Function (Oxford, England)最新文献

{"title":"Dietary salt impairs circadian physiological metabolic adaptations in salt-sensitive hypertension.","authors":"Lashodya V Dissanayake, Adrian Zietara, Ratnakar Tiwari, Melissa Lowe, Olha Kravtsova, Vladislav Levchenko, Ruslan Bohovyk, Michelle L Gumz, Alexander Staruschenko","doi":"10.1152/function.106.2025","DOIUrl":"10.1152/function.106.2025","url":null,"abstract":"<p><p>The body's circadian rhythm is coordinated by core clock proteins [period (PER), cryptochrome circadian regulator (CRY), circadian locomotor output cycles kaput (CLOCK), and basic helix-loop-helix ARNT-like protein 1 (BMAL1)] that function in both the central hypothalamic and peripheral tissue molecular clocks. Our recent study demonstrated that deletion of <i>Per1</i> in Dahl salt-sensitive (SS) rats (SS^Per1-/-) exacerbated SS hypertension (HTN), kidney injury, and disrupted blood pressure rhythms. To define time-of-day-, genotype-, and diet-dependent alterations in the renal transcriptome and proteome associated with SS HTN, kidney cortex samples were collected from SS and SS^Per1-/- rats fed either a normal-salt (NS, 0.4% NaCl) or high-salt (HS, 4% NaCl) diet, during both the active (night) and inactive (day) periods. Dietary challenges were conducted for 3 wk in male rats. Bulk RNA-sequencing was performed on both NS- and HS-fed groups, and proteomic analyses were performed in HS-fed groups. In SS rats, HS intake blunted time-of-day-dependent transcriptional changes. Pathway analyses predicted significant stress and immune responses, as well as metabolic adaptations, induced by the HS diet. Specifically, the remodeling of the pyruvate dehydrogenase complex was identified as a key prediction in both transcriptomic and phosphoproteomic datasets. As expected, <i>Per1</i> deletion further exacerbated disruptions in immune regulation and metabolic adaptation. Collectively, these findings demonstrate that numerous renal genes exhibit diurnal oscillations under physiological conditions and are profoundly disrupted in SS HTN, likely contributing to impaired kidney function and circadian misalignment of blood pressure regulation.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e1062025"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13053008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147438163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial CD44 cleavage by ADAM17 impairs shear stress mechanotransduction.","authors":"Gavin Power, Min Jeong Cho, Jesus H Beltran-Ornelas, Marc A Augenreich, Natnicha Imkaew, Olubodun M Lateef, Francisco I Ramirez-Perez, Larissa Ferreira-Santos, Camila Manrique-Acevedo, Luis A Martinez-Lemus, Jaume Padilla","doi":"10.1152/function.113.2025","DOIUrl":"https://doi.org/10.1152/function.113.2025","url":null,"abstract":"<p><p>In individuals with type 2 diabetes (T2D), blood flow-mediated increases in endothelial shear stress fail to elicit a robust vasodilatory response. This defective flow-mediated dilation (FMD) is associated with loss of the endothelial glycocalyx, a mechanosensitive extracellular structure that lines the luminal side of blood vessels. Hyaluronan (HA), a polysaccharide constituent of the glycocalyx, is anchored to the plasma membrane by its primary cell-surface receptor, CD44, which is implicated in mechanotransduction of shear stress. Critically, CD44 is also a substrate of a disintegrin and metalloprotease 17 (ADAM17), a sheddase which is elevated in T2D. However, it is currently unknown whether elevated ADAM17 activity enhances CD44 cleavage from the endothelium and whether this contributes to impaired mechanotransduction and reduced FMD in T2D. Herein, we report elevated plasma HA and ADAM17 activity in a cohort of women and men with T2D and impaired FMD. Moreover, reduced endothelial CD44 is coupled with impaired FMD in arteries isolated from diabetic (<i>db</i>/<i>db</i>) mice. We also provide support for CD44 as a mechanotransducer of HA-associated shear stress mechanosensation and ADAM17-mediated cleavage of CD44 attenuating shear stress mechanotransduction. Finally, using an in-vitro assay and surface plasmon resonance, we show that active recombinant human ADAM17 (ADAM17-r) cleaves recombinant human CD44 and that intraluminal incubation of isolated arteries with ADAM17-r reduces FMD. Collectively, this work supports the role of ADAM17-mediated cleavage of CD44 in impairing endothelial shear stress mechanotransduction.