Comprehensive Physiology最新文献

{"title":"The Exosome-Lactate-Lactylation Axis: A Metabolic-Epigenetic Circuit Driving Tumor Immune Evasion.","authors":"Yuan Chen, Yuan Yuan, Zhen Zhang, Yihai Shi","doi":"10.1002/cph4.70114","DOIUrl":"10.1002/cph4.70114","url":null,"abstract":"<p><p>Lactylation, as a post-translational modification, plays a role in tumor proliferation, metabolism, and the remodeling of the tumor microenvironment (TME). Emerging studies have revealed that exosomes regulate lactate metabolism by delivering functional molecules (such as lncRNAs, metabolic enzymes, etc.) thereby driving protein lactylation and establishing a novel intercellular communication mechanism. Furthermore, acidic microenvironments induce the release of immunosuppressive exosomes, amplifying immune evasion. Here, we summarize the current understanding of lactylation and exosome regulation in the TME and their impact on immune evasion. We explore the pivotal role of the \"exosome-lactate-lactylation\" axis in tumor metabolic reprogramming, metastasis, and immunosuppression, proposing targeted strategies against this axis.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70114"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Look Who Is Talking: Extracellular Vesicles as Mediators of Intercellular and Interorgan Communication.","authors":"Michela Saviana, Giulia Romano, Daniel Del Valle-Morales, Mario Acunzo, Patrick Nana-Sinkam","doi":"10.1002/cph4.70128","DOIUrl":"10.1002/cph4.70128","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are produced by every organ, serving as vehicles for communication. By circulating throughout the body and targeting both neighboring and distant cells and organs, they can drive downstream signaling. EVs play a role as effectors of cell-to-cell communication in the tissue microenvironment and have demonstrated their importance in driving downstream biological processes, maintenance of homeostasis and response to stimuli. New methodologies supporting the study of EV-mediated long-distance communication have revealed a whole new unexplored function in maintaining homeostasis of the organism and serving as indicators of pathological conditions. In this review, we provide the most recent update on the role of EVs as mediators of intercellular and interorgan communication.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70128"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13055575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Glucagonocentric Basis of Diabetic Cardiomyopathy: Pancreas-Heart Crosstalk Linking α-Cell Dysregulation to Cardiac Metabolic Stress and Fibrosis.","authors":"Nila Ganamurali, Madhupriya Prabhakaran, Sarvesh Sabarathinam","doi":"10.1002/cph4.70145","DOIUrl":"10.1002/cph4.70145","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is increasingly recognized as a disorder of inappropriate glucagon secretion in addition to β-cell dysfunction and insulin resistance. Chronic hyperglucagonemia, driven by α-cell dysregulation, contributes directly to the development of diabetic cardiomyopathy (DCM) through hepatic, systemic, and myocardial mechanisms. Emerging evidence shows that glucagon receptor (GCGR) signaling is active in cardiomyocytes, endothelial cells, and vascular smooth muscle, where persistent activation promotes cAMP/PKA-mediated stress, calcium dysregulation, oxidative injury, and adverse remodeling. Hyperglucagonemia further exacerbates metabolic toxicity by enhancing fatty acid flux, lipotoxic intermediate accumulation, and amino-acid driven proteolysis. These changes converge on myocardial fibrosis, diastolic dysfunction, and cardiac steatosis characteristic of DCM. Therapeutic interventions that modulate glucagon biology including glucagon receptor antagonists (GRAs), GLP-1 receptor agonists, and multi-agonist incretin therapies demonstrate cardioprotective potential by restoring glucagon-insulin balance and attenuating glucagon-driven metabolic stress. This mini-review highlights mechanistic links and therapeutic implications.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70145"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanisms of Lipid-Modifying Enzymes in Cellular Adaptation and Systemic Glucose Homeostasis.","authors":"Nila Ganamurali, Sarvesh Sabarathinam, Navodi Sandamini Jayathilaka, Evelyn Sharon Sukumaran","doi":"10.1002/cph4.70125","DOIUrl":"10.1002/cph4.70125","url":null,"abstract":"<p><p>Lipid-modifying enzymes dynamically regulate membrane architecture, signaling compartmentalization, and inter-organ metabolic communication, thereby influencing systemic glucose homeostasis. Advances in lipidomics and structural enzymology reveal how enzymatic remodeling of phospholipids, sphingolipids, and acyl chains governs insulin receptor organization, PI3K-AKT signaling, and GLUT4 trafficking. Dysregulated lipid flux mediated by factors such as FABP4, ceramides, and diacylglycerols disrupts membrane microdomains, impairs β-cell function, and promotes hepatic gluconeogenesis and skeletal muscle insulin resistance. Conversely, omega-3 polyunsaturated fatty acids enhance membrane fluidity and anti-inflammatory signaling. Integrating lipid enzymology with metabolic physiology establishes a unified mechanistic framework linking membrane remodeling to insulin responsiveness and diabetes pathogenesis.