Adrenocortical function in 4-APP treated rats: a coupled stereological and biochemical study

Adrenocortical function in 4-APP-induced (4-aminopyrazolo[3,4-d]pyrymidine) lipoprotein-deficient rats was studied in relation to quantitative morphologic changes in the gland. 4-APP treatment results in enlargement of the adrenal cortex and its zona fasciculata and reticularis cells. In enlarged livers, cholesterol and free fatty acid concentrations were similar to that of control rats, however a marked accumulation of triglycerides with a concomitant drop in hepatic delta 4-steroid hydrogenase activity was found. A profound drop in serum cholesterol in both, high and low density lipoproteins, as well as triglycerides and plasma corticosterone concentrations was accompanied by a marked lowering of cholesterol and corticosterone concentration in the adrenal gland. Corticosterone output by adrenal homogenates was higher in 4-APP treated rats than in control animals. Such a treatment did not change cholesterol side-chain cleavage, 11 beta-hydroxylase, 3 beta-ol dehydrogenase-isomerase, steroid 5 alpha-reductase and neutral lipase activities when expressing results per unit weight of tissue or protein. However, when calculating per adrenocortical cell, adenine analogue applied increased 11 beta-hydroxylase, steroid 5 alpha-reductase and neutral lipase activities. Thus, coupled biochemical and stereologic studies revealed a complex and multidirectional effect of 4-APP on the rat adrenal cortex. This effect may be caused by serum lipoprotein deficiency and by toxic and stressful action of the adenine analogue on the rat. Also a direct effect of 4-APP on rat adrenal cortex may not be excluded.     

Nucleolar alterations induced by 4-aminopyrazolo(3,4-d)pyrimidine in adrenal cortex and liver cells of rat

Summary The nucleolar ultrastructural changes produced in adrenal zona fasciculata cells and hepatocytes of rats by 4-aminopyrazolo(3,4-d) pyrimidine (4-APP), an inhibitor of the lipoprotein synthesis, are described. Male rats were injected intraperitoneally for three consecutive days with 4-APP in sodium phosphate buffer (50 mg/Kg/day). On the 4th day, the animals were sacrificed and their adrenals and liver were processed for EM. The nucleoli of the adrenal zona fasciculata cells showed nucleolar fragmentation with loss of their normal reticular appearance, separation of fibrillar and granular components, extensive vacuolization and evidence of fibrillar centers. The hepatocyte nucleoli also exhibited fragmentation. These changes seem to be the morphological counterpart of alterations in rRNA synthesis and processing, since 4-APP inhibits de novo purine synthesis and thus interferes with its incorporation into RNA and DNA.     

Effects of the hypocholesterolemic drug, 4-aminopyrazolo (3,4-d) pyrimidine (4-APP), on the hamster adrenal cortex. An ultrastructural and functional study.

The aim of this study was to gain insight into the effects of 4-aminopyrazolo(3,4-d)pyrimidine (4-APP), a hypocholesterolemic drug, on the adrenal cortex of the hamster, representing an animal species in which steroidogenesis primarily relies on utilization of cholesterol synthesized de novo in the gland. 4-APP administration (1.5 mg/animal day for 3 days) to intact or dexamethasone-suppressed hamsters resulted in a marked proliferation of adrenocortical cells. However, the volume of parenchymal cells was unchanged in intact animals and lowered in the zona glomerulosa (ZG) and zona reticularis (ZR) of dexamethasone-administered hamsters. In both groups of animals, 4-APP strikingly increased the volume of the lipid-droplet compartment and markedly reduced the surface area of smooth endoplasmic reticulum in ZF cells, without significantly affecting the volume of the mitochondrial compartment and the surface area of mitochondrial cristae. These morphologic changes displayed no evident correlation with adrenal cortisol content and secretion. Since most of the 4-APP-induced changes were not prevented by dexamethasone, it seems legitimate to suggest that they could mainly depend on a direct effect of 4-APP on the hamster adrenocortical cells.     

