bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deletion of p22phox‐dependent reactive oxygen species (ROS) in the paraventricular nucleus (PVN) protects against diet‐induced obesity (DIO) by increasing thermogenesis and lipolysis.
Authors: Lob Heinrich E , Song Jiunn , Mark Allyn L , Davisson Robin L 
Published: June 2021

Oxidative stress is implicated in the onset of obesity. We reported that deletion of p22phox, the required subunit for NADPH oxidase activity, in the PVN, prevents DIO by increasing energy expenditure and brown adipose tissue (BAT). Here we tested the hypothesis that reducing p22phox‐dependent ROS in the PVN protects against DIO by increasing β3‐adrenoreceptor (β3‐AR) activity, thereby enhancing BAT thermogenesis and white adipose tissue (WAT) lipolysis. We performed PVN‐targeted injection of an adenovirus encoding Cre recombinase (AdCre) or control AdLacZ in 6 week old p22phox/flox mice. Two weeks later, mice were fed a high fat diet (HFD, 42%) for 10 weeks. In AdCre vs AdLacZ treated DIO mice, we observed increases in β3‐AR mRNA (+2.6±0.6 fold, n=4, p<0.05) and PGC‐1α mRNA (+1.6±0.17 fold, n=5, p<0.05) in BAT. Lipolysis of subcutaneous WAT was also increased in AdCre vs AdLacZ DIO mice as measured by hormone‐sensitive lipase (HSL, +2.3±0.5 fold, n=6, p<0.05) and β3‐AR mRNA (+2.7±0.7 fold n=4, p<0.05). Blockade of β3‐AR with SR59230A (i.p., 2 mg/kg/day) reversed the increases in energy expenditure, BAT mass and mRNA levels of PGC‐1α, β3‐AR and HSL in BAT and WAT to AdLacZ levels. These data indicate that disrupting oxidative stress in the PVN during DIO increases β3‐AR in BAT and WAT, thereby increasing thermogenic metabolism and lipolysis and reducing adiposity.12SDG9160010, HL063887, HL084207
Impact of physical activity on age‐related insulin resistance: The contribution of post‐transcriptional gene silencing.
Authors: Bunprajun Tipwadee , Chatsudthipong Varanuj , Pedersen Bente K. , Green Charlotte J. 
Published: June 2021

Insulin sensitivity decreases during aging, reflected by impaired insulin‐stimulated glucose uptake into skeletal muscle. It has been suggested that lifestyle changes, especially physical activity, may enhance insulin action in aged muscle. To investigate how physical activity improves age‐related insulin resistance, we studied muscle satellite cells isolated from young, ageing sedentary and ageing active participants matched for BMI. Ageing sedentary myocytes had markedly reduced insulin‐stimulated glucose uptake compared to young myocytes whereas ageing active myocytes retained insulin sensitivity. However, PKB phosphorylation in response to insulin remained intact in all groups. Interestingly, there was an up‐regulation of microRNA (miR) 193b and 195 expressions in ageing sedentary but not ageing active myocytes when compared to young. Our findings indicate that physical activity may help to maintain insulin sensitivity in ageing muscle potentially via a microRNA dependent and PKB independent mechanism.This work was supported by the Royal Golden Jubilee Program and FP7 EU consortium, myoage.
Carboxylesterase 1 gene duplication and mRNA expression in adipose tissue are linked to obesity and metabolic function
Authors: Friedrichsen Martin , Poulsen Pernille , Wojtaszewski Jørgen , Hansen Peter Riis , Vaag Allan , Rasmussen Henrik Berg 
Published: June 2021

