Endoplasmic Reticulum Stress Increases DUSP5 Expression via PERK-CHOP Pathway, Leading to Hepatocyte Death.

Hepatocyte death is critical for the pathogenesis of liver disease progression, which is closely associated with endoplasmic reticulum (ER) stress responses. However, the molecular basis for ER stress-mediated hepatocyte injury remains largely unknown. This study investigated the effect of ER stress on dual-specificity phosphatase 5 (DUSP5) expression and its role in hepatocyte death. Analysis of Gene Expression Omnibus (GEO) database showed that hepatic DUSP5 levels increased in the patients with liver fibrosis, which was verified in mouse models of liver diseases with ER stress. DUSP5 expression was elevated in both fibrotic and acutely injured liver of mice treated with liver toxicants. Treatment of ER stress inducers enhanced DUSP5 expression in hepatocytes, which was validated in vivo condition. The induction of DUSP5 by ER stress was blocked by either treatment with a chemical inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, or knockdown of C/EBP homologous protein (CHOP), whereas it was not affected by the silencing of IRE1 or ATF6. In addition, DUSP5 overexpression decreased extracellular-signal-regulated kinase (ERK) phosphorylation, but increased cleaved caspase-3 levels. Moreover, the reduction of cell viability under ER stress condition was attenuated by DUSP5 knockdown. In conclusion, DUSP5 expression is elevated in hepatocytes by ER stress through the PERK-CHOP pathway, contributing to hepatocyte death possibly through ERK inhibition.

Ganglioside GD1a enhances osteogenesis by activating ERK1/2 in mesenchymal stem cells of Lmna mutant mice.

Mutations in Lmna usually cause a series of human disorders, such as premature aging syndrome (progeria) involving the skeletal system. Gangliosides are known to be involved in cell surface differentiation and proliferation of stem cells. However, the role of gangliosides in Lmna dysfunctional mesenchymal stem cells (MSCs) is unclear. Therefore, Ganglioside's role in osteogenesis of Lmna dysfunctional MSCs analyzed. As a result of the analysis, it was confirmed that the expression of ganglioside GD1a was significantly reduced in MSCs derived from LmnaDhe/+ mice and in MSCs subjected to Lamin A/C knockdown using siRNA. Osteogenesis-related bone morphogenetic protein-2 and Osteocalcin protein, and gene expression were significantly decreased due to Lmna dysfunction. A result of treating MSCs with Lmna dysfunction with ganglioside GD1a (3 µg/ml), significantly increased bone differentiation in ganglioside GD1a treatment to Lmna-mutated MSCs. In addition, the level of pERK1/2, related to bone differentiation mechanisms was significantly increased. Ganglioside GD1a was treated to Congenital progeria LmnaDhe/+ mice. As a result, femur bone volume in ganglioside GD1a-treated LmnaDhe/+ mice was more significantly increased than in the LmnaDhe/+ mice. Therefore, it was confirmed that the ganglioside GD1a plays an important role in enhancing osteogenic differentiation in MSC was a dysfunction of Lmna.

Regional Differences in Chronic Stress-induced Alterations in Mast Cell and Protease-activated Receptor-2-positive Cell Numbers in the Colon of Ws/Ws Rats.

BACKGROUND/AIMS: There have been no reports on the effect of chronic psychological stress on colonic immune cells or the regional differences. We aimed to investigate the effect of chronic psychological stress on the number of mast cells and protease-activated receptor (PAR)-2-positive cells in the rat colonic mucosa. METHODS: Six-week-old and 14-week-old Ws/Ws rats, which lack mast cells after 10 weeks, were used as control and mast cell-deficient groups, respectively. The rats were divided into stress and sham-treated groups. Rats in the stressed group were exposed to water avoidance stress (WAS, 1 hour/day) for 13 days. Fecal pellet output and the number of mast cells and PAR-2-positive cells in colonic mucosa were compared between the WAS and sham groups. RESULTS: In 6-week-old rats, the WAS group showed a significantly higher number of mast cells compared to the sham group. In 14-week-old rats, mast cells were nearly absent in the colonic mucosa. WAS significantly increased PAR-2-positive cells in 14-week-old rats, but not in 6-week-old rats. Indirect estimation of PAR-2-positive mast cells in 6-week-old rats suggested that the majority of increased mast cells following WAS did not express PAR-2. WAS increased mast cells and PAR-2-positive cells mainly in the proximal colon. Fecal pellet output was continuously higher in the WAS group than in the sham group, and the difference was significant for both 6-week-old and 14-week-old rats. CONCLUSIONS: Chronic psychological stress increased the number of mast cells and PAR-2-positive cells in rat colonic mucosa, and these increases were more prominent in the proximal colon.