Pflugers Archiv : European journal of physiology最新文献

{"title":"Novel neural pathways targeted by GLP-1R agonists and bariatric surgery.","authors":"Mohammed K Hankir, Thomas A Lutz","doi":"10.1007/s00424-024-03047-3","DOIUrl":"10.1007/s00424-024-03047-3","url":null,"abstract":"<p><p>The glucagon-like peptide 1 receptor (GLP-1R) agonist semaglutide has revolutionized the treatment of obesity, with other gut hormone-based drugs lined up that show even greater weight-lowering ability in obese patients. Nevertheless, bariatric surgery remains the mainstay treatment for severe obesity and achieves unparalleled weight loss that generally stands the test of time. While their underlying mechanisms of action remain incompletely understood, it is clear that the common denominator between GLP-1R agonists and bariatric surgery is that they suppress food intake by targeting the brain. In this Review, we highlight recent preclinical studies using contemporary neuroscientific techniques that provide novel concepts in the neural control of food intake and body weight with reference to endogenous GLP-1, GLP-1R agonists, and bariatric surgery. We start in the periphery with vagal, intestinofugal, and spinal sensory nerves and then progress through the brainstem up to the hypothalamus and finish at non-canonical brain feeding centers such as the zona incerta and lateral septum. Further defining the commonalities and differences between GLP-1R agonists and bariatric surgery in terms of how they target the brain may not only help bridge the gap between pharmacological and surgical interventions for weight loss but also provide a neural basis for their combined use when each individually fails.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"171-185"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791771","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":"Estrogen hindrance escalates inflammation and neurodegeneration in the hippocampal regions of collagen-induced arthritis female Sprague-Dawley rats.","authors":"Zuo Hao Lee, Wong Siew Tung, Kabileshvaran A/L Jana Santhiran, Huma Shahzad, Nelli Giribabu, Naguib Salleh","doi":"10.1007/s00424-024-03032-w","DOIUrl":"10.1007/s00424-024-03032-w","url":null,"abstract":"<p><p>This study aims to investigate the effect of estrogen hindrance, i.e., menopause in women for instance with rheumatoid arthritis on the brain hippocampal region by using collagen-induced arthritis (CIA) female rat model (RA). CIA was induced in female rats by injecting bovine type II collagen and incomplete Freund's adjuvant. Estrogen receptor antagonist, fulvestrant (Ful), was given to RA rats to create estrogen hindrance. Control (C) and RA rats were injected with saline and DMSO, respectively, while RA + Ful rats received a 7-day fulvestrant injection. Following experiment completion, rats were sacrificed, and brains were harvested. Brains were stained with H&E and cresyl violet staining and morphological changes in the hippocampus were identified. Additionally, oxidative stress, inflammatory, and apoptosis markers' levels in the hippocampus were analyzed by qPCR, ELISA, and immunohistochemistry techniques. RA + Ful rats showed neuronal atrophy and reduced neurogenesis in the hippocampal regions. NOX4, NF-κB, IL-1β, IL-6, TNF-α, IKK-β, and Bax protein expression levels in the hippocampus were increased, whereas hippocampal Bcl-2, caspase-3, caspase-9, and IGF-1R protein expression levels were decreased. Furthermore, RA + Ful rats had lower levels of antioxidants PON-1 and catalase in the hippocampal regions. The changes in these molecular markers were statistically significant when compared to RA rats without Ful treatment (p < 0.05). Estrogen hindrance exaggerated oxidative stress, inflammation, and apoptosis which resulted in neuronal degeneration in the hippocampal regions in rheumatoid arthritis.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"317-332"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682405","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":"Fatiguing high-intensity intermittent exercise depresses maximal Na⁺-K⁺-ATPase activity in human skeletal muscle assessed using a novel NADH-coupled assay.","authors":"Jeppe F Vigh-Larsen, Sara M Frangos, Kristian Overgaard, Graham P Holloway, Magni Mohr","doi":"10.1007/s00424-024-03036-6","DOIUrl":"10.1007/s00424-024-03036-6","url":null,"abstract":"<p><p>The Na⁺-K⁺-ATPase is a critical regulator of ion homeostasis during contraction, buffering interstitial K⁺ accumulation, which is linked to muscle fatigue during intense exercise. Within this context, we adopted a recently reported methodology to examine exercise-induced alterations in maximal Na⁺-K⁺-ATPase activity. Eighteen trained healthy young males completed a repeated high-intensity cycling protocol