Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products. ROS can play, and in fact they do it, several physiological roles (i.e., cell signaling), and they are normally generated as by-products of oxygen metabolism; despite this, environmental stressors (i.e., UV, ionizing radiations, pollutants, and heavy metals) and xenobiotics (i.e., antiblastic drugs) contribute to greatly increase ROS production, therefore causing the imbalance that leads to cell and tissue damage (oxidative stress). Several antioxidants have been exploited in recent years for their actual or supposed beneficial effect against oxidative stress, such as vitamin E, flavonoids, and polyphenols. While we tend to describe oxidative stress just as harmful for human body, it is true as well that it is exploited as a therapeutic approach to treat clinical conditions such as cancer, with a certain degree of clinical success. In this review, we will describe the most recent findings in the oxidative stress field, highlighting both its bad and good sides for human health.
Superoxide radicals (O2•−), hydrogen peroxide (H2O2), hydroxyl radicals (•OH), and singlet oxygen (1O2) are commonly defined reactive oxygen species (ROS); they are generated as metabolic by-products by biological systems [
ROS are mainly produced by mitochondria, during both physiological and pathological conditions, that is, O2•− can be formed by cellular respiration, by lipoxygenases (LOX) and cyclooxygenases (COX) during the arachidonic acid metabolism, and by endothelial and inflammatory cells [
Cells deploy an antioxidant defensive system based mainly on enzymatic components, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), to protect themselves from ROS-induced cellular damage [
ROS production basically relies on enzymatic and nonenzymatic reactions. Enzymatic reactions able to generate ROS are those involved in respiratory chain, prostaglandin synthesis, phagocytosis, and cytochrome P450 system [
Even nonenzymatic reactions can be responsible for free radical production, that is, when oxygen reacts with organic compounds or when cells are exposed to ionizing radiations. Nonenzymatic free radical production can occur as well during mitochondrial respiration [
Free radicals are generated from both endogenous and exogenous sources. Immune cell activation, inflammation, ischemia, infection, cancer, excessive exercise, mental stress, and aging are all responsible for endogenous free radical production. Exogenous free radical production can occur as a result from exposure to environmental pollutants, heavy metals (Cd, Hg, Pb, Fe, and As), certain drugs (cyclosporine, tacrolimus, gentamycin, and bleomycin), chemical solvents, cooking (smoked meat, used oil, and fat), cigarette smoke, alcohol, and radiations [
When maintained at low or moderate concentrations, free radicals play several beneficial roles for the organism. For example, they are needed to synthesize some cellular structures and to be used by the host defense system to fight pathogens. In fact, phagocytes synthesize and store free radicals, in order to be able to release them when invading pathogenic microbes have to be destroyed [
As stated before, if in excess, free radicals and oxidants give rise to a phenomenon known as oxidative stress; this is a harmful process that can negatively affect several cellular structures, such as membranes, lipids, proteins, lipoproteins, and deoxyribonucleic acid (DNA) [
Even DNA is prone to oxidative stress-related lesions, the most representative of which is the 8-oxo-2′-deoxyguanosine (8-OHdG) formation; this is a particularly pernicious DNA lesion, which can be responsible for both mutagenesis, as pointed out by Nishida et al. [
If not strictly controlled, oxidative stress can be responsible for the induction of several diseases, both chronic and degenerative, as well as speeding up body aging process and cause acute pathologies (i.e., trauma and stroke).
Cancer onset in humans is a complex process, which requires both cellular and molecular alterations mediated by endogenous and/or exogenous triggers. It is already well known that oxidative DNA damage is one of those stimuli responsible for cancer development [
Cardiovascular diseases (CVDs) are clinical entities with a multifactorial etiology, generally associated with a very large amount of risk factors, the most broadly recognized of which are hypercholesterolaemia, hypertension, smoking habit, diabetes, unbalanced diet, stress, and sedentary life [
Oxidative stress has been linked to several neurological diseases (i.e., Parkinson’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, depression, and memory loss) [
Several researches pointed out that lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), determined by systemic and local chronic inflammation, are linked to oxidative stress [
Rheumatoid arthritis is a chronic inflammatory disorder affecting the joints and surrounding tissues, characterized by macrophages and activated T cell infiltration [
Oxidative stress is involved in a plethora of diseases affecting renal apparatus such as glomerulo- and tubule-interstitial nephritis, renal failure, proteinuria, and uremia [
Several authors pointed out that oxidative stress could be responsible for a delayed sexual maturation and puberty onset [
Summarizing, we can affirm that oxidative stress and free radicals are confirmed to be responsible for several pathological conditions affecting different tissues and systems, thus being one of the most important and pervasive harms to human health.
