Genotoxicity and morphological changes induced by the alkaloid monocrotaline, extracted from Crotalaria retusa, in a model of glial cells

Silva-Neto, J.P.; Barreto, Rafael; Pitanga, Bruno Penas Seara; Souza, Catiane; Silva, V.D.; Silva, A.R.; Velozo, Eudes da Silva; Cunha, S.D.; Batatinha, Maria José Moreira; Tardy, M.; Ribeiro, Cátia S.; Costa, M.F.D.; El-Bachá, Ramon dos Santos; Costa, Sílvia Lima

doi:10.1016/j.toxicon.2009.07.007

Cited by 32 publications

(23 citation statements)

References 79 publications

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“…In astrocytes, the monocrotaline pyrrole can induce DNA damage by generating DHP-derived DNA adducts, which induce DNA cross links, DNA-celullar protein conjugates, and apoptosis (46,71,81). MCT-induced DNA damage is reflected in persistent cell cycle arrest and is responsible for the cyto-and karyomegaly (megalocytosis) described in pneumocytes, human pulmonary endothelial cells, glial cells, and hepatocytes of MCT-treated animals (38,71,83,84). Particularly, type II pneumocytes seem to be highly affected by MCT-induced mitotic inhibition (85), which is partially mediated by altered polyamine metabolism (3).…”

Section: Monocrotaline Pyrrole Toxicity and The "Mct Syndrome"mentioning

confidence: 99%

The monocrotaline model of pulmonary hypertension in perspective

Gomez-Arroyo

Farkas

Alhussaini

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

349

291

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Severe forms of pulmonary arterial hypertension (PAH) are characterized by various degrees of remodeling of the pulmonary arterial vessels, which increases the pulmonary vascular resistance and right ventricular afterload, thus contributing to the development of right ventricle dysfunction and failure. Recent years have seen advances in the understanding of the pathobiology of PAH; however, many important questions remain unanswered. Elucidating the pathobiology of PAH continues to be critical to design new effective therapeutic strategies, and appropriate animal models of PAH are necessary to achieve the task. Although the monocrotaline rat model of PAH has contributed to a better understanding of vascular remodeling in pulmonary hypertension, we question the validity of this model as a preclinically relevant model of severe plexogenic PAH. Here we review pertinent publications that either have been forgotten or ignored, and we reexamine the monocrotaline model in the context of human forms of PAH.

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Section: Monocrotaline Pyrrole Toxicity and The "Mct Syndrome"mentioning

confidence: 99%

The monocrotaline model of pulmonary hypertension in perspective

Gomez-Arroyo

Farkas

Alhussaini

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

349

291

View full text Add to dashboard Cite

show abstract

“…The authors suggested that HepG2 cells catalyzed the activation reaction, leading to DNA strand breaks. Glial cells from the human glioblastoma cell line GL-15 were treated with 1-5000 μM monocrotaline and the DNA strand breaks were measured using the Comet assay (Silva-Neto et al, 2010). The data showed that the treatment caused signifi cant dose-response increases in cell DNA breaks.…”

Section: Dna Strand Breakagementioning

confidence: 99%

Genotoxicity of pyrrolizidine alkaloids

Chen

Mei

2010

J of Applied Toxicology

178

133

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“…This effect was accompanied by an up-regulation of the LC3 pathway and accumulation of autophagosomes (Figs 4–8). On the one hand, it may be concentration-dependent because in many other studies, the high concentrations were usually used to explore the toxic mechanism of PAs, such as 50 μM and 100 μM for clivorine [7, 20] and 500 μM for monocrotaline [8], in which no autophagy but apoptosis or necrosis (depending on treatment time) was definitely observed. According to our results, the clivorine-induced autophagy occurred at its nontoxic concentration of 3.125 μM, developed or peaked at 6.25 μM (a concentration around its IC 0 value), and decreased at 12.5 μM (around IC 10 ); on the contrary, apoptosis become prominent at 6.25 μM and increased with the increase of concentration (Figs 3 and 6).…”

Section: Discussionmentioning

confidence: 99%

“…Broadly, more than 660 PAs and PA N -oxides have been identified so far, which are mainly divided into three types: retronecine-type, otonecine-type and platyphylline-type [3, 4]. The former two types (Fig 1) are believed to have hepatotoxicity [4–6], genotoxicity [5], neurotoxicity [7, 8], pneumotoxicity [5, 9] and embryotoxicity [10]. The apparent insults in humans after exposure of these PAs have been manifested as hepatic sinusoidal obstructive syndrome (HSOS) accompanied by hepatic megalocytosis, ascites, jaundice, and chronic cirrhosis [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Differential induction of apoptosis and autophagy by pyrrolizidine alkaloid clivorine in human hepatoma Huh-7.5 cells and its toxic implication

Liu

Zhou

et al. 2017

PLoS ONE

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Growing evidence suggests that the pyrrolizidine alkaloids (PAs)-induced hepatotoxicity is mediated by multiple cell death/defence modalities. However, the detailed mechanisms are still lacking. In this study, the hepatotoxic effects of four PAs including three retronecine-type ones (senecionine, seneciphylline and monocrotaline) and one otonecine-type (clivorine) on the proliferation of Huh-7.5 cells and the possible mechanisms were investigated. The results showed that all the PAs could inhibit cell proliferation and induce apoptosis in a concentration-dependent manner. Among them clivorine was the most significant one. In addition to its effect on apoptosis, clivorine treatment could promote autophagy in Huh-7.5 cells, as evidenced by the accumulation of autophagosomes, the enhancement of LC3B expression at the concentrations close to its IC0 value, and the increased conversion of LC3B-I to LC3B-II in the presence of lysosomal inhibitor (chloroquine) and decreased formation of green fluorescent protein (GFP)-LC3 positive puncta in the presence of autophagic sequestration inhibitor (3-methyladenine). Among the other tested PAs, senecionine and seneciphylline also activated autophagy at the same concentrations used for clivorine but monocrotaline did not. Furthermore, our study demonstrated that suppression or enhancement of autophagy resulted in the remarkable enhancement or suppression of senecionine, seneciphylline and clivorine-induced apoptosis at the concentration close to the IC10 for clivorine, respectively, indicating a protective role of autophagy against the PA-induced apoptosis at the low level of exposure. Collectively, our data suggest that PAs in different structures may exert different toxic disturbances on the liver cells. Apoptosis may be one of the most common models of the PA-induced cytotoxicity, while autophagy may be a structure-dependent defence model in the early stage of PA intoxication. Differential induction of apoptosis and autophagy probably depending on the concentration is essential for the cytotoxic potency of clivorine.

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Genotoxicity and morphological changes induced by the alkaloid monocrotaline, extracted from Crotalaria retusa, in a model of glial cells

Cited by 32 publications

References 79 publications

The monocrotaline model of pulmonary hypertension in perspective

The monocrotaline model of pulmonary hypertension in perspective

Genotoxicity of pyrrolizidine alkaloids

Differential induction of apoptosis and autophagy by pyrrolizidine alkaloid clivorine in human hepatoma Huh-7.5 cells and its toxic implication

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