Asthma is one of the most common chronic inflammatory diseases. Although the scorpion and centipede (SC) significantly ameliorates asthma and changes exosomal miRNAs, the molecular mechanism is still obscure. Here, we show that SC improves inflammation in asthmatic mice and increases M2 macrophage-derived exosomes (M2Φ-Exos) by promoting M2 macrophage polarization. The M2Φ-Exos remarkably inhibits airway epithelial cell pyroptosis by reducing the expression of NLRP3, caspase-1, and LI-1β and mitochondrial swelling. Furthermore, miR-30b-5p is up-regulated in M2Φ-Exos compared with M1Φ-Exos. Overexpression of miR-30b-5p in M2Φ-Exos prevents airway epithelial cell pyroptosis, while down-regulation of miR-30b-5p promotes pyroptosis. We also uncover that pyroptosis is increased in asthmatic mice, while SC blocks pyroptosis. Moreover, miR-30b-5p overexpressed M2Φ-Exos further enhances the ameliorative effect of SC, which significantly down-regulates IRF7 expression. Our results collectively reveal that M2Φ-Exos induced by SC could carry miR-30b-5p to mitigate severe asthma by inhibiting airway epithelial cell pyroptosis. Most importantly, our findings may provide a potential clinical application of M2Φ-Exos for treating severe asthma.
Asthma is a common respiratory disease with inflammation in the lungs. Exosomes and microRNAs (miRNAs) play crucial role in inflammation, whereas the role of exosomal miRNA in asthma remains unknown. Here, we aimed to identify the key exosomal miRNAs and their underlying mechanisms involved in scorpio and centipede (SC) treatment in asthma. Eighteen mice were randomly divided into three groups: control group, asthma group, and SC treatment group. Effect of SC was assessed by hematoxylin-eosin staining and real-time PCR. Exosomes from asthma and SC treatment groups were analyzed by small RNA-seq. Results revealed SC significantly alleviated the pathogenesis of asthma and suppressed the release of inflammatory cytokines. A total of 328 exosomal miRNAs were differentially expressed between the exosomes from asthma and SC-treated mice, including 118 up- and 210 downregulated in SC-treated mice. The altered exosomal miRNAs were primarily involved in the function of transcription, apoptotic process, and cell adhesion; and pathway of calcium, Wnt, and MAPK signaling. Real-time PCR verified exosomal miR-147 was downregulated, while miR-98-5p and miR-10a-5p were upregulated in SC-treated mice compared to asthma mice. Moreover, the target genes of miR-147-3p, miR-98-5p, and miR-10a-5p were mainly enriched in Wnt and MAPK inflammatory signaling. miR-10a-5p promoted the proliferation of mouse lung epithelial cells and downregulated the expression of Nfat5 and Map2k6. These data suggest SC-induced exosomal miRNAs might mediate the inflammatory signaling and might be involved in the SC treatment in asthma. The exosomal miRNAs might be promising candidates for the treatment of asthma.
KeChuanLiuWei‐Mixture (KCLW) is widely used as a Chinese medicine prescription to treat severe asthma. However, the underlying therapeutic mechanism of KCLW remains unclear. In this study, a network pharmacology method was used to identify the chemical constituents of KCLW by the TCMSP database and ultra‐performance liquid chromatography coupled with time‐of‐flight mass spectrometry. Differential expression identification, protein–protein interaction (PPI) network and functional enrichment analysis were used to screen key targets of KCLW for severe asthma. Our results confirmed that quercetin, luteolin, kaempferol, and wogonin are the most critical active ingredients in KCLW. Moreover, the 16 relevant severe asthma‐related targets of KCLW were obtained by overlapping the PPI networks of the KCLW putative targets and severe asthma‐related genes, among which the most important targets were IL‐6, NOS2, VEGFA, CXCL2, and PLAT. Functionally, the 16‐targets and their interacting differentially expressed genes were primarily related to biological functions and pathways related to immunity and inflammation, such as inflammatory response, T cell differentiation, Nrf2/HO‐1 signaling pathway, TGF‐β/Smad signaling pathway, and NF‐κB signaling pathway. KCLW inhibited inflammation in PDGF‐BB‐induced airway smooth muscle cells. In summary, this study demonstrates the active substance and potential therapeutic mechanism of KCLW in severe asthma, and offers a clinical direction for KCLW against severe asthma.
