American journal of physiology. Regulatory, integrative and comparative physiology最新文献

{"title":"The Antidipsogenic Action of Nesfatin-1 Requires Activation of a GLP-1 Receptor.","authors":"Colleen R Bocke, Gina L C Yosten, Willis K Samson","doi":"10.1152/ajpregu.00087.2025","DOIUrl":"https://doi.org/10.1152/ajpregu.00087.2025","url":null,"abstract":"<p><p>Nesfatin-1 is a potent inhibitor of food and water ingestion, and it has been reported that the anorexigenic and antidipsogenic actions of glucagon-like peptide-1 [GLP-1] require recruitment of nesfatin-1-producing neurons in brain. Multiple neuropeptides appear to interact in reciprocal fashion to control ingestive behaviors. We demonstrate now that the antidipsogenic action of nesfatin-1 can be significantly reversed by pretreatment with the GLP-1 antagonist, exendin-3. Our prior work indicated that the antidipsogenic and anorexigenic actions of nesfatin also could be abrogated by blockage of melanocortin, corticotropin releasing factor and oxytocin signaling. We now propose a novel neuronal circuit activated by nesfatin-1, including those other peptide-expressing neurons.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor necrosis factor-alpha in mediation of acute salt loading induced natriuresis in mice; evidence for its physiological role in regulating kidney function.","authors":"Dewan S A Majid, Alexander Castillo","doi":"10.1152/ajpregu.00253.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00253.2024","url":null,"abstract":"<p><p>Tumor necrosis factor-alpha (TNF-α) exerts natriuresis via activation of its receptor type 1 in the kidney. Although chronic high salt (HS) intake produces this cytokine by immune activation of the mononuclear phagocyte cells, it has not yet been examined whether acute salt loading produces this cytokine and can induce consequent natriuresis. Here, we measured the changes in plasma level and urinary excretion rate of TNF-α (U_TNFαV) during intravenous infusion of isotonic saline (0.9% NaCl), first at euvolemic conditions (3 µL/min for 60 min; Baseline period) and then at an enhanced infusion rate (12 µL/min for 90 min; Salt-loading period) in control mice (n=7) and TNF-α inactivator, etanercept (ETN; 0.5 mg/kg intraperitoneally once daily for 3 days prior to the experiment day; n=7) treated mice. TNF-α concentration in samples were determined using ELISA kit (Bioscience, Woburn, MA). During Baseline period, TNF-α level in plasma was undetected but it increased during salt-loading period in both control (3.7±1.3 pg/mL) and ETN treated (3.3±1.2 pg/mL) mice. In control mice, the baseline U_TNFαV was minimal (0.01±0.002 pg/min/g) but increased to 0.1±0.03 pg/min/g (P<0.05) with associated increase in urinary sodium excretion (U_NaV; 0.5±0.2 to 4.8 ±1.2 µmol/min/g; P<0.05) during salt-loading period. In ETN treated mice, both the U_TNFαV (0.01±0.004 to 0.02±0.01 pg/min/g) and U_NaV (0.4±0.6 to 1.1±0.3 µmol/min/g) responses to salt-loading were markedly attenuated. These findings demonstrate that TNF-α contributes to saline induced natriuresis, suggesting a physiological role for this cytokine in regulating renal excretory function during acute salt loading.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"THE IMPACT OF ADULT AND LIFELONG HYPOXIA ON VENTRICLE PHENOTYPE IN ZEBRAFISH (<i>DANIO RERIO</i>).","authors":"Brandt Smith, Gil Martinez-Bautista, Steven Williams, Warren W Burggren, Dane A Crossley","doi":"10.1152/ajpregu.00033.2025","DOIUrl":"https://doi.org/10.1152/ajpregu.00033.2025","url":null,"abstract":"<p><p>Hypoxia occurs naturally in a wide range of aquatic ecosystems. However, the physiological and morphological effects of prolonged hypoxia on organ systems remain poorly understood, especially in the cardiovascular system of fishes. We assessed contractile force of isolated hearts from adult zebrafish from control conditions (PO₂ = 