Triiodothyronine effect on some parameters of carbohydrate metabolism in rat blood and liver. I. In vivo effect of triiodothyronine on liver glycogen content, blood metabolites and serum glycogenolytic activity

Short (7 days) T3-treatment has no influence on the plasma glucose and FFA concentration and blood lactate level, as well as on the hepatic glycogen content in the rats. The rise in T3 levels, observed in our study, was accompanied by a fall in T4 concentrations, indicating suppression of the endogenous T4 production. On the other hand, glycogenolytic activity of rat serum in vitro is the highest in the system: control liver slices-serum of rats pretreated with T3 as compared to the system: control liver slices-control serum. These observations may lead to conclusions, that serum of rats pretreated with T3 contains factors exhibiting the greater ability to mobilize glucose from liver slices than the control serum (euthyroid). The possibility, that pretreatment with T3 may cause a decrease in the number and/or affinity of beta-adrenergic receptors in the rat liver, is discussed.     

Circadian Rhythm of Liver Parameters (Cellular Structures, Mitotic Activity, Glycogen and Lipids in Liver and Serum) During Three Consecutive Cycles in Phenobarbital-Treated Rats

The circadian rhythm of gastric content, serum alkaline phosphatase (alk.P.), serum lipids, body weight (wt), relative (rel.) liver wt, cellular structures (by light- and electron-microscopy), mitotic activity of hepatocytes, glycogen content, protein and lipids in liver was studied in 180 male Sprague-Dawley rats orally treated at 0830-1030 with 50 mg/kg phenobarbital (PB) for 7 days. Thereafter, five PB-treated males and five controls each were studied at 4-hr intervals at 0600, 1000, 1400, 1800, 2200 and 0200 on 3 consecutive days. The lighting schedule in the colony was 12:12 = light/dark (light from 0600 to 1800). Following the rhythm of gastric emptying, the rel. liver wt showed a clear circadian rhythm with a peak at 0800. The rel. liver wt was raised in PB-treated rats at all times of the day. The circadian rhythm of cellular structures was closely related to the hepatic glycogen content which exhibited a clear rhythm with the peak also at 0800, but lowered values were found in PB-treated rats. The mitotic activity of hepatocytes was significantly increased in PB-treated rats but displayed the same circadian rhythm as controls with peaks at noon and troughs at midnight. The well-known hypertrophy of the smooth endoplasmic reticulum in PB-treated rats was not found at 0600, but was fully developed at 1400 and 2200. PB-treatment increased significantly the liver content of cholesterol, triglycerides and phospholipids. Liver cholesterol showed a clear circadian rhythm with peaks at 1800. No rhythm of liver protein, triglycerides and phospholipids was observed. In serum, levels of cholesterol were significantly elevated, those of triglycerides and alk.P. significantly lowered, while those of phospholipids were not affected by the treatment. The three serum lipids, alk.P. and beta-lipoprotein exhibited a clear circadian rhythm, while serum glucose and non-esterified fatty acids did not.     

Circadian Rhythm of Liver Parameters (Cellular Structures,Mitotic Activity,Glycogen and Lipids in Liver and Serum) During Three Consecutive Cycles in Phenobarbital-Treated Rats

