American journal of physiology. Cell physiology最新文献

{"title":"Effects of calcineurin inhibition on renal tubular transport.","authors":"Wouter H van Megen, Johannes Loffing","doi":"10.1152/ajpcell.00254.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00254.2026","url":null,"abstract":"<p><p>Calcineurin inhibitors (CNIs), including tacrolimus and cyclosporin A, are potent immunosuppressive drugs that exert their effects by inhibiting protein phosphatase 3, also known as calcineurin. CNIs are widely used clinically, particularly for preventing organ rejection following transplantation. However, their use is frequently associated with significant adverse effects. In particular, CNIs commonly affect the kidney and can lead to acute and chronic kidney injury. In addition, they interfere with renal electrolyte reabsorption resulting in electrolyte disturbances (e.g., hyperkalemia, hypomagnesemia) and hypertension. Notably, calcineurin subunits are abundantly expressed throughout the nephron. Consequently, calcineurin inhibition affects electrolyte transport in virtually all nephron segments. In this review, we summarize the current knowledge on the effects of CNIs on renal tubular ion transport processes and highlight the underlying mechanism by which these effects contribute to CNI-induced electrolyte disturbances.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-intensity interval training via electrical stimulation enhances endurance by preserving sarcoplasmic reticulum Ca²⁺ transients in mouse skeletal muscle.","authors":"Luke D Flewwelling, Masih Jafari, Shahrzad Khajehzadehshoushtar, Takashi Yamada, Christopher G R Perry, Arthur J Cheng","doi":"10.1152/ajpcell.00795.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00795.2025","url":null,"abstract":"<p><p>This study investigated the effects of high/low-intensity interval training (HIIT/LIIT) via electrical stimulation (ES) on muscle performance, specifically focusing on fatigue resistance and cytoplasmic free calcium ([Ca²⁺]_i) dynamics in mouse skeletal muscle. Thirty 9-week-old female C57BL6 mice underwent four weeks of involuntary IT-ES in hindlimb plantar flexor muscles <i>in vivo</i>, with stimulation frequencies set at either 20 Hz (LIIT) or 100 Hz (HIIT). Our results showed that IT-ES significantly enhanced fatigue resistance, particularly with HIIT, evidenced by improved muscle torque output and better preservation of tetanic [Ca²⁺]_i levels during repeated contractions. Additionally, IT-ES led to increases in sarcoplasmic reticulum (SR) Ca²⁺ handling proteins, such as SR Ca²⁺ ATPase 1 (SERCA1) and the ryanodine receptor 1 (RyR1), as well as mitochondrial respiratory complex proteins, indicating enhanced metabolic adaptations. The results suggest that HIIT-ES is an effective intervention for improving muscle function, intracellular Ca²⁺ management, and mitochondrial content, providing a foundation for future consideration in rehabilitation and clinical settings.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Glabridin on Ion Transport Across Primary Human Bronchial Epithelial Cells.","authors":"Aaron Kolski-Andreaco, John Sembrat, Michael B Butterworth, Daniel C Devor","doi":"10.1152/ajpcell.00216.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00216.2026","url":null,"abstract":"<p><p><i>Glycyrrhiza glabra</i> is one of 30 species of licorice which has been prescribed for centuries for a wide range of ailments and conditions. In particular, licorice root extract, as well as its main isoflavonoid constituent, glabridin, have been used to treat a variety of respiratory diseases, ranging from infection to asthma. As glabridin has been shown to modulate the activity of ion channels in other tissues, we determined the effect of glabridin on K⁺ and Cl⁻ secretion across primary human bronchial epithelial cells (HBEs), as these may represent therapeutic targets. Glabridin stimulated BK_Ca-dependent transepithelial potassium secretion across HBEs. In contrast, the glabridin derivative, vutiglabridin failed to stimulate K⁺ secretion and inhibited the glabridin-dependent K⁺ secretory current. Whole-cell patch-clamp studies on HEK cells expressing BK_Ca demonstrate that glabridin activates, whereas vutiglabridin inhibits, BK_Ca. We further demonstrate glabridin inhibits forskolin-mediated transepithelial Cl⁻ secretion across HBEs, while vutiglabridin has little effect. Using Fisher Rat Thyroid (FRT) cells stably expressing either wild type (FRT-WT) or F508del CFTR (FRT-F508del), we demonstrate glabridin neither potentiates WT CFTR nor corrects F508del CFTR. In contrast, whole-cell patch-clamp studies demonstrate glabridin inhibits KCa3.1 stably expressed in HEK cells. We previously demonstrated a role for KCa3.1 in forskolin-mediated Cl⁻ secretion across HBEs, likely explaining the inhibition of Cl⁻ secretion observed. In summary, we show that glabridin both stimulates BK_Ca-dependent K⁺ secretion and inhibits cAMP-mediated Cl⁻ secretion across HBEs. These findings support a role for BK_Ca in the therapeutic effects of glabridin in airway.