KR101730607B1 - Composition comprising extracellular vesicles derived from fermented food, and use thereof - Google Patents
Composition comprising extracellular vesicles derived from fermented food, and use thereof Download PDFInfo
- Publication number
- KR101730607B1 KR101730607B1 KR1020160029638A KR20160029638A KR101730607B1 KR 101730607 B1 KR101730607 B1 KR 101730607B1 KR 1020160029638 A KR1020160029638 A KR 1020160029638A KR 20160029638 A KR20160029638 A KR 20160029638A KR 101730607 B1 KR101730607 B1 KR 101730607B1
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- endoplasmic reticulum
- inflammatory
- extracellular endoplasmic
- extracellular
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Abstract
본 발명은 발효식품에서 분리한 세포밖 소포체를 이용하여 염증성 질환 및 암을 치료 또는 예방하는 방법 등에 관한 것이다. 구체적으로, 본 발명은 발효식품에서 유래된 세포밖 소포체를 유효성분으로 함유하는 염증성 질환 및 암의 예방 및/또는 치료용 조성물, 상기 세포밖 소포체를 유효성분으로 함유하는 염증성 질환 및 암의 치료 또는 예방용 백신을 제공한다. 또한, 본 발명의 발효식품 유래 세포밖 소포체를 이용하여 발효식품의 안전성을 진단할 수 있다.The present invention relates to a method for treating or preventing an inflammatory disease and cancer using an extracellular endoplasmic reticulum isolated from a fermented food. Specifically, the present invention relates to a composition for prevention and / or treatment of inflammatory diseases and cancers containing an extracellular endoplasmic reticulum derived from a fermented food as an active ingredient, a composition for the treatment or prophylaxis of inflammatory diseases and cancers containing the extracellular endoplasmic reticulum as an active ingredient, Prevention vaccine. Further, the safety of the fermented food can be diagnosed by using the extracellular endoplasmic reticulum derived from the fermented food of the present invention.
Description
본 발명은 발효식품에서 분리한 세포밖 소포체를 유효성분으로 함유하는 염증성 질환 및 암의 치료 또는 예방용 조성물, 및 상기 세포밖 소포체를 이용한 식품의 안전성 진단 방법 등에 관한 것이다. The present invention relates to a composition for treating or preventing an inflammatory disease and cancer containing an extracellular endoplasmic reticulum isolated from a fermented food as an active ingredient, and a method for diagnosing the safety of a food using the extracellular endoplasmic reticulum.
염증(Inflammation)은 세포 및 조직의 손상이나 감염에 대한 국소적인 또는 전신적인 방어 기작이다. 염증은 주로 면역계를 이루는 수많은 체액성 매개체(humoral mediator)가 직접 반응하거나 국소적 또는 전신적 작동 시스템(effector system)을 자극함으로써 일어나는 연쇄적인 생체반응에 의해 유발된다. 이러한 염증반응에 관여하는 매개체들로는 조력 T 림프구 (helpher T lymphocyte, Th cell), cytotoxic T lymphocyte (Tc cell) 등과 같은 면역세포, 대식세포 (macrophage), 호중구 (neutrophil), 호산구 (eosinophil), 비만세포 (mast cell) 등과 같은 염증세포와 이들 세포에서 분비되는 사이토카인 등이 있다. 염증성 질환은 특히, 염증성 사이토카인의 분비, 이로 인한 조직손상과 치유의 불균형에 의한 조직개형을 특징으로 한다. 현재까지 알려진 주요한 염증성 사이토카인으로는 대식세포 및 단핵구 세포에 의해 생성되는 TNF-α(tumor necrosis factor-α), IL-1 (interleukin-1, 인터루킨-1), IL-6, 및 IL-8 등이 있다. 이와 같은, 염증성 사이토카인의 불균형에 의한 염증성 질환을 치료하기 위하여 상기 염증성 사이토카인을 억제하고자 하는 연구가 다양하게 이루어지고 있다. Inflammation is a local or systemic defense mechanism for damage or infection of cells and tissues. Inflammation is mainly caused by a series of biological reactions, which are caused by a number of humoral mediators that make up the immune system, either directly or by stimulating a local or systemic effector system. The mediators involved in this inflammatory reaction include immune cells such as helper T lymphocytes (Th cells), cytotoxic T lymphocytes (Tc cells), macrophages, neutrophils, eosinophils, (mast cells) and the like, and cytokines secreted from these cells. Inflammatory diseases are particularly characterized by the secretion of inflammatory cytokines, tissue remodeling due to tissue imbalance and healing imbalance. The major inflammatory cytokines known so far include TNF-α, IL-1 (interleukin-1, interleukin-1), IL-6, and IL-8 produced by macrophages and monocytes . There have been various studies to inhibit the inflammatory cytokine in order to treat inflammatory diseases caused by the imbalance of inflammatory cytokines.
