Journal of Physiology-London最新文献

{"title":"Impact of the metabolic disease status in obesity and surgical weight loss on human adipose tissue bioenergetics.","authors":"Aryane Cruz Oliveira Pinho, André Lazaro, Pedro Barbosa, Craig Porter, José G Tralhão, Eugenia Carvalho","doi":"10.1113/JP286103","DOIUrl":"https://doi.org/10.1113/JP286103","url":null,"abstract":"<p><p>Obesity is associated with insulin resistance (IR) development, a risk factor for type 2 diabetes (T2D). How mitochondrial bioenergetics, in adipose tissue (AT), differs according to distinct metabolic profiles (i.e. insulin sensitive (IS), IR normoglycaemic (IR-NG), pre-diabetes (PD) and T2D) is still poorly understood. The purpose of this study was to evaluate and compare bioenergetics and energy substrate preference by omental AT (OAT) and subcutaneous AT (SAT) from subjects with obesity (OB, n = 40) at distinct metabolic stages. Furthermore, AT bioenergetics was also evaluated pre- and post-bariatric/metabolic surgery (BMS). High-resolution respirometry (HRR) was used to measure the real-time oxidative phosphorylation (OXPHOS) capacity and mitochondrial substrate preferences in both tissues. Substrate-uncoupler-inhibitor titration protocols were used: SUIT-P1 (complex I and II-linked mitochondrial respiration) and SUIT-P2 (fatty acid oxidation (FAO)-linked mitochondrial respiration). Flux control ratios (FCRs) were calculated. In SUIT-P1, lower OXPHOS capacity was observed in AT, particularly in SAT, during the establishment of IR (OB-IR-NG) and in the T2D group, due to alterations of mitochondrial coupling, evaluated by FCRs. In SUIT-P2, the OXPHOS coupling efficiency was highest in the OB-IR-NG group. AT from OB-IS, OB-IR-NG and OB-IR-PD preferred pyruvate, malate and glutamate oxidation and/or FAO during OXPHOS, whereas AT from T2D preferred succinate oxidation. BMS enhanced mitochondrial respiration in OAT, even under poor OXPHOS coupling efficiency. In conclusion, real-time OXPHOS analysis by HRR may be a sensitive biomarker of mitochondrial fitness, particularly in AT. Interventions based on modulating energetic substrate availability may become a good tool for obesity treatment stratification. KEY POINTS: Omental adipose tissue shows higher oxidative phosphorylation (OXPHOS) capacity compared to subcutaneous adipose tissue in paired explants from subjects with obesity. The OXPHOS capacity of adipose tissue differs through the progression of metabolic disease. Subjects with obesity and diabetes have the lowest OXPHOS capacity in paired explants of subcutaneous and omental adipose tissues. Bariatric surgery enhanced the OXPHOS capacity in omental adipose tissue, even under poor OXPHOS coupling efficiency. Assessment of the oxidative capacity in fresh adipose tissue explants could be a sensitive tool for early diagnosis of metabolic disease.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587848","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":"MC3R signalling in the medial hypothalamus: new insights on energy rheostasis and implications for obesity therapies.","authors":"Nathalie Krauth, Sofie Amalie Olsen","doi":"10.1113/JP288505","DOIUrl":"https://doi.org/10.1113/JP288505","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587852","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":"Clinical neurocardiology: defining the value of neuroscience-based cardiovascular therapeutics – 2024 update","authors":"Olujimi A. Ajijola,&nbsp;Tolga Aksu,&nbsp;Rishi Arora,&nbsp;Italo Biaggioni,&nbsp;Peng-Sheng Chen,&nbsp;Gaetano De Ferrari,&nbsp;Veronica Dusi,&nbsp;Marat Fudim,&nbsp;Jeffrey J. Goldberger,&nbsp;Alexander L. Green,&nbsp;Neil Herring,&nbsp;Sahib S. Khalsa,&nbsp;Rajesh Kumar,&nbsp;Edward Lakatta,&nbsp;Reena Mehra,&nbsp;Christian Meyer,&nbsp;Sunny Po,&nbsp;Stavros Stavrakis,&nbsp;Virend K. Somers,&nbsp;Alex Y. Tan,&nbsp;Miguel Valderrabano,&nbsp;Kalyanam Shivkumar","doi":"10.1113/JP284741","DOIUrl":"10.1113/JP284741","url":null,"abstract":"<p>The intricate role of the autonomic nervous system (ANS) in regulating cardiac physiology has long been recognized. Aberrant function of the ANS is central to the pathophysiology of cardiovascular diseases. It stands to reason, therefore, that neuroscience-based cardiovascular therapeutics hold great promise in the treatment of cardiovascular diseases in humans. A decade after the inaugural edition, this White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology and pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.\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 7","pages":"1781-1839"},"PeriodicalIF":4.