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Query: UNIPROT:P06889 (Mol)
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The movement of testosterone (T) from blood across the blood-brain barrier (BBB) is thought to reflect the combined effects of T's lipid solubility and the presence of circulating binding proteins for T such as albumin or sex hormone binding globulin (SHBG). Since the adult rat lacks a circulating specific high affinity sex steroid binding protein, examination of the disappearance from serum and uptake into cerebrospinal fluid (CSF) of [3H]T before and after SHBG or albumin infusion should provide insight into the function of these two proteins with respect T transport. Three groups of adult male Sprague-Dawley rats were cannulated at the femoral vein and cisterna magna. In a control group (n = 8), [3H]T was given as an intravenous bolus beginning at time zero; multiple serum and CSF collections were assayed for counts per min (cpm) during the subsequent 45 min. Data from these animals were then compared to those seen in animals that received either purified human SHBG (hSHBG) (n = 7) or human albumin (hALB) (n = 6) 10 min prior to the [3H]T infusion. High performance liquid chromatography was used to monitor the metabolic fate of the steroid infusate at the end of each study period. Infusion of hSHBG increased serum concentrations from undetectable to 93.8 nM/l (mean +/- SEM, n = 6). Administration of hALB significantly increased (25.0 +/- 1.2 g/l at baseline, 33.4 +/- 1.6 g/l post-infusion, mean +/- SEM, P less than 0.03, n = 5) the circulating albumin concentration. Comparison of data from each group of animals demonstrated that (1) following an i.v. injection of radiolabeled T, the initial decline in serum [3H]T was significantly reduced (P less than 0.03) in the presence of hSHBG, (2) hALB did not affect the movement of [3H]T out of serum, (3) the time to peak appearance of [3H]T in the CSF was significantly delayed (P less than 0.02) by the presence of circulating hSHBG, and (4) the net quantity of [3H]T found in the cSF under steady-state conditions was not affected by serum SHBG or albumin levels. This study demonstrates that high-affinity steroid binding proteins do modulate the transport of sex steroids across the BBB. Specifically, SHBG delays the clearance of T from serum and slows the rate of T uptake into the CSF during non-equilibrium conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1992 Jul
PMID:The effects of sex hormone binding globulin (SHBG) on testosterone transport into the cerebrospinal fluid. 163 26

We have reported previously that fish oil rich in omega-3 fatty acids added to a butter-cholesterol atherogenic diet for swine resulted in marked retardation of the atherosclerotic process which many regard as largely an inflammatory response to injury by excessive lipids in the intima. In this report on the same swine we present serum levels of several eicosanoids derived from arachidonic acid via the cyclooxygenase and lipoxygenase pathways. The study involves six swine fed a high fat, high cholesterol diet (BT group) for 4 months, six swine fed the same diet but with 30 ml/day fish oil added (BT + FO), and five swine fed a low fat, low cholesterol mash diet (MA). The serum eicosanoids were measured by radioimmunoassay. Thromboxane B2 levels (ng/dl: means +/- SEM) were 543 +/- 49 for MA, 231 +/- 12 for BT, and 105 +/- 20 for BT + FO, and all differences were statistically highly significant, 6-Keto PGF1 alpha (a relatively stable prostacyclin metabolite) levels were 249 +/- 31 for MA, 184 +/- 12 for BT, and 101 +/- 10 for BT + FO, and all differences were significant. Leukotriene B4 levels at 4 months were 151 +/- 25 for MA, 112 +/- 11 for BT, and 84 +/- 11 for BT + FO. BT + FO was significantly different from both MA and BT, but BT was not significantly different from MA. Leukotriene C4 levels were not significantly different among the three groups. Of special interest was the effect of the BT diet without the FO additive in reducing several eicosanoid levels compared to MA values. The affected eicosanoid levels were reduced still further by the fish oil additive, indicating its ability to inhibit both the cyclooxygenase and the lipoxygenase pathways. The relation of the fish oil-induced inhibition to the observed retardation of atherogenesis is not as yet clear but there are several theoretical possibilities, including reduction in recruitment of monocytes and in proliferation of smooth muscle cells.
Exp Mol Pathol 1991 Aug
PMID:Reductions in serum thromboxane, prostacyclin, and leukotriene B4 levels in swine fed a fish oil supplement to an atherogenic diet. 165 49

