Combination of Vildagliptin and Ischemic Postconditioning in Diabetic Hearts as a Working Strategy to Reduce Myocardial Reperfusion Injury by Restoring Mitochondrial Function and Autophagic Activity

Purpose: Diabetic hearts are resistant to cardioprotection by ischemic-postconditioning (IPostC). Protection of diabetic hearts and finding related interfering mechanisms would have clinical benefits. This study investigated the combination effects of vildagliptin (Vilda) and IPostC on cardioprotection and the levels of autophagy and mitochondrial function following myocardial ischemia/reperfusion (I/R) injury in type-II diabetic rats. Methods: Diabetes was established by high fat diet/low dose of streptozotocin and lasted for 12 weeks. The diabetic rats received Vilda (6 mg/kg/day, orally) for one month before I/R. Myocardial regional ischemia was induced through the ligation of left coronary artery, and IPostC was applied immediately at the onset of reperfusion. The infarct size was assessed by a computerised planimetry and left ventricles samples were harvested for cardiac mitochondrial function studies (ROS production, membrane potential and staining) and western blotting was used for determination of autophagy markers. Results: None of Vilda or IPostC but combination of them could significantly reduce the infarct size of diabetic hearts, comparing to control (P<0.001). IPostC could not significantly affect p62 expression level in diabetic hearts, but pre-treatment with Vilda alone (p<0.05) and in combination with IPostC (p<0.01) more significantly decreased p62 expression in comparison with corresponding control group. The expression of LC3B-II and LC3BII/LC3BI as well as mitochondrial ROS production were decreased significantly in treatment groups (p<0.001). Mitochondrial membrane depolarization was significantly higher and mitochondrial density was lower in untreated diabetic I/R hearts than treated groups (p<0.001). IPostC in combination with vildagliptin prevented the mitochondrial membrane depolarization and increased the mitochondrial content more potent than IPostC alone in diabetic hearts. Conclusion: Combination of vildagliptin and IPostC in diabetic hearts was a well-working strategy to reduce myocardial I/R damages by restoring mitochondrial membrane potential and ROS production and modulating the autophagic activity in I/R hearts

Effect of Cinnamon extract on COX-2 gene expression level in liver and lipid profile alterations in serum of healthy broiler chickens and those infected with E. coli

The use of herbal medicine instead of antibiotics for treatment of livestock and poultry disease could have many beneficial implication due to their multiplex activities. This study has investigated the effects of cinnamon extract on cyclooxygenase-2 (COX-2) gene expression level in liver and lipid profile alterations in serum of healthy and Escherichia coli infested broiler chickens. Ninety Ross-308 broilers in healthy or E.coli-infected groups were received normal diet or diet supplemented with cinnamon extract in concentrations of 100 or 200 mg/kg of diet. E. coli suspension (108cfu/ml) was injected subcutaneously after 12 days of cinnamon administration. Seventy-two hours after E. coli injection, blood samples were taken for analysis of lipid profile alterations in serum, and then liver tissue samples were obtained for detection of COX-2 gene expression using real-time PCR. Infection with E. coli significantly decreased the levels of COX-2 gene expression as well as some variables of lipid profile including triglyceride level as compared with the control group (

Troxerutin, a Bioflavonoid, Improves Oxidative Stress in Blood of Streptozotocin-Induced Type-1 Diabetic Rats: Troxerutin improves oxidative stress in diabetic rats

