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Shinichi Kume - One of the best experts on this subject based on the ideXlab platform.
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effects of Coumestrol administration to maternal mice during pregnancy and lactation on immunoblogulin a secreting cells in mammary glands
Animal Science Journal, 2013Co-Authors: Mengdong Wang, Miki Sugimoto, Shuntaro Ikeda, Shinichi KumeAbstract:Mortality and morbidity of neonates continue to be major problems in humans and animals, and immunoblogulin A (IgA) provides protection against microbial antigens at mucosal surfaces. The present study was conducted to clarify the effects of Coumestrol administration to maternal mice during pregnancy and lactation on IgA antibody-secreting cells (ASC) in mammary glands in lactating mice. From 6.5 to 16.5 days post coitus and 1 to 13 days post partum (dpp), maternal mice were administered Coumestrol at 200 μg/kg body weight/day. Coumestrol administration increased the number of IgA ASC and the messenger RNA expression of IgA C-region and vascular cell adhesion molecule-1 in mammary glands of maternal mice at 14 dpp, but Coumestrol administration had no effect on the number of IgA ASC in the ileum. Coumestrol administration increased serum IgA concentration in maternal mice at 14 dpp, but IgA concentrations in serum, stomach contents, intestine and feces of neonatal mice were not affected by treatment. These results imply that Coumestrol administration to maternal mice during pregnancy and lactation is effective in increasing the numbers of IgA ASC in mammary glands during lactation owing to the activated messenger RNA expressions of IgA C-region and vascular cell adhesion molecule-1 in mammary gland.
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effects of Coumestrol administration to maternal mice during pregnancy and lactation on renal ca metabolism in neonatal mice
Animal Science Journal, 2012Co-Authors: Michihisa Ueda, Miki Sugimoto, Yoshihiro Horiguchi, Shuntaro Ikeda, Shinichi KumeAbstract:The present study was conducted to clarify the effects of Coumestrol administration to maternal mice during pregnancy and lactation on serum Ca and Ca metabolism in their neonatal mice. From 6.5 to 16.5 days post coitus and from 3 to 10 days after parturition, maternal mice were administered at 200 µg/kg body weight/day of Coumestrol. Coumestrol administration did not affect weight gains, serum Ca and the expression of vitamin D receptor (VDR) protein in the kidney of neonatal mice, but weight gains of maternal mice were decreased by Coumestrol administration. Coumestrol administration increased the messenger RNA (mRNA) expressions of epithelial Ca channels 1 (ECaC1) and VDR in the kidney of neonatal mice, and also increased the mRNA expressions of ECaC2 in the kidney and small intestine of male neonatal mice. The mRNA expressions of ECaC1, ECaC2, calbindin-D(9k) (CaBP-9k) and estrogen receptor (ER)α in the kidney and VDR in the small intestine of male neonatal mice were higher than those of female mice. Thus, Coumestrol administration to maternal mice during pregnancy and lactation may affect renal Ca metabolism in neonatal mice, especially male neonatal mice via maternal milk.
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effects of Coumestrol administration to pregnant and lactating mice on intestinal alkaline phosphatase activity
Phytotherapy Research, 2011Co-Authors: Yuka Kirihata, Miki Sugimoto, Yoshihiro Horiguchi, Michihisa Ueda, Shuntaro Ikeda, Shinichi KumeAbstract:The present study was conducted to clarify the effects of Coumestrol administration on Ca metabolism during pregnancy and in lactating mice. From 6.5 to 16.5 days post coitus (dpc), pregnant mice were administered Coumestrol at 200 µg/kg body weight/day. The duodenum, jejunum and blood samples were obtained at 17.5 dpc or 10 days after parturition (dap). Coumestrol administration decreased alkaline phosphatase (ALP) activity and mRNA expression of IAP and estrogen responsive genes, c-fos and vascular endothelial growth factor (VEGF), in the duodenum and jejunum of pre-delivery mice. In lactating mice, the ALP activity and mRNA expression of IAP were not changed, although Coumestrol administration decreased mRNA expression of c-fos in the duodeum and VEGF in the jejunum. Coumestrol did not affect serum Ca and the expression of vitamin D receptor protein in the duodenum and jejunum. Thus, Coumestrol administration during pregnancy may decrease the mRNA expression of IAP and the ALP activity in the intestine of the pre-delivery mice through ERα, but Coumestrol had little effect on intestinal ALP activity at 10 days after parturition. Copyright © 2010 John Wiley & Sons, Ltd.
