title: Saireito (TJ-114), a Japanese traditional herbal medicine, reduces 5-fluorouracil-induced intestinal mucositis in mice by inhibiting cytokine-mediated apoptosis in intestinal crypt cells.
abstract: Clinical chemotherapy frequently causes intestinal mucositis as a side effect, which is accompanied by severe diarrhea. We recently showed that the cytokine-mediated apoptotic pathway might be important for the development of intestinal mucositis induced by 5-fluorouracil (5-FU). Saireito, the traditional Japanese herbal (Kampo) medicine, is widely used to treat diarrhea and various inflammatory diseases in Japan. In the present study, we investigated the effect of saireito on 5-FU-induced intestinal mucositis in mice, especially in relation to apoptosis in the intestinal crypt. Male C57BL/6 mice were given 5-FU (50 mg/kg), i.p. once daily for 6 days. Intestinal mucositis was evaluated histochemically. Saireito (100-1000 mg/kg) was administered p.o. twice daily for 6 days. Repeated 5-FU treatment caused severe intestinal mucositis including morphological damage, which was accompanied by body weight loss and diarrhea. Daily administration of saireito reduced the severity of intestinal mucositis in a dose-dependent manner. Body weight loss and diarrhea during 5-FU treatment were also significantly attenuated by saireito administration. The number of apoptotic and caspase-3-activated cells in the intestinal crypt was increased, and was accompanied by up-regulated tumor necrosis factor (TNF)-α and interleukin (IL)-1β mRNA within 24 h of the first 5-FU injection. However, all of these measures were significantly lower after saireito administration. These results suggest that saireito attenuates 5-FU-induced intestinal mucositis. This action may come from the reduction of apoptosis in the intestinal crypt via suppression of the up-regulation of inflammatory cytokines. Therefore, saireito may be clinically useful for the prevention of intestinal mucositis during cancer chemotherapy.
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kato
authors.affiliation: Division of Gastrointestinal Pathophysiology, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Sugitani, Toyama 930-0194, Japan.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Yumeno
authors.initials: Y
authors.lastname: Kitahara
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Koyo
authors.initials: K
authors.lastname: Nagasawa
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Aono
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Shibata
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Utsumi
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.affiliation: Division of Gastrointestinal Pathophysiology, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Sugitani, Toyama 930-0194, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D005472:Fluorouracil / Q000633:toxicity; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology* / Q000473:pathology; D007564:Japan; D008297:Male; D020835:Medicine, Kampo; D008519:Medicine, Traditional; D051379:Mice; D008810:Mice, Inbred C57BL; D052016:Mucositis / Q000139:chemically induced / Q000188:drug therapy*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D053583:Interleukin-1beta; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C080903:sairei-to; C052994:interleukin-1beta (163-171); D053148:Caspase 3; D005472:Fluorouracil