bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acetaminophen induces oligodendrocyte precursor cell death and reactive astroglia in a primary mixed glial cell culture
Authors: Perez María Julia , Tallis Silvina , Novak Analia , Delfante Amalia , Rubio Modesto Carlos , Ghanem Carolina Inés 
Published: June 2021

Brain damage in acetaminophen (AP) overdose is associated with liver failure but its direct effects has not been evaluated.AimTo study the effect of toxic and non‐toxic doses of AP on astrocyte and oligodendrocyte precursor cell (OPC) viability in a primary mixed glial cell culture.MYMPrimary cultures of mixed glial cells were carried out according to McCarthy and de Vellis (1980). Cells were treated with vehicle (DMSO) or AP (1 and 20 mM). After 48 hs cell viability was assessed; astrocyte marker (GFAP) and OPC marker (PDGFR‐alpha) expression was evaluated by western‐blot (WB) and immunocytochemistry.ResultsThe 1 mM dose of AP did not produce significant differences in cell viability, while 20 mM exposure decreased in 40% cell viability (P<0.001). The 20 mM dose produced the death of the 90% of the OPC in the culture and a decrease of 89% of PDGFR‐alpha expression (P<0.001) with an increase in GFAP optical density/cell and WB expression (47% and 97% respectively) (P<0.05). The 1mM dose did not produce significant changes in GFAP but produce a 25% significant decreased in PDGFR‐alpha expression (p<0.05).ConclusionAP produces direct toxic effects on glial cells characterized by oligodendrocyte death and the induction of reactive astroglia.
G Protein Estrogen Receptor (GPER) Regulates Kv11.1 Ion Channel Activity in ERneg Breast Cancer Cells
Authors: Gentile Saverio 
Published: June 2021

Breast cancer is a major cause of death among women worldwide, and novel strategies need to be developed to lessen its morbidity. Although, the mechanism of breast cancer proliferation is poorly understood, it has been established that in cancer cells displaying an E2 receptor positive (ERpos) or E2 receptor negative (ERneg) phenotype, proliferation can be mediated by an E2‐dependent mechanism. Interestingly, recent studies have demonstrated that E2 effects on proliferation of ERneg breast cancer cells can be mediated by the G protein‐coupled receptor, GPER. However, very little is known about the biochemical signaling cascade activated by E2 via GPER.Clinical heterogeneity of breast cancers indicates new subsets of gene expression that can create novel molecular pathways mediating estrogen's (E2) effects on proliferation. The human ether‐a‐go‐go related gene (hERG) encodes the voltage‐gated potassium channel Kv11.1, which is primarily expressed in electrically excitable cells.Interestingly, recent translational research in cancer biology has revealed that Kv11.1 is robustly expressed in cancers of varying histogeneses, including breast cancer. Although, it is well established that Kv11.1 plays a major role in regulating membrane potential nothing is known about its role in breast cancer and its contribution in proliferation.Our experiments show that changes of Kv11.1 activity determine variation of proliferation rate in ERneg breast cancer cells. Electrophysiological, biochemical analyses show that Kv11.1 ion channel activity is stimulated by an E2‐activated signaling cascade via GPER in ERneg breast cancer cells. In addition, stimulation of Kv11.1 activity led to increase of intracellular calcium. Understanding the role of hormonal regulation of Kv11.1 ion channel will lead to discovery of a myriad of new potential drug target for cancer treatment.
Overexpression and nuclear translocation of glyceraldehyde‐3‐phosphate dehydrogenase in acetaminophen acutely intoxicated rats
Authors: Delfante Amalia , Ruiz María Laura , DiCarlo María Biatriz , Perazzo Juan Carlos , Mottino Aldo Domingo , Ghanem Carolina Inés 
Published: June 2021