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Coumestrol decreases intestinal alkaline phosphatase activity in post delivery mice but does not affect vitamin d receptor and calcium channels in post delivery and neonatal mice
Journal of Reproduction and Development, 2008Co-Authors: Yuka Kirihata, Tetsu Kawarabayashi, Satoshi Imanishi, Miki Sugimoto, Shinichi KumeAbstract:In this study, we investigated the effects of administration of Coumestrol during pregnancy on calcium (Ca) metabolism in post-delivery maternal and neonatal mice. From 6.5 to 16.5 days post coitus (dpc), pregnant females were administered daily doses of Coumestrol (200 microg/kg body weight/day). One day after parturition, blood samples and the kidneys, liver, jejunum and duodenum were obtained from each of maternal mouse, and blood samples and the kidneys and liver were obtained from neonatal mice. Coumestrol did not have any significant effect on the Ca and inorganic phosphorus concentrations in the sera of the maternal and neonatal mice. No notable effects of Coumestrol were observed in relation to Vitamin D receptor expression in the maternal and neonatal mice by immunohistochemical analysis. Coumestrol did not affect the Vitamin D receptor and epithelial calcium channel and 2 mRNA levels in any of the organs investigated. Enzyme histochemical analysis showed that Coumestrol decreased intestinal alkaline phosphatase activity in the maternal jejunum and duodenum. In the duodenum, Coumestrol decreased expression of intestinal alkaline phosphatase, c-fos and vascular endothelial growth factor at the mRNA level. However, we did not observe any significant effects of Coumestrol on the expression of these genes. In conclusion, Coumestrol decreased intestinal alkaline phosphatase activity in the small intestines of maternal mice at the level used in the present study, and the mechanisms underlying this effect are different for the jejunum and duodenum.
Gwonhwa Song - One of the best experts on this subject based on the ideXlab platform.
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Coumestrol induces mitochondrial dysfunction by stimulating ros production and calcium ion influx into mitochondria in human placental choriocarcinoma cells
Molecular Human Reproduction, 2017Co-Authors: Whasun Lim, Muhah Jeong, Fuller W Bazer, Changwon Yang, Gwonhwa SongAbstract:STUDY QUESTION Does Coumestrol inhibit proliferation of human placental choriocarcinoma cells? SUMMARY ANSWER Coumestrol promotes cell death in the choriocarcinoma cells by regulating ERK1/2 MAPK and JNK MAPK signaling pathways and through disruption of Ca2+ and ROS homeostasis. WHAT IS KNOWN ALREADY A number of patients who suffer from choriocarcinomas fail to survive due to delayed diagnosis or a recurrent tumor and resistance to traditional chemotherapy using platinum-based agents and methotrexate. To overcome these limitations, it is important to discover novel compounds which have no adverse effects yet can inhibit the expression of a target molecule to develop, as a novel therapeutic for prevention and/or treatment of choriocarcinomas. STUDY DESIGN, SIZE, DURATION Effects of Coumestrol on human placental choriocarcinoma cell lines, JAR and JEG3, were assessed in diverse assays in a dose- and time-dependent manner. PARTICIPCANTS/MATERIALS, SETTING, METHODS Effects of Coumestrol on cell proliferation, apoptosis (annexin V expression, propidium iodide staining, TUNEL and invasion assays), mitochondria-mediated apoptosis, production of reactive oxygen species (ROS), lipid peroxidation, glutathione levels and endoplasmic reticulum (ER) stress proteins in JAR and JEG3 cells were determined. Signal transduction pathways in JAR and JEG3 cells in response to Coumestrol were determined by western blot analyses. MAIN RESULTS AND THE ROLE OF CHANCE Results of the present study indicated that Coumestrol suppressed proliferation and increased apoptosis in JAR and JEG3 cells by inducing pro-apoptotic proteins, Bax and Bak. In addition, Coumestrol increased ROS production, as well as lipid peroxidation and glutathione levels in JAR and JEG3 cells. Moreover, Coumestrol-induced depolarization of mitochondrial membrane potential (MMP) and increased cytosolic and mitochondrial Ca2+ levels in JAR and JEG3 cells. Consistent with those results, treatment of JAR and JEG3 cells with a Ca2+ chelator and an inhibitor of IP3 receptor decreased Coumestrol-induced depolarization of MMP and increased proliferation in JAR and JEG3 cells. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION A lack of in vivo animal studies is a major limitation of this research. The effectiveness of Coumestrol to induce apoptosis of human placental choriocarcinoma cells requires further investigation. WIDER IMPLICATIONS OF THE FINDINGS Our results indicate that Coumestrol induces apoptotic effects on placental choriocarcinoma cells by regulating cell signaling and mitochondrial-mediated functions, with a potential to impair progression of the cancer. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0810 awarded to G.S. and HI17C0929 awarded to W.L.).
