bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Statin on Chemotherapy‐Induced Cardiotoxicity
Authors: Enoma Efosa , Wei Lan , Chen Howard 
Published: June 2021

Tyrosine Kinase Inhibitors (TKIs) are chemotherapy agents that can damage cardiomyocytes resulting in cardiotoxicity and heart failure. TKIs target enzymes that control diverse biological pathways such as cell metabolism and apoptosis. Autophagy is a self‐degradative process involving the translocation of light chain 3 (LC3) proteins onto the autophagosome membrane, followed by fusion with lysosome for degradation. In cardiomyocytes, autophagy activation has been shown to be either protective or detrimental. We previously demonstrated autophagy to be cardioprotective of ischemia‐reperfusion injuries, presumably through maintaining cell homeostasis by removing damaged organelles such as mitochondria. Recent studies have shown that statins, HMG‐CoA reductase inhibitors commonly used to lower cholesterol levels, enhance cardiomyocyte autophagy. We hypothesize that TKIs disrupts cardiomyocyte autophagy, and autophagy activation protects cardiomyocytes from TKI‐induced toxicity. As a proof of concept, we chose the well‐established TKI dasatinib due to its high risk for heart failure in patients. We treated H9c2 rat myoblast cells with dasatinib either alone or in combination with commonly used statins: simvastatin, atorvastatin, pravastatin, and rosuvastatin. We performed MTT colorimetric assays on 96‐well plates to quantify H9c2 viability, and dual‐channel flow cytometry to assess autophagy levels with an autophagy detection nanoparticle (ADN) developed in‐house, and cell membrane integrity with propidium. We further confirmed autophagy protein, LC3, expression by western blot. After 24‐hour exposure, dasatinib significantly reduced H9c2 myocyte cell survival and ADN fluorescence. Atorvastatin and dasatinib co‐treatment significantly enhanced H9c2 survival. Interestingly, the reduction in cell death was associated with the restoration of H9c2 autophagy homeostasis, detected by ADN fluorescence. The autophagy increase was confirmed by western blot. Statin treatment thus causes a robust cytoprotective effect in H9c2 myocytes against dasatinib, presumably through autophagy activation.Support or Funding InformationFunding: R25‐HL007785, R00‐HL121152.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exosome Mediated Globular Adiponectin's Cardioprotective Role via the Adiponectin receptor‐dependent Uptake mechanism
Authors: Wang Yajing , Gan Lu , Xie Dina , Lau Wayne Bond , Liu Jing , Zhang Ling , Gao Erhe , Koch Walter , Ma Xinliang 
Published: June 2021

ObjectivesGlobular domain isotype adiponectin (gAPN) exerts cardioprotective effect against cardiac ischemia injury. T‐Cadherin (TCad) and adiponectin receptors are key molecules mediated adiponectin's cardioprotection. However, whether these receptors mediate the cardioprotective effects of gAPN, the isotype with more potent biological activity, most commonly utilized in metabolic/cardiovascular investigations, remains unclear.Methods and ResultsAdult male WT, AdipoR1KO, and TCadKO mice were subjected to MI, treated with vehicle or gAPN, and observed for 4 weeks. The cardioprotective effects of gAPN were abolished in AdipoR1 Knockout mice, but not Tcad, indicating that AdipoR1, but not Tcad, mediates gAPN cardioprotection. Unexpectedly, we observed that gAPN cardioprotection was significantly attenuated in animals pre‐treated with GW4869 (an exosome generation inhibitor). To further determine whether gAPN regulates exosome biological process, we investigated exosome's biogenesis and/or uptake and the precise involvement of AdipoRs., The effects of gAPN and HMW (high molecular weight APN isoform) upon exosome generation and uptake were determined on cardiomyocytes were isolated from adult AdipoR1KO and TCadKO mice. Surprisingly, cardiomyocyte exosome production increased markedly (8‐fold) when cells were treated with gAPN, but not with HMW. Moreover, gAPN increases cardiomyocyte exosome production in a receptor‐independent fashion, via regulation of the ESCRT‐multivesicular body (MVB) pathway. Furthermore, gAPN‐stimulated exosome uptake and cellular protection in WT cardiomyocytes were abolished in cardiomyocytes derived from AdipoR1KO, but not TCadKO, mice.ConclusionsThese data demonstrate that gAPN and HMW cardioprotection exhibits differential receptor dependence, and is mediated by distinct mechanisms. Whereas HMW protects the heart via TCad‐dependent mechanisms, gAPN promotes exosome biogenesis in a receptor‐independent fashion, and stimulating exosome uptake and cardioprotection in an AdipoR1‐dependent manner. Our results suggest gAPN is superior to HMW with respect to cardioprotection against ischemia heart injury, and represents a promising therapeutic strategy in patients with coronary artery disease.Support or Funding InformationNIH RO1, ADAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Protective Effects of Phosphodiesterase 5 Inhibitors "Sildenafil & Ordonafil” on Ischemia‐Reperfusion Injury
Authors: Khatib Said Younes 
Published: June 2021

