Advanced oxidation protein products (AOPPs) constitute a class of complex protein compounds composed of dimethyltyrosine, pentosidine, and carbonyl residues. AOPPs originate from oxidative stress reactions involving plasma proteins and chlorinated oxidants. The principal mechanism driving AOPPs generation involves the activated myeloperoxidase-H₂O₂-chloride system in neutrophils, with myeloperoxidase serving as the sole enzyme capable of generating chlorinated oxidants (Figure 2) (72, 73). Hypochlorous acid (HOCl) produced by this system is indicative of AOPPs production. In hemodialysis patients, elevated levels of AOPPs have exhibited a positive correlation with plasma myeloperoxidase activity (74) and oxidized fibrinogen was identified as a principal molecule contributing to the positive chemical reaction to AOPPs (75, 76). In 1996, the first detection of this biomarker of oxidative stress was proposed for plasma in patients with chronic uremia (77). Compared to healthy individuals, AOPPs levels in patients with advanced chronic kidney failure who had not yet undergone dialysis were nearly threefold higher.

As markers of oxygen-mediated protein damage, AOPPs have been identified as indicators of oxidative protein damage and proinflammatory mediators (78, 79). Elevated AOPPs levels have been associated with the advancement of various human diseases and their associated complications, thus serving as markers of oxidative stress across diverse pathologies. Monitoring AOPPs can help predict the development of diseases associated with oxidative stress. In addition to significantly elevated plasma AOPPs levels observed in patients with chronic uremia, similar findings have been demonstrated in other conditions such as cutaneous burns (80). In both groups of second and third degree thermal burns, AOPPs levels were reduced following treatment as a result of decreased levels of oxidative stress. Notably, ROS may contribute to oxidized protein damage within the stratum corneum, thereby disrupting barrier function and exacerbating AD (55). Currently, studies have shown that compared to healthy individuals, patients with AD and chronic urticaria exhibit elevated levels of AOPPs (52). Moreover, an association between AOPPs levels and age has been documented in patients with AD, underscoring the potential utility of AOPPs as biomarkers for disease severity and progression (52).

Advanced glycation end-products (AGEs) and AOPPs share structural similarities and exert comparable biological effects. Their accumulation in biological systems results in analogous clinical outcomes. In the context of protein oxidation, the relationship between AGEs and the generation of AOPPs is noteworthy (75). Both AOPPs and AGEs possess similar structures that induce comparable biological effects, and their accumulation in biological systems leads to similar clinical consequences. AGEs, a diverse group of biologically active compounds, were initially identified by French researchers. They are produced through a non-enzymatic glycation process called the Maillard reaction, which uses the carbonyl groups of reducing sugars and the free amino groups of proteins as substrates (Figure 2) (81). AGEs are categorized into endogenous and exogenous sources (82). Endogenous AGEs are generated during normal physiological processes and aging, while exogenous AGEs primarily originate from dietary sources, with their content varying across different foods.

AGEs are produced in a slow and controlled process, accumulating in the body, including the skin (83). The skin is particularly reactive to changes in AGE levels. Their accumulation increases free radical production, stimulates the release of pro-inflammatory factors, and exacerbates inflammatory reactions. AGEs disrupt the dynamic balance of the skin (84), alter the normal substance composition and structure of different skin layers, impair the skin barrier function, and trigger skin issues. The skin barrier function is essential in the onset and progression of AD. Research has documented that AGEs levels are elevated in the keratinocytes of AD patients compared to healthy individuals, with severe AD patients exhibiting significantly higher levels than those with mild AD. However, no significant difference in serum AGE levels was found between typical AD patients and healthy controls (53). Pentosidine, a specific AGE, is closely associated with oxidative stress, with accelerated production observed in oxidative stress-related diseases (85). Pentosidine can serve as a marker for detecting AD (54). Urine tests in AD patients have shown significantly higher levels of pentosidine compared to the healthy controls. Pentosidine levels were significantly higher in AD patients in the acute phase, but reduced during the recovery process, mirroring trends observed for another AD biomarker, 8-OHdG. The consumption of exogenous AGEs increases the risk of developing AD (86), with pregnant women consuming high-AGEs foods potentially exposing their fetus to a higher AGEs environment, thereby increasing the likelihood of AD development.

