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C A Powers

Publications and source records attributed to C A Powers.

At least 19 recordsLinked to original sources
PubMed2001

Estrogen and tamoxifen interplay with T(3) in male rats: pharmacologically distinct classes of estrogen responses affecting growth, bone, and lipid metabolism, and their relation to serum GH and IGF-I.

Estrogen (E) and T(3) regulate gene expression by receptor mechanisms that may enable hormonal interplay affecting growth and metabolism. Prior studies of E and tamoxifen (TM) interplay with T(3) in female rats identified a subset of E responses that required T(3) for expression and exhibited large agonist responses to TM. In contrast, TM acted more like an antagonist in most T(3)-independent E responses. This study used male rats to further explore the role of T(3) in E effects on growth and metabolism, and the relation of such effects to changes in serum GH and IGF-I. Orchidectomized, hypothyroid rats were treated 6 wk with vehicle, E2 benzoate (E2B), or TM with or without T(3). The following parameters were measured: body weight change; tibia length and bone mineral density; heart and kidney weight; food intake and body temperature; serum levels of glucose, cholesterol, triglycerides, GH, and IGF-I; seminal vesicle weight; and anterior pituitary levels of GH, PRL, glandular kallikrein, and total protein. Interplay with T(3) contributed to multiple E effects on growth and metabolism, and some E responses involved both T(3)-dependent and T(3)-independent components. Both E2B and TM increased serum GH, but the increases were poorly coupled to IGF-I. Correlation/regression analysis of individual rat data sets suggested distinct roles for GH and IGF-I in specific E effects. E2B and TM effects on somatic growth exhibited positive correlations with IGF-I and negative correlations with GH; effects on bone mineral density and triglycerides exhibited positive correlations with GH and negative correlations with IGF-I. Three pharmacologically distinct classes of in vivo E responses were identified in this study, and TM displayed a profile of biological activity that may be useful for men undergoing androgen-deprivation therapy.

Animals↗
PubMed1999

Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation.

The cloning, expression, and function of the murine (m) homologue of human (h) monocyte-derived chemokine (MDC) is reported here. Like hMDC, mMDC is able to elicit the chemotactic migration in vitro of activated lymphocytes and monocytes. Among activated lymphocytes, Th2 cells were induced to migrate most efficiently. mMDC mRNA and protein expression is modulated during the course of an allergic reaction in the lung. Neutralization of mMDC with specific Abs in a model of lung inflammation resulted in prevention of airway hyperreactivity and significant reduction of eosinophils in the lung interstitium but not in the airway lumen. These data suggest that mMDC is essential in the transit/retention of leukocytes in the lung tissue rather than in their extravasation from the blood vessel or during their transepithelial migration into the airways. These results also highlight the relevance of factors, such as mMDC, that regulate the migration and accumulation of leukocytes within the tissue during the development of the key physiological endpoint of asthma, airway hyperreactivity.

Amino Acid Sequence↗
PubMed1998

TLS (translocated-in-liposarcoma) is a high-affinity interactor for steroid, thyroid hormone, and retinoid receptors.

Nuclear receptors for steroid hormones, thyroid hormone, retinoids, and vitamin D are thought to mediate their transcriptional effects in concert with coregulator proteins that modulate receptor interactions with components of the basal transcription complex. In an effort to identify potential coregulators, receptor fusions with glutathione-S-transferase were used to isolate proteins in nuclear extracts capable of binding nuclear hormone receptors. Glutathione-S-transferase fusions with mouse retinoid X receptor-alpha enabled the selective isolation of a 65-kDa protein (p65) from nuclear extracts of rat and human cells. Binding of p65 to mouse retinoid X receptor-alpha was centered around the DNA-binding domain. p65 also bound regions encompassing the DNA-binding domain in estrogen, thyroid hormone, and glucocorticoid receptors. p65 was identified as TLS (translocated-in-liposarcoma), a recently identified member of the RNP family of nuclear RNA-binding proteins whose members are thought to function in RNA processing. The N-terminal half of TLS bound to thyroid hormone receptor with high affinity while the receptor was bound to appropriate DNA target sites. Functional studies indicated that the N-terminal half of TLS can interact with thyroid hormone receptor in vivo. TLS was originally discovered as part of a fusion protein arising from a chromosomal translocation causing human myxoid liposarcomas. TLS contains a potent transactivation domain whose translocation-induced fusion with a DNA-binding protein (CHOP) yields a powerful transforming oncogene and transcription factor. The transactivation and RNA-binding properties of TLS and the nature of its interaction with nuclear receptors suggest a novel role in nuclear receptor function.

