Harmine alleviates LPS-induced acute lung injury by inhibiting CSF3-mediated MAPK/NF-κB signaling pathway
Abstract Background Acute lung injury (ALI) is a life-threatening inflammatory lung disease that lacks safe and effective treatment strategies. Harmine, an alkaloid derived from Peganum harmala L plants, exhibits anti-inflammatory activity. However, the protective effect of harmine against ALI and i...
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| Format: | Article |
| Language: | English |
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BMC
2025-03-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-025-03196-8 |
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| author | Yihui Zhai Kejie Chen Zichuang Xu Xiaojian Chen Jiaying Tong Yeying He Chaoyue Chen Meiqing Ding Guang Liang Xiaohui Zheng |
| author_facet | Yihui Zhai Kejie Chen Zichuang Xu Xiaojian Chen Jiaying Tong Yeying He Chaoyue Chen Meiqing Ding Guang Liang Xiaohui Zheng |
| author_sort | Yihui Zhai |
| collection | DOAJ |
| description | Abstract Background Acute lung injury (ALI) is a life-threatening inflammatory lung disease that lacks safe and effective treatment strategies. Harmine, an alkaloid derived from Peganum harmala L plants, exhibits anti-inflammatory activity. However, the protective effect of harmine against ALI and its underlying mechanism remain unknown. This study aimed to elucidate the therapeutic effects and molecular mechanisms of harmine against ALI. Methods The therapeutic effects of harmine were assessed in LPS-induced ALI mice. Serum, bronchoalveolar lavage fluid (BALF), lung tissues were routinely analyzed to evaluated disease severity. The anti-inflammatory mechanism was elucidated in LPS-simulated RAW264.7 cells using a series assays, including RNA-seq, gene silencing, immunofluorescence, western blotting, co-immunoprecipitation and bioinformatic analysis. The biological safety of harmine was determined both in vitro and in vivo through cytotoxicity test, long-term cell proliferation test, acute toxicity test in mice, and assessments of liver and kidney function and structural changes. Results The results showed that harmine inhibited the expression and secretion of LPS-induced inflammatory factors (IL-6, IL-1β and TNF-α) and reduced inflammatory cell infiltration in the lungs, resulting in alleviated LPS-induced histopathological changes and injury in mice. Mechanically, the findings revealed that harmine does not disrupt the TLR4-MD2 interaction but instead attenuates inflammation by suppressing CSF3 transcription and expression, leading to the inhibition of the MAPK/NF-κB signaling pathway activation induced by LPS stimulation. Additionally, both in vitro and in vivo studies demonstrated that harmine administration does not exhibit obvious cytotoxicity or long-term cell proliferation inhibition, nor does it cause functional or organic lesions the liver and kidney in mice, or other acute toxic effects. Conclusions These findings elucidated that the anti-inflammatory activity of harmine was achieved through the CSF3-mediated inactivation of the MAPK/NF-κB signaling pathway, suggesting that harmine could serve as a promising therapeutic drug for ALI and other inflammatory diseases. |
| format | Article |
| id | doaj-art-f4bf814778c64fc39daeec4bb1029478 |
| institution | OA Journals |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj-art-f4bf814778c64fc39daeec4bb10294782025-08-20T02:10:20ZengBMCRespiratory Research1465-993X2025-03-0126111610.1186/s12931-025-03196-8Harmine alleviates LPS-induced acute lung injury by inhibiting CSF3-mediated MAPK/NF-κB signaling pathwayYihui Zhai0Kejie Chen1Zichuang Xu2Xiaojian Chen3Jiaying Tong4Yeying He5Chaoyue Chen6Meiqing Ding7Guang Liang8Xiaohui Zheng9School of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversityAbstract Background Acute lung injury (ALI) is a life-threatening inflammatory lung disease that lacks safe and effective treatment strategies. Harmine, an alkaloid derived from Peganum harmala L plants, exhibits anti-inflammatory activity. However, the protective effect of harmine against ALI and its underlying mechanism remain unknown. This study aimed to elucidate the therapeutic effects and molecular mechanisms of harmine against ALI. Methods The therapeutic effects of harmine were assessed in LPS-induced ALI mice. Serum, bronchoalveolar lavage fluid (BALF), lung tissues were routinely analyzed to evaluated disease severity. The anti-inflammatory mechanism was elucidated in LPS-simulated RAW264.7 cells using a series assays, including RNA-seq, gene silencing, immunofluorescence, western blotting, co-immunoprecipitation and bioinformatic analysis. The biological safety of harmine was determined both in vitro and in vivo through cytotoxicity test, long-term cell proliferation test, acute toxicity test in mice, and assessments of liver and kidney function and structural changes. Results The results showed that harmine inhibited the expression and secretion of LPS-induced inflammatory factors (IL-6, IL-1β and TNF-α) and reduced inflammatory cell infiltration in the lungs, resulting in alleviated LPS-induced histopathological changes and injury in mice. Mechanically, the findings revealed that harmine does not disrupt the TLR4-MD2 interaction but instead attenuates inflammation by suppressing CSF3 transcription and expression, leading to the inhibition of the MAPK/NF-κB signaling pathway activation induced by LPS stimulation. Additionally, both in vitro and in vivo studies demonstrated that harmine administration does not exhibit obvious cytotoxicity or long-term cell proliferation inhibition, nor does it cause functional or organic lesions the liver and kidney in mice, or other acute toxic effects. Conclusions These findings elucidated that the anti-inflammatory activity of harmine was achieved through the CSF3-mediated inactivation of the MAPK/NF-κB signaling pathway, suggesting that harmine could serve as a promising therapeutic drug for ALI and other inflammatory diseases.https://doi.org/10.1186/s12931-025-03196-8Acute lung injuryMAPK/NF-κB signaling pathwayHarmineInflammatoryGranulocyte Colony-Stimulating factor (CSF3) |
| spellingShingle | Yihui Zhai Kejie Chen Zichuang Xu Xiaojian Chen Jiaying Tong Yeying He Chaoyue Chen Meiqing Ding Guang Liang Xiaohui Zheng Harmine alleviates LPS-induced acute lung injury by inhibiting CSF3-mediated MAPK/NF-κB signaling pathway Respiratory Research Acute lung injury MAPK/NF-κB signaling pathway Harmine Inflammatory Granulocyte Colony-Stimulating factor (CSF3) |
| title | Harmine alleviates LPS-induced acute lung injury by inhibiting CSF3-mediated MAPK/NF-κB signaling pathway |
| title_full | Harmine alleviates LPS-induced acute lung injury by inhibiting CSF3-mediated MAPK/NF-κB signaling pathway |
| title_fullStr | Harmine alleviates LPS-induced acute lung injury by inhibiting CSF3-mediated MAPK/NF-κB signaling pathway |
| title_full_unstemmed | Harmine alleviates LPS-induced acute lung injury by inhibiting CSF3-mediated MAPK/NF-κB signaling pathway |
| title_short | Harmine alleviates LPS-induced acute lung injury by inhibiting CSF3-mediated MAPK/NF-κB signaling pathway |
| title_sort | harmine alleviates lps induced acute lung injury by inhibiting csf3 mediated mapk nf κb signaling pathway |
| topic | Acute lung injury MAPK/NF-κB signaling pathway Harmine Inflammatory Granulocyte Colony-Stimulating factor (CSF3) |
| url | https://doi.org/10.1186/s12931-025-03196-8 |
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