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Sitta A.,Servico de Genetica Medica HCPA | Deon M.,Programa de Pos Graduacao em Ciencias Farmaceuticas | Wajner M.,Programa de Pos Graduacao em Ciencias Biologicas Bioquimica
Cellular and Molecular Neurobiology | Year: 2017

Homocystinuria is an inborn error of amino acid metabolism caused by deficiency of cystathionine ß-synthase (CBS) activity, biochemically characterized by homocysteine (Hcy) and methionine (Met) accumulation in biological fluids and high urinary excretion of homocystine. Clinical manifestations include thinning and lengthening of long bones, osteoporosis, dislocation of the ocular lens, thromboembolism, and mental retardation. Although the pathophysiology of this disease is poorly known, the present review summarizes the available experimental findings obtained from patients and animal models indicating that oxidative stress may contribute to the pathogenesis of homocystinuria. In this scenario, several studies have shown that enzymatic and non-enzymatic antioxidant defenses are decreased in individuals affected by this disease. Furthermore, markers of lipid, protein, and DNA oxidative damage have been reported to be increased in blood, brain, liver, and skeletal muscle in animal models studied and in homocystinuric patients, probably as a result of increased free radical generation. On the other hand, in vitro and in vivo studies have shown that Hcy induces reactive species formation in brain, so that this major accumulating metabolite may underlie the oxidative damage observed in the animal model and human condition. Taken together, it may be presumed that the disruption of redox homeostasis may contribute to the tissue damage found in homocystinuria. Therefore, it is proposed that the use of appropriate antioxidants may represent a novel adjuvant therapy for patients affected by this disease. © 2017 Springer Science+Business Media New York

Bittencourt L.S.,Federal University of Santa Maria | Machado D.C.,Grande Rio University | Machado M.M.,Federal University of Pampa | Dos Santos G.F.F.,Federal University of Santa Maria | And 7 more authors.
Food and Chemical Toxicology | Year: 2013

The antioxidant effects of the hydro-alcoholic guaraná extract (Paullinia cupana var. sorbilis Mart.) on nitric oxide (NO) and other compounds generated from the degradation of sodium nitroprusside (SNP) in an embryonic fibroblast culture (NIH-3T3 cells) were evaluated. The guaraná bioactive compounds were initially determined by high-performance liquid chromatography: caffeine = 12.240. mg/g, theobromine = 6.733. mg/g and total catechins = 4.336. mg/g. Cells were exposed to 10 μM SNP during a 6. h period because the cells exhibited >90% mortality at this concentration. Guaraná was added to the cultures in five concentrations (0.5, 1, 5, 10 and 20. mg/mL). The guaraná antioxidant effect was evaluated by viability assays, biochemical oxidation [lipid peroxidation, catalase and superoxide dismutase (SOD) activity] and genotoxicity (DNA Comet assay) analysis. Additionally, oxidative stress was evaluated by a 2,7-dihydrodichlorofluorescein diacetate fluorescence assay. Guaraná reverted the SNP toxicity mainly at lower concentrations (<5. mg), which decreased cell mortality, lipid peroxidation, DNA damage and cell oxidative stress as well as increased the SOD levels. These results demonstrate that guaraná has an antioxidant effect on NO metabolism in situations with higher cellular NO levels. © 2012 Elsevier Ltd.

Goncalves R.M.,State University of Maringá | Lemos C.O.T.,State University of Maringá | Leal I.C.R.,Federal University of Rio de Janeiro | Nakamura C.V.,Programa de Pos Graduacao em Ciencias Farmaceuticas | And 4 more authors.
Molecules | Year: 2013

Calophyllum brasiliense is a rich source of bioactive coumarins, xanthones and biflavonoids. The aim of the study was to compare the phenol contents and the antioxidant activity of C. brasiliense extracts obtained by conventional and supercritical fluid extraction (SFE) methods, as well as the quantification of crude extracts and (-)-mammea A/BB yields. Dichloromethane and hexane were used as solvents for the conventional extractions and SFE was developed using supercritical CO2; the kinetic curves were modeled using a second-order empirical model. The dichloromethane extract presented the best total yield, although it showed the lowest content of (-)-mammea A/BB. The concentration of the coumarin was considerably higher in extracts obtained by the supercritical fluid method and a higher antioxidant activity was assigned to extracts obtained by this technique. Concerning the total phenolic contents, both the dichloro-methane and the supercritical extractions produced satisfactory amounts. The SFE method proved to be more promising than conventional methods. © 2013 by the authors.