Type 1 diabetes is a chronic disease characterized by the body's inability to produce insulin due to destruction of the beta cells. There is increasing evidence that reactive oxygen species (ROS) play a major role in the development of diabetic complications. The purpose of this study is to investigate the effects of troxerutin administration on oxidative stress markers in blood of STZ-induced diabetic rats. Male Wistar rats were divided into 4 groups as: control (con), control-troxerutin (CON-TRX), diabetes (Dia), diabetic-troxerutin (DIA-TRX). Type 1 diabetes was induced by injection of streptozotocin (STZ) (i.p, 55mg/kg) and lasted for 10 weeks. Animals received oral administration of troxerutin (150 mg/kg) for 4 weeks. At the end of study, malondialdehyde (MDA, the main product of lipid peroxidation), activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) were measured spectrophotometrically. Induction of diabetes with STZ resulted in increased MDA levels and decreased blood antioxidant capacity as compared with those of controls (P&lt;0.05). Pre-treatment of diabetic rats with troxerutin significantly decreased the levels of MDA (P&lt;0.01) and increased the activity of antioxidant enzymes SOD, GPX, and CAT compared to untreated-diabetic groups. Troxerutin had no significant influence on non-diabetic rats. These findings showed that troxerutin may prevent oxidative complications of diabetic circumstances by elevating antioxidant enzymes activities and reducing lipid peroxidation

Effect of amlodipine on blood and aortic tissue concentration of endothelin in male rabbits receiving atherogenic diet

Background: Different factors are involved in the induction and progress of atherosclerosis. One of these factors is endothelin-1. Since, in atherosclerotic vessels, there are certain obvious changes, with abnormality in the transfer of calcium ions, some researchers have suggested that calcium channel blockers can slow down the process of atherosclerosis. In this study, we evaluated the effects of amlodipine and/or a high cholesterol diet on the blood and aortic concentration of endothelin in rabbits. Materials and Methods: Thirty-six male New Zealand white rabbits were divided into four groups: the normal control group, normal diet plus amlodipine group, high-cholesterol diet group, and high-cholesterol diet plus amlodipine group. After 8 weeks all animals were anesthetized and blood or tissue samples were collected. Results and Conclusions: Eight weeks of amlodipine treatment significantly reduced total cholesterol, low density lipoproteins (LDL), and triglycerides (TG) in the hypercholesterolemic diet group. Although amlodipine treatment tended to enhance HDL/LDL and HDL/cholesterol ratios in the mentioned group, these effects were not statistically significant. The observed significant increase in plasma high density lipoprotein cholesterol (HDL-C) and decrease in TG is considered to be the main effect of amlodipine treatment on the serum lipid profile in the control group. The plasma level of endothelin-1 in the atherosclerotic model group was significantly increased as compared to the control group ( P < 0.01). After treatment with amlodipine, the ET-1 level reduced significantly in the control and high-cholesterol diet rabbits ( P < 0.01). A high-cholesterol diet induced atherosclerotic lesions and thickening of the intima in the thoracic aorta. Amlodipine consumption reduced atherotic injuries in high-cholesterol diet rabbits. There were no lesions in the normal diet groups or the normal diet with amlodipine group. High cholesterol causes increase in plasma and tissue endothelin. Amlodipine treatment reduced the levels of total cholesterol, LDL, and TG and, in a high lipid intake situation reduced endothelin levels in plasma and aortic tissue. Our data shows that amlodipine treatment may be considered as one of the important interventions for prevention and regression of atherosclerosis

Effect of ischemic postconditioning on myocardial protection in patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass

Introduction: Reperfusion injury is a well-known phenomenon following restoration of the coronary circulation after coronary artery bypass grafting (CABG) that impairs myocardial function. In order to control the severity of this injury, we aimed to investigate the effect of a new conditioning strategy namely ischemic postconditioning (IPOC) along with controlled aortic root reperfusion (CARR) on myocardial protection in CABG surgery with cardiopulmonary bypass. Methods: In a doubled blind clinical trial study, 51 patients undergoing first-time elective CABG were randomly divided in three groups: CARR, IPOC, and combination of IPOC and CARR. At the end of procedure and just before aortic cross-clamp removal, reperfusion was started as following: In CARR-receiving groups, the reperfusion was started with low perfusion pressures for 10 minutes, and in IPOC-receiving groups, three cycles of 1 minute episodes of ischemia separated by 1 minute episodes of reperfusion was applied as postconditioning protocol. Left ventricular ejection fraction (EF) (by echocardiography), inotrope requirement index, and myocardial arrhythmias were measured up to 72 hours after operation. Results: Echocardiography revealed that the recovery of EF after operation in IPOC group was significantly higher than those of two other groups (P < 0.05). Inotropic support requirement was significantly lower in IPOC groups. In addition, the incidence of atrial and ventricular arrhythmias after opening of aortic clamp and in intensive care unit (ICU) as well as recovery time of cardiac rhythm upon reperfusion were lowered by administration of IPOC, as compared with CARR group. Conclusion: The study suggests that IPOC may provide clinical benefits against reperfusion injury in patients undergoing CABG surgery and maintain the post ischemic left ventricular performance