Cells obtained from 6 adult human adrenals or adrenal fragments were cultured in serum-free synthetic medium (McCoy's) in order to study the isolated effects of IGF-I on steroidogenesis and its interactions with ACTH. After addition of peptide, changes in the activities of steroidogenic enzymes were assessed by measuring certain steroids in the spent medium. These included pregnenolone, 17-hydroxypregnenolone (17-OH-Preg), dehydroepiandrosterone (DHA), 17-hydroxyprogesterone (17-OH-P), androstenedione (AD), 11-deoxycortisol and glucocorticoids (chiefly cortisol and its immediate precursors, 11-deoxycortisol and 17-OH-P) and cortisol itself. The steroid responses obtained with repeated doses of IGF-I (40 ng/ml approximately 10(-9) M), added at 0, 48 and 72 h, over 4 days' culture were quite different from those obtained with repeated doses of ACTH (0.25 ng/ml approximately 10(-10) M). All the steroids measured increased with time of culture under the influence of ACTH and, apart from pregnenolone which peaked, tended to reach a plateau. With IGF-I, by contrast, DHA, AD, 11-deoxycortisol and glucocorticoid production increased initially, then decreased progressively, whereas pregnenolone, 17-OH-Preg and 17-OH-P production was either absent or negative. Cumulative steroid production over 4 days reached similar levels in response to a single dose of IGF-I and/or ACTH, with two major exceptions: pregnenolone dropped significantly with IGF-I [46% +/- 6 (SEM) as opposed to 93% +/- 11 with ACTH, P less than 0.005, n = 5], as did 17-OH-P (48% +/- 11 vs 113% +/- 8 with ACTH, P less than 0.001, n = 6). Increased formation of down-stream metabolites (DHA, AD, 11-deoxycortisol and glucocorticoids) would suggest that IGF-I induced stimulation of the 17 alpha-, 21- and 11 beta-hydroxylases. The responses to ACTH stimulation of cells which 4 days previously had been pre-treated with an initial and single dose of IGF-I and/or ACTH emphasized the impact of IGF-I on the 3-hydroxylation steps in cortisol biosynthesis. Compared with ACTH pre-treatment, the effects of which faded in the long term, pre-treatment with IGF-I resulted in a significantly increased steroidogenic response (P between less than 0.05 and less than 0.01). With the single exception of pregnenolone (43% +/- 4.7), production of all the metabolites was amplified: 17-OH-Preg: 348% +/- 88; DHA: 643% +/- 127; 17-OH-P: 193% +/- 36; AD: 725% +/- 200; 11-deoxycortisol: 573% +/- 110; cortisol: 1000%.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1991 Dec
PMID:Effects of insulin-like growth factor I (IGF-I) on enzymatic activity in human adrenocortical cells. Interactions with ACTH. 166 Nov 28

The tachykinins substance P (SP) and neurokinin A (NKA) were studied in human inferior turbinate nasal mucosa by radioimmunoassay, immunohistochemistry, and autoradiography and for their effect upon mucus release in an in vitro culture system in order to infer their potential functions in the upper respiratory tract. Similar amounts of SP (1.03 +/- 0.12 pmol/g wet weight; mean +/- SEM; n = 26) and NKA (0.76 +/- 0.23; n = 7) were found. NKA and SP immunoreactive nerve fibers were found in the walls of arterioles, venules, and sinusoids and as individual fibers in gland acini, near the basement membrane, and in the epithelium. [125I]SP bound to arterioles, venules, and glands. [125I]NKA bound only to arterioles. In short-term explant culture of fragments of human nasal mucosa, both 1 microM SP and 1 microM NKA stimulated release of [3H]glucosamine-labeled respiratory glycoconjugates. These results indicate that SP and NKA have similar distributions in nociceptive sensory nerves in human nasal mucosa. The distribution of [125I]SP binding sites is consistent with a role for SP as a vasodilator and mucous secretagogue. The presence of [125I] NKA binding sites on vessels suggests a primary role for NKA in regulating vasomotor tone.
Am J Respir Cell Mol Biol 1991 Mar
PMID:Substance P and neurokinin A in human nasal mucosa. 170 9

