Vitamins C and vitamin E are the most extensively studied antioxidants (Li et al., 2014). Vitamin C, also known as ascorbic acid, is a water-soluble substance found in various fruit and vegetables (Doseděl et al., 2021). The antioxidant effect of vitamin C is based on the reaction of reducing ROS, such as O₂•− and singlet oxygen containing HOO− or OH− by dehydrogenation to form dehydroascorbate and reduced ROS products, such as water, as described in Li et al. (2014).

Due to the fact that vitamin C is water-soluble, it is able to protect cells from external ROS molecules present in the bloodstream (Li et al., 2014). Some studies had shown the protective role of vitamin C in patients with hyperlipidemia and essential hypertension (Shidfar et al., 2003; Schneider et al., 2005). Beneficial effect of vitamin C is primarily associated with the antioxidant protection of blood vessels, i.e., it reduced the content of low-density lipoproteins (LDL) that cause chronic inflammation-associated atherosclerotic vascular damage, the underlying cause of CVDs (Shidfar et al., 2003). More recent data obtained from both preclinical and clinical studies also showed that vitamin C plays an important role in several of processes involved in the pathogenesis of CVD (Morelli et al., 2020). Vitamin C can improve endothelial function, reduce NAD(P)H oxidase activity and superoxide production, and increase eNOS activity and production of nitric oxide (Morelli et al., 2020). In particular, endothelial dysfunction, characterized by reduced nitric oxide bioactivity, is an early sign of type 2 diabetes mellitus and is involved in the pathophysiology of atherosclerosis. A systematic review summarized clinical studies that reported the effects of vitamin C intake on CVD-related outcomes in people with metabolic syndrome and type 2 diabetes (Dludla et al., 2022) Some studies reporting positive effects are presented in Table 1.

Apart ROS scavenging capacity, vitamin C has a more remarkable effect on inflammatory signaling in cells, where it can clearly reduce the expression of pro-inflammatory mediators, hence inhibiting the inflammatory response (Tan et al., 2005). The major known pro-inflammatory signaling pathway influenced by vitamin C is the nuclear factor κB/tumor necrosis factor alpha (NFκB/TNFα) pathway. Remarkably, three staple targets (phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, signal transducer and activator of transcription-3 (STAT3), and prothrombin) of vitamin C with therapeutic potential for CVD have been identified (Zhu et al., 2021). This study showed that the protective effects of vitamin C on CVD were attributed to its anti-inflammatory property with the most relevant molecular pathways, such as the JAK/signal transduction and transcription activation, programmed cell death protein 1, the epidermal growth factor receptor, the Forkhead box O, and chemokines signaling pathways. In addition, the administration of vitamin C to patients with congestive heart failure (CHF) suppressed apoptosis in endothelial cells (Rössig et al., 2001; Aimo et al., 2020). Noteworthy, both systemic inflammation and increased oxidative stress are implicated in the pathogenesis of CHF.

