• Environmental Mutagens and Carcinogens
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• v.26 no.1
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• pp.12-19
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• 2006

Cadmium, a human carcinogen, can induce toxicity in various cell lines and organs. Despite extensive research, the mechanisms of cadmium-induced cell toxicity and estrogenic potential in human are not clear. This study was performed to investigate cadmium-induced toxicity on human breast cancer cells: MCF-7 cells, an estrogen receptor (ER) positive breast cancer cells, and MDA-MB-231 cells, an ER negative breast cancer cells. MCF-7 cells was proved to be more sensitive than the other cell lines (IC50 = $50\;{\mu}M$ at MCF-7 cells and $120{\mu}M$ at MDA-MB-231). The expression of JNK and AP-1 transcription factors such as c-Jun and c-Fos dependent transcription were increased by cadmium treatment. Inhibition of ER activation by ER antagonist (tamoxifen or ICI 182,780) significantly recovered the viablity and inhibited apoptotic cell death. This suggested that cadmium-induced cell death in ER (+) cells was mediated by JNK/AP-1 pathway and this pathway was more stimulated by ER activated by cadmium. Co-treatment of antioxidants such as selenium (Se), butylated hydroxyanisole (BHA), glutathione (GSH), or N-acetyl-L-cysteine (NAC) recovered the cadmium-induced cell death in MCF-7 cells. Cadmium-induced lipid peroxidation was decreased by GSH, NAC, or BHA in MCF-7 cells. The expression of SOD protein was decreased by cadmium ($100{\mu}M$) but recovered by GSH, NAC, BHA, or Se. Our data showed that the cadmium-induced cell toxicity in human breast cancer cells could be protected by the antioxidants (Se, BHA, NAC, GSH, or NAC) and ER antagonist (tamoxifen or ICI 182,780). Therefore, toxicity of cadmium in breast cancer were mediated by oxidative stress and $ER{\alpha}$.

• Journal of the korean academy of Pediatric Dentistry
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• v.36 no.1
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• pp.139-144
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• 2009

Laron syndrome was first described by Dr. Laron. Administration of exogenous growth hormone failed to stimulate insulin-like growth factor-I(IGF-I) production which was related to postnatal growth, because these patients lacked receptors in the liver for this hormone. The diagnosis of this syndrome is based on the typical features of GH resistance such as normal or elevated serum GH, low serum IGF-I, and impaired IGF-I response to hGH. Laron syndrome patients showed characteristically severe postnatal growth failure and markedly reduced adult height. This report describes the oral and maxillofacial manifestations of children associated with Laron syndrome. Children with Laron syndrome have several dental and skeletal irregularities. Relatively little is known of the direct effect of Laron syndrome on dental development. Further research should be needed.

• Development and Reproduction
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• v.11 no.1
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• pp.1-11
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• 2007

Specific endometrial preparation should occur during periimplantation period. That is a progress of serial differentiation and is absolute in implantation of embryo and successful pregnancy. Remodeling of tissues shown during embryogenesis is regulated by various factors including extracellular matrix (ECM). Marked changes during pregnancy are including embryo migration, decidual response, and differentiation of placenta in placental animals including human. These changes to successful implantation in embryo and uterus have to prepare the competence for attachment of embryo and uterus, and invasion defense of uterus. During these changes, ECM dramatically changes for maintaining the uterine and embryonic functions. The major component of most connective tissue is collagens. It is very complex and hard to explore the mechanisms for ECM modulation. Recently using high throughput methodology, PCR-select cDNA subtraction method, microarray, many candidate genes have been identified. Steroid hormones have fundamental role in implantation and maintenance of pregnancy. Dermatopontin, a regulator of collagen accumulation, is regulated spatio-temporally in the uterus by primarily progesterone through progesterone receptors at the time of implantation. Modulation of extracellular matrix is critically regulated by cascade of gene net-works which are regulated by cascade of sex steroid hormones. Pathological regulation of uterine extracellular matrix reported in diabetic patients. To know the extracellular modulation is essential to understanding implantation, feto-placental development and overcome the paths involved in female reproduction. Though ECM composed with very various components and it is complex, the present review focused on the fate of collagens during periimplantation period.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.1
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• pp.37-43
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• 2010

The serine/threonine kinase Akt has been shown to play a role of multiple cellular signaling pathways and act as a transducer of many functions initiated by growth factor receptors that activate phosphatidylinositol 3-kinase (PI3K). It has been reported that phosphorylated Akt activates eNDS resulting in the production of NO and that NO stimulates soluble guanylate cyclase (sGC), which results in accumulation of cGMP and subsequent activation of the protein kinase G (PKG). It has been also reported that PKG activates PI3K/Akt signaling. Therefore, it is possible that PI3K, Akt, eNOS, sGC, and PKG form a loop to exert enhanced and sustained activation of Akt. However, the existence of this loop in eNOS-expressing cells, such as endothelial cells or astrocytes, has not been reported. Thus, we examined a possibility that Akt phosphorylation might be enhanced via eNOS/sGC/PKG/PI3K pathway in astrocytes in vivo and in vitro. Phosphorylation of Akt was detected in astrocytes after KA treatment and was maintained up to 72 h in mouse hippocampus. 2 weeks after KA treatment, astrocytic Akt phosphorylation was normalized to control. The inhibition of eNOS, sGC, and PKG significantly decreased Akt and eNDS phosphorylation induced by KA in astrocytes. In contrast, the decreased phosphorylation of Akt and eNDS by eNDS inhibition was significantly reversed with PKG activation. The above findings in mouse hippocampus were also observed in primary astrocytes. These data suggest that Akt/eNOS/sGC/PKG/PI3K pathway may constitute a loop, resulting in enhanced and sustained Akt activation in astrocytes.

