KR101841023B1 - Novel Bacillus subtilis strain having advanced glycation end product inhibitory activity effects and use of the same - Google Patents
Novel Bacillus subtilis strain having advanced glycation end product inhibitory activity effects and use of the same Download PDFInfo
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- KR101841023B1 KR101841023B1 KR1020170044949A KR20170044949A KR101841023B1 KR 101841023 B1 KR101841023 B1 KR 101841023B1 KR 1020170044949 A KR1020170044949 A KR 1020170044949A KR 20170044949 A KR20170044949 A KR 20170044949A KR 101841023 B1 KR101841023 B1 KR 101841023B1
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- bacillus subtilis
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- kccm11981p
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Abstract
Description
본 발명은 최종당화산물 저감 활성을 갖는 신규한 바실러스 서브틸리스 균주및 이의 용도에 관한 것이다.The present invention relates to a novel Bacillus subtilis strain having an ultimate saccharide reducing activity and a use thereof.
단백질의 비효소적 당화반응(Nonenzymatic glycation reaction)이란, 단백질의 리신 잔기 등의 아미노산 그룹과 환원당이 효소의 작용 없이 일어나는 마이얄 반응(Maillard reaction)으로, 이 반응의 결과로 최종당화산물(Advanced glycation end products, AGEs)이 형성된다. 단백질의 비효소적 당화반응은 단백질의 유리 아미노기인 리신 (lysine)이나, 알기닌(arginine)과 환원당의 카르보닐기 (carbonyl group)가 반응하여 초기 당화반응 생성물인 쉬프 염기(Shciff base)를 형성하고 이때 형성된 화합물들이 계속적으로 축합, 재전위, 산화, 분열, 고리화 등의 일련의 복잡한 반응을 통하여 갈색의 화합물 (melanoidine)을 만들어 총체적인 개념의 비가역적 최종당화산물을 형성하는 반응이다. The nonenzymatic glycation reaction of proteins is a Maillard reaction in which amino acid groups such as lysine residues of proteins and reducing sugars do not act on enzymes. As a result of this reaction, the final glycation product end products, AGEs) are formed. The nonenzymatic glycation of proteins is performed by reacting lysine, which is a free amino group of protein, or arginine with a carbonyl group of reducing sugar to form an initial glycation reaction product, Shciff base, It is a reaction in which a compound forms a non-irreversible final glycation product by forming a brown compound (melanoidine) through a series of complex reactions such as condensation, redox potential, oxidation, cleavage, and cyclization.
최종당화산물은 비가역적인 반응산물이므로 일단 생성되면 혈당이 정상적으로 회복되어도 분해되지 않고 단백질의 생존기간 동안 조직에 축적되어 조직의 구조와 기능을 비정상적으로 변화시킨다. 비교적 반감기가 긴 콜라겐(collagen)은 쉽게 당화반응이 일어나고 이미 형성된 최종당화산물과 콜라겐의 교차결합 (cross-linking)을 형성하여 체내의 구조 및 기타 단백질 결합 조직 등의 비정상적인 물리화학적 변화를 초래한다. 또한, 다양한 세포 타입에 대한 특이적 수용체에 의해 인식되어 당뇨병성 망막병증(retinopathy), 당뇨병성 신경병증(diabetic neuropathy) 당뇨병성 백내장 (cataract), 당뇨병성 신증 (nephropathy) 등과 같은 당뇨합병증과 당뇨, 만성 신장질환, 심장질환, 혈관질환 및 노화의 질병을 일으키는 원인이 된다.Since the final glycation products are irreversible reaction products, they are not degraded even if blood glucose is normally recovered once they are formed, and accumulate in the tissues during the protein survival period to abnormally change the structure and function of tissues. Collagen with a relatively long half-life readily undergoes a glycation reaction and forms cross-linking between the already formed final glycation products and collagen, resulting in abnormal physical and chemical changes in the structure of the body and other protein-binding tissues. It is also recognized by specific receptors for a variety of cell types to be useful in the treatment of diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic cataract, diabetic nephropathy, Chronic kidney disease, heart disease, vascular disease and aging diseases.
따라서 이러한 최종당화산물의 생성을 억제하려는 연구가 진행되고 있으며, 대표적인 합성의약품으로 아미노구아니딘이 있는데 이는 친핵성 히드라진 (hydrazine)으로 축합반응의 산물과 결합하여 최종당화산물의 생성을 억제함을 통해 합병증으로 진전되는 것을 방지한다. 또한 아미노구아니딘은 당뇨합병증의 예방 및 치료에 가장 유망한 의약품으로 제3상 임상시험까지 진행되었으나, 장기간 투여 시 독성이 유발되는 문제점이 있어 더욱 안전한 약제의 개발이 필요한 실정이다.Thus, studies are under way to inhibit the production of such final glycation products. Aminoguanidine is a typical synthetic drug, which is a nucleophilic hydrazine which binds to the product of the condensation reaction and inhibits the production of the final glycation end product. . In addition, aminoguanidine is the most promising drug for the prevention and treatment of diabetic complications, and it has been progressed to the phase III clinical trial. However, there is a problem that the long-term administration of the drug causes toxicity, so it is necessary to develop more safe drugs.
이에 인체 부작용이 없고 안정성이 확보되면서도 최종당화산물을 억제 및 저감시킬 수 있는 새로운 소재의 개발이 필요한 실정이다.Therefore, it is necessary to develop a new material capable of suppressing and reducing the final glycation products while securing stability without human side effects.
이러한 점에서 본원발명은 최종당화산물을 우수하게 저감할 수 있는 새로운 균주를 분리 및 동정하고 이의 활성을 확인함으로써 본 발명을 완성하였다.In view of the above, the present invention has accomplished the present invention by isolating and identifying a novel strain capable of excellently reducing the final glycation end product and confirming its activity.
따라서 본 발명의 목적은 신규한 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주를 제공하는 것이다.Therefore, an object of the present invention is to provide a novel strain of Bacillus subtilis KF11 (Accession No. KCCM11981P).
본 발명의 다른 목적은 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는 최종당화산물 저감 활성을 갖는 식품 조성물을 제공하는 것이다. Another object of the present invention is to provide a food composition having a final glycation end product-reducing activity comprising a disruption product of a strain of Bacillus subtilis KF11 (Accession No. KCCM11981P) or a culture thereof as an active ingredient.
또한 본 발명의 다른 목적은 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는 최종당화산물 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease associated with a final glycation end product comprising, as an active ingredient, a bacterium of Bacillus subtilis KF11 (Accession No. KCCM11981P) or a culture thereof.
또한 본 발명의 다른 목적은 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는 정장용조성물, 생균제 조성물, 사료용 조성물 및 발효제품을 제공하는 것이다.Another object of the present invention is to provide a dressing composition, a biocidal composition, a feed composition, and a fermented product comprising a crushed product of Bacillus subtilis KF11 (Accession No. KCCM11981P) strain or a culture thereof as an active ingredient.
나아가 본 발명의 다른 목적은 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는 최종당화산물 생성 억제제를 제공하는 것이다.Further, another object of the present invention is to provide a final glycation endogenesis inhibitor comprising Bacillus subtilis KF11 (Accession No. KCCM11981P) strain, a lysate thereof or a culture thereof as an active ingredient.
