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The aim of this work was to compare the anti-inflammatory and antioxidant effects of three natural coumarins: 1,2-benzopyrone, umbelliferone and esculetin. The antioxidant capacity of coumarins was evaluated using both chemical and biological in vitro assays. Chemical assays included DPPH and ABTSâ+ radical scavenging as well as ferric ion reducing ability power (FRAP) assay. Inhibition of mitochondrial ROS generation and lipid peroxidation in brain homogenates were used as biological in vitro assays. The experimental method of carrageenan-induced pleurisy in rats was used for the in vivo investigation of the anti-inflammatory activity. In silico molecular docking analysis was undertaken to predict the affinity of COX-2 to the coumarins. Considering the antioxidant capacity, esculetin was the most efficient one as revealed by all employed assays. Particularly, the mitochondrial ROS generation was totally abolished by the compound at low concentrations (IC50 = 0.57 µM). As for the anti-inflammatory effects, the COX-2 enzyme presented good affinities to the three coumarins, as revealed by the molecular docking analyses. However, considering the in vivo anti-inflammatory effects, 1,2-benzopyrone was the most efficient one in counteracting pleural inflammation and it potentiated the anti-inflammatory actions of dexamethasone. Umbelliferone and esculetin treatments failed to reduce the volume of pleural exudate. Overall, therefore, our results support the notion that this class of plant secondary metabolites displays promising effects in the prevention and/or treatment of inflammation and other diseases associated with oxidative stress, although the singularities regarding the type of the inflammatory process and pharmacokinetics must be taken into account.
Assuntos
Antioxidantes , Cumarínicos , Ratos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Espécies Reativas de Oxigênio , Ciclo-Oxigenase 2/metabolismo , Simulação de Acoplamento Molecular , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Extratos Vegetais/farmacologiaRESUMO
The present study prepared, optimized, and characterized solid lipid microparticles that contained trans-anethole (SLMAN), evaluated their antiinflammatory activity in acute and chronic inflammation models, and investigated their effects on the gastric mucosa in arthritic rats. The microparticles were obtained by a hot homogenization process and characterized by physicochemical analyses. The acute inflammatory response was induced by an intradermal injection of 0.1 ml of carrageenan solution (200 µg) in the hind paw. The rats were treated orally with a single dose of SLMAN 1 h before induction of the inflammatory response. The chronic inflammatory response was induced by the subcutaneous application of 0.1 ml of complete Freund's adjuvant suspension (500 µg) in the hind paw. SLMAN was orally administered, starting on the day of arthritis induction, and continued for 21 days. The results showed that SLMAN was obtained with good encapsulation efficiency. Treatment with SLMAN at doses of 25 and 50 mg/kg was as effective as trans-anethole (AN) at a dose of 250 mg/kg on acute and chronic inflammatory responses. Histological analyses showed that treatment with SLMAN did not aggravate lesions in the gastric mucosa in arthritic rats. These results indicated that treatment with SLMAN at a dose that was 5-10 times lower than non-encapsulated AN exerted an inhibitory effect on acute and chronic inflammatory responses, suggesting the better bioavailability and efficacy of microencapsulated AN without aggravating lesions in the gastric mucosa in arthritic rats.
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Artrite Experimental , Ratos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , LipídeosRESUMO
BACKGROUND: Invasion of the intestinal mucosa by T. gondii elicits a local immune response of variable intensity. These reactions can be lethal in C57BL/6 mice. The tissue damage caused by inflammation and the functional effects depend on the host immunity, strain, and developmental form of the parasite. We investigated the effects of acute oral infection with T. gondii on histoarchitecture, enteric nervous system (ENS), and inflammatory markers in the jejunum and ileum of mice. METHODS: Female C57BL/6 mice were divided into a control group and a group orally infected with 1000 sporulated T. gondii oocysts (ME-49 strain). After 5 days, jejunum and ileum were collected and processed for analyzes (e.g., histological and histopathological examinations, ENS, cytokine dosage, myeloperoxidase, nitric oxide activity). MAIN RESULTS: In infected mice, we observed a significant increase in serotonin-immunoreactive cells (5-HT IR) in the intestinal mucosa, as well as cellular infiltrates in the lamina propria, periganglionitis, and ganglionitis in the myenteric plexus. We also noted decreased neuron density in the jejunum, increased population of enteric glial cells in the ileum, histomorphometric changes in the intestinal wall, villi, and epithelial cells, remodeling of collagen fibers, and increased myeloperoxidase activity, cytokines, and nitric oxide in the intestine. CONCLUSIONS AND INFERENCES: Acute infection of female mice with T. gondii oocysts resulted in changes in ENS and a marked increase in 5-HT. These changes are consistent with its modulatory role in the development of moderate acute inflammation. The use of this experimental model may lend itself to studies aimed at understanding the pathophysiological mechanisms of intestinal inflammation in humans involving ENS.