Animals↗
PubMed1998

Comparison of tamoxifen effects on the actions of triiodothyronine or growth hormone in the ovariectomized-hypothyroid rat.

Recent studies have suggested that a subset of estrogen responses arise via modulation of triiodothyronine (T3) actions, and depend on T3 for expression: other estrogen responses are not T3-dependent. Moreover, tamoxifen acts as a full estrogen agonist in T3-dependent responses but behaves as an antiestrogen in T3-independent responses. T3 directly induces a variety of metabolic enzymes and proteins, and also induces rat growth hormone (GH). Thus, some T3-dependent tamoxifen effects might reflect modulation of GH rather than T3 actions. To address this issue, tamoxifen effects on somatotropic and metabolic actions of T3 and GH were compared in ovariectomized rats with methimazole-induced hypothyroidism. Rats were given T3 (10 micrograms/kg/day) or ovine GH (2 mg/kg/day) with or without tamoxifen (0.5 mg/kg/day) for 30 days. GH was poorly effective in producing a sustained increase in somatic growth in hypothyroid rats compared to T3; nonetheless, GH effects to increase body weight, tibia length and serum insulin-like growth factor I while decreasing fat mass and evoking small increases in body temperature were not inhibited by tamoxifen. Tamoxifen also did not inhibit GH trends to increase tibia bone mineral density. T3 increased body temperature, insulin-like growth factor I levels and all measures of somatic growth and, unlike GH, increased food intake and tended to decrease tibia bone mineral density. Tamoxifen inhibited the somatotropic actions of T3 (including increases in insulin-like growth factor I levels), and produced significant increases in tibia bone mineral density only in T3-treated rats. Tamoxifen had no effect on T3 actions to increase food intake or body temperature. T3 alone increased fat mass and exhibited a tendency to decrease serum triglycerides: tamoxifen had no effect on these parameters in the absence of T3. However, coadministration of tamoxifen with T3 produced a marked decrease in fat mass and increased serum triglycerides. GH had no effect on serum triglycerides in either the presence or absence of tamoxifen. Serum glucose levels appeared normal in all groups. The data indicate that multiple tamoxifen effects on growth and metabolism may reflect modulation of T3 rather than GH actions.

Animals↗
PubMed1997

Tamoxifen and ICI 182,780 interactions with thyroid hormone in the ovariectomized-thyroidectomized rat.

Studies of estradiol and tamoxifen actions to modulate the actions of thyroid hormone (triiodothyronine, T3) in the rat have shown that a subset of estrogen responses require T3 for expression. Also, tamoxifen acts as a partial agonist in estrogen responses that are T3 independent, but acts as a full estrogen agonist in T3-dependent responses. This study examined whether the differing behavior of tamoxifen (a triphenylethylene antiestrogen) in T3-independent and T3-dependent estrogen responses would be shared with ICI 182,780, a steroidal antiestrogen. An ovariectomized-thyroidectomized rat model was used. Drug vehicle, tamoxifen alone (0.4 mg/kg), ICI 182,780 alone (2 mg/kg) or tamoxifen plus ICI 182,780 were given for 3 weeks to ovariectomized-thyroidectomized rats with or without T3 replacement (10 microg/kg). T3-independent estrogen responses measured were the induction of uterine growth and induction of pituitary growth hormone (GH) in the absence of T3. T3-dependent estrogen responses measured were antagonism of T3-evoked increases in pituitary GH, body weight, tibia length and hepatic malic enzyme, and increases in serum triglycerides. Tamoxifen acted as a partial agonist in T3-independent estrogen responses, whereas ICI 182,780 acted as a potent pure antagonist in such responses; it lacked agonist efficacy and totally blocked tamoxifen effects. In T3-dependent estrogen responses, tamoxifen acted as a full estrogen agonist. ICI 182,780 acted as a weak agonist in some T3-dependent responses and lacked agonist efficacy in others. Moreover, ICI 182,780 had poor efficacy in blocking tamoxifen actions in T3-dependent responses. The results indicate that ICI 182,780, like tamoxifen, displays a duality in its pharmacological behavior which pivots on the T3 dependence of the estrogen response.

