2O2 by upregulating the Nox4-p22phox, making Nox4 a critical mediator of oncogenic Ras-induced DNA damage [
Significant studies have shown that ROS interacts with cellular macromolecules such as DNA, proteins, and lipids interfering with vital cellular functions. ROS causes oxidative modifications such as DNA base alterations, strand breaks, damage to tumor suppressor genes, and expression of proto-oncogenes resulting in the transformation of normal cells into malignant cells. One of the most abundant oxidative DNA lesions produced is 8-hydroxydeoxy guanosine (8-OHdG), which is mutagenic [ 120 ] and is found elevated in various human cancers. The transcription factor Nrf2 controls the expression of antioxidant enzyme genes and also genes that control immune and inflammatory responses, carcinogenesis, and metastasis. It combats oxidative stress by induction of cytoprotective enzymes, such as GST, GPx, and oxidoreductases. Cancer patients exhibit disrupted Nrf2-Keap1 interaction through somatic mutations [ 121 122 ]. BRCA1 a tumor suppressor gene found mutated in many cancers, is a caretaker gene, responsible for repairing DNA ultimately helping the cells to cope with oxidative stress [ 123 124 ]. It controls the activity of the transcription factors Nrf2 and NFκB and hence can upregulate several genes involved in the antioxidant response. The redox factor 1/AP endonuclease 1 (Ref1/APE1) has also been found to reduce the generation of ROS in breast cancer cells [ 125 ]. Ras activation in tumors has been associated with point mutations and has been observed in 30% of the tumors [ 126 ]. The Ras gene family includes G proteins, Ha-ras, N-ras, and Ki-ras, which participate in cell signaling and mutations in this oncogene render the proteins constitutively active [ 127 128 ]. Mutant Ras has been found to increase mitochondrial mass and ROS levels leading to DNA damage contributing to transformation [ 129 ]. Mutant Ras produces Hby upregulating the Nox4-p22phox, making Nox4 a critical mediator of oncogenic Ras-induced DNA damage [ 130 ]. DNA strand breakage and levels of peroxides have been found to increase significantly with the activation of mutant K-ras in non-transformed epithelial cells. Of the three mitochondrial sirtuins, Sirt3 which belongs to a class of proteins that possess histone deacetylase has been linked to longevity in humans, acting as a tumor suppressor protein [ 131 ]. The expression of an oncogene, Myc or Ras, in Sirt3 enhances ROS production by increasing glycolysis and decreasing oxidative phosphorylation. Under hypoxic conditions loss of Sirt3 increases tumorigenesis in cancer cells in a ROS-dependent manner by the activation of by HIF-1α [ 132 ]. Oxidative stress and antioxidative stress genes that are considerably altered in tumor cells include-GPX8, ATOX1, PRDX2, PRDX6, PTGS1, SEPP1, and DEFB122 that are upregulated, while there was a decrease in expression of SIRT2, TTN, CYBA, UCP2, and AKR1B1 [ 133 ]. TNF-α may also play an important role in tumor initiation by stimulating the production of intracellular ROS that may damage DNA and lead to genomic mutations [ 134 ]. A study exogenously applied ROS-induced G1 arrest in proliferating fibroblasts showing that oxidative stress could play a role in the accumulation of p53 and the activation of cdc2 [ 135 ]. Increased ROS levels are associated with the inactivation of certain genes like FoxO3, TP53, and ATM [ 136 ]. The tumor suppressor p53 gene TP53 has been found to be significantly and progressively downregulated in cancer cells caused by the excessive oxidation of DNA. The TP53 gene plays an important role in protecting the genome from oxidation by ROS similarly the ataxia telangiectasia mutated (ATM) gene mediates the cellular response to DNA and oxidative damage. The FoxO3 gene decreases ROS levels by influencing the regulation of ATM [ 24 ]. Research is being carried out to relate polymorphisms in antioxidant genes to cancer progression as it can lead to altered enzyme activity. Damage to DNA repair enzymes is also associated with an increase in the level of oxidative DNA damage.
Oxidative stress is an imbalance of free radicals and antioxidants in the body, which can lead to cell and tissue damage. Oxidative stress occurs naturally and plays a role in the aging process.
A large body of scientific evidence suggests that long-term oxidative stress contributes to the development in a range of chronic conditions. Such conditions include cancer, diabetes, and heart disease.
In this article, we explore what oxidative stress is, how it affects the body, and how to reduce it.
What is oxidative stress?
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Many lifestyle factors can contribute to oxidative stress.
Oxidative stress can occur when there is an imbalance of free radicals and antioxidants in the body.
The body’s cells produce free radicals during normal metabolic processes. However, cells also produce antioxidants that neutralize these free radicals. In general, the body is able to maintain a balance between antioxidants and free radicals.
Several factors contribute to oxidative stress and excess free radical production. These factors can include:
- diet
- lifestyle
- certain conditions
- environmental factors such as pollution and radiation
The body’s natural immune response can also trigger oxidative stress temporarily. This type of oxidative stress causes mild inflammation that goes away after the immune system fights off an infection or repairs an injury.
