bluuebunny/crossref_metadata_2025_split huggingface dataset:
AGE‐RAGE Signaling Is Intersected by Rap1a Crosstalk in Fibroblasts in Diabetic Hearts
Authors: Stewart James A. , Langford Jaslyn , Zhao Jia , Worsham Rebecca 
Published: November 2023

Rap1a is a member of the Ras GTPase superfamily that acts as a molecular switch coupling extracellular events to intracellular signaling. The purpose of this study was to identify a role for Rap1a in the AGE/RAGE signaling cascade. We hypothesized that Rap1a GTPase intersects the downstream signaling modulators of the AGE/RAGE signaling cascade to promote extracellular remodeling and fibroblast function in the diabetic heart. Initial observations demonstrated significantly elevated Rap1a protein expression levels in cardiac fibroblasts isolated from diabetic hearts. Therefore, a series of studies were performed to alter Rap1a activity and protein levels to determine the influence of Rap1a in AGE/RAGE signaling cascade. Cardiac fibroblasts were isolated from diabetic (db/db) fibroblasts and non‐diabetic (het) fibroblasts. A Rap1a‐EPAC agonist was used to increase Rap1a activity and protein levels resulting in elevated AGE/RAGE signaling markers, such as PKC‐ζ and ERK1/2 phosphorylation, α‐SMA, and RAGE protein levels. Furthermore, silencing Rap1a protein expression decreased PKC‐ζ and ERK1/2 phosphorylation, α‐SMA, and RAGE as a result of Rap1a siRNA treatment. These studies demonstrated that Rap1a crosstalk occurred in the AGE/RAGE cascade. Rap1a involvement in the AGE/RAGE cascade identifies a new molecular mechanism, which could further potentiate fibroblast differentiation and ECM remodeling in diabetes. Deactivation of this mechanism represents a potential therapeutic approach to regulate fibroblast phenotype changes, collagen accumulation, and RAGE expression.Support or Funding InformationThis research was supported by the American NIH Academic Research Enhancement Award (R15)(PA‐13‐313, JAS), and Department of Defense Peer Reviewed Medical Research Program ‐ Investigator‐Initiated Research Award PR150906 ‐ GRANT12018632, JAS.
Effects of Essential Oil on Fear Memory and the Immune Response: A Potential Alternative Therapy for Post Traumatic Stress Disorder (PSTD)
Authors: Moshfegh Cassandra , Swiercz Adam P , Hopkins Lauren , Hurr Chansol , Young Colin N , Marvar Paul J 
Published: November 2023

Chronic stress plays an integral role in activation and exacerbation of inflammation in the peripheral immune system. Peripherally circulating immune cells are also capable of crossing the blood‐brain barrier and can promote inflammation in the central nervous system (CNS), which has been suggested to contribute to mental health disorders, such as post traumatic stress disorder (PTSD). However, the association between fear memory and the immune system is not well characterized. Moreover, there are only two FDA‐‐approved medications currently for PTSD. Therefore we sought to examine orange essential plant oil (OEPO), previously been found to have CNS depressant‐‐like effects, on fear memory and immune cell activation in a mouse model of PTSD (Pavlovian Fear Conditioning). The treatment group (n=8) was administered 25% OEPO via olfactory exposure prior to and after fear conditioning. Mice exposed to 25% OEPO showed no difference in percent freezing during fear acquisition compared to controls. However, when tested for extinction retention 48 hours later the treatment group experienced a significant decrease in freezing behavior (17.1 ± 1.6 % (p < 0.01) versus control (3.67 ± 2.13%), suggesting that OEPO affects extinction of fear memory in mice. Next we examined the peripheral and central immune response following extinction of fear memory using flow cytometry analysis. A significant decrease in the number of effector memory T cells CD62loCD44hi 7.955(± 0.48)% was observed in the treatment group relative to control 12.05(± 0.708)% (p < 0.05). To evaluate the effect of OEPO on the central immune response, we performed an immunological challenge with intraperitoneal injected lipopolysaccharide (LPS) and assessed immune cell populations in the meningeal compartment. Our preliminary evidence suggest that LPS injected mice treated with OEPO for 2hrs have decreased CD45+CD11b+ cells 54.2% compared to LPS injected mice treated with water 68.7%. These data suggest that OEPO may modulate the neuroimmune response during fear memory recall. Further studies are required to determine the neuroimmune mechanism(s) responsible for the extinction of fear memory in OEPO treated mice.Support or Funding InformationNIH R00 HL107675‐‐03
The effects of lisinopril on the development of renal injury associated with prepubertal obesity
Authors: Pennington Alyssa Paige , McPherson Kasi , Williams Jan 
Published: November 2023

