Suppression by Chai-hu-gui-zhi-tang of the development of liver lesions induced by N-nitrosomorpholine in Sprague-Dawley rats.

The effects of Chai-hu-gui-zhi-tang (TJ-10) on the development of liver lesions induced by N-nitrosomorpholine and on labeling and apoptotic indices were investigated in male Sprague-Dawley rats. Rats were given chow pellets containing 0.5 or 1.0% TJ-10 and, from the beginning of the experiment, were given drinking water containing N-nitrosomorpholine for 8 weeks. Visible white liver nodules, cellular alteration foci, and hepatic foci staining positively for glutathione-S-transferase, placental type, were examined macroscopically or histochemically. In week 16, TJ-10 at both dosages significantly reduced the incidence, and/or number of visible white nodules and hepatic lesions. Quantitative histologic analysis also showed that prolonged feeding of TJ-10 at both dosages significantly reduced the number of hepatic foci positive for glutathione-S-transferase, placental type. Administration of TJ-10 at both dosages also significantly decreased the labeling index of adjacent liver and significantly increased the apoptotic index of adjacent liver but had no significant effect on those of neoplastic lesions. These findings indicate that TJ-10 suppresses the development of liver lesions and suggest that this effect might be related to TJ-10's inhibition of cell proliferation and induction of apoptosis in adjacent hepatocytes.

Attenuation by d-limonene of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effects of prolonged administration of d-limonene, a monocyclic monoterpene, on sodium chloride-enhanced induction of gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine, the labeling and apoptotic indices, and ornithine decarboxylase (ODC) activity of gastric cancers were investigated in Wistar rats. After 25 weeks of carcinogen treatment, rats were given chow pellets containing 10% sodium chloride and 1% limonene ad libitum. In week 52, the incidence of gastric cancers, the labeling index and ODC activity were significantly higher and the apoptotic index was significantly lower in rats given sodium chlolide than in untreated control rats. However, in rats given both sodium chloride and d-limonene, the incidence of gastric cancers, the labeling index and ODC activity were significantly lower and the apoptotic index was significantly higher than in rats given sodium chloride alone. Our findings suggest that limonene attenuates the gastric carcinogenesis enhanced by sodium chloride via increased apoptosis and decreased ODC activity in gastric cancers.

Inhibition by D-limonene of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged oral administration of D-limonene on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on the labeling and apoptotic indices of gastric cancers were investigated in Wistar rats. After 25 weeks of the carcinogen treatment, rats were given chow pellets containing 1% or 2% limonene. In week 52, long-term oral administration of 2%, but not 1%, limonene significantly decreased the incidence of gastric cancers. Limonene also significantly decreased the labeling index and significantly increased the apoptotic index of gastric cancers. No K-ras mutations were detected in gastric cancers induced by MNNG in either group. These findings indicate that limonene inhibits the development of gastric cancers through increased apoptosis and decreased DNA synthesis of gastric cancers, but not through ras oncoprotein plasma membrane association.

Attenuation by all-trans-retinoic acid of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged administration of all-trans-retinoic acid (RA) on sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labelling and apoptotic indices and immunoreactivity of transforming growth factor (TGF) alpha in the gastric cancers was investigated in Wistar rats. After 25 weeks of carcinogen treatment, the rats were given chow pellets containing 10% sodium chloride and subcutaneous injections of RA at doses of 0.75 or 1.5 mg kg(-1) body weight every other day. In week 52, oral supplementation with sodium chloride significantly increased the incidence of gastric cancers compared with the untreated controls. Long-term administration of RA at both doses significantly reduced the incidence of gastric cancers, which was enhanced by oral administration of sodium chloride. RA at both doses significantly decreased the labelling index and TGF-alpha immunoreactivity of gastric cancers, which were enhanced by administration of sodium chloride, and significantly increased the apoptotic index of cancers, which was lowered by administration of sodium chloride. These findings suggest that RA attenuates gastric carcinogenesis, enhanced by sodium chloride, by increasing apoptosis, decreasing DNA synthesis, and reducing TGF-alpha expression in gastric cancers.

