bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attenuation of FFA‐Induced Skeletal Muscle Insulin Resistance by Carnosic and Rosmarinic Acid
Authors: Hartogh Danja Den , Valvcheski Filip , Tsiani Evangelia 
Published: June 2021

Impaired insulin action in muscle leads to insulin resistance and Type 2 diabetes mellitus, a disease on the rise. Elevated blood free fatty acids (FFAs), as seen in obesity, are associated with insulin resistance and studies have shown increased serine phosphorylation of the insulin receptor substrate (IRS‐1) and reduced insulin‐stimulated glucose uptake in muscle cells exposed to FFA palmitate. A number of serine/threonine kinases including JNK, IKKβ, mTOR and p70 6SK have been implicated in serine phosphorylation of IRS‐1 and insulin resistance. On the other hand, activation of the energy sensor AMP‐activated protein kinase (AMPK) increases glucose uptake and has become an important target to counteract insulin resistance. We reported recently that rosemary extract (RE) increased skeletal muscle cell glucose uptake and activated AMPK. The polyphenols carnosic acid (CA) and rosmarinic acid (RA) are found in high concentration in RE and in the present study we investigated their effect on palmitate‐induced insulin resistant L6 muscle cells. Glucose uptake was measured using [3H]‐2‐deoxy‐D‐glucose and the signaling molecules involved were investigated by immunoblotting.Exposure of L6 myotubes to the FFA palmitate (P) (0.2 mM, 16 hours) resulted in significant reduction of insulin‐stimulated glucose uptake (I: 201±1.21% , P+I: 117±15.6% of control, P<0.001) indicating insulin resistance. Importantly, in the presence of 2 mM CA or 5 mM RA, the insulin‐stimulated glucose uptake was restored (CA+P+I: 185±7.8%, RA+P+I: 181±14.4% of control, P<0.001). Treatment with palmitate increased serine phosphorylation of IRS‐1, increased the phosphorylation/activation of JNK, mTOR and p70 6SK and significantly decreased the insulin‐stimulated phosphorylation of Akt. The effects of CA and RA on these signaling molecules are under investigation. Our data indicate that treatment with CA or RA attenuates the FFA‐induced muscle insulin resistance. These polyphenols may have potent effects against insulin resistance and deserve further study.Support or Funding InformationThe research was funded by the Natural Sciences and Engineering Research Council (NSERC) grant to ET.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Antidiabetic Effects of Hispidulin in Streptozotocin‐Induced Insulin Deficient Mice
Authors: Wang Yao , Alkhalidy Hana , Luo Jing , Liu Dongmin 
Published: June 2021

In both Type 1 and type 2 diabetes, pancreatic beta‐cell failure plays an important role in the deterioration of glycemic control. In this study, we investigated whether hispidulin, a naturally occurring flavone, can be used to ameliorate diabetes in an animal model of insulin deficiency. Here, we report that oral administration of hispidulin (20 mg/kg) alleviates streptozotocin‐induced hyperglycemia in C57/BL6 male mice. Hispidulin effectively mitigates postprandial and fasting hyperglycemia and glucose tolerance, which was associated with higher circulating plasma insulin concentrations and improved glucose stimulated‐insulin secretion (GSIS). In addition, treatment with hispidulin reduced expression of pyruvate carboxylase and glucose 6‐phosphatase in the livers. In vitro, hispidulin suppressed glucose production in mouse primary hepatocytes, but potentiated GSIS in insulin‐secreting cells and mouse islets. These findings suggest that hispidulin could be a dual action, natural compound that exerts antidiabetic action via promoting beta‐cell function and suppressing hepatic glucose production.Support or Funding InformationThe work was supported by grants from NCCIH of NIH (1R01AT007077, 1R01AT007566)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Defining the role of CEBP/α in Functional β‐cell mass
Authors: Smith Courtn J , Leifer Aaron H , Ray Jason D. , Tessem Jeffery Sivert 
Published: June 2021

