KR101972309B1 - Composition for Treating and Preventing Inflammatory Disease Comprising Culture Fluid Extract or Fraction of Endophytic Fungal Strain Isolated from the Rhizome of Reed Plant as an Active Ingredient - Google Patents
Composition for Treating and Preventing Inflammatory Disease Comprising Culture Fluid Extract or Fraction of Endophytic Fungal Strain Isolated from the Rhizome of Reed Plant as an Active Ingredient Download PDFInfo
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
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Abstract
본 발명은 갈대 내생균 배양액 추출물 또는 분획물을 유효성분으로 포함하는 염증성 질환 치료 및 예방용 조성물에 관한 것이다.
본 발명에 따른 갈대 내생균 배양액 추출물 또는 분획물은 우수한 항염증 활성을 보유하여 이를 이용한 약학적 조성물, 식품 조성물 등의 용도로 유용하게 사용될 수 있다.The present invention relates to a composition for treating and preventing an inflammatory disease comprising an extract or a fraction of a live bacterial culture solution in a reed as an active ingredient.
The extract or fraction of live cell culture broth according to the present invention has excellent anti-inflammatory activity and can be usefully used for pharmaceutical composition, food composition and the like.
Description
본 발명은 염증성 질환 치료 및 예방용 조성물에 관한 것으로, 더욱 구체적으로 갈대 내생균 배양액 추출물 또는 분획물을 유효성분으로 포함하는 염증성 질환 치료 및 예방용 조성물에 관한 것이다.The present invention relates to a composition for treating and preventing an inflammatory disease, and more particularly, to a composition for treating and preventing inflammatory diseases, which comprises an extract or fraction of a live bacterial culture solution in a reed as an active ingredient.
지질-폴리사카라이드 복합 화합물인 리포폴리사카라이드(LPS, Lipopolysaccharide)는 그람 음성 박테리아의 세포벽에서 발견되는 내독소 O-항원으로서, 박테리아 LPS는 전형적으로는 리피드 A(내독소), 비반복성 코어 올리고사카라이드, 및 폴리사카라이드(O-항원)로 구성되어 있다. 지질 부분(리피드 A)은 글리코사이드 결합을 통해 코어 폴리사카라이드 부분과 복합체를 형성한다. 코어 부분은 반복되는 올리고사카라이드 유닛으로 구성된 고도의 면역원성과 가변성을 갖는 O-사슬 폴리사카라이드, 즉 3번째의 외부 부위인 O-항원 부위와 연결된다. Lipopolysaccharide (LPS), a lipid-polysaccharide complex compound, is an endotoxin O-antigen found in the cell wall of gram negative bacteria. Bacterial LPS is typically found in lipid A (endotoxin), non- Saccharide, and polysaccharide (O-antigen). The lipid moiety (lipid A) complexes with the core polysaccharide moiety through a glycosidic bond. The core moiety is linked to an O-chain polysaccharide having a high degree of immunogenicity and variability consisting of a repeated oligosaccharide unit, i.e., the O-antigen site, which is the third external site.
산화질소(NO, Nitric oxide)는 면역시스템에서 다양한 생리학적 메커니즘을 조절하는데 관여하는 중요한 세포 내 및 세포 간 신호전달 분자이다. 산화질소는 수퍼옥사이드와 반응하여 퍼옥시나이트라이트(peroxynitrite) 이온을 생성하고, 생성된 이온은 과도한 염증 활성을 유도하며, 패혈증(sepsis), 궤양성 대장염(ulcerative colitis), 관절염(arthritis), 루푸스(systemic lupus erythematosus, SLE) 및 쇼그렌증후군(Sjogren's syndrome, SS) 등의 질환을 발생시키는 것으로 알려져 있다. 활성산소종(Reactive oxygen species, ROS) 및 산화질소(nitric oxide, NO)는 신호전달과정의 중간 매개자로서 매우 중요한 생리학적 역할을 담당한다. 그러나, 내인성 및/또는 외인성 ROS 및 NO의 과도한 생성은 염증성 질환 및 암의 발병에 관련되어 있다. 또한, 산화환원-민감성 전사인자인 NF-κB는 산화스트레스, 외인성 ROS와 산화질소(NO, Nitric oxide) 등과 같은 염증성 매개자에 의해 활성화된다. NF-κB가 활성화되면, IκB는 IκB 키나아제(IKK) 복합체에 의해 인산화 되고, IκB는 유비퀴틴화(ubiquitinated)되어 분해된다. IκB로부터 분리된 자유 NF-κB는 핵 속으로 이동하고, 핵 내에서 세포 성장조절, 아팝토시스, 면역반응, 염증 및 암에 관련된 유전자를 전사시킨다. 또한, NF-κB는 만성염증성질환 및 다양한 인간 암의 발병기전에 중요한 역할을 한다고 보고되었다. Nitric oxide (NO) is an important intracellular and intercellular signaling molecule involved in regulating a variety of physiological mechanisms in the immune system. Nitric oxide reacts with the superoxide to produce peroxynitrite ions and the resulting ions induce excessive inflammatory activity and are known to cause sepsis, ulcerative colitis, arthritis, , systemic lupus erythematosus (SLE), and Sjogren's syndrome (SS). Reactive oxygen species (ROS) and nitric oxide (NO) play an important physiological role as mediators of signal transduction. However, excessive production of endogenous and / or exogenous ROS and NO has been implicated in the pathogenesis of inflammatory diseases and cancer. In addition, NF-κB, a redox-sensitive transcription factor, is activated by inflammatory mediators such as oxidative stress, exogenous ROS and nitric oxide (NO). When NF-κB is activated, IκB is phosphorylated by the IκB kinase (IKK) complex, and IκB is ubiquitinated and degraded. Free NF-κB isolated from IκB migrates into the nucleus and transcribes genes related to cell growth regulation, apoptosis, immune response, inflammation and cancer in the nucleus. In addition, NF-κB has been reported to play an important role in chronic inflammatory diseases and pathogenesis of various human cancers.
따라서, NF-κB 활성을 유발하는 NO 발생을 억제하는 물질을 탐색하면, 다양한 염증성 질환의 예방 및 치료에 효과적인 물질로 판명할 수 있다는 것을 의미한다. Therefore, searching for a substance that inhibits NO generation that induces NF-kB activity means that it can be proved to be effective for the prevention and treatment of various inflammatory diseases.
또한, 세포내 다양한 염증 조절 인자들은 유도형 일산화질소 합성효소(inducible nitric oxide synthase; iNOS)나 사이클로-옥시제나제 (cyclo-oxygenase-2; COX-2)에 의해 생체 내 대식세포와 같은 염증 세포들이 활성화 되면서 염증 매개인자인 일산화질소(Nitric oxide; NO), 프로스타글란딘(Prostaglandin; PG), 인터루킨-1 베타(Interleukin-1 beta; IL-1β), 종양괴사인자-알파 (Tumor necrosis factor-alpha; TNF-α), 사이토카인(cytokine) 등이 다량 생산 된다(Jun-Ho Son. et.al., Anti-Inflammatory Effect of Ligularia fischeri, Solidago virga-aurea and Aruncus dioicus Complex Extracts in Raw 264.7 Cells, Journal of Life Science, 2011, Vol. 21, No. 5, 678~683쪽). 또한, 염증성 사이토카인(cytokine)인 인터루킨-1(IL-1), 종양괴사인자-α(TNF-α) 등을 유도시키게 되는데 이로 인하여 근육, 건, 인대 등과 같은 조직에도 영향을 끼쳐 심한 통증을 일으킨다(Fernandes J. C. et al., The role of cytokines in osteoarthritis pathophysiology, 2002, 39, 237-246쪽).Various intracellular inflammatory regulators may also be involved in inflammatory cells such as in vivo macrophages by inducible nitric oxide synthase (iNOS) or cyclo-oxygenase-2 (COX-2) Nitric oxide (NO), prostaglandin (PG), interleukin-1 beta (IL-1 beta), Tumor necrosis factor-alpha TNF-a, cytokine, and the like (Jun-Ho Son et al., Anti-Inflammatory Effect of Ligularia fischeri, Solidago virga-aurea and Aruncus dioicus Complex Extracts in Raw 264.7 Cells, Journal of Life Science, 2011, Vol. 21, No. 5, pp. 678-683). It also induces inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), which can affect tissues such as muscles, tendons and ligaments, (Fernandes JC et al., The role of cytokines in osteoarthritis pathophysiology, 2002, 39, 237-246).
