The Application of Oxidative Stress Evaluation in Diseases Researches

Abstract: Oxidative stress, the pathological condition with the imbanlance of oxidation and antioxidation, has been proved to make contribution to the accurance and development of multiple kinds of diseases. This paper mainly refers to recent researches in diabetes, ischemia-reperfusion injury, indiopathic oligospermia, nuerodegenerative diseases, cancer treatment and so on. Biomarkers of oxidative stress had been widely used in the evaluations of related diseases judgement and drug treatment, which shows the importance of oxidative stress evaluation in disease research and drug development.

The following sections will be discussed in this article,

○ ○ Introduction of oxidative stress

○ ○ Oxidative stress evaluation in diseases research

○ Diabetes

○ Ischemia- reperfusion

○ Reproductive system diseases

○ Neurodegenerative diseases

○ Cancer

○ Other diseases

○ ○ Summary

○ ○ Metabolism indicators and product recommendations

○ ○ Reference

Introduction of Oxidative Stress

Oxidative stress is the imbanlanced situation between oxidation and antioxidation in some abnormal conditons. During this situation, the produced free redical is too much to be eliminated by the antioxidant system of body, that will end up with the accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and leads to oxidatice damage^[1]。

Oxidative stress is clesely related to many kinds of diseases, especially some of the senile and chronic diseases including diabetes mellitus^[2], cardiovascular diseases^[3], inflammatory and immune diseases^[4], hypertension^[5], ischemia-reperfusion injury^[6], neurodegenerative diseases^[7] and so on.。

Figure 1. Diseases that proved to be related to oxidative stress^[8]

Oxidative stress could be evaluated through the changing of oxidants, antioxidants or oxidation products as the increasing of oxidant capability and decreasing of antioxidant capability could be observed.

Figure 2. Biomarkers for oxidative stress evaluation^[9]

The relationship between oxidative stress and mechanism of diseases and their potential treatment could be investigated through direct or indirect measurement of oxidative stress biomarkers that can be mainly devided in three types: ROS, antioxidant and oxidation products.

Oxidative Stress Evaluation in Diseases Research

1. Diabetes research

① The machenism of diabetes induced by oxidative stress

Diabetes is a metabolic disease characterized by hyperglycemia, which is mainly caused by impaired insulin secretion or physiological effects. Insulin deficiency induced by islet B cell apoptosis causing by excess ROS will end up with hyperglycemia, which will lead to complications with chronic damage and dysfunction of nerves, heart, blood vessels, liver, kidney, eyes et al.

② The application of oxidative stress biomarkers in diabetes research

Oxidative stress evaluation was mainly been applied in the researches of accurence machenism and treatment effet of complications with diabetes. Mimiranpour^[10] found that electron beam irradiation can relieve oxidative stress and assist in the treatment of diabetes symptoms by evaluating hydrogen peroxide (H2O2), malondialdehyde (MDA), Glutathione reductase (GR), et al. Alagal^[2] figured out the protective function of Fesitin for cardiomyocyte protection in type I diabetes rat by reducing ROS and MDA. Ogunlabi^[11] and Akinnuga^[12] investigated the palliative and therapeutic effects of natural prodicts in diabetes and liver complication by combining the evaluation of oxidative stress biomarkeres like superoxide dismutase (SOD) and MDA together with liver function biomarkers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The supression effect of drugs and natural product in diabetic nephropathy thearapy was investigated by Periandavan^[13], Mebuza^[14] and Akinnuga^[15] using oxidative stress biomarkeres with kidney function biomarkers like urea (BUN), uric acid (UA) and creatinine.

In addition, decreasing of SOD, catalase (CAT) and reduced glutathion (GSH) can be observed in both arsenic^[16] and bisphenol A^[17] reduced diabetes. The risk of diabetes-induced rentinopathy could be induced with SOD and glutathion peroxidase (GPx) activity decreasing and MDA increasing^[18], while the risk could be reduced by essential oil from Fructus Alpiniae zerumbet^[19]. The relationship between diabetes and high fat diet^[20] induced cardiovascular^[21], nervous^[22] and inflammatory^[23] diseases were also been investigated.

Table 1. Application of oxidative stress biomarkers in diabetes researches

2. Ischemia-reperfusion

Ischemia-reperfusion (I-R) injury obtains quite complex mechanism, it is one of the important factors affecting the success rate of cardiopulmonary bypass, cardiopulmonary cerebral resuscitation, limb replantation, organ transplantation and so on. I-R injury is now beliened to be related to oxidative damage, calcium overloading and inflammatory response causing by neutrophils, in which the production of large amount of oxidative free redicals played an important role during the process^[24].The free redicals produced by I-R consumed the endougenous antioxidants rapidly, destroyed the structure and function of endothelial cells, leaded to tissue edema, bleeding and exudation. It also destoryed the non cellular structure and function of intercellular matrix, end up with further aggravates organ damage at same time^[25].

