• BMB Reports
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• 제52권9호
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• pp.566-571
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• 2019

Lymphoma is one of the most curable types of cancer. However, drug resistance is the main challenge faced in lymphoma treatment. Peroxisomal acyl-CoA oxidase 1 (ACOX1) is the rate-limiting enzyme in fatty acid ${\beta}$-oxidation. Deregulation of ACOX1 has been linked to peroxisomal disorders and carcinogenesis in the liver. Currently, there is no information about the function of ACOX1 in lymphoma. In this study, we found that upregulation of ACOX1 promoted proliferation in lymphoma cells, while downregulation of ACOX1 inhibited proliferation and induced apoptosis. Additionally, overexpression of ACOX1 increased resistance to doxorubicin, while suppression of ACOX1 expression markedly potentiated doxorubicin-induced apoptosis. Interestingly, downregulation of ACOX1 promoted mitochondrial location of Bad, reduced mitochondrial membrane potential and provoked apoptosis by activating caspase-9 and caspase-3 related apoptotic pathway. Overexpression of ACOX1 alleviated doxorubicin-induced activation of caspase-9 and caspase-3 and decrease of mitochondrial membrane potential. Importantly, downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. Also, overexpression of ACOX1 significantly reduced stability of p73 protein thereby reducing p73 expression. Thus, our study indicated that suppression of ACOX1 could be a novel and effective approach for treatment of lymphoma.

• Animal Bioscience
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• 제35권4호
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• pp.533-543
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• 2022

Objective: Caspase-mediated apoptosis plays a crucial role in the regulation of endometrial and placental function in females. Caspase activity is tightly controlled by members of the inhibitors of apoptosis proteins (IAPs) family. However, the expression and regulation of IAPs at the maternal-conceptus interface has not been studied in pigs. Therefore, we determined the expression of IAP family members baculovirus IAP repeat-containing 1 (BIRC1) to BIRC6 at the maternal-conceptus interface in pigs. Methods: We obtained endometrial tissues from pigs at various stages of the estrous cycle and pregnancy, conceptus tissues during early pregnancy, and chorioallantoic tissues during mid- to late pregnancy and analyzed the expression of IAPs. Furthermore, we determined the effects of the steroid hormones estradiol-17β (E2) and progesterone on the expression of IAPs in endometrial explant tissue cultures. Results: During the estrous cycle, BIRC2 and BIRC5 expression varied cyclically, and during pregnancy, endometrial BIRC1, BIRC2, BIRC3, BIRC4, and BIRC5 expression varied in a stage-specific manner. Conceptus and chorioallantoic tissues also expressed IAPs during pregnancy. The BIRC2 and BIR3 mRNAs were localized to luminal epithelial cells, and BIRC4 proteins to glandular epithelial cells in the endometrium. Exposure of endometrial tissues to E2 increased the expression of BIRC6, while progesterone increased the expression of BIRC1, BIRC4, and BIRC6 in a dose-dependent manner. Conclusion: These results indicated that IAPs were expressed in the endometrium during the estrous cycle and at the maternal-conceptus interface during pregnancy in a stage-specific manner. In addition, steroid hormones were found to be responsible for the expression of some IAPs in pigs. Together, the results suggested that IAPs may play important roles in endometrial and placental functions by regulating caspase action and apoptosis at the maternal-conceptus interface.

• 한국식품영양과학회지
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• 제45권10호
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• pp.1422-1429
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• 2016

본 연구에서는 홍차버섯이라고 알려진 콤부차(Kombucha, K)에 플라보노이드 성분 및 각종 기능성 물질이 풍부한 감귤액을 첨가하여 감귤의 생리활성 물질들이 콤부차로 이행되는 효과를 기대하여 감귤 콤부차(citrus Kombucha, CK)를 배양한 후 항산화 능력 및 인체 방광암세포(T-24와 5637)를 이용한 항암 효과를 확인하고 더 나아가 암의 증식을 억제시킬 수 있는 천연소재 탐색을 목적으로 연구를 진행하였다. 항산화 및 총페놀 함량 결과는 K보다 CK의 항산화 능력과 페놀 함량이 높게 확인되었으며 방광암세포 T-24와 5637에 K 혹은 CK를 24시간 처리한 후 MTT assay를 통해 세포독성을 확인한 결과 농도 의존적으로 생존율이 감소하였다. 특히 T-24 세포에서는 CK를 처리하였을 때 현저한 세포의 형태적 변화를 확인하였다. Western immunoblot을 통해 apoptosis 관련 단백질들의 발현을 확인하였는데 T-24에 CK 처리하였을 때 Bcl-2의 발현은 크게 감소하였으며, pro-caspase-9, pro-caspase-8, pro-caspase-3는 농도가 높아질수록 감소하였으며, cleaved caspase-9, cleaved caspase-8, cleaved caspase-3는 농도가 높아질수록 증가하는 경향을 보였다. 또한, cleaved PARP가 증가함을 확인할 수 있었다. 이상의 결과에서 일반 콤부차보다 감귤액을 첨가한 감귤 콤부차가 인체 방광암세포 T-24에 caspase에 의한 apoptosis가 유도됐음을 확인할 수 있었다.

