bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lysophosphatidic acid receptor and Ral signaling in breast cancer cell migration and invasion
Authors: Li Timothy Tsz‐Tim , Au‐Yeung Catherine , Alemayehu Mistre , Pape Cynthia , Pampillo Macarena , Laird Dale , Babwah Andy V , Bhattacharya Moshmi 
Published: June 2021

Lysophosphatidic acid (LPA) is a simple lipid molecule that mediates a variety of processes such as cell survival and growth, and plays a role in the progression of a variety of cancers, stimulating cell proliferation, migration and invasion. The effects of LPA are mediated via the activity of its G protein‐coupled receptors, LPA1‐3. Recently, LPA has been shown to enhance metastasis of breast cancer to bone. However, the mechanisms by which LPA receptor signaling regulates cell migration and invasion of breast cancer cells remains unclear. Breast cancer cell proliferation has been shown to be stimulated by the small G protein Ral. Ral activity can be regulated by its guanine‐nucleotide exchange factors (RalGEFs) and the multifunctional protein β‐arrestin. We compared expression of LPA receptors, Ral, RalGDS, and β‐arrestin in the non‐tumorigenic mammary cell line MCF‐10A and the invasive breast cancer cell lines MDA‐MB‐435 and MDA‐MB‐231. Our data shows for the first time that both breast cancer cell lines have higher expression of β‐arrestin compared to MCF‐10A cells. Furthermore, MDA‐MB‐231, but not MCF‐10A cells migrate and invade in response to LPA via pertussis toxin‐sensitive G proteins and via a β‐arrestin‐Ral pathway. In summary, our data demonstrates a novel mechanism by which LPA receptors may regulate breast cancer cell migration and invasion.Research is funded by CIHR awarded to Dr. M Bhattachary
Involvement of the hypothalamic paraventricular nucleus on the cardiovascular responses to noradrenaline microinjected into the bed nucleus of the stria terminalis of unanesthetized rats
Authors: Crestani Carlos Cesar , Tavares Rodrigo Fiacori , Busnardo Cristiane , Alves Fernando Henrique Ferrari , Correa Fernando Morgan Aguiar 
Published: June 2021

It was previously demonstrated that noradrenaline (NA) microinjected into the bed nucleus of the stria terminalis (BST) evokes pressor and bradycardiac responses, which are mediated by acute systemic vasopressin release. The aim of the present study was to evaluate the involvement of the paraventricular (PVN) or supraoptic (SON) hypothalamic nuclei that synthesize vasopressin, on the cardiovascular responses to NA microinjected into the BST of unanesthetized rats.For this purpose, male Wistar rats had guide cannulas implanted in the BST and ipsilaterally in the PVN or SON and a polyethylene catheters was implanted into the femoral artery for mean arterial pressure (MAP) and heart rate (HR) recording.PVN pretreatment with the nonselective synapse blocker CoCl2 (1mM) significantly reduced the pressor (32±4 vs 7±2 mmHg; t=6, p<0.05) and bradycardiac (−39±7 vs −6±2 bpm; t=7, p<0.05) responses to NA microinjected into the BST when compared to the response before PVN treatment. However, CoCl2 microinjected into the SON previously to NA microinjection into the BST did not affect the pressor (30±3 vs 29±2 mmHg; t=0.2, p>0.05) and bradycardiac (−34±3 vs −34±5 bpm; t=0.1, p>0.05) response.Thus, our results suggest that the PVN but not the SON is involved in the mediation of the cardiovascular responses to NA microinjected into the BSTResearch support: FAPESP and FAEPA
Long‐term recording of renal sympathetic nerve activity in conscious rats via telemetry
Authors: Van Vliet Bruce N. , Guild Sarah‐Jane , Barrett Carolyn , McBryde Fiona , Malpas Simon 
Published: June 2021

