RESUMO
We investigated how maternal gestational diabetes (GDM) impacts the metabolic status of offspring. GDM was induced in CD1 mice consuming a fast-food diet (FFD) by repeated low-dose streptozotocin injections before mating. Offspring of normoglycemic standard chow or the FFD consuming dams served as controls. In 4-week-old offspring weaned to standard chow, plasma concentrations of extracellular DNA, inflammatory markers, and parameters of the cardiometabolic status (glycemia, liver lipid content; body, organ, and fat weight) were determined. Two-factor analysis of variance indicated that the male offspring of GDM dams manifest postnatal growth retardation and lower relative kidney weight. Regardless of sex, GDM offspring manifest the lowest IL-1α levels, and other inflammatory markers showed mild and inconsistent alterations. Offspring of dams consuming the FFD displayed higher liver triacylglycerols content. The three groups of offspring showed no significant differences in glycemia and extracellular DNA. Partial least squares-discriminant analysis indicated that male GDM offspring present lower kidney, body, and brown adipose tissue weights; lower IL-1α levels, and higher concentrations of GM-CSF and IL-10 compared with their FFD counterparts. The model failed to select discriminative variables in females. In conclusion, in mice, maternal GDM in the absence of obesity adversely affects the early growth of juvenile male offspring.
Assuntos
Diabetes Gestacional , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Feminino , Camundongos , Masculino , Animais , Diabetes Gestacional/metabolismo , Dieta , Obesidade/complicações , Fígado/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
The purpose of this study was to characterize the testicular profile of Zucker diabetic fatty (ZDF) rats presenting with type 2 diabetes mellitus (DM2) in the absence or presence of obesity. To achieve this, testes were collected from 270-day-old male Wistar (n = 15), ZDF nonobese (n = 15), and ZDF obese rats (n = 16). Changes to the testicular structure were quantified morphometrically, while immunocytochemistry was employed to assess caspase-3 activity. Reactive oxygen species (ROS) production, fluctuations of major antioxidant molecules, and the extent of damage to the proteins and lipids were assessed in tissue lysates. Levels of selected interleukins (ILs) were determined by enzyme-linked immunosorbent assay. The results reveal significant alterations to the testicular structure accompanied by caspase-3 overexpression, particularly in ZDF obese rats. The most notable disruption of the oxidative balance, characterized by ROS overproduction, antioxidant deficiency, protein, and lipid deterioration was recorded in ZDF rats suffering from both DM2 and obesity. Accordingly, the highest concentrations of pro-inflammatory IL-1, IL-6, and IL-18 accompanied by reduced levels of the anti-inflammatory IL-10 were found in testicular tissue collected from ZDF obese rats. This study highlights the vulnerability of male gonads to pathophysiological changes caused by hyperglycemia, which are further exacerbated by excessive adipose tissue.
RESUMO
It is currently unknown why obesity leads in some patients to prediabetes and metabolic syndrome. Microinflammation potentially caused by extracellular DNA is supposed to be involved. The aim of this cross-sectional study in healthy mice was to analyze the association between plasma extracellular DNA and glucose metabolism. Fasting glycemia and insulin were measured in healthy adult female mice that subsequently underwent an oral glucose tolerance test. Indices of glucose metabolism and insulin sensitivity were calculated. DNA was isolated from plasma and quantified fluorometrically. Deoxyribonuclease (DNase) activity of plasma was measured using the single radial enzyme diffusion method. Fasting glycemia correlated negatively with both, extracellular DNA and DNase (r = -0.44 and r = -0.32, respectively). DNase was associated positively with the incremental area under curve (r = 0.35), while extracellular DNA correlated negatively with total area under curve of glycemia during oral glucose tolerance test (r = -0.34). Measures of insulin sensitivity were found to be associated with neither extracellular DNA, nor DNase. The hypothesis of an association of low DNase with increased fasting glucose was partially proved. Surprisingly, low extracellular DNA is associated with higher fasting glucose and lower glucose tolerance in mice. As novel therapeutic targets for prediabetes and metabolic syndrome are highly needed, this study provides novel unexpected associations within the limitations of the focus on physiological variability as it was conducted on healthy mice. The causality of these associations should be proved in further interventional experiments.
