KR20160022425A - Compositions for Preventing, Improving, or Treating Liver Disorders Comprising Substances of Fermented Soy Bean Using Bacillus subtilis subsp. inaquosorum as an Active Ingredient - Google Patents
Compositions for Preventing, Improving, or Treating Liver Disorders Comprising Substances of Fermented Soy Bean Using Bacillus subtilis subsp. inaquosorum as an Active Ingredient Download PDFInfo
- Publication number
- KR20160022425A KR20160022425A KR1020140107611A KR20140107611A KR20160022425A KR 20160022425 A KR20160022425 A KR 20160022425A KR 1020140107611 A KR1020140107611 A KR 1020140107611A KR 20140107611 A KR20140107611 A KR 20140107611A KR 20160022425 A KR20160022425 A KR 20160022425A
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- South Korea
- Prior art keywords
- subsp
- bacillus subtilis
- present
- inactosum
- composition
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Abstract
Description
본 발명은 바실러스 서브틸리스 인아쿠오소럼 아종(Bacillus subtilis subsp. inaquosorum)에 의한 콩 발효물을 유효성분으로 포함하는 간 질환 예방, 개선 또는 치료용 조성물에 관한 것이다.
The present invention is Bacillus subtilis inah Kuo soreom subspecies (Bacillus subtilis subsp. inaquosorum ) as an active ingredient. The present invention also relates to a composition for preventing, ameliorating or treating liver disease.
2011년 우리나라 주요 사망원인 별 사망률 추이 통계에 따르면 간 질환 관련 사망률은 10만명 당 약 13.5명 정도로 전체사망자 중 약 2.6%를 차지하며 이는 사망원인 8위에 해당하는 것으로 나타났다(Statistics Korea, 2012). 간 질환은 다양한 원인에 의해 간이 손상을 받기 시작하면 간섬유화, 간경화를 거쳐 간암으로 진행되는 것으로 알려져있다. 반복되는 간손상으로 인해 간성상세포가 자극을 받아 활성화되면서 근섬유모세포와 유사한 활성상태의 세포로 전환이 일어나며, 이때 알파-평활근액틴(α-SMA: α-smooth muscle actin)이 발현되어 교원질(collagen)과 피브로넥틴(fibronectin)의 합성을 촉진시키는 것으로 알려져있다(Mcgee & Patrick, 1972). 그러나 만성적인 간 손상은 반복적인 섬유용해(fibrolysis)와 간 손상복구를 위한 섬유생성(fibrogenesis) 과정 간의 밸런스가 무너져 세포 외 기질(ECM: Extracellular matrix)이 이상증식되는 간섬유증으로 진행된다. 정상간의 교원질은 전체무게의 약 0.5%이나, 간경변에서는 10배 이상 증가하며 간 섬유증 역시 간 내 교원질 증가가 원인인 것으로 알려져있다(Lee, 2006). According to the statistics of death rate by major causes of death in 2011, the mortality rate related to liver disease is about 13.5 per 100,000 people, accounting for about 2.6% of all deaths, which is the 8th cause of death (Statistics Korea, 2012). Liver disease is known to progress to liver cancer after liver fibrosis and cirrhosis when liver damage starts to be caused by various causes. The liver is damaged by repeated hepatic injury and is activated by stimulation of the hepatic stellate cells. The α-smooth muscle actin (α-SMA) is expressed in the collagen, And fibronectin synthesis (Mcgee & Patrick, 1972). However, chronic hepatic damage progresses to liver fibrosis where the balance between repetitive fibrolysis and fibrogenesis processes for repairing liver damage breaks down and the extracellular matrix (ECM) is abnormally proliferated. It is known that the amount of collagen in normal liver is about 0.5% of the total weight, but in liver cirrhosis it increases more than 10 times, and liver fibrosis is also caused by increase of intra-liver collagen (Lee, 2006).
간 질환의 종착역 격인 간암에 사용되는 의약품은 현재 바이엘사의 넥사바가 거의 유일한데, 이 또한 일본에서 간부전과 간성뇌증 등의 부작용을 일으킨다는 보고가 있으며 임상시험에서 나온 결과는 치료가 아닌 생존기간의 연장(약 ~9개월)에 중점을 두고 있다고 알려져 있다(Josep et al., 2008). 이로 인해 간 질환 초기단계에 적용가능한 간보호 기능성 물질 발굴에 대한 학계와 의약업계의 노력이 계속되고 있으며 현재는 엉겅퀴과에서 분리된 실리마린(silymarin)이 간보호 작용을 하는 기능성 물질로 알려져 항바이러스제와 같이 치료에 사용되고 있다. 현재까지 간보호 기능성을 가진것으로 밝혀진 식품은 강황(curcumin), 벌꿀(CAPE, caffeic acid phenethyl ester), 브로콜리(sulphoraphane) 및 와사비(6-HITC, 6(methylsulfiny) hexylisothiocyanate) 등이 있으나(Surh, 2003), 간섬유화나 간경화를 효과적으로 저해하는 물질은 아직 개발되지 못했다. 최근에는 국내외적으로 의약품의 부작용과 식품의 안전성을 절충시킨 대체의학에 대한 관심이 증폭되면서 식품에서 그 해결책을 찾으려는 연구가 점점 늘어나고 있다(Tanaka et al., 2009; Hsu et al., 2009). 최근에는 천연물 의약품(herbal medicine)에서 간섬유화 치료 소재를 찾으려는 연구가 진행되고 있으며(Zou et al., 2008), 그 중 식물에서 추출한 제니스테인(genistein)의 항산화 효과와 연관된 약리학적 연구(Hsieh et al., 2010; Ji et al., 2011; Valsecchi et al., 2011)와 사염화탄소 투여에 의한 급성 간손상에 대한 간보호 효과(Kuzu et al., 2007) 및 HepG2의 성장 저해에 의한 괴사 유도(Chodon et al., 2007) 등의 연구결과가 다수 보고되고 있다. 특히, 피막이(Hydrocotyle sibthorpioides)로부터 추출한 제니스테인을 알코올과 같이 장기간 식이 섭취시킨 랫트 실험에서 간 효소와 관련 염증 매개인자의 수치을 감소시켰으며, 간조직 내에서 콜라겐의 퇴적과 간섬유화의 바이오마커들을 감소시키는 것으로 보고되었다(Quanfang et al., 2013).There are reports that Bacillus Nexavar is the only drug currently used for hepatocellular carcinoma, which is the terminal region of liver disease, and that it also causes side effects such as hepatic insufficiency and hepatic encephalopathy in Japan. The results of clinical trials show that the prolongation of survival (About ~ 9 months) (Josep et al., 2008). As a result, the academia and the pharmaceutical industry have been working on the development of a liver-protecting functional substance that can be applied in the early stages of liver disease. Silymarin, which is isolated from thistle, is now known as a liver-protecting functional substance. Has been used in therapy. The foods that have been shown to have liver protective function until now include curcumin, caffeic acid phenethyl ester, sulphoraphane and 6-HITC, hexylisothiocyanate (Surh, 2003 ), Substances that effectively inhibit liver fibrosis and cirrhosis have not yet been developed. In recent years, there has been an increasing number of researchers seeking to find solutions in foods as the interest in alternative medicine, which compromises the adverse effects of medicines and the safety of foods, has increased in domestic and overseas (Tanaka et al., 2009; Hsu et al., 2009) . In recent years, studies have been carried out to find a therapeutic agent for hepatic fibrosis in herbal medicine (Zou et al., 2008), a pharmacological study related to the antioxidative effect of plant-derived genistein (Hsieh et (Kuzu et al., 2007) and necrosis induced by growth inhibition of HepG2 (Kuzu et al., 2010; Ji et al., 2011; Valsecchi et al., 2011) Chodon et al., 2007) have been reported. Particularly, in a rat experiment in which long-term dietary intake of genistein extracted from hydrocotyle sibthorpioides was reduced, the levels of hepatic enzymes and inflammatory mediators were decreased, and collagen deposition and hepatic fibrosis biomarkers were reduced in liver tissues (Quanfang et al., 2013).
