High-dose testosterone and dehydroepiandrosterone induce cardiotoxicity in rats

2015 ◽  
Vol 35 (5) ◽  
pp. 562-572 ◽  
Author(s):  
E Emer ◽  
O Yildiz ◽  
M Seyrek ◽  
S Demirkol ◽  
T Topal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Locomotor Activity ◽  
Muscle Strength ◽  
Left Ventricular ◽  
Oxidative Stress Marker ◽  
High Dose ◽  
Cell Nuclei ◽  
Myocardial Fibers ◽  
The Impact

The aim of this study is to assess cardiotoxic effect of testosterone (TES) and dehydroepiandrosterone (DHEA) in Sprague Dawley rats. We compared the impact of subacute (14 days) and subchronic (90 days) administration of suprapharmacologic doses of TES and DHEA on body weight, locomotor activity, muscle strength, echocardiographic parameters, heart histopathology, and oxidative stress markers with the control group. Testosterone (10, 30, and 100 mg/100 g body weight) and DHEA (10 mg/100 g body weight) administration decreased the body weights and locomotor activity ( p < 0.05), and the combination of both increased muscle strength ( p < 0.05) in rats. In our histopathological evaluation, misshapen cell nuclei, disorganized myocardial fibers, and leukocytic infiltrates were observed in high-dose TES (100 mg/100 g)-treated rats, especially on day 14. On day 90, mild changes such as misshapen cell nuclei, disorganized myocardial fibers, and leukocytic infiltrates were observed in TES and DHEA-treated groups. According to our echocardiographic study on day 14 and day 90, TES, especially at high doses, induced increase in left ventricular posterior wall diameter and ejection fraction ( p < 0.05). In this study, blood oxidative stress marker malondialdehyde was increased slightly but not significantly in TES and DHEA groups. On the other hand, antioxidant enzymes such as SOD and glutathione peroxidase (GSH-Px) levels were slightly but not significantly increased in TES and DHEA groups. These data demonstrate that the potential risk to cardiac health due to exogenous androgen use may be related to oxidative stress in rats.

scholarly journals Liraglutide protects cardiac function in diabetic rats through the PPARα pathway

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Qian Zhang ◽  
Xinhua Xiao ◽  
Jia Zheng ◽  
Ming Li ◽  
Miao Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Cardiac Dysfunction ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Serum Adiponectin ◽  
Diabetic Rat ◽  
Lv Function ◽  
High Dose ◽  
And Oxidative Stress

Increasing evidence shows that diabetes causes cardiac dysfunction. We hypothesized that a glucagon-like peptide-1 (GLP-1) analog, liraglutide, would attenuate cardiac dysfunction in diabetic rats. A total of 24 Sprague–Dawley (SD) rats were divided into two groups fed either a normal diet (normal, n=6) or a high-fat diet (HFD, n=18) for 4 weeks. Then, the HFD rats were injected with streptozotocin (STZ) to create a diabetic rat model. Diabetic rats were divided into three subgroups receiving vehicle (diabetic, n=6), a low dose of liraglutide (Llirag, 0.2 mg/kg/day, n=6), or a high dose of liraglutide (Hlirag, 0.4 mg/kg/day, n=6). Metabolic parameters, systolic blood pressure (SBP), heart rate (HR), left ventricular (LV) function, and whole genome expression of the heart were determined. Diabetic rats developed insulin resistance, increased blood lipid levels and oxidative stress, and impaired LV function, serum adiponectin, nitric oxide (NO). Liraglutide improved insulin resistance, serum adiponectin, NO, HR, and LV function and reduced blood triglyceride (TG), total cholesterol (TC) levels, and oxidative stress. Moreover, liraglutide increased heart nuclear receptor subfamily 1, group H, member 3 (Nr1h3), peroxisome proliferator activated receptor (Ppar) α (Pparα), and Srebp expression and reduced diacylglycerol O-acyltransferase 1 (Dgat) and angiopoietin-like 3 (Angptl3) expression. Liraglutide prevented cardiac dysfunction by activating the PPARα pathway to inhibit Dgat expression and oxidative stress in diabetic rats.

