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. 2020 Sep 4:11:533841.
doi: 10.3389/fphar.2020.533841. eCollection 2020.

Formononetin Attenuates Airway Inflammation and Oxidative Stress in Murine Allergic Asthma

La Yi  1 , Jie Cui  1   2 , Wenqian Wang  1   2 , Weifeng Tang  1   2 , Fangzhou Teng  1   2 , Xueyi Zhu  1   2 , Jingjing Qin  1   2 , Tulake Wuniqiemu  1   2 , Jing Sun  1   2 , Ying Wei  1   2 , Jingcheng Dong  1   2
Affiliations

Formononetin Attenuates Airway Inflammation and Oxidative Stress in Murine Allergic Asthma

V体育安卓版 - La Yi et al. Front Pharmacol. .

Abstract

Allergic asthma has been considered as a respiratory disorder with pathological features of airway inflammation and remodeling, which involves oxidative stress. Formononetin (FMT) is a bioactive isoflavone obtained from Chinese herb Radix Astragali, and has been reported to have notable anti-inflammatory and antioxidant effects in several diseases. The purpose of our study was to elaborate the effects of FMT on asthma and the underlying mechanisms. To establish allergic asthma model, BALB/c mice were given ovalbumin (OVA) sensitization and challenge, treated with FMT (10, 20, 40 mg/kg) or dexamethasone (2 mg/kg). The effects of FMT on lung inflammation and oxidative stress were assessed. In OVA-induced asthmatic mice, FMT treatments significantly ameliorated lung function, alleviated lung inflammation including infiltration of inflammatory cells, the elevated levels of interleukin (IL)-4, IL-5, and IL-13, immunoglobulin (Ig) E, C-C motif chemokine ligand 5 (CCL5, also known as RANTES), CCL11 (also called Eotaxin-1), and IL-17A. In addition, FMT treatments eminently blunted goblet cell hyperplasia and collagen deposition, and remarkably reduced oxidative stress as displayed by decreased reactive oxygen species (ROS), and increased superoxide diamutase (SOD) activity. Furthermore, to clarify the potential mechanisms responsible for the effects, we determined the inflammation and oxidation-related signaling pathway including nuclear factor kappa β (NF-κB), c-Jun N-terminal kinase (JNK), and the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). FMT treatments appeared to dramatically inhibit the activation of NF-κB and JNK, significantly elevated the expression of heme oxygenase 1 (HO-1) but failed to activate expression of Nrf2. In conclusion, our study suggested that FMT had the therapeutic effects in attenuating airway inflammation and oxidative stress in asthma. VSports手机版.

Keywords: airway inflammation; asthma; c-Jun N-terminal kinase; formononetin; nuclear factor erythroid 2-related factor 2; nuclear factor kappa β; oxidative stress. V体育安卓版.

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Figures

Figure 1
Figure 1
The chemical structure of Formononetin and the flow chart of OVA-induced asthmatic model and treatment (A). The chemical structure of Formononetin (FMT, 7-Hydroxy-4'-methoxy-isoflavone) (B). Asthmatic model and treatment protocol. Mice were grouped, sensitized, challenged, administered and sacrificed from day 0 to 49. Sensitization was performed on day 0 and 14. Challenged and treatment were performed every other day from day 21 to 48. After 24h, mice were sacrificed.
Figure 2
Figure 2
Effect of FMT treatments on lung function in murine asthmatic model. (A, B) Increase of lung resistance (RL%) (A) and decrease of lung dynamic compliance (Cydn%) (B). Data are shown as the mean ± SD analyzed b two-way ANOVA. (C, D) Increase of RL% (C) and decrease of Cydn % (D) at Mch dose of 12.5 mg/ml. Data are shown as the mean ± SD analyzed by one-way ANOVA. N = 4-6 mice/group. *p < 0.05, **p < 0.01, ***p < 0.001 vs NC group, #p < 0.05, ##p < 0.01, ###p < 0.001 vs Asthma group.
Figure 3
Figure 3
Effects of FMT on OVA-induced airway inflammation and remodeling in lung tissue. (magnification: x200). (A, B) H&E-staining and scores of airway inflammation. (C, D) Periodic acid-Schiff (PAS) staining and the percentage of PAS + epithelial cells. (E, F) Masson’s trichrome staining and collage and volume faction. Bars, 100 μm. Data were shown as mean ± SD analyzed by one-way ANOVA. N = 5 mice/group. ***p < 0.001 vs NC group. #p < 0.05, ##p < 0.0.1, ###p < 0.001 vs Asthma group.
Figure 4
Figure 4
The effect of FMT treatments on lung eosinophils. Th17 and Treg cells in murine asthmatic model. (A–C) Flow cytometric identification of lung of each group. (D–F) Percentages of eosinophils (D), Th17 cells (E) and Tregg cells (F) in each group. Bar shows the mean ± SD (samples from 4 to 5 mice/group) ***p < 0.001 vs NC group, #p < 0.05, ##p < 0.01, ###p < 0.001 vs Asthma group determined use one-way ANOVA.
Figure 5
Figure 5
Effects of EMT on inflammatory cells and inflammatory mediators in BALF. (A) The number of leukocytes. (B–H) The levels of Ig E, CCL5, CCL11, IL-4, IL-5, IL-13, and IL-17A. Data are shown as mean ± SD by one-way ANOVA. N = 4-7/mice/group. *p < 0.05, **p < 0.01, ***p < 0.001 vs NC group, #p < 0.05, ##p < 0.001, ###p < 0.001 vs Asthma group.
Figure 6
Figure 6
Effects of FMT on oxidative stress in lung tissue. (A, B) The level of in situ ROS, stained with DHE in frozen lung tissue (magnification: x200) The fluorescence values are expressed as the areal density, the ratio of the integrated optical density value (IOD) to the pixel area of the tissue (AREA). (C) The level of NO. (D) Total SOD activity in lung tissue. Data are shown as mean ± SD. N = 4–7mice/group. Bars 100 μm. *p < 0.05, **p < 0.01, ***p < 0.001 vs NC group, #p < 0.05, ##p < 0.01 vs Asthma group.
Figure 7
Figure 7
Effect of FMT on inflammation and oxidative stress signaling pathway. (A) The protein expression of NF-κB and JNK, as well as Nrf2/HO-1 and SOD 1, was determined by western blotting. (B, C) The relative density quantification of NFkb and JNK. The results were expressed as the ratio of phosphorylated proteins relative to total proteins. (D–F) The relative density quantifications of Nrf2, HO-1, and SOD1. The results were expressed as the ratio of Nrf2, HO-1, and SOD1 relative to GAPDH, respectively. Data were shown as mean ± SD analyzed by one-way ANOVA. N = 4 mice/group. *p < 0.05, ***p < 0.001 vs NC group, #p < 0.05, ##p < 0.01, ###p < 0.001 vs Asthma group.
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