2-基二醇通过呼吸道光滑肌细胞中的雌激素受体β激活来调节细胞外基质沉积
Ashish Kumar1, Mohammad Irshad Reza1, Anurag Banerjee2
1Section of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, The University of Oklahoma Health Campus, Oklahoma City, OK, USA; Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
2-基二醇 (2-HE) 通过通过雌激素受体β (ERβ) 抑制细胞外基质的产生来减少喘中的呼吸道重塑. 这种代谢物可能为喘治疗提供新的治疗策略.
科学领域:
- *内分泌学和呼吸系统医学
- * 分子和细胞生物学
背景情况:
- *喘的特征是气道重塑,涉及气道光滑肌肉 (ASM) 细胞增加细胞外基质 (ECM) 沉积.
- *17β-雌激醇 (E2) 通过雌激素受体 (ERα和ERβ) 对ASM重塑有差异性影响,但其代谢物的作用尚不清楚.
- *2-乙二醇 (2-HE) 和16-乙二醇 (16αHE) 是E的下游代谢产物,在ASM重塑过程中具有很大程度上尚未探索的功能.
研究的目的:
- * 研究2-HE和16αHE2对ASM细胞中ECM重塑的作用.
- *阐明这些影响背后的机制,包括ER结合和下游信号通路.
主要方法:
- * 评估ECM mRNA和蛋白质表达和沉积,使用西式涂抹,qRT-PCR和细胞内西式分析.
- *分子对接研究,以预测代谢物-ER相互作用.
- * 露西法酶记者测定用于监测雌激素反应元素 (ERE) 活性和使用ERα和ERβ敲击ASM细胞的验证.
主要成果:
- *2-HE显著抑制了转化生长因子-β (TGF-β) 诱导的ECM产生,而16αHE没有显著的影响.
- *分子对接和ERE试验表明16αHE2结合ERα,而2-HE优先结合ERβ.
- *在ERβ淘汰细胞中,2-HE阻断了TGF-β诱导的SMAD2/3,AKT和ERK1/2的酸化,并降低了AP-1和NF-κB的转录活性.
结论:
- *2-HE减轻TGF-β诱导的ASM细胞中的ECM重塑,主要通过ERβ.
- *这些发现将2-HE确定为针对喘呼吸道重塑的潜在治疗剂.
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