{"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118250","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/37081616","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=396816","label":"url"}],"paper_title":{"en":"Vascular Endothelial Function Is Associated with eGFR Slope in Female and Non-Smoking Male Individuals with Cardiovascular Risk Factors: A Pilot Study on the Predictive Value of FMD for Renal Prognosis.","ja":"Vascular Endothelial Function Is Associated with eGFR Slope in Female and Non-Smoking Male Individuals with Cardiovascular Risk Factors: A Pilot Study on the Predictive Value of FMD for Renal Prognosis."},"authors":{"en":[{"name":"Masuda Shiho"},{"name":"Hara Tomoyo"},{"name":"Yamagami Hiroki"},{"name":"Mitsui Yukari"},{"name":"Kurahashi Kiyoe"},{"name":"Yoshida Sumiko"},{"name":"Harada Takeshi"},{"name":"Otoda Toshiki"},{"name":"Yuasa Tomoyuki"},{"name":"Nakamura Shingen"},{"name":"Kuroda Akio"},{"name":"Endo Itsuro"},{"name":"Matsumoto Toshio"},{"name":"Matsuhisa Munehide"},{"name":"Abe Masahiro"},{"name":"Aihara Ken-ichi"}],"ja":[{"name":"桝田 志保"},{"name":"原 倫世"},{"name":"山上 紘規"},{"name":"Mitsui Yukari"},{"name":"倉橋 清衛"},{"name":"吉田 守美子"},{"name":"原田 武志"},{"name":"乙田 敏城"},{"name":"湯浅 智之"},{"name":"中村 信元"},{"name":"黒田 暁生"},{"name":"遠藤 逸朗"},{"name":"松本 俊夫"},{"name":"松久 宗英"},{"name":"安倍 正博"},{"name":"粟飯原 賢一"}]},"description":{"en":"In individuals with cardiovascular risk factors, evaluation of vascular endothelial function enables prediction of renal prognosis in females and non-smoking males.","ja":"In individuals with cardiovascular risk factors, evaluation of vascular endothelial function enables prediction of renal prognosis in females and non-smoking males."},"publication_date":"2023-04-19","publication_name":{"en":"Journal of Atherosclerosis and Thrombosis","ja":"Journal of Atherosclerosis and Thrombosis"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.5551/jat.63987"],"issn":["1880-3873"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118313","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36670994","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=395239","label":"url"}],"paper_title":{"en":"The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2.","ja":"The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2."},"authors":{"en":[{"name":"Higa Yoshiki"},{"name":"Hiasa Masahiro"},{"name":"Tenshin Hirofumi"},{"name":"Nakaue Emiko"},{"name":"Tanaka Mariko"},{"name":"Kim Sooha"},{"name":"Nakagawa Motosumi"},{"name":"Shimizu Sou"},{"name":"Tanimoto Kotaro"},{"name":"Teramachi Jumpei"},{"name":"Harada Takeshi"},{"name":"Oda Asuka"},{"name":"Oura Masahiro"},{"name":"Sogabe Kimiko"},{"name":"Hara Tomoyo"},{"name":"Sumitani Ryohei"},{"name":"Maruhashi Tomoko"},{"name":"Yamagami Hiroki"},{"name":"Endo Itsuro"},{"name":"Matsumoto Toshio"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"}],"ja":[{"name":"比嘉 佳基"},{"name":"日浅 雅博"},{"name":"天眞 寛文"},{"name":"中上 絵美子"},{"name":"田中 茉里子"},{"name":"金 秀河"},{"name":"中川 宗純"},{"name":"清水 宗"},{"name":"谷本 幸多朗"},{"name":"寺町 順平"},{"name":"原田 武志"},{"name":"Oda Asuka"},{"name":"大浦 雅博"},{"name":"曽我部 公子"},{"name":"Hara Tomoyo"},{"name":"住谷 龍平"},{"name":"Maruhashi Tomoko"},{"name":"山上 紘規"},{"name":"遠藤 逸朗"},{"name":"松本 俊夫"},{"name":"田中 栄二"},{"name":"安倍 正博"}]},"description":{"en":"Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.","ja":"Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating."},"publication_date":"2023-01-05","publication_name":{"en":"Antioxidants","ja":"Antioxidants"},"volume":"Vol.12","number":"No.1","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/antiox12010133"],"issn":["2076-3921"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36424386","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=395915","label":"url"}],"paper_title":{"en":"Osteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis.","ja":"Osteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis."},"authors":{"en":[{"name":"Dong Bingzi"},{"name":"Hiasa Masahiro"},{"name":"Higa Yoshiki"},{"name":"Ohnishi Yukiyo"},{"name":"Endo Itsuro"},{"name":"Kondo Takeshi"},{"name":"Takashi Yuichi"},{"name":"Tsoumpra Maria"},{"name":"Kainuma Risa"},{"name":"Sawatsubashi Shun"},{"name":"Kiyonari Hiroshi"},{"name":"Shioi Go"},{"name":"Sakaue Hiroshi"},{"name":"Nakashima Tomoki"},{"name":"Kato Shigeaki"},{"name":"Abe Masahiro"},{"name":"Fukumoto Seiji"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"Dong Bingzi"},{"name":"日浅 雅博"},{"name":"Higa Yoshiki"},{"name":"Ohnishi Yukiyo"},{"name":"遠藤 逸朗"},{"name":"近藤 剛史"},{"name":"髙士 祐一"},{"name":"Tsoumpra Maria"},{"name":"Kainuma Risa"},{"name":"沢津橋 俊"},{"name":"Kiyonari Hiroshi"},{"name":"Shioi Go"},{"name":"阪上 浩"},{"name":"Nakashima Tomoki"},{"name":"Kato Shigeaki"},{"name":"安倍 正博"},{"name":"福本 誠二"},{"name":"松本 俊夫"}]},"description":{"en":"did not exhibit any abnormalities. We demonstrate that osteoblast/osteocyte-derived IL-11 controls both osteogenesis and systemic adiposity in response to mechanical loading, an important insight for our understanding of osteoporosis and metabolic syndromes.","ja":"did not exhibit any abnormalities. We demonstrate that osteoblast/osteocyte-derived IL-11 controls both osteogenesis and systemic adiposity in response to mechanical loading, an important insight for our understanding of osteoporosis and metabolic syndromes."},"publication_date":"2022-11-23","publication_name":{"en":"Nature Communications","ja":"Nature Communications"},"volume":"Vol.13","number":"No.1","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/s41467-022-34869-3"],"issn":["2041-1723"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118258","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36244745","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=393955","label":"url"}],"paper_title":{"en":"Plasma Heparin Cofactor II Activity Is Inversely Associated with Hepatic Fibrosis of Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus.","ja":"Plasma Heparin Cofactor II Activity Is Inversely Associated with Hepatic Fibrosis of Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus."},"authors":{"en":[{"name":"Hara Tomoyo"},{"name":"Uemoto Ryoko"},{"name":"Sekine Akiko"},{"name":"Mitsui Yukari"},{"name":"Masuda Shiho"},{"name":"Yamagami Hiroki"},{"name":"Kurahashi Kiyoe"},{"name":"Yoshida Sumiko"},{"name":"Otoda Toshiki"},{"name":"Yuasa Tomoyuki"},{"name":"Kuroda Akio"},{"name":"Ikeda Yasumasa"},{"name":"Endo Itsuro"},{"name":"Honda Soichi"},{"name":"Yoshimoto Katsuhiko"},{"name":"Kondo Akira"},{"name":"Tamaki Toshiaki"},{"name":"Matsumoto Toshio"},{"name":"Matsuhisa Munehide"},{"name":"Abe Masahiro"},{"name":"Aihara Ken-ichi"}],"ja":[{"name":"原 倫世"},{"name":"Uemoto Ryoko"},{"name":"Sekine Akiko"},{"name":"Mitsui Yukari"},{"name":"桝田 志保"},{"name":"山上 紘規"},{"name":"倉橋 清衛"},{"name":"吉田 守美子"},{"name":"乙田 敏城"},{"name":"湯浅 智之"},{"name":"黒田 暁生"},{"name":"池田 康将"},{"name":"遠藤 逸朗"},{"name":"Honda Soichi"},{"name":"吉本 勝彦"},{"name":"Kondo Akira"},{"name":"玉置 俊晃"},{"name":"松本 俊夫"},{"name":"松久 宗英"},{"name":"安倍 正博"},{"name":"粟飯原 賢一"}]},"description":{"en":"Plasma HCII activity was inversely associated with clinical hepatic fibrosis indices including FIB-4 index, NFS and APRI and with the prevalence of advanced hepatic fibrosis in patients with T2DM. The results suggest that HCII can serve as a novel biomarker for assessment of hepatic fibrosis of NAFLD in patients with T2DM.","ja":"Multiple regression analysis including confounding factors showed that plasma HCII activity independently contributed to decreases in FIB-4 index (p<0.001), NFS (p<0.001) and APRI (p=0.004). In addition, logistic regression analysis for the prevalence of advanced hepatic fibrosis defined by the cutoff points of the clinical scores showed that plasma HCII activity was the sole and common negative factor for prevalence of advanced hepatic fibrosis (FIB-4 index: p=0.002, NFS: p=0.026 and APRI: p=0.012)."},"publication_date":"2022-10-14","publication_name":{"en":"Journal of Atherosclerosis and Thrombosis","ja":"Journal of Atherosclerosis and Thrombosis"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.5551/jat.63752"],"issn":["1880-3873"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/117150","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390573947533793024/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=395394","label":"url"}],"paper_title":{"en":"Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival","ja":"Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival"},"authors":{"en":[{"name":"Shimizu Sou"},{"name":"Teramachi Jumpei"},{"name":"Harada Takeshi"},{"name":"Hiasa Masahiro"},{"name":"Tenshin Hirofumi"},{"name":"Oda A"},{"name":"Seki A"},{"name":"Inoue Y"},{"name":"Tanimoto Kotaro"},{"name":"Higa Yoshiki"},{"name":"Oura M"},{"name":"Sogabe K"},{"name":"Harada Takeshi"},{"name":"Sumitani Ryohei"},{"name":"Maruhashi T"},{"name":"Yamagami H"},{"name":"Sawa Y"},{"name":"Endo Itsuro"},{"name":"Tsuneyama K"},{"name":"Matsumoto Toshio"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"}],"ja":[{"name":"清水 宗"},{"name":"寺町 順平"},{"name":"原田 武志"},{"name":"日浅 雅博"},{"name":"天眞 寛文"},{"name":"Oda A"},{"name":"Seki A"},{"name":"Inoue Y"},{"name":"谷本 幸多朗"},{"name":"比嘉 佳基"},{"name":"Oura M"},{"name":"Sogabe K"},{"name":"原田 武志"},{"name":"住谷 龍平"},{"name":"Maruhashi T"},{"name":"Yamagami H"},{"name":"Sawa Y"},{"name":"遠藤 逸朗"},{"name":"Tsuneyama K"},{"name":"松本 俊夫"},{"name":"田中 栄二"},{"name":"安倍 正博"}]},"description":{"en":"
The serine/threonine kinase TAK1 is constitutively overexpressed and auto-phosphorylated in multiple myeloma (MM) cells. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which dephosphorylates proteins phosphorylated by various serine/threonine kinases to regulate multiple cellular functions. We recently reported that the serine/threonine kinase TGF-β-activated kinase-1 (TAK1) is highly expressed and auto-phosphorylated to mediate critical growth and survival signaling in MM cells. We demonstrate here that regulation of PP2A activity inversely affects the phosphorylation levels of TAK1 in MM cells, and that MM cells aberrantly overexpress cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor for PP2A. CIP2A gene silencing as well as treatment with the CIP2A inhibitor TD52 potently induced MM cell death along with suppression of TAK1 expression in MM cells. These results suggest the critical role of PP2A inactivation via CIP2A upregulation in TAK1 phosphorylation and its protein expression and thereby MM cell growth and survival, posing the CIP2A-PP2A axis as an important therapeutic target.
","ja":"The serine/threonine kinase TAK1 is constitutively overexpressed and auto-phosphorylated in multiple myeloma (MM) cells. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which dephosphorylates proteins phosphorylated by various serine/threonine kinases to regulate multiple cellular functions. We recently reported that the serine/threonine kinase TGF-β-activated kinase-1 (TAK1) is highly expressed and auto-phosphorylated to mediate critical growth and survival signaling in MM cells. We demonstrate here that regulation of PP2A activity inversely affects the phosphorylation levels of TAK1 in MM cells, and that MM cells aberrantly overexpress cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor for PP2A. CIP2A gene silencing as well as treatment with the CIP2A inhibitor TD52 potently induced MM cell death along with suppression of TAK1 expression in MM cells. These results suggest the critical role of PP2A inactivation via CIP2A upregulation in TAK1 phosphorylation and its protein expression and thereby MM cell growth and survival, posing the CIP2A-PP2A axis as an important therapeutic target.
