Pflugers Archiv : European journal of physiology最新文献

{"title":"Guinea pig δβγ-ENaC is locked in an open state and uncoupled from regulation by proteases.","authors":"Rene Yufenyuy Lawong, Etang Collins Etang, Fabian May, Philipp Vorrat, Oliver Rauh, Mike Althaus","doi":"10.1007/s00424-026-03173-0","DOIUrl":"10.1007/s00424-026-03173-0","url":null,"abstract":"<p><p>The epithelial sodium channel (ENaC) plays a key role in salt and water homeostasis in tetrapod vertebrates. There are four ENaC subunits (α, β, γ and δ) which form heterotrimeric αβγ- or δβγ-ENaC assemblies. ENaC activity is tightly coupled to proteolytic processing of ENaC subunits, but this effect is specific to ENaC subunit assembly and mechanistically not completely understood. Guinea pig αβγ- or δβγ-ENaCs were heterologously expressed in Xenopus oocytes and their control by extracellular proteases was investigated using protein biochemistry, two-electrode voltage-clamp and patch-clamp electrophysiology. Guinea pig αβγ-ENaC activity was tightly coupled to cleavage of its α- and γ-subunits by the endoprotease furin and extracellular chymotrypsin or trypsin. By contrast, δβγ-ENaC activity was not affected by proteases, despite cleavage of its γ-subunit by chymotrypsin. Experiments using a βS521C-ENaC substitution, which locks ENaC in an open state after exposure to the sulfhydryl-reagent [2-(trimethylammonium)ethyl] methanethiosulfonate (MTSET), demonstrated that guinea pig δβS521Cγ-ENaCs are almost fully open when expressed in Xenopus oocytes. On-cell single-channel patch-clamp recordings confirmed that the open probability of guinea pig δβγ-ENaC is nearly 90%. These data indicate that guinea pig δβγ-ENaC is locked in an open state and thereby uncoupled from channel control by proteases.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147778213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of autonomic receptors in ethyl ferulate-induced cardiovascular effects in normotensive and hypertensive female rats.","authors":"Francisca Valdirene de S Nunes, Samuel S P Araujo, Juliana A da Silva, José Guilherme V de Assunção, Ariell A de Oliveira, Carlos E R Dourado, Vandercley de O Damasceno, Aldeídia P de Oliveira, Maria do Carmo C Martins, Mayara C de Morais, Damião P de Sousa, Thyago M de Queiroz, Renato N Soriano, Luiz G S Branco, Helio C Salgado, João Paulo J Sabino","doi":"10.1007/s00424-026-03170-3","DOIUrl":"10.1007/s00424-026-03170-3","url":null,"abstract":"","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147778349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proximal TGF-β Signaling in Chronic Injury: from a notorious fibrotic factor to a repair ally.","authors":"Stellor Nlandu Khodo","doi":"10.1007/s00424-026-03168-x","DOIUrl":"10.1007/s00424-026-03168-x","url":null,"abstract":"<p><p>Transforming growth factor beta (TGF-β) is a pleiotropic factor that plays a key role in the pathophysiology of chronic kidney disease (CKD). However, targeting TGF-β inhibition failed to mitigate CKD in practice. The proximal tubule (PT), the most vulnerable renal segment, plays a central role in post-injury repair or the drift to CKD. Despite its well-documented profibrotic effects, recent studies revealed benefits of TGF-β signaling in PT response to CKD, raising the question of its therapeutic potential. This review highlights mechanisms by which TGF-β signaling mediates the PT adaptive response to chronic injury and provides perspectives for developing novel CKD therapy.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147778322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effects of vitamin E and quercetin against MDMA-induced cardiac and hematological dysfunction in male wistar rats.","authors":"Ayodeji Folorunsho Ajayi, David Tolulope Oluwole, Moses Agbomhere Hamed, Ayomide Jonathan Jegede, Florence Bukola Adisa, Lateef Olabisi Okeleji, Toluwalope Oluwafisayo Iyiola, Oyedayo Phillips Akano","doi":"10.1007/s00424-026-03169-w","DOIUrl":"10.1007/s00424-026-03169-w","url":null,"abstract":"<p><p>3,4-Methylenedioxymethamphetamine (MDMA), a synthetic psychoactive amphetamine derivative widely abused as the recreational drug “ecstasy,” is associated with oxidative stress–mediated cardiotoxicity and hematological disturbances. Despite documented antioxidant properties of quercetin and vitamin E individually, limited evidence exists regarding their combined protective efficacy against MDMA-induced cardiovascular dysfunction. This study evaluated the combined and complementary effects of quercetin and vitamin E on cardiac, hematological, lipid, and electrocardiographic alterations induced by MDMA in adult male Wistar rats. Thirty-five male Wistar rats (10–12 weeks old) were randomized into seven groups (n = 5 per group): Control, MDMA only (10 mg/kg/day), QUE only (50 mg/kg/day), VE only (100 mg/kg/day), MDMA + QUE, MDMA + VE, and MDMA + QUE + VE. All treatments were administered orally for 60 days. Parameters assessed include: cardiac injury markers (troponin I, LDH, CK-NAC), oxidative stress (MDA, SOD, CAT, GSH), inflammatory mediators (TNF-α, IL-1β, MPO), hematological parameters (RBC, WBC, platelets, and blood indices parameters), lipid profile (TC, TG, HDL, LDL), and myocardial histopathology. MDMA alone significantly elevated MDA, TNF-α, IL-1β, MPO, troponin I, LDH, CK-NAC, induced dyslipidemia, and caused pronounced myocardial degeneration. Neither QUE nor VE treatment