bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk factor modification in pre‐diabetic adults consuming white button mushrooms rich in the anti‐oxidant, ergothioneine (117.4)
Authors: Calvo Mona , Beelman Robert , Mehrotra Anita , Nadkarni Girish , Wang Lingzhi , Boon Cher Goh , Uribarri Jaime 
Published: June 2021

Oxidative stress & vitamin D (vitD) deficiency increase reactive oxygen species & low‐grade inflammation contributing to type 2 diabetes (T2D). To determine the effects of nutrition intervention with an antioxidant from WBM on T2D risk, we conducted 20 analyses of results from a study of health effects of vitD‐enriched‐WBM in pre‐diabetics. Group vitD intakes varied, but had no influence on oxidative risk factors. All of the 37 pre‐diabetic subjects consumed 100g WBM/d for 4 m in this study, enabling us to assess changes from baseline of risk factors associated with ergothioneine (ergo) antioxidant intake from WBM. As shown below, we used paired‐t‐tests to assess significant change from baseline for serum ergo & biomarkers of risk at 4 m (P1), and at 5 m (P2) [1m after diet ended]. Early analyses show significant (P<0.01) decreases from baseline of pro‐oxidant, advanced glycation end products with WBM‐ergo intake. Significant increases from baseline occurred for serum ergo, adiponectin & ORAC, at 4 & at 5 m, for all but ORAC. We conclude WBM are bioavailable food sources for the antioxidant ergo in older pre‐diabetic adults & their consumption effectively modifies risk factors for T2D.
Changes of biomarkers during the study

Biomarker
Baseline
4 months
5 months
p1
p2

Isoprostane
178±88
166±72
176±79
.38
.71

Leptin
24.3±14.3
24.9±15.6
24±14
.95
.98

Adiponectin
7.9±3.2
8.8±3.5
9.5±4.3
.02
.02

ORAC
5570±1683
6088±1696
5740±1523
.02
.70

Ergothioneine
317±163
677±497
496±340
.01
.01
Reducing circulating levels of plant sterols by ezetimibe favorably increases platelet counts in sitosterolemia patients (117.7)
Authors: Othman Rgia , Myrie Semone , Mymin David , Merkens Louise , Roullet Jean‐Baptiste , Steiner Robert , Jones Peter 
Published: June 2021

Macrothrombocytopenia and hemolytic anemia is correlated with increased plant sterol (PS) levels in patients (pts) with sitosterolemia (STSL). To determine if ezetimibe (EZ), a sterol‐absorption inhibitor, improves platelet count and morphology, and reduces markers of red blood cell hemolysis (RBCH: serum lactate dehydrogenase and bilirubin), 8 STSL pts were first taken off their EZ therapy for 14 wks then treated with EZ (10 mg/d) for another 14 wks. Blood samples were collected at the end of each study phase (off and on EZ). Plasma (pl) and RBC sterol concentrations were analysed by gas chromatography. Complete blood cell count and serum RBCH markers were determined by automated analyzers. In pts off EZ, platelet count was inversely related to pl campesterol (r=‐0.85, p<0.05), total PS (r=‐0.77, p<0.05) and total PS‐to‐cholesterol ratio (PS/Chol, r=‐0.96, p<0.01, n=7). Platelet size was positively correlated with pl total PS and PS/Chol ratio (all r=0.93, p<0.05, n=5), and RBC PS and PS/Chol were inversely related to mean corpuscular hemoglobin (Hb) concentration (MCHC) (p<0.01). EZ reduced pl and RBC sitosterol (‐35±4 and ‐28±3%), campesterol (‐47±4 and ‐40±4%), total PS (‐37±4 and ‐28±3%, all p<0.0001) and PS/Chol (‐27±4 and ‐28±4%, p<0.01). EZ increased platelet count (+23±9%, p<0.05), decreased platelet size (‐10±3%, p<0.05), and had no effect on RBCH, RBC mean corpuscular volume, or Hb concentration but slightly increased (p=0.03) MCHC. MCHC was negatively correlated with RBC (r=‐0.76) and pl (r=‐0.85, all p<0.05) campesterol in pts on EZ. In pts off EZ, RBC Chol was inversely related to sitosterol (p<0.05), total PS (p<0.05) and PS/Chol (p<0.01), suggesting reciprocity between Chol and PS. EZ tended to lower pl Chol concentrations (‐12±6%, p=0.09) but not RBC Chol (+0.3±3%, NS). These results indicated that EZ reduced pl and RBC PS contents, increased platelet count and decreased platelet size without affecting RBC Chol levels in STSL pts.Grant Funding Source: NIH, CIHR
Neurovascular control following small muscle mass exercise in humans (1170.10)
Authors: Buck Tahisha , Romero Steven , Ely Matt , Sieck Dylan , Abdala Pedro , Halliwill John 
Published: June 2021

