Abstract : SHP2 is an unusual protein phosphatase that functions as an activator for several signaling pathways, including the RAS pathway, while most other phosphatases suppress their downstream signaling cascades. The physiological and pathophysiological roles of SHP2 have been extensively studied in the field of cancer research. Mutations in the PTPN11 gene which encodes SHP2 are also highly associated with developmental disorders, such as Noonan syndrome (NS), and cognitive deficits including learning disabilities are common among NS patients. However, the molecular and cellular mechanism by which SHP2 is involved in cognitive functions is not well understood. Recent studies using SHP2 mutant mice or pharmacological inhibitors have shown that SHP2 plays critical role in learning and memory and synaptic plasticity. Here, we review the recent studies demonstrating that SHP2 is involved in synaptic plasticity, and learning and memory, by the regulation of the expression and/or function of glutamate receptors. We suggest that each cell type may have distinct paths connecting the dots between SHP2 and glutamate receptors, and these paths may also change with aging.
Abstract : Ulcerative colitis (UC) is associated with intestinal immune imbalance and inflammatory response. Because dehydrolovastatin (DLVT), a derivative of lovastatin, has been recently shown to inhibit inflammation and relieve immune arthritis induced by chemical stimuli, we studied its effect and possible mechanism on UC induced by dextran sulfate sodium. The BALB/c mice were classified into six groups: normal control group, model group, DLVT high dose group, DLVT low dose group, salazosulfapyridine (SASP) group and lovastatin (LVT) group. The disease activity indices of UC and pathological changes were investigated. The myeloperoxidase (MPO) activity in colon tissue and inflammatory factors such as IL-6, IL-10, IL-17, and TNF-α in the serum were analyzed by ELISA, while the expression of NF-ΚB p65 protein in colon tissue was detected by immunohistochemistry and western blot. DLVT relieved the disease activity indices and pathological damage of the UC mice. Furthermore, DLVT significantly decreased MPO activity and improved the imbalance of inflammatory cytokines through inhibiting the expression of NF-ΚB p65. Meanwhile, the positive drug of SASP has a similar effect to DLVT, but the effect of DLVT in both decreasing IL-17, TNF-α, and increasing IL-10 was significantly stronger than that of SASP. These results suggest that DLVT may ameliorates the symptoms of UC.
Jeong-Hwan Kim, Chang-Taek Oh, Tae-Rin Kwon, Jong Hwan Kim, Dong-Ho Bak, Hyuk Kim, Won-Seok Park, and Beom Joon Kim
Abstract : Sodium 2-mercaptoethanesulfonate (mesna) is a protective agent that is widely used in medicine because of its antioxidant effects. Recently, reactive oxygen species (ROS) were shown to increase pigmentation. Thus, ROS scavengers and inhibitors of ROS production may suppress melanogenesis. Forkhead box-O3a (FoxO3a) is an antimelanogenic factor that mediates ROS-induced skin pigmentation. In this study, we aimed to investigate the whitening effect of mesna and the signaling mechanism mediating this effect. Human melanoma (MNT-1) cells were used in this study. mRNA and protein expression were measured by real-time quantitative PCR and Western blotting analysis to track changes in FoxO3a-related signals induced by mesna. An immunofluorescence assay was performed to determine the nuclear translocation of FoxO3a. When MNT-1 melanoma cells were treated with mesna, melanin production and secretion decreased. These effects were accompanied by increases in FoxO3a activation and nuclear translocation, resulting in downregulation of four master genes of melanogenesis: MITF, TYR, TRP1, and TRP2. We found that mesna, an antioxidant and radical scavenger, suppresses melanin production and may therefore be a useful agent for the clinical treatment of hyperpigmentation disorders.
Yoon-Hee Cheon, Min Seob Kim, Ju-Young Kim, Dong Hyun Kim, Seung Yoon Han, and Jae-Hoon Lee
Abstract : Chronic inflammatory airway diseases, such as chronic rhinosinusitis, chronic obstructive pulmonary disease, and asthma, are associated with excessive mucus production. Hence, the regulation of mucus production is important for the treatment of upper and lower airway diseases. Eupatilin is a pharmacologically active ingredient obtained from Artemisia asiatica Nakai (Asteraceae) and exerts potent anti-inflammatory, anti-allergic, and anti-tumor activities. In the present study, we investigated the effect of eupatilin on phorbol 12‐myristate 13‐acetate (PMA)-induced MUC5AC and MUC5B expression in human airway epithelial cells. We found that eupatilin treatment significantly inhibited PMA-induced mucus secretion in PAS staining. In addition, qRT-PCR results showed that eupatilin dose-dependently decreased the mRNA expression of MUC5AC in human airway epithelial cells. Western blot and immunofluorescence assay also showed that PMA-induced protein expression of MUC5AC was inhibited by eupatilin treatment. Finally, we investigated MAPKs activity after stimulation with PMA using western blot analysis in human airway epithelial cells. The results showed that eupatilin downregulated the levels of phosphorylated p38, ERK, and JNK. In summary, the anti-inflammatory activities of eupatilin, characterized as the suppression of MUC5AC expression and secretion in human airway epithelial cells, were found to be associated with the inhibition of p38/ERK/JNK MAPKs signaling pathway of MUC5AC secretion.
Jun-Sub Jung, A Ra Kho, Song Hee Lee, Bo Young Choi, Shin-Hae Kang, Jae-Young Koh, Sang Won Suh, and Dong-Keun Song
Abstract : Ischemic and traumatic brain injuries are the major acute central nervous system disorders that need to be adequately diagnosed and treated. To find biomarkers for these acute brain injuries, plasma levels of some specialized pro-resolving mediators (SPMs, i.e., lipoxin A4 [LXA4], resolvin [Rv] E1, RvE2, RvD1 and RvD2), CD59 and interleukin (IL)-6 were measured at 0, 6, 24, 72, and 168 h after global cerebral ischemic (GCI) and traumatic brain injuries (TBI) in rats. Plasma LXA4 levels tended to increase at 24 and 72 h after GCI. Plasma RvE1, RvE2, RvD1, and RvD2 levels showed a biphasic response to GCI; a significant decrease at 6 h with a return to the levels of the sham group at 24 h, and again a decrease at 72 h. Plasma CD59 levels increased at 6 and 24 h post-GCI, and returned to basal levels at 72 h post-GCI. For TBI, plasma LXA4 levels tended to decrease, while RvE1, RvE2, RvD1, and RvD2 showed barely significant changes. Plasma IL-6 levels were significantly increased after GCI and TBI, but with different time courses. These results show that plasma LXA4, RvE1, RvE2, RvD1, RvD2, and CD59 levels display differential responses to GCI and TBI, and need to be evaluated for their usefulness as biomarkers.