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP284741","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587845","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":"Oxygen chemoreceptor inhibition by dopamine D₂ receptors in isolated zebrafish gills.","authors":"Maddison Reed, Michael G Jonz","doi":"10.1113/JP287824","DOIUrl":"https://doi.org/10.1113/JP287824","url":null,"abstract":"<p><p>Dopamine is an essential modulator of oxygen sensing and control of ventilation and is the most well described and abundant neurotransmitter in the mammalian carotid body. Little is known of the evolutionary significance of dopamine in oxygen sensing, or whether it plays a similar role in anamniotes. In the model vertebrate, zebrafish (Danio rerio), presynaptic dopamine D₂ receptor (D₂R) expression was demonstrated in gill neuroepithelial cells (NECs), analogues of mammalian oxygen chemoreceptors; however, a mechanism for dopamine and D₂R in the gills had not been defined. The present study tested the hypothesis that presynaptic D₂Rs provide a feedback mechanism attenuating the chemoreceptor response to hypoxia. Using an isolated gill preparation from Tg(elavl3:GCaMP6s) zebrafish, we measured hypoxia-induced changes in intracellular Ca²⁺ concentration ([Ca²⁺]_i) in NECs and postsynaptic neurons. Activation of D₂R with dopamine or specific D₂R agonist, quinpirole, decreased hypoxic responses in NECs; whereas D₂R antagonist, domperidone, had the opposite effect. Addition of SQ22536, an adenylyl cyclase (AC) inhibitor, decreased the effect of hypoxia on [Ca²⁺]_i, similar to dopamine. Activation of AC by forskolin partially recovered the suppressive effect of dopamine on the Ca²⁺ response to hypoxia. Furthermore, we demonstrate that the response to hypoxia in postsynaptic neurons was dependent upon innervation with NECs, and was subject to modulation by activation of presynaptic D₂R. Our results provide the first evidence of neurotransmission of the hypoxic signal at the NEC-nerve synapse in the gill and suggest that a presynaptic, modulatory role for dopamine in oxygen sensing arose early in vertebrate evolution. KEY POINTS: For the first time, we present an experimental model that permits imaging of intracellular Ca²⁺ in identified oxygen chemoreceptors in zebrafish using GCaMP in a whole/intact sensing organ. The hypoxic response of zebrafish chemoreceptors is attenuated by dopamine through a mechanism involving D₂ receptors and adenylyl cyclase. Zebrafish oxygen chemoreceptors send a hypoxic signal to postsynaptic (sensory) neurons. Postsynaptic neuronal responses to hypoxia are modulated by presynaptic D₂ receptors, suggesting a link between chemoreceptor inhibition by dopamine and modulation of the hypoxic ventilatory response. Our results suggests that a modulatory role for dopamine in oxygen sensing arose early in vertebrate evolution.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587887","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":"Cellular and molecular cross-talk in atrial fibrillation: The role of non-cardiomyocytes in creating an arrhythmogenic substrate.","authors":"Zhenyu Dong, Ruben Coronel, Joris R de Groot","doi":"10.1113/JP286978","DOIUrl":"https://doi.org/10.1113/JP286978","url":null,"abstract":"<p><p>Atrial fibrillation (AF) is a complex arrhythmia. Various modulating factors influence its triggers and substrate. Fibroblasts, adipocytes, inflammatory cells and the coagulation system can disrupt cardiomyocyte function. Cardiomyocytes and fibroblasts release inflammatory cytokines that promote local and systemic inflammation, enhancing fibroblast activation and extracellular matrix deposition, leading to myocardial fibrosis. Fibrosis is essential for the induction of reentrant arrhythmias, including AF. Adipocytes contribute to arrhythmogenesis by secreting pro-inflammatory and pro-fibrotic factors, exacerbating inflammation and metabolic dysregulation. Inflammatory mediators activate the coagulation system, which augments this vicious cycle by producing factors promoting inflammation, fibrosis and arrhythmias at the same time as increasing the risk of thrombosis. Understanding these interconnected roles in the development and progress of the atrial arrhythmogenic substrate may point to potential novel therapeutic targets to stabilise or antagonise the atrial substrate and eventually prevent AF. This review examines the role of the interplay between cardiomyocytes, fibroblasts, adipocytes, inflammation and the coagulation system in contributing to the arrhythmogenic substrate for AF initiation and perpetuation.