2021/12/26 更新

写真a

エグチ ジュン
江口 潤
EGUCHI Jun
所属
医歯薬学域 准教授
職名
准教授
連絡先
メールアドレス
外部リンク

学位

  • 医学博士 ( 2005年3月   岡山大学 )

研究キーワード

  • メタボリックシンドローム

  • 脂質異常症

  • 2型糖尿病

研究分野

  • ライフサイエンス / 代謝、内分泌学

  • ライフサイエンス / 実験動物学

  • ライフサイエンス / 分子生物学

所属学協会

  • 日本痛風・尿酸核酸学会

委員歴

  • 日本動脈硬化学会   評議員  

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    団体区分:学協会

  • 日本糖尿病・妊娠学会   評議員  

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    団体区分:学協会

  • 日本肥満学会   評議員  

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    団体区分:学協会

  • 日本内科学会   中国支部評議員  

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    団体区分:学協会

 

論文

  • Adipocyte-specific inhibition of Mir221/222 ameliorates diet-induced obesity through targeting Ddit4 査読

    Satoshi Yamaguchi, Dongxiao Zhang, Akihiro Katayama, Naoko Kurooka, Ryosuke Sugawara, Haya H. Albuayjan, Atsuko Nakatsuka, Jun Eguchi and Jun Wada

    Frontiers in Endocrinology   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  • Author Correction: Lgals9 deficiency ameliorates obesity by modulating redox state of PRDX2. 国際誌

    Tomokazu Nunoue, Satoshi Yamaguchi, Sanae Teshigawara, Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Toshiro Niki, Jun Wada

    Scientific reports   11 ( 1 )   18611 - 18611   2021年9月

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  • Longitudinal observation of insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes mellitus: A report of two cases. 国際誌

    Noriko Fujiwara, Mayu Watanabe, Akihiro Katayama, Yohei Noda, Jun Eguchi, Hitomi Kataoka, Shunsuke Kagawa, Jun Wada

    Clinical case reports   9 ( 9 )   e04574   2021年9月

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    記述言語:英語  

    Immune checkpoint inhibitor-induced diabetes mellitus is a rare immune-related adverse event. This report illustrates clinical data and insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes.

    DOI: 10.1002/ccr3.4574

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  • A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease. 国際誌

    Atsuko Nakatsuka, Satoshi Yamaguchi, Jun Eguchi, Shigeru Kakuta, Yoichiro Iwakura, Hitoshi Sugiyama, Jun Wada

    Communications biology   4 ( 1 )   373 - 373   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. Vaspin-/- obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78 kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD.

    DOI: 10.1038/s42003-021-01902-y

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  • Lgals9 deficiency ameliorates obesity by modulating redox state of PRDX2. 国際誌

    Tomokazu Nunoue, Satoshi Yamaguchi, Sanae Teshigawara, Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Toshiro Niki, Jun Wada

    Scientific reports   11 ( 1 )   5991 - 5991   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The adipose tissue is regarded as an endocrine organ and secretes bioactive adipokines modulating chronic inflammation and oxidative stress in obesity. Gal-9 is secreted out upon cell injuries, interacts with T-cell immunoglobulin-3 (Tim-3) and induces apoptosis in activated Th1 cells. Gal-9 also binds to protein disulfide isomerase (PDI), maintains PDI on surface of T cells, and increases free thiols in the disulfide/thiol cycles. To explore the molecular mechanism of obesity, we investigated Gal-9-/- and Gal-9wt/wt C57BL/6J mice fed with high fat-high sucrose (HFHS) chow. Gal-9-/- mice were resistant to diet-induced obesity associated with reduction of epididymal and mesenteric fat tissues and improved glucose tolerance compared with Gal-9wt/wt mice. However, the number of M1, M2 macrophages, and M1/M2 ratio in epididymal fat were unaltered. Under HFHS chow, Gal-9-/- mice receiving Gal-9-/- or Gal-9wt/wt bone marrow-derived cells (BMCs) demonstrated significantly lower body weight compared with Gal-9wt/wt mice receiving Gal-9-/- BMCs. We identified the binding between Gal-9 and peroxiredoxin-2 (PRDX2) in sugar chain-independent manner by nanoLC-MS/MS, immunoprecipitation, and pull-down assay. In 3T3L1 adipocytes, Gal-9 knockdown shifts PRDX2 monomer (reduced form) dominant from PRDX2 dimer (oxidized form) under oxidative stress with H2O2. The inhibition of Gal-9 in adipocytes may be a new therapeutic approach targeting the oxidative stress and subsequent glucose intolerance in obesity.

    DOI: 10.1038/s41598-021-85080-1

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  • Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients With Type 2 Diabetes: A Multicenter Prospective Study With 5-Year Follow Up (U-CARE Study 2). 国際誌

    Koki Mise, Mariko Imamura, Satoshi Yamaguchi, Mayu Watanabe, Chigusa Higuchi, Akihiro Katayama, Satoshi Miyamoto, Haruhito A Uchida, Atsuko Nakatsuka, Jun Eguchi, Kazuyuki Hida, Tatsuaki Nakato, Atsuhito Tone, Sanae Teshigawara, Takashi Matsuoka, Shinji Kamei, Kazutoshi Murakami, Ikki Shimizu, Katsuhiro Miyashita, Shinichiro Ando, Tomokazu Nunoue, Michihiro Yoshida, Masao Yamada, Kenichi Shikata, Jun Wada

    Frontiers in cardiovascular medicine   8   668059 - 668059   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear. Methods: Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease. Results: During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24-2.55, P = 0.002) and Calsepa [High-Man (Man2-6)]: 1.56 (1.19-2.04, P = 0.001). Common glycan binding to these lectins was high-mannose type of N-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001-0.055, P = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045-0.692, P = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively]. Conclusion: The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal N-glycosylation occurring in patients with diabetes at higher risk of CVE. Trial Registration: This study was registered with the University Hospital Medical Information Network on June 26, 2012 (Clinical trial number: UMIN000011525, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000013482).

    DOI: 10.3389/fcvm.2021.668059

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  • Upregulation of Mir342 in Diet-Induced Obesity Mouse and the Hypothalamic Appetite Control. 国際誌

    Dongxiao Zhang, Satoshi Yamaguchi, Xinhao Zhang, Boxuan Yang, Naoko Kurooka, Ryosuke Sugawara, Haya Hamed H Albuayjan, Atsuko Nakatsuka, Jun Eguchi, Takeshi Y Hiyama, Atsunori Kamiya, Jun Wada

    Frontiers in endocrinology   12   727915 - 727915   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In obesity and type 2 diabetes, numerous genes are differentially expressed, and microRNAs are involved in transcriptional regulation of target mRNAs, but miRNAs critically involved in the appetite control are not known. Here, we identified upregulation of miR-342-3p and its host gene Evl in brain and adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. Mir342 (-/-) mice fed with HFHS chow were protected from obesity and diabetes. The hypothalamic arcuate nucleus neurons co-express Mir342 and EVL. The percentage of activated NPY+pSTAT3+ neurons were reduced, while POMC+pSTAT3+ neurons increased in Mir342 (-/-) mice, and they demonstrated the reduction of food intake and amelioration of metabolic phenotypes. Snap25 was identified as a major target gene of miR-342-3p and the reduced expression of Snap25 may link to functional impairment hypothalamic neurons and excess of food intake. The inhibition of miR-342-3p may be a potential candidate for miRNA-based therapy.

    DOI: 10.3389/fendo.2021.727915

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  • Roles of transmembrane Protein 97 (TMEM97) in Adipose Tissue and Skeletal Muscle 査読

    Masafumi Tenta, Jun Eguchi, and Jun Wada

    Acta Medica Okayama   2021年

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  • Dysfunction of CD8 + PD-1 + T cells in type 2 diabetes caused by the impairment of metabolism-immune axis. 国際誌

    Ichiro Nojima, Shingo Eikawa, Nahoko Tomonobu, Yoshiko Hada, Nobuo Kajitani, Sanae Teshigawara, Satoshi Miyamoto, Atsuhito Tone, Haruhito A Uchida, Atsuko Nakatsuka, Jun Eguchi, Kenichi Shikata, Heiichiro Udono, Jun Wada

    Scientific reports   10 ( 1 )   14928 - 14928   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8 + splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8 + splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8 + PD-1 + T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

    DOI: 10.1038/s41598-020-71946-3

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  • The hypoglycemia-prevention effect of sensor-augmented pump therapy with predictive low glucose management in Japanese patients with type 1 diabetes mellitus: a short-term study.

    Akihiro Katayama, Atsuhito Tone, Mayu Watanabe, Sanae Teshigawara, Satoshi Miyamoto, Jun Eguchi, Atsuko Nakatsuka, Kenichi Shikata, Jun Wada

    Diabetology international   11 ( 2 )   97 - 104   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Aims/introduction: The predictive low glucose management (PLGM) system was introduced in March 2018 in Japan. Although there are some reports demonstrating the benefit of PLGM in preventing hypoglycemia, no data are currently available in Japanese patients with type 1 diabetes mellitus (T1DM). The aim of the present study is to evaluate the effect of PLGM with sensor-augmented pump therapy in the prevention of hypoglycemia in Japanese patients. Materials and methods: We included 16 patients with T1DM who used the MiniMed®640G system after switching from the MiniMed®620G system. We retrospectively analysed the data of the continuous glucose monitoring system in 1 month after switching to MiniMed®640G. Results: The area under the curve (AUC) of hypoglycemia of < 70 mg/dL was lowered from 0.42 ± 0.43 mg/dL day to 0.18 ± 0.18 mg/dL day (P = 0.012). Correspondingly, the duration of severe hypoglycemia (< 54 mg/dL) was reduced significantly from 15.3 ± 21.7 min/day to 4.8 ± 6.9 min/day (P = 0.019). The duration of hypoglycemia was reduced, but the reduction was not significant. Regarding the AUC for hyperglycemia > 180 mg/dL and the duration of hyperglycemia did not change. With the PLGM function, 79.3% of the predicted hypoglycemic events were avoided. Conclusions: The hypoglycemia avoidance rate was comparable to those in previous reports. In addition, we demonstrated that PLGM can markedly suppress severe hypoglycemia without deteriorating glycemic control in Japanese T1DM patients. It is necessary to further investigate the effective use of the PLGM feature such as establishing a lower limit and the timing of resumption.

    DOI: 10.1007/s13340-019-00408-7

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  • A Patient with Type 3 Autoimmune Polyglandular Syndrome who Developed Systemic Lupus Erythematosus 8 years after the Diagnosis of Autoimmune Hepatitis.

    Tomoyo Mifune-Morioka, Haruhito A Uchida, Kazuhiko Fukushima, Mayu Watanabe, Chihiro Ouchi, Koki Mise, Chieko Kawakita, Yuzuki Kano, Akifumi Onishi, Kishio Toma, Jun Eguchi, Nozomu Wada, Fusao Ikeda, Erika Sasaki, Yu Suganami, Masayuki Kishida, Hitoshi Sugiyama, Hiroyuki Okada, Jun Wada

    Acta medica Okayama   73 ( 4 )   367 - 372   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Eight years prior to her present admission, a 61-year-old Japanese woman was diagnosed with autoimmune hepatitis, slowly progressive insulin-dependent diabetes mellitus, and chronic thyroiditis; she had been treated with oral prednisolone (PSL). After she suddenly discontinued PSL, she newly developed systemic lupus erythematosus. A combination therapy of oral PSL and intravenous cyclophosphamide resulted in remission. She was finally diagnosed with autoimmune polyglandular syndrome (APS) type 3 (3A ,3B, 3D), complicated with four different autoimmune diseases. Since patients with type 3 APS may present many manifestations over a long period of time, they should be carefully monitored.

    DOI: 10.18926/AMO/56940

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  • Effect of an enhanced recovery after surgery protocol in patients undergoing pancreaticoduodenectomy: A randomized controlled trial. 国際誌

    Kosei Takagi, Ryuichi Yoshida, Takahito Yagi, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Shiro Hinotsu, Takashi Matsusaki, Hiroshi Morimatsu, Jun Eguchi, Jun Wada, Masuo Senda, Toshiyoshi Fujiwara

    Clinical nutrition (Edinburgh, Scotland)   38 ( 1 )   174 - 181   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND & AIMS: Evidence of the advantages of enhanced recovery after surgery (ERAS) protocols following pancreaticoduodenectomy (PD) is limited. The aim of this study was to examine the efficiency of ERAS protocols in patients following PD. METHODS: Between June 2014 and October 2016, patients undergoing PD were randomly assigned to receive ERAS protocols or standard care. The primary endpoint was the postoperative length of stay. Secondary endpoints included postoperative complications, postoperative quality-of-life (QoR-40J), readmission, and medical cost. RESULTS: Of 80 eligible patients, 74 were analyzed in intention-to-treat principles: 37 in the control group and 37 in the ERAS group. The mean length of stay in the ERAS group was significantly shorter than that in the control group (20.1 ± 5.4 vs 26.9 ± 13.5 days, P < 0.001). The ERAS group had a significantly lower percentage of postoperative complications (32.4% vs 56.8%, P = 0.034) and readmissions (0% vs 8.1%, P = 0.038). Quality-of-life was also significantly better in the ERAS group (184 ± 12.4 vs 177 ± 14.5, P = 0.022). The total medical cost was lower in the ERAS group, but not significantly ($25,445 ± 5065 vs $28,384 ± 9999, P = 0.085). CONCLUSIONS: The optimization of ERAS protocols in patients undergoing PD is safe and accelerates perioperative recovery and quality-of-life, thereby reducing the length of stay. Morbidity was significantly decreased in the ERAS group without compromising surgical outcome. REGISTRATION NUMBER: UMIN000014068.

