Pflugers Archiv : European journal of physiology最新文献

{"title":"Acid-sensing ion channels in the vasculature: emerging roles in systemic and pulmonary circulations.","authors":"Nikki L Jernigan","doi":"10.1007/s00424-026-03196-7","DOIUrl":"10.1007/s00424-026-03196-7","url":null,"abstract":"<p><p>Acid-sensing ion channels (ASICs) are proton-gated members of the degenerin/epithelial sodium channel family that are emerging as multifaceted regulators of cardiovascular function. ASICs expressed in baroreceptor, cardiac, and skeletal muscle afferents contribute to reflex control of blood pressure, cardiac function, and sympathetic outflow. In vascular smooth muscle and endothelial cells, ASICs integrate mechanical, metabolic, and humoral signals to regulate vascular tone. In the systemic circulation, ASIC2 contributes to pressure-dependent vasoconstriction of renal and cerebral arteries, supporting blood flow autoregulation and protection against organ injury. In contrast, ASIC1a promotes vasodilation, contributing to nitric oxide-dependent dilation in the cerebral arteries and to endothelium-dependent hyperpolarization and vasodilation in mesenteric arteries. In the pulmonary vascular smooth muscle cells, ASIC1a plays a central role in acute hypoxic- and receptor-mediated vasoconstriction, a role that becomes increasingly important in chronic hypoxia-induced pulmonary hypertension. Under these conditions, metabolic reprogramming drives extracellular acidification and enhances ASIC1a trafficking to the plasma membrane, promoting sustained depolarization, augmented store-operated calcium entry, and a hyperproliferative, apoptosis-resistant smooth muscle phenotype. ASIC1a additionally regulates mitochondrial homeostasis by modulating mitochondrial membrane potential, redox balance, and apoptotic susceptibility. Chronic hypoxia redistributes ASIC1a from mitochondria to the plasma membrane, leading to mitochondrial dysfunction and cell survival signaling, key features of pulmonary vascular disease. This review summarizes current understanding of ASIC function in the systemic and pulmonary vasculature and highlights non-proton-mediated signaling mechanisms, emerging mitochondria-specific mechanisms, sex-related differences, and therapeutic opportunities and challenges in targeting ASIC-dependent signaling pathways in vascular disease.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 8","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13357609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430862","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":"DuBois-Reymond prize lecture 2024: Multi-neuron patch-clamp to uncover the neuronal and synaptic physiology in the human neocortex.","authors":"Yangfan Peng, Franz Xaver Mittermaier","doi":"10.1007/s00424-026-03176-x","DOIUrl":"10.1007/s00424-026-03176-x","url":null,"abstract":"<p><p>The physiology of neurons and synapses determines how networks in the brain process information. While these properties are well described in rodents, they are less well established for the human brain. Increasing availability of surgically resected human brain tissue, together with advances in electrophysiology, has enabled new insights into species-specific differences of the human cortical microcircuit. This review highlights recent progress in the physiology of layer 2 and 3 pyramidal neurons of the human temporal cortex, focusing on the multi-neuron patch-clamp approach. Methodological developments such as automated pipette cleaning now allow large-scale mapping of cellular electrophysiology and synaptic connectivity in human cortex. This approach reveals substantial functional heterogeneity among layer 2 and 3 pyramidal neurons with distinct intrinsic properties, morphology, and connectivity patterns. Complex network analyses further uncover human-specific properties, such as a directed network topology with random reciprocity and a decoupling of synaptic strength from connectivity. Network simulations suggest that these wiring patterns expand the computational capacity of cortical microcircuits. Together, these studies showcase the potential of multipatch recordings to bridge rodent and human neurophysiology and to establish an empirical basis for how cellular and synaptic diversity shapes human cortical microcircuits.