Phosphodiesterase type‐5 (PDE‐5) inhibitors, Sildenafil (SILD), Vardenafil (VAR) and Ordonafil (ORD), have been developed for erectile dysfunction. Recently SILD and VAR were shown to have cardioprotective effect by reducing the infarct size in ischemic/reperfusion injury. To support the suggestion that this effect is a generalized "class" effect we decided to test the cardioprotective effect of ORD and to compare it to that of SILD. Isolated rabbit's hearts, perfused using Langendorff system, were subjected to 30 min of global ischemia followed by 2 hrs of reperfusion. At end of perfusion the heart was sliced into 5–6 cuts, 2 mm thick and incubated in 1 % triphenyltetrazolium chloride. The area of infarction and the whole left ventricle (LV) were measured by computer morphometry using image tool software. The infarct size was expressed as % of LV. Creatine kinase enzyme (CK) as a marker of infarction, was determined in the perfusate pre‐ and post‐ischemia by enzyme bioassay. The drugs, SILD or ORD at 1 mg/L, perfused the heart for 5 min before induction of ischemia. The results of both drugs showed significant cardioprotective effect and the infarct size ( as % of LV) was reduced from 38 ± 12 % in the control group to 5±2 and 9±6 %, mean±SD, n=6–8, P<0.004 for ORD and SILD respectively). Similarly the increase in CK was attenuated from 32 times increase in the control group to 20 times and 26 times for ORD and SILD respectively. Theses results support the notation that the class of PDE‐5 inhibitors has protective effect in the ischemic heart beside their effect in the treatment of erectile dysfunction.Support or Funding InformationDeanship of researchThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Kinetin is Sufficient to Accelerate Mitophagy Flux in H9c2 Cardiac Myoblast Cells
Authors: Nagaria Omar , Singh Suprit , Kabir Rizowana , Kobayashi Satoru , Kobayashi Tamayo , Liang Qiangrong 
Published: June 2021

The lysosomal degradation of dysfunctional mitochondria is vital for cellular health. Although widely known for their role in oxidative phosphorylation, mitochondria also generate reactive oxygen species (ROS) that are cytotoxic. Mitochondria themselves are susceptible to ROS damage, which can render them dysfunctional and eventually lead to various modes of cell death. Therefore, to maintain a healthy population of mitochondria, it is crucial for cells to eliminate injured mitochondria through the autophagy‐lysosomal pathway, a process termed mitophagy. Previous studies have identified Kinetin (KTN) as an activator of PTEN‐induced kinase (PINK‐1), a mitochondrial kinase that is activated in response to mitochondrial damage and orchestrates downstream mitophagy processes. While KTN has been shown to induce mitophagy in human‐derived neural cells, its role in cardiomyocytes remains unknown. In the present study, we tested the ability of KTN to induce mitophagy in H9c2 cardiac myoblast cells. The cells were treated with KTN, and a subset of cells was additionally treated with lysosomal protease inhibitors: pepstatin A (pepA) and E64d. Mitochondrial fractions were isolated and the expression levels of LC3‐II (Microtubule‐associated protein 1A/1B‐light chain 3), an established marker of autophagic vesicles, were analyzed using Western blotting. Our results showed that pepA/ E64d treatment led to a much larger increase in LC3‐II levels among KTN‐treated cells relative to the vehicle‐treated cells, suggesting that KTN was sufficient to accelerate mitophagy flux in cardiomyocytes. This result was confirmed by a novel dual fluorescent mitophagy reporter. Our lab is currently investigating whether KTN can protect cardiomyocytes against stress‐induced cellular injury through upregulation of mitophagy.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High‐fat Medium‐chain Triglyceride Diet Attenuates Weight Gain, but Does Not Affect Insulin‐stimulated Glucose Uptake in Male Rats
Authors: Brothwell Marisa J , Connolly Gavin , Sharma Naveen 
Published: June 2021

