Flavokawain B alleviates LPS-induced acute lung injury via targeting myeloid differentiation factor 2

Luo, Wei; Yang, Liman; Qian, Changtao; Ma, Bo; Manjengwa, Gloria M.; Miao, Xiaomin; Wang, Jie; Hu, Chenghong; Jin, Bo; Zhang, Lingxi; Zheng, Chao; Liang, Guang; Wang, Yi

doi:10.1038/s41401-021-00792-4

Cited by 17 publications

(5 citation statements)

References 38 publications

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“…LPS is a bacterial endotoxin identified in gram-negative bacteria, and this serves as a classical inducer to construct inflammation models. 42 LPS-induced CSS models were generated in vitro, and the results revealed that QFPD can inhibit TNF-α and IL6. In addition, the QFPD treatment reduced the inflammation in the lungs, as evidenced by the reduction in neutrophil infiltration and alveolar congestion.…”

Section: Discussionmentioning

confidence: 99%

Qingfei Paidu Decoction Inhibits LPS-induced Acute Lung Injury by Targeting the Complement Pathway

Shi¹,

Ge²,

Liu³

et al. 2023

Explor Res Hypothesis Med

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Background and objectives: Qingfei Paidu decoction (QFPD) is a compounded Chinese herbal medicine used to treat mild and severe cases of COVID-19. Acute lung injury (ALI) is a common clinical manifestation of COVID-19, and this mainly manifests through lung inflammation and epithelial cell damage. However, the mechanism by which QFPD ameliorates ALI remains unclear. The present study aims to determine the role and molecular mechanism of QFPD in lipopolysaccharide (LPS)-induced ALI in mice. Methods:After the administration of QFPD treatment in LPS-induced ALI mice, the therapeutic effect was evaluated through the H&E staining of lung tissues and the level of inflammatory factors in vivo. The RNA sequencing in mouse peritoneal macrophages and subsequent network pharmacological analysis were used to explore the molecular mechanisms of QFPD. Experimental validation was also performed by immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), and western blot.Results: QFPD inhibited the LPS-induced inflammatory cytokines in macrophages, ameliorated ALI in mice, and prolong its survival at the lethal dose of LPS. Furthermore, the complement-related pathway was enriched through the network pharmacology and transcriptome analysis of the gene expression. The quantitative real-time PCR and apoptotic analysis further confirmed that QFPD inhibited ALI through the classical complement pathway as no additive changes were observed when its key components were silenced plus QFPD treatment.Conclusions: QFPD applied for the treatment of COVID-19 can attenuate ALI through the classical complement pathway. The present study provides a practical basis and directional guide for the further exploration of the use of QFPD in treating ALI.

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Section: Discussionmentioning

confidence: 99%

Qingfei Paidu Decoction Inhibits LPS-induced Acute Lung Injury by Targeting the Complement Pathway

Shi¹,

Ge²,

Liu³

et al. 2023

Explor Res Hypothesis Med

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“…Two chalcone derivatives, 7w and 7x, which possess anti‐inflammatory activity, have been shown to interact with the PHE151 of MD2 through the benzene ring (Y. L. Zhang et al, 2022). Flavokawain B, a natural chalcone isolated from kava kava, has also been shown to interact with MD2 in the same way ( Luo, Yang, et al, 2021). These findings suggest that chalcone compounds might be a reliable source for the development of new MD2 inhibitors with therapeutic potential for both acute and chronic inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

Licochalcone A protects against LPS‐induced inflammation and acute lung injury by directly binding with myeloid differentiation factor 2 (MD2)

