Progress in Pharmacological Research of Natural Products for the Treatment of Atopic Dermatitis

Atopic dermatitis (AD) is a T-cell-mediated chronic inflammatory skin disease with strong heterogeneity, clinically manifesting as erythema, papules, lichenification, severe pruritus, and other symptoms. The causes and pathogenesis of atopic dermatitis are not fully understood. In recent years, it is generally believed that genetic factors, metabolic disorders, infections, immune dysfunction, and other factors may be important contributors to its development. Additionally, seasonal changes, humidity, psychological trauma, or surgery may also trigger the onset of atopic dermatitis.

Genetic factors are the strongest risk factor for AD, and studies have shown that children of parents with AD have a higher incidence rate. The major disease-related genes are primarily related to skin barrier function, innate immune response, and specific immune response. The main immune response involved in AD is the imbalance of Th1/Th2, leading to abnormal cytokine secretion. During the acute phase of AD, Th2 is dominant, and activated Th2 cells induce B cells to produce immunoglobulin E (IgE) by releasing cytokines such as interleukin (IL)-4, IL-5, IL-6, IL-9, IL-10, and IL-13, which increases IgE levels. The produced IL-5 cytokine prolongs the survival time of eosinophils, causing an increase in systemic eosinophils and aggravating local skin inflammation. In the chronic phase of AD, Th1 is dominant, and Th1 cells produce cytokines such as interferon-γ (IFN-γ), TNF-β, IL-2, IL-12, and IL-18, which participate in cell-mediated inflammatory responses.

Environmental factors, including air pollution, secondhand smoke, and environmental allergens such as house dust mites and pollen, can increase the prevalence of AD. Antigens in the environment stimulate antigen-presenting cells through damaged skin barriers, leading to interactions between Th2 cells and T/B cells in local lymph nodes, resulting in excessive IgE switching. Additionally, memory T cells redistribute into the blood circulation, worsening AD through T-cell skin infiltration and spreading to other areas of the body, leading to other atopic diseases.

AD patients often have defects in skin barrier function, which are mainly manifested in abnormal secretion of epidermal proteins, abnormal expression profiles of epidermal lipids, abnormal expression of aquaporins (AQPs), impaired function of epidermal cell tight junctions (TJ), and dysregulation of antimicrobial peptides (AMPs). Furthermore, mental stress, anxiety, and depression are also significant factors contributing to the worsening of AD in patients.

Natural products are an important source for new drug development, and China enjoys a natural advantage in the development and utilization of natural products due to its rich foundation in traditional Chinese medicine research. Numerous basic studies have shown that natural products possess high safety and effectiveness, which can significantly improve allergic inflammation and oxidative stress in AD by inhibiting NF-κB-related signaling pathways.

1.Flavonoids

Baicalin Flavone II (SFII), a flavonoid isolated from Scutellaria baicalensis, possesses anti-inflammatory, antibacterial, and antioxidant effects. In vitro studies have found that SFII can inhibit the expression of chemokines and inflammatory mediators such as thymus and activation-regulated chemokine (TARC/CCL17), macrophage-derived chemokine (MDC/CCL22), and CTSS by regulating signal transducer and activator of transcription (STAT) 1, NF-κB, and p38 MAPK signaling pathways. Baicalin, another active compound extracted from Scutellaria baicalensis, has been found to improve skin barrier function by regulating the Th1/Th2 balance and upregulating the expression of barrier proteins such as filaggrin (FLG), involucrin (IVL), and loricrin (LOR). It can also restore the abundance of intestinal probiotics in AD mice to regulate intestinal dysbiosis and inhibit AD-like inflammation by inhibiting the activation of NF-κB and Janus kinase (JAK)/STAT pathways. Quercetin, a glycosylated form of flavonoid compounds found in most edible fruits and vegetables, has effective antioxidant and anti-inflammatory properties. Studies have found that oral quercetin not only reduces the development and histopathological changes of AD-like skin lesions induced by dust mite extract (DFE) in NC/Nga mice, but also downregulates the levels of inflammatory factors such as cytoplasmic HMGB1, RAGE, and nuclear p-NF-κB, p-ERK1/2, COX-2, TNF-α, IL-1β, IL-2Rα, IFN-γ, and IL-4. At the same time, it upregulates the nuclear Nrf2 level, indicating that quercetin has the potential to become a therapeutic drug for AD by regulating HMGB1/RAGE/NF-κB signaling and inducing Nrf2 protein. Chrysin, a natural flavonoid derived from propolis, vegetables, and fruits, has an inhibitory effect on mast cell-mediated allergic reactions. Studies have found that oral chrysin can reduce AD-like symptoms induced by dinitrochlorobenzene (DNCB)/DFE as well as serum IgE, IgG2a, and histamine levels. It can also inhibit the related inflammatory responses of Th1/Th2/Th17/Th22 in mouse lymph nodes and ear tissue. In vitro experiments have shown that chrysin can reduce pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and Th2 chemokines such as CCL17 and CCL22 by downregulating the activation of p38 MAPK, NF-κB, and STAT1. It can also inhibit the innate immune system by downregulating IL-33 expression in TNF-α/IFN-γ-stimulated HaCaT cells and mouse primary keratinocytes. Morusin G and mulberroside are flavonoid compounds extracted from mulberry trees. In vitro studies have shown that morusin G can reduce the release of chemokine ligands 5 (RANTES/CCL5), TARC, and MDC by downregulating STAT1 and NF-κB p65 signaling in TNF-α/IFN-γ-stimulated HaCaT cells. It can also inhibit histamine production and 5-lipoxygenase (5-LO) activation in PMA/A23187-stimulated MC/9 mast cells. Mulberroside inhibits the secretion of RANTES and TARC by inhibiting STAT1 and NF-κB p65 phosphorylation in TNF-α/IFN-γ-stimulated HaCaT cells, and inhibits histamine production and LTC4 release induced by 5-LO activation in PMA/A23187-stimulated MC/9 mast cells. Leukotrienes (LTs) are lipid mediators synthesized from arachidonic acid under the action of 5-LO, LTA4 hydrolase, and LTC4 synthase, which play an important role in inflammatory responses. It can be seen that morusin G and mulberroside have the potential to treat allergic and inflammatory skin diseases.