• Reproductive and Developmental Biology
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• v.34 no.1
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• pp.33-40
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• 2010

Equine chorionic gonadotropin (eCG) is a heavily glycosylated glycoprotein composed of non-covalently linked $\alpha$- and $\beta$-subunits. To study the function and signal transduction of tethered recombinant-eCG (rec-eCG), a single chain eCG molecule was constructed, and the rec-eCG protein was prepared. In this study, we constructed 5 mutants (${\Delta}1$, ${\Delta}2$, ${\Delta}3$, ${\Delta}4$, and ${\Delta}5$) of rec-eCG using data about known glycoprotein hormones to analyze the role of specific follicle stimulating homone (FSH)-like activity. Three amino acids of certain specific sites were replaced with alanine. The expression vectors were transfected into CHO cells and subjected to G418 selection for 2~3 weeks. The media were collected and the quantity of secreted tethered rec-eCGs was quantified by ELISA. The LH- and FSH-like activities were assayed in terms of cAMP production by rat LH/CG and rat FSH receptors. Then, the metabolic clearance rate analyzed by the injection of rec-eCG (5 IU) into the tail vein was analyzed. The mutant eCGs (${\Delta}l$, ${\Delta}4$, and ${\Delta}5$) were transcripted, but not translated into proteins. Rec-eCG A2 was secreted in much lower amounts than the wild type. Only the rec-eCG ${\Delta}3$ ($\beta$-subunit: $Gln^{94}-Ile^{95}-Lys^{96}{\rightarrow}Ala^{94}-Ala^{95}-Ala^{96}$) was efficiently secreted. Although activity is low, its LH-like activity was similar to that of tethered $eCG{\beta\alpha}$. However, the FSH-like activity of rec-$eCG{\beta\alpha\Delta}3$ was completely flat. The result of the analysis of the metabolic clearance rate shoed the persistence of the mutant in the blood until 4 hours after the injection. After then, it almost disappeared at 8 hours. Taken together, these data suggest that 94~96 amino acid sequences in eCG $\beta$-subunit appear to be of utmost importance for signal transduction of the FSH receptor.

• The Korean Journal of Pharmacology
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• v.24 no.1
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• pp.17-29
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• 1988

The author examined the effects of lidocaine on the veratrine-or potassium-induced release of neurotransmitters to determine the possible role of amino acid neurotransmitters in lidocaine-induced convulsion. The examined transmitters were gamma-aminobutyric acid (GABA), aspartic acid, glutamic acid and norepinephrine which are released from the synaptosomes. Furthermore, the effects of lidocaine on the binding to receptors and synaptosomal uptake of the two transmitters, GABA and glutamic acid, were determined in crude synaptic membranes and synaptosomes. In addition, the effects of propranolol, norepinephrine and serotonin on the release of amino acid neurotransmitters were also examined. The veratrine-induced release of GABA was most severely inhibited by lidocaine and propranolol, while norepinephrine and serotonin reduced the release of aspartic acid and glutamic acid more than the GABA release. Generally the potassium-induced release was much more resistant to the lidocaine action than the veratrine-induced release. Among the neurotransmitters examined, the aspartic acid release was most prone to the lidocaine action, while the GABA release was most resistant. Concentrations of lidocaine below 1 mM did not significantly change the GABA and glutamic acid receptor binding and uptake. These results indicate that the blocking of sodium channels by lidocaine can result in the selective depression of the GABA release. This may result in unlimited excitation of the central nervous system.

• The Korean Journal of Physiology and Pharmacology
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• v.6 no.4
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• pp.215-223
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• 2002

