Emergent immunoregulatory properties of combined glucocorticoid and anti-glucocorticoid steroids in a model of tuberculosis.
In Balb/c mice with pulmonary tuberculosis, there is a switch from a protective Th1-dominated cytokine profile to a non-protective profile with a Th2 component. This switch occurs while the adrenals are undergoing marked hyperplasia. Treatment with the anti-glucocorticoid hormones dehydroepiandrosterone or 3 beta, 17 beta-androstenediol, during the period of adrenal hyperplasia, maintains Th1 dominance and is protective. We investigated the effects of these hormones as therapeutic agents by administering them from day 60, when the switch to the non-protective cytokine profile was already well established. Given at this time (day 60), doses that were protective when given early (from day 0) were rapidly fatal. A physiological dose of the glucocorticoid corticosterone was also rapidly fatal. However when the corticosterone and the anti-glucocorticoid (AED or DHEA) were co-administered, there was protection, with restoration of a Th1-dominated cytokine profile, enhanced DTH responses, and enhanced expression of IL-1 alpha and TNF alpha. Therefore this combination of steroids has an emergent property that is quite unlike that of either type of steroid given alone. It may be possible to exploit the ant-inflammatory properties of glucocorticoids while preserving a Th1 bias, by combining glucocorticoids with DHEA or suitable metabolites. (+info)
Class I P-glycoproteins (Pgp) confer multidrug resistance in tumors, but the physiologic function of Pgp in normal tissues remains uncertain. In cells derived from tissues that normally express Pgp, recent data suggest a possible role for Pgp in cholesterol trafficking from the plasma membrane to the endoplasmic reticulum. We investigated the esterification of plasma membrane cholesterol under basal conditions and in response to sphingomyelinase treatment in transfected and drug-selected cell lines expressing differing amounts of functional class I Pgp. Compared with parental NIH 3T3 fibroblasts, cells transfected with human multidrug resistance (MDR1) Pgp esterified more cholesterol both without and with sphingomyelinase. Esterification also was greater in drug-selected Dox 6 myeloma cells than parental 8226 cells, which express low and non-immunodetectable amounts of Pgp, respectively. However, no differences in total plasma membrane cholesterol were detected. Transfection of fibroblasts with the multidrug resistance-associated protein (MRP) did not alter esterification, showing that cholesterol trafficking was not generally affected by ATP-binding cassette transporters. Steroidal (progesterone, dehydroepiandrosterone) and non-steroidal antagonists (verapamil, PSC 833, LY335979, and GF120918) were evaluated for effects on both cholesterol trafficking and the net content of 99mTc-Sestamibi, a reporter of drug transport activity mediated by Pgp. In Pgp-expressing cells treated with nonselective and selective inhibitors, both the kinetics and efficacy of inhibition of cholesterol esterification differed from the antagonism of drug transport mediated by Pgp. Thus, although the data show that greater expression of class I Pgp within a given cell type is associated with enhanced esterification of plasma membrane cholesterol in support of a physiologic function for Pgp in facilitating cholesterol trafficking, the molecular mechanism is dissociated from the conventional drug transport activity of Pgp. (+info)
Preventive effects of dehydroepiandrosterone acetate on the fatty liver induced by orotic acid in male rats.
Preventive effects of dehydroepiandrosteone acetate (DHEA-A) and clofibrate (positive control substance) on the fatty liver induced by orotic acid (OA) were examined on the male Sprague-Dawley rats fed a high sucrose based diet containing 1% OA and this diet further mixed with 0.5% DHEA-A or 0.5% clofibrate for 2 weeks. Numerous lipid droplets were observed in the hepatocytes of the rats treated with OA alone, but not in those treated with DHEA-A or clofibrate. In comparison to the group with OA alone, the DHEA-A or clofibrate treated rats showed a larger relative liver weight (to body weight) which was accompanied by increased peroxisomes in the hepatocytes. These results indicate that DHEA-A, as well as clofibrate, may prevent OA-induced fatty liver. (+info)
YM116, 2-(1H-imidazol-4-ylmethyl)-9H-carbazole, decreases adrenal androgen synthesis by inhibiting C17-20 lyase activity in NCI-H295 human adrenocortical carcinoma cells.
