Mechanic study based on untargeted metabolomics of Pi-pa-run-fei-tang on pepper combined with ammonia induced chronic cough model mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Pi-pa-run-fei-tang (PPRFT), a traditional Chinese medicine formula with long-standing history, demonstrated beneficial effect on chronic cough. However, the mechanism underlying efficacy unclear. In current research, we explored the impact and molecular mechanism of chronic cough mouse stimulating with capsaicin combined with ammonia. AIM OF THE STUDY: To investigate the metabolic modulating effects, and potential mechanisms underlying the therapeutic effect of PPRFT in chronic cough. MATERIALS AND METHODS: Chronic cough mouse models were created by stimulating mice by capsaicin combined with ammonia. Number of coughs and cough latency within 2 min were recorded. With lung tissue and serum samples collected for histopathology, metabolomics, RT-qPCR, immunohistochemistry, and WB analysis. Lymphocytes were isolated and flow cytometric assays were conducted to evaluate the differentiation between Th17 and Treg cell among CD4+ cells. RESULTS: Results indicated that PPRFT obviously reduced the number of coughs, prolonged cough latency, reduced inflammatory cell infiltration and lung tissues damage, and decreased the serum level of IL-6, IL-1ß, TNF-α, and IL-17 while increasing IL-10 levels. Notably, PPRFT suppressed Th17 cell divergence and promoted Treg cell divergence. Furthermore, serum metabolomic assays showed that 46 metabolites differed significantly between group, with 35 pathways involved. Moreover, mRNA levels of IL-6, NF-κB, IL-17, RORγT, JAK2, STAT3, PI3K and AKT in lung tissues remarkably reduced and mRNA levels of IL-10 and FOXP3 were elevated after PPRFT pretreatment. Additionally, PPRFT treatments decreased the protein levels of IL-6, NF-κB, IL-17, RORγT, p-JAK2, p-STAT3, p-PI3K, and p-AKT and increased the protein levels of IL-10 and FOXP3, but no significantly effects to the levels on JAK2, STAT3, PI3K, and AKT in the lungs. CONCLUSION: Conclusively, our result suggested the effect with PPRFT on chronic cough may be mediated through IL-6/JAK2/STAT3 and PI3K/AKT/NF-κB pathway, which regulate the differentiation between Th17 and Treg cell. This beneficial effect of PPRFT in capsaicin and ammonia-stimulated chronic cough mice indicates its potential application in treating chronic cough.

Pi-Pa-Run-Fei-Tang alleviates lung injury by modulating IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB signaling pathway and balancing Th17 and Treg in murine model of OVA-induced asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Pi-Pa-Run-Fei-Tang (PPRFT) is an empirical TCM prescription for treating asthma. However, the underlying mechanisms of PPRFT in asthma treatment have yet to be elucidated. Recent advances have revealed that some natural components could ameliorate asthma injury by affecting host metabolism. Untargeted metabolomics can be used to better understand the biological mechanisms underlying asthma development and identify early biomarkers that can help advance treatment. AIM OF THE STUDY: The aim of this study was to verification the efficacy of PPRFT in the treatment of asthma and to preliminarily explore its mechanism. MATERIALS AND METHODS: A mouse asthma model was built by OVA induction. Inflammatory cell in BALF was counted. The level of IL-6, IL-1ß, and TNF-α in BALF were measured. The levels of IgE in the serum and EPO, NO, SOD, GSH-Px, and MDA in the lung tissue were measured. Furthermore, pathological damage to the lung tissues was detected to evaluate the protective effects of PPRFT. The serum metabolomic profiles of PPRFT in asthmatic mice were determined by GC-MS. The regulatory effects on mechanism pathways of PPRFT in asthmatic mice were explored via immunohistochemical staining and western blotting analysis. RESULTS: PPRFT displayed lung-protective effects through decreasing oxidative stress, airway inflammation, and lung tissue damage in OVA-induced mice, which was demonstrated by decreasing inflammatory cell levels, IL-6, IL-1ß, and TNF-α levels in BALF, and IgE levels in serum, decreasing EPO, NO, and MDA levels in lung tissue, elevating SOD and GSH-Px levels in lung tissue and lung histopathological changes. In addition, PPRFT could regulate the imbalance in Th17/Treg cell ratios, suppress RORγt, and increase the expression of IL-10 and Foxp3 in the lung. Moreover, PPRFT treatment led to decreased expression of IL-6, p-JAK2/Jak2, p-STAT3/STAT3, IL-17, NF-κB, p-AKT/AKT, and p-PI3K/PI3K. Serum metabolomics analysis revealed that 35 metabolites were significantly different among different groups. Pathway enrichment analysis indicated that 31 pathways were involved. Moreover, correlation analysis and metabolic pathway analysis identified three key metabolic pathways: galactose metabolism; tricarboxylic acid cycle; and glycine, serine, and threonine metabolism. CONCLUSION: This research indicated that PPRFT treatment not only attenuates the clinical symptoms of asthma but is also involved in regulating serum metabolism. The anti-asthmatic activity of PPRFT may be associated with the regulatory effects of IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB mechanistic pathways.