상기와 같은 본 발명의 목적을 달성하기 위해서, 본 발명은 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주를 제공한다.In order to achieve the above object of the present invention, the present invention provides a strain of Bacillus subtilis KF11 (Accession No. KCCM11981P).
본 발명의 일실시예에 있어서, 상기 균주는 최종당화산물(AGEs; Advanced glycation end products) 저감 활성을 갖는 것일 수 있다. In one embodiment of the present invention, the strain may have an activity of reducing advanced glycation end products (AGEs).
또한 본 발명은 본 발명의 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는 최종당화산물 저감 활성을 갖는 식품 조성물을 제공한다. The present invention also provides a food composition having the activity of reducing the glycation end product comprising Bacillus subtilis KF11 (Accession No. KCCM11981P) strain of the present invention, a lysate thereof or a culture thereof as an active ingredient.
본 발명의 일실시예에 있어서, 상기 조성물은 최종당화산물로 유발될 수 있는 당뇨병, 당뇨합병증, 만성 신장질환, 심장질환, 혈관질환 또는 노화를 예방 또는 개선할 수 있다. In one embodiment of the present invention, the composition may prevent or ameliorate diabetes, diabetic complications, chronic kidney disease, heart disease, vascular disease or aging which may be induced by the final glycation end product.
또한 본 발명은 본 발명의 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는, 최종당화산물 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for preventing or treating a disease caused by endogenous saccharides, comprising the strain of Bacillus subtilis KF11 (Accession No. KCCM11981P) of the present invention, a lysate thereof or a culture thereof as an active ingredient.
본 발명의 일실시예에 있어서, 상기 질환은 당뇨병, 당뇨합병증, 만성 신장질환, 심장질환, 혈관질환 및 노화로 이루어진 군 중에서 선택되는 것일 수 있다.In one embodiment of the present invention, the disease may be selected from the group consisting of diabetes, diabetic complications, chronic kidney disease, heart disease, vascular disease and aging.
또한 본 발명은 본 발명의 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는, 정장용 조성물을 제공한다.The present invention also provides a dressing composition comprising as an active ingredient a strain of Bacillus subtilis KF11 (Accession No. KCCM11981P) of the present invention, a lysate thereof, or a culture thereof.
또한 본 발명은 본 발명의 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는, 생균제 조성물을 제공한다.The present invention also provides a probiotic composition comprising the strain Bacillus subtilis KF11 (Accession No. KCCM11981P) of the present invention, a lysate thereof or a culture thereof as an active ingredient.
또한 본 발명은 본 발명의 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는, 사료용 조성물을 제공한다.The present invention also provides a composition for feed comprising Bacillus subtilis KF11 (Accession No. KCCM11981P) strain of the present invention, a lysate thereof or a culture thereof as an active ingredient.
또한 본 발명은 본 발명의 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는, 발효제품을 제공한다.The present invention also provides a fermented product comprising the strain of Bacillus subtilis KF11 (Accession No. KCCM11981P) of the present invention, a crushed product thereof or a culture thereof as an active ingredient.
또한 본 발명은 본 발명의 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는 최종당화산물 생성 억제제를 제공한다.The present invention also provides a final glycation endogenesis inhibitor comprising the strain of Bacillus subtilis KF11 (Accession No. KCCM11981P) of the present invention, a lysate thereof or a culture thereof as an active ingredient.
본 발명은 신규한 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주 및 이의 용도에 관한 것으로, 본 발명의 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물은 최종당화산물을 효과적으로 저감시킬 수 있는 활성이 있어, 최종당화산물로 유발되는 질환들의 예방 또는 치료용 의약품 및 기능성 식품의 제조에 사용될 수 있는 효과가 있으며, 나아가 정장용, 생균제, 사료용 조성물 및 발효 제품의 제조에도 사용될 수 있는 효과가 있다.The present invention relates to a novel strain of Bacillus subtilis KF11 (Accession No. KCCM11981P) and a use thereof, wherein the strain of Bacillus subtilis KF11 (Accession No. KCCM11981P) of the present invention, a crushed product thereof or a culture thereof, Which can be used in the production of medicines and functional foods for the prevention or treatment of diseases induced by the final glycation products and further can be used for the preparation of compositions for diets, It is effective.
도 1은 본 발명의 일실시예에서 대조군으로 사용한 시판되는 프로바이오틱스 제품들을 나타낸 것이다.
도 2는 본 발명의 바실러스 서브틸리스 KF11 균주와 다른 유산균을 대상으로 CML 저감 활성을 비교 분석한 결과이다.
도 3은 시판되는 프로바이오틱스 제품들의 CML 저감 활성을 분석한 결과이다.
도 4는 CML 표준폼과 본 발명의 바실러스 서브틸리스 KF11 균주에 대한 CML 저감 활성을 비교 분석한 결과이다.Figure 1 shows commercially available probiotic products used as a control in one embodiment of the present invention.
FIG. 2 shows the results of comparative analysis of CML abatement activity of Bacillus subtilis KF11 strain of the present invention and other lactic acid bacteria.
FIG. 3 shows the results of analysis of CML reducing activity of commercially available probiotic products.
FIG. 4 shows the results of a comparative analysis of the CML reducing activity against the CML standard form and the Bacillus subtilis KF11 strain of the present invention.
본 발명은 신규한 바실러스 서브틸리스 KF11 균주 및 상기 균주의 용도를 제공하는 것으로, 본 발명의 바실러스 서브틸리스 KF11 균주가 최종당화산물의 생성을 현저하게 억제하는 활성이 있음을 규명한 점에 특징이 있다.The present invention provides a novel strain of Bacillus subtilis KF11 and the use of the strain. It is characterized in that the Bacillus subtilis KF11 strain of the present invention has an activity of remarkably inhibiting the production of a final glycation product .
최종당화산물은 비가역적 반응산물로서 일단 생성되면 혈당이 정상적으로 회복되어도 분해되지 않고 단백질의 생존기간 동안 조직에 축적되어 조직의 구조와 기능을 비정상적으로 변화시켜, 당뇨병, 당뇨합병증, 만성 신장질환, 심장질환, 혈관질환 또는 노화와 같은 질환을 유발시키는 원인이 된다.Once the glycoconjugate is produced as an irreversible reaction product, it is not degraded even when blood glucose is normally recovered, but accumulates in the tissue during the lifetime of the protein, thereby abnormally changing the structure and function of the tissue, resulting in diabetes, diabetic complication, chronic renal disease, Diseases, vascular diseases or diseases such as aging.
따라서 최종당화산물의 생성을 억제 또는 감소시킴을 통해 최종당화산물로부터 유래되는 각종 질환을 예방, 개선 또는 치료할 수 있다. Thus, by inhibiting or reducing the production of the final glycation endproduct, various diseases derived from the final glycation endproduct can be prevented, improved or treated.
이에 본 발명자들은 최종당화산물의 저감 활성을 갖는 새로운 신균주인 바실러스 서브틸리스 KF11 균주를 분리 및 동정하였고, 이를 국제미생물기탁기관인 한국미생물보존센터(KCCM)에 2017년 2월 24일자로 기탁하여 기탁번호 KCCM 11981P를 부여받았다.Thus, the present inventors isolated and identified a new strain of Bacillus subtilis KF11, which has a reducing activity of the final glycation end product, and deposited this on the Korean Microorganism Conservation Center (KCCM), an international microorganism depository institution, on February 24, 2017 The deposit number KCCM 11981P.
