Experimental Physiology最新文献

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Mitochondrial transplantation combined with mitoquinone and melatonin: A survival strategy against myocardial reperfusion injury in aged rats.
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-31 DOI: 10.1113/EP092292
Behnaz Mokhtari, Mitra Delkhah, Reza Badalzadeh, Samad Ghaffari
{"title":"Mitochondrial transplantation combined with mitoquinone and melatonin: A survival strategy against myocardial reperfusion injury in aged rats.","authors":"Behnaz Mokhtari, Mitra Delkhah, Reza Badalzadeh, Samad Ghaffari","doi":"10.1113/EP092292","DOIUrl":"https://doi.org/10.1113/EP092292","url":null,"abstract":"<p><p>Myocardial ischaemia-reperfusion (IR) injury poses a severe threat to cardiac health, particularly in the ageing population, where susceptibility to such damage is significantly heightened owing to age-related declines in mitochondrial function, thus highlighting mitochondria as crucial targets for innovative therapies. The aim of this study was to investigate the combined modality therapy involving mitochondrial transplantation and the mitochondrial boosters mitoquinone and melatonin to address myocardial IR injury in aged rats. A total of 54 male Wistar rats, aged 22-24 months, were randomly divided into groups that either received IR injury or not, and were subjected to various treatments, both individually and in combination. Myocardial IR injury was induced by temporarily blocking and reopening the left anterior descending coronary artery. Mitoquinone was given intraperitoneally for 14 days prior to ischaemia, while melatonin and isolated mitochondria were administered intraperitoneally and intramyocardially, respectively, at the onset of reperfusion. Finally, we evaluated changes in haemodynamic indices, creatine kinase-MB levels, mitochondrial function endpoints and the expression of mitochondrial biogenesis genes, including sirtuin 1 (SIRT-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear respiratory factor 2 (NRF-2). The triple therapy enhanced myocardial function, decreased creatine kinase-MB levels and improved mitochondrial function along with the expression of mitochondrial biogenesis genes in aged IR rats. This combined approach elicited significant cardioprotection in comparison to single or dual therapies. The triple therapy provided substantial cardioprotection in aged rat hearts by improving mitochondrial function and biogenesis through enhanced SIRT-1/PGC-1α/NRF-2 profiles, suggesting a promising strategy for mitigating IR injury in elderly patients.</p>","PeriodicalId":12092,"journal":{"name":"Experimental Physiology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751785","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}
引用次数: 0
Exertional heat stress and intestinal barrier injury: Does chronic disease add fuel to the fire?
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-31 DOI: 10.1113/EP092759
Oliver R Gibson, Zachary J McKenna
{"title":"Exertional heat stress and intestinal barrier injury: Does chronic disease add fuel to the fire?","authors":"Oliver R Gibson, Zachary J McKenna","doi":"10.1113/EP092759","DOIUrl":"https://doi.org/10.1113/EP092759","url":null,"abstract":"","PeriodicalId":12092,"journal":{"name":"Experimental Physiology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751782","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}
引用次数: 0
Muscle wasting in cancer cachexia: Mechanisms and the role of exercise.
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-30 DOI: 10.1113/EP092544
Zoe P Libramento, Louisa Tichy, Traci L Parry
{"title":"Muscle wasting in cancer cachexia: Mechanisms and the role of exercise.","authors":"Zoe P Libramento, Louisa Tichy, Traci L Parry","doi":"10.1113/EP092544","DOIUrl":"https://doi.org/10.1113/EP092544","url":null,"abstract":"<p><p>Cancer cachexia (CC) is a multifactorial disease marked by a severe and progressive loss of lean muscle mass and characterized further by inflammation and a negative energy/protein balance, ultimately leading to muscle atrophy and loss of muscle tissue. As a result, patients experiencing cachexia have reduced muscle function and thus less independence and a lower quality of life. CC progresses through stages of increasing severity: pre-cachexia, cachexia and refractory cachexia. Two proposed underlying mechanisms that drive cancer-induced muscle wasting are the autophagy-lysosome and ubiquitin-proteasome systems. An increase in autophagic flux and proteolytic activity leads to atrophy of both cardiac and skeletal muscle, ultimately mediated by tumour or immune-secreted inflammatory cytokines. These pathways occur at a basal level to maintain cellular homeostasis; therefore, it is the overactivation of the pathways that leads to muscle atrophy. Recent evidence demonstrates the ability of aerobic and resistance training to restore these pathways to their basal levels. The mechanism is not yet understood, and more research is needed to determine exactly how exercise influences each pathway. However, exercise has great promise as a therapeutic strategy for CC because of the evidence for it preserving muscle mass and function, and attenuating protein degradative pathways. The extent to which exercise affects the ubiquitin-proteasome and autophagy-lysosome systems is determined by the frequency, intensity and duration of the exercise protocol. As such, an ideal exercise prescription is lacking for individuals with CC.</p>","PeriodicalId":12092,"journal":{"name":"Experimental Physiology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751786","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}
引用次数: 0
Intestinal epithelial injury and inflammation after physical work in temperate and hot environments in older men with hypertension or type 2 diabetes.
