bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Human Antigen R (HuR) as a central mediator of cardiac fibrosis
Authors: Green Lisa C. , Anthony Sarah R. , Lanzillotta Lindsey , Jones Shannon , Nieman Michelle , Lorenz John , Wu Xiaoqing , Xu Liang , Tranter Michael 
Published: June 2021

Human Antigen R (HuR) is an RNA binding protein that regulates the stability of target RNA through binding to AU rich regions in the 3′UTR. HuR‐dependent upregulation of genes has been linked to a number of pathologies, including cancer and cardiovascular diseases. Previously, our lab determined that ablation of HuR in the cardiomyocytes was cardio‐protective in a transverse aortic constriction (TAC) model of heart failure. When compared to control mice, the mice with cardiomyocyte‐HuR deletion exhibited less cardiac hypertrophy, preserved cardiac function, and a reduction in cardiac fibrosis post‐TAC.In this current study, we sought to determine whether the protective effect of HuR deletion is attributable to a reduction in pro‐fibrotic signaling in the hypertrophic heart. Interestingly, in the control mice we observed that activation of HuR following TAC occurred most strongly localized around regions of cardiac fibrosis. Histological analysis showed less interstitial and total fibrosis in the myocyte‐specific HuR−/− hearts. A strong reduction in fibrosis was also observed when mice were treated with a pharmacological HuR inhibitor starting at 4 weeks post‐TAC, a more clinically relevant time point following the initial onset of pathological cardiac hypertrophy. Western blot and qRT‐PCR analysis of protein and RNA expression reveal decreased expression of pro‐fibrotic markers such as TGFβ, fibronectin, and periostin in the hearts from mice treated with HuR inhibitor. To identify a potential underlying mechanism for direct reduction in fibrosis via HuR inhibition, we performed RNA stability assays using isolated primary myocytes in vitro to determine the role of HuR on mRNA transcript stability of TGFβ, a driving factor in fibrotic initiation and progression. Our results show a decrease in TGFβ mRNA stability upon inhibition of HuR, suggesting HuR may play a central role controlling expression of TGFβ during cardiac hypertrophy, thereby acting as an initiating factor of pro‐fibrotic signaling. In conclusion, these results suggest that HuR is a promising therapeutic target for the reduction of cardiac fibrosis.Support or Funding InformationThis work was partially funded by an AHA Scientist Development Grant and NIH R01 HL132111 (MT).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of α9* nicotinic acetylcholine receptor in Murine Dextran Sodium Sulfate‐Induced Colitis Model
Authors: AlSharari Shakir , Toma Wisam , McIntosh Michael , Imad Damaj 
Published: June 2021

Ulcerative colitis (UC) is largely a disease of nonsmokers and ex‐smokers and tobacco smoking affects on the disease course and severity. It has been suggested that smoking may protect against ulcerative colitis. Nicotine seems to be a key mediator of this response. Nicotinic acetylcholine receptors can regulate inflammation primarily through the vagus nerve via cholinergic anti‐inflammatory pathway. α9α10 nAChRs are new promising target of the neuronal nicotinic acetylcholine receptor, especially after the discovery of a novel selective α9α10 conotoxin antagonist. Administration of α9α10 selective α‐conotoxin antagonists have antinociception effect in neuropathic and tonic inflammatory pain animal models. However, little is known about the role of α9α10 nAChRs in experimental colitis. To our knowledge, we reported the first observation of the role of α9α10 nAChRs in the experimental animal colitis model.MethodsC57BL6 Male adult mice were given DSS solution freely in the drinking water for 7 consecutive days after which tap water was given on the 8th day. We measured a Disease Activity Index (DAI) that includes body weight loss, blood presence in stools, stool consistency, local rectal irritation and length of the colon. The mice were then sacrificed on day 8 to allow examination of the entire colon. Disease severity and colon tissue histology and tumor necrosis factor‐α (TNFα) were evaluated. TNF α was determined by enzyme‐linked immunosorbent assay analysis of colon samples.The present study seeks to determine the effect of α‐conotoxin RgIA (α‐RgIA) in DSS‐induced colitis model in adult male C57Bl/6 mice. Low doses of α‐conotoxin RgIA (α‐RgIA) treatment in DSS‐treated mice displayed a significantly decreased in DAI value as well as colonic level of TNF‐α (p<0.05) compared to the control group but high dose of α‐RgIA showed significant decrease in total histological damage scores. The highest dose partially reverse the shortening of the colon. The availability of α9* selective conotoxins against other nAChR subtypes has opened new avenues in pharmacology research and potential targets in the inflammatory disorders.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Restoration of delayed gastric emptying and impaired gastric compliance by anethole in an animal model of functional dyspepsia
Authors: Asano Teita , Takenaga Mitsuko 
Published: June 2021

