Paeoniflorin inhibits PRAS40 interaction with Raptor to activate mTORC1 to reverse excessive autophagy in airway epithelial cells for asthma.

BACKGROUND: Bronchial asthma is a chronic condition characterized by airway inflammation and remodeling, which pose complex pathophysiological challenges. Autophagy has been identified as a practical strategy to regulate inflammation and remodeling processes in chronic inflammatory diseases with pathological characteristics, such as asthma. PF (Paeoniflorin) is a potential new autophagy regulatory compound. Previous studies have reported that PF can inhibit airway inflammation to alleviate allergic asthma, but whether this is mediated through the regulation of autophagy and the molecular mechanism of action remains unclear. PURPOSE: The aim of this study was to evaluate the inhibitory effect of natural small molecule PF on asthma by regulating epithelial autophagy. METHODS: The rat asthma model was established through intraperitoneal injection of OVA and aluminum hydroxide suspension, followed by atomized inhalation of OVA for a period of two weeks. Following treatment with PF, histopathology was observed using Masson and H&E staining, while airway Max Rrs was evaluated using a pulmonary function apparatus. Levels of inflammatory cells in BALF were detected using a blood cell analyzer, and levels of inflammatory factors in BALF were detected through Elisa. Expressions of p-PRAS40 and p-Raptor were observed through immunohistochemistry, and levels of Beclin1 and LC3B were observed through immunofluorescence. The structure and quantity of autophagosomes and autophagolysosomal were observed through TEM. An autophagy model of 16HBE cells was established after treatment with 10ng/mL IL13 for 30 minutes. PRAS40 (AKT1S1) overexpression and mutation of PF and Raptor binding site (K207M& L302I& Q417H) were introduced in 16HBE cells. Autophagy in cells was measured by mFRP-GFP-LC3 ADV fluorescent tracer. The binding sites of PF and Raptor were analyzed using the Autodock Tool. The p-mTOR, p-Raptor, p-PRAS40, LC3II/LC3I were detected through Western blot, and interaction between PRAS40-Raptor and Raptor-mTOR was detected through Co-IP. RESULTS: The results showed that PF effectively reduced airway inflammation, improved airway pathological changes and remodeling, and maintained lung function. Additionally, PF was found to reverse excessive autophagy in airway epithelial cells. Interestingly, PF activated the mTORC1 subunit PRAS40 and Raptor in airway epithelial cells by regulating their phosphorylation. PRAS40 is an endogenous mTOR inhibitor that promotes autophagy. PF competitively binds Raptor to PRAS40, promoting Raptor-mTOR interactions to activate mTORC1, an outcome that can be reversed by PRAS40 overexpression and site-specific amino acid codon mutations in Raptor. CONCLUSION: These findings suggest that PF intervention and inhibition of PRAS40-Raptor interaction are effective treatments for bronchial asthma. By activating mTORC1, PF effectively reverses excessive autophagy in airway epithelial cells, leading to improved airway function and reduced inflammation.