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147505603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The systems that transport ions and their impact on sperm function and male fertility.","authors":"Mumtarin Jannat Oishee, Beth Baum, Gustavo Blanco","doi":"10.1152/function.083.2025","DOIUrl":"10.1152/function.083.2025","url":null,"abstract":"<p><p>Sperm are highly specialized cells whose primary function is to transport and deliver the paternal genetic information to the oocyte. Although morphologically complete after being produced in the testis, sperm acquire fertilizing competence through a series of post-testicular maturation steps. During this journey, cues from the surrounding luminal fluids play a crucial role in sperm functional maturation. Among these signals, changes in the ion composition of the extracellular medium are particularly important. Sperm detect these ion fluctuations and regulate their intracellular ion concentrations through membrane ion transport systems. While some of these transporters are shared with somatic cells, others have evolved as specialized molecular variants uniquely adapted to meet the specific physiological demands of sperm. Genetic mutations and dysfunction of certain ion transporters have been associated to male infertility. Consequently, ion transporters represent promising diagnostic markers for the detection of male infertility and are attractive pharmacological targets for the development of therapies to enhance or inhibit male fertility. This review provides a comprehensive analysis of the ion transport systems that operate in sperm membranes and discusses their function, regulation, and contribution to the overall physiology of sperm.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147438209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracellular calcium release activates carotid body afferents by fentanyl.","authors":"Ying-Jie Peng, Oren Kabil, Ning Wang, Zheng Xie, Aaron P Fox, Nanduri R Prabhakar","doi":"10.1152/function.078.2025","DOIUrl":"10.1152/function.078.2025","url":null,"abstract":"<p><p>We recently reported [Peng YJ, Nanduri J, Wang N, Xie Z, Fox AP, Prabhakar NR. <i>Function</i> (Oxf) 6: zqaf020, 2025] that fentanyl activates carotid body (CB) afferents via kappa opioid receptors (KORs), while CB denervation exacerbates, coadministration of fentanyl with a KOR agonist attenuates opioid-induced respiratory depression (OIRD). These findings indicated that CB chemoreflex activation by fentanyl may counteract OIRD. The present study investigated the cellular mechanisms underlying CB afferent activation by fentanyl. We hypothesized that Ca²⁺ signaling in glomus cells mediates CB activation by fentanyl. Using Fura-2 calcium imaging in rat glomus cells, we observed that fentanyl increased intracellular Ca²⁺ even in the absence of extracellular calcium. Pretreatment with thapsigargin, which depletes internal Ca²⁺ stores, abolished Ca²⁺ response, suggesting that fentanyl releases Ca²⁺ from intracellular stores. In human embryonic kidney cells expressing KOR and G protein alpha q subunit (Gαq), fentanyl promoted KOR-Gαq complex formation and stimulated phospholipase C (PLC), elevating inositol trisphosphate (IP₃) levels in the CB. Pharmacological blockade of KOR, Gαq, PLC, or IP₃ receptors prevented both the rise in [Ca²⁺]_i and CB afferent activation. Collectively, these results identify a previously uncharacterized KOR-Gαq-PLC-IP₃R-Ca²⁺ signaling pathway in glomus cells that mediates CB afferent activation by fentanyl, providing new mechanistic insight into how CB chemoreflex activation by fentanyl may mitigate OIRD.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0782025"},"PeriodicalIF":3.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12790850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timing matters: circadian rhythm disruption in alcohol-associated peripheral organ pathophysiology.","authors":"Shannon M Bailey","doi":"10.1152/function.099.2025","DOIUrl":"10.1152/function.099.2025","url":null,"abstract":"<p><p>Circadian rhythms influence the pathophysiological effects of alcohol. This review examines how alcohol disrupts circadian regulation in peripheral organs, particularly the liver, intestine, cardiovascular system, and skeletal muscle, and how circadian disruption exacerbates metabolic dysfunction and organ injury. Evidence from preclinical and human studies indicates that both genetic and environmental circadian disruption increases alcohol-induced gut permeability, systemic inflammation, and liver disease. This review also presents how other lifestyle and environmental factors such as diet, smoking, and shift work worsen circadian disruption and alcohol-related toxicity. Emerging circadian-based therapeutic strategies and key research priorities are discussed. Advancing understanding of alcohol-circadian interactions is essential for developing more effective, personalized treatments for alcohol-associated diseases.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0992025"},"PeriodicalIF":3.