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-30 DOI: 10.1113/EP092567
Ben J Lee, Tessa R Flood, Sophie L Russell, James J McCormick, Kelli E King, Naoto Fujii, Tatsuro Amano, Sean Notley, Glen P Kenny
{"title":"Intestinal epithelial injury and inflammation after physical work in temperate and hot environments in older men with hypertension or type 2 diabetes.","authors":"Ben J Lee, Tessa R Flood, Sophie L Russell, James J McCormick, Kelli E King, Naoto Fujii, Tatsuro Amano, Sean Notley, Glen P Kenny","doi":"10.1113/EP092567","DOIUrl":"https://doi.org/10.1113/EP092567","url":null,"abstract":"<p><p>We tested whether older adults with well-controlled type 2 diabetes or hypertension, compared with age-matched adults without chronic disease, exhibit greater intestinal damage, microbial translocation and inflammation during exertional heat stress. Twelve healthy men (age 59 years, SD 4 years), nine with type 2 diabetes (age 60 years, SD 5 years) and nine with hypertension (age 60 years, SD 4 years) walked for 180 min at 200 W/m<sup>2</sup> in temperate conditions (wet-bulb globe temperature 16°C) and high-heat stress conditions (wet-bulb globe temperature 32°C). Serum intestinal fatty acid binding protein (IFABP), plasma soluble cluster of differentiation 14, lipopolysaccharide-binding protein (LBP), interleukin-6 and tumour necrosis factor-alpha were measured pre- and postexercise and after 60 min recovery. Total exercise duration was lower in men with hypertension and diabetes (p ≤ 0.049), but core temperature did not differ. All markers increased more in heat versus temperate conditions (p < 0.002). In the heat, individuals with type 2 diabetes had greater postexercise increases in IFABP [+545 pg/mL (95% confidence interval: 222, 869)] and LBP [+3.64 µg/mL (1.73, 5.56)] relative to healthy control subjects (p < 0.048), but these resolved after recovery. Despite reduced exercise duration, hypertensive individuals showed similar increases in IFABP and LBP to control subjects. Our findings suggest that older workers with well-controlled type 2 diabetes or hypertension might have greater vulnerability to heat-induced gastrointestinal barrier disturbance and downstream inflammatory responses when compared with otherwise healthy, age-matched adults during prolonged exercise in the heat.</p>","PeriodicalId":12092,"journal":{"name":"Experimental Physiology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751783","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}
引用次数: 0
Effects of acute selective cyclooxygenase-2 inhibition on skeletal muscle microvascular oxygenation and exercise tolerance.
