Title 天然物由来物質における抗炎症作用機序の解明とラットモデルを用いたその活用に関する研究( 内容と審査の要旨 (Summary) ) Author(s) 米澤, 豊 Report No.(Doctoral Degree) 博士(獣医学) 甲第519号 Issue Date 2019-03-13 Type 博士論文 Version ETD URL http://hdl.handle.net/20.500.12099/77950 ※この資料の著作権は、各資料の著者・学協会・出版社等に帰属します。
Ặྡ㸦ᮏ㸦ᅜ㸧⡠㸧 ⡿ ⃝ ㇏㸦ி㒔ᗓ㸧 ᣦ ᑟ ᩍ ဨ Ặ ྡ ᖏᗈ␆⏘Ꮫ ᩍᤵ ᑠ ᕝ ᬕ Ꮚ Ꮫ ࡢ ✀ 㢮 ༤ኈ㸦⋇་Ꮫ㸧 Ꮫ グ ␒ ྕ ⋇་༤⏥➨㸳㸯㸷ྕ Ꮫ ᤵ ᖺ ᭶ ᪥ ᖹᡂ㸱㸯ᖺ㸱᭶㸯㸱᪥ Ꮫ ᤵ ࡢ せ ௳ Ꮫつ๎➨㸲᮲➨㸯㡯ヱᙜ ◊ ✲ ⛉ ཬ ࡧ ᑓ ᨷ 㐃ྜ⋇་Ꮫ◊✲⛉ ⋇་Ꮫᑓᨷ ◊✲ᣦᑟࢆཷࡅࡓᏛ ᖏᗈ␆⏘Ꮫ Ꮫ ㄽ ᩥ 㢟 ┠ ኳ↛≀⏤᮶≀㉁࠾ࡅࡿᢠ⅖స⏝ᶵᗎࡢゎ᫂ࣛࢵࢺ ࣔࢹࣝࢆ⏝࠸ࡓࡑࡢά⏝㛵ࡍࡿ◊✲ ᑂ ᰝ ጤ ဨ ᰝ ᖏᗈ␆⏘Ꮫ ᩍ ᤵ ▼ ᫂ ᰝ ᖏᗈ␆⏘Ꮫ ᩍ ᤵ ᑠ ᕝ ᬕ Ꮚ ᰝ ᒾ ᡭ Ꮫ ᩍ ᤵ Ᏹ ሯ 㞝 ḟ ᰝ ᮾி㎰ᕤᏛ ᩍᤵ బࠎᮌ ୍ ᰝ ᒱ 㜧 Ꮫ ᩍ ᤵ ᾏ 㔝 ᖺ ᘯ Ꮫㄽᩥࡢෆᐜࡢせ᪨ ⌧௦♫࠾࠸࡚, ࡀࢇࡸ⏕ά⩦័ࢆ௦⾲ࡍࡿ៏ᛶᝈࢆண㜵࣭ไᚚࡍࡿࡇࡣ㔜 せ࡞ㄢ㢟࡛࠶ࡿࡀ, ࡇࢀࡽᝈࡢែᙧᡂࡣ៏ᛶ⅖ࡀ῝ࡃ㛵ࢃࡿ⪃࠼ࡽࢀ࡚࠸ࡿࠋ ៏ᛶ⅖࡛ࡣ㸪㓟ࢫࢺࣞࢫ࡞ࡢ่⃭ࡼࡗ࡚⏕యෆ࡛ᵝࠎ࡞⣽⬊ࡽᨺฟࡉࢀࡿ≀㉁ ࡀ㸪࣐ࢡࣟࣇ࣮ࢪࡼࡾㄆ㆑ࡉࢀ㸪ࢧࢺ࢝ࣥ㸪ࣉࣟࢫࢱࢢࣛࣥࢪࣥ(PG) E2㸪୍㓟 ❅⣲ (NO) ࢆࡣࡌࡵࡍࡿᵝࠎ࡞⅖ᛶ࣓ࢹ࢚࣮ࢱ࣮ࡀ⏘⏕ࡉࢀ㸪ࡑࡢ⤖ᯝ, ⅖ᛂ ࡀㄏᑟࡉࢀࡿࠋࡑࡢࡓࡵ, ⅖ᛂ㛵ࡍࡿ࣐ࢡࣟࣇ࣮ࢪࡢᛂࢆไᚚࡍࡿ᪂つྜ ≀ࡢⓎ᥀ࡣ, ៏ᛶᝈࡢไᚚ㈉⊩ࡍࡿྍ⬟ᛶࡀ࠶ࡿࠋ Hydroxytyrosol (HT) ࡣ, ࣮࢜ࣜࣈࡢⴥࡸᐇ㇏ᐩྵࡲࢀࡿపศᏊࣇ࢙ࣀ࣮ࣝྜ≀ ࡛࠶ࡿࠋࡇࢀࡲ࡛ࡢ◊✲࡛, HT ࡣᢠ⅖㸪ᢠ㓟㸪ᢠ࢘ࣝࢫཬࡧᢠ⳦స⏝ࢆ♧ࡍࡇࡀ ᫂ࡽࡉࢀ, ኳ↛≀⏤᮶࡛Ᏻᛶࡶ㧗࠸ࡇࡽ, ᵝࠎ࡞ศ㔝࡛ὀ┠ࡉࢀࡿ≀㉁࡛࠶ࡿࠋ ୍᪉, ྛ✀స⏝ࡘ࠸࡚ࡢ࣓࢝ࢽࢬ࣒ࡣᮍࡔ᫂࡞Ⅼࡀከࡃ, ᭦࡞ࡿ◊✲ࡀồࡵࡽࢀ࡚࠸ ࡿࠋࡑࡇ࡛㸪ᮏ◊✲࡛ࡣ, in vitro ᐇ㦂࡛ HT ࡢᢠ⅖ຠᯝࡢస⏝ᶵᗎࢆ᫂ࡽࡍࡿࡶ 㸪ື≀ࣔࢹࣝࢆ⏝࠸࡚HT ࡢ᭷⏝ᛶࢆホ౯ࡍࡿࡇࢆ┠ⓗࡋࡓࠋ ➨ 1 ❶࡛ࡣ, ࣐࢘ࢫ࣐ࢡࣟࣇ࣮ࢪᵝ⣽⬊ᰴ RAW264.7 ࢆ⏝࠸࡚㸪lipopolysaccharide (LPS) ㄏⓎᛶ⅖ᑐࡍࡿ HT ࡢᢠ⅖స⏝ࢆホ౯ࡋࡓࠋࡑࡢ⤖ᯝ㸪HT ࡣ 12.5 μg/mL ࡢ⃰ ᗘ࡛ࡣnuclear κB (NF-κB) ࢩࢢࢼࣝఏ㐩⤒㊰ࢆᢚไࡍࡿࡇ࡛㸪tumor necrosis factor-α (TNF-factor-α) ࡢ㑇ఏᏊⓎ⌧㸪interleukin (IL) -1β ࡢ⏘⏕㸪cyclooxygenase-2 (COX-2)- PGE2ཬࡧ inducible nitric oxide synthase (iNOS) -NO ⣔ࢆᢚไࡋ㸪12.5 μg/mL ࡼࡾప࠸⃰ᗘ࡛ࡣูࡢࢩ
ࢢࢼࣝఏ㐩⤒㊰ࢆࡋ࡚⅖ᛂࢆㄪ⠇ࡍࡿྍ⬟ᛶࡀ࠶ࡿࡇࢆ♧ࡋࡓࠋ୍᪉㸪HT ࡣ LPS
ㄏⓎᛶࡢ⣽⬊እࢩࢢࢼࣝㄪ⠇࢟ࢼ࣮ࢮ (p44/42 mitogen-activated protein kinase; ERK1/2) ࡢ ࣜࣥ㓟ࢆᢚไࡋ࡞࠸ࡇࡶ᫂ࡽࡋࡓࠋ
➨2 ❶࡛ࡣ㸪NF-κB ཬࡧ ERK1/2㸪c-Jun N ᮎ➃࢟ࢼ࣮ࢮ (JNK)㸪p38㸪௨ୖ 3 ࡘࡢศಁ
㐍ᅉᏊάᛶࢱࣥࣃࢡ㉁࢟ࢼ࣮ࢮ (MAPK) ᑐࡍࡿ HT ࡢస⏝ࡘ࠸࡚᫂ࡽࡍࡿ┠ ⓗ࡛, ࡑࢀࡒࢀࡢ⤒㊰ࢆ㜼ᐖࡍࡿ inhibitor ࢆ⏝࠸࡚ホ౯ࡋࡓࠋࡑࡢ⤖ᯝ㸪MAPK ࡢ㜼ᐖ ࡼࡾTNF-α ཬࡧ PGE2ࡢ⏘⏕ࡀపୗࡋ㸪HT ࡢῧຍࡼࡾࡑࢀࡽ⏘⏕㔞ࡣࡉࡽపୗࡍࡿࡇ ࢆ☜ㄆࡋࡓࠋNO ࡢ⏘⏕㔞ࡘ࠸࡚ࡣ MAPK ࡢ㜼ᐖࡼࡾኚࡋ࡞ࡗࡓࡀ㸪HT ࡢῧ ຍࡼࡾపୗࡍࡿࡇࡶ☜ㄆࡋࡓࠋࡇࢀࡽࡢ⤖ᯝࡼࡾ㸪HT ࡢస⏝Ⅼࡣ ERK1/2㸪JNK, p38 ࡢ࠸ࡎࢀࡢ⤒㊰ୖࡶ࡞ࡃ㸪ࡲࡓNF-κB ⤒㊰ࡼࡾࡶୗὶ࠶ࡿྍ⬟ᛶࡀ㧗࠸ࡇࢆ᫂ࡽ ࡋࡓࠋ➨1 ❶➨ 2 ❶ࡢ⤖ᯝࢆ⥲ྜࡍࡿ㸪HT ࡣ 12.5 μg/mL ࡢ⃰ᗘ࡛ࡣ NF-κB ࢩࢢࢼ
