JP6654824B2 - Blood uric acid level reducer - Google Patents
Blood uric acid level reducer Download PDFInfo
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- JP6654824B2 JP6654824B2 JP2015153508A JP2015153508A JP6654824B2 JP 6654824 B2 JP6654824 B2 JP 6654824B2 JP 2015153508 A JP2015153508 A JP 2015153508A JP 2015153508 A JP2015153508 A JP 2015153508A JP 6654824 B2 JP6654824 B2 JP 6654824B2
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- bifidobacterium
- uric acid
- purine
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- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 title claims description 34
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 title claims description 34
- 229940116269 uric acid Drugs 0.000 title claims description 34
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- 239000003638 chemical reducing agent Substances 0.000 title claims description 7
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Classifications
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- G—PHYSICS
- G05—CONTROLLING; REGULATING
- G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
- G05B19/00—Programme-control systems
- G05B19/02—Programme-control systems electric
- G05B19/18—Numerical control [NC], i.e. automatically operating machines, in particular machine tools, e.g. in a manufacturing environment, so as to execute positioning, movement or co-ordinated operations by means of programme data in numerical form
- G05B19/416—Numerical control [NC], i.e. automatically operating machines, in particular machine tools, e.g. in a manufacturing environment, so as to execute positioning, movement or co-ordinated operations by means of programme data in numerical form characterised by control of velocity, acceleration or deceleration
-
- G—PHYSICS
- G05—CONTROLLING; REGULATING
- G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
- G05B15/00—Systems controlled by a computer
- G05B15/02—Systems controlled by a computer electric
-
- G—PHYSICS
- G05—CONTROLLING; REGULATING
- G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
- G05B2219/00—Program-control systems
- G05B2219/30—Nc systems
- G05B2219/42—Servomotor, servo controller kind till VSS
- G05B2219/42191—Adjust proportionality factor to optimize slave axis movement
-
- G—PHYSICS
- G05—CONTROLLING; REGULATING
- G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
- G05B2219/00—Program-control systems
- G05B2219/30—Nc systems
- G05B2219/43—Speed, acceleration, deceleration control ADC
- G05B2219/43048—Step change in reference, soft start, smoothing reference
-
- G—PHYSICS
- G05—CONTROLLING; REGULATING
- G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
- G05B2219/00—Program-control systems
- G05B2219/30—Nc systems
- G05B2219/50—Machine tool, machine tool null till machine tool work handling
- G05B2219/50234—Synchronize two spindles, axis, electronic transmission, line shafting
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- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Automation & Control Theory (AREA)
- General Engineering & Computer Science (AREA)
- Human Computer Interaction (AREA)
- Manufacturing & Machinery (AREA)
- Dairy Products (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
本発明は、血中尿酸値低減作用を有する乳酸菌およびその利用方法、ならびに、乳酸菌を含む高尿酸血症の予防および/または治療用の食品または医薬品に関する。 TECHNICAL FIELD The present invention relates to a lactic acid bacterium having a blood uric acid level-reducing action and a method for using the same, and a food or pharmaceutical product containing lactic acid bacterium for preventing and / or treating hyperuricemia.
血中に存在する尿酸の血中濃度が異常に高い状態(男女共に7.0mg/dL以上)を高尿酸血症と呼ぶ。日本では近年、食生活の欧米化に伴って高尿酸血症を発症する人が増加しており、特に中高年の男性にその傾向が見られる。高尿酸血症は通風や動脈硬化、腎機能低下等の様々な疾患の原因となることが分かっている。尿酸はプリン骨格と呼ばれる共通の構造を有するプリン体が代謝されて生じる化合物である。このプリン体は体細胞の新陳代謝やATP、GTPなどのエネルギー源、日々摂取する食事などに由来しており、特に食事由来のプリン体は肉や魚、ビールなどに多く含まれている(非特許文献1)。 A condition in which the concentration of uric acid in the blood is abnormally high (7.0 mg / dL or more in both sexes) is called hyperuricemia. In recent years, in Japan, the number of people who develop hyperuricemia due to the westernization of eating habits has been increasing, and the tendency is particularly observed in middle-aged and elderly men. It is known that hyperuricemia causes various diseases such as gout, arteriosclerosis, and renal dysfunction. Uric acid is a compound formed by metabolizing purines having a common structure called a purine skeleton. This purine body is derived from the metabolism of somatic cells, energy sources such as ATP and GTP, and daily meals, etc. In particular, dietary purine bodies are abundant in meat, fish, beer, etc. Reference 1).
高尿酸血症の治療薬は尿酸を作らないようにする尿酸生成抑制薬と尿酸を外に出す尿酸排泄促進薬の2種類に分類される。前者は、プリン体を尿酸に分解する過程で必要な酵素であるキサンチンオキシターゼ(XO)を阻害する事で尿酸生成を抑えるものである。一方、後者は腎臓の近位尿細管に存在するURAT1と呼ばれる尿酸再吸収を行う尿酸トランスポーター分子を阻害する事で、尿酸排出を促進するものである。 Drugs for treating hyperuricemia are classified into two types: uric acid production inhibitors that prevent the production of uric acid, and uric acid excretion enhancers that release uric acid. The former suppresses uric acid production by inhibiting xanthine oxidase (XO), a necessary enzyme in the process of decomposing purines into uric acid. On the other hand, the latter promotes uric acid excretion by inhibiting a uric acid transporter molecule called URAT1, which is present in the proximal tubule of the kidney and performs uric acid reabsorption.