Inhibition by shi-quan-da-bu-tang (TJ-48) of experimental hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats.

The effect of Shi-Quan-Da-Bu-Tang (TJ-48) on hepatocarcinogenesis induced by N-nitrosomorpholine (NNM) was investigated in male Sprague-Dawley rats. Rats were given drinking water containing NNM for 8 weeks, and also from the start of the experiment, regular chow pellets containing 2.0 or 4.0% TJ-48 until the end of the experiment. Preneoplastic and neoplastic lesions staining for the placental type of glutathione-S-transferase (GST-P) or gamma-glutamyl transpeptidase (GGT) were examined histochemically. In week 15, quantitative histological analysis showed that prolonged administration of either 2.0 or 4.0% TJ-48 in the diet significantly reduced the size, volume and/or number of GST-P-positive and GGT-positive hepatic lesions. This treatment also caused a significant increase in the proportion of interleukin-2 receptor-positive lymphocytes among the lymphocytes infiltrating the tumours as well as a significant decrease in the labelling index of preneoplastic lesions. These findings indicate that TJ-48 inhibits the growth of hepatic enzyme-altered lesions, and suggests that its effect may be in part due to activation of the immune system.

Effect of treatment with liu-jun-zi-tang (TJ-43) on gastric emptying and gastrointestinal symptoms in dyspeptic patients.

The effects of treatment with the Chinese herbal medicine Liu-Jun-Zi-Tang (TJ-43) on gastric emptying and gastrointestinal symptoms were investigated in 42 patients with chronic idiopathic dyspepsia. By random allocation, 22 patients received oral treatment with 2.5 g TJ-43 three times daily, and 20 patients received placebo. Gastric emptying was measured by the acetaminophen absorption method. After 7 days of treatment, gastric emptying was significantly accelerated and gastrointestinal symptoms were significantly reduced in patients treated with TJ-43. Placebo treatment produced no significant effects. These findings indicate that TJ-43 had a prokinetic action on gastric emptying and that it was useful in treating chronic dyspepsia.

Inhibition by xiao-chai-hu-tang (TJ-9) of development of hepatic foci induced by N-nitrosomorpholine in Sprague-Dawley rats.

The effect of Xiao-chai-hu-tang (TJ-9) on hepatocarcinogenesis induced by N-nitrosomorpholine (NNM) was investigated in male Sprague-Dawley rats. Rats were given normal chow pellets containing 0.5% or 1.0% TJ-9 until the end of the experiment, and drinking water containing NNM for 8 weeks. Pre-neoplastic and neoplastic lesions staining for gamma-glutamyl transpeptidase (GGT) or the placental type of glutathione-S-transferase (GST-P) were examined histochemically. In Week 15, quantitative histological analysis showed that prolonged treatment with 0.5% TJ-9 significantly reduced the number and volume of GGT-positive and GST-P-positive hepatic lesions. Treatment with 1.0% TJ-9 inhibited the development of GGT-positive and GST-P-positive lesions, but was less effective than 0.5% TJ-9. Administration of 0.5% TJ-9 also caused a significant increase in the proportion of helper T lymphocytes and a significant decrease in the labeling index of pre-neoplastic lesions. These findings indicate that TJ-9 inhibits the development of hepatic foci.

Enhanced induction of gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine in deoxycorticosterone acetate-NaCl hypertensive rats and its inhibition by potassium chloride.