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573777","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":"Distinct age-related alterations in alpha-beta neural oscillatory activity during verbal working memory encoding in children and adolescents.","authors":"Augusto Diedrich, Yasra Arif, Brittany K Taylor, Zhiying Shen, Phillip M Astorino, Wai Hon Lee, Ryan W McCreery, Elizabeth Heinrichs-Graham","doi":"10.1113/JP287372","DOIUrl":"https://doi.org/10.1113/JP287372","url":null,"abstract":"<p><p>Emerging imaging studies of working memory (WM) have identified significant WM-related oscillatory events that are unique to each phase of working memory (e.g. encoding, maintenance). Although many previous imaging studies have shown age-related changes within the frontoparietal network when performing a WM task, understanding of the age-related changes in the oscillatory dynamics underlying each phase of WM during development and their relationships to other cognitive function is still in its infancy. To this end, we enrolled a group of 74 typically-developing youths aged 7-15 years to perform a letter-based Sternberg WM task during magnetoencephalography. Trial-wise data were transformed into the time-frequency domain, and significant oscillatory responses during the encoding and maintenance phases of the task were independently imaged using beamforming. Our results revealed widespread age-related power differences in alpha-beta oscillatory activity during encoding throughout left frontal, parietal, temporal, occipital and cerebellar regions. By contrast, age-related differences in maintenance-related activity were limited to a small area in the superior temporal gyrus and parieto-occipital regions. Follow-up exploratory factor analysis of age-related encoding alpha-beta activity revealed two distinct factors, and these factors were each found to significantly mediate age-related improvements in both verbal and non-verbal cognitive ability. Additionally, late maintenance alpha activity was related to reaction time on the task. Taken together, our results indicate that the neural dynamics in the alpha and beta bands are uniquely sensitive to age-related changes throughout this developmental period and are related to both task performance and other aspects of cognitive development. KEY POINTS: Understanding of the age-related changes in neural oscillatory dynamics serving verbal working memory function is in its infancy. This study identified the age-related neural alterations during each phase of working memory processing in youths. Developmental differences during working memory processing were primarily isolated to alpha-beta activity during the encoding phase. Alpha-beta activity during encoding significantly mediated age-related improvements in both verbal and non-verbal ability. This study establishes new brain-behaviour relationships linking working memory function to other aspects of cognitive development.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574303","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 proteostasis and cellular health: insights from chaperones and autophagy.","authors":"Yuvraj Anandrao Jagtap, Akash Choudhary, Sumit Kinger, Prashant Kumar, Sudipta Bhattacharyya, Hem Chandra Jha, Rohan Dhiman, Vivek Sharma, Anil K Suresh, Krishna Mohan Poluri, Amit Mishra","doi":"10.1113/JP287635","DOIUrl":"https://doi.org/10.1113/JP287635","url":null,"abstract":"<p><p>Mitochondria are a cell's powerhouse and also have a vital part in cellular processes. The emerging role of mitochondria in several crucial processes highlights their cellular and physiological importance. Mitochondrial homeostasis mechanisms, including proteostasis pathways, are vital for mitochondrial health. Failure of these processes has an important role in establishment of numerous complex disease conditions, such as neurodegeneration and imperfect ageing. However, details of mitochondrial impairments and their contribution to the pathology of neurodegeneration are poorly understood. This review systematically discusses the involvement of mitochondrial homeostasis mechanisms and their role in rejuvenating cellular health and fitness. We also focus on various cellular protein quality control mechanisms essential for mitochondrial proteostasis and how their failure leads to mitochondrial functional disturbances observed in disease conditions. We discuss recent findings based on mitostasis-associated chaperones, mitoproteases, and autophagy responses, which can lead to emergence of new possible therapeutic interventions against complex diseases.