Benzylidenemalononitrile compounds as activators of cell resistance to oxidative stress and modulators of multiple signaling pathways. A structure-activity relationship study

Benzylidenemalononitrile (BMN) tyrphostins are well known as potent tyrosine kinase inhibitors. Moreover, in recent years it has been recognized that members of the tyrphostin family possess additional biological activities independent of their ability to inhibit protein tyrosine kinases. In this study, we examined the relationship between the structure of 49 BMNs and related compounds, and their capacity to induce heme oxygenase 1 (HO-1) gene expression in U937 human monocytic cells, to activate upstream signaling pathways and to protect cells against menadione-induced oxidative stress. It was found that the electron-withdrawing (NO₂, CN, halogen) groups in BMN molecules and double meta-MeO substituents increased the HO-1 gene induction, while the electron-donating groups in ortho/para position (OH, MeO and N-morpholino) significantly decreased it. The magnitude of activation of c-Jun, Nrf2, p38 MAPK, and p70S6K correlated with specific substitution patterns in the BMN structure. BMN-dependent maximal up-regulation of HO-1 required parallel increase in Nrf2 and phospho-c-Jun cellular levels. Liquid chromatography mass spectrometry (LC–MS) analysis revealed that BMNs can generate conjugates with one or two glutathione equivalent(s). This study supports the hypothesis that BMNs induce the expression of protective genes by alkylating sensitive cysteine residues of regulatory factors.     

XRCC1 gene variants and possible links with chromosome aberrations and micronucleus in active and passive smokers

Tobacco addiction is a major risk for diseases such as cancers, heart attack, etc. Tobacco smoke constitutes environmental toxins that are the major preventable leading cause of death worldwide. We investigated the influence of tobacco smoke on cytogenetic parameters (chromosomal aberrations and micronuclei) and the influence of XRCC1 arg399gln polymorphism on the cytogenetic parameters of the exposed subjects. The cases for this study include active and passive smokers. They were divided into three groups in accordance with duration of exposure to tobacco smoke. We observed changes in the frequency of chromosomal aberrations and micronuclei among the exposed subjects and controls. Of the three groups of exposed subjects, group III of active smokers and group III of passive smokers showed higher number of chromosomal aberrations and micronuclei when compared to controls, group I and group II of active and passive smokers. The XRCC1 arg399gln polymorphic variant gln/gln, influenced the extent of genotoxic damage in chromosomes and frequency of in micronuclei the three variants (arg/arg, arg/gln and gln/gln), gln/gln harbored significantly (P < 0.05) higher number of aberrations than the arg/arg and arg/gln. In this context, the results observed in our study indicated that the single nucleotide polymorphism on XRCC1codon 399 influenced the frequencies of chromosomal aberrations and micronuclei.