"},"publication_date":"2022-06-17","publication_name":{"en":"International Journal of Myeloma","ja":"International Journal of Myeloma"},"volume":"Vol.12","number":"No.2","starting_page":"14","ending_page":"23","languages":["eng"],"referee":true,"identifiers":{"doi":["10.57352/ijm.12.2_14"],"issn":["2187-3143"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116715","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/34788982","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=386812","label":"url"}],"paper_title":{"en":"Mechanical unloading aggravates bone destruction and tumor expansion in myeloma.","ja":"Mechanical unloading aggravates bone destruction and tumor expansion in myeloma."},"authors":{"en":[{"name":"Tanimoto Kotaro"},{"name":"Hiasa Masahiro"},{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Oda Asuka"},{"name":"Harada Takeshi"},{"name":"Higa Yoshiki"},{"name":"Sogabe Kimiko"},{"name":"Oura Masahiro"},{"name":"Sumitani Ryohei"},{"name":"Hara Tomoyo"},{"name":"Endo Itsuro"},{"name":"Matsumoto Toshio"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"}],"ja":[{"name":"谷本 幸多朗"},{"name":"日浅 雅博"},{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"Oda Asuka"},{"name":"原田 武志"},{"name":"比嘉 佳基"},{"name":"曽我部 公子"},{"name":"Oura Masahiro"},{"name":"住谷 龍平"},{"name":"原 倫世"},{"name":"遠藤 逸朗"},{"name":"松本 俊夫"},{"name":"田中 栄二"},{"name":"安倍 正博"}]},"publication_date":"2022-03-01","publication_name":{"en":"Haematologica","ja":"Haematologica"},"volume":"Vol.107","number":"No.3","starting_page":"744","ending_page":"749","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3324/haematol.2021.278295"],"issn":["1592-8721"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/117260","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/35079379","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=386837","label":"url"}],"paper_title":{"en":"TGF-β-activated kinase-1 inhibitor LL-Z1640-2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF-α and RANKL expression.","ja":"TGF-β-activated kinase-1 inhibitor LL-Z1640-2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF-α and RANKL expression."},"authors":{"en":[{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Ashtar Mohannad"},{"name":"Hiasa Masahiro"},{"name":"Inoue Yusuke"},{"name":"Oda Asuka"},{"name":"Tanimoto Kotaro"},{"name":"Shimizu Sou"},{"name":"Higa Yoshiki"},{"name":"Harada Takeshi"},{"name":"Oura Masahiro"},{"name":"Sogabe Kimiko"},{"name":"Hara Tomoyo"},{"name":"Sumitani Ryohei"},{"name":"Maruhashi Tomoko"},{"name":"Sebe Mayu"},{"name":"Tsutsumi Rie"},{"name":"Sakaue Hiroshi"},{"name":"Endo Itsuro"},{"name":"Matsumoto Toshio"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"}],"ja":[{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"ASHTAR MOHANNAD"},{"name":"日浅 雅博"},{"name":"井上 雄介"},{"name":"Oda Asuka"},{"name":"谷本 幸多朗"},{"name":"清水 宗"},{"name":"比嘉 佳基"},{"name":"原田 武志"},{"name":"大浦 雅博"},{"name":"曽我部 公子"},{"name":"原 倫世"},{"name":"住谷 龍平"},{"name":"丸橋 朋子"},{"name":"Sebe Mayu"},{"name":"堤 理恵"},{"name":"阪上 浩"},{"name":"遠藤 逸朗"},{"name":"松本 俊夫"},{"name":"田中 栄二"},{"name":"安倍 正博"}]},"description":{"en":"TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome-mediated inflammation and RANKL-induced osteoclastic bone destruction in joints alongside its potent suppression of TNF-α and IL-6 production and proteinase-mediated pathological processes in RA.","ja":"TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome-mediated inflammation and RANKL-induced osteoclastic bone destruction in joints alongside its potent suppression of TNF-α and IL-6 production and proteinase-mediated pathological processes in RA."},"publication_date":"2022-01-19","publication_name":{"en":"Clinical & translational immunology","ja":"Clinical & translational immunology"},"volume":"Vol.11","number":"No.1","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/cti2.1371"],"issn":["2050-0068"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116283","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/34458594","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=381536","label":"url"}],"paper_title":{"en":"Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span.","ja":"Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span."},"authors":{"en":[{"name":"Takashi Yuichi"},{"name":"Sawatsubashi Shun"},{"name":"Endo Itsuro"},{"name":"Ohnishi Yukiyo"},{"name":"Abe Masahiro"},{"name":"Matsuhisa Munehide"},{"name":"Kawanami Daiji"},{"name":"Matsumoto Toshio"},{"name":"Fukumoto Seiji"}],"ja":[{"name":"髙士 祐一"},{"name":"沢津橋 俊"},{"name":"遠藤 逸朗"},{"name":"Ohnishi Yukiyo"},{"name":"安倍 正博"},{"name":"松久 宗英"},{"name":"Kawanami Daiji"},{"name":"松本 俊夫"},{"name":"福本 誠二"}]},"description":{"en":"Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of , whose product works to increase FGF23 production . In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level . We generated late-osteoblast/osteocyte-specific -knockout mice ( ) by crossing the and the floxed mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of in the bone, the body weight and life span. A selective ablation of aborted the increase of serum active full-length FGF23 and the enhanced expression of in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span.","ja":"Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of , whose product works to increase FGF23 production . In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level . We generated late-osteoblast/osteocyte-specific -knockout mice ( ) by crossing the and the floxed mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of in the bone, the body weight and life span. A selective ablation of aborted the increase of serum active full-length FGF23 and the enhanced expression of in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span."},"publication_date":"2021-08-17","publication_name":{"en":"Biochemistry and Biophysics Reports","ja":"Biochemistry and Biophysics Reports"},"volume":"Vol.27","starting_page":"101107","ending_page":"101107","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.bbrep.2021.101107"],"issn":["2405-5808"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116545","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/34043882","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=376531","label":"url"}],"paper_title":{"en":"Plasma Heparin Cofactor II Activity Is Inversely Associated with Albuminuria and Its Annual Deterioration in Patients with Diabetes.","ja":"Plasma Heparin Cofactor II Activity Is Inversely Associated with Albuminuria and Its Annual Deterioration in Patients with Diabetes."},"authors":{"en":[{"name":"Hara Tomoyo"},{"name":"Uemoto Ryoko"},{"name":"Sekine Akiko"},{"name":"Mitsui Yukari"},{"name":"Masuda Shiho"},{"name":"Kurahashi Kiyoe"},{"name":"Yoshida Sumiko"},{"name":"Otoda Toshiki"},{"name":"Yuasa Tomoyuki"},{"name":"Kuroda Akio"},{"name":"Ikeda Yasumasa"},{"name":"Endo Itsuro"},{"name":"Honda Soichi"},{"name":"Yoshimoto Katsuhiko"},{"name":"Kondo Akira"},{"name":"Tamaki Toshiaki"},{"name":"Matsumoto Toshio"},{"name":"Matsuhisa Munehide"},{"name":"Abe Masahiro"},{"name":"Aihara Ken-ichi"}],"ja":[{"name":"原 倫世"},{"name":"Uemoto Ryoko"},{"name":"Sekine Akiko"},{"name":"Mitsui Yukari"},{"name":"桝田 志保"},{"name":"倉橋 清衛"},{"name":"吉田 守美子"},{"name":"乙田 敏城"},{"name":"湯浅 智之"},{"name":"黒田 暁生"},{"name":"池田 康将"},{"name":"遠藤 逸朗"},{"name":"Honda Soichi"},{"name":"吉本 勝彦"},{"name":"Kondo Akira"},{"name":"玉置 俊晃"},{"name":"松本 俊夫"},{"name":"松久 宗英"},{"name":"安倍 正博"},{"name":"粟飯原 賢一"}]},"description":{"en":"The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early-stage DKD development, as represented by albuminuria.","ja":"The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early-stage DKD development, as represented by albuminuria."},"publication_date":"2021-05-27","publication_name":{"en":"Journal of Diabetes Investigation","ja":"Journal of Diabetes Investigation"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/jdi.13602"],"issn":["2040-1124"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116529","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32273474","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=377110","label":"url"}],"paper_title":{"en":"TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma","ja":"TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma"},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Tenshin Hirofumi"},{"name":"Hiasa Masahiro"},{"name":"Oda Asuka"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Harada Takeshi"},{"name":"Nakamura Shingen"},{"name":"Ashtar Mohannad"},{"name":"Shimizu Sou"},{"name":"Iwasa Masami"},{"name":"Sogabe Kimiko"},{"name":"Oura Masahiro"},{"name":"Fujii Shiroh"},{"name":"Kagawa Kumiko"},{"name":"Miki Hirokazu"},{"name":"Endo Itsuro"},{"name":"Haneji Tatsuji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"寺町 順平"},{"name":"天眞 寛文"},{"name":"日浅 雅博"},{"name":"小田 明日香"},{"name":"Ariunzaya Bat-Erdene"},{"name":"原田 武志"},{"name":"中村 信元"},{"name":"ASHTAR MOHANNAD"},{"name":"清水 宗"},{"name":"岩佐 昌美"},{"name":"曽我部 公子"},{"name":"大浦 雅博"},{"name":"藤井 志朗"},{"name":"賀川 久美子"},{"name":"三木 浩和"},{"name":"遠藤 逸朗"},{"name":"羽地 達次"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-β-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.","ja":"Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-β-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM."},"publication_date":"2021-05-01","publication_name":{"en":"Haematologica","ja":"Haematologica"},"volume":"Vol.106","number":"No.5","starting_page":"1401","ending_page":"1413","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3324/haematol.2019.234476"],"issn":["1592-8721"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/33057808","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=374515","label":"url"}],"paper_title":{"en":"RANKL as a target for the treatment of osteoporosis","ja":"RANKL as a target for the treatment of osteoporosis"},"authors":{"en":[{"name":"Matsumoto Toshio"},{"name":"Endo Itsuro"}],"ja":[{"name":"松本 俊夫"},{"name":"遠藤 逸朗"}]},"description":{"en":"Osteoporosis is characterized by compromised bone strength, predisposing to an increased risk of fracture. Because bone is constantly remodeled, and bone mass and structure are determined by the balance between bone resorption and bone formation, it is important to maintain normal bone turnover. Therefore, therapies that reduce bone resorption have been the mainstream of osteoporosis treatment. Receptor activator of nuclear factor-kappa B ligand (RANKL)-RANK signaling was found to play a pivotal role in the regulation of osteoclastic bone resorption, and inhibition of RANKL-RANK system has become an important therapeutic target for the treatment of osteoporosis. Denosumab, a fully human monoclonal anti-RANKL neutralizing antibody, is developed as a drug for the treatment of osteoporosis. This review summarized pharmacokinetic and pharmacodynamic properties of denosumab, clinical studies including phase 2 dose-ranging and its extension study, phase 3 fracture prevention study (FREEDOM) with extension up to 10 years, studies on male osteoporosis (ADAMO study), and on glucocorticoid-induced osteoporosis, along with relevant clinical studies in Japan. In addition, mechanism of denosumab action that can explain its long-term sustained effects, combination and sequential treatment as well as the problems in discontinuation of denosumab, and finally safety of denosumab therapy is discussed.","ja":"Osteoporosis is characterized by compromised bone strength, predisposing to an increased risk of fracture. Because bone is constantly remodeled, and bone mass and structure are determined by the balance between bone resorption and bone formation, it is important to maintain normal bone turnover. Therefore, therapies that reduce bone resorption have been the mainstream of osteoporosis treatment. Receptor activator of nuclear factor-kappa B ligand (RANKL)-RANK signaling was found to play a pivotal role in the regulation of osteoclastic bone resorption, and inhibition of RANKL-RANK system has become an important therapeutic target for the treatment of osteoporosis. Denosumab, a fully human monoclonal anti-RANKL neutralizing antibody, is developed as a drug for the treatment of osteoporosis. This review summarized pharmacokinetic and pharmacodynamic properties of denosumab, clinical studies including phase 2 dose-ranging and its extension study, phase 3 fracture prevention study (FREEDOM) with extension up to 10 years, studies on male osteoporosis (ADAMO study), and on glucocorticoid-induced osteoporosis, along with relevant clinical studies in Japan. In addition, mechanism of denosumab action that can explain its long-term sustained effects, combination and sequential treatment as well as the problems in discontinuation of denosumab, and finally safety of denosumab therapy is discussed."},"publication_date":"2021-01","publication_name":{"en":"Journal of Bone and Mineral Metabolism","ja":"Journal of Bone and Mineral Metabolism"},"volume":"Vol.39","number":"No.1","starting_page":"91","ending_page":"105","languages":["eng"],"referee":true,"invited":true,"identifiers":{"doi":["10.1007/s00774-020-01153-7"],"issn":["1435-5604"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31420749","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=358616","label":"url"}],"paper_title":{"en":"Circulating FGF23 is not associated with cardiac dysfunction, atherosclerosis, infection or inflammation in hemodialysis patients.","ja":"Circulating FGF23 is not associated with cardiac dysfunction, atherosclerosis, infection or inflammation in hemodialysis patients."