    DOI: 10.1016/j.clnu.2018.01.002

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  • Acquired partial lipoatrophy as graft-versus-host disease and treatment with metreleptin: two case reports. 国際誌

    Yusuke Shibata, Atsuko Nakatsuka, Jun Eguchi, Satoshi Miyamoto, Yukari Masuda, Motoharu Awazawa, Akinobu Takaki, Ryuichi Yoshida, Takahito Yagi, Jun Wada

    Journal of medical case reports   12 ( 1 )   368 - 368   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Acquired partial lipoatrophy has been reported after bone marrow transplantation during childhood; however, no adult cases have previously been reported. We herein report two adult cases of acquired partial lipoatrophy after transplantation. CASE PRESENTATION: A 28-year-old Japanese woman developed diabetic ketoacidosis and received insulin therapy after bone marrow transplantation. She manifested partial lipoatrophy of the extremities, prominent insulin resistance, hyperglycemia, hypertriglyceridemia, and fatty liver. A 40-year-old Japanese woman underwent liver transplantation from a living donor for alcoholic liver disease after abstinence from alcohol. She newly developed non-alcoholic steatohepatitis and diabetes. Non-alcoholic steatohepatitis progressed to liver failure, and a second liver transplantation from a brain-dead donor was performed at 42 years of age. She demonstrated loss of subdermal fat of the upper and lower extremities, prominent insulin resistance, hyperglycemia, and hypertriglyceridemia. In both cases, the injection of recombinant methionyl human leptin reversed all of the metabolic abnormalities. CONCLUSIONS: Acquired partial lipoatrophy after transplantation is a manifestation of chronic graft-versus-host disease in adults. This entity is associated with diabetes with prominent insulin resistance and severe hypertriglycemia and can be successfully treated with metreleptin for the long term.

    DOI: 10.1186/s13256-018-1901-y

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  • Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy. 国際誌

    Keiko Tanaka, Hitoshi Sugiyama, Toshio Yamanari, Koki Mise, Hiroshi Morinaga, Masashi Kitagawa, Akifumi Onishi, Ayu Ogawa-Akiyama, Katsuyuki Tanabe, Jun Eguchi, Yasukazu Ohmoto, Kenichi Shikata, Jun Wada

    Nephrology (Carlton, Vic.)   23 ( 9 )   855 - 862   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIM: Trefoil factor 3 (TFF3) is a small peptide that is involved in mucosal protection. TFF3 is widely expressed in multiple tissues including kidney tissue. Previous studies have reported that the levels of urinary TFF3 are significantly increased in patients with chronic kidney disease. The aim of this study is to detect the TFF3 mRNA in kidney and elucidate the relationship between renal TFF3 mRNA and tubulointerstitial fibrosis in IgA nephropathy (IgAN). METHODS: We investigated the renal mRNA expression of TFF3 by real-time PCR analysis in biopsy specimens from patients with IgAN, other glomerulonephritis (OGN) and minor glomerular abnormalities (MGA). We also determined the renal localization of TFF3 and the levels of urinary TFF3 by immunostaining and ELISA, respectively. RESULTS: The renal TFF3 mRNA expression was significantly associated with the urinary TFF3 secretion and the tubulointerstitial fibrosis score in the IgAN group alone. Immunostaining of the renal specimen of IgAN patients revealed that TFF3 is located in the renal tubular epithelial cells. The locations were almost the same as those that showed uromodulin positivity; specifically, the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule. The urinary TFF3 levels were positively correlated with the levels of urinary biomarkers of tubulointerstitial injury in such patients. CONCLUSION: Renal TFF3 mRNA is associated with renal tubulointerstitial fibrosis in IgAN patients. The TFF3 located in the renal tubular epithelial cells may play a role in the progression of tubulointerstitial fibrosis in IgAN patients.

    DOI: 10.1111/nep.13444

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  • Identification of Novel Urinary Biomarkers for Predicting Renal Prognosis in Patients With Type 2 Diabetes by Glycan Profiling in a Multicenter Prospective Cohort Study: U-CARE Study 1. 国際誌

    Koki Mise, Mariko Imamura, Satoshi Yamaguchi, Sanae Teshigawara, Atsuhito Tone, Haruhito A Uchida, Jun Eguchi, Atsuko Nakatsuka, Daisuke Ogawa, Michihiro Yoshida, Masao Yamada, Kenichi Shikata, Jun Wada

    Diabetes care   41 ( 8 )   1765 - 1775   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Because quantifying glycans with complex structures is technically challenging, little is known about the association of glycosylation profiles with the renal prognosis in diabetic kidney disease (DKD). RESEARCH DESIGN AND METHODS: In 675 patients with type 2 diabetes, we assessed the baseline urinary glycan signals binding to 45 lectins with different specificities. The end point was a decrease of estimated glomerular filtration rate (eGFR) by ≥30% from baseline or dialysis for end-stage renal disease. RESULTS: During a median follow-up of 4.0 years, 63 patients reached the end point. Cox proportional hazards analysis revealed that urinary levels of glycans binding to six lectins were significantly associated with the outcome after adjustment for known indicators of DKD, although these urinary glycans, except that for DBA, were highly correlated with baseline albuminuria and eGFR. Hazard ratios for these lectins were (+1 SD for the glycan index) as follows: SNA (recognizing glycan Siaα2-6Gal/GalNAc), 1.42 (95% CI 1.14-1.76); RCA120 (Galβ4GlcNAc), 1.28 (1.01-1.64); DBA (GalNAcα3GalNAc), 0.80 (0.64-0.997); ABA (Galβ3GalNAc), 1.29 (1.02-1.64); Jacalin (Galβ3GalNAc), 1.30 (1.02-1.67); and ACA (Galβ3GalNAc), 1.32 (1.04-1.67). Adding these glycan indexes to a model containing known indicators of progression improved prediction of the outcome (net reclassification improvement increased by 0.51 [0.22-0.80], relative integrated discrimination improvement increased by 0.18 [0.01-0.35], and the Akaike information criterion decreased from 296 to 287). CONCLUSIONS: The urinary glycan profile identified in this study may be useful for predicting renal prognosis in patients with type 2 diabetes. Additional investigation of glycosylation changes and urinary glycan excretion in DKD is needed.

    DOI: 10.2337/dc18-0030

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  • Marked hypertriglyceridemia induced by interferon-β1a therapy in a clinically isolated syndrome patient. 国際誌

    Yuko Kawahara, Toru Yamashita, Yasuyuki Ohta, Kota Sato, Keiichiro Tsunoda, Mami Takemoto, Nozomi Hishikawa, Jun Eguchi, Koji Abe

    Journal of the neurological sciences   373   144 - 146   2017年2月

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  • IRF3 promotes adipose inflammation and insulin resistance and represses browning. 国際誌

    Manju Kumari, Xun Wang, Louise Lantier, Anna Lyubetskaya, Jun Eguchi, Sona Kang, Danielle Tenen, Hyun Cheol Roh, Xingxing Kong, Lawrence Kazak, Rasheed Ahmad, Evan D Rosen

    The Journal of clinical investigation   126 ( 8 )   2839 - 54   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat-fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis.

    DOI: 10.1172/JCI86080

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  • Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice. 国際誌

    Takashi Hatanaka, Daisuke Ogawa, Hiromi Tachibana, Jun Eguchi, Tatsuyuki Inoue, Hiroshi Yamada, Kohji Takei, Hirofumi Makino, Jun Wada

    Pharmacology research & perspectives   4 ( 4 )   e00239   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    It is unclear whether the improvement in diabetic nephropathy by sodium glucose cotransporter 2 (SGLT2) inhibitors is caused by a direct effect on SGLT2 or by the improvement in hyperglycemia. Here, we investigated the effect of dapagliflozin on early-stage diabetic nephropathy using a mouse model of type 1 diabetes and murine proximal tubular epithelial cells. Eight-week-old Akita mice were treated with dapagliflozin or insulin for 12 weeks. Body weight, urinary albumin excretion, blood pressure, as well as levels of blood glucose and hemoglobin A1c were measured. Expansion of the mesangial matrix, interstitial fibrosis, and macrophage infiltration in kidneys were evaluated by histology. Oxidative stress and apoptosis were evaluated in kidneys and cultured proximal tubular epithelial cells. Compared with nontreated mice, dapagliflozin and insulin decreased blood glucose and hemoglobin A1c levels equally. Urine volume and water intake increased significantly in the dapagliflozin-treated group compared with those in the insulin-treated group, but there were no differences in body weight or blood pressure between the two groups. Macrophage infiltration and fibrosis in renal interstitium improved significantly in the dapagliflozin group compared with the insulin group. Oxidative stress was attenuated by dapagliflozin, and suppression occurred in a dose-dependent manner. RNAi knockdown of SGLT2 resulted in reduced oxidative stress. Dapagliflozin ameliorates diabetic nephropathy by suppressing hyperglycemia-induced oxidative stress in a manner independent of hyperglycemia improvement in Akita mice. Our findings suggest that dapagliflozin may be a novel therapeutic approach for the treatment of diabetic nephropathy.

    DOI: 10.1002/prp2.239

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  • Antiobesity Action of ACAM by Modulating the Dynamics of Cell Adhesion and Actin Polymerization in Adipocytes. 国際誌

    Kazutoshi Murakami, Jun Eguchi, Kazuyuki Hida, Atsuko Nakatsuka, Akihiro Katayama, Miwa Sakurai, Haruki Choshi, Masumi Furutani, Daisuke Ogawa, Kohji Takei, Fumio Otsuka, Jun Wada

    Diabetes   65 ( 5 )   1255 - 67   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junction-associated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of ∼10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 μm, where ACAM and γ-actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity.

    DOI: 10.2337/db15-1304

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  • Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis. 国際誌

    Atsuko Nakatsuka, Makoto Matsuyama, Satoshi Yamaguchi, Akihiro Katayama, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Daisuke Ogawa, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Eijiro Watanabe, Jun Wada

    Scientific reports   6   21721 - 21721   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/- mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/- mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

    DOI: 10.1038/srep21721

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  • The gender specific risk factors for prolonged hospitalization due to acute pyelonephritis in a Japanese tertiary emergency center. 国際誌

    Risa Muneishi, Ryuta Tanimoto, Koichiro Wada, Philip Hsiao, Jun Eguchi, Motoo Araki, Toyohiko Watanabe, Yasutomo Nasu, Naoki Akebi

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   22 ( 2 )   108 - 11   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: The aim of this study is to characterize the potential differences between male and female patients with acute pyelonephritis (AP) and to predict the severity of AP based on the length of hospital stay. METHODS: We conducted a retrospective medical chart review of 172 consecutive adult patients who were hospitalized in Tsuyama Central Hospital due to AP from January 2007 through June 2012. We analyzed the length of hospital stay by the proportional hazard model. RESULTS: A total of 172 patients were identified who were admitted to our hospital with a diagnosis of AP. Of them, 62% (106/172) were female. Except for urological malignancy, there was no significant difference between men and women in underlying disease. Out of 26 variables, univariate analysis in male showed that only urolithiasis (OR 1.75, p = 0.0294) was significantly associated with longer hospital stay, while septic shock (OR 3.18, P = 0.003), urological malignancy (OR 2.94, P = 0.002), age over 65 (OR 1.66, p = 0.018) and neurogenic bladder (OR 1.92, p = 0.014) were all associated with longer hospital stay in female patients. CONCLUSIONS: This is the first report to identify the risk factors for prolonged hospital stay for the patients who were admitted with AP in the Japanese population. The risk factors causing prolonged hospital stay were totally different between males and females. Reviewing the medical history based on sex gender might enable a clinician to predict the severity of acute pyelonephritis during the initial evaluation.

    DOI: 10.1016/j.jiac.2015.11.007

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  • Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis. 国際誌

    Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Motoko Kanzaki, Tomokazu Nunoue, Kazuyuki Hida, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto, Hiroshi Kiyonari, Hirofumi Makino, Jun Wada

    Scientific reports   5   16920 - 16920   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.

    DOI: 10.1038/srep16920

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  • Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes. 国際誌

    Yu Wang, Akihiro Katayama, Takahiro Terami, Xiaoying Han, Tomokazu Nunoue, Dongxiao Zhang, Sanae Teshigawara, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Daisuke Ogawa, Yasuhide Furuta, Hirofumi Makino, Jun Wada

    Metabolism: clinical and experimental   64 ( 6 )   677 - 88   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: In obesity and type 2 diabetes, the impairment of mitochondrial function in white adipose tissue (WAT) is linked to a reduction in whole body insulin sensitivity. Timm44 is upregulated in the kidneys of streptozotocin-induced diabetic mice. In the inner mitochondrial membrane, Timm44 anchors mitochondrial heat-shock protein 70 (mtHsp70) to the translocase of inner mitochondrial membrane 23 (TIM23) complex and facilitates the import of mitochondria-targeted preproteins into the mitochondrial matrix dependent on the inner membrane potential and ATP hydrolysis on ATPase domain of mtHsp70. METHODS: We generated the aP2-promoter driven Timm44 transgenic (Tg) mouse model and investigated whether Timm44 Tg mice fed high-fat/high-sucrose (HFHS) chow are protected from type 2 diabetes and obesity. RESULTS: The body weight of aP2-promoter driven Timm44 Tg mice was lower than that of wild type mice, and insulin sensitivity was greater in Timm44 Tg mice than in wild type mice. Although WAT weight was not altered in Timm44 Tg mice fed HFHS chow, adipocyte size was reduced, and mitochondrial fusion associated with decreased expression of fission genes, such as Dnm1l and Fis1, was observed. In addition, when fed standard (STD) chow, the expressions of the fusion genes Opa1, Mfn1 and Mfn2, and Mfn1 were significantly increased in Timm44 Tg mice compared to wild type mice, and fused mitochondria were also observed in Timm44 Tg mice fed STD chow. CONCLUSIONS: The Timm44 gene may be a new target for the treatment of type 2 diabetes.