Context and aimsCarboxylesterase 1 (CES1) plays an important role in the control of the metabolism of triglycerides and cholesterol in various cell types including adipocytes and hepatocytes. In this study we investigated CES1 mRNA expression in adipose tissue as well as CES1 gene duplication and their association with measures of adiposity and metabolic function in a large twin population.Methodology295 monozygotic and dizygotic twins (62–83 years) were subjected to a standard OGTT and excision of abdominal subcutaneous fat biopsies. Levels of CES1 mRNA and DNA copy number of the CES1 gene were assessed by quantitative PCR.ResultsCES1 mRNA expression in adipose tissue was positively associated with BMI (P<0.001), insulin resistance ([HOMA], P=0.003) and fasting levels of glucose (P=0.002), insulin (P=0.006), and triglycerides (P=0.003). Gene duplication of CES1 was not linked to altered CES1 mRNA expression (P=0.63). Nonetheless, CES1 gene duplication was associated with increased glucose tolerance (P=0.03) and decreased insulin resistance (P=0.02).ConclusionCES1 mRNA expression in adipocytes as well as CES1 gene duplication were associated with measures of glucose metabolism, which raises the possibility of a potential role for this enzyme in the development of type 2 diabetes.
Glutaredoxin 1 regulates endothelial barrier function via activation of AKT/eNOS pathway
Authors: Han Jingyan , Cohen Richard , Matsui Reiko 
Published: June 2021

The integrity and barrier function of the endothelial cell (EC) monolayer lining the vasculature are critical for the maintenance of cardiovascular homeostasis. Vascular hyper‐permeability is an essential component of inflammation, atherosclerosis and tumor metastasis. Glutaredoxin1 (Glrx), a cytosolic enzyme that reduces S‐glutathionylation (R‐SSG), may activate signaling molecules that are inhibited by R‐SSG including Akt and eNOS. We investigated the role of Glrx in endothelial barrier function. We found that adenoviral Glrx overexpression in human umbilical vein endothelial cells (HUVEC) increased the EC permeability manifested by elevated FITC‐dextran influx across the HUVEC monolayer. This was accompanied by increased phosphorylation of Akt (S473) and eNOS (S1177). Inhibition of eNOS by L‐NAME decreased Glrx‐mediated EC permeability indicating the importance of nitric oxide. Glrx‐induced eNOS phosphorylation was diminished by siRNA‐mediated depletion of Akt1. The PI3K inhibitor, LY294002, completely abolished Grx1‐induced phosphorylation of Akt and eNOS. These results together suggest that Glrx, at least in part via activation of the PI3K/Akt1/eNOS signaling pathway, increases the basal endothelial permeability.Funding: R37 HL104017
C‐type natriuretic peptide treatment and cardiovascular function in spontaneously hypertensive rats.
Authors: Costa María Angeles , Caniffi Carolina , Cerniello Micaela , Romero Mariana , Sueiro Laura , Radionovas Vanesa , Arranz Cristina 
Published: June 2021

The aim was to evaluate the effects of C‐type natriuretic peptide (CNP) on systolic blood pressure (SBP), cardiac and vascular function, and nitric oxide synthase (NOS) activity on cardiac left ventricle (LV) and aorta artery (AA), in spontaneously hypertensive rats (SHR).Methods12 weeks‐old male SHR were infused (14 days, osmotic pumps) with CNP (0,75 μg/hr.rat) or saline (S). SBP (mmHg) was recorded and echocardiography was performed. Animals were decapitated and NOS activity (pmol 14C L‐citrulline/g.tissue. min) was measured in AA and LV. Vascular reactivity in AA was studied, evaluating maximal response to phenylephrine (Rmax) and concentration of acetylcholine (expressed as negative log molar) producing 50% of maximum relaxation (pEC50). Statistics: t‐test.

S
CNP

SBP
175±3
159±5*

Heart rate (bpm)
435±10
434±15

End‐diastolic volume (ml)
0,16±0,02
0,23±0,03*

End‐systolic volume (ml)
0,05±0,02
0,07±0,03

Stroke volume (ml/min)
0,11±0,01
0,16±0,02*

Cardiac output (ml)
47,8±2,0
68,8±7,4*

Ejection fraction %
69±6
71±6

Fractional shortening %
34±5
35±4

NOS LV
255±5
371±8*

NOS AA
117±16
202±4*

Rmax
1,01±0,16
0,46±0.06*

pEC50
7,4±0,1
9,3±0.2*

Values are means ± SEM.
p<0.05 vs S; n=6 rats/group.

