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PubMed1992

Histamine increases cytosolic Ca2+ in HL-60 promyelocytes predominantly via H2 receptors with an unique agonist/antagonist profile and induces functional differentiation.

Histamine H1 receptors mediate activation of phospholipase C, with subsequent increases in cytosolic Ca2+ concentration ([Ca2+]i), and H2 receptors mediate accumulation of cAMP. HL-60 promyelocytes possess H2 receptors, but it is not known whether these cells also possess H1 receptors. We studied the effects of histamine on [Ca2+]i and the functional importance of histamine receptors in HL-60 promyelocytes. In these cells, histamine and dimaprit increased [Ca2+]i with EC50 values of 15 microM and 30 microM, respectively. Diphenhydramine inhibited the effect of histamine (100 microM) on [Ca2+]i up to 40%, with an IC50 of 100 nM. Famotidine and cimetidine diminished the effect of histamine (100 microM) up to 75%, with IC50 values of 85 nM and 300 nM, respectively. Diphenhydramine plus famotidine abolished histamine-induced rises in [Ca2+]i. Impromidine, with an IC50 of 100 nM, abolished the effect of histamine (100 microM) on [Ca2+]i. Diphenhydramine, famotidine, cimetidine, and impromidine showed marked noncompetitive antagonism with histamine. Histamine-induced increases in [Ca2+]i were largely due to influx of Ca2+ from the extracellular space. Ca2+ influx was inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl)-1H-imida zole hydrochloride (SK&F 96365). Histamine activated phospholipase C. Histamine induced expression of formyl peptide receptors, which effect was abolished by famotidine. In U-937 promonocytes and in the human erythroleukemia cell lines HEL and K-562, histamine did not induce rises in [Ca2+]i. Our data suggest the following. (i) In HL-60 promyelocytes, histamine increases [Ca2+]i predominantly via H2 receptors and to a lesser extent via H1 receptors. (ii) The agonist/antagonist profile of the H2 receptor-mediated increases in [Ca2+]i differs markedly from that for cAMP accumulation, suggesting the involvement of different H2 receptor subtypes. (iii) In HL-60 promyelocytes, histamine activates nonselective cation channels and induces functional differentiation via H2 receptors.

Adenosine Triphosphate↗

PubMed2007

Morphological and functional differentiation in the lumbar spine of lorisids and galagids.

The striking contrast in positional behavior exhibited by lorisids (slow quadrupedalism/suspension) and galagids (leaping/quadrupedalism) is well reflected in their postcranial morphology, particularly in the limbs. Although they exhibit very different spinal postures and movements, vertebral adaptations have been less well explored in these taxa. This study addressed morphological and functional differentiation in the lumbar vertebrae of four species of lorisids and five species of galagids. Linear and angular measurements of lumbar vertebrae were compared among taxa using canonical variates analysis (CVA) in conjunction with pairwise comparisons among selected variables. The results were interpreted in the context of a broader comparative sample, including the addition of indriids to the CVA. Compared to galagids, lorisids have relatively shorter lumbar spinous processes that are more perpendicularly (to caudally) oriented relative to a coronal plane. Lorisids also have relatively wider laminae and more transversely oriented prezygapophyses. These features promote lumbar stability and reflect antipronogrady, multiplane spinal movements, and upside-down suspension. Within lorisids, vertebral body length and height vary with body size, reflecting the additional resistance to bending that is required for larger body sizes. Galagid lumbar shape is influenced by body size, but does not show strong variation in accordance with positional behavior differences as defined here. Galagids, indriids, and lorisids are distinct in lumbar morphology and function, but their similarities in lumbar length reduction are suggestive of antipronograde postures in the common ancestor of the galagids, including those who have shifted to a more quadrupedal locomotor repertoire.

Animals↗

PubMed1999

Regulation of functional differentiation of the placental villous syncytiotrophoblast by estrogen during primate pregnancy.