},"authors":{"en":[{"name":"Takashi Yuichi"},{"name":"Wakino Shu"},{"name":"Minakuchi Hitoshi"},{"name":"Ishizu Masashi"},{"name":"Kuroda Akio"},{"name":"Shima Hisato"},{"name":"Tashiro Manabu"},{"name":"Miya Keiko"},{"name":"Okada Kazuyoshi"},{"name":"Minakuchi Jun"},{"name":"Kawashima Shu"},{"name":"Matsuhisa Munehide"},{"name":"Matsumoto Toshio"},{"name":"Fukumoto Seiji"}],"ja":[{"name":"髙士 祐一"},{"name":"Wakino Shu"},{"name":"Minakuchi Hitoshi"},{"name":"石津 将"},{"name":"黒田 暁生"},{"name":"Shima Hisato"},{"name":"Tashiro Manabu"},{"name":"Miya Keiko"},{"name":"Okada Kazuyoshi"},{"name":"Minakuchi Jun"},{"name":"Kawashima Shu"},{"name":"松久 宗英"},{"name":"松本 俊夫"},{"name":"福本 誠二"}]},"description":{"en":"Fibroblast growth factor (FGF) 23 is a bone-derived hormone regulating serum inorganic phosphate (Pi) concentration. FGF23 is also involved in the development of chronic kidney disease (CKD)-mineral and bone disorder. Serum FGF23 concentration begins to increase early in the progression of CKD and can be remarkably high in hemodialysis patients with end-stage renal disease. It has been reported that high FGF23 concentration is a risk factor for cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. FGF23 was also shown to induce cardiac hypertrophy directly acting on cardiomyocytes. However, it is still controversial whether high FGF23 is causing cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. In the current study, we investigated whether FGF23 concentration is associated with cardiac dysfunction, atherosclerosis, infection or systemic inflammation in Japanese hemodialysis patients. We recruited 119 hemodialysis patients and examined the association between serum FGF23 concentration and several parameters concerning mineral metabolism, cardiac dysfunction, atherosclerosis, infection, and systemic inflammation. Serum FGF23 concentration was independently associated with serum calcium and Pi concentration (β = 0.276, p < 0.001; β = 0.689, p < 0.001). However, serum FGF23 concentration was not associated with parameters of cardiac dysfunction, atherosclerosis, infection, and systemic inflammation, either. Our results do not support the hypothesis that high FGF23 in dialysis patients is the cause of cardiac dysfunction, atherosclerosis, infection or systemic inflammation.","ja":"Fibroblast growth factor (FGF) 23 is a bone-derived hormone regulating serum inorganic phosphate (Pi) concentration. FGF23 is also involved in the development of chronic kidney disease (CKD)-mineral and bone disorder. Serum FGF23 concentration begins to increase early in the progression of CKD and can be remarkably high in hemodialysis patients with end-stage renal disease. It has been reported that high FGF23 concentration is a risk factor for cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. FGF23 was also shown to induce cardiac hypertrophy directly acting on cardiomyocytes. However, it is still controversial whether high FGF23 is causing cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. In the current study, we investigated whether FGF23 concentration is associated with cardiac dysfunction, atherosclerosis, infection or systemic inflammation in Japanese hemodialysis patients. We recruited 119 hemodialysis patients and examined the association between serum FGF23 concentration and several parameters concerning mineral metabolism, cardiac dysfunction, atherosclerosis, infection, and systemic inflammation. Serum FGF23 concentration was independently associated with serum calcium and Pi concentration (β = 0.276, p < 0.001; β = 0.689, p < 0.001). However, serum FGF23 concentration was not associated with parameters of cardiac dysfunction, atherosclerosis, infection, and systemic inflammation, either. Our results do not support the hypothesis that high FGF23 in dialysis patients is the cause of cardiac dysfunction, atherosclerosis, infection or systemic inflammation."},"publication_date":"2020","publication_name":{"en":"Journal of Bone and Mineral Metabolism","ja":"Journal of Bone and Mineral Metabolism"},"volume":"Vol.38","number":"No.1","starting_page":"70-77","ending_page":"70-77","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s00774-019-01027-7"],"issn":["1435-5604"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32422295","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=374514","label":"url"}],"paper_title":{"en":"MInodronate","ja":"MInodronate"},"authors":{"en":[{"name":"Matsumoto Toshio"},{"name":"Endo Itsuro"}],"ja":[{"name":"松本 俊夫"},{"name":"遠藤 逸朗"}]},"description":{"en":"Minodronate is a heterocyclic nitrogen-containing bisphosphonate with high potency in inhibiting bone resorption, and is developed for clinical use in Japan. Minodronate has very high potency in inhibiting farnesyl pyrophosphate synthase, and shows lower affinity for bone matrix hydroxyapatite at both neutral and acidic pH. As a result, small amount of minodronate is deposited in bone but can exert strong anti-resorptive activity in vivo. In this review on minodronate, we summarize the mechanism of action, physico-chemical properties, effects on bone quality in animals, and effects on bone turnover, bone mineral density and fracture prevention, as well as safety in the treatment of patients with osteoporosis.","ja":"Minodronate is a heterocyclic nitrogen-containing bisphosphonate with high potency in inhibiting bone resorption, and is developed for clinical use in Japan. Minodronate has very high potency in inhibiting farnesyl pyrophosphate synthase, and shows lower affinity for bone matrix hydroxyapatite at both neutral and acidic pH. As a result, small amount of minodronate is deposited in bone but can exert strong anti-resorptive activity in vivo. In this review on minodronate, we summarize the mechanism of action, physico-chemical properties, effects on bone quality in animals, and effects on bone turnover, bone mineral density and fracture prevention, as well as safety in the treatment of patients with osteoporosis."},"publication_date":"2020-08","publication_name":{"en":"Bone","ja":"Bone"},"volume":"Vol.137","starting_page":"115432","ending_page":"115432","languages":["eng"],"referee":true,"invited":true,"identifiers":{"doi":["10.1016/j.bone.2020.115432"],"issn":["1873-2763"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115041","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32283857","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=365352","label":"url"}],"paper_title":{"en":"The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat.","ja":"The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat."},"authors":{"en":[{"name":"Ashtar Mohannad"},{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Hiasa Masahiro"},{"name":"Oda Asuka"},{"name":"Tanimoto Kotaro"},{"name":"Shimizu Sou"},{"name":"Higa Yoshiki"},{"name":"Harada Takeshi"},{"name":"Oura Masahiro"},{"name":"Sogabe Kimiko"},{"name":"Nakamura Shingen"},{"name":"Fujii Shiroh"},{"name":"Sumitani Ryohei"},{"name":"Miki Hirokazu"},{"name":"Udaka Kengo"},{"name":"Takahashi Mamiko"},{"name":"Kagawa Kumiko"},{"name":"Endo Itsuro"},{"name":"Tanaka Eiji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"ASHTAR MOHANNAD"},{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"Ariunzaya Bat-Erdene"},{"name":"日浅 雅博"},{"name":"Oda Asuka"},{"name":"谷本 幸多朗"},{"name":"清水 宗"},{"name":"比嘉 佳基"},{"name":"原田 武志"},{"name":"大浦 雅博"},{"name":"曽我部 公子"},{"name":"中村 信元"},{"name":"藤井 志朗"},{"name":"住谷 龍平"},{"name":"三木 浩和"},{"name":"宇髙 憲吾"},{"name":"Takahashi Mamiko"},{"name":"賀川 久美子"},{"name":"遠藤 逸朗"},{"name":"田中 栄二"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox's anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.","ja":"Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox's anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage."},"publication_date":"2020-04-09","publication_name":{"en":"Cancers","ja":"Cancers"},"volume":"Vol.12","number":"No.4","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/cancers12040929"],"issn":["2072-6694"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31940280","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=363547","label":"url"}],"paper_title":{"en":"Dystrobrevin alpha gene is a direct target of the vitamin D receptor in muscle.","ja":"Dystrobrevin alpha gene is a direct target of the vitamin D receptor in muscle."},"authors":{"en":[{"name":"Tsoumpra Maria"},{"name":"Sawatsubashi Shun"},{"name":"Imamura Michihiro"},{"name":"Fukumoto Seiji"},{"name":"Takeda Shin'ichi"},{"name":"Matsumoto Toshio"},{"name":"Aoki Yoshitsugu"}],"ja":[{"name":"Tsoumpra Maria"},{"name":"沢津橋 俊"},{"name":"今村 道博"},{"name":"福本 誠二"},{"name":"武田 伸一"},{"name":"松本 俊夫"},{"name":"青木 吉嗣"}]},"description":{"en":"The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response elements (VDRE) and activate target genes. Upregulation of VDR in murine skeletal muscle cells occurs concomitantly with transcriptional regulation of key myogenic factors upon VD3 administration, reinforcing the notion that VD3 exerts beneficial effects on muscle. Herein we elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a member of dystrophin-associated protein complex (DAPC). In C2C12 cells, Dtna and VDR gene and protein expression were upregulated by 1-50 nM of VD3 during all stages of myogenic differentiation. In the dystrophic-derived H2K-mdx52 cells, upregulation of DTNA by VD3 occurred upon co-transfection of VDR and RXR expression vectors. Silencing of MyoD1, an E-box binding myogenic transcription factor, did not alter the VD3-mediated Dtna induction, but Vdr silencing abolished this effect. We also demonstrated that VD3 administration enhanced the muscle-specific Dtna promoter activity in presence of VDR/RXR only. Through site-directed mutagenesis and chromatin immunoprecipitation assays, we have validated a VDRE site in Dtna promoter in myogenic cells. We have thus proved that the positive regulation of Dtna by VD3 observed during in vitro murine myogenic differentiation is VDR mediated and specific. The current study reveals a novel mechanism of VDR-mediated regulation for Dtna, which may be positively explored in treatments aiming to stabilize the DAPC in musculoskeletal diseases.","ja":"The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response elements (VDRE) and activate target genes. Upregulation of VDR in murine skeletal muscle cells occurs concomitantly with transcriptional regulation of key myogenic factors upon VD3 administration, reinforcing the notion that VD3 exerts beneficial effects on muscle. Herein we elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a member of dystrophin-associated protein complex (DAPC). In C2C12 cells, Dtna and VDR gene and protein expression were upregulated by 1-50 nM of VD3 during all stages of myogenic differentiation. In the dystrophic-derived H2K-mdx52 cells, upregulation of DTNA by VD3 occurred upon co-transfection of VDR and RXR expression vectors. Silencing of MyoD1, an E-box binding myogenic transcription factor, did not alter the VD3-mediated Dtna induction, but Vdr silencing abolished this effect. We also demonstrated that VD3 administration enhanced the muscle-specific Dtna promoter activity in presence of VDR/RXR only. Through site-directed mutagenesis and chromatin immunoprecipitation assays, we have validated a VDRE site in Dtna promoter in myogenic cells. We have thus proved that the positive regulation of Dtna by VD3 observed during in vitro murine myogenic differentiation is VDR mediated and specific. The current study reveals a novel mechanism of VDR-mediated regulation for Dtna, which may be positively explored in treatments aiming to stabilize the DAPC in musculoskeletal diseases."},"publication_date":"2020-04","publication_name":{"en":"Journal of Molecular Endocrinology","ja":"Journal of Molecular Endocrinology"},"volume":"Vol.64","number":"No.3","starting_page":"195","ending_page":"208","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1530/JME-19-0229"],"issn":["1479-6813"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32020289","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=363545","label":"url"}],"paper_title":{"en":"Management manual for cancer treatment-induced bone loss (CTIBL): position statement of the JSBMR.","ja":"Management manual for cancer treatment-induced bone loss (CTIBL): position statement of the JSBMR."},"authors":{"en":[{"name":"Fukumoto Seiji"},{"name":"Soen Satoshi"},{"name":"Taguchi Tetsuya"},{"name":"Ishikawa Takashi"},{"name":"Matsushima Hisashi"},{"name":"Terauchi Masakazu"},{"name":"Horie Shigeo"},{"name":"Yoneda Toshiyuki"},{"name":"Sugimoto Toshitsugu"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"福本 誠二"},{"name":"Soen Satoshi"},{"name":"Taguchi Tetsuya"},{"name":"Ishikawa Takashi"},{"name":"Matsushima Hisashi"},{"name":"Terauchi Masakazu"},{"name":"Horie Shigeo"},{"name":"Yoneda Toshiyuki"},{"name":"Sugimoto Toshitsugu"},{"name":"松本 俊夫"}]},"description":{"en":"Androgen deprivation therapy and aromatase inhibitors are known to cause a decrease in bone mineral density and an increase in fractures. Patients receiving these treatments have been shown to have a fracture risk equal to or greater than that of patients with osteoporosis with prevalent fractures. This manual was created to prevent fractures in patients with cancer treatment-induced bone loss with high fracture risks who cannot be treated under the current Japanese guideline for the prevention and treatment of osteoporosis. This manual recommends drug treatment for patients with BMD - 2.0 T score < - 1.5 with the family history of hip fracture or 15% or more 10-year probability of major osteoporotic fractures by FRAX; or in patients with BMD T score < - 2.0. It is important to verify whether the use of this manual can reduce fractures and improve the quality of life of patients with cancer treatment-induced bone loss by prospective studies.","ja":"Androgen deprivation therapy and aromatase inhibitors are known to cause a decrease in bone mineral density and an increase in fractures. Patients receiving these treatments have been shown to have a fracture risk equal to or greater than that of patients with osteoporosis with prevalent fractures. This manual was created to prevent fractures in patients with cancer treatment-induced bone loss with high fracture risks who cannot be treated under the current Japanese guideline for the prevention and treatment of osteoporosis. This manual recommends drug treatment for patients with BMD - 2.0 T score < - 1.5 with the family history of hip fracture or 15% or more 10-year probability of major osteoporotic fractures by FRAX; or in patients with BMD T score < - 2.0. It is important to verify whether the use of this manual can reduce fractures and improve the quality of life of patients with cancer treatment-induced bone loss by prospective studies."