Fundamental Principles of Oxidative Stress in Metabolism and Reproduction: Prevention and Management

Fundamental Principles of Oxidative Stress in Metabolism and Reproduction: Prevention and Management is a comprehensive resource for anyone needing awareness and recognition of oxidative stress as a basic component of disease to determine the precise treatment plan considering the cause of the disease. It describes the effects of oxidative stress in the human body, the detection of metabolic changes, psychological impact and effect on reproductive outcomes. In addition, it discusses alterations at the cellular level occurring due to oxidative stress along with the genetic aspects involved in its pathogenesis.

• Provides a holistic approach to the impact of oxidative stress on various systems
• Incorporates recent advances in basic sciences for improvement in oxidative stress leading to better prognosis of metabolic conditions
• Summarizes knowledge to detect oxidative stress for improvement of fertility outcomes

• Language: English
• Publisher: Academic Press
• Release date: Apr 7, 2024
• ISBN: 9780443188060

Book preview

Section I

Overview: Cause and mechanisms

Outline

Chapter 1. Introduction to oxidative stress

Chapter 2. Role of free radicals in normal human physiology

Chapter 3. Role of diet in the development of oxidative stress

Chapter 4. Occupational hazards and oxidative stress

Chapter 5. Role of radio-frequency electromagnetic waves in causing oxidative stress

Chapter 6. Genetic variations and lifestyle in oxidative stress

Chapter 7. Aging: Generation of oxidative stress

Chapter 1: Introduction to oxidative stress

Faiza Alam¹, Rakhshaan Khan², and Fatima Syed³     ¹PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Bandar Seri Begawan, Brunei Darussalam     ²iCAT Transmission, Public Health, Karachi, Pakistan     ³Department of Pathology, Fazaia Ruth Pfau Medical College, Air University, SMC- Jinnah Sindh Medical University, Karachi, Pakistan

Abstract

During regular bodily functions like breathing, digestion, and metabolism, various oxygen-based radicals known as reactive oxygen species (ROS) are generated, such as the superoxide anion, hydroxyl radical, and singlet oxygen. Similarly, nitrogen-based radicals derived from compounds involving nitric oxide are referred to as reactive nitrogen species (RNS). In small quantities, these radicals play a role in cell signaling, but an excess can harm cells. To counteract this, the body employs an effective antioxidant system to eliminate excessive free radicals and protect itself. Antioxidants contribute electrons to stabilize these radicals, reducing their harmful reactivity within cells. Oxidative stress occurs when there is an imbalance between free radicals and the body's antioxidant enzymes. Both RNS and ROS collaborate, leading to nitrosative stress and cellular damage.

Keywords

Cellular process; Oxidative biomarkers; Oxidative stress; Physiological process; Types of oxidants

Oxidative stress

What is oxidative stress?

During normal physiological processes such as respiration, digestion, and metabolism, many harmful oxygen-containing radicals are produced that can exist independently. These free radicals (FRs) are called reactive oxygen species (ROS) and include superoxide anion, radical, hydroxyl radical, hydroperoxyl radical, and singlet oxygen (Jankauskas et al., 2023). Similarly, many nitrogen-containing radicals derived from nitric oxide compounds are termed reactive nitrogen species (RNS). When present in lesser amounts, these FRs have the responsibility to regulate the signaling of cells. Excess of these FRs may damage the cells, so nature eliminates them through an effective antioxidant system and protects the human body (Kurutas, 2016). An antioxidant donates its own electron to make the FR stable and least reactive to cause any harm to the cell. The term oxidative stress (OS) thus represents a poor balance between FRs in the human body and their corresponding antioxidant enzymes. Both RNS and ROS work together to induce nitrosative stress and thus damage cells (Metodiewa & Kośka, 1999). According to Lushchak, Oxidative stress is a situation when steady-state ROS concentration is transiently or chronically enhanced, disturbing cellular metabolism and its regulation and damaging cellular constituents (Lushchak, 2014).

