Comprehensive Physiology最新文献

{"title":"Re: MiR-21-5p Protects Embryonic Growth and Heart Function During Developmental Hypoxia by Dampening HIF Responses and Altering Gene Expression.","authors":"Maajid Mohi Ud Din Malik","doi":"10.1002/cph4.70193","DOIUrl":"https://doi.org/10.1002/cph4.70193","url":null,"abstract":"","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70193"},"PeriodicalIF":5.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197778","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":"The Acyltransferase Transmembrane Protein 68 Promotes Neutral Lipid Storage in Mouse Adipocytes.","authors":"Tingting Li, Christoph Heier, Chunyan Zhang, Shiyu Su, Yuhang Liu, Haonan Wang, Feifei Huang, Xingxin Fu, Huimin Pang, Pingan Chang","doi":"10.1002/cph4.70175","DOIUrl":"10.1002/cph4.70175","url":null,"abstract":"<p><p>Transmembrane protein 68 (TMEM68) is a recently identified TAG synthase that is highly expressed in the brain and regulates central nervous lipid homeostasis. The global deficiency of TMEM68 in mice causes reduced adipose tissue mass indicating a role in energy homeostasis. In this study we further explored the role of TMEM68 in adipocyte TAG metabolism and whole-body energy metabolism. We show that TMEM68 deficient mice exhibit a delay in fat mass gain with reduced adipocyte size and TAG levels starting between 3 and 4 weeks of age. This is accompanied by reduced serum leptin levels and impaired glucose tolerance but unchanged cold tolerance. While TMEM68 deficient mice were fully responsive to pharmacological lipolytic stimulation, they failed to maintain plasma fatty acid levels upon fasting. Assessment of in vitro differentiated adipocytes confirmed TMEM68 as a positive regulator of adipocyte TAG storage and revealed an additional function in regulating adipocyte glycerophospholipids and polyunsaturated fatty acids. In summary, our data indicate that TMEM68 functions beyond brain lipid metabolism in regulating adipocyte lipids and whole-body energy homeostasis.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70175"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147962451","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":"Right Ventricular End-Ejection Pressure Predicts Mortality in Patients With Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.","authors":"Elizabeth S Tarras, Adith S Arun, Phillip Joseph, Paul M Heerdt, Inderjit Singh","doi":"10.1002/cph4.70187","DOIUrl":"10.1002/cph4.70187","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is a syndrome in which right ventricular (RV) dysfunction influences prognosis. Conventional hemodynamic indices incompletely capture pulsatile components of RV afterload, which may contribute to inconsistent prognostic associations. We evaluated whether RV pressure (RVP) waveform analysis identifies determinants of prognosis in PH-HFpEF beyond traditional measures.</p><p><strong>Methods: </strong>We conducted a retrospective study of PH-HFpEF patients between 2019 and 2025. RVP waveforms were analyzed to derive the pressure across the cardiac cycle and indices of pulsatile afterload. Associations with all-cause mortality were assessed using LASSO-penalized logistic regression and Cox proportional hazards models. Discrimination was evaluated using cross-validated area under the receiver operating characteristic curve (AUC), time-dependent AUCs, and Kaplan-Meier analysis.</p><p><strong>Results: </strong>80 patients (mean age 67; 65% female) were included (80% with combined post- and pre-capillary pulmonary hypertension). Over median follow-up of 985 days, 14 patients (17.5%) died. RV end-ejection pressure (RVEEP), a late-systolic measure reflecting RV pressure at pulmonic valve closure, was the only variable consistently retained in cross-validated penalized regression analysis and demonstrated good discrimination for mortality (mean cross-validated AUC 0.77). In a non-penalized model, higher RVEEP was strongly associated with mortality (β = 1.39, p = 0.00027; AUC 0.81). In multivariable Cox analysis incorporating RVEEP, right atrial/pulmonary arterial wedge pressure ratio, and NT-proBNP, higher RVEEP remained independently associated with mortality (hazard ratio 1.82, 95% CI 1.11-2.99; p = 0.018).</p><p><strong>Conclusions: </strong>Late-systolic RV pressure dynamics captured by RVEEP are strongly associated with mortality in PH-HFpEF, outperforming traditional hemodynamic indices for risk discrimination.