Identification of Dihydrobenzofuran Neolignans as Novel PDE4 Inhibitors and Evaluation of Antiatopic Dermatitis Efficacy in DNCB-Induced Mice Model.

Atopic dermatitis is a chronic relapsing skin disease characterized by recurrent, pruritic, localized eczema, while PDE4 inhibitors have been reported to be effective as antiatopic dermatitis agents. 3',4-O-dimethylcedrusin (DCN) is a natural dihydrobenzofuran neolignan isolated from Magnolia biondii with moderate potency against PDE4 (IC50 = 3.26 ± 0.28 µM) and a binding mode similar to that of apremilast, an approved PDE4 inhibitor for the treatment of psoriasis. The structure-based optimization of DCN led to the identification of 7b-1 that showed high inhibitory potency on PDE4 (IC50 = 0.17 ± 0.02 µM), good anti-TNF-α activity (EC50 = 0.19 ± 0.10 µM), remarkable selectivity profile, and good skin permeability. The topical treatment of 7b-1 resulted in the significant benefits of pharmacological intervention in a DNCB-induced atopic dermatitis-like mice model, demonstrating its potential for the development of novel antiatopic dermatitis agents.

Ursodeoxycholic acid alleviates atopic dermatitis-associated inflammatory responses in HaCaT and RBL-2H3 cells and DNCB/DFE-treated mice.

AIMS: Ursodeoxycholic acid (UDCA) is a hydrophilic dihydroxy bile acid used for cholestatic liver disease and exhibits antioxidant, antitumor, and anti-inflammatory effects. However, its potential effects on atopic dermatitis (AD) have not been elucidated. This study aimed to evaluate the efficacy of UDCA in inhibiting the inflammatory response and alleviating lesions in AD-like mice. MAIN METHODS: To investigate the efficacy of UDCA in AD-like inflammatory responses, tumor necrosis factor-alpha (TNF-α)- and interferon-gamma (IFN-γ)-stimulated HaCaT cells and anti-dinitrophenyl immunoglobulin E (DNP-IgE)- and human serum albumin (HSA)-stimulated RBL-2H3 cells were used to investigate the levels of inflammatory factors and their mechanisms. AD-like lesions were induced by applying DNCB/DFE to mice. The effect of UDCA administration in AD-like mice was analyzed by assessing organ weight, serum IgE and inflammatory cytokine levels, and histopathological changes using immunohistochemical and immunofluorescent staining. KEY FINDINGS: In HaCaT cells, UDCA significantly diminished TARC, MDC, MCP-1, and IL-6 expression by inhibiting the phosphorylation of nuclear NF-κB and cytoplasmic IκB, and also increased the levels of skin barrier protein. In RBL-2H3 cells, UDCA reduced ß-hexosaminidase and IL-4 levels. In AD-like mice, UDCA suppressed organ hypertrophy, ear edema, SCORAD index, DFE-specific IgE levels, inflammatory cytokine levels, skin hypertrophy, mast cell invasion, skin barrier loss, and thymic stromal lymphopoietin-positive areas. SIGNIFICANCE: UDCA suppressed the expression of pro-inflammatory cytokines by keratinocytes and mast cells. It also alleviated atopy by suppressing symptoms without organ toxicity in AD-like mice. UDCA may be an effective and safe treatment for AD.

Supercritical CO2 fluid extract from Stellariae Radix ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis by inhibit M1 macrophages polarization via AMPK activation.

