• Biomedical Science Letters
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• v.11 no.2
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• pp.175-183
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• 2005

The two major isoflavones in soy, genistein and daidzein, are well known to prevent hormone-dependent cancers by their anti estrogenic activity. The exact molecular mechanisms for the protective action are, however, not provided yet. It has been reported that genistein and daidzein have a potential anticancer activity through their antiproliferative effect in many hormone-dependent cancer cell lines. Transforming growth $factor-\beta1(TGF-\beta1)$ has also been found to have cell growth inhibitory effect, especially in mammary epithelial cells. This knowledge led to a hypothetical mechanism that the soy isoflavones-induced growth inhibitory effect can be derived from the regulation of $TGF-\beta1$ and $TGF-\beta$ receptors. In order to test this hypothesis, the effects of the soy isoflavones at various concentrations and periods on the expression of $TGF-\beta1$and $TGF-\beta$ receptors were investigated by using Northern blot analysis in human breast carcinoma epithelial cell lines, an estrogen receptor positive cell line (MCF-7) and an estrogen receptor negative cell line (MDA-MB-231). As a result, only genistein has shown a profound dose-dependent effect on $TGF-\beta1$ expression in the $ER^+$ cell line within the range of doses tested, and the expression levels are correspondent to their inhibitory activities of cell growth. Moreover, daidzein showed down-regulated $TGF-\beta1$ expression at a low dose, the cell growth proliferation was promoted at the same condition. Therefore, antiproliferative activity of the soy isoflavones can be mediated by $TGF-\beta1$ expression, and the effects are mainly, if not all, occurred by ER dependent pathway. The expression of $TGF-\beta$ receptors was induced at a lower dose than the one for $TGF-{\beta}1$ induction regardless of the presence of ER, and the expression patterns are similar to those of the cell growth inhibition. These results indicated that the regulation of $TGF-\beta$ receptor expression as well, prior to $TGF-\beta1$ expression, may be involved in the antiproliferative activity of soy isoflavones. Little or no expression of $TGF-\beta$ receptors was found in the MCF-7 and MDA-MB-231 cells, suggesting refractory properties of the cells to growth inhibitory effect of the $TGF-\beta$. The soy isoflavones can seemingly restore the sensitivity of growth inhibitory responses to $TGF-\beta1$ by re-inducing $TGF-\beta$ receptors expression. In conclusions, our findings presented in this study show that the antitumorigenic activity of the soy isoflavones could be mediated by not only $TGF-\beta1$induction but $TGF-\beta$ receptor restoration. Thus, soy isoflavones could be good model molecules to develop new nonsteroidal antiestrogenic chemopreventive agents, associated with, regulation of $TGF-\beta$ and its receptors.

• The Korean Journal of Physiology and Pharmacology
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• v.12 no.1
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• pp.13-23
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• 2008

The aim of the present study was designed to establish comparatively the inhibitory effects of $D_1$-like and $D_2$-like dopaminergic receptor agonists, SKF81297 and R(-)-TNPA on the release of catecholamines (CA) evoked by cholinergic stimulation and membrane depolarization from the isolated perfused model of the rat adrenal medulla. SKF81297 $(30{\mu}M)$ and R-(-)-TNPA $(30{\mu}M)$ perfused into an adrenal vein for 60 min, produced great inhibition in the CA secretory responses evoked by ACh $(5.32{\times}10^{-3}\;M)$, DMPP $(10^{-4}\;M)$, McN-A-343 $(10^{-4}\;M)$, high $K^+$ $(5.6{\times}10^{-2}\;M)$, Bay-K-8644 $(10{\mu}M)$, and cyclopiazonic acid $(10{\mu}M)$, respectively. For the release of CA evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid, the following rank order of inhibitory potency was obtained: SKF81297>R-(-)-TNPA. However, R(+)-SCH23390, a selectve $D_1$-like dopaminergic receptor antagonist, and S(-)-raclopride, a selectve $D_2$-like dopaminergic receptor antagonist, enhanced the CA secretory responses evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid only for $0{\sim}4$ min. The rank order for the enhancement of CA release evoked by high $K^+$, McN-A-343 and cyclopiazonic acid was R(+)-SCH23390>S(-)-raclopride. Also, the rank order for ACh, DMPP and Bay-K-8644 was S(-)-raclopride > R(+)-SCH23390. Taken together, these results demonstrate that both SKF81297 and R-(-)-TNPA inhibit the CA release evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors and the membrane depolarization from the isolated perfused rat adrenal gland without affecting the basal release, respectively, but both R(+)-SCH23390 and S(-)-raclopride facilitate the CA release evoked by them. It seems likely that the inhibitory effects of SKF81297 and R-(-)-TNPA are mediated by the activation of $D_1$-like and $D_2$-like dopaminergic receptors located on the rat adrenomedullary chromaffin cells, respectively, whereas the facilitatory effects of R(+)-SCH23390 and S(-)-raclopride are mediated by the blockade of $D_1$-like and $D_2$-like dopaminergic receptors, respectively: this action is possibly associated with extra- and intracellular calcium mobilization. Based on these results, it is thought that the presence of dopaminergic $D_1$ receptors may play an important role in regulation of the rat adrenomedullary CA secretion, in addition to well-known dopaminergic $D_2$ receptors.

