Stereoselective effects of 3-hydroxybutyrate on glucose utilization of rat cardiomyocytes

In researches of ketone bodies, D-3-hydroxybutyrate (D-3HB) is usually the major one which has been investigated; in contrast, little attention has been paid to L-3-hydroxybutyrate (L-3HB), because of its presence in trace amounts, its dubious metabolism, and a lack of knowledge about its sources. In the present study we determined the distributions of enantiomers of 3-hydroxybutyrate (3HB) in rat brain, liver, heart, and kidney homogenates, and we found the heart homogenate contained an enriched amount of L-3HB (37.67 microM/mg protein) which generated a significant ratio of 66/34 (D/L). The ratio was altered to be 87/13 in the diabetic rat heart homogenate. We subsequently found this changed ratio of D/L-3HB may contribute to reduce glucose utilization in cardiomyocytes. Glucose utilization by cardiomyocytes with 5 mM of D-3HB was decreased to 61% of the control, but no interference was observed when D-3HB was replaced with L-3HB, suggesting L-3HB is not utilized for the energy fuel as other ketone bodies are. In addition, the reduced glucose utilization caused by D-3HB gradually recovered in a dose-dependent manner with administration of additional L-3HB. The results gave the necessity of taking L-3HB together with D-3HB into account with regard to glucose utilization, and L-3HB may be a helpful substrate for improving inhibited cardiac pyruvate oxidation caused by hyperketonemia.     

Identification of L-3-hydroxybutyrate as an original ketone body in rat serum by column-switching high-performance liquid chromatography and fluorescence derivatization

L-3-Hydroxybutyrate (L-3HB), the enantiomer of D-3-hydroxybutyrate (D-3HB), has traditionally been regarded the "unnatural" ketone body in mammals, although there is suspicion that it is a more-favorable energy fuel for mammalian tissues than D-3HB. In this study, we demonstrated that L-3HB is an original substance in rat serum by applying fluorescence derivatization and a column-switching high-performance liquid chromatography system as the analysis technique. Racemic 3HB in rat serum derivatized using 4-nitro-7-piperazino-2,1,3-benzoxadiazole was first separated by an ODS column and was further confirmed by verifying the disappearance of the racemic 3HB peak after pretreating rat serum with D-3-hydroxybutyryl dehydrogenase. A switching valve was used to simultaneously introduce isolated racemic 3HB to the enantiomeric separation by two CHIRALCEL OD-RH columns connected in tandem. An L isomer was found to accompany the D isomer, which were quantified to be 3.98 microM (3.61%) and 106.20 microM (96.39%), respectively. Using the present analytical method, the dubious interpretation of the existence of L-3HB was clarified.     

Effects of diabetes and insulin on ketone bodies metabolism in heart

This work investigates the effect of alloxan-induced short-term diabetes (24 h) on D-3-hydroxybutyrate metabolism at physiological and non-physiological concentrations of the ketone body in the isolated non-working perfused rat heart. Also the effect of insulin (2 mU.ml⁻¹) on D-3-hydroxybutyrate metabolism was investigated in hearts from normal and diabetic rats. The rates of D-3-hydroxybutyrate utilization and oxidation and of acetoacetate production were proportional to D-3-hydroxybutyrate concentration. The utilization of D-3-hydroxybutyrate showed saturation kinetics in hearts from normal and diabetic rats, in the presence and absence of insulin. Acute short-term diabetes augmented D-3-hydroxybutyrate utilization and oxidation at 1.25 and 2.5 mM DL-3-HB, with no significant effect at higher concentrations, but increased acetoacetate production at all investigated concentrations. In hearts from normal rats, insulin enhanced D-3-hydroxybutyrate utilization and oxidation at 2.5, 5, and 10 mM DL-3-HB, but no effect was observed at the lowest (1.25 mM) and highest (16 mM) DL-3-HB concentrations. Insulin had no effect on D-3-hydroxybutyrate metabolism in hearts from diabetic rats. No significant effect of insulin on the rate of acetoacetate production in normal and diabetic states was observed.     