Asthma is considered as a difficult chronic disease with prolonged inflammation, reversible obstruction and remodeling in the airway. The present work aimed to examine the therapeutic efficacy of Bergenin-loaded Cationic Liposome (B-CLs) in asthma. We applied the thin film dispersion approach to prepare B-CLs, which were administered orally to asthma mice. Bronchoalveolar lavage fluid (BALF), cytokine contents and histopathological results were obtained and examined by transmission electron microscope (TEM), enzyme linked immunosorbent assay (ELISA) kits, together with histopathological study separately. B-CLs had a mean size of 158.33 ± 5.88 nm with positive potential of 24.51 ± 0.51 mV. In pharmacokinetics, the area under curve (AUC0–∞) and half-life (T1/2) of B-CLs were 3.33 and 3.92 times higher than free Bergenin. Compared with model group, alveolus and airway wall lesions in hematoxylin-eosin (H&E) staining of B-CLs-Medium/High dose groups declined as the wall-infiltrating inflammatory cell number declined. The thicknesses of airway wall and bronchial smooth muscle, together with the counts of bronchial smooth nuclei in B-CLs decreased significantly (P < 0.01). Specially, the ultrastructural airway changes were markedly-reversed in the B-CLs-High (P < 0.01). The changes of cytokines indicated the decrease in inflammation and improvement of the balance between T helper 1 cytokines (Th1) and T helper 2 cytokines (Th2). B-CLs could significantly enhance the dissolution, bioavailability and more inhibit airway inflammation as well as improve the lung histopathological condition.
Background. Qinggan Huoxue recipe (QGHXR), a traditional Chinese medicinal formula, has a protective effect against liver fibrosis. However, the underlying mechanisms remain unclear. Objective. This study investigated the antifibrotic role of QGHXR and its underlying mechanisms. Methods. The composition of QGHXR was determined using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Female C57BL/6J mice were fed either a Lieber–DeCarli liquid diet or pair-fed control diet and intraperitoneally injected with CCl4 for 8 weeks (n = 8). In week 5, the mice were administered 100, 200, and 400 mg/kg QGHXR via oral gavage daily for 4 weeks. Results. UPLC-MS result showed that QGHXR contained 45 compounds including salvianolic acid A, scutellarin, baicalin, rutin, and chai saponin D. QGHXR alleviated pathological alterations in the liver. The alanine aminotransferase (ALT) level was reduced to 44.88 ± 4.39 U/L, aspartate aminotransferase (AST) to 76.25 ± 4.17 U/L, alkaline phosphatase (ALP) to 60.75 ± 5.41 U/L, and acetaldehyde to 38.54 ± 1.01 U/L compared with that of the control group (ALT 72.38 ± 5.19 U/L, AST 119.63 ± 9.82 U/L, and ALP 98.63 ± 6.71 U/L and acetaldehyde 64.86 ± 4.70 U/L). QGHXR inhibited lipid overproduction and fibrotic gene expression. The serum concentration of chemokine C-X-C ligand 16 (CXCL16) was reduced to 62.83 ± 6.80 pg/ml compared with that of the control group (130.91 ± 13.72 pg/mL). QGHXR downregulated CXCL16 mRNA and protein expressions. Pharmacological CXCL16 treatment reversed the QGHXR-induced protective effects in ethanol plus CCl4 fed mice. QGHXR reduced CXCL16 levels (91.97 ± 5.86 pg/ml) in LPS-stimulated RAW264.7 cells compared with that of the control group (148.68 ± 8.62 pg/ml) and inhibited toll-like receptor 4 and nuclear factor-kappa B phosphorylation. Conclusions. This study demonstrated that QGHXR mitigates experimental alcoholic liver fibrosis by CXCL16 inhibition, and may be considered a potential therapeutic agent for treating liver fibrosis.
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