2. Academic Validation
  3. Gramine improves sepsis-induced myocardial dysfunction by binding to NF-κB p105 and inhibiting its ubiquitination

Gramine improves sepsis-induced myocardial dysfunction by binding to NF-κB p105 and inhibiting its ubiquitination

  • Phytomedicine. 2024 Mar:125:155325. doi: 10.1016/j.phymed.2023.155325.
Ling Dao 1,  Hengdao Liu 1,  Ruizhen Xiu 2,  Tianbao Yao 3,  Renyang Tong 4,  Longwei Xu 5
Affiliations

Affiliations

  • 1 Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, Henan 450052, China.
  • 2 Department of Radiology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
  • 3 Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongtinan Road, Beijing 100020, China. Electronic address: [email protected].
  • 5 Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, Henan 450052, China. Electronic address: [email protected].
PMID: 38295663 DOI: 10.1016/j.phymed.2023.155325
Abstract

Background: Sepsis and its associated heart failure are among the leading causes of death. Gramine, a natural indole alkaloid, can be extracted from a wide variety of raw Plants, and it exhibits therapeutic potential in pathological cardiac hypertrophy. However, the effect of gramine on inflammatory cardiomyopathy, particularly sepsis-induced myocardial injury, remains an unexplored area.

Purpose: To determine the role of gramine in sepsis-induced myocardial dysfunction and explore its underlying mechanism.

Study design and methods: In mice, sepsis was established by intraperitoneally injecting lipopolysaccharide (LPS, 10 mg/kg). Subsequently, the effects of gramine administration (50 or 100 mg/kg) on LPS-triggered cardiac dysfunction in mice were investigated. For in vitro studies, isolated primary cardiomyocytes were used to assess the effect of gramine (25 or 50 µM) on LPS-induced Apoptosis and inflammation. Additionally, molecular docking, co-immunoprecipitation and ubiquitination analyzes were conducted to explore the underlying mechanisms.

Results: Gramine visibly ameliorated sepsis-induced cardiac dysfunction, inflammatory response, and mortality in vivo. Moreover, it significantly alleviated LPS-induced apoptotic and inflammatory responses in vitro. Furthermore, target prediction for gramine using the SuperPred website indicated that the nuclear factor NF-κB p105 subunit was one of the molecules ranked in priority order with a high model accuracy and a high probability score. Molecular docking studies demonstrated that gramine effectively docked to the death domain of NF-κB p105. Mechanistic studies revealed that gramine suppressed the processing of NF-κB p105 to p50 by inhibiting NF-κB p105 ubiquitination. Additionally, the protective effect of gramine on cardiac injury was almost abolished by overexpressing NF-κB p105.

Conclusion: Gramine is a promising bioactive small molecule for treating sepsis-induced myocardial dysfunction, which acts by docking to NF-κB p105 and inhibiting NF-κB p105 ubiquitination, thus preventing its processing to NF-κB p50. Therefore, gramine holds potential as a clinical drug for treating myocardial depression during sepsis.

Keywords

Cardiac dysfunction; Gramine; NF-κB p105; Sepsis.

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