Rutin inhibits the in vitro formation of advanced glycation products and protein oxidation more efficiently than quercetin

Supplementary Materia

In Vitro Antiglycation Potential of Erva-Baleeira (<i>Varronia curassavica</i> Jacq.)

Background: Varronia curassavica Jacq. (Boraginaceae) is traditionally used in the treatment of inflammatory processes. The ethanolic extract of its leaves (EEVc) showed anti-inflammatory properties and low toxicity. Medicinal plants have aroused interest for their antiglycation activities. The formation and accumulation of advanced glycation end products (AGEs) are associated with several chronic diseases. The objective of this study was to evaluate the antiglycation potential of EEVc and two isolated compounds. Methods: The compounds brickellin and cordialin A were obtained by chromatographic methods and identified by spectrometric techniques. Analysis of fluorescent AGEs, biomarkers of amino acid residue oxidation, protein carbonyl groups and crosslink formation were performed in samples obtained from an in vitro model system of protein glycation with methylglyoxal. Results: EEVc, brickellin and cordialin A significantly reduced the in vitro formation of AGEs, and reduced the damage caused by oxidative damage to the protein. Conclusions: According to the results, EEVc, brickellin and cordialin A are potential candidates against AGEs formation, which opens the way to expand the therapeutic arsenal for many pathologies resulting from glycoxidative stress

Insulin Suppresses Atrophy- and Autophagy-related Genes in Heart Tissue and Cardiomyocytes Through AKT/FOXO Signaling

Insulin is an important regulator of the ubiquitin-proteasome system (UPS) and of lysosomal proteolysis in cardiac muscle. However, the role of insulin in the regulation of the muscle atrophy-related Ub-ligases atrogin-1 and MuRF1 as well as in autophagy, a major adaptive response to nutritional stress, in the heart has not been characterized. We report here that acute insulin deficiency in the cardiac muscle of rats induced by streptozotocin increased the expression of atrogin-1 and MuRF1 as well as LC3 and Gabarapl1, 2 autophagy-related genes. These effects were associated with decreased phosphorylation levels of Akt and its downstream target Foxo3a; this phenomenon is a well-known effect that permits the maintenance of Foxo in the nucleus to activate protein degradation by proteasomal and autophagic processes. The administration of insulin increased Akt and Foxo3a phosphorylation and suppressed the diabetes-induced expression of Ub-ligases and autophagy-related genes. In cultured neonatal rat cardiomyocytes, nutritional stress induced by serum/glucose deprivation strongly increased the expression of Ub-ligases and autophagy-related genes; this effect was inhibited by insulin. Furthermore, the addition of insulin in vitro prevented the decrease in Akt/Foxo signaling induced by nutritional stress. These findings demonstrate that insulin suppresses atrophy- and autophagy-related genes in heart tissue and cardiomyocytes, most likely through the phosphorylation of Akt and the inactivation of Foxo3a. © Georg Thieme Verlag KG

Chemical sympathectomy further increases muscle protein degradation of acutely diabetic rats

The present work investigated the role of the sympathetic nervous system (SINS) in the control of protein degradation in skeletal muscles from rats with streptozotocin (STZ)-induced diabetes. Diabetes (1, 3, and 5 days after STZ) induced a significant increase in the norepinephrine content of soleus and EDL muscles, but it did not affect plasma catecholamine levels. Chemical sympathectomy induced by guanethidine (100 mg/kg body weight, for 1 or 2 days) reduced muscle norepinephrine content to negligible levels (less than 5%), decreased plasma epinephrine concentration, and further increased the high rate of protein degradation in muscles from acutely diabetic rats. The rise in the rate of proteolysis (nmol.mg wet wt(-1).2h(-1)) in soleus from 1-day diabetic sympathectomized rats was associated with increased activities of lysosomal (0.127 +/- 0.008 vs. 0.086 +/- 0.013 in diabetic control) and ubiquitin (Ub)-proteasome-dependent proteolytic pathways (0.154 +/- 0,007 vs. 0.121 +/- 0.006 in diabetic control). Increases in Ca2+-depenclent (0.180 +/- 0.007 vs. 0.121 +/- 0.011 in diabetic control) and Ub-proteasome-dependent proteolytic systems (0.092 +/- 0.003 vs. 0.060 +/- 0.002 in diabetic control) were observed in EDL from 1-day diabetic sympathectomized rats. The lower phosphorylation levels of AKT and Foxo3a in EDL muscles from 3-day diabetic rats were further decreased by sympathectomy. The data suggest that the SNS exerts acute inhibitory control of skeletal muscle proteolysis during the early stages of diabetes in rats, probably involving the AKT/Foxo signaling pathway

