Annual review of physiology最新文献

Cell division is essential for organismal growth and development and is associated with changes in signaling dynamics, including Ca2+ signaling, to meet structural, functional, and energetic needs. The process of cell division must ensure equal separation of both the genetic material and cellular organelles. Organelle segregation to the daughter cells is in most cases associated with their remodeling to support equal distribution. Here, we review the concurrent remodeling of organelles and Ca2+ signaling during cell division. Interesting patterns emerge, showing that organelle dynamics, specifically the plasma membrane, endoplasmic reticulum, and mitochondria, underlie Ca2+ signaling remodeling during cell division.

In 2019, a novel membrane protein, PAC (also known as TMEM206), was identified as the long-sought molecular carrier of an acid- or proton-activated chloride current observed ubiquitously in mammalian cells. This discovery has led to rapid progress in revealing its trimetric architecture and biophysical properties, including the pH-sensing mechanism, anion selectivity, and lipid regulation. In addition to the cell surface, the PAC channel predominantly localizes to intracellular organelles (endosomes, phagosomes, and macropinosomes), where it mediates pH-dependent chloride flux to regulate luminal pH and organelle volume. Here, we review these exciting findings and discuss the many aspects of the PAC channel that remain largely unexplored, including its pharmacology, physiological function, and potential role in disease.

Cardiorenal syndrome (CRS) represents a complex interplay of pathophysiological processes that create a self-perpetuating cycle of heart and kidney dysfunction. While it is clearly understood how hemodynamic changes connect pathogenesis in the two organs, other processes are also in play. Some are the structural changes involving both the cellular and extracellular compartments that precede functional alterations. Fibrosis, which is initiated by an inflammatory response triggering myofibroblast activation and excessive extracellular matrix production, is a common denominator of heart and kidney pathology in CRS. This review focuses on fibroblast activities as a crucial factor in disease onset and progression in CRS. We explore how fibrosis in one organ can trigger or worsen dysfunction in the other organ, and we describe the key pathological signaling pathways of cardiorenal fibrosis, the extracellular matrix-derived biomarkers that can aid clinical management and drug development, and the therapeutic opportunities that can be beneficial in CRS by targeting fibroblast activities.

Major adverse cardiovascular events resulting from atherosclerotic plaque instability account for a plurality of deaths worldwide despite the use of highly effective lipid lowering therapies. Over the last three decades, the role of inflammation in atherogenesis has been tested extensively. Although preclinical studies demonstrate a clear role for inflammation in atherogenesis, clinical studies using global anti-inflammatory therapies have not been as successful as hoped, encouraging the search for new therapeutic strategies. Thanks to the advent of cell-specific lineage tracing, we have begun to appreciate the multifaceted role of smooth muscle cell phenotypic switching in modulating plaque stability. Here, we review the mechanisms controlling smooth muscle cell phenotypic switching during early and late-stage pathogenesis, which may inspire future therapies to stabilize plaques.

The discovery of leptin as an adipocyte-secreted hormone encoded by the ob gene whose absence produces severe obesity that is corrected by leptin repletion in both mice and humans was a transformative event in metabolic science. Leptin's discovery in 1994 accelerated the identification of central neuronal circuitry responsive to peripheral signals that regulate energy balance as well as metabolic, neuroendocrine, and other vital functions. Leptin's primary physiological role was initially viewed as preventing obesity by its levels rising, but subsequent research has emphasized the key role of falling levels to signal starvation. Resistance to leptin action, though partial, characterizes common forms of obesity. Despite much being learned about leptin signal transduction over 30 years, the precise molecular mechanisms for leptin resistance and common obesity remain unclear. Leptin therapy is effective in rare patients with congenital leptin deficiency and other low leptin conditions but not common obesity. Interestingly, reducing hyperleptinemia may prove useful in treating common obesity.