Human body put in place several strategies to counteract the effects of free radicals and oxidative stress, based on enzymatic (e.g., SOD, CAT, and GPx) and nonenzymatic (e.g., lipoic acid, glutathione, ʟ-arginine, and coenzyme Q10) antioxidant molecules, all of them being endogenous antioxidants. Beside these, there are several exogenous antioxidant molecules of animal or vegetal origin, mainly introduced by diet or by nutritional supplementation.
Here, we will discuss the most relevant nutritional antioxidants and their protective effects for human health.
The term vitamin E encompasses a constellation of lipophilic molecules (
The most active form of vitamin E, RRR-
Macrophage transition to foam cells is one of the earlier and important steps in atherosclerotic lesion formation; CD36 receptor is one of the key players involved, being a scavenger receptor responsible for oxidized-LDL (oxLDL) uptake from bloodstream [
Several studies described that vitamin E is able to prevent CD36 mRNA expression induced by cholesterol, thus playing a beneficial role in preventing foam cell formation. This was true in vivo, as well as in vitro on human macrophages and vascular smooth muscle cells [
Vitamin E modulates the oxidative stress-induced NF-
A degree of CD36 mRNA reduction was also observed in animals undergoing to vitamin E supplementation under a regimen of high-fat diet [
RRR-
Each form of vitamin E seems to have different regulatory effects when it comes to recruit leukocytes to allergic inflammation site, which is however strictly dependent on vascular cell adhesion molecule-1 (VCAM-1) [
Endothelial cells pretreated with
Interestingly, a research found a correlation between the prevalence of asthma and the average plasma tocopherol in several countries, based on nutritional consumption of foods and oils rich in tocopherol. Briefly, countries with an average plasma
Olive and sunflower oils, which have little or not at all
A large prospective study, covering 4500 individuals and spanning 20 years, demonstrated an association between
It has been also observed, from in vivo experiments, that
It is known that (i) proper dendritic cell development and responsiveness are crucial for an optimal allergen sensitization, (ii) it relies on PKC isoforms activity, and (iii) all of the PKCs include a C1A regulatory domain, which is targeted by both
In mice prone to allergic disease, supplementing allergic mothers (at the time of mating) with
These differences in allergic response development exerted by
Summarizing,
Flavonoids are a class of polyphenolic compounds with a benzo-
Their antioxidant activity relies on the conformational disposition of functional groups; configuration, substitution, and total number of hydroxyl groups are important factors in determining mechanisms of antioxidant activity like ROS/RNS scavenging and metal chelation [
Flavonoid determines (i) ROS synthesis suppression, inhibition of enzymes, or chelation of trace elements responsible for free radical generation; (ii) scavenging ROS; and (iii) improvement of antioxidant defenses [
Genistein is a soy isoflavone that is probably the most interesting and well-studied flavonoid compound, due to its broad pharmacological activities.
Genistein has been extensively employed as antioxidant in a plethora of studies, showing the potential to scavenge ROS and RNS with a high degree of efficacy. This flavonoid compound is able to improve the antioxidant defenses of a cell, thus prevents apoptotic process through the modulation of several genes and proteins [
Briefly, flavonoids are a class of natural compounds extensively present in foods of vegetal origin (fruits, oils, seeds, etc.) showing a good potential in terms of usefulness for human health, as antioxidant molecules but also because of some ancillary yet pharmacologically interesting properties. Nonetheless, they need to be managed carefully, and their supplementation into the diet (as diet enrichment or as nutraceuticals) have to take in account also some potential drawback concerning human health and wellness.
