Journal of Physiology-London最新文献

{"title":"Warburg redefined: Metabolites, mitochondria and macrophages in immune regulation.","authors":"Yukun Min, Órlaith C Henry, Luke A J O'Neill","doi":"10.1113/JP291073","DOIUrl":"https://doi.org/10.1113/JP291073","url":null,"abstract":"<p><p>Nearly 100 years ago, Otto Warburg observed that cancer cells preferentially use glycolysis even in the presence of oxygen, supporting rapid cell growth. Since then, the concept of the Warburg effect has expanded far beyond tumour bioenergetics and is now recognised as a key feature of immune cell activation. A notable example is in macrophages, which, following pro-inflammatory stimulation, undergo Warburg-like metabolic reprogramming, characterised by increased glycolysis. Recent studies have shown that accumulated metabolites such as lactate have a range of immunoregulatory functions that shape macrophage inflammatory responses. In addition, glycolytic enzymes have been found to exert non-canonical functions that directly regulate macrophage immune signalling. Mitochondria, once considered suppressed during Warburg reprogramming, also undergo profound changes, with the electron transport chain generating reactive oxygen species and metabolites such as succinate, fumarate and itaconate playing complex immunoregulatory roles, and mitochondrial dynamics actively shaping metabolism and immune responses. Together, these findings redefine the Warburg effect in macrophages as a coordinated metabolic and signalling process that integrates glycolysis, mitochondrial function and immunometabolite signalling to optimise context-dependent immune responses.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197700","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":"A structure-based model that describes activation and inactivation of a sodium channel","authors":"D'Artagnan Greene,&nbsp;Sofia Perez,&nbsp;Yohannes Shiferaw","doi":"10.1113/JP291836","DOIUrl":"10.1113/JP291836","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;While the Hodgkin–Huxley formalism successfully describes sodium channel gating, the molecular origin of its nonlinear voltage dependence remains unclear. We developed a structure-based model of Na&lt;sub&gt;v&lt;/sub&gt;1.4 representing the four voltage-sensing domains, the isoleucine-phenylalanine-methionine (IFM) motif and the S6 gate as interacting binary variables, with activation parameters constrained by domain-specific fluorescence measurements. The fitted model reveals strongly heterogeneous voltage sensors whose interactions produce cooperative activation, suppressing channel opening at subthreshold voltages. Using timescale separation, we coarse-grain the 64-microstate system to obtain the Hodgkin–Huxley-like factorization &lt;i&gt;P&lt;/i&gt;&lt;sub&gt;o&lt;/sub&gt; = &lt;i&gt;m&lt;/i&gt; × &lt;i&gt;h&lt;/i&gt;, where &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;mi&gt;m&lt;/mi&gt;\u0000 &lt;annotation&gt;$m$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; represents cooperative activation and &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;mi&gt;h&lt;/mi&gt;\u0000 &lt;annotation&gt;$h$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; represents availability. The reduced theory shows that the voltage dependence of &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;mrow&gt;\u0000 &lt;msub&gt;\u0000 &lt;mi&gt;h&lt;/mi&gt;\u0000 &lt;mi&gt;∞&lt;/mi&gt;\u0000 &lt;/msub&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mo&gt;(&lt;/mo&gt;\u0000 &lt;mi&gt;V&lt;/mi&gt;\u0000 &lt;mo&gt;)&lt;/mo&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;annotation&gt;${{h}_infty }( V )$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; is inherited from the domain-IV voltage sensor. Because domain IV activates at more hyperpolarized voltages than the collective activation of domains I–III required for opening, availability declines before the channel reaches its main activation range. Coupling of domain IV to IFM engagement and S6 gate closure further controls the magnitude of this shift. Thus, the model identifies the molecular origin of the separation between activation and availability curves.\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;Sodium channels are proteins in nerve and muscle cells that open briefly to trigger electrical signals, then close. The 1952 Hodgkin–Huxley model captures this behaviour by treating the channel's four voltage sensors as independent.