• Journal of Ginseng Research
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• 제39권1호
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• pp.69-75
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• 2015

Background: Ginseng has been shown to exert antistress effects both in vitro and in vivo. However, the effects of ginseng on stress in brain cells are not well understood. This study investigated how Korean Red Ginseng (KRG) controls hydrogen peroxide-induced apoptosis via regulation of phosphatidylinositol-3 kinase (PI3K)/Akt and estrogen receptor (ER)-${\beta}$ signaling. Methods: Human neuroblastoma SK-N-SH cells were pretreated with KRG and subsequently exposed to $H_2O_2$. The ability of KRG to inhibit oxidative stress-induced apoptosis was assessed in MTT cytotoxicity assays. Apoptotic protein expression was examined byWestern blot analysis. The roles of ER-${\beta}$, PI3K, and p-Akt signaling in KRG regulation of apoptosis were studied using small interfering RNAs and/or target antagonists. Results: Pretreating SK-N-SH cells with KRG decreased expression of the proapoptotic proteins p-p53 and caspase-3, but increased expression of the antiapoptotic protein BCL2. KRG pretreatment was also associated with increased ER-${\beta}$, PI3K, and p-Akt expression. Conversely, ER-${\beta}$ inhibition with small interfering RNA or inhibitor treatment increased p-p53 and caspase-3 levels, but decreased BCL2, PI3K, and p-Akt expression. Moreover, inhibition of PI3K/Akt signaling diminished p-p53 and caspase-3 levels, but increased BCL2 expression. Conclusion: Collectively, the data indicate that KRG represses oxidative stress-induced apoptosis by enhancing PI3K/Akt signaling via upregulation of ER-${\beta}$ expression.

• 생명과학회지
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• 제19권2호
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• pp.249-255
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• 2009

Esculetin, a coumarin compound, has been known to inhibit proliferation and induce apoptosis in several types of human cancer cells. However, the molecular mechanisms involved in esculetin-induced apoptosis are still uncharacterized in human leukemia cells. In this study, we have investigated whether esculetin exerts anti-proliferative and apoptotic effects on human leukemia U937 cells. It was found that esculetin could inhibit cell viability in a time-dependent manner, which was associated with the induction of apoptotic cell death such as increased populations of apoptotic- sub G1 phase. Apoptosis of U937 cells by esculetin was associated with an inhibition of Bcl-2/Bax binding activity, formation of tBid, down-regulation of X-linked inhibitor of apoptotic protein (XIAP) expression, and up-regulation of death receptor 4 (DR4) and FasL expression. Esculetin treatment also induced the degradation of ${\beta}$-catenin and DNA fragmentation factor 45/inhibitor of caspase-activated DNase (DFF45/ICAD). Furthermore, a caspase-3 specific inhibitor, z-DEVD-fmk, significantly inhibited sub-G1 phase DNA content, morphological changes and degradation of ${\beta}$-catenin and DEE45/ICAD. These results indicated that a key regulator in esculetin-induced apoptosis was caspase-3 in human leukemia U937 cells.

• 한국식품영양과학회지
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• 제32권2호
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• pp.217-222
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• 2003

본 연구에서는 일반적으로 여러 종류의 질병에 약리 효과가 있다고 알려진 버섯류 중 표고버섯과 새송이 버섯을 택하여 열수추출하고 이 추출물을 인간의 대장암 세포인 HT-29및 Caco-2와 한국인 위암세포인 SNU484에 첨가한 후 세포증식과 세포사멸을 이끄는 caspase-3 활성을 알아보고자 하였다. 대장암 세포인 H-'29와 Caco-2에 표고버섯과 새송이버섯 추출물을 첨가한 결과 대조군에 비하여 유의 적으로 세포 수가 감소하였으며 첨가량이 많아질수록 유의적으로 세포증식이 더 억제되었다. 표고버섯과 새송이버섯을 HT-29에 첨가 후 배양시간에 따른 세포증식 억제효과를 살펴보았더니 배양시간이 경과함에 따라 세포증식이 억제되는 경향을 나타내었으며 특히 96시간의 처리에 HT-29증식이 매우 억제됨을 볼 수가 있었다. 세포의 caspase-3활성을 측정한 결과 표고버섯과 새송이버섯을 48 mg/mL 이 상의 농도로 첨가하였을 때 2배 이상 casuase-3 활성이 증가였으므로 알에서 본 HT-29세포의 증식억제는 세포사멸의 증가에 기인한다고 짐작된다. 위 암세포인 SNU484에 표고버섯과 새송이버섯을 첨가한 경우에는 세포증식의 억제효과가 없었을 뿐만 아니라 caspase-3 활성도 유의하게 증가하지는 않았다. 즉 위암에는 이 두 종류의 버섯은 효능이 없음을 알 수 있었다. 그러므로 표고버섯과 새송이버섯은 caspase-3 활성 을 증가 시켜 대장암세포의 증식을 억제하므로 대장암에 대한 항암 물질로 개발할 필요가 있을 것으로 사료된다

