RESUMO
This study investigated the antitumoral, anti-inflammatory and oxidative effects of polysaccharides from tucum (Bactris setosa, TUC) using the Ehrlich carcinoma as a tumor model. Additionally, the glycogen content, cytochrome P levels, and gluconeogenesis from lactate were assessed in the liver of healthy animals. Tumor-bearing female mice were orally treated with 50 and 100 mg.kg-1 of TUC or vehicle, once a day, or with 1.5 mg.kg-1 methotrexate via i.p., every 3 days, along 21 days. Both doses of TUC reduced the tumor weight and volume. In the tumor tissue, it decreased GSH and IL-1ß levels, and increased LPO, NAG, NO and TNF-α levels. The tumor histology showed necrosis and leukocytes infiltration. The metabolic effects of TUC were investigated by measurement of total cytochrome P (CYP) and glycogen in tumor-bearing mice, and by ex vivo liver perfusion on non-bearing tumor male mice, using lactate as gluconeogenic precursor. Metabolically, the hepatic glucose and pyruvate productions, oxygen uptake, and the total CYP concentration were not modified by TUC. Thus, tucum-do-cerrado polysaccharides have antitumor effects through the modulation of oxidative stress and inflammation, without impairing glucose production from lactate in the liver, the main organ responsible for the metabolism of organic and xenobiotic compounds.
Assuntos
Gluconeogênese , Fígado , Polissacarídeos , Animais , Polissacarídeos/farmacologia , Polissacarídeos/química , Camundongos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Gluconeogênese/efeitos dos fármacos , Feminino , Masculino , Antineoplásicos/farmacologia , Antineoplásicos/química , Estresse Oxidativo/efeitos dos fármacos , Frutas/química , Glicogênio/metabolismo , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Carcinoma de Ehrlich/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/químicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Eryngium cymosum F. Delaroche was detected as a traditional remedy against type 2 diabetes consumed by patients of Tlanchinol in the state of Hidalgo, Mexico. AIM OF THE STUDY: Assessing the hypoglycemic effect and safety of the traditional extract of E. cymosum and relating it to key glucose-lowering mechanisms both in fasting and postprandial state. MATERIALS AND METHODS: The aqueous extract of E. cymosum was subjected to HPLC analysis to identify its main components. Hyperglycaemic STZ-NA Wistar rats were administered with the extract to evaluate its effect on blood glucose levels and a possible dose-dependence. Afterward, it was evaluated in both pyruvate and maltose tolerance tests in STZ-NA rats to characterize its effect on gluconeogenesis and carbohydrate breakdown, two of the main mechanisms responsible for fasting and postprandial hyperglycaemia in type 2 diabetes patients. In addition, the inhibitory capacity of the extract was evaluated on key enzymes involved in gluconeogenesis and a-glucosidases. Moreover, insulin concentrations were measured in normoglycemic rats in both conditions to establish a link between the hypoglycaemic effect of the extract with insulin release and functioning. RESULTS: Caffeic acid (1), chlorogenic acid (2), and rosmarinic acid (3) were identified as the main constituents of the aqueous extract of E. cymosum, which exerted a hypoglycaemic effect in hyperglycaemic STZ-NA rats. It has a significant antihyperglycemic effect in the pyruvate tolerance test, and it was able to reduce the postprandial hyperglycaemia in maltose tolerance tests significantly. Moreover, it effectively reduced the activity of both gluconeogenic enzymes reaching almost 100% of inhibition, while it presented a modest 32% inhibition of aglucosidases. On the other hand, the extract decreased insulin levels after its oral administration in healthy rats in both nutritional states, without affecting normoglycemia in normal curves and reducing the postprandial peak in glucose load curves. CONCLUSIONS: The traditional consumed form of aerial parts of E. cymosum is safe and regulated glucose levels both in fasting and in postprandial state.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Eryngium/química , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Jejum , Gluconeogênese/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/isolamento & purificação , Insulina/sangue , México , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/isolamento & purificação , Ratos , Ratos WistarRESUMO
Distinct environmental insults might interact with fructose consumption and contribute to the development of metabolic disorders. To address whether in utero glucocorticoid exposure and fructose intake modulate metabolic responses, adult female Wistar rats were exposed to dexamethasone (DEX) during pregnancy, and the offspring were administered fructose at a later time. Briefly, dams received DEX during the third period of pregnancy, while control dams remained untreated. Offspring born to control and DEX-treated mothers were defined as CTL-off and DEX-off, respectively, while untreated animals were designated CTL-off-CTL and DEX-off-CTL. CLT-off and DEX-off treated with 10% fructose in the drinking water for 8 weeks are referred to as CTL-off-FRU and DEX-off-FRU. We found that fructose promoted glucose intolerance and whole-body gluconeogenesis in both CTL-off-FRU and DEX-off-FRU animals. On the other hand, hepatic lipid accumulation was significantly stimulated in DEX-off-FRU rats when compared to the CTL-off-FRU group. The DEX-off-FRU group also displayed impaired very-low-density lipoprotein (VLDL) production and reduced hepatic expression of apoB, mttp, and sec22b. DEX-off-FRU has lower hepatic levels of autophagy markers. Taken together, our results support the unprecedented notion that in utero glucocorticoid exposure exacerbates hepatic steatosis caused by fructose consumption later in life.
