bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular Effects Following a Single Inhalation Exposure to Crude Oil Vapor
Authors: Krajnak Kristine , Mckinney Walter , Waugh Stacey , Hong Kan , Kashon Michael , Fedan Jeffrey 
Published: June 2021

Inhalation of crude oil vapor fumes has resulted in serious health effects in worker working in oil extraction, drilling, processing and refinement. These vapors can negatively affect functioning of the pulmonary, cardiovascular, central nervous, renal and reproductive systems. In this study, the effects of a single exposure to crude oil vapor on the peripheral and cardiovascular systems were assessed using a rat inhalation model. Rats received a single 6 hour long exposure to either filtered air or 300 PPM of total volatile organic compounds (TVOC) released from crude oil heated to 85°F, and the effects on the cardiovascular system were measured 1 and 28 days following the exposure. Inhalation of crude oil vapors resulted in reductions in diastolic and mean arterial blood pressures and baseline left ventricular diastolic pressure one day following the exposure. These changes in cardiovascular function were accompanied by a decreased vasoconstriction in response to the β‐adrenergic agonist, dobutamine, and an increase in hydrogen peroxide concentrations in the heart. There were also transient increases in the expression of the pro‐inflammatory factor, tumor necrosis factor‐α (TNFα) and hypoxia‐induced factor‐1 (HIF‐1), but reductions in the expression of interleukin‐6 and the apoptotic factor Bcl2 in the heart. There were no changes in the responsiveness of the ventral tail artery to phenylephrine‐induced vasoconstriction or acetylcholine induced re‐dilation. Twenty‐eight days following exposure, only the expression of TNFα was increased. The other inflammatory factors returned to baseline levels. Based on the results of this experiment, there are effects of crude oil inhalation on cardiovascular function that may be then result of transient hypoxia and longer‐term, low level of inflammation in the heart. Longer‐term exposures will determine whether the effects seen with an acute exposure are maintained, and lead to additional symptoms of cardiac dysfunction, and identify biomarkers that can be used to monitor these changes.Support or Funding InformationThis work was funded as part of the authors official duties as an employee at NIOSHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Metformin, Aminoguanidine, and Pyridoxamine on Methylglyoxal Induced Cardiac Myocytes Injury
Authors: Harvey Amanda , Ahmed Hafsa , Delgado Dean , Kim Alisa , Colangeli Julia , Sandu Robinderpal , Martorana Rose , Barsotti Robert , Young Lindon , Chen Qian 
Published: June 2021

In diabetics, formation of advanced glycation end (AGE) products has been closely associated with cardiovascular complications. In order to mitigate the injury caused by AGEs, it is critical to understand the influence of the AGE precursor methylglyoxal. Methylglyoxal is a glycation intermediate and it has been found to be elevated in the blood of diabetic patients. The impact of methylglyoxal on cardiac cells is not well elucidated. In this study, the effects of methylglyoxal on H9C2 myoblast cell viability were evaluated. Thereafter, methylglyoxal induced cell injury was investigated by co‐treatment of methylglyoxal with metformin, aminoguanidine hydrochloride, or pyridoxamine dihydrochloride. Cell viability was evaluated after incubation of drugs for 24 hours by measuring absorbance at 450 nm by using tetrazolium to differentiate metabolically active and inactive cells (e.g., CCK‐8 kit). We found that methylglyoxal (1200 μM) significantly reduced cell viability by 72±6% when compared to the untreated control (n=4, p<0.05). By contrast, co‐treatment of metformin (1–80 mM) significantly reduced methylglyoxal‐induced cell injury and increased cell viability to 69% – 122± 6% (n=4, p<0.05 vs. methylglyoxal) when compared to the untreated control. Similarly, aminoguanidine hydrochloride (250–1000 μM) treated cells significantly increased cell viability to 77% – 109±10% (n=4, p<0.05 vs. methylglyoxal) when compared to the untreated control. Additionally, pyridoxamine dihydrochloride (0.1–15 μM, n=4) showed dose‐dependent protection to increase cell viability. Highest pyridoxamine (15 μM) treated cells completely abolished methylglyoxal induced cell injury by increasing cell viability to 99± 4% (p<0.05 vs. methylglyoxal) when compared to the untreated control. However, when the three drugs were washed out from the medium prior to the addition of the methylglyoxal, the protective effects were lost and cell viability was reduced similarly as methylglyoxal (n=1). Administration of all three drugs alone did not affect cell viability after incubation for 24 hours. The preliminary data suggests that metformin, aminoguanidine hydrochloride, or pyridoxamine dihydrochloride, when incubated concurrently with a high concentration of methylglyoxal, protect cardiac cells from methylglyoxal‐induced cell injury. The mechanism underlying the protective effects will be further investigated.Support or Funding InformationThis study was supported by the Center for Chronic Disorders of Aging, the Division of Research and the Department of Bio‐Medical Sciences at Philadelphia College of Osteopathic Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Carvedilol Repurposing in Orofacial Pain: Preclinical Findings in Adult Zebrafish
Authors: Barros Adriana Rolim Campos , Santos Sacha Aubrey Alves Rodrigues , Matias Bruna Barbosa , Vieira‐Neto Antonio Eufrásio , Magalhães Francisco Ernani Alves , Júnior Otacilio Benvindo Deocleciano 
Published: June 2021

