curcumin and Diabetic-Cardiomyopathies

Diabetic cardiomyopathy (DCM) is described as impaired cardiac diastolic and systolic functions. Diabetes mellitus (DM), a related cardiovascular disease, has become one of the major causes of death in DM patients. Mortality in these diseases is 2 to 3 times higher than in non-DM patients with cardiovascular disease. The progression of DCM and the cellular and molecular perturbations associated with the pathogenesis are complex and multifactorial. Although considerable progress has been achieved, the molecular etiologies of DCM remain poorly understood. There is an expanding need for natural antidiabetic medicines that do not cause the side effects of modern drugs. Curcumin, a pleiotropic molecule, from Curcuma longa, is known to possess numerous impacts such as scavenging free radical, antioxidant, antitumor, and antiinflammatory activities. The reports from preclinical and clinical findings revealed that curcumin can reverse insulin resistance, hyperglycemia, obesity, and obesity-related metabolic diseases. The current review provides an updated overview of the possible molecular mechanism of DCM and multitarget approach of curcumin in alleviating DCM and diabetic complication. Additionally, we mentioned the approaches that are currently being implemented to improve the bioavailability of this promising natural product in diabetes therapeutics.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Curcuma; Curcumin; Diabetic Cardiomyopathies; Disease Models, Animal; Heart; Humans; Hypoglycemic Agents; Oxidative Stress; Plant Extracts

Targeting autophagy is a new therapeutic strategy for the complications of diabetes,such as diabetic cardiomyopathy (DCM). During diabetes, increased or insufficient autophagic activity causes aberrations in cellular homeostasis. Regarding the conflicting and unclear results regarding the effect of HIIT and curcumin supplementation on the expression of genes associated to autophagy, this study aimed to assess whether 4-week high-intensity interval training (HIIT) and curcumin supplementation are able to influence the expression of autophagy-related genes in myocardial cells of diabetic rats.. In an experimental design, 24 male Wistar rats were randomly divided into 4 groups: non-diabetic control (NC), diabetic control (DC), diabetes + HIIT (D + HIIT), and diabetes + curcumin (D + CU). After HIIT program and curcumin treatment, the genes expression of autophagy pathway were assessed in the myocardium by real-time PCR Tanique.. The results indicated that the expression levels of ATG1, Beclin1, ATG5, and LAMP-2 genes were significantly reduced in the DC group compared to the NC group (p < 0.001). Following 4-week HIIT, the expression of Beclin1, ATG-5, and LAMP-2 improved considerably compared to the DC group (p < 0.001, p < 0.001, and p < 0.05, respectively). In addition, after 4 weeks of curcumin supplementation, the expression levels of ATG-5 and Beclin-1 were significantly improved compared to the DC group (p < 0.001, p < 0.05, respectively). It seems HIIT and curcumin supplementation can be an effective approach for inducing autophagy and improving cardiac function in DCM rats.However, HIIT seems more effective than curcumin in this regard.

Topics: Animals; Autophagy; Beclin-1; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dietary Supplements; High-Intensity Interval Training; Male; Physical Conditioning, Animal; Rats; Rats, Wistar

This study is aimed at exploring whether curcumin can regulate the AKT pathway, promote the transfer of Nrf2 into the nucleus, and inhibit cell pyroptosis in diabetic cardiomyopathy. Diabetic rats and cardiomyocytes were treated with curcumin to study its effect on myocardial pyroptosis. Whether curcumin can promote the transfer of Nrf2 into the nucleus through AKT pathway regulation was assessed by western blotting and immunofluorescence. The Nrf2 knockout vector and ml385 were used to block the Nrf2 pathway, and the differences between the different groups in the expression of pyroptosis protein, cell activity, and incidence of apoptosis were evaluated to verify the relationship between the effect of curcumin on pyroptosis inhibition and the Nrf2 pathway. Curcumin promoted the transfer of Nrf2 into the nucleus through the AKT pathway and increased the expression of the antioxidant factors HO-1 and GCLC. These effects reduced reactive oxygen species accumulation and mitochondrial damage in diabetic myocardium and inhibited diabetes-induced pyroptosis. However, in cardiomyocytes with a blocked Nrf2 pathway, the ability of curcumin to inhibit pyroptosis was significantly reduced, and the protective effect on the cells was lost. Curcumin can reduce the accumulation of superoxide in the myocardium through AKT/Nrf2/ARE pathway activation and inhibit pyroptosis. It also has a role in diabetic cardiomyopathy treatment. This study provides new directions for evaluating the mechanism of diabetic cardiomyopathy and treating diabetic myocardium.