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypertensive stretch regulates endothelial cell inflammation and apoptosis through ceramide metabolism.","authors":"Julia G Pietromicca-Victor, Shweta Chitkara, Erik Muñoz, Zahid A Manzar, Anu P Bharathi Rajan, Erhard Bieberich, G Ekin Atilla-Gokcumen, B Rita Alevriadou","doi":"10.1152/ajpcell.00283.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00283.2026","url":null,"abstract":"<p><p>Hypertension and cardiovascular disease (CVD) are associated with elevated plasma levels of ceramides (Cer), a type of membrane sphingolipids (SPLs). Increased cellular Cer levels are known to cause vascular endothelial cell (EC) dysfunction. However, Cer metabolism changes due to EC exposure to high-magnitude \"hy-pertensive\" cyclic stretch (HCS) and their role in EC dysfunction are poorly defined. Cultured human ECs exposed to HCS (15% elon¬gation at 1 Hz, 24 h) exhibited increased oxidative stress, upreg¬ulation of genes for cytokines and leukocyte adhe¬sion molecules, increased inflammatory response to a low concentration of tumor necrosis factor-α, and increased apoptosis compared to ECs exposed to \"normotensive\" CS (NCS; 5% elongation at 1 Hz, 24 h). Lipidomics analysis of EC pellets at 4 or 24 h of CS detected no differ¬ence in Cer levels and significantly higher sphingomyelin (SM) levels at 24 h of HCS compared to NCS. Cer immunostaining showed significantly higher Cer levels at both the perinuclear and peripheral subcellular regions in HCS compared to the corresponding regions in NCS. HCS signifi¬cantly increased the concentrations of certain long-chain Cer in the extracellular media compared to NCS. Phar¬macological inhibition of key enzymes in Cer biosynthesis, i.e., <i>de novo</i> synthesis and SM hy¬drolysis pathways, significantly inhibited HCS-induced EC inflammation and apoptosis, sug¬gesting that Cer generated from SM, via the sphingomyelinase family of enzymes, and accumulated at specific sub¬cellular compartments may be respon¬sible for the HCS-induced EC dysfunction. In summary, Cer act as mechanotransducers that connect hypertensive stretch to EC inflamma-tion and apoptosis, and promote CVD.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Paradigm for Old Hormones: The Case for 17α-Estradiol as an Acute Therapeutic in Male Volumetric Muscle Loss.","authors":"Jarrod A Call, William T Juckett, McLane M Montgomery, Sarah M Greising","doi":"10.1152/ajpcell.00455.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00455.2026","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular cues and cellular conversations: The molecular choreography of embryo implantation.","authors":"Janice K Jeschke, Verena Nordhoff, Martin Götte, Konstantina Kyriakopoulou","doi":"10.1152/ajpcell.00048.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00048.2026","url":null,"abstract":"<p><p>Infertility affects millions of people globally with recent statistics indicating that one in six adults is experiencing reproductive challenges at some point. For female infertility in particular, the global health burden is continuously intensifying with significant disparities across countries. Female infertility has a complex multifactorial etiology and understanding the underlying mechanisms is crucial in order to reduce the health burden and enhance patient well-being. For a pregnancy, successful embryo implantation is a pivotal step, requiring precise spatiotemporal synchronization between a competent blastocyst and a receptive endometrium during the window of implantation (WOI). This review provides an overview of recent developments around the molecular and clinical aspects of this process, with a specific focus on the extracellular microenvironmental cues and maternal-embryo interaction. Specifically, we detail the extensive extracellular matrix (ECM) remodeling that facilitates embryo adhesion and invasion, while shedding light on microRNAs as signaling and communication mediators that govern cell-cell and maternal-fetal interactions. Finally, we examine current limitations in the clinical assessment of receptivity and discuss future perspectives for non-invasive biomarkers and possibilities for more personalized solutions in assisted reproduction.