Prepubertal childhood obesity has emerged as an epidemic and major health problem in the United States. Recent studies suggest that that childhood obesity is associated with increased risk of renal injury in children. Approximately 37% of obese children develop microalbuminuria. However, an understanding of the mechanisms involved in prepubertal obesity‐mediated renal disease remains unclear due to lack of an appropriate animal model. In studies characterizing the Dahl salt‐sensitive leptin receptor mutant (SSLepRmutant) rat, we observed that this model mimics several features of prepubertal obesity (PPO strain). Recently, we reported that the PPO strain displays proteinuria and podocyte injury as early as 6 weeks of age independent of hyperglycemia and elevations in arterial pressure. The standard care of treatment for children whom suffer from PPO is an angiotensin converting enzyme inhibitor (ACEi).ObjectiveTherefore, in the current study, we examined whether treatment with lisinopril, an ACEi, prevents the early development of proteinuria in the PPO model.MethodsExperiments were performed on six week‐old Control (lean) and PPO rats that were either treated with vehicle or lisinopril and measured proteinuria at 6, 8, and 10 weeks of age.ResultsAt 6 weeks of age (baseline) proteinuria was significantly higher in the PPO strain versus the control rats (130±29 vs.14±3 mg/day, respectively). Treatment with lisinopril had no effect on the progression of proteinuria in control rats. However, lisinopril decreased proteinuria in PPO by 50%.ConclusionThese data indicate that treatment with lisinopril slowed the progression of proteinuria in PPO rats and suggest that the renin‐angiotensin plays important role in the development of progression of proteinuria in this novel model of PPO.Support or Funding InformationThis work was supported by the APS STRIDE Summer Research Fellowship (1 R25 HL115473‐01) awarded to A.P. This work was also supported by an AHA SDG 12DG9440034 and by the National Institute of General Medical Sciences of the National Institutes of Health under Award number P20GM104357 awarded to J.M.W.
Impact of treadmill exercise on endothelial function during estrogen deficiency in ovariectomized db/db female mice
Authors: Song Wencong , Huang Yu 
Published: November 2023

PurposeCardiovascular disease (CVD), obesity and diabetes are major health problem worldwide. The majority of diabetics died of cardiovascular and renal events, largely as the consequence of initial endothelial dysfunction.Postmenopausal women with type 2 diabetes experience higher risks for cardiovascular diseases than age‐matched men and pre‐menopausal women. Current drug therapies have limited effect on the CVD prevention and they also produce side effects and drug resistance. Physical exercise is gaining a growing attention in terms of preventive measure against vasculopathy in obesity and diabetes. This study aims to investigate the possible protective effects of regular physical exercise on vascular endothelial function in ovariectomized diabetic db/db mice.Methods and resultsWe created the ovariectomized (OVX) db/db mice to mimics the postmenopausal state in women with type 2 diabetes, and studied the effects of exercise on restoring of endothelial function and metabolic profile in the OVX db/db mice. Running exercise (10 m/min, 30 min/time, 3 times a week for 4 weeks) resulted in slight improvement of acetylcholine‐induced endothelium‐dependent relaxations without affecting endothelium‐independent relaxations induced by sodium nitroprusside in OVX db/db mouse aortas. Exercise also improved glucose metabolism and insulin sensitivity. qPCR analysis of mouse aortas shows that exercise increased the mRNA expression of SOD2 while it slightly reduced the mRNA of NOX4.ConclusionsThe preliminary results indicate that regular physical exercise is beneficial to increase anti‐oxidant defense, to improve endothelial function and to enhance insulin sensitivity during estrogen deficiency in OVX diabetic mice. Ongoing experiments will examine the impact of longer period of exercise and different exercise intensity on vascular function, oxidative stress and inflammation, and metabolic function in other metabolic organs such as liver and skeletal muscle.Support or Funding InformationResearch Grants Council of Hong Kong (CUHK2/CRF/12G, T12‐402/13N), National Natural Science Foundation of China (91339117)
A role for REDD1 on insulin‐stimulated signaling activation following acute treadmill exercise
Authors: Dungan Cory M , Williamson David L 
Published: November 2023

