bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selectively silencing Nitric Oxide Synthase 1 Adaptor Protein in the Nucleus Tractus Solitarius leads to QT Interval Prolongation via Glutamate‐mediated neurotoxicity
Authors: SINGH NEHA , ZHONG TIECHENG , O'ROURKE STEPHEN T. , SUN CHENGWEN 
Published: June 2021

Variants of the nitric oxide synthase 1 adaptor protein (NOS1AP) locus are strongly related to QT interval prolongation and sudden cardiac death (SCD) in human. Our aim was to study the action of NOS1AP in the NTS by knockdown of NOS1AP using lentiviral vector‐mediated shRNA (Lv‐NOS1AP‐shRNA). qPCR data showed NOS1AP mRNA levels were expressed in NTS 3‐fold higher than organs such as kidney and heart in SD rats. Microinjection of Lv‐NOS1AP‐shRNA in NTS caused significant reduction in NOS1AP expression in SD rats. NOS1AP knockdown in NTS did not alter blood pressure (BP), heart rate (HR) recorded by radiotelemetry. ECG analysis revealed heart rate variability (HRV) was significantly reduced (SDNN, 51.2±5.6 vs 5.0±1.3 ms, P< .001) and QTc interval was markedly prolonged (72.4±4 vs 105±11 ms, P< .05) in NOS1AP knockdown rats. To study the cellular mechanism underlying NOS1AP action, we studied the effect of NOS1AP knockdown on glutamate‐induced neurotoxicity in Cath‐a cells. Treatment of cells with Lv‐NOS1AP‐shRNA significantly reduced NOS1AP expression, and was associated with increased glutamate‐induced neurotoxicity, suggesting a protective effect of NOS1AP. In summary, all results indicate that NOS1AP dysfunction in NTS might play an important role in the pathogenesis of cardiac arrhythmia which, in part, could be due to increased sensitivity to glutamate induced neurotoxicity.Research Support: NDSU‐COBRE
Nicotine Paradoxically Alters The Facilitatory Action Of Estrogen And Progesterone On Adenosine Receptor‐Mediated Renal Vasodilations
Authors: Gohar Eman M , El‐gowilly Sahar M , El‐Gowelli Hanan M , El‐Mas Mahmoud M 
Published: June 2021

We tested the hypotheses: (i) nicotine modifies the interaction of ovarian hormones with adenosine receptor‐mediated renal vasodilations, and (ii) nitric oxide synthase (NOS) and heme oxygenase (HO) modulate this interaction. Vasodilations caused by NECA, adenosine analogue, in perfused kidneys were reduced in ovariectomized (OVX) rats and restored after estrogen (E2) or medroxyprogesterone acetate (MPA) supplementation. The E2 or MPA effect was abolished after blockade of respective receptors by ICI 182780 and mifepristone, and after NOS (L‐NAME) but not HO (ZnPP) inhibition. NECA vasodilations were increased and decreased by nicotine (1 mg/kg/day, 2 weeks) in OVX/E2 and OVX/MPA kidneys, respectively. By contrast, NECA responses were resistant to nicotine in rats with deficient (OVX) or balanced (sham or E2/MPA‐replaced OVX) hormonal milieu. Nicotine enhancement of NECA responses in OVX/E2 kidneys was abolished by L‐NAME but not ZnPP. Alternatively, nicotine attenuation of NECA responses in OVX/MPA kidneys disappeared in presence of hemin (HO inducer) but not L‐arginine (NOS substrate). The hemin effect was compromised by ZnPP. Thus, NOS facilitation and HO inhibition mediate the opposite effects of nicotine on NECA responses in E2‐ or MPA‐replaced OVX rats, respectively.This project was supported financially by the Science and Technology Development Fund (STDF), Egypt, Grant No. 502.
Effects of Maternal Ethanol Intake during the Pregnancy and Lactation on the Expression of NMDA Receptors in Hippocampus of Pups at Different Stages of Brain Development
Authors: Cheregatto Nathálie Neves , Soler João Antonio , Mussi Sara Eleodoro , Fiorillo Henrique Mascioli , Borges Brunna Oliveira , de Oliveira Jamila Dib , Defendi Paola Galassi , da Silva Danilo Fernandes , Iyomasa Melina Mizusaki , Rosa Maria Luiza Nunes Mamede 
Published: June 2021