Metabolic diseases, such as obesity and diabetes, continue to rise exponentially across the globe. More than 68.8% of adults are considered to be overweight or obese, with more than 14% of Americans suffering from diabetes. Prolonged states of hyperlipidemia and hyperglycemia are characteristic phenotypes of diabetes. Identifying genes involved in the regulation of blood glucose and adipogenesis are essential for establishing a more comprehensive treatment for diabetes. CCAAT‐enhancer binding protein‐α (CEBPα) has been shown to play a key role in hepatic regulation of blood glucose and adipogenesis. Inactivating CEBPα, results in dysregulation of adipose tissue browning and inhibition of glycemia regulation. These data demonstrate that CEBPα expression is necessary for energy metabolism. We have previously shown that the transcription factor Nkx6.1 is sufficient to upregulates genes necessary for inducing β‐cell proliferation, increasing cell survival and improving insulin secretion. Our previous microarray indicated a potential interaction between Nkx6.1 and CEBPα. We hypothesize that CEBPα is an intermediate which is necessary for Nkx6.1 to increase functional β‐cell mass. Here we demonstrate the effect of CEBPα mediated β‐cell proliferation, insulin secretion and cell survival. Furthermore, we demonstrate that knockdown of CEBPα downregulates c‐Fos, which is required for Nkx6.1 enhancement of functional β‐cell mass. These data demonstrate the role of CEBPα in increasing functional β‐cell mass.Support or Funding InformationADA 1‐17‐IBS‐101 to JSTThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Susceptibility of Mice Lacking Renin‐b to Chronic Angiotensin II Infusion
Authors: Nakagawa Pablo , Nair Anand , Zhang Shao Yang , Lu Ko‐Ting , Zanaty Mario , Gomez Javier , Grobe Justin L , Sigmund Curt D 
Published: June 2021

Previous experience to various hypertensive conditions enhances the response to subsequent hypertensive challenges. Importantly, the activation of the brain renin angiotensin system (RAS) is required for the sensitization to these hypertensive challenges. We previously reported that the brain‐specific renin isoform (Ren‐b) tonically inhibits the activation of the brain RAS and that ablation of Ren‐b (Ren‐b KO) results in brain RAS disinhibition leading to mild hypertension. Retrospective analysis of five cohorts of mice indicated that Ren‐b KO model exhibits a high degree of variability in blood pressure (BP) and heart rate, which may be attributed to the susceptibility to stress. Therefore, we hypothesized that Ren‐b KO mice are sensitized to a hypertensive challenge such as angiotensin II (Ang II). Wildtype (WT) or Ren‐b KO mice were infused with either vehicle or Ang II (400 ng/kg/min; sc) via osmotic minipumps for 4 weeks. All data was expressed as mean ± SE and unpaired t‐test was used for statistical analysis. P <0.05 was considered significant. Ang II significantly increased BP in both WT and Ren‐b KO to the same degree (WT+veh: 103±4 vs WT+Ang: 120±4 mmHg; p = 0.0143 (n=10–12) and KO+veh: 104±3 vs KO+Ang: 118±5 mmHg; p = 0.0291 (n=10–14)). Although the BP between Ren‐b KO and WT mice was elevated equally, Ang II induced an exaggerated suppression of plasma renin in Ren‐b KO compared to WT (WT+Ang: 14.8±2.1 vs KO±Ang: 7.2±2.6 ng/ml; p = 0. 0251; n=7–9). Ren‐b KO exhibited enhanced Ang II‐induced dipsogenic response (WT+Ang: 3.7±0.3 vs KO+Ang: 4.6±0.4 ml/day; p = 0. 0495; n=10–12) and exhibited elevated heart weight (WT+Ang: 4.8±0.2 vs KO±Ang: 5.2±0.1 mg/g of body weight; p = 0.026; n=10–12) concomitant with a 87% increase in cardiac collagen type I alpha‐2 mRNA expression (p = 0.0275; n=7–9). Altogether, this data indicates that in the presence of Ang II, Ren‐b KO exhibits susceptibility to cardiovascular disease including cardiac hypertrophy and fibrosis. After successive breeding and backcrossing Ren‐b KO mice at baseline developed a milder and more variable BP elevation compared to our initial cohorts. This suggests that epigenetic silencing or other physiological mechanisms, such as downregulation of peripheral RAS, might compensate for some, but not all, of the cardiovascular alterations driven by the genetic deletion of renin‐b. Studies of a conditional Ren‐b KO model will be used to elucidate the physiological and/or pathophysiological consequences of an acute downregulation of renin‐b in adulthood.Support or Funding InformationNHLBI PPG P01 HL084207This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Acute and Chronic Anti‐Hypertensive Effects of Plantaginis Semen on Spontaneous Hypertension Rats
Authors: Chen Ping Chen , Lue Sheng‐I , Chen Sih‐Pei , Lu Tzong‐Shi , Weng Ching‐Feng , Fu Yaw‐Syan 
Published: June 2021