Vitamin E, also known as tocopherol, is a fat-soluble compound contained in vegetable fats, the high contents of which were found in nuts and seeds (Rizvi et al., 2014). Unlike vitamin C, which primarily provides extracellular protection, vitamin E, contained in lipid membranes, which are the most common targets of ROS, inhibits lipid peroxidation (Rizvi et al., 2014). In addition, vitamin E prevents the oxidation of nucleic acids, directly removes O₂•− and increases the activity of SOD, thus acting as an enhancer of the cellular antioxidant defense (Surai and Fisinin, 2015). Vitamin E was found to act as a scavenger of the peroxyl radical with the rate of reaction and scavenging much higher than the rate of peroxidation of lipid molecules by this radical (Khadangi and Azzi, 2019; Niki, 2021). The effects of vitamin E had been studied for potential treatment of CVDs, oncological diseases, as well as neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, reviewed in Li et al. (2014), Rizwana et al. (2022). In particular, the role of dietary vitamin E (α-tocopherol) as an antioxidant and bioactive molecule in supporting vascular health has been explored (Garg and Lee, 2022). Nevertheless, the protective function of vitamin E against CVD, for example, is not solely due to its ability to scavenge free radicals. A foremost part of its anti-inflammatory role occurs via the inhibition of NFκB (Rashidi et al., 2017) and reduction of the activity of protein kinase C involved in the endothelial cell adhesion molecule signaling (Cook-Mills, 2013). In this way, vitamin E can suppress atherogenesis and atherosclerosis development, the most common disease associated with oxidative stress and chronic inflammation. Moreover, the suppressive effect of vitamin E to tumors has been long-established. Early study using high performance liquid chromatographic analysis reported that the content of vitamin E in women with breast cancer is significantly lower than that in the cancer-free group, suggesting that vitamin E can reduce the risk of breast cancer (Sundaram et al., 1981). More recent study also found that alpha-tocopheryl succinate, the most efficient form of vitamin E, has tremendous anti-cancer potential (Wu et al., 2020). This study indicated that nanoparticle-delivered vitamin E in combination with interferon gamma (IFN-γ) represents a valuable strategy for cancer treatment. Combined application of nanoparticle-delivered vitamin E with IFN-γ significantly increased the anticancer effect in terms of apoptosis initiation and migration inhibition, as well as upregulated the anticancer immunity through the expression of downregulating program death ligand 1 (PD-L1). Besides, this combination therapy modulated the cytotoxic lymphocyte infiltration into the tumor microenvironment for its elimination. A review summarized a significant number of studies demonstrating the effects of vitamin E related to the suppression or overexpression of main tumorigenic pathways, mostly associated with breast cancer progression, proliferation, metastasis, tumor energy metabolism, and its effects in combination with chemotherapy drugs (de Oliveira et al., 2021). Nevertheless, conflicting results have been observed in randomized clinical trials evaluating vitamin E isoforms in human cancer treatment and pathophysiological processes associated with anticancer drugs (Donnelly et al., 2022). These results do not allow to make a meaningful conclusion on the beneficial role of vitamin E in cancer therapy.

A recent review summarized the scientific evidence published between 2000 and 2023 on the effects of vitamin E supplementation on neuroprotection and neurodegeneration markers in animal models of neurodegenerative diseases (da Cunha Germano et al., 2023). The studies considered in this review provided evidence that vitamin E supplementation can reduce oxidative stress (lipid peroxidation) and inflammatory process in the brain in murine models of neurodegenerative diseases. Increased brain oxidative stress, which chiefly manifests as lipid peroxidation, is a crucial feature of the Alzheimer’s disease. The pathogenesis of Alzheimer’s disease is also associated with soluble beta-amyloid (Aβ) oligomers (Bright et al., 2015) and neuroinflammation (Onyango et al., 2021). In Parkinson`s disease, oxidative stress and systemic inflammation also stimulate the development of neuronal dysfunction caused by specific elements, Aβ, α-synuclein, tau or prion (Forloni et al., 2021; Chakrabarti and Bisaglia, 2023). Table 2 presents some studies on the positive effects of vitamin E supplementation in animal models of Alzheimer’s and Parkinson’s diseases.

The protective action of vitamin E on Alzheimer’s disease and Parkinson’s disease has been also studied in humans (Schirinzi et al., 2019; de Leeuw et al., 2020). The studies showed that vitamin E may be a potential, beneficial agent for patients with these diseases. Further, dietary intervention clinical trials are required to verify effects of vitamin E.