consisting of three periods (EX1-EX3) of intermittent exercise. Each period comprised 10 × 45-s cycling at ~ 105% W_max and a repeated sprint test. Muscle biopsies were sampled at baseline and after EX3 for determination of maximal in vitro Na⁺-K⁺-ATPase activity. Blood was drawn after each period and in association with a 2-min cycling test at a standardized high intensity (~ 90% W_max) performed before and after the session to assess plasma K⁺ accumulation. Further, a 5-h recovery period with the ingestion of carbohydrate or placebo supplementation was implemented to explore potential effects of carbohydrate availability before sampling a final biopsy and repeating all tests. A ~ 12% reduction in maximal Na⁺-K⁺-ATPase activity was demonstrated following EX3 compared to baseline (25.2 ± 3.9 vs. 22.4 ± 4.8 μmol·min^-1·g^-1 protein, P = 0.039), which was sustained at the recovery time point (~ 15% decrease compared to baseline to 21.6 ± 5.9 μmol·min^-1·g^-1 protein, P = 0.008). No significant effect of carbohydrate supplementation was observed on maximal Na⁺-K⁺-ATPase activity after recovery (P = 0.078). In conclusion, we demonstrate an exercise-induced depression of maximal Na⁺-K⁺-ATPase activity following high-intensity intermittent exercise, which was sustained during a 5-h recovery period and unrelated to carbohydrate availability under the present experimental conditions. This was shown using a novel NADH coupled assay and confirms previous findings using other methodological approaches.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"303-316"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623480","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":"Spatio-temporal segregation between sensory relay and swallowing pre-motor population activities by optical imaging in the rat nucleus of the solitary tract.","authors":"Shinya Fuse, Yoichiro Sugiyama, Rishi R Dhingra, Shigeru Hirano, Mathias Dutschmann, Yasumasa Okada, Yoshitaka Oku","doi":"10.1007/s00424-025-03065-9","DOIUrl":"https://doi.org/10.1007/s00424-025-03065-9","url":null,"abstract":"<p><p>The nucleus tractus solitarius (NTS) contains neurons that relay sensory swallowing commands information from the oropharyngeal cavity and swallowing premotor neurons of the dorsal swallowing group (DSG). However, the spatio-temporal dynamics of the interplay between the sensory relay and the DSG is not well understood. Here, we employed fluorescence imaging after microinjection of the calcium indicator into the NTS in an arterially perfused brainstem preparation of rat (n = 8) to investigate neuronal population activity in the NTS in response to superior laryngeal nerve (SLN) stimulation. Respiratory and swallowing motor activities were determined by simultaneous recordings of phrenic and vagal nerve activity (PNA, VNA). The analysis of SLN stimulation near the threshold triggering a swallowing allowed us to analyze Ca²⁺ signals related to the sensory relay and the DSG. We show that activation of sensory relay neurons triggers spatially confined Ca²⁺ signals exclusively unilateral to the stimulated SLN at short latencies (114.3 ± 94.4 ms). However, SLN-evoked swallowing triggered Ca²⁺ signals bilaterally at longer latencies (200 ± 145.2 ms) and engaged anatomically distributed DSG activity across the dorsal medulla oblongata. The Ca²⁺ signals originating from the DSG preceded evoked VNA swallow motor bursts, thus the swallowing premotor neurons that drive laryngeal motor pools are located outside the DSG. In conclusion, the study illuminates the spatial-temporal features of sensory-motor integration of swallowing in the NTS and further supports the hypothesis that the NTS harbors swallowing pre-motor neurons that may generate the swallowing motor activity, while first-order pre-motor pools are located outside the DSG.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040911","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":"Epidemiology of metabolic syndrome.","authors":"Iris Pigeot, Wolfgang Ahrens","doi":"10.1007/s00424-024-03051-7","DOIUrl":"https://doi.org/10.1007/s00424-024-03051-7","url":null,"abstract":"<p><p>The global increase of overweight and obesity in children and adults is one of the most prominent public health threats, often accompanied by insulin resistance, hypertension, and dyslipidemia. The simultaneous occurrence of these health problems is referred to as metabolic syndrome. Various criteria have been proposed to define this syndrome, but no general consensus on the specific markers and the respective cut-offs has been achieved yet. As a consequence, it is difficult to assess regional variations and temporal trends and to obtain a comprehensive picture of the global burden of this major health threat. This limitation is most striking in childhood and