Faculty Profiles - ARIMA, Hiroshi

Hypothalamic glial cells isolated by MACS reveal that microglia and astrocytes induce hypothalamic inflammation via different processes under high-fat diet conditions Reviewed International journal

Mariko Sugiyama, Ryoichi Banno, Hiroshi Yaginuma, Keigo Taki, Akira Mizoguchi, Taku Tsunekawa, Takeshi Onoue, Hiroshi Takagi, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Okiru Komine, Koji Yamanaka, Hiroshi Arima

Neurochemistry International Vol. 136 page： 104733 - 104733 2020.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

Glial cells can mediate hypothalamic inflammatory processes induced in response to a high-fat diet (HFD). We used magnetic-activated cell sorting (MACS) to isolate microglia and astrocytes from hypothalamus of mice fed HFD and examined changes in expression of inflammation-related cytokines and markers related to glial cell activation status. Hypothalamus from male C57BL6 mice fed a chow diet (chow) or HFD for 1, 3, or 28 days were collected and microglia and astrocytes were isolated by MACS. After confirming cell viability by fluorescence activated cell sorting, mRNA expression levels of inflammation-related cytokines and markers of glial cell activation status were examined by qRT-PCR, which revealed that both glial cell types isolated by MACS retained specificity. On day 3 of HFD, both CD86 and TNFα mRNA expression was significantly increased in microglia relative to the chow group. In astrocytes, TNFα mRNA expression levels were similar between the chow and HFD groups on day 3, but anti-inflammatory cytokine IL-10 levels were significantly increased. On day 7 of HFD, TNFα expression in microglia decreased to levels comparable to the chow group while that in astrocytes remained unchanged. On day 28 of HFD, TNFα levels were significantly increased in both microglia and astrocytes, which had increased mRNA expression of CD86 and MAO-B, respectively. For both glial cell types, results for TNFα expression assessed by RT-PCR and immunohistochemical analysis were similar. These results indicate that the role of microglia and astrocytes in hypothalamic inflammation under HFD conditions changed with time and these changes were accompanied by changes in the activation status of glial cells. Our data suggest that early after initiating HFD, hypothalamic astrocytes suppress diet-induced inflammation at least in part by secreting IL-10, whereas continued HFD feeding impairs this suppressive function such that both microglia and astrocytes promote hypothalamic inflammation.

DOI： 10.1016/j.neuint.2020.104733

Anti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study. Reviewed International journal Open Access

Norio Okada, Shintaro Iwama, Takayuki Okuji, Tomoko Kobayashi, Yoshinori Yasuda, Eri Wada, Takeshi Onoue, Motomitsu Goto, Mariko Sugiyama, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Masahiro Morise, Mitsuro Kanda, Kenji Yokota, Naozumi Hashimoto, Masahiko Ando, Yasushi Fujimoto, Masato Nagino, Yasuhiro Kodera, Mitsuhiro Fujishiro, Hideharu Hibi, Michihiko Sone, Hitoshi Kiyoi, Momokazu Gotoh, Yuichi Ando, Masashi Akiyama, Yoshinori Hasegawa, Hiroshi Arima

British journal of cancer Vol. 122 ( 6 ) page： 771 - 777 2020.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

BACKGROUND: Anti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified. METHODS: A total of 209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline. RESULTS: Of the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 [34.1%] vs. 4/165 [2.4%], p < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 [56.5%] vs. 1/19 [5.3%], p = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period. CONCLUSIONS: The risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline. TRIAL REGISTRATION: UMIN000019024.

DOI： 10.1038/s41416-020-0736-7

甲状腺自己抗体は抗PD-1抗体による甲状腺機能異常症の高リスク因子となる

Other Link： http://www.nature.com/articles/s41416-020-0736-7

小林朋子, 岩間信太郎, 伊藤雅晃, 奥地剛之, 岡田則男, 安田康紀, 有馬寛

日本内分泌学会雑誌 Vol. 95 ( 4 ) page： 1446 - 1446 2020.2

岡田則男, 岩間信太郎, 伊藤雅晃, 奥地剛之, 小林朋子, 安田康紀, 有馬寛

日本内分泌学会雑誌 Vol. 95 ( 4 ) page： 1332 - 1332 2020.2

両側乳癌手術前にバセドウ病合併が判明し甲状腺全摘術を施行した一例

半田朋子, 高野悠子, 尾上剛史, 高木博史, 有馬寛

日本内分泌学会雑誌 Vol. 95 ( 4 ) page： 1375 - 1375 2020.2

Dipeptidyl peptidase-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels in patients with type 2 diabetes: A randomized controlled trial. Reviewed International journal Open Access

Takeshi Onoue, Motomitsu Goto, Eri Wada, Mariko Furukawa, Takayuki Okuji, Norio Okada, Tomoko Kobayashi, Shintaro Iwama, Mariko Sugiyama, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Yoshiaki Morishita, Yusuke Seino, Hidetaka Suga, Ryoichi Banno, Yoji Hamada, Masahiko Ando, Etsuko Yamamori, Hiroshi Arima

PloS one Vol. 15 ( 1 ) page： e0228004 2020.1

Language：English Publishing type：Research paper (scientific journal)

Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.