21kPa), from adults after a 4-week exposure to hypoxia (PO₂ = 10kPa), or from adults exposed to lifelong hypoxia (PO₂ = 10kPa) throughout development, from egg to adult. Isolated ventricle contractility measurements were conducted during two challenges: increasing stimulation frequency (force-frequency) and during acute hypoxia exposure. All contractile parameters were at least 35% greater in lifelong hypoxic fish compared to control fish while heart mass was significantly smaller in lifelong hypoxic fish compared to controls. However, there were no differences in in the response to force-frequency protocol or graded acute hypoxia. Thickness of the ventricle's compact myocardium was increased ~35% by lifelong hypoxia but not by 4 weeks of hypoxia as adults compared to the control fish. Further, mitochondrial abundance did not significantly change. Collectively, these data suggest that early life hypoxia has major effects on remodeling cardiac tissue and performance in zebrafish.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Influence of Aortic Compliance on Pulsatile Cerebral Blood Flow in Young Healthy Men: Insight from Endurance Training Intervention.","authors":"Tsubasa Tomoto, Hiroshi Kumagai, Takashi Tarumi, Jun Sugawara","doi":"10.1152/ajpregu.00038.2025","DOIUrl":"https://doi.org/10.1152/ajpregu.00038.2025","url":null,"abstract":"<p><p>Aortic compliance reflects the ability to buffer arterial pulsations generated by the left ventricle (LV) and attenuate pulsatile cerebral blood flow (CBF). Endurance training is associated with increased stroke volume (SV) and enhanced LV systolic function, potentially increasing arterial pulsations to the brain. This study investigated the contribution of aortic compliance to the heart-brain hemodynamic interaction, providing insights from endurance training intervention and lower body negative pressure (LBNP) stimulus. Ten male collegiate tennis players underwent an eight-month endurance training program to improve cardiac function. SV and LV systolic function were measured using echocardiography and applanation tonometry. Pulsatile cerebral blood velocity in the middle cerebral artery was assessed by transcranial Doppler. Aortic compliance was calculated as the ratio between estimated SV via Modelflow and aortic pulse pressure via transfer function from radial arterial pressure. The release of -30 mmHg LBNP was used to initiate a rapid recovery of limited venous return and consequent increases in SV and CBF to assess dynamic recovery slopes. Endurance training increased SV, LV systolic function, and aortic compliance at rest, whereas pulsatile CBF was unchanged. The recovery slopes of SV and aortic compliance were steeper after endurance training, while the slopes of pulsatile CBF remained similar. The change in the slope of aortic compliance was negatively correlated with the change in the slope of pulsatile CBF (r=-0.758, P=0.011). These results suggest that improved aortic compliance after endurance training may accommodate increased SV and LV systolic function and buffer potential increases in arterial pulsations to the brain.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence for potentiation in sympathetic neurovascular transduction following exercise in normotensive adults.","authors":"Massimo Nardone, Julian C Bommarito, Kathryn N Pfundt, Samuel Amanual, Yeshale Chetty, Philip J Millar","doi":"10.1152/ajpregu.00084.2025","DOIUrl":"https://doi.org/10.1152/ajpregu.00084.2025","url":null,"abstract":"<p><p>Following a single bout of dynamic exercise, vascular conductance increases while sympathetic nerve traffic appears unchanged. Discordance between vascular and sympathetic responses may reflect modulation in vasoconstrictor responsiveness. The primary objective was to evaluate sympathetic neurovascular transduction following cycling exercise. The secondary objective was to explore mechanisms