Animals ; Diabetes Mellitus, Experimental/drug therapy* ; Fibrosis/prevention & control* ; Hyperglycemia/prevention & control* ; Hypoglycemic Agents/pharmacology* ; Inflammation/prevention & control* ; Male ; Rats ; Rats, Sprague-Dawley ; Stilbenes/pharmacology*

The study aimed to investigate the intervening role of Didang decoction (DDD) at different times in macrovascular endothelial defense function, focusing on its effects on the AMP-activated protein kinase (AMPK) signaling pathway. The effects of DDD on mitochondrial energy metabolism were also investigated in rat aortic endothelial cells (RAECs). Type 2 diabetes were induced in rats by streptozotocin (STZ) combined with high fat diet. Rats were randomly divided into non-intervention group, metformin group, simvastatin group, and early-, middle-, late-stage DDD groups. Normal rats were used as control. All the rats received 12 weeks of intervention or control treatment. Western blots were used to detect the expression of AMP-activated protein kinase α1 (AMPKα1) and peroxisome proliferator-activated receptor 1α (PGC-1α). Changes in the intracellular AMP and ATP levels were detected with ELISA. Real-time-PCR was used to detect the mRNA level of caspase-3, endothelial nitric oxide synthase (eNOS), and Bcl-2. Compared to the diabetic non-intervention group, a significant increase in the expression of AMPKα1 and PGC-1α were observed in the early-stage, middle-stage DDD groups and simvastatin group (P < 0.05). The levels of Bcl-2, eNOS, and ATP were significantly increased (P < 0.05), while the level of AMP and caspase-3 were decreased (P < 0.05) in the early-stage DDD group and simvastatin group. Early intervention with DDD enhances mitochondrial energy metabolism by regulating the AMPK signaling pathway and therefore may play a role in strengthening the defense function of large vascular endothelial cells and postpone the development of macrovascular diseases in diabetes.
AMP-Activated Protein Kinases ; metabolism ; Adenosine Triphosphate ; metabolism ; Animals ; Aorta ; drug effects ; metabolism ; Cardiovascular Diseases ; metabolism ; prevention & control ; Caspase 3 ; metabolism ; Diabetes Mellitus, Experimental ; complications ; drug therapy ; metabolism ; Diabetes Mellitus, Type 2 ; complications ; drug therapy ; metabolism ; Diptera ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Endothelial Cells ; drug effects ; metabolism ; Endothelium, Vascular ; drug effects ; metabolism ; Energy Metabolism ; drug effects ; Leeches ; Mitochondria ; drug effects ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; metabolism ; Phytotherapy ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Prunus persica ; Rats, Sprague-Dawley ; Rheum ; Signal Transduction

OBJECTIVETo investigate the protective effect and mechanism of Shenqi Compound on diabetic angiopathy modeled rats.

METHODSTotally 18 SD rats were randomized into 3 groups, i.e., the normal control group, the diabetic mellitus (DM) group, and Shenqi Compound group, 6 in each group. The DM rat model was established by feeding high-fat diet (to induce hyperlipidemia) +intraperitoneal injection of small dose streptozotocin (STZ). Shenqi Compound was given to rats in the Shenqi Compound group at the daily dose of 2 g/kg. Equal volume of normal saline was given to rats in the model group and the normal control group by gastrogavage. All treatment was lasted for 12 weeks. Then 2-D and ultrasonic integrated backscatter technique were used to evaluate structural and functional changes of abdominal aorta in the progression of diabetic macroangiopathy. The fibrosis degree of the aorta vessel and myocardium capillaries were observed by using HE and Masson trichrome staining. The tension of the aortic vascular ring was determined. The transforming growth factor beta (TGF-beta) mRNA expression was detected by real time PCR (RT-PCR). The protein expression of TGF-beta, collagen I, collagen III, connective tissue growth factor (CTGF), and phosphorylation P38 MAPK were detected by Western blot.