Animals↗
PubMed1996

Essential fatty acid deficiency and predisposition to lung disease in cystic fibrosis.

UNLABELLED: Essential fatty acid (EFA) deficiency is a predisposing factor for pulmonary infection with Staphylococcus aureus and Pseudomonas aeruginosa, the two major pathogenic microorganisms in cystic fibrosis (CF). OBJECTIVE: The goal of this study was to investigate the essential fatty acid status of CF patients from infancy to 20 years old. MATERIALS AND METHODS: Plasma fatty acid profiles for phospholipid (PL) were determined for cord (n = 6), 4 months (n = 40), 16 months (n = 25), 3 y (n = 8), 5-10 y (n = 10), and 10-20 y (n = 10) aged CF patients and compared to their respective control; cord (n = 22), 1-36 months (n = 38) and adult (n = 100). Significance was established by Student's t-test (p < 0.05). RESULTS: The plasma PL fatty acid profile for all CF patients, except cord, revealed consistent deficiency in omega 3 and omega 6 EFAs. These deficiencies were most marked at infancy and more pronounced for patients with meconium ileus. CONCLUSIONS AND RELEVANCE: EFA deficiency may contribute to the predisposition of CF infants to develop respiratory disease and to the excess cytotoxic activity found in bronchoalveolar lavage fluid at 2 months of age in the majority of screened infants.

Adult↗
PubMed1996

Lack of antidiuretic activity of lanreotide in the diabetes insipidus rat.

Lanreotide is a somatostatin analog which possesses antidiuretic activity in the rat. To determine whether vasopressin participates in the antidiuretic response to lanreotide, experiments were performed with diabetes insipidus (DI) rates homozygous for vasopressin deficiency. Lanreotide significantly increased urine osmolality and decreased urine volume and free water clearance during the 2-h period after injecting 400 microgram/kg s.c. in 12 awake Wistar-Kyoto rats that were undergoing water diuresis. Although lanreotide decreased serum growth hormone levels (24.2 +/- 6.1 vs. 0.9 +/- 0.1 ng/ml, P < .01), administration of recombinant human growth hormone (1 mg/kg s.c.) did not affect the renal response. Lanreotide (200 microgram/kg s.c.) also significantly increased urine osmolality and free water reabsorption and tended to decrease urine volume in 15 water-loaded Long-Evans rats. In contrast, lanreotide (200 or 400 microgram/kg s.c.) did not affect urine osmolality, urine volume or free water clearance when administered acutely or chronically to DI rats. These results suggest that vasopressin plays a role in the renal response to lanreotide in the rat

Animals↗
PubMed1995

Estradiol and tamoxifen interactions with thyroid hormone in the ovariectomized-thyroidectomized rat.

Receptors for estrogens and thyroid hormone (T3) have related DNA-binding domains that interact with closely related DNA target sequences which enable transcriptional control. In vitro molecular studies have raised the possibility that estrogen and T3 receptors may compete for binding to certain DNA target sites (cross-talk). However, there have been no physiological studies evaluating the abilities of estrogens or T3 to mimic or inhibit each other in vivo in a manner consistent with a mechanism involving receptor cross-talk. To address this issue, the effects of estradiol, tamoxifen (an antiestrogen), and T3 were studied in an ovariectomized-thyroidectomized rat model designed to minimize hormone interplay occurring via neuroendocrine or pharmacokinetic mechanisms. The T3 responses examined included induction of GH, somatic growth, and hepatic malic enzyme, and suppression of TSH secretion. The estrogen responses examined included induction of pituitary kallikrein, PRL, and uterine weight; increases in serum triglycerides; and suppression of LH secretion. Estradiol and tamoxifen acted as partial T3 agonists on GH induction, with agonist or antagonist effects depending upon T3's presence. Estradiol and tamoxifen acted as pure T3 antagonists on T3 induction of somatic growth and malic enzyme. Similarly, estradiol blocked T3-evoked decreases in bone mineral density and had no effect on bone in T3's absence. In contrast, estradiol or tamoxifen did not alter T3 feedback inhibition of TSH release or T3 induction of PRL. T3 partially mimicked estrogen actions to suppress LH, but did not mimic or inhibit other estrogen responses. Interestingly, the effect of estradiol and tamoxifen to increase serum triglycerides was totally T3 dependent even though T3 tended to decrease triglyceride levels. The results indicate that physiological effects of estrogens on GH, somatic growth, bone, malic enzyme, and serum triglycerides exhibit properties suggestive of a mechanism involving cross-talk with T3 receptors. Tamoxifen fully mimicked the effects of estradiol arising by an apparent antagonism of T3 actions, but acted as an antiestrogen in other responses.

