KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS

Neurons in the adult mammalian CNS decrease in intrinsic axon growth capacity during development in concert with changes in Krüppel-like transcription factors (KLFs). KLFs regulate axon growth in CNS neurons including retinal ganglion cells (RGCs). Here, we found that knock-down of KLF9, an axon growth suppressor that is normally upregulated 250-fold in RGC development, promotes long-distance optic nerve regeneration in adult rats of both sexes. We identified a novel binding partner, MAPK10/JNK3 kinase, and found that JNK3 (c-Jun N-terminal kinase 3) is critical for KLF9\u27s axon-growth-suppressive activity. Interfering with a JNK3-binding domain or mutating two newly discovered serine phosphorylation acceptor sites, Ser106 and Ser110, effectively abolished KLF9\u27s neurite growth suppression in vitro and promoted axon regeneration in vivo. These findings demonstrate a novel, physiologic role for the interaction of KLF9 and JNK3 in regenerative failure in the optic nerve and suggest new therapeutic strategies to promote axon regeneration in the adult CNS

Potential Neuroprotective Effects of an LSD1 Inhibitor in Retinal Ganglion Cells via p38 MAPK Activity

Citation: Tsutsumi T, Iwao K, Hayashi H, et al. Potential neuroprotective effects of an LSD1 inhibitor in retinal ganglion cells via p38 MAPK activity. Invest Ophthalmol Vis Sci. 2016;57:6461-6473. DOI:10.1167/ iovs.16-19494 PURPOSE. The epigenetic mechanisms associated with ocular neurodegenerative diseases remain unclear. The present study aimed to determine the role of lysine-specific demethylase 1 (LSD1), which represses transcription by removing the methyl group from methylated lysine 4 of histone H3, in retinal ganglion cell (RGC) survival, and to investigate the details of the neuroprotective mechanism of tranylcypromine, a major LSD1 inhibitor. METHODS. The authors evaluated whether tranylcypromine contributes to neuronal survival following stress-induced damage using primary cultured rat RGCs and in vivo N-methyl-Daspartate (NMDA)-induced excitotoxicity. Additionally, the molecules associated with tranylcypromine treatment were assessed by microarray and immunoblot analysis. RESULTS. Tranylcypromine significantly suppressed neuronal cell death following glutamate neurotoxicity and oxidative stress. Microarray and immunoblot analyses revealed that p38 mitogen-activated protein kinase (MAPK)c was a key molecule involved in the neuroprotective mechanisms induced by tranylcypromine because the significant suppression of p38 MAPKc by glutamate was reversed by tranylcypromine. Moreover, although pharmacologic inhibition of the phosphorylation of the total p38 MAPKs interfered with neuroprotective effects of tranylcypromine, the specific inhibition of p38 MAPKa and p38 MAPKb did not influence RGC survival. This suggests that the non-p38 MAPKa/b isoforms have important roles in neuronal survival by tranylcypromine. Additionally, the intravitreal administration of tranylcypromine significantly saved RGC numbers in an in vivo glaucoma model employing NMDA-induced excitotoxicity. CONCLUSIONS. These findings indicate that tranylcypromine-induced transcriptional and epigenetic regulation modulated RGC survival via the promotion of p38 MAPKc activity. Therefore, pharmacologic treatments that suppress LSD1 activity may be a novel therapeutic strategy that can be used to treat neurodegenerative diseases

園芸学部研究業績紹介(目次)

<p>Multivariable analysis to determine prognostic factors for surgical failure of 2^nd operated trabeculectomy using Cox proportional hazards regression models among the successful 1^st operated eyes.</p

第1084回千葉医学会例会・第21回千葉精神科集談会

<p>The comparison of the successful 2^nd operated eyes versus failed 2^nd operated eyes among successful 1^st operated eyes, Criterion C: n = 30.</p

Fracture toughness distribution of alumina-titanium functionally graded materials fabricated by spark plasma sintering

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Factors Influencing Aqueous Proinflammatory Cytokines and Growth Factors in Uveitic Glaucoma.

