NCP-2454 prevented MCT-induced PH by suppressing intracellular inflammatory cascades, an upstream molecular change of which is the disruption of Cav-1 expression.

To identify the cellular gene target for Tat, we performed gene expression profile analysis and found that Tat up-regulates the expression of the OGG1 (8-oxoguanine-DNA glycosylase-1) gene, which encodes an enzyme responsible for repairing the oxidatively damaged guanosine, 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG). We observed that Tat induced OGG1 gene expression by enhancing its promoter activity without changing its mRNA stability. We found that the upstream AP-4 site within the OGG1 promoter is responsible and that Tat interacted with AP-4 and removed AP-4 from the OGG1 promoter by in vivo chromatin immunoprecipitation assay. Thus, Tat appears to activate OGG1 expression by sequestrating AP-4. Interestingly, although Tat induces oxidative stress known to generate 8-oxo-dG, which causes the G:C to T:A transversion, we observed that the amount of 8-oxo-dG was reduced by Tat. When OGG1 was knocked down by small interfering RNA, Tat increased the amount of 8-oxo-dG, thus confirming the role of OGG1 in preventing the formation of 8-oxo-dG. These findings collectively indicate the possibility that Tat may play a role in maintenance of the genetic integrity of the proviral and host cellular genomes by upregulating OGG1 as a feed-forward mechanism.

Although its potential for vaccine development is already known, the introduction of recombinant human immunodeficiency virus (HIV) genes to Mycobacterium bovis bacille Calmette-Guérin (BCG) has thus far elicited only limited responses. In order to improve the expression levels, we optimized the codon usage of the HIV type 1 (HIV-1) p24 antigen gene of gag (p24 gag) and established a codon-optimized recombinant BCG (rBCG)-p24 Gag which expressed a 40-fold-higher level of p24 Gag than did that of nonoptimized rBCG-p24 Gag. Inoculation of mice with the codon-optimized rBCG-p24 Gag elicited effective immunity, as evidenced by virus-specific lymphocyte proliferation, gamma interferon ELISPOT cell induction, and antibody production. In contrast, inoculation of animals with the nonoptimized rBCG-p24 Gag induced only low levels of immune responses. Furthermore, a dose as small as 0.01 mg of the codon-optimized rBCG per animal proved capable of eliciting immune responses, suggesting that even low doses of a codon-optimized rBCG-based vaccine could effectively elicit HIV-1-specific immune responses.

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Human periodontal ligament fibroblast (HPLF) cultured on tissue culture dishes (TCD), irrespective of the presence of serum, showed only a spreading form. In contrast, using polyelectrolyte complex (PEC) as a matrix, HPLF showed spreading, round, and aggregate forms. Cells of the inner part of the aggregate contacted with each other to form a three-dimensional structure, and this condition corresponded to typical tissues in vivo. These seemed to be related to the interrelation between growth and morphology; that is, the HPLF of the spreading form was considered to belong to a proliferation phase, and the HPLF of the round and aggregate forms, with a little growth, seemed to belong to a functional phase of the cell cycle, indicating that PEC is able to control such cell functions as proliferation, morphology, and differentiation. The cell aggregate was observed only on PEC with carboxymethyl residues and was stained by alizarin red (AR), which suggested mineralization. The spreading cells on PEC containing sulfate residues were not stained by AR. Therefore, it was found that there was a certain relationship between cell growth and morphology, and that PEC affected the cell cycle and promoted proliferation and differentiation of HPLF.