The present study was undertaken to investigate the effect of doxorubicin (DX) on secretion of catecholamines (CA) evoked by ACh, high $K^+,$ DMPP and McN-A-343 from the isolated perfused rat adrenal gland and to establish the mechanism of its action. DX $(10^{-7}{\sim}10^{-6}\;M)$ perfused into an adrenal vein for 60 min produced relatively dose- and time-dependent inhibition of CA secretory responses evoked by ACh $(5.32{\times}10^{-3}\;M),$ DMPP $(10^{-4}\;M)$ and McN-A-343 $(10^{-4}\;M).$ However, lower dose of DX did not affect CA secretion by high $K^+\;(5.6{\times}10^{-2}\;M),$ but its higher doses depressed time-dependently CA secretion evoked by high $K^+.$ DX itself did also fail to affect basal CA output. In adrenal glands loaded with DX $(3{\times}10^{-7}\;M),$ CA secretory responses evoked by Bay-K-8644, an activator of L-type $Ca^{2+}$ channels and cyclopiazonic acid, an inhibitor of cytoplasmic $Ca^{2+}-ATPase$ were time-dependently inhibited. Furthermore, daunorubicin $(3{\times}10^{-7}\;M),$ given into the adrenal gland for 60 min, attenuated CA secretory responses evoked by ACh, high $K^+,$ DMPP and McN-A-343. Taken together, these results suggest that DX causes relatively dose- and time-dependent inhibition of CA secretory responses evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors from the isolated perfused rat adrenal gland. However, lower dose of DX did not affect CA secretion by high $K^+,$ and higher doses of DX reduced time-dependently CA secretion of high $K^+.$ It is thought that these effects of DX may be mediated by inhibiting both influx of extracellular calcium into the rat adrenomedullary chromaffin cells and intracelluar calcium release from the cytoplasmic store. Also, there was no difference in the mode of action between DX and daunorubicin in rat adrenomedullary CA secretion.

• The Korean Journal of Physiology
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• v.24 no.1
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• pp.161-170
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• 1990

The effects of $H^{+}$ on the arterial contraction and their mechanisms were investigated in the renal artery of a rabbit. The helical strips of isolated renal artery were immersed in the HEPES-buffered or $CO_{2}/HCO_{3}^{-}$-buffered Tyrode's solution. The contractions induced by agonists (norepinephrine, histamine, serotonin and angiotensin II) or high $K^{+}$ were observed with change of extracellular or intracellular $H^{+}$ concentration. The contractions induced by norepinephrine, histamine, serotonin, angiotensin II or high $K^{+}$ in HEPES-buffered Tyrode's solution were inhibited by increase in extracellular $H^{+}$ concentration and potentiated by decrease in extracellular $H^{+}$ concentration. The degrees of these effects were most evident in the contraction induced by serotonin and angiotensin II, moderate in those by histamine and high $K^{+}$, and least in those by norepinephrine. Maximal contraction by norepinephrine, histamine and high $K^{+}$ were not influenced by change in extracellular $H^{+}$ concentration, but influenced in those contration by serotonin and angiotensin II. The attenuated contractions by an acidic pH were not returned to the level of contraction at normal pH (7.4) by elevation of extracellular $Ca{2+}$ concentration. The agonists (norepinephrine, histamine and serotonin)-induced contractions in $Ca{2+}$-free Tyrode's solution were also attenuated by increase in extracellular $H^{+}$ concentration and potentiated by decrease in extracellular $H^{+}$ concentration. Elevation of $Pco_{2}$ in the $CO_{2}/HCO_{3}^{-}$-buffered Tyrode's solution, which increase the intracellular $H^{+}$ concentration, at constant extracellular pH (7.4), increased the contraction by 30 mM $K^{+}$. From the above results, it is suggested that the decrease in contractions by increase in extracellular $H^{+}$ concentration may be resulted from that $H^{+}$ make the receptors less sensitive to agonists and cell membrane hyperpolarize and then inhibit the $Ca{2+}$ influx as well as $Ca{2+}$ release from intracellular $Ca{2+}$ storage site.

• IMMUNE NETWORK
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• v.5 no.3
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• pp.179-185
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• 2005

Background: Psoriasis is a multifactorial autoimmune skin disease with a pathogenesis that has remained obscure. Recently, T cells bearing natural killer receptors (NKRs) were precisely and strongly targeted as new putative pathogenic immunocytes in psoriasis. Among NKRs, killer cell immunoglobulin-like receptor (KIR) is the major molecule recognizing HLA class I allotypes and might be closely related to psoriasis. Methods: To investigate the association of KIR genotype and patients with psoriasis in Korean, we defined the 14 KIR genotypes in 96 patients with psoriasis and 86 healthy controls using PCR-SSP methods. Results: The frequencies of KIR2DS4 and KIR3DL1 were significantly decreased in psoriasis compared with controls (RR=0.21, p<0.02). When patients were divided into two subgroups at the age of onset, type I (<30 years) and type II ($({\geq}30$ years) respectively, these phenomena were similarly observed independent of groups divided (type I: RR=0.26, p<0.005; type II: RR=0.14, p<0.0006). When the patients were divided into subgroups according to the age of onset and family history, the frequencies of KIR2DS4, KIR3DL1, and KIR2DS3 were significantly decreased in type I compared with type II psoriasis (3DL1, 2DS4: p<0.004; 2DS3: p<0.04) and were significantly decreased in psoriasis without family history compared to with family history (3DL1, 2DS4: p<0.007; 2DS3: p<0.05). The frequency of haplotype combination BB was significantly increased in psoriasis compared with controls (RR=2.74, p<0.009). Conclusion: These results suggest that KIR genotype is a factor for the occurrence and development of psoriasis and in future how combinations of HLA and KIR genes influence psoriasis needs to be defined.

• Biomolecules & Therapeutics
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• v.25 no.6
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• pp.578-585
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• 2017

Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.