Yin chai hu (Radix Stellariae) is a root medicine that is frequently used in Chinese traditional medicine to treat fever and malnutrition. In modern medicine, it has been discovered to have anti-inflammatory, anti-allergic, and anticancer properties. In a previous study, we were able to extract lipids from Stellariae Radix using supercritical CO2 extraction (SRE), and these sterol lipids accounted for up to 88.29% of the extract. However, the impact of SRE on the development of atopic dermatitis (AD) has not yet been investigated. This study investigates the inhibitory effects of SRE on AD development using a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. Treatment with SRE significantly reduced the dermatitis score and histopathological changes compared with the DNCB group. The study found that treatment with SRE resulted in a decrease of pro-inflammatory cytokines TNF-α, CXC-10, IL-12, and IL-1ß in skin lesions. Additionally, immunohistochemical analysis revealed that SRE effectively suppressed M1 macrophage infiltration into the AD lesion. Furthermore, the anti-inflammatory effect of SRE was evaluated in LPS + INF-γ induced bone marrow-derived macrophages (BMDMs) M1 polarization, SRE inhibited the production of TNF-α, CXC-10, IL-12, and IL-1ß and decreased the expression of NLRP3. Additionally, SRE was found to increase p-AMPKT172, but had no effect on total AMPK expression, after administration of the AMPK inhibitor Compound C, the inhibitory effect of SRE on M1 macrophages was partially reversed. The results indicate that SRE has an inhibitory effect on AD, making it a potential therapeutic agent for this atopic disorder.

Immunomodulatory and anti-angiogenesis effects of excavatolide B and its derivatives in alleviating atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin condition primarily driven by T helper 2 (Th2) cytokines, resulting in skin barrier defects, angiogenesis, and inflammatory responses. The marine natural product excavatolide B (EXCB), isolated from the Formosan Gorgonian coral Briareum stechei, exhibits anti-inflammatory and analgesic properties. To enhance solubility, EXCB is chemically modified into the derivatives EXCB-61 salt and EXCB-79. The study aims to investigate the therapeutic effects of these compounds on dinitrochlorbenzene (DNCB)-induced skin damage and to elucidate the underlying anti-inflammatory and anti-angiogenesis mechanism. In vitro, using lipopolysaccharide (LPS)-induced RAW 264.7 cells, all compounds at 10 µM significantly inhibited expression of inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase-2), vascular endothelial growth factor (VEGF), and cytokines (interleukin (IL)-1ß, IL-6, and IL-17A). In vivo, topical application of these compounds on DNCB-induced AD mice alleviated skin symptoms, reduced serum levels of IgE, IL-4, IL-13, IL-17, and interferon-γ, and moderated histological phenomena such as hyperplasia, inflammatory cell infiltration, and angiogenesis. The three compounds restored the expression of skin barrier-related proteins (loricrin, filaggrin, and claudin-1) and reduced the expression of angiogenesis-related proteins (VEGF and platelet endothelial cell adhesion molecule-CD31) in the tissues. This is the first study to indicate that EXCB, EXCB-61 salt, and EXCB-79 can treat AD disease by reducing inflammation and angiogenesis. Hence, they may be considered potential candidates for the development of new drugs for AD.

Safety, Tolerability, Pharmacokinetics, and pharmacodynamics of YH35324, a novel Long-Acting High-Affinity IgETrap-Fc protein in subjects with Atopy: Results from the First-in-Human study.

BACKGROUND: YH35324, a long-acting IgETrap-Fc fusion protein, is a novel therapeutic agent for immunoglobulin E (IgE)-mediated allergic diseases. This randomized, double-blind, placebo/active-controlled, single ascending dose Phase 1 study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of YH35324 in subjects with atopy. METHODS: Eligible subjects were healthy subjects or atopic adults with mild allergic rhinitis, atopic dermatitis, food allergy, or urticaria, and a serum total IgE level of 30-700 IU/mL (Part A) or > 700 IU/mL (Part B). In Part A, 35 subjects in 5 cohorts received YH35324 (0.3, 1, 3, 6, and 9 mg/kg), 8 received omalizumab (300 mg), and 9 received placebo. In Part B, 8 subjects received YH35324 and 8 received omalizumab. RESULTS: Twenty subjects (38.5 %) in Part A (YH35324: 37.1 %, omalizumab: 50.0 %, placebo: 33.3 %) and 10 subjects (62.5 %) in Part B (YH35324: 100 %; omalizumab: 25.0 %) experienced treatment-emergent adverse events (TEAEs). TEAEs were mostly grade 1/2; no serious AEs, AE-related treatment discontinuation, or anaphylaxis were reported. YH35324 exhibited dose-proportional increase in Cmax and AUClast over the dose range of 0.3-9 mg/kg. YH35324 rapidly suppressed serum-free IgE levels to a significant extent (< 25 and < 82.8 ng/mL, both P < 0.05) and with longer duration than omalizumab. CONCLUSION: This study showed that YH35324 has a favorable safety profile and is effective in reducing serum-free IgE levels in subjects with atopic conditions.