How to reduce I-R injury has always been the focus and difficulty of medical research. Through evaluated oxidative stress biomarkers including SOD, MDA, GPx, myeloperoxidase (MPO), total antioxidant capacity (TAC) together with the indicator of liver, kidney, blood and lipid metabolism, El-Baset[26]、Pang[27]、Albadrani[28]、Zheng[7]、Soliman[29]、Mustafa[30] investigated the usage of Mesna, TGP, quercetin, parecobix, propolis and Tadalafi in repressing the I-R injury of lung, kidney, heart, intestine, cerebral nerve and liver respectively. Liu[31]has developed a kind of nanoparticle for antioxidant transportation to neutralize inflammatory factors, the material was proved to aliviate I-R induced acute kidney injury, providing a novel stradegy for I-R treatment.

Table 2. Application of oxidative stress biomarkers in I-R injury researches

3. Reproductive system diseases research

① Idiopathic oligozoospermia

Idiopathic oligozoospermia (asthenospermia) is one of the most common factors of adult male infertility. The sperm density, survival rate and activity are significantly lower than the normal standard after excluding immune, infection, injury, chromosome abnormalities and other factors^[32]. It has been proved that the concentration of nitrogen oxide in semen is negatively corelated with sperm activity, while the lower SOD level was obtained in idiopathic oligozoospermia patient^[33] with the increasing of protein phosphorylation and DNA fragmentation.

Antioxidants, including vitamin C and vitamin E and others, having the ability of inhibiting the oxidation products of adenosine, can helpavoiding low sperm motility. Luo^[34] found that diet-induced obesity can downregulate the sperm activity related gene, lead to sterility in male rat while causing high cholesterol and hyperlipidemia. Alahmar^[35-37] improved the quality of sperm from idiopathic oligozoospermia patient using coenzyme Q10, reducing of ROS, NO and DNA fragmentation can be observed during the process with the increasing of antioxidase activities. Wang^[38] improved the avtivity and viability of defrozed sperm with quercetin, obtaining lower ROS and MDA levels and higher antioxidase levels. Opuwari^[39] figured out that the water extraction of Moringa olifera leaf had the similar function of androgen in increaseing sperm activity.

② Researches in other reproductive system diseases

A variety of reproductive system related diseases can be inhibited or alleviated by enhancing the antioxidant capacity of the body. The application of sodium hydrogen suldife is useful in alleviating the morphological and functional changes of obstructive penis (ED)^[40]. And the application of vitamin E and selenium can reverse the reproductive toxicity causing by acetamiprid^[41], ivermecin and doramecin^[42] induced oxidative stress.

Table 3. Application of oxidative stress biomarkers in reproductive system researches

4. Neurodegenerative diseases researches

① Introduction of neurodegenerative diseases

Neurodegenerative disease, inclusing acute and chronic type, is a kind of disease state with the loss of neurons in the brain and spinal cord, mainly characterized by the loss of a large number of specific neurons. Injury and loss of neurons can be obtained in both acute type like stroke and chronic type like Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (hd), amyotrophic lateral sclerosis (ALS) and so on.

The incidence rate of such diseases is rising with the population aging and the common in elderly, while the treatment of these diseases has great diffculty due to the complexity of nerve and brain function.

② Oxidative stress invastigation in neurodegenerative diseases therapy

The free redical-induced oxidative damage was found in many of the neorudegenerative diseases like AD, PD, ALS et al^[43]. Aflatoxin B1 was found to attenuate the antioxidant capability and creatine kinase activity in brain, and lead to chronic neurodegeneration^[44], while the pathology could be alleviated with antioxidants for neuron protection. Bilgea^[45]investigate the neuroprotective action of agmatine in Parkinson’s disease by enhancing the activities of oxidase in brain. Perindopril ameliorated Alzheimer’s disease progression in Basim’s experiment^[46], while the increasing of SOD activity and GSH amount was observed. Resveratrol prevents cognitive deficits by attenuating oxidative damage and inflammation causing by diabetes induced vascular dementia^[22].

The regulation effects of antioxidants can be applied not only in chronic neurodegenerative diseases, but also in acute type. Both tannic acid^[47] and pramipexole^[48] are reported to ameliorate brain injury induced behavioral decline, oxidative damage and mitochondrial dysfunction, oxidative stress situations were significantly been alliviated during the processes. The compounds synthesized by Shah^[49] can reduce the products of ischemic stroke and weaken the neuroinflammatory response by upregulating the activity of endogenous antioxidant enzymes. It is considered to have the application value to deal with neuroinflammation and neurodegenerative diseases.

Table 4. Application of oxidative stress biomarkers in neurodegenerative diseases researches

5. Cancer therapy

① Revusion of cancer cell apoptosis by regulating oxidative stress

Oxidative stress is proved to be a factor of cancer. DNA damage and replication error induced by oxidative stress will lead to the activation of cancer gene or inactivation of tumor suppressor gene which will end up with the accurance of cancer. Thus, some antioxidants, like quercetin, had the ability of reversing DNA damage and protein oxidation by alliviating oxidative stress, and could be useful in cancer prevention^[50].

