Effect of metformin on renal microsomal proteins, lipid peroxidation and antioxidant status in dexamethasone-induced type-2 diabetic mice.

An SDS-PAGE analysis of renal microsomal fraction of albino mice was performed to study the involvement of proteins in dexamethasone-induced type-2 diabetes mellitus (DM) and their alterations by metformin, a widely accepted oral antidiabetic drug. In addition, changes in renal lipid peroxidation (LPO), activities of superoxide dismutase (SOD) and catalase (CAT), reduced glutathione (GSH) content, as well as renal somatic index (RSI) and daily rate of water consumption were also investigated. While dexamethasone administration (1.0 mg/kg for 21 days) expressed two renal proteins (43 kDa and 63.23 kDa), in addition to the increased fasting serum levels of glucose and insulin, renal LPO, RSI and daily rate of water consumption, a parallel decrease in renal SOD, CAT and GSH was also observed. Treatment with metformin normalized these alterations including the renal proteins and LPO, confirming its efficacy in ameliorating dexamethasone-induced type-2 DM and also the association of two proteins with type-2 DM.

Vitamin E prevents nonylphenol-induced oxidative stress in testis of rats.

In the present study we have investigated if administration of nonylphenol-induced oxidative stress in various subcellular fractions of adult rat testis and the effect of vitamin E on reactive oxygen species mediated nonylphenol toxicity. Male rats were administered orally with nonylphenol at 1, 10 and 100 microg/kg body weight per day for 45 days with and without supplementation of vitamin E (20 mg/kg body weight). In nonylphenol-treated rats the activities of antioxidant enzymes superoxide dismutase and glutathione reductase decreased significantly while the levels of lipid peroxidation increased significantly in the crude homogenate and in the mitochondrial and microsome-rich fractions of testis. Co-administration of nonylphenol and vitamin E did not cause changes in the activities of antioxidant enzymes in various subcellular fractions of rat testis. The results suggest that graded doses of nonylphenol elicit depletion of antioxidant defence system in rat testis, indicating nonylphenol induced oxidative stress in the testis of rats which could be reversed by the administration of vitamin E.

Morphologic and biochemical changes in male rat lung after surgical and pharmacological castration

The morphology of the rat lung was studied by light microscopy in different situations: after surgical and pharmacological castration and after administration of testosterone to the castrated rat to determine if the androgen is required to maintain the normal morphology of the lung. We also determined the effect of flutamide on the phospholipid composition of both the surfactant and microsomes of the lung. Rats were separated into five groups: I - control non-castrated rats, II - castrated rats sacrificed 21 days after castration, III - castrated rats that received testosterone daily from day 2 to day 21 after castration, IV - castrated rats that received testosterone from day 15 to day 21 after castration, and V - control rats injected with flutamide for 7 days. The amount of different phospholipids in the surfactant and microsomes of the lung was measured in group I and V rats. At the light microscopy level, the surgical and pharmacological castration provoked alterations in the morphology of the lung, similar to that observed in human lung emphysema. The compositions of surfactant and microsomes of the lung were similar to those previously reported by us for the surgically castrated rats. These results indicate that androgens are necessary for the normal morphology as well as for some metabolic aspects of the lung.

Inhibition of rat microsomal lipid peroxidation by the oral administration of D002

The effect of D002, a defined mixture of higher primary alcohols purified from bee wax, on in vivo and in vitro lipid peroxidation was studied. The extent of lipid peroxidation was measured on the basis of the levels of thiobarbituric acid reactive substances (TBARS). When D002 (5-100 mg/kg body weight) was administered orally to rats for two weeks, a partial inhibition of the in vitro enzymatic and non-enzymatic lipid peroxidation was observed in liver and brain microsomes. Maximal protection (46 percent) occurred at a dose of 25 mg/kg. D002 behaved differently depending on both the presence of NADPH and the integrity of liver microsomes, which suggests that under conditions where microsomal metabolism was favored the protective effect of D002 was increased. D002 (25 mg/kg) also completely inhibited carbon tetrachloride- and toluene-induced in vivo lipid peroxidation in liver and brain. Also, D002 significantly lowered in a dose-dependent manner the basal level of TBARS in liver (19-40 percent) and brain (28-44 percent) microsomes. We conclude that the oral administration of D002 (5, 25 and 100 mg/kg) for two weeks protected rat liver and brain microsomes against microsomal lipid peroxidation in vitro and in vivo. Thus, D002 could be useful as a dietary natural antioxidant supplement. More studies are required before these data can be extrapolated to the recommendation for the use of D002 as a dietary antioxidant supplement for humans