Background and AimsFunctional dyspepsia (FD) is a functional gastrointestinal disorder characterized by persistent or recurrent postprandial upper‐abdominal discomfort and epigastric pain. Although FD markedly reduces the patient's quality of life, involving elevates health‐care costs, treatment of this condition by methods other than prescribed medicines, such as natural products, could be beneficial. Delayed gastric emptying and impaired gastric accommodation play important roles in pathogenesis of FD. Anethole (1‐methoxy‐4‐((E)‐propenyl)‐benzene), a major component in essential fennel oil has been used in flavouring, alcoholic beverage production and pharmaceutical formulations. In this study, we examined the effects of anethole on delayed gastric emptying and impaired gastric compliance in animals.MethodsGastric emptying was monitored by phenol red marker method in mice. Induction of delayed gastric emptying was performed by the administration of clonidine, dopamine or a 5‐HT3 receptor agonist m‐CPBG. Gastric accommodation (compliance test) was examined in rats by a pressure‐volume control device, barostat. Acetylcholinesterase activity was measured using assay kitResultsOral administration of anethole restored delayed gastric emptying induced by clonidine administration. The dose of anethole did not affect gastric emptying in non‐stressed mice. We also found that fennel oil, which contains about 86% anethole, suppressed clonidine‐induced delayed gastric emptying. Furthermore, a Japanese herbal medicine An‐chu‐san containing anethole improved the gastric emptying in the presence of clonidine. Pharmacological and biochemical analyses suggested that anethole restores gastric emptying independently of D2, 5‐HT3, 5‐HT4 receptors and acetylcholinesterase. Finally, anethole stimulated gastric compliance in rats both with and without wrap restraint stress.ConclusionsTaken together, our results suggest that anethole could be beneficial for treatment of postprandial distress and early satiety in patients with FD.Support or Funding InformationThis research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endothelial Function And Cardiovascular Stress Markers After A Single Dive In Aging Rats (ApoE Knockout Rats)
Authors: Ardestani simin Berenji , Eftedal Ingrid , Matchkov Vladimir , Pedersen Micahel 
Published: June 2021

The compressed gas breath during diving augments partial pressure of oxygen causing the oxygen concentration of the blood to increase above normal (hyperoxia). Hyperoxia in combination with gas bubbles that develop during the decompression (ascent) phase, likely causing oxidative stress, including transient endothelial dysfunction in venous and arterial vessels. The number of aging divers is rising and aging itself is associated with a gradual impairment of endothelial function. These alterations play a central role in the pathogenesis of atherosclerosis and coronary artery disease. While diving and aging are independent modulators of cardiovascular function, little is known about their combined effect. Thus, the central question is does diving expose old divers to more oxidative stress or not?MethodApoE homozygous knockouts rats with impaired cardiovascular function were used as a model for aging. 10 ApoE rats (male and female) exposed to 500 kPa heliox gas (80% helium/20% oxygen) for 1 hr in a pressure chamber to simulate diving. Endothelial function examined in‐vitro by myograph in pulmonary and mesenteric artery. The oxidative stress biomarkers measured in the plasma (collected from heart) and lung tissue via TBARS assay. 10 ApoE rats served as a control group.Results and conclusionThe results of this study demonstrated that a single dive causes endothelial dysfunction in pulmonary arteries of rats with aging cardiovascular system. This seems to be caused by reduction in NO synthesis (Fig. 1). These responses were observed just in male rats.Support or Funding InformationThis project was funded by Aarhus University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
In vivo Endothelial Cell‐specific Expression of AMPKα Attenuates Cold‐induced Pulmonary Vascular Dysfunction and Hypertension by Mitigating Inflammation
Authors: Wang Shirley , Xing Yu , Xu Yuechi , Chen Kai , Ali Quaisar , Ullah Mujib , Sun Zhongjie 
Published: June 2021

