bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial Mineralocorticoid Receptor Mediates Cerebrovascular Dysfunction in Parenchymal Arterioles during Angiotensin II‐Hypertension
Authors: Diaz‐Otero Janice M , Yen Ting‐Chieh , Jaffe Iris Z , Jackson William F , Dorrance Anne M 
Published: June 2021

Mineralocorticoid receptor (MR) activation causes cerebral parenchymal arteriole (PA) remodeling, impaired endothelium‐dependent dilation and cognitive dysfunction in hypertension. We used a mouse model of angiotensin II (AngII)‐induced hypertension to test the hypothesis that endothelial cell mineralocorticoid receptor (EC‐MR) activation impairs parenchymal arteriole (PA) transient receptor potential vanilloid 4 (TRPV4)‐mediated dilation and cognitive function. 16–18‐week‐old MR‐intact and endothelial mineralocorticoid receptor knockout (ECMRKO) mice were treated with AngII (800ng/kg/min) for 4 weeks; shams served as controls. Data are presented as means ± SEM; n=5–14 per group. EC‐MR deletion under control conditions did result in vascular changes. EC‐MR deletion prevented the impaired PA carbachol (CCh)‐mediated dilation in hypertension but not the increased myogenic tone. The TRPV4 inhibitor, GSK2193874 (10−7M) was used to confirm the importance of TRPV4 activation in CCh‐mediated dilation. TRPV4 inhibition blunted the CCh‐mediated dilation in all groups. Dilation in response to the TRPV4 agonist GSK1016790A (10−9–10−5mol/L) and IKCa/SKCa agonist NS309 (10−9–10−5mol/L) were also reduced in the hypertensive mice and this was corrected by EC‐MR deletion. Hypertensive mice had impaired cognitive function, but this was not corrected by EC‐MR deletion. Plasma protein oxidation was not altered by EC‐MR deletion or AngII treatment. The mRNA expression of markers for neuronal support and synapse proteins, synaptophysin (SYP), brain derived neurotrophic factor (BDNF) were not altered by AngII. However, the mRNA expression of doublecortin (DC) was reduced by AngII and EC‐MR deletion prevented this. Our data shows that EC‐MR signaling mediates PA endothelium‐dependent dilation but not cognitive function and suggests that the MR is a potential therapeutic target to improve cerebrovascular function during hypertension.Support or Funding InformationR01‐HL‐137694‐01 and PO1‐HL‐070687 to WF Jackson and AMDorrance 5T32GM092715‐04 and F31NS090866 ‐ J.M. Diaz‐OteroR01‐HL095590 ‐ I.Z. Jaffe. J.M.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Serum Liver Enzymes and Oxidative Stress Biomarkers in Resveratrol Treated Cholesterol Diet Induced Type 2 Diabetes Mellitus in Rabbits
Authors: Abdulazeez Jimoh , Olusegun Ayo Joseph , Tanko Yusuf , Abubakar Ahmed , Bello Umar Muhammed , Ahmed Muhammed Kabir , Aliyu Mohammed 
Published: June 2021

Fat accumulation in the body has been implicated in the increased generation of ROS and oxidative stress which enhances hepatocellular damage. Increase in serum liver enzymes have been widely used as an index of liver dysfunction and that higher ALT concentrations predicted development of type 2 diabetes. Thirty rabbits were randomly divided into six groups, each of five animals: Group 1 = control (C), Group 2 = cholesterol diet (CD) only, Group 3 = resveratrol 200 mg/kg (R200), Group 4 = resveratrol 400 mg/kg (R400), Group 5 = CD + R200 and group 6 = CD + R400. The preparations were administered for 8 weeks of experimental protocol. Blood glucose level was measured on week zero and the 8th week of the treatment. At the end of the study period, the rabbits were placed under light anesthesia (ketamine) to remain unconscious. Blood sample of about 3ml was drawn via cardiac puncture for serum extraction which were evaluated for serum concentration of liver enzymes (alanine aminotransferase ALT, aspartate aminotransferase AST and alkaline phosphatase ALP) and oxidative stress biomarkers (superoxide dismutase SOD, catalase CAT and glutathione peroxidase GPx). Blood glucose level was significantly higher in CD group compared to groups that received resveratrol supplement. Serum Liver enzymes activities showed significant (P < 0.05) decrease in ALT, AST and ALP levels in groups that were administered resveratrol with CD compared with CD alone. Significant decrease in antioxidant enzymes activities (SOD, CAT and GPx) in resveratrol treated groups (P < 0.05) were recorded when compared to CD alone group. In conclusion, the observed decreased in blood glucose level, liver enzymes and biomarkers of oxidative stress with resveratrol administration despite CD consumptions, elucidated the therapeutic potential of resveratrol.Support or Funding Information1. SelfThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The lncRNA profile in control and ischemically injured kidneys of old mice
Authors: Hamar Péter , Kaucsár Tamás , Tod Pál , Róka Beáta , Godó Mária , Sárközy Henrietta , Kiss Norbert , Szénási Gábor 
Published: June 2021

