NOVEL CHAPERONE INDUCERS FOR LIVER TRANSPLANTATION

为了应对各种环境压力，哺乳动物细胞会产生一组称为热休克蛋白（HSP）的蛋白质。过量产生热休克蛋白，特别是应激诱导的70-kDa蛋白（Hsp70），导致获得对各种类型胁迫的耐受性。在过去的10年里，人们利用热休克动物和基因靶向动物进行了各种实验来检验Hsp70的临床应用。同时，几个组引入安全、选择性诱导Hsp70的伴侣诱导剂。首次引入无环类异戊二烯类香叶酮（geranylgeranylacetone， GGA）作为无毒Hsp70诱导剂，在体外培养的豚鼠胃粘膜细胞和大鼠胃粘膜中选择性、安全地诱导Hsp70，并分别抑制乙醇诱导的细胞损伤和应激性溃疡的形成。当暴露于随后的应激时，GGA也可以诱导其他类型的细胞增强Hsp70的诱导。大鼠肝、小肠、心脏缺血再灌注损伤，95%肝切除和肝移植后生存率提高。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种无环类多异戊二烯衍生物，发现香叶香叶醇（geranylgeraniol， GGO）是最有效的Hsp70诱导剂，对这些细胞具有最有效的细胞保护作用。通过大鼠肝脏缺血再灌注损伤证实了GGO对hsp70的诱导作用。然而，我们未能在大鼠肝移植模型中发现任何有益作用。GGA可通过多个步骤阻断胰岛素诱导的凋亡通路；通过与Apafl结合，抑制c-Jun n端激酶的激活，抑制线粒体膜电位的下降，抑制凋亡细胞的形成。最近，GGA被证明可以诱导硫氧还蛋白和抗病毒基因，这表明GGA可能具有独立于Hsp70诱导的细胞保护作用。除了Hsp70诱导剂，如GGA或GGO，靶向ER伴侣的新化合物可能对折叠疾病的治疗有用。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