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-30 DOI: 10.1113/EP092518
Michael D Belbis, Michael J Holmes, Joseph Yao, Christopher W Kinnick, Christopher K Kargl, Carly Day, Nicole L Noel, Timothy P Gavin, Bruno T Roseguini, Daniel M Hirai
{"title":"Effects of acute selective cyclooxygenase-2 inhibition on skeletal muscle microvascular oxygenation and exercise tolerance.","authors":"Michael D Belbis, Michael J Holmes, Joseph Yao, Christopher W Kinnick, Christopher K Kargl, Carly Day, Nicole L Noel, Timothy P Gavin, Bruno T Roseguini, Daniel M Hirai","doi":"10.1113/EP092518","DOIUrl":"https://doi.org/10.1113/EP092518","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The cyclooxygenase (COX) pathway regulates vascular tone and, therefore, local O&lt;sub&gt;2&lt;/sub&gt; delivery-utilization matching. The two main isoforms, COX-1 and COX-2, may promote opposing effects on contracting muscle O&lt;sub&gt;2&lt;/sub&gt; transport in health by inducing vasoconstriction and vasodilatation, respectively. Whether COX-2 and its main vasodilatory product (prostacyclin, PGI&lt;sub&gt;2&lt;/sub&gt;) modulate microvascular O&lt;sub&gt;2&lt;/sub&gt; transport to skeletal muscle and thus exercise tolerance is unknown. We tested the hypothesis that acute selective COX-2 inhibition (SC2I) would impair cardiorespiratory and skeletal muscle microvascular responses from rest to exercise, thereby reducing exercise tolerance in healthy adults. Twelve individuals participated in a randomized, double-blind, crossover study to receive SC2I (200 mg celecoxib) or placebo (control, CON). Moderate and severe intensity cycling were performed with measurements of heart rate, arterial blood pressure, pulmonary oxygen uptake ( &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${dot V_{{{mathrm{O}}_2}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ), leg muscle microvascular oxygenation ( &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mi&gt;S&lt;/mi&gt; &lt;mrow&gt;&lt;mi&gt;t&lt;/mi&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;/msub&gt; &lt;annotation&gt;${S_{{mathrm{t}}{{mathrm{O}}_2}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ; near-infrared spectroscopy) and time to exhaustion. Leg muscle &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mi&gt;S&lt;/mi&gt; &lt;mrow&gt;&lt;mi&gt;t&lt;/mi&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;/msub&gt; &lt;annotation&gt;${S_{{mathrm{t}}{{mathrm{O}}_2}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; was also assessed during cuff occlusion protocols. SC2I decreased the plasma concentration of the stable PGI&lt;sub&gt;2&lt;/sub&gt; metabolite 6-keto prostaglandin F&lt;sub&gt;1α&lt;/sub&gt; (CON: 203 (54) pg/mL; SC2I: 108 (54) pg/mL; P = 0.002). There was no difference in exercise tolerance (CON: 278 (55) s; SC2I: 298 (75) s), arterial blood pressure, heart rate, pulmonary &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${dot V_{{{mathrm{O}}_2}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; or leg muscle &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mi&gt;S&lt;/mi&gt; &lt;mrow&gt;&lt;mi&gt;t&lt;/mi&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;/msub&gt; &lt;annotation&gt;${S_{{mathrm{t}}{{mathrm{O}}_2}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; from rest to moderate or severe exercise between conditions (P &gt; 0.05 for all). Moreover, there was no significant difference in &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mi&gt;S&lt;/mi&gt; &lt;mrow&gt;&lt;mi&gt;t&lt;/mi&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;/msub&gt; &lt;annotation&gt;${S_{{mathrm{t}}{{mathrm{O}}_2}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; during cuff occlusion protocols between conditions. Contrary to our hypothesis, these data indicate that COX-2 is not obligatory for the regulation of skeletal muscle microvascular oxygenation at rest or during moderate or severe intensity exercise, and therefore does not modulate exercise tolerance in","PeriodicalId":12092,"journal":{"name":"Experimental Physiology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751778","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}
引用次数: 0
Methacholine hyperresponsiveness in mice with house dust mite-induced lung inflammation is not associated with excessive airway constriction ex vivo.
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-28 DOI: 10.1113/EP092522
Andrés Rojas-Ruiz, Magali Boucher, Cyndi Henry, Louis Gélinas, Rosalie Packwood, Percival Graham, Jorge Soliz, Ynuk Bossé
{"title":"Methacholine hyperresponsiveness in mice with house dust mite-induced lung inflammation is not associated with excessive airway constriction ex vivo.","authors":"Andrés Rojas-Ruiz, Magali Boucher, Cyndi Henry, Louis Gélinas, Rosalie Packwood, Percival Graham, Jorge Soliz, Ynuk Bossé","doi":"10.1113/EP092522","DOIUrl":"https://doi.org/10.1113/EP092522","url":null,"abstract":"<p><p>The role of excessive airway constriction in the hyperresponsiveness to nebulized methacholine in mice with experimental asthma is still contentious. Yet, there have been very few studies investigating whether the increased in vivo response to methacholine caused by experimental asthma is associated with a corresponding increase in ex vivo airway constriction. Herein, the responses to nebulized methacholine in vivo and airway constriction in lung slices ex vivo were studied in 8- to 10-week-old male mice of two strains, BALB/c and C57BL/6. Experimental asthma was induced by administering house dust mites (HDM) intranasally, once daily, for 10 consecutive days. Complementary ex vivo studies were conducted with excised tracheas to measure and compare isometric force. As expected, the in vivo response to methacholine, and especially the hyperresponsiveness caused by HDM, was greater in BALB/c than in C57BL/6 mice. In contrast, there were no differences in maximal airway constriction between mouse strains, and the hyperresponsiveness to nebulized methacholine caused by HDM in both mouse strains was not associated with a corresponding increase in ex vivo airway constriction. The experiments with excised tracheas demonstrated no differences in isometric force between strains and between mice with and without experimental asthma. It is concluded that the hyperresponsiveness to nebulized methacholine in an acute mouse model of asthma induced by repeated HDM exposures is not associated with excessive airway constriction ex vivo.</p>","PeriodicalId":12092,"journal":{"name":"Experimental Physiology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735654","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}
引用次数: 0
Weighted cart pull: A novel outcome measure for sustained motor function in mice.