Redox hypothesis

In an oxidation–reduction or redox reaction, there is a transfer of electrons between two substances. Some substances lose electrons and become oxidized, while others gain electrons and get reduced. The concept of the redox hypothesis suggests that the disproportion of prooxidants and antioxidants in OS interrupts the redox phenomenon causing molecular damage (Jones, 2015).

Sources of ROS that influence the human body

FRs are produced as a consequence of many internal and external factors (Fig. 1.1).

Exogenous sources/factors: These include changes in the environment that increase ROS production in cells such as (Antunes dos Santos et al., 2018)

• Exposure to ultraviolet light (Marchitti et al., 2011) and ionizing radiation (Spitz & Hauer-Jensen, 2014)

• Cigarette smoke (Caliri et al., 2021), E-cigarettes (Kuntic et al., 2020), and ozone (O³) in the air (Enweasor et al., 2021)

• Heavy metals such as iron, cadmium, copper, nickel, and arsenic (Mahajan et al., 2018)

• Environmental pollution from industries (Man et al., 2020)

• Lifestyle and behaviors (Man et al., 2020)

Endogenous sources/factors: Endogenous or intracellular factors include

• Drug metabolism, carcinogenic xenobiotics, alcohol, and increased cyt-450 monooxygenase (Man et al., 2020)

• ROS due to metabolic disorders: will increase activities of oxidases (xanthine, urate, and aldehyde)

Figure 1.1  Oxidative stress mechanism: an overview. Cat, catalase; G6PDH, glucose 6 phosphate dehydrogenase; GPx, glutathione-dependent peroxidase; GR, glutathione reductase; Grx, glutaredoxine; GSH, reduced glutathione; GST, glutothionine S reductase; ICDH, isocitrate dehydrogenase; NADIH- CoQH2, Ubiquinol; MSR, methionine sulfoxide reductase; Prx, peroxiredoxin; SOD, superoxide dismutase; Trx, thioredoxine; ЎGC, Ў glutamylcysteine synthetase.

• ROS due to mitochondrial diseases (Bhat et al., 2015):

• Inhibition or loss of subunits of respiratory chain complexes

• Slowing of respiratory efficiency with age can produce unnecessary hydroxyl radicals, superoxide anions, hydrogen peroxide, nitrous dioxide, and peroxynitrite.

• Redox reactions: inhibition of enzymes that repair oxidized molecules (Schieber & Chandel, 2014)

• Inhibition of antioxidant enzymes and decreased production or utilization of dietary bio reductants also raise the amounts of ROS/RNS, for example, COVID-19 (Jankauskas et al., 2023)

• Aging (Liguori et al., 2018)

Fig. 1.1.

Influence of ROS on body functions

Oxidation is a normal healthy process vital for life, and small amounts of FRs thus produced can even be beneficial. Whenever the body is unable to fight against them, some signs and symptoms of inflammation suggest the presence of oxidative stress (Hannoodee & Nasuruddin, 2022).

Signs in the body suggestive of OS

1. The feeling of fatigue: since the body is under oxidative stress, energy is continuously being used to fight against this inflammation. Maintaining energy reserves gives the feeling of fatigue.

2. Poor concentration and focus—suggest oxidative stress

3. Waking up with sore joints and muscles and feeling fatigued even after normal activity suggest that the body is running short of antioxidants

4. Environmental pollutants suggest that the body reserves have been used in the detoxification of FRs. Signs of stress and anxiety prevail due to stressful environments, such as disturbed sleep, lack of focus, generalized aches/pains, and poor motivation

OS and the defense of the human body

Whenever there is any impairment in the creation and detoxification of reactive species (ROS/RNS), the resultant deposit of these species is harmful to the body termed oxidative stress (OS). Research suggests that FRs initiate the development of several pathologies, extending from chronic illnesses to cancer (Pizzino et al., 2017). However, in the initial stages, the human defense mechanism devises many strategies to neutralize the hazards of FRs and OS through endogenous antioxidants.

