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Low-Grade Chronic Inflammation: a Shared Mechanism for Chronic Diseases. 低度慢性炎症:慢性疾病的共同机制。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-07-30 DOI: 10.1152/physiol.00021.2024
Mariana Cifuentes, Hugo E Verdejo, Pablo F Castro, Alejandro H Corvalan, Catterina Ferreccio, Andrew F G Quest, Marcelo J Kogan, Sergio Lavandero

Inflammation is an important physiological response of the organism to restore homeostasis upon pathogenic or damaging stimuli. However, the persistence of the harmful trigger or a deficient resolution of the process can evolve into a state of low-grade, chronic inflammation. This condition is strongly associated with the development of several increasingly prevalent and serious chronic conditions, such as obesity, cancer, and cardiovascular diseases, elevating overall morbidity and mortality worldwide. The current pandemic of chronic diseases underscores the need to address chronic inflammation, its pathogenic mechanisms, and potential preventive measures to limit its current widespread impact. The present review discusses the current knowledge and research gaps regarding the association between low-grade chronic inflammation and chronic diseases, focusing on obesity, cardiovascular diseases, digestive diseases, and cancer. We examine the state of the art in selected aspects of the topic and propose future directions and approaches for the field.

炎症是机体在受到致病性或破坏性刺激时恢复平衡的一种重要生理反应。然而,有害诱因的持续存在,或这一过程的解决不力,会演变成一种低水平的慢性炎症状态。这种状态与肥胖症、癌症和心血管疾病等几种日益普遍和严重的慢性疾病的发生密切相关,导致全球总体发病率和死亡率上升。目前慢性疾病的流行凸显了解决慢性炎症、其致病机制和潜在预防措施的必要性,以限制其目前的广泛影响。本综述以肥胖、心血管疾病、消化系统疾病和癌症为重点,讨论了有关低度慢性炎症与慢性疾病之间关系的现有知识和研究缺口。我们探讨了该主题某些方面的最新进展,并提出了该领域的未来发展方向和方法。
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引用次数: 0
Is Your Love for Salt Putting Your Health at Risk? 你对盐的爱会危及你的健康吗?
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-12-26 DOI: 10.1152/physiol.00059.2024
Babatunde S Anidu
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引用次数: 0
How is Laughter the Best Medicine? 笑为什么是最好的药?
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-12-26 DOI: 10.1152/physiol.00061.2024
Connor T A Brenna
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引用次数: 0
Not So Fast: Intermittent Fasting Fails to Improve Metabolic Flexibility in Mice With Obesity and Type 2 Diabetes. 不要那么快:间歇性禁食不能改善肥胖和2型糖尿病小鼠的代谢灵活性。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-12-24 DOI: 10.1152/physiol.00060.2024
Meghan O Conn, Daniel M Marko, Jonathan D Schertzer
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引用次数: 0
The Spectrum of Renal "TFEopathies": Flipping the mTOR Switch in Renal Tumorigenesis. TFEopathies "谱系--翻转肾脏肿瘤发生过程中的 mTOR 开关。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-16 DOI: 10.1152/physiol.00026.2024
Nicola Alesi, Kaushal Asrani, Tamara L Lotan, Elizabeth P Henske

The mammalian target of Rapamycin complex 1 (mTORC1) is a serine/threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However, recent studies have indicated that mTORC1 may be active toward its canonical substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6 kinase (S6K), involved in mRNA translation and protein synthesis, and inactive toward TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt-Hogg-Dubé syndrome (BHD) and, recently, tuberous sclerosis complex (TSC). Furthermore, increased TFEB and TFE3 nuclear localization in these syndromes, and in translocation renal cell carcinomas (tRCC), drives mTORC1 activity toward the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity toward 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies." Currently, there are no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.