The circadian rhythm of gastric content, serum alkaline phosphatase (alk.P.), serum lipids, body weight (wt), relative (rel.) liver wt, cellular structures (by light- and electron-microscopy), mitotic activity of hepatocytes, glycogen content, protein and lipids in liver was studied in 180 male Sprague-Dawley rats orally treated at 0830-1030 with 50 mg/kg phenobarbital (PB) for 7 days. Thereafter, five PB-treated males and five controls each were studied at 4-hr intervals at 0600, 1000, 1400, 1800, 2200 and 0200 on 3 consecutive days. The lighting schedule in the colony was 12:12 = light/dark (light from 0600 to 1800). Following the rhythm of gastric emptying, the rel. liver wt showed a clear circadian rhythm with a peak at 0800. The rel. liver wt was raised in PB-treated rats at all times of the day. The circadian rhythm of cellular structures was closely related to the hepatic glycogen content which exhibited a clear rhythm with the peak also at 0800, but lowered values were found in PB-treated rats. The mitotic activity of hepatocytes was significantly increased in PB-treated rats but displayed the same circadian rhythm as controls with peaks at noon and troughs at midnight. The well-known hypertrophy of the smooth endoplasmic reticulum in PB-treated rats was not found at 0600, but was fully developed at 1400 and 2200. PB-treatment increased significantly the liver content of cholesterol, triglycerides and phospholipids. Liver cholesterol showed a clear circadian rhythm with peaks at 1800. No rhythm of liver protein, triglycerides and phospholipids was observed. In serum, levels of cholesterol were significantly elevated, those of triglycerides and alk.P. significantly lowered, while those of phospholipids were not affected by the treatment. The three serum lipids, alk.P. and beta-lipoprotein exhibited a clear circadian rhythm, while serum glucose and non-esterified fatty acids did not.     

Mechanism of bromocriptine-induced hyperglycaemia

Results reveal that bromocriptine at a dose of 6 mg/kg. I.P. in mice caused a significant hyperglycaemic effect which was accompanied by a marked increase in liver glycogen. After adrenalectomy, the effect of bromocriptine on serum glucose level was reduced whereas its effect on liver glycogen content was abolished. In rats, administration of bromocriptine (17.5 mg/kg I.P.) induced a significant rise in serum glucose level which was associated with marked reduction in serum insulin activity and increase in serum corticosterone level with no effect on serum triiodothyronine (T3) or thyroxine (T4) levels. It could be concluded that bromocriptine-induced hyperglycaemia might be attributed at least partially to inhibition of insulin release and stimulation of corticosterone secretion.     

Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells

The aim of this study was to investigate whether matrix metalloproteinases (MMP-13, 9) of Kupffer cells induced by gadolinium chloride (GdCl(3)) treatment can reverse dimethylnitrosamine (DMN)-induced liver fibrosis (in vivo) and the effect of GdCl(3) on MAP kinase activity (in vitro). Male Wistar rats 6 weeks of age received DMN (10 mg/kg) three successive days a week for 4 weeks. Then two groups of rats (n = 6 each) were treated twice weekly with either GdCl(3) (7 mg/kg) or saline solution intravenously for the next 4 weeks. Animals were sacrificed to estimate the degree of liver fibrosis. Isolated Kuppfer cells were treated with GdCl(3) and the expressions of MMPs, MAP kinase activity (ERK, SAPK/JNK, P38) as well as apoptosis were also examined. Rats that received DMN for 4 weeks followed by GdCl(3) injection for 4 weeks showed an reduced liver hydroxyproline content compared to rats treated with DEN followed by saline (277 +/- 22 VS 348 +/- 34 microg/g, n = 6 each, P < 0.01). There were significantly increased MMP-13 mRNA levels in GdCl(3)-treated rats. However, no significant change was observed in procollagen type I mRNA levels. Isolated Kuppfer cells treated with GdCl(3) showed increased MAP kinase activity, especially P38 pathway as well as MMP-13, 9 mRNA and type I collagen-degrading activity leading to apoptosis. SB203580, inhibitor of P38 pathway diminished these activation and prevented apoptosis. These results suggest that Kuppfer cells can reverse liver fibrosis via the expression of MMPs mainly through P38 pathway.     

Induction of rat kidney gluconeogenesis during acute liver intoxication by carbon tetrachloride.