RESULTSCompared with the normal control group, abdominal aortic systolic inner diameter, diastolic inner diameter, Peterson elastic modulus, stiffness index, and backscatter integral significantly increased; the rangeability of integral backscatter and the extension coefficient of cross section significantly decreased in the DM group (all P < 0.05). After 12 weeks aforesaid indices were obviously improved in the Shenqi Compound group (P < 0.05). Results of HE and Masson staining showed that the fibrosis degree of the aorta vessel and myocardium capillaries was obviously alleviated in rats of the Shenqi Compound group (P < 0.05). Results of the aortic vascular ring tension showed that acetylcholine induced vasodilatation and maximum diastolic percent were obviously elevated in the Shenqi Compound group (P < 0.05). Compared with the normal control group, the mRNA expression of TGF-beta, and the protein expression of TGF-beta, collagen I, and collagen III, and phosphorylation of P38 MAPK all significantly increased in the DM group (P < 0.05). Compared with the DM group, the mRNA expression of TGF-beta, and the protein expression of TGF-beta, collagen I, and collagen III, and phosphorylation of P38 MAPK all decreased (P < 0.05).

CONCLUSIONSShenqi Compound could effectively improve the arterial function in diabetic marcoangiopathy and microvascular dysfunction. The mechanism might be due to the down-regulating the expression of TGF-beta, and further suppressing the phosphorylation of P38 MAPK, reducing the synthesis of collagen I and collagen III, therefore, ameliorating arterial and myocardial interstitial fibrosis.

Animals ; Collagen Type I ; metabolism ; Collagen Type III ; metabolism ; Diabetes Mellitus, Experimental ; drug therapy ; Diabetic Angiopathies ; prevention & control ; Drugs, Chinese Herbal ; pharmacology ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1 ; metabolism ; p38 Mitogen-Activated Protein Kinases ; metabolism

BACKGROUNDDiabetic cardiovascular complication is a major cause of mortality in type 2 diabetic patients. Hyperglycemia markedly increases the risk of cardiovascular disease. Endothelial dysfunction is common in type 2 diabetes mellitus (DM) and is an early indicator of diabetic vascular disease. Therefore, it is necessary to identify the effect of different hypoglycemic agents on vascular endothelium. The aim of the study was to examine and compare the effects of metformin and gliquidone on atherosclerotic lesions in streptozotocin-induced diabetic rats.

METHODSForty male Sprague-Dawley rats (age, 8 weeks; weight, 180-200 g) were included in this study and fed with a normal chow diet for 1 week. Rats (n = 10) served as the normal control group (NC group) were fed with a normal chow for another 2 weeks and received an injection of saline. The rest 30 rats fed with a high-fat diet for 2 weeks and injected streptozotocin were randomly assigned to three groups (n = 10 rats per group) as follow: type 2 DM group (DM group), DM + gliquidone group (GLI group) and DM + metformin group (MET group). Five weeks later, all rats were fasted overnight and taken tail blood samples for biochemical determinations. Then rats in the NC and DM groups were administrated with normal saline, while rats in the MET and GLI groups were administrated with metformin (100 mg/kg) or gliquidone (10 mg/kg), respectively. All medicines were given via intragastric administration for 8 weeks. After 16 weeks, plasma triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) were measured. The aortic arch was isolated from diabetic rats and was assessed by pathological sectioning using H&E staining.

RESULTSMetformin treatment prevented weight gain ((315.80 ± 52.16) g vs. (318.70 ± 68.48) g, P = 0.773), improved plasma TG, HDL-C and LDL-C levels (P = 0.006, 0.003, 0.001, respectively, all P < 0.05). However, gliquidone showed no significant effects on plasma TG and TC levels (P = 0.819, 0.053, respectively). LDL-C and HDL-C in the GLI group changed ((0.46 ± 0.10) mmol/L vs. (0.36 ± 0.14) mmol/L, P = 0.007; (0.99 ± 0.27) mmol/L vs. (1.11 ± 0.18) mmol/L, P = 0.049). Both metformin and gliquidone treatment lowered blood glucose levels (P = 0.001, 0.004, respectively, P < 0.05). Under light microscopy, no changes were observed in the aortic wall structure of each layer; the intima was smooth and the membrane elastic fibers were normal in the NC group. In the DM group, the aortic wall structure was unclear, the intima was thickened with irregular intima, and membrane elastic fibers collapsed. The aortic intima in the MET and GLI groups was smoother compared with the DM group, but the endothelial structure of the MET group was closer to that of the NC group.

CONCLUSIONSBoth metformin and gliquidone have anti-atherosclerotic effects. But the endothelial structure of the MET group was closer to that of the NC group. Metformin and gliquidone therapy can reduce serum level of LDL-C and increase level of HDL-C, whereas gliquidone therapy did not lose weight and decrease serum level of TG. These data may have important implications for the treatment of patients with type 2 DM.