Carvedilol is a non‐selective β‐adrenergic antagonist that is used in the treatment of heart diseases. β‐blockers are known to have an anti‐inflammatory effect that contributes to its analgesic effect. Here we show the acute orofacial antinociceptive effect of carvedilol in adult zebrafish (Danio rerio). Acute nociception was induced by capsaicin (4.93 μM; TRPV1 agonist), formalin (0.1 %; TRPA1 agonist) or menthol (1.2 μM; TRPM8 agonist) into in the upper lip (5.0 μL) of adult wild (short‐fin phenotype) zebrafish. Corneal nociception was induced with hypertonic saline (TRPV1 agonist; 5.0 M NaCl; 5.0 μL) applied into the surface of the right or left eye of the fishes. Then, animals (n=6/group) were placed in a glass Petri dish (10 × 15 cm), divided into quadrants, and the nociceptive response was registered after capsaicin (10 – 20 min), formalin (0 – 5 and 15 – 30 min), menthol (0 – 10 min) or hypertonic saline (0 – 5 min) application. Zebrafish were pretreated by gavage (20 μL) with vehicle (Control; 3 % Tween 80) or carvedilol (0.03; 0.1 or 0.3 mg/mL) 60 min before induction. The effect of carvedilol on zebrafish locomotor behavior was evaluated with the open field test (0 – 5 min). Naive groups (n=6) were included. The interaction between carvedilol and TRPV1 was analyzed using molecular docking. The HEX software was used for molecular docking calculations and the direct action of carvedilol on TRPV1 was viewed using PyMOL v1.4.7. The experimental protocols followed the ethical guidelines of CONCEA (Brazilian Council for the Control of Animal Experimentation) and were approved by the UECE Animal Research Ethics Committee (#7210149/2016). Pre‐treatment with carvedilol (0.03 and 0.1 mg/mL) was associated with a reduction in nociceptive behavior induced by capsaicin and hypertonic saline (TRPV1 agonists; (*p<0.05 vs Control), but not by formalin, or menthol. Carvedilol per se promoted no alteration on the locomotor activity of zebrafish. In the docking experiments, the interaction between carvedilol and the TRPV1 channel showed high reproducibility. It was possible to observe a direct action of carvedilol on TRPV1 amino acids (Asn687, Asn687, Asn687, Asn687, Ala680 and Gly683). The results indicate the potential clinical application of carvedilol an inhibitor of orofacial nociception and that this effect may be due to the modulation of TRPV1 channel.Support or Funding InformationNational Council for Scientific and Technological Development ‐ CNPqCoordination for the Improvement of Higher Education Personnel ‐ CapesResearch Support Foundation of Ceará State ‐ FuncapEdson Queiroz Foundation ‐ FEQThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Treatment of aged mice with the mitochondria targeted antioxidative peptide SS‐31 protects against hypertension‐induced cerebral microhemorrhages
Authors: Tarantini Stefano , Kiss Tamas , Yabluchanskiy Andriy , Balasubramanian Priya , Csipo Tamas , Lipecz Agnes , Sonntag William Edmund , Csiszar Anna , Ungvari Zoltan 
Published: June 2021

