The present study indicated that IPostC or CsA failed to affect NO levels and failed to protect the diabetic myocardium against ischemia/reperfusion injury. Moreover, concomitant administration of CsA and IPostC at reperfusion can increase NO content and protect the diabetic myocardium.

Ischemic heart disease is one of the major causes of death worldwide. Ischemia is a condition in which blood flow of the myocardium declines, leading to cardiomyocyte death. However, reperfusion of ischemic regions decreases the rate of mortality, but it can also cause later complications. In a clinical setting, ischemic heart disease is always coincident with other co-morbidities such as diabetes. The risk of heart disease increases 2-3 times in diabetic patients. Apoptosis is considered to be one of the main pathophysiological mechanisms of myocardial ischemia-reperfusion injury. Diabetes can disrupt the anti-apoptotic intracellular signaling cascades involved in myocardial protection. Therefore, targeting these changes may be an effective cardioprotective approach in the diabetic myocardium against ischemia-reperfusion injury. In this article, we review the interaction of diabetes with the pathophysiology of myocardial ischemia-reperfusion injury, focusing on the contribution of apoptosis in this context, and then discuss the alterations of pro-apoptotic or anti-apoptotic pathways probably responsible for the loss of cardioprotection in diabetes.

No abstract

Multidrug resistance in tumor cells is still a big challenge in cancer treatment. Therefore, identification ofsafe and effective multidrug resistance-reversing compounds with minimal side effects is an important approach in cancer treatment. Here, we investigated the role and potential mechanisms of peroxisome proliferator-activated receptor γ in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effect of doxorubicin on cell viability following treatment with balaglitazone, a peroxisome proliferator-activated receptor γ agonist, was evaluated using trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Rhodamine123 assay was used to determine the activity of two common drug efflux membrane transporters P-glycoprotein and multidrug resistance protein-1. P-glycoprotein, multidrug resistance protein-1, and phosphatase and tensin homolog deleted on chromosome 10 messenger RNA/protein expression levels were measured by quantitative reverse transcription polymerase chain reaction and western blot analyses. Annexin V/fluorescein isothiocyanate assay was also employed to investigate apoptosis. We showed that balaglitazone considerably enhanced the cytotoxicity of doxorubicin. Balaglitazone also significantly downregulated P-glycoprotein expression and activity in K562/DOX cells and reduced multidrug resistance through elevation of intracellular doxorubicin in cells. Furthermore, upon balaglitazone treatment, phosphatase and tensin homolog deleted on chromosome 10 expression could be restored in K562/DOX cells in a peroxisome proliferatoractivated receptor γ-dependent manner. We concluded that peroxisome proliferator-activated receptor γ agonist, balaglitazone, could reverse multidrug resistance by inducing phosphatase and tensin homolog deleted on chromosome 10 and peroxisome proliferator-activated receptor/ phosphatase and tensin homolog deleted on chromosome 10 signaling pathway. These findings suggest that targeting peroxisome proliferator-activated receptor γ might serve as an effective approach for circumventing multidrug resistance in chemotherapy of cancerous patients.

Ischemic heart diseases are the major reasons for disability and mortality in elderly individuals. In this study, we tried to examine the combined effects of nicotinamide mononucleotide (NMN) preconditioning and melatonin postconditioning on cardioprotection and mitochondrial function in ischemia/reperfusion (I/R) injury of aged male rats. Sixty aged Wistar rats were randomly allocated to 5 groups, including sham, control, NMN-receiving, melatonin-receiving, and combined therapy (NMN+melatonin). Isolated hearts were mounted on Langendorff apparatus and then underwent 30-minue ligation of left anterior descending coronary artery to induce regional ischemic insult, followed by 60 minutes of reperfusion. Nicotinamide mononucleotide (100 mg/kg/d intraperitoneally) was administered for every other day for 28 days before I/R. Melatonin added to perfusion solution, 5 minutes prior to the reperfusion up to 15 minutes early reperfusion. Myocardial hemodynamic and infarct size (IS) were measured, and the left ventricles samples were obtained to evaluate cardiac mitochondrial function and oxidative stress markers. Melatonin postconditioning and NMN had significant cardioprotective effects in aged rats; they could improve hemodynamic parameters and reduce IS and lactate dehydrogenase release compared to those of control group. Moreover, pretreatment with NMN increased the cardioprotection by melatonin. All treatments reduced oxidative stress and mitochondrial reactive oxygen species (ROS) levels and improved mitochondrial membrane potential and restored NAD+/NADH ratio. The effects of combined therapy on reduction of mitochondrial ROS and oxidative status and improvement of mitochondrial membrane potential were greater than those of alone treatments. Combination of melatonin and NMN can be a promising strategy to attenuate myocardial I/R damages in aged hearts. Restoration of mitochondrial function may substantially contribute to this cardioprotection.