대부분의 염증 질환의 치료제로서 널리 사용되고 있는 제제인 비스테로이드성 소염제(non-steroidal anti-inflammatory drugs, NSAIDS)는 사이클로옥시게나제(cyclooxygenase, COX)라고 하는 아라키돈산(arachidonic acid)으로부터 프로스타글란딘(prostaglandin)의 생합성에 관여하는 효소 활성을 억제함으로써, 항염증 작용을 나타내는데, 주 치료 작용 외에 위장관 장애, 간장애, 신장애 등의 심각한 부작용을 야기하므로 장기간의 사용에 있어서 제약이 따르는 실정이다. 따라서, 특허 등록 제10-0532633호, 특허등록 제10-1390084호, 특허등록 제10-1160488호 등 천연에서 유래한 식물추출물을 이용한 염증성 질환 치료용 조성물에 관한 연구가 진행된 바 있다. 상기 비스테로이드성 소염제를 대체하여 부작용이 없이 장기간 사용하는데 무리가 없으면서 항염증 효능에 탁월한 새로운 소염 진통제의 개발이 절실하게 요구되고 있으며, 이는 최근 천연 자원으로부터의 효능 검증을 통한 소재 개발 연구가 활성화되고 있는 이유이기도 하다.Nonsteroidal anti-inflammatory drugs (NSAIDS), which are widely used as agents for the treatment of most inflammatory diseases, are produced from arachidonic acid called prostaglandin, called cyclooxygenase (COX) Inhibition of the enzymatic activity involved in biosynthesis of the glycosaminoglycans, exhibits an anti-inflammatory action. In addition to the main therapeutic effect, it causes severe side effects such as gastrointestinal disorders, hepatic disorders, renal diseases and the like. Therefore, studies have been conducted on compositions for the treatment of inflammatory diseases using plant extracts derived from natural sources such as Patent Registration No. 10-0532633, Patent Registration No. 10-1390084, and Patent Registration No. 10-1160488. There is a desperate need for the development of a new anti-inflammatory analgesic agent which is excellent in anti-inflammatory efficacy without overcoming the above-mentioned non-steroidal anti-inflammatory agent and having no adverse effect for a long period of use. That's why.
한편, 식물 내생균은 생활사의 일부가 건강한 식물 조직에 외형적 변형을 일으키지 않고 공존하는 미생물이다. 내생균의 공생은 기주식물과의 상호관계, 즉 내생균과 기주식물 파트너의 특성이나 환경적 영향에 따라 공생, 편리 공생 및 기생 등의 형태(balanced symbiotic continuum)로 정의될 수 있다. 내생균은 기주식물의 생장 촉진, 병해충 저항성 증대, 냉해나 건조 등의 환경변화에 대한 적응력 증대, 대사물질 형성 촉진 등 식물에 이로운 영향을 주기도 하나, 일부 내생균의 경우 기주식물에 잠복하여 병원균으로 작용하는 등 해로운 영향을 주기도 하고, 죽은 식물 조직의 일차 분해자로 작용하여 생태계 물질 순환을 촉진하는 역할을 하기도 한다. On the other hand, live bacteria in plants are microorganisms in which part of life history coexists without causing external transformation to healthy plant tissue. The symbiosis of living organisms can be defined as a symbiotic continuum in terms of symbiotic, convenient symbiotic and parasitic depending on the interrelationship with host plants, that is, the characteristics and environmental influences of host organisms and host plant partners. Mycorrhizae may have a beneficial effect on plants such as promoting growth of host plants, increasing resistance to pest insects, increasing adaptability to environmental changes such as cold weather and drying, and promoting metabolism formation. In some cases, however, It acts as a primary decomposer of the dead plant tissue and promotes ecosystem material circulation.
또한, 식물 내생균은 그 자체가 항암 또는 항균 등의 활성을 갖는 유용한 이차대사산물을 생산하는 것으로 알려져 있는데, 가장 대표적인 예로는 주목나무에서 분리된 탁소미세스 속 내생균(Taxomyces andreanae)으로 차세대 항암제로 주목받고 있는 택솔(paclitaxel)을 생산하는 내생균이다. 이러한 내생균의 상업적 성공으로 인해 다양한 약리적 효능을 가진 신규 생리활성 물질을 보유한 새로운 식물 내생균을 찾기 위한 연구개발 노력이 지속적으로 이루어지고 있다. In addition, live bacteria in plants are known to produce useful secondary metabolites that have activities such as anticancer or antibacterial activity. The most representative example is Taxomyces andreanae, a taxane isolated from a tree, It is an endogenous bacillus producing paclitaxel which is getting attention. Due to the commercial success of these endophytic bacteria, research and development efforts have been continuously carried out to find new live bacteria in a new plant having various physiologically active substances with various pharmacological effects.
그러나, 이러한 연구결과에도 불구하고 아직까지 식물 내생균을 이용한 신규 약제 개발과 관련된 연구 성과는 미미한 상태이다. However, despite the results of these studies, the research results related to the development of new medicines using live bacteria in the plant are still insufficient.
이에, 본 발명자들은 염증반응에 관여하는 산화질소의 발생을 효과적으로 억제하는 천연소재를 발굴하기 위해 예의 연구노력한 결과, 갈대 내생균 배양액 추출물 또는 분획물이 산화질소의 발생을 효과적으로 억제하여 다양한 염증성 질환의 예방 및 치료에 효과적으로 활용할 수 있음을 확인하고, 본 발명을 완성하게 되었다.Accordingly, the present inventors have made intensive researches to discover natural materials that effectively inhibit the generation of nitric oxide involved in the inflammatory reaction, and as a result, it has been found that the extract or fraction of the live medium in the reed effectively inhibits the generation of nitric oxide, And the present invention has been completed.
따라서, 본 발명의 주된 목적은 염증성 질환 치료 및 예방에 효과가 있는 갈대 내생균 배양액 추출물 또는 분획물을 제공하는 데에 있다.Therefore, it is a main object of the present invention to provide an extract or fraction of a live medium culture broth which is effective for the treatment and prevention of inflammatory diseases.
본 발명의 다른 목적은 상기 갈대 내생균 배양액 추출물 또는 분획물을 유효성분으로 포함하는 염증성 질환의 치료 또는 예방용 조성물을 제공하는 데에 있다.It is another object of the present invention to provide a composition for treating or preventing an inflammatory disease, which comprises the extract or fraction of live broth of the reed as an active ingredient.
본 발명의 목적 및 장점은 하기의 발명의 상세한 설명, 청구의 범위 및 도면에 의해 보다 명확하게 된다.The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
본 발명의 한 양태에 따르면, 본 발명은 갈대 내생균 배양액 추출물 또는 분획물을 유효성분으로 포함하는 염증성 질환 치료 및 예방용 약학적 조성물을 제공한다.According to one aspect of the present invention, there is provided a pharmaceutical composition for the treatment and prevention of inflammatory diseases, comprising an extract or fraction of a live bacterial culture solution in a reed as an active ingredient.
본 발명자들은 염증 매개인자의 발현을 억제하여 염증성 질환에 효능이 있는 물질을 찾고자 여러 가지 천연물질들 중에서 유효한 물질을 검색한 결과, 갈대 내생균 배양액 추출물 또는 분획물이 산화질소의 발생을 효과적으로 억제하여 다양한 염증성 질환의 예방 및 치료에 효과적으로 활용할 수 있음을 확인하였고, 또한 안전성에도 문제가 없음을 확인하였다. The present inventors have searched for a substance effective for inflammatory diseases by inhibiting the expression of an inflammatory mediator, and found that the extract or fraction of the live culture medium in the reed effectively inhibits the generation of nitric oxide It is confirmed that the present invention can be effectively used for the prevention and treatment of inflammatory diseases, and it is confirmed that there is no problem in safety.
구체적으로 본 발명자들은 갈대에서 분리된 내생균인 고이마노마이세스(Gaeumannomyces) 속 균주의 일종인 고이마노마이세스(Gaeumannomyces) JS0464(NIBRFGC000146694) 균주(수탁번호: KACC83010P)를 동정하고, 상기 균주의 배양액 추출물 또는 분획물이 항염증 활성을 갖는 것을 확인하였다. Specifically, the present inventors identified Gaeumannomyces JS0464 (NIBRFGC000146694) strain (Accession No .: KACC83010P), which is a kind of strain of the genus Gaeumannomyces, which is an endogenous bacterium isolated from reeds, The extract or fraction was found to have anti-inflammatory activity.