ここで、一般の人が高尿酸血症を予防する為に、プリン体の含有量を低減したアルコール類等が市販されている。しかし、摂取するプリン体を低減するだけでは十分ではなく、日常的に摂取可能な、高尿酸血症を緩和する食品やサプリメントが求められており、乳酸菌やビフィズス菌が着目されている。
例として、ラクトバチルス・ガセリPA−3株はプリン体の分解物であるプリンヌクレオシドをプリン塩基へと分解する活性が高く、消化菅からのプリンヌクレオシドの吸収を抑制することが分かっている(非特許文献2)。ラットを用いた試験でもラクトバチルス・ガセリPA−3株は、血中の尿酸値上昇抑制効果を有することが確認されている。更に、特許文献では、ラクトバチルス・ガセリOLL2922株が血清尿酸値の上昇を抑えることや(特許文献1)、ビフィドバクテリウム・ロンガムBB536株が高尿酸血症の予防剤となること(特許文献2)が報告されている。
Here, in order to prevent hyperuricemia by ordinary people, alcohols and the like having a reduced purine content are commercially available. However, it is not enough to reduce ingested purines, and there is a demand for foods and supplements that can be taken on a daily basis and that alleviate hyperuricemia, and lactic acid bacteria and bifidobacteria are attracting attention.
As an example, Lactobacillus gasseri PA-3 strain has a high activity of decomposing purine nucleosides, which are decomposed products of purines, into purine bases, and suppresses the absorption of purine nucleosides from the digestive tract (non-purine nucleosides). Patent Document 2). Tests using rats also confirmed that Lactobacillus gasseri PA-3 strain has an effect of suppressing an increase in blood uric acid level. Furthermore, in the patent literature, Lactobacillus gasseri OLL2922 strain suppresses an increase in serum uric acid level (Patent Document 1), and Bifidobacterium longum BB536 strain becomes a preventive agent for hyperuricemia (Patent Document 1). 2) has been reported.
既存の報告では、ラクトバチルス・ガセリOLL2922株やビフィドバクテリウム・ロンガムBB536が血清尿酸値を抑える傾向があることが報告されているが、その他の乳酸菌やビフィズス菌についての報告は無い。そこで、本発明では上記2つの菌株以外にプリン体の分解能を有する乳酸菌やビフィズス菌を提供する事を課題とする。 Existing reports have reported that Lactobacillus gasseri OLL2922 strain and Bifidobacterium longum BB536 tend to suppress serum uric acid levels, but there are no reports on other lactic acid bacteria or bifidobacteria. Therefore, an object of the present invention is to provide a lactic acid bacterium and a bifidobacterium having purine resolution in addition to the above two strains.
本発明は、下記のいずれかの構成からなる発明である。
(1)下記(A)〜(D)のうちいずれかに属する1又は2種以上の菌、該菌含有物および/またはその処理物を有効成分とする血中尿酸値低減剤。
(A) ビフィドバクテリウム・シュードロンガム(Bifidobacteriumu pseudolongum)
(B) ビフィドバクテリウム・アニマリス・サブスピーシーズ・アニマリス(Bifidobacterium animalis ssp.animalis)
(C) ラクトバチルス・ヘルベティカス(Lactobacillus helveticus)
(D) ビフィドバクテリウム・インファンティス(Bifidobacterium infantis)
(2)下記(E)〜(J)のうちいずれか1つ及び又は2種以上の菌株、該菌株含有物および/またはその処理物を有効成分とする血中尿酸値低減剤。
(E) ビフィドバクテリウム・シュードロンガム(Bifidobacteriumu pseudolongum )SBT2908株(FERM P-10138)
(F) ビフィドバクテリウム・シュードロンガム(Bifidobacteriumu pseudolongum) 基準株
(G) ビフィドバクテリウム・アニマリス・サブスピーシーズ・アニマリス(Bifidobacterium animalis ssp.animalis)基準株
(H) ラクトバチルス・ヘルベティカス(Lactobacillus helveticus) SBT2161株(NITE ABP-01707)
(I) ラクトバチルス・ヘルベティカス(Lactobacillus helveticus)SBT2171株(FERM BP-5445)
(J)ビフィドバクテリウム・インファンティス(Bifidobacterium infantis) 基準株
(3)(1)または(2)に記載の血中尿酸値低減剤を含むことを特徴とする血中尿酸値低減用飲食品、血中尿酸値低減用栄養組成物、又は血中尿酸値低減用医薬品。
The present invention is an invention having any one of the following configurations.
(1) A blood uric acid level reducing agent comprising one or more bacteria belonging to any of the following (A) to (D), a substance containing the bacteria and / or a processed product thereof as an active ingredient.
(A) Bifidobacterium pseudolongum
(B) Bifidobacterium animalis subspecies animalis
(C) Lactobacillus helveticus
(D) Bifidobacterium infantis
(2) A blood uric acid level reducing agent comprising, as an active ingredient, any one and / or two or more of the following (E) to (J), and a strain-containing substance and / or a processed product thereof.
(E) Bifidobacterium pseudolongum SBT2908 strain (FERM P-10138)
(F) Bifidobacterium pseudolongum (B) Reference strain (G) Bifidobacterium animalis subspecies animalis (Bifidobacterium animalis ssp.animalis) reference strain (H) Lactobacillus helveticus ) SBT2161 strain (NITE ABP-01707)
(I) Lactobacillus helveticus SBT2171 strain (FERM BP-5445)
(J) Reference strain of Bifidobacterium infantis
(3) A food and drink for reducing blood uric acid level, a nutritional composition for reducing blood uric acid level, or a blood uric acid level, which comprises the blood uric acid level reducing agent according to (1) or (2). Drugs for reduction.
