Basal and glucocorticoid induced changes of hepatic glucocorticoid receptor during aging: relation to activities of tyrosine aminotransferase and tryptophan oxygenase

The characteristics of glucocorticoid receptors, their sensitivity to glucocorticoid as well as the basal and glucocorticoid induced thyrosine aminotranferase (TAT) and tryptophan oxygenase (TO) activities were studied in rat liver during aging. The concentration (N) and dissociation constant (K-d) of glucocorticoid receptor (GR) significantly change during the aging both in untreated and dexamethasone treated animals. The level of receptors was lower in dexamethasone treated rats of all analyzed aged groups compared to untreated animals. In comparison to untreated groups, there was no correlation between the changes of N and K-d during the lifespan. According to immunochemical analysis, the decline of receptor protein content occurs during lifespan. Dexamethasone treatment reduced the level of receptor protein compare to respective age group of untreated rats. The glucocorticoid-receptor (G-R) complexes from both untreated and treated animals underwent thermal activation, although the extent of activation was more pronounced in the case of untreated groups compared to treated animals. The magnitude of heat activation of receptor complexes was more pronounced in the liver of the youngest untreated rats compared to elderly ones, while the receptor activation between treated groups of studied ages has shown less significant differences. Besides, basal as well as induced TAT and TO activities after dexamethasone injection also showed age-related alterations. The observed alterations in GR might play a role in the changes of the cell responses to glucocorticoid during the age. This presumption is supported by detected changes in basal and dexamethasone induced TAT and TO activities during aging

Chemical and biological properties of verapamil labeled with technetium-99m: A potential myocardial imaging agents

On the base of property to enter into myocardial cells as a calcium channel blocker, verapamil was labeled with technetium-99m in order to investigate the possibility to obtain new radiopharmaceutical for myocardial imaging. The conditions of labeling verapamil with technetium-99m for different ammounts of stannous(II) ion, mannitol, cystein and pH range 2.5-3.5 were examined. Investigation of radiochemical purity ( GT 95%) and biodistribution of (9)9mTc-verapamil in rats showed that it was stable during 2 hours after labeling. Accumulation of Tc-99m-verapamil in heart was 1.2% and in liver 9.4%, 5 minutes after injection. Biodistribution of Tc-99m-verapamil in rats in conditions of stress, pharmacologically caused by dipiridamol, showed that the elimination of Tc-99m-verapamil from the heart was slower related to the control group. In the group of rats previously treated with isoproterenol uptake of Tc-99m-verapamil in heart was lower related to the control group (0.7% versus 1.0%) 5 minutes after injection. Lipophilicity of (9)9mTc-verapamil was examined by determination of partition coefficient (log P = 0.62) and protein binding (79%). Imaging studies on dogs provided relatively good myocardial images with partially overlap of activity in the lung and liver

Age-related changes of insulin receptors, plasma insulin and glucose level

The effects of aging on hepatic and erythrocyte insulin receptors have been investigated in 6, 12, 18 and 21-months-old compare to 3-months-old rats. Plasma insulin was elevated in 6, 12 and 18-months-old rats. Specific binding of insulin in liver was increased at the age of 18 months and accompanied with increase in concentration of low affinity binding sites, while specific binding to erythrocytes as well as concentration of both classes of binding sites was increased in 6-months-old rats. The protein and mRNA content of hepatic receptor were decreased only in the oldest animals. Plasma glucose was elevated starting from 12-months-old rats, while, after decrease in 6-months-old animals, citrulline was raised in the oldest group. The results demonstrating that specific binding of insulin in liver and erythrocytes and the concentration of binding sites in both tissues were not decreased during aging, as well as the absence of changes in affinity of insulin binding sites do not point out to occurrence of insulin resistance. However, the increase in insulinemia in the middle of lifespan, elevated plasma glucose and citrulline as well as decrease of hepatic receptor protein and mRNA content in the oldest animals indicate some age-related changes in insulin signaling

The effect of 17 beta-estradiol on the content of insulin signaling molecules in liver and uterus of ovariectomized rats

IUBMB 50th Anniversary Symposium, Jul 02-07, 2005, Budapest, Hungar

The effect of 17 beta-estradiol on the content of insulin signaling molecules in liver and uterus of ovariectomized rats

IUBMB 50th Anniversary Symposium, Jul 02-07, 2005, Budapest, Hungar

The responses of rat liver glucocorticoid receptors and genes for tyrosine aminotransferase, alpha-2-macroglobulin and gamma-fibrinogen to adrenalectomy-, dexamethasone- and inflammation-induced changes in the levels of glucocorticoids and proinflammatory cytokines