We have established a method for recording renal sympathetic nerve activity (RSNA) by radio‐telemetry in conscious rats. Telemeters with appropriate high sensitivity and bandwidth (model TR46S, Telemetry Research, Auckland, NZ) were implanted in the abdominal cavity under isoflurane anesthesia. Electrode wires were secured to the renal nerves using a rapidly setting silicone elastomer via a retroperitoneal approach. In some cases, a blood pressure telemeter (TA11PaC40, Data Sciences, Minneapolis, MN) was also installed in the peritoneal cavity.In conscious rats, RSNA exhibited pulse synchronous activity, was abolished by ganglionic blockade (15–50 mg/kg pentolinium), and was greatly activated by the nasopharyngeal reflex response to smoke. High quality recordings could be routinely obtained for 1 to 2 weeks, but in some cases were found to continue working (e.g. as long as 98 days) when left longer. Application of this method will allow us to investigate the regulation of RSNA and its contribution to long‐term blood pressure control in freely behaving rats. Supported by grants from the Canadian Institutes of Health Research and the Health Research Council of New Zealand.
Pressor responses produced by peripheral osmoreceptor activation in commissural nucleus of the solitary tract‐lesioned rats.
Authors: Blanch Graziela Torres , Freiria‐Oliveira Andre Henrique , Colombari Eduardo , Menani Jose Vanderlei , Colombari Debora Simoes Almeida 
Published: June 2021

Previous studies demonstrated that intragastric (ig) 2 M NaCl load (that activates peripheral and central osmoreceptors) produced increases in mean arterial pressure (MAP) and enhanced dipsogenic responses in commissural nucleus of the solitary tract (commNTS) lesioned rats. Lesions of commNTS also increased water intake produced by ig 0.6 M NaCl load (that activates peripheral, not central, osmoreceptors ‐ Am. J. Physiol., 269: R 1085, 1995), which suggests that commNTS mechanisms inhibit peripheral osmoreceptor‐induced thirst. In the present study we investigated the effects of ig 0.6 M NaCl load on MAP and heart rate (HR) in commNTS lesioned rats. Male Holtzman rats (300–330 g, n = 5–8/group) with chronic (15 days) sham or electrolytic lesions (1 mA, 10 s) of the commNTS were used. MAP and HR were measured 60 min before and 60 min after ig 0.6 M NaCl load (2 ml). Plasma Na+ concentration was analyzed after ig 0.15 M or 0.6 M NaCl in the same animals, 3 days after MAP and HR recordings. Ig 0.6 M NaCl induced pressor responses in commNTS lesioned rats (11 ± 3 mmHg), but did not affect MAP in sham rats (−3 ± 2 mmHg) or HR in both groups. Ig 0.6 M NaCl produced no change on plasma Na+ concentration in sham (142 ± 3 vs. 0.15 M NaCl: 140 ± 1.2 mEq/l) or in commNTS lesioned rats (144 ± 0.4 vs. 0.15 M NaCl: 141 ± 1 mEq/l). The results suggest that similar to water intake, commNTS mechanisms also inhibit peripheral osmoreceptor‐induced pressor responses.Supported by: FAPESP, CNPq.
Influences of dehydration and angiotensin receptor blockade on control of sympathetic nerve activity in healthy humans
Authors: Sharpe Emily Elizabeth , Strom Nicholas A , Roberts Shelly K. , Kingsley‐Berg Shirley , Curry Timothy B , Eisenach John H. , Charkoudian Nisha 
Published: June 2021

