Natural products as promising therapeutics for fine particulate matter–induced skin damage: a review of pre-clinical studies on skin inflammation and barrier dysfunction

Search strategy

In this study, our aim was to update and integrate the information contained in publications retrieved from Google Scholar and PubMed, which are the top academic search engines related to the medical field. The search included articles published from 1999 to 2024. The search was performed using the following search terms, together with relevant Medical Subject Headings (MeSH) terms identified for individual databases: (((“particulate matter”[MeSH Terms] OR (“particulate”[All Fields] AND “matter”[All Fields]) OR “particulate matter”[All Fields]) AND (“biological products”[MeSH Terms] OR (“biological”[All Fields] AND “products”[All Fields]) OR “biological products”[All Fields] OR (“natural”[All Fields] AND “products”[All Fields]) OR “natural products”[All Fields]) AND (“skin”[MeSH Terms] OR “skin”[All Fields])) NOT (“clinical trial”[Publication Type] OR “clinical trials as topic”[MeSH Terms] OR “clinical trial”[All Fields])) AND (1999:2024[pdat]). The publications were selected according to specific inclusion and exclusion criteria to identify the most appropriate manuscripts retrieved from these two databases.

Eligibility criteria

The research question was constructed and developed according to the Population, Intervention, Comparison, Outcome, and Study Design (PICOS) framework. To be eligible for inclusion in this study, a research article had to meet the following inclusion and exclusion criteria: the study design should be focused on a skin cell line exposed to particulate matter 2.5, rather than other pollutants (e.g., particulate matter 10 µm (PM10), ambient air, air pollutants, or dust particles); the study should be focused on treatments using natural products rather than synthetic chemical products; the study should include preclinical experiments conducted in vitro or in vivo; the article should be published in English as well as an original full research article. We excluded narrative reviews, experts’ opinions, and articles published in other languages.

A total of 78 articles were selected and identified by their appropriate titles as manuscripts contributing to cell analysis. Subsequent screening was based on the contents of the abstract and the presence of keywords such as “natural products,” “active compounds,” “phytochemicals,” “antioxidants,” “skin,” “keratinocytes,” “fibroblast,” and “particulate matter less than 2.5 or PM2.5.” Approximately 37 of the 78 articles were excluded based on the inclusion and exclusion criteria established for this review. Overall, references were extracted from 41 articles for this review.

Importance of natural products as protectants against PM2.5-induced skin damage

Many recent studies have reported the use of natural products to protect the skin from particulate matter. Natural products and their structural counterparts have traditionally made a significant contribution to pharmacotherapy and have played a crucial role in drug development. Previously, Centella asiatica, a medicinal plant widely used in Southeast Asia, has long served as an alternative medicine for atopic dermatitis, a skin condition characterized by an abnormal immune response triggered by environmental factors, such as air pollution (Lee et al., 2020). It is the secondary plant metabolites present in medicinal plants that impart their medicinal properties. For example, phenolic compounds (PCs) are naturally occurring antioxidants whose chemical structure contains hydroxyl groups that may give these metabolites the ability to scavenge free radicals, such as ROS (Platzer et al., 2022). Similarly, the presence of hydroxyl groups in flavonoid compounds can impart protective antioxidant, anti-inflammatory, and anti-aging effects when flavonoids are applied to the skin (Diao et al., 2021). Flavonoids are also known for their scavenging activity, which can neutralize free radicals (Panche, Diwan & Chandra, 2016). Phytosterols (PS), another class of secondary metabolites that can be isolated from plants, also have anti-inflammatory, antioxidant, antidiabetic, and chemopreventive effects (Salehi et al., 2021). The PS function through the NF-κB and MAPK signaling pathways to suppress the expressions of COX-2, PGE2, and proinflammatory cytokines, thereby reducing the levels of inflammatory mediators (Diao et al., 2021).