本発明は、食経験のあるビフィドバクテリウム・シュードロンガム(Bifidobacteriumu pseudolongum)やビフィドバクテリウム・アニマリス・サブスピーシーズ・アニマリス(Bifidobacterium animalis ssp.animalis)やラクトバチルス・ヘルベティカス(Lactobacillus helveticus)やビフィドバクテリウム・インファンティス(Bifidobacterium infantis)に属する菌を用いる事によって、プリンヌクレオシドをプリン塩基へと分解出来るので、プリンヌクレオシドが消化管から吸収される事を抑制する。その結果、血中尿酸値が低減されるので、高尿酸血症、通風や動脈硬化、腎機能低下などの疾患の予防または治療に有効である。 The present invention relates to Bifidobacterium pseudolongum (Bifidobacterium animalis subsp. By using a bacterium belonging to Bifidobacterium infantis, purine nucleosides can be decomposed into purine bases, thereby suppressing purine nucleosides from being absorbed from the digestive tract. As a result, the uric acid level in the blood is reduced, which is effective in preventing or treating diseases such as hyperuricemia, ventilation, arteriosclerosis, and decreased renal function.
本発明は、上記した課題を解決するためになされたものであって、本発明者らは、目的とする乳酸菌をスクリーニングするに際し、次のような基準を新たに設定し目的に合致する株を選定した。すなわち、本発明者らは、数多くの乳酸菌及びビフィズス菌のうち、プリンヌクレオシドをプリン塩基へと分解する能力の高いものを得る為に、菌株の選定につき鋭意研究を重ねた。スクリーニングの結果、上記条件に合致する菌種として、ビフィドバクテリウム・シュードロンガム(Bifidobacteriumu pseudolongum)、ビフィドバクテリウム・アニマリス・サブスピーシーズ・アニマリス(Bifidobacterium animalis ssp.animalis)、ラクトバチルス・ヘルベティカス(Lactobacillus helveticus)、ビフィドバクテリウム・インファンティス(Bifidobacterium infantis)に属する乳酸菌が得られた。このうちでも特に以下の菌株が好ましい。
なお、FERM P−10138、NITE BP−01707、FERM BP−5445は、下記の寄託番号により独立行政法人産業技術総合研究所特許微生物寄託センターに寄託されている。ATCC25526、ATCC25527はAmerican Type Culture Collectionから入手可能である。JCM1222は理化学研究所 微生物材料開発室から入手可能である。
なお、本発明では、乳酸菌及びビフィズス菌を合わせて乳酸菌ということがあり、特に区別しない限りは両方を含む意味で用いる。
The present invention has been made in order to solve the above-mentioned problems, and the present inventors, when screening for a target lactic acid bacterium, set a new standard as follows and strains that meet the purpose. Selected. That is, the present inventors have conducted intensive research on the selection of strains in order to obtain, from among many lactic acid bacteria and bifidobacteria, those having a high ability to degrade purine nucleosides into purine bases. As a result of the screening, as strains meeting the above conditions, Bifidobacterium pseudolongum (Bifidobacteriumu pseudolongum), Bifidobacterium animalis subspecies animalis (Bifidobacterium animalis ssp.animalis), Lactobacillus helveticus ( Lactobacillus helveticus) and lactic acid bacteria belonging to Bifidobacterium infantis were obtained. Among these, the following strains are particularly preferred.
FERM P-10138, NITE BP-01707, and FERM BP-5445 have been deposited at the National Institute of Advanced Industrial Science and Technology, Patent Microorganisms Depositary under the following deposit numbers. ATCC 25526 and ATCC 25527 are available from the American Type Culture Collection. JCM1222 is available from the RIKEN Microbial Materials Development Office.
In the present invention, a lactic acid bacterium and a bifidobacterium are sometimes collectively referred to as a lactic acid bacterium, and are used to include both unless otherwise specified.
菌株
ビフィドバクテリウム・シュードロンガムSBT2908株(FERM P−10138)
ビフィドバクテリウム・シュードロンガム基準株(ATCC25526)
ビフィドバクテリウム・アニマリス・サブスピーシーズ・アニマリス基準株(ATCC25527)
ラクトバチルス・ヘルベティカスSBT2161株(NITE BP−01707)
ラクトバチルス・ヘルベティカス SBT2171株(FERM BP−5445)
ビフィドバクテリウム・インファンティス基準株(JCM1222)
Strain Bifidobacterium pseudolongum SBT2908 strain (FERM P-10138)
Bifidobacterium pseudolongum reference strain (ATCC 25526)
Bifidobacterium animalis subspecies animalis reference strain (ATCC 25527)
Lactobacillus helveticus SBT2161 strain (NITE BP-01707)
Lactobacillus helveticus SBT2171 strain (FERM BP-5445)
Bifidobacterium infantis reference strain (JCM1222)
本発明のビフィドバクテリウム・シュードロンガム、ビフィドバクテリウム・アニマリス・サブスピーシーズ・アニマリス、ラクトバチルス・ヘルベティカス、ビフィドバクテリウム・インファンティスに属する菌を培養する培地としては、乳培地または乳成分を含む培地、これを含まない半合成培地等、種々の培地を用いることができる。このような培地としては、脱脂乳を還元して加熱殺菌した還元脱脂乳培地を例示することができる。
培養法は、静置培養またはpHを一定にコントロールした中和培養で行うが、菌が良好
に生育する条件であれば特に培養法に制限はない。
As a medium for culturing bacteria belonging to Bifidobacterium pseudolongum, Bifidobacterium animalis subspecies animaris, Lactobacillus helveticus, Bifidobacterium infantis, a milk medium or Various media such as a medium containing a milk component and a semi-synthetic medium not containing the same can be used. Examples of such a medium include a reduced skim milk medium obtained by reducing skim milk and heat-sterilizing the skim milk.
