Atorvastatin inhibits hyperglycemia-induced expression of osteopontin in the diabetic rat kidney via the p38 MAPK pathway

Osteopontin (OPN), a large phosphoglycoprotein adhesion molecule, which is up-regulated in the kidneys of humans and mice with diabetes, has emerged as a potentially key pathophysiological contributor in diabetic nephropathy. Here, we investigated the role of OPN in kidney injury caused by diabetic nephropathy and the effect of atorvastatin on the expression of OPN and on diabetic nephropathy. Diabetes was induced with streptozotocin in rats, and atorvastatin (5 mg/kg) was orally administered once a day for 8 weeks. We analyzed the expression and regulation of OPN in the kidneys of streptozotocin-induced diabetic Sprague–Dawley albino rats by immunohistochemistry and western blot analysis. The expression of OPN was increased in diabetic rat kidney, and atorvastatin inhibited this process. Atorvastatin also decreased the expression and phosphorylation of p38. In vitro, atorvastatin inhibited the high glucose-induced OPN expression in Madin-Darby canine kidney epithelial cells through the p38 MAPK signaling pathway. These results suggested that atorvastatin reduced the expression of OPN through inhibition of the p38 MAPK pathway. The expression of OPN was associated with kidney injury. These molecules may represent therapeutic targets for the prevention of acute kidney injury induced by diabetes.     

Growth inhibition, morphology change, and cell cycle alterations in NFBD1-depleted human esophageal cancer cells

Diabetic nephropathy (DN) is one of the foremost causes of renal failure and a primary cause of diabetes mellitus related death. Previously, we have reported that aqueous extract of Enicostemma littorale has potential antidiabetic activity. In the present study, we have investigated the effect of aqueous extract of E. littorale 1 g/kg, p.o. and swertiamarin 50 mg/kg, p.o. daily for 3 weeks in type 1 DN complications in SD rats. DN was assessed by serum urea, creatinine, lipid profile and water intake levels. Treatment with aqueous extract of E. littorale and swertiamarin significantly decreased serum urea and creatinine and other parameters associated with the development of DN in type 1 diabetic rats. We have also found considerable improvement in histology of glomerular function of aqueous extract of E. littorale and swertiamarin-treated animals.     

ACE gene polymorphism and serum ACE activity in Iranians type II diabetic patients with macroalbuminuria

There are controversial results related to the contribution of insertion (I)/deletion (D) polymorphism of the angiotensin I-converting enzyme (ACE) in the development of diabetic nephropathy. To assess the distribution of this polymorphism in diabetic patients with and without nephropathy we studied 140 unrelated type 2 diabetic patients from the Kermanshah Province of Iran with ethnic background of Kurds including 68 patients with macroalbuminuria and 72 normoalbuinuric diabetic patients as controls. Genotyping was done by polymerase chain reaction (PCR). The frequency of D allele in nephropathic and normoalbuminuric patients were 69.1 and 58.3%, respectively (P = 0.061). In individuals with DD genotype the risk of macroalbuminuria increased 2.87-fold (P = 0.057). Significant lower level of serum ACE activity was found in the normoalbuminuric (59.76 IU/l) compared to macroalbuminuric (97.43 IU/l) patients. The serum ACE activity was significantly higher in macroalbuminuric patients with ID (105.7 IU/l) and ID + DD (100.7 IU/l) genotypes compared to normoalbuminuric patients with the same genotypes (63.5 and 64.2 IU/l, respectively). Treatment with captopril significantly (P = 0.045) reduced the serum ACE activity in normoalbuminuric patients with DD genotype compared to macroalbuminuric patients with the same genotype (33.6 vs. 73.8 IU/l). However, the greatest benefit effect of losartan therapy on ACE activity was observed only in macroalbuminuric patients with DD genotype compared to that in normoalbuminuric patients (61.0 vs. 109.0 IU/l, P = 0.06). Our study suggests the importance of ethnic origin in the development of diabetic nephropathy and demonstrates different responses to therapy according to genotype and stage of diabetes.     