Topics: Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; NF-E2-Related Factor 2; Oxidative Stress; Proto-Oncogene Proteins c-akt; Pyroptosis; Rats

Diabetes causes lipid peroxide to accumulate within cardiomyocytes. Furthermore, lipid peroxide buildup is a risk factor for ferroptosis. This study is aimed at examining whether curcumin can ameliorate ferroptosis in the treatment of diabetic cardiomyopathy. Hematoxylin and eosin and Masson sections were used to examine the morphology, arrangement, and degree of fibrosis of the myocardium of diabetic rabbit models. The expression levels of nuclear Nrf2, Gpx4, Cox1, and Acsl4 in diabetic animal and cell models were quantitatively analyzed using immunofluorescence and western blotting. Nrf2-overexpression lentivirus vectors were transfected into cardiomyocytes, and the protective effects of curcumin and Nrf2 on cardiomyocytes under high glucose stimulation were assessed using terminal deoxynucleotidyl transferase dUTP nick-end labelling and reactive oxygen species probes. Diabetes was found to disorder myocardial cell arrangement and significantly increase the degree of myocardial fibrosis and collagen expression in myocardial cells. Curcumin treatment can increase nuclear transfer of Nrf2 and the expression of Gpx4 and HO-1, reduce glucose induced myocardial cell damage, and reverse myocardial cell damage caused by the ferroptosis inducer erastin. This study confirmed that curcumin can promote the nuclear translocation of Nrf2, increase the expression of oxidative scavenging factors, such as HO-1, reduce excessive Gpx4 loss, and inhibit glucose-induced ferroptosis in cardiomyocytes. This highlights a potentially new therapeutic route for investigation for the treatment diabetic cardiomyopathy.

Topics: Animals; Apoptosis; Curcumin; Diabetes Mellitus; Diabetic Cardiomyopathies; Ferroptosis; Glucose; Lipid Peroxides; NF-E2-Related Factor 2; Rabbits

The hallmark feature of Diabetes mellitus (DM) is hyperglycemia which can lead to excess production of reactive oxygen species (ROS) in the myocardium, contributing to diabetic cardiomyopathy (DCM). Nuclear factor erythroid2-related factor2 (Nrf2), a transcriptional activator, enhances its ability to resist oxidative stress by activating multiple downstream anti-oxidants, anti-inflammatory proteins, and detoxifying enzymes. However, the mechanism of Nrf2 signaling in HG-induced DCM is unclear. In this study, we used HG pretreated H9c2 cells as the experimental basis in vitro, and established a high fat-diet, streptozotocin (STZ) induced Type 2 diabetic rat model in vivo. Meanwhile, we used shRNA-Nrf2 and curcumin (CUR) (as an activator) to affect H9c2 cells, to verify the role of the Nrf2 signaling pathway in DCM. The results showed that the excessive production of ROS caused by HG, which could inhibit the activation of Nrf2-related signaling, resulting in a decrease in cell energy metabolism and an increase in cell apoptosis. Surprisingly, we found that the activation of the Nrf2 signaling pathway significantly increased cardiomyocyte viability, reduced ROS formation, increased antioxidant enzyme activity, and inhibited cardiomyocyte apoptosis. In conclusion, these findings conclusively infer that CUR activation of the Nrf2/HO-1 signaling pathway exerts myocardial protection by reducing ROS formation.

Topics: Animals; Antioxidants; Apoptosis; Curcumin; Diabetes Mellitus; Diabetic Cardiomyopathies; NF-E2-Related Factor 2; Oxidative Stress; Rats; Reactive Oxygen Species; Signal Transduction