alone altered baseline parameters, but each markedly attenuated MDMA-induced oxidative stress, inflammation, enzyme release, lipid abnormalities, and histological damage. The combined QUE + VE regimen produced the most comprehensive protection, nearly restoring redox homeostasis, normalizing inflammatory and injury markers, improving lipid profiles, and preserving myocardial architecture. Hematological disruptions from MDMA were also partially corrected by both antioxidants, with the greatest improvement in the combination group. Quercetin and vitamin E confer significant cardio-protective and hematological benefits against MDMA toxicity in rats. Their combined use achieves superior mitigation of oxidative stress, inflammation, lipid derangements, and myocardial injury, suggesting potential for adjunctive therapy in MDMA-related cardiotoxicity.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147778282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mask slipped: wakeable nociceptors express OSMR/SST.","authors":"Michael J M Fischer, Peter W Reeh","doi":"10.1007/s00424-026-03172-1","DOIUrl":"10.1007/s00424-026-03172-1","url":null,"abstract":"","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Active bile acid metabolism could contribute to muscle preservation in hibernating bears via the TGR5 pathway.","authors":"Reiko Nakao, Lydie Humbert, Isabelle Chery, Guillemette Gauquelin-Koch, Jonas Kindberg, Andrea L Miller, Alexandra Thiel, Etienne Lefai, Stéphane Blanc, Dominique Rainteau, Fabrice Bertile","doi":"10.1007/s00424-026-03171-2","DOIUrl":"10.1007/s00424-026-03171-2","url":null,"abstract":"<p><p>Hibernation is an adaptive strategy that enables certain mammals to survive prolonged periods of starvation and physical inactivity, while maintaining muscle mass. Although some bile acids (BA) have been shown to regulate proteostasis in cell models, their possible role during hibernation has not yet been examined in detail. In the present study, we comprehensively compared serum and feces BA profiles in brown bears (Ursus arctos) during hibernation and the active season and examined bear muscle expression levels of main actors in the BA-mediated signaling pathways and bear microbiota composition. Total serum BA concentration was significantly reduced in hibernating bears; however, the ratio of concentrations of secondary BA to primary BA was higher during hibernation. This indicates that BA metabolism remains active during hibernation, the mechanisms of which we were able to link to both hepatic pathways (transcriptomics) and bear microbiota. Nevertheless, we noted a drastic increase in taurolithocholic acid (TLCA) levels in hibernating bears. Analysis of BA signaling pathways in bear muscle enabled us to show that the BA/TGR5 axis appears to be maintained, presumably to help maintain mitochondrial biogenesis and preserve muscle cell differentiation capacity. This study investigates and suggests potential new mechanisms for the preservation of skeletal muscle during hibernation, which builds the foundation for the development of future treatments for muscle atrophy in humans.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-sensitive and insensitive endocrine responses and infradian changes while trekking in the Himalayas.","authors":"Danilo Bondi, Sofia Bonan, Simone Cantarelli, Francesca Ietta, Ilenia Casini, Alberto Taverna, Riccardo Rua, Maria Teresa Guagnano, Arcangelo Barbonetti, Suwas Bhandari, Ashish Shrestha, Anna Maria Aloisi, Vittore Verratti","doi":"10.1007/s00424-026-03166-z","DOIUrl":"10.1007/s00424-026-03166-z","url":null,"abstract":"<p><p>Various studies have explored the effects of altitude hypoxia on hormonal changes. However, most research has been conducted on small samples and focused solely on male subjects. This project aimed to examine the effects of high-altitude trekking on the hypothalamic-pituitary-gonadal axis and the hormonal stress response, with particular attention to potential gender differences in hormonal fluctuations. A Himalayan expedition was conducted with 21 volunteers (12 men, 9 women), aged 43 ± 15 years, with a BMI of 24.2 ± 3.70 kg/m². Participants took a 250 mg pill of acetazolamide once daily. Blood samples were collected before, during, and after the ascent to a Pyramid Laboratory - Observatory (altitude approximately 5,000 m above sea level). Five females were premenopausal, all in the follicular phase of their menstrual cycle. A longer cycle duration was observed in all of them in response to the high-altitude expedition. Gonadotropin levels remained unchanged in both sexes. Differential trends according to sex emerged for: 17β-estradiol, as females showed a decrease from low to high altitude, while males’ reductions were delayed; prolactin, whose decline at high altitude was more pronounced in females; progesterone, as males exhibited higher values at high altitude than at low altitude, whereas the overall trend was flat in females. The dysregulation of the endocrine system at high altitude is subclinical and reversible in both sexes, at least up to 5,000 m a.s.l. The significant prolongation of the menstrual cycle in response to hypoxia warrants further detailed analyses.