Aconitine induces autophagy via activating oxidative DNA damage-mediated AMPK/ULK1 signaling pathway in H9c2 cells

Wang, Wenlin; Jiang, Jialuo; Huang, Yan; Fu, Peng; Hu, Tingting; Wu, Jiayang; Pan, Xiaoqi; Rao, Chaolong

doi:10.1016/j.jep.2021.114631

Cited by 18 publications

(10 citation statements)

References 47 publications

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“…Of them, the animals used in three studies ( Liang et al, 1991 ; Zhang et al, 2012 ; Sun et al, 2014 ) comprised Sprague–Dawley (SD) and Wistar rats, and two studies ( Deng, 2010 ; Wang, 2013 ) guinea pigs. The weight of rats ranged from 150 to 350 g, and the weight of guinea pigs ranged from 300 to 350 g. Among which, zebrafish embryos were employed in seven studies ( Fang et al, 2012 ; Cui et al, 2018 ; Liu et al, 2019 ; Wang S. et al, 2020 ; Li et al, 2020 ; Xia et al, 2021 ; Ye et al, 2021 ), H9c2 cell in nine studies ( Gao, 2018 ; Gao et al, 2018 ; Hu et al, 2018 ; Zhang et al, 2018 ; Li et al, 2020 ; Peng et al, 2020 ; Zhang et al, 2020 ; Yang et al, 2021 ; Wang W. et al, 2022 ), primary cardiomyocytes of SD rats in 10 studies ( Meng, 2006 ; Fu, 2007 ; Wang, 2007 ; Wang et al, 2007 ; Zhang, 2007 ; Xu, 2008 ; Liu, 2009 ; Zhou et al, 2013 ; Yu, 2015 ; Li et al, 2018 ), primary cardiomyocytes of Wistar rats in three studies ( Liu, 2007 ; Sun et al, 2014 ; Zhou et al, 2020 ). Meanwhile, three studies chose primary cardiomyocytes of guinea pigs ( Wang, 2013 ) and AC-16 cells ( Cui et al, 2018 ; Zhou et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to ATP production and yield, mitochondrial oxidative stress signaling had also been implicated in the cardiotoxicity of aconitine, such as mitochondrial reactive oxygen species (mtROS) and 8-hydroxy-2 deoxyguanosine (8-OHDG) oxidative damage indicators. Once the cardiomyocyte’s redox state was broken up by aconitine, massive mtROS and 8-OHDG would accumulate in the cytoplasm, ( Xu, 2008 ; Gao, 2018 ; Wang S. et al, 2020 ; Peng et al, 2020 ; Xia et al, 2021 ; Wang W. et al, 2022 ), further exacerbating the mitochondrial structure and function disorder. In retrospect, we reconsidered that mitochondrial energy metabolism and oxidative stress damage may be nonnegligible and momentous molecular mechanisms of aconitine-evoked cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…From the available evidence, excessive NLRP3 inflammasome activation may be a potential signaling pathway for aconitine-induced cardiotoxicity. However, considering NLRP3’s pivotal role in determining cell fate, its mediated oxidative stress, mitochondrial energy metabolism, as well autophagy, and apoptosis events are consequential and meaningful targets for further exploration of aconitine-induced cardiotoxicity ( Wang W. et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

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An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Jiang

Zhang²,

Zhang³

et al. 2022

Front. Pharmacol.

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Background: Most Aconitum species in traditional Chinese medicine have the effect of dispelling wind, dehumidifying, warming the meridian, and relieving pain. Aconitine is the characteristic chemical component with the function of anti-inflammation, analgesic, and heart-strengthening effects. However, improper use will produce cardiotoxicity and neurotoxicity. Currently, the mechanisms of cardiotoxicity caused by aconitine are wheels within wheels without being fully disclosed. The systematic review and meta-analysis were therefore conducted to summarize the available evidence of myocardial toxicity caused by aconitine.Methods: We searched PubMed, Embase, Web of Science, National Knowledge Infrastructure, WANFANG, and VIP information database for relevant preclinical studies. All the data were analyzed by RevMan version 5.3.Results: Thirty-two studies met the final inclusion criteria, including both in vivo and in vitro study types. After aconitine treatment, the heart rate of animals was obviously abnormal, and the morphology and function of myocardial cells were significantly changed. Aconitine can induce changes in the electrophysiological activity of cardiac myocytes by regulating Na+, Ca2+, and K+ currents. Meanwhile, the mechanisms of cardiotoxicity of aconitine may be related to triggering mitochondrial dysfunction by inducing mitochondrial apoptosis and autophagy. It should not be ignored that the overactivation of NLRP3 inflammasome also exacerbates aconitine’s cardiotoxicity.Conclusion: The altered ion channels and mitochondrial function, as well as the signaling pathways interacting with NLRP3, may deserve further study for aconitine-induced cardiotoxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Jiang