Assuntos
DNA , Desoxirribonucleases , Resistência à Insulina , Síndrome Metabólica , Estado Pré-Diabético , Animais , Glicemia/metabolismo , Estudos Transversais , DNA/sangue , Desoxirribonucleases/sangue , Feminino , Insulina/metabolismo , Resistência à Insulina/fisiologia , CamundongosRESUMO
Chronic D-galactose administration induces accelerated aging in rodents. The aim of the study was to find by in vivo31P MRS suitable markers of early stages of brain degeneration on this metabolic model in rats. Additionally, we studied the therapeutic effect of antidiabetic drug metformin. The study has been extended by in vitro determination of mitochondrial function in brain, skeletal muscle and liver mitochondria, oxidative stress parameter thiobarbituric acid reactive substances (TBARS), and lipophilic antioxidants levels. In vivo31P MRS revealed lower intracellular pH (pHi) and lower inorganic phosphate to ATP ratio (Pi/ATP), with higher index of oxidative phosphorylation - phosphocreatine (PCr) to Pi ratio - in brain of rats chronically administered with D-galactose. The function of brain mitochondria was not affected. Administration of metformin diminished changes in brain pHi and plasma TBARS. The function of skeletal muscle mitochondria and their coenzyme Q (CoQ) content were considerably reduced after D-galactose administration. Metformin administered simultaneously with D-galactose did not prevent these changes. The results of in vivo31P MRS revealed evidence of early stage of neurodegeneration that may indicate pre-inflammation. Our data show different susceptibility of brain, skeletal muscle, and liver to the chronic exposure to D-galactose and metformin. The D-galactose model presented in the literature as a model for "age-related dementia" had much more devastating effects on skeletal muscle than on the brain.
Assuntos
Galactose , Metformina , Trifosfato de Adenosina/metabolismo , Envelhecimento/metabolismo , Animais , Encéfalo/metabolismo , Metabolismo Energético , Galactose/farmacologia , Fígado/metabolismo , Metformina/farmacologia , Músculo Esquelético/metabolismo , Estresse Oxidativo , Ratos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Mitochondria are the major source of cellular energy metabolism. In the cardiac cells, mitochondria produce by way of the oxidative phosphorylation more than 90% of the energy supply in the form of ATP, which is utilized in many ATP-dependent processes, like cycling of the contractile proteins or maintaining ion gradients. Reactive oxygen species (ROS) are by-products of cellular metabolism and their levels are controlled by intracellular antioxidant systems. Imbalance between ROS and the antioxidant defense leads to oxidative stress and oxidative changes to cellular biomolecules. Molecular hydrogen (H2) has been proved as beneficial in the prevention and therapy of various diseases including cardiovascular disorders. It selectively scavenges hydroxyl radical and peroxynitrite, reduces oxidative stress, and has anti-inflammatory and anti-apoptotic effects. The effect of H2 on the myocardial mitochondrial function and coenzyme Q levels is not well known. In this paper, we demonstrated that consumption of H2-rich water (HRW) resulted in stimulated rat cardiac mitochondrial electron respiratory chain function and increased levels of ATP production by Complex I and Complex II substrates. Similarly, coenzyme Q9 levels in the rat plasma, myocardial tissue, and mitochondria were increased and malondialdehyde level in plasma was reduced after HRW administration. Based on obtained data, we hypothesize a new metabolic pathway of the H2 effect in mitochondria on the Q-cycle and in mitochondrial respiratory chain function. The Q-cycle contains three coenzyme Q forms: coenzyme Q in oxidized form (ubiquinone), radical form (semiquinone), or reduced form (ubiquinol). H2 may be a donor of both electron and proton in the Q-cycle and thus we can suppose stimulation of coenzyme Q production. When ubiquinone is reduced to ubiquinol, lipid peroxidation is reduced. Increased CoQ9 concentration can stimulate electron transport from Complex I and Complex II to Complex III and increase ATP production via mitochondrial oxidative phosphorylation. Our results indicate that H2 may function to prevent/treat disease states with disrupted myocardial mitochondrial function.
