Background Asthma is a chronic airway disorder with a hallmark feature of airflow obstruction that associated with the remodeling and inflammation in the airway wall. Effective therapy for controlling both remodeling and inflammation is still urgently needed. Leonuride is the main pharmacological component identified from Bu-Shen-Yi-Qi-Tang (BSYQT) which has been traditionally used in treatment of lung diseases. However, no pharmacological effects of leonuride in asthma were reported. Purpose Here we aimed to investigated whether leonuride provided a therapeutic efficacy in reversing asthma airway remodeling and inflammation and uncover the underlying mechanisms. Study design and methods Mouse models of chronic asthma were developed with ovalbumin (OVA) exposure for 8 weeks. Respiratory mechanics, lung histopathology and asthma-related cytokines were examined. Lung tissues were analyzed using RNA sequencing to reveal the transcriptional profiling changes. Results After oral administration with leonuride (15 mg/kg or 30 mg/kg), mice exhibited a lower airway hyperresponsiveness in comparison to asthmatic mice. Leonuride suppressed airway inflammation evidenced by the significant reductions in accumulation of inflammatory cells around bronchi and vessels, leukocyte population counts and the abundance of type 2 inflammatory mediators (OVA specific IgE, IL-4, IL-5 and IL-13) in bronchoalveolar lavage fluid (BALF). On the other hand, leonuride slowed down the process of active remodeling as demonstrated by weaker goblet cell metaplasia and subepithelial fibrosis in lung histopathology and lower transforming growth factor (TGF)-β1 levels in serum and BALF in comparison to mice treated with OVA only. Furthermore, we uncovered transcriptional profiling alternations in lung tissue of mice after OVA exposure and leonuride treatment. Gene sets belonging to type-2 cytokine/chemokine activity stood out in leonuride target transcripts. Those upregulated (Bmp10, Ccl12, Ccl22, Ccl8, Ccl9, Cxcl15, Il13, Il33, Tnfrsf9, Il31ra, Il5ra, Il13ra2 and Ccl24) or downregulated (Acvr1c and Il18) genes in asthmatic mice, were all reversely regulated by leonuride treatment. Conclusions Our results revealed the therapeutic efficacy of leonuride in experimental chronic asthma for the first time, and implied that its anti-inflammatory and antifibrotic properties might be mediated by regulation of type-2 high cytokine/chemokines responses.
Ethnopharmacological relevance In traditional Chinese medicine (TCM) and modern pharmacodynamics , dried Rehmannia Radix (DRR) possesses prominent anti-thrombotic activity that decreases after processing by nine steaming and drying cycles to develop processed Rehmannia Radix (PRR). Due to the complexity of the DRR components, the chemical mechanism leading to efficacy changes of DRR caused by processing is still unclear. Aim of study This study aimed to trace the anti-thrombotic active compounds of DRR and different degrees of processed RR (PRR) and to evaluate the synergistic effects among different active components. Materials and methods The anti-thrombotic active chemical fraction of DRR extracts was evaluated. Targeted fractions of the processed products of RR were prepared at different processing stages. The changes in monosaccharides , oligosaccharides and secondary metabolites during processing were characterized by multidimensional high-performance liquid chromatography (HPLC). The anti-thrombotic effects of targeted fractions of different RR samples were evaluated by analyzing the length of tail thrombus (LT) and serum biochemical indicators in carrageenan-induced tail-thrombus mice. The spectrum-effect relationships were investigated by partial least squares regression (PLSR) analysis and gray correlation analysis (GRA). Finally, the active compounds were screened by spectrum-effect relationship analysis and validated in vivo , and their synergistic effects were determined by Webb's fraction multiplication method. Results Six ingredients highly associated with anti-thrombotic activities were screened out by the spectrum-effect relationship analysis, of which oligosaccharides (stachyose, sucrose and raffinose) and iridoid glycosides (catalpol, leonuride and melitoside) possessed a synergistic effect on tumor necrosis factors (TNF-α), interleukin 1β (IL-1β) and plasminogen activator inhibitor 1 (PAI-1)/tissue-type plasminogen activator (t-PA) ratio in vivo with synergistic coefficient (SC) > 1. Conclusion The main material basis of the anti-thrombotic activities of DRR is oligosaccharide components of stachyose, raffinose and sucrose, iridoid glycosides components of catalpol , leonuride and melittoside. The two kinds of components exert synergistic anti-thrombotic effects by inhibiting the expression of inflammatory factors and regulating the balance of the fibrinolysis system.
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