또한, 상기 고이마노마이세스(Gaeumannomyces) 속 균주는 수탁번호 KACC 83010P로 부다페스트 조약 하의 국제기탁기관인 국립농업과학원 농업유전자원정보센터에(KACC)에 국제기탁하여 수탁번호 KACC 83010P를 부여받았다. The strain of the genus Gaeumannomyces was deposited under the Budapest Treaty with the accession number KACC 83010P and deposited with the National Institute of Agricultural Science and Technology, National Institute of Agricultural Science and Technology (KACC) under the Budapest Treaty under the accession number KACC 83010P.
따라서, 본 발명에서 상기 갈대 내생균은 고이마노마이세스 속 균주이고, 상기 고이마노마이세스 속 균주는 JS0464(NIBRFGC000146694)(수탁번호: KACC 83010P) 균주이며, 그 배양액 추출물 또는 분획물은 항염증 활성을 갖는다. Therefore, in the present invention, the live bacteria in the reeds are a strain of genus Koimanomyces, and the genus Goimanomyces is a strain of JS0464 (NIBRFGC000146694) (Accession No .: KACC 83010P), and the culture extract or fraction thereof has anti- .
본 발명의 일 실시예에서는 순천만 갈대 뿌리로부터 순수 분리된 고이마노마이세스(Gaeumannomyces) 속 JS0464(NIBRFGC000146694) 균주를 동정하기 위하여 생리적, 형태학적인 검사를 수행하였다(도 1 및 도 2 참조). In one embodiment of the present invention, physiological and morphological tests were performed to identify strains of genus Gaeumannomyces JS0464 (NIBRFGC000146694) purely isolated from the reed roots of Sunchon bay (FIGS. 1 and 2).
그 결과, 상기 균주는 PDA(potato dextrose agar), Czapek dox agar 배지 및 Czapek dox agar 배지를 기본으로 하고 서로 다른 9개의 탄소원으로 구성된 배지에서 균사생장의 차이가 없으며, V8 주스 아가(juice agar)와 오트밀 아가 배지나, 워터 아가(Water agar)에 멸균된 갈대 줄기 조각을 올린 갈대 배지 상에서 고이마노마이세스(Gaeumannomyces) 속 특유의 자실체를 형성하였다. 자낭과 내에는 8개의 자낭포자가 들어 있었다. PDA 배지 상에서는 후막포자를 형성하였다.As a result, the strains were based on PDA (potato dextrose agar), Czapek dox agar medium and Czapek dox agar medium, and there was no difference in mycelial growth in a medium composed of nine different carbon sources, and V8 juice agar Oatmeal spermatogonium, and a fruiting body specific to the genus Gaeumannomyces was formed on a reed medium on which a piece of reed stalks was sterilized on a Water agar. The inner part of the acanthosis contained 8 ascospores. On the PDA medium, thick membrane spores were formed.
또한, ITS1 및 ITS4 프라이머를 이용한 ITS(internal transcribed spacer) 분석 결과, 상기 고이마노마이세스(Gaeumannomyces) 속 JS0464(NIBRFGC000146694) 균주는 유성기(sexual stage)에는 고이마노마이세스(Gaeumannomyces) 속의 특징을, 무성기(asexual stage)에는 피알로포라 속(Phialophora sp.)의 특징을 보였다. Furthermore, ITS (internal transcribed spacer) analysis results, the Goi agate My process (Gaeumannomyces) in JS0464 (NIBRFGC000146694) strains using the ITS1 and ITS4 primers phonograph (sexual stage), the Goi agate My process (Gaeumannomyces) in the characteristics of, silent In the asexual stage, Phialophora sp.
생리적, 형태학적 특성과 ITS 염기서열 분석을 기초로 JS0464(NIBRFGC000146694) 균주를 고이마노마이세스(Gaeumannomyces) 속 균주로 동정하였으며, 국립농업과학원 농업유전자원정보센터에 2017년 07월 25일자로 기탁하고, 수탁번호 KACC83010P를 부여받았다.Based on the physiological and morphological characteristics and ITS sequence analysis, JS0464 (NIBRFGC000146694) strain was identified as a strain of genus Gaeumannomyces and deposited at the National Institute of Agricultural Science and Technology , National Institute of Agricultural Science and Technology on Jul. 25, 2017 , And accession number KACC 83010P.
본 발명에서 사용되는 용어, "추출물"은 식물의 추출 처리에 의하여 얻어지는 추출액, 상기 추출액의 희석액이나 농축액, 상기 추출액을 건조하여 얻어지는 건조물, 상기 추출액의 조정제물이나 정제물, 또는 이들의 혼합물 등, 추출액 자체 및 추출액을 이용하여 형성 가능한 모든 제형의 추출물을 포함한다. 본 발명의 상기 추출물은 바람직하게 추출 후 건조 분말 형태로 제조되어 사용될 수 있다. The term " extract " used in the present invention refers to an extract obtained by extracting a plant, a diluted solution or concentrate of the extract, a dried product obtained by drying the extract, a controlled preparation or a purified product of the extracted solution, Extracts themselves and extracts of all formulations which can be formed using extracts. The extract of the present invention can be preferably prepared in the form of a dry powder after extraction.
또한, 본 발명의 용어 "분획물"은 다양한 구성성분을 포함하는 혼합물로부터 특정성분 또는 특정 그룹을 분리하는 분획방법에 의하여 얻어진 결과물을 의미한다. 본 발명에서는 바람직하게는 갈대 내생균 JS0464(NIBRFGC000146694) 배양액의 에틸아세테이트 추출물을 실리카 겔 컬럼 크로마토그리피 하에서 n-헥산, 에틸아세테이트, 및 메탄올의 용매를 이용한 용매분획방법으로 분획한 결과물일 수 있으며, 극성 용매 분획물과 비극성 용매 분획물을 모두 포함하며, 구체적으로는 헥산 분획물, 에틸아세테이트 분획물 및 메탄올 분획물 등이 모두 사용될 수 있다. 또한 HPLC 방식을 적용하여 분리된 분획물일 수도 있다.The term " fraction " of the present invention means a product obtained by a fractionation method for separating a specific component or a specific group from a mixture containing various constituents. In the present invention, the ethyl acetate extract of the culture broth of the live broth JS0464 (NIBRFGC000146694) in the reeds may be the result of fractionation by a solvent fractionation method using a solvent of n-hexane, ethyl acetate, and methanol under silica gel column chromatography, The solvent fraction and the non-polar solvent fraction are all included, and specifically, hexane fraction, ethyl acetate fraction and methanol fraction can be used. It may also be a fraction isolated by HPLC.
본 발명에서, 상기 배양액 추출물 또는 분획물은 염증성 질환의 예방 또는 치료에 효과가 있는 것을 특징으로 한다. In the present invention, the culture medium extract or fraction is characterized by being effective for the prevention or treatment of inflammatory diseases.
본 발명에서 사용되는 용어, “치료”는 (a) 염증성 질환, 질병 또는 증상의 발전의 억제; (b) 염증성 질환, 질병 또는 증상의 경감; 또는 (c) 염증성 질환, 질병 또는 증상을 제거하는 것을 의미한다. 또한, 용어 “예방”은 본 발명의 조성물의 투여로 염증성 질환의 진행을 지연시키는 모든 행위를 의미한다. 본 발명의 조성물은 LPS로 염증 반응이 유도된 소신경교세포(microglia BV-2)에서 산화질소의 생성을 억제시켜 염증반응을 억제함으로써 염증 증상의 발전을 억제하거나, 이를 제거하거나 또는 경감시키는 역할을 한다. The term " treatment ", as used herein, refers to (a) inhibiting the development of an inflammatory disease, disease or condition; (b) relief of an inflammatory disease, disease or condition; Or (c) eliminating an inflammatory disease, disease, or condition. In addition, the term " prophylactic " means any act that delays the progression of an inflammatory disease upon administration of the composition of the present invention. The composition of the present invention inhibits the production of nitric oxide in microglia BV-2, an inflammatory response induced by LPS, thereby suppressing the inflammatory reaction, thereby suppressing the development of inflammatory symptoms, or eliminating or alleviating the inflammatory symptoms do.