What is an antioxidant?

Although the hazards of ROS/RNS have been acknowledged for decades, their exact role in disease progression has recently been explored and also highlighted the benefits of antioxidants for the body (Liu, 2020). An antioxidant is thus defined as a substance that delays, prevents, or removes oxidative damage to a target molecule (Halliwell, 2007).

Types of antioxidants

Antioxidants make the reactive species stable. They oxidize and destroy FRs by donating an electron. Poor availability of dietary antioxidants can be attributed to their impaired metabolism by microorganisms in the intestine or poor absorption from the mucosa of the intestine, and/or massive breakdown of the amount absorbed in the liver and kidneys. The types include endo- and exogenous antioxidants that must be balanced to maintain redox harmony.

1. Endogenous antioxidants

a. Enzymatic

    In normal circumstances, the body produces sufficient amounts of endogenous or intrinsic antioxidants to counter OS. Endogenous antioxidants are produced by the stimulation of nuclear factor erythroid 2-related factor 2 (Nrf2) (Kang, 2020). They either prevent the invasion of radicals, facilitate the repair process, or destroy reactive harmful products. They are enzymatic in nature, and based on the nature of defense provided, they may be.

• Primary enzymes: They form the first and the most effective line of defense and include superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and peroxiredoxin (Prxs) (Ighodaro & Akinloye, 2018).

• Secondary enzymes: They form the second line of defense and include glutathione reductase (GR), glucose-6 phosphatase dehydrogenase

b. Nonenzymatic:

    They are preventive in nature and have the ability to attack and disable radicals and oxidants. This group includes metal-binding proteins (MBPs), glutathione (GSH), uric acid (UA), melatonin (MEL), bilirubin (BIL), ʟ-arginine, coenzyme (Q10), lipoic acid, thiol, and polyamines (PAs). Examples of proteins that circulate in the plasma are ceruloplasmin, ferritin, metallothionein, transferrin, and albumin, which bind with metal ions and prevent the growth of reactive species (Mirończuk-Chodakowska et al., 2018).

2. Exogenous/dietary antioxidants (Yadav et al., 2016)

    They fall into the category of nonenzymatic antioxidants (Carlsen et al., 2010). They may be:

• Natural

• Vitamins are present in many fruits, vegetables, nuts, and cereal products and form the chief class of antioxidants. These may be water-soluble (vitamin C) (Zou et al., 2016), or fat-soluble (vitamins A and E).

Figure 1.2  Types of antioxidants: various types of antioxidants come into play to prevent oxidative stress. Adopted from Ighodaro, O. M., Akinloye, O. A. First line of defense antioxidants. https://doi.org/10.1016/j.ajme.2017.09.001. Endogenous nonenzymatic antioxidants. https://doi.org/10.1016/j.advms.2017.05.005. ◄ https://doi.org/10.1016/j.foodchem.

• Minerals such as zinc, manganese, copper, and selenium

• Polyphenols (flavonoids, phenolic acids, stilbenes, lignans)

• Carotenoids

• Synthetically prepared: supplements/plant extracts

Fig. 1.2.

Antioxidants—Mechanism of protection

Antioxidants may act as scavengers or buffers or chelators.

They can be divided into:

True scavengers or pervasive scavengers form complexes with transition metals and thus skirt the free availability of the byproducts of oxidation. These include phenolic complexes, ligands, flavonoids, and phenolic acids (Di Lorenzo et al., 2021). Those derived from plant sources also fall in the same category, such as fruits, vegetables, and tea.

• Heavy metals that buffer proteins fall under two categories:

1. Essential metals including Zn, Cu, Fe, and Co are necessary for biological activities and are not dangerous for the body in fewer amounts (Rakshit et al., 2018).