By using the baboon as an in vivo model for the study of the endocrinology of human pregnancy, studies in the authors' laboratories have shown that the primate placenta is an estrogen target tissue and that estrogen, via interaction with the estrogen receptor, regulates functional differentiation of the syncytiotrophoblast, which is manifest as an upregulation of key components of the progesterone biosynthetic pathway and the metabolism of corticosteroids critical to placental-fetal development. Thus, estrogen exerts specific stimulatory effects on the receptor-mediated uptake of low density lipoprotein by, and expression of, the P-450 cholesterol side-chain cleavage enzyme within the syncytiotrophoblast, thereby promoting the production of progesterone. Concomitantly, there is an estrogen-dependent developmental regulation of the 11beta-hydroxysteroid dehydrogenase enzyme system in the syncytiotrophoblast, which enhances transplacental oxidation of maternal cortisol to cortisone and leads to maturation of the fetal hypothalamic pituitary adrenocortical axis late in gestation. Consequently, estrogen has a central, integrative role in modulating the dialogue and signaling system operating between the placenta and fetus that results in the maintenance of pregnancy and the development of adrenocortical self-sufficiency that are essential for maturation of the fetus and neonatal survival after birth.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1995

Hydrocortisone and progesterone regulation of the proliferation, morphogenesis, and functional differentiation of normal rat mammary epithelial cells in three dimensional primary culture.

The mechanisms of action of, and resistance to, the steroidal regulators of normal mammary epithelial and breast cancer cell development are only partially understood. A major obstacle to research progress has been the difficulty in supporting physiologically relevant development of normal mammary epithelial cells (MEC) under defined serum-free conditions. A primary culture system was developed in our laboratory that permits nonfunctional rat MEC to undergo extensive proliferation, functional differentiation, as well as multilobular and lobuloductal branching alveolar morphogenesis. In the studies reported here, the contributions of hydrocortisone and progesterone during the coordinate induction of cellular proliferation, organoid morphogenesis, and functional capacity were assessed. Hydrocortisone (0.1-10 microgram/ml) induced alveolar and multilobular branching morphogenesis, suppressed lobuloductal branching morphogenesis, and enhanced casein accumulation. Hydrocortisone also played a role in maintaining alveolar as well as multilobular branching morphogenesis and casein levels. Progesterone (0.01-1 microgram/ml) induced cellular proliferation as well as multilobular and lobuloductal branching morphogenesis, and suppressed casein accumulation. At a supraphysiological concentration (10 micrograms/ml), progesterone inhibited cell growth, alveolar branching morphogenesis, and casein accumulation. MEC cultured without progesterone for up to 1 week retained the ability to respond when subsequently exposed to this steroid. Reversibility studies suggested that progesterone was required for the induction, but not the maintenance of the mitogenic, morphogenic, and lactogenic effects. This physiologically relevant primary culture system can be used to study the factors that regulate steroid responsiveness as well as the cross-talk between steroid and growth factor receptor signaling pathways in normal MEC and breast cancer cells.

Animals↗

PubMed1980

Induction of morphological and functional differentiation of human promyelocytic leukemia cells (HL-60) by componuds which induce differentiation of murine leukemia cells.

Various compounds active in promoting in vitro differentiation of certain murine leukemia cell lines (Friend erythroleukemia cells and mouse myeloid leukemia cells) were tested for their capacity to induce differentiation of HL-60 cells, a human promyelocytic leukemia cell line capable of terminally differentiating in vitro to functionally mature granulocytes. Polar planar compounds including hexamethylene bisacetamide (HMBA), certain purines (particularly hypoxanthine), and actinomycin-D induced morphological and functional (as assessed by the capacity to reduce NBT dye) differentiation of HL-60. In contrast, hemin, ouabain, prostaglandin E1, X-irradiation, dexamethasone and some other anti-leukemic chemotherapeutic agents induced little if any significant differentiation of HL-60 cells. These results, together with previous observations with murine leukemia cells, suggest that the human HL-60 cells share common cellular target sites for the inducing action of polar planar compounds, hypoxanthine and actinomycin-D with some murine leukemic cells. In contrast, hemin, ouabain and prostaglandin E1 may be specific for mouse erythroleukemia cells, while X-irradiation and chemotherapeutic agents induce differentiation of both types (erythroid and myeloid) of mouse leukemic cells, but have little effect on HL-60 cells.

