1. Processed Buthus martensii Karsch scorpions ameliorate diet-induced NASH in mice by attenuating Kv1.3-mediated macrophage activation.
- Author
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Xu, Erjin, Sang, Ming, Xu, Wenhao, Chen, Yonggen, Wang, Zhiheng, Zhang, Yuxin, Lu, Wuguang, and Cao, Peng
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NON-alcoholic fatty liver disease , *ANTI-inflammatory agents , *CHINESE medicine , *NF-kappa B , *MACROPHAGES , *BONE marrow , *POLYMERASE chain reaction , *ENZYME-linked immunosorbent assay , *ARTHROPOD venom , *CELLULAR signal transduction , *DESCRIPTIVE statistics , *MICE , *GENE expression , *LIVER cells , *INSULIN resistance , *FIBROSIS , *ANIMAL experimentation , *FATTY acids , *INFLAMMATION , *CYTOKINES , *IMMUNOBLOTTING , *OBESITY , *TUMOR necrosis factors , *PHARMACODYNAMICS - Abstract
Processed Buthus martensii Karsch (BmK) scorpion, also known as Quan-Xie, is a traditional Chinese medicine that is clinically used for the treatment of NAFLD due to its Tong-Luo-San-Jie effects. Our previous study showed that aqueous extract of processed BmK scorpion venom gland (pVg AE) inhibited macrophage inflammation by targeting Kv1.3 and identified the thermostable peptide BmKK2 as a potent Kv1.3 blocker. This study examined the therapeutic effects of processed BmK scorpions on NASH, specifically focusing on the involvement of their anti-inflammatory effects mediated by macrophage-expressed Kv1.3 in NASH. In the present study, the anti-NASH effects of pVg AE were evaluated in high-fat diet (HFD)-induced NASH mouse models. Additionally, the in vitro anti-inflammatory mechanisms of pVg AE and BmKK2 were assessed using a palmitic acid (PA)-induced mouse bone marrow-derived macrophages (BMDMs) inflammation model. Protein and cytokine expression related to the Kv1.3-NF-κB pathway was analyzed by real-time PCR, immunoblotting and ELISA. The effect of pVg AE and BmKK2 on potassium channels was detected by whole-cell voltage-clamp recordings on transfected HEK293T cells or mouse BMDMs. Calcium ion imaging was used to evaluate intracellular calcium signaling. Furthermore, the study utilized Kv1.3 siRNA and a BMDMs and hepatocytes co-culture model to investigate the specific role of Kv1.3 in mediating the anti-NASH effects of pVg AE and BmKK2. Lipid accumulation upregulated Kv1.3 expression in macrophages in vivo and in vitro. However, pVg AE significantly reduced Kv1.3 expression and Kv1.3-positive macrophage infiltration. Treatment with pVg AE improved obesity, insulin resistance (IR), hepatic steatosis (HS), inflammation, and fibrosis in HFD-fed mice. Mechanistically, pVg AE and BmKK2 inhibited macrophage inflammation by targeting Kv1.3, which reduced PA-induced intracellular Ca2+ levels, resulting in the inhibition of the NF-κB pathway and TNFα release. This study demonstrates that Kv1.3-mediated macrophage inflammation is involved in the pathogenesis and treatment of NASH. pVg AE effectively alleviates metabolic stress-induced NASH by inhibiting this inflammation. [Display omitted] • We demonstrated the role of Kv1.3 in the pathogenesis of NASH. • pVg AE mitigated metabolic stress-induced NASH by inhibiting Kv1.3-mediated inflammation in liver macrophages. • pVg AE and BmKK2 inhibited macrophage activation through Kv1.3-Calcium-NF-κB signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2025
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