Modulatory effects of Pycnogenol® in a rat model of insulin-dependent diabetes mellitus: biochemical, histological, and immunohistochemical evidences

A number of experimental and clinical findings have consistently demonstrated the protective effects of Pycnogenol® (PYC) in the management of diabetes. However, the protective mechanism by which PYC provides protection in a model type I diabetes has not been studied. This study examines the beneficial effect of PYC on hyperglycemia, inflammatory markers, and oxidative damage in diabetic rats. We also evaluated the possible mechanism of action of PYC which might be that it stimulates beta islet expression, which has been implicated in the process of insulin secretion and diabetes management. Diabetes was induced in rats by an intraperitoneal injection of streptozotocin (STZ; 60 mg/kg body weight) followed by free access to 5 % glucose for the next 24 h. Four days after STZ injection, rats were supplemented with PYC (10 mg/kg body weight) for 4 weeks. At the end of the experiment, blood was drawn, and rats were then sacrificed, and their livers and pancreases were dissected for biochemical and histological assays. The level of fasting blood glucose and glycosylated hemoglobin significantly increased but amylase, insulin, and hepatic glycogen level decreased in the STZ group. PYC significantly augmented these effects in STZ?+?PYC group. The STZ group showed elevated level of nitric oxide, tumor necrosis factor-α, and interleukin-1beta in serum which were decreased by PYC treatment. Moreover, PYC significantly ameliorated increased thiobarbituric reactive substances, protein carbonyl, and decreased levels of glutathione, glutathione-s-transferase, and catalase activity in the liver and pancreas of the STZ rats. Histopathological and immunohistochemical examination also revealed a remarkable protective effect of PYC. The study suggests that PYC is effective in reducing diabetic-related complications in a type I model of diabetes and might be beneficial for the treatment of diabetic patients.     

Clinical and anti-aging effect of mud-bathing therapy for patients with fibromyalgia

This study focuses on two inflammatory diseases, viz., “diabetes mellitus (DM)” that causes serious complications such as retinopathy, nephropathy, and neuropathy, and “ischemic colitis” which is evoked by DM. Ischemic colitis originates from the reduction in mesenteric blood flow to the colon with existence of the occlusive or non-occlusive reasons. Our study objective was to provide early diagnostic approach for ischemic colitis in streptozotocin (STZ)-induced diabetic rats. Sprague-Dawley rats were divided into four groups: (i) control use of 0.1 M citrate buffer, the solvent of streptozotocin (C), (ii). induced ischemia (I), (iii) rats subjected to 60 mg/kg STZ intraperitoneally to induce type 1 diabetes (D) (48 h after STZ injection, blood glucose levels >200 mg/dl were considered as diabetic), and (iv) diabetic rats subjected to intestinal ischemia (D+I). The third diabetic group (D) was not operated. At the end of the experimental period, rats were sacrificed, C-reactive protein (CRP) and calprotectin levels were measured in the serum and colon tissue specimens. Tissue specimens were also analyzed histologically. We found that serum and colon calprotectin levels were elevated in the D+I group compared to the D and/or I group alone, but relatively calprotectin levels increased in I as compared to C group in colon tissues. CRP levels were significantly increased with ischemic colitis in diabetes, while colon CRP levels were decreased. These results provide evidence for the existence of inflammation in the STZ-induced diabetic rats with ischemic colitis. In conclusion, our measurements of serum calprotectin levels of STZ-induced diabetic rats with ischemic colitis provide a practical approach for an early diagnosis of ischemic colitis. Furthermore, these biochemical analyses correlate well with the histopathologic findings of STZ-induced diabetic rats with ischemic colitis. Future studies would be desirable to further strengthen the role of calprotectin in the early diagnosis of ischemic colitis in diabetics clinical settings.     

Reduced Levels of Brain Derived Neurotrophic Factor (BDNF) in the Serum of Diabetic Retinopathy Patients and in the Retina of Diabetic Rats

