JP2009126826A - Anti-stress agent - Google Patents
Anti-stress agent Download PDFInfo
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- JP2009126826A JP2009126826A JP2007303598A JP2007303598A JP2009126826A JP 2009126826 A JP2009126826 A JP 2009126826A JP 2007303598 A JP2007303598 A JP 2007303598A JP 2007303598 A JP2007303598 A JP 2007303598A JP 2009126826 A JP2009126826 A JP 2009126826A
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- Prior art keywords
- stress
- agent
- csf
- isothiocyanate
- food
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Abstract
Description
本発明は、ストレス負荷後のACTH(副腎皮質刺激ホルモン)の分泌を抑制する作用および/またはストレス負荷後の炎症性サイトカイン増加を抑制する作用を有し、医薬品、食品などとして利用される抗ストレス剤、ならびに、生体に対する負荷が心身の障害を来すメカニズムに対する拮抗剤および緩和剤に関する。 The present invention has an action of suppressing the secretion of ACTH (adrenocorticotropic hormone) after stress loading and / or the action of suppressing increase of inflammatory cytokines after stress loading, and is used as a drug, food, etc. The present invention relates to an agent, and an antagonist and a relieving agent for a mechanism in which a load on a living body causes mental and physical disorders.
精神的および/または肉体的ストレスは、神経、内分泌および免疫系を含む宿主の防御に影響を及ぼす(非特許文献1および2)。ストレス負荷時には、種々の炎症性サイトカイン(例えば、IL−18、IL−1β、IL−6、TNF−αなど)の血中濃度が上昇し(非特許文献3)、免疫、生体防御系を攪乱することが知られている(非特許文献4)。また、本発明者は、ストレス負荷による炎症性サイトカイン増加が活性酸素分子により引き起こされることを報告している(非特許文献5)。
Mental and / or physical stress affects host defense, including nerve, endocrine and immune systems (Non-Patent
最近の研究では、IL−18mRNAは副腎において副腎皮質刺激ホルモン(ACTH)および寒冷ストレスに応答して発現することが報告されている(非特許文献6)。また、副腎と免疫細胞とではIL−18mRNAについては異なるプロモーターを使用していることが報告されている(非特許文献7)。しかしながら、成熟型のIL−18の誘導は、前記両研究では示されていない。他方、精神医学的患者において、血漿中のIL−18の上昇が報告されている(非特許文献8)。 Recent studies have reported that IL-18 mRNA is expressed in the adrenal gland in response to adrenocorticotropic hormone (ACTH) and cold stress (Non-patent Document 6). In addition, it has been reported that the adrenal gland and immune cells use different promoters for IL-18 mRNA (Non-patent Document 7). However, induction of mature IL-18 has not been shown in both studies. On the other hand, an increase in plasma IL-18 has been reported in psychiatric patients (Non-patent Document 8).
現代社会においては、ヒトは様々なストレスに曝されて労働し、生活している。一般に、ストレスの感じ方には個人差があり、ストレスの有無や強弱について明確な指標がなかった。本発明者は、これまでの研究によりストレスがIL−18などのサイトカインの上昇を招いていることを見出し、IL−18をストレスカスケードの頂点とする情報伝達の流れを明らかにしてストレスの客観的評価を可能にした(特許文献1、非特許文献9および10)。
In modern society, humans work and live under various stresses. In general, there are individual differences in how stress is felt, and there is no clear indicator of the presence or absence or strength of stress. The present inventor has found that stress has caused an increase in cytokines such as IL-18, and has clarified the flow of information transmission using IL-18 as the apex of the stress cascade. Evaluation was made possible (
6−メチルスルフィニルヘキシルイソチオシアネートは、本わさび(Wasabia Japonica)の根茎に含まれる芥子油の一種であり、解毒作用、血流改善作用、抗酸化作用(特許文献2)、細胞周期停止作用(特許文献3)、グルタチオン−S−トランスフェラーゼ活性誘導作用(特許文献4)、エラスターゼ活性阻害作用(特許文献5)などの作用を有することが知られている。本発明者は、特許文献1において、前記イソチオシアネートを始めとする抗酸化剤がストレスカスケードのシグナル伝達を阻害して精神的ストレスを緩和する可能性を示唆しているが、どの抗酸化剤がより有効であるのか不明のままであった。
本発明の課題は、生体へのストレス負荷による生体内の応答を緩和する安全かつ有効な抗ストレス剤を提供することにある。 The subject of this invention is providing the safe and effective anti-stress agent which relieve | moderates the response in the living body by the stress load to a biological body.
本発明者は、上記課題を解決するために鋭意研究した結果、本わさびの根茎に多く含まれる6−メチルスルフィニルヘキシルイソチオシアネートが抗ストレス作用に優れていることを見出し、本発明を完成するに至った。
すなわち、本発明は、以下のものを提供する。
〔1〕 ω−メチルスルフィニルアルキルイソチオシアネート(ただし、アルキル基の炭素数が4〜8である)を有効成分として含有し、ストレス負荷後のACTHの分泌および/またはサイトカイン、ケモカイン増加を抑制することを特徴とする抗ストレス剤または生体負荷が心身の障害を来すことに対する拮抗剤もしくは緩和剤。
〔2〕 前記〔1〕において、ω−メチルスルフィニルアルキルイソチオシアネートが本わさび、西洋わさび、キャベツ、クレソン、芽キャベツ、カリフラワー、大根、からみ大根、ナタネ、ブロッコリー、タカナ、カラシナ、カブ、およびハクサイのアブラナ科植物群から選択される一種または複数種から得られるものである、前記〔1〕に記載の剤。
〔3〕 ω−メチルスルフィニルアルキルイソチオシアネートが、アブラナ科植物の粉砕もしくはすりおろしの物理的手段、溶媒による抽出手段、乾燥手段、またはこれらの組み合わせによって得られる、前記〔2〕に記載の剤。
〔4〕 アブラナ科植物が本わさびである、前記〔2〕または〔3〕に記載の剤。
〔5〕 前記〔4〕において、本わさびが本わさび葉または本わさび根茎である、前記〔4〕に記載の剤。
〔6〕 サイトカインがIL-1β、IL-1ra、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-15、IL-17、IL-18、Eotaxin、FGF basic、G-CSF、GM-CSF、IFN-γ、IFN-α、IP-10、MCP-1、MIP-1α、MIP-1β、PDGF-BB、RANTES、TNF-α、VEGF、CSF-2、TGF-β、ニューロトロフィン5、MCP-3、β-2-microglobulin、アンギオテンシンII、CSF-3、CXCケモカインリガンド1、CXCケモカインリガンド5、HGF、IL-1α、IL-2ra、IL-16、CTACK、GRO-α、HGF、ICAM-1、IFN-α2、LIF、MCP-3、M-CSF、MIF、MIG、β-NGF、SCF、SCGF-β、SDF1a、TNF-βおよびVCAM-1の群から選択される、前記〔1〕〜〔5〕のいずれかに記載の剤。
〔7〕 サイトカインがIL−18である、前記〔6〕に記載の剤。
〔8〕 ω−メチルスルフィニルアルキルイソチオシアネート(ただし、アルキル基の炭素数が4〜8である)を有効成分として含有し、
IL-1β、IL-1ra、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-15、IL-17、IL-18、Eotaxin、FGF basic、G-CSF、GM-CSF、IFN-γ、IFN-α、IP-10、MCP-1、MIP-1α、MIP-1β、PDGF-BB、RANTES、TNF-α、VEGF、CSF-2、TGF-β、ニューロトロフィン5、MCP-3、β-2-microglobulin、アンギオテンシンII、CSF-3、CXCケモカインリガンド1、CXCケモカインリガンド5、HGF、IL-1α、IL-2ra、IL-16、CTACK、GRO-α、HGF、ICAM-1、IFN-α2、LIF、MCP-3、M-CSF、MIF、MIG、β-NGF、SCF、SCGF-β、SDF1a、TNF-βおよびVCAM-1からなる群より選ばれるストレス因子または疲労因子の生体内の量を調節することを特徴とする抗ストレス剤、または生体負荷が心身の障害を来すことに対する拮抗剤もしくは緩和剤。
〔9〕 ω−メチルスルフィニルアルキルイソチオシアネートが6−メチルスルフィニルヘキシルイソチオシアネートである、前記〔1〕〜〔8〕のいずれかに記載の剤。
〔10〕 前記〔1〕〜〔9〕のいずれかに記載の剤を含有する医薬品。
〔11〕 前記〔1〕〜〔9〕のいずれかに記載の剤を含有する食品。
〔12〕 保健機能食品またはダイエタリーサプリメントである、前記〔11〕に記載の食品。
〔13〕 保健機能食品が特定保健用食品または栄養機能食品である、前記〔12〕に記載の食品。
As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that 6-methylsulfinylhexyl isothiocyanate contained in a lot of horseradish rhizomes is excellent in anti-stress action, thereby completing the present invention. It came.