},"publication_date":"2020-02-04","publication_name":{"en":"Journal of Bone and Mineral Metabolism","ja":"Journal of Bone and Mineral Metabolism"},"volume":"Vol.38","number":"No.2","starting_page":"141","ending_page":"144","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s00774-020-01087-0"],"issn":["1435-5604"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31797064","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=361583","label":"url"}],"paper_title":{"en":"How do we sense phosphate to regulate serum phosphate level?","ja":"How do we sense phosphate to regulate serum phosphate level?"},"authors":{"en":[{"name":"Fukumoto Seiji"},{"name":"Takashi Yuichi"},{"name":"Tsoumpra Maria"},{"name":"Sawatsubashi Shun"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"福本 誠二"},{"name":"髙士 祐一"},{"name":"Tsoumpra Maria"},{"name":"沢津橋 俊"},{"name":"松本 俊夫"}]},"description":{"en":"Abnormal phosphate levels result in several pathological conditions such as rickets/osteomalacia and ectopic calcification indicating that there must be a system that regulates phosphate level within a narrow range. FGF23 has been shown to be an essential hormone regulating serum phosphate level. FGF23 binds to Klotho-FGF receptor complex to reduce serum phosphate level. Several reports suggested that FGF receptor is involved in the regulation of FGF23 production. It has been also shown that high extracellular phosphate can activate several intracellular signaling pathways. However, it has been unclear whether and how phosphate regulates FGF23 production in vivo. Our recent results indicate that high extracellular phosphate directly activates FGF receptor 1 and the downstream intracellular signaling enhances FGF23 production. Thus, there is a negative feedback system for the regulation of serum phosphate level involving FGF receptor and FGF23. We propose that FGF receptor works at least as one of phosphate sensors in the maintenance of serum phosphate level.","ja":"Abnormal phosphate levels result in several pathological conditions such as rickets/osteomalacia and ectopic calcification indicating that there must be a system that regulates phosphate level within a narrow range. FGF23 has been shown to be an essential hormone regulating serum phosphate level. FGF23 binds to Klotho-FGF receptor complex to reduce serum phosphate level. Several reports suggested that FGF receptor is involved in the regulation of FGF23 production. It has been also shown that high extracellular phosphate can activate several intracellular signaling pathways. However, it has been unclear whether and how phosphate regulates FGF23 production in vivo. Our recent results indicate that high extracellular phosphate directly activates FGF receptor 1 and the downstream intracellular signaling enhances FGF23 production. Thus, there is a negative feedback system for the regulation of serum phosphate level involving FGF receptor and FGF23. We propose that FGF receptor works at least as one of phosphate sensors in the maintenance of serum phosphate level."},"publication_date":"2020-01-03","publication_name":{"en":"Journal of Bone and Mineral Metabolism","ja":"Journal of Bone and Mineral Metabolism"},"volume":"Vol.38","number":"No.1","starting_page":"1","ending_page":"6","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s00774-019-01066-0"],"issn":["1435-5604"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115088","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31257147","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=361179","label":"url"}],"paper_title":{"en":"Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases.","ja":"Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases."},"authors":{"en":[{"name":"Tsoumpra Maria"},{"name":"Fukumoto Seiji"},{"name":"Matsumoto Toshio"},{"name":"Takeda Shin'ichi"},{"name":"Wood J. A. Matthew"},{"name":"Aoki Yoshitsugu"}],"ja":[{"name":"Tsoumpra Maria"},{"name":"福本 誠二"},{"name":"松本 俊夫"},{"name":"武田 伸一"},{"name":"Wood J. A. Matthew"},{"name":"青木 吉嗣"}]},"description":{"en":"Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle degeneration, caused by the absence of dystrophin. Exon skipping by antisense oligonucleotides (ASOs) has recently gained recognition as therapeutic approach in DMD. Conjugation of a peptide to the phosphorodiamidate morpholino backbone (PMO) of ASOs generated the peptide-conjugated PMOs (PPMOs) that exhibit a dramatically improved pharmacokinetic profile. When tested in animal models, PPMOs demonstrate effective exon skipping in target muscles and prolonged duration of dystrophin restoration after a treatment regime. Herein we summarize the main pathophysiological features of DMD and the emergence of PPMOs as promising exon skipping agents aiming to rescue defective gene expression in DMD and other neuromuscular diseases. The listed PPMO laboratory findings correspond to latest trends in the field and highlight the obstacles that must be overcome prior to translating the animal-based research into clinical trials tailored to the needs of patients suffering from neuromuscular diseases.","ja":"Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle degeneration, caused by the absence of dystrophin. Exon skipping by antisense oligonucleotides (ASOs) has recently gained recognition as therapeutic approach in DMD. Conjugation of a peptide to the phosphorodiamidate morpholino backbone (PMO) of ASOs generated the peptide-conjugated PMOs (PPMOs) that exhibit a dramatically improved pharmacokinetic profile. When tested in animal models, PPMOs demonstrate effective exon skipping in target muscles and prolonged duration of dystrophin restoration after a treatment regime. Herein we summarize the main pathophysiological features of DMD and the emergence of PPMOs as promising exon skipping agents aiming to rescue defective gene expression in DMD and other neuromuscular diseases. The listed PPMO laboratory findings correspond to latest trends in the field and highlight the obstacles that must be overcome prior to translating the animal-based research into clinical trials tailored to the needs of patients suffering from neuromuscular diseases."},"publication_date":"2019-06-27","publication_name":{"en":"EBioMedicine","ja":"EBioMedicine"},"volume":"Vol.45","starting_page":"630","ending_page":"645","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ebiom.2019.06.036"],"issn":["2352-3964"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/113621","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31097591","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=352089","label":"url"}],"paper_title":{"en":"Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation","ja":"Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation"},"authors":{"en":[{"name":"Takashi Yuichi"},{"name":"Kosako Hidetaka"},{"name":"Sawatsubashi Shun"},{"name":"Kinoshita Yuka"},{"name":"Ito Nobuaki"},{"name":"Tsoumpra K. Maria"},{"name":"Nangaku Masaomi"},{"name":"Abe Masahiro"},{"name":"Matsuhisa Munehide"},{"name":"Kato Shigeaki"},{"name":"Matsumoto Toshio"},{"name":"Fukumoto Seiji"}],"ja":[{"name":"髙士 祐一"},{"name":"小迫 英尊"},{"name":"沢津橋 俊"},{"name":"木下 祐加"},{"name":"伊東 伸朗"},{"name":"Tsoumpra K. Maria"},{"name":"南学 正臣"},{"name":"安倍 正博"},{"name":"松久 宗英"},{"name":"加藤 茂明"},{"name":"松本 俊夫"},{"name":"福本 誠二"}]},"description":{"en":"Fibroblast growth factor (FGF) 23 produced by bone is a hormone that decreases serum phosphate (Pi). Reflecting its central role in Pi control, serum FGF23 is tightly regulated by serum Pi alterations. FGF23 levels are regulated by the transcriptional event and posttranslational cleavage into inactive fragments before its secretion. For the latter, O-glycosylation of FGF23 by gene product prevents the cleavage, leading to an increase in serum FGF23. However, the molecular basis of Pi sensing in the regulation of serum FGF23 remains elusive. In this study, we showed that high Pi diet enhanced the skeletal expression of , but not , with expected increases in serum FGF23 and Pi in mice. induction by high Pi was further observed in osteoblastic UMR 106 cells, and this was mediated by activation of the extracellular signal-regulated kinase (ERK) pathway. Through proteomic searches for the upstream sensor for high Pi, we identified one subtype of the FGF receptor (FGFR1c), which was phosphorylated by high Pi in the absence of FGFs. The mode of unliganded FGFR activation by high Pi appeared different from that of FGFR bound to a canonical FGFR ligand (FGF2) when phosphorylation of the FGFR substrate 2α and ERK was monitored. Finally, we showed that an FGFR inhibitor and conditional deletion of in osteoblasts/osteocytes abrogated high Pi diet-induced increases in serum FGF23 and femoral expression in mice. Thus, these findings uncover an unrecognized facet of unliganded FGFR function and illustrate a Pi-sensing pathway involved in regulation of FGF23 production.","ja":"Fibroblast growth factor (FGF) 23 produced by bone is a hormone that decreases serum phosphate (Pi). Reflecting its central role in Pi control, serum FGF23 is tightly regulated by serum Pi alterations. FGF23 levels are regulated by the transcriptional event and posttranslational cleavage into inactive fragments before its secretion. For the latter, O-glycosylation of FGF23 by gene product prevents the cleavage, leading to an increase in serum FGF23. However, the molecular basis of Pi sensing in the regulation of serum FGF23 remains elusive. In this study, we showed that high Pi diet enhanced the skeletal expression of , but not , with expected increases in serum FGF23 and Pi in mice. induction by high Pi was further observed in osteoblastic UMR 106 cells, and this was mediated by activation of the extracellular signal-regulated kinase (ERK) pathway. Through proteomic searches for the upstream sensor for high Pi, we identified one subtype of the FGF receptor (FGFR1c), which was phosphorylated by high Pi in the absence of FGFs. The mode of unliganded FGFR activation by high Pi appeared different from that of FGFR bound to a canonical FGFR ligand (FGF2) when phosphorylation of the FGFR substrate 2α and ERK was monitored. Finally, we showed that an FGFR inhibitor and conditional deletion of in osteoblasts/osteocytes abrogated high Pi diet-induced increases in serum FGF23 and femoral expression in mice. Thus, these findings uncover an unrecognized facet of unliganded FGFR function and illustrate a Pi-sensing pathway involved in regulation of FGF23 production."},"publication_date":"2019-05-16","publication_name":{"en":"Proceedings of the National Academy of Sciences of the United States of America","ja":"Proceedings of the National Academy of Sciences of the United States of America"},"volume":"Vol.116","number":"No.23","starting_page":"11418","ending_page":"11427","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1073/pnas.1815166116"],"issn":["1091-6490"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31372589","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=356144","label":"url"}],"paper_title":{"en":"Persistent Activation of Calcium-Sensing Receptor Suppresses Bone Turnover, Increases Microcracks, and Decreases Bone Strength.","ja":"Persistent Activation of Calcium-Sensing Receptor Suppresses Bone Turnover, Increases Microcracks, and Decreases Bone Strength."