    DOI: 10.1016/j.metabol.2015.02.004

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  • Identification of circulating miR-101, miR-375 and miR-802 as biomarkers for type 2 diabetes. 国際誌

    Chigusa Higuchi, Atsuko Nakatsuka, Jun Eguchi, Sanae Teshigawara, Motoko Kanzaki, Akihiro Katayama, Satoshi Yamaguchi, Naoto Takahashi, Kazutoshi Murakami, Daisuke Ogawa, Sakiko Sasaki, Hirofumi Makino, Jun Wada

    Metabolism: clinical and experimental   64 ( 4 )   489 - 97   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: The unique circulating microRNAs (miRNAs) observed in patients with type 2 diabetes (T2D) are candidates as new biomarkers and therapeutic targets. In order to identify circulating miRNAs relevant to the disease process in case of type 2 diabetes, we performed the Illumina sequencing of miRNAs derived from the serum, liver and epididymal white adipose tissue (WAT) of diet-induced obese male C57BL/6J mice. BASIC PROCEDURES: We selected four miRNAs, miR-101, miR-335, miR-375, and miR-802, which are increased in the sera and tissues of obese mice, and measured the serum levels of miRNAs in T2D and subjects with normal glucose tolerance (NGT). MAIN FINDINGS: The serum concentrations of miRNAs, log(10)miR-101, log(10)miR-375, and log(10)miR-802, were significantly increased in the T2D patients compared with NGT subjects (1.41±2.01 v.s. -0.57±1.05 (P=1.36×10(-5)), 0.20±0.58 v.s. 0.038±1.00 (P=3.06×10(-6)), and 2.45±1.27 v.s. 0.97±0.98 (P=0.014), respectively). The log(10)miR-335 values did not demonstrate any significant differences between the T2D and NGT groups (-1.08±1.35 v.s. -0.38±1.21 (P=0.25)). According to the stepwise regression analysis, the HbA1c was an independent predictor of miR-101. Regarding the serum miR-802 levels, eGFR, HbA1c and HDL-C values were identified as significant determinants. PRINCIPAL CONCLUSIONS: The present findings demonstrated that the circulating miR-101, miR-375 and miR-802 levels are significantly increased in T2D patients versus NGT subjects and they may become the new biomarkers for type 2 diabetes.

    DOI: 10.1016/j.metabol.2014.12.003

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  • Structural design and synthesis of arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists based on the helix12-folding inhibition hypothesis. 国際誌

    Masao Ohashi, Kanae Gamo, Yuta Tanaka, Minoru Waki, Yoko Beniyama, Kenji Matsuno, Jun Wada, Masafumi Tenta, Jun Eguchi, Makoto Makishima, Nobuyasu Matsuura, Takuji Oyama, Hiroyuki Miyachi

    European journal of medicinal chemistry   90   53 - 67   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are candidates for treatment of type 2 diabetes, obesity and osteoporosis. However, few rational design strategies are currently available. Here, we utilized the helix12 (H12)-folding inhibition hypothesis, in combination with our previously determined X-ray crystal structure of PPARγ agonist MEKT-21 (6) complexed with the PPARγ ligand-binding domain, to design and develop a potent phenylalkynyl amide-type PPARγ antagonist 9i, focusing initially on pinpoint structural modification of the propanoic acid moiety of 6. Since 9i retained very weak, but distinct, PPARγ agonist activity, we next modified the distal benzene ring of 9i, aiming to delete the residual PPARγ agonist activity while retaining the antagonist activity. Introduction of a chlorine atom at the 2-position of the distal benzene ring afforded 9p, which exhibited potent, PPARγ-selective full antagonist activity without detectable agonist activity. We found that 9p stabilized the corepressor-PPARγ complex and suppressed basal PPARγ activity. This compound showed anti-adipogenesis activity at the cellular level. This agonist-antagonist switching concept based on the H12-folding inhibition hypothesis should also be applicable for designing other classes of PPARγ full antagonists.

    DOI: 10.1016/j.ejmech.2014.11.017

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  • Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice. 国際誌

    Hiromi Tachibana, Daisuke Ogawa, Norio Sogawa, Masato Asanuma, Ikuko Miyazaki, Naoto Terami, Takashi Hatanaka, Chikage Sato Horiguchi, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

    American journal of physiology. Renal physiology   306 ( 1 )   F105-15   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT(-/-)) and MT(+/+) mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT(-/-) mice compared with diabetic MT(+/+) mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT(-/-) mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

    DOI: 10.1152/ajprenal.00034.2013

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  • Nuclear hormone receptor expression in mouse kidney and renal cell lines. 国際誌

    Daisuke Ogawa, Jun Eguchi, Jun Wada, Naoto Terami, Takashi Hatanaka, Hiromi Tachibana, Atsuko Nakatsuka, Chikage Sato Horiguchi, Naoko Nishii, Hirofumi Makino

    PloS one   9 ( 1 )   e85594   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-γ (PPARγ) and PPARα, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPARδ was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor α in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.

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  • Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. 国際誌

    Naoto Terami, Daisuke Ogawa, Hiromi Tachibana, Takashi Hatanaka, Jun Wada, Atsuko Nakatsuka, Jun Eguchi, Chikage Sato Horiguchi, Naoko Nishii, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

    PloS one   9 ( 6 )   e100777   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic β-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-β, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, β-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.

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  • Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy. 国際誌

    Mayu Watanabe, Atsuko Nakatsuka, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Chigusa Higuchi, Akihiro Katayama, Sanae Teshigawara, Jun Eguchi, Daisuke Ogawa, Eijiro Watanabe, Jun Wada, Hirofumi Makino

    PloS one   9 ( 3 )   e92647   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt-/-mice, the glomerular hypertrophy and albuminuria in Pemt-/- mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt-/- diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis.

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  • Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization. 国際誌

    Jun Eguchi, Xingxing Kong, Masafumi Tenta, Xun Wang, Sona Kang, Evan D Rosen

    Diabetes   62 ( 10 )   3394 - 403   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Interferon regulatory factors (IRFs) play functionally diverse roles in the transcriptional regulation of the immune system. We have previously shown that several IRFs are regulators of adipogenesis and that IRF4 is a critical transcriptional regulator of adipocyte lipid handling. However, the functional role of IRF4 in adipose tissue macrophages (ATMs) remains unclear, despite high expression there. Here we show that IRF4 expression is regulated in primary macrophages and in ATMs of high-fat diet-induced obese mice. Irf4(-/-) macrophages produce higher levels of proinflammatory cytokines, including interleukin-1β and tumor necrosis factor-α, in response to fatty acids. In coculture experiments, IRF4 deletion in macrophages leads to reduced insulin signaling and glucose uptake in 3T3-L1 adipocytes. To determine the macrophage-specific function of IRF4 in the context of obesity, we generated myeloid cell-specific IRF4 knockout mice, which develop significant insulin resistance on a high-fat diet, despite no difference in adiposity. This phenotype is associated with increased expression of inflammatory genes and decreased insulin signaling in adipose tissue, skeletal muscle, and liver. Furthermore, Irf4(-/-) ATMs express markers suggestive of enhanced M1 polarization. These findings indicate that IRF4 is a negative regulator of inflammation in diet-induced obesity, in part through regulation of macrophage polarization.

    DOI: 10.2337/db12-1327

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  • Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex. 国際誌

    Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

    Circulation research   112 ( 5 )   771 - 80   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    RATIONALE: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. OBJECTIVE: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. METHODS AND RESULTS: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using (125)I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10(-9) m) by the treatment of 5 μM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca(2+) influx and subsequent apoptosis. CONCLUSIONS: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.

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  • Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease. 国際誌

    Yuko Kurose, Jun Wada, Motoko Kanzaki, Sanae Teshigawara, Atsuko Nakatsuka, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Mayu Watanabe, Chigusa Higuchi, Jun Eguchi, Nobuyuki Miyatake, Hirofumi Makino

    BMC nephrology   14   23 - 23   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Galectin-9 (Gal-9) induces apoptosis in activated T helper 1 (TH1) cells as a ligand for T cell immunoglobulin mucin-3 (Tim-3). Gal-9 also inhibits the G1 phase cell cycle arrest and hypertrophy in db/db mice, the hallmark of early diabetic nephropathy, by reversing the high glucose-induced up-regulation of cyclin dependent kinase inhibitors such as p27(Kip1) and p21(Cip1). METHODS: We investigated the serum levels of Gal-9 in the patients with type 2 diabetes and various stages of chronic kidney disease (CKD) (n=182). RESULTS: Serum Gal-9 levels in the patients with type 2 diabetes were 131.9 ± 105.4 pg/ml and Log(10)Gal-9 levels significantly and positively correlated with age (r=0.227, p=0.002), creatinine (r=0.175, p=0.018), urea nitrogen (r=0.162, p=0.028) and osmotic pressure (r=0.187, p=0.014) and negatively correlated with estimated glomerular filtration rate (eGFR) (r=-0.188, p=0.011). Log(10)Gal-9 levels increased along with the progression of GFR categories of G1 to G4, and they were statistically significant by Jonckheere-Terpstra test (p=0.012). Log(10)Gal-9 levels remained similar levels in albuminuria stages of A1 to A3. CONCLUSION: The elevation of serum Gal-9 in the patients with type 2 diabetes is closely linked to GFR and they may be related to the alteration of the immune response and inflammation of the patients with type 2 diabetes and CKD.

    DOI: 10.1186/1471-2369-14-23

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  • Urinary fetuin-A is a novel marker for diabetic nephropathy in type 2 diabetes identified by lectin microarray. 国際誌

    Kentaro Inoue, Jun Wada, Jun Eguchi, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Daisuke Ogawa, Takahiro Terami, Akihiro Katayama, Atsuhito Tone, Izumi Iseda, Kazuyuki Hida, Masao Yamada, Tomohisa Ogawa, Hirofumi Makino

    PloS one   8 ( 10 )   e77118   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n = 17) and measured urinary excretion of fetuin-A (n = 85). The increased signals of urine samples were observed in Siaα2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography-tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40 ± 0.43; A2, 0.60 ± 0.53; A3 1.57 ± 1.13 ng/gCr; p = 7.29 × 10(-8)) and of GFR stages (G1, 0.39 ± 0.39; G2, 0.49 ± 0.45; G3, 1.25 ± 1.18; G4, 1.34 ± 0.80 ng/gCr; p = 3.89 × 10(-4)). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR<60 mL/min. Fetuin-A is demonstrated as a risk factor for both microalbuminuria and reduction of GFR in diabetic nephropathy with the odds ratio of 4.721 (1.881-11.844) and 3.739 (1.785-7.841), respectively. Collectively, the glycan profiling analysis is useful method to identify the urine biomarkers and fetuin-A is a candidate to predict the progression of diabetic nephropathy.

    DOI: 10.1371/journal.pone.0077118

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  • Urinary angiotensinogen is a marker for tubular injuries in patients with type 2 diabetes. 国際誌

    Takahiro Terami, Jun Wada, Kentaro Inoue, Atsuko Nakatsuka, Daisuke Ogawa, Sanae Teshigawara, Kazutoshi Murakami, Akihiro Katayama, Jun Eguchi, Hirofumi Makino

    International journal of nephrology and renovascular disease   6   233 - 40   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Urinary angiotensinogen has been reported as a marker for the activation of intrarenal renin-angiotensin system (RAS) in various kidney diseases. To investigate the importance of urinary angiotensinogen in diabetic nephropathy, we compared the urinary levels of angiotensinogen, albumin, and α1-microglobulin. MATERIALS AND METHODS: Japanese patients with type 2 diabetes at various stages of nephropathy (n=85) were enrolled, and we measured albumin/creatinine ratio (ACR) and urinary excretion of angiotensinogen and α1-microglobulin. We also compared the clinical data of the patients treated with or without angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (RAS inhibitors [+], n=51; RAS inhibitors [-], n=34). RESULTS: Urinary angiotensinogen levels positively correlated with ACR (r=0.367, P=3.84×10(-4)) and urinary α1-microglobulin (r=0.734, P=1.32 × 10(-15)), while they negatively correlated with estimated glomerular filtration ratio (eGFR) (r=-0.350, P=1.02 × 10(-3)) and high-density lipoprotein cholesterol (r=-0.216, P=0.049). Multiple regression analysis was carried out to predict urinary angiotensinogen levels by employing eGFR, ACR, and urinary α1-microglobulin as independent variables; only urinary α1-microglobulin entered the regression equation at a significant level. Although ACR was higher in the RAS inhibitors (+) group, urinary α1-microglobulin and angiotensinogen did not show significant increase in the RAS inhibitors (+) group. CONCLUSION: Urinary angiotensinogen is well correlated with urinary α1-microglobulin and reflected the tubular injuries which may be associated with the intrarenal RAS activation in patients with type 2 diabetes.

    DOI: 10.2147/IJNRD.S51829

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  • Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex. 国際誌

    Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Chikage Sato Horiguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

    Diabetes   61 ( 11 )   2823 - 32   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK. Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions.

    DOI: 10.2337/db12-0232

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  • Activation of liver X receptor inhibits osteopontin and ameliorates diabetic nephropathy. 国際誌

    Hiromi Tachibana, Daisuke Ogawa, Yuichi Matsushita, Dennis Bruemmer, Jun Wada, Sanae Teshigawara, Jun Eguchi, Chikage Sato-Horiguchi, Haruhito Adam Uchida, Kenichi Shikata, Hirofumi Makino

    Journal of the American Society of Nephrology : JASN   23 ( 11 )   1835 - 46   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.

    DOI: 10.1681/ASN.2012010022

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  • Serum vaspin concentrations are closely related to insulin resistance, and rs77060950 at SERPINA12 genetically defines distinct group with higher serum levels in Japanese population. 国際誌

    Sanae Teshigawara, Jun Wada, Kazuyuki Hida, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Izumi Iseda, Yuichi Matsushita, Nobuyuki Miyatake, John F McDonald, Kikuko Hotta, Hirofumi Makino

    The Journal of clinical endocrinology and metabolism   97 ( 7 )   E1202-7   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CONTEXT: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats. OBJECTIVE: We investigated genetic and nongenetic factors that define serum concentrations of vaspin. DESIGN, SETTING AND PARTICIPANTS: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138). RESULTS: The level of serum vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum vaspin levels in T2D were significantly higher than healthy subjects (0.99 ± 0.04 vs. 0.86 ± 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum vaspin levels, i.e. CC (0.6 ± 0.4 ng/ml), CA (18.4 ± 9.6 ng/ml), and AA (30.5 ± 5.1 ng/ml) (P < 2 × 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950. CONCLUSIONS: Serum vaspin levels were related to insulin resistance, and higher levels of serum vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950.

    DOI: 10.1210/jc.2011-3297

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  • RXR antagonism induces G0 /G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21(Cip1) pathway in adipocytes. 国際誌

    Atsuko Nakatsuka, Jun Wada, Kazuyuki Hida, Aya Hida, Jun Eguchi, Sanae Teshigawara, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Daisuke Ogawa, Hiroyuki Kagechika, Hirofumi Makino

    The Journal of pathology   226 ( 5 )   784 - 95   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The peroxisome proliferator activated receptor-γ (PPARγ) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G0/G1 cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G0 + G1 ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G0 /G1 cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G0/G1 cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes.