That is, the present invention provides the following.
[1] It contains ω-methylsulfinylalkyl isothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) as an active ingredient, and inhibits the secretion of ACTH and / or increases in cytokines and chemokines after stress loading. An anti-stress agent or an antagonist or alleviating agent against physical and mental disorders caused by biological stress.
[2] In [1], ω-methylsulfinylalkyl isothiocyanate is horseradish, horseradish, cabbage, watercress, brussels sprouts, cauliflower, radish, entangled radish, rapeseed, broccoli, Takana, mustard, turnip, and Chinese cabbage rape. The agent according to [1] above, which is obtained from one or more species selected from the family plant family.
[3] The agent according to the above [2], wherein the ω-methylsulfinylalkylisothiocyanate is obtained by physical means of crushing or scouring cruciferous plants, extraction means by a solvent, drying means, or a combination thereof.
[4] The agent according to [2] or [3], wherein the cruciferous plant is Wasabi.
[5] The agent according to [4], wherein, in [4], the wasabi is a wasabi leaf or a wasabi rhizome.
[6] Cytokines are IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL -11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP- 1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, Neurotrophin 5, MCP-3, β-2-microglobulin, Angiotensin II, CSF- 3,
[7] The agent according to [6] above, wherein the cytokine is IL-18.
[8] containing ω-methylsulfinylalkyl isothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) as an active ingredient,
IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL- 12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP-1α , MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF-3,
[9] The agent according to any one of [1] to [8], wherein the ω-methylsulfinylalkyl isothiocyanate is 6-methylsulfinylhexyl isothiocyanate.
[10] A pharmaceutical comprising the agent according to any one of [1] to [9].
[11] A food containing the agent according to any one of [1] to [9].
[12] The food according to [11] above, which is a health functional food or a dietary supplement.
[13] The food according to [12], wherein the health functional food is a food for specified health use or a food with a nutritional function.
本発明の抗ストレス剤は、ω−メチルスルフィニルアルキルイソチオシアネートを有効成分として含有し、これを食品として、あるいは医薬品として摂取することにより、生体に対するストレス負荷後のACTHおよびグルココルチコイドの分泌および/またはストレス負荷後のサイトカイン・ケモカイン増加を抑制し、生体の過剰反応を低減させるという効果を奏する。本発明の抗ストレス剤は、生体負荷が心身の障害を来すことに対する拮抗剤または緩和剤としても作用する。生体の過剰反応は様々な疾患と関連するため、本発明は、ストレスを起因とする疾患の予防または治療への応用も可能である。 The anti-stress agent of the present invention contains ω-methylsulfinylalkyl isothiocyanate as an active ingredient, and by ingesting this as a food or a pharmaceutical, secretion of ACTH and glucocorticoid after stress loading on a living body and / or It suppresses an increase in cytokines and chemokines after stress loading, and has the effect of reducing excessive reactions in the living body. The anti-stress agent of the present invention also acts as an antagonist or alleviating agent against a physical load causing mental and physical disorders. Since an excessive reaction of a living body is associated with various diseases, the present invention can be applied to prevention or treatment of diseases caused by stress.
本発明は、抗ストレス剤、生体負荷が心身の障害を来すことに対する拮抗剤または緩和剤(以下、本発明の剤)を提供する。 The present invention provides an anti-stress agent, an antagonist or a relieving agent (hereinafter referred to as the agent of the present invention) against a physical load causing a physical and mental disorder.
本発明において「ストレス」とは、生体の精神および肉体に対する化学的、物理的、精神的、言語的または労作的な臨時の負荷が加わったこと(ストレス負荷)による生体の様々な応答を意味する。また、「ストレス」とは、生体内部からの恒常的な負荷が加わったこと(ストレス負荷)による生体の様々な応答も意味する。 In the present invention, the term “stress” means various responses of the living body due to the extraordinary chemical, physical, mental, verbal or exertional stress on the mental and physical body (stress load). . Further, “stress” also means various responses of the living body due to the application of a constant load from inside the living body (stress load).
本発明が緩和対象とする「ストレス」としては、具体的には、高温、低温、高圧、低圧、騒音、放射線、紫外線などによる物理的ストレス、酸素欠乏、重金属、ヒ素などの有害化学物質による化学的ストレス、怒り、不安、恐怖、緊張、拘束などによる精神的ストレス、労働および作業による労作ストレスが例示できるが、本発明においては物理的ストレス、化学的ストレス、労作ストレス、精神的ストレス、が好ましく、精神ストレスとしては拘束ストレスがより好ましく、特に長時間の拘束ストレスが好ましい。ここで、長時間とは生物や個体差により一概には言えないが、動物の場合で6時間以上が例示される。物理的ストレスとしては、紫外線照射によるストレスが好ましく、化学的ストレスとしては、有害化学物質曝露によるストレスが好ましい。 Specific examples of “stress” to be alleviated by the present invention include physical stress caused by high temperature, low temperature, high pressure, low pressure, noise, radiation, ultraviolet rays, chemistry caused by harmful chemical substances such as oxygen deficiency, heavy metals, and arsenic. Mental stress due to physical stress, anger, anxiety, fear, tension, restraint, and labor stress due to labor and work can be exemplified, but in the present invention, physical stress, chemical stress, labor stress, and mental stress are preferable. As the mental stress, restraint stress is more preferable, and long-term restraint stress is particularly preferable. Here, the long time cannot be generally described due to living organisms or individual differences, but in the case of animals, 6 hours or more are exemplified. As physical stress, stress due to ultraviolet irradiation is preferable, and as chemical stress, stress due to exposure to harmful chemical substances is preferable.
ストレス負荷は、視床下部−下垂体−副腎(HPA)軸を活性化してACTH(副腎皮質刺激ホルモン)の分泌を誘導し、グルココルチコイドを誘導する一方で、IL−18などのサイトカインおよびケモカインを誘導する。また、IL18に代表される生体内サイトカイン増加は、さらなるACTH、グルココルチコイドの分泌を引き起こす。従って、本発明において「ストレス」とは、具体的にはACTHの分泌および/または生体内サイトカインおよびケモカイン増加(好ましくは血中濃度の上昇)をいい、さらにこれらに伴う生体の過剰反応ならびにそれらに起因する疾患をも含む意である。 Stress loading activates the hypothalamic-pituitary-adrenal (HPA) axis to induce the secretion of ACTH (adrenocorticotropic hormone) and induces glucocorticoids while inducing cytokines and chemokines such as IL-18 To do. In addition, increases in vivo cytokines represented by IL18 cause further secretion of ACTH and glucocorticoid. Therefore, in the present invention, “stress” specifically refers to the secretion of ACTH and / or the increase of cytokines and chemokines in vivo (preferably an increase in blood concentration). It is meant to include the disease caused by it.