Protective effects of natural products based on the classification of their phytochemical structures

Phenolic compounds, which are present in a variety of foods, including fruits, vegetables, and beverages, which can exhibit antioxidant, anti-inflammatory, anti-allergic, and anticancer properties. Due to their cardioprotective and other health-promoting benefits, they are widely incorporated into functional foods (Alara, Abdurahman & Ukaegbu, 2021). One class of phenolic compounds—polyphenols—is a group of chemical molecules that contain multiple hydroxyl structural units on aromatic rings that impart strong antioxidant properties. Differences in the molecular backbone structure of polyphenols have led to their general categorization into phenolic acids, flavonoids, stilbenes, and lignans. Flavonoids, as the largest group of polyphenols, are divided into seven subgroups according to their chemical and biological properties: flavanols (yellow), flavanones (purple), flavones (light blue), flavonols (red), isoflavones (dark blue), anthocyanins (green), and others (orange) (Wang et al., 2022a; Zhang et al., 2022). The flavonoid colors are useful for visually distinguishing the different flavonoid subgroups based on their structural characteristics. Other types of compounds, saponins are a type of triterpene glycoside with a bitter taste. Structurally, saponins are glycosides; that is, sugars are bound to one or more organic molecules. In this review, the effects of bioactive compounds extracted from natural products are presented based on plant organic chemicals (Fig. 1), and the compounds showing protective action against particulate matter–induced skin damage are summarized in Table 1.

Phenolic compounds—sulforaphane from broccoli and sprouts

Sulforaphane is a polyphenolic compound found in cruciferous vegetables, such as broccoli. It is produced through the enzymatic conversion of glucoraphanin by myrosinase, an enzyme presents in plants. Sulforaphane is metabolized via the mercapturic acid pathway, where it conjugates with glutathione and undergoes biotransformation, leading to the formation of active metabolites (Kensler et al., 2013; Vanduchova, Anzenbacher & Anzenbacherova, 2018). Sulforaphane contains an isothiocyanate group that plays a critical role in protecting against electrophilic toxicities of ROS by inducing phase II biotransformation enzymes, which function as an indirect antioxidant defense system e.g., catalases, glutathione S-transferases, etc. (Fahey & Talalay, 1999). This makes sulforaphane highly versatile and effective in safeguarding cells from various oxidative stresses and ROS. Growing evidence now demonstrates that the sulforaphane enhances the antioxidant capacity of animal cells, improving their ability to withstand oxidative stress (Barton & Ollis, 1979). A dermatological study revealed that sulforaphane supports collagen homeostasis while suppressing melanogenesis, potentially mitigating the premature aging effects induced by PM2.5 exposure (Andres et al., 2018). Additionally, sulforaphane disrupts melanogenic paracrine mediators, thereby inhibiting the production of melanogenic proteins and melanin in melanocytes (Jung et al., 2013). In keratinocytes, sulforaphane reduces the expression of NF-κB-mediated cytokines such as tumor necrosis factor α, interleukin-1β, interleukin-6 and cyclooxygenase-2 (Fernando et al., 2019). Sulforaphane has been reported to decrease the expression of matrix metalloproteinase-1, phospho-NF-κB, and cysteine-rich protein while significantly increasing the production of procollagen type I, indicating an anti-inflammatory effect and remodeling of the human skin fibroblasts (Quan et al., 2012).

Phenolic compounds—rosmarinic acid from rosemary, sage, and peppermint

Rosmarinic acid (RA), a phenolic compound present in herbs such as rosemary, sage, and peppermint, exhibits protective effects against PM2.5-induced skin damage. This response is primarily attributed to the antioxidant, anti-inflammatory, and antiapoptotic properties of RA (Zhou et al., 2022). RA protects skin keratinocytes by reducing oxidative stress, as indicated by reductions in stress markers, such as lipid peroxidation, protein carbonylation, and DNA damage, which are associated with the critical macromolecules needed to maintain cellular integrity under environmental stress conditions. In addition, RA stabilizes intracellular calcium levels and mitochondrial membrane potential and prevents mitochondrial dysfunction and apoptosis, primarily by downregulating proapoptotic proteins, such as Bax and caspases, while upregulating antiapoptotic proteins, such as Bcl-2 (Herath et al., 2024). RA also exerts anti-inflammatory effects by modulating the NF-κB signaling pathway, which plays an important role in inflammation and immune responses. In models of allergic rhinitis exposed to PM2.5, RA treatment has been shown to reduce inflammation by decreasing proinflammatory cytokines, such as IL-4 and IL-13, and by increasing IFN-γ, thereby balancing the Th1/Th2 response (Zhou et al., 2022). This response suggests that the protective role of RA against PM2.5-induced damage extends beyond its antioxidant activity to include the modulation of inflammatory pathways (Zhou et al., 2022). Overall, RA provides multilayered protection against PM2.5-induced skin damage, highlighting its potential as a therapeutic agent that could alleviate skin problems caused by environmental pollutants.

