Free radicals and oxidative stress: signaling mechanisms, redox basis for human diseases, and cell cycle regulation

Abstract

: Free radical contained one or more unpaired electrons in its valence shell, thus making it unstable, short-lived and highly reactive specie. Excessive generation of these free radicals ultimately leads to oxidative stress causing oxidation and damage to significant macromolecules in the living system and essentially disrupting signal transduction pathways and antioxidants equilibrium. At lower concentrations, ROS serves as “second messengers” influencing many physiological processes in the cell. However, at higher concentrations beyond cell capacity causes oxidative stress, which contributes to much human pathology such as diabetes, cancer, Parkinson’s disease, cardiovascular diseases, cataract, asthma, hypertension, atherosclerosis, arthritis and Alzheimer’s disease. Signaling pathways such as NF-κB, MAPKs, PI3K/Akt/ mTOR and Keap1-Nrf2-ARE modulates the detrimental effects of oxidative stress by increasing the expression of cellular antioxidant defenses, phase II detoxification enzymes and decreased production of ROS. Free radicals such as H2O2 are indeed needed for the advancement of cell cycle as these molecules influences DNA, proteins and enzymes in the cell cycle pathway. In the course of cell cycle progression, the cellular redox environment becomes more oxidized moving from G1 phase, becomes higher in G2/M and moderate in S phase. Signals in the form of an increase in cellular pro-oxidant levels are required and these signals are often terminated by a rise in the amount of antioxidants and MnSOD with a decrease in the level of cyclin D1 proteins. Therefore, understanding the mechanism of cell cycle redox regulation will help in therapy of many diseases.