또한 본 발명자들은 본 발명의 바실러스 서브틸리스 KF11 균주의 최종당화산물 저감 활성을 분석하기 위해, 최종당화산물을 함유한 시료에 본 발명의 균주와 비교 균주들을 각각 처리한 후, 배양액 내의 최종당화산물의 함량을 측정한 결과, 바실러스 서브틸리스 속에 속하는 균주인 g12에 비해 본 발명의 균주가 월등히 우수한 최종당화산물 저감 효과를 보이는 것으로 나타났고, 엔테로코커스 및 락토바실러스 속 균주에 비해서도 월등히 우수한 최종당화산물 저감 효과를 보였으며, 시판중인 프로바이오틱스 제품에 비해서도 더 우수한 활성이 있는 것으로 나타났다(도 2 내지 도 3 참조 및 표 2 참조). In order to analyze the activity of reducing the final glycation end product of Bacillus subtilis KF11 strain of the present invention, the inventors of the present invention treated each of the strain and comparative strain of the present invention with a sample containing the final glycation end product, As a result, it was found that the strain of the present invention showed a remarkably superior effect of reducing the final glycation end product, compared with the strain g12 which belongs to the genus Bacillus subtilis. The end saccharification product which is superior to that of Enterococcus and Lactobacillus sp. (See FIG. 2 to FIG. 3 and Table 2). The results are shown in FIG.
따라서 본 발명자들은 바실러스 서브틸리스 KF11 균주를 최종당화산물 저감용 기능성 제품들의 제조에 유용하게 사용할 수 있음을 알 수 있었다.Thus, the present inventors have found that Bacillus subtilis KF11 strain can be usefully used for the production of functional products for reducing the final glycation end product.
그러므로 본 발명은 신규한 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주를 제공할 수 있으며, 또한 본 발명은 바실러스 서브틸리스 KF11 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는 최종당화산물 저감 활성을 갖는 식품 조성물을 제공할 수 있다. Therefore, the present invention can provide a novel strain of Bacillus subtilis KF11 (Accession No. KCCM11981P), and the present invention also provides a method for producing a strain of Bacillus subtilis KF11, a fragment thereof or a culture thereof, To provide a food composition having an activity.
본 발명의 식품 조성물은 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강식품(health food) 및 식품 첨가제(food additives) 등의 모든 형태를 포함한다. 상기 유형의 식품 조성물은 당 업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다. 예를 들면, 건강식품으로는 본 발명의 바실러스 서브틸리스 KF11 균주 자체, 이의 파쇄물 및 상기 균주 배양물 군 중 하나 이상을 차, 쥬스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화 하여 섭취할 수 있다. 또한, 본 발명의 바실러스 서브틸리스 KF11 균주, 이의 파쇄물 및 배양물 군 중 하나 이상을 최종당화산물 저감 효과가 있다고 알려진 공지의 물질 또는 활성 성분과 함께 혼합하여 조성물의 형태로 제조할 수 있다. 또한, 기능성 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예: 과일통조림, 병조림, 잼, 마아말 레이드 등), 어류, 육류 및 그 가공식품(예: 햄, 소시지콘비이프 등), 빵류 및 면류(예: 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예: 버터, 치이즈 등), 식용식물유지, 마아가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예: 된장, 간장, 소스 등) 등에 본 발명의 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 및 배양물 군 중 하나 이상을 첨가하여 제조할 수 있다. The food composition of the present invention includes all forms such as functional food, nutritional supplement, health food and food additives. Food compositions of this type may be prepared in a variety of forms according to conventional methods known in the art. For example, as a health food, one or more of the Bacillus subtilis KF11 strain itself of the present invention, the crushed product thereof and the culture of the strain may be prepared in the form of tea, juice and drink for drinking, granulated, It can be taken in powder form. In addition, one or more of the Bacillus subtilis KF11 strain of the present invention, the disruption thereof, and the culture group may be mixed with a known substance or active ingredient known to be effective in reducing the final glycation end product, thereby preparing a composition. Functional foods also include beverages (including alcoholic beverages), fruits and their processed foods (e.g., canned fruits, bottled, jam, maalmalade, etc.), fish, meat and processed foods such as ham, Etc.), breads and noodles (eg udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, , A retort food, a frozen food, various kinds of seasonings (for example, soybean paste, soy sauce, sauce, etc.) by adding at least one of the strains of Bacillus subtilis KF11 (Accession No. KCCM11981P) have.
본 발명의 식품 조성물 중 상기 본 발명의 바실러스 서브틸리스 KF11 균주, 이의 파쇄물 및 배양물 등의 바람직한 함유량으로는 이에 한정되지 않지만 바람직하게는 최종적으로 제조된 식품 중 0.01 내지 50 중량%이다. 또한, 본 발명의 바실러스 서브틸리스 KF11 균주, 이의 파쇄물 및 배양물로 이루어진 군에서 선택된 하나 이상을 유효성분으로서 식품 첨가제의 형태로 사용하기 위해서는 분말 또는 농축액 형태로 제조하여 사용할 수 있다.The preferred content of the Bacillus subtilis KF11 strain of the present invention, the crushed product thereof, and the culture thereof in the food composition of the present invention is not particularly limited, but is preferably 0.01 to 50% by weight in the finally prepared food. In addition, in order to use, as a food additive, at least one selected from the group consisting of Bacillus subtilis KF11 strain of the present invention, a crushed product thereof and a culture, it can be used in the form of powder or concentrate.
또한 본 발명은 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 또는 이의 배양물을 유효성분으로 포함하는, 최종당화산물로 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제공할 수 있으며, 상기 질환으로는 이에 제한되지는 않으나, 당뇨병, 당뇨합병증, 만성 신장질환, 심장질환, 혈관질환 또는 노화일 수 있다.The present invention also provides a pharmaceutical composition for preventing or treating diseases caused by a final glycation end product comprising Bacillus subtilis KF11 (Accession No. KCCM11981P) strain, a lysate thereof or a culture thereof as an active ingredient, Such diseases include, but are not limited to, diabetes, diabetic complications, chronic kidney disease, heart disease, vascular disease or aging.
상기 약학적 조성물에는 약학적으로 허용 가능한 염을 단독으로 함유하거나 또는 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 함유할 수 있다. 약학적으로 허용되는 담체로는 예컨대, 경구 투여용 담체 또는 비경구 투여용 담체를 추가로 포함할 수 있다. 경구 투여용 담체는 락토스, 전분, 셀룰로스 유도체, 마그네슘 스테아레이트, 스테아르산 등을 포함할 수 있다. 또한, 비경구 투여용 담체는 물, 적합한 오일, 식염수, 수성 글루코스 및 글리콜 등을 포함할 수 있으며, 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸- 또는 프로필-파라벤 및 클로로부탄올이 있다. 그 밖의 약학적으로 허용되는 담체로는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다(Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995). The pharmaceutical composition may contain a pharmaceutically acceptable salt alone or may further contain one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, the carrier for parenteral administration may contain water, a suitable oil, a saline solution, an aqueous glucose and a glycol, and may further contain a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).
