RESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease of knee joints involving pain and inflammation. Rhoifolin is a plant flavonoid known to have antioxidant and anti-inflammatory properties. This study was taken to identify the effect of rhoifolin on complete Freund's adjuvant (CFA)-induced arthritis in the rat model. Treatment with rhoifolin (10 and 20 mg/kg) showed a significant improvement in the overall health parameters such as paw edema and weight loss. This improvement in morphological parameters corroborated the findings with gross morphological changes observed in the histopathological analysis. Rhoifolin treatment also caused a significant decrease in oxidative stress, evident from changes in intracellular levels of glutathione, glutathione peroxidase, malondialdehyde, and superoxide dismutase in the articular cartilage tissue. Moreover, proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin(IL)-1ß, and IL-6 showed a significant downregulation of gene expression and intracellular protein concentration levels. The NF-κB pathway showed a significant attenuation as evident in the significant reduction in the levels of NF-κB p65 and p-IκB-α. These results indicated that rhoifolin can be a natural therapeutic alternative to the extant regimens, which include non-steroidal anti-inflammatory drugs and immunosuppressants. Additionally, the antioxidant and anti-inflammatory action of rhoifolin was probably mediated by the NF-κB pathway. However, the exact target molecules of this pathway need to be determined in further studies.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Citocinas/sangre , Disacáridos/administración & dosificación , Flavonoides/administración & dosificación , Adyuvante de Freund/administración & dosificación , Glicósidos/administración & dosificación , FN-kappa B/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Biomarcadores/sangre , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , FN-kappa B/metabolismo , Ratas , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease of knee joints involving pain and inflammation. Rhoifolin is a plant flavonoid known to have antioxidant and anti-inflammatory properties. This study was taken to identify the effect of rhoifolin on complete Freund's adjuvant (CFA)-induced arthritis in the rat model. Treatment with rhoifolin (10 and 20 mg/kg) showed a significant improvement in the overall health parameters such as paw edema and weight loss. This improvement in morphological parameters corroborated the findings with gross morphological changes observed in the histopathological analysis. Rhoifolin treatment also caused a significant decrease in oxidative stress, evident from changes in intracellular levels of glutathione, glutathione peroxidase, malondialdehyde, and superoxide dismutase in the articular cartilage tissue. Moreover, proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin(IL)-1β, and IL-6 showed a significant downregulation of gene expression and intracellular protein concentration levels. The NF-κB pathway showed a significant attenuation as evident in the significant reduction in the levels of NF-κB p65 and p-IκB-α. These results indicated that rhoifolin can be a natural therapeutic alternative to the extant regimens, which include non-steroidal anti-inflammatory drugs and immunosuppressants. Additionally, the antioxidant and anti-inflammatory action of rhoifolin was probably mediated by the NF-κB pathway. However, the exact target molecules of this pathway need to be determined in further studies.
Asunto(s)
Animales , Masculino , Ratas , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Flavonoides/administración & dosificación , Adyuvante de Freund/administración & dosificación , Citocinas/sangre , Estrés Oxidativo/efectos de los fármacos , Disacáridos/administración & dosificación , Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Biomarcadores/sangre , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Interleucina-6/sangre , Factor de Necrosis Tumoral alfa/sangre , Interleucina-1beta/sangre , Glicósidos/administración & dosificaciónRESUMEN
Oral diabetes-specific nutritional supplements (ONS-D) induce favourable postprandial responses in subjects with type 2 diabetes (DM2), but they have not been correlated yet with incretin release and subjective appetite (SA). This randomised, double-blind, cross-over study compared postprandial effects of ONS-D with isomaltulose and sucromalt versus standard formula (ET) on glycaemic index (GI), insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and SA in 16 individuals with DM2. After overnight fasting, subjects consumed a portion of supplements containing 25 g of carbohydrates or reference food. Blood samples were collected at baseline and at 30, 60, 90, 120, 150 and 180 min; and SA sensations were assessed by a visual analogue scale on separate days. Glycaemic index values were low for ONS-D and intermediate for ET (p < 0.001). The insulin area under the curve (AUC0-180 min) (p < 0.02) and GIP AUC (p < 0.02) were lower after ONS-D and higher GLP-1 AUC when compared with ET (p < 0.05). Subjective appetite AUC was greater after ET than ONS-D (p < 0.05). Interactions between hormones, hunger, fullness and GI were found, but not within the ratings of SA; isomaltulose and sucromalt may have influenced these factors.
