Effects of selected food phytochemicals in reducing the toxic actions of TCDD and p,p′-DDT in U937 macrophages

To assess the effectiveness of selected food phytochemicals in reducing the toxic effects of the environmental toxicants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and p,p′-DDT (DDT), we tested the potencies of auraptene, nobiletin, zerumbone, and (±)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA) in reversing the inflammatory action of these toxicants in U937 human macrophages. Using quantitative RT–PCR as the initial screening assay, we identified antagonistic actions of zerumbone and auraptene against the action of TCDD and DDT in up-regulating the mRNA expressions of COX-2 and VEGF. The functional significance of the inhibitory action of zerumbone on COX-2 expression was confirmed by demonstrating its suppression of TCDD-induced activation of COX-2 gene expression in mouse MMDD1 cells. We tested auraptene on DDT-induced reactive oxygen species (ROS) formation in U937 macrophages and found that auraptene is a powerful agent antagonizing this action of DDT. To confirm the significance of these actions of zerumbone and auraptene at the cellular level, we assessed their influence on TCDD-induced apoptosis resistance in intact U937 macrophages and found that they are capable of reversing this action of TCDD. In conclusion, zerumbone and auraptene were identified to be the most effective agents in protecting U937 macrophages from developing these cell toxic effects of TCDD and DDT

Trinucleotide repeat expansions in human breast cancer-susceptibility genes: relevant targets for aspirin chemoprevention?

Purpose Defining novel molecular mechanisms pertinent to aspirin chemoprevention of breast cancer (BC) and to explain controversial epidemiological results in this regard

Hemoglobins as new players in multiple sclerosis: metabolic and immune aspects

Basic science investigations and clinical observations in recent years indicate that hemoglobins (Hbs) may have important roles in the pathogenesis of multiple sclerosis (MS). These findings can be summarized as follows: 1- Erythrocyte fragility is higher in MS patients, the released free Hb damages blood-brain barrier, myelin basic protein and also triggers iron overload and inflammation. 2- Free Hb may further activate the inflammatory responses through Toll-like receptor 4 (TLR4), present on microglia and other innate immunocytes. 3- Hbs are expressed in neural cells including dopaminergic neurons. Also, several studies have demonstrated that Hbs are expressed in astrocytes and oligodendroglia. 4- Hb overexpression in neural cells upregulate mitochondrial complex I-V subunits. The comparison of the mitochondrial proteome between healthy and patients with MS revealed only four differentially expressed proteins including Hb beta-chain. 5- Microarray analysis of 8300 genes in monocytes of twins with and without MS showed a difference in 25 genes that include genes encoding alpha- and beta-globins as well. 6- beta- and alpha-globin gene clusters reside at chromosomal regions 11p15.5 and 16p13.3, respectively. Whole genome screen (WGS) in Sardinian MS families using 327 markers revealed linkage in 3 regions including 11p15.5 loci. Further, 11p15.5 and 16p13.3 were part of the 17 regions identified in the WGS study of 136 sibling-pairs in Nordic countries analyzing 399 microsatellite markers. In the light of these findings, we propose that free Hb released from dying erythrocytes is detrimental. On the contrary, intracellular Hbs in neural cells are protective in MS. The genomic linkage findings can be explained by common haematologically-silent Hb variants that may lower the protective function of intracellular Hbs, and therefore, enhance the risk for MS. In the absence of such variants, aberrations in the translational and post-translational mechanisms controlling synthesis of neural Hbs may also enhance the vulnerability to MS. Alternatively, such genetic variants may perturb the metabolism of anti-inflammatory hemorphins produced via cleavage of Hbs

Lithium for treatment and chemo-sensitization: Testing the hypothesis on SH-SY5Y cells in monolaver and 3D-spheroids

1st International Conference on Nitric Oxide and Cancer -- NOV 26-28, 2007 -- Paris, FRANCEWOS: 00025083600006