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마이토마이신씨에 의해 유도된 인간 테논낭 섬유아세포의 자가포식현상
박찬희,박래길,유성광,이동욱,Channy Park,PhD,Raekil Park,MD,PhD,Seong Kwang Ryu,MD,Dong Wook Lee,MD,PhD 대한안과학회 2011 대한안과학회지 Vol.52 No.11
Purpose: The present study investigated whether an autophagic process is involved in the apoptotic death of human tenon’s capsule fibroblasts (HTCFs) caused by mitomycin-C. Methods: An autophagic phenotype was tested using fluorescence microscopy and flow cytometry with specific biological staining dyes including monodansylcadaverine and acridine orange and microtubule-associated protein 1 light chain 3 (LC3). Results: Treatment with mitomycin-C (0.4 mg/ml) increased the acidic vesicular organelles of tenon’s capsule fibroblasts in a time dependent manner. Mitomycin-C induced both LC3-II cleavage and beclin-1 expression. 3-MA, a pharmacological inhibitor of autophagy, inhibited the mitomycin-C induced increase of acidic vesicular organelleS. Conclusions: Autophagy was induced with 0.4 mg/ml mitomycin-C in tenon’s capsule fibroblasts. And, autophagic mechanisms may be involved in the early stage of apoptosis of fibroblasts. J Korean Ophthalmol Soc 2011;52(11):1337-1343
시스플라틴에 의한 염증성 사이토카인의 청각유모세포 사멸 효과
이정한(Jeong-Han Lee),박찬희(Channy Park),박래길(Raekil Park) 한국생명과학회 2008 생명과학회지 Vol.18 No.4
Cisplatin은 임상적으로 다양한 종류의 종양 치료에 사용되는 중요한 항암제 중의 하나이다. 그러나 cisplatin은 이독성, 신장독성, 골수독성, 위장독성 및 말초신경독성 등의 심각한 부작용으로 인하여 사용이 제한적이다. Cisplatin에 의한 청각장애에서 organ of Corti 외측 유모세포(outer hair cells) 손상이 유발한다. Cisplatin에 의한 세포독성에 대한 연구가 진행중이지만 pro-inflammatory cytokine과 관련된 청각세포사멸에 대한 연구는 미비하다. 이 연구에서 cisplatin은 청각세포주 HEI-OC1 세포와 렛트 cochlear explant에서 염증성 사이토카인인 TNF-α, IL-1β 및 IL-6의 유전자 발현과 분비를 현저히 증가시켰다. 이들 염증성 사이토카인은 organ of Corti 청각유 모세포에 직접적인 세포독성을 나타내어 외측 및 내측 유모세포와 배열을 파괴하였다. 염증반응에서 중요한 TNF-α를 cisplatin을 처리한 실험군에서 immunocytochemistry를 통하여 관찰 한 결과 organ of Corti에서의 발현이 현저히 증가됨을 관찰하였다. 염증성 사이토카인에 대한 중화항체를 처리하여 cisplatin에 의한 세포독성이 현저히 감소됨을 HEI-OC1 세포와 청각유모세포에서 확인하였다. 또한 GSH, NAC와 같은 항산화제를 처리하여 세포독성이 현저히 감소됨을 확인하였다. 이상의 결과는 cisplatin에 의한 청각유모세포의 죽음에서 TNF-α, IL-1β 및 IL-6와 같은 염증성 사이토카인이 병리 생리학적으로 중요한 역할을 하고 있음을 시사한다. Cisplatin (cis-diamminedichloroplatinum Ⅱ: CDDP) is the most widely used anticancer drug against a variety of human neoplasms. However, its clinical use is limited by the onset of severe side effects, including ototoxicity and nephrotoxicity. Even though a number of evidences in cytotoxic mechanism of cisplatin have been suggested, the role of pro-inflammatory cytokines in cisplatin cytotoxicity of auditory cells has not yet been demonstrated. Herein our data clearly demonstrated that cisplatin decreased the viability of HEI-OC1 auditory cells, which was inhibited by the addition of neutralizing anti-TNF-α, anti-IL-1β and anti-IL-6 antibodies. Consistently, Neutralization with antibodies against pro-inflammatory cytokines ameliorated the cell death and disarrangement of cochlea hair cell layers in the rat primary cochlear explants which were treated with cisplatin. Furthermore, exogeneous supplementation with free radical scavengers, including GSH and NAC, significantly prevented the cytotoxicity of cisplatin in the rat primary cochlea explants. We also observed that TNF-α was predominantly expressed in Deiters and Hensen's cells located in hair cell zone of cisplatin-treated cochlear explants. These findings suggest that pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, may play a pivotal role in the pathophysiology of hair cell damages caused by ototoxic drug cisplatin.
Apicidin, Histone Deacetylase Inhibitor에 의한 Human Promyelocytic U937 세포고사
정은현(Eun-Hynu Jung),박찬희(Channy Park),임창인(Chang-In Lim),이황희(Hwanghee Blaise Lee),송훈섭(Hoon-Seob Song),염성섭(Seong-Seob Yeom),정은배(Eun-Bae Jung),이병곤(Byeong-Gon Lee),김영훈(Young-Hoon Kim),박래길(Raekil Park) 한국독성학회 2003 Toxicological Research Vol.19 No.3
Apicidin, a histone-deacetylase inhibitor, has been successfully used to inhibit the growth of cancer cells. In this study, the apoptotic potential and mechanistic insights of apicidin were<br/> investigated in human myeloid leukemia U937 cells. Treatment of U937 cells with apicidin resulted in a decrease of cell viability with apoptotic characteristics, including chromatin condensation and ladderpattern fragmentation of genomic DNA. Apicidin converted the procaspase-3 protease to catalytically active effector protease, resulting in subsequent cleavage of poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated deoxyribonuclease (ICAD). In addition, apicidin induced the activation of caspase-9 protease and the cytosolic release of mitochondrial cytochrome c with mitochondrial membrane potential transition. Moreover, apicidin transiently increased the expression of Fas and Fas ligand proteins. Taken together, the results suggest that apicidin induces apoptosis of U937 cells through activation of intrinsic caspase cascades and Fas/FasL system with mitochondrial dysfunction.