Diabetic retinopathy (DR) is widely recognized as a neurovascular disease. Retina, being a neuronal tissue of the eye, produces neurotrophic factors for its maintenance. However, diabetes dysregulates their levels and thereby may damage the retina. Among neurotrophins, brain derived neurotrophic factor (BDNF) is the most abundant in the retina. In this study, we investigated the level of BDNF in the serum of patients with DR and also in the serum and retina of streptozotocin-induced diabetic rats. The level of BDNF was significantly decreased in the serum of proliferative diabetic retinopathy patients as compared to that of non-diabetic healthy controls (25.5 ± 8.5–10.0 ± 8.1 ng/ml, p < 0.001) as well as compared to that of diabetic patients with no retinopathy (21.8 ± 4.7–10.0 ± 8.1 ng/ml, p < 0.001), as measured by ELISA techniques. The levels of BDNF in the serum and retina of diabetic rats were also significantly reduced compared to that of non-diabetic controls (p < 0.05). In addition, the expression level of tropomyosin-related kinase B (TrkB) was significantly decreased in diabetic rat retina compared to that of non-diabetic controls as determined by Western blotting technique. Caspase-3 activity was increased in diabetic rat retina after 3 weeks of diabetes and remained elevated until 10 weeks, which negatively correlated with the level of BDNF (r = ?0.544, p = 0.013). Our results indicate that reduced levels of BDNF in diabetes may cause apoptosis and neurodegeneration early in diabetic retina, which may lead to neuro-vascular damage later in DR.     

<Emphasis Type="Italic">SUMO4</Emphasis> 163 G&gt;A variation is associated with kidney disease in Indian subjects with type 2 diabetes

Genetic susceptibility probably plays a role in the development and/or progression of diabetic kidney disease. Small ubiquitin-related modifier 4 (SUMO4) mRNA is expressed in human kidney. Substitution of methionine with valine at codon 55 (M55V) of SUMO4 gene induces higher nuclear factor-kB activity, which is known to mediate the development of kidney disease in individuals with diabetes. We investigated the association between the SUMO4 M55V (rs237025, c.163 G>A) and kidney disease in north Indian subjects with diabetes. A case–control analysis was performed using genomic DNA samples from 216 diabetic patients without nephropathy (DM) and 201 diabetic with nephropathy (DN). The SUMO4 c.163 G>A polymorphism was genotyped using polymerase chain reaction amplification followed by restriction digestion. The duration of diabetes was significantly greater in DN. The genotypic and allelic frequencies were different in DM and DN groups: GG genotype was significantly more frequent in DN as compared to DM (p = 0.018, OR 1.72, 95 % CI 1.1–2.7). Similarly the G allele was more frequent in DN compared to DM (p = 0.017, OR 1.4, 95 % CI 1.1–1.8). This study suggests that SUMO4 c.163 G>A polymorphism is associated with the susceptibility to diabetic nephropathy in north Indian subjects with type 2 diabetes.     

Resveratrol Attenuates Copper and Zinc Homeostasis and Ameliorates Oxidative Stress in Type 2 Diabetic Rats

Diabetes is a common metabolic disorder characterized by elevated blood glucose level. Trace element homeostasis causes disturbances in diabetes due to hyperglycemia. Superoxide dismutase (SOD), an antioxidant enzyme, contains zinc and copper ions as its cofactors. Defects in SOD level and activity have been observed in diabetes. Resveratrol (RSV) has displayed hypoglycemic effects and is proven to improve oxidative stress. The aim of the present study was to examine the possible effects of RSV on blood glucose level, serum copper and zinc levels, SOD, and a number of other oxidative markers in type 2 diabetic rats. Diabetes was induced in male Wistar rats with administration of streptozotocin and nicotine amide. The studied groups containing six animals per group were as follows: group 1 normal control group; group 2 diabetic control group; groups 3, 4, and 5 diabetic rats that received 1, 5, and 10 mg/kg body weight of RSV, respectively for 30 days. Serum glucose, copper, zinc, SOD activity, total oxidant status (TOS) as well as thiol groups were all measured. Blood glucose in RSV treated groups significantly decreased. Similarly, copper significantly decreased in diabetic groups treated with RSV. Treatment with 10 mg/kg RSV resulted in significantly increased serum zinc. Furthermore, Cu/Zn ratio was observed to decrease in treated groups compared with untreated diabetic control group. RSV treated groups revealed an increased level of SOD activity as well as improved oxidative status. In summary, the results showed that RSV has potential hypoglycemic effect, attenuates trace element homeostasis, and consequently increases SOD activity level.     