本発明において「抗ストレス」とは、具体的にはストレス負荷後のACTH分泌の抑制および/または生体内サイトカイン増加(好ましくは血中濃度の上昇)の抑制をいい、さらにこれらに伴う生体の過剰反応の低減ならびにそれらに起因する疾患の予防または治療をも含む意である。 In the present invention, “anti-stress” specifically refers to suppression of ACTH secretion after stress loading and / or suppression of in vivo cytokine increase (preferably an increase in blood concentration), and the excess of the living body associated therewith. It also includes the reduction of response as well as the prevention or treatment of diseases resulting therefrom.
本発明においてサイトカイン・ケモカインとは、IL-1β、IL-1ra、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-15、IL-17、IL-18、Eotaxin、FGF basic、G-CSF、GM-CSF、IFN-γ、IFN-α、IP-10、MCP-1、MIP-1α、MIP-1β、PDGF-BB、RANTES、TNF-α、VEGF、CSF-2、TGF-β、ニューロトロフィン5、MCP-3、β-2-microglobulin、アンギオテンシンII、CSF-3、CXCケモカインリガンド1、CXCケモカインリガンド5、HGF、IL-1α、IL-2ra、IL-16、CTACK、GRO-α、HGF、ICAM-1、IFN-α2、LIF、MCP-3、M-CSF、MIF、MIG、β-NGF、SCF、SCGF-β、SDF1a、TNF-βおよびVCAM-1などが挙げられる。特に好ましくは、サイトカインはTNF-α、EotaxinおよびIL−18である。
In the present invention, cytokine chemokine refers to IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL -10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP- 10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, Neurotrophin 5, MCP-3, β-2-microglobulin, Angiotensin II, CSF-3, CXC
ω−メチルスルフィニルアルキルイソチオシアネートは化学的に合成された物質であってもよく、また、アブラナ科植物から得られた抽出物としての天然物であってもよい。これら物質として、具体的には5−メチルスルフィニルペンチルイソチオシアネート、6−メチルスルフィニルヘキシルイソチオシアネート、7−メチルスルフィニルヘプチルイソチオシアネートおよび8−メチルスルフィニルオクチルイソチオシアネートが挙げられるが、本発明の目的を達成するためには、特に6−メチルスルフィニルヘキシルイソチオシアネートが好ましい。 The ω-methylsulfinylalkylisothiocyanate may be a chemically synthesized substance or a natural product as an extract obtained from a cruciferous plant. Specific examples of these substances include 5-methylsulfinylpentyl isothiocyanate, 6-methylsulfinyl hexyl isothiocyanate, 7-methylsulfinyl heptyl isothiocyanate, and 8-methylsulfinyl octyl isothiocyanate. In particular, 6-methylsulfinylhexyl isothiocyanate is preferred.
天然物の場合、ω−メチルスルフィニルアルキルイソチオシアネートは、本わさび、西洋わさび、キャベツ、クレソン、芽キャベツ、カリフラワー、大根、からみ大根、ナタネ、ブロッコリー、タカナ、カラシナ、カブ、ハクサイなどのアブラナ科植物群から選択される一種または複数種から得られるものが好ましい。その中で、6−メチルスルフィニルヘキシルイソチオシアネートの含有率が高い本わさび(Wasabia Japonica)がより好ましく、本わさび葉または本わさび根茎いずれを用いてもよいが、より含有率の高い本わさび根茎が特に好ましい。 In the case of natural products, ω-methylsulfinylalkyl isothiocyanate is a group of cruciferous plants such as horseradish, horseradish, cabbage, watercress, brussels sprouts, cauliflower, radish, leach radish, rapeseed, broccoli, Takana, mustard, turnip, Chinese cabbage, etc. Those obtained from one or more selected from the above are preferred. Among them, Japanese wasabi (Wasabia Japonica) having a high content of 6-methylsulfinylhexyl isothiocyanate is more preferable, and either Japanese wasabi leaf or Japanese wasabi rhizome may be used. Particularly preferred.
ω−メチルスルフィニルアルキルイソチオシアネートの合成方法を説明すると、次のとおりである。 A method for synthesizing ω-methylsulfinylalkylisothiocyanate will be described as follows.
原理的にはKiaerらの方法に従う(Kiaer et al. Acta chem. Scand、11、1298、1957年)。出発物質としてω−クロロアルケノールを用い、CH3−SNaと還流してω−メチルチオアルケノールを得、これにSOCl2 を作用させてω−クロロアルケノールメチルサルファイドを得る。 In principle, the method of Kiaer et al. Is followed (Kiaer et al. Acta chem. Scand, 11, 1298, 1957). Ω-Chloroalkenol is used as a starting material and refluxed with CH 3 -SNa to give ω-methylthioalkenol, which is reacted with SOCl 2 to give ω-chloroalkenol methyl sulfide.
次に、Gabriel法を用いてアミノ基を導入し、N−(ω−メチルチオアルキル)−フタルイミドを生成し、これにヒドラジン水化物を加えて還流し、ω−メチルチオアルキルアミンを得る。さらに、Liらの方法(Li et al. J. Org. Chem.、62、4539、1997年)に従い、チウラムジスルフィドを経て得られたω−メチルチオアルキルイソチオシアネートをmCPBAでメチルチオ基を酸化し、ω−メチルスルフィニルアルキルイソチオシアネートを得る。 Next, an amino group is introduced using the Gabriel method to produce N- (ω-methylthioalkyl) -phthalimide, and hydrazine hydrate is added thereto to reflux to obtain ω-methylthioalkylamine. Further, according to the method of Li et al. (Li et al. J. Org. Chem., 62, 4539, 1997), ω-methylthioalkylisothiocyanate obtained via thiuram disulfide was oxidized with mCPBA to oxidize the methylthio group, and ω -Obtaining a methylsulfinylalkylisothiocyanate.
ω−メチルスルフィニルアルキルイソチオシアネートのアブラナ科植物からの抽出に当たっては、植物体を粉砕もしくはすりおろしの物理的手段で抽出の前処理に供し、水やメタノール、エタノール、アセトン、酢酸エチル、ジエチルエーテル、ジクロロメタン、ジクロロエタンなどの有機溶媒で抽出するか、水蒸気蒸溜や分子蒸溜などの蒸溜法で抽出することが好ましいが、特にこれらの方法に限定されるものではない。 In extracting ω-methylsulfinylalkyl isothiocyanate from Brassicaceae plants, the plant body is subjected to extraction pretreatment by physical means such as grinding or grated, water, methanol, ethanol, acetone, ethyl acetate, diethyl ether, Extraction with an organic solvent such as dichloromethane or dichloroethane, or extraction with a distillation method such as steam distillation or molecular distillation is preferred, but it is not particularly limited to these methods.