The protein, regulated in development and DNA damage 1 (REDD1), has been suggested to be a required molecule for normal insulin‐stimulated signaling, as a loss of REDD1 reduces insulin signaling, potentially through hyperactive mechanistic target of rapamycin (mTOR) signaling. Aerobic exercise inhibits mTORC1 activation and improves insulin signaling protein responses to insulin. Thus, the goal of this study was to determine if an acute bout of aerobic exercise was sufficient to improve insulin signaling in mice lacking REDD1. REDD1 wildtype (WT) and REDD1 knockout (KO) mice underwent an acute bout of treadmill exercise for 30 minutes at 20m/min on a 5% grade or remained sedentary. The plantar flexor complex group was then removed from the lower limbs before or after receiving acute insulin treatment (0.5 IU/kg BW) Changes to skeletal muscle insulin (IRS‐1 Y1222, Akt S473) and mTOR (4E‐BP1 S37/46, S6K1 T389) signaling intermediates, along with markers of acute aerobic exercise (REDD1, AMPK T172, ERK1/2 T202/Y204), were determined immediately after the exercise bout, before and after IP insulin treatment (10 min). Despite no effect of insulin, aerobic exercise significantly increased (p<0.05) REDD1 expression in the WT mice versus sedentary mice. As expected, there was no observable REDD1 protein expression in the KO mice. AMPK activation was significantly elevated (p<0.05) following the acute bout of exercise in both WT and KO versus sedentary mice, though no effect of insulin was observed. Conversely, a significantly greater reduction (p<0.05) in 4E‐BP1 and S6K1 activation was observed in the exercised KO mice versus the exercised WT mice, which then contributed to significantly greater responses (p<0.05 versus exercise+insulin WT mice) to insulin by the exercised KO mice. Lastly, a significantly greater activation (p<0.05) of IRS‐1 and ERK1/2 was observed in response to insulin in the exercise+insulin KO mice versus exercise+insulin WT mice. Our data show that an acute bout of aerobic exercise is sufficient to improve insulin‐stimulated signaling in the absence of REDD1, but REDD1 is still required for a normal insulin signaling response independent of exercise.Support or Funding InformationMark Diamond Foundation
Cardiac chronotropic competence to beta‐adrenergic stimulation in insulin resistance
Authors: Barreto Andre Sales , Macedo Fabricio Nunes , Araujo Joao Eliakim S. , Melo Vitor Ulisses , Dantas Cacia Oliveira , de Souza Siqueira Barreto Rosana , Guimaraes Adriana Gibara , de Souza Siqueira Quintans Jullyana , Quintans‐Junior Lucindo Jose , Santos Marcio Roberto Viana , Santana‐Filho Valter Joviniano 
Published: November 2023

Insulin resistance (IR) precedes clinical manifestation of diseases such as diabetes mellitus and hypertension and is associated with increased sympathetic modulation. However, in the dexamethasone‐induced IR no changes have been noted in heart rate (HR). Therefore, we evaluated the heart chronotropic competence through beta‐adrenergic agonist stimulation in dexamethasone‐induced IR. Young male rats were divided into two groups: Control (CT)(n=6) and IR (n=6). CT and IR groups received vehicle or dexamethasone (DEX) (2mg/kg/day) i.p during seven days, respectively. To confirm Insulin resistance, insulin tolerance test (ITT) was performed after 6h fasted. Left femoral artery and vein were cannulated to measure blood pressure (2 kHz sampling rate) and isoproterenol (4μg/kg) administration respectively, 24h before evaluation. IR group presented attenuated decrease in glycaemia during ITT (CT: 42.5 ± 5 vs IR: 110.7 ± 14), hypertension (CT: 100 ± 2 vs IR: 135 ± 9 mmHg) without heart rate changes. In addition, increased cardiac sympathetic modulation by spectral analysis (LF/HF ratio CT: 0.52 ± 0.03 vs IR: 0.69 ± 0.04 un). After beta‐adrenergic stimulation IR group showed lower variation from basal level (ΔHR CT: 179 ± 4 vs IR: 78 ± 5 bpm). The reduction in heart chronotropic competence observed in this IR model could be a defense mechanism due cardiac sympathetic over activity.Support or Funding InformationFapitec‐SE; CAPES; CNPq.
Endoplasmic reticulum stress associated with purinergic stimulation
Authors: Reyes Juan Pablo , Castillo‐Hernández Jesús Ramón , Maldonado‐Cervantes Martha Imelda , Maldonado‐Cervantes Enrique 
Published: November 2023

