bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rostrocaudal changes in the protein expression of GABAA receptor subunits in the rostral ventrolateral medulla (RVLM) of sedentary and physically active rats
Authors: Mueller Patrick J , Dombrowski Maryetta D , Fyk‐Kolodziej Bozena E 
Published: November 2023

It has been well established that GABA is the major inhibitory neurotransmitter in the RVLM, acting primarily through GABAA receptors to regulate tonic activity of pre‐sympathetic RVLM neurons. We have reported that GABAergic modulation of sympathoexcitation in the RVLM is enhanced in sedentary versus physically active rats, despite an overall increase in sympathoexcitation in sedentary animals. The purpose of the present study was to test the hypothesis that sedentary conditions enhance protein expression of GABAA receptor subunits within the RVLM. Physically active or sedentary, male Sprague‐Dawley rats (n=3 ea.) were sacrificed after 10 weeks of wheel running or sedentary conditions, respectively. The brainstem was cryosectioned serially (80 μm) and bilateral micropunches were collected for Western blotting. Punched sections were stained with cresyl violet to verify the rostrocaudal boundary of RVLM and orient pooled punches relative to the caudal pole of the facial nucleus (FN). GABAAα1 and GABAAα2 subunit expressions were normalized to GAPDH and examined in two caudal (FN −480 μm, FN −240 μm) and two rostral (FN +240 μm, FN +480 μm) regions. GABAAα1 expression was significantly lower in sedentary vs. physically active rats overall (p<0.05, main effect), but was higher in rostral vs. caudal regions in both groups (p<0.05, main effect, no interaction). In contrast, GABAAα2 expression did not exhibit a significant rostrocaudal distribution, but was still lower in sedentary vs. physically active (p<0.05, main effect, no interaction). These results suggest that GABAAα1 and GABAAα2 subunit expressions are not responsible for enhanced GABAergic modulation of sympathoexcitation in the RVLM of sedentary rats. Despite results contrary to our original hypothesis, our studies further demonstrate activity‐dependent neuroplasticity in the region of the RVLM involved in control of sympathetic outflow. Further studies including examination of other receptor subunits and the time course by which activity‐dependent neuroplasticity occurs in the RVLM will be important in elucidating and better understanding the mechanisms by which a sedentary lifestyle promotes cardiovascular disease via influences on the sympathetic nervous system.Support or Funding InformationSupported by HL096787‐05; HL096787‐05S1; AHA25810010.
Acute Effects of Intermittent Hypoxia on Leptin‐Mediated Increases in Adiponectin Expression
Authors: Becari Christiane , Somers Kiran R , Polonis Katarzyna , Pfeifer Michaela A. , Prachi Singh 
Published: November 2023

BackgroundObstructive sleep apnea (OSA) patients have elevated levels of plasma leptin and are exposed to repeated nocturnal intermittent hypoxia (IH). Leptin induces increased adiponectin expression, suggesting that adiponectin should be increased in OSA. However, levels of plasma adiponectin, an anti‐atherogenic and insulin‐sensitizing adipokine, are inconsistent in OSA, and adiponectin levels are often low. Both increases in leptin and decreases in adiponectin may contribute to increased cardiometabolic risk in OSA. In this study we sought to examine the interactions between IH, leptin, and adiponectin. Using an in‐vitro approach in differentiated human white preadipocytes (dHWP), we tested the hypothesis that adiponectin expression in response to acute IH‐mediated increases in leptin may be modulated in the presence of hypoxia.MethodsdHWP were exposed to 24 cycles of IH (30 min 0.1% O2 followed by 30 min exposure to 21% O2), continuous hypoxia (0.1% O2) or continuous normoxia (21% O2, control). Secretion of leptin and adiponectin in the 24h conditioned media was determined by ELISA and intracellular changes in adiponectin were determined by Western blot analysis.ResultsWe show that acute 24 hour exposure to IH or sustained hypoxia increased leptin secretion (p = 0.013) but did not alter adiponectin secretion (p = 0.48). In fact, the intracellular expression of adiponectin actually decreased during the acute exposure to both IH and to continuous hypoxia (p = 0.02). Also, while leptin increased intracellular adiponectin expression in normoxic conditions (p = 0.03), it was unable to do so in the presence of IH and hypoxia (p = 0.36).ConclusionsAcute IH and continuous hypoxia mediate increases in leptin, but not in adiponectin secretion. Furthermore, although leptin increases adiponectin in normoxic conditions, IH and continuous hypoxia cause decreases in intra‐cellular adiponectin expression and also attenuate leptin‐mediated increases in adiponectin expression. These hypoxia‐effects on adiponectin expression may help explain the low adiponectin levels in OSA, which may contribute to increased cardiovascular and diabetes risk.Support or Funding InformationChristiane Becari was supported by a grant from CNPq Brazil (# 203802/2014‐4); Michaela Pfeifer was supported by the APS STRIDE summer undergraduate research fellowship (NHLBI 1R25HL115473‐01); Prachi Singh was supported by AHA scientist development grant 11SDG7260046.
Geographic distribution and functionality of cuticular hydrocarbons in Drosophila athabasca
Authors: Harvey Taylor , Yukilevich Roman 
Published: November 2023