우리나라의 전통 발효식품은 오랜역사를 가진 안전성을 대표하는 식품의 한 형태로 특히 된장은 원료인 대두로부터 전이된 다이제인(daidzein), 제니스테인(genistein)과 같은 아이소플라본(isoflavones), 그리고 토코페롤(tocopherol) 및 페놀산(phenolic acids) 등의 성분으로 인한 항산화 활성을 가지고 있는 것으로 보고되었다(Ahn et al., 2012). 이외에도 된장은 항비만효과(Bas et al., 2013; Kwon et al., 2006), 항당뇨활성(Lee et al., 2012) 및 항암활성(Lim et al., 2004) 등의 기능성이 있다고 보고되고 있지만, 간 질환과 관련된 기능성에 대한 연구는 미비한 실정이다. 이는 국내 식문화에서 차지하는 된장의 비중과 기능성 일상식(daily food)으로서의 역할을 고려할 때 연구되어질 가치가 충분한 것으로 여겨진다.
Traditional fermented foods in Korea are a type of food that represents safety with a long history. In particular, soybean paste contains isoflavones such as daidzein, genistein, and tocopherol, ), And phenolic acids (Ahn et al., 2012). In addition, miso has been reported to have functional properties such as anti-obesity effect (Bas et al., 2013; Kwon et al., 2006), antidiabetic activity (Lee et al., 2012) and anticancer activity (Lim et al., 2004) However, there are few studies on the function related to liver disease. This is considered to be worthy of study considering the role of soybean paste in domestic food culture and its role as a daily food.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
본 발명자들은, α-SMA 발현을 억제함으로써 간 섬유화를 억제시킬 수 있는 방법을 개발하고자 예의 연구 노력하였다. 그 결과, 전통발효식품인 메주로부터 콩 발효 활성을 가지는 신규한 바실러스 서브틸리스 인아쿠오소럼 아종(Bacillus subtilis subsp . inaquosorum) FA0718(기탁번호 KCCM 11280P) 균주를 선별하고, 상기 균주에 의한 콩 발효물을 처리한 경우 대조군 및 시판 콩 발효물을 처리한 경우보다 α-SMA 발현억제율이 현저함을 발견한 바, 간 섬유화를 효과적으로 억제할 수 있다는 사실을 확인함으로써, 본 발명을 완성하게 되었다.The present inventors have made extensive efforts to develop a method capable of inhibiting liver fibrosis by inhibiting? -SMA expression. As a result, a novel strain of Bacillus subtilis subsp . Inaquosorum FA0718 (accession number KCCM 11280P) having soybean fermentation activity was selected from meju, which is a traditional fermented food, and a soybean fermentation product The present inventors completed the present invention by confirming that the inhibition rate of? -SMA expression is remarkably higher than that in the case of treatment with the control and commercially available fermented soybean, and that the fibrosis of the liver can be effectively inhibited.
따라서 본 발명의 목적은 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물을 유효성분으로 포함하는 간 질환 예방, 개선 또는 치료용 조성물을 제공하는 데 있다.Accordingly, an object of the present invention is to provide a composition for prevention, improvement or treatment of liver disease comprising soybean fermented product of Bacillus subtilis inocosarum subsp. As an effective ingredient.
본 발명의 다른 목적은 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718(기탁번호 KCCM 11280P) 균주을 포함하는 콩 발효용 조성물을 제공하는 데 있다.Another object of the present invention is to provide a composition for soybean fermentation comprising a strain of Bacillus subtilis inactosum subsp. FA0718 (Accession No. KCCM 11280P).
본 발명의 또 다른 목적은 콩 발효 활성을 갖는 신규한 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718(기탁번호 KCCM 11280P) 균주를 제공하는 데 있다.
It is still another object of the present invention to provide a novel strain of Bacillus subtilis inactosum subsp. FA0718 (accession number KCCM 11280P) having soybean fermentation activity.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
본 발명의 일 양태에 따르면, 본 발명은 바실러스 서브틸리스 인아쿠오소럼 아종(Bacillus subtilis subsp . inaquosorum)에 의한 콩 발효물을 유효성분으로 포함하는 간 질환 예방, 개선 또는 치료용 조성물을 제공한다.
According to one aspect of the present invention, the present invention relates to a method for the treatment of Bacillus subtilis inactosum subsp. subtilis subsp . The present invention also provides a composition for preventing, ameliorating or treating liver disease comprising soybean fermented product by inaquosorum as an active ingredient.
본 발명자들은, α-SMA 발현을 억제함으로써 간 섬유화를 억제시킬 수 있는 방법을 개발하고자 예의 연구 노력하였다. 그 결과, 전통발효식품인 메주로부터 콩 발효 활성을 가지는 신규한 바실러스 서브틸리스 인아쿠오소럼 아종(Bacillus subtilis subsp . inaquosorum) FA0718(기탁번호 KCCM 11280P) 균주를 선별하고, 상기 균주에 의한 콩 발효물을 처리한 경우 대조군 및 시판 콩 발효물을 처리한 경우보다 α-SMA 발현억제율이 현저함을 발견한 바, 간 섬유화를 효과적으로 억제할 수 있다는 사실을 확인하였다.The present inventors have made extensive efforts to develop a method capable of inhibiting liver fibrosis by inhibiting? -SMA expression. As a result, a novel strain of Bacillus subtilis subsp . Inaquosorum FA0718 (accession number KCCM 11280P) having soybean fermentation activity was selected from meju, which is a traditional fermented food, and a soybean fermentation product , The inhibition rate of α-SMA expression was remarkably higher than that of the control and commercial soybean fermented product, and thus it was confirmed that the inhibition of liver fibrosis can be effectively inhibited.
따라서 본 발명은 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물을 유효성분으로 포함하는 간 질환 예방, 개선 또는 치료용 조성물에 관한 것이다.Accordingly, the present invention relates to a composition for preventing, ameliorating or treating liver disease comprising soybean fermented product of Bacillus subtilis inocosarum subsp. As an effective ingredient.
본 발명에서 이용되는 콩의 종류는 특별히 한정되지 않으며, 당업계에서 일반적으로 사용되는 어떠한 콩(soybean)도 포함한다. 본 발명의 일 구현예에 따르면, 본 발명의 콩은 대두이다.The kind of soybeans used in the present invention is not particularly limited and includes any soybean generally used in the art. According to one embodiment of the present invention, the soybeans of the present invention are soybeans.
본 명세서에서 용어 “발효”는 미생물이 자신이 가지고 있거나 생산하는 효소를 이용해 유기물을 분해시키는 과정을 의미하고, 당업계의 어떠한 발효 방법도 포함한다.As used herein, the term " fermentation " means a process in which a microorganism decomposes an organic substance using an enzyme possessed or produced by the microorganism, and includes any fermentation method in the art.
