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

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Stimulatory effect of methylglyoxal on capsaicin-sensitive lung vagal afferents in rats: role of TRPA1. 甲基乙二醛对大鼠对辣椒素敏感的肺迷走神经传入的刺激作用:TRPA1 的作用。
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-05-01 Epub Date: 2024-03-18 DOI: 10.1152/ajpregu.00297.2023
You Shuei Lin, Nai-Ju Chan, Pei-Yu Xiao, Ching Jung Lai
{"title":"Stimulatory effect of methylglyoxal on capsaicin-sensitive lung vagal afferents in rats: role of TRPA1.","authors":"You Shuei Lin, Nai-Ju Chan, Pei-Yu Xiao, Ching Jung Lai","doi":"10.1152/ajpregu.00297.2023","DOIUrl":"10.1152/ajpregu.00297.2023","url":null,"abstract":"<p><p>Methylglyoxal (MG), a reactive metabolic byproduct of glycolysis, is a causative of painful diabetic neuropathy. Patients with diabetes are associated with more frequent severe asthma exacerbation. Stimulation of capsaicin-sensitive lung vagal (CSLV) afferents may contribute to the pathogenesis of hyperreactive airway diseases such as asthma. However, the possibility of the stimulatory effect of MG on CSLV afferents and the underlying mechanisms remain unknown. Our results showed that intravenous injection of MG (25 mg/kg, MG25) in anesthetized, spontaneously breathing rats elicited pulmonary chemoreflexes characterized by apnea, bradycardia, and hypotension. The MG-induced apneic response was reproducible and dose dependent. MG25 no longer evoked these reflex responses after perineural capsaicin treatment of both cervical vagi to block C-fibers' conduction, suggesting that the reflexes were mediated through the stimulation of CSLV afferents. Pretreatment with HC030031 [an antagonist of transient receptor potential ankyrin subtype 1 protein (TRPA1)] or AP18 (another TRPA1 antagonist), but not their vehicle, markedly attenuated the apneic response induced by MG25. Consistently, electrophysiological results showed that pretreatment with HC030031 largely attenuated the intense discharge in CSLV afferents induced by injection of MG25 in open-chest and artificially ventilated rats. In isolated CSLV neurons, the perfusion of MG evoked an abrupt and pronounced increase in calcium transients in a concentration-dependent manner. This stimulatory effect on CSLV neurons was also abolished by HC030031 treatment but not by its vehicle. In conclusion, these results suggest that MG exerts a stimulatory effect on CSLV afferents, inducing pulmonary chemoreflexes, and such stimulation is mediated through the TRPA1 activation.<b>NEW & NOTEWORTHY</b> Methylglyoxal (MG) is implicated in the development of painful diabetic neuropathy. A retrospective cohort study revealed an increased incidence of asthma exacerbations in patients with diabetes. This study demonstrated that elevated circulating MG levels stimulate capsaicin-sensitive lung vagal afferents via activation of TRPA1, which in turn triggers respiratory reflexes. These findings provide new information for understanding the pathogenic mechanism of diabetes-associated hyperreactive airway diseases and potential therapy.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142550","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}
引用次数: 0
Activation of cardiac parasympathetic and sympathetic activity occurs at different skin temperatures during face cooling. 在面部降温过程中,不同的皮肤温度会激活心脏副交感神经和交感神经活动。
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-05-01 Epub Date: 2024-03-04 DOI: 10.1152/ajpregu.00196.2023
Felipe Gorini Pereira, Muhamed McBryde, Morgan Reynolds, James R Sackett, Christopher L Chapman, Elizabeth A Gideon, Zachary J Schlader, Blair D Johnson
{"title":"Activation of cardiac parasympathetic and sympathetic activity occurs at different skin temperatures during face cooling.","authors":"Felipe Gorini Pereira, Muhamed McBryde, Morgan Reynolds, James R Sackett, Christopher L Chapman, Elizabeth A Gideon, Zachary J Schlader, Blair D Johnson","doi":"10.1152/ajpregu.00196.2023","DOIUrl":"10.1152/ajpregu.00196.2023","url":null,"abstract":"<p><p>Sufficiently cold-water temperatures (<7°C) are needed to elicit the sympathetic response to the cold pressor test using the hand. However, it is not known if stimulating the trigeminal nerve via face cooling, which increases both sympathetic and cardiac parasympathetic activity, also