The Efficacy & Molecular Mechanisms of a Terpenoid Compound Ganoderic Acid C1 on Corticosteroid-Resistant Neutrophilic Airway Inflammation: In vivo and in vitro Validation

Zhen-Zhen Wang; Hang Li; Anish R Maskey; Kamal Srivastava; Changda Liu; Nan Yang; Taoyun Xie; Ziyi Fu; Junxiong Li; Xiaohong Liu; Hugh A Sampson; Xiu-Min Li

doi:10.2147/JIR.S433430

The Efficacy & Molecular Mechanisms of a Terpenoid Compound Ganoderic Acid C1 on Corticosteroid-Resistant Neutrophilic Airway Inflammation: In vivo and in vitro Validation

J Inflamm Res. 2024 Apr 25:17:2547-2561. doi: 10.2147/JIR.S433430. eCollection 2024.

Authors

Zhen-Zhen Wang^#^{1

2

3}, Hang Li^#⁴, Anish R Maskey^#², Kamal Srivastava^#^{2

5}, Changda Liu^#⁶, Nan Yang^{2

5}, Taoyun Xie⁷, Ziyi Fu⁸, Junxiong Li⁹, Xiaohong Liu¹⁰, Hugh A Sampson⁶, Xiu-Min Li^{2

11}

Affiliations

¹ Academy of Chinese Medical Science, Henan University of Chinese Medicine, Zhengzhou, Henan, People's Republic of China.
² Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY, USA.
³ Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou, Henan, People's Republic of China.
⁴ Central Lab, Shenzhen Bao'an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, People's Republic of China.
⁵ General Nutraceutical Technology, Elmsford, NY, USA.
⁶ Department of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.
⁸ The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China.
⁹ Guangdong Province Hospital of Integrated Chinese and Western Medicine, Foshan, Guangdong, People's Republic of China.
¹⁰ Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China.
¹¹ Department of Otolaryngology, Westchester Medical Center New York Medical College, Valhalla, NY, USA.

^# Contributed equally.

Abstract

Introduction: Neutrophil predominant airway inflammation is associated with severe and steroid-resistant asthma clusters. Previously, we reported efficacy of ASHMI, a three-herb TCM asthma formula in a steroid-resistant neutrophil-dominant murine asthma model and further identified Ganoderic Acid C1 (GAC1) as a key ASHMI active compound in vitro. The objective of this study is to investigate GAC1 effect on neutrophil-dominant, steroid-resistant asthma in a murine model.

Methods: In this study, Balb/c mice were systematically sensitized with ragweed (RW) and alum and intranasally challenged with ragweed. Unsensitized/PBS challenged mice served as normal controls. Post sensitization, mice were given 4 weeks of oral treatment with GAC1 or acute dexamethasone (Dex) treatment at 48 hours prior to challenge. Pulmonary cytokines were measured by ELISA, and lung sections were processed for histology by H&E staining. Furthermore, GAC1 effect on MUC5AC expression and on reactive oxygen species (ROS) production in human lung epithelial cell line (NCI-H292) was determined by qRT-PCR and ROS assay kit, respectively. Computational analysis was applied to select potential targets of GAC1 in steroid-resistant neutrophil-dominant asthma. Molecular docking was performed to predict binding modes between GAC1 and Dex with TNF-α.

Results: The result of the study showed that chronic GAC1 treatment, significantly reduced pulmonary inflammation (P < 0.01-0.001 vs Sham) and airway neutrophilia (P < 0.01 vs Sham), inhibited TNF-α, IL-4 and IL-5 levels (P < 0.05-0.001 vs Sham). Acute Dex treatment reduced eosinophilic inflammation and IL-4, IL-5 levels, but had no effect on neutrophilia and TNF-α production. GAC1 treated H292 cells showed decreased MUC5AC gene expression and production of ROS (P < 0.001 vs stimulated/untreated cells). Molecular docking results showed binding energy of complex GAC1-TNF was -10.8 kcal/mol.

Discussion: GAC1 may be a promising anti-asthma botanical drug for treatment of steroid-resistant asthma.

Keywords: Ganoderma; asthma; ganoderic acid; mouse model; neutrophilic inflammation.

Grants and funding

This work was supported by the National Institutes of Health /National Center for Complementary and Integrative Health grant # PO1 AT002647 and by Sean P Parker Foundation to X-ML.