A number of evidences suggest that P2X7 receptors (P2X7R) stimulation is related to cytotoxic events and cell death, yet not so deleterious effects may also result in cellular stress, including endoplasmic reticulum stress. Here, we describe our approach into the study of P2X7R‐induced endoplasmic reticulum stress, using P2X7R‐expressing HEK‐293 cells and Thioflavin‐T as stress indicator. We present the results in our hands so far. We are just beginning in this approach and we estimate that feedback from other researchers in the hallmark of this Meeting could be much beneficial for our purposes.Support or Funding InformationThe present work was supported by Programa para el Desarrollo Profesional Docente (PRODEP)‐Apoyo a la Incorporacion de Nuevos PTC of Secretaria de Educacion Publica (SEP) from the Mexican Government under grant DSA/103.5/16/10419 and by Fondo de Apoyo a la Investigación (FAI) under grant C16‐FAI‐09‐20.20 from Universidad Autónoma de San Luis Potosí (UASLP), Mexico
Knockdown of angiopoietin‐like 2 mimics the benefits of intermittent fasting on weight loss and insulin sensitivity in mice
Authors: Pinçon Anthony , Martel Cécile , Bélanger Alexandre , Gillis Marc‐Antoine , Thorin‐Trescases Nathalie , Thorin Éric 
Published: November 2023

Obesity and elevated body fat are generally associated with a higher risk of metabolic diseases such as type 2 diabetes, but the mechanisms involved are not clear. Angiopoietin‐like 2 (ANGPTL2), a circulating pro‐inflammatory glycoprotein mainly secreted by adipose tissues, is now considered as a key mediator linking obesity to insulin resistance. Accordingly, high levels of ANGPTL2 in humans are associated with obesity and the development of diabetes, and in Angptl2−/− mice exposed to a high fat diet, body fat is lower and insulin sensitivity better than in wild‐type (WT) mice. Various approaches have been developed to promote weight loss and increase insulin sensitivity such as intermittent fasting, an efficient but strenuous lifestyle intervention that involves alternating cycles of fasting and eating. Our objective was to investigate whether the knockdown of ANGPTL2 in mice reproduces or improves the benefits of intermittent fasting in WT mice on weight and insulin sensitivity. Intermittent fasting (one day of fasting/one day of free access to food) for 4 months reduced (p<0.05) Angptl2 mRNA expression by 53% in adipose tissue from WT mice. Both intermittent fasting for 4 months and knockdown of ANGPTL2 similarly decreased (p<0.05) feeding efficiency by 55%, weight gain by 55%, liver (38%) and adipose (around 55%) tissue weights and similarly increased (p<0.05) insulin sensitivity (measured by the insulin tolerance test). All measured parameters were similar between WT mice fed with an intermittent fasting regimen and ANGPTL2 knockdown mice fed ad libitum, suggesting that knockdown of ANGPTL2 reproduces the benefits of intermittent fasting on weight loss and insulin sensitivity. Finally, intermittent fasting in ANGPTL2 knockdown mice did not further reduce weight gain, adipose tissue and liver weight, and did not further improve insulin sensitivity. We therefore propose that lowering ANGPTL2 could be a useful and promising strategy to limit obesity and prevent insulin resistance. The development of pharmacological inhibitors of ANGTPL2 is needed.Support or Funding InformationCanadian Institutes of Health Research
Identification of Novel Circadian Clock Target Genes Associated With Renal Pathophysiology
Authors: Gumz Michelle L , Solocinski Kristen , Cheng Kit‐Yan , Wu Gang , Hogenesch John , Montgomery Darrice , Alli Abdel A. 
Published: November 2023