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148423137","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":"A conceptual review of intracellular pH as a regulator of the adenosine-L-arginine-nitric oxide (ALANO) axis in human fetoplacental endothelial dysfunction in gestational diabetes mellitus.","authors":"Gonzalo Fuentes, Paola Valero, Marcelo Cornejo, Marco A Ramírez, Katherin Silva, Luis Sobrevia","doi":"10.1007/s00424-026-03193-w","DOIUrl":"10.1007/s00424-026-03193-w","url":null,"abstract":"<p><p>This conceptual review provides a synthesising narrative of the interdependent regulation of intracellular pH (pHi), nitric oxide (NO), and adenosine-the pHi-NO-adenosine triad-in fetoplacental endothelial dysfunction associated with gestational diabetes mellitus (GDM). GDM is associated with fetoplacental endothelial dysfunction, involving altered nitric oxide (NO) synthesis, reduced adenosine uptake, and dysregulated intracellular pH (pHi). Human umbilical vein endothelial cells (HUVECs) from GDM pregnancies exhibit increased endothelial NO synthase activity and decreased adenosine transport via human equilibrative nucleoside transporters, processes modulated by NO and pHi. These changes converge in the ALANO (Adenosine/L-Arginine/Nitric Oxide) signalling pathway, which enhances NO synthesis through increased L-arginine uptake. Importantly, similar mechanisms are observed in both macrovascular and microvascular endothelial cells, suggesting widespread placental vascular involvement. Maternal pre-pregnancy body mass index stratification reveals further heterogeneity in these responses. Disruptions in this signalling triad, i.e. NO, adenosine, and pHi, may impair placental perfusion, nutrient delivery, and fetal development, with potential long-term cardiometabolic consequences. Understanding these interrelated mechanisms provides a framework for targeted interventions in GDM, emphasizing the need for personalized approaches in maternal-foetal medicine.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148423112","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":"Repeated aluminum ingestion alters human intestinal structure: focus on advanced 3D tissue models.","authors":"Giulia De Negri Atanasio, Lorenzo Dondero, Francesca Tardanico, Giorgia Allaria, Erica Lertora, Giacomo Rosa, Chiara Barisione, Caterina Ivaldo, Francesca Rispo, Tommaso Filippini, Ilaria Demori, Sara Ferrando, Maria Cristina Gagliani, Katia Cortese, Mario Passalacqua, Jan Markus, Silvia Letasiova, Elena Grasselli","doi":"10.1007/s00424-026-03191-y","DOIUrl":"10.1007/s00424-026-03191-y","url":null,"abstract":"<p><p>Aluminum (Al³⁺) is a widespread environmental metal with potential effects on the intestinal epithelium. In this study, we evaluated the impact of dietary concentrations of aluminum on barrier integrity, histological organization, and gene expression in a 3D human intestinal tissue model. Tissues were exposed to increasing concentrations of aluminum (0, 5, 20, and 50 ppm) for 12 days to mimic environmental chronic exposure through ingestion. Transepithelial electrical resistance (TEER) measurements revealed a significant decrease only at the highest dose (50 ppm) on day 12, indicating a damage to the epithelial permeability. This was supported by a marked downregulation of OCLN and CLDN-5 expression, key genes involved in tight junction integrity. Aluminum permeation across the tissue was confirmed via Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES), indicating dose-dependent penetration. Furthermore, gene expression analysis showed significant upregulation of MT-1E and MT-2 A (markers of cellular response to metal exposure) while MT-1 A remained unchanged. The present data demonstrate that repeated exposure to 50 ppm of Al3+ impacts intestinal barrier function and alters the tissue organization in the human intestinal epithelium.