Yanghepingchuan granule improves airway inflammation by inhibiting autophagy via miRNA328-3p/high mobility group box 1/Toll-like receptor 4 targeting of the pathway of signaling in rat models of asthma.

Background: As a type of traditional Chinese medicine, Yanghepingchuan granules (YHPCG) are used to treat inflammatory diseases of the lungs, including asthma. However, the underlying molecular mechanism of the ability of YHPCG to reduce airway inflammation remains unknown. Methods: By sensitizing rats to aluminum hydroxide and ovalbumin, an asthma model was established. During the 14-day treatment period, the rats received YHPCG, TAK242 (TLR4 inhibitor), and a combination of the two treatments. Histopathology and goblet cell hyperplasia were observed in rats with ovalbumin-induced asthma by using hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining. Immunohistochemical, autophagy-related immunofluorescence, and western blotting analyses were performed to determine autophagic activity. The effects of YHPCG on high mobility group box 1 (HMGB1)-mediated Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway-related proteins and inflammatory factors in rats were evaluated via western blotting, PCR analysis, and enzyme-linked immunosorbent assay. A dual luciferase method was used to detect the interaction between miRNA328-3p and HMGB1. Results: YHPCG inhibit the HMGB1/TLR4/NF-κB pathway by upregulating miR-328-3p, reducing autophagosome production, inhibiting autophagy, and effectively preventing the progression of lung inflammation. Conclusions: Asthma airway inflammation can be treated with YHPCG by inhibiting autophagy via miRNA328-3p/HMGB1/TLR4/NF-κB signaling pathways.

Bu-Fei Yi-Shen Granules Reduce Acute Exacerbations in Patients with GOLD 3-4 COPD: A Randomized Controlled Trial.

Purpose: Chronic obstructive pulmonary disease (COPD) is a disease characterized by frequent acute exacerbations (AEs), especially in severe and very severe cases. We aimed to evaluate the efficacy and safety of Bu-fei Yi-shen granules (BYGs) for COPD. Patients and Methods: We conducted a multicenter, randomized, double-blinded, placebo-controlled trial of 348 COPD patients with GOLD 3-4 COPD. The patients were randomly assigned into experimental or control groups in a 1:1 ratio. Patients in the experimental group were prescribed BYG, while those in the control group were administered a placebo, orally, twice daily, with 5 days on and 2 days off per week for 52 weeks. The outcomes included AEs, pulmonary function, clinical signs and symptoms, dyspnea scores (mMRC), quality of life scores, and a 6-minute walk test (6MWT). Results: A total of 280 patients completed the trial, including 135 patients in the experimental group and 145 in the control group. Compared to the control group, significant differences were observed in frequencies of AEs (mean difference: -0.35; 95% CI: -0.61, -0.10; P = 0.006) and AE-related hospitalizations (-0.18; 95% CI: -0.36, -0.01; P = 0.04), 6MWD (40.93 m; 95% CI: 32.03, 49.83; P < 0.001), mMRC (-0.57; 95% CI: -0.76, -0.37; P < 0.001), total symptoms (-2.18; 95% CI: -2.84, -1.53; P < 0.001), SF-36 (11.60; 95% CI: 8.23, 14.97; P < 0.001), and mCOPD-PRO (-0.45; 95% CI: -0.57, -0.33; P < 0.001) after treatment. However, there were no significant differences in mortality, pulmonary function, and mESQ-PRO scores (P > 0.05). No obvious adverse events were observed. Conclusion: BYG, as compared to a placebo, could significantly reduce the frequencies of AEs and AE-related hospitalizations for GOLD 3-4 COPD patients. Clinical symptoms, treatment satisfaction, quality of life, and exercise capacity improved. There was no significant improvement in mortality and pulmonary function.

[Bioinformatic analysis of key targets and potential mechanism of Sangbaipi Decoction in the treatment of acute exacerbation of chronic obstructive pulmonary disease].