Effect of methyl-prednisone and cyclosporine on the lipid pattern and polyunsaturated fatty acid biosynthesis in the rat

The hyperlipidemia posttransplant has been largely attributed to immunosuppressant agents. In the present work we evaluated the effect of oral administration of cyclosporine (5 mg/kg/day) and/or methyl1-prednisone (1 mg/kg/day) on lipid composition and polyunsaturated fatty acid biosynthesis in normal adult male rats. The results obtained showed that both agents produced a delay on the growth together with a significant loss of body weight. In liver microssomal fraction from rats treated with methyl1-prednisone, a depression in delta 6 and delta 5 desaturation activited, was observed. This effect was corroborated in the fatty acid pattern through the enhancement of linoleic and dihomo-gamma-linolenic acids, and a depression of arachidonic acid. Similar results were noticed in those rats treated with both drugs when compared to the controls. No changes were observed either in the amount of liver microsomal total lipids or in the fatty acid composition of kidney and testis microsomes, as well as in erythrocyte membranes, among the different groups studied. Cyclosporine alone produced a significant depression in plasma triglycerides and showed no modifications in the other lipid parameters studied compared to the controls. Fluorescence anisotropy measured in the different membranes was not modified by the several treatments used. In view of the aforementioned data, in can be stated that methyl-prednisone would be the responsible for many of the lipid disorders that can be observed in posttransplant patients when they are subjected to the combined immunotherapy with cyclosporine.

Protective role of anion channel blocker in lipid peroxidation caused by H2O2 in microsomes of bovine pulmonary arterial smooth muscle tissue.

The role of hydroxyl radical (OH.) in H2O2-mediated stimulation of lipid peroxidation in microsomes of bovine pulmonary arterial smooth muscle tissue and the protective effects of DIDS, the anion channel blocker have been studied. Treatment of microsomes with H2O2 (1 mM) stimulate iron release, OH. production and lipid peroxidation. Pretreatment with DFO (an iron chelator) or DMTU (a hydroxyl radical scavenger) prevents OH. production and thereby reduces lipid peroxidation without any appreciable reduction of iron release. Simultaneous treatment of either DFO or DMTU with H2O2 significantly reduces lipid peroxidation and prevents OH. production without any significant reduction of iron release. However, addition of DFO or DMTU 2 min after treatment of the microsome with H2O2 does not produce any significant reduction of lipid peroxidation, OH production and iron release. Pretreatment of microsomes with DIDS markedly reduces the stimulation of lipid peroxidation without appreciably altering the increase in OH. production and iron release caused by H2O2.

Effect of policosanol on the hepatic cholesterol biosynthesis of normocholesterolemic rats

We have suggested previously, measuring 14C-acetate incorporation into free cholesterol, that oral administration of policosanol inhibits hepatic cholesterol biosynthesis in rats. Nevertheless, since acetate has limitations to study cholesterol synthesis in vivo, we now investigate rates of incorporation of labeled water into hepatic sterol after policosanol treatment. Absolute rates of incorporation of 3H-water in sterols were depressed by policosanol by about 20 percent, giving a more accurate degree of cholesterol biosynthesis inhibition in this species. Since policosanol did not inhibit labeled mevalonate incorporation into cholesterol in rat liver, we also studied the effect of policosanol on hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase. Reductase activity assayed in microsomes treated with policosanol remained unchanged, suggesting that cholesterol synthesis is not inhibited by a direct action of policosanol on this enzyme

Effect of alpha-tocopherol on doxorubicin-induced changes in rat liver and heart microsomes.

Rats were treated with doxorubicin (2.5 mg/kg body wt, iv) once a week for 8 weeks. Alpha-Tocopherol (400 mg/kg body wt/day) was co-administered orally for 2 months. Cytochrome-P450 (Cyt-P450) and Cytochrome-b5 (Cyt-b5) levels decreased significantly in doxorubicin treated rats. Significant decreases were observed in glucose-6-phosphatase, Cyt-P450 and Cyt-b5 reductase activities. In vitro lipid peroxidation study showed that alpha-tocopherol significantly minimises the lipid peroxide formation by doxorubicin. There was a significant change in microsomal cholesterol and phospholipid levels. Alpha-Tocopherol co-administration reduced the alterations in xenobiotic metabolising system and microsomal lipid levels. The results were discussed with reference to drug metabolising enzymes, lipid peroxidation and antioxidant nature of alpha-tocopherol.