The mechanism of acetaminophen (AAP) hepatotoxicity involves glutathione depletion, oxidative stress and mitochondrial dysfunction leading to necrosis. Recently, glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) was highlighted as a mediator of cell death.AimTo evaluate GAPDH expression and subcellular distribution in liver of AAP acute intoxicated rats.M&MMale Wistar rats were injected i.p. with 1 g/kg b.w. of AAP (AAP group) or vehicle (C group) (n=4). After 24 h, liver GAPDH expression (mRNA and protein) was studied by RT‐PCR and Western‐Blot (WB). Nuclear, mitochondrial, and cytosolic GAPDH content was evaluated in hepatic subcellular fractions by WB. Results were expressed as mean±SD and statistically analized with Student‐t‐test (* p<0.05 vs C).ResultsGAPDH mRNA (AAP:408±221*; C:100±26) and protein expression (AAP:292±127*; C:100±7) were significantly increased in treated rats. Subcellular distribution of GAPDH changed for nucleus (AAP:232±95*; C:100±49) but not for mitochondrial and cytosolic fractions.ConclusionAAP acute intoxication increased GAPDH expression due to a transcriptional mechanism, which questions its use as a housekeeping gene for either RT‐PCR or WB studies. Under AAP overdose, the GAPDH increase its content in the nucleus sugesting a role in AAP toxicity.
Functional Assessment of Stenosis Severity by Contrast‐Induced Submaximal Hyperemia
Authors: Nolte F , van de Hoef T P , de Klerk W , Spaan J AE , Piek J J , Siebes M 
Published: June 2021

IntroductionThe hemodynamic effect of a stenosis is uniquely characterized by the relationship between pressure drop across (ΔP) and velocity (v) distal to it (ΔP‐v relationship). Normally this relationship is assessed after a bolus injection of adenosine (ADO). However, ADO is not readily available everywhere. We therefore aimed to establish whether vasodilation by contrast medium (CM) results in the same ΔP‐v relationship or is affected by factors like viscosity.MethodsIn 21 patients scheduled for percutaneous coronary intervention, measurements were performed in a stenotic vessel before treatment. Aortic pressure (Pa), intracoronary pressure (Pd) and v were recorded during sequential periods covering control and response to ADO and CM injections. ΔP‐v relationships were fitted using the equation ΔP=0+Av+Bv2. The similarity between CM and ADO curves was established by comparing the predicted pressure drop at v=50 cm/s (ΔPv50).ResultsΔP‐v relationships showed good agreement between CM and ADO. Hyperemic v was 35.5±17.6 cm/s during ADO and reduced to 81% after CM (p<0.01). ΔPv50 was 50.5±12.5 with ADO and 76.8±24.6 mmHg after CM (NS).ConclusionCM does not alter the shape of the ΔP‐v relationship. Consequently, although CM does not result in full vasodilation it can be used to assess functional stenosis severity based on the shape of this curve.Supported by NHF grant 2006B186
The causal role of PKC in Reduced Endothelial Ca2+ Signaling and Impaired EDHF‐Mediated Uterine Vasodilation in Diabetic Pregnancy
Authors: Gokina Natalia I , Linder Erika 
Published: June 2021

Increased PKC activity is an essential mechanism of diabetic vascular complications. To characterize the role of PKC in uterine vascular dysfunction during diabetic pregnancy we: (1) defined the effects of PKC activation (PDBu) or inhibition (bisindolylmaleimide, BIS) on EDHF‐mediated responses to ACh; (2) elucidated PKC dependence of ACh‐induced endothelial cell (EC) [Ca2+]i.Diabetes was induced by streptozotocin (STZ) injection. ACh was tested in uterine arteries from control and diabetic pregnant rats in the presence of L‐NNA and indomethacin. Fura‐2 based SMC or EC [Ca2+]i responses were studied as well. Diabetes reduced EDHF‐mediated vasodilation from 90 ± 4 % to 26 ± 9 % at 10 μM ACh. SMC and EC [Ca2+]i responses were markedly reduced as well. PDBu inhibited ACh‐evoked vasodilation (14 ± 5 %) and associated SMC [Ca2+]i responses of control vessels. BIS partially restored EDHF‐mediated vasodilation (to 72 ± 10 %) and SMC [Ca2+]i in diabetic vessels. PDBu reduced EC [Ca2+]i responses of control vessels to ACh by 50 ± 7 %. BIS significantly restored EC [Ca2+]i elevations to ACh in diabetic arteries.PKC‐dependent reduction in EC Ca2+ signaling underlies impaired EDHF‐mediated uterine vasodilation during diabetic pregnancy. Inhibition of PKC may serve as a therapeutic strategy to improve uterine vasodilation in pregnancies complicated with diabetes. Supported by NIH HL088245
Resveratrol prevents accumulation and secretion of the pro‐hypertrophic high molecular weight FGF‐2 by rat and human cardiac myofibroblasts
Authors: Santiago Jon-Jon , McNaughton Leslie J , Fandrich Robert F , Arora Rakesh C , Kardami Elissavet 
Published: June 2021