Beneficial Effect of Metformin on Nerve Regeneration and Functional Recovery After Sciatic Nerve Crush Injury in Diabetic Rats

Neuroprotective effects of metformin have been increasingly recognized in both diabetic and non-diabetic conditions. Thus far, no information has been available on the potential beneficial effects of metformin on peripheral nerve regeneration in diabetes mellitus. The present study was designed to investigate such a possibility. Diabetes was established by a single injection of streptozotocin at 50 mg/kg in rats. After sciatic nerve crush injury, the diabetic rats were intraperitoneally administrated daily for 4 weeks with metformin (30, 200 and 500 mg/kg), or normal saline, respectively. The axonal regeneration was investigated by morphometric analysis and retrograde labeling. The functional recovery was evaluated by electrophysiological studies and behavioral analysis. It was found that metformin significantly enhanced axonal regeneration and functional recovery compared to saline after sciatic nerve injury in diabetic rats. In addition, metformin at 200 and 500 mg/kg showed better performance than that at 30 mg/kg. Taken together, metformin is capable of promoting nerve regeneration after sciatic nerve injuries in diabetes mellitus, highlighting its therapeutic values for peripheral nerve injury repair in diabetes mellitus.     

Effects of vitamin E on microsomal Ca(2+) -ATPase activity and calcium levels in streptozotocin-induced diabetic rat kidney

Vitamin E treatment has been found to be beneficial in preventing or reducing diabetic nephropathy. Increased tissue calcium and abnormal microsomal Ca(2+)-ATPase activity have been suggested as contributing factors in the development of diabetic nephropathy. This study was undertaken to test the hypothesis that vitamin E reduces lipid peroxidation and can prevent the abnormalities in microsomal Ca(2+)-ATPase activity and calcium levels in kidney of streptozotocin (STZ)-induced diabetic rats. Male rats were rendered diabetic by a single STZ injection (55 mg x kg(-1) i.p.). After diabetes was verified, diabetic and age-matched control rats were untreated or treated with vitamin E (400-500 IU kg(-1) x day(-1), orally) for 10 weeks. Ca(2+)-ATPase activity and lipid peroxidation (MDA) were determined spectrophotometrically. Blood glucose levels increased approximately five-fold (> 500 mg x dl(-1)) in untreated-diabetic rats but decreased to 340+/-27 mg x dl(-1) in the vitamin E treated-diabetic group. Kidney MDA levels did not significantly change in the diabetic state. However, vitamin E treatment markedly inhibited MDA levels in both control and diabetic animals. Ca(2+)-ATPase activity was 0.483+/-0.008 U l(-1) in the control group and significantly increased to 0.754+/-0.010 U l(-1) in the STZ-diabetic group (p < 0.001). Vitamin E treatment completely prevented the diabetes-induced increase in Ca(2+)-ATPase activity (0.307+/-0.025 U l(-1), p < 0.001) and also reduced the enzyme activity in normal control rats. STZ-diabetes resulted in approximately two-fold increase in total calcium content of kidney. Vitamin E treatment led to a significant reduction in kidney calcium levels of both control and diabetic animals (p < 0.001). Thus, vitamin E treatment can lower blood glucose and lipid peroxidation, which in turn prevents the abnormalities in kidney calcium metabolism of diabetic rats. This study describes a potential biochemical mechanism by which vitamin E supplementation may delay or inhibit the development of cellular damage and nephropathy in diabetes.     

The Antioxidant Activity of Copper(II) (3,5-Diisopropyl Salicylate)4 and Its Protective Effect Against Streptozotocin-Induced Diabetes Mellitus in Rats

Oxidative stress has been suggested as a potential contributor to the development of diabetic complications. In this study, we investigated the protective effect of a strong antioxidant copper complex against streptozotocin (STZ)-induced diabetes in animals. Out of four copper complexes used, copper(II) (3,5-diisopropyl salicylate)₄ (Cu(II)DIPS) was found to be the most potent antioxidant–copper complex. Pretreatment with Cu(II)DIPS (5 mg/kg) twice a week prior to the injection of streptozotocin (50 mg/kg) has reduced the level of hyperglycemia by 34 % and the mortality rate by 29 %. Injection of the same dosage of the ligand 3,5-diisopropyl salicylate has no effect on streptozotocin-induced hyperglycemia. The same copper complex has neither hypoglycemic activity when injected in normal rats nor antidiabetic activity when injected in STZ-induced diabetic rats. The protective effect of Cu(II)DIPS could be related to its strong antioxidant activity compared to other copper complexes median effective concentration (MEC)?=?23.84 μg/ml and to Trolox MEC?=?29.30 μg/ml. In addition, it reduced serum 8-hydroxy-2′-deoxyguanosine, a biomarker of oxidative DNA damage, by 29 %. This effect may explain why it was not effective against diabetic rats, when β Langerhans cells were already destroyed. Similar protective activities were reported by other antioxidants like Trolox.     