Recent studies demonstrate that aging exacerbates hypertension‐induced cognitive decline, but the specific age‐related mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function. To determine whether aging exacerbates hypertension‐induced CMHs young (3 mo) and aged (24 mo) mice were treated with angiotensin‐II plus L‐NAME. We found that the same level of hypertension led to significantly earlier onset and increased incidence of CMHs in aged mice than in young mice, as shown by neurological examination, gait analysis and histological assessment of CMHs in serial brain sections. Our data suggest that aging promotes CMHs in mice likely by exacerbating hypertension‐induced oxidative stress and MMP activation. We found that hypertension increased mitochondrial free radical production in the wall of cerebral arteries. Treatment of aged mice with the mitochondria‐targeted antioxidative tetrapeptide SS‐31 exerted significant vasoprotective effects and significantly delayed the onset and reduced the incidence of CMHs. Thus, therapeutic strategies that reduce mitochondrial oxidative stress may be useful for the prevention of CMHs in the aged brain.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Age‐related alterations in gait function in freely moving male C57BL/6 mice: translational relevance of decreased cadence and increased gait variability
Authors: Tarantini Stefano , Yabluchanskiy Andriy , Fulop Gabor Aaron , Kiss Tamas , Perz Aleksandra , O'Connor Daniel , Johnson Emily , Sorond Farzaneh , Ungvari Zoltan , Csiszar Anna 
Published: June 2021

Age‐related gait dysfunction and balance disorders are a major cause of falls and injury in the elderly population. Epidemiological studies have shown that disturbances in gait coordination which manifest with age are associated with increased morbidity and mortality, impaired cognitive capacity, as well as reduced level of function and loss of independence. In geroscience mice are the most frequently used model system to test efficiency of anti‐aging interventions. Despite the clinical importance of age‐related gait abnormalities in older adults, the impact of aging on mouse gait coordination is not well documented in the literature. To characterize the effect of aging on mouse gait, we assessed gait function in young (3 month old) and aged (24 month old) freely moving C57BL/6 mice using the semi‐automated, highly sensitive, Catwalk XT system for quantitative assessment of footfall and motor performance. We found that aged mice exhibited significantly decreased cadence and increased stride time variability. Aging also tended to alter footfall patterns. In aged mice speed, swing speed, stride length, duty cycle, base of support, terminal dual stance, the regularity index and the gait symmetry index were unaltered. Thus, aging is associated with characteristic alterations in gait function in C57BL/6 mice, which could potentially be assessed as clinically relevant endpoints in geroscience studies testing the effects of anti‐aging interventions.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mir‐1976 Downregulation and Phosphorylation of LARP6 are Associated with Insulin‐like Growth Factor‐1 (IGF1)‐induced Collagen Upregulation in Vascular Smooth Muscle Cells
Authors: Danchuk Svitlana , Delafontaine Patrice , Higashi Yusuke 
Published: June 2021