Assuntos
Hidrogênio/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ubiquinona/análogos & derivados , Animais , Antioxidantes/farmacologia , Complexo I de Transporte de Elétrons/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Oxirredução/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/metabolismoRESUMO
The rooibos tea (RT) is a source of valuable dietary dihydrochalcones ï aspalathin, and nothofagin and other polyphenols. Many in vitro and in vivo studies have shown that RT flavonoids have strong antioxidant effect and significantly reduce oxidative stress. We investigated the antioxidant activity and protective effect of an aqueous extract of RT on the liver mitochondria oxidative phosphorylation in rats with carbon tetrachloride-induced (CCl4-induced) liver damage. Mitochondrial respiration and ATP production was determined amperometrically using a Clark-type oxygen electrode. We found significantly decreased parameters of oxidative phosphorylation in the group having received CCl4 for 10 weeks. Simultaneous administration of RT increased oxygen uptake stimulated with ADP, and the rate of ATP generation in the mitochondria of rats, both having been impaired in rats treated with CCl4 only. Treatment with RT significantly decreased CCl4-induced elevated enzyme levels, improved capacity of the respiratory chain and energy production, presumably due to its potent and direct antioxidant activity, including inhibition of mitochondrial lipid peroxidation. Improved histological features support the view of antioxidant and membrane-stabilizing activity of RT. This fact may play a significant role in the protection of the liver from injury caused by known toxins, and from subsequent development of steatosis and fibrosis..
Assuntos
Aspalathus/química , Respiração Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Metabolismo Energético/efeitos dos fármacos , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Chá/química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Extratos Vegetais/química , RatosRESUMO
Maternal exposure to a Western type diet during pregnancy might predispose the offspring to manifestation of metabolic and behavioral disturbances in later life. The Western type diet contains large amounts of advanced glycation end products (AGEs). In humans and experimental rodents, the intake of an AGE-rich diet (AGE-RD) negatively affected glucose homeostasis, and initiated the production of reactive oxygen species. Rats consuming the AGE-RD presented changes in behavior. It remains unclear whether maternal intake of the AGE-RD might affect developmental plasticity in offspring. We examined early somatic (weight, incisor eruption, ear unfolding, and eye opening) and neuromotor development, oxidative status, insulin sensitivity (HOMA index) and locomotor activity assessed in PhenoTyper cages in the offspring of mice fed during pregnancy with either the AGE-RD (25% bread crusts/75% control chow) or control chow. Until weaning, the somatic development of offspring did not differ between the two dietary groups. The AGE-RD offspring manifested physiological reflexes (auditory startle, eye lid, ear twitch and righting reflexes) earlier. As young adults, the male offspring of the AGE-RD dams were heavier and less insulin sensitive compared with their control counterparts. The AGE-RD offspring showed higher locomotor activity during the active phase. Our data indicate that the maternal AGE-RD during pregnancy might accelerate the maturation of reflexes in offspring, predispose the male progeny to weight gain and affect their glucose homeostasis. These effects manifest without the direct consumption of the AGE-RD by offspring. Further work is needed to determine the mechanisms by which the maternal AGE-RD affects neurobehavioral pathways in offspring, as well as sex differences in adverse metabolic responses.
Assuntos
Fast Foods/efeitos adversos , Produtos Finais de Glicação Avançada/metabolismo , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Produtos Finais de Glicação Avançada/efeitos adversos , Humanos , Insulina/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , ReflexoRESUMO
N-acetyl-L-cysteine (NAC) is a drug routinely used in several health problems, e.g. liver damage. There is some information emerged on its negative effects in certain situations. The aim of our study was to examine its ability to influence liver damage induced by long-term burden. We induced liver damage by CCl4 (10 weeks) and monitored the impact of parallel NAC administration (daily 150 mg/kg of b.w.) on liver morphology and some biochemical parameters (triacylglycerols, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, proteins, albumins and cholinesterase). NAC significantly decreased levels of bile acids and bilirubin in plasma and triacylglycerols in liver, all of them elevated by impairment with CCl4. Reduction of cholesterol induced by CCl4 was completely recovered in the presence of NAC as indicated by its elevation to control levels. NAC administration did not improve the histological parameters. Together with protective effects of NAC, we found also its deleterious properties: parallel administration of CCl4 and NAC increased triacylglycerols, ALT and AST activity and significantly increased plasma cholinesterase activity. We have observed nonsignificantly increased percentage of liver tissue fibrosis. Our results have shown that NAC administered simultaneously with liver damaging agent CCl4, exhibits not only protective, but also deleterious effects as indicated by several biochemical parameters.