DOI： 10.1371/journal.pone.0228004

Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects International journal Open Access

Kawakubo Mitsuhiro, Tanaka Miyako, Ochi Kozue, Watanabe Akiko, Saka-Tanaka Marie, Kanamori Yohei, Yoshioka Naoki, Yamashita Satoko, Goto Moritaka, Itoh Michiko, Shirakawa Ibuki, Kanai Sayaka, Suzuki Hiromi, Sawada Makoto, Ito Ayaka, Ishigami Masatoshi, Fujishiro Mitsuhiro, Arima Hiroshi, Ogawa Yoshihiro, Suganami Takayoshi

SCIENTIFIC REPORTS Vol. 10 ( 1 ) page： 983 - 983 2020.1

Language：English Publishing type：Research paper (scientific journal)

Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor-deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism-independent effects of anagliptin on NASH and HCC development.

DOI： 10.1038/s41598-020-57935-6

Hypothalamic Contribution to Pituitary Functions Is Recapitulated In Vitro Using 3D-Cultured Human iPS Cells. Reviewed International journal Open Access

Takatoshi Kasai, Hidetaka Suga, Mayu Sakakibara, Chikafumi Ozone, Ryusaku Matsumoto, Mayuko Kano, Kazuki Mitsumoto, Koichiro Ogawa, Yu Kodani, Hiroshi Nagasaki, Naoko Inoshita, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Yoshihiro Ito, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Motomitsu Goto, Ryoichi Banno, Jun Takahashi, Hiroshi Arima

Cell reports Vol. 30 ( 1 ) page： 18 - + 2020.1

Language：English Publishing type：Research paper (scientific journal)

The pituitary is a major hormone center that secretes systemic hormones responding to hypothalamus-derived-releasing hormones. Previously, we reported the independent pituitary induction and hypothalamic differentiation of human embryonic stem cells (ESCs). Here, a functional hypothalamic-pituitary unit is generated using human induced pluripotent stem (iPS) cells in vitro. The adrenocorticotropic hormone (ACTH) secretion capacity of the induced pituitary reached a comparable level to that of adult mouse pituitary because of the simultaneous maturation with hypothalamic neurons within the same aggregates. Corticotropin-releasing hormone (CRH) from the hypothalamic area regulates ACTH cells similarly to our hypothalamic-pituitary axis. Our induced hypothalamic-pituitary units respond to environmental hypoglycemic condition in vitro, which mimics a life-threatening situation in vivo, through the CRH-ACTH pathway, and succeed in increasing ACTH secretion. Thus, we generated powerful hybrid organoids by recapitulating hypothalamic-pituitary development, showing autonomous maturation on the basis of interactions between developing tissues.

DOI： 10.1016/j.celrep.2019.12.009

Flash glucose monitoring helps achieve better glycemic control than conventional self-monitoring of blood glucose in non-insulin-treated type 2 diabetes: a randomized controlled trial Reviewed Open Access

Wada Eri, Onoue Takeshi, Kobayashi Tomoko, Handa Tomoko, Hayase Ayaka, Ito Masaaki, Furukawa Mariko, Okuji Takayuki, Okada Norio, Iwama Shintaro, Sugiyama Mariko, Tsunekawa Taku, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Suga Hidetaka, Banno Ryoichi, Kuwatsuka Yachiyo, Ando Masahiko, Goto Motomitsu, Arima Hiroshi

BMJ OPEN DIABETES RESEARCH & CARE Vol. 8 ( 1 ) 2020.1

ペムブロリズマブ使用中にバセドウ病が増悪した一例

岡田則男, 岩間信太郎, 伊藤雅晃, 奥地剛之, 小林朋子, 安田康紀, 恒川卓, 有馬寛

日本内分泌学会雑誌 Vol. 95 ( 3 ) page： 1125 - 1125 2020.1

Diagnosis and treatment of autoimmune and IgG4-related hypophysitis: clinical guidelines of the Japan Endocrine Society Reviewed Open Access

Takagi Hiroshi, Iwama Shintaro, Sugimura Yoshihisa, Takahashi Yutaka, Oki Yutaka, Akamizu Takashi, Arima Hiroshi

ENDOCRINE JOURNAL Vol. 67 ( 4 ) page： 373 - 378 2020

Language：English Publishing type：Research paper (scientific journal)

Hypophysitis, which is often accompanied by pituitary dysfunction, is classified into several subtypes based on the cause, histology, and the location of inflammation in the pituitary gland. A definitive diagnosis requires pituitary biopsy, which is invasive, and the process is limited to specialized clinical settings. In this opinion paper, we review the literature associated with hypophysitis, and provide the guidelines of the Japan Endocrine Society for the diagnosis and treatment of autoimmune and IgG4-related hypophysitis.

DOI： 10.1507/endocrj.EJ19-0569

Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study. Reviewed International journal Open Access

Tomoko Kobayashi, Shintaro Iwama, Yoshinori Yasuda, Norio Okada, Takayuki Okuji, Masaaki Ito, Takeshi Onoue, Motomitsu Goto, Mariko Sugiyama, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Ryoichi Banno, Kenji Yokota, Tetsunari Hase, Masahiro Morise, Naozumi Hashimoto, Masahiko Ando, Yasushi Fujimoto, Hideharu Hibi, Michihiko Sone, Yuichi Ando, Masashi Akiyama, Yoshinori Hasegawa, Hiroshi Arima

Journal for immunotherapy of cancer Vol. 8 ( 2 ) page： e000779 2020

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Several immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM). METHODS: A total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint. RESULTS: Pituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05). CONCLUSIONS: In our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone. CLINICAL TRIALS REGISTRATION: UMIN000019024.

DOI： 10.1136/jitc-2020-000779