Lee June, Mailar Karabasappa, Yoo Ok-Kyung, Choi Won Jun, Keum Young-Sam
College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University, 32 Dongguk-ro, Goyang, Gyeonggi-do 10326, South Korea.
College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University, 32 Dongguk-ro, Goyang, Gyeonggi-do 10326, South Korea.
Eur J Med Chem. 2018 Apr 25;150:113-126. doi: 10.1016/j.ejmech.2018.02.068. Epub 2018 Feb 23.
Heme oxygenase-1 (HO-1) catalyzes the enzymatic degradation of heme to produce three anti-oxidant molecules: carbon monoxide (CO), ferrous ion (Fe), and biliverdin. Induction of HO-1 is currently considered as a feasible strategy to treat oxidative stress-related diseases. In the present study, we identified marliolide as a novel inducer of HO-1 in human normal keratinocyte HaCaT cells. Mechanism-based studies demonstrated that the induction of HO-1 by marliolide occurred through activation of NRF2/ARE via direct binding of marliolide to KEAP1. Structure-activity relationship revealed chemical moieties of marliolide critical for induction of HO-1, which renders a support for Michael reaction as a potential mechanism of action. Finally, we observed that marliolide significantly inhibited the papilloma formation in DMBA/TPA-induced mouse skin carcinogenesis model and this event was closely associated with lowering the formation of 8-OH-G and 4-HNE in vivo. Together, our study provides the first evidence that marliolide might be effective against oxidative stress-related skin disorders.
血红素加氧酶-1（HO-1）催化血红素的酶促降解，产生三种抗氧化分子：一氧化碳（CO）、亚铁离子（Fe）和胆绿素。目前，诱导HO-1被认为是治疗氧化应激相关疾病的一种可行策略。在本研究中，我们鉴定出马里欧内酯是人类正常角质形成细胞HaCaT中HO-1的一种新型诱导剂。基于机制的研究表明，马里欧内酯对HO-1的诱导是通过马里欧内酯与KEAP1直接结合激活NRF2/ARE而发生的。构效关系揭示了马里欧内酯中对诱导HO-1至关重要的化学基团，这为迈克尔反应作为一种潜在作用机制提供了支持。最后，我们观察到马里欧内酯在二甲基苯并蒽/十四酰佛波醇乙酯诱导的小鼠皮肤癌发生模型中显著抑制乳头瘤形成，并且这一事件与体内8-羟基鸟嘌呤（8-OH-G）和4-羟基壬烯醛（4-HNE）的形成减少密切相关。总之，我们的研究提供了首个证据，表明马里欧内酯可能对氧化应激相关的皮肤疾病有效。
