Physiological reviews最新文献

Disruption of cellular communication that regulates normal physiology is often a key factor in the development of disease, including cancer. Extracellular vesicles (EVs) are mediators of cell-cell communication, modulating local and distant microenvironments and playing an important role influencing tumor progression at both early and late stages. Indeed, EV-mediated communication participates in the initial steps of primary tumor transformation and proliferation as well as the preparation of the premetastatic niche and subsequent metastasis. In this context, the presence of DNA in EVs (EV-DNA) is particularly intriguing, with important biological implications and significant potential as a biomarker in liquid biopsies. In this review we discuss the mechanisms involved in EV-shed DNA and the potential impact in tumor evolution. In addition, it has become apparent in recent years that the secretion of EVs also influences the behavior of the surrounding microenvironment. An important unresolved challenge in oncology is the resistance of tumors to treatment, one of the primary causes of high cancer mortality. The role of EVs in therapy resistance has garnered considerable interest. In the latter part of this review, we also examine the potential involvement of EVs in resistance to therapy.

Nanosized extracellular vesicles (EVs) are released by all cells to convey cell-to-cell communication. EVs, including exosomes and microvesicles, carry an array of bioactive molecules, such as proteins and RNAs, encapsulated by a membrane lipid bilayer. Epithelial cells, endothelial cells, and various immune cells in the lung contribute to the pool of EVs in the lung microenvironment and carry molecules reflecting their cellular origin. EVs can maintain lung health by regulating immune responses, inducing tissue repair, and maintaining lung homeostasis. They can be detected in lung tissues and biofluids such as bronchoalveolar lavage fluid and blood, offering information about disease processes, and can function as disease biomarkers. Here, we discuss the role of EVs in lung homeostasis and pulmonary diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis, and lung injury. The mechanistic involvement of EVs in pathogenesis and their potential as disease biomarkers are discussed. Finally, the pulmonary field benefits from EVs as clinical therapeutics in severe pulmonary inflammatory disease, as EVs from mesenchymal stem cells attenuate severe respiratory inflammation in multiple clinical trials. Further, EVs can be engineered to carry therapeutic molecules for enhanced and broadened therapeutic opportunities, such as the anti-inflammatory molecule CD24. Finally, we discuss the emerging opportunity of using different types of EVs for treating severe respiratory conditions.

During critical illness, systemic inflammation causes organ-specific metabolic changes. In the immune and inflammatory compartments, predominantly anabolic reprogramming supports cellular replication and inflammatory response execution. Pari passu, catabolism of adipose tissue and skeletal muscle supplies carbon skeletons and enthalpy for inflammatory and immune cell anabolism. The liver plays a key role during these metabolic shifts in enabling adequate supply of glucose and ketone bodies to the circulation. Although often perceived as passive surrogates of prehospitalization frailty, body mass constituents are active parties of an overarching metabolic trade-off that is key for survival after acute insults. Muscle and adipose tissue remodel in response to critical illness and thus profoundly influence the systemic metabolic landscape during and after hospitalization. Whether obesity's effect on patient systemic metabolism and survival is paradoxically beneficial or not remains controversial. Substrate-induced epigenetic changes lead to abnormal transcriptional programs that in turn regulate metabolic pathways critical to patient survival. We present a summary of major mechanisms involved in the flux of energy in critical illness from body mass into immune response execution and suggest future research avenues focused on perturbed immune-metabolic and epigenetic programs that could lead to improved understanding of these processes, and eventually to better outcomes for the critically ill.

In 2005, the Arabidopsis thaliana two-pore channel TPC1 channel was identified as a vacuolar Ca²⁺-release channel. In 2009, three independent groups published studies on mammalian TPCs as nicotinic acid adenine dinucleotide phosphate (NAADP)-activated endolysosomal Ca²⁺ release channels, results that were eventually challenged by two other groups, claiming mammalian TPCs to be phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2]-activated Na⁺ channels. By now this dispute seems to have been largely reconciled. Lipophilic small molecule agonists of TPC2, mimicking either the NAADP or the PI(3,5)P₂ mode of channel activation, revealed, together with structural evidence, that TPC2 can change its selectivity for Ca²⁺ versus Na⁺ in a ligand-dependent fashion (N- vs. P-type activation). Furthermore, the NAADP-binding proteins Jupiter microtubule-associated homolog 2 protein (JPT2) and Lsm12 were discovered, corroborating the hypothesis that NAADP activation of TPCs only works in the presence of these auxiliary NAADP-binding proteins. Pathophysiologically, loss or gain of function of TPCs has effects on autophagy, exocytosis, endocytosis, and intracellular trafficking, e.g., LDL cholesterol trafficking leading to fatty liver disease or viral and bacterial toxin trafficking, corroborating the roles of TPCs in infectious diseases such as Ebola or COVID-19. Defects in the trafficking of epidermal growth factor receptor and β1-integrin suggested roles in cancer. In neurodegenerative lysosomal storage disease models, P-type activation of TPC2 was found to have beneficial effects on both in vitro and in vivo hallmarks of Niemann-Pick disease type C1, Batten disease, and mucolipidosis type IV. Here, we cover the latest on the structure, function, physiology, and pathophysiology of these channels with a focus initially on plants followed by mammalian TPCs, and we discuss their potential as drug targets, including currently available pharmacology.