This study was designed to investigate the anti-arrhythmic effect of diosgenin preconditioning in myocardial reperfusion injury in rat, focusing on the involvement of the nitric oxide (NO) system and mitochondrial ATP-dependent potassium (mitoKATP) channels in this scenario. After isolation of the hearts of male Wister rats, the study was conducted in an isolated buffer-perfused heart model. Global ischemia (for 30 min) was induced by interruption of the aortic supply, which was followed by 90-min reperfusion. Throughout the experiment, the electrocardiograms of hearts were monitored using three golden surface electrodes connected to a data acquisition system. Arrhythmias were assessed based on the Lambeth convention and were categorized as number, duration and incidence of ventricular tachycardia (VT), ventricular fibrillation (VF), and premature ventricular complexes (PVC), and arrhythmic score. Additionally, lactate dehydrogenase (LDH) levels in coronary effluent were estimated colorimetrically. Diosgenin pre-administration for 20 min before ischemia reduced the LDH release into the coronary effluent, as compared with control hearts (P < 0.05). In addition, the diosgenin-receiving group showed a lower number of PVC, VT and VF, a reduced duration and incidence of VT and VF, and less severe arrhythmia at reperfusion phase, in comparison with controls. Blocking the mitoKATP channels using 5-hydroxydecanoate as well as inhibiting the NO system through prior administration of L-NAME significantly reduced the positive effects of diosgenin. Our finding showed that pre-administration of diosgenin could provide cardioprotection through anti-arrhythmic effects against ischemia-reperfusion (I/R) injury in isolated rat hearts. In addition, mitoKATP channels and NO system may be the key players in diosgenin-induced cardioprotective mechanisms.

Background:Diabetes is associated with micro- and macro-vascular complications affecting several organs. Oxidative stress plays a crucial role in the etiology of vascular disease in diabetes.Objectives:The present study aimed to investigate the beneficial effect of troxerutin on diabetes-induced histopathological damages in rat aorta with focusing on its antioxidative actions.Materials and Methods:Male Wistar rats were randomly divided into four groups (n = 8/each): control, control plus troxerutin, diabetic and diabetic plus troxerutin. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (50 mg/kg) and lasted for 10 weeks. Troxerutin was administered orally in concentration of 150 mg/kg/daily for one month before killing rats. At the end of treatment period, thoracic aorta was isolated and divided into two parts; one part was immersed in 10% formalin for histopathological evaluations and the other was frozen by liquid nitrogen for assessment of malondialdehyde (MDA, the main product of lipid peroxidation), activity of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPX).Results:Lipid deposition in tunica intimae and media, thickening and structural deformity of vascular tissues as well as the level of plasma glucose and aortic tissue levels of lipid peroxidation were significantly increased in diabetic rats compared to control ones (P < 0.05). Troxerutin significantly reduced the severity of all vascular histopathological damages in treated versus untreated diabetic rats. In addition, treatment of diabetic rats with troxerutin significantly decreased the levels of MDA (5.1 ± 0.3 vs. 9.3 ± 1.2 nmol/mL) (P < 0.01) and increased the activity of antioxidant enzyme GPX compared to untreated-diabetic groups.Conclusions:Troxerutin may reduce the vascular complications and tissue injuries induced by chronic diabetes in rat aorta through increasing the activity of tissue antioxidant system and reducing the level of lipid peroxidation.

Protective effects of ischemic postconditioning in myocardial ischemia/reperfusion (I/R) injury have been ever demonstrated, but the exact mechanisms remain unclear. Because of their multiplex activities, using natural pharmaceuticals seems to be clinically interesting. The aim of present study was to investigate the effects of troxerutin preconditioning and ischemic postconditioning on inflammatory responses after myocardial I/R injury in a rat model. Twenty-four Wistar rats were divided into four groups as the control, troxerutin receiving (TXR), postconditioning receiving (PostC), and combined therapy (TXR + PostC). Rats' isolated hearts underwent 30-min LAD regional ischemia followed by 45-min reperfusion. Troxerutin was orally administered for a month before I/R. Ischemic PostC was applied by alternative three cycles of 30-s R/I at the onset of reperfusion. The coronary effluent and ischemic left ventricular samples were used to determine the activities of creatine kinase (CK), intercellular adhesion molecule-1 (ICAM-1), interlukin-1beta (IL-1β), tumor-necrosis factor (TNF-α), and also histopathological studies. Pretreatment of rats with troxerutin significantly reduced myocardial inflammatory cytokines TNF-α and IL-1β levels and ICAM-1 activity after I/R insult compared to those of control I/R hearts (P < 0.05). Application of PostC showed similar impacts on those parameters. In fact, anti-inflammatory mechanisms of both treatments were associated with their protective effects against myocardial damages causing from I/R injury. Pretreatment with troxerutin as well as postconditioning can induce cardioprotection through prevention of the cell-cell interaction and release of inflammatory mediators, minimizing I/R pathological changes in myocardial cells. These two treatments may share same mechanisms in their actions since they showed no significant additive effects.