1. Glucose production from L-lactate was completely inhibited 24h after carbon tetrachloride treatment in liver from 48h-starved rats. The activities of phosphoenolpyruvate carboxykinase, fructose diphosphatase and glucose 6-phosphatase were decreased by this treatment in fed and starved rats, whereas lactate dehydrogenase activity was only decreased in fed animals. 2. The production of glucose by renal cortical slices from fed rats previously treated with carbon tetrachloride was enhanced when L-lactate, pyruvate and glutamine but not fructose were used as glucose precursors. Renal phosphoenolpyruvate carboxykinase activity was increased in this condition. 3. This increase was counteracted by cycloheximide or actinomycin D, suggesting that the effect was due to the synthesis de novo of the enzyme. 4. The pattern of hepatic gluconeogenic metabolites in treated animals was characterized by an increase in lactate, pyruvate, malate and citrate as well as a decrease in glucose 6-phosphate, suggesting an impairment of liver gluconeogenesis in vivo. 5. In contrast, the profile of renal metabolites suggested that gluconeogenesis was operative in the treated rats, as indicated by the marked increase in the content of phosphoenolpyruvate, 2-phosphoglycerate, 3-phosphoglycerate and glucose 6-phosphate. 6. It is postulated that renal gluconeogenesis could contribute to the maintenance of glycaemia in carbon tetrachloride-treated rats.     

Effects of pycnogenol treatment on oxidative stress in streptozotocin-induced diabetic rats

Free radicals and oxidative stress have been implicated in the etiology of diabetes and its complications. This in vivo study has examined whether subacute administration of pycnogenol, a French pine bark extract containing procyanidins that have strong antioxidant potential, alters biomarkers of oxidative stress in normal and diabetic rats. Diabetes was induced in female Sprague-Dawley rats by a single injection of streptozotocin (90 mg/kg body weight, ip), resulting (after 30 days) in subnormal body weight, increased serum glucose concentrations, and an increase in liver weight, liver/body weight ratios, total and glycated hemoglobin, and serum aspartate aminotransferase activity. Normal and diabetic rats were treated with pycnogenol (10 mg/kg body weight/day, ip) for 14 days. Pycnogenol treatment significantly reduced blood glucose concentrations in diabetic rats. Biochemical markers for oxidative stress were assessed in the liver, kidney, and heart. Elevated hepatic catalase activity in diabetic rats was restored to normal levels after pycnogenol treatment. Additionally, diabetic rats treated with pycnogenol had significantly elevated levels of reduced glutathione and glutathione redox enzyme activities. The results demonstrate that pycnogenol alters intracellular antioxidant defense mechanisms in streptozotocin-induced diabetic rats.     

Effect of 4-aminopyrazolo[3,4-d]pyrimidine on the catabolism of high-density lipoprotein apolipoprotein A-I in the rat

The in vivo turnover and sites of catabolism of O-(4-diazo-3-[125I]iodobenzoyl)sucrose-labelled rat high-density lipoprotein (HDL) apolipoprotein A-I were studied in rats treated for 3 days with 4-aminopyrazolo-[3,4-d]pyrimidine (4APP). It was found that 4APP treatment decreases the serum cholesterol concentration to 6 mg/dl and stimulates the serum decay of labelled HDL. The latter effect could be attributed to an increased catabolism of radioactive HDL apolipoprotein A-I by the liver. When the serum cholesterol concentration was raised to physiological levels by a bolus injection of unlabelled rat HDL, at the time of administration of the labelled HDL, the serum decays and the tissue uptakes of apolipoprotein A-I labelled HDL were identical in 4APP-treated rats and control animals. When a bolus injection of unlabelled human low-density lipoprotein (LDL) was administered to 4APP-treated rats, the serum decay and tissue uptake of apolipoprotein A-I labelled HDL remained rapid. The recovery of radioactivity in the adrenal glands was increased almost 10 fold by 4APP treatment, a phenomenon which was reversed by a bolus injection of unlabelled HDL, but not by injection of unlabelled LDL. It is concluded that treatment of rats with 4APP does not affect the rate of catabolism of rat HDL apolipoprotein A-I, when the serum HDL concentration in the treated animals is restored to physiological levels.     