BackgroundResveratrol (Resv) is known to prevent cardiac hypertrophy by a mechanism attributed to direct effects on cardiomyocytes. Cardiac fibroblasts are known to mediate the paracrine induction of hypertrophy, by secreting bioactive agents including the pro‐hypertrophic high molecular weight (Hi) FGF‐2. Here, we examined the effects of Resv on the angiotensin II (Ang II)‐induced HiFGF‐2 upregulation and release by cardiac myofibroblasts.ResultsCardiac non‐myocytes, isolated from the hearts of neonatal rats or from human cardiac atrial tissue, expressed proteins characteristic of myofibroblastic phenotype at passage P2, as indicated by expression of extra domain A‐fibronectin, non‐muscle myosin heavy chain, and α‐smooth muscle actin. Stimulation with Ang II promoted the upregulation of both total and exported HiFGF‐2. Secreted HiFGF‐2 was capable of inducing cardiomyocyte hypertrophy in culture. Resv prevented both total and exported HiFGF‐2 upregulation, in both rat and human heart cells. Studies have shown that the effects of Resv can be mediated by inhibition of ERK and MMP‐2 activities; in agreement, we found that inhibition of these pathways diminished the Ang II‐induced HiFGF2 upregulation and release.ConclusionsOur data suggest that the anti‐hypertrophic effect of Resv may be mediated in part by its effects on cardiac fibroblasts, preventing HiFGF‐2 accumulation and secretion.Grant Funding Source: CIHR
Mechanical Stress activates NFATc4 in Cardiac Fibroblasts via Syndecan‐4
Authors: Herum Kate Louise Møller , Lunde Ida Gjervold , Behmen Dina , Florholmen Geir , Carlson Cathrine Rein , Christensen Geir 
Published: June 2021

Cardiac fibroblasts differentiate into myofibroblasts in response to left ventricular pressure overload. Myofibroblasts have contractile properties and produce excessive amounts of extracellular matrix, thereby increasing myocardial stiffness. The objective of this study was to investigate the role of the focal adhesion transmembrane protein syndecan‐4 as a stress‐sensor activating nuclear factor of activated T‐cells (NFAT) and thereby inducing myofibroblast differentiation. Aortic banding increased mRNA levels of the myofibroblast marker gene smooth muscle α‐actin, as well as collagen I and III in wild‐type left ventricles but not in the syndecan‐4 knockout (KO) hearts. Stretch caused translocation of GFP‐NFATc4 fusion proteins to the nucleus indicating activation of this isoform. Furthermore, NFATc4 was dephosphorylated (activated) following stretch in a calcineurin‐and syndecan‐4‐dependent manner. Finally, overexpressing NFATc4 caused an increase in the myofibroblast‐associated myocardin‐related transcription factor A. In conclusion, we show that syndecan‐4 activates NFATc4 signaling following stretch and this may cause myofibroblast differentiation.Source of research support: Norwegian Health Association
Mobile phone radiation effects into ERK1, ERK2 and PKCα signaling pathway of Wistar rats pituitary
Authors: de Caires Luiz Carlos , da Silveira Goulart Guimarães Ernesto , Musso Camila Manso , Vasconcellos Rebecca , Assis Diego , de Mendoça José Paulo Rodrigues Furtado , Garcia Raúl Marcel González 
Published: June 2021

