背景:慢性阻塞性肺疾病(COPD)是一种主要归因于氧化应激等多种病理因素的难治性呼吸系统疾病,感染性炎症,和特发性纤维化数十年。药用植物甘草提取物(ULE)在中国被广泛用于控制呼吸系统疾病。然而,支持ULE在COPD治疗中获益的科学证据的调节机制非常有限.
目的:本研究旨在通过多靶点策略发现ULE对COPD的潜在保护机制。
方法:本研究通过多靶点策略确定ULE对COPD的潜在保护作用。使用香烟烟雾和脂多糖建立COPD的体内和体外模型以评估ULE的保护作用。通过测量炎性细胞因子和评估肺部病理变化进行评估。HPLC用于验证使用HERB收集和筛选的潜在化合物的活性化合物。文学作品,和ADME工具。使用转录组学方法探索ULE治疗COPD的机制,连通性地图,和网络药理学方法。利用RT-PCR进一步研究了相关靶标,westernblot,和免疫组织化学。HCK抑制剂(iHCK-37)用于评估ULE活性化合物预防COPD的潜在机制。
结果:ULE有效保护COPD小鼠的肺部免受氧化应激,炎症,和纤维化损害。在使用ADME性质和HPLC进行筛选和验证后,在ULE中鉴定了4种活性化合物:甘草苷(LQ),licochalconeB(LCB),licochalconeA(LCA),和棘突素(ET)。结合转录组学分析的网络药理学显示,ULE减轻了氧化应激,炎症,通过抑制HCK在COPD中的纤维化。LCB和LQ的组合被优化用于抗炎,抗氧化,和抗纤维化活性。iHCK-37通过抑制HCK发挥抗氧化作用,进一步验证了LCB和LQ对COPD的预防性治疗,抗炎,和抗纤维化作用。LCB和LQ的组合,以1:1的比例,发挥协同抗氧化作用,抗炎,以及通过下调HCK治疗COPD的抗纤维化作用。
结论:LCB和LQ的组合通过下调HCK发挥了显著的抗COPD作用。
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a refractory respiratory disease mainly attributed to multiple pathological factors such as oxidative stress, infectious inflammation, and idiopathic fibrosis for decades. The medicinal plant Glycyrrhiza uralensis extract (ULE) was widely used to control respiratory diseases in China. However, the regulatory mechanism of scientific evidence to support the therapeutic benefits of ULE in the management of COPD is greatly limited.
OBJECTIVE: This study aims to discover the potential protection mechanism of ULE on COPD via a muti-targets strategy.
METHODS: The present study set out to determine the potential protective effects of ULE on COPD through a multi-target strategy. In vivo and in vitro models of COPD were established using cigarette smoke and lipopolysaccharide to assess the protective effects of ULE. It was evaluated by measuring inflammatory cytokines and assessing pulmonary pathological changes. HPLC was used to verify the active compounds of the potential compounds that were collected and screened using HERB, works of literature, and ADME tools. The mechanisms of ULE in the treatment of COPD were explored using transcriptomics, connectivity-map, and network pharmacology approaches. The relevant targets were further investigated using RT-PCR, western blot, and immunohistochemistry. The HCK inhibitor (iHCK-37) was used to evaluate the potential mechanism of ULE\'s active compounds in the prevention of COPD.
RESULTS: ULE effectively protected the lungs of COPD mice from oxidative stress, inflammation, and fibrosis damage. After screening and verification using ADME properties and HPLC, 4 active compounds were identified in ULE: liquiritin (LQ), licochalcone B (LCB), licochalcone A (LCA), and echinatin (ET). Network pharmacology integrated with transcriptomics analysis showed that ULE mitigated oxidative stress, inflammation, and fibrosis in COPD by suppressing HCK. The combination of LCB and LQ was optimized for anti-inflammation, antioxidation, and anti-fibrosis activities. The iHCK-37 further validated the preventive treatment of LCB and LQ on COPD by inhibiting HCK to exert antioxidant, anti-inflammatory, and anti-fibrotic effects. The combination of LCB and LQ, in a 1:1 ratio, exerted synergistic antioxidative, anti-inflammatory, and anti-fibrotic effects in the treatment of COPD by downregulating HCK.
CONCLUSIONS: The combination of LCB and LQ performed a significant anti-COPD effect via downregulating HCK.