Animals↗

PubMed1979

Simultaneous loss of multiple differentiated functions in aerial mycelium-negative isolates of streptomycetes.

Germination and outgrowth of spores of Streptomyces alboniger, Streptomyces scabies, and Streptomyces violaceus-ruber in the presence of intercalating dyes resulted in a high frequency (2 to 20%) of occurrence of aerial mycelium-negative (Amy-) isolates. Coincident with the appearance of the Amy- trait was the loss of several differentiated functions, including the characteristic pigments and earthy odor of the wild types. All S. alboniger, 27% of S. scabies, and 39% of the S. violaceus-ruber Amy- isolates were arginine auxotrophs. The missing enzyme step was identified as argininosuccinate synthetase by using a sensitive microassay for estimation of enzyme activity. The remainder of the S. scabies and S. violaceus-ruber isolates were prototrophs. In addition, S. alboniger Amy- isolates failed to produce or respond to the stimulator of aerial mycelium formation isolated from the wild type. The Amy- isolates did not revert to either Amy+ of Arg+. The lack of any detectable reversion, coupled with the high frequency of curing, supports the idea that a deletion of genetic material, possibly a plasmid, has occurred.

Acridine Orange↗

PubMed2000

Hepatocyte adhesion, growth and differentiated function on RGD-containing proteins.

There is currently much interest in designing synthetic substrates incorporating the cell binding motif RGD for tissue engineering. In this paper, hepatocyte function was examined on two synthetic RGD substrates and compared to that on fibronectin (Fn). One is a 2.3 kD RGD peptide (P-2) containing a single RGD, a short spacer in the middle and an end basic sequence to enhance adsorption. On bacteriological plastic, P-2 induced a rounded cell shape, enhanced differentiated function, and inhibited DNA synthesis. The other, a 73 kD synthetic RGD protein Pronectin F (PnF), contains repeating RGD units interspersed with a structural peptide. PnF induced cell spreading, dedifferentiation, and enhanced DNA synthesis, similar to Fn. In addition, only P-2 showed distinct differences in cell shape and DNA synthesis when coated on bacteriological plastic, or on Immulon II plastic, both intrinsically non-adhesive to cells. On bacteriologic plates coated with P-2, cells were round and showed diminished DNA synthesis while on Immulon II plates, they were spread and showed enhanced DNA synthesis. These results demonstrate that synthetic RGD peptides can induce very different hepatocyte function depending on the context in which they are presented to cells. It is likely that the RGD peptide conformation determines the specificity of cellular response.

Animals↗

PubMed1990

Effects of bryostatins 1 and 2 on morphological and functional differentiation of SH-SY5Y human neuroblastoma cells.

SH-SY5Y human neuroblastoma cells can be induced to differentiate to mature ganglion cells when treated with the phorbol ester tetradecanoylphorbol acetate (TPA). Bryostatins are a new class of protein kinase C activators that are structurally unrelated to phorbol esters. This paper describes the effects of bryostatins 1 and 2 on morphological and functional differentiation of SH-SY5Y cells. Both bryostatins induced a rapid translocation of protein kinase C from the cytosol to the membrane fraction. Within 24 h, the bryostatins had caused a nearly complete down-regulation of the enzyme. Bryostatin 1 competed for [3H]phorbol-12,13-dibutyrate binding in intact cells with potency equal to that of TPA, in contrast to bryostatin 2, which exhibited a Ki value 1 order of magnitude higher than those of the two other agents. Bryostatins induced morphological changes similar to those induced by TPA. These changes were, however, only transient, occurring during the first 6 h of incubation in the presence of these compounds. By 72 h, the cells had acquired a morphology typical of untreated cells and, although a wide range of bryostatin concentrations were used, morphological changes characteristic of differentiated SH-SY5Y cells were not detected at 72 h. Bryostatin 1 at 5 nM and bryostatin 2 at 100 nM inhibited DNA synthesis, as measured by incorporation of [3H]thymidine by SH-SY5Y cells, although to a significantly lesser degree than TPA. In spite of the fact that bryostatins failed to induce morphological differentiation in SH-SY5Y cells, these compounds down-regulated c-myc mRNA expression. Bryostatins were significantly weaker in stimulating noradrenaline synthesis, compared with TPA, and high concentrations of these agents blocked the effect of the phorbol ester when they were included together with TPA. When SH-SY5Y cells were incubated in the presence of high concentrations of bryostatins, a decreased sensitivity of cells to muscarinic agonist-induced increases in cytosolic free Ca2+ was observed. The results suggest that down-regulation of protein kinase C activity and c-myc mRNA expression do not necessarily correlate with the morphological differentiation of SH-SY5Y cells.

