Comprehensive Physiology最新文献

{"title":"Systemic Consequences of Chronic Ethanol Intake: From Microbiome Shifts to Metabolic Impairment.","authors":"Muni Swamy Ganjayi, Thomas A Krauss, Gage E Demster, Sehyung Park, Garrett B Anspach, Sarah R Anthony, Shaohua Wang, Michael Tranter, Robert N Helsley, Cory W Baumann","doi":"10.1002/cph4.70132","DOIUrl":"10.1002/cph4.70132","url":null,"abstract":"<p><p>Chronic ethanol (EtOH) consumption is a major contributor to multi-organ dysfunction, yet its systemic effects remain incompletely understood. To address this, we utilized a physiologically relevant long-term mouse model, administering 20% EtOH in drinking water for 60 weeks, to investigate the integrated consequences of chronic exposure. EtOH-consuming mice (0.4-0.5 mL/day) exhibited > 30% reductions in chow and fluid intake, resulting in a 12% decrease in total caloric intake compared to controls (p < 0.001). Body mass remained similar until Week 52, after which EtOH-treated mice had lower body mass due to reductions in both lean and fat mass (p ≤ 0.004). Functional assessments revealed impaired treadmill endurance (-17%) and grip strength (-11%) (p ≤ 0.037), while motor coordination remained unaffected (p = 0.203). Chronic EtOH exposure significantly altered gut microbiota composition, reducing Lactobacillus and enriching Faecalibaculum, Clostridium, and Bifidobacterium at the genus level. These changes were accompanied by marked depletion of short-chain fatty acids (p ≤ 0.05). Indirect markers of gut permeability (serum LPS & zonulin) and liver injury (serum ALT & AST, hepatic amyloid content) were elevated, alongside increased total cholesterol and > 62% upregulation of hepatic TNFα, IL-6 & serum amyloid A (p ≤ 0.046). EtOH also induced dyslipidemia and glucose intolerance (p ≤ 0.041), although transcriptomic changes in white adipose tissue were minimal despite elevated free fatty acids. In conclusion, chronic EtOH consumption disrupts energy balance, compromises gut barrier integrity, and impairs hepatic metabolism, collectively driving systemic and metabolic dysfunction. These findings underscore the gut-liver axis as a key mediator of EtOH-induced pathology and highlight the gut microbiome as a promising therapeutic target.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70132"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13022470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520308","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":"Brain Amylin Signaling, Feeding, and Reward.","authors":"Elizabeth G Mietlicki-Baase","doi":"10.1002/cph4.70120","DOIUrl":"10.1002/cph4.70120","url":null,"abstract":"<p><p>Obesity is a disease that is both costly and prevalent, and although the development and use of glucagon-like peptide-1 receptor agonists has dramatically altered the landscape of obesity treatment, there remains a need to identify alternate approaches to reduce body weight. Amylin, a pancreatic hormone, has been viewed as a favorable candidate for novel obesity pharmacotherapies due to its ability to suppress feeding and body weight through its actions in the brain. Although research initially focused on hindbrain sites of action for amylin, more recent work has identified other central nuclei at which amylin influences food intake and food reward. This review discusses the growing body of literature suggesting that amylin signaling in mesolimbic structures of the brain influences food intake and reward processing. These effects are observed for palatable food as well as other reinforcing stimuli such as drugs of abuse. This is an important area of research as the broad effects of amylin-based pharmacotherapies should be considered when developing new obesity medications.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70120"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13001112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369439","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":"Stratification of Motor Cortex Excitability to Transcranial Stimulation Uncovers Functional Network Differences in Healthy Older Adults as Revealed by Resting State EEG Functional Coupling in Brain Network.","authors":"Lorenzo Nucci, Federico Frasca, Chiara Pappalettera, Francesca Ginatempo, Nicola Loi, Lucia Ventura, Mohammed Zeroual, Paolo Maria Rossini, Franca Deriu, Fabrizio Vecchio","doi":"10.1002/cph4.70136","DOIUrl":"10.1002/cph4.70136","url":null,"abstract":"<p><strong>Background: </strong>Understanding the neural organization underlying motor function is essential for explaining individual differences in motor performance and the impact of aging.</p><p><strong>Methods: </strong>We examined 87 healthy older adults who underwent, in different sessions, resting state electroencephalography (EEG) recordings and Transcranial Magnetic Stimulation (TMS) applied to the hand muscles representation area in the primary motor cortex to elicit Motor Evoked Potentials (MEPs). Furthermore, Mini-Mental State Examination (MMSE) and handgrip strength evaluations were carried out on subjects. Subjects were split into two groups, Low MEP (L-MEP) and High MEP (H-MEP) groups, based on individual MEP amplitude, and age, sex, and education matched. Functional connectivity was analyzed through Magnitude-Squared Coherence (MSCoh) and Total Coherence (TotCoh) in different frequency bands and brain regions of interest.