Over the last few years, the mobile communication system has increased significantly. Some researches about the radiation emitted by mobile phones have been trying to verify possible modifications on gland functions. ERK1, ERK2 and PKCα enzymes have pivotal role on controlling synthesis and secretion of pituitary and hypothalamic hormones. Thus, the aim of this work was to evaluate the effect of the radiation emitted by mobile phones into the expression and activity of ERK1 and ERK2 and expression of PKCα in Wistar rats pituitary cells. Wistar male rats, 60 days old, were exposed to the radiation emitted by mobile phone (1800 MHz) during 1 or 3 hours uninterrupted. The pituitary gland of the animals was removed in order to analyze the expression of those enzymes and activity of ERK1 and ERK2, by Western Blot. After 1 hour of exposure, it was not observed any significant modification in the expression of ERK1, ERK2 and PKCα. The activity of ERK1 and ERK2 was shown to be reduced in the exposed animals. After 3 hours of exposure, the expression of ERK1 and ERK2 was not altered, although the activity of these enzymes and expression of PKCα was reduced in the exposed animals. According to these data, the exposure to this kind of radiation may alter the signaling pathways in which ERK's and PKCα are involved, and, consequently, the normal physiology of pituitary cells.Financial Support: CNPq, Capes, Fapemig and UFJF.
Blue native PAGE resolution of renal sodium transporters
Authors: Lee Donna H , McDonough Alicia A. 
Published: June 2021

Blue native polyacrylamide gel electrophoresis (BN‐PAGE) is used to separate protein complexes from biological membranes under native conditions.AimDetermine size of native complexes of renal Na+ transporters and their putative associated regulators by BN‐PAGE (Invitrogen). 15–20 μg of rat cortical membranes (200K x g pellet) were resolved on 3–12% Bis‐Tris gels and blotted onto PVDF.Results and ConclusionsNHE3 (mw ~75kD) is detected at 460 kD with a minor band at 550 kD. NHE3‐pS552 is also detected at 460 kD. The NHE3 regulator DPPIV (100kDa), is detected at: 430 kD (40% of the signal) near NHE3, at 525 kD (10%) and 330 kD (50%). Membrane bound Myosin VI (150kD), an actin‐based motor associated with NHE3‐DPPIV, resolves at 340 – 400 kDa, below NHE3. NKCC (150kD) is detected at 625 kD. Anti‐NKCC‐pT96,pT101 detects two bands: with NKCC at 625kD (55% of signal) and at 400 kD raising the possibility that the anti‐NKCC epitope is masked in the 400 kD complex. NCC (150 kD) is detected at both 610 kD (66% of signal) and 380 kD (33%). NCCpS71 or pT53 were detected only at 610 kD suggesting phosphorylation provokes 610kD complex (or –p epitopes are masked at 380kD). γ‐Adducin (100 kD), an auxiliary protein that interacts with NCC, is detected at 600kDa (40% of signal) near NCC and NCC‐p, and at 700 kD (60%). Na,K‐ATPase α1 (100kD) is detected at 285 kD. Na,K‐ATPase β, ENaCs and SPAK were not detected using this amount of protein. DK0837854
Overexpression of HSP10 in transgenic mice protects skeletal muscle against endotoxic shock‐induced loss of force generation
Authors: Kayani Anna Charlotte , Routley Claire , Douramani Maria Touramani , Dillmann Wolfgang , Mestril Ruben , Jackson Malcolm 
Published: June 2021

Impairment of skeletal muscle function and wasting are consistent and severe features of sepsis and are associated with poor outcome. The rate of loss of muscle in septic patients with multiple organ failure is between 2 and 4% per day. We have demonstrated that overexpression of the mitochondrial chaperone HSP10 prevents age related loss of maximum force generation and cross sectional area and we hypothesised that HSP10 would be beneficial in preventing the loss of muscle function during sepsis.WT and HSP10 overexpressor mice were treated with LPS at 2.5mg/Kg and maximum force generation of EDL muscles was measured after 24hrs. Overexpression of HSP10 resulted in significant protection against LPS induced loss of maximum force generation compared with WT mice and additionally protected against the systemic symptoms of endotoxic shock observed in WT mice. HSP10 overexpression significantly reduced serum protein levels and muscle mRNA content of TNF‐α and IL‐6 compared with WT mice. Muscle fibres were isolated from FDB muscles and treated with LPS at 1μg/ml for 5hr. A significant reduction in the TNF‐α release was observed from fibres from HSP10 overexpressor mice compared with WT.These data suggest that anti‐inflammatory effects of HSP10 protect against the loss of maximum force and the severity of systemic illness during endotoxic shock and therefore provides a potential therapeutic target in sepsis. Funded by MRC.
Type 1 Diabetes in young women is associated with decreased circulatory response to hypovolemic stress
Authors: Lindenberger Marcus , Lindström Torbjörn , Länne Toste 
Published: June 2021

