NOVEL CHAPERONE INDUCERS FOR LIVER TRANSPLANTATION

哺乳动物细胞在应对各种环境应激时，会诱导一组称为热休克蛋白（HSP）的蛋白质。HSP，特别是应激诱导的70-kDa蛋白（Hsp 70）的过量产生导致获得对各种类型的应激的耐受性。在过去的10年里，已经进行了各种实验，以检查热休克动物和基因靶向动物的Hsp 70的临床应用。与此同时，几个小组引入了安全和选择性诱导Hsp 70的伴侣诱导剂。首次引入了一种无毒的类异戊二烯--香叶基香叶基丙酮（GGA）作为热休克蛋白70（Hsp 70）的诱导剂，该诱导剂能安全地选择性诱导培养的豚鼠胃粘膜细胞和大鼠胃粘膜细胞中的Hsp 70，并分别抑制乙醇诱导的细胞损伤和应激性溃疡的形成。当暴露于后续应激时，GGA还可以引发其他类型的细胞以增强Hsp 70的诱导。用该化合物预处理大鼠 关于我们 显著减轻大鼠肝脏、小肠或心脏的缺血-再灌注损伤，提高95%肝切除和肝移植后的存活率。本研究利用原代培养的豚鼠胃粘膜细胞和大鼠肝细胞筛选了12种无环类聚异戊二烯衍生物，发现香叶基香叶醇（GGO）是Hsp 70最有效的诱导剂，对这些细胞具有最强的细胞保护作用。通过大鼠肝脏缺血再灌注损伤实验证实了GGO对Hsp 70的诱导作用。然而，我们未能检测到任何有益的影响，大鼠肝移植模型。GGA可以在多个步骤中阻断胰岛素诱导的凋亡途径;它通过与Apafl结合抑制c-Jun N-末端激酶的激活、线粒体膜电位的下降和线粒体的形成。最近，GGA已被证明诱导硫氧还蛋白和抗病毒基因，这表明GGA可能表现出独立于Hsp 70诱导的细胞保护作用。除了Hsp 70诱导剂如GGA或GGO之外，靶向ER分子伴侣的新化合物可用于治疗折叠疾病。少

In response to various environmental stresses, mammalian cells induce a set of proteins called heat shock proteins (HSP). Overproduction of HSP, particularly a stress-inducible 70-kDa protein (Hsp70), results in the acquisition of tolerance against various types of stresses. Over the last 10 years, various experiments have been performed to examine clinical applications of Hsp70, using heat-shocked animals and gene targeting animals. At the same time, several groups introduced chaperone inducers that safely and selectively induce Hsp70. An acyclic isoprenoid, geranylgeranylacetone (GGA), was introduced for the first time as a non-toxic Hsp70 inducer, which selectively and safely induced Hsp70 in cultured guinea pig gastric mucosal cells and rat gastric mucosa, and suppressed ethanol-induced cell damage and stress ulcer formation, respectively. GGA can also prime other types of cells for enhanced induction of Hsp70, when exposed to subsequent stress. Pretreatment of rats with this compo … More und markedly rendered ischemia-reperfusion injury of the rat liver, small intestine, or heart, and improved survival after 95% hepatectomy as well as liver transplantation. In this study, we screened 12 derivatives of acyclic polyisoprenoid using primary cultured guinea pig gastric mucosal cells and rat hepotocytes and found that geranylgeraniol (GGO) was the most effective inducer for Hsp70 and exerted the most potent cytoprotective actions on these cells. The Hsp70-inducing action of GGO was confirmed by ischemia-reperfusion injury of rat livers. However, we failed to detect any beneficial effects on a rat liver transplantation model. GGA can block insult-induced apoptotic pathways at multiple steps ; it inhibited activation of c-Jun N-terminal kinases, decline of mitochondrial membrane potential, and formation of apoptosome by binding with Apafl. Recently, GGA has been shown to induce thioredoxin and anti-viral genes, suggesting that GGA may exhibit cytoprotective actions independently of Hsp70 induction. In addition to the Hsp70 inducer, such as GGA or GGO, new compounds targeting ER chaperones may be useful for the treatment of folding diseases. Less