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Biomedical subjects

P M Driver

Publications and source records attributed to P M Driver.

16 recordsLinked to original sources
PubMed2003

Characterization of human trophoblast as a mineralocorticoid target tissue.

In mineralocorticoid target tissues, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) confers mineralocorticoid receptor selectivity by metabolizing hormonally active cortisol to inactive cortisone, allowing aldosterone access to the receptor. This enzyme is also expressed in high abundance in fetal tissues, particularly in placental trophoblast, where a role has been proposed in regulating fetal growth and development by protecting the fetus from maternal hypercortisolaemia and modulating local glucocorticoid receptor (GR), rather than mineralocorticoid receptor-mediated responses. As such the placenta has not been considered a mineralocorticoid target tissue. We have used conventional RT-PCR and real-time quantitative RT-PCR to demonstrate that primary cultures of term human cytotrophoblast express the mineralocorticoid-responsive genes Na/K-ATPase (alpha1 and beta1 subunits), epithelial sodium channel (ENaC, alpha and gamma subunits) and the serum and glucocorticoid-inducible kinase (SGK). SGK expression was found to be rapidly and strongly induced by corticosteroids (24- and 38-fold by 10(-7) mol/l aldosterone and 10(-7) mol/l dexamethasone respectively after 1 h). Dexamethasone-, but not aldosterone-stimulated SGK induction was inhibited by GR antagonist (RU38486), confirming the presence of a functional mineralocorticoid receptor and suggesting that placental trophoblast expresses a functional mineralocorticoid receptor, which is in part responsible for the corticosteroid regulation of SGK expression. Placental 11beta-HSD2 may protect the MR in a fashion analogous to classical mineralocorticoid tissues to modulate trophoblast sodium transport.

Adult↗
PubMed2003

Placental iodothyronine deiodinase expression in normal and growth-restricted human pregnancies.

We have described the expression of specific iodothyronine deiodinase mRNAs (using quantitative RT-PCR) and activities in normal human placentas throughout gestation and compared our findings to those in placentas from pregnancies affected by intrauterine growth restriction (IUGR). The predominant deiodinase expressed in placenta was type III (D3); type II (D2) was also present. In general terms, the activities of the enzymes D2 and D3 (and mRNAs encoding these enzymes) were higher earlier in gestation (<28 wk) than at term and displayed an inverse relationship with the duration of gestation (P < 0.05). Comparison of the relative expressions of mRNAs encoding D2 and D3 as well as their activities in placentas associated with IUGR (early and late gestational groups) with findings from normal placentas of similar gestational ages revealed no significant differences. Immunolocalization of D2 and D3 in syncytiotrophoblast (including syncytial sprouts) and cytotrophoblast of human placentas was demonstrated at both early and late gestation. Treatment of primary cultures of term cytotrophoblast cells in vitro with increasing doses of T(3) (1, 10, and 100 nM) resulted in increased expression of mRNAs encoding both D2 and D3 at 100-nM concentrations (P < 0.01) compared with control. Experiments with JEG-3 choriocarcinoma cells demonstrated a similar effect on D3 mRNA at 10 and 100 nM T(3) (P < 0.01). The demonstrated changes in iodothyronine deiodinase expression in the placenta across pregnancy are likely to contribute to regulation of the thyroid hormone supply to the developing fetus. The lack of difference in deiodinase expression in normal placentas and those found in IUGR argues against placental deiodinases being responsible for the hypothyroxemia in circulating fetal thyroid hormones observed in this condition.

Adult↗
PubMed2001

Synergistic growth inhibition of prostate cancer cells by 1 alpha,25 Dihydroxyvitamin D(3) and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A.

Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1 alpha,25 Dihydroxyvitamin D(3) (1 alpha,25(OH)(2)D(3)) in regulating the growth and differentiation of the normal prostate gland yet prostate cancer cells appear significantly less sensitive to this action. Vitamin D(3) receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative effects of 1 alpha,25(OH)(2)D(3) and therefore it is unclear why prostate cancer cell lines are significantly less sensitive to this action. We hypothesized that the antiproliferative responses of prostate cancer cells to 1 alpha,25(OH)(2)D(3) are suppressed by a process involving histone deacetylation. Sodium butyrate (NaB) and trichostatin A (TSA) are inhibitors of histone deacetylase (HDAC) activity. Low doses of NaB or TSA (300 microM and 15 nM respectively), which alone were relatively inactive, synergized with 1 alpha,25(OH)(2)D(3) in liquid and semi-solid agar to inhibit the growth of LNCaP, PC-3 and DU-145 prostate cancer cells. Still greater synergy was observed between vitamin D(3) hexafluoride analogs and either NaB or TSA. The mechanism appeared to involve neither the cyclin-dependent kinase inhibitor, p21((waf1/cip1)) nor cell cycle arrest, but rather induction of apoptosis. These data suggest that cells dysregulate the normal pro-apoptotic signals of 1 alpha,25(OH)(2)D(3) during prostate cancer development by a mechanism involving histone deacetylation. Combination therapy with potent vitamin D(3) analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgen-dependent and independent prostate cancer.

Antineoplastic Agents↗
PubMed2001

Expression of 11 beta-hydroxysteroid dehydrogenase isozymes and corticosteroid hormone receptors in primary cultures of human trophoblast and placental bed biopsies.