ConclusionChronic treatment with CNP decreased blood pressure, activating cardiovascular NOS, improving cardiac efficiency and vascular function, in this model of hypertension. Supported by: UBA‐Conicet.
Circulating fragmented mitochondria induce maternal hypertension, placental inflammation and apoptosis in pregnant rats
Authors: Goulopoulou Styliani , Matsumoto Takayuki , Wenceslau Camilla F , Spitler Kathryn , McCarthy Cameron G , Webb R. Clinton 
Published: June 2021

Mitochondrial fragments released from necrotic cells (mitochondrial damage‐associated molecular patterns, mitDAMPs) have pro‐inflammatory and immunogenic properties. Placentas from pregnancies with preeclampsia (PE) show exaggerated rates of cell death. We tested the hypothesis that circulating fragmented mitochondria would increase maternal blood pressure and induce placental inflammation and apoptosis in pregnant rats. Mitochondria were isolated from rat liver and sonication was used to disrupt their integrity. Pregnant rats were injected with fragmented mitochondria (mit‐treated; 4 mg/tissue) or saline (control) on gestational day (gd) 15. On gd17, systolic blood pressure, as measured with the tail cuff method, was increased in mit‐treated compared to saline‐treated dams (mit‐treated vs. control: 140±3 vs. 114±6 mmHg, p<0.05). Protein levels of cyclooxygenase 1 (COX1) and 2 (COX2) and pro‐apoptotic protein BAX were increased in placentas from mit‐treated rats (mit‐treated vs. control: COX1, 6.3±1.8 vs. 1.9±1.3; COX2, 2.6±0.2 vs. 1.7±0.3; BAX: 9.1±1.3 vs. 4.4±0.02, p<0.05). Systemic treatment with fragmented mitochondria increases maternal blood pressure, placental inflammation and apoptosis in pregnant rats. MitDAMPs released from necrotic trophoblasts may be the source of maternal hypertension and placental dysfunction in pregnancies with PE.Support: NIH, SWHR
Ablation of MMP‐9 gene ameliorates paracellular permeability and fibrinogen‐amyloid beta plaque formation during hyperhomocysteinemia
Authors: Muradashvili Nino , Tyagi Reeta , Tyagi Suresh C. , Lominadze David 
Published: June 2021

Many inflammatory and cognitive disorders including Alzheimer's disease are accompanied by hyperhomocysteinemia (HHcy). We tasted the hypothesis that HHcy increases microvascular permeability affecting mainly paracellular transport via activation of matrix metalloproteinase‐9 (MMP‐9) leading to an increased formation of fibrinogen (Fg) and β‐amyloid (Aβ) complex.Using a dual‐tracer probing method, changes in cerebrovascular permeability were assessed in male wild type (WT, C57BL/6J), cystathionine β‐synthase heterozygote (CBS+/−, a genetic model of HHcy), MMP‐9 gene knockout (MMP9−/−), and CBS and MMP‐9 double‐knockout (CBS+/−/MMP9−/−) mice. Expression of vascular endothelial cadherin (VE‐cadherin) and Fg‐Aβ plaque formation was assessed in mouse brain cryo‐sections.We found that cerebrovascular permeability in CBS+/− mice was mainly via paracellular transport pathway and it was greater than that in other groups. Expression of VE‐cadherin was lowest and Fg‐Aβ plaque formation was greatest in CBS+/− mice. Absence of MMP‐9 activity in MMP9−/− mice ameliorated these effects.Thus, HHcy increases cerebrovascular permeability by downregulating VE‐cadherin through MMP‐9 activation and enhances Fg‐Aβ plaque formation. These data may lead to identification of new targets for therapeutic intervention that can modulate inflammation‐induced cerebrovascular permeability.
Aging influences the expression of early response genes following acute resistance exercise in trained skeletal muscle
Authors: Liu Dongmei , Sartor Maureen , Pistilli Emidio , Nader Gustavo , Visich Paul , Hoffman Eric , Gordon Paul 
Published: June 2021