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-28 DOI: 10.1113/EP092658
Charles D Brennan, Nathan R Kerr, Jose A Viteri, Zachary Williard, Harper Snyder, Gabriella Meier, Sam Cairns, Fereshteh B Darvishi, Anna R Dashtmian, Peter J Moore, Sindhuja N Ayyagari, Meifang Wang, W David Arnold
{"title":"Weighted cart pull: A novel outcome measure for sustained motor function in mice.","authors":"Charles D Brennan, Nathan R Kerr, Jose A Viteri, Zachary Williard, Harper Snyder, Gabriella Meier, Sam Cairns, Fereshteh B Darvishi, Anna R Dashtmian, Peter J Moore, Sindhuja N Ayyagari, Meifang Wang, W David Arnold","doi":"10.1113/EP092658","DOIUrl":"https://doi.org/10.1113/EP092658","url":null,"abstract":"<p><p>Sarcopenia, the pathological age-related decline in muscle mass and strength, compromises independence and quality of life in older adults. Currently, no effective treatments are available. To enhance translational research using aged mouse models, we developed and validated the weighted cart pull (WCP) as a novel assessment of sustained motor function. The WCP test involved attaching a weighted cart to the tail of a mouse as it climbed a ramp to a 'resting house'. Mass was increased incrementally until failure, defined as either five consecutive hindquarter pokes without progress or sliding backwards. In experiment 1, reliability (inter- and intra-rater) was evaluated in middle-aged mice (9 months, n = 10, 50% female). In experiment 2, young (n = 8, 50% female) and old (n = 8, 50% female) mice were tested on WCP, all-limb grip and rotarod. In experiment 3, middle-aged mice (7-9 months, n = 20, 50% female) underwent behavioural tests, in vivo electrophysiology and muscle physiology to correlate WCP with assessments of neuromuscular function. WCP showed high intra-rater repeatability [intraclass correlation coefficient = 0.611, P = 0.018, 95% confidence interval (CI) = (0.046, 0.885)]. WCP demonstrated phenotypic differences between young and old mice (Student's unpaired t-test, P < 0.0001). WCP was significantly correlated with all-limb grip [Pearson's r = 0.5820, P = 0.0071, 95% CI = (0.1878, 0.8147)], percentage decrement upon repetitive nerve stimulation at 50 Hz [Pearson's r = 0.4613, P = 0.0468, 95% CI = (0.008973, 0.7569)], twitch torque [Pearson's r = 0.6241, P = 0.0033, 95% CI = (0.2509, 0.8358)], tetanic torque [Pearson's r = 0.5100, P = 0.0216, 95% CI = (0.08718, 0.7771)] and bilateral gastrocnemius and soleus muscle mass [Pearson's r = 0.5878, P = 0.0064, 95% CI = (0.1964, 0.8177)]. The WCP provides a cost-effective, comprehensive measure of strength and sustained motor function, improving preclinical assessments.</p>","PeriodicalId":12092,"journal":{"name":"Experimental Physiology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735659","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}
引用次数: 0
The mood stabilizers lithium and valproate disrupt hepatic and intestinal farnesoid X receptor signalling and increase bile synthesis in the rat.