adolescence, when metabolic parameters change with developmental stage. Obesity and related metabolic disorders develop early in life and then track into adulthood, i.e., the metabolic syndrome seems to originate in the early life course. Thus, it would be important to monitor the trajectories of cardio-metabolic parameters from early on. We will summarize selected key studies to provide a narrative overview of the global epidemiology of the metabolic syndrome while considering the limitations that hinder us to provide a comprehensive full picture of the problem. A particular focus will be given to the situation in children and adolescents and the risk factors impacting on their cardio-metabolic health. This summary will be complemented by key findings of a pan-European children cohort and first results of a large German adult cohort.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040888","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":"Physiological simulation of atrial-ventricular mechanical interaction in male rats during the cardiac cycle.","authors":"Alexandr Balakin, Yuri Protsenko","doi":"10.1007/s00424-024-03015-x","DOIUrl":"10.1007/s00424-024-03015-x","url":null,"abstract":"<p><p>Adequate assessment of the contribution of the different phases of atrial mechanical activity to the value of ejection volume and pressure developed by the ventricle is a complex and important experimental and clinical problem. A new method and an effective algorithm for controlling the interaction of isolated rat right atrial and right ventricular strips during the cardiac cycle were developed and tested in a physiological experiment. The presented functional model is flexible and has the ability to change many parameters (temperature, pacing rate, excitation delay, pre- and afterload levels, transfer length, and force scaling coefficients) to simulate different types of cardiac pathologies. For the first time, the contribution of the duration of the excitation delay of the right ventricular strips to the amount of work performed by the muscles during the cardiac cycle was evaluated. Changes in the onset of atrial systole and the delay in activation of ventricular contraction may lead to a reduction in cardiac stroke volume, which should be considered in the diagnosis and treatment of cardiovascular disease and in resynchronization therapy.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"159-167"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120430","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":"Cellular mechanisms of synchronized rhythmic burst generation in the ventromedial hypothalamus.","authors":"Kamon Iigaya, Hiroshi Onimaru, Keiko Ikeda, Makito Iizuka, Masahiko Izumizaki","doi":"10.1007/s00424-024-03031-x","DOIUrl":"10.1007/s00424-024-03031-x","url":null,"abstract":"<p><p>The ventromedial hypothalamus (VMH) plays an important role in feeding behavior and control of the sympathetic nervous system (SNS). The VMH includes a group of neurons that exhibit strong synchronized rhythmic burst firing (so-called VMH oscillation). This VMH oscillation is glucose inhibited, responsive to feeding-related peptides, and is functionally coupled to outputs of the SNS. However, the details of its rhythm generation and synchronization mechanisms are unknown. In the present study, we investigated cellular mechanisms of VMH oscillation by means of electrophysiological recordings and calcium imaging in juvenile rat slice preparations including the VMH. In the electrophysiological study, we performed membrane potential recording from neurons in the vicinity of pipettes for field potential recording. We found that the rhythmic bursts in the VMH were preserved in low Ca²⁺/high Mg²⁺ synaptic transmission blockade solution. During membrane hyperpolarization by current injection, the action potential was largely inhibited, but fluctuation of the membrane potential remained with a frequency similar to that at resting potential level. The electric VMH oscillation disappeared after application of either a gap junction blocker, carbenoxolone (100 µM), or a persistent sodium channel blocker, riluzole (20 µM). Membrane potentials and input resistances of rhythmic burst neurons in the VMH were not significantly changed during these manipulations. A calcium imaging study revealed that all VMH cells exhibiting synchronized rhythmic activity detected by intracellular calcium increases were silenced following the application of carbenoxolone. These results suggest that VMH oscillation arises from the activation of persistent sodium channels and coupling via gap junctions.