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70125"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucagon-Like Peptide-1 Receptor Agonism and Muscle Health: Vascular and Myocellular Effects on Glucose and Protein Metabolism.","authors":"Christos S Katsanos, Zhenqi Liu, Philip J Atherton","doi":"10.1002/cph4.70126","DOIUrl":"10.1002/cph4.70126","url":null,"abstract":"<p><p>Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) improve glycaemia and reduce body weight, yet their organ-level actions on skeletal muscle remain incompletely defined. Framing skeletal muscle as an integrated unit of vasculature and muscle cells, we synthesize evidence with emphasis on glucose and protein metabolism. GLP-1 and GLP-1 RAs recruit microvasculature in muscle, expanding capillary surface area and increasing delivery of insulin, glucose, and amino acids. Microvascular recruitment increases interstitial insulin availability and potentiates insulin-stimulated glucose uptake and glycogen synthesis, whereas direct effects of GLP-1 on muscle cells remain under investigation. For protein metabolism, microvascular recruitment can enhance muscle protein synthesis when plasma amino acid availability is elevated, whereas effects under basal (fasted) conditions remain unclear. Elucidating the uncertainty regarding GLP-1 receptor localization in human muscle cells will clarify whether direct signaling occurs within muscle cells, thereby improving our understanding of the relative contribution of direct versus perfusion-mediated actions of GLP-1 RAs. Clinically, GLP-1 RAs reduce lean body mass, likely reflecting energy-deficit-mediated effects, but studies directly assessing muscle mass are still limited. Overall, current evidence indicates that GLP-1 RAs exert beneficial effects on muscle vasculature and muscle glucose metabolism. However, their influence on muscle protein turnover remains unclear-primarily due to observed reductions in muscle mass-despite preclinical data suggesting potential favorable effects on muscle protein metabolism that remain to be confirmed in humans.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70126"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DJ-1 (PARK7) as a Redox-Responsive Integrator of Pancreatic, Hepatic, and Adipose Crosstalk in Glucose Homeostasis.","authors":"Jayasingha Mudiyanselage Pavithra Sewwandi Jayasingha, Mallika Arachchige Hasantha Madushan, Navodi Sandamini Jayathilaka, Sarvesh Sabarathinam","doi":"10.1002/cph4.70123","DOIUrl":"10.1002/cph4.70123","url":null,"abstract":"<p><p>DJ-1 (PARK7), originally characterized in Parkinson's disease, is increasingly recognized as a redox-sensitive regulator of systemic metabolism. Acting through oxidation-dependent modulation of Cys106, DJ-1 integrates cellular redox cues with mitochondrial function, insulin signaling, and stress adaptation pathways. In pancreatic β-cells, it preserves stimulus secretion coupling by stabilizing mitochondrial ATP production. In liver and adipose tissue, DJ-1 maintains insulin responsive signaling and metabolic flexibility through PTEN-PI3K-Akt and antioxidant networks. Loss or over-oxidation of DJ-1 disrupts interorgan glucose coordination, linking chronic redox imbalance to dysglycemia. This review positions DJ-1 as a metabolic sentinel translating oxidative inputs into integrated glucose regulatory outputs.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70123"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"ATGL From iWAT and BAT Is Crucial for Cardiac Remodeling and Metabolism After Myocardial Ischemia/Reperfusion\".","authors":"","doi":"10.1002/cph4.70157","DOIUrl":"10.1002/cph4.70157","url":null,"abstract":"","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70157"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13484217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactobacillus acidophilus Postbiotics Differentially Modulate Nutrient Sensing, Intestinal Barrier Integrity, and Inflammatory Signaling in Broiler.","authors":"Meng Yu, Zhiyun Qin, Atique Ahmed Behan, Shabbir Ahmed, Muhammad Asif Arain, Nazrin Malikli, Jameel Ahmed Budar, Hesham Hassanien","doi":"10.1002/cph4.70139","DOIUrl":"10.1002/cph4.70139","url":null,"abstract":"<p><p>The global restriction of antibiotic growth promoters (AGPs) has accelerated the search for sustainable nutritional alternatives that support growth performance and intestinal health of poultry. Postbiotics and their bioactive metabolites derived from probiotic microorganisms have emerged as promising candidates due to their