bluuebunny/crossref_metadata_2025_split huggingface dataset:
Azilsartan, New Angiotensin II Type 1 Receptor Blocker, Would Suppress Morning Surge in Hypertension
Authors: Isegawa Kengo , Hirooka Yoshitaka , Kishi Takuya , Sunagawa Kenji 
Published: June 2021

BackgroundRecent investigations on circadian variations of blood pressure have shown that the suppression of morning surge is crucial in optimal management of hypertension. The pressure surge is often observed in the neurohormonal transitional phase from the rest to active phase. Azilsartan (AZL), a new angiotensin II type 1 receptor blocker (ARB), is a powerful and long‐acting antihypertensive agent. We examined if AZL suppress the elevation of blood pressure from the light‐rest to dark‐active phase in spontaneously hypertensive rats.Methods and ResultsSHR were divided into three groups, treated at 5:00 for 28 days with orally administered azilsartan (AZL; 1mg/kg/day), candesartan (CAN; 1mg/kg/day), or vehicle (VEH). Telemetric mean arterial pressures (MAP) for 24 hours were similarly lower in AZL and CAN, than vehicle (AZL 108±4, CAN 116±7, VEH 134±5 mmHg, p<0.01). Both in the light‐rest (from 6:00 AM to 6:00 PM) and dark‐active phase (from 6:00 PM to 6:00 AM), MAP were similarly lower in AZL and CAN than in VEH. However, the changes in MAP between the last 4 hours in light‐rest phase and the first 2 hours in dark‐active phase were significantly lower in AZL than in CAN (−2±2 vs. 3±1 mmHg, p<0.05).ConclusionAZL is capable of lowering the elevation of blood pressure from the rest to active phase, indicating that AZL may benefit hypertensive patients with pressure surge in the early morning.
Relief of endoplasmic reticulum (ER) stress in the brain subfornical organ (SFO) selectively prevents high fat diet (HFD)‐induced hepatic dysfunction but not the development of adiposity or hypertension
Authors: Young Colin N. , Horwath Julie A. , Butler Scott D. , Mark Allyn L. , Davisson Robin L. 
Published: June 2021

Fatty liver, in concert with obesity and hypertension, are hallmarks of metabolic syndrome. ER stress in the brain has been suggested to contribute, although the precise neural regions involved remain unclear. We tested the hypothesis that ER stress in the SFO mediates HFD‐induced obesity, hypertension, and hepatic dysfunction. C57Bl/6 mice were instrumented with radiotelemeters for measurement of mean arterial pressure (MAP) and underwent SFO‐targeted microinjections of an adenovirus encoding the ER chaperone GRP78 (AdGRP78), an approach we have shown to reduce ER stress. Mice were fed normal chow (NC) or HFD for 10 weeks. Relative to NC, HFD control (AdLacZ, n=7) and SFO‐targeted AdGRP78 (n=7) mice demonstrated similar significant increases in body weight (Δ19±1 vs 18±1 g, AdLacZ vs AdGRP78, p>;0.05), adiposity and MAP (Δ7±2 vs 8±2 mmHg, AdLacZ vs AdGRP78, p>;0.05). However, HFD induced profound hepatomegaly (0.98±0.02 vs 1.88±0.11 g, NC vs AdLacZ, p<0.05), that was prevented with SFO‐targeted AdGRP78 (1.31±0.08 g). SFO‐targeted AdGRP78 also prevented obesity‐induced lipid accumulation in the liver and upregulation of hepatic gluconeogenic markers (e.g. Pepck mRNA 1.6±0.1 vs 0.7±0.2 fold NC, AdLacZ vs AdGRP78, p<0.05). These findings suggest that ER stress in the SFO selectively mediates obesity‐induced hepatic dysfunction, but not the development of adiposity or hypertension.HL63887, HL96571, HL84207
Respiratory Sensory Gating in Children Measured by the Respiratory‐Related Evoked Potentials
Authors: Chan Pei‐Ying Sarah , Li Chieh‐Wen , Chen Ying‐Jhen 
Published: June 2021