Lycopene in Combination with Insulin Triggers Antioxidant Defenses and Increases the Expression of Components That Detoxify Advanced Glycation Products in Kidneys of Diabetic Rats

Background: Biochemical events provoked by oxidative stress and advanced glycation may be inhibited by combining natural bioactives with classic therapeutic agents, which arise as strategies to mitigate diabetic complications. The aim of this study was to investigate whether lycopene combined with a reduced insulin dose is able to control glycemia and to oppose glycoxidative stress in kidneys of diabetic rats. Methods: Streptozotocin-induced diabetic rats were treated with 45 mg/kg lycopene + 1 U/day insulin for 30 days. The study assessed glycemia, insulin sensitivity, lipid profile and paraoxonase 1 (PON-1) activity in plasma. Superoxide dismutase (SOD) and catalase (CAT) activities and the protein levels of advanced glycation end-product receptor 1 (AGE-R1) and glyoxalase-1 (GLO-1) in the kidneys were also investigated. Results: An effective glycemic control was achieved with lycopene plus insulin, which may be attributed to improvements in insulin sensitivity. The combined therapy decreased the dyslipidemia and increased the PON-1 activity. In the kidneys, lycopene plus insulin increased the activities of SOD and CAT and the levels of AGE-R1 and GLO-1, which may be contributing to the antialbuminuric effect. Conclusions: These findings demonstrate that lycopene may aggregate favorable effects to insulin against diabetic complications resulting from glycoxidative stress

Fruit of the jambolan tree (Eugenia jambolana Lam.) and experimental diabetes

The fruit of Indian Eugenia jambolana have been shown to have therapeutic properties, but because the therapeutic potential of a plant is related to the geographic region in which the plant was grown and to the part of the plant used, we investigated Brazilian Eugenia jambolana fruit using the same preparation and experimental methods as have been used in India. The well-established metabolic cage model was used to evaluate the physiological and metabolic parameters associated with streptozotocin-induced diabetes in rats (n = 10) which had been administered, by gavage, 50 mg per day of lyophilised Eugenia jambolana fruit-pulp extract for 41 days. We found that, compared to untreated controls, rats treated with the lyophilised fruit-pulp showed no observable difference in body weight, food or water intake, urine volume, glycaemia, urinary urea and glucose, hepatic glycogen, or on serum levels of total cholesterol, HDL cholesterol or triglycerides. No change was observed in the masses of epididymal or retroperitoneal adipose tissue or of soleus or extensor digitorum longus muscles. This lack of any apparent effect on the diabetes may be attributable to the regional ecosystem where the fruit was collected and/or to the severity of the induced diabetes. (C) 2004 Elsevier B.V.. All rights reserved

Anti-diabetic activity of Bauhinia forficata decoction in streptozotocin-diabetic rats

The effects of using Bauhinia forficata leaf decoction (150 g leaf/l water; 35.2+/-7.8 ml/100 g body weight mean daily dose) as a drinking-water substitute for about I month on streptozotocin-diabetes (STZ-diabetes) in male Wistar rats were investigated. The physico-metabolic parameters measured were: body weight, food and liquid intake, urinary volume, hepatic glycogen, serum triglycerides and cholesterol, plasma glucose, urinary glucose and urea, and the weight of epididymal and retroperitoneal adipose tissue and soleus and extensor digitorum longus muscles. The STZ-diabetic rats treated with decoction showed a significant reduction in serum and urinary glucose and urinary urea as compared to the STZ-diabetic control, no difference being seen between decoction-treated and -untreated non-diabetic rats. The other physico-metabolic factors showed no changes in treated STZ-diabetic rats. The improvement in carbohydrate metabolism seen in the rats treated with Bauhinia forficata decoction does not appear to be linked to the inhibition of glycogenolysis or the stimulation of glycogenesis nor does it appear to act in a way similar to insulin or the sulfonylureas, although it may act by the inhibition of neoglycogenesis in a manner similar to that of the biguanides. (C) 2002 Elsevier B.V. Ireland Ltd. All rights reserved