scholarly journals A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: the MET-REMODEL trial

2019 ◽  
Vol 40 (41) ◽  
pp. 3409-3417 ◽  
Author(s):  
Mohapradeep Mohan ◽  
Shaween Al-Talabany ◽  
Angela McKinnie ◽  
Ify R Mordi ◽  
Jagdeep S S Singh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Coronary Artery Disease ◽  
Body Weight ◽  
Coronary Artery ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Haemoglobin A1c ◽  
Metformin Treatment ◽  
Artery Disease

Abstract Aim We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. Methods and results We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference −1.37 (95% confidence interval: −2.63 to −0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study. Conclusion Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.

scholarly journals A Novel Wistar Rat Model of Obesity-Related Nonalcoholic Fatty Liver Disease Induced by Sucrose-Rich Diet

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Maria Luíza R. P. Lima ◽  
Laura H. R. Leite ◽  
Carolina R. Gioda ◽  
Fabíola O. P. Leme ◽  
Claudia A. Couto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Physical Training ◽  
Fatty Liver Disease ◽  
Density Lipoprotein ◽  
Oxidative Stress Marker ◽  
Nonalcoholic Fatty Liver ◽  
The Impact

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is not fully understood, and experimental models are an alternative to study this issue. We investigated the effects of a simple carbohydrate-rich diet on the development of obesity-related NAFLD and the impact of physical training on the metabolic abnormalities associated with this disorder. Sixty Wistar rats were randomly separated into experimental and control groups, which were fed with sucrose-enriched (18% simple carbohydrates) and standard diet, respectively. At the end of each experimental period (5, 10, 20, and 30 weeks), 6 animals from each group were sacrificed for blood tests and liver histology and immunohistochemistry. From weeks 25 to 30, 6 animals from each group underwent physical training. The experimental group animals developed obesity and NAFLD, characterized histopathologically by steatosis and hepatocellular ballooning, clinically by increased thoracic circumference and body mass index associated with hyperleptinemia, and metabolically by hyperglycemia, hyperinsulinemia, hypertriglyceridemia, increased levels of very low-density lipoprotein- (VLDL-) cholesterol, depletion of the antioxidants liver enzymes superoxide dismutase and catalase, and increased hepatic levels of malondialdehyde, an oxidative stress marker. Rats that underwent physical training showed increased high-density lipoprotein- (HDL-) cholesterol levels. In conclusion, a sucrose-rich diet induced obesity, insulin resistance, oxidative stress, and NAFLD in rats.

scholarly journals The Benefits of Fasting to Improve Health Conditions and to Prevent Cardiovascular Disease

Jurnal NERS ◽  
2020 ◽  
Vol 14 (3) ◽  
pp. 383
Author(s):  
Wahyu Sukma Samudera ◽  
Gracia Victoria Fernandez ◽  
Rahmatul Fitriyah ◽  
Hidayat Arifin ◽  
Shenda Maulina Wulandari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Cardiovascular Disease ◽  
At Risk ◽  
Body Weight ◽  
Endothelial Dysfunction ◽  
Fasting Blood Glucose ◽  
Abdominal Circumference ◽  
Oxidative Stress Marker ◽  
Amyloid A

