Astragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-κB-mediated inflammatory genes expression

Accumulating evidence suggests that inflammatory processes are involved in the development of diabetic nephropathy (DN). However, there are no effective interventions for inflammation in the diabetic kidneys. Here, we tested the hypothesis that Astragaloside IV(AS-IV), a novel saponin purified from Astragalus membranaceus (Fisch) Bge, ameliorates DN in streptozotocin (STZ)-induced diabetic rats through anti-inflammatory mechanisms. Diabetes was induced with STZ (65 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats were divided into three groups (n = 8/each group), namely, diabetic rats, diabetic rats treated with AS-IV at 5 and 10 mg kg^?1 d^?1, p.o., for 8 weeks. The normal rats were chosen as nondiabetic control group (n = 8). The rats were sacrificed 10 weeks after induction of diabetes. AS-IV ameliorated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. Renal NF-κB activity, as wells as protein and mRNA expression were increased in diabetic kidneys, accompanied by an increase in mRNA expression and protein content of TNF-α, MCP-1 and ICAM-1 in kidney tissues. The α₁-chain type IV collagen mRNA was elevated in the kidneys of diabetic rats. All of these abnormalities were partially restored by AS-IV. AS-IV also decreased the serum levels of TNF-α, MCP-1 and ICAM-1 in diabetic rats. These findings suggest that AS-IV, a novel anti-inflammatory agent, attenuated DN in rats through inhibiting NF-κB mediated inflammatory genes expression.     

Effects of fermented rooibos (Aspalathus linearis) on adipocyte differentiation

Rooibos (Aspalathus linearis) contains a rich complement of polyphenols, including flavonoids, considered to be largely responsible for its health promoting effects, including combatting obesity. The purpose of this study was to examine the effect of fermented rooibos hot water soluble solids on in vitro adipocyte differentiation by using differentiating 3T3-L1 adipocytes. Hot water soluble solids were obtained when preparing an infusion of fermented rooibos at “cup-of-tea” strength. The major phenolic compounds (>5 mg/g) were isoorientin, orientin, quercetin-3-O-robinobioside and enolic phenylpyruvic acid-2-O-β-d-glucoside. Treatment of 3T3-L1 adipocytes with 10 μg/ml and 100 μg/ml of the rooibos soluble solids inhibited intracellular lipid accumulation by 22% (p < 0.01) and 15% (p < 0.05), respectively. Inhibition of adipogenesis was accompanied by decreased messenger RNA (mRNA) expression of PPARγ, PPARα, SREBF1 and FASN. Western blot analysis exhibited decreased PPARα, SREBF1 and AMPK protein expression. Impeded glycerol release into the culture medium was observed after rooibos treatment. None of the concentrations of rooibos hot water soluble solids was cytotoxic, in terms of ATP content. Interestingly, the higher concentration of hot water soluble solids increased ATP concentrations which were associated with increased basal glucose uptake. Decreased leptin secretion was observed after rooibos treatment. Our data show that hot water soluble solids from fermented rooibos inhibit adipogenesis and affect adipocyte metabolism, suggesting its potential in preventing obesity.     

Anti-diabetic effect of a novel N-Trisaccharide isolated from Cucumis prophetarum on streptozotocin–nicotinamide induced type 2 diabetic rats

