MALONN, Maíra Casali. FRANCO, Fernando Wendel. Antioxidants and free radicals: an approach linking diseases with natural product therapy. Revista Científica Multidisciplinar Núcleo do Conhecimento. Year 07, Ed. 01, Vol. 02, pp. 120-131. January 2022. ISSN:2448-0959, Access link in: https://www.nucleodoconhecimento.com.br/health/approach-linking
Excess free radicals play an important role in the pathogenesis of many diseases. From these compounds, new antioxidants or even new drugs are developed to prevent diseases or damage induced by reactive species. To develop more specific molecules in the treatment of diseases, one can search for drug collections and/or natural product libraries, or even couple an antioxidant group to other pharmacological groups. The most rationally engineered multifunctional antioxidants are structurally different from their naturally occurring counterparts, based on structural improvements and synthesis. The objective of this work is to bring a review of the main diseases caused by free radicals such as skin cancer, arteriosclerosis and autoimmune diseases, based on a review of the scientific literature citing some of the most relevant works in the area. From this study it can be concluded that natural products are an abundant source of antioxidants. In some cases, the structure found in nature is used directly as a medicine.
Keywords: Oxidative stress, Free radicals, antioxidants.
Radicals are atoms, molecules, or ions with unpaired electrons, which are highly active for chemical reactions with other molecules. In biological systems, free radicals are often derived from oxygen, nitrogen, and sulfur molecules (HALLIWEL et al., 2001). These free radicals are part of groups of molecules called reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS). For example, ROS includes free radicals such as superoxide anion (O2 •), peroxyl radical (HO2 •), hydroxyl radical (• OH), nitric oxide and other species, such as hydrogen peroxide (H2O2), singlet oxygen (1O2), hypochlorite acid (HOCl) and peroxynitrite (ONOO) (KESHARI et al., 2019).
Also, RNS are derived from nitric oxide by reacting with (O2 •) to form (ONOO). RSS is easily formed from thiols by reacting with ROS. They are produced during cell metabolism and functional activities and have important roles in cell signaling, apoptosis, gene expression, and ion transport (GRUHLKE et al., 2012).
Antioxidants are molecules that can neutralize free radicals by accepting or donating electrons to eliminate the unpaired condition of the radical. Antioxidant molecules can react directly with reactive radicals and destroy them, while they can become new free radicals that are less active, last longer, and are less dangerous than the same ones they neutralized (CAROCHO et al., 2012). They can be neutralized by other antioxidants or other mechanisms to eliminate their radical state. Many antioxidants have aromatic ring structures and can displace the unpaired electron (APAK et al., 2016).
2. FREE RADICALS AND ANTIOXIDANTS IN NATURAL PRODUCTS
In recent years, there has been a significant rise in research and discovery of natural and safe antioxidants, particularly those derived from plants (SHAH et al., 2014). Ginseng, turmeric, ginkgo, rosemary, green tea, grapes, ginger, and garlic are just a few of the natural chemicals found in fruits, vegetables, spices, cereals, and herbs. They include phenolic compounds (phenol and polyphenols), flavonoids, carotenoids, steroids, and thiol compounds, among other antioxidant chemicals. These antioxidants can help prevent oxidative stress-induced cell damage and lower the risk of chronic illnesses (KOOLEN et al., 2013).
Ginseng, for example, includes ginsenosides, which are steroid-like substances with antioxidant properties in the vascular endothelium (LU et al., 2009). Ginkgo biloba, for example, has been shown to have high antioxidant properties thanks to flavone glycosides that scavenge free radicals. Flavonoids like catechin and epicatechin, which are found in green tea and grape seed extracts, may be responsible for their powerful antioxidant properties (BINGHAM et al., 2006; PARIHAR et al., 2015). According to Franco et al., 2019, Curcuma longa, a curcumin-rich vegetal species, has a significant potential to reduce oxidative stress induced by bacterial infections.