AimWe investigated the influence of aging on the lncRNA profile after renal ischemia‐reperfusion (IR) injury in old mice.MethodsThe left renal pedicle of adult (9.4±0.3 months, n=7) and old (28.5±1.2 months, n=8) C57BL/6N mice was clamped for 20 min. The right kidney was left intact. Plasma urea and urine NGAL (uNGAL) were measured prior to and 7 days after reperfusion. On day 7 tubular injury was evaluated by histology (PAS, HE) and KIM1 mRNA (qPCR). Fibrosis (FN1) and senescence (p21) was analyzed with qPCR and long non‐coding RNA profile (90 lnc) with qPCR array.ResultsOlder mice had higher baseline uNGAL (old: 285.7±93.8 ng/mg Crea vs. adult: 78.0±9.1 ng/mg Crea, p<0.05) and milder kidney injury (p<0.05). KIM1 (8.3x; p<0.001), FN1 (2x; p=0.05) and p21 (3.8x; p<0.05) mRNA levels were higher in their non‐ischemic kidneys relative to the adult group. Baseline plasma urea levels however, were similar (old: 75.9±10.2 mg/dl vs. adult: 57.6±5.3 mg/dl). Following IR tubular injury increased in both groups (p<0.05) with KIM1 (adult: 202x, old: 19.5x, p<0.0001) and FN1 (adult: 8.5x, old: 3x, p< 0.001) mRNA compared to the contralateral kidneys. uNGAL was higher after IR compared to baseline (old: 3817±1975 ng/mg Crea, p<0.0001; adult: 2833±1201 ng/mg Crea, p<0.001). p21 mRNA increased only in the ischemic kidneys (4.5x, p<0.01), compared to the contralateral control. The plasma urea concentration increased only in the old group following 7 days of reperfusion (140.7±25.6 mg/dl, p<0.01). From the 81 measureable lncRNAs 8 increased and 1 decreased only by IR. Old age only influenced 1 lncRNA expression. Further 12 lncRNA expression was influenced by both IR and old age.ConclusionOur results demonstrated significant tubular damage and decreased renal function in the kidneys of old mice, in accordance with the literature. We have also found that several lncRNAs were differentially expressed in old and adult mice in both the control and ischemic kidneys.New National Excellence Program (Human Resources Department), OTKAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Embryonic Stem Cell‐Derived Exosomes Inhibit Doxorubicin‐Induced Pyroptosis in Cardiac Cells
Authors: Dargani Zahra Tavakoli , Singla Dinender K 
Published: June 2021