Vitamin C and E in combination have a synergistic antioxidant effect, which was manifested as an increase in the expression of antioxidant enzymes, such as CAT, SOD, and GPx (Soylu et al., 2006). The simultaneous use of vitamin C can support the effect of vitamin E in the treatment of cardiovascular (Jha et al., 1995; Ashor et al., 2014) and neurodegenerative diseases (Martin et al., 2002; Sindhu et al., 2022). As for the latter, the combined use of vitamins C and E targeting oxidative stress and mitochondrial dysfunction can be a useful strategy for the treatment of neurodegenerative diseases (Dumont et al., 2010; Wu et al., 2019). In particular, Nrf2/antioxidant response element (ARE) pathway is a promising antioxidant target to counteract mitochondrial dysfunction (Hegazy et al., 2019). Mitochondrial dysfunction is a prominent feature in the pathogenesis of neurodegenerative diseases. A meta-analysis revealed that combined supplementation with vitamins A and E resulted in a small but significant reduction in arterial stiffness (Ashor et al., 2014). An increased arterial stiffness correlates with CVD events (Sharif et al., 2019). The beneficial effects of these vitamins on vascular stiffness may be explained by the reduction of the detrimental effects of ROS on structural and functional components of the vascular walls (Plantinga et al., 2007). Antioxidant vitamins C and E neutralize ROS, diminish inflammation, and thus improve arterial elasticity and protect the integrity of the vessel wall (Kals et al., 2006). Furthermore, vitamin C can play a role in the prevention of endothelial dysfunction, an early sign of atherosclerosis and future cardiovascular events, since it is capable of preventing leucocytes adhesion to endothelial cells triggered by both oxidized LDL and cigarette smoke (Carr and Maggini, 2017). This effect of ascorbic acid is associated with the recovery of α-tocopherol (Doseděl et al., 2021). Oxidative modification of the protein portion of LDL can be caused by oxidative stress through ROS produced, for example, by leukocytes. In this case, the first line of antioxidant defense is α-tocopherol, which is the utmost antioxidant in LDL. However, the generated α-tocopherol radical can act as a prooxidant if not removed. Here, ascorbic acid appears to be of fundamental importance because it can reduce α-tocopherol to form the free radical ascorbate (ascorbyl), also known as monodehydroascorbate or hemidehydroascorbate (Carr and Maggini, 2017). The resulting ascorbate (ascorbyl) radical is relatively stable and can be detected in biological fluids in a concentration of 10 nM (Padayatty et al., 2003). The main reaction of this radical is the formation of dehydroascorbic acid. Also, it can be converted to ascorbic acid by NADH-dependent or NADPH-dependent enzymes, such as thioredoxin reductase and cytochrome b5 reductase. There are molecular mechanisms by which vitamins C and E improve endothelial function (Ungvari et al., 2010), including the reversal of NF-κB-driven systemic chronic inflammation, which can accelerate aging through the ROS-mediated aggravation of telomere dysfunction and cell senescence (Jurk et al., 2014). Oxidative stress initiates the activity of redox-sensitive transcription factors, such as the activator protein (AP-1) and NF-κB, which enhances the expression of cytokines, adhesion molecules, and pro-inflammatory enzymes (El Assar De La Fuente et al., 2012). These factors promote the pro-inflammatory microenvironment and support the development of vascular dysfunction (Pashkow, 2011). Besides, both antioxidant vitamins C and E increase the bioavailability of nitric oxide, a vasodilator and anti-inflammatory substance (Correia and Haynes, 2007). However, a systematic review and meta-analysis of randomized controlled trials examining the effects of vitamins C and E supplements on endothelial function have yielded conflicting results (co-administration of these vitamins was ineffective) (Ashor et al., 2015).

The second group of known natural antioxidants includes carotenoids, including β-carotene, lycopene, and astaxanthin (Li et al., 2014). The direct interaction of carotenoids with ROS can be divided into three types of reactions: (i) electron transfer from the carotenoid molecule to ROS, (ii) dehydrogenation of the carotenoid, and (iii) ROS binding to the carotenoid molecule through the addition reaction (Li et al., 2014). Astaxanthin is also able to increase the activity of antioxidant enzymes SOD and GPx (Wu et al., 2014). The positive effects of β-carotene were reported in murine models of diabetic retinopathy, a low-grade chronic inflammatory disease (Kern, 2007; Kowluru et al., 2014). Lycopene and astaxanthin were investigated in pre-clinical settings for the treatment of neurodegenerative diseases (Liu et al., 2013; Ye et al., 2013; Min and Min, 2014). Other animal studies on the effects and molecular mechanisms of carotenoids in chronic inflammatory diseases are presented in Table 3.

