Review Article

Unveiling the Mysteries of Oxidative Stress: An Insightful Review of Recent Studies

Baraa Najim Al-Okaily

Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Baghdad, Iraq.

Received | February 14, 2024; Accepted | May 21, 2024; Published | August 20, 2024

*Correspondence | Baraa Najim Al-Okaily, Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Baghdad, Iraq; Email: [email protected]

Citation | Al-Okaily BN (2024). Unveiling the mysteries of oxidative stress: an insightful review of recent studies. J. Anim. Health Prod. 12(3): 395-412.

DOI | http://dx.doi.org/10.17582/journal.jahp/2024/12.3.395.412

ISSN (Online) | 2308-2801

 

 

Copyright: 2024 by the authors. Licensee ResearchersLinks Ltd, England, UK.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

INTRODUCTION

Stress as a term refers to the reaction of the organism leading to the responses of humans trying to adapt daily life challenges. To understand the basic concepts of stress, it is necessary to deeply search what does stress mean. Stress is an inescapable phenomenon which can lead to a set of numerous physiological disorders (Del Giudice et al., 2018).

Previously, it was thought that free radicals are reactive oxygen species (ROS), but later it was found that they include another subgroup called reactive nitrogen species (RNS) that consist of nitrogen molecules and both are responsible for regulating normal cellular functions when present in physiological amounts, but at high concentrations they can cause molecular damage (Valko et al., 2007; Doshi et al., 2012; Sies and Jones, 2020). The term “oxidative stress” and “nitrosative stress” are used to describe these types of damage (Aruoma, 1998). Hydrogen peroxide lack of free electrons makes it a reactive oxygen species (Droge, 2002). Because of their capacity to interact with biomolecules and induce damage to cells, they are classified as reactive oxygen species (Victor et al., 2004). H2O2 can be produced and consumed by peroxisomes under physiological conditions. In addition, the catalase enzyme is in the peroxisome and aids in the breakdown of hydrogen peroxide into water, thereby preserving a state of homeostatic equilibrium (Barja, 2004). An imbalance in this equilibrium results in the interaction between hydrogen peroxide and reduced transition metals, such as copper and iron, leading to the creation of hydroxyl radical (•OH) through the Fenton reaction (Fridovich, 1978; Nunes-Silva and Freitas-Lima, 2015). Moreover, the superoxide anion (O2• ─) can engage with hydrogen peroxide in the presence of a metal ion via the Haber-Weiss reaction, resulting in the generation of the extremely reactive hydroxyl radical, in conjunction with the Fenton reaction (Sen, 2001) as shown in Figure-1. This leads to the alteration of large molecules in cellular structures, causing lipid peroxidation (LPO) and the development of oxidative stress. This process is frequently highlighted in the development of different degenerative diseases (Apostolova et al., 2011). Liver is the largest organ in the body which contributes in protein synthesis, metabolism of protein, fat, carbohydrate and bilirubin, storage of vitamins and detoxification (Osna et al., 2017; Ozougwu, 2017). Liver illnesses encompass a wide range of conditions spanning from initial steatosis to more severe fibrosis, cirrhosis, and hepatitis. Liver disease is a highly prevalent condition worldwide, primarily caused by various risk factors such as alcohol consumption, fibrosis, obesity, exposure to toxins, and the use of certain drugs that contribute to oxidative stress. The significance of oxidative stress and inflammation in the progression of hepatic diseases has been extensively studied and highlighted over the past few decades (Al-Okaily et al., 2012; Obert et al., 2015; Li et al., 2016; Muriel and Gordillo, 2016; de la Rosa et al., 2022).

Numerous factors contribute to the development of liver cellular injury through the excessive production of ROS. These factors include alcohol consumption, high-calorie diet, drug overdose, environmental pollutants, and heavy metals. Additionally, mitochondria and endoplasmic reticulum in hepatocytes play a significant role in ROS generation in distinct types of liver diseases (Jadeja et al., 2017; Ramadhan et al., 2023). Homeostasis maintenance requires the kidneys to perform many essential functions, making them unique organs (Eaton and Pooler., 2018; Samuel et al., 2018). The kidney receives approximately 20% of the blood pumped by the heart, and the oxygen consumption rates of renal mitochondria are greater than those of other organs (Cancherini et al., 2003) and release of hydrogen peroxide about 0.1% to 0.2% of total consumed oxygen (Tahara et al., 2009) that triggers the formation of various ROS types (Schiffer and Friederich-Persson, 2017; Ishimoto et al., 2018) associated with most of mitochondrial diseases such as, tubulopathies and focal segmental sclerosis (O’Toole, 2014; Al-Okaily and Mohammed, 2018).

To increase the understanding of oxidative stress and its pathophysiological effects on liver and kidney regarding to most recent studies, this article is designed.