Doxorubicin (Dox) is a potent antineoplastic drug used to treat various cancers. Unfortunately, Dox administration is limited due to induction of adverse cardiotoxicity (DIC), which is mediated through oxidative stress, ER stress, and inflammation. However, it is unknown whether Dox induces an inflammasomne‐mediated cell death, called “pyroptosis” in heart. Pyroptosis occurs via activation of TLR‐4 receptor and generation of NLRP3 inflammasome in response to damage‐associated pattern molecules (DAPMs). This would follow‐up with stimulation of caspase‐1 cascade and secretion of pro‐inflammatory cytokines from the dead cells. This study is undertaken to determine whether Dox generates pyroptosis in cardiac cell culture model. Furthermore, to elucidate the protective effects of embryonic stem cell‐derived exosomes (ES‐Exos) in inhibiting pyroptotic cell death. For this purpose, we designed a cell culture model using H9c2 cadiomyoblasts. To generate DIC, H9c2 were exposed to Dox (2 μM for 24 hrs) to induce pyroptosis and accordingly treated with exosomes (10 μg for additional 24 hrs). Cells were assigned into 4 groups: Control, Dox, Dox+ES‐Exos, and Dox+MEF‐Exos (as negative control). According to western blot analysis, immunohistochemical staining and ELISA data, Dox administration caused significant increase in expression of inflammasome markers, TLR‐4 and NLRP3, (p<0.05), pyroptotic markers, caspase‐1, IL1‐β, Caspase‐11, and gasdermin‐D, (p<0.05), as well as pro‐inflammatory cytokines, TNF‐α and IL‐6, (p<0.05) in H9c2 cells. Conversely, increased pyroptosis and inflammation post‐Dox treatment were attenuated significantly upon ES‐Exos treatment in H9c2 cells (p<0.05). However, MEF‐Exos treatment did not make significant changes vs Dox group (non‐significant vs Dox). Overall, our data shows Dox induces pyroptosis and inflammation within cardiac cells, which can be inhibited following treatment with ES‐exosomes. The significance of this study is a new mechanistic insight on the pathophysiological role of NLRP3 inflammasome‐mediated pyroptosis in Dox‐induced cardiotoxicity.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Alternative splicing of the clathrin heavy chain impacts skeletal muscle physiology and protects hearts from failure
Authors: Giudice Jimena , Black Adam J , Blue R. Eric , Engels Nichlas M 
Published: June 2021

Alternative splicing is a posttranscriptional mechanism that produces multiple protein isoforms from a single gene. More than 90% of human genes undergo alternative splicing1,2. Coordinated splicing networks regulate organ development and tissue identity3 and genes encoding trafficking proteins are highly regulated by alternative splicing4. In particular, alternative splicing of the clathrin heavy chain (Cltc) gene regulates the expression of specific splice variants during striated muscle development5,6. CLTC is the main driver of clathrin mediated endocytosis; but also regulates the formation and maintenance of the costamere in skeletal muscles7. Nothing is known about the physiological impact of CLTC splicing, leading us to hypothesize that splicing regulation of CLTC contributes to heart and skeletal muscle physiology. We are using our new CRISPR mouse model where the endogenous Cltc splicing transition is blocked: homozygous Cltc‐ho mice express exclusively the fetal isoform throughout development while in wild type Cltc‐wt mice normal Cltc splicing transition takes place8.We first characterized Cltc splicing patterns of in wild type animals during development in different tissues and demonstrated that exon 31 is skipped in neonates but included in adulthood exclusively in the heart, skeletal muscles, and brain. We observed the developmental regulation in human samples. Furthermore, splicing of Cltc gene reverted to neonatal patterns in mouse hearts after aortic constriction (TAC), a well‐established model of heart failure. Physiologically, Cltc‐ho mice exhibited a higher body and skeletal muscle weights than Cltc‐wt littermates that is accompanied by the downregulation of myostatin expression and the AMPK‐signaling pathway. Notably, hearts are similar in basal conditions; however, when TAC surgeries were performed in these animals, Cltc‐wt mice developed heart failure and hypertrophy whereas Cltc‐ho littermates were protected from cardiac dysfunction. Our ongoing experiments are investigating the different signaling pathways that control the observed phenotypes. Alternative splicing and membrane trafficking are fundamental cellular processes; however, we do not know how splicingtrafficking networks modulate tissue identity acquisition and maintenance, or cellular architecture. Therefore, the interaction between alternative splicing and trafficking is the knowledge gap inspiring our present and future work.Support or Funding InformationStart‐up funds, Junior Faculty Development Award, Nutrition Obesity Research Center (NORC) Pilot and Feasibility Grant (P30DK056350) from The University of North Carolina at Chapel Hill (to JG).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Th1 Inflammatory Cytokines Induce Corticosteroid Resistance in Pediatric Airway Smooth Muscle Cells
Authors: Jackson Devine , Walum Josh , Britt Rodney Deon 
Published: June 2021

