Preventive and Therapeutic Benefits of Natural Ingredients in Photo-Induced Epidermal Dysfunction

In our daily life, our skin inevitably exposes to sunlight, which mainly consists of three wavelengths, i.e., UVA (315–400 nm), UVB (280–315 nm), and UVC (100–280 nm). All UVC and 90% of UVB are absorbed by ozone, water vapour, oxygen, and carbon dioxide when sunlight passes through the atmosphere. But UVA is not significantly absorbed by the atmosphere [1]. The depth of UVB penetration into the skin is about 20–40 μm (within the epidermis) on the dorsal forearm [2, 3] although small portion of UVB can penetration into the dermis. Thus, the epidermis is the major victim of UVB irradiation. Acute UVB exposure induces erythema, DNA damage, disruption of epidermal permeability barrier and activation of cortisol [4‒8]. Chronic UVB irradiation causes hyperpigmentation, epidermal hyperproliferation, basal, and squamous cell carcinomas [9‒11]. Moreover, UVB irradiation increases in cytokine release in the skin [12‒15] although one study showed reductions in serum IL-10 and TNF-α levels in mice after 2-day UVB irradiation [16]. UVB irradiation also increases infiltrates of neutrophils in the dermis [15, 17], which can migrate to extracutaneous tissues such as the kidney, lung, and spleen, resulting in extracutaneous inflammation [17]. UVB irradiation-induced increase in epidermal IL-8 likely contributes to neutrophil infiltration in the dermis [15]. Collectively, UVB irradiation can alter multiple epidermal functions, which can possibly change immune function in extracutaneous tissues.

Because of the negative effects of UVB irradiation on epidermal functions, it is of great importance to prevent and/or attenuate UVB irradiation-induced alterations in epidermal functions. Topical application of sunscreen is a common approach to prevent ultraviolet (UV) irradiation-induced skin damages. The functional ingredients in sunscreens include organic and inorganic compounds, which both absorb UVA and UVB [18]. However, applications of sunscreens that completely absorb UVB can potentially cause deficiency in active vitamin D (1,25 dihydroxy vitamin D) [19], a molecule required for bone formation, keratinocyte differentiation, immune and neurological functions [20‒23]. Moreover, sunscreen cannot be used to treat the UVB-induced abnormalities in epidermal functions although it exerts preventive effect. An alternative approach to attenuate the harmful effects of UVB is via improvements in epidermal functions, including epidermal permeability barrier, stratum corneum hydration, antioxidative stress, and inhibition of cutaneous inflammation. A bulk of evidence indicates the benefits of natural ingredients in attenuation of UVB irradiation-induced alterations in epidermal functions. Here, we performed a literature search on PubMed and Google Scholar, using the terms “natural ingredients,” “herb,” “sun exposure,” “UV,” “skin,” and “epidermis,” and briefly review the benefits of some natural ingredients in UV radiation-induced alterations in epidermal functions and the possible underlying mechanisms (Tables 1, 2) [24‒69].

Epidermal permeability barrier primarily resides in the stratum corneum, the outermost layer of the skin, which is vulnerable to a variety of external insults, including UVB irradiation. Solar-simulated UV irradiation at a dose of 0.75–3 minimal erythema dose induces dose-dependent increases in transepidermal water loss rates (TEWL), an indicator of epidermal permeability barrier function, in mice [70]. Single UVB irradiation-induced elevation in TEWL can remain up to 5 days after irradiation [7]. Notably, sun exposure-induced permeability barrier dysfunction is more severe in males than in females [71]. Because of the regulatory role of epidermal permeability barrier in multiple cutaneous functions, prevention and treatment of UVB-induced epidermal permeability barrier abnormality can benefit the skin and possibly overall health condition of the humans. Studies have demonstrated that either topical or oral administration of natural ingredients can attenuate UVB-induced alteration in epidermal permeability barrier function.