AimTo investigate whether ethanol consumption during pregnancy and lactation might induce changes on the expression of NR1 and NR2A in the hippocampus of pups at different stages of brain development. Female rats were exposed to water (controls, n=8) or ethanol 10% (alcoholic, n=8) for 60 days, from mating to weaning. The pups were studied at PND30–90 (n=8–13). Immunohistochemistry. Positive cells were quantified. ANOVA. Maternal ethanol intake induced changes in NR1 expression only in pups at PND21 (p<0,001) increasing in CA1 (30%) and decreasing in both CA3 (25%) and HDG (28%). Controls or alcoholic pups compared within the same treatment showed discrepant results in CA1, CA3 or HDG along the development. NR2A expression was reduced in CA1 of alcoholic pups at PND21 and 60 (25 and 44%, respectively), reduced in CA3 at PND30 (23%), increased in CA3 at PND90 (37%) (p<0,001) and no changed in HDG. Comparisons within the same treatment showed predominant reduction in NR2A expression along the development of both controls and alcoholic pups (18–38%, p<0,001). Maternal ethanol intake during pregnancy and lactation induces different changes on the expression of NMDA receptors in hippocampus of pups in different periods of development, which may reflect alterations in both glutamatergic neurotransmission during the brain maturation and hippocampal function at adulthood. Support: FPA.
Grape powder supplementation improves blood pressure, anxiety‐like behavior and learning and memory function in ovariectomized rats.
Authors: Salim Samina , Patki Gaurav , Chugh Gaurav , Bohat Ritu , Allam Farida , Jafri Faizan , Saleem Mohammad , Asghar Mohammad , Alkadhi Karim A 
Published: June 2021

Estrogen is of prime importance to normal brain function; and its depletion at menopause may account, at least in part, for cognitive decline as well as hypertension. Here, we examined the effect of grape powder treatment on anxiety‐like behavior, learning and memory impairment and blood pressure in ovariectomized (OVR) rats. Four groups of Wistar female rats were used. Group 1 and 2 included controls for sham and sham‐grape powder treated, group 3 was OVR, and group 4 was OVR and grape powder treated for 2 weeks. At the end of the 2 weeks, body weights, food and water intake, blood pressure were recorded, anxiety‐like behavior (open‐field and light‐dark) and learning‐memory (radial water maze) tests were conducted. We observed a significant increase in systolic and diastolic blood pressure in OVR rats as compared to sham‐controls. Furthermore, ovariectomy increased anxiety‐like behavior and caused learning and memory impairment in rats as compared to the sham‐control group. Interestingly, supplementation with grape powder to OVR rats for 2 weeks was marked with restoration of both systolic and diastolic blood pressure, improvement in the anxiety‐like behavior and learning and memory function. This supports our hypothesis that grape powder may be an attractive target for estrogen replacement therapy. Oxidative stress data points towards interesting mechanistic clues to these observations.Grant Support: NIH R15 G103327
Antiproliferative mechanism of novel imidazoline compound in PC12 cells
Authors: McLean Lancelot Stuart , Crane Louis , Baziard‐Mouysset Genevieve , Edwards Lincoln 
Published: June 2021

Common anti‐diabetic agents that cause release of insulin such as sulfonylurea drugs are linked to an increased risk of cancer. Clinically useful novel I1‐imidazoline receptor agonists such as moxonidine have pleiotropic effects, including antihypertensive and insulin sensitization effects. Recently, some of these compounds have been associated with cell death in vitro, however the mechanism of action is not fully elucidated. Our objective was to investigate the antiproliferative mechanism of the novel imidazoline compound, S43126 in PC12 pheochromocytoma cells. One group of cells were treated time dependently with vehicle or S43126 (1mM). A second group of cells were pretreated for 2 hours with z‐VAD‐fmk, NAC, SP600125, SB202190, followed by S43126 (1mM). Cells were then analyzed for apoptosis, ROS formation, mitochondrial membrane permeabilization, caspase activation and MAPK phosphorylation. Our results showed that in PC12 cells, stress activated MAPKs and caspases are involved in the antiproliferative activity of S43126. Our data also showed that in PC12 cells, S43126 increased oxidative stress and mitochondrial membrane permeabilization. These results indicate that S43126‐ induced PC12 cell death is partly mediated by oxidative stress, stress activated MAPKs, and caspases.These studies were supported in part by the Center for Dental Research at Loma Linda University
Pharmacogenomics of vincristine‐induced neurotoxicity in pediatric cancer patients
Authors: Amstutz Ursula , Loo Tenneille T , Gylling Helene M , Rassekh Rod , Hukin Juliette , Zada Yassamin Faroz , Dubé Marie‐Pierre , Brown Andrew M , Phillips Michael S , Hayden Michael R , Ross Colin J , Carleton Bruce C 
Published: June 2021