본 발명의 약학적 조성물은 인간을 비롯한 포유동물에 어떠한 방법으로도 투여할 수 있다. 예를 들면, 경구 또는 비경구적으로 투여할 수 있다. 비경구적인 투여방법으로는 이에 한정되지는 않으나, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장내 투여일 수 있다. 바람직하게는 본 발명의 약학적 조성물은 경구 또는 경피 투여될 수 있다. The pharmaceutical composition of the present invention can be administered to mammals including humans by any method. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration Lt; / RTI > Preferably, the pharmaceutical composition of the present invention can be administered orally or transdermally.
본 발명의 약학적 조성물은 상술한 바와 같은 투여 경로에 따라 경구 투여용 또는 비경구 투여용 제제로 제형화 할 수 있다. The pharmaceutical composition of the present invention can be formulated into oral preparations or parenteral administration preparations according to the administration route as described above.
경구 투여용 제제의 경우에 본 발명의 조성물은 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 슬러리제, 현탁액 등으로 당업계에 공지된 방법을 이용하여 제형화될 수 있다. 예를 들어, 경구용 제제는 활성성분을 고체 부형제와 배합한 다음 이를 분쇄하고 적합한 보조제를 첨가한 후 과립 혼합물로 가공함으로써 정제 또는 당의정제를 수득할 수 있다. 적합한 부형제의 예로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨 및 말티톨 등을 포함하는 당류와 옥수수 전분, 밀 전분, 쌀 전분 및 감자 전분 등을 포함하는 전분류, 셀룰로즈, 메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 하이드록시프로필메틸-셀룰로즈 등을 포함하는 셀룰로즈류, 젤라틴, 폴리비닐피롤리돈 등과 같은 충전제가 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있다. 나아가, 본 발명의 약학적 조성물은 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다. In the case of a preparation for oral administration, the composition of the present invention may be formulated into a powder, a granule, a tablet, a pill, a sugar, a tablet, a liquid, a gel, a syrup, a slurry, . For example, an oral preparation can be obtained by combining the active ingredient with a solid excipient, then milling it, adding suitable auxiliaries, and then processing the mixture into a granular mixture. Examples of suitable excipients include, but are not limited to, sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches including corn starch, wheat starch, rice starch and potato starch, Cellulose such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose and the like, fillers such as gelatin, polyvinylpyrrolidone and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may optionally be added as a disintegrant. Further, the pharmaceutical composition of the present invention may further comprise an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.
비경구 투여용 제제의 경우에는 주사제, 크림제, 로션제, 외용연고제, 오일제, 보습제, 겔제, 에어로졸 및 비강 흡입제의 형태로 당업계에 공지된 방법으로 제형화할 수 있다. 이들 제형은 모든 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour)에 기재되어 있다. In the case of a preparation for parenteral administration, it can be formulated by a method known in the art in the form of injection, cream, lotion, external ointment, oil, moisturizer, gel, aerosol and nasal aspirate. These formulations are described in Remington's Pharmaceutical Science, 15th edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a commonly known formulary for all pharmaceutical chemistries.
본 발명의 균주 자체, 이의 파쇄물 및 상기 균주 배양물 등의 총 유효량은 단일 투여량(single dose)으로 환자에게 투여될 수 있으며, 다중 투여량(multiple dose)으로 장기간 투여되는 분할 치료 방법(fractionated treatment protocol)에 의해 투여될 수 있다. 본 발명의 약학적 조성물은 질환의 정도에 따라 유효성분의 함량을 달리할 수 있다. 바람직하게는 본 발명의 균주, 이의 파쇄물 및 배양물의 바람직한 전체 용량은 1일당 환자 체중 1 ㎏ 당 약 0.01ug 내지 1,000 mg, 가장 바람직하게는 0.1 ug 내지 100 mg일 수 있다. 그러나 상기 본 발명의 균주 자체, 이의 파쇄물 및 상기 균주 배양물 등의 용량은 약학적 조성물의 투여 경로 및 치료 횟수뿐만 아니라 환자의 연령, 체중, 건강 상태, 성별, 질환의 중증도, 식이 및 배설율 등 다양한 요인들을 고려하여 환자에 대한 유효 투여량이 결정되는 것이므로, 이러한 점을 고려할 때 당 분야의 통상적인 지식을 가진 자라면 상기 본 발명의 균주, 이의 파쇄물 및 배양물을 면역기능 증진제로서의 특정한 용도에 따른 적절한 유효 투여량을 결정할 수 있을 것이다. 본 발명에 따른 약학적 조성물은 본 발명의 효과를 보이는 한 그 제형, 투여 경로 및 투여 방법에 특별히 제한되지 아니한다. The total effective amount of the strain of the present invention, its lysate, and the culture of the strain, etc., may be administered to a patient in a single dose and may be administered in a fractionated treatment administered at multiple doses < / RTI > protocol). In the pharmaceutical composition of the present invention, the content of the active ingredient may be varied depending on the degree of the disease. Preferably, the preferred total dose of the strain, the lysate thereof and the culture of the present invention may be from about 0.01 μg to 1,000 mg, and most preferably from 0.1 μg to 100 mg, per kg body weight of the patient per day. However, the dose of the strain itself, the disruption thereof, and the culture of the strain of the present invention, as well as the administration route and the number of treatments of the pharmaceutical composition, as well as the age, weight, health condition, sex, disease severity, In view of the above, it will be understood by those skilled in the art that the strain, the disruption thereof and the culture thereof according to the specific use as the immune function-enhancing agent A suitable effective dose will be determined. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, administration route and administration method as long as the effect of the present invention is exhibited.
또한, 본 발명은 바실러스 서브틸리스 KF11(수탁번호 KCCM11981P) 균주, 이의 파쇄물 및 배양물로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는 정장용, 생균제, 사료용 조성물을 제공한다. 본 발명의 바실러스 서브틸리스 KF11 균주는 최종당화산물 저감 활성이 있는 균주로 인간 및 동물의 건강 증진을 위한 용도, 즉, 정장용, 생균제 또는 사료용 조성물로 사용될 수 있다. 상기 조성물은 상기 균주 자체, 이의 파쇄물 및 상기 균주 배양물 등을 유효성분으로 포함할 수 있으며, 부형제 또는 담체를 추가로 포함할 수 있다. 상기 조성물은 액체배지에서 배양한 배양액 자체, 상기 배양액을 여과 또는 원심분리 하여 균주를 제거한 여액(원심분리한 상등액) 등을 포함한다. 조성물 내 상기 본 발명의 균주 함량은 조성물의 용도 및 제형에 따라 달라질 수 있다. Also, the present invention provides a composition for rectal preparation, prophylactic agent, and feed comprising at least one selected from the group consisting of Bacillus subtilis KF11 (Accession No. KCCM11981P) strain, a crushed product thereof and a culture thereof as an active ingredient. The Bacillus subtilis KF11 strain of the present invention is a strain having an activity of reducing the final glycation end product and can be used as a composition for a health promotion of humans and animals, that is, a composition for a dressing, a probiotic agent or a feed. The composition may contain the strain itself, a crushed product thereof and a culture of the strain as an active ingredient, and may further include an excipient or carrier. The composition includes a culture medium itself cultured in a liquid medium, a filtrate obtained by removing the strain by filtration or centrifugation of the culture medium (centrifuged supernatant), and the like. The amount of the strain of the present invention in the composition may vary depending on the use of the composition and the formulation.