Assuntos
Acetilcisteína/administração & dosagem , Acetilcisteína/efeitos adversos , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
Evidence from clinical observational studies and animal experiments suggests that hypogonadism is associated with the metabolic syndrome. In most of the experiments, androgen deficiency is induced by gonadectomy in the adulthood and relatively short-term effects of hypogonadism on metabolic parameters are usually observed. The purpose of this study was to evaluate the metabolic effects of long-term androgen deficiency starting before puberty in middle-aged male rats. The components of the metabolic syndrome were examined in male, female and gonadectomized male rats at the age of 18months. Sex differences were observed in plasma testosterone, cholesterol, high-density lipoproteins and also in body weight and in glycemia dynamics during oral glucose tolerance test. Gonadectomy and long-term hypogonadism did not affect most of the analyzed metabolic parameters such as blood pressure, glycemia, plasma insulin and uric acid. The only exception was the significantly higher liver enzymes in plasma and triacylglycerol in liver found in gonadectomized males. Except low-density lipoprotein, neither treatment of middle-aged males and females with letrozole, nor supplementation of estradiol as the metabolite of testosterone in gonadectomized male rats changed any of the observed metabolic parameters. Our results suggest that long-term hypogonadism started before puberty does not induce metabolic syndrome in middle-aged male rats, but may affect the liver. Sex differences in metabolic parameters in middle-aged rats are not mediated by testosterone. Whether hypogonadism predispose to metabolic syndrome in combination with other risk factors needs further clarification.
Assuntos
Andropausa , Hipogonadismo/complicações , Hepatopatias/etiologia , Fígado/metabolismo , Síndrome Metabólica/etiologia , Testosterona/deficiência , Fatores Etários , Animais , Inibidores da Aromatase/administração & dosagem , Biomarcadores/sangue , Glicemia/metabolismo , Pressão Sanguínea , Colesterol/sangue , Modelos Animais de Doenças , Estradiol/administração & dosagem , Feminino , Terapia de Reposição Hormonal , Hipogonadismo/sangue , Hipogonadismo/tratamento farmacológico , Hipogonadismo/fisiopatologia , Letrozol , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Hepatopatias/sangue , Hepatopatias/fisiopatologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/fisiopatologia , Nitrilas/administração & dosagem , Orquiectomia , Ovariectomia , Ratos Endogâmicos Lew , Fatores Sexuais , Desenvolvimento Sexual , Testosterona/sangue , Triazóis/administração & dosagem , Ácido Úrico/sangueRESUMO
The aim of study was to search for new biomarkers with a magnetic resonance technique to identify the early stages of dementia, induced by D-galactose, and evaluate Simvastatin therapy. Localized proton magnetic resonance spectroscopy measurements showed a significant decrease in the concentration of N-acetylaspartate+N-acetylaspartylglutamate and myo-inositol in the D-galactose group compared to the control group, and, conversely, an increase of N-acetylaspartate+N-acetylaspartylglutamate in the D-galactose/Simvastatin group. Using a saturation transfer experiment, with phosphorus magnetic resonance spectroscopy, we observed a significant elevation of the forward rate constant of the creatine kinase reaction in the brains of the D-galactose group compared to controls, and subsequently, a significant reduction of this reaction in the D-galactose/Simvastatin group. Spatial learning and memory were evaluated using the modified Morris water maze test. The dynamics of the learning process represented by the learning index revealed a significant reduction in learning in the D-galactose group, but the deficits as a consequence of the D-galactose effects were recovered in the D-galactose/Simvastatin group, in which the learning dynamics resembled those of the control group. By determining the thiobarbituric acid reactive substances and total coenzyme Q9 in plasma, we have shown that long-term administration of D-galactose created conditions for oxidative stress, and that the administration of Simvastatin decreased oxidative stress in plasma. Volumetry analyses from the hippocampal area show a reduction in the segmented area in the D-galactose group, compared with the control group, and an enlarged area in the hippocampus in the d-galactose/Simvastatin group.