Micronutrient cooperation in the suppression of HIV production in chronically and latently infected cells.

Nutrients are known to display pharmacologic activity against viruses and to exert cooperative effects in cells. To study the influence of nutrient cooperation on HIV production in chronically infected T lymphocytes, we evaluated the individual and combined effects of nutrients on HIV-1 reverse transcriptase (RT) released into the culture supernatant. In unstimulated cells, low concentrations of single nutrients, namely ascorbic acid (AA), green tea polyphenols (GT) or lysine, did not significantly suppress HIV-1 RT production. However, when GT (25 µg/ml) and AA (32-64 µg/ml) were combined and applied to cells, extracellular RT was significantly reduced relative to the control. Combining GT (25 µg/ml) with lysine (25 µg/ml) also reduced the RT level to a greater extent (51% of control) than was observed wih lysine alone, and the addition of AA (16 µg/ml) to the combination further decreased RT to 17% of the control (p=0.06). Under the same assay conditions, the nucleoside analog azidothymidine did not significantly suppress HIV production at low to moderate concentrations (0.5-1.0 µg/ml), but did reduce the RT level to 40% of the control (p=0.02) at the highest dose tested (2 µg/ml). In unstimulated cells as well as in latently infected cells stimulated with mitogen (PMA or TNF-α), a nutrient mixture containing GT, AA and amino acids imparted significantly greater RT suppression than equivalent concentrations of key individual components. Nutrient effects on RT suppression were virus-specific and were not due to non-specific cellular toxicity. These results suggest that relatively non-toxic micronutrient combinations are more potent than single nutrients in suppressing virus production in chronically infected T cells, indicating that the constituent nutrients have a cooperative effect in HIV inhibition.

Differential sensitivity of various human tumour-derived cell types to apoptosis by organic derivatives of selenium.

Selenium is an important trace element with anti-cancer properties. In the present study, the apoptosis-inducing effects of organic selenium derivatives, namely methyl-L-selenocysteine and selenomethionine, were evaluated in vitro on human tumour-derived cell lines from breast, liver, colon, brain, skin and a non-tumorigenic line of epithelial origin. Apoptosis was assessed by cell-death detection immunoassay on cytoplasmic cell lysates. Breast carcinoma cells were highly sensitive to the organic selenium compounds, manifesting apoptosis at concentrations as low as 0.113 microm (0.0205 microg/ml) selenium. By contrast, non-tumorigenic mammary epithelial cells displayed poor sensitivity to selenium, requiring a substantially high concentration of the trace element of 87.9 microm (16.0 microg/ml). The cell lines derived from hepatoma and neuroblastoma showed intermediate sensitivity, with colon carcinoma cells manifesting the lowest sensitivity to the trace element. These results indicate intrinsic differences in the sensitivity of human tumour derivatives to selenium-mediated apoptosis, providing experimental support for the development of organic selenium compounds as anti-neoplastic agents against solid tumours displaying selective apoptotic sensitivity to these compounds.

Restoration of blood total glutathione status and lymphocyte function following alpha-lipoic acid supplementation in patients with HIV infection.

OBJECTIVES: To determine whether supplementation with alpha-lipoic acid (ALA), a glutathione-replenishing disulfide, modulates whole blood total glutathione (GSH + GSSG) levels and improves lymphocyte function in human immunodeficiency virus (HIV)-infected subjects with history of unresponsiveness to highly active antiretroviral treatment (HAART). DESIGN AND SETTING: Randomized, double-blinded, placebo-controlled trial conducted at two study sites: an eye clinic at a county hospital in San Jose and a research clinic in San Francisco, California. SUBJECTS: A total of 33 HIV-infected men and women with viral load >10,000 copies/cm(3), despite HAART, aged 44-47 years, approximately 36% nonwhite, were enrolled. INTERVENTION: Patients were randomly assigned to receive either ALA (300 mg three times a day) or matching placebo for 6 months. MAIN OUTCOME MEASURES: The change over 6 months in blood total glutathione status, lymphocyte proliferation response to T-cell mitogens, CD4 cell count, and viral load in patients receiving ALA compared to placebo. RESULTS: The mean blood total glutathione level in ALA-supplemented subjects was significantly elevated after 6 months (1.34+/-0.79 vs. 0.81+/-0.18 mmol/L) compared to insignificant change (0.76+/-0.34 vs. 0.76+/-0.22 mmol/L) in the placebo group (ALA vs. placebo: p=0.04). The lymphocyte proliferation response was significantly enhanced or stabilized after 6 months of ALA supplementation compared to progressive decline in the placebo group (ALA vs. placebo: p<0.001 with phytohemagglutinin; p=0.02 with anti-CD3 monoclonal antibody). A positive correlation was seen between blood total glutathione level and lymphocyte response to anti-CD3 stimulation (R(2)=0.889). There was no significant change in either HIV RNA level or CD4 count over 6 months in the ALA-supplemented compared to the control group. CONCLUSION: Supplementation with alpha-lipoic acid may positively impact patients with HIV and acquired immune deficiency syndrome by restoring blood total glutathione level and improving functional reactivity of lymphocytes to T-cell mitogens.

Microcompetition and the origin of cancer.

Abnormal gene expression is a common observation in cancer cells. Although genetic alterations via somatic mutations or DNA modifications are considered to be the cause of cancer, they do not explain the observed abnormal gene expression of many wild-type genes in cancer. Now, a new theory, called "Microcompetition", identifies a non-genetic-alteration event as the cause of the observed abnormal gene expression, and therefore, the cause of cancer and other chronic diseases.