DNA Methylation Signature of Epileptic Encephalopathy-Related Pathogenic Genes Encoding Ion Channels in Temporal Lobe Epilepsy.

Epilepsy is characterized by highly abnormal synchronous discharge of brain neurons, and ion channels are fundamental in the generation and modulation of neural excitability. Considering that abnormal methylation can either activate or repress genes, this study was designed to explore the DNA methylation signature of pathogenic genes encoding ion channels in temporal lobe epilepsy (TLE). In total, 38 TLE patients and 38 healthy controls were enrolled in the study, and genomic DNA and total protein of the lymphocytes were extracted from peripheral blood samples to assess methylation and protein levels. The DNA methylation levels of all 12 genes examined were significantly lower in the TLE group than in the control group. After false-positive correction, 83.3% (10/12) of these genes, namely, gamma-aminobutyric acid type A receptor subunit beta1 (GABRB1), gamma-aminobutyric acid type A receptor subunit beta2 (GABRB2), gamma-aminobutyric acid type A receptor subunit beta1 (GABRB3), glutamate ionotropic receptor NMDA type subunit 1 (GRIN1), glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B), hyperpolarization activated cyclic nucleotide gated potassium channel 1 (HCN1), potassium voltage-gated channel subfamily A member 2 (KCNA2), potassium voltage-gated channel subfamily B member 1 (KCNB1), and potassium sodium-activated channel subfamily T member 1 (KCNT1), were still differentially expressed. Among these ion channels, HCN1 and KCNA2 were selected to evaluate the effects of DNA methylation, and the levels of these proteins were inversely upregulated in the TLE group compared to the control group. As the genes identified as having differential methylation levels are involved in both excitatory and inhibitory ion channels, this study observed by binary logistic regression that hypermethylated GARAB1 was an independent risk factor for TLE, indicating that the overwhelming effect of ion channels on TLE is probably inhibitory from the perspective of DNA methylation. All these findings support the involvement of DNA methylation in TLE pathologies, but the mechanisms need to be further investigated.

Genetic Effects of the Schizophrenia-Related Gene DTNBP1 in Temporal Lobe Epilepsy.

Recent studies have reported patients who concurrently exhibit conditions of epilepsy and schizophrenia, indicating certain shared pathologies between them. This study aimed to investigate the genetic effects of the schizophrenia-related gene DTNBP1 in temporal lobe epilepsy (TLE). A total of 496 TLE patients and 528 healthy individuals were successfully genotyped for six DTNBP1 polymorphisms (rs760665, rs1011313, rs2619528, rs2619522, rs909706, and rs2619538), including 335 TLE patients and 325 healthy controls in cohort 1, and 161 TLE patients and 203 healthy controls in cohort 2. The frequency of the TT genotype at rs909706 T > C was lower in TLE patients than in normal controls in the initial cohort (cohort 1), which was confirmed in an independent cohort (cohort 2). However, the intronic T allele failed to be in linkage disequilibrium (LD) with any functional variations nearby; thus, together with the CCAC and TCAT haplotypes (rs1011313-rs2619528-rs2619522-rs909706) observed in the study, this allele acts only as a protective factor against susceptibility to TLE. Meanwhile, a novo mutant allele rs2619538 T > A was exclusively observed in TLE patients, and a dual-luciferase assay revealed that the mutant allele was increased by approximately 22% in the DTNBP2 promoter compared with the wild-type allele. Together with the trend of increasing DTNBP1 expression in epilepsy patients and animal models in this study, these are the first findings to demonstrate the genetic association of DTNBP1 with TLE. Homozygous mutation of rs2619538 T > A likely promotes DTNBP1 expression and facilitates subsequent processes in epilepsy pathologies. Thus, the role of DTNBP1 in TLE deserves further exploration in the future.

The effect of nonpharmacologic therapy on global cognitive functions in patients with Alzheimer's disease: an updated meta-analysis of randomized controlled trials.

Background: The effectiveness of non-pharmacologic therapy (NPT) in treating the global cognition dysfunction associated with Alzheimer's disease (AD) has not been clearly demonstrated. Therefore, we performed a meta-analysis to address this issue.Methods: The Cochrane Central Register of Controlled Trials, PUBMED, EMBASE and other databases were searched, and outcomes measured by the Mini-Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) were analysed.Results: Seven types of NPT were included, 25 randomized controlled trials (RCTs) were selected and 3238 participants were included in the meta-analysis. There were significant differences between the NPT and control groups in the MMSE and ADAS-cog scores.Conclusions: Although more extensive trials need to be performed, NPT has been observed to be beneficial in AD patients.

SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy.

D-serine is a predominant N-methyl-D-aspartate receptor co-agonist with glutamate, and excessive activation of the receptor plays a substantial role in epileptic seizures. Serine racemase (SRR) is responsible for transforming L-serine to D-serine. In this study, we aimed to investigate the genetic roles of SRR and a neighbouring gene, nonsense-mediated mRNA decay factor (SMG6), in temporal lobe epilepsy (TLE). Here, a total of 496 TLE patients and 528 healthy individuals were successfully genotyped for three SRR tag single nucleotide polymorphisms. The frequencies of the GG genotype at rs4523957 T > G were reduced in the TLE cases in the initial cohort (cohort 1) and were confirmed in the independent cohort (cohort 2). An analysis of all TLE cases in cohort 1 + 2 revealed that the seizure frequency and drug-resistant incidence were significantly decreased in carriers of the GG genotype at rs4523957. Intriguingly, the activity of the SMG6 promoter with the mutant allele at rs4523957 decreased by 22% in the dual-luciferase assay, and up-regulated expression of SMG6 was observed in an epilepsy rat model. This study provides the first demonstration that the GG genotype is a protective marker against TLE. In particular, variation at rs4523957 likely inhibits SMG6 transcription and plays a key role against susceptibility to and severity of TLE. The significance of SMG6 hyperfunction in epileptic seizures deserves to be investigated in future studies.

Silencing of the ABCC4 gene by RNA interference reverses multidrug resistance in human gastric cancer.

The identification of genes associated with recurrent drug resistance in gastric cancer and the elucidation of the underlying molecular mechanisms associated with recurrent drug resistance in gastric cancer are important for the effective treatment and prognosis of this cancer. Variations in the expression level of the ATP-binding cassette subfamily C member 4 (ABCC4) gene are correlated with the recurrence, development and chemotherapeutic susceptibility of various types of cancers. In the present study, we demonstrated that the ABCC4 gene was highly expressed in multiple types of gastric cancer cells, and ABCC4 expression was even more prominent in the drug-resistant gastric cancer cells. Conversely, in normal gastric mucosal cells, ABCC4 expression was very low or undetectable. We used RNA interference to decrease the expression of ABCC4 in drug-resistant gastric cancer cells, which resulted in an increase in apoptosis and cell cycle arrest in the G1 phase. In addition, we found that ABCC4 knockdown in 5-fluorouracil (5-FU)-resistant cancer cells restored 5-FU sensitivity, resulting in the inhibition of cell proliferation and tumour growth in nude mice. Our results showed that inhibition of ABCC4 gene expression can inhibit the proliferation of multidrug-resistant gastric cancer cells and can enhance gastric cancer cell sensitivity to chemotherapeutic drugs.