Animals ; Aorta ; drug effects ; Diabetes Mellitus, Experimental ; drug therapy ; Diabetic Angiopathies ; prevention & control ; Hypoglycemic Agents ; therapeutic use ; Male ; Metformin ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Sulfonylurea Compounds ; therapeutic use

OBJECTIVETo evalueate hepatoprotective effects Feronia elephantum (F. elephantum) correa against thioacetamide (TA) induced liver necrosis in diabetic rats.

METHODSMale wistar rats were made diabetic with alloxan (160 mg/kg) on day 0 of the study. They were intoxicated with hepatotoxicant (thioacetamide, 300 mg/kg, ip) on day 9 of study to produce liver necrosis. Effects of 7 day daily once administration (day 2 to day 9) of EF (400 and 800 mg/kg, po) were evaluated on necorosis of liver in terms of mortality, liver volume, liver weight, serum aspartate aminotransferase (AST) and serum alanine transaminase (ALT), and histopathology of liver sections (for signs of necorosis and inflammation) on day-9 of the study. Separate groups of rats with treated only with alloxan (DA control), thioacetamide (TA control) and both (TA+DA control) were maintained.

RESULTSFE significantly lowered the mortality rate and showed improvement in liver function parameters in TA-induced diabetic rats without change in liver weight, volume and serum glucose levels.

CONCLUSIONSFE showed promising activity against TA-induced liver necorsis in diabetic rats and so might be useful for prevention of liver complications in DM.

Animals ; Blood Glucose ; drug effects ; Chemical and Drug Induced Liver Injury ; drug therapy ; mortality ; pathology ; prevention & control ; Diabetes Mellitus, Experimental ; Disease Models, Animal ; Liver Function Tests ; Male ; Necrosis ; Plant Extracts ; administration & dosage ; chemistry ; pharmacology ; Protective Agents ; Rats ; Rutaceae ; chemistry ; Thioacetamide ; adverse effects

OBJECTIVETo study the protective effect of the Mixture of Shengmai Powder and Danshen Decoction (, abbreviated as the Mixture) in the rat model with type 2 diabetic cardiomyopathy in the rat model with type 2 diabetic cardiomyopathy, abbreviated as the Mixture) in the rat model with type 2 diabetic cardiomyopathy (DCM).

METHODSForty-two SD rats with DCM model, established by the combination of insulin resistance by a high-fat diet with the damage of pancreatic islet β cells by intraperitoneal injection of high dose streptozotocin (50 mg/kg) once, were evaluated in the damage of the myocardium by electrocardiogram at the end of 12 weeks of grouping and intervention administration; the extent of damage in the myocardial subcellular structure was observed by electron microscopy; the content of myocardial collagen in the left cardiac ventricle was quantified by Masson staining test; the myocardial cell apoptosis was determined by TUNEL; the changes in the mRNA expression levels of thrombospodin-1 (TSP-1) and tribbles homolog 3 (TRB-3) by real-time quantitative PCR, the expression levels of myocardial TSP-1, tumor growth factorβ1 (TGF-β1), TRB-3, and chymase were detected by immunohistochemistry, and the changes in the expression levels of myocardial TSP-1, active-TGF-β1 (A-TGF-β1) and latent-TGF-β1 (L-TGF-β1) protein were tested by Western blotting.

RESULTSCompared with the control group, the myocardial tissue was less damaged, and the extent of damage in the myocardial subcellular structure was less; the collagen fiber content and the cell apoptosis were reduced; the expression levels of TSP-1mRNA and TRB-3 mRNA, the expression levels of myocardial TSP-1, TGF-β1, TRB-3, and chymase, as well as the average expression levels of the myocardial TSP-1, A-TGFβ1, and L-TGF-β1 protein were decreased in the Mixture group.

CONCLUSIONThe Mixture of Shengmai Powder and Danshen Decoction could inhibit the process of myocardial fibrosis in the rat myocardium of DCM through multiple pathways and significantly delay the genesis and progress of DCM in hyperglycemic rats.