Background and AimIn lung biopsies from patients with pulmonary hypertension (PH), mononuclear cells are often observed in pulmonary arterial plexiform lesions, mainly consisting of leukocytes and macrophages. Endothelial AMP‐activated protein kinase α (AMPKα) is downregulated in the pulmonary arteries of patients with PH. AMPK is involved in the cellular response to metabolic stress. AMPKα expression was decreased in pulmonary arteries in a rat model of PH induced by exposure to cold. The aim of this study is to investigate whether in vivo endothelial cell‐specific expression of AMPKα attenuates cold‐induced inflammation and PH.MethodsTo investigate the role of AMPKα1 in PH, we generated Lentivirus carrying AMPKα1 full‐length cDNA driven by an endothelial‐specific promoter, Tie2 (Tie2.AMPKα1). Lentivirus with Tie2.LacZ was used as the control construct. Four groups of Sprague‐Dawley male rats (7/each group) received IV delivery of PBS, PBS, Tie2.LacZ and Tie2.AMPKα1 respectively. Following injection, one PBS group was kept at the room temperature and serve as a control. Other three groups were exposed to cold temperatures (5±1°C). The right ventricular (RV) pressure was measured by end‐point cannulation after 11 weeks of cold‐exposure.ResultsRV systolic pressure was elevated in cold‐PBS and cold‐Tie2.LacZ groups compared with the warm‐PBS controls, suggesting that continuous cold exposure causes pulmonary vascular dysfunction and pulmonary PH, namely cold‐induced PH (CIPH). By contrast, AAV delivery of Tie2.AMPKα1 prevented cold‐induced elevation of RV pressure, suggesting that downregulation of endothelial AMPK α1 plays a critical role in the pathogenesis of cold‐induced pulmonary vascular dysfunction and CIPH. RV developed hypertrophy as evidenced by a significant increase in the RV weight in cold‐exposed rats. Western blot and RT‐PCR data confirmed that Tie2.AMPKα1 effectively rescued the cold‐induced downregulation of AMPK α1 and eNOS expression in the lung. Cold exposure caused strong inflammatory responses as seen with robust infiltration of leukocytes and macrophages in cold‐exposed rats. Cold‐induced activation of macrophages also led to upregulation of TNFα and IL‐1β levels in the lung. Tie2.AMPKα1 effectively attenuated cold‐induced infiltration of leukocytes and macrophages and elevation of TNFα and IL‐1β levels.ConclusionCold exposure causes pulmonary vascular dysfunction and CIPH via downregulation of endothelial AMPKα expression. In vivo endothelial cell‐specific expression of AMPK α1 attenuates CIPH partially by suppressing cold‐induced inflammatory responses.Support or Funding InformationNIH R01 HL116863, HL122166.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High Salt Diet May Stimulate Fructose Uptake in Brain Neurons and Contribute to Neuronal Apoptosis
Authors: Hahka Taija H. , Fan Yuan Yuan , Chen Qing Hui , Shan Zhiying Jenny 
Published: June 2021