Animals↗
PubMed1993

Cellular mechanisms of estrogen- and dopamine-induced control of glandular kallikrein in the anterior pituitary of the rat.

Glandular kallikrein (GK, a trypsin-like serine protease) exhibits estrogen induction and dopamine repression in rat pituitary lactotrophs. Steroid induction may reflect primary actions to increase selectively the synthesis of specific proteins, or may be part of broad cellular responses secondary to steroid-induced phenotype transitions. This study examined the cellular mechanisms underlying estrogen and dopaminergic control of lactotroph GK using a quantified immunocytochemical approach. Pituitaries from ovariectomized rats exhibited little GK staining. Estradiol treatment for 10 days produced dose-dependent increases in pituitary mass, the percentage of lactotrophs (indicating lactotroph proliferation) and the percentage of GK-positive cells. Also, GK staining intensity was dependent upon estradiol dose, increasing 4-fold between 5 micrograms and 50 micrograms/48 h. Dopamine receptor blockade with haloperidol (2.5 mg/kg/24 h) elicited weak GK immunostaining in 46% of the lactotrophs in the absence of estradiol, and markedly potentiated GK staining intensity elicited with low but not high doses of estradiol. The results suggest that GK induction is a primary estrogen effect, and is not secondary to a phenotype transition: the induction is enhanced by estrogen-induced lactotroph proliferation. Dopaminergic systems strongly inhibit GK induction by low estradiol levels. This dopaminergic modulation may shift the induction of lactotroph GK to physiological events associated with high estradiol levels or low dopaminergic tone.

Animals↗
PubMed1993

Carnitine metabolites in infants with cystic fibrosis: a prospective study.

Acylcarnitine is low in cord blood in patients with cystic fibrosis, suggesting that fatty acid metabolism is disturbed in utero. Carnitine metabolites (total, free, short- and long-chain acylcarnitine) were measured prospectively in 23 newly diagnosed infants with cystic fibrosis treated with a carnitine-containing, predigested formula for 6-12 months. Total (p < 0.002), free (p < 0.004), and long-chain (p < 0.001) plasma concentrations of carnitines were significantly less than controls (n = 48) at diagnosis. Total and free concentrations were corrected with nutritional management, whereas short- and long-chain acylcarnitines remained unchanged. By three years of age all plasma concentrations of carnitine metabolites were significantly less than controls despite a carnitine-containing diet. Urinary carnitine metabolites were increased at diagnosis and follow-up. The physiological significance of these observations in cystic fibrosis is unknown, but could be compatible with disturbed regulatory control with resultant increased utilization.

Acetylcarnitine↗
PubMed1993

Characterization of cysteamine induction of the 22K prolactin variant in the rat pituitary.

