American journal of physiology. Cell physiology最新文献

{"title":"The blueprint of neurocardiac crosstalk in arrhythmic syndromes.","authors":"Tania Zaglia, Induja Perumal Vanaja, Anna Guazzo, Marco Mongillo","doi":"10.1152/ajpcell.00558.2025","DOIUrl":"10.1152/ajpcell.00558.2025","url":null,"abstract":"<p><p>Inherited arrhythmogenic syndromes encompass a spectrum of genetic cardiac disorders unified by heightened vulnerability to sympathetic stimulation and risk of sudden cardiac death. Traditionally categorized as either functional (e.g., catecholaminergic polymorphic ventricular tachycardia, CPVT) or structural (e.g., arrhythmogenic cardiomyopathy, ACM), these syndromes are increasingly recognized to share a common reliance on neurocardiac signaling. In this review, we examine CPVT and ACM as representative extremes of the functional-structural continuum, highlighting how sympathetic activation acts not only as an acute arrhythmic trigger but also as a chronic driver of disease progression. We dissect the roles of β-adrenergic signaling, neuropeptide Y (NPY), and regional innervation patterns in shaping myocardial excitability, remodeling, and arrhythmogenesis. While CPVT exemplifies a trigger-dependent, Ca²⁺-driven arrhythmia in structurally normal hearts, ACM demonstrates a substrate-amplified phenotype involving maladaptive autonomic remodeling and neurogenic fibrofatty infiltration. We discuss the emerging relevance of neuromodulatory and peptidergic therapies-including β-blockade, left cardiac sympathetic denervation, and NPY antagonism-and propose an integrated framework for arrhythmia classification and management based on autonomic mechanisms. By reframing inherited arrhythmias as disorders of integrated neural and myocardial physiology, we highlight new opportunities for mechanistic insight, biomarker development, patient stratification, and translational therapy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1038-C1045"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938957","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":"The role of carnitine palmitoyl transferase 2 in the progression of salt-sensitive hypertension.","authors":"Lashodya V Dissanayake, Brody A Smith, Adrian Zietara, Vladislav Levchenko, Melissa Lowe, Olha Kravtsova, Abigail Shapiro, Gunjan Upadhyay, Ganesh V Halade, Aron M Geurts, Oleg Palygin, Alexander Staruschenko","doi":"10.1152/ajpcell.00485.2025","DOIUrl":"10.1152/ajpcell.00485.2025","url":null,"abstract":"<p><p>Carnitine palmitoyl transferase 2 (CPT2) is a key enzyme in mitochondrial fatty acid oxidation (FAO), a process critical for renal energy homeostasis. Disruption of FAO and accumulation of plasma acylcarnitines (fatty acids conjugated to carnitine) have been implicated in renal and vascular diseases. Although the kidney relies heavily on FAO, the specific renal consequences of CPT2 deficiency remain poorly understood. Clinical data suggest that CPT2 expression may be associated with increased lifespan in patients on antihypertensive therapy, yet a direct link between CPT2 and hypertension has not been established. Our previous work in salt-sensitive (SS) hypertension showed that a high-salt (HS) diet increases FAO while reducing renal acylcarnitine levels. To investigate how CPT2 deficiency affects renal function and metabolic regulation under dietary stress, we generated a novel CPT2-deficient rat model on the Dahl SS background. Homozygous knockouts were embryonically lethal; thus, heterozygous (<i>SS</i>^Cpt2+/-) rats were used for further studies. At baseline, <i>SS</i>^Cpt2+/- rats exhibited lower urinary excretion of tricarboxylic acid cycle metabolites compared with wild-type littermates, suggesting altered mitochondrial metabolism. Under an HS diet, <i>SS</i>^Cpt2+/- rats had no significant differences in blood pressure. However, when faced with a high-salt ketogenic diet, these rats exhibited somewhat contradictory effects, showing lower blood pressure alongside lipid dysregulation and accumulation of long-chain acylcarnitines. Collectively, our findings reveal a complex role for CPT2 in the metabolic and pathophysiological responses to SS hypertension, with implications for renal and cardiovascular outcomes under dietary stress.<b>NEW & NOTEWORTHY</b> Although high-salt diets have been shown to negatively impact cardiovascular health, the ketogenic diet has demonstrated beneficial effects. In the current study, we created a model of CPT2 deficiency on a salt-sensitive background and showed that the combination of both diets has an unexpected effect on a model of fatty acid dysregulation, seemingly reducing the development of hypertension. Our data suggest a complex role for CPT2, extending beyond fatty acid oxidation, in regulating blood pressure.