Respiratory neural gating function in the cortices was measured in healthy children using the paired respiratory‐related evoked potential (RREP) measured elicited by inspiratory occlusions. We hypothesized that respiratory sensory gating of healthy children would be normal as represented by a reduced amplitude of the second stimulus (S2) compared by the first stimulus (S1) for the short latency Nf, P1, and N1 peaks. We further hypothesized that the gating peak would be normal as represented by a N1 peak S2/S1 ratio of less than 0.5.Paired 150‐msec inspiratory occlusions with an inter‐stimulus‐interval of 500 milliseconds were given to the subjects. The RREP was recorded with a 40‐channel electroencephalography system. A minimum of 100 paired occlusions were collected for data analysis. The RREP Nf, P1, and N1 peaks were identified in latencies and amplitudes. The S2/S1 ratio was calculated for the amplitudes for each peak.Our preliminary data showed that the averaged latencies for the Nf, P1, and N1 peaks were 40 and 42, 55 and 48, 94 and 81 msec, respectively. The averaged S2/S1 ratio for the RREP Nf, P1, and N1 peak amplitudes were 0.97, 1.13, and 0.64, respectively.The result suggested that young children may have a decreased respiratory gating function represented by increased P1 and N1 peak S2/S1 ratios for the first order neural information processing.Supported by: NSC100–2320‐B‐182–018, CMRPD1A0021, CMRPD1A0022
Relationship of Internet Game Addiction and Autonomic Function in Adolescents
Authors: Kim Na‐Hyun , Kong In Deok 
Published: June 2021

The purpose of this study was to identify the relationship of internet game addiction and autonomic function in adolescents. The subjects of this study were 140 high school students. Data were collected from July to September, 2012, using a questionnaire for measuring internet game addiction, stress and anxiety, and blood serum cortisol level for autonomic function. Data were analyzed using descriptive analysis, t‐test, ANOVA and Pearson correlation coefficient with SPSS/WIN 15.0. The stress level of internet game addiction group was significant higher than the stress level of the non‐addiction group (t=−5.06, p<.001). The anxiety score was also significant high in the group of internet game addiction (t=−4.90, p<.001). Serum cortisol level was higher in internet game addiction group than non‐addiction adolescents. There were significant positive correlations between daily internet game time and the score of stress and anxiety.These results showed that internet game addiction could increase sympathetic activities in high school adolescents. Thus, nursing approach to relieve the internet game addiction could be helpful to prevent cardiovascular distress due to autonomic imbalance in their future.[This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012R1A1A4A01012884)]
Aldosterone‐mediated cardiac regulation of microRNA‐21
Authors: Romero Damian G. , Price Jana E. , Hall Michael E , Bandyopadhyay Sibali , Yanes Licy L. 
Published: June 2021

Excess aldosterone (ALDO), along with high salt intake, causes cardiac damage. The molecular mechanisms of ALDO‐mediated cardiac injury are poorly understood. MicroRNAs (miRNAs) are endogenous, non‐coding RNAs that have important roles in cell proliferation and differentiation.We previously reported that treatment of rats with ALDO/SALT increases cardiac left ventricle miR‐21 expression and downregulation of miR‐21 exacerbated cardiac injury.We aimed to identify the cardiac cells in which miR‐21 is regulated by ALDO/SALT. Uninephrectomized male Sprague Dawley rats were treated with ALDO/SALT or vehicle for 2 weeks. Cardiomyocytes and fibroblasts were isolated and sorted using cell‐specific markers and miR‐21 expression quantified by qPCR. Cardiac fibroblasts were isolated from control rats, cultured, treated with ALDO for 24 h and miR‐21 expression quantified by qPCR.ALDO/SALT treatment increased miR‐21 expression only in the fibroblasts. In situ hybridization confirmed these results. In vitro treatment of cardiac fibroblasts with ALDO dose‐dependently increased miR‐21 expression.In summary, these results suggest that cardiac fibroblasts are a direct target of ALDO both in vitro and in vivo and modulation of cardiac fibroblast miR‐21 levels may be a novel therapeutic approach to mitigate ALDO/SALT‐mediated cardiac injury.Supported by American Heart Association Grant 12SDG8980032.
Pulmonary inflammation‐induced muscle atrophy involves a GSK‐3beta‐GR signaling axis
Authors: Langen Ramon , Verhees Koen , Schols Annemie 
Published: June 2021