Determination of time-dependent accumulation of D-lactate in the streptozotocin-induced diabetic rat kidney by column-switching HPLC with fluorescence detection

For better understanding the complete metabolism and the physiological role of D-lactate, the concentrations of D-lactate in the serum, liver and kidney of normal and diabetic rats were determined by our established column-switching HPLC method with pre-column fluorescence derivatization. Eight-week-old male Sprague-Dawley rats were administered with streptozotocin (STZ) (80 mg/kg) or citrate buffer intraperitoneally. The tissues were then removed and homogenized after 4, 8, 12 and 16 weeks of drug administration, respectively. The homogenates were centrifuged at 1200 × g for 10 min, then the supernatants were derivatized with a fluorescent reagent, 4-nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ), separated on an ODS column followed by a Chiralpak AD-RH chiral column for enantioseparation. The results showed that the D-lactate content elevated in all the 3 examined tissues under diabetic stages. In addition, D-lactate concentrations in rat kidney were accumulated significantly and time-dependently in diabetic groups after receiving STZ for 4, 8, 12 and 16 weeks (2.99, 13.11, 18.19, 23.23 vs. 0.79 μmol/mg protein as control group). Moreover, the kidney of induced 12-week diabetic rat renal showed some histological changes of progressive diabetic nephropathy. The results suggest that D-lactate may be used as a marker of diabetic nephropathy.     

The effects of quercetin on bone minerals, biomechanical behavior, and structure in streptozotocin-induced diabetic rats

This study was designed to investigate the effect of quercetin (QE) on bone minerals and biomechanics in insulin-dependent diabetic rats. Diabetes was induced by 50 mg kg(-1) intraperitoneal streptozotocin (STZ) in a single dose. The rats were randomly allotted into four experimental groups: A (control), B (non-diabetic + QE), C (diabetic), and D (diabetic + QE) each containing 10 animals. The diabetic rats received QE (15 mg kg(-1) day(-1)) for 4 weeks following 8 weeks of STZ injection. Blood samples were taken to determine glucose, insulin, calcium, and magnesium levels. The rats' femora were assessed biomechanically at femoral mid-diaphysis and neck. It was found that QE treatment increased insulin, calcium, and magnesium levels. Three-point bending of the femoral mid-diaphysis and necks showed significantly lower maximum load values (F max) in animals in the STZ group than the QE + STZ or control groups (p < 0.05). The results support the conclusion that QE treatment may decrease blood glucose and increase plasma insulin, calcium, and magnesium. QE treatment may also be effective in bone mineral metabolism, biomechanical strength, and bone structure in STZ-induced diabetic rats.     

Increased hepatic lipid soluble antioxidant capacity as compared to other organs of streptozotocin-induced diabetic rats: a cyclic voltammetry study

It has been suggested that oxidative stress plays an important role in the chronic complications of diabetes. The experimental findings regarding the changes in tissue antioxidant enzymes and lipid peroxidation of diabetic tissues have been inconsistent. Previous studies in our laboratory demonstrated that the reducing power of a specific tissue correlates with its low molecular weight antioxidant (LMWA) capacity. In the present study, the overall LMWA capacity (reducing equivalents) of plasma and tissues of streptozotocin (STZ)-induced diabetic rats (1-4 weeks) and insulin treated diabetic rats were measured by cyclic voltammetry. Levels of water and lipid soluble LMWA capacity progressively decreased in the diabetic plasma, kidney, heart and brain, while the diabetic liver, at 2, 3 and 4 weeks after STZ injection, showed a significant increase in the overall lipid soluble LMWA capacity (p < 0.001). Subsequently, analysis of specific components by high pressure liquid chromatography (electrochemical detection) showed decreased levels of ascorbic acid in plasma, kidney, heart and brain of diabetic animals. The alpha-tocopherol level dropped in all tissues, except for the liver in which there was a significant increase (p < 0.01 and p < 0.001 at 2-4 weeks). Lipid peroxidation was assessed by conjugated diene levels, which increased significantly in all diabetic tissues except the liver. Insulin treatment that was started after 3 weeks of diabetes and continued for 3 weeks showed no change in the conjugated dienes and in the overall LMWA capacity in all organs. Our results suggest a unique behavior of the liver in the STZ-induced diabetic rats to the stress and indicate its higher capacity to cope with oxidative stress as compared to other organs.     