Various races of Drosophila athabasca exhibit differences in cuticular hydrocarbon profiles. Races Eastern A and West Northern exemplify these morphologies and thus were used for experimentation. Despite previous work postulating a connection between these traits and sexual selection, we have found that they play little to no role in female choice. Rather, we believe that cuticular hydrocarbons are instead used to aid in desiccation resistance. These waxy molecules provide a layer of protection for the flies against water loss as a result of environmental conditions. Flies were placed into vials containing silica gel in order to induce desiccation and show which lines were able to survive the for the longest period of time. We will construct mortality curves of D. athabasca from various geographic areas in which each race is found in order to determine which pheromone profile is best equipped to resist desiccation. Further, we aim to explore differences within each race based on geographic range of the populations collected. We hypothesize that lines of D. athabasca that inhabit warmer and drier climates will have a pheromone profile that is more resistant to desiccation.Support or Funding InformationUnion College Undergraduate Research Committee
High glucose‐mediated oxidative stress impairs vasodilation of small resistance skeletal muscle arteries from mourning doves (Zenaida macroura)
Authors: Ahmed Zoha S , Jarrett Catherine L , Faust James J , Sweazea Karen L 
Published: November 2023

Plasma glucose concentrations are naturally 1.5–2 times higher in birds than mammals of similar body mass. In mammals, hyperglycemia is associated with superoxide‐mediated endothelial dysfunction resulting in hypertension. In contrast to mammals with hyperglycemia, oxidative stress is typically low in birds. This apparent avian resistance to oxidative stress may be attributed to higher antioxidant status. Therefore, we hypothesized that endothelium‐dependent vasodilation of isolated arteries from mourning doves (Zenaida macroura) would not change after acute exposure to high glucose. Mourning doves were captured in Tempe, Arizona using walk‐in style funnel traps. Following euthanasia with sodium pentobarbital (200 mg/kg body mass), small resistance cranial tibial arteries were isolated, cannulated and pressurized in a vessel chamber. Isolated arteries were then exposed to either physiological (20 mM/L) or high (30 mM/L) glucose concentrations for 1 hour at 41°C (normal dove body temperature). Vessels were then pre‐constricted to 50% of resting inner diameter with phenylephrine in the superfusate. Next, vessels were exposed to increasing concentrations of the endothelium‐dependent vasodilator acetylcholine (ACh, 10‐9 to 10‐3 M, 5 mins each step) in the presence or absence of the superoxide dismutase mimetic, tiron (10 mM/L). Following the concentration response curve, vessels were exposed to a calcium‐free solution containing the chelator EDTA to obtain passive inner diameter from which percent vasodilation was calculated. A separate set of arteries from each bird was exposed to the superoxide indicator dihydroethidium (DHE, 10mM) in the presence or absence of tiron (10mM/L), embedded in optimal cutting compound, frozen in isopentane cooled by dry ice, and 12μm cryosections were collected onto glass microscope slides. Fluorescence intensity was measured by confocal microscopy. Contrary to our hypothesis, exposure to high glucose increased vascular superoxide concentrations by 168.9±42% (p=0.0072) and impaired endothelium‐mediated vasodilation (p<0.05). Moreover, vasodilation of vessels pre‐treated with tiron (10 mM/L) was not different from controls. These results demonstrate that although doves have naturally higher blood glucose concentrations, isolated arteries are not endogenously protected from glucose‐mediated increases in oxidative stress and impaired vasodilation.Support or Funding InformationFunding was provided by the Graduate and Professional Student Association and School of Life Sciences Undergraduate Researcher program, ASU.
Endothelial Dysfunction Predicts Systolic Blood Pressure Slope During Whole Body Maximal Exercise In Patients With Chronic Kidney Disease
Authors: Downey Ryan M. , Liao Peizhou , Millson Erin C. , Quyyumi Arshed A. , Park Jeanie 
Published: November 2023