Right atrial diameter and outcome of catheter ablation of atrial fibrillation.

PURPOSE: While AF is considered more like a left atrial (LA) disease, to what extent the right atrium contributes to the pathogenesis and ablation outcome of AF remains unclear. This study aimed to identify if right atrial diameter (RAD) could predict arrhythmia recurrence after catheter ablation of atrial fibrillation (AF). METHODS: Four hundred and seventy patients with drug-resistant AF [paroxysmal AF (PAF) 196; non-PAF 274] who underwent primary catheter ablation were enrolled. Ablation strategy included complete bilateral pulmonary vein isolation (PVI) in all patients and additional linear ablation across mitral isthmus, LA roof, and tricuspid isthmus in non-PAF cases. Risk factors associated with recurrence were determined by a Cox regression model, and the predictive power was evaluated by using receiver operating characteristic curve. RESULTS: After 24.3 ± 18.0 months, 284 patients (60.6%) experienced atrial tachyarrhythmia recurrence (111 in PAF, 173 in non-PAF). RAD was moderately associated with LA diameter (r = 0.371, P < 0.001), left ventricular ejection fraction (r = -0.205, P < 0.001), and left ventricular end-diastolic diameter (r = 0.319, P < 0.001). Multivariate Cox regression analysis demonstrated that RAD was an independent predictor for recurrence only in PAF patients with LAD ≥35 mm (HR 1.044, 95% CI 1.007-1.082, P = 0.021). The RAD cutoff value of 35.5 mm predicts atrial tachyarrhythmia recurrence with 85.4% sensitivity and 29.2% specificity. Kaplan-Meier analysis indicated that RAD over 35.5 mm is associated with more recurrence after PAF ablation (log-rank P = 0.034), comparing to those with RAD <35.5 mm. CONCLUSIONS: RAD predicts outcome of ablation only in patients with PAF and concurrent LA enlargement. Under this condition, RAD <35.5 mm is associated with a more favorable recurrence-free survival at over 2-year follow-up.

Uptake of evidence-based statin therapy among atrial fibrillation patients in China: A report from the CAFR (Chinese Atrial Fibrillation Registry) Study.