contributing to altered sympathetic neurovascular transduction by manipulating limb vascular conductance using local heating of the foot. We hypothesized that sympathetic neurovascular transduction would decrease following cycling exercise but would be unchanged by lower limb heating. Sixteen adults (22 ± 3 years; 43 ± 8 mL/kg/min; 8 female) underwent measurements of heart rate (electrocardiography), mean arterial pressure (MAP; photoplethysmography), muscle sympathetic nerve activity (MSNA; microneurography), and femoral vascular conductance (FVC; Duplex ultrasound) across 3 interventions: cycling exercise (60-min, 60%VO_2peak, n=16), time-control (60-min, n=16), and lower limb heating (foot submersion into 40°C water, n=9). MSNA-FVC transduction was quantified using signal averaging. Compared to control, exercise did not alter MSNA (<i>P</i>=0.72), but increased FVC (<i>P</i><0.01) and MSNA-FVC transduction (-8.6 ± 4.5 vs. -15.1±5.7 mL/min/100mmHg; <i>P</i><0.01). Compared to exercise, heating did not alter MSNA (<i>P</i>=0.71) and tended evoke larger increases in resting FVC (<i>P</i>=0.09). However, increases in MSNA-FVC transduction following exercise tended to persist when compared to heating (-8.7 ± 8.0 vs. -15.1 ± 5.9 mL/min/100mmHg; <i>P</i>=0.06). Contrary to our hypothesis, these findings provide evidence for potentiated sympathetic neurovascular transduction following acute cycling exercise in healthy adults. The observed increase in neurovascular transduction appears independent of resting vasomotor tone.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endogenous muscarinic acetylcholine receptor signaling blunts α₁-adrenergic vasoconstriction during higher-intensity handgrip exercise in humans.","authors":"Janée D Terwoord, Frank A Dinenno, Jennifer C Richards, Christopher M Hearon","doi":"10.1152/ajpregu.00305.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00305.2024","url":null,"abstract":"<p><p>Muscarinic acetylcholine receptors (mAChRs) are expressed ubiquitously in the human skeletal muscle vasculature. Prior studies have been unable to identify a contribution of mAChR signaling to exercise-mediated vasodilation; however, no studies have determined whether endogenous mAChR signaling regulates the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction, a phenomenon called \"functional sympatholysis.\" We tested the hypothesis that endogenous mAChR signaling contributes to functional sympatholysis in humans. In healthy volunteers (8 F, 8 M; 26 ± 5 yr), changes in forearm vascular conductance (ΔFVC) were calculated in response to intra-arterial infusions of phenylephrine (PE; α₁-agonist) during <i>1</i>) infusion of a \"nonmetabolic\" vasodilator at rest (rest; adenosine or sodium nitroprusside), <i>2</i>) dynamic handgrip exercise at 15% maximal voluntary contraction (MVC), and <i>3</i>) higher-intensity exercise (25% MVC). Conditions were completed before and after intra-arterial infusion of atropine (mAChR antagonist). Under control conditions, vasoconstriction to PE was limited in parallel with exercise intensity (PE-induced %ΔFVC, rest: -40 ± 13%, 15% MVC: -20 ± 7%, 25% MVC: -12 ± 8%; <i>P</i> < 0.0001). There was no effect of atropine on PE vasoconstriction during rest (-38 ± 12%; <i>P</i> = 0.60 vs. control) or 15% MVC exercise (-23 ± 7%, <i>P</i> = 0.34 vs. control). However, PE-mediated vasoconstriction was approximately twofold greater during 25% MVC exercise after blockade of mAChRs (-22 ± 9%, <i>P</i> < 0.001 vs. control). These results provide evidence of a novel physiological role of endogenous mAChR signaling as a modulator of α₁-adrenergic vasoconstriction during higher-intensity handgrip exercise in humans.