The culture method is a static culture or a neutralization culture in which the pH is controlled at a constant value. However, the culture method is not particularly limited as long as the bacteria can grow well.
本発明は、上述のようにして得られる培養物及び/または菌体を有効成分とする。また
乾燥した粉末を有効成分としてもよい。これらの乾燥は凍結乾燥で行なうことが菌体を変
質させることなく乾燥することができるので好ましい。
これらの有効成分は経口摂取することが望ましい。また、これらの粉末は乳糖等の適当
な賦形剤と混合し、粉剤、錠剤、丸剤、カプセル剤または粒剤等として経口投与すること
ができる。投与量は、投与対象者の症状、年齢等を考慮してそれぞれ個別に適宜決定され
る。
In the present invention, a culture and / or a cell obtained as described above is used as an active ingredient. Dried powder may be used as an active ingredient. It is preferable that the drying is performed by freeze-drying because the cells can be dried without deteriorating the cells.
These active ingredients are preferably taken orally. These powders can be mixed with a suitable excipient such as lactose and administered orally as powders, tablets, pills, capsules or granules. The dose is appropriately determined individually in consideration of the symptoms, age and the like of the subject.
また、本発明の有効成分は、飲食品の製造工程中に原料に添加してもよい。飲食品としてはどのような飲食品でもよく、その例として、乳飲料、発酵乳、チーズ、果汁飲料、ゼリー、キャンディー、乳製品、マヨネーズ等の卵加工品、バターケーキ等の菓子パン類等の食品を挙げることができる。また、マイクロカプセル等の従来技術を採用して、加熱を避ける手段を講じてもよい。
さらにまた、本発明における飲食品は、前述した菌を使用して乳酸発酵を行なって製造されたヨーグルト等であっても良い。
Further, the active ingredient of the present invention may be added to raw materials during the production process of food and drink. The food or drink may be any food or drink, such as milk drink, fermented milk, cheese, fruit drink, jelly, candy, dairy products, processed egg products such as mayonnaise, and confectionery bread such as butter cake. Can be mentioned. In addition, conventional technology such as microcapsules may be employed to take measures to avoid heating.
Furthermore, the food or drink in the present invention may be yogurt or the like produced by performing lactic acid fermentation using the above-mentioned bacteria.
本発明において、プリン体とはプリン骨格を持つ物質の総称で、プリン塩基(アデニン、グアニン、ヒポキサンチン)、プリンヌクレオシド(アデノシン、イノシン、グアノシン)、プリンヌクレオチド(ATP、ADP、AMP、ITP、IDP、IMP、GMP、GDP、GTP)等の総称である。 In the present invention, purines are a general term for substances having a purine skeleton, and include purine bases (adenine, guanine, hypoxanthine), purine nucleosides (adenosine, inosine, guanosine), purine nucleotides (ATP, ADP, AMP, ITP, IDP). , IMP, GMP, GDP, GTP).
本発明においてプリン体分解能とは、プリンヌクレオシドを分解する能力を言う。プリンヌクレオシド(アデノシン、イノシン、グアノシン)を分解する事で、プリン塩基(アデニン、グアニン、ヒポキサンチン)となる以外に、更に別の化合物へと変換される事も本発明に含む。 In the present invention, purine resolution refers to the ability to degrade purine nucleosides. The present invention also includes that by decomposing purine nucleosides (adenosine, inosine, guanosine), the compound is converted into another compound in addition to a purine base (adenine, guanine, hypoxanthine).
生体内におけるプリン体の代謝は公知である。プリンヌクレオチドであるAMPは代謝によりプリンヌクレオシドであるアデノシンとなり、アデノシンは代謝によりプリン塩基であるアデニンとなる。同様に、プリンヌクレオチドであるIMPはプリンヌクレオシドであるイノシンとなり、イノシンはプリン塩基であるヒポキサンチンとなる。また、プリンヌクレオチドであるGMPはプリンヌクレオシドであるグアノシンとなり、グアノシンはプリン塩基であるグアニンとなる。グアニンやヒポキサンチンは更に代謝され、最終的に尿酸となる。 Purine metabolism in vivo is known. AMP, a purine nucleotide, is metabolized to adenosine, a purine nucleoside, and adenosine is adenine, a purine base, by metabolism. Similarly, IMP, a purine nucleotide, becomes inosine, a purine nucleoside, and inosine becomes hypoxanthine, a purine base. GMP, which is a purine nucleotide, becomes guanosine, which is a purine nucleoside, and guanosine becomes guanine, which is a purine base. Guanine and hypoxanthine are further metabolized to ultimately become uric acid.
プリンヌクレオチドやプリンヌクレオシドは消化管において吸収されやすい。その結果、血中にプリンヌクレオチドやプリンヌクレオシドが増加する。血中でプリンヌクレオチドやプリンヌクレオシドの上記代謝が進むことにより、血中尿酸値が上昇し、高尿酸血症となる。一方本発明の血中尿酸値低減剤を用いる事により、消化管に吸収される前にプリンヌクレオシドが分解され、プリンヌクレオチドやプリンヌクレオシドと比較して消化管に吸収されにくいプリン塩基等に変換される。その結果、血中のプリンヌクレオチドやプリンヌクレオシドが低下し、代謝物であるプリン体濃度が低下する事により、血中尿酸値の上昇が防止される。 Purine nucleotides and purine nucleosides are easily absorbed in the digestive tract. As a result, purine nucleotides and purine nucleosides increase in blood. As the above-mentioned metabolism of purine nucleotides and purine nucleosides proceeds in blood, blood uric acid level increases, resulting in hyperuricemia. On the other hand, by using the blood uric acid level reducing agent of the present invention, purine nucleosides are decomposed before being absorbed into the digestive tract, and are converted into purine bases and the like which are less easily absorbed into the digestive tract as compared with purine nucleotides and purine nucleosides. You. As a result, purine nucleotides and purine nucleosides in blood decrease, and the concentration of metabolite purine decreases, thereby preventing an increase in blood uric acid level.