2. Nonessential metals include Cd, Hg, As, and Cr and are highly deadly even in minimal quantities

• Heavy metals function as chelators for:

1. Redox-active metals (Fe, Mn, Cu)

2. Redox-stable metals (Zn, Cd)

Influence of oxidative stress: From health to disease

In the absence of any effective control system, both OS and (FRs) have a detrimental effect on antioxidant enzymes, lipids, proteins, genetic materials (RNA and DNA), and cellular structures. The effect on the mitochondria raises the levels of ROS/RNS further so that mitochondrial proteins, lipids, and DNA are oxidized (Keshari et al., 2015).

Research evidence suggests that FRs initiate the development of several pathologies, extending from chronic illnesses to cancer (Pizzino et al., 2017). Prolonged and unattended OS is harmful enough to produce apoptosis and necrosis. Almost every pathological condition in the body has a component of OS that may be acute or chronic. The effects on various systems include the following:

OS and cardiovascular diseases

The term cardiovascular disease (CVD) includes many diseases (coronary artery, cerebrovascular, peripheral artery, and congenital heart diseases), hypertension, heart failure, and stroke (Nicholson et al., 2008). The role of OS is also associated with cardiac diseases such as myocardial infarction, ischemia/reperfusion, or failure of the heart (D'Oria et al., 2020; Lakshmi et al., 2009).

Reactive species (ROS/RNS) and OS in joint problems

The environment adjoining the implant should be free of ROC/RNS species for optimal performance of the implant and successful joint replacement. OS affects not only the host but also the implant and impairs signaling pathways. To prevent implant degradation and to improve the longevity of the implant special attention should be given to the status of OS before arthroplasty (Hameister et al., 2020).

OS and the brain

Research has identified that OS has a key role in many conditions of the brain stroke, trauma, or neurodegenerative diseases (NDDs).

1. OS: Key role in NDDs

    The chemical integrity of the brain determines the healthy functioning of the central nervous system (CNS). The brain and the neurons are rich in lipid content and high consumption of oxygen makes them more prone to ROS. OS causes the oxidation of mitochondrial proteins, lipids, and DNA contributing to many NDDs (Islam, 2017). Mitochondrial dynamics have a role in neurodegenerative diseases (Panchal & Tiwari, 2019). Normally, a balance exists between the fission and fusion processes of mitochondria, and any change in these processes can damage adenosine triphosphate (ATP) biogenesis causing several NDDs.

    Evidence suggests that RNS affects the neurons that produce dopamine resulting in the degeneration of the nigral-striatal pathway in Parkinson's disease (Stykel & Ryan, 2022).

2. OS and stroke

    Clinical and investigational studies have identified a strong relationship between OS and the severity of an acute stroke and its consequences (Elsayed et al., 2020).

OS and the eyes

Nature has protected the eyes with tears that have many antioxidants (vitamin C, lactoferrin, uric acid, and cysteine) to prevent damage to the eye. Research suggests that OS decreases the level of these antioxidants leading to diseases, such as cataracts in old age, macular degeneration, and inflammation of the uvea, retina, and cornea (Dogru et al., 2018).

OS and the respiratory system

Lungs have a large surface area and exogenous prooxidants such as smoke make the lungs prone to oxidative stress-mediated injury. Studies show that patients having chronic lung problems (COPD) have increased OS and decreased antioxidants. Antioxidants such as N-acetylcysteine have a supportive role in the management of COPD cases (Santus et al., 2014). Ozone is found to induce asthma due to OS (Enweasor et al., 2021).

OS and the skin

The skin is exposed to multiple exogenous factors that produce reactive species and other oxidants that cause inflammation and derangement of collagen fibers that affect functions of cells of the skin, eventually leading to chronic skin ailments and maybe cancer. Research suggests a positive role of physical activity to minimize OS in the of control skin diseases. Both physical activity and exogenous antioxidants have been found to be effective in the prevention and therapy of many skin problems (Kruk & Duchnik, 2014). Atopic dermatitis (AD) is allergic in nature, and research relates air pollution as the cause of atopic dermatitis (Pan et al., 2023).

