• Archives of Pharmacal Research
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• v.28 no.3
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• pp.351-357
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• 2005

Endosulfan is one of the organochlorine pesticides, which are well-known endocrine disruptors (EDs), and it acts as an estrogen agonist. Estrogen is a group of hormones that play an important role in mammary gland function and are implicated in mammary carcinogenesis. In the present study, we studied the effects of endosulfan on nodule like alveolar lesion (NLAL) formation in mouse mammary gland development using a mouse mammary gland organ culture (MMOC) system. Although endosulfan-treated mammary glands did not form NLALs, more alveolar buds were formed in this group than in the negative control (vehicle-treated) group. In addition, telomerase reverse transcriptase (TERT) mRNA expression levels were increased in endosulfan-treated mammary glands in a dose-dependent manner. Telomerase can be activated by estrogen, therefore, we examined the effects of endosulfan on telomerase activity, and found that the telomerase activity in estrogen receptor-positive MCF-7 cells was up-regulated by endosulfan treatment. Moreover, this activation was accompanied by the up­regulation of the TERT mRNA expression. Also, transient expression assays using CAT reporter plasm ids containing various fragments of the TERT promoter showed that this imperfect palindromic estrogen-responsive element is almost certainly responsible for the transcriptional activation by endosulfan. These results may help elucidate the endocrine disrupting mechanism of endosulfan.

• Journal of Life Science
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• v.20 no.7
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• pp.1113-1120
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• 2010

This study investigated the efficacy of macelignan and hot water with Chinese traditional herb (CTH) extract on altering severe diabetic conditions in C57BL/KsJ-db/db mice. Previously, the anti-diabetic effects of macelignan were partly reported as a PPAR $\alpha/\gamma$-dual agonist. Here, we futher studied whether a combination of macelignan and CTH had more beneficial effects or not. The macelignan and CTH compound significantly decreased fasting blood glucose and HbA1c compared to macelignan-treated mice, and also significantly improved postprandial glucose, insulin sensitivity, and plasma lipid profiles (FFA, and TG). On the other hand, insulin levels were not significantly changed compared to the diabetic control group. There were no significant changes in the concentrations of total cholesterol and HDL-cholesterol, but there were changes in HTR and AI. These results suggest that the macelignan and CTH compound ameliorates hyperglycemia and efficiently improves postprandial glucose, insulin sensitivity, and hyperlipidemia compared with macelignan in db/db mice. Moreover, the macelignan and CTH compound seems to be more potent in affecting diabetic complications than macelignan.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.6
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• pp.447-453
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• 2012

TLR6 forms a heterodimer with TLR2 and TLR4. While proinflammatory roles of TLR2 and TLR4 are well documented, the role of TLR6 in inflammation is poorly understood. In order to understand mechanisms of action of TLR6 in inflammatory responses, we investigated the effects of FSL-1, the TLR6 ligand, on expression of chemokine CCL2 and cytokine IL-$1{\beta}$ and determined cellular factors involved in FSL-1-mediated expression of CCL2 and IL-$1{\beta}$ in mononuclear cells. Exposure of human monocytic leukemia THP-1 cells to FSL-1 resulted not only in enhanced secretion of CCL2 and IL-$1{\beta}$, but also profound induction of their gene transcripts. Expression of CCL2 was abrogated by treatment with OxPAPC, a TLR-2/4 inhibitor, while treatment with OxPAPC resulted in partially inhibited expression of IL-$1{\beta}$. Treatment with FSL-1 resulted in enhanced phosphorylation of Akt and mitogen-activated protein kinases and activation of protein kinase C. Treatment with pharmacological inhibitors, including SB202190, SP6001250, U0126, Akt inhibitor IV, LY294002, GF109203X, and RO318220 resulted in significantly attenuated FSL-1-mediated upregulation of CCL2 and IL-$1{\beta}$. Our results indicate that activation of TLR6 will trigger inflammatory responses by upregulating expression of CCL2 and IL-$1{\beta}$ via TLR-2/4, protein kinase C, PI3K-Akt, and mitogen-activated protein kinases.

• Biomolecules & Therapeutics
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• v.30 no.3
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• pp.232-237
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• 2022

Autism spectrum disorder (ASD) having core characteristics of social interaction problems and repetitive behaviors and interests affects individuals at varying degrees and comorbidities, making it difficult to determine the precise etiology underlying the symptoms. Given its heterogeneity, ASD is difficult to treat and the development of therapeutics is slow due to the scarcity of animal models that are easy to produce and screen with. Based on the theory of excitation/inhibition imbalance in the brain with ASD which involves glutamatergic and/or GABAergic neurotransmission, a pharmacologic agent to modulate these receptors might be a good starting point for modeling. N-methyl-D-aspartic acid (NMDA) is an amino acid derivative acting as a specific agonist at the NMDA receptor and therefore imitates the action of the neurotransmitter glutamate on that receptor. In contrast to glutamate, NMDA selectively binds to and regulates the NMDA receptor, but not other glutamate receptors such as AMPA and kainite receptors. Given this role, we aimed to determine whether NMDA administration could result in autistic-like behavior in adolescent mice. Both male and female mice were treated with saline or NMDA (50 and 75 mg/kg) and were tested on various behavior experiments. Interestingly, acute NMDA-treated mice showed social deficits and repetitive behavior similar to ASD phenotypes. These results support the excitation/inhibition imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model of ASD-like behaviors.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.26 no.3
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• pp.254-261
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• 2000

