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ABSTRACT: Patients with diabetes often develop hypertension and atherosclerosis leading to cardiovascular disease. However, some diabetic patients develop heart failure without hypertension and coronary artery disease, a process termed diabetic cardiomyopathy. Phlorizin has been reported to be effective as an antioxidant in treating diabetes mellitus, but little is known about its cardioprotective effects on diabetic cardiomyopathy. In this study, we investigated the role of phlorizin in preventing diabetic cardiomyopathy in db/db mice. We found that phlorizin significantly decreased body weight gain and the levels of serum fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and advanced glycation end products (AGEs). Morphologic observations showed that normal myocardial structure was better preserved after phlorizin treatment. Using isobaric tag for relative and absolute quantitation (iTRAQ) proteomics, we identified differentially expressed proteins involved in cardiac lipid metabolism, mitochondrial function, and cardiomyopathy, suggesting that phlorizin may prevent the development of diabetic cardiomyopathy by regulating the expression of key proteins in these processes. We used ingenuity pathway analysis (IPA) to generate an interaction network to map the pathways containing these proteins. Our findings provide important information about the mechanism of diabetic cardiomyopathy and also suggest that phlorizin may be a novel therapeutic approach for the treatment of diabetic cardiomyopathy.
Journal of diabetes research. 01/2013; 2013:263845.
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ABSTRACT: Although phlorizin has been used in the treatment of diabetes mellitus for over 100 years, the underlying molecular mechanisms have not been fully elucidated. This study investigated the effect of phlorizin on body weight, blood glucose, blood triglycerides (TG), blood total cholesterol (TC), as well as overall changes in protein expression in db/db diabetic mouse liver. Phlorizin significantly decreased body weight gain and the levels of glucose, TC and TG in blood. Isobaric tag for relative and absolute quantitation (iTRAQ) quantitative proteomics profiling revealed that phlorizin interfered with the processes of carbohydrate metabolism, fatty acid biosynthesis and β-oxidation, cholesterol biosynthesis, and free radical scavenging by affecting the expression of key proteins in these processes. Ingenuity Pathway Analysis successfully established several pathway networks, in which many differentially expressed proteins were involved. The differential expression of several proteins was validated by western blotting. Our study offers important information on the mechanism of phlorizin treatment in diabetes mellitus, particularly in the liver.
Molecular Medicine Reports 02/2012; 5(5):1285-94. · 0.42 Impact Factor
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Fei Yu,
Bao-Ying Li,
Xiao-Li Li,
Qian Cai,
Zhen Zhang,
Mei Cheng, Mei Yin,
Jun-Fu Wang,
Jian-Hua Zhang,
Wei-da Lu,
Rui-Hai Zhou,
Hai-Qing Gao
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ABSTRACT: Atherosclerosis is one of the major complications of type 2 diabetic patients (T2DM), leading to morbidity and mortality. Grape seed procyanidin B2 (GSPB2) has demonstrated protective effect against atherosclerosis, which is believed to be, at least in part, a result of its antioxidative effects. The aim of this study is to identify the target protein of GSPB2 responsible for the protective effect against atherosclerosis in patients with DM.
GSPB2 (30 mg/kg body weight/day) were administrated to db/db mice for 10 weeks. Proteomics of the aorta extracts by iTRAQ analysis was obtained from db/db mice. The results showed that expression of 557 proteins were either up- or down-regulated in the aorta of diabetic mice. Among those proteins, 139 proteins were normalized by GSPB2 to the levels comparable to those in control mice. Among the proteins regulated by GSPB2, the milk fat globule epidermal growth factor-8 (MFG-E8) was found to be increased in serum level in T2DM patients; the serum level of MFG-E8 was positively correlated with carotid-femoral pulse wave velocity (CF-PWV). Inhibition of MFG-E8 by RNA interference significantly suppressed whereas exogenous recombinant MFG-E8 administration exacerbated atherogenesis the db/db mice. To gain more insights into the mechanism of action of MFG-E8, we investigated the effects of MFG-E8 on the signal pathway involving the extracellular signal-regulated kinase (ERK) and monocyte chemoattractant protein-1 (MCP-1). Treatment with recombinant MFG-E8 led to increased whereas inhibition of MFG-E8 to decreased expression of MCP-1 and phosphorylation of ERK1/2.
Our data suggests that MFG-E8 plays an important role in atherogenesis in diabetes through both ERK and MCP-1 signaling pathways. GSPB2, a well-studied antioxidant, significantly inhibited the arterial wall changes favoring atherogenesis in db/db mice by down-regulating MFG-E8 expression in aorta and its serum level. Measuring MFG-E8 serum level could be a useful clinical surrogate prognosticating atherogenesis in DM patients.
PLoS ONE 01/2012; 7(12):e52541. · 4.09 Impact Factor
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ABSTRACT: Advanced glycation end product (AGE)-induced vascular smooth muscle cell (VSMC) proliferation is vital to the progression of diabetic vasculopathy. A grape seed procyanidin extract has been reported to possess anti-oxidative and anti-inflammatory properties and to display a significant cardiovascular protective effect, but little is know about the underlying mechanism. The objective of this present study was to determine whether GSPB2 (grape seed procyanidin B2), which is a dimeric procyanidin and more biologically active, could inhibit AGE-induced VSMC proliferation by affecting the production of ubiquitin COOH-terminal hydrolase 1 (UCH-L1), the degradation of IκB-α and nuclear translocation of NF-κB in human aortic smooth muscle cells (HASMCs). Our data show that GSPB2 preincubation markedly inhibited AGE-induced proliferation and migration of HASMCs in a dose-dependent manner and upregulated the protein level of UCH-L1. Further studies revealed that the GSPB2 pretreatment markedly attenuated the degradation of IκB-α and nuclear translocation of NF-κB by modulating ubiquitination of IκB-α in AGE-exposed HASMCs. These results collectively suggest that AGE-induced HASMC proliferation and migration was suppressed by GSPB2 through regulating UCH-L1 and ubiquitination of IκB-α. GSPB2 may therefore have therapeutic potential in preventing and treating vascular complications of diabetes mellitus.
Bioscience Biotechnology and Biochemistry 09/2011; 75(9):1692-7. · 1.28 Impact Factor