例えば、本わさびの有機溶剤での具体的抽出方法を示すと、本わさびの根茎をすりおろした後、酢酸エチル溶媒で抽出し、この抽出液を無水硫酸ナトリウムで脱水の後、エバポレータで濃縮し、ω−メチルスルフィニルアルキルイソチオシアネートを得る。この方法は特に6−メチルスルフィニルヘキシルイソチオシアネートの抽出に最適である。6−メチルスルフィニルヘキシルイソチオシアネートは、市販のものを用いてもよく、例えば、金印株式会社製のわさびスルフィニル(登録商標)(6−MSITC(登録商標))が挙げられる。 For example, the specific extraction method of this wasabi with an organic solvent is as follows. After the rhizome of this wasabi is grated, it is extracted with an ethyl acetate solvent, and this extract is dehydrated with anhydrous sodium sulfate and then concentrated with an evaporator. Ω-methylsulfinylalkylisothiocyanate. This method is particularly suitable for the extraction of 6-methylsulfinylhexyl isothiocyanate. Commercially available 6-methylsulfinylhexyl isothiocyanate may be used, for example, Wasabi sulfinyl (registered trademark) (6-MISTC (registered trademark)) manufactured by Kinshi Co., Ltd.
ω−メチルスルフィニルアルキルイソチオシアネートのクレソンからの抽出の場合も、本わさびと同様に抽出される。例えば、クレソンをすりつぶした後、酢酸エチル溶媒で抽出し、この抽出液を無水硫酸ナトリウムで脱水の後、エバポレータで濃縮し、ω−メチルスルフィニルアルキルイソチオシアネートを得る。この方法は特に、7−メチルスルフィニルヘプチルイソチオシアネートや8−メチルスルフィニルオクチルイソチオシアネートの抽出に最適である。 In the case of extraction of ω-methylsulfinylalkylisothiocyanate from watercress, it is extracted in the same manner as this wasabi. For example, after crushing watercress, it is extracted with an ethyl acetate solvent, and the extract is dehydrated with anhydrous sodium sulfate and then concentrated with an evaporator to obtain ω-methylsulfinylalkylisothiocyanate. This method is particularly suitable for the extraction of 7-methylsulfinyl heptyl isothiocyanate and 8-methylsulfinyl octyl isothiocyanate.
なお、上述抽出液は抽出、濃縮の後、液液分配法、クロマトグラフィー、分子蒸溜、精留など、任意の方法によって精製される。精製手段の前後に、熱風乾燥、凍結乾燥などの乾燥手段を組み合わせてもよい。 The above-mentioned extract is extracted and concentrated, and then purified by an arbitrary method such as a liquid-liquid distribution method, chromatography, molecular distillation, or rectification. Before and after the purification means, drying means such as hot air drying and freeze drying may be combined.
本発明の抗ストレス剤の有効成分として、ω−メチルスルフィニルアルキルイソチオシアネート以外に、アピゲニンやルテオリン、ケンフェロールといったフラボノイド類やそれらの配糖体・多量体、フェルラ酸やシナピン酸といったフェニルプロパノイド類やそれらの配糖体・多量体、他のイソチオシアネート類、その他のポリフェノール類を含んでもよい。これらの成分は単独であっても複数種組み合わせて用いてもよい。 In addition to ω-methylsulfinylalkylisothiocyanate, flavonoids such as apigenin, luteolin and kaempferol, glycosides and multimers thereof, and phenylpropanoids such as ferulic acid and sinapinic acid as active ingredients of the antistress agent of the present invention And their glycosides / multimers, other isothiocyanates, and other polyphenols. These components may be used alone or in combination of two or more.
他のイソチオシアネート類としては、具体的には、アリルイソチオシアネート、第2級ブチルイソチオシアネート、3−ブテニルイソチオシアネート、4−ペンテニルイソチオシアネート、5−ヘキセニルイソチオシアネート、5−メチルチオペンチルイソチオシアネート、6−メチルチオヘキシルイソチオシアネート、7−メチルチオヘプチルイソチオシアネート、8−メチルチオオクチルイソチオシアネートなどが挙げられる。 Specific examples of the other isothiocyanates include allyl isothiocyanate, secondary butyl isothiocyanate, 3-butenyl isothiocyanate, 4-pentenyl isothiocyanate, 5-hexenyl isothiocyanate, 5-methylthiopentyl isothiocyanate, Examples include 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, and 8-methylthiooctyl isothiocyanate.
ω−メチルスルフィニルアルキルイソチオシアネート以外の有効成分は、上述の方法により植物体から抽出する以外に、各種化学合成法により合成されてもよい。当業者は、当該分野で周知の方法によりこれらの有効成分を合成することができる。 Active ingredients other than ω-methylsulfinylalkylisothiocyanate may be synthesized by various chemical synthesis methods in addition to extraction from a plant by the above-described method. Those skilled in the art can synthesize these active ingredients by methods well known in the art.
本発明の剤は、医薬および食品などとして有用であり、その投与対象としては、哺乳動物(例えば、ヒト、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サルなど)などが挙げられる。なお、ヒト以外の哺乳動物に適応する場合、本発明の剤の摂取量は、動物の体重もしくは大きさに応じて適宜加減すればよい。 The agent of the present invention is useful as a medicine, food, and the like, and examples of its administration include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.). It is done. In addition, when adapted to mammals other than humans, the intake of the agent of the present invention may be appropriately adjusted according to the body weight or size of the animal.
本発明の剤が医薬である場合、一般に、有効成分と担体とを含む。担体としては、医薬として許容される担体であれば特に限定されないが、例えば後述の製剤用物質(例、賦形剤、溶剤など)が挙げられる。
ここで、本発明の医薬の投与形態は特に限定されないが、経口投与、直腸投与、注射、輸液による投与などの一般的な投与経路を経ることが出来る。経口投与の剤形としては、顆粒剤、細粒剤、粉剤、被覆錠剤、錠剤、坐剤、散剤、(マイクロ)カプセル剤、チュアブル剤、シロップ、ジュース、液剤、懸濁剤、乳濁液など、また注射剤としては静脈直接注入用、点滴投与用、活性物質の放出を延長する製剤などの医薬製剤一般の剤型を採用することができる。
When the agent of the present invention is a medicine, it generally contains an active ingredient and a carrier. The carrier is not particularly limited as long as it is a pharmaceutically acceptable carrier, and examples thereof include a substance for formulation described below (eg, excipient, solvent, etc.).
Here, the administration form of the medicament of the present invention is not particularly limited, but can be performed through general administration routes such as oral administration, rectal administration, injection, administration by infusion. Oral dosage forms include granules, fine granules, powders, coated tablets, tablets, suppositories, powders, (micro) capsules, chewables, syrups, juices, liquids, suspensions, emulsions, etc. In addition, general dosage forms of pharmaceutical preparations such as direct intravenous injection, infusion administration, and preparations that prolong the release of active substances can be adopted as injections.
これらの医薬は、常法により製剤化することができる。製剤上の必要に応じて、薬理学的に許容し得る各種の製剤用物質(補助剤などとして)を配合することができる。製剤用物質は製剤の剤型により適宜選択することができるが、例えば、賦形剤、希釈剤、添加剤、崩壊剤、結合剤、被覆剤、潤滑剤、滑走剤、滑沢剤、風味剤、甘味剤、可溶化剤、溶剤などが挙げられる。更に、製剤用物質を具体的に例示すると、炭酸マグネシウム、二酸化チタン、ラクトース、マンニトールおよびその他の糖類、タルク、牛乳蛋白、ゼラチン、澱粉、セルロースおよびその誘導体、動物および植物油、ポリエチレングリコール、および溶剤、例えば滅菌水および一価または多価アルコール、例えばグリセロールなどを挙げることができる。 These medicaments can be formulated by conventional methods. Various pharmacologically acceptable substances for preparation (as adjuvants and the like) can be blended as necessary in the preparation. The substance for the preparation can be appropriately selected depending on the dosage form of the preparation. For example, the excipient, the diluent, the additive, the disintegrant, the binder, the coating agent, the lubricant, the lubricant, the lubricant, and the flavoring agent. , Sweeteners, solubilizers, solvents and the like. Furthermore, specific examples of the pharmaceutical substance include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents, Examples include sterilized water and mono- or polyhydric alcohols such as glycerol.