따라서, 본 발명의 조성물은 그 자체로 염증성 질환의 치료 조성물이 될 수도 있고, 혹은 다른 항염증 조성물과 함께 투여되어 이들 질환에 대한 치료 보조제로 적용될 수도 있다. 이에, 본 명세서에서 용어“치료”또는“치료제”는“치료 보조”또는“치료 보조제”의 의미를 포함한다.Thus, the composition of the present invention may itself be a therapeutic composition for an inflammatory disease, or may be administered in combination with other anti-inflammatory compositions and as a therapeutic adjunct for these diseases. Herein, the term " treatment " or " therapeutic agent " includes the meaning of " therapeutic aid "
본 발명의 조성물은 산화질소(NO)의 분비를 억제함으로써 항염증 활성을 갖는 것을 특징으로 한다. 본 발명의 일 실시예에서는 본 발명의 갈대 내생균 배양액 추출물 또는 분획물의 세포 독성을 측정한 결과, 세포 독성이 없음을 확인하여 약학적 조성물로의 사용 가능성을 확인하였으며, 염증 유발 인자인 산화질소(NO)의 생산 및 분비를 억제하는 효과가 우수함을 확인함으로써, 염증성 질환의 치료 및 예방 효과가 우수함을 확인할 수 있었다(도 3 및 도 6).The composition of the present invention is characterized by having anti-inflammatory activity by inhibiting the secretion of nitric oxide (NO). In one embodiment of the present invention, the cytotoxicity of the extract or fraction of live cell culture broth in the reeds of the present invention was confirmed to be cytotoxic and confirmed to be usable as a pharmaceutical composition. NO) production and secretion, it was confirmed that the treatment and prevention of inflammatory diseases are excellent (FIGS. 3 and 6).
본 발명의 염증성 질환 치료 및 예방용 약학적 조성물은, 조성물 총 중량에 대하여 상기 화학식 1의 화합물을 0.0001 내지 99.9 중량%로, 바람직하게는 0.001 내지 10 중량%로 포함할 수 있다.The pharmaceutical composition for treating and preventing an inflammatory disease according to the present invention may contain 0.0001 to 99.9% by weight, preferably 0.001 to 10% by weight, of the compound of formula (I) based on the total weight of the composition.
본 발명에서 용어, "염증성 질환"은 염증을 주병변으로 하는 질병을 총칭하는 의미로서, 이에 제한되지는 않으나, 바람직하게는 부종, 피부염, 알레르기, 아토피, 천식, 결막염, 치주염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 대장염, 치질, 통풍, 강직성 척추염, 류마티스 열, 루푸스, 섬유근통(fibromyalgia), 건선관절염, 골관절염, 류마티스 관절염, 견관절주위염, 건염, 건초염, 근육염, 간염, 방광염, 신장염, 쇼그렌 증후군(sjogren's syndrome) 또는 다발성 경화증일 수 있다.The term " inflammatory disease " in the present invention means a general disease of inflammation as a main lesion, and includes, but is not limited to, edema, dermatitis, allergy, atopy, asthma, conjunctivitis, periodontitis, rhinitis, otitis media, Rheumatism, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, shoulder inflammation, tendonitis, nephritis, myositis, hepatitis, inflammatory bowel disease, inflammatory bowel disease, , Cystitis, nephritis, sjogren's syndrome or multiple sclerosis.
본 발명의 약학적 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용 가능한 담체를 포함하는 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제환제, 산제, 과립제, 캡슐제 등이 포함될 수 있으며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함될 수 있다. 비수성용제, 현탁용제로는 프로필렌 글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. Compositions comprising a pharmaceutically acceptable carrier can be of various oral or parenteral formulations. In the case of formulation, it can be prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used. Solid formulations for oral administration may include tablet pills, powders, granules, capsules and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
또한, 본 발명의 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수용성용제, 동결건조제제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있다.In addition, the pharmaceutical composition of the present invention may be in any form selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, ≪ / RTI >
본 발명의 약학적 조성물은 그 투여용량에 특별한 제약은 없고, 체내 흡수도, 체중, 환자의 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 변화될 수 있다. 일반적으로, 일일 투여량은 바람직하게는 화학식 1의 화합물의 양을 기준으로 0.0001 내지 100 mg/kg일 수 있으며, 보다 바람직하게는 0.001 내지 100 mg/kg일 수 있다. 본 발명의 약학적 조성물은 유효량 범위를 고려하여 제조하도록 하며, 이렇게 제형화된 단위 투여형 제제는 필요에 따라 약제의 투여를 감시하거나 관찰하는 전문가의 판단과 개인의 요구에 따라 전문화된 투약법을 사용하거나 일정 시간 간격으로 수회 투여할 수 있다.The dosage form of the pharmaceutical composition of the present invention is not particularly limited and may be varied depending on the degree of absorption, body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, have. In general, the daily dose may preferably be from 0.0001 to 100 mg / kg, more preferably from 0.001 to 100 mg / kg, based on the amount of the compound of formula (1). The pharmaceutical composition of the present invention is prepared in consideration of an effective dose range, and the unit dosage formulations thus formulated are classified according to the judgment of the expert who monitors or observes the administration of the drug, if necessary, Or may be administered several times at a predetermined time interval.
또 다른 하나의 양태로서, 본 발명은 갈대 내생균 배양액 추출물 또는 분획물을 유효성분으로 포함하는 염증성 질환 치료 및 예방용 건강기능식품을 제공한다.In another aspect, the present invention provides a health functional food for the treatment and prevention of inflammatory diseases, which comprises an extract or fraction of live cell culture solution in reeds as an active ingredient.
본 발명의 건강기능식품에서, 상기 갈대 내생균은 고이마노마이세스(Gaeumannomyces) 속 균주인 것을 특징으로 하고, 상기 고이마노마이세스(Gaeumannomyces) 속 균주는 고이마노마이세스(Gaeumannomyces) JS0464(NIBRFGC000146694)(수탁번호: KACC 83010P)인 것을 특징으로 한다. In the health functional food of the present invention, the live bacteria in the reeds are Gaeumannomyces strains, and the strain of Gaeumannomyces is Gaeumannomyces JS0464 (NIBRFGC000146694) (Accession number: KACC 83010P).
본 발명의 건강기능식품에서, 상기 배양액 추출물 또는 분획물은 염증성 질환의 예방 또는 치료에 효과가 있는 것을 특징으로 하고, 상기 염증성 질환은 부종, 피부염, 알레르기, 아토피, 천식, 결막염, 치주염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 대장염, 치질, 통풍, 강직성 척추염, 류마티스 열, 루프스, 섬유근통(fibromyalgia), 건선관절염, 골관절염, 류마티스관절염, 견관절주위염, 건염, 건초염, 근육염, 간염, 방광염, 신장염, 쇼그렌 증후군(sjogren's syndrom) 및 다발성 경화증으로 구성된 군으로부터 선택된 것을 특징으로 한다. In the health functional food of the present invention, the above-mentioned culture medium extract or fraction is characterized in that it is effective for the prevention or treatment of an inflammatory disease. The inflammatory disease is selected from the group consisting of edema, dermatitis, allergy, atopy, asthma, conjunctivitis, periodontitis, Rheumatoid arthritis, osteoarthritis, rheumatoid arthritis, shoulder inflammation, tendonitis, nephritis, myositis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, Hepatitis, cystitis, nephritis, sjogren's syndrome and multiple sclerosis.
또한, 상기 염증성 질환은 산화질소(Nitric oxide, NO) 매개 염증성 질환인 것을 특징으로 한다.In addition, the inflammatory disease is characterized by being a nitric oxide (NO) mediated inflammatory disease.
상기 갈대 내생균 및 그 배양액 또는 추출물에 대해서는 상기에서 설명한 바와 같으며, 과도한 설명을 피하기 위해 공통된 내용은 반복 기재에 따른 명세서의 과도한 복잡성을 피하기 위하여, 그 기재를 생략한다.The living cells in the reeds and the culture broth or extract thereof are as described above, and in order to avoid the excessive explanation, the common description is omitted in order to avoid the excessive complexity of the specification according to the repetitive description.
본 발명의 조성물을 건강기능식품 첨가물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 건강기능식품 또는 건강기능식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합량은 사용 목적에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 조성물은 원료에 대하여 바람직하게는 15 중량부 이하, 보다 바람직하게는 10 중량부 이하의 양으로 첨가할 수 있다. 그러나, 건강 조절 및 위생을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안정성 면에서 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용할 수 있다.When the composition of the present invention is used as a health functional food additive, the composition may be added as it is or may be used together with other health functional foods or health functional food ingredients, and may be appropriately used according to a conventional method. The amount of the active ingredient to be mixed can be appropriately determined depending on the purpose of use. Generally, the composition of the present invention may be added in an amount of preferably not more than 15 parts by weight, more preferably not more than 10 parts by weight, based on the raw material, in the production of food or beverage. However, in the case of long-term intake intended for health control and hygiene, the amount may be less than the above range, and since there is no problem in terms of stability, the active ingredient may be used in an amount in the above range.
본 발명의 건강기능식품의 종류에는 특별한 제한은 없다. 상기 조성물을 첨가할 수 있는 건강기능식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있고, 통상적인 의미에서의 건강기능식품을 모두 포함할 수 있으며, 동물을 위한 사료로 이용되는 식품을 포함할 수 있다.There is no particular limitation on the kind of the health functional food of the present invention. Examples of the health functional food to which the composition can be added include dairy products such as meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen and other noodles, gums, ice cream, Alcoholic beverages, and vitamin complexes, and may include all the health functional foods in the conventional sense, and foods used as feeds for animals.
또한, 본 발명의 건강기능식품 조성물이 음료의 형태로 사용될 경우에는 통상의 음료와 같이 여러 가지 감미제, 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 수크로스와 같은 디사카라이드, 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 및 자일리톨, 소르비톨, 에리트리톨과 같은 당알콜일 수 있다. 상기 천연 탄수화물의 비율은 이에 제한되지는 않으나, 본 발명의 조성물 100 ㎖ 당 바람직하게는 약 0.01 내지 0.04g, 보다 바람직하게는 0.02 내지 0.03g일 수 있다. 상기 감미제는 타우마틴, 스테비아 추출물과 같은 천연 감미제 및 사카린, 아스파르탐과 같은 합성 감미제일 수 있다.In addition, when the health functional food composition of the present invention is used in the form of a drink, it may contain various sweetening agents, flavoring agents, or natural carbohydrates as additional components such as ordinary beverages. The natural carbohydrates may be polysaccharides such as disaccharides such as monosaccharides such as glucose and fructose, maltose, sucrose, dextrin, cyclodextrins, and sugar alcohols such as xylitol, sorbitol and erythritol. The ratio of the natural carbohydrate is not limited thereto, but may be about 0.01 to 0.04 g, more preferably 0.02 to 0.03 g per 100 ml of the composition of the present invention. The sweeteners may be natural sweeteners such as tau martin and stevia extract, and synthetic sweeteners such as saccharin and aspartame.
상기 외에 본 발명의 건강기능식품 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the above, the health functional food composition of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, , Alcohols, carbonating agents used in carbonated drinks, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks.
또 다른 하나의 양태로서, 본 발명은 수탁번호 KACC 83010P의 고이마노마이세스(Gaeumannomyces) 속 균주 JS0464(NIBRFGC000146694)를 제공한다. 상기 균주는 상기 균주는 염증성 질환 치료 및 예방을 위한 배양액을 생산할 수 있으며, 상기 배양액의 추출물 또는 분획물을 이용하여 염증성 질환의 치료 및 예방용 조성물을 생산할 수 있다.In yet another aspect, the present invention provides a process Goi agate MY (Gaeumannomyces) in strain JS0464 (NIBRFGC000146694) of KACC accession No. 83010P. The strain may produce a culture solution for treating or preventing an inflammatory disease, and the extract or fraction of the culture solution may be used to produce a composition for treating or preventing an inflammatory disease.
상기 고이마노마이세스(Gaeumannomyces) JS0464(NIBRFGC000146694)(수탁번호: KACC83010PP) 균주에 대해서는 상기에서 설명한 바와 같다.The strain of Gaeumannomyces JS0464 (NIBRFGC000146694) (accession number: KACC83010PP) is as described above.
본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:
(i) 본 발명의 갈대 내생균 배양액 추출물 또는 분획물은 미세교세포에서 LPS 처리에 의해 유도되는 산화질소(NO)의 과생성을 억제한다.(i) The extract or fraction of the live cell culture solution in the reeds of the present invention inhibits the overproduction of nitric oxide (NO) induced by LPS treatment in microglia.
(ⅱ) 본 발명의 갈대 내생균 배양액 추출물 또는 분획물은 산화질소 과생성을 저해함으로써 다양한 염증성질환의 치료제로 사용될 수 있다.(Ii) The extract or fraction of the live broth culture solution in the reed of the present invention can be used as a therapeutic agent for various inflammatory diseases by inhibiting nitric oxide and production.
도 1은 본 발명의 고이마노마이세스(Gaeumannomyces) 속 균주 JS0464가 감자한천배지 상에서 생장하는 모습 및 형성된 후막포자에 대한 사진이다.
도 2는 본 발명의 고이마노마이세스(Gaeumannomyces) 속 균주 JS0464가 V8 juice agar 배지 상에서 생장하는 모습을 나타내는 사진이다.
도 3은 본 발명의 고이마노마이세스(Gaeumannomyces) 속 균주 JS0464의 배양액 추추물이 농도 의존적으로 산화질소(NO) 생성 억제를 통해 항염증 활성을 나타냄을 보여주는 그래프이다.
도 4는 본 발명의 고이마노마이세스(Gaeumannomyces) 속 균주 JS0464(NIBRFGC000146694)의 배양액 추추물의 세포독성 실험 결과를 나타내는 그래프이다.
도 5는 본 발명의 분획물에 존재하는 화학식 1 내지 화학식 6의 화합물의 세포독성 실험 결과를 나타내는 그래프이다.
도 6은 본 발명의 분획물에 존재하는 유효성분인 화학식 1 내지 화학식 6의 화합물이 산화질소(NO) 생성 억제를 통해 항염증 활성을 나타냄을 보여주는 그래프이다.
도 7은 고이마노마이세스(Gaeumannomyces) 속 균주 JS0464의 계통도이다.Brief Description of the Drawings Fig. 1 is a photograph showing growth of Gaeumannomyces sp. Strain JS0464 of the present invention on a potato agar culture medium and formed thick-film spores.
2 is a photograph showing the growth of Gaeumannomyces sp. Strain JS0464 of the present invention on a V8 juice agar medium.
FIG. 3 is a graph showing that the culture supernatant of Gaeumannomyces sp. Strain JS0464 of the present invention shows anti-inflammatory activity through inhibition of nitric oxide (NO) production in a concentration-dependent manner.
FIG. 4 is a graph showing the cytotoxicity test results of the culture supernatant of Gaeumannomyces sp. Strain JS0464 (NIBRFGC000146694) of the present invention. FIG.
FIG. 5 is a graph showing the cytotoxicity test results of the compounds of formulas (1) to (6) present in the fractions of the present invention.
FIG. 6 is a graph showing that the compounds of
7 is a flow diagram of Gaeumannomyces sp. Strain JS0464.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention, and it is to be understood by those skilled in the art that the present invention is not limited thereto It will be obvious.
실시예Example
본 명세서 전체에 걸쳐, 특정 물질의 농도를 나타내기 위하여 사용되는 “%“는 별도의 언급이 없는 경우, 고체/고체는 (중량/중량) %, 고체/액체는 (중량/부피) %, 그리고 액체/액체는 (부피/부피) %이다.Throughout this specification, "%" used to denote the concentration of a particular substance is intended to include solids / solids (wt / wt), solid / liquid (wt / The liquid / liquid is (vol / vol)%.
실시예 1. 균주 분리Example 1 Isolation of Strain
항염증 활성이 있는 식물 내생균을 수집하기 위해 먼저 식물 시료로 갈대 뿌리를 확보하였다. In order to collect live bacteria in plants with anti-inflammatory activity, reed roots were first obtained as plant samples.