Dehydration in humans decreases orthostatic tolerance and alters sympathetic neural control of the circulation, but the mechanisms involved are unclear. Our goal was to evaluate the role of angiotensin II (AngII) in altering the sympathetic control mechanisms in dehydration. We hypothesized that dehydration would increase resting muscle sympathetic nerve activity (MSNA) and increase sensitivity of baroreflex control of MSNA and that these changes are mediated in part by AngII via AT1 receptors. We measured resting MSNA and baroreflex control of MSNA in healthy young adults under two conditions: euhydration and dehydration after 24 hr fluid restriction. We continuously measured heart rate (ECG), beat‐to‐beat blood pressure (Finometer), central venous pressure (peripherally inserted central catheter) and MSNA (peroneal microneurography) in both conditions. In each condition, measurements were taken before and after 50 mg losartan (AT1 antagonist). Dehydration was associated with a ~52 % increase in resting MSNA, but losartan did not consistently influence resting MSNA. Contrary to our hypothesis, baroreflex sensitivity increased ~39 % following losartan administration during dehydration. Our results confirm the sympathoexcitatory influence of dehydration, but the role of AngII in this process requires further evaluation.Supported by AHA 0750036Z and NIH CTSA UL1‐RR24150.
Serotonin produces MAO dependent oxidative stress in human heart valves
Authors: Silva Ricardo Alfonso Pena , Miller Jordan D , Heistad Donald D 
Published: June 2021

Serotonin (5HT) from carcinoid tumors and drugs (fen‐phen interactions) may contribute to development of valvulopathies and pulmonary hypertension. We determined whether 5HT induces oxidative stress in human heart valves, and examined mechanisms that may produce ROS. Superoxide (O2•−) was measured in heart valves from explanted human hearts that were rejected for transplantation. Superoxide levels (lucigenin‐enhanced chemoluminescence) were increased in valves and pulmonary artery after incubation with 5HT. Inhibitors of 5HT1 (GR55562) and 5HT2 receptors (ketanserin), and a selective serotonin reuptake blocker (fluoxetine) surprisingly did not prevent increases in superoxide. DPI (non‐specific inhibitor of flavin‐containing enzymes), tranylcypromine and clorgiline (inhibitors of MAO) abolished the increase in O2•−. Apocynin (inhibitor of NAD(P)H oxidase) and catalase did not prevent increase in O2•−. Addition of 5HT to human recombinant purified MAO‐A generated superoxide, and this effect was inhibited by a MAO inhibitor.Conclusion: Superoxide is increased in human vessels and heart valves exposed to high levels of 5HT by a mechanism that is independent of 5HT receptors. MAO is functional in the heart valves and mediates the increase in O2•− induced by serotonin.
Opening of Mitochondrial KATP Channel Improving Long‐Term Hypothermic Preservation Heart by upregulation of HSP 70 protein
Authors: Zhang Shu‐luo , Fang Shan , OU Ying , Zhu Li , Chen Ying‐ying , Shen Yue‐liang 
Published: June 2021

The aim of this study is to investigate the mechanism of cardioprotective effects of diazoxide, a selective opener of mitochondrial ATP‐sensitive potassium channel (mitoKATP) in preserved heart. The isolated rat heart Langendorff model was used. The hearts were stored in 4°C Celsior solution in the presence or absence of diazoxide for 3, 6 or 9 h followed by 60 min of reperfusion. Apoptotic cardiomyocytes were detected by terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling (TUNEL) method. The expression of heat shock protein 70 (HSP 70) was also evaluated by western blotting analysis. The results showed that the percentage of apoptotic cells increased in a time‐dependent manner after hypothermic preservation. When compared with the 9 h control group, diazoxide (15, 30 or 45 μmol/L) reduced the percentage of apoptotic cells and increased the expression of HSP 70 protein in rat hearts suffered from 9 h of hypothermic preservation in a dosedependent manner. These results indicate that diazoxide could alleviate rat myocardial injury induced by ischemia‐ reperfusion through upregulation of HSP 70 protein expression.(This work was supported by the National Natural Science Foundation of China (No.30470635))
Changes in muscle volume and strength following prolonged bed rest
Authors: Heinicke Katja , Wyrick Phil , Krainski Felix , Hastings Jeffrey L. , Pacini Eric , Palmer Dean , Haller Ronald G. , Levine Benjamin D. 
Published: June 2021

