Chen, Guanliang



School of Medicine, Department of Obstetrics and Gynecology (Gynecology) (Shinanomachi)


Project Assistant Professor (Non-tenured)/Project Research Associate (Non-tenured)/Project Instructor (Non-tenured)

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Career 【 Display / hide

  • 2019.11

    Keio University School of Medicine, Division of Cellular Signaling Institute for Advanced Medical Research, Project Assistant Professor

Academic Background 【 Display / hide

  • 2015.10

    Kanazawa University, Graduate School of Medical Science, Department of Metabolism and Nutrition , Cell Metabolism and Nutrition

    Japan, Graduate School, Graduated, Doctoral course

Academic Degrees 【 Display / hide

  • Doctor (Medicine), Kanazawa University, Dissertation, 2019.09


Papers 【 Display / hide

  • Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice

    Nishikawa T., Nagata N., Shimakami T., Shirakura T., Matsui C., Ni Y., Zhuge F., Xu L., Chen G., Nagashimada M., Yamashita T., Sakai Y., Yamashita T., Mizukoshi E., Honda M., Kaneko S., Ota T.

    Scientific Reports (Scientific Reports)  10 ( 1 )  2020.12

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    © 2020, The Author(s). Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.

  • Lactobacillus pentosus strain S-PT84 improves steatohepatitis by maintaining gut permeability

    Sakai Y., Zhuge F., Xu L., Chen G., Nagata N., Suzuki T., Kaneko S., Ota T., Nagashimada M.

    Journal of Endocrinology (Journal of Endocrinology)  247 ( 2 ) 169 - 181 2020.11

    ISSN  00220795

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    © 2020 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain Intestinal mucosal barrier dysfunction is closely related to the pathogenesis of nonalcoholic steatohepatitis (NASH). Gut immunity has been recently demonstrated to regulate gut barrier function. The Lactobacillus pentosus strain S-PT84 activates helper T cells and natural killer/natural killer T cells. In this study, we examined the effect of S-PT84 on NASH progression induced by high-cholesterol/high-fat diet (CL), focusing on the immune responses involved in gut barrier function. C57BL/6 mice were fed a normal chow or CL diet with or without 1 × 1010 S-PT84 for 22 weeks. S-PT84 administration improved hepatic steatosis by decreasing triglyceride and free fatty acid levels by 34% and 37%, respectively. Furthermore, S-PT84 inhibited the development of hepatic inflammation and fibrosis, suppressed F4/80+ macrophage/Kupffer cell infiltration, and reduced liver hydroxyproline content. Administration of S-PT84 alleviated hyperinsulinemia and enhanced hepatic insulin signalling. Compared with mice fed CL diet, mice fed CL+S-PT84 had 71% more CD11c-CD206+ M2 macrophages, resulting in a significantly decreased M1/M2 macrophage ratio in the liver. Moreover, S-PT84 inhibited the CL diet-mediated increase in intestinal permeability. Additionally, S-PT84 reduced the recruitment of interleukin-17-producing T cells and increased the levels of intestinal tight junction proteins, including zonula occludens-1, occludin, claudin-3, and claudin-7. In conclusion, our findings suggest that S-PT84 attenuates diet-induced insulin resistance and subsequent NASH development by maintaining gut permeability. Thus, S-PT84 represents a feasible approach to prevent the development of NASH.

  • DPP-4 Inhibition with Anagliptin Reduces Lipotoxicity-Induced Insulin Resistance and Steatohepatitis in Male Mice

    Sakai Y., Chen G., Ni Y., Zhuge F., Xu L., Nagata N., Kaneko S., Ota T., Nagashimada M.

    Endocrinology (Endocrinology)  161 ( 10 )  2020.10

    ISSN  00137227

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    © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: Excessive hepatic lipid accumulation drives the innate immune system and aggravates insulin resistance, hepatic inflammation, and fibrogenesis, leading to nonalcoholic steatohepatitis (NASH). Dipeptidyl peptidase-4 (DPP-4) regulates glucose metabolism and is expressed in many different cell types, including the cells of the immune system. In addition, DPP-4 may be involved in macrophage-mediated inflammation and insulin resistance. This study investigated the effects of anagliptin (Ana), an inhibitor of DPP-4, on macrophage polarity and phenotype in the livers of mice with steatohepatitis. We investigated the effects of Ana on steatohepatitis induced via a high-cholesterol high-fat (CL) diet or a choline-deficient L-amino acid-defined, high-fat (CDAHF) diet. DPP-4 activity, liver histology, and insulin sensitivity were evaluated, and liver DPP-4+ macrophages were quantified using fluorescence-activated cell sorting (FACS). Liver and plasma DPP-4 activity increased significantly in mice on both diets. FACS revealed that, compared with chow-fed mice, the CL-fed mice exhibited a significant increase in the proportion of DPP-4+ liver macrophages, particularly the M1-type macrophages. Ana decreased hepatic lipid and M1 macrophage accumulation and stimulated M2 macrophage accumulation in the liver, thereby attenuating insulin resistance, steatohepatitis, and fibrosis. Importantly, Ana alleviated hepatic fibrosis and steatohepatitis in mice fed CL diet and CDAHF diet. Using Ana to inhibit DPP-4 reduced lipotoxicity-induced hepatic insulin resistance through regulating the M1/M2 macrophage status.