In murine model, repeated UVB irradiation for 4 weeks increases TEWL by over 1-fold. Following each UVB irradiation, topical application of perilla oil significantly decreases TEWL [25]. Similarly, following each UVB irradiation topical application of Ginseng extract decreases TEWL by 50% in comparison to vehicle treatment [30‒32]. Topical applications of Styela clava tunics extract also significantly lower TEWL in chronic UV(UVA+UVB)-irradiated mice [35]. This evidence indicates topical natural ingredients can alleviate UV irradiation-induced abnormality in epidermal permeability barrier function.

In addition to topical applications, oral administrations of natural ingredients can also attenuate UVB irradiation-induced alteration in epidermal permeability barrier. For example, UVB irradiation of mice for 10 weeks increases TEWL by over 1-fold, whereas feeding UVB-irradiated mice with a diet containing 0.1% of gallic acid significantly lowers TEWL compared to that fed with normal diet [33]. Oral administrations of several other plant extracts also exhibit similar benefit in mice irradiated with UVB (detailed in Table 1). Moreover, oral intake of some animal extracts decreases TEWL in mice irradiated with UVB. Previous studies demonstrated that over the entire course of chronic UVB irradiation, oral collagen hydrolysate induces dose-dependent reduction in TEWL [42, 43]. Interestingly, TEWL is significantly lower in mice fed with versus without collagen hydrolysate if pre-feeding mice with fish scale collagen hydrolysate (2 g/kg body weight) daily for 7 days followed by a single UVB irradiation (20 mJ/cm²) [44]. One study showed that oral intake of several insect extracts decreased TEWL by ≈ 30% in mice irradiated with UVB for 12 weeks [41]. Regarding aloe vera gel, one study showed that while mice were subjected to UVB irradiation for 7 weeks, oral intake of diet containing up to 120 ppm of aloe vera gel extract did not significantly affect TEWL [56]. On contrary, other study demonstrated that pre-feeding mice with diet containing 0.3% of aloe vera gel extract 2 weeks prior to UVB irradiation dramatically decreased TEWL compared to UVB-irradiation alone [57]. The discrepant results between the studies are possibly due to differences in study protocol (pre-feeding vs. feeding while subject to UVB irradiation). Nevertheless, a bulk of evidence indicates that either oral or topical administrations of some natural ingredients can attenuate UVB-induced abnormality in epidermal permeability barrier.

Regarding the underlying mechanisms whereby natural ingredients attenuate UVB-induced epidermal permeability dysfunction, evidence suggests the involvement of several possible mechanisms. During keratinocyte differentiation, cell plasma membrane is replaced with cornified envelope, mainly consisting of loricrin, involucrin, and filaggrin. The cornified envelope is further covalently bound to ω-hydroxy ceramides by transglutaminase to form corneocyte lipid bound envelope, providing scaffold for intercellular lipid bilayers, the critical structure for permeability barrier [72]. Hence, agents that upregulate expression of differentiation marker-related proteins can benefit epidermal permeability barrier. Previous studies showed that topical applications of ginseng extract increase expression levels of filaggrin and involucrin in UVB-irradiated skin and keratinocytes [30, 31]. Likewise, preincubation of keratinocytes with honeybush extract increases expression levels of mRNA for filaggrin, loricrin, and involucrin by over 3-fold [40]. Moreover, orally given either Hydrangea serrata leaf or Bouea macrophylla extracts completely prevents UVB-induced reductions in expression of filaggrin, involucrin, and loricrin in mouse skin [58, 63]. Furthermore, oral administrations of collagen hydrolysate for 1 week significantly upregulate 135 genes, including keratinocyte differentiation- and lipid synthesis-related genes, in mice [73]. Thus, stimulation of keratinocyte differentiation accounts for one mechanism by which natural ingredients attenuate UVB-induced epidermal permeability barrier abnormality.