M, in single and multiple doses on hypatic microsomal aminopyrine n-demethylase and aniline hydroxylase activities in the rat: comparison with the effects of skf 525-A

The effects of diclofenac sodium administration, in single and repeated doses, on hepatic microsomal activities of aminopyrine N- demethylase and aniline hydroxylase were evaluated in rats. Two groups of rats treated with SKF 525-A, were used to demonstrate the inhibition and induction of these enzymes. In rats treated with a single dose [50 mg/kg] of SKF 525-A, aminopyrine N-demethylase and aniline hydroxylase activities were significantly decreased, compared with control values. Under similar experimental conditions, diclofenac sodium administration, in a dose of 2.5 mg/kg, did not affect the activities of these enzymes. With repeated daily administration of diclofenac sodium for 15 days, a dose-dependent induction of the microsomal enzymes was evident. With a dose of 2.5 mg/kg/day, a significant increase in the activities of the two enzymes was observed. The extent of this induction was greater than that caused by repeated doses [50 mg/kg/day] of SKF 525-A. Rats treated with a smaller dose of the drug [1.25 mg/kg/day], did not show a similar response. In conclusion, repeated administration of daily doses of diclofenac sodium may induce hepatic microsomal drug metabolism depending on the dose used

Effect of alpha-tocopherol on the microsomal lipid peroxidation induced by doxorubicin: influence of ascorbic acid.

alpha-Tocopherol (40 mg/rat/day) was administered, orally, to doxorubicin treated rats (2 mg/kg, twice weekly, for 4 weeks) singly and also in combination with ascorbic acid (1 g/100 ml/day) in drinking water. The vitamin therapy was carried out for a period of 1 month. The microsomal lipid peroxide levels in liver and heart were found to be increased in doxorubicin treated rats. alpha-tocopherol and ascorbic acid treatment decreased the lipid peroxide level and also NADPH-dependent lipid peroxidation. A significant depletion of glutathione in liver and heart of doxorubicin treated animals was found to be ameliorated by vitamin therapy. Ascorbic acid was found to maintain the level of microsomal alpha-tocopherol. The activities of the detoxifying enzymes like catalase, superoxide dismutase and glutathione peroxidase were suppressed in doxorubicin treated rats and vitamins coadministration maintained the levels of these enzymes. Ascorbic acid was found to potentiate the antioxidant nature of alpha-tocopherol.

Estudios sobre el mecanismo bioquímico de acción del flavonoide silyvina: relación con sus propiedades terapéuticas / Studies on the biochemical mechanism of action of the flavonoid silyvin: relationship with its therapeutic properties

Este estudio presenta en forma sucinta los aspectos más relevantes de nuestro trabajo de investigación con el flavonoide silyvina. Su mecanismo de acción como citoprotector se relacionaría con una acción a tres niveles: como antioxidante, evitando la lipoperoxidación celular inducida por xenobióticos; aumentando la concentración intracelular de glutatión, permitiendo mejorar la función protectora y de desintoxicación de este tripéptido, y regulando la permeabilidad de las membranas celulares en forma relativamente específica a la entrada o salida de metabolitos. Se discuten las proyecciones terapéuticas del flavonoide, así como su efecto protector específico en la toxicidad hepática de la fenilhidrazina, el etanol y el acetaminofeno

Effect of high carbohydrate and high protein diets on microsomal fatty acid composition, fluidity and delta 6 desaturation activity in kidney and lung

La administración dietas hiperglucídicas e hiperproteicas suministradas a ratas durante 3 días produce respectivamente una disminución y un aumento en el cociente araquidonato/linoleato en los lípidos totales de microsomas de pulmón, riñon e hígado. En el hígado y el riñon este efecto está correlacionado con un significativo descenso de la actividad de la delta6 desaturasa para el caso de la dieta hiperflucídica y con un aumento de la misma actividad enzimática en la dieta hiperproteica. La actividad de la delta6 desaturasa, medida a través de la conversión del ácido 1-14**C linoleico a ácido alfa-linolénico, no se detectó en los microsomas de pulmón debido probablemente a la poca capacidad de este tejido para producir el éster de CoA del sustrato usado, y a que el cociente 20:4/18:2 en este tejido fue similar al del hígado bajo las condiciones dietéticas analizadas. La anisotropía de fluorescencia (r) del definilhexatrieno mostró diferencias significativas entre los tres tejidos analizados, efecto que se correlacionó con sus respectivos cocientes colesterol/fosfolípidos. Ambos parámetros fueron inferiores en los microsomas hepáticos que en los de los otros tejidos y permanecieron sin modificarse bajo los diferentes regímenes estudiados. Los resultados indican que el efecto de las dietas hiperhidrocarbonada e hiperproteica sobre la delta6 desaturasa no conduce a alteraciones aparentes en las propiedades físicas de las membranas microsomales