Most aspects of physiological function exhibit circadian variation. Increasing evidence supports the importance of maintaining circadian rhythms for overall health. Disrupted circadian rhythms in sleep/wake patterns and blood pressure are strongly associated with negative cardiovascular outcomes. Less is known about the consequences of circadian disruption in other tissues, such as the kidney. It is well established that renal function exhibits a circadian pattern of oscillation. Large scale transcriptomic studies have demonstrated that the molecular circadian clock acts as a master regulator of gene expression in most tissues, including the kidney. In order to better understand the importance of this regulatory mechanism for renal function, we interrogated publically available databases. The goal of this study was to identify novel circadian clock target genes known to be associated with disease processes related to the kidney. Genes identified included Heat shock protein a5 (Hspa5), associated with diabetic kidney disease, salt‐inducible kinase 1 (Sik1), associated with hypertension and diabetic kidney disease, and Endothelin‐1 (Edn1), also associated with hypertension and diabetic kidney disease. In independent kidney tissue samples collected at two distinct time points over the circadian cycle from wild type male C57BL/6 mice, we confirmed time‐dependent regulation of these genes. Hspa5 mRNA exhibited a 2.5× difference in expression between noon and midnight in the renal cortex (P<0.05). Sik1 expression varied by 25% (P<0.05) in these samples. Edn1 mRNA expression varied by ~33% (P<0.05). Because altered expression of these genes is associated with diabetic kidney disease, we also tested whether timed regulation of renal function was disrupted in diabetic mice. Split urine collections were made in order to compare urinary sodium and potassium excretion during the night (mouse active phase) versus the day (mouse inactive phase). Consistent with previous reports, control mice exhibited significant day/night differences in urinary [Na] and [K] of 1.5 to 2 fold (P<0.05). In contrast, diabetic mice did not exhibit a day/night difference in urinary [Na] and [K]. Together these data suggest that the circadian clock mechanism is critical for regulation of normal gene expression in the kidney with consequences for normal circadian renal function.Support or Funding InformationNIH NIDDKUF Department of Medicine, Division of NephrologyAmerican Society of NephrologyUF Hypertension CenterT32 Grant # 2T32HL083810 AHA
Impaired blood pressure response in Btg2 mutant female rats
Authors: Hoffman Matthew J , Imam Sara , Schilling Rebecca , Takizawa Akiko , Grzybowski Michael , Geurts Aron , Dwinell Melinda R. 
Published: November 2023

Sex‐specific blood pressure loci were previously identified on chromosome 13 using SS‐BN13 congenic rat strains. Previous work identified Btg2 as a candidate gene for salt‐sensitive hypertension in female rats. Two small congenic SS‐BN13 lines were developed that differed by 23 Kb with only Btg2 residing within this region. The strain containing BN Btg2 allele had significantly higher mean arterial pressure (MAP) (186±3.1 mmHg) than SS Btg2allele in females (151±5.8mmHg). Subsequent qRT‐PCR analysis demonstrated significant difference in Btg2 expression between these strains in kidney cortex (Btg2BN: 1.8±0.2 fold change, Btg2SS: 0.4±.01). Based on this previous data we hypothesized that mutating Btg2BN would mitigate the elevated blood pressure response we had seen in rats with the Btg2BN allele. TALEN and CRISPR/Cas9 reagents were used to target exon 1 of Btg2 and generate three mutant lines on the SS‐BN13 congenic with Btg2BN allele: m7 (TALEN) with 44bp deletion, m11 (CRISPR/Cas9) with 3bp deletion and 1bp insertion, and m13 (CRISPR/Cas9) with 16 bp deletion. Following telemetry transmitter implantation, blood pressure was measured in male and female rats on low salt and during 21 days of 8% NaCl diet. On day 17 of high salt, urine was collected for determination of protein and microalbumin. After 21 days on high salt, female homozygous m7 mutant rats MAP was 8 mmHg higher compared to female wild type littermates (167±8mmHg vs. 175±7mmHg). Urinary microalbumin and protein measurement in these female rats demonstrated a similar trend both showing a 1.4 fold increase in homozygous compared to wild type (93±18mg/day vs.131±41mg/day, 135±21mg/day vs.186±54mg/day respectively). Normalized kidney weight showed a 6% increase in female homozygous versus wildtype animals (0.0118±0.0002g/g vs.0.0125±0.0004g/g). Male homozygous and wild type m7 rats were not different after 21 days of high salt for these phenotypes. Preliminary results in the m13 mutant Btg2 rats suggest similar trends in the female vs. male rats. Taken together, our hemodynamic, urinary and morphometric data suggest the m7 mutant Btg2 allele produces an impaired blood pressure and renal response in female rats.Support or Funding InformationFunding: The National Heart, Lung, and Blood Institute of the National Institutes of Health, R24HL114474