Identification of 14-hydroxy-retro-retinol and 4-hydroxy-retinol as endogenous retinoids in rats throughout neonatal development

14-Hydroxy-retro-retinol was previously described as an in vivo and in vitro metabolite of retinol. Furthermore, the retinoid 4-hydroxy-retinol was identified as an endogenous occurring retinoid in the amphibian organism and an in vitro metabolite of retinol. We describe in the present study that 14-hydroxy-retro-retinol and 4-hydroxy-retinol are present in normal neonatal rat serum as endogenous occurring retinoids in normal non-vitamin A supplemented mammals (rats). Both retinoids were detected in serum and liver of neonatal rats at days 3 and 11 after birth. The respective concentrations at day 11 after birth were 41.8 +/- 2.8 ng/ml (serum)/ 104 +/- 6 ng/g (liver) for 4-hydroxy-retinol and 23 +/- 4.6 ng/ml (serum)/ 285 +/- 5 ng/g (liver) for 14-hydroxy-retro-retinol. Both retinoids could not be detected in adult rat serum and liver. From our experiments important physiological functions of these retinoids during postnatal development could be postulated.     

Assessment of In Vivo Antidiabetic Properties of Umbelliferone and Lupeol Constituents of Banana (Musa sp. var. Nanjangud Rasa Bale) Flower in Hyperglycaemic Rodent Model

Banana is an extensively cultivated plant worldwide, mainly for its fruit, while its ancillary product, the banana flower is consumed as a vegetable and is highly recommended for diabetics in the traditional Indian medicine system. This study is based on an investigation of the in vivo antihyperglycaemic activity of Umbelliferone (C1) and Lupeol (C2) isolated from the ethanol extract of banana flower (EF) in alloxan induced diabetic rat model. Diabetic rats which were administered with C1, C2 and EF (100 and 200 mg/kg b. wt.) for 4 weeks showed deterioration in fasting hyperglycaemia and reversal of abnormalities in serum/urine protein, urea and creatinine, when compared to the diabetic control group of rats. The diabetic group of rats fed with EF, C1 and C2 (100 mg/kg b. wt.) once daily, for a period of 28 days resulted in a significant reduction of diabetic symptoms viz., polyphagia, polydipsia, polyuria and urine sugar together with an improved body weight. HbA1c extent was reduced whereas levels of insulin and Hb were increased. Both the extract and compounds wielded positive impacts in diabetic rats by reversal of altered activities of hepatic marker enzymes viz., aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP); glycolytic enzyme (hexokinase); shunt enzyme (glucose-6-phosphate dehydrogenase); gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase, lactate dehydrogenase) and pyruvate kinase. The characteristic diabetic complications such as hypercholesterolemia and hypertriacylglycerolemia also significantly reverted to normal in the serum/liver of diabetic rats. Besides these, the treatment increased the activities of enzymatic and non-enzymatic antioxidants in the serum and liver. The histological observations revealed a marked regeneration of the β-cells in the drug treated diabetic rats. In conclusion, the present study illustrates that EF, C1 and C2 enhances the glycolytic activities, besides increasing the hepatic glucose utilization in diabetic rats by stimulating insulin secretion from the remnant β-cells along with potential enzymatic and non-enzymatic antioxidant activities.     

Status of phosphatase activities in the liver and kidney of rats treated with isosaline leaf and stem-bark extracts of Harungana madagascariensis (L)

The activities of phosphatases and other biochemical parameters were examined in rats treated with isosaline leaf and stem-bark extracts of Harungana madagascariensis (L). Results show that both the leaf and stem-bark extracts significantly increased the activities of serum and liver alkaline phosphatase, liver acid phosphatase, liver and kidney glucose-6-phosphatase, fructose-1,6-diphosphatase and glycogen in the treated rats. While the stem-bark extract significantly elevated the activities of fructose-1,6-diphosphatase and glycogen in the kidney, these biochemical parameters were not affected by treatment with the leaf extract. The activity of serum acid phosphatase was unaffected by the two extracts. The results obtained clearly show that these extracts caused a marked increase in gluconeogenesis in the liver and kidney of the treated rats. While the stem-bark extract increased gluconeogenesis in both liver and kidney, the leaf extract caused an increase in gluconeogenesis only in the liver. The increased serum alkaline phosphatase activity caused by these extracts may, aside from having other tissues contributing to it, be due to damage caused by these extracts to the hepatocytes. The extent of pathological changes as well as the implications of these findings to folklore medicine requires further investigation.     