Plantaginis semen (PS) is the seed of Plantago asiatica L., and it is widely used as a herbal medicine with antioxidant, diuretic and anti‐inflammatory effects. Hypertension is a cardiovascular disorder and it may lead to many cardiovascular diseases, such as stroke, cardiac hypertrophy, or heart failure. We focused on the acute and chronic anti‐hypertensive effects of Plantaginis semen extract (PSE) on spontaneous hypertensive rat (SHR) and our new inbred spontaneous phase‐1 hypertension (P1‐HT) modeling rats.We used the rats with age of 8~10 weeks. Under anesthesia, continuous femoral arterial pressure of SHR and P1‐HT rats were recorded by intravascular catheter for 5 minutes prior the drug administration. In acute anti‐hypertensive effect test, the rats were orally administered with 0.36 g/kg/ml of PSE that homogenized and suspended in distilled water. The arterial pressure of each rat was consecutively recorded for more than 1hr after drug administration. In chronic anti‐hypertensive effect test, we orally administered the rats with 0.36 g/kg/ml per‐day of PSE for 4 weeks and measured blood pressure. We used Students–t test and one‐way ANOVA to test the effects of PSE treatment on blood pressure.The pretreated mean arterial pressures of animals were 146±10mmHg in SHR rats, and 115±8mmHg in P1‐HT rats. The acute anti‐hypertensive effects of PSE could be observed within 15min after oral gavage and lasting more than 1hr. This acute effect of PSE could significant decrease the mean arterial pressure for 15mmHg on SHR rats, and 22mmHg on P1‐HT rats. The PSE treatment could slow down the heart rhythm significantly in both SHR and P1‐HT rats. The results of acute test of PSE indicate its anti‐hypertensive effects did not only act on diuretic pathway. In chronic tests, daily oral administrated with PSE did not change the pretreated reference value of blood pressure and its anti‐hypertensive effects.In conclusion, our new inbred P1‐HT modeling rats are more sensitive than SHR rats on anti‐hypertensive test of PSE. It may be suitable for other anti‐hypertensive drugs development testing. Oral administrated with PSE may have a rapid anti‐hypertensive effect, and can last for a period of time. Daily administration with PSE can be considered as a treatment strategy for hypertension.Support or Funding InformationNSYSUKMU107‐I001‐3This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
ATP release mediates the over‐activation of adaptive immune response associated with hypertension
Authors: Zhao Tuantuan , Li Yu , Bernstein Kenneth , Shen Xiao(Gregory) 
Published: June 2021

The cause of most hypertensive disease is unclear, but inflammation appears critical in disease progression. However, how an elevated blood pressure (BP) initiates inflammation is unknown and the effects of high BP on immune responses are unfathomed. To study this, we immunized angiotensin II (Ang II) induced hypertensive mice and normotensive mice with ovalbumin (OVA) and adjuvants for 7 days. 2‐fold more OVA‐specific CD8+ T cells were present in the blood (2.7 ± 0.23% vs. 1.2 ± 0.47%, P<0.05) and the spleen (2.62 ± 0.31% vs. 1.31 ± 0.17%, P<0.05) of hypertensive mice as compared to normotensive animals. Two models of autoimmune disease were studied to determine if the exaggerated T cell responses in hypertension translate into increased tissue pathology. RIP‐mOVA is a transgenic mouse line that expresses OVA in pancreatic islet β cells. These mice were made hypertensive with either Ang II or L‐NAME. When OVA‐specific OT‐I T cells were infused into RIP‐mOVA mice, the hypertensive mice had significantly more OT‐I T cells infiltration into the pancreas (AngII 75%, L‐NAME 73%, control 13%) and developed severer diabetes (Blood glucose: AngII 331, L‐NAME 315, control 168 mg/dl). Concanavalin A induced hepatitis was also significantly worsened by hypertension as compared to the pathology observed in normotensive mice. A critical difference in hypertensive mice was the upregulation of CD86 on antigen presenting cells (APCs) (MFI:1928 ± 24.01 vs.1798 ± 20.96, P<0.05). Plasma ATP levels rose as early as 3 days after the induction of hypertension and reach a peak level of 3 μM after 2 weeks of hypertension, which exactly parallel the kinetics of CD86 expression on APCs. Hydrolyzing ATP or blocking the P2X7 receptor normalized CD86 expression and eliminated hypertension‐induced T cell over‐activation. Further, blind analysis shows untreated hypertensive patients have substantially elevated plasma ATP levels (2.21 ± 0.99 μM, n = 27) compared to treated hypertensive patients (0.94 ± 0.34 μM, n = 17) or normotensive controls (0.63 ± 0.38 μM, n =30). A linear trend was observed between ATP levels and systolic BP and diastolic BP among all subjects. These studies indicate ATP and CD86 as loci to potentially control hypertension associated inflammation.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Obesity and Chagas Disease: Cardiovascular, Oxidative and Metabolic Aspects of this Relationship
Authors: Martins‐Pinge Marli Cardoso , Lucchetti Bruno Fernando Cruz , Lopes Fernanda Novi Cortegoso , Pinge‐Filho Phileno 
Published: June 2021