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Coumestrol inhibits proliferation and migration of prostate cancer cells by regulating akt erk1 2 and jnk mapk cell signaling cascades
Journal of Cellular Physiology, 2017Co-Authors: Whasun Lim, Muhah Jeong, Fuller W Bazer, Gwonhwa SongAbstract:Coumestrol is the one of the major phytoestrogens which is abundant in soybeans, legumes, brussel sprouts, and spinach. The beneficial effects of Coumestrol are well known in various biological processes including; neuroprotective effects on the nervous system, function of the female reproductive system, anti-bacterial properties, and anti-cancer effects. Although the anti-tumor activity of Coumestrol has been demonstrated for ovarian, breast, lung, and cervical cancers, little is known of its effects on prostate cancer. Therefore, in the present study, we investigated the chemotherapeutic effects of Coumestrol on two prostate cancer cell lines, PC3 and LNCaP. Our results showed that Coumestrol decreased proliferation and migration and induced apoptosis in both PC3 and LNCaP cells. Moreover, effects of Coumestrol on cell signaling pathways were investigated and it increased phosphorylation of ERK1/2, JNK, P90RSK, and P53 proteins in a dose- and time-dependent manner whereas phosphorylation of AKT was reduced by Coumestrol under the same conditions for culture of PC3 and LNCaP cells. In addition, mitochondrial dysfunction was induced by Coumestrol as evidenced by a significant loss of mitochondrial membrane potential. Furthermore, cleavage of caspase-3 and caspase-9, the apoptotic proteins associated with mitochondria, also changed in response to Coumestrol. Coumestrol also caused mitochondrial dysfunction resulting in an increase in ROS production in PC3 and LNCaP cells. These results suggest that Coumestrol can inhibit progression of prostate cancer and may be a novel chemotherapeutic agent for treatment of prostate cancer via effects mediated via the PI3K/AKT and ERK1/2 and JNK MAPK cell signaling pathways. J. Cell. Physiol. 232: 862-871, 2017. © 2016 Wiley Periodicals, Inc.
