송지혜 (한국식품연구원)

한빛사논문

조회229

송지혜Ji-Hye Song

한국식품연구원

Phytomedicine, Apr 12 2024, 129 S0944-7113(24)00292-7 | https://doi.org/10.1016/j.phymed.2024.155633 Hydroethanolic extract of Cirsium setidens ameliorates doxorubicin-induced cardiotoxicity by AMPK-PGC-1α-SOD-mediated mitochondrial protection

Ji-Hye Song ^a, Min-Sun Kim ^a, Seung-Hyun Lee ^b,c,d, Jin-Taek Hwang ^a, Soo-Hyun Park ^a, Sahng Wook Park ^b,c, Sae-Bom Jeon ^b, Ru-Ri Lee ^b, Jangho Lee^a, Hyo-Kyoung Choi ^a

^aKorea Food Research Institute, Jeollabukdo 55365, South Korea

^bDepartment of Biochemistry and Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, South Korea

^cInstitution of Genetic Science, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea

^dDivision of Cardiology, Department of Medicine, Johns Hopkins University, MD, 21205, Baltimore, USA

Corresponding authors : Jangho Lee, Hyo-Kyoung Choi

Abstract

Background: Doxorubicin (DOX) is an effective anticancer agent. However, the clinical outcomes of DOX-based therapies are severely hampered by their significant cardiotoxicity.

Purpose: We investigated the beneficial effects of an ethanol extract of Cirsium setidens (CSE) on DOX-induced cardiomyotoxicity (DICT).

Methods: UPLC-TQ/MS analysis was used to identify CSE metabolite profiles. H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells were used to evaluate the effects of CSE on DICT-induced cell death. To elucidate the mechanism underlying it, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma co-activator l-alpha (PGC1-α), nuclear respiratory factor 1 (NRF1), NRF2, superoxide dismutase (SOD1), and SOD2 expression was detected using western blot analysis. The oxygen consumption rate (OCR), cellular ROS, and mitochondrial membrane potential were measured. Finally, we confirmed the cardioprotective effect of CSE against DICT in both C57BL/6 mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) by observing various parameters, such as electrophysiological changes, cardiac fibrosis, and cardiac cell death.

Results: Chlorogenic acid and nicotiflorin were the major compounds in CSE. Our data demonstrated that CSE blocked DOX-induced cell death of H9c2 cells without hindrance of its apoptotic effects on MDA-MB-231 cells. DOX-induced defects of OCR and mitochondrial membrane potential were recovered in a CSE through upregulation of the AMPK-PGC1-α-NRF1 signaling pathway. CSE accelerated NRF1 translocation to the nucleus, increased SOD activity, and consequently blocked apoptosis in H9c2 cells. In mice treated with 400 mg/kg CSE for 4 weeks, electrocardiogram data, creatine kinase and lactate dehydrogenase levels in the serum, and cardiac fibrosis, were improved. Moreover, various electrophysiological features indicative of cardiac function were significantly enhanced following the CSE treatment of hiPSCCMs.

Conclusion: Our findings demonstrate CSE that ameliorates DICT by protecting mitochondrial dysfunction via the AMP- PGC1α-NRF1 axis, underscoring the therapeutic potential of CSE and its underlying molecular pathways, setting the stage for future investigations into its clinical applications.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-23)
연구진국내(교신)+국외 연구진
분야 생명과학 > 식품학

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