• 동의생리병리학회지
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• 제18권6호
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• pp.1860-1868
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• 2004

Geijibokryunghwan has a wide range of therapeutic applications, and some reports have indicated that it has protective activity against atherosclerosis, and more specifically stroke and myocardial infarction. A recent report showed that atherosclerotic plaque volume can be reduced by supplying Geijibokryunghwan extracts for several years. In this study, we used a component of Geijibokryunghwan, which has been used for the prevention of atherosclerosis in Korea for several years, and has proven to be useful in lowering the occurrence of cerebral infarction. In a preliminary study, we found that Geijibokryunghwan potently suppressed platelet aggregation induced by various agonists. In this study, we sought to explore the mechanism by which Geijibokryunghwan inhibits platelet aggregations.

• Asian Pacific Journal of Cancer Prevention
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• 제16권14호
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• pp.5883-5887
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• 2015

Despite recent advances in therapeutic strategies for lung cancer, mortality still is increasing. In the present study, we investigated the anti-cancer effects of KMU-193, 2-(4-Ethoxy-phenyl)-N-{5-[2-fluoro-4-(4-methylpiperazine-1-carbonyl)-phenylamino]-1H-indazol-3-yl}-acetamide in a human non-small cell lung cancer cell line A549. KMU-193 strongly inhibited the proliferation of A549 cells, but it did not have anti-proliferative effect in other types of cancer cell lines. KMU-193 further induced apoptosis in association with activation of caspase-3 and cleavage of PLC-${\gamma}1$. However, KMU-193 had no apoptotic effect in untransformed cells such as TMCK-1 and BEAS-2B. Interestingly, pretreatment with z-VAD-fmk, a pan-caspase inhibitor, strongly abrogated KMU-193-induced apoptosis. KMU-193 treatment enhanced the expression levels of p53 and PUMA. Importantly, p53 siRNA transfection attenuated KMU-193-induced apoptosis. Collectively, these results for the first time demonstrate that KMU-193 has strong apoptotic effects on A549 cells and these are largely mediated through caspase-3- and p53-dependent pathways.

• 동의생리병리학회지
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• 제22권3호
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• pp.630-641
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• 2008

Gamisamgibopae-tang (GMSGBPT) is a traditional Korean medicine, which has been used for patients suffering from a lung disease in Oriental medicine. In the present study, we examined the biochemical mechanisms of apoptosis by GMSGBPT in NCI-H460 and A549 human non-small-cell lung cancer cell lines. It was found that GMSGBPT could inhibit the cell proliferation of A549 cells in a concentration-dependent manner, however GMSGBPT did not affect the cell proliferation of NCI-H460 cells. Apoptotic cell death in A549 cells were detected using DAPI staining and annexin V fluorescein methods. The induction of apoptotic cell death by GMSGBPT was connected with a down-regulation of anti-apoptotic Bcl-2 and Bcl-xL expression, and proteolytic activation of caspase-3 and caspase-9 in A549 cells. However, GMSGBPT did not affect the levels of pro-apoptotic Bax and Bad expression, and activity of caspase-8. GMSGBPT treatment also concomitant degradation and/or inhibition of poly (ADP-ribose) polymerase (PARP), ${\beta}$-catenin, phospholipase C-1 (PLC${\gamma}$1) and DNA fragmentation factor 45/inhibitor of caspase-activated DNase (DFF45/ICAD). Taken together, these findings suggest that GMSGBPT may be a potential chemotherapeutic agent for the control of human non-small-cell lung cancer cells and further studies will be needed to identify the active compounds that confer the anti-cancer activity of GMSGBPT.

• The Korean Journal of Physiology and Pharmacology
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• 제13권5호
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• pp.349-356
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• 2009

We previously reported that glial cell line-derived neurotropic factor (GDNF) receptor ${\alpha}$ 1 (GFR ${\alpha}$ 1) is a direct target of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1). In the present study, we further analyzed the physiological roles of Ape1/Ref-1-induced GFR ${\alpha}$ 1 expression in Neuro2a mouse neuroblastoma cells. Ape1/Ref-1 expression caused the clustering of GFR ${\alpha}$ 1 immunoreactivity in lipid rafts in response to GDNF. We also found that Ret, a downstream target of GFR ${\alpha}$ 1, was functionally activated by GDNF in Ape1/Ref-1-expressing cells. Moreover, GDNF promoted the proliferation of Ape1/Ref-1-expressing Neuro2a cells. Furthermore, GFR ${\alpha}$ 1-specific RNA experiments demonstrated that the downregulation of GFR ${\alpha}$ 1 by siRNA in Ape1/Ref-1-expressing cells impaired the ability of GDNF to phosphorylate Akt and PLC ${\gamma}$-1 and to stimulate cellular proliferation. These results show an association between Ape1/Ref-1 and GDNF/GFR ${\alpha}$ signaling, and suggest a potential molecular mechanism for the involvement of Ape1/Ref-1 in neuronal proliferation.