has a threshold temperature. We tested the hypothesis that peak autonomic activation during a progressive face cooling challenge would be achieved when the stimulus temperature is ≤7°C. Twelve healthy participants (age: 25 ± 3 yr, four women) completed our study. Six pliable bags, each containing water or an ice slurry (34°C, 28°C, 21°C, 14°C, 7°C, and 0°C) were applied sequentially to participants' forehead, eyes, and cheeks for 5 min each. Mean arterial pressure (photoplethysmography; index of sympathetic activity) and heart rhythm (3-lead ECG) were averaged in 1-min increments at the end of baseline and throughout each temperature condition. Heart rate variability in the time [(root mean square of successive differences (RMSSD)] and frequency [high-frequency (HF) power] domains was used to estimate cardiac parasympathetic activity. Data are presented as the increase from baseline ± SD. Mean arterial pressure only increased from baseline in the 7°C (13.1 ± 10.3 mmHg; <i>P</i> = 0.018) and 0°C (25.2 ± 7.8 mmHg; <i>P</i> < 0.001) conditions. Only the 0°C condition increased RMSSD (160.6 ± 208.9 ms; <i>P</i> = 0.009) and HF power (11,450 ± 14,555 ms<sup>2</sup>; <i>P</i> = 0.014) from baseline. Our data indicate that peak increases in sympathetic activity during face cooling are initiated at a higher forehead skin temperature than peak increases in cardiac parasympathetic activity.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140020775","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}
引用次数: 0
A modeling analysis of whole body potassium regulation on a high-potassium diet: proximal tubule and tubuloglomerular feedback effects. 高钾饮食对全身钾调节的模型分析:近端肾小管和肾小球的反馈效应
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-05-01 Epub Date: 2024-03-11 DOI: 10.1152/ajpregu.00283.2023
Melissa M Stadt, Anita T Layton
{"title":"A modeling analysis of whole body potassium regulation on a high-potassium diet: proximal tubule and tubuloglomerular feedback effects.","authors":"Melissa M Stadt, Anita T Layton","doi":"10.1152/ajpregu.00283.2023","DOIUrl":"10.1152/ajpregu.00283.2023","url":null,"abstract":"<p><p>Potassium (K<sup>+</sup>) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, and hormone secretion and action. Indeed, maintaining K<sup>+</sup> balance is critical for normal cell function, as too high or too low K<sup>+</sup> levels can have serious and potentially deadly health consequences. K<sup>+</sup> homeostasis is achieved by an intricate balance between the intracellular and extracellular fluid as well as balance between K<sup>+</sup> intake and excretion. This is achieved via the coordinated actions of regulatory mechanisms such as the gastrointestinal feedforward effect, insulin and aldosterone upregulation of Na<sup>+</sup>-K<sup>+</sup>-ATPase uptake, and hormone and electrolyte impacts on renal K<sup>+</sup> handling. We recently developed a mathematical model of whole body K<sup>+</sup> regulation to unravel the individual impacts of these regulatory mechanisms. In this study, we extend our mathematical model to incorporate recent experimental findings that showed decreased fractional proximal tubule reabsorption under a high-K<sup>+</sup> diet. We conducted model simulations and sensitivity analyses to investigate how these renal alterations impact whole body K<sup>+</sup> regulation. Model predictions quantify the sensitivity of K<sup>+</sup> regulation to various levels of proximal tubule K<sup>+</sup> reabsorption adaptation and tubuloglomerular feedback. Our results suggest that the reduced proximal tubule K<sup>+</sup> reabsorption under a high-K<sup>+</sup> diet could achieve K<sup>+</sup> balance in isolation, but the resulting tubuloglomerular feedback reduces filtration rate and thus K<sup>+</sup> excretion.<b>NEW & NOTEWORTHY</b> Potassium homeostasis is maintained in the body by a complex system of regulatory mechanisms. This system, when healthy, maintains a small extracellular potassium concentration, despite large fluctuations of dietary potassium. The complexities of the system make this problem well suited for investigation with mathematical modeling. In this study, we extend our mathematical model to consider recent experimental results on renal potassium handling on a high potassium diet and investigate the impacts from a whole body perspective.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140093212","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}