Cardiac inflammation is an important pathological process in diabetic cardiomyopathy (DCM). Curcumin is a natural compound found in the rhizome of Curcuma longa and has been shown to possess multifunctional bioactivities. In the present study, we identified a new curcumin-derived compound, JM-2, and investigated its therapeutic effects against DCM in mouse models of streptozotocin-induced type 1 diabetes mellitus (T1DM) and HFD-induced type 2 diabetes (T2DM). Treatment with JM-2 (10 mg/kg) prevented cardiac functional and structural deficits effectively and reduced cardiac inflammation and fibrosis. JM-2 administration attenuated DCM by inhibiting nuclear factor kappa-B (NF-κB) activation in the heart of both models. In addition, treatment with JM-2 completely prevented the increase in proinflammatory factors and macrophage infiltration in T1DM and T2DM mice. RNA-seq analysis showed that the anti-inflammatory activity of JM-2 was associated with the inhibition of NF-κB activation. In vitro, JM-2 suppressed high glucose (HG)-induced myocardial hypertrophy and fibrosis in H9c2 cells, accompanied by inhibition of HG-induced NF-κB activation. Collectively, our results showed that JM-2, a new curcumin analog, provides strong protection against DCM via inhibition of the NF-κB-mediated inflammation. In summary, our data suggest that the curcumin analog JM-2 may be a potential therapeutic agent for DCM.

Topics: Animals; Curcumin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Fibrosis; Inflammation; Mice; Myocytes, Cardiac; NF-kappa B

Topics: Animals; Blood Glucose; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiotonic Agents; Curcumin; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Drug Therapy, Combination; Hypoglycemic Agents; Interleukin-6; Male; Myocardium; NF-kappa B; Oxidative Stress; Pioglitazone; PPAR gamma; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the protective effect of curcumin (Cu) on myocardial injury in diabetic cardiomyopathy in vivo and in vitro. Serum and myocardial glucose, inflammatory cytokines, and cardiac function indexes of type 2 diabetes db/db mice were measured. The mechanism of action was confirmed by immunohistochemistry, immunofluorescence, and western blot experiments. H9C2 cells stimulated by glucose (Glu) were used as cell models in vitro. Cu treatment improved glucose tolerance and lipid profile and reduced the production of inflammatory cytokines. In addition, Cu decreased the serum biochemical indexes. Cu inhibits high mobility group box 1 (HMGB1) signaling pathway in db/db mice. Cu treatment also significantly inhibited pa-induced inflammatory signaling pathway in H9C2 cells. HMGB1 inhibitor or HMGB1 knockdown counteracted the effects of Cu on diabetic cardiomyopathy. The present study showed the protective effects of Cu on myocardial injury via HMGB1 pathway in diabetic cardiomyopathy in vivo and in vitro.

Topics: Animals; Cardiotonic Agents; Caspase 1; Cell Line; Cell Survival; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Electrocardiography; Gene Expression Regulation; Glucose; Glucose Tolerance Test; HMGB1 Protein; Hypoglycemic Agents; Interleukin-1beta; Male; Metformin; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

Type 2 diabetes mellitus (DM)-induced cardiomyopathy is a multifactorial and complex disease involving oxidative stress, lipids, and fibrosis. It is based on metabolic disorders and microvascular disease and causes extensive focal necrosis of the heart muscle. Curcumin (CUR) is a natural polyphenol isolated from turmeric rhizomes and plays an important role in the antioxidant, anti-apoptotic and anti-inflammatory effects of diabetes. Therefore, we established a mouse model of diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice in our study. We divided the experiment into three groups: the control group, DM group and DM + CUR group.We performed cardiac dissection on mice treated in different conditions and conducted special pathological staining on isolated cardiac tissue. We were surprised to find that a high glucose environment can promote cardiomyocyte apoptosis by TUNEL assay. In addition, after detecting dihydroethiidine (DHE), hematoxylin-eosin (H&E) and Oil Red O staining, we unexpectedly found that CUR can inhibit the production of reactive oxygen species (ROS), reduce myocardial apoptosis, and myocardial lipid accumulation. CUR upregulated the expression of Bcl-2, and downstream the expression of Bax and Caspase-3 proteins by immunohistochemical determination and western blotting. Therefore, these results suggest that CUR has a certain protective effect on diabetic cardiomyopathy by inhibiting the production of ROS.