Chronic kidney disease (CKD) patients have exercise intolerance and poor physical capacity that increases the risk of adverse cardiovascular events during and after physical activity. Previous studies in our lab demonstrate that CKD patients have exaggerated increases in blood pressure (BP) and sympathetic nervous system activation during handgrip exercises. However, whether CKD patients also have exaggerated increases in BP during whole‐body exercise or high intensity exercise is unknown. Furthermore, CKD patients often have endothelial dysfunction which could potentially lead to an impaired ability to vasodilate during exercise. Whether this might contribute to the augmented pressor response in CKD is also unknown. We hypothesized that CKD patients have exaggerated increases in BP during maximal whole body exercise and that endothelial dysfunction predicts a greater pressor response during exercise in these patients. 56 participants (35 CKD, 21 age‐matched controls) underwent maximal treadmill exercise using the modified Balke protocol. BP, heart rate (HR), and rate of perceived exertion were continuously monitored. Levels of mixed expired oxygen, carbon dioxide, and ventilation were recorded at rest and every 30 seconds during exercise. The peak oxygen uptake (VO2 max) was defined as the highest VO2 rate observed during maximal exercise. Endothelial function was assessed via brachial artery flow‐mediated dilation (FMD) just before and repeated 1 hour after exercise. CKD patients had significantly lower VO2 max compared to controls (21.8±1.1 ml/min/kg vs. 30.3±1.7, p<0.001). There was no significant difference in maximal systolic BP (SBP), diastolic BP, or mean arterial pressure achieved during exercise between groups. However, CKD patients had a greater slope of rise in SBP (10.3 mmHg/stage vs. 7.7, p<0.001). Maximum achieved HR was significantly lower in CKD versus controls (134.9±4.4 bpm vs. 150.0±3.6, p=0.011). Similar to BP response, the slope of rise in HR was significantly steeper in CKD patients (11.9 bpm/stage vs. 10.7, p=0.032). Before exercise, FMD (2.76±0.42% vs. 5.84±0.97, p=0.007), and FMD controlled for peak shear rate (FMDshear) (4.01±0.62% vs. 6.85±1.11, p=0.033) were significantly lower in CKD patients. A lower pre‐exercise FMD (p=0.039) and FMDshear (p<0.001) were significantly associated with a greater slope of rise in SBP during exercise in CKD, but not in controls. There was no significant change in FMD before and after exercise in either group. CKD patients exhibit an accelerated rise in SBP and HR during whole body maximal exercise compared to controls. Further, impaired FMD predicts an accelerated SBP and HR response during exercise in CKD patients, but not in controls. These data suggest that endothelial dysfunction is associated with the exaggerated pressor response during exercise in CKD patients.Support or Funding InformationSupported by NIH HL‐098744.
Sex‐differences in the Cardio‐metabolic and Hormonal Responses to Long‐duration Spaceflight
Authors: Hughson Richard L , Shoemaker Kevin , Rush James , Arbeille Philippe 
Published: November 2023

