NOVEL CHAPERONE INDUCERS FOR LIVER TRANSPLANTATION

哺乳动物细胞在应对各种环境压力时，会产生一系列称为热休克蛋白(HSP)的蛋白质。HSP的过度产生，特别是应激诱导的70 kDa蛋白(Hsp70)的过度产生，导致对各种类型的逆境的耐受。在过去的10年里，人们利用热休克动物和基因打靶动物进行了各种实验，以检查Hsp70的临床应用。与此同时，几个小组引入了安全和选择性地诱导Hsp70的伴侣诱导剂。首次引入非环类异戊二烯香叶基香叶内酮(GGA)作为一种无毒的HSP70诱导剂，选择性、安全地诱导豚鼠胃粘膜细胞和大鼠胃粘膜HSP70，并分别抑制乙醇诱导的细胞损伤和应激性溃疡形成。当暴露在随后的压力下时，GGA也可以启动其他类型的细胞以增强Hsp70的诱导。该复方…对大鼠的预处理作用能明显减轻大鼠肝脏、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。在本研究中，我们利用原代培养的豚鼠胃粘膜细胞和大鼠肝细胞筛选了12种开环多异戊二烯类化合物，发现香叶香叶醇(GGO)是最有效的Hsp70诱导剂，对这些细胞具有最强的细胞保护作用。大鼠肝脏缺血再灌注损伤实验证实了GGO对HSP70的诱导作用。然而，我们未能在大鼠肝移植模型上检测到任何有益的影响。GGA可多步骤阻断损伤诱导的细胞凋亡通路，通过与Apafl结合，抑制c-jun氨基末端激酶的激活、线粒体膜电位的下降和凋亡体的形成。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可能具有不依赖于Hsp70诱导的细胞保护作用。除了Hsp70诱导剂，如GGA或GGO，针对内质网伴侣的新化合物可能对折叠疾病的治疗有用。较少

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