Previous studies also showed that the interaction of hyaluronic acid with its receptor, CD44, regulates the epidermal permeability barrier. CD44 deficiency disturbs the formation of tight junction barrier and localization of lamellar body in embryonic mice, resulting in a defective epidermal permeability barrier [74]. In adult mice, CD44 deficiency delays epidermal permeability barrier recovery, resulting from decreased keratinocyte differentiation and lipid production [75]. Conversely, topical applications of hyaluronic acid stimulate keratinocyte differentiation and improve epidermal permeability barrier in aged mice [76]. During the entire course of 2-week UVB irradiation, topical applications of either ginseng extract or its phenolic acid (2 mg/cm²) daily induce 2-fold increases in expression levels of hyaluronan synthase mRNA compared to UVB irradiation alone [31]. In keratinocyte cultures, UVB irradiation of keratinocytes decreases hyaluronic acid content by >70% [40]. Preincubation of keratinocytes with 100 μg/mL of honeybush extract completely prevents UVB-induced reduction in hyaluronic acid content. Likewise, orally given several insect extracts completely prevent the decreases in hyaluronic acid content in the chronic UVB-irradiated skin (12-week irradiation) [41]. Moreover, either oral collagen peptide or Agastache rugosa Kuntze extract increases expression levels of hyaluronic acid synthase mRNA, while decreasing hyaluronidase mRNA, leading to an increase in hyaluronic acid content in the skin of repeated UVB-irradiated mice [43, 69]. Hence, increase in hyaluronic acid is another mechanism by which natural ingredients improve epidermal permeability barrier in UVB-irradiated skin.

Additionally, desmoglein-1 is a component of intercellular structural protein required for keratinocyte differentiation in the epidermis [77]. Desmoglein-1 deficiency increases cutaneous proinflammatory cytokines [78, 79] and decreases epidermal permeability [80]. In the stratum corneum, chymotryptic enzyme degrades desmoglein-1, resulting a compromised epidermal permeability barrier [81]. Treatment of UVB-irradiated mice with ginseng extract decreases expression levels of chymotrypsin-like kallikrein-related peptidase 7, consequently increasing desmoglein-1 expression in the epidermis [30]. Therefore, increased desmoglein-1 expression is additional mechanism whereby natural ingredients improve epidermal permeability barrier in UVB-irradiated skin.

Chronic sun-exposure decreases stratum corneum hydration levels in humans [82]. In murine models, repeated UVB irradiation lowers the stratum corneum hydration levels [25, 26, 28]. Low stratum corneum hydration levels have been linked to cutaneous inflammation and possibly systemic inflammation [83‒86]. Conversely, improvement in stratum corneum hydration levels can lower expression levels of proinflammation in both the skin and circulation [83, 87, 88]. Thus, maintenance of normal stratum corneum hydration levels can benefit some health conditions. Numerous studies have demonstrated the beneficial effects of natural ingredients on stratum corneum hydration in UVB-irradiated skin.

A number of studies demonstrated that either topical or oral administrations of natural ingredients increase stratum corneum hydration levels in UVB-irradiated mice. For instance, topical perilla oil induces ≈20% increases in stratum corneum hydration levels in UVB-irradiated mouse skin [25]. Similarly, topical applications of ginseng extract (1–2 mg/cm²) increase stratum corneum hydration levels by over 50% in a murine model of chronic UVB irradiation [29‒33]. In addition to topical treatment, oral administrations of natural ingredients also improve stratum corneum hydration levels in UVB-irradiated skin. Previous studies showed that orally given gallic acid for 10 weeks significantly increases stratum corneum hydration levels in comparison to UVB irradiation alone [33]. Likewise, oral administration of Protaetia brevitarsis seulensis extract increases stratum corneum hydration levels by 50% in mice repeatedly exposed to UVB for 12 weeks [41]. Moreover, oral collagen hydrolysate dose-dependently increases stratum corneum hydration levels in mice irradiated with UVB for 4 weeks [43]. Taken together, this evidence demonstrates the benefit of natural ingredients in prevention of UVB-induced reduction in stratum corneum hydration.