The effects of resveratrol on cyclooxygenase-1 and -2, nuclear factor kappa beta, matrix metalloproteinase-9, and sirtuin 1 mRNA expression in hearts of streptozotocin-induced diabetic rats

Resveratrol (RSV) has a beneficial role in the prevention of diabetes and alleviates some diabetic complications, such as cardiomyopathy. We investigated cyclooxygenase-1 (COX-1), COX-2, nuclear factor κB (NF-κB), matrix metalloproteinase-9 (MMP-9), and sirtuin 1 (SIRT1) mRNA expression levels in heart tissue after RSV treatment in streptozotocin (STZ)-induced diabetic rats. After induction of chronic diabetes with STZ, 10 mg RSV/kg per day was administered to DM and DM+RSV groups for four weeks. At the end of the experiment, all rats were sacrificed and heart tissues were stored at -80°C; mRNA expression levels of COX-1, COX-2, NF-κB, MMP-9, and SIRT1 genes were analyzed with quantitative real-time PCR. We did not find any significant effect of RSV on MMP-9, COX-1, COX-2, or NF-κB mRNA levels among the groups. However, SIRT1 mRNA levels decreased in the DM group compared to controls and increased in the DM+RSV group when compared to the DM group. SIRT1 is activated by RSV treatment in diabetic heart tissue. Activation of SIRT1 by RSV may lead to a new therapeutic approach for diabetic heart tissue. We conclude that RSV treatment can alleviate heart dysfunction by inhibiton of inflammatory gene expression such as SIRT1.     

Effects of acidosis on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin-induced diabetic rats

We have investigated the effects of acute acidosis on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin (STZ)-induced diabetic rat. Shortening and intracellular Ca2+ were measured in electrically stimulated myocytes superfused with either normal Tyrode solution pH adjusted to either 7.4 (control solution) or 6.4 (acid solution). Experiments were performed at 35-36 degrees C. At 8-12 weeks after treatment, the rats that received STZ had lower body and heart weights compared to controls, and blood glucose was characteristically increased. Contractile defects in myocytes from diabetic rat were characterized by prolonged time to peak shortening. Superfusion of myocytes from control and diabetic rats with acid solution caused a significant reduction in the amplitude of shortening; however, the magnitude of the response was not altered by STZ treatment. Acid solution also caused significant and quantitatively similar reductions in the amplitude of Ca2+ transients in myocytes from control and diabetic rats. Effects of acute acidosis on amplitude of myocyte contraction and Ca2+ transient were not significantly altered by STZ treatment. Altered myofilament sensitivity to Ca2+ and altered mechanisms of sarcoplasmic reticulum Ca2+ transport might partly underlie the acidosis-evoked reduction in amplitude of shortening in myocytes from control and STZ-induced diabetic rat.     