In addition to AOPPs and AGEs, protein carbonylation (PC) serves as another marker of protein oxidation in patients with AD. From a medical perspective, protein carbonylation has been emphasized as markers of protein oxidation, oxidative stress, and disease progression (52). The oxidative modification of proteins, characterized by the formation and/or introduction of carbonyl groups into proteins, represents a primary indicator of oxidative damage to proteins (87–89). PC, an irreversible oxidative modification (88), is classified into two types based on the origin of the carbonylated product (Figure 2). Consequently, changes in protein conformation following modification typically result in the loss of protein function (90). Proteins undergoing carbonylation exhibit diverse biological significance within biological systems, leading to varied biological effects (88, 91–93). PC is reflected in various diseases, including brain diseases, inflammatory diseases, autoimmune diseases, and aging (94–96), showing important connections between carbonyls in oxidized proteins, oxidative stress, and disease.

Oxidative stress plays an important role in the pathogenesis of AD, with studies demonstrating elevated levels of PC in dry skin and AD skin lesions (56). Levels of PC in the skin of AD patients are elevated and positively correlated with the severity of the disease (55). Sampling from AD patients utilizing the tape stripping method has revealed increased levels of PC in the stratum corneum, a phenomenon similarly observed in patients with psoriasis (97). The accumulation of PC in the skin contributes to transepidermal water loss and altered dermal matrix accumulation (98). ROS are implicated in inducing damage to cuticular oxidation proteins, disrupting skin barrier function, and exacerbating the development of AD.

Lipids are the most impacted biomolecules in oxidative stress-induced damage, and the identification of these end-products in inflammatory diseases suggest that lipid peroxidation is crucial in such diseases (99). Malondialdehyde (MDA), an important metabolite of arachidonic acid and unsaturated fatty acids possessing multiple unsaturated C-C double bonds in lipids, was the main and most widely studied compound (100) derived from lipid peroxidation following oxidative damage from oxygen radical attack (Figure 3) (101, 102). Upon exposure to oxidative stress, excessive accumulation of ROS disrupts the structure and function of the cell membrane, alters its permeability, and causes lipid peroxidation, inducing the production of MDA.

Malondialdehyde is produced in vivo through both enzymatic and non-enzymatic oxidation, making it a widely monitored biomarker for oxidative stress across various diseases and particularly favored for characterizing oxidative stress in AD patients (57). A likely correlation exists between serum antioxidant levels and MDA in individuals with eczema (58), with an inverse correlation between antioxidant levels and MDA levels and decreased serum levels of antioxidant vitamins in patients than in healthy persons. In children with AD, serum levels of MDA were found to be on average 0.055 units higher, while melatonin (a hormone with antioxidant activity) levels were approximately 3.05 units higher compared to controls. The increase in serum melatonin in AD might represent a compensatory mechanism to reduce skin inflammation by attempting to alleviate excessive oxidant production (59). For the antioxidant properties of quercetin, liposomes incorporating quercetin gel have demonstrated both protective and therapeutic effects on skin eczema (103). Treatment with quercetin-loaded liposomes resulted in significantly reduced skin pathological symptoms compared to untreated counterparts, accompanied by reduced levels of MDA in both liver and skin tissues.

4-hydroxy-2-nonenal (4-HNE) is a lipid peroxide produced by polyunsaturated fatty acids (PUFAs) in response to oxidative stress (Figure 3). It belongs to the same class of lipid peroxidation products as MDA. Both 4-HNE and MDA are extensively studied markers of lipid peroxidation, with MDA recognized as a mutagenic product of lipid peroxidation and 4-HNE recognized as the most toxic product of lipid oxidation (104), worsening the damage resulting from oxidative stress (105, 106). 4-HNE is classified as an α, β-unsaturated aldehyde and possesses three functional groups: carbon-carbon double bonds, carbonyl groups and hydroxyl groups. Due to the existence of the conjugated system of C = C bonds and carbonyl groups, 4-HNE can provide partial positive charge to the carbon at position three and become efficient electrophiles, allowing it to react with essential biological molecules, including proteins and DNA (107–109). 4-HNE can also be generated through both enzymatic and non-enzymatic reactions from the breakdown of ω-6 PUFAs. However, the chemical reaction mechanism of 4-HNE formation remains unclear. Several mechanisms have been proposed over the years. The earliest suggestion was that 4-HNE was formed from PUFAs catalyzed by transition metal ions (102, 110). The formation mechanism of 4-HNE is attributed to the observation of hydroperoxides as an intermediate product.

