Journal of Physiology-London最新文献

{"title":"Metabolic override: Adding neuropeptide Y to the list of vasoconstrictors attenuated by exercise.","authors":"Julian C Bommarito, Philip J Millar","doi":"10.1113/JP289205","DOIUrl":"https://doi.org/10.1113/JP289205","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seizure-related death exhibits a circadian rhythm independent of seizure timing or sleep in a mouse model of Dravet syndrome.","authors":"Benjamin L Kreitlow, Ana T Novella-Maciel, Ariana M Hernández Vázquez, Gordon F Buchanan","doi":"10.1113/JP288697","DOIUrl":"https://doi.org/10.1113/JP288697","url":null,"abstract":"<p><p>Sudden unexpected death in epilepsy (SUDEP) is the most extreme consequence of epilepsy. SUDEP typically occurs at night. Because humans sleep at night, these nighttime deaths are often attributed to seizures arising from sleep. Nocturnal mice also experience more seizure-associated deaths during the nighttime. This could represent timing that is under circadian control. To examine this, male and female Scn1a^R1407X/+ mice, a model of the epileptic encephalopathy Dravet syndrome, in which patients experience spontaneous seizures that often result in death, were housed in constant darkness and the timing of seizure associated death was assessed. We found that the timing of sudden death following seizures persists in constant darkness and peaks during the subjective nighttime. This circadian rhythm of death was independent of the timing of potentially fatal seizures and more frequently occurred while awake. Potentially fatal seizures resulted in prolonged unconsciousness, which also exhibited a circadian rhythm peaking during the subjective night. These findings provide support for circadian regulation, independent of seizure timing and sleep, in the nighttime risk of seizure-associated death. Nighttime seizures may increase risk of SUDEP via multiple mechanisms, as evident by peak spontaneous sudden death and profoundly impaired consciousness following seizures during the subjective night. KEY POINTS: Sudden unexpected death in epilepsy, or SUDEP, is a devastating outcome of intractable epilepsy. Converging lines of evidence indicate that there is a time-of-day preference for SUDEP, with more SUDEP occurring during the night. Several animal models of the epileptic encephalopathy Dravet syndrome (DS), including the one employed in our study, recapitulate key features of DS in patients, including a high rate of seizure-related death and more of the deaths occurring at night. Here, we removed light/dark photocycles, by housing animals in constant darkness, and identify nighttime preponderance of death, suggesting that this is under circadian regulation. We further carefully characterize fatal vs. non-fatal seizures in our animals and identify features that may prove to be useful biomarkers to predict which seizures may become fatal.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insight into the initiation of spreading depolarizations: Is it really all about potassium?","authors":"Rachel Ricks,&nbsp;Connie MacKenzie-Gray Scott,&nbsp;Andrew J. Trevelyan,&nbsp;R. Ryley Parrish","doi":"10.1113/JP288809","DOIUrl":"10.1113/JP288809","url":null,"abstract":"<p>Cortical tissue, when subjected to certain electrical, mechanical, thermal or chemical disturbances, can undergo a widescale disruption of neuronal ionic electrochemical gradients, termed spreading depolarization (SD). SDs propagate slowly across the brain (∼2–9 mm min⁻¹), coinciding with the depression of spontaneous and evoked electrophysiological activity; hence, the near synonymous term spreading depression (Somjen, <span>2004</span>). It was this suppression of activity, discerned in rabbit models of experimental epilepsy, that first alerted Aristides Leão to the phenomenon in (Leao, <span>1944</span>).</p><p>Since then, various technological developments have provided new ways to identify and characterize SDs. Intracellular recordings show the near complete breakdown in ionic concentration gradients during SD, causing a sustained shift in neuronal intracellular potential to near 0 mV (Somjen, <span>2004</span>). The disturbance propagates outward from the point of stress in a regenerative, all-or-nothing wave, independent of the stimulus. The neuronal depolarization is accompanied by glial depolarization as extracellular potassium, [K⁺]_o, increases and, importantly, normally reverses after a few seconds to minutes. Transient alterations in blood flow and metabolic rate, cellular swelling, and the release of most neurotransmitters and neuromodulators within the depolarized tissue occur concomitantly. The cellular swelling causes subtle changes in reflectance and light scattering, allowing SDs to be easily visualized using intrinsic optical imaging (Somjen, <span>2004</span>). Clinically, the recent introduction of wide-band recording facilities is helping record SDs in humans, whereas previously, most EEG machines used high-pass filtering to prevent drift in the recordings from overloading the amplifier, excluding SD events identified from DC shifts and low frequency components of the local field potential. The recognition that SDs are a prominent feature in many human pathologies has greatly increased interest in understanding these events.