bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short‐ and long‐term effects of ActRIIB receptor ligand trapping agents on muscle mass and downstream signaling in dystrophic (mdx) limb and respiratory musculature (1102.44)
Authors: Potter Ross , Desai Pooja , Nielsen Cory , Corbell Kathryn , Mellon Christopher , Danishyar Amina , Gatti Francesca , Grinberg Asya , Kumar Ravi , Carroll Chad , Carlson C. George 
Published: June 2021

These studies examined the translational efficacy and the signaling consequences of in vivo treatment with two soluble ActRIIB receptor ligand trapping agents (Acceleron Pharma) in the mdx mouse model for Duchenne muscular dystrophy. A one month treatment of 30 day old mdx mice with RAP‐031 (10 mg/kg; subcutaneously, twice weekly) produced significant (p<0.05) increases in the body mass of both male (14% increase) and female (22% increase) mice. These increases were associated with proportionately larger increases in limb musculature (gastrocnemius; 30%) than in respiratory musculature (costal diaphragm; 12%). Longer periods of treatment (3 months) with RAP‐435 induced 30% increases in body mass and again produced larger proportional increases in the mass of the gastrocnemius (about 90%) than the costal diaphragm (about 43%). The 1 month RAP‐031 treatment produced relatively moderate increases in fiber density and diameter in the severely dystrophic mdx triangularis sterni (TS) muscle. However, the 3 month treatment with RAP‐435 substantially increased TS muscle mass by producing large increases in both fiber density and fiber diameter. Collagen expression and crosslinking in the mdx costal diaphragm was not influenced by treatment with RAP‐031 for periods of 1 or 3 months. The total expression of smads 2 and 3 were unaffected by RAP‐031 treatment. RAP‐031 treatment increased the expression of Smad 4 in the gastrocnemius but not in the costal diaphragm. The expression of Akt was unaffected by RAP‐031 treatment in either muscle preparation, while the proportion of phosphorylated Akt was slightly increased by RAP‐031 treatment in the gastrocnemius. These results further demonstrate the efficacy of the ActRIIB receptor ligand trapping agents in increasing dystrophic muscle mass, and suggest that muscle‐specific differences in TGF‐beta expression or smad and Akt signaling may contribute to differential effects in the limb and respiratory musculature.Grant Funding Source: Supported by NIHR15AR055360 to CGC
Thermoregulatory dysfunction in multiple sclerosis patients during moderate exercise in a thermoneutral environment (1104.17)
Authors: Huang Mu , Morris Nathan , Jay Ollie , Davis Scott 
Published: June 2021

Impairments in sudomotor function during passive heat stress have been reported in multiple sclerosis (MS), a demyelinating disease of the CNS that disrupts autonomic function. However, little is known regarding exercise induced increases in core body temperature on thermoregulatory mechanisms in MS. Thus, the aim of this study was to test the hypothesis that thermoregulatory function is impaired in MS patients compared to healthy controls (CN) during moderate exercise. Thermoregulatory function in five patients diagnosed with relapsing‐remitting MS and five mass‐matched healthy controls were compared during a single bout of cycling exercise (fixed workload of 70 Watts) for 30‐60 minutes in a climate‐controlled room (25°C, 30% RH). Sweating thermosensitivity (MS: 0.56±0.15 vs CN: 0.81±0.13, p=0.04) was significantly lower while a delay in sweating onset time (MS: 14.8±10.0 min vs CN: 5.6±1.6 min, p=0.07) approached significance in MS patients compared to controls. These altered mechanisms of body temperature regulation likely contributed to a greater observed change in core body temperature measured rectally (MS: 0.84±0.34 °C vs CN: 0.37±0.27 °C, p=0.04) in patients with MS. This observed thermoregulatory dysfunction in MS patients may intensify disease symptoms limiting exercise tolerance.Grant Funding Source: Kuzell Institute and National MS Society Grant RG4043A1/1
Local 5‐methyltetrahydrofolate administration augments NO‐dependent vasodilation in aged human skin (1106.11)
Authors: Stanhewicz Anna , Alexander Lacy , Kenney W. 
Published: June 2021