本発明の医薬における有効成分の投与量は、経口投与の場合、投与する患者の症状、年齢、投与方法によって異なるが、成人(体重60kgとして)に対する有効成分の一日当たりの投与量は、通常10 pg〜5g程度、好ましくは100ng〜10mg程度、より好ましくは0.5mg〜3mg程度である。例えば、有効成分が6−メチルスルフィニルヘキシルイソチオシアネートの場合、6−メチルスルフィニルヘキシルイソチオシアネートの一日当たりの投与量は、通常10 pg〜5g程度、好ましくは 100ng〜10mg程度、より好ましくは0.5mg〜3mg程度である。通常、上記の量を1日1回から3回程度に分けて投与される。
また、点滴投与、注射投与(経静脈投与)など、非経口投与(摂取)する場合の有効成分の投与量については、前記経口投与についての好ましい投与量(摂取量)範囲の10〜20分の1程度を投与することができる。通常、上記の量を1日1回から3回程度に分けて投与される。
In the case of oral administration, the dose of the active ingredient in the medicament of the present invention varies depending on the symptom, age and administration method of the patient to be administered, but the daily dose of the active ingredient for an adult (weight 60 kg) is usually 10 About pg to 5 g, preferably about 100 ng to 10 mg, more preferably about 0.5 mg to 3 mg. For example, when the active ingredient is 6-methylsulfinylhexyl isothiocyanate, the daily dose of 6-methylsulfinylhexyl isothiocyanate is usually about 10 pg to 5 g, preferably about 100 ng to 10 mg, more preferably 0.5 mg to About 3 mg. Usually, the above dose is divided into 1 to 3 times a day.
In addition, the dosage of the active ingredient in the case of parenteral administration (ingestion), such as infusion administration, injection administration (intravenous administration), etc., is 10 to 20 minutes which is a preferable dosage (intake) range for the oral administration. About 1 can be administered. Usually, the above dose is divided into 1 to 3 times a day.
また、本発明の医薬は他の薬剤を併用(含有)してもよく、かかる薬剤としては、例えば他の抗ストレス剤、ビタミン剤、ホルモン剤、栄養剤、消化性潰瘍治療剤、ステロイド、抗腫瘍剤、抗ウイルス剤、抗菌剤、抗うつ薬、抗精神病薬、精神安定剤等が挙げられる。これらは一種または二種以上を併用(含有)することができる。 In addition, the medicament of the present invention may be combined (contained) with other drugs. Examples of such drugs include other anti-stress agents, vitamins, hormones, nutrients, peptic ulcers, steroids, Examples include tumor agents, antiviral agents, antibacterial agents, antidepressants, antipsychotics, and tranquilizers. These can use together (contain) 1 type, or 2 or more types.
本発明の剤は、ストレス負荷後のACTHの分泌および/または炎症性サイトカイン増加を抑制する。ストレス負荷後の炎症性サイトカイン増加は、生体の過剰反応を引き起こすことにより様々な疾患と密接に関連する。従って、本発明の剤は、ストレスを起因とする疾患を予防または治療するのにも有用である。ストレスを起因とする疾患には、IL−18などのサイトカイン群が関与して発症、悪化または再発する疾患も含まれる。これらの疾患の例としては、うつ病、PTSD、不安神経症、強迫神経症、統合失調症、心身症、虫垂炎、消化性潰瘍、胃潰瘍、十二指腸潰瘍、腹膜炎、膵炎、潰瘍性、偽膜性、急性および虚血性の大腸炎、憩室炎、喉頭蓋炎、アカラシア、胆管炎、胆嚢炎、肝炎、クローン病、腸炎、ホイップル病、(気管支)喘息、アレルギー、アナフィラキシーショック、免疫複合体疾患、臓器の虚血、再灌流傷害、臓器の壊死、枯草熱、セプシス、敗血症、エンドトキシンショック、悪液質、異常高熱症、好酸球性肉芽腫、肉芽腫症、サルコイドーシス、敗血性流産、精巣上体炎、膣炎、前立腺炎、尿道炎、気管支炎、肺気腫、肺水腫、鼻炎、嚢胞性線維症、肺炎、肺塵症、肺胞炎、細気管支炎、咽頭炎、胸膜炎、副鼻腔炎、インフルエンザ、呼吸器合胞体ウィルス感染、ヘルペス感染、HIV感染、B型肝炎ウィルス感染、C型肝炎ウィルス感染、播種性菌血症、デング熱、カンジダ症、マラリア、フィラリア症、アメーバ症、包虫嚢胞、火傷、皮膚炎、皮膚筋炎、日焼け、じんま疹、いぼ、膨疹、血管炎、脈管炎、心内膜炎、動脈炎、アテローム性動脈硬化症、血栓性静脈炎、心外膜炎、心筋炎、心筋虚血、結節性動脈周囲炎、リウマチ熱、アルツハイマー病、セリアック病、鬱血性心不全、成人呼吸窮迫症候群、髄膜炎、脳炎、多発性硬化症、脳梗塞、脳卒中、ギラン−バレー症候群、神経炎、神経痛、脊髄損傷、麻痺、ブドウ膜炎、関節炎疹、関節痛、骨髄炎、筋膜炎、パジェット病、痛風、歯周病、リウマチ様関節炎、滑膜炎、重症筋無力症、筋萎縮性側索硬化症、甲状腺炎、全身性エリテマトーデス(SLE)、グッドパスチャー症候群、ベーチェット症候群、同種移植の拒絶反応、移植片対宿主病、I型糖尿病、強直性脊椎炎、バーガー病、II型糖尿病、ライター症候群、ホジキン病、肝硬変、腎不全、アレルギー性喘息、腎炎、心筋梗塞、シェーグレン症候群、接触性皮膚炎、アトピー性皮膚炎、鬱病、摂食障害、異食症、味覚障害、尋常性坐瘡、天疱瘡、魚鱗癬、乾癬、熱傷、光線過敏症、紫外線皮膚障害、または放射性障害、一酸化炭素中毒、低酸素症もしくはそれらの二次性障害などがあげられる。 The agent of the present invention suppresses the secretion of ACTH and / or increase in inflammatory cytokines after stress loading. Increases in inflammatory cytokines after stress loading are closely associated with various diseases by causing excessive responses in the body. Therefore, the agent of the present invention is also useful for preventing or treating diseases caused by stress. Diseases caused by stress include diseases that develop, worsen, or recur due to cytokine groups such as IL-18. Examples of these diseases include depression, PTSD, anxiety, obsessive-compulsive disorder, schizophrenia, psychosomatic disease, appendicitis, peptic ulcer, gastric ulcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute And ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple disease, (bronchial) asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia Reperfusion injury, organ necrosis, hay fever, sepsis, sepsis, endotoxin shock, cachexia, hyperthermia, eosinophilic granulomas, granulomatosis, sarcoidosis, septic abortion, epididymis, vaginal Inflammation, prostatitis, urethritis, bronchitis, emphysema, pulmonary edema, rhinitis, cystic fibrosis, pneumonia, pneumoconiosis, alveolitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory organs Endoplasmic reticulum virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, dengue fever, candidiasis, malaria, filariasis, amoebiasis, hydatid cyst, burn, dermatitis, Dermatomyositis, sunburn, hives, warts, wheal, vasculitis, vasculitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, epicarditis, myocarditis, myocardial ischemia , Periarteritis nodosa, rheumatic fever, Alzheimer's disease, celiac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, stroke, Guillain-Barre syndrome, neuritis, neuralgia Spinal cord injury, paralysis, uveitis, arthritis, arthralgia, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, amyotrophic lateral cord Sclerosis, thyroiditis, all Systemic lupus erythematosus (SLE), Goodpasture syndrome, Behcet's syndrome, allograft rejection, graft-versus-host disease, type I diabetes, ankylosing spondylitis, Burger disease, type II diabetes, Reiter's syndrome, Hodgkin's disease, cirrhosis, kidney Failure, allergic asthma, nephritis, myocardial infarction, Sjogren's syndrome, contact dermatitis, atopic dermatitis, depression, eating disorders, dysphagia, taste disorders, acne vulgaris, pemphigus, ichthyosis, psoriasis, burns , Photosensitivity, ultraviolet skin disorder, or radioactive disorder, carbon monoxide poisoning, hypoxia or secondary disorders thereof.
