Epimedin A ameliorates DNFB-induced allergic contact dermatitis in mice: Role of NF-κB/NLRP3-driven pyroptosis, Nrf2/HO-1 pathway, and inflammation modulation
Introduction
Allergic contact dermatitis (CD) is a common multifactorial, pruritic, inflammatory skin disease with complex etiology [1]. It affects approximately 5–20% of children and 7–14% of adults worldwide, with a significant global social and economic burden [2]. Clinically, the CD develops eczematous lesions, with itching, erythema, edema, dry skin, and recurrent skin infections that affect sleep, quality of life, and patient's physical and mental health [3]. However, therapeutic agents available for CD treatment provide temporary relief of symptoms; nevertheless, they are associated with many side effects over long-term therapy, such as skin atrophy, immunosuppression, loss of efficacy, and insufficient effect over time [3]. Therefore, the search for potential therapeutic targets or effective agents against CD remains an urge.
The NOD-like receptor containing protein 3 (NLRP3) is widely identified in epithelial cells such as skin keratinocytes, which construct an important inflammasome together with an apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and procaspase-1 [4]. Furthermore, NLRP3 inflammasome activation by the nuclear factor kappa B (NF-κB) signal pathway is a crucial regulator of allergic contact dermatitis development, as it triggers NLRP3 inflammasome assembly, caspase-1 activation, release, and maturation of interleukin (IL) -1β and IL-18, with cleavage of gasdermin D (GSDMD), and augmentation of pro-inflammatory cytokines production with pyroptosis induction [5], [6], [7]. Therefore, NLRP3 inflammasome regulation could be a potential therapeutic strategy for treating CD.
Moreover, the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) signaling pathway plays a critical role in maintaining the skin barrier and preventing the development of CD [8]. Nrf2 is a transcription factor that remains inactive in the cytosol, but is activated during inflammatory states, migrates to the nuclei, and interacts with the genes involved to promote the production of antioxidant enzymes, which in turn facilitate the synthesis of the antioxidant molecules, and counteracts the oxidative stress molecules [9], [10]. Furthermore, activation of the Nrf2 signaling pathway inhibits the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, thus dampening skin inflammation [11].
Epimedin A, a prenylated flavanol glycoside, is one of the main active ingredients in Herba Epimedii, which are popular Chinese herbs that have been used for centuries to strengthen bones, muscles, and tendons, and to treat rheumatism, cardiovascular disease, diabetes, infertility, and amnesia [12], [13]. Recent studies documented that Herba Epimedii amends various disease models by suppressing of NF-κB singling pathway, NLRP3 inflammasome assembly, pro-inflammatory cytokines secretion, and enhancing the antioxidant system [14], [15], [16]. Therefore, in the present study, we aimed to investigate the potential of epimedin A to treat CD using a DNFB mouse model, emphasizing its potential modulating activities on NF-κB/NLRP3 and Nrf2/HO-1 singling pathways.
Section snippets
Chemicals and reagents
The following chemicals and reagents were bought commercially, 2,4-dinitrofluorobenzene (DNFB), acetone, prednisone, epimedin A, bovine serum albumin (BSA), mouse monoclonal anti-dinitrophenyl (DNP) -IgE and Masson trichrome stain from Sigma, St. Louis, MO, USA, carboxymethylcellulose (CMC), phosphate-buffered saline (PBS), formalin-buffered saline, and hematoxylin & eosin stains from El Gomhuria Co., Tanta, Egypt, thiopental sodium from EIPICO, Tenth of Ramadan City, Egypt, and rat monoclonal
Epimedin A alleviates DNFB-induced mice's scratching behavior and dermatitis score
To understand the therapeutic potential of epimedin A in the context of CD, we administered sequentially increasing doses of epimedin A to a mouse model of DNFB-induced CD. We assessed the disease severity by measuring animal scratching behavior and dermatitis scores. The untreated CD group had significantly higher scratching episodes and dermatitis scores than the CON group. Additionally, the groups of animals treated with epimedin A showed a dose-dependent significant reduction of scratching
Discussion
Allergic contact dermatitis (CD) is a common multifactorial, pruritic, inflammatory skin disease with complex etiology [1]. However, therapeutic agents available for its treatment provide temporary relief of symptoms, are associated with many side effects over long-term therapy, and have insufficient effect over time [3]. Therefore, finding potential therapeutic targets or effective agents against CD remains urgent.
In the present study, we investigated the potential of epimedin A to treat
Conclusions
In conclusion, the present study demonstrated the efficacy of oral administration of epimedin A against DNFB-induced CD, in a dose-dependent manner, by suppressing ear tissue inflammatory responses and cellular pyroptosis and enhancing the ear tissue antioxidant system. Additionally, the potential of epimedin A in CD is partially mediated by inhibiting NF-κB, NLRP3, and caspase-8 signal pathways and potentiating the Nrf2/HO-1 signal pathway and suppressing inflammatory cytokine production.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Mohamed F. Balaha: Conceptualization, Methodology, Investigation, Formal analysis, Writing – original draft, Writing – review & editing. Nehad J. Ahmed: Methodology, Investigation, Formal analysis, Writing – original draft. Ziyad S. Almalki: Methodology, Investigation, Formal analysis, Writing – original draft. Abdullah K. Alahmari: Methodology, Investigation, Formal analysis, Writing – original draft. Ahmed M. Alshehri: Methodology, Investigation, Formal analysis, Writing – original draft.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References (50)
- et al.
Interleukin-1β maturation triggers its relocation to the plasma membrane for gasdermin-D-dependent and-independent secretion
Cell Rep.
(2018) - et al.
Simultaneous extraction of epimedin A, B, C and icariin from Herba Epimedii by ultrasonic technique
Ultrason. Sonochem.
(2008) - et al.
A novel herbal formulation consisting of red ginseng extract and Epimedium koreanum Nakai-attenuated dextran sulfate sodium-induced colitis in mice
J.Ginseng Res.
(2020) - et al.
Epimedin officinalis inhibits NFkB, ERK and JNK signaling and enhances nuclear translocation of the glucocorticoid receptor: implications for reversing steroid-resistance
J. Allergy Clin. Immunol.
(2020) - et al.
Total glucosides of paeony inhibit the inflammatory responses of mice with allergic contact dermatitis by restoring the balanced secretion of pro-/anti-inflammatory cytokines
Int. Immunopharmacol.
(2015) - et al.
Determination of serum proteins by means of the biuret reaction
J. Biol. Chem.
(1949) - et al.
New insights into the regulation of apoptosis, necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8
Curr. Opin. Cell Biol.
(2020) - et al.
TMT induces apoptosis and necroptosis in mouse kidneys through oxidative stress-induced activation of the NLRP3 inflammasome
Ecotoxicol. Environ. Saf.
(2022) - et al.
The senescent bystander effect is caused by ROS-activated NF-κB signalling
Mech. Ageing Dev.
(2018) - et al.
Gene expression changes induced by skin sensitizers in the KeratinoSensTM cell line: discriminating Nrf2-dependent and Nrf2-independent events
Toxicol. in Vitro
(2013)