ObjectivesDiabetic cardiomyopathy (DCM), characterized by myocardial structural and functional changes, is an independent cardiomyopathy that develops in diabetic individuals. The present study was sought to investigate the effect of curcumin on modulating DCM and the mechanisms involved.MethodsAn experimental diabetic rat model was induced by low dose of streptozoticin(STZ) combined with high energy intake on rats. Curcumin was orally administrated at a dose of 100 or 200 mg·kg−1·d−1, respectively. Cardiac function was evaluated by serial echocardiography. Myocardial ultrastructure, fibrosis area and apoptosis were assessed by histopathologic analyses. Metabolic profiles, myocardial enzymes and oxidative stress were examined by biochemical tests. Inflammatory factors were detected by ELISA, and interrelated proteins were measured by western blot.ResultsRats with DCM showed declined systolic myocardial performance associated with myocardial hypertrophy and fibrosis, which were accompanied with metabolism abnormalities, aberrant myocardial enzymes, increased AGEs (advanced glycation end products) accumulation and RAGE (receptor for AGEs) expression, elevated markers of oxidative stress (MDA, SOD, the ratio of NADP+/NADPH, Rac1 activity, NADPH oxidase subunits expression of gp91phox and p47phox ), raised inflammatory factor (TNF-α and IL-1β), enhanced apoptotic cell death (ratio of bax/bcl-2, caspase-3 activity and TUNEL), diminished Akt and GSK-3β phosphorylation. Remarkably, curcumin attenuated myocardial dysfunction, cardiac fibrosis, AGEs accumulation, oxidative stress, inflammation and apoptosis in the heart of diabetic rats. The inhibited phosphorylation of Akt and GSK-3β was also restored by curcumin treatment.ConclusionsTaken together, these results suggest that curcumin may have great therapeutic potential in the treatment of DCM, and perhaps other cardiovascular disorders, by attenuating fibrosis, oxidative stress, inflammation and cell death. Furthermore, Akt/GSK-3β signaling pathway may be involved in mediating these effects.

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Aim: The present study was designed to determine the possible pathway underlying the enhancement of apoptosis induced by the combined use of arsenic trioxide (As2O3) and ascorbic acid (AA). Methods: The level of intracellular reactive oxygen species (ROS) was detected by means of flow cytometry analysis with an oxidation‐sensitive fluorescent probe (6‐carboxy‐2′,7′dichlorodihydrofluorescein diacetate) uploading. The activity of glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were detected by biochemical methods. The mitochondrial membrane potential was measured by flow cytometry analysis with rhodamine 123 staining. Bcl‐2, Bax, and p 17 subunit of caspase‐3 were analyzed using the Western blot method. The apoptosis rate was determined by flow cytometry with annexin‐V/propidium iodide staining. Results: Compared with As2O3 (2.0 μmol/L) treated alone, As2O3 (2.0 μmol/L) in combination with AA (100 μmol/L) decreased intracellular GSH content from 101.30±5.76 to 81.91±3.12 mg/g protein, and increased ROS level from 127.61±5.12 to 152.60±5.88, which was represented by the 2, 7‐dichlorofluorescein intensity. The loss of mitochondria membrane potential was increased from 1269.97±36.11 to 1540.52±52.63, which was presented by fluorescence intensity. The p17 subunit of caspase‐3 expression was increased approximately 2‐fold. However, SOD and GPx depletion and the ratio of Bcl‐2 to Bax were equal to that of As2O3 treated alone (P>0.05). When the ROS scavenger, N‐acetyl‐L‐cysteine, was added to As2O3 and AA combined treatment group, the apoptosis rate decreased from 15.60 %±1.14% to 9.48%±0.67%, and the ROS level decreased from 152.60±5.88 to 102.77±10.25. Conclusion: AA potentiated As2O3‐induced apoptosis through the oxidative pathway by increasing the ROS level. This may be the result of depleting intracellular GSH. It may influence the downstream cascade following ROS, including mitochondria depolarization and caspase‐3 activation. However, SOD and GPx depletion and the ratio of Bcl‐2 to Bax influenced by As2O3was not found to be potentiated by AA.