OS and renal functions

Oxidative stress is high in patients with renal pathologies due to an increase in oxidants and decreases in antioxidants. Any prevalent inflammatory process adds further to the production of ROS in these patients (Kao et al., 2010). A study conducted on Korean men showed a positive association between air pollution and renal functions (Kim et al., 2018).

OS and gastrointestinal tract

Research conducted on obese people associates the role of OS with motility and postinfectious disorders of the gastrointestinal tract (Vona et al., 2021). ROS affects the microorganisms present in the intestinal flora and contributes to the prevalence of many pathologies such as irritable bowel syndrome (Gyuraszova et al., 2017).

OS and the immune system

The immune response at the site of infection/injury is facilitated by Chemokine CXCL8, which mediates the activation and migration of neutrophils. The oxidative burst generates RNS (peroxynitrite) to limit acute inflammation (Thompson et al., 2023). Nitrated nucleotides have been identified for their prominent role in signaling pathways of ROC/RNS (Petřivalský & Luhová, 2020). A positive role of antioxidants has been observed in interventions against ROS and the treatment of diabetes (Zhang et al., 2020).

OS and multiple organs

OS may be involved in the pathologies affecting multiple organs in the body (Toro-Pérez & Rodrigo, 2021). The consequences include aging and early onset of age-related complications (Liguori et al., 2018) (Table 1.1).

Diagnosis: Biomarkers of OS

A biomarker is used to assess the status of the disease due to OS. Biomarkers assess the following:

• ROS are measured directly in living cells using flow cytometry;

• Indirect measure of the levels of DNA/RNA damage, lipid peroxidation, and protein oxidation/nitration;

• Assessing enzymes of redox status;

• Total antioxidant capacity of body fluids (Marrocco et al., 2017)

Antioxidant defense and therapeutic implications

Irrespective of the source antioxidant enzymes defend the human body against oxidative injury either through prevention or repair of injury. Antioxidant therapy is all about the role of these agents in the prevention and disease. Some evidence-based examples of therapeutic implications that boost defense mechanisms include:

Table 1.1

4-HNE, trans-4-hydroxy-2-nonenal; 8-OHdG, 8-hydroxy-20-deoxyguanosine; 8oxodG, 7,8-dihydro-8-oxo-2′-deoxyguanosine; 8oxoGuo, 7,8-dihydro-8-oxoguanosine; ADMA, asymmetric dimethyl L-arginine; AGEs, advanced glycation end products; BSP, bone sialoprotein; F2-IsoPs, F2-isoprostanes; HYL, Hydroxylysine; MDA, malondialdehyde; MPO, myeloperoxidase; NT, nitrotyrosine; OP, osteopontin; oxLDL, oxidized low-density lipoprotein; PC, protein carbonyl; Prx, peroxiredoxins; P-VASP, phosphorylated vasodilator-stimulated phosphoprotein; Trx, thioredoxin; ά PMCID: PMC7952990 ΦPMID: 33440661☻PMID: 29731617 ●PMC8835903 XPMID: 33014278 @https://doi.org/10.1038/s41573-021-00233-1

• Hydrogen sulfide has been successfully used in OS-related NDDs (Tabassum & Jeong, 2019)

• The use of vitamin D Receptor has been successful in the treatment of some NDDs (Alzheimer's and Parkinson's) (Lasoń et al., 2023).

• Therapeutic use of phytochemicals to address Nrf2-mediated OS in trauma to the brain (Wu et al., 2022)

• Polyphenols are gaining interest due to their wide applications in different pathological situations (Woźniak, 2003; Ďuračková, 2010).

• The use of nonenzymatic antioxidants and macrominerals in psychiatric patients (Xu et al., 2023).

• Efficacy of dietary polyphenols in rheumatoid arthritis (Christman & Gu, 2020).

• Flavanones are also effective in neurogenic inflammation induced by xylene

• Citrus flavones along with their respective glycosides, promote the body's defenses against OS to prevent CVDs, atherosclerosis, and cancer (Christman & Gu, 2020).

