Lack of causal association between epilepsy and dementia: A Mendelian randomization analysis.

OBJECTIVE: Epidemiological studies have reported an association between epilepsy and dementia. However, the causal relationship between epilepsy and the risk of dementia is not clear. We aimed to inspect the causal effect of epilepsy on memory loss and dementia. METHODS: We analyzed summary data of epilepsy, memory loss, and dementia from the genome-wide association study (GWAS) using the two-sample Mendelian randomization (MR) method. We used the estimated odds ratio of memory loss and dementia associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures: all epilepsy, focal epilepsy (including focal epilepsy with hippocampal sclerosis, lesion-negative focal epilepsy, and focal epilepsy with other lesions), and genetic generalized epilepsy (including childhood absence epilepsy, generalized tonic-clonic seizures alone, Juvenile absence epilepsy, and Juvenile myoclonic epilepsy). RESULTS: According to the result of MR using the inverse variance weighted method (IVW), we found that genetically predicted epilepsy did not causally increase the risk of memory loss and dementia (p > 0.05). Results of the MR-Egger and weighted median method were consistent with the IVW method. CONCLUSIONS: No evidence has been found to support the notion that epilepsy can result in memory loss and dementia. The associations observed in epidemiological studies could be attributed, in part, to confounding or nongenetic determinants.

The causal relationship between circulating biomarkersand the risk of bipolar disorder: A two-sample Mendelian randomization study.

OBJECTIVE: To identify susceptible biomarkers for the development of bipolar disorder (BD), we conducted a Mendelian Randomization (MR) design to screen circulating proteins for the potential risk of bipolar disorder systematically. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to estimate the causality of 4782 human circulating proteins on the risk of bipolar disorder. 376 circulating biomarkers were selected in MR estimation (4406 circulating proteins with less than 3 SNPs were excluded) with 5368 European descents. GWAS meta-analysis of the potential role of all-cause bipolar disorder arose from the Psychiatric Genomics Consortium (41,917 cases, 371,549 controls). RESULTS: After IVW and sensitivity analysis, 4 circulating proteins having causal effects on bipolar disorder were identified. ISG15, as a key player in the innate immune response, decreased the risk of bipolar disorder causally (OR = 0.92, 95% CI = 0.89-0.94, P = 1.46e-09). Furthermore, MLN decreased the risk of bipolar disorder causally (OR = 0.94, 95% CI = 0.91-0.97, P = 1.04e-04). In addition, SFTPC (OR = 0.91, 95% CI = 0.86-0.96, P = 4.47e-04) and VCY (OR = 0.86, 95% CI = 0.77-0.96, P = 8.55e-03) presented a suggestive association with bipolar disorder. CONCLUSIONS: Our findings indicated that ISG15 and MLN showed evidence of causality in bipolar disorder and provided a promising target for the diagnosis and treatment of diseases.

Salidroside protects PC-12 cells against amyloid ß-induced apoptosis by activation of the ERK1/2 and AKT signaling pathways.

Alzheimer's disease (AD) is one of the most frequent diseases in elderly people and causes high mortality. Its incidence is increasing annually and no effective therapeutic treatment currently exists. In the present study, salidroside, a major active ingredient of Rhodiola rosea, was able to protect PC­12 cells from the toxicity and apoptosis induced by AD inducer amyloid (A)ß1­42. Salidroside significantly protected PC­12 cells by inhibiting Aß1­42­induced cytotoxicity and mitochondria­mediated endogenous caspase apoptotic pathways. Mechanistic studies demonstrated that salidroside significantly activated the extracellular signal regulated kinase (ERK)1/2 and protein kinase B (AKT) signaling pathways. This observation was further confirmed using the ERK1/2 inhibitor PD98059 and the AKT inhibitor LY294002, which demonstrated that salidroside promoted PC­12 cell survival and proliferation by activating the ERK1/2 and AKT signaling pathways. Salidroside is a therapeutic candidate for the treatment of AD and provides a basis for further drug development.

Interhemispheric functional connectivity for Alzheimer's disease and amnestic mild cognitive impairment based on the triple network model.

The purpose of this study was to explore the differences in interhemispheric functional connectivity in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) based on a triple network model consisting of the default mode network (DMN), salience network (SN), and executive control network (ECN). The technique of voxel-mirrored homotopic connectivity (VMHC) analysis was applied to explore the aberrant connectivity of all patients. The results showed that: (1) the statistically significant connections of interhemispheric brain regions included DMN-related brain regions (i.e. precuneus, calcarine, fusiform, cuneus, lingual gyrus, temporal inferior gyrus, and hippocampus), SN-related brain regions (i.e. frontoinsular cortex), and ECN-related brain regions (i.e. frontal middle gyrus and frontal inferior); (2) the precuneus and frontal middle gyrus in the AD group exhibited lower VMHC values than those in the aMCI and healthy control (HC) groups, but no significant difference was observed between the aMCI and HC groups; and (3) significant correlations were found between peak VMHC results from the precuneus and Mini Mental State Examination (MMSE) and Montreal Cognitive Scale (MOCA) scores and their factor scores in the AD, aMCI, and AD plus aMCI groups, and between the results from the frontal middle gyrus and MOCA factor scores in the aMCI group. These findings indicated that impaired interhemispheric functional connectivity was observed in AD and could be a sensitive neuroimaging biomarker for AD. More specifically, the DMN was inhibited, while the SN and ECN were excited. VMHC results were correlated with MMSE and MOCA scores, highlighting that VMHC could be a sensitive neuroimaging biomarker for AD and the progression from aMCI to AD.

HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling.

It is well accepted that HBx plays the major role in hepatocarcinogenesis associated with hepatitis B virus (HBV) infections. However, little was known about its role in regulating long noncoding RNAs (lncRNAs), a large group of transcripts regulating a variety of biological processes including carcinogenesis in mammalian cells. Here we report that HBx upregulates UCA1 genes and downregulates p27 genes in hepatic LO2 cells. Further studies show that the upregulated UCA1 promotes cell growth by facilitating G1/S transition through CDK2 in both hepatic and hepatoma cells. Knock down of UCA1 in HBx-expressing hepatic and hepatoma cells resulted in markedly increased apoptotic cells by elevating the cleaved caspase-3 and caspase-8. More importantly, UCA1 is found to be physically associated with enhancer of zeste homolog 2 (EZH2), which suppresses p27Kip1 through histone methylation (H3K27me3) on p27Kip1 promoter. We also show that knockdown of UCA1 in hepatoma cells inhibits tumorigenesis in nude mice. In a clinic study, UCA1 is found to be frequently up-regulated in HBx positive group tissues in comparison with the HBx negative group, and exhibits an inverse correlation between UCA1 and p27Kip1 levels. Our findings demonstrate an important mechanism of hepatocarcinogenesis through the signaling of HBx-UCA1/EZH2-p27Kip1 axis, and a potential target of HCC.