JP2021528961A - 魚タンパク質加水分解物粉末および医薬としての使用のための前記粉末を含む組成物 - Google Patents
魚タンパク質加水分解物粉末および医薬としての使用のための前記粉末を含む組成物 Download PDFInfo
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Abstract
Description
本発明は、魚タンパク質加水分解物粉末を生成するための酵素加水分解プロセスに関する。さらに、本発明は、このプロセスによって得られた魚タンパク質加水分解物粉末および医薬としての、好ましくは、消化器系および中枢神経系の酸化的損傷の予防または処置のための上記粉末を含む組成物の使用に関する。
1またはこれより多くの酸化的ストレス関連遺伝子のアップレギュレート/ダウンレギュレートは、酸化的傷害に曝された組織に細胞保護を付与し得る考えられる機構として提唱されている。分子酸素は、ほぼ全ての真核生物の生存に必須であるが、生理学的条件下でのその処理は、代謝副生成物として、過酸化水素、スーパーオキシド、ペルオキシナイトライト、およびヒドロキシルラジカルのような活性酸素種(ROS)を生成する。適切な防御機構の非存在下において、ROSおよび求電子剤の蓄積は、細胞膜およびDNAの損傷、変異原性、組織の変性、早老、アポトーシス性細胞死およびがんをもたらす[Ward, J. F. (1994) The complexity of DNA damage: relevance to biological consequences. Int. J. Radiat Biol. 66, 427−432 ; Goetz, M. E., and Luch, A. (2008) Reactive species: A cell damaging rout assisting to chemical carcinogens. Cancer Lett. 266, 73−83 ; Strassburg, C. P., Manns, M. P., and Tukey, R. H. (1997) Differential Down−Regulation of the UDP−Glucuronosyltransferase 1A Locus Is an Early Event in Human Liver and Biliary Cancer. Cancer Res. 57, 2979−2985]。
抗酸化特性を有し、ROSを不活性化することができ、ROSで開始される反応を防止することができる酵素としては、スーパーオキシドジスムターゼ、カタラーゼ、およびグルタチオンペルオキシダーゼが挙げられる。それらは、「直接」フェーズ1抗酸化酵素(“direct” Phase 1 antioxidant enzymes)といわれる群に属する[Auten, R. L., O’Reilly, M. A., Oury, T. D., Nozik−Grayck, E., and Whorton, M. H. (2006) Transgenic extracellular superoxide dismutase protects postnatal alveolar epithelial proliferation and development during hyperoxia. Am. J. Physiol. Lung Cell Mol. Physiol. 290, L32−40]。
本発明は、種々の器官および組織における酸化的損傷に対して保護を提供する、ヒト酸化保護遺伝子の機能を調節することにおける経口使用のための魚タンパク質加水分解物粉末およびその成分ペプチドを提供する。本発明に従う魚タンパク質加水分解物粉末は、経口製剤に組み込まれる酸化保護遺伝子調節活性を有する1またはこれより多くのペプチド化合物を含む。
本発明を詳細に記載する前に、本明細書で使用される用語法が、特定の実施形態を記載する目的のために過ぎず、限定することを意図しないことは理解されるべきである。本明細書および添付の請求項において使用される場合、単数形「1つの、ある(a)」、「1つの、ある(an)」、および「上記、その、この(the)」は、状況が別段明らかに示さなければ、複数形への言及を包含することは、注記されなければならない。
i)すり潰した魚タンパク質材料と水とを混合し、加熱する工程;
ii)エンドペプチダーゼ酵素を上記i)の混合物に添加し、撹拌する工程;
iii)カルボキシペプチダーゼの形態にあるエキソペプチダーゼ酵素を上記ii)の混合物に添加し、撹拌する工程;
iv)上記酵素加水分解を熱不活性化によって停止させる工程;
v)上記魚加水分解物画分および残りの固体材料を、濾過によって分離する工程;ならびに
