INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Wenyao Yang,Juanzhu Han,Liping Zhang,Yunsong Sun,Yuchen Zhu,Yiyu Liu,Jingyu Chen,Xiaoyao Liao,Hui Liao,Weizhuo Xu,Yongbo Song
Skeletal muscle inflammation associated with sepsis has been identified as a critical pathological process contributing to metabolic dysfunction and poor clinical outcomes. Voltage-gated sodium channels (VGSCs) have been implicated in immune modulation; however, their specific roles in skeletal muscle inflammation remain poorly understood. In this study, the VGSC subtype Nav1.5 was investigated as a potential regulator of inflammation, and the therapeutic efficacy of a novel recombinant scorpion peptide, DKK678, was evaluated. An in vitro model using lipopolysaccharide (LPS)-stimulated C2C12 cells and an in vivo cecal ligation and puncture (CLP) model in septic mice were established. In both models, Nav1.5 expression was significantly upregulated in response to inflammatory stimuli, while Nav1.4 expression remained unchanged. The nuclear factor kappa B (NF-κB) signaling pathway was found to be activated, contributing to increased expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), adhesion molecules (VCAM-1), and gap junction proteins (Cx43). Suppression of VGSC activity using lidocaine resulted in the inhibition of NF-κB phosphorylation and downregulation of inflammatory markers, while the expression of interleukin-10 (IL-10) and interleukin-4 (IL-4) were restored. Tetrodotoxin (TTX) treatment did not replicate these effects, suggesting Nav1.5-specific involvement. DKK678 was developed through bioinformatic design and molecular docking simulations, which predicted a stronger binding affinity and structural stability with Nav1.5 compared to Nav1.4. These predictions were validated through functional experiments. In vitro, DKK678 treatment dose-dependently inhibited LPS-induced NF-κB pathway activation and reversed abnormal expression of VCAM-1 and Cx43. In vivo, DKK678 significantly ameliorated CLP-induced skeletal muscle damage, suppressed inflammatory cytokine production, and improved tissue histopathology. Furthermore, the structural integrity of immune organs such as the thymus and spleen was preserved in DKK678-treated septic mice, with partial restoration of lymphocyte populations and organ indices. Notably, Nav1.5 expression was downregulated by DKK678, while Nav1.4 expression remained unaffected. These results demonstrate that Nav1.5 serves as a critical inflammatory modulator in skeletal muscle and immune tissues. Its upregulation was shown to drive NF-κB pathway activation and inflammatory cytokine production. By targeting Nav1.5, DKK678 was able to exert dual protective effects on both skeletal muscle and immune organs under septic conditions. The therapeutic potential of DKK678 was found to be comparable to that of dexamethasone (DEX) at high doses, without altering Nav1.4 expression. In conclusion, the present study provides new mechanistic insight into the role of Nav1.5 in skeletal muscle inflammation and identifies DKK678 as a promising peptide therapeutic that targets Nav1.5 to suppress NF-κB-mediated inflammatory injury. These findings suggest that Nav1.5 inhibition represents a viable strategy for the treatment of sepsis-associated myositis and related inflammatory disorders.
研究领域:
免疫学
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药理学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 21
·7417
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IF 4.6
Wei Yang,Wenping Wang,Song Cai,Peng Li,Die Zhang,Jinhua Ning,Jin Ke,Anguo Hou,Linyun Chen,Yunshu Ma,Wenbin Jin
Malignant cardiac arrhythmias with high morbidity and mortality have posed a significant threat to our human health. Scutellarein, a metabolite of Scutellarin which is isolated fromScutellaria altissimaL., presents excellent therapeutic effects on cardiovascular diseases and could further be metabolized into methylated forms. A series of 22 new scutellarein derivatives with hydroxyl-substitution based on the scutellarin metabolite in vivo was designed, synthesized via the conjugation of the scutellarein scaffold with pharmacophores of FDA-approved antiarrhythmic medications and evaluated for their antiarrhythmic activity through the analyzation of the rat number of arrhythmia recovery, corresponding to the recovery time and maintenance time in the rat model of barium chloride-induced arrhythmia, as well as the cumulative dosage of aconitine required to induce VP, VT, VF and CA in the rat model of aconitine-induced arrhythmia. All designed compounds could shorten the time of the arrhythmia continuum induced by barium chloride, indicating that 4′-hydroxy substituents of scutellarein had rapid-onset antiarrhythmic effects. In addition, nearly all of the compounds could normalize the HR, RR, QRS, QT and QTc interval, as well as the P/T waves’ amplitude. The most promising compound10eshowed the best antiarrhythmic activity with long-term efficacy and extremely low cytotoxicity, better than the positive control scutellarein. This result was also approved by the computational docking simulation. Most importantly, patch clamp measurements on Nav1.5 and Cav1.2 channels indicated that compound10ewas able to reduce the INa and ICa in a concentration-dependent manner and left-shifted the inactivation curve of Nav1.5. Taken together, all compounds were considered to be antiarrhythmic. Compound10eeven showed no proarrhythmic effect and could be classified as Ib Vaughan Williams antiarrhythmic agents. What is more, compound10edid not block the hERG potassium channel which highly associated with cardiotoxicity.Keywords:antiarrhythmic;scutellarein derivatives;Nav1.5 channel blockers;Cav1.2 channel blockers;electrophysiology
研究领域:
药理学
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心脏病学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2022
·
IF 6.633
Miao Zhao,Meng Han,Lina Liang,Qixue Song,Xia Li,Yimei Du,Dongping Hu,Yu Cheng,Qing K. Wang,Tie Ke
Our earlier studies identified MOG1 as a Nav1.5-binding protein that promotes Nav1.5 intracellular trafficking to plasma membranes. Genetic studies have identified MOG1 variants responsible for cardiac arrhythmias. However, the physiological functions of MOG1 in vivo remain incompletely characterized. In this study, we generated Mog1 knockout ( Mog1 −/− ) mice. Mog1 −/− mice did not develop spontaneous arrhythmias at the baseline, but exhibited a prolongation of QRS duration. Mog1 −/− mice treated with isoproterenol (ISO), but not with flecainide, exhibited an increased risk of arrhythmias and even sudden death. Mog1 −/− mice had normal cardiac morphology, however, LV systolic dysfunction was identified and associated with an increase in ventricular fibrosis. Whole-cell patch-clamping and Western blotting analysis clearly demonstrated the normal cardiac expression and function of Nav1.5 in Mog1 −/− mice. Further RNA-seq and iTRAQ analysis identified critical pathways and genes, including extracellular matrix ( Mmp2 ), gap junction ( Gja1 ), and mitochondrial components that were dysregulated in Mog1 −/− mice. RT-qPCR, Western blotting, and immunofluorescence assays revealed reduced cardiac expression of Gja1 in Mog1 −/− mice. Dye transfer assays confirmed impairment of gap-junction function; Cx43 gap-junction enhancer ZP123 decreased arrhythmia inducibility in ISO-treated Mog1 −/− mice. Transmission electron microscopy analysis revealed abnormal sarcomere ultrastructure and altered mitochondrial morphology in Mog1 −/− mice. Mitochondrial dynamics was found to be disturbed, and associated with a trend toward increased mitochondrial fusion in Mog1 −/− mice. Meanwhile, the level of ATP supply was increased in the hearts of Mog1 −/− mice. These results indicate that MOG1 plays an important role in cardiac electrophysiology and cardiac contractile function.
研究领域:
心脏病学
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分子生物学
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电生理学
✓ 已验证
DOI
PubMed
高影响因子
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