Journal of Physiology-London最新文献

{"title":"Calcium-activated chloride channels in pericytes and their role in regulating organ blood flow.","authors":"Paolo Tammaro, Hikaru Hashitani","doi":"10.1113/JP287607","DOIUrl":"https://doi.org/10.1113/JP287607","url":null,"abstract":"<p><p>Pericytes are mural cells of the microvasculature, characterised by a distinctive 'bump-on-a-log' morphology and elongated processes extending along the abluminal surface of capillary and pre- and post-capillary segments. They are widely distributed across organs and exhibit functional heterogeneity. Contractile pericytes directly regulate local blood flow, whereas non-contractile pericytes contribute to electrical signalling by generating depolarising or hyperpolarising events that propagate to upstream vessels and coordinate tissue perfusion. These functions are closely linked to intracellular ion homeostasis. Recent evidence highlights a role for Ca²⁺-activated Cl^- channels (CaCCs), particularly TMEM16A (ANO1), in coupling intracellular Ca² ⁺ signals to membrane depolarisation and pericyte activity. In contractile pericytes, TMEM16A-mediated currents promote depolarisation to activate L-type voltage-gated Ca² ⁺ channels, facilitating Ca²⁺ entry to support contraction. In non-contractile capillary pericytes, periodically generated TMEM16A-dependent depolarisations contribute to the initiation and propagation of spontaneous electrical activity, supporting intercellular synchrony within microvascular networks. Alternatively, asynchronous TMEM16A-dependent depolarisations could sum with each other to maintain resting membrane potentials and basal vascular tone. In this review, we summarise current understanding of CaCC channel function in pericytes across organs, and discuss emerging directions for future research and therapeutic targeting.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845304","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 dynamics and oxidative metabolism: an emerging role for Septin7 in skeletal muscle.","authors":"Márcio Augusto Campos-Ribeiro, Rudá Prestes E Albuquerque, Thiago N Menezes, Vanessa Morais Lima","doi":"10.1113/JP291379","DOIUrl":"https://doi.org/10.1113/JP291379","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845402","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":"Modulation of pain by affective touch: effects of childhood trauma, depression, chronic pain, and spinal segment.","authors":"Benedetta Albinni, Marisa Zimmerman, Vincent Alasha, Jacob Ross, Lindsey Crankshaw, Emrys Jones, Jeffery Lewis, Sandy R Hu, Nathaniel Schuster, Laura Case","doi":"10.1113/JP290242","DOIUrl":"https://doi.org/10.1113/JP290242","url":null,"abstract":"<p><p>Chronic pain is highly prevalent, and non-pharmacological tools are a crucial part of a multimodal approach to reducing burden of pain. Among these touch-based interventions such as massage have long been popular, yet their underlying pain-relieving mechanisms are poorly understood. Touch-based therapies often involve gentle stroking associated with the C-tactile afferent pathway and deep pressure. Although chronic pain patients often find touch less pleasant than individuals without pain, the effects of chronic pain on touch-pain modulation have not been directly studied. In the current study we systematically investigated two affective forms of touch - gentle brushing and deep pressure (compression) - on heat pain perception, testing their effects both within-segment and between-segment to explore their neural mechanism. We compared touch-pain modulation effects in pain-free controls and patients with fibromyalgia (FM), a condition characterized by sensory hypersensitivity and affective alterations, hypothesizing that touch-pain modulation would be reduced in FM. We further examined the role of trauma and depression, which are highly prevalent in FM. Significant touch-pain modulation occurred only for between-segment brushing. No significant differences in touch-pain modulation were observed between FM patients and controls. Notably, trauma history and depression emerged as the strongest predictors of touch-pain modulation. These findings suggest that touch-pain modulation involves supraspinal mechanisms that are preserved in FM and are strongly shaped by trauma history and psychological factors. Our results provide novel insight into biopsychosocial determinants of touch-related pain relief and its relevance to FM. KEY POINTS: Touch-based interventions such as massage are common non-pharmacological approaches for chronic pain, but their mechanisms are poorly understood. Chronic pain patients often exhibit reduced touch pleasantness and endogenous pain