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In human dermal fibroblasts, brought to quiescence (G H ) by serum starvation, the S phase peaked 24 h and G P /M phases 36 h after serum re-addition. Under the same conditions, ornithine decarboxylase mRNA peaked at 12 h, decreased markedly in S phase and remained low until 48 h. Conversely, ornithine decarboxylase antizyme transcript dropped to its lowest level at 12 h, while reaching its highest values between 24 and 48 h. Ornithine decarboxylase activity followed essentially the pattern of its mRNA, but relative changes were much greater. S-Adenosylmethionine decarboxylase transcript and enzyme activity also peaked at around 12 h, decreasing thereafter. Spermidine/spermine N I -acetyltransferase mRNA and activity reached the highest values at 36^48 h. Putrescine concentration increased up to 18 h and fell dramatically in the S phase, remaining low thereafter. Both spermidine and spermine reached peaks at 18 h and decreased in the S phase, but not nearly as much as putrescine. We discuss how this comprehensive study may help to understand the involvement of polyamines in the control of cell proliferation.z 1999 Federation of European Biochemical Societies.

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The aim of this study was to analyze (i) phenotype, (ii) in vitro spontaneous and induced apoptosis, (iii) glutathione (GSH) intracellular content and (iv) inhibitors of apoptosis of potential therapeutical use in peripheral blood mononuclear cells (PBMC) from HIV+ long term non progressors (LTNP), in comparison with progressors (HIV+P) and seronegative controls (HIV7). Three groups of subjects were studied: 15 HIV+P (patients losing 4150 CD4+/year), 9 LTNP (subjects infected by HIV for at least 7 years without clinical and immunological signs of progression, with a mean of 898 CD4+/mL) and 18 HIV7. All subjects were living in a large community for former drug addicts, and were matched for age and sex.We used flow cytometry for analyzing PBMC phenotype and apoptosis; high performance liquid chromatography for measuring intracellular GSH content. PBMC phenotype of LTNP shared characteristics with those of both HIV7 and HIV+P. Indeed, LTNP showed a normal number CD4+ cells (an inclusioncriteria),butsignificantlyincreasednumbersofCD8+ lymphocytes, activated T cells, CD19+, CD5+ B lymphocytes and CD57+ cells, as well as a decrease in CD19+, CD57 B lymphocytes and CD16+ cells. In LTNP, spontaneous apoptosis was similar to that of HIV7 and significantly lower than that of HIV+P. Adding interleukin-2 (IL-2) or nicotinamide (NAM)significantlydecreasedspontaneousapoptosisinLTNP and HIV+P. Pokeweed mitogen-induced apoptosis was also similar in LTNP and HIV7, but significantly lower than that of HIV+P. In HIV+P, but also in LTNP, spontaneous apoptosis was inversely correlated to the absolute number and percentage of CD4+ cells and directly correlated to the number and percentageofactivatedTcellspresentinperipheralblood.GSH intracellular content was greatly decreased in PBMC from HIV+P and slightly, but significantly, reduced in LTNP. Adding 2-deoxy-D-ribose, an agent provoking apoptosis through GSH depletion, to quiescent PBMC resulted in similar levels of massive cell death in the three groups. This phenomenon was equally prevented in the three groups by N-acetyl-cysteine but not by IL-2.A complex immunological situation seems to occur in LTNP. Indeed, PBMC from LTNP are characterized by a normal in vitro tendencytoundergoapoptosisdespitethepresenceofastrong activation of theirimmune system,unexpectedly similar tothat of HIV+P. Our data suggest that NAM and IL-2 are possible candidates for reducing spontaneous apoptosis in HIV infection.

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