Skeletal muscle atrophy is induced by raised glucocorticoid (GC) levels and reduced insulin/IGF‐1‐Akt signaling. Glycogen synthase kinase‐3 beta (GSK‐3b) is a downstream kinase of Akt involved in regulation of muscle protein turnover.We hypothesized that muscle GC receptor (GR) and GSK‐3b are required for muscle atrophy in response to pulmonary inflammation.Control, muscle specific‐GR (mGRKO) or ‐GSK‐3b (mGSK‐3bKO) mice were subjected to intra‐tracheal LPS instillation to induce acute pulmonary inflammation.Increases in circulating corticosterone levels following IT‐LPS were similar in control, mGRKO and mGSK‐3KO mice, but accompanied by substantial muscle atrophy in control mice only. Accordingly, increases in mRNA transcripts encoding effectors of the Ub 26S‐proteasome (MuRF1 and Atrogin‐1) and autophagy‐lysosomal (Bnip3, LC3b) systems were strongly attenuated in muscle of mGRKO or mGSK‐3KO mice. Interestingly, increased expression of GC‐sensitive genes (Glul, KLF15 and REDD1) and FOXO1 and ‐3a following IT‐LPS, was suppressed in skeletal muscle of GRKO and GSK‐3KO mice. This dependency of GR signaling on GSK‐3b was confirmed in cultured muscle cells.We conclude that pulmonary inflammation‐induced muscle atrophy is dependent on an intact GSK‐3b‐GR signaling axis.Support: Dutch Astma Foundation (3.2.07.017) and Dutch Top Institute Pharma (T1–201)
Docosahexaenoic acid antagonizes palmitate‐induced protein degradation in myotubes
Authors: Woodworth‐Hobbs Myra , Hudson Matt , Zheng Bin , Zoromsky Sara , Franch Harold , Price S. Russ 
Published: June 2021

Muscle atrophy is a debilitating consequence of many chronic diseases, some of which are characterized by accumulation of lipids in skeletal muscle. High levels of saturated fatty acids (i.e. palmitic acid, PA) cause dysregulated protein metabolism in cultured myotubes, whereas the omega‐3 fatty acid docosahexaenoic acid (DHA) has beneficial metabolic effects. We hypothesized that DHA prevents PA‐induced muscle atrophy by counteracting its effects on protein degradation. To test our hypothesis, we studied C2C12 myotubes treated with 500uM PA and/or 100uM DHA. PA significantly increases the rate of protein degradation, and the response is reversed by co‐treatment with DHA. The protein kinase Akt is a key regulator of protein balance and inhibits the FoxO3 transcription factor. PA reduces the ratio of phospho‐to‐total Akt and increases the mRNA and total and nuclear protein levels of FoxO3. It also increases the levels of mRNA encoding three FoxO3 targets, the MuRF‐1 and atrogin‐1/MAFbx E3 ubiquitin ligases and the autophagy mediator Bnip3. DHA attenuates the effects of PA on Akt, FoxO3, and all three atrogenes mRNAs. These data indicate that PA induces protein degradation by inducing the ubiquitin‐proteasome and autophagic proteolytic systems and that DHA counters the catabolic effects of PA by improving Akt signaling.Support NIH DK95610, AHA GRNT 7660020
Increased Mechano‐Growth Factor (MGF) expression in Crohn's disease mediates smooth muscle hypertrophy in intestinal strictures via activation of Erk5
Authors: Li Chao , Grider John , Kuemmerle John 
Published: June 2021