Ethnopharmacological relevanceCucumis prophetarum (L.) is used in traditional Indian medicine for the treatment of inflammation related problems.Aim of the studyThe present investigation was designed to study the effect of N-Trisaccharide (a new compound isolated from the fruit of C. prophetarum (L.)) on hyperglycemia in streptozotocin (STZ)–nicotinamide (NA) induced type 2 diabetic rats.Materials and methodsDifferent doses of N-Trisaccharide (25 and 50 mg/kg b.w.) were administered once daily for 28 days to STZ–NA induced diabetic rats. Plasma insulin and glycogen levels were measured. The activities of hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase were measured. Further, histological studies on pancreas were also carried out.ResultsThe active compound at doses of 25 and 50 mg/kg b.w. given orally for 14 days showed 47.7% and 69.3% antihyperglycemic activity, respectively. Treatment at the same doses for 28 days provided complete protection against STZ–NA challenge (65 and 230 mg/kg b.w., respectively), intraperitoneally. N-Trisaccharide significantly (p ≤ 0.05) increased the plasma insulin and liver glycogen levels in diabetic rats. The altered enzyme activities of carbohydrate metabolism in the liver and kidney of the diabetic rats were significantly (p ≤ 0.05) improved. Additionally, N-Trisaccharide increased glycogen synthase and decreased glycogen phosphorylase activity in diabetic rats. Histological studies confirmed an increase in insulin level is due to stimulation of injured pancreatic β-cells.ConclusionThe results of the study suggested that N-Trisaccharide possesses propitious effect on STZ–NA induced type 2 diabetes, indicating its usefulness in diabetes management.     

Effects of Canarium odontophyllum leaves on plasma glucose and T lymphocyte population in streptozotocin-induced diabetic rats

Type 1 diabetes mellitus is a chronic disease characterized by lack of insulin production. Immune mechanisms are implicated in the pathogenesis of Type 1 diabetes. Canarium odontophyllum (CO) fruits and leaves have been shown to possess high antioxidant activity. This study was conducted to evaluate the effects of CO leaves aqueous extract on the blood glucose and T lymphocyte population in the spleen of streptozotocin (STZ)-induced diabetic rats. Nineteen male Sprague–Dawley rats were randomly divided into three groups: normal, diabetic control and CO treated diabetic groups. Diabetes was induced by a single intraperitoneal injection of 65 mg STZ/kg body weight. The extract of CO leaves was administered orally by force feeding daily at the dose of 300 mg/kg for 28 days. The rats were sacrificed at the end of the study and the spleen was harvested for flow cytometry analysis. The results showed a significant decrease in body weight of diabetic and CO treated diabetic groups compared with the normal group (p < 0.05). The fasting blood glucose level of CO treated diabetic group was significantly lower than the diabetic group (p < 0.05). Diabetic and CO treated diabetic groups showed a significant increase in the percentage of spleen CD3⁺ CD4⁺ T lymphocytes (p < 0.05) when compared with the normal group. However, there was no significant difference in the percentage of spleen CD3⁺ CD8⁺ T lymphocytes among all experimental groups. The finding suggested that an aqueous extract of CO leaves has the ability to reduce blood glucose levels in diabetic rats.     

Placental antiangiogenic prolactin fragments are increased in human and rat maternal diabetes

Introduction/objectivesThe role of the placenta in diabetic mothers on fetal development and programming is unknown. Prolactin (PRL) produced by decidual endometrial cells may have an impact. Although full-length PRL is angiogenic, the processed form by bone morphogenetic protein-1 (BMP-1) and/or cathepsin D (CTSD) is antiangiogenic.The objectives were to investigate the involvement of decidual PRL and its antiangiogenic fragments in placentas from type-1 diabetic women (T1D) and from pregnant diabetic rats with lower offspring weights than controls.MethodsPRL, BMP-1, and CTSD gene expressions and PRL protein level were assessed in T1D placentas (n = 8) at delivery and compared to controls (n = 5). Wistar rats received, at day 7 of pregnancy, streptozotocin (STZ) (n = 5) or nicotinamide (NCT) plus STZ (n = 9) or vehicle (n = 9). Placental whole-genome gene expression and PRL western blots were performed at birth.ResultsIn human placentas, PRL (p < 0.05) and BMP-1 (p < 0.01) gene expressions were increased with a higher amount of cleaved PRL (p < 0.05) in T1D than controls. In rats, diabetes was more pronounced in STZ than in NCT–STZ group with intra-uterine growth restriction. Decidual prolactin-related protein (Dprp) (p < 0.01) and Bmp-1 (p < 0.001) genes were up-regulated in both diabetic groups, with an increased cleaved PRL amount in the STZ (p < 0.05) and NCT–STZ (p < 0.05) groups compared to controls. No difference in CTSD gene expression was observed in rats or women.ConclusionsAlterations in the levels of the PRL family are associated with maternal diabetes in both rats and T1D women suggesting that placental changes in these hormones impact on fetal development.     