• These flavones also have antiinflammatory, antiviral, and antimicrobial properties used in many therapies (Christman & Gu, 2020).

• The neuroprotective properties of H2S have been found to improve learning, recall, and recognition.

• Vitamin supplementation benefits the improvement in the clinical symptoms of Parkinson's disease (Mendonça-Junior et al., 2019).

Prevention

A balance in diet, lifestyle, exercise, sleep routines, and reduced pollutants prevent FRs. Physical training lessens the harmful effects of OS, by increasing the activity of antioxidant enzymes (Woźniak, 2003).

References

1. Antunes dos Santos Alessandra, Ferrer Beatriz, Marques Gonçalves Filipe, Tsatsakis Aristides, Renieri Elisavet, Skalny Anatoly, Farina Marcelo, Rocha João, Aschner Michael.Oxidative stress in methylmercury-induced cell toxicity. Toxics. 2018;6(3):47. doi: 10.3390/toxics6030047.

2. Bhat A.H, Dar K.B, Anees S, Zargar M.A, Masood A, Sofi M.A, Ganie S.A. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomedicine & Pharmacotherapy. 2015;74:101–110. doi: 10.1016/j.biopha.2015.07.025.

3. Caliri Andrew W, Tommasi Stella, Besaratinia Ahmad. Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer. Mutation Research/Reviews in Mutation Research. 2021;787:108365. doi: 10.1016/j.mrrev.2021.108365.

4. Carlsen M.H, Halvorsen B.L, Holte K, Bøhn S.K, Dragland S, Sampson L, Willey C, Senoo H, Umezono Y, Sanada C, Barikmo I, Berhe N, Willett W.C, Phillips K.M, Jacobs D.R, Blomhoff R.The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide. Nutrition Journal. 2010;9(1) doi: 10.1186/1475-2891-9-3.

5. Christman L.M, Gu L. Efficacy and mechanisms of dietary polyphenols in mitigating rheumatoid arthritis. Journal of Functional Foods. 2020;71 doi: 10.1016/j.jff.2020.104003.

6. Ďuračková Z. Some current insights into oxidative stress. Physiological Research. 2010;59(4):459–469.

7. D'Oria R, Schipani R, Leonardini A, Natalicchio A, Perrini S, Cignarelli A, Laviola L, Giorgino F.The role of oxidative stress in cardiac disease: From physiological response to injury factor. Oxidative Medicine and Cellular Longevity. 2020;2020 doi: 10.1155/2020/5732956.

8. Di Lorenzo Chiara, Colombo Francesca, Biella Simone, Stockley Creina, Restani Patrizia.Polyphenols and human health: The role of bioavailability. Nutrients. 2021;13(1):273. doi: 10.3390/nu13010273.

9. Dogru Murat, Kojima Takashi, Simsek Cem, Tsubota Kazuo. Potential role of oxidative stress in ocular surface inflammation and dry eye disease. Investigative Opthalmology & Visual Science. 2018;59(14):DES163. doi: 10.1167/iovs.17-23402.

10. Elsayed W.M, Abdel-Gawad E.H.A, Mesallam D.I.A, El-Serafy T.S. The relationship between oxidative stress and acute ischemic stroke severity and functional outcome. Egyptian Journal of Neurology, Psychiatry and Neurosurgery. 2020;56(1) doi: 10.1186/s41983-020-00206-y.

11. Enweasor C, Flayer C.H, Haczku A. Ozone-induced oxidative stress, neutrophilic airway inflammation, and glucocorticoid resistance in asthma. Frontiers in Immunology. 2021;12 doi: 10.3389/fimmu.2021.631092.

12. Gyuraszova M, Kovalcikova A, Gardlik R. Association between oxidative status and the composition of intestinal microbiota along the gastrointestinal tract. Medical Hypotheses. 2017;103:81–85. doi: 10.1016/j.mehy.2017.04.011.