modulation, but effects of chronic pain on touch-pain modulation have not been directly studied. We tested the effects of gentle brushing and deep pressure (compression) on heat pain perception, testing both within-segment (same dermatome) and between-segment (between dermatome) conditions in no-pain controls and patients with fibromyalgia (FM). Brushing significantly reduced heat pain in the between-segment condition and did not differ by pain status; trauma history and depression emerged as the strongest predictors of touch-pain modulation. These findings suggest that touch-pain modulation involves supraspinal mechanisms that are preserved in FM and strongly shaped by trauma history and psychological factors.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845444","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":"Human placental exposure to pollutant nanoparticles: uptake, translocation and functional impact.","authors":"Katherine L Bethell, Andrew C Povey, Edward D Johnstone, Peter T Ruane","doi":"10.1113/JP289591","DOIUrl":"https://doi.org/10.1113/JP289591","url":null,"abstract":"<p><p>Nanoparticles are abundant in the natural environment as a result of an exponential increase in the production of engineered particles and pollutants. Due to their small size, nanoparticles can cross mucosal barriers, entering the blood stream and reaching a variety of different tissue types. Pregnant women and their developing fetuses are particularly vulnerable to nanoparticles, with the placenta acting as the critical barrier for fetal exposure. It has not yet been determined how protective the placental barrier is against nanoparticle translocation, with conflicting evidence regarding the mechanisms of nanoparticle uptake and the physicochemical factors that influence their transport. Here we summarise current findings on nanoparticle transit across the placenta and the associated impacts on placental development and function. Together, these insights highlight key considerations for future research in this area.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845406","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":"Is oxysterol accumulation a central physiological trigger of inflammaging?","authors":"Nila Ganamurali, Sarvesh Sabarathinam","doi":"10.1113/JP291339","DOIUrl":"https://doi.org/10.1113/JP291339","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845434","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 deletion of HSP60 in cholinergic neurons alleviates LPS-induced depressive-like behaviours in mice by reducing neuroinflammation.","authors":"Xiangzan Wei, Xiaoni Zhong, Yu Ouyang, Yongxiang Liu, Weirong Qin","doi":"10.1113/JP290049","DOIUrl":"https://doi.org/10.1113/JP290049","url":null,"abstract":"<p><p>Depression is a significant global health issue characterized by complex underlying mechanisms. This study aimed to investigate the role of cholinergic neuron-specific heat shock protein 60 (HSP60) in modulating lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviours in mice. Cholinergic neuron-specific HSP60 knockout mice were generated by crossing Hsp60-flox mice with Chat-cre mice. Genotyping confirmed the successful creation of the knockout. The effects of LPS on weight loss, behavioural changes, cytokine levels, neuroinflammation markers and signalling pathway proteins were assessed. Behavioural assessments included the tail suspension test and sucrose preference test. HSP60 knockout mice exhibited mitigated weight loss in response to LPS. Behavioural tests indicated that HSP60 deficiency alleviated LPS-mediated depressive-like behaviours without affecting locomotor activity. In the hippocampus, LPS treatment significantly altered cytokine levels, increasing pro-inflammatory cytokines at the same time as decreasing anti-inflammatory cytokines. HSP60 knockout mice partially reversed these effects, showing increased anti-inflammatory and decreased pro-inflammatory cytokines. LPS-induced upregulation of neuroinflammation markers such as glial fibrillary acidic protein, NLRP3 (i.e. NOD-, LRR- and pyrin domain-containing protein 3) and p-IKKα/β [i.e. the phosphorylated forms of the catalytic subunits of the IκB kinase (IKK) complex, specifically IKKα (CHUK) and IKKβ] was significantly reduced in HSP60 knockout mice. Additionally, LPS-induced elevation of phosphorylated eukaryotic translation initiation factor 2α levels in the hippocampus was attenuated by HSP60 deficiency, without affecting other signalling pathway proteins. These findings suggest that HSP60 in cholinergic neurons plays a critical role in regulating LPS-induced neuroinflammation and depressive-like behaviours. Targeting HSP60 in cholinergic