Asunto(s)
Regulación del Apetito , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/dietoterapia , Suplementos Dietéticos , Disacáridos/administración & dosificación , Fructosa/administración & dosificación , Índice Glucémico , Isomaltosa/administración & dosificación , Hormonas Peptídicas/sangre , Administración Oral , Biomarcadores/sangre , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/psicología , Disacáridos/efectos adversos , Método Doble Ciego , Femenino , Fructosa/efectos adversos , Polipéptido Inhibidor Gástrico/sangre , Péptido 1 Similar al Glucagón/sangre , Humanos , Insulina/sangre , Isomaltosa/efectos adversos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Maternal hypercaloric exposure during pregnancy and lactation is a risk factor for developing diseases associated with inflammation such as obesity, diabetes and, neurological diseases in the offspring. Neuroinflammation might modulate neuronal activation and flavonoids are dietary compounds that have been proven to exert anti-inflammatory properties. Thus, the aim of the present study is to evaluate the effect of maternal supplementation with flavonoids (kaempferol-3-O-glucoside and narirutin) on the prevention of depression-like behaviour in the female offspring of dams fed with an obesogenic diet during the perinatal period. Maternal programming was induced by high fat (HFD), high sugar (HSD), or cafeteria diets exposure and depressive like-behaviour, referred to as swimming, climbing, and immobility events, was evaluated around postnatal day 56â»60 before and after 30 mg/kg i.p. imipramine administration in the female offspring groups. Central inflammation was analyzed by measuring the TANK binding kinase 1 (TBK1) expression. We found that the offspring of mothers exposed to HSD programming failed to show the expected antidepressant effect of imipramine. Also, imipramine injection, to the offspring of mothers exposed to cafeteria diet, displayed a pro-depressive like-behaviour phenotype. However, dietary supplementation with flavonoids reverted the depression-like behaviour in the female offspring. Finally, we found that HSD programming increases the TBK1 inflammatory protein marker in the hippocampus. Our data suggest that maternal HSD programming disrupts the antidepressant effect of imipramine whereas cafeteria diet exposure leads to depressive-like behaviour in female offspring, which is reverted by maternal flavonoid supplementation.
Asunto(s)
Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Depresión/metabolismo , Flavonoides/farmacología , Fenómenos Fisiologicos Nutricionales Maternos/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Antidepresivos/administración & dosificación , Dieta , Disacáridos/administración & dosificación , Disacáridos/farmacología , Interacciones Farmacológicas , Femenino , Flavanonas/administración & dosificación , Flavanonas/farmacología , Flavonoides/administración & dosificación , Imipramina/administración & dosificación , Imipramina/farmacología , Inflamación/metabolismo , Inflamación/prevención & control , Quempferoles/administración & dosificación , Quempferoles/farmacología , Masculino , Monosacáridos/administración & dosificación , Monosacáridos/farmacología , Embarazo , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas WistarRESUMEN
Iron is involved in the formation as well as in the scavenging of reactive oxygen and nitrogen species. Thus, iron can induce as well as inhibit both oxidative and nitrosative stress. It also has a key role in reactive oxygen and nitrogen species-mediated apoptosis. We assessed the differences in tyrosine nitration and caspase 3 expression in the liver, heart, and kidneys of rats treated weekly with intravenous ferumoxytol, iron isomaltoside 1000, iron dextran, iron sucrose and ferric carboxymaltose (40 mg iron/kg body weight) for 5 weeks. Nitrotyrosine was quantified in tissue homogenates by Western blotting and the distribution of nitrotyrosine and caspase 3 was assessed in tissue sections by immunohistochemistry. Ferric carboxymaltose and iron sucrose administration did not result in detectable levels of nitrotyrosine or significant levels of caspase 3 vs. control in any of the tissue studied. Nitrotyrosine and caspase 3 levels were significantly (p<0.01) increased in all assessed organs of animals treated with iron dextran and iron isomaltoside 1000, as well as in the liver and kidneys of ferumoxytol-treated animals compared to isotonic saline solution (control). Nitrotyrosine and caspase 3 levels were shown to correlate positively with the amount of Prussian blue-detectable iron(III) deposits in iron dextran- and iron isomaltoside 1000-treated rats but not in ferumoxytol-treated rats, suggesting that iron dextran, iron isomaltoside 1000 and ferumoxytol induce nitrosative (and oxidative) stress as well as apoptosis via different mechanism(s).