As a secondary messenger of free radicals and growth regulators, 4-HNE participates in various pathophysiological processes and act as a bioactive marker, especially in oxidative stress related to diseases (111). Skin homeostasis plays an important role in the development of AD. Studies have found that cigarette smoke can trigger the generation of ROS (112). Exposure to cigarette smoke can affect skin homeostasis due to oxidative and inflammatory reactions, as well as inducing lipid peroxidation, leading to increased levels of 4-HNE (113). In a study examining oxidative stress markers in exhaled breath condensates of children with AD, 4-HNE levels were elevated in AD patients but did not differ significantly from those in healthy children (60). Another study found a similar phenomenon by measuring serum 4-HNE levels in AD patients, with 4-HNE concentrations comparable to those in healthy subjects.

Nitric oxide (NO), a free radical gas containing unpaired electrons, is the smallest biologically active molecule produced by mammalian cells. It exhibits lipophilicity and possesses a high degree of diffusivity in tissues and cells (114). NO is primarily synthesized in organisms by nitric oxide synthase (NOS), an enzyme divided into three subtypes: inducible iNOS, endothelial eNOS, and neurogenic nNOS (115). Additionally, NO can be produced via non-canonical pathways, either through the reduction of nitrite to NO or by the sequential conversion of nitrate to nitrite and then to NO (116). With diverse biological functions, NO is essential for regulating the body in both healthy and disease states (117). In dermatology, NO is implicated in mechanisms underlying inflammatory or immune-mediated dermatoses, skin infections, skin cancers, and wound healing (118). Skin inflammation is significantly affected by NO (119). Keratinocytes, fibroblasts, and immune cells synthesize NO, and each contributing to the occurrence of inflammatory responses. The importance of NO as a mediator of skin inflammation is underscored by the delicate balance between its production and degradation, which is closely related to the onset and development of inflammatory skin diseases. Overproduction of NO has been linked to conditions such as AD and psoriasis (120–122).

Direct measurement of nitric oxide (NO) presents challenges due to its extremely short half-life in the bloodstream, typically disappearing within seconds, and its involvement in various biochemical reactions within living organisms (123, 124). NO is highly reactive owing to its unpaired electrons, capable of engaging in oxidative stress by reacting with free radicals, with the primary oxidative metabolites being nitrite and nitrate (125). A study found elevated levels of IgE, nitrite, and nitrate in the plasma of AD patients (61). Furthermore, a study involving 88 cases of AD and 12 cases of non-AD founded that serum nitrate levels not only showed a significant increase in children with AD, but also associated with the severity of the disease (62).

Thiols have emerged as a novel marker of oxidative stress, representing a class of organic compounds containing sulfhydryl groups. These sulfhydryl groups, commonly known as thiols, consist of sulfur and hydrogen atoms bonded to carbon atoms (126). The sulfhydryl groups within thiols provide protection against oxidative stress by scavenging ROS through enzymatic or non-enzymatic mechanisms. Thiols serve as physiological agents for neutralizing free radicals and other ROS (127). Through a series of reactions, thiols undergo modifications and react with oxidants to form disulfide bonds (128). The oxidation of thiols to disulfides is facilitated by through various processes, crucially involving three distinct mechanisms (129). Disulfide compounds formed as a result of these reactions can undergo reversible conversion to a thiol structure, thereby maintaining the dynamic balance of thiol/disulfide equilibrium (130).

Disruption of this balance has associated with the development of certain inflammatory diseases. In infants diagnosed with AD, thiols have been found to be significantly reduced compared to in comparison to healthy controls, while disulfide levels were markedly elevated, indicative of dysregulation in the thiol/disulfide balance favoring peroxidation (63). However, contrasting findings were observed in another study (64), which serum disulfide levels were observed to decrease in AD children in comparison to healthy children, leading to a reduction in the disulfide/natural thiol and disulfide/total thiol ratios.

Biopyrrin is a metabolite derived from the oxidation of bilirubin. Bilirubin, acting as a potent ROS scavenger, reacts with ROS, thereby exerting a robust antioxidant effect (131). Upon oxidation, bilirubin is converted into various forms of bilirubin oxidation metabolites (BOMs), comprising at least seven hydrophilic metabolites that are promptly excreted into urine because of their hydrophilic nature (132). These metabolites, including biopyrrin, can be detected by anti-bilirubin monoclonal antibody 24G7 (133, 134). A key advantage of using biopyrrin as an oxidative stress marker is its ability to provide real-time insights into the dynamic changes of oxidative stress through urine detection, thereby reflecting the oxidative stress status associated with various disease states.

