Physiological reviews最新文献

{"title":"Transitional Cell States at the Crossroad of Development, Disease, and Repair-Regeneration.","authors":"Xiangyi Ke,Wellington V Cardoso","doi":"10.1152/physrev.00041.2025","DOIUrl":"https://doi.org/10.1152/physrev.00041.2025","url":null,"abstract":"Cells undergoing transitional states have been broadly referred to as plastic intermediates emerging between stable identities in multiple biological contexts. Once regarded as indistinct midpoints on lineage trajectories, these states are now recognized as discrete, biologically meaningful epigenetically permissive states, exquisitely responsive to environmental and stress signals at critical junctures of biological events that confer competence to proceed along their trajectories. These high-plasticity nodes have emerged as central regulators of developmental progression and determinants of disease outcomes, serving as functional bottlenecks in which resolution or persistence dictates normal or maladaptive pathological responses. Recent single-cell and multiomiocs technologies enabled their detection with unprecedented resolution, revealing conserved regulatory themes, including stress-response activation and striking context-dependence shaped by niche cues and tissue architecture. Yet challenges remain in capturing their rapid heterogeneous dynamic in the multiple contexts, and defining their function, in vivo. Here we summarize current concepts on the identification, diversity, role and regulation of these cell states in events from early development to adult homeostasis, repair and diseases. The increasing recognition that transitional states can be productive conduits or pathological traps underscores their relevance in these processes and potential for the identification of therapeutic targets for intervention in disease, cancer and regenerative medicine.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"136 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147726319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endocrine Disruptions in Thermal Injuries: Exploring Immune System Interactions","authors":"Fadi Khalaf, Stephanie Wojtowicz-Piotrowski, Zachary Ricciuti, Ghazaleh Dadashizadeh, Dalia Barayan, Marc G. Jeschke","doi":"10.1152/physrev.00035.2025","DOIUrl":"https://doi.org/10.1152/physrev.00035.2025","url":null,"abstract":"Physiological Reviews, Ahead of Print. <br/>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"283 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147666431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholangiocyte Biology in Primary Sclerosing Cholangitis and Other Cholangiopathies: Pathogenesis, Clinical Insights, and Experimental Tools","authors":"Nidhi Jalan-Sakrikar, Abid A. Anwar, Ahmad Ali, Navine Nasser-Ghodsi, Antonia Felzen, Robert C. Huebert, Nicholas F. LaRusso, Steven P. O'Hara","doi":"10.1152/physrev.00022.2025","DOIUrl":"https://doi.org/10.1152/physrev.00022.2025","url":null,"abstract":"Physiological Reviews, Ahead of Print. <br/>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"10 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147666432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Cell with Many Faces: Lung Macrophage Plasticity and Function in Response to Environmental and Pathogenic Insults.","authors":"Shubham Dubey,Junaid Khan,A S Alishlash,Sadis Matalon","doi":"10.1152/physrev.00038.2025","DOIUrl":"https://doi.org/10.1152/physrev.00038.2025","url":null,"abstract":"Alveolar macrophages (AM) are pivotal immune sentinels, essential for maintaining tissue homeostasis and mediating immune responses to inhaled particles and pathogens. They demonstrate remarkable plasticity by transitioning from pro-inflammatory (M1) and anti-inflammatory/reparative (M2) phenotypes in response to local signals. Upon exposure to environmental agents, such as particulate matter, atypical respiratory pathogens opportunistic gram-negative bacteria, or respiratory viruses they undergo dynamic activation that profoundly influences their functional repertoire. Acute or chronic environmental/biological insults disrupt normal AM activities such as phagocytosis, efferocytosis, cytokine production, inciting oxidative stress, inflammasome activation, and in some cases, forms of programmed cell death such as pyroptosis. Although these responses are indispensable for eliminating noxious particles and pathogens, such as Mycoplasma pneumoniae or Klebsiella pneumoniae, Influenza A, or SARS-CoV-2, they can also derail the resolution phase by perpetuating inflammation, driving tissue remodeling and fibrosis, and thereby fueling chronic lung disorders such as chronic obstructive pulmonary disease (COPD), pneumoconiosis, and post-COVID interstitial lung disease. Moreover, environmental and microbial exposures modify AM by altering receptor repertoires, intracellular phenotype by signaling cascades, and crosstalk with epithelial and mesenchymal cells that collectively determine the disease trajectory. Elucidating how diverse environmental agents, together with pathogens such as Mycoplasma pneumoniae, Klebsiella pneumoniae, Influenza A, and SARS-CoV-2, shape AM biology is therefore pivotal for understanding the pathogenesis of COPD, pneumoconiosis, and progressive fibrotic lung disease, and COVID-19 related pulmonary sequelae. This review brings together the current insights into exposure-driven modulation of AM functions, highlighting recent advances and identifying knowledge gaps relevant for therapeutic targeting of exposure-induced and pathogen-mediated lung pathology.