Free Radicals

The research on free radicals (FRs) and their impact on biological systems has been of great interest for many years. Denham Harman was the first to report on this topic in 1956, and since then, he has highlighted the function of free radicals in the aging process (Harman, 1992). In addition, the discovery made by McCord and Fridovich in 1969 on the biological significance of superoxide dismutase provides support for the importance of free radicals in biological systems. In 1977, Mittal and Murad showed that the hydroxyl radical activates guanylate cyclase and promotes the production of cyclic guanosine monophosphate, which is known as the “second messenger”. This discovery marked the beginning of the third phase of research on free radicals (Droge, 2002). Following that, considerable evidence has been gathered to demonstrate that biological systems have developed to coexist with free radicals have been used productively in various physiological functions (Lushchak, 2014; Obeagu, 2018).

The high reactivity and short-lived nature of FRs is due to their small size and unpaired electrons, which also make it highly reactive diffusible molecules (Ziech et al., 2010). Initially, it was thought that free radicals are ROS because they contain single oxygen centered and eventually, it was discovered that RNS is another subgroup, and all are a product of normal cellular metabolism. Both ROS and RNS play a beneficial regulatory role in cell signaling processes (at low to moderate concentration) as shown in Figure- 2, but on the other hand they have harmful effects at high concentration on biological systems (Droge, 2002; Valko et al., 2007). The disruption of normal physiological processes by free radicals leads to a series of harmful chain events resulting in the deterioration of molecular structures in biological tissues and signaling mechanisms (Victor et al., 2004). The deleterious effect caused by ROS/RNS in biological tissues is termed oxidative stress (Aruoma, 1998).

Reactive Oxygen Species

Reactive oxygen species are created during oxygen metabolism and have the ability to act as free radicals, including hydroxyl radical (•OH), superoxide anion (O2• ─) lipid peroxyl (•LOO) and thiyl (•RS ) or non-radicals, such as hydrogen peroxide (H2O2), singlet oxygen ( O2), zone (O3), lipid peroxide (LOOH) and peroxynitrite (ONOO-) (Ahmad et al., 2019). ROS sources can be derived from both extracellular and intracellular sources. Ultraviolet (UV) light, ionizing radiation, heavy or transition metals, and other sources that will be revised later are included as extracellular sources. Intracellular sources consist of mitochondria, peroxisomes, the ER, and nicotinamide adenine dinucleotide phosphohydrogen (Wallace, 2012). Super oxide anion   and H2O2 are produced by more than fifty enzymes in human cells from endogenous sources, with mitochondria and NADPH oxidases being the main sources (Go et al., 2015). The most prominent instances of ROS include superoxide anion, hydrogen peroxide, and hydroxyl radicals. Cells possess the capacity to generate ROS both internally and externally. They employ these ROS for intracellular communication and to activate redox-sensitive signaling pathways, which in turn modify the cellular makeup of cytoprotective regulatory proteins (Drog, 2002; Zhang et al., 2016). So, it essentially the presence of both ROS and RNS at physiological levels for regulation of normal cellular functions, such as the fight against infection, cell defense, activation of G protein-coupled receptors and ion channels, hormone synthesis, different intercellular signaling pathways, gene expression and facilitating normal maturation and fertilization in reproductive systems (Briegera et al.,2012; Sedeek et al., 2013; Ahmad et al., 2019). Due to not easy to scavenge the hydroxyl radical, so it considered as the most damaging radical on the cells (Nunes-Silva and Freitas-Lima, 2015). Both mitochondria and NADPH oxidases are one of the main sources of ROS in cells during the physiological process of ATP production, and a variety of diseases are thought to be caused by the cellular ROS (Bulua et al., 2011). Xanthin oxidase (XO) is another pathway that helps to produce ROS, as it converts hypoxanthine into xanthine and XO into xanthin into uric acid to yield superoxide radical (Aziz and Jamil, 2020). Reactive oxygen species, such as superoxide and hydrogen peroxide are integral components of multiple cellular pathways even though excessive or inappropriately localized ROS damage cells (Bulua et al., 2011). However, during the process of energy transfer, a small number of electrons escape, resulting in an incomplete conversion of around 1-2% of molecular oxygen into peroxide in the form of anion radicals. Superoxide radicals display limited chemical reactivity due to their inability to traverse the lipid membrane and their rapid conversion to H2O2 by SOD (Collins, 2019). Too much production of ROS through oxidative phosphorylation leads to the promotion of damage of the macromolecules and DNA that maintain cellular normal function (Ratliff et al., 2016). Various cells inside our body generate diverse types of deleterious compounds, such as ROS and RNS. These compounds have the potential to induce a range of illnesses. Within human cells, several organelles, including mitochondria, endoplasmic reticulum, peroxisomes, lysosomes, and specific enzymes in the cell’s membrane or cytoplasm, have the ability to generate detrimental compounds known as ROS and RNS. In addition, extracellular metals such as copper and iron can potentially generate both ROS and RNS (Lambert and Brand, 2009).