Glandular kallikrein (GK) is an estrogen-induced and dopamine-repressed lactotroph protease postulated to play a role in the processing of prolactin (PRL) to novel hormonal forms. Recent studies have shown that GK can process PRL in vitro from a 25K form to a 22K form in the presence of thiols--which appear to transform PRL into conformations (folding states) that are GK substrates. We and others have reported 22K PRL variants in the rat pituitary which can be increased by the administration of cysteamine (CSH), a biological thiol known to alter PRL conformation in vitro and in vivo. The present study further characterized CSH induction of the 22K PRL variant. Estrogen-primed rats were used in dose-response and time-course studies with CSH. CSH effects on 22K PRL levels were studied by Western blot analysis of reduced pituitary extracts (disulfides reduced with dithiothreitol before electrophoresis). Changes in PRL conformation were studied by Western blot analysis of nonreduced samples (thiols and disulfides trapped with iodoacetamide). CSH increased 22K PRL in a dose-dependent manner that was well correlated with the dose-response curve for changes in PRL conformation. CSH at 300 mg/kg produced 10- to 15-fold increases in pituitary levels of 22K PRL. In the time course study, 22K PRL levels peaked within 2 h, plateaued between 2 and 16 h, and approached control levels by 24 h after CSH dosing. CSH-elicited changes in PRL conformation peaked within 1 h, plateaued between 2 and 8 h, and reached control levels within 16 h of CSH dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

The 22K variant of rat prolactin: evidence for identity to prolactin-(1-173), storage in secretory granules, and regulated release.

Western blot analyses of the rat pituitary have detected a 22K PRL variant distinct from intact PRL (25K). We recently reported that glandular kallikrein (GK), an estrogen-induced lactotroph protease, can process PRL in vitro from a 25K form to a 22K form in a thiol-dependent cleavage at Arg174-Arg175 to remove 23 amino acids. We also detected an estrogen- and thiol-induced 22K PRL variant in the rat pituitary comigrating with a PRL product generated by in vitro processing with GK and carboxypeptidase-B. This study addressed whether the in vivo 22K PRL variant originates through a GK-like cleavage and is a regulated secretory product of the rat pituitary. A polyclonal antipeptide antiserum was raised against a synthetic peptide [PRL-(163-173)] representing the new C-terminus after GK and carboxypeptidase-B processing. In slot and Western blots, this antiserum (CT-antiserum) specifically recognized PRL processed in vitro by GK and carboxypeptidase-B and did not recognize intact PRL or PRL cleaved by GK alone. Western blot analysis of rat pituitary extracts with CT-antiserum specifically detected an estrogen- and thiol-induced 22K band that comigrated with a PRL product generated by in vitro processing with GK and carboxypeptidase-B. This 22K band was concentrated in subcellular fractions of the pituitary enriched in secretory granules. During short term incubations in medium 199, pituitaries from normal adult female rats released substantial amounts of 22K PRL; in contrast, male pituitaries did not release detectable 22K PRL. The release of 22K PRL from female pituitaries was powerfully blocked by bromocriptine, a dopaminergic agonist. GK was also released from pituitaries of female, but not male, rats, and GK release was inhibited by bromocriptine. The results identify the 22K PRL variant as PRL-(1-173), which is consistent with GK-like processing at Arg174-Arg175, followed by carboxypeptidase-B-like processing. The results also show that 22K PRL is a natural female-specific secretory product of the rat pituitary under inhibitory dopaminergic control.

Amino Acid Sequence↗
PubMed1992

Hormonal regulation of pituitary glandular kallikrein: a morphometric study.

We have previously identified the lactotrophs as the Glandular Kallikrein (GK) containing cells in the rat anterior pituitary using immunocytochemistry, this localization has been independently confirmed with similar methods by other groups. The purpose of the present work was to evaluate the estrogen and dopaminergic control of the GK-containing cells using a morphometric analysis. Female (200-250 g) ovariectomized rats (n = 40) were treated with estradiol (5, 10, 50 micrograms/rat) in the presence or absence of haloperidol (2.5 mg/Kg). The pituitaries were fixed by perfusion with Bouin's and immunostained for prolactin (PRL) or GK. The number of cells and the intensity of the staining were determined by morphometric analysis. Little GK staining was observed in pituitaries from ovariectomized rats, whereas estradiol treatment produced a marked increase in GK staining; GK-positive lactotrophs increased from 4% in control to 75% with 5 micrograms of estradiol, higher doses produced little further increase. However, GK staining intensity in lactotrophs was markedly dependent upon estradiol dose increasing 4-fold between 5 micrograms and 50 micrograms. Haloperidol (2.5 mg/Kg) elicited weak GK staining in 46% of the lactotrophs in the absence of estradiol, and potentiated GK staining intensity elicited with low doses of estradiol. Estradiol also produced a dose-dependent increase in pituitary mass and % lactotrophs indicating lactotroph proliferation. Estradiol produced a dose dependent increase in pituitary wet weight, % PRL-positive cells and % GK-positive cells. Pituitary weight was correlated with % lactotrophs (r = 0.992), and % GK cells (r = 0.874), and % lactotrophs was correlated with % GK cells (r = 0.978).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Biological thiols elicit prolactin proteolysis by glandular kallikrein and permit regulation by biochemical pathways linked to redox control.