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stimulatory effects of Coumestrol on embryonic and fetal development through akt and erk1 2 mapk signal transduction
Journal of Cellular Physiology, 2016Co-Authors: Whasun Lim, Gwonhwa SongAbstract:Successful establishment of pregnancy is required for fetal-maternal interactions regulating implantation, embryonic development and placentation. A uterine environment with insufficient growth factors and nutrients increases the incidence of intrauterine growth restriction (IUGR) leading to an impaired uterine environment. In the present study, we demonstrated the effects of the phytoestrogen Coumestrol on conceptus development in the pig that is regarded as an excellent biomedical animal model for research on IUGR. Results of this study indicated that Coumestrol induced migration of porcine trophectoderm (pTr) cells in a concentration-dependent manner. In response to Coumestrol, the phosphorylation of AKT, P70S6K, S6, ERK1/2 MAPK, and P90RSK proteins were activated in pTr cells and ERK1/2 MAPK and P90RSK phosphorylation was prolonged for a longer period than for the other proteins. To identify the signal transduction pathway induced by Coumestrol, pharmacological inhibitors U0126 (an ERK1/2 inhibitor) and LY294002 (a PI3K inhibitor) were used to pretreat pTr cells. The results showed that Coumestrol-induced phosphorylation of ERK1/2 MAPK and P90RSK was blocked by U0126. In addition, the increased phosphorylation in response to Coumestrol was completely inhibited following pre-treatment incubation of pTr cells in the presence of LY294002 and U0126. Furthermore, these two inhibitors suppressed the ability of Coumestrol to induce migration of pTr cells. Collectively, these findings suggest that Coumestrol affects embryonic development through activation of the PI3K/AKT and ERK1/2 MAPK cell signal transduction pathways and improvement in the uterine environment through Coumestrol supplementation may provide beneficial effects of enhancing embryonic and fetal survival and development. J. Cell. Physiol. 231: 2733-2740, 2016. © 2016 Wiley Periodicals, Inc.
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Coumestrol suppresses proliferation of es2 human epithelial ovarian cancer cells
Journal of Endocrinology, 2016Co-Authors: Whasun Lim, Wooyoung Jeong, Gwonhwa SongAbstract:Coumestrol, which is predominantly found in soybean products as a phytoestrogen, has cancer preventive activities in estrogen-responsive carcinomas. However, effects and molecular targets of Coumestrol have not been reported for epithelial ovarian cancer (EOC). In the present study, we demonstrated that Coumestrol inhibited viability and invasion and induced apoptosis of ES2 (clear cell-/serous carcinoma origin) cells. In addition, immunoreactive PCNA and ERBB2, markers of proliferation of ovarian carcinoma, were attenuated in their expression in Coumestrol-induced death of ES2 cells. Phosphorylation of AKT, p70S6K, ERK1/2, JNK1/2, and p90RSK was inactivated by Coumestrol treatment in a dose- and time-dependent manner as determined in western blot analyses. Moreover, PI3K inhibitors enhanced effects of Coumestrol to decrease phosphorylation of AKT, p70S6K, S6, and ERK1/2. Furthermore, Coumestrol has strong cancer preventive effects as compared to other conventional chemotherapeutics on proliferation of ES2 cells. In conclusion, Coumestrol exerts chemotherapeutic effects via PI3K and ERK1/2 MAPK pathways and is a potentially novel treatment regimen with enhanced chemoprevention activities against progression of EOC.
Miki Sugimoto - One of the best experts on this subject based on the ideXlab platform.
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effects of Coumestrol administration to maternal mice during pregnancy and lactation on immunoblogulin a secreting cells in mammary glands
Animal Science Journal, 2013Co-Authors: Mengdong Wang, Miki Sugimoto, Shuntaro Ikeda, Shinichi KumeAbstract:Mortality and morbidity of neonates continue to be major problems in humans and animals, and immunoblogulin A (IgA) provides protection against microbial antigens at mucosal surfaces. The present study was conducted to clarify the effects of Coumestrol administration to maternal mice during pregnancy and lactation on IgA antibody-secreting cells (ASC) in mammary glands in lactating mice. From 6.5 to 16.5 days post coitus and 1 to 13 days post partum (dpp), maternal mice were administered Coumestrol at 200 μg/kg body weight/day. Coumestrol administration increased the number of IgA ASC and the messenger RNA expression of IgA C-region and vascular cell adhesion molecule-1 in mammary glands of maternal mice at 14 dpp, but Coumestrol administration had no effect on the number of IgA ASC in the ileum. Coumestrol administration increased serum IgA concentration in maternal mice at 14 dpp, but IgA concentrations in serum, stomach contents, intestine and feces of neonatal mice were not affected by treatment. These results imply that Coumestrol administration to maternal mice during pregnancy and lactation is effective in increasing the numbers of IgA ASC in mammary glands during lactation owing to the activated messenger RNA expressions of IgA C-region and vascular cell adhesion molecule-1 in mammary gland.