Propranolol is a widely used, non-selective β-adrenergic receptor antagonist with proven efficacy in treating cardiovascular disorders and in the prevention of migraine headaches. At plasma concentrations exceeding those required for β-adrenergic receptor inhibition, propranolol also exhibits anti-arrhythmic (“membrane stabilizing”) effects that are not fully explained by β-blockade. Previous in vitro studies suggested that propranolol may have local anesthetic effects. We directly tested the effects of propranolol on heterologously expressed recombinant human cardiac (NaV1.5) and brain (NaV1.1, NaV1.2, NaV1.3) sodium channels using whole-cell patch-clamp recording. We found that block was not stereospecific as we observed approximately equal IC50 values for tonic and use-dependent block by R-(+) and S-(−) propranolol (tonic block: R: 21.4 μM vs S: 23.6 μM; use-dependent block: R: 2.7 μM vs S: 2.6 μM). Metoprolol and nadolol did not block NaV1.5 indicating that sodium channel block is not a class effect of β-blockers. The biophysical effects of R-(+)-propranolol on NaV1.5 and NaV1.1 resembled that of the prototypical local anesthetic lidocaine including the requirement for a critical phenylalanine residue (F1760 in NaV1.5) in the domain 4 S6 segment. Finally, we observed that brain sodium channels exhibited less sensitivity to R-(+)-propranolol than NaV1.5 channels. Our findings establish sodium channels as targets for propranolol and may help explain some beneficial effects of the drug in treating cardiac arrhythmias, and may explain certain adverse central nervous system effects.

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Inhibition of platelet responsiveness is important to control pathologic thrombus formation. Platelet-endothelial cell adhesion molecule-1 (PECAM-1) and the Src family kinase Lyn inhibit platelet activation by the glycoprotein VI (GPVI) collagen receptor; however, it is not known whether PECAM-1 and Lyn function in the same or different inhibitory pathways. In these studies, we found that, relative to wild-type platelets, platelets derived from PECAM-1-deficient, Lyn-deficient, or PECAM-1/Lyn double-deficient mice were equally hyperresponsive to stimulation with a GPVI-specific agonist, indicating that PECAM-1 and Lyn participate in the same inhibitory pathway. Lyn was required for PECAM-1 tyrosine phosphor- IntroductionRapid formation of platelet thrombi at sites of vessel injury is important to prevent blood loss, but thrombus formation must be regulated to prevent vessel ischemia and occlusion. Thrombus formation depends on platelet adhesion to, and activation on, exposed subendothelial collagen. Platelets adhere to collagen via the integrin ␣ 2 ␤ 1 , and activation depends on signals transduced by the platelet-specific glycoprotein VI (GPVI) and Fc receptor ␥-chain (FcR␥) collagen receptor complex (GPVI/FcR␥) as previously reviewed. [1][2][3] Signal transduction by GPVI is initiated by Src family kinase (SFK)-mediated phosphorylation of 2 tyrosine residues within the FcR␥ immunoreceptor tyrosine-based activation motif (ITAM), which supports binding and activation of the tyrosine kinase p72 syk , assembly of a signaling complex that activates phospholipase C ␥2, mobilization of calcium and activation of protein kinase C to trigger granule release, and integrin activation to enable platelet aggregation as reviewed previously. 1,2 Among the SFKs expressed by platelets, Fyn and Lyn physically associate with, and participate in, signal transduction by the GPVI/FcR␥ complex. [4][5][6] Whereas Fyn plays only a stimulatory role, Lyn has been reported to initially stimulate and subsequently inhibit platelet responses to GPVI-specific agonists. 7 The stimulatory function of Lyn has recently been found to rely on its constitutive interaction with a unique proline-rich domain within the GPVI cytoplasmic tail that activates the enzyme, 8 and to be important for activating a phosphatidylinositol 3 kinase-Akt pathway that induces secretion of platelet granule contents, which amplify platelet activation. 9 The mechanism underlying Lynmediated inhibition of GPVI-specific responses is, however, not yet defined. In hematopoietic cells other than platelets, Lyn has been shown to inhibit the activity of ITAM-coupled receptors by phosphorylating immunotyrosine-based inhibitory motif (ITIM)-containing receptors that bind tyrosine or inositol phosphatases, thereby dampening cellular activation. 10,11 PECAM-1 is a wellcharacterized ITIM-containing receptor that inhibits platelet responses to stimulation via GPVI. [12][13][14] In the present study, we demonstrate that Lyn inhibitory function in platelets depends on its ability to ph...

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