Drinking green tea is associated with decreased frequency of cancer development. This review outlines the wide range of mechanisms by which epigallocatechin gallate (ECGC) and other green and black tea polyphenols inhibit cancer cell survival. EGCG suppressed androgen receptor expression and signalling via several growth factor receptors. Cell cycle arrest or apoptosis involved caspase activation and altered Bcl-2 family member expression. EGCG inhibited telomerase activity and led to telomere fragmentation. While at high concentrations polyphenols had pro-oxidative activities, at much lower levels, anti-oxidative effects occurred. Nitric oxide production was reduced by EGCG and black tea theaflavins by suppressing inducible nitric oxide synthase via blocking nuclear translocation of the transcription factor nuclear factor-kappaB as a result of decreased IkappaB kinase activity. Polyphenols up- or down-regulated activity of a number of key enzymes, including mitogen-activated protein kinases and protein kinase C, and increased or decreased protein/mRNA levels, including that of cyclins, oncogenes, and tumor suppressor genes. Metastasis was inhibited via effects on urokinase and matrix metalloproteinases. Polyphenols reduced angiogenesis, in part by decreasing vascular endothelial growth factor production and receptor phosphorylation. Recent work demonstrated that EGCG reduced dihydrofolate reductase activity, which would affect nucleic acid and protein synthesis. It also acted as an aryl hydrocarbon receptor an-tagonist by directly binding the receptor's molecular chaperone, heat shock protein 90. In conclusion, green and black tea polyphenols act at numerous points regulating cancer cell growth, survival, and metastasis, including effects at the DNA, RNA, and protein levels.

Lack of disease in long-term nonprogressors with human immunodeficiency virus type 1 (HIV-1) infection was strongly associated with very low copy numbers of HIV-1 DNA and RNA in peripheral blood mononuclear cells and plasma and the presence of high levels of anti-HIV-1 CD8 ؉ memory cytotoxic T lymphocytes specific for Gag, Pol, and Env, compared with levels present in intermediate and advanced progressors. CD8 ؉ memory cytotoxic T lymphocytes may have an important role in controlling HIV-1 replication and preventing disease in long-term nonprogressors.

Cytotoxic T lymphocytes (CTL) may play an important role in host defense against HIV-1 infection. In this study, we examined the responses of circulating effector CTL (CTLe) specific for Gag, Pol, Env, and Tat in 57 HIV-1-infected men, 49 of whom were asymptomatic and had documented time since seroconversion of < 8 years. CTLe responses to at least one of the four HIV-1 gene products were detected in 83% of the subjects. The magnitude and prevalence of the anti-Tat responses were significantly less than the responses to Gag, Pol, and Env. Cell depletion studies indicated that the lytic activity against the HIV-1 structural proteins was mediated by CD8+ T cells, although 30% of Env-specific lysis was mediated by CD16+ natural killer cells. Anti-HIV-1 CTLe responses against Gag and Pol were significantly less in subjects infected for over 6 years as compared to those infected for shorter periods of time. We found no correlation, however, between anti-HIV-1 CTLe responses and either CD4+ or CD8+ T cell counts, rates of CD4+ T cell loss, HIV-1 infectious viral load, use of antiviral medications, or subsequent progression to AIDS. Our results indicate that anti-HIV-1 CTLe activity is relatively stable in asymptomatic subjects infected < 6 years, and is not an early marker for risk of disease progression.

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The acute phase of Chagas' disease is accompanied by immunosuppression. To explore the underlying mechanism(s), we used an in vitro culture system in which the capacities of activated human peripheral blood mononuclear cells to express interleukin-2 receptors (IL-2R) and proliferate are markedly inhibited in the presence of Trypanosoma cruzi, the etiologic agent. The present work was designed to define the earliest time at which T. cruzi-induced suppression is manifested in terms of IL-2R expression on the cell surface and establish whether expression of other lymphocyte activation markers is also suppressed by the parasite. We found that expression of IL-2R by human peripheral blood mononuclear cells cocultured with T. cruzi and stimulated with either phytohemagglutinin or anti-CD3 (a monoclonal antibody specific for an epitope of the T cell receptor complex T3-Ti) was significantly suppressed as early as 12 h after culture initiation. Both the percentage of IL-2R+ cells and the surface density of IL-2R, measured by flow cytometry, were affected. However, expression of EA1, a human lymphocyte activation antigen known to be expressed 4 to 6 h after stimulation, was not altered by T. cruzi whether phytohemagglutinin or anti-CD3 was used. On the other hand, expression of transferrin receptors (TfR), which first occurs between 20 and 24 h after lymphocyte activation, was markedly suppressed by T. cruzi. This effect was denoted by significant reductions in both the percentage of TfR+ cells and the cell surface density of TfR whether phytohemagglutinin or anti-CD3 was used as the mitogen and was observed at all test times, i.e., at 24, 48, 72, and 96 h. Because expression of IL-2R and TfR is required for lymphoproliferation but that of the EAl lymphocyte activation marker is apparently not, these results are consistent with the possibility that T. cruzi, at a relatively early stage during lymphocyte activation, selectively affects certain key events on which clonal expansion is dependent. Inhibition of IL-2R and TfR expression by the parasite might play a role in causing the suppressive effects associated with acute Chagas' disease.

Melanocortin 4 receptor (MC4R) variants contribute to human obesity, and rats lacking functional MC4R (Mc4rK314X/K314X) are obese. We investigated the hypothesis that low energy expenditure (EE) and physical activity contribute to this obese phenotype in male rats, and determined whether lack of functional MC4R conferred protection from weight loss during 50% calorie restriction. Though Mc4rK314X/K314X rats showed low brown adipose Ucp1 expression and were less physically active than rats heterozygous for the mutation (Mc4r+/K314X) or wild-type (Mc4r+/+) rats, we found no evidence of lowered EE in Mc4rK314X/K314X rats once body weight was taken into account using covariance. Mc4rK314X/K314X rats had a significantly higher respiratory exchange ratio. Compared to Mc4r+/+ rats, Mc4rK314X/K314X and Mc4r+/K314X rats lost less lean mass during calorie restriction, and less body mass when baseline weight was accounted for. Limited regional overexpression of Mc3r was found in the hypothalamus. Although lower physical activity levels in rats with nonfunctional MC4R did not result in lower total EE during free-fed conditions, rats lacking one or two functional copies of Mc4r showed conservation of mass, particularly lean mass, during energy restriction. This suggests that variants affecting MC4R function may contribute to individual differences in the metabolic response to food restriction.

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