PubMed | Federal University of Rio Grande do Sul, Federal University of Amazonas and Programa de Pos Graduacao em Ciencias Farmaceuticas
Type: | Journal: International journal of nanomedicine | Year: 2015

Rheumatoid arthritis (RA) is the most common autoimmune disease in the word, affecting 1% of the population. Long-term prognosis in RA was greatly improved following the introduction of highly effective medications such as methotrexate (MTX). Despite the importance of this drug in RA, 8%-16% of patients must discontinue the treatment because of adverse effects. Last decade, we developed a promising new nanocarrier as a drug-delivery system, lipid-core nanocapsules.The aim of the investigation reported here was to evaluate if methotrexate-loaded lipid-core nanocapsules (MTX-LNC) reduce proinflammatory and T-cell-derived cytokines in activated mononuclear cells derived from RA patients and even in functional MTX-resistant conditions. We also aimed to find out if MTX-LNC would reduce inflammation in experimentally inflammatory arthritis at lower doses than MTX solution.Formulations were prepared by self-assembling methodology. The adjuvant arthritis was induced in Lewis rats (AIA) and the effect on edema formation, TNF- levels, and interleukin-1 beta levels after treatment was evaluated. Mononuclear cells obtained from the synovial fluid of RA patients during articular infiltration procedures were treated with MTX solution and MTX-LNC. For in vitro experiments, the same dose of MTX was used in comparing MTX and MTX-LNC, while the dose of MTX in the MTX-LNC was 75% lower than the drug in solution in in vivo experiments.Formulations presented nanometric and unimodal size distribution profiles, with D[4.3] of 17517 nm and span of 1.60.2. Experimental results showed that MTX-LNC had the same effect as MTX on arthritis inhibition on day 28 of the experiment (P<0.0001); however, this effect was achieved earlier, on day 21 (P<0.0001), by MTX-LNC, and this formulation had reduced both TNF- (P=0.001) and IL-1 (P=0.0002) serum levels by the last day of the experiment. Further, the MTX-LNC were more effective at reducing the cytokine production from mononuclear synovial cells than MTX.The MTX-LNC were better than the MTX solution at reducing proinflammatory cytokines and T-cell-derived cytokines such as interferon-gamma and interleukin-17A. This result, combined with the reduction in the dose required for therapy, shows that MTX-LNC are a very promising system for the treatment of RA.

PubMed | National Institute of Amazonian Research, Policlinica Cardoso Fontes, Federal University of Amazonas and Programa de Pos Graduacao em Ciencias Farmaceuticas
Type: Journal Article | Journal: PloS one | Year: 2016

Immunogenetic host factors are associated with susceptibility or protection to tuberculosis (TB). Strong associations of HLA class II genes with TB are reported. We analyzed the HLA-DRB1*04 alleles to identify subtypes associated with pulmonary TB and their interaction with risk factors such as alcohol, smoking, and gender in 316 pulmonary TB patients and 306 healthy individuals from the Brazilian Amazon. The HLA-DRB1*04 was prevalent in patients with pulmonary TB (p<0.0001; OR = 2.94; 95% CI = 2.12 to 4.08). Direct nucleotide sequencing of DRB1 exon 2 identified nine subtypes of HLA-DRB1*04. The subtype HLA-DRB1*04:11:01 (p = 0.0019; OR = 2.23; 95% CI = 1.34 to 3.70) was associated with susceptibility to pulmonary TB while DRB1*04:07:01 (p<0.0001; OR = 0.02; 95% CI = 0.001 to 0.33) to protection. Notably, the interaction between alcohol and HLA-DRB1*04:11:01 increased the risk for developing pulmonary TB (p = 0.0001; OR = 51.3; 95% CI = 6.81 to 386). Multibacillary pulmonary TB, the clinical presentation of disease transmission, was strongly associated with interaction to alcohol (p = 0.0026; OR = 11.1; 95% CI = 3.99 to 30.9), HLA-DRB1*04:11:01 (p = 0.0442; OR = 2.01; 95% CI = 1.03 to 3.93) and DRB1*04:92 (p = 0.0112; OR = 8.62; 95% CI = 1.63 to 45.5). These results show that HLA-DRB1*04 are associated with pulmonary TB. Interestingly, three subtypes, DRB1*04:07:01, DRB1*04:11:01 and DRB1*04:92 of the HLA-DRB1*04 could be potential immunogenetic markers that may help to explain mechanisms involved in disease development.