The use of the anticancer agent vincristine is limited by debilitating neurotoxicity (VIN), for which a genetic basis has been suggested. Here, we investigated variation in 315 genes involved in drug absorption, metabolism, distribution, excretion (ADME) and toxicity in the context of VIN in children with cancer.We genotyped 4536 ADME variants in a pilot cohort of 140 children with Wilms tumor and rhabdomyosarcoma. To replicate findings, known variants in CYP3A5 and ABCB1 as well as variants with evidence for association (p<0.01) in the pilot cohort were analyzed in 422 patients with acute lymphoblastic leukemia (ALL).No association of variants in CYP3A5 or ABCB1 with VIN was observed. Of the candidates identified in the pilot cohort, the association of a variant in ABCA4 with VIN was replicated in patients with ALL (combined cohort OR: 1.7; P = 2.9×10−4).This study was the first to broadly screen genetic variation in the context of VIN in pediatric cancer patients and serves as a starting point for further study of the genetic basis of VIN, providing novel hypotheses for mechanisms underlying the susceptibility to VIN and the possibility for predictive genetic testing to identify patients at risk.Funded by CIHR/CFI
Decreased Nuclear Receptor Activity Mediates Down‐ Regulation of Drug Metabolizing Enzymes in Chronic Kidney Disease Through Epigenetic Modulation.
Authors: Velenosi Thomas , Feere David , Sohi Gurjeev , Hardy Daniel , Fu A , Urquhart Brad 
Published: June 2021

ObjectiveTo determine the mechanism of hepatic drug metabolizing enzyme down‐regulation in chronic kidney disease (CKD).MethodsHepatic CYP3A1, CYP3A2 and CYP2C11 mRNA expression were determined in rats with surgically induced CKD. Chromatin Immunoprecipitation (ChIP) was performed to determine nuclear receptor and epigenetic mediated differences in the promoter region of these enzymes.ResultsHepatic CYP3A and CYP2C11 mRNA expression was significantly decreased in CKD rats compared to controls (P<0.05). RNA polymerase II binding to the CYP3A and CYP2C11 promoter regions was decreased in CKD rats (P<0.05). ChIP also revealed a decreased PXR binding to the CYP3A2 promoter in CKD rats (P<0.05). HNF4α binding to the CYP3A and CYP2C11 promoter regions was also decreased compared to controls (P<0.05). The decrease in PXR and HNF4α binding was concurrent with diminished histone 4 acetylation in the CYP3A2 promoter locus for nuclear receptor activation.ConclusionsWe demonstrate a novel mechanism of drug metabolizing enzyme regulation in CKD. Our results show that decreased CYP3A and CYP2C11 mRNA expression is secondary to decreased PXR and HNF4α binding as a result of histone modulation in CKD. This research is supported by the Natural Sciences and Engineering Research Council.
Regulation of Cardiolipin Remodeling in Human Lymphoblasts
Authors: Mejia Edgard , Taylor William , Vandel Marilyne , Hatch Grant 
Published: June 2021