Protective effects of the volatile oil of Nigella sativa seeds on β-cell damage in streptozotocin-induced diabetic rats: a light and electron microscopic study

The aim of this study was to evaluate the possible protective effects of the volatile oil of Nigella sativa (NS) seeds on insulin immunoreactivity and ultrastructural changes of pancreatic β-cells in STZ-induced diabetic rats. STZ was injected intraperitoneally at a single dose of 50 mg/kg to induce diabetes. The rats in NS treated groups were given NS (0.2 ml/kg) once a day orally for 4 weeks starting 3 days prior to STZ injection. To date, no ultrastructural changes of pancreatic β-cells in STZ induced diabetic rats by NS treatment have been reported. Islet cell degeneration and weak insulin immunohistochemical staining was observed in rats with STZ-induced diabetes. Increased intensity of staining for insulin, and preservation of β-cell numbers were apparent in the NS-treated diabetic rats. The protective effect of NS on STZ-diabetic rats was evident by a moderate increase in the lowered secretory vesicles with granules and also slight destruction with loss of cristae within the mitochondria of β-cell when compared to control rats. These findings suggest that NS treatment exerts a therapeutic protective effect in diabetes by decreasing morphological changes and preserving pancreatic β-cell integrity. Consequently, NS may be clinically useful for protecting β-cells against oxidative stress.     

Effect of sarpogrelate on altered STZ-diabetes induced cardiovascular responses to 5-hydroxytryptamine in rats

Sarpogrelate, a specific 5-HT_2A receptor antagonist is reported to produce a number of beneficial cardiovascular effects in diabetes mellitus. In the present investigation we have studied the effects of sarpogrelate on 5-HT receptors in heart and platelets in streptozotocin (STZ)-diabetic rats. Diabetes was induced by a single tail vein injection of STZ (45 mg/kg) and sarpogrelate (1 mg/kg, i.p.) was administered daily for 6 weeks. Injection of STZ produced significant loss of body weight, polyphagia, polydypsia, hyperglycemia, hypoinsulinemia, hypertension and bradycardia. Treatment with sarpogrelate significantly lowered fasting glucose levels with corresponding increase in insulin levels. It also significantly prevented STZ-induced polydypsia, hyperphagia, hypertension, and bradycardia but not the loss of body weight. 5-HT produced dose-dependent positive inotropic effect that was found to be decreased significantly in STZ-diabetic rats. Hearts obtained from sarpogrelate treated diabetic rats did not show any decrease in responsiveness to 5-HT. Relative platelet aggregation per se was found to be higher in STZ-diabetic rats as compared to control and this was significantly prevented by sarpogrelate treatment. 5-HT produced a dose-dependent increase in platelet aggregation in non-diabetic and sarpogrelate treated diabetic rats. However, 5-HT failed to produce any increase in platelet aggregation in untreated diabetic rats. Our data suggest that STZ-induced diabetes may produce down-regulation of cardiac 5-HT_2A receptors and increased platelet aggregation. Treatment with sarpogrelate seems to prevent STZ-induced down-regulation of 5-HT receptors and increase in platelet activity in diabetic rats.     

Beneficial effects of soy protein in the initiation and progression against dimethylbenz [a] anthracene-induced breast tumors in female rats

