RESUMEN
Preclinical studies conducted to date suggest that depression could be elicited by the elevated expression of proinflammatory molecules: these play a key role in the mediation of neurochemical, neuroendocrine and behavioral changes. Thus, this study investigates the effect of chronic mild stress (CMS) and administration of venlafaxine (SSRI) on the expression and methylation status of new target inflammatory genes: TGFA, TGFB, IRF1, PTGS2 and IKBKB, in peripheral blood mononuclear cells (PMBCs) and in selected brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or venlafaxine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our results indicate that both CMS and chronic treatment with venlafaxine were associated with changes in expression of the studied genes and their promoter methylation status in PMBCs and the brain. Moreover, the effect of antidepressant administration clearly differed between brain structures. Summarizing, our results confirm at least a partial association between TGFA, TGFB, IRF1, PTGS2 and IKBKB and depressive disorders.
Asunto(s)
Encéfalo/metabolismo , Metilación de ADN , Leucocitos Mononucleares/metabolismo , Inhibidores de Captación de Serotonina y Norepinefrina/farmacología , Estrés Psicológico/genética , Transcriptoma , Clorhidrato de Venlafaxina/farmacología , Animales , Encéfalo/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Factor 1 Regulador del Interferón/genética , Factor 1 Regulador del Interferón/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Inhibidores de Captación de Serotonina y Norepinefrina/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Clorhidrato de Venlafaxina/uso terapéuticoRESUMEN
Recent studies imply that there is a tight association between epigenetics and a molecular mechanism of major depressive disorder (MDD). Epigenetic modifications, i.e., DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA), are able to influence the severity of the disease and the outcome of the therapy. This article summarizes the most recent literature data on this topic, i.e., usage of histone deacetylases as therapeutic agents with an antidepressant effect and miRNAs or lncRNAs as markers of depression. Due to the noteworthy potential of the role of epigenetics in MDD diagnostics and therapy, we have gathered the most relevant data in this area.
RESUMEN
Preclinical studies conducted so far suggest that oxidative stress processes may be associated with the mechanism of depression development. This study shows the effects of chronic administration of agomelatine on expression and the methylation status of Sod1, Sod2, Gpx1, Gpx4, Cat, Nos1, and Nos2 in the brain stricture and blood in the chronic mild stress (CMS) animal model of depression. The animals were exposed to the CMS procedure and treatment with agomelatine (10 mg/kg/day, IP) for five weeks and then were sacrificed. TaqMan Gene Expression Assay, Western blot, and methylation-sensitive high-resolution melting techniques were used to evaluate mRNA and protein expression of the genes, and the methylation status of their promoters. Gpx1, Gpx4, and Sod2 expression in the PBMCs and Sod1 and Sod2 expression in the brain were reduced in the stressed group after agomelatine administration. CMS caused an increase in the methylation of the third Gpx4 promoter in peripheral blood mononuclear cells and Gpx1 promoter in the cerebral cortex. Additionally, stressed rats treated with agomelatine displayed a significantly lower Gpx4 level in the hypothalamus. The results confirm the hypothesis that the CMS procedure and agomelatine administration change the expression level and methylation status of the promoter region of genes involved in oxidative and nitrosative stress.
Asunto(s)
Acetamidas/farmacología , Depresión/tratamiento farmacológico , Estrés Oxidativo/genética , Estrés Psicológico/tratamiento farmacológico , Animales , Antidepresivos/farmacología , Catalasa/genética , Metilación de ADN/efectos de los fármacos , Depresión/genética , Depresión/patología , Modelos Animales de Enfermedad , Glutatión Peroxidasa/genética , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo II/genética , Estrés Oxidativo/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Ratas , Estrés Psicológico/genética , Estrés Psicológico/patología , Superóxido Dismutasa/genética , Superóxido Dismutasa-1/genética , Glutatión Peroxidasa GPX1RESUMEN
The nanoparticles (NPs) exposure-related oxidative stress is considered among the main causes of the toxic effects induced by these materials. However, the importance of this mechanism has been mostly explored at short term. Previous experience with cells chronically exposed to ZnO and Co NPs hinted to the existence of an adaptative mechanism contributing to the development of oncogenic features. MTH1 is a well-described enzyme expressed exclusively in cancer cells and required to avoid the detrimental consequences of its high prooxidant microenvironment. In the present work, a significantly marked overexpression was found when MTH1 levels were monitored in long-term ZnO and Co NP-exposed cells, a fact that correlates with acquired 2.5-fold and 3.75-fold resistance to the ZnO and Co NPs treatment, respectively. The forced stable inhibition of Mth1 expression by shRNA, followed by 6 additional weeks of exposure, significantly reduced this acquired resistance and sensitized cells to the oxidizing agents H2O2 and KBrO3. When the oncogenic phenotype of Mth1 knock-down cells was evaluated, we found a decrease in several oncogenic markers, including proliferation, anchorage-independent cell growth, and migration and invasion potential. Thus, MTH1 elicits here as a relevant player in the NPs-induced toxicity and carcinogenicity. This study is the first to give a mechanistic explanation for long-term NPs exposure-derived effects. We propose MTH1 as a candidate biomarker to unravel NPs potential genotoxic and carcinogenic effects, as its expression is expected to be elevated only under exposure conditions able to induce DNA damage and the acquisition of an oncogenic phenotype.