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Demência/tratamento farmacológico , Demência/metabolismo , Nootrópicos/farmacologia , Sinvastatina/farmacologia , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Biomarcadores/metabolismo , Encéfalo/patologia , Demência/patologia , Dipeptídeos/metabolismo , Modelos Animais de Doenças , Galactose , Inositol/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Tamanho do Órgão , Isótopos de Fósforo , Prótons , Ratos Wistar , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Resultado do Tratamento , Ubiquinona/sangueRESUMO
The study determined the effect of intravenous administration of acutely toxic or sub-lethal doses of Na-oleate-coated Fe3O4 (OC-Fe3O4) nanoparticles (NPs) on liver structure and function in Wistar rats, compared to titanium dioxide (TiO2) NPs and saline-injected controls. The acute study, using a modified OECD 425 progressive dosing procedure, found LD50 values of 59.22 and 36.42 mg/kg for TiO2 and OC-Fe3O4 NPs, respectively. In the sub-lethal study, rats were either injected with saline (negative controls), a sub-lethal reference (0.592 mg/kgTiO2 NPs, equal to 1% of LD50 on a body weight basis) or OC-Fe3O4 NPs in doses equivalent to 0.1, 1 or 10% of the LD50, respectively (corresponding to 0.0364, 0.364 and 3.64 mg Fe3O4/kg body weight). Animals were sampled 24 h, 1, 2 and 4 weeks post-injection for adverse effects. Mitochondrial respiration was significantly increased 2 weeks after injection of 10% OC-Fe3O4 NPs compared to controls, but the effect was transient. Cholesterol and triacylglycerol concentrations in the liver tissue did not increase in any treatment. There were some disturbances to antioxidant enzymes after OC-Fe3O4 NPs treatment in the livers of animals 1 week post-exposure; with the most sensitive changes occurring in glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities. Lipidosis and mild necrosis with changes in sinusoid space were also observed in histological sections of the liver. Overall, these data suggest that the liver likely retains functional integrity with acute and sub-lethal doses of OC-Fe3O4 NPs, albeit with some stimulation of redox defences and evidence of some tissue injury.
Assuntos
Compostos Férricos/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Nanopartículas/administração & dosagem , Nanopartículas/toxicidade , Ácido Oleico/toxicidade , Titânio/administração & dosagem , Titânio/toxicidade , Animais , Antioxidantes/metabolismo , Compostos Férricos/administração & dosagem , Compostos Férricos/química , Glutationa Peroxidase/metabolismo , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Injeções Intravenosas , Fígado/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nanopartículas/química , Necrose/induzido quimicamente , Necrose/patologia , Ácido Oleico/administração & dosagem , Ácido Oleico/química , Estresse Oxidativo , Ratos , Titânio/químicaRESUMO
OBJECTIVE: This study has been focused on the effect of an n-6 polyunsaturated fatty acid (PUFA) rich plant oil on oxidation and glycooxidation stress markers as well as on antioxidant enzyme activities in male Wistar rats with streptozotocin-induced diabetes. METHODS: The non-diabetic and diabetic groups of Wistar rats were administered plant oil at concentrations of 100 and 500 mg/kg body weight and controls without plant oil. The parameters of glycaemic control, lipid profile, total antioxidant status, antioxidant enzyme activities, together with oxidative and glycooxidative stress markers were measured in the blood. RESULTS: The intake of the plant oil did not significantly influence the parameters of glycaemic control and significantly increased the levels of all lipid profile parameters in the diabetic rats. Plant oil administration significantly decreased the total antioxidant status and glutathione peroxidase activity and the activity of Cu/Zn superoxide dismutase was significantly increased. The plant oil also increased the levels of lipoperoxides and advanced the glycation end products. DISCUSSION: These results suggest that the plant oil with high concentrations of n-6 PUFA - linoleic acid, acts prooxidatively when administered to the rats.