Sympathetic vascular transduction is blunted and the arterial baroreflex curve is reset to a lower operating pressure after dynamic large muscle mass exercise in humans. It is unknown whether these neural adaptations contribute to sustained post‐exercise vasodilation in small muscle mass exercise. The purpose of this study was to determine if cardiovagal, vascular, and integrated baroreflex sensitivity as well as sympathetic neurovascular transduction were altered following dynamic knee extension (DKE) exercise. It was hypothesized that sympathetic vascular transduction would be reduced after DKE, the arterial baroreflex would be reset to a lower operating point, and baroreflex sensitivity would be enhanced. Eleven healthy, college‐aged subjects completed one‐leg DKE exercise for one hour at 60% of peak power. Neurovascular transduction was estimated by measuring the percent change in femoral vascular conductance due to external neck pressure. There was no effect of exercise on transduction (P = 0.46) and no difference in integrated baroreflex sensitivity across time (P = 0.77). Cardiovagal baroreflex sensitivity increased 25% relative to baseline and had not recovered at 60 minutes post‐exercise (P = 0.02). Vascular baroreflex sensitivity was reduced in both the exercised (P = 0.05) and rested leg (P = 0.09). There is likely no effect of small muscle mass exercise on postexercise sympathetic transduction, the carotid baroreflex, or integrated baroreflex sensitivity. Cardiovagal baroreflex sensitivity was augmented and vascular baroreflex sensitivity was reduced after exercise and this has not been previously shown after small muscle mass exercise.Grant Funding Source: NIH R01 HL115027
Activation of KIR channels and Na+/K+‐ATPase is not obligatory to blunt sympathetic vasoconstriction in contracting human skeletal muscle (1170.6)
Authors: Crecelius Anne , Luckasen Gary , Larson Dennis , Dinenno Frank 
Published: June 2021

Activation of inwardly‐rectifying potassium (KIR) channels and Na+/K+‐ATPase regulates muscle blood flow during mild exercise; whether these pathways are involved in the blunting of sympathetic α‐adrenergic vasoconstriction in active muscle is unknown. We tested the hypothesis that α1‐adrenergic vasoconstriction (phenylephrine; PE) is augmented during exercise after inhibition of KIR channels and Na+/K+‐ATPase. Young adults (n=11) were instrumented with a brachial artery catheter (drug infusions and blood pressure) and forearm blood flow (Doppler ultrasound) was measured and vascular conductance (FVC) calculated at rest, during minute 4 of steady‐state hyperemic conditions (moderate handgrip exercise or adenosine; ADO), and after 2 min of PE in these conditions: control (saline), combined inhibition of nitric oxide (NO; L‐NMMA) and prostaglandins (PGs; ketorolac) and combined inhibition of NO, PGs, KIR channels and Na+/K+‐ATPase (L‐NMMA+ketorolac+BaCl2+ouabain). In control, exercise blunted PE‐mediated vasoconstriction (%ΔFVC) compared to ADO (‐21±3% vs ‐46±6%; P<0.05) and this was unchanged with L‐NMMA+ketorolac (‐24±3% vs ‐47±5%). The addition of BaCl2+ouabain had no effect on vasoconstriction during exercise (‐27±3%), indicating that activation of KIR channels and Na+/K+‐ATPase is not obligatory to blunt sympathetic vasoconstriction in contracting human muscle.Support HL102720
Sex differences in forearm vasoconstrictor response to voluntary apnea (1171.1)
Authors: Muller Matthew , Patel Hardikkumar , Heffernan Matthew , Ross Amanda 
Published: June 2021

