Preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation in rats.

AIM: The aim of this study was to examine the preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation (BDL) in rats. METHODS: ME3738 (20 mg/day) was administered orally for 21 days immediately after BDL. Fibrosis was assessed by measuring hepatic hydroxyproline (Hyp) content. Activated hepatic stellate cells (HSCs) were assessed by alpha-smooth muscle actin (alpha-SMA) immunostaining. Hepatic thiobarbituric acid-reactive substance (TBARS), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) immunostaining were used to analyze oxidative stress. The gene expressions of collagen-I, transforming growth factor-beta1 (TGF-beta1), tissue inhibitor of metalloproteinases-1 (TIMP-1), interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) in the liver were examined by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Hepatic Hyp content and the area of hepatic fibrosis in BDL rats treated with ME3738 were reduced by 24% and 39% compared with non-treated BDL rats (hepatic Hyp, 9.40 +/- 2.85 vs. 12.39 +/- 3.91 mg/liver; P = 0.036; area of hepatic fibrosis, 13.1 +/- 3.8 vs. 21.5 +/- 10.9; P = 0.045). Furthermore, alpha-SMA-positive cells were significantly reduced by 40% (22.3 +/- 14.8 vs. 37.6 +/- 14.2; P = 0.011), collagen-I mRNA by 83% (6.5 +/- 2.2 vs. 38.3 +/- 9.1; P = 0.002), HO-1 mRNA by 58% (4.13 +/- 1.22 vs. 9.73 +/- 1.80; P = 0.018) and hepatic HO-1 content by 26% (2.13 +/- 0.80 vs. 2.87 +/- 0.19; P = 0.01) following ME3738 treatment. The hepatic expression of TBARS, 4-HNE, 8-OHdG and mRNA levels of TGF-beta1, TIMP-1 and IL-6 in the liver were unchanged by ME3738 treatment. CONCLUSION: Oral ME3738 administration may prevent the progression of hepatic fibrosis in BDL rats through suppression of the activation and collagen synthesis of HSC and, in part, oxidative stress. ME3738 has potential as a therapeutic drug for cholestatic liver fibrosis.

Usefulness of preoperative FDG-PET for detection of gastric cancer.

BACKGROUND: Positron emission tomography (PET), using 18F-fluoro-2-deoxy-D-glucose (FDG) as a tracer, can detect malignant neoplasms with altered glucose metabolism. To clarify the usefulness of FDG-PET for detecting gastric cancer, we evaluated preoperative PET imaging in gastric cancer patients. METHODS: Sixty-two gastric cancer patients who underwent FDG-PET imaging and gastric resection with lymphadenectomy were evaluated. RESULTS: For primary tumor assessment by PET, detection rates were significantly different in the following order: tumor size 30 mm or more (76.7%) > tumor size less than 30 mm (16.8%); advanced gastric cancer (AGC, 82.9%) > early gastric cancer (EGC; 25.9%); with nodal involvement (79.3%) > without nodal involvement (39.4%). In EGCs, the detection rate of the intestinal type, according to Lauren's classification (43.8%) was significantly higher than that of the diffuse type (0%). Two of the 7 EGC patients who were PET-positive had nodal involvement and their tumors were the intestinal type. For the assessment of nodal involvement, the accuracy of nodal involvement detection was 67.7% with PET and 75.8% with computed tomography (CT). Preoperative FDG-PET revealed colon cancer in 2 patients, adrenal tumor in 1 patient, lung cancer in 1 patient, and lung metastasis in 1 patient. CONCLUSION: Larger or more advanced tumors with nodal involvement had a higher detection rate by PET. In EGCs, only the intestinal type was detectable by PET. PET-positive EGC may be aggressive, and an adequate lymphadenectomy must be done. Preoperative PET was useful for the detection of other malignancies and distant metastasis.

Protective effects of alpha1-acid glycoprotein and serum amyloid A on concanavalin A-induced liver failure via interleukin-6 induction by ME3738.

We examined whether the 22beta-methoxyolean-12-ene-3beta,24(4beta)-diol (ME3738)-mediated selective induction of interleukin-6 increased alpha1-acid glycoprotein and serum amyloid A expression, and whether these proteins protected against liver injury in vitro and in vivo. ME3738 treatment in male mice increased gene expression of alpha1-acid glycoprotein subtypes and serum amyloid A 2 genes, and plasma concentration of serum amyloid A. Treatment with alpha1-acid glycoprotein at 5 mg/animal or serum amyloid A at 0.03 and 0.1 mg/animal prior to concanavalin A administration reduced multifocal necrosis in the liver. Treatment with alpha1-acid glycoprotein and serum amyloid A, but not alpha1-antitrypsin, protected Hep G2 cells against cell injury. These results suggest that alpha1-acid glycoprotein and serum amyloid A, increased by ME3738-induced interleukin-6, might protect against concanavalin A-induced liver injury.