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Toxoplasma , Ratos , Humanos , Feminino , Camundongos , Animais , Toxoplasma/fisiologia , Serotonina , Peroxidase , Oocistos , Óxido Nítrico , Ratos Wistar , Camundongos Endogâmicos C57BL , Intestinos , Inflamação , Citocinas , ColágenoRESUMO
Objective: In the present study, the hepatoprotective effects of ß-myrcene (MYR) on acetaminophen-induced hepatotoxicity were investigated. Materials and Methods: A total of 40 Balb/c mice were randomly divided into five groups as follows: 1) Normal control group which received only carboxymethylcellulose (CMC), the vehicle used to dissolve acetaminophen (N-acetyl-p-aminophenol, APAP, paracetamol) and MYR; 2) APAP group which received a single dose of acetaminophen (250 mg/kg) orally on day 7; 3) Silymarin group which received 200 mg/kg/day of silymarin; and 4 and 5) pretreatment groups in which, mice were treated with 100 or 200 mg/kg/day of MYR. Liver and blood samples were collected to analyze serum aminotransferases, inflammatory response, oxidative stress markers, and histopathological insults. Results: Our results showed that MYR pretreatment attenuated liver damage and restored liver cells function and integrity as it decreased the leakage of serum aminotransferases (alanine and aspartate aminotransferases (ALT and AST, respectively)) into the blood (p<0.01). MYR treatment also reduced levels of myeloperoxidase (MPO) activity and nitric oxide (NO) (p<0.001). In addition, MYR pretreatment demonstrated significant antioxidant activity by decreasing malondialdehyde (MDA), reactive oxygen species (ROS), and reduced glutathione (GSH) levels (p<0.001). Furthermore, it restored the hepatic level of superoxide dismutase (SOD), catalase (CAT), and oxidized glutathione (GSSG) (p<0.001). Conclusion: For the first time, our results showed that MYR treatment significantly improved liver function by reducing oxidative stress and the inflammatory response induced by APAP.
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Abstract Exopolysaccharides (EPS) produced by Klebsiella oxytoca are of environmental, pharmaceutical, and medicinal interest. However, studies about the anti-inflammatory activity of EPS produced by this microorganism still remain limited. The aim of this study was to produce, characterize, and evaluate the anti-inflammatory activity of EPS from K. oxytoca in a pleurisy model. Colorimetric analysis revealed that precipitated crude exopolysaccharides (KEPSC) and deproteinated exopolysaccharides (KEPS) present high levels of total carbohydrates (65.57% and 62.82%, respectively). Analyses of uronic acid (7.90% in KEPSC and 6.21% in KEPS) and pyruvic acid (3.01% in KEPSC and 1.68% in KEPS) confirm that the EPS are acidic. Gas chromatography-mass spectrometry analyses demonstrated that the EPS consisted of rhamnose (29.83%), glucose (11.21%), galactose (52.45%), and mannose (6.50%). The treatment of an experimental pleurisy model in rats through subcutaneous administration of 50, 100, 200, and 400 mg/kg of KEPS decreased both the volume of inflammatory exudate and the number of leukocytes recruited to the pleural cavity. The present data showed that EPS production by K. oxytoca using the method described is easy to perform and results in a good yield. In addition, we show that KEPS exhibit anti-inflammatory activity when administered subcutaneously in rats.
