TY - JOUR
T1 - Rhodiola crenulata extract inhibits cell pyroptosis to ameliorate pulmonary vascular remodeling in rats through the regulation of decadienylcarnitine/NLRP3/GSDMD axis
AU - Liu, Junjie
AU - Liu, Jingjing
AU - Qiao, Yuxin
AU - Zhong, Hanxin
AU - Wei, Jiaoxia
AU - Han, Dongyang
AU - Peng, Jin
AU - Feng, Yongzhou
AU - Wang, Danni
AU - Cheng, Yujie
AU - Lu, Haitao
AU - Yao, Li
N1 - Funding information:
This work was supported by Natural Science Foundation of Heilongjiang Province, (Grant No. LH2021H016), Harbin Medical University Marshal Initiative Funding (Grant No. HMUMIF-21026), the Fundamental Research Funds for the Central Universities (Grant No. 22X010201564), the opening grant provided by Key Laboratory of Systems Biomedicine (Ministry of Education) in Shanghai Jiao Tong University (Grant No. KLSB2022KF-02), Science Foundation for Traditional Chinese Medicine of Administration of Traditional Chinese Medicine of Heilongjiang (Grant No. ZHY2024-135), the opening grant provided by State Key Laboratory of Component-based Chinese Medicine (Grant No. CBCM2024105).
Publisher copyright:
© 2025 Published by Elsevier B.V.
PY - 2025/8/22
Y1 - 2025/8/22
N2 - Ethnopharmacological relevance: Our previous work verified that decadienyl-L-carnitine (C10:2) biosynthesis has therapeutic-target capacity for RCE inhibiting pulmonary vascular remodeling to modulate experimental pulmonary hypertension(PH). However, the profound molecular mechanism remains incompletely elucidated. Aim of study: This study aims to investigate whether C10:2 biosynthesis regulates pulmonary vascular remodeling by activating cell pyroptosis. Materials and methods: Rats and pulmonary artery smooth musle cells (PASMCs) model with PH were successfully induced with monocrataline (MCT) and platelet-derived growth factor-BB (PDGF-BB) in present study. Following RCE treatment, cell targeted metabolomics assay combining biological information analysis and molecular biological methods were used to investigate the modulatory function of C10:2 on pulmonary vascular remodeling by activating cell pyroptosis and accordingly pharmacological mechanism of RCE against cell pyroptosis. Results: We found that C10:2 activated NLRP3/Caspase-1/GSDMD signaling pathway to promote PASMCs pyroptosis, and decreased the level of azelaic acid in PASMCs. RCE can significantly upregulate miR-149–5p to targeting bind Cpt1a mRNA, thus, to decrease CPT1A expression, by which low level of C10:2 was maintained to further promote the biosynthesis of anti-inflammatory azelaic acid in vivo, along with this functional molecule is also one main compound of RCE. Our data further demonstrated that the biosynthesis of azelaic acid directly regulates NLRP3/Caspase1/GSDMD axis to inhibit pyroptosis by targeting NLRP3, we therefore argue that azelaic acid is a key functional compound of RCE for treating PH by inhibiting cell pyroptosis. Conclusion: Collectively, our work characterized that azelaic acid is a key functional compound in RCE to express pharmacological efficacy against PH, which was observed to inhibit cell pyroptosis to ameliorate pulmonary vascular remodeling in rats through the regulation of decadienyl-L-carnitine/NLRP3/GSDMD axis. Such work will provide essentially molecular basis for developing anti-PH strategy and associated drug discovery.
AB - Ethnopharmacological relevance: Our previous work verified that decadienyl-L-carnitine (C10:2) biosynthesis has therapeutic-target capacity for RCE inhibiting pulmonary vascular remodeling to modulate experimental pulmonary hypertension(PH). However, the profound molecular mechanism remains incompletely elucidated. Aim of study: This study aims to investigate whether C10:2 biosynthesis regulates pulmonary vascular remodeling by activating cell pyroptosis. Materials and methods: Rats and pulmonary artery smooth musle cells (PASMCs) model with PH were successfully induced with monocrataline (MCT) and platelet-derived growth factor-BB (PDGF-BB) in present study. Following RCE treatment, cell targeted metabolomics assay combining biological information analysis and molecular biological methods were used to investigate the modulatory function of C10:2 on pulmonary vascular remodeling by activating cell pyroptosis and accordingly pharmacological mechanism of RCE against cell pyroptosis. Results: We found that C10:2 activated NLRP3/Caspase-1/GSDMD signaling pathway to promote PASMCs pyroptosis, and decreased the level of azelaic acid in PASMCs. RCE can significantly upregulate miR-149–5p to targeting bind Cpt1a mRNA, thus, to decrease CPT1A expression, by which low level of C10:2 was maintained to further promote the biosynthesis of anti-inflammatory azelaic acid in vivo, along with this functional molecule is also one main compound of RCE. Our data further demonstrated that the biosynthesis of azelaic acid directly regulates NLRP3/Caspase1/GSDMD axis to inhibit pyroptosis by targeting NLRP3, we therefore argue that azelaic acid is a key functional compound of RCE for treating PH by inhibiting cell pyroptosis. Conclusion: Collectively, our work characterized that azelaic acid is a key functional compound in RCE to express pharmacological efficacy against PH, which was observed to inhibit cell pyroptosis to ameliorate pulmonary vascular remodeling in rats through the regulation of decadienyl-L-carnitine/NLRP3/GSDMD axis. Such work will provide essentially molecular basis for developing anti-PH strategy and associated drug discovery.
KW - Azelaic acid
KW - Cell metabolomics
KW - Decadienyl-L-carnitine
KW - Pulmonary vascular remodeling
KW - Rhodiola crenulata extract
KW - miR-149-5p
UR - http://www.scopus.com/inward/record.url?scp=105014592671&partnerID=8YFLogxK
U2 - 10.1016/j.jep.2025.120439
DO - 10.1016/j.jep.2025.120439
M3 - Journal article
SN - 0378-8741
VL - 354
JO - Journal of Ethnopharmacology
JF - Journal of Ethnopharmacology
M1 - 120439
ER -
