Characterization of cytotoxic effects of aristolochic acids on the vascular endothelium

Youl, Estelle; Husson, Cécile; Khattabi, Charaf El; Mere, Salma El; Declèves, Anne‐Emilie; Pochet, Stéphanie; Nortier, Joëlle; Antoine, Marie-Hélène

doi:10.1016/j.tiv.2020.104811

Cited by 7 publications

(7 citation statements)

References 60 publications

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“…The cytotoxic concentration range for AA in the endothelial cell line was determined in our previous study [10]. Using the EAhy926 cell line, we confirmed that exposure to 50 µM AA for 24 h and 48 h significantly reduced the viability of EAhy926 cells compared to a control group (Figure 1A,B).…”

Section: Nebivolol Protects Eahy926 Cells Against Aa-induced Cytotoxi...supporting

confidence: 80%

“…A growing number of studies show that ROS play an important role in AAN [25,26]. Moreover, we previously demonstrated that AA produced oxidative stress in endothelial cells, which may contribute to endothelial dysfunction and cell death [10].…”

Section: Discussionmentioning

confidence: 87%

“…Among the mechanisms explaining capillary loss, Toxins 2022, 14, 132 2 of 15 the death of endothelial cells by apoptosis via the PI3K/Akt signaling pathway has been proposed [9]. Our studies have previously demonstrated that AAs induce oxidative stress in endothelial cells [10]. Excessive production of reactive oxygen species (ROS) may contribute to decreased nitric oxide (NO) bioavailability, leading to endothelial dysfunction and apoptosis or necrosis [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Nebivolol against Oxidative Stress Induced by Aristolochic Acids in Endothelial Cells

Antoine

Husson

Yankep

et al. 2022

Toxins

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Aristolochic acids (AAs) are powerful nephrotoxins that cause severe tubulointerstitial fibrosis. The biopsy-proven peritubular capillary rarefaction may worsen the progression of renal lesions via tissue hypoxia. As we previously observed the overproduction of reactive oxygen species (ROS) by cultured endothelial cells exposed to AA, we here investigated in vitro AA-induced metabolic changes by 1H-NMR spectroscopy on intracellular medium and cell extracts. We also tested the effects of nebivolol (NEB), a β-blocker agent exhibiting antioxidant properties. After 24 h of AA exposure, significantly reduced cell viability and intracellular ROS overproduction were observed in EAhy926 cells; both effects were counteracted by NEB pretreatment. After 48 h of exposure to AA, the most prominent metabolite changes were significant decreases in arginine, glutamate, glutamine and glutathione levels, along with a significant increase in the aspartate, glycerophosphocholine and UDP-N-acetylglucosamine contents. NEB pretreatment slightly inhibited the changes in glutathione and glycerophosphocholine. In the supernatants from exposed cells, a decrease in lactate and glutamate levels, together with an increase in glucose concentration, was found. The AA-induced reduction in glutamate was significantly inhibited by NEB. These findings confirm the involvement of oxidative stress in AA toxicity for endothelial cells and the potential benefit of NEB in preventing endothelial injury.

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Section: Nebivolol Protects Eahy926 Cells Against Aa-induced Cytotoxi...supporting

confidence: 80%

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Nebivolol against Oxidative Stress Induced by Aristolochic Acids in Endothelial Cells

Antoine

Husson

Yankep

et al. 2022

Toxins

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“…The results of this study show that AA-I promoted the accumulation of ROS and MDA, and the suppression of SOD, T-AOC and GSH performance, indicating that continuous exposure to an overdose of AA-I breaks down the redox homeostasis and induces oxidative stress in the hepatocytes of Tianfu broilers. It has been reported that AA-N induces endothelial cell toxicity by the elevation of intracellular ROS levels and inhibition of cellular antioxidant function [ 40 ]. Additionally, Zhang et al [ 41 ] indicated that exposure to AA-I perturbed the progression of oocyte meiotic and fertilization capacity by the induction of excessive oxidative stress, which led to DNA damage and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Aristolochic Acid I-Induced Hepatotoxicity in Tianfu Broilers Is Associated with Oxidative-Stress-Mediated Apoptosis and Mitochondrial Damage

