No abstract

We investigated blood-brain barrier (BBB) permeability in white matter lesions of Binswanger’s disease (BD) with contrast-enhanced MRI. Three subject groups were studied: 17 patients with BD and periventricular hyperintensities (PVH) on MRI, 10 patients with ischemic cerebrovascular events and with PVH but no dementia, and 14 age-matched control subjects without PVH. BBB permeability was quantified by calculation of T₁ change defined as [(T_1post – T_1pre)/T_1pre] ×100, where T_1pre and T_1post represent the T₁ relaxation times before and after Gd-DTPA administration. T₁ change in PVH of BD patients significantly decreased in comparison with that observed in PVH of the nondemented patients and in normal white matter of the control subjects, but no significant T₁ change was observed between the PVH of the nondemented patients and normal white matter of the controls. There was a significant correlation between the Mini-Mental State Examination score and T₁ change for areas of PVH in BD. These results suggest that BBB permeability increases in areas of PVH in BD and that a BBB dysfunction is related to a progression of cognitive impairment.

Origin recognition complex (ORC), a six-protein complex (Orc1p-6p), is the most likely initiator of chromosomal DNA replication in eukaryotes. Although ORC of Saccharomyces cerevisiae has been studied extensively from biochemical and genetic perspectives, its quaternary structure remains unknown. Previous studies suggested that ORC has functions other than DNA replication, such as gene silencing, but the molecular mechanisms of these functions have not been determined. In this study, we used yeast two-hybrid analysis to examine the interaction between ORC subunits and to search for ORC-binding proteins. As well as the known Orc4p-Orc5p interaction, we revealed strong interactions between Orc2p and Ord3p (2p-3p), Orc2p and Ord5p (2p-5p), Orc2p and Ord6p (2p-6p) and Orc3p and Ord6p (3p-6p) and weaker interactions between Orc1p and Ord4p (1p-4p), Orc3p and Ord4p (3p-4p), Orc2p and Ord3p (3p-5p) and Orc5p and Ord3p (5p-6p). These results suggest that 2p-3p-6p may form a core complex. Orc2p and Orc6p are phosphorylated in vivo, regulating initiation of DNA replication. However, replacing the phosphorylated amino acid residues with others that cannot be phosphorylated, or that mimic phosphorylation, did not affect subunit interactions. We also identified several proteins that interact with ORC subunits; Sir4p and Mad1p interact with Orc2p; Cac1p and Ykr077wp with Orc3p; Rrm3p and Swi6p with Orc5p; and Mih1p with Orc6p. We discuss roles of these interactions in functions of ORC.

No abstract

In line with improvements in diagnostic procedures to detect intestinal lesions, it has become clear that nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin induce lesions not only in the stomach but also in the small intestine. However, clinical protocols for the treatment of NSAID-induced lesions of the small intestine have not been established. It is known that heat shock proteins (HSPs), particularly HSP70, confer protection against various stressors, and more recently, the anti-inflammatory activity of HSP70 was revealed. In this study, we examined the effect of expression of HSP70 on indomethacin-induced lesions of the small intestine. The extent of indomethacin-induced lesions to the small intestine was reduced in transgenic mice expressing HSP70 compared with controls. Oral administration of indomethacin increased the expression of HSP70 in the small intestine. Administration of indomethacin also induced mucosal cell apoptosis and expression of proinflammatory cytokines in the small intestines of control mice, with both of these responses suppressed in the transgenic mice. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, increased expression of HSP70 in the small intestine and suppressed indomethacin-induced lesions of the small intestines in wild-type mice. These results suggest that indomethacin-induced increase in HSP70 expression reduces the extent of lesions to the small intestine by suppressing mucosal cell apoptosis and inflammatory responses. The HSP-inducing activity of GGA seems to contribute to the protective effect of drug against the lesions. Based on these results, we propose that nontoxic HSP70-inducers, such as GGA, would be therapeutically beneficial for treating NSAID-induced lesions of the small intestine.Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of drugs, and the anti-inflammatory actions of NSAIDs are mediated through their inhibitory effects on cyclooxygenase (COX)