Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium.

IntroductionAcid-sensing ion channel 3 (ASIC3) is expressed in synoviocytes, activated by decreases in pH, and reduces inflammation in animal models of inflammatory arthritis. The purpose of the current study was to characterize potential mechanisms underlying the control of inflammation by ASIC3 in fibroblast-like synoviocytes (FLS).MethodsExperiments were performed in cultured FLS from wild-type (WT) and ASIC3-/- mice, ASIC1-/- mice, and people with rheumatoid arthritis. We assessed the effects of acidic pH with and without interleukin-1β on FLS and the role of ASICs in modulating intracellular calcium [Ca(2+)](i), mitogen activated kinase (MAP kinase) expression, and cell death. [Ca(2+)](i) was assessed by fluorescent calcium imaging, MAP kinases were measured by Western Blots; ASIC, cytokine and protease mRNA expression were measured by quantitative PCR and cell death was measured with a LIVE/DEAD assay.ResultsAcidic pH increased [Ca(2+)](i) and decreased p-ERK expression in WT FLS; these effects were significantly smaller in ASIC3-/- FLS and were prevented by blockade of [Ca(2+)]i. Blockade of protein phosphatase 2A (PP2A) prevented the pH-induced decreases in p-ERK. In WT FLS, IL-1β increases ASIC3 mRNA, and when combined with acidic pH enhances [Ca(2+)](i), p-ERK, IL-6 and metalloprotienase mRNA, and cell death. Inhibitors of [Ca(2+)](i) and ERK prevented cell death induced by pH 6.0 in combination with IL-1β in WT FLS.ConclusionsDecreased pH activates ASIC3 resulting in increased [Ca(2+)](i), and decreased p-ERK. Under inflammatory conditions, acidic pH results in enhanced [Ca(2+)](i) and phosphorylation of extracellular signal-regulated kinase that leads to cell death. Thus, activation of ASIC3 on FLS by acidic pH from an inflamed joint could limit synovial proliferation resulting in reduced accumulation of inflammatory mediators and subsequent joint damage

Shibusawa Eiichi\u27s View of Japan\u27s Foreign Affairs: Focusing on His Influences on the Meiji Government

From the mid-nineteenth century, Asia, including China and Japan, has been involved in the trend of modernization that was triggered by the activities of European and American powers in this area. In a time of drastic changes, Shibusawa Eiichi (1840-1931) assumed several roles successively: he served as retainer during the bakumatsu period, as official in the Meiji government, and afterwards as businessman, philanthropist, and non-official diplomat. During his service in the Meiji government from 1869 to 1873 and as an entrepreneur from 1873 to 1909, Shibusawa played a key role in devising economic and diplomatic policies for the Meiji government. He is even considered a major designer of modem Japanese economic systems and society. This paper examines Shibusawa Eiichi\u27s view of Japan\u27s foreign affairs and focuses on the way he influenced the Meiji government

Organization of the Expert-Methodological Work, As a Way of Solving Problems in the System of Corporate Governance of Subsidiaries and Dependent Organizations

The article presents the experience of solving the problem of support of the system of corporate governance of subsidiaries and dependent organizations with the necessary information as well as training of specialists for the control system of the group of companies “Delicate moving”. Article is an invitation for discussion and interaction

Structure of amyloid-beta peptides in a complex-with model membranes

Structures of amyloid-beta peptides Aβ1-40. Aβ10-35, β13-23 and Aβ16-22 in a complex with model membranes in solution were obtained on the analysis of NMR experimental data. It has been established that the process of peptide-micelle complex formation occurs through the amino acid residues LI7, F19, F20 and G29-M35

Structure of amyloid-beta peptides in a complex with model membranes

Structures of amyloid-beta peptides Aβ1-40, Aβ10-35, Aβ13-23 and Aβ16-22 in a complex with model membranes in solution were obtained on the analysis of NMR experimental data. It has been established that the process of peptide-micelle complex formation occurs through the amino acid residues L17, F19, F20 and G29-M35

Cerebellar anaplastic astrocytoma in adult patients: 15 consecutive cases from a single institution and literature review

Adult cerebellar anaplastic astrocytomas (cAA) are rare entities and their clinical and genetic appearances are still ill defined. Previously, malignant gliomas of the cerebellum were combined and reviewed together (cAA and cerebellar glioblastomas (cGB), that could have possibly affected overall survival (OS) and progression-free survival (PFS). We present characteristics of 15 adult patients with cAA and compared them to a series of 45 patients with a supratentorial AA (sAA) in order to elicit the effect of tumor location on OS and PFS. The mean age at cAA diagnosis was 39.3 years (range 19–72). A history of neurofibromatosis type I was noted in 1 patient (6.7%). An IDH-1 mutation was identified in 6/15 cases and a methylated MGMT promoter in 5/15 cases. Patients in study and control groups were matched in age, sex and IDH-1 mutation status. Patients in a study group tended to present with longer overall survival (50 vs. 36.5 months), but the difference did not reach statistical significance. In both cAA and supratentorial AA groups presence of the IDH-1 mutation remains a positive predictor for the prolonged survival. The present study suggests that adult cAA constitute a group of gliomas with relatively higher rate of IDH-1 mutations and prognosis similar to supratentorial AA. The present study is the first to systematically compare cAA and supratentorial AA with respect to their genetic characteristics and suggests that both groups show a similar survival prognosis