Cryptotanshinone inhibits IgE‑mediated degranulation through inhibition of spleen tyrosine kinase and tyrosine‑protein kinase phosphorylation in mast cells

Abstract

Atopic dermatitis (AD) is a type of chronic skin inflammation and one of the most common relapsing allergic diseases, which presents with a severe rash and itchy skin lesions. The pathogenesis of AD is primarily associated with hyper‑activated mast cells, which makes them an effective treatment target. After cross‑linking the antigen/immunoglobulin (Ig) E complex binds to its high affinity receptor FcεRl on the surface of mast cells. The cells subsequently secrete excessive pro‑inflammatory mediators, including histamine and cytokines, which lead to pruritus and immune cell infiltration in the skin lesions. The present study screened natural compounds that have an inhibitory effect on IgE/antigen‑mediated secretory activity. It was revealed that cryptotanshinone (CRT), a natural compound extracted from Salvia miltiorrhiza Bunge, had inhibitory effects on the IgE/antigen complex. The underlying mechanism by which CRT exerted an anti‑allergy/inflammatory function was investigated using rat basophilic leukaemia (RBL) cells for degranulation assays and a 1‑chloro‑2,4‑dinitrobenzene (DNCB)‑induced AD Balb/c mouse model for in vivo study. CRT effectively mitigated the secretion of pro‑inflammatory cytokines, including tumor necrosis factor‑α and interleukin 1β, as well as immune cell infiltration into skin lesions in a mouse model of AD‑like skin disease induced by dinitrochlorobenzene. The inhibitory effect of CRT on IgE‑mediated mast cell degranulation was mediated by the inhibition of tyrosine kinase‑dependent degranulation signalling pathways involving spleen tyrosine kinase and Lyn. The present study revealed CRT as an inhibitor of mast cell degranulation. Therefore, CRT may be considered for development as a therapeutic drug to treat IgE‑mediated skin diseases.

Chrysin Inhibits NF-κB-Dependent CCL5 Transcription by Targeting IκB Kinase in the Atopic Dermatitis-Like Inflammatory Microenvironment

“…A histopathological analysis, which involved hematoxylin and eosin (H&E) staining, and a morphometric analysis showed that the DNCB-induced increase in epidermal and dermal thickenings reduced significantly ( p < 0.001, n = 5) upon the topical application of chrysin ( Figure 5 C). Previous studies have reported that DNCB increases the phosphorylation of p65 NF-κB in BALB/c mice models [ 18 , 19 ]. We also observed that the epidermal levels of phosphorylated p65 NF-κB were high in mice challenged with DNCB; however, the levels decreased substantially upon the topical application of chrysin ( Figure 5 D).…”

Discovery of a Natural Syk Inhibitor from Chinese Medicine through a Docking-Based Virtual Screening and Biological Assay Study

“…Choiet al reported that tanshinones possibly exert their anti-allergic activities by affecting FcεRI-mediated tyrosine phosphorylation of ERK and PLCγ2 [30]. Buyanravjikh et al reported that cryptotanshinone, a natural compound extracted from Salvia miltiorrhiza Bunge, had an inhibitory effect on IgE/antigen-mediated mast cell degranulation through the inhibition of tyrosine kinase-dependent degranulation signalling pathways [4]. This study demonstrates, for the first time, that tanshinone I is a direct Syk inhibitor and has anti-mast cell degranulation activity in vitro, which may provide a perspective for elucidating the molecular mechanism of tanshinone I for its anti-allergic and other pharmacological effects.…”

“…Inhibition of Syk-mediated immunoreceptor (B-cell receptors, T-cell receptors and Fc receptors) signalling leads to inhibition of mast cells, macrophages and B-cell activation and subsequent release of inflammatory modulators [3]. Recently, Buyanravjikh et al reported that cryptotanshinone could inhibit IgE-mediated mast cell degranulation through theinhibition of tyrosine kinase-dependent degranulation signalling pathways involving Syk and Lyn [4]. Therefore, seeking safe Syk small molecule inhibitors has attracted considerable interest in a number of therapeutic areas, including the treatment of allergic asthma, rhinitis, rheumatoid arthritis and chronic lymphocytic leukaemia [5,6,7].…”

Exploring the Mechanism of Danshen against Myelofibrosis by Network Pharmacology and Molecular Docking

“…plant, the dried root of Salvia miltiorrhiza Bunge) is a common and important Chinese medicine with well-defined phytochemicals. As a type of complementary and alternative medicine, it has been used widely for a long time and shown significant clinical outcomes in terms of anticoagulant, antioxidant, and anti-inflammatory activities to benefits for vascular protection and cancer treatment [7–10]. The major biologically active components of Danshen include water-soluble phenolic acids and lipophilic tanshinones.…”

“…It also has reports indicating that Danshen has excellent anticancer effects, including inhibition of proliferation, restraint of angiogenesis and metastasis, and circumvention of multidrug resistance [9]. For example, Sumiyasuren Buyanravjikh et al [10] found that cryptotanshinone (CRT), a natural product extracted from Danshen, effectively decreased secretion of proinflammatory cytokines including interleukin-1 β and tumor necrosis factor- α . Furthermore, Danshen inhibited hyperproliferative fibroblasts, according to a report [12].…”