neurons may provide a therapeutic approach for mitigating neuroinflammation and associated depressive symptoms. KEY POINTS: Specific knockout of HSP60 in cholinergic neurons could protect against LPS-induced physiological and behavioral impairments, including mitigated weight loss, improved depressive-like behaviors, and unaffected locomotor activity. Cholinergic neuron-specific HSP60 deletion could attenuate neuroinflammation by reversing LPS-induced cytokine imbalance, suppressing key inflammatory markers (GFAP, NLRP3, cGAS, p-IKKα/β), and crucially, by preserving hippocampal acetylcholine levels, a key neurotransmitter with established anti-inflammatory properties. HSP60 deficiency selectively reduces the LPS-induced phosphorylation of the eukaryotic translation initiation factor 2α (p-eIF2α) in the hippocampus, indicating a targeted modulation of the cellular stress and protein synthesis regulation pathway, without altering other major signaling molecules.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845476","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":"Hypoxia-induced vulnerability of the somatosensory nervous system.","authors":"Jack Corbett, Richard P Hulse","doi":"10.1113/JP290625","DOIUrl":"https://doi.org/10.1113/JP290625","url":null,"abstract":"<p><p>Hypoxia exerts a strong influence on nervous system behaviour, with its effects most apparent in tissues where metabolic demand is high. This includes the somatosensory system. The stability of metabolic processes within nociceptive neural circuits is essential for their survival and integrity of sensory signalling. These neurones rely heavily on oxygen to maintain fundamental components of neurocommunication. Because of this dependence, pain pathways are particularly vulnerable to even modest reductions in oxygen supply and utilisation that can arise from vascular insufficiency, environmental exposure or systemic conditions including ageing, diabetes, obesity and inherited forms of sensory neuropathy. Reductions in oxygen tissue tension impairs neuronal respiration, leading to a compensatory shift towards less efficient metabolic routes. This transition disrupts cellular energy balance, affects neurocommunication, and can trigger structural and functional changes within sensory circuits. Over time, these alterations contribute to maladaptive processing, modifying how individuals perceive and respond to sensory input. Resulting phenotypes may include heightened sensitivity and/or sensory neurodegeneration, depending on the severity and duration of oxygen limitation. Recognising how hypoxia shapes sensory neurophysiology is particularly important in contexts where pain perception is already altered, such as in ageing or metabolic disease. These conditions often combine impaired perfusion with increased metabolic strain, placing additional pressure on vulnerable sensory neuronal populations. Integrating molecular, metabolic and neurophysiological perspectives emphasises hypoxia as a central driver of nociceptive disturbance and provides a coherent framework for targeting neurometabolic pathways in the treatment of chronic pain.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845355","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":"Braking bad: do environmental hypoxia and contractile activity really work well together to support muscle angiogenesis?","authors":"Emilie Roudier, Pierre Lemieux","doi":"10.1113/JP291258","DOIUrl":"https://doi.org/10.1113/JP291258","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845293","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":"Parasympathetic overdrive as a cause of overactive bladder in a high-fat-diet-induced obesity mouse model.","authors":"Ayu Sugiura, Retsu Mitsui, Kyoko Miwa-Nishimura, Hikaru Hashitani","doi":"10.1113/JP291127","DOIUrl":"https://doi.org/10.1113/JP291127","url":null,"abstract":"<p><p>Overactive bladder (OAB) is a highly prevalent condition characterized by urinary urgency that negatively affects quality of life. Because obesity and metabolic syndrome (MetS) are known as major risk factors for OAB, we explored the mechanisms underlying obesity-/MetS-associated OAB using a high-fat-diet (HFD)-induced obesity mouse model. Four-week-old male C57BL6 mice were subjected to either a HFD (60 kcal% fat) or a normal diet (ND, 10 kcal% fat). Cystometry and bladder afferent activity recordings in anaesthetized mice, isometric tension recordings in detrusor smooth muscle (DSM) strips and intravesical pressure recordings in isolated whole bladders were performed after 12 weeks of ND or HFD feeding. Bladder morphology was examined using histochemistry. HFD mice exhibited a MetS phenotype