Plasticity of myeloid cells, characterized by their ability to undergo reprogramming in response to environmental cues, is a fundamental feature enabling their versatile functions during immune responses. Macrophages and neutrophils, the primary myeloid cell types, exhibit distinct polarization states. Classical polarization states of macrophages and neutrophils are associated with antimicrobial activity, inflammation promotion, and tissue remodeling. Pathological polarization, observed in chronic inflammation, cancer, and other conditions, is marked by enhanced immune-suppressive activity, aberrant enzymatic activity, and atypical cytokine production, diverging from their classical functions. This review delves into the most up-to-date characterization of those polarization states, the transcriptional and epigenetic factors, and the metabolic pathways governing myeloid cell reprogramming, highlighting the influence of cytokines and tissue-specific conditions, such as hypoxia in tumors, on this process. Understanding the mechanisms underlying the pathological polarization of myeloid cells offers a promising avenue to modulate their activity for targeted therapeutic interventions.

Approximately two-thirds of cases of chronic obstructive pulmonary disease (COPD) and adult asthma are in part driven by impaired lung development related to early-life events. Many children who suffer insults to their lungs during the first few years of life experience abnormal lung development, growth, and/or maturation, leading to impaired lung function, which may persist throughout their lifespan. This abnormal lung trajectory may be exacerbated by lung dysanapsis, genetic and epigenetic alterations, oxidative stress and/or inflammation in the airways related to environmental factors including exposure to active or secondhand smoke, air pollution, poor nutrition and social deprivation, and repeated childhood respiratory tract infections. Children with asthma may transition to COPD in adulthood if their asthma is poorly controlled or in the presence of other risk factors such as smoking. As many of these factors are modifiable, prompt diagnosis and implementation of preventive measures should be considered as early as possible in children at risk for abnormal lung development. This review provides an update on the interplay between genetic, environmental, and socioeconomic factors, their cumulative impact on lung development, and its implication for the risk and burden of asthma and COPD in the global population.

The gut microbiota is a salient contributor to the development of type 2 diabetes mellitus (T2D) as a vast and complex metabolic cross talk that exists between the bacteria residing in the gastrointestinal tract and the host. This cross talk is largely influenced by external factors including diet, highlighting a potential avenue to effectively manipulate the gut microbiota to treat metabolic diseases such as diabetes. In this review, we discuss the influence of the gut microbiota on T2D development and targeting gut microbiota in both current and novel treatments for T2D, highlighting potential alternative therapies including fecal microbiota transplant, prebiotics, probiotics, synbiotics, or xenobiotics. A better understanding of both the impact of the gut microbiota in the etiology of diabetes and the therapeutic potential for manipulating the gut microbiota in metabolic disease could usher in a new approach to targeted treatment options to ameliorate T2D.

Sex differences in blood pressure are evident from puberty through menopause, with premenopausal females exhibiting lower blood pressure than males. This review discusses key factors contributing to sex differences in blood pressure, focusing on the normotensive state. Key contributions from a number of systems are discussed, including cardiovascular and renal function, oxidative stress, immune cell involvement, the microbiome, and the roles of the nervous system and renin-angiotensin-aldosterone system. Additionally, we highlight novel advances in the field, including findings related to the G protein-coupled estrogen receptor (GPER), Klotho, olfactory receptor 558 (OLFR558), and the four-core genotype (FCG) model. Insights from clinical data and their implications for hypertension management are also considered. In sum, this review aims to integrate current knowledge on sex differences in blood pressure regulation to inform future research and clinical care.

The importance of biological sex on disease etiology and outcomes has long been underinvestigated. While recent focus on characterizing sex differences in cardiac pathophysiology has led to improved inclusion of both sexes in scientific studies and clinical trials, much is still unknown about underlying differences in normal cardiac physiology. This is particularly true for the atria, where the most common arrhythmia, atrial fibrillation (AF), occurs. AF is associated with adverse structural, electrophysiological, and calcium handling remodeling that leads to patient morbidity and mortality. Differences in the onset, prevalence, presentation, and prognosis of AF are known to differ between males and females, yet the sex-specific baseline phenotypes from which AF arises are not well characterized. This review examines what is currently known about sex differences in atrial physiology, the alterations that occur in AF, potential mechanisms underlying sex divergence, and the need for sex-targeted therapeutic strategies.