Antineoplastic Agents↗

PubMed1984

Changes of an androgen-dependent nuclear protein during functional differentiation and by dedifferentiation of the dorsolateral prostate of rats.

Nuclei of the dorsolateral prostate of rats contain a large amount of androgen-dependent non-histone protein (20K-NHP) (mol. wt. not equal to 20,000; pI not equal to 11.5) (Matuo et al. (1]. Its content in the nuclei increased most markedly during 4-8 weeks of age, when functional differentiation of the prostate was most active on the basis of the changes of major cytosol proteins and zinc. Nuclei of the Dunning tumors originating in the dorsolateral prostate were found to lack 20K-NHP regardless of androgen dependency, indicating the disappearance of the 20K-NHP from the nuclei by dedifferentiation. These suggest that the 20K-NHP is an important nuclear protein for differentiation of the dorsolateral prostate cells.

Aging↗

PubMed1987

Enhanced responsiveness to parathyroid hormone and induction of functional differentiation of cultured rabbit costal chondrocytes by a pulsed electromagnetic field.

Pulsed electromagnetic fields promote healing of delayed united and ununited fractures by triggering a series of events in fibrocartilage. We examined the effects of a pulsed electromagnetic field (recurrent bursts, 15.4 Hz, of shorter pulses of an average of 2 gauss) on rabbit costal chondrocytes in culture. A pulsed electromagnetic field slightly reduced the intracellular cyclic adenosine 3',5'-monophosphate (cAMP) level in the culture. However, it significantly enhanced cAMP accumulation in response to parathyroid hormone (PTH) to 140% of that induced by PTH in its absence, while it did not affect cAMP accumulation in response to prostaglandin E1 or prostaglandin I2. The effect on cAMP accumulation in response to PTH became evident after exposure of the cultures to the pulsed electromagnetic field for 48 h, and was dependent upon the field strength. cAMP accumulation in response to PTH is followed by induction of ornithine decarboxylase, a good marker of differentiated chondrocytes, after PTH treatment for 4 h. Consistent with the enhanced cAMP accumulation, ornithine decarboxylase activity induced by PTH was also increased by the pulsed electromagnetic field to 170% of that in cells not exposed to a pulsed electromagnetic field. Furthermore, stimulation of glycosaminoglycan synthesis, a differentiated phenotype, in response to PTH was significantly enhanced by a pulsed electromagnetic field. Thus, a pulsed electromagnetic field enhanced a series of events in rabbit costal chondrocytes in response to PTH. These findings show that exposure of chondrocytes to a pulsed electromagnetic field resulted in functional differentiation of the cells.

Alprostadil↗

PubMed1982

Differentiated function in cultured epithelia derived from thick ascending limbs.

Medullary thick ascending limbs were dissected from rabbit kidney and cultured on thin collagen membranes. The collagen membranes were supported by a special device that limited the exposed surface area to a disk 1 mm in diameter. The cells usually proliferated to form a confluent epithelial monolayer covering the collagen membrane within 8-10 days. Transepithelial voltage was measured between bridges immersed in the solutions bathing the bottom of the collagen membrane and the apical (upper) surface of the epithelium. The voltage typically was oriented positive toward the apical surface and persisted for a few weeks. Furosemide but not amiloride reduced the voltage reversibly. Both the orientation of the voltage and its reduction by furosemide are characteristic of thick ascending limbs. Therefore, the observed voltage supports the identification of the epithelial cells in culture and is evidence of differentiated function.

