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Products of lipid peroxidation include a number of reactive lipid aldehydes such as malondialdehyde, 4-hydroxy-nonenal, 4-oxo-nonenal, and isolevuglandins (IsoLGs). Although these all contribute to disease processes, the most reactive are the IsoLGs, which rapidly adduct to lysine and other cellular primary amines, leading to changes in protein function, cross-linking and immunogenicity. Their rapid reactivity means that only IsoLG adducts, and not the unreacted aldehyde, can be readily measured. This high reactivity also makes it challenging for standard cellular defense mechanisms such as aldehyde reductases and oxidases to dispose of them before they react with proteins and other cellular amines. This led us to seek small molecule primary amines that might trap and inactivate IsoLGs before they could modify cellular proteins or other endogenous cellular amines such as phosphatidylethanolamines to cause disease. Our studies identified 2-aminomethylphenols including 2-hydroxybenzylamine as IsoLG scavengers. Subsequent studies showed that they also trap other lipid dicarbonyls that react with primary amines such as 4-oxo-nonenal and malondialdehyde, but not hydroxyalkenals like 4-hydroxy-nonenal that preferentially react with soft nucleophiles. This review describes the use of these 2-aminomethylphenols as dicarbonyl scavengers to assess the contribution of IsoLGs and other amine-reactive lipid dicarbonyls to disease and as therapeutic agents.
Copyright © 2019. Published by Elsevier Inc.
Great progress has been made in cancer therapeutics. However, metastasis remains the predominant cause of death from cancer. Importantly, metastasis can manifest many years after initial treatment of the primary cancer. This is because cancer cells can remain dormant before forming symptomatic metastasis. An important question is whether metastasis research should focus on the early treatment of metastases, before they are clinically evident ("overt"), or on developing treatments to stop overt metastasis (stage IV cancer). In this commentary we want to clarify why it is important that all avenues of treatment for stage IV patients are developed. Indeed, future treatments are expected to go beyond the mere shrinkage of overt metastases and will include strategies that prevent disseminated tumor cells from emerging from dormancy.
This review will provide an overview of the principles of pharmacogenomics from basic discovery to implementation, encompassing application of tools of contemporary genome science to the field (including areas of apparent divergence from disease-based genomics), a summary of lessons learned from the extensively studied drugs clopidogrel and warfarin, the current status of implementing pharmacogenetic testing in practice, the role of genomics and related tools in the drug development process, and a summary of future opportunities and challenges.
© 2018 American Heart Association, Inc.