• Journal of Life Science
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• v.33 no.1
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• pp.102-113
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• 2023

This review discusses the cellular and molecular mechanisms by which the endometrial estrogen and progesterone receptors regulate local estrogen production, expression of the specific estrogen receptors, progesterone resistance, inflammatory responses and the differentiation and survival of endometriotic cells in endometrial inflammation. The epigenetic aberrations of endometrial stromal cells play an important role in the pathogenesis and progression of endometriosis. In particular, differential methylation of the estrogen receptor genes changes in the stromal cells the dominancy of estrogen receptor from ERα into ERβ, and results in the abnormal estrogen responses including inflammation, progesterone resistance and the disturbance of retinoid synthesis. These stromal cells also stimulate local estrogen production in response to PGE2 and the SF-1 mediated induction of steroidogenic enzyme expression, and the increased estradiol then feeds back into the ERβ to repeat the vicious inflammatory cycle through the activation of COX-2. In addition, high levels of ERβ expression may also change the chromatin structure of endometrial mesenchymal stem cells, and together with the repeated menstrual cycles can induce formation of the endometriotic tissue. The cascade of these serial events then leads to cell adhesion, angiogenesis and survival of the differentiation-disregulated stromal cells through the action of inflammatory factors such as ERβ-mediated estrogen, TNF-α and TGF-β1. Therefore, understanding of the dynamic hormonal changes during the menstrual cycle and the corresponding signal transduction mechanisms of the related nuclear receptors in endometrium would provide new insights for treating inflammatory diseases such as the endometriosis.

• BMB Reports
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• v.43 no.5
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• pp.305-310
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• 2010

Syndecans, cell surface heparansulfate proteoglycans, have been proposed to act as cell surface receptors and/or coreceptors to play critical roles in multiple cellular functions. However, recent reports suggest that the function of syndecans can be further extended through shedding, a cleavage of extracellular domain. Shedding constitutes an additional level for controlling the function of syndecans, providing a means to attenuate and/or regulate amplitude and duration of syndecan signals by modulating the activity of syndecans as cell surface receptors. Whether these remaining cleavage products are still capable of functioning as cell surface receptors to efficiently transduce signals inside of cells is not clear. However, shedding transforms cell surface receptor syndecans into soluble forms, which, like growth factors, may act as novel ligands to induce cellular responses by association with other cell surface receptors. It is becoming interestingly evident that shed syndecans also contribute significantly to syndecan functions in cancer biology. This review presents current knowledge about syndecan shedding and its functional significance, particularly in the context of cancer.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.6
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• pp.639-645
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• 1997

The purpose of the present study is to determine the role of muscarinic cholinergic receptors of posterior hypothalamus in the central blood pressure regulation when respiration is controlled. In anesthetized and artificially ventilated rats, vasodepressor response was evoked by injection of L-glutamate(10 nmol) neuroexcitatory amino acid into the posterior hypothalamic area. The injection of $carbachol(0.5{\sim}8\;nmol)$ into the same area induced dose-dependent vasodepressor and bradycardic responses. Pretreatment with atropine(4 nmol) completely blocked the vasodepressor response to carbachol(2 nmol). In contrast, in spontaneously breathing rats, the injection of carbachol(8 nmol) into the posterior hypothalamic area induced the vasopressor and tachycardic responses. These results suggest that the muscarinic cholinergic receptors in the posterior hypothalamic area primarily play an inhibitory role in the central regulation of blood pressure and heart rate.

• The Korean Journal of Physiology and Pharmacology
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• v.4 no.4
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• pp.311-318
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• 2000

We cultured the rabbit inner medullary collecting duct (IMCD) cells as monolayers on collagen-coated membrane filters, and investigated distribution of the P2Y receptors by analyzing nucleotide-induced short circuit current $(I_{sc})$ responses. Exposure to different nucleotides of either the apical or basolateral surface of cell monolayers stimulated $I_{sc}.$ Dose-response relationship and cross-desensitization studies suggested that at least 3 distinct P2Y receptors are expressed asymmetrically on the apical and basolateral membranes. A $P2Y_2-like$ receptor, which responds to UTP and ATP, is expressed on both the apical and basolateral membranes. In addition, a uracil nucleotide receptor, which responds to UDP and UTP, but not ATP, is expressed predominantly on the apical membrane. In contrast, a $P2Y_1-like$ receptor, which responds to ADP and 2-methylthio-ATP, is expressed predominantly on the basolateral membrane. These nucleotides stimulated intracellular cAMP production with an asymmetrical profile, which was comparable to that in the stimulation of $I_{sc}.$ Our results suggest that the adenine and uracil nucleotides can interact with different P2Y nucleotide receptors that are expressed asymmetrically on the apical and basolateral membranes of the rabbit IMCD cells, and that both cAMP- and $Ca^{2+}-dependent$ signaling mechanisms underlie the stimulation of $I_{sc}$.