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70187"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053121","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":"The Role of Fecal Microbiome Transplantation in Steroid Hyporesponsive Asthma.","authors":"Narjes Saheb Sharif-Askari, Mariam Wed Eladham, Bushra Mdkhana, Priyadharshini Sekar, Shirin Hafezi, Sarra B Shakartalla, Ibrahim Hachim, Fatemeh Saheb Sharif-Askari, Rabih Halwani","doi":"10.1002/cph4.70196","DOIUrl":"https://doi.org/10.1002/cph4.70196","url":null,"abstract":"<p><p>Asthma is a chronic inflammatory airway disease characterized by airflow obstruction, airway hyperresponsiveness, and structural remodeling. Corticosteroids remain the mainstay of asthma therapy; however, a substantial proportion of patients with severe disease develop steroid hyporesponsiveness, limiting therapeutic efficacy and increasing disease burden. Emerging evidence implicates the gut microbiome as a key regulator of systemic immune responses, with growing relevance to asthma pathogenesis and treatment responsiveness. In this study, we investigated whether gut microbiota dysbiosis contributes to steroid hyporesponsive lung inflammation and whether fecal microbiota transplantation (FMT) can restore steroid responsiveness. Using a steroid-hyporesponsive asthma model, we demonstrate that the disease is associated with significant gut microbial dysregulation, characterized by reduced microbial diversity and depletion of immunoregulatory taxa. FMT partially restored gut microbial diversity, normalized community structure, and selectively replenished beneficial commensal bacteria, including Akkermansia muciniphila and Faecalibacterium prausnitzii, while suppressing pathogenic taxa. Importantly, restoration of gut microbial balance was associated with attenuation of lung inflammation and improved steroid responsiveness. These findings support a functional gut-lung axis in steroid hyporesponsive asthma and identify modulation of gut microbiota as a potential therapeutic strategy. Incorporating microbiota-directed interventions such as FMT may represent a novel adjunct approach for the management of refractory steroid-hyporesponsive asthma.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70196"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276352","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":"Reduced Cardiorespiratory Fitness and Its Physiological Determinants in Patients With Cirrhosis: Evidence of Cirrhosis-Induced Myopathy.","authors":"Couret Alexis, Rannou Fabrice, Pereira Bruno, Marcantei Camille, Le Calvez François, Julian Valérie, Duclos Martine, Costes Frédéric, Muti Léon, Buchard Benjamin, Arbogast Sarah, King James A, Weil-Verhoeven Delphine, Abergel Armand, Ennequin Gaël","doi":"10.1002/cph4.70195","DOIUrl":"10.1002/cph4.70195","url":null,"abstract":"<p><strong>Background: </strong>Cirrhosis induces multi-organ dysfunction, yet the specific physiological determinants underlying reduced cardiorespiratory fitness (CRF) remain poorly defined.</p><p><strong>Aim: </strong>To compare patients with cirrhosis to healthy controls to assess and identify their major CRF physiological contributors.</p><p><strong>Methods: </strong>Forty-five patients with cirrhosis and 45 age- and sex-matched controls underwent incremental cardiopulmonary exercise testing (CPET) on a cycle ergometer. The pulmonary, cardiac, vascular, and muscular components of CRF were measured, including peak oxygen uptake (VO_2Peak), ventilatory efficiency (VE/VCO₂), oxygen uptake efficiency slope (OUES), and chronotropic response. Non-invasive hemodynamic monitoring (Physioflow) was used to estimate cardiac output and arteriovenous oxygen difference (a-vO₂).</p><p><strong>Results: </strong>Patients with cirrhosis exhibited markedly reduced CRF compared with controls (VO_2Peak: 15.4 ± 5.5 vs. 29.3 ± 7.5 mL.min^-1.kg^-1, p < 0.001) and the decline was proportional to Child-Pugh score. Kinetic parameters (OUES, Lowest VE/VCO₂, Wilkoff index) were also significantly impaired and chronotropic incompetence was highly prevalent (89%). Cardiac output was preserved but a-vO₂ was lower (10.7 ± 3.0 vs. 14.1 ± 1.1 mlO₂.dL^-1, p = 0.002), indicating a defective peripheral oxygen extraction in patients with cirrhosis. Multivariate regression analysis (r² = 0.79) identified maximal heart rate and muscle performance (5-sit to stand) as independent predictors of VO_2Peak.</p><p><strong>Conclusion: </strong>Reduced CRF in cirrhosis appears to primarily result from impaired skeletal muscle oxygen utilization, compounded by chronotropic incompetence. These findings emphasize the value of integrative functional evaluation in cirrhosis management.