vi)上記魚加水分解物画分を濃縮および乾燥させて、魚タンパク質加水分解物粉末を得る工程。
に関する。
サケタンパク質加水分解物粉末を、捌いて切り身にした後のサケ(salmo salar)頭部および背骨の酵素加水分解によって生成する。1000グラムのすり潰した頭部および背骨を、1000mlの水に添加し、その混合物を50℃に加熱する。これに、10gのエンドペプチダーゼ酵素 − ペプシン −を添加し、30分間撹拌する。これに、10gのエキソペプチダーゼ酵素 − カルボキシペプチダーゼ −をさらに添加し、15分間撹拌する。これに、5グラムの酵素Flavourzyme(R)(aspergillus oryzaeに由来するプロテアーゼ)をさらに添加し、その混合物を10分間撹拌する。次いで、その混合物全体を、85℃に加熱し、上記温度で15分間維持し、濾過する。上記加水分解物画分を、従来のエバポレーター中で30% 乾燥物へと濃縮し、スプレー乾燥して、本発明に従う魚タンパク質加水分解物粉末を、本明細書中の実施例6〜11に示される生物学的有効性を有する淡黄色の自由流動粉末として得る。
サケタンパク質加水分解物粉末を、使用されるエキソペプチダーゼが、カルボキシペプチダーゼの代わりにアミノペプチダーゼであることを除いて、上記の実施例1に示されるとおりに生成する。生物学的有効性を有しない粉末を得た(データは示さず)。
サケタンパク質加水分解物粉末を、エキソペプチダーゼ(カルボキシペプチダーゼ)が、エンドペプチダーゼの前に添加されることを除いて、上記の実施例1に示されるとおりに生成する。生物学的有効性を有しない粉末を得た(データは示さず)。
サケタンパク質加水分解物粉末を、第3の酵素の添加を省略し、エキソペプチダーゼの作用時間を延長することを除いて、上記の実施例1に示されるとおりに生成する。本明細書中の実施例6〜11に示される生物学的有効性を有する粉末を得た。
サケタンパク質加水分解物粉末を、使用されるエンドペプチダーゼ酵素が、ペプシンの代わりにトリプシンであることを除いて、上記の実施例1に示されるとおりに生成する。本明細書中の実施例6〜11に示される生物学的有効性を有する粉末を得た。
本発明に従うサケタンパク質加水分解物粉末(SPH)を、以下の実験において試験した。HGEPp細胞(プールした初代ヒト歯肉上皮細胞)を、CellnTec Advanced Cell Systems AGから購入した。The RNEasy Plus Micro Kit、RNase−free DNase Set、RT2 Easy First Strand Kit(DNA generator)およびRT2 SYBR(登録商標) Green fluor qPCRマスターミックスを、Qiagen N.V., USAから購入した。Oxidative Stress RT2プロファイラーPCRアレイ(84種の保護遺伝子)を、Qiagen N.V., USAから購入した。Bio−Rad Inc., USAのThe iCycler PCRシステムを、RT−PCRのために使用した。
グルタチオンペルオキシダーゼ(GPx):
GPX1、GPX2、GPX3、GPX4、GPX5、GPX6、GPX7、GSTP1、GSTZ1。
ペルオキシレドキシン(TPx):
PRDX1、PRDX2、PRDX3、PRDX4、PRDX5、PRDX6。
他のペルオキシダーゼ:
CAT、CYBB、CYGB、DUOX1、DUOX2、EPX、LPO、MGST3、MPO、PTGS1(COX1)、PTGS2(COX2)、PXDN、TPO、TTN。
他の抗酸化剤:
ALB、APOE、GSR、MT3、SOD1、SOD3、SRXN1、TXNRD1、TXNRD2、VIMP。
スーパーオキシドジスムターゼ(SOD):
SOD1、SOD2、SOD3。
他のスーパーオキシド代謝遺伝子:
ALOX12、CCS、DUOX1、DUOX2、GTF2I、MT3、NCF1、NCF2、NOS2、NOX4、NOX5、PREX1、UCP2。
他の活性酸素種(ROS)代謝遺伝子:
AOX1、BNIP3、EPHX2、MPV17、SFTPD。
酸化的ストレス応答遺伝子:
APOE、ATOX1、CAT、CCL5、CYGB、DHCR24、DUOX1、DUOX2、DUSP1、EPX、FOXM1、FTH1、GCLC、GCLM、GPX1、GPX2、GPX3、GPX4、GPX5、GPX6、GPX7、GSR、GSS、HMOX1、HSPA1A、KRT1、LPO、MBL2、MPO、MSRA、NQO1、NUDT1、OXR1、OXSR1、PDLIM1、PNKP、PRDX2、PRDX5、PRDX6、PRNP、RNF7、SCARA3、SEPP1、SIRT2、SOD1、SOD2、SQSTM1、SRXN1、STK25、TPO、TTN、TXN、TXNRD1、TXNRD2、VIMP。
CYGB、MB
