JP2018177667A - 炎症性腸疾患の予防又は治療用組成物 - Google Patents
炎症性腸疾患の予防又は治療用組成物 Download PDFInfo
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Abstract
Description
(2)組成物100重量%中、ゼオライトの焼成物及び貝殻の焼成物を合計して20重量%〜80重量%、クエン酸を20重量%〜40重量%、紅麹を10重量%〜30重量%含む上記(1)に記載の炎症性腸疾患の予防又は治療用組成物。
(3)ゼオライトの焼成物と貝殻の焼成物の配合比が、5:95〜20:80(重量比)である上記(1)又は(2)に記載の炎症性腸疾患の予防又は治療用組成物。
(4)医薬である、上記(1)〜(3)のいずれかに記載の炎症性腸疾患の予防又は治療用組成物。
(5)栄養補助食品である、上記(1)〜(3)のいずれかに記載の炎症性腸疾患の予防又は治療用組成物。
(6)食品である、上記(1)〜(3)のいずれかに記載の炎症性腸疾患の予防又は治療用組成物。
本発明の炎症性腸疾患の予防又は治療用組成物は、ゼオライトの焼成物、貝殻の焼成物、クエン酸及び紅麹を含むことを特徴とする。この組成物は、腸内の炎症状態を改善し、アポトーシスを抑制し、さらに大腸粘膜の上皮防御機能及びバリア機能を維持する機能を有するため、炎症性腸疾患の予防又は治療に用いることができる。
(1)組成物の調製
天然ゼオライトを650℃で15時間焼成し、15μm以下に粉砕した。同様に、牡蠣殻を700℃で17時間焼成し、15μm以下に粉砕した。続いて、ゼオライトの焼成物と牡蠣殻の焼成物を混合し、得られた混合物を温水にて十分にイオン交換させ、高温で水分を除去した。ゼオライトの焼成物と牡蠣殻の焼成物の配合比は、1:9(重量比)とした。次に、ゼオライトの焼成物及び牡蠣殻の焼成物の上記混合物を47.6重量%、クエン酸(33.3重量%)、紅麹(Monascus)(16.7重量%)及び固結防止剤としてステアリン酸カルシウム(2.4重量%)を混合し、目的の組成物(以下「ゼオライト含有組成物」又は「HY」と呼ぶ)を調製した。
Charles River Japan(Tokyo、Japan)から入手した7週齢雄性C57BL6マウスを、制御された温度(23±2℃)、相対湿度(50%〜60%)、実験全体を通じて12時間ダーク/ライトサイクルの照明条件で個々のケージに収容した。3日間の馴化後、各群が6〜8匹のマウスからなる、等しい平均体重を有する4つの群に割り当てた。(1)HY8群は、0.8重量%のゼオライト含有組成物(HY)の粉末を添加したAIN-93G基本飼料と滅菌水道水を実験全体を通じて摂取させた。(2)CON群は、AIN-93G基本飼料と滅菌水道水を実験全体を通じて摂取させた。(3)DSS群は、AIN-93G基本飼料及び滅菌水道水を11日間与えた後、1.5重量%のDSS(DSS分子量:40kDa;MP Biomedicals、Irvine、CA、USA)含有滅菌水道水を9日間与えた。(4)DHY8群は、0.8重量%のHY粉末を添加したAIN-93G基本飼料と滅菌水道水を11日間与えた後、1.5重量%DSS含有滅菌水道水を9日間与えた。餌の組成を表1に示す。この実験における0.8重量%のHYの配合量は、予備実験に基づいて決定した。なお、この実験は、東京大学の動物用ケア及び使用委員会によって承認された(承認番号P13-739)。
疾患活性指数(DAI)は、DSSをマウスに与えた後の3つのスコア(体重減少、血便、及び下痢)の平均値である。スコアの基準は次の通りである:体重減少率(0:<1%、1:1〜5%、2:5〜10%、3:10〜15%、4:>15%)、血便(0:血便なし、2:++、4:+++)及び下痢程度(0:正常、2:軟質、4:下痢)。
実験の終了時に、ペントバルビタールナトリウムで全てのマウスを深く麻酔した後、頸動脈から出血させた。得られた血液を1000g、15分間4℃で遠心分離して血漿を得た。大腸長は、回腸と盲腸接合部と近位直腸との間で測定され、また、この測定値は大腸炎の程度の基準の1つとして使用した。肝臓、切除された大腸、腸間膜脂肪及び後腹膜脂肪組織を液体窒素中で急速凍結し、分析時まで-80℃で保存した。
大腸ミエロペルオキシダーゼ(MPO)活性は、MPO Activity Colorimetric Assayキット(BioVision、Palo Alto、CA、USA)を製造元のマニュアルに従って使用し、比色法により測定した。