Even in the absence of overt cardiovascular disease, older men and women have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)‐dependent cutaneous vasodilation (VD) during local heating. Folic acid and its metabolite 5‐methyltetrahydrofolate (5‐MTHF) improve conduit vessel function, possibly through NO‐dependent mechanisms. We hypothesized that local 5‐MTHF administration would augment NO‐dependent VD in aged skin. Two intradermal microdialysis fibers were placed in the forearm skin of 7 young (Y, 23±1 years) and 7 older (O, 77±3 years) subjects for local delivery of Ringer’s solution (control) or 5mM 5‐MTHF. Red cell flux was measured over each site by laser‐Doppler flowmetry (LDF) during standardized local heating to 42°C. After cutaneous vascular conductance (CVC = LDF/MAP) plateaued, 20mM L‐NAME was perfused at each site to quantify NO‐dependent VD. Data were normalized as %CVCmax (28mM SNP and local heat, 43°C). Local heating plateau (O: 82±3 vs. Y: 96±1%CVCmax; p=0.002) and NO‐dependent VD (O: 26±6 vs. Y: 49±5%CVCmax; p=0.03) were attenuated at the control site in O. 5‐MTHF administration augmented overall (91±2%CVCmax; p=0.03) and NO‐dependent (43±9%CVCmax; p=0.04) VD in O but not Y. Local 5‐MTHF administration restores cutaneous VD through augmented NO‐dependent VD, suggesting that exogenous 5‐MTHF increases NO synthesis in aged cutaneous microvasculature.Grant Funding Source: Supported by NIH RO1‐AG07004‐25
Is sustained post‐exercise vasodilation associated with an exercise‐induced mast cell activation? (1106.19)
Authors: Romero Steven , Ely Mathew , Sieck Dylan , Buck Tahisha , MacLean David , Halliwill John 
Published: June 2021

An acute bout of aerobic exercise elicits a sustained post‐exercise vasodilation which is histamine‐receptor mediated. However, the source of the histamine which activates histamine receptors during recovery from exercise remains unknown. One possible source is degranulation of mast cells. We tested the hypothesis that tryptase, a marker of mast cell degranulation, is elevated during or after exercise. In 11 healthy subjects (6 men; 5 women), we measured interstitial tryptase via microdialysis of the vastus lateralis before, during, and through 90 min after exercise (1 hr of unilateral dynamic knee extension at 60% of peak power; 6 subjects) or rest (1 hr seated upright; 5 subjects). Compared with baseline, interstitial tryptase was increased more during exercise (Δ 60 ± 7%) than during rest (Δ 10 ± 9%, P < 0.05) and tended to remain elevated during recovery (exercise Δ 44 ± 14% vs rest Δ 16 ± 7%, P = 0.11). Thus, localized mast cell degranulation occurs in exercising muscle, and appears to contribute in part to sustained post‐exercise histaminergic vasodilation. This suggests that exercise produces an anaphylactoid signal which may influence skeletal muscle blood flow during exercise.Grant Funding Source: NIH grant HL115027
Neurovascular responses to whole‐body cold stress in aged humans (1106.6)
Authors: Greaney Jody , Kenney W. , Alexander Lacy 
Published: June 2021

