芹菜素通过ROS-ASK1-MAPK途径改善慢性肥胖哮喘的非嗜酸性炎症、失调的免疫稳态和线粒体介导的气道上皮细胞凋亡
2023/03/21
摘要
背景：肥胖型哮喘是近年来受到广泛关注的重要哮喘表型之一。过度的氧化应激和不同的炎症内型可能是肥胖哮喘症状复杂、频繁加重、对传统治疗方法产生耐药性的重要原因。芹菜素(Apigenin, API)是一种黄酮类天然小分子化合物，对多种疾病具有良好的抗炎和抗氧化活性，并被证明对对抗肥胖型哮喘有潜在疗效。
方法：本研究在体内采用高脂饮食(HFD)喂养C57BL/6 J小鼠12周，然后用OVA刺激6周，建立慢性肥胖型哮喘模型，同时采用不同剂量口服API或地塞米松进行治疗干预。在体外，本研究使用HDM刺激人支气管细胞(HBEs)建立模型，并用API或Selonsertib (SEL)干预。
结果：本研究明确了OVA在长期高脂饮食的肥胖雄性小鼠中诱导了一种伴有嗜中性粒细胞和嗜酸性粒细胞升高的混合性粒细胞性哮喘，同时还表现出混合性TH17/TH1/TH2炎症。芹菜素有效地抑制了这种复杂的炎症，并充当了免疫稳态的调节剂。同时，芹菜素通过ROS-ASK1-MAPK通路降低肥胖哮喘小鼠的AHR、炎症细胞浸润、气道上皮细胞凋亡、气道胶原沉积和肺氧化应激。在体外，本研究发现芹菜素改变了TRAF6与ASK1的结合状态，抑制了ASK1的磷酸化，并保护了ASK1的泛素依赖性降解，提示ROS激活的ASK1可能是芹菜素发挥抗炎和抗凋亡作用的重要靶点。为了进一步验证其干预机制，本研究明确了芹菜素通过干扰ROS-ASK1-MAPK通路提高细胞活力和线粒体功能，抑制细胞凋亡。
结论：本研究首次证实了芹菜素对慢性肥胖性哮喘的治疗作用，进一步明确了其潜在的治疗靶点。此外，本研究明确了慢性肥胖性哮喘的特异性，为其治疗提供了新的选择。
Apigenin ameliorates non-eosinophilic inflammation, dysregulated immune homeostasis and mitochondria-mediated airway epithelial cell apoptosis in chronic obese asthma via the ROS-ASK1-MAPK pathway
Hang Yu , Xi Huang , Hua-He Zhu
Abstrast
Background: Obese asthma is one of the important asthma phenotypes that have received wide attention in recent years. Excessive oxidative stress and different inflammatory endotypes may be important reasons for the complex symptoms, frequent aggravation, and resistance to traditional treatments of obese asthma. Apigenin (API), is a flavonoid natural small molecule compound with good anti-inflammatory and antioxidant activity in various diseases and proved to have the potential efficacy to combat obese asthma.
Methods: In vivo, this study fed C57BL/6 J mice with high-fat diets(HFD)for 12 weeks and then stimulated them with OVA for 6 weeks to establish a model of chronic obese asthma, while different doses of oral API or dexamethasone were used for therapeutic interventions. In vitro, this study used HDM to stimulate human bronchial cells (HBEs) to establish the model and intervened with API or Selonsertib (SEL).
Results: This study clarified that OVAinduced a type of mixed granulocytic asthma with elevated neutrophils and eosinophils in obese male mice fed with long-term HFD, which also exhibited mixed TH17/TH1/TH2 inflammation. Apigenin effectively suppressed this complex inflammation and acted as a regulator of immune homeostasis. Meanwhile, apigenin reduced AHR, inflammatory cell infiltration, airway epithelial cell apoptosis, airway collagen deposition, and lung oxidative stress via the ROS-ASK1-MAPK pathway in an obese asthma mouse model. In vitro, this study found that apigenin altered the binding status of TRAF6 to ASK1, inhibited ASK1 phosphorylation, and protected against ubiquitin-dependent degradation of ASK1, suggesting that ROS-activated ASK1 may be an important target for apigenin to exert anti-inflammatory and anti-apoptotic effects. To further verify the intervention mechanism, this study clarified that apigenin improved cell viability and mitochondrial function and inhibited apoptosis by interfering with the ROS-ASK1-MAPK pathway.
Conclusions: This study demonstrates for the first time the therapeutic effect of apigenin in chronic obese asthma and further clarifies its potential therapeutic targets. In addition, this study clarifies the specificity of chronic obese asthma and provides new options for its treatment.