In vitro alpha-amylase inhibition and in vivo antioxidant potential of Momordica dioica seeds in streptozotocin-induced oxidative stress in diabetic rats

Momordica dioica Roxb. Commonly known as “Kakora” in Telugu, is used in the Indian traditional system of medicine for the treatment of diabetes. The aim of this study was to investigate the antidiabetic activity of methanolic extract of M. dioica seeds (MEMD) in streptozotocin (STZ) induced diabetic rats. The in vitro α-amylase inhibitory activity of the MEMD was done by spectrophotometric method. Diabetes was induced by STZ (45 mg/kg; i.p), MEMD (100 & 200 mg/kg; b.wt) and standard drug metformin (50 mg/kg; b.wt) were administered to the diabetic rats. Blood glucose was estimated on the 11th day and the level of MDA, SOD and CAT was estimated in the liver tissue homogenate after the 15 days of experimental period. MEMD showed significant inhibition of alpha amylase activity and the IC₅₀ was found to be 48 μg/ml. Oral administration of MEMD significantly reduced blood glucose level (P < 0.05), diminished the MDA level and refurbished depleted antioxidant enzymes and Insulin level to normalcy. These findings revealed that M. dioica seeds possess antihyperglycemic, antioxidant and anti lipid peroxidative activity and thus mitigate STZ-induced oxidative damage.     

Efficacy of natural diosgenin on cardiovascular risk,insulin secretion,and beta cells in streptozotocin (STZ)-induced diabetic rats

Costus igneus, has been prescribed for the treatment of diabetic mellitus in India for several years. The aim of this study is to investigate the effects of plant derived diosgenin on cardiovascular risk, insulin secretion, and pancreatic composition through electron microscopical studies of normal and diabetic rats. Diosgenin at a dose of 5 or 10 mg/kg per body weight (bw) was orally administered as a single dose per day to diabetic induced rats for a period of 30 days. The effect of diosgenin on blood glucose, HbA1c, PT, APTT, Oxy-LDL, serum lipid profile, electron microscopical studies of pancreas, antioxidant enzymes (in liver, kidney, pancreas) and hepatoprotective enzymes in plasma and liver were measured in normal and diabetic rats. The results showed that fasting blood glucose, PT, APTT, Oxy-LDL, TC, TG, LDL, ALT, AST, ALP, glucose-6-phosphatase, fructose-1,6-bisphosphatase and LPO levels were significantly (p < 0.05) increased, whereas HDL, SOD, CAT, GSH and the glycolytic enzyme glucokinase levels were significantly (p < 0.05) decreased in the diabetes induced rats and these levels were significantly (p < 0.05) reversed back to normal in diabetes induced rats after 30 days of treatment with diosgenin. Electron microscopical studies of the pancreas revealed that the number of beta cells and insulin granules were increased in streptozotocin (STZ) induced diabetic rats after 30 days of treatment with diosgenin. In conclusion, the data obtained from the present study strongly indicate that diosgenin has potential effects on cardiovascular risk, insulin secretion and beta cell regeneration in STZ induced diabetic rats, these results could be useful for new drug development to fight diabetes and its related cardiovascular diseases.     

Antihyperlipidemic effect of chlorogenic acid and tetrahydrocurcumin in rats subjected to diabetogenic agents

