Free Radicals and Oxidative Stress: Signaling Mechanisms, Redox Basis for Human Diseases, and Cell Cycle Regulation

Free radicals contain one or more unpaired electrons in their valence shell, thus making them unstable, short-lived, and highly reactive species. 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, higher concentrations beyond cell capacity cause oxidative stress, contributing to human pathologies such as diabetes, cancer, Parkinson's disease, cardiovascular diseases, cataract, asthma, hypertension, atherosclerosis, arthritis, and Alzheimer's disease. Signaling pathways such as NF-kappa B, MAPKs, PI3K/Akt/ mTOR, and Keap1-Nrf2ARE modulate 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 the cell cycle as these molecules influence 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 the G1 phase, becoming higher in G2/ M and moderate in the 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 the therapy of many diseases.

Automated summary

Free radicals with unpaired electrons are unstable, short-lived, and highly reactive. Excessive generation of these radicals leads to oxidative stress, causing damage to macromolecules, disrupting cell signaling pathways and antioxidants equilibrium. While lower concentrations of ROS serve as second messengers, higher concentrations cause oxidative stress and contribute to various human pathologies. Signaling pathways like NF-kappa B, MAPKs, PI3K/Akt/mTOR, and Keap1-Nrf2ARE modulate oxidative stress by increasing antioxidant defenses and decreasing ROS production. Understanding the mechanism of cell cycle redox regulation is important for disease therapy.