The fungal metabolite (+)-terrein abrogates osteoclast differentiation via suppression of the RANKL signaling pathway through NFATc1

Pathophysiological bone resorption is commonly associated with periodontal disease and involves the excessive resorption of bone matrix by activated osteoclasts. Receptor activator of nuclear factor (NF)-κB ligand (RANKL) signaling pathways have been proposed as targets for inhibiting osteoclast differentiation and bone resorption. The fungal secondary metabolite (+)-terrein is a natural compound derived from Aspergillus terreus that has previously shown anti-interleukin-6 properties related to inflammatory bone resorption. However, its effects and molecular mechanism of action on osteoclastogenesis and bone resorption remain unclear. In the present study, we showed that 10 µM synthetic (+)-terrein inhibited RANKL-induced osteoclast formation and bone resorption in a dose-dependent manner and without cytotoxicity. RANKL-induced messenger RNA expression of osteoclast-specific markers including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), the master regulator of osteoclastogenesis, cathepsin K, tartrate-resistant acid phosphatase (Trap) was completely inhibited by synthetic (+)-terrein treatment. Furthermore, synthetic (+)-terrein decreased RANKL-induced NFATc1 protein expression. This study revealed that synthetic (+)-terrein attenuated osteoclast formation and bone resorption by mediating RANKL signaling pathways, especially NFATc1, and indicated the potential effect of (+)-terrein on inflammatory bone resorption including periodontal disease

The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-kappa B Ligand-Induced Osteoclastogenesis by Suppressing Protein Kinase-C alpha/beta II Phosphorylation

Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKC alpha/beta II, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis

ダイガク キョウイク イインカイ ガッコウ ト レンケイ シタ キョウイク カイゼン ニ カンスル ジッセン キョウイク VII : ホンガク ト スズカシ キョウイク イインカイ ト ノ レンケイ ジギョウ ニ カンスル ガッコウ シエン ノ ケイカ

教職大学院を中心組織として，本学と鈴鹿市教育委員会は，平成２３年３月連携事業に関する協定書を交わした。事業内容は，以下の５点である。 ①本学教職大学院教員による公立学校を対象とした訪問指導 ②本学教職大学院教員による教育委員会及び校長会等への指導・助言の実施 ③鈴鹿市教育委員会による本学教職大学院への教員派遣の協力 ④鈴鹿市教育委員会による本学教職大学院が実施する教育実践研究に関する協力 ⑤その他，本学教職大学院と鈴鹿市教育委員会の協議結果に基づき実施する事業 この協定に基づき実施している連携事業の具体的方法を示すことを通して，大学，教育委員会，学校の三者の連携のあり方について考察した。本稿は，大学・教育委員会・学校と連携した教育改善に関する実践研究（I），（V）（VI）の継続論文である。On March 2011,Naruto University of Education, putting Advanced Practice of School Education as a center organization, signed an Agreement of Cooperative Project with Suzuka Board of Education. The five areas of the project are as follows: 1. On-site coaching to public schools by professors of Graduate School of Education. 2. Providing advices and instructions to the Board of Education and the principals by professors of Graduate School of Education. 3. Cooperation of teacher visits by Suzuka Board of Education to Graduate School of Education. 4. Suzuka Board of Education\u27s cooperation to practical educational research conducted by Graduate School of Education. 5. Other projects based on the discussion and agreement between Graduate School of Education and Suzuka Board of Education. Through concrete methods of this cooperative project based on this agreement, we studied the cooperation among universities, boards of education, and schools. This Study is a sequel of "Practical Study on Educational Improvement through Partnership among University, School and The Board of Education(I),(V)and(VI)

ダイガク キョウイク イインカイ ガッコウ ト レンケイ シタ キョウイク カイゼン ニ カンスル ジッセン ケンキュウ VI : ホンガク ト スズカシ キョウイク イインカイ トノ レンケイ ジギョウ ニ カンスル ガッコウ シエン ノ ケイカ

教職大学院を中心組織として，本学と鈴鹿市教育委員会は，平成２３年３月連携事業に関する協定書を交わした。事業内容は，以下の５点である。①本学教職大学院教員による公立学校を対象とした訪問指導②本学教職大学院教員による教育委員会及び校長会等への指導・助言の実施③鈴鹿市教育委員会による本学教職大学院への教員派遣の協力④鈴鹿市教育委員会による本学教職大学院が実施する教育実践研究に関する協力⑤その他，本学教職大学院と鈴鹿市教育委員会の協議結果に基づき実施する事業 この協定に基づき実施している連携事業の具体的方法を示すことを通して，大学，教育委員会，学校の三者の連携のあり方について考察した。本稿は，大学・教育委員会・学校と連携した教育改善に関する実践研究（I），（V）の継続論文である。On March 2011, Naruto University of Education, putting Advanced Practice of School Education as a center organization, signed an Agreement of Cooperative Project with Suzuka Board of Education. The five areas of the project are as follows: 1. On-site coaching to public schools by professors of Graduate School of Education. 2. Providing advices and instructions to the Board of Education and the principals by professors of Graduate School of Education. 3. Cooperation of teacher visits by Suzuka Board of Education to Graduate School of Education. 4. Suzuka Board of Education’s cooperation to practical educational research conducted by Graduate School of Education. 5. Other projects based on the discussion and agreement between Graduate School of Education and Suzuka Board of Education. Through concrete methods of this cooperative project based on this agreement, we studied the cooperation among universities, boards of education, and schools. This Study is a sequel of“ Practical Study on Educational Improvement through Partnership among University, School and The Board of Education (I) and (V).