Atopic Dermatitis as a Paradoxical Reaction to Secukinumab in a Patient With Plaque Psoriasis.

Paradoxical reactions to biologic agents used in the treatment of psoriasis are rare but have been reported with tumor necrosis factor (TNF) blockers and, more recently, with interleukin (IL)-17A inhibitors. Secukinumab, an IL-17A inhibitor, is an effective treatment for moderate-to-severe plaque psoriasis but has been implicated in the development or exacerbation of eczematous-like reactions in rare cases. We present a patient with a history of plaque psoriasis who developed an eczematous eruption after four months of secukinumab therapy, necessitating systemic intervention for adequate control. Five months after a loading dose of dupilumab, the patient appeared in the clinic with the return of classic, thick psoriatic plaques, affecting 15% BSA. The patient declined further treatment and was subsequently lost to follow-up despite multiple attempts to contact her. This case adds to the limited, but growing body of knowledge on IL-17 blocker-induced eczematous reactions and underscores the need for careful monitoring and prompt recognition of this adverse event in patients receiving this class of drugs. J Drugs Dermatol. 2024;23(2):97-99.     doi:10.36849/JDD.7639  .

Erigeron annuus Extract Improves DNCB-Induced Atopic Dermatitis in a Mouse Model via the Nrf2/HO-1 Pathway.

Atopic dermatitis (AD) is a persistent inflammatory skin condition resulting from an intricate interplay among genetic, immunological, and environmental factors. Erigeron annuus (EA), an annual winter plant belonging to the family Asteraceae, possesses anti-inflammatory, cytoprotective, and antioxidant activities. In this study, we hypothesized that Erigeron annuus extract (EAE) could be an effective agent for ameliorating AD-like symptoms. To confirm this hypothesis in vitro, we used H2O2-stimulated human keratinocytes (HaCaT cells) to demonstrate that pre-treatment with EAE protected against oxidative stress. HaCaT cells pretreated with EAE and stimulated with H2O2 showed decreased intracellular malondialdehyde content, increased superoxide dismutase activity, and reduced intracellular reactive oxygen species accumulation. To verify the in vivo hypothesis based on the intracellular results, an AD disease mouse model was induced with 1-chloro-2,4-dinitrobenzene (DNCB), and EAE was orally administered at a non-toxic concentration according to the toxicity evaluation results. The results showed that AD disease models in BALB/c mice exhibited reduced ear epidermal thickness, scratching behavior, and mast cell infiltration. In conclusion, our results indicate that EAE has the potential to improve AD by upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway.

Ozonated Sunflower Oil (OSO) Alleviates Inflammatory Responses in Oxazolone-Induced Atopic Dermatitis (AD)-Like Mice and LPS-Treated RAW 264.7 Cells.