주요 염증성 질환으로는 천식, 만성폐쇄성폐질환, 비염 등의 호흡기질환, 아토피 피부염 등의 피부질환, 위염, 위궤양, 염증성 장염 등의 소화기질환이 포함되며, 기타 감염성 비염, 알레르기성 비염, 만성 비염, 급성 부비동염 및 만성 부비동염 등과 같은 비염 및 부비동염; 급성화농성 중이염 및 만성화농성 중이염 등과 같은 중이염; 세균성 폐렴, 기관지 폐렴, 대엽성 폐렴, 레지오렐라 폐렴 및 바이러스성 폐렴 등과 같은 폐렴; 급성 또는 만성 위염; 감염성 소장결장염, 크론씨 병(Crohn's disease), 특발성 궤양성 대장염, 위막성 대장염 등과 같은 장염; 화농성 관절염, 결핵성 관절염, 퇴행성 관절염 및 류마티스 관절염 등과 같은 관절염; 및 당뇨병, 동맥경화증 등이 있다. Major inflammatory diseases include gastrointestinal diseases such as asthma, chronic obstructive pulmonary disease, respiratory diseases such as rhinitis, skin diseases such as atopic dermatitis, gastritis, gastric ulcer and inflammatory bowel disease, and other infectious rhinitis, allergic rhinitis, Rhinitis and sinusitis such as acute sinusitis and chronic sinusitis; Otitis media such as acute purulent otitis media and chronic purulent otitis media; Pneumonia such as bacterial pneumonia, bronchopneumonia, lobar pneumonia, Legorella pneumonia and viral pneumonia; Acute or chronic gastritis; Enteritis such as infectious enterocolitis, Crohn's disease, idiopathic ulcerative colitis, pseudomembranous colitis; Arthritis such as pyogenic arthritis, tuberculous arthritis, degenerative arthritis and rheumatoid arthritis; And diabetes, arteriosclerosis, and the like.
암의 발생에 염증이 중요하다는 가설은 수세기 이전부터 제기되어 왔었고, 만성 염증에 따른 조직손상과 이의 치유과정의 잘못으로 암이 발생한다고 제안되었다. 또한, 대장에 발생하는 염증성 장염의 발생에 장내 세균이 중요하다고 알려져 있다. 염증성 장염에는 크게 Th1 면역반응을 특징으로 하는 크론병과 Th17 면역반응을 특징으로 하는 궤양성대장염이 있다. 만성 염증성 장염이 대장암의 위험인자로 주목을 받고 있는데, 특히 궤양성 대장염 환자에서 대장암의 발생률이 현저히 증가한다고 알려져 있다. Th17 면역반응의 발생에는 IL-6의 역할이 매우 중요하고, 이는 STAT3를 통한 신호전달경로를 통해 naive T 세포에 대하여 IL-17을 분비하는 Th17 세포로 분화를 유도한다. The hypothesis that inflammation is important in the development of cancer has been raised since centuries ago, and it has been suggested that cancer is caused by tissue damage caused by chronic inflammation and the healing process. It is also known that intestinal bacteria are important for the development of inflammatory bowel disease in the large intestine. Inflammatory enteritis is largely characterized by Crohn's disease characterized by a Th1 immune response and ulcerative colitis characterized by a Th17 immune response. Chronic inflammatory bowel disease is a risk factor for colorectal cancer, especially in patients with ulcerative colitis, the incidence of colorectal cancer is known to be significantly increased. The role of IL-6 in the development of Th17 immune response is very important and induces differentiation into Th17 cells that secrete IL-17 to naive T cells through the pathway through STAT3.
최근 보고에 의하면 장내 세균 중에서 metalloprotease toxin을 분비하는 Bactroides fragillus 균이 IL-6 분비를 유도하고, 이는 STAT3 신호를 통해 Th17 면역반응을 유도하여, 대장암을 발생시킨다는 동물실험결과가 주목을 받고 있다. Recent reports have shown that Bactroides fragillus, which secretes metalloprotease toxin from intestinal bacteria, induces IL-6 secretion, which induces Th17 immunoreactivity through STAT3 signaling, resulting in the development of colorectal cancer.