Objective To identify the key targets and molecular mechanisms of Sangbaipi decoction in the treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) by using network pharmacology. Methods The active components of Sangbaipi Decoction were searched in Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, with the corresponding targets predicted. The related targets of AECOPD were searched within gene banks, OMIM and Drugbank.The names of prediction targets and disease targets were standardized by UniProt, and the intersection targets were selected. TCM component target network diagram was drawn and analyzed by Cytoscape 3.6.0. The common targets were imported into the metascape database for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and molecular docking was carried out by using auto dock tools software. Results A total of 126 active ingredients in Sangbaipi decoction, 1351 predicted corresponding targets and 2296 disease-related targets were detected. The main active ingredients include quercetin, luteolin, kaempferol, wogonin ß. The core targets of sitosterol involve tumor necrosis factor (TNF), interleukin-6 (IL-6), tumor protein p53 (TP53), mitogen activated protein kinase 8 (MAPK8) and MAPK14. A total of 2720 signals were obtained from GO enrichment analysis and 334 signal pathways were obtained from KEGG enrichment analysis. The molecular docking results showed that the main active components can bind to the core target, at a stable the binding conformation. Conclusion Sangbaipi decoction may have anti-inflammatory, anti-oxidant and other biological effects through multiple active ingredients, multiple targets and signal pathways, thus effectively treating AECOPD.

[The increased expression of stromal cell-derived factor-1 (SDF-1) alleviates airway inflammation in asthmatic rats by promoting the migration of bone marrow mesenchymal stem cells (BMSCs)].

Objective To observe the correlation of stromal cell-derived factor 1 (SDF-1) with bone marrow mesenchymal stem cell (BMSCs) migration and airway inflammation in asthmatic rats. Methods Twenty-four clean SD rats were randomly divided into normal control (NC) group, model control (MC) group, and BMSCs group. Asthma model was established by OVA. In the BMSCs group, 1×106 BMSCs (1 mL) were transplanted into the tail vein on the day the model was completed. Pathological changes in lung tissues were evaluated by HE staining. The count of inflammatory cells in bronchoalveolar lavage fluid(BALF) was evaluated by Wright-Giemsa staining. The concentrations of IL-4, IL-5, IL-13, IgE, IgG1 and IgG2a in BALF were tested by ELISA. The expression of SDF-1 and STAT6 mRNA in lung tissue was measured by real time quantitative PCR. The expression of SDF-1 protein in bronchial epithelial cells were evaluated by Immunofluorescence staining. The expression of SDF-1 and STAT6 protein in lung tissue were measured by Western blot analysis. Results Compared with the normal group, the number of relative inflammatory cell counts and the concentrations of IL-4, IL-5, IL-13, IgE, IgG1, and IgG2a in BALF of the MC group increased significantly. The mRNA and protein expression of SDF-1 and STAT6 in lung tissue increased significantly. Compared with the MC group, inflammatory cells and inflammatory cytokines of BALF of BMSCs group were decreased in numbers, as was the expression of SDF-1 and STAT6 in lung tissues. Compared with the MC group, the expression of SDF-1 gene in lung tissues was increased, as was the expression of SDF-1 protein in bronchial epithelial cells. Conclusion In the process of asthmatic inflammation, the expression of chemokine SDF-1 in the damaged site increases, and promotes the migration of exogenous BMSCs to the lung tissue of asthmatic rats. BMSCs can regulate immune imbalance of Th1/Th2 cells by homing to damaged lung tissue, thus inhibiting asthmatic airway inflammation.

A Novel Hybrid Algorithm for the Forward Kinematics Problem of 6 DOF Based on Neural Networks.

The closed kinematic structure of Gough-Stewart platforms causes the kinematic control problem, particularly forward kinematics. In the traditional hybrid algorithm (backpropagation neural network and Newton-Raphson), it is difficult for the neural network part to train different datasets, causing training errors. Moreover, the Newton-Raphson method is unable to operate on a singular Jacobian matrix. In this study, in order to solve the forward kinematics problem of Gough-Stewart platforms, a new hybrid algorithm is proposed based on the combination of an artificial bee colony (ABC)-optimized BP neural network (ABC-BPNN) and a numerical algorithm. ABC greatly improves the prediction ability of neural networks and can provide a superb initial value to numerical algorithms. In the design of numerical algorithms, a modification of Newton's method (QMn-M) is introduced to solve the problem that the traditional algorithm model cannot be solved when it is trapped in singular matrix. Results show that the maximal improvement in ABC-BPNN error optimization was 46.3%, while the RMSE index decreased by 42.1%. Experiments showed the feasibility of QMn-M in solving singular matrix data, while the percentage improvement in performance for the average number of iterations and required time was 14.4% and 13.9%, respectively.