PURPOSETo determine the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during bed rest.METHODS: Muscle volume and peak torque (Pk T) were assessed before (Pre) and following 5 weeks of −6° head down tilt bed rest in 5 (exercise) and 3 (sedentary group) healthy subjects. Training consisted of rowing (6x/wk) and resistance (2x/wk) training. The sedentary group did no training. Each subject underwent MRI (1.5T) quantification of segmental volumes of 15 contiguous 0.6 cm thick transaxial images of calf and thigh muscles. Peak isokinetic torque during ankle plantar/dorsiflexion and knee extension/flexion was determined. Correlation coefficients for muscle volume and Pk T were determined for leg anti‐gravity muscles.RESULTS: Calf muscle volume decreased slightly by 4% while Pk T increased 31% Pre to Post in the exercise group. In sedentary corresponding values were −15% and −20%. Thigh muscle volume decreased 4% while Pk T decreased 5% Pre to Post in the exercise group. In sedentary corresponding values were −7% and −10%.CONCLUSION: The loss of calf and thigh muscle volume was attenuated but could not be completely eliminated by exercise training during 5 weeks of bed rest. However, muscle function was well preserved with no clinically relevant loss of strength in anti‐gravity muscles.Supported by NASA grant CA00701.
PGC‐1[alpha] and upstream regulators in human skeletal muscle
Authors: Norrbom Jessica , Rundqvist Helene , Sundberg Carl Johan , Jansson Eva , Gustafsson Thomas 
Published: June 2021

A central component in skeletal muscle remodelling to regular exercise is a higher mitochondrial density. The co‐activator PGC‐1α has been described as a central player in mitochondrial biogenesis and several signaling pathways have been shown to influence PGC‐1α transcription such as calcineurin, MAPK p38 and AMPK in various experimental settings.The aim of the present study was to evaluate the importance of the above‐mentioned pathways and their effect on exercise‐induced PGC‐1α transcription. Skeletal muscle biopsies were obtained from the vastus lateralis muscle from 12 healthy males before, directly after and 2 h after 45 min one‐legged knee extension exercise. One leg exercised with restricted blood flow (R‐leg), the other with non‐restricted blood flow (NR‐leg).Results & Conclusion: PGC‐1α mRNA expression increased significantly 2 h after exercise in the R‐leg, but not in the NR‐leg. The p38 phosphorylation and MCIP‐1 mRNA (a marker of calcineurin activation) increased following exercise regardless of blood flow condition. For pAMPK there was an increased activation in the R‐leg, which could be a possible explanation for the differential regulation of PGC‐1α.
Twelve weeks of endurance training increases mitochondrial density and percent IMCL touching mitochondria and alters IMCL storage distribution
Authors: Devries Michaela C. , Hamadeh Mazen J. , McCready Colin , Sischek Stephanie , Tarnopolsky Mark A. 
Published: June 2021

Intramyocellular lipids (IMCL) are elevated in obesity and are correlated with insulin resistance (IR); however, elite athletes have elevated IMCL but are highly insulin sensitive. We postulate that the IMCL‐mitochondria physical relationship delineates whether IMCL are metabolically active.Methods:Muscle biopsies from 24 women (12 lean; 12 obese) were analyzed for IMCL and mitochondria ultrastructure using electron microscopy prior to and following a 12‐week progressive endurance training protocol.Results:In obese women, there was a strong trend for higher IMCL area density in the intermyofibrillar (IMF) region (P = 0.053) vs. lean. Training increased IMF IMCL size (P = 0.008), total fiber mitochondrial size (P = 0.006 and number (P = 0.009), subsarcolemmal (SS) (P = 0.01) and total fiber (P < 0.0001) mitochondrial area density, and the % IMCL touching mitochondria in the SS (P = 0.04), IMF (P < 0.0001) and total fiber (P < 0.0001), whereas it decreased SS #IMCL/area (P = 0.001). Following training, IMCL area density decreased in SS (P = 0.009), increased in IMF (P = 0.07), and did not change in the total fiber. HOMA‐IR was higher in obese women (P = 0.002), with no training effect.Discussion: The increase in IMCL‐mitochondrial proximity and mitochondrial density suggests an increased capacity to utilize IMCL following endurance training. Training‐induced IMCL mobilization from SS into IMF may be more favorable, as SS IMCL could prevent signal transduction and GLUT‐4 mediated glucose uptake. (Supported by CIHR).
Ibuprofen and acetaminophen promote muscle hypertrophy and strength gains during resistance exercise in the elderly
Authors: Carroll Chad C , Dickinson Jared M , LeMoine Jennifer K , Haus Jacob M , Weinheimer Eileen M , Hollon Christopher J , Trappe Todd A 
Published: June 2021