以下に、実施例及び試験例を示し、本発明についてより詳細に説明するが、これらは単に例示するのみであり、本発明はこれらによって何ら限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but these are merely examples, and the present invention is not limited thereto.
[試験例1]
[プリンヌクレオシド分解能の評価]
各乳酸菌と、プリンヌクレオシドとしてアデノシン、イノシン、グアノシンを反応させ、反応前後でのプリンヌクレオシド量を測定する事により、各乳酸菌のプリンヌクレオシド分解能を評価した。
[1.試料の準備]
表1に示す9株を供試菌として使用した。乳酸菌はMRS液体培地、ビフィズス菌はGAM+1%Glc液体培地を用いて37℃、16時間静置培養した。遠心分離(1,912×g,4℃,15min)により菌体を回収し、滅菌PBSを用いて3回洗浄した。回収した菌体を100mM リン酸カリウム緩衝液(1mM MgSO4添加、pH7)に再懸濁した。
[Test Example 1]
[Evaluation of purine nucleoside resolution]
Each lactic acid bacterium was reacted with adenosine, inosine, and guanosine as purine nucleosides, and the purine nucleoside resolution of each lactic acid bacterium was evaluated by measuring the amount of purine nucleoside before and after the reaction.
[1. Preparation of sample]
Nine strains shown in Table 1 were used as test bacteria. Lactic acid bacteria were cultured in an MRS liquid medium, and bifidobacteria were cultured in a GAM + 1% Glc liquid medium at 37 ° C. for 16 hours. The cells were collected by centrifugation (1,912 × g, 4 ° C., 15 min) and washed three times with sterile PBS. The collected cells were resuspended in 100 mM potassium phosphate buffer (1 mM MgSO 4 added, pH 7).
[2.プリン体分解反応]
プリンヌクレオシドとして、グアノシン、イノシン、アデノシンを使用した。1.25 mMの各種プリンヌクレオシドを含有する菌体懸濁液(生菌数1.0×109cfu/ml程度)を調製し、37℃にて140rpm、1時間振とうした。反応上清を遠心回収(1,912×g,4℃,15min)し、HPLCにてプリンヌクレオシド(基質)およびプリン塩基(反応産物)を定量した。
[2. Purine decomposition reaction]
Guanosine, inosine, and adenosine were used as purine nucleosides. A cell suspension (about 1.0 × 10 9 cfu / ml viable cells) containing 1.25 mM of various purine nucleosides was prepared and shaken at 140 ° C. for 1 hour at 37 ° C. The reaction supernatant was collected by centrifugation (1,912 × g, 4 ° C., 15 min), and purine nucleoside (substrate) and purine base (reaction product) were quantified by HPLC.
[3.HPLC分析]
HPLCは1200シリーズ(アジレントテクノロジー株式会社)を使用した。溶離液A(25mM KH2PO4(0.1% Methanol))で平衡化したODSカラム(Hydrosphere C18 粒子径(μm)S−5,細孔径4.6X250,品番 HS12S05−2546WT,YMC社製)に分析サンプルを10μlインジェクトし、溶離液B(25mM KH2PO4(0.1% Methanol)/Methanol=75:25V/V)の濃度勾配によってリニアグラディエントで分離溶出を行った(表2)。カラムオーブンは30℃とし、検出はUVディテクター(254nm)を利用した。分析サンプルは、780μlの溶離液Aに反応液200μlおよび内部標準として20μlの1.5mg/mlの5−ブロモウラシルを混合し、フィルターろ過(0.22μm)したものを使用した。
[3. HPLC analysis]
The HPLC used was a 1200 series (Agilent Technology Co., Ltd.). ODS column (Hydrosphere C18 particle diameter (μm) S-5, pore diameter 4.6 × 250, product number HS12S05-2546WT, manufactured by YMC) equilibrated with eluent A (25 mM KH 2 PO 4 (0.1% methanol)) 10 μl of the analysis sample was injected into the column, and separation and elution were carried out with a linear gradient using a concentration gradient of eluent B (25 mM KH 2 PO 4 (0.1% methanol) / methanol = 75: 25 V / V) (Table 2). . The column oven was set at 30 ° C., and detection was performed using a UV detector (254 nm). The analysis sample used was prepared by mixing 780 μl of eluent A with 200 μl of the reaction solution and 20 μl of 1.5 mg / ml 5-bromouracil as an internal standard, followed by filtration through a filter (0.22 μm).
[4.プリンヌクレオシド分解能の評価]
各供試菌によるプリンヌクレオシドの分解率を図1に示した。今回試験した中で最も高い分解率を示したのは、ビフィドバクテリウム・アニマリス・サブスピーシーズ・アニマリスATCC25527でアニマリスの基準株であった(分解率90%)。
また、ビフィドバクテリウム・シュードロンガムや(SBT2908株、基準株(ATCC25526))、ラクトバチルス・ヘルベティカス(SBT2171株、SBT2161株、基準株)にもプリン体分解能があることが示された。
一方、ラクトバチルス・ガセリ(基準株JCM1131)やビフィドバクテリウム・アドセンティス(基準株ATCC15703)にはプリン体の分解活性はほとんど認められなかった(分解率5%未満)。
[4. Evaluation of purine nucleoside resolution]
FIG. 1 shows the degradation rates of purine nucleosides by each test microorganism. The highest degradation rate tested in this experiment was Bifidobacterium animalis subspecies animalis ATCC 25527, the standard strain of animalis (90% degradation rate).