各大腸スライスをOCT(Optimal Cutting Temperature)化合物(Sakura Finetek、Torrance、CA、USA)に包埋し、次いで液体窒素中で急速冷凍した。各5μm厚の組織切片を作り、ヘマトキシリン及びエオシン(H&E)で染色し、次いで光学顕微鏡(オリンパスBX51顕微鏡、Olympus Optical、Tokyo、Japan)でスキャンした。
全RNA分離キットNucleoSpin(登録商標)RNA plus(Macherey-Nagel、Duren、Germany)を使用して、製造元の指示に従って大腸粘膜から全RNAを抽出した。RNAの濃度及び純度は、NanoDrop ND-1000分光光度計(NanoDrop Technologies、Wilmington、DE、USA)を用いて測定した。
(i)DNAマイクロアレイ調製
各群の個々のマウスからの大腸RNAサンプルをプールし(n=6〜8)、その後、ゲノム全体発現のプロファイリングのために、プローブが40,000を超えるAffymetrix Mouse Genome 430 2.0 Array Genechips(Affymetrix、Santa Clara、CA、USA)を用いてマイクロアレイ分析を行った。
(ii)マッピングと機能解析
Microarray Suite ver.5.0ソフトウェア(Affymetrix)を利用し画像をスキャンした後、DSS群とCON群及びDHY8群とDSS群の遺伝子発現を比較した。1.5倍を超える発現比を有意な発現とみなした。
遺伝子の発現を確認するために、逆転写ポリメラーゼ連鎖反応(RT-PCR)を実施した。そのプライマー配列を表2に示す。それぞれの遺伝子の発現レベルを、大腸粘膜における60S酸性リボソームタンパク質p1(Rplp1)の発現に対して正規化した。
溶解緩衝液を用いて大腸粘膜からタンパク質を抽出し、次いでそれを12,000g、4℃、30分間で遠心分離した。タンパク質濃度はBradfordアッセイにより測定した。4-plex iTRAQラベリングキット(AB Sciex、Framingham、MA、USA)のマニュアルに従って、システインブロッキング及び消化のためにタンパク質(100μg)をプールし、次に質量分析計(NanoLC-MS/MS;AB Sciex)に連結されたナノスケール液体クロマトグラフィーによるさらなる分析のために、以下のようにアイソバリックタグで標識した。CON:115タグ、DSS:114タグ、DHY8:116タグ。
データは、平均値±標準誤差(SE)として示し、二元配置分散分析(ANOVA)により分析した。有意差が、p<0.05のレベルをTukey法で評価した。グラフ中、a、b、cの符号は、異符号間に統計的に有意差があることを示しており、p≦0.05:有意差あり、0.05<p<0.1:傾向あり、としている。
(1)一般的な特性
DHY8群とDSS群の摂食量に有意差は認められなかったが、CON群とDSS群で摂食量に有意な差が認められた(DHY8:76.4±3.3g、DSS:73.1±1.7g、CON:82.8±3.5g、HY8:76.7±2.6g)。HY8群とDSS群(HY8:84.8±2.3ml、DSS:70.3±2.1ml、CON:73.7±1.9ml、DHY8:72.2±1.4ml)の間で水分摂取に有意差があった。DSS投与後に体重減少、血便及び下痢程度が変化し、CON群と比較してDAI値が有意に増加した。HYの摂取により、体重減少は改善され、IBDの病態が抑制された。これは第6〜9日のDAI値によっても示された(図1A〜図1D)。DSSにより誘発された大腸長の短縮及び腸間膜脂肪重量の減少、大腸MPO活性の増加は、HY摂取により改善される傾向があったが、後腹膜脂肪組織の重量には変化がなかった(図1E〜図1H)。
DSSは粘膜上皮細胞の構造的な障害を誘発し、粘膜及び粘膜下組織への炎症細胞の浸潤が増加する可能性がある。HY摂取により、炎症細胞の浸潤は減少し、粘膜上皮細胞の構造的な障害が改善された(図1I)。
合計5,238個の遺伝子が有意に発現し、そのうち2,300個がDSSマウスと比較してDHY8マウスで有意にアップレギュレートされ、CONマウスと比較してDSSマウスでダウンレギュレートされた。一方、2,938個の遺伝子がDSS群と比較してDHY8群で顕著にダウンレギュレーションされ、DSS群ではCON群と比較してアップレギュレートされた。
