Annual review of physiology最新文献

β-Arrestin-1 and -2 (also known as arrestin-2 and -3, respectively) are ubiquitously expressed cytoplasmic proteins that dampen signaling through G protein-coupled receptors. However, β-arrestins can also act as signaling molecules in their own right. To investigate the potential metabolic roles of the two β-arrestins in modulating glucose and energy homeostasis, recent studies analyzed mutant mice that lacked or overexpressed β-arrestin-1 and/or -2 in distinct, metabolically important cell types. Metabolic analysis of these mutant mice clearly demonstrated that both β-arrestins play key roles in regulating the function of most of these cell types, resulting in striking changes in whole-body glucose and/or energy homeostasis. These studies also revealed that β-arrestin-1 and -2, though structurally closely related, clearly differ in their metabolic roles under physiological and pathophysiological conditions. These new findings should guide the development of novel drugs for the treatment of various metabolic disorders, including type 2 diabetes and obesity.

Urinary tract infection (UTI) is the most common type of urogenital disease. UTI affects the urethra, bladder, ureter, and kidney. A total of 13.3% of women, 2.3% of men, and 3.4% of children in the United States will require treatment for UTI. Traditionally, bladder (cystitis) and kidney (pyelonephritis) infections are considered independently. However, both infections induce host defenses that are either shared or coordinated across the urinary tract. Here, we review the chemical and biophysical mechanisms of bacteriostasis, which limit the duration and severity of the illness. Urinary bacteria attempt to overcome each of these defenses, complicating description of the natural history of UTI.

Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous, smoking-related disease of significant global impact. The complex biology of COPD is ultimately driven by a few interrelated processes, including proteolytic tissue remodeling, innate immune inflammation, derangements of the host-pathogen response, aberrant cellular phenotype switching, and cellular senescence, among others. Each of these processes are engendered and perpetuated by cells modulating their environment or each other. Extracellular vesicles (EVs) are powerful effectors that allow cells to perform a diverse array of functions on both adjacent and distant tissues, and their pleiotropic nature is only beginning to be appreciated. As such, EVs are candidates to play major roles in these fundamental mechanisms of disease behind COPD. Furthermore, some such roles for EVs are already established, and EVs are implicated in significant aspects of COPD pathogenesis. Here, we discuss known and potential ways that EVs modulate the environment of their originating cells to contribute to the processes that underlie COPD.

Inflammation-adapted hematopoietic stem and progenitor cells (HSPCs) have long been appreciated as key drivers of emergency myelopoiesis, thereby enabling the bone marrow to meet the elevated demand for myeloid cell generation under various stress conditions, such as systemic infection, inflammation, or myelosuppressive insults. In recent years, HSPC adaptations were associated with potential involvement in the induction of long-lived trained immunity and the emergence of clonal hematopoiesis of indeterminate potential (CHIP). Whereas trained immunity has context-dependent effects, protective in infections and tumors but potentially detrimental in chronic inflammatory diseases, CHIP increases the risk for hematological neoplastic disorders and cardiometabolic pathologies. This review focuses on the inflammatory regulation of HSPCs in the aforementioned processes and discusses how modulation of HSPC function could lead to novel therapeutic interventions.

Cerebral small vessel disease (SVD) is highly prevalent and a common cause of ischemic and hemorrhagic stroke and dementia, yet the pathophysiology is poorly understood. Its clinical expression is highly varied, and prognostic implications are frequently overlooked in clinics; thus, treatment is currently confined to vascular risk factor management. Traditionally, SVD is considered the small vessel equivalent of large artery stroke (occlusion, rupture), but data emerging from human neuroimaging and genetic studies refute this, instead showing microvessel endothelial dysfunction impacting on cell-cell interactions and leading to brain damage. These dysfunctions reflect defects that appear to be inherited and secondary to environmental exposures, including vascular risk factors. Interrogation in preclinical models shows consistent and converging molecular and cellular interactions across the endothelial-glial-neural unit that increasingly explain the human macroscopic observations and identify common patterns of pathology despite different triggers. Importantly, these insights may offer new targets for therapeutic intervention focused on restoring endothelial-glial physiology.

Noncommunicable diseases are chronic diseases that contribute to death worldwide, but these diseases can be prevented and mitigated with regular exercise. Exercise activates signaling molecules and the transcriptional network to promote physiological adaptations, such as fiber type transformation, angiogenesis, and mitochondrial biogenesis. AMP-activated protein kinase (AMPK) is a master regulator that senses the energy state, promotes metabolism for glucose and fatty acid utilization, and mediates beneficial cellular adaptations in many vital tissues and organs. This review focuses on the current, integrative understanding of the role of exercise-induced activation of AMPK in the regulation of system metabolism and promotion of health benefits.

The body depends on its physical barriers and innate and adaptive immune responses to defend against the constant assault of potentially harmful microbes. In turn, successful pathogens have evolved unique mechanisms to adapt to the host environment and manipulate host defenses. Helicobacter pylori (Hp), a human gastric pathogen that is acquired in childhood and persists throughout life, is an example of a bacterium that is very successful at remodeling the host-pathogen interface to promote a long-term persistent infection. Using a combination of secreted virulence factors, immune subversion, and manipulation of cellular mechanisms, Hp can colonize and persist in the hostile environment of the human stomach. Here, we review the most recent and relevant information regarding how this successful pathogen overcomes gastric epithelial host defense responses to facilitate its own survival and establish a chronic infection.

Each heartbeat is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and activates a cycle of calcium influx via voltage-gated calcium channels, calcium release via ryanodine receptors, and calcium reuptake and efflux via calcium-ATPase pumps and sodium-calcium exchangers. Agonists of the sympathetic nervous system bind to adrenergic receptors in cardiomyocytes, which, via cascading signal transduction pathways and protein kinase A (PKA), increase the heart rate (chronotropy), the strength of myocardial contraction (inotropy), and the rate of myocardial relaxation (lusitropy). These effects correlate with increased intracellular concentration of calcium, which is required for the augmentation of cardiomyocyte contraction. Despite extensive investigations, the molecular mechanisms underlying sympathetic nervous system regulation of calcium influx in cardiomyocytes have remained elusive over the last 40 years. Recent studies have uncovered the mechanisms underlying this fundamental biologic process, namely that PKA phosphorylates a calcium channel inhibitor, Rad, thereby releasing inhibition and increasing calcium influx. Here, we describe an updated model for how signals from adrenergic agonists are transduced to stimulate calcium influx and contractility in the heart.

Contrary to earlier beliefs, every cell in the individual is genetically different due to somatic mutations. Consequently, tissues become a mixture of cells with distinct genomes, a phenomenon termed somatic mosaicism. Recent advances in genome sequencing technology have unveiled possible causes of mutations and how they shape the unique mutational landscape of the tissues. Moreover, the analysis of sequencing data in combination with clinical information has revealed the impacts of somatic mosaicism on disease processes. In this review, we discuss somatic mosaicism in various tissues and its clinical implications for human disease.