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12915498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orexin facilitates the peripheral chemoreflex in the active phase via corticotropin-releasing hormone neurons that project to the nucleus of the solitary tract.","authors":"Ruwaida Ben Musa, Fateme Khodadadi-Mericle, David D Kline, Eileen M Hasser, Kevin J Cummings","doi":"10.1152/function.084.2025","DOIUrl":"10.1152/function.084.2025","url":null,"abstract":"<p><p>Projections from the paraventricular nucleus (PVN) of the hypothalamus to the nucleus of the solitary tract (nTS) facilitate the peripheral chemoreflex. A significant proportion of this projection is composed of corticotropin-releasing hormone (CRH) neurons. Orexin neurons in the perifornical hypothalamus augment the peripheral chemoreflex, project to the PVN, and facilitate the hypoxia-induced activation of nTS-projecting CRH neurons. We hypothesized that nTS-projecting CRH neurons are necessary for the full reflex, and that orexin facilitates the reflex via the CRH-nTS pathway. We chemogenetically silenced or activated nTS-projecting CRH neurons during normoxia and acute hypoxia. For each rat, reflex strength was tested in both inactive and active phases as the activity of orexin neurons is phase dependent. Testing was done following vehicle, Compound 21 (1 mg/kg) to activate Gi- or Gq-DREADDs, and after systemic Ox1R blockade (SB-334867; 1 mg/kg). We performed immunohistochemistry to assess how chemogenetic manipulation of nTS-projecting CRH neurons influenced their activation by hypoxia (via cFos). Activating the CRH-nTS pathway had no effect on the chemoreflex in either phase. Silencing the pathway in the active phase, but not inactive phase, reduced the strength of the reflex by ∼50% and prevented further inhibition by Ox1R blockade, suggesting orexin acts via Ox1R on CRH neurons. Pathway silencing reduced the proportion of nTS-projecting CRH neurons activated by hypoxia, consistent with the effects of pathway silencing on the reflex. These data suggest that orexin augments the peripheral chemoreflex in the active phase via the CRH-nTS pathway.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0842025"},"PeriodicalIF":3.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12850509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From blood vessels to lymphatics and back again.","authors":"Walter L Murfee, Jerome W Breslin","doi":"10.1152/function.102.2025","DOIUrl":"10.1152/function.102.2025","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e1022025"},"PeriodicalIF":3.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12782043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anesthesia blocks the cardiovascular response to baroreceptor unloading in rats.","authors":"Michelle L Nieman, Srikumaran Sakthivel, Bryan Mackenzie, John N Lorenz","doi":"10.1152/function.093.2025","DOIUrl":"10.1152/function.093.2025","url":null,"abstract":"<p><p>Baroreflex responsiveness and orthostatic stability in humans can be assessed by a variety of approaches, including exposure to graded levels of lower body negative pressure (LBNP). However, such approaches have limited applicability in animal studies owing to the need to anesthetize or sedate the animal. We recently reported a novel approach for the assessment of baroreceptor responsiveness in the awake rat using LBNP and presented preliminary findings that 3% isoflurane anesthesia completely blocked the normally robust baroreflex. In the present study, we sought to extend these findings by studying the effects of several common anesthetics on LBNP responsiveness. Blood pressure (BP) and heart rate (HR) responses to progressive levels of LBNP were first made in awake rats (male and female), followed by measurements under various anesthetics regimens: <i>1</i>) pentobarbital; <i>2</i>) ketamine plus xylazine; <i>3</i>) isoflurane at 3%, 2%, and 1.5%; <i>4</i>) urethane delivered as an intraperitoneal bolus, slow intraperitoneal infusion, and slow intravenous infusion. As previously reported, BP in awake rats was well maintained up to -15 mmHg LBNP, accompanied by a robust baroreflex tachycardia. Despite varying effects on steady-state BP and HR, all of the anesthetics tested severely or completely blocked the ability to maintain BP during LBNP and completely blocked reflex tachycardia. BP, but not reflex tachycardia, during LBNP was partially preserved only in those rats treated with intravenous urethane. These data confirm that the functional baroreflexes that normally maintain BP during orthostatic challenge are blocked by commonly used anesthetics.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0932025"},"PeriodicalIF":3.