• The Korean Journal of Physiology and Pharmacology
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• v.4 no.5
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• pp.355-359
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• 2000

Cocaine induces immediate early gene expression and behavioral changes by blocking dopamine transporters in the terminals of nigrostriatal neurons in the striatum. The pharmacological role of serotonin 2/1C (5HT2/1C) receptors in cocaine-induced expression of zif268 (NGFI-A, egr1 and Krox-24) mRNA, a member of the zinc finger, was investigated using quantitative in situ hybridization histochemistry in vivo. Behavioral alterations induced by cocaine were also monitored in relation with blockade of the receptors. Systemic injection of ritanserin (1 mg/kg, s.c.), a 5HT2/1C receptor antagonist, did not reverse behavioral alterations and zif268 mRNA gene expression induced by 15 mg/kg cocaine, i.p., in the dorsal and ventral striatum. These data indicate that ritanserin-sensitive 5HT2/1C receptors are not necessary for cocaine-induced behavioral alterations and zif268 mRNA gene expression in the striatum.

• BMB Reports
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• v.31 no.5
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• pp.419-426
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• 1998

The nuclear hormone receptor superfamily currently includes approximately equal numbers of conventional receptors and orphan receptors, which do not have known ligands. Here, we review recent progress from this laboratory on three orphans, two of which are moving from orphan to conventional receptor status. Perhaps the most unusual is CAR, which is a constitutive transactivator in the absence of ligands but becomes transcriptionally inactive in the presence of its ligands, which are androgen metabolites. The response of CAR to its ligands is thus opposite to that of the conventional receptor paradigm. RIP14 (also known as FXR) is activated by both all-trans retinoic acid and a synthetic retinoid previously thought to specifically target the retinoic acid receptors (RARs), and thus appears to be a novel retinoid receptor. Finally, SHP is a novel orphan that lacks a DNA binding domain and interacts with a number of other receptor superfamily members. While it generally inhibits its targets, including CAR, the retinoid X receptor (RXR), and the estrogen receptor (ER), it stimulates transactivation by the orphan SF-1.

• BMB Reports
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• v.47 no.4
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• pp.184-191
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• 2014

Respiratory syncytial virus (RSV) is the leading cause of respiratory infection in infants and young children. Severe clinical manifestation of RSV infection is a bronchiolitis, which is common in infants under six months of age. Recently, RSV has been recognized as an important cause of respiratory infection in older populations with cardiovascular morbidity or immunocompromised patients. However, neither a vaccine nor an effective antiviral therapy is currently available. Moreover, the interaction between the host immune system and the RSV pathogen during an infection is not well understood. The innate immune system recognizes RSV through multiple mechanisms. The first innate immune RSV detectors are the pattern recognition receptors (PRRs), including toll-like receptors (TLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), and nucleotide-biding oligomerization domain (NOD)-like receptors (NLRs). The following is a review of studies associated with various PRRs that are responsible for RSV virion recognition and subsequent induction of the antiviral immune response during RSV infection.

• The Korean Journal of Pharmacology
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• v.5 no.2
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• pp.115-119
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• 1969

The authors studied the adrenotropic receptors of isolated urinary bladder from Sebastes inermis, using adrenergic activators such as epinephrine, nor-epinephrine, isoproterenol and phenylephrine and adrenergic blocking agents such as phenoxybenzamine, pronethalol and propranolol. The studies have revealed the following results. 1) The spontaneous motility of isolated bladder from Sebastes inermis was inhibited by epinephrine nor-epinephrine, isoproterenol and phenylephrine. 2) The inhibitory effect of phenylephrine on the Sebastes inermis bladder was blocked by phenoxybensamine. 3) The inhibitory effect of isoproterenol was blocked by pronethalol and propranolol. 4) The effect of epinephrine and nor-epinephrine on the Sebastes inermis bladder was usually not blocked by either kind of blocking agent alone, but was blocked by a combination of ${\alpha}\;and\;{\beta}$ blockades. 5) It is, therefore, concluded that the Sebastes inermis bladder has alpha and that both receptors, and that both receptors subserve retaxation or inhibition.