Asunto(s)
Apoptosis/efectos de los fármacos , Disacáridos/efectos adversos , Compuestos Férricos/efectos adversos , Óxido Ferrosoférrico/efectos adversos , Ácido Glucárico/efectos adversos , Complejo Hierro-Dextran/efectos adversos , Maltosa/análogos & derivados , Tirosina/análogos & derivados , Administración Intravenosa , Animales , Caspasa 3/biosíntesis , Disacáridos/administración & dosificación , Femenino , Compuestos Férricos/administración & dosificación , Sacarato de Óxido Férrico , Óxido Ferrosoférrico/administración & dosificación , Ácido Glucárico/administración & dosificación , Complejo Hierro-Dextran/administración & dosificación , Riñón/metabolismo , Hígado/metabolismo , Masculino , Maltosa/administración & dosificación , Maltosa/efectos adversos , Modelos Animales , Miocardio/metabolismo , Ratas , Tirosina/metabolismoRESUMEN
BACKGROUND: There is a growing need to improve heart preservation benefit the performance of cardiac operations, decrease morbidity, and more important, increase the donor pool. Therefore, the objective of this study was to evaluate the cardioprotective effects of Krebs-Henseleit buffer (KHB), Bretschneider-HTK (HTK), St. Thomas No. 1 (STH-1), and Celsior (CEL) solutions infused at 10°C and 20°C. METHODS: Hearts isolated from male albino Wistar rats and prepared according to Langendorff were randomly divided equally into 8 groups according to the temperature of infusion (10°C or 20°C) and cardioprotective solutions (KHB, HTK, STH-1, and CEL). After stabilization with KHB at 37°C, baseline values were collected (control) for heart rate (HR), left ventricle systolic pressure (LVSP), coronary flow (CF), maximum rate of rise of left ventricular pressure during ventricular contraction (+dP/dt) and maximum rate of fall of left ventricular pressure during left ventricular relaxation (-dP/dt). The hearts were then perfused with cardioprotective solutions for 5 minutes and kept for 2 hours in static ischemia at 20°C. Data evaluation used analysis of variance (ANOVA) in all together randomized 2-way ANOVA and Tukey's test for multiple comparisons. The level of significance chosen was P < .05. RESULTS: We observed that all 4 solutions were able to recover HR, independent of temperature. Interestingly, STH-1 solution at 20°C showed HR above baseline throughout the experiment. An evaluation of the corresponding hemodynamic values (LVSP, +dP/dt, and -dP/dt) indicated that treatment with CEL solution was superior at both temperatures compared with the other solutions, and had better performance at 20°C. When analyzing performance on CF maintenance, we observed that it was temperature dependent. However, when applying both HTK and CEL, at 10°C and 20°C respectively, indicated better protection against development of tissue edema. Multiple comparisons between treatments and hemodynamic variable outcomes showed that using CEL solution resulted in significant improvement compared with the other solutions at both temperatures. CONCLUSION: The solutions investigated were not able to fully suppress the deleterious effects of ischemia and reperfusion of the heart. However, these results allow us to conclude that temperature and the cardioprotective solution are interdependent as far as myocardial protection. Although CEL solution is the best for in myocardial protection, more studies are needed to understand the interaction between temperature and perfusion solution used. This will lead to development of better and more efficient cardioprotective methods.
Asunto(s)
Soluciones Cardiopléjicas/administración & dosificación , Isquemia Fría/efectos adversos , Paro Cardíaco Inducido/métodos , Hipotermia Inducida/efectos adversos , Daño por Reperfusión Miocárdica/prevención & control , Animales , Bicarbonatos/administración & dosificación , Cloruro de Calcio/administración & dosificación , Disacáridos/administración & dosificación , Edema Cardíaco/etiología , Edema Cardíaco/prevención & control , Electrólitos/administración & dosificación , Glucosa/administración & dosificación , Glutamatos/administración & dosificación , Glutatión/administración & dosificación , Frecuencia Cardíaca , Histidina/administración & dosificación , Magnesio/administración & dosificación , Masculino , Manitol/administración & dosificación , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/fisiopatología , Cloruro de Potasio/administración & dosificación , Procaína/administración & dosificación , Ratas , Ratas Wistar , Cloruro de Sodio/administración & dosificación , Factores de Tiempo , Trometamina/administración & dosificación , Función Ventricular Izquierda , Presión VentricularRESUMEN
The physicochemical characteristics of intravenous iron complexes affect the extent of weakly-bound iron and thus the degree of oxidative stress. The new preparation iron isomaltoside 1000 (IIM) was compared to iron sucrose (IS) and a control group in terms of biochemistry, oxidative stress, inflammatory markers and iron deposition in the liver, heart and kidneys of healthy rats. Renal function was significantly impaired in the IIM group versus both IS and controls. Liver enzymes were also significantly higher in IIM-treated animals versus the other groups, indicative of hepatic injury. Systolic blood pressure was significantly lower following IIM administration compared to IS or control animals. Oxidative stress in the liver, heart and kidneys was greater in the IIM group, as indicated by significantly increased levels of malondialdehyde and antioxidant enzyme activity, accompaniedby a significantly lower ratio of reduced to oxidized glutathione. Microscopy demonstrated more extensive positive staining for iron, and a smaller area of ferritin staining, in the liver, heart and kidneys of rats treated with IIM versus IS.Levels of the inflammatory markers TNF-alpha and IL6 were both significantly higher in the IIM group versus IS in all assessed tissues. These findings indicate that IIM has a less favorable safety profile than IS in healthy rats, adversely affecting iron deposition, oxidative stress and inflammatory responses, with impaired liver and renal function.