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"9 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The nonexcitable smooth muscle: Remodeling the smooth muscle ion transport toolkit in disease.","authors":"Martin T Johnson,Mohamed Trebak","doi":"10.1152/physrev.00031.2025","DOIUrl":"https://doi.org/10.1152/physrev.00031.2025","url":null,"abstract":"Smooth muscle is vital to hollow organs such as vessels, airways, bladder, prostate, uterus, and gastrointestinal tract. Its ability to contract and relax is essential for organ function. In vessels, vascular smooth muscle cells-or arterial myocytes-help regulate blood pressure and ensure proper blood flow to tissues. However, during disease such as atherosclerosis, hypertension, and restenosis, these myocytes undergo a major transformation. They shift from a quiescent, contractile state to an active, synthetic one. In this synthetic state, they behave like inflammatory cells: secreting cytokines and signaling molecules, remodeling the surrounding matrix, and becoming migratory and proliferative. This shift is tied to a remodeling of their ion transport repertoire. Here, we build and refine a cohesive model whereby synthetic myocytes adopt a phenotype resembling non-excitable cells. We propose that their ion transport toolkit changes as a coordinated unit, creating a distinct calcium signaling signature that supports their new roles in growth, movement, inflammation and secretion-while sacrificing their contractile features. Focusing mainly on arterial myocytes, we examine how disease-driven changes in ion transport reshape the calcium signaling landscape. This shift moves away from classical excitation-contraction-mediated by L-type calcium channels and ryanodine receptors-and toward channels such as store-operated STIM/Orai and transient receptor potential (TRP) channels, which are activated by growth and vasoactive factors and operate best at hyperpolarized membrane potentials. We also explore the remodeling of ion channels, transporters and pumps within internal organelles and emphasize how understanding these changes could reveal new therapeutic targets for treating disease.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"16 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147524781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody-drug conjugate design and mechanisms of action for cancer treatment: state of the art and beyond.","authors":"Anthony Cheung,Yi Liu,Alicia M Chenoweth,Hanieh Montaseri,Benjamina Esapa,Vijay Chudasama,James R Baker,David E Thurston,Sophia N Karagiannis","doi":"10.1152/physrev.00039.2025","DOIUrl":"https://doi.org/10.1152/physrev.00039.2025","url":null,"abstract":"Antibody-drug conjugates (ADCs) are a leading area of targeted cancer therapeutics, typically combining a tumour-associated antigen-specific antibody conjugated to a toxic payload that targets key cellular mechanisms, such as mitosis and survival. The global ADC clinical trial landscape has been expanding significantly, with over 430 ADCs reaching early to late clinical studies in the past two decades, up from just 90 between 2004 and 2014. The US Food and Drug Administration (FDA) has so far approved 14 ADCs for use in clinical oncology. This growth is likely driven by significant advances in antibody technology and conjugation methods enabling more effective and precise delivery to cancer cells and more effective payloads that target vital cancer biology. Here, we review the ADCs that have reached clinical approval as well as current and emerging trends in ADC development, and we discuss these from multiple perspectives, including ADC mechanisms of action, emerging antigen targets, linker and conjugation chemistry, payloads, combination of ADC with checkpoint inhibitor immunotherapy and antibody Fc-engineering. We also consider how the field is evolving through the application of artificial intelligence (AI) and pathology-based biomarker discovery. Combined, innovative and emerging ADC design coupled with precision medicine and patient stratification strategies hold great promise to develop diverse and personalised cancer treatments with improved therapeutic indices, and to enhance tolerability compared to traditional chemotherapy and current established ADCs. This review aims to assist researchers in exploring the evolution, characteristics, and development trends in ADC design and to provide new directions for future research.