iTRAQを用いたプロテオーム解析により5,000を超えるタンパク質が確認された。発現比が1.5倍を超えるタンパク質を変動があったタンパク質とみなし、この基準により、668のタンパク質が変動しており、そのうち332はDSS群と比較してDHY8群でアップレギュレーションされ、CONと比較してDSS群でダウンレギュレーションされていた。DSS群と比較してDHY8群でダウンレギュレーションされたが、CONと比較してDSSマウスではアップレギュレートされたタンパク質は336あった。
マイクロアレイ分析では、HYの摂取が以下の炎症性腸疾患経路:Il12posIl12rβ1posStat4posIfngposTlr5posTnfα/Il6/Il1βに関与する遺伝子の発現を抑制することによりマウスの炎症状態を改善したことが明らかになった。図3は、DSS誘発性大腸炎におけるHYの摂取により変動した炎症性腸疾患経路の模式図である。この経路では、Stat4チロシンリン酸化はIL12により誘導される。これはサイトカインIFNγのT細胞非依存性誘導に必要であり、次いでTLR刺激に応答して、リンパ系細胞及び非リンパ系細胞の両方が前炎症性サイトカインIL6を産生することができる。これは、TNFα及びIL1βとともに、主要な前炎症性サイトカインであると考えられている。炎症性腸疾患経路のダウンレギュレーションは、主に、DSSにより誘発される前炎症性サイトカインのレベルの低下をもたらし、HY摂取による炎症度の軽減をもたらす。
前炎症性サイトカインのダウンレギュレーション、トランスクリプトーム及びプロテオーム解析による抗炎症因子の発現の増加により、HYが炎症性腸疾患経路の発現を抑制し、したがってDSS誘発大腸炎における炎症の程度を減少させるものと考えられた。HYは、P53のような相関的な遺伝子を阻害し、他の上皮維持関連遺伝子やタンパク質も大きく変化させることで、DSSに起因する細胞周期障害をある程度改善してアポトーシスを抑制し、粘膜免疫ホメオスタシスを維持するものと考えられる。したがって、統合オミックス分析の結果は、DSS誘発大腸炎に対するHYの効果が、主に炎症状態の改善、アポトーシスの程度の改善、並びに大腸粘膜の上皮防御機能及びバリア機能の維持に基づくことを示しており、HYが、炎症性腸疾患の予防又は治療に有効であることが示唆された。
Claims (6)
- ゼオライトの焼成物、貝殻の焼成物、クエン酸及び紅麹を含む炎症性腸疾患の予防又は治療用組成物。
- 組成物100重量%中、ゼオライトの焼成物及び貝殻の焼成物を合計して20重量%〜80重量%、クエン酸を20重量%〜40重量%、紅麹を10重量%〜30重量%含む請求項1に記載の炎症性腸疾患の予防又は治療用組成物。
- ゼオライトの焼成物と貝殻の焼成物の配合比が、5:95〜20:80(重量比)である請求項1又は2に記載の炎症性腸疾患の予防又は治療用組成物。
- 医薬である、請求項1〜3のいずれか1項に記載の炎症性腸疾患の予防又は治療用組成物。
- 栄養補助食品である、請求項1〜3のいずれか1項に記載の炎症性腸疾患の予防又は治療用組成物。
- 食品である、請求項1〜3のいずれか1項に記載の炎症性腸疾患の予防又は治療用組成物。
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JP2021035926A (ja) * | 2019-08-30 | 2021-03-04 | ポッカサッポロフード&ビバレッジ株式会社 | アンジオテンシンIIType1受容体拮抗剤 |
JP2022136301A (ja) * | 2022-04-28 | 2022-09-15 | 小林製薬株式会社 | 固形製剤 |
CN115300530A (zh) * | 2022-06-29 | 2022-11-08 | 东北农业大学 | 支链脂肪酸在制备预防或者治疗胃肠病的产品中应用 |
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JP7395288B2 (ja) | 2019-08-30 | 2023-12-11 | ポッカサッポロフード&ビバレッジ株式会社 | アンジオテンシンIIType1受容体拮抗剤 |
JP2022136301A (ja) * | 2022-04-28 | 2022-09-15 | 小林製薬株式会社 | 固形製剤 |
CN115300530A (zh) * | 2022-06-29 | 2022-11-08 | 东北农业大学 | 支链脂肪酸在制备预防或者治疗胃肠病的产品中应用 |
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