Clinical evidence indicates that obstructive sleep apnea is more common and more severe in men compared to women. Sex differences in the vasoconstrictor response to hypoxemia‐induced sympathetic activation might contribute to this clinical observation. In the current laboratory study, we determined sex differences in the acute physiological responses to maximal voluntary end‐expiratory apnea (MVEEA) during wakefulness in healthy young subjects (ten women, nine men, 26 ± 1 yrs). In addition, we studied eight postmenopausal women (62 ± 2 yrs) to determine the effect of menopause status. Mean arterial pressure (MAP), heart rate (HR), brachial artery blood flow velocity (BBFV, Doppler ultrasound) and cutaneous vascular conductance (CVC, laser Doppler flowmetry) were measured and changes in physiological parameters from baseline were compared between groups. The breath hold duration and oxygen saturation nadir were similar between groups. In response to MVEEA, young women had significantly less forearm vasoconstriction compared to young men (ΔBBFV: 2 ± 7 versus ‐25 ± 6% and ΔCVC: ‐5 ± 4 versus ‐31 ± 4 %) whereas ΔMAP (12 ± 2 versus 16 ± 3 mmHg) and ΔHR (4 ± 2 versus 6 ± 3 bpm) were comparable between groups. The attenuated forearm vasoconstriction in young women was not observed in postmenopausal women (ΔBBFV ‐21 ± 5%). We conclude that young women have blunted forearm vasoconstriction in response to MVEEA compared to young men and this effect is not evident in older postmenopausal women. These data suggest that female sex hormones dampen neurogenic vasoconstriction in response to apnea‐induced hypoxemia.Grant Funding Source: Supported by NIH P01 HL096570 and UL1 TR000127
Relationship between muscle sympathetic nerve activity and aortic wave reflection characteristics in aerobic and resistance athletes (1172.1)
Authors: Smith Michael , Hamlin Robert , Devor Steven 
Published: June 2021

Recent reports have indicated that resistance exercise training performed absent an aerobic exercise program may increase arterial stiffness. Our purpose was to compare the augmentation index (AIx) and left ventricular wasted pressure energy (LVEW) as markers of arterial stiffness and ventricular‐vascular coupling efficiency in young aerobic (AT) and resistance (RT) trained athletes. We also investigated the relationship between muscle sympathetic nerve activity (MSNA) and AIx to determine if sympathetic outflow could explain any observed differences in arterial stiffness.Methods: MSNA (via microneurography of the peroneal nerve) was measured in 15 male subjects (8 RT, 7 AT). Aortic pressure waveforms were synthesized using applanation tonometry of the radial artery to derive AIx and LVEW values.Results: RT subjects had greater AIx (12 ± 3 vs. ‐7 ± 2; P<0.01), LVEW (429 ± 111 vs. ‐360 ± 77; P<0.01) and MSNA burst incidence (109 ± 23 vs. 31 ± 5; P<0.01) than AT subjects. MSNA burst incidence was also significantly related to AIx in all subjects (R2=0.61; P<0.01).Conclusions: A positive association was found between MSNA and AIx in young males. Furthermore, a history of RT is associated with increased arterial stiffness and elevated sympathetic outflow.
Muscle metaboreflex activation during dynamic exercise evokes epinephrine release resulting in β2‐mediated vasodilation (1172.2)
Authors: Kaur Jasdeep , Spranger Marty , Hammond Robert , Krishnan Abhinav , Alvarez Alberto , Augustyniak Robert , O’Leary Donal 
Published: June 2021

