ROS: Oxidative Stress and Diseases Allegedly Associated with It

Are free radicals a necessary evil?

In 1956, Denham Harman, known as the father of free radical aging theory, developed a theory based on the hypothesis that free radicals are the cause of aging in all living things, and described free radicals as a "Pandora's box of evil." [1] Since then, many studies have continued and by the early 21st century, it has been suggested that organisms have not only adapted well to the uncomfortable symbiosis with these free radicals but have developed mechanisms to utilize them for various physiological processes. These processes include regulating vascular tone, sensing oxygen tension, controlling functions affected by oxygen concentration, enhancing signal transmission from various membrane receptors including antigen receptors of lymphocytes, and maintaining redox-oxidation balance as an oxidative stress response.[2] In 1985, German biochemist Helmut Sies first introduced the concept of 'oxidative stress', highlighting the damage that an imbalance between oxidants and antioxidant defenses can cause to biological systems. This was called redox biology and since then it has advanced to the field of physiological redox signaling and has been studied from the aspect of pathology [3]. In other words, despite the various risks it carries, free radicals also play essential roles in various cellular processes, illustrating their complex and multifaceted nature in living organisms.

Definition of oxidative stress

Oxidative stress refers to a phenomenon that occurs due to an imbalance between the production and accumulation of reactive species in cells and tissues and the capacity of biological systems to detoxify these reactive products. Essentially, it occurs when there is an excess of free radicals being generated in cells, tissues, or the entire body, surpassing the ability to neutralize, detoxify, or eliminate them [4]. Additionally, oxidative stress is defined as the disruption of the balance between oxidants and antioxidants, which consequently disturbs the signaling and regulation of redox reactions or leads to molecular damage [5].

Reactive oxygen species are an undesirable by-product that is inevitably generated in the process of performing various physiological roles every day, such as immune response to protect the human body, energy production to maintain vital activities and intercellular signaling. Factors like mental stress, aging, and intense exercise can also contribute to the generation of free radicals. However, our remarkable human body has evolved mechanisms to counteract these oxygen radicals. The key lies in maintaining a delicate balance between the production of free radicals and the body's antioxidant defenses. The challenge lies in achieving and preserving this balance, ensuring that neither side dominates excessively.

External factors unrelated to the body's natural metabolic activities can also contribute to the production of reactive oxygen species (ROS). These include exposure to excessive ultraviolet rays, ionizing radiation, certain drugs (such as anti-inflammatory agents), environmental pollutants, heavy metals, chemicals, smoke from cooking, tobacco smoke, and alcohol consumption. While it may be challenging to completely avoid exposure to these factors, adopting healthy lifestyle habits and minimizing exposure where possible can help reduce ROS production from external sources.

In the previous articles, we looked at the process by which various free radicals are created as a single electron undergoes oxidation step by step, and we used them as signaling substances and various antioxidant enzymes as a detoxification device to weaken the potential harm that can be done to the human body in advance. We will also closely look at the mechanisms of enzymes and the interconnected antioxidant network between antioxidant enzymes in the human body in the following articles. Through this exploration, I've come to appreciate that each component in our biological system has its own distinct purpose and responsibility. I also realized that it is not wise to overly rely on antioxidants, as an excessive approach can disrupt this delicate equilibrium. As the saying goes, too much is too little. Striking the balance and keeping the moderation seems to be the most practical approach that I can take.

While an optimal concentration of ROS is crucial for normal cellular functions, excessive levels can lead to damage to cellular macromolecules such as DNA, lipids, and proteins, ultimately resulting in necrosis and cell death. For instance, when proteins undergo oxidation, their structure can be altered, leading to impaired enzyme activity. DNA is particularly susceptible to oxidative damage, with each human cell experiencing as many as 10,000 oxidative events per day.[6] However, the human body is equipped with seven repair pathways, including base excision repair and nucleotide excision repair, which are activated to rectify damage. Moreover, in instances of excessive DNA damage, signaling pathways that trigger programmed cell death(apoptosis) are activated, preventing the propagation of genetic errors and maintaining tissue integrity. Lipid oxidation, particularly of unsaturated fatty acids in phospholipids that make up cell membranes, can be fatal as it can trigger a rapid chain reaction, damaging numerous lipid molecules. Let’s take a closer look at the numerous diseases and symptoms that are related to oxidative stress, which arises when the balance is broken.

Oxidative stress and related diseases

Cancer and oxidative stress

It is well established that oxidative DNA damage is a key factor contributing to cancer development. Cancer can arise from chromosomal abnormalities or the activation of oncogenes triggered by oxidative stress. The hydrolysis of DNA bases resulting from DNA oxidation is considered a critical event in cancer progression, as it disrupts the normal transcriptome profile and leads to genetic mutations that inhibit regular cell growth. Additionally, oxidative stress can induce various modifications in DNA, including structural changes, DNA-protein cross-links, strand breaks, and the formation of sites without bases. These alterations contribute to the initiation and progression of cancer.