},"authors":{"en":[{"name":"Bingzi Dong"},{"name":"Endo Itsuro"},{"name":"Yukoyo Ohnishi"},{"name":"Yukari Mitsui"},{"name":"Kurahashi Kiyoe"},{"name":"Kanai Mai"},{"name":"Hiasa Masahiro"},{"name":"Teramachi Jumpei"},{"name":"Tenshin Hirofumi"},{"name":"Fukumoto Seiji"},{"name":"Abe Masahiro"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"Bingzi Dong"},{"name":"遠藤 逸朗"},{"name":"大西 幸代"},{"name":"三井 由加里"},{"name":"倉橋 清衛"},{"name":"金井 麻衣"},{"name":"日浅 雅博"},{"name":"寺町 順平"},{"name":"天眞 寛文"},{"name":"福本 誠二"},{"name":"安倍 正博"},{"name":"松本 俊夫"}]},"description":{"en":"Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 exhibit similar features to patients with hypoparathyroidism, including reduced serum parathyroid hormone (PTH) and Ca with low bone turnover. Although persistent suppression of bone turnover may increase bone fragility, bone strength in ADH1 patients has been unclear. We created knock-in mice harboring the A843E activating mutation of CaSR, mimicking severe features of ADH1 patients. The severe form of ADH1 model mice showed smaller body and bone size with lower bone mineral density (BMD) and cortical area of the femur compared with age-matched wild-type (WT) mice. Bone strength in the femur was lower in ADH1 mice even after correction by bone geometry and/or BMD. Microcracks were markedly increased in ADH1 mice, but were rarely detected in WT mice. There was a negative correlation between bone strength corrected by bone geometry and/or BMD and microcrack number or density in ADH1 and WT mice. Among ADH1 mice, negative correlation was still observed between bone strength and microcrack number or density. Microcracks increased with age in ADH1 mice, and were negatively correlated with bone strength. Treatment with PTH(1-34) or a calcilytic, JTT-305, increased bone turnover, reduced microcracks, and increased bone strength to similar levels to those in WT mice. The increase in microcracks was associated with a reduction in bone strength in ADH1 mice, and aging aggravates these changes. These results demonstrate that activating mutation of CaSR causes reduction in PTH secretion with suppressed bone turnover, that reduced bone turnover is associated with an age-dependent increase in microcracks with a reduction in bone strength, and that both PTH(1-34) and calcilytic ameliorate all these changes in bone turnover and strength. It is suggested that fracture susceptibility may be increased in severe types of ADH1 patients especially in the elderly. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.","ja":"Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 exhibit similar features to patients with hypoparathyroidism, including reduced serum parathyroid hormone (PTH) and Ca with low bone turnover. Although persistent suppression of bone turnover may increase bone fragility, bone strength in ADH1 patients has been unclear. We created knock-in mice harboring the A843E activating mutation of CaSR, mimicking severe features of ADH1 patients. The severe form of ADH1 model mice showed smaller body and bone size with lower bone mineral density (BMD) and cortical area of the femur compared with age-matched wild-type (WT) mice. Bone strength in the femur was lower in ADH1 mice even after correction by bone geometry and/or BMD. Microcracks were markedly increased in ADH1 mice, but were rarely detected in WT mice. There was a negative correlation between bone strength corrected by bone geometry and/or BMD and microcrack number or density in ADH1 and WT mice. Among ADH1 mice, negative correlation was still observed between bone strength and microcrack number or density. Microcracks increased with age in ADH1 mice, and were negatively correlated with bone strength. Treatment with PTH(1-34) or a calcilytic, JTT-305, increased bone turnover, reduced microcracks, and increased bone strength to similar levels to those in WT mice. The increase in microcracks was associated with a reduction in bone strength in ADH1 mice, and aging aggravates these changes. These results demonstrate that activating mutation of CaSR causes reduction in PTH secretion with suppressed bone turnover, that reduced bone turnover is associated with an age-dependent increase in microcracks with a reduction in bone strength, and that both PTH(1-34) and calcilytic ameliorate all these changes in bone turnover and strength. It is suggested that fracture susceptibility may be increased in severe types of ADH1 patients especially in the elderly. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research."},"publication_date":"2019-03-06","publication_name":{"en":"JBMR Plus","ja":"JBMR Plus"},"volume":"Vol.3","number":"No.7","starting_page":"e10182","ending_page":"e10182","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/jbm4.10182"],"issn":["2473-4039"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/112935","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27748523","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=321702","label":"url"}],"paper_title":{"en":"Pim-2 is a critical target for treatment of osteoclastogenesis enhanced in myeloma.","ja":"Pim-2 is a critical target for treatment of osteoclastogenesis enhanced in myeloma."},"authors":{"en":[{"name":"Teramachi Jumpei"},{"name":"Hiasa Masahiro"},{"name":"Oda Asuka"},{"name":"Harada Takeshi"},{"name":"Nakamura Shingen"},{"name":"Amachi Ryota"},{"name":"Tenshin Hirofumi"},{"name":"Iwasa Masami"},{"name":"Fujii Shiroh"},{"name":"Kagawa Kumiko"},{"name":"Miki Hirokazu"},{"name":"Kurahashi Kiyoe"},{"name":"Yoshida Sumiko"},{"name":"Endo Itsuro"},{"name":"Haneji Tatsuji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"寺町 順平"},{"name":"日浅 雅博"},{"name":"Oda Asuka"},{"name":"Harada Takeshi"},{"name":"中村 信元"},{"name":"天知 良太"},{"name":"天眞 寛文"},{"name":"Iwasa Masami"},{"name":"藤井 志朗"},{"name":"賀川 久美子"},{"name":"三木 浩和"},{"name":"倉橋 清衛"},{"name":"吉田 守美子"},{"name":"遠藤 逸朗"},{"name":"羽地 達次"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"publication_date":"2018-02-17","publication_name":{"en":"British Journal of Haematology","ja":"British Journal of Haematology"},"volume":"Vol.180","number":"No.4","starting_page":"581","ending_page":"585","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/bjh.14388"],"issn":["1365-2141"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/112400","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29330493","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85043529637&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=348363","label":"url"}],"paper_title":{"en":"Development of versatile non-homologous end joining-based knock-in module for genome editing.","ja":"Development of versatile non-homologous end joining-based knock-in module for genome editing."},"authors":{"en":[{"name":"Sawatsubashi Shun"},{"name":"Joko Yudai"},{"name":"Fukumoto Seiji"},{"name":"Matsumoto Toshio"},{"name":"Sugano S. Shigeo"}],"ja":[{"name":"沢津橋 俊"},{"name":"上甲 裕大"},{"name":"福本 誠二"},{"name":"松本 俊夫"},{"name":"Sugano S. Shigeo"}]},"description":{"en":"CRISPR/Cas9-based genome editing has dramatically accelerated genome engineering. An important aspect of genome engineering is efficient knock-in technology. For improved knock-in efficiency, the non-homologous end joining (NHEJ) repair pathway has been used over the homology-dependent repair pathway, but there remains a need to reduce the complexity of the preparation of donor vectors. We developed the versatile NHEJ-based knock-in module for genome editing (VIKING). Using the consensus sequence of the time-honored pUC vector to cut donor vectors, any vector with a pUC backbone could be used as the donor vector without customization. Conditions required to minimize random integration rates of the donor vector were also investigated. We attempted to isolate null lines of the VDR gene in human HaCaT keratinocytes using knock-in/knock-out with a selection marker cassette, and found 75% of clones isolated were successfully knocked-in. Although HaCaT cells have hypotetraploid genome composition, the results suggest multiple clones have VDR null phenotypes. VIKING modules enabled highly efficient knock-in of any vectors harboring pUC vectors. Users now can insert various existing vectors into an arbitrary locus in the genome. VIKING will contribute to low-cost genome engineering.","ja":"CRISPR/Cas9-based genome editing has dramatically accelerated genome engineering. An important aspect of genome engineering is efficient knock-in technology. For improved knock-in efficiency, the non-homologous end joining (NHEJ) repair pathway has been used over the homology-dependent repair pathway, but there remains a need to reduce the complexity of the preparation of donor vectors. We developed the versatile NHEJ-based knock-in module for genome editing (VIKING). Using the consensus sequence of the time-honored pUC vector to cut donor vectors, any vector with a pUC backbone could be used as the donor vector without customization. Conditions required to minimize random integration rates of the donor vector were also investigated. We attempted to isolate null lines of the VDR gene in human HaCaT keratinocytes using knock-in/knock-out with a selection marker cassette, and found 75% of clones isolated were successfully knocked-in. Although HaCaT cells have hypotetraploid genome composition, the results suggest multiple clones have VDR null phenotypes. VIKING modules enabled highly efficient knock-in of any vectors harboring pUC vectors. Users now can insert various existing vectors into an arbitrary locus in the genome. VIKING will contribute to low-cost genome engineering."},"publication_date":"2018-01-12","publication_name":{"en":"Scientific Reports","ja":"Scientific Reports"},"volume":"Vol.8","number":"No.1","starting_page":"593","ending_page":"593","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/s41598-017-18911-9"],"issn":["2045-2322"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/111724","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29296860","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=336276","label":"url"}],"paper_title":{"en":"TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects.","ja":"TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects."},"authors":{"en":[{"name":"Tenshin Hirofumi"},{"name":"Teramachi Jumpei"},{"name":"Oda Asuka"},{"name":"Amachi Ryota"},{"name":"Hiasa Masahiro"},{"name":"Bat-Erdene Ariunzaya"},{"name":"Watanabe Keiichiro"},{"name":"Iwasa Masami"},{"name":"Harada Takeshi"},{"name":"Fujii Shiroh"},{"name":"Kagawa Kumiko"},{"name":"Sogabe Kimiko"},{"name":"Nakamura Shingen"},{"name":"Miki Hirokazu"},{"name":"Kurahashi Kiyoe"},{"name":"Yoshida Sumiko"},{"name":"Aihara Kenichi"},{"name":"Endo Itsuro"},{"name":"Tanaka Eiji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"天眞 寛文"},{"name":"寺町 順平"},{"name":"Oda Asuka"},{"name":"天知 良太"},{"name":"日浅 雅博"},{"name":"Ariunzaya Bat-Erdene"},{"name":"渡邉 佳一郎"},{"name":"岩佐 昌美"},{"name":"原田 武志"},{"name":"藤井 志朗"},{"name":"賀川 久美子"},{"name":"曽我部 公子"},{"name":"中村 信元"},{"name":"三木 浩和"},{"name":"倉橋 清衛"},{"name":"吉田 守美子"},{"name":"Aihara Kenichi"},{"name":"遠藤 逸朗"},{"name":"田中 栄二"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) agonists induce tumor-specific apoptosis indicating that they may be an attractive therapeutic strategy against cancers, including multiple myeloma (MM). Osteoclastogenesis is highly induced in MM, which in turn enhances MM growth, thereby forming a vicious cycle between MM tumor expansion and bone destruction. However, the effects of TRAIL on MM-enhanced osteoclastogenesis remain largely unknown. Here, we show that TRAIL induced apoptosis in MM cells, but not in osteoclasts (OCs), and that it rather facilitated receptor activator of NF-B ligand-induced osteoclastogenesis along with upregulation of cellular FLICE inhibitory protein (c-FLIP). TRAIL did not induce death-inducing signaling complex formation in OCs, but formed secondary complex (complex II) with the phosphorylation of transforming growth factor -activated kinase-1 (TAK1), and thus activated NF-B signaling. c-FLIP knockdown abolished complex II formation, thus permitting TRAIL induction of OC cell death. The TAK1 inhibitor LLZ1640-2 abrogated the TRAIL-induced c-FLIP upregulation and NF-B activation, and triggered TRAIL-induced caspase-8 activation and cell death in OCs. Interestingly, the TRAIL-induced caspase-8 activation caused enzymatic degradation of the transcription factor Sp1 to noticeably reduce c-FLIP expression, which further sensitized OCs to TRAIL-induced apoptosis. Furthermore, the TAK1 inhibition induced antiosteoclastogenic activity by TRAIL even in cocultures with MM cells while potentiating TRAIL's anti-MM effects. These results demonstrated that osteoclastic lineage cells use TRAIL for their differentiation and activation through tilting caspase-8-dependent apoptosis toward NF-B activation, and that TAK1 inhibition subverts TRAIL-mediated NF-B activation to resume TRAIL-induced apoptosis in OCs while further enhancing MM cell death in combination with TRAIL.","ja":"Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) agonists induce tumor-specific apoptosis indicating that they may be an attractive therapeutic strategy against cancers, including multiple myeloma (MM). Osteoclastogenesis is highly induced in MM, which in turn enhances MM growth, thereby forming a vicious cycle between MM tumor expansion and bone destruction. However, the effects of TRAIL on MM-enhanced osteoclastogenesis remain largely unknown. Here, we show that TRAIL induced apoptosis in MM cells, but not in osteoclasts (OCs), and that it rather facilitated receptor activator of NF-B ligand-induced osteoclastogenesis along with upregulation of cellular FLICE inhibitory protein (c-FLIP). TRAIL did not induce death-inducing signaling complex formation in OCs, but formed secondary complex (complex II) with the phosphorylation of transforming growth factor -activated kinase-1 (TAK1), and thus activated NF-B signaling. c-FLIP knockdown abolished complex II formation, thus permitting TRAIL induction of OC cell death. The TAK1 inhibitor LLZ1640-2 abrogated the TRAIL-induced c-FLIP upregulation and NF-B activation, and triggered TRAIL-induced caspase-8 activation and cell death in OCs. Interestingly, the TRAIL-induced caspase-8 activation caused enzymatic degradation of the transcription factor Sp1 to noticeably reduce c-FLIP expression, which further sensitized OCs to TRAIL-induced apoptosis. Furthermore, the TAK1 inhibition induced antiosteoclastogenic activity by TRAIL even in cocultures with MM cells while potentiating TRAIL's anti-MM effects. These results demonstrated that osteoclastic lineage cells use TRAIL for their differentiation and activation through tilting caspase-8-dependent apoptosis toward NF-B activation, and that TAK1 inhibition subverts TRAIL-mediated NF-B activation to resume TRAIL-induced apoptosis in OCs while further enhancing MM cell death in combination with TRAIL."