The responses of liver glucocorticoid receptor (GR) and genes coding for a glucocorticoid-inducible tyrosine aminotransferase (TAT) and two acute-phase proteins (APP) [alpha (2)-macroglobulin (alpha (2)-M) and gamma -fibrinogen (Fb)] to changes in glucocorticoid (GC) and proinflammatory (AP) cytokine contents have been examined in rats after single or combined treatments with turpentine oil, dexamethasone (Dex) and adrenalectomy. Activation of two APP genes in turpentine-induced inflammation was accompanied by an increase in the level of GR mRNA and a preferential translocation of GR-GC complexes to the nucleoplasm, while the expression of TAT remained unaltered. Dex alone caused a decrease in the levels of GR and Fb mRNAs, activation of TAT and alpha (2)-M genes, a decrease in the affinity of hormone binding sites and redistribution of translocated GR-Dex complexes within the nuclei. Inflammation potentiated the effect which Dex alone exerted on the GIR content and the number of GR binding sites but counteracted its influence on the affinity of GR binding sites and nuclear distribution of GR-Dex complexes

The responses of rat liver glucocorticoid receptors and genes for tyrosine aminotransferase, alpha-2-macroglobulin and gamma-fibrinogen to adrenalectomy-, dexamethasone- and inflammation-induced changes in the levels of glucocorticoids and proinflammatory cytokines

The responses of liver glucocorticoid receptor (GR) and genes coding for a glucocorticoid-inducible tyrosine aminotransferase (TAT) and two acute-phase proteins (APP) [alpha (2)-macroglobulin (alpha (2)-M) and gamma -fibrinogen (Fb)] to changes in glucocorticoid (GC) and proinflammatory (AP) cytokine contents have been examined in rats after single or combined treatments with turpentine oil, dexamethasone (Dex) and adrenalectomy. Activation of two APP genes in turpentine-induced inflammation was accompanied by an increase in the level of GR mRNA and a preferential translocation of GR-GC complexes to the nucleoplasm, while the expression of TAT remained unaltered. Dex alone caused a decrease in the levels of GR and Fb mRNAs, activation of TAT and alpha (2)-M genes, a decrease in the affinity of hormone binding sites and redistribution of translocated GR-Dex complexes within the nuclei. Inflammation potentiated the effect which Dex alone exerted on the GIR content and the number of GR binding sites but counteracted its influence on the affinity of GR binding sites and nuclear distribution of GR-Dex complexes

The radioprotective activities of turpentine-induced inflammation and alpha(2)-macroglobulin: The effect of dexamethasone on the radioprotective efficacy of the inflammation

This work was aimed at the radioprotective efficacy of turpentine oil (TO), alpha(2)-Macroglobulin (alpha(2)-M), Amifostine (Ami) and/or dexamethasone (Dex). These agents were administrated, alone or in combination, prior to irradiation of rats with 6.7 Gy (LD50/30). The survival was recorded daily for 4 weeks after irradiation and body weight, peripheral leukocytes and thrombocytes were measured. The plasma concentration of alpha(2)-M and other acute phase proteins were determined by crossed immunoelectrophoresis. All rats receiving alpha(2)-M and Ami alone or in combination survived the radiation injury, whereas the rate of survival of TO-treated rats was 90%. Radiation and therapy-induced changes in the expression of acute phase protein genes were atypical for the acute phase reaction. Dex alone was lethal for 45% and 55% of control and irradiated rats, respectively. Pretreatment with 1mg Dex reduced radioprotective efficacy of TO and Ami to 30% and 40%, respectively. Given together TO and Ami provided 70% protection to rats receiving Dex. The TO and GYM enhanced the rate of survival from 50% to 90% and 100%, respectively. In the presence of 1 mg Dex the TO-induced radioprotectors and Ami exhibited radiosensitizing rather than radioprotecting activities

Glucocorticoid receptors in lymphocytes and stability of kidney graft function

The glucocorticoid receptors in lymphocytes of patients treated with glucocorticoids after kidney transplantation have been studied in order to determine whether abnormalities in corticosteroid binding and trans-activation of steroid-receptor complexes, i.e., their translocation into nuclei, may contribute to the resistance of patients to glucocorticoid therapy. The patients were divided into two groups, according to graft stability: patients with stable graft function and those with chronic allograft rejection. The study revealed changes in both level and binding affinity of glucocorticoid receptors in peripheral blood lymphocytes from patients with chronic graft rejection, compared with control level, as well as with values of patients with stable graft function. Those data indicate that sensitivity to glucocorticoids depends, at least in part, on the alterations of glucocorticoid receptors. The receptor translocation into nuclei indicates that unknown post-receptor events might also be involved in glucocorticoid resistance that seriously impair successive glucocorticoid therapy after organ transplantation. Further examination of glucocorticoid receptors in cases of organ transplantation seems warranted