Assuntos
Dexametasona/toxicidade , Açúcares da Dieta/toxicidade , Fígado Gorduroso/induzido quimicamente , Frutose/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Animais , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Idade Gestacional , Gluconeogênese/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipoproteínas VLDL/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Gravidez , Proteínas R-SNARE/genética , Proteínas R-SNARE/metabolismo , Ratos WistarRESUMO
Tordon® is the commercial name of a mixture of two organo-chlorinated herbicides, 2,4-D and picloram. Both compounds affect energy transduction in isolated mitochondria and the present study aimed at characterizing the actions of these two compounds on liver metabolism and their cellular distribution in the isolated perfused rat liver. 2,4-D, but not picloram, increased glycolysis in the range from 10 to 400⯵M. The redox potential of the cytosolic NAD+-NADH couple was also increased by 2,4-D. Both compounds inhibited lactate gluconeogenesis. Inhibitions by 2,4-D and picloram were incomplete, reaching maximally 46% and 23%, respectively. Both compounds diminished the cellular ATP levels. No synergism between the actions of 2,4-D and picloram was detected. Biotransformations of 2,4-D and picloram were slow, but their distributions occurred at high rates and were concentrative. Molecular dynamics simulations revealed that 2,4-D presented low affinity for the hydrophobic lipid bilayers, the opposite occurring with picloram. Inhibition of energy metabolism is possibly a relevant component of the toxicity of 2,4-D and of the commercial product Tordon®. Furthermore, the interactions of 2,4-D with the membrane lipid bilayer can be highly destructive and might equally be related to its cellular toxicity at high concentrations.
Assuntos
Ácido 2,4-Diclorofenoxiacético/toxicidade , Membrana Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Herbicidas/toxicidade , Bicamadas Lipídicas/metabolismo , Fígado/efeitos dos fármacos , Picloram/toxicidade , Ácido 2,4-Diclorofenoxiacético/metabolismo , Animais , Membrana Celular/metabolismo , Membrana Celular/patologia , Gluconeogênese/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Herbicidas/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Cinética , Fígado/metabolismo , Fígado/patologia , Masculino , Simulação de Dinâmica Molecular , NAD/metabolismo , Oxirredução , Perfusão , Picloram/metabolismo , Ratos WistarRESUMO
Gluconeogenesis overstimulation due to hepatic insulin resistance is the best-known mechanism behind elevated glycemia in obese subjects with hepatic steatosis. This suggests that glucose production in fatty livers may differ from that of healthy livers, also in response to other gluconeogenic determinant factors, such as the type of substrate and modulators. Thus, the aim of this study was to investigate the effects of these factors on hepatic gluconeogenesis in cafeteria diet-induced obese adult rats submitted to a cafeteria diet at a young age. The livers of the cafeteria group exhibited higher gluconeogenesis rates when glycerol was the substrate, but lower rates were found when lactate and pyruvate were the substrates. Stearate or glucagon caused higher stimulations in gluconeogenesis in cafeteria group livers, irrespective of the gluconeogenic substrates. An increased mitochondrial NADH/NAD⺠ratio and a reduced rate of 14CO2 production from [14C] fatty acids suggested restriction of the citric acid cycle. The higher glycogen and lipid levels were possibly the cause for the reduced cellular and vascular spaces found in cafeteria group livers, likely contributing to oxygen consumption restriction. In conclusion, specific substrates and gluconeogenic modulators contribute to a higher stimulation of gluconeogenesis in livers from the cafeteria group.