Diabetes mellitus is associated with dyslipidemia, which is a significant risk factor for cardiovascular complications. The present study was carried out to evaluate the effects of tetrahydrocurcumin (THC) and chlorogenic acid (CGA) alone and in combination on alterations in lipids, lipoproteins and enzymes involved in lipid metabolism in streptozotocin (STZ)–nicotinamide (NA)-induced type 2 diabetic rats. A significant (p < 0.05) increase in the concentrations of plasma and tissue (liver and kidney) lipids (cholesterol, triglycerides (TGs), free fatty acids (FFAs) and phospholipids (PLs)) and low density and very low-density lipoproteins (LDL and VLDL), and a decrease in the concentration of high-density lipoproteins (HDL) were noticed in STZ administered diabetic rats. In addition, the activity of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase increased significantly (p < 0.05) in the liver and kidney whereas the activities of lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) were decreased significantly (p < 0.05) in the plasma of diabetic rats. Combined administration of CGA (5 mg/kg b.w.) and THC (80 mg/kg b.w.) for 45 days remarkably reduced the STZ-induced changes in lipids, lipoproteins and lipid metabolising enzymes when compared to the effects of CGA or THC alone in diabetic rats. These results indicate that combination of THC and CGA can potentially ameliorate lipid abnormalities in experimental type 2 diabetes.     

Insulinotropic effect of cinnamaldehyde on transcriptional regulation of pyruvate kinase,phosphoenolpyruvate carboxykinase,and GLUT4 translocation in experimental diabetic rats

Diabetes mellitus is a chronic metabolic disorder affecting about 6% of population worldwide with its complications and is rapidly reaching epidemic scale. Cinnamomum zeylanicum is widely used in alternative system of medicine for treatment of diabetes. In the present study, we have performed bioassay guided fractionation of chloroform extract of C. zeylaniucm and identified cinnamaldehyde (CND) as an active principle against diabetes. In continuation to it, a detailed study was undertaken to elucidate its mode of antidiabetic action in STZ induced diabetic rats. Oral administration of CND (20 mg/kg bw) to diabetic rats for 2 months showed significant improvement (p < 0.001) in muscle and hepatic glycogen content. In vitro incubation of pancreatic islets with CND enhanced the insulin release compared to glibenclamide. The insulinotropic effect of CND was found to increase the glucose uptake through glucose transporter (GLUT4) translocation in peripheral tissues. The treatment also showed a significant improvement in altered enzyme activities of pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK) and their mRNA expression levels.Furthermore, the median lethal dose (LD₅₀) of CND could not be obtained even at 20 times (0.4 g/kg bw) of its effective dose. With the high margin of safety of CND, it can be developed as a potential therapeutic candidate for the treatment of diabetes.     

Effects of resveratrol on nucleotide degrading enzymes in streptozotocin-induced diabetic rats

AimsDiabetes mellitus is associated with platelet alterations that may contribute to the development of cardiovascular complications. The present study investigates the effects of resveratrol (RSV), an important compound with cardioprotective activities, on NTPDase, ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP), 5′-nucleotidase and adenosine deaminase (ADA) activities in platelets from streptozotocin (STZ)-induced diabetic rats.Main methodsThe animals were divided into six groups (n = 8): control/saline; control/RSV 10 mg/kg; control/RSV 20 mg/kg; diabetic/saline; diabetic/RSV 10 mg/kg; diabetic/RSV 20 mg/kg. RSV was administered during 30 days and after this period the blood was collected for enzymatic assay.Key findingsThe results demonstrated that NTPDase, E-NPP and 5′-nucleotidase activities were significantly higher in the diabetic/saline group (P < 0.05) compared to control/saline group. Treatment with RSV significantly increased NTPDase, 5′-nucleotidase and E-NPP activities in the diabetic/RSV10 and diabetic/RSV20 groups (P < 0.05) compared to diabetic/saline group. When RSV was administered per se there was also an increase in the activities of these enzymes in the control/RSV10 and control/RSV20 groups (P < 0.05) compared to control/saline group. ADA activity was significantly increased in the diabetic/saline group (P < 0.05) compared to control/saline group. The treatment with RSV prevented this increase in the diabetic/RSV10 and diabetic/RSV20 groups. No significant differences in ADA activity were observed in the control/RSV10 and control/RSV20 compared to control/saline group.SignificanceThe present findings demonstrate alterations in nucleotide hydrolysis in platelets of STZ-induced diabetic rats and treatment with RSV was able to modulate adenine nucleotide hydrolysis, which may be important in the control of the platelet coagulant status in diabetes.     