Ligustrazine Inhibits Lung Phosphodiesterase Activity in a Rat Model of Allergic Asthma.

OBJECTIVES: This study sought to examine whether ligustrazine was capable of inhibiting phosphodiesterase (PDE) activity and improving lung function in a rat model of asthma. METHODS: Rats were initially sensitized using ovalbumin (OVA) and then were challenged daily with aerosolized OVA beginning 14 days later (30 min/day) to generate a rat model of asthma. Changes in airway function following methacholine (MCh) injection were evaluated by monitoring lung resistance (R L) and dynamic lung compliance (C dyn) values using an AniRes2005 analytic system. In addition, serum IgE was measured via ELISA, while PDE expression was evaluated via qPCR and western blotting. Key Findings. Ligustrazine significantly impaired allergen-induced lung hyperresponsivity and inflammation in this asthma model system. Ligustrazine treatment was also associated with reduced expression of PDEs including PDE4 in the lungs of these rats. CONCLUSIONS: Ligustrazine suppresses airway inflammation and bronchial hyperresponsivity in this rat model system, and these changes are associated with decreased PDE expression at the protein and mRNA levels.

[miR-139 promotes homing of bone marrow mesenchymal stem cells (BMSCs) to lung tissues of asthmatic rats to inhibit inflammatory response of Th2 cells by down-regulating Notch1/Hes1 pathway].

Objective To study the effects of microRNA-139 (miR-139) regulating Notch signaling pathway on bone mesenchymal stem cells (BMSCs) homing and asthma airway inflammation. Methods Twenty-four SD rats were randomly divided into normal control group, model control group and BMSCs group. The rats were challenged with ovalbumin and then BMSCs were transplanted into the rats. Pathological changes in lung tissues were observed by HE staining. The expression of BMSCs marker C-X-C motif chemokine receptor 4 (CXCR4) in the lung tissues was examined by flow cytometry, and the expression of CXCR4 in bronchial epithelial cells was observed by immunofluorescence staining. The expression of interferon-γ (IFN-γ) and interleukins-4 (IL-4) were detected by ELISA, and the expression of Notch1, Jagged1 and Hes1 in the lung tissues were tested by Western blot analysis. Results Compared with the normal control group, the expression of CXCR4, IL-4, Notch1 and Hes1 in the lung tissues of the model control group increased significantly, and the ratio of Th1/Th2 cells and the level of miR-139 mRNA decreased. Compared with the model control group, the expression of CXCR4 in the lung tissues and bronchial epithelial cells increased, so were the ratio of Th1/Th2 cells and the level of miR-139 mRNA, while the expression of Notch1 and Hes1 decreased. Correlation analysis showed that the expression of CXCR4 in the lung tissues was positively correlated with the expression of CXCR4 in bronchial epithelial cells, the ratio of Th1/Th2 cells, and miR-139. The expression of CXCR4 in bronchial epithelial cells was positively correlated with the ratio of Th1/Th2 cells, the expression of miR-139, and negatively correlated with the expression of Notch1. The ratio of Th1/Th2 cells was positively correlated with the expression of miR-139. Conclusion miR-139 can down-regulate the Notch pathway and promote BMSCs homing in asthmatic lung tissues, thus suppressing the inflammatory response of Th2 cells through immune regulation.

[Yanghe Pingchuan granule promotes BMSCs homing in asthmatic rats by upregulating miR-139-5p and downregulating Notch1/Hes1 pathway].