</p><p>SDs have now been implicated in multiple different clinical neurological conditions, including migraine with aura, traumatic brain injury, intracranial and subarachnoid haemorrhage, ischaemic stroke, seizure and sudden unexpected death in epilepsy (SUDEP). Identifying the distinct molecular and electrophysiological mechanisms underlying SD initiation is essential to understanding their role in neuronal health and disease and, more importantly, what therapeutic approaches may be taken to reduce brain injury resulting from these various neuropathologies. In this review, we discuss how our understanding of SD initiation has been shaped by the choice of experimental models, and how new models of SD induction invite us to reexamine the underlying mechanism.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3269-3273"},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288809","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Symptom-modifying strategy to treat upper respiratory tract infections: a clinical and mechanistic evidence of ColdZyme","authors":"Maulana A. Empitu,&nbsp;Jevon Aaron Lesmana,&nbsp;Derren D.C.H. Rampengan,&nbsp;Roy Nofri Ramadhan","doi":"10.1113/JP289112","DOIUrl":"10.1113/JP289112","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3289-3291"},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial oxidative stress, calcium and dynamics in cardiac ischaemia-reperfusion injury.","authors":"Emily Rozich, Ulas Ozkurede, Shanmugasundaram Pakkiriswami, Ryan Gemilere, Samira M Azarin, Julia C Liu","doi":"10.1113/JP287770","DOIUrl":"https://doi.org/10.1113/JP287770","url":null,"abstract":"<p><p>Ischaemia-reperfusion injury (IRI) is a major cause of cardiomyocyte damage and death from myocardial infarction. Oxidative stress, dysregulated calcium (Ca²⁺) handling and disrupted mitochondrial dynamics are all key factors in IRI and can play a role in cell death. Mitochondria are a primary source of oxidative stress, which is generated by electron leak from the respiratory chain complexes and the oxidation of accumulated succinate upon reperfusion. The mitochondrial permeability transition pore (mPTP), a high conductance channel that forms following reperfusion of ischaemic mitochondria, has been implicated in reperfusion-induced cell death. Although factors including mitochondrial Ca²⁺ overload and oxidative stress that regulate mPTP opening have been well characterized, the composition of the mPTP is still actively investigated. Clinically, mPTP opening and IRI complicate treatment of myocardial infarction. Therefore, many possible therapeutics to reduce the damaging effects of reperfusion are under investigation. Antioxidants, pharmaceutical approaches, postconditioning and synthetic polymers have all been investigated for use in IRI. Still, many of these therapeutics of interest have shown mixed evidence underlying their use in preclinical and clinical research. In this review we discuss our current understanding of the contributions of mitochondrial oxidative stress, mitochondrial Ca²⁺ and mitochondrial dynamics to cardiomyocyte damage and death in IRI, and where further clarification of these mechanisms is needed to identify potential therapeutic targets.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetes meets exercise: Myonuclear gene transcription stays put","authors":"Gretchen A. Meyer,&nbsp;Bettina Mittendorfer","doi":"10.1113/JP289113","DOIUrl":"10.1113/JP289113","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3277-3278"},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-homogeneous distribution of inhibitory inputs among motor units in response to nociceptive stimulation at moderate contraction intensity","authors":"François Hug,&nbsp;François Dernoncourt,&nbsp;Simon Avrillon,&nbsp;Jacob Thorstensen,&nbsp;Manuela Besomi,&nbsp;Wolbert van den Hoorn,&nbsp;Kylie Tucker","doi":"10.1113/JP288504","DOIUrl":"10.1113/JP288504","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Pain significantly influences movement, yet the neural mechanisms underlying the range of observed motor adaptations remain unclear. This study combined experimental data and &lt;i&gt;in silico&lt;/i&gt; models to investigate the contribution of inhibitory and neuromodulatory inputs to motor unit behaviour in response to nociceptive stimulation during contractions at 30% of maximal torque. Specifically, we aimed to unravel the distribution pattern of inhibitory inputs to the motor unit pool. Seventeen participants performed isometric knee extension tasks under three conditions: Control, Pain (induced by injecting hypertonic saline into the infra-patellar fat pad) and Washout. We identified large samples of motor units in the vastus lateralis (up to 53/participant) from high-density electromyographic signals, leading to three key observations. First, while motor unit discharge rates significantly decreased during Pain, a substantial proportion of motor units (14.8–24.8%) did not show this decrease and, in some cases, even exhibited an increase. Second, using complementary approaches, we found that pain did not significantly affect neuromodulation, making it unlikely to be a major contributor to the observed changes in motor unit behaviour. Third, we observed a significant reduction in the proportion of common inputs to motor units during Pain. To explore potential neurophysiological mechanisms underlying these results, we simulated the behaviour of motor unit pools with varying distribution patterns of inhibitory inputs. Our simulations support the hypothesis that a non-homogeneous distribution of inhibitory inputs, not strictly organised according to motor unit size, is a key mechanism underlying the motor response to nociceptive stimulation during moderate contraction intensity.