Cardiovascular disease and oxidative stress

Although there may be many causes of cardiovascular diseases, most causes are known to share one important pathological mechanism, namely oxidative stress. [7] Oxidative stress can cause endothelial dysfunction, a major early phenomenon in atherosclerosis. When the endothelium, the cell layer that covers the inside of blood vessels, is damaged by excessive ROS, problems such as impaired vasodilation, increased vascular inflammation, and increased vascular permeability occur. Additionally, oxidative stress promotes the oxidation of low-density cholesterol (LDL), causing greater damage to endothelial cells and promoting the progression of atherosclerosis. When blood vessels eventually become narrowed or blocked due to atherosclerosis, it can lead to circulation problems in the organs served by those specific individual blood vessels. Problems can occur in the coronary arteries that supply blood to the heart, the cerebral and carotid arteries that supply blood to the brain, and the renal arteries that supply blood to the kidneys, which can eventually lead to serious diseases such as angina pectoris, myocardial infarction, cerebral infarction, stroke, and renal failure.

Neuropathy and oxidative stress

Oxidative stress has been implicated in various neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Amyotrophic lateral sclerosis, memory loss, and depression. In Alzheimer's disease, for instance, both experimental and clinical studies have demonstrated the significant contribution of oxidative damage to neuronal loss and the progression of dementia. Reactive oxygen species (ROS) are known to generate toxic peptides called β-amyloid, which are commonly found in the brains of Alzheimer's patients and play an important role in the neurodegenerative process. [8] Recent research also suggests that increased oxidative stress may play a significant role in the development of Autism Spectrum Disorder (ASD). [9]

Diabetes and oxidative stress

Diabetes is largely divided into two types: Type 1 diabetes, an autoimmune disease in which the beta cells in the pancreas that produce insulin are attacked and destroyed by the immune system, resulting in little or no production of the insulin hormone; and Type 2 diabetes, which is characterized by insulin resistance, where cells in the body fail to respond effectively to insulin, leading to insufficient entry of glucose into the cells and causing metabolic disorders. There is increasing evidence supporting the role of oxidative stress in the development of both Type 1 and Type 2 diabetes.[10] Oxidative stress can damage beta cells, disrupt cell signaling pathways related to glucose metabolism, promote inflammation that interferes with normal insulin action, and also destroy important components in blood sugar regulation within cells, which then can have a negative effect on the development of insulin resistance.

Lung disease and oxidative stress

Chronic Obstructive Pulmonary Disease (COPD), asthma, and lung cancer are also known to be related to oxidative stress in the lung. In the case of chronic obstructive pulmonary disease, when mucosal inflammation occurs due to cigarette smoke, air pollution, and indoor air pollution in the home, the lungs activate the immune system to deal with this, and in this process, excessive ROS production by neutrophils and macrophages leads to oxidative stress. Chronic inflammation that occurs as a result of oxidative stress, accelerated cellular aging and lung aging, autoimmune reactions, fibrosis causing peripheral airway stiffening and thickening, and excessive mucus secretion, further aggravate the lung function. [11]

Kidney disease and oxidative stress

Oxidative stress is associated with various diseases affecting the renal organs, such as glomerular and interstitial nephritis, renal failure, proteinuria, and uremia. The kidneys are negatively affected by oxidative stress due to the production of ROS, which attracts inflammatory cells and triggers the production of inflammatory cytokines. When oxidative stress stimulation acts chronically on kidney tissue, the initial inflammatory response can later lead to the formation of fibrous tissue that can impair organ function, potentially leading to kidney failure.

In addition, numerous other symptoms have been reported to be related to oxidative stress, including aging and age-related sarcopenia[12], rheumatoid arthritis, precocious puberty, cataracts, and retinal disease. However, it's important to note that the relationship between oxidative stress and these various diseases is still undergoing investigation through numerous studies, and no definitive conclusions have been reached.

"Will it be medicine or poison? The devil is in the .......dosage."

Perhaps the term “necessary evil” best describes free radicals. It should not be condemned as a bad substance that is unconditionally harmful to the human body and therefore must be suppressed, nor should it be allowed to become excessive beyond the appropriate level that our body can handle. However, if we can keep reactive oxygen species within the Goldilocks zone at the most appropriate level, neither too much nor too little, then perhaps we would not need to be afraid of them.

I wonder if the ROS was one of the primary concerns for humans in the era of hunter-gatherers or even a few centuries ago. With regards to ROS, among the new and convenient lifestyles that have come along with advanced civilization, there are some aspects that we cannot change as an individual and therefore we must accept and live with, while others can be avoided by sacrificing some inconvenience. I believe the choice remains up to each one of us. However, let us not forget the importance of striking a balance without going one extreme.

[Reference articles]

[1] Free radicals, oxidative stress and the Pandora box

https://www.medigraphic.com/cgi-bin/new/resumenI.cgi?IDARTICULO=100790

[2] Free Radicals in the Physiological Control of Cell Function

https://pubmed.ncbi.nlm.nih.gov/11773609/

[3] Targeting oxidative stress in disease: promise and limitations of antioxidant therapy

https://www.nature.com/articles/s41573-021-00233-1

[4] Oxidative Stress: Harms and Benefits for Human Health

https://www.hindawi.com/journals/omcl/2017/8416763/

[5] Oxidative Stress: Concept and Some Practical Aspects

https://www.mdpi.com/2076-3921/9/9/852

[6] Oxidants, antioxidants, and the degenerative diseases of aging.