2.Alkaloids

Methylcorynoline, a small molecule compound isolated from the green embryo of mature lotus seeds, has been found to inhibit the expression of cytokines (IL-1β, IL-6, IL-8, TSLP), chemokines (TARC, MDC, RANTES), and the phosphorylation of NF-κB and MAPK. Additionally, it significantly reduces skin barrier damage, transepidermal water loss, scratching behavior, and epidermal hyperplasia in mouse models, while increasing skin hydration. Pseudoephedrine (PSE), an alkaloid derived from Ephedra sinica and Ephedra intermedia, has been approved as a sympathomimetic drug for relieving nasal congestion during common colds due to its vasoconstrictive effect. Research has shown that oral PSE can improve DNCB-induced AD-like dermatitis, skin hydration, and scratching behavior. It inhibits the levels of serum TNF-α and IgE, reduces the expression of various cytokines and chemokines such as CCL2 and matrix metalloproteinase (MMP)-9 in skin tissue, and inhibits the release of inflammatory factors TNF-α, IL-1β, and IL-23 in TNF-α/IFN-γ-induced HaCaT cells. Furthermore, PSE inhibits the activation of MAPK and NF-κB signaling pathways both in vivo and in vitro.

3.Phenols

Curcumin and bisdemethoxycurcumin (BDMC) are components derived from the rhizome of the traditional Chinese medicine turmeric. Research has confirmed that curcumin has a regulatory effect on skin inflammation, proliferation, and infectious diseases. BDMC is more stable than curcumin, has better water solubility and permeability, and can inhibit the mRNA expression of chemokines and inflammatory cytokines as well as the activation of MAPK and NF-κB signaling pathways, thus alleviating AD inflammatory responses. Resveratrol, a polyphenol that exists abundantly in red grape skins, has effective anti-inflammatory and anti-aging properties. Studies have found that resveratrol inhibits the HMGB1-RAGE, PI3K, ERK1/2, and NF-κB pathways, suggesting its potential as an effective target for anti-inflammatory treatment. Other research has shown that resveratrol can improve cellular infiltration, inhibit the activation of skin mast cells and the expression of chemokines, reduce the activation of sphingosine kinase 1 (SphK1) that produces sphingosine-1-phosphate (S1P), and participate in the activation of STAT3 and NF-κB p65 involved in chemokine production. The activation of mast cells by the bioactive sphingolipid metabolite S1P can trigger extensive skin remodeling.

4.Terpenes

The plant Inula helenium from the Asteraceae family is well-known for its anti-inflammatory properties and is widely used in cosmetics and pharmaceuticals. Igalan, a sesquiterpene lactone isolated from Inula helenium, has been shown in vitro studies to inhibit the activation of NF-κB and STAT pathways, downregulate inflammatory mediators such as TARC, MDC, and RANTES, and promote skin barrier function by upregulating the mRNA levels of FLG, LOR, keratin 10 (KRT10), and desmoglein 1 (DSC1) through inhibiting JAK/STAT3 signaling. Additionally, Igalan can induce the Nrf2 pathway and regulate cellular antioxidant responses through the modulation of genes such as HO-1 or NAD(P)H quinone dehydrogenase 1 (NQO1). Moreover, Igalan inhibits the expression of iNOS, which synthesizes NO, helping to prevent the risk of reactive oxygen species in AD.