In addition, cancer cells lose normal contact inhibition and continue to proliferate as transduction system is interfered by oxidative stress. Both ROS level and ROS tolerance of cancer cells are higher than that of normal cells^[51]. This tolerance and adaptation promotes the malignancy, metastasis and drug resistance of tumors, and inhibits the cell apoptosis. That shows the importance of investigating the mechanism of ROS tolerance and oxidative stress regulation in destory cancer cells.

The copper-dependent ferroptosis in incolorectal cancer cells induced by Elesclomol was ingestigated by Gao^[52]. Jia^[53] found that mitochondrial apoptosis induces by physcion can be used for anti-breast cancer property. Zhou^[54] figured out that the sensitivity of ROS induced cell apoptosis can be increased by upregulating DRP1 expression, which leads to a therapeutic effect on non-small cell lung cancer.

Besides drug actions, Razaie^[55] observed the accumulation of ROS and the increase of cell apoptosis in breast cancer cells using ionizing radiation as treatment. Xiang^[56,57] developed a solid lipid coated calcium peroxide nanocarrier for cancer chemo/chemodynamic therapy with O2/H2O2 self-sufficien.

② Antioxidation inhibits side effects in cancer treatment

The negetive effects like inflammation, ulcer, liver and kidney function damage et al on normal tissue and organ during the cancer therapy process of drugs, is called side-effects, and regarded as adverse factors affecting the effect of cancer treatment.

As one of the most widely used broad spectrum antitumor drugs, cisplatin was proved to have toxicities in liver, kidney, heart, digestive system and nervous system^[58], marked with oxidative damage like MDA increasing and oxidase downregulation. Usage of coenzyme Q10 and memantine for increasing antioxidants capability were proved by Rabeea^[59] and Salih^{[60], showing protective effects on kidney and liver seperatly. In addition, Veradiano[61] alleviated the damage cauing by colorectal cancer using smallanthus sonchifolius to prevented oxidative stress and and intestinal alterations.}

Table 5. Application of oxidative stress biomerkers in anticancer researches

6. Other diseases researches

In addition to the above related diseases, most inflammation was proved to be able of being treated by enhancing antioxidant capacity^[62]. Tao^[63] invesgated the application of vitamin D in alliviating crystalline silica-induced pulmonary inflammatory damage. Saleem^[64] investigated Alternanthera bettzickiana extraction in Antiarthritic Potential. Rini^[65] investigated the effect of Green Betle Leaf Gel in root planing treatment through total antioxidants capacity accumulation. Gallic acid was proved to help against ethanol-induced gastric ulcer^[66] by upregulating GSH, SOD, CAT and down regulating thiobarbituric acid reactant (TBARS). Nonalcoholic fatty liver causing by high-fat diet was also proved to be related to oxidative stress.

In addition, abduljawad^[68] verified the correlation between antioxidant capacity and immunity. Wen^[69] disinfect waterborne fungal spores with sequential use of UV-LEDs irradiation and chlorine to increased the ROS accumulation for membrane permeability change.(Figure 3)

Figure 3. Sequential use of UV-LEDs and chlorine promoted the oxidative stress in fungal spores. Activities of SOD and CAT were increased in early stage to eliminate excess ROS, while the activities were suppressed with deep oxidative stress.

In terms of environmental research, the oxidative stress fact of lead biotoxicity and therapeutic effect of melatonin were proved by Adeyemi^[70]. And Shekha^[71] investigated the potential of redox balance in mussel as a reference of ecotoxicity test as its sensitivity in environmental polution. (Figure 4)

Figure 4. The redox balance in mussel gill changed sensitively with the concentration of Carbamate Pesticide Carbaryl

Table 6. Application of oxidative stress biomarkers in other diseases researches

Summary

During the process of oxidative stress, oxidative damege causing by free redicals can be happened on most of biological macromolecules, that leads to the relationship between oxidative and various diseases in different organs of the body. The quantitative determination of oxidative biomarkers have a worthy reference for the basic judgment of body health or disease degree, and is widely used in the evaluation of systemic health status, the identification of etiology, the degree of progress related to oxidative stress and the evaluation of prognosis.

Through the published paper above, the most widely used biomarkers were MDA, GSH, SOD, CAT and so on. MDA is one of the main products of oxidative damage, with its determination could be seen in most of the oxidative stress researches. The level of MDA will have positive correlation to the degree of oxidative stress, while the reduction can be observed after treatments.

ROS is the indicator that directly evaluated the content of free redicals, which has a similar trend with oxidative stress like MDA.

GSH is one of the most commonly used indicators of non-enzymatic antioxidants, similarly as TAC which measures the total amount of all nonenzymatic antioxidants. A significant decreasing of GSH or TAC can be observed in oxidative stress situation, and the amount can be reversed with treatment.

In additon, enhencement of some common antioxidase indicators like SOD and CAT may be observed during the early stage of oxidative stress, indicating that the antioxidant system being overexpressed to eliminate the excess free redicals. With the aggravation of oxidative stress, however, the function of antioxidant system will be completely inhibited, and these indicators will eventually show a significant decline in varying degrees. The alleviation effects of some drugs on oxidative stress were achieved by promoting the activities of SOD or CAT./span>

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