Expression of the IGF‐IEc splice variant, MGF, increases in inflamed muscle and mediates cell hypertrophy. Smooth muscle cell (SMC) hypertrophy is a feature of intestinal strictures in patients with Crohn's disease.AimsTo determine whether MGF increases in stricturing Crohn's disease and whether it regulates SMC hypertrophy.MethodsSMC isolated from strictured and normal intestine in the same patient with Crohn's disease were used to prepare mRNA, protein lysates, or primary cell cultures. MGF transcripts were measured by qRT‐PCR and protein by ELISA. Cell hypertrophy in response to 100 nM C‐terminal MGF peptide was measured over 4d by confocal microscopy and by total protein/105 cells. Phosphorylated Erk5(Thr218/Tyr220) was measured by immunoblot analysis and immunofluorescence.ResultsMGF transcripts were increased 18 fold and MGF protein was increased 10 fold in SMC of strictured intestine compared to normal margin and was accompanied by a concomitant increase in Erk5 phosphorylation. MGF caused a time‐dependent, 2–19 fold increase, in SMC hypertrophy that was accompanied by nuclear localization of phospho‐Erk5. These effects were abolished by 30 Âμm BIX02188, a selective Erk5 inhibitor. MGF did not elicit IGF‐IR phosphorylation or SMC proliferation.ConclusionsIncreased MGF expression in Crohn's disease mediates smooth muscle hypertrophy via activation of Erk5.Supported by NIH DK49691
The protective role of PGC‐1α in the recovery of muscle disuse atrophy
Authors: Kang Choung‐Hun , Goodman Craig A , Hornberger Troy A , Ji Li Li 
Published: June 2021

Prolonged inactivity results in skeletal muscle atrophy including increased reactive oxygen species (ROS) generation, inflammation and protein degradation. Over‐expression of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) has been shown to increase mitochondrial biogenesis and reduce oxidative stress.MethodsFemale FVB/N mice (N=48) were randomly divided into 4 groups: (1) control (CON) & injected with GFP (Con‐GFP); (2) CON & PGC‐1α in vivo transfection (Con‐PGC‐1α); (3) two wks of hindlimb immobilization (IM) followed by 5 days remobilization (IM‐RM) & injected with GFP (IM‐RM‐GFP); and (4) IM‐RM & PGC‐1α in vivo transfection (IM‐RM‐PGC‐1α). GFP or PGC‐1α was injected into tibialis anterior (TA) muscle of one of the hindlimbs with an electroporation system.ResultsPGC‐1α induced SIRT3 and SOD2 binding in CON and IM‐RM by enhancing SIRT3 promoter activity and protein expression. Basal SOD2 acetylation level was increased by 57% in IM‐RM, however PGC‐1α decreased SOD acetylation by 30% (P<0.05) in IM‐RM. Thus, PGC‐1α over‐expression resulted in a 15% increase in superoxide dismutase (SOD) 2 protein content and activity in IM‐RM vs CON (p<0.05). IM‐RM increased mitochondrial H2O2 generation in both GFP and PGC‐1α groups, whereas PGC‐1α attenuate IM‐RM‐induced ROS generation by 18% (P<0.05).
Positive association between physical activity and bone in children with Prader‐Willi Syndrome
Authors: Duran Andrea Tiana , Castner Diobel Mendoza , Tucker Jared M , Rubin Daniela A 
Published: June 2021