Chagas disease (CD) is one of the leading neglected tropical infectious diseases, and people living in endemic regions are at potential risk for developing CD. The incidence of obesity has been increasing lately in countries endemic to DC, leading to high blood pressure, insulin resistance, increased levels of inflammation and oxidative stress. This picture promoted by obesity may have effects on the development of CD. In the present study, we evaluated the influence of obesity on acute infection by Trypanosoma cruzi, on cardiovascular, inflammatory parameters and insulin resistance. Obese swiss mice, on the 70th day of life were submitted to intraperitoneal infection with 5×102 trypomastigote forms of the Y strain. The cardiovascular parameters were evaluated before and during infection. The parasitemia and the survival up to 30º dpi were analyzed. In the 13th dpi the tissue was collected. Cytokines were determined using commercial kit CBA. Nitric oxide (NO) was determined by the cadmium and Griess technique. The antioxidant capacity and levels of oxidative stress were determined by the ABTS, FRAP, NBT and TBARS assays. Obese animals had higher blood pressure. We observed a higher parasitemia in the infected obese group (OI) compared to the infected control (CI) on days 13 and 15 post infection. All animals in the OI group died until the 19th day after infection while 87.5% of the IC survived to 30º. We observed a drop in mean arterial pressure in OI from the 9th dpi remaining until the end of the evaluation. No changes in blood pressure were found in the IC group. An increase in plasma NO in adipose tissue and aorta in OI was observed. Higher concentrations of INF‐Y and MCP‐1, and a lower concentration of IL‐10 was observed in OI vs CI. It was found a lower insulin sensitivity in obese animals and accentuated after infection. Higher parasitic load was found in adipose and hepatic tissue, and increased levels of oxidative stress in cardiac, hepatic and adipose tissue in the OI group. Our results suggest that the association of obesity and CD during the acute phase promote greater damage to infected animals.Support or Funding InformationCAPES (felowship)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Extracellular Superoxide Dismutase (SOD3) Links Tumor Necrosis Factor‐alpha Receptor 1 to Integrin Signaling
Authors: Choi Hyehun , Raja Benjamin S , Miller Michael , Stark Ryan J , Lamb Fred S 
Published: June 2021

