黄芩苷通过靶向FSTL1/DIP2A信号通路改善肥胖性肺损伤的机制研究OA

This study aims to explore the therapeutic potential of baicalin for obesity-related lung injury and its underlying molecular mechanisms,with a particular focus on its regulatory effects on the follistatin-like protein 1(FSTL1)/disco-interacting protein 2 homolog A(DIP2A)signaling pathway.A total of 56 C57BL/6J mice were randomly allocated into 7 groups(n=8):control,high-fat diet(HFD,model),low-dose baicalin(HFD+BA-L,50 mg·kg-1),high-dose baicalin(HFD+BA-H,100 mg·kg-1),dexamethasone(HFD+DXMS,5 mg·kg-1,positive control),DIP2A gene knockout(DIP2A-KO+HFD),and DIP2A gene knockout combined with baicalin(DIP2A-KO+HFD+BA,100 mg·kg-1).An obesity model was established in mice via a high-fat diet.Except for the control and HFD groups,which were administered an equal volume of normal saline by gavage,the other groups were treated with the corresponding doses of baicalin or dexamethasone for 14 days.One hour after the final treatment,the control group was intratracheally instilled with sterile normal saline,while the other groups were instilled with lipopolysaccharide(LPS)to induce an acute lung injury model.The results showed that compared with the control group,the HFD group exhibited severe alveolar structural destruction and fibrosis,with a significant increase in the lung tissue wet-to-dry weight ratio(W/D).The intervention with baicalin(HFD+BA-L,HFD+BA-H)significantly alleviated the pathological damage,enhanced the activity of superoxide dismutase(SOD),and reduced the content of malondialdehyde(MDA),which indicated the alleviation of oxidative stress.Additionally,the mRNA and protein levels of α-smooth muscle actin(α-SMA),N-cadherin,collagen Ⅰ,interleukin(IL)-6,IL-1β,tumor necrosis factor-α(TNF-α),FSTL1,phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT),and Kelch-like ECH-associated protein 1(Keap1)were significantly downregulated,whereas those of E-cadherin,IL-10,nuclear factor E2-related factor 2(Nrf2),heme oxygenase-1(HO-1),and DIP2A were significantly upregulated.In the DIP2A-KO+HFD+BA group,the protective effect of baicalin on the lung and its downregulation of FSTL1 expression were both significantly weakened.This study revealed that baicalin may upregulate DIP2A expression and inhibit FSTL1 and PI3K/AKT expression to activate the Nrf2/HO-1 antioxidant pathway and regulate the expression of epithelial-mesenchymal transition(EMT)-related proteins,thereby exerting its lung-protective effects.