본 발명에 따른 정장용 또는 생균제 조성물은 다양한 제형과 방법으로 제조 및 투여될 수 있다. 예를 들어, 바실러스 서브틸리스 KF11 균주, 이의 파쇄물 및 이의 배양물을 약제학적 분야에서 통상적으로 사용하는 담체 및 향료와 혼합하여 정제 (tablet), 트로키(troche), 캡슐(capsule), 엘릭실(elixir), 시럽(syrup), 산제(powder), 현탁제(suspension) 또는 과립제(granule) 등의 형태로 제조 및 투여될 수 있다. The dressing or probiotic composition according to the present invention can be manufactured and administered in a variety of formulations and methods. For example, the Bacillus subtilis KF11 strain, its lysate and its culture are mixed with carriers and flavoring agents commonly used in the pharmaceutical field to form tablets, troche, capsules, and may be prepared and administered in the form of elixir, syrup, powder, suspension or granule.
담체로는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제 등을 사용할 수 있다. 투여방식은 경구, 비경구 또는 도포법을 사용할 수 있으나, 바람직하게는 경구투여하는 것이 바람직하다. 또한, 투여용량은 체내에서 활성성분의 흡수도, 불활성율 및 배설속도, 피투여자의 연령, 성별, 상태 등에 따 라 적절히 선택할 수 있다. 또한, 본 발명에 따른 사료용 조성물은 발효사료, 배합 사료, 펠렛 형태 및 사일레지(silage) 등의 형태로 제조될 수 있다. Examples of the carrier include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents and the like. The administration method may be oral, parenteral or application, but is preferably orally administered. In addition, the dosage can be appropriately selected depending on the degree of absorption, inactivation rate and excretion rate of the active ingredient in the body, age, sex, and condition of the subjects. In addition, the composition for feed according to the present invention can be produced in the form of a fermented feed, a compounded feed, a pellet form, a silage or the like.
상기 발효사료는 본 발명의 바실러스 서브틸리스 KF11와 여러 가지 미생물균 또는 효소들을 첨가함으로써 유기물을 발효시켜 제조될 수 있으며, 상기 배합사료는 여러 종류의 일반 사료와 본 발명의 균주를 혼합하여 제조할 수 있다. 펠렛 형태의 사료는 상기 발효사료 또는 배합사료를 펠렛기로 제형화하여 제조될 수 있으며, 사일레지는 청예사료를 본 발명에 따른 균주를 발효시킴으로서 제조될 수 있다. The fermented feed can be prepared by fermenting an organic material by adding Bacillus subtilis KF11 of the present invention and various microbial bacteria or enzymes, and the mixed feed is prepared by mixing various kinds of general feed and the strain of the present invention . Feeds in the form of a pellet can be prepared by formulating the fermented feed or compound feed into a pelletizer, and the silage can be produced by fermenting the fermented feed according to the present invention.
또한, 본 발명의 바실러스 서브틸리스 KF11, 이의 파쇄물 및 배양물로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는 발효제품을 제공한다. 발효제품의 제조방법은 통상적으로 원료의 준비, 유산균의 첨가, 발효, 완성된 제품의 회수 등의 과정으로 이루어진다. 원료의 준비 단계는 발효 대상이 되는 재료를 준비하고, 발효가 잘 이루어지도록 발효 조건을 준비하는 단계이다. 유산균의 첨가는 발효 대상의 양에 따라 적량의 균을 첨가하는 것으로 본 발명에서는 본 발명의 균주를 사용하는 것을 특징으로 한다. 발효는 통상의 발효균의 발효조건에 따라 수행되는 것으로 바람직하게는 37 내지 43℃에서 4 내지 168시간동안 수행된다. 완성된 제품의 회수는 발효물에서 불필요한 부산물이나 미발효된 재료를 제거하는 것에서부터 저장, 운반을 용이하게 하기 위한 모든 후처리과정 및 포장 등을 포함한다. 상기의 방법에 따라 제조하는 발효제품은 바람직하게는 음료일 수 있으며, 이 음료는 예를 들어, 본 발명의 균주를 배양하여 젖산 발효시킨 것에 살균수를 가해서 희석하고 당분, 향료 등을 가한 다음 용기에 충전한 제품을 나타낸다. 이 음료에는 일반적으로 유산균이 살아 있는 채로 함유되어 있으므로, 음용 후 장(腸) 안에서의 정장작용을 기대할 수 있다.The present invention also provides a fermented product comprising at least one selected from the group consisting of Bacillus subtilis KF11 of the present invention, a crushed product thereof and a culture thereof as an active ingredient. The fermented product is usually prepared by preparing a raw material, adding a lactic acid bacterium, fermenting, and recovering a finished product. The preparation step of the raw material is a step of preparing a material to be fermented and preparing a fermentation condition so that the fermentation is performed well. The addition of the lactic acid bacterium is carried out by adding an appropriate amount of bacteria according to the amount of the fermented object, and the present invention is characterized by using the strain of the present invention. The fermentation is carried out according to the fermentation conditions of conventional fermenting bacteria, preferably at 37 to 43 캜 for 4 to 168 hours. Recovery of the finished product includes removal of unwanted by-products or unfermented materials from fermentation, all post-treatment processes and packaging to facilitate storage and transport. The fermented product produced according to the above method is preferably a beverage. For example, the fermented product of the present invention is cultured and lactic acid fermented by adding sterilized water to dilute it, adding sugar, flavor, etc., And the like. Since the lactic acid bacterium is generally contained in the beverage, it can be expected to have a formal effect in the intestine after drinking.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.
<< 실시예Example 1> 1>
바실러스Bacillus 서브틸리스Subtilis KF11 균주의 분리 및 동정 Isolation and Identification of KF11 Strain
본 발명자들은 최종당화산물의 저감 활성을 갖는 새로운 균주를 된장으로부터 분리하기 위해 다음과 같은 실험을 수행하였다. 된장을 0.85% 생리식염수에 현탁하고 현탁액 일부를 TSB 고체 배지에 도말한 후 37℃에서 배양하였다. 배양 후 형성된 콜로니를 취하여 TSB 배지에 획선 배양하여 오염되지 않은 수순한 단일 콜로니를 확보하였다. 확보된 균주로부터 16S rDNA를 분리하여 시퀀싱 분석을 수행하였다. The present inventors conducted the following experiment to isolate a new strain having a reducing activity of the final glycation product from doenjang. The doenjang was suspended in 0.85% physiological saline and a part of the suspension was plated on a solid medium of TSB and cultured at 37 ° C. The colonies formed after culturing were taken and cultured on TSB medium to obtain a single colony which was not contaminated. Sequencing analysis was performed by isolating 16S rDNA from the obtained strains.
