAN. These findings demonstrate that dLAN promotes hepatic lipid accumulation in mice via a short-wavelength-dependent manner, and exogenous melatonin is a potential therapeutic approach. This study strengthens the relationship between ALAN and hepatic lipid metabolism and provides insights into directing ambient light.

夜间人造光(ALAN)是一种威胁公众健康的新兴环境污染物。最近,ALAN 被确定为肥胖症的一个风险因素;然而,ALAN 及其光波长在肝脏脂质代谢平衡中的作用仍未确定。我们的研究表明,长期暴露于暗光(约 5 lx)ALAN(dLAN)会显著促进肥胖或糖尿病小鼠肝脏脂质的积累,其中蓝光的影响最为严重,而绿光或红光的影响很小。这些代谢表型归因于蓝色而非绿色或红色 dLAN 干扰了肝脏脂质代谢,尤其是脂肪生成和脂肪分解。进一步研究发现,蓝色 dLAN 通过抑制肝脏 REV-ERBs 干扰了肝脏脂肪生成和脂肪分解过程。从机理上讲,摄食行为介导了dLAN对肝脏REV-ERBs的调节。此外,夜间光波长对肝脏REV-ERB的不同影响取决于皮质酮(CORT)/糖皮质激素受体(GR)轴的激活。蓝色 dLAN 能显著激活 CORT/GR 轴,而其他波长则不能。值得注意的是,我们证明外源性褪黑素能有效抑制肝脏脂质积累,并恢复被蓝色 dLAN 破坏的肝脏 GR/REV-ERBs 轴。这些研究结果表明,dLAN 通过短波长依赖性方式促进小鼠肝脏脂质积累,而外源性褪黑激素是一种潜在的治疗方法。这项研究加强了 ALAN 与肝脏脂质代谢之间的关系,并为引导环境光提供了启示。
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引用次数: 0
Melatonin reduces brain injury following inflammation-amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy 在一项新生儿脑病转化研究中,褪黑素能减轻炎症加重缺氧缺血后的脑损伤。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-22 DOI: 10.1111/jpi.12962
Raymand Pang, Christopher Meehan, George Maple, Georgina Norris, Ellie Campbell, Katie Tucker, Alison Mintoft, Francisco Torrealdea, Alan Bainbridge, Mariya Hristova, John Barks, Xavier Golay, Joseph Standing, Nicola J. Robertson

There is a need to develop therapies for neonatal encephalopathy (NE) in low- and middle-income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation-amplified hypoxia–ischaemia (IA-HI) in the newborn piglet. The IA-HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N-acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA-HI by carotid artery occlusion and reduction in FiO2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 μg/kg bolus + 1 μg/kg/h over 12 h). At 1 h after IA-HI, piglets were randomised to HI-saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15–30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI-saline, melatonin was associated with a reduction of 0.197 log10 units (95% CrI [−0.366, −0.028], Pr(sup) 98.8%) in basal-ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [−0.676, 0.164], Pr(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI-saline (Pr(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr(sup) 95.4%). Compared to HI-saline, melatonin was associated with increased NeuN+ cell density (Pr(sup) 99.3%) across five of eight regions and reduction in TUNEL-positive cell death (Pr(sup) 89.7%). This study supports the translation of melatonin to early-phase clinical trials. Melatonin is protective following IA-HI where HT is not effective. These data guide the design of future dose-escalation studies in the next phase of the translational pipeline.