In vivo treatment with stobadine prevents lipid peroxidation,protein glycation and calcium overload but does not ameliorate Ca2+ -ATPase activity in heart and liver of streptozotocin-diabetic rats: comparison with vitamin E

Hyperglycemia leads to excess production of reactive oxygen species (ROS), lipid peroxidation and protein glycation that may impair cellular calcium homeostasis and results in calcium sequestration and dysfunction in diabetic tissues. Stobadine (ST) is a pyridoindole antioxidant has been postulated as a new cardio- and neuroprotectant. This study was undertaken to test the hypothesis that the treatment with ST inhibits calcium accumulation, reduces lipid peroxidation and protein glycation and can change Ca2+,Mg2+-ATPase activity in diabetic animals. The effects of vitamin E treatment were also evaluated and compared with the effects of combined treatment with ST. Diabetes was induced by streptozotocin (STZ, 55 mg/kg i.p.). Some of diabetic rats and their age-matched controls were treated orally with a low dose of ST (24.7 mg/kg/day), vitamin E (400-500 IU/kg/day) or ST plus vitamin E for 10 weeks. ST and vitamin E separately produced, in a similar degree, reduction in diabetes-induced hyperglycemia. Each antioxidant alone significantly lowered the levels of plasma lipid peroxidation, cardiac and hepatic protein glycation in diabetic rats but vitamin E treatment was found to be more effective than ST treatment alone. Diabetes-induced increase in plasma triacylglycerol levels was not significantly altered by vitamin E treatment but markedly reduced by ST alone. The treatment with each antioxidant completely prevented calcium accumulation in diabetic heart and liver. Microsomal Ca2+,Mg2+-ATPase activity significantly decreased in both tissues of untreated diabetic rats. ST alone significantly increased microsomal Ca2+,Mg2+-ATPase activity in the heart of normal rats. However, neither treatment with ST nor vitamin E alone, nor their combination did change cardiac Ca2+,Mg2+-ATPase activity in diabetic heart. In normal rats, neither antioxidant had a significant effect on hepatic Ca2+,Mg2+-ATPase activity. Hepatic Ca2+,Mg2+-ATPase activity of diabetic rats was not changed by single treatment with ST, while vitamin E alone completely prevented diabetes-induced inhibition in microsomal Ca2+,Mg2+-ATPase activity in liver. Combined treatment with ST and vitamin E provided more benefits in the reduction of hyperglycemia and lipid peroxidation in diabetic animals. This study describes potential mechanisms on cellular effects of ST in the presence of diabetes-induced hyperglycemia that may delay or inhibit the development of diabetic complications. The use of ST together with vitamin E can better control hyperglycemia-induced oxidative stress.     

Increased hepatic lipid soluble antioxidant capacity as compared to other organs of streptozotocin-induced diabetic rats: A cyclic voltammetry study

It has been suggested that oxidative stress plays an important role in the chronic complications of diabetes. The experimental findings regarding the changes in tissue antioxidant enzymes and lipid peroxidation of diabetic tissues have been inconsistent. Previous studies in our laboratory demonstrated that the reducing power of a specific tissue correlates with its low molecular weight antioxidant (LMWA) capacity. In the present study, the overall LMWA capacity (reducing equivalents) of plasma and tissues of streptozotocin (STZ)-induced diabetic rats (1–4 weeks) and insulin treated diabetic rats were measured by cyclic voltammetry. Levels of water and lipid soluble LMWA capacity progressively decreased in the diabetic plasma, kidney, heart and brain, while the diabetic liver, at 2, 3 and 4 weeks after STZ injection, showed a significant increase in the overall lipid soluble LMWA capacity (p < 0.001). Subsequently, analysis of specific components by high pressure liquid chromatography (electrochemical detection) showed decreased levels of ascorbic acid in plasma, kidney, heart and brain of diabetic animals. The α-tocopherol level dropped in all tissues, except for the liver in which there was a significant increase (p < 0.01 and p < 0.001 at 2–4 weeks). Lipid peroxidation was assessed by conjugated diene levels, which increased significantly in all diabetic tissues except the liver. Insulin treatment that was started after 3 weeks of diabetes and continued for 3 weeks showed no change in the conjugated dienes and in the overall LMWA capacity in all organs. Our results suggest a unique behavior of the liver in the STZ-induced diabetic rats to the stress and indicate its higher capacity to cope with oxidative stress as compared to other organs.     

