Single-Base Gene Variants in MIR-146A and SCN1A Genes Related to the Epileptogenic Process in Drug-Responsive and Drug-Resistant Temporal Lobe Epilepsy-A Preliminary Study in a Brazilian Cohort Sample.

The drug-resistant temporal lobe epilepsy (TLE) has recently been associated with single nucleotide variants (SNVs) in microRNA(miR)-146a (MIR-146A) (rs2910164) and Sodium Voltage-Gated Channel Alpha Subunit 1 (SCN1A) (rs2298771 and rs3812718) genes. Moreover, no studies have shown an association between these SNVs and susceptibility to drug-resistant and drug-responsive TLE in Brazil. Thus, deoxyribonucleic acid (DNA) samples from 120 patients with TLE (55 drug-responsive and 65 drug-resistant) were evaluated by real-time polymerase chain reaction (RT-PCR). A total of 1171 healthy blood donor individuals from the Online Archive of Brazilian Mutations (ABraOM, from Portuguese Arquivo Brasileiro On-line de Mutações), a repository containing genomic variants of the Brazilian population, were added as a control population for the studied SNVs. MIR-146A and SCN1A relative expression was performed by quantitative RT-PCR (qRT-PCR). The statistical analysis protocol was performed using an alpha error of 0.05. TLE patient samples and ABraOM control samples were in Hardy-Weinberg equilibrium for all studied SNVs. For rs2910164, the frequencies of the homozygous genotype (CC) (15.00% vs. 9.65%) and C allele (37.80% vs. 29.97%) were superior in patients with TLE compared to controls with a higher risk for TLE disease [odds ratio (OR) = 1.89 (95% confidence interval (95%CI) = 1.06-3.37); OR = 1.38 (95%CI = 1.04-1.82), respectively]. Drug-responsive patients also presented higher frequencies of the CC genotype [21.81% vs. 9.65%; OR = 2.58 (95%CI = 1.25-5.30)] and C allele [39.09% vs. 29.97%; OR = 1.50 (95%CI = 1.01-2.22)] compared to controls. For rs2298771, the frequency of the heterozygous genotype (AG) (51.67% vs. 40.40%) was superior in patients with TLE compared to controls with a higher risk for TLE disease [OR = 2.42 (95%CI = 1.08-5.41)]. Drug-resistant patients presented a higher AG frequency [56.92% vs. 40.40%; OR = 3.36 (95%CI = 1.04-17.30)] compared to the control group. For rs3812718, the prevalence of genotypes and alleles were similar in both studied groups. The MIR-146A relative expression level was lower in drug-resistant compared to drug-responsive patients for GC (1.6 vs. 0.1, p-value = 0.049) and CC (1.8 vs. 0.6, p-value = 0.039). Also, the SCN1A relative expression levels in samples from TLE patients were significantly higher in AG [2.09 vs. 1.10, p-value = 0.038] and GG (3.19 vs. 1.10, p-value < 0.001) compared to the AA genotype. In conclusion, the rs2910164-CC and rs2298771-AG genotypes are exerting significant risk influence, respectively, on responsive disease and resistant disease, probably due to an upregulated nuclear factor kappa B (NF-kB) and SCN1A loss of function.

Hydrolyzed Rutin Decreases Worsening of Anaplasia in Glioblastoma Relapse.

BACKGROUND: Gliomas are aggressive and resilient tumors. Progression to advanced stages of malignancy, characterized by cell anaplasia, necrosis, and reduced response to conventional surgery or therapeutic adjuvant, are critical challenges in glioma therapy. Relapse of the disease poses a considerable challenge for management. Hence, new compounds are required to improve therapeutic response. As hydrolyzed rutin (HR), a compound modified via rutin deglycosylation, as well as some flavonoids demonstrated antiproliferative effect for glioblastoma, these are considered potential epigenetic drugs. OBJECTIVE: The purpose of this study was to determine the antitumor activity and evaluate the potential for modifying tumor aggressivity of rutin hydrolysates for treating both primary and relapsed glioblastoma. METHODS: The glioblastoma cell line, U251, was used for analyzing cell cycle inhibition and apoptosis and for establishing the GBM mouse model. Mice with GBM were treated with HR to verify antitumor activity. Histological analysis was used to evaluate HR interference in aggressive behavior and glioma grade. Immunohistochemistry, comet assay, and thiobarbituric acid reactive substance (TBARS) values were used to evaluate the mechanism of HR action. RESULTS: HR is an antiproliferative and antitumoral compound that inhibits the cell cycle via a p53- independent pathway. HR reduces tumor growth and aggression, mainly by decreasing mitosis and necrosis rates without genotoxicity, which is suggestive of epigenetic modulation. CONCLUSION: HR possesses antitumor activity and decreases anaplasia in glioblastoma, inhibiting progression to malignant stages of the disease. HR can improve the effectiveness of response to conventional therapy, which has a crucial role in recurrent glioma.

Optogenetics: the new molecular approach to control functions of neural cells in epilepsy, depression and tumors of the central nervous system.

The optogenetic tools have been described as valuable techniques to study neural activity through light stimulation, as well as potential neuromodulator approaches in the management of several central nervous system (CNS) diseases. Since the first bacteriorhodopsin protein described as a single-component light-activated regulator of transmembrane ion flow description, in 1980's, the focus has been on channel proteins for neurobiology; however, the advances in engineering techniques showed involvement changes in cellular biological behavior in several types of proteins involved in cell cytoskeleton regulation, motility and gene expression. Although the use of this technology has been published in many papers, a question still remains regarding real results and potential clinical applicability in CNS diseases, as well as the publications scarcity that systematically analyses the published results. Lastly, the aim of this review is to discuss the experimental results, molecular mechanisms and potential clinical applications of optogenetic tools in epilepsy and depression treatment, as well as its applicability in the treatment of CNS tumors.

Literature Evidence and ARRIVE Assessment on Neuroprotective Effects of Flavonols in Neurodegenerative Diseases' Models.

BACKGROUND AND OBJECTIVE: This paper was based on a literature search of PubMed and Scielo databases using the keywords "Flavonoids, Neuroprotection, Quercetin, Rutin, Isoquercitrin, Alzheimer, Parkinson, Huntington" and combinations of all the words. METHOD: We collected relevant publications, during the period of 2000 to 2016, emphasizing in vivo and in vitro studies with neurological assessment of flavonol's potentials, as well as classifying studies according to evidence levels, in order to elucidate evidence-based literature and its application on clinical research. In addition, we highlight the importance of flavonols in modern research fields, indicating their neuroprotective potential and use thereof as preventive and therapeutic treatment of numerous neurodegenerative disease. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, represent worldwide a major health problem with great financial impact. They are multifactorial diseases, hallmarked by similar pathogenesis that covers conditions such as oxidative stress, formation of free radicals, abnormal protein dynamics (degradation and aggregation), mitochondrial dysfunction, lipid peroxidation and cellular death or senescence. Flavonols are polyphenolic compounds, widely distributed in the plant kingdom and found in high concentrations in vegetables, fruits and teas. Their neuroprotective effects are mainly related to their antioxidant, anti-proliferative and anti-inflammatory properties. CONCLUSION: It was this paper's intention to contribute with an evidence analysis of recent studies approaching neuroprotective effects of flavonols and the potential to conduct human clinical studies.