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-28 DOI: 10.1113/EP092451
Sofia Cussotto, Anna V Golubeva, Alvaro Lopez Gallardo, Thomaz F S Bastiaanssen, Alexander V Zhdanov, Gerard M Moloney, Caitriona Scaife, Jane A English, Susan A Joyce, Timothy G Dinan, John F Cryan
{"title":"The mood stabilizers lithium and valproate disrupt hepatic and intestinal farnesoid X receptor signalling and increase bile synthesis in the rat.","authors":"Sofia Cussotto, Anna V Golubeva, Alvaro Lopez Gallardo, Thomaz F S Bastiaanssen, Alexander V Zhdanov, Gerard M Moloney, Caitriona Scaife, Jane A English, Susan A Joyce, Timothy G Dinan, John F Cryan","doi":"10.1113/EP092451","DOIUrl":"https://doi.org/10.1113/EP092451","url":null,"abstract":"<p><p>The mood stabilizers lithium and valproate are psychotropic medications widely used in clinical practice. Despite their proven benefits, many individuals stop their treatment due to the adverse effects. Chronic diarrhoea is a common reason for discontinuation of these drugs; however, the underlying mechanisms are unknown. Excessive loss of bile acids (BA) into the colon is a major cause of diarrhoea. Therefore, we aimed to investigate the effects of these drugs on BA metabolism. We measured BA levels in the liver, plasma and faeces of Sprague-Dawley rats treated with lithium or valproate for 4 weeks. Next, we analysed changes in the expression of genes and proteins involved in BA production and enterohepatic circulation. Lithium and valproate markedly increased BA levels across all body sites. This was accompanied by the up-regulation of hepatic cytochrome P450 7A1 (Cyp7a1), the rate-limiting enzyme in de novo BA synthesis. Under normal conditions, elevated levels of BAs suppress Cyp7a1 via activation of the hepatic farnesoid X receptor (Fxr)/small heterodimer partner (Shp) and intestinal Fxr/fibroblast growth factor 19 (Fgf19) pathways. This signalling was disrupted in both treatment groups. The Fxr-mediated responses in the expression of Ntcp, Asbt, Ilbp and Ostα/β bile transporters were also affected by treatment. In conclusion, lithium and valproate disrupted farnesoid X receptor signalling at the hepatic and intestinal levels, inducing sustained overproduction of bile in rats. These findings provide novel insights into the peripheral effects of these drugs. Given that similar changes in bile circuits underlie the pathophysiology of primary BA diarrhoea in humans, this study suggests a potential mechanism behind chronic diarrhoea in patients undergoing lithium or valproate therapy.</p>","PeriodicalId":12092,"journal":{"name":"Experimental Physiology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735656","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}
引用次数: 0
Cardiac conduction system and the electrocardiogram of the common hippopotamus (Hippopotamus amphibius).
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-28 DOI: 10.1113/EP092519
Morten B Thomsen, Peter Agger, Henrik Lauridsen, Vibeke Sødring Elbrønd, Camilla Rensch Davidsen, Emma Smedsgaard Byskov, Frederik Stig Scharling, Tobias Wang, Sara Andreia Rodrigues Abreu, Stamatios Alan Tahas, Carsten Grøndahl, Mads Frost Bertelsen, Kirstine Calloe
{"title":"Cardiac conduction system and the electrocardiogram of the common hippopotamus (Hippopotamus amphibius).","authors":"Morten B Thomsen, Peter Agger, Henrik Lauridsen, Vibeke Sødring Elbrønd, Camilla Rensch Davidsen, Emma Smedsgaard Byskov, Frederik Stig Scharling, Tobias Wang, Sara Andreia Rodrigues Abreu, Stamatios Alan Tahas, Carsten Grøndahl, Mads Frost Bertelsen, Kirstine Calloe","doi":"10.1113/EP092519","DOIUrl":"https://doi.org/10.1113/EP092519","url":null,"abstract":"<p><p>The common hippopotamus (Hippopotamus amphibius) shares a common terrestrial ancestor with whales (Cetacea) and has independently evolved similar physiological adaptations to their aquatic lifestyle. Although several studies have explored the electrical signalling in whale hearts, the understanding of the conduction system and electrical activation of the hippopotamus heart remains sparse. We set out to map the conduction system within the hippopotamus heart and determine the sequence of electrical activation, including the mean electrical axis of ventricular activation. ECGs were recorded from three anaesthetized hippopotamuses. Histological samples were collected from two of these animals and from an additional animal. The hearts of the hippopotamuses constituted ∼0.3% of body mass and as in whales, the hearts were situated more cranially in the thoracic cavity compared to most terrestial mammals, and were spanning from the first to the fourth intercostal space. The network of Purkinje fibre strands extended deep into the ventricular walls and consisted of large, ovoid cells. Orthogonal ECG recordings revealed a mean electrical axis pointing towards the neck of the animal, indicating that electrical activation takes place in an apex-to-base direction.</p>","PeriodicalId":12092,"journal":{"name":"Experimental Physiology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735651","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}
引用次数: 0
Durability as an index of endurance exercise performance: Methodological considerations.
IF 2.6 4区 医学
Experimental Physiology Pub Date : 2025-03-27 DOI: 10.1113/EP092120
Ben Hunter, Ed Maunder, Andrew M Jones, Gabriele Gallo, Daniel Muniz-Pumares
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