It was also shown that Bifidobacterium pseudolongum, (SBT2908 strain, reference strain (ATCC25526)) and Lactobacillus helveticus (SBT2171 strain, SBT2161 strain, reference strain) also have purine resolution.
On the other hand, in Lactobacillus gasseri (reference strain JCM1131) and Bifidobacterium adcentis (reference strain ATCC15703), almost no purinase-degrading activity was observed (degradation rate of less than 5%).
[5.プリン塩基生成量の評価]
各供試菌によるプリンヌクレオシドの分解物であるプリン塩基の生成量を図2に示した。
プリン塩基の生成量は、プリン塩基であるグアニン(G)、ヒポキサンチン(H)、アデニン(A)の合成量を各分析における内部標準5−ブロモウラシル量で割った値を合算した数値(GHA/5Bu)で示した。結果は上記4.で示したプリンヌクレオシドの分解率と相関していた。
[5. Evaluation of Purine Base Production Amount]
FIG. 2 shows the production amount of purine bases, which are degradation products of purine nucleosides, by each test microorganism.
The amount of purine base produced is a numerical value (GHA) obtained by summing the values obtained by dividing the amounts of synthesis of purine bases guanine (G), hypoxanthine (H), and adenine (A) by the amount of internal standard 5-bromouracil in each analysis. / 5Bu). The result is 4. And correlated with the degradation rate of purine nucleoside.
[実施例1.乾燥粉末]
ラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株及びビフィドバクテリウム・シュードロンガム基準株をそれぞれ10%還元脱脂乳培地(121℃、10分加熱)で培養し、本培養物を凍結乾燥し粉末化し、本発明の高尿酸血症予防剤を調製した。
Example 1 Dry powder]
Lactobacillus helveticus SBT2161 strain, Lactobacillus helveticus SBT2171 strain, Bifidobacterium pseudolongum SBT2908 strain and Bifidobacterium pseudolongum reference strain were each reduced by 10% reduced skim milk medium (heated at 121 ° C. for 10 minutes). ), And the main culture was freeze-dried and powdered to prepare the anti-hyperuricemia agent of the present invention.
[実施例2.発酵乳]
ラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株及びビフィドバクテリウム・シュードロンガム基準株をそれぞれGAM+1%Glc液体培地にて培養した。対数増殖期にある各培養液を、0.3%の酵母エキスを添加した10%還元脱脂乳(115℃、20分間滅菌)に1%接種し、個々マザーカルチャーを作成した。
これをヨーグルトミックス(10%の還元脱脂乳を添加し、100℃にて10分間加熱したもの)に各2.5%添加して調製した。発酵は37℃で行い、乳酸酸度0.85に到達した時点で冷却し、発酵を終了させ、本発明の高尿酸血症予防作用を有する発酵乳を調製した。
Example 2 Fermented milk]
Lactobacillus helveticus SBT2161 strain, Lactobacillus helveticus SBT2171 strain, Bifidobacterium pseudolongum SBT2908 strain and Bifidobacterium pseudolongum reference strain were each cultured in a GAM + 1% Glc liquid medium. Each culture in the logarithmic growth phase was inoculated at 1% to 10% reduced skim milk (sterilized at 115 ° C. for 20 minutes) to which 0.3% of yeast extract was added to prepare an individual mother culture.
This was prepared by adding 2.5% each to a yogurt mix (10% reduced skim milk added and heated at 100 ° C. for 10 minutes). The fermentation was performed at 37 ° C., and when the lactic acid acidity reached 0.85, the fermentation was terminated by terminating the fermentation to prepare a fermented milk having a hyperuricemia-preventing action of the present invention.
[実施例3.製剤例1]
ラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株及びビフィドバクテリウム・シュードロンガム基準株を、それぞれの液体培養物から対数増殖期にある菌体を、4℃、7,000rpmで15分間遠心分離して滅菌水による洗浄を行い、これを3回繰り返して洗浄菌体を得た。これを凍結乾燥処理して菌体粉末を得た。この菌体粉末1部に脱脂乳4部を混合し、この粉末を打錠機により1gずつ定法により打錠して、菌体200mgを含む錠剤を調製した。また、上記のラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株及びビフィドバクテリウム・シュードロンガム基準株のいずれかを含有する発酵乳を凍結乾燥し、得られた粉末を用いて直接打錠した。
Example 3 Formulation Example 1]
Lactobacillus helveticus SBT2161 strain, Lactobacillus helveticus SBT2171 strain, Bifidobacterium pseudolongum SBT2908 strain and Bifidobacterium pseudolongum reference strain were obtained from the respective liquid cultures in a logarithmic growth phase. Was centrifuged at 7,000 rpm for 15 minutes at 4 ° C., and washed with sterile water. This was repeated three times to obtain washed cells. This was freeze-dried to obtain a cell powder. One part of this cell powder was mixed with 4 parts of skim milk, and this powder was tableted by a tableting machine by a standard method in an amount of 1 g to prepare a tablet containing 200 mg of cells. Further, the fermented milk containing any one of the above-mentioned Lactobacillus helveticus SBT2161, Strain Lactobacillus helveticus SBT2171, Strain Bifidobacterium pseudolongum SBT2908 and the reference strain of Bifidobacterium pseudolongum is freeze-dried. Then, tableting was performed directly using the obtained powder.