본 발명의 용어 “콩 발효물”은 당업계에서 콩의 발효에 의하여 생성되는 모든 물질(예컨대, 메주, 간장, 된장, 고추장, 청국장 및 낫토 등)을 포함하고, 본 발명의 일 구현예에 따르면 된장, 청국장 또는 낫토이며, 본 발명의 특정 구현예에 따르면 청국장이다.The term " soybean fermented product " of the present invention includes all substances (e.g., meju, soy sauce, miso, kochujang, chongkukjang and natto, etc.) produced by fermentation of soybean in the art and according to one embodiment of the present invention Soybean paste, soybean paste, chongkukjang or natto, according to a specific embodiment of the present invention.
본 발명의 콩 발효물은 당업계의 어떠한 종류의 콩 발효물도 포함한다. 본 발명의 일 구현예에 따르면, 본 발명에서 이용되는 콩 발효물질은 콩 발효물 추출물, 콩 발효물 엑기스, 콩 발효물 농축액 또는 콩 발효물 분말이고, 본 발명의 특정 구현예에 따르면, 콩 발효물 추출물이다. The soybean fermentation product of the present invention includes soybean fermentation products of any kind in the art. According to one embodiment of the present invention, the soybean fermentation substance used in the present invention is soybean fermentation water extract, soybean fermentation product extract, soybean fermentation product concentrate or soybean fermentation product powder. According to a specific embodiment of the present invention, It is water extract.
본 발명의 조성물에서 이용되는 콩 발효물 추출물은 콩 발효물에 추출용매를 처리하여 수득하는 경우에는, 다양한 추출용매가 이용될 수 있다. 본 발명의 일 구현예에 따르면, 본 발명에서 이용되는 추출용매는 극성 용매 또는 비극성 용매를 이용할 수 있다. 상기 극성 용매로서 적합한 것은, (i) 물, (ii) 알코올(예컨대, 메탄올, 에탄올, 프로판올, 부탄올, 노말-프로판올, 이소-프로판올, 노말-부탄올, 1-펜탄올, 2-부톡시에탄올 및 에틸렌글리콜), (iii) 아세트산, (iv) DMFO(dimethyl-formamide) 또는 (v) DMSO(dimethyl sulfoxide)를 포함한다. 상기 비극성 용매로서 적합한 것은, 아세톤, 아세토나이트릴, 에틸 아세테이트, 메틸 아세테이트, 플루오로알칸, 펜탄, 헥산, 2,2,4-트리메틸펜탄, 데칸, 사이클로헥산, 사이클로펜탄, 디이소부틸렌, 1-펜텐, 1-클로로부탄, 1-클로로펜탄, o-자일렌, 디이소프로필 에테르, 2-클로로프로판, 톨루엔, 1-클로로프로판, 클로로벤젠, 벤젠, 디에틸 에테르, 디에틸 설파이드, 클로로포름, 디클로로메탄, 1,2-디클로로에탄, 어닐린, 디에틸아민, 에테르, 사염화탄소 또는 THF를 포함한다.The soybean fermentation extract used in the composition of the present invention can be obtained by treating various fermented soybean extracts with various extraction solvents. According to one embodiment of the present invention, the extraction solvent used in the present invention may be a polar solvent or a non-polar solvent. Suitable as the polar solvent are (i) water, (ii) alcohols such as methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, Ethylene glycol), (iii) acetic acid, (iv) dimethyl-formamide (DMFO) or (v) dimethyl sulfoxide (DMSO). Suitable examples of the nonpolar solvent include acetone, acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclohexane, cyclopentane, diisobutylene, Chlorophenyl, 1-chlorobutane, o-xylene, diisopropyl ether, 2-chloropropane, toluene, 1-chloropropane, chlorobenzene, benzene, diethyl ether, diethylsulfide, chloroform, Dichloromethane, 1,2-dichloroethane, aniline, diethylamine, ether, carbon tetrachloride or THF.
본 발명의 다른 구현예에 따르면, 본 발명에서 이용되는 추출용매는 (a) 물, (b) 탄소수 1-4의 무수 또는 함수 저급 알코올(메탄올, 에탄올, 프로판올, 부탄올 등), (c) 상기 저급 알코올과 물과의 혼합용매, (d) 아세톤, (e) 에틸 아세테이트, (f) 클로로포름, (g) 부틸아세테이트, (h) 1,3-부틸렌글리콜, (i) 헥산 또는 (j) 디에틸에테르를 포함한다. 본 발명의 어떠한 구현예에 따르면, 본 발명의 추출물은 물, 에탄올 또는 이의 조합을 콩 발효물에 처리하여 수득하고, 본 발명의 특정 구현예에 따르면, 물을 처리하여 수득한다.According to another embodiment of the present invention, the extraction solvent used in the present invention may be selected from the group consisting of (a) water, (b) an anhydrous or hydric alcohol having 1 to 4 carbon atoms (methanol, ethanol, propanol, butanol, (E) ethyl acetate, (f) chloroform, (g) butyl acetate, (h) 1,3-butylene glycol, (i) hexane, or (j) Diethyl ether. According to certain embodiments of the present invention, the extract of the present invention is obtained by treating water, ethanol or a combination thereof with soybean fermentation and, according to certain embodiments of the present invention, by treating water.
본 명세서에서 사용되는 용어 “추출물”은 당업계에서 조추출물(crude extract)로 통용되는 의미를 갖지만, 광의적으로는 추출물을 추가적으로 분획(fractionation)한 분획물도 포함한다. 즉, 콩 발효물은 상술한 추출용매를 이용하여 얻은 것뿐만 아니라, 여기에 정제과정을 추가적으로 적용하여 얻은 것도 포함한다. 예컨대, 상기 추출물을 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 얻은 분획, 다양한 크로마토그래피(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)에 의한 분리 등, 추가적으로 실시된 다양한 정제 방법을 통해 얻어진 분획도 본 발명의 콩 발효물에 포함되는 것이다.As used herein, the term " extract " has the meaning conventionally used in the art as a crude extract, but broadly it also includes fractions in which the extract is further fractionated. That is, not only the soybean fermentation product obtained by using the above-mentioned extraction solvent, but also the soybean fermentation product obtained by further applying the purification process thereto. For example, a fraction obtained by passing the above extract through an ultrafiltration membrane having a constant molecular weight cut-off value, and a separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity) The fraction obtained by the purification method is also included in the soybean fermentation product of the present invention.
본 발명에서 이용되는 콩 발효물은 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말 상태로 제조될 수 있다.The soybean fermentation product used in the present invention may be prepared in powder form by an additional process such as vacuum distillation and freeze-drying or spray-drying.
본 명세서에서 용어 “유효성분으로 포함하는”이란 하기의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물의 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다. 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 식품으로부터 분리한 미생물 균주 또는 천연발효물인바 과량 투여하여도 인체에 부작용이 없으므로 상기 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물이 본 발명의 조성물에 포함된 양적 상한은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.As used herein, the term " comprising as an active ingredient " is meant to include an amount sufficient to achieve the efficacy or activity of the soybean fermented product by the subspecies Bacillus subtilis inactosum subsp. Since the soybean fermented product of the Bacillus subtilis inactosum subsp. Of the present invention is a microorganism strain isolated from a food or a natural fermented product, there is no side effect on the human body even when administered in an excessive amount. Therefore, soybean fermentation by the subspecies of Bacillus subtilis inactosum subsp. The quantitative upper limit in which water is included in the composition of the present invention can be selected by a person skilled in the art within a suitable range.