Protective effects of the flavonoid family compounds

Flavonols—Quercetin from berry fruit extracts

A study focusing on an extract from the leaves of Thunberia laurifolia (STLE) suggested that STLE effectively inhibits PM2.5-induced oxidative stress in keratinocytes by upregulating Nrf2 and enhancing the nuclear translocation and upregulation of p62 (Jirabanjerdsiri et al., 2022). STLE is a natural antioxidant mixture that contains caffeic acid, rosmarinic acid, quercetin, isoquercetin, catechin, and apigenin. Among these secondary metabolites, quercetin is a flavonoid found in fruits and vegetables and has shown potential health-promoting effects, such as anti-inflammation, antioxidant activity, and the alleviation of allergy symptoms. Another flavonoid, rutin, is a glycoside of quercetin, and it is found in many plants, including citrus fruits, mulberries, and cranberries. Thus, flavonoid compounds have common health benefits that can be attributed to their antioxidant properties, which could reduce oxidative stress and inflammation (Muvhulawa et al., 2022). In dermatology, quercetin has known benefits for the skin: It can protect against skin-damaging factors, such as UV radiation, histamine, and toxic chemical compounds, and it also displays anti-allergic properties by reducing irritation and itching caused by the release of histamine (Qi et al., 2022).

Flavanols—Catechins from green tea extracts

Catechins, a group of flavonoids found in green tea, are considered a potential treatment for skin diseases because of their antioxidant and anti-aging effects (Aljuffali et al., 2022). The bioactive components found in green tea are catechins, which include epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG) (Cardoso et al., 2020; Tian et al., 2021). The various catechins differ in their chemical structures, but all show the ability to scavenge ROS, which contributes to their antioxidant, anti-inflammatory, and anticarcinogenic effects (Wang, Chou & Hung, 2022b). EGCG has the greatest anti-inflammatory potential due to the presence of hydroxyl groups that provide it with ROS scavenging capabilities (Cardoso et al., 2020). Catechins can also chelate metal ions, further enhancing their antioxidant activity. EGCG has been shown to inhibit TPA-induced DNA binding of NF-kappaB and the cAMP response element binding protein (CREB) by blocking p38 MAPK activation and causing an inactivation of the CREB transcription. This result explains how EGCG inhibits COX-2 in the mouse skin model (Kundu & Surh, 2007). Some studies have found that green tea extract (GTE) mitigates the damage caused by PM2.5 exposure through anti-inflammatory and antioxidant mechanisms. In addition, the restoration of impaired epidermal lipid homeostasis also plays an important role in reducing skin damage, suggesting that one effect of GTE is the restoration of PM2.5-altered gene expression in keratinocytes. Liao, Nie & Sun (2020) used MTT assays, morphological studies, and mass spectrometry to investigate the effect of a GTE concentration on keratinocytes growing in a three-dimensional epidermal tissue model. The polyphenol content of the GTE sample was 750 µg/mL (Liao, Nie & Sun, 2020). They found that GTE worked primarily by reducing the effects of PM2.5 on keratinocytes. Treatment with GTE triggered a downregulation of cytokine signaling associated with the immune system and wound healing, including the HMGCS1 and LDLR genes, which are strongly associated with the inflammatory response (Liao, Nie & Sun, 2020).