Topics: Animals; Antioxidants; Cardiotonic Agents; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Reactive Oxygen Species

Topics: Animals; Apoptosis; Blood Glucose; Cell Survival; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Male; Myocardium; Myocytes, Cardiac; Nerve Tissue Proteins; Oxidative Stress; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirtuin 1

High blood glucose in diabetic patients often causes cardiovascular diseases (CVDs) that threats to human life. Curcumin (Cur) is known as an antioxidant agent, possesses anti-inflammatory activity, and prevents CVDs. However, the clinical application of curcumin was limited due to its low bioavailability. This study aimed to investigate the ameliorative effects of chitosan-encapsulated curcumin (CEC) on heart and kidney damages in streptozotocin-induced type-1 diabetes C57BL/6 mice model. The results showed that Cur- and CEC-treatments downregulated the blood sugar and total cholesterol level as well as enhanced insulin secretion. However, blood pressure, triglycerides content, and very low-density lipoprotein-cholesterol content were not changed. Histochemistry analysis revealed that both curcumin and chitosan-encapsulated curcumin ameliorated cell hypertrophy and nucleus enlargement in the left ventricular of heart and reduced fibrosis in the kidney, especially after the chitosan-encapsulated curcumin treatment. Our study suggested that chitosan can effectively enhance the protective effect of curcumin on the heart and kidney damages in type-1 diabetes mice model.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chitosan; Curcumin; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Diabetic Nephropathies; Disease Models, Animal; Heart; Kidney; Male; Mice; Mice, Inbred C57BL; Streptozocin

Topics: AMP-Activated Protein Kinases; Animals; Collagen Type I; Collagen Type III; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Fibroblasts; Fibrosis; Glucose; Humans; Male; Myocardium; p38 Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transforming Growth Factor beta1

The objective of this study was to survey the therapeutic function of curcumin-encapsulated poly(gamma-benzyl l-glutamate)-poly(ethylene glycol)-poly(gammabenzyl l-glutamate) (PBLG-PEG-PBLG) (P) on diabetic cardiomyopathy (DCM) via cross regulation effect of calcium-sensing receptor (CaSR) and endogenous cystathionine-γ-lyase (CSE)/hydrogen sulfide (H. Diabetic rats were preconditioned with 20 mg/kg curcumin or curcumin/P complex continuously for 8 weeks. The blood and myocardiums were collected, the level of serum H. PBLG-PEG-PBLG could improve water-solubility and bioactivity of curcumin and curcumin/PBLG-PEG-PBLG significantly alleviated diabetic cardiomyopathy.

Topics: Animals; Calmodulin; Curcumin; Cystathionine gamma-Lyase; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Drug Delivery Systems; Drug Liberation; Magnetic Resonance Spectroscopy; Myocardium; Nanoparticles; Polyethylene Glycols; Polyglutamic Acid; Rats, Sprague-Dawley; Receptors, Calcium-Sensing

Modified herbal medicines implicate the combination of several therapeutic practices of native systems of medicine that may extend many earlier generations, which frequently afford valuable therapeutic benefits.. In this study, the role of nano-curcumin and aged garlic extract (AGE) as two modified phytomedicines on alleviating both of advanced glycation end products (AGEPs) and oxidative stress (OS) in streptozotocin (STZ) induced diabetic rats were investigated during this study.. Nano-curcumin and AGE suspension were orally administrated at a dose of 300, 500 mg/kg body weight respectively. Serum glucose, insulin, total cholesterol, triglycerides and myocardial enzyme activities including creatine kinase-isoenzyme (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) were determined biochemically, while quantitative real-time polymerase chain reaction (qRT-PCR)-test had been used to determine relative of manganese-superoxide dismutase (Mn-SOD) and receptor for advanced glycation end products (RAGE) gene expressions in the heart tissue of rats. Structure of rat's heart tissue was examined by histopathological analysis (H&E).. AGE increased the body weight and insulin concentration, while, it decreased serum glucose concentration, CK-MB, and LDH enzyme activities in comparing with the diabetic group. In addition, total cholesterol, triglycerides, and AST didn't show any significant changes in serum values of AGE compared to diabetic rats. Nano-curcumin suspension decreased the serum levels of triglycerides, CK- MB, LDH, and AST. While, there were non-significant changes in the body weight, glucose, insulin, and total cholesterol level of the same group compared with the STZ- untreated induced diabetic rats. The transcript quantity of manganese-superoxide dismutase gene (Mn-SOD) was highly accumulated (3.25 and 3.87-fold) in the heart tissue sample of the induced diabetic rats in response to both nano-Curcumin and AGE suspension respectively. While AGE was the most potent treatment where it caused down regulation of the receptor for advanced glycation end products gene (RAGE) expression (1.79-fold). Results of histopathological analyses under the light microscope showed restoring the structural integrity of the myocytes towards normalization in diabetic hearts treated with each of nano-curcumin and AGE suspension compared with the untreated diabetic heart samples.. Nano-curcumin and AGE suspension have a great therapeutic potential in the treatment of DCM, Diabetic cardiomyopathy, by attenuating cardiac inflammation, myocardial fibrosis, and programmed myocardial cell deaths through inhibiting OS and AGEPs accumulation in diabetic heart tissue. Furthermore, the hypoglycemic antioxidant properties of AGE resulted in more potent therapeutic effect than nano-curcumin in the treatment of diabetic hearts.