The recent NASA review on Sex and Gender effects on cardiovascular adaptations to spaceflight acknowledged the differences between men and women in orthostatic tolerance but suggested more research is required to assess impact on cardiovascular health. The study Vascular had the opportunity to compare responses of 4 men and 4 women who lived on the International Space Station (ISS) for approximately 6‐months. Carotid artery stiffness indicators were obtained pre‐ and immediately post‐flight, and measurements of overnight fasting blood samples were collected twice pre‐flight and twice in the final 30‐days of flight to assess metabolic and hormonal control. Carotid artery distensibility coefficient was reduced ~20% after spaceflight with no sex differences, but carotid artery beta‐stiffness index increased more in women. Sex differences were also seen in glucose regulation with increases in fasting glucose and greater increase in the homeostatic model assessment of insulin resistance in men. No sex differences were seen in glycated albumin, but the change in glucose was correlated with the change in glycated albumin (r2=0.52). Hormones associated with fluid regulation had significant spaceflight by sex interaction terms for renin and aldosterone, with greater increases in women than in men. Atrial natriuretic peptide decreased in men and women. Plasma superoxide dismutase tended to be increased more in women than men. Sex‐differences were found in blood biomarkers that might be related to arterial stiffness; however, the direction of change was not consistent between men and women. Greater glucose and insulin resistance found in men, or the elevation in aldosterone in women might be associated with increased stiffness, while greater superoxide dismutase would be expected to be associated with reduced stiffness. Carotid artery stiffness in spaceflight is probably associated with elevated local arterial pressures in the absence of gravity. Future studies need to consider potential sex‐differences in metabolic and hormonal biomarkers during investigations of cardiovascular adaptations to spaceflight.Support or Funding InformationSupported by Canadian Space Agency
GLP‐1‐producing Neurons in the Control of Glucose Homeostasis and Insulin Sensitivity
Authors: Shi Xuemei , Chacko Shaji , Li Depei , Li Feng , Guan Xinfu 
Published: November 2023

Background and ObjectiveGlucagon‐like peptides (GLP‐1/2) are co‐released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the nucleus of the solitary tract (NTS) of the brainstem; and are key signals for the control of energy balance and glucose homeostasis. It is unknown if PPG neurons fine‐tunes central autonomic outputs to improve peripheral metabolism and insulin sensitivity. Our objective was to define if acute activation of PPG neurons enhances peripheral glycemic control and insulin sensitivity.Methods and Results1) Establishment of a pharmacogenetics mouse model for the remote control of activation of PPG neurons in vivo. First, we generated glucagon (Gcg) promoter‐driven Cre transgenic mouse line in which Gcg‐Cre expression was co‐localized to GLP‐1‐positive neurons in the brainstem. Second, we created a remote control of activation of PPG neurons in vivo mouse model using the DREADD approach. Cre‐dependent, excitatory AAV‐hM3Dq‐mCherry vectors were injected into the brainstem NTS of 8‐wk old Gcg‐Cre mice. 2) Validation of Gcg Cre‐dependent hM3Dq activation: The hM3Dq expression in the brainstem was validated using Gcg‐Cre::Rosa26‐eGFP reporter mice, in which hM3Dq‐mCherry was faithfully expressed in GFP‐positive neurons (identified by Gcg‐Cre‐mediated eGFP). Moreover, excitation of hM3Dq‐expressing neurons was confirmed by the whole‐cell patch clamp. Membrane potential and firing rate of Gcg‐Cre::hM3Dq‐mCherryNTS neurons were recorded in brains slices. 3) Central neural function of PPG neuronal activation: Activation of hM3Dq‐expressing neurons‐mediated neural circuitry was mapped by immuostaining c‐Fos in the brain after ip clozapine‐N‐oxide (CNO). Increased c‐fos expression was mainly localized to central autonomic regions. Moreover, PPG neurons‐mediated neurotransmitter profiling was quantified by LC‐MS/MS‐based metabolomics. As major neurotransmitters, GLP‐1/2 were released from activated PPG neurons. Upon CNO stimulus, the hM3Dq receptors rapidly activate infected PPG neurons in vivo. 4) Peripheral metabolic impact of PPG neuronal activation: With glucose tolerance test and hyperinsulinemic euglycemic clamp, glucose homeostasis and insulin sensitivity were quantified in conscious Gcg‐Cre mice injected with Cre‐dependent hM3Dq vectors. Fasting glucose was decreased while glucose tolerance was enhanced in the Gcg‐Cre mice after ip CNO. Glucose infusion rate was increased as resulted from augmentation of insulin‐mediated stimulation of glucose disposal and insulin‐mediated suppression of endogenous glucose production upon ip CNO.ConclusionsAcute activation of PPG neurons in the brainstem NTS improves glucose tolerance and augments insulin sensitivity, suggesting that PPG neurons play an important physiological role in glycemic control and insulin sensitivity.Support or Funding InformationThe USDA CRIS grant 6250‐51000‐059 and the National NSFC grant 81570722.
The Role of Ankrd2 in Obesity‐Induced Inflammation and Insulin Resistance
Authors: Hernandez‐Carretero Angelina Marie , Weber Natalie , Doan Nhu Y Thi , Osborn Olivia 
Published: November 2023

