2. Academic Validation
  3. Honokiol alleviates ulcerative colitis by targeting PPAR-γ-TLR4-NF-κB signaling and suppressing gasdermin-D-mediated pyroptosis in vivo and in vitro

Honokiol alleviates ulcerative colitis by targeting PPAR-γ-TLR4-NF-κB signaling and suppressing gasdermin-D-mediated pyroptosis in vivo and in vitro

  • Int Immunopharmacol. 2022 Oct;111:109058. doi: 10.1016/j.intimp.2022.109058.
Nan Wang 1,  Rui Kong 2,  Wei Han 3,  Wen Bao 3,  Yihai Shi 4,  LiPing Ye 5,  Jie Lu 6
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, China; Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province; Department of Gastroenterology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China; Department of Gastroenterology, Gongli Hospital, School of Medicine, Shanghai University, Shanghai 200135, China.
  • 2 Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, China; Department of Gastroenterology, Gongli Hospital, School of Medicine, Shanghai University, Shanghai 200135, China.
  • 3 Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, China.
  • 4 Department of Gastroenterology, Gongli Hospital, School of Medicine, Shanghai University, Shanghai 200135, China.
  • 5 Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China. Electronic address: yelp@enzemed.com.
  • 6 Department of Gastroenterology, Gongli Hospital, School of Medicine, Shanghai University, Shanghai 200135, China. Electronic address: kennisren@hotmail.com.
PMID: 35901530 DOI: 10.1016/j.intimp.2022.109058
Abstract

Ulcerative colitis (UC) is a chronic, idiopathic relapsing inflammatory bowel disease. Honokiol is a major active component of the traditional Chinese medicinal herb Magnolia officinalis, which has been widely used in traditional prescriptions to treat tumors, inflammation, and gastrointestinal disorders. In this study, we investigated the ability of this polyphenolic compound to suppress UC in mice and the possible regulatory mechanism. A mouse model of UC induced with dextran sulfate sodium (DSS) in 40 male C57BL/6J mice was used for the in vivo study, and in vitro experiments were performed in mouse RAW264.7 macrophages. Lipopolysaccharide was used to induce the inflammatory response. The mouse bodyweights, stool consistency, and bleeding were determined and the disease activity indices calculated. RAW264.7 macrophages were cultured with or without either honokiol or lipopolysaccharide. Gene and protein expression was analyzed with RT-PCR and western blotting, respectively. GW6471 and GW9662 were used to interrupt the transcription of peroxisome proliferator activated receptor alpha (PPAR-α) and peroxisome proliferator activated receptor gamma (PPAR-γ). Both the in vivo and in vitro experimental results showed that the oral administration of honokiol markedly attenuated the severity of UC by reducing the inflammatory signals and restoring the integrity of the colon. Honokiol dramatically reduced the proinflammatory cytokines TNF-α, IL6, IL1β, and IFN-γ in mice with DSS-induced UC. It also upregulated PPAR-γ expression, and downregulated the TLR4-NF-κB signaling pathway. Moreover, honokiol inhibited gasdermin-D-mediated cell Pyroptosis. These findings demonstrate for the first time that honokiol exerts a strong anti-inflammatory effect in a mouse model of UC, and that its underlying mechanism is associated with the activation of the PPAR-γ-TLR4-NF-κB signaling pathway and gasdermin-D-mediated macrophage Pyroptosis. Therefore, honokiol may be a promising new drug for the clinical management of UC.

Keywords

Gasdermin D; Honokiol; PPAR-γ–TLR4–NF-κB pathway; Pyroptosis; Ulcerative colitis.

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