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Low levels of xanthine dehydrogenase and cellular retinol binding protein in tumor mammary epithelial cells are responsible of the retinoic acid deficit
No full textLow levels of both xanthine dehydrogenase and cellular retinol binding protein are responsible of the retinoic acid deficiency in malignant human mammary epithelial cells (abstract)
No full textProtective Effect of Sildenafil against Estradiol-induced ROS production
No full textSeveral reports suggest that xanthine dehydrogenase (XDH) and its oxidase form (XO) play an important role in various forms of ischemic and vascular injuries. Recently we have demonstrated that 17β-estradiol (E2) induces a significant decrease of the expression and activity of XDH and its conversion to XO in human mammary epithelial cells. E2 is known to induce upregulation of eNOS gene expression in aortic endothelial cells. In light of the ability of XO-derived O2• ̄ to combine with •NO to yield ONOO ̄, and considering that ONOO ̄ converts XDH to XO, it is important to protect tissues against the XO increased activity and ROS increased production, that would in turn react with •NO to augment ONOO ̄ production, thus creating a vicious cycle of oxidative stress. Our previous studies have indicated that sildenafil has a protective effect on human mammary epithelial cells as a consequence of the inhibition of XO and of the resulting decrease of free oxygen radical that may influence the expression of NADPH oxidase and PDE-5. We report that the contemporary inhibitory effect played by sildenafil on XO and PDE-5 is due to the structural modification induced by O2• ̄, which involves the release of a piperazine group able to inhibit XO
Estradiol Decreases Xanthine Dehydrogenase Enzyme Activity and Protein Expression in Non-Tumorigenic and Malignant Human Mammary Epithelial Cells
No full textThe retinoic acid deficiency in breast tumour epithelial cells has been ascribed to an insufficient expression of either the enzyme(s) involved in its biosynthesis or the cellular retinol binding protein (CRBP) or both. In an attempt to define the mechanisms underpinning retinoic acid deficiency in these cell model systems, we have investigated the potential regulatory effect of oestrogen (17b-estradiol) on one key player in retinoic acid biosynthesis, the xanthine dehydrogenase (XDH). This enzyme is consistently expressed and very active in non-malignant human mammary epithelial cells (HMEC), as opposed to tumour MDA-MB231 and MCF7 cells. In these latter two cell lines, as opposed to
HMEC cells, we observe a residual ability of XDH to produce retinoic acid from retinaldehyde and the inability to use retinol, as a consequence of a deficit in CRBP. In addition, estradiol treatment of MDA-MB231 and MCF7 cells decreases protein expression and activity of the enzyme, with no modification of the mRNA transcript levels, eventually leading to deteriorate further retinoic acid production
Low levels of both xanthine dehydrogenase and of cellular retinol binding protein are responsible for retinoic acid deficiency in malignant human mammary epithelial cells
No full textThe seeming impairment of retinoid metabolism in human breast tumor cells has been attributed to the lower expression of cellular retinol binding proteins (CRBPs), of alcohol/retinol dehydrogenases, or aldehyde/retinaldehyde dehydrogenases. In a previous study we indicated that xanthine dehydrogenase (XDH) is able to oxidize actively both all-trans-retinol (t-ROL) bound to the CRBP (holo-CRBP) and all-trans-retinaldehyde (t-RAL) to all-trans-retinoic acid (t-RA) in human mammary epithelial cells (HMEC). Since both XDH and CRBP are required for the biosynthesis of t-RA, we have inspected their bioavailability in both estrogen-responsive and nonresponsive human mammary epithelial cancer cells. The XDH activity, as assessed in the crude and purified extracts of both MCF7 and MDA-MB 231 cells by measuring the substrate t-RAL (that unlike t-ROL does not need CRBP), was 6 to 10 times lower than that previously encountered in normal HMEC. In addition, CRBP expression was absent in either cell line. Based on this preliminary evidence, we propose here that the low levels of XDH activity and the associated absence of CRBP in both MCF7 and MDA-MB 231 human breast cancer cells might be responsible for the retinoic acid deficiency observed in these cell model systems. This defect may be the crux of the impairment to stem cell differentiation and, hence, may be primarily implicated in human mammary carcinogenesis
Sildenafil inhibits the ROS production by xanthine oxidase
No full textXanthine oxidase (XO) catalyzes the hydroxylation of a wide variety of substrates, including purines, pirimidines, pterins d aldehydes, to acids1. At relatively high oxygen pressure, it generates reactive oxygen species (ROS) as superoxides and hydroxyl radicals. The XO, detected in endothelial and epithelial cell outer surface, has been involved in ischemia/reperfusion injury1,2. Furthermore, XO-ROS production has been implicated in chronic hearth failure, inflammatory diseases, LDL oxidation, atherosclerosis, hypertension, cancer, aging1.
Allopurinol, a hypoxanthine analogue developed as xanthine oxidase inhibitor 30 years ago, and oxypurinol, its oxidation product, have proved to be effective in the treatment of these conditions both in experimental animals and human clinical trials1. Recent studies have shown the significant benefits of sildenafil, an inhibitor of type 5 phosphodiesterase, in patients with pulmonary hypertension, and an endothelium enhancing effect in preconditioning prior to ischemia/reperfusion3,4. As allopurinol/oxypurinol and sildenafil exhibit a marked structural analogy, we assayed the effect of this drug on the purified enzyme and in human prostatic cell cultures. The 80-100% inhibition of the ROS production by the enzyme bound to the external membrane of prostatic cells suggests that this mechanism may be of primary importance for the protective effects of the drug on epithelial cell
Sildenafil protects human mammary epithelial cells against ROS production induced by estradiol
No full textSeveral studies suggest that xanthine dehydrogenase (XDH) and its oxidase form (XO) play an important role in various types of ischemic and vascular injuries. Recently, we have demonstrated that estradiol (E2) induces a significant decrease of the expression and activity of XDH and of its conversion to XO in human mammary epithelial cells. E2 is known to induce upregulation of eNOS gene expression in aortic endothelial cells. Because the XO-derived O2•– combines with •NO to yield ONOO–, and considering that ONOO– converts XDH to XO, the resulting increase of XO activity and reactive oxygen species production would eventually lead to a further increase of ONOO– production, thus creating a vicious cycle of oxidative stress. Our previous study has indicated that sildenafil has a protective effect on human mammary epithelial cells as a consequence of XO inhibition and of the resulting decrease of free oxygen radicals that can impair the expression of NADPH oxidase and type 5 phosphodiesterase (PDE-5). In the present study, we report that the dual inhibitory effect exerted by sildenafil on both XO and PDE-5 is a consequence of a structural modification induced by O2•–, also consisting of the release of a piperazine group that could in turn inhibit the XO enzyme
A role for sex steroids in autoimmune diseases: a working hypothesis and supporting data.
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