Topics: Animals; Antioxidants; Apoptosis; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Fibrosis; Garlic; Hypoglycemic Agents; Insulin; Male; Myocardium; Nanoparticles; Oxidative Stress; Plant Extracts; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Superoxide Dismutase

The effects of curcumin on regulating cardiac apoptosis and autophagy were analyzed in diabetic models both in vivo and in vitro. In vivo, experimental diabetes was induced in mice by low-dose STZ injection combined with a high-fat diet. In vitro, cultured H9c2 cardiomyoblasts were exposed to high d-glucose concentrations combined with palmitate. Our results showed that apoptosis was increased and autophagy was suppressed in the hearts of diabetic mice, which was ameliorated by curcumin treatment, ultimately improving cardiac function. Moreover, the inhibition of autophagy exacerbated apoptotic death in cardiac cells under diabetic condition. Curcumin activated AMPK and JNK1, which phosphorylated Bcl-2 and Bim and subsequently disrupted their interactions with Beclin1, thereby promoting autophagy and alleviating apoptosis respectively. In addition, AMPK-mediated inhibition of mTORC1 pathway likely played a role in regulating autophagy by curcumin under diabetic condition. Our study suggests that curcumin protects against diabetic cardiomyopathy by modulating the crosstalk between autophagic and apoptotic machinery. Modulation of autophagy may be an effective strategy for the treatment of cardiovascular diseases associated with diabetes.

Topics: Animals; Apoptosis; Autophagy; Biomarkers; Cell Line; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Echocardiography; Heart Function Tests; Male; MAP Kinase Signaling System; Mechanistic Target of Rapamycin Complex 1; Mice; Myocardium; Phosphorylation; Protective Agents; Rats; Signal Transduction

Diabetic cardiomyopathy is an independent cardiac injury that can develop in diabetic individuals. Our previous study showed that C66, a curcumin analogue, protects against diabetes-induced cardiac damage. The present study sought to reveal the underlying mechanisms of C66-mediated cardioprotection.. Neither C66 treatment nor JNK2 knockout affected body weight or plasma glucose levels. Cardiac inflammation, fibrosis, oxidative stress, and apoptosis were increased in WT diabetic compared to WT control mice, all of which were attenuated by C66 treatment. However, these pathological and molecular changes induced by diabetes were eliminated in JNK2. Our results indicate that C66 ameliorates diabetic cardiomyopathy by inhibiting JNK2 relative pathways.

Topics: Animals; Apoptosis; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diabetic Nephropathies; Fibrosis; Humans; Inflammation; Mice; Mice, Inbred NOD; Mitogen-Activated Protein Kinase 9; Oxidative Stress; Phosphorylation

Hyperglycemia-induced inflammation and fibrosis have important roles in the pathogenesis of diabetic nephropathy and cardiomyopathy. With inflammatory cytokines and signaling pathways as important mediators, targeting inflammation may be an effective approach to new avenue for treating diabetic complications. J17, a molecule with structural similarities to curcumin, exhibited good anti-inflammatory activities by inhibiting LPS-induced inflammatory response in macrophages. However, its ability to alleviate hyperglycemia-induced injury via its anti-inflammatory actions remained unclear. Thus, we reported that J17 exerts significant inhibitory effects on hyperglycemia-induced inflammation and fibrosis in NRK-52E cells, H9C2 cells and a streptozotocin-induced diabetic mouse model. We also found that the anti-inflammatory and anti-fibrosis activities of J17 are associated with the inhibition of the P38 and AKT signal pathway, respectively. In vivo oral administration of J17 suppressed hyperglycemia-induced inflammation, hypertrophy and fibrosis, thereby reducing key markers for renal and cardiac dysfunction and improving in fibrosis and pathological changes in both renal and cardiac tissues of diabetic mice. The results of this study indicated that J17 can be potentially used as a cardio- and reno-protective agent and that targeting the P38 and AKT pathways may be an effective therapeutic strategy for diabetic complications.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Cell Line; Curcumin; Cytokines; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diabetic Nephropathies; Fibrosis; Inflammation Mediators; Kidney; Male; Mice, Inbred C57BL; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Streptozocin; Time Factors

