Toxicology in vitro : an international journal published in association with BIBRA
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(-)-epigallocatechin-3-gallate (EGCG), the main component of green tea, has long been explored in the treatment and/or prevention of central nervous system (CNS) disorders. However, EGCG has been recently shown to exhibit acute and subacute toxicity. Although a lot of work has been done, the mechanisms of EGCG-induced mitochondrial dysfunction has not been delineated in primary astrocyte. ⋯ As a result, mitochondrial dysfunction was induced, including the opening of the mitochondrial permeability transition pore (mPTP), mitochondrial membrane depolarization, an increasing in reactive oxygen species (ROS), and cytochrosome c (cyt c) releasing. Therefore, more apoptotic cells were observed in 50 μM EGCG group than that of in 1 μM EGCG group. These findings suggested that a high dose of EGCG was toxic to astrocytes partly by targeting mitochondria via calcium pathway, which would extend our understanding of the toxicity of EGCG and the underlying mechanisms.
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The aim of this study was to determine the steroidogenic endocrine disrupting effect of three widely used serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol, using two in vitro models, the H295R assay and a recombinant CYP17 enzyme assay. Steroid hormones were quantified using LC-MS/MS. Duloxetine showed endocrine disrupting effects at 5-20μM with CYP17 being the main target. ⋯ Overall, results from the recombinant CYP17 assay confirmed the results from the H295R cell assay. Using testosterone as end point, the margin of safety (defined as NOAEL/Cmax) for duloxetine was 1.6 indicating that duloxetine may have endocrine disrupting effects. In contrast, venlafaxine and tramadol showed higher margins of safety (venlafaxine: 24; tramadol: 157) indicating a lower potential to disrupt the human steroidogenesis.
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Long non-coding RNAs (lncRNAs) display multiple functions including regulation of neuronal injury. However, their impact in methamphetamine (METH)-induced neurotoxicity has rarely been reported. Here, using microarray analysis, we investigated the expression profiling of lncRNAs and mRNAs in primary cultured prefrontal cortical neurons after METH treatment. ⋯ Furthermore, an lncRNA-mRNA co-expression sub-network for aberrantly expressed terms revealed possible interactions of lncRNA NR_110713 and NR_027943 with their related genes. Afterwards, three lncRNAs (NR_110713, NR_027943, GAS5) and two mRNAs (Ddit3, Casp12) were targeted to validate the microarray data by qRT-PCR. This presented an overview of lncRNA and mRNA expression profiling and indicated that lncRNA might participate in METH-induced neuronal apoptosis by regulating the coding genes of neurons.
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d-2-hydroxyglutaric (D-2-HGA) and l-2-hydroxyglutaric (L-2-HGA) acidurias are rare neurometabolic disorders biochemically characterized by increased levels of d-2-hydroxyglutaric acid (D-2-HG) and l-2-hydroxyglutaric acid (L-2-HG) respectively, in biological fluids and tissues. These diseases are caused by mutations in the specific enzymes involved in the metabolic pathways of these organic acids. In the present work, we first investigated whether D-2-HG and L-2-HGA could provoke DNA oxidative damage in blood leukocytes and whether l-carnitine (LC) could prevent the in vitro DNA damage induced by these organic acids. ⋯ We also evaluated oxidative stress parameters in urine of L-2-HGA patients and observed a significant increase of oxidized guanine species and di-tyrosine, biomarkers of oxidative DNA and protein damage, respectively. In contrast, no significant changes of urinary isoprostanes and reactive nitrogen species levels were observed in these patients. Taken together, our data indicate the involvement of oxidative damage, especially on DNA, in patients affected by these diseases and the protective effect of LC.