Nitrovasodilators increase both cyclic GMP and cyclic AMP in isolated platelets (Maurice DH, Haslam RJ. Mol Pharmacol 1990;37:671-81). To determine whether this occurs in blood, platelet cyclic[3H]GMP and cyclic [3H]AMP were measured in prelabeled rabbit platelets resuspended in modified Tyrode's solution or citrated blood. In the former medium, increases in cyclic [3H]nucleotides in response to nitroprusside (NP) and 3-morpholinosydnonimine (SIN-1) were maximal by 1 min; in blood, maximal increases were observed only after 10 min and were much smaller. In blood, SIN-1 was more effective than the same concentration of NP. After 10 min, 100 microM SIN-1 increased platelet cyclic[3H )GMP by 475 +/- 58% and cyclic[3H]AMP by 29 +/- 7% (means +/- SEM, 18 experiments). Supraadditive increases in platelet cyclic [3H]AMP in blood were observed when SIN-1 was combined with prostaglandin E1 (PGE1). Thus, after 10 min, SIN-1 (100 microM), PGE1 (20 nM), and SIN-1 + PGE1 increased cyclic[3H]AMP by 25 +/- 7, 35 +/- 6, and 130 +/- 17%, respectively (four experiments). In the same experiments, release of platelet [14C]serotonin by platelet-activating factor (PAF) was inhibited by 22 +/- 5, 2 +/- 2, and 61 +/- 5%, respectively. Increases in platelet cyclic[3H]GMP with SIN-1 were unaffected by PGE1. These results suggest that although cyclic GMP may mediate the effects of SIN-1 alone on platelet function, cyclic AMP mediates the synergistic action of SIN-1 and PGE1. M&B 22,948 (a selective cyclic GMP phosphodiesterase inhibitor) enhanced the increases in platelet cyclic[3H]GMP and cyclic[3H]AMP caused by SIN-1 and also increased the associated inhibition of [14C]serotonin release. M&B 22,948 also augmented the synergistic increases in cyclic[3H]AMP and inhibition of platelet function caused by SIN-1 + PGE1. The results show that a selected nitrovasodilator (e.g., SIN-1), a prostaglandin and a cyclic GMP phosphodiesterase inhibitor can exert synergistic effects on platelets in blood. This may be relevant to the pharmacologic management of thromboembolic disease.
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PMID:Effects of nitrovasodilators on platelet cyclic nucleotide levels in rabbit blood; role for cyclic AMP in synergistic inhibition of platelet function by SIN-1 and prostaglandin E1. 171 4

1. The neurons of the retina have electrical properties that are different from those of most of the other neurons of the central nervous system. To identify the voltage-gated ion channels found in the retina, we screened mouse retinal cDNA libraries with oligonucleotide probes homologous to the mammalian K+ channel MBK1 (Kv1.1) and ligated two partial clones to produce a full-length clone with no significant differences from MBK1. 2. Expression of MBK1 mRNA was determined by RNAse protection. MBK1 mRNA was detected in retinal RNA and was also detected in brain, liver, and heart RNAs. 3. We transcribed the full-length clone, injected it into oocytes of Xenopus laevis, and measured the membrane currents 2 to 6 days later. Depolarization from a holding voltage of -90mV induced a slowly activated outward current with a peak value as large as 20 microA. The current inactivated very slowly with a single exponential time course [mean time constant, 6.5 +/- 0.4 sec (SEM) for activation voltage of -10mV]. 4. The outward current was reduced to half-maximal by 0.42 mM tetraethylammonium, 1.1 mM 4-aminopyridine, and 3.2 mM Ba2+ but was not significantly attenuated by Co2+ (1 mM). 5. The reversal potential (measured with tail currents) changed by 53mV per decade change of [K+] from 1 to 77 mM. 6. The voltage for half-maximal activation of the conductance was -26.6mV (+/- 1.7mV), and the voltage required for an e-fold increase in conductance was 6.9mV (+/- 0.5mV). 7. Thus, the mRNA for MBK1 found in the mouse retina causes the expression of a voltage-dependent K+ current which has properties suitable for may retinal neurons.
Cell Mol Neurobiol 1991 Dec
PMID:The potassium channel MBK1 (Kv1.1) is expressed in the mouse retina. 172 58

Chronic pulmonary hypertension is associated with arterial structural remodeling. Insulin-like growth factor I (IGF-I) has been proposed as one of the mediators of vascular change because of its ability to stimulate proliferation in, and elastin production by, cultured vascular smooth muscle cells. We have shown previously that 12 days of continuous air embolization into the pulmonary arterial circulation of sheep results in the functional and structural changes of chronic pulmonary hypertension. In the present study, measurements of IGF-I (by radioimmunoassay) and IGF-I binding protein activity in sheep lung lymph and plasma were made before and during the 12 days of air embolization in six sheep. Two untreated animals served as controls. Baseline lung lymph contained 23.5 +/- 3.6 ng/ml (mean +/- SEM) of IGF-I, and there was a slight increase to 36.7 +/- 9.8 on day 3, but by day 6 levels were back to baseline. The flux of IGF-I from the lung (concentration times lymph flow) increased significantly by day 2 embolization and remained elevated through day 12 (baseline = 37.2 +/- 11.1 ng/15 min; day 2 = 237.7 +/- 55.8; day 5 = 190.2 +/- 53.4; day 6 = 82.6 +/- 21.9; day 12 = 78.7 +/- 12.5). IGF-I binding protein activity was also present in lung lymph at baseline (29.6 +/- 3.0%) and was unchanged during air embolization. Plasma levels of IGF-I and plasma binding protein activity remained at baseline throughout the 12 days of embolization (71.51 +/- 34.48 ng/ml and 36.4 +/- 3.5%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Jan
PMID:Insulin-like growth factor I and pulmonary hypertension induced by continuous air embolization in sheep. 172 99

