Physiological reviews最新文献

Depending on cell type, environmental inputs, and disease, the cells in the human body can have widely different sizes. In recent years, it has become clear that cell size is a major regulator of cell function. However, we are only beginning to understand how the optimization of cell function determines a given cell's optimal size. Here, we review currently known size control strategies of eukaryotic cells and the intricate link of cell size to intracellular biomolecular scaling, organelle homeostasis, and cell cycle progression. We detail the cell size-dependent regulation of early development and the impact of cell size on cell differentiation. Given the importance of cell size for normal cellular physiology, cell size control must account for changing environmental conditions. We describe how cells sense environmental stimuli, such as nutrient availability, and accordingly adapt their size by regulating cell growth and cell cycle progression. Moreover, we discuss the correlation of pathological states with misregulation of cell size and how for a long time this was considered a downstream consequence of cellular dysfunction. We review newer studies that reveal a reversed causality, with misregulated cell size leading to pathophysiological phenotypes such as senescence and aging. In summary, we highlight the important roles of cell size in cellular function and dysfunction, which could have major implications for both diagnostics and treatment in the clinic.

Representing severe morbidity and mortality globally, respiratory infections associated with chronic respiratory diseases, including complicated pneumonia, asthma, interstitial lung disease, and chronic obstructive pulmonary disease, are a major public health concern. Lung health and the prevention of pulmonary disease rely on the mechanisms of airway surface fluid secretion, mucociliary clearance, and adequate immune response to eradicate inhaled pathogens and particulate matter from the environment. The antimicrobial proteins and peptides contribute to maintaining an antimicrobial milieu in human lungs to eliminate pathogens and prevent them from causing pulmonary diseases. The predominant antimicrobial molecules of the lung environment include human α- and β-defensins and cathelicidins, among numerous other host defense molecules with antimicrobial and antibiofilm activity such as PLUNC (palate, lung, and nasal epithelium clone) family proteins, elafin, collectins, lactoferrin, lysozymes, mucins, secretory leukocyte proteinase inhibitor, surfactant proteins SP-A and SP-D, and RNases. It has been demonstrated that changes in antimicrobial molecule expression levels are associated with regulating inflammation, potentiating exacerbations, pathological changes, and modifications in chronic lung disease severity. Antimicrobial molecules also display roles in both anticancer and tumorigenic effects. Lung antimicrobial proteins and peptides are promising alternative therapeutics for treating and preventing multidrug-resistant bacterial infections and anticancer therapies.

Coenzyme Q (CoQ), also known as ubiquinone, comprises a benzoquinone head group and a long isoprenoid side chain. It is thus extremely hydrophobic and resides in membranes. It is best known for its complex function as an electron transporter in the mitochondrial electron transport chain (ETC) but is also required for several other crucial cellular processes. In fact, CoQ appears to be central to the entire redox balance of the cell. Remarkably, its structure and therefore its properties have not changed from bacteria to vertebrates. In metazoans, it is synthesized in all cells and is found in most, and maybe all, biological membranes. CoQ is also known as a nutritional supplement, mostly because of its involvement with antioxidant defenses. However, whether there is any health benefit from oral consumption of CoQ is not well established. Here we review the function of CoQ as a redox-active molecule in the ETC and other enzymatic systems, its role as a prooxidant in reactive oxygen species generation, and its separate involvement in antioxidant mechanisms. We also review CoQ biosynthesis, which is particularly complex because of its extreme hydrophobicity, as well as the biological consequences of primary and secondary CoQ deficiency, including in human patients. Primary CoQ deficiency is a rare inborn condition due to mutation in CoQ biosynthetic genes. Secondary CoQ deficiency is much more common, as it accompanies a variety of pathological conditions, including mitochondrial disorders as well as aging. In this context, we discuss the importance, but also the great difficulty, of alleviating CoQ deficiency by CoQ supplementation.

Whereas studying the aortic valve in isolation has facilitated the development of life-saving procedures and technologies, the dynamic interplay of the aortic valve and its surrounding structures is vital to preserving their function across the wide range of conditions encountered in an active lifestyle. Our view is that these structures should be viewed as an integrated functional unit, here referred to as the aortic valve apparatus (AVA). The coupling of the aortic valve and root, left ventricular outflow tract, and blood circulation is crucial for AVA's functions: unidirectional flow out of the left ventricle, coronary perfusion, reservoir function, and support of left ventricular function. In this review, we explore the multiscale biological and physical phenomena that underlie the simultaneous fulfillment of these functions. A brief overview of the tools used to investigate the AVA, such as medical imaging modalities, experimental methods, and computational modeling, specifically fluid-structure interaction (FSI) simulations, is included. Some pathologies affecting the AVA are explored, and insights are provided on treatments and interventions that aim to maintain quality of life. The concepts explained in this article support the idea of AVA being an integrated functional unit and help identify unanswered research questions. Incorporating phenomena through the molecular, micro, meso, and whole tissue scales is crucial for understanding the sophisticated normal functions and diseases of the AVA.

