Nrf2 regulates downstream genes by targeting miR-29b in severe asthma and the role of grape seed proanthocyanidin extract in a murine model of steroid-insensitive asthma.

Yan Qian, Yun Sun, Yi Chen, Zhengdao Mao, Yujia Shi, Di Wu, Bin Gu, Zhiguang Liu, Qian Zhang

Pharmaceutical biology 2022 Dec

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Grape seed proanthocyanidin extract (GSPE) is effective in treating severe asthma (SA). To examine the relationship between Nrf2-miR-29b axis and SA, and to detect whether preventive use of GSPE relieves SA via it. We recruited 10 healthy controls, 10 patients with non-severe asthma (nSA), and 9 patients with SA from February 2017 to December 2017. Peripheral blood mononuclear cells from these volunteers were extracted. A murine model of steroid-insensitive asthma was established in six-week-old female BALB/c mice that were sensitised and challenged with OVA, Al(OH)3 and LPS for 31 days. Mice in the treated groups were injected with DXM (5 mg/kg/d), with or without GSPE (100 mg/kg/d). Control group received PBS. We performed quantitative real-time PCR, western blot and luciferase reporter assay in animal and cell models. SA group demonstrated significantly lower concentrations of Nrf2 protein, Nrf2 mRNA, and miR-29b than nSA group and control group. Conversely, higher levels of platelet derived growth factor C (PDGFC), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), and collagen type III alpha 1 (COL3A1) were measured in SA than in the other two groups. PDGFC, PIK3R1, and COL3A1 were the target genes of miR-29b. GSPE + DXM significantly elevated the expression of Nrf2 (+188%), Nrf2 mRNA (+506%), and miR-29b (+201%), and significantly reduced the expression of PDGFC (-72%), PIK3R1 (-40%), and COL3A1 (-65%) compared with OVA + LPS. Nrf2-miR-29b axis is involved in the pathogenesis of SA. GSPE, as an adjuvant drug, maybe a potential therapeutic agent for SA.

Citation

Yan Qian, Yun Sun, Yi Chen, Zhengdao Mao, Yujia Shi, Di Wu, Bin Gu, Zhiguang Liu, Qian Zhang. Nrf2 regulates downstream genes by targeting miR-29b in severe asthma and the role of grape seed proanthocyanidin extract in a murine model of steroid-insensitive asthma. Pharmaceutical biology. 2022 Dec;60(1):347-358