ࣝఏ㐩⤒㊰ࢆᢚไࡍࡿࡇ࡛ TNF-α 㑇ఏᏊⓎ⌧㸪IL-1β ⏘⏕㸪COX-2-PGE2ཬࡧ iNOS-NO
⣔ࢆᢚไࡋ㸪12.5 μg/mL ࡼࡾప࠸⃰ᗘ࡛ࡣ NF-κB ⤒㊰ࡼࡾࡶୗὶ࠶ࡿࢩࢢࢼࣝ⤒㊰స ⏝ࡋ࡚࠸ࡿ⪃࠼ࡽࢀࡓࠋࡍ࡞ࢃࡕ, HT ࡣ, స⏝⃰ᗘࡼࡗ࡚␗࡞ࡿᶵᗎ࡛ᢠ⅖స⏝ࢆ Ⓨࡍࡿ≀㉁࡛࠶ࡿྍ⬟ᛶࡀ♧ࡉࢀࡓࠋ ➨3 ❶࡛ࡣ㸪ࣛࢵࢺ࢝ࣛࢤࢽࣥㄏⓎ⫥ᾋ⭘ࣔࢹࣝࢆ⏝࠸࡚㸪HT ࡢᢠ⅖స⏝ࡘ࠸᳨࡚ ウࡋࡓࠋ࢝ࣛࢤࢽࣥᢞ๓ཬࡧᢞᚋ1ࠥ5 㛫࠾ࡅࡿ⫥ᐜ✚ࡢኚ㔞ࢆᣦᶆᢠ⅖ຠ ᯝࢆホ౯ࡋ, ᑐ↷⸆ࡋ࡚⏝࠸ࡓ㑅ᢥⓗ COX-2 㜼ᐖ࡛࠶ࡿࢭࣞࢥ࢟ࢩࣈཬࡧ㠀ࢫࢸࣟ ࢻᛶᢠ⅖⸆ࡢࣥࢻ࣓ࢱࢩࣥࡢຠᯝẚ㍑ࡋࡓࠋࡑࡢ⤖ᯝ㸪HT ࡣࢭࣞࢥ࢟ࢩࣈཬࡧࣥ ࢻ࣓ࢱࢩࣥࡼࡾ⫥ᾋ⭘ᢚไస⏝ࡣᙅ࠸ࡶࡢࡢ㸪ࡑࡢຠᯝࡣ㛫ࡶቑຍࡋࡓࠋ୍᪉㸪 ࢭࣞࢥ࢟ࢩࣈཬࡧࣥࢻ࣓ࢱࢩࣥࡢຠᯝࡣ㛫ࡶῶᑡࡋࡓࠋࡇࢀࡽ⤖ᯝࡼࡾ㸪HT ࡣ 㐜⾜ᛶࡢᢠ⅖స⏝ࢆᣢࡘྍ⬟ᛶࡀ࠶ࡾ㸪ࢭࣞࢥ࢟ࢩࣈࡲࡓࡣࣥࢻ࣓ࢱࢩࣥ⤌ྜࡏ࡚ ⒪⏝࠸ࡿࡇࡼࡾ, ᣢ⥆ⓗ࡞ᢠ⅖ຠᯝࡀᚓࡽࢀࡿྍ⬟ᛶࡀ♧၀ࡉࢀࡓࠋ ➨4 ❶࡛ࡣ㸪ࣛࢵࢺࢫࣆࣜࣥㄏⓎ⫶₽⒆ࣔࢹࣝࢆ⏝࠸࡚, HT ࡢస⏝ࡘ࠸᳨࡚ウࡋ ࡓࠋᑐ↷⸆ࡋࡓࢭࣞࢥ࢟ࢩࣈཬࡧࣥࢻ࣓ࢱࢩࣥࡣ, ࢫࣆࣜࣥྠ⤒ཱྀᢞࡍࡿ ᫂░࡞⫶㞀ᐖࢆᘬࡁ㉳ࡇࡋࡓࡢᑐࡋ㸪HT ࢫࣆࣜࣥࡢྠᢞ࡛ࡣ⫶㞀ᐖࡣ⏕ࡌ࡞ ࠸ࡇࢆ☜ㄆࡋࡓࠋHT ࡣ, 㧗⏝㔞 (2 g/kg)࡛ࡶẘᛶࢆ♧ࡉ࡞࠸ࡇࡀ▱ࡽࢀ, 㣗ရࡸᰤ㣴 ⿵ຓ㣗ရࡋ࡚ᕷ㈍ࡉࢀ࡚࠸ࡿࠋᮏ◊✲࠾࠸࡚ HT ࡀࢫࣆࣜࣥㄏⓎ⫶₽⒆ࢆᘬࡁ㉳ࡇ ࡉ࡞ࡗࡓࡇࡣ,Ᏻᛶࡀ㧗࠸ࡇࢆࡅࡓࡶ⪃࠼ࡽࢀࡿࠋ➨ 3 ❶ࡢᐇ㦂⤖ᯝࡽ⪃ ࠼ࡿ, HT ࡢ COX-2 㜼ᐖస⏝ࡀࢭࣞࢥ࢟ࢩࣈࡸࣥࢻ࣓ࢱࢩࣥࡼࡾࡶᙅ࠸ࡇࡀ,⫶㞀ᐖ ࡢ㍍ῶ⧅ࡀࡗ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡓࠋ ᮏ◊✲ࡼࡾ, HT ࡢᢠ⅖స⏝ࡢᶵᗎࡢ୍➃ࡀ᫂ࡽ࡞ࡗࡓࠋస⏝ᶵᗎࡢᐜࢆ⌮ゎ ࡍࡿࡓࡵࡢ᭦࡞ࡿ◊✲ࡀồࡵࡽࢀࡿࡀ, HT ࡣ⏕యෆ࠾࠸࡚㛗㛫㸪స⏝ࢆ♧ࡍࡇ࡞ ࡃᢠ⅖స⏝ࢆⓎࡋ⥆ࡅࡿྍ⬟ᛶࡀ♧ࡉࢀࡓࡓࡵ, ᪂ࡋ࠸ᢠ⅖⸆ࡋࡢ㛤Ⓨࡀᮇᚅࡉ ࢀࡿࠋ ᑂ ᰝ ⤖ ᯝ ࡢ せ ᪨ ኳ↛≀⏤᮶≀㉁࡛࠶ࡿHydroxytyrosol (HT) ࡣ࣮࢜ࣜࣈࡢⴥࡸᐇ㇏ᐩྵࡲࢀࡿపศᏊ ࣇ࢙ࣀ࣮ࣝྜ≀࡛࠶ࡾ㸪in vitro ࡛ᢠ⅖㸪ᢠ㓟㸪ᢠ࢘ࣝࢫཬࡧᢠ⳦స⏝ࢆ♧ࡍࡇ ࡀሗ࿌ࡉࢀ࡚࠸ࡿࡀ㸪ࡑࡢస⏝ᶵᗎࡣ᫂࡞Ⅼࡀከ࠸ࠋᮏ◊✲࡛ࡣ, HT ࡘ࠸࡚ᢠ⅖ຠ ᯝࡢస⏝ᶵᗎࢆ᫂ࡽࡍࡿࡶ㸪ࣛࢵࢺࣔࢹࣝࢆ⏝࠸࡚ࡑࡢ᭷⏝ᛶࢆホ౯ࡍࡿࡇ ࢆ┠ⓗࡋࡓࠋ ➨1 ❶࡛ࡣ, ࣐࢘ࢫ࣐ࢡࣟࣇ࣮ࢪᵝ⣽⬊ᰴࢆ⏝࠸࡚㸪lipopolysaccharide (LPS) ㄏⓎᛶ⅖ ᑐࡍࡿ HT ࡢᢠ⅖స⏝ࢆホ౯ࡋࡓࠋࡑࡢ⤖ᯝ㸪12.5 μg/mL ࡢ⃰ᗘࡢ HT ࡣ, nuclear
factor-κB (NF-κB)ࢩࢢࢼࣝఏ㐩⤒㊰ࢆᢚไࡍࡿࡇ࡛㸪tumor necrosis factor-α (TNF-α)ࡢ㑇ఏ ᏊⓎ⌧㸪interleukin (IL) -1β ࡢ⏘⏕㸪cyclooxygenase-2 (COX-2)- PGE2ཬࡧinducible nitric oxide synthase (iNOS) -NO ⣔ࢆᢚไࡍࡿࡇ, ୍᪉࡛ 12.5 μg/mL ࡼࡾప࠸⃰ᗘࡢ HT ࡣูࡢࢩࢢ ࢼࣝఏ㐩⤒㊰ࢆࡋ࡚⅖ᛂࢆㄪ⠇ࡍࡿྍ⬟ᛶࡀ࠶ࡿࡇࢆ♧ࡋࡓࠋࡉࡽ, HT ࡣ LPS
ㄏⓎᛶࡢp44/42 mitogen-activated protein kinase (ERK1/2) ࡢࣜࣥ㓟ࢆᢚไࡋ࡞࠸ࡇࡶ♧ ࡋࡓࠋ ➨2 ❶࡛ࡣ㸪HT ࡀస⏝ࡍࡿࢩࢢࢼࣝఏ㐩⤒㊰ࢆࡉࡽ᫂ࡽࡍࡿࡓࡵ㸪NF-κB ཬࡧ ERK1/2㸪c-Jun N ᮎ➃࢟ࢼ࣮ࢮ (JNK)㸪p38, ௨ୖ 3 ࡘࡢศಁ㐍ᅉᏊάᛶࢱࣥࣃࢡ㉁࢟ ࢼ࣮ࢮᑐࡍࡿinhibitor ࢆ⏝࠸ࡓᐇ㦂ࢆ⾜࡞ࡗࡓࠋࡑࡢ⤖ᯝ㸪HT ࡢస⏝Ⅼࡣ ERK1/2㸪JNK, p38 ࡢ࠸ࡎࢀࡢ⤒㊰ୖࡶ↓ࡃ㸪NF-κB ⤒㊰ࡼࡾࡶୗὶ࠶ࡿྍ⬟ᛶࢆ♧ࡋࡓࠋ௨ୖ, ➨ 1 ❶ཬࡧ➨2 ❶ࡼࡾ, HT ࡣ 12.5 μg/mL ௨ୖࡢ⃰ᗘ࡛ࡣ NF-κB ࢩࢢࢼࣝఏ㐩⤒㊰ᑐࡋ࡚, 12.5 μg/mL ࡼࡾప࠸⃰ᗘ࡛ࡣ NF-κB ⤒㊰ࡼࡾࡶୗὶࡢࢩࢢࢼࣝ⤒㊰స⏝ࡍࡿࡇࢆ᫂ࡽ ࡋࡓࠋ ➨ 3 ❶࡛ࡣ㸪࢝ࣛࢤࢽࣥㄏⓎ⫥ᾋ⭘ࣔࢹࣝࢆ⏝࠸࡚ HT ࡢᢠ⅖స⏝ࢆホ౯ࡋࡓࠋࡑࡢ ⤖ᯝ, HT ࡣᑐ↷⸆ࡢࢭࣞࢥ࢟ࢩࣈཬࡧࣥࢻ࣓ࢱࢩࣥࡼࡾ⫥ᾋ⭘ᢚไస⏝ࡣᙅ࠸ࡶࡢࡢ㸪 ᑐ↷⸆ࡣ␗࡞ࡾ㛫⤒㐣క࠸ຠᯝࡀቑຍࡍࡿࡇࢆ♧ࡋࡓࠋࡇࡢ⤖ᯝࡼࡾ, ᑐ↷⸆ HT ࢆ⤌ྜࡏࡿࡇࡼࡗ࡚, ࡼࡾᣢ⥆ⓗ࡞ᢠ⅖ຠᯝࡀᚓࡽࢀࡿྍ⬟ᛶࢆ♧ࡋࡓࠋ ➨4 ❶࡛ࡣ㸪HT ࡢ⤒ཱྀᢞࡼࡿࢫࣆࣜࣥㄏⓎ⫶₽⒆ࡢᙳ㡪ࢆ᳨ウࡋࡓࠋࡑࡢ⤖ᯝ, ᑐ↷⸆ࡢࢭࣞࢥ࢟ࢩࣈཬࡧࣥࢻ࣓ࢱࢩࣥࡢᢞࡣ᫂░࡞⫶㞀ᐖࢆᘬࡁ㉳ࡇࡍࡢᑐࡋ㸪 HT ᢞࡣ⫶㞀ᐖࢆᘬࡁ㉳ࡇࡉ࡞࠸ࡇࢆ♧ࡋࡓࠋ௨ୖ, ➨ 3 ❶ཬࡧ➨ 4 ❶࡛ࡣ, HT ࡀ ⫶㞀ᐖࡢస⏝࡞ࡃ㛗㛫ࡢᢠ⅖స⏝ࢆⓎࡍࡿྍ⬟ᛶࢆ♧ࡋ, ᪂ࡓ࡞ᢠ⅖⸆ࡋ࡚ ࡢ᭷⏝ᛶࢆ♧ࡍ▱ぢࢆᥦ౪ࡋࡓࠋ ௨ୖࡘ࠸࡚㸪ᑂᰝጤဨဨ୍⮴࡛ᮏㄽᩥࡀᒱ㜧ᏛᏛ㝔㐃ྜ⋇་Ꮫ◊✲⛉ࡢᏛㄽ ᩥࡋ࡚༑ศ౯್ࡀ࠶ࡿㄆࡵࡓࠋ ᇶ♏࡞ࡿᏛ⾡ㄽᩥ
㸯㸧㢟 ┠㸸Anti-inflammatory effects of olive-derived hydroxytyrosol on lipopolysaccharide-induced inflammation in RAW264.7 cells
ⴭ ⪅ ྡ㸸Yonezawa, Y., Miyashita, T., Nejishima, H., Takeda, Y., Imai, K. and Ogawa, H. Ꮫ⾡㞧ㄅྡ㸸The Journal of Veterinary Medical Science
ᕳ࣭ྕ࣭㡫࣭Ⓨ⾜ᖺ㸸In press
᪤Ⓨ⾲Ꮫ⾡ㄽᩥ
㸯㸧㢟 ┠㸸Evaluation of skin phototoxicity study using SD rats by transdermal and oral administration
ⴭ ⪅ ྡ㸸Yonezawa, Y., Ohsumi, T., Miyashita, T., Kataoka, A., Hashimoto, K., Nejishima, H. and Ogawa, H.
