Free radicals, metals and antioxidants in oxidative stress-induced cancer

Fish bioaccumulation and biomarkers in environmental risk assessment: a review

https://link.springer.com/content/pdf/10.1097%2FWOX.0b013e3182439613.pdf

Oxidative Stress and Antioxidant Defense

Transcription factor Nrf2 is essential for the antioxidant responsive element (ARE)-mediated induction of phase II detoxifying and oxidative stress enzyme genes. Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain. The closest homolog of Keap1 is a Drosophila actin-binding protein called Kelch, implying that Keap1 might be a Nrf2 cytoplasmic effector. We then showed that electrophilic agents antagonize Keap1 inhibition of Nrf2 activity in vivo, allowing Nrf2 to traverse from the cytoplasm to the nucleus and potentiate the ARE response. We postulate that Keap1 and Nrf2 constitute a crucial cellular sensor for oxidative stress, and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel Nrf2 nuclear shuttling mechanism. The activation of Nrf2 leads in turn to the induction of phase II enzyme and antioxidative stress genes in response to electrophiles and reactive oxygen species.

/pdf/keap1-represses-nuclear-activation-of-antioxidant-responsive-4szbzl5y9i.pdf

Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain

https://agrilinks.org/sites/default/files/resource/files/Williams_Aflatoxicosis_AJCN_2004.pdf

Human aflatoxicosis in developing countries: a review of toxicology, exposure, potential health consequences, and interventions

Ins(1,4,5)P3 metabolism was examined in Saccharomyces cerevisiae extracts. S. cerevisiae contains readily detectable Ins(1,4,5)P3 kinase activity that is predominantly soluble, but phosphomonoesterase activity acting on Ins(1,4,5)P3 was not detected in either soluble or particulate preparations from this organism. We have purified the kinase activity approximately 685-fold in a rapid four-step process, and obtained a stable preparation. The enzyme has an apparent native molecular mass of approximately 40 kDa, and displays Michaelis-Menten kinetics with respect to its two substrates, ATP and Ins(1,4,5)P3. The Km for ATP was 2.1 mM, and that for Ins(1,4,5)P3 was 7.1 microM. The enzyme appeared to be the first step in the conversion of Ins(1,4,5)P3 into an InsP5, and the partially purified preparation contained another activity that converted the InsP4 product into an InsP5. The InsP4 product of the partially purified kinase was not metabolized by human erythrocyte ghosts and co-chromatographed with an Ins(3,4,5,6)P4 [L-Ins(1,4,5,6)P4] standard, identifying it as D-Ins(1,4,5,6)P4. The yeast enzyme is thus an Ins(1,4,5)P3 6-kinase. This activity may be an important step in the production of inositol polyphosphates such as InsP5 and InsP6 in S. cerevisiae.

Inositol trisphosphate metabolism in Saccharomyces cerevisiae: identification, purification and properties of inositol 1,4,5-trisphosphate 6-kinase.

A number of xenobiotics, including the synthetic antioxidant ethoxyquin, inhibit aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in the rat. Two detoxification enzymes that mediate ethoxyquin-induced chemoprotection against AFB1 have been identified by protein purification: a glutathione S-transferase (GST) Yc2 subunit with at least 100-fold greater activity towards AFB1-8,9-epoxide than previously studied transferases, and a unique aldehyde reductase with activity towards the dialdehydic form of AFB1-8,9-dihydrodiol. Molecular cloning has revealed that the Yc2 subunit is a class alpha GST and that the aflatoxin-metabolizing aldehyde reductase (AFAR) is a distant member of the aldo-keto reductase superfamily. Enzyme assay and western blotting have shown that many chemoprotectors, such as ethoxyquin, butylated hydroxyanisole, butylated hydroxytoluene, oltipraz and indole-3-carbinol, that inhibit AFB1-mediated hepatocarcinogenesis induce both GST Yc2 and AFAR. However, western blotting suggests that these enzymes are not always coordinately regulated, as treatment with phenobarbital and beta-naphthoflavone results in differences in the relative increase in hepatic GST Yc2 and AFAR. These findings indicate that GST Yc2 and AFAR represent important resistance mechanisms against AFB1 in the rat. This conclusion is supported by the observation that GST Yc2 and AFAR are overexpressed in rat liver preneoplastic nodules, which display pleiotropic drug resistance.

Regulation of glutathione S-transferases and aldehyde reductase by chemoprotectors: studies of mechanisms responsible for inducible resistance to aflatoxin B1.

Alzheimer’s disease (AD) is a complex, multifactorial disease that is incurable in the aging population. The success of genome‐wide association studies (GWAS), as a cross sectional design, to identify novel genetic risk factors for AD in recent years is well known; however, case‐control studies are less likely to uncover genetic factors that influence other aspects of the disease, such as progression and onset.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/alz.062479

David J. Pulford

Papers

Inositol trisphosphate metabolism in Saccharomyces cerevisiae: identification, purification and properties of inositol 1,4,5-trisphosphate 6-kinase.

Regulation of glutathione S-transferases and aldehyde reductase by chemoprotectors: studies of mechanisms responsible for inducible resistance to aflatoxin B1.

Identification of novel genetic variants and biomarkers for cognitive decline in Alzheimer’s disease