Collagen content in atherosclerotic plaque is a hallmark of plaque stability. We have shown that insulin‐like growth factor‐1 (IGF1) increased collagen content in atherosclerotic plaques of Apoe−/− mice. We have identified LARP6 (La Ribonucleoprotein Domain Family, Member 6), a collagen mRNA binding protein, as a mediator of IGF1‐dependent collagen I upregulation and increased mature fibril formation in smooth muscle cells (SMCs), however specific mechanisms have not been elucidated yet. A total of six micro RNAs (miRs), including miR‐1976, have been shown to bind to LARP6 mRNA. In fact, miR‐1976 mimic (20 nM) decreased LARP6 by 67% and reduced procollagen I by 85% (both are P<0.05), indicating that miR‐1976 negatively regulates LARP6 expression. We found that IGF1 significantly downregulated miR‐1976 by 41±5% in SMCs after 3h of exposure. Moreover, miR‐1976 mimic inhibited IGF1‐induced LARP6 upregulation, suggesting that the downregulation of miR‐1976 mediates IGF1 upregulation of LARP6.It has been reported that LARP6 phosphorylation is critical for regulating translation of collagen polypeptides. To investigate whether IGF1 induces LARP6 phosphorylation, we assessed LARP6 electrophoretic mobility shift by SDS‐PAGE and immunoblotting. SMCs were serum‐starved and treated for 0–48h either with 10 ng/ml IGF1, or 2 ng/ml IFNy, or 2 ng/ml IL‐1b, or 2 ng/ml TNFa, or 10 ng/ml IL‐6. LARP6 protein was detected on immunoblots as a single 65kDa band in untreated SMCs. However, additional 67kDa LARP6 band was evident after 6h of cell treatment with IGF1 or with IL‐6. The density of 67kDa LARP6 band was gradually increased up to 18h of treatment. IGF1 and IL‐6 also increased expression levels of procollagen I and collagen I in a time‐dependent manner, with a peak at 18h. IFNy, IL‐1b, and TNFa did not induce 67kDa LARP6 band or increase in expression level of collagen in SMCs.Taken together, our data suggest that IGF1 promotes collagen expression by upregulating LARP6 levels via a downregulation of miR‐1976 and also by inducing phosphorylation of LARP6. Suggested mechanisms by which IGF1 induces collagen expression in vascular SMCs and thus potentially in atherosclerotic plaques would provide novel insights for a therapeutic approach increasing plaque stability.Support or Funding InformationNIH/NHLBI R01HL070241 (PD)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reduction of Vascular Reactivity with Dantrolene in Type 1 Diabetic Rats is Dose‐dependent
Authors: Roman Marie , Ramirez Jose , Torres Ricardo , Marrero Victor , Garcia Laura , Morales Myrna , Torres Hector , Crespo Maria J 
Published: June 2021

Diabetics have a greater predisposition for developing cerebral vasospasms (CVSPs) than nondiabetics, even when under glycemic control. The etiology of CVSPs is associated with increased vascular tone, secondary to augmented intracellular Ca+2 in vascular smooth muscle. Current pharmacological treatments are ineffective in reducing CVSPs. The combination of the ryanodine receptor blocker dantrolene (50 μM) and the Ca+2 channel blocker nimodipine significantly decreases vascular reactivity in streptozotocin (STZ)‐induced diabetic rats. In order to determine if the beneficial effects observed at 50 μM are also maintained at a much lower concentration with less potentially harmful secondary effects, we evaluated the vascular effects of 10 μM dantrolene, alone and in combination with 50 nM nimodipine. Dose‐response curves for the phenylephrine (PHE)‐induced contraction (0.1 nM to 10 μM) and acetylcholine (ACh)‐induced relaxation (1 nM to 10 μM) were performed on aortic rings from STZ‐diabetic rats, both before and after a 30‐minute incubation period with dantrolene alone or in combination with nimodipine. Whereas 50 μM dantrolene reduced PHE‐induced contraction by 47% in diabetic rats and 29% in controls, 10 μM dantrolene failed to reduce this parameter in either group. Moreover, 50 μM dantrolene reduced PHE‐induced contraction by about 80% in both diabetic and controls when combined with nimodipine. The combination of 10 μM dantrolene and nimodipine, however, does not increase the reduction of 35% in diabetic rats and 47% in controls obtained with nimodipine alone. In addition, only 50 μM dantrolene increased ACh‐induced relaxation by 50% (N=9, P<0.05) in diabetic rats. These results suggest that both, improved endothelial‐dependent relaxation and reduced vascular contraction with dantrolene are dosedependent. Thus, careful titration should be performed in order to achieve a significant reduction in hyper‐reactivity in both diabetics and nondiabetics.Support or Funding InformationThis work was supported by Grants from the National Institute of Health (MBRS‐RISE Grant R25GM061838), the NIMHD‐RCMI Program (Grant G12‐MD007600), and the Anesthesiology Department of the University of Puerto Rico‐School of Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Blockade of Cardiac Hypertrophy and Fibrosis by TGF‐Beta 1 Receptor Antagonist in Npr1 Gene‐Knockout Mice
Authors: Samivel Ramachandran , Subramanian Umadevi , Oakes Joshua M , Chen Helene , Zhao Hanqing , Gardner Jason D , Pandey Kailash N 
Published: June 2021