To identify the influence of age on skeletal muscle transcriptional responses to resistance exercise (RE), we recruited 14 young (<40 y) and 8 older (>;60 y) participants. They underwent 12‐week unilateral arm RE training, and conducted one bout of acute RE one week later. Biceps brachii muscle biopsies were obtained 4h and 24h post exercise (PE). Gene expression was assessed using Affymetrix U133A microarrays, and analyzed using an intensity‐based Bayesian moderated paired t‐test. The immediate‐early response genes FOS, EGR1, JUNB, and NR4A3, and other key genes for muscle metabolism including IL6R, PRKAG2, EIF2AK3, HEY1, and ANKRD1, showed striking differences between young and old muscle. They were dramatically up‐regulated PE in the young, but highly down‐regulated in the old (Table 1). This age effect might implicate the diminished metabolic and hypertrophic benefits of RE with aging.Funding for this study was provided by NIH RO1 NS40606–01
Effect of ageing and physical activity on cardiovascular function
Authors: Munch Gregers Druedal Wibe , Calbet José Antonio Lopez , Boushel Robert , Pedersen Bente Klarlund , Saltin Bengt , Mortensen Stefan Peter 
Published: June 2021

Ageing is associated with vascular dysfunction and a reduced capacity of the central circulation to deliver O2 to the contracting muscles. The purpose of present study was to investigate whether a physical active lifestyle can maintain a sufficient exercise hyperemia and the influence of the active muscle mass. Central and limb hemodynamics were determined in 8 young (Y) (23±1 years), 8 lifelong sedentary elderly (LSE) (66±2 years) and lifelong active elderly (LAE) (62±2 years) men during incremental cycling with and without simultaneous arm cycling (50w). Peak workload was higher in the LAE compared to Y and LSE (294±15; 216±10; 213±8 W; P<0.05). Leg blood flow (LBF) increased similarly in LAE and LSE, but peak values were higher in LAE and Y compared to LSE (7.8±0.5; 8.6±0.4 vs. 6.4±0.4 l/min; P<0.05). Leg a‐vO2 difference was higher in LAE compared to the Y and LSE at all workloads (P<0.05), whereas leg VO2 was higher in LAE and Y compared to LSE at exhaustion (P<0.05). During combined arm and leg cycling LBF, leg a‐vO2 difference and VO2 was lower in Y and LSE compared to leg cycling alone (P<0.05). Mean arterial pressure increased in all groups but was lower in Y (P<0.05). These results demonstrate that lifelong physical activity can maintain aerobic power despite a lower exercise hyperemia by an increase in O2 extraction.Supported by the Lundbeck Foundation and Augustinus Foundation
Interval training program improves cardiac function and physical performance in heart failure mice
Authors: ABAD CESAR CAVINATO CAL , Mostarda Cristiano Teixeira , Nascimento Ademir Manuel , Santos Mirailton Alves dos , Souza Leandro Eziquiel , Figueroa Diego M. T. , Santos Fernando , de Souza Pâmella Ramona Moraes , De Angelis Kátia , Irigoyen Maria Claudia 
Published: June 2021

This study was designed to verify the effect of an eight week interval training program (IT) in systolic and diastolic functions and physical performance in heart failure mice (C57B16, n=24). The animals were divided in three groups: 1) Intact sedentary (C), 2) infarcted sedentary (MI‐s); and 3) infarcted trained (MI‐i). At the begining (M1) and at the end of IT (M2), time of maximal running performance (Tvmáx) was quantified. The ejection fraction (EF), shortening fraction (SF) and isovolumetric relaxation time (IVRT) were accessed by echocardiography in M2. At 60 days after coronary artery occlusion the IT was started (4min at 80% Vmáx × 4min at 40% Vmáx during 60min). The results are presented in mean and SEM. Myocardial infarction area was not different between groups in both evaluation time (M1vsM2). The EF and SF in MI‐s were lower than C (44±3.7vs58±3.0% and 22±2vs31±2%, respectively; p≤0.05) but similar between MI‐i and C (56±5vs58±3% and 25±3vs31±2%, respectively). The IVRT was higher (p≤0.05) in MI‐s (25.6±4ms) than C (13±1ms) while similar in MI‐i (15±0.8ms) and C. At the M1 both MI‐s and MI‐i Tvmáx decreased in comparison with C (620±16 and 644±28vs840±17s, respectively). At the M2, Tvmáx delta percent was higher in MI‐i than MI‐s (64±8vs15±6%, respectively; p≤0.05) and C (0.53±3%). The results suggest that IT improves cardiac function and physical performance in heart failure mice.Financial Suport: CnPq.
Validity of the oxygen uptake efficiency slope to assess aerobic fitness following bed rest
Authors: Scott Jessica , Goetchius Elizabeth , Buxton Roxanne , Ploutz‐Snyder Lori 
Published: June 2021