Obesity‐induced chronic inflammation is a key component in the pathogenesis of insulin resistance. Skeletal muscle is the major site of postprandial glucose uptake and in insulin resistance states, such as type 2 diabetes, insulin‐stimulated glucose disposal in skeletal muscle is markedly impaired. In this study we used RNA‐seq to discover differentially expressed genes between lean and obese/diabetic muscle that were also conserved across species in both mouse and human samples. We found that expression of ankyrin repeat domain protein 2 (Ankrd2) was reduced in both mouse and human muscle from obese/diabetic samples compared with control, lean muscle. We hypothesized that Ankrd2 contributes to muscle insulin sensitivity and that reduction of Ankrd2 may impair insulin‐stimulated glucose uptake. We used siRNA‐mediated knockdown of Ankrd2 in rat L6 myotube cells and performed glucose uptake assays. Preliminary results show that ~75% knockdown of Ankrd2 expression impairs insulin‐stimulated glucose uptake by 1.5‐fold. Furthermore, this knockdown of Ankrd2 led to changes in inflammatory gene expression. This study will determine whether Ankrd2 is a potential therapeutic target to enhance insulin sensitivity.Support or Funding InformationA.H. is supported by National Institutes of Health IRACDA K12 GM068524 grant award
Epigenetic Regulation of Macrophage Polarization and Renal Inflammation
Authors: Pushpakumar Sathnur , Ren Lu , Biswas Raktim , Sen Utpal 
Published: November 2023

Elevated level of homocysteine known as hyperhomocysteinemia (HHcy), is associated with hypertension and consistently reported in chronic kidney disease and occurs in >85% of patients suffering from end‐stage renal disease. HHcy can cause or potentiate renal injury by a variety of mechanisms including inflammation, oxidative stress, apoptosis and cellular proliferation. Recent studies suggest epigenetic factors may regulate some of these mechanisms. The purpose of this study was to investigate whether HHcy‐induced DNA methylation and histone modification causes macrophage polarization toward inflammatory M1 phenotype and thus persistent inflammation leading to progressive glomerular and microvascular injury. We also determined whether epigenetic inhibitor, 5‐Aza‐2′‐deoxycytidine (5‐Aza) will mitigate renal inflammation. Wild type (WT, C57BL/6J), and CBS+/− mice representing HHcy were treated without or with 5‐Aza. Control mice received saline. In vitro studies were done on RAW264.7 cells. Compared to WT groups, CBS+/− mice exhibited increased pro‐inflammatory mediators (TNFα, IL‐6) and chemokine expression (MCP‐1, CXCL2). Macrophage isolation and flow cytometry revealed increased expression of F4/80+/CD40+ cells suggesting M1 phenotype in CBS+/− mice compared to WT. Classically activated M1 macrophage was associated with hypomethylation of pro‐inflammatory mediators (TNFα, IL‐6) and hypermethylation of anti‐inflammatory mediators (IL‐4, IL10). 5‐Aza treatment in CBS+/−, mice resulted in reversal of methylation levels and reduction of inflammation. Measurement of iNOS/Arginase‐1 activity revealed increased M1/M2 ratio in hyperhomocysteinemia compared to normal homocysteine levels. 5‐Aza treatment decreased M1/M2 ratio suggesting increase in alternately activated M2 macrophage. The results above combined with mRNA and immunohistochemistry suggested persistent inflammation in the kidney during hyperhomocysteinemia.ConclusionEpigenetic alterations during HHcy promote macrophage polarization toward pro‐inflammatory response and therapeutic intervention with epigenetic inhibitor 5‐Aza has the potential to abrogate renal inflammation.Support or Funding InformationAHA: 15SDG25840013NIH: HL104103