BackgroundBarth Syndrome (BTHS) is a rare X‐linked genetic disorder caused by mutations in the TAZ gene. The TAZ gene product, tafazzin, is responsible for remodeling Cardiolipin (CL) with the necessary acyl species. TAZ mutations can result in cardiomyopathy. Monolysocardiolipin acyltransferase‐1 (MLCL AT‐1) is another enzyme capable of CL remodeling.ObjectiveTo examine if MLCL AT‐1 complements tafazzin in the remodeling of CL.MethodsLymphoblasts from normal or BTHS patients were transfected with TAZ and/or MLCL AT‐1 RNAi or an MLCL AT‐1 carrying plasmid. TAZ and MLCL AT‐1 gene expression were analyzed. Other analyses included measuring CL mass, MLCL AT‐1 enzyme activity and radiolabelling studies. Our studies also include using BN PAGE to analyse mitochondrial complexes in normal and BTHS lymphoblasts.ResultsMLCL AT‐1 gene expression increased when TAZ was knocked down. Expression of MLCL AT‐1 elevated CL levels, increased [1‐14C] Linoleic acid incorporation into CL and raised MLCL AT‐1 enzyme activity in normal and BTHS cells in which TAZ was knocked down. The double knockdown results are not lower than TAZ knockdown alone. Results show that MLCL AT‐1 over‐expression is able to elevate mitochondrial complex I formation in BTHS lymphoblasts.ConclusionMLCL AT‐1 over‐expression may serve as a potential therapeutic approach to treat BTHS.Funding:CIHR, Barth Syndrome Foundations of USA and Canada
Is Human Double Minute‐2 a new marker of angiogenesis in exercised human skeletal muscle?
Authors: Aiken Julian , Slopack Dara , Gouzi Fares , Mercier Jacques , Hayot Maurice , Haas Tara L , Gustafsson Thomas , Birot Olivier , Roudier Emilie 
Published: June 2021

Protein expression of the E3 ubiquitin ligase Murine Double Minute‐2 (Mdm2) is increased in response to exercise training in mouse skeletal muscle. By regulating endothelial cell proliferation and migration in the muscle tissue, Mdm2 is indispensable for exercise‐induced angiogenesis to occur (Roudier et al., FASEB J 2012).ObjectiveHere, we investigated in human skeletal muscle if exercise training exerts a similar effect on Human Double Minute‐2 (Hdm2), the human homologue of Mdm2 protein, and if a link is present between Hdm2 and the endothelial marker Platelet Endothelial Cell Adhesion Molecule‐1 (PECAM‐1).MethodProtein levels for Hdm2 and PECAM‐1 were measured by western blot in vastus lateralis muscle biopsies from 16 young and 14 senior subjects enrolled in a 6‐week training program.ResultsExercise training significantly increased Hdm2 and PECAM‐1 protein expression. In the young population, a significant correlation was observed between exercise‐induced increases in Hdm2 and PECAM‐1 proteins.ConclusionResults from our previous study in rodents translate here to human subjects and suggest that Hdm2 might represent a key regulator of exercise‐induced angiogenesis in human skeletal muscle.This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC).
Lag and Causality in Baroreceptor Response during Passive Head‐up Tilt
Authors: Shykoff Barbara E , Florian John P 
Published: June 2021

Multiple methods measure baroreflex sensitivity as effect of blood pressure (BP) on heart rate or interbeat interval (IBI). However, most consider only magnitude, not phase or lag. Also, in the closed‐loop IBI‐BP system, many methods do not differentiate between cause and effect. We postulated that long lag or loss of causality between changes in BP and IBI would predispose to unstable BP. Beat‐to‐beat systolic BP (Finometer) and IBI signals were considered as input and output respectively. Cross covariance (XCV) functions calculated using 40 to 80 heartbeats from cardiovascular steady state were examined for lag for one quarter of their length. Lag, the beat number at maximum XCV with changes in BP leading, was converted to time using average IBI. Significant (p<0.05) correlation at that lag indicated causality. Of 21 subjects with 15 minutes of 70° head‐up tilt, correlation in early tilt (ET) was significant in 19, with lag (mean ± SEM) 0.9±0.2 s. In late tilt, correlation was significant in 16, with lag 2.2±0.4 s. After 5 days of 6‐hour water immersion in 7 subjects, 2 became presyncopal during tilt and lost correlation. ET causal lag was 2.2±0.4 vs. 0.4±0.2 s pre‐immersion (p<0.01).Support: ONR and NAVSEA DSBDP
Neuroprotective Mechanisms of Methylene Blue
Authors: Ryou Myoung‐Gwi , Choudhury Gourav Roy , Mallet Robert T , Yang Shaohua 
Published: June 2021