characterized by abdominal obesity, hyperglycaemia and insulin resistance. HFD mice developed enlarged non-voiding contractions (NVCs) during bladder filling associated with enhanced afferent activity. Both were attenuated by intravenous administration of atropine (1 mg/kg) or pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), a P2X purinoceptor antagonist (10 mg/kg), or by bilateral pelvic nerve transection. In ND mice these drugs attenuated NVCs but not afferent activity. Spontaneous or nerve-evoked DSM contractions or transient pressure increases in isolated whole bladders were unaltered in HFD mice. DSM thickness, collagen deposition or parasympathetic nerve density in HFD bladders was unaltered. Thus the OAB phenotype in HFD mice appears to primarily results from the increased parasympathetic neural activity during the bladder storage phase. These results provide the basis of the clinical effectiveness of anti-muscarinic agents on OAB as well as the enhanced purinergic transmission in OAB patients known as 'atropine resistance'. KEY POINTS: High-fat-diet (HFD)-induced obese mice exhibiting metabolic syndrome phenotype display overactive bladder (OAB) phenotype characterized by enlarged non-voiding contractions (NVCs) associated with bladder afferent overactivity. Both enlarged NVCs and afferent overactivity in HFD mice are reversed by intravenous administration of atropine or the P2X receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), or by bilateral pelvic nerve transection. Detrusor muscle strip contractility, corresponding spontaneous pressure increases in isolated whole bladder and bladder morphology are unaltered in HFD mice. The OAB phenotype in HFD-induced obese mice primarily results from excessive parasympathetic activity during the bladder storage phase. These findings provide a basis for the clinical effectiveness of anti-muscarinic drugs on bladder storage symptoms as well as the relevance of enhanced purinergic transmission in OAB patients known as 'atropine resistance'.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845510","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":"Chronic attenuation of brain leptin signalling is associated with early metabolic dysfunction in lean rats.","authors":"Cristina Pintado, Lorena Mazuecos, Óscar Gómez-Torres, Beatriz Merino, Elena Casanueva-Álvarez, Blanca Rubio, Emma Burgos-Ramos, Sara Artigas-Jerónimo, Eduardo Moltó, Inés María Ramos, Justa María Poveda, Germán Perdomo, Irene Cózar-Castellano, Carmen Arribas, Ernesto Bernal-Mizrachi, Antonio Andrés, Nilda Gallardo","doi":"10.1113/JP290832","DOIUrl":"https://doi.org/10.1113/JP290832","url":null,"abstract":"<p><p>Brain leptin signalling plays a central role in the regulation of energy balance and glucose homeostasis, yet its contribution to early metabolic dysfunction preceding overt obesity remains uncertain. In the present study, we examined the metabolic consequences of sustained attenuation of central leptin receptor signalling in lean rats. Adult animals received chronic i.c.v. infusion of a rat-specific leptin receptor antagonist (SLA) or vehicle for 21 days. SLA administration increased food intake with modest gains in body weight and visceral adiposity at the same time as maintaining normoleptinemia, and induced hepatic and pancreatic lipid accumulation, hyperinsulinemia, impaired glucose tolerance and hyperglucagonemia. These alterations were accompanied by hepatic glucagon resistance, as indicated by attenuated gluconeogenic gene induction and reduced CREB phosphorylation following in vivo glucagon stimulation. SLA-infused rats also exhibited elevated circulating total and branched-chain amino acids, reduced hepatic branched-chain α-ketoacid dehydrogenase activity and increased fibroblast growth factor 21 levels, consistent with disrupted glucagon-amino acid signalling. Together, these findings indicate that impaired central leptin signalling induces co-ordinated endocrine and metabolic disturbances in the absence of obesity, supporting a role for altered central neuroendocrine regulation in the early development of metabolic dysfunction. KEY POINTS: Chronic attenuation of brain leptin signalling is associated with early metabolic dysfunction in lean rats. Central leptin disruption leads to hyperglucagonemia, hepatic glucagon resistance and altered amino acid metabolism. Elevated fibroblast growth factor 21 levels and impaired branched-chain amino acid catabolism reflect early liver-α-cell axis dysregulation. This model provides insight into neuroendocrine drivers of non-obese prediabetes.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845411","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}