Muscle metaboreflex‐induced increases in mean arterial pressure (MAP) during submaximal dynamic exercise are mediated principally by increases in cardiac output. To what extent, if any, the peripheral vasculature contributes to this rise in MAP is debatable. In several studies we observed that in response to muscle metaboreflex activation (MMA; induced by partial hindlimb ischemia), small but significant vasodilation occurred within the non‐ischemic vasculature (termed non‐ischemic vascular conductance; NIVC). We hypothesized that these increases in NIVC may stem from a metaboreflex‐induced release of epinephrine (Epi) resulting in β2‐mediated dilation. We measured NIVC and arterial plasma Epi levels in chronically instrumented dogs during rest, mild exercise (3.2 kph) and MMA before and after β‐blockade (propanolol; 2 mg/kg), α‐blockade (prazosin; 50 µg/kg) and α+β‐blockade. Both Epi and NIVC increased significantly from exercise to MMA: 81.9 ± 18.6 to 141.3 ± 22.8 pg/ml and 33.8 ± 1.5 to 37.6 ± 1.6 ml/min/mmHg, respectively. These metaboreflex‐induced increases in NIVC were abolished after β‐blockade (27.6 ± 1.8 to 27.5 ± 1.7 ml/min/mmHg) and potentiated after α‐blockade (36.6 ±2.0 to 49.7 ±2.9 ml/min/mmHg) while α+β‐blockade also abolished any vasodilation (33.7 ± 2.9 to 30.4 ± 1.9ml/min/mmHg). We conclude that MMA at mild exercise induces epinephrine release causing β2‐mediated vasodilation.Grant Funding Source: HL‐55743
Influence of fitness on the pressor response following spontaneous bursts of muscle sympathetic nerve activity (1172.6)
Authors: Restaino Robert , Credeur Daniel , Holwerda Seth , Fadel Paul 
Published: June 2021

Previous studies suggest that high fit (HF) subjects may exhibit altered vascular responses to reflex mediated increases in muscle sympathetic nerve activity (MSNA). Whether the ability of MSNA to modulate arterial blood pressure (BP) on a beat‐to‐beat basis is affected by fitness is unknown. In 7 HF (VO2 max=67±2 ml/kg/min) and 7 average fit (AF; VO2=44±2 ml/kg/min) young men, MSNA (microneurography) and blood pressure (Finapres) were continuously measured at rest for 10 minutes. Signal averaging was used to characterize beat‐by‐beat changes in mean arterial pressure (MAP) for 10 cardiac cycles following each individual MSNA burst and a peak response calculated. Variations in MSNA burst pattern were considered by comparing single (bordered by >1 heartbeat lacking MSNA) vs. multiple bursts. Changes in MAP were also calculated following heartbeats without MSNA (i.e., non‐bursts). In response to single MSNA bursts, no significant difference was noted in MAP (HF: +2.8±1.2 vs. AF: +1.8±0.34 mmHg, P>0.05); however, multiple bursts produced a significantly greater increase in MAP in HF subjects (HF: +4.8±0.5 vs. AF: +3.4±0.3 mmHg, P<0.05). Also, following non‐bursts, HF subjects tended to have a greater reduction in MAP (HF: ‐1.3±0.3 vs. AF: ‐0.7±0.1, P=0.053). These preliminary findings suggest a greater role for spontaneous MSNA bursts in modulating BP on a beat‐to‐beat basis in HF compared to AF subjects.Grant Funding Source: Supported by NIH Grant RO1 HL093167 (PJF)
Elucidation of the structural determinants of ARB binding to the human AT1R (1173.4)
Authors: Taylor Temy , Nguyen Jenny , Liu Tammy , Roshankar Mina , Chen Haixiang , LaCuran Alecander , Oelschlaeger Peter , Nistala Ravi , Luo Yun , Andresen Bradley 
Published: June 2021