Additionally, certain types of cells, such as endothelial cells and lymphocytes, could produce significant amounts of ROS. This production is facilitated by the tumor necrosis factor (TNF) pathway in endothelial cells and the 5-lipoxygenase (5-LO) pathway in lymphocytes. Moreover, the activation of cyclo-oxygenase-1 by various chemicals, including TNFα, interleukin-1, bacterial lipopolysaccharide, and tumor promoter 4-O-tetradecanoylphorbol-13-acetate (TPA), leads to the generation of ROS (Chen et al., 2008; Ha et al., 2011; Aggarwal et al., 2019). Noteworthy, the oxidation of dopamine can make ROS that can cause a problem with the brain and lead to degenerative diseases like Parkinson’s (Basu et al., 2015; 2023).

Hydrogen Peroxide And Its Effect

Hydrogen peroxide does not exhibit free radical behavior due to the absence of unpaired electrons, it is liposoluble and can therefore it diffuse easily through the cell membrane also, it generated by the dismutation of O2•− or by the direct reduction of O2, and it is mainly produced by enzyme reactions (Droge, 2002; Winterbourn, 2013).

H2O2 is classified as a reactive oxygen species due to its capacity to interact with biomolecules and pose a threat to cells (Victor et al., 2004). H2O2 is a significant harmful radical that contributor to reactive oxygen species produced by mitochondria. It is formed by the dismutation process of superoxide radicals by Mn-SOD. H2O2 serves as a substrate in numerous physiological and pathological chemical reactions that occur both inside and outside of cells (Kuciel and Mazurkiewicz, 2004; Tsang et al., 2014).

Under normal circumstances, peroxisomes can produce and consume H2O2 due to its high solubility in aqueous solution making it easy to penetrate the biological membranes, thus giving it highly detrimental activities (De Duve and Baudhuin, 1966; Boveris et al., 1972). At these conditions to maintain a homeostatic balance, catalase found in peroxisome decomposes H2O2 to H2O (Barja, 2004). Disturbance of this equilibrium may result in detrimental effects such as the deterioration of heme proteins, the liberation of iron, deactivation of -SH groups in proteins, keto acids, enzymes, and the oxidation of DNA and lipids (Halliwell, 2011). Also, hydrogen peroxide represents as serves as a source of the formation of more toxic species such as •OH and hypochlorous acid HOCI (Droge, 2002; Castagna et al., 2008).The interplay between hydrogen peroxide and copper and iron (as reduced transition metals) results in the Fenton reaction, which leads to the formation of hydroxyl radical. As well, exposure of water molecules to ionizing radiation can also result in the production of hydroxyl radical (Fridovich, 1978; Nunes-Silva, and Freitas-Lima, 2015). One more instance of a redox reaction is the Haber-Weiss reaction. Superoxide anions can interact with hydrogen peroxide in the presence of a metal ion through a reaction Haber-Weiss reaction to fabricate important highly reactive hydroxyl radical along with Fenton reaction (Sen, 2001).

In vivo H2O2 can be generated by several reactions through a broad difference of enzymes including monooxygenase and oxidase, causing damage to the cell membrane, decreasing cell capability due to inducted oxidative damage to genomic DNA and mitochondrial DNA (Mikhed et al., 2015). 3% of H2O2 is commonly used to disinfect wounds externally because due is a powerful oxidizing agent that kills bacteria, viruses, and fungi, besides, hydrogen peroxide is used extensively at higher concentrations in the food, chemical, and agricultural industries as a water purifier, disinfectant, bleaching agent, mouthwashes, and toothpaste (Watt et al., 2004).

Effect Of Ros On Liver

The liver primarily performs detoxification, protein synthesis, and the manufacture of enzymes that aid in food digestion. The liver is the sole organ capable of regeneration. Alcohol is the primary factor responsible for liver damage (Osna et al., 2017). The liver receives blood from two primary sources, which distinguishes it from other organs. The portal vein transports nutrients from the digestive system, while the hepatic artery delivers oxygenated blood from the heart. The liver is composed of lobules, which are the functional components of the organ. These lobules are comprised of hepatocytes, which are the liver cells numbering in the millions. The liver performs several crucial roles, such as producing bile, metabolizing proteins, fats, carbohydrates, and bilirubin, storing vitamins A, D, E, K, and B12, conducting metabolic detoxification, and filtering the blood. The liver performs endocrine and immunological activities alongside its synthesis of albumin (Ozougwu, 2017).

Comporti and colleagues (1965) firstly describe the presence of ROS with an increased level of lipid peroxidation (LPO) in rats after exposure to carbon tetrachloride (CCL4), also Di Luzio and Hartman reported the LOP in fatty liver induced by ethanol, thereafter, other researchers suggested that ROS is a major factor that causes liver damage (Le et al., 2017).

