• 대한물리치료과학회지
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• 제10권1호
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• pp.190-197
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• 2003

본 연구는 수컷 생식기관내 에스트로겐 작용을 구명하기 위한 과정의 일환으로 항에스트로겐 물질인 ICI 182,780을 투여하고, 이로 인한 수출소관의 형태적 변화를 관찰하였다. 대조군과 처리군 간에 수출소관의 관강 직경은 처리후 8일째에 팽창하기 시작하여 59일째까지 지속되었고, 처리군 마우스의 수출소관내의 상피세포 높이는 대조군과 비교해 볼 때, 처리 후 경과기간 내내 감소되었다. 사이세포 높이가 최대로 감소된 곳은 처리된 마우스 수출소관의 근위부로 38% 감소하였으며, 수출소관 상피세포내의 핵상 세포질의 높이는 처리군 마우스의 근위부, 원추부, 원위부에서 각각 46%, 39%, 33% 감소된 것으로 나타났다. 항에스트로겐, ICI 182,780을 수컷 마우스에 투여한 본 실험에서, ${\alpha}ERKO$ 유전자 변형 동물에서 관찰되었던 것과 유사한 생식기관의 형태적 변화가 나타났다. 즉 항에스트로겐이 에스트로겐 수용체와 결합하여 에스트로겐의 기능을 차단하고 이로 인해 수출관의 관강 분비물 재흡수가 억제되어 분비물이 축적됨으로써 다양한 형태적 변환가 초래된 것으로 사료된다. 따라서 수컷 생식기관내의 중요한 에스트로겐 기능중의 하나는 수출소관 부위의 분비물 재흡수 작용이라고 할 수 있다.

• The Korean Journal of Physiology and Pharmacology
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• 제6권4호
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• pp.187-191
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• 2002

Tamoxifen, an antiestrogen, has previously been shown to induce apoptosis in HepG2 human hepatoblastoma cells through activation of the pathways independent of estrogen receptors, i.e., intracellular $Ca^{2+}$ increase and generation of reactive oxygen species (ROS). However, the mechanism of tamoxifen to link increased intracellular $Ca^{2+}$ to ROS generation is currently unknown. Thus, in this study we investigated the possible involvement of calmodulin, a $Ca^{2+}$ activated protein, and $Ca^{2+}$/calmodulin-dependent protein kinase II in the above tamoxifen-induced events. Treatment with calmodulin antagonists (calmidazolium and trifluoroperazine) or specific inhibitors of $Ca^{2+}$/calmodulin-dependent protein kinase II (KN-93 and KN-62) inhibited the tamoxifen-induced apoptosis in a dose-dependent manner. In addition, these agents blocked the tamoxifen-induced ROS generation in a concentration-dependent fashion, which was completely suppressed by intracellular $Ca^{2+}$ chelation. These results demonstrate for the first time that, despite of its well-known direct calmodulin-inhibitory activity, tamoxifen may generate ROS and induce apoptosis through indirect activation of calmodulin and $Ca^{2+}$/calmodulin-dependent protein kinase II in HepG2 cells.

• 대한수의학회지
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• 제27권1호
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• pp.9-17
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• 1987

The present study has been carried out to elucidate the antiestrogenic effects of tamoxifen in immature rat uterus. The content of DNA and protein and uterine wet weight were measured after the injections of $5{\mu}g$ of estradiol-$17{\beta}$, $50{\mu}g$ of tamoxifen, a combination of both, or vehicle only subcutaneously. The results obtained were summarized as follows: 1. DNA content in uterus was increased at 48 hours after estradiol-$17{\beta}$ or tamoxifen injection (p<0.01). 2. The increament rate of uterine DNA content was significantly (p<0.01) lower in tamoxifen treated group than that in estradiol-$17{\beta}$ treated group. 3. Antiestrogenic effect of tamoxifen on protein content in uterus was apparent at 72 hours after simultaneous administration of both drugs. 4. The uterine wet weight was started to increase at three hours after the injection of estradiol-$17{\beta}$ or tamoxifen. 5. While estradiol-$17{\beta}$ increased steadily uterine wet weight up to 138.5mg at 72 hours after the injection, but tamoxifen failed to increase it after 48 hours. Tamoxifen inhibited significantly (p<0.01) the effect of estradiol-$17{\beta}$ on it thereafter.

• 대한수의학회지
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• 제25권2호
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• pp.187-195
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• 1985

The Present study has been carried out to elucidate the antiestrogenic effects of tamoxifen in uteri of immature rats. Immature female Sprague-Dawley rats were allocated into 4, groups and injected with $5{\mu}g$ of estradiol-$17{\beta}$, $50{\mu}g$ of tamoxifen, a combination of both or vehicle only subcutaneously three times after an interval of 24 hours respectively. The concentrations, of cytosol estradiol receptor in uterus were measured by DCC method before and 1, 3, 6, 12, 24, 48 and 72 hours after the above treatments and those of nuclear estradiol were measured by protamine exchange method 72 hours and those of nuclear estradiol were measured by protamine exchange method 72 hours after the above treatments. The results obtained were summarized as follows: 1. The binding affinity of tamoxifen to estradiol receptor in uterine cytosol was lower than that of estradiol-$17{\beta}$, accordingly the translocation of estradiol receptor into the nucleus was found to be delayed. 2. Tamoxifen caused the retention of estradiol receptor in nucleus over 24 hours and inhibited the replenishment of the receptor from nucleus to cytosol in uterus.