The development of diabetic cardiomyopathy is attributed to diabetic oxidative stress, which may be related to the mitogen-activated protein kinase (MAPK) c-Jun NH2-terminal kinase (JNK) activation. The present study tested a hypothesis whether the curcumin analog C66 [(2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene) cyclohexanone] as a potent antioxidant can protect diabetes-induced cardiac functional and pathogenic changes via inhibition of JNK function. Diabetes was induced with a single intraperitoneal injection of streptozotocin in male C57BL/6 mice. Diabetic and age-matched control mice were randomly divided into three groups, each group treated with C66, JNK inhibitor (JNKi, SP600125), or vehicle (1% CMC-Na solution) by gavage at 5 mg/kg every other day for 3 mo. Neither C66 nor JNKi impacted diabetic hyperglycemia and inhibition of body-weight gain, but both significantly prevented diabetes-induced JNK phosphorylation in the heart. Compared with basal line, cardiac function was significantly decreased in diabetic mice at 3 mo of diabetes but not in C66- or JNKi-treated diabetic mice. Cardiac fibrosis, oxidative damage, endoplasmic reticulum stress, and cell apoptosis, examined by Sirius red staining, Western blot, and thiobarbituric acid assay, were also significantly increased in diabetic mice, all which were prevented by C66 or JNKi treatment under diabetic conditions. Cardiac metallothionein expression was significantly decreased in diabetic mice but was almost normal in C66- or JNKi-treated diabetic mice. These results suggest that, like JNKi, C66 is able to prevent diabetic upregulation of JNK function, resulting in a prevention of diabetes-induced cardiac fibrosis, oxidative stress, endoplasmic reticulum stress, and cell death, along with a preservation of cardiac metallothionein expression.

Topics: Animals; Apoptosis; Benzylidene Compounds; Blood Pressure; Blotting, Western; Coloring Agents; Curcumin; Cyclohexanones; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Echocardiography; Endoplasmic Reticulum Stress; Fibrosis; Heart; JNK Mitogen-Activated Protein Kinases; Lipid Peroxidation; Male; Metallothionein; Mice; Mice, Inbred C57BL; Myocardium; Oxidative Stress; Phosphorylation; Protein Kinase Inhibitors; Real-Time Polymerase Chain Reaction

Cardiovascular diseases as leading causes of the mortality world-wide are related to diabetes. The present study was to explore the protective effect of curcumin analogue C66 on diabetes-induced pathogenic changes of aortas. Diabetes was induced in male C57BL/6 mice with a single intraperitoneal injection of streptozotocin. Diabetic mice and age-matched non-diabetic mice were randomly treated with either vehicle (Control and Diabetes), C66 (C66 and Diabetes/C66) or c-Jun N-terminal kinase (JNK) inhibitor (sp600125, JNKi and Diabetes/JNKi). All three treatments were given by gavage at 5 mg/kg every other day for 3 months. Aortic inflammation, oxidative stress, fibrosis, cell apoptosis and proliferation, Nrf2 expression and transcription were assessed by immunohistochemical staining for the protein level and real-time PCR method for mRNA level. Diabetes increased aortic wall thickness and structural derangement as well as JNK phosphorylation, all of which were attenuated by C66 treatment as JNKi did. Inhibition of JNK phosphorylation by C66 and JNKi also significantly prevented diabetes-induced increases in inflammation, oxidative and nitrative stress, apoptosis, cell proliferation and fibrosis. Furthermore, inhibition of JNK phosphorylation by C66 and JNKi significantly increased aortic Nrf2 expression and transcription function (e.g. increased expression of Nrf2-downstream genes) in normal and diabetic conditions. These results suggest that diabetes-induced pathological changes in the aorta can be protected by C66 via inhibition of JNK function, accompanied by the up-regulation of Nrf2 expression and function.