Liver illnesses encompass a wide range of conditions, spanning from initial steatosis to more severe fibrosis, cirrhosis, hepatitis, and hepatocellular carcinoma (HCC). Chronic liver disease is a highly prevalent condition globally, which can be induced by various risk factors including alcohol, fibrosis, obesity, toxins, and other medicines. It is intricately linked to the development of oxidative stress. The involvement of inflammation and oxidative stress in the development of hepatic disorders has been extensively described and underlined during the past decades (Obert et al., 2015; Li et al., 2016, Amer et al., 2024), various degenerative diseases (Apostolova et al., 2011). Immediate exposure to elevated amounts of reactive oxygen species can have harmful consequences in the body, particularly in situations of hepatic ischemia/reperfusion (I/R). The involvement of oxidant agents in cells is an intricate matter that relies on the equilibrium between oxidant/antioxidant status and the defensive mechanisms of cells against ROS, facilitated by various enzymatic and non-enzymatic antioxidants. When the efficiency of this antioxidant system diminishes, the level of ROS increases (Kurutas, 2016; Moussa, et al., 2019; Dawood and Alghetaa, 2023). Prooxidants are ROS that are generated in liver cell organelles (Figure-3) and can cause tissue liver damage when its levels may be increased by certain drugs, infection, external exposures, tissue injury, and so forth (Muriel and Gordillo, 2016).These ROS affect several amino acids rich in tyrosine and particularly cysteine, as well as induce alterations of mitochondrial membrane potential, Therefore, these alterations stimulate the liberation of pro-apoptotic substances (such as cytochrome C), enhance the activation of caspase-3 within cells, and ultimately result in the breakage of mitochondrial DNA (Wang et al., 2003; Cesaratto et al., 2004; Sinha et al., 2013). The cellular injury induced by this effect cause depletes the endogenous antioxidants and subsequently fails to counteract the ROS (Khudair and Al-Okaily, 2021). A range of factors contribute to the development of liver disease or injury caused by reactive oxygen species, including environmental contaminants, heavy metal exposure, alcohol intake, high-calorie diet, drug overdose, and other similar factors (Jadeja et al., 2017). Cholesterol has become a significant factor in liver damage, which is characterized by ongoing inflammation and fibrosis. Moreover, the effects of excessive cholesterol in the liver can cause the development of obstructive cholestasis, which we induced experimentally in mice by blocking the bile duct. These mice showed increased oxidative stress and cell death, as well as reduced growth of liver cells (Nuño-Lámbarri et al., 2016; Maretti-Mira et al., 2022).

 

ROS/RNS can directly stimulate hepatic stellate cells (HSCs) and cause them to transition from a resting state to an active state. This transition is marked by increased production and accumulation of extracellular matrix (ECM) proteins, particularly pyroptosis in hepatocytes. It can lead to the development of fibrosis, cirrhosis, and hepatocellular cancer (Ramos-Tovar and Muriel, 2020). The cross-linkage between parenchyma and non-parenchymal cells is considered the most important step in the development of liver damage and fibrogenesis, following ethanolic and non-alcoholic fatty liver disease, cigarette smoking (Chen et al., 2020; Le et al., 2020; Oni et al., 2020), hepatitis B virus and liver cancer (Yu, 2020), as well as, low oxygen tension, participate in reducing oxidative phosphorylation and generation of O2˙− and ˙NO, which in turn initiates the formation of different types of ROS and RNS (Ratliff et al., 2016; Schiffer, and Friederich-Persson, 2017; Ishimoto et al., 2018). The CYP enzyme which considered a significant role in phase I metabolism of xenobiotic and drug metabolism reactions in the liver causing the generation of ROS and initiation of oxidative stress which contributes to hepatic diseases (Cederbaum, 2017; Lu, 2018; Veith and Moorthy, 2018; Okkay et al., 2024).