引用次数: 0
Pioglitazone does not enhance exogenous glucose oxidation or metabolic clearance rate during aerobic exercise in men under acute high altitude exposure 吡格列酮不会提高男性在急性高海拔地区进行有氧运动时的外源性葡萄糖氧化率或代谢清除率
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-04-29 DOI: 10.1152/ajpregu.00064.2024
Lee M. Margolis, Marques Wilson, Devin J. Drummer, Christopher T. Carrigan, Nancy E Murphy, Jillian T Allen, M. Alan Dawson, Christos S Mantzoros, Andrew J Young, Stefan M Pasiakos
{"title":"Pioglitazone does not enhance exogenous glucose oxidation or metabolic clearance rate during aerobic exercise in men under acute high altitude exposure","authors":"Lee M. Margolis, Marques Wilson, Devin J. Drummer, Christopher T. Carrigan, Nancy E Murphy, Jillian T Allen, M. Alan Dawson, Christos S Mantzoros, Andrew J Young, Stefan M Pasiakos","doi":"10.1152/ajpregu.00064.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00064.2024","url":null,"abstract":"Insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR) during aerobic exercise in unacclimatized lowlanders at high altitude (HA). Whether use of an oral insulin sensitizer prior to acute HA exposure enhances exogenous glucose oxidation is unclear. This study investigated the impact of Pioglitazone (PIO) on exogenous glucose oxidation and glucose turnover compared to placebo (PLA) during aerobic exercise at HA. Using a randomized, crossover design, native lowlanders (n=7 males, mean±SD, age: 23±6 yr, body mass: 84±11 kg) consumed 145 g (1.8 g/min) glucose while performing 80-min of steady-state (1.43±0.16 V̇O<sub>2 </sub>L/min) treadmill exercise at HA (460 mmHg) following short-term (5 days) use of PIO (15 mg oral dose per day) or PLA (microcrystalline cellulose pill). Substrate oxidation and glucose turnover were determined using indirect calorimetry and stable isotopes (<sup>13</sup>C-glucose and [6,6-<sup>2</sup>H<sub>2</sub>]-glucose). Exogenous glucose oxidation was not different between PIO (0.31±0.03 g/min) and PLA (0.32±0.09 g/min). Total carbohydrate oxidation (PIO: 1.65±0.22 g/min, PLA: 1.68±0.32 g/min) or fat oxidation (PIO: 0.10±0.0.08 g/min, PLA: 0.09±0.07 g/min) were not different between treatments. There was no treatment effect on glucose rate of appearance (PIO: 2.46±0.27, PLA: 2.43±0.27 mg/kg/min), disappearance (PIO: 2.19±0.17, PLA: 2.20 ± 0.22 mg/kg/min), or MCR (PIO: 1.63±0.37, PLA: 1.73±0.40 mL/kg/min). Results from this study indicate that PIO is not an effective intervention to enhance exogenous glucose oxidation or MCR during acute HA exposure. Lack of effect with PIO suggests the etiology of glucose metabolism dysregulation during acute HA exposure may not result from insulin resistance in peripheral tissues.","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841059","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}
引用次数: 0
Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance 苯肾上腺素会改变慢性疲劳综合征伴直立性不耐受时脑血流速度与血压之间的相位同步性
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-04-29 DOI: 10.1152/ajpregu.00071.2024
Marvin S. Medow, Julian M. Stewart
{"title":"Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance","authors":"Marvin S. Medow, Julian M. Stewart","doi":"10.1152/ajpregu.00071.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00071.2024","url":null,"abstract":"Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neuro-cognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between Arterial Pressure (AP) and cerebral blood velocity (CB<sub>V</sub>) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age=24.1 years) and 15 ME/CFS patients (mean age=21.8 years). All ME/CFS patients had postural tachycardia syndrome (POTS). A 10-minute 60⁰ head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P &lt;0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P &lt; 0.05) and decreased end-tidal CO<sub>2</sub> (ETCO<sub>2</sub>; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P &lt; 0.05) in ME/CFS vs. control. In ME/CFS, HUT significantly decreased CB<sub>V</sub> compared to control (-22.5% vs -8.7%, p&lt;0.005). To mitigate the orthostatic CB<sub>V</sub> reduction, we administered supplemental CO<sub>2</sub>, phenylephrine