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between SARS-CoV-2 and the angiotensin system: Clinical implications.","authors":"Safa Kinaneh, Shadi Hamoud, Yara Knany, Samuel N Heyman, Zaid Abassi","doi":"10.1152/ajpcell.00786.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00786.2025","url":null,"abstract":"<p><p>ACE2, serving as a receptor to SARS-CoV-2, is a key player in RAAS. Consequent ACE2 depletion disrupts the balance between the Ang II/ AT1R and Ang (1-7)/MasR arms of the angiotensin system, promoting intense inflammation. A crosstalk existing between the angiotensin system and ACE2/spike proteins may affect the infection severity, with potential therapeutic implications. Evaluating such potential interactions and their relevance to the severity of COVID-19, which is directly affected by ACE2 abundance or indirectly by RAAS axis dysregulation. The intensity of SARS-CoV-2 infection was assessed using a cell-to-cell fusion assay and AT1R activation was assessed using AT1R-Tango approach. We demonstrate the critical function of ACE2 in mitigating AT1R activation, which is disrupted following SARS-CoV-2 infection. Moreover, we show that the spike protein indirectly intensifies AT1R activation. Beyond its established role in activating MasR, Ang1-7 was found to function as a biased agonist for AT1R, without altering ACE2 levels or affecting SARS-CoV-2 entry. In contrast, AVE0991, a MasR agonist, was observed to increase ACE2 levels and enhance SARS-CoV-2 infection. Angiotensin receptor blockers (ARBs) effectively inhibited AT1R activity and had minimal impact on viral entry. Our data supports the likelihood that AT1R blockers (ARBs) may be effective in managing COVID-19 since they inhibit AT1R activation and its deleterious subsequent effects, with no impact on SARS-CoV-2 entry. By contrast, MasR and its agonist AVE0991, by increasing ACE2 levels, may restore RAAS physiological balance, but facilitate host cell invasion by SARS-CoV-2.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subcellular regulation of ferroptosis: roles of individual intracellular organelles and cross talk.","authors":"Chanon Piamsiri, Judith K Gwathmey, Lai-Hua Xie","doi":"10.1152/ajpcell.00334.2026","DOIUrl":"10.1152/ajpcell.00334.2026","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation. Emerging evidence indicates that susceptibility to ferroptosis is not governed solely by cytosolic signaling pathways, but instead results from the coordinated actions of multiple intracellular organelles, including mitochondria, lysosomes, the endoplasmic reticulum (ER), and lipid droplets (LDs). Mitochondria play dual roles in ferroptosis by integrating metabolic activity, redox balance, and mitochondrial quality control; thereby influencing reactive oxygen species (ROS) generation and lipid peroxidation. Lysosomes regulate ferroptotic sensitivity through iron mobilization, inter-organelle iron transfer, lysosomal redox activity/lipid peroxidation, lysosomal signaling hub, and ferritinophagy. The ER contributes to ferroptosis by coordinating lipid biosynthesis, membrane polyunsaturated fatty acid composition, and unfolded protein response signaling, as well as by disrupting antioxidant defenses and iron homeostasis, especially during ER stress. Lipid droplets function as dynamic lipid reservoirs that buffer oxidizable fatty acids or, upon mobilization, supply substrates that fuel ferroptosis-associated lipid peroxidation. Here, we provide a comprehensive review of current mechanistic insights and recent advances in organelle-specific regulation and inter-organelle cross talk during ferroptosis, highlighting emerging therapeutic opportunities and key experimental challenges. An integrated understanding of this multi-organelle regulatory network is essential for modulating ferroptosis in human diseases.