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Ozone alleviates MSU-induced acute gout pain via upregulating AMPK/GAS6/MerTK/SOCS3 signaling pathway
Wen Fan1, Chong Liu1, Dacai Chen2,3
1Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.
Background:
Gout pain seriously affects the quality of patients' life. There is still no effective treatment. The inflammatory response is the main mechanism of gout. Here, we found that ozone can reduce the inflammatory reaction in the joints of gouty mice and relieve gout pain, and we further explore its protective mechanism.
Methods:
MSU was used to establish the gouty mice model. Nociception was assessed by Von Frey hairs. Cell signaling assays were performed by western blotting and immunohistochemistry. The mouse leukemia cells of monocyte macrophage line RAW264.7 were cultured to investigate the effects of ozone administration on macrophage.
Results:
Ozone reduced inflammation, relieved gout pain and improved the paw mean intensity and duty cycle of the gouty mice. Ozone increased the phosphorylation of AMP-activated protein kinase (AMPK), induced suppressor of cytokine signaling 3 (SOCS3) expression and inhibited metallopeptidase 9 (MMP9) expression. In vivo, ozone activated AMPK to induce Gas6 release, and upregulated MerTK/SOCS3 signaling pathway to reduce inflammation in mouse macrophage line RAW264.7. Inhibitors of AMPK and MerTK, respectively abolished the analgesic and anti-inflammatory effects of ozone in vivo and in vitro. Gas6 knockout cancelled the protectively effects of ozone on gout pain and the paw mean intensity and duty cycle of gouty mice. Additionally, the level of Gas6 and protein S in plasma of patients with hyperuricemia was significantly higher than that of healthy contrast group.
Conclusion:
Ozone reduces inflammation and alleviates gout pain by activating AMPK to up-regulate Gas6/MerTK/SOCS3 signaling pathway.
Insights
Ozone therapy effectively reduces gout pain and inflammation in mice by activating the AMPK pathway, which upregulates the Gas6/MerTK/SOCS3 signaling pathway. This study reveals a novel mechanism for ozone's therapeutic effects in gout.
Area of Science:
- Biomedical research
- Inflammation and immunology
- Pain management
Background:
- Gout pain significantly impacts patient quality of life, with limited effective treatments.
- Inflammation is the primary mechanism driving gout pathology.
- Investigating novel therapeutic strategies for gout is crucial.
Purpose of the Study:
- To investigate the anti-inflammatory and analgesic effects of ozone in a mouse model of gout.
- To elucidate the underlying molecular mechanisms of ozone's protective effects in gout.
Main Methods:
- Gouty mice were induced using monosodium urate (MSU) crystals.
- Nociception was evaluated using Von Frey hairs.
- Cell signaling pathways were analyzed via western blotting and immunohistochemistry.
- Ozone's effects on macrophage function were assessed in vitro using RAW264.7 cells.
Main Results:
- Ozone administration reduced joint inflammation and alleviated gout pain in mice.
- Ozone treatment increased AMP-activated protein kinase (AMPK) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression, while inhibiting metallopeptidase 9 (MMP9) expression.
- In vitro studies demonstrated that ozone activated AMPK, induced Gas6 release, and upregulated the MerTK/SOCS3 signaling pathway in macrophages.
- Inhibition of AMPK or MerTK abolished ozone's therapeutic effects, and Gas6 knockout negated its benefits.
- Elevated levels of Gas6 and Protein S were observed in hyperuricemia patients.
Conclusions:
- Ozone effectively reduces inflammation and alleviates gout pain.
- The therapeutic mechanism involves ozone activating AMPK to upregulate the Gas6/MerTK/SOCS3 signaling pathway.
- This study identifies a novel therapeutic pathway for gout management using ozone.
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