There have been a great deal of human research on the role of carotenoids in chronic diseases. An evidence-based review focused on human clinical trials summarized and discussed astaxanthin favorable effects in Alzheimer, Parkinson, CVDs and cancer (Donoso et al., 2021). There are numerous human studies on the anti-cancer activity of lycopene, summarized in Kapała et al. (2022). Remarkably, lycopene benefit was verified by most of the studies. This review also provided the evidence obtained from multiple in vivo studies on molecular mechanisms involved in lycopene anti-tumor activity, including inhibition of angiogenesis via reduction of in vascular endothelial growth factor (VEGF) activity, reduction of oxidative DNA damage, enhancing cytotoxicity and cell apoptosis. In addition, a recent meta-analysis of randomized controlled trials arrived at the conclusion that β-Carotene supplementation has no beneficial or harmful effect on cancer incidence; however, it might have potentially damaging effects on lung cancer, especially in smokers (Zhang et al., 2023).

Polyphenols are another group of natural antioxidants (Singla et al., 2019). The antioxidant properties of its well-established representative, curcumin, a natural polyphenol component derived from Curcuma longa, were recently reviewed (Rizwana et al., 2022). The most common group of plant polyphenols includes flavonoids, flavones, isoflavones, anthocyanins, and xanthonoids (Li et al., 2014; Aziz et al., 2019). The main mechanism of action of flavonoids, for example, is based on the reduction of ROS and lipid radicals by dehydration (Shen et al., 2022). Flavonoids are also able to activate the expression of antioxidant enzymes such as SOD and GPx (Aziz et al., 2019). Several examples of antioxidant and anti-inflammatory effects of other natural plant-derived polyphenols are presented in Table 4.

The distinctive antioxidant mechanism of polyphenols action is the inhibition of enzymes responsible for the synthesis of ROS. Thus, it was shown that polyphenols could inhibit the expression of the NADPH oxidase subunits p22phox and p67phox, therefore acting as an inhibitors of ROS generation at the onset of the inflammatory reaction (Aziz et al., 2019). Polyphenols exhibited favorable an antioxidant effect in chronic inflammation-related diseases, such as alcoholic fatty liver disease, atherosclerosis, coronary heart disease, Alzheimer’s disease, and type 2 diabetes (Li et al., 2014).

Natural antioxidants have other biological functions unrelated to their antioxidant activity. For instance, vitamin C is primarily acts as a cofactor of an enzyme involved in the reaction of collagen formation (Institute of Medicine Committee on International Nutrition--Vitamin C in Food Aid Commodities, 1997). Vitamin E, in addition to suppressing oxidative stress, inhibits platelet aggregation and enhances both humoral and cellular immunity in infectious diseases (Rizvi et al., 2014).

Overall, natural oxidants hold robust potential for the prevention and therapy of diseases with an inflammatory, redox, or malignant component.

New synthetic compounds with increased antioxidant properties have been developed in recent years (Salehi et al., 2018; Parcheta et al., 2021). Some of the synthetic antioxidants have been tested in different phases of clinical trials, the results of which have been discussed (Barteková et al., 2021). The results of these studies may justify a competitive advantage of new antioxidants over already approved drugs and dietary supplements. However, further safety check should be carried out carefully because of the possibility of some antioxidants at certain concentrations to cause the effect opposite to their main activity, i.e., the oxidative stress (Sotler et al., 2019).