Assuntos
Antioxidantes/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ácidos Graxos Insaturados/uso terapêutico , Óleos de Plantas/uso terapêutico , Animais , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Peróxidos Lipídicos/metabolismo , Masculino , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Óleos de Plantas/química , Ratos , Ratos Wistar , Fatores de Risco , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
OBJECTIVES: This study was focused on the monitoring how the anti-inflammatory substance, N(1)-methylnicotinamide (MNA), could influence oxidation and glycooxidation stress markers in rats under conditions of streptozotocin (STZ)-induced diabetes mellitus. METHODS: Diabetes mellitus was induced in 60 male Wistar rats by intraperitoneal injection of STZ and after 7 days diabetic animals were allocated to five groups according to the dose of MNA administered for 7 weeks. The degree of DNA damage in lymphocytes, as well as advanced glycation endproducts (AGEs), protein carbonyls, lipid peroxides, and total antioxidant capacity (TEAC) in plasma were measured. RESULTS: Glycation damage to proteins (represented by AGEs level) was significantly increased in all diabetic groups compared to untreated non-diabetic animals. MNA did not affect TEAC of plasma in any group of diabetic rats. Supplementation of diabetic rats with MNA at the dose of 200 mg/kg resulted in decreased protein carbonyls (from 0.0818±0.0091 to 0.0558±0.0044 nmol/mg proteins; P<0.05, n=15) and DNA oxidation, reflected by the levels of 8-oxoG (0.6302±0.085 vs. 0.9213±0.108 8-oxoG/10(6) G; P<0.05, n=15), compared to untreated diabetic animals. DISCUSSION: Our results demonstrated that MNA at suitable concentrations could influence oxidative modifications of proteins and DNA.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Niacinamida/análogos & derivados , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Biomarcadores/análise , Dano ao DNA , Diabetes Mellitus Experimental/patologia , Avaliação Pré-Clínica de Medicamentos , Produtos Finais de Glicação Avançada/análise , Peroxidação de Lipídeos/efeitos dos fármacos , Peróxidos Lipídicos/sangue , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Niacinamida/farmacologia , Oxirredução , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , EstreptozocinaRESUMO
BACKGROUND: Increase of blood pressure is accompanied by functional and morphological changes in the vascular wall. The presented study explored the effects of curcuma and black pepper compounds on increased blood pressure and remodeling of aorta in the rat model of experimental NO-deficient hypertension. METHODS: Wistar rats were administered for 6 weeks clear water or L-NAME (40 mg/kg/day) dissolved in water, piperine (20 mg/kg/day), curcumin (100 mg/kg/day) or their combination in corn oil by oral gavage. The systolic blood pressure was measured weekly. Histological slices of thoracic aorta were stained with hematoxylin and eosin, Mallory's phosphotungstic acid hematoxylin (PTAH), orcein, picrosirius red and van Gieson staining and with antibodies against smooth muscle cells actin. Microscopic pictures were digitally processed and morphometrically evaluated. RESULTS: The increase of blood pressure caused by L-NAME was partially prevented by piperine and curcumin, but the effect of their combination was less significant. Animals with hypertension had increased wall thickness and cross-sectional area of the aorta, accompanied by relative increase of PTAH positive myofibrils and decrease of elastin, collagen and actin content. Piperine was able to decrease the content of myofibrils and slightly increase actin, while curcumin also prevented elastin decrease. The combination of spices had similar effects on aortic morphology as curcumin itself. CONCLUSIONS: Administration of piperine or curcumin, less their combination, is able to partially prevent the increase of blood pressure caused by chronic L-NAME administration. The spices modify the remodeling of the wall of the aorta induced by hypertension. Our results show that independent administration of curcumin is more effective in preventing negative changes in blood vessel morphology accompanying hypertensive disease.