시퀀싱 분석결과, 상기 균주의 16s rDNA 염기서열은 기존의 바실러스 서브틸리스 KCTC 13429(T) 균주와 99%의 상동성을 보여 본원발명에서 동정한 균주가 바실러스 서브틸리스에 속하는 균주임을 알 수 있었고, 16s rDNA 염기서열은 서열번호 1에 나타내었다. 이후 분리된 균주는 TSB 배지를 이용하여 배양조건 pH 7.0 ± 0.2, 온도 37℃ 및 24시간에서 교반하며 배양하였고, 산소요구성은 통성혐기성이고 동결건조보존 또는 세포현탁액 동결을 통해 균주를 보존시켰다. As a result of sequencing analysis, it was found that the 16s rDNA sequence of the strain was 99% homologous with the existing Bacillus subtilis KCTC 13429 (T) strain, indicating that the strain identified in the present invention belonged to Bacillus subtilis , And the 16s rDNA nucleotide sequence is shown in SEQ ID NO: 1. The isolated strains were cultured using TSB medium at pH 7.0 ± 0.2, 37 ℃, and 24 hrs. The oxygen requirement was anaerobic, and preserved by freeze - drying or cell suspension freezing.
이후 본 발명자들은 분리된 상기 균주를 바실러스 서브틸리스 KF11로 명명하였고, 국제미생물기탁기관인 한국미생물보존센터(KCCM)에 2017년 2월 24일자로 기탁하였으며, 기탁번호 KCCM 11981P를 부여받았다.Then, the present inventors named the isolated strain as Bacillus subtilis KF11, deposited it on Feb. 24, 2017 at the Korean Microorganism Conservation Center (KCCM), which is an international microorganism depository institution, and received the deposit number KCCM 11981P.
<< 실시예Example 2> 2>
바실러스Bacillus 서브틸리스Subtilis KF11 균주의 Of KF11 strain 최종당화산물The final glycation product 저감효능Abatement efficacy 분석 analysis
본 발명자들은 상기 본 발명의 바실러스 서브틸리스 KF11 균주가 최종당화산물 저감 효능이 있는지 분석하기 위해, 우유 내 최종당화산물의 저감활성을 다음과 같은 방법을 통해 확인하였다.In order to analyze whether the Bacillus subtilis KF11 strain of the present invention has the effect of reducing the final glycation end product, the inventors of the present invention have confirmed the activity of reducing the final glycated product in milk by the following method.
<2-1> <2-1> 최종당화산물The final glycation product 함유 식품 제조 Food manufacturing
본 발명의 균주가 최종당화산물의 한 종류인 CML(Nε-(Carboxymethyl)-L-lysine)을 저감시키는 활성이 있는지의 여부를 분석하기 위해 먼저 CML을 함유한 식품을 제조하였다. 즉, 우유의 열처리 공정 중 생성되는 CML을 저감하기 위해 유단백질인 카제인과 유당인 락토스를 이용하였는데, sodium caseinate와 D-lactose는 ㈜이에스 식품원료와 Sigma-Aldrich에서 각각 구매하여 사용하였다. 우유 내 카제인과 락토스 비율을 고려하여 우유단백질(카제인)과 당(락토스)을 1:7의 비율로 섞어 140℃ 온도에서 80분간 반응하여 균주의 CML 저감 효능 평가에 사용하였다. 이때 카제인과 락토스의 마이얄 반응에 의한 CML 함량은 8.24 ug/mL로 확인되었다.To analyze whether the strain of the present invention has activity to reduce CML (N? - (Carboxymethyl) -L-lysine), which is one kind of the final glycation products, a food containing CML was first prepared. In order to reduce the CML produced during the heat treatment process of milk, milk protein casein and lactose were used. Sodium caseinate and D-lactose were purchased from Eisse Foods and Sigma-Aldrich, respectively. The milk protein (casein) and sugar (lactose) were mixed at a ratio of 1: 7 in consideration of the ratio of casein and lactose in milk, and the mixture was reacted at 140 ° C for 80 minutes to evaluate the CML reduction efficacy of the strain. At this time, the CML content due to the myelin reaction of casein and lactose was confirmed to be 8.24 ug / mL.
<2-2> <2-2> CMLCML 함량분석을 위해 사용한 균주 The strains used for the content analysis
본 발명자들은 본 발명에 따른 균주의 CML 저감 효능을 하기 표에 기재된 다른 균주 및 상용화되고 있는 프로바이오틱스 제품을 대조군으로 사용하여 분석하였다. 하기 표에서 대조군으로 사용된 다른 균주들은 한국식품연구원 전통식품 미생물 균주은행으로부터 구입한 것을 사용하였고, 프로바이오틱스 제품은 각 시중에서 판매되고 있는 것을 구입하여 사용하였으며, 프로바이오틱스 제품은 도 1에 나타내었다. 또한, 하기 실험에 사용된 균주의 배양을 위한 배지들은 Difco사에서 구매하였으며, 유산균주의 배양을 위해 Lactobacilli MRS agar와 Lactobacilli MRS broth를 사용하였고, 바실러스속 균주의 배양배지로 TSA(tryptic soy agar)와 TSB(tryptic soy broth)를 사용하였다. 유산균 및 바실러스균의 CML 저감을 위한 본 배양에는 M9 minimal medium(MB cell)를 사용하였는데, M9 배지를 제조시 glucose 2g/L, CaCl2 0.015g/L, MgSO4 0.5g/L를 첨가하여 사용하였다. 구체적으로 본 배양은 바실러스균 콜로니를 TSA에 도말하여 37℃ 배양기에서 48시간 1차 배양한 후, 이를 다시 TSB 10 ml에 접종하여 37℃ 배양기에서 48시간 2차 배양한 후 CML(8.24 ug/mL)이 함유된 M9 배지 상에서 24시간 본 배양하였다.The present inventors analyzed the CML reduction efficacy of the strain according to the present invention using the other strains shown in the following table and commercially available probiotic products as a control group. Other strains used as a control group in the following table were purchased from Korea Food Research Institute's Traditional Food Microorganism Bank, and probiotic products were purchased from the market, and the probiotic products were shown in FIG. Lactobacilli MRS agar and Lactobacilli MRS broth were used for culture of lactic acid bacteria. TSA (tryptic soy agar) was used as a culture medium for Bacillus sp. Strain, TSB (tryptic soy broth) was used. The culture is M9 minimal medium (MB cell) were used to use was added to M9 in the manufacture of medium glucose 2g / L, CaCl 2 0.015g / L, MgSO 4 0.5g / L for CML reduction of lactic acid bacteria and Bacillus bacteria Respectively. Specifically, Bacillus colony was cultured in TSA at 37 ° C for 48 hours, then cultured in TSB (10 ml), cultured in a 37 ° C incubator for 48 hours, and then cultured in CML (8.24 ug / ml ) For 24 hours on M9 medium.