Biopyrrin holds promise as a novel biomarker for AD (66). Urinary excretion of biopyrrin was markedly increased in pediatric patients experiencing acute exacerbations of AD, with levels averaging 1.8 times higher than those observed in healthy individuals (65). Bilirubin oxidation was enhanced in the diseased skin of patients with AD and levels of the oxidized metabolite biopyrrin detected in urine correlated with the severity of AD (24). Moreover, urinary biopyrrin levels were positively correlated with serum IgE and TARC/CCL17 expression. Biopyrrin expression was higher in AD lesions compared to normal skin, as detected by the 24G7 antibody. These findings highlight the potential utility of biopyrrin as a valuable biomarker for assessing oxidative stress and the severity of AD.

Plants typically contain several highly active antioxidant compounds that can be extracted using various technical methods (146). The antioxidant effects of plant extracts are related to the chemical and physical properties of these compounds and operate through multiple mechanisms (147–149). The therapeutic potential of natural extracts for treating AD has been thoroughly explored through both in vivo and in vitro studies. A study involving 20 patients with mild to moderate AD demonstrated that a cream containing 100,000 IU of superoxide dismutase (SOD) and 4% plant extracts significantly alleviated AD symptoms and was effective across all phases of the disease (150). The therapeutic efficacy of this cream is attributed to the synergistic actions of SOD and the plant extracts, including antioxidant, anti-inflammatory, and additional beneficial properties. Resveratrol, a naturally occurring polyphenol abundant in grapes and berries, has shown positive therapeutic effects on skin disorders (151), potentially affecting inflammation through its antioxidant activity and free radical scavenging properties (152). Intragastric administration of resveratrol has been shown to ameliorate AD in mice induced by dinitrochlorobenzene (DNCB), by downregulating chemokine and proinflammatory factor levels and upregulating the expression of skin barrier proteins (153). Another study also demonstrated that topical formulations based on the antioxidant properties of resveratrol can reduce ROS, inhibit inflammatory responses, and improve skin barrier function (154). Analysis of the chemical composition of Lentinula edodes ethanolic extract revealed that polyphenols are the main antioxidant components, along with flavonoids, β-carotene, and lycopene. This ethanolic extract has shown to decrease serum IgE levels, downregulate the expression of inflammatory cytokines, and alleviate AD symptoms (155). Additionally, some natural extracts can exert antioxidant and anti-inflammatory effects and regulate the Nrf2/HO-1/NQO1 and NF-κB/MAPK signaling pathways to treat AD (156, 157).

Vitamins are a group of organic compounds crucial for maintaining normal physiological functions in the body and can be categorized into fat-soluble and water-soluble groups (158). Most vitamins are obtained through the daily diet. The primary sources of vitamins A, C, and E are fresh vegetables and fruits, while vitamin D is primarily biosynthesized through the skin under sunlight. These four vitamins inherently possess antioxidant properties, allowing them to function as antioxidants (159, 160).

There is a significant connection between vitamins and skin diseases. Maintaining a reasonable and stable vitamin level is crucial for preserving normal skin health (161). β-carotene (provitamin A) exhibits antioxidant and immunomodulatory effects, enhancing skin barrier function and reducing inflammation levels in hairless mice with oxazolone-induced AD (162). Vitamin C contributes to the formation of skin structure and skin antioxidation (163), ameliorating chronic inflammation and positively impacting AD. In groups supplemented with vitamin E, levels of oxidative stress markers were decreased, and a reduction in vitamin E concentration contributed to the progressing of AD in dogs (164). Another study supports that vitamin E supplementation can lower IgE levels in AD patients and improve AD symptoms (165). Vitamin D supplementation is beneficial for AD treatment and can be used to treat AD in children and dogs (166, 167). Furthermore, these vitamins can work synergistically to enhance AD treatment. For instance, the dermatitis score was lower in the group receiving both vitamin D and vitamin E compared to groups receiving either vitamin alone (168). However, there are differing views on the efficacy of vitamins in improving AD. Diets rich in antioxidant compounds can reduce the risk of AD. Taking in β-carotene and vitamin E is negatively correlated with AD, whereas vitamin C intake does not show a consistent correlation (169). Additionally, higher concentrations of vitamin C in breast milk are linked to a lower risk of atopy in infants, whereas vitamin E shows no consistent relationship with AD (170).