Expanding understanding of the role of mitochondria in physiological and pathological conditions is paralleled by expanding research into compounds that can mimic SOD, the endogenous antioxidant defense of mitochondria necessary for the existence of almost all eukaryotes. It is worth mentioning that the use of SOD as a therapeutic agent has significant disadvantages, as follows: (i) the large size of the molecule, which prevents penetration into the cell, (ii) a short half-life in the bloodstream, (iii) the increased immunogenicity and high costs for protein production (Bonetta, 2018). Mimetics of SOD are a class of antioxidants, which resemble the activity of this enzyme by initiating the reaction of converting the superoxide anion into H₂O₂ (i.e., the dismutation reaction), the sequential reduction/oxidation of metal ions (Barteková et al., 2021). In the structure of almost every SOD mimetic, there is an active center containing a metal atom that directly participates in the reaction (Zhao et al., 2021). There are several classes of compounds used as SOD mimetics: cyclic manganese polyamines, metallic porphyrins, salen-manganese complexes, fullerenes, nitroxides, and metal nanoparticles (Li et al., 2020; Forman and Zhang, 2021). In particular, Mn-based SOD mimics such as the Mn(III) porphyrins (MnPs) have been vigorously studied (Batinic-Haberle et al., 2018). The most potent MnPs can oxidize and reduce O₂•− with close to identical rate constants of SOD (>10⁷ M⁻¹·s⁻¹) (Batinic-Haberle et al., 2015). Remarkably, SOD-like MnPs exhibit both anti- and pro-oxidative activities in vivo, which may lead to either anti- or pro-oxidative (in cancer cells) therapeutic outcomes. MnPs counteract oxidative stress under physiological conditions, supporting normal tissue survival, and promote apoptotic processes in tumors and normal tissues under conditions of increased oxidative stress (Batinic-Haberle et al., 2018). MnPs can only be considered as antioxidant protection in combination with H₂O₂ removal systems. A growing body of evidence indicates that such systems fail in cancer cells. Reports suggest a decrease or inactivation of GPx and Prx enzymes with a concomitant increase in SOD levels during cancer progression (Celic et al., 2014; Tovmasyan et al., 2014). In turn, H₂O₂ is accumulated and utilized by a tumor cell for its proliferation; under such conditions, MnPs increase oxidative stress and can no longer be considered as an antioxidative defense (Batinic-Haberle et al., 2014). It was demonstrated that H₂O₂ is generated through cycling of MnP with ascorbate (Tovmasyan et al., 2016; Batinic-Haberle et al., 2021), which can be further metabolized to the hydroxyl radical (˙OH) via the Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + ˙OH + OH⁻), the second part of the Haber-Weiss mechanism (Kremer, 2019) (Figure 4). In this way, MnPs can accelerate the rate of ascorbate radical oxidation, enhancing H₂O₂ flux and causing ascorbate-induced cytotoxicity. This redox cycling is the foundation of the therapeutic potential of the combination of MnPs/ascorbate for the treatment of cancers. Of note, MnPs can react in vivo with other redox active species, including glutathione, cysteines, H₂O₂, ONOO⁻, ^•NO, tetrahydrobiopterin, hypochlorite (ClO⁻), and sulfite (SO₃ ²⁻), as well as act as catalytic (redox-cycling) agents by catalyzing protein S-glutathionylation (Batinic-Haberle and Tome, 2019). Therefore, MnPs have the potential to universally modulate redox regulatory signaling networks in cells.