The benefit of natural ingredients in stratum corneum hydration can be ascribed to increased production of natural moisturizers because the stratum corneum hydration levels are determined by the content of natural moisturizers in the stratum corneum. Several studies showed elevation in the content of epidermal natural moisturizers in UVB-irradiated skin following the treatment with natural ingredients. Aquaporin 3 is a glycerol transporter in the epidermis while glycerol is one of the major natural moisturizers in the stratum corneum [89, 90]. Mice with aquaporin 3 deficiency exhibit lower stratum corneum hydration levels compared to the wild-type controls [91], while stimulation of aquaporin 3 expression increases stratum corneum hydration [92]. UVB irradiation decreases aquaporin 3 expression [30, 58], whereas treatment of UVB-irradiated keratinocytes with ginseng extract significantly increases expression levels of both aquaporin 3 mRNA and protein [30]. Moreover, hyaluronic acid is also a key regulator of stratum corneum hydration [93‒95]. Some natural ingredients such as ginseng extract increase expression levels of hyaluronan synthase mRNA by 2–3 folds in UVB-irradiated mouse skin [31]. Oral administration of Oxya chinensis sinuosa Mishchenko extract almost completely normalizes expression levels of hyaluronic acid in UVB-irradiated skin to that in the normal controls [39]. Furthermore, epidermal filaggrin can be degraded to urocanic acid and 2-pyrrolidone-5-carboxylic acid, which both are natural moisturizers in the stratum corneum [96]. UVB irradiation lowers expression levels of epidermal filaggrin by 30% from normal controls [30]. Topical applications of Saussurea involucrata polysaccharide twice daily for 5 days markedly increase epidermal filaggrin expression in UVB-irradiated mice [38]. Oral Hydrangea serrata leaf extract at a daily dose of 5 mg/kg body weight for 7 weeks induces 4-fold increase in epidermal filaggrin content [58]. In addition, topical S. involucrata polysaccharide also increases epidermal lipid content, possibly via upregulation of epidermal peroxisome proliferator-activated receptor α [38], a nuclear hormone receptor upregulating keratinocyte differentiation and lipid synthesis [97, 98]. Hence, natural ingredients improve stratum corneum hydration in UVB-irradiated skin through stimulation of lipid synthesis and upregulation of natural moisturizer expression.

Oxidative stress is a hallmark of UVB irradiation-induced alterations in the epidermis. For example, UVB irradiation induces dose-dependent reduction in glutathione (GSH) (up to 68%) and increases in the myeloperoxidase activity (up to 2,700%) after 6 h [99]. Similarly, GSH levels are decreased by 24% 24 h and by 56% 1 month after a single UVB irradiation [65]. Repeated UVB irradiation for 10 days significantly decreases superoxide dismutase (SOD) activity (by 48%) compared to normal controls [100]. UV irradiation lowers vitamin E, an antioxidant, in the stratum corneum, leading to a further reduction in antioxidant capacity of the skin [101]. Reduced antioxidant ability can increase oxidation of the stratum corneum lipids [102], the key component for epidermal permeability barrier. A number of natural ingredients exhibit antioxidant property via upregulation of antioxidant enzyme expression and reduction in reactive oxygen species. For instance, coffee bean extract at a concentration of 500 μg/mL completely inhibits UVB-induced increase in reactive oxygen species production in keratinocyte cultures [26]. Topical application of S. clava tunics extract to UVB-irradiated mouse skin markedly lowers cutaneous malondialdehyde levels while increasing SOD activity [35]. Likewise, orally given Corn Silk extract significantly increases in plasma GSH levels and cutaneous levels of mRNA for catalase and SOD in UVB-irradiated mice [54]. Some natural ingredients, such as Alchemilla mollis and corn silk extract, upregulate nuclear factor erythroid-2-related factor 2 expression, consequently increasing expression of a whole panel of antioxidant genes, including redox cycling enzymes [103]. In humans, oral supplements of natural products such carotenoid-ascorbic acid- and polyphenol-enriched products increase antioxidant capacity of the epidermis [104]. UV radiation-induced oxidative stress contributes to the development of skin cancers. Topical applications of resveratrol, an antioxidant, decrease the incidence of UVB-induced skin tumour and inflammatory infiltration [105]. Similarly, topical application of epigallocatechin-3-gallat, an active compound in green tea, either prior to or after UV (solar simulator) radiation decreases number of sunburn cells and UV-induced DNA damage in humans [106, 107]. Consumption of antioxidant-enriched food can prevent skin cancers, resulting from reduction in oxidative stress [108]. Additionally, oral carotenoids and vitamin E protect UVA and UVB radiation-induced skin erythema, likely via antioxidative stress in humans [109, 110].

