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Background and Purpose: D-Serine, the endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptors, has been recognized as an important gliotransmitter in the mammalian brain. D-serine has been shown to prevent psychostimulant-induced decrease in hippocampal neurogenesis. However, the mechanism whereby D-serine regulates neurogenesis has not been fully characterized. Therefore, this study was designed to investigate the impacts of D-serine on the proliferation, migration, and differentiation of primary cultured neural stem cells (NSCs)., Methods and Results: Immunohistochemistry analysis revealed NSCs expressed D-serine as well as serine racemase (SR). Degradation of endogenous D-serine with D-amino acid oxidase (DAAO) significantly inhibited the proliferation and neuronal differentiation of NSCs, but failed to affect their radial migration. Reversely, addition of exogenous D-serine did not affect the proliferation and migration of NSCs, but promoted NSC differentiation into neurons. Furthermore, DAAO could suppress the amplitude of glutamate-induced Ca(2+) transient, and thereby, inhibited the phosphorylation of glycogen synthase kinase3β (GSK3β), extracellular signal-regulated kinases1/2 (ERK1/2), and cAMP-responsive element-binding protein (CREB)., Conclusions: Our findings demonstrate for the first time that NSCs can synthesize D-serine and, thereby, promote themselves proliferation and neuronal differentiation, which may afford a novel therapeutic strategy for the neurological disorders that require nerve cell replenishment, such as neurodegenerative diseases and stroke., (© 2012 Blackwell Publishing Ltd.)

Our previous study indicated that streptozotocin (STZ)‐induced diabetes leads to colonic platelet‐derived growth factor receptor‐α‐positive (PDGFRα+) cell proliferation accompanied by slow colonic transit in mice; however, the mechanism of this effect is unclear. The present study used western blotting, immunohistochemistry, and quantitative PCR to investigate whether proteinase‐activated receptor 2 (PAR2) mediates PDGFRα+ cell proliferation. Our results showed that PDGFRα, PAR2, and Ki‐67 coexpression was increased in the diabetic colonic muscle layer. PDGFRα and PAR2 mRNA and protein expression levels were also markedly enhanced in the diabetic colonic muscle layer. Mice treated with 2‐furoyl‐LIGRLO‐amide (2‐F‐L‐a), a PAR2 agonist, exhibited significant colon elongation and increased smooth muscle weight. In the 2‐F‐L‐a‐treated mice, PDGFRα, PAR2, and Ki‐67 coexpression was increased and PDGFRα and PAR2 mRNA and protein expression was significantly enhanced in the colonic smooth muscle layer. 2‐F‐L‐a also increased proliferation and PDGFRα expression in NIH/3T3 cells cultured in high glucose, while LY294002, a PI3K antagonist, decreased cell proliferation and PDGFRα expression. PI3K and Akt protein and mRNA expression and p‐Akt protein expression in diabetic and 2‐F‐L‐a‐treated mice were markedly reduced in colonic smooth muscle. 2‐F‐L‐a also reduced PI3K, Akt, and p‐Akt protein expression in NIH/3T3 cells, while the PI3K antagonist LY294002 increased this expression. The results indicate that PAR2 is involved in the proliferation of PDGFRα+ cells through the PI3K/Akt signaling pathway in the colon of STZ‐induced diabetic mice, which may contribute to the slow transit and constipation that are associated with diabetes. [ABSTRACT FROM AUTHOR]

Epidermal growth factor (EGF) plays an important role in epithelial cell proliferation and apoptosis. Our recent studies found that EGF-attenuated tumor necrosis factor-α induced HaCaT keratinocyte apoptosis, and this effect was accompanied by up-regulation of the expression of peroxisome proliferator-activated receptor β (PPARβ). However, little is known about whether PPARβ is functionally involved in the inhibition of keratinocyte apoptosis by EGF. Here, we showed that EGF up-regulated the DNA-binding and transcriptional regulation activities of PPARβ. Antisense phosphorothioate oligonucleotides against PPARβ markedly inhibited de novo synthesis of PPARβ and attenuated the protective effect of EGF on tumor necrosis factor-α–induced apoptosis. L165041, a specific PPARβ ligand, significantly enhanced the transcriptional regulation activity of PPARβ and increased the protective effect of EGF. These results suggest a molecular mechanism by which EGF protects HaCaT keratinocytes against apoptosis in a PPARβ-dependent manner. [ABSTRACT FROM AUTHOR]