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Parathyroid hormone–PTH1R signaling in cardiovascular disease and homeostasis 心血管疾病和稳态中的甲状旁腺激素-PTH1R 信号转导
Pub Date : 2024-02-29 DOI: 10.1016/j.tem.2024.02.005
Dwight A. Towler
Primary hyperparathyroidism (pHPT) afflicts our aging population with an incidence approaching 50 per 100 000 patient-years at a female:male ratio of ~3:1. Decisions surrounding surgical management are currently driven by age, hypercalcemia severity, presence of osteoporosis, renal insufficiency, or hypercalciuria with or without nephrolithiasis. Cardiovascular (CV) disease (CVD) is not systematically considered. This is notable since the parathyroid hormone (PTH) 1 receptor (PTH1R) is biologically active in the vasculature, and adjusted CV mortality risk is increased almost threefold in individuals with pHPT who do not meet contemporary recommendations for surgical cure. We provide an overview of epidemiology, pharmacology, and physiology that highlights the need to: (i) identify biomarkers that establish a healthy ‘set point’ for CV PTH1R signaling tone; (ii) better understand the pharmacokinetic–pharmacodynamic (PK-PD) relationships of PTH1R ligands in CV homeostasis; and (iii) incorporate CVD risk assessment into the management of hyperparathyroidism.
原发性甲状旁腺功能亢进症(pHPT)困扰着我们的老龄人口,发病率接近每 10 万患者年 50 例,男女比例约为 3:1。目前,手术治疗的决定因素包括年龄、高钙血症的严重程度、是否存在骨质疏松症、肾功能不全或伴有或不伴有肾结石的高钙尿症。心血管(CV)疾病(CVD)未得到系统考虑。这一点值得注意,因为甲状旁腺激素(PTH)1 受体(PTH1R)在血管中具有生物活性,而患有 pHPT 且不符合当代手术治疗建议的患者,其调整后的心血管疾病死亡风险几乎增加了三倍。我们对流行病学、药理学和生理学进行了概述,强调需要(i)确定生物标志物,为心血管PTH1R信号调节建立一个健康的 "设定点";(ii)更好地理解PTH1R配体在心血管平衡中的药代动力学-药效学(PK-PD)关系;以及(iii)将心血管疾病风险评估纳入甲状旁腺功能亢进症的管理中。
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引用次数: 0
Vitamin K-dependent carboxylation in β-cells and diabetes β细胞中依赖维生素 K 的羧化作用与糖尿病
Pub Date : 2024-02-29 DOI: 10.1016/j.tem.2024.02.006
Julie Lacombe, Mathieu Ferron
Vitamin K is an essential micronutrient and a cofactor for the enzyme γ-glutamyl carboxylase, which adds a carboxyl group to specific glutamic acid residues in proteins transiting through the secretory pathway. Higher vitamin K intake has been linked to a reduced incidence of type 2 diabetes (T2D) in humans. Preclinical work suggests that this effect depends on the γ-carboxylation of specific proteins in β-cells, including endoplasmic reticulum Gla protein (ERGP), implicated in the control of intracellular Ca levels. In this review we discuss these recent advances linking vitamin K and glucose metabolism, and argue that identification of γ-carboxylated proteins in β-cells is pivotal to better understand how vitamin K protects from T2D and to design targeted therapies for this disease.
维生素 K 是人体必需的微量营养素,也是γ-谷氨酰羧化酶的辅助因子,γ-谷氨酰羧化酶可将羧基添加到通过分泌途径转运的蛋白质中的特定谷氨酸残基上。维生素 K 摄入量的增加与人类 2 型糖尿病(T2D)发病率的降低有关。临床前研究表明,这种效应取决于β细胞中特定蛋白质的γ-羧基化,包括与细胞内Ca水平控制有关的内质网Gla蛋白(ERGP)。在这篇综述中,我们讨论了这些将维生素 K 与糖代谢联系起来的最新进展,并认为鉴定 β 细胞中的γ-羧化蛋白对于更好地理解维生素 K 如何保护人们免受 T2D 的侵害以及设计治疗该疾病的靶向疗法至关重要。
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引用次数: 0
Lysine lactylation in the regulation of tumor biology 调控肿瘤生物学的赖氨酸乳化作用
Pub Date : 2024-02-22 DOI: 10.1016/j.tem.2024.01.011
Zijian Yang, Yingqi Zheng, Qiang Gao
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引用次数: 0
Dietary methionine restriction in cancer development and antitumor immunity 膳食蛋氨酸限制在癌症发展和抗肿瘤免疫中的作用
Pub Date : 2024-02-20 DOI: 10.1016/j.tem.2024.01.009
Ming Ji, Qing Xu, Xiaoling Li
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引用次数: 0
Advisory Board and Contents 咨询委员会和内容
Pub Date : 2024-02-12 DOI: 10.1016/s1043-2760(24)00005-5
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引用次数: 0
Subscription and Copyright Information 订阅和版权信息
Pub Date : 2024-02-12 DOI: 10.1016/s1043-2760(24)00008-0
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引用次数: 0
Exercise is also medicine for iron homeostasis 运动也是促进铁平衡的良药
Pub Date : 2024-02-02 DOI: 10.1016/j.tem.2024.01.010
Abel Plaza-Florido, Alejandro Lucia, Carmen Fiuza-Luces

High-intensity interval training (HIIT) is gaining popularity as an effective exercise modality to improve cardiometabolic health. Combining high-throughput/sensitivity proteome analyses in subcutaneous adipose tissue with biochemical blood measures, Larsen et al. recently provided mechanistic insights into a potential beneficial role of this exercise modality on iron homeostasis at the whole-body level.