さらに、本発明の剤は、食品に含有されても良い。食品に含有される場合には、本発明の有効成分を含む一般的な食事形態であれば如何なるものでも良い。例えば、適当な風味を加えてドリンク剤、例えば清涼飲料、粉末飲料とすることもできる。具体的には、例えば、ジュース、牛乳、菓子、ゼリー、ヨーグルト、飴などに混ぜて飲食することができる。
また、このような食品を、保健機能食品またはダイエタリーサプリメントとして提供することも可能である。この保健機能食品には、特定保健用食品および栄養機能食品なども含まれる。特定保健用食品は、例えば、ストレスの予防または低減など、特定の保健の目的が期待できることを表示できる食品である。また、栄養機能食品は、1日あたりの摂取目安量に含まれる栄養成分量が、国が定めた上・下限値の規格基準に適合している場合その栄養成分の機能の表示ができる食品である。ダイエタリーサプリメントには、いわゆる栄養補助食品または健康補助食品などが含まれる。本発明において、特定保健用食品には、ストレスの予防または低減などの用途に用いるものであるという表示を付した食品、さらには、かかる用途に用いるものである旨を記載した書類(いわゆる能書き)などをパッケージとして包含する食品なども含まれるものとする。
さらに、本発明の剤を濃厚流動食や、食品補助剤として利用することも可能である。食品補助剤として使用する場合、例えば錠剤、カプセル、散剤、顆粒、懸濁剤、チュアブル剤、シロップ剤などの形態に調製することができる。本発明における食品補助剤とは、食品として摂取されるもの以外に栄養を補助する目的で摂取されるものをいい、栄養補助剤、サプリメントなどもこれに含まれる。
例えば、有効成分が6−メチルスルフィニルヘキシルイソチオシアネートの場合、6−メチルスルフィニルヘキシルイソチオシアネートの一日当たりの投与量は、通常10 pg〜5g程度、好ましくは100ng〜10mg程度、より好ましくは0.5mg〜3mg程度である
Furthermore, the agent of the present invention may be contained in food. When contained in food, any form may be used as long as it is a general meal form containing the active ingredient of the present invention. For example, drinks such as soft drinks and powdered drinks can be prepared by adding an appropriate flavor. Specifically, for example, it can be mixed with juice, milk, confectionery, jelly, yogurt, rice cake, etc. to eat and drink.
It is also possible to provide such foods as health functional foods or dietary supplements. This health functional food includes food for specified health use and food with nutritional function. The food for specific health is a food that can indicate that a specific health purpose can be expected, for example, prevention or reduction of stress. In addition, functional nutritional food is a food that can indicate the function of the nutritional component when the amount of nutritional component included in the daily intake standard amount conforms to the national and national standards for upper and lower limits. is there. Dietary supplements include so-called nutritional supplements or health supplements. In the present invention, the food for specified health use is a food with a label indicating that it is used for applications such as prevention or reduction of stress, and further a document (so-called notation) describing that it is used for such applications. Foods that include the above as a package are also included.
Furthermore, the agent of the present invention can be used as a concentrated liquid food or a food supplement. When used as a food supplement, it can be prepared in the form of tablets, capsules, powders, granules, suspensions, chewables, syrups and the like. The food supplement in the present invention refers to those taken for the purpose of supplementing nutrition in addition to those taken as food, and also includes nutritional supplements and supplements.
For example, when the active ingredient is 6-methylsulfinylhexyl isothiocyanate, the daily dose of 6-methylsulfinylhexyl isothiocyanate is usually about 10 pg to 5 g, preferably about 100 ng to 10 mg, more preferably 0.5 mg to About 3mg
食品として摂取する場合、摂取量は摂取対象の症状、年齢、体重、剤形、摂取方法などによって異なるが、成人1日あたり、有効成分1 pg/kg体重〜800 mg/kg体重を目安とする。例えば、有効成分が6−メチルスルフィニルヘキシルイソチオシアネートの場合、好ましくは、成人1日あたり、6−メチルスルフィニルヘキシルイソチオシアネート15 ng/kg体重〜1.5 mg/kg体重、より好ましくは10ng/kg体重〜50ng/kg体重程度が好ましい。本発明の食品において、上記1日あたりの量を一度にもしくは数回に分けて摂取することができる。また摂取期間は特に限定されない。 When ingested as food, the intake varies depending on the symptoms, age, weight, dosage form, method of intake, etc. of the subject of intake, but the active ingredient is 1 pg / kg body weight to 800 mg / kg body weight per day for adults. . For example, when the active ingredient is 6-methylsulfinyl hexyl isothiocyanate, it is preferable that 6-methylsulfinyl hexyl isothiocyanate is 15 ng / kg body weight to 1.5 mg / kg body weight, more preferably 10 ng / kg body weight per day for an adult. About 50 ng / kg body weight is preferable. In the food of the present invention, the amount per day can be taken at once or divided into several times. The intake period is not particularly limited.
本発明の食品は、ストレス負荷後のACTHの分泌および/または炎症性サイトカイン増加を抑制する。ストレス負荷後の炎症性サイトカイン増加は、生体の過剰反応を引き起こすことにより様々な疾患と密接に関連する。従って、本発明の食品は、ストレスを起因とする疾患を予防または改善するのにも有用である。ストレスを起因とする疾患としては、上述と同様のものが挙げられる。 The food of the present invention suppresses the secretion of ACTH and / or increase in inflammatory cytokines after stress loading. Increases in inflammatory cytokines after stress loading are closely associated with various diseases by causing excessive responses in the body. Therefore, the food of the present invention is also useful for preventing or ameliorating a disease caused by stress. Examples of the disease caused by stress include those described above.
本発明においては、ω−メチルスルフィニルアルキルイソチオシアネートを有効成分として含有する剤には、ストレスの予防または低減などに使用することができる、または使用すべきであることを記載した記載物を含む、商業的パッケージも含まれる。 In the present invention, the agent containing ω-methylsulfinylalkylisothiocyanate as an active ingredient includes a description that can be used or should be used for prevention or reduction of stress, etc. Commercial packages are also included.
本明細書中で挙げられた特許および特許出願明細書を含む全ての刊行物に記載された内容は、本明細書での引用により、その全てが明示されたと同程度に本明細書に組み込まれるものである。 The contents of all publications, including patents and patent application specifications cited in this specification, are hereby incorporated by reference herein to the same extent as if all were explicitly stated. Is.
以下に実施例を用いて本発明を詳述するが、本発明は以下の実施例に限定されるものではない。 Hereinafter, the present invention will be described in detail using examples, but the present invention is not limited to the following examples.