Animals ; Cytoprotection ; drug effects ; Diabetes Mellitus, Experimental ; complications ; drug therapy ; Diabetic Cardiomyopathies ; pathology ; prevention & control ; Disease Models, Animal ; Drug Combinations ; Drug Evaluation, Preclinical ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Heart ; drug effects ; Male ; Myocardium ; cytology ; pathology ; Rats ; Rats, Sprague-Dawley ; Streptozocin

BACKGROUNDDiabetic nephropathy is a major cause of renal failure in diabetes mellitus (DM). It has been known that renin-angiotensin system (RAS) blockers have a renal protective effect. This study aimed to investigate whether treatment with angiotensin II receptor blocker, olmesartan, could modify renal hemodynamic variables and vascular structural properties, then attenuate renal injury in streptozotocin (STZ)-induced DM rats.

METHODSDM was induced in male Wistar rats by intraperitoneal administration of STZ. The rats were then randomized to a DM group and an olmesartan treatment (OLM + DM) group. The normal group (non-DM) were administered only citrate buffer. At the end of the 14th week, blood glucose, kidney weight/body weight and urinary protein-to-creatinine ratio were determined. Further, the flow-pressure and pressure-glomerular filtration rate (GFR) relationships were determined for maximally vasodilated, perfused kidneys. From the relationship, 3 indices of vascular structural properties were estimated: slope of flow-pressure (minimal renal vascular resistance, reflecting overall luminal dimensions of preglomerular and postglomerular vasculature), slope of pressure-GFR (glomerular filtration capacity against pressure) and threshold pressure for beginning filtration at pressure-GFR (preglomerular to postglomerular vascular resistance ratio). Kidneys were then perfusion fixed for histological analysis. The renal histopathology was observed by light microscopy.

RESULTSThe body weight of DM rats was lower than that of non-DM rats. Blood glucose, kidney weight/body weight, urinary protein-to-creatinine ratio were significantly greater in DM rats than in non-DM rats. The parameters such as kidney weight/body weight, urinary protein-to-creatinine ratio in OLM + DM rats had dramatically decreased compared with those in DM rats. However, the treatment with olmesartan had no effect on blood glucose levels. The slope of flow-pressure relationship was greater in DM rats than that in non-DM rats (P < 0.05). But the slope of the pressure-GFR relationship was lower in DM rats than that in non-DM rats (P < 0.05) with the x-intercept of the line similar between the two groups. The slope of the flow-pressure relationship was decreased in DM rats group treated with olmesartan (P < 0.05). Moreover, olmesartan significantly increased the slope of the pressure-GFR relationship in DM rats (P < 0.05). The x-intercept of the pressure-GFR relationship reduced following olmesartan in DM rats.

CONCLUSIONSTreatment with olmesartan reduced urinary protein-to-creatinine ratio independent of blood glucose and increased average renal vessel lumen diameter in the perfused kidneys of STZ-induced DM rats, predominantly in preglomerular vessels, and then improved renal excretory capability. These findings were consistent with remodeling of the preglomerular vasculature in our hisological measurements.

Angiotensin II Type 1 Receptor Blockers ; therapeutic use ; Animals ; Blood Glucose ; drug effects ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; physiopathology ; Diabetic Nephropathies ; drug therapy ; prevention & control ; Hemodynamics ; drug effects ; Imidazoles ; Kidney ; drug effects ; metabolism ; pathology ; Male ; Organ Size ; drug effects ; Rats ; Rats, Wistar ; Tetrazoles