<b>NEW & NOTEWORTHY</b> The present study demonstrates that muscarinic acetylcholine receptor (mAChR) signaling attenuates postjunctional α₁-adrenergic signaling during higher-intensity exercise specifically within contracting skeletal muscle, thereby revealing endogenous mAChR signaling as a potential mechanism of functional sympatholysis. This is the first study to identify an endogenous signaling pathway that selectively modulates α₁-adrenergic vasoconstriction specifically in contracting muscle in humans. These findings establish a novel physiological role for endogenous mAChR signaling in the regulation of muscle blood flow during exercise.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":"328 6","pages":"R619-R627"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cooling-induced changes in intracellular hydrogen peroxide and gene expression in mouse skeletal muscle in vivo.","authors":"Ryotaro Kano, Reo Takeda, Yuta Sotani, Ryo Takagi, Ayaka Tabuchi, Hideki Shirakawa, David C Poole, Yutaka Kano, Daisuke Hoshino","doi":"10.1152/ajpregu.00014.2025","DOIUrl":"10.1152/ajpregu.00014.2025","url":null,"abstract":"<p><p>Changes in intracellular hydrogen peroxide concentration ([H₂O₂]) constitute an important signal-controlling cellular adaptations. In response to cooling, decreases in [H₂O₂] and changes in antioxidant-related gene expression have been observed in skeletal muscle. However, the specific temperature dependence of cooling-induced [H₂O₂] changes and their quantitative relationship to induced gene expression are unknown. This investigation tested the hypothesis that differences in muscle cytosolic and mitochondrial [H₂O₂] changes during cooling/rewarming determine the pattern of H₂O₂-related gene expression. H₂O₂-sensitive cytosolic (HyPer7) and mitochondrial (MLS-HyPer7) fluorescent proteins were expressed into tibialis anterior (TA) muscle of male C57BL/6J mice. The temperature dependence of [H₂O₂] was determined via in vivo imaging during a 3-min cooling protocol from 35°C to 0°C. Two cooling patterns [6 bouts of intermittent cooling (I-Cool) vs. sustained cooling (S-Cool); both to 13°C] were applied over 60 min. Three hours after cooling, the muscles were removed, and gene expression was evaluated using real-time PCR. The decrease in [H₂O₂] was observed in both cytosolic and mitochondrial compartments from 35°C to 13°C but was of greater magnitude in the cytosol; in contrast, further cooling from 12°C to 0°C induced a rebound increase especially in cytosolic [H₂O₂]. I-Cool increased the mRNA level of Nrf2 (+15%, <i>P</i> < 0.001). S-Cool decreased the mRNA levels of Sod2, Cat, and Ucp3 (i.e., -20, -23, and -30%, respectively, <i>P</i> < 0.05). In conclusion, the greatest decrease in temperature-dependent [H₂O₂] occurred at 13°C in the cytosolic and mitochondrial compartments of muscle fibers, and I-Cool increased Nrf2 mRNA expression, whereas S-Cool decreased several antioxidant-related genes.<b>NEW & NOTEWORTHY</b> This in vivo model successfully characterized the effects of cooling on cytosolic and mitochondrial [H₂O₂] in mouse tibialis anterior skeletal muscle. Cooling decreased [H₂O₂] down to ∼13°C, but the effect was reversed at still lower temperatures. Sustained cooling decreased mRNA levels of antioxidant-related genes (Sod2, Cat, and Ucp3), whereas intermittent cooling increased Nrf mRNA expression. These results help elucidate the mechanistic bases for skeletal muscle adaptation to cooling.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R758-R766"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heat exposure, heat strain, and off-work recovery of Guatemalan sugarcane workers.","authors":"Lyndsay Krisher, Karely Villarreal Hernandez, Yaqiang Li, Jaime Butler-Dawson, Diana Jaramillo, Hillary A Yoder, Kevin E Miller, Evan C Johnson, Katherine A James, Miranda Dally, Elizabeth J Carlton, Daniel Pilloni Alessio, Alex Cruz, Joshua Schaeffer, John L Adgate, Lee S Newman","doi":"10.1152/ajpregu.00004.2025","DOIUrl":"10.1152/ajpregu.00004.2025","url":null,"abstract":"<p><p>Agricultural workers are at high