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effects of Coumestrol administration to maternal mice during pregnancy and lactation on renal ca metabolism in neonatal mice
Animal Science Journal, 2012Co-Authors: Michihisa Ueda, Miki Sugimoto, Yoshihiro Horiguchi, Shuntaro Ikeda, Shinichi KumeAbstract:The present study was conducted to clarify the effects of Coumestrol administration to maternal mice during pregnancy and lactation on serum Ca and Ca metabolism in their neonatal mice. From 6.5 to 16.5 days post coitus and from 3 to 10 days after parturition, maternal mice were administered at 200 µg/kg body weight/day of Coumestrol. Coumestrol administration did not affect weight gains, serum Ca and the expression of vitamin D receptor (VDR) protein in the kidney of neonatal mice, but weight gains of maternal mice were decreased by Coumestrol administration. Coumestrol administration increased the messenger RNA (mRNA) expressions of epithelial Ca channels 1 (ECaC1) and VDR in the kidney of neonatal mice, and also increased the mRNA expressions of ECaC2 in the kidney and small intestine of male neonatal mice. The mRNA expressions of ECaC1, ECaC2, calbindin-D(9k) (CaBP-9k) and estrogen receptor (ER)α in the kidney and VDR in the small intestine of male neonatal mice were higher than those of female mice. Thus, Coumestrol administration to maternal mice during pregnancy and lactation may affect renal Ca metabolism in neonatal mice, especially male neonatal mice via maternal milk.
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effects of Coumestrol administration to pregnant and lactating mice on intestinal alkaline phosphatase activity
Phytotherapy Research, 2011Co-Authors: Yuka Kirihata, Miki Sugimoto, Yoshihiro Horiguchi, Michihisa Ueda, Shuntaro Ikeda, Shinichi KumeAbstract:The present study was conducted to clarify the effects of Coumestrol administration on Ca metabolism during pregnancy and in lactating mice. From 6.5 to 16.5 days post coitus (dpc), pregnant mice were administered Coumestrol at 200 µg/kg body weight/day. The duodenum, jejunum and blood samples were obtained at 17.5 dpc or 10 days after parturition (dap). Coumestrol administration decreased alkaline phosphatase (ALP) activity and mRNA expression of IAP and estrogen responsive genes, c-fos and vascular endothelial growth factor (VEGF), in the duodenum and jejunum of pre-delivery mice. In lactating mice, the ALP activity and mRNA expression of IAP were not changed, although Coumestrol administration decreased mRNA expression of c-fos in the duodeum and VEGF in the jejunum. Coumestrol did not affect serum Ca and the expression of vitamin D receptor protein in the duodenum and jejunum. Thus, Coumestrol administration during pregnancy may decrease the mRNA expression of IAP and the ALP activity in the intestine of the pre-delivery mice through ERα, but Coumestrol had little effect on intestinal ALP activity at 10 days after parturition. Copyright © 2010 John Wiley & Sons, Ltd.
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Coumestrol decreases intestinal alkaline phosphatase activity in post delivery mice but does not affect vitamin d receptor and calcium channels in post delivery and neonatal mice
Journal of Reproduction and Development, 2008Co-Authors: Yuka Kirihata, Tetsu Kawarabayashi, Satoshi Imanishi, Miki Sugimoto, Shinichi KumeAbstract:In this study, we investigated the effects of administration of Coumestrol during pregnancy on calcium (Ca) metabolism in post-delivery maternal and neonatal mice. From 6.5 to 16.5 days post coitus (dpc), pregnant females were administered daily doses of Coumestrol (200 microg/kg body weight/day). One day after parturition, blood samples and the kidneys, liver, jejunum and duodenum were obtained from each of maternal mouse, and blood samples and the kidneys and liver were obtained from neonatal mice. Coumestrol did not have any significant effect on the Ca and inorganic phosphorus concentrations in the sera of the maternal and neonatal mice. No notable effects of Coumestrol were observed in relation to Vitamin D receptor expression in the maternal and neonatal mice by immunohistochemical analysis. Coumestrol did not affect the Vitamin D receptor and epithelial calcium channel and 2 mRNA levels in any of the organs investigated. Enzyme histochemical analysis showed that Coumestrol decreased intestinal alkaline phosphatase activity in the maternal jejunum and duodenum. In the duodenum, Coumestrol decreased expression of intestinal alkaline phosphatase, c-fos and vascular endothelial growth factor at the mRNA level. However, we did not observe any significant effects of Coumestrol on the expression of these genes. In conclusion, Coumestrol decreased intestinal alkaline phosphatase activity in the small intestines of maternal mice at the level used in the present study, and the mechanisms underlying this effect are different for the jejunum and duodenum.