MnPs oxidize O₂•− in step one (I) and reduce it in step two (II); both reactions undergo with rate constants (k_cat) identical to that of SOD enzymes. Dismutation of O₂•− by MnPs involves MnIII/MnII redox couple. The dismutation reaction demonstrated here conveys the important information that SOD mimics MnP exhibit pro- and anti-oxidative actions during the dismutation of the O₂•−. MnPs catalyze ascorbate oxidation, producing H₂O₂. In the presence of abundant peroxide removal systems, this activity will result in an antioxidant effect. However, if peroxide-removing enzymes are scarce, the H₂O₂ levels may rise and initiate cellular transcription, which would sequentially perpetuate oxidative stress. In these conditions, the ability of MnPs to catalyze ascorbate oxidation would promote oxidative stress. The metal site of MnP redox cycles between Mn + 3 and +2 oxidation steps simultaneously transferring an electron to ascorbate and forming ascorbyl radical, A⁻. The reoxidation of MnIIP to MnIIIP may take place with O₂ or O₂•−, and H₂O₂ would be ultimately generated. The resulting H₂O₂ may generate the hydroxide ion HO⁻ via the Fenton reaction in the presence of Fe²⁺. Production of H₂O₂ depends on the MnIII/MnII reduction potential and is needed to increase tumor cell death. MnP potency in catalyzing ascorbate oxidation is in a direct relationship with MnP/ascorbate-induced cytotoxicity. Notably, anti- or pro-oxidative in vivo effects of MnPs will depend upon the following conditions: (i) the cellular ROS levels, (ii) endogenous antioxidants, (iii) oxygen availability, superoxide/peroxide-removing enzymes ratio, and (iv) MnPs redox potential, their localization in a cell, and bioavailability.

A review summarized the evidence indicating that SOD mimetics have a significant efficacy in several animal models that mimic oxidative stress injuries (Bonetta, 2018). Several compounds have been synthesized and investigated for their O₂•− dismutation activity and some of them, such as Mn(III) meso-tetrakis (N- methylpyridinium-2-yl)porphyrin (MnTM2-pYp5⁺) and Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-pYp5⁺), demonstrated a powerful SOD activity (Batinic-Haberle et al., 2015). Both protective and therapeutic effects of MnTE-2-pYp5⁺ and also Mn(III) meso-tetrakis (di-N-ethylimidazole) porphyrin (MnTDE-2-ImP5⁺) have been shown in animal models of inflammation-associated conditions such as breast tumor (Rabbani et al., 2009) and cardiovascular system damage (Ganesh et al., 2016). Moreover, MnTE-2-PyP5⁺ was found to amend oxidative stress-induced inflammation and enhance insulin sensitivity and glucose tolerance in a high-fat diet-induced mouse model of type 2 diabetes (Coudriet et al., 2017). These effects were attributed to ROS scavenging capacity of MnTE-2-PyP5⁺, resulting in a decrease in the pro-inflammatory cytokine secretion, by inhibiting of the action of NF-κB. The increased oxidative stress and inflammation play a chief role in the etiology of insulin resistance and type 2 diabetes (Henriksen et al., 2011). Figure 5A shows chemical structures of mentioned above MnP compounds.

One of the best-known representatives of SOD mimetics is the drug 4-Hydroxy-TEMPO (TEMPOL), which had shown effectiveness in a number of preclinical and clinical studies of the treatment of autoimmune, cardiovascular diseases, and oncological diseases (Bonetta, 2018; Barteková et al., 2021). TEMPOL belongs to the class of nitroxides and, unlike most SOD mimetics, the active component of the reaction is not a metal ion, but an oxoammonium cation (Bonetta, 2018). Additionally, TEMPOL can be used in the treatment of pain conditions; the ability of TEMPOL to suppress thermal and mechanical hyperalgesia has been demonstrated (Kim et al., 2016).