Rat glandular kallikrein (GK), a trypsin-like serine protease, cleaves rat prolactin (PRL) in vitro to novel forms detectable in vivo and likely to be of physiological significance. PRL proteolysis by GK is thiol-dependent, with thiols acting upon PRL to refold the molecule into novel conformations that are GK substrates. This study compared several natural and synthetic thiols for their ability to elicit PRL proteolysis by GK. Rat PRL was incubated with rat GK in the presence of various thiols and 0.5% Triton X-100, which enhances thiol-elicited proteolysis. Cleavage was analyzed by gel electrophoresis under reducing and nonreducing conditions. In the presence of Triton X-100, all low molecular weight thiols elicited PRL cleavage by GK. The order of potency was dithiothreitol greater than mercaptoethanol greater than lipoic acid greater than cysteamine = glutathione (GSH) = coenzyme A greater than cysteine. In the absence of Triton, however, dithiothreitol, coenzyme A, and mercaptoethanol were most effective in eliciting GK proteolysis. Triton X-100 enhanced PRL cleavage by 4-19-fold, depending upon the thiol used. Folding isomers of processed PRL observed following cleavage included disulfide-liked homodimers, oxidized monomers, reduced monomers and mixed disulfides; the folding isomers generated varied depending upon the thiol used. GSH potency in eliciting PRL proteolysis increased 10-fold in the presence of biochemical pathways shuttling reducing equivalents to GSH disulfide (GSSG). PRL cleavage by GK could be controlled by substrates, enzymes, and cofactors making up the reducing shuttle when GSSG was used. Thioredoxin (a protein disulfide oxidoreductase) potently elicited PRL proteolysis by GK in the presence of a reducing shuttle and Triton X-100.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Estrogen induction of growth hormone in the thyroidectomized rat.

GH production in the rat is almost completely dependent upon T3. Estrogens also stimulate GH in some rat models, and androgens have well documented stimulatory effects. This study examined estrogen and androgen effects on pituitary GH in rats with differing thyroid status. Diethylstilbesterol (DES; a potent synthetic estrogen, 5 mg Silastic implant), estradiol benzoate (50 micrograms/kg.48 h), or testosterone propionate (10 mg/kg.48 h) were administered for 3 weeks to ovariectomized rats that were either thyroid-intact or thyroid-ectomized. In intact rats, DES produced a 40% decrease in pituitary GH, whereas estradiol (at a lower relative dose) had no effect; testosterone produced a 65% increase in pituitary GH. Thyroidectomy decreased pituitary GH to less than 0.5% of intact values. DES and estradiol produced 50- to 70-fold increases in pituitary GH in thyroidectomized rats--reaching 23-36% of intact levels. In contrast, testosterone had no effect in thyroidectomized rats. Tamoxifen (an antiestrogen; 1 mg/kg.24 h) increased GH by 15-fold in thyroidectomized rats and completely blocked further GH induction by estradiol. T3 (20 micrograms/kg.24 h) increased pituitary GH levels by 200-fold in thyroidectomized rats--totally reversing the decrease produced by thyroidectomy; tamoxifen inhibited GH induction by T3 by 63%. The results indicate that estrogens powerfully induce pituitary GH in thyroidectomized but not intact rats through an estrogen receptor-mediated process. The DNA-binding domains of estrogen and T3 receptors, as well as their hormone response elements, share structural similarities. The present results are consistent with the hypothesis that estrogens and estrogen receptors may induce GH through unoccupied T3 response elements of the GH gene in thyroidectomized rats.

Animals↗