Objective: Although recent studies link altered cellular redox state to protein dysfunction in various disease-states, such associations are least studied in clinical diabetes. Therefore, this study assessed the levels of reduced glutathione (GSH) and Na⁺/K⁺ ATPase activities in type 2 diabetic patients with and without microangiopathy. Methods: The study group comprised of a total of 160 subjects, which included non-diabetic healthy controls (n = 40) and type 2 diabetic patients without (n = 60) and with microangiopathy (n = 60), defined as presence of retinopathy with or without nephropathy. Erythrocyte Na⁺/K⁺ ATPase activity and GSH levels were estimated spectrophotometrically and fluorometry was used to determine the plasma thiobarbituric acid reactive substances (TBARS) and serum advanced glycation end products (AGEs). Results: GSH levels in diabetic subjects without (4.8± 0.15 μmol/g Hb) and with microangiopathy (5.2± 0.14 μmol/g Hb) were significantly lower (p < 0.001) compared to control subjects (6.3± 0.14 μmol/g Hb). Erythrocyte Na⁺/K⁺ ATPase activity was significantly reduced (p < 0.001) in diabetes subjects with (272± 7 nmol Pi/mg protein/h) and without microangiopathy (304 ± 8) compared to control (374 ± 6) subjects. TBARS were significantly higher (p < 0.001) in diabetes subjects with (10.65± 0.81 nM/ml) and without microangiopathy (9.90± 0.5 nM/ml) compared to control subjects (5.18± 0.18 nM/ml). Advanced glycation end product levels were also significantly (p < 0.001) elevated in diabetic subjects with microangiopathy (8.2± 1.8 AU) when compared to diabetes subjects without microangiopathy (7.0± 2.0 AU) and control subjects (4.6± 1.9 AU). On multivariate regression analysis, GSH levels showed a positive association with the Na⁺/K⁺ ATPase activity and negative association with TBARS and AGE levels. Conclusion: Hypoglutathionemia and increased oxidative stress appears to be early biochemical aberrations in diabetes, and through protein alterations, oxidative stress and redox modifications may contribute to pathogenesis of diabetic microangiopathy.     

Inhibition of carbohydrate and lipid digestive enzymes activities by Zygophyllum album extracts: effect on blood and pancreas inflammatory biomarkers in alloxan-induced diabetic rats

Zygophyllum album has been used as herbal medicine in Southern Tunisia to treat several diseases such as diabetes mellitus. This study is aimed to reveal the mechanisms underlying the antihyperglycemic potential, the anti-inflammatory and the protective hematological proprieties of this plant in diabetic rats. The inhibition of the α-amylase activity by different solvent-extract fractions of Z. album was tested in vitro. The fraction endowed with the powerful inhibitory activity against α-amylase was administered to surviving diabetic rats for 30 days. Data from in vitro indicated that each extract from the medicinal plant showed moderate inhibition of α-amylase enzyme except the ethyl acetate extract which was ineffective. The powerful inhibition was achieved by ethanol extract of Z. album (EZA) with an IC50 of 43.48 μg/ml as compared to acarbose (Acar) with an IC50 of 14.88 μg/ml. In vivo, the results showed that EZA decreased the α-amylase levels in serum, pancreas and intestine of diabetic rats by 40 %, 45 % and 46 %, respectively, associated with considerably reduction in blood glucose rate by 61 %. Moreover, the EZA helped to protect the structure and function of the β-cells. Interestingly, EZA had a potent anti-inflammatory effect which is manifested by decreases in CRP and TNF-α levels. Overall, a notable reduction in lipase activity both in serum and small intestine of treated diabetic rats resulted in the improvement of serum and liver lipids profile. Z. album showed a prominent antidiabetic effect via inhibition of carbohydrate and lipid digestive enzymes and ameliorated the inflammation and the disturbance of hematological biomarkers in diabetes.     

Mitochondrial Dysfunction in Brain Cortex Mitochondria of STZ-Diabetic Rats: Effect of l-Arginine

Mitochondrial dysfunction has been implicated in many diseases, including diabetes. It is well known that oxygen free radical species are produced endogenously by mitochondria, and also nitric oxide (NO) by nitric oxide synthases (NOS) associated to mitochondrial membranes, in consequence these organelles constitute main targets for oxidative damage. The aim of this study was to analyze mitochondrial physiology and NO production in brain cortex mitochondria of streptozotocin (STZ) diabetic rats in an early stage of diabetes and the potential effect of l-arginine administration. The diabetic condition was characterized by a clear hyperglycaemic state with loose of body weight after 4 days of STZ injection. This hyperglycaemic state was associated with mitochondrial dysfunction that was evident by an impairment of the respiratory activity, increased production of superoxide anion and a clear mitochondrial depolarization. In addition, the alteration in mitochondrial physiology was associated with a significant decrease in both NO production and nitric oxide synthase type I (NOS I) expression associated to the mitochondrial membranes. An increased level of thiobarbituric acid-reactive substances (TBARS) in brain cortex homogenates from STZ-diabetic rats indicated the presence of lipid peroxidation. l-arginine treatment to diabetic rats did not change blood glucose levels but significantly ameliorated the oxidative stress evidenced by lower TBARS and a lower level of superoxide anion. This effect was paralleled by improvement of mitochondrial respiratory function and a partial mitochondrial repolarization.In addition, the administration of l-arginine to diabetic rats prevented the decrease in NO production and NOSI expression. These results could indicate that exogenously administered l-arginine may have beneficial effects on mitochondrial function, oxidative stress and NO production in brain cortex mitochondria of STZ-diabetic rats.     