Topics: Animals; Anthracenes; Anti-Inflammatory Agents, Non-Steroidal; Aorta; Apoptosis; Blotting, Western; Cell Proliferation; Cells, Cultured; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; JNK Mitogen-Activated Protein Kinases; Male; Mast Cells; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Phosphorylation; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Hyperglycemia-induced inflammation and apoptosis have important roles in the pathogenesis of diabetic cardiomyopathy. We recently found that a novel curcumin derivative, C66, is able to reduce the high glucose (HG)-induced inflammatory response. This study was designed to investigate the protective effects on diabetic cardiomyopathy and its underlying mechanisms. Pretreatment with C66 significantly reduced HG-induced overexpression of inflammatory cytokines via inactivation of nuclear factor-κB in both H9c2 cells and neonatal cardiomyocytes. Furthermore, we showed that the inhibition of Jun NH2-terminal kinase (JNK) phosphorylation contributed to the protection of C66 from inflammation and cell apoptosis, which was validated by the use of SP600125 and dominant-negative JNK. The molecular docking and kinase activity assay confirmed direct binding of C66 to and inhibition of JNK. In mice with type 1 diabetes, the administration of C66 or SP600125 at 5 mg/kg significantly decreased the levels of plasma and cardiac tumor necrosis factor-α, accompanied by decreasing cardiac apoptosis, and, finally, improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia. Thus, this work demonstrated the therapeutic potential of the JNK-targeting compound C66 for the treatment of diabetic cardiomyopathy. Importantly, we indicated a critical role of JNK in diabetic heart injury, and suggested that JNK inhibition may be a feasible strategy for treating diabetic cardiomyopathy.

Topics: Animals; Apoptosis; Curcumin; Diabetic Cardiomyopathies; Glucose; Inflammation; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; NF-kappa B; Phosphorylation

Topics: Animals; Apoptosis; Curcumin; Diabetic Cardiomyopathies; Inflammation; JNK Mitogen-Activated Protein Kinases; Male; Myocytes, Cardiac

The development of diabetic cardiomyopathy is accompanied with a high membrane-bound protein kinase C (PKC) levels. Curcumin is a naturally occurring compound which is known to inhibit PKC activity. However, the effects of curcumin on ameliorating diabetic cardiomyopathy are still undefined. We evaluated whether curcumin treatment is associated with the modulation of PKC-α and -β₂-mitogen-activated protein kinase (MAPK) pathway in experimental diabetic cardiomyopathy. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (STZ). Curcumin (100mg/kg/day) was started three weeks after STZ injection and was given for 8 weeks. We demonstrate that curcumin significantly prevented diabetes-induced translocation of PKC-α and -β2 to membranous fraction and diabetes-induced increased phosphorylation of p38MAPK and extracellular regulated-signal kinase (ERK)1/2 in left ventricular tissues of diabetic rats. Curcumin treatment also markedly decreased NAD(P)H oxidase subunits (p67phox, p22phox, gp91phox), growth factors (transforming growth factor-β, osteopontin) and myocyte enhancer factor-2 protein expression as well as inhibited NF-κB activity at nuclear level. Furthermore, curcumin decreased the mRNA expression of transcriptional coactivator p300 and atrial natriuretic peptide, decreased accumulation of ECM protein and reversed the increment of superoxide production in left ventricular tissues, as evidenced by dihydroethidium staining. It is also significantly lowered plasma glucose and attenuated oxidative stress, as determined by lipid peroxidation and activity of anti-oxidant enzyme, and as a result attenuated cardiomyocyte hypertrophy, myocardial fibrosis and left ventricular dysfunction. Taken together, it is suggested that curcumin by inhibiting PKC-α and -β₂-MAPK pathway may be useful as an adjuvant therapy for the prevention of diabetic cardiomyopathy.

Topics: Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Fibrosis; Glutathione Peroxidase; Heart Ventricles; Hemodynamics; Hyperglycemia; Lipid Peroxidation; Male; Myocytes, Cardiac; Oxidative Stress; Protein Kinase Inhibitors; Protein Kinases; Rats; Rats, Sprague-Dawley

Diabetic 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.. An 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.. Rats 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 gp91(phox) and p47(phox) ), 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.. Taken 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.

Topics: Animals; Apoptosis; Cell Death; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Fibrosis; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heart; Inflammation; Male; Myocardium; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Ventricular Dysfunction, Left