Effects of Cinnamon extract on biochemical enzymes, TNF-α and NF-κB gene expression levels in liver of broiler chickens inoculated with Escherichia coli

Abstract: Infection with Escherichia coli (E. coli) is a common disease in poultry industry. The use of antibiotics to treat diseases is facing serious criticism and concerns. The medicinal plants may be effective alternatives because of their multiplex activities. The aim of this study was to investigate the effects of cinnamon extract on the levels of liver enzymes, tumor necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB) gene expressions in liver of broiler chickens infected with E. coli. Ninety Ross-308 broilers were divided into healthy or E. coli-infected groups, receiving normal or cinnamon extract (in concentrations of 100 or 200mg/kg of food) supplemented diets. E. coli suspension (108cfu) was injected subcutaneously after 12 days cinnamon administration. Seventy-two hours after E. coli injection, the blood samples were taken for biochemical analysis of liver enzymes in serum (spectrophotometrically), and liver tissue samples were obtained for detection of gene expression of inflammatory markers TNF-α and NF-κB, using real-time PCR. Infection with E. coli significantly increased the levels of TNF-α and NF-κB gene expressions as well as some liver enzymes including creatine-kinase (CK), lactate-dehydrogenase (LDH), alanine-transferase (ALT) and aspartate-transferase (AST) as compared with control group (P<0.05). Pre-administration of cinnamon extract in broilers diet (in both concentrations) significantly reduced the tissue levels of TNF-α and NF-κB gene expressions and enzymes CK and ALT in serum of broiler chickens inoculated with E. coli in comparison with E. coli group (P<0.05 and P<0.01). The levels of LDH and AST were significantly decreased only by 200mg/kg cinnamon extract in infected broilers. The level of alkaline-phosphatase (ALP) was not affected in any groups. Pre-administration of cinnamon extract in diets of broiler chickens inoculated with E. coli could significantly reduce the gene expression levels of pro-inflammatory mediators and liver enzymes activities, thereby protecting the liver against this pathologic condition

The Role of Mitochondrial ATP-Sensitive Potassium Channels in Cardioprotective and Anti-Inflammatory Effects of Troxerutin in Myocardial Reperfusion Injury: Mitochondrial ATP-sensitive Potassium Channel as Target of Troxerutin in Cardioprotection

A major clinical challenge in ischemic heart disease is the prevention of myocardial injury following ischemia/reperfusion (I/R). Application of natural pharmaceuticals seems to be clinically interesting due to their multiplex activities. Protective effects of troxerutin (TXR) in myocardial I/R injury have been ever demonstrated, nevertheless, the purpose of this study is to explore the role of mitochondrial adenosine triphosphate -sensitive potassium (mitoKATP) channels and toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) pathway in cardioprotective effects of TXR against I/R injury in rats. Male Wistar rats (n=72, 250–300 g, 12 weeks old) were randomized into groups with/without I/R and/or TXR and 5-hydroxydecanoate (5-HD), alone or in combination. To induce I/R model, the langendorff-perfused hearts were subjected to left anterior descending coronary artery (LAD) ligation and re-opening. TXR (150mg/kg/day) was administered for 4 weeks before I/R. Moreover, 5-HD (100 µM) was added to the perfusion solution before the ischemia. Finally, myocardial infarct size, LDH release, protein expression levels of TLR4 and NF-κB, and the levels of pro-inflammatory cytokines (TNF-α and IL-1β) were assessed. TXR preconditioning significantly reduced IS and LDH release (P&lt;0.05). Furthermore, it decreased the expression of TLR4 and NF-κB and the level of pro-inflammatory cytokines (P&lt;0.05 to P&lt;0.01). Inhibition of mitoKATP channels by 5-HD significantly reversed the cardioprotective effects of TXR. This work shed some light on the knowledge about the mechanisms involved in the anti-inflammatory effect of TXR preconditioning in myocardial I/R injury. This effect may be partly mediated through mitoKATP channels opening and subsequent suppression of the TLR4/NF-κB pathway