13. Halliwell B. Biochemistry of oxidative stress. Biochemical Society Transactions. 2007;35(5):1147–1150. doi: 10.1042/bst0351147.

14. Hameister R, Kaur C, Dheen S.T, Lohmann C.H, Singh G. Reactive oxygen/nitrogen species (ROS/RNS) and oxidative stress in arthroplasty. Journal of Biomedical Materials Research - Part B Applied Biomaterials. 2020;108(5):2073–2087. doi: 10.1002/jbm.b.34546.

15. Hannoodee S, Nasuruddin D.N. Acute inflammatory response. In StatPearls. StatPearls Publishing; 2022.

16. Ighodaro O.M, Akinloye O.A. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid. Alexandria Journal of Medicine. 2018;54(4):287–293. doi: 10.1016/j.ajme.2017.09.001.

17. Islam M.T. Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurological Research. 2017;39(1):73–82. doi: 10.1080/01616412.2016.1251711.

18. Jankauskas Stanislovas S, Kansakar Urna, Sardu Celestino, Varzideh Fahimeh, Avvisato Roberta, Wang Xujun, Matarese Alessandro, Marfella Raffaele, Ziosi Marcello, Gambardella Jessica, Santulli Gaetano.COVID-19 causes ferroptosis and oxidative stress in human endothelial cells. Antioxidants. 2023;12(2):326. doi: 10.3390/antiox12020326. .

19. Jones D.P. Redox theory of aging. Redox Biology. 2015;5:71–79. doi: 10.1016/j.redox.2015.03.004.

20. Kang T.C. Nuclear factor-erythroid 2-related factor 2 (Nrf2) and mitochondrial dynamics/mitophagy in neurological diseases. Antioxidants. 2020;9(7):1–20. doi: 10.3390/antiox9070617.

21. Kao M.P.C, Ang D.S.C, Pall A, Struthers A.D. Oxidative stress in renal dysfunction: Mechanisms, clinical sequelae and therapeutic options. Journal of Human Hypertension. 2010;24(1):1–8. doi: 10.1038/jhh.2009.70.

22. Keshari A.K, Verma A.K, Kumar T, Srivastava R. Oxidative stress: A review. The International Journal of Science and Technoledge. 2015;3(7).

23. Kim H.J, Min J.y, Seo Y.S, Min K.b. Association between exposure to ambient air pollution and renal function in Korean adults. Annals of Occupational and Environmental Medicine. 2018;30(1) doi: 10.1186/s40557-018-0226-z.

24. Kruk J, Duchnik E. Oxidative stress and skin diseases: Possible role of physical activity. Asian Pacific Journal of Cancer Prevention. 2014;15(2):561–568. doi: 10.7314/APJCP.2014.15.2.561.

25. Kuntic M, Oelze M, Steven S, Kröller-Schön S, Stamm P, Kalinovic S, Frenis K, Vujacic-Mirski K, Jimenez M.T.B, Kvandova M, Filippou K, Al Zuabi A, Brückl V, Hahad O, Daub S, Varveri F, Gori T, Huesmann R, Hoffmann T, … Münzel T. Short-term e-cigarette vapour exposure causes vascular oxidative stress and dysfunction: Evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX-2). European Heart Journal. 2020;41(26):2472–2483. doi: 10.1093/eurheartj/ehz772.

26. Kurutas E.B. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: Current state. Nutrition Journal. 2016;15(1) doi: 10.1186/s12937-016-0186-5.

27. Lakshmi S.V.V, Padmaja G, Kuppusamy P, Kutala V.K. Oxidative stress in cardiovascular disease. Indian Journal of Biochemistry & Biophysics. 2009;46(6):421–440.

28. Lasoń Władysław, Jantas Danuta, Leśkiewicz Monika, Regulska Magdalena, Basta-Kaim Agnieszka.The vitamin D receptor as a potential target for the treatment of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's diseases: A narrative review. Cells. 2023;12(4):660. doi: 10.3390/cells12040660.

29. Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D, Gargiulo G, Testa G, Cacciatore F, Bonaduce D, Abete P.Oxidative stress, aging, and diseases. Clinical Interventions in Aging. 2018;13:757–772. doi: 10.2147/CIA.S158513.

30. Liu Zai-Qun. Bridging free radical chemistry with drug discovery: A promising way for finding novel drugs efficiently. European Journal of Medicinal Chemistry. 2020;189:112020. doi: 10.1016/j.ejmech.2019.112020.

31. Lushchak V.I. Free radicals, reactive oxygen species, oxidative stress and its classification. Chemico-Biological Interactions. 2014;224:164–175. doi: 10.1016/j.cbi.2014.10.016.

32. Mahajan L, Verma P.K, Raina R, Pankaj N.K, Sood S, Singh M. Alteration in thiols homeostasis, protein and lipid peroxidation in renal tissue following subacute oral exposure of imidacloprid and arsenic in Wistar rats. Toxicology Reports. 2018;5:1114–1119. doi: 10.1016/j.toxrep.2018.11.003.

33. Man A.W.C, Li H, Xia N. Impact of lifestyles (diet and exercise) on vascular health: Oxidative stress and endothelial function. Oxidative Medicine and Cellular Longevity. 2020;2020 doi: 10.1155/2020/1496462.

34. Marchitti S.A, Chen Y, Thompson D.C, Vasiliou V. Ultraviolet radiation: Cellular antioxidant response and the role of ocular aldehyde dehydrogenase enzymes. Eye and Contact Lens: Science and Clinical Practice. 2011;37(4):206–213. doi: 10.1097/ICL.0b013e3182212642.

35. Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxidative Medicine and Cellular Longevity. 2017;2017 doi: 10.1155/2017/6501046.

36. Mendonça-Junior F.J.B, Scotti M.T, Nayarisseri A, Zondegoumba E.N.T, Scotti L.Natural bioactive products with antioxidant properties useful in neurodegenerative diseases. Oxidative Medicine and Cellular Longevity. 2019;2019 doi: 10.1155/2019/7151780.

37. Metodiewa Diana, Kośka Czesław. Reactive oxygen species and reactive nitrogen species: Relevance to cyto(neuro)toxic events and neurologic disorders. An overview. Neurotoxicity Research. 1999;1(3):197–233. doi: 10.1007/bf03033290.

38. Mirończuk-Chodakowska I, Witkowska A.M, Zujko M.E. Endogenous non-enzymatic antioxidants in the human body. Advances in Medical Sciences. 2018;63(1):68–78. doi: 10.1016/j.advms.2017.05.005.

39. Nicholson S.K, Tucker G.A, Brameld J.M. Effects of dietary polyphenols on gene expression in human vascular endothelial cells. Proceedings of the Nutrition Society. 2008;67(1):42–47. doi: 10.1017/S0029665108006009.

40. Pan Zhouxian, Dai Yimin, Akar-Ghibril Nicole, Simpson Jessica, Ren Huali, Zhang Lishan, Hou Yibo, Wen Xueyi, Chang Christopher, Tang Rui, Sun Jin-Lyu.Impact of air pollution on atopic dermatitis: A comprehensive review. Clinical Reviews in Allergy and Immunology. 2023 doi: 10.1007/s12016-022-08957-7.

41. Panchal K, Tiwari A.K. Mitochondrial dynamics, a key executioner in neurodegenerative diseases. Mitochondrion. 2019;47:151–173. doi: 10.1016/j.mito.2018.11.002.

58. Petřivalský M, Luhová L. Nitrated nucleotides: New players in signaling pathways of reactive nitrogen and oxygen species in plants. Frontiers in Plant Science. 2020;11:598.

42. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, Squadrito F, Altavilla D, Bitto A.Oxidative stress: Harms and benefits for human health. Oxidative Medicine and Cellular