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1188-C1202"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938960","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":"Mitochondrial DNA-driven senescence-associated secretory phenotype promotes the development of bronchopulmonary dysplasia.","authors":"Yang Meng, Hui Shi, Hui Xu, Yazhou Sun, Xingyun Wang, Rui Wang, Yongjun Zhang","doi":"10.1152/ajpcell.00040.2025","DOIUrl":"10.1152/ajpcell.00040.2025","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and disrupted vascular growth in preterm infants. Although cellular senescence has been well established in age-related diseases, such as chronic lung diseases, its role in developmental lung diseases originating in the neonatal period remains largely unknown. Here, we investigated the role and underlying mechanisms of the senescence-associated secretory phenotype (SASP) in BPD using targeted inhibitor treatments and rescue strategies. Key SASP factors, including interleukin-6, interleukin-1β, matrix metalloproteinase 12, and transforming growth factor-β₁, were significantly elevated after hyperoxia exposure, indicating their involvement in BPD pathogenesis. Confocal imaging revealed that hyperoxia-induced partial mitochondrial outer membrane permeabilization triggered mitochondrial DNA (mtDNA) leakage, establishing mitochondrial dysfunction as a key driver of BPD progression. Further experiments demonstrated the role of the voltage-dependent anion channel 1 (VDAC1) oligomerization and the cGAS-STING pathway in mediating mtDNA release and SASP, respectively. Collectively, these findings define a molecular cascade where VDAC1 oligomerization causes mtDNA leakage, activating cGAS-STING to drive SASP during BPD progression. Targeting the cGAS-STING pathway holds therapeutic potential for alleviating the chronic impact of BPD.<b>NEW & NOTEWORTHY</b> We uncovered a novel pathway in bronchopulmonary dysplasia (BPD) development, where mitochondrial dysfunction triggers mtDNA release, activating the cGAS-STING pathway and regulating the senescence-associated secretory phenotype (SASP). This cascade impacts lung epithelial cell function in oxidant-induced injury, providing new insights into BPD pathogenesis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1332-C1342"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051569","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":"Diet-induced obesity disrupts sexually dimorphic gene expression in mice.","authors":"Vicent Ribas, Samantha Morón-Ros, Helena Marí, Albert Gracia-Batllori, Laura Brugnara, Alba Herrero-Gómez, Elena Eyre, Marc Claret, Irene Marco-Rius, Anna Novials, Joan-Marc Servitja","doi":"10.1152/ajpcell.00098.2025","DOIUrl":"10.1152/ajpcell.00098.2025","url":null,"abstract":"<p><p>Biological sex significantly influences the prevalence, incidence, and severity of numerous human diseases, yet it remains an underappreciated variable in biomedical research. Although sexually dimorphic genes contribute to sex-specific traits and disease manifestations, their regulation under metabolic stress is poorly understood. To explore sex-specific metabolic adaptations, we analyzed responses to high-fat diet (HFD)-induced obesity in male and female mice, focusing on the regulation of sex-biased genes. Despite similar adiposity, HFD-fed males displayed more severe metabolic impairments than females, highlighting divergent metabolic outcomes. To investigate the basis for these sex-specific differences, we performed whole transcriptomic profiling of liver and white adipose tissue (WAT) at early (2 wk) and late (12 wk) stages of HFD exposure. Our analysis revealed marked sex-specific gene expression changes across multiple categories, particularly pronounced in male WAT after prolonged HFD feeding. Strikingly, genes exhibiting sexual dimorphism under normal conditions were preferentially modulated in both sexes, comprising up to 46% of all HFD-regulated genes. This led to a substantial loss of sex-biased gene expression in both liver and WAT after HFD exposure, correlating with metabolic dysfunction. Male-biased genes associated with cilia function and estrogen response were among the most affected, showing significant downregulation in male WAT under HFD. Our findings provide a novel perspective on how obesity disrupts sex-specific gene expression in key metabolic tissues, particularly targeting sex-biased genes. By revealing that a considerable proportion of sex-biased genes exhibit HFD-regulated modulation, our study highlights the critical role of these genes in maintaining metabolic health.<b>NEW & NOTEWORTHY</b> Biological sex shapes metabolic tissue physiology, largely through sex-biased gene regulation. Our comprehensive transcriptomic analysis reveals that sex-biased genes in liver and white adipose tissue undergo the most significant regulation during obesity-driven metabolic dysfunction, resulting in a loss of their bias. This disruption highlights a previously unrecognized role of sex-biased genes in maintaining metabolic health in both males and females.