2. Academic Validation
  3. Isoforskolin modulates AQP4-SPP1-PIK3C3 related pathway for chronic obstructive pulmonary disease via cAMP signaling

Isoforskolin modulates AQP4-SPP1-PIK3C3 related pathway for chronic obstructive pulmonary disease via cAMP signaling

  • Chin Med. 2023 Oct 10;18(1):128. doi: 10.1186/s13020-023-00778-w.
Haochang Lin 1,  Sha Cheng 1 2 3,  Songye Yang 1,  Qian Zhang 1,  Lueli Wang 1,  Jiangya Li 1,  Xinyue Zhang 1,  Liju Liang 1,  Xiaoqian Zhou 1,  Furong Yang 1,  Jingfeng Song 4,  Xue Cao 5 6,  Weimin Yang 7,  Zhiying Weng 8
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, No. 1168, Chunrong West Road, Yuhua Street, Chenggong New Town, Kunming, 650500, China.
  • 2 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou, China.
  • 3 Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, 550014, Guizhou, China.
  • 4 School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, No. 1168, Chunrong West Road, Yuhua Street, Chenggong New Town, Kunming, 650500, China. 462759891@qq.com.
  • 5 School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, No. 1168, Chunrong West Road, Yuhua Street, Chenggong New Town, Kunming, 650500, China. dir1865@163.com.
  • 6 Department of Laboratory Animal Science, Kunming Medical University, Kunming, 650500, China. dir1865@163.com.
  • 7 School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, No. 1168, Chunrong West Road, Yuhua Street, Chenggong New Town, Kunming, 650500, China. ywmbessie@yeah.net.
  • 8 School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, No. 1168, Chunrong West Road, Yuhua Street, Chenggong New Town, Kunming, 650500, China. weng_zy@sina.com.
PMID: 37817209 DOI: 10.1186/s13020-023-00778-w
Abstract

Background: Cyclic adenosine monophosphate (cAMP) levels are directly activated by Adenylate Cyclase (AC) and play an anti-inflammatory role in chronic obstructive pulmonary disease (COPD). Previously, we have shown that isoforskolin (ISOF) can effectively activate AC1 and AC2 in vitro, improve pulmonary ventilation and reduce the inflammatory response in COPD model rats, supporting that ISOF may be a potential drug for the prevention and treatment of COPD, but the mechanism has not been explored in detail.

Methods: The potential pharmacological mechanisms of ISOF against COPD were analyzed by network pharmacology and multi-omics based on pharmacodynamic study. To use specific agonists, inhibitors and/or SiRNA for gene regulation function studies, combined qPCR, WB were applied to detect changes in mRNA and protein expression of important targets PIK3C3, Akt, mTOR, SPP1 and AQP4 which related to ISOF effect on COPD. And the key inflammatory factors detected by ELISA.

Results: Bioinformatics suggested that the anti-COPD pharmacological mechanism of ISOF was related to PI3K-AKT signaling pathway, and suggested target protein like PIK3C3, AQP4, SPP1, Akt, mTOR. Using the AQP4 inhibitor,or inhibiting SPP1 expression by siRNA-SPP1 could block the PIK3C3-AKT-mTOR pathway and ameliorate chronic inflammation. ISOF showed cAMP-promoting effect then suppressed AQP4 expression, together with decreased level of IL-1β, IL-6, and IL-8.

Conclusions: These findings demonstrate ISOF controlled the cAMP-regulated PIK3C3-AKT-mTOR pathway, thereby alleviating inflammatory development in COPD. The cAMP/AQP4/PIK3C3 axis also modulate Th17/Treg differentiation, revealed potential therapeutic targets for this disease.

Keywords

AQP4-SPP1-PIK3C3 signaling; Anti-inflammation; COPD; ISOF; cAMP.

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