This study examined the influence of chronic consumption of ibuprofen or acetaminophen during 12 weeks of knee‐extensor resistance training (3d/wk, 70% 1RM) in the elderly. Thirty‐six individuals were randomly assigned to one of three groups and consumed the drugs in double‐blind placebo‐controlled fashion: Placebo (67±2 y; 8M, 4F), Ibuprofen (64±1 y; 9M, 4F; 1.2g/d), or Acetaminophen (64±1 y; 7M, 4F; 4g/d). Resistance training alone (Placebo) increased (p<0.05) quadriceps muscle volume (M only: 8±2%; M+F: 9±1%) and muscle strength (M only: 20±3%; M+F: 23±2%). Compared to Placebo, muscle volume increases were greater in the Ibuprofen (M only: 11±2%, p<0.05; M+F: 11±2%, p=0.06) and Acetaminophen (M only: 13±1%, p<0.05; M+F: 13±1%, p=0.06) groups. Muscle strength increases were also greater than Placebo in the Ibuprofen (M only: 29±4%, p<0.05; M+F: 30±3%, p=0.06) and Acetaminophen (M only: 26±3%, p<0.05; M+F: 28±3%, p=0.06) groups. These results suggest that chronic consumption of ibuprofen or acetaminophen during resistance training induces intramuscular changes that enhance the metabolic response to resistance exercise, which promotes additional muscle hypertrophy and strength gains during resistance training in the elderly.NIH R01 AG020532 (TT), APS Postdoctoral Initiative Award (CC)
Response of prostaglandins and nutritive blood flow to 7 days of exercise training in young and aged human skeletal muscle
Authors: Choi Myung Dong , Carrithers JA , Gavin TP , Kraus RM , Evans CA , Ruster RS , Knapp DJ , McCartney JS , Garry JP , Hickner RC 
Published: June 2021

The purpose of this study was to determine if prostaglandins regulate alterations in muscle nutritive blood flow response to short‐term exercise training in young and aged individuals. Local thigh muscle nutritive flow and 6‐keto‐prostaglandin F1α (PGF1α) were monitored using microdialysis. Dialysate samples were collected continuously during acute exercise before and after 7 days of exercise training from 27 healthy subjects (6 young men (YM), 8 young women (YW), 7 aged men (AM), and 6 aged women (AW)). The exercise regimen consisted of 7 consecutive days of training for 1hr/day at 70% VO2peak. PGF1α content was higher during exercise after, compared to before, training in YM (43.6 ± 1.9 vs. 36.4 ± 1.3 pg/ml, respectively; P<.05) without a significant difference in nutritive flow. PGF1α content and nutritive flow during exercise was not changed in response to exercise training in YW, AW, and AM. There was a higher PGF1α content during exercise in YM than in YW and AM after training (43.6 ± 1.9 vs. 35.7 ± 1.1 and 33.6 ± 0.7 pg/ml, respectively; P<.05), but there were no differences in nutritive flow between these groups. These data demonstrate that PGF1α response to acute exercise increases with training in YM, and suggest changes in exercise‐induced PGF1α with training may not result in training‐induced alterations in muscle nutritive blood flow response to acute exercise.NIH AG‐19209 (Hickner); MD Choi supported by EAS
The Radiosensitivity of Satellite Cells: Cell Cycle Regulation and Apoptosis
Authors: Caiozzo Vincent J , Giedzinski Erich , Baker Mike , Limoli Charlie 
Published: June 2021

