Nobiletin, as a Novel PDE4B Inhibitor, Alleviates Asthma Symptoms by Activating the cAMP-PKA-CREB Signaling Pathway

被引：1

作者：

Zhang, Yan ^{[1
]}

Yang, Yaping ^{[1
]}

Liang, Huicong ^{[1
]}

Liang, Yuerun ^{[1
]}

Xiong, Guixin ^{[1
]}

Lu, Fang ^{[1
]}

Yang, Kan ^{[1
]}

Zou, Qi ^{[1
]}

Zhang, Xiaomin ^{[1
]}

Du, Guanhua ^{[2
]}

Xu, Ximing ^{[1
,2
,3
]}

Hao, Jiejie ^{[1
,2
]}

机构：

[1] Ocean Univ China, Sch Med & Pharm, Qingdao 266003, Peoples R China

[2] Marine Biomed Res Inst Qingdao, Qingdao 266071, Peoples R China

[3] Qingdao Marine Sci & Technol Ctr, Qingdao 266237, Peoples R China

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2024年 / 25卷 / 19期

关键词：

asthma; cAMP-PKA-CREB signaling pathway; nobiletin; reverse docking; traditional chinese medicine; ALLERGIC AIRWAY INFLAMMATION; NF-KAPPA-B; SMOOTH-MUSCLE; HYPERRESPONSIVENESS; CONSTITUENTS; DECOCTION; CHILDREN; TARGETS; CELLS; PEEL;

D O I：

10.3390/ijms251910406

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Asthma is a chronic airway inflammation that is considered a serious public health concern worldwide. Nobiletin (5,6,7,8,3 ',4 '-hexamethyl flavonoid), an important compound isolated from several traditional Chinese medicines, especially Citri Reticulatae Pericarpium, is widely used for a number of indications, including cancer, allergic diseases, and chronic inflammation. However, the mechanism by which nobiletin exerts its anti-asthmatic effect remains unclear. In this research, we comprehensively demonstrated the anti-asthmatic effects of nobiletin in an animal model of asthma. It was found that nobiletin significantly reduced the levels of inflammatory cells and cytokines in mice and alleviated airway hyperresponsiveness. To explore the target of nobiletin, we identified PDE4B as the target of nobiletin through pharmacophore modeling, molecular docking, molecular dynamics simulation, SPR, and enzyme activity assays. Subsequently, it was found that nobiletin could activate the cAMP-PKA-CREB signaling pathway downstream of PDE4B in mouse lung tissues. Additionally, we studied the anti-inflammatory and anti-airway remodeling effects of nobiletin in LPS-induced RAW264.7 cells and TGF-beta 1-induced ASM cells, confirming the activation of the cAMP-PKA-CREB signaling pathway by nobiletin. Further validation in PDE4B-deficient RAW264.7 cells confirmed that the increase in cAMP levels induced by nobiletin depended on the inhibition of PDE4B. In conclusion, nobiletin exerts anti-asthmatic activity by targeting PDE4B and activating the cAMP-PKA-CREB signaling pathway.

引用

页数：24