The effect of s.c. administration of deoxycorticosterone acetate (DOCA) plus p.o. treatment with NaCl solution on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine and the effect of p.o. potassium supplementation on the enhanced induction of gastric carcinogenesis in DOCA-NaCl rats were investigated in Wistar rats. After 25 weeks of p.o. treatment with the carcinogen, rats received s.c. injections of DOCA (50 mg/kg) twice a week and were given 1% NaCl solution with and without 1% KCl as drinking water. In Week 52, the blood pressure, the incidence of gastric cancer, and the number of cancers per rat were significantly greater in DOCA-NaCl rats than in the untreated group. Prolonged p.o. treatment of DOCA-NaCl hypertensive rats with potassium significantly reduced their blood pressure, the incidence of gastric cancers, and their number per rat. All gastric tumors were in the glandular portions of the stomach. The norepinephrine concentration in the gastric wall and the labeling indices of gastric mucosa were significantly greater in DOCA-NaCl hypertensive rats than in the untreated group, but p.o. potassium supplementation significantly reduced the norepinephrine concentration in the gastric wall and the labeling indices of the gastric mucosa in DOCA-NaCl rats. Thus, administration of DOCA and NaCl increased the norepinephrine concentration in the gastric wall and promoted gastric carcinogenesis, and p.o. potassium supplementation decreased the norepinephrine concentration in the gastric rats. Inasmuch as the norepinephrine concentration has been used as a marker of sympathetic nervous activity, these findings suggest that the sympathetic nervous system plays an important role in gastric carcinogenesis, probably associated with cell proliferation of antral epithelial cells.

Protective effect by potassium chloride against gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in spontaneously hypertensive rats.

The effects of oral potassium supplementation on the enhanced induction of gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in spontaneously hypertensive rats (SHR), and the norepinephrine concentration in their gastric wall were investigated. The SHR and normotensive Wistar Kyoto rats (WKY) as controls were given a solution of the carcinogen for 25 weeks and then 1% KCl solution or tap water to drink. In Week 52, the incidence of gastric cancers and their number per rat and the norepinephrine concentration in the gastric wall were significantly greater in SHR than in WKY. Prolonged oral treatment of SHR with potassium significantly reduced the incidence of gastric cancers and their number per rat, as well as the blood pressure and the norepinephrine concentration in the antral portion of the gastric wall. These findings indicate that prolonged treatment with KCl attenuated the enhancement of gastric carcinogenesis by MNNG in SHR.

Inhibition by gamma-amino-n-butyric acid and baclofen of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of gamma-amino-n-butyric acid (GABA), the GABA(A) receptor agonist muscimol (5-aminomethyl-3-hydroxyisoxazole), and the GABA(B) receptor agonist baclofen [4-amino-3-(4-chlorophenyl)butanoic acid] on the incidence and number of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in Wistar rats. Rats received alternate-day i.p. injections of 500 or 1000 mg/kg of body weight GABA, 0.25 or 0.5 mg/kg of body weight muscimol, or 4 or 8 mg/kg of body weight baclofen after 25 wk of p.o. treatment with the carcinogen. Prolonged administration of GABA at 1000 mg/kg of body weight, but not at 500 mg/kg of body weight, and of baclofen at 4 and 8 mg/kg of body weight significantly decreased the incidence and number of gastric cancers of the glandular stomach in Wk 52, but long-term muscimol administration had no influence. Histologically, GABA at the high dosage and baclofen at both dosages significantly decreased the labeling index of the antral mucosa and significantly increased the serum gastrin level. Furthermore, baclofen at both dosages significantly decreased antral pH and significantly increased gastric acid secretion. These findings indicate that GABA inhibits gastric carcinogenesis via the GABAB receptor and that this effect may be related to its effect in decreasing the proliferation of antral mucosa.

Protection by oral phenylalanine against gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of oral administration of L-phenylalanine on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in inbred Wistar rats. Oral administration of 6% phenylalanine after 25 weeks of treatment with the carcinogen significantly reduced the incidence and number of adenocarcinomas of the glandular stomach at experimental week 52. Oral administration of high dose phenylalanine significantly increased the basal serum gastrin level and significantly decreased the norepinephrine concentration in the antral portion of the gastric wall, as well as the labelling indices of antral mucosa. These findings indicate that orally administered phenylalanine inhibits the development of gastric cancers.