The present study has attempted to look into the mechanism of ras-induced carcinogenesis in a human epithelial cell system. Human epithelial cells immortalized with Ad12-SV40 hybrid virus were used to assess carcinogenic potential of the ras-oncogene. Cells transfected with pSV2-ras showed characteristics of cellular transformation. The transformation parameters such as cell density, soft-agar colony formation, and cell aggregation were significantly increased in the cells expressing ras oncoprotein. In addition, the duration required for the appearance of foci was shortened in the ras-transfected cells. Consistent with other reports, our results demonstrated an evidence that the ras-oncogene induced the cellular transformation of human epithelial cell system. When a high concentration of glucocorticoid was added into the media, transformation process was accelerated. It is speculated that glucocorticoid may provide an advantageous environment for the proliferation of the transformed cells. The induction of the intracellular free calcium concentrations following agonist treatment was significantly lower in the transformed cells than in the control cells. These effects were more manifested in the presence of extracellular cacium, indicating that the transformation process may alter the influx pathway of extracellular calcium. The induction of $IP_3$ following agonist treatment was also lower in the transformed cells than in the control cells. Thus, it is suggested that phospholipase C-coupled pathway was down-regulated in the process of the ras-induced transformation. While the levels of $TGF-{\beta}_1$ and PAI-2 mRNAs were decreased, the level of fibronectin mRNA was increased. The results indicate that mechanism of the ras-induced transformation may be associated with the altered expressions of growth regulatory factors. The present study demonstrates an evidence that the ras-induced cellular transformation may be associated with alteration of signal transduction and growth regulatory factors. The study will contribute to improve the understanding of molecular mechanism of epithelium-derived cancers including oral cancer.

• Journal of Embryo Transfer
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• v.20 no.3
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• pp.191-200
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• 2005

Many studies have shown that the development of mouse early 2-cell embryos in vitro is related with the intracellular $Ca^{2+}$ changes. In ICR strain mouse, the development of embryos arrests at early 2-cell stage, but the arrested early 2-cell embryos can be rescued by the addition of $Ca^{2+}$-related materials. Acetylcholine (ACh) increases intracellular $Ca^{2+}$ concentration ([$Ca^{2+}$]i) via the mAChR-PLC-IP3 pathway in mouse oocytes. We examined whether ACh rescues 2-cell block in mouse. In early 2-cell embryos, ACh increased [$Ca^{2+}$]i in a dose-dependent manner (p<0.001), and had an effect on rescue of 2-cell block and embryonic development. To identify the signal pathway involved in ACh-induced rescue of 2-cell block, we first applied an agonist of ACh receptor (AChR). Like ACh, carbachol increased intracellular $Ca^{2+}$ concentration ([$Ca^{2+}$]i) and atropine, an antagonist of ACh receptor, blocked the ACh-induced $Ca^{2+}$ increase. In $Ca^{2+}$-free medium, ACh also increased [$Ca^{2+}$]i, indicating that $Ca^{2+}$ increased by ACh is mainly released from the intracellular $Ca^{2+}$ store. The ACh-induced $Ca^{2+}$ increase was blocked by PLC inhibitor (U73122), ryanodine receptor (RyR) antagonist (dantrolene), and CaM KII inhibitor (KN-93), but not by IP3R antagonists (xestospongin C). These results show that ACh increases intracellular $Ca^{2+}$ concentration via mAChR/PLC/RyR, and this contributes to the rescue of 2-cell block.

• Korean Journal of Veterinary Research
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• v.41 no.3
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• pp.319-325
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• 2001

Several recent studies demonstrate that cAMP accumulation evokes marked changes in magnesium ($Mg^{2+}$) homeostasis. The goal of this study was to investigate the effect of melatonin, the principal hormone of the vertebral pineal gland, on $Mg^{2+}$ regulation in perfused guinea pig hearts. We hypothesized that melationin would regulate $Mg^{2+}$ efflux induced by adrenergic drugs and cAMP analogues because melatonin inhibites adneylate cyclase (AC) and phospholipase C(PLC) in the hearts. The $Mg^{2+}$ content in the perfusate was significantly higher in the presence than in the absence of melatonin. The addition of forskolin, isoproterenol or dimaprit to perfused hearts induced a marked $Mg^{2+}$ efflux. These effluxes were not inhibited by melatonin. The $Mg^{2+}$ efflux could also be induced by phenylephrine, a ${\alpha}_1$-adrenoceptor agonist. This phenylephrine-induced $Mg^{2+}$ efflux was inhibited by melatonin. In addition, the phenylephrine-induced $Mg^{2+}$ efflux was potentiated by PMA, a protein kinase C(PKC) activator. This $Mg^{2+}$ efflux was inhibited by melatonin. In conclusion, these data suggest that melatonin regulates $Mg^{2+}$ homeostasis and the inhibitory effect of melatonin on ${\alpha}_1$-adrenoceptor-stimulated $Mg^{2+}$ efflux may occur through an inhibition of PLC pathway in perfused guinea pig hearts.