Ozone, a highly reactive oxidant molecule, is widely used as a complementary therapy for various skin diseases, including wound healing, pressure ulcers, diabetic foot, and infections. However, there is limited research on the effectiveness of ozone for atopic dermatitis (AD). Ozonated sunflower oil (OSO) is an active ingredient obtained from partially ozonated sunflower oil (SO). OSO markedly reduced the LPS-induced increase in IL-1ß and nitric oxide (NO) levels in RAW 264.7 mouse macrophage cells. Oxazolone (OXZ) was applied to hairless mice to induce AD-like skin symptoms and immune response. OSO significantly alleviated the OXZ-induced increases in the number of infiltrating mast cells, epidermal thickness, AD symptoms, thymic stromal lymphopoietin (TSLP), and filaggrin, as well as the serum levels of NO, IgE, IL-1ß, and TNF-α. Furthermore, OSO inhibited the IL-4/STAT3/MAPK pathway and the expression of NF-κB. Our results suggest that OSO treatment could relieve AD-mediated skin damage through its anti-inflammatory and antioxidant activities. Therefore, it can be used as a therapeutic agent against AD-related skin diseases.

Qing-Re-Chu-shi decoction ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis in NC/Nga mice through anti-inflammation and immunoregulatory mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Qing-Re-Chu-Shi Decoction (QRCSD), a traditional Chinese herbal formula, has been employed as a complementary and alternative therapy for inflammatory skin diseases. However, its active constituents and the mechanistic basis of its action on atopic dermatitis remain in adequately understood. AIM OF THE STUDY: Atopic dermatitis (AD) is an allergic dermatitis marked by eczematous lesions and pruritus. The study aimed to elucidate the underlying effects of QRCSD on AD and to identify the components responsible for its therapeutic efficacy in a mouse model. MATERIALS AND METHODS: Network pharmacology and UPLC-mass analysis were used to anticipate the pharmacological mechanisms and to identify active components of QRCSD, respectively. A DNCB-induced AD-like model was established in NC/Nga mice. QRCSD or prednisolone (as a positive control) was administered via gavage every other day from day14 to day 21. Dermatitis severity score, scratching behavior, skin barrier function, spleen index, Th1/Th2 lymphocyte ratio, and serum IgE levels were evaluated. Protein arrays, including 40 inflammatory cytokines, were performed on skin lesions, followed by confirmation experiments of Western blotting in dorsal skin lesions. RESULTS: The construction of a QRCSD-AD-Network and topological analysis firstly proposed potential targets of QRCSD acting on AD. Animal experiments demonstrated that oral administration of QRCSD ameliorated AD-like lesions, reduced epidermal thickness and mast cell count, decreased serum IgE levels, augmented tight junction protein (Claudin 1, Occludin) levels, and regulated the Th1/Th2 balance in the spleen, as well as spleen index. Elevated levels of interleukin (IL)-4, IL-5, IL-6, IL-17, and Eotaxin were revealed in AD-like skin lesions by protein arrays. Western blotting confirmed that the phosphorylation levels of ERK, P38, JNK, STAT3 and P65 were downregulated, and IL-6 expression was also reduced following QRCSD treatment. CONCLUSIONS: The study enhances the understanding of the anti-inflammatory and immunomodulatory effects of QRCSD, showcasing its significant protective role against atopic dermatitis. Treatment with QRCSD may be considered as a viable candidate for complementary and alternative therapy in managing atopic dermatitis.

Dictamnine Ameliorates DNFB-Induced Atopic Dermatitis Like Skin Lesions in Mice by Inhibiting M1 Macrophage Polarization and Promoting Autophagy.

Autophagy and M1 macrophage polarization play important roles in the regulation of inflammation in atopic dermatitis (AD). Dictamnine is one of the main ingredients in Cortex Dictamni, a widely used traditional Chinese medicine for the treatment of dermatitis. In the present study, we investigated the anti-inflammatory effects of dictamnine on AD like skin lesions and M1 macrophage polarization. A 2,4-dinitrofluorobenzene (DNFB) triggered AD like skin lesions models in mice was established to identify the ameliorative effects of dictamnine on AD in vivo. In addition, an M1 macrophage polarization model was co-stimulated by lipopolysaccharide (LPS) and interferon-γ (IFN-γ) using phorbol myristate acetate (PMA) differentiated THP-1 cells, to investigate the effect of dictamnine on promoting autophagy and inhibiting inflammatory factor release. Dictamnine suppressed DNFB-induced skin inflammation by inhibiting M1 macrophage polarization, up-regulating the expression of microtubule-associated protein 1A/1B-light chain 3 (LC3) expression, and promoting macrophage autophagy at inflammatory sites. Dictamnine also could reduce the release of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8), and down-regulate the mRNA expression of these genes in LPS-IFN-γ triggered M1 polarized macrophages. Dictamnine ameliorates AD like skin lesions by inhibiting M1 macrophage polarization and promoting autophagy. Hence, dictamnine is expected to be a potential therapeutic candidate for AD.