Fibrinolytic activity of prostacyclin and iloprost in patients with peripheral arterial disease

We studied the effect of prostacyclin /PGI₂/ and its stable analog, iloprost, on blood fibrinolytic activity in 33 patients with peripheral arterial disease. Ten subjects /group A/ received three 5-hour infusions of iloprost on three consecutive days. The remaining 23 patients received three different 5-hour infusions /placebo, iloprost 2 ng/kg/min, PGI₂ 5 ng/kg/min/. Tissue plasminogen activator /t-PA/, total plasma fibrinolytic activity and euglobulin clot lysis time /ECLT/ were determined in patients before and after each infusion, both in freely flowing blood samples and following 10 min venous occlusion. In patients of group A, ECLT at rest was significantly shortened after all three iloprost infusions /on average by about 5–11%/. First and third infusions produced also shortening of ECLT after venostasis /by 21 and 32%/. Statistically significant rise in t-PA activity /by about 68% on average/ accompanied only the first infusion. In patients of the group B iloprost provoked significant fall in ECLT at rest /by about 19% on average/ only. PGI₂ shortened ECLT both at rest and after venous occlusion /by about 17% and 20% on average, respectively/ and led to a rise in t-PA activity after venous occlusion by about 33% on average. Our results indicate that prostacyclin and its stable analog, iloprost, enhance fibrinolytic activity in man by releasing or facilitating the release of tissue plasminogen activator from the vessel wall.     

Ameliorating effect of eugenol on hyperglycemia by attenuating the key enzymes of glucose metabolism in streptozotocin-induced diabetic rats

Epidemiological studies have demonstrated that diabetes mellitus is a serious health burden for both governments and healthcare providers. This study was hypothesized to evaluate the antihyperglycemic potential of eugenol by determine the activities of key enzymes of glucose metabolism in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced into male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg body weight (b.w.)). Eugenol was administered to diabetic rats intragastrically at 2.5, 5, and 10 mg/kg b.w. for 30 days. The dose 10 mg/kg b.w. significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, and liver marker enzymes (AST, ALT, and ALP), creatine kinase and blood urea nitrogen in serum and blood of diabetic rats were significantly reverted to near normal levels by the administration of eugenol. Further, eugenol administration to diabetic rats improved body weight and hepatic glycogen content demonstrated the antihyperglycemic potential of eugenol in diabetic rats. The present findings suggest that eugenol can potentially ameliorate key enzymes of glucose metabolism in experimental diabetes, and it is sensible to broaden the scale of use of eugenol in a trial to alleviate the adverse effects of diabetes.     

Rapid change of glucose concentration promotes mesangial cell proliferation via VEGF: inhibitory effects of thiazolidinedione

Diabetic nephropathy is a common complication in diabetes mellitus (DM). Thiazolidinedione (TZD) is thought to ameliorate diabetic nephropathy, however, the mechanism has not been elucidated. We hypothesized that VEGF participates in the pathogenesis of diabetic nephropathy and that TZD may be beneficial for the treatment of diabetic nephropathy through its effect on VEGF. Increased VEGF expression was demonstrated in the glomeruli of DM rats and rat mesangial cells (RMC) incubated with high medium glucose. It was also demonstrated that VEGF promoted mesangial cell proliferation, which was inhibited by TZD. It was shown that a rapid fall and rise of ambient glucose concentration induces more VEGF production and cell proliferation in RMC than in cells with continuously high glucose medium, which was also inhibited by TZD. Prostaglandin J2 and protein C kinase inhibitors significantly inhibited [3H]thymidine incorporation in RMC incubated with VEGF, which was inhibited by TZD. These findings indicate that a rapid change of glucose concentration promotes RMC proliferation by the increased production of VEGF. TZD has an inhibitory action through, at least in part, PPAR-gamma.