BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Yelin Tang,Wenxin Zhang,Liqin Wu,Bin Bai,Bin Zheng,Mengying Li,Yue Tang,Xiaona Zhu,Yali Zhang,Yi Wang,Bing Zhang
Purpose Acute lung injury (ALI) is a fatal acute inflammatory illness with restricted therapeutic choices clinically. Piperlongumine (PL) is recognized as an alkaloid separated from Piper longum L, which was suggested to exhibit multiple pharmacological activities (e.g., anti-inflammatory activity). However, the effects of PL on LPS-triggered ALI and its anti-inflammatory target remain unclear. This paper intended to assess the roles of PL in LPS-triggered ALI, as well as its underlying mechanism and target. Methods In vivo, ALI was induced by intratracheal injection of LPS to evaluate protective effects of PL and assessed by the changes of histopathological. In vitro, the anti-inflammatory activity and mechanism of PL were investigated by ELISA, RT-qPCR, transcription factor enrichment analysis, Western blotting and Immunofluorescence assay. The binding affinity of PL to MD2 was analyzed using computer docking, surface plasmon resonance , ELISA and immunoprecipitation assay. Results It was reported here that PL treatment alleviated LPS-induced pulmonary damage, inflammatory cells infiltration and inflammatory response in mice. In culture cells, PCR array showed that PL significantly inhibited LPS-induced inflammatory cytokines, chemokines , and type I IFNs genetic expression, along with the inhibition of TAK1 and TBK1 pathway. It is noteworthy that PL is capable of straightly binding to MD2 and inhibiting MD2/TLR4 complex formation and TLR4 dimerization . Conclusions As revealed from this study, PL directly binding to MD2 to block cytokines expression by inhibiting the activation of TAK1 and TBK1 pathway, which then exerted its pulmonary protective activity. Accordingly, PL may act as an underlying candidate for treating LPS-triggered ALI.
研究领域:
药理学
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免疫学
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肺医学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Immunology
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2026
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IF 5.9
Jiangjiang Fu,Gangchen Cheng,Zhongxi Lyu,Zezhi Fan,Feiyang Li,Zhifang Xu,Bo Chen,Yongming Guo,Yuhan Liu,Hui Zhang,Yuan Xu,Yi Guo
Introduction: The acupuncture acupoint is the critical initial site for the therapeutic efficacy of electroacupuncture (EA). Previous studies have confirmed that the NF-κB pathway within the acupoint region mediates the therapeutic effects of acupuncture. Therefore, this study focuses on an in-depth investigation of the MD2/TLR4/NF-κB axis. Methods: The mouse model of adjuvant-induced arthritis (AIA) was established via intraplantar injection of Complete Freund’s Adjuvant (CFA). EA intervention was applied bilaterally to the Zusanli (ST36) acupoints, and behavioral, molecular, and immunological approaches were integrated to investigate the role of MD2 in EA-mediated analgesia. Results: EA increased paw thermal withdrawal thresholds (PTWTs) in AIA mice (P < 0.05), accompanied by higher levels of MD2, TLR4, p65, and the phosphorylated form of p65 (p-p65) at the acupoint. Co-immunoprecipitation (Co-IP) confirmed binding between MD2 and TLR4 in ST36 acupoint, while immunofluorescence (IF) revealed co-localization of TLR4 with fibroblasts and mast cells in ST36, suggesting these immune cells are critical targets for signal activation. Lentivirus-mediated knockdown of MD2 in the acupoint partially reversed EA’s analgesic effects and suppressed downstream TLR4/NF-κB pathway activation, whereas MD2 overexpression elicited a partial analgesic effect and promoted pathway activation. Together with spinal cord proteomics data, these findings indicate that modulating MD2 in the acupoint can regulate spinal cord-related signaling pathways. Mechanistically, EA dynamically regulates the equilibrium of the Grem1/BMP4/COX2 axis in the spinal dorsal horn via activation of the MD2/TLR4/NF-κB pathway cascade, achieving systemic analgesia. Conclusion: This study provides molecular evidence supporting the "acupoint priming" theory in acupuncture and highlights MD2 as a potential therapeutic target for pain management.
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产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
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2024
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IF 3.5
Shipeng Li,Ping Yang,Zhenghan Wu,Wenqiang Huang,Xiaofeng Zhu,Lianmei Zhong
Objective Research has shown that cerebral ischemia-reperfusion injury (CIRI) involves a series of physiological and pathological mechanisms, including inflammation, oxidative stress, and cell apoptosis. The cannabinoid receptor 2 agonist AM1241 has been found to have anti-inflammatory and anti-oxidative stress effects. However, it is unclear whether AM1241 has a protective effect against brain ischemia-reperfusion injury, and its underlying mechanisms are not yet known. Methods In this study, we investigated the anti-inflammatory, anti-oxidative stress, and anti-apoptotic effects of AM1241 and its mechanisms in BV2 cells stimulated with H 2 O 2 and in a C57BL/6 mouse model of CIRI in vitro and in vivo , respectively. Results In vitro , AM1241 significantly inhibited the release of pro-inflammatory cytokines TNF-α and IL-6, reactive oxygen species (ROS), and the increase in Toll-like receptor 4/myeloid differentiation protein 2 (MD2/TLR4) complex induced by H 2 O 2 . Under H 2 O 2 stimulation, MD2 overexpression resulted in increased levels of MD2/TLR4 complex, TNF-α, IL-6, NOX2, BAX, and Cleaved-Caspase3 (C-Caspase3), as well as the activation of the MAPK pathway and NF-κB, which were reversed by AM1241. In addition, molecular docking experiments showed that AM1241 directly interacted with MD2. Surface Plasmon Resonance (SPR) experiments further confirmed the binding of AM1241 to MD2. In vivo , AM1241 significantly attenuated neurofunctional impairment, brain edema, increased infarct volume, oxidative stress levels, and neuronal apoptosis in CIRI mice overexpressing MD2. Conclusion Our study demonstrates for the first time that AM1241 alleviates mouse CIRI by inhibiting the MD2/TLR4 complex, exerting anti-inflammatory, anti-oxidative stress and anti-apoptotic effects.
研究领域:
神经科学
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药理学
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分子生物学
✓ 已验证
DOI
高影响因子
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