Anti-allergic effect of α-cubebenoate isolated from Schisandra chinensis using in vivo and in vitro experiments

doi:10.1016/j.jep.2015.07.049

Journal of Ethnopharmacology

Volume 173, 15 September 2015, Pages 361-369

https://doi.org/10.1016/j.jep.2015.07.049 Get rights and content

Abstract

Aim of the study

In Oriental countries, the dried fruits of Schisandra chinensis are extensively used in traditional medicine to treat asthma, gonorrhea, and other diseases. Recently, α-cubebenoate was isolated as an anti-inflammatory component from Schisandra chinensis. In the present study, the authors examined the anti-allergic effect of α-cubebenoate using in vivo and in vitro experiments.

Materials and methods

α-Cubebenoate was isolated from an extract of Schisandra chinensis fruits. Antigen-induced degranulation and Ca²⁺ mobilization were measured in RBL-2H3 mast cells. In addition, BALB/c mice were sensitized with ovalbumin and aluminum hydroxide, and then challenged with ovalbumin for three consecutive days. α-Cubebenoate (1 mg/kg) was administered intraperitoneally 30 min before each ovalbumin challenge.

Results

In RBL-2H3 mast cells, α-cubebenoate inhibited antigen-induced degranulation and increase of intracellular Ca²⁺ concentrations. In the ovalbumin-induced asthma model, α-cubebenoate suppressed bronchiolar structural changes induced by ovalbumin challenge. Furthermore, α-cubebenoate strongly inhibited accumulations of eosinophils, macrophages, and lymphocytes in bronchoalveolar lavage fluid. α-Cubebenoate also suppressed Th2 cytokines (IL-4 and IL-13) and TGF-β1 in lung tissues and in immune cells at the mRNA and protein levels.

Conclusion

α-Cubebenoate has an inhibitory effect on allergic inflammation and could be utilized as an agent for the treatment of asthma.

Graphical abstract

Introduction

In the genus Schisandra (family Magnoliaceae), Schisandra chinesis (Turcz.) Baill. and Schisandra repanda have a history of medicinal use (Panossian and Wikman, 2008). Schisandra chinensis grows wild in China, Korea, Japan, and Russia, and has been used for more than 40 years as an anti-fatigue tonic by the medical profession in Russia (Mashkovskij, 2000). In Oriental countries, the dried fruits of Schisandra chinensis are extensively used in traditional medicine to treat asthma, gonorrhea, enuresis, dysentery, protracted diarrhea, thirst, diabetes, and other diseases (Liu, 1989, Panossian and Wikman, 2008). In atopic dermatitis and asthma models, Schisandra chinensis extract has been reported to have suppressive effects (Kang and Shin, 2012, Kim et al., 2014), and in a guinea pig model of asthma, Wuwei Dilong decoction (Schisandra fruit and earthworm decoction) was found to inhibit the infiltration and diffusion of inflammatory cells and to regulate leukotriene B₄ and interferon-γ (Li et al., 2009). Schisandra fruit is also the main active constituent of bakumijiogan, an herbal formula used in traditional Chinese medicine, which suppresses atopic dermatitis-like symptoms by correcting Th1/Th2 imbalance (Makino et al., 2008). However, the active constituents responsible for the anti-allergic and anti-asthma effects of Schisandra chinensis fruits have not been identified. Previously, we isolated α-cubebenoate from Schisandra chinensis fruits and showed its anti-inflammatory effect on peritoneal macrophages (Kang et al., 2014).

Bronchial asthma is a common chronic immune disease of the lungs, and affects 4–5% of the population (Wills-Karp, 2004). Airway hyper-responsiveness, reversible airflow obstruction, and bronchial hyper-responsiveness are characteristic features of this disease (Busse and Rosenwasser, 2003), and its pathogenesis is associated with increased inflammatory cell infiltration and excessive mucus secretion into airways (Wills-Karp, 2004). A variety of cell types, such as, lymphocytes (Th2), mast cells, and eosinophils are involved in asthma. Mast cells are the predominant cells of allergic responses, and when activated by allergen binding to IgE attach to high affinity receptors for IgE (FcεRI), they release cytokines, chemokines, leukotrienes, and secretory granules (Lane and Lee, 1996). T lymphocytes play a pivotal role in the pathogenesis by producing Th2 cytokines (IL-4 and IL-13) (Wills-Karp, 2004), which importantly drive IgE production by B cells and mucus hyper-secretion (Wenzel, 2012). Transforming growth factor-β1 (TGF-β1) is also an important factor. It is involved in fibrosis and causes vascular malformation and the induces the proliferation and hypertrophy of airway smooth muscle cells, the hypertrophy of goblet cells, and the destruction of epithelial cells (Makinde et al., 2007, Wen et al., 2003).