A Review of Dupilumab-Induced Adverse Events to Dermatologists and the Potential Pathogenesis in the Treatment of Atopic Dermatitis.

Dupilumab, a monoclonal antibody targeting interleukin-4 antibody, is approved for use in many type 2 inflammatory diseases, including atopic dermatitis. It is generally well tolerated with no need of routine laboratory monitoring. However, several adverse events have been reported during real-world practice and in pivotal trials. We conducted a systematic literature research of the PubMed, Medline, and Embase databases to identify articles recording the clinical manifestation and potential pathogenesis of these adverse events with interests (AEIs) to dermatologists. In total, 547 cases from 134 studies have developed 39 AEIs 1 day to 2.5 years after dupilumab treatment. The most common AEIs are facial and neck dermatitis (299 cases), psoriasis (70 cases), arthralgia (56 cases), alopecia (21 cases), cutaneous T cell lymphoma (19 cases), severe ocular diseases (19 cases), and drug eruption (6 cases). Most of the AEIs recorded in this review resolved or improved after dupilumab discontinuation or the addition of another treatment, whereas 3 of the cases died of severe AEI. The potential pathogenesis included T help type 1 (Th1)/T help type 2 (Th2) imbalance, Th2/T help type 17 (Th17) imbalance, immune reconstitution, hypersensitivity reaction, transient hypereosinophilia related, and Th1 suppression. Clinicians should be alert of these AEIs for timely diagnosis and appropriate treatment.

Exploration of costunolide derivatives as potential anti-inflammatory agents for topical treatment of atopic dermatitis by inhibiting MAPK/NF-κB pathways.

Atopic dermatitis (AD) is a common inflammatory disease and it is very difficult to treat. In the present work, a series of costunolide derivatives have been prepared, and in vitro and in vivo anti-inflammatory activities have evaluated. The results showed that most derivatives displayed good inhibition of NO generation with low cytotoxicity, and 7d could inhibit the phosphorylation of P38, P65 NF-κB and IκB-α in LPS-induced RAW264.7 model. The in vivo researches showed that 7d could improve skin injury symptoms, decrease Th2-type cytokine levels, inhibit HIS levels, alleviate scratching and repaire the damaged skin barrier through the inhibition of phosphorylation of MAPK and NF-κB signaling pathways on MC903-induced AD model. Therefore, costunolide derivatives may be new potent anti-AD agents for further study.

Anti-Atopic Dermatitis Effect of TPS240, a Novel Therapeutic Peptide, via Suppression of NF-κB and STAT3 Activation.

Atopic dermatitis (AD) is a relapsing skin disease with persistent inflammation as a causal factor for symptoms and disease progression. Current therapies provide only temporary relief and require long-term usage accompanied by side effects due to persistent relapses. A short peptide, TPS240, has been tested for its potential to subside AD. In this study, we confirmed the anti-atopic effect of TPS240 in vivo and in vitro using a DNCB-induced AD mouse model and TNF-α/IFN-γ-stimulated HaCaT cells. In the AD mouse model, topical treatment with TPS240 diminished AD-like skin lesions and symptoms such as epidermal thickening and mast cell infiltration induced by DNCB, similar to the existing treatment, dexamethasone (Dex). Furthermore, skin atrophy, weight loss, and abnormal organ weight changes observed in the Dex-treated group were not detected in the TPS240-treated group. In TNF-α/IFN-γ-stimulated HaCaT cells, TPS240 reduced the expression of the inflammatory chemokines CCL17 and CCL22 and the pruritic cytokines TSLP and IL-31 by inhibiting NF-κB and STAT3 activation. These results suggest that TPS240 has an anti-atopic effect through immunomodulation of AD-specific cytokines and chemokines and can be used as a candidate drug for the prevention and treatment of AD that can solve the safety problems of existing treatments.