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;However, experiments show ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8450-8466"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149041817","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":"Uncovering strategies to rescue muscle mass in ageing","authors":"Joelina Lienau","doi":"10.1113/JP291783","DOIUrl":"10.1113/JP291783","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8310-8313"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881766","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":"Metabolism meets modulation: Lactate's redox-driven control of NMDARs","authors":"Cullan Voelkner,&nbsp;Grace Sargeant,&nbsp;Juan F. Casas,&nbsp;Emma L. Cook,&nbsp;Sarah Bellaflor","doi":"10.1113/JP291856","DOIUrl":"10.1113/JP291856","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8307-8309"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148876737","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":"When does sweating change during puberty? Revisiting the developmental timing of sex differences in sweating capacity","authors":"KarLee Lefebvre,&nbsp;Amine Dahhak,&nbsp;Nicolas Pamart,&nbsp;Hsen Hsouna,&nbsp;Katia Oubouchou,&nbsp;Nathan Bélanger,&nbsp;Farah Bouhlel,&nbsp;Luc Souilla","doi":"10.1113/JP291692","DOIUrl":"10.1113/JP291692","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8314-8316"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963922","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":"Macrophage-derived CD38 mediates colitis through NAD+ depletion","authors":"Yanni Wu,&nbsp;Xiaohan Yang,&nbsp;Xianyang Jin,&nbsp;Xuemei Jiang,&nbsp;Chao Jin,&nbsp;Bin Feng,&nbsp;Lianqiang Che,&nbsp;Shengyu Xu,&nbsp;Yan Lin,&nbsp;De Wu,&nbsp;Lun Hua,&nbsp;Yong Zhuo","doi":"10.1113/JP291548","DOIUrl":"10.1113/JP291548","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>Colitis, a chronic inflammatory bowel disease (IBD), is pathologically linked to immune dysregulation; however, the contribution of cellular metabolic alterations to its pathogenesis remains incompletely understood. In this study, untargeted metabolomic analysis revealed marked disruption of NAD⁺ metabolism, accompanied by increased expression of CD38, a major NAD⁺-glycohydrolase, in colitis. Restoring NAD⁺ levels through supplementation with its precursors or pharmacological inhibition of CD38 activity effectively alleviated the pathological symptoms of colitis. Mechanistically, colitis induced a pronounced upregulation of CD38 specifically in macrophages. Myeloid-specific deletion of <i>Cd38 s</i>ignificantly attenuated both metabolic disturbances and inflammatory responses associated with colitis. These findings identify macrophage CD38 as a critical regulator of intestinal inflammation and highlight the CD38/NAD⁺ axis as a potential therapeutic target for IBD.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Altered NAD⁺ metabolism is closely associated with intestinal inflammation, yet the specific cellular mechanisms contributing to this decline remain to be fully elucidated.</li>\u0000 \u0000 <li>By supplementing with nicotinamide mononucleotide or inhibiting the enzyme CD38 that consumes NAD⁺ with drugs, the NAD⁺ level can be effectively restored, which can alleviate the colitis induced by dextran sulphate sodium to a certain extent.</li>\u0000 \u0000 <li>During intestinal inflammation, the upregulation of CD38 is predominantly driven by infiltrating macrophages.</li>\u0000 \u0000 <li>Myeloid-specific deletion of CD38 preserves NAD⁺ homeostasis and ameliorates colitis, highlighting its essential role in disease progression.</li>\u0000 \u0000 <li>Targeting macrophage CD38 establishes a key regulatory link between NAD⁺ metabolism and intestinal inflammation, providing a potential therapeutic strategy for inflammatory bowel diseases.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8484-8500"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082646","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":"DA neuronal pacemaking and psychostimulant sensitization: Gated by NALCN channels","authors":"Jing Wang,&nbsp;Hailin Zhang","doi":"10.1113/JP292544","DOIUrl":"10.1113/JP292544","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8299-8300"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128952","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":"PKCδ and pharmacomechanical control of cerebral arterial tone","authors":"Muhammad Talha","doi":"10.1113/JP292343","DOIUrl":"10.1113/JP292343","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8320-8322"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148972156","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":"Myostatin-dependent detrusor remodelling mediates contractility impairment in diabetic rats’ bladder – a maximal elastance analysis","authors":"Cheng-Yuan Lai,&nbsp;Hui-Hsuan Lau,&nbsp;Ming-Chun Hsieh,&nbsp;Hsien-Yu Peng,&nbsp;Dylan Chou,&nbsp;Tsung-Hsien Su,&nbsp;Tzer-Bin Lin","doi":"10.1113/JP291025","DOIUrl":"10.1113/JP291025","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;The role of myostatin, an endogenous myokine mediating the pathological progression of myopathy, in contractility impairments of the chronically diabetic bladder remains unclear. This study examined whether maximal elastance (mE) reliably and validly assesses bladder contractility &lt;i&gt;in vivo&lt;/i&gt; and investigated the role of myostatin-associated tissue remodelling in the contractility deficits in diabetic bladder. Eighty-three female Sprague–Dawley rats were assigned to control (CON), streptozotocin-treated (STZ; 30 mg/kg twice, &lt;span&gt;i.p.