In addition, spectrophotometric techniques based on the use of O2– and OH, DPPH, ABTS+, and N, N-dimethyl-p-phenylenediamine cationic dihydrochloride (DMPD+) are among the most widely used for evaluating the antioxidant capacity of foods, drinks, and plant extracts (CORRAL-AGUAYO et al., 2008). Due to their easy, quick, sensitive, and repeatable processes, DPPH and ABTS+ elimination techniques have been the most widely employed to test the antioxidant activity of the substances (GULCIN et al., 2012).
Free radicals (such as O2– and OH) interact with antioxidants, providing direct proof that antioxidants destroy free radicals. It’s been frequently utilized to evaluate antioxidants’ capacity to scavenge free radicals. More stable radicals are used as probes in radical scavenging studies for models. DPPH, galvinoxil, ABTS+, and DMPD+ are stable and colorful radicals (KOTORA et al., 2016; UTTARA et al., 2009).
The antioxidant must bind an electron or an active hydrogen atom, such as an inactive hydroxyl group, to scavenge free radicals. Antioxidants with active hydroxyl groups, such as vitamins E and C, which are made up of polyphenol and flavonol, are powerful radical scavengers. Liu and colleagues discovered that ecdysteroids, which lack active hydroxyl groups, are also potent antioxidants and free radical scavengers (KUMAR et al., 2013). H-9, which is allyl hydrogen, maybe the most active hydrogen in the ecdysteroid, and conjugation with the 6-carbonyl group weakens the C – H-9 link even more. The fact that allylic hydrogens are very active and quickly absorbed by free radicals is well recognized (YU-JUN et al., 2002).
Because it possesses an unshared electron, a carbon radical is very reactive and unstable. By removing a proton and an electron from another molecule, the carbon radical can become a stable molecule and become part of a pair of binding electrons (JIN et al., 2013). They are electrically unstable and hence very reactive, capable of reacting with any surrounding chemical and perhaps exceeding its functionalities. Free radicals generated from oxygen occur in a variety of metabolic processes in our bodies, and they play a vital part in the human body’s functioning. They carry electrons in the respiratory chain and, in some cells, have the potential to kill germs (VALKO et al., 2007).
Oxidative stress occurs when you have an excessive rise in your production or a reduction in antioxidant agents. Excess free radicals can be generated in two ways: internally and externally. Internal: cancer, anemia, arteriosclerosis, heart attack, and so on. cigarette smoke, alcoholic drinks, air pollution, sunshine and X-rays, high fat intake, fried meals, and red meat are all external influences (LIGUORI et al., 2018).
3. FREE RADICALS AND ANTIOXIDANT SYSTEMS
Free radicals are unpaired reactive molecules that react with a cell’s DNA, changing its genetic coding and causing chaotic cell growth. The interaction of radical species with fatty acids can promote plaque formation on arterial walls, reducing flexibility, causing arterial hypertension, and artery blockage (ALIQUE et al., 2018; CACCIAPUOTI et al., 2016).
They work on cells by changing their membranes, causing “old cells” to emerge that would usually be removed from our bodies. Our immune system fails to remove the changed cells when the amount of radical is adjusted. Some of them survive and behave improperly in tissues, organs, and the entire body, proliferating uncontrollably, resulting in tumors, cataracts, and other problems (KIRKWOOD et al., 2012).
There are two ways to remove Free Radicals from the body in an animal organism: enzymatic and enzymatic systems. Catalases, glutathione, peroxidases, and other enzymes that can “sweep” Free Radicals are produced by the human body (MAHANTESH et al., 2012). The bulk of non-enzymatic systems must be consumed through a balanced diet. They are split into two categories: antioxidants and precursors. Vitamin E, pro-vitamin A, and beta-carotene are fat-soluble vitamins. Vitamin C is a water-soluble vitamin. Zn, Cu are trace elements (KHADIM et al., 2021).
