APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions

Abstract

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1α, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a ‘hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed.

Placental aging and oxidation damage in a tissue micro-array model: an immunohistochemistry study

“…In addition, increased APE1 levels may be of importance. Should future research confirm these findings, APE1 levels could be decreased by diet supplementations-perhaps to be targeted at high-risk pregnancies (e.g., Catechins isolated from the leaves of green tea associated with Curcumin) (Thakur et al 2014). SASP may also exacerbate the effect of placental aging by establishing a vicious mechanism due to cytokines such IL-6.…”

The extracellular role of DNA damage repair protein APE1 in regulation of IL-6 expression

“…DNA repair enzyme OGG1 was found to be involved in inflammation [64]. In this vein, the altered expression as well as the sub-cellular localization of APE1 has long been associated with cancer, neurodegenerative, cardiovascular, and other diseases [65]. Indeed, auto-antibodies against APE1 have been identified in systemic lupus erythematous patients [66].…”

Essential Roles of Natural Products and Gaseous Mediators on Neuronal Cell Death or Survival

“…Therefore, the need for research on pathogenesis, therapeutic agents, and useful biomarkers are increasing. Oxidative stress is recognized as one of the critical factors in many neurodegenerative diseases under conditions of hypoxia/ischemia [1,2,3]. Antioxidant compounds derived from natural products have demonstrated neuroprotective activity in models of neuronal cell death and neurodegeneration in vitro and in vivo [4].…”