中低收入国家(LMICs)的新生儿脑病(NE)负担最重,而治疗性低温疗法(HT)效果不佳,因此有必要在这些国家开发新生儿脑病疗法。我们的目的是评估褪黑素在新生仔猪发生炎症-加重缺氧-缺血(IA-HI)后的疗效。IA-HI模型考虑了感染/炎症在这种情况下的作用,而HT不具有细胞保护作用。我们假设,静脉注射褪黑素(5% 乙醇,20 毫克/千克,2 小时,HI 后 1 小时 + 10 毫克/千克/12 小时,24 至 60 小时)是安全的,并且与以下方面有关:(i) 磁共振波谱乳酸/N-乙酰天冬氨酸(MRS Lac/sNAA)减少;(ii) 磷MRS磷酸肌酸/磷酸盐交换池(PCr/Epp)保留;(iii) aEEG/EEG恢复改善;(iv) 免疫组化的细胞保护。在大肠杆菌脂多糖致敏(2 μg/kg 注射+1 μg/kg/h 12小时)4小时后,雌雄仔猪通过颈动脉闭塞接受IA-HI,并将FiO2降至6%。IA-HI后1小时,仔猪随机接受HI-盐水(n = 12)或褪黑素(n = 11)治疗。各组之间的损伤严重程度没有差异。褪黑素在 3 小时内达到目标水平(15-30 毫克/升),血液乙醇水平在基底神经节和丘脑 Lac/NAA 中为 10 单位(95% CrI [-0.366, -0.028],Pr(sup) 98.8%),在白质 Lac/NAA 中为 0.257 单位(95% CrI [-0.676, 0.164],Pr(sup) 89.3%)。PCr/Epp 在褪黑激素与 HI-saline 相比更高(Pr(sup) 97.6%)。褪黑素与 19 至 24 小时内较早的 aEEG/EEG 恢复有关(Pr(sup) 95.4%)。与HI-saline相比,褪黑激素与八个区域中五个区域的NeuN+细胞密度增加(Pr(sup) 99.3%)和TUNEL阳性细胞死亡减少(Pr(sup) 89.7%)有关。这项研究支持将褪黑素应用于早期临床试验。褪黑素对IA-HI后HT无效的情况具有保护作用。这些数据为下一阶段转化研究中未来剂量递增研究的设计提供了指导。
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引用次数: 0
Melatonin in energy control: Circadian time-giver and homeostatic monitor 能量控制中的褪黑激素:昼夜节律时间提供者和平衡监测器。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-15 DOI: 10.1111/jpi.12961
Etienne Challet, Paul Pévet

Melatonin is a neurohormone synthesized from dietary tryptophan in various organs, including the pineal gland and the retina. In the pineal gland, melatonin is produced at night under the control of the master clock located in the suprachiasmatic nuclei of the hypothalamus. Under physiological conditions, the pineal gland seems to constitute the unique source of circulating melatonin. Melatonin is involved in cellular metabolism in different ways. First, the circadian rhythm of melatonin helps the maintenance of proper internal timing, the disruption of which has deleterious effects on metabolic health. Second, melatonin modulates lipid metabolism, notably through diminished lipogenesis, and it has an antidiabetic effect, at least in several animal models. Third, pharmacological doses of melatonin have antioxidative, free radical-scavenging, and anti-inflammatory properties in various in vitro cellular models. As a result, melatonin can be considered both a circadian time-giver and a homeostatic monitor of cellular metabolism, via multiple mechanisms of action that are not all fully characterized. Aging, circadian disruption, and artificial light at night are conditions combining increased metabolic risks with diminished circulating levels of melatonin. Accordingly, melatonin supplementation could be of potential therapeutic value in the treatment or prevention of metabolic disorders. More clinical trials in controlled conditions are needed, notably taking greater account of circadian rhythmicity.

褪黑素是一种神经激素,由饮食中的色氨酸在松果体和视网膜等多个器官中合成。在松果体中,褪黑激素是在位于下丘脑上核的主时钟控制下于夜间产生的。在生理条件下,松果体似乎是循环褪黑激素的唯一来源。褪黑激素以不同方式参与细胞代谢。首先,褪黑激素的昼夜节律有助于维持适当的体内时间,而昼夜节律的破坏会对新陈代谢健康产生有害影响。其次,褪黑激素可调节脂质代谢,特别是通过减少脂肪生成,至少在几种动物模型中具有抗糖尿病作用。第三,在各种体外细胞模型中,药理剂量的褪黑激素具有抗氧化、清除自由基和抗炎特性。因此,褪黑素既可被视为昼夜节律时间的提供者,也可被视为细胞新陈代谢的稳态监测器,其作用机制多种多样,但尚未完全定性。衰老、昼夜节律紊乱和夜间人工光照是新陈代谢风险增加和褪黑激素循环水平降低的综合条件。因此,补充褪黑激素对治疗或预防代谢紊乱具有潜在的治疗价值。需要在受控条件下进行更多的临床试验,特别是要更多地考虑昼夜节律性。
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引用次数: 0
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 ENDOCRINOLOGY & METABOLISM 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 ENDOCRINOLOGY & METABOLISM 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 ENDOCRINOLOGY & METABOLISM 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 ENDOCRINOLOGY & METABOLISM 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 ENDOCRINOLOGY & METABOLISM 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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Journal of Pineal Research
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