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148412619","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":"Expression of protein kinase A catalytic subunits in healthy and diseased mouse kidneys.","authors":"Sally Fuchs, Michael Majer, Yuliang Ma, Manuela Harloff, Susan Taylor, Jens Schlossmann","doi":"10.1007/s00424-026-03190-z","DOIUrl":"10.1007/s00424-026-03190-z","url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is characterized by a decline in renal function resulting from hyperglycaemia and is often requiring dialysis or renal transplantation. Yet, the signalling events causing DN and the effective treatment options are poorly understood. Changes in the signalling of cyclic nucleotides and their regulated kinases are hypothesized to be involved in its development. Protein kinase A (PKA) signalling pathways are known to modulate extracellular matrix metabolism and exert antifibrotic effects. Multiple isoforms of PKA regulatory and catalytic subunits exist, leading to functional specificities of the kinase arising from different combinations of these isoforms. However, localization of the specific PKA subunits, as well as other signalling proteins involved in this pathway, still need to be explored comprehensively. To gain an overview about PKA distribution, kidneys were analysed by immunohistochemistry and stained for different PKA subunits. Type 1 diabetes was induced by streptozotocin in wildtype (WT) and endothelial NOS knockout (eNOS-KO) mice. The catalytic subunit expression was quantified and compared between healthy and diabetic kidneys. Analysis of expression patterns of the PKA catalytic subunits Cα and Cβ reveal differences across segments of the kidney and in intracellular localization. Cα exhibited ubiquitous expression in all renal cell types. In contrast, Cβ only shows a high expression in proximal tubules, while its expression in other segments is comparatively weak. No significant changes in Cα or Cβ expression are detectable in diabetic mice or eNOS-KO mice compared to WT mice.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13303448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148331865","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":"Localization of O₂‑sensing ADO‑RGS pathway components in mouse and human kidneys under normoxia, hypoxia and renal fibrosis.","authors":"Bkm Firmke, A-L Forst, C Daniel, G Schley, Kae Broeker","doi":"10.1007/s00424-026-03188-7","DOIUrl":"10.1007/s00424-026-03188-7","url":null,"abstract":"<p><p>Cellular adaptation to hypoxia is essential for maintaining function and survival. While most hypoxic responss are mediated by hypoxia‑inducible factor signaling, the oxygen‑dependent ADO-RGS (2‑Aminoethanethiol-Dioxygenase-Regulator of G‑Protein Signaling) pathway has recently been implicated in oxygen‑sensitive regulation of G‑protein signaling. The kidneys are particularly vulnerable to hypoxia, a major contributor to chronic kidney disease. Because a systematic characterization of ADO and its RGS substrates across renal cell types is lacking, this study examined their spatial expression patterns in mouse and human kidneys under (patho)physiological conditions. Ado and Rgs4, Rgs5, and Rgs16 expression was mapped in mouse kidney sections under normoxic, hypoxic, and fibrotic conditions using RNAscope™, complemented by RT‑qPCR. Mouse data were compared with ADO-RGS expression patterns in human biopsies. Ado expression was uniform across renal regions, cell types, and conditions. Besides its baseline presence in vascular cells, Rgs4 showed strong induction in cortical and outer medullary fibroblasts during anemia. It was also upregulated in fibroblasts and proximal tubules within fibrotic lesions. Rgs5 was highly expressed in vascular structures and demonstrated hypoxia‑induced upregulation in medullary fibroblasts and vasa recta, with moderate induction under fibrotic conditions. Tubular epithelial expression also occurred during fibrosis. Rgs16 was mostly expressed in Pdgfrb⁺ interstitial cells in fibrotic kidneys. Human kidney-disease biopsies also displayed distinct RGS4 and RGS5 expression patterns. Overall, these findings suggest that while ADO is consistently present, the functional impact of ADO-RGS signaling may be driven by dynamic, cell‑type‑specific regulation of RGS genes during acute and chronic hypoxic stress.