本発明に従うサケタンパク質加水分解物粉末(SPH)を、以下の実験において試験した。HIEC−6細胞(ヒト腸上皮細胞)を、ATCC, USAから購入した。The RNEasy Plus Micro Kit、RNase−free DNase Set、RT2 Easy First Strand Kit(DNA generator)およびRT2 SYBR(登録商標) Green fluor qPCRマスターミックスを、Qiagen N.V., USAから購入した。Oxidative Stress RT2プロファイラーPCRアレイ(84種の保護遺伝子)を、Qiagen N.V., USAから購入した。Bio−Rad Inc., USAのThe iCycler PCRシステムをRT−PCRのために使用した。
アップレギュレートされた酸化的ストレス遺伝子
SPHでのHGEPp細胞の処理は、16種のヒト酸化的ストレス関連遺伝子 − APOE、CYGB、EPX、FTH1、GCLC、GPX1、GSR、GSTZ1、HMOX1、MBL2、MSRA、NOS2、NQO1、PRDX5、SELS、SOD1に関して2より高い倍率変化を有するアップレギュレーションを示した一方で、SPHでのHIEC−6細胞の処理は、100μM/ml SPH濃度において11種のヒト酸化的ストレス関連遺伝子 − APOE、EPX、FTH1、GCLC、GSS、HMOX1、MBL2、NOS2、NQO1、PRDX5、SOD1の2より高い倍率変化を有するアップレギュレーションを示した(表1および2)。上記DMSOブランク処理は、上記アレイにおいていかなる遺伝子の調節におけるいかなる変化も示さなかった。10種の遺伝子が、両方の細胞株において共通するアップレギュレーションを示した − APOE、EPX、FTH1、GCLC、HMOX1、MBL2、NOS2、NQO1、PRDX5、SOD1。
表1 SPH処理後のHGEPp細胞におけるアップレギュレートされた酸化的ストレス関連遺伝子
SPHでのHGEPp細胞の処理は、9種のヒト酸化的ストレス関連遺伝子 − ALOX12、EPHX2、MGST3、MPO、NCF1、NOX5、PRDX1、PTGS2、SRXN1の50%未満の倍率変化を有するダウンレギュレーションを示した一方で、SPHでのHIEC−6細胞の処理は、100μM/ml SPH濃度において7種のヒト酸化的ストレス関連遺伝子(ALOX12、MGST3、MPO、NCF1、NOX5、PTGS2、SRXN1)に関して50%未満の倍率変化を有するダウンレギュレーションを示した(表3および4)。7種の共通する遺伝子は、両方の細胞株においてダウンレギュレーションを示した − ALOX12、MGST3、MPO、NCF1、NOX5、PTGS2、SRXN1。
表3 SPH処理後のHGEPp細胞におけるダウンレギュレートされた酸化的ストレス関連遺伝子
さらに2種のアップレギュレートされた遺伝子、HGEPp細胞におけるFTH1およびHMOX1、ならびに3種のアップレギュレートされた遺伝子、HIEC−6細胞におけるAPOE、FTH1およびHMOX1は、25μM/mlおよび50μM/mlの2種の低用量のSPH処理において、用量依存性結果を示した。ALOX12遺伝子は、HGEP細胞およびHIEC−6細胞の両方において用量依存性ダウンレギュレーションを示した(表5)。他の遺伝子のいずれも、SPH濃度を50μM/mlおよび25μM/mlに低減した場合に、アップレギュレーションにおける2より高い倍率変化も、ダウンレギュレーションにおける50%未満の倍率変化も示さなかった。
表5 HGEP細胞およびHIEC−6細胞の両方におけるSPH用量依存性遺伝子調節
HMOX1遺伝子発現は、酸化的ストレスによって誘導され、細胞保護を付与するようである。得られたHO1酵素は、ヘムの分解を触媒し、これはビリベルジン、第1鉄、および一酸化炭素を生じる。それは、α−メチレン架橋においてヘム環を開裂して、ビリベルジンを形成し、ビリベルジンは、ビリベルジンレダクターゼによってビリルビンに変換される。ヘムオキシゲナーゼ反応から放出された一酸化炭素はまた、血管緊張および一酸化窒素シンターゼの機能に影響を及ぼすことが示されている。
メタボリックシンドロームは、以下の医学的状態: 異常な(中心性)肥満、血圧の上昇、絶食時血漿グルコースの上昇(または明らかな糖尿病(overt diabetes))、高血清トリグリセリド、および低い高密度リポタンパク質(HDL)レベルのうち、少なくとも3/5がまとまって起こる場合に使用される用語である
Claims (12)
- 魚タンパク質加水分解物粉末を生成するための酵素加水分解プロセスであって、前記プロセスは、以下の連続する工程:
i)魚タンパク質材料に由来するすり潰した副生成物と水とを混合し、加熱する工程;
ii)エンドペプチダーゼ酵素を前記i)の混合物に添加し、撹拌する工程;