[표 1] 기주식물 [Table 1] Host plants
채집한 식물 시료는 흐르는 수돗물로 표면에 붙은 흙먼지를 씻고 물기를 닦은 후, 내생균 분리에 사용하였다. 먼저 뿌리 조직은 0.5×0.5cm 크기의 단편으로작게 조각낸 후, 2% 차아염소산나트륨 용액에 1분 동안 살균하고, 다시 70% 에탄올에 1분간 표면 살균한 후, 다시 멸균된 증류수에 1분간 세척하고, 균주 분리용 배지에 치상하였다. 균주분리용 배지는 MEA(malt extract agar, Difco)와 PDA에 50ppm 로즈 벵갈(Rose Bengal), 100ppm 카나마이신(Kanamycin), 100ppm 스트렙토마이신(Streptomycin)을 첨가하여 조제하였다. 표면 살균한 갈대 조각을 균주분리용 배지에 치상한 후, 22℃ 암 조건에서 7일간 배양 후, 자라나오는 균사조각을 다시 PDA(potato dextrose agar, Difco) 배지로 옮겨 순수 배양한 후, 분리된 균주를 넘버링 하고, 국립생물자원관(National Institute of Biological Resources)의 야생 유전자원 은행(Wildlife Genetic Resources Bank)의 액체질소탱크에 20% 글리콜 스탁(glycerol stocks)으로 보관하였다(도 1 및 도 2 참조).The collected plant samples were washed with flowing tap water, and the dirt was wiped off and then used for segregation of endogenous bacteria. First, the root tissue was cut into small pieces with a size of 0.5 × 0.5 cm, sterilized in 2% sodium hypochlorite solution for 1 minute, sterilized in 70% ethanol for 1 minute and then washed again in sterilized distilled water for 1 minute , And subjected to a strain-separating medium. The culture broth was prepared by adding MEA (malt extract agar, Difco) and 50 ppm of Rose Bengal, 100 ppm of kanamycin, and 100 ppm of streptomycin to the PDA. The surface-sterilized reed pieces were placed in a culture medium for strain isolation, cultured for 7 days under a dark condition at 22 ° C., and mycelium pieces were transferred to a PDA (potato dextrose agar, Difco) medium for pure culture. And stored in 20% glycerol stocks in a liquid nitrogen tank of the Wildlife Genetic Resources Bank of the National Institute of Biological Resources (see Figures 1 and 2).
실시예 2. 갈대 내생균 배양액 추출물의 항염증 활성 분석Example 2. Analysis of Anti-inflammatory Activity of Extracts of Live Cell Cultures in Reed
상기 실시예 1에서 분리한 갈대 내생균의 항염증 활성 분석을 위해, 갈대 내생균들을 PD(potato dextrose) broth에서 3주간 진탕배양 후, 배양여액을 에틸 아세테이트로 추출하여 갈대 내생균 배양액 추출물을 수득하였다. For the analysis of the anti-inflammatory activity of the live cells in the reed separated from the above Example 1, the live bacteria in the reed were cultured in PD (potato dextrose) broth for 3 weeks, and then the culture filtrate was extracted with ethyl acetate to obtain a live bacterial culture extract Respectively.
경희대학교 오명숙 교수 연구실에서 제공받은 BV-2(murine microglial cells) 세포를 4g/L의 글루코오스, 3.7 g/L 소듐 바이카보네이트, 10% FBS(fetal bovine serum) 및 항생물질(100units/ml 페니실린 및 100μg/ml 스트렙토마이신)을 포함하는 낮은 글루코오스 농도의 DMEM(pH 7.2 - 7.4) 배지를 이용하여, 5% CO2, 37℃, 습윤 조건 하에서 배양하였다.BV-2 (murine microglial cells) cells provided by Professor Oh, Myung-Sook of Kyung Hee University were treated with 4 g / L glucose, 3.7 g / L sodium bicarbonate, 10% fetal bovine serum and antibiotics (100 units / ml penicillin and 100 μg / ml streptomycin) at a low glucose concentration in DMEM (pH 7.2-7.4) medium at 5% CO 2 , 37 ° C.
상기 배양된 BV-2(murine microglial cells) 세포를 5×104(세포/웰) 농도로 96-웰 클리어 바텀 플레이트(Costar, Cambridge, MA)에서 하루 동안 세포를 배양한 후, 각각 24시간 동안 1μ농도의 LPS(Lipopolysaccharide, Sigma-Aldrich, St. Louis, U.S.A)를 처리하여 배양하여 대조군으로 사용하였다. 상기 LPS 처리 3시간 전에, DMEM 배지(0.5% DMSO 포함)에 용해된 상기 갈대 내생균 배양액 추출물들을 각각 10ppm, 25ppm, 및 50ppm 농도로 처리하여 시험군으로 사용하였다. The cultured BV-2 (murine microglial cells) cells were cultured in a 96-well clear bottom plate (Costar, Cambridge, Mass.) At a concentration of 5 × 10 4 cells / well for 24 hours (Lipopolysaccharide, Sigma-Aldrich, St. Louis, USA) was used as a control. Three hours before the LPS treatment, the live cell culture extracts in the reeds dissolved in DMEM medium (including 0.5% DMSO) were treated at concentrations of 10 ppm, 25 ppm, and 50 ppm, respectively, and used as a test group.
산화질소를 검출하기 위해서, 세포 배양액의 상등액으로 그리스 시약(Griess reagent) 변색 반응을 수행하였다. LPS 처리 24시간 후, 수득한 50㎕의 세포 배양액 상등액을 그리스 시약과 1:1 부피비로 혼합하고, 96-웰 마이크로플레이트 리더 흡광도 측정기(Synergy HT, Bio-Tek Instruments, Inc., Winooski, VT)를 시용하여 540nm에서 흡광도를 측정하였다. In order to detect nitric oxide, a Griess reagent discoloration reaction was performed with the supernatant of the cell culture liquid. After 24 hours of LPS treatment, 50 占 퐇 of the cell culture supernatant was mixed with a grease reagent at a volume ratio of 1: 1, and a 96-well microplate reader absorbance meter (Synergy HT, Bio-Tek Instruments, Inc., Winooski, And the absorbance at 540 nm was measured.
상기 BV-2 세포주을 통한 NO 생성 억제 효과 확인실험의 결과를 도 3에 나타내었다.FIG. 3 shows the results of the experiment for confirming the inhibition of NO production through the BV-2 cell line.
그 결과, 갈대 내생균 JS0464(NIBRFGC000146694)의 배양액 추출물을 처리한 시험군은 LPS 단독 처리군에 비해, 각각 15.1%(10ppm), 35.3%(25ppm), 및 71.1%(50ppm) 개선된 NO 생성 억제 효과를 보여, 농도 의존적으로 염증반응 억제 효과가 있는 것으로 나타났으며, 10ppm 농도 처리군에서도 LPS 단독 처리군과 비교하여 유의한 차이를 보이는 것으로 나타났다.As a result, the test group treated with the culture extract of live yeast strain JS0464 (NIBRFGC000146694) in the reeds showed 15.1% (10 ppm), 35.3% (25 ppm) and 71.1% (50 ppm) The results showed that there was a significant effect on the inhibition of inflammation response in the concentration - dependent manner. In the 10 ppm concentration treatment group, there was a significant difference compared to the LPS alone treatment group.
실시예 3. 갈대 내생균 배양액 추출물의 분획물 분리Example 3. Fractionation of Extracts of Live Bacterium Culture Solution in Reed
감자한천액체배지(PD broth)에서 배양한 갈대 내생균 JS0464 (NIBRFGC000146694)의 배양여액을 에틸 아세테이트(EtOAc) 용매를 동량으로 혼합후 재분리하는 방법으로 3회 추출하였다. The culture filtrate of the reed broth JS0464 (NIBRFGC000146694) cultivated in potato agar broth (PD broth) was extracted three times by mixing the same amount of ethyl acetate (EtOAc) solvent and re-separating.
추출된 혼합 용액을 45℃ 감압조건 하에서 건조하여 에틸아세테이트 추출물을 수득하였다. 이렇게 수득한 에틸아세테이트 추출물 70g을 실리카 겔 컬럼 크로마토그리피[n-Hexane-EtOAc-MeOH 농도 구배(v/v/v, 50:1:0 → 2:1:0.1 → 0:0:1) 용액]를 이용하여 크로마토그래피를 진행하고, A에서 F까지 6개의 분획물을 수득하였다. The extracted mixed solution was dried under reduced pressure at 45 캜 to obtain an ethyl acetate extract. 70 g of the thus-obtained ethyl acetate extract was purified by silica gel column chromatography [n-Hexane-EtOAc-MeOH gradient (v / v / v, 50: 1: 0 -> 2: 1: 0.1 -> 0: , And six fractions A to F were obtained.
상기 분획물 E를 HPLC를 이용하여 정제하였고, 다시 실리카 겔 컬럼 크로마토그래피[n-Hexane-EtOAc-MeOH 농도구배(v/v/v, 8:1:0 → 2:1:0.1]를 이용하여 크로마토그래피를 진행하여, E1에서 E12까지의 분획물을 수득하였다. The fraction E was purified by HPLC and further purified by silica gel column chromatography [n-Hexane-EtOAc-MeOH gradient (v / v / v, 8: 1 → 0 → 2: 1: 0.1] And the fraction was eluted from E1 to E12.