PURPOSE:To analyze the effects of factors on aqueous humor proinflammatory cytokine and growth factor levels in patients with uveitic glaucoma (UG). METHODS:In this cross-sectional study, we enrolled 143 participants: 1) UG patients (n = 39); 2) primary open-angle glaucoma (POAG) patients (n = 36); and 3) cataract surgery patients, as a comparative group (n = 68). Aqueous humor samples were obtained at the start of surgery. Aqueous cytokine levels were determined using a multiplex immunoassay (xMAP and the Human Cytokine/Chemokine Panel I). RESULTS:In UG cases, mean interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-α, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, and VEGF levels were 171.1, 214.5, 2791.7, 3.5, 23.9, 5.4, and 168.9 pg/mL, respectively, and were higher than those in cataract (non-glaucomatous) cases except PDGF. Levels of IL-6, MCP-1, and VEGF were higher in UG cases than in POAG cases. UG cases with a history of phacoemulsification displayed significantly higher levels of IL-6 (P = 0.0164), IL-8 (P = 0.0003), MCP-1 (P = 0.0465), and PDGF-AB/BB (P = 0.0062) compared to the phakic cases. The presence of cells in the anterior chamber was related to higher levels of IL-8 (P = 0.0002), TNF-α (P = 0.0037), and PDGF-AB/BB (P = 0.0009). The level of PDGF-AB/BB was higher in infectious uveitis than in non-infectious uveitis (P = 0.0211). The level of transforming growth factor (TGF)-β2 was negatively correlated with the levels of MCP-1 (adjusted R2 = 0.28, t = -2.45, P = 0.031) and TNF-α (adjusted R2 = 0.27, t = -2.43, P = 0.032). CONCLUSION:A history of phacoemulsification, the presence of cells in the anterior chamber, and infectious uveitis were related to aqueous proinflammatory cytokine levels in patients with UG. TGF-β2 might be an anti-inflammatory factor in aqueous humor of UG patients

Efficacy and safety of Ex-PRESS® mini shunt surgery versus trabeculectomy for neovascular glaucoma: a retrospective comparative study

Abstract Background The objective of this study is to evaluate and compare the short-term efficacy and safety of Ex-PRESS® mini shunt surgery and trabeculectomy for neovascular glaucoma (NVG). Methods Patients with NVG who underwent Ex-PRESS® mini shunt surgery or trabeculectomy as a primary glaucoma surgery between March 2013 and October 2015 were included in the study, and their medical charts were retrospectively reviewed. The Ex-PRESS® and trabeculectomy groups included 14 eyes and 30 eyes, respectively. Surgical failure was defined by an intraocular pressure (IOP) of ≥21 mmHg (condition A) or ≥ 18 mmHg (condition B); Kaplan–Meier survival analyses and the multivariable Cox proportional hazards model were used to assess efficacies. Results Kaplan–Meier survival analyses indicated that the probabilities of success at 1 year for the Ex-PRESS® group were 25.7 and 31.8% based on complete and qualified success under condition A, respectively. The corresponding values for the trabeculectomy group were 47.8 and 69.3%, and there was a significant difference in qualified success with condition A (Fig. 1; P = 0.018), while there were no significant differences in the other criteria. Ex-PRESS® mini shunt surgery and higher intraocular pressure were independent prognostic factors using Cox proportional hazards model analyses in qualified success as in condition A (P = 0.012 and 0.0495, respectively). The occurrences of postsurgical hyphema and bleb leaks were significantly higher in the trabeculectomy group (P = 0.005 and 0.008, respectively). Conclusion During a 1 year follow-up, Ex-PRESS® mini shunt surgery was a less effective, but safer treatment for NVG compared with trabeculectomy

The Influence of Phacoemulsification on Surgical Outcomes of Trabeculectomy with Mitomycin-C for Uveitic Glaucoma.

To evaluate the influence of phacoemulsification after trabeculectomy on the postoperative intraocular pressure (IOP) in eyes with uveitic glaucoma (UG).Kumamoto University Hospital, Kumamoto, Japan.A retrospective cohort study.The medical records of patients with UG who had trabeculectomy with mitomycin-C (MMC) were reviewed. Complete and qualified surgical failures were defined by an IOP of ≥21 mmHg (condition A), ≥18 mmHg (condition B), or ≥15 mmHg (condition C) without and with glaucoma eye drops, respectively. Kaplan-Meier survival analysis, generalized by the Wilcoxon test, and the Cox proportional hazards model analysis were conducted. Post-trabeculectomy phacoemulsification was treated as a time-dependent variable. In 24 (30%) of the included 80 eyes, phacoemulsification was included, and they were divided into two groups: groups I (8 eyes with phacoemulsification within 1 year after trabeculectomy) and group II (16 eyes after 1 year following trabeculectomy).Multivariable Cox proportional hazards model analysis showed post-trabeculectomy phacoemulsification was a significant factor in both complete success and qualified success based upon condition C (P = 0.0432 and P = 0.0488, respectively), but not for the other conditions. Kaplan-Meier survival analyses indicated significant differences in success probabilities between groups I and group II for complete success and qualified success based upon condition C (P = 0.020 and P = 0.013, respectively). There was also a significant difference for qualified success based upon condition B (P = 0.034), while there was no significant difference for the other conditions.Post-trabeculectomy phacoemulsification, especially within 1 year, can cause poor prognosis of IOP control of UG eyes after trabeculectomy with MMC