Introduction: Fasting is defined as the voluntary abstinence from eating for variable time intervals and it has been associated with potential beneficial impacts on human health. The study was to review the benefits of fasting on cardiovascular health in humans with or without cardiovascular disease.Methods: The databases search was done using the keywords ‘fasting’ and ‘cardiovascular system’ using Scopus, Science Direct and ProQuest, limited to between 2013 and 2019 for publication year. A total of 3.619 articles were obtained and 15 articles involving experimental and non-experimental studies were used as the reference material.Results: The findings showed that in people who are healthy, fasting can reduce the inflammatory markers (IL-1 & IL-6, TNF-α), the oxidative stress marker (Malondialdehyde), body weight, abdominal circumference, fasting blood glucose, LDL, triglyceride and blood pressure. In people at risk or with cardiovascular disease, fasting can reduce body weight, body mass index, abdominal circumference, fat percentage, blood pressure, triglyceride, the biomarker of inflammation (serum amyloid A), the biomarker of oxidative stress (protein carbonyl), the biomarker of endothelial dysfunction (asymmetric dimethylarginine) and increase the vascular endothelial growth factor.Conclusion: Based on these findings, fasting can improve the health condition of people at risk or with cardiovascular disease by improving the risk factors such as blood pressure, overweight and endothelial dysfunction. In people who are healthy, fasting can be used for the prevention of cardiovascular disease by helping to maintain their weight, blood pressure, LDL and triglyceride within the normal limits.

Impact of anthocyanin-rich whole fruit consumption on exercise-induced oxidative stress and inflammation: a systematic review and meta-analysis

2019 ◽  
Vol 77 (9) ◽  
pp. 630-645 ◽  
Author(s):  
Taylor K Bloedon ◽  
Rock E Braithwaite ◽  
Imogene A Carson ◽  
Dorothy Klimis-Zacas ◽  
Robert A Lehnhard
Keyword(s):  
Oxidative Stress ◽  
Systematic Review ◽  
Inflammatory Marker ◽  
Data Extraction ◽  
Meta Analysis ◽  
Cochrane Collaboration ◽  
Oxidative Stress Marker ◽  
Exercise Induced ◽  
The Impact ◽  
And Oxidative Stress

Abstract Context Supplementing with fruits high in anthocyanins to reduce exercise-induced oxidative stress and inflammation has produced mixed results. Objective This systematic review and meta-analysis aims to discuss the impact of whole fruits high in anthocyanins, including processing methods and the type and amount of fruit, on inflammation and oxidative stress. Data Sources PICOS reporting guidelines and a customized coding scheme were used to search 5 databases (SPORTDiscus, Science Direct, Web of Science [BIOSIS], Medline [Pubmed], and the Cochrane Collaboration) with additional cross-referencing selection. Data Extraction A random-effects meta-analysis was used to measure effects of the fruit supplements with 3 statistics; the QTotal value based on a χ2 distribution, τ2 value, and I2 value were used to determine homogeneity of variances on 22 studies (out of 807). Outliers were identified using a relative residual value. Results A small significant negative summary effect across the sum of all inflammatory marker outcomes (P < 0.001) and a moderate negative effect for the sum of all oxidative stress marker outcomes (P = 0.036) were found. Moderator analyses did not reveal significant (P > 0.05) differences between subgrouping variables. Conclusions Results indicate that consumption of whole fruit high in anthocyanins can be beneficial for reducing inflammation and oxidative stress.

Bevacizumab Allows Preservation of Liver Function and its Regenerative Capacity after Major Hepatectomy

2019 ◽  
Vol 19 (11) ◽  
pp. 1388-1398
Author(s):  
Amparo Valverde ◽  
Rubén Ciria ◽  
Javier Caballero-Villarraso ◽  
Patricia Aguilar-Melero ◽  
Gustavo Ferrín ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Liver Regeneration ◽  
Major Hepatectomy ◽  
High Dose ◽  
Histopathological Analysis ◽  
Liver Resections ◽  
Tnf Α ◽  
Toxicity Analysis ◽  
The Impact