iii)カルボキシペプチダーゼの形態にあるエキソペプチダーゼ酵素を、前記ii)の混合物に添加し、撹拌する工程;
iv)前記酵素加水分解を熱不活性化によって停止させる工程;
v)前記魚加水分解物画分および残りの固体材料を、濾過によって分離する工程;ならびに
vi)前記魚加水分解物画分を濃縮および乾燥させて、魚タンパク質加水分解物粉末を得る工程、
を包含するプロセス。 - 前記プロセスは、aspergillus oryzaeに由来するプロテアーゼ酵素を、前記iii)の混合物に添加し、撹拌する工程という第3の加水分解工程をさらに包含する、請求項1に記載のプロセス。
- 前記魚タンパク質材料は、魚類、好ましくはサケ類、より好ましくはsalmo salarに由来する、請求項1に記載のプロセス。
- 前記エンドペプチダーゼは、ペプシンまたはトリプシン、またはこれらの任意の組み合わせからなる群より選択される、請求項1に記載のプロセス。
- 医薬としての使用のための、請求項1〜4のいずれかに記載のプロセスによって得られ得る、魚タンパク質加水分解物粉末。
- 請求項5に記載の魚タンパク質加水分解物粉末を、医薬としての使用のための少なくとも1種の薬理学的に受容可能なキャリアまたは賦形剤を一緒に含む組成物。
- 消化器系または中枢神経系の障害または疾患の予防または処置における使用のための、請求項5に記載の魚タンパク質加水分解物粉末または請求項6に記載の組成物。
- 前記消化器系の障害または疾患は、胃食道逆流症、胃腸炎、過敏性腸症候群、小腸結腸炎、セリアック病および直腸炎の疾患を含む群より選択される、消化器系の障害または疾患の予防または処置における使用のための、請求項5に記載の魚タンパク質加水分解物粉末または請求項6に記載の組成物。
- 前記中枢神経系の障害または疾患は、神経変性疾患、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、脳血管障害、脱髄疾患、および精神障害を含む群から選択される、神経系の障害または疾患の予防または処置における使用のための、請求項5に記載の魚タンパク質加水分解物粉末または請求項6に記載の組成物。
- 酸化保護遺伝子の発現の改変による、消化器系または中枢神経系の障害または疾患の予防または処置における使用のための、請求項5に記載の魚タンパク質加水分解物粉末または請求項6に記載の組成物。
- 前記酸化保護遺伝子は、赤血球系転写因子2関連転写因子2(Nrf2)および調節される遺伝子セット内に存在する、酸化保護遺伝子の発現の改変による、消化器系または中枢神経系の障害または疾患の予防または処置における使用のための、請求項5に記載の魚タンパク質加水分解物粉末または請求項6に記載の組成物。
- 前記酸化保護遺伝子は、アポリポプロテインE、サイトグロビン、好酸球ペルオキシダーゼ、フェリチン重鎖ポリペプチド1、グルタミン−システインリガーゼ、グルタチオンペルオキシダーゼ1、グルタチオンシンセターゼ、グルタチオントランスフェラーゼζ1、ヘムオキシゲナーゼ1、マンノース結合レクチン2、メチオニンスルホキシドレダクターゼA、一酸化窒素シンターゼ2、NAD(P)Hデヒドロゲナーゼキノン1、ペルオキシレドキシン5、セレノプロテインS、スーパーオキシドジスムターゼ1、アラキドン酸12−リポキシゲナーゼ、エポキシドヒドロラーゼ2、ミクロソームグルタチオンSトランスフェラーゼ3、ミエロペルオキシダーゼ、好中球サイトゾル因子1、NADPHオキシダーゼ、ペルオキシレドキシン1、プロスタグランジンエンドペルオキシドシンターゼ2、スルフィレドキシンである、酸化保護遺伝子の発現の改変による、消化器系または中枢神経系の障害または疾患の予防または処置における使用のための、請求項5に記載の魚タンパク質加水分解物粉末または請求項6に記載の組成物。
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PCT/NO2019/050125 WO2019245380A1 (en) | 2018-06-20 | 2019-06-17 | Fish protein hydrolysate powder and a composition comprising said powder for use as a medicament |
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US4473589A (en) | 1981-04-22 | 1984-09-25 | Freeman Leon D | Protein liquefication process and products |
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