Prooxidant agents, beside their well-known detrimental effects on human health, have been investigated and, in some cases, actually used, as therapeutic agents mainly against cancer diseases.
Here, we will briefly discuss two emerging prooxidant compounds showing interesting pharmacological activities, such as ascorbic acid (AA) and polyphenols, and the most well-known and employed prooxidant in therapy, ionizing radiation.
Ascorbic acid (vitamin C) is a water-soluble compound classified under the group of natural antioxidants. Ascorbate reacts with ROS, quenching them and promoting the conversion into semihydroascorbate radical, which is a poorly reactive chemical species, thus efficiently reducing the risk of cancer by suppressing free radicals and oxidative stress [
Apart from this, ascorbate also reduces metal ions like Fe3+ and Cu3+, thus promoting a reaction that gives rise to highly reactive free radical (by the so-called Fenton reaction) [
This effect seems to be more relevant on cancer cells, in fact while normal cells take advantage from redundant mechanisms for H2O2 clearing and/or repair of H2O2-induced damage, to counteract the effects of pro-oxidant concentrations of AA; cancer cells lacking of these compensatory mechanisms (e.g., catalase deficiency, mutated DNA repair, and tumor suppressor genes) are more susceptible to pharmacologic ascorbate concentrations [
Despite these somehow surprising but still very interesting results, there is the urge of conducting more researches, both in vitro and in vivo, to definitely assess the mode of action and efficacy of AA as prooxidative anticancer agent.
Under conditions like high concentrations, high pH, and the presence of redox-active metals, phenolic compounds can acquire a prooxidant behavior [
Polyphenols can as well induce oxidative stress via transition metals, promoting the generation of hydroxyl radicals through Fenton and Fenton-like reactions; it is important to note that transition metal ions are more represented into cancer than into normal cells [
Prooxidant polyphenols seem to exert their cytotoxic activity by inducing apoptosis and cell cycle arrest via several pathways. Anthocyanins, pigments present in red wine and berry (
Esculetin, a coumarin derivative present in plants such as chicory (
Curcumin, a compound extracted from
During the last years, a very large amount of in vitro studies investigated the prooxidative effects of polyphenols against cancer cell proliferation and survival, all of them presenting interesting results that nonetheless need to be confirmed by more in-depth researches [
Although polyphenols showed the pharmacological potential to inhibit tumorigenesis and arrest cancer cell proliferation in animal models, the role of ROS generation is still poorly understood, mainly because a large majority of the in vivo studies are limited to cancer growth arrest and apoptosis evaluation, and rarely or not at all they go deeper in the mechanistic explanation of a potential prooxidant action in vivo [
The ability of ionizing radiation to counteract proliferation of cancer cells is well explained [
Radiotherapy plays a key role in cancer treatment, so that almost 40% of cancer patients have been treated with this approach at least once [
Oxidative stress and free radicals are generally known to be detrimental to human health. A large amount of studies demonstrates that in fact free radicals contribute to initiation and progression of several pathologies, ranging from CVD to cancer.
Antioxidants, as class of compounds able to counteract oxidative stress and mitigate its effects on individuals’ health, gained enormous attention from the biomedical research community, because these compounds not only showed a good degree of efficacy in terms of disease prevention and/or treatment but also because of the general perception that they are free from important side effects. If it is true that antioxidants can be very useful in preventing, managing, or treating human pathologies, it is true as well that they are not immune to generating adverse effects. On the other hand, some prooxidant compounds or agents can be as well useful to human health, particularly regarding cancer treatment.
We can reach to the conclusion that oxidative stress, as phenomenon, although being one of the major harms to individuals’ wellness and health, it can also be exploited as a treatment tool when and if we will be able to operate a fine tuning of this process inside human organism.
The authors state no conflict of interest.
Gabriele Pizzino and Natasha Irrera equally contributed to this paper.
The authors are thankful to all members of the Squadrito laboratory for the technical support.