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147634280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of T-type voltage-dependent Ca²⁺ channels in activated hepatic stellate cells promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis.","authors":"Naoki Kawata, Rubii Kondo, Mizuki Hashizume, Yoshiaki Suzuki, Hisao Yamamura","doi":"10.1007/s00424-026-03164-1","DOIUrl":"10.1007/s00424-026-03164-1","url":null,"abstract":"<p><p>Activation of hepatic stellate cells (HSCs) is a pivotal event in the development of liver fibrosis, a pathological process that precedes cirrhosis and hepatocellular carcinoma and for which effective therapies remain limited. The molecular mechanisms underlying HSC activation, particularly the ion channels that regulate cytosolic Ca²⁺ signaling that promote fibrogenesis, remain incompletely understood. In this study, the expression and functional roles of Ca²⁺ channels in human and mouse HSCs were investigated using quantitative real-time PCR, Western blotting, whole-cell patch-clamp electrophysiology, Ca2+ imaging, and histological analyses. RNA sequencing of human HSCs revealed upregulation of CaV3.2 transcripts upon activation. In activated human HSCs (LX-2 cells), CaV3.2 protein was detected, and transient inward currents sensitive to the T-type voltage-dependent Ca²⁺ channel (T-VDCC) blocker Z944 were recorded. Z944 concentration-dependently reduced both resting cytosolic Ca2+ concentration ([Ca2+]cyt) and mRNA levels of activation markers (ACTA2 and COL3A1) in LX-2 cells. In mouse HSCs, CaV3.1 and CaV3.2 mRNA and protein expression increased during activation and were accompanied by Z944-sensitive inward currents. Among T-VDCC isoforms, CaV3.2 was identified as the predominant contributor to both T-type Ca²⁺ currents and resting [Ca2+]cyt. In a mouse model of metabolic dysfunction-associated steatohepatitis (MASH), CaV3.2 expression was selectively elevated in HSCs. Notably, administration of Z944 significantly attenuated MASH-associated liver fibrosis compared with controls. Collectively, these findings demonstrate that CaV3.2 expression and activity are upregulated during HSC activation, resulting in enhanced cytosolic Ca²⁺ signaling and fibrogenic responses. CaV3.2 may therefore represent a potential therapeutic target for liver fibrosis.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathophysiology of homocysteine: insights into ion channel dysfunction.","authors":"Nikola Chmúrčiaková, Robin N Stringer, Leoš Cmarko, Alzbeta Filipova, Lubica Lacinova, Norbert Weiss","doi":"10.1007/s00424-026-03165-0","DOIUrl":"10.1007/s00424-026-03165-0","url":null,"abstract":"<p><p>Homocysteine is a non-proteinogenic amino acid formed during the metabolism of methionine to cysteine and plays a critical role in maintaining cellular homeostasis. Although multiple enzymatic pathways tightly regulate homocysteine levels, their dysfunction can lead to elevated circulating homocysteine, which is recognized as a risk factor for various cardiovascular and neurological disorders. While most evidence linking homocysteine to specific pathologies comes from observational studies, emerging data suggest that dysregulation of ion channels may be an important underlying mechanism. In this review, we summarize the effects of homocysteine on the expression and function of key ion channel families including calcium, sodium, and potassium channels, and discuss their potential pathophysiological implications.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of elevated phosphate on the kidney - damaging the gatekeeper.","authors":"Tanecia Mitchell, Vivek Verma, Abul Fajol, Christian Faul","doi":"10.1007/s00424-026-03160-5","DOIUrl":"10.1007/s00424-026-03160-5","url":null,"abstract":"<p><p>The kidney is a major regulator of phosphate metabolism. The body can lower systemic phosphate levels by increasing renal phosphate excretion, and kidney injury results in elevated serum phosphate concentrations (hyperphosphatemia). Chronic kidney disease (CKD) is associated with various organ injuries, including vascular calcification and cardiovascular disease, where hyperphosphatemia acts as a pathologic driver. Here we discuss hyperphosphatemia not as a consequence of kidney disease but as a potential contributor to kidney damage. We describe how increases in renal tubular phosphate levels (hyperphosphaturia), rather than hyperphosphatemia contribute to kidney injury in CKD. Tubular phosphate can form microcrystals with calcium which damages renal epithelial cells, induces fibrosis and inflammation, and causes parenchymal calcification. Calcium phosphate microcrystals can grow and form larger deposits in the renal collecting system, and potentially contribute to the formation of kidney stones. Therefore, hyperphosphaturia might not only contribute to kidney damage in CKD, but could also cause kidney injury in genetic diseases with reduced renal phosphate uptake. Finally, since high dietary phosphate intake increases renal phosphate excretion, we discuss if prolonged phosphate loading in the absence of CKD can induce kidney damage. We propose that a better understanding of the pathologic actions of phosphate on the kidney will help to identify novel therapeutic strategies to prevent renal injury and disease progression in patients with CKD and in other renal conditions, such as kidney stone formation. Lowering dietary phosphate intake might not only have reno-protective effects in patients with pre-existing kidney damage but also in healthy individuals.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13033467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}