Trace minerals, also known as trace elements, play an important role in maintaining overall nutrition and health (171), playing vital roles in the metabolism and physiological processes of the body. Several trace elements are involved in the redox reaction process. Selenium (Se) is an essential trace mineral that forms a key part of selenoproteins, which primarily exert their nutritional functions through a family of 25 selenoproteins. Se is an enzymatic antioxidant that has no antioxidant effect by itself but participates in selenoproteins as redox-active selenoenzymes to safeguard against oxidative damage (172, 173). Inhibiting iron death by regulating selenoprotein GPx4 plays a significant role in improving skin inflammation (174). Keratinocytes, which are integral to the skin barrier function, are also implicated in skin disorders such as AD. The supplementation of Se and selenoprotein SEPP1 can alleviate the oxidative stress and toxicity of 4-ClBQ-induced keratinocytes (175). Nevertheless, a 12 weeks study revealed that selenium-enriched yeast supplementation did not result in significant improvements in AD severity, indicating no substantial difference before and after supplementation (176).

Zinc, another essential nutrient for skin health, is abundantly present in the epidermis (177). Although zinc itself is not an antioxidant and is redox-inert, it contributes to oxidative defense through several mechanisms (178, 179). Decreased zinc levels have been observed in AD patients, taking zinc supplements orally may help those who are zinc deficient to manage AD (180). Zinc is commonly used as a nutritional supplement for cosmetic purposes and in the management of AD. However, caution is warranted regarding zinc concentration, as excessive intake can lead to zinc toxicity (181). The efficacy of zinc supplementation in treating AD remains controversial, with some studies suggesting no significant benefit, while others indicate potential therapeutic effects (182).

Among antioxidant nanomaterials, several types possess inherent antioxidant properties, most of which are metal nanoparticles. These nanomaterials can mimic the efficacy of antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx). The antioxidant enzyme activity of nanomaterials is influenced by factors including size, morphology, surface modification, and composition (185). Catalase-like nanoenzymes, a category of nanomaterials with intrinsic CAT activity, operate by decomposing H₂O₂ into H₂O and O₂ (186). Superoxide radicals (O_2∙^–), a type of ROS generated during metabolic processes, are converted into H₂O₂ and O₂ by SOD, using metal as a cofactor (187). GPx, the final antioxidant enzyme, catalyzes the reduction of H₂O₂ or organic hydrogen peroxide to H₂O or alcohol in the presence of reduced glutathione (188). Cerium oxide nanoparticles (189) exhibit SOD-like activity, and their PEGylation can enhance the survival rate of keratinocytes while significantly reducing intracellular ROS levels. Cobalt oxide nanoparticles, synthesized via a one-pot method, demonstrate three enzymatic catalytic activities. These nanoparticles can protect keratinocytes from hydrogen peroxide-induced ROS and toxicity, alleviating the symptoms of AD (190). Furthermore, hematoxylin and eosin and toluidine blue staining indicated a decrease in epidermal thickness and a reduction in the number of mast cells in the treated group.

Most antioxidants have low bioavailability due to their inherent properties (191, 192). However, nanotechnology can enhance the antioxidant effect by preparing nanoparticles as carriers for these antioxidants, allowing for targeted and controlled release (193). Currently, a variety of antioxidant delivery systems have been developed to transport natural and synthetic antioxidants, antioxidant gases, genes, and other antioxidant compounds, thereby significantly expanding the scope of antioxidant delivery nanomaterials (194). Nanoparticles prepared with the natural polyphenol antioxidant hydroxytyrosol, hydrocortisone, and chitosan have shown significant improvement in the pathological characteristics of AD in mice. Compared to the AD group, the treatment group exhibited decreased expression levels of IgE, histamine, PGE2, VEGF-α, and AD-related Th1 and Th2 cytokines. Histological examination also demonstrated that HC-HT-CS-NPs exerted a therapeutic effect on AD (195). Additionally, HC-HT-CS-NPs demonstrated favorable safety in healthy individuals (196).