The elimination of ROS in the mitochondria themselves and thereby preventing the oxidative damage of cells at the earliest stages is also a strategy of the antioxidant therapy. A study demonstrated that the drug OP2113 can reduce the production of O₂•− in the mitochondrial complex I of electron transport chain without having a negative effect on the ATP production (Detaille et al., 2019). Moreover, one approach that selectively block mitochondrial oxidative damage and prevent some types of cell death in order to develop mitochondria-targeted antioxidants was investigated (Murphy, 2008). In this respect, it was demonstrated that targeting bioactive molecules to mitochondria by conjugating them to lipophilic cations is a useful method (Murphy, 2008). The drug mitoTEMPO, which is a nitroxide of piperidine Tempo (a derivative of TEMPOL, mentioned above) with an attached lipophilic triphenylphosphonium cation is one characteristic example of mitochondria-targeting synthetic antioxidant compounds (Trnka et al., 2008). MitoTEMPO showed a greater effectiveness in the treatment of hepatotoxicity in a mouse model compared to TEMPO (Du et al., 2017). Also, it was shown that mitoTEMPO reduced the state of cardiomyopathy in mice with type 1 and type 2 diabetes (Ni et al., 2016). Diabetic cardiomyopathy is linked to chronic inflammation (Jia et al., 2018). Figure 5B shows chemical structures of the reported SOD mimic drugs.

In addition, the control of the mitochondrial oxidative stress, in particular, modulation of mitochondrial glutathione levels can have an impact on the disease progression, and therapies aimed at increasing mitochondrial glutathione levels have great potential for the treatment of numerous inflammatory diseases (Marí et al., 2009). A more recent study describes the use of the S-D-lactoylglutathione to supply mitochondria with mitochondrial glutathione, including the parent molecules that generate mitochondrial glutathione while located within the mitochondrial matrix (Armeni et al., 2014).

Another candidate for potential antioxidant therapeutic agents is nanoparticles with improved pharmacokinetics and high biological activity. Based on their different mechanisms of action, ROS-scavenging nanoparticles can be divided into the following categories: 1) nanozymes, 2) free-radical trapper nanoparticles, and redox ROS-scavenging nanoparticles. Several representatives of these nanoparticles are presented in Table 5.

Nanoparticles that had shown their effectiveness in the treatment of ROS-associated inflammatory diseases in preclinical studies include fullerenes, metal oxide nanoparticles (cerium, manganese, vanadium), and metal nanoparticles (platinum, vanadium, zirconium, molybdenum, manganese) (Li et al., 2020). Moreover, recent advances in ROS scavenging-based nanotherapeutics research and the mechanisms underlying the applied nanomaterial s have been thoroughly reviewed (Huang et al., 2021). In addition, adeno-associated virus mediated SOD gene therapy can be used to alleviate oxidative stress and improve mitochondrial dysfunction, the key features of inflammatory conditions (Jiang et al., 2016). This can be especially effective in the treatment of chronic diseases, characterized by low-grade oxidative stress and inflammation, where long-term treatment is required.

According to review data, a promising class of compounds are salen-manganese complexes, which mimic both SOD and CAT activities with broad pharmacological efficacy (Doctrow et al., 1997). Preclinical studies showed that salen-manganese complexes are effective in oxidative-stress-related conditions (Jung et al., 2001; McDonald et al., 2003; Rouco et al., 2020). In particular, Mn-3-methoxy N, N′-bis (salicylidene) ethylenediamine chloride (EUK-34) is a cell permeable mimetic of SOD and CAT enzymes capable to counteract redox stress (Himori et al., 2017). At present, EUK-134 is a component of many anti-ageing skincare products due to its antioxidant properties. Moreover, mitochondrial targeted antioxidant such as Mn(salen) chloride (EUK-8), another SOD and CAT mimetic, exhibited a strong potential to become a multi-target inhibitory molecule capable of mitigating inflammatory processes and thus to be a greater choice for the development of a powerful anti-inflammatory drug. In an in vivo experiment, EUK-8 significantly reduced the phosphorylation level of several inflammatory proteins such as p38 member of MAPK pathway, protein kinase B (Akt), and transcription factor p65, and inhibited pro-inflammatory cytokine interleukin-6 and chemokine CXCL1 (Jayachandra et al., 2023). A recent study reported a synthesis of new glycosalen-Mn(III) complexes of EUK-108 with glucose and galactose (Lanza and Vecchio, 2023). These complexes showed both SOD- and CAT-like activities and could be advantageous for future clinical applications. Notably, both antioxidant and prooxidant properties of EUK-8 have been determined (van Empel et al., 2006; Amaral and Espósito, 2008). Figure 6 shows chemical structures of EUK-34 and EUK-8 with glycoconjugates.

