Physiology最新文献

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.

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.

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.

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.

Brown adipose tissue (BAT) thermogenesis results from the uncoupling of mitochondrial inner membrane proton gradient mediated by the uncoupling protein 1 (UCP-1), which is activated by lipolysis-derived fatty acids. Norepinephrine (NE) secreted by sympathetic innervation not only activates BAT lipolysis and UCP-1, but uniquely in brown adipocytes, promotes "futile" metabolic cycles and enhances BAT thermogenic capacity by increasing UCP-1 content, mitochondrial biogenesis and brown adipocyte hyperplasia. NE exerts these actions by triggering signaling in the canonical G protein coupled b adrenergic receptors, cAMP and protein kinase A (PKA) pathway which, in brown adipocyte, is under a complex and intricated crosstalk with important growth-promoting signaling pathways such as those of mechanistic target of rapamycin (mTOR) complexes 1 (mTORC1) and 2 (mTORC2). This article reviews evidence suggesting that mTOR complexes are modulated by and participate in the thermogenic, metabolic, and growth-promoting effects elicited by NE in BAT and discusses current gaps and future directions in this field of research.

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from key lysine residues on histone and non-histone proteins and thereby regulate gene transcription. They have been implicated in several biological processes in both healthy and pathologic settings. This review discusses the role of HDACs in multiple metabolically active tissues and highlights their contribution to the pathogenesis of tissue-specific maladaptation and diseases. We also summarize the current knowledge gaps and potential ways to address them in future studies.

Quiescence is operationally defined as a reversible proliferation arrest. This cellular state is central for both organism development and homeostasis, its dysregulation causing many pathologies. The quiescent state encompasses very diverse cellular situations depending on the cell type and its environment. Further, quiescent cell properties evolve with time, a process that is thought to be at the origin of aging in multicellular organisms. Microtubules are found in all eukaryotes, and are essential for cell proliferation as they support chromosome segregation and intracellular trafficking. Upon proliferation cessation and quiescence establishment, the microtubule cytoskeleton was shown to undergo significant remodeling. The purpose of this review is to examine the literature in search of evidence to determine whether the observed microtubule reorganizations are merely a consequence of quiescence establishment or if they somehow participate in this cell fate decision.

Multiple insect lineages have successfully reinvaded the aquatic environment, evolving to complete either part or all of their life cycle submerged in water. While these insects vary in their reliance on atmospheric oxygen, with many having the ability to extract dissolved oxygen directly from the water, all retain an internal air-filled respiratory system, their tracheal system, due to their terrestrial origins. However, carrying air within their tracheal system, and even augmenting this volume with additional air bubbles carried on their body, dramatically increases their buoyancy which can make it challenging to remain submerged. But by manipulating this air volume a few aquatic insects can deliberately alter or regulate their position in the water column. Unlike cephalopods and teleost fish that control the volume of gas within their hydrostatic organs by either using osmosis to pull liquid from a rigid chamber or secreting oxygen at high pressure to inflate a flexible chamber, insects have evolved hydrostatic control mechanisms that rely either on the temporary stabilization of a compressible air-bubble volume using O₂ unloaded from hemoglobin, or the mechanical expansion and contraction of a gas-filled volume with rigid, gas-permeable walls. The ability to increase their buoyancy while submerged separates aquatic insects from the buoyancy compensation achieved by other air-breathing aquatic animals which also use air within their respiratory systems to offset their submerged weight. The mechanisms they have evolved to achieve this are unique and provide new insights into the function and evolution of mechanochemical systems.

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.

High levels of oxidant stress in the form of reactive oxidant species are prevalent in the circulation and tissues in various types of cardiovascular disease including heart failure, hypertension, peripheral arterial disease, and stroke. Here we review the role of nuclear factor erythroid 2-related factor 2 (Nrf2), an important and widespread antioxidant and anti-inflammatory transcription factor that may contribute to the pathogenesis and maintenance of cardiovascular diseases. We review studies showing that downregulation of Nrf2 exacerbates heart failure, hypertension, and autonomic function. Finally, we discuss the potential for using Nrf2 modulation as a therapeutic strategy for cardiovascular diseases and autonomic dysfunction.