Recently, there has been increased dietary consumption of medium‐chain triglycerides (MCT; triglycerides containing fatty acids chains C6:0‐C12:0) for purported ergogenic and weight loss effects. Diets high in fat are known to contribute to insulin resistance, but the impact of high MCT‐based diets on glucose uptake and insulin signaling are not well‐known. Therefore, we investigated the effect of a high‐MCT diet on insulin‐stimulated glucose uptake in rat skeletal muscle. Male Sprague‐Dawley rats, ages 7–17 months, were assigned to one of 3 isocaloric dietary groups: 1) low‐fat control group (CON; 20% protein, 70% carbohydrate, 10% fat mostly from MCT), 2) high‐fat group (HF; 20% protein, 35% carbohydrate, 45% fat mostly from lard) and 3) high‐fat MCT group (MCT; 20% protein, 35% carbohydrate, 45% fat mostly from MCTs). All rats had ad libitum access to their respective diets and water for 8 weeks. Body masses and food consumption were recorded weekly. During the terminal study, a soleus muscle from eat rat was excised, split into equal thirds, and placed in vials containing physiological buffer including 1 of 3 insulin concentrations (0, 0.6, or 30nM). Muscles were then incubated in the presence of radioisotopes to determine glucose (2‐deoxyglucose; 2‐DG) uptake. Homogenates were also used for Western blotting to assess phosphorylation and abundance of key insulin signaling proteins. The MCT group consumed the least amount of food daily and gained the least weight at the end of 8wks. We observed a main effect of insulin (p<0.05) in regards to 2‐DG uptake, but no differences associated with diet. We found similar results regarding phospho‐AktSer473. We report that a high‐fat diet consisting of MCTs will lead to less weight gain compared to a high‐fat diet consisting of lard. However, the fat source did not affect insulin‐stimulated glucose uptake in isolated muscle, suggesting that diets high in MCTs may not improve insulin sensitivity compared to high lard‐based diets despite reduced weight gain. These results imply that a diet high in MCTs may translate to greater meal satiety and better weight maintenance, compared to other high‐fat and even lower‐fat diets.Support or Funding InformationOffice of Research and Graduate Studies and the Herbert H. & Grace A Dow College of Health Profession at Central Michigan UniversityThis 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 Nicorandil and Chronic Physical Exercise on Glycemia in Diabetic Rats Induced by Streptozotocin
Authors: Sánchez‐Duarte Elizabeth , Sánchez‐Duarte Sarai , Vera‐Delgado Karla S. , Montoya‐Pérez Rocío , Caudillo‐Cisneros Cipriana , Cordova Victor , Sánchez‐Briones Luis A. , Márquez‐Gamiño Sergio 
Published: June 2021