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C987-C1003"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783218","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 vesicles from post-COVID-19 patients alter endothelial function under protein restriction.","authors":"Geiza Rafaela Bobato, Juliana Quinholi Rocha, Daniele Mendes Guizoni, Natalia Ribeiro Cabacinha Nóbrega, Ludmilla David de Moura, Matheus Lavorenti Rocha, Licio Augusto Velloso, Everardo Magalhães Carneiro, Ligia de Moraes Antunes-Correa, Ana Paula Davel","doi":"10.1152/ajpcell.00450.2025","DOIUrl":"10.1152/ajpcell.00450.2025","url":null,"abstract":"<p><p>The COVID-19 pandemic worsened global food insecurity and malnutrition. Protein restriction increases the risk of poor COVID-19 outcomes and cardiovascular disease. Post-COVID-19 syndrome remains a public health concern, although its underlying mechanisms are not yet fully understood. Extracellular vesicles (EVs), released by most cell types in response to infections, have been implicated in endothelial dysfunction during the post-COVID phase. We hypothesized that EV contribute to endothelial cell (EC) dysfunction in long-term COVID-19, particularly in the setting of protein malnutrition. Circulating EVs were isolated from patients at 1 and 6 months (mo) after hospital discharge due to severe COVID-19. Endothelial relaxation was assessed in mouse aortas after a 3-mo normoprotein or low-protein diet (LP). LP feeding reduced endothelium-dependent relaxation to acetylcholine, but EVs from post-COVID patients (1 and 6 mo) restored endothelium-dependent relaxation. This EV effect was abolished by catalase, but not by l-NAME (a nitric oxide synthase inhibitor) or indomethacin (a cyclooxygenase inhibitor). Aortas from LP mice incubated with post-COVID EVs exhibited reduced catalase expression and increased 4-hydroxynonenal (4-HNE) adducts. In vitro amino acid restriction increased EC death (Hoechst/Pi), and reduced nitric oxide (Diaminofluorescein-FM diacetato) and H₂O₂ (Amplex red) levels. Incubation with post-COVID EVs for 24 h increased H₂O₂ only in amino acid-restricted EC. EVs had no significant effect on acetylcholine-induced relaxation in normoprotein-fed mice or on EC parameters in vitro under control conditions. These findings suggest that EVs from patients 1 and 6 mo after severe COVID-19 impact aortic endothelial function by increasing H₂O₂ contribution under conditions of malnutrition.<b>NEW & NOTEWORTHY</b> Our study demonstrated that circulating extracellular vesicles (EVs) from patients 1 and 6 mo after severe COVID-19 altered endothelial function under protein restriction but not in healthy vessels. Post-COVID EVs enhanced the contribution of H₂O₂ to endothelium-dependent relaxation, associated with reduced catalase and increased 4-HNE-modified protein expression. These findings identified EVs from long COVID patients as potential mediators of endothelial dysfunction particularly under malnutrition-related conditions.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1121-C1129"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938750","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":"Unconventional myosin VI is involved in regulation of muscle energy metabolism.","authors":"Dominika Wojton, Dorota Dymkowska, Damian Matysniak, Malgorzata Topolewska, Maria Jolanta Redowicz, Lilya Lehka","doi":"10.1152/ajpcell.00300.2025","DOIUrl":"10.1152/ajpcell.00300.2025","url":null,"abstract":"<p><p>Mitochondria are essential for the regulation of the metabolic state of skeletal muscle, making their structure and function crucial for muscle performance. Myosin VI (MVI), an unconventional minus-end-directed motor, is expressed in skeletal muscle and myogenic cells. To explore its role in mitochondrial function and muscle metabolism, we used MVI knockout mice (<i>Snell's waltzer</i>, <i>SV</i> MVI-KO) and their heterozygous littermates. We analyzed muscle samples from newborn (P0) and adult mice (3- and 12-mo-old) and found that both MVI mRNA and protein levels were highest in newborn muscles and decreased with age. MVI expression also varied by muscle type, being highest in the slow-twitch soleus muscle (SOL) of adult mice. Loss of MVI had the most significant effects on SOL, which contains the highest number of mitochondria compared with fast-twitch muscles. MVI loss resulted in reduced respiratory capacity and adenosine-5'-triphosphate production in myogenic cells, indicating impaired mitochondrial function. Furthermore, MVI deficiency caused a shift from glycolytic to oxidative fiber types, especially in SOL. We also observed increased phospho-AMP-activated protein kinase levels in MVI-KO SOL across all time points, along with downregulation of the mammalian target of rapamycin pathway and upregulation of proteins involved in lipolysis. These findings highlight MVI as a novel regulator of metabolic processes in skeletal muscle.<b>NEW & NOTEWORTHY</b> Myosin VI (MVI), a motor protein, regulates mitochondrial function and metabolism in skeletal muscle. In MVI-knockout mice, its expression peaked in neonatal muscles and remained highest in adult soleus. MVI loss impaired mitochondrial respiration, reduced ATP production, and promoted a shift toward oxidative fibers. It also increased AMPK, suppressed mTOR signaling, and altered lipid metabolism, including reduced triacylglycerol levels. These findings reveal MVI's important role in energy balance, protein synthesis, and lipid regulation in muscle.