• Biomolecules & Therapeutics
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• 제24권3호
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• pp.320-327
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• 2016

Columbianadin (CBN), a natural coumarin from Angelica decursiva (Umbelliferae), is known to have various biological activities including anti-inflammatory and anti-cancer effects. In this study, the anti-proliferative mechanism of actions mediated by CBN was investigated in HCT-116 human colon cancer cells. CBN effectively suppressed the growth of colon cancer cells. Low concentration (up to $25{\mu}M$) of CBN induced apoptosis, and high concentration ($50{\mu}M$) of CBN induced necroptosis. The induction of apoptosis by CBN was correlated with the modulation of caspase-9, caspase-3, Bax, Bcl-2, Bim and Bid, and the induction of necroptosis was related with RIP-3, and caspase-8. In addition, CBN induced the accumulation of ROS and imbalance in the intracellular antioxidant enzymes such as SOD-1, SOD-2, catalase and GPx-1. These findings demonstrate that CBN has the potential to be a candidate in the development of anti-cancer agent derived from natural products.

• 환경생물
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• 제21권3호
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• pp.303-307
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• 2003

Tributyltin (TBT) used world-wide in antifouling paints toy ships is a wide-spread environmental pollutant. At low doses, antiproliferative modes of action have been shown to be involved, whereas at higher doses apoptosis seems to be the mechanism of toxicity in reproductive organs by TBT. In this study, we investigated that the mechanisms underlying apoptosis induced by TBT in R2C cell. Effects of TBT on intracellular $Ca^{2+}$ level and reactive oxygen species (ROS) were investigated in R2C cells by fluorescence detector. TBT significantly induced intracellular $Ca^{2+}$ level in a time-dependent manner. The rise in intracellular $Ca^{2+}$ level was followed by a time-dependent generation of reactive oxygen species (ROS) at the cytosol level. Simultaneously, TBT induced the release of cytochrome c from the mitochondrial membrane into the cytosol. Furthermore, ROS production and the release of cytochrome c were reduced by BAPTA, an intracellular $Ca^{2+}$ chelator, indicating the important role of $Ca^{2+}$ in R2C during these early intracellular events. In addition, Z-DEVD FMB, a caspase -3 inhibitor, decreased apoptosis by TBT. Taken together, the present results indicated that the apoptotic pathway by TBT might start with an increase in intracellular $Ca^{2+}$ level, continues with release of ROS and cytochrome c from mitochondria, activation of caspases, and finally results in DNA fragmentation.

• Molecules and Cells
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• 제21권2호
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• pp.218-223
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• 2006

The effect of poly(ADP-ribosyl)ation on the stability of p53 in SK-HEP1 cells treated with UV light was examined. Intracellular levels of p53 increased in cells treated with a low dose of UV light ($20J/m^2$), whereas they increased but then declined after a higher dose of UV ($100J/m^2$). Intracellular levels of p53 in the UV treated SK-HEP1 cells were dependent on the UV dose. Use of proteasome inhibitors revealed that p53 is degraded by proteasomal proteolysis after high doses of UV light. We present evidence that, at low doses, poly(ADP-ribose)polymerase (PARP) poly(ADP-ribosyl) ates p53 and protects it from proteasomal degradation before caspase-3 is activated, whereas at high doses the cells undergo UV induced apoptosis and PARP is cleaved by caspase-3 before it can protect p53 from degradation. Destabilization of p53 by cleavage of PARP may be important in cell fate decision favoring apoptosis.

• 대한치과교정학회지
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• 제48권4호
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• pp.253-261
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• 2018

Objective: Orthodontic root resorption (ORR) due to orthodontic tooth movement is a difficult treatment-related adverse event. Caspases are important effector molecules for apoptosis. At present, little is known about the mechanisms underlying ORR and apoptosis in the cementum. The aim of the present in vivo study was to investigate the expression of tartrate-resistant acid phosphatase (TRAP), caspase 3, caspase 8, and receptor activator of nuclear factor kappa-B ligand (RANKL) in the cementum in response to a heavy or an optimum orthodontic force. Methods: The maxillary molars of male Wistar rats were subjected to an orthodontic force of 10 g or 50 g using a closed coil spring. The rats were sacrificed each experimental period on days 1, 3, 5, and 7 after orthodontic force application. And the rats were subjected to histopathological and immunohistochemical analyses. Results: On day 7 for the 50-g group, hematoxylin and eosin staining revealed numerous root resorption lacunae with odontoclasts on the root, while immunohistochemistry showed increased TRAP- and RANKL-positive cells. Caspase 3- and caspase 8-positive cells were increased on the cementum surfaces in the 50-g group on days 3 and 5. Moreover, the number of caspase 3- and caspase 8-positive cells and RANKL-positive cells was significantly higher in the 50-g group than in the 10-g group. Conclusions: In our rat model, ORR occurred after apoptosis was induced in the cementum by a heavy orthodontic force. These findings suggest that apoptosis of cementoblasts is involved in ORR.