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Pain affects movement, but the neural mechanisms underlying these motor adaptations are not well defined.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The traditional view is that pain causes uniform (homogeneous) inhibition among motor units.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Recent research has observed differential motor unit responses to experimental pain – some with decreased discharge rates and others with increased discharge rates.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Combining experimental data with modelling, we provide compelling evidence of increased inhibition that is non-uniformly distributed across motor units, regardle","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3445-3461"},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of metformin on placental ageing in humans and mice","authors":"Grace J. Hattersley,&nbsp;Liu Yang,&nbsp;Jane L. Tarry-Adkins,&nbsp;Antonia Hufnagel,&nbsp;Kwun Kiu Wong,&nbsp;Denise S. Fernandez-Twinn,&nbsp;Maria Chukanova,&nbsp;India G. Robinson,&nbsp;Amanda J. Drake,&nbsp;Rebecca M. Reynolds,&nbsp;Susan E. Ozanne,&nbsp;Catherine E. Aiken","doi":"10.1113/JP288710","DOIUrl":"10.1113/JP288710","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Placental ageing refers to the physiological accumulation of a senescent phenotype over a healthy pregnancy. In pregnancies affected by complications such as pre-eclampsia and fetal growth restriction, placental ageing is notably accelerated and observed at an earlier gestational age. Metformin is used during pregnancy for an increasing variety of indications, including treatment of gestational diabetes, and may have a role in slowing cellular ageing. It is therefore essential to understand the potential impact of metformin on placental ageing. Placental samples (&lt;i&gt;n&lt;/i&gt; = 105) were obtained from women with body mass index ≥30 kg/m&lt;sup&gt;2&lt;/sup&gt; and who were randomized to treatment with metformin or placebo during pregnancy. Ageing was assessed by measuring telomere length, histological examination, and using array-based technologies to investigate gene expression and methylation. Results were validated using isolated human trophoblasts treated &lt;i&gt;in vitro&lt;/i&gt; with metformin, and in a complementary mouse model. There were no differences between metformin-exposed and control placentas in terms of telomere length, fibrosis or calcification. There were no differences in placental gene expression or methylation patterns by metformin status. In our mouse model, no genes classically associated with cellular ageing were differentially expressed and no senescence pathway showed evidence of enrichment with metformin treatment. There was no evidence that metformin either slows or accelerates placental ageing pathways in the complementary models that we investigated. Our findings are reassuring with regard to the safety of metformin used to treat gestational diabetes, but do not support a role for metformin in the prevention of adverse pregnancy outcomes in non-diabetic women.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Accelerated placental ageing, where the senescent phenotype that normally accumulates over a healthy pregnancy is observed at a premature gestational age, is associated with adverse pregnancy outcomes.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Metformin has been proposed as an anti-ageing drug elsewhere. Therefore, metformin could alter the trajectory of placental ageing and prevent associated pregnancy complications.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The present study incorporated human data from a randomized clinical trial and complementary models. Metformin did not impact methylation-predicted gestational age, telomere length, gene expression or","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3463-3477"},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288710","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bariatric surgery and metabolic profile modulate mitochondrial plasticity of adipose tissue","authors":"Ana Claudia Rossini-Venturini,&nbsp;Caroline Fogagnolo,&nbsp;Bianca Monteiro Silva,&nbsp;Sofia Germano Travieso,&nbsp;Marcela Coffacci de Lima Viliod","doi":"10.1113/JP288888","DOIUrl":"10.1113/JP288888","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3281-3283"},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bayliss–Starling Prize Lecture: KATP channel pathophysiology – a whole-body odyssey","authors":"Colin G. Nichols","doi":"10.1113/JP287415","DOIUrl":"10.1113/JP287415","url":null,"abstract":"<p>First identified 40 years ago in cardiac myocytes, ATP-sensitive potassium (K_ATP) channels have been found in almost all excitable tissues, with paradigmatic inhibition by ATP and activation by ADP underlying their physiological role in coupling cellular metabolism to electrical activity. Cloning of the underlying genes, 30 years ago, revealed their unique assembly as four Kir6.x pore-forming subunit proteins and four sulfonylurea receptor (SURx) subunit proteins and has since led to discovery of a spectrum of monogenic diseases resulting from gain- (GOF) or loss-of-function (LOF) mutations, in turn leading to recognition of novel physiological roles and pathophysiological consequences throughout the body. With this perspective, this lecture represents a personal view of these discoveries and the potential for future pathophysiological insights.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3293-3305"},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}