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Lignans from Machilus thunbergii as Thymic Stromal Lymphopoietin Inhibitors.

ABSTRACT: Thymic stromal lymphopoietin (TSLP) plays an important role in the pathophysiology of various allergic diseases that are mediated by T helper cell type-2 (Th2) responses, including asthma and atopic dermatitis. The primary focus of this study was the identification of potent inhibitors of the TSLP signaling pathway for potential therapeutic use. The 80% methanol extract of Machilus thunbergii bark significantly inhibited the signal transducer and activator of transcription 5 (STAT5) phosphorylation in human mast cell (HMC)-1 cells. Through activity-guided isolation, three lignans (1-3) were obtained and identified as (+)-galbelgin (1), meso-dihydroguaiaretic acid (2), and machilin A (3). Among them, two lignans (1 and 2) significantly inhibited STAT5 phosphorylation and TSLP/TSLPR interaction, as determined by ELISA. Our results indicated that lignans isolated from M. thunbergii are a promising resource for the treatment of allergic diseases.

SUBMITTER: Shin H

PROVIDER: S-EPMC8398558 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Lignans from <i>Machilus thunbergii</i> as Thymic Stromal Lymphopoietin Inhibitors.

Shin Hyeji H Han Yoo Kyong YK Byun Youngjoo Y Jeon Young Ho YH Lee Ki Yong KY

Molecules (Basel, Switzerland) 20210808 16

Thymic stromal lymphopoietin (TSLP) plays an important role in the pathophysiology of various allergic diseases that are mediated by T helper cell type-2 (Th2) responses, including asthma and atopic dermatitis. The primary focus of this study was the identification of potent inhibitors of the TSLP signaling pathway for potential therapeutic use. The 80% methanol extract of <i>Machilus thunbergii</i> bark significantly inhibited the signal transducer and activator of transcription 5 (STAT5) phosp ...[more]

PMID: 34443392

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Project description:Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.

Dataset Information

Lignans from Machilus thunbergii as Thymic Stromal Lymphopoietin Inhibitors.

Publications

Lignans from <i>Machilus thunbergii</i> as Thymic Stromal Lymphopoietin Inhibitors.

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