Flavanols—Fisetin from various fruits and vegetables

Fisetin, a bioactive flavonoid found in various fruits and vegetables such as strawberries, apples, persimmons, onions, cucumbers, and grapes, is known for its potent antioxidant, anti-inflammatory, and antiapoptotic properties. Fisetin has been demonstrated to protect skin keratinocytes by inhibiting PM2.5-induced oxidative stress and apoptosis, primarily through the suppression of ER stress responses (Molagoda et al., 2021). It effectively downregulates ER stress markers, such as glucose-regulated protein 78 (GRP78), phosphorylated eIF2α, ATF4, and CHOP, thereby reducing ER stress-induced apoptosis. Fisetin also reduces the production of ROS, lowers cytosolic calcium levels, and prevents mitochondrial dysfunction, which are critical steps for attenuating cell damage caused by PM2.5 exposure. By modulating the expression of proapoptotic proteins, such as Bax and caspases, while upregulating antiapoptotic proteins, such as Bcl-2, fisetin provides comprehensive protection against PM2.5-induced keratinocyte apoptosis (Molagoda et al., 2021).

Flavonoids—from Cornus officinalis extract

Cornus officinalis extracts, and particularly its ethanol extract (EECF), have shown significant protective effects against PM2.5-induced skin damage by attenuating oxidative stress, mitochondrial dysfunction, and apoptosis in skin cells. EECF exerts its protective effect by scavenging ROS and reducing oxidative damage. EECF has been shown to attenuate lipid peroxidation, protein oxidation, and DNA damage in PM2.5-exposed keratinocytes (Fernando et al., 2020). In addition, EECF has been demonstrated to reduce intracellular and mitochondrial Ca2+ levels, protecting cells from mitochondrial depolarization—a key event leading to cell apoptosis. EECF has also been shown to inhibit the upregulation of proapoptotic proteins, such as Bax and cleaved caspase-3, while enhancing the expression of antiapoptotic proteins, such as Bcl-2, to further prevent PM2.5-induced apoptosis. These results suggest that a Cornus officinalis extract could be an effective ingredient in skin care products designed to protect the skin from environmental pollutants, such as PM2.5 (Fernando et al., 2020).

Flavonoids—Isovitexin, an isomer of vitexin from bamboo leaves, mung beans, and fenugreek seeds

Isovitexin, an isomer of vitexin, is a naturally occurring flavonoid with significant antioxidant and protective properties against PM2.5-induced skin damage. Isovitexin has been shown to reduce PM2.5-induced ROS in human keratinocytes, thereby mitigating oxidative stress and preventing cell damage. Isovitexin protects skin cells by inhibiting ROS production, as demonstrated in studies in which pretreatment with isovitexin significantly reduced intracellular ROS levels in keratinocytes exposed to PM2.5. The compound exhibits potent free radical scavenging activity against DPPH, ABTS, and superoxide anion radicals, indicating a strong antioxidant capacity. In addition, isovitexin enhances stem cell properties in keratinocytes by upregulating the expression of stem cell markers, such as CD133 and β-catenin, which play roles in skin regeneration and repair (Chowjarean et al., 2019). These results suggest that isovitexin not only protects the skin from the damaging effects of PM2.5 but also promotes skin health by enhancing the regenerative capacity of keratinocytes.

