No abstract

Lysophosphatidic acid (LPA) is a bioactive phospholipid that stimulates cell proliferation and migration, and protects cells from apoptosis. It interacts with specific G protein-coupled transmembrane receptors. Recently, frequent mutations of the LPA receptor-1 (LPA1) gene were detected in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (BHP). In this study, to evaluate the involvement of other LPA receptor gene alterations during lung carcinogenesis, we investigated mutations of the LPA2, LPA3, LPA4 and LPA5 genes in lung adenocarcinomas induced by BHP in rats. Fifteen male Wistar rats, 6 weeks of age, were given 2000 ppm BHP in their drinking water for 12 weeks and then maintained without further treatment until sacrifice at 25 weeks, and 15 adenocarcinomas were obtained. Genomic DNAs were extracted from frozen tissues, and the LPA2, LPA3, LPA4 and LPA5 genes were examined for mutations, using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. No mutations of LPA2, LPA3, LPA4 and LPA5 were detected in the 15 adenocarcinomas. These results suggest that alterations due to LPA2, LPA3, LPA4 and LPA5 gene mutations might not be involved in the development of lung adenocarcinomas induced by BHP in rats.

The level of plasma dopamine-beta-hydroxylase (DBH) activity in subjects at rest was found to be significantly lower in 12 patients on long-term hemodialysis than in a healthy 8-member control group: 28.3 ± 7.2 and 13.6 ± 7.6 IU/l, respectively (p < 0.01). Following immersion of one hand of each subject into cold water (4°C) for 1 min, a significant rise was observed in both groups, 6.1 ± 4.8 IU/l for the control and 1.6 ± 1.4 IU/l for the patient group (p < 0.01). Upon tilting up the head of all subjects, activity in both groups increased significantly, but a markedly smaller rise was found in the patient group: 5.8 ± 4.8 and 1.1 ± 1.6 IU/l for the two groups, respectively (p < 0.01). The data suggest an autonomic nervous dysfunction in patients on long-term hemodialysis.

Serial studies of serum lipids were performed on five patients with acute renal failure (ARF) due to five different causes (Of five patients one did not achieve complete recovery.). There were striking alterations in serum lipid levels at the period of oliguria in all patients, characterized by an increase in triglycerides (TG) and an extreme decrease in HDL-cholesterol (HDL-C). These conditions gradually returned to normal as the patients improved. The restoration to normal of the altered lipid levels were preceded by normalization of serum creatinine (S-Cr) and followed by creatinine clearance (Ccr). These fluctuational patterns of the lipid levels in the course of illness were observed similarly in all patients who recovered, despite the difference in the cause of their diseases. Improvement of the lipid metabolism was not observed in the one patient who did not recover. These results suggest that the alteration in lipid metabolism of ARF is due to renal impairment and not related to uremic state per se.

The purposes of the present study were to investigate the modifying effects of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a genotoxic carcinogen produced during cooking of protein-rich foods, and elucidate underlying mechanisms in a two-stage hepatocarcinogenesis mice model. Six-week-old B6C3F1 mice were subjected to two-thirds partial hepatectomy at the beginning of the study, followed by an intraperitoneal injection of diethylnitrosamine on day 1. Starting 1 week later, they were fed diets containing IQ at doses of 30, 100, or 300 ppm for 39 weeks. A dose-dependent trend for increase in eosinophilic altered foci as well as eosinophilic hepatocellular adenomas was observed, along with significant elevation in the incidence of hepatocellular carcinomas in the 100- and 300-ppm IQ groups as compared with initiation control group. Furthermore, IQ elevated the protein expression levels of Wnt1, transforming growth factor-β (TGF-β), TGF-β receptors 1 and 2 (TβR1 and TβR2), and phosphorylated c-Jun (p-c-Jun), while suppressing those of E-cadherin and p21(WAF1/Cip1). Moreover, translocation of β-catenin to the nuclei as well as upregulated nuclear expression of c-Myc and cyclin D1, which are downstream targets of β-catenin and p-c-Jun, were detected at 100 and 300 ppm. These findings suggest that IQ exerts dose-dependent promoting effects on mice hepatocarcinogenesis by activating TGF-β and Wnt/β-catenin signaling pathways and inhibiting cell adhesion.