Yin

Lin

et al. 2021

Animals

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Aristolochic acid (AA) is a component of traditional Chinese herbs and commonly used for farm animals in China. Over-exposure of AA has been proven to be associated with hepatotoxicity; however, the mechanism of action of AA-I-induced hepatotoxicity remains unknown. In the current study, a subchronic toxicity test was conducted to evaluate the mechanism of AA-induced hepatotoxicity in Tianfu broilers. According to the results, AA-I-induced hepatotoxicity in Tianfu broilers was evidenced by the elevation of liver weight, levels of serum glutamic oxalacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT). Furthermore, hepatocyte swelling, vesicular degeneration and steatosis were observed. Additionally, AA-I elevated the production of reactive oxygen species (ROS) and induced oxidative stress, which further led to excessive apoptosis, characterized by mitochondrial depolarization, upregulation of Bax, and down-regulation of Bcl-2 expression. In conclusion, the mechanism of AA-I-induced hepatotoxicity was associated with oxidative-stress-mediated apoptosis and mitochondrial damage.

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“…Acute AAN in humans results in AA-induced acute kidney injury and may progress to chronic kidney disease (CKD, as necroinflammation, an auto amplification loop between tubular cell death/apoptosis and interstitial inflammation, results in continued renal injury and tubulointerstitial fibrosis ( 67 – 69 ). Halting the progression of CKD following AA exposure by inhibition or even resolution of AA-induced renal tubular injury and tubulointerstitial fibrosis should be considered as a potential therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

Zhu

Wang

et al. 2020

Mol Med Rep

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in acute aristolochic acid nephropathy (aan), aristolochic acid (aa) induces renal injury and tubulointerstitial fibrosis. However, the roles of micrornas (mirnas/mirs) and mrnas involved in aan are not clearly understood. The aim of the present study was to examine aa-induced genome-wide differentially expressed (de) mirnas and de mrnas using deep sequencing in mouse kidneys, and to analyze their regulatory networks. in the present self-controlled study, mice were treated with 5 mg/kg/day aa for 5 days, following unilateral nephrectomy. AA-induced renal injury and tubulointerstitial fibrosis were detected using hematoxylin and eosin staining and Masson's trichrome staining in the mouse kidneys. a total of 82 DE miRNAs and 4,605 DE mRNAs were identified between the aa-treated group and the self-control group. of these de mirnas and mrnas, some were validated using reverse transcription-quantitative Pcr. expression levels of the profibrotic miR-21, miR-433 and miR-132 families were significantly increased, whereas expression levels of the anti-fibrotic miR-122-5p and let-7a-1-3p were significantly decreased. Functions and signaling pathways associated with the de mirnas and mrnas were analyzed using Gene ontology and Kyoto encyclopedia of Genes and Genomes (KeGG). a total of 767 de pairs (in opposing directions) of mirnas and their mrna targets were identified. among these, regulatory networks of mirnas and mrnas were analyzed using KeGG to identify enriched signaling pathways and extracellular matrix-associated pathways. in conclusion, the present study identified genome-wide de mirnas and mrnas in the kidneys of aa-treated mice, as well as their regulatory pairs and signaling networks. The present results may improve the understanding of the role of de mirnas and their mrna targets in the pathophysiology of acute aan.

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Characterization of cytotoxic effects of aristolochic acids on the vascular endothelium

Cited by 7 publications

References 60 publications

Protective Effect of Nebivolol against Oxidative Stress Induced by Aristolochic Acids in Endothelial Cells

Protective Effect of Nebivolol against Oxidative Stress Induced by Aristolochic Acids in Endothelial Cells

Aristolochic Acid I-Induced Hepatotoxicity in Tianfu Broilers Is Associated with Oxidative-Stress-Mediated Apoptosis and Mitochondrial Damage

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

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