Whasun Lim - One of the best experts on this subject based on the ideXlab platform.
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Coumestrol induces mitochondrial dysfunction by stimulating ros production and calcium ion influx into mitochondria in human placental choriocarcinoma cells
Molecular Human Reproduction, 2017Co-Authors: Whasun Lim, Muhah Jeong, Fuller W Bazer, Changwon Yang, Gwonhwa SongAbstract:STUDY QUESTION Does Coumestrol inhibit proliferation of human placental choriocarcinoma cells? SUMMARY ANSWER Coumestrol promotes cell death in the choriocarcinoma cells by regulating ERK1/2 MAPK and JNK MAPK signaling pathways and through disruption of Ca2+ and ROS homeostasis. WHAT IS KNOWN ALREADY A number of patients who suffer from choriocarcinomas fail to survive due to delayed diagnosis or a recurrent tumor and resistance to traditional chemotherapy using platinum-based agents and methotrexate. To overcome these limitations, it is important to discover novel compounds which have no adverse effects yet can inhibit the expression of a target molecule to develop, as a novel therapeutic for prevention and/or treatment of choriocarcinomas. STUDY DESIGN, SIZE, DURATION Effects of Coumestrol on human placental choriocarcinoma cell lines, JAR and JEG3, were assessed in diverse assays in a dose- and time-dependent manner. PARTICIPCANTS/MATERIALS, SETTING, METHODS Effects of Coumestrol on cell proliferation, apoptosis (annexin V expression, propidium iodide staining, TUNEL and invasion assays), mitochondria-mediated apoptosis, production of reactive oxygen species (ROS), lipid peroxidation, glutathione levels and endoplasmic reticulum (ER) stress proteins in JAR and JEG3 cells were determined. Signal transduction pathways in JAR and JEG3 cells in response to Coumestrol were determined by western blot analyses. MAIN RESULTS AND THE ROLE OF CHANCE Results of the present study indicated that Coumestrol suppressed proliferation and increased apoptosis in JAR and JEG3 cells by inducing pro-apoptotic proteins, Bax and Bak. In addition, Coumestrol increased ROS production, as well as lipid peroxidation and glutathione levels in JAR and JEG3 cells. Moreover, Coumestrol-induced depolarization of mitochondrial membrane potential (MMP) and increased cytosolic and mitochondrial Ca2+ levels in JAR and JEG3 cells. Consistent with those results, treatment of JAR and JEG3 cells with a Ca2+ chelator and an inhibitor of IP3 receptor decreased Coumestrol-induced depolarization of MMP and increased proliferation in JAR and JEG3 cells. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION A lack of in vivo animal studies is a major limitation of this research. The effectiveness of Coumestrol to induce apoptosis of human placental choriocarcinoma cells requires further investigation. WIDER IMPLICATIONS OF THE FINDINGS Our results indicate that Coumestrol induces apoptotic effects on placental choriocarcinoma cells by regulating cell signaling and mitochondrial-mediated functions, with a potential to impair progression of the cancer. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0810 awarded to G.S. and HI17C0929 awarded to W.L.).