Piperine, a natural bioenhancer, nullifies the antidiabetic and antioxidant activities of curcumin in streptozotocin-diabetic rats

Knowing that curcumin has low bioavailability when administered orally, and that piperine has bioenhancer activity by inhibition of hepatic and intestinal biotransformation processes, the aim of this study was to investigate the antidiabetic and antioxidant activities of curcumin (90 mg/kg) and piperine (20 or 40 mg/kg), alone or co-administered, incorporated in yoghurt, in streptozotocin (STZ)-diabetic rats. The treatment for 45 days of STZ-diabetic rats with curcuminenriched yoghurt improved all parameters altered in this experimental model of diabetes: the body weight was increased in association with the weight of skeletal muscles and white adipose tissues; the progressive increase in the glycemia levels was avoided, as well as in the glycosuria, urinary urea, dyslipidemia, and markers of liver (alanine and aspartate aminotransferases and alkaline phosphatase) and kidney (urinary protein) dysfunction; the hepatic oxidative stress was decreased, since the activities of the antioxidant enzymes superoxide dismutase, catalase and gluthatione peroxidase were increased, and the levels of malondialdehyde and protein carbonyl groups were reduced. The dose of 20 mg/kg piperine also showed antidiabetic and antioxidant activities. The treatment of STZ-diabetic rats with both curcumin and 20 mg/kg piperine in yoghurt did not change the antidiabetic and antioxidant activities of curcumin; notably, the treatment with both curcumin and 40 mg/kg piperine abrogated the beneficial effects of curcumin. In addition, the alanine aminotransferase levels were further increased in diabetic rats treated with curcumin and 40 mg/kg piperine in comparison with untreated diabetic rats. These findings support that the co-administration of curcumin with a bioenhancer did not bring any advantage to the curcumin effects, at least about the antidiabetic and antioxidant activities, which could be related to changes on its biotransformation.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Repeated Exposition to Mercury (II) Chloride Enhances Susceptibility to S. schenckii sensu stricto Infection in Mice

Sporotrichosis is a subcutaneous mycosis that has re-emerged in several tropical and subtropical regions over the last decades. Growing findings suggest that the interplay of host, pathogen, and environment has a determinant effect on the diversity, local distribution, and virulence of Sporothrix schenckii sensu lato, the etiologic agent. Among the environmental factors, we have studied the potential role of repeated exposures to mercury (Hg), a known immunotoxic xenobiotic that is widely used in gold mining regions where sporotrichosis outbreaks are frequently reported. In this study, male Swiss mice received subcutaneous injections of either 300 or 1200 &micro;g/kg of mercury (II) chloride (HgCl2) for 14 days, three times a week. A control group was injected with the vehicle Phosphate Buffered Saline (PBS). Treatment with HgCl2 impaired several immunologic parameters that are involved in host response to Sporothrix infection, such as the production of TNF&alpha;, IL-1, and nitric oxide by macrophages, and Th1/Th2/Th17 populations and their respective cytokines. The consequences of these effects on the host resistance to S. schenckii infection were subsequently evaluated. Hg-exposed mice exhibited a higher fungal load in the fungal inoculation site associated to systemic dissemination to spleen and liver on 14 days post-infection and a higher production of specific IgG1 and mild reduction of IgG2a. These findings suggest that repeated exposition to Hg enhances susceptibility to S. schenckii infection in mice and can be a factor associated to sporotrichosis outbreaks in endemic and highly Hg-polluted areas