Dosage effect of streptozotocin on rat tissue enzyme activities and glycogen concentration

The effect of different dosages of streptozotocin (STZ) on selected rat tissue enzyme activities and glycogen concentration were investigated. The rats were administered STZ intravenously at 60 (STZ-60), 80 (STZ-80), 100 (STZ-100), and 150 (STZ-150) mg/kg body weight. They were used 3 weeks postinjection. Mortality prior to kill occurred only in the STZ-100 and STZ-150 rats. All diabetic rats showed reduced growth rate, hyperglycemia, hypoinsulinemia, and hyperlipemia. Phosphofructokinase (PFK) and succinate dehydrogenase (SDH) activities were significantly reduced in the red gastrocnemius muscle of all diabetic rats, and in the white gastrocnemius and soleus of STZ-100 and STZ-150 groups. PFK activity in the heart remained unaltered, but SDH activity was below normal. Liver SDH activity was not affected by insulin deficiency. Glycogen content was markedly increased in the heart and decreased in the liver of all diabetic rats. Glycogen content in the skeletal muscle was similar to the controls, except for the lower values in the soleus of STZ-100 and STZ-150 rats. When STZ-80 and STZ-150 rats were given insulin therapy, the STZ-80 rats showed a greater response to the treatment. Despite similar levels of plasma immunoreactive insulin among all groups of diabetic rats, the STZ-100 and STZ-150 rats had higher mortality, greater loss in body weight, and alterations in enzyme activities and glycogen content in the tissues studied.     

Improved Hypolipidemic Effects of Xanthan Gum-Galactomannan Mixtures in Rats

This study describes the effects of mixtures of xanthan gum and galactomannan, guar gum, or locust bean gum, on the lipids in plasma and liver in non-diabetic and diabetic rats. Non-diabetic rats were fed cholesterol-free diets with 3% guar gum, locust bean gum, or xanthan gum (3G, 3L, and 3X), or a mixture of xanthan gum and guar gum or locust bean gum (1:2, w/w) (2G1X, 2L1X) for 2 weeks. Rats fed diets not containing these polysaccharides were used as controls. The total cholesterol in plasma and the triacylglycerol in liver were significantly lowered in rats fed the 2G1X diet. The 3G, 3X, 3L, and 2L1X diets showed no significant effect on the total cholesterol and triacylglycerol in plasma and liver. In the streptozotocin-induced (STZ) diabetic rats, the total cholesterol in plasma was lowered in rats fed the 3G, 3X or 2G1X diet for 4 weeks, and the 2G1X diet was more effective than the 3G and 3X diets. The triacylglycerol in plasma in STZ diabetic rats was also significantly lowered by the 2G1X diet. These results showed that a mixture of xanthan gum and guar gum has an improved hypolipidemic effect on non-diabetic and STZ diabetic rats. The effects of the 2G1X diet on the diabetic symptoms in STZ diabetic rats, suppression of food and water intakes, decrease in glucose in urine, and lowering of plasma glucose, were also observed.     

Improved hypolipidemic effects of xanthan gum-galactomannan mixtures in rats

This study describes the effects of mixtures of xanthan gum and galactomannan, guar gum, or locust bean gum, on the lipids in plasma and liver in non-diabetic and diabetic rats. Non-diabetic rats were fed cholesterol-free diets with 3% guar gum, locust bean gum, or xanthan gum (3G, 3L, and 3X), or a mixture of xanthan gum and guar gum or locust bean gum (1:2, w/w) (2G1X, 2L1X) for 2 weeks. Rats fed diets not containing these polysaccharides were used as controls. The total cholesterol in plasma and the triacylglycerol in liver were significantly lowered in rats fed the 2G1X diet. The 3G, 3X, 3L, and 2L1X diets showed no significant effect on the total cholesterol and triacylglycerol in plasma and liver. In the streptozotocin-induced (STZ) diabetic rats, the total cholesterol in plasma was lowered in rats fed the 3G, 3X or 2G1X diet for 4 weeks, and the 2G1X diet was more effective than the 3G and 3X diets. The triacylglycerol in plasma in STZ diabetic rats was also significantly lowered by the 2G1X diet. These results showed that a mixture of xanthan gum and guar gum has an improved hypolipidemic effect on non-diabetic and STZ diabetic rats. The effects of the 2G1X diet on the diabetic symptoms in STZ diabetic rats, suppression of food and water intakes, decrease in glucose in urine, and lowering of plasma glucose, were also observed.     