    DOI: 10.1002/path.3001

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  • FOSL2 promotes leptin gene expression in human and mouse adipocytes. 国際誌

    Christiane D Wrann, Jun Eguchi, Aline Bozec, Zhao Xu, Tarjei Mikkelsen, Jeffrey Gimble, Heike Nave, Erwin F Wagner, Shao-En Ong, Evan D Rosen

    The Journal of clinical investigation   122 ( 3 )   1010 - 21   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The adipocyte-derived hormone leptin is a critical regulator of many physiological functions, ranging from satiety to immunity. Surprisingly, very little is known about the transcriptional pathways that regulate adipocyte-specific expression of leptin. Here, we report studies in which we pursued a strategy integrating BAC transgenic reporter mice, reporter assays, and chromatin state mapping to locate an adipocyte-specific cis-element upstream of the leptin (LEP) gene in human fat cells. Quantitative proteomics with affinity enrichment of protein-DNA complexes identified the transcription factor FOS-like antigen 2 (FOSL2) as binding specifically to the identified region, a result that was confirmed by ChIP. Knockdown of FOSL2 in human adipocytes decreased LEP expression, and overexpression of Fosl2 increased Lep expression in mouse adipocytes. Moreover, the elevated LEP expression observed in obesity correlated well with increased FOSL2 levels in mice and humans, and adipocyte-specific genetic deletion of Fosl2 in mice reduced Lep expression. Taken together, these data identify FOSL2 as a critical regulator of leptin expression in adipocytes.

    DOI: 10.1172/JCI58431

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  • Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes. 国際誌

    Motoko Kanzaki, Jun Wada, Koichi Sugiyama, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Jun Eguchi, Hisaya Akiba, Hideo Yagita, Hirofumi Makino

    Endocrinology   153 ( 2 )   612 - 20   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Galectin-9 (Gal-9), a ligand for T cell Ig mucin-3 (Tim-3), induces apoptosis in cluster of differentiation 4 (CD4)(+) Tim-3(+) T helper 1 (T(H)1) cells via the Gal-9-Tim-3 pathway and negatively regulates T(H)1 immunity. In turn, Gal-9 activates dendritic cells (DC) to produce TNF-α, which promotes the T(H)1 response. We investigated the efficacy of Gal-9 against T(H)1-mediated autoimmune diabetes in NOD mice and compared with anti-Tim-3 monoclonal antibody (RMT3-23), which inhibited the binding between Tim-3-Ig and Gal-9 in a solid-phase binding assay. mRNA expression of Gal-9 was prominently induced by the treatment of interferon-γ in MIN6 cells, and Gal-9 was also expressed in the pancreatic β-cells in NOD mice, suggesting Gal-9 may be released from pancreatic β-cells to terminate T(H)1-mediated inflammation. Long-term injection of Gal-9 exhibits preventive efficacy for development of diabetes in NOD mice, but RMT3-23 demonstrated further prominent therapeutic potential compared with Gal-9. Gal-9 induced apoptosis of CD4(+)Tim-3(+) T(H)1 cells at the concentration of 0.2 μM, whereas RMT3-23 failed to enhance the apoptosis of CD4(+)Tim-3(+) T(H)1 cells. In contrast, Gal-9 induced TNF-α production in cultured DC in a dose-dependent manner; however, RMT3-23 inhibited Gal-9-induced TNF-α production in a dose-dependent manner. Although Gal-9 exhibited certain therapeutic potential against autoimmune diabetes by enhancing apoptosis of CD4(+)Tim-3(+) T(H)1 cells, RMT3-23 exhibited prominent therapeutic efficacy by suppressing the TNF-α production and activation of DC. Taken together, the inhibition of the Gal-9-Tim-3 pathway on DC, upstream of T(H)1 response, may be a new target for the treatment of type 1 diabetes.

    DOI: 10.1210/en.2011-1579

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  • Telmisartan attenuates diabetic nephropathy by suppressing oxidative stress in db/db mice. 国際誌

    Chikage Sato-Horiguchi, Daisuke Ogawa, Jun Wada, Hiromi Tachibana, Ryo Kodera, Jun Eguchi, Atsuko Nakatsuka, Naoto Terami, Kenichi Shikata, Hirofumi Makino

    Nephron. Experimental nephrology   121 ( 3-4 )   e97-e108   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIMS: Telmisartan, an angiotensin II type 1 receptor blocker, is widely used to treat hypertension and kidney diseases, including diabetic nephropathy, because of its renoprotective effects. However, the mechanism by which telmisartan prevents proteinuria and renal dysfunction in diabetic nephropathy is still unclear. In this study, we examined the effects of telmisartan against diabetic nephropathy in db/db mice. METHODS: Telmisartan was administered at a dose of 5 mg/kg/day for 3 weeks to db/db (diabetic) and db/m (control) mice. Urinary albumin excretion, renal histology, and the gene expression of oxidative stress and inflammatory markers in renal tissue were determined. To evaluate the effects of telmisartan on reactive oxygen species (ROS) production, superoxide was detected by dihydroethidium (DHE) staining in vivo and in vitro. RESULTS: Telmisartan reduced albuminuria, mesangial matrix expansion, macrophage infiltration, and the expression of ROS markers (NADPH oxidase 4- and 8-hydroxydeoxyguanosine) and inflammatory cytokines (monocyte chemoattractant protein-1, osteopontin, and transforming growth factor-β) in the kidney. DHE staining showed that telmisartan decreased ROS generation in the kidney and in cultured mesangial and proximal tubular epithelial cells. CONCLUSIONS: Taken together, these findings indicate that telmisartan protects against diabetic nephropathy by reducing diabetes-induced oxidative stress.

    DOI: 10.1159/000343102

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  • Transcriptional control of adipose lipid handling by IRF4. 国際誌

    Jun Eguchi, Xun Wang, Songtao Yu, Erin E Kershaw, Patricia C Chiu, Joanne Dushay, Jennifer L Estall, Ulf Klein, Eleftheria Maratos-Flier, Evan D Rosen

    Cell metabolism   13 ( 3 )   249 - 59   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adipocytes store triglyceride during periods of nutritional affluence and release free fatty acids during fasting through coordinated cycles of lipogenesis and lipolysis. While much is known about the acute regulation of these processes during fasting and feeding, less is understood about the transcriptional basis by which adipocytes control lipid handling. Here, we show that interferon regulatory factor 4 (IRF4) is a critical determinant of the transcriptional response to nutrient availability in adipocytes. Fasting induces IRF4 in an insulin- and FoxO1-dependent manner. IRF4 is required for lipolysis, at least in part due to direct effects on the expression of adipocyte triglyceride lipase and hormone-sensitive lipase. Conversely, reduction of IRF4 enhances lipid synthesis. Mice lacking adipocyte IRF4 exhibit increased adiposity and deficient lipolysis. These studies establish a link between IRF4 and the disposition of calories in adipose tissue, with consequences for systemic metabolic homeostasis.

    DOI: 10.1016/j.cmet.2011.02.005

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  • Transcriptional targets in adipocyte biology. 国際誌

    Evan Rosen, Jun Eguchi, Zhao Xu

    Expert opinion on therapeutic targets   13 ( 8 )   975 - 86   2009年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The global burden of metabolic disease demands that we develop new therapeutic strategies. Many of these approaches may center on manipulating the behavior of adipocytes, which contribute directly and indirectly to a host of disease processes including obesity and type 2 diabetes. One way to achieve this goal will be to alter key transcriptional pathways in fat cells, such as those regulating glucose uptake, lipid handling, or adipokine secretion. In this review, we look at what is known about how adipocytes govern their physiology at the gene expression level, and discuss novel ways that we can accelerate our understanding of this area.

    DOI: 10.1517/14728220903039706

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  • Collectrin is involved in the development of salt-sensitive hypertension by facilitating the membrane trafficking of apical membrane proteins via interaction with soluble N-ethylmaleiamide-sensitive factor attachment protein receptor complex. 国際誌

    Akihiro Yasuhara, Jun Wada, Sandra M Malakauskas, Yanling Zhang, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Motoko Kanzaki, Sanae Teshigawara, Kazuya Yamagata, Thu H Le, Hirofumi Makino

    Circulation   118 ( 21 )   2146 - 55   2008年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic beta cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1alpha and -1beta. Because collectrin interacts with the soluble N-ethylmaleiamide-sensitive factor attachment protein receptor (SNARE) complexes, we investigated whether collectrin is involved in sodium handling in hypertension by vesicle trafficking of apical membrane proteins. METHODS AND RESULTS: Collectrin physically interacts with the SNARE complex: snapin, synaptosomal-associated protein 23 kDa, syntaxin-4, and vesicle-associated membrane protein-2 in mIMCD-3 cells. siRNA knockdown of collectrin resulted in a reduction in membrane-associated aquaporin-2, alpha-epithelial Na+ channel, and H+-ATPase. Collectrin and SNARE proteins were abundantly expressed in collecting ducts of Wistar-Kyoto rats. Wistar-Kyoto rats and spontaneously hypertensive rats 7 weeks of age were subjected to normal-salt (1% NaCl) and high-salt (8% NaCl) chow for 10 weeks. High-salt chow prominently elevated blood pressure, oral intake, and urinary excretion of NaCl and water in both groups. Although urinary excretion of aldosterone was significantly suppressed in both groups, collectrin expression was upregulated and associated with the maintenance of aquaporin-2, alpha-epithelial Na+ channel, and H+-ATPase in membrane fractions. Collectrin promoter activities and mRNA and protein expressions were upregulated and ubiquitinated collectrin was reduced by high NaCl (175 to 225 mmol/L) and not altered by 1 micromol/L aldosterone in mIMCD-3 cells. CONCLUSIONS: Upregulation of collectrin by high NaCl independent of aldosterone functionally links to the trafficking of apical membrane proteins via the SNARE complex, and collectrin may be responsible for the sodium retention in salt-sensitive hypertension.

    DOI: 10.1161/CIRCULATIONAHA.108.787259

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  • The orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor II is a critical regulator of adipogenesis. 国際誌

    Zhao Xu, Songtao Yu, Chung-Hsin Hsu, Jun Eguchi, Evan D Rosen

    Proceedings of the National Academy of Sciences of the United States of America   105 ( 7 )   2421 - 6   2008年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; Nr2f2) is expressed in adipose tissue in vivo and declines during differentiation. Overexpression of COUP-TFII prevents adipogenesis, whereas shRNA-mediated reduction of COUP-TFII promotes differentiation, as shown by increased lipid accumulation and elevated expression of fat cell marker proteins. Furthermore, reduction of COUP-TFII allows uncommitted fibroblasts to be differentiated into fat cells. COUP-TFII represses the expression of a number of proadipogenic factors in adipocytes, with direct action noted at the CAAT enhancer-binding protein alpha promoter. We show that COUP-TFII acts downstream of hedgehog signaling and is required for the full antiadipogenic effect of this pathway. This effect is mediated in part by interaction with GATA factors. COUP-TFII and GATA2 are physically associated and repress target gene expression in an additive manner. Taken together, our data demonstrate that COUP-TFII represents an endogenous suppressor of adipogenesis, linking antiadipogenic extracellular signals to the core transcriptional cascade.

    DOI: 10.1073/pnas.0707082105

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  • Interferon regulatory factors are transcriptional regulators of adipogenesis. 国際誌

    Jun Eguchi, Qing-Wu Yan, Dustin E Schones, Michael Kamal, Chung-Hsin Hsu, Michael Q Zhang, Gregory E Crawford, Evan D Rosen

    Cell metabolism   7 ( 1 )   86 - 94   2008年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We have sought to identify transcriptional pathways in adipogenesis using an integrated experimental and computational approach. Here, we employ high-throughput DNase hypersensitivity analysis to find regions of altered chromatin structure surrounding key adipocyte genes. Regions that display differentiation-dependent changes in hypersensitivity were used to predict binding sites for proteins involved in adipogenesis. A high-scoring example was a binding motif for interferon regulatory factor (IRF) family members. Expression of all nine mammalian IRF mRNAs is regulated during adipogenesis, and several bind to the identified motifs in a differentiation-dependent manner. Furthermore, several IRF proteins repress differentiation. This analysis suggests an important role for IRF proteins in adipocyte biology and demonstrates the utility of this approach in identifying cis- and trans-acting factors not previously suspected to participate in adipogenesis.

    DOI: 10.1016/j.cmet.2007.11.002

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  • The role for HNF-1beta-targeted collectrin in maintenance of primary cilia and cell polarity in collecting duct cells. 国際誌

    Yanling Zhang, Jun Wada, Akihiro Yasuhara, Izumi Iseda, Jun Eguchi, Kenji Fukui, Qin Yang, Kazuya Yamagata, Thomas Hiesberger, Peter Igarashi, Hong Zhang, Haiyan Wang, Shigeru Akagi, Yashpal S Kanwar, Hirofumi Makino

    PloS one   2 ( 5 )   e414   2007年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Collectrin, a homologue of angiotensin converting enzyme 2 (ACE2), is a type I transmembrane protein, and we originally reported its localization to the cytoplasm and apical membrane of collecting duct cells. Recently, two independent studies of targeted disruption of collectrin in mice resulted in severe and general defects in renal amino acid uptake. Collectrin has been reported to be under the transcriptional regulation by HNF-1alpha, which is exclusively expressed in proximal tubules and localized at the luminal side of brush border membranes. The deficiency of collectrin was associated with reduction of multiple amino acid transporters on luminal membranes. In the current study, we describe that collectrin is a target of HNF-1beta and heavily expressed in the primary cilium of renal collecting duct cells. Collectrin is also localized in the vesicles near the peri-basal body region and binds to gamma-actin-myosin II-A, SNARE, and polycystin-2-polaris complexes, and all of these are involved in intracellular and ciliary movement of vesicles and membrane proteins. Treatment of mIMCD3 cells with collectrin siRNA resulted in defective cilium formation, increased cell proliferation and apoptosis, and disappearance of polycystin-2 in the primary cilium. Suppression of collectrin mRNA in metanephric culture resulted in the formation of multiple longitudinal cysts in ureteric bud branches. Taken together, the cystic change and formation of defective cilium with the interference in the collectrin functions would suggest that it is necessary for recycling of the primary cilia-specific membrane proteins, the maintenance of the primary cilia and cell polarity of collecting duct cells. The transcriptional hierarchy between HNF-1beta and PKD (polycystic kidney disease) genes expressed in the primary cilia of collecting duct cells has been suggested, and collectrin is one of such HNF-1beta regulated genes.