哺乳动物雷帕霉素靶标复合体 1(mTORC1)是一种丝氨酸苏氨酸激酶,它将营养物质和生长因子信号传导与细胞对新陈代谢的控制结合起来,并在癌症的异常增殖中发挥着重要作用。然而,最近的研究表明,在一些病理情况下,mTORC1 对其典型底物 4EBP1 和 S6K(参与 mRNA 翻译和蛋白质合成)可能具有活性,而对 TFEB 和 TFE3(参与溶酶体生物生成调控的转录因子)则不具有活性。这些病症包括 Birt Hogg Dube(BHD)和最近的结节性硬化综合症(TSC)。此外,在这些综合征以及易位肾细胞癌(tRCC)中,TFEB 和 TFE3 的超活化通过 Rag GTP 酶的转录激活,促使 mTORC1 的活性朝向规范底物,从而将 TFEB 和 TFE3 定位在 mTORC1 活性的上游,朝向 4EBP1 和 S6K。TFEB 和 TFE3 在这些肾脏疾病发病机制中的重要性不断扩大,因此我们将其称为 "TFEopathies",这是一个新的临床分组。目前,还没有直接针对 TFEB 和 TFE3 的治疗方案,这是癌症研究中极具挑战性和亟需的途径。
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引用次数: 0
Extrarenal Benefits of SGLT2 Inhibitors in the Treatment of Cardiomyopathies. SGLT2 抑制剂治疗心肌病的肾外获益。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-06-18 DOI: 10.1152/physiol.00008.2024
Veera Ganesh Yerra, Kim A Connelly

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as pivotal medications for heart failure, demonstrating remarkable cardiovascular benefits extending beyond their glucose-lowering effects. The unexpected cardiovascular advantages have intrigued and prompted the scientific community to delve into the mechanistic underpinnings of these novel actions. Preclinical studies have generated many mechanistic theories, ranging from their renal and extrarenal effects to potential direct actions on cardiac muscle cells, to elucidate the mechanisms linking these drugs to clinical cardiovascular outcomes. Despite the strengths and limitations of each theory, many await validation in human studies. Furthermore, whether SGLT2 inhibitors confer therapeutic benefits in specific subsets of cardiomyopathies akin to their efficacy in other heart failure populations remains unclear. By examining the shared pathological features between heart failure resulting from vascular diseases and other causes of cardiomyopathy, certain specific molecular actions of SGLT2 inhibitors (particularly those targeting cardiomyocytes) would support the concept that these medications will yield therapeutic benefits across a broad range of cardiomyopathies. This article aims to discuss the important mechanisms of SGLT2 inhibitors and their implications in hypertrophic and dilated cardiomyopathies. Furthermore, we offer insights into future research directions for SGLT2 inhibitor studies, which hold the potential to further elucidate the proposed biological mechanisms in greater detail.

钠-葡萄糖共转运体 2(SGLT2)抑制剂已成为治疗心力衰竭的关键药物,其显著的心血管疗效超出了降糖作用的范畴。这些意想不到的心血管优势引起了科学界的兴趣,并促使他们深入研究这些新作用的机理基础。临床前研究提出了许多机理理论,从肾脏和肾脏外效应到对心肌细胞的潜在直接作用,以阐明这些药物与临床心血管结果之间的关联机制。尽管每种理论都有其优势和局限性,但许多理论仍有待人体研究的验证。此外,SGLT2 抑制剂在特定心肌病亚群中的疗效是否与其在其他心衰人群中的疗效相似,目前仍不清楚。通过研究血管性疾病导致的心力衰竭与其他原因导致的心肌病之间的共同病理特征,SGLT2 抑制剂的某些特定分子作用(尤其是那些靶向心肌细胞的作用)将支持这样一种观点,即这些药物将在广泛的心肌病中产生治疗效果。本文旨在讨论 SGLT2 抑制剂的重要机制及其对肥厚型和扩张型心肌病的影响。此外,我们还对 SGLT2 抑制剂研究的未来研究方向提出了见解,这些研究方向有可能进一步更详细地阐明所提出的生物机制。
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引用次数: 0
The Promise of a Pointillist Perspective for Comparative Immunology. 比较免疫学的点彩视角的前景。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-05-29 DOI: 10.1152/physiol.00012.2024
Cynthia J Downs, Marissa E Sobolewski

