Kwonseop Kim

Background In our previous study, we showed simvastatin exerts an antidepressant effect and inhibits neuroinflammation. Given the role of synaptic impairment in depression development, we investigate the effect of simvastatin on synaptic plasticity in depression and the related mechanisms. Methods Electrophysiological analysis, Golgi staining, and transmission electron microscope were performed to analyze the effect of simvastatin on synaptic impairment in depression. In addition, the localization and reactivity of N-methyl-D-aspartate receptor (NMDAR) subunits and the downstream signaling were investigated to explore the mechanism of simvastatin’s effect on synaptic plasticity. Results Simvastatin ameliorated the reduction of the magnitude of long-term potentiation (LTP) in Schaffer collateral-CA1, restored hippocampal dendritic spine density loss, improved the number of spine synapses, reversed the reduction in BrdU-positive cells in chronic mild stress (CMS)-induced depressed mice, and ameliorated NMDA-induced neurotoxicity in hippocampal neurons. Dysfunction of NMDAR activity in the hippocampus is associated with depression. Simvastatin treatment reversed the surface expression and phosphorylation changes of NMDAR subunits in NMDA-treated hippocampal neurons and depressed mice. In addition, simvastatin further increased the levels of mature BDNF, activating TrkB-Akt-mTOR signaling, which is critical for synaptic plasticity. Conclusions These findings suggest that simvastatin can improve the dysfunction of NMDAR and ameliorate hippocampal synaptic plasticity impairment in depressed mice.

Bromopropane (BP) compounds, including 1-bromopropane, 2-bromopropane, and 1,2-dibromopropane, are used in industry for various purposes, and their deleterious effects on human health are becoming known. In this study, we examined the effects of BP compounds on the stemness of colorectal cancer cells. At low, non-cytotoxic concentrations, BP compounds significantly increased spheroid formation in CSC221, DLD1, Caco2, and HT29 cells. In addition, the levels of cancer stem cell markers, such as aldehyde dehydrogenase-1, cluster of differentiation 133 (CD133), CD44, Lgr5, Musashi-1, Ephrin receptor, and Bmi-1 increased after exposure to BP compounds. BP compounds increased the transcriptional activity of the TOPflash and glioma-associated oncogene homolog zinc finger protein (Gli) promoters in reporter assays and increased the expression of Gli-1, Gli-2, Smoothened (SMO), and β-catenin by RT-PCR. These results demonstrate for the first time that BP compounds have the potential to promote cancer stemness.

δ‐Catenin and β‐catenin belong to different subfamilies of armadillo proteins but share some common binding partners, such as E‐cadherin. This is the first study that demonstrated a novel common binding partner for δ‐catenin and β‐catenin, lymphoid enhancer factor‐1 (LEF‐1). We found that the N‐terminus of δ‐catenin (amino acids 85–325) bound to the middle region of LEF‐1 unlike β‐catenin. Overexpressed δ‐catenin entered the nucleus and inhibited LEF‐1‐mediated transcriptional activity in Bosc23 and DLD‐1 cell lines. The current study provided novel insights that will provide a better understanding of the effects of δ‐catenin on Wnt/LEF‐1‐mediated transcriptional activity.

Accumulated evidence suggests that aberrant regulation of δ‐catenin leads to pathological consequences such as mental retardation and cognitive dysfunction. This study revealed that 14‐3‐3ɛ/ζ stabilizes δ‐catenin, with different binding regions involved in the interaction. Furthermore, the specific inhibition of the interaction of 14‐3‐3 with δ‐catenin reduced levels of δ‐catenin and significantly impaired the capacity of δ‐catenin to induce dendritic branching in both NIH3T3 fibroblasts and primary hippocampal neurons. However, the S1094A δ‐catenin mutant, which cannot interact with 14‐3‐3ζ, still retained the capability of inducing dendrogenesis. Taken together, these results elucidate the underlying events that regulate the stability of δ‐catenin and δ‐catenin‐induced dendrogenesis.

Neuronal synaptic junction protein δ-catenin (CTNND2) is often overexpressed in prostatic adenocarcinomas but the mechanisms of its activation are unknown. To address this question, we studied the hypothesis that Hes1, human homolog of Drosophila Hairy and enhancer of split (Hes) 1, is a transcriptional repressor of δ-catenin expression and plays an important role in molecular carcinogenesis.

Background: δ-Catenin is a unique member of β-catenin/armadillo domain superfamily proteins and its primary expression is restricted to the brain. However, δ-catenin is upregulated in human prostatic adenocarcinomas, although the effects of δ-catenin overexpression in prostate cancer are unclear. We hypothesized that δ-catenin plays a direct role in prostate cancer progression by altering gene profiles of cell cycle regulation and cell survival. Results: We employed gene transfection and small interfering RNA to demonstrate that increased δ-catenin expression promoted, whereas its knockdown suppressed prostate cancer cell viability. δ-Catenin promoted prostate cancer cell colony formation in soft agar as well as tumor xenograft growth in nude mice. Deletion of either the amino-terminal or carboxyl-terminal sequences outside the armadillo domains abolished the tumor promoting effects of δ-catenin. Quantitative RT² Profiler™ PCR Arrays demonstrated gene alterations involved in cell cycle and survival regulation. δ-Catenin overexpression upregulated cyclin D1 and cdc34, increased phosphorylated histone-H3, and promoted the entry of mitosis. In addition, δ-catenin overexpression resulted in increased expression of cell survival genes Bcl-2 and survivin while reducing the cell cycle inhibitor p21^Cip1. Conclusion: Taken together, our studies suggest that at least one consequence of an increased expression of δ-catenin in human prostate cancer is the alteration of cell cycle and survival gene profiles, thereby promoting tumor progression.