Effects of acidosis on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin-induced diabetic rats

We have investigated the effects of acute acidosis on ventricular myocyte shortening and intracellular Ca²⁺ in streptozotocin (STZ)-induced diabetic rat. Shortening and intracellular Ca²⁺ were measured in electrically stimulated myocytes superfused with either normal Tyrode solution pH adjusted to either 7.4 (control solution) or 6.4 (acid solution). Experiments were performed at 35–36°C. At 8–12 weeks after treatment, the rats that received STZ had lower body and heart weights compared to controls, and blood glucose was characteristically increased. Contractile defects in myocytes from diabetic rat were characterized by prolonged time to peak shortening. Superfusion of myocytes from control and diabetic rats with acid solution caused a significant reduction in the amplitude of shortening; however, the magnitude of the response was not altered by STZ treatment. Acid solution also caused significant and quantitatively similar reductions in the amplitude of Ca²⁺ transients in myocytes from control and diabetic rats. Effects of acute acidosis on amplitude of myocyte contraction and Ca²⁺ transient were not significantly altered by STZ treatment. Altered myofilament sensitivity to Ca²⁺ and altered mechanisms of sarcoplasmic reticulum Ca²⁺ transport might partly underlie the acidosis-evoked reduction in amplitude of shortening in myocytes from control and STZ-induced diabetic rat. (Mol Cell Biochem 261: 227–233, 2004)     

Effects of cod liver oil on tissue antioxidant pathways in normal and streptozotocin-diabetic rats

Lipid disorders and increased oxidative stress may exacerbate some complications of diabetes mellitus. Previous studies have implicated the beneficial effects of some antioxidants, omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the protection of cells from the destructive effect of increased lipids and lipid peroxidation products. This study, therefore, was designed to investigate the effects of cod liver oil (CLO, Lysi Ltd. Island), which comprises mainly vitamin A, PUFAs, EPA and DHA. Effects were monitored on plasma lipids, lipid peroxidation products (MDA) and the activities of antioxidant enzymes, glutathione peroxidase (GSHPx) and catalase in heart, liver, kidney and lung of non-diabetic control and streptozotocin (STZ)-induced-diabetic rats. Two days after STZ-injection (55 mg kg(-1) i.p.), non-diabetic control and diabetic rats were divided randomly into two groups as untreated or treated with CLO (0.5 ml kg(-1) rat per day) for 12 weeks. Plasma glucose, triacylglycerol and cholesterol concentrations were significantly elevated in 12-week untreated-diabetic animals; CLO treatment almost completely prevented these abnormalities in triacylglycerol and cholesterol, but hyperglycaemia was partially controlled. CLO also provided better weight gain in diabetic animals. In untreated diabetic rats, MDA markedly increased in aorta, heart and liver but was not significantly changed in kidney and lung. This was accompanied by a significant increase in both GSHPx and catalase enzyme activities in aorta, heart, and liver of diabetic rats. In kidney and lung, diabetes resulted in reduced catalase while GSHPx was significantly activated. In aorta, heart, and liver, diabetes-induced changes in MDA were entirely prevented by CLO treatment. In the tissues of CLO-treated diabetic animals, GSHPx activity paralleled those of control animals. CLO treatment also caused significant improvements in catalase activities in every tissue of diabetic rats, but failed to affect MDA and antioxidant activity in control animals. The current study suggests that the treatment of diabetic rats with CLO provides better control of glucose and lipid metabolism, allows recovery of normal growth rate, prevents oxidative/peroxidative stress and ameliorates endogenous antioxidant enzyme activities in various tissues. Because CLO contains a plethora of beneficial compounds together, its use for the management of diabetes-induced complications may provide important advantages.     