functional stability and immunometabolic regulatory potential. This study evaluated the effects of Lactobacillus acidophilus-derived postbiotics on growth performance, nutrient sensing, intestinal barrier integrity, immune response, antioxidant status, and gut microbiota in broiler chickens. For this purpose, a total of 400 day-old broilers were randomly assigned to four dietary treatments with graded postbiotic supplementation (0.0%, 0.5%, 1.0%, and 2.0%) for 42 days. Growth performance, immune and antioxidant indices, intestinal and hepatic histomorphology, gene expression, and cecal microbial composition were assessed. Broilers receiving 1.0% and 2.0% postbiotics exhibited significantly higher average daily gain and feed intake compared with controls (p < 0.05). Postbiotic supplementation enhanced systemic immunity, reflected by increased serum IgA, IgG, and IgM levels and elevated spleen and bursa indices. Improved intestinal morphology was evidenced by increased duodenal villus height and villus height-to-crypt depth ratio, while hepatic tissues showed reduced inflammation and fibrosis. Molecular analyzes revealed upregulation of nutrient transporters (SGLT1, PepT1), tight junction protein ZO-1, and antioxidant enzyme GPX1, alongside downregulation of pro-inflammatory cytokines (IL-1β and IL-6). Additionally, postbiotics increased the abundance of beneficial cecal taxa, including coliforms, Lactobacillus, and total plate count. Collectively, L. acidophilus-derived postbiotics improve broiler performance by coordinating nutrient transporter regulation, antioxidant signaling, and inflammatory control, supporting their application as a sustainable AGPs alternative.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70139"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhaled 5-HT_1B _/1D Receptor Antagonist Attenuates Sumatriptan-Induced Sensitization of Capsaicin-Sensitive Lung Vagal Afferents: Implications for Preventing Sumatriptan-Associated Adverse Chest Symptoms.","authors":"Nai-Ju Chan, Zung Fan Yuan, Chang-Chih Kuo, Chun-Chun Hsu","doi":"10.1002/cph4.70121","DOIUrl":"10.1002/cph4.70121","url":null,"abstract":"<p><strong>Background: </strong>Sumatriptan, an antimigraine drug, is known to cause adverse chest symptoms such as dyspnea and chest tightness. We previously showed that sumatriptan sensitized capsaicin-sensitive lung vagal (CSLV) afferents in rats, a mechanism potentially underlying these symptoms. This sensitizing effect was abolished by intravenous GR127935, a 5-HT_1B/1D receptor antagonist. Therefore, to develop a potential therapeutic strategy, we hypothesized that targeting GR127935 to the lungs, rather than delivering it systemically, could prevent sumatriptan-induced chest discomfort by reducing CSLV-afferent sensitization without compromising sumatriptan's antimigraine efficacy within the trigeminovascular system.</p><p><strong>Methods: </strong>Experiments were performed in anesthetized male Brown-Norway rats. CSLV-afferent excitability and afferent-mediated airway reflexes were assessed using single-fiber recordings and respiratory pattern monitoring. The antimigraine efficacy of sumatriptan was evaluated based on its inhibitory effect on dural plasma protein extravasation evoked by unilateral electrical stimulation of the trigeminal ganglion.</p><p><strong>Results: </strong>Intravenous sumatriptan potentiated capsaicin-evoked CSLV-afferent discharges and afferent-mediated airway responses. However, pretreatment with inhaled GR127935 significantly blocked this potentiating effect. The sumatriptan's antimigraine efficacy was not affected by inhaled GR127935, but was reduced by intravenous GR127935. Consistently, intravenous, but not inhaled GR127935, altered sumatriptan-induced hypotension, indicating that pulmonary delivery minimized systemic effects. Moreover, inhaled GR127935 did not change baseline cardiorespiratory parameters or fiber activity, suggesting it is unlikely to cause adverse cardiorespiratory effects.</p><p><strong>Conclusions: </strong>Inhalation of a 5-HT_1B/1D receptor antagonist effectively prevented sumatriptan-induced sensitization of CSLV afferents without diminishing sumatriptan's antimigraine efficacy. Our findings suggest that inhaled 5-HT_1B/1D antagonists may offer a promising strategy to prevent or treat sumatriptan-induced adverse chest symptoms.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70121"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12980051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"The Impact of High-Intensity Exercise in Normobaric Hypoxia on Right Ventricular Function in Trained and Untrained Men-An Echocardiographic Study\".","authors":"","doi":"10.1002/cph4.70124","DOIUrl":"10.1002/cph4.70124","url":null,"abstract":"","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70124"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13484243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}