},"publication_date":"2017-10-26","publication_name":{"en":"Blood Advances","ja":"Blood Advances"},"volume":"Vol.1","number":"No.24","starting_page":"2124","ending_page":"2137","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1182/bloodadvances.2017008813"],"issn":["2473-9529"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115483","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28592707","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=325954","label":"url"}],"paper_title":{"en":"Endothelial Nitric Oxide Synthase-Independent Pleiotropic Effects of Pitavastatin Against Atherogenesis and Limb Ischemia in Mice.","ja":"Endothelial Nitric Oxide Synthase-Independent Pleiotropic Effects of Pitavastatin Against Atherogenesis and Limb Ischemia in Mice."},"authors":{"en":[{"name":"Mitsuhashi Takeshi"},{"name":"Uemoto Ryoko"},{"name":"Ishikawa Kazue"},{"name":"Yoshida Sumiko"},{"name":"Ikeda Yasumasa"},{"name":"Yagi Shusuke"},{"name":"Matsumoto Toshio"},{"name":"Akaike Masashi"},{"name":"Aihara Ken-ichi"}],"ja":[{"name":"Mitsuhashi Takeshi"},{"name":"Uemoto Ryoko"},{"name":"Ishikawa Kazue"},{"name":"吉田 守美子"},{"name":"池田 康将"},{"name":"八木 秀介"},{"name":"松本 俊夫"},{"name":"赤池 雅史"},{"name":"粟飯原 賢一"}]},"description":{"en":"Pitavastatin exerts eNOS-independent protective effects against atherogenesis and hind-limb ischemia in mice, which may occur via modifications on key molecules such as AMPK and diverse molecules.","ja":"In Study 1, pitavastatin attenuated plaque formation and medial fibrosis of the aortic root with decreased macrophage infiltration in eNOS(-/-) ApoE(-/-) mice. PCR array analysis showed reductions in aortic gene expression of proatherogenic factors, including Ccl2 and Ccr2 in pitavastatin-treated double mutant mice. In addition, pitavastatin activated not only atherogenic p38MAPK and JNK but also anti-atherogenic ERK1/2 and ERK5 in the aorta of the double mutant mice. In Study 2, pitavastatin prolonged hind-limb survival after the surgery with increased BCL2-to-BAX protein ratio and inactivated JNK. Enhanced expression of anti-apoptotic genes, including Vegf, Api5, Atf5, Prdx2, and Dad1, was observed in the ischemic limb of pitavastatin-treated eNOS(-/-) mice. Furthermore, pitavastatin activated both aortic and skeletal muscle AMPK in the eNOS-deficient vascular injury models."},"publication_date":"2017-06-06","publication_name":{"en":"Journal of Atherosclerosis and Thrombosis","ja":"Journal of Atherosclerosis and Thrombosis"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.5551/jat.37747"],"issn":["1880-3873"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/110925","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28502917","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=325955","label":"url"}],"paper_title":{"en":"The Role of Heparin Cofactor in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice.","ja":"The Role of Heparin Cofactor in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice."},"authors":{"en":[{"name":"Kurahashi Kiyoe"},{"name":"Inoue Seika"},{"name":"Yoshida Sumiko"},{"name":"Ikeda Yasumasa"},{"name":"Morimoto Kana"},{"name":"Uemoto Ryoko"},{"name":"Ishikawa Kazue"},{"name":"Kondo Takeshi"},{"name":"Yuasa Tomoyuki"},{"name":"Endo Itsuro"},{"name":"Miyake Masato"},{"name":"Oyadomari Seiichi"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"},{"name":"Sakaue Hiroshi"},{"name":"Aihara Ken-ichi"}],"ja":[{"name":"倉橋 清衛"},{"name":"Inoue Seika"},{"name":"吉田 守美子"},{"name":"池田 康将"},{"name":"森本 佳奈"},{"name":"Uemoto Ryoko"},{"name":"Ishikawa Kazue"},{"name":"近藤 剛史"},{"name":"湯浅 智之"},{"name":"遠藤 逸朗"},{"name":"三宅 雅人"},{"name":"親泊 政一"},{"name":"松本 俊夫"},{"name":"安倍 正博"},{"name":"阪上 浩"},{"name":"粟飯原 賢一"}]},"description":{"en":"The present studies provide evidence to support the idea that HC plays an important role in the maintenance of glucose homeostasis by regulating insulin sensitivity in both humans and mice. Stimulators of HC production may serve as novel therapeutic tools for the treatment of type 2 diabetes.","ja":"The present studies provide evidence to support the idea that HC plays an important role in the maintenance of glucose homeostasis by regulating insulin sensitivity in both humans and mice. Stimulators of HC production may serve as novel therapeutic tools for the treatment of type 2 diabetes."},"publication_date":"2017-05-15","publication_name":{"en":"Journal of Atherosclerosis and Thrombosis","ja":"Journal of Atherosclerosis and Thrombosis"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.5551/jat.37739"],"issn":["1880-3873"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85013200573&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=325275","label":"url"}],"paper_title":{"en":"A Pirot study comparing the CGM-assessed glycemic profiles of patients with type 1 diabetes on insulin degludec and insulin glargine","ja":"A Pirot study comparing the CGM-assessed glycemic profiles of patients with type 1 diabetes on insulin degludec and insulin glargine"},"authors":{"en":[{"name":"Kuroda Akio"},{"name":"Miho Tsuruo"},{"name":"Nanako Aki"},{"name":"Kondo Takeshi"},{"name":"Yukari Oguro"},{"name":"Tamaki Motoyuki"},{"name":"Aihara Ken-ichi"},{"name":"Endo Itsuro"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"},{"name":"Matsuhisa Munehide"}],"ja":[{"name":"黒田 暁生"},{"name":"Miho Tsuruo"},{"name":"Nanako Aki"},{"name":"近藤 剛史"},{"name":"Yukari Oguro"},{"name":"田蒔 基行"},{"name":"粟飯原 賢一"},{"name":"遠藤 逸朗"},{"name":"松本 俊夫"},{"name":"安倍 正博"},{"name":"松久 宗英"}]},"publication_date":"2017-03","publication_name":{"en":"Diabetology International","ja":"Diabetology International"},"volume":"Vol.8","number":"No.1","starting_page":"112","ending_page":"115","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s13340-016-0289-4"],"issn":["2190-1678"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/113048","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27626482","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=323181","label":"url"}],"paper_title":{"en":"A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration.","ja":"A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration."},"authors":{"en":[{"name":"Amachi Ryota"},{"name":"Hiasa Masahiro"},{"name":"Teramachi Jumpei"},{"name":"Harada Takeshi"},{"name":"Oda Asuka"},{"name":"Nakamura Shingen"},{"name":"Hanson Derek"},{"name":"Watanabe Keiichiro"},{"name":"Fujii Shiroh"},{"name":"Miki Hirokazu"},{"name":"Kagawa Kumiko"},{"name":"Iwasa Masami"},{"name":"Endo Itsuro"},{"name":"Kondo Takeshi"},{"name":"Yoshida Sumiko"},{"name":"Aihara Ken-ichi"},{"name":"Kurahashi Kiyoe"},{"name":"Kuroda Yoshiaki"},{"name":"Horikawa Hideaki"},{"name":"Tanaka Eiji"},{"name":"Abe Masahiro"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"天知 良太"},{"name":"日浅 雅博"},{"name":"寺町 順平"},{"name":"原田 武志"},{"name":"小田 明日香"},{"name":"中村 信元"},{"name":"Derek James Hanson"},{"name":"渡邉 佳一郎"},{"name":"藤井 志朗"},{"name":"三木 浩和"},{"name":"賀川 久美子"},{"name":"岩佐 昌美"},{"name":"遠藤 逸朗"},{"name":"近藤 剛史"},{"name":"吉田 守美子"},{"name":"粟飯原 賢一"},{"name":"倉橋 清衛"},{"name":"黒田 芳明"},{"name":"堀川 秀昌"},{"name":"田中 栄二"},{"name":"安倍 正博"},{"name":"松本 俊夫"}]},"description":{"en":"Myeloma (MM) cells and osteoclasts are mutually interacted to enhance MM growth while creating acidic bone lesions. Here, we explored acid sensing of MM cells and its role in MM cell response to acidic conditions. Acidic conditions activated the PI3K-Akt signaling in MM cells while upregulating the pH sensor transient receptor potential cation channel subfamily V member 1 (TRPV1) in a manner inhibitable by PI3K inhibition. The acid-activated PI3K-Akt signaling facilitated the nuclear localization of the transcription factor Sp1 to trigger the expression of its target genes, including TRPV1 and HDAC1. Consistently, histone deacetylation was enhanced in MM cells in acidic conditions, while repressing a wide variety of genes, including DR4. Indeed, acidic conditions deacetylated histone H3K9 in a DR4 gene promoter and curtailed DR4 expression in MM cells. However, inhibition of HDAC as well as either Sp1 or PI3K was able to restore DR4 expression in MM cells suppressed in acidic conditions. These results collectively demonstrate that acid activates the TRPV1-PI3K-Akt-Sp1 signaling in MM cells while inducing HDAC-mediated gene repression, and suggest that a positive feedback loop between acid sensing and the PI3K-Akt signaling is formed in MM cells, leading to MM cell response to acidic bone lesions.","ja":"Myeloma (MM) cells and osteoclasts are mutually interacted to enhance MM growth while creating acidic bone lesions. Here, we explored acid sensing of MM cells and its role in MM cell response to acidic conditions. Acidic conditions activated the PI3K-Akt signaling in MM cells while upregulating the pH sensor transient receptor potential cation channel subfamily V member 1 (TRPV1) in a manner inhibitable by PI3K inhibition. The acid-activated PI3K-Akt signaling facilitated the nuclear localization of the transcription factor Sp1 to trigger the expression of its target genes, including TRPV1 and HDAC1. Consistently, histone deacetylation was enhanced in MM cells in acidic conditions, while repressing a wide variety of genes, including DR4. Indeed, acidic conditions deacetylated histone H3K9 in a DR4 gene promoter and curtailed DR4 expression in MM cells. However, inhibition of HDAC as well as either Sp1 or PI3K was able to restore DR4 expression in MM cells suppressed in acidic conditions. These results collectively demonstrate that acid activates the TRPV1-PI3K-Akt-Sp1 signaling in MM cells while inducing HDAC-mediated gene repression, and suggest that a positive feedback loop between acid sensing and the PI3K-Akt signaling is formed in MM cells, leading to MM cell response to acidic bone lesions."},"publication_date":"2016-10-25","publication_name":{"en":"Oncotarget","ja":"Oncotarget"},"volume":"Vol.7","number":"No.43","starting_page":"70447","ending_page":"70461","languages":["eng"],"referee":true,"identifiers":{"doi":["10.18632/oncotarget.11927"],"issn":["1949-2553"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27698446","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=326829","label":"url"}],"paper_title":{"en":"Expansion of Th1-like V9V2T cells by new-generation IMiDs, lenalidomide and pomalidomide, in combination with zoledronic acid.","ja":"Expansion of Th1-like V9V2T cells by new-generation IMiDs, lenalidomide and pomalidomide, in combination with zoledronic acid."},"authors":{"en":[{"name":"Harada Takeshi"},{"name":"Miki Hirokazu"},{"name":"Cui Q"},{"name":"Oda A"},{"name":"Amachi Ryota"},{"name":"Teramachi Jumpei"},{"name":"Bat-Erdene A"},{"name":"Sogabe K"},{"name":"Iwasa M"},{"name":"Fujii Shiroh"},{"name":"Nakamura Shingen"},{"name":"Kagawa Kumiko"},{"name":"Yoshida Sumiko"},{"name":"Endo I"},{"name":"Aihara Ken-ichi"},{"name":"Ozaki Shuji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"原田 武志"},{"name":"三木 浩和"},{"name":"Cui Q"},{"name":"Oda A"},{"name":"天知 良太"},{"name":"寺町 順平"},{"name":"Bat-Erdene A"},{"name":"Sogabe K"},{"name":"Iwasa M"},{"name":"藤井 志朗"},{"name":"中村 信元"},{"name":"賀川 久美子"},{"name":"吉田 守美子"},{"name":"Endo I"},{"name":"粟飯原 賢一"},{"name":"尾崎 修治"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"publication_date":"2016-10-04","publication_name":{"en":"Leukemia","ja":"Leukemia"},"volume":"Vol.31","number":"No.1","starting_page":"258","ending_page":"262","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/leu.2016.273"],"issn":["1476-5551"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/109666","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26877258","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84964267287&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=311144","label":"url"}],"paper_title":{"en":"Serum carboxy-terminal telopeptide of type I collagen levels are associated with carotid atherosclerosis in patients with cardiovascular risk factors.","ja":"Serum carboxy-terminal telopeptide of type I collagen levels are associated with carotid atherosclerosis in patients with cardiovascular risk factors."