Background: Parallel to the safety of liver resections, new chemotherapy drugs have emerged for the control of liver metastases. However, there is unclear evidence about the combination of intensive BVZ-therapy and extended resections. The main aim was to analyse the impact of Bevacizumab (BVZ) in terms of liver safety and tolerability in two experimental models: a basal-toxicity situation and after major hepatectomy. Methods: Eighty male-Wistar rats were grouped as toxicity analysis (sham-operated rats-OS-) and regenerationafter- surgery analysis (hepatectomy rats-H-). Eight further subgroups were created according to sacrifice (6- hours-6h- or 24-hours-24h-) and dose (μg) of BVZ (none, 100, 200, 400). Several measurements were performed, including biochemical serum samples, histopathological analysis, cytokines (IL-6, TNF-α, TGF-β), oxidative-stress (GSH/GSSG, ATP), lipid-peroxidation (TBARS) and epidermal and vascular endothelium growth-factors (EGF and VEGF). Results: In the toxicity analysis, safe results with BVZ were observed, with no significant differences among the groups. A trend towards a lower oxidative status was observed in the OS 6 h-100, -200 and -400 versus the OS 6 h-none group. Similar results were observed in the hepatectomy model, with stable oxidative-stress-index and IL-6, TNF- α, and TGF- β levels. Despite higher lipid peroxidation status, overall regeneration was preserved. As expected, VEGF was almost undetectable in BVZ-treated groups after resection, but not in the non-resection group. Conclusion: It was concluded that liver status was not impaired by BVZ even at the high-dose. Similarly, liver regeneration after extended hepatectomy in BVZ-treated animals was well-preserved. Extended liver resections may be encouraged in BVZ-treated patients due to its excellent tolerability and good liver regeneration status.

Liver Damage Produced by Malnutrition is Improved by Dietary Supplementation in Mice: Assessment of a Supplement based on Buriti (a Cerrado Fruit) and Dairy by-Products

2021 ◽  
Vol 11 ◽  
Author(s):  
Audrey Handyara Bicalho ◽  
Fabio Ribeiro do Santos ◽  
Daniele Cristina Moreira ◽  
Luis Paulo Oliveira ◽  
Amanda Souto Machado ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Liver Damage ◽  
Low Cost ◽  
Dietary Supplementation ◽  
Food Supplement ◽  
Food Supplementation ◽  
Body Weight Reduction ◽  
The Impact ◽  
By Products

Background: Malnutrition induced by dietary restriction produces several metabolic changes that affect body weight, the digestive system, and annex organs, including the liver. Malnutrition generates a pro-inflammatory state and increases oxidative stress. The liver is one of the vital organs of our body, so it is necessary to analyze the impact of food supplementation on the repair of possible changes that may occur in this organ due to malnutrition. Aims: To evaluate the effects of an inexpensive supplementation derived from Buriti and dairy by-products on liver recovery in malnourished mice, focusing on the expression of oxidative stress-related genes, as well as biochemical and histological parameters. Methods: Swiss mice were divided into six groups and submitted to two treatment phases: food restriction, for malnutrition onset; and renutrition, with mice being fed different diets. Results: Our results indicate that dietary supplementation was successful in recovering liver damage caused by malnutrition in animal models. The new supplement has been shown to recover liver damage with similar or superior results compared to the commercial reference supplement on the market. Conclusion: Our work presents a new composition of low cost food supplement based on buriti and milk derivatives, tested and proven to be effective in the treatment of malnutritvion. The improvements were proven through the recovery of body weight, reduction of inflammation and oxidative stress.

Cardiac aging is regulated by autophagic disorder mediated by chronic inflammation via the Rubicon/NOX4 pathway

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Kamihara ◽  
Y.K Bando ◽  
T Murohara
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Chronic Inflammation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Cardiomyocyte Hypertrophy ◽  
Autophagic Flux ◽  
Cardiac Aging ◽  
Ventricular Ejection Fraction ◽  
The Impact