Wayhs C.A.Y.,Programa de Pos Graduacao em Ciencias Farmaceuticas | Manfredini V.,Programa de Pos Graduacao em Ciencias Farmaceuticas | Sitta A.,Servico de Genetica Medica | Sitta A.,Federal University of Rio Grande do Sul | And 9 more authors.
Metabolic Brain Disease | Year: 2010

Diabetes may modify central nervous system functions and is associated with moderate cognitive deficits and changes in the brain, a condition that may be referred to as diabetic encephalopathy. The prevalence of depression in diabetic patients is higher than in the general population, and clonazepam is being used to treat this complication. Oxidative stress may play a role in the development of diabetes complications. We investigated oxidative stress parameters in streptozotocin-induced diabetic rats submitted to forced swimming test (STZ) and evaluated the effect of insulin (STZ-INS) and/or clonazepam (STZ-CNZ and STZ-INS-CNZ) acute treatment on these animal model. Oxidative damage to proteins measured as carbonyl content in plasma was significantly increased in STZ group compared to STZ treated groups. Malondialdehyde plasma levels were significantly reduced in STZ-INS and STZ-INS-CNZ groups when compared to STZ rats, being significantly reduced in STZ-INS-CNZ than STZ-INS rats. The activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase showed no significant differences among all groups of animals. These findings showed that protein and lipid damage occurs in this diabetes/depression animal model and that the associated treatment of insulin and clonazepam is capable to protect against oxidative damage in this experimental model. © 2010 Springer Science+Business Media, LLC.

Wayhs C.A.Y.,Programa de Pos Graduacao em Ciencias Farmaceuticas | Tortato C.,Federal University of Rio Grande do Sul | Mescka C.P.,Federal University of Rio Grande do Sul | Pasquali M.A.,Federal University of Rio Grande do Sul | And 6 more authors.
Pharmaceutical Biology | Year: 2013

Context: It is known that oxidative stress occurs in peripheral blood in an experimental animal model of diabetes and depression, and acute treatment with insulin and clonazepam (CNZ) has a protective effect on oxidative stress in this model. Objective: This study evaluated the effect of insulin plus CNZ on oxidative stress parameters in the liver of diabetic male rats induced with streptozotocin (STZ) and subjected to forced swimming test (FST). Materials and methods: Diabetes was induced by a single intraperitoneal (i.p.) dose of STZ 60mg/kg in male Wistar rats. Insulin (4IU/kg) plus CNZ acute i.p. treatment (0.25mg/kg) was administered 24, 5 and 1h before the FST. Nondiabetic control rats received i.p. injections of saline (1mL/kg). Protein oxidative damage was evaluated by carbonyl formation and the antioxidant redox parameters were analyzed by the measurements of enzymatic activities of the superoxide dismutase (SOD), catalase and glyoxalase I (GLO). Glycemia levels also were determined. Results: Our present study has shown an increase in carbonyl content from diabetic rats subjected to FST (2.04±0.55), while the activity of catalase (51.83±19.02) and SOD (2.30±1.23) were significantly decreased in liver from these animals, which were reverted by the treatment. Also, the activity of GLO (0.15±0.02) in the liver of the animals was decreased. Discussion and conclusion: Our findings showed that insulin plus CNZ acute treatment ameliorate the antioxidant redox parameters and protect against protein oxidative damage in the liver of diabetic rats subjected to FST. © 2013 Informa Healthcare USA, Inc.

PubMed | Autonomous University of Yucatán, Vale do Itajai University and Programa de Pos Graduacao em Ciencias Farmaceuticas
Type: | Journal: Journal of ethnopharmacology | Year: 2016