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  • [ACAM, vaspin].

    Jun Wada, Kazuyuki Hida, Jun Eguchi, Hirofumi Makino

    Nihon rinsho. Japanese journal of clinical medicine   64 Suppl 9   297 - 9   2006年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms. 国際誌

    Tatsuo Okada, Jun Wada, Kazuyuki Hida, Jun Eguchi, Izumi Hashimoto, Masako Baba, Akihiro Yasuhara, Kenichi Shikata, Hirofumi Makino

    Diabetes   55 ( 6 )   1666 - 77   2006年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Thiazolidinediones are ligands for peroxisome proliferator-activated receptor (PPAR)-gamma, widely used as insulin sensitizer in type 2 diabetic patients and implicated in apoptosis, cell proliferation, and cell cycle regulation. Here, the effect of thiazolidinediones on G1-phase cell cycle arrest, the hallmark in diabetic nephropathy, was investigated. Eight-week-old male Otsuka Long-Evans Tokushima fatty rats were treated with pioglitazone (1 mg x kg body wt(-1) x day(-1)) until 50 weeks of age and compared with insulin treatment. Although similar HbA(1c) levels were observed in both groups, pioglitazone significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion compared with the insulin-treated group. In addition, pioglitazone significantly reduced the number of glomerular p27(Kip1)-positive cells. Because prominent expression of PPAR-gamma was observed in podocytes in glomeruli and cultured cells, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mmol/l D-glucose supplemented with pioglitazone. Pioglitazone inhibited cell hypertrophy revealed by [(3)H]thymidine and [(3)H]proline incorporation, and pioglitazone reversed high glucose-induced G1-phase cell cycle arrest, i.e., an increase in G0/G1 phase and decrease in S and G2 phases. Pioglitazone suppressed high glucose-induced phosphorylation of p44/42 mitogen-activated protein kinase and reduced Bcl-2 and p27(Kip1) protein levels. Besides glucose-lowering action, pioglitazone ameliorates diabetic nephropathy via cell cycle-dependent mechanisms.

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  • Elevated serum monocyte chemoattractant protein-4 and chronic inflammation in overweight subjects. 国際誌

    Izumi Hashimoto, Jun Wada, Aya Hida, Masako Baba, Nobuyuki Miyatake, Jun Eguchi, Kenichi Shikata, Hirofumi Makino

    Obesity (Silver Spring, Md.)   14 ( 5 )   799 - 811   2006年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Chronic inflammation observed in obesity has been reported to be implicated in the development of atherosclerosis. We screened candidate chemokines that link chronic inflammation and obesity. RESEARCH METHODS AND PROCEDURES: Japanese overweight (n = 39, BMI 28.7 +/- 0.65 kg/m(2)) and normal-weight (n = 24, BMI 22.3 +/- 0.45 kg/m(2)) subjects were enrolled. Using antibody-based protein microarray, spot intensities of monocyte chemoattractant protein (MCP)-4, eotaxin, and eotaxin-2 correlated with anthropometric parameters. We further measured serum concentration of these chemokines and mRNA levels in adipose tissues obtained from volunteers. RESULTS: Serum MCP-4 levels showed positive correlation with BMI (r = 0.318, p = 0.014), waist (r = 0.316, p = 0.018), and waist-to-hip ratio (WHR) (r = 0.264, p = 0.049). Furthermore, MCP-4 correlated with homeostasis model assessment of insulin resistance (r = 0.392, p = 0.002), high-sensitivity C-reactive protein (hsCRP) (r = 0.350, p = 0.006). In step-wise multiple regression analyses, hsCRP independently correlated with MCP-4 levels. The expression of MCP-4 mRNA in visceral adipose tissue positively correlates with BMI. Serum eotaxin levels correlate with BMI (r = 0.262, p = 0.045) and WHR (r = 0.383, p = 0.003). Serum eotaxin-2 levels correlated with BMI (r = 0.464, p < 0.001), waist (r = 0.333, p = 0.017), and WHR (r = 0.278, p = 0.048). However, eotaxin and eotaxin-2 levels did not show significant correlation with hsCRP. DISCUSSION: Serum levels of MCP-4, eotaxin, and eotaxin-2, which belong to CC chemokine family and share CC chemokine receptor 3, correlated with BMI. These chemokines, especially MCP-4, may be critical molecules that link obesity and chronic inflammation.

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  • Therapeutic approach for diabetic nephropathy using gene delivery of translocase of inner mitochondrial membrane 44 by reducing mitochondrial superoxide production. 国際誌

    Yanling Zhang, Jun Wada, Izumi Hashimoto, Jun Eguchi, Akihiro Yasuhara, Yashpal S Kanwar, Kenichi Shikata, Hirofumi Makino

    Journal of the American Society of Nephrology : JASN   17 ( 4 )   1090 - 101   2006年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hyperglycemia-induced overproduction of mitochondrial reactive oxygen species has emerged as a major player in diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane 44 (TIM44) was identified by upregulation in diabetic mouse kidneys. TIM44 functions as a membrane anchor of mitochondrial heat-shock protein 70 (mtHsp70) to TIM23 complex and is involved in the import of mitochondria-targeted preproteins into mitochondrial matrix. The process is dependent on inner membrane potential and ATP hydrolysis on ATPase domain of mitochondrial heat-shock protein 70. Hemagglutination virus of Japan-envelope vector that carries pcDNA3.1 plasmid that contains the full-length cDNA of TIM44 and control plasmid were injected weekly into the tail vein of uninephrectomized streptozotocin-induced diabetic CD-1 mice. The gene delivery alleviated proteinuria and renal hypertrophy at 8 wk after the injection, inhibited renal cell proliferation and apoptosis, and suppressed superoxide production. In vitro experiments, using human proximal tubular (HK2) cells, revealed that the gene delivery of TIM44 reversed high glucose-induced metabolic and cellular abnormalities such as enhanced reactive oxygen species production, increased ATP contents, alterations in inner membrane potential, increased cell proliferation, and apoptosis. Transfection with siRNA and expressing vector of TIM44 revealed that TIM44 facilitates import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase into mitochondria. The gene delivery of TIM44 therefore seems to be beneficial for the maintenance of mitochondrial function and is a novel therapeutic approach for diabetic nephropathy.

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  • Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. 国際誌

    Masako Baba, Jun Wada, Jun Eguchi, Izumi Hashimoto, Tatsuo Okada, Akihiro Yasuhara, Kenichi Shikata, Yashpal S Kanwar, Hirofumi Makino

    Journal of the American Society of Nephrology : JASN   16 ( 11 )   3222 - 34   2005年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Galectins are beta-galactoside-binding lectins that are involved in various biologic processes, such as apoptosis, cell proliferation, and cell-cycle regulation. Galectin-9 (Gal-9) was identified previously and demonstrated to have apoptotic potential to thymocytes in mice and activated CD8(+) T cells in nephrotoxic serum nephritis model. In this study, the effect of Gal-9 on G1-phase cell-cycle arrest, one of the hallmark pathologic changes in early diabetic nephropathy, was investigated. Eight-week-old male db/db mice received injections of recombinant Gal-9 or vehicle for 8 wk. The injection of Gal-9 into db/db mice significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion. Gal-9 reduced glomerular expression of TGF-beta1 and the number of p27(Kip1)- and p21(Cip1)-positive cells in glomeruli. Double staining with nephrin and type IV collagen revealed that podocytes were mainly positive for p27(Kip1). For further confirming the cell-cycle regulation by Gal-9, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mM d-glucose supplemented with Gal-9. Cell-cycle distribution analyses revealed that Gal-9 maintained further progression of cell cycle from the G1 phase. Gal-9 reversed the high-glucose-mediated upregulation of p27(Kip1) and p21(Cip1) and inhibited cell-cycle-dependent hypertrophy, i.e., reduced [(3)H]proline incorporation. The data suggest that Gal-9 plays a central role in inducing their successful progression from G1 to G2 phase by suppressing glomerular expression of TGF-beta1 and inhibition of cyclin-dependent kinase inhibitors. Gal-9 may give an impetus to develop new therapeutic tools targeted toward diabetic nephropathy.

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  • Gene delivery of Tim44 reduces mitochondrial superoxide production and ameliorates neointimal proliferation of injured carotid artery in diabetic rats. 国際誌

    Takashi Matsuoka, Jun Wada, Izumi Hashimoto, Yanling Zhang, Jun Eguchi, Norio Ogawa, Kenichi Shikata, Yashpal S Kanwar, Hirofumi Makino

    Diabetes   54 ( 10 )   2882 - 90   2005年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hyperglycemia induces the production of reactive oxygen species (ROS) from mitochondria, which is closely related to diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane (Tim)44 was identified by upregulation in streptozotocin (STZ)-induced diabetic mouse kidneys; Tim44 functions as a membrane anchor of mtHsp70 to TIM23 complex and is involved in the import of preproteins with mitochondria-targeted presequence into mitochondrial matrix. The process is dependent on inner membrane potential (Delta psi) and ATP hydrolysis on ATPase domain of mtHsp70. Here, we show that the gene delivery of Tim44 using pcDNA3.1 vector (pcDNA3.1/TIM44) into the balloon injury model of STZ-induced diabetic rats ameliorated neointimal proliferation. ROS production, inflammatory responses, and cell proliferation in injured carotid artery were diminished by delivery of pcDNA3.1/TIM44. In vitro experiments using human aortic smooth muscle cells (HASMCs) revealed that the gene delivery of Tim44 normalized high-glucose-induced enhanced ROS production and increased ATP production, alterations in inner membrane potential, and cell proliferation. Transfection of siRNA and pcDNA3.1/TIM44 using HASMC culture clarified that import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase was facilitated by Tim44. Tim44 and its related molecules in mitochondrial import machinery complex are novel targets in the therapeutic interventions for diabetes and its vascular complications.

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  • Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. 国際誌

    Kazuyuki Hida, Jun Wada, Jun Eguchi, Hong Zhang, Masako Baba, Aya Seida, Izumi Hashimoto, Tatsuo Okada, Akihiro Yasuhara, Atsuko Nakatsuka, Kenichi Shikata, Shinji Hourai, Junichiro Futami, Eijiro Watanabe, Yasushi Matsuki, Ryuji Hiramatsu, Shigeru Akagi, Hirofumi Makino, Yashpal S Kanwar

    Proceedings of the National Academy of Sciences of the United States of America   102 ( 30 )   10610 - 5   2005年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    There is a rapid global rise in obesity, and the link between obesity and diabetes remains somewhat obscure. We identified an adipocytokine, designated as visceral adipose tissue-derived serpin (vaspin), which is a member of serine protease inhibitor family. Vaspin cDNA was isolated by from visceral white adipose tissues (WATs) of Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model of abdominal obesity with type 2 diabetes. Rat, mouse, and human vaspins are made up of 392, 394, and 395 amino acids, respectively; exhibit approximately 40% homology with alpha1-antitrypsin; and are related to serine protease inhibitor family. Vaspin was barely detectable in rats at 6 wk and was highly expressed in adipocytes of visceral WATs at 30 wk, the age when obesity, body weight, and insulin levels peak in OLETF rats. The tissue expression of vaspin and its serum levels decrease with worsening of diabetes and body weight loss at 50 wk. The expression and serum levels were normalized with the treatment of insulin or insulin-sensitizing agent, pioglitazone, in OLETF rats. Administration of vaspin to obese CRL:CD-1 (ICR) (ICR) mice fed with high-fat high-sucrose chow improved glucose tolerance and insulin sensitivity reflected by normalized serum glucose levels. It also led to the reversal of altered expression of genes relevant to insulin resistance, e.g., leptin, resistin, TNFalpha, glucose transporter-4, and adiponectin. In DNA chip analyses, vaspin treatment resulted in the reversal of expression in approximately 50% of the high-fat high-sucrose-induced genes in WATs. These findings indicate that vaspin exerts an insulin-sensitizing effect targeted toward WATs in states of obesity.

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  • Identification of adipocyte adhesion molecule (ACAM), a novel CTX gene family, implicated in adipocyte maturation and development of obesity. 国際誌

    Jun Eguchi, Jun Wada, Kazuyuki Hida, Hong Zhang, Takashi Matsuoka, Masako Baba, Izumi Hashimoto, Kenichi Shikata, Norio Ogawa, Hirofumi Makino

    The Biochemical journal   387 ( Pt 2 )   343 - 53   2005年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Few cell adhesion molecules have been reported to be expressed in mature adipocytes, and the significance of cell adhesion process in adipocyte biology is also unknown. In the present study, we identified ACAM (adipocyte adhesion molecule), a novel homologue of the CTX (cortical thymocyte marker in Xenopus) gene family. ACAM cDNA was isolated during PCR-based cDNA subtraction, and its mRNA was shown to be up-regulated in WATs (white adipose tissues) of OLETF (Otsuka Long-Evans Tokushima fatty) rats, an animal model for Type II diabetes and obesity. ACAM, 372 amino acids in total, has a signal peptide, V-type (variable) and C2-type (constant) Ig domains, a single transmembrane segment and a cytoplasmic tail. The amino acid sequence in rat is highly homologous to mouse (94%) and human (87%). ACAM mRNA was predominantly expressed in WATs in OLETF rats, and increased with the development of obesity until 30 weeks of age, which is when the peak of body mass is reached. Western blot analysis revealed that ACAM protein, approx. 45 kDa, was associated with plasma membrane fractions of mature adipocytes isolated from mesenteric and subdermal adipose deposits of OLETF rats. Up-regulation of ACAM mRNAs in obesity was also shown in WATs of genetically obese db/db mice, diet-induced obese ICR mice and human obese subjects. In primary cultured mouse and human adipocytes, ACAM mRNA expression was progressively up-regulated during differentiation. Several stably transfected Chinese-hamster ovary K1 cell lines were established, and the quantification of ACAM mRNA and cell aggregation assay revealed that the degree of homophilic aggregation correlated well with ACAM mRNA expression. In summary, ACAM may be the critical adhesion molecule in adipocyte differentiation and development of obesity.