BackgroundThe phenothiazine dye methylene blue (MB) has antioxidant properties and augments ATP production, and is selectively internalized by neurons after systemic injection into rats.HypothesisMB protects neurons against hypoxia‐reoxygenation (H/R) injury by enhancing ATP production and activating the Akt/mTOR signaling pathway.MethodsHT22 cells were subjected to 3h oxygen‐glucose deprivation (OGD; 0.5% O2) followed by 24 h reoxygenation (H/R protocol). Cell viability (Calcein AM), and contents of hypoxia inducible factor‐1α, Akt/mTOR pathway components, and actin (immunoblot), erythropoietin (EPO; immunocytochemistry) and ATP content (microplate assay) were analyzed. P values <0.05 were considered statistically different.ResultsOGD reduced cell viability by 40% vs. normoxia, but 50 and 100 nM MB prevented H/R induced cell death. MB (10–1000 nM) concentration‐dependently increased cellular ATP content, in parallel with increased HIF‐1α content and EPO expression. MB (500 μM) increased Akt phosphorylation fourfold and mTOR phosphorylation by 45% vs. H/R control.ConclusionMB protects HT22 cells by both enhancing ATP production and activating EPO's anti‐apoptotic signaling.
Acute Effects of Conjugate Equine Estrogen on Postischemic Pial Arteriole Vasodilation and Microvascular Cyclooxygenase Expression in Young and Aged Female Rats
Authors: Zeynalov Emil , Ma Li , Rezvani Niloofar , Littleton‐Kearney Marguerite T 
Published: June 2021

ObjectivesIn these studies we evaluated the effects of acute conjugated equine estrogens (CEE) on postischemic pial vasodilatory capacity of young ovariectomized (OVX) and aged, reproductively senescent (RS) rats. Additionally, we evaluated expression of cyclooxygenase‐1 (COX‐1) in isolated pial arterioles in OVX and RS rats.MethodsFirst, OVX and RS female rats were anesthetized; a closed cranial window was placed. Rats were then subjected to 15‐ min reversible forebrain ischemia, followed by 2 hr. reperfusion. At the onset of reperfusion CEE (1 mg/kg, I.V.) or vehicle was administered. Pial artery dilatory responses to Ach were tested before and after ischemia. Pial arteries were isolated and analyzed for COX‐1 expression using western blot techniques.ResultsCEE treatment partially preserved postischemic vasodilatory responses (22 ± 5 % vs. 15 ± 6 %) of OVX rats which coincided with increased microvascular expression of COX‐1 protein (0.07±0.01 vs. 0.21 ± 0.03, COX‐1/Actin). However, CEE failed to restore postischemic vasodilatory responses (21 ± 7 % vs. 1 ± 6 %) of RS rats. Increases in COX‐1 expression were diminished by half in RS rats (0.04 ±0.007 vs.0.11 ± 0.03, COX‐1/Actin).ConclusionIncreases in postischemic pial arteriole COX‐1 expression after acute CEE treatment is associated with improvements of postischemic pial arteriole vasodilatory capacity in OVX, but not RS rats.
Inhibition of COX‐1 ameliorates endotoxemia‐induced fall in GFR in mice
Authors: Mederle Katharina , Castrop Hayo , Schweda Frank , Höcherl Klaus 
Published: June 2021