Assuntos
Dieta/efeitos adversos , Ácidos Graxos/metabolismo , Fígado Gorduroso/induzido quimicamente , Glucagon/metabolismo , Gluconeogênese/efeitos dos fármacos , Animais , Ingestão de Energia , Comportamento Alimentar , Glucose/metabolismo , Ácido Láctico/administração & dosagem , Ácido Láctico/farmacologia , Masculino , Obesidade/induzido quimicamente , Consumo de Oxigênio , Ácido Pirúvico/administração & dosagem , Ácido Pirúvico/farmacologia , Ratos , Ratos WistarRESUMO
Dietary phytochemicals may improve glucose metabolism while iron excess seems to be associated to impaired glucose homeostasis and insulin responses. This study investigated the effect of tucum-do-cerrado (Bactris setosa Mart.) consumption on the carbohydrate metabolism and redox response in rats supplemented or not with dietary iron. Male wistar rats were treated with one of the following diets: CT: control diet (AIN- 93G); +Fe: iron-enriched diet; Tuc: control diet +15% tucum-do-cerrado or Tucâ¯+â¯Fe: iron-enriched diet +15% tucum-do-cerrado. Iron supplementation increased muscle lipid and protein oxidation, hepatic glucokinase (GK) and phosphofrutokinase 1 (PFK1) activities and decreased hepatic glucose-6-phosphatase (G6Pase), intestinal Scl2a2 and muscle Slc2a4 and Prkaa2α mRNA levels compared to CT group. Tucum-do-cerrado consumption (Tuc) increased hepatic Slc2a2, Prkaa1α, Prkaa2α and intestinal Slc5a1 mRNA levels, also decreased hepatic G6Pase activity, muscle Slc2a4 and Prkaa2α in relation to CT group. The association of tucum-do-cerrado with iron-enriched diet increased hepatic Prkaa1 and Pck1 compared to the CT andâ¯+â¯Fe groups, intestinal Slc2a2 mRNA levels compared to the +Fe group, while decreased hepatic G6Pase activity in relation to the CT, +Fe and Tucâ¯+â¯Fe groups and muscle Slc2a4 and Prkaa2α compared to CT group. These results suggest that tucum-do-cerrado consumption might induce Prkaa1α and Prkaa2α expression, which may inhibit gluconeogenic rate limiting enzyme, G6Pase, and upregulates GLUT2 hepatic glucose uptake. In addition, moderate iron supplementation improves intracellular hepatic glucose response, stimulating the glycolytic rate limiting enzymes GK and PFK1 while inhibiting gluconeogenic enzyme G6Pase.
Assuntos
Arecaceae/química , Gluconeogênese/efeitos dos fármacos , Transportador de Glucose Tipo 2/metabolismo , Glucose/metabolismo , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Quinases Proteína-Quinases Ativadas por AMP , Animais , Glicólise/efeitos dos fármacos , Ferro/administração & dosagem , Fígado/metabolismo , Masculino , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Proteínas Quinases/metabolismo , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacosRESUMO
The current study investigated the action of ß-caryophyllene, the major constituent of copaiba oil, on the systemic inflammation, oxidative status, and liver cell metabolism of rats with adjuvant-induced arthritis, a model for rheumatoid arthritis. This study also compared the actions of ß-caryophyllene with those previously reported for copaiba oil on arthritic rats. For this purpose, Holtzman healthy and arthritic rats received 215 and 430 mg·kg-1 ß-caryophyllene orally once a day during 18 days. Both doses of ß-caryophyllene reduced the adjuvant-induced paw edema, swollen of lymph nodes, and number of circulating and articular leukocytes. ß-Caryophyllene, at the dose of 430 mg·kg -1 , abolished the increases of protein carbonyl groups and myeloperoxidase activity in the liver and plasma of arthritic rats and, at both doses, it restored the increased levels of reactive oxygen species and reduced glutathione in the arthritic liver. These beneficial actions were of the same extension as those of copaiba oil ( Copaifera reticulata) and, therefore, ß-caryophyllene is possibly responsible for the anti-inflammatory and antioxidant actions of the oil. Hepatic gluconeogenesis was 40% lower in arthritic rats, which also presented a reduced number of hepatocytes per liver area (-23%) associated with increased hepatocyte area (+18%) and liver weight (+50%). None of these hepatic alterations were improved by ß-caryophyllene, but not even by ibuprofen. However, unlike copaiba oil, ß-caryophyllene did not modify the hepatic morphology and metabolism of healthy rats. These results reveal that ß-caryophyllene improves the systemic inflammation and oxidative status of arthritic rats and, in addition, it was not associated with hepatotoxicity.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Fabaceae/química , Gluconeogênese/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Óleos de Plantas/química , Sesquiterpenos Policíclicos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/químicaRESUMO
Polyphenol-rich cagaita (Eugenia dysenterica DC.) extracts (PCE) have previously shown to prevent body weight and adiposity induced by high-fat/high-sucrose (HFS) diet. Whether PCE also exerts protective effects in already developed obesity is unknown. In order to test this hypothesis, male C57BL/6J obese mice (previously feed with a HFS diet for six weeks) were treated with PCE at two doses, 7mg gallic acid equivalent (GAE)/kg body weight (PCE I group), and 14mg GAE/kg body weight (PCE II group) or water (HFS and Chow groups) by oral gavage for eight weeks. PCE did not affect body weight and adiposity of obese mice. However, PCE did protect against dyslipidemia, fasting hyperglycemia, and glucose intolerance, and attenuated both hepatic gluconeogenesis and inflammation as observed by the expression of tumor necrosis factor-α and transcriptional factor NF-κB. These results indicate that PCE improves glucose homeostasis of obese mice by attenuating hepatic gluconeogenesis and inflammation.