Prader‐Willi Syndrome (PWS) presents hypotonia, congenital obesity, and low lean mass; perhaps leading to less physical activity (PA) and poor bone health.PurposeTo explore associations between PA and bone in children with PWS, accounting for body fat. Nine boys and 9 girls with PWS participated (mean age: 11.0±2.2 y, body fat: 46.2±8.5 %). PA was assessed by accelerometry (minimum of 3 compliant weekdays and 1 compliant weekend day) and classified into moderate (MPA), vigorous (VPA), and moderate plus vigorous (MVPA). Fat mass, bone mineral content (BMC), bone mineral density (BMD), and BMD z‐score (BMDz) of the hip and full body minus the head (body) were measured by dual energy x‐ray absorptiometry. MPA was associated with hip BMD and BMDz (r=0.595, r=0.650, respectively). VPA was associated with hip BMC and BMD (r=0.589, r=0.592, respectively) and body BMC and BMD (r=0.549, r=0.572, respectively). MVPA was associated to hip BMC, BMD and BMDz (r=0.523, r=0.653, r=0.607, respectively), and body BMC, BMD and BMDz (r=0.518, r=0.555, r=0.638, respectively). Associations were significant at p<0.05. MVPA had moderate positive associations with all bone parameters. Both MPA and VPA were independently associated with bone. However, VPA showed stronger associations with BMC than MPA. As in other children, intensity of PA appears an important determinant of bone health. Supported by USAMRAA Award W81XWH‐09–1‐0682
Post‐exercise heart rate recovery is impaired in soccer athletes during a competitive season
Authors: Callegaro Carine Cristina , dos Santos Corrêa Ana Paula , Viecili Paulo Ricardo Nazario 
Published: June 2021

IntroductionPost‐exercise heart rate recovery is mediated by the cardiac vagal reactivation. Since vagal control of the heart rate is impaired in athletes at the competition period, we hypothesized that soccer athletes engaged in a competitive season would exhibit an impaired heart rate recovery after exercise.MethodsWe studied 7 male soccer athletes (23 ± 5 years old) and 9 male sedentary individuals (26 ± 1 years old). Heart rate variability at rest was assessed by spectral analysis using the fast Fourier transform. Heart rate was measured at rest, during treadmill exercise test and recovery period.ResultsThe athletes had a lower heart rate at rest than sedentary individuals. Low frequency and high frequency component of the heart rate were similar in the soccer athletes and in the sedentary individuals. During the exercise the athletes had a greater increase in heart rate (114 ± 20 bpm vs. 90 ± 18 bpm, P = 0.02) than in sedentary individuals. Soccer athletes showed a higher maximal oxygen consumption (63 ± 5 ml.kg−1.min−1) than sedentary individuals (47 ± 5 ml.kg−1.min−1; P= 0.001). Heart rate recovery in the first minute after exercise was similar in both groups.ConclusionOur data suggests that high‐intensity exercise performed at the competition season may impair heart rate recovery in soccer athletes.
Gastric Sonic Hedgehog Acts as a Chemoattractant for Macrophages During Tissue Regeneration
Authors: Engevik Amy Christine , Martin Jason R. , Tritschler Julie A. , Feng Rui , Schumacher Michael A. , Yang Li , Zavros Yana 
Published: June 2021

Sonic Hedgehog (Shh) has been shown to regulate wound healing in various tissues. Immune cells such as macrophages (Mø) are also known to regulate repair. Despite its known function in tissue regeneration the role of Shh as a regulator of the immune system during gastric tissue repair remains unknown.HypothesisShh secreted from the gastric epithelium mediates the recruitment of Møs that drives tissue repair. A mouse model expressing a parietal cell‐specific deletion of Shh (PC‐ShhKO) and a mouse model expressing a myeloid cell‐specific deletion of Hedgehog receptor Smoothened (LysMCre/SmoKO) were used. Acetic acid ulcers were induced and samples collected. In controls, ulcers healed within 7 days. Tissue regeneration was accompanied by the recruitment of Møs to the stomach within 48 hours post injury. Control mice had elevated expression of cytokines and the pro‐angiogenic factor VEGF that correlated with an increased Shh tissue concentration within 3 days post injury. PC‐ShhKO mice showed complete loss of ulcer repair, the absence of Mø recruitment and reduced Shh tissue concentrations. LysMCre/SmoKO mice exhibited delayed repair of ulcerated tissue. While in vitro Møs migrated towards the Shh gradient, cells isolated from LysMCre/SmoKO mice failed to respond. Gastric Shh facilitates tissue repair by acting as a Mø chemoattractant. Funding: ACS Research Scholar Award 119072‐RSG‐10–167‐01‐MPC (Y. Zavros)
microRNA‐29b Functions as a Repressor of Intestinal Mucosal Growth by Targeting Cyclin‐dependent Kinase 2
Authors: Xiao Lan , Rao Jaladanki N. , Gorospe Myriam , Wang Jian‐Ying 
Published: June 2021