본 발명의 일 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종은 바실러스 서브틸리스 인아쿠오소럼 아종(Bacillus subtilis subsp . inaquosorum) FA0718(기탁번호 KCCM 11280P) 균주이다.According to one embodiment of the present invention, Bacillus subtilis of the present invention inah Kuo soreom subspecies Bacillus subtilis inah Kuo soreom subspecies (Bacillus subtilis subsp . inaquosorum ) FA0718 (Accession No. KCCM 11280P).
본 발명의 일 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종은 메주로부터 분리된 균주이다.According to one embodiment of the present invention, the Bacillus subtilis inactosum subsp. Of the present invention is a strain isolated from meju.
본 발명의 주요한 특징은 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물이 α-SMA 발현억제활성을 가진다. 하기 실시예에서 입증한 바와 같이 시중에서 판매하는 일반 콩 발효물은 α-SMA 발현억제활성을 갖지 않는다. 상기 일반 콩 발효물은 공지된 청국장 발효 균주(예컨대, 바실러스 서브틸리스(Bacillus subtilis), 바실러스 리체니포미스(Bacillus licheniformis) 및 바실러스 메가테리움(Bacillus megaterium) 등)에 의한 콩 발효물이다.The main feature of the present invention is that the soybean fermented product of Bacillus subtilis inocosarum subsp. Of the present invention has an α-SMA inhibitory activity. As demonstrated in the following examples, commercially available soybean fermented products do not have an? -SMA expression inhibiting activity. The common soybean fermented product is a known fermented soybean fermentation strain (for example, Bacillus subtilis subtilis), Bacillus piece nipo Miss (Bacillus licheniformis ) and Bacillus megaterium megaterium ) and the like.
본 발명의 일 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 대조군에 대하여 α-SMA 발현을 10-90% 억제시킨다. 본 발명의 다른 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 대조군에 대하여 α-SMA 발현을 10-80%, 15-80% 또는 15-70% 억제시킨다. 본 발명의 다른 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 대조군에 대하여 α-SMA 발현을 10-70% 억제시킨다. 본 발명의 다른 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 대조군에 대하여 α-SMA 발현을 30-90%, 40-90%, 50-90%, 50-80%, 50-75% 또는 55-75% 억제시킨다. 본 발명의 다른 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 대조군에 대하여 α-SMA 발현을 40-80%, 40-70%, 50-70% 또는 55-70% 억제시킨다. 본 발명의 다른 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 대조군에 대하여 α-SMA 발현을 60-90%, 60-80%, 60-75%, 65-75% 또는 65-70% 억제시킨다. According to one embodiment of the present invention, the soybean fermented by Bacillus subtilis inactosum subsp. Of the present invention inhibits? -SMA expression by 10-90% in the control group. According to another embodiment of the present invention, the soybean fermented by Bacillus subtilis inactosum subsp. Of the present invention inhibits? -SMA expression by 10-80%, 15-80% or 15-70% against the control group . According to another embodiment of the present invention, the soybean fermented by Bacillus subtilis inactosum subsp. Of the present invention inhibits? -SMA expression by 10-70% against the control group. According to another embodiment of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention can inhibit? -SMA expression by 30-90%, 40-90%, 50-90%, 50 -80%, 50-75%, or 55-75%. According to another embodiment of the present invention, the soybean fermented product of the Bacillus subtilis inactosum subsp. Of the present invention can inhibit? -SMA expression by 40-80%, 40-70%, 50-70% or 55 -70% inhibition. According to another embodiment of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention has a 60-90%, 60-80%, 60-75%, 65 -75% or 65-70%.
본 발명의 일 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 농도가 20-500 μg/mL이다. 본 발명의 다른 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 농도가 30-500, 40-500, 45-500, 45-400, 45-300, 45-250, 45-220 또는 50-200 μg/mL이다. 본 발명의 다른 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 농도가 30-400, 40-400, 40-300, 40-250 또는 40-220 μg/mL이다. 본 발명의 다른 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 농도가 70-500, 70-400, 70-300, 70-250 또는 70-220 μg/mL이다. 본 발명의 다른 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 농도가 80-500, 80-400, 80-300, 80-250 또는 80-220 μg/mL이다. 본 발명의 어떠한 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 농도가 90-500, 90-400, 90-300, 90-250 또는 90-220 μg/mL이다. 본 발명의 어떠한 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 농도가 50-200, 70-200, 70-150, 90-150 또는 90-120 μg/mL이다. 본 발명의 특정 구현예에 따르면, 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 농도가 100-200 μg/mL이다.According to one embodiment of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention has a concentration of 20-500 μg / mL. According to another embodiment of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention has a concentration of 30-500, 40-500, 45-500, 45-400, 45-300, 45- 250, 45-220, or 50-200 μg / mL. According to another embodiment of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention has a concentration of 30-400, 40-400, 40-300, 40-250 or 40-220 μg / mL to be. According to another embodiment of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention has a concentration of 70-500, 70-400, 70-300, 70-250 or 70-220 μg / mL to be. According to another embodiment of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention has a concentration of 80-500, 80-400, 80-300, 80-250 or 80-220 μg / mL to be. According to some embodiments of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention has a concentration of 90-500, 90-400, 90-300, 90-250 or 90-220 μg / mL to be. According to some embodiments of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention has a concentration of 50-200, 70-200, 70-150, 90-150 or 90-120 μg / mL to be. According to a specific embodiment of the present invention, the soybean fermented product of Bacillus subtilis inactosum subsp. Of the present invention has a concentration of 100-200 μg / mL.
본 발명에서, 상기 “간 질환”은 급성 간 질환, 만성 간 질환 또는 유전적 간 기능 손상 등을 포함하는 것으로, 구체적으로 간염, C형 간염(hepatitis C), 육종증, 약물 알레르기, 지방간, 알코올성 간 질환, 간암, 간경변증, 임신중독증, 비호지킨 림프종, 라이 증후군, 기타 신생아 황달, 가와사끼병, 루푸스, 칸디다증, 말라리아, 렙토스피라증, 뎅기열, 간흡충증, 급성 간경화, 만성 간경화, 선천성 대사 이상(inherited metabolic diseases) 및 담관질환(bile duct disease) 등이 포함되나 이에 한정되지 않는다.In the present invention, the " liver disease " includes acute liver disease, chronic liver disease or genetic liver damage, and specifically includes hepatitis C, hepatitis C, sarcoma, drug allergy, fatty liver, Inherited metabolic diseases include liver disease, liver cancer, liver cirrhosis, pregnancy addiction, non-Hodgkin's lymphoma, Lyme syndrome, other neonatal jaundice, Kawasaki disease, lupus, candidiasis, malaria, leptospirosis, dengue fever, clonorchiasis, acute liver cirrhosis, And bile duct disease, and the like.
본 발명의 일 구현예에 따르면, 본 발명의 간 질환은 간 섬유화에 의하여 유발된다.According to one embodiment of the present invention, the liver disease of the present invention is caused by liver fibrosis.