In addition to UVB, natural ingredients also alleviate UVA-induced epidermal damages. For example, topical application of epigallocatechin-3-gallat 30 min prior to UVA radiation markedly decreases the number of sunburn cells and inflammatory infiltration in the rat epidermis [111]. Similarly, topical applications of Brown Macroalgae Sargassum cristaefolium extract alleviate UVA-induced increases in epidermal thickness and DNA damage in mice [112]. Collectively, the antioxidant can account for additional mechanism whereby natural ingredients protect the epidermis from UVB damages.

Inflamed skin displays elevated skin pH, which can increase Kallikrein-related peptidases and protease-activated receptor-2 activity [113‒115]. Activation of either Kallikrein-related peptidases or protease-activated receptor-2 activity can further provoke and/or exacerbate inflammation [116, 117]. UVB irradiation increases expression levels of epidermal Kallikrein-related peptidases and protease-activated receptor-2 [118]. The former can degrade structural proteins in the stratum corneum, resulting in a compromised epidermal permeability barrier and activation of proinflammatory cytokines such as pro-IL-1β, while activation of protease-activated receptor-2 inhibits keratinocyte differentiation and induces inflammation [119, 120]. Topical applications of Panax ginseng extract dramatically attenuate UVB-induced increases in Kallikrein-related peptidase 7 expression in the mouse epidermis [30]. In keratinocyte cultures, UVB irradiation increases expression levels of mRNA for both Kallikrein-related peptidases 5 and 7 while decreasing expression levels of Kazal type-5, inhibitor of serine protease. Treatment of UVB-irradiated keratinocytes with P. ginseng extract largely overrides the effect of UVB on the expression levels of these mRNAs [30]. In keratinocyte cultures, S. confusum extract inhibits UVB-induced increase in expression of protease-activated receptor-2 protein [118]. Thus, inhibition of Kallikrein-related peptidases and protease-activated receptor-2 expression can contribute to the photoprotective benefit of natural ingredients in epidermal function.

Previous studies have shown an induction of cutaneous inflammation by UVB irradiation. For example, repeated UVB irradiation for 12 weeks significantly increases expression levels of mRNA for proinflammatory cytokines such as IL-1β, IL-6, and TNF-α in the mouse skin (≈0.5–2-fold increases) [41]. Orally given extract of Allomyrina dichotoma larva completely prevents the UVB-irradiation-induced increases in these proinflammatory cytokines in mice [41]. Similarly, oral aloe vera gel extract lowers the expression levels of IL-1β and TNF-α by 23% and 57%, respectively, in the skin of UVB-irradiated mice compared to that without oral aloe vera gel extract [56]. The fermented honeybush extract also markedly inhibits UVB-induced increases in expression levels of mRNA for IL-1β, IL-6, and IL-8, at least, in keratinocyte cultures [121]. Interestingly, topical applications of S. clava tunics extract also markedly decrease IL-6 content and mast cell density in the dermis of mouse skin in comparison to UV-irradiated mice treated with vehicle alone [35]. Natural ingredients attenuate UVB-induced inflammation likely via inhibition of UVB-induced phosphorylation of MEK, AKT, and ERK [34, 55]. Nevertheless, this line of evidence indicates that natural ingredients can attenuate UVB-induced increases in epidermal proinflammatory cytokine expression.