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70195"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307404","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":"Pancreatic Islet Cell Crosstalk: Insight Into α-/β-Cell Compensatory Mechanisms.","authors":"Štěpánka Benáková, Blanka Holendová, Jurij Dolenšek, Monika Křivonosková, Andraž Stožer, Lydie Plecitá-Hlavatá","doi":"10.1002/cph4.70158","DOIUrl":"10.1002/cph4.70158","url":null,"abstract":"<p><p>To investigate the compensatory role of α-cell-derived paracrine signaling through glucagon and GLP-1 receptors in maintaining β-cell function when insulin secretion is compromised. A β-cell-specific Nox4 knockout mouse (Nox4^βKO) displays defective glucose-stimulated insulin secretion and develops a prediabetic phenotype. To uncover the adaptive changes, we ran a detailed analysis of Nox4^βKO pancreatic islets. We analyzed their composition, hormone secretion dynamics, receptor expression profiles, and downstream signaling pathways by immunocytochemistry, flow cytometry, RNA sequencing, cAMP assays, and insulin or glucagon secretion assays using both isolated islets and pancreatic slices across different glucose levels and receptor-modulating conditions. Prediabetic Nox4^βKO islets showed increased α-cell numbers, expansion of bihormonal cells, and elevated production of glucagon and GLP-1. Receptor profiling revealed a shift in receptor engagement: whereas GLP-1R dominated in wild-type islets, GCGR signaling gained prominence in Nox4^βKO islets. This functional rebalancing is consistent with an adaptive response to emerging β-cell dysfunction. Functional assays demonstrated that insulin secretion in prediabetic islets became increasingly reliant on glucagon-driven potentiation of GLP-1R and cAMP-dependent pathways. Transcriptomic and signaling data confirmed enhanced expression of cAMP-related intermediates and calcium-handling components, indicating partial preservation of insulin secretory capacity despite underlying defects. α-cell remodeling and flexible engagement of glucagon and GLP-1 receptors act as key compensatory mechanisms that may help to sustain insulin secretion during early β-cell stress. The context-dependent plasticity of intra-islet receptor activation highlights a coordinated multicellular adaptation in prediabetes and suggests that targeting intra-islet endocrine crosstalk may help preserve β-cell function in prediabetes.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70158"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811833","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":"Nanomaterial-Based Strategies to Modulate Placental Dysfunction in Preeclampsia.","authors":"Yizi Wang, Sishi Liu, Ying Shen, Xue Zhang, Shizhuo Wang, Jing Sun, Xiaolin Tan, Wei Zhang, Guannan Yu","doi":"10.1002/cph4.70199","DOIUrl":"https://doi.org/10.1002/cph4.70199","url":null,"abstract":"<p><p>Preeclampsia is a pregnancy-specific disorder characterized by hypertension and multi-organ dysfunction, originating primarily from placental abnormalities rather than maternal pathology alone. Impaired trophoblast invasion, defective spiral artery remodeling, angiogenic imbalance, oxidative stress, and sterile inflammation collectively drive placental dysfunction and subsequent systemic endothelial injury. Current clinical management remains largely supportive, highlighting the urgent need for mechanism-based therapeutic strategies that directly target the placenta while minimizing fetal risk. Nanomaterial-based approaches offer unique advantages in this context, enabling selective placental delivery, controlled drug release, and precise modulation of pathogenic pathways. Recent advances have demonstrated the potential of placenta-targeted nanomedicine to attenuate oxidative stress, suppress inflammatory signaling, restore angiogenic balance, and regulate gene expression within the placental microenvironment. This review summarizes key pathological features of placental dysfunction in preeclampsia, discusses design principles for pregnancy-safe nanomaterials, and evaluates emerging therapeutic strategies and preclinical models. Finally, we address translational challenges and outline future directions toward precision nanomedicine for preeclampsia.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70199"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293687","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":"Immune-Endometrial Crosstalk in Heavy Menstrual Bleeding: Interorgan Dynamics and Systemic Implications of Monocyte Dysregulation.","authors":"Emmanuel Ifeanyi Obeagu","doi":"10.1002/cph4.70200","DOIUrl":"https://doi.org/10.1002/cph4.70200","url":null,"abstract":"<p><p>Heavy menstrual bleeding (HMB) is a common gynecological disorder increasingly recognized as a complex systemic condition involving dysregulated interactions between the immune system and the endometrium. Beyond traditional uterine-centered explanations, growing evidence highlights the importance of immune-endometrial crosstalk in regulating menstruation, vascular integrity, inflammation, tissue breakdown, and endometrial repair. This narrative review examines the role of monocyte and macrophage dysregulation in the pathophysiology of HMB and explores the broader interorgan dynamics contributing to disease progression. Monocytes and macrophages are central regulators of endometrial remodeling, angiogenesis, extracellular matrix turnover, and hemostasis throughout the menstrual cycle. Dysregulated recruitment, polarization, and activation of these immune cells contribute to excessive inflammatory signaling, impaired