高强度间歇训练(HIIT)作为一种改善心脏代谢健康的有效运动方式,越来越受到人们的青睐。最近,Larsen 等人结合皮下脂肪组织的高通量/灵敏度蛋白质组分析和血液生化指标,从机理上揭示了这种运动方式对全身铁稳态的潜在有益作用。
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引用次数: 0
Establishing evidence for immune surveillance of β-cell senescence 建立免疫监视β细胞衰老的证据
Pub Date : 2024-02-02 DOI: 10.1016/j.tem.2024.01.003
Nayara Rampazzo Morelli, Jasmine Pipella, Peter J. Thompson

Cellular senescence is a programmed state of cell cycle arrest that involves a complex immunogenic secretome, eliciting immune surveillance and senescent cell clearance. Recent work has shown that a subpopulation of pancreatic β-cells becomes senescent in the context of diabetes; however, it is not known whether these cells are normally subject to immune surveillance. In this opinion article, we advance the hypothesis that immune surveillance of β-cells undergoing a senescence stress response normally limits their accumulation during aging and that the breakdown of these mechanisms is a driver of senescent β-cell accumulation in diabetes. Elucidation and therapeutic activation of immune surveillance mechanisms in the pancreas holds promise for the improvement of approaches to target stressed senescent β-cells in the treatment of diabetes.

细胞衰老是一种细胞周期停滞的程序化状态,涉及复杂的免疫原性分泌组,引起免疫监视和衰老细胞清除。最近的研究表明,在糖尿病的情况下,胰腺β细胞的一个亚群会发生衰老;然而,这些细胞是否通常会受到免疫监视尚不清楚。在这篇观点性文章中,我们提出了一个假设,即对发生衰老应激反应的β细胞的免疫监视通常会限制它们在衰老过程中的积累,而这些机制的破坏是糖尿病中β细胞衰老积累的驱动因素。阐明和治疗性激活胰腺中的免疫监视机制有望改进针对受压衰老β细胞的方法,从而治疗糖尿病。
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引用次数: 0
Modeling hypothalamic pathophysiology in vitro for metabolic, circadian, and sleep disorders 针对代谢、昼夜节律和睡眠障碍的体外下丘脑病理生理学建模
Pub Date : 2024-02-01 DOI: 10.1016/j.tem.2024.01.001
Helena Leal, Catarina Carvalhas-Almeida, Ana Rita Álvaro, Cláudia Cavadas

The hypothalamus, a small and intricate brain structure, orchestrates numerous neuroendocrine functions through specialized neurons and nuclei. Disruption of this complex circuitry can result in various diseases, including metabolic, circadian, and sleep disorders. Advances in in vitro models and their integration with new technologies have significantly benefited research on hypothalamic function and pathophysiology. We explore existing in vitro hypothalamic models and address their challenges and limitations as well as translational findings. We also highlight how collaborative efforts among multidisciplinary teams are essential to develop relevant and translational experimental models capable of replicating intricate neural circuits and neuroendocrine pathways, thereby advancing our understanding of therapeutic targets and drug discovery in hypothalamus-related disorders.

下丘脑是一个小而复杂的大脑结构,它通过专门的神经元和神经核来协调多种神经内分泌功能。这一复杂回路的破坏可导致各种疾病,包括代谢、昼夜节律和睡眠障碍。体外模型的进步及其与新技术的整合极大地促进了对下丘脑功能和病理生理学的研究。我们探讨了现有的体外下丘脑模型,并论述了它们所面临的挑战和局限性以及转化研究成果。我们还强调了多学科团队之间的合作对于开发能够复制复杂神经回路和神经内分泌通路的相关转化实验模型的重要性,从而促进我们对下丘脑相关疾病的治疗靶点和药物发现的理解。
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引用次数: 0
Pathophysiology of human mitochondrial tRNA metabolism 人类线粒体 tRNA 代谢的病理生理学
Pub Date : 2024-02-01 DOI: 10.1016/j.tem.2024.01.002
Jian-Hui Zhang, Gilbert Eriani, Xiao-Long Zhou

Mitochondria play multiple critical roles in cellular activity. In particular, mitochondrial translation is pivotal in the regulation of mitochondrial and cellular homeostasis. In this forum article, we discuss human mitochondrial tRNA metabolism and highlight its tight connection with various mitochondrial diseases caused by mutations in aminoacyl-tRNA synthetases, tRNAs, and tRNA-modifying enzymes.

线粒体在细胞活动中发挥着多种关键作用。其中,线粒体翻译在调节线粒体和细胞平衡中起着关键作用。在本论坛文章中,我们将讨论人类线粒体 tRNA 代谢,并强调其与氨基酸-tRNA 合成酶、tRNA 和 tRNA 修饰酶突变导致的各种线粒体疾病之间的密切联系。
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引用次数: 0
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Trends in Endocrinology & Metabolism
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