Human aging is associated with an augmented pressor response to cold stress; however, whether this is due to alterations in sympathetic nervous system activation remains unclear. We hypothesized that whole‐body cold stress elicits greater sympathetic nervous system responses in older (O) compared to young (Y) adults. Reflex vasoconstriction was induced in 7 Y (24±1 yr) and 6 O adults (66±2 yr) by lowering mean skin temperature (Tsk) from 34 to 30.5℃ using a water‐perfused suit. BP, muscle sympathetic nerve activity (MSNA; peroneal microneurography), and red blood cell flux (laser Doppler flowmetry; dorsum of foot) were measured continuously. Cutaneous vascular conductance (CVC=flux/mean BP) was expressed as a percent change from baseline. The increase in systolic BP during whole‐body cold stress was greater in O adults (∆2±1 Y v. ∆10±2 O mmHg; P<0.05); however, the increase in mean BP was not different (∆5±1 Y v. ∆6±1 O mmHg; P>0.05). Reflex cutaneous vasoconstriction was attenuated in O adults (‐31±6 Y v. ‐14±3 O %∆CVC; P<0.05). MSNA was greater in O adults at baseline (Tsk=34℃; 14±3 Y v. 25±2 O burst/min) and during cooling (Tsk=30.5℃; 14±4 Y v. 37±3 O burst/min; both P<0.05). MSNA increased during cooling in O, but not Y, adults (∆‐1±1 Y v. ∆12±3 O burst/min; P<0.05). These data suggest the MSNA response to cold stress is augmented, but peripheral vascular response is attenuated, in healthy aging.Grant Funding Source: Supported by HL120471‐01 (JLG), AG007004‐23 (WLK), HL093238‐04 (LMA).
NanoSOD reduces adipose tissue inflammation in obesity (1107.10)
Authors: Saraswathi Viswanathan , Murali Ganesan , Desouza Cyrus , Manickam Devika , Bronich Tatiana , Kabanov Alexander 
Published: June 2021

Obesity‐linked hypertension is resistant to antihypertensive drugs and, adipose tissue (AT) inflammation is considered to mediate the pathological consequences of obesity. The objective of this study is to determine the effectiveness of nanoformulated copper/zinc superoxide dismutase (nanoSOD) in reducing AT inflammation in obesity. Wild type mice were fed a high fat (HF) diet (45% fat) for 8 or 13 wk followed by 2 wk treatment with native or nanoSOD. The drug uptake studies showed that nanoSOD was accumulated in the visceral AT to a greater extent than native SOD in obese mice. The mice fed a HF diet for 8 wk followed by 2 wk treatment with nanoSOD showed an increase in SOD content in stromal vascular cells (SVCs) collected from AT and in the plasma. These mice also showed a reduction in nitrotyrosine level, a marker of superoxide induced oxidative stress, in SVCs. The AT inflammatory markers showed a trend towards a decrease. The serum toxicity markers did not alter in nanoSOD compared to other groups suggesting that the nanoSOD is safe to use in vivo. After 13 wk on a HF diet followed by 2 wk treatment, the SVCs derived from AT of nanoSOD treated mice showed a decrease in the mRNA levels of MCP‐1 and MIP‐1α. Also, the MCP‐1 mRNA and protein levels in total AT was reduced to a greater extent in nanoSOD compared to native SOD treated mice. Our data suggest that nanoSOD may be a potential therapeutic agent to ameliorate obesity‐linked cardiovascular risk factors, in particular, systemic hypertention.Grant Funding Source: National Institutes of Health (NIH‐NIGMS)
Expression of the glycine transporter type 1 (GlyT‐1A) is upregulated by ATF‐4 following physiological stress in human intestinal epithelial cells (1109.14)
Authors: Fultang Livingstone , Howard Alison , Hirst Barry 
Published: June 2021