Chrysophyllum cainito L. (Sapotaceae), commonly known as caimito or star apple, is a neotropical tree valued for its ornamental quality and edible fruits. Besides its culinary use, the leaves are also popularly used to treat diabetes mellitus and several inflammatory diseases.This study aimed to complement previous data obtained about the anti-hypersensitivity effects of the crude methanol extract (CME), CHCl3 fraction and isolated compounds obtained from C. cainito.The CME, CHCl3 fraction and two isolated triterpenes identified as 3-Lup-20(29)-en-3-yl acetate (1) and Lup-20(29)-en-3-O-hexanoate (2) were evaluated regarding their effects using clinical pain models, such as post-operative, inflammatory and neuropathic pain. Acute inflammatory pain models induced by PGE2, epinephrine, LPS and CFA were also used to improve the knowledge about the mechanism of action.The animals treated with the CME and submitted to PGE2, epinephrine, LPS or CFA had the mechanical hypersensitivity significantly reduced. When repeatedly administered, the CME enhanced the mechanical withdrawal threshold of mice submitted to post-operative pain model, CFA-induced chronic inflammatory pain and two different models of neuropathic pain. In turn, the CHCl3 fraction presented anti-hypersensitivity effect against epinephrine- or LPS-induced hypersensitivity, with a more prominent activity in both the neuropathic pain models. The compound 1 seems to present the same profile of the CHCl3, whereas compound 2 exhibited activity similar to the CME.This data suggests that the CME effect involves interference in the production, release or action of some chemical mediators, such as PGE2, sympathetic amines, cytokines, etc. Part of these effects was observed with the CHCl3 fraction, emphasizing the prominent inhibition of neuropathic pain. The results also demonstrated that part of the CME effects are due to the presence of the triterpenes 1 and 2, but it is important to mention that we cannot discard the effects of countless other compounds presented in the crude extract, acting in a synergic way.

PubMed | Programa de Pos Graduacao em Ciencias Farmaceuticas
Type: | Journal: International journal of nanomedicine | Year: 2012

Neuroinflammation, characterized by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of Alzheimers disease (AD). Epidemiological studies suggesting that nonsteroidal anti-inflammatory drugs decrease the risk of developing AD have encouraged further studies elucidating the role of inflammation in AD. Nanoparticles have become an important focus of neurotherapeutic research because they are an especially effective form of drug delivery. Here, we investigate the potential protective effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNCs) against cell damage and neuroinflammation induced by amyloid beta (A)1-42 in AD models. Our results show that IndOH-LNCs attenuated A-induced cell death and were able to block the neuroinflammation triggered by A1-42 in organotypic hippocampal cultures. Additionally, IndOH-LNC treatment was able to increase interleukin-10 release and decrease glial activation and c-jun N-terminal kinase phosphorylation. As a model of A-induced neurotoxicity in vivo, animals received a single intracerebroventricular injection of A1-42 (1 nmol/site), and 1 day after A1-42 infusion, they were administered either free IndOH or IndOH-LNCs (1 mg/kg, intraperitoneally) for 14 days. Only the treatment with IndOH-LNCs significantly attenuated the impairment of this behavior triggered by intracerebroventricular injection of A1-42. Further, treatment with IndOH-LNCs was able to block the decreased synaptophysin levels induced by A1-42 and suppress glial and microglial activation. These findings might be explained by the increase of IndOH concentration in brain tissue attained using drug-loaded lipid-core NCs. All these findings support the idea that blockage of neuroinflammation triggered by A is involved in the neuroprotective effects of IndOH-LNCs. These data provide strong evidence that IndOH-LNC treatment may represent a promising approach for treating AD.

PubMed | Programa de Pos Graduacao em Ciencias Farmaceuticas .
Type: Journal Article | Journal: Pharmaceutical development and technology | Year: 2013

The non-invasive ophthalmic therapy has a drawback: low residence time in the eye socket. Nanoparticles and contact lenses have been studied as promising ocular drug delivery systems.To develop a nanoemulsion and evaluate its compatibility with a soft contact lens as a potential strategy for ocular delivery.The formulations were developed by spontaneous emulsification and fully characterized. Two drops of nanoemulsion were instilled on the surface of a commercial contact lens and its transparency was measured using a UV-Vis spectrophotometer. Before and after the instillation of the drops, the morphology (scanning electron microscopy - SEM) and ion permeability of the lenses were analyzed.The formulations had a mean particle size of 234nm, polydispersity below 0.16, zeta potential of -8.563.49mV, slightly acid pH, viscosity 1.2mPas(-1) and spherical-shaped particles. Nanoemulsion was non-irritant (hens egg test-chorioallantoic membrane), which was confirmed by the cytotoxicity studies in the SIRC cell cultures. After instillation, SEM analysis showed nanodroplets inside and on the surface of the lenses, although their transparency remained near 100%. No significant differences were found between lens ion permeability coefficients before and after instillation.Formulations presented appropriate physicochemical characteristics and suitability for ocular application. The contact lens remained transparent and ion-permeable after association with the formulation.

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