Asunto(s)
Disacáridos/toxicidad , Compuestos Férricos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Animales , Biomarcadores/sangre , Presión Sanguínea/efectos de los fármacos , Creatinina/sangre , Disacáridos/administración & dosificación , Disacáridos/farmacocinética , Compuestos Férricos/administración & dosificación , Compuestos Férricos/farmacocinética , Sacarato de Óxido Férrico , Ferritinas/sangre , Ácido Glucárico , Hemoglobinas/metabolismo , Inmunohistoquímica , Inflamación/sangre , Inflamación/inducido químicamente , Inyecciones Intravenosas , Hierro/sangre , Complejo Hierro-Dextran/toxicidad , Riñón/metabolismo , Riñón/patología , Hígado/metabolismo , Hígado/patología , Pruebas de Función Hepática , Masculino , Peso Molecular , Miocardio/metabolismo , Miocardio/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Asthma is a chronic respiratory disease characterized by airway inflammation and airway hyperresponsiveness (AHR). One strategy to treat allergic diseases is the development of new drugs. Flavonoids are compounds derived from plants and are known to have antiallergic, anti-inflammatory, and antioxidant properties. To investigate whether the flavonoid kaempferol glycoside 3-O-[beta-d-glycopiranosil-(1-->6)-alpha-l-ramnopiranosil]-7-O-alpha-l-ramnopiranosil-kaempferol (GRRK) would be capable of modulating allergic airway disease (AAD) either as a preventive (GRRK P) or curative (GRRK C) treatment in an experimental model of asthma. At weekly intervals, BALB/c mice were subcutaneously (sc) sensitized twice with ovalbumin (OVA)/alum and challenged twice with OVA administered intranasally. To evaluate any preventive effect, GRRK was administered 1h (hour) before each OVA-sensitization and challenge, while to analyze the curative effect, mice were first sensitized with OVA, followed by GRRK given at day 18 through 21. The onset of AAD was evaluated 24h after the last OVA challenge. Both treatments resulted in a dose-dependent reduction in total leukocyte and eosinophil counts in the bronchoalveolar lavage fluid (BAL). GRRK also decreased CD4(+), B220(+), MHC class II and CD40 molecule expressions in BAL cells. Histology and lung mechanic showed that GRRK suppressed mucus production and ameliorated the AHR induced by OVA challenge. Furthermore, GRRK impaired Th2 cytokine production (IL-5 and IL-13) and did not induce a Th1 pattern of inflammation. These findings demonstrate that GRRK treatment before or after established allergic lung disease down-regulates key asthmatic features. Therefore, GRRK has a potential clinical use for the treatment of allergic asthma.