In view of conflicting reports concerning the effect of macrophage activation on arachidonic acid metabolism, we examined the effect of the macrophage activator, interferon-gamma (IFN-gamma), on the 5-lipoxygenase pathway in rat lung macrophages. Rat lung macrophages were conditioned in the presence or absence of 10(2) U/ml IFN-gamma for 4 h before stimulation with 1 microM A23187 for 15 min or 100 micrograms/ml opsonized zymosan for 60 min at 37 degrees C as well as other stimuli. Lipoxygenase products in extracted cell supernatants were identified and analyzed by high-pressure liquid chromatography and ultraviolet spectroscopy. The predominant lipoxygenase products included leukotriene (LT) B4, LTC4, and 5-hydroxyeicosatetraenoic acid (5-HETE). These products were not qualitatively altered by conditioning with IFN-gamma. However, 5-lipoxygenase pathway activity, as measured by LTB4 release, was maximally increased 2-fold after conditioning with IFN-gamma and stimulating with either A23187 or opsonized zymosan. IFN-gamma-conditioned macrophages, stimulated with A23187, released greater quantities of lipoxygenase products in comparison with control cells (307.6 +/- 13.3 versus 167.6 +/- 3.9 pmol LTB4/10(6) cells) (mean +/- SEM) (P less than 0.05). Similar results were obtained with the less potent stimulus, opsonized zymosan. IFN-gamma had no direct stimulatory effect on the 5-lipoxygenase pathway. No effect was observed with a variety of other stimuli with or without IFN-gamma conditioning.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Jan
PMID:Effect of interferon-gamma on the 5-lipoxygenase pathway of rat lung macrophages. 172 2

Previous hemizona assay (HZA) results have illustrated a positive and significant correlation between the percentage of morphologically normal spermatozoa in the semen and the number of spermatozoa tightly bound to the zona pellucida. The present study was designed to evaluate the morphologic features using strict criteria of spermatozoa tightly bound to the zona pellucida. Semen samples of 4 normozoospermic and 11 teratozoospermic men were used to compare the percentage of normal spermatozoa in the semen with that found 1) after swim-up separation and 2) bound to the zona under HZA conditions. The mean (+/- SEM) % normal forms for normozoospermic men in semen, after swim-up and zona-bound spermatozoa were 21.5 +/- 1.6, 27.5 +/- 2.9, and 44.8 +/- 3.4, respectively. A significantly higher % of normal forms were found among zona-bound sperm compared to swim-up forms (p = 0.02) and seminal sperm (p = 0.02). The mean % of normal sperm forms present in semen, after swim-up and zona pellucida-binding for teratozoospermic men, were 3.7 +/- 0.9, 5.8 +/- 1.6 and 15.6 +/- 3.1, respectively. Significant differences existed between the % of normal sperm forms found in the swim-up and zona-bound spermatozoa (P = less than 0.01 and P = less than 0.0003, respectively) compared to the original ejaculates. Results indicate that a selective process against abnormal spermatozoa occurs at the site of the zona pellucida.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Reprod Dev 1991 Dec
PMID:Sperm selection capacity of the human zona pellucida. 175 Oct 39

Senescence in primary cultures of mammalian cells is characterised by cessation of growth after a number of cell divisions; this may be associated with loss of some differentiated functions. Recent studies on bovine adrenocortical cells have suggested that expression of simian virus-40 (SV40) early region in these cells may prevent phenotypic losses due to senescence. We report here data on growth and differentiated function of two human thyrocyte cell lines (SGHTL-34 and -45) generated by the transfection of primary thyrocytes with the plasmid pSV3neo which contains the SV40 early region. Growth was assessed by fluorometric DNA estimations and calculation of cell population doubling time; function was assessed by binding studies using 125I-bovine thyrotrophin (TSH) and measurement of cyclic adenosine 3',5'-monophosphate (cAMP) response to stimulation with TSH, forskolin and cholera toxin. After 3-12 months in stable culture there was a gradual increase in the doubling time of both cell lines over a 3-month period (SGHTL-34 cells, early 34.5 +/- 4.5 h, late 301 +/- 111.6 h; SGHTL-45 cells, early 53.4 +/- 4.4 h, late 148.3 +/- 26.3 h; mean +/- SEM). Scatchard analysis demonstrated a loss of the high affinity TSH receptor over the same time period. The increase in cAMP in response to 1000 microU/ml TSH declined until the cells became unresponsive (SGHTL-34 early, cAMP 10.3 +/- 0.7 pmol/well; late, cAMP -0.4 +/- 0.3 pmol/well; SGHTL-45 early, cAMP 11.3 +/- 1.1 pmol/well, late, cAMP 0.3 +/- 0.1 pmol/well). The cAMP responses to forskolin and cholera toxin were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1991 Dec
PMID:Effects of ageing on the growth and differentiated function of transfected human thyrocytes. 179 5


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