본 명세서의 용어 간 질환의 예방 또는 개선은 간 질환을 야기하는 것으로 알려진 인자들에 의한 섬유성 반흔 조직의 축적같은 간 조직에서 발생하는 손상의 해로움을 예방하거나 또는 약화시키는 것을 의미하며, 상기 인자들은 알코올성 간 질환, 만성 바이러스 간염(B형 및 C형), 만성담관 차단, 윌슨병, 혈색소침착증, 약물 및 독소에의 노출, 자가면역성 간염, 낭포성 섬유증, 알파 항-트립신 결핍증, 비만 및 주혈흡충증을 포함하지만, 이에 한정되는 것은 아니다.The term " preventing or ameliorating liver disease " as used herein means preventing or attenuating damage to liver tissue, such as accumulation of fibrous scar tissue by factors known to cause liver disease, Alcoholic liver disease, chronic viral hepatitis (type B and C), chronic biliary duct obstruction, Wilson's disease, hemochromatosis, exposure to drugs and toxins, autoimmune hepatitis, cystic fibrosis, alpha-anti-trypsin deficiency, obesity and schistosomiasis But are not limited thereto.
본 명세서의 용어 치료(treatment 또는 treating)는 소망하는 약리학적 및/또는 생리학적 효과를 얻는 것을 의미한다. 상기 효과는 질병 또는 증후를 완벽하게 또는 부분적으로 예방하거나 및/또는 질병 및/또는 그 질병에 기여하는 부작용에 대해 완벽하게 또는 부분적으로 치료하는 것이다. 즉, 본 명세서에서 사용되는 용어 치료는 포유동물, 바람직하게는 인간에서 질병의 모든 치료를 의미하며, 이는 다음을 포함한다: (a) 질병에 걸리기 쉽지만 아직 진단되지 않은 대상(subject)에서 일어나는 질병을 예방하는 것; (b) 질병을 억제하는 것, 즉 질병의 발달을 어레스트하는 것; 및 (c) 질병을 회복시키는 것.The term treatment or treatment herein means obtaining a desired pharmacological and / or physiological effect. The effect is to fully or partially prevent the disease or symptom and / or to fully or partially treat the illness and / or side effects that contribute to the disease. That is, the term treatment as used herein refers to all treatments of the disease in a mammal, preferably a human, including: (a) a disease that is susceptible to disease but not yet diagnosed ; (b) inhibiting disease, ie, arresting the development of disease; And (c) restoring the disease.
본 발명의 조성물은 약제학적 조성물, 식품 조성물, 기능성 식품 조성물 또는 사료 조성물이다.The composition of the present invention is a pharmaceutical composition, a food composition, a functional food composition or a feed composition.
본 발명의 조성물은 약제학적 조성물로 제조될 수 있다.The compositions of the present invention may be prepared with pharmaceutical compositions.
본 발명의 일 구현예에 따르면, 본 발명의 조성물은 (a) 상술한 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물의 약제학적 유효량; 및 (b) 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물이다. 본 명세서에서 용어 “약제학적 유효량”은 상술한 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물의 효능 또는 활성을 달성하는 데 충분한 양을 의미한다.According to one embodiment of the present invention, the composition of the present invention comprises (a) a pharmaceutically effective amount of the soybean fermented product of the above-mentioned Bacillus subtilis inactivosum subsp. Of the present invention; And (b) a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically effective amount" means an amount sufficient to achieve the efficacy or activity of the soybean fermented product by the Bacillus subtilis inactosum subspecies described above.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above-mentioned components. Suitable pharmaceutically acceptable carriers and formulations include, but are not limited to,Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물은 경구 또는 비경구 투여할 수 있으며, 본 발명의 일 구현예에 따르면 경구 투여 방식으로 적용된다.The pharmaceutical composition of the present invention may be administered orally or parenterally, and may be administered orally in accordance with an embodiment of the present invention.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물에 포함된 생리활성물질인 콩 발효물의 투여량은 성인 기준으로 0.001-100 ㎎/kg 범위 내이다.The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The dose of the fermented soybean, which is a physiologically active substance contained in the pharmaceutical composition of the present invention, is within the range of 0.001-100 mg / kg on an adult basis.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
본 발명의 조성물은 식품 조성물로 제공될 수 있다.The composition of the present invention can be provided as a food composition.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로서 본 발명의 콩 발효물 뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.When the composition of the present invention is prepared as a food composition, it contains not only the soybean fermentation product of the present invention as an active ingredient but also a component that is ordinarily added at the time of food production, for example, protein, carbohydrate, fat, And flavoring agents. Examples of the above-mentioned carbohydrates are monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavorings (saccharine, aspartame, etc.) can be used as flavorings.
예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 콩 발효물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다. For example, when the food composition of the present invention is prepared as a drink, it may further contain citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, mulberry extract, jujube extract, licorice extract, .
본 발명의 조성물은 기능성 식품 조성물로 제공될 수 있다.The composition of the present invention may be provided as a functional food composition.
기능성 식품이란 식품의약품안전청에서 개별인정을 통하여 약리 효과가 인정되는 식품을 의미한다.Functional foods means foods that are recognized as pharmacological effects through individual accreditation by the Korea Food and Drug Administration.
본 발명의 기능성식품은 본 발명의 유효성분인 상기 화합물 1을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용시 발생할 수 있는 부작용 등이 없는 장점이 있다.The functional food of the present invention is a food prepared by adding the
본 발명의 기능성식품에 있어 본 발명의 콩 발효물의 첨가량은, 식품의 종류에 따라 달라 일률적으로 규정할 수 없지만, 식품 본래의 맛을 손상시키지 않는 범위에서 첨가하면 되며, 상기 기능성식품이 분말, 과립, 정제, 캡슐 또는 음료의 형태인 경우 대상 식품에 대하여 통상 0.001-100 중량%, 0.01-100 중량% 또는 0.1-100 중량%의 범위로 첨가될 수 있다.In the functional food of the present invention, the addition amount of the soybean fermented product of the present invention varies depending on the kind of the food, but it may be added within a range that does not impair the inherent taste of the food, , Tablets, capsules or beverages, it may be added usually in the range of 0.001-100% by weight, 0.01-100% by weight or 0.1-100% by weight based on the target food.
본 발명의 조성물은 사료 조성물로 제조될 수 있다.The composition of the present invention may be prepared from a feed composition.
본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물을 유효성분 포함하는 항알레르기용 조성물이 사료 조성물로 제조되는 경우, 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물을 그대로, 또는 사료 제조시 통상적으로 첨가되는 첨가제 등을 가하여 제조할 수 있다. 예컨대, 비타민, 아미노산류, 미네랄 등의 각종 양분, 항산화제, 항생물질, 항균제 및 기타의 첨가제이다. 그 형상에는 분체, 과립, 펠릿 또는 현탁액 등이 포함된다.When the antiallergic composition comprising the soybean fermented product of the Bacillus subtilis inactosum subsp. Subsp. Of the present invention is prepared from the feed composition, the soybean fermentation product of Bacillus subtilis inactosum subsp. And additives usually added in the production of feeds. For example, various nutrients such as vitamins, amino acids and minerals, antioxidants, antibiotics, antibacterial agents and other additives. The shape includes powders, granules, pellets or suspensions, and the like.
본 발명의 조성물이 사료 조성물로 제조되는 경우, 육상 또는 수상 동물에 대하여 단독으로 또는 사료에 혼합하여 공급할 수 있다. 본 발명의 사료에는 분말사료, 고형사료, 모이스트 펠릿사료, 드라이 펠릿사료, EP(Extruder Pellet) 사료, 날먹이 등이 포함되며, 이에 한정되는 것은 아니다.