The concentrations of androstenedione and dehydroepiandrosterone, products of C17-20 lyase, in the medium after a 6-hr incubation of NCI-H295 cells were decreased by YM116 (2-(1H-imidazol-4-ylmethyl)-9H-carbazole) (IC50: 3.6 and 2.1 nM) and ketoconazole (IC50: 54.9 and 54.2 nM). 17Alpha-hydroxyprogesterone, a product of 17alpha-hydroxylase, was increased by YM116 (1-30 nM) and by ketoconazole (10-300 nM) and then was decreased at higher concentrations of both agents (IC50: 180 nM for YM116, 906 nM for ketoconazole), indicating that YM116 and ketoconazole were 50- and 16.5-fold more specific inhibitors of C17-20 lyase, respectively, than 17alpha-hydroxylase. Compatible with these findings, progesterone, a substrate of 17alpha-hydroxylase, was increased by these agents. Cortisol production was inhibited by YM116 and ketoconazole (IC50: 50.4 and 80.9 nM, respectively). YM116 was a 14-fold more potent inhibitor of androstenedione production than cortisol production, whereas ketoconazole was a nonselective inhibitor of the production of both steroids. YM116 and ketoconazole inhibited the C17-20 lyase activity in human testicular microsomes (IC50: 4.2 and 17 nM, respectively). These results demonstrate that YM116 reduces the synthesis of adrenal androgens by preferentially inhibiting C17-20 lyase activity. (+info)
Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits.
The effect of natural androgens on serum lipids and atherosclerosis is controversial. We therefore studied this important issue prospectively in an animal model of atherosclerosis. Eighty male rabbits were randomized to bilateral castration, and 20 animals were sham operated. The castrated rabbits were randomized to 500 mg oral dehydroepiandrosterone (DHEA) daily, 80 mg oral testosterone undecanoate (TU) daily, or 25-mg intramuscular injection of testosterone enanthate (TE) twice weekly, whereas the fourth castrated group (placebo) and the sham-operated rabbits did not receive any hormones. All animals were fed a cholesterol-rich diet during the 30-week treatment period. Average serum lipids and atherogenic lipoproteins were higher in the placebo group than in the other groups (ANOVA, P<0.0001). Aortic atherosclerosis, as evaluated by the cholesterol content (nmol/mg protein), was also highest in the placebo group (308+/-39) and lowest in the TE group (61+/-12), but was intermediate in the DHEA (155+/-30), TU (191+/-43), and sham operation (162+/-29) groups (ANOVA, P<0.0001). ANCOVA indicated that the androgen effect on aortic atherosclerosis was only in part explained by the changes in lipoproteins. Aortic estrogen receptor contents were significantly lower in the androgen-treated groups than in the control groups, whereas there was no difference in aortic androgen receptor contents between groups. Natural androgens inhibit aortic atherosclerosis in castrated male rabbits only partly through a lipid-mediated effect. (+info)
The effect of chronic treatment with GH on gonadal function in men with isolated GH deficiency.