Antioxidants are not able to treat diseases caused by oxidative stress; rather, they are utilized to prevent, manage, or mitigate diseases that have already developed, originated, or are exacerbated by reactive species imbalance (VONA et al., 2021).
4. RELATED DISEASES
4.1 SKIN CANCER
Free radicals are continuously forming in our bodies, causing harmful damage to our cells. These free radicals are produced by the oxidation of the cell membrane and are responsible for a variety of illnesses and degenerative processes in humans. Because free radicals react non-specifically with all cellular components, they induce cellular damage. As a result, depending on the location and amount, they cause diverse chemical changes that damage certain cellular structures and functions, increasing aging and other diseases (STORZ et al., 2005). Free radicals’ harmful effects are regulated by the body’s defense system, which uses antioxidant molecules to avoid oxidative stress and tissue damage. UV light, for example, creates free radicals, which are linked to skin cancer (ALLEGRA et al., 2020).
UV light causes damage to normal cells through several mechanisms. The most significant of these processes is probably oxidative stress. UV light generates large amounts of reactive oxygen species (ROS), which overwhelm antioxidant mechanisms like glutathione. The melanosome is most likely the primary generator of ROS in skin cells and, more importantly, in melanocytes. Furthermore, after UV exposure, the skin’s extracellular matrix (ECM) is likely to be a major source of reactive oxygen species (ROS). When ECM proteins like elastin and collagen were introduced to dermal fibroblasts after they had been pre-irradiated with UV, the oxidative stress in the cells increased.
Excessive levels of reactive oxygen species (ROS) encourage abnormal cell development, DNA damage, and epigenetic modifications, as well as the beginning of a variety of illnesses, including cancers. In Xeroderma pigmentosum group C (XPC) deficiency, ROS has been shown to have an oncogenic effect. Loss of XPC leads to changes in cellular metabolism induced by ROS, as well as changes in numerous signaling pathways associated with carcinogenesis. For example, ROS can alter the activating protein-1 pathway, epidermal growth factor receptor, NF-B, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and p38 MAPK, all of which are active in various cancers (CHO et al., 2019).
The buildup of lipids and inflammatory cells in the walls of medium and large arteries is the hallmark of atherosclerosis, a chronic inflammatory disease. Atherosclerosis is caused by the activation of pro-inflammatory signaling pathways, the production of cytokines and chemokines, and a rise in oxidative stress (KATTOOR et al., 2017).
Increased production of reactive oxygen species (ROS) and/or a reduction in the body’s inherent antioxidant defense mechanisms are both signs of oxidative stress. ROS are involved in inflammatory reactions, apoptosis, cell proliferation, and vascular tone changes, as well as the oxidation of LDL cholesterol, which is considered to be more significant in atherogenesis than native-LDL. Hypertension, diabetes, smoking, and dyslipidemia all enhance ROS generation in the artery wall, which is a risk factor for atherosclerotic cardiovascular disease (INCALZA et al., 2018).
4.3 AUTOIMMUNE DISEASES
Free radicals can be produced as a result of oxidative stress, which can alter proteins. Self-antigen changes can trigger the onset of autoimmune disorders (SMALLWOOD et al., 2018). Cells may create an excess of ROS/RNS in response to oxidative stress, which reacts with and alter lipids and proteins in the cell. The results of these reactions might be stable compounds like 3-chlorothyrosine and 3-nitrotyrosine, which could inhibit normal tyrosine biotransformation like phosphorylation while also changing the protein’s antigenic profile. The oxidative alteration of proteins not only alters their antigenic profile but also increases their antigenicity (FAN et al., 2015). Systemic lupus erythematosus (60 kD Ro ribonucleoprotein), diabetes mellitus (high molecular weight complexes of glutamic acid decarboxylase), and diffuse scleroderma (oxidation of beta-2-glycoprotein) are just a few examples of autoimmune diseases resulting from oxidative modifications of self-proteins (SOTLER et al., 2019).