PYR-41, an inhibitor of ubiquitin-activating enzyme E1, attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in mice.

PYR-41 is an irreversible and cell permeable inhibitor of ubiquitin-activating enzyme E1, and has been reported to inhibit the degradation of IκB protein. Previous studies have shown that PYR-41 has effects on anti-inflammatory, but whether it has therapeutic effects on allergic dermatitis is unclear. The aim of this research was to explore the therapeutic effects of PYR-41 on atopic dermatitis. The effects of PYR-41 on the activation of NF-κB signaling pathway and the expression of inflammatory genes in HaCat cells were tested by western blot and qPCR. A mouse model was built, and the AD-like skin lesions were induced by 2,4-dinitrochlorobenzene (DNCB). Then, the treatment effects of PYR-41 were examined by skin severity score, ear swelling, ELISA, and qPCR. The results showed that PYR-41 can significantly reduce the K63-linked ubiquitination level of nuclear factor-κB essential modulator (NEMO) and tumor necrosis factor receptor associated factor 6 (TRAF6), inhibit the proteasomal degradation of IκBα, thereby activate TNF-α-induced NF-κB signaling pathway in HaCat cells. In addition, DNCB-treated mice have significant reduction in symptoms after treated by PYR-41, including reduced ear thickening and reduced skin damage. Serum tests showed that PYR-41 significantly reduced the expression of IgE, IFN-γ, and TNF-α. In conclusion, the current results suggest that PYR-41 has potential to reduce the symptoms of atopic dermatitis.

Double Emulsion-Mediated Delivery of Polyphenol Mixture Alleviates Atopic Dermatitis.

Although the polyphenols have been studied to alleviate inflammation, there are still challenges to delivering the polyphenols with stabilized formulation due to their low water solubility and susceptibility to oxidation. Herein, the transdermal delivery system of polyphenol mixture (PM), including quercetin (Q), phloretin (P), and ellagic acid (E), is developed using double emulsion for applying to atopic dermatitis (AD). Through the in vitro anti-degranulation assay, the optimal molar ratio of each polyphenol (Q:P:E = 5:1:1) is obtained, and the PM shows at most a 43.6% reduction of degranulation of immune cells, which is the primary factor of AD. Moreover, the water-in-oil-in-water double emulsion (W/O/W) enhances the PM's stability and has a higher anti-degranulation effect than the oil-in-water emulsion (O/W). In the in vivo 1-chloro-2,4-dinitrobenzene (DNCB)-induced mice AD model, PM reduces more AD symptoms than every single polyphenol. The PM-encapsulated W/O/W (PM_W/O/W) shows the most effectiveness in AD by decreasing dermatitis score, i.e., skin/ear thickness, mast cells, and serum IgE level. Finally, this suggests that the findings on the optimal ratio of PM and double emulsion-based delivery would be beneficial in treating AD and can be applied to other allergic diseases.

Zhenxin Anshen formula ameliorates atopic der-matitis-like skin dysfunction in mice and regulation of transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 in Neural pathways.