Amiloride↗

PubMed1999

Evolution of the archaeal rhodopsins: evolution rate changes by gene duplication and functional differentiation.

The amino acid sequences of 25 archaeal retinal proteins from 13 different strains of extreme halophiles were analyzed to establish their molecular phylogenetic relationship. On the basis of amino acid sequence similarity, these proteins apparently formed a distinct family designated as the archaeal rhodopsin family (ARF), which was not related to other known proteins, including G protein-coupled receptors. The archaeal rhodopsin family was further divided into four clusters with different functions; H+ pump (bacteriorhodopsin), Cl- pump (halorhodopsin), and two kinds of sensor (sensory rhodopsin and phoborhodopsin). These four rhodopsin clusters seemed to have occurred by gene duplication(s) before the generic speciation of halophilic archaea, based on phylogenetic analysis. Therefore, the degrees of differences in amino acid sequences within each cluster simply reflected the divergent evolution of halophilic archaea. By comparing the branch lengths after speciation points of the reconstituted tree, we calculated the relative evolution rates of the four archaeal rhodopsins bacteriorhodopsin:halorhodopsin:sensory rhodopsin: phoborhodopsin to be 5:4:3:10. From these values, the degrees of functional and structural restriction of each protein can be inferred. The branching topology of four clusters grouped bacteriorhodopsin and halorhodopsin versus sensory rhodopsin and phoborhodopsin by likelihood mapping. Using bacteriorhodopsin (and halorhodopsin) as an outgroup, the gene duplication point of sensory rhodopsin/phoborhodopsin was determined. By calculating the branch lengths between the gene duplication point and each halophilic archaea speciation point, we could speculate upon the relative evolution rate of pre-sensory rhodopsin and pre-phoborhodopsin. The evolution rate of pre-sensory rhodopsin was fivefold faster than that of pre-phoborhodopsin, which suggests that the original function of the ancestral sensor was similar to that of phoborhodopsin, and that sensory rhodopsin evolved from pre-sensory rhodopsin by the accumulation of mutations. The changes in evolution rate by gene duplication and functional differentiation were demonstrated in the archaeal rhodopsin family using the gene duplication date and halobacterial speciation date as common time stamps.

Amino Acid Sequence↗

PubMed1992

SV40-immortalization of rabbit articular chondrocytes: alteration of differentiated functions.

Cell lines were established from rabbit articular chondrocytes following transfection with a plasmid encoding SV40 early function genes. This resulted in cell immortalization (130 passages have been completed for the oldest cell line) with acquisition of characteristics of partial transformation such as reduced serum requirements for normal and clonal growth. The immortalized chondrocytes, called SVRAC, did not form multilayer foci when maintained in postconfluent culture. Their ability to form colonies in soft agar was not increased in comparison with normal chondrocytes, but they were weakly tumorigenic in nude mice. SVRAC lost the ability to synthesize type II collagen and Alcian blue-stainable matrix, which are markers of the differentiated chondrocyte phenotype, and synthesized predominantly type I collagen. Studies of collagen gene expression showed that pro alpha 1 (II) mRNA was undetectable, whereas pro alpha 1 (I) collagen mRNA was expressed even in late passage cultures. Unlike normal dedifferentiated chondrocytes, SVRAC were unable to re-express the differentiated phenotype in response to tridimensional culture or microfilament depolymerization. Cell lines obtained from chondrocytes transfected either in primary culture or just after release of cells from cartilage displayed the same behaviour. Thus SV40 early genes were able to immortalize rabbit articular chondrocytes, but the resulting cell lines displayed an apparently irreversibly dedifferentiated phenotype. These cell lines can be used as models to identify regulatory pathways that are required for the maintenance or reexpression of differentiated function in chondrocytes.

Animals↗

PubMed1998

Differential functions of hypothalamic galanin cell grows in the regulation of eating and body weight.