Effect Of Ros On Kidney

Kidneys are unique structural organs, which perform several essential functions such as regulation of blood pressure, body fluids, water and electrolytes, excretion of waste products, vitamin D activity and red blood cell production (Eaton and Pooler., 2018). Kidney diseases are a worldwide health concern that result in a substantial number of illnesses and fatalities, particularly among adults (Finkel, 2011; Samuel et al., 2018). The kidney receives 20% of the cardiac output. Oxygen shunt diffusion leads to a comparatively low oxygen concentration in the renal tissue (Evans et al., 2008; Liu et al., 2017). Kidney mitochondria exhibit higher rates of oxygen consumption compared to other organs (Cancherini et al., 2003). Hydrogen peroxide, on the other hand, releases around 0.1% to 0.2% of the total oxygen consumed (Tahara et al., 2009). In kidney cells, the numbers of mitochondria differ from cell to cell. Tubulopathies and focal segmental sclerosis are the most of mitochondrial diseases associated with elevated ROS (O’Toole, 2014). There is a relationship between ROS and RNS in kidney cells (Figure 4). It is crucial to note that maintaining low levels of ROS and RNS is essential for normal redox signaling, which supports cell survival, proliferation, growth, renal vascular function, and serves as a sensor for hypoxia in cells. (Holmstrom and Finkel, 2014; Honda et al., 2019). However, in stressed tissues, the elimination of ROS and RNS is lost due to up-regulated ROS/RNS formation and/or reduced antioxidant activity resulting in the accumulation of these molecules and causing cell damage and impaired tissue function (Ratliff et al., 2016; Khudair and Al-Okaily, 2022). In addition, the generation of ROS can be stimulated in mesangial cells (MCs) and its activity is suppressed by glucocorticoids through a process involving receptors (Sedeek et al., 2013). Furthermore, elevated glucose levels stimulate the growth of mesangial cells and the expression of fibronectin by means of NADPH oxidase-mediated generation of reactive oxygen species and angiotensin-II. These variables play a crucial role in the development of diabetic nephropathy (Kashihara et al., 2010; Zhang et al., 2012; Kamiyama et al., 2013; Akaishi et al., 2019).

Oxidative stress has a detrimental impact on the kidneys by generating reactive oxygen species, which leads to the attraction of inflammatory cells and the generation of proinflammatory cytokines. This process initiates an inflammatory stage in the kidneys. TNF-alpha and IL-1b play a significant role in the early phase as proinflammatory mediators, together with NF-κB as transcriptional factors necessary to maintain the inflammatory process. The latter stage is marked by a rise in TGF-beta production and creation of extensive fibrotic tissue that compromises organ function potentially leading to renal failure. Some medicines, including cyclosporine, tacrolimus, gentamycin, and bleomycin, have been identified as nephrotoxic, leading to a higher incidence of oxidative stress (Sadeg et al., 1993; Massicot et al., 1997). Besides, heavy (Cd, Hg, Pb, and As) and transition metals (Fe, Cu, Co, and Cr), operate as powerful inducers of oxidative stress and accountable for many forms of nephropathy, and some types of cancers (Valko et al., 2005; Valko et al., 2006).

 

Induction Of Oxidative Stress In Liver And Kidney

Oxidative stress is characterized by an imbalance between the production of ROS and the levels of antioxidants. This imbalance disrupts the cell membrane and biomolecules, resulting in the formation of lipid peroxidation. The formation of LPO is implicated in the onset and progression of various diseases, including diabetes, ischemic heart diseases, atherosclerosis, and hepatic and renal toxicity (Nahar et al., 2017; Adwas et al., 2019). Humans and animals are exposed to several compounds and contaminants that cause oxidative stress in the liver and kidney. This occurs through various molecular processes, as outlined in Table -1.

Lipid Peroxidation

Lipid peroxidation is a cascade of reactions that take place during oxidative stress, resulting in the creation of several biologically active substances such as propanediol and 4-hydroxynonenal (HNE), which cause harm to cells. It supplies a constant amount of FRs that contribute to further peroxidation. During a toxicity study examining the oxidative products, it was observed that peroxide (LOOH) exhibited higher toxicity compared to 4-hydroxynonenal (HNE) and significantly higher toxicity than MDA. The LPO reaction in living cells can be split into three distinct stages: initiation, propagation, and termination. LPO can be triggered by any chemical species capable of abstracting

 

Table 1: Summary of the conditions inducing oxidative stress with their mechanisms in the liver and kidney.