Gonadotropin modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in desensitized luteinized rat ovary

These studies were done to examine the effect of gonadotropin on rat luteal 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity (the rate-limiting step in cholesterol biosynthesis) in ovaries of pregnant mare's serum gonadotropin (PMSG)-human chorionic gonadotropin (hCG) primed rats. Administration of hCG stimulated HMG CoA reductase activity in a time- and dose-dependent manner: significant increases were noted within 4 h, with maximum effects (30-40-fold increases) seen 24 h after hCG (25 IU) administration. This effect was specific in that only LH, of several hormones tested, was as effective as hCG in stimulating HMG CoA reductase activity, and no change in the activity of either liver microsomal HMG CoA reductase or luteal microsomal NADPH-cytochrome c reductase was seen after hCG. The gonadotropin-induced increase in HMG CoA reductase activity seemed to be due to a net increase in enzyme activity, not to a change in the phosphorylated/dephosphorylated state of the enzyme. Pretreatment of animals with aminoglutethimide, an inhibitor of the conversion of cholesterol to steroid (pregnenolone), prevented the hCG-induced rise in HMG CoA reductase activity, whereas treatment with 4-aminopyrazolo[3,4-d]pyrimidine (4-APP), which depletes cellular cholesterol content, led to striking increases in enzyme activity. However, the combined effects of 4-APP and hCG were additive, suggesting that the stimulating effect of hCG on HMG CoA reductase activity is not entirely due to a depletion of cellular sterol content of luteinized ovaries. Similarly, cholesteryl ester and cholesterol syntheses as measured by [14C]acetate conversion were also increased by hCG and 4-APP treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacologic effects of 4-chlorophenol in rats: comparison to clofibrate

4-Chlorophenol (4-CP) is an identified trace contaminant in commercial clofibrate preparations and the pharmacologic effects of 4-CP have not yet been widely established. We have examined the dose-dependent effects of oral 4-CP and clofibrate administration on selected hepatic parameters and on serum glucose, cholesterol, and triglyceride concentrations in male rats. 4-CP treatment (0.00125-0.08 mmol/kg, twice a day) of rats for 2 weeks increased hepatic microsomal protein (20-30%) and cytochrome P-450 (20-190%) contents without changing liver/body weight ratios. Both 4-CP (0.0025 mmol/kg body wt, twice a day) and CPIB (0.4 mmol/kg body wt, twice a day) treatment to rats for 2 weeks caused significant elevations in microsomal cytochrome P-450 content and in the maximal activities of ethylmorphine, aminopyrine, and benzphetamine N-demethylase, but not in the activity of zoxazolamine 6-hydroxylase. With the same dose of 4-CP, time-dependent increases in hepatic microsomal protein, cytochrome P-450, and the activity of benzphetamine N-demethylase were observed for a 4-week period, and the induction of hepatic microsomal benzphetamine N-demethylase activity by 4-CP was associated with an increased enzyme synthesis. 4-CP treatment produced a marked morphologic change in liver cell ultrastructure, including a proliferation of mitochondria and endoplasmic reticulum at lower 4-CP doses. A clustering of intracellular organelles (mitochondria and endoplasmic reticulum) and a foamy cytoplasm were seen at doses greater than 0.01 mmol/kg, twice a day for 2 weeks, and at 0.0025 mmol/kg, twice a day for greater than 4 weeks. The effects of 4-CP and clofibrate on fasting blood glucose and fasting serum lipid levels were also monitored throughout an 8-week period. Both 4-CP (0.005 mmol/kg body wt, twice a day) and clofibrate (0.2 mmol/kg body wt, twice a day) produced significant elevations in fasting serum glucose levels, but this dosage of 4-CP did not alter serum lipid and lipoprotein parameters, whereas clofibrate significantly reduced serum total cholesterol and high density lipoprotein cholesterol levels. These results lead us to conclude that 4-CP does not contribute to the antilipidemic effects of clofibrate.     