Genetic disruption of guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) gene (Npr1) in mice triggers cardiac hypertrophy, fibrosis, and remodeling associated with heart failure. However, the specific mechanisms of cardiac defects in Npr1 null mutant mice is not well understood. The objective of this study was to determine the mechanisms regulating the development of cardiac hypertrophy and fibrosis in Npr1 gene‐knockout mice. The Npr1 null mutant (Npr1−/−, 0‐copy), heterozygous (Npr1+/−, 1‐copy), and wild‐type (Npr1+/+, 2‐copy) mice were orally administered with transforming growth factor‐beta 1 (TGF‐β1) receptor antagonist GW788388 (1 mg/kg/day) for 28 days, the hearts were isolated, weighted, and used for quantification of hypertrophic and fibrotic markers using real time quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) and Western blot analyses. Together, systolic blood pressure (SBP), heart weight‐to‐body weight (HW/BW) ratio, and cardiac fibrosis were analyzed. HW/BW ratio was significantly higher in Npr1 knockout mice than wild‐type control mice. The Npr1−/− mice showed significant induction of cardiac hypertrophy and fibrosis with markedly induced expression of hypertrophic marker collagen‐1α (3.5‐fold) and fibrotic markers monocyte chemoattractant protein (4‐fold), connective tissue growth factor (CTGF, 5‐fold), alpha‐smooth muscle actin (α‐SMA, 4‐fold), and SMAD proteins (SMAD‐2, 5‐fold; SMAD‐3, 3‐fold) compared with wild‐type control mice. In addition, the expression of phosphorylated extracellular‐regulated kinase 1/2 (pERK1/2) proteins were also increased in Npr1−/−mice. On the other hand, Npr1−/−mice treated with GW788388 showed significant inhibition of cardiac hypertrophy and fibrosis and reduced expression of fibrotic markers and SMAD proteins compared to vehicle‐treated wild‐type mice. In contrast, the expressions of pERK1/2 proteins were unaffected in drug‐treated animals. The results of the present study suggest that development of cardiac hypertrophy and fibrosis in Npr1−/− mice is regulated independently through TGF‐β1‐mediated SMAD‐dependent pathways.Support or Funding InformationThis work was supported by NIH grants (HL057531 and HL062147).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
SGLT2 Inhibition Is Predicted to Reduce LV End Diastolic Pressure: A Mathematical Modeling Analysis
Authors: Basu Sanchita , Boulton David , Hallow Melissa Karen 
Published: June 2021

In the recent cardiovascular outcomes trials, Sodium Glucose Cotransporter‐2 Inhibitors (SGLT2i) were shown to reduce heart failure hospitalization, but the mechanisms underlying this effect remain unclear. While SGLT2i's direct mechanism of action is in the kidney, the consequences of its renal mechanisms may indirectly induce changes that improve cardiac hemodynamics. We sought to use a mathematical modeling approach to predict the effect of SGLT2i on cardiac hemodynamics in healthy and diabetic virtual subjects.We conjugated a mathematical model of cardiorenal hemodynamics and volume homeostasis with clinical measures of plasma and urinary sodium, water, and creatinine in healthy volunteers who were subjected to dapagliflozin for 7 days. We have shown in our previous study that accounting for direct SGLT2 inhibition, coupled NHE3 downregulation and osmotic diuresis, allowed the model to describe the renal response to SGLT2i. We then simulated the effect of SGLT2i on cardiac hemodynamics.Our simulations predicted a considerable decrease in left ventricle end diastolic pressure (LV EDP) as well as a small decrease in mean arterial pressure (MAP) from the baseline in healthy virtual subjects. In diabetic virtual patients, the predicted decrease in LV EDP was greater than that of healthy volunteers. Ejection fraction (EF) and cardiac output (CO) were minimally changed. While experimental validation is needed, a decrease in LV EDP, without a commiserate decrease in EF and CO, would be expected to reduce fluid congestion and edema, and may help explain how SGLT2i prevent the development of congestion and edema in patients at risk for heart failure. We are currently evaluating the expected effect of SGLT2i on cardiac hemodynamics in virtual patients with existing heart failure. This model provides a means for quantitatively understanding the link between SGLT2i's renal mechanisms and their consequent effects on the failing heart.Support or Funding InformationThis research is funded by AstraZeneca, Pfizer and Merck.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.