Wedelolactone Mitigates Alcoholic Steatohepatitis via Modulating the TLR4/MyD88/NF-κB Pathway
Background. Wedelolactone (WEL) has demonstrated anti-inflammatory properties. However, the therapeutic effect and underlying mechanisms of WEL against alcoholic steatohepatitis (ASH) remain unclear. This study aimed to investigate these aspects using animal and cell models. Methods and Results. The...
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Wiley
2024-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2024/9185668 |
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| author | Tao Jiang Bingde Hu Yongxia Li Shuihong Yu |
| author_facet | Tao Jiang Bingde Hu Yongxia Li Shuihong Yu |
| author_sort | Tao Jiang |
| collection | DOAJ |
| description | Background. Wedelolactone (WEL) has demonstrated anti-inflammatory properties. However, the therapeutic effect and underlying mechanisms of WEL against alcoholic steatohepatitis (ASH) remain unclear. This study aimed to investigate these aspects using animal and cell models. Methods and Results. The animals were categorized into the Pair-fed, ethanol-fed, ethanol + low-dose WEL, and ethanol + high-dose WEL groups. The serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in the ethanol + WEL group exhibited a dose-dependent decrease. Histopathological evaluations revealed that WEL mitigated liver injury, lipid accumulation, and macrophage infiltration provoked by alcohol consumption and a high-fat diet in mice. Network pharmacology analysis identified the toll-like receptor 4 (TLR4) pathway as the primary target of WEL in treating ASH. Molecular docking simulations demonstrated WEL’s strong binding affinity with TLR4. Immunofluorescence results highlighted that WEL downregulated the heightened TLR4 expression induced by alcohol and a high-fat diet. Additionally, RAW264.7 and AML-12 cells were stimulated with ethanol to establish an in vitro model. WEL treatment resulted in reduced mRNA and protein levels of alcohol-induced inflammatory mediators, downregulation of TLR4 and myeloid differentiation factor 88 (MyD88) expression, and inhibition of nuclear translocation of NF-κB-P65. Cellular immunofluorescence analyses demonstrated WEL’s ability to reduce alcohol-induced TLR4 expression. Flow cytometry and western blotting analyses confirmed WEL’s protective effect against ethanol-induced hepatocyte apoptosis. Conclusion. WEL may mitigate the impact of ASH by modulating the TLR4/MyD88/NF-κB pathway. |
| format | Article |
| id | doaj-art-86b407694a9649149cbdfdddcf6abab1 |
| institution | Kabale University |
| issn | 1466-1861 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-86b407694a9649149cbdfdddcf6abab12025-02-03T00:12:11ZengWileyMediators of Inflammation1466-18612024-01-01202410.1155/2024/9185668Wedelolactone Mitigates Alcoholic Steatohepatitis via Modulating the TLR4/MyD88/NF-κB PathwayTao Jiang0Bingde Hu1Yongxia Li2Shuihong Yu3Anqing 116 Hospital affiliated to Anqing Medical CollegeAnqing 116 Hospital affiliated to Anqing Medical CollegeAnqing 116 Hospital affiliated to Anqing Medical CollegeSchool of Basic Medical SciencesBackground. Wedelolactone (WEL) has demonstrated anti-inflammatory properties. However, the therapeutic effect and underlying mechanisms of WEL against alcoholic steatohepatitis (ASH) remain unclear. This study aimed to investigate these aspects using animal and cell models. Methods and Results. The animals were categorized into the Pair-fed, ethanol-fed, ethanol + low-dose WEL, and ethanol + high-dose WEL groups. The serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in the ethanol + WEL group exhibited a dose-dependent decrease. Histopathological evaluations revealed that WEL mitigated liver injury, lipid accumulation, and macrophage infiltration provoked by alcohol consumption and a high-fat diet in mice. Network pharmacology analysis identified the toll-like receptor 4 (TLR4) pathway as the primary target of WEL in treating ASH. Molecular docking simulations demonstrated WEL’s strong binding affinity with TLR4. Immunofluorescence results highlighted that WEL downregulated the heightened TLR4 expression induced by alcohol and a high-fat diet. Additionally, RAW264.7 and AML-12 cells were stimulated with ethanol to establish an in vitro model. WEL treatment resulted in reduced mRNA and protein levels of alcohol-induced inflammatory mediators, downregulation of TLR4 and myeloid differentiation factor 88 (MyD88) expression, and inhibition of nuclear translocation of NF-κB-P65. Cellular immunofluorescence analyses demonstrated WEL’s ability to reduce alcohol-induced TLR4 expression. Flow cytometry and western blotting analyses confirmed WEL’s protective effect against ethanol-induced hepatocyte apoptosis. Conclusion. WEL may mitigate the impact of ASH by modulating the TLR4/MyD88/NF-κB pathway.http://dx.doi.org/10.1155/2024/9185668 |
| spellingShingle | Tao Jiang Bingde Hu Yongxia Li Shuihong Yu Wedelolactone Mitigates Alcoholic Steatohepatitis via Modulating the TLR4/MyD88/NF-κB Pathway Mediators of Inflammation |
| title | Wedelolactone Mitigates Alcoholic Steatohepatitis via Modulating the TLR4/MyD88/NF-κB Pathway |
| title_full | Wedelolactone Mitigates Alcoholic Steatohepatitis via Modulating the TLR4/MyD88/NF-κB Pathway |
| title_fullStr | Wedelolactone Mitigates Alcoholic Steatohepatitis via Modulating the TLR4/MyD88/NF-κB Pathway |
| title_full_unstemmed | Wedelolactone Mitigates Alcoholic Steatohepatitis via Modulating the TLR4/MyD88/NF-κB Pathway |
| title_short | Wedelolactone Mitigates Alcoholic Steatohepatitis via Modulating the TLR4/MyD88/NF-κB Pathway |
| title_sort | wedelolactone mitigates alcoholic steatohepatitis via modulating the tlr4 myd88 nf κb pathway |
| url | http://dx.doi.org/10.1155/2024/9185668 |
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