Downstream of activating transcription factor 4 (ATF‐4) in Caco‐2 cells in response to stress. In the present study we show that increased expression of the GlyT‐1a gene following stress is dependent on elements contained within the 5’untranslated region (UTR). Caco‐2 cells transfected with plasmid constructs containing sequences representative of the GlyT‐1a proximal promoter and 5’UTR upstream of a beta‐galactosidase reporter showed increased reporter activity following treatment with thapsigargin (Tg), tunicamycin (Tu), amino acid (AA) starvation, tertbutylhydroquinone(tBHQ) or Diethyl maleate (DEM). Short labeled DNA probes containing a potential amino acid response element (AARE) located in exon 1 of the GLYT‐1a gene demonstrated binding by ATF‐4 in gel shift and super shift assays. qPCR assays performed on short genomic DNA fragments isolated from Caco‐2 cells by chromatin immunoprecipitation (ChIP) with antibodies against ATF4 demonstrated 9, 5 and 2‐fold enrichment of the ATF‐4/AARE interaction at the 5’‐UTR region of GlyT1a following Tu, AA starvation and DEM treatment respectively. Our data suggests that response elements within the 5’UTR including exon 1 and the first 85 bases of exon 2 are required for transcriptional induction of GlyT1a. We propose the direct interaction of ATF‐4 at the identified AARE drives transcriptional up‐regulation of GlyT‐1a following nutrient, oxidative and endoplasmic reticulum stress.Grant Funding Source: University of Newcastle
Epigenetic impact of curcumin‐primed exosomes in amelioration of blood‐brain barrier dysfunction (1120.9)
Authors: Kalani Anuradha , Kamat Pardip , Familtseva Anastasia , Tyagi Suresh , Tyagi Neetu 
Published: June 2021

Exosomes are nano‐units (<200nm), released from diverse cell types in extracellular body fluids. Since exosomes carry biological information from their cells of origin, the idea is to prepare improved molecular conservatory for therapeutics by priming the cells to release improved cellular contents through exosomes. Curcumin provides a promising treatment for cerebral diseases and therefore, the aim of the study is to establish that mouse brain endothelial cells when primed with curcumin (7.5µM), release alleviated exosomal population to recover blood‐brain barrier (BBB) permeability. Homocysteine‐treated endothelial cells were used as a model of BBB disruption and curcumin‐primed (CU‐primed) exosomes were utilized to check BBB disruption along with associated epigenetic measurements. We determined that CU‐primed exosomes reprogrammed endothelial cells, in part, by alleviating epigenetic alterations and improving junction proteins that ameliorate vascular permeability. These results pave the way for the novel translational therapies for cerebral diseases by maintaining and establishing therapeutic conservatories via primed exosomes. Additionally, the shortcomings of the gene therapy can be overcome by using these potentially primed exosomes containing the effector molecules.Grant Funding Source: HL107640
Analysis of cerebrospinal fluid flow in hydrocephalic mouse models of primary ciliary dyskinesia (1125.1)
Authors: Johnson Katherine , Finn Rozzy , Lee Lance 
Published: June 2021

Patients with primary ciliary dyskinesia (PCD) suffer from a variety of disorders that include chronic sinusitis, otitis media, infertility, situs inversus, and hydrocephalus. We have shown that two mouse models of PCD, nm1054 and bgh, have hydrocephalus characterized by dilatation of the lateral ventricles. These models also have male infertility and sinus abnormalities that result from a decrease in respiratory ciliary beat frequency. We therefore hypothesize that the hydrocephalus results from dysfunction of ependymal cilia that prevents proper cerebrospinal fluid (CSF) flow. To investigate CSF flow in vivo, we injected India ink into the lateral ventricles of live mice and histologically demonstrated that ink migrated through the ventricular system of wild type mice but failed to progress past the cerebral aqueduct of either mutant. To validate that this defect was directly due to ciliary dysfunction, we used an ex vivo method to measure ink flow rate over the ependymal cells on dissected ventricular walls. This method demonstrated a decreased flow rate and altered directional flow in the mutant brains, confirming that ependymal ciliary function is required for proper CSF flow.Grant Funding Source: Supported by the NIH NIGMS (1P20GM103620‐01A1) and an NSF REU (1262744)
The role of TNF‐α in femoral artery occlusion‐augmented autonomic responsiveness (1132.6)
Authors: Lu Jian , Xing Jihong , Li Jianhua 
Published: June 2021