Additionally, some natural ingredients, such as ginseng, Aloe vera gel and S. siliquastrum extracts, inhibit UVB-induced keratinocyte apoptosis and DNA damage via antioxidative stress [29, 56, 122]. The natural ingredient-induced reduction in epidermal thickness in UVB-irradiated skin can be ascribed to alleviation of both inflammation and oxidative stress, which both are well-known to stimulate keratinocyte proliferation [123‒125]. Other natural ingredients such as Scutellaria radix extract and silk attenuate UV-induced skin damage by absorption of UV light [112, 126, 127]. Thus, natural ingredients protect the epidermis from UVB-induced multiple functional abnormalities via divergent mechanisms (Table 2; Fig. 1).

UVB irradiation can alter multiple epidermal function. A number of natural ingredients that are either topically or orally administrated can protect the skin from UVB irradiation-induced skin damage. Some natural ingredients, such as hesperidin, vitamin E, and green tea extract, have been widely used in skincare products to protect and/or mitigate UV-induced skin damages. The benefits of well-known ingredients such as carotenoids, vitamin E, flavonoids, and green tea extract have been well-reviewed by others [105, 128]. Hence, this review focuses on other ingredients. Natural ingredients can mitigate UVB-induced multiple alterations in epidermal functions, including epidermal permeability barrier, stratum corneum hydration, oxidative stress, inflammation, DNA damage as well as keratinocyte apoptosis. The underlying mechanisms whereby natural ingredients benefit epidermal functions include stimulation of epidermal lipid production, keratinocyte differentiation, upregulation of NRF2 expression and inhibition of phosphorylation of MEK and ERK (Fig. 1).

The positive impacts of natural ingredients on photodamage have been demonstrated in several clinical trials. For example, pre-oral green tea catechins with vitamin C decrease inflammatory mediator, 12-hydroxyeicosatetraenoic acid, in human skin irradiated with solar simulator [129]. Likewise, oral intake of astaxanthin for 9 weeks increases minimal erythema dose and stratum corneum hydration levels as compared to placebo in UVB-irradiated humans [130]. Similarly, oral β-carotene and α-tocopherol increases minimal erytherma dose [109]. Moreover, topical applications of extract of P. ginseng and Crataegus pinnatifida improve global photodamage scores [131]. Furthermore, either topical or oral administrations of lutein or zeaxanthin decrease lipid oxidation, while increasing stratum corneum hydration levels in UVB-irradiated human skin. Interestingly, a more profound photoprotective effect are observed in combination of lutein and zeaxanthin [132]. Additionally, some natural ingredients such as silymarin and lignin display UV filter property [133]. In our daily life, we expose to various extent of UV irradiation, which can impair cutaneous structure and function and possibly cause extracutaneous disorders [134]. Because of the photoprotective benefits of some natural ingredients, use of those ingredients either orally or topically can prevent and/or attenuate UV-induced alterations in cutaneous and extracutaneous function.

However, the benefits of natural ingredients in epidermal function are largely demonstrated in animal models although there are limited number of human studies. Substantial portion of natural ingredients which benefit epidermal function in animal models have not been deployed in humans. And the influences of natural ingredients on epidermal function are inconsistent in clinical trials. For instance, studies showed no photoprotective effects of either oral β-carotene or green extract in humans [135, 136]. Thus, further clinical trials are warranted to determine whether and which natural ingredients protect the skin against photo-induced epidermal dysfunctions in humans.

No conflicts of interest.

This work was supported by the Health Bureau of Tianjin City (TJW2022QN088).

Dongyun Lei, Li Ye, and Si Wen performed literature search, acquisition of data and analysis, and drafting; Junling Zhang and Litao Zhang critically reviewed the manuscript; Mao-Qiang Man originated the concept, drafted, and revised the manuscript. All authors gave final approval of the version to be published, agreed on the journal to which the article has been submitted, and agreed to be accountable for all aspects of the work.