Assuntos
Fármacos Antiobesidade/farmacologia , Eugenia , Frutas , Obesidade/tratamento farmacológico , Polifenóis/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Fármacos Antiobesidade/isolamento & purificação , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica , Sacarose Alimentar , Modelos Animais de Doenças , Eugenia/química , Frutas/química , Gluconeogênese/efeitos dos fármacos , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Hipolipemiantes/isolamento & purificação , Hipolipemiantes/farmacologia , Mediadores da Inflamação/metabolismo , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Obesidade/sangue , Obesidade/fisiopatologia , Polifenóis/isolamento & purificação , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: Despite increasing evidence that pharmacologic concentrations of biotin modify glucose metabolism, to our knowledge there have not been any studies addressing the effects of biotin supplementation on glucagon production and secretion, considering glucagon is one of the major hormones in maintaining glucose homeostasis. The aim of this study was to investigate the effects of dietary biotin supplementation on glucagon expression, secretion, and action. METHODS: Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7 mg biotin/kg diet) for 8 wk postweaning. Glucagon gene mRNA expression was measured by the real-time polymerase chain reaction. Glucagon secretion was assessed in isolated islets and by glucagon concentration in plasma. Glucagon action was evaluated by glucagon tolerance tests, phosphoenolpyruvate carboxykinase (Pck1) mRNA expression, and glycogen degradation. RESULTS: Compared with the control group, glucagon mRNA and secretion were increased from the islets of the biotin-supplemented group. Fasting plasma glucagon levels were higher, but no differences between the groups were observed in nonfasting glucagon levels. Despite the elevated fasting glucagon levels, no differences were found in fasting blood glucose concentrations, fasting/fasting-refeeding glucagon tolerance tests, glycogen content and degradation, or mRNA expression of the hepatic gluconeogenic rate-limiting enzyme, Pck1. CONCLUSIONS: These results demonstrated that dietary biotin supplementation increased glucagon expression and secretion without affecting fasting blood glucose concentrations or glucagon tolerance and provided new insights into the effect of biotin supplementation on glucagon production and action.
Assuntos
Biotina/administração & dosagem , Glucagon/metabolismo , Glucagon/farmacologia , Animais , Dieta , Suplementos Nutricionais , Expressão Gênica/efeitos dos fármacos , Glucagon/genética , Gluconeogênese/efeitos dos fármacos , Glicogênio/metabolismo , Ilhotas Pancreáticas/química , Ilhotas Pancreáticas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , RNA Mensageiro/análiseRESUMO
A systematic study on the effects of diuron on the hepatic metabolism was conducted with emphasis on parameters linked to energy metabolism. The experimental system was the isolated perfused rat liver. The results demonstrate that diuron inhibited biosynthesis (gluconeogenesis) and ammonia detoxification, which are dependent of ATP generated within the mitochondria. Conversely, it stimulated glycolysis and fructolysis, which are compensatory phenomena for an inhibited mitochondrial ATP generation. Furthermore, diuron diminished the cellular ATP content under conditions where the mitochondrial respiratory chain was the only source of this compound. Besides the lack of circulating glucose due to gluconeogenesis inhibition, one can expect metabolic acidosis due to excess lactate production, impairment of ammonia detoxification and cell damage due to a deficient maintenance of its homeostasis. Some of the general signs of toxicity that were observed in diuron-treated rats can be attributed, partly at least, to the effects of the herbicide on energy metabolism.