Abstract Background and introduction Aging is known to one of the primary causes of heart failure, in particular in the case of heart failure with preserved left-ventricular ejection fraction (HFpEF). Interestingly, recent evidences demonstrated that DNA damage occurred in aging causes autophagic disorder that contributes to aging phenotype via Rubicon (Run domain Beclin-1 interacting and cysteine-rich containing protein) in non-cardiac tissues. Purpose To elucidate whether aging-related autophagic disorder may lead to myocardial remodeling via chronic inflammation by Rubicon activation. Methods As an aging model with DNA injury, we employed mice model of progeria (mouse model of Werner syndrome that was generated by amino acid mutation exhibiting the functional deletion of DNA helixase; WRN-K577M). Results Cardiac aging markers (PARP-1, p53 and γ H2AX), and apoptosis (TUNEL) were augmented in WRN-K577M (male 18 week-old) as compared to the wild type counterpart. Consistently, cardiac oxidative stress that was measured by DHE was elevated in WRN-K577M with significant increase in oxidative stress enhancer NOX4. WRN-K577M exhibited cardiomegaly and diastolic left-ventricular (LV) dysfunction with preserved systolic LV function. Histological analysis revealed that WRN-K577M exhibited enhanced cardiac fibrosis and cardiomyocyte hypertrophy. Consistently, DNA microarray revealed significant upregulation of sixteen genes, of which ontology was hypertrophy, fibrosis, inflammation. Changes in autophagic activity was assessed by use of LC3 turnover assay and autophagic flux was evaluated by application of pharmacological inhibitor of autolysosome fusion (chloroquine) and fluorescence indicators for monitoring turnover of autophagosome (DAP green) and autolysosome (DAL green) to specify the essential step(s) of the aging-induced changes in the autophagic flux of heart. The LC3 turnover assay revealed that autophagic turnover was pathologically increased in myocardium of WRN-K577M at baseline and chloroquine (50 microg/g body weight) had no effect in WRN-K577M. Furthermore, DAL-positive spots were decreased in cardiomyocytes of WRN-K577M at rest, indicating that the impairment of autophagic flux particularly via impaired lysosome fusion may be responsible for the augmented autophagic turnover in WRN-K577M. Furthermore, we tested the impact of Rubicon. Rubicon was upregulated in heart of WRN-K577M and, more interestingly, Rubicon was found to be co-localized specifically with NOX4 in heart. Using CRISPER-CAS9 system, we generated Rubicon-KD H9C2 and Rubicon-activated HEK293. Upregulation of Rubicon revealed augmented LC3II, p62 and Beclin1 similar to WRN-K577M and augmented oxidative stress and, in contrast, downregulation of Rubicon had no effect on autophagy markers. Conclusion(s) Rubicon, the dual regulator of autophagy and inflammation is essential for autophagic disorder occurred in cardiac aging and the related oxidative stress via NOX4. Funding Acknowledgement Type of funding source: None

Abstract 146: Glucagon-like Peptide-1 Receptor Activation Promotes Dual Benefits For Reversing Microvasculopathy And Mitochondrial Damage In Diabetic Heart.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Akio Monji ◽  
Yasuko K Bando ◽  
Toko Mitsui ◽  
Morihiko Aoyama ◽  
Hiroya Kawase ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Receptor Activation ◽  
Left Ventricular ◽  
Mitochondrial Damage ◽  
Wall Thickening ◽  
Mouse Heart ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Impact

PURPOSE: Glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex4) is a remedy for type 2 diabetes mellitus (T2DM). Ex4 ameliorates cardiac dysfunction in preclinical and clinical settings. However, it remains unclear whether the impact of Ex4 on cardiac remodeling in diabetic cardiomyopathy (DMC), of which primary characteristics are microvasculopathy and mitochondrial damage. Methods and Results: Diet-induced T2DM (DIO) mice and age- and gender-matched lean control mice were allocated into EX4 (24 nmole/kg/day for 40 days; DIO-Ex4 and LEAN-Ex4) and vehicle groups (DIO-veh and LEAN-veh). We first confirmed the GLP-1R expression in every single chamber of mouse heart by immunoblotting and PCR. Ex4 treatment ameliorated both systemic and cardiac insulin resistance without affecting body weight in DIO. Cardiac capillary density of DIO-veh was reduced compared to those LEAN-veh, which were reversed by Ex4 treatment. Tube formation assay and immunoblot analysis using culture endothelial cells revealed that Ex4 directly enhanced in vitro angiogenesis in a PKA/eNOS-dependent fashion. Systolic and diastolic left-ventricular (LV) dysfunctions observed in DIO-veh were restored by Ex4 with decline in LV wall thickening. Myocardial fibrosis detected using sirius-red staining and tissue oxidative stress detected by a fluorescence indicator DHE were attenuated in DIO-Ex4. Of note, analyses using transmission electron microscopy and a fluorescence indicator for damaged mitochondria (mitotracker red) revealed that Ex4 treatment reversed cardiac mitochondrial remodeling and increased healthy mitochondria. Ex4 treatment modulated cardiac oxidative stress balance by upregulating antioxidative molecules (SOD, thioredoxin, glutathione peroxidase) and reduction of NOX4 level; whereas it had no influence on NOX2 level. Conclusions: Ex4 enhances cardiac angiogenesis via GLP-1R-mediated activation of PKA/eNOS axis and accelerates reverses remodeling of myocardial mitochondria, at least in part, via its facilitating effects on antioxidative defense.