Furthermore, like in the case of insulin-producing beta cells in the islet of Langerhans, oxidative stress offers an extra hazard to the target tissues. Furthermore, autoimmune disorders frequently affect just one tissue, even though additional tissues may have the same antigen but lack the oxidative stress needed to begin the process. The diagnosis of autoimmune disorders is further complicated by pathological autoreactivity directed towards redox-modified self-antigens and diagnostic tests designed to evaluate its cross-reactivity to normal self-antigens (RAHAL et al., 2014).
There is a possibility that psychological stress, as well as key stress hormones, have a role in the etiology of autoimmune illness. It is thus assumed that stress-induced neuroendocrine hormones cause immune system dysregulation, eventually leading to autoimmune disorders, by altering and amplifying cytokine production (SANFORD et al., 2014).
Reactive oxygen species, for example, are thought to play an essential role in the development of Rheumatoid arthritis. ROS causes lipid peroxidation by attacking polyunsaturated fatty acids in cell membranes. In Rheumatoid arthritis, increased levels of lipid peroxidation, hydrogen peroxide, and superoxide in plasma and red blood cells cause oxidative stress (VESELINOVIC et al., 2014).
Oxidative stress is the imbalance between oxidants and antioxidants in favor of oxidants that are formed as a normal product of aerobic metabolism, but during pathophysiological conditions, they can be produced at a high rate. Both enzymatic and non-enzymatic strategies are involved in antioxidant defense, and the antioxidant effectiveness of any molecule depends on the pro-oxidant. Proven free radical scavengers can be pro-oxidants unless they are associated with a deposit of free radicals. Furthermore, as free radicals share a physiological and pathological role in the body, the same antioxidant molecule just because of its free radical scavenging activity can act as a disease promoter, neutralizing the physiologically desired ROS molecules, and as a disease reliever, removing excessive levels of ROS species (ALI et al., 2020).
Advances in the field of biochemistry, including enzymology, have led to the use of several enzymes, as well as low molecular weight endogenous and exogenous antioxidants that can inhibit the harmful effect of oxidants. Understanding genetic changes and the molecular mechanism is certainly helping to reveal the interaction of free radicals and their role in proteomics, genomics, and the disease development process. In addition, the pro-oxidant or antioxidant behavior of universally accepted antioxidant molecules is now duly expressed in terms of dependence on the actual molecular conditions prevailing in tissues (RAHAL et al., 2014).
Thus, oxidative stress caused by ROS results in an increased risk for many diseases, such as inflammatory diseases, cardiovascular diseases, cancer, diabetes, Alzheimer’s disease, cataracts, autism, and aging. Antioxidants can react directly with reactive radicals to destroy them, accepting or donating electron (s) to eliminate the unpaired condition of the radical. They can also decrease the formation of free radicals by inhibiting the activities or expressions of radical-generating enzymes by increasing the activities and expressions of other antioxidant enzymes (PISOCHI et al., 2021).
Many research models have been established in chemical and biological systems to study the mechanisms of action of antioxidants and to identify new antioxidants, especially natural substances. We review the antioxidant and pro-oxidant mechanisms and enzymatic activities in chemical and cellular systems with a focus on compounds from natural products. But most natural compounds need some modification to work as a medicine. Some need to be stabilized because they degrade very quickly. Others need changes that favor their absorption and distribution in the human body. Others still need its effect to be enhanced. Thus, nature provides important clues about how the concept of structural design of natural products implies the discovery of new drugs or antioxidants through structural formula improvement.
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 Master’s student in Analytical Chemistry. Graduation in Chemistry Degree. ORCID: 0000-0002-2600-5964.
 Doctor in Pharmacology. Master in Toxicological Biochemistry. Postgraduate in Clinical Analysis. Graduated in Pharmacy. ORCID: 0000-0002-4762-5855.
Enviado: Maio, 2021.
Aprovado: Janeiro, 2022.