Alterations in kidney tissue following zinc supplementation to STZ-induced diabetic rats

Diabetes mellitus is a chronic disease characterized by anomalies forming in carbohydrate, lipid, protein metabolisms and the incidence of this disease varies widely throughout the world. Zinc is an important element which is essential for life and is present in nature. In this study, the animals were divided into four groups. These groups were named as untreated; zinc sulfate; streptozotocin (STZ); STZ and zinc sulfate. STZ (65 mg/kg) was dissolved in a freshly prepared 0.01 M pH 4.5 citrate buffer and given with intraperitoneal injection in a single dose. Zinc sulfate (100 mg/kg) was dissolved in distilled water and given to the animals by gavage at a daily dose for 60 days. The rats were sacrificed under ether anesthesia. This study was aimed to investigate histological and biochemical changes of zinc supplementation on the kidney tissue in STZ-induced diabetic rats. In the current study, histological and histochemical observations showed that the occurred degenerative changes decreased after giving zinc in the kidney tissue of diabetic group. Kidney glutathione (GSH) levels decreased and lipid peroxidation (LPO), nonenzymatic glycosylation (NEG), urea and creatinine levels increased in diabetic rats. GSH levels increased, while LPO, NEG, urea and creatinine levels decreased in the kidney with administration of zinc to diabetic rats. As a result, we observed curative effects of zinc given to diabetic rats. We can say that zinc may be an important antioxidant for the treatment of secondary complications of diabetes in kidney tissue.     

In vivo anti-diabetic,antioxidant and molecular docking studies of 1, 2, 8-trihydroxy-6-methoxy xanthone and 1, 2-dihydroxy-6-methoxyxanthone-8-O-β-d-xylopyranosyl isolated from Swertia corymbosa

1, 2, 8-trihydroxy-6-methoxy xanthone (1) and 1, 2- dihydroxy-6-methoxyxanthone-8-O-β-d-xylopyranosyl (2) are the main constituents of petroleum ether and ethyl acetate extracts from Swertia corymbosa (Gentinaceae), a medicinal plant used in Indian traditional system for the treatment of diabetes. The present study was designed to examine the antihypoglycemic, antihyperlipidemic and antioxidant effect of compounds 1 and 2 in streptozotocin (STZ) induced diabetic rats. Diabetes was induced in male Wistar rats by a single intraperitoneal injection of STZ (60 mg/kg b.w.). The isolated compounds 1 and 2 at a dose of 50 mg/kg b.w., produced the maximum fall of 83% in the blood glucose level in the diabetic rats after 3 h of the treatment. The administration of 1 and 2 (50 mg/kg b.w.) daily for 28 days in STZ induced diabetic rats, resulted in a significant decrease in blood glucose, glycosylated hemoglobin, SGOT, SGPT, ALP serum urea and creatinine with significant rise in plasma insulin level. Test compounds 1 and 2 showed antihyperlipidemic activities as evidenced by significant decrease in serum TC, TG, LDL-C, VLDL-C levels coupled together with elevation of HDL-C level in diabetic treated rats when compared to diabetic untreated rats, indicate the protective role against liver and kidney damage. The results of histopathology also showed 1 and 2 protected tissues (pancreas, liver and kidney) against peroxidation damage and maintained tissue integrity. Further, the molecular interaction study of the ligands 1, 2 and glibenclamide with various diabetes mellitus related protein targets like glucokinase (PDB ID: 1V4S), fructose-1, 6-bisphosphatase 1 (PDB ID: 2JJK) 11-β-hydroxysteroid dehydrogenase (PDB ID: 2BEL) and modeled protein sulfonylurea receptor 1 (SUR1) showed that ligand 1 and 2 possess binding affinity with all protein targets except for 2BEL target protein for which ligand 1 has no interaction. The ligand pose with 2BEL and SUR1 protein target of ligand 2 gave the best binding conformation. Hence 1 and 2 can be considered for developing into a potent antidiabetic drug.     