risk for heat-related illnesses when performing heavy labor in hot conditions. Occupational heat strain, the physiological response to heat stress, is hypothesized to be common in this worker population but has rarely been measured objectively through core body temperature (T_c). The objective of this study was twofold: <i>1</i>) evaluate workday heat strain and <i>2</i>) examine the trajectory of heat exposure and T_c from the workday through the off-work hours to advance understanding of the recovery process and conditions of heat-exposed agricultural workers. Among 55 male Guatemalan agricultural workers, individual heat exposure (using ambient temperature loggers) and T_c (via an ingestible pill) were measured across a 24-h period, including workday and off-work hours. Urine samples were collected to assess hydration status on and off-work. Workers reported off-work activities, hydration practices, sleep, and nutrition through a survey. Data were summarized using descriptive statistics and visualizations. Workers experienced excessive heat strain (44% with T_c > 38.0°C, 16% with T_c > 38.3°C, and 6% with T_c > 38.5°C) during the workday. Approximately 29% achieved a higher maximal T_c during off-work hours than during the workday. Nearly 15% of workers reported sleeping <7 h. There is a need to understand off-work conditions, practices, and resources available to workers to mitigate heat strain and related illnesses. Heat stress and T_c monitoring should extend to postwork shift for assessment of workers' physiological recovery and to inform more comprehensive interventions to protect worker health.<b>NEW & NOTEWORTHY</b> This study examined the trajectory of heat exposure and core body temperature (T_c) across the workday into off-work hours among agricultural workers at risk of heat-related illness. Workday heat strain was common, and a significant proportion of workers experienced higher off-work T_c compared with their workday T_c. Survey and environmental data collected from workers provide insights into the off-work practices and conditions of the home environment that could influence the recovery of workers.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R703-R717"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corticosterone induces fatty liver syndrome in chickens via glucocorticoid receptor and inhibition of mitochondrial supercomplex formation.","authors":"Huimin Chen, Ke Zhang, Hui Yu, Ziting Guan, Ruqian Zhao, Lei Wu","doi":"10.1152/ajpregu.00313.2024","DOIUrl":"10.1152/ajpregu.00313.2024","url":null,"abstract":"<p><p>Stress is a primary contributor to fatty liver syndrome (FLS) in chickens. Mitochondrial functionality is pivotal in FLS progression, with diminished supercomplex (SC) formation disrupting electron transport and escalating reactive oxygen species (ROS) production. However, the impact of stress on mitochondrial SC in chicken FLS remains elusive. This study used corticosterone (CORT) to model chronic stress and examined its consequences on mitochondrial performance and SC configuration in both in vivo and in vitro FLS models. Notably, the CORT-treated hepatocytes exhibited elevated triglyceride content (<i>P</i> < 0.05), accompanied by increased mitochondrial ROS (<i>P</i> < 0.01). Moreover, CORT-exposed broilers displayed reduced body weight (<i>P</i> < 0.05) alongside heightened liver-to-body weight ratio (<i>P</i> < 0.01), indicative of liver steatosis with increased triglyceride levels in both liver and plasma (<i>P</i> < 0.01). Mitochondrial alterations in reduced ATP content (<i>P</i> < 0.05). Gene expression analysis revealed enrichment in the mitochondrial respiratory chain pathway, with downregulated mRNA expression of complex I-associated SC assembly factors NADH: ubiquinone oxidoreductase complex assembly factor 5 (<i>NDUFAF5</i>), NADH: ubiquinone oxidoreductase complex assembly factor, and