Dimethyl Fumarate Protects against Lipopolysaccharide- (LPS-) Induced Sepsis through Inhibition of NF-κB Pathway in Mice
Sepsis is one of the most severe complications and causes of mortality in the clinic. It remains a great challenge with no effective treatment for clinicians worldwide. Inhibiting the release of proinflammatory cytokines during sepsis is considered as an important strategy for treating sepsis and im...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2023-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2023/5133505 |
| _version_ | 1797660814903083008 |
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| author | He Fang Xingtong Wang Mahendra Damarla Rongju Sun Qingli He Ruojing Li Pengfei Luo Jun O. Liu Zhaofan Xia |
| author_facet | He Fang Xingtong Wang Mahendra Damarla Rongju Sun Qingli He Ruojing Li Pengfei Luo Jun O. Liu Zhaofan Xia |
| author_sort | He Fang |
| collection | DOAJ |
| description | Sepsis is one of the most severe complications and causes of mortality in the clinic. It remains a great challenge with no effective treatment for clinicians worldwide. Inhibiting the release of proinflammatory cytokines during sepsis is considered as an important strategy for treating sepsis and improving survival. In the present study, we have observed the effect of dimethyl fumarate (DMF) on lipopolysaccharide- (LPS-) induced sepsis and investigated the possible mechanism. By screening a subset of the Johns Hopkins Drug Library, we identified DMF as a novel inhibitor of nitric oxide synthesis in LPS-stimulated RAW264.7 cells, suggesting that DMF could be a potential drug to treat sepsis. To further characterize the effect of DMF on LPS signaling, TNF-α, MCP-1, G-CMF, and IL-6 expression levels were determined by using cytokine array panels. In addition, an endotoxemia model with C57BL/6 mice was used to assess the in vivo efficacy of DMF on sepsis. The survival rate was assessed, and HE staining was performed to investigate histopathological damage to the organs. DMF was found to increase the survival of septic mice by 50% and attenuate organ damage, consistent with the reduction in IL-10, IL-6, and TNF-α (inflammatory cytokines) in serum. In vitro experiments revealed DMF’s inhibitory effect on the phosphorylation of p65, IκB, and IKK, suggesting that the primary inhibitory effects of DMF can be attributed, at least in part, to the inhibition of phosphorylation of IκBα, IKK as well as nuclear factor-κB (NF-κB) upon LPS stimulation. The findings demonstrate that DMF dramatically inhibits NO and proinflammatory cytokine production in response to LPS and improves survival in septic mice, raising the possibility that DMF has the potential to be repurposed as a new treatment of sepsis. |
| first_indexed | 2024-03-11T18:36:17Z |
| format | Article |
| id | doaj.art-d8b0f382743a4722b4a140d20d69ea8a |
| institution | Directory Open Access Journal |
| issn | 1466-1861 |
| language | English |
| last_indexed | 2024-03-11T18:36:17Z |
| publishDate | 2023-01-01 |
| publisher | Hindawi Limited |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj.art-d8b0f382743a4722b4a140d20d69ea8a2023-10-13T00:00:02ZengHindawi LimitedMediators of Inflammation1466-18612023-01-01202310.1155/2023/5133505Dimethyl Fumarate Protects against Lipopolysaccharide- (LPS-) Induced Sepsis through Inhibition of NF-κB Pathway in MiceHe Fang0Xingtong Wang1Mahendra Damarla2Rongju Sun3Qingli He4Ruojing Li5Pengfei Luo6Jun O. Liu7Zhaofan Xia8Department of Burn SurgeryDepartment of Burn SurgeryDepartment of Pulmonary and Critical Care MedicineDepartment of Burn SurgeryDepartment of Pharmacology and Molecular SciencesDepartment of Pharmacology and Molecular SciencesDepartment of Burn SurgeryDepartment of Pharmacology and Molecular SciencesDepartment of Burn SurgerySepsis is one of the most severe complications and causes of mortality in the clinic. It remains a great challenge with no effective treatment for clinicians worldwide. Inhibiting the release of proinflammatory cytokines during sepsis is considered as an important strategy for treating sepsis and improving survival. In the present study, we have observed the effect of dimethyl fumarate (DMF) on lipopolysaccharide- (LPS-) induced sepsis and investigated the possible mechanism. By screening a subset of the Johns Hopkins Drug Library, we identified DMF as a novel inhibitor of nitric oxide synthesis in LPS-stimulated RAW264.7 cells, suggesting that DMF could be a potential drug to treat sepsis. To further characterize the effect of DMF on LPS signaling, TNF-α, MCP-1, G-CMF, and IL-6 expression levels were determined by using cytokine array panels. In addition, an endotoxemia model with C57BL/6 mice was used to assess the in vivo efficacy of DMF on sepsis. The survival rate was assessed, and HE staining was performed to investigate histopathological damage to the organs. DMF was found to increase the survival of septic mice by 50% and attenuate organ damage, consistent with the reduction in IL-10, IL-6, and TNF-α (inflammatory cytokines) in serum. In vitro experiments revealed DMF’s inhibitory effect on the phosphorylation of p65, IκB, and IKK, suggesting that the primary inhibitory effects of DMF can be attributed, at least in part, to the inhibition of phosphorylation of IκBα, IKK as well as nuclear factor-κB (NF-κB) upon LPS stimulation. The findings demonstrate that DMF dramatically inhibits NO and proinflammatory cytokine production in response to LPS and improves survival in septic mice, raising the possibility that DMF has the potential to be repurposed as a new treatment of sepsis.http://dx.doi.org/10.1155/2023/5133505 |
| spellingShingle | He Fang Xingtong Wang Mahendra Damarla Rongju Sun Qingli He Ruojing Li Pengfei Luo Jun O. Liu Zhaofan Xia Dimethyl Fumarate Protects against Lipopolysaccharide- (LPS-) Induced Sepsis through Inhibition of NF-κB Pathway in Mice Mediators of Inflammation |
| title | Dimethyl Fumarate Protects against Lipopolysaccharide- (LPS-) Induced Sepsis through Inhibition of NF-κB Pathway in Mice |
| title_full | Dimethyl Fumarate Protects against Lipopolysaccharide- (LPS-) Induced Sepsis through Inhibition of NF-κB Pathway in Mice |
| title_fullStr | Dimethyl Fumarate Protects against Lipopolysaccharide- (LPS-) Induced Sepsis through Inhibition of NF-κB Pathway in Mice |
| title_full_unstemmed | Dimethyl Fumarate Protects against Lipopolysaccharide- (LPS-) Induced Sepsis through Inhibition of NF-κB Pathway in Mice |
| title_short | Dimethyl Fumarate Protects against Lipopolysaccharide- (LPS-) Induced Sepsis through Inhibition of NF-κB Pathway in Mice |
| title_sort | dimethyl fumarate protects against lipopolysaccharide lps induced sepsis through inhibition of nf κb pathway in mice |
| url | http://dx.doi.org/10.1155/2023/5133505 |
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