Prior studies demonstrated that metabolically sensitive receptors in thin‐fiber muscle afferents contribute to the amplified responses of sympathetic nerve activity and arterial blood pressure observed in rats with femoral artery occlusion (24‐72 hrs). The purpose of this study was to examine the role played by TNF‐α in augmented sympathetic responsiveness induced by stimulation of muscle metabolic receptors following 72 hrs of femoral artery occlusion. First, the results of this study show that the levels of TNF‐α are increased in dorsal root ganglion (DRG) neurons of limbs with 72 hrs of femoral artery occlusion. Second, protein expression of TNF‐α is dominantly observed within DRG neuron supply C‐fiber muscle afferent nerves and TNF‐α receptor type 1 (TNFR1) is largely identified in DRG compared with TNFR2. Third, TNF‐α synthesis suppressor pentoxifylline (PTX) administered previously into the hindlimb muscles significantly attenuates sympathetic and blood pressure responses induced by arterial injection of capsaicin into the hindlimb muscles. Capsaicin was applied to stimulate metabolically sensitive receptors in thin‐fiber muscle afferents nerves. Overall, our data suggest that TNF‐α plays a role in modulating augmented sympathetic responsiveness via metabolic receptors of thin fiber muscle afferent nerves when arterial blood supply to the hindlimb is deficient under ischemic conditions.Grant Funding Source: NIH P01 HL096570 and AHA EIA 0840130N
PDGF receptor antagonism prevents the increase in kidney ANG II levels in Cyp1a1‐Ren2 transgenic rats with ANG II‐dependent malignant hypertension (1136.1)
Authors: Thompson David , Seth Dale , Davis Porcha , Mitchell Kenneth 
Published: June 2021

This study was performed to determine if chronic PDGF receptor blockade prevents the augmentation of intrarenal ANG II levels in Cyp1a1‐Ren2 transgenic rats with ANG II‐dependent malignant hypertension. Male Cyp1a1‐Ren2 rats (n=5/group) were induced to develop malignant hypertension by dietary administration of indole‐3‐carbinol (I3C, 0.3% wt/wt) for 10 days. Systolic blood pressures (SBP) were measured daily by tail‐cuff plethysmography. On day 10 of I3C administration, rats were subjected to conscious decapitation and trunk blood was collected for measurement of plasma renin activity (PRA) and plasma ANG II levels. The kidneys were harvested for determination of total kidney ANG II levels. Dietary I3C resulted in increases in SBP (130±5 to 171±9 mmHg, P<0.05), PRA (64±6 vs. 5±1 ng ANG I/ml/hr, P<0.001), plasma ANG II levels (186±26 vs. 139±10 fmol/ml, P<0.05), and total kidney ANG II content (550±31 vs. 253±24 fmol/g, P<0.001). Chronic imatinib administration (60 mg/kg/day, oral gavage) did not prevent the development of hypertension (187±10 vs. 141±2 mmHg, P<0.001) or the increase in PRA (72±6 vs. 5±1 ng ANG I/ml/hr, P<0.001), but prevented the I3C‐induced augmentation of intrarenal ANG II levels (285±128 vs. 253±24 fmol/g). The present findings indicate that PDGF receptor activation contributes to the increase in the elevations of intrarenal ANG II levels in ANG II‐dependent malignant hypertension.Grant Funding Source: 5P30GM103337
AT2 receptor protects high sodium‐induced decrease in ACE2/Mas receptor expression and increase in blood pressure in obese rats (1136.8)
Authors: Ali Quaisar , Hussain Tahir 
Published: June 2021