Condition	Mechanisms	References
Diabetes-mellitus	1-Diabetes contributes to increased oxidative stress and an aberrant inflammatory response. 2-Unbalance of oxidative stress in the liver cells may interplay a relevant role in the genesis of the diabetic chronic liver disease and progression to steatohepatitis and cirrhosis. 3-activates the transcription of pro-apoptotic genes in liver and kidney. 4- stimulates the immune system, release, and aggregation of inflammatory cells, and the formulation of inflammatory cytokines, growth factors, and transcription factors related to the pathological changes in renal tubular structure and function leading to nephropathy.	Ozbek, E. (2012); Lucchesi et al.m(2013); Jha et al., (2016) ; Mohamed et al., (2016); Mahmoodnia et al., (2017); Mehta et al., (2017); Klisic et al., (2018); Amorim et al., (2019); He et al., (2020); Wang et al., 2021; Jin et al., (2023).
Hypertension	Angiotensin-II induce hypertension causing an elevation of ROS production via increased expression and activity of NADPH oxidase subunit p22phox leading to endothelial dysfunction of afferent arterioles, as well as dysregulation of other enzymes such as, nitric oxide synthase (NOS), xanthine oxidase, mitochondrial enzymes or SOD that generate •O2−, H2O2 and hydroxyl radical, subsequently resulted to worsening of renal function and ischemic nephropathy.	Wang et al., (2003);  Xu and Touyz, (2006); Lasseque et al., (2004); Pellegrino et al.,(2019); Thaha et al., ( 2019)
Obesity	Obesity- induce systemic oxidative stress through , generation of superoxide from NADPH oxidases., activation of protein kinase C leading to renal ischemia-perfusion injury. Obesity caused hepatosteatosis, and increased hepatic transcription of insulin receptor substrate-1.	Hensley et al., (2000); Quigley et al., (2009); Alwahsh et al., (2014); Sharma, (2014) ; Manna and Jain, ( 2015). Imafidon et al., (2019); Jovanović et al., (2023)
Urinary obstruction, urolithiasis	Increase of free radicals , an increase of leukocytes and defective / decrease of antioxidant enzyme activities	Huang et al., (2002); Dendooven et al., (2011); Yeh et al., (2011); Ozbek, E. (2012), Kaeidi et al., (2020)
Antibiotics (Aminoglycosides), immunosuppressant, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesic agents.	Excess production of ROS and depressed antioxidant defense mechanism are responsible for hepatic damage and nephrotoxicity	Hosohata, (2016); Oyouni et al., (2018); Guillouzo and Gugillouzo, (2020 ); Akhtar et al., (2020); Ely et al., (2014); Utzeri and Usai, (2017; Sood and Khudiar, 2018; Al-Ghareebawi et al., 2020).
Alcohol,	1-Significant decrease in the levels of the antioxidant enzyme. 2-Decreases renal tubular reabsorption and reduces renal function. 3-Induced lipid peroxidation. 4- Hepatic lipids accumulation.	Bailey and Cunningham, (1998); Rodrigo and Rivera, (2002); Adaramoye and Aluko, (2011); Ojeda et al.,( 2012); Goc et al., (2019)
Smoking, Nicotine	Cigarette smoking caused tissue damage involving aberrant inflammatory and cellular responses, leading to increased hepatic iron which –induces oxidative stress that leads to inflammation, programmed cell death, development of diabetic nephropathy and fibrosis of the liver.	Orth et al., (1998); Cigremis et al., (2004) ; El-Zayadi, (2006). ; Cigremis et al. (2006); Mizumura et al., (2014); Hamady and Al-Okaily, (2022a,b).
Environmental Toxins and Radiation	Depletion of antioxidant enzymes and increase inflammatory cytokines.	Wang et al., (2009) ; Khudair and Ahmed, 2012; Al-Gubory, ( 2014); Veraet et al., (2017); Kuo et al., (2019); Ling and Kuo, (2018). Samet and Wages, (2019).
Mobile Phones	Electromagnetic radiation (EMR)- induced degenerative and apoptotic changes through-induced oxidative stress.	Ozguner et al., (2005); Devrim et al., ( 2008); De Iuliis et al., (2009); Ozorak et al., (2013); Ma et al., (2015)

 

a hydrogen atom from the side chain of a polyunsaturated fatty acid (PUFA), such as arachidonic acid (an omega-6 fatty acid). These fatty acids have multiple consecutive methylene double bonds, which function as a reservoir of hydrogen atoms for the FRs. Arachidonic acid is typically found in cell membranes, the brain, muscles, and liver. It stimulates platelets to generate significant quantities of MDA. Vinblastine inhibits the conversion of arachidonate to MDA mediated by human platelet microsomes. Furthermore, the synthesis of MDA by platelets can be inhibited by the administration of aspirin or indomethacin. Lipid peroxides, originating from polyunsaturated fatty acids, exhibit instability and undergo rapid decomposition, resulting in the formation of a diverse array of chemicals, including MDA. This product acts as a dependable biomarker for oxidative stress (Dawood et al., 2023; Brammer et al., 1982; Michiels and Remacle, 1991; Dąbrowska and Wiczkowski, 2017; Barrera et al., 2018).

Biomarkers Of Oxidative Stress

Reactive oxygen species and reactive nitrogen species have a role in various signaling pathways that control differentiation, cell proliferation, mitogenic responses, apoptosis, inflammatory processes, and oxygen sensing. Furthermore, these molecules engage in the immune system’s defense response (Harman, 1981). Multiple studies have shown that oxidative stress is a significant factor in the development of liver and renal diseases. Therefore, it is imperative to assess these alterations by measuring many parameters (Abdelazeim et al., 2020; Hasan et al., 2020; Ullah et al., 2020). Various new biomarkers that can confirm the occurrence of acute renal failure (ARF) have been discovered, including kidney injury molecule-1 (KIM-1) (Han et al., 2002), interleukin-18 (IL-18) (Ojala and Sutinen, 2017), neutrophil gelatinase-associated lipocalin (NGAL) (Mishra et al., 2005), and hepatocyte growth factor (HGF) (Taman et al., 1997). Nevertheless, there is a scarcity of research investigating the levels of salivary indicators such as malondialdehyde, advanced oxidation protein products (AOPP), and advanced glycation end products (AGEs) that could potentially indicate renal disease. (Gyurászová et al., 2020). These proteins are detectable either in serum, urine, or renal tissue and had been advocated as new markers for the diagnosis of ischaemic and nephrotoxic ARI. However, there are few studies on whether oxidative stress markers are related to hydrogen peroxide-induced hepatotoxicity or nephrotoxicity, if it can be increased in serum or urine, and can predict the development of liver or kidney dysfunction.