<2-3> <2-3> CMLCML 함량분석 Content analysis
유산균 및 프로바이오틱스 제품을 CML이 함유된 배양액에서 24시간 본 배양시킨 후 Nε-(carboxymethyl)lysine (CML)의 변화량을 CML ELISA kit (CircuLex, Ina, Nagano, Japan)를 이용하여 측정하였다. CML-BSA로 사전 코팅된 96 well에 상등액 또는 표준 시료와 anti-CML-adduct monoclonal antibody를 첨가하여 실온에서 1시간 반응시켰다. 세척버퍼로 4회 세척한 후 HRP conjugated detection antibody 100 μl를 첨가하여 1시간 반응시킨 후 세척버퍼로 4회 세척하고, 기질 함유 용액 100 μl를 첨가하여 20분간 빛을 차단한 조건 하에서 반응 시킨 다음, 정지용액 100 μl를 첨가하고 마이크로 플레이트 리더기를 이용하여 450 nm에서 흡광도를 측정하였다.Lactobacillus and probiotic products were cultured in culture medium containing CML for 24 hours. The changes of N ε - (carboxymethyl) lysine (CML) were measured by CML ELISA kit (CircuLex, Ina, Nagano, Japan). The supernatant or standard sample and anti-CML-adduct monoclonal antibody were added to 96 wells precoated with CML-BSA and reacted at room temperature for 1 hour. After washing four times with washing buffer, 100 μl of HRP conjugated detection antibody was added and reacted for 1 hour. Then, the plate was washed 4 times with washing buffer, 100 μl of substrate-containing solution was added, 100 μl of stop solution was added and the absorbance was measured at 450 nm using a microplate reader.
상기 표 2에서 음성대조군(CON; control)은 유산균을 전혀 첨가하지 않은 상기 <2-1>의 마이얄 반응으로 측정된 CML이 8.24 ug/mL 함량으로 포함된 군을 사용한 것이며, 음성대조군을 CML 함량 100%로 기준하여 측정된 결과들이다.The negative control (CON; control) in Table 2 was a group containing CML (8.24 ug / mL) as measured by the Maillard reaction of the above <2-1> in which no lactic acid bacteria were added, The results are based on 100% content.
분석결과, 상기 실시예 <2-1>에서 CML 저감 효능을 분석하기 위해 준비한 CML이 8.24 ug/mL 농도로 함유된 카제인과 락토스의 마이얄 반응 생성물을 기준으로 배양액에 상기 표 1 및 도 1의 각각의 유산균들을 접종한 후, CML 함량을 측정한 결과, 다른 대조군들 대비 본원발명의 균주를 접종한 군이 현저하게 CML 함량이 감소되어 있는 것으로 나타났는데, 특히 동일 속에 속하는 바실러스속 균주인 g12에 비해 본 발명의 균주가 약 2.4배 더 우수한 저감 효과를 보이는 것으로 나타났고, 엔테로코커스 및 락토바실러스 속 균주에 비해서는 최소 3.8배 이상 더 우수한 저감 효과를 보였으며, 시판중인 프로바이오틱스 제품에 비해서도 본 발명의 균주가 더 우수한 최종당화산물의 저감 효과를 보이는 것으로 나타났다(도 2 내지 도 3 참조 및 상기 표 2 참조).As a result of the analysis, CML prepared for analyzing the CML abatement efficacy in Example <2-1> was added to the culture solution based on the myial reaction product of casein and lactose contained at a concentration of 8.24 ug / mL, As a result of measuring the CML content after inoculation of each of the lactic acid bacteria, the CML content of the group inoculated with the strain of the present invention was significantly decreased compared to the other control groups. In particular, the CML content of the same strain belonging to the genus Bacillus, g12 Compared to the strain of Enterococcus and Lactobacillus sp., And showed a reduction effect of at least 3.8 times higher than that of the Enterococcus and Lactobacillus sp. Strains. In addition to the commercially available probiotic products, The strain showed a more excellent effect of reducing the final glycation end product (see Figs. 2 to 3 and Table 2 above).
<< 실시예Example 3> 3>
CMLCML 표준폼을Standard form 이용한 Used 바실러스Bacillus 서브틸리스Subtilis KF11 균주의 Of KF11 strain 최종당화산물The final glycation product 저감효능Abatement efficacy 검증 Verification
상기 실시예의 결과를 통해 본 발명자들은 본 발명의 바실러스 서브틸리스 KF11 균주가 종래 CML 저감 활성을 갖는 균주 및 시제품들에 비해 월등히 우수한 CML저감 효능이 있음을 확인하였다. 이에 CML 저감효능의 재검증을 위해 최종당화산물 중 가장 대표적인 Nε-(1-carboxymethyl)-L-lysine (CAS: 5746-04-3)을 Santa Cruz Biotechnology사에서 구매하여 이의 저감 활성을 다시 한번 분석하였다. 순도 99%의 CML 포준폼을 사용하였고, CML 저감 분석은 상기 실시예 2와 동일한 방법으로 분석하였다.The inventors of the present invention have confirmed that the Bacillus subtilis KF11 strain of the present invention has a far superior CML reducing efficacy to strains and prototypes having a conventional CML abatement activity. In order to re-verification of CML reduced efficacy advanced glycation end products of the most representative N ε - (1-carboxymethyl) -L-lysine (CAS: 5746-04-3) a purchase from Santa Cruz Biotechnology Inc. Once again, the reduction activity thereof Respectively. A CML formulation with a purity of 99% was used and the CML abatement analysis was analyzed in the same manner as in Example 2 above.
분석 결과, 도 4에 나타낸 바와 같이, 본 발명의 균주 처리 시, 100%의 CML의 함량이 약 28%로 감소되어 있는 것으로 나타나, 약 72%의 높은 CML 저감활성을 보이고 있음을 확인하였다.As a result, as shown in FIG. 4, when the strain of the present invention was treated with 100% CML, the CML content was reduced to about 28%, indicating that CML reduction activity was about 72%.
이상의 결과를 통해, 본 발명자들은 본 발명에서 분리 및 동정한 신균주인 바실러스 서브틸리스 KF11 균주가 최종당화산물을 효과적으로 저감시킬 수 있는 활성이 있음을 확인함으로써, 최종당화산물로 유발될 수 있는 각종 질환에 대한 의약품 제조 및 기능성 식품 제조에 유용하게 사용될 수 있음을 알 수 있었다.From the above results, the present inventors confirmed that the Bacillus subtilis KF11 strain, which is a new strain isolated and identified in the present invention, has an activity to effectively reduce the final glycation products, and thus can produce various kinds of glycoproteins It can be used for the manufacture of medicines for diseases and functional foods.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.