外源性精胺抑制高尔基体应激减轻高糖诱导的心肌损伤*

目的:观察糖尿病心肌病(DCM)是否有高尔基体应激(GAS)参与及外源性精胺心肌保护作用是否与调控GAS有关。方法:60只Wistar大鼠随机分为正常对照组(Control),糖尿病组(T1D,STZ 60 mg/kg一次性腹腔注射)和精胺组(T1D+Sp,精胺5 mg/(kg·d)腹腔注射),饲养12周。H9C2系大鼠心肌细胞随机分为正常对照组(Control,10%的FBS-DMEM培养)、高糖组(HG,10% FBS-DMEM+40 mmol/L葡萄糖)和精胺组(HG +Sp,10% FBS-DMEM+40 mmol/L葡萄糖+5 μmol/L精胺)。ELISA检测大鼠血清心肌肌酸激酶同工酶 (CK-MB)、心肌肌钙蛋白T (cTnT);Western blot测定高尔基体蛋白GOLPH3,GM130以及Cleaved Caspase3蛋白表达;免疫荧光检测GOLPH3细胞定位。结果:动物模型中,与正常组相比,糖尿病组大鼠血糖,血清心肌酶CK-MB和cTnT显著升高明显升高;体重,射血分数(EF)显著降低;心肌超微结构损伤明显(肌丝断裂,润盘消失等);同时GOLPH3和Cleaved Caspase3表达上调,GM130表达下调。细胞模型与大体结果一致,免疫荧光显示高尔基体出现应激性碎片化。外源性精胺处理可显著干预上述改变。结论:给予外源性精胺对糖尿病,诱导的心肌损伤具有干预作用,其机制与减轻高尔基体应激有关。     

Lipid peroxidation and activity of antioxidant enzymes in diabetic rats

We hypothesized that oxygen free radicals (OFRs) may be involved in pathogenesis of diabetic complications. We therefore investigated the levels of lipid peroxidation by measuring thiobarbituric acid reactive substances (TBARS) and activity of antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)] in tissues and blood of streptozotocin (STZ)-induced diabetic rats. The animals were divided into two groups: control and diabetic. After 10 weeks (wks) of diabetes the animals were sacrificed and liver, heart, pancreas, kidney and blood were collected for measurement of various biochemical parameters. Diabetes was associated with a significant increase in TBARS in pancreas, heart and blood. The activity of CAT increased in liver, heart and blood but decreased in kidney. GSH-Px activity increased in pancreas and kidney while SOD activity increased in liver, heart and pancreas. Our findings suggest that oxidative stress occurs in diabetic state and that oxidative damage to tissues may be a contributory factor in complications associated with diabetes.     

Effects of melatonin on oxidative-antioxidative status of tissues in streptozotocin-induced diabetic rats

In view of the antioxidant properties of melatonin, the effects of melatonin on the oxidative-antioxidative status of tissues affected by diabetes, e.g. liver, heart and kidneys, were investigated in streptozotocin (STZ)-induced diabetic rats in the present study. Concentrations of malondialdehyde (MDA) and reduced glutathione (GSH), and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the tissues were compared in three groups of 10 rats each (control non-diabetic rats (group I), untreated diabetic rats (group II) and diabetic rats treated with melatonin (group III)). In the study groups, diabetes developed 3 days after intraperitoneal (i.p.) administration of a single 60 mg kg(-1) dose of STZ. Thereafter, while the rats in group II received no treatment, the rats in group III began to receive a 10 mg kg(-1) i.p. dose of melatonin per day. After 6 weeks, the rats in groups II and III had significantly lower body weights and higher blood glucose levels than the rats in group I (p < 0.001 and p < 0.001, respectively). MDA levels in the liver, kidney and heart of group II rats were higher than that of the control group (p < 0.01, p < 0.05, p < 0.01, respectively) and diabetic rats treated with melatonin (p < 0.05). The GSH, GSH-Px and SOD levels increased in diabetic rats. Treatment with melatonin changed them to near control values. Our results confirm that diabetes increases oxidative stress in many organs such as liver, kidney and heart and indicate the role of melatonin in combating the oxidative stress via its free radical-scavenging and antioxidant properties.     