Asunto(s)
Asma/tratamiento farmacológico , Disacáridos/administración & dosificación , Eosinófilos/efectos de los fármacos , Glicósidos/administración & dosificación , Quempferoles/administración & dosificación , Leucocitos/efectos de los fármacos , Pulmón/efectos de los fármacos , Animales , Antígenos CD/biosíntesis , Antígenos CD/genética , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , Disacáridos/química , Disacáridos/aislamiento & purificación , Eosinófilos/patología , Femenino , Glicósidos/química , Glicósidos/aislamiento & purificación , Antígenos de Histocompatibilidad Clase II/biosíntesis , Antígenos de Histocompatibilidad Clase II/genética , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Quempferoles/química , Quempferoles/aislamiento & purificación , Leucocitos/patología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Moco/metabolismo , Ovalbúmina/inmunología , Células Th2/inmunologíaRESUMEN
Introdução: Constipação funcional é uma das mais freqüêntes causas de consulta médica em gastroenterologiae apenas 60por cento dos casos respondem ao aumento de fibras na dieta. A lactulose é um açucar semi-sintético, cuja formulação líquida contém outros açucares, aos quais muitos de seus efeitos adversos são atribuídos. Lactulose em cristais, uma forma altamente purificada deste dissacarídeo, poderia diminuir a incidência de tais reações adversas. Objetivos: Avaliar a eficácia, segurança e tolerabilidade da lactulose em cristais como medicamento auxiliar à dieta no tratamento da constipação intestinal funcional. Casuística e métodos: Pacientes com idade de 20 a 60 anos portadores de constipação intestinal funcional foram inicialmente submetidos a dieta laxativa por três dias. Aqueles sem resposta ao tratamento dietético receberam lactulose em cristais 20g/dia por quatro semanas, além de preencher um diário sobre hábito intestinal, sintomas gastrointestinais e a freqüência do uso de suporsitórios e clisteres como tratamento alternativo. Resultados: Oitenta pacientes completaram o tratamento. Houve melhora da constipação intestinal em 74 e, destes, 77por cento referiram normalização do hábito intestinal. A média de tempo necessário para ação da droga foi de 1,5 dia, embora para cinco pacientes esse tempo tenha ultrapassado quatro dias. Reações adversas relacionaram-se ao trato gastrointestinal: 67,8por cento referiram cólicas abdominais; 63,3por cento flatulência; e 89,0por cento, náuseas, que regridiram com o decorrer do tratameno (p<0,001), o qual foi interrompido apenas em dois casos. A aceitação da medicação foi referida com muito boa ou boa por 97,5por cento dos pacientes. Conclusão: lactulose em cristais é eficaz e segura como droga auxiliar à dieta no tratamento da constipação intestinal funcional
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estreñimiento , Lactulosa , Estudios Multicéntricos como Asunto , Estreñimiento , Sacarosa en la Dieta , Disacáridos/administración & dosificaciónRESUMEN
Several oligosaccharides containing the terminal structure Gal(alpha)1-3Gal (alphaGal) and different side chains were tested in vitro for their ability to block natural anti(alpha)Gal antibodies. A di-and a trisaccharide (di(alpha)Gal and tri(alpha)Gal) were selected. A blood group B baboon, having IgG and IgM natural antipig titers of 1:256 and 1:1024 and a hemolytic titer (to pig red blood cells, RBCs) of 1:8, was chosen to measure pharmacokinetic parameters of the saccharides and to assess the extent of in vivo neutralization of the antibodies. Three grams each of the di(alpha)Gal and the tri(alpha)Gal dissolved in saline were administered by bolus intravenous (i.v.) injection. Blood samples were collected at various times and urine was collected at 8 and 24 h. Plasma and urine concentrations of the alphaGal saccharides were estimated by an ELISA specially developed for this study. A fast distribution phase followed by equilibrium and excretion phases were observed, indicating a T1/2 in the order of 1 h. Fifty-eight per cent of the saccharides were recovered in the urine within 24 h. Determination of antipig antibody binding by FACS analysis and of serum cytotoxicity titers for pig endothelial cells demonstrated that a 70% reduction in binding and cytotoxicity could be achieved with plasma saccharide levels of 300-400 microg/ml. Six months later, a pig heart was transplanted heterotopically into the baboon. A 3-g bolus of the saccharide mixture (1.5 g of each saccharide) was given i.v. before allowing blood reperfusion of the transplanted heart, followed by an i.v. infusion of 1 g/hr for 1 hr and 0.5 g/hr for the 3 succeeding hours. Blood concentrations of the saccharides, CH50, hematology and cytotoxicity for PK15 cells were estimated in blood samples taken at various times. Heart function was observed to be satisfactory for 8 h, but was found to have ceased at 18 h. Myocardial biopsies taken at 3 and 5 h showed congestion only, suggestive of minimal vascular rejection, but by 18 h demonstrated severe vascular rejection. In conclusion, alphaGal saccharide therapy given for a period of 4 h delayed, but did not totally prevent, the development of vascular rejection in the pig-to-baboon heart transplant model. alphaGal saccharide therapy may be one of several useful approaches for the prevention of hyperacute rejection in pig-to-primate organ transplantation.