Achieving true peak oxygen uptake (VO2peak) is often difficult after the deconditioning that results from musculoskeletal unloading via bed rest or spaceflight. Consequently, submaximal measures predicting VO2peak are crucial for the effective assessment of cardiorespiratory functional reserve. One proposed index, oxygen uptake efficiency slope (OUES), is effort independent; however, its sensitivity to change in aerobic performance because of disuse and exercise training is unknown. Twenty‐five subjects performed a maximal exercise test before and after 14 days of 6° head‐down tilt bed rest. During bed rest, 9 subjects completed a high‐intensity exercise program (EX) while 16 were sedentary (CONT). In addition to VO2peak and ventilatory threshold (VT), OUES at 75% and 100% of total exercise time were determined. VO2peak (−13%), VT (−17%), OUES100 (−12%), and OUES75 (−10%) decreased in the CONT group; while VO2peak (+10%), VT (+8%), OUES100 (+6%), and OUES75 (+10%) increased in the EX group. The change in both OUES100 and OUES75 was significantly related to the change in VO2peak (OUES100: r = 0.85; OUES75: r = 0.75; P < 0.05). Bland‐Altman plots showed high agreement between OUES and VO2peak. These findings indicate that OUES is an objective submaximal index that can detect changes in cardiopulmonary reserve following deconditioning and exercise training.Support: NASA Johnson Space Center Human Research Program
Ethanol induces skeletal muscle autophagy and sarcopenia by an AMPK independent, PI3K dependent mechanism
Authors: Dasarathy Srinivasan , Thapaliya Samjhana , Runkana Ashok , Garber Ari , McMullen Megan , Nagy Laura E , Prasad Sathyamangala V Naga 
Published: June 2021

Loss of skeletal muscle mass or sarcopenia is the most common but understudied complication of alcoholic liver disease. Skeletal muscle proteolysis due to ethanol has not been systematically evaluated.A comprehensive approach was used to study the proteolytic pathways in muscle of patients with alcoholic cirrhosis and alcohol fed rodent along with in vitro studies in C2C12 myotubes exposed to 100mM ethanol for 24 hrs. Ubiquitin proteasome activity and autophagy were studied using immunoblots, real time PCR, proteasome activity, standard autophagy readouts including LC3 lipidation, p62 degradation and Beclin overexpression. C2C12 cells transfected with GFP‐LC3 and GFP‐mCherry‐LC3 reporter were also studied. Pulse chase experiments were performed with and without 3‐methyladenine. Immunoblots for components of the PI3K pathway‐Akt, mTOR, p70s6k and 4EBP activation, pAMPK as well as protein phosphatase 2A and PI3Kγ activity were quantified by thin layer chromatography. Ubiquitin proteasomal activity was unaltered and autophagy was increased in the myotubes and in vivo with ethanol. mTOR and its target protein phosphorylation was lower with ethanol exposure. Increased PP2A activity resulted in an AMPK independent mTOR dependent increase in autophagy.
Influence of Inhaled Amiloride on Lung Fluid Regulation During Normobaric Hypoxia in Healthy Humans
Authors: Baker Sarah E , Wheatley Courtney M , Miller Andrew D , Kasak Alexander J , Carlson Alex R , Taylor Bryan J , Hulsebus Minelle L , Snyder Eric M , Johnson Bruce D 
Published: June 2021

