• BMB Reports
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• 제54권1호
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• pp.12-20
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• 2021

In the last decade, we have witnessed an unprecedented clinical success in cancer immunotherapies targeting the programmed cell-death ligand 1 (PD-L1) and programmed cell-death 1 (PD-1) pathway. Besides the fact that PD-L1 plays a key role in immune regulation in tumor microenvironment, recently a plethora of reports has suggested a new perspective of non-immunological functions of PD-L1 in the regulation of cancer intrinsic activities including mesenchymal transition, glucose and lipid metabolism, stemness, and autophagy. Here we review the current understanding on the regulation of expression and intrinsic protumoral activity of cancer-intrinsic PD-L1.

• Asian Pacific Journal of Cancer Prevention
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• 제13권7호
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• pp.3073-3076
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• 2012

Terpinen-4-ol is a terpene found in the rhizome of Plai (Zingiber montanum (Koenig) Link ex Dietr.). In this study apoptogenic activity and mechanisms of cell death induced by terpinen-4-ol were investigated in the human leukemic MOLT-4 cell line. Terpinen-4-ol exhibited cytotoxicity in MOLT-4 cells, with characteristic morphological features of apoptosis by Wright's staining. The mode of cell death was confirmed to be apoptosis by flow cytometric analysis after staining with annexin V-FITC and propidium iodide. A sub-G1 peak in DNA histograms of cell cycle assays was observed. Terpinen-4-ol induced-MOLT-4 cell apoptosis mediated through an intrinsic pathway involving the loss of mitochondrial transmembrane potential (MTP) and release of cytochrome c into the cytosol. In addition, terpinen-4-ol also induced apoptosis via an extrinsic pathway by caspase-8 activation resulting in the cleavage of cytosolic Bid. Truncated-Bid (tBid) translocated to mitochondria and activated the mitochondrial pathway in conjunction with down-regulation of Bcl-2 protein expression. Caspase-3 activity also increased. In conclusion, terpinen-4-ol can induce human leukemic MOLT-4 cell apoptosis via both intrinsic and extrinsic pathways.

• Natural Product Sciences
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• 제23권4호
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• pp.227-234
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• 2017

Moringa oleifera Lam (M. oleifera, Moringaceae) is a tree of the Moringaceae family that can reach a height of between 5 and 10 m. The current paper presents cytotoxic effect of M. oleifera fruits and its flavonoids 1 and 2. The viability of HCT116 human colon cancer cells were 38.5% reduced by $150{\mu}g/mL$ of ethanolic extracts in a concentration-dependent manner; in addition, we observed the apoptotic features of cell shrinkage and decreased cell size. Bcl-2 family proteins were regulated as determined by Western blotting analysis, suggesting that M. oleifera fruits and their flavonoids 1 and 2 induced apoptosis through an intrinsic pathway. Based on our findings, 70% ethanolic extracts of M. oleifera fruits and flavonoids 1 and 2 might be useful as cytotoxic agents in colorectal cancer therapy.

• Journal of Microbiology and Biotechnology
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• 제25권3호
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• pp.334-342
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• 2015

4-O-Methylhonokiol (MH), a bioactive compound derived from Magnolia officinalis, is known to exhibit antitumor effects in various cancer cells. However, the precise mechanism of its anticancer activity in cervical cancer cells has not yet been studied. In this study, we demonstrated that MH induces apoptosis in SiHa cervical cancer cells by enhancing peroxisome proliferator-activated receptor-gamma (PPARγ) activation, followed by inhibition of the PI3K/Akt pathway and intrinsic pathway induction. MH upregulated PPARγ and PTEN expression levels while it decreased p-Akt in the MH-induced apoptotic process, thereby supporting the fact that MH is a PPARγ activator. Additionally, MH decreased the expression of Bcl-2 and Bcl-XL, inducing the intrinsic pathway in MH-treated SiHa cells. Furthermore, MH treatment led to the activation of caspase-3/caspase-9 and proteolytic cleavage of polyADP ribose polymerase. The expression levels of Fas (CD95) and E6/E7 oncogenes were not altered by MH treatment. Taken together, MH activates PPARγ/PTEN expression and induces apoptosis via suppression of the PI3K/Akt pathway and mitochondria-dependent pathways in SiHa cells. These findings suggest that MH has potential for development as a therapeutic agent for human cervical cancer.