• 동의생리병리학회지
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• 제21권6호
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• pp.1437-1449
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• 2007

In this study, the effect of extract of Corydalis yanhusuo (ECT) used in Oriental medicine therapy was investigated on the cell growth and apoptosis of HepG2 human hepatoma cells. It was found that ECT could inhibit the cell growth effectively in a dose-dependent manner, which was associated with morphological change and apoptotic cell death such as formation of apoptotic bodies, DNA fragmentation and increased populations of apoptotic-sub G1 phase. And we observed the effects of ECT on loss of mitochondrial membrane potential (MMP), using the JC-1 probe by DNA flow cytometric analysis. Apoptosis of HepG2 cells by ECT was associated with a down-regulation of anti apoptotic Bcl-2 expression, inhibitor of apoptosis proteins (IAPs) expression and proteolytic activation of caspase-3 and caspase-9. However, ECT did not affect the pro-apoptotic Bax expression and activity of caspase-8. ECT treatment also concomitant degradation and /or inhibition of poly (ADP-ribose) polymerase (PARP), phospholipase C-1 ($PLC{\gamma}1$). Furthermore, ECT treatment caused a dose-dependent inhibition of iNOS and cyclooxygenase-2 (Cox-2). Additionally ECT have been implicated in the regulation of telomerase expression. ECT treatment induced the down-regulation of telomerase reverse transcriptase mRNA (hTERT) expression of HepG2 cells. Taken together, these findings suggest that ECT may be a potential chemotherapeutic agent for the control of HepG2 human hepatoma cells.

• 동의생리병리학회지
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• 제20권6호
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• pp.1584-1592
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• 2006

Houttuynia cordata Thunb, well known as 'E-Sung-Cho' in Korea, is traditional medicinal plant generally used in Oriental medicine therapy. We previously reported that the water extract of H. cordata inhibited cell proliferation and induced apoptosis in human breast carcinoma cells. In the present study, we investigated the biochemical mechanisms of anti-proliferative effects by the methanol extract of H. cordata (MEHC) in human lung carcinoma A549 cells. It was found that MEHC could inhibit the cell growth in a dose-dependent manner, which was associated with morphological change and apoptotic cell death as determined by formation of apoptotic bodies, DNA fragmentation and increased populations of apoptotic-sub G1 phase cells. Apoptosis of A549 cells by MEHC was also connected with a down-regulation of anti-apoptotic Bcl-2 and inhibitor of apoptosis proteins (IAPs) expression. MEHC treatment induced the proteolytic activation of caspase-3, caspase-8 and caspase-9, and a concomitant inhibition of poly(ADP-ribose) polymerase (PARP), ${\beta}$-catenin and phospholipase (PLC)-${\gamma}$1 protein expression. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of H. cordata.

• Biomolecules & Therapeutics
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• 제27권3호
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• pp.311-317
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• 2019

Mast cells are the most prominent effector cells of Type 1 hypersensitivity immune responses. CYC116 [4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl] pyrimidin-2-amine] is under development to be used as an anti-cancer drug, but the inhibitory effects of CYC116 on the activation of mast cells and related allergy diseases have not reported as of yet. In this study, we demonstrated, for the first time, that CYC116 inhibited the degranulation of mast cells by antigen stimulation ($IC_{50}$, ${\sim}1.42{\mu}M$). CYC116 also inhibited the secretion of pro-inflammatory cytokines including TNF-${\alpha}$ ($IC_{50}$, ${\sim}1.10{\mu}M$), and IL-6 ($IC_{50}$, ${\sim}1.24{\mu}M$). CYC116 inhibited the mast cell-mediated allergic responses, passive cutaneous anaphylaxis (ED50, ~22.5 mg/kg), and passive systemic anaphylaxis in a dose-dependent manner in laboratory experiments performed on mice. Specifically, CYC116 inhibited the activity of Fyn in mast cells and inhibited the activation of Syk and Syk-dependent signaling proteins including LAT, $PLC{\gamma}$, Akt, and MAP kinases. Our results suggest that CYC116 could be used as an alternative therapeutic medication for mast cell-mediated allergic disorders, such as atopic dermatitis and allergic rhinitis.

• 생명과학회지
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• 제23권4호
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• pp.518-528
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• 2013