Most studies in comparative immunology involve investigations into the detailed mechanisms of the immune system of a nonmodel organism. Although this approach has been insightful, it has promoted a deep understanding of only a handful of species, thus inhibiting the recognition of broad taxonomic patterns. Here, we call for investigating the immune defenses of numerous species within a pointillist framework, that is, the meticulous, targeted collection of data from dozens of species and investigation of broad patterns of organismal, ecological, and evolutionary forces shaping those patterns. Without understanding basic immunological patterns across species, we are limited in our ability to extrapolate and/or translate our findings to other organisms, including humans. We illustrate this point by focusing predominantly on the biological scaling literature with some integrations of the pace of life literature, as these perspectives have been the most developed within this framework. We also highlight how the more traditional approach in comparative immunology works synergistically with a pointillist approach, with each approach feeding back into the other. We conclude that the pointillist approach promises to illuminate comprehensive theories about the immune system and enhance predictions in a wide variety of domains, including host-parasite dynamics and disease ecology.

大多数比较免疫学研究都涉及对非模式生物免疫系统详细机制的调查。虽然这种方法很有见地,但它只促进了对少数物种的深入了解,从而阻碍了对广泛的分类模式的认识。在此,我们呼吁在点阵框架内研究众多物种的免疫防御系统,即细致、有针对性地收集数十个物种的数据,并研究影响这些模式的生物、生态和进化力量的广泛模式。如果不了解跨物种的基本免疫学模式,我们就很难将我们的研究结果推断和/或转化到包括人类在内的其他生物体上。为了说明这一点,我们将主要关注生物规模文献,并结合一些生命节奏文献,因为这些观点在这一框架内得到了最充分的发展。我们还强调了比较免疫学中更为传统的方法是如何与点阵方法协同工作的,每种方法都会反作用于另一种方法。我们的结论是,点阵方法有望阐明有关免疫系统的综合理论,并增强对宿主-寄生虫动力学和疾病生态学等多个领域的预测。
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引用次数: 0
Liver Transplantation: A Test of Cellular Physiology, Preservation, and Injury. 肝脏移植:细胞生理、保存和损伤的考验。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-30 DOI: 10.1152/physiol.00020.2024
B Martins, J Mossemann, F Aguilar, S Zhao, P J Bilan, B A Sayed

Liver transplantation has evolved into a mature clinical field, but scarcity of usable organs poses a unique challenge. Expanding the donor pool requires novel approaches for protecting hepatic physiology and cellular homeostasis. Here we define hepatocellular injury during transplantation, with an emphasis on modifiable cell death pathways as future therapeutics.

肝移植已发展成为一个成熟的临床领域,但可用器官的稀缺性带来了独特的挑战。扩大供体库需要采用新的方法来保护肝脏生理和细胞稳态。在这里,我们定义了移植过程中的肝细胞损伤,重点是作为未来疗法的可改变的细胞死亡途径。
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引用次数: 0
Uterus Transplantation: the Translational Evolution of a Clinical Breakthrough. 子宫移植:临床突破的转化演变。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-02 DOI: 10.1152/physiol.00011.2024
Mats Brännström, Eli Y Adashi, Joseph H Wu, Panagiotis Tsiartas, Catherine Racowsky

Women suffering from absolute uterine factor infertility (AUFI), due to either lack of a uterus or one unable to sustain neonatal viability, presented as one of the last frontiers in conquering infertility. Following systematic animal research for over a decade, uterus transplantation was tested as a treatment for AUFI in 2012, which culminated in the first human live birth in 2014. The development of uterus transplantation from mouse to human has followed both the Moore criteria for introduction of a surgical innovation and the IDEAL concept for evaluation of a novel major surgical procedure. In this article we review the important preclinical animal and human studies that paved the way for the successful introduction of human uterus transplantation a decade ago. We discuss this in the context of the Moore criteria and describe the different procedures of preparation, surgeries, postoperative monitoring, and use of assisted reproduction in human uterus transplantation. We review the worldwide activities and associated results in the context of the IDEAL concept for evaluation of surgical innovation and appraise the ethical considerations relevant to uterus transplantation. We conclude that rigorous application of the Moore criteria and strict alignment with the IDEAL concept have resulted in the establishment of uterus transplantation as a novel, safe, and effective infertility therapy that is now being used worldwide for the treatment of women suffering from AUFI.