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C705-C721"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of cyst growth in autosomal dominant polycystic kidney disease: mechanistic insights and therapeutic opportunities.","authors":"Raluca Ursu, Bjoern Buchholz, Kathrin Skoczynski","doi":"10.1152/ajpcell.00222.2026","DOIUrl":"10.1152/ajpcell.00222.2026","url":null,"abstract":"<p><p>Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited kidney disorders and is characterized by the progressive formation and expansion of fluid-filled cysts, ultimately leading to kidney failure. Although caused by reduced dosage of the polycystin proteins, the disease phenotype arises from a broad disruption of epithelial physiology rather than a single linear pathway. Loss of polycystin function destabilizes epithelial homeostasis and sensitizes cyst-lining cells to proliferative and secretory cues. A central consequence is the emergence of a self-reinforcing signaling environment in which cyclic AMP, Ca²⁺, and purinergic pathways amplify one another, promoting chloride-driven fluid secretion and epithelial proliferation. In parallel, cyst epithelia exhibit disturbed cell turnover, including altered proliferation, apoptosis, autophagy, and ferroptotic stress, which reshape luminal architecture and sustain a prosecretory microenvironment. Metabolic reprogramming, characterized by enhanced glycolysis, mitochondrial dysfunction, and redox imbalance, provides energetic support for these processes and further strengthens proliferative and secretory signaling. Hypoxia-inducible factor-1α (HIF-1α) integrates hypoxic, metabolic, and mechanical cues into transcriptional programs that reinforce cyst expansion. This review synthesizes these interconnected mechanisms and highlights potential therapeutic strategies, including restoration of polycystin expression, modulation of cAMP and purinergic signaling, inhibition of chloride secretion, metabolic targeting, and HIF-1α pathway intervention. Together, these insights support a model in which cyst growth arises from mutually reinforcing signaling, metabolic, and transcriptional programs. Effective disease modification will likely require multinodal therapeutic approaches that address this integrated network.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C605-C622"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxic eNOS uncoupling as a consequence of DHFR downregulation in various human endothelial cell lines: the crucial role of the BH₄ regeneration pathway.","authors":"Anna Janaszak-Jasiecka, Adrianna Radulska, Anna Siekierzycka, Agata Płoska, Tomasz Borkowski, Iwona T Dobrucki, Rafał Bartoszewski, Leszek Kalinowski","doi":"10.1152/ajpcell.00171.2026","DOIUrl":"10.1152/ajpcell.00171.2026","url":null,"abstract":"<p><p>Tetrahydrobiopterin (BH₄) is an essential cofactor for endothelial nitric oxide synthase (eNOS), which produces nitric oxide (NO) to maintain vascular homeostasis. When BH₄ is deficient, eNOS becomes uncoupled, generating superoxide ([Formula: see text]) instead of NO, contributing to endothelial dysfunction and cardiovascular disease. The cellular BH₄ concentration is determined by its de novo synthesis via GTP cyclohydrolase I (GTPCH), oxidation of BH₄ to BH₂, and the regeneration of BH₄ from BH₂ by dihydrofolate reductase (DHFR). A diminished BH₄/BH₂ ratio, often due to DHFR dysregulation, promotes eNOS uncoupling. This study investigates how hypoxia affects eNOS activity and NO bioavailability in human endothelial cells (ECs) derived from various vascular beds. We show that hypoxia downregulates eNOS and DHFR, impairs BH₄ regeneration, and induces eNOS uncoupling in all human EC types tested. We also demonstrate that human ECs exhibit low basal BH₄ levels, which may result from limited GTPCH expression; consequently, the BH₄/BH₂ ratio appears to depend substantially on DHFR activity. Importantly, we show for the first time that BH₄-dependent regulation of eNOS uncoupling varies between ECs derived from distinct vascular beds. This variability is driven by cell-type-specific differences in the relative levels of eNOS and DHFR under hypoxia. In particular, human aortic endothelial cells (HAECs) display high eNOS expression and low DHFR levels, making them especially prone to hypoxic eNOS uncoupling. These findings suggest that certain vascular beds may be intrinsically more susceptible to hypoxia-induced endothelial dysfunction, driven by greater eNOS uncoupling that depends on DHFR activity, highlighting DHFR as a potential therapeutic target.<b>NEW & NOTEWORTHY</b> This study identifies DHFR-dependent BH₄ regeneration as the key determinant of eNOS coupling in human endothelial cells with intrinsically low BH₄ levels. We show that hypoxia disrupts this pathway, leading to eNOS uncoupling in a vascular bed-specific manner. Notably, human aortic endothelial cells are particularly susceptible due to high eNOS and low DHFR expression, highlighting DHFR as a potential therapeutic target in hypoxia-driven endothelial dysfunction.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C653-C663"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}