[実施例5.製剤例2]
ラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株及びビフィドバクテリウム・シュードロンガム基準株を、それぞれMRS液体培地(Difco社製)5Lに接種後、37℃、18時間静置培養を行った。上記4菌株をそれぞれ脱脂乳5Lに接種後、37℃、18時間静置培養を行った。培養終了後、7,000rpmで15分間遠心分離を行い、培養液の1/50量のそれぞれの濃縮菌体を得た。次いで、この濃縮菌体を脱脂粉乳10%(重量)、グルタミン酸ソーダ1%(重量)を含む分散媒と同量混合し、pH7に調整後、凍結乾燥を行った。得られた凍結乾燥物を60メッシュのフルイで整粒化し、凍結乾燥菌末を得た。
第13改正日本薬局方解説書製剤総則「散剤」の規定に準拠し、上記で得られた凍結乾燥菌末1gにラクトース(日局)400g、バレイショデンプン(日局)600gを加えて均一に混合し、散剤を製造した。
Example 5 Formulation Example 2]
Lactobacillus helveticus SBT2161 strain, Lactobacillus helveticus SBT2171 strain, Bifidobacterium pseudolongum SBT2908 strain and Bifidobacterium pseudolongum reference strain were each inoculated into 5 L of MRS liquid medium (manufactured by Difco). At 37 ° C. for 18 hours. After inoculating 5 L of skim milk with each of the above four strains, static culture was performed at 37 ° C. for 18 hours. After the completion of the culture, centrifugation was performed at 7,000 rpm for 15 minutes to obtain 1/50 volume of each concentrated bacterial cell of the culture solution. Next, the concentrated cells were mixed with the same amount of a dispersion medium containing 10% (by weight) of skim milk powder and 1% (by weight) of sodium glutamate, adjusted to pH 7, and lyophilized. The obtained freeze-dried product was sized with a 60-mesh sieve to obtain freeze-dried bacterial powder.
According to the 13th revision of the Japanese Pharmacopoeia, instructions for preparations in the Japanese Pharmacopoeia, the general rule of "powder", 400 g of lactose (JP) and 600 g of potato starch (JP) are added to 1 g of the freeze-dried bacterial powder obtained above and mixed uniformly. To produce a powder.
[実施例6.製剤例3]
次の配合により高尿酸血症予防剤を製造し
(1)ラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株及びビフィドバクテリウム・シュードロンガム基準株のそれぞれの脱脂粉乳培地における培養物の凍結乾燥物50g、
(2)ラクトース90g、
(3)コーンスターチ29g、
(4)ステアリン酸マグネシウム1g、
この混合物を圧縮錠剤機により圧縮して、1錠あたり有効成分を40 mg含有する錠剤100個をそれぞれ製造した。
Example 6 Formulation Example 3]
A hyperuricemia-preventing agent was produced by the following formulation (1) Lactobacillus helveticus SBT2161 strain, Lactobacillus helveticus SBT2171 strain, Bifidobacterium pseudolongum SBT2908 strain and Bifidobacterium pseudolongum standard Freeze-dried 50 g of the culture in each skim milk medium of the strain,
(2) lactose 90g,
(3) 29 g of corn starch,
(4) 1 g of magnesium stearate,
This mixture was compressed using a compression tablet machine to produce 100 tablets each containing 40 mg of the active ingredient per tablet.
[実施例7.製剤例4]
ラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株及びビフィドバクテリウム・シュードロンガム基準株をそれぞれホエー培地(0.5%酵母エキス、0.1%トリプチケースペプトン添加)で培養後遠心分離で菌体を回収した。この培養物1gを乳糖5gと混合し顆粒状に成形して顆粒剤を得た。
Example 7 Formulation Example 4]
Lactobacillus helveticus SBT2161 strain, Lactobacillus helveticus SBT2171 strain, Bifidobacterium pseudolongum SBT2908 strain and Bifidobacterium pseudolongum reference strain were each added to a whey medium (0.5% yeast extract, 0.1% % Trypticase peptone), and the cells were collected by centrifugation. 1 g of this culture was mixed with 5 g of lactose and formed into granules to obtain granules.
[実施例8.飲料の製造]
洗浄菌体の凍結乾燥粉末をラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株又はビフィドバクテリウム・シュードロンガム基準株がそれぞれ108個以上含まれるように200mlの牛乳と混合して、本発明の高尿酸血症予防剤入り飲料を得た。良好な風味を有していた。
[Embodiment 8. Production of beverages]
Contain lyophilized powder washed cells SBT2161 strain Lactobacillus helveticus, Lactobacillus helveticus SBT2171 strain, Bifidobacterium shoe drone gum SBT2908 strain or Bifidobacterium shoe drone gum reference strains each 10 8 or more The mixture was mixed with 200 ml of milk to obtain a hyperuricemia-preventing agent-containing beverage of the present invention. It had a good flavor.
[実施例9.ヨーグルトの製造]
ラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株及びビフィドバクテリウム・シュードロンガム基準株をそれぞれヨーグルトミックス(生乳に2%脱脂乳を添加し、100℃、10分加熱した)に接種し、20℃で24時間培養した。紙カップに充填し冷却後、ヨーグルトとした製品中のラクトバチルス・ヘルベティカスSBT2161株、ラクトバチルス・ヘルベティカスSBT2171株、ビフィドバクテリウム・シュードロンガムSBT2908株又はビフィドバクテリウム・シュードロンガム基準株の生菌数濃度は、100g当たり108個以上であった。
[Embodiment 9. Production of yogurt]
Lactobacillus helveticus SBT2161 strain, Lactobacillus helveticus SBT2171 strain, Bifidobacterium pseudolongum SBT2908 strain and Bifidobacterium pseudolongum reference strain were each added to yogurt mix (2% skim milk was added to raw milk, (Heated at 100 ° C. for 10 minutes) and cultured at 20 ° C. for 24 hours. After filling into a paper cup and cooling, yogurt is used to produce Lactobacillus helveticus SBT2161 strain, Lactobacillus helveticus SBT2171 strain, Bifidobacterium pseudolongum SBT2908 strain or Bifidobacterium pseudolongum reference strain The bacterial concentration was at least 10 8 per 100 g.