and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n=4 N-back during HUT in ME/CFS similar to control (ME/CFS=38.5±5.5 vs. ME/CFS+PE= 65.6±5.7 vs. Control 56.9±7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. While CO<sub>2 </sub>and Acetazolamide had no effect on PhSI in ME/CFS, PE caused a significant reduction in PhSI (ME/CFS=0.80±0.03 vs ME/CFS+PE= 0.69±0.04, p&lt; 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in ME/CFS patients, perhaps related to improved neurovascular coupling, cerebral autoregulation and maintenance of CB<sub>V</sub>.","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841268","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}
引用次数: 0
Exercise intensity- and body region-specific differences in sweating in middle-aged-to-older men with and without type 2 diabetes 患有和未患有 2 型糖尿病的中年至老年男性在运动强度和身体区域方面的出汗差异
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-04-29 DOI: 10.1152/ajpregu.00037.2024
Nathalie V. Kirby, Robert D. Meade, Martin P. Poirier, Sean R. Notley, Ronald J. Sigal, Pierre Boulay, Glen P. Kenny
{"title":"Exercise intensity- and body region-specific differences in sweating in middle-aged-to-older men with and without type 2 diabetes","authors":"Nathalie V. Kirby, Robert D. Meade, Martin P. Poirier, Sean R. Notley, Ronald J. Sigal, Pierre Boulay, Glen P. Kenny","doi":"10.1152/ajpregu.00037.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00037.2024","url":null,"abstract":"Type 2 diabetes is associated with reduced whole-body sweating during exercise-heat stress. However, it is unclear if this impairment is related to exercise intensity and whether it occurs uniformly across body regions. We evaluated whole-body (direct calorimetry) and local (ventilated-capsule technique; chest, back, forearm, thigh) sweat rates in physically active men with type 2 diabetes (T2D; aged 59 (7) years; V̇O<sub>2peak</sub> 32.3 (7.6) mL·kg<sup>-1</sup>·min<sup>-1</sup>; <i>n</i>=26; HbA<sub>1c</sub> 5.1-9.1%) and without diabetes (Control; aged 61 (5) years; V̇O<sub>2peak</sub> 37.5 (5.4) mL·kg<sup>-1</sup>·min<sup>-1</sup>;<i> n</i>=26) during light (~40%V̇O<sub>2peak</sub>), moderate (~50%V̇O<sub>2peak</sub>), and vigorous (~65%V̇O<sub>2peak</sub>) intensity exercise (elicited by fixing metabolic heat production at ~150, 200, 250 W·m<sup>-2</sup>, respectively) in 40°C, ~17% relative humidity. Whole-body sweating was ~11% (T2D-Control mean difference [95% confidence interval]: -37 [-63, -12] g·m<sup>-2</sup>·h<sup>-1</sup>) and ~13% (-50 [-76, -25] g·m<sup>-2</sup>·h<sup>-1</sup>) lower in the T2D compared to the Control group during moderate- and vigorous- (<i>p</i>≤0.001), but not light-intensity exercise (-21 [-47, 4] g·m<sup>-2</sup>·h<sup>-1</sup>; <i>p</i>=0.128). Consequently, the diabetes-related reductions in whole-body sweat rate were 2.3 [1.6, 3.1] times greater during vigorous relative to light exercise (<i>p</i>&lt;0.001). Further, these diabetes-related impairments in local sweating were region-specific during vigorous-intensity exercise (group × region interaction: <i>p</i>=0.024), such that the diabetes-related reduction in local sweat rate at the trunk (chest, back) was 2.4 [1.2, 3.7] times greater than that at the limbs (thigh, arm). In summary, when assessed under hot, dry conditions, diabetes-related impairments in sweating are exercise intensity-dependent and greater at the trunk compared to the limbs.","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841269","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}
引用次数: 0
Interactive effects of exercise intensity and recovery posture on post-exercise hypotension 运动强度和恢复姿势对运动后低血压的交互影响
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-04-22 DOI: 10.1152/ajpregu.00036.2024
Xueer Lu, Richie Philip Goulding, Toby Mundel, Zachary J. Schlader, James D. Cotter, Shunsaku Koga, Naoto Fujii, I-Lin Wang, Ziyang Liu, Hao-Yu Li, Hui Wang, Huixin Zheng, Narihiko Kondo, Chin-Yi Gu, Tze-Huan Lei, Faming Wang
{"title":"Interactive effects of exercise intensity and recovery posture on post-exercise hypotension","authors":"Xueer Lu, Richie Philip Goulding, Toby Mundel, Zachary J. Schlader, James D. Cotter, Shunsaku Koga, Naoto Fujii, I-Lin Wang, Ziyang Liu, Hao-Yu Li, Hui Wang, Huixin Zheng, Narihiko Kondo, Chin-Yi Gu, Tze-Huan Lei, Faming Wang","doi":"10.1152/ajpregu.00036.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00036.2024","url":null,"abstract":"American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Ahead of Print. <br/>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140636159","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}