Tannins—Diphloroethohydroxycarmalol, a phlorotannin, from algae extracts

Diphloroethohydroxycarmalol (DPHC), a bioactive compound classified as an algal polyphenol, is derived from Ishige okamurae, a type of brown algae (Bak et al., 2023; Diao et al., 2021). DPHC has been previously reported to provide health benefits, including antioxidant and radioprotective effects (Ahn et al., 2011). Because of its health benefits and antioxidant effects, dermatological studies have been published using DPHC, which was found to reduce PM2.5-induced skin dysfunction, oxidative stress, autophagy, ER stress, mitochondrial damage, and apoptosis (Zhen et al., 2019). DPHC enhances cell viability by preventing oxidative stress–induced DNA damage, with a consequent inhibition of matrix metalloproteinase-1 (MMP-1), also known as collagenase enzyme, and activation of the nucleotide excision repair system (Zhen et al., 2019). Other findings also support a protective effect of DPHC that arises through the inhibition of lipid peroxidation and cell damage (Zhang et al., 2021). Treatment with DPHC in HepG2 hepatocytes cell line can reduce the production of CCAAT-enhancer-binding protein (CHOP), GRP78, and inositol-requiring enzyme 1-α, and all three of these proteins are involved in cell apoptosis via the activating transcription factor 6 signaling pathway (Zhang et al., 2021). Notably, DPHC demonstrates effects similar to those of hesperidin in terms of mitigating PM2.5-induced mitochondrial damage arising from increased mitochondrial ROS and disruptions in the membrane permeability balance. DPHC plays a role in decreasing Bcl-associated X protein and increasing antiapoptotic Bcl-2 proteins, thereby suppressing PM2.5-induced mitochondrial damage (Zhang et al., 2021).

Stilbenes—Resveratrol from grape extracts

Resveratrol (3,5,4′-trihydroxy-trans-stilbene), a natural polyphenol that can be found and extracted from grape skins and seeds (Salehi et al., 2018), has many health benefits, most notably antioxidant and anti-inflammatory activities and protective effects against cardiovascular disease and cancer (Meng et al., 2020). Resveratrol can also inhibit PM2.5-induced inflammation on the skin (Shin et al., 2020). Resveratrol has been reported to be safe for use on skin cells, including human keratinocytes, at a concentration of one µM or less (Shin et al., 2020). Pharmacokinetics studies on resveratrol have shown that 70% of resveratrol is absorbed via the gastrointestinal tract but then later metabolized, resulting in extremely low bioavailability (Shaito et al., 2020). Previous study on the larger size of particulate matter (PM) showed a reduction in intracellular ROS observed in cells pretreated with resveratrol, as resveratrol can inhibit AhR activation by PM and thus inhibit the AhR pathway. Resveratrol can also suppress the JNK/MAPK signaling pathway, which regulates COX2/PGE2 and the inflammatory cytokines induced by PM (Shin et al., 2020). Resveratrol can also reduce the expression of proinflammatory cytokines and IL-8, which contribute to skin inflammation and photoaging. Additionally, resveratrol treatment lowers the levels of MMP-1 and MMP-9, which are enzymes responsible for degrading the skin’s extracellular matrix (Michalak-Stoma et al., 2021; Shin et al., 2020). A dosage of resveratrol of 0.1–1 µM shows the most beneficial effects (Shin et al., 2020).

Saponin—Ginsenoside from ginseng extracts

Ginsenosides, a class of saponins found in ginseng, are characterized by hydroxyl groups attached to a steroid-like backbone with sugars and a distinctive four-ring structure (Khan, Tosun & Kim, 2015). Ginsenoside Rb1 has shown a protective effect against PM2.5-induced ROS production. Pretreatment with ginsenoside Rb1 increased cell viability from about 70% (without pretreatment) to 90% (with pretreatment). The scavenging capacity of ginsenoside Rb1 has been confirmed by a reduction in the superoxide anion signal, as measured by a xanthine oxidase system, from 2241 to 2024 signal value, and the hydroxyl radical generated by the Fenton reaction was reduced from 2844 to 2065 (Piao et al., 2019). Ginsenoside Rb1 protected against PM2.5-induced DNA degradation and apoptosis in HaCaT keratinocytes and normal human dermal fibroblasts (NHDF) through the proapoptotic protein Bax and the antiapoptotic proteins Bcl-2 and Mcl-1. Ginsenoside Rb1 also protected against PM2.5-induced mitochondrial damage by decreasing ROS production and reducing Ca2+ overload, as confirmed by the measurement of ATP levels in HaCaT and NHDF cells. The cells exposed to PM2.5 alone had ATP levels of 0.795 and 0.233, respectively, while cells pretreated with ginsenoside Rb1 showed increased ATP levels of 0.94 and 0.283, respectively (Wee, Mee Park & Chung, 2011). Ginsenoside Rb1 at a dosage of 40 µM was effective in protecting cells via multiple mechanisms that led to reductions in ROS, oxidative stress, apoptosis, and mitochondrial damage (Wee, Mee Park & Chung, 2011). Ginseng has a wide range of health benefits, such as boosting the immune system, improving central nervous system function, alleviating stress, and scavenging free radicals (2024; Wee, Mee Park & Chung, 2011; Leung & Wong, 2010).

