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The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model.
Yoshioka, Naoki; Tanaka, Miyako; Ochi, Kozue; Watanabe, Akiko; Ono, Kenji; Sawada, Makoto; Ogi, Tomoo; Itoh, Michiko; Ito, Ayaka; Shiraki, Yukihiro; Enomoto, Atsushi; Ishigami, Masatoshi; Fujishiro, Mitsuhiro; Ogawa, Yoshihiro; Suganami, Takayoshi.
Afiliación
  • Yoshioka N; Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Tanaka M; Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: tanaka@riem.nagoya-u.ac.jp.
  • Ochi K; Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
  • Watanabe A; Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
  • Ono K; Department of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Molecular Pharmacokinetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Sawada M; Department of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Molecular Pharmacokinetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Ogi T; Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Itoh M; Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Kanagawa Institute of Industrial Science and Technology, Ebina, Japan.
  • Ito A; Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Shiraki Y; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Enomoto A; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Ishigami M; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Fujishiro M; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Ogawa Y; Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • Suganami T; Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: suganami@riem.nagoya-u.ac.jp.
Biomed Pharmacother ; 140: 111738, 2021 Aug.
Article en En | MEDLINE | ID: mdl-34029949
BACKGROUND: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. METHODS: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. FINDINGS: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. INTERPRETATION: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Bencidrilo / Enfermedad del Hígado Graso no Alcohólico / Inhibidores del Cotransportador de Sodio-Glucosa 2 / Glucósidos / Neoplasias Hepáticas Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Biomed Pharmacother Año: 2021 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Francia
Texto completo
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Bencidrilo / Enfermedad del Hígado Graso no Alcohólico / Inhibidores del Cotransportador de Sodio-Glucosa 2 / Glucósidos / Neoplasias Hepáticas Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Biomed Pharmacother Año: 2021 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Francia