A Candidate Drug Screen Strategy: The Discovery of Oroxylin A in Scutellariae Radix Against Sepsis via the Correlation Analysis Between Plant Metabolomics and Pharmacodynamics

Lingyu Han; Yue Yuan; Xinyi Chen; Jian Huang; Guan Wang; Chao Zhou; Jianjian Dong; Na Zhang; Yuxin Zhang; Hang Yin; Yunyao Jiang

doi:10.3389/fphar.2022.861105

A Candidate Drug Screen Strategy: The Discovery of Oroxylin A in Scutellariae Radix Against Sepsis via the Correlation Analysis Between Plant Metabolomics and Pharmacodynamics

Front Pharmacol. 2022 May 19:13:861105. doi: 10.3389/fphar.2022.861105. eCollection 2022.

Authors

Lingyu Han¹, Yue Yuan¹, Xinyi Chen¹, Jian Huang^{2

3}, Guan Wang⁴, Chao Zhou⁵, Jianjian Dong¹, Na Zhang¹, Yuxin Zhang², Hang Yin^{1

2}, Yunyao Jiang¹

Affiliations

¹ School of Pharmaceutical Sciences, Institute for Chinese Materia Medica, Tsinghua University, Beijing, China.
² Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
³ Department of Molecular Biology, Princeton University, Princeton, NJ, United States.
⁴ Beijing Huisheng Biotechnology Co., Ltd., Beijing, China.
⁵ Waters Technologies (Shanghai) Ltd., Beijing, China.

Abstract

Sepsis is an acute systemic infectious disease with high mortality, which urgently needs more effective treatment. Scutellariae radix (SR), a commonly used traditional Chinese medicine (TCM) for clearing heat and detoxification, contains rich natural products possessing anti-inflammatory activity. In previous studies, it was found that the anti-inflammatory activities of SR extracts from different ecological conditions varied wildly. Based on this, in the present study, a screening strategy of antisepsis active components from SR based on correlation analysis between plant metabolomics and pharmacodynamics was established, and the mechanism was explored. First of all, a mass spectrum database of SR (above 240 components) was established to lay the foundation for the identification of plant metabolomics by liquid chromatography tandem mass spectrometry (LC-MS/MS). Through the correlation analysis between plant metabolomics and anti-inflammatory activity of SR from different ecology regions, 10 potential components with high correlation coefficients were preliminarily screened out. After the evaluation of anti-inflammatory activity and toxicity at the cellular level, the pharmacodynamic evaluation in vivo found that oroxylin A had the potentiality of antisepsis both in LPS- and CLP-induced endotoxemia mice. Network pharmacology and Western blot (WB) results indicated that oroxylin A significantly inhibited the toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway, which was further confirmed by secreted embryonic alkaline phosphatase (SEAP) assay. Moreover, the molecular docking analysis indicated that oroxylin A might competitively inhibit LPS binding to myeloid differentiation 2 (MD-2) to block the activation of TLR4. The study provided a feasible research strategy for the screening and discovery of antisepsis candidate drugs from TCM.

Keywords: Scutellariae radix; TLR4/NF-κB pathway; anti-sepsis; oroxylin A; plant metabolomics.