</p><p><strong>Findings: </strong>The L-MEP presented decreased MSCoh in the Alpha 2 and Beta 1 bands, and decreased TotCoh in the Alpha 2 band within the Temporal region as well as in the Beta 1 band across Parietal, Occipital, and Temporal regions. No significant difference in grip strength was found while the MMSE score of L-MEP group was significantly lower compared to the H-MEP one. These findings indicate that reduced motor cortex excitability reflects decreased network integration, particularly in regions associated with cognitive and sensorimotor processing. These findings may reflect early neurophysiological vulnerability.</p><p><strong>Conclusions: </strong>These results underscore the resting state EEG as a non-invasive, highly sensitive tool monitoring subtle alterations in brain functional networks that may precede clinical symptoms, offering a powerful tool for monitoring and individualized intervention.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70136"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13022471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520314","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 Thoracic Lymphatic Vasculature: Interorgan Strategies to Achieve an Optimal Tissue Function.","authors":"Daniela Negrini, Eleonora Solari, Cristiana Marcozzi, Andrea Moriondo","doi":"10.1002/cph4.70143","DOIUrl":"10.1002/cph4.70143","url":null,"abstract":"<p><p>In thoracic tissues, the lymphatic vasculature not only contributes to fluid and solute homeostasis but also plays a critical role in shaping overall tissue physiology. Although the general morphology of lymphatic vessels and their organization within the vascular circuit are largely conserved inter-organs, thoracic lymphatics exhibit highly specialized structural features, such as the presence of stomata and large lacunae, which are exclusively found in pleural and peritoneal mesothelia. These distinct anatomical specializations characterize thoracic lymphatics, which extensively supply organs such as the lung and the heart, as well as serosal compartments including the pleural space and the suprahepatic subdiaphragmatic peritoneal regions, and are associated with equally specialized mechanisms that sustain lymph formation and propulsion. While lymph flow in all tissues may rely on spontaneous contraction of the lymphatic muscles located within the vessel wall and/or on extrinsic tissue motion, the thoracic lymphatic vasculature displays an exceptional diversity of morphological and functional solutions that allow these mechanisms to be exploited with high efficiency, in close adaptation to local anatomical and mechanical environments. Accordingly, this Review focuses on the inter-organ strategies developed by thoracic lymphatics to match local drainage requirements, highlighting how structural specialization and mechanical integration with surrounding tissues optimize lymphatic function and, ultimately, overall tissue performance.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70143"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13071358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147671243","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":"A Review of Vagus Nerve Stimulation for Disease: Comprehensive Theory and Evidence for Mechanisms of Action.","authors":"Yifeng Bu, Alex Liang, Benjamin U Hoffman, Dawn M Schiehser, Oliver Case, Alan Simmons, Ruth Klaming, Andres Gottfried-Blackmore, Ravinder K Mittal, Christopher Puleo, Hubert Lim, Imanuel Lerman","doi":"10.1002/cph4.70109","DOIUrl":"10.1002/cph4.70109","url":null,"abstract":"<p><p>Vagus nerve stimulation (VNS) is an established neuromodulatory therapy approved for epilepsy, depression, obesity, stroke rehabilitation, rheumatoid arthritis, migraine, and cluster headaches. Its therapeutic potential has expanded dramatically, with growing evidence supporting its efficacy across a wide spectrum of neurological, psychiatric, cardiovascular, immunological, metabolic, and gastrointestinal disorders. Despite this progress, the field has lacked a comprehensive synthesis that unifies mechanistic insights with translational applications across organ systems. This review addresses that gap by systematically integrating current knowledge in the multifactorial mechanisms through which VNS modulates central and peripheral functions, including neuromodulator release, synaptic plasticity, autonomic regulation, neuroimmune control, and endocrine integration. In addition, this review identifies key limitations of VNS, including biological heterogeneity, technical constraints, and methodological variability, and proposes future innovations such as selective fiber targeting, closed-loop systems, and artificial intelligence-guided personalization. By providing a rigorous, system-level overview of VNS mechanisms and their translational relevance, this article serves as a foundational resource for advancing the science and clinical deployment and helping illustrate future directions for precision neuromodulation and bioelectronic medicine.