IntroductionSteroid‐based therapies are anti‐inflammatory and commonly used to manage asthmatic symptoms in pediatric patients. Although manageable for most children, some patients with moderate‐severe asthma require administrations of high doses of steroids, which is relatively ineffective in limiting asthmatic symptoms. Airway smooth muscle (ASM) plays a central role by contributing to airway inflammation, remodeling, and hyperreactivity in asthma. ASM contributes to airway inflammation during responses to allergen exposures (Th2 inflammation) and infection (Th1 inflammation). Previous studies have suggested that adult ASM exposed to Th1 cytokines, TNFα and IFNγ, reduce steroid sensitivity and efficacy. In the present study, we examined the effects of TNFα and IFNγ on steroid sensitivity in pediatric ASM.Methods and ResultsHuman ASM was isolated from trachea of patients (1–10 years old) undergoing tracheal reconstruction surgery (approved by NCH IRB). Cultured ASM were treated with vehicle (0.01% DMSO), 10 nM fluticasone propionate (FP), 10 ng/mL TNFα, and/or 25 ng/mL IFNγ for 24 h. Cells were harvested to measure mRNA levels of pro‐inflammatory genes (CCL5, CXCL10, p65) and glucocorticoid receptor target genes (FKBP5, GILZ) by qRT‐PCR. Media was collected to measure CCL5 levels by ELISA. Effects of TNFα or IFNγ alone on CCL5 and CXCL10 mRNA levels were inhibited by FP, however CCL5 and CXCL10 mRNA levels remained increased in cells treated with TNFα/IFNγ and FP. Similarly, TNFα‐induced CCL5 secretion was reduced by FP, but this anti‐inflammatory effect was absent in cells treated with TNFα/IFNγ. Transcription of glucocorticoid receptor target genes, FKBP5 and GILZ, were increased by FP, evidence of glucocorticoid receptor activity. In contrast to FKBP5, GILZ mRNA levels were attenuated by TNFα and IFNγ treatment, and blunted by TNFα/IFNγ. Treatment with TNFα/IFNγ substantially increased mRNA expression of the NFκB subunit, p65, an effect that remained in the presence of FP.ConclusionsTogether these findings suggest that TNFα/IFNγ induce steroid resistance in pediatric ASM. Although there is evidence of glucocorticoid receptor activity, we speculate that interactions between TNFα‐ and IFNγ‐mediated pathways promotes inflammation in the presence of steroids. Th1‐mediated inflammation may contribute to development of steroid resistance in children with severe asthma.Support or Funding InformationThis study is funded by National Institutes of Health R00 HL131682 (RDB).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evaluating sex differences in miR‐106a expression in a mouse model of lung inflammation and asthma
Authors: Steckbeck Rachel Joy , Fuentes Nathalie , Weaver Ashley , Rivera Lidys , Nicoleau Marvin , Silveyra Patricia 
Published: June 2021

MicroRNAs (miRNAs) are oligonucleotides involved in various processes in the cell, including gene expression regulation. MicroRNA‐106a is involved in transcription regulation of the gene coding for interleukin 10 (IL‐10), an anti‐inflammatory cytokine, and has been implicated in asthma exacerbation in mice. However, despite the well‐known sex differences in human asthma incidence, no studies have been done evaluating sex differences on the impact of miR‐106a in asthma. In this study, we hypothesized that there are sex differences in miR‐106a expression in the lungs of asthmatic mice, under normal conditions and in response to air pollution challenge. To test this hypothesis, both male and female mice were exposed to house dust mites (HDM) or phosphate‐buffered saline (control) for 5 weeks to trigger the asthma phenotype. Mice were subsequently subjected to ozone challenge (2ppm, 3 hours) to model asthma exacerbations. The asthma phenotype was confirmed by lung histology, lung function testing using a rodent ventilator, and expression of inflammatory markers by Real Time PCR. To measure miRNA expression, lungs were harvested, total RNA was extracted and converted to cDNA. We performed Real Time PCR with specific primers for miR‐106a and the small RNA U6 (normalization control) using the miRCURY LNA® RT® kit. Our results show sex differences in expression of miR‐106a upon HDM and ozone challenge. Ozone exposure increased miR‐106a expression in non‐asthmatic females and asthmatic males when compared to filtered air exposed mice (p<0.0001 and p<0.05, respectively). Male asthmatic mice had higher miR‐106a expression than non‐asthmatic male mice (p<0.0001). However, the interaction between ozone exposure and sex was significant in non‐asthmatic mice only. We conclude that the observed differences in miR‐106a expression may be a result of different lung immune cells recruited to the male and female asthmatic lung. Understanding the mechanisms behind these sex differences may lead to future development of novel treatments for asthma.Support or Funding InformationThanks to the American Physiological Society Undergraduate Summer Research Fellowship for allowing me to do this research and to the NIH grants HL133520 and HL141618 for supporting this work.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
HIF‐1 alpha Mediates Sex‐specific miR‐30a Expression in Neonatal Hyperoxic Lung Injury: Implications for Bronchopulmonary Dysplasia
Authors: Zhang Yuhao , Dong Xiaoyu , Lingappan Krithika 
Published: June 2021