Echinocystic acid (ECA), a pentacyclic triterpene extracted from the fruit of Gleditsia sinensis, exhibits strong anti-inflammatory, antioxidant, and anti-tumor activities. ECA improves skin barrier function by restoring filaggrin expression and skin hydration, and inhibits the expression of cytokines derived from T helper cells in the skin and lungs of AD mice induced by dust mites, the phosphorylation of ERK and STAT1, and the translocation of NF-κB in keratinocytes. This suggests its potential as an anti-atopic and anti-allergic treatment to prevent the progression of atopic disorders.

Oleanolic acid (OA), a pentacyclic triterpene compound found abundantly in plants of the Oleaceae family, has been shown to inhibit mast cell-mediated allergic inflammation. OA inhibits the expression of Th2-type cytokines and chemokines by blocking Akt, NF-κB, and STAT1.

Asiatic acid, a pentacyclic triterpene compound found in plants such as Centella asiatica, kiwi, and guava, has been found to downregulate Th1/Th2-related cytokines and the expression of COX-2, C-X-C chemokine ligand (CXCL) 9, and CXCL8. Additionally, it inhibits the activity of NF-κB, p-Akt, and MAPK signaling pathways.

Perillyl alcohol, a natural diterpene compound extracted from the leaves and flowers of Perilla frutescens, has been found to significantly reduce symptoms, serum IgE levels, and local skin proinflammatory cytokine concentrations in AD mouse models when administered intraperitoneally. It also inhibits T cell activation.

5.Coumarins

Psoralen is a furanocoumarin compound derived from the fruit of Psoralea corylifolia, which possesses anti-inflammatory and anti-infective properties. Studies have found that gastric administration of psoralen can alleviate DNCB/DFE-induced AD-like skin inflammation, inhibit the expression of Th2-related cytokines and chemokines such as IL-4, IL-13, IL-31, and CCL17 in ear tissue, and reduce the levels of total IgE, DFE-specific IgE, and IgG2a in mouse serum. In vitro experiments have shown that psoralen not only inhibits the expression of inflammatory mediators but also inhibits STAT1 phosphorylation, IκBα degradation, and NF-κB nuclear translocation.

Umbelliferone (UMB), a coumarin derivative found in the roots and bark of plants such as Angelica decursiva and Artemisia capillaris, has anti-inflammatory, anti-diabetic, anti-cancer, and liver-protecting effects. Research shows that oral administration of UMB can significantly reduce the serum levels of IgE, IgG1, IgG2a, TNF-α, and IL-4 in AD mice induced by DNCB/DFE. Additionally, UMB improves AD-related symptoms and inflammation by regulating the MAPK, NF-κB, and STAT1 signaling pathways, reducing the secretion of proinflammatory cytokines and chemokines stimulated by TNF-α/IFN-γ.

Aesculin, a coumarin compound extracted from the bark of Fraxinus mandshurica, exhibits anti-inflammatory effects in asthma animal models and regulates the phenotypic switching of airway smooth muscle cells. Studies have shown that oral administration of aesculin can also improve DFE/DNCB-induced AD-like symptoms and histological changes, reduce serum levels of IgE, IgG2a, and histamine, and inhibit the production of Th1/Th2/Th17-related cytokines in tissues. In vitro experiments have also confirmed its ability to inhibit TNF-α/IFN-γ-stimulated NF-κB and STAT1 activation.

6.Others

Schisantherin M2 (GM2), a lignan isolated from Schisandra chinensis, possesses anti-inflammatory, anti-allergic, antiviral, and anticancer effects. Studies have found that GM2 can significantly inhibit the levels of inflammatory mediators such as IL-1β, IL-6, CXCL8, and CCL22 by inhibiting STAT1 phosphorylation and NF-κB nuclear translocation.

Emodin methyl ether, an anthraquinone derived from rhubarb (a traditional Chinese medicine), has various pharmacological properties including anti-inflammatory, antimicrobial, and antitumor effects. Both in vitro and in vivo studies have shown that emodin methyl ether can improve AD-like skin lesions by inhibiting TSLP levels through the Caspase-1/MAPK/NF-κB signaling pathway.

Crocin, also known as saffron pigment, is a water-soluble carotenoid. The external application of crocin can block the NF-κB and STAT6 signaling pathways in AD mice induced by DFE, inhibiting the expression of Th2-related cytokines and chemokines.

References

[1] Gou Li, Liu Bingmei, Wei Yannan. Research Progress on the Treatment of Atopic Dermatitis with Chinese and Western Medicine [J]. Chinese Scientific and Technological Periodicals Database (Abstract Edition): Medicine and Health, 2023, (Issue 11).

[2] Li Xiang, Dong Lingling, Guo Tao, et al. Research Progress on the Treatment of Atopic Dermatitis with Natural Products Based on the NF-κB Signaling Pathway [J/OL]. Chinese Journal of Experimental Traditional Medical Formulae, 1-10.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.