Malondialdehyde

Malondialdehyde is formed because of lipid peroxidation of polyunsaturated fatty acids. It is widely utilized as a biomarker to assess oxidative stress in biological domains. MDA levels have been utilized in numerous biological systems for both in-vivo and in-vitro studies as a biomarker to indicate lipid peroxidation in diverse health problems, including hypertension, diabetes, atherosclerosis, heart failure, chronic periodontitis, and cancer. Lipid peroxidation is a sequential process that leads to the creation of several reactive substances, causing harm to cells. Patients diagnosed with lung cancer, complex regional pain syndrome, and glaucoma exhibit elevated levels of MDA. Furthermore, the MDA test has been reported as a dependable tool for assessing oxidative stress in various disease pathologies (Singh and Pai, 2014; Cordiano et al., 2023; Mohideen et al., 2023).

Malondialdehyde (MDA) is classified as a Thiobarbituric Acid Reactive Substance (TBARS), which serves as an indicator of lipid peroxidation. Measuring MDA levels in blood plasma or tissue homogenates is a valuable approach for predicting the extent of oxidative damage. The occurrence of MDA within cells during oxidative stress and its subsequent interaction with DNA forms MDA-2DNA adducts are the primary biomarkers of endogenous DNA damage (Murad and Al-Okaily, 2020; Davidovic et al., 2021). Various biochemical methodologies are employed to quantify the levels of MDA in various samples, such as serum, plasma, or tissues. The Thiobarbituric acid (TBA) assay is a widely employed technique for quantifying MDA levels. Nevertheless, the TBA assay lacks specificity for MDA since TBA can also react with other aldehydes that might be found in biological samples. Novel analytical techniques, such as high performance- liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS), have been devised to enhance the examination of the MDA-TBA adduct by enabling its separation and quantification (Korchazhkina et al., 2003; Mateos et al., 2004).

Protein Carbonyl

Protein carbonyl (PC) refers to the process of oxidizing several amino acids, including lysine, arginine, and proline, through the action of reactive oxygen species and reactive nitrogen species. PC serves as indicators of oxidative stress. Protein carbonyl is formed through various processes, including oxidative cleavage of the peptide backbone via the α-amidation pathway, oxidative cleavage of glutamyl residues, formation of protein-protein cross-linked derivatives, and cell membrane damage caused by lipid oxidation products. These processes result in the production of reactive aldehydes and ketones (Berlett and Stadtman, 1997; Dean, 1997; Stadtman and Levine, 2000). Plasma protein carbonyl levels exhibited elevated values in individuals with chronic kidney disease (CKD) and those undergoing hemodialysis, in comparison to individuals without these conditions (Himmelfarb et al., 2000; Song et al., 2020). Furthermore, the process of carbonylation of albumin in individuals with CKD exhibited a progressive rise as the disease progressed, as observed by (Mitrogianni et al., 2009). The levels of protein carbonyls showed an inverse correlation with the glomerular filtration rate. Furthermore, a noteworthy decrease in plasma carbonyls was seen following renal transplantation (Aveles et al., 2010).

Nucleic Acid Oxidation

Oxidative stress induces damage to DNA by several mechanisms, including the generation of fragmentation products, single and double-strand breaks, inter and intra-strand cross-links, DNA protein cross-links, and damage to DNA bases (Tucker et al., 2013). The primary indicators for DNA damage are 8-hydroxyguanosine (8-OHG) and 8-hydroxy-2′-deoxyguanosine (8-OHdG). The levels of 8-OHdG in CKD patients were higher in peripheral leukocyte DNA seen in peritoneal dialysis patients compared to healthy controls. Additionally, there was an inverse correlation between 8-OHdG levels and renal creatinine clearance in CKD patients who were not undergoing dialysis (Tarng et al., 2002). Conversely, an increased 8-OHdG level in leukocyte DNA was pointed out in hemodialysis patients (Tarng et al., 2000). The buildup of ROS leads to DNA damage, which in turn contributes to genetic instability. This process triggers signal transduction pathways by continuously activating oncogenes and transcription factors. In addition, the oxidation of proteins by ROS can potentially facilitate the advancement of tumors by enhancing the spread and invasion of tumor cells into neighboring organs. Consequently, the cells that have increased amounts of unaddressed, unplanned DNA damage demonstrate modified capacities to withstand further, external oxidative stress (Feig et al., 1994; Toyokuni et al., 1995; Jackson et al., 1998).