The effects of rosiglitazone on oxidative stress and lipid profile in left ventricular muscles of diabetic rats

We investigated the effect of rosiglitazone (RSG), a high-affinity ligand for the peroxisome proliferator-activated receptor gamma which mediates insulin-sensitizing actions, on the lipid profile and oxidative status in streptozotocin (STZ)-induced Type 2 diabetes mellitus (DM) rats. Wistar albino male rats were randomly divided into an untreated control group (C), a C + RSG group which was treated with RSG (4 mg kg(-1)) two times a day by gavage, a diabetic group (D) that was treated with a single intraperitoneal injection of STZ (45 mgkg(-1)), D + RSG group which were treated with RSG two times a day by gavage, respectively. Lipid profiles, HbA(1c) and blood glucose levels in the circulation and malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) levels in left ventricular muscle were measured. Treatment of D rats with RSG resulted in a time-dependent decrease in blood glucose. We found that the lipid profile and HbA(1c) levels in D + RSG group reached the C rat values at the end of the treatment period. There was a statistically significant difference between the C + RSG and C groups in 3-NT levels. In group D, 3-NT and MDA levels were found to be increased when compared with C, C + RSG and D + RSG groups. In the D + RSG group, MDA levels were found to be decreased when compared with C and C + RSG. Our study suggests that the treatment of D rats with RSG for 8 weeks may decrease the oxidative/nitrosative stress in left ventricular tissue of rats. Thus in diabetes-related vascular diseases, RSG treatment may be cardioprotective.     

Effects of Nigella sativa and its Major Constituent, Thymoquinone on Sciatic Nerves in Experimental Diabetic Neuropathy

The aim of this study was designed to investigate the possible beneficial effects of Nigella sativa (NS) and thymoquinone (TQ) on histopathological changes of sciatic nerves in streptozotocin-induced diabetic rats. The rats were randomly allotted into one of four experimental groups: A (control), B (diabetic untreated), C (diabetic treated with NS) and D (diabetic treated with TQ); each group contain ten animals. B, C and D groups received streptozotocin (STZ) to induce diabetes. The rats in NS and TQ treated groups were given NS (in a dose of 400 mg/kg body weight) and TQ (50 mg/kg body weight) once a day orally by using intra-gastric intubation for 12 weeks starting 2 days after STZ injection, respectively. Blood and tissue samples were obtained for biochemical and histopathological investigation. The treatment of both NS and TQ caused a sharp decrease in the elevated serum glucose (P < 0.01, 0.05, respectively), and an increase in the lowered serum insulin concentrations (P < 0.01, 0.05, respectively), in STZ-induced diabetic rats. STZ induced a significant decrease in the area of insulin immunoreactive β-cells (P < 0.0001). NS (P < 0.001) and TQ (P < 0.01) treatment resulted in increased area of insulin immunoreactive β-cells significantly. To date, no histopathological changes of sciatic nerves in STZ induced diabetic rats by NS and TQ treatment have been reported. In this study, histologic evaluation of the tissues in diabetic animals treated with TQ and especially NS showed fewer morphologic alterations. Myelin breakdown decreased significantly after treatment with NS and TQ. The ultrastructural features of axons also showed remarkable improvement. We believe that further preclinical research into the utility of NS and TQ may indicate its usefulness as a potential treatment on peripheral neuropathy (PN) in STZ induced diabetic rats.