Clinical studies have been leaning toward the role that the central nervous system (CNS) is one of the main controls of blood pressure regulation such as the onset of fructose‐induced hypertension. The CNS is by far the most energy demanding and consuming organ in our body and it can metabolize fructose but that has consequences. However, the connection between fructose and hypertension within the CNS is still lacking in definition. Here we tested the hypothesis that a high fructose diet contributes to hypertension via increase neuronal apoptosis. Eight‐week‐old male Sprague Dawley (SD) rats were divided into 4 groups and were fed a normal salt (NS: 0.4% NaCI chow), high salt (HS: 4% NaCl chow), NS diet with fructose (F: 20% fructose drinking water), and high salt plus fructose (HS+F: 4%NaCl chow and 20% drinking water) diet, respectively, for 3 consecutive weeks. Their blood pressure was measured prior and post each diet treatment using the non‐invasive tail‐cuff technologies. All rats were then euthanized, then their blood and cerebrospinal fluid (CSF) was withdrawn for fructose measurements. HS+F rats showed an increase in mean arterial blood pressure (MAP) 126 mmHg compared to control 90 mmHg (p<0.0001). There is no significant MAP alterations in HS or F alone groups compared to NS group. Fructose measurement demonstrated that the serum fructose concentration is significantly increased in the F group (359 μM), and HS+F (409 μM) compared to control NS group (253 μM), while no significant alterations were observed in serum fructose in HS alone group (229 μM). In contrast, CSF fructose concentration is dramatically decreased in F (230 μM) and HS+F (231 μM) groups compared to NS control group (290 μM). In addition, immunostaining showed that HS+F group significantly promoted immunoreactivity of GLUT5, a fructose transporter in the brain paraventricular nucleus (PVN). Furthermore, incubation of brain neurons isolated from neonatal SD rats with 1 mM fructose for 6 hours stimulated neuronal apoptosis (27%) compared to the control (20%, P<0.05). In summary, this study demonstrated that HS+F diet decreases CSF fructose concentration, increases PVN GLUT5 expression, and results in hypertension in normal SD rats. These results suggest that HS facilitates brain neurons to uptake fructose into neuronal cells, resulting in an increase in intracellular fructose, which in turn, stimulate cell apoptosis. Increased neuronal apoptosis may contribute to hypertension.Support or Funding InformationFunding support: R15‐HL122952, Qinghui Chen; R15‐HL129213, Zhiying Shan; Michigan Tech and portage health Foundation REF, Zhiying ShanThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Albumin induces CD44 expression in glomerular parietal epithelial cells by activating the ERK signaling pathway
Authors: Zhao Xueying , Chen Xiaoming , Cobbs Alyssa , George Jasmine , Zhang Yuanyuan , Chima Ashmeer , Emmett Nerimiah 
Published: June 2021

De novo expression of CD44 in glomerular parietal epithelial cells (PECs) leads to a pro‐sclerotic and migratory PEC phenotype in focal segmental glomerulosclerosis. However, the mechanisms underlying CD44 induction in activated PECs remain largely unknown. This study was performed to examine CD44 expression in rat PECs under proteinuric condition and its regulatory mechanisms. CD44 gene and protein levels were examined in Zucker diabetic (ZD) rat kidneys and primary cultured rat PECs exposed to exogenous albumin. Gene microarray and real‐time PCR confirmed an upregulation of CD44 mRNA in renal cortex and glomeruli of ZD rats. Immunofluorescence staining of kidney sections revealed an increase in CD44 signal in claudin‐1‐positive PECs. Enhanced CD44 staining was observed in activated PECs localized in Bowman's capsule and migrated into the glomerular tuft. Moreover, anti‐proteinuric treatment with losartan, an angiotensin II receptor blocker, significantly reduced CD44 protein level in the diabetic rat kidney. In primary cultured rat PECs, administration of rat serum albumin (RSA, 0.25 – 1 mg/ml) resulted in an activation of ERK1/2 MAPK signaling and upregulation of CD44 and claudin‐1 protein expression. This increase in claudin‐1 and CD44 protein was significantly attenuated in the presence of specific ERK1/2 inhibitor U0126. Taken together, our results demonstrate that albumin activates PECs and induces CD44 expression, at least partially via the activation of ERK signaling pathway.Support or Funding InformationNIH SC1DK112151, NIH/NCRR/RCMI 8G12MD007602 & 8U54MD007588This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mathematical model of megalin trafficking in differentiated proximal tubule cells
Authors: Shipman Katherine E. , Long Kimberly R. , Rbaibi Youssef , Baty Catherine J. , Weisz Ora A. 
Published: June 2021