원핵세포 또는 진핵세포는 세포밖 소포체를 분비하고, 분비된 세포밖 소포체는 여러 기능들이 있음이 최근 보고 되었다. 그람 음성균에서 분비된 세포밖 소포체는 내독소(lipopolysacharide, LPS)와 세균 유래 단백질들을 함유하고 있고, 염증성 질환을 유도하는 것으로 알려져 있다. 또한, 여러 종의 암세포에서 유래된 세포밖 소포체는 암세포의 성장 및 전이에 필요한 단백질들을 함유하고 있음이 보고되었다. Prokaryotic or eukaryotic cells secrete extracellular endoplasmic reticulum, and secreted extracellular endoplasmic reticulum has various functions. The extracellular endoplasmic reticulum secreted by Gram-negative bacteria contains lipopolysaccharide (LPS) and bacterial-derived proteins and is known to induce inflammatory diseases. In addition, it has been reported that the extracellular endoplasmic reticulum derived from various cancer cells contains proteins necessary for growth and metastasis of cancer cells.
최근 본 발명자들은 그람 양성균이 세포밖 소포체를 분비하고, 프로테옴 분석을 통해 소포체 내에 질병을 일으키는 단백질이 포함되어 있음을 보고하였고, 이를 피부에 투여하였을 때 아토피피부염이 발생함을 보고하였다. Recently, the present inventors have reported that Gram-positive bacteria secrete extracellular endoplasmic reticulum and proteins that cause disease in the endoplasmic reticulum through proteome analysis and that atopic dermatitis occurs when administered to skin.
한편, 발효식품은 세균 혹은 효모 등이 원래 식품이 가지고 있는 기질을 대사함으로 인해 발효 이전의 성분과는 전혀 다른 성분을 함유하고 있다. 발효 산물의 항염증 및 항암 효과에 대해 수많은 보고가 있었지만, 아직까지 발효식품 내 발효를 일으키는 세균 혹은 효모에 의한 세포밖 소포체의 생성 유무, 이의 역할 및 임상적인 중요성에 대해서는 알려진 바 없다. Fermented foods, on the other hand, contain substances that are completely different from the components before fermentation, since bacteria or yeast metabolize the substrate of the original food. There have been many reports on the anti-inflammatory and anti-cancer effects of fermented products. However, the production of extracellular endoplasmic reticulum by bacterial or yeast causing fermentation in fermented foods, its role and clinical significance are not known.
본 발명은 발효식품에서 유래하는 세포밖 소포체를 이용하여 염증성 질환 및 암을 예방 및/또는 치료하는 방법을 제공하고자 한다. 구체적으로, 본 발명은 상기 세포밖 소포체를 유효성분으로 함유하는, 염증성 질환 및 암의 예방 및/또는 치료용 조성물, 염증성 질환 및 암의 치료 또는 예방용 백신을 제공한다. 이에 더하여, 본 발명은 발효식품에서 유래하는 세포밖 소포체를 이용하여 발효식품의 안정성을 진단하는 방법 등을 제공한다. The present invention provides a method for preventing and / or treating an inflammatory disease and cancer using an extracellular endoplasmic reticulum derived from a fermented food. Specifically, the present invention provides a composition for the prevention and / or treatment of inflammatory diseases and cancer, a vaccine for the treatment or prevention of inflammatory diseases and cancer, containing the extracellular endoplasmic reticulum as an active ingredient. In addition, the present invention provides a method for diagnosing the stability of a fermented food using an extracellular endoplasmic reticulum derived from a fermented food.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다. However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
본 발명은 발효식품에서 유래된 세포밖 소포체를 유효 성분으로 함유하는, 염증성 질환 및 암의 치료 또는 예방용 조성물을 제공한다. 상기 염증성 질환은 호흡기질환, 소화기질환, 피부질환, 등의 국소 염증질환, 패혈증, 동맥경화증, 관절염, 뇌질환 등의 전신 염증질환, 및 이의 합병증 등을 포함한다. The present invention provides a composition for treating or preventing inflammatory diseases and cancer, which contains an extracellular endoplasmic reticulum derived from a fermented food as an effective ingredient. The inflammatory diseases include systemic inflammatory diseases such as respiratory diseases, digestive diseases, local inflammatory diseases such as skin diseases, sepsis, arteriosclerosis, arthritis, brain diseases, and complications thereof.
