👤 Muren Huhe

The human genome is widely transcribed, with part of these transcribed regions producing stably expressed protein-coding or non-coding RNAs. Long intergenic non-coding RNAs (lincRNAs) are significantly differentially expressed in various cell lines and tissues. However, the influence of their transcription events remains unclear. In this study, we constructed a human genomic interaction network and found frequent interactions between lincRNA genes and protein-coding genes that are highly related to the occupancy of RNA polymerase II on the lincRNA gene. Interestingly, in the human genome interaction networks, the degree of lincRNA genes was significantly higher than that of protein-coding genes. The promoter regions of the protein-coding genes interacting with the lincRNA genes are enriched with R-loop structures, indicating that lincRNA may influence the target genes through R-loop structures. These promoters were enriched in more transcription factor binding sites. Furthermore, the whole network and sub-network could be utilized to explore potential biomarkers of leukemia. We found that zinc finger protein 668 (ZNF668), eosinophil granule ontogeny transcript (EGOT), and glutamate metabotropic receptor 7 (GRM7) could serve as novel biomarkers for acute myeloid leukemia (LMAL). Pasireotide acetate (CAS No. 396091-76-2) represents a potential drug for LMAL patients. These results suggested that potential biomarkers and corresponding drugs for cancer could be identified based on lincRNA-promoter network/sub-network topological parameters. Show less

The β-secretase BACE1 initiates amyloid-β (Aβ) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aβ reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose. We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range. The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aβ deposition. Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12 months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the β-amyloidogenic processing of amyloid precursor protein or Aβ levels in 5XFAD mouse brains. A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy. Show less