OBJECTIVE: To investigate the efficacy of Zhenxin Anshen formula (, ZXAS) on atopic dermatitis (AD) by transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) signalling pathway in mice and . METHODS: AD-like lesions were induced by 1-chloro-2,4-dinitrobenzene (DNCB) to the shaved dorsal skin of BALB/c mice. BALB/c mice were divided into five groups: normal control, model control, cetirizine, low-, medium-, and high-dose of ZXAS. After ZXAS in-tervention, the skin lesions and blood samples were collected for hematoxylin and eosin-stained and measuring the concentrations of inflammatory cytokines. Immun-oglobulin E (IgE), interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin (TSLP) were de-tected by Enzyme-linked immunosorbent assay (ELISA). The spinal cords were collected for measuring the expression of gastrin-releasing peptide receptor (GRPR), TRPV1, and TRPA1 by using immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. In addition, 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, ELISA, and Western blotting were conducted for analysis of primary dorsal root ganglia (DRG) neurons . RESULTS: ZXAS treatment improved DNCB-induced AD-like lesions through reducing dermatitis score, number of scratching and epidermal thickness, accompanied by the de-creased IgE and Th2 inflammatory cytokines. ZXAS also supressed the mRNA and protein expression of GRPR, TRPV1, and TRPA1 in the spinal cord. The medicated sera of ZXAS decreased capsaicin-induced Ca influx and downregulated the expression of TRPV1, TRPA1, and phospholipase C in DRG neurons. CONCLUSIONS: The therapeutic effect of ZXAS on AD may be related to the regulation of TRPV1 and TRPA1 and inhibition of Ca2+ signals in neurons.

Coffea arabica Extract Attenuates Atopic Dermatitis-like Skin Lesions by Regulating NLRP3 Inflammasome Expression and Skin Barrier Functions.

Atopic dermatitis (AD) is a common skin disease worldwide. The major causes of AD are skin barrier defects, immune dysfunction, and oxidative stress. In this study, we investigated the anti-oxidation and anti-inflammation effects of Coffea arabica extract (CAE) and its regulation of the skin barrier and immune functions in AD. In vitro experiments revealed that CAE decreased the reactive oxygen species levels and inhibited the translocation of nuclear factor-κB (NF-κB), further reducing the secretion of interleukin (IL)-1ß and IL-6 induced by interferon-γ (IFN-γ)/tumor necrosis factor-α (TNF-α). Moreover, CAE decreased IFN-γ/TNF-α-induced NLR family pyrin domain-containing 3 (NLRP3), caspase-1, high-mobility group box 1 (HMGB1), and receptor for advanced glycation end products (RAGE) expression levels. It also restored the protein levels of skin barrier function-related markers including filaggrin and claudin-1. In vivo experiments revealed that CAE not only reduced the redness of the backs of mice caused by 2,4-dinitrochlorobenzene (DNCB) but also reduced the levels of pro-inflammatory factors in their skin. CAE also reduced transepidermal water loss (TEWL) and immune cell infiltration in DNCB-treated mice. Overall, CAE exerted anti-oxidation and anti-inflammation effects and ameliorated skin barrier dysfunction, suggesting its potential as an active ingredient for AD treatment.

Vitamin D attenuates DNCB-induced atopic dermatitis-like skin lesions by inhibiting immune response and restoring skin barrier function.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease causing erythema and itching. The etiology of AD is complex and not yet clear. Vitamin D is a fat-soluble vitamin that promotes skin cell growth and differentiation and regulates immune function. This study aimed to explore the therapeutic effect of calcifediol, the active metabolite of vitamin D, on experimental AD and the possible mechanism of action. We found that the levels of vitamin D binding protein (VDBP) and vitamin D receptor (VDR) in biopsy skin samples from AD patients decreased compared with controls. We used 2,4-dinitrochlorobenzene (DNCB) to induce an AD mouse model on the ear and back of BALB/c mice. A total of five groups were used: the control group, the AD group, the AD + calcifediol group, the AD + dexamethasone group, and the calcifediol alone group. Under calcifediol treatment, mice exhibited reduced spinous layer thickening, reduced inflammatory cell infiltration, downregulated aquaporin 3 (AQP3) expression, and restored the barrier function of the skin. Simultaneous calcifediol treatment decreased STAT3 phosphorylation, inhibited inflammation and chemokine release, decreased AKT1 and mTOR phosphorylation, and suppressed epidermal cell proliferation and abnormal differentiation. In conclusion, our study demonstrated that calcifediol significantly protected mice against DNCB-induced AD. In a mouse model of AD, calcifediol may reduce inflammatory cell infiltration and chemokines by inhibiting the phosphorylation of STAT3 and may restore skin barrier function through the downregulation of AQP3 protein expression and inhibition of cell proliferation.

