[Basic principles of interpretation of hepatocellular hypertrophy in risk assessment in Japan].

This article provided a scientific basis for determining whether liver hypertrophy, a common change in the liver induced by xenobiotics in toxicological studies, is an adaptive or adverse event. To maintain homeostasis in the whole organism, the liver frequently responds to xenobiotic exposure by increasing metabolic capacity via nuclear receptor activation. The resuiting hepatic adaptive responses (hepatocellular hypertrophy and increased relative liver weight) are potentially beneficial to the organism in providing increased capacity to respond to chemical-induced stress.

New parameter that supports speculation on the possible mechanism of hypothyroidism induced by chemical substances in repeated-dose toxicity studies.

Hypothyroidism induced by xenobiotic treatment was analyzed for possible underlying mechanism(s) on the basis of different responses of the thyroid gland and the liver, using a newly-created database of repeated-dose toxicity of 500 chemicals. Two mechanisms are proposed: direct inhibition of thyroid hormone biosynthesis in the thyroid gland, and stimulated degradation of thyroid hormone by induction of hepatic drug-metabolizing enzymes. In the database there were 10 chemicals inducing hypertrophy/hyperplasia of follicular cells in the thyroid gland and having data on thyroid glands.

Specific 3'-terminal modification of DNA with a novel nucleoside analogue that allows a covalent linkage of a nuclear localization signal and enhancement of DNA stability.

We report a straightforward method for the site-specific modification of long double-stranded DNA by using a maleimide adduct of deoxycytidine. This novel nucleoside analogue was efficiently incorporated at the 3'-termini of DNA by terminal deoxynucleotidyl transferase (TdT). Thiol-containing compounds can be covalently linked to the maleimide moieties.

Effects on RNAi of the tight structure, sequence and position of the targeted region.

RNA interference (RNAi) is a gene-silencing phenomenon that involves the double-stranded RNA-mediated cleavage of mRNA, and small interfering RNAs (siRNAs) can cause RNAi in mammalian cells. There have been many attempts to clarify the mechanism of RNAi, but information about the relationship between the sequence and structure, in particular, a tight structure, of the target RNA and the activities of siRNAs are limited. In the present study, we examined this relationship by introducing the TAR element, which adopts a very stable secondary structure, at different positions within target RNAs.

A reappraisal, based on (31)P NMR, of the direct coordination of a metal ion with the phosphoryl oxygen at the cleavage site of a hammerhead ribozyme.

It has been generally accepted, on the basis of kinetic studies with phosphorothioate-containing substrates and analyses by NMR spectroscopy, that a divalent metal ion interacts directly with the pro-Rp oxygen at the cleavage site in reactions catalyzed by hammerhead ribozymes. However, results of our recent kinetic studies (Zhou, D.-M.

Kinetic Analysis of Diamine-Catalyzed RNA Hydrolysis.

The catalysis of various amines for the hydrolysis of RNA has been kinetically investigated, and the catalytic rate constants for each of the ionic states of these amines are determined. Ethylenediamine and 1,3-propanediamine are highly active under the physiological conditions, mainly because they preferentially take the catalytically active monocationic forms. The catalysis of these diamines is further promoted by the intramolecular acid-base cooperation of the neutral amine and the ammonium ion.