When the composition of the present invention is prepared from a feed composition, it may be supplied to the land or aquatic animals singly or in a feed mixture. The feed of the present invention includes, but is not limited to, powdered feed, solid feed, moist pellet feed, dry pellet feed, extruder pellet (EP) feed,
본 발명의 또 다른 양태에 따르면, 본 발명은 바실러스 서브틸리스 인아쿠오소럼 아종을 이용하여 콩을 발효시키는 단계를 포함하는 간 질환 예방, 개선 또는 치료용 조성물의 제조방법을 제공한다.According to still another aspect of the present invention, there is provided a method for preparing a composition for preventing, ameliorating or treating liver diseases comprising fermenting soybeans with Bacillus subtilis inocosarum subsp.
본 발명의 일 구현예에 따르면, 본 발명의 발효는 바실러스 서브틸리스 인아쿠오소럼 아종을 콩의 0.1-3 중량%가 되도록 접종하여, 습도 60-80% 및 온도 30-45℃에서 1-5일 동안 실시한다. 본 발명의 다른 구현예에 따르면, 본 발명의 발효는 바실러스 서브틸리스 인아쿠오소럼 아종을 콩의 0.5-2중량%가 되도록 접종하여, 습도 65-75% 및 온도 35-40℃에서 2-4일 동안 실시한다.According to one embodiment of the present invention, the fermentation of the present invention is carried out by inoculating Bacillus subtilis inocosarum subsp. To 0.1-3% by weight of soybeans, incubating the cells at a temperature of 60-80% Day. According to another embodiment of the present invention, the fermentation of the present invention is carried out by inoculating Bacillus subtilis inocosarum subsp. To 0.5-2% by weight of soybeans and cultivating the strain at a temperature of 35-40 < 0 & Day.
본 발명의 방법은 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종을 이용하기 때문에, 이 둘 사이에 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여, 그 기재를 생략한다.
Since the method of the present invention utilizes the Bacillus subtilis inactosum subsp. Of the present invention, the description common to both is omitted in order to avoid the excessive complexity of the present specification.
본 발명의 또 다른 양태에 따르면, 본 발명은 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718(기탁번호 KCCM 11280P) 균주를 포함하는 콩 발효용 조성물을 제공한다.
According to still another aspect of the present invention, there is provided a soybean fermentation composition comprising a strain of Bacillus subtilis inactosum subsp. FA0718 (Accession No. KCCM 11280P).
본 발명의 특징 및 이점을 요약하면 다음과 같다: The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물을 유효성분으로 포함하는 간 질환 예방, 개선 또는 치료용 조성물 및 이의 제조방법을 제공한다.(a) The present invention provides a composition for preventing, improving or treating liver diseases comprising soybean fermented product of Bacillus subtilis inactivosum subsp. as an active ingredient, and a method for producing the same.
(b) 본 발명은 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718(기탁번호 KCCM 11280P) 균주를 포함하는 콩 발효용 조성물을 제공한다.(b) The present invention provides a composition for soybean fermentation comprising a strain of Bacillus subtilis INAquosorum subsp. FA0718 (accession number KCCM 11280P).
(c) 본 발명은 콩 발효 활성을 갖는 신규한 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718(기탁번호 KCCM 11280P) 균주를 제공한다.(c) The present invention provides a novel strain of Bacillus subtilis inactosum subsp. FA0718 (accession number KCCM 11280P) having soybean fermentation activity.
(d) 본 발명의 바실러스 서브틸리스 인아쿠오소럼 아종에 의한 콩 발효물은 α-SMA 발현억제활성을 가짐으로써 간 섬유화를 억제할 수 있어 간 질환 예방, 개선 또는 치료용 조성물로 사용이 가능한 이점이 있다.
(d) The soybean fermented product of Bacillus subtilis inactosum subsp. of the present invention has inhibitory activity on the expression of [alpha] -SMA to inhibit hepatic fibrosis, and thus can be used as a composition for prevention, improvement or treatment of liver disease .
도 1은 α-SMA 발현억제활성의 웨스턴 블롯 결과를 나타낸다.Figure 1 shows the Western blot results of the inhibitory activity of? -SMA.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
실시예Example
실험 방법 및 실험 재료Experimental Methods and Materials
시약reagent
세포배양을 위한 DMEM(Dulbecco's Modified Eagle's Medium), 우태아 혈청 (FBS: fetal bovine serum), 0.05% 트립신(Trypsin) 및 페니실린-스트렙토마이신(penisillin-streptomycin)은 모두 깁코(Gibco, Life technology, 미국) 제품을 사용하였으며, SDS-PAGE와 블롯 완충액(blot buffer) 및 웨스턴 ECL 기질(western ECL substrate)은 바이오-래드社(Bio-rad, 미국), 그 외의 관련 시약들은 시그마 알드리치社(sigma aldrich, 미국)에서 구매하여 사용하였다.
Dulbecco's Modified Eagle's Medium, FBS (fetal bovine serum), 0.05% trypsin and penicillin-streptomycin for cell culture are all available from Gibco (Life technology, USA) SDS-PAGE, blot buffer and western ECL substrate were purchased from Bio-Rad, USA, and other related reagents were purchased from Sigma Aldrich, USA ).
균주의 분리 및 동정Isolation and Identification of Strain
균주는 재래식으로 제조된 메주로부터 분리하였다. 대두 성분을 트립톤으로 처리한 배지(TSB: Trytic soy broth, Difco 236950, 미국)에서 pH 7.3 ± 0.2, 37℃ 조건에서 배양이 가능하고 동결건조보존 또는 세포현탁액 동결을 통해 균주 보존이 가능하였으며, 16S rDNA 염기서열(서열목록 제1서열)은 시퀀싱 결과 기존의 바실러스 서브틸리스 인아쿠오소럼 아종 BGSC 3A28(T)균주와 99.4%의 상동성을 보였는바 바실러스 서브틸리스 인아쿠오소럼 아종(Bacillus subtilis subsp . inaquosorum)로 동정하였다. 상기 균주를 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718(Bacillus subtilis subsp . inaquosorum FA0718)으로 명명하고, 국제미생물기탁기관인 한국미생물보존센터(KCCM)에 2012년 6월 14일자로 기탁하였으며, 기탁번호 KCCM 11280P를 부여받았다.
The strain was isolated from conventionally produced meju. Soybean components were cultivated at pH 7.3 ± 0.2 and 37 ℃ in tryptone - treated medium (TSB: Trytic soy broth, Difco 236950, USA) and preserved by freeze - drying preservation or cell suspension freezing. 16S rDNA sequence (SEQ ID NO: 1) was sequenced result conventional Bacillus subtilis subspecies inah Kuo soreom BGSC 3A28 (T) boyeotneun the strains and 99.4% homology with Bacillus subtilis bar inah Kuo soreom subspecies (Bacillus subtilis subsp . inaquosorum ). The strain Bacillus subtilis inah Kuo soreom FA0718 subspecies (Bacillus subtilis subsp . inaquosorum FA0718), deposited at the Korean Microorganism Conservation Center (KCCM), an international microorganism depository, on June 14, 2012, and assigned the deposit number KCCM 11280P.
콩발효물Soybean fermentation product 및 이의 추출물의 제조 And preparation of its extract
콩발효물인 청국장 제조를 위해 대두를 세척하고 하룻밤 동안 침지한 후 물기를 제거하고 114℃에서 50분 동안 증자하였다. 증자한 후 식힌 대두 200 g에 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718을 대두량의 1%가 되도록 접종하고 습도 70%, 온도 37℃ 항온기에서 3일 동안 발효시켜 청국장을 제조하였다. 제조한 청국장은 동결건조한 후 증류수에 녹인 다음 5000 rpm에서 10분 동안 원심분리하여 얻은 상등액을 실험에 이용하였다.