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Coumestrol inhibits proliferation and migration of prostate cancer cells by regulating akt erk1 2 and jnk mapk cell signaling cascades
Journal of Cellular Physiology, 2017Co-Authors: Whasun Lim, Muhah Jeong, Fuller W Bazer, Gwonhwa SongAbstract:Coumestrol is the one of the major phytoestrogens which is abundant in soybeans, legumes, brussel sprouts, and spinach. The beneficial effects of Coumestrol are well known in various biological processes including; neuroprotective effects on the nervous system, function of the female reproductive system, anti-bacterial properties, and anti-cancer effects. Although the anti-tumor activity of Coumestrol has been demonstrated for ovarian, breast, lung, and cervical cancers, little is known of its effects on prostate cancer. Therefore, in the present study, we investigated the chemotherapeutic effects of Coumestrol on two prostate cancer cell lines, PC3 and LNCaP. Our results showed that Coumestrol decreased proliferation and migration and induced apoptosis in both PC3 and LNCaP cells. Moreover, effects of Coumestrol on cell signaling pathways were investigated and it increased phosphorylation of ERK1/2, JNK, P90RSK, and P53 proteins in a dose- and time-dependent manner whereas phosphorylation of AKT was reduced by Coumestrol under the same conditions for culture of PC3 and LNCaP cells. In addition, mitochondrial dysfunction was induced by Coumestrol as evidenced by a significant loss of mitochondrial membrane potential. Furthermore, cleavage of caspase-3 and caspase-9, the apoptotic proteins associated with mitochondria, also changed in response to Coumestrol. Coumestrol also caused mitochondrial dysfunction resulting in an increase in ROS production in PC3 and LNCaP cells. These results suggest that Coumestrol can inhibit progression of prostate cancer and may be a novel chemotherapeutic agent for treatment of prostate cancer via effects mediated via the PI3K/AKT and ERK1/2 and JNK MAPK cell signaling pathways. J. Cell. Physiol. 232: 862-871, 2017. © 2016 Wiley Periodicals, Inc.
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stimulatory effects of Coumestrol on embryonic and fetal development through akt and erk1 2 mapk signal transduction
Journal of Cellular Physiology, 2016Co-Authors: Whasun Lim, Gwonhwa SongAbstract:Successful establishment of pregnancy is required for fetal-maternal interactions regulating implantation, embryonic development and placentation. A uterine environment with insufficient growth factors and nutrients increases the incidence of intrauterine growth restriction (IUGR) leading to an impaired uterine environment. In the present study, we demonstrated the effects of the phytoestrogen Coumestrol on conceptus development in the pig that is regarded as an excellent biomedical animal model for research on IUGR. Results of this study indicated that Coumestrol induced migration of porcine trophectoderm (pTr) cells in a concentration-dependent manner. In response to Coumestrol, the phosphorylation of AKT, P70S6K, S6, ERK1/2 MAPK, and P90RSK proteins were activated in pTr cells and ERK1/2 MAPK and P90RSK phosphorylation was prolonged for a longer period than for the other proteins. To identify the signal transduction pathway induced by Coumestrol, pharmacological inhibitors U0126 (an ERK1/2 inhibitor) and LY294002 (a PI3K inhibitor) were used to pretreat pTr cells. The results showed that Coumestrol-induced phosphorylation of ERK1/2 MAPK and P90RSK was blocked by U0126. In addition, the increased phosphorylation in response to Coumestrol was completely inhibited following pre-treatment incubation of pTr cells in the presence of LY294002 and U0126. Furthermore, these two inhibitors suppressed the ability of Coumestrol to induce migration of pTr cells. Collectively, these findings suggest that Coumestrol affects embryonic development through activation of the PI3K/AKT and ERK1/2 MAPK cell signal transduction pathways and improvement in the uterine environment through Coumestrol supplementation may provide beneficial effects of enhancing embryonic and fetal survival and development. J. Cell. Physiol. 231: 2733-2740, 2016. © 2016 Wiley Periodicals, Inc.