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13294159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148318570","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":"Inhibition of (interstitial) P2Y₆ receptors attenuates fibrosis progression.","authors":"Lena Marie Süß, Anna Petzendorfer, Minh Linh Tran, Bettina Firmke, Anja Süß, Richard Warth, Katharina Anna-Elisabeth Broeker, Anna-Lena Forst","doi":"10.1007/s00424-026-03187-8","DOIUrl":"10.1007/s00424-026-03187-8","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) affects over 850 million people worldwide and is characterized by progressive renal fibrosis driven by activated interstitial fibroblasts. Signaling by extracellular nucleotides and P2 receptors plays an important role in renal pathophysiology, yet its contribution to fibroblast activation and fibrosis remains poorly understood. Here, we investigated the expression and function of G_q/11-coupled P2Y receptors in renal interstitial fibroblasts and their involvement in experimental kidney fibrosis. Using highly selective RNA in situ hybridization, we detected P2Y₁ (P2ry1) and P2Y₆ (P2ry6) receptor expression in interstitial fibroblasts. Notably, P2Y₆ expression was markedly upregulated in several experimental mouse models of renal fibrosis. Functional assays in primary cultured renal fibroblasts confirmed G_q/11-coupled P2Y receptor activity, as evidenced by transient intracellular Ca²⁺ elevations upon nucleotide stimulation. Primary cultured renal fibroblasts exhibited enhanced migration in response to extracellular uridine diphosphate (UDP). To assess the contribution of interstitial P2Y₆ receptors to fibrosis progression, we employed an adenine-induced nephropathy model with or without the selective P2Y₆ antagonist MRS2578. Pharmacological inhibition of P2Y₆ significantly reduced the mRNA expression of the myofibroblast marker α-smooth muscle actin and collagen I. Collectively, these findings suggest that upregulated P2Y₆ receptor signaling promotes the transition of resident interstitial cells into myofibroblasts during renal fibrosis, likely by modulating fibroblast migration. Inhibition of P2Y₆ signaling could represent a new strategy for reducing excessive renal fibrosis.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13272249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265711","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":"Cholesterol-depleting dextrin depolarizes sarcolemma: the contribution of sodium / calcium channels and membrane integrity.","authors":"Arina D Tupitsyna, Nikita S Fedorov, Venera R Khabibrakhmanova, Julia N Valitova, Farida V Minibayeva, Artem I Malomouzh, Alexey M Petrov","doi":"10.1007/s00424-026-03189-6","DOIUrl":"10.1007/s00424-026-03189-6","url":null,"abstract":"<p><p>Skeletal muscle function is critically dependent on the metabolism of cholesterol and its sarcolemmal levels. Decreased cholesterol availability is associated with various pathological conditions, causing muscle weakness. Here, we tested the hypothesis that a reduction in cholesterol content can affect the resting membrane potential, an essential parameter for membrane transport and electro-mechanical coupling in fibers of mouse diaphragm, the main respiratory muscle. 20-min exposure to methyl-β-cyclodextrin (MβCD) concentration-dependently reduced the level of muscle cholesterol. This effect was more pronounced in surface muscle fibers, where MβCD at a concentration of 30 mM decreased cholesterol content by 40% and depolarized the membranes by approximately 20 mV in both junctional and extrajunctional regions of the muscle fibers. MβCD-induced depolarization was inhibited by approximately 20%, 19%, 34%, and 42% with GIIIB µ-conotoxin (Nav1.4 channel inhibitor), nitrendipine (L-type Ca²⁺ channel blocker), A-784,168 (TRPV1 antagonist), and ruthenium red (nonselective blocker of Ca²⁺ channels), respectively. MβCD increased sarcoplasmic Ca²⁺ levels at resting conditions and interfered with sarcolemma integrity in some muscle fibers. Finally, 30 mM MβCD aggravated muscle fatigue and disrupted the recovery of the contraction force at direct stimulation. These results indicate that plasma membrane cholesterol is essential for the maintenance of resting membrane potential due to restricting the activity of Ca²⁺ (TRPV1, Cav1.1) and Na⁺ (Nav1.4) channels as well as keeping membrane integrity in skeletal muscle. Cholesterol depletion-induced membrane depolarization might be a potential reason for muscle weakness.