実施例1
(方法)
雄性C57/B6マウス10週齢;Seac Yoshitomiより購入)を、6−MSITC(登録商標)(金印株式会社製)を0.5 ng 重量%含有する飲料水を自由摂取させて飼育した。6−MSITC(登録商標)投与開始後1週間目と2週間目に、マウスを拘束器(27mmの直径の丸型プラスティックチューブ)中に固定し、拘束ストレスを6時間まで負荷した。
拘束ストレスから解除した直後に心臓採血し、血清を4℃、2500rpmで10分間遠心分離により分離し、血清中のACTH、IL−18濃度を測定した。ACTH濃度はRIA法による測定をSRL社に依頼し、IL−18濃度はQuantikineTMイムノアッセイキット(R&Dシステムズ)を用いるELISAでそれぞれ測定した。
Example 1
(Method)
Male C57 / B6 mice 10 weeks of age; purchased from Seac Yoshitomi) were bred with free drinking of drinking water containing 0.5 ng wt% of 6-MSITC (registered trademark) (manufactured by Kinshi Co., Ltd.). At 1 and 2 weeks after the start of 6-MSITC® administration, the mice were fixed in a restraint (27 mm diameter round plastic tube) and restraint stress was applied for up to 6 hours.
Immediately after the release from restraint stress, blood was collected from the heart, and the serum was separated by centrifugation at 2500 rpm for 10 minutes at 4 ° C., and the ACTH and IL-18 concentrations in the serum were measured. ACTH concentration was measured by SRL for measurement by RIA method, and IL-18 concentration was measured by ELISA using Quantikine ™ immunoassay kit (R & D Systems).
(結果)
図1および3より、6−MSITC(登録商標)を摂取したマウスは、摂取しないマウスに比べて、拘束ストレス負荷後の血清ACTHの上昇が抑制された。図3より、2週間投与群では、長時間(6時間)のストレス後のACTH上昇(第2相)反応も強く抑制されていた。6−MSITC(登録商標)によるACTHの抑制作用は、ストレスによるACTHの上昇に対してのみ作用し、定常レベルのACTH濃度には影響しないことがわかった。
図2および4より、6−MSITC(登録商標)を摂取したマウスは、摂取しないマウスに比べて、拘束ストレス負荷後の血清IL−18の上昇が抑制された。
これら6−MSITC(登録商標)の抑制作用は、1週間投与群(図2)よりも2週間投与群(図4)の方において強くみとめられた。
さらに、6−MSITC(登録商標)を摂取したマウスは、飼育中にけんかが少なく、ストレス負荷時にも穏やかであった。
(考察)
6−MSITC(登録商標)が急性ストレス反応の抑制効果を有することが明らかとなった。6−MSITC(登録商標)は、ストレスによる炎症増悪を防止するだけでなく、肥満や糖尿病に関連する視床下部下垂体副腎系への負荷を軽減することも明らかになった。
今後、炎症性サイトカイン抑制とACTH上昇抑制機構を明らかにすることで、健康食品、療法食、消炎鎮痛剤、精神安定剤、抗うつ剤、抗精神病薬、抗不安剤、抗認知症剤、内分泌調整剤、抗炎症剤、などの成分として用いることができる可能性がある。
(result)
1 and 3, the increase in serum ACTH after restraint stress loading was suppressed in mice that received 6-MSITC (registered trademark) compared to mice that did not. From FIG. 3, in the 2-week administration group, the ACTH increase (phase 2) reaction after long-time (6 hours) stress was also strongly suppressed. It was found that the inhibitory action of ACTH by 6-MSITC (registered trademark) acts only on the increase of ACTH due to stress and does not affect the steady-state ACTH concentration.
2 and 4, the increase in serum IL-18 after restraint stress load was suppressed in mice that received 6-MSITC (registered trademark) compared to mice that did not.
The inhibitory action of these 6-MSITC (registered trademark) was observed more strongly in the 2-week administration group (FIG. 4) than in the 1-week administration group (FIG. 2).
Furthermore, the mice ingesting 6-MSITC (registered trademark) were less quarreled during breeding and were mild during stress loading.
(Discussion)
It was revealed that 6-MSITC (registered trademark) has an effect of suppressing acute stress response. 6-MSITC (registered trademark) has been shown not only to prevent exacerbation of inflammation due to stress but also to reduce the load on the hypothalamic-pituitary adrenal system related to obesity and diabetes.
In the future, by clarifying the suppression mechanism of inflammatory cytokines and ACTH elevation, health food, therapeutic diet, anti-inflammatory analgesic, tranquilizer, antidepressant, antipsychotic, anxiolytic, antidementia, endocrine There is a possibility that it can be used as a component such as a regulator or an anti-inflammatory agent.
実施例2
ヒトを対象とした抗疲労効果検証プロトコル
4週間摂取、2試験区クロスオーバー試験
(対象者)
夜勤を行う医師および看護師を対象に試験を行う。なお、本試験は、研究の内容を十分に説明した上で、文書によるインフォームド・コンセントを得て行う。
(被験者数)
42名(1グループ21名)
(方法)
試験食:天然わさびより抽出した6-MSITC50ng を含むソフトカプセル剤
試験食(またはプラセボ)摂取前の夜勤の前と後に以下の検査を7日間実施する。片方のグループには試験食を毎日20−21時の間に3粒4週間摂取させ、他方のグループにはプラセボを同様の摂取スケジュールで摂取させる。4週間の試験食(またはプラセボ)摂取後に、同様に夜勤の前と後に以下の検査を14日間実施する。なお、試験食またはプラセボ摂取開始日を0日とする。
(試験期間中の被験者管理)
・全試験期間中の生活記録日誌(睡眠時間、飲酒、薬)の記録
・試験食(またはプラセボ)摂取期間中の食事(朝、昼、晩)の記録
・万歩計(登録商標)による歩数の記録
(検査)
1)性格、自覚症評価
TEG(東大式エゴグラム)(−1週目のみ)
CMI、SDS、MAS(0、4、6週目)
採血ごと:GHQ、自覚症調べ(労働衛生研究所)
クレペリン該当者は夜勤終了するはずの時刻のクレペリンテストを0点で施行。
2)疲労感の定量的解析
VAS (Visual Analogue Scale):採血毎
疲労質問票:−1、0、4、6週目
3)理学的検査
血圧、脈拍、体重、身長、体脂肪率、歩数(市販の万歩計(登録商標)利用)
血圧・脈拍は−1、0、4、6週目の就労前・後。
それ以外は−1、0、4、6週目の就労後。
4)生活記録(調査)
(食事内容・飲酒量)睡眠時間、就労時間、(試験終了時、試験食の効果についてのアンケート調査)
5)血液検査(−1、0、4、6週目)
一般生化学
末梢血液一般検査、白血球分画、TP、ALB、g−GTP、AST(GOT)、ALT(GPT)、ALP、CPK、LDH、UN、Cre、UA、TG、Tcho、HDL−cho、LDL−cho、Na、K、Cl、遊離脂肪酸、血糖、サイトカインの網羅的測定
( )の項目についてはオプション
特殊項目
クエン酸、乳酸、ピルビン酸、ケトン体分画、ビタミンC、ビタミンE、コルチゾール、ACTH、(グルタチオン、システイン、d−ROMs、カルニチン分画、DHEA、DHEAS、CoQ酸化還元比)、IL-1β、IL-1ra、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-15、IL-17、IL-18、Eotaxin、FGF basic、G-CSF、GM-CSF、IFN-γ、IFN-α、IP-10、MCP-1、MIP-1α、MIP-1β、PDGF-BB、RANTES、TNF-α、VEGF、CSF-2、TGF-β、ニューロトロフィン5、MCP-3、β-2-microglobulin、アンギオテンシンII、CSF-3、CXCケモカインリガンド1、CXCケモカインリガンド5、HGF、IL-1α、IL-2ra、IL-16、CTACK、GRO-α、HGF、ICAM-1、IFN-α2、LIF、MCP-3、M-CSF、MIF、MIG、β-NGF、SCF、SCGF-β、SDF1a、TNF-βおよびVCAM-1
6)唾液検査
コルチゾール、アミラーゼ
7)生理学的検査
一部被験者において、夜勤後クレペリンテストを施行。
Example 2
Anti-fatigue effect verification protocol for humans Ingestion for 4 weeks, 2 cross-over studies (subjects)
Tests are performed for doctors and nurses who work night shifts. This study will be conducted with full informed consent after a thorough explanation of the study.