• 한국미생물·생명공학회지
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• 제35권2호
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• pp.81-97
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• 2007

Punica granatum, L. (Pomegranate) has 613 seeds which accidentally corresponds to the 613 commandments in the Bible. Accordingly, the fruit has been worshipped by the Jewish and other religious people from the ancient. Pomegranate's seed, peel and juice contain a variety of ethnomedical components so much as the sum of three kinds of other common fruits. The number of published papers related to the pomegranate in recent 7 years flourished 7 times more than before at the bases of Medline record. Since the containments of estrogen, as $17{\alpha}-estradiol,\;17{\beta}-estradiol$, estrone, and estradiol, etc., in pomegranate have been reported, public interests and commercial values of pomegranate arose considerably. The report was disproved later, however, merits of this fruit remained yet; clinical efficacy for preventing and remediating cancers including breast and prostate cancers by oral administration of the juice, seed oil, and peel extract is still believed to be true. In this review, target components of pomegranate such as antioxidants, anticancers, antiestrogens and ethnomedical components were analyzed and discussed along with examining its pharmaceutical efficacy and prescription to postmenopausal lesion, cardiosclerosis, cosmetic beautification, viral and allergic symptoms, and diabetes mellitus, etc.

• The Korean Journal of Physiology and Pharmacology
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• 제10권4호
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• pp.199-205
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• 2006

The functional expression of potassium $(K^+)$ channels has electrophysiologically been studied in bone cells from several species, however, their identity and regulation of gene expressions in bone cells are not well known. In the present study, to investigate how $K^+$ channel expressions are regulated by estrogen, we measured changes of transcript levels of various $Ca^{2+}$-activated ($K_{Ca}$) and ATP-sensitive $K^+$ channels in rat osteoblastic ROS 17/2.8 cells after treatment with estrogen. Application of 17${\beta}$-estradiol $(E_2)$ for 24 h and 48 h increased mRNA and protein expressions of inwardly rectifying $K^+$ channel (Kir) 6.2 and type 2 small conductance $K_{Ca}$ channel (SK2), respectively. Combined treatment of cells with 17${\beta}-E_2$ and ICI 182,780, a pure antiestrogen, suppressed 17${\beta}-E_2$-induced alterations of SK2 and Kir6.2 mRNA levels. In addition, treatment of cells with U0126, a specific inhibitor of extracellular receptor kinases (ERK)1/2, and SP600125, a specific inhibitor of c-jun N-terminal kinase (JNK) blocked the enhancing effects of 17${\beta}-E_2$ on SK2 and Kir6.2 protein expressions. On the other hand, blocking of p38 mitogen-activated protein kinase had no effect. Taken together, these results indicate that 17${\beta}-E_2$ modulates SK2 and Kir6.2 expressions through the estrogen receptor, involving ERK1/2 and JNK activations.

• 대한수의학회지
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• 제26권1호
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• pp.31-37
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• 1986

The present study has been carried out to elucidate the antiestrogenic effects of tamoxifen on RNA and protein synthesis in uteri of immature rats. Immature female Sprague-Dawley rats were allocated into 4 groups and injected with $5{\mu}g$ of estradiol-$17{\beta}$, $50{\mu}g$ of tamoxifen, a combination of both, or vehicle only subcutaneously three times with an interval of 24 hours respectively. The specific activities of $^3H$-uridine incorporation into uterine RNA and those of $^3H$-leucine incorporation into uterine protein were measured before and 1, 3, 6, 12, 24, 48 and 72 hours after the above treatments. The results obtained were summarized as follows; 1. Tamoxifen itself increased RNA synthesis an hour after treatment(169.18% of control), but it's specific activity was reduced to control level after 3 hours. Tamoxifen inhibited significantly (p<0.01) the activity of RNA synthesis of estradiol-$17{\beta}$. 2. The increasing rate of protein synthesis was lower in tamoxifen treated group than that in estradiol-$17{\beta}$ treated group. While the rate was steadily increased up to 357.4% of control by estradiol-$17{\beta}$ in 72 hours, tamoxifen itself failed to increase the rate after 24 hours and significantly (p<0.01) inhibited the activity of estradiol-$17{\beta}$(-167.4%).

