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Pimpinellin ameliorates macrophage inflammation by promoting RNF146-mediated PARP1 ubiquitination
Liuye Yang1,2, Meng Du1,2,3,4, Kaiyuan Liu1,2
1Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Phytotherapy Research : PTR
|February 7, 2024
Summary
Pimpinellin, a novel compound, combats sepsis by inhibiting macrophage inflammation. It targets Poly (ADP-ribose) polymerase 1 (PARP1) activation and promotes its degradation, offering a new therapeutic strategy for sepsis.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Macrophage inflammation is critical in sepsis development and progression.
- Parthanatos regulation of macrophages presents a novel anti-inflammatory therapy target.
Purpose of the Study:
- To investigate the therapeutic potential and mechanism of pimpinellin in lipopolysaccharide (LPS)-induced sepsis.
- To explore pimpinellin's effect on macrophage activation and inflammatory pathways.
Main Methods:
- Western blot and immunohistochemistry to detect Poly (ADP-ribose) polymerase 1 (PARP1) and PAR activation.
- Flow cytometry and western blot for cell death assessment.
- Seahorse XFe24 extracellular flux analyzer for cell metabolism.
- In vivo studies using C57, PARP1 knockout, and PARP1 conditional knock-in mice models of LPS-induced sepsis.
Main Results:
- Pimpinellin specifically inhibited LPS-induced macrophage PARP1 and PAR activation.
- Pimpinellin reduced inflammatory cytokine expression and signal pathway activation in macrophages by inhibiting PARP1.
- Pimpinellin increased survival rates in LPS-treated mice and attenuated sepsis in PARP1 overexpressing mice.
- PARP1 knockdown abolished the protective effects of pimpinellin.
Conclusions:
- Pimpinellin demonstrates therapeutic potential against LPS-induced sepsis.
- Pimpinellin inhibits excessive inflammatory responses by promoting the ubiquitin-mediated degradation of PARP1 via RNF146.
- This study reveals a novel mechanism for pimpinellin's anti-inflammatory action in sepsis.