},"authors":{"en":[{"name":"Kondo Takeshi"},{"name":"Endo Itsuro"},{"name":"Aihara Ken-ichi"},{"name":"Yukiyo Ohnishi"},{"name":"Bingzi Dong"},{"name":"Yukari Oguro"},{"name":"Kurahashi Kiyoe"},{"name":"Yoshida Sumiko"},{"name":"Fujinaka Yuichi"},{"name":"Kuroda Akio"},{"name":"Matsuhisa Munehide"},{"name":"Fukumoto Seiji"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"近藤 剛史"},{"name":"遠藤 逸朗"},{"name":"粟飯原 賢一"},{"name":"Yukiyo Ohnishi"},{"name":"Bingzi Dong"},{"name":"Yukari Oguro"},{"name":"倉橋 清衛"},{"name":"吉田 守美子"},{"name":"藤中 雄一"},{"name":"黒田 暁生"},{"name":"松久 宗英"},{"name":"福本 誠二"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"Carboxy-terminal telopeptide of type I collagen (ICTP) is generated through matrix metalloproteinase (MMP)-dependent type I collagen digestion, and has been widely utilized as a biomarker for bone turnover. The fact that atherosclerotic lesions are rich in both type I collagen and MMP-producing macrophages led to the hypothesis that serum ICTP concentrations may serve as a non-invasive clinical biomarker for atherosclerosis. Therefore, the association of serum ICTP concentrations with the maximum intima-media thickness (IMT) of carotid arteries, a surrogate index of systemic atherosclerosis, or brachial-ankle pulse wave velocity (baPWV) in patients with atherosclerotic risk factors was evaluated. A total of 52 male and 65 female (mean age: 62.8 yrs) patients without renal failure, malignancies or bone diseases known to affect serum ICTP concentrations were recruited. Patients with max IMTs ≥1.1 mm showed significantly higher serum ICTP concentrations compared with patients with max IMTs <1.1 mm (3.33 ± 0.97 vs 2.82 ± 0.65 ng/mL, p<0.05). Serum ICTP concentration was also positively correlated with max IMT (p<0.001) or baPWV values (p<0.05). Multivariate analyses also revealed that serum ICTP concentrations were correlated with max IMT (p<0.001; 95% CI 0.200 to 0.454). These results suggest that serum ICTP concentrations can be used as a non-invasive biomarker for systemic atherosclerosis.","ja":"Carboxy-terminal telopeptide of type I collagen (ICTP) is generated through matrix metalloproteinase (MMP)-dependent type I collagen digestion, and has been widely utilized as a biomarker for bone turnover. The fact that atherosclerotic lesions are rich in both type I collagen and MMP-producing macrophages led to the hypothesis that serum ICTP concentrations may serve as a non-invasive clinical biomarker for atherosclerosis. Therefore, the association of serum ICTP concentrations with the maximum intima-media thickness (IMT) of carotid arteries, a surrogate index of systemic atherosclerosis, or brachial-ankle pulse wave velocity (baPWV) in patients with atherosclerotic risk factors was evaluated. A total of 52 male and 65 female (mean age: 62.8 yrs) patients without renal failure, malignancies or bone diseases known to affect serum ICTP concentrations were recruited. Patients with max IMTs ≥1.1 mm showed significantly higher serum ICTP concentrations compared with patients with max IMTs <1.1 mm (3.33 ± 0.97 vs 2.82 ± 0.65 ng/mL, p<0.05). Serum ICTP concentration was also positively correlated with max IMT (p<0.001) or baPWV values (p<0.05). Multivariate analyses also revealed that serum ICTP concentrations were correlated with max IMT (p<0.001; 95% CI 0.200 to 0.454). These results suggest that serum ICTP concentrations can be used as a non-invasive biomarker for systemic atherosclerosis."},"publication_date":"2016-02-17","publication_name":{"en":"Endocrine Journal","ja":"Endocrine Journal"},"volume":"Vol.63","number":"No.4","starting_page":"397","ending_page":"404","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1507/endocrj.EJ15-0589"],"issn":["1348-4540"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/109501","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26384349","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84946086135&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=310845","label":"url"}],"paper_title":{"en":"Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation.","ja":"Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation."},"authors":{"en":[{"name":"Hanson Derek James"},{"name":"Nakamura Shingen"},{"name":"Amachi Ryota"},{"name":"Hiasa Masahiro"},{"name":"Oda Asuka"},{"name":"Tsuji Daisuke"},{"name":"Itoh Kohji"},{"name":"Harada Takeshi"},{"name":"Horikawa Kazuki"},{"name":"Teramachi Jumpei"},{"name":"Miki Hirokazu"},{"name":"Matsumoto Toshio"},{"name":"Abe Masahiro"}],"ja":[{"name":"Hanson Derek James"},{"name":"中村 信元"},{"name":"天知 良太"},{"name":"日浅 雅博"},{"name":"Oda Asuka"},{"name":"辻 大輔"},{"name":"Itoh Kohji"},{"name":"Harada Takeshi"},{"name":"堀川 一樹"},{"name":"寺町 順平"},{"name":"三木 浩和"},{"name":"松本 俊夫"},{"name":"安倍 正博"}]},"description":{"en":"Cancer cells robustly expel lactate produced through enhanced glycolysis via monocarboxylate transporters (MCTs) and maintain alkaline intracellular pH. To develop a novel therapeutic strategy against multiple myeloma (MM), which still remains incurable, we explored the impact of perturbing a metabolism via inhibiting MCTs. All MM cells tested constitutively expressed MCT1 and MCT4, and most expressed MCT2. Lactate export was substantially suppressed to induce death along with lowering intracellular pH in MM cells by blockade of all three MCT molecules with -cyano-4-hydroxy cinnamate (CHC) or the MCT1 and MCT2 inhibitor AR-C155858 in combination with MCT4 knockdown, although only partially by knockdown of each MCT. CHC lowered intracellular pH and severely curtailed lactate secretion even when combined with metformin, which further lowered intracellular pH and enhanced cytotoxicity. Interestingly, an ambient acidic pH markedly enhanced CHC-mediated cytotoxicity, suggesting preferential targeting of MM cells in acidic MM bone lesions. Furthermore, treatment with CHC suppressed hexokinase II expression and ATP production to reduce side populations and colony formation. Finally, CHC caused downregulation of homing receptor CXCR4 and abrogated SDF-1-induced migration. Targeting tumor metabolism by MCT blockade therefore may become an effective therapeutic option for drug-resistant MM cells with elevated glycolysis.","ja":"Cancer cells robustly expel lactate produced through enhanced glycolysis via monocarboxylate transporters (MCTs) and maintain alkaline intracellular pH. To develop a novel therapeutic strategy against multiple myeloma (MM), which still remains incurable, we explored the impact of perturbing a metabolism via inhibiting MCTs. All MM cells tested constitutively expressed MCT1 and MCT4, and most expressed MCT2. Lactate export was substantially suppressed to induce death along with lowering intracellular pH in MM cells by blockade of all three MCT molecules with -cyano-4-hydroxy cinnamate (CHC) or the MCT1 and MCT2 inhibitor AR-C155858 in combination with MCT4 knockdown, although only partially by knockdown of each MCT. CHC lowered intracellular pH and severely curtailed lactate secretion even when combined with metformin, which further lowered intracellular pH and enhanced cytotoxicity. Interestingly, an ambient acidic pH markedly enhanced CHC-mediated cytotoxicity, suggesting preferential targeting of MM cells in acidic MM bone lesions. Furthermore, treatment with CHC suppressed hexokinase II expression and ATP production to reduce side populations and colony formation. Finally, CHC caused downregulation of homing receptor CXCR4 and abrogated SDF-1-induced migration. Targeting tumor metabolism by MCT blockade therefore may become an effective therapeutic option for drug-resistant MM cells with elevated glycolysis."},"publication_date":"2015-10-20","publication_name":{"en":"Oncotarget","ja":"Oncotarget"},"volume":"Vol.6","number":"No.32","starting_page":"33568","ending_page":"33586","languages":["eng"],"referee":true,"identifiers":{"doi":["10.18632/oncotarget.5598"],"issn":["1949-2553"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26301197","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84939780057&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=302708","label":"url"}],"paper_title":{"en":"Predictive factors for efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus.","ja":"Predictive factors for efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus."},"authors":{"en":[{"name":"Yagi Shusuke"},{"name":"Aihara Ken-ichi"},{"name":"Akaike Masashi"},{"name":"Fukuda Daiju"},{"name":"Salim HM"},{"name":"Ishida Masayoshi"},{"name":"Matsuura Tomomi"},{"name":"Ise Takayuki"},{"name":"Yamaguchi Koji"},{"name":"Iwase Takashi"},{"name":"Yamada Hirotsugu"},{"name":"Soeki Takeshi"},{"name":"Wakatsuki Tetsuzo"},{"name":"Shimabukuro Michio"},{"name":"Matsumoto Toshio"},{"name":"Sata Masataka"}],"ja":[{"name":"八木 秀介"},{"name":"粟飯原 賢一"},{"name":"赤池 雅史"},{"name":"福田 大受"},{"name":"Salim HM"},{"name":"石田 昌義"},{"name":"松浦 朋美"},{"name":"伊勢 孝之"},{"name":"山口 浩司"},{"name":"岩瀬 俊"},{"name":"山田 博胤"},{"name":"添木 武"},{"name":"若槻 哲三"},{"name":"島袋 充生"},{"name":"松本 俊夫"},{"name":"佐田 政隆"}]},"description":{"en":"BACKGROUND: Predictive factors for the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors for lowering glycosylated hemoglobin (HbA1c) remain unclear in patients with type 2 diabetes mellitus. The aim of this study is therefore to clarify predictive factors of the efficacy of DPP-4 inhibitors for lowering HbA1c after 12 months of treatment.METHODS: A total of 191 consecutive type 2 diabetic patients (male sex 55%, mean age, 68.3±35.8 years), who had been treated with DPP-4 inhibitors for 12 months, were enrolled in this study and evaluated retrospectively.RESULTS: After 12 months of DPP-4 inhibitor treatment, random blood glucose level, and HbA1c level, decreased from 167±63 to 151±49 mg/dL (P<0.01), and from 7.5%±1.3% to 6.9%±0.9% (P<0.01) respectively, without severe side effects. Multiple regression analysis showed that predictors of DPP-4 inhibitor treatment efficacy in lowering HbA1c level after 12 months were a decrease in HbA1c level after 3 months of treatment, a high baseline HbA1c level, a low baseline body mass index, and the absence of coronary artery disease.CONCLUSION: Most suitable candidates for treatment with DPP-4 inhibitors are diabetics who are not obese and do not have coronary artery disease. In addition, long-term efficacy of DPP-4 inhibitors can be predicted by decrement of HbA1c after 3 months of treatment.","ja":"BACKGROUND: Predictive factors for the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors for lowering glycosylated hemoglobin (HbA1c) remain unclear in patients with type 2 diabetes mellitus. The aim of this study is therefore to clarify predictive factors of the efficacy of DPP-4 inhibitors for lowering HbA1c after 12 months of treatment.METHODS: A total of 191 consecutive type 2 diabetic patients (male sex 55%, mean age, 68.3±35.8 years), who had been treated with DPP-4 inhibitors for 12 months, were enrolled in this study and evaluated retrospectively.RESULTS: After 12 months of DPP-4 inhibitor treatment, random blood glucose level, and HbA1c level, decreased from 167±63 to 151±49 mg/dL (P<0.01), and from 7.5%±1.3% to 6.9%±0.9% (P<0.01) respectively, without severe side effects. Multiple regression analysis showed that predictors of DPP-4 inhibitor treatment efficacy in lowering HbA1c level after 12 months were a decrease in HbA1c level after 3 months of treatment, a high baseline HbA1c level, a low baseline body mass index, and the absence of coronary artery disease.CONCLUSION: Most suitable candidates for treatment with DPP-4 inhibitors are diabetics who are not obese and do not have coronary artery disease. In addition, long-term efficacy of DPP-4 inhibitors can be predicted by decrement of HbA1c after 3 months of treatment."},"publication_date":"2015-08","publication_name":{"en":"Diabetes & Metabolism Journal","ja":"Diabetes & Metabolism Journal"},"volume":"Vol.39","number":"No.4","starting_page":"342","ending_page":"347","languages":["eng"],"referee":true,"identifiers":{"doi":["10.4093/dmj.2015.39.4.342"],"issn":["2233-6079"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26197863","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84940796363&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=303599","label":"url"}],"paper_title":{"en":"Pathogenesis and diagnostic criteria for rickets and osteomalacia-proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society.","ja":"Pathogenesis and diagnostic criteria for rickets and osteomalacia-proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society."