The polarized epithelial cells that comprise the proximal tubule (PT) have a specialized apical endocytic pathway that allows for high‐capacity endocytosis which is necessary to recover essential nutrients and to maintain a protein‐free urine. Megalin, a multi‐ligand receptor at the apical surface of the epithelial cells, binds proteins in the ultrafiltrate and internalizes them via receptor‐mediated endocytosis. Ligands are sorted from receptors in endocytic compartments, and the receptors are recycled back to the surface. The molecular identities of the compartments involved in sorting and recycling in PT cells and the kinetics of megalin trafficking through them are unknown. When the endocytosis in the proximal tubule is dysfunctional, low molecular weight (LMW) proteinuria results. LMW proteinuria is often an early sign of kidney damage and is observed in many clinical settings, including genetic disorders, diabetes, sickle cell disease, and after renal transplantation. A significant barrier to understanding the regulation of receptor‐mediated apical endocytosis of filtered proteins has been the lack of a highly differentiated cell culture model that retains the organization and high capacity of the PT apical endocytic pathway. We previously discovered that OK cells cultured under continuous fluid shear stress develop morphological and functional features similar to that of the PT in vivo, including high apical endocytic capacity and increased megalin expression. We present an ordinary differential equation (ODE) model of megalin trafficking describing surface and internalized pools of megalin with kinetic parameters estimated from experiments using this system. Using biochemical techniques, we have estimated endocytic and recycling rates and the half‐life of surface megalin. The model is capable of achieving a steady‐state with a much larger pool of internalized megalin compared to surface within a range of realistic parameters; this is consistent with observations made by our biochemical assays and by indirect immunofluorescence of endogenous megalin. Future work includes estimated surface delivery kinetics and defining the structure and markers of the apical endocytic pathway in OK cells and mouse kidney sections using quantitative imaging. With these data, our model can be expanded and used to predict changes in megalin trafficking in response to changes in filtration rates, hormones, and in disease states.Support or Funding InformationNIH R01 DK101484, R01 DK100357This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Training Heart Failure Patients with Reduced Ejection Fraction Attenuates their Muscle Metaboreflex and Lowers Muscle Sympathetic Nerve Activity at Rest and During Mild Dynamic Exercise
Authors: Notarius Catherine Frances , Millar Philip J. , Keir Daniel A. , Murai Hisa , Haruki Nobuhiko , O'Donnell Emma , Marzolini Susan , Oh Paul , Floras John S. 
Published: June 2021

We have shown that muscle sympathetic nerve activity (MSNA) is elevated at rest in patients with heart failure due to reduced ejection fraction (HFrEF) and, in contrast to healthy subjects, increases during moderate dynamic 1‐leg exercise. We hypothesized that exercise training in HFrEF may reduce MSNA during both mild and moderate intensity 1‐leg dynamic exercise and static handgrip; attenuate the muscle metaboreflex; and improve skin blood flow. We studied 27 stable, medicated HFrEF patients (6 women; mean age 65 ± 2 SE [range 42 to 80] years; mean left ventricular ejection fraction 30 ± 1% [range 12–40]); of either ischemic (n=18) or non‐ischemic (n=9) etiology, both before and after 6 months of cardiac rehabilitation (aerobic exercise for 45 minutes, 5 times per week at 60–70 % of VO2peak); plus 18 healthy, age and sex‐matched, medication‐free volunteers (6 women; mean age 57 ± 2 [range 48 to 72]). Before and after training, we assessed VO2peak (open‐circuit spirometry); the skin blood flow (SBF) response to reactive hyperemia (laser flowtometry); and fibular MSNA (microneurography) at rest (n=18), during 1‐leg cycling (2 min each unloaded and at 50% of VO2peak, n=16) and, to assess the muscle metaboreflex, during post‐handgrip ischemia (PHGI) after 2 min of 30% static handgrip (HG). In HFrEF, pre‐training VO2peak and skin vasodilatation were lower (P<0.001) and resting MSNA higher compared to controls (P=0.01). Exercise training improved VO2peak by 3.0±1.0 ml·kg−1·min−1 (P<0.001) and increased the SBF vasdilatory response in HFrEF to a mean value similar to controls (P=0.78). Relative to pre‐training, resting MSNA decreased by 6.0±2.0 bursts/min (P=0.01, N=18) and 7.3±3.4 burst/100 heartbeats (P=0.04). During 1‐leg cycling, MSNA decreased in control (P=0.01) but increased in HFrEF (P<0.001). Exercise training attenuated MSNA burst frequency and incidence during unloaded (P=0.04) but not loaded cycling (P=0.34). The rise in MSNA burst frequency during HG in HFrEF was unaffected by training, but its elevation during PHGI was abolished (P<0.05). We conclude that the exaggerated metaboreflex of HFrEF is attenuated by exercise training. This may contribute to a lower MSNA during mild but not moderate intensity cycling.Support or Funding InformationSupported by Heart and Stroke Foundation of Ontario and Canadian Institutes for Health ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.