Zhu

Jin

Yang

et al. 2022

British J Pharmacology

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Background and Purpose Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a challenging clinical syndrome that leads to various respiratory sequelae and even high mortality in patients with severe disease. The novel pharmacological strategies and therapeutic drugs are urgently needed. Natural products have played a fundamental role and provided an abundant pool in drug discovery. Experimental Approach A compound library containing 160 natural products was used to screen potential anti‐inflammatory compounds. Mice with LPS‐induced ALI was then used to verify the preventive and therapeutic effects of the selected compounds. Key Results Licochalcone A was discovered from the anti‐inflammatory screening of natural products in macrophages. A qPCR array validated the inflammation‐regulatory effects of licochalcone A and indicated that the potential targets of licochalcone A may be the upstream proteins in LPS pro‐inflammatory signalling. Further studies showed that licochalcone A directly binds to myeloid differentiation factor 2 (MD2), an assistant protein of toll‐like receptor 4 (TLR4), to block both LPS‐induced TRIF‐ and MYD88‐dependent pathways. LEU61 and PHE151 in MD2 protein are the two key residues that contribute to the binding of MD2 to licochalcone A. In vivo, licochalcone A treatment alleviated ALI in LPS‐challenged mice through significantly reducing immunocyte infiltration, suppressing activation of TLR4 pathway and inflammatory cytokine induction. Conclusion and Implications In summary, our study identified MD2 as a direct target of licochalcone A for its anti‐inflammatory activity and suggested that licochalcone A might serve as a novel MD2 inhibitor and a potential drug for developing ALI/ARDS therapy.

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“…The TLR4/MD2 complexes then internalize the endosome network to encode a type I interferon via TRAM/TRIF recruitment [ 5 , 6 , 26 ]. Targeting the TLR4 signaling pathway by various mechanisms, including blocking TLR4 dimerization or TLR4/MD2 complex formation, has been conducted extensively in the studies of natural products [ 27 , 28 , 29 ]. Our data revealed that OE exhibited an anti-inflammatory effect by inhibiting the TLR4/MD2 complex.…”

Section: Discussionmentioning

confidence: 99%

Oxybaphus himalaicus Mitigates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting TLR4/MD2 Complex Formation

Zhan

Long

et al. 2022

Antioxidants

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Acute kidney injury (AKI) is described as the abrupt decrease in kidney function always accompanied by inflammation. The roots of Oxybaphus himalaicus Edgew. have long been used in Tibetan folk medicine for the treatment of nephritis. Nevertheless, modern pharmacological studies, especially about the underlying mechanism of O. himalaicus medications, are still lacking. Here, in lipopolysaccharide (LPS)-induced RAW264.7 macrophages, the O. himalaicus extract (OE) showed significant anti-inflammatory activity with the dose dependently reducing the LPS-stimulated release of nitric oxide and the mRNA level and protein expression of inflammatory cytokines and reversed the activation of nuclear factor kappa B (NF-κB). Co-immunoprecipitation assay indicated that OE inhibited Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD2) complex formation and further suppressed both myeloid differentiation factor 88 (MyD88)-dependent and TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent cascades activation. In addition, OE could restrain NADPH oxidase 2 (NOX2) endocytosis by blocking TLR4/MD2 complex formation to prevent reactive oxygen species production. In LPS-induced AKI mice, OE treatment mitigated renal injury and inflammatory infiltration by inhibiting TLR4/MD2 complex formation. UPLC-MS/MS analysis tentatively identified 41 components in OE. Our results indicated that OE presented significant anti-inflammatory activity by inhibiting TLR4/MD2 complex formation, which alleviated LPS-induced AKI in mice.

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Flavokawain B alleviates LPS-induced acute lung injury via targeting myeloid differentiation factor 2

Cited by 17 publications

References 38 publications

Qingfei Paidu Decoction Inhibits LPS-induced Acute Lung Injury by Targeting the Complement Pathway

Qingfei Paidu Decoction Inhibits LPS-induced Acute Lung Injury by Targeting the Complement Pathway

Licochalcone A protects against LPS‐induced inflammation and acute lung injury by directly binding with myeloid differentiation factor 2 (MD2)

Oxybaphus himalaicus Mitigates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting TLR4/MD2 Complex Formation

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