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265684","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":"Renal NHE3 is required to limit hypokalemia and metabolic acidosis during dietary potassium deficiency.","authors":"Jennifer Nogueira Coelho, Natalie Hayslip, Rebecca Zoe Halter, Sima Al-Masri, Adriana C C Girardi, Maryam Tahmasbi, Jessica A Dominguez Rieg, Timo Rieg","doi":"10.1007/s00424-026-03178-9","DOIUrl":"10.1007/s00424-026-03178-9","url":null,"abstract":"<p><p>The sodium-hydrogen exchanger isoform 3 (NHE3) is a critical mediator of proximal tubule and thick ascending limb Na⁺ reabsorption and H⁺/NH₄⁺ secretion, yet the physiological implications of its upregulation during low K⁺ intake remain poorly understood. We hypothesized that renal NHE3 is important for the acid-base response during K⁺ depletion. To test this, we utilized kidney-specific NHE3 knockout (NHE3^KS-KO) mice. Following 10 days of a K⁺-deficient diet (< 30 ppm), NHE3^KS-KO mice exhibited exacerbated hypokalemia compared to control mice, despite near complete elimination of urinary K⁺ excretion and comparable levels of ROMK and BKα protein abundance in both genotypes. Control and NHE3^KS-KO mice developed hypernatremia secondary to a urinary concentrating defect; however, this was associated with a ~ 2-fold greater fluid intake in NHE3^KS-KO mice. These effects occurred without changes in glomerular filtration rate. Both genotypes developed metabolic acidosis, which was significantly more severe in NHE3^KS-KO mice. This exacerbated acidosis correlated with a ~ 60% lower mRNA expression of glutamine synthetase and a lower urinary NH₄⁺/creatinine ratio. Furthermore, early histopathological signs of hypokalemic nephropathy were observed exclusively in some of the NHE3^KS-KO mice. Our findings demonstrate that renal NHE3 attenuates the severity of hypokalemia and metabolic acidosis during K⁺ restriction, possibly via NH₄⁺ formation/transport, which might accelerate the development of hypokalemic nephropathy.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13246878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204988","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":"Xenin-25 improves indomethacin-induced acute gastric injury in rats.","authors":"Sevil Arabacı Tamer, Gamze Güney Eskiler, Feriha Ercan, Berrak Ç Yeğen","doi":"10.1007/s00424-026-03186-9","DOIUrl":"10.1007/s00424-026-03186-9","url":null,"abstract":"<p><p>Putative gastroprotective effects of xenin-25 were investigated in an indomethacin-induced acute ulcer model. Male Sprague-Dawley rats were randomly assigned to control, saline-treated ulcer, xenin-25-treated ulcer groups. Gastric ulcer was induced with indomethacin (25 mg/kg, subcutaneously) and xenin-25 (0.2, 2, 20 µg/kg) or saline was given subcutaneously immediately after and at 2 h following indomethacin injection. In order to investigate whether the effects of xenin-25 depend on vagal afferent fibres, two additional groups underwent vagal afferent denervation (VAD) by bilateral perivagal capsaicin application (1%). Following a 2-week recovery, rats with VAD were induced with ulcer, after which they received either xenin-25 (2 µg/kg) or saline. All animals were sacrificed 4 h after ulcer induction, and gastric tissues were collected for biochemical, molecular, and histopathological analyses. Indomethacin administration resulted in significant increases in malondialdehyde and myeloperoxidase levels, accompanied by glutathione depletion, upregulation of nuclear factor-κB and Bax, and downregulation of Bcl2 expression. Xenin-25 treatment markedly attenuated oxidative stress, inflammatory responses, apoptotic markers, and histopathological gastric damage. Xenin-25-induced reductions in lesion length, malondialdehyde, and myeloperoxidase levels were abolished in VAD rats, but all the other anti-inflammatory and anti-apoptotic effects of Xenin-25 were preserved even in the absence of vagal afferents. Xenin-25 exhibits gastroprotective effects in acute gastric injury through its antioxidant, anti-inflammatory, and anti-apoptotic actions, which are independent of vagal afferent fibers.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13246553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205023","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}