BACKGROUND: Atrial fibrillation (AF) is associated with increased incidence of cardiovascular disease, and hence, statin therapy is indicated in majority of AF patients. METHODS AND RESULTS: We analyzed data from the Chinese Atrial Fibrillation Registry (CAFR) involving 11,496 AF patients from 2011 to 2014. Practice patterns of statin therapy and factors associated with statin underuse were analyzed. Based on the 2013 ACC/AHA cholesterol management guidelines, statins should be recommended for 67.4% (7720/11,461) of AF participants in CAFR, but only 43.4% (3352/7720) with appropriate indications were taking statins. Statin underuse in AF patients was independently associated with male sex, tertiary hospital treatment, outpatient attendance, and absence of 'high risk' cardiovascular risk factors (overweight, diabetes, coronary heart disease, stroke/transient ischemic attack/peripheral embolism and hypertension). CONCLUSIONS: A high proportion of Chinese AF patients had indications for statin therapy. Evidence-based statin prescribing was suboptimal in this population. Greater efforts should be made to improve a holistic approach to cardiovascular risk management in the Chinese AF population.

Predictors of recurrence after a repeat ablation procedure for paroxysmal atrial fibrillation: role of left atrial enlargement.

AIMS: This study sought to explore the predictors of recurrence in patients with paroxysmal atrial fibrillation (AF) undergoing repeat catheter ablation, especially the impact of left atrial (LA) remodelling after the original procedure on the outcome of repeat procedure. METHODS AND RESULTS: Ninety-five patients undergoing repeat ablation were enrolled in this study. Repeat procedure endpoints were pulmonary vein isolation, linear block when linear ablation is performed, and non-inducibility of atrial tachyarrhythmia by burst pacing. Patients with LA enlargement between the pre-original procedure and pre-repeat procedure were categorized as Group 1 (35 patients), while individuals with no change or decrease of LA diameter were categorized as Group 2 (60 patients). The mean duration from the original procedure to the repeat procedure was 12 months (1-40 months). After 29.6 ± 20.5 (3-73) months follow-up from the repeat procedure, 33 patients experienced recurrence (34.7%). The recurrence rate was significantly higher in Group 1 than in Group 2 (51.4 VS. 25.0%, P = 0.017). In univariate analysis, LA remodelling was the only predictor of recurrence. In multivariate analysis, after adjustment for age and LA diameter, Group 1 had a greater risk of recurrence after the repeat procedure (hazard ratio = 2.22, 95% confidence interval: 1.02-4.81, P = 0.043). CONCLUSIONS: Left atrial enlargement after undergoing the original catheter ablation of paroxysmal AF was an independent risk factor of recurrence after repeat ablation.

Electrophysiological and hemodynamic characteristics associated with obesity in patients with atrial fibrillation.

OBJECTIVES: The authors sought to characterize the left atrial (LA) and pulmonary vein (PV) electrophysiological and hemodynamic features in obese patients with atrial fibrillation (AF). BACKGROUND: Obesity is associated with increased risk for AF. METHODS: A total of 63 consecutive patients with AF who had normal left ventricular (LV) ejection fraction and who underwent catheter ablation were studied. Atrial and PV electrophysiological studies were performed at the time of ablation with hemodynamic assessment by cardiac catheterization, and LA/LV structure and function by echocardiography. Patients were compared on the basis of body mass index (BMI): <25 kg/m(2) (n = 19) and BMI ≥30 kg/m(2) (n = 44). RESULTS: At a 600-ms pacing cycle length, obese patients had shorter effective refractory period (ERP) in the left atrium (251 ± 25 ms vs. 233 ± 32 ms, p = 0.04), and in the proximal (207 ± 33 ms vs. 248 ± 34 ms, p < 0.001) and distal (193 ± 33 ms vs. 248 ± 44 ms, p < 0.001) PV than normal BMI patients. Obese patients had higher mean LA pressure (15 ± 5 mm Hg vs. 10 ± 5 mm Hg, p < 0.001) and LA volume index (28 ± 12 ml/m(2) vs. 21 ± 14 ml/m(2), p = 0.006), and lower LA strain (5.5 ± 3.1% vs. 8.8 ± 2.8%; p < 0.001) than normal BMI patients. CONCLUSIONS: Increased LA pressure and volume, and shortened ERP in the left atrium and PV are potential factors facilitating and perpetuating AF in obese patients with AF.