꿀풀과(Labiatae)에 속하는 황금(黃芩, S. baicalensis)은 한국, 중국, 몽골 및 시베리아 동부 등지에 분포하는 여러해살이 초본식물로서 예로부터 민간처방 약재로 사용되었으며, 한방에서는 뿌리 말린 것을 이질, 발열 및 황달의 치료제로 사용되고 있다. 또한 최근 연구에 따르면 황금 추출물은 항염증, 항당뇨, 항균, 항알레르기, 항바이러스, 항고혈압, 항산화 및 항암 효능을 가지는 것으로 알려져 있으나 신세포암에서의 항암효능 및 분자생물학적 기전에 대해서는 명확히 밝혀져 있지 않다. 본 연구에서는 인체 신세포암 Caki-1 세포에서 황금 에탄올 추출물(ethanol extract of S. baicalensis, EESB)이 유발하는 항암효과 및 항암기전을 조사하였다. 본 연구의 결과에 의하면 EESB 처리에 의한 Caki-1 세포의 증식억제는 apoptosis 유발과 밀접한 연관이 있었으며, 이는 DR4 Fas ligand 및 Bax 단백질의 발현 증가와 Bid, XIAP 및 cIAP-1의 발현 억제와 관련이 있었다. EESB는 또한 미토콘드리아의 기능 손상과 caspase-3의 기질단백질인 PARP, ${\beta}$-catenin 및 $PLC{\gamma}$-1 단백질의 단편화를 유발하였다. 그러나 EESB 처리에 의하여 유발되었던 apoptosis가 pan-caspases inhibitor인 z-VED-fmk를 이용하여 caspases의 활성을 억제하였을 경우 현저하게 감소되어, EESB에 의한 apoptosis 과정에 caspase의 활성 증대가 중요한 역할을 한다는 것을 알 수 있었다. 이러한 결과들은 황금의 항암작용을 이해하는데 중요한 자료가 될 것이고 나아가 향후 수행될 추가 실험을 위한 기초 자료로서 그 가치가 매우 높을 것으로 생각된다.

• 한국식품영양과학회지
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• 제40권5호
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• pp.649-659
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• 2011

연구에서는 콩다닥냉이 추출물의 항암활성을 조사하기 위하여 잎 및 뿌리의 열수 추출물(WELVL 및 WELVR)이 HCT116 대장암세포의 증식 억제와 연관된 apoptosis 유도 기전에 관한 연구를 시도하였다. 본 연구의 결과에 의하면 HCT116 세포에 WELVL 및 WELVR을 처리하였을 경우에 유발되는 증식 억제 및 형태 변화는 apoptosis 유발과 밀접한 연관이 있었으며, 증식억제 및 apoptosis 유도 효과는 WELVL에 비하여 WELVR에서 높게 나타났다. 특히 WELVR에 의한 apoptosis 유발에는 FasL의 발현 증가를 통한 caspase-8의 활성화와 이로 인한 Bid 단백질의 단편화와 함께 Bcl-2 family의 발현 변화를 통한 mitochondria의 기능 이상과 이로 인한 caspase-9 및 -3의 활성화, 그리고 기질단백질들의 분해가 중요한 역할을 하는 것으로 나타났다. 또한 IAP family의 발현 감소로 인한 caspase의 활성 증가도 어느 정도 관여하는 것으로 생각되어진다. 따라서 WELVR 처리에 의하여 유발되는 apoptosis는 extrinsic pathway 및 intrinsic pathway를 모두 경유하는 multiple apoptotic pathway에 의하여 조절되는 것으로 생각되며, 이러한 결과들은 인체 암세포에서 콩다닥냉이의 항암작용을 이해하는데 중요한 자료가 될 것이고 나아가 콩다닥냉이 추출물을 포함한 그와 유사한 항암제 후보물질들의 연구 기초자료로서 사용될 수 있을 것으로 생각된다.

• 생명과학회지
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• 제31권9호
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• pp.787-795
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• 2021

등골나물은 오랫동안 음식으로 사용되어 왔으며 한방에서 한약재로 사용되어왔으며, 특히 등골나물 추출물은 항염 및 항산화 효과가 보고되었다. 심혈관 질환인 동맥경화증은 동맥 혈관에서 발생하는 만성 염증이며 다양한 질환에 관여하고 있다. 재협착 및 신경병증 증식과 같은 심혈관 질환은 주로 혈관 평활근 세포의 다중 성장인자로 인한 비정상적인 성장과 이동으로 인해 발생하며, 혈소판유래 성장인자는 손상된 혈관벽에서 방출되며 혈관 평활근 세포의 증식 및 이동에 관여한다. 본 연구에서는 혈관 평활근 세포의 비정상적인 증식 및 이동에 대한 등골나물 추출물의 효과를 확인하였고, 혈소판유래 성장인자로 유도된 혈관 평활근 세포내에서 신호전달 경로를 조사하였다. 혈소판유래 성장인자로 유도된 혈관 평활근 세포에서 등골나물 추출물의 전처리는 세포 증식 및 이동을 효과적으로 감소시켰다. 또한, 세포 내 신호전달 경로 AKT, phospholipase C gamma (PLC-γ) 및 mitogen-activated protein kinase (MAPK)의 웨스턴 블롯 실험 결과, 이들 경로의 인산화 억제를 확인하였다. 유세포분석 데이터는 혈관 평활근 세포의 세포주기가 등골나물 추출물에 의해 차단되었음을 보여주었다. 이 결과는 혈소판유래 성장인자가 세포주기와 세포 내 신호전달 인자를 조절하여 혈관 평활근 세포의 증식과 이동을 억제 할 수 있음을 시사한다. 또한, 이는 등골나물 추출물이 혈관 평활근 세포의 비정상적인 증식 및 이동을 차단하여 심혈관 질환 예방에 하나의 소재로 사용될 수 있음을 시사한다.