Glucose tolerance and insulin action in monosodium glutamate (MSG) obese exercise-trained rats

The present study was designed to evaluate the effects of chronic aerobic exercise (swimming, 1h/day, 5 days/week, with an overload of 5% body weight) on glucose metabolism in obese male Wistar rats. Hypothalamic obesity was induced through administration of monosodium glutamate (MSG) at 4 mg/g of body weight every other day from birth to 14 days old. Fourteen weeks after drug administration, the rats were separated into two groups: MSG-S (sedentary) and MSG-T (swimming for 10 weeks). Rats of the same age and strain, receiving saline in place of MSG, were used as control (C), and subdivided into two groups: C-S and C-T. At the end of the experimental period, an oral glucose tolerance test was performed and serum glucose (AG) and insulin (AI) were evaluated. A constant for serum glucose decrease (Kitt) in response to exogenous insulin was calculated. Soleus muscle strips and adipose tissue samples were incubated and insulin stimulated glucose uptake determined. No differences were observed in AG among the 4 groups. MSG-S rats showed higher Al (418%) and lower Kitt (92.3%) than C-S rats. T-rats showed higher glucose uptake by muscle (224.0%) and adipose tissues (94.1%) than S-rats. Among trained rats, glucose uptake by muscle was higher in MSG-T (5.4%) than in C-T, while the opposite was observed in adipose tissue (39% higher in C-T). Chronic aerobic exercise was able to improve glucose tolerance and reduce insulin resistance in MSG-obese rats. These effects were associated to an increase in glucose uptake by muscle and adipose tissue in response to insulin.     

A survey of adenine and 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) as inhibitors of ribosome-inactivating proteins (RIPs)

The inhibitory power of adenine and 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) on the RNA-N-glycosidase activity catalyzed by bacterial (Shiga toxin 1) and plant (ricin, gelonin, momordin, bryodin-R, PAP-S, luffin, trichosantin, saporin 6 and barley) RIPs has been compared. The behavior of the two inhibitors is largely variable. While Shiga toxin 1 is preferentially inhibited by 4-APP, plant RIPs are either preferentially inhibited by adenine, or equally inhibited by the two compounds or, finally, only slightly more by 4-APP. Sequence variabilities involved in these different behaviors are discussed. The experimental data clearly indicate that, in spite of the same mechanism of action, RIPs differ widely in the ability to fit small ring molecules in the active cleft. While the strong inhibitory power of 4-APP on Shiga toxin 1 opens perspectives of therapeutic interventions, the ineffectiveness of the compound on ricin precludes its use as a suitable antidote in poisoning.     

Efficiency of propolis extract against mitochondrial stress induced by antineoplasic agents (doxorubicin and vinblastin) in rats

To assess the oxidative stress and mitochondrial dysfunction associated with disease, toxic process and aging, in vivo and in vitro preventive effect of propolis extract against mitochondrial oxidative stress induced by two anticancer drugs (doxorubicin and vinblastin) have been investigated in female wistar rat using liver and heart mitochondria. The results show that doxorubicin and vinblastin altered mitochondrial functions as observed by a decrease in respiratory control value, an activation of swelling and overproduction of superoxide anion. Myocardial tissue from doxorubicin treated rats showed a marked increase in malondialdehyde production, a depletion of reduced glutathione contents and an inhibition of catalase and superoxide dismutase activities. Similar results were also observed in liver tissue. Pretreatment of rats with propolis extract (100 mg/kg/day po) (10(-4) M ip) administered 4 days prior to doxorubicin (20 mg/kg) and/or vinblastin (2 mg/kg) injection, substantially reduced the peroxidative damage in myocardium and hepatic tissues and markedly restored the tissues catalase and SOD activities. The results strongly suggest that propolis extract protects heart and liver tissues from oxidative stress by protecting the mitochondria.