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70109"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12960021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147354141","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 Metabolic Dialogue Between the Gut and Distant Organs: From Microbial Products to Host Responses.","authors":"Lei Chen, Ming Li, Xin Wang, Wei-Ting Hu, Ying Pan, Yun Wang","doi":"10.1002/cph4.70127","DOIUrl":"10.1002/cph4.70127","url":null,"abstract":"<p><p>The gut microbiota, through its extensive metabolic repertoire, plays a pivotal role in regulating systemic physiological processes and contributing to the pathogenesis of extraintestinal diseases. Key microbial metabolites, including short-chain fatty acids (SCFAs), tryptophan derivatives, bile acids, and trimethylamine N-oxide (TMAO), act as molecular mediators that link the gut to distant organs. Despite substantial advances, significant knowledge gaps remain regarding the precise mechanisms by which these metabolites influence organ function and disease progression. This review aims to address these gaps by providing a comprehensive overview of the current understanding of the \"gut-organ axes,\" with a focus on how microbial metabolites influence the brain, lungs, liver, kidneys, and heart through specific receptors and signaling pathways. It also highlights recent advances in bioinformatics and multi-omics integration that facilitate the decoding of these interactions and the identification of therapeutic targets. Furthermore, the translational potential of microbiota-based interventions is discussed, along with key challenges hindering their clinical implementation. By presenting a systems-level perspective on gut-organ metabolic crosstalk, this review proposes a framework for microbiota-targeted strategies to tackle complex diseases, highlighting crucial areas for future research.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70127"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497724","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":"Microbiome Guided Precision Pharmacology in Pregnancy: Organ Crosstalk, Maternal-Fetal Drug Disposition, and PBPK-Informed Dosing.","authors":"Nila Ganamurali, Mohanapriya Devarajan, Sarvesh Sabarathinam","doi":"10.1002/cph4.70138","DOIUrl":"10.1002/cph4.70138","url":null,"abstract":"<p><p>Drug therapy during pregnancy poses unique challenges, requiring a balance between maternal benefit and fetal safety. Profound physiological changes, including altered plasma volume, protein binding, hepatic metabolism, renal clearance, and placental transfer, transform pregnancy pharmacology into a dynamic process. Classical concepts such as initiation, loading, maintenance, tapering, and therapeutic monitoring remain fundamental but demand gestation-specific adaptations. This overview integrates fundamental pharmacological concepts with clinical practices tailored for pregnancy, such as personalized dosing, therapeutic monitoring, and structured tapering. Recent studies further underscore the role of the maternal gut microbiome in shaping drug metabolism, absorption, and overall exposure. Variations in how individuals respond to medication during pregnancy may stem from microbial enzymes and metabolites that interact with the body's pharmacokinetic processes. By merging microbiome data with physiologically based pharmacokinetic modeling and pharmacometric tools, clinicians can enhance drug disposition forecasts and refine precision dosing strategies in obstetric care.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70138"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527215","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":"Mechanosensory Silence During Cardiac Stress.","authors":"Duc Huy Hoang Nguyen","doi":"10.1002/cph4.70122","DOIUrl":"10.1002/cph4.70122","url":null,"abstract":"<p><p>Despite being one of the most densely innervated organs in the thorax, the human heart exhibits a relative insensitivity to chronic visceral pain. Unlike other viscera or enlarging visceral masses of comparable size, progressive mechanical or volumetric stress typically fails to elicit persistent nociception; pain arises predominantly during acute events. Clinical and epidemiological observations show that many individuals with hypertrophied hearts can remain asymptomatic for decades, highlighting a paradox of silent cardiac enlargement. This suggests that cardiac sensory processing is not merely deficient but subject to selective gating. Integrating insights from cardiac mechanobiology, neurophysiology, and myocardial energetics, we propose the Cardiac Mechanoafferent Silencing Model (CMSM) as a conceptual gating framework, consistent with selective attenuation of chronic visceral nociceptive signaling while preserving sensitivity to acute ischemic and inflammatory threats. Furthermore, we outline anatomically and physiologically constrained buffering processes that may limit the emergence of other types of cardiac pain under physiological conditions. CMSM offers a testable conceptual framework to reconcile the dissociation between structural stress and perception, and to prioritize future experimental and translational investigations.