背景：肥胖型哮喘是近年来受到广泛关注的重要哮喘表型之一。过度的氧化应激和不同的炎症内型可能是肥胖哮喘症状复杂、频繁加重、对传统治疗方法产生耐药性的重要原因。芹菜素(Apigenin, API)是一种黄酮类天然小分子化合物，对多种疾病具有良好的抗炎和抗氧化活性，并被证明对对抗肥胖型哮喘有潜在疗效。
方法：本研究在体内采用高脂饮食(HFD)喂养C57BL/6 J小鼠12周，然后用OVA刺激6周，建立慢性肥胖型哮喘模型，同时采用不同剂量口服API或地塞米松进行治疗干预。在体外，本研究使用HDM刺激人支气管细胞(HBEs)建立模型，并用API或Selonsertib (SEL)干预。
结果：本研究明确了OVA在长期高脂饮食的肥胖雄性小鼠中诱导了一种伴有嗜中性粒细胞和嗜酸性粒细胞升高的混合性粒细胞性哮喘，同时还表现出混合性TH17/TH1/TH2炎症。芹菜素有效地抑制了这种复杂的炎症，并充当了免疫稳态的调节剂。同时，芹菜素通过ROS-ASK1-MAPK通路降低肥胖哮喘小鼠的AHR、炎症细胞浸润、气道上皮细胞凋亡、气道胶原沉积和肺氧化应激。在体外，本研究发现芹菜素改变了TRAF6与ASK1的结合状态，抑制了ASK1的磷酸化，并保护了ASK1的泛素依赖性降解，提示ROS激活的ASK1可能是芹菜素发挥抗炎和抗凋亡作用的重要靶点。为了进一步验证其干预机制，本研究明确了芹菜素通过干扰ROS-ASK1-MAPK通路提高细胞活力和线粒体功能，抑制细胞凋亡。
结论：本研究首次证实了芹菜素对慢性肥胖性哮喘的治疗作用，进一步明确了其潜在的治疗靶点。此外，本研究明确了慢性肥胖性哮喘的特异性，为其治疗提供了新的选择。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(Phytomedicine 2023 Mar; 111: 154646. doi: 10.1016/j.phymed.2023.154646. IF: 4.268)
(Phytomedicine 2023 Mar; 111: 154646. doi: 10.1016/j.phymed.2023.154646. IF: 4.268)
Apigenin ameliorates non-eosinophilic inflammation, dysregulated immune homeostasis and mitochondria-mediated airway epithelial cell apoptosis in chronic obese asthma via the ROS-ASK1-MAPK pathway
Hang Yu , Xi Huang , Hua-He Zhu
Abstrast
Background: Obese asthma is one of the important asthma phenotypes that have received wide attention in recent years. Excessive oxidative stress and different inflammatory endotypes may be important reasons for the complex symptoms, frequent aggravation, and resistance to traditional treatments of obese asthma. Apigenin (API), is a flavonoid natural small molecule compound with good anti-inflammatory and antioxidant activity in various diseases and proved to have the potential efficacy to combat obese asthma.
Methods: In vivo, this study fed C57BL/6 J mice with high-fat diets(HFD)for 12 weeks and then stimulated them with OVA for 6 weeks to establish a model of chronic obese asthma, while different doses of oral API or dexamethasone were used for therapeutic interventions. In vitro, this study used HDM to stimulate human bronchial cells (HBEs) to establish the model and intervened with API or Selonsertib (SEL).
Results: This study clarified that OVAinduced a type of mixed granulocytic asthma with elevated neutrophils and eosinophils in obese male mice fed with long-term HFD, which also exhibited mixed TH17/TH1/TH2 inflammation. Apigenin effectively suppressed this complex inflammation and acted as a regulator of immune homeostasis. Meanwhile, apigenin reduced AHR, inflammatory cell infiltration, airway epithelial cell apoptosis, airway collagen deposition, and lung oxidative stress via the ROS-ASK1-MAPK pathway in an obese asthma mouse model. In vitro, this study found that apigenin altered the binding status of TRAF6 to ASK1, inhibited ASK1 phosphorylation, and protected against ubiquitin-dependent degradation of ASK1, suggesting that ROS-activated ASK1 may be an important target for apigenin to exert anti-inflammatory and anti-apoptotic effects. To further verify the intervention mechanism, this study clarified that apigenin improved cell viability and mitochondrial function and inhibited apoptosis by interfering with the ROS-ASK1-MAPK pathway.
Conclusions: This study demonstrates for the first time the therapeutic effect of apigenin in chronic obese asthma and further clarifies its potential therapeutic targets. In addition, this study clarifies the specificity of chronic obese asthma and provides new options for its treatment.
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木犀草素通过抑制IL-36γ分泌介导的MAPK通路缓解中性粒细胞性哮喘
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