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1004-C1021"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870898","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":"Unveiling serine protease activity profiles in Netherton syndrome skin across clinical subtypes by noninvasive analysis.","authors":"Evgeniya Petrova, Antoine Duthoit, Ioannis Prassas, Alain Hovnanian","doi":"10.1152/ajpcell.01027.2024","DOIUrl":"10.1152/ajpcell.01027.2024","url":null,"abstract":"<p><p>Uncontrolled kallikrein-related peptidase (KLK) activity underlies Netherton syndrome (NS). However, whether KLK expression and activity vary between lesional and nonlesional skin, or across NS clinical subtypes, remains unclear, which could be crucial for treatment optimization. Using noninvasive skin sampling and skin biopsies, we profiled the expression and activity of five NS-relevant KLKs (the trypsin-like KLK5, KLK6, KLK13, and KLK14, and the chymotrypsin-like KLK7) in lesional and nonlesional skin from 20 patients with NS with the two clinical subtypes. We found that KLK5 and KLK7 were strongly expressed in the upper epidermis of healthy controls and patients with NS, regardless of lesion status. In contrast, KLK6 and KLK13 were predominantly increased in NS lesional skin. KLK14 showed weak expression in NS epidermis and healthy control skin, but was more strongly expressed in nonepithelial cells, including neutrophils and mast cells. Regarding protease activity, total trypsin-like serine protease activity (comprising KLK5, KLK6, KLK13, and KLK14 activities) and KLK7-like activity in lesional and nonlesional NS skin, regardless of clinical subtype, were higher as compared with healthy controls. Notably, within each clinical subtype, lesional and nonlesional skin displayed similar protease activity levels. However, patients with scaly erythroderma (SE) subtype showed higher KLK7-like protease activity in lesional superficial skin than patients with ichthyosis linearis circumflexa subtype. In one patient with NS-SE undergoing partially effective secukinumab therapy, superficial skin protease activity showed no significant change. Measurement of KLK activity from tape strips revealed distinct proteolytic patterns among patients with NS and represents a noninvasive tool for evaluating treatment efficacy in NS clinical trials.<b>NEW & NOTEWORTHY</b> This study identifies differences in kallikrein-related peptidase (KLK) expression and activity between healthy skin and Netherton syndrome (NS) skin, distinguishing lesional and nonlesional areas in the two major clinical subtypes. Increased expression of KLK6 and KLK13 is characteristic of the epidermis in NS lesional skin. KLK14 can be expressed by both keratinocytes and immune cells. Patients with scaly erythroderma subtype NS show higher KLK7-like activity in lesional skin, highlighting subtype-specific differences.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1139-C1149"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999443","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 serine proteases activate amiloride-insensitive ENaC channels and decrease migration and invasion ability of human leukemia cell lines.","authors":"Daria V Lysikova, Polina I Kirillova, Irina O Vassilieva, Maxim L Bychkov, Vladislav I Chubinskiy-Nadezhdin, Anastasia V Sudarikova","doi":"10.1152/ajpcell.00584.2024","DOIUrl":"10.1152/ajpcell.00584.2024","url":null,"abstract":"<p><p>Epithelial sodium channels (ENaCs) have been reported to affect cancer cell development, including the processes of proliferation, apoptosis, and cell motility. Previously, we have shown the stimulating effect of extracellular serine protease trypsin on the activity of amiloride-insensitive ENaC-like channels in human leukemia K562 cells, where the expression of all ENaC subunits was found. However, the effect of serine proteases of various specificities on sodium channels and its functional role in the regulation of cancer progression in transformed blood cells remains unclear. In this study, using a single-channel whole cell patch-clamp approach, we established that serine proteases α-chymotrypsin and plasmin directly activate sodium channels in leukemia K562 and U937 cell lines. δ-ENaC knockdown (KD) in K562 cells prevents the activation of the channels by α-chymotrypsin, confirming the involvement of δ-ENaC in protease-induced channel formation. Using an in vitro migration assay, we have shown for the first time that α-chymotrypsin and plasmin significantly reduced migration and invasion rate of K562 cells; δ-ENaC KD partially abolished this effect. The same effect of α-chymotrypsin was confirmed on the migration of different human leukemia cell lines (U937 and HL-60). Incubation of the cells with serine proteases in the presence of their inhibitors (soybean trypsin inhibitor or α₂-antiplasmin) did not affect cell migration/invasion, indicating an important role of their proteolytic activity. Moreover, there was no effect of α-chymotrypsin on the migration of MOLT-4 leukemia cells, which do not express functionally active ENaCs. Our data imply that extracellular serine proteases, as universal regulators of sodium permeability via ENaC, decrease leukemia cell migration.