High sodium (Na) intake is a risk factor for the pathogenesis of hypertension, especially in obesity. Whereas high Na diet increases blood pressure (BP) associated with a decrease in renal MasR/ACE2 expression, chronic AT2R stimulation lowers BP concomitant with an increase in MasR/ACE2 expression in obese Zucker rats. However, role of AT2R in high Na‐induced hypertension and regulation of ACE2/MasR expression in obesity is not known. Male obese rats were treated with AT2R agonist C21 (1mg/kg/day oral) while maintained on either normal (NSD, 0.4%) or high Na diet (HSD, 4%) for 2‐weeks. Telemetry monitoring of BP showed an increase in systolic BP (SBP) by 20 mm Hg in obese HSD compared to NSD group; which was prevented by C21 treatment. Compared to control, HSD caused diuresis which was further increased in HSD+C21 group. The rats on HSD had increase in body and kidney weight; which was lowered by C21 treatment. HSD reduced the cortical MasR and ACE2 activity which was increased by C21 treatment. AT2R, ACE expression and renin activity were same in all the groups. However AT1R, although unchanged with HSD or C21 treatment, was decreased in HSD+C21 group. This study clearly demonstrate that chronic AT2R agonist treatment prevents high Na‐induced increase in BP which was associated with an increase in the beneficial ACE2/MasR axis in obese rats indicating the potential role of AT2R against Na‐sensitive hypertension in obesity.Grant Funding Source: NIH R01‐DK61578
Intronic mutations in GLA causes Fabry disease (1138.5)
Authors: Ortolano Saida , Vieitez Irene , Souto Olga , Garcia‐Jimenez Concepcion , Pintos Guillem , Navarro Carmen 
Published: June 2021

INTRODUCTION: Fabry disease (FD) is a rare X‐linked disorder, due to a defect of lysosomal α‐Galactosidase A (GalA), which determines cellular storage of globotryalosil ceramide (Gb3), eventually causing multysistemic dysfunctions. Male patients are diagnosed by enzyme activity assay and female patients by genetic study. AIMS: To characterize molecular defects in a family of patients with unconfirmed diagnosis of FD. PATIENTS & METHODS: Male with impaired GalA activity and his 7 years old daughter, presenting FD symptoms. Patients carry genetic defects in GLA up to date validated as polymorphisms (rs207122, rs2071397). RT‐PCR was performed to asses GLA transcripts levels in patient's derived leukocytes. GalA and Gb3 expression were evaluated by immunofluorescence in daughter's skin biopsy. RESULTS: GLA transcript levels are significantly reduced in both patients. Immunofluorescence of skin biopsy revealed lysosomal inclusions of Gb3 mainly in dermal fibroblasts, while GalA present lower expression, compared to a control biopsy. CONCLUSIONS: The association of the intronic mutations rs207122, rs2071397 affects transcription of GLA and causes Gb3 accumulation, determining FD phenotype.Grant Funding Source: Instituto Carlos III Spain
Cytotoxicity of peracetic acid in L929 fibroblasts (1139.2)
Authors: Faria Gisele , Viola Kennia , Carlos Iracilda , Kuga Milton , Guerreiro‐Tanomau Juliane , Tanomaru‐Filho Mario 
Published: June 2021

Recently peracetic acid (PA) has been reported in the dental literature as a possible root canal irrigating solution. It has the advantage of bringing together in one product antibacterial activity and ability to remove smear layer. For selection of root canal irrigating solution it should take into account not only its therapeutic benefits, but also the possible cytotoxic effects, since it can contact the periapical tissues. The aim of this study was to evaluate the cytotoxicity of PA at different concentrations in comparison with 2.5% sodium hypochlorite (NaOCl) through the study of the L929 fibroblasts metabolism and the cytoskeleton. L929 fibroblasts in culture were exposed to different concentrations of PA and NaOCl and to the culture medium for 24 hours (control). After this period, it was evaluated the cell metabolism by methyl tetrazolium (MTT) assay and the cytoskeleton by staining actin and α‐tubulin. Data were analyzed by two‐way ANOVA and Bonferroni post test (α = 0.05). The solutions had an effect on cell viability/metabolism in a dose‐dependent manner. The cell viability decreased progressively as the concentration of irrigating solutions was increased. 0.5% AP showed similar cytotoxicity to 2.5% NaOCl (p>0.5); the AP at concentrations of 1%, 2% and 2.5% showed higher cytotoxicity than 2.5% NaOCl (p<0.5). The cytoskeleton suffered progressive structural changes as the concentrations of the solutions were increased. It was concluded that the AP is more cytotoxic than NaOCl. However, further studies evaluating other cell parameters and employing other PA‐based solutions need to be performed.Grant Funding Source: Supported by São Paulo Research Foundation (FAPESP) #2012/18203‐2