Ꮫ⾡㞧ㄅྡ㸸The Journal of Toxicological Sciences ᕳ࣭ྕ࣭㡫࣭Ⓨ⾜ᖺ㸸40 (6) : 667-683, 2015
㸰㸧㢟 ┠㸸Evaluation for a mutagenicity of aristolochic acid by Pig-a and PIGRET assays in rats
ⴭ ⪅ ྡ㸸Koyama, N., Yonezawa, Y., Nakamura, M. and Sanada, H.
Ꮫ⾡㞧ㄅྡ㸸Mutation Research/Genetic Toxicology and Environmental Mutagenesis ᕳ࣭ྕ࣭㡫࣭Ⓨ⾜ᖺ㸸811 : 80-85, 2016
㸱㸧㢟 ┠㸸Evaluation of a general toxicity study incorporating phototoxicity assessments in Sprague-Dawley rats
ⴭ ⪅ ྡ㸸Yonezawa, Y., Miyashita, T., Ashizawa, H., Hashimoto, K., Nejishima, H. and Ogawa, H.
ᕳ࣭ྕ࣭㡫࣭Ⓨ⾜ᖺ㸸42 (2) : 145-157, 2017
㸲㸧㢟 ┠㸸Suppression of epithelial restitution using an inhibitor against Rho-associated coiled-coil containing protein kinase aggravates colitis through reduced epithelial expression of A-kinase anchor protein 13
ⴭ ⪅ ྡ㸸Kangawa, Y., Yoshida, T., Yonezawa, Y., Maruyama, K., Hayashi, S. M. and Shibutani, M.
Ꮫ⾡㞧ㄅྡ㸸Experimental and Toxicologic Pathology ᕳ࣭ྕ࣭㡫࣭Ⓨ⾜ᖺ㸸69 (8) : 557-563, 2017