Specific functioning of Cav3.2 T-type calcium and TRPV1 channels under different types of STZ-diabetic neuropathy

Streptozotocin (STZ)-induced type 1 diabetes in rats leads to the development of peripheral diabetic neuropathy (PDN) manifested as thermal hyperalgesia at early stages (4th week) followed by hypoalgesia after 8 weeks of diabetes development. Here we found that 6–7 week STZ-diabetic rats developed either thermal hyper- (18%), hypo- (25%) or normalgesic (57%) types of PDN. These developmentally similar diabetic rats were studied in order to analyze mechanisms potentially underlying different thermal nociception. The proportion of IB4-positive capsaicin-sensitive small DRG neurons, strongly involved in thermal nociception, was not altered under different types of PDN implying differential changes at cellular and molecular level. We further focused on properties of T-type calcium and TRPV1 channels, which are known to be involved in Ca^2 + signaling and pathological nociception. Indeed, TRPV1-mediated signaling in these neurons was downregulated under hypo- and normalgesia and upregulated under hyperalgesia. A complex interplay between diabetes-induced changes in functional expression of Cav3.2 T-type calcium channels and depolarizing shift of their steady-state inactivation resulted in upregulation of these channels under hyper- and normalgesia and their downregulation under hypoalgesia. As a result, T-type window current was increased by several times under hyperalgesia partially underlying the increased resting [Ca^2 +]_i observed in the hyperalgesic rats. At the same time Cav3.2-dependent Ca^2 + signaling was upregulated in all types of PDN. These findings indicate that alterations in functioning of Cav3.2 T-type and TRPV1 channels, specific for each type of PDN, may underlie the variety of pain syndromes induced by type 1 diabetes.     

Kolaviron,a biflavonoid complex of Garcinia kola seeds modulates apoptosis by suppressing oxidative stress and inflammation in diabetes-induced nephrotoxic rats

Diabetic nephropathy is a complex disease that involves increased production of free radicals which is a strong stimulus for the release of pro-inflammatory factors. We evaluated the renal protective effect of kolaviron (KV) – a Garcinia kola seed extract containing a mixture of 5 flavonoids, in diabetes-induced nephrotoxic rats. Male Wistar rats were divided into 4 groups: untreated controls (C); normal rats treated with kolaviron (C + KV); untreated diabetic rats (D); kolaviron treated diabetic rats (D + KV). A single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg) was used for the induction of diabetes. Renal function parameters were estimated in a clinical chemistry analyzer. Markers of oxidative stress in the kidney homogenate were analyzed in a Multiskan Spectrum plate reader and Bio-plex Promagnetic bead-based assays was used for the analysis of inflammatory markers. The effect of kolaviron on diabetes-induced apoptosis was assessed by TUNEL assay. In the diabetic rats, alterations in antioxidant defenses such as an increase in lipid peroxidation, glutathione peroxidase (GPX) activity and a decrease in catalase (CAT) activity, glutathione (GSH) levels and oxygen radical absorbance capacity (ORAC) were observed. There was no difference in superoxide dismutase (SOD) activity. Diabetes induction increased apoptotic cell death and the levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α with no effect on IL-10. Kolaviron treatment of diabetic rats restored the activities of antioxidant enzymes, reduced lipid peroxidation and increased ORAC and GSH concentration in renal tissues. Kolaviron treatment of diabetic rats also suppressed renal IL-1β. The beneficial effects of kolaviron on diabetes-induced kidney injury may be due to its inhibitory action on oxidative stress, IL-1β production and apoptosis.     

Neuroprotective effect of ischemic preconditioning via modulating the expression of adropin and oxidative markers against transient cerebral ischemia in diabetic rats