ダイガク キョウイク イインカイ ガッコウ ト レンケイ シタ キョウイク カイゼン ニ カンスル ジッセン ケンキュウ VII : スズカシ チュウガッコウ ニオケル ガッコウ シンダン シツモンシ ノ コウセイ ニツイテ II

平成２３年度より，教職大学院を中心組織として，本学と鈴鹿市教育委員会は，平成２３年３月連携事業に関する協定書を交わした。この事業の一環として，平成２３・２４年度に鈴鹿市内の中学校において，生徒用，教職員用並びに保護者用の質問紙調査を実施した。本研究では，平成２３年度版の保護者用の調査項目の構成を検討して作成した平成２４年度版の学校診断質問紙の構成について検証した。平成２４年度版では汎用化のために，保護者用については３領域６下位領域の３３項目を設定した。平成２４年１１〜１２月に実施した調査結果に関する主成分分析の結果，保護者用では４因子が抽出された。設定領域との対照では，若干の項目については異なった関連性を示したが，多くの項目については設定領域の診断項目としての妥当性が示された。On March 2011, Naruto University of Education, putting Advanced Practice of School Education as a center organization, signed an Agreement of Cooperative Project with Suzuka Board of Education. We carried out the questionnaire survey of junior high school students, teachers and parents of the students in Suzuka City at 2011 and 2012 on this Project. The construction of the school assessment questionnaires for the parents of the 2012 version that examines those of the 2011 version are studied. In the 2012 version of the school assessment questionnaires, 33 items in the 3 categories / 6 subcategories at the parents were set up for generalized use. As a result of principal component analysis of survey data on November and December 2012, 4 factors were extracted in for the parents. Although a little item showed different relevancy from the setting, many items showed the validity as the assessment items of that

The Fungal Metabolite (+)-Terrein Abrogates Inflammatory Bone Resorption via the Suppression of TNF-&alpha; Production in a Ligature-Induced Periodontitis Mouse Model

Current periodontal treatment focuses on the mechanical removal of the source of infection, such as bacteria and their products, and there is no approach to control the host inflammatory response that leads to tissue destruction. In order to control periodontal inflammation, we have previously reported the optimization of (+)-terrein synthesis methods and the inhibitory effect of (+)-terrein on osteoclast differentiation in vitro. However, the pharmacological effect of (+)-terrein in vivo in the periodontitis model is still unknown. In this study, we investigated the effect of synthetic (+)-terrein on inflammatory bone resorption using a ligature-induced periodontitis mouse model. Synthetic (+)-terrein (30 mg/kg) was administered intraperitoneally twice a week to the mouse periodontitis model. The control group was treated with phosphate buffer. One to two weeks after the induction of periodontitis, the periodontal tissues were harvested for radiological evaluation (micro-CT), histological evaluation (HE staining and TRAP staining), and the evaluation of inflammatory cytokine production in the periodontal tissues and serum (quantitative reverse-transcription PCR, ELISA). The synthetic (+)-terrein-treated group suppressed alveolar bone resorption and the number of osteoclasts in the periodontal tissues compared to the control group (p &lt; 0.05). In addition, synthetic (+)-terrein significantly suppressed both mRNA expression of TNF-&alpha; in the periodontal tissues and the serum concentration of TNF-&alpha; (both p &lt; 0.05). In conclusion, we have demonstrated that synthetic (+)-terrein abrogates alveolar bone resorption via the suppression of TNF-&alpha; production and osteoclast differentiation in vivo. Therefore, we could expect potential clinical effects when using (+)-terrein on inflammatory bone resorption, including periodontitis

Study protocol : multicenter double-blind, randomized, placebo-controlled trial of rituximab for the treatment of childhood-onset early-stage uncomplicated frequently relapsing or steroid-dependent nephrotic syndrome (JSKDC10 trial)

Background: Eighty percent of children with idiopathic nephrotic syndrome respond well to steroid therapy, but up to 50% of patients with steroid-sensitive nephrotic syndrome exhibit frequently relapsing (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Several studies identified the chimeric anti-CD20 monoclonal antibody rituximab as an effective treatment for patients with complicated FRNS/SDNS. Recent studies suggested that rituximab could also be a first-line treatment for early-stage uncomplicated FRNS/SDNS, although further studies are required to confirm its efficacy and safety. Methods/design: We are conducting a multicenter, double-blind, randomized placebo controlled trial to investigate the efficacy and safety of rituximab for the treatment of childhood-onset early-stage uncomplicated FRNS/SDNS. Patients will be allocated to receive two 375 mg/m(2) doses (maximum dose: 500 mg) of either rituximab or placebo. Investigators are permitted to request the disclosure of a subject's allocation code if he or she exhibits treatment failure. Additionally, if placebo-treated subjects display early relapse (a sign of treatment failure), they have the option to receive rituximab in an unblinded phase. The primary endpoint is relapse-free survival during the observation period. Discussion: The results will provide important data on the use of rituximab for patients with uncomplicated FRNS/SDNS. In the future, rituximab treatment will enable most patients with uncomplicated FRNS/SDNS to discontinue or reduce steroid therapy without relapse, and it is possible that rituximab could represent an immunosuppressive therapy for these diseases