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"9 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal ensembles in cortical function and disease.","authors":"Rafael Yuste","doi":"10.1152/physrev.00003.2025","DOIUrl":"https://doi.org/10.1152/physrev.00003.2025","url":null,"abstract":"Neuronal ensembles, defined as groups of coactive neurons, are physiological modules of the cerebral cortex. Calcium imaging and optogenetics have enabled mapping and manipulating ensembles with single cell resolution in mouse visual cortex, providing evidence of their importance. Ensembles dominate cortical activity, are generated endogenously or by sensory stimulation. Ensembles are imprinted by activating neurons synchronously and can be reactivated by \"pattern completion\" trigger cells. Intrinsic excitability mediates ensemble coactivation and reactivation, while UP states shield ongoing ensembles from external inputs. Neurons can belong to different ensembles, forming a combinatorial system that encodes visual stimuli accurately and stably. Ensembles contain pyramidal neurons and interneurons and inhibited \"offsemble\" cells. Cross-inhibition makes ensembles orthogonal from one another, while astrocytic activation increases ensemble occurrence. Ensembles can last for weeks, providing a substrate for long-term information storage, and they capture the recent history of stimulus presentation, implementing short-term memory. Optogenetic manipulation of ensembles demonstrates that they are necessary and sufficient for visual discrimination and perceptual states. Ensembles are altered in mouse models of epilepsy, schizophrenia, Alzheimer's disease, autism spectrum disorders and medically-induced loss of consciousness. An ensemble model of the cortex is proposed in which ensembles are functional units that activate each other via trigger cells and silence non-desired ensembles by cross-inhibition. This generates a map of orthogonal attractor states, forming a computationally powerful memory and processing system. Ensembles are likely involved in many brain diseases, so manipulating them could offer avenues for new therapeutics.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"70 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fueling the Fire: Metabolic Dysfunction and Senescence as Drivers of Lung Aging and Disease.","authors":"Corrine R Kliment,Aditi U Gurkar,Nayra Cárdenes,Richard Ramonell,Toren Finkel,Melanie Königshoff","doi":"10.1152/physrev.00024.2025","DOIUrl":"https://doi.org/10.1152/physrev.00024.2025","url":null,"abstract":"With a rapidly expanding human population at advanced ages and age as the main driver for chronic diseases, we face the challenge of understanding tissue aging and devising new therapeutic interventions. Cellular senescence is an important hallmark of all aging tissues and has emerged as a potential key driver of chronic lung diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and asthma. This comprehensive review recapitulates current knowledge of pathways and processes involved in cellular senescence with emphasis on the role of mitochondrial dysfunction and the \"4 Ms\" (morphology, mitophagy, metabolism, and metabolites). We review our current knowledge of healthy lung aging, discuss which pathomechanisms in chronic lung disease are characterized by senescence, and summarize current target therapeutics and their impact on lung disease. Within this exponentially growing field, we propose emerging concepts and current gaps in knowledge which need to be addressed to develop better opportunities for therapeutic strategies and future investigations.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"3 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epithelial plasma membrane transporters as drug targets","authors":"Alan S. Verkman","doi":"10.1152/physrev.00045.2025","DOIUrl":"https://doi.org/10.1152/physrev.00045.2025","url":null,"abstract":"Physiological Reviews, Ahead of Print. <br/>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"93 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147351030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Systems, Human Non-Coding Sequence Variants, and Blood Pressure.","authors":"Qiongzi Qiu,Mingyu Liang","doi":"10.1152/physrev.00029.2025","DOIUrl":"https://doi.org/10.1152/physrev.00029.2025","url":null,"abstract":"The human genome harbors millions of non-coding sequence variants. Genome-wide association studies (GWAS) have identified thousands of robust associations linking non-coding variants to human physiological traits and complex diseases. Integrative approaches, including expression quantitative trait locus mapping, epigenomic profiling, and precise genome editing in trait-relevant cell types, enable the identification of effector genes and underlying regulatory mechanisms, such as long-range chromatin interactions, that mediate the effects of non-coding variants. Investigations of blood pressure (BP)-associated non-coding sequence variants have uncovered previously unrecognized roles of genes in BP regulation, reinforced the human genetic relevance of established BP regulatory pathways, and elucidated specific regulatory mechanisms by which non-coding variants influence gene expression and BP. Studies of orthologous non-coding genomic regions in animal models corresponding to human genomic regions harboring BP-associated variants have demonstrated substantial effects on BP, suggesting that the phenotypic impact of non-coding sequence variants may be large within human subgroups. Continued expansion of functional studies of trait-associated non-coding sequence variants, together with advances in mapping molecular quantitative trait loci and epigenomic landscapes, will provide novel insights directly relevant to human biology and disease and essential for understanding humans as molecular systems.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"82 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}