Because of the traditional use of the dried fruits of Schisandra chinensis to treat asthma, we sought to determine whether α-cubebenoate has anti-allergic activity against ovalbumin-induced asthma in vitro using rat RBL-2H3 mast cells, and subsequently, we investigated its in vivo anti-allergic effects using an ovalbumin (OVA)-induced mouse model of asthma.

Section snippets

Materials

The fruits of Schisandra chinensis (Turcz.) Baill were collected in September 2010 in Moonkyong (South Korea). A voucher specimen (accession no. SC-PDRL-2) has been deposited in the Herbarium at the Pusan National University. The plant was identified by one of the authors (Y.W. Choi). The isolation and structural determination of α-cubebenoate were described in a previous study (Kang et al., 2014).

Extraction of α-cubebenoate

The dried fruits of Schisandra chinensis (1.0 kg) were ground to a fine powder. Then, they

α-Cubebenoate inhibited antigen-induced degranulation and intracellular Ca²⁺ increases in RBL-2H3 mast cells

FcεRI exists on the membrane of mast cells and traps circulating IgE. Antigen exposure induces cross-linking of the cell-bound IgE, which results in degranulation (Lane and Lee, 1996). Degranulation induces release of prostaglandins, histamins and cytokines through increase of intracellular Ca²⁺ concentration. Degranulation in antigen-exposed mast cells is a key step in allergic response. Therefore, degranulation was used to test anti-allergic activity of α-cubebenoate. Degranulation was

Discussion

The dried fruits of Schisandra chinensis are used traditionally to treat asthma in the Orient (Liu, 1989, Panossian and Wikman, 2008). Extracts of Schisandra chinensis fruits or mixtures containing Schisandra chinensis fruits have been shown to possess anti-allergic and anti-asthma effects. For example, Schisandra chinensis extract was found to have a suppressive effect in an atopic dermatitis model and in an OVA-induced asthma model (Kang and Shin, 2012, Kim et al., 2014), and a decoction of

Conclusion

The present study shows that α-cubebenoate from Schisandra chinensis fruits exerts anti-allergy effects by inhibiting antigen-induced degranulation and [Ca²⁺]_i increases in mast cells and by suppressing Th2 cytokine secretion in BALF and TGF-β1 expression in the lung tissues and BALF from OVA-induced asthma mice. We believe these findings indicate α-cubebenoate could be utilized to develop anti-allergic and anti-asthma treatments.

Acknowledgement

This research was supported by the High Value-added Food Technology Development Program (Grant no. 111135-03-2-SB030) of the Korean Ministry for Food, Agriculture, Forestry, and Fisheries and by the Korean National Research Foundation funded by the Korean government (MSIP) (Grant no. 2009-0083538).

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Anti-allergic effect of α-cubebenoate isolated from Schisandra chinensis using in vivo and in vitro experiments

Abstract

Aim of the study

Materials and methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Materials

Extraction of α-cubebenoate

α-Cubebenoate inhibited antigen-induced degranulation and intracellular Ca2+ increases in RBL-2H3 mast cells

Discussion

Conclusion

Acknowledgement

Biochem. Biophys. Res. Commun.

J. Allergy Clin. Immunol.

Toxicology

Pulm. Pharmacol. Ther.

J. Allergy Clin. Immunol.

J. Ethnopharmacol.

J. Ethnopharmacol.

Int. Immunopharmacol.

J. Tradit. Chin. Med.

Cell

Life Sci.

J. Ethnopharmacol.

J. Allergy Clin. Immunol.

Genes of tolerance

Allergy

Ionotropic and metabotropic proton-sensing receptors involved in airway inflammation in allergic asthma

Mediat. Inflamm.

Inflammatory changes in the airways of mice caused by cigarette smoke exposure are only partially reversed after smoking cessation

Respir. Res.

Gomisin N has anti-allergic effect and inhibits inflammatory cytokine expression in mouse bone marrow-derived mast cells

Immunopharmacol. Immunotoxicol.

IgE generation and mast cell effector function in mice deficient in IL-4 and IL-13

J. Immunol.

Requirement for IL-13 independently of IL-4 in experimental asthma

Science

α-Cubebenoate inhibited antigen-induced degranulation and intracellular Ca²⁺ increases in RBL-2H3 mast cells