• Animal cells and systems
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• 제15권3호
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• pp.189-196
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• 2011

We investigated the in vitro effects of nonylphenol (NP) and 3,3',4,4',5-pentachlorobiphenyl (PCB126) on steroidogenesis in redlip mullet, Chelon haematocheilus, oocytes. In experiment 1, we investigated the effects of NP and PCB126 on steroid production from exogenous steroid precursors. Vitellogenic oocytes (0.75 mm in diameter) were incubated with 10 and 100 ng/ml NP or PCB126 with $[^3H]17{\alpha}$-hydroxyprogesterone as a precursor. The major metabolites produced were androstenedione, testosterone (T), estrone, and estradiol-$17{\beta}$ ($E_2$). Both NP and PCB126 increased T production and decreased $E_2$ production, except for 100 ng/ml PCB126. In experiment 2, oocytes (0.65-0.75 mm in diameter) were exposed to NP and PCB126 at different concentrations (0.01, 0.1, 1, 10, and 100 ng/mL). After the incubation, T and $E_2$ production was measured by radioimmunoassay. NP inhibited $E_2$ production at concentrations of 0.01 and 0.1 ng/ml in 0.75-mm-diameter oocytes. NP at 1 and 100 ng/mL stimulated T production, but had no observable effect on $E_2$ production. PCB126 treatment did not affect $E_2$ production at any of the concentrations tested. NP alone at 0.1 ng/mL resulted in a significant decrease in $E_2$ production in 0.65-mm-diameter oocytes. PCB126 did not show any significant effects on either T or $E_2$ production at all concentrations tested. These results suggest that NP acts like an antiestrogen at lower concentrations (0.01-0.1 ng/ml) in vitellogenic oocytes of redlip mullet.

• Biomolecules & Therapeutics
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• 제20권3호
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• pp.313-319
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• 2012

In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. But their precise mechanism of action has not been elucidated. In this study, a novel synthetic inhibitor of HDAC, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide [IN-2001] was examined for its antitumor activity and the underlying molecular mechanisms of any such activity on human breast cancer cell lines. IN-2001 effectively inhibited cellular HDAC activity ($IC_{50}$ = 0.585 nM) inMDA-MB-231 human breast cancer cells. IN-2001 caused a significant dose-dependent inhibition of cell proliferation in estrogen receptor (ER) negative MDA-MB-231human breast cancer cells. Cell cycle analysis revealed that the growth inhibitory effects of IN-2001 might be attributed to cell cycle arrest at $G_0/G_1$ and/or $G_2$/Mphase and subsequent apoptosis in human breast cancer cells. These events are accompanied by modulating several cell cycle and apoptosis regulatory genes such as CDK inhibitors $p21^{WAF1}$ and $p27^{KIP1}$ cyclin D1, and other tumor suppressor genes such as cyclin D2. Collectively, IN-2001 inhibited cell proliferation and induced apoptosis in human breast cancer cells and these findings may provide new therapeutic approaches, combination of antiestrogen together with a HDAC inhibitor, in the hormonal therapy-resistant ER-negative breast cancers. In summary, our data suggest that this histone deacetylase inhibitor, IN-2001, is a novel promising therapeutic agent with potent antitumor effects against human breast cancers.

• 대한핵의학회지
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• 제34권5호
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• pp.410-417
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• 2000

목적: 현재 유방암 치료제로서 임상실험 제 2단계에 들어간 idoxifene은 항에스트로겐 의약품으로서 기존의 tamoxifen보다도 많은 장점을 가지고 있는 것으로 연구결과 밝혀졌다. 또한 방사성 동위원소 $[^{123}I]$를 표지한 $[^{123}I]$idoxifene은 SPECT을 이용한 유방암세포를 영상화하여 조기에 진단할 수 있는 진단시약으로서 널리 각광 받고 있다. 따라서 본 연구에서는 idoxifene의 전구체를 합성하고 $[^{123}I]$를 표지하여 세포 내 섭취론 관찰하였다. 대상 및 방법: $[^{123}I]$idoxifene을 위한 전구체는 McCague가 연구 발표한 자료를 바탕으로 (2-chloroethoxy)benzene과 2-phenylbutanoic acid를 출발물질로 하여 합성하였다. 표지는 $[^{123}I]$를 사용하였으며 분리는 Silica Sep-Pak을 사용하였으며 세포 내 섭취실험은 에스트로겐 리셉터를 가진 MCF-7과 대조군으로서 에스트로겐 리셉터가 없는 MDA-MB-468을 이용하였다. 결과 및 결론: Idoxifene의 전구체인 4-stannylated 화합물의 합성수율은 약 30%이었으며, $[^{123}I]$ 표지는 60분 경과에서 $90{\sim}92%$로 최대의 표지수율을 보였으며 방사화학적 순도는 98%이상이었다. 또한 세포 내 섭취실험에서 실험군과 대조군 사이에 섭취비율은 180분에서 1.7:1로 나타나 idoxifence은 항에스트로겐 효과가 아주 높은 것으로 판명되었다. 이를 바탕으로 배양세포와 동물모델을 이용한 추가적인 실험이 필요하며, 유방암 환자에게도 임상이용이 기대된다.