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"131-145"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472224","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":"ACE2 and TMPRSS2 in human kidney tissue and urine extracellular vesicles with age, sex, and COVID-19.","authors":"Marie Lykke Bach, Sara Laftih, Jesper K Andresen, Rune M Pedersen, Thomas Emil Andersen, Lone W Madsen, Kirsten Madsen, Gitte R Hinrichs, Rikke Zachar, Per Svenningsen, Lars Lund, Isik S Johansen, Lennart Friis Hansen, Yaseelan Palarasah, Boye L Jensen","doi":"10.1007/s00424-024-03022-y","DOIUrl":"10.1007/s00424-024-03022-y","url":null,"abstract":"<p><p>SARS-CoV-2 virus infects cells by engaging with ACE2 requiring protease TMPRSS2. ACE2 is highly expressed in kidneys. Predictors for severe disease are high age and male sex. We hypothesized that ACE2 and TMPRSS2 proteins are more abundant (1) in males and with increasing age in kidney and (2) in urine and extracellular vesicles (EVs) from male patients with COVID-19 and (3) SARS-CoV-2 is present in urine and EVs during infection. Kidney cortex samples from patients subjected to cancer nephrectomy (male/female; < 50 years/˃75 years, n = 24; ˃80 years, n = 15) were analyzed for ACE2 and TMPRSS2 protein levels. Urine from patients hospitalized with SARS-CoV-2 infection was analyzed for ACE2 and TMPRSS2. uEVs were used for immunoblotting and SARS-CoV-2 mRNA and antigen detection. Tissue ACE2 and TMPRSS2 protein levels did not change with age. ACE2 was not more abundant in male kidneys in any age group. ACE2 protein was associated with proximal tubule apical membranes in cortex. TMPRSS2 was observed predominantly in the medulla. ACE2 was elevated significantly in uEVs and urine from patients with COVID-19 with no sex difference compared with urine from controls w/wo albuminuria. TMPRSS2 was elevated in uEVs from males compared to female. ACE2 and TMPRSS2 did not co-localize in uEVs/apical membranes. SARS-CoV-2 nucleoprotein and mRNA were not detected in urine. Higher kidney ACE2 protein abundance is unlikely to explain higher susceptibility to SARS-CoV-2 infection in males. Kidney tubular cells appear not highly susceptible to SARS-CoV-2 infection. Loss of ACE2 into urine in COVID could impact susceptibility and angiotensin metabolism.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"83-98"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392405","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":"K_2P2.1 channels modulate the pH- and mechanosensitivity of pancreatic stellate cells.","authors":"Micol Rugi, Verena Hofschröer, Zoltán Pethő, Benjamin Soret, Thorsten Loeck, Albrecht Schwab","doi":"10.1007/s00424-024-03021-z","DOIUrl":"10.1007/s00424-024-03021-z","url":null,"abstract":"<p><p>Pancreatic stellate cells (PSCs) are central in the development of acute pancreatitis and tumor fibrosis in pancreatic ductal adenocarcinoma (PDAC). Fibrosis and a unique pH landscape represent characteristic properties of the PDAC microenvironment. Mechanosensitive ion channels are involved in the activation of PSCs. Among these channels, K_2P2.1 has not yet been studied in PSCs. K_2P2.1 channels are pH- and mechanosensitive. We confirmed K_2P2.1 expression in PSCs by RT-qPCR and immunofluorescence. PSCs from K_2P2.1^+/+ and K_2P2.1^-/- mice were studied under conditions mimicking properties of the PDAC microenvironment (acidic extracellular pH (pH_e), ambient pressure elevated by + 100 mmHg). Migration and the cell area were taken as surrogates for PSC activation and evaluated with live cell imaging. pH_e-dependent changes of the membrane potential of PSCs were investigated with DiBAC₄(3), a voltage-sensitive fluorescent dye. We observed a correlation between morphological activation and progressive hyperpolarization of the cells in response to changes in pH_e and pressure. The effect was in part dependent on the expression of K_2P2.1 channels because the membrane potential of K_2P2.1^+/+ PSCs was always more hyperpolarized than that of K_2P2.1^-/- PSCs. Cell migration velocity of K_2P2.1^+/+ cells decreased upon pressure application when cells were kept in an acidic medium (pH_e 6.6). This was not the case in K_2P2.1^-/- PSCs. Taken together, our study highlights the critical role of K_2P2.1 channels in the combined sensing of environmental pressure and pH_e by PSCs and in coordinating cellular morphology with membrane potential dynamics. Thus, K_2P2.1 channels are important mechano-sensors in murine PSCs.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"147-157"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351798","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":"An Editor-in-Chief's farewell.","authors":"Armin Kurtz","doi":"10.1007/s00424-024-03054-4","DOIUrl":"10.1007/s00424-024-03054-4","url":null,"abstract":"","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"1"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812960","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}