Soybean was washed and soybean was soaked overnight to make soybean fermented product. Then, water was removed and it was heated at 114 ° C for 50 minutes. Bacillus subtilis inactosum subsp. Subsp. FA0718 was inoculated in 200 g of chilled soybeans to 1% of the soybean yield and fermented for 3 days in a thermostat at a temperature of 37 ° C and a humidity of 70% to prepare chungkukjang. The prepared chungkookjang was lyophilized, dissolved in distilled water, and centrifuged at 5000 rpm for 10 minutes.
마우스 배아 섬유아세포(MEF) 배양Mouse embryonic fibroblast (MEF) culture
서울대학교 약학대학 약물학실로부터 분양받은 마우스 배아 섬유아세포(MEF: Mouse embryonic fibroblast)를 DMEM(FBS 10% 함유) 배지를 사용하여 37℃, 5% CO2 배양기(Sanyo, 일본)에서 세포 밀도가 80-90% 정도 될 때까지 약 2일 동안 배양하였다. 배양 상등액을 제거한 후 트립신/EDTA(0.25%/0.53 mM, Sigma, 미국)를 처리하여 37℃, 5% CO2 배양기에서 약 2분 동안 반응시켰다. 200×g에서 2분 동안 원심 분리하여 부착된 세포를 수거한 후 3×105 세포/웰이 되도록 6웰 플레이트로 옮긴 뒤 37℃, 5% CO2 배양기에서 하루 동안 더 배양하였다. 배지 상등액을 제거한 뒤, 새로운 DMEM(FBS 제외)배지에서 6-12시간 동안 스타베이션(starvation)시킨 후 시료를 농도별(50, 100 및 200 μg/mL)로 처리하여 37℃, 5% CO2 배양기에서 24시간 배양하였다.
Mouse embryonic fibroblast (MEF), which was purchased from the Pharmacology Department of the College of Pharmacy, Seoul National University, was cultured in a DMEM (containing 10% FBS) medium at 37 ° C in a 5% CO 2 incubator (Sanyo, Japan) And cultured for about 2 days until it was about -90%. After removing the culture supernatant, trypsin / EDTA (0.25% / 0.53 mM, Sigma, USA) was treated and reacted in a 5% CO 2 incubator at 37 ° C for about 2 minutes. After the return of 2 minutes, cell attachment and centrifuged at 200 × g for more were cultured for a day at 3 × 10 5 cells / well so that the back 37 ℃ transferred to 6-well plate, 5% CO 2 incubator. Removal of the culture supernatant after, by treatment with new DMEM (FBS excluded) for 6-12 hours in medium star Renovation (starvation) of the sample (50, 100 and 200 μg / mL) by the concentration was 37 ℃, 5% CO 2 And cultured in an incubator for 24 hours.
웨스턴 블롯Western blot
바실러스 서브틸리스 인아쿠오소럼 아종 FA0718로 제조한 청국장 추출물을 50, 100 및 200 μg/mL 농도로 각각 처리한 경우 대조군에 비해 α-SMA 발현억제율이 각각 약 16%, 68% 및 59%인 것으로 나타났다(표 1). 간보호 작용을 하는 기능성 물질로 알려져 항바이러스제와 같이 치료에 사용되고 있는 실리마린(silymarin)의 α-SMA 발현억제율이 77%인바, 상기 100 및 200 μg/mL 농도의 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718로 제조한 청국장 추출물을 각각 처리한 경우의 α-SMA 발현억제활성은 각각 실리마린의 88.3% 및 76.6%에 이르는 활성을 보이는 것을 알 수 있다.The inhibition rates of α-SMA expression were about 16%, 68% and 59%, respectively, when the extracts of Chungkukjang prepared with Bacillus subtilis inactosum subsp. FA0718 were treated at 50, 100 and 200 μg / (Table 1). The inhibition rate of α-SMA expression by silymarin, which is used for treatment such as antiviral drugs, is 77%. In the case of the above-mentioned 100 and 200 μg / mL Bacillus subtilis inactosum subsp. FA0718 The inhibitory activity of α-SMA on the activity of silymarin was 88.3% and 76.6%, respectively.
더불어, 시중에서 판매되는 일반청국장(참고을, 대한민국)을 처리한 경우 α-SMA 발현억제율은 0%로 α-SMA 발현억제활성이 없는 것으로 나타난바, 이는 콩 발효물에 있어 종균의 종류가 α-SMA 발현억제활성에 영향을 미침을 의미한다.In addition, the inhibition rate of α-SMA expression was 0% in the case of the general cheonggukjang sold in the market (reference, Korea), indicating that α-SMA inhibitory activity was not inhibited, SMA < / RTI > expression inhibitory activity.
따라서 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718로 청국장을 제조함으로 인하여 청국장의 α-SMA 발현억제활성이 나타나며, 이는 기존의 간보호 기능성 물질인 실리마린의 활성에 근접한바, 바실러스 서브틸리스 인아쿠오소럼 아종 FA0718에 의한 콩 발효물이 α-SMA 발현을 억제하여 간 질환의 예방, 개선 또는 치료 효과가 있을 것으로 예상된다.Therefore, the production of chungkukjang by Bacillus subtilis inactosum subsp. Subsp. FA0718 shows an inhibitory effect on α-SMA expression of chungkukjang, which is close to the activity of silymarin, which is a conventional liver-protecting functional substance, and the activity of Bacillus subtilis inactivosum subsp. It is expected that soybean fermented product by FA0718 inhibits? -SMA expression, thereby preventing, improving or treating liver disease.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
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18. Lim SY, Rhee SH, Park KY. 2004. Inhibitory effect of methanol extracts of doenjang on growth and DNA synthesis of human cancer cells. J. Korean Soc . Food Sci . Nutr . 33: 936-940.
