2. Academic Validation
  3. Hypersampsonone H attenuates ulcerative colitis via inhibition of PDE4 and regulation of cAMP/PKA/CREB signaling pathway

Hypersampsonone H attenuates ulcerative colitis via inhibition of PDE4 and regulation of cAMP/PKA/CREB signaling pathway

  • Int Immunopharmacol. 2024 Jan 12:128:111490. doi: 10.1016/j.intimp.2024.111490.
Yanzhen Li 1,  Mingqiang Wang 1,  Jianhui Su 1,  Ruimin Zhong 2,  Sheng Yin 3,  Zhongxiang Zhao 4,  Zhanghua Sun 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 2 Guangdong Provincial Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region, Shaoguan University, Shaoguan 512005, China.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 4 State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. Electronic address: zzx37@gzucm.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region, Shaoguan University, Shaoguan 512005, China. Electronic address: sysuszh@126.com.
PMID: 38218008 DOI: 10.1016/j.intimp.2024.111490
Abstract

Background and objectives: Ulcerative colitis (UC) is a recurrent intestinal inflammatory disease which poses a serious threat to the life of patients. However, there are no specific drugs for UC yet. Hypericum sampsonii Hance (HS) is a Chinese herbal medicine traditionally used to treat enteritis and dysentery. Our previous studies have demonstrated that HS holds potential anti-UC effects, and a novel compound named Hypersampsonone H (HS-1) isolated from HS possesses significant anti-inflammatory activity. However, the beneficial effects of HS-1 on UC remain unclear. This study aimed to investigate the therapeutic effects of HS-1 on UC and its potential mechanisms, both in vitro and in vivo.

Methods: The in vitro model was employed using LPS-induced RAW264.7 cells to investigate the anti-inflammatory effects of HS-1 and its possible mechanisms. Furthermore, the therapeutic efficacy and potential mechanisms of HS-1 against dextran sulfate sodium (DSS)-induced acute colitis were assessed through histopathological examination, biochemical analysis, and molecular docking.

Results: In vitro, HS-1 significantly reduced LPS-induced inflammatory responses, as indicated by inhibiting NO production, down-regulating the overexpression of COX-2 and iNOS, as well as regulating the imbalanced levels of IL-6, TNF-α, and IL-10. Moreover, HS-1 also inhibited the expression of PDE4, elevated the intracellular cAMP level, and promoted the phosphorylation of CREB, thereby activating the PKA/CREB pathway in RAW264.7 cells. In vivo, HS-1 demonstrated therapeutic capacity against DSS-induced colitis by alleviating the symptoms of colitis mice, regulating the abnormal expression of inflammatory mediators, protecting the integrity of intestinal epithelial barrier, and reducing tissue fibrosis. Consistently, HS-1 was found to decrease the expression of PDE4 isoforms, subsequently activating the cAMP/PKA/CREB signaling pathway. Furthermore, the molecular docking results indicated that HS-1 exhibited a high affinity for PDE4, particularly PDE4D. Further mechanistic validation in vitro demonstrated that HS-1 possessed a synergistic effect on forskolin and an antagonistic effect on H-89 dihydrochloride, thereby exerting anti-inflammatory effects through the cAMP/PKA/CREB signaling pathway.

Conclusion: We disclose that HS-1 serves as a promising candidate drug for the treatment of UC by virtue of its ability to reduce DSS-induced colitis via the inhibition of PDE4 and the activation of cAMP/PKA/CREB signaling pathway.

Keywords

Hypersampsonone H; PDE4; Ulcerative colitis; cAMP/PKA/CREB.

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