From a clinical perspective, skeletal muscles and their resident myogenic stem cells (i.e., satellite cells) are commonly exposed to significant doses of radiation. To ascertain whether irradiation inhibits satellite cell cycle progression, cells were given 5 Gy and assessed for DNA content using standard FACS methodologies. Soon after irradiation (6 hrs) satellite cells showed a marked increase (2.5‐fold) in cells at the G2/M border, the fraction of cells with a 2n complement of DNA remained high over the course of the experiment (48h). The increase in G2/M cells comes at the expense of replicating cells, as 5 Gy led to a steady decline in S‐phase cells over the first 18h following irradiation. The fraction of S‐phase cells did not recover over the subsequent 30h. As cells gradually escaped the initial block at G2/M they traversed into the block at G1/S by 12h where they accumulated at ~1.3‐fold higher levels. Poly(ADP‐ribose)polymerases (PARP) cleavage assays were used to determine if irradiated satellite cells undergo apoptosis. Apoptosis was generally increased and found to be dose‐responsive, with a relative peak occurring at 48h where apoptosis was elevated by ~1.7 fold over controls set to unity. Collectively, these data demonstrate that satellite cells are sensitive to clinically relevant doses of radiation. Further studies are needed to determine how this impacts the growth of skeletal muscle.This work was supported by NIH grant HD050837 to establish the National Skeletal Muscle Research Center (NSMRC) at the University of California, San Diego
Catalase over‐expression protects dystrophic skeletal muscle
Authors: Selsby Joshua Taylor , Tian Zouzhen , Barton Elisabeth R. , Sweeney H. Lee 
Published: June 2021

Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by the absence of a functional dystrophin protein and is modeled by the mdx mouse. Oxidant stress has been previously reported in dystrophic skeletal muscle. Efforts to target this have been largely unsuccessful both in mdx mice and in early clinical trials. In an effort to reduce oxidant stress and improve muscle function, AAV 2/8 was used to over‐express the antioxidant catalase (Cat) in single hind limbs of mdx mice while the contralateral limbs served as control (Con). Animals were injected within the first five days of life with 1×1012 gc of AAV‐Cat and killed at 4 (n=6) or 6 wks of age (n=5), during and following the initial necrotic bout. At 4 and 6 wks, specific tension was increased in the Cat EDL by 15% (p<0.05), while the soleus remained unchanged. The EDL was 30% more resistant to damage caused by eccentric contractions at 6 wk (p<0.05), but not at 4 weeks and the soleus was more fatigue resistant at both time points. These data show that an effective antioxidant can protect dystrophic skeletal muscle and improve muscle function. Further, they may also serve as the ground work for future clinical trials using more powerful and/or appropriate antioxidants or antioxidant cocktails.Supported by F32AR055005‐01 and U54AR052646‐03
A grid service‐based workflow for in‐silico screening of chemical inhibitors of phosphatases
Authors: Levesque Marshall , Chien Shu , Haga Jason 
Published: June 2021

In many cases, grid computing offers the powerful alternative of sharing resources on a worldwide scale, across a number of different institutions to run computationally intensive applications without the need for a large, centralized supercomputer. This paper presents a scalable, reusable workflow assembled to choreograph large virtual screening experiments over a computational Grid using the molecular docking application DOCK. Software components were applied on multiple levels to create automated workflows that perform data delivery, job scheduling, job status query, and the collection of results to be displayed in a manageable fashion for further analysis. This was achieved using Opal OP to wrap the application as a Grid service and PERL for data manipulation purposes, alleviating the requirement for extensive knowledge of Grid infrastructure and security. With the workflow in place, a screening was performed with the ZINC 2,066,906 ligand “druglike” subset database against the catalytic site of the phosphatase SHP‐1 using the MPI version of DOCK 5.4 on the PRAGMA Grid testbed, utilizing 200 processors over 7 clusters. This is the first successful use of Grid computing to identify chemical inihibitors of enzymatic activity through virtual screening.This project was supported by PRIME (NSF 0407508), PRIUS, PRAGMA, and Calit2.