• 한국식품영양과학회지
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• 제38권2호
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• pp.136-141
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• 2009

스피루리나를 세포벽 가수분해효소와 단백질 가수분해효소로 처리하여 조제한 스피루리나 가수분해물(enzymatic hydrolysate of spirulina, EHS)의 생리활성을 조사하였다. 효소처리 가수분해물의 유산균 증식효과, 항산화능, 암세포 증식저해 활성, 항혈전 활성을 분석한 결과 EHS는 유산균 증식활성과 항산화능에 큰 영향을 미치지 않았으며, 자궁경부암세포(HeLa)에 대해 1.42 mg/L의 농도에서 15% 미만의 증식저해효과를 나타내었다. 반면 항혈전 활성을 공통 경로(common pathway), 내인성 경로(intrinsic pathway), 외인성 경로(extrinsic pathway)로 구분하여 측정한 결과, 공통경로, 내인성 경로와 유사한 항혈전 활성이 있음을 확인하였다. 공통 경로를 thrombin time assay로 측정한 결과 EHS의 농도가 100 mg/L일 때 155.6초를 나타내었다. 내인성 경로는 activated partial thromboplastin time assay로 측정하였고, EHS의 농도가 1000 mg/L일 때 95.8초를 나타내었다. 외인성 경로를 prothrombin time assay로 측정한 결과 EHS의 농도가 1000 mg/L일 때 10.6초를 나타내었다. 결과적으로 스피루리나 효소가수분해물(EHS)이 항혈전경로 중 공통경로와 내인성 경로에 활성이 있음을 알 수 있었으며, 이를 토대로 신규의 항혈전 기능성 원료로 개발될 수 있을 것으로기대된다.

• Molecules and Cells
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• 제39권2호
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• pp.119-128
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• 2016

Angelica polymorpha Maxim root extract (APRE) is a popular herbal medicine used for treating stomachache, abdominal pain, stomach ulcers, and rheumatism; however the effect of APRE on cancer cells has not yet been explored. Here, we examined APRE cytotoxicity seen on target neuroblastoma cells (NB) using cell viability assays, DAPI visualization of fragmented DNA, and Western blotting analysis of candidate signaling pathways involved in proliferation and apoptosis. We demonstrated that APRE reduced cell viability in NB to a greater extent than in fibroblast cells. In addition, we found that APRE could inhibit the three classes of MAPK proteins and could also down-regulate the PI3K/AKT/GSK-$3{\beta}$ activity all being relevant for proliferation and survival. APRE could also up-regulate Bax expression and down-regulate Bcl-2 and Mcl-1. With APRE treatment, depolarization of mitochondria membrane potential and activation of caspase-3 was demonstrated in the SH-SY5Y cells. We could not found increased activity of death receptor and caspase-8 as markers of the extrinsic apoptosis pathway for the APRE treated cells. In presence of a caspase-3 siRNA and a pan-caspase inhibitor, APRE could not reduce the viability of NB cells to a significant degree. So we predicted that with APRE, the intrinsic pathway was solely responsible for inducing apoptosis as we also showed that the non-caspase autophagy pathway or ER stress-ROS mediated pathways were not involved. These findings demonstrate that an intrinsic mitochondria-mediated apoptosis pathway mediates the apoptotic effects of APRE on SH-SY5Y cells, and that APRE shows promise as a novel agent for neuroblastoma therapy.

• 한국식품영양과학회지
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• 제29권2호
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• pp.335-341
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• 2000

허브를 비롯한 식용되는 채소류로부터 항응고 활성을 검색하기 위하여 93종을 대상으로 냉수(Fr. I), 메탄올(Fr. ll), 열수(Fr. lll)추출물을 각각 조제하였다. 내인성 경로에 작용하는 항응고 활성은 수용성 획분인 Fr. I과 Fr.lll를 대상으로 activated partial thromboplastin time(APTT)으로 검색한 결과 양파, 마늘, 정향, 쑥, 울금 등이 높은 활성을 보였으며, 외인성 경로와 공통경로에 작용하는 항응고 활성은 저분자임을 감안하여 Fr. I과 Fr. II를 대상으로 각각 prothrombin time(PT) 과 thrombin time(TT)으로 검색한 결과 민트, 이탈리안 시즈닝, 로즈메리, 타라곤, 울금, 백리향, 와사비는 공통경로에 항응고 활성을 나타내였으나 외인성 경로에 단독으로 항응고 활성을 나타내는 시료는 없었다. 1, 2차 검색 결과 가장 높은 항응고 활성을 보인 정향(Eugenia caryophyllate, clove)을 대상으로 산지를 달리하여 항응고 활성을 검색한 결과 홀랜드산 정향의 활성이 가장 높았다.