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Animais , Ratos , Pleurisia/tratamento farmacológico , Polissacarídeos Bacterianos/uso terapêutico , Klebsiella oxytoca/química , Anti-Inflamatórios/uso terapêutico , Polissacarídeos Bacterianos/isolamento & purificação , Ratos Wistar , Modelos Animais de Doenças , Anti-Inflamatórios/isolamento & purificaçãoRESUMO
This study investigated the effect of prostaglandin E1 (PGE-1) treatment on the biochemical and histopathological changes in a model of nephropathy that was induced using renal microembolism in rats. Wistar rats were assigned to three groups: a control group (C, normal), a renal microembolism (RM) group, and a renal microembolism treated with PGE-1 (RM + PGE-1) group. The renal microembolism was induced by an arterial injection of polymethylmethacrylate microbeads into the remaining kidney of nephrectomized rats. Intramuscular treatment with PGE-1 was initiated on the day of the induction of the renal microembolism and continued once weekly for up to 60 days. At the end of the treatment period, blood samples were taken to assess the serum creatinine and urea concentrations, and 24-h urine samples were collected to determine the total protein levels. The rats' kidneys were removed and processed for histopathological analysis using the hematoxylin and eosin, periodic acid-Schiff, Mallory-Azan, and Picro-Sirius techniques. An immunohistochemical assay with vascular endothelial growth factor receptor-2 (anti-VEGFR-2) was also performed. The results showed that the PGE-1 treatment prevented vascular, glomerular, tubular, and interstitial alterations and reduced the biochemical changes, thus improving the renal function in rats that were subjected to renal microembolism. These effects could be partially attributable to an increase in the PGE-1-induced angiogenesis, because we observed an increase in the tissue expression of VEGFR-2, a specific marker of angiogenesis.
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Este estudo avaliou os efeitos da suplementação diária de vitamina D na resposta inflamatória aguda em modelo experimental por diferentes agentes flogísticos: carragenina, prostaglandina e dextrana. Os animais (ratos) receberam por via oral (gavagem), dose única de vitamina D ou suplementação diária durante 7, 15 ou 30 dias antes da indução do edema de pata. A suplementação com vitamina D por 15 e 30 dias reduziu significativamente o processo inflamatório induzido por carragenina, o que poderia ser explicado, pelo menos parcialmente, pela redução dos níveis de fator de necrose tumoral α (TNFα). Os resultados indicam que a suplementação de vitamina D pode ser um útil adjuvante terapêutico para o controle do processo inflamatório agudo.
This study evaluated the effects of daily vitamin D supplementation on the acute inflammatory response in experimental model by different phlogistic agents: carrageenan, prostaglandin and dextran. Animals (rats) orally received (gavage) a single dose of vitamin D or daily supplementation for 7, 15 or 30 days prior to paw edema induced. Vitamin D supplementation for 15 and 30 days significantly reduced the carrageenan-induced inflammatory process, which could be at least partially explained by the reduction of tumor necrosis factor α levels (TNFα). Results indicate that vitamin D supplementation may be a useful therapeutic adjuvant for controlling the acute inflammatory process.
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Anethole (AN) is a natural compound that has attracted great scientific interest because of its numerous biological activities, including anti-inflammatory effects. However, these effects were obtained with high doses of AN, which may be one limitation of its therapeutic use. This study evaluated the effects of a low-dose AN and ibuprofen (IB) combination on inflammatory parameters in Freund's complete adjuvant-induced arthritis (AIA) and arthritis-induced hepatic metabolic changes. Holtzman rats were used and divided into groups: normal, AIA (control), arthritics treated with IB, arthritics treated with AN, and arthritics treated with AN + IB. The volume of the paws, the appearance of secondary lesions, and the number of synovial leukocytes were evaluated. Gluconeogenesis and ureagenesis from alanine were determined in the rat liver in isolated perfusion. The AN + IB (62.5 + 8.75 mg/kg) treatment exerted an inhibitory effect on inflammatory parameters and partially prevented hepatic metabolic changes that was similar to the effect of high-dose IB (35 mg/kg) and AN (250 mg/kg) treatment. This effect of the treatments on hepatic metabolism can be, partly at least, explained by the preservation of both the alanine aminotransferase (ALT) activity and the cytosolic NADH/NAD+ redox potential in the liver. Taken together, the data obtained provided evidence that the AN + IB combination at lower doses than AN and IB treatment alone had beneficial inhibitory potential for the treatment of AIA and attenuated metabolic changes in the liver. Graphical Abstract.