Evidence suggests that hypothalamic galanin (GAL) has a variety of functions related to energy and nutrient balance, reproduction, water balance, and neuroendocrine regulation. The focus of this chapter is the role of GAL in eating and body weight regulation. Findings described herein demonstrate that GAL, in a cell group of the anterior region of the paraventricular nucleus (aPVN) that projects to the median eminence, has a role in the control of fat intake, fat metabolism, and body fat. This function of aPVN GAL neurons is carried out in close relation to circulating insulin and glucose. Galanin-expressing perikarya in the medial preoptic area (MPOA) have a similar function, although GAL here operates in association with the female steroids estrogen and progesterone. These GAL cell groups of the aPVN and MPOA contrast with those in the arcuate nucleus as well as the magnocellular vasopressin-containing neurons of the PVN and supraoptic nucleus, which show no relation to fat balance. This evidence reveals differential functions for the distinct GAL neuronal cell groups of the hypothalamus.

Animals↗

PubMed1988

Effects of rat gamma- and non-gamma-interferons on the expression of Ia antigen, growth, and differentiated functions of FRTL5 cells.

We undertook the present studies with several objectives in mind: 1) to determine whether recombinant rat gamma-interferon (r gamma IFN) would induce expression of the class II major histocompatibility antigen (Ia) in rat thyroid follicular cells (FRTL5) in culture as human gamma IFN does in cultured human thyrocytes; 2) to characterize the properties of this response, if it does indeed occur; 3) to ascertain whether r gamma IFN has any effect on the growth or differentiated function of FRTL5 cells; and 4) to determine how, if at all, effects of r gamma IFN on the growth and function of FRTL5 cells might be related to expression of the Ia antigen. At concentrations between 1 and 30 U/ml, r gamma IFN induced expression of Ia antigen in a concentration-dependent manner. With a supramaximal concentration of r gamma IFN, Ia antigen first appeared between 4 and 16 h and reached a maximum concentration at about 36 h. After removal of r gamma IFN, the Ia antigen concentration remained constant for about 24 h and then declined, becoming undetectable by 72 h. Induction could not be detected in FRTL5 cells cultured with human gamma IFN, rat non-gamma IFN, Concanavalin-A, phytohemagglutinin, or bovine TSH (bTSH). Over the same range of concentrations that induced the Ia antigen, r gamma IFN proved to be a potent inhibitor of the growth of FRTL5 cells induced by a variety of agents. It produced a concentration-dependent inhibition of the stimulation of [3H] thymidine incorporation and cell replication in FRTL5 cells induced by bTSH. This effect was unaccompanied by any inhibition of either the binding of bTSH to FRTL5 cells or the bTSH-induced increase in cellular cAMP concentration induced therein. However, r gamma IFN did inhibit the stimulation of [3H] thymidine incorporation into DNA induced by (Bu)2cAMP. r gamma IFN also inhibited the stimulation of DNA synthesis and cell replication induced by insulin-like growth factor I (IGF-I) without affecting the specific binding of IGF-I, and decreased the extent of stimulation of [3H]thymidine incorporation induced by the phorbol ester tetradecanoyl phorbol acetate (TPA). Thus, r gamma IFN inhibited both the cAMP-dependent pathway of growth activated by TSH, doing so at some post-cAMP locus, and the cAMP-independent pathways of growth regulation that are activated by IGF-I and TPA.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminoisobutyric Acids↗

PubMed1995

Prolactin and epidermal growth factor regulation of the proliferation, morphogenesis, and functional differentiation of normal rat mammary epithelial cells in three dimensional primary culture.