BackgroundFluid flux in the lungs is influenced by factors altering accumulation or removal (e.g., stimulation of epithelium sodium channels, ENaC).PurposeTo determine if ENaC are necessary in the normal fluid regulation with simulated altitude exposure.Methods/ResultsOn separate occasions, 19 healthy subjects (27 ± 5 y) received either nebulized amiloride (ENaC antagonist) or placebo (nebulized saline) during 17 h normobaric hypoxia (FIO2 = 12.5%) in a randomized, double‐blind fashion. Lung diffusing capacity for carbon monoxide (DLCO), alveolar‐capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) were measured via a rebreathe method before and after hypoxic exposure. DLCO was not different at baseline for the amiloride vs. placebo treatments (19 ± 5 vs. 21 ± 8 mL/min/mmHg). Hypoxic exposure increased Vc but did not change Dm in both treatments (Placebo: Vc = 43 ± 22 vs. 59±23 mL p=0.011, Dm = 35 ± 10 vs. 37 ± 12 mL/min/mmHg p=0.312; Amiloride: Vc = 38 ± 17 vs. 57 ± 22 mL p<0.01, Dm = 31 ± 8 vs. 34 ± 10 mL/min/mmHg p= 0.206).ConclusionNormobaric hypoxia did not differentially affect alveolar‐capillary conductance in amiloride and placebo conditions, suggesting that ENaC do not have a role in normal lung fluid regulation during acute hypoxic exposure. HL71478
Heart rate variability at rest during repeated 6‐hour water immersions
Authors: Marrs Kevin L. , Simmons Erin E. , Chon Ki H. , Shykoff Barbara E. , Florian John P 
Published: June 2021

Short‐duration water immersion (WI) alters heart rate variability (HRV), but the responses to long‐duration and repeated (WI) in comfortably warm water are unknown. Ten healthy young men were exposed to a 6‐hr resting WI breathing air (1.35 ATA) on 5 consecutive days. Heart rate (HR), SDNN and RMSSD (statistical measures of NN intervals), ApEn (approximate entropy), LFPSD and HFPSD (low and high frequency components of power spectral density), LFnPSD and HFnPSD (normalized units from PSD), and cardiac sympathetic and parasympathetic nervous system (SNS and PNS) dynamics using principal dynamic mode (PDM) analysis were measured. Data were compared to pre‐dive baseline HRV data and post‐dive recovery data obtained from the subjects. Compared to baseline, LFPSD increased on dive days 4 (p < 0.0001) and 5 (p=0.0005); HFPSD increased on dive days 2 (p=0.0066) and 3(p=0.0004); SNS increased on dive day 2 (p=0.0086); SDNN increased during dives 2–5 (p < 0.0001); RMSSD decreased during dive days 2 and 3(p < 0.0001). Significant and consistent decreases in ApEn measures compared with baseline were observed across dive days 1–5 (p < 0.0001). The results suggest that 1) the complexity of HR responses (ApEn) is reduced during single and repeated WI, and 2) time‐and frequency‐domain measures of HRV are altered with repeated WI.Support: ONR and NAVSEA DSBDP
The effects of hypoventilation on the physiological and biochemical properties of hindlimb muscles
Authors: IMAGIATA HIDETAKA , YAMAGAMI TAKU , OKADA KEISUKE , KAWATA SHINNOSUKE 
Published: June 2021

The purpose of this study was to determine physiological and biochemical properties of hindlimb muscles after bilateral phrenic nerve denervation (DNV).Male Wistar rats (10 wk) underwent DNV (n=18) by cutting the phrenic nerve at the cervical level under the stereomicroscope or sham surgery (n=18, CON). Analyses were performed 4, 8 and 12 wks after surgery. The myosin heavy chain (MHC) isoform profile and in vitro isometric contractile properties of the soleus (SOL) and extensor digitram longus (EDL) were analyzed.DNV induced changes in SpO2 characteristic of hypoventilation syndromes. After 12 wks, increases in MHC 1 and decreases in MHC 2a (both p<0.05) were observed in the DNV SOL. Increases in MHC 1 (7%), MHC 2a (7%) and MHC 2d (9%) and decreases in MHC 2b (23%) (all p<0.05) were measured in the DNV EDL. After 8 wks and 12 wks of DNV, the peak twitch force of EDL decreased (~30%) and after 12 wks the fatigue index increased (19%) (all p<0.05). However, DNV did not affect the contractile properties of SOL.In conclusion chronically low SpO2 and decreased hindlimb contractile activity induced by DNV resulted in a unique fast‐to‐slow MHC shift in SOL and EDL. This was accompanied by enhanced fatigue resistance and impaired contractile function in the EDL but not the SOL.This work was supported by Grants‐in‐Aid for Scientific Research from the Japanese Ministry of Science and Technology, no 24500628.