translocase of inner mitochondrial membrane domain containing 1 (<i>P</i> < 0.05). Meanwhile, the glucocorticoid receptor (GR) protein level and its specific binding to the <i>NDUFAF5</i> gene promoter were reduced in the CORT group (<i>P</i> < 0.01 and <i>P</i> < 0.05, respectively), accompanied by a decrease in NDUFAF5 protein expression in liver, primary hepatocytes, and AML12 cells (<i>P</i> < 0.05). GR knockdown in AML12 cells reduced NDUFAF5 protein expression (<i>P</i> < 0.05). Thus, these findings imply that GR-mediated transcriptional regulation of complex I assembly factor NDUFAF5 may influence SC assembly, shedding light on stress-induced FLS mechanisms in broilers.<b>NEW & NOTEWORTHY</b> This study reveals the pivotal role of GR-mediated transcriptional regulation in stress-induced FLS in chickens. Chronic stress modeled with CORT disrupted mitochondrial SC assembly, impairing electron transport, elevated ROS production, and liver steatosis. Notably, the downregulation of complex I assembly factors (<i>NDUFAF5</i>, <i>NDUFAF7</i>, and <i>TIMMDC1</i>) and reduced GR binding to <i>NDUFAF5</i> were key mechanisms. These findings provide new insights into stress-driven mitochondrial dysfunction in broiler FLS.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R770-R782"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of CYP450 pathways reduces functional sympatholysis in healthy young adults.","authors":"Alexander A Buelow, Jacob E Matney, Sarah M Skillett, John D Ashley, Jiwon Song, Chris Mixon, Amir Akbari Fakhrabadi, Matthew Stanford, Debra A Bemben, Daniel J Larson, J Mikhail Kellawan","doi":"10.1152/ajpregu.00173.2024","DOIUrl":"10.1152/ajpregu.00173.2024","url":null,"abstract":"<p><p>Functional sympatholysis, the blunting of sympathetic vasoconstriction during exercise, is critical for regulating exercise hyperemia. The role of cytochrome P450-2C9 (CYP450) pathways in functional sympatholysis remains unclear. A total of 21 participants (11 females) completed three study visits (2 experimental). Participants ingested a placebo (PLA) or CYP450 inhibitor fluconazole (FLZ) 120 min before testing in a double-blind, randomized, crossover design. Forearm blood flow (FBF) and mean arterial pressure (MAP) were continuously measured to calculate forearm vascular conductance (FVC) during baseline, -20 mmHg lower body negative pressure (LBNPrest), rhythmic handgrip exercise (Ex) at 20% maximum voluntary contraction, and exercise with LBNP (LBNPex). FLZ did not change FVC at baseline or during Ex (<i>P</i> > 0.05). However, adding LBNPex to Ex reduced FVC in the FLZ condition compared with PLA (PLA: 2 ± 12 Δ% vs. FLZ: -12 ± 13 Δ%, <i>P</i> < 0.001, <i>d</i>: 0.9). A significant change in FVC across time (baseline + LBNPrest vs. Ex + LBNPex) was observed (<i>P</i> < 0.001, [Formula: see text]: 0.8), along with significant effects of condition (PLA vs. FLZ) (<i>P</i>: 0.003, [Formula: see text]: 0.4) and their interaction (<i>P</i>: 0.05, [Formula: see text]: 0.2). Functional sympatholysis magnitude differed between conditions (PLA: 107 ± 41% vs. FLZ: 67 ± 50%, <i>P</i>: 0.001, <i>r</i>: 0.7). Therefore, CYP450 pathways are mechanistically involved in functional sympatholysis. However, CYP450 inhibition does not augment resting or exercising vascular responses without constrictor stimuli.<b>NEW & NOTEWORTHY</b> Evidence suggests that functional sympatholysis is an endothelial-dependent, nitric oxide and prostaglandin-independent process. We found that cytochrome P450-2C9 (CYP450-2C9) inhibition attenuated sympatholytic responses during dynamic handgrip exercise with superimposed lower body negative pressure. These data indicate that CYP450 pathways contribute to functional sympatholysis in young healthy humans.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":"328 6","pages":"R642-R650"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}