Zhang²,

Zhang³

et al. 2022

Front. Pharmacol.

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“…KEGG enrichment analysis showed that autophagy and AMPK signaling pathways were significantly up-regulated. AMPK is a key energy sensor and regulator for maintaining energy homeostasis in eukaryotic cells and can be activated by various factors, including environmental stress, starvation, and hypoxia (Hardie et al, 2012;Wang et al, 2022). As a positive regulator of autophagy, AMPK activates and stimulates autophagy by directly activating ULK1, thereby initiating the process of autophagy (Kim et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Aspergillus induces autophagy in triple-negative breast cancer cells through the AMPK/ ULK1 signaling axis (Cao et al, 2018). By activating the AMPK/ ULK1 signaling pathway, aconitine can induce autophagy in H9c2 cardiomyocytes mediated by DNA oxidative damage (Wang et al, 2022). AMPK directly promotes the occurrence of autophagy by phosphorylating and activating ULK1, inducing the initiation of autophagy (Fan et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Salvia chinensia Benth induces autophagy in esophageal cancer cells via AMPK/ULK1 signaling pathway

et al. 2022

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Salvia chinensia Benth (Shijianchuan in Chinese, SJC) has been used as a traditional anti-cancer herb. SJC showed good anti-esophageal cancer efficacy based on our clinical application. However, the current research on SJC is minimal, and its anti-cancer effect lacks scientific certification. This study aims to clarify the inhibitory effect of SJC on esophageal cancer and explore its underlying mechanism. Q-Orbitrap high-resolution LC/MS was used to identify the primary chemical constituents in SJC. Cell proliferation and colony formation assays showed that SJC could effectively inhibit the growth of esophageal tumor cells in vitro. To clarify its mechanism of action, proteomic and bioinformatic analyses were carried out by combining tandem mass labeling and two-dimensional liquid chromatography-mass spectrometry (LC-MS). Data are available via ProteomeXchange with identifier PXD035823. The results indicated that SJC could activate AMPK signaling pathway and effectively promote autophagy in esophageal cancer cells. Therefore, we further used western blotting to confirm that SJC activated autophagy in esophageal cancer cells through the AMPK/ULK1 signaling pathway. The results showed that P-AMPK and P-ULK1 were significantly up-regulated after the treatment with SJC. The ratio of autophagosomes marker proteins LC3II/I was significantly increased. In addition, the expression of the autophagy substrate protein P62 decreased with the degradation of autophagosomes. Using lentiviral transfection of fluorescent label SensGFP-StubRFP-LC3 protein and revalidation of LC3 expression before and after administration by laser confocal microscopy. Compared with the control group, the fluorescence expression of the SJC group was significantly enhanced, indicating that it promoted autophagy in esophageal cancer cells. Cell morphology and the formation of autophagosomes were observed by transmission electron microscopy. Our study shows that the tumor suppressor effect of SJC is related to promoting autophagy in esophageal tumor cells via the AMPK/ULK1 signaling pathway.

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Structural feature-based strategy for the identification of diterpene alkaloids in Aconitum carmichaeli Debeaux

Liu,

Li,

Luo

et al. 2024

Fitoterapia

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Aconitine induces autophagy via activating oxidative DNA damage-mediated AMPK/ULK1 signaling pathway in H9c2 cells

Cited by 18 publications

References 47 publications

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Salvia chinensia Benth induces autophagy in esophageal cancer cells via AMPK/ULK1 signaling pathway

Structural feature-based strategy for the identification of diterpene alkaloids in Aconitum carmichaeli Debeaux

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