In this study, we investigated the impact of COX‐1‐ and COX‐2‐derived prostanoids on lipopolysaccharide (LPS)‐induced decrease in glomerular filtration rate (GFR) in mice.Injection of LPS (3 mg/kg; i.p.; n=8) decreased GFR and the amount of thrombocytes to about 50% of basal values. Plasma, urine and renocortical tissue levels of TxB2 were increased about 10‐, 7‐ and 2‐fold in response to LPS, respectively. Pretreatment with the COX‐1 inhibitor SC‐560 (20 mg/kg) attenuated the LPS‐induced fall in GFR and in thrombocytes to about 75% of basal levels (n=8; p<0.01). Further, SC‐560 abolished the increase in plasma, urine and renocortical tissue levels of TxB2 in response to LPS. Pretreatment with the COX‐2 inhibitor SC‐236 (10 mg/kg) further enhanced the LPS‐induced fall in GFR to about 40% of basal values (n=6; p<0.05 vs. LPS). SC‐236 did not alter thrombocyte levels nor the LPS‐induced increase in plasma, urine and renocortical tissue levels of TxB2. Pretreatment with the P2Y12 antagonist Clopidogrel (n=6; 50 mg/kg × d; oral) for two days inhibited the LPS‐induced fall in thrombocytes, but did not attenuate the LPS‐induced decrease in GFR.This study demonstrates that endotoxemia‐induced decrease in GFR is mediated in part by COX‐1 derived prostanoids. Our data further suggest that vascular‐rather than thrombocyte‐derived thromboxane is responsible for the fall in GFR in response to LPS.
CD40 ligand contributes to angiotensin‐II induced vascular inflammation, oxidative stress and endothelial dysfunction
Authors: Daub Steffen , Hausding Michael , Jurk Kerstin , Becker Christian , Kroeller‐Schoen Swenja , Oelze Matthias , Schwenk Melanie , Stein Judith , Kerahrodi Jasmin Ghaemi , Kossmann Sabine , Schulz Eberhard , Wenzel Philip , Reske‐Kunz Angelika , Münzel Thomas , Grabbe Stephan , Daiber Andreas 
Published: June 2021

Methods and ResultsAngiotensin‐II (1mg/kg/d for 7d) was infused in C57/Bl6 (control) and CD40L−/− mice using osmotic minipumps. Vascular function was recorded by isometric tension studies, reactive oxygen species (ROS) were monitored in blood and heart of the mice by enhanced chemiluminescence. ELISA of CD4+ T cell supernatants, Western blot analysis and real‐time RT‐PCR were used to analyze pro‐inflammatory cytokines, NAPDH oxidase subunits, T cell transcription factors and other genes of interest. CD40L−/− mice showed an ameliorated endothelial function and decreased oxidative stress in the heart and blood after angiotensin‐II treatment compared to their wild‐type littermates. Moreover, CD40L−/− mice displayed significantly decreased levels of TH1 cytokines released by splenic CD4+ T cells. This observation was accompanied by lower expression levels of NOX‐2 in aortic tissue, T‐bet in splenic cells, as well as P‐selectin in heart tissue from CD40L−/− mice.ConclusionsOur results demonstrate that CD40L−/− deficiency improves angiotensin‐II induced vascular inflammation, dysfunction and oxidative stress. These data further support our previous observations [Wenzel et al. Circulation, 2011] that immune cells and inflammatory pathways significantly contribute to angiotensin‐II induced arterial hypertension.Research supportThis work was supported by funds from the Federal Ministry of Education and Research (BMBF 01EO1003) to A.D., S.G., P.W. and T.M; S.K.‐S., E.S., A.D. and T.M. hold grants from the Stiftung Mainzer Herz.
The effects of mouth guard usage on neuromuscular activation and muscle performance
Authors: Veicsteinas Arsenio , Limonta Eloisa , Cè Emiliano , Rampichini Susanna , Esposito Fabio 
Published: June 2021

To assess the effects of a commercially‐available mouth guard (Brux Ltd.) on neuromuscular activation and muscle performance, 8 participants completed a balanced and randomized study with (S‐MG) and without (Con) a sport mouth guard. Each participant performed two tests with both elbow flexors and knee extensors muscles: a 1‐min contraction at 100% of maximum voluntary contraction (MVC) and an 80% MVC until exhaustion. During 100% MVC, force decay (ΔF%) and root mean square (RMS) of electromyogram (EMG) were calculated. During 80% MVC, the time into force target (t‐target) and force coefficient of variation (CV) were determined. MVC was significantly higher in S‐MG than in Con in both muscle groups (P<0.05). ΔF% was significantly lower in S‐MG than in Con in the knee‐extensors (61.1±1.7% and 68.9±1.3% in S‐MG and Con, respectively; P<0.05) but not in the elbow flexors. At 80% MVC, higher t‐target values were observed in S‐MG compared to Con for the knee‐extensors (18.1±2.5 s and 12.9±2.7 s in S‐MG and Con, respectively; P<0.05), but not for the elbow flexors. CV was significantly lower in S‐MG compared to Con in both muscle groups. These findings indicate that despite neuromuscular activation was not altered, the mouth guard usage increased maximum force production, endurance time and force stability, especially in the lower limb muscles.The study was partially funded by a grant of the University of Milan.