• Korean Journal of Veterinary Research
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• v.55 no.4
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• pp.233-240
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• 2015

Although the effects of the rice bran have recently been investigated, there is no information regarding platelet physiology available. However, it is well known that fermented natural plants have a beneficial effect on cardiovascular diseases. Therefore, this study was conducted to investigate whether fermented rice bran extract (FRBE) with several plants (Artemisia princeps, Angelica Gigantis Radix, Cnidium officinale, and Camellia sinensis) affected agonist-induced platelet aggregation, and if so, what the underlying mechanism of its activity was. We performed several experiments, including in vitro platelet aggregation, intracellular calcium concentration and adenosine triphosphate release. In addition, the activation of integrin ${\alpha}_{II}b{\beta}3$ was determined using fibrinogen binding. Thrombus formation was also evaluated in vivo using an arterio-venous shunt model. The FRBE inhibited collagen-induced platelet aggregation in a concentration-dependent manner. FRBE significantly and dose dependently attenuated thrombus formation using rat arterio-venous shunt. FRBE suppressed the intracellular calcium mobilization in collagen-stimulated platelets. We also found that FRBE inhibited extracellular stimuli-responsive kinase 1/2, p38-mitogen-activated protein kinases and c-Jun N-terminal kinase phosphorylation. These results suggested that FRBE inhibited collagen-induced platelet aggregation, which was mediated by modulation of downstream signaling molecules. In conclusion, FRBE could be developed as a functional food against aberrant platelet activation-related cardiovascular diseases.

• Korean Journal of Fisheries and Aquatic Sciences
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• v.40 no.6
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• pp.374-379
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• 2007

Two experiments were designed to examine short-term effects of human chorionic gonadotropin (hCG), and long-term effects of gonadotropin-releasing hormone agonist (GnRHa), $17{\alpha}-hydroxyprogesterone$ (17P), and $17{\alpha},20{\beta}-dihydroxy-4-pregnen-3-one\;(17,20{\beta}P)$, alone or in combination, on milt production of the starry flounder Platichthys stellatus. In the first experiment, fish were injected with either 200 IU hCG/kg body weight or the same volume of marine fish Ringer's solution (MFRS). In the second experiment, each fish was implanted with a blank cholesterol pellet (control), $200\;{\mu}g$ GnRHa, $500\;{\mu}g$ 17P, or $100\;{\mu}g\;17,20{\beta}P/kg$ body weight alone or in combination. In the first experiment, hCG injection resulted in an increase in the expressible milt volume and a decrease in the spermatocrit (Sct). After pellet implantation in the second experiment, the milt volume was increased in males treated with GnRHa, GnRHa+17P, or $GnRHa+17,20{\beta}P$. On day 7 after hormone pellet implantation, the milt volume began to increase, and on day 14, the milt volume in the $GnRHa+500\;{\mu}g$ 17P group was significantly higher than that in the control group. Compared with the control group, the hormone pellet-treated groups had a significant reduction in the mean Sct and sperm concentration (Sc) at day 7 after pellet implantation, while there were no differences in total sperm number. The results suggest that increases in milt volume are generally associated with decreases in Sct and SC, suggesting that the main mechanism for the increase in milt volume was milt hydration.

• Journal of Physiology & Pathology in Korean Medicine
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• v.28 no.6
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• pp.614-620
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• 2014

Kainic acid (KA) is a excitatory agonist causing epileptic seizure and excitotoxicity in the hippocampus. Gastrodia Elata (GE) is known to have anti-convulsant and anti-oxidant effects. This study was investigated a possible role of GE in suppressing epileptic seizure using KA-induced epilepsy mouse model. Eight-week-old male C57BL/6 mice were administrated GE (50 or 500 mg/kg) once a day for 5 days, and then injected KA (30 mg/kg) intraperitoneally. Behavioral changes in mice by KA were evaluated for 90 minutes immediately after the KA administration. Six hours after the KA administration, their brains were harvested and the expressions of glutamate decarboxylase 67 (GAD-67) and K+-Cl- cotransporter 2 (KCC2) in the hippocampus of the mice were measured by immunohistochemistry.GE delayed the onset of epileptic seizure after KA administration, suppressed the severity of the seizure and decreased the number of severe seizures dose dependently. Moreover, GAD-67 and KCC2 expressions in the cornu ammonis (CA) 1 and CA3 of 500 mg/kg GE administrated mice were significantly increased compared to those in KA-treated mice.GAD-67 and KCC2 play an important role in regulating GABAergic system. Our results suggest that GE has anti-convulsant effect against KA-induced epileptic seizure through enhancing GABAergic system.