Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis
文献类型：期刊论文
| 作者 | Li, Heng1,2; Zhang, Yao3; Liu, Moting1,2; Fan, Chen1; Feng, Chunlan1; Lu, Qiukai1,2; Xiang, Caigui1,2; Lu, Huimin1,2; Yang, Xiaoqian1; Wu, Bing1,2 |
| 刊名 | ACTA PHARMACEUTICA SINICA B
 |
| 出版日期 | 2022 |
| 卷号 | 12期号:1页码:228-245 |
| ISSN号 | 2211-3835 |
| 关键词 | Ulcerative colitis Mucosal homeostasis Gut microbiota Epithelial barrier PDE4 |
| DOI | 10.1016/j.apsb.2021.04.007 |
| 通讯作者 | Zou, Duowu(zdw12125@rjh.com.cn) ; Tang, Wei(tangwei@simm.ac.cn) |
| 英文摘要 | Phosphodiesterase-4 (PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate (cAMP) and inhibition of PDE4 has been proven to be a competitive strategy for dermatological and pulmonary inflammation. However, the pathological role of PDE4 and the therapeutic feasibility of PDE4 inhibitors in chronic ulcerative colitis (UC) are less clearly understood. This study introduced apremilast, a breakthrough in discovery of PDE4 inhibitors, to explore the therapeutic capacity in dextran sulfate sodium (DSS)-induced experimental murine chronic UC. In the inflamed tissues, overexpression of PDE4 isoforms and defective cAMP-mediating pathway were firstly identified in chronic UC patients. Therapeutically, inhibition of PDE4 by apremilast modulated cAMP-predominant protein kinase A (PKA)-cAMP-response element binding protein (CREB) signaling and ameliorated the clinical symptoms of chronic UC, as evidenced by improvements on mucosal ulcerations, tissue fibrosis, and inflammatory infiltrations. Consequently, apremilast maintained a normal intestinal physical and chemical barrier function and rebuilt the mucosal homeostasis by interfering with the cross-talk between human epithelial cells and immune cells. Furthermore, we found that apremilast could remap the landscape of gut microbiota and exert regulatory effects on antimicrobial responses and the function of mucus in the gut microenvironment. Taken together, the present study revealed that intervene of PDE4 provided an infusive therapeutic strategy for patients with chronic and relapsing UC. |
| WOS关键词 | INFLAMMATORY-BOWEL-DISEASE ; GUT ; APREMILAST ; MICROBIOTA |
| 资助项目 | National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-006-011] ; Science & Technology Commission of Shanghai Municipality, China[18431907100] ; CAS Key Laboratory of Receptor Research, China[SIM-M1904YKF-01] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences, China[XDA12020231] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES |
| WOS记录号 | WOS:000747012200003 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/300516]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zou, Duowu; Tang, Wei |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat & Immunopharmacol, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China 3.Shanghai Jiao Tong Univ, Dept Gastroenterol, Ruijin Hosp, Sch Med, Shanghai 200025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Heng,Zhang, Yao,Liu, Moting,et al. Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis[J]. ACTA PHARMACEUTICA SINICA B,2022,12(1):228-245. |
| APA | Li, Heng.,Zhang, Yao.,Liu, Moting.,Fan, Chen.,Feng, Chunlan.,...&Tang, Wei.(2022).Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis.ACTA PHARMACEUTICA SINICA B,12(1),228-245. |
| MLA | Li, Heng,et al."Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis".ACTA PHARMACEUTICA SINICA B 12.1(2022):228-245. |
入库方式： OAI收割
来源：上海药物研究所
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