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiological relevance of autocrine melatonin signaling in pineal and extrapineal sites: a systematic review.","authors":"Gaudence Ndinganire, Gaspard Ntamukunzi, Abdullateef Isiaka Alagbonsi","doi":"10.1152/function.101.2025","DOIUrl":"10.1152/function.101.2025","url":null,"abstract":"<p><p>Beyond the pineal gland, melatonin is produced locally in many extrapineal organs, where it mediates local tissue homeostasis. However, little attention is paid to the physiological role of autocrine melatonin signaling across body organs. This study synthesizes original data to address this gap, as gaining insight into this topic could lead to new therapeutic approaches for diseases associated with melatonin. This systematic review used a narrative synthesis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline standards to synthesize original articles published between January 2000 and July 2025, using the Wiley Online Library and PubMed databases. From the 41 studies reviewed, various targets for the physiological relevance of autocrine melatonin signaling in pineal and extrapineal sites were noted. In descending order, the targets were immunoregulatory switch (8 studies), ovary and reproductive system (7 studies), pineal gland (6 studies), gut (5 studies), skin and hair follicles (3 studies), retina (3 studies), testes (3 studies), liver and metabolic tissues (2 studies), bone (2 studies), cardiovascular/endothelial compartment (1 study), and mitochondria (1 study). A layer of melatoninergic biology that is different from the traditional pineal endocrine signal and has biological and clinical significance is autocrine melatonin signaling in the pineal and numerous extrapineal locations. Although there is a translational potential, thorough mechanistic human research and better assays are required due to model heterogeneity and scarcity of human data.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e1012025"},"PeriodicalIF":3.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12915497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145999527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opportunities for RNA sequencing in physiology: from big data to understanding homeostasis and heterogeneity.","authors":"Jeremy W Prokop, Stephanie M Bilinovich, Ember Tokarski, Sangeetha Vishweswaraiah, Sophie VanderWeele, Akansha S Das, Surya B Chhetri, Alexander Dao, Sanjana Arora, Austin Goodyke, Katie L Buelow, Mason Westgate, Elizabeth A VanSickle, Claudia J Edell, Lance N Benson, Daniel B Campbell, Caleb P Bupp, Amanda Holsworth, Nicholas L Hartog, Jena M Krueger, Marcos Cordoba, Matthew Sims, Maximiliano A Tamae Kakazu, Angela M Peraino, Stewart F Graham, Tim Triche, Elora Hussain, Mara L Leimanis-Laurens, Connie M Krawczyk, Jennifer S Pollock, Surender Rajasekaran","doi":"10.1152/function.019.2025","DOIUrl":"10.1152/function.019.2025","url":null,"abstract":"<p><p>The quantity of physiological data has grown exponentially, yielding insights into mechanisms of phenotypic and disease pathways. Among the powerful tools for physiological omics is the study of RNA, where broad sequencing of RNA leads to hypothesis generation and testing while providing observational discovery. Emphasis has been placed on RNA molecules that code for proteins, even though they represent a minority of total RNA. Diverse sequencing methods have rapidly expanded the identification of non-protein-coding molecules, including nonsense-mediated decay and long non-coding RNAs (lncRNA), which now represent the most diverse class of RNA. Increasing attention needs to be paid to the data processing of RNA sequencing to interpret transcript-level mapping data in the context of protein biology, as many protein-coding genes have diverse noncoding transcripts. Over the past several years, single-cell and spatial transcriptomics have yielded unprecedented insights into cellular, tissue, and organ physiology. Building on these advancements, bulk RNA sequencing tools have begun producing robust deconvolution methods that enhance the analysis of human genes, the detection of foreign RNA from bacteria and viruses, and provide deep insights into complex immunological events, such as B- and T-cell recombination. Over a million RNA-sequencing datasets have been generated, providing resources for data scientists to reprocess data and expand larger databases. From model organisms to complex human diseases, RNA sequencing resources continue to transform our knowledge of the complexity of personalized disease insights. Observational science is at the core of physiology, and growth of RNA sequencing represents a significant tool for physiologists.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0192025"},"PeriodicalIF":3.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12790856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}