Effectiveness and safety of Xingbei Zhike granules in patients with postinfectious cough: A multicenter, randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Postinfectious cough (PIC) is a common symptom following a respiratory tract infection. Xingbei Zhike (XBZK) granules, a Chinese patent medicine, has been widely used for PIC in clinics. However, there is a lack of evidence on the effectiveness. PURPOSE: To investigate whether treatment with XBZK granules is effective for PIC. STUDY DESIGN: A multicenter, randomized, double-blinded, placebo-controlled trial. METHODS: Eligible participants from fourteen hospitals were randomly assigned in 3:1 ratio to receive either XBZK granules or placebo for 14 days. The primary outcome was the area under the curve (AUC) of a visual analogue scale (VAS) for cough symptoms. Secondary outcomes included cough symptom score (CSS), time and probability of recovery from cough, traditional Chinese medicine (TCM) syndrome score, relief rates of individual symptoms, Leicester Cough Questionnaire (LCQ) score, and the use of reliever drug. RESULTS: A total of 235 patients (176 in XBZK and 59 in placebo groups) were included in the analysis. The AUC for cough VAS scores was lower in the XBZK than placebo group (-8.10, 95 % CI -14.12 to -2.07, p = 0.009), indicating superiority. XBZK decreased CSS (-0.68 points, 95 % CI -1.13 to -0.22, p = 0.01), shortened time to cough recovery (-2 days, hazard ratio [HR] 1.48, 95 % CI 1.03 to 2.13, p = 0.02), enhanced the probability of cough recovery (risk ratio [RR] 1.66, 95 % CI 1.07 to 2.58, p = 0.03), lowered TCM syndrome score (-0.99 points, 95 % CI -1.58 to -0.40, p = 0.004), increased the rate of daytime (RR 1.84, 95 % CI 1.07 to 3.15, p = 0.02) and nighttime (RR 2.07, 95 % CI 1.29 to 3.35, p = 0.004) cough recovery, and reduced the viscosity of sputum (RR 2.92, 95 % CI 1.66 to 5.13, p < 0.001) compared to placebo. There were no significant differences in LCQ scores and taking reliever drugs between groups. No severe adverse events were reported in either group. CONCLUSIONS: XBZK granules are a promising therapy against PIC, effective in lowering the overall severity of cough, shortening the time to cough recovery, and reducing the viscosity of sputum.

Efficacy of Yiqi Wenyang Huoxue method in treating adult bronchial asthma: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Bronchial asthma (BA) is a chronic inflammatory disease of the airway, which has the characteristics of recurrent attacks and difficult to cure. Glucocorticoid and bronchodilator are the primary treatment drugs for asthma. Although the treatment has made some progress, the control status is still not ideal. According to clinical reports, the Yi-qi Wen-yang Huo-xue method (YQWYHXM) of Traditional Chinese Medicine (TCM) is safe and effective in the treatment of BA, but there is not enough evidence to prove it. Based on it, we conducted this systematic evaluation. METHODS: Eight databases and Clinical trial registries (Embase, Cochrane, PubMed, CNKI, CBM, Wanfang, VIP, China Clinical Trial Registry and Clinical Trails) were searched from the establishment of those until January 22, 2021 with the following terms for retrieval: BS, TCM, Chinese medicinal herb, Chinese herbal medicine and randomized controlled trial. Data analysis was performed by 2 researchers using RevMan 5.3 and SATA 16.0 separately from the Cochrane Collaboration. RESULTS: This study will be able to provide definitive evidence to clarify all the suspicions we seek, confirming the effectiveness of YQWYHXM in the treatment of adults with BA. CONCLUSION: This study will prove that YQWYHXM is a safe and effective TCM adjuvant therapy for BA. REGISTRATION: Efficacy of Yiqi Wenyang Huoxue method in Treating Adult Bronchial Asthma. ASTHMA: A protocol for Systematic Review and Meta-Analysis of Randomized Controlled Trials. PROSPERO 2021 CRD42021256791. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021256791.

Xiaoqinglong granules as add-on therapy for asthma: latent class analysis of symptom predictors of response.

Xiaoqinglong granules (XQLG) has been shown to be an effective therapy in asthma animal models. We reviewed the literature and conducted this study to assess the impact of XQLG as an add-on therapy to treatment with fluticasone/salmeterol (seretide) in adult patients with mild-to-moderate, persistent asthma. A total of 178 patients were randomly assigned to receive XQLG and seretide or seretide plus placebo for 90 days. Asthma control was assessed by asthma control test (ACT), symptoms scores, FEV(1), and PEF. Baseline patient-reported Chinese medicine (CM)-specific symptoms were analyzed to determine whether the symptoms may be possible indicators of treatment response by conducting latent class analysis (LCA). There was no statistically significant difference in ACT score between two groups. In the subset of 70 patients with symptoms defined by CM criteria, XQLG add-on therapy was found to significantly increase the levels of asthma control according to global initiative for asthma (GINA) guidelines (P = 0.0329). There was no significant difference in another subset of 100 patients with relatively low levels of the above-mentioned symptoms (P = 0.1291). Results of LCA suggest that patients with the six typical symptoms defined in CM may benefit from XQLG.