Glucagon's ability to promote hepatic glucose production has been known for over a century, with initial observations touting this hormone as a diabetogenic agent. However, glucagon receptor agonism [when balanced with an incretin, including glucagon-like peptide 1 (GLP-1) to dampen glucose excursions] is now being developed as a promising therapeutic target in the treatment of metabolic diseases, like metabolic dysfunction-associated steatotic disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH), and may also have benefit for obesity and chronic kidney disease. Conventionally regarded as the opposing tag-team partner of the anabolic mediator insulin, glucagon is gradually emerging as more than just a "catabolic hormone." Glucagon action on glucose homeostasis within the liver has been well characterized. However, growing evidence, in part thanks to new and sensitive "omics" technologies, has implicated glucagon as more than just a "glucose liberator." Elucidation of glucagon's capacity to increase fatty acid oxidation while attenuating endogenous lipid synthesis speaks to the dichotomous nature of the hormone. Furthermore, glucagon action is not limited to just glucose homeostasis and lipid metabolism, as traditionally reported. Glucagon plays key regulatory roles in hepatic amino acid and ketone body metabolism, as well as mitochondrial turnover and function, indicating broader glucagon signaling consequences for metabolic homeostasis mediated by the liver. Here we examine the broadening role of glucagon signaling within the hepatocyte and question the current dogma, to appreciate glucagon as more than just that "catabolic hormone."

Mass spectrometry-based proteomics is a sophisticated identification tool specializing in portraying protein dynamics at a molecular level. Proteomics provides biologists with a snapshot of context-dependent protein and proteoform expression, structural conformations, dynamic turnover, and protein-protein interactions. Cardiac proteomics can offer a broader and deeper understanding of the molecular mechanisms that underscore cardiovascular disease, and it is foundational to the development of future therapeutic interventions. This review encapsulates the evolution, current technologies, and future perspectives of proteomic-based mass spectrometry as it applies to the study of the heart. Key technological advancements have allowed researchers to study proteomes at a single-cell level and employ robot-assisted automation systems for enhanced sample preparation techniques, and the increase in fidelity of the mass spectrometers has allowed for the unambiguous identification of numerous dynamic posttranslational modifications. Animal models of cardiovascular disease, ranging from early animal experiments to current sophisticated models of heart failure with preserved ejection fraction, have provided the tools to study a challenging organ in the laboratory. Further technological development will pave the way for the implementation of proteomics even closer within the clinical setting, allowing not only scientists but also patients to benefit from an understanding of protein interplay as it relates to cardiac disease physiology.

The endomembrane system consists of organellar membranes in the biosynthetic pathway [endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles] as well as those in the degradative pathway (early endosomes, macropinosomes, phagosomes, autophagosomes, late endosomes, and lysosomes). These endomembrane organelles/vesicles work together to synthesize, modify, package, transport, and degrade proteins, carbohydrates, and lipids, regulating the balance between cellular anabolism and catabolism. Large ion concentration gradients exist across endomembranes: Ca²⁺ gradients for most endomembrane organelles and H⁺ gradients for the acidic compartments. Ion (Na⁺, K⁺, H⁺, Ca²⁺, and Cl^-) channels on the organellar membranes control ion flux in response to cellular cues, allowing rapid informational exchange between the cytosol and organelle lumen. Recent advances in organelle proteomics, organellar electrophysiology, and luminal and juxtaorganellar ion imaging have led to molecular identification and functional characterization of about two dozen endomembrane ion channels. For example, whereas IP3R1-3 channels mediate Ca²⁺ release from the ER in response to neurotransmitter and hormone stimulation, TRPML1-3 and TMEM175 channels mediate lysosomal Ca²⁺ and H⁺ release, respectively, in response to nutritional and trafficking cues. This review aims to summarize the current understanding of these endomembrane channels, with a focus on their subcellular localizations, ion permeation properties, gating mechanisms, cell biological functions, and disease relevance.

The complexity of cardiac electrophysiology, involving dynamic changes in numerous components across multiple spatial (from ion channel to organ) and temporal (from milliseconds to days) scales, makes an intuitive or empirical analysis of cardiac arrhythmogenesis challenging. Multiscale mechanistic computational models of cardiac electrophysiology provide precise control over individual parameters, and their reproducibility enables a thorough assessment of arrhythmia mechanisms. This review provides a comprehensive analysis of models of cardiac electrophysiology and arrhythmias, from the single cell to the organ level, and how they can be leveraged to better understand rhythm disorders in cardiac disease and to improve heart patient care. Key issues related to model development based on experimental data are discussed, and major families of human cardiomyocyte models and their applications are highlighted. An overview of organ-level computational modeling of cardiac electrophysiology and its clinical applications in personalized arrhythmia risk assessment and patient-specific therapy of atrial and ventricular arrhythmias is provided. The advancements presented here highlight how patient-specific computational models of the heart reconstructed from patient data have achieved success in predicting risk of sudden cardiac death and guiding optimal treatments of heart rhythm disorders. Finally, an outlook toward potential future advances, including the combination of mechanistic modeling and machine learning/artificial intelligence, is provided. As the field of cardiology is embarking on a journey toward precision medicine, personalized modeling of the heart is expected to become a key technology to guide pharmaceutical therapy, deployment of devices, and surgical interventions.