ObjectiveDiabetes is associated with hemodynamic instability, e.g. during anaesthesia. Young men with type 1 diabetes (DM‐1) have impaired circulatory response to hypovolemic stress. The effect of DM‐1 on cardiovascular response to hypovolemia in young women is unknown however.Design and MethodsLower body negative pressure (LBNP) of 30 cm H2O was used to create rapid hypovolemic stress in fifteen young women with DM‐1 as well as sixteen healthy women. Cardiovascular response and the compensatory mobilisation of venous capacitance blood (capacitance response) and net fluid absorption were measured with volumetric technique.ResultsCapacitance response was both reduced and developed slower in DM‐1, P < 0.01. Fluid absorption was almost halved in women with DM‐1, P < 0.01. Arterial vasoconstriction also developed slower in DM‐1, P < 0.05.ConclusionsYoung women with DM‐1 present with decreased as well as slower mobilisation of venous capacitance blood and decreased net fluid absorption that could make women with type 1 diabetes prone to hemodynamic instability. Cardiovascular autonomic neuropathy could play a role, but also differences in the venous circulation and microcirculation.
Pseudomonas aeruginosa produce autoantibodies against HSP60 in rats
Authors: Havnes Marianne , Ahlén Catrine , Brubakk Alf , Iversen Ole-Jan 
Published: June 2021

Skin and ear infections, primarily caused by Pseudomonas aeruginosa (P. aeruginosa) are recurrent problems for saturation divers, while infections caused by P. aeruginosa are seldom observed in healthy people outside saturation chambers. Cystic fibrosis (CF) patients suffer from pulmonary infections by P. aeruginosa and it has been demonstrated that CF patients have high levels of anti‐HSP60 compared to controls, probably induced by P. aeruginosa. The present study investigated whether rats immunized with P. aeruginosa produced autoantibodies against their own HSP60 and whether diving influenced the level of circulating anti‐ HSP60 antibodies.MethodsRats were randomly assigned to one of three groups. Group 1 and 3 were immunized with P. aeruginosa, every other week. Groups 2 and 3 were exposed to simulated air dives to 400 kPa (4 ata) with 45 min bottom time, every week for seven weeks. The amount of anti‐HSP60 rat antibodies in the serum was analyzed by ELISA.ResultsThe immunized rats showed a significant increase in the level of autoantibodies against HSP60, while no autoantibodies were detected in the dived rats. The rats both immunized and dived show no significant increase in circulating autoantibodies against HSP60. A possible explanation may be that HSP60 is expressed during diving and that cross reacting antibodies are bound.
Baseline plasma cGMP levels correlates with breath hold capacity in competitive breath hold divers
Authors: Lindholm Peter , Schiffer Tomas A , Lundberg Jon O , Weitzberg Eddie 
Published: June 2021

Breath‐hold (BH) duration depends on oxygen stores and consumption. Strong peripheral vasoconstriction and reduction in cardiac output (diving response) reduce oxygen consumption during apnea. A healthy reactive endothelium may be important for an efficient diving response. Endothelium‐derived nitric oxide (NO) is deeply involved in endothelial function and plasma cGMP is considered as a marker of endothelial NO synthase activity.ObjectiveTo evaluate the association between plasma cGMP and BH capacity in trained BH divers.MethodsNine BH divers performed BHs of maximal duration after inhalation to 80% of vital capacity. Oxygen consumption was evaluated with pulse oximetry (SpO2) and exhaled O2 fraction (EtFO2) at end of apnea. Baseline plasma cGMP was measured before and 10min after the apnea protocol.ResultsA strong positive correlation was found between baseline plasma cGMP levels and maximum BH duration (344±13 sec, R2=0.63, P=0.011), SpO2 at 4min (R2=0.53, P=0.026) and EtFO2 at breath‐holds aborted at 4min (R2=0.50, P=0.026). Mean plasma cGMP increased from 4.3±0.8 to 7,8±1.8nM as a result of the apnea protocol (P=0.024).ConlusionBaseline plasma cGMP predicts breath hold capacity and oxygen consumption during apnea in trained breath hold divers. This indicates that endothelial NOS activity could be important in the vascular part of the diving response.
Lack of Testosterone (TST) Worsens Ischemia/Reperfusion– Induced Acute Kidney Injury (I/R‐AKI) and its Deleterious Cardiac Effects
Authors: Soljancic Andrea , Lopez-Ruiz Arnaldo , Chandrashekar Kiran , Maranon Rodrigo , Mahgoub Mohanad , Liu Ruisheng , Juncos Luis A 
Published: June 2021