The angiotensin (Ang) II type 1 receptor (AT1R) is the target for a widely used class of drugs named angiotensin receptor blockers (ARBs). Polymorphisms in the ARB binding site are known to alter affinity. Mutagenesis studies identifying the binding site are limited as the site can be distorted simply by altering helical rotation/position. Previously, we demonstrated that wild‐type (wt) opossum (o) AT1R does not bind ARBs. Therefore, we made a model of the human (h) AT1R and oAT1R based on the structure of the mu‐opioid receptor through an iterative process. The models were optimized using all atomic molecular dynamics (MD) simulation with explicit membrane bilayer and water solvent. Utilizing docking and MD simulations the ARB binding pocket was elucidated; currently, both K199 in the 3rd helix and the backbone near the lipid‐solvent interface appear to be involved in binding. Additionally, we cloned the hAT1R and made individual point mutations reflecting the differences between hAT1R and oAT1R. Each receptor was stably transfected into HEK cells and characterized to determine if there are alterations in Ang II signaling as well as ARB‐mediated inhibition of signaling. Iterations of modeling and wet lab work will refine the ARB binding site allowing for identification of ARB resistant patients.Grant Funding Source: T. Taylor was supported by an APS Frontiers in Physiology Fellowship.
Genetic blockade of (pro)renin receptor in adipose tissue modulate the mice body weight and glucose homeostasis (1173.6)
Authors: Shamansurova Zulaykho , Ahmed Basma , Kajla Sonia , Michel Catherine , Lavoie Julie 
Published: June 2021

Introduction: The (Pro)Renin receptor [(P)RR] local effects realizes by angiotensin depended and independent pathways were shown by many authors. Study the role of (P)RR in adipose tissue in regulation of the body weight and glucose homeostasis present the aim of the presentation. Material and methods: Specific in adipose tissue (P)RR receptor knockout mice (KO) created by crelox technology, where the male mice was homozygous (MHm) and female mice heterozygous (FHt). In adult mice fed high‐fat high‐carbohydrate diet (HF/HC) or regular chow (ND) the body weight (BW) assessed weekly, glucose homeostasis evaluated by oral glucose tolerant (OGTT) and intra‐peritoneal insulin tolerant (IP‐ITT) tests. Results: The BW curve in KO mice was significantly lower and more pronounced in MHm. OGTT test show higher glycemia, AUC of glucose and glucose/insulin ratio at basal and stimulated state in MHm on ND. IP‐ITT results show higher glycemia and AUC of glucose in FHt mice on HF/HC. This results accompanied by lower (P)RR gene (40%, p<0,05) and protein (40%) expression in adipocytes. Conclusion: The (P)RR specific deletion in adipose tissue accompanied by lower BW, glucose intolerance in MHm on ND, insulin insensitivity in FHt on HF/HC.Grant Funding Source: Suppoerted by CDA, MERK‐FROST
Augmentation of kidney angiotensinogen expression and urinary angiotensinogen excretion by an intracellular angiotensin II fusion protein (1173.8)
Authors: Navar L. Gabriel , Kobori Hiroyuki , Satou Ryosuke , Katsurada Akemi , Zhuo Jia , Li Xiao 
Published: June 2021

Long‐term angiotensin II (ANG II) administration significantly increases ANG II levels in the kidney through two major mechanisms; AT1 receptor‐mediated augmentation of angiotensinogen (AGT) expression and uptake of circulating ANG II by the proximal tubule. However, it is not known if intracellular ANG II also stimulates AGT expression and secretion in the proximal tubule of the kidney. In the present study, we performed intrarenal adenoviral transfer of an intracellular cyan fluorescent fusion of ANG II (Ad‐sglt2‐ECFFP/ANG II) selectively in the proximal tubule using the sodium and glucose co‐transporter 2 (sglt2) promoter. AGT mRNA expression in the renal cortex and 24 h urinary AGT excretion were determined 2 and 4 weeks after ECFP/ANG II transfer. ECFP/ANG II was expressed in the proximal tubule in a time‐dependent manner, which was associated with significant increases in blood pressure 4 weeks after ECFP/ANG II transfer (p<0.01). AGT mRNA expression in the cortex was significantly increased at Week 4 by 61 ± 16% (p<0.05). Urinary AGT excretion rates were increased from 48.7 ± 5.7 (n=13) to 102 ± 13.5 (n=13) ng/24 h (p<0.05). However, plasma AGT levels were not altered. These results support the hypothesis that intracellular ANG II stimulates AGT expression in the proximal tubule leading to increased AGT formation and secretion into the tubular fluid.Grant Funding Source: Supported by P30GM10337 and RO1DK067299
Proline‐rich tyrosine kinase regulates NF‐κB and PPARγ to promote hypoxia‐induced proliferative phenotype of human pulmonary artery smooth muscle cells (1175.1)
Authors: Bijli Kaiser , Kang Bum‐Yong , Adesina Sherry , Murphy Tamara , Kleinhenz Jennifer , Hart C 
Published: June 2021