本発明の高尿酸血症予防剤によれば、血中尿酸値が低減されるので、通風や動脈硬化、腎機能低下などの疾患の予防または治療に有効である。 ADVANTAGE OF THE INVENTION According to the hyperuricemia prevention agent of this invention, since the uric acid level in blood is reduced, it is effective in prevention or treatment of diseases, such as ventilation, arteriosclerosis, and renal function decline.
[寄託生物材料への言及]
(1)ビフィドバクテリウム・シュードロンガム(Bifidobacterium pseudolongum)SBT2908
イ 当該生物材料を寄託した寄託機関の名称及び住所
独立行政法人 産業技術総合研究所 特許生物寄託センター
日本国茨城県つくば市東1丁目1番3号
ロ イの寄託機関に生物材料を寄託した日付
昭和63年7月20日(1988年7月20日)(原寄託日)
ハ イの寄託機関が寄託について付した受託番号
FERM P−10138
(2)ラクトバチルス・ヘルベティカス(Lactobacillus helveticus)SBT2161
イ 当該生物材料を寄託した寄託機関の名称及び住所
独立行政法人製品評価技術基盤機構特許微生物寄託センター
千葉県木更津市かずさ鎌足2−5−8
ロ イの寄託機関に生物材料を寄託した日付
2013年9月18日
ハ イの寄託機関が寄託について付した受託番号
NITE BP−01707
(3)ラクトバチルス・ヘルベティカス(Lactobacillus helveticus)SBT2171
イ 当該生物材料を寄託した寄託機関の名称及び住所
独立行政法人 産業技術総合研究所 特許生物寄託センター
日本国茨城県つくば市東1丁目1番3号
ロ イの寄託機関に生物材料を寄託した日付
平成6年6月22日(1994年6月22日)(原寄託日)
平成8年3月6日(1996年3月6日)(原寄託によりブタペスト条約に基づく寄託への移管日)
ハ イの寄託機関が寄託について付した受託番号
FERM BP−5445
[Reference to deposited biological material]
(1) Bifidobacterium pseudolongum SBT2908
B.Name and address of the depositary institution that deposited the biological material The National Institute of Advanced Industrial Science and Technology (AIST) Patent Organism Depositary Center 1-3-1 Higashi, Tsukuba-shi, Ibaraki, Japan July 20, 1988 (July 20, 1988) (Original deposit date)
Accession number FERM P-10138 assigned by the depositary institution for the deposit
(2) Lactobacillus helveticus SBT2161
B. Name and address of the depository institution that deposited the biological material 2-5-8 Kazusa Kamatari, Kisarazu-shi, Chiba Pref.
Lo. Deposit date of biological material to the depositary institution September 18, 2013 Accession number NITE BP-01707 assigned to the deposit by the hi depositary institution
(3) Lactobacillus helveticus SBT2171
B. The name and address of the depositary institution that deposited the biological material The National Institute of Advanced Industrial Science and Technology (AIST) June 22, 1994 (June 22, 1994) (Original deposit date)
March 6, 1996 (March 6, 1996) (Transfer date to original deposit based on the Budapest Treaty)
Accession number FERM BP-5445 assigned by the depositary institution for the deposit.
Claims (3)
(A) ビフィドバクテリウム・シュードロンガム(Bifidobacteriumu pseudolongum)
(B) ビフィドバクテリウム・アニマリス・サブスピーシーズ・アニマリス(Bifidobacte rium animalis ssp.animalis)
(C) ラクトバチルス・ヘルベティカス(Lactobacillus helveticus)
(D) ビフィドバクテリウム・インファンティス(Bifidobacterium infantis) A blood uric acid level-reducing agent comprising one or more bacteria belonging to any of the following (A) to (D), a substance containing the bacteria and / or a culture thereof as an active ingredient.
(A) Bifidobacterium pseudolongum
(B) Bifidobacterium animalis subspecies animalis (Bifidobacterium animalis ssp.animalis)
(C) Lactobacillus helveticus
(D) Bifidobacterium infantis
(E) ビフィドバクテリウム・シュードロンガム(Bifidobacteriumu pseudolongum )SBT 2908株(FERM P-10138)
(F) ビフィドバクテリウム・シュードロンガム(Bifidobacteriumu pseudolongum) 基準株
(G) ビフィドバクテリウム・アニマリス・サブスピーシーズ・アニマリス(Bifidobacte rium animalis ssp.animalis)基準株
(H) ラクトバチルス・ヘルベティカス( Lactobacillus helveticus)SBT2161株 (NITE BP-01707)
(I) ラクトバチルス・ヘルベティカス(Lactobacillus helveticus )SBT2171株 (FERM BP-5445)
(J)ビフィドバクテリウム・インファンティス(Bifidobacterium infantis)基準株 A blood uric acid level reducing agent comprising , as an active ingredient, one or more strains of any one of the above (E) to (J), and a strain-containing substance and / or a culture thereof .
(E) Bifidobacterium pseudolongum SBT 2908 strain (FERM P-10138)
(F) Bifidobacterium pseudolongum reference strain
(G) Bifidobacterium animalis subspecies animalis (Bifidobacterium animalis ssp.animalis) reference strain (H) Lactobacillus helveticus SBT2161 strain (NITE B P-01707)
(I) Lactobacillus helveticus SBT2171 strain (FERM BP-5445)
(J) Bifidobacterium infantis reference strain
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