Mechanisms of rolipram-induced increase in the incidence of mammary adenocarcinoma: histopathological study of a 104-week oral carcinogenicity study in female Sprague-Dawley rats.

The present study was carried out to elucidate the mechanisms behind an increase in the incidence of malignant or multiple mammary tumors as a result of oral administration of rolipram in a 104-week carcinogenicity study. The organs and tissues of Sprague-Dawley (SD) rats of both sexes, which had been subjected to a 104-week oral carcinogenicity study at doses of 0.2, 0.6 and 2.0 mg/kg, were examined. No treatment-related effects were seen in males; however, in females, there was a significant increase in the number of malignant or multiple mammary tumor bearers at a dose of 2.0 mg/kg. No other target organs were identified and the incidence of other tumor types were within the female control range. To clarify the mechanisms behind a rolipram-induced increase in the incidence of mammary adenocarcinoma at time points earlier than 104 weeks, the hormonal changes associated with pituitary adenoma were identified, and estrous cycling in the ovary, uterus, and vagina were examined in female rats treated with rolipram for 52 weeks. The plasma prolactin (PRL) concentration in all female groups exceeded the control value at Week 52, and all these differences were statistically significant. There was also a dose-dependent relationship with PRL-producing pituitary adenomas. Changes in estrous cycling in the uterus and vagina and a decrease in the size and number of corpora lutea in the ovaries of female rats treated with rolipram at 2.0 mg/kg for 52 weeks indicated that an increase in the estrus phase of the cycle corresponded to a marked decrease in the diestrus phase, which might result from the increased plasma estrogen concentration. Together, all of the above mentioned data suggest that rolipram not only stimulates an increase in the number and size of PRL adenomas in the pituitary gland but also in the estrus phase of the estrous cycle. These events might cause progression of the mammary gland tissues from hyperplasia to carcinoma.

[Aging and magnesium].

The aim of this article is to clarify the relationships between aging or age-related diseases and magnesium (Mg). The mutation of mitochondrial DNA can occur in both aging and Mg deficiency, resulting in peroxidation, intracellular Ca(2+) accumulation and apoptosis. The capability against peroxidation decreases in aging and Mg deficiency. DNA polymerase I, RNA polimerase and DNA helicase require Mg for their activities. Under Mg deficiency the replication, transcription and translation of DNA become erroneous. The dysfunctions of vascular endothelial cell occur in aging and Mg deficiency. In comparison between adult and old rats using the rings of rat thoracic aortae, vasorelaxation by acetylcholine and isoproterenol is lower in old rats, but can be improved through high Mg concentration. Although women with menopause are suffered from osteoporosis due to estrogen deficiency, bone fragility increases with additive Mg deficiency. High Ca intake is recommended for women with menopause, but adequate Mg intake is necessary to lower dietary Ca/Mg ratio, because the high ratio prompts blood coagulation. About lipid metabolism Mg can play a statin-like activity. Mg deficiency is complicated with lifestyle-related diseases, osteoporosis, bone fragility, depression and elderly dementia.

Preventive effects of soyasapogenol B derivatives on liver injury in a concanavalin A-induced hepatitis model.

To shed light on the structure-activity relationship, various soyasapogenol B derivatives were synthesized and evaluated for preventive effects on liver injury in the concanavalin A (Con A)-induced hepatitis model in mice. Con A injection into mice induces some pathophysiology of human liver disease such as autoimmune or viral hepatitis. Two hydroxyl groups on the A ring of soyasapogenol B are required for amelioration of liver damage. Modification of the C-22 hydroxyl moiety with an acyloxy or alkyloxy group, or removal of the hydroxyl group, resulted in a greatly enhanced percentage of alleviation. Among the series of soyasapogenol B derivatives examined, six compounds exhibited preventive effects on liver damage.

Dietary cadmium inhibits spontaneous hepatocarcinogenesis in C3H/HeN mice and hepatitis in A/J mice, but not in C57BL/6 mice.

Cadmium is known to be a potent carcinogenic and mutagenic metal. However, we demonstrated that dietary supplementation with 50 ppm cadmium inhibits spontaneous carcinogenesis in C3H/HeN and spontaneous hepatitis in A/J mice. We found that the frequencies of spontaneous hepatocarcinogenesis in C3H/HeN mice and of spontaneous hepatitis in A/J mice fed low-dose cadmium for 54 weeks were significantly lower than those in the respective control groups. A cadmium-induced increase in metallothionein production itself and/or metallothionein-associated increases in hepatic zinc concentrations may be involved in the observed preventive effects of cadmium. Our results suggest that low doses of cadmium in the diet or environment may play a beneficial role in the prevention of hepatic disease in humans and animals.