Eleven adult males, previously submitted to neurosurgery because of a pituitary lesion (three with craniopharyngioma, three with clinically non-functioning adenoma and five with macroprolactinoma) were treated with recombinant GH for 12 months after the diagnosis of GH deficiency was made. Circulating FSH, LH, prolactin, testosterone, 17 beta-estradiol (E2), dehyroepiandrosterone (DHEA-S), androstenedione. 17-OH-progesterone (17OHP), IFG-I, and steroid hormone-binding protein (SHBG) levels were assayed before and after CG test at study entry and 6 and 12 months after GH treatment. A significant increase in plasma IGF-I levels was obtained after 6 and 12 months of GH treatment. In addition, CG-stimulated, but not baseline, testosterone levels showed a significant increase after 6 and 12 months of GH treatment when compared with study entry (9.6 +/- 0.5 and 9.9 +/- 0.5 vs 7.9 +/- 0.5 ng/ml; P < 0.05). Baseline, but not CG-stimulated, serum 17OHP levels were significantly increased only after 12 months of GH treatment (1.7 +/- 0.1 vs 1.4 +/- 0.1 ng/ml; P < 0.05). No significant difference was found as far as both basal and CG-stimulated E2, androstenedione, DHEA-S and SHBG were concerned. With regards to the semen analysis, only seminal plasma volume was significantly increased after 12 months of GH treatment (2.9 +/- 0.3 vs 1.7 +/- 0.3 ml; P < 0.05). No significant change in sperm count, motility and abnormal forms was observed. These data show that GH treatment displays a clear-cut effect upon Leydig cell function and increases the production of seminal plasma volume in fertile adult males with isolated GH deficiency. (+info)
Androstenediol and dehydroepiandrosterone protect mice against lethal bacterial infections and lipopolysaccharide toxicity.
The protective effects of the hormones androstenediol (androstene-3beta, 17beta,-diol; AED) and dehydroepiandrosterone (5-androsten-3beta-ol-17-one; DHEA) on the pathophysiology of two lethal bacterial infections and endotoxin shock were examined. The infections included a gram-positive organism (Enterococcus faecalis) and a gram-negative organism (Pseudomonas aeruginosa). Both hormones protected mice from the lethal bacterial infections and from lipopolysaccharide (LPS) challenge. Treatment of animals lethally infected with P. aeruginosa with DHEA resulted in a 43% protection whereas treatment with AED gave a 67% protection. Both hormones also protected completely animals infected with an LD50 dose of E. faecalis. Similarly, the 88% mortality rate seen in LPS challenge was reduced to 17% and 8.5%, by treatment with DHEA and AED, respectively. The protective influences of both steroids were shown not to be directly antibacterial, but primarily an indirect antitoxin reaction. DHEA appears to mediate its protective effect by a mechanism that blocks the toxin-induced production of pathophysiological levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1. AED usually had greater protective effects than DHEA; however, the AED effect was independent of TNF-alpha suppression, both in vivo and in vitro. The data suggest that both DHEA and AED may have a role in the neuro-endocrine regulation of antibacterial immune resistance. (+info)
Prevention of immune dysfunction and vitamin E loss by dehydroepiandrosterone and melatonin supplementation during murine retrovirus infection.
Female C57BL/6 mice infected with the LP-BM5 leukaemia retrovirus developed murine acquired immune-deficiency syndrome (AIDS). Dehydroepiandrosterone (DHEA) and melatonin (MLT) modify immune dysfunction and prevent lipid peroxidation. We investigated whether DHEA and MLT could prevent immune dysfunction, excessive lipid peroxidation, and tissue vitamin E loss induced by retrovirus infection. Retrovirus infection inhibited the release of T helper 1 (Th1) cytokines, stimulated secretion of Th2 cytokines, increased hepatic lipid peroxidation, and induced vitamin E deficiency. Treatment with DHEA or MLT alone, as well as together, largely prevented the reduction of B- and T-cell proliferation as well as of Th1 cytokine secretion caused by retrovirus infection. Supplementation also suppressed the elevated production of Th2 cytokines stimulated by retrovirus infection. DHEA and MLT simultaneously reduced hepatic lipid peroxidation and prevented vitamin E loss. The use of DHEA plus MLT was more effective in preventing retrovirus-induced immune dysfunction than either DHEA or MLT alone. These results suggest that supplementation with DHEA and MLT may prevent cytokine dysregulation, lipid oxidation and tissue vitamin E loss induced by retrovirus infection. Similarly, hormone supplementation also modified immune function and increased tissue vitamin E levels in uninfected mice. (+info)