상기 분획물 E11을 H2O-MeOH 용매(v/v, 95:5 → 0:100) 농도구배 시스템을 적용한 C-18 컬럼 크로마토그래피를 이용한 HPLC를 수행하여, 본 발명의 상기 화학식 1의 화합물(38.4mg)을 수득하였다. Solvent the fraction E11 H 2 O-MeOH (v / v, 95: 5 → 0: 100) by performing HPLC using a C-18 column chromatography applying the gradient system, the compound of formula (I) of the present invention ( 38.4 mg).
[화학식 1][Chemical Formula 1]
또한, 상기 분획물 E12를 MeOH-H2O 용매(v/v, 1:1 → 4:1) 농도구배 시스템을 적용한 C-18 컬럼 크로마토그래피를 이용하여, 본 발명의 상기 화학식 2의 화합물(6.2mg)을 수득하였다. Further, MeOH-H 2 O solvent the fraction E12 (v / v, 1: 1 → 4: 1) applying a gradient system using a C-18 column chromatography to give the compound of
[화학식 2](2)
상기 분획물 F를 세파덱스 LH-20(Sephadex LH-20)에 넣고, 메탄올 등용매용리(isocratic) 방식의 크로마토그래피를 진행하여, F1에서 F20까지의 분획물을 수득하였다.The fraction F was added to Sephadex LH-20 (Sephadex LH-20) and chromatographed using an isocratic method such as methanol to obtain fractions from F1 to F20.
상기 분획물 F14를 H2O-MeOH 용매(v/v, 95:5 → 0:100) 농도구배 시스템을 적용한 C-18 컬럼 크로마토그래피를 이용한 HPLC를 수행하여, 본 발명의 상기 화학식 3의 화합물(1.8mg)을 수득하였다. The fractions F14 to H 2 O-MeOH solvent (v / v, 95: 5 → 0: 100) concentration of applying the gradient system by performing HPLC using a C-18 column chromatography to give the compound of formula (III) of the present invention ( 1.8 mg).
[화학식 3](3)
또한, 상기 E8 분획물을 결정화화여 본 발명의 상기 화학식 4의 화합물(2.8 mg)을 수득하였다. Further, the E8 fraction was crystallized to obtain the compound of Formula 4 (2.8 mg) of the present invention.
[화학식 4][Chemical Formula 4]
분획물 C를 다시 실리카 겔 컬럼 크로마토그래피[n-Hexane-EtOAc 농도구배(v/v, 100:1 → 7:1)]를 이용하여 크로마토그래피를 진행하여, 본 발명의 상기 화학식 5의 화합물(총량 4.0mg)을 수득하였다. The fraction C was further subjected to chromatography using silica gel column chromatography [n-Hexane-EtOAc gradient (v / v, 100: 1 - > 7: 1)] to obtain the compound of the formula 4.0 mg).
[화학식 5][Chemical Formula 5]
상기 E7 분획물을 아세톤, 메탄올, 및 물로 농도구배[Acetone-MeOH-Water (v/v/v, 0:1:1 → 7:7:1)]한 용매 시스템을 적용한 C-18 컬럼 크로마토그래피(C-18 column chromatography)를 이용하여, 본 발명의 상기 화학식 5의 화합물(7.0mg), 및 상기 화학식 6의 화합물(5.7 mg)을 각각 수득하였다.The above E7 fraction was subjected to C-18 column chromatography using a solvent system with a concentration gradient [Acetone-MeOH-Water (v / v, 0: 1: 1 → 7: 7: 1)] with acetone, methanol and water C-18 column chromatography, the compound of Formula 5 (7.0 mg) of the present invention and the compound of Formula 6 (5.7 mg) were obtained, respectively.
[화학식 6][Chemical Formula 6]
실시예 4. 세포 독성 검정Example 4. Cytotoxicity assay
상기 실시예 2의 내생균 배양여액 추출물과 상기 실시에 3의 화학식 1 내지 6의 화합물들이 마우스 BV-2(murine microglial cells) 세포의 생장에 미치는 효과를 아래와 같은 방법으로 확인하였다. The effect of the extract solution of the live bacteria in Example 2 on the growth of mouse BV-2 (murine microglial cells) was confirmed by the following method.
상기 BV-2(murine microglial cells) 세포를 4g/L의 글루코오스, 3.7 g/L 소듐 바이카보네이트, 10% FBS(fetal bovine serum) 및 항생물질(100units/ml 페니실린 및 100μg/ml 스트렙토마이신)을 포함하는 낮은 글루코오스 농도의 DMEM(pH 7.2 - 7.4) 배지를 이용하여, 5% CO2, 37℃, 습윤 조건 하에서 배양하였다.The BV-2 (murine microglial cells) cells were incubated with 4 g / L glucose, 3.7 g / L sodium bicarbonate, 10% fetal bovine serum and antibiotics (100 units / ml penicillin and 100 ug / ml streptomycin) The cells were cultured in DMEM (pH 7.2-7.4) medium with low glucose concentration under 5% CO 2 , 37 ° C, wet conditions.
배양된 BV-2(murine microglial cells) 세포를 5×104(세포/웰) 농도로 96-웰 클리어 바텀 플레이트(Costar, Cambridge, MA)에서 하루 동안 세포를 배양한 후, DMEM 배지(0.5% DMSO 포함)에 용해된 상기 내생균 배양액 추출물과 상기 화학식 1 내지 6의 화합물(50μM)을 처리하여 시험군으로 사용하였다.The cultured BV-2 (murine microglial cells) cells were cultured in 96-well clear bottom plates (Costar, Cambridge, Mass.) At a concentration of 5 × 10 4 cells / DMSO) and the compound of the
세포 생존율은 MTS 분석 키트(Promega, Madison, WI)를 사용하여 제조사 매뉴얼에 따라 분석하였다. 미토콘드리아 디하이드로게나아제의 활성에 직접적으로 비례하는 포마잔(formazan) 생성물의 양은 490nm에서 측정하였다.Cell viability was analyzed according to the manufacturer's manual using an MTS assay kit (Promega, Madison, Wis.). The amount of formazan product directly proportional to the activity of mitochondrial dehydrogenase was measured at 490 nm.
R i386 3.3.0 소프트웨어를 사용하여 Student's t-test를 수행하였다. 모든 수치는 적어도 3회 이상의 독립적인 실험값에 대한 평균±표준오차로 표시하였다. Student's t-test was performed using R i386 3.3.0 software. All values are expressed as mean ± standard error for at least 3 independent experiments.
그 결과, 상기 실시예 2의 내생균 배양액 추출물(도 4 참조)과 화학식 1 내지 6의 화합물(도 5 참조)을 처리한 경우, 마우스 BV-2(murine microglial cells) 세포의 생존율에 크게 영향을 미치지 않는 것으로 확인되었으며, 특히, 상기 화학식 2의 화합물을 처리한 군에서는 무처리 군에 비해 세포생존율이 17.2% 증가하는 현상을 관찰 할 수 있었다(도 5 참조). 이러한 결과를 통해 본 발명의 내생균 배양액 추출물과 상기 화합물들이 인체에 독성을 나타내지 않음을 확인할 수 있었다. As a result, the survival rate of mouse BV-2 (murine microglial cells) cells was significantly influenced by the treatment with the extract of endogenous culture broth of Example 2 (see FIG. 4) and the compounds of
실시예 5. 분획물 포함되어 있는 유효 화합물에 대한 항염증 활성 검정Example 5. Anti-inflammatory Activity Assay for Active Compounds Containing Fractions
상기 실시예 3에서 배양된 BV-2(murine microglial cells) 세포를 5×104(세포/웰) 농도로 96-웰 클리어 바텀 플레이트(Costar, Cambridge, MA)에서 하루 동안 세포를 배양한 후, 각각 24시간 동안 1μ농도의 LPS(Lipopolysaccharide, Sigma-Aldrich, St. Louis, U.S.A)를 처리하여 배양하여 대조군으로 사용하였다. 상기 LPS 처리 3시간 전에, DMEM 배지(0.5% DMSO 포함)에 용해된 상기 화학식 1 내지 6의 화합물(50μM)을 처리하여 시험군으로 사용하였다. Cells of BV-2 (murine microglial cells) cultured in Example 3 were cultured in a 96-well clear bottom plate (Costar, Cambridge, Mass.) At a concentration of 5 × 10 4 cells / (Lipopolysaccharide, Sigma-Aldrich, St. Louis, USA) at a concentration of 1 μg for 24 hours and then used as a control. Three hours before the LPS treatment, the compounds of the formulas (1) to (6) (50 μM) dissolved in DMEM medium (containing 0.5% DMSO) were treated and used as a test group.