RESUMO
We studied the effect of food restriction, overfeeding, and normofeeding on cachexia, inflammatory and metabolic parameters, and insulin sensitivity in chronic adjuvant arthritis (AA) in rats. Food restriction during AA increased circulating ghrelin, corticosterone, decreased leptin, and ameliorated arthrogram score and systemic inflammation compared to normofeeding. Overfeeding worsened arthrogram score and systemic inflammation, and led to lipid accumulation in the liver, but not to alterations of adipokine and ghrelin plasma levels relative to normofeeding. Independently of feeding status, AA induced cachexia, in which modulation of mRNA expressions for appetite-regulating neuropeptides (NPY, AgRP, POMC, CART) in the arcuate nucleus (ARC) does not play a primary role. The overexpression of IL-1ß mRNA in the ARC suggests its role in the mechanisms of impaired energy balance during AA under all feeding conditions. Normal HOMA index in all arthritic groups does not indicate the development of insulin resistance by feeding interventions in these rats.
Assuntos
Ração Animal , Artrite/terapia , Caquexia/metabolismo , Quimioterapia Adjuvante/métodos , Insulina/metabolismo , Adipocinas/metabolismo , Corticosteroides/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Artrite/dietoterapia , Grelina/metabolismo , Inflamação , Leptina/metabolismo , Masculino , Neuropeptídeos/química , Ratos , Ratos Endogâmicos LewRESUMO
Effect of captopril treatment on capability of heart and kidney mitochondria to produce ATP was investigated in spontaneously hypertensive rats (SHR). Heart mitochondria from SHR responded to hypertension with tendency to compensate the elevated energy demands of cardiac cells by moderate increase in mitochondrial Mg2+-ATPase activity, membrane fluidity (MF) and in majority of functional parameters of the mitochondria (p>0.05). Significant increase exhibited only the oxygen consumption (QO2; p<0.01-0.001) and oxidative phosphorylation rate (OPR; p<0.003) with glutamate+malate (GLUT+MAL) as substrates. Lowering the blood pressure (p<0.02) captopril also eliminated the above compensatory response and impaired the oxidative ATP production by decreasing OPR (p<0.001). Kidney mitochondria of SHR experienced serious disarrangement in parameters of oxidative ATP production: increase in Mg2+-ATPase activity (p<0.05) but, also scattered QO2 values (p<0.03-0.01) leading to decrease in OPR and the ADP:O (p<0.05-0.01) values with both GLUT+MAL and succinate as substrates. Captopril treatment does not alleviated but even worsened the above alterations. Mg2+-ATPase became also decreased and the depression of ADP:O became aggravated (p<0.0001).
Assuntos
Trifosfato de Adenosina/biossíntese , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Animais , Anti-Hipertensivos/farmacologia , ATPase de Ca(2+) e Mg(2+)/metabolismo , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos WistarRESUMO
Diabetes-induced injury related to hyperglycaemia is associated with impaired function of mitochondria. Regardless of their cytotoxicity, PAMAM [poly(amido)amine] G4 dendrimers lower plasma glucose and suppress long-term markers of diabetic hyperglycaemia in experimental diabetes. In the present study, we aimed at verifying whether such modulatory effects of PAMAM G4 (0.5 micromol/kg of body weight daily for 60 days) may contribute to improved respiration in heart and liver mitochondria from streptozotocin-diabetic rats. PAMAM G4 alleviated long-term markers of hyperglycaemia and reduced blood and tissue lipophilic antioxidants in diabetic animals, but did not restore mitochondrial function. In hearts, but not livers, dendrimers further reduced respiratory function and oxidative phosphorylation. Thus ameliorating effects of PAMAM G4 on glycation and glycoxidation in experimental diabetes are not sufficient to restore the impaired mitochondrial function in diabetes.
Assuntos
Dendrímeros/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Hepáticas/metabolismo , Nylons , Fosforilação Oxidativa , Ratos , Ratos Wistar , Tocoferóis/farmacologia , Ubiquinona/farmacologiaRESUMO
In acute diabetic myocardium, calcium signals propagated by intracellular calcium transients participate in the protection of cell energetics via upregulating the formation of mitochondrial energy transition pores (ETP). Mechanisms coupling ETP formation with an increase in membrane fluidity and a decrease in transmembrane potential of the mitochondria are discussed. Our results indicate that the amplification of calcium transients in the diabetic heart is associated with an increase in their amplitude. Moreover, the signals transferred by calcium transients also regulated ETP formation in nondiabetic myocardium. Evidence for the indispensable role of calcium in the regulation of transition pore formation is provided whereby an exchange of cadmium for calcium ions led to a rapid and dramatic decrease in the amount of ETP. Another possible regulatory factor of the mitochondrial function may be radical-induced damage to the diabetic heart. Nevertheless, our data indicate that radical-induced changes in mitochondria predominantly concern the respiratory chain and have no appreciable effect on the fluidity of the mitochondrial membranes. The residual mitochondrial production of ATP owing to its augmented transfer to the cytosol proved to be adequate to preserve sufficient levels of adenine nucleotides in the acute diabetic myocardium.