IntroductionIschemic preconditioning (IPreC) can render the brain more tolerant to a subsequent potential lethal ischemic injury. Hyperglycemia has been shown to increase the size of ischemic stroke and worsen the clinical outcome following a stroke, thus exacerbating oxidative stress. Adropin has a significant association with cardiovascular disease, especially with diabetes. In this study, we aimed to evaluate the role of the IPreC due to modulating the expression of adropin and oxidative damage markers against stroke by induced transient middle cerebral artery occlusion (MCAo) in streptozotocin (STZ)-induced diabetic rats.Material-method72 male Spraque Dawley rats were allocated to 8 groups. In order to evaluate alterations of anti/oxidative status and adropin level, we induced transient MCAo seven days after STZ-induced diabetes. Also we performed IPreC 72 h before transient MCAo to assess whether IPreC could have a neuroprotective effect against ischemia-reperfusion injury.ResultsThe general characteristics of STZ-treated rats (STZ) included reduced body weight and elevated blood glucose levels compared to non-diabetic ones. Ischemic preconditioning before cerebral ischemia significantly reduced infarction size compared with the other groups [IPreC + MCAo (27 ± 11 mm³) vs. MCAo (109 ± 17 mm³) p < 0.001; STZ + IPreC + MCAo (38 ± 10 mm³) vs. STZ + MCAo (165 ± 45 mm³) p < 0.001, respectively]. The mean total antioxidant status level in IPreC groups was higher than other groups (p ≤ 0.05). Moreover, IPreC considerably decreased mean adropin levels compared with other groups (p ≤ 0.05).ConclusionThe study results supported the neuroprotective effects of ischemic preconditioning in MCA infarcts correlated with the level of oxidative damage markers and adropin.     

Ameliorative effects of Anchomanes difformis aqueous extract against oxidative stress in the testes and epididymis of streptozotocin-induced diabetic male Wistar rats

Hyperglycemia is a central trait of diabetes mellitus (DM) and is linked to an increase in free radical generation and oxidative stress in the testes, resulting in testicular tissue damage and male infertility. Synthetic medicines are commonly used to manage diabetes; however, they are costly and associated with adverse effects. As a result, the search for a safer and affordable alternative from medicinal plants that contain antioxidants has become imperative to scavenge free radicals caused by hyperglycaemia, thereby alleviating male reproductive dysfunction. Therefore, the present aimed to investigate the ameliorative effects of Anchomanes difformis aqueous extract against oxidative stress in the testes and epididymis of streptozotocin-induced diabetic male Wistar rats. A total of 64 male Wistar rats (eight weeks old) weighing 180 ± 10 mg/kg were divided into seven groups at random. Type 2 diabetic mellitus (T2DM) was induced by streptozotocin (STZ) and a 10% fructose injection intraperitoneally using 40 mg/kg body weight rats. The levels of malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, and ferric reducing antioxidant (FRAP) as well as 2, 2-diphenyl-1-picrylhydrazyl (DPPH) values were used to establish the testicular oxidative status. It was found that A. difformis extract significantly (p < 0.05) lowered MDA levels in diabetic rats. Both CAT and SOD activity were significantly (p < 0.05) lower following induction of DM and increased (p < 0.05) after treating with A. difformis. The findings of this study show that A. difformis extract could be a promising source of lead compounds for the development of a therapeutic agent to treat male infertility caused by DM complications.     

Hypoglycemic activity of a polyphenolic oligomer-rich extract of Cinnamomum parthenoxylon bark in normal and streptozotocin-induced diabetic rats

Cinnamon bark has been reported to be effective in the alleviation of diabetes through its antioxidant and insulin-potentiating activities. The water-soluble polyphenolic oligomers found in cinnamon are thought to be responsible for this biological activity. In this study, the hypoglycemic activity of a polyphenolic oligomer-rich extract from the barks of Cinnamomum parthenoxylon (Jack) Nees was studied in normal, transiently hyperglycemic, and streptozotocin (STZ)-induced diabetic rats. Oral administration of the extract at doses of 100, 200, and 300 mg/kg body wt. caused significant changes in body weight loss and fasting blood glucose levels of normal rats. In STZ-induced diabetic rats, after administration of the extract at doses of 100, 200, and 300 mg/kg body wt. over 14 days, the blood glucose levels were decreased by 11.1%, 22.5%, and 38.7%, respectively, and the plasma insulin levels were significantly increased over pre-treatment levels. In an oral glucose tolerance test, the extract produced a significant decrease in glycemia 90 min after the glucose pulse. These results suggest that Cinnamomum parthenoxylon polyphenolic oligomer-rich extract could be potentially useful for post-prandial hyperglycemia treatment.     