Renal I/R‐AKI results in systemic inflammation, including the heart. We recently reported that plasma TST is reduced during AKI, and its supplementation improves renal injury and inflammation by increasing cytoprotective factors. We now extended this study to test whether the lack of TST exacerbates I/R‐AKI and its cardiac abnormalities. Intact and castrated males (Cast) SD rats were treated with either vehicle or TST (20 ng/kg/min × 10min IV) given 3 hours after subjecting the rats to 40 min of bilateral renal I/R. After 48 hs, we harvested the kidney and the heart, and evaluated renal function and injury (PlCr ‐KIM‐1), cardiac stress (pro‐BNP), and cytoprotective factors (renal and cardiac heme oxygenase‐ HO‐1).

PlCr mg/dl
KIM‐1 pg/ml
BNP ng/ug
Renal HO‐1 ng/ml
Cardiac HO‐1 ng/ml

Sham
0.4 ±0.3
712 ±53
0.18 ±0.02
0.52±0.4
0.4 ±0.06

AKI
1.9 ±1.9*
4576 ±185*
3.8 ±0.1*
5.8±1.2*
5 ±0.1*

AKI‐Cast
2.5 ±2.3&
8972 ±708&
4.4 ±1&
3±0.1&
3.7 ±0.1&

AKI‐Cast‐TST
1.6 ±1#
2348 ±85 #
2.4 ±0.6#
4.4±0.2#
4.6 ±0.1#

Data: Mean±SEM:
p<0.05 vs Sham;
vs AKI;
vs AKI‐CT
Lack of TST exacerbates I/R‐AKI and cardiac stress. Despite the increased injury, HO‐1 is decreased, suggesting that TST may be facilitating HO‐1 expression post AKI.
Pulmonary inflammation and airway hyperresponsiveness associated with placental ischemia induced hypertension in rat dams and offspring
Authors: Johnson Alex C , Eskuri Ryan S , Gilbert Jeffrey S , Regal Jean F 
Published: June 2021

Preeclamptic mothers have vascular inflammation with neutrophil infiltration, and post‐partum preeclamptic mothers have increased pulmonary resistance to methacholine i.e. airway hyperresponsiveness (AHR). Since growth restricted offspring of preeclamptic pregnancies are at increased risk for respiratory disease, we hypothesized placental ischemia induced hypertension is associated with neutrophil infiltration into lung and AHR in mother and offspring. On gestation day 14 rats underwent sham surgery or clips were placed on abdominal aorta and ovarian arteries to create reduced uterine perfusion pressure (RUPP) and hypertension by day 19. Dynamic pulmonary resistance in response to increasing doses of methacholine was determined on day 19 using forced oscillation (Scireq). Myeloperoxidase (MPO) in homogenized lungs was assayed as an indicator of neutrophil infiltration. MPO significantly increased in RUPP vs Sham dams (p<0.05) with no difference in AHR. RUPP offspring were growth restricted at birth but not at 8–10 wks of age. Male RUPP offspring, but not female, had increased methacholine response compared to Sham offspring (p<0.05). These data indicate placental ischemia is accompanied by pulmonary inflammation but not AHR in the mother. However, adverse pulmonary reactivity is evident in growth restricted male offspring of a hypertensive pregnancy.Support: U of M Grant‐in‐Aid & HL109843.