Yoko Shinagawa-Kobayashi1, Kenya Kamimura2, Ryo Goto1, Kohei Ogawa1, Ryosuke Inoue1, Takeshi Yokoo1, Norihiro Sakai1, Takuro Nagoya1, Akira Sakamaki1, Satoshi Abe1, Soichi Sugitani3, Masahiko Yanagi4, Koichi Fujisawa5, Yoshizu Nozawa6, Naoto Koyama7, Hiroshi Nishina8, Makoto Furutani-Seiki9, Isao Sakaida5, Shuji Terai10. 1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan. 2. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan. Electronic address: kenya-k@med.niigata-u.ac.jp. 3. Department of Gastroenterology, Murakami General Hospital, Murakami, Niigata, Japan. 4. Department of Gastroenterology, Ojiya General Hospital, Ojiya, Niigata, Japan. 5. Department of Gastroenterology and Hepatology, Yamaguchi University, Graduate School of Medicine, Ube, Yamaguchi, Japan. 6. Institute of Food Sciences & Technologies, Ajinomoto Co. Inc., Kawasaki, Kanagawa, Japan. 7. Institute for Innovation, Ajinomoto Co. Inc., Kawasaki, Kanagawa, Japan. 8. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan. 9. Department of Systems Biochemistry in Pathology and Regeneration, Yamaguchi University Graduate School of Medicine, Ube, Japan. 10. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan. Electronic address: terais@med.niigata-u.ac.jp.
Abstract
BACKGROUND: Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. METHODS: The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. RESULTS: Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. CONCLUSION: We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow.
BACKGROUND:Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. METHODS: The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. RESULTS: Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. CONCLUSION: We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow.
Authors: Rubén Marín-Juez; Hadil El-Sammak; Christian S M Helker; Aosa Kamezaki; Sri Teja Mullapuli; Sofia-Iris Bibli; Matthew J Foglia; Ingrid Fleming; Kenneth D Poss; Didier Y R Stainier Journal: Dev Cell Date: 2019-11-18 Impact factor: 13.417