Expression of aromatase,androgen and estrogen receptors in peripheral target tissues in diabetes

Our previous studies have shown that diabetes in the male streptozotocin (STZ)-induced diabetic rat is characterized by a decrease in circulating testosterone and concomitant increase in estradiol levels. Interestingly, this increase in estradiol levels persists even after castration, suggesting extra-testicular origins of estradiol in diabetes. The aim of the present study was to examine whether other target organs of diabetes may be sources of estradiol. The study was performed in male Sprague–Dawley non-diabetic (ND), STZ-induced diabetic (D) and STZ-induced diabetic castrated (Dcas) rats (n = 8–9/group). 14 weeks of diabetes was associated with decreased testicular (ND, 26.3 ± 4.19; D, 18.4 ± 1.54; P < 0.05), but increased renal (ND, 1.83 ± 0.92; D, 7.85 ± 1.38; P < 0.05) and ocular (D, 23.4 ± 3.66; D, 87.1 ± 28.1; P < 0.05) aromatase activity. This increase in renal (Dcas, 6.30 ± 1.25) and ocular (Dcas, 62.7 ± 11.9) aromatase activity persisted after castration. The diabetic kidney also had increased levels of tissue estrogen (ND, 0.31 ± 0.01; D, 0.51 ± 0.11; Dcas, 0.45 ± 0.08) as well as estrogen receptor alpha protein expression (ND, 0.63 ± 0.09; D, 1.62 ± 0.28; Dcas, 1.38 ± 0.20). These data suggest that in male STZ-induced diabetic rats, tissues other than the testis may become sources of estradiol. In particular, the diabetic kidney appears to produce estradiol following castration, a state that is associated with a high degree or renal injury. Overall, our data provides evidence for the extra-testicular source of estradiol that in males, through an intracrine mechanism, may contribute to the development and/or progression of end-organ damage associated with diabetes.     

Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment

Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although we previously identified a compound (2) with potent VAP-1 inhibitory activity in rats, the human activity was relatively weak. Here, to improve the human VAP-1 inhibitory activity of compound 2, we first evaluated the structure–activity relationships of guanidine bioisosteres as simple small molecules and identified a 1H-benzimidazol-2-amine (5) with potent activity compared to phenylguanidine (1). Based on the structure of compound 5, we synthesized a highly potent VAP-1 inhibitor (37b; human IC₅₀ = 0.019 μM, rat IC₅₀ = 0.0051 μM). Orally administered compound 37b also markedly inhibited ocular permeability in streptozotocin-induced diabetic rats after oral administration, suggesting it is a promising compound for the treatment of diabetic macular edema.     

Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo

Cardiac inflammation and oxidative stress play a key role in the pathogenesis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho has been found to protect cells from inflammation and oxidative stress. The current study aimed to explore the cardioprotective effects of Klotho on DCM and the underlying mechanisms. H9c2 cells and neonatal cardiomyocytes were incubated with 33 mM glucose in the presence or absence of Klotho. Klotho pretreatment effectively inhibited high glucose-induced inflammation, ROS generation, apoptosis, mitochondrial dysfunction, fibrosis and hypertrophy in both H9c2 cells and neonatal cardiomyocytes. In STZ-induced type 1 diabetic mice, intraperitoneal injection of Klotho at 0.01 mg/kg per 48 h for 3 months completely suppressed cardiac inflammatory cytokines and oxidative stress and prevented cardiac cell death and remodeling, which subsequently improved cardiac dysfunction without affecting hyperglycemia. This study revealed that Klotho may exert its protective effects by augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression and inactivating nuclear factor κB (NF-κB) activation both in vitro and in vivo. Thus, this work demonstrated for the first time that the anti-aging protein Klotho may be a potential therapeutic agent to treat DCM by inhibiting oxidative stress and inflammation. We also demonstrated the critical roles of the Nrf2 and NF-κB pathways in diabetes-stimulated cardiac injuries and indicated that they may be key therapeutic targets for diabetic complications.