<110> KOREA FOOD RESEARCH INSTITUTE <120> Compositions for Preventing, Improving, or Treating Liver Disorders Comprising Substances of Fermented Soy Bean Using Bacillus subtilis subsp. inaquosorum as an Active Ingredient <130> PN140013 <160> 1 <170> KopatentIn 2.0 <210> 1 <211> 1480 <212> DNA <213> Bacillus subtilis subsp. inaquosorum_FA0718 <400> 1 tgctcaggac gaacgctggc ggcgtgccta atacatgcaa gtcgagcgga cagatgggag 60 cttgctccct gatgttagcg gcggacgggt gagtaacacg tgggtaacct gcctgtaaga 120 ctgggataac tccgggaaac cggggctaat accggatggt tgtttgaacc gcatggttca 180 gacataaaag gtggcttcgg ctaccactta cagatggacc cgcggcgcat tagctagttg 240 gtgaggtaac ggctcaccaa ggcgacgatg cgtagccgac ctgagagggt gatcggccac 300 actgggactg agacacggcc cagactccta cgggaggcag cagtagggaa tcttccgcaa 360 tggacgaaag tctgacggag caacgccgcg tgagtgatga aggttttcgg atcgtaaagc 420 tctgttgtta gggaagaaca agtgccgttc aaatagggcg gcaccttgac ggtacctaac 480 cagaaagcca cggctaacta cgtgccagca gccgcggtaa tacgtaggtg gcaagcgttg 540 tccggaatta ttgggcgtaa agggctcgca ggcggtttct taagtctgat gtgaaagccc 600 ccggctcaac cggggagggt cattggaaac tggggaactt gagtgcagaa gaggagagtg 660 gaattccacg tgtagcggtg aaatgcgtag agatgtggag gaacaccagt ggcgaaggcg 720 actctctggt ctgtaactga cgctgaggag cgaaagcgtg gggagcgaac aggattagat 780 accctggtag tccacgccgt aaacgatgag tgctaagtgt tagggggttt ccgcccctta 840 gtgctgcagc taacgcatta agcactccgc ctggggagta cggtcgcaag actgaaactc 900 aaaggaattg acgggggccc gcacaagcgg tggagcatgt ggtttaattc gaagcaacgc 960 gaagaacctt accaggtctt gacatcctct gacaatccta gagataggac gtccccttcg 1020 ggggcagagt gacaggtggt gcatggttgt cgtcagctcg tgtcgtgaga tgttgggtta 1080 agtcccgcaa cgagcgcaac ccttgatctt agttgccagc attcagttgg gcactctaag 1140 gtgactgccg gtgacaaacc ggaggaaggt ggggatgacg tcaaatcatc atgcccctta 1200 tgacctgggc tacacacgtg ctacaatgga cagaacaaag ggcagcgaaa ccgcgaggtt 1260 aagccaatcc cacaaatctg ttctcagttc ggatcgcagt ctgcaactcg actgcgtgaa 1320 gctggaatcg ctagtaatcg cggatcacat gcgcgggggg aaatacgttc ccgggccttg 1380 tacacaccgc ccgtcacacc acgagagttt gtaacacccg aagtcggtga ggtaaccttt 1440 ttaggagcca gccgccgaag gtgggacaga tgattggggt 1480 <110> KOREA FOOD RESEARCH INSTITUTE <120> Compositions for Preventing, Improving, or Treating Liver Disorders Comprising Substances of Fermented Soy Bean Using Bacillus subtilis subsp. inaquosorum as an Active Ingredient <130> PN140013 <160> 1 <170> Kopatentin 2.0 <210> 1 <211> 1480 <212> DNA <213> Bacillus subtilis subsp. inaquosorum_FA0718 <400> 1 tgctcaggac gaacgctggc ggcgtgccta atacatgcaa gtcgagcgga cagatgggag 60 cttgctccct gatgttagcg gcggacgggt gagtaacacg tgggtaacct gcctgtaaga 120 ctgggataac tccgggaaac cggggctaat accggatggt tgtttgaacc gcatggttca 180 gacataaaag gtggcttcgg ctaccactta cagatggacc cgcggcgcat tagctagttg 240 gtgaggtaac ggctcaccaa ggcgacgatg cgtagccgac ctgagagggt gatcggccac 300 actgggactg agacacggcc cagactccta cgggaggcag cagtagggaa tcttccgcaa 360 tggacgaaag tctgacggag caacgccgcg tgagtgatga aggttttcgg atcgtaaagc 420 tctgttgtta gggaagaaca agtgccgttc aaatagggcg gcaccttgac ggtacctaac 480 cagaaagcca cggctaacta cgtgccagca gccgcggtaa tacgtaggtg gcaagcgttg 540 tccggaatta ttgggcgtaa agggctcgca ggcggtttct taagtctgat gtgaaagccc 600 ccggctcaac cggggagggt cattggaaac tggggaactt gagtgcagaa gaggagagtg 660 gaattccacg tgtagcggtg aaatgcgtag agatgtggag gaacaccagt ggcgaaggcg 720 actctctggt ctgtaactga cgctgaggag cgaaagcgtg gggagcgaac aggattagat 780 accctggtag tccacgccgt aaacgatgag tgctaagtgt tagggggttt ccgcccctta 840 gtgctgcagc taacgcatta agcactccgc ctggggagta cggtcgcaag actgaaactc 900 aaaggaattg acgggggccc gcacaagcgg tggagcatgt ggtttaattc gaagcaacgc 960 gaagaacctt accaggtctt gacatcctct gacaatccta gagataggac gtccccttcg 1020 ggggcagagt gacaggtggt gcatggttgt cgtcagctcg tgtcgtgaga tgttgggtta 1080 agtcccgcaa cgagcgcaac ccttgatctt agttgccagc attcagttgg gcactctaag 1140 gtgactgccg gtgacaaacc ggaggaaggt ggggatgacg tcaaatcatc atgcccctta 1200 tgacctgggc tacacacgtg ctacaatgga cagaacaaag ggcagcgaaa ccgcgaggtt 1260 aagccaatcc cacaaatctg ttctcagttc ggatcgcagt ctgcaactcg actgcgtgaa 1320 gctggaatcg ctagtaatcg cggatcacat gcgcgggggg aaatacgttc ccgggccttg 1380 tacacaccgc ccgtcacacc acgagagttt gtaacacccg aagtcggtga ggtaaccttt 1440 ttaggagcca gccgccgaag gtgggacaga tgattggggt 1480
Claims (11)
Bacillus subtilis inah Kuo soreom subspecies (Bacillus subtilis subsp . A composition for preventing, ameliorating or treating liver disorders comprising soybean fermented product by inaquosorum as an active ingredient.
2. The composition according to claim 1, wherein the Bacillus subtilis inactosum subsp. Bacillus subtilis inactosum subsp. Subsp. FA0718 (accession number KCCM 11280P).
The composition according to claim 1, wherein the soybean fermented by the Bacillus subtilis inactosum subsp. Subsp. Is chungkukjang.
The composition according to claim 1, wherein the soybean fermented by the Bacillus subtilis inactosum subsp. Subsp. Has an alpha-SMA inhibiting activity.
2. The composition of claim 1, wherein the soybean fermented by the Bacillus subtilis inactosum subsp. Subunit inhibits? -SMA expression by 10-90% relative to the control.
The composition according to claim 1, wherein the soybean fermented by the Bacillus subtilis inactosum subsp. Subsp. Is at a concentration of 20-500 μg / mL.
2. The composition of claim 1, wherein the liver disease is caused by liver fibrosis.
8. A composition according to any one of claims 1 to 7, wherein the composition is a pharmaceutical composition.
8. A composition according to any one of claims 1 to 7, wherein the composition is a food composition.
Bacillus subtilis inactosum subsp. Subsp. FA0718 (accession number KCCM 11280P).
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| CN116790699A (en) * | 2023-06-21 | 2023-09-22 | 江苏恰瑞生物科技有限公司 | Preparation method of protein hydrolysate for treating acute alcoholic liver injury cell repair |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100374013B1 (en) * | 2000-01-26 | 2003-02-26 | 김종규 | Doenjang composition fermented by Bacillus sp. PM3 (KCTC 8486P) with usage for prevention of liver cancer |
| KR20070028997A (en) * | 2005-09-08 | 2007-03-13 | 강원대학교산학협력단 | A strain having high productivity for alpha glucosidase inhibitor and a method for preparing the strain |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR100374013B1 (en) * | 2000-01-26 | 2003-02-26 | 김종규 | Doenjang composition fermented by Bacillus sp. PM3 (KCTC 8486P) with usage for prevention of liver cancer |
| KR20070028997A (en) * | 2005-09-08 | 2007-03-13 | 강원대학교산학협력단 | A strain having high productivity for alpha glucosidase inhibitor and a method for preparing the strain |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116790699A (en) * | 2023-06-21 | 2023-09-22 | 江苏恰瑞生物科技有限公司 | Preparation method of protein hydrolysate for treating acute alcoholic liver injury cell repair |
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