산화질소를 검출하기 위해서, 세포 배양액의 상등액으로 그리스 시약(Griess reagent) 변색 반응을 수행하였다. LPS 처리 24시간 후, 수득한 50㎕의 세포 배양액 상등액을 그리스 시약과 1:1 부피비로 혼합하고, 96-웰 마이크로플레이트 리더 흡광도 측정기(Synergy HT, Bio-Tek Instruments, Inc., Winooski, VT)를 시용하여 540nm에서 흡광도를 측정하였다. In order to detect nitric oxide, a Griess reagent discoloration reaction was performed with the supernatant of the cell culture liquid. After 24 hours of LPS treatment, 50 占 퐇 of the cell culture supernatant was mixed with a grease reagent at a volume ratio of 1: 1, and a 96-well microplate reader absorbance meter (Synergy HT, Bio-Tek Instruments, Inc., Winooski, And the absorbance at 540 nm was measured.
상기 BV-2 세포주을 통한 NO 생성 억제 효과 확인실험의 결과를 도 6에 나타내었다.The results of the experiment for confirming the inhibition of NO production through the BV-2 cell line are shown in FIG.
그 결과, 본 발명의 화학식 1 내지 6의 화합물을 처리한 시험군은 LPS 단독 처리군에 비해, 각각 41.7%(화학식 1), 23.7%(화학식 2), 68.7%(화학식 3), 57.1%(화학식 4), 97.6%(화학식 5), 및 35.1%(화학식 6) 개선된 염증억제 효과를 보였다. As a result, the test group treated with the compounds of formulas (1) to (6) of the present invention showed 41.7% (Formula 1), 23.7% (Formula 2), 68.7% (Formula 3), 57.1% (Formula 4), 97.6% (Formula 5), and 35.1% (Formula 6).
상기와 같은 결과를 통해 배양액 추출물의 분획물이 산화질소(NO) 생성 억제 기전을 통해 염증반응 억제 효과가 있는 것을 알 수 있었다.From the above results, it was found that the fraction of the culture extract had an inhibitory effect on inflammation through the inhibition mechanism of nitric oxide (NO) production.
실시예 6. JS0464(NIBRFGC000146694) 균주의 염기서열 분석을 통한 동정Example 6. Identification by Sequence Analysis of the JS0464 (NIBRFGC000146694) Strain
상기 실시예 1에서 분리된 JS0464(NIBRFGC000146694) 균주부터 DNA를 분리하였다. 분리된 DNA를 ITS1 및 ITS4 프라이머를 이용하여 ITS(Internal Transcribed Spacer) 서열을 증폭하였고, ITS 염기서열을 확보하였다(Gardes and Bruns, 1993; White et al., 1990). DNA was isolated from the strain JS0464 (NIBRFGC000146694) isolated in Example 1 above. The isolated DNA was amplified with ITS1 and ITS4 primers to obtain ITS sequences (Gardes and Bruns, 1993; White et al., 1990).
확보된 염기서열은 서열분석(Sequencher) 프로그램을 이용하여 고품질 영역을 확보하고 조립하여 컨센서스 서열(consensus sequence)을 확정하고, NCBI의 뉴클레오타이드 데이터베이스를 대상으로 BLAST 검색을 수행하였다. 다중정렬 및 계통유연관계 분석은 MEGA 프로그램을 이용하였다.The obtained nucleotide sequences were sequenced using a Sequencher program to assure high-quality regions and to assemble a consensus sequence, and BLAST searches were performed on NCBI's nucleotide database. Multiple alignment and phylogenetic relationships were analyzed using the MEGA program.
ITS 염기서열 정보를 바탕으로 수행한 NCBI Blast 검색에서, JS0464(NIBRFGC000146694) 균주는 고이마노마이세스(Gaeumannomyces)(유성기)-피알로포라(Phialophora)(무성기) 속(Genus)의 종복합체(species complex)로 분류되었다(도 7 참조). In the NCBI Blast search performed on the basis of ITS nucleotide sequence information, the strain JS0464 (NIBRFGC000146694) was isolated from the genome of the genus Gaeumannomyces (phloem) -phialophora (genera) complex (see Fig. 7).
상기 JS0464(NIBRFGC000146694) 균주가 얇은 콜로니형, 파이알형(phial-like) 분생자 자루(conidiophores) 또는 겸형(sickle-shaped) 분생자(conidia) 등의 특징을 갖는 하르포포라 속과는 다른 표현형을 갖는 것을 고려하여 잠정적으로 고이마노마이세스(Gaeumannomyces) 속 균주 JS0464(NIBRFGC000146694)로 명명하고, 국립농업과학원 농업유전자원정보센터에 기탁번호(KACC 83010P)로 기탁하였다. The JS0464 (NIBRFGC000146694) strain has a phenotype different from that of the Harpofora, which has the characteristics of a thin colony type, phial-like conidiophores or sickle-shaped conidia (NIBRFGC000146694), and deposited it with the accession number (KACC 83010P) to the National Institute of Agricultural Science and Technology Information Center of the National Academy of Sciences.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 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. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (14)
[화학식 1]
[화학식 3]
[화학식 4]
[화학식 5]
[Chemical Formula 1]
(3)
[Chemical Formula 4]
[Chemical Formula 5]
상기 배양액 추출물 또는 분획물은 산화질소(Nitric oxide, NO) 매개 염증성 질환의 예방 또는 치료에 효과가 있는 것을 특징으로 하는 염증성 질환 치료 및 예방용 약학적 조성물.The method according to claim 1,
Wherein the culture medium extract or fraction is effective for the prevention or treatment of nitric oxide (NO) mediated inflammatory diseases.
상기 배양액 추출물 또는 분획물을 전체 조성물의 0.001 내지 10 중량% 포함하는 것을 특징으로 하는 약학적 조성물.The method according to claim 1,
Wherein said culture medium extract or fraction comprises 0.001 to 10% by weight of the total composition.
[화학식 1]
[화학식 3]
[화학식 4]
[화학식 5]
[Chemical Formula 1]
(3)
[Chemical Formula 4]
[Chemical Formula 5]
상기 염증성 질환은 산화질소(Nitric oxide, NO) 매개 염증성 질환인 것을 특징으로 하는 염증성 질환의 예방용 건강기능식품.9. The method of claim 8,
Wherein said inflammatory disease is nitric oxide (NO) mediated inflammatory disease.
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| KR20210065274A (en) | 2019-11-26 | 2021-06-04 | 단국대학교 천안캠퍼스 산학협력단 | Anti-inflammatory composition for prevention or treatment comprising ion-emitted bioactive glass nanoparticle |
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| KR102194460B1 (en) * | 2019-01-14 | 2020-12-23 | 전남대학교산학협력단 | Immunostimulative, antifungal and nematicidal agent comprising Chaetomium novozelandicum CNUFC-DDS9-1 strain and the method for immunostimulative activation and biocontrol using the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101151718B1 (en) | 2010-04-23 | 2012-06-15 | 중앙대학교 산학협력단 | Composition for Skin Moisturizing or Treating Dermatitis or Atopic Dermatitis Comprising Extract from Phragmitis Rhizoma |
| KR101897644B1 (en) * | 2016-08-24 | 2018-11-01 | 대한민국 | Novel Compounds Derived from Endophytic Fungal Strain Isolated from the Rhizome of Reed Plant and Composition for Treating and Preventing Inflammatory Disease Comprising the Same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101151718B1 (en) | 2010-04-23 | 2012-06-15 | 중앙대학교 산학협력단 | Composition for Skin Moisturizing or Treating Dermatitis or Atopic Dermatitis Comprising Extract from Phragmitis Rhizoma |
| KR101897644B1 (en) * | 2016-08-24 | 2018-11-01 | 대한민국 | Novel Compounds Derived from Endophytic Fungal Strain Isolated from the Rhizome of Reed Plant and Composition for Treating and Preventing Inflammatory Disease Comprising the Same |
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| British Journal of Pharmacology, Vol. 150, Pages 209-219(온라인 공개일: 2006. 12. 11.). |
| 이상선 외 3명, Arbusschlar 내생균근 균의 포트 배양에 관한 연구, 한국균학회지, 1993, Vol(21), No(1), pp38-50 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20210065274A (en) | 2019-11-26 | 2021-06-04 | 단국대학교 천안캠퍼스 산학협력단 | Anti-inflammatory composition for prevention or treatment comprising ion-emitted bioactive glass nanoparticle |
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