<b>NEW & NOTEWORTHY</b> In clinical practice, leukemia cells can exhibit drug resistance to standard treatments; therefore, identification of new therapeutic strategies is needed to prevent leukemia relapse. Here, it was shown for the first time that serine proteases α-chymotrypsin and plasmin significantly inhibit the motility of leukemia cells that express functionally active ENaCs. Thus, extracellular serine proteases as regulators of Na⁺ handling via ENaC channels could be considered as new suppressors of leukemia cell locomotion.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1022-C1036"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870897","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":"Neuronal activity-dependent gene dysregulation in <i>C9orf72</i> i³Neuronal models of ALS/FTD pathogenesis.","authors":"Layla T Ghaffari, Emily A Welebob, Sarah E B Newton, Ashley V Boehringer, Kelly L Cyliax, Piera Pasinelli, Davide Trotti, Aaron R Haeusler","doi":"10.1152/ajpcell.00238.2025","DOIUrl":"10.1152/ajpcell.00238.2025","url":null,"abstract":"<p><p>The GGGGCC nucleotide repeat expansion (NRE) mutation in the <i>C9ORF72</i> (C9) gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE-induced pluripotent stem cell-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization or a blockade of K⁺ channels, followed by RNA sequencing, induces a temporally divergent activity-dependent transcriptome of C9-NRE cortical neurons compared with healthy controls. This study provides new insights into how neuronal activity influences the ALS/FTD-associated transcriptome, offering a dataset that enables further exploration of pathways necessary for conferring neuronal resilience or degeneration.<b>NEW & NOTEWORTHY</b> A recent study using iPSC-derived cortical neurons reveals how neuronal activity drives gene dysregulation in <i>C9ORF72</i>-linked ALS/FTD. We uncover synaptic dysfunction, peroxisomal dysregulation, and NPAS4-linked transcriptional shifts, highlighting key disease-modifying pathways. Could these insights pave the way for new therapeutic targets? Explore our research and generate your own discoveries using our interactive dataset included in the link in the article.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1085-C1100"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938969","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":"Vascular effects of SGLT2 inhibitors: evidence and mechanisms.","authors":"Beatriz R Góes-Santos, Paulo C Castro, Adriana C C Girardi, Lígia M Antunes-Correa, Ana P Davel","doi":"10.1152/ajpcell.00569.2025","DOIUrl":"10.1152/ajpcell.00569.2025","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed as glucose-lowering agents for type 2 diabetes mellitus (T2DM). However, robust clinical evidence has demonstrated that their therapeutic benefits extend beyond glycemic control. SGLT2i reduce hospitalization for heart failure (HF), slow the progression of chronic kidney disease (CKD), and provide cardiorenal protection even in individuals without diabetes but with cardiovascular disease. These pleiotropic effects include favorable actions on both macrovascular and microvascular functions, which may contribute to their broad cardiovascular, renal, and metabolic benefits. Although the mechanisms underlying these vascular effects remain incompletely understood, they appear to involve both hemodynamic modulation and direct cellular actions that vary according to disease context and vascular bed. Elucidating these mechanisms is essential to refining therapeutic strategies and guiding optimal patient selection. This short review highlights the multifaceted vascular benefits of SGLT2i, summarizing current clinical and mechanistic insights into their vascular actions, with a particular mention of their role in the context of malignancy. SGLT2i contribute to improved cell viability, proliferation, and angiogenesis by attenuating endothelial cell apoptosis, ferroptosis, and pyroptosis, while also influencing inflammatory and oxidative signaling pathways, and enhancing eNOS phosphorylation and deacetylation. In addition to their endothelial effects, we explore the impact of SGLT2i on vascular smooth muscle cells and perivascular nerves, which can lead to reduced vascular stiffness, calcification, and improved vasodilation. Sex-specific differences in clinical outcomes and mechanisms are also discussed. Finally, we identify key areas for future investigation to better harness the full therapeutic potential of SGLT2i.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1150-C1160"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999433","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}