Changes to PUFA-PPAR pathway during mesaconitine induced myocardial coagulative necrosis

Chen, Qian; Deng, Xinqi; Zhang, Kai; Kang, Yingquan; Jiao, Mingjie; Zhang, Jia; Wang, Chunguo; Li, Fei

doi:10.1016/j.fct.2023.113831

Cited by 4 publications

(3 citation statements)

References 65 publications

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“…Diester diterpenoid alkaloids (DDAs), represented by mesaconitine (C 33 H 45 NO 11 , CAS: 2752-64-9, MA), are the main toxic components of aconitums ( Wei et al, 2019 ; Chen et al, 2023 ). The toxicity of MA is quite potent; the median lethal dose (LD 50 ) of oral administration, subcutaneous injection, intraperitoneal injection, and intravenous injection in mice is 1.9 mg/kg, 0.20 mg/kg ∼ 0.38 mg/kg, 0.20 mg/kg ∼ 0.30 mg/kg, 0.068 mg/kg ∼ 0.13 mg/kg, respectively ( Liu et al, 2016b ; Yang et al, 2018 ; Chan et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

Song,

Mi,

Zhao

et al. 2024

Front. Pharmacol.

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Background: In traditional Mongolian or Tibetan medicine in China, Chebulae Fructus (CF) is widely used to process or combine with aconitums to decrease the severe toxicity of aconitums. Researches in this area have predominantly focused on tannins, with few research on other major CF components for cardiotoxicity mitigation. The present study aimed to clarify whether triterpenoids can attenuate the cardiotoxicity caused by mesaconitine (MA) and investigate the mechanism of cardiotoxicity attenuation.Methods: Firstly, the pharmacophore model, molecular docking, and 3D-QSAR model were used to explore the mechanism of CF components in reducing the toxicity of MA mediated by the TRPV1 channel. Then three triterpenoids were selected to verify whether the triterpenoids had the effect of lowering the cardiotoxicity of MA using H9c2 cells combined with MTT, Hoechst 33258, and JC-1. Finally, Western blot, Fluo-3AM, and MTT assays combined with capsazepine were used to verify whether the triterpenoids reduced H9c2 cardiomyocyte toxicity induced by MA was related to the TRPV1 channel.Results: Seven triterpenoids in CF have the potential to activate the TRPV1 channel. And they exhibited greater affinity for TRPV1 compared to other compounds and MA. However, their activity was relatively lower than that of MA. Cell experiments revealed that MA significantly reduced H9c2 cell viability, resulting in diminished mitochondrial membrane potential and nuclear pyknosis and damage. In contrast, the triterpenoids could improve the survival rate significantly and counteract the damage of MA to the cells. We found that MA, arjungenin (AR), and maslinic acid (MSA) except corosolic acid (CRA) upregulated the expression of TRPV1 protein. MA induced a significant influx of calcium, whereas all three triterpenoids alleviated this trend. Blocking the TRPV1 channel with capsazepine only increased the cell viability that had been simultaneously treated with MA, and AR, or MSA. However, there was no significant difference in the CRA groups treated with or without capsazepine.Conclusion: The triterpenoids in CF can reduce the cardiotoxicity caused by MA. The MSA and AR function as TRPV1 agonists with comparatively reduced activity but a greater capacity to bind to TRPV1 receptors, thus antagonizing the excessive activation of TRPV1 by MA.

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Section: Introductionmentioning

confidence: 99%

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

Song,

Mi,

Zhao

et al. 2024

Front. Pharmacol.

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“…MA exposure induces cardiac malformations, pericardial effusion, and cardiac arrest in zebrafish embryos ( Ye et al, 2021 ). Additionally, it causes coagulation necrosis of the rat myocardium ( Chen et al, 2023 ). Whole-cell patch-clamp recordings conducted on isolated guinea pig ventricular cardiomyocytes have demonstrated that MA treatment depolarizes the resting membrane potential and reduces action potential amplitude ( Wang X. C. et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Involvement of autophagy in mesaconitine-induced neurotoxicity in HT22 cells revealed through integrated transcriptomic, proteomic, and m6A epitranscriptomic profiling

Lin,

Zhang,

et al. 2024

Front. Pharmacol.

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Background: Mesaconitine (MA), a diester-diterpenoid alkaloid extracted from the medicinal herb Aconitum carmichaelii, is commonly used to treat various diseases. Previous studies have indicated the potent toxicity of aconitum despite its pharmacological activities, with limited understanding of its effects on the nervous system and the underlying mechanisms.Methods: HT22 cells and zebrafish were used to investigate the neurotoxic effects of MA both in vitro and in vivo, employing multi-omics techniques to explore the potential mechanisms of toxicity.Results: Our results demonstrated that treatment with MA induces neurotoxicity in zebrafish and HT22 cells. Subsequent analysis revealed that MA induced oxidative stress, as well as structural and functional damage to mitochondria in HT22 cells, accompanied by an upregulation of mRNA and protein expression related to autophagic and lysosomal pathways. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed a correlation between the expression of autophagy-related genes and N6-methyladenosine (m6A) modification following MA treatment. In addition, we identified METTL14 as a potential regulator of m6A methylation in HT22 cells after exposure to MA.Conclusion: Our study has contributed to a thorough mechanistic elucidation of the neurotoxic effects caused by MA, and has provided valuable insights for optimizing the rational utilization of traditional Chinese medicine formulations containing aconitum in clinical practice.

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“…MA exposure induces cardiac malformations, pericardial effusion, and cardiac arrest in zebrafish embryos (Ye et al, 2021). Additionally, it causes coagulation necrosis of the rat myocardium (Chen et al, 2023). Whole-cell patchclamp recordings conducted on isolated guinea pig ventricular cardiomyocytes have demonstrated that MA treatment depolarizes the resting membrane potential and reduces action potential amplitude (Wang X. C. et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Changes to PUFA-PPAR pathway during mesaconitine induced myocardial coagulative necrosis

Cited by 4 publications

References 65 publications

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

Involvement of autophagy in mesaconitine-induced neurotoxicity in HT22 cells revealed through integrated transcriptomic, proteomic, and m6A epitranscriptomic profiling

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