scholarly journals A Polyphenol-Rich Muscadine Grape Extract Inhibits HER + Breast Cancer and Protects Against Trastuzumab-Induced Cardiotoxicity

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 334-334
Author(s):  
Jessica Mackert ◽  
Patricia Gallagher ◽  
Elisabeth Tallant
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Tumor Growth ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Oxidative Stress Marker ◽  
Her2 Receptor ◽  
Ventricular Ejection Fraction ◽  
Her2 Breast Cancer ◽  
Muscadine Grape

Abstract Objectives Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is characterized by overexpression of the HER2 receptor. Although targeted HER2 drugs such as trastuzumab (TRZ) are effective for some patients, many patients experience resistance and cardiotoxicity, highlighting the need for additional therapies. The objective of this study was to determine the effects of a polyphenol-rich muscadine grape skin/seed extract (MGE) on TRZ-sensitive and –resistant HER2 + BC and TRZ cardiotoxicity. Methods Human HER2 + BC cells were treated with MGE and/or TRZ and proliferation was analyzed using the IncuCyte® ZOOM. Synergy was assessed using the Chou-Talalay method. Tumor growth and cardiotoxicity were measured in HER2 + xenografts treated with MGE and/or TRZ. TRZ-resistant JIMT-1 cells (2 × 106) were injected in the fourth mammary fat pad of female nude mice and, when tumors reached 50 mm3, mice were divided into four groups: control, MGE, TRZ, MGE + TRZ (n = 10/group, five week treatment). Cardiac parameters were measured using echocardiography and markers of proliferation/oxidative stress were measured by immunohistochemistry. Results The combination of MGE and TRZ inhibited proliferation to a greater extent than either agent alone and was synergistic in TRZ-sensitive SKBR3 cells at five dose combinations. MGE reduced TRZ-resistant JIMT-1 tumor volume by 35% (p ≤ 0.05); however MGE + TRZ inhibited tumor growth to a greater extent (62%) than either agent alone [combination vs. MGE (p ≤ 0.05); combination vs. TRZ (p ≤ 0.01)]. In tumors, MGE + TRZ reduced Ki-67 and activated AKT to a greater extent than MGE or TRZ alone [combination vs. MGE (p ≤ 0.05); combination vs. TRZ (p ≤ 0.0001)]. TRZ significantly reduced left ventricular ejection fraction and fractional shortening, which was prevented by MGE (p ≤ 0.01). Additionally, MGE significantly attenuated the 3-fold TRZ-induced increase in the oxidative stress marker 4-hydroxynonenal in the left ventricle (p ≤ 0.0001). Conclusions MGE inhibited the proliferation of HER2 + BC and was synergistic when combined with TRZ while protecting against TRZ cardiotoxicity. Thus, MGE may serve as an effective therapeutic either administered singly or in combination with TRZ for the treatment of HER2 + BC. Funding Sources Chronic Disease Research Fund.

Sign in / Sign up

Export Citation Format

Share Document