Tumor necrosis factor‐α (TNFα) signaling requires superoxide (O2•−) to be produced extracellularly by NADPH oxidase 1 (Nox1). Extracellular superoxide dismutase (ecSOD) can convert this O2•− to hydrogen peroxide (H2O2). ecSOD is anchored to the cell surface by interaction with either heparin sulfate proteoglycan via a heparin binding domain, or by binding to fibulin‐5 (Fib5), an extracellular matrix protein which interacts with integrin receptors. Fib5 binding does not activate integrins, but blocks interaction with other components of the extracellular matrix. The physiologic significance of ecSOD‐Fib5‐integrin interaction has not been well defined. We hypothesized that ecSOD regulates extracellular redox signaling of TNFα/Nox1 by modulating secondary effects on integrin signaling. We analyzed TNFα‐induced interleukin‐6 (IL‐6) production and NF‐κB activation in cultured vascular smooth muscle cells (VSMC). Knockdown of ecSOD by siRNA blocked TNFα‐mediated IL‐6 (siControl+TNFα 2922±354, si ecSOD+TNFα 952.5±99 pg/mL, p<0.05, n=8–9) and NF‐κB activation (siControl+TNFα 10.8±1.0, si ecSOD+TNFα 4.0±0.3 fold change, p<0.05, n=7). Similar inhibitory effects were observed following knockdown of Fib5 (IL‐6; siControl+TNFα 2372±123, siFib5+TNFα 1686±124 pg/mL, p<0.05, n=4. NF‐κB activation; siControl+TNFα 10.8±1.0, siFib5+TNFα 5.4±0.3 fold change, p<0.05, n=7). We next sought to determine how ecSOD affected integrin signaling. Focal adhesion kinase (FAK) and integrin‐linked kinase (ILK) are critical downstream effectors of integrin activation. TNFα induced phosphorylation of both FAK and Akt, which was used as a surrogate for ILK activation. This approach was validated by the ability of ILK inhibition (Cpd22; 3 μM) to prevent Akt phosphorylation. Both FAK and Akt phosphorylation in response to TNFα were inhibited by an anti‐integrin β1 antibody. Knockdown of ecSOD significantly enhanced TNFα‐induced phosphorylation of both FAK and Akt. FAK inhibition (FAK inhibitor 14; 2 μM) blocked while ILK inhibition (Cpd22; 3 μM) markedly potentiated NF‐κB activation. These results suggest that TNFα transactivates β1 integrins and therefore FAK and ILK in VSMCs. We speculate that ecSOD localizes H2O2 production to the vicinity of integrin receptors via physical association with Fib5 and provides tonic suppression of β1integrin receptor activation. Knockdown of either ecSOD or Fib5 would promote ILK‐dependent inhibition of NF‐κB activation and IL‐6 secretion which occurs via direct TNFR1‐dependent signaling.Support or Funding InformationAmerican Heart Association (16SDG30610002)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of living at moderate altitude on pulmonary vascular function and exercise capacity in mice with sickle cell anemia
Authors: Ferguson Scott Kohman , Stenmark Kurt R , Buehler Paul , Irwin David C. 
Published: June 2021

Exposure to high altitude worsens symptoms and crises in patients with sickle cell disease (SCD). However, it remains unclear if prolonged exposure to low barometric pressures exacerbates SCD etiologies or impairs quality of life. We tested the hypothesis that, relative to wild‐type (WT) mice, Berkley sickle cell mice (BERK‐SS) residing at sea level, mild (1609 m) and moderate (2438 m) altitude would have a higher rate of hemolysis, impaired cardiac function, and reduced exercise tolerance and that the level of altitude would worsen these decrements. Following 3 months of altitude exposure, right ventricular systolic pressures (RVSP) were measured (solid‐state transducer). In addition, the adaptive balance between pulmonary vascular endothelial nitric oxide synthase and endothelin was assessed in lung tissue to determine differences in pulmonary vascular adaptation and the speed/duration relationship (critical speed, CS) was used to evaluate treadmill exercise tolerance. At all altitudes, BERK‐SS mice had a significantly lower %Hct and higher total bilirubin and free hemoglobin concentration (P<0.05 for all). RVSPs in BERK‐SS were higher than WT at moderate altitude and when compared to BERK‐SS at sea level (P<0.05, for both). CS was significantly lower in BERK‐SS at mild and moderate altitude (P<0.05). BERK‐SS demonstrated exacerbated SCD complications and reduced exercise capacity associated with an increase in altitude. These results suggest that exposure to mild and moderate altitude enhances the progression of SCD in BERK‐SS mice compared to healthy WT cohorts and BERK‐SS mice at sea level and provides crucial information for the clinical counseling of SCD patients.Support or Funding InformationThis study was supported by the National Heart, Lung and Blood Institute Grants 1R01HL125642‐01A1 (Irwin DC), 1R01HL086680‐07 (Nozik‐Grayck E), 5P01HL014985‐38 (Stenmark KR), and T32‐HL007171 (Stenmark KR), Colorado Sickle Cell Treatment and Research Center (Hassell K and Nuss R).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.