},"authors":{"en":[{"name":"Fukumoto Seiji"},{"name":"Ozono Keiichi"},{"name":"Michigami Toshimi"},{"name":"Minagawa Masanori"},{"name":"Okazaki Ryo"},{"name":"Sugimoto Toshitsugu"},{"name":"Takeuchi Yasuhiro"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"福本 誠二"},{"name":"Ozono Keiichi"},{"name":"Michigami Toshimi"},{"name":"Minagawa Masanori"},{"name":"Okazaki Ryo"},{"name":"Sugimoto Toshitsugu"},{"name":"Takeuchi Yasuhiro"},{"name":"松本 俊夫"}]},"description":{"en":"Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations have revealed that the causes of rickets and osteomalacia are quite variable. Although these diseases can severely impair the quality of life of affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose diagnostic criteria and a flowchart for the differential diagnosis of various causes of these diseases. We hope that these criteria and the flowchart are clinically useful for the proper diagnosis and management of these diseases.","ja":"Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations have revealed that the causes of rickets and osteomalacia are quite variable. Although these diseases can severely impair the quality of life of affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose diagnostic criteria and a flowchart for the differential diagnosis of various causes of these diseases. We hope that these criteria and the flowchart are clinically useful for the proper diagnosis and management of these diseases."},"publication_date":"2015-07-22","publication_name":{"en":"Journal of Bone and Mineral Metabolism","ja":"Journal of Bone and Mineral Metabolism"},"volume":"Vol.33","number":"No.5","starting_page":"467","ending_page":"473","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s00774-015-0698-7"],"issn":["1435-5604"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/109486","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/25967373","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84945482381&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=318262","label":"url"}],"paper_title":{"en":"Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH).","ja":"Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)."},"authors":{"en":[{"name":"Dong Bingzi"},{"name":"Endo Itsuro"},{"name":"Ohnishi Yukiyo"},{"name":"Kondo Takeshi"},{"name":"Hasegawa Tomoka"},{"name":"Amizuka Norio"},{"name":"Kiyonari Hiroshi"},{"name":"Shioi Go"},{"name":"Abe Masahiro"},{"name":"Fukumoto Seiji"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"Dong Bingzi"},{"name":"遠藤 逸朗"},{"name":"Ohnishi Yukiyo"},{"name":"近藤 剛史"},{"name":"Hasegawa Tomoka"},{"name":"Amizuka Norio"},{"name":"Kiyonari Hiroshi"},{"name":"Shioi Go"},{"name":"安倍 正博"},{"name":"福本 誠二"},{"name":"松本 俊夫"}]},"description":{"en":"Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a novel therapeutic agent for ADH.","ja":"Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a novel therapeutic agent for ADH."},"publication_date":"2015-07-16","publication_name":{"en":"Journal of Bone and Mineral Research","ja":"Journal of Bone and Mineral Research"},"volume":"Vol.30","number":"No.11","starting_page":"1980","ending_page":"1993","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/jbmr.2551"],"issn":["1523-4681"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26135520","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84942935508&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=303600","label":"url"}],"paper_title":{"en":"Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment.","ja":"Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment."},"authors":{"en":[{"name":"Endo Itsuro"},{"name":"Fukumoto Seiji"},{"name":"Ozono Keiichi"},{"name":"Namba Noriyuki"},{"name":"Inoue Daisuke"},{"name":"Okazaki Ryo"},{"name":"Yamauchi Mika"},{"name":"Sugimoto Toshitsugu"},{"name":"Minagawa Masanori"},{"name":"Michigami Toshimi"},{"name":"Nagai Masaki"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"遠藤 逸朗"},{"name":"福本 誠二"},{"name":"Ozono Keiichi"},{"name":"Namba Noriyuki"},{"name":"井上 大輔"},{"name":"Okazaki Ryo"},{"name":"Yamauchi Mika"},{"name":"Sugimoto Toshitsugu"},{"name":"Minagawa Masanori"},{"name":"Michigami Toshimi"},{"name":"Nagai Masaki"},{"name":"松本 俊夫"}]},"description":{"en":"A nationwide epidemiologic survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases was conducted in 2010 to clarify the prevalence and the clinical presentations of the disorders. A questionnaire inquiring the experience of patients with these diseases was sent to randomly selected hospitals throughout Japan. The estimated annual incidence of the diseases was 117 cases (95% CI 75 - 160), 55 males (95% CI 30 - 81) and 62 females (95% CI 40 - 84). Tumor-induced osteomalacia (TIO) and X-linked hypophosphatemic rickets (XLH) were the most prevalent causes of acquired and genetic FGF23-related hypophosphatemic diseases, respectively. The estimated incidence of XLH was about 1 in 20,000. We have also collected clinical data of the patients by a secondary survey. These patients showed FGF23 levels of above 30 pg/ml by intact assay in the presence of hypophosphatemia. While complete resection of responsible tumors improved biochemical abnormalities in patients with TIO, treatment with phosphate and/or active vitamin D3 did not normalize serum phosphate and tubular maximum transport of phosphate in patients with XLH. Our results suggest that there is no racial difference in the incidence of XLH. While FGF23 measurement is useful for the diagnosis of FGF23-related hypophosphatemic diseases, the better management is necessary especially for patients with genetic hypophosphatemic rickets caused by excessive actions of FGF23.","ja":"A nationwide epidemiologic survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases was conducted in 2010 to clarify the prevalence and the clinical presentations of the disorders. A questionnaire inquiring the experience of patients with these diseases was sent to randomly selected hospitals throughout Japan. The estimated annual incidence of the diseases was 117 cases (95% CI 75 - 160), 55 males (95% CI 30 - 81) and 62 females (95% CI 40 - 84). Tumor-induced osteomalacia (TIO) and X-linked hypophosphatemic rickets (XLH) were the most prevalent causes of acquired and genetic FGF23-related hypophosphatemic diseases, respectively. The estimated incidence of XLH was about 1 in 20,000. We have also collected clinical data of the patients by a secondary survey. These patients showed FGF23 levels of above 30 pg/ml by intact assay in the presence of hypophosphatemia. While complete resection of responsible tumors improved biochemical abnormalities in patients with TIO, treatment with phosphate and/or active vitamin D3 did not normalize serum phosphate and tubular maximum transport of phosphate in patients with XLH. Our results suggest that there is no racial difference in the incidence of XLH. While FGF23 measurement is useful for the diagnosis of FGF23-related hypophosphatemic diseases, the better management is necessary especially for patients with genetic hypophosphatemic rickets caused by excessive actions of FGF23."},"publication_date":"2015-07-01","publication_name":{"en":"Endocrine Journal","ja":"Endocrine Journal"},"volume":"Vol.62","number":"No.9","starting_page":"811","ending_page":"816","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1507/endocrj.EJ15-0275"],"issn":["1348-4540"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/111266","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26399335","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84942054596&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=318273","label":"url"}],"paper_title":{"en":"Non-invasive Measurement of Skin Autofluorescence as a Beneficial Surrogate Marker for Atherosclerosis in Patients with Type 2 Diabetes","ja":"Non-invasive Measurement of Skin Autofluorescence as a Beneficial Surrogate Marker for Atherosclerosis in Patients with Type 2 Diabetes"},"authors":{"en":[{"name":"Temma Jin"},{"name":"Matsuhisa Munehide"},{"name":"Horie Toru"},{"name":"Kuroda Akio"},{"name":"Mori Hiroyasu"},{"name":"Tamaki Motoyuki"},{"name":"Endo Itsuro"},{"name":"Aihara Ken-ichi"},{"name":"Abe Masahiro"},{"name":"Matsumoto Toshio"}],"ja":[{"name":"Temma Jin"},{"name":"松久 宗英"},{"name":"Horie Toru"},{"name":"黒田 暁生"},{"name":"森 博康"},{"name":"田蒔 基行"},{"name":"遠藤 逸朗"},{"name":"粟飯原 賢一"},{"name":"安倍 正博"},{"name":"松本 俊夫"}]},"description":{"en":"Advanced glycation end-products (AGEs) are thought to play a major role in the pathogenesis of diabetic vascular complications. Skin autofluorescence (AF) was recently reported to represent tissue AGEs accumulation with a non-invasive method. The aim of the present study was to evaluate association between AF value and diabetic vascular complications, such as retinopathy, nephropathy and cervical atherosclerosis using the carotid intima-media thickness (IMT), an established marker of cardiovascular disease in patients with type 2 diabetes. A total of 68 patients with type 2 diabetes were enrolled in a cross-sectional manner. AGEs accumulation was measured with AF reader. Clinical parameters were collected at the time of AF and IMT measurement. Max-IMT was correlated with age and AF (r=0.407, p=0.001), but not with HbA1c, GA, and pentosidine. Also, AF was not correlated with HbA1c, GA and pentosidine, but was correlated with age (r=0.560, p<0.001), duration of diabetes (r=0.256, p<0.05). Multivariate regression analysis revealed that AF, but not age, was an independent determinant of max-IMT. In conclusion, AF might be a beneficial surrogate marker for evaluating carotid atherosclerosis in patients with type 2 diabetes non-invasively. J. Med. Invest. 62: 126-129, August, 2015.","ja":"Advanced glycation end-products (AGEs) are thought to play a major role in the pathogenesis of diabetic vascular complications. Skin autofluorescence (AF) was recently reported to represent tissue AGEs accumulation with a non-invasive method. The aim of the present study was to evaluate association between AF value and diabetic vascular complications, such as retinopathy, nephropathy and cervical atherosclerosis using the carotid intima-media thickness (IMT), an established marker of cardiovascular disease in patients with type 2 diabetes. A total of 68 patients with type 2 diabetes were enrolled in a cross-sectional manner. AGEs accumulation was measured with AF reader. Clinical parameters were collected at the time of AF and IMT measurement. Max-IMT was correlated with age and AF (r=0.407, p=0.001), but not with HbA1c, GA, and pentosidine. Also, AF was not correlated with HbA1c, GA and pentosidine, but was correlated with age (r=0.560, p<0.001), duration of diabetes (r=0.256, p<0.05). Multivariate regression analysis revealed that AF, but not age, was an independent determinant of max-IMT. In conclusion, AF might be a beneficial surrogate marker for evaluating carotid atherosclerosis in patients with type 2 diabetes non-invasively. J. Med. Invest. 62: 126-129, August, 2015."},"publication_date":"2015-07","publication_name":{"en":"The Journal of Medical Investigation : JMI","ja":"The Journal of Medical Investigation : JMI"},"volume":"Vol.62","number":"No.3-4","starting_page":"126","ending_page":"129","languages":["eng"],"referee":true,"identifiers":{"doi":["10.2152/jmi.62.126"],"issn":["1349-6867"]},"published_paper_type":"scientific_journal"}} {"insert":{"user_id":"1000013246","type":"published_papers"},"force":{"see_also":[{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84905378195&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=278032","label":"url"}],"paper_title":{"en":"Increase in serum triglyceride was associated with coronary plaque vulnerability in a patient with rheumatoid arthritis.","ja":"Increase in serum triglyceride was associated with coronary plaque vulnerability in a patient with rheumatoid arthritis."},"authors":{"en":[{"name":"Yagi Shusuke"},{"name":"Fujimura M"},{"name":"Akaike Masashi"},{"name":"Aihara Ken-ichi"},{"name":"Iwase Takashi"},{"name":"Tada M"},{"name":"Ueda Yuka"},{"name":"Ise Takayuki"},{"name":"Yamaguchi Koji"},{"name":"Wakatsuki Tetsuzo"},{"name":"Matsumoto Toshio"},{"name":"Sata Masataka"}],"ja":[{"name":"八木 秀介"},{"name":"Fujimura M"},{"name":"赤池 雅史"},{"name":"粟飯原 賢一"},{"name":"岩瀬 俊"},{"name":"Tada M"},{"name":"上田 由佳"},{"name":"伊勢 孝之"},{"name":"山口 浩司"},{"name":"若槻 哲三"},{"name":"松本 俊夫"},{"name":"佐田 政隆"}]},"description":{"en":"Rates of morbidity and mortality from cardiovascular disease are high in patients with rheumatoid arthritis (RA); however, the mechanisms and biomarkers that reflect coronary plaque vulnerability have not yet been established. We present a case of acute coronary syndrome (ACS) presumably caused by exacerbation of chronic inflammation of RA, in which an abrupt increase in serum triglyceride was seen on the day of onset of ACS but not during effort angina. This case suggests that RA patients with an abrupt increase in triglyceride need intensive care including anti-platelet and statin therapy for the prevention of coronary plaque rupture.