Hypoxia stimulates pulmonary hypertension in part by increasing the proliferation of pulmonary vascular wall cells via sustained activation of MAP kinase ERK 1/2, NF‐κB, and downregulation of PPARγ levels. However, the upstream signaling events that mediate NF‐κB upregulation and PPARγ downregulation remain unknown. We examined the role of Proline‐rich tyrosine kinase 2 (Pyk2) in hypoxia‐induced proliferation of human pulmonary artery smooth muscle cells (HPASMC). Exposure of HPASMC to hypoxia (1% O2) for 72 hrs resulted in the activation of Pyk2. siRNA‐mediated Pyk2 depletion or its pharmacological inhibition attenuated hypoxia‐induced HPASMC proliferation. Pyk2 inhibition attenuated hypoxia‐induced: 1) ERK 1/2 activation, 2) NF‐κB transcriptional activity and 3) reductions in PPARγ mRNA levels. Conversely, siRNA‐mediated PPARγ depletion enhanced, whereas PPARγ overexpression attenuated HPASMC Pyk2 activation. Exposing C57BL/6 mice to 10% O2 for 3 weeks reduced lung PPARγ but increased Pyk2 levels compared to normoxic mice. Also, Pyk2 levels were higher in pulmonary vascular tissues of smooth muscle‐specific PPARγ knockout mice compared to control mice. Taken together, these findings point to a crucial role of Pyk2 in the mechanism that promotes hypoxia‐induced proliferative phenotype of HPASMC.Grant Funding Source: Supported by: grants from VA Research Service (1I01BX001910, CMH), NIH (HL102167, CMH), and AHA‐SDG
Dehydroepiandrosterone promotes pulmonary artery relaxation by NADPH oxidation‐elicited subunit dimerization of protein kinase G1α (1175.9)
Authors: Patel Dhara , Kandhi Sharath , Kelly Melissa , Neo Boon Hwa , Wolin Michael 
Published: June 2021

The activity of glucose‐6‐phosphate dehydrogenase (G6PD) controls a vascular smooth muscle relaxing mechanism promoted by the oxidation of cytosolic NADPH, which has been associated with activation of the 1α form of protein kinase G (PKG1α) by a thiol oxidation‐elicited subunit dimerization. This PKG1α‐activation mechanism appears to contribute to responses of isolated endothelium‐removed bovine pulmonary arteries (BPA) elicited by peroxide, cytosolic NADPH oxidation resulting from G6PD inhibition and hypoxia. Dehydroepiandrosterone (DHEA) is a steroid hormone with pulmonary vasodilator activity, which has beneficial effects in treating pulmonary hypertension. Since one of the known actions of DHEA is inhibiting G6PD, we investigated if it promoted relaxation associated with NADPH oxidation, PKG1α dimerization and PKG activation detected by increased vasodilator‐stimulated phosphoprotein (VASP) phosphorylation. Relaxation of BPA to DHEA under aerobic or hypoxic conditions was associated with NADPH oxidation, PKG1α dimerization and increased VASP phosphorylation. The vasodilator activity of DHEA was markedly attenuated in pulmonary arteries and aorta from a PKG knockin mouse containing a serine in place of a cysteine involved in PKG dimerization. DHEA promoted increased PKG dimerization in lungs from wild type mice, which was not detected in the PKG knockin mouse model. Thus, PKG1α dimerization is a major contributing factor to the vasodilator actions of DHEA, and perhaps its beneficial effects in treating pulmonary hypertension.Grant Funding Source: Supported by NIH Grant R01HL115124