Diabetes is a chronic metabolic disease characterized by persistent hyperglycemia caused by a decrease or deficiency of insulin secretion and/or peripheral insulin resistance. Regular physical exercise could improves glucose metabolism and insulin sensitivity, which is essential for preventing diabetic complications. Moreover, there is evidence that the opening of ATP sensitive potassium (KATP) channels contributes to cytoprotective effects under metabolic stress, therefore KATP channels could be a therapeutic target in this disease. Thus, the purpose of this study was to assess the impact of the potential effects of nicorandil (KATP channel opener) after a chronic exercise training program on levels glicemic in diabetic rats.Male Wistar rats (23–25 days old) were randomly divided into six groups, among them: sedentary control, trained control, sedentary diabetic, trained diabetic, sedentary diabetic plus nicorandil, trained diabetic plus nicorandil. Diabetes was induced by a single streptozotocin injection (100 mg/kg body weight), animals with fasting blood glucose levels ≥ 250 mg/dL were considered as diabetic. Training comprised 8 weeks of treadmill running (30 minutes daily, 5 days/week); at week 4, nicorandil (3 mg/kg) was administered for to 4 weeks. Fasting blood glucose (FBG) level was recorded every week for 8 consecutive weeks. At the end of experimental protocol, insulin tolerance test (ITT) was evaluated in all groups, rats received a application of insulin (0.75UI/kg body weight), with blood samples drawn after 0, 30, 60, 90 and 120 min postinjection. Blood glucose response to ITT was calculated as area under the curve (AUC‐ITT) of the blood glucose excursion along 120 minutes after intra‐peritoneal insulin injection and correlated with the corresponding fasting values according to the trapezoidal method.Treatment with nicorandil and the chronic exercise exerted remarkable effects on hyperglycemic status in diabetic rats by decreases FBG levels (47.51± 10.2 %) and inducing significant increases in the insulin sensitivity (P< 0.05) compared with sedentary diabetic rats and trained diabetic rats. Our results suggest than opening KATP channels by nicorandil mediates potential benefits the chronic physical exercise on glycemic in diabetes.Support or Funding InformationWe thank Universidad de Guanajuato, Campus León. We acknowledge the financing PRODEP (Programa para el Desarrollo Profesional Docente en Educación Superior, ESD (511‐6/18‐8876).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sleepiness and Mortality Risk in Patients without Sleep Apnea
Authors: Lu Dongmei , St Louis Erik K. , Chahal C. Anwar , Covassin Naima , Mohamed Essa A. , Mansukhani Meghna P. , Xie Jiang , Lipford Melissa C. , Li Nanfang , Ramar Kannan , Caples Sean M. , Gay Peter C. , Olson Eric J. , Morgenthaler Timothy I. , Somers Virend K. 
Published: June 2021

BackgroundThe prevalence of excessive daytime sleepiness (EDS) in the general population is reported to be 9 to 28 percent. Various social and biological factors have been reported to contribute to the development of EDS, such as cardiovascular disease, metabolic disorders as well as socioeconomic status. Medically, EDS is associated with poorer prognosis in patients with sleep disorders. However, whether sleepiness is an independent negative prognostic indicator in patients without sleep apnea is poorly understood.ObjectiveTo evaluate the relationship between self‐reported excessive daytime sleepiness (assessed by Epworth Sleepiness Scale) and the risk of all‐cause mortality in patients without obstructive sleep apnea (OSA).MethodsWe performed a retrospective cohort study in a large registry of patients seen at the Mayo Clinic Center for Sleep Medicine between November 17th, 2009 and April 15th, 2017. All patients received a diagnostic polysomnography and had completed Epworth Sleepiness Scale (ESS). The primary outcome of all‐cause mortality risk was computed using the Kaplan‐Meier analysis and Cox‐proportional hazard model with age, sex, body mass index (BMI), baseline comorbidities and sleep measurements as confounders.ResultsA total of 2746 non‐OSA patients were identified. The overall median age (IQR) was computed as 53 (40, 63) with 45% of patients identifying as males. The median follow‐up time was approximately 2.3 years. In a univariate analysis, daytime sleepiness was associated with the female sex, younger age and higher BMI. No significant differences were observed in vascular related diseases between sleepy and non‐sleepy patients. EDS was not significantly associated with all‐cause mortality with an adjusted hazard ratio of 1.23 (95% CI 0.86, 1.76; p=0.257). In addition, there was no significant association of EDS and the risk of all‐cause mortality even after stratifying by sex, age and BMI in non‐OSA patients.ConclusionEDS is not associated with all‐cause mortality in non‐OSA patients. Further prospective studies are needed to confirm this finding.Support or Funding InformationThis research was supported by NIH HL65176 and NIH HL114024.
Kaplan–Meier survival curve of 8 years all‐cause mortality of non‐OSA patients with and without excessive daytime sleepiness (EDS) at baseline.imageKaplan–Meier survival curve of 8 years all‐cause mortality of non‐OSA patients with and without excessive daytime sleepiness (EDS) at baseline.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Association between type 2 diabetes mellitus risk factors with breast cancer in Mexican women
Authors: Soto‐Piña Alexandra Estela , Cardoso‐Peña Elías , de Jesús Garduño‐García Jose , Gómez‐Villanueva Ángel , López‐Chávez Emilio 
Published: June 2021