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  • The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats. 国際誌

    Keita Hiragushi, Jun Wada, Jun Eguchi, Takashi Matsuoka, Akihiro Yasuhara, Izumi Hashimoto, Tetsuji Yamashita, Kazuyuki Hida, Yoshio Nakamura, Kenichi Shikata, Naoto Minamino, Kenji Kangawa, Hirofumi Makino

    Kidney international   65 ( 2 )   540 - 50   2004年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity-modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy. METHODS: Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release. RESULTS: STZ rats showed glomerular hypertrophy and increased urinary NO2- and NO3- excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 +/- 360 fmol/day vs. control 110 +/- 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, d-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides. CONCLUSION: Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes.

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  • Multicentric Castleman's disease associated with glomerular microangiopathy and MPGN-like lesion: does vascular endothelial cell-derived growth factor play causative or protective roles in renal injury? 国際誌

    Aya Seida, Jun Wada, Yoshitaka Morita, Masako Baba, Jun Eguchi, Norihisa Nishimoto, Takeshi Okino, Koichi Ichimura, Tadashi Yoshino, Hirofumi Makino

    American journal of kidney diseases : the official journal of the National Kidney Foundation   43 ( 1 )   E3-9   2004年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A 52-year-old Japanese man presented with fever spikes, generalized fatigue, anorexia, and anasarca. The patient was referred for the evaluation of fever of unknown origin in association with swelling of cervical, axillary, and inguinal lymph nodes. He also manifested nephrotic syndrome, acute renal failure, hepatosplenomegaly, massive pleural effusion, ascites, disseminated intravascular coagulation, and hypergammaglobulinemia. C-reactive protein was positive and plasma vascular endothelial cell-derived growth factor (VEGF) and serum interleukin-6 levels were markedly elevated. Lymph node biopsy results showed that findings were compatible with Castleman's disease of hyaline vascular type associated with interfollicular plasmacytosis. In conjunction with the clinical findings, a diagnosis of multicentric Castleman's disease was made. The patient underwent renal biopsy because of nephrotic syndrome, and the results showed proliferation of mesangial cells, lobulation of glomeruli, and tram track pattern of the capillary wall without immune complex deposition. Electron microscopy showed widening of the subendothelial space. No electron-dense deposits were present in both mesangial and subendothelial regions. Pathologic features were compatible with glomerular microangiopathy and membranoproliferative glomerulonephritis-like lesions. With corticosteroid therapy, systemic symptoms disappeared; both VEGF and interleukin-6 levels were normalized, and he went into complete remission of nephrotic syndrome. In this article, the role VEGF plays in the pathogenesis of nephrotic syndrome and glomerular microangiopathy is discussed.

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  • [Management of diabetic nephropathy with nephrotic syndrome].

    Jun Eguchi, Jun Wada, Hirofumi Makino

    Nihon rinsho. Japanese journal of clinical medicine   60 Suppl 10   430 - 6   2002年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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書籍等出版物

  • 肥満関連腎臓病に対する効果 査読

    江口 潤、和田 淳( 担当: 共著)

    メディカ出版  2020年10月 

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    担当ページ:185-189   記述言語:日本語 著書種別:学術書

MISC

  • 2型糖尿病患者を対象とした服薬アドヒアランス~良好な血糖管理に必要な服薬遵守度・遵守率の検討~

    黒岡直子, 江口潤, 芦田真理, 中島倫子, 和田淳, 中島弘文

    糖尿病(Web)   63 ( 9 )   2020年

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  • バスピンとメタボリックシンドローム

    和田淳, 中司敦子, 江口潤

    日本動脈硬化学会総会・学術集会プログラム・抄録集(Web)   52nd   2020年

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  • 持続血糖モニタリングによる1型糖尿病合併妊婦の血糖管理-正常耐糖能妊婦,妊娠糖尿病妊婦の分娩前血糖変動の比較検討-

    渡邉真由, 牧尉太, 片山晶博, 勅使川原早苗, 利根淳仁, 江口潤, 片岡仁美, 増山寿, 和田淳

    糖尿病と妊娠   20 ( 1 )   2020年

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  • 高齢2型糖尿病罹患女性における長期的SGLT2阻害薬投与が骨格筋量および筋力に及ぼす変化の検討

    神野文香, 渡邉真由, 中島弘文, 中島倫子, 江口潤, 和田淳

    糖尿病(Web)   63 ( Suppl )   2020年

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  • 尿細管間質障害におけるHSPA1Lの意義

    中司敦子, 江口潤, 和田淳

    日本腎臓学会誌(Web)   62 ( 4 )   2020年

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  • 2型糖尿病に対するメトホルミンの抗腫瘍効果

    野島一郎, 榮川伸吾, 梶谷展生, 勅使川原早苗, 宮本聡, 利根淳仁, 内田治仁, 中司敦子, 江口潤, 四方賢一, 鵜殿平一郎, 和田淳

    糖尿病(Web)   63 ( Suppl )   2020年

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  • 糖尿病発症までの継時的変化を観察しえた抗PD-1抗体関連1型糖尿病の2症例

    渡邉真由, 江口潤, 片山晶博, 片岡仁美, 和田淳

    糖尿病(Web)   63 ( 9 )   2020年

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  • メタボリックシンドロームにおけるmir221/222の機能解析

    山口哲志, 片山晶博, 樋口千草, 勅使川原早苗, 中司敦子, 江口潤, 和田淳

    日本糖尿病・肥満動物学会年次学術集会プログラム・講演抄録集   34th   2020年

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  • 当院におけるTime-In-Range(TIR)とHbA1cとの関連についての検討

    片山晶博, 野島一郎, 樋口千草, 渡邉真由, 宮本聡, 中司敦子, 江口潤, 四方賢一, 和田淳

    糖尿病(Web)   63 ( Suppl )   2020年

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  • 糖尿病患者1000人の服薬遵守率の検討~適切な服薬遵守率は95%以上である~

    黒岡直子, 芦田真理, 中島倫子, 江口潤, 和田淳, 中島弘文

    糖尿病(Web)   62 ( Suppl )   2019年

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  • 膵頭十二指腸切除術を受けた患者における術後回復の強化プロトコールの影響:ランダム化比較試験

    高木弘誠, 吉田龍一, 八木孝仁, 楳田祐三, 信岡大輔, 杭瀬崇, 樋之津史郎, 松崎孝, 森松博史, 江口潤, 和田淳, 千田益生, 藤原俊義

    学会誌JSPEN(Web)   1 ( Supplement )   2019年

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  • 糖尿病における近位尿細管細胞のGRP78局在変化とバスピンの受容体としての意義

    中司敦子, 江口潤, 和田淳

    日本腎臓学会誌   61 ( 3 )   2019年

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  • 肥満糖尿病の近位尿細管障害におけるHSPsの新規作用機序の解明

    中司敦子, 山口哲志, 江口潤, 和田淳

    日本肥満学会・日本肥満症治療学会合同学術集会プログラム・抄録集   40th-37th   2019年

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  • インスリンポンプ療法からSAP療法への治療変更効果に関する後ろ向き観察研究

    山口哲志, 利根淳仁, 勅使川原早苗, 渡邊真由, 片山晶博, 宮本聡, 江口潤, 中司敦子, 樋口千草, 小川大輔, 四方賢一, 和田淳

    糖尿病(Web)   62 ( 5 )   2019年

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  • 糖尿病手症候群を呈した2型糖尿病の1例

    山口哲志, 片山晶博, 宮脇義亜, 江口潤, 中原龍一, 和田淳

    糖尿病(Web)   62 ( 2 )   2019年

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  • Fetuin-Aの糖尿病腎症進展における役割

    三瀬広記, 中司敦子, 山口哲志, 勅使川原早苗, 田邊克幸, 江口潤, 和田淳

    糖尿病(Web)   62 ( Suppl )   2019年

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  • 2型糖尿病患者における尿中糖鎖排泄量と腎・心血管イベントおよび総死亡との関連の検討

    今村麻理子, 三瀬広記, 中塔辰明, 清水一紀, 安藤晋一郎, 松岡孝, 宮下雄博, 肥田和之, 江口潤, 中司敦子, 四方賢一, 和田淳

    糖尿病(Web)   62 ( 2 )   2019年

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  • mir342ノックアウトマウスにおける肥満・糖代謝の改善メカニズム

    張冬暁, 山口哲志, 黒岡直子, 中司敦子, 江口潤, 和田淳

    日本肥満学会・日本肥満症治療学会合同学術集会プログラム・抄録集   40th-37th   2019年

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  • Prader-Willi症候群に合併した糖尿病の1例

    柴田祐助, 江口潤, 高橋寛子, 山口哲志, 野島一郎, 樋口千草, 渡邉真由, 中司敦子, 和田淳

    糖尿病(Web)   62 ( 2 )   2019年

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  • SGLT2阻害薬による降圧と腎保護にはRAS阻害薬の併用が有用である

    高橋寛子, 中島倫子, 江口潤, 和田淳, 中島弘文

    糖尿病(Web)   62 ( Suppl )   2019年

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  • Tim44(translocase of inner mitochondrial membrane 44)とメタボリックシンドロームにおける機能解析

    和田淳, 王玉, 片山晶博, 寺見隆宏, 布上朋和, 中司敦子, 村上和敏, 勅使川原早苗, 江口潤

    糖尿病   58 ( Supplement 1 )   2015年

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  • 脂肪組織と骨格筋を制御する新規膜蛋白の同定とメタボリック症候群における病態生理学的意義

    江口潤

    第一三共生命科学研究振興財団研究報告集   31   2015年

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  • 脂肪細胞特異的PDK1欠損マウスを用いた代謝異常症およびNASHの病態における脂肪細胞の機能不全の意義の解明

    細岡哲也, 松木核, 野村和弘, 松居翔, 佐々木努, 北村忠弘, 江口潤, ROSEN Evan D., 中江淳, ACCILI Domenico, 春日雅人, 小川渉

    日本糖尿病・肥満動物学会年次学術集会プログラム・講演抄録集   29th   2015年

     詳細を見る

  • インスリンを使用せずインスリン非依存状態を維持しているGAD抗体強陽性高齢者糖尿病の1例

    野島一郎, 江口潤, 堀口千景, 四方賢一, 和田淳

    糖尿病   58 ( 1 )   2015年

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  • 肥満関連腎症におけるvaspinの意義

    中司敦子, 村上和敏, 勅使川原早苗, 山口哲志, 柴田祐助, 天田雅文, 片山晶博, 江口潤, 和田淳

    肥満研究   21 ( Supplement )   2015年

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  • 代謝異常症およびNASHの病態における脂肪細胞の機能不全の意義と分子機構の解明

    細岡哲也, 松木核, 野村和弘, 松居翔, 佐々木努, 北村忠弘, 江口潤, ROSEN Evan D, 中江淳, ACCILI Domenico, 春日雅人, 小川渉

    日本内分泌学会雑誌   91 ( 1 )   2015年

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  • メタボリックシンドロームにおけるGalectin-9の意義

    布上朋和, 勅使川原早苗, 山口哲志, 柴田祐助, 天田雅文, 片山晶博, 村上和敏, 中司敦子, 江口潤, 和田淳

    糖尿病   58 ( Supplement 1 )   2015年

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  • インスリン抵抗性・糖代謝異常の病態における脂肪細胞のPDK1-FoxO1経路の意義の解明

    細岡哲也, 松木核, 野村和弘, 松居翔, 佐々木努, 北村忠弘, 江口潤, ROSEN Evan D., 中江淳, ACCILI Domenico, 春日雅人, 小川渉

    糖尿病   58 ( Supplement 1 )   2015年

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  • 糖尿病モデルマウスにおいて,ダパグリフロジンは酸化ストレスを軽減し糖尿病性腎症を改善させる

    畑中崇志, 小川大輔, 寺見直人, 西井尚子, 中司敦子, 江口潤, 和田淳

    糖尿病   58 ( Supplement 1 )   2015年

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  • メタボリックシンドロームにおけるphosphatidylethanolamine N-methyltransferase(PEMT)が関与する脂肪肝炎と肝再生機構

    中司敦子, 村上和敏, 勅使川原早苗, 片山晶博, 天田雅文, 布上朋和, 山口哲志, 江口潤, 小川大輔, 和田淳

    糖尿病   58 ( Supplement 1 )   2015年

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  • 糖尿病腎症の分子機構と診断・治療への展開

    和田淳, 中司敦子, 江口潤

    糖尿病学の進歩   49th   2015年

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  • 肥満症と腎疾患

    和田淳, 中司敦子, 勅使川原早苗, 村上和敏, 江口潤

    肥満研究   21 ( Supplement )   2015年

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  • メタボリックシンドロームにおけるmicroRNAの機能解析

    山口哲志, 片山晶博, 樋口千草, 中司敦子, 江口潤, 村上和敏, 勅使川原早苗, 和田淳

    肥満研究   21 ( Supplement )   2015年

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  • 脂肪細胞特異的Creトランスジェニックマウス

    江口潤

    医学のあゆみ   250 ( 9 )   2014年

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  • 転写因子IRF(Interferon Regulatory Factor)ファミリーによるメタボリック症候群における代謝制御機構の解明

    江口潤

    医科学応用研究財団研究報告(CD-ROM)   31   2014年

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  • 脂肪細胞における接着とアクチン重合を介したACAMの抗肥満作用

    村上和敏, 江口潤, 中司敦子, 和田淳

    肥満研究   20 ( Supplement )   2014年

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  • 肥満により脂肪組織に誘導される膜蛋白Gpnmbの脂肪肝炎抑制効果

    片山晶博, 和田淳, 中司敦子, 江口潤, 村上和敏, 勅使川原早苗, 樋口千草, 布上朋和, 天田雅文, 肥田和之, 槇野博史

    糖尿病   57 ( Supplement 1 )   2014年

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  • ACAM(adipocyte adhesion molecule)/CLMPの一次繊毛機能を介した脂肪細胞分化と肥満症における意義