BackgroundBronchopulmonary Dysplasia (BPD) is characterized by an arrest in lung development with severe impairment of alveolar septation and vascular development. Premature male neonates are at a greater risk of developing bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. Neonatal female mice have improved alveolarization and pulmonary vascular development compared to male littermates in a murine model of BPD. Analysis of the pulmonary transcriptome suggests that miR‐30a, may modulate these sex‐specific differences in gene expression. HIF‐1α plays an important role in post‐natal lung development, especially in recovery from hyperoxic injury and acute lung injury. We hypothesized that differential sex‐specific expression of miR‐30a is mediated through HIF‐1α.MethodsMale and female neonatal WT (C57BL6) mice were exposed to hyperoxia (P1–P5; saccular stage of lung development) and euthanized on P7 or P21 after recovery in normoxia. Human pulmonary microvascular endothelial cells (HPMECs; from 18–24 weeks gestation donors; 3 male and 3 female) were obtained from ScienCell (Carlsbad, California). They were cultured in endothelial cell media per protocol. Cells from passage from 3 to 6 were used for experiments. For hyperoxic exposure, cells were incubated in 95% O2 and 5% CO2 at 37 °C for upto 72 hours. Cells in normoxia were maintained in air and 5% CO2. miR‐30a and Dll4 (miR‐30a target) expression was measured. Hif‐1α binding to its targets genes (by ChIP‐qPCR) and expression was measured in vivo. To further establish potential regulation of miR‐30a by Hif‐1α, miR‐30a expression after Hif‐1α inhibition was measured in neonatal HPMECs.ResultsExpression of miR‐30a was increased and Dll4 decreased on PND21 in hyperoxia‐exposed neonatal female mice compared to males. On PND21, hyperoxia‐ exposed female mice showed a significant increase in Hif‐1α binding to target genes compared to room air controls and hyperoxia‐exposed male mice. In contrast to male mice, females did not show a decrease in Hif‐1α expression at PND21 after early hyperoxia exposure and this was accompanied by a significant decrease in Phd2 expression in female mice, which metabolizes Hif‐1α. Motif analysis revealed a hypoxia response element (HRE) [AG]CGTG site 428 base pairs upstream of miR‐30a. siRNA mediated loss of Hif‐1α expression in human pulmonary microvascular endothelial cells decreased miR‐30a and increased Dll4 mRNA and protein expression.ConclusionsHif‐1α mediated differential sex‐specific miR‐30a expression may contribute to protection from hyperoxic lung injury in female neonatal mice and contribute to the sex‐specific differences seen in BPD.Support or Funding InformationK08 HL‐127103R03 HL‐141572This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Creatine‐Monohydrate on Cognitive Function in Healthy Male and Female Subjects
Authors: Monsanto Nathan , Hopkins Derek , Deschenes Ashni , Scott Laurie , Skelton Michele 
Published: June 2021

The purpose of this study was to examine the effects of 4 weeks of creatine supplementation on cognitive function using the ImPACT test in healthy male and female subjects. In a randomized, double‐blind placebo‐controlled study, twenty‐five subjects were divided into two groups. One group received creatine while the other group received a placebo. Subjects completed a 5‐day loading phase (20 grams per day) followed by a 24‐day maintenance phase (5 grams per day). Cognitive function was assessed prior to supplementation and immediately after a 4‐week supplementation phase. The ImPACT test was used and provides 6 measures of cognitive function. There were no significant changes in any of the cognitive measures between groups. However, females in the creatine group scored significantly higher than males on the visual memory test. Preliminary analysis suggests that acute supplementation of creatine does not enhance cognition in healthy subjects. A gender difference was observed in the treatment group suggesting that females may respond differently than males with regard to cognitive benefits with creatine supplementation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.