PURPOSE: The vascular endothelial growth factor (VEGF) expression of podocyte is one of the well-known major factors in development of diabetic nephropathy. In this study, we investigated the effects of aldose reductase inhibitor, fidarestat on diabetic nephropathy, and renal VEGF expression in a type 1 diabetic rat model. MATERIALS AND METHODS: Twenty four Sprague-Dawley male rats which were performed intraperitoneal injection of streptozotocin and normal six rats were divided into four groups including a normal control group, untreated diabetic control group, aldose reductase (AR) inhibitor (fidarestat, 16 mg.kg(-1).day(-1)) treated diabetic group, and angiotensin receptor blocker (losartan, 20 mg.kg(-1).day(-1)) treated diabetic group. We checked body weights and blood glucose levels monthly and measured urine albumin-creatinine ratio (ACR) at 8 and 32 weeks. We extracted the kidney to examine the renal morphology and VEGF expressions. RESULTS: The ACR decreased in fidarestat and losartan treated diabetic rat groups than in untreated diabetic group (24.79 +/- 11.12, 16.11 +/- 9.95, and 84.85 +/- 91.19, p < 0.05). The renal VEGF messenger RNA (mRNA) and protein expression were significantly decreased in the fidarestat and losartan treated diabetic rat groups than in the diabetic control group. CONCLUSION: We suggested that aldose reductase inhibitor may have preventive effect on diabetic nephropathy by reducing renal VEGF overexpression.
Aldehyde Reductase/*antagonists & inhibitors ; Animals ; Antihypertensive Agents/therapeutic use ; Diabetes Mellitus, Experimental/*drug therapy/*metabolism ; Diabetic Nephropathies/prevention & control ; Imidazolidines/*therapeutic use ; Kidney/*drug effects/*metabolism/pathology ; Losartan/therapeutic use ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Angiotensin/*antagonists & inhibitors ; Vascular Endothelial Growth Factor A

NF-kappaB activation has been implicated as a key signaling mechanism for pancreatic beta-cell damage. Sulfuretin is one of the main flavonoids produced by Rhus verniciflua, which is reported to inhibit the inflammatory response by suppressing the NF-kappaB pathway. Therefore, we isolated sulfuretin from Rhus verniciflua and evaluated if sulfuretin could inhibit cytokine- or streptozotocin-induced beta-cell damage. Rat insulinoma RINm5F cells and isolated rat islets were treated with IL-1beta and IFN-gamma to induce cytotoxicity. Incubation of cells and islets with sulfuretin resulted in a significant reduction of cytokine-induced NF-kappaB activation and its downstream events, iNOS expression, and nitric oxide production. The cytotoxic effects of cytokines were completely abolished when cells or islets were pretreated with sulfuretin. The protective effect of sulfuretin was further demonstrated by normal insulin secretion of cytokine-treated islets in response to glucose. Treatment of mice with streptozotocin resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by immunohistochemical staining of islets. However, the diabetogenic effects of streptozotocin were completely prevented when mice were pretreated with sulfuretin. The anti-diabetogenic effects of sulfuretin were also mediated by suppression of NF-kappaB activation. Collectively, these results indicate that sulfuretin may have therapeutic value in preventing beta-cell damage.
Animals ; Benzofurans/*pharmacology/therapeutic use ; Cell Line ; Cytokines/*adverse effects ; Diabetes Mellitus, Experimental/drug therapy/*prevention & control ; Flavonoids/pharmacology/therapeutic use ; Hypoglycemic Agents/pharmacology/therapeutic use ; Insulin-Secreting Cells/*drug effects ; Male ; Mice ; Mice, Inbred ICR ; NF-kappa B/*metabolism ; Rats ; Rats, Sprague-Dawley ; Rhus/chemistry

OBJECTIVEUse laser confocal microscopy overspeed camera technique and fluorescence albumin labeling to study the acting mechanism of Qishen Yiqi Drop Pill (QYDP) for intervening irido-microangiopathy (IMAP) in diabetic rats.

METHODSRat model of diabetes mellitus type 1 (DM1) was established by intraperitoneal injection of streptozocin (STZ). The model rats were randomly divided into three groups, the treatment group, the model group and the control group. At the same time a normal control group was set up. The treatment group was medicated with QYDP (prepared into liquid form), and the control group with Duobeisi liquor (1 g/kg per day) for 10 months. The dynamic state of iris microcirculation in rats was observed using laser confocal microscopy overspeed camera.

RESULTSCompared with the treatment group, blood flow in iris of model rats was slower significantly (P < 0.01); the fluorescence density and leakage area of inside and outside iris vessels, and the iris vascular diameter were significantly higher in the model group than those in the treatment group (P < 0.01).

CONCLUSIONQYDP has definite effect in improving iris microcirculation, which can accelerate the blood flow, inhibit the abnormal expansion of vessels and improve the increased iris micro-vascular permeability.

Animals ; Capillary Permeability ; drug effects ; Diabetes Mellitus, Experimental ; complications ; drug therapy ; Diabetes Mellitus, Type 1 ; complications ; drug therapy ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Iris ; blood supply ; Iris Diseases ; etiology ; prevention & control ; Male ; Phytotherapy ; Rats ; Rats, Sprague-Dawley