OBJECTIVE: To observe the effect of Yanghe Pingchuan (YHPC) granule on miR-139-5p, Notch1/Hes1 pathway and homing of bone marrow-derived mesenchymal stem cells (BMSCs) in asthmatic rats. METHODS: Fifty SD rats were randomized divided into normal control (NC) group, asthmatic model group, BMSCs transplantation group, BMSCs + dexamethasone (0.0625 mg/kg daily) group, and BMSCs+YHPC granule (3.5 g/kg daily) group. In all but the normal control group, asthmatic rat models were established by ovalbumin challenge, and BMSCs (1×106/mL) transplantation via the tail vein was performed in the latter 3 groups on last day of ovalbumin challenge. In all the groups, lung pathologies of the rats were evaluated using HE staining after the treatments. Flow cytometry was employed to detect pulmonary expression of CXCR4 protein, and ELISA was used to determine the expressions of interferon-γ (IFN-γ) and interleukin-4 (IL-4) in the lung tissue. The expressions of CXCR4, Notch1 and Hes1 in bronchial epithelial cells was examined using immunofluorescence assay. RT-PCR was used to detect the expressions of miR-139-5p, Notch1, Jagged1, RBP-J and Hes1 mRNAs, and the protein expressions of Notch1, Jagged1 and Hes1 were detected with Western blotting. RESULTS: Compared with the normal control rats, the asthmatic rats exhibited significantly increased expressions of CXCR4, IL-4, Notch1, Jagged1, RBP-J, and Hes1 mRNA and Notch1, Jagged1, and Hes1 proteins and lowered expressions of INF-γ mRNA and miR-139-5p in the lung tissues (P < 0.05 or 0.01). Compared with those in the asthmatic model group, the mRNA expressions of CXCR4, IFN-γ, and miR-139-5p increased and the expressions of IL-4, Notch1, Jagged1, RBP-J, and Hes1 mRNA and Notch1, Jagged1, and Hes1 proteins decreased significantly in the 3 groups with BMSCs transplantation (P < 0.05 or 0.01). The rats in BMSCs+YHPC granule group showed significantly higher CXCR4, IFN-γ, and miR-139-5p mRNA expressions and lower IL-4 and Notch1 mRNA expressions than those in BMSCs transplantation group (P < 0.05). CONCLUSIONS: YHPC granule can enhance the inhibitory effect of BMSCs homing on Th2 inflammatory response in asthmatic rats by up-regulating miR-139-5p and down-regulating Notch1/Hes1 pathway.

Ligustrazine improves blood circulation by suppressing Platelet activation in a rat model of allergic asthma.

Chuan-xiong (Ligusticum wallichii) is a traditional herbal medicine in Eastern Asia, but the effect of its active component ligustrazine remains unclear. We explored its effect and possible mechanism in a well-characterized rat model of allergic asthma. Ligustrazine suppressed bronchial hyper-responsiveness to methacholine, and suppressed lung inflammation in asthmatic rats. Ligustrazine exhibited potent immuno-modulatory and anti-inflammatory effects: it suppressed lymphocyte and eosinophil mobilization, and reduced cytokine IL-5 and IL-13 production significantly in lung tissues from asthmatic rats (P<0.05). Further histological examinations clearly demonstrated that ligustrazine improved blood circulation and ameliorated platelet activation, aggregation and adhesion, which induced sustained infiltration and activation of various inflammatory cells, including lymphocytes and eosinophils, followed by synthesis and release of a variety of pro-inflammatory mediators and cytokines. The present study suggests that ligustrazine is a potent agent for the treatment of allergic asthma due to its strong anti-inflammatory and immuno-modulatory properties.

[Effect of yifei jianpi recipe on inflammatory cells, levels of interleukin-8 and tumor necrosis factor-alpha in sputum from patients with chronic obstructive pulmonary disease].

OBJECTIVE: To explore the effect and the mechanism of yifei jianpi recipe (YFJPR) on patients with chronic obstructive pulmonary disease (COPD). METHODS: Forty patients with COPD in stable phase were randomly divided into two groups, the treated group and the control group. Indexes including the total and differential count of inflammatory cell in sputum, levels of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), as well as the percentage of forced expiratory volume in one second in its predicted value (FEV1%) and ratio of FEV1/forced vital capacity (FVC) in patients were measured before and after treatment, and compared with those in 20 healthy subjects. RESULTS: All the indexes measured in patients before and after treatment were significantly different from those in healthy subjects (P < 0.01). Differential count of polymorphonuclear neutrophil (PMN) and levels of IL-8 and TNF-alpha in sputum in the treated group significantly decreased after treatment (P < 0.01), while the non-PMN differential count and levels of FEV1% and FEV1/FVC significantly increased (P < 0.01). But in the control group, changes only showed in increasing of FEV1% and FEV1/FVC (P < 0.05 or P < 0.01). And the effects in the treated group were better than those in the control group (P < 0.01). CONCLUSION: YFJPR can play a therapeutic role on patients with COPD by way of reducing the airway inflammatory reaction.