Lycium barbarum polysaccharide—from Lycium barbarum (goji berry)

Lycium barbarum polysaccharide (LBP), extracted from the fruit of Lycium barbarum, has demonstrated protective effects against PM2.5-induced skin damage through its antioxidant, anti-inflammatory, and antiapoptotic activities. LBP protects skin cells, especially HaCaT keratinocytes, by inhibiting oxidative stress markers, reducing ROS levels, and restoring the activities of antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx). In addition, LBP alleviates ER stress by downregulating stress-related proteins, such as GRP78 and CHOP, which are involved in apoptotic pathways. By mitigating these stress responses, LBP reduces apoptosis, demonstrating its ability to maintain the viability of skin cells exposed to PM2.5. Furthermore, LBP modulates autophagy, a process that is often dysregulated in response to PM2.5, by affecting the expression of autophagy-related proteins, such as LC3-II and p62. This regulation helps maintain cellular homeostasis and prevents excessive autophagy, which could otherwise lead to cell death. The combined antioxidant, antiapoptotic, and autophagy-regulating properties of LBP make it a promising therapeutic agent against PM2.5-induced skin damage (Zhu et al., 2022).

Farnesol—a natural benzyl semiterpene

Farnesol, a component of essential oil from various plants, such as citronella, lemongrass, tuberose, cyclamen, rose, neroli, balsam, and musk, has anti-inflammatory and antioxidant properties and therefore provides a significant protective effect against PM2.5-induced skin damage because of its tissue-reparative properties. Farnesol exerts its protective effect by reducing the production of proinflammatory cytokines, such as IL-6 and TNF-α, which are elevated in response to PM2.5 exposure. In addition, liposomes loaded with farnesol (Lipo-Fern) can enhance the therapeutic efficacy of farnesol by improving skin penetration and reducing cytotoxicity. Studies have shown that Lipo-Fern can effectively alleviate acute and chronic inflammation, restore damaged epidermis and dermis, and promote hair follicle regeneration. This underlines its potential as a therapeutic agent against PM2.5-induced skin damage (Wu et al., 2021).

4-O-Feruloylquinic acid—from Phellodendron amurense

An extract (PAE) from Phellodendron amurense, also known as the Amur cork tree, has shown significant protective effects against PM2.5-induced skin damage through its anti-inflammatory and antioxidant properties. PAE has been demonstrated to mitigate skin damaging effects by inhibiting calcium influx and regulating signaling via proteinase-activated receptor-2 (PAR-2), which plays a key role in inflammatory responses. Studies have shown that PM2.5 induces an intracellular calcium influx (Ca2+) that triggers inflammatory pathways in keratinocytes. PAE significantly reduces this Ca2+ influx and thus attenuates the inflammation caused by PM2.5. In addition, PAE downregulates proinflammatory cytokines, such as IL-6, IL-8, and TNF-α, which are upregulated by PM2.5 exposure. In addition to its anti-inflammatory effects, PAE also helps maintain the integrity of the skin barrier by preventing the downregulation of proteins, such as zonula occludens-1 and occludin, both of which are crucial for tight junctions in skin cells. In addition, Phellodendron amurense contains 4-O-feruloylquinic acid (FQA), a compound responsible for its protective effect. FQA replicates the protective effect of PAE by inhibiting Ca2+ influx and reducing the expression of PAR-2. This suggests that Phellodendron amurense extract, and particularly the FQA it contains, provides significant protection against PM2.5-induced skin damage by modulating inflammatory pathways and maintaining the skin’s barrier function (Choi et al., 2020).