geranylgeranylacetone and Liver-Cirrhosis

Portal hypertensive gastropathy (PHG) is now recognized as a distinct entity; however, the angiogenesis in the portal hypertensive gastric mucosa has yet to be elucidated. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in both physiological and pathological angiogenesis. The aim of this study was thus to examine the function of VEGF in the portal hypertensive and non-portal hypertensive gastric mucosa.. Forty-five cirrhotic patients were divided into 3 groups as follows. Group I included 15 patients without PHG who were treated with 1.5 g teprenone/day for 8 weeks: PHG(-)-t. Group II included 15 patients with PHG who were not treated with teprenone: PHG(+)-n. Group III included 15 patients with PHG who were treated with teprenone for 8 weeks: PGH(+)-t. The gastric mucosal blood flow (GMBF), the concentration of gastric mucosal VEGF and hexosamine and the endoscopic findings were studied both before and after medication.. Before teprenone treatment, the GMBF in the antrum, fundus, fornix were significantly higher in PHG(+)-n than PHG(-)-t. After treatment, the GMBF in the fundus and fornix significantly decreased more than before treatment in the PHG(+)-t. After treatment, the GMBF in the antrum increased significantly more than before treatment in PHG(-)-t. The gastric VEGF and hexoxamine concentration in the antrum were significantly higher in PHG(+)-n than in PHG(-)-t. After treatment, the gastric VEGF and hexosamine concentration in the antrum significantly decreased in PHG(+)-t while no change in concentration was recognized in PHG(+)-n. In the endoscopic findings, a decrease in the PHG score was recognized in 2 patients in PHG(+)-t.. Portal hypertensive gastric mucosal change was thus found to trigger a high concentration of VEGF and hexosamine. Such increased activity of VEGF and hexosamine may thus account for the presence of active congestion in PHG.

Topics: Adult; Aged; Anti-Ulcer Agents; Biopsy, Needle; Diterpenes; Dose-Response Relationship, Drug; Endothelial Growth Factors; Female; Gastric Mucosa; Gastroscopy; Hexosamines; Humans; Hypertension, Portal; Liver Cirrhosis; Lymphokines; Male; Middle Aged; Probability; Reference Values; Regional Blood Flow; Stomach Diseases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

We have evaluated gastric mucus generation (study 1) and the effects of tetraprenylacetone on gastric mucus generation (study 2) in cirrhotic patients with portal hypertension. Study 1: Included were 50 noncirrhotics (group A), 25 cirrhotics without portal hypertension (group B), and 25 cirrhotics with portal hypertension (group C). The antrum, corpus, and fundus mucus generation was assessed by hexosamine concentration using biopsy specimens. In groups A and B, the antrum hexosamine concentration was significantly higher compared with the corpus (P < 0.01, P < 0.01) and the fundus (P < 0.01). In contrast, the hexosamine concentration at each location was similar in group C. Furthermore, the antrum hexosamine concentration of group C was significantly lower compared with that of group A (P < 0.05). In study 2, a double-blind design, 300 mg of tetraprenylacetone was administered for four weeks in 10 cirrhotics with portal hypertension and placebo in 10. The regional hexosamine concentrations were measured before and after drug administration. Placebo administration did not change hexosamine concentration at each location. In contrast, tetraprenylacetone increased the antrum and corpus hexosamine concentration (P < 0.01, P < 0.05), although the fundus concentration did not change. These data suggest that cirrhotics with portal hypertension have reduced gastric antral mucus generation and tetraprenylacetone normalizes this.

Topics: Anti-Ulcer Agents; Diterpenes; Female; Gastric Mucosa; Hexosamines; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Mucus; Reference Values; Stomach

Increasing evidence has demonstrated that the heat shock protein 70 (HSP70) gene may be closely associated with tissue fibrosis; however, the association between HSP70 and liver fibrosis remains to be fully elucidated. The present study hypothesized that geranylgeranylacetone (GGA) exerts beneficial effects on liver fibrosis though upregulation of the expression of HSP70. Liver fibrosis was induced in rats using carbon tetrachloride (CCl4). The rats were subsequently divided into three groups: Control group, CCl4 model group and CCl4 model + GGA group. Liver fibrosis in the rats was evaluated using hematoxylin and eosin staining, Masson's trichrome staining and Sirius red staining. The levels of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin were determined using an automated biochemistry analyzer. The levels of total hepatic hydroxyproline were also determined. The expression levels of α‑smooth muscle actin (α‑SMA) and transforming growth factor‑β1 (TGF‑β1) were determined using immunofluorescence staining and western blotting, and the protein expression levels of HSP70 were determined using western blotting. The CCl4‑induced rats exhibited liver fibrosis, increased hydroxyproline content, impaired liver function, upregulated expression levels of the α‑SMA and TGF‑β1 pro‑fibrogenic proteins, and increased expression of HSP70, compared with the control group. These changes were attenuated by treatment with GGA. These results demonstrated that GGA exerted beneficial effects in CCl4‑induced liver fibrosis via upregulating the expression of HSP70.

Topics: Actins; Alanine Transaminase; Animals; Aspartate Aminotransferases; Bilirubin; Carbon Tetrachloride; Disease Models, Animal; Diterpenes; HSP70 Heat-Shock Proteins; Hydroxyproline; Liver; Liver Cirrhosis; Male; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1; Up-Regulation