Interconversion of active and inactive glucocorticoids, e.g. cortisol (F) and cortisone (E) is catalysed by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) which exists as two isoforms. We have used human placental bed biopsies and an in-vitro cytotrophoblast cell culture system to examine the expression and activity of the 11 beta-HSD isoforms along with that of the glucocorticoid and mineralocorticoid receptors (GR and MR). Immunohistochemistry localized 11 beta-HSD1 to decidualized stromal cells and 11 beta-HSD2 to villous cytotrophoblast, syncytiotrophoblasts and trophoblast cells invading the placental bed and maternal vasculature. In primary cultures of human cytotrophoblast, 11 beta-HSD2, GR and MR mRNA were expressed. Low levels of 11 beta-HSD1 mRNA were noted in these cultured cells, but could be explained on the basis of contaminating, vimentin-positive decidual stromal cells (< or =5%). Enzyme activity studies confirmed the presence of a high-affinity, NAD-dependent dehydrogenase activity (K(m) 137 nmol/l and V(max) 128 pmol E/h/mg protein), indicative of the 11 beta-HSD2 isoform. No reductase activity was observed. The presence of functional MR and GR was determined using Scatchard analyses of dexamethasone and aldosterone binding (MR K(d) 1.4 nmol/l B(max) 3.0; GR K(d) 6.6 nmol/l B(max) 16.2 fmol/ng protein). The expression of 11 beta-HSD1 in maternal decidua and 11 beta-HSD2 in adjacent trophoblast suggests an important role for glucocorticoids in determining trophoblast invasion. The presence of the MR within trophoblast indicates that some of the effects of cortisol could be MR- rather than GR-mediated.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed1981

Episodic growth hormone secretion in sheep in relation to time of feeding, spontaneous meals and short term fasting.

1. Blood samples were taken every 20 min (for at least 28 hr) from five castrate male and two anoestrus female and libitum fed sheep. Analysis for plasma growth hormone (GH) showed that two of the males, on two occasions, had regular, although individually specific, patterns of GH secretion (peaks 3.5-5 hr). The other animals all had irregular patterns of GH release. 2. Throughout the experiments, meal sizes and frequency were recorded and it was found that out of eighty spontaneous meals of at least 50 g, 57 (71%) occurred in the hour after GH peaks, which accounted for 50% of the total time. Furthermore, on twenty out of twenty-four occasions GH levels were found to be falling before the 'expected' feeding time when fresh food was offered and the animals normally consumed a large meal. The removal of the food from three of the males for 10 hr during an experiment prompted an increase both in the size and frequency of the GH peaks. After re-feeding, GH levels immediately fell and remained low for 1-2 hr. 3. We believe that these results show an association between GH secretion and meal feeding in sheep, and that GH secretion quickly responds to fasting. As GH levels fell before, or in the early stages of meals, this indicates a neural reflex in the inhibition of GH before a meal.

Animals↗
PubMed1979

Hormones, feeding and temperature in sheep following cerebroventricular injections of neurotransmitters and carbachol.

1. The neural mechanisms involved in the control of prolactin and growth hormone secretion, body temperature and feeding in castrated male sheep were investigated by the lateral cerebroventricular injection of several putative neurotransmitters and carbachol. 2. Feeding was inhibited by 10 and 20 microgram carbachol and by 400 microgram histamine. 100 microgram Noradrenaline stimulated, but 200 microgram inhibited, feeding; however, both results were non-significant compared with controls. 3. 20 microgram Carbachol elicited a highly significant rise in plasma growth hormone, suggesting a cholinergic component in the neural control of growth hormone in sheep. Noradrenaline, dopamine and 5-hydroxytryptamine, but not melatonin, significantly depressed plasma prolactin concentration indicating a similar neural control for the hormone's release in sheep as in other species. 4. Deep body temperature appeared unaffected by any ofthe injected drugs. 5. The possible interrelationships between feeding behaviour and the circulating levels of growth hormone in ruminants is discussed. 6. A method for the radioimmunoassay of ovine growth hormone is described and validated.

Animals↗
PubMed1975

The effect of daylength and level of feeding on serum prolactin in growing lambs.

Twenty-four castrated male lambs initially maintained on a photoperiod of 12 h light:12 h dark were allocated to a factorial experiment with two daylengths (8 h L: 16 h D or 16 h L: 8 h D) and two levels of feeding (restricted or ad libitum). Blood samples were taken every 4 h for 24 h during the introductory period and after 24, 51 and 79 days of treatment. There were highly significant positive effects of daylength and level of feeding on serum prolactin: mean concentrations increased from a mean of 38 plus or minus 1 ng/ml during the introductory period until at day 79 they were: 8L: 16D (restricted diet), 81 ng/ml; (food ad libitum), 167 ng/ml; 16L:8D (restricted diet), 262 ng/ml; (food ad libitum), 262 ng/ml (S.E. of treatment mean plus or minus 4). Long daylength and feeding ad libitum also significantly increased growth rate.

Animals↗
PubMed1967

Erratic display as a device against predators.

Prey animals in many different taxonomic groups behave erratically when attacked by predators. This reaction is not accidental, but acts as a specific antipredator device. Observational data and theoretical considerations indicate that such protean displays function to confuse and disorient the predator and to increase its reaction time. Thus the survival of the prey is assisted, and the selective advntage whereby such erratic patterns of the prey animals may have evolved is created.

Aggression↗