绝对子宫因素不孕症(AUFI)是由于缺乏子宫或子宫无法维持新生儿存活能力而导致的妇女不孕症,是征服不孕症的最后前沿之一。经过十多年的系统动物研究,2012 年,子宫移植作为一种治疗 AUFI 的方法进行了试验,并于 2014 年实现了首例人类活产。子宫移植从小鼠到人类的发展过程遵循了引进外科创新的摩尔标准和评估新型主要外科手术的 IDEAL 概念。在本文中,我们回顾了为十年前成功引入人类子宫移植铺平道路的重要临床前动物和人体研究。我们根据摩尔标准对此进行了讨论,并介绍了人类子宫移植手术的准备、手术、术后监测和辅助生殖的使用等不同程序。我们以评估手术创新的 IDEAL 概念为背景,回顾了全球范围内的活动和相关成果,并评估了与子宫移植相关的伦理因素。我们的结论是,对摩尔标准的严格应用和对 IDEAL 概念的严格遵守已使子宫移植成为一种新型、安全和有效的不孕不育疗法,目前已在全球范围内用于治疗患有 AUFI 的妇女。
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引用次数: 0
Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease. 线粒体钙对健康和疾病中心脏代谢的调节。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-05-07 DOI: 10.1152/physiol.00014.2024
Enrique Balderas, Sandra H J Lee, Neeraj K Rai, David M Mollinedo, Hannah E Duron, Dipayan Chaudhuri

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca2+) in health and disease. In physiological states, Ca2+ enters via the mitochondrial Ca2+ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca2+ homeostasis is critical: insufficient Ca2+ impairs stress adaptation, and Ca2+ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia. Several themes emerge from recent data. First, mitochondrial Ca2+ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca2+ regulates both the production and response to reactive oxygen species (ROS), and the balance between its pro- and antioxidant effects is key to how it contributes to physiological and pathological states. Third, Ca2+ exerts localized effects on the electron transport chain (ETC), not through traditional allosteric mechanisms but rather indirectly. These effects hinge on specific transporters, such as the uniporter or the Na+/Ca2+ exchanger, and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca2+ transporters are acutely or chronically modified. Perturbations in these novel relationships during disease states may either serve as compensatory mechanisms or exacerbate impairments in oxidative phosphorylation. Consequently, targeting mitochondrial Ca2+ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.

在健康和疾病状态下,氧化磷酸化受线粒体钙(Ca2+)的调节。在生理状态下,Ca2+ 通过线粒体 Ca2+ 单通道进入线粒体,并迅速增强 NADH 和 ATP 的生成。然而,维持 Ca2+ 的平衡至关重要:Ca2+ 不足会影响应激适应,而 Ca2+ 过载则会引发细胞死亡。在这篇综述中,我们将深入探讨进一步明确线粒体 Ca2+ 动态与氧化磷酸化之间关系的最新见解。我们的重点是这种调节如何影响健康和疾病中的心脏功能,包括心力衰竭、缺血再灌注、心律失常、儿茶酚胺能多形性室性心动过速、线粒体心肌病、巴特综合征和弗里德里希共济失调。最近的数据提出了几个主题。首先,线粒体 Ca2+ 调节对燃料底物选择、代谢产物输入和 ATP 供需匹配至关重要。其次,线粒体 Ca2+ 调节活性氧(ROS)的产生和反应,其促氧化作用和抗氧化作用之间的平衡是线粒体 Ca2+ 如何促进生理和病理状态的关键。第三,Ca2+ 对电子传递链(ETC)产生局部效应,但不是通过传统的异构机制,而是间接的。这些影响取决于特定的转运体,如单向转运体或 Na+-Ca2+ 交换体,而且在急性期可能并不明显,表型的形成取决于 Ca2+ 转运体是急性改变还是慢性改变。在疾病状态下,这些新型关系的紊乱可能会成为一种补偿机制,也可能会加剧氧化磷酸化的损伤。因此,以线粒体 Ca2+ 为靶点有望成为以收缩功能衰竭或心律失常为特征的多种心脏疾病的治疗策略。
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引用次数: 0
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