    村上和敏, 和田淳, 佐藤美和, 江口潤, 布上朋和, 片山晶博, 中司敦子, 小川大輔, 四方賢一, 槇野博史

    糖尿病   57 ( Supplement 1 )   2014年

     詳細を見る

  • レクチンマイクロアレイによる糖尿病性腎症の新規バイオマーカーの同定

    和田淳, 勅使川原早苗, 中司敦子, 江口潤

    日本腎臓学会誌   56 ( 6 )   2014年

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  • エクソーム解析を行った若年発症糖尿病の1例

    布上朋和, 江口潤, 天田雅文, 和田淳, 四方賢一, 槇野博史

    糖尿病   57 ( Supplement 1 )   2014年

     詳細を見る

  • メタボリックシンドロームにおけるGalectin-9の意義

    布上朋和, 勅使川原早苗, 柴田祐助, 天田雅文, 片山晶博, 村上和敏, 江口潤, 中司敦子, 和田淳

    肥満研究   20 ( Supplement )   2014年

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  • メタボリックシンドロームにおける脂肪組織と骨格筋の機能異常を制御する新規因子の探索

    天田雅文, 江口潤, 柴田祐助, 布上朋和, 片山晶博, 勅使川原早苗, 村上和敏, 中司敦子, 和田淳

    肥満研究   20 ( Supplement )   2014年

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  • 2型糖尿病マウスにおけるSGLT2阻害薬ダパグリフロジンの腎保護効果の検討

    小川大輔, 寺見直人, 畑中崇志, 橘洋美, 江口潤, 中司敦子, 和田淳, 槇野博史

    糖尿病   57 ( Supplement 1 )   2014年

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  • 2型糖尿病患者に合併したFisher症候群の1例

    天田雅文, 和田淳, 片山晶博, 江口潤, 佐藤恒太, 河野祥一郎, 出口健太郎, 四方賢一, 槇野博史

    糖尿病   57 ( 8 )   2014年

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  • メタボリックシンドロームに伴う脂肪肝炎とPemtの意義

    中司敦子, 村上和敏, 勅使川原早苗, 片山晶博, 布上朋和, 天田雅文, 山口哲志, 江口潤, 和田淳

    肥満研究   20 ( Supplement )   2014年

     詳細を見る

  • SGLT2阻害薬ダパグリフロジンの糖代謝改善作用および腎保護作用の検討

    小川大輔, 寺見直人, 畑中崇志, 西井尚子, 江口潤, 中司敦子, 和田淳, 槇野博史

    糖尿病合併症   28 ( Supplement 1 )   2014年

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  • 新規PPARγアンタゴニスト/インバースアゴニストの創製

    大橋雅生, 蒲生佳奈恵, 田中雄大, 紅山容子, 脇稔, 松浦信康, 槇島誠, 大山拓次, 松野研司, 天田雅文, 和田淳, 江口潤, 宮地弘幸

    日本薬学会年会要旨集(CD-ROM)   134th   2014年

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  • 下肢の異常感覚と脱力で発症し糖尿病性筋萎縮症が疑われた1例

    柴田祐助, 江口潤, 小松原基史, 和田淳, 四方賢一, 出口健太郎, 阿部康二, 槇野博史

    糖尿病   57 ( 8 )   2014年

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  • メタボリックシンドロームにおけるphosphatidylethanolamine N-methyltransferase(PEMT)の意義

    中司敦子, 和田淳, 村上和敏, 勅使川原早苗, 片山晶博, 渡邊真由, 樋口千草, 天田雅文, 布上朋和, 江口潤, 小川大輔, 槇野博史

    糖尿病   57 ( Supplement 1 )   2014年

     詳細を見る

  • 糖尿病腎症第1期および第2期における腎機能低下要因の解析

    小比賀美香子, 四方賢一, 小野哲一郎, 小寺亮, 江口潤, 廣田大昌, 村上和敏, 中司敦子, 小川大輔, 和田淳, 片岡仁美, 槇野博史

    糖尿病   57 ( Supplement 1 )   2014年

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  • 統合失調症をもつ妊娠糖尿病患者への他職種での連携支援

    料治三恵, 佐藤久恵, 上杉明子, 箱崎文香, 吉田由理, 野口絢子, 岡本真由美, 高樽由美, 大橋睦子, 高取佐智子, 坂本八千代, 江口潤, 瀬川友功, 和田淳, 四方賢一, 平松祐司

    糖尿病と妊娠   14 ( 2 )   2014年

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  • 糖尿病性腎症の糖鎖プロファイリングによる新規バイオマーカーの同定(U-CARE研究)

    和田淳, 井上謙太郎, 中司敦子, 江口潤, 村上和敏, 寺見隆宏, 勅使川原早苗, 片山晶博, 小川智央, 山田雅雄, 四方賢一, 槇野博史

    日本腎臓学会誌   55 ( 3 )   2013年

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  • ACAM(adipocyte adhesion molecule)/CLMPの脂肪分化と肥満症における意義

    村上和敏, 和田淳, 江口潤, 中司敦子, 寺見隆宏, 井上謙太郎, 片山晶博, 勅使川原早苗, 槇野博史

    糖尿病   56 ( Supplement 1 )   2013年

     詳細を見る

  • Vaspinによる小胞体ストレス制御と糖尿病性腎症の治療

    中司敦子, 和田淳, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 片山晶博, 村上和敏, 江口潤, 小川大輔, 槇野博史

    日本腎臓学会誌   55 ( 3 )   2013年

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  • 糖尿病性腎症の糖鎖プロファイリングの検討

    井上謙太郎, 和田淳, 小川大輔, 中司敦子, 江口潤, 村上和敏, 神崎資子, 寺見隆宏, 勅使川原早苗, 片山晶博, 小川智央, 山田雅雄, 四方賢一, 槇野博史

    糖尿病   56 ( Supplement 1 )   2013年

     詳細を見る

  • 脂肪細胞における転写因子IRF4の機能

    江口潤

    医学のあゆみ   245 ( 11 )   2013年

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  • マウス腎および培養腎細胞における核内受容体の発現と高糖濃度刺激による発現変化の検討

    寺見直人, 小川大輔, 橘洋美, 堀口千景, 小寺亮, 江口潤, 中司敦子, 和田淳, 四方賢一, 槇野博史

    日本腎臓学会誌   55 ( 3 )   2013年

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  • 若年性白内障および糖尿病を契機に発見された筋強直性ジストロフィーの1例

    片山晶博, 水野智文, 畑中崇志, 原孝行, 和田淳, 江口潤, 中司敦子, 小川大輔, 四方賢一, 槇野博史

    糖尿病   56 ( 5 )   2013年

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  • 糖尿病性腎症におけるPEMT阻害の意義

    中司敦子, 和田淳, 渡辺真由, 勅使川原早苗, 村上和敏, 井上謙太郎, 寺見隆宏, 片山晶博, 江口潤, 小川大輔, 槇野博史

    日本腎臓学会誌   55 ( 3 )   2013年

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  • 嚢胞形成の新規分子機構-ACAM/CLMP欠損マウスの解析-

    村上和敏, 和田淳, 江口潤, 中司敦子, 佐藤美和, 寺見直人, 小川大輔, 槇野博史

    日本腎臓学会誌   55 ( 3 )   2013年

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  • 内臓脂肪蓄積に伴って強発現する膜蛋白Gpnmbの脂肪肝炎抑制効果と可溶性分泌型の関与

    片山晶博, 和田淳, 中司敦子, 江口潤, 村上和敏, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 渡邉真由, 樋口千草, 肥田和之, 四方賢一, 槇野博史

    糖尿病   56 ( Supplement 1 )   2013年

     詳細を見る

  • メタボリックシンドロームにおけるGalectin-9-Tim-3経路の意義

    勅使川原早苗, 和田淳, 神崎資子, 江口潤, 中司敦子, 村上和敏, 井上謙太郎, 寺見隆宏, 片山晶博, 槇野博史

    糖尿病   56 ( Supplement 1 )   2013年

     詳細を見る

  • 肥満で脂肪組織に誘導される膜蛋白Gpnmbの脂肪肝炎抑制効果

    片山晶博, 和田淳, 中司敦子, 江口潤, 村上和敏, 勅使川原早苗, 寺見隆宏, 樋口千草, 布上朋和, 天田雅文, 四方賢一, 肥田和之, 槇野博史

    肥満研究   19 ( Supplement )   2013年

     詳細を見る

  • 全身倦怠感を契機に診断した若年発症糖尿病の1例

    布上朋和, 江口潤, 天田雅文, 渡辺晴樹, 三好智子, 和田淳, 四方賢一, 槇野博史

    糖尿病   56 ( 4 )   2013年

     詳細を見る

  • 2型糖尿病患者に対するレパグリニドの有効性の検討

    寺見直人, 橘洋美, 堀口千景, 中司敦子, 江口潤, 小川大輔, 和田淳, 四方賢一, 槇野博史

    糖尿病   56 ( 5 )   2013年

     詳細を見る

  • メタボリックシンドロームにおけるphosphatidylethanolamine N-methyltransferase(PEMT)の意義

    中司敦子, 和田淳, 村上和敏, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 片山晶博, 渡邉真由, 樋口千草, 江口潤, 小川大輔, 槇野博史

    糖尿病   56 ( Supplement 1 )   2013年

     詳細を見る

  • 日本と米国における脂肪細胞研究体験記

    江口潤

    日本動脈硬化学会総会・学術集会プログラム・抄録集(Web)   45th   2013年

     詳細を見る

  • 肥満においてPemt欠損がもたらす脂肪肝炎とエピゲノム

    中司敦子, 和田淳, 渡邊真由, 樋口千草, 天田雅文, 布上朋和, 片山晶博, 寺見隆宏, 勅使川原早苗, 村上和敏, 江口潤, 槇野博史

    肥満研究   19 ( Supplement )   2013年

     詳細を見る

  • 糖尿病マウス腎および高糖濃度刺激下での培養腎細胞における核内受容体の発現解析

    寺見直人, 小川大輔, 橘洋美, 堀口千景, 小寺亮, 江口潤, 中司敦子, 和田淳, 四方賢一, 槇野博史

    糖尿病   56 ( Supplement 1 )   2013年

     詳細を見る

  • メタボリックシンドロームにおける脂肪組織由来血清miRNAの同定

    樋口千草, 和田淳, 中司敦子, 村上和敏, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 片山晶博, 渡邉真由, 江口潤, 槇野博史

    糖尿病   56 ( Supplement 1 )   2013年

     詳細を見る

  • 新規アセチレンアミド型PPARγアンタゴニストの創製

    大橋雅生, 蒲生佳奈恵, 田中雄大, 紅山容子, 脇稔, 松浦信康, 槇島誠, 松野研司, 天田雅文, 和田淳, 江口潤, 宮地弘幸

    メディシナルケミストリーシンポジウム講演要旨集   31st   2013年

     詳細を見る

  • 糖尿病マウス腎および培養腎細胞における核内受容体の発現の検討

    寺見直人, 小川大輔, 橘洋美, 堀口千景, 江口潤, 中司敦子, 畑中崇史, 小寺亮, 和田淳, 四方賢一, 槇野博史

    糖尿病合併症   27 ( Supplement 1 )   2013年

     詳細を見る

  • 糖尿病性腎症の糖鎖プロファイリングの検討

    井上謙太郎, 和田淳, 中司敦子, 江口潤, 村上和敏, 神崎資子, 寺見隆宏, 勅使川原早苗, 黒瀬祐子, 片山晶博, 樋口千草, 渡邊真由, 小川智央, 山田雅雄, 四方賢一, 槇野博史

    糖尿病   55 ( Supplement 1 )   2012年

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  • グライコーム解析による糖尿病性腎症バイオマーカーの探索

    井上謙太郎, 和田淳, 中司敦子, 江口潤, 村上和敏, 神崎資子, 寺見隆宏, 黒瀬祐子, 片山晶博, 樋口千草, 渡邉真由, 小川智央, 山田雅雄, 四方賢一, 槇野博史

    日本腎臓学会誌   54 ( 3 )   2012年

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  • メタボリックシンドロームにおけるGalectin-9の機能解析

    神崎資子, 和田淳, 江口潤, 中司敦子, 村上和敏, 勅使川原早苗, 寺見隆宏, 井上謙太郎, 片山晶博, 四方賢一, 平島光臣, 槇野博史

    糖尿病   55 ( Supplement 1 )   2012年

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  • メタボリックシンドロームにおけるGpnmbの意義

    片山晶博, 和田淳, 中司敦子, 江口潤, 村上和敏, 神崎資子, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 渡邉真由, 樋口千草, 肥田和之, 四方賢一, 槇野博史

    糖尿病   55 ( Supplement 1 )   2012年

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  • メタボリック症候群におけるマクロファージIRF4(Interferon Regulatory Factor4)の病態生理学的意義

    江口潤, 和田淳, 槇野博史, ROSEN Evan, ROSEN Evan

    糖尿病   55 ( Supplement 1 )   2012年

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  • 肥満によるインスリン抵抗性におけるマクロファージIRF4(Interferon Regulatory Factor4)の意義

    江口潤, 和田淳, 槇野博史, ROSEN Evan

    肥満研究   17 ( Supplement )   2011年

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  • ヒト血中Vaspin濃度の検討とメタボリックシンドロームにおける意義

    勅使川原早苗, 和田淳, 中司敦子, 堀田紀久子, 肥田和之, 村上和敏, 神崎資子, 井上謙太郎, 寺見隆宏, 松下裕一, 片山晶博, 江口潤, 槇野博史

    肥満研究   17 ( Supplement )   2011年

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  • 肥満症におけるGalectin-9-Tim-3経路の意義

    神崎資子, 和田淳, 杉山晃一, 中司敦子, 村上和敏, 勅使川原早苗, 寺見隆宏, 井上謙太郎, 片山晶博, 江口潤, 平島光臣, 槇野博史

    肥満研究   17 ( Supplement )   2011年

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  • コレクトリンはSNARE複合体との相互作用を介して管腔側膜蛋白の膜輸送を促進し食塩感受性高血圧の発症に関与している

    安原章浩, 和田淳, 江口潤, 中司敦子, 村上和敏, 神崎資子, 勅使川原早苗, 槇野博史

    岡山医学会雑誌   122 ( 1 )   2010年

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  • 内臓脂肪組織に由来するセリンプロテアーゼ阻害剤:Vaspinの同定 肥満状態でインスリン感受性を高める新規アディポサイトカイン

    肥田和之, 和田淳, 江口潤, HONG Zhang, 馬場雅子, 清田綾, 橋本泉, 岡田達夫, 安原章浩, 中司敦子, 赤木滋, 四方賢一, 宝来真志, 二見淳一郎, 渡辺英二郎, 松木泰, 平松隆司, 槇野博史, KANWAR Yashpal S.

