Hirota Kiichi, Nakamura Hajime, Masutani Hiroshi, Yodoi Junji
BioMedical Special Research Unit, Human Stress Signal Research Center, National Institute of Advanced Science and Technology (AIST), Ikeda, Osaka 563-8577, Japan.
Ann N Y Acad Sci. 2002 May;957:189-99. doi: 10.1111/j.1749-6632.2002.tb02916.x.
Mammalian thioredoxin (TRX) with redox-active dithiol in the active site plays multiple roles in intracellular signaling and resistance against oxidative stress. TRX is induced by a variety of stresses including infectious agents as well as hormones and chemicals. TRX is secreted from activated cells such as HTLV-I-transformed T-cells as a redox-sensitive molecule with cytokine-like and chemokine-like activities. The promoter of the TRX gene contains a series of stress-responsive elements. In turn, TRX promotes activation of transcription factors such as NF-kappa B, AP-1, and p53. We have reported that natural substances including estrogen, prostaglandins, and cAMP induce mRNA, protein, and secretion of TRX. These agents seemed to exert their physiological functions including cytoprotective actions partly through the induction of TRX without massive oxidative stress, which induces TRX strongly as well as other stress proteins. We report here a new TRX inducer substance, geranylgeranylacetone (GGA), which is originally derived from a natural plant constituent and has been used in the clinical field as an anti-ulcer drug. We have demonstrated that GGA induces the messenger RNA and protein of TRX and affects the activation of transcription factors, AP-1 and NF-kappa B, and that GGA blunted ethanol-induced cytotoxicity of cultured hepatocytes and gastrointestine mucosal cells. We will discuss a possible novel molecular mechanism of GGA, which is to protect cells via the induction of TRX and activation of transcription factors such as NF-kappa B and AP-1. Identification of the particular TRX-inducing components may contribute to the elucidation of the molecular basis of the "French Paradox," in which good red wines are beneficial for the cardiovascular system.
哺乳动物硫氧还蛋白（TRX）在活性位点含有具有氧化还原活性的二硫醇，在细胞内信号传导和抗氧化应激中发挥多种作用。TRX可由多种应激诱导产生，包括病原体、激素和化学物质。TRX作为一种具有细胞因子样和趋化因子样活性的氧化还原敏感分子，从活化细胞如人嗜T淋巴细胞病毒I型（HTLV-I）转化的T细胞中分泌出来。TRX基因的启动子包含一系列应激反应元件。反过来，TRX促进转录因子如核因子κB（NF-κB）、活化蛋白-1（AP-1）和p53的激活。我们曾报道，包括雌激素、前列腺素和环磷酸腺苷（cAMP）在内的天然物质可诱导TRX的信使核糖核酸（mRNA）、蛋白质表达及分泌。这些物质似乎部分通过诱导TRX发挥其生理功能，包括细胞保护作用，而无需大量氧化应激，大量氧化应激会强烈诱导TRX以及其他应激蛋白。我们在此报告一种新的TRX诱导物质，香叶基香叶基丙酮（GGA），它最初源自一种天然植物成分，已在临床领域用作抗溃疡药物。我们已证明，GGA可诱导TRX的信使核糖核酸和蛋白质表达，并影响转录因子AP-1和NF-κB的激活，且GGA可减轻乙醇诱导的培养肝细胞和胃肠黏膜细胞的细胞毒性。我们将讨论GGA可能的新分子机制，即通过诱导TRX以及激活转录因子如NF-κB和AP-1来保护细胞。鉴定特定的TRX诱导成分可能有助于阐明“法国悖论”的分子基础，即优质红酒对心血管系统有益。