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70122"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590719","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":"A Single Bout of Aerobic Exercise Increases Neuronal Extracellular Vesicle-Derived Insulin Signaling Biomarkers in Adults With Cardiometabolic Risk.","authors":"Steven K Malin, Daniel J Battillo, Michal S Beeri, Maja Mustapic, Dimitrios Kapogiannis","doi":"10.1002/cph4.70131","DOIUrl":"10.1002/cph4.70131","url":null,"abstract":"<p><p>Exercise may lower Alzheimer's Disease and Related Dementia (ADRD) risk. While insulin has been proposed to benefit cognition, the effect of exercise on neuronal insulin signaling in humans is unclear.</p><p><strong>Purpose: </strong>We tested the hypothesis that a single bout of aerobic exercise would raise insulin signaling mediators from plasma-derived neuronal extracellular vesicles (nEVs).</p><p><strong>Methods: </strong>Fifteen sedentary adults with obesity (12F; ~56y; ~31 kg/m²) completed an evening rest and acute exercise condition (70% maximal oxygen consumption (VO₂max)) in a randomized, counterbalanced order. Following an overnight fast, plasma was collected for analysis of nEV insulin signaling biomarkers before and after intranasal insulin spray (INI, 40 IU) as well as 60 min following a 75 g oral glucose tolerance test (OGTT). Plasma glucose and insulin were also measured at 30 and 60 min during the OGTT, and total area under the curve (tAUC) was calculated.</p><p><strong>Results: </strong>Exercise tended to lower glucose tAUC_0-150min (p = 0.08, d = 0.50), independent of insulin tAUC_0-150min (p = 0.99, d = 0.00). Exercise increased pIR-Tyr1162/Tyr1163 (p = 0.05, η² = 0.05), pIRS-1-Ser636 (p = 0.02, η² = 0.07), pAkt-Ser473 (p = 0.03, η² = 0.06), and pTSC2-Ser939 (p = 0.01, η² = 0.08) with medium effect sizes across blood draws, compared with the resting condition. Exercise also raised fasting and decreased pp70S6K-Thr412 before and after the OGTT, compared with increased levels after rest during the OGTT (p = 0.02, η² = 0.10). Exercise had no effect on other insulin signaling proteins (e.g., pmTOR-Ser2448, pGSK3β-Ser9, etc.).</p><p><strong>Conclusions: </strong>A single bout of aerobic exercise increases some nEV-associated insulin signaling phosphoproteins in people with cardiometabolic risk. Additional work is warranted to determine if changes in brain insulin signaling translate to lower ADRD risk.</p><p><strong>Clinical trials registration: </strong>NCT05853913.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70131"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13013089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147510457","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 Brain-Gut Axis in Parkinson's Disease Pathology.","authors":"Kudret Selin Ozkaya, Kirsteen N Browning","doi":"10.1002/cph4.70137","DOIUrl":"10.1002/cph4.70137","url":null,"abstract":"<p><p>Parkinson's disease, characterized by the motor deficits that result from the loss of dopaminergic neurons in the Substantia Nigra pars compacta, is the second most common neurodegenerative disorder worldwide. Parkinson's disease is also commonly associated with severe non-motor symptoms, including hyposmia and sleep disorders, as well as gastrointestinal dysfunction and dysregulation of the brain-gut axis. Increasing evidence indicates that pathology in the \"body-first\" subtype of Parkinson's disease may originate in the gastrointestinal (GI) tract and then spread to the brain via the vagus nerve. GI dysfunction may also arise, however, from \"top-down\" or \"brain-first\" mechanisms, reflecting bidirectional brain-gut interactions. Systemic environmental factors, such as exposure to pesticides and heavy metals, are hypothesized to initiate this pathology and promote α-synuclein (α-syn) misfolding and the formation of Lewy Bodies. A growing body of evidence suggests, however, that oxidative stress and glial activation may emerge in the enteric nervous system and the dorsal motor nucleus of the vagus long before the onset of neurodegeneration, and that these early changes may be sufficient to drive the retrograde spread of pathology to higher brain regions. The purpose of this review is to discuss the progression of PD pathology across the brain-gut axis, providing insights into the contribution of oxidative stress and glial activation to neuronal loss, and highlighting the importance of these mechanisms for potential therapeutic intervention at the earliest stages of PD.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70137"},"PeriodicalIF":6.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13033474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572700","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}