    岡山医学会雑誌   118 ( 3 )   2007年

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  • Vaspin(visceral Adipose Tissue-derived Serine Protease Inhibitor)とインスリン抵抗性

    中司敦子, 和田淳, 村上和敏, 肥田和之, 肥田綾, 江口潤, 江口雅子, 伊勢田泉, 安原章浩, 岡田達夫, 四方賢一, 槙野博史

    糖尿病   49 ( Supplement 1 )   2006年

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  • Adipocyte adhesion molecule(ACAM)のC/EBPβによる発現制御と脂肪分化における役割

    村上和敏, 和田淳, 中司敦子, 肥田和之, 肥田綾, 江口潤, 江口雅子, 伊勢田泉, 安原章浩, 岡田達夫, 四方賢一, 槙野博史

    糖尿病   49 ( Supplement 1 )   2006年

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  • 糖尿病性腎症に対するPioglitazoneの治療効果と作用メカニズムの検討

    岡田達夫, 和田淳, 肥田和之, 江口潤, 馬場雅子, 橋本泉, 安原章浩, 中司敦子, 肥田綾

    糖尿病   48 ( Supplement 2 )   2005年

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  • 白色脂肪特異的新規膜蛋白Adipocyte adhesion molecule(ACAM)の機能解析

    江口潤, 和田淳, 肥田和之, 馬場雅子, 中司敦子, 橋本泉, 安原章浩, 岡田達夫, 四方賢一

    糖尿病   48 ( Supplement 2 )   2005年

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  • 白色脂肪組織特異的新規膜蛋白Adipocyte adhesion molecule(ACAM)の同定

    江口潤, 和田淳, 槙野博史

    肥満研究   11 ( 2 )   2005年

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  • 日本人肥満者における血中ケモカインのプロテオミクス解析

    橋本泉, 和田淳, 肥田綾, 馬場雅子, 宮武伸行, 江口潤, 四方賢一, 槙野博史

    糖尿病   48 ( Supplement 2 )   2005年

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  • 新規アディポサイトカインVaspin(visceral adipose tissue specific serpin)の機能解析

    肥田和之, 和田淳, 江口潤, 松岡孝至, 馬場雅子, 四方賢一, 槙野博史

    肥満研究   10 ( Supplement )   2004年

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  • 脂肪細胞特異的新規膜蛋白Adipocyte cell adhesion molecule(ACAM)の機能解析

    江口潤, 和田淳, 肥田和之, 馬場雅子, 松岡孝至, 四方賢一, 横野博史

    肥満研究   10 ( Supplement )   2004年

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  • リコンビナントGalectin-9慢性投与はdb/db糖尿病マウスの糸球体肥大を抑制する

    馬場雅子, 和田淳, 岡田達夫, 安原章浩, 橋本泉, 清田綾, 江口潤, 中司敦子, 松岡孝至

    糖尿病   47   2004年

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  • Fournier壊その1例

    渡辺直美, 村上和春, 村松友義, 橋本泉, 江口潤, 四方賢一, 槙野博史

    糖尿病   47 ( 4 )   2004年

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  • 血糖コントロールにより精神神経症状の改善をみた糖尿病合併MELASの1例

    松岡孝至, 城戸雄一, 橋本泉, 江口潤, 和田淳, 四方賢一, 槙野博史

    糖尿病   47 ( 4 )   2004年

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  • 新規膜蛋白Adipocyte adhesion molecule(ACAM)の同定と機能解析

    江口潤, 和田淳, 肥田和之, 岡田達夫, 安原章浩, 橋本泉, 清田綾, 中司敦子, 松岡孝至

    糖尿病   47   2004年

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  • 糖尿病性腎症に対するPioglitazoneの作用メカニズムの検討

    岡田達夫, 和田淳, 肥田和之, 江口潤, 橋本泉, 馬場雅子, 松岡孝至, 安原章浩, 清田綾

    糖尿病   47   2004年

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  • 糖尿病大血管障害におけるミトコンドリア機能異常の関与

    松岡孝至, 和田淳, 江口潤, 橋本泉, 清田綾, 岡田達夫, 安原章浩, 中司敦子, 馬場雅子

    糖尿病   47   2004年

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  • 白色脂肪特異的新規膜蛋白(OL-16)の同定と発現調節

    江口潤, 和田淳, 肥田和之, 松岡孝至, 馬場雅子, 清田綾, 橋本泉, 四方賢一, 槙野博史

    糖尿病   46 ( Supplement 1 )   2003年

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  • 内臓脂肪特異的蛋白VASPIN(visceral adipose tissue specific SERPIN)の肥満における病態生理学的意義

    肥田和之, 和田淳, 松岡孝至, 江口潤, 馬場雅子, 清田綾, 橋本泉, 四方賢一, 槙野博史

    糖尿病   46 ( Supplement 1 )   2003年

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  • 比較的早期より腎性貧血を認めた1型糖尿病の一例

    馬場雅子, 四方賢一, 城戸雄一, 永瀬亮, 江口潤, 松田充浩, 和田淳, 槙野博史

    糖尿病   45 ( 2 )   2002年

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  • 新時代の糖尿病学 (4) 病因・診断・治療研究の進歩 F. 糖尿病に起因する合併症 合併症(併存症)を有する糖尿病の病態と治療 糖尿病性腎症に伴うネフローゼ症候群

    江口潤, 和田淳, 槙野博史

    日本臨床   60   2002年

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  • 成人病・生活習慣病診療の常識・非常識 II 糖尿病患者のネフローゼ症候群にステロイド薬は禁忌?

    和田淳, 江口潤, 槙野博史

    成人病と生活習慣病   32 ( 8 )   2002年

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  • OLEFTラット内臓脂肪組織よりクローニングした白色脂肪特異的膜蛋白(OL-16)の構造解析

    江口潤, 和田淳, 肥田和之, 松岡孝至, 馬場雅子, 永瀬亮, 城戸雄一, 山下哲二, 槙野博史

    糖尿病   45 ( Supplement 2 )   2002年

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  • OLETFラット内臓脂肪特異的分泌蛋白のvaspin(visceral adipose tissue specific SERPIN)のPioglitazoneによる発現調節

    山下哲二, 和田淳, 松岡孝至, 江口潤, 山下哲二, 馬場雅子, 永瀬亮, 城戸雄一, 槙野博史

    糖尿病   45 ( Supplement 2 )   2002年

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  • 糖尿病に著明な甲状腺機能低下症を合併した2症例

    江口潤, 藤田基寛, 村上典彦, 横田敏彦, 高橋健二, 楠本亨

    糖尿病   44 ( 3 )   2001年

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  • ガス産生を伴う下腹部壊死性筋膜炎を併発した高齢2型糖尿病の一例

    南部拓央, 藤田基寛, 江口潤, 高橋健二, 村上典彦, 横田敏彦, 楠本亨

    糖尿病   44 ( 3 )   2001年

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  • OLETFラットにおけるpioglitazone投与および運動療法の長期効果

    松岡孝至, 和田淳, 肥田和之, 江口潤, 馬場雅子, 山下哲二, 平櫛恵太, 四方賢一, 槙野博文

    糖尿病   44 ( Supplement 1 )   2001年

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  • OLETFラット内臓脂肪特異的遺伝子OL-64とその遺伝子産物vaspin(visceral adipose tissue specific SERPIN)の同定 (第3報)

    肥田和之, 和田淳, 松岡孝至, 国富三絵, 江口潤, 馬場雅子, 四方賢一, 槙野博史

    糖尿病   44 ( Supplement 1 )   2001年

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  • 2型と考えられた糖尿病の経過中すい酵素上昇を伴うDKAを発症しインスリンが枯渇した1例

    藤井雅邦, 高橋健二, 藤原大介, 江口潤, 佐藤千景, 藤田基寛, 村上典彦, 横田敏彦, 楠本亨

    糖尿病   44 ( 3 )   2001年

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  • 2型糖尿病における血中CPR分析からみた内因性インスリン分泌能の評価と考え方

    藤田基寛, 高橋健二, 江口潤, 村上典彦, 横田敏彦, 楠本亨

    糖尿病   43 ( Supplement 1 )   2000年

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  • インスリン依存状態への進行が経時的に確認し得た1型糖尿病の1例

    江口潤, 藤田基寛, 高橋健二, 村上典彦, 横田敏彦, 楠本亨, 三宅康夫

    糖尿病   43 ( 3 )   2000年

     詳細を見る

▼全件表示

共同研究・競争的資金等の研究

  • 脂肪組織の機能不全を制御する新規蛋白の同定と病態生理的意義

    研究課題/領域番号:20K08908  2020年04月 - 2023年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    江口 潤

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • 脂肪組織のリモデリングを制御する新規蛋白の同定と病態生理学的意義

    研究課題/領域番号:16K09783  2016年04月 - 2019年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    江口 潤

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    メタボリックシンドロームの治療法の探索のため, Prelpの機能解析を行った。Prelpは結合組織や軟骨に発現し、早老症の原因遺伝子であることが報告されている。肥満したマウスの脂肪組織では, Prelpの発現が著しく亢進していた。さらに, 培養脂肪細胞の検討において, Prelpを減少させた脂肪細胞では, インスリン応答性の糖取り込みが亢進していた。また, Prelpを脂肪組織に過剰発現させたマウスでは, 脂肪組織の繊維化や全身のインスリン抵抗性が悪化していた。Prelpは, メタボリックシンドロームに合併する種々の疾患の発症に関与していることが示唆された。

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  • 一次繊毛機能を介したACAM/CLMPの脂肪細胞分化と肥満症における意義

    研究課題/領域番号:26461362  2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    村上 和敏, 和田 淳, 江口 潤, 中司 敦子

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    脂肪細胞は余剰エネルギーにより肥大化すると、アディポカイン分泌異常などにより代謝調節機能が障害されメタボリックシンドロームや糖尿病を発症する。我々は、肥満ラットの内臓脂肪組織からホモフィリックな細胞接着に関わる細胞接着分子ACAMを発見した。脂肪細胞でACAMを過剰発現したマウスを高脂肪高蔗糖食で飼育すると、肥満、糖尿病の発症が予防された。このマウスでは脂肪細胞同士がACAMにより接着し、その接着部位に表層アクチン(F-actin)を形成し、電子顕微鏡で同部位にzonula adherens形成を認めた。ACAMは細胞接着と表層アクチン形成により脂肪細胞肥大化を抑制し、肥満や糖尿病を予防する。

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  • 脂肪組織と骨格筋を制御する膜蛋白同定とメタボリック症候群における病態生理学的意義

    研究課題/領域番号:25461354  2013年04月 - 2016年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    江口 潤

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    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    メタボリック症候群では脂肪組織量と骨格筋量の不均衡(肥満サルコペニア)が生じている。肥満サルコペニアは, 全身のインスリン抵抗性や代謝異常を引き起こす。肥満サルコペニアを改善することはメタボリック症候群を基盤とした2型糖尿病をはじめとした様々な疾患の治療や発症抑制に効果があり, 国民の健康維持, 増進に有用であると考えられる。我々は、肥満サルコペニアによる全身のインスリン抵抗性発症に関与している可能性がある新規蛋白としてTmem97 (Transmembrane protein 97)を同定した。今後、Tmem97のインスリン抵抗性発症機序の詳細について検討していく。

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  • IRF4のメタボリック症候群における慢性炎症制御機構と創薬への展開

    研究課題/領域番号:23890116  2011年 - 2012年

    日本学術振興会  科学研究費助成事業 研究活動スタート支援  研究活動スタート支援

    江口 潤

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    配分額:3250000円 ( 直接経費:2500000円 、 間接経費:750000円 )

    メタボリック症候群における慢性炎症が全身のインスリン抵抗性を引き起こしている。Interferon regulatory factor 4 (IRF4)は、高脂肪食負荷で誘導される慢性炎症に対して抑制的に働く転写因子であり、その発現低下がメタボリック症候群における慢性炎症の発症に関与している可能性が示唆された。IRF4は、メタボリック症候群に対する新たな治療法に結びつく可能性のある分子である。

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担当授業科目

  • メタボリックシンドローム特論 (2021年度) 特別  - その他

  • 先端医療疾病管理論 (2021年度) 前期  - その他

  • 免疫系(臓器・系別統合講義) (2021年度) 特別  - その他

  • 内分泌・代謝系(臓器・系別統合講義) (2021年度) 特別  - その他

  • 内科学 (2021年度) 1・2学期  - [第1学期]月4,月5,水6, [第2学期]月4,月5,金6

  • 基礎病態演習 (2021年度) 前期

  • 成人疾病論(内科系) (2021年度) 前期

  • 歯学部隣接医学(内科学) (2021年度) 前期

  • 腎・免疫・内分泌代謝内科学(基本臨床実習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(講義・演習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(講義・演習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(演習・実習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(講義・演習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(講義・演習) (2021年度) 特別  - その他

  • 免疫系(臓器・系別統合講義) (2020年度) 特別  - その他

  • 内分泌・代謝系(臓器・系別統合講義) (2020年度) 特別  - その他

  • 内科学 (2020年度) 1・2学期  - [第1学期]月4,月5,水6, [第2学期]月4,月5,金6

  • 基礎病態演習 (2020年度) 前期

  • 歯学部隣接医学(内科学) (2020年度) 前期

  • 看護と病態整理1 (2020年度) 前期

  • 腎・免疫・内分泌代謝内科学(基本臨床実習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(講義・演習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(講義・演習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(演習・実習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(演習・実習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(講義・演習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(講義・演習) (2020年度) 特別  - その他

  • 基礎病態演習 (2019年度) 前期

  • 歯学部隣接医学(内科学) (2019年度) 前期

  • 看護と病態整理1 (2019年度) 前期

▼全件表示