(Number of subjects)
42 people (21 people per group)
(Method)
Test meal: Soft capsule containing 50 ng of 6-MSITC extracted from natural wasabi The following tests are conducted for 7 days before and after the night shift before taking the test meal (or placebo). One group will receive the test meal every day between 20-21 o'clock for 4 weeks and the other group will receive a placebo on a similar intake schedule. Following the 4-week test meal (or placebo), the following tests are also performed for 14 days before and after night shift. In addition, the start date of intake of the test meal or placebo is defined as
(Subject management during study period)
・ Record of daily life log (sleeping time, alcohol, medicine) during the whole test period ・ Record of meal (morning, noon, evening) during test meal (or placebo) intake period ・ Steps by pedometer (registered trademark) Record (inspection)
1) Personality and subjective evaluation TEG (Tokyo University Egogram) (-1 week only)
CMI, SDS, MAS (0, 4, 6 weeks)
Every blood collection: GHQ, subjective research (Occupational Health Research Institute)
Those who are eligible for the Kraepelin test will receive a 0 point for the Kraepelin test at the time when the night shift should end.
2) Quantitative analysis of feeling of fatigue VAS (Visual Analogue Scale): Every blood sampling Fatigue questionnaire: -1, 0, 4, 6 weeks 3) Physical examination Blood pressure, pulse, weight, height, body fat percentage, steps ( Commercial pedometer (registered trademark) use)
Blood pressure and pulse are before, after work at -1, 0, 4, 6 weeks.
Other than that, after working at -1, 0, 4, 6 weeks.
4) Life record (survey)
(Meal content / drinking amount) sleeping time, working hours, (questionnaire survey on the effects of the test meal at the end of the test)
5) Blood test (-1, 0, 4, 6 weeks)
General biochemical peripheral blood general examination, leukocyte fractionation, TP, ALB, g-GTP, AST (GOT), ALT (GPT), ALP, CPK, LDH, UN, Cre, UA, TG, Tcho, HDL-cho, Optional for comprehensive measurement () items for LDL-cho, Na, K, Cl, free fatty acids, blood glucose, cytokines
Special items Citric acid, lactic acid, pyruvic acid, ketone body fraction, vitamin C, vitamin E, cortisol, ACTH, (glutathione, cysteine, d-ROMs, carnitine fraction, DHEA, DHEAS, CoQ redox ratio), IL- 1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP-1α, MIP -1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, HGF, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β -NGF, SCF, SCGF-β, SD F1a, TNF-β and VCAM-1
6) Saliva test Cortisol, amylase 7) Physiological test In some subjects, a night-time Kraepelin test was performed.
Claims (13)
IL-1β、IL-1ra、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-15、IL-17、IL-18、Eotaxin、FGF basic、G-CSF、GM-CSF、IFN-γ、IFN-α、IP-10、MCP-1、MIP-1α、MIP-1β、PDGF-BB、RANTES、TNF-α、VEGF、CSF-2、TGF-β、ニューロトロフィン5、MCP-3、β-2-microglobulin、アンギオテンシンII、CSF-3、CXCケモカインリガンド1、CXCケモカインリガンド5、HGF、IL-1α、IL-2ra、IL-16、CTACK、GRO-α、HGF、ICAM-1、IFN-α2、LIF、MCP-3、M-CSF、MIF、MIG、β-NGF、SCF、SCGF-β、SDF1a、TNF-βおよびVCAM-1からなる群より選ばれるストレス因子または疲労因子の生体内の量を調節することを特徴とする抗ストレス剤、または生体負荷が心身の障害を来すことに対する拮抗剤もしくは緩和剤。 ω-methylsulfinylalkyl isothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) as an active ingredient,
IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL- 12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP-1α , MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, HGF, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG , Β-NGF, SCF, SCGF-β, SDF1a, TNF-β and an anti-stress agent characterized by regulating the in vivo amount of stress factor or fatigue factor selected from the group consisting of VCAM-1 Antagonists or mitigators against stress and physical and mental disabilities
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2010084661A1 (en) * | 2009-01-23 | 2010-07-29 | 金印株式会社 | Composition, food, food material, pharmaceutical preparation, cosmetic and commodity each containing isothiocyanate compound |
JP2010184892A (en) * | 2009-02-12 | 2010-08-26 | Kinjirushi Kk | Medicine, quasi-drug, cosmetic, food and beverage and animal feed presenting male hormone-like action |
CN102697045A (en) * | 2012-06-09 | 2012-10-03 | 东莞市照燕生物科技有限公司 | Healthcare product capable of promoting red blood cell growth |
WO2015056922A1 (en) * | 2013-10-16 | 2015-04-23 | 주식회사 파미니티 | Composition including extract of brassica oleracea for improving, preventing or treating cranial nerve diseases |
KR101641902B1 (en) * | 2015-06-24 | 2016-07-22 | 주식회사 네이처센스 농업회사법인 | Composition for releasing stress |
WO2017061614A1 (en) * | 2015-10-08 | 2017-04-13 | 神戸ウェルネスサイエンス株式会社 | Inhibitor of muscle damage or muscle fatigue |
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JP2003081939A (en) * | 2001-09-10 | 2003-03-19 | New Food Creation Gijutsu Kenkyu Kumiai | Method for producing isothiocyanate from cruciferous plant |
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JP2003081939A (en) * | 2001-09-10 | 2003-03-19 | New Food Creation Gijutsu Kenkyu Kumiai | Method for producing isothiocyanate from cruciferous plant |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010084661A1 (en) * | 2009-01-23 | 2010-07-29 | 金印株式会社 | Composition, food, food material, pharmaceutical preparation, cosmetic and commodity each containing isothiocyanate compound |
JP2010184892A (en) * | 2009-02-12 | 2010-08-26 | Kinjirushi Kk | Medicine, quasi-drug, cosmetic, food and beverage and animal feed presenting male hormone-like action |
CN102697045A (en) * | 2012-06-09 | 2012-10-03 | 东莞市照燕生物科技有限公司 | Healthcare product capable of promoting red blood cell growth |
WO2015056922A1 (en) * | 2013-10-16 | 2015-04-23 | 주식회사 파미니티 | Composition including extract of brassica oleracea for improving, preventing or treating cranial nerve diseases |
KR20150044486A (en) * | 2013-10-16 | 2015-04-27 | 주식회사 파미니티 | Composition for Improving, Preventing or Treating Neurological Diseases comprising Brassica oleracea Extracts |
KR101643737B1 (en) | 2013-10-16 | 2016-07-29 | 주식회사 파미니티 | Composition for Improving, Preventing or Treating Neurological Diseases comprising Brassica oleracea var. botrytis aut italiana L. Extracts |
KR101641902B1 (en) * | 2015-06-24 | 2016-07-22 | 주식회사 네이처센스 농업회사법인 | Composition for releasing stress |
WO2017061614A1 (en) * | 2015-10-08 | 2017-04-13 | 神戸ウェルネスサイエンス株式会社 | Inhibitor of muscle damage or muscle fatigue |
US10471038B2 (en) | 2015-10-08 | 2019-11-12 | Productive Aging Laboratory, Co., Ltd. | Inhibitor of muscle damage or muscle fatigue |
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