Breast cancer is a neoplasic disorder in women worldwide and the comorbidity with type 2 diabetes mellitus (T2DM) is increasing. However, it is not clear how T2DM risk factors such as high waist circumference, hyperglycemia (>100 mg/dL) and dyslipidemia participate in the appearance and development of breast cancer. The aim of this study was to compare T2DM risk factors between women with and without breast cancer. This study included two groups of women 40–60 years old: the control group (n=3) included women with BIRADS 1, 2 and 3 mammograms, and the group with breast cancer (n=3) comprised women in stages I and II of breast cancer. Data were analyzed using Mann‐Whitney test. The results showed that women with breast cancer presented a non‐significant increase (p=0.40) in the mean concentration of glucose (92.7 ±8.7 mg/dL) compared to the control group (80.0 ±4.3 mg/dL). The mean percentage of glycosylated hemoglobin in women with breast cancer was 5.3 ±0.5 % and the one in the control group was 5.4 ±0.1 %. Additionally, women with breast cancer showed a wider waist circumference (98.7 ±13.2 cm) than the control participants (83.3 ±5.2cm); however, these variables were not significantly different. In summary, there were no significant differences between women with and without breast cancer in the assessed T2DM risk factors; nonetheless, there are clear trends towards altered value limits in these risk factors, therefore, further analyses increasing the sample number are required to confirm the association between T2DM risk factors with breast cancer in this population of women.Support or Funding InformationSupport provided by Universidad Autónoma del Estado de México.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 Modest Weight Gain On Circulating Free Fatty Acids
Authors: Pinzon Jeffer , Medina Inojosa Jose R. , Covassin Naima , Huang An , Somers Virend K. , Jensen Michael D. , Singh Prachi 
Published: June 2021

BackgroundIncreases in circulating free‐fatty acids (FFAs) contribute to obesity‐associated cardiometabolic pathology and may be considered a surrogate marker for adipose tissue dysfunction. However, alterations in FFA metabolism resulting from modest weight gain have not been previously evaluated.ObjectiveExamine the changes in FFAs during modest weight gain in healthy individuals and to investigate the relationship between regional fat depots.Study DesignWe evaluated the effects of overfeeding in 8 healthy, non‐obese participants (4 men; age 29 ± 5.7 years; BMI: 25.1 ± 2.1 kg/m2). FFA concentrations were measured using liquid chromatography/mass spectrometry under fasting conditions and during oral‐glucose tolerance test (OGTT) at baseline and after 8 weeks of weight gain. Prior to the baseline and weight gain visits, subjects consumed isocaloric macro‐nutrient stable diet for three days (50% carbohydrate, 35% fat and 15% protein). Body composition and regional fat depots were assessed using dual‐energy X‐ray absorptiometry and abdominal computed tomography scans.ResultsOverfeeding was accompanied by 3.9 ± 1.6 kg weight gain (p=0.01) resulting from 2.9 ± 0.9 kg (p=0.01) increase in fat mass and 1.0 ± 0.9 kg (p=0.04) increase in fat‐free mass. Compared to baseline, fasting FFA (439 ± 162 μM vs. 368 ± 123 μM, p=0.55) and area under the curve (AUC) for FFA during OGTT (23319 ± 11686 μM. min−1 vs. 20495 ± 4847 μM.min−1, p=0.55) did not change with weight gain. However, at 120 min. of the OGTT FFA were significantly greater after weight gain (60 ± 18 μM vs. 77 ± 34 μM, p=0.04). We found a negative relationship between relative changes in visceral fat area and FFA at 120 min of glucose challenge (rho=−0.76, p=0.03). Furthermore, relative changes in fasting FFA and AUC for FFA during OGTT with weight gain were associated with baseline total fat mass (fasting FFA: rho=0.76, p=0.03; AUC FFA: rho=0.81; p=0.02) and baseline abdominal fat area (fasting FFA: rho=0.76, p=0.03; AUC FFA: rho=0.79; p=0.02).ConclusionsModest weight gain does not alter fasting FFA or overall FFA response to oral glucose challenge. However, our data suggest development of early stages of adipose tissue insulin resistance which is apparent via lesser suppression of FFA at 120 min. of OGTT. Furthermore, the relationships between fasting FFA, AUC‐FFA, and baseline fat mass suggest that individuals with high baseline adiposity may be more susceptible to develop adipose tissue insulin resistance with weight gain.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.