Uncontrolled oxidative stress can accelerate the aging process and may contribute to the development of a number of conditions.
What are free radicals?
Free radicals, including reactive oxygen species, are molecules with one or more unpaired electron. Examples of free radicals include:
- superoxide
- hydroxyl radical
- nitric oxide radical
Cells contain small structures called mitochondria, which work to generate energy in the form of adenosine triphosphate (ATP).
Mitochondria combine oxygen and glucose to produce carbon dioxide, water, and ATP. Free radicals arise as byproducts of this metabolic process.
External substances, such as cigarette smoke, pesticides, and ozone, can also cause the formation of free radicals in the body.
What are antioxidants?
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Fresh berries and other fruits contain antioxidants.
Antioxidants are substances that neutralize or remove free radicals by donating an electron. The neutralizing effect of antioxidants helps protect the body from oxidative stress. Examples of antioxidants include vitamins A, C, and E.
Like free radicals, antioxidants come from several different sources. Cells naturally produce antioxidants such as glutathione.
A person’s diet is also an important source of antioxidants. Foods such as fruits and vegetables provide many essential antioxidants in the form of vitamins and minerals that the body cannot create on its own.
Effects of oxidative stress
The effects of oxidative stress vary and are not always harmful. For example, oxidative stress that results from physical activity may have beneficial, regulatory effects on the body.
Exercise increases free radical formation, which can cause temporary oxidative stress in the muscles. However, the free radicals formed during physical activity regulate tissue growth and stimulate the production of antioxidants.
Mild oxidative stress may also protect the body from infection and diseases. In a 2015 study, scientists found that oxidative stress limited the spread of melanoma cancer cells in mice.
However, long-term oxidative stress damages the body’s cells, proteins, and DNA. This can contribute to aging and may play an important role in the development of a range of conditions.
We discuss some of these conditions below:
Chronic inflammation
Oxidative stress can cause chronic inflammation.
Infections and injuries trigger the body’s immune response. Immune cells called macrophages produce free radicals while fighting off invading germs. These free radicals can damage healthy cells, leading to inflammation.
Under normal circumstances, inflammation goes away after the immune system eliminates the infection or repairs the damaged tissue.
However, oxidative stress can also trigger the inflammatory response, which, in turn, produces more free radicals that can lead to further oxidative stress, creating a cycle.
Chronic inflammation due to oxidative stress may lead to several conditions, including diabetes, cardiovascular disease, and arthritis.
Neurodegenerative diseases
The effects of oxidative stress may contribute to several neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease.
The brain is particularly vulnerable to oxidative stress because brain cells require a substantial amount of oxygen. According to a 2018 review, the brain consumes 20 percent of the total amount of oxygen the body needs to fuel itself.
Brain cells use oxygen to perform intense metabolic activities that generate free radicals. These free radicals help support brain cell growth, neuroplasticity, and cognitive functioning.
During oxidative stress, excess free radicals can damage structures inside brain cells and even cause cell death, which may increase the risk of Parkinson’s disease.
Oxidative stress also alters essential proteins, such as amyloid-beta peptides. According to one 2018 systematic review, oxidative stress may modify these peptides in way that contributes to the accumulation of amyloid plaques in the brain. This is a key marker of Alzheimer’s disease.
Risk factors for oxidative stress
Factors that may increase a person’s risk of long-term oxidative stress include:
- obesity
- diets high in fat, sugar, and processed foods
- exposure to radiation
- smoking cigarettes or other tobacco products
- alcohol consumption
- certain medications
- pollution
- exposure to pesticides or industrial chemicals
Prevention
It is important to remember that the body requires both free radicals and antioxidants. Having too many or too few of either may lead to health problems.
Lifestyle and dietary measures that may help reduce oxidative stress in the body include:
- eating a balanced, healthful diet rich in fruits and vegetables
- limiting intake of processed foods, particularly those high in sugars and fats
- exercising regularly
- quitting smoking
- reducing stress
- avoiding or reducing exposure to pollution and harsh chemicals
Maintaining a healthy body weight may help reduce oxidative stress. According to a 2015 systematic review, excess fat cells produce inflammatory substances that trigger increased inflammatory activity and free radical production in immune cells.
Summary
Oxidative stress is a state that occurs when there is an excess of free radicals in the body’s cells. The body produces free radicals during normal metabolic processes.
Oxidative stress can damage cells, proteins, and DNA, which can contribute to aging. It may also play a role in development of a range of health conditions, including diabetes, cancer, and neurodegenerative diseases such as Alzheimer’s.
The body naturally produces antioxidants to counteract these free radicals. A person’s diet is also an important source of antioxidants.
Making certain lifestyle and dietary changes may help reduce oxidative stress. These may include maintaining a healthy body weight, regularly exercising, and eating a balanced, healthful diet rich in fruits and vegetables.