• Genomics & Informatics
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• 제6권4호
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• pp.202-209
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• 2008

Biological pathways are known as collections of knowledge of certain biological processes. Although knowledge about a pathway is quite significant to further analysis, it covers only tiny portion of genes that exists. In this paper, we suggest a model to extend each individual pathway using a microarray expression data based on the known knowledge about the pathway. We take the Rosetta compendium dataset to extend pathways of Saccharomyces cerevisiae obtained from KEGG (Kyoto Encyclopedia of genes and genomes) database. Before applying our model, we verify the underlying assumption that microarray data reflect the interactive knowledge from pathway, and we evaluate our scoring system by introducing performance function. In the last step, we validate proposed candidates with the help of another type of biological information. We introduced a pathway extending model using its intrinsic structure and microarray expression data. The model provides the suitable candidate genes for each single biological pathway to extend it.

• Journal of Microbiology and Biotechnology
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• 제25권3호
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• pp.343-352
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• 2015

H9 is an ethanol extract prepared from nine traditional/medicinal herbs. This study was focused on the anticancer effect of H9 in non-small-cell lung cancer cells. The effects of H9 on cell viability, apoptosis, mitochondrial membrane potential (MMP; ${\Delta}\psi_{m}$), and apoptosisrelated protein expression were investigated in A549 human lung cancer cells. In this study, H9-induced apoptosis was confirmed by propidium iodide staining, expression levels of mRNA were determined by reverse transcriptase polymerase chain reaction, protein expression levels were checked by western blot analysis, and MMP (${\Delta}\psi_{m}$) was measured by JC-1 staining. Our results indicated that H9 decreased the viability of A549 cells and induced cell morphological changes in a dose-dependent manner. H9 also altered expression levels of molecules involved in the intrinsic signaling pathway. H9 inhibited Bcl-xL expression, whereas Bax expression was enhanced and cytochrome C was released. Furthermore, H9 treatment led to the activation of caspase-3/caspase-9 and proteolytic cleavage of poly(ADP-ribose) polymerase; the MMP was collapsed by H9. However, the expression levels of extrinsic pathway molecules such as Fas/FasL, TRAIL/TRAIL-R, DR5, and Fas-associated death receptor were downregulated by H9. These results indicated that H9 inhibited proliferation and induced apoptosis by activating intrinsic pathways but not extrinsic pathways in human lung cancer cells. Our results suggest that H9 can be used as an alternative remedy for human non-small-cell lung cancer.

• The Korean Journal of Physiology and Pharmacology
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• 제14권6호
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• pp.407-412
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• 2010

3-Deazaadenosine (DZA), a potent inhibitor of S-adenosylhomocysteine hydrolase, was previously proposed to induce intrinsic apoptosis in human leukemic cells. In the present study, we analyzed the mechanism underlying the DZA-induced intrinsic apoptotic pathway. DZA activated typical caspase-dependent apoptosis in HL-60 cells, as demonstrated by an accumulation of hypo-diploidic cells, the processing of multiple procaspases and an inhibitory effect of z-VAD-Fmk on this cell death. During DZA-induced apoptosis, cytochrome c (cyt c) was released into the cytosol. This was neither prevented by z-VAD-Fmk and nor was it associated with the dissipation of mitochondrial membrane potential (${\Delta}{\Psi}_m$). Prior to the release of cyt c, BAX was translocated from the cytosol to mitochondria and underwent oligomerization. Finally, the overexpression of BCL-XL protected HL-60 cells from apoptosis by blocking both the cyt c release and BAX oligomerization. Collectively, these findings suggest that DZA may activate intrinsic apoptosis by stimulating BAX activation and thereby the release of cyt c.