Integrity of the intestinal epithelium is tightly regulated by numerous factors including microRNAs. We recently found that mucosal growth inhibition associates with an increase in microRNA‐29b (miR‐29b), but its exact role in epithelial homeostasis remains unknown. This study determined if miR‐29b inhibits intestinal mucosal growth by repressing cyclin‐dependent kinase (CDK) 2.MethodsStudies were conducted in mice and IEC‐6 cells, and miR‐29b function was examined by its ectopic overexpression and silencing.ResultsmiRNA‐29b silencing by the systemic delivery of LNA‐antimiR‐29b not only increased CDK2 but also stimulated small intestinal mucosal growth in mice. In contrast, increased levels of miRNA‐29b in IEC‐6 cells repressed CDK2 expression and caused growth arrest in G1 phase. miR‐29b repressed CDK4 translation through direct interaction with the CDK2 mRNA, and point mutation of miR‐29b binding‐site on the 3′‐untranslated region of the CDK2 mRNA prevented miR‐29b‐induced repression of CDK2 translation. CDK2 gene transcription was also inhibited by miRNA‐29b through a process involving p53. miR‐29b increased p53, whereas deletion of p53 binding‐site in the CDK2‐promoter blocked miRNA‐29b‐induced repression of CDK2 transcription.ConclusionsThese results indicate that miRNA‐29b inhibits intestinal mucosal growth by repressing CDK2 expression through distinct mechanisms. NIH Grant DK‐57819
A genetically based GPCR‐mediated central molecular mechanism underlying the pathophysiology of salt‐sensitive hypertension
Authors: Wainford Richard David , Carmichael Casey Yumi , Kuwabara Jill Toshiko 
Published: June 2021

AimWe have demonstrated endogenous up‐regulation of hypothalamic paraventricular nucleus (PVN) Gαi2‐proteins is required to suppress norepinephrine (NE) mediated sodium retention during high salt intake in the Sprague‐Dawley rat. In these studies we examined the role(s) of central Gαi2 proteins in sodium homeostasis and blood pressure regulation following elevated dietary salt‐intake in Brown Norway (BN), Dahl salt‐resistant (DSR), Dahl salt‐sensitive (DSS) and DSSBN8 congenic rat strains.MethodsBN, DSR, DSS or DSSBN8 rats were maintained on a normal (0.4% NaCl) or high (8% NaCl) diet for 21‐days Additional groups of DSR and DSS rats received a 21‐day i.c.v. infusion of a Gαi2 targeted oligodeoxynucleotide during high salt‐intake. On day‐21 MAP, 24h metabolic balance, plasma NE and PVN Gαi2 protein levels were determined (N=5/group).ResultsHS‐intake did not alter MAP, suppressed plasma NE (P<0.05), and evoked a site‐specific increase in PVN Gαi2 protein levels in salt‐resistant BN and DSR (4.8 and 4.2‐fold respectively, P<0.05), but not hypertensive DSS, rats. Brain Gαi2 protein downregulation evoked hypertension, sodium retention and elevated plasma NE content in DSR rats (P<0.05) and profoundly exacerbated DSS hypertension (P<0.05). In DSSBN8 rats BN chromosome 8 substitution attenuated hypertension, sodium retention and global sympathoexcitation vs. DSS rats (P<0.05) and restored PVN specific Gαi2 protein up‐regulation.ConclusionPVN Gαi2 protein‐gated pathways represent a genetically conserved central molecular mechanism that suppresses NE mediated renal sodium reabsorption to maintain a salt‐resistant phenotype. Owing to SNP's in the GNAI2 gene correlating with hypertension in human subjects our findings have translational implications for human hypertension ‐ HL107330.