Arsenic and 17-ß-estradiol bind to each other and neutralize each other's signaling effects.

We report that arsenic trioxide (ATO) and 17-beta-estradiol (E2) abolish each other's independent cell signaling effects in respect of cell survival and proliferation/migration of breast cancer (MCF-7) cells. The possibility that this is due to binding of ATO to E2 was confirmed through difference absorption spectroscopy, chromatography-coupled voltammometry and 1-D (1)H and (13)C NMR spectroscopy. Binding leads to attenuation of E2's hydroxyl (1)H peaks at its C17 and C3 carbon positions. The results suggest that ATO and E2 can titrate each other's levels, potentially explaining why sustained arsenic exposure tends to be associated with delays in age of menarche, advanced age of menopause, poorer sperm quality, higher overall morbidity in men, and lower incidences of breast cancer in women in some arsenic-contaminated areas.

Calcium binding to beta-2-microglobulin at physiological pH drives the occurrence of conformational changes which cause the protein to precipitate into amorphous forms that subsequently transform into amyloid aggregates.

Using spectroscopic, calorimetric and microscopic methods, we demonstrate that calcium binds to beta-2-microglobulin (ß2m) under physiological conditions of pH and ionic strength, in biological buffers, causing a conformational change associated with the binding of up to four calcium atoms per ß2m molecule, with a marked transformation of some random coil structure into beta sheet structure, and culminating in the aggregation of the protein at physiological (serum) concentrations of calcium and ß2m. We draw attention to the fact that the sequence of ß2m contains several potential calcium-binding motifs of the DXD and DXDXD (or DXEXD) varieties. We establish (a) that the microscopic aggregation seen at physiological concentrations of ß2m and calcium turns into actual turbidity and visible precipitation at higher concentrations of protein and ß2m, (b) that this initial aggregation/precipitation leads to the formation of amorphous aggregates, (c) that the formation of the amorphous aggregates can be partially reversed through the addition of the divalent ion chelating agent, EDTA, and (d) that upon incubation for a few weeks, the amorphous aggregates appear to support the formation of amyloid aggregates that bind to the dye, thioflavin T (ThT), resulting in increase in the dye's fluorescence. We speculate that ß2m exists in the form of microscopic aggregates in vivo and that these don't progress to form larger amyloid aggregates because protein concentrations remain low under normal conditions of kidney function and ß2m degradation. However, when kidney function is compromised and especially when dialysis is performed, ß2m concentrations probably transiently rise to yield large aggregates that deposit in bone joints and transform into amyloids during dialysis related amyloidosis.

Role of estrogen receptors in pro-oxidative and anti-oxidative actions of estrogens: a perspective.

BACKGROUND: Estrogens are steroid hormones responsible for the primary and secondary sexual characteristics in females. While pre-menopausal women use estrogens as the main constituents of contraceptive pills, post-menopausal women use the same for Hormone Replacement Therapy. Estrogens produce reactive oxygen species by increasing mitochondrial activity and redox cycling of estrogen metabolites. The phenolic hydroxyl group present at the C3 position of the A ring of estrogens can get oxidized either by accepting an electron or by losing a proton. Thus, estrogens might act as pro-oxidant in some settings, resulting in complicated non-communicable diseases, namely, cancer and cardiovascular disorders. However, in some other settings the phenolic hydroxyl group of estrogens may be responsible for the anti-oxidative beneficial functions and thus protect against cardiovascular and neurodegenerative diseases. SCOPE OF REVIEW: To date, no single review article has mentioned the implication of estrogen receptors in both the pro-oxidative and anti-oxidative actions of estrogens. MAJOR CONCLUSION: The controversial role of estrogens as pro-oxidant or anti-oxidant is largely dependent on cell types, ratio of different types of estrogen receptors present in a particular cell and context specificity of the estrogen hormone responses. Both pro-oxidant and anti-oxidant effects of estrogens might involve different estrogen receptors that can have either genomic or non-genomic action to manifest further hormonal response. GENERAL SIGNIFICANCE: This review highlights the role of estrogen receptors in the pro-oxidative and anti-oxidative actions of estrogens with special emphasis on neuronal cells.