Oral administration of geranylgeranylacetone plus local somatothermal stimulation: A simple, effective, safe and operable preconditioning combination for conferring tolerance against ischemia-reperfusion injury in rat livers

AIM： To explore a simple, effective, safe and operable pretreatment for conferring tolerance against ischemia- reperfusion （I-R） injury in rat livers. METHODS： Forty-five rats were divided into five groups （each group n = 9）. Group C： control group; group G： geranylgeranylacetone （GGA） was administered without heat stress; group S： local heat stress alone; group WG： GGA plus whole-body heat stress; group SG： GGA administration plus local heat stress. After completion of the I-R procedure, the ischemic-reperfused liver lobes in five groups were resected and tested for heat shock protein （HSP70） by RT-PCR, Western blotting analysis and immunohistochemical staining. The blood samples were collected for ALT and AST measurement at the end of occlusion of blood supply, 30 min after reperfusion, 24, 48, 72 h after surgery from the inferior vena cava. Survival was monitored for 1 wk. RESULTS： The production of HSP70 after I-R injury increased, the liver enzyme levels after reperfusion decreased rapidly, and the survival rates increased in groups C-SG. CONCLUSION： The combination of GGA plus local somatothermal stimulation is a simple, effective, safe and operable pretreatment to induce HSP70 in patients with liver tumor and cirrhosis before hepatectomy and in donors before harvesting graft for liver transplantation.2005 The WJG Press and Elsevier Inc. All rights reserved.

Preventive effects of geranylgeranylacetone on rat ethanolinduced gastritis

AIM:To establish a rat ethanol gastritis model,we evaluated the effects of ethanol on gastric mucosa and studied the preventive effects of geranylgeranylacetone on ethanol-induced chronic gastritis.METHODS:One hundred male Sprague-Dawley rats were randomly divided into 4 equal groups:normal control group,undergoing gastric perfusion of normal saline(NS) by gastrogavage;model control group and 2 model therapy groups that underwent gastric perfusion with ethanol(distillate spirits with 56% ethanol content) by gastrogavage for 4 wk.Low or high doses of geranylgeranylacetone were added 1 h before ethanol perfusion in the 2 model therapy groups,while the same amount of NS,instead of geranylgeranylacetone was used in that model control group.The rats were then sacrificed and stomachs were removed.The injury level of the gastric mucosa was observed by light and electron microscopy,and the levels of prostaglandin 2(PGE 2),endothelin-1(ET-1) and nitric oxide(NO) were measured by radioimmunoassay and the Griess method.RESULTS:The gastric mucosal epidermal damage score(EDS;4.5) and ulcer index(UI;12.0) of the model control group were significantly higher than that of the normal control group(0 and 0 respectively,all P = 0.000).The gastric mucosal EDS and UI of the 2 model therapy groups(EDS:2.5 and 2.0;UI:3.5 and 3.0) were significantly lower than that of the model control group(all P < 0.01).There was no statistically significant difference between the low-dose and high-dose model therapy groups.The expression value of plasma ET-1 of the model control group was higher than that of the normal control group(P < 0.01) and the 2 model therapy groups(all P < 0.01).The expression values of gastric mucosal PGE 2 and serum NO of the model control group were lower than those of the normal control group(all P < 0.05) and the 2 model therapy groups(all P < 0.05).The thickness of the gastric mucous layerand the hexosamine content in the model control group were significantly lower than that in the normal control group(all P < 0.01) and the 2 model therapy groups(all P < 0.05).Scanning and transmission electron microscopy observation showed that in the model control group,the epithelial junctions were vague,the intercellular joints disappeared and damage of the intracellular organelles were significantly worse than those in the normal control group.However,in the 2 model therapy groups,damage to the intercellular joints and organelles was ameliorate relative to the model control group.CONCLUSION:Administration of geranylgeranylacetone was correlated with a more favorable pattern of gastric mucosa damage after ethanol perfusion.The mechanism could be related to regulation of ET-1,NO and PGE 2.

Thioredoxin-1 and Geranylgeranylacetone Resist Neurotoxicity of Amyloid-β

Objective:Alzheimer’s disease( AD) is the most common neurodegenerative disorder which is characterized by amyloid-β( Aβ) aggradation in the brain and impairment of cognitive function. Thioredoxin-1( Trx-1) is a redox regulating protein,and plays roles in resisting the oxidative stress and protecting neurons. Our previous study found that Trx-1 improved the cognitive function of Parkinson’s Disease( PD) mice. Geranylgeranylacetone( GGA) is an antiulcer drug and induces the expression of Trx-1 in vivo and in vitro. However,whether Trx-1 improves cognitive functions in mice of APP/PS1 or GGA protects SH-SY5 Y cells from cytotoxicity induced by Aβ is still unknown. The objective of present is to investigate the roles of Trx-1 and GGA in inhibiting neurotoxicity of Aβ. Methods:We used MTT assay to test the cell viability induced by Aβ(25-35) and western blot to detect the expression of Trx-1 in SH-SY5 Y cells. Trx-1 overexpression transgenic mice were hybridized with APP/PS1 transgenic mice to get control,Trx-1,Tx-1/APP/PS1 and APP/PS1 mice. Then we used Morris water maze,high plus maze and object recognition test to detect the cognitive function of different kinds of mice. We also used RT-PCR and western blot to test the mRNA level and expression of Trx-1,APP,PS1 and Aβ. Results:In our present study,we demonstrated that Aβ(25-35) decreased the cell viability and the expression of Trx-1 in SH-SY5 Y cells. The cell viability and the expression of Trx-1 were reversed by GGA. Our results showed that the escape latency in APP/PS1 mice was longer when compared with the Trx-1/APP/PS1 mice in Morris water maze and high plus maze. Whereas navigational experiments in Morris water maze result showed that the total number of crossings and the percentage of time spent in the target quadrant were significantly decreased in APP/PS1 mice when compared to Trx-1/APP/PS1 mice. Object recognition test the discrimination index was significantly decreased in APP/PS1 mice when compared with Trx-1/APP/PS1 mice. The mRNA levels and the expression of APP,PS1 and Aβ were decreased in Trx-1/APP/PS1 mice when compared to APP/PS1 mice. Conclusion:These results suggest that GGA protects SH-SY5 Y cells from cytotoxicity induced by Aβ(25-35) and restored the expression of Trx-1. Trx-1 overexpression improves cognitive function of APP/PS1 mice. Trx-1 may be a potential therapeutic target for the clinical management of AD.