There are compounds that mimic the activity of selenocysteine-containing GPx enzyme. In particular, diselenides are capable GPx mimics (Arai et al., 2021). Several organoselenium compounds such as ebselen and diselenides, which can mimic GPx activity hold a potential in drug development (Figure 7) (Nogueira et al., 2021). Various GPx mimics encompassing diverse selenium functionality have been reviewed, with the aminoselenide ebselen reaching phase 3 clinical trials for a number of diseases associated with oxidative stress (Barbosa et al., 2017; Sands et al., 2018).

In addition, the antioxidant properties of other compounds such as melatonin and lactic acid that can be utilized for the treatment of neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease) have been described in the review of Rizwana et al. (2022). Their review summarized the evidence indicating that melatonin can reduce the harmful effects of ROS by reducing the activity of NOS and stimulating antioxidant enzymes, such as SOD, GPx, and glutathione reductase, and lactic acid has prominent free radical scavenging effect.

The inhibition of NADPH oxidase, a ROS-producing enzyme, is an alternative approach to the antioxidant therapy. The inhibition of NADPH oxidase can be achieved through inhibition of catalytic activity and disruption of the assembly of NADPH oxidase complex consisting of several protein subunits (Forman and Zhang, 2021). To date, a number of synthetic compounds with high inhibitory activity against NADPH oxidase and therapeutic efficacy in the treatment of inflammatory diseases in animal models have been described (Altenhöfer et al., 2015). In particular, an individual NOX inhibitor VAS2870 has had a positive effect on experimental disease models associated with chronic inflammation such as stroke (Kleinschnitz et al., 2010) and Alzheimer’s disease (Abubaker et al., 2019).

The Nrf2 pathway is the main signaling pathway regulating the synthesis of antioxidant enzymes, which plays pivotal roles in inflammation (Ahmed et al., 2017). Therefore, the activation of the Nrf2 pathway is the most comprehensive and reliable measure of antioxidant and anti-inflammatory protection in comparison with other therapeutic strategies described above. According the mechanism of action, Nrf2 activators can be divided into the following categories: (i) activators of the transcription/translation of Nrf2, (ii) inhibitors of the Keap1 protein that binds and degrades Nrf2, (iii) inhibitors of other Nrf2 suppressors, such as glycogen synthase kinase-3 beta (in the cytoplasm) and (iv) Bach1 (in the nucleus), and (Forman and Zhang, 2021). To date, the most successful Nrf2 activator is fumaric acid ester dimethyl fumarate (DMF), which was approved in 2013 by the United States Food and Drug Administration (FDA) and the European Medicines Agency as a first-line therapy for adult patients with relapsing-remitting multiple sclerosis (immune-mediated inflammatory disorder) (Xu et al., 2015). A randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing–remitting multiple sclerosis from 198 sites in 28 countries was previously conducted (Gold et al., 2012). These data are also consistent with results from preclinical studies, in which DMF has been demonstrated to have favorable effects in animal models via direct neuroprotective and immunomodulatory mechanisms (Ghoreschi et al., 2011; Linker et al., 2011). The summary of fumaric acid esters, which were either approved for human use or tested in human or animal trials, was presented in the review of Kourakis et al. (2020). The main risk of therapeutic use of Nrf2 activators is associated with their possible impact on other signaling pathways and disruption of related biological functions. For example, sulforaphane exposure caused cell cycle arrest as a result of inhibition of the PI3K/Akt and MAPK/extracellular signal-regulated kinase (Erk) signaling pathways (Roy et al., 2010). Nevertheless, there have been significant advances in drug development to overcome systemic side effects of Nrf2 activators (Satoh and Lipton, 2017).