引用次数: 0
Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types 锌螯合BET溴链抑制剂同样靶向胰岛内分泌细胞类型
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-04-15 DOI: 10.1152/ajpregu.00259.2023
Rachel A. Jones Lipinski, Jennifer S Stancill, Raymundo Nuñez, Sarah L Wynia-Smith, Daniel J Sprague, Joshua A Nord, Amir Bird, John A Corbett, Brian C Smith
{"title":"Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types","authors":"Rachel A. Jones Lipinski, Jennifer S Stancill, Raymundo Nuñez, Sarah L Wynia-Smith, Daniel J Sprague, Joshua A Nord, Amir Bird, John A Corbett, Brian C Smith","doi":"10.1152/ajpregu.00259.2023","DOIUrl":"https://doi.org/10.1152/ajpregu.00259.2023","url":null,"abstract":"Inhibition of the bromodomain and extraterminal domain (BET) protein family is a potential strategy to prevent and treat diabetes; however, the clinical use of BET bromodomain inhibitors (BETi) is associated with adverse effects. Here, we explore a strategy for targeting BETi to β-cells by exploiting the high zinc (Zn<sup>2+</sup>) concentration in β-cells relative to other cell types. We report the synthesis of a novel, Zn<sup>2+</sup>-chelating derivative of the pan-BETi (+)-JQ1, (+)-JQ1-DPA, in which (+)-JQ1 was conjugated to dipicolyl amine (DPA). As controls, we synthesized (+)-JQ1-DBA, a non-Zn<sup>2+</sup>-chelating derivative, and (-)-JQ1-DPA, an inactive enantiomer that chelates Zn<sup>2+</sup>. Molecular modeling and biophysical assays showed that (+)-JQ1-DPA and (+)-JQ1-DBA retain potent binding to BET bromodomains in vitro. Cellular assays demonstrated (+)-JQ1-DPA attenuated NF-ĸB target gene expression in β-cells stimulated with the pro-inflammatory cytokine interleukin 1β. To assess β-cell selectivity, we isolated islets from a mouse model that expresses green fluorescent protein in insulin-positive β-cells and mTomato in insulin-negative cells (non-β-cells). Surprisingly, Zn<sup>2+</sup>-chelation did not confer β-cell selectivity as (+)-JQ1-DPA was equally effective in both β- and α-cells; however, (+)-JQ1-DPA was less effective in macrophages, a non-endocrine islet cell type. Intriguingly, the non-Zn<sup>2+</sup>-chelating derivative (+)-JQ1-DBA displayed the opposite selectivity, with greater effect in macrophages compared to (+)-JQ1-DPA, suggesting potential as a macrophage-targeting molecule. These findings suggest that Zn<sup>2+</sup>-chelating small molecules confer endocrine cell selectivity rather than β-cell selectivity in pancreatic islets and provide valuable insights and techniques to assess Zn<sup>2+</sup>-chelation as an approach to selectively target small molecules to pancreatic β-cells.","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591060","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}
引用次数: 0
ß-cell selective regulation of gene expression by nitric oxide 一氧化氮对 ß 细胞基因表达的选择性调控
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-04-08 DOI: 10.1152/ajpregu.00240.2023
Aaron Naatz, Chay Teng Yeo, Neil Hogg, John A Corbett
{"title":"ß-cell selective regulation of gene expression by nitric oxide","authors":"Aaron Naatz, Chay Teng Yeo, Neil Hogg, John A Corbett","doi":"10.1152/ajpregu.00240.2023","DOIUrl":"https://doi.org/10.1152/ajpregu.00240.2023","url":null,"abstract":"American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Ahead of Print. <br/>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140590981","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}
引用次数: 0
Weight loss in adult male Wistar rats by Roux-en-Y gastric bypass is primarily explained by caloric intake reduction and pre-surgery body weight. 成年雄性 Wistar 大鼠通过 Roux-en-Y 胃旁路手术减轻体重的主要原因是热量摄入减少和手术前体重增加。
IF 2.8 3区 医学
American journal of physiology. Regulatory, integrative and comparative physiology Pub Date : 2024-04-08 DOI: 10.1152/ajpregu.00169.2023
C. Warner Hoornenborg, Edit Somogyi, Jan E. Bruggink, Christina N Boyle, Thomas A. Lutz, Marloes Emous, André P. van Beek, Csaba Nyakas, Gertjan van Dijk
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