  • Tumor-infiltrating lymphocytes predict survival outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy

    Ohno A., Iwata T., Katoh Y., Taniguchi S., Tanaka K., Nishio H., Nakamura M., Morisada T., Chen G., Saito M., Yaguchi T., Kawakami Y., Aoki D.

    Gynecologic Oncology (Gynecologic Oncology)  159 ( 2 ) 329 - 334 2020

    ISSN  00908258

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    © 2020 Elsevier Inc. Objectives: To (i) identify correlations between selected immunogenic factors and clinicopathological characteristics, (ii) determine whether intratumoral abundance of various specific tumor-infiltrating lymphocytes (TILs) is a prognostic indicator in women with Stage II and III cervical cancer who undergo treatment with cisplatin-based concurrent chemoradiotherapy (CCRT), and (iii) investigate subtypes of FOXP3+ T cells in 15 fresh samples of cervical cancer. Methods: In this retrospective study, intratumoral lesions in colposcopic biopsies from 55 women with advanced cervical cancer who subsequently underwent CCRT at our institution were subjected to automatic immunological staining using the following six mouse monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD206, and anti-FOXP3. Associations between the findings on automatic scoring of the number of each type of TIL in each specimen and various clinicopathological characteristics were analyzed, as were associations between the abundance of various specific types of TIL and survival. Subtypes of FOXP3+ TILs in 15 additional fresh tumor samples were also investigated using flow cytometry. Results: Infiltration with CD8+ TILs was associated with pelvic lymph node metastasis. Abundant infiltration by CD3+, CD4+, CD8+, CD206+, and FOXP3+ TILs were statistically significant indicators of better progression-free and overall survival. Regarding subtypes of FOXP3+ TILs, non-Tregs (Fr-III) were found in all samples tested for this. Conclusions: The abundance of various specific intratumoral TILs may be prognostic indicators in patients with advanced cervical cancer undergoing CCRT.

  • Lycopene Alleviates Obesity-Induced Inflammation and Insulin Resistance by Regulating M1/M2 Status of Macrophages

    Chen G., Ni Y., Nagata N., Zhuge F., Xu L., Nagashimada M., Yamamoto S., Ushida Y., Fuke N., Suganuma H., Kaneko S., Ota T.

    Molecular Nutrition and Food Research (Molecular Nutrition and Food Research)  63 ( 21 )  2019.11

    ISSN  16134125

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    © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Scope: Adipose tissue macrophage (ATM) recruitment and polarization are pivotal in the development of insulin resistance. However, treatment modalities targeting ATMs remain limited. The effects of lycopene, an antioxidant carotenoid compound, on adipose tissue inflammation and insulin resistance in high fat (HF)-diet-induced obese mice are examined. Methods and results: C57BL/6J mice are fed an HF diet or an HF diet containing lycopene (HF+LY) for 8 weeks. Lycopene attenuates HF-diet-induced glucose intolerance and hyperinsulinemia. Compared with HF mice, HF+LY mice exhibit attenuated adipocyte hypertrophy and macrophage infiltration in epididymal white adipose tissue (eWAT) and hepatic steatosis and inflammation. Flow cytometry analysis of ATMs demonstrates that lycopene attenuated the increased number of ATMs in HF diet-fed mice. In addition, HF+LY mice have 23% fewer M1-polarized ATMs and 60% more M2-polarized ATMs than HF mice, resulting in the predominance of M2 over M1 in the ATM population. M2-dominant polarization is also seen in hepatic macrophages in HF+LY mice. Moreover, lycopene promotes IL-4-induced M2 polarization by increasing the phosphorylation levels of STAT6 and Akt in Raw 264.7 macrophages. Conclusions: Lycopene facilitates M2-dominant polarization in ATM, thereby attenuating HF diet-induced inflammation and insulin resistance in eWAT and the liver.

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