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Derivados de Alilbenzenos/administração & dosagem , Anisóis/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Ibuprofeno/administração & dosagem , Fígado/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Adjuvante de Freund/toxicidade , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
There are different varieties of mushrooms not yet studied spread all over the planet. The objective of this study was to evaluate biochemical properties and effects on mitochondrial respiration of eight Basidiomycete mushrooms: Flaviporus venustus EF30, Hydnopolyporus fimbriatus EF41 and EF44, Inonotus splitgerberi EF46, Oudemansiella canarii EF72, Perenniporia sp. EF79, Phellinus linteus EF81, and Pleurotus albidus EF84. Total phenols, ABTS, TEAC, FRAP, and ORAC were measured in order to determine the antioxidant capacity. Antimicrobial potential was studied by disc-diffusion and microdilution method. Cytotoxicity was determined in murine peritoneal macrophages. The bioenergetic aspects were evaluated by the uncoupling of the oxidative phosphorylation in mitochondrias. The H. fimbriatus mushroom was the one that presented the most significant results for the antioxidant assays. Three mushrooms presented antimicrobial activity, indicating a potential for formulation of drugs. The results suggest that I. spligerberi has an uncoupling activity, even at the lowest concentration tested, dissipating the mitochondrial electrochemical gradient. On the other hand, P. albidus has effect only on succinate-oxidase activity without influencing mitochondrial respiratory efficiency. Therefore, both interfere negatively in mitochondrial respiration. In relation with the cytotoxicity in peritoneal macrophages, O. canarii and F. venustus were cytotoxic in this type of cells.
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Basidiomycota/química , Mitocôndrias/efeitos dos fármacos , Fenóis/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/metabolismo , Basidiomycota/metabolismo , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Mitocôndrias/metabolismo , Oxirredução , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Fenóis/isolamento & purificação , Fenóis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Ácido Succínico/químicaRESUMO
(-)-α-Bisabolol (BISA) is an unsaturated monocyclic sesquiterpenes compound, mainly found in the essential oil of chamomile (Matricaria chamomilla). It has been reported that this compound has several biological activities, but there are few studies evaluating the activity of this compound in the systemic inflammatory response in infectious processes. The aim of this study was to evaluate the effect of BISA on the inflammatory response and survival rate in a systemic infection model, and in vitro neutrophils phagocytic activity. BISA at concentration of 3, 10, 30, and 90 µg/ml did not presented in vitro cytotoxicity in MTT assay, and at concentrations of 1 and 3 µg/ml the BISA treatment increased in vitro phagocytic neutrophil activity. For the inflammatory response study, we verified the BISA treatment effect in a cecal ligation and puncture (CLP)-induced systemic infection model in mice; in this model, we demonstrate that BISA at dose of 100 mg/kg reduced the leukocyte recruitment in peritoneal cavity; at dose of 200 mg/kg, the NO concentration was increased in the peritoneal cavity. The bacteria CFU number was reduced in mice blood in the BISA treatment, at doses of 100 and 200 mg/kg. The BISA treatment at doses of 50 and 100 mg/kg increased the myeloperoxidase activity and reduction NO production in lung tissue of mice in CLP model. At dose of 100 mg/kg, the BISA treatment was able to reduce the mortality rate of mice submitted to CLP-induced sepsis and observed for 7 days. The results suggest an effect of BISA on inflammatory response, with activity on leukocyte chemotactic and NO production, in addition to increasing the survival rate of animals submitted to CLP model.