vascular stability, delayed tissue repair, and abnormal menstrual blood loss. Key inflammatory mediators implicated include tumor necrosis factor-alpha, interleukin-6, CCL2, vascular endothelial growth factor, prostaglandins, matrix metalloproteinases, and NF-κB-associated pathways. The review further highlights systemic interactions involving the bone marrow, liver, vascular endothelium, endocrine system, and gut-immune axis, emphasizing HMB as a multisystem inflammatory disorder. Emerging evidence suggests that inflammatory biomarkers, immune profiling, and molecular characterization may improve disease stratification and support precision medicine approaches. Understanding HMB through the framework of immune-endometrial crosstalk provides new opportunities for biomarker development, targeted immunomodulatory therapies, and individualized patient management aimed at improving reproductive and overall health outcomes.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70200"},"PeriodicalIF":5.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249639","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 Dialogues in the Mitochondria-Microbiome Crosstalk: Metabolites, Signaling, and Immunity.","authors":"Rumiana Koynova-Tenchov","doi":"10.1002/cph4.70164","DOIUrl":"10.1002/cph4.70164","url":null,"abstract":"<p><p>The bidirectional dialogue between mitochondria and the human microbiota-the mitochondria-microbiome axis-plays a pivotal role in regulating host metabolism, immune signaling, and overall physiological homeostasis. Growing evidence underscores the role of microbial metabolites-including short-chain fatty acids, secondary bile acids, and lipopolysaccharides-as direct modulators of mitochondrial bioenergetics, redox balance, and inflammatory cascades. Conversely, mitochondrial integrity governs the microbial landscape by regulating local oxygen tension, modulating immune-mediated selection, and secreting metabolic byproducts that shape commensal populations. Disruptions to this bidirectional crosstalk are linked to a diverse pathological spectrum. These include metabolic syndromes like obesity, type 2 diabetes, and NAFLD; neurodegenerative disorders such as Parkinson's and Alzheimer's; and systemic inflammatory conditions, notably inflammatory bowel disease and various autoimmune pathologies. Therapeutic interventions designed to modulate this axis-ranging from targeted probiotics, dietary interventions, and mitochondrial boosters-offer significant potential for reinstating physiological homeostasis. This review explores the molecular foundations of mitochondria-microbiome crosstalk, its role in disease pathogenesis, and the potential for microbiome-targeted therapies to restore mitochondrial health. Unraveling this complex dialogue may open new avenues for treating diseases rooted in metabolic and microbial dysbiosis. On the basis of a wide-ranging literature survey, the frontiers of the molecular dialogues involved in the mitochondria-microbiome communications are evaluated. By analyzing publication trends, we identify nascent perspectives and transformative concepts, mapping the mitochondria-microbiome axis research, aiming to bridge the gap between basic science and translational applications. This synthesis offers a fresh lens for treating diseases rooted in this intricate biological interplay.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70164"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927093","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":"Osteopontin in Kidney-Heart-Lung Crosstalk: A Metabolic and Inflammatory Mediator of Remote Organ Injury.","authors":"Sarvesh Sabarathinam","doi":"10.1002/cph4.70183","DOIUrl":"10.1002/cph4.70183","url":null,"abstract":"<p><p>Cardiorenal syndrome (CRS) has traditionally been explained through hemodynamic and neurohormonal mechanisms; however, emerging evidence highlights a critical role for immune-metabolic signaling. Osteopontin (OPN), a damage-associated molecular pattern released from injured renal tubular cells, functions as a circulating alarmin that drives inter-organ communication. Renal-derived OPN promotes cardiac fibrosis, metabolic reprogramming, and diastolic dysfunction by suppressing fatty acid oxidation and enhancing glycolysis. Simultaneously, it contributes to pulmonary endothelial injury and inflammation, establishing a kidney-heart-lung axis of dysfunction. The kidney-heart-lung axis refers to the interconnected inflammatory and metabolic communication between injured renal tissue and distant cardiac and pulmonary organs. Elevated circulating OPN correlates with adverse clinical outcomes, underscoring its potential as both a biomarker and therapeutic target in cardiorenal disease progression.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70183"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013949","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}