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Coniferyl aldehyde derivatives for HSF1 activation

Title
Coniferyl aldehyde derivatives for HSF1 activation
Other Titles
HSF1의 활성을 유도하는 Coniferyl aldehyde의 활성부위 규명
Authors
최슬기
Issue Date
2016
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
이윤실
Abstract
Almost 50% of patients with cancer have used radiation therapy and plays an essential role in 25% of cancer therapy. Despite advances in radiation therapy techniques, radiation toxicity to normal tissue remains the severe side effects. Most patients treated with radiation therapy suffer from some degree of acute effects, with symptoms such as abdominal pain, nausea, fatigue, and diarrhea and late effects such as fibrosis, observed in ~10% of patients and atrophy, vascular damage, infertility. Thus, reducing radiation-induced normal cell damage is important to improve cancer treatment and quality of patients life. Coniferyl aldehyde(CA) is a phenolic compound extracted from plants such as Cinnamomum cassia, Senra incana, Ficus foveolata, and Eucommia ulmoides, all of which are well-known herbal components of Asian traditional medicines that are used to reinforce muscles and bones, to treat hypertension, and to recover damaged liver and kidney functions. Our previous study revealed a novel functions of CA as a potent inducer of heat shock factor 1 (HSF1), which upregulates heat shock proteins(HSPs), including HSP27 and HSP70 through increased protein stability of HSF1 by powerful phosphorylation at Ser326. In this study, we further examined the active structural moieties of CA for activation of HSF1. For this purpose, we compared CA and its hydroxyl derivative, coniferyl alcohol(COH) for activation of HSF1 along with induction of HSPs. We also compared there protective functions in combined with radiation or anticancer drugs such as cisplatin and taxol using normal like lung cell line.;HSF1(Heat Shock Factor1)은 모든 진핵세포에서 빈번하게 발현되며 ischemic damage, reperfusion injury, infection, neurodegeneration, inflammation 등 다양한 질병에 깊이 관련되어 있다. HSF1은 스트레스 조건에서 HSP(Heat Shock Protein) 유전자를 조절하는 전사인자이다. 많은 연구결과 HSF1이 방사선, 항암제 및 활성산소에 대한 다양한 방어 기작에 관련이 되어 있다고 제안해왔다. 따라서 최근 많은 연구에서 HSF1을 유도하는 약물이 크게 주목받고 있다. 본 연구에서는 HSF1의 활성을 유도한다고 알려진 Coniferyl aldehyde의 활성부위를 규명하는 것에 목표를 두었다. 따라서 SAR(Structure Activity Relationship)을 고려하여 Coniferyl aldehyde와 구조가 아주 유사한 Coniferyl alcohol, Guaiacol, beta-hydroxypropiovanilone으로 HSF1을 비롯한 HSP70, HSP27의 활성을 실험해 본 결과, Coniferyl aldehyde의 hydroxyl derivative인 Coniferyl alcohol이 Coniferyl aldehyde와 같이 HSF1을 유도함으로써 normal cell에서 cytotoxic drug 또는 radiation로 유도되는 손상에 대해 cytoprotection effect를 갖는다는 것을 확인하였고 추가적으로 CA와 COH가 아주 비슷한 효과를 지니고 있음에도 불구하고 COH가 CA보다 normal cell system에서 더 낮은 cytotoxicity를 지니고 있음을 마찬가지로 확인하였다. 따라서 연구 결과, Coniferyl alcohol과 Coniferyl aldehyde의 benzene vinyl moiety가 HSF1의 활성을 유도한다는 것을 확인하였으며, 이러한 결과는 정상세포에서 HSF1을 유도하는 cytoprotector 또는 radioprotector 개발에 크게 유용할 것으로 예상된다.
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