The Anti-Inflammatory and Skin Barrier Function Recovery Effects of Schisandra chinensis in Mice with Atopic Dermatitis.

Background and Objectives: The fruit of Schisandra chinensis (Turcz.) Baill. is widely used medicinally to treat coughs, asthma, exhaustion, eczema, and pruritus in Northeast Asian countries, including Korea, China, and Japan. This study was designed to investigate the effects of S. chinensis on dermatitis in mice with calcipotriol (MC-903)-induced atopic dermatitis (AD), and its effects on skin barrier dysfunction was also investigated. Materials and Methods: The inhibitory effects of an ethanolic extract of S. chinensis (EESC) on skin lesions, water content, water-holding capacity (WHC), histopathological abnormalities, and inflammatory cytokine and chemokine levels were evaluated in mice with AD induced by MC903. Results: Topical EESC ameliorated skin lesions, reduced skin water content, and increased MC903-induced WHC. EESC also prevented MC-903-induced histopathological abnormalities such as epidermal disruption, hyperkeratosis, spongiotic changes, and immune cell infiltration in inflamed tissue. Moreover, topical EESC reduced MC-903-induced levels of pro-inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-4, IL-6, IL-8, monocyte chemotactic protein (MCP)-1, and thymic stromal lymphopoietin (TSLP). Furthermore, unlike dexamethasone, EESC did not reduce the spleen/body weight ratio. Conclusions: These results suggest that S. chinensis can be used as an alternative to external corticosteroids and that its anti-inflammatory and skin barrier dysfunction-restoring effects are related to the downregulation of pro-inflammatory cytokines and chemokines, such as TNF-α, IL-4, IL-6, IL-8, and TSLP.

Effects of Varying Ratios of Glycyrrhiza uralensis and Donkey Hide Gelatin Water Extracts on Dinitrochlorobenzene-Induced Atopic Dermatitis in NC/Nga Mice.

Atopic dermatitis is a chronic skin disease that affects millions of people all over the world. The objective of this study was to evaluate the inhibitory effects of the roots of Glycyrrhiza uralensis (GU) and Donkey Hide Gelatin (DHG) water extracts on DNCB-induced NC/Nga mice and TNF-α/IFN-γ treated keratinocytes or LPS-stimulated macrophages. The combined treatment using the water extracts of GU and DHG improved the skin symptom evaluation score and skin histology, with increased expression of the skin barrier proteins Claudin 1 and Sirt 1 in lesion areas. The IFN-γ activity was promoted in PBMCs, ALN, and dorsal skin tissue, while the absolute cell number was reduced for T cells so that the production and expression of serum IgE and cytokines were suppressed. In TNF-α/IFN-γ induced HaCaT cells, IL-6, IL-8, MDC, and RANTES were all inhibited by GU and DHG water extracts, while ICAM-1 and COX-2 levels were similarly downregulated. In addition, GU and DHG water extracts decreased LPS-mediated nitric oxide, IL-6, TNF-α, and PGE2 in RAW 264.7 cells, and the expression of iNOS and COX-2 also decreased. Notably, the DHG:GU ratio of 4:1 was shown to have the best effects of all ratios. In conclusion, GU and DHG have anti-skin inflammatory potentials that can be used as alternative ingredients in the formula of functional foods for people with atopic dermatitis.