Protective Effect of Diosgenin and Exercise Training on Biochemical and ECG Alteration in Isoproterenol-Induced Myocardial Infarction in Rats

Abstract Objective(s) Several studies have reported improved response of exercised hearts to myocardial infarction (MI). This study was aimed to evaluate the preventive role of treadmill exercise and diosgenin on cardiac marker enzymes, thiobarbituric acid reactive substances (TBARS), total antioxidant status (TAS), lipids, and electrocardiographic (ECG) patterns in isoproterenol (ISO)-induced myocardial infarction (MI) in male Wistar rats. Materials and Methods One hundred Wistar rats were divided into ten groups: Control rats (C), saline (S), L-cremephor (LC), exercise (E), diosgenin dissolved in L-cremephor (15 mg/kg/day) (D), exercise+ diosgenin (E+D), ISO injected (150 mg/kg) (ISO), exercise + ISO (E+ISO), diosgenin + ISO (D+ISO) and exercise+ diosgenin+ ISO (E+D+ISO). At the end of the experiment all animals anesthetized and blood samples were collected for biochemical estimation and also the ECG patterns were recorded. Results Exercise and diosgenin pretreatment significantly decreased the lactate dehydrogenase (LDH) and TBARS level in ISO injected animals. Exercise and diosgenin pretreatment significantly decreased serum total cholesterol and increased high density lipoprotein (HDL-C). ISO-treated rats showed pathological Q waves along with elevated ST segments. The altered electrocardiograms (ECG) of ISO-treated rats were also restored to near normal by diosgenin and exercise, but exercise and diosgenin had synergistic effects. Conclusion The present investigation demonstrates that combination of diosgenin and exercise exhibited significant protection against ISO induced electrocardiographical and biochemical changes. The cadioprotective mechanism(s) appear to be through changing lipid metabolism

Effects of low-level lead exposure on blood pressure and function of the rat isolated heart

Objective: Exposure to low levels of lead acetate can induce hypertension in both humans and experimental animals. The exact mechanisms of lead-induced hypertension are not well understood, but its pathogenesis could be explained by the changes in heart rate and contractility. Materials and Methods: In the present study, the effects of exposure to 100 ppm of lead in drinking water (for periods of 4, 8, and 12 weeks) on blood pressure and some physiologic parameters (eg, electrocardiography [ECG], heart rate [HR], cardiac contractility, and coronary flow) of isolated beating rat heart was investigated using the Langendorff isolated heart apparatus. The isolated hearts were perfused with Krebs-Henseleit solution (37°C; pH 7.4; gassed with 95% O 2 + 5% CO 2 ). All data were digitized by a software program for further analysis. Results: The blood pressure in the 8- and 12-week lead-exposed groups was significantly increased as compared to the control group. The ECG showed arrhythmias and conduction abnormalities only in the late phases of exposure (12 weeks). The HR and contractility were significantly higher in the 8- and 12-week lead-treated rats but not in the 4-week group. No significant changes were observed in coronary flow. Conclusion: These results indicate that: 1) low levels of lead exposure do not significantly affect the ECG in the early phase, 2) low levels of lead exposure causes ECG changes in the late phases of exposure, and 3) this level of lead exposure can increase HR and cardiac contractility but has no effect on coronary flow