Age-specific findings on lifestyle and trajectories of cognitive function from the Korean Longitudinal Study of Aging.

OBJECTIVES: Few longitudinal studies have explored age-related differences in the relationship between lifestyle factors and cognitive decline. This study investigated lifestyle factors at baseline that slow the longitudinal rate of cognitive decline in young-old (55-64 years), middle-old (65-74 years), and old-old (75+ years) individuals. METHODS: We conducted an 11-year follow-up that included 6,189 older adults from the Korean Longitudinal Study of Aging, which is a cohort study of community-dwelling older Koreans. Lifestyle factors, including physical activity, social activity (SA), smoking, and alcohol consumption were assessed at baseline. Cognitive function was measured at 2-year intervals over 11 years. Latent growth modeling and multi-group analysis were performed. RESULTS: The influence of lifestyle factors on the rate of cognitive decline differed by age. Smoking at baseline (-0.05; 95% confidence interval [CI], -0.11 to -0.00, per study wave) accelerated cognitive decline in young-old individuals, whereas frequent participation in SA at baseline (0.02; 95% CI, 0.01 to 0.03, per study wave) decelerated cognitive decline in middle-old individuals. None of the lifestyle factors in this study decelerated cognitive decline in old-old individuals. CONCLUSIONS: Cognitive strategies based on modifiable lifestyle factors such as smoking cessation in young-old individuals and frequent SA participation in middle-old age individuals may have great potential for preventing cognitive decline. Because the influence of lifestyle factors varied by age group, age-specific approaches are recommended to promote cognitive health.

The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells.

The epigenetic reader, bromodomain-containing 4 (BRD4), is overexpressed in hepatocellular carcinoma (HCC), and BRD4 inhibition is considered as a new therapeutic approach. The BRD inhibitor JQ1 is known to inhibit the enrichment of BRD4 at enhancer sites. Gene network analyses have implicated long non-coding RNAs (lncRNAs) in the effects of JQ1, but the precise molecular events remain unexplored. Here, we report that in HepG2 cells, JQ1 significantly reduced various proliferation-related lncRNAs, but up-regulated the known liver tumor marker, MALAT1. Using ChIP-sequencing data, ChIP-qPCR, luciferase reporter assays, and chromatin conformation capture (3C), we characterized the MALAT1 gene locus. We found that JQ1 elicited a rearrangement of its chromatin looping conformation, which involved the putative enhancers E1, E2, E3, the gene body, and the promoter. We further found that the forkhead box protein A2 (FOXA2) binds to E2 and the promoter; suppression of FOXA2 expression resulted in MALAT1 up-regulation and increased cell proliferation. These results suggest that the inhibition of MALAT1 may improve the effect of BET inhibitors as an anti-cancer therapy and that FOXA2 would be a suitable target for that approach.

Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and poor prognosis. Emerging evidence suggests that epigenetic alterations play a crucial role in HCC, suggesting epigenetic inhibition as a promising therapeutic approach. Indeed, the bromodomain and extra-terminal (BET) inhibitors inhibit the proliferation and invasion of various cancers but still lack a strong mechanistic rationale. Here, we identified the differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) in human HCC cell line HepG2 treated with the BET inhibitors, JQ1, OTX015, or ABBV-075. We analyzed the correlation between DEmRNAs and DElncRNAs in common for the three inhibitors based on their expression profiles and performed functional annotation pathway enrichment analysis. Most of these shared DEmRNAs and DElncRNAs, including some novel transcripts, were downregulated, indicating decreased proliferation/adhesion and increased apoptosis/inflammation. Our study suggests that BET proteins play a crucial role in regulating cancer progression-related genes and provide a valuable resource for novel putative biomarkers and therapeutic targets in HCC.

Targeting of noncoding RNAs encoded by a novel MYC enhancers inhibits the proliferation of human hepatic carcinoma cells in vitro.

The proto-oncogene MYC is important for development and cell growth, however, its abnormal regulation causes cancer. Recent studies identified distinct enhancers of MYC in various cancers, but any MYC enhancer(s) in hepatocellular carcinoma (HCC) remain(s) elusive. By analyzing H3K27ac enrichment and enhancer RNA (eRNA) expression in cultured HCC cells, we identified six putative MYC enhancer regions. Amongst these, two highly active enhancers, located ~ 800 kb downstream of the MYC gene, were identified by qRT-PCR and reporter assays. We functionally confirmed these enhancers by demonstrating a significantly reduced MYC expression and cell proliferation upon CRISPR/Cas9-based deletion and/or antisense oligonucleotide (ASO)-mediated inhibition. In conclusion, we identified potential MYC enhancers of HCC and propose that the associated eRNAs may be suitable targets for HCC treatment.

BET inhibitor suppresses migration of human hepatocellular carcinoma by inhibiting SMARCA4.

Hepatocellular carcinoma (HCC) is one of the most prevalent and poorly responsive cancers worldwide. Bromodomain and extraterminal (BET) inhibitors, such as JQ1 and OTX-015, inhibit BET protein binding to acetylated residues in histones. However, the physiological mechanisms and regulatory processes of BET inhibition in HCC remain unclear. To explore BET inhibitors' potential role in the molecular mechanisms underlying their anticancer effects in HCC, we analyzed BET inhibitor-treated HCC cells' gene expression profiles with RNA-seq and bioinformatics analysis. BET inhibitor treatment significantly downregulated genes related to bromodomain-containing proteins 4 (BRD4), such as ACSL5, SLC38A5, and ICAM2. Importantly, some cell migration-related genes, including AOC3, CCR6, SSTR5, and SCL7A11, were significantly downregulated. Additionally, bioinformatics analysis using Ingenuity Knowledge Base Ingenuity Pathway Analysis (IPA) revealed that SMARCA4 regulated migration response molecules. Furthermore, knockdown of SMARCA4 gene expression by siRNA treatment significantly reduced cell migration and the expression of migration-related genes. In summary, our results indicated that BET inhibitor treatment in HCC cell lines reduces cell migration through the downregulation of SMARCA4.

Effectiveness of eccentric viewing training for daily visual activities for individuals with age-related macular degeneration: a systematic review and meta-analysis.

BACKGROUND: Eccentric viewing training can be successfully applied in the clinical setting based on positive evidence. Nonetheless, published research should be integrated to provide a conclusive perspective of the efficacy of eccentric viewing training. OBJECTIVE: Meta-analysis was conducted to examine effectiveness of eccentric viewing training on daily visual activities for individuals with age-related macular degeneration (AMD). METHODS: The papers used in this study were located through PubMed, Ovid, ProQuest, EBSCOhost, RISS, and KMbase on studies published between January, 1990 and December, 2012. The keywords for searching were "age-related macular degeneration" and "eccentric viewing", "eccentric fixation", "peripheral vision" or "preferred retinal loci". The effect sizes were calculated using Comprehensive Meta-Analysis 2.0 and interpreted according to Cohen's criteria. RESULTS: A total of 258 studies were found, among which five papers suited the main selection criteria for final analysis. The entire effect size was 0.660 (95% CI, 0.232 ~ 1.088), indicating a moderate effect size of the eccentric viewing training for individuals with AMD in their daily visual activities (p < 0.05). CONCLUSIONS: The results of this study demonstrated the clinical effectiveness of eccentric viewing training for individuals with AMD. This result should be interpreted cautiously, though, given the possibility of publication bias.