The epithelial cell-specific effects of prolactin and epidermal growth factor (EGF) on the development of normal rat mammary epithelial cells (MEC) were evaluated using a three dimensional primary culture model developed in our laboratory. Non-milk-producing MEC were isolated as spherical end bud-like mammary epithelial organoids (MEO) from pubescent virgin female rats. The cultured MEO developed into elaborate multilobular and lobuloductal alveolar organoids composed of cytologically and functionally differentiated MEC. Prolactin (0.01-10 micrograms/ml) and EGF (1-100 ng/ml) were each required for induction of cell growth, extensive alveolar, as well as multilobular branching morphogenesis, and casein accumulation. MEO cultured without prolactin for 14 days remained sensitive to the mitogenic, morphogenic, and lactogenic effects of prolactin upon subsequent exposure. Similarly, cells cultured in the absence of EGF remained sensitive to the mitogenic and lactogenic effects of EGF, but were less responsive to its morphogenic effects when it was added on day 14 of a 21-day culture period. If exposure to prolactin was terminated after the first week, the magnitude of the mitogenic and lactogenic effects, but not the morphogenic response was decreased. Removal of EGF on day 7 also reduced the mitogenic response, but did not have any effect on the magnitude of the lactogenic or morphogenic responses. These studies demonstrate that physiologically relevant development of normal MEC can be induced in culture and that this model system can be used to study the mechanisms by which prolactin and EGF regulate the complex developmental pathways operative in the mammary gland.

Animals↗

PubMed1998

Time-course effects of human recombinant luteinizing hormone on porcine Leydig cell specific differentiated functions.

Since recombinant hormones are considered as safer and more reliable in their bioactivity than extractive hormones, the recently available human recombinant luteinizing hormone (r-hLH), will probably replace hCG in the near future, for clinical purposes. This prompted us to investigate whether or not, and by which mechanisms, r-hLH can induce a desensitization of signal transduction and/or an up-regulation of steroidogenic capacity in Leydig cells. The effects of a 30 min to 24 h exposure to r-hLH (10(-9) M) on the differentiated functions of cultured immature porcine Leydig cells were studied by measuring the following parameters: LH/hCG receptor number and mRNA, hCG-, cholera toxin- and forskolin-induced cAMP production, G protein alphas subunit content of the membrane, hCG-, cholera toxin-, forskolin-, 8Br-cAMP-, 22R-OH-cholesterol-, progesterone-, 170H-progesterone-, DHEA-, delta4-androstenedione-induced testosterone secretion and StAR, 3beta-HSD, cytochrome P-450scc and P-450c17 mRNAs. hCG binding sites and LH/hCG receptor mRNA were slowly down regulated by r-hLH, reaching 47+/-1 and 18+/-7% of control at 24 h, respectively. Down-regulation of both hCG- and cholera toxin-induced cAMP production occurred earlier and was more marked, and at 24 h represented only 2.7+/-0.5 and 12.5+/-3.6% of control. Due to the synergistic effect of r-hLH and forskolin on cAMP production, the forskolin-induced cAMP was higher in r-hLH treated than in control cells, but this response also declines with time and was, at 24 h, only 32% of that observed at 30 min. This decreased cAMP production was associated with a less marked decline in the amount of membrane content of Galphas protein. The testosterone production in response to hCG, cholera toxin, forskolin and 8Br-cAMP declined to reach a nadir at 6 h but increased thereafter and at 24 h was significantly higher than in control cells. In contrast, the conversion of several precursors into testosterone remained stable or increased slightly during the first hours of r-hLH treatment and significantly increased at 24 h and this was associated with an increase of StAR, 3beta-HSD, P-450scc and P-450c17 mRNAs. Taken together, the present results indicate that, despite the marked down-regulation of transmembrane signaling, r-hLH increased the steroidogenic capacity of Leydig cells by increasing the expression of several genes encoding the proteins involved in testosterone synthesis.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1990

[The hormonal mechanisms of the programming and regulation of liver function differentiation by sex].

Crucial role of androgens and estrogens in programming and regulation of the sex-dependent expression of a specific estrogen-binding protein, androgenous and estrogenous receptors and corticosteroid-binding globulin, was shown. Both types of the sex steroids effects were shown to be realized in the hepatocytes through respective hormonal receptors. The realization of physiological effects of the sex hormones demands the participation of STH as a permissive factor. Some theoretical and practical aspects of the sex differentiation of the liver functions, are discussed.

Androgens↗