Assuntos
Sinalização do Cálcio/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Coração/fisiopatologia , Miocárdio/metabolismo , Nucleotídeos de Adenina/análise , Animais , Cálcio/metabolismo , Cálcio/fisiologia , Sinalização do Cálcio/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Coração/efeitos dos fármacos , Masculino , Fluidez de Membrana/efeitos dos fármacos , Fluidez de Membrana/fisiologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Microscopia de Fluorescência , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/fisiologia , Miocárdio/química , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Ratos , Ratos WistarRESUMO
There is good evidence supporting the notion that aminoguanidine(AG)-derived compounds prevent glycation/glycooxidation-dependent processes and therefore inhibit late diabetic complications. The aim of the present work was to analyse the antithrombotic action and antiglycation activity of beta-resorcylidene aminoguanidine (RAG) in comparison with another commonly used aminoguanidine (AG)-derived compound, pyridoxal aminoguanidine (PAG). In vitro RAG and PAG prevented exhaustive glycation and glycooxidation of BSA to a similar extent. However, merely RAG showed almost complete binding to sepharose-immobilized heparin, while PAG and other AG derivatives had much poorer affinities. In the model of in vivo thrombosis in Wistar rats with extracorporeal circulation RAG (i.v. 30 mg/kg), but not PAG, produced sustained (2 h) antithrombotic effect, which was abrogated by indomethacin (5 mg/kg) and rofecoxib (1 mg/kg). The 60-day treatment of streptozotocin-diabetic animals with RAG (p.o. 4 mg/kg) significantly decreased plasma concentration of a thromboxane B(2) and reduced whole blood platelet aggregability triggered by ADP or collagen. In conclusion, although RAG and PAG displayed similar antiglycation and antioxidation activities in vitro, only RAG showed antithrombotic activity in vivo that involved activation of COX-2/PGI(2) pathway. Our results indicate that designing novel RAG derivatives with optimal antithrombotic and antiglycation activities may prove useful to treat diabetic complications.
Assuntos
Fibrinolíticos/uso terapêutico , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Produtos Finais de Glicação Avançada/metabolismo , Guanidinas/uso terapêutico , Trombose/tratamento farmacológico , Trombose/metabolismo , Animais , Bovinos , Fibrinolíticos/farmacologia , Glicosilação/efeitos dos fármacos , Guanidinas/farmacologia , Masculino , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Ratos Wistar , Soroalbumina Bovina/metabolismo , Trombose/fisiopatologiaRESUMO
Oxidative damage is considered to play an important role in the pathogenesis of several diseases, such as diabetes mellitus (DM), atherosclerosis, cardiovascular complications and chronic renal failure. DM is associated with the oxidative stress and formation of advanced glycation end products (AGEs). Different drugs inhibit oxidative stress and formation of advanced glycation end products. Aminoguanidine (AG) has been proposed as a drug of potential benefit in prophylaxis of the complications of DM. Recent reports show a pro-oxidant activity of AG. Therefore we examined the effect of structural analogue of AG, its Schiff base with pyridoxal-pyridoxylidene aminoguanidine (PAG) on the level of selected markers of oxidative stress. We found that PAG decreased total damage to DNA in controls as well as in diabetic group of rats. However, we also found that PAG supplementation increases susceptibility of lipoproteins to oxidation and formation of conjugated dienes in both, diabetic as well as control animals. Its administration to diabetic rats decreases antioxidant capacity of plasma. Therefore, it is necessary to search for other structural modifications of AG that would combine its higher anti-diabetic activity with less toxicity.