Lipid peroxidation: Reactive carbonyl species, protein/DNA adducts, and signaling switches in oxidative stress and cancer.

Under the exposure of lipids to reactive oxygen species (ROS), lipid peroxidation proceeds non-enzymatically and generates an extremely heterogeneous mixture of reactive carbonyl species (RCS). Among them, HNE, HHE, MDA, methylglyoxal, glyoxal, and acrolein are the most studied and/or abundant ones. Over the last decades, significant progress has been achieved in understanding mechanisms of RCS generation, protein/DNA adduct formation, and their identification and quantification in biological samples. In our review, we critically discuss the advancements in understanding the roles of RCS-induced protein/DNA modifications in signaling switches to provide adaptive cell response under physiological and oxidative stress conditions. At non-toxic concentrations, RCS modify susceptible Cys residue in c-Src to activate MAPK signaling and Cys, Lys, and His residues in PTEN to cause its reversible inactivation, thereby stimulating PI3K/PKB(Akt) pathway. RCS toxic concentrations cause irreversible Cys modifications in Keap1 and IKKß followed by stabilization of Nrf2 and activation of NF-κB, respectively, for their nuclear translocation and antioxidant gene expression. Dysregulation of these mechanisms causes diseases including cancer. Alterations in RCS, RCS detoxifying enzymes, RCS-modified protein/DNA adducts, and signaling pathways have been implicated in various cancer types.

Cytochrome P450 monooxygenase systems: Diversity and plasticity for adaptive stress response.

Superfamily of cytochromes P450 (CYPs) is composed of heme-thiolate-containing monooxygenase enzymes, which play crucial roles in the biosynthesis, bioactivation, and detoxification of a variety of organic compounds, both endogenic and exogenic. Majority of CYP monooxygenase systems are multi-component and contain various redox partners, cofactors and auxiliary proteins, which contribute to their diversity in both prokaryotes and eukaryotes. Recent progress in bioinformatics and computational biology approaches make it possible to undertake whole-genome and phylogenetic analyses of CYPomes of a variety of organisms. Considerable variations in sequences within and between CYP families and high similarity in secondary and tertiary structures between all CYPs along with dramatic conformational changes in secondary structure elements of a substrate binding site during catalysis have been reported. This provides structural plasticity and substrate promiscuity, which underlie functional diversity of CYPs. Gene duplication and mutation events underlie CYP evolutionary diversity and emergence of novel selectable functions, which provide the involvement of CYPs in high adaptability to changing environmental conditions and dietary restrictions. In our review, we discuss the recent advancements and challenges in the elucidating the evolutionary origin and mechanisms underlying the CYP monooxygenase system diversity and plasticity. Our review is in the view of hypothesis that diversity of CYP monooxygenase systems is translated into the broad metabolic profiles, and this has been acquired during the long evolutionary time to provide structural plasticity leading to high adaptative capabilities to environmental stress conditions.

Differentially expressed non-coding RNAs and their regulatory networks in liver cancer.

The vast majority of human transcriptome is represented by various types of small RNAs with little or no protein-coding capability referred to as non-coding RNAs (ncRNAs). Functional ncRNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which are expressed at very low, but stable and reproducible levels in a variety of cell types. ncRNAs regulate gene expression due to miRNA capability of complementary base pairing with mRNAs, whereas lncRNAs and circRNAs can sponge miRNAs off their target mRNAs to act as competitive endogenous RNAs (ceRNAs). Each miRNA can target multiple mRNAs and a single mRNA can interact with several miRNAs, thereby creating miRNA-mRNA, lncRNA-miRNA-mRNA, and circRNA-miRNA-mRNA regulatory networks. Over the past few years, a variety of differentially expressed miRNAs, lncRNAs, and circRNAs (DEMs, DELs, and DECs, respectively) have been linked to cancer pathogenesis. They can exert both oncogenic and tumor suppressor roles. In this review, we discuss the recent advancements in uncovering the roles of DEMs, DELs, and DECs and their networks in aberrant cell signaling, cell cycle, transcription, angiogenesis, and apoptosis, as well as tumor microenvironment remodeling and metabolic reprogramming during hepatocarcinogenesis. We highlight the potential and challenges in the use of differentially expressed ncRNAs as biomarkers for liver cancer diagnosis and prognosis.