<110> Korea Food Research Institute <120> Novel Bacillus subtilis strain having advanced glycation end product inhibitory activity effects and use of the same <130> NPDC60269 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 1459 <212> DNA <213> Artificial Sequence <220> <223> KCCM 11981P 16s rDNA sequence <400> 1 accccaatca tctgtcccac cttcggcggc tggctcctaa aaggttacct caccgacttc 60 gggtgttaca aactctcgtg gtgtgacggg cggtgtgtac aaggcccggg aacgtattca 120 ccgcggcatg ctgatccgcg attactagcg attccagctt cacgcagtcg agttgcagac 180 tgcgatccga actgagaaca gatttgtggg attggcttaa cctcgcggtt tcgctgccct 240 ttgttctgtc cattgtagca cgtgtgtagc ccaggtcata aggggcatga tgatttgacg 300 tcatccccac cttcctccgg tttgtcaccg gcagtcacct tagagtgccc aactgaatgc 360 tggcaactaa gatcaagggt tgcgctcgtt gcgggactta acccaacatc tcacgacacg 420 agctgacgac aaccatgcac cacctgtcac tctgcccccg aaggggacgt cctatctcta 480 ggattgtcag aggatgtcaa gacctggtaa ggttcttcgc gttgcttcga attaaaccac 540 atgctccacc gcttgtgcgg gcccccgtca attcctttga gtttcagtct tgcgaccgta 600 ctccccaggc ggagtgctta atgcgttagc tgcagcacta aggggcggaa accccctaac 660 acttagcact catcgtttac ggcgtggact accagggtat ctaatcctgt tcgctcccca 720 cgctttcgct cctcagcgtc agttacagac cagagagtcg ccttcgccac tggtgttcct 780 ccacatctct acgcatttca ccgctacacg tggaattcca ctctcctctt ctgcactcaa 840 gttccccagt ttccaatgac cctccccggt tgagccgggg gctttcacat cagacttaag 900 aaaccgcctg cgagcccttt acgcccaata attccggaca acgcttgcca cctacgtatt 960 accgcggctg ctggcacgta gttagccgtg gctttctggt taggtaccgt caaggtaccg 1020 ccctattcga acggtacttg ttcttcccta acaacagagc tttacgatcc gaaaaccttc 1080 atcactcacg cggcgttgct ccgtcagact ttcgtccatt gcggaagatt ccctactgct 1140 gcctcccgta ggagtctggg ccgtgtctca gtcccagtgt ggccgatcac cctctcaggt 1200 cggctacgca tcgttgcctt ggtgagccgt tacctcacca actagctaat gcgccgcggg 1260 tccatctgta agtggtagcc gaagccacct tttatgtttg aaccatgcgg ttcaaacaac 1320 catccggtat tagccccggt ttcccggagt tatcccagtc ttacaggcag gttacccacg 1380 tgttactcac ccgtccgccg ctaacatcag ggagcaagct cccatctgtc cgctcgactt 1440 gcatgtatta ggcacgccg 1459 <110> Korea Food Research Institute <120> Novel Bacillus subtilis strain having advanced glycation end product inhibitory activity effects and use of the same <130> NPDC60269 <160> 1 <170> KoPatentin 3.0 <210> 1 <211> 1459 <212> DNA <213> Artificial Sequence <220> <223> KCCM 11981P 16s rDNA sequence <400> 1 cccgactc gggtgttaca aactctcgtg gtgtgacggg cggtgtgtac aaggcccggg aacgtattca 120 ccgcggcatg ctgatccgcg attactagcg attccagctt cacgcagtcg agttgcagac 180 tgcgatccga actgagaaca gatttgtggg attggcttaa cctcgcggtt tcgctgccct 240 ttgttctgtc cattgtagca cgtgtgtagc ccaggtcata aggggcatga tgatttgacg 300 tcatccccac cttcctccgg tttgtcaccg gcagtcacct tagagtgccc aactgaatgc 360 tggcaactaa gatcaagggt tgcgctcgtt gcgggactta acccaacatc tcacgacacg 420 agctgacgac aaccatgcac cacctgtcac tctgcccccg aaggggacgt cctatctcta 480 ggattgtcag aggatgtcaa gacctggtaa ggttcttcgc gttgcttcga attaaaccac 540 atgctccacc gcttgtgcgg gcccccgtca attcctttga gtttcagtct tgcgaccgta 600 ctccccaggc ggagtgctta atgcgttagc tgcagcacta aggggcggaa accccctaac 660 acttagcact catcgtttac ggcgtggact accagggtat ctaatcctgt tcgctcccca 720 cgctttcgct cctcagcgtc agttacagac cagagagtcg ccttcgccac tggtgttcct 780 ccacatctct acgcatttca ccgctacacg tggaattcca ctctcctctt ctgcactcaa 840 gttccccagt ttccaatgac cctccccggt tgagccgggg gctttcacat cagacttaag 900 aaaccgcctg cgagcccttt acgcccaata attccggaca acgcttgcca cctacgtatt 960 accgcggctg ctggcacgta gttagccgtg gctttctggt taggtaccgt caaggtaccg 1020 ccctattcga acggtacttg ttcttcccta acaacagagc tttacgatcc gaaaaccttc 1080 atcactcacg cggcgttgct ccgtcagact ttcgtccatt gcggaagatt ccctactgct 1140 gcctcccgta ggagtctggg ccgtgtctca gtcccagtgt ggccgatcac cctctcaggt 1200 cggctacgca tcgttgcctt ggtgagccgt tacctcacca actagctaat gcgccgcggg 1260 tccatctgta agtggtagcc gaagccacct tttatgtttg aaccatgcgg ttcaaacaac 1320 catccggtat tagccccggt ttcccggagt tatcccagtc ttacaggcag gttacccacg 1380 tgttactcac ccgtccgccg ctaacatcag ggagcaagct cccatctgtc cgctcgactt 1440 gcatgtatta ggcacgccg 1459
Claims (11)
상기 조성물은 최종당화산물인 CML(N ε -(Carboxymethyl)-L-lysine)로 유발되는 질환인 당뇨병, 만성신장질환, 심장질환, 혈관질환, 당뇨병성 망막병증, 당뇨병성 신경병증, 당뇨병성 백내장 및 당뇨병성 신증으로 이루어진 군 중에서 선택되는 질환을 예방 또는 개선할 수 있는 것을 특징으로 하는 식품 조성물.The method of claim 3,
The composition may be used for the treatment and / or prophylaxis of diseases which are caused by CML (N 竜 - (Carboxymethyl) -L-lysine), a final glycation product, such as diabetes, chronic kidney disease, heart disease, vascular disease, diabetic retinopathy, diabetic neuropathy, And diabetic nephropathy can be prevented or ameliorated.
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| KR1020170044949A KR101841023B1 (en) | 2017-04-06 | 2017-04-06 | Novel Bacillus subtilis strain having advanced glycation end product inhibitory activity effects and use of the same |
| EP18781871.1A EP3611252A4 (en) | 2017-04-06 | 2018-04-06 | Novel strain having activity of reducing advanced glycation end products and use thereof |
| CN201880023333.2A CN110506106A (en) | 2017-04-06 | 2018-04-06 | With the active novel strain and application thereof for reducing advanced glycation end products |
| US16/500,913 US20200270709A1 (en) | 2017-04-06 | 2018-04-06 | Novel Strain Having Activity Of Reducing Advanced Glycation End Products And Use Thereof |
| PCT/KR2018/004076 WO2018186710A1 (en) | 2017-04-06 | 2018-04-06 | Novel strain having activity of reducing advanced glycation end products and use thereof |
| BR112019021036-9A BR112019021036A2 (en) | 2017-04-06 | 2018-04-06 | NEW CEPA WITH ACTIVITY TO REDUCE FINAL PRODUCTS OF ADVANCED GYM, COMPOSITION, FERMENTED PRODUCT, METHOD TO INHIBIT FINAL PRODUCTS OF ADVANCED GAS |
| AU2018249789A AU2018249789B2 (en) | 2017-04-06 | 2018-04-06 | Novel strain having activity of reducing advanced glycation end products and use thereof |
| CA3058383A CA3058383C (en) | 2017-04-06 | 2018-04-06 | Novel strain having activity of reducing advanced glycation end products and use thereof |
| JP2020504082A JP6880307B2 (en) | 2017-04-06 | 2018-04-06 | New strains with advanced glycation end product reducing activity and their uses |
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| KR20190111839A (en) * | 2018-03-22 | 2019-10-02 | 한국식품연구원 | Composition for inhibiting non-fluorescent advanced glycation end products and use of the same |
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