In vivo platelet response to lipopolysaccharide in mice: proposed method for evaluating new antiplatelet drugs.

We previously found evidence (based on the use of 5HT as a marker) that i.v. injection of a lipopolysaccharide (LPS) into mice induces a rapid accumulation of platelets in liver and lung. Our previous studies lacked measurement of the platelet count itself, but we have now compared the LPS-induced changes in 5HT levels with the change in platelet count. We also examined the effects on the platelet response of some drugs that act on platelets. In mice, sublethal doses of LPS induced parallel decreases in platelets and 5HT in the blood. The 5HT lost from the blood accounted well for the 5HT accumulated in liver and lung. Soon after this accumulation, the levels of platelets and 5HT in the blood recovered in parallel, and these recoveries corresponded well with the decreases in 5HT occurring in liver and lung. Aspirin and dexamethasone were effective at both reducing pulmonary platelet-accumulation and promoting their return to the circulation. By contrast, oestrogen tended to reduce the return of platelets from lung to circulation. Heparin did not inhibit pulmonary platelet-accumulation but it did decrease their return to the circulation. These results suggest that (i) in response to sublethal doses of LPS, platelets translocate into the liver and lung, then return to the circulation; (ii) this platelet response involves mechanisms that can be modified by drugs; and (iii) the use of this platelet response as a tool for drug evaluation might help identify new drugs with therapeutic potential.

Inhibition of early 3-methyl-4-dimethylaminoazobenzene-induced hepatocarcinogenesis by gomisin A in rats.

The effects of gomisin A, a lignan component of Schizandra fruits, on hepatocarcinogenesis caused by 3'-methyl-4- dimethylaminoazobenzene (3'-MeDAB) in male Donryu rats were investigated. Gomisin A significantly inhibited the appearance of foci stained for glutathione S-transferase placental form (GST-P) in the liver of rats given feed with 0.06% 3'-MeDAB. Gomisin A (30 mg/kg/daily, po) decreased the concentration of 3'-MeDAB-related azo dyes in the liver, and increased their excretion in the bile. The ratio of diploid to tetraploid nuclei increased during ingestion of 3'-MeDAB, but gomisin A delayed the increase. After the withdrawal of 3'-MeDAB, carcinogen-related azo dyes were not detected in the liver or bile, but the proportion of diploid nuclei remained high, although it decreased with a 0.03% gomisin A diet. The results suggested that the effects of gomisin A are related to improved liver function and reversal of abnormal ploidization.

Inhibition by gomisin A, a lignan compound, of hepatocarcinogenesis by 3'-methyl-4-dimethylaminoazobenzene in rats.

The effects of gomisin A, a lignan compound of Schizandra fruits, on hepatocarcinogenesis induced by 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) in rats were investigated. Gomisin A inhibited both increases of the number and size of glutathione S-transferase placental form (GST-P)-positive foci, a marker enzyme of preneoplasm, and the population of diploid nuclei, as a proliferative state of hepatocytes, in the liver from rats simultaneously treated with 3'-MeDAB. Gomisin A increased GST activity in the liver, by raising the level of GST 1 and 2 isozymes. 3'-MeDAB increased GST activity and GST-P expression. This high level of GST-P induced by 3'-MeDAB was suppressed by additional treatment with gomisin A. In an experiment on simultaneous treatment, gomisin A increased the biliary excretion of 3'-MeDAB-related aminoazo dyes and decreased the content in the liver of rats fed with 0.06%-3'-MeDAB containing diet. In an experiment on pretreatment with 3'-MeDAB, even though no aminoazo dye was detectable in the liver or bile 2-weeks after cessation of 3'-MeDAB-feeding, gomisin A showed a tendency to reduce the preneoplastic changes of increases in GST-P positive foci and diploid nuclei in the liver. These results suggest that gomisin A inhibits the hepatocarcinogenesis induced by 3'-MeDAB by enhancing the excretion of the carcinogen from the liver and by reversing the normal cytokinesis.

Gomisin A, a lignan component of Schizandora fruits, inhibits development of preneoplastic lesions in rat liver by 3'-methyl-4-dimethylamino-azobenzene.

The effects of gomisin A, a lignan component of Schizandra fruits, on development of preneoplastic lesions in the liver after a short-term (3 weeks) feeding of 3'-methyl-4-dimethyl-aminoazobenzene (3'-MeDAB) to male Donryu rats were investigated, and compared with the effects of phenobarbital. Gomisin A inhibited both increases of the level of glutathione-S-transferase placental form (GST-P) and the number and size of GST-P positive foci in the liver increased after treatment with 3'-MeDAB. Moreover, although the population of diploid nuclei was increased and that of tetraploid nuclei was decreased by pretreatment with 3'-MeDAB, gomisin A returned this to near the normal ploidy pattern. But phenobarbital increased the level of GST-P and the number and size of GST-P positive foci with little affect on the ploidy population changed by 3'-MeDAB. Thus, the effect of gomisin A on hepatocarcinogenesis was inhibitory in contrast with that of phenobarbital. This study suggests that gomisin A is a candidate for a chemopreventive drug inhibiting the promotion process in hepatocarcinogenesis.