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Coumestrol suppresses proliferation of es2 human epithelial ovarian cancer cells
Journal of Endocrinology, 2016Co-Authors: Whasun Lim, Wooyoung Jeong, Gwonhwa SongAbstract:Coumestrol, which is predominantly found in soybean products as a phytoestrogen, has cancer preventive activities in estrogen-responsive carcinomas. However, effects and molecular targets of Coumestrol have not been reported for epithelial ovarian cancer (EOC). In the present study, we demonstrated that Coumestrol inhibited viability and invasion and induced apoptosis of ES2 (clear cell-/serous carcinoma origin) cells. In addition, immunoreactive PCNA and ERBB2, markers of proliferation of ovarian carcinoma, were attenuated in their expression in Coumestrol-induced death of ES2 cells. Phosphorylation of AKT, p70S6K, ERK1/2, JNK1/2, and p90RSK was inactivated by Coumestrol treatment in a dose- and time-dependent manner as determined in western blot analyses. Moreover, PI3K inhibitors enhanced effects of Coumestrol to decrease phosphorylation of AKT, p70S6K, S6, and ERK1/2. Furthermore, Coumestrol has strong cancer preventive effects as compared to other conventional chemotherapeutics on proliferation of ES2 cells. In conclusion, Coumestrol exerts chemotherapeutic effects via PI3K and ERK1/2 MAPK pathways and is a potentially novel treatment regimen with enhanced chemoprevention activities against progression of EOC.
Kihun Park - One of the best experts on this subject based on the ideXlab platform.
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Coumestrol induces senescence through protein kinase ckii inhibition mediated reactive oxygen species production in human breast cancer and colon cancer cells
Food Chemistry, 2013Co-Authors: Young Hoon Lee, Heung Joo Yuk, Kihun Park, Youngseuk BaeAbstract:Abstract An inhibitor of the protein kinase CKII (CKII) was purified from leaves of Glycine max (L.) Merrill and was identified as Coumestrol by structural analysis. Coumestrol inhibited the phosphotransferase activity of CKII toward β-casein, with an IC50 of about 5 μM. It acted as a competitive inhibitor with respect to ATP as a substrate, with an apparent Ki value of 7.67 μM. Coumestrol at 50 μM resulted in 50% and 30% growth inhibition of human breast cancer MCF-7 and colorectal cancer HCT116 cells, respectively. Coumestrol promoted senescence through the p53-p21Cip1/WAF1 pathway by inducing reactive oxygen species (ROS) production in MCF-7 and HCT116 cells. The ROS scavenger N-acetyl- l -cysteine (NAC), NADPH oxidase inhibitor apocynin and p22phox siRNA almost completely abolished this event. Overexpression of CKIIα antagonised cellular senescence mediated by Coumestrol, indicating that this compound induced senescence via a CKII-dependent pathway. Since senescence is an important tumour suppression process in vivo, these results suggest that Coumestrol can function by inhibiting oncogenic disease, at least in part, through CKII inhibition-mediated cellular senescence.
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effect of soybean Coumestrol on bradyrhizobium japonicum nodulation ability biofilm formation and transcriptional profile
Applied and Environmental Microbiology, 2012Co-Authors: Kihun Park, Dipen Sangurdekar, Woo Suk ChangAbstract:Flavonoids, secondary plant metabolites which mainly have a polyphenolic structure, play an important role in plant-microbe communications for nitrogen-fixing symbiosis. Among 10 polyphenolic compounds isolated from soybean roots in our previous study, Coumestrol showed the highest antioxidant activity. In this study, its effect on the soybean nodulation was tested. The soybean symbiont Bradyrhizobium japonicum USDA110 pretreated with 20 μM Coumestrol enhanced soybean nodulation by increasing the number of nodules 1.7-fold compared to the control. We also tested the effect of Coumestrol on B. japonicum biofilm formation. At a concentration of 2 μM, Coumestrol caused a higher degree of biofilm formation than two major soybean isoflavonoids, genistein and daidzein, although no biofilm formation was observed at a concentration of 20 μM each compound. A genome-wide transcriptional analysis was performed to obtain a comprehensive snapshot of the B. japonicum response to Coumestrol. When the bacterium was incubated in 20 μM Coumestrol for 24 h, a total of 371 genes (139 upregulated and 232 downregulated) were differentially expressed at a 2-fold cutoff with a q value of less than 5%. No common nod gene induction was found in the microarray data. However, quantitative reverse transcription-PCR (qRT-PCR) data showed that incubation for 12 h resulted in a moderate induction (ca. 2-fold) of nodD1 and nodABC, indicating that soybean Coumestrol is a weak inducer of common nod genes. In addition, disruption of nfeD (bll4952) affected the soybean nodulation by an approximate 30% reduction in the average number of nodules.