&lt;/span&gt;) and STZ with non-specific IgG (STZ + IgG; 2 mg/kg, &lt;span&gt;i.p.&lt;/span&gt;) or Myo-029 (a myostatin-neutralizing antibody; STZ + MYO; 2 mg/kg, &lt;span&gt;i.p.&lt;/span&gt;). The slope of the end-emission pressure–volume relationship obtained from pressure–volume analysis was calculated as mE. mE remained relatively constant under altered preload and afterload but increased dose dependently with muscarine infusion (10 and 100 µM, 0.002 mL/min, &lt;span&gt;i.a.&lt;/span&gt;) and decreased with atropine infusion (10 and 100 µM, 0.002 mL/min, &lt;span&gt;i.a.&lt;/span&gt;). Compared to CON the STZ group showed decreased mE, reduced muscle-to-collagen ratio, increased myostatin expression, decreased myosin heavy chain 11 (MHC 11) and smoothelin expressions, as well as upregulated α-smooth muscle actin (SMA) and collagen type I alpha 1 (COL1A1) expressions. Treatment with Myo-029 in STZ animals reversed the reductions in the MHC 11 and smoothelin expressions, muscle-to-collagen ratio and mE, as well as the STZ-upregulated SMA and COL1A1 expression. Collectively mE effectively assessed bladder contractility &lt;i&gt;in vivo&lt;/i&gt;. Moreover myostatin contributes to diabetes-associated deficits in bladder contractility by regulating detrusor remodelling, suggesting that myostatin may represent a potential therapeutic target for diabetes-associated cystopathy.\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;Developing a methodology capable of precisely assessing bladder contractility &lt;i&gt;in vivo&lt;/i&gt; is warranted to elucidate the underlying pathophysiology of bladder contractility impairments.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The pathological progression of diabetic cystopathy has been linked to myogenic dysfunction of the detrusor, resulting in impaired bladder contractility.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Maximal elastance (mE) is a bladder contractility–sensitive parameter that is independent of bladder preload and afterload.&lt;/li&gt;\u0000 \u0000 ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8428-8449"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP291025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002667","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 last-step integrator thesis: Heterarchical control of the mammalian gastrointestinal tract","authors":"William Bechtel,&nbsp;Leonardo Bich","doi":"10.1113/JP291403","DOIUrl":"10.1113/JP291403","url":null,"abstract":"<p>To perform the work necessary to maintain themselves in diverse situations, organisms orchestrate the operations of a host of production mechanisms that individually perform specific physiological and behavioural activities. Effective orchestration depends upon control mechanisms that acquire and integrate information about conditions in the organism and its environment and deploy the results to adjust the operation of production mechanisms. How are control mechanisms organized? A common assumption is that they need to be organized in a pyramid, with controllers at a higher level overseeing the activities of numerous subordinate mechanisms, procuring information from them and sending directives to them. In this article, we challenge this view and argue that physiological control is organized heterarchically. To illustrate the distinctive features of heterarchical control, we examine the current understanding of the regulation of the mammalian gastrointestinal tract. We show that individual production mechanisms can be acted on by multiple control mechanisms. However, the activity of a production mechanism is not dictated by these control inputs, which can conflict: one may recommend one action, another a different action. It is up to the local production mechanism to integrate these inputs with its own current state in determining its operation. The integration of control signals that determines what action is performed is therefore not carried out at a highest level by a central decider issuing directives to a host of executors, but it is ultimately executed at the last step, within the controlled mechanism itself, and this is what we call the ‘last-step integrator.’\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":"604 20","pages":"8323-8344"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP291403","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963873","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}