Oxidative Stress influences on Animals

Oxidative Stress has pivotal effects on the health and production of animals. However, due to variety of species, breeds, living environment, management conditions, housing, and too many variables, it is not easy to frame all the etiological factors that could lead to OS (Bażanów et al., 2020).

It is well-documented that a wide range of agents drive the OS in animals, but according to numerous studies it is interestingly to shed the light on some major factors. Homocysteine (Hys) is a non-proteinogenic substance which could by methylated into methionine or transsulfuration to cysteine with yielding of hydrogen sulfide that plays pathophysiological roles in endothelial cells as well as nervous system (Hermann and Sitdikova, 2021). Shono et al. (2020) reported that the reactive oxygen metabolite and biological antioxidant potential levels are following the health status of horses. In OS status, erythrocytes catabolize the methionine into Hys which in turn increases the capability of body to tolerate the detrimental effects of ROS (Gołyński et al., 2023; Ye et al., 2023). Furthermore, the well-trained horses showed higher levels of Hys in their serum post a trainer which may result in combat the yielded ROS during the training (Arfuso et al., 2022). However, OS does not affect the mare’s capability of producing healthy embryonic vesicle during stress status simultaneously with fertilization and developing of blastocyst in vitro (Hedia et al., 2024). In recent study, a group of researchers found that even within one breed the gender-affect is regulating the concentrations of oxidant and antioxidants in the serum of Arabian equine as well as commercial or seminatural living horses (Bażanów et al., 2020).

Furthermore, homocystein also can be useful as a biomarker for renal and cardiovascular disorders in dogs (Rossi et al., 2008; Benvenuti et al., 2020) as well as in patients with chronic kidney disease (Badri et al., 2023). Some pathological conditions in dogs such leishmaniasis also showed significant increase in oxidative stress (Quintavalla et al., 2021) as well as heart failure (Rubio et al., 2020).

In the cattle infected with viral lumpy skin disease, it was found that the concentrations of OS biomarkers were elevated due to the immunological responses along with reduction of dismutase enzyme concentrations (Ul-Rahman et al., 2023). In the same streamline, Kuhn et al. (2021) found that the calving process increases the vulnerability of cattle to diseases due to increase the OS around the time of parturition through enhancing of degradation of unsaturated fatty acids by cytochrome P450. Even in lactating period, the dairy cows show higher levels of MDA in comparison with late-pregnancy periods (Tufarelli et al., 2023). While another researchers have found that an infection with Brucellosis leads to increase the OS status in cattle (Hussain et al., 2022). In addition, short transportation of cattle could induce OS due to exacerbating of B-cell proliferation and survival via transcriptomic study in accompany with increase of serum lipid profile (Zhao et al., 2021).

In other hand, the oxidative stress in cattle and other animals could be combatted systemically by using antioxidant supplements such as vitamin C (Gordon et al., 2020), selenium and vitamin E (Xiao et al., 2021), resveratrol (Khudair and Al-Okaily, 2021; Abdullah and Al-Okaily, 2022, Dawood and Alghetaa, 2023, Dawood et al., 2023; Subhi and Al-Okaily, 2024), sodium butyrate (Ahmed and Mohammed, 2022a,b), sodium thiosulfate (Al-Tamemi and Al-Okaily, 2024), Gallic acid (Ramadhan et al., 2023), melatonin in dogs (Pongkan et al., 2022; Uchendu et al., 2022). Furthermore, the supplementation of vitamin E with fish oil to dogs improved the seminal plasma quality by decreasing the oxidative stress markers and increase the antioxidant biomolecules (Risso et al., 2021), this came aligned with results of adding resveratrol as an anti-oxidant to protect the canine against the cryopreservation of semen (Ahmed et al., 2022).

Conclusions

The oxidative stress is normal when there is a balance between the production rate of byproducts of oxidative processes and scavenger rate. However, it could be detrimental when the ability of the body is insufficient to control the production rate or incapable to remove the harmful byproducts resulted from oxidative stress. In animals, the redox system homeostasis is essential to maintain the well-being health and effective production rates.

acknowledgements

I would like to express my sincere gratitude to Assist. Prof. Dr. Hasan Alghetaa for his support throughout this research.

CONFLICTS OF INTEREST

The author states there is no conflict of interest.

novelty statement

This review offers a unique perspective on oxidative stress by exploring its role on liver and kidneys. Unlike previous studies that focused on routine approach, we were employed to investigate how different methods can induce oxidative stress in these organs. Simply, the novelty of this manuscript emphasizes the unique contribution of this work to the field.

AuTHoR’S CONTRIBUTIONS

The author declares there is not any other author who contributed to this paper.

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