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568752","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":"The apical mucus layer alters the pharmacological properties of the airway epitheliumy.","authors":"Daniela Guidone, Martina de Santis, Emanuela Pesce, Valeria Capurro, Nicoletta Pedemonte, Luis J V Galietta","doi":"10.1113/JP287891","DOIUrl":"https://doi.org/10.1113/JP287891","url":null,"abstract":"<p><p>Electrogenic transepithelial ion transport can be measured with the short-circuit current technique. Such experiments are frequently used to evaluate the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel that is defective in cystic fibrosis, one of the most frequent genetic diseases. Typically, CFTR activity is estimated from the effect of CFTR_inh-172, a selective CFTR inhibitor. Unexpectedly, we found that CFTR_inh-172, in addition to PPQ-102, another CFTR inhibitor, caused only partial inhibition of CFTR function, particularly in epithelia in pro-inflammatory conditions, which are characterized by abundant mucus secretion. We hypothesized that the mucus layer was responsible for the poor activity of CFTR inhibitors. Therefore, we treated the epithelial surface with the reducing agent dithiothreitol to remove mucus. Removal of mucus, confirmed by immunofluorescence, resulted in highly enhanced sensitivity of CFTR to pharmacological inhibition. Our results show that the mucus layer represents an important barrier whose presence limits the activity of pharmacological agents. This is particularly relevant for CFTR and the evaluation of therapeutic approaches for correction of the basic defect in cystic fibrosis. KEY POINTS: Activity of the cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel can be evaluated by measuring the inhibition elicited by the selective blockers CFTR_inh-172 and PPQ-102. In short-circuit current recordings on human airway epithelia, CFTR inhibitors had only a partial effect on cAMP-dependent chloride secretion, suggesting the possible contribution of other ion channels. The mucus layer covering the epithelial surface was removed with the reducing agent dithiothreitol. Treatment of epithelia with dithiothreitol markedly improved the efficacy of CFTR inhibitors. The partial effect of CFTR inhibitors might be explained by the presence of the mucus layer acting as a barrier.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568754","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":"The brain baroreflex - a hidden guardian of the cerebral circulation.","authors":"Christabel Osei-Boateng, Jenna C McCrone, Michael M Tymko","doi":"10.1113/JP288604","DOIUrl":"https://doi.org/10.1113/JP288604","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568756","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":"ESM-1 and GBP-1 are associated with endothelial dysfunction: emerging biomarkers or key players in the pathophysiology of preeclampsia?","authors":"Ines Pronk, Joost H N Schuitemaker, Marijke M Faas, Alexandra M Smink","doi":"10.1113/JP285934","DOIUrl":"https://doi.org/10.1113/JP285934","url":null,"abstract":"<p><p>Preeclampsia is a hypertensive disorder of pregnancy and is one of the most prevalent causes of maternal and fetal morbidity and mortality. The disease is thought to originate from impaired placental development or restricted villous perfusion, villous constraints and placental senescence at the end of pregnancy, which in turn cause defective placental functioning and eventually systemic endothelial dysfunction. Because the precise pathophysiology of this pregnancy complication is still not clear and diagnosis is only made when it is clinically visible, considerable research is being performed on biomolecules that could play a role in the development of the disease and could have a predictive, diagnostic or prognostic value. In the present review, we focus on two proteins, associated with endothelial dysfunction, which have changed levels in pregnant women during preeclampsia. These two proteins, endothelial specific molecule-1 (ESM-1) and guanylate binding protein-1 (GBP-1), are known to be involved in processes such as angiogenesis, inflammation and endothelial activation. ESM-1 is increased during preeclampsia and GBP-1 is decreased during preeclampsia, and their potential as biomarkers for preeclampsia could therefore be assessed. In addition to assessing their potential to serve as biomarkers, we will go into potential pathophysiological mechanisms of preeclampsia in which these proteins might be involved. We are proposing that ESM-1 and GBP-1 might play a role in impaired angiogenesis and vascular maladaptation, impaired immune regulation and oxidative stress, which ultimately could lead to endothelial dysfunction and preeclampsia.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568751","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}