본 발명의 예시적 구현예에 있어서, 상기 세포밖 소포체는 포유동물의 세포에서 염증성 매개체의 분비를 억제하는 것일 수 있으나, 이에 제한되는 것은 아니다. 상기 세포는 상피세포 및 염증세포를 포함한다. 상기 염증세포는 대식세포 및 호산구를 포함한다. In an exemplary embodiment of the invention, the extracellular endoplasmic reticulum may be, but is not limited to, inhibiting the secretion of inflammatory mediators in the cells of a mammal. The cells include epithelial cells and inflammatory cells. The inflammatory cells include macrophages and eosinophils.
본 발명의 예시적 구현예에 있어서, 상기 염증성 매개체는 인터루킨 6(IL-6)일 수 있으나, 이에 제한되는 것은 아니다. In an exemplary embodiment of the invention, the inflammatory mediator may be, but is not limited to, interleukin 6 (IL-6).
본 발명의 예시적 구현예에 있어서, 상기 세포밖 소포체는 세균에 의해 발효된 발효식품에서 유래된 것 및 곰팡이에 의해 발효된 발효식품에서 유래된 것을 포함한다. 상기 세포밖 소포체는 발효식품에 존재하는 효모 유래의 세포밖 소포체일 수 있으나, 이에 제한되는 것은 아니다. 또한, 상기 세포밖 소포체는 발효식품에 존재하는 세균 유래의 세포밖 소포체일 수 있으나, 이에 제한되는 것은 아니다.In an exemplary embodiment of the invention, the extracellular endoplasmic reticulum includes those derived from fermented foods fermented by bacteria and those derived from fermented foods fermented by fungi. The extracellular endoplasmic reticulum may be a yeast-derived extracellular endoplasmic reticulum present in a fermented food, but is not limited thereto. Further, the extracellular endoplasmic reticulum may be an extracellular endoplasmic reticulum derived from bacteria present in a fermented food, but is not limited thereto.
본 발명의 세포밖 소포체는 평균 직경이 20 nm 내지 200 nm 일 수 있으나, 이에 제한되는 것은 아니다. The extracellular endoplasmic reticulum of the present invention may have an average diameter of 20 nm to 200 nm, but is not limited thereto.
본 발명의 조성물은 약학적 조성물, 식품 조성물, 화장료 조성물 등일 수 있으나, 이에 제한되는 것은 아니다. The composition of the present invention may be, but not limited to, a pharmaceutical composition, a food composition, a cosmetic composition, and the like.
또한, 본 발명은 발효식품에서 유래된 세포밖 소포체를 유효성분으로 함유하는, 염증성 질환 및 암의 치료 또는 예방용 백신을 제공한다. 상기 백신은 세포밖 소포체를 단독으로 사용하거나, 상기 세포밖 소포체와 병원성 소포체를 혼합하여 사용할 수 있다. 상기 병원성 소포체는 체내 공생 세균에서 유래한 병원성 소포체, 그람 양성 세균에서 유래한 병원성 소포체, 및 공기에 존재하는 병원성 소포체 등을 포함한다. The present invention also provides a vaccine for the treatment or prevention of inflammatory diseases and cancer, comprising an extracellular endoplasmic reticulum derived from a fermented food as an effective ingredient. The vaccine may be used by using the extracellular endoplasmic reticulum alone or by mixing the extracellular endoplasmic reticulum with a pathogenic endoplasmic reticulum. The pathogenic endoplasmic reticulum includes a pathogenic endoplasmic reticulum derived from a symbiotic bacterium in the body, a pathogenic endoplasmic reticulum derived from a gram-positive bacterium, and a pathogenic endoplasmic reticulum present in the air.
또한, 본 발명은 발효식품에서 유래된 세포밖 소포체를 치사량 미만으로 포유동물에게 투여하는 단계를 포함하는, 질환의 예방 또는 치료 방법을 제공한다. 상기 질환은 염증성 질환 및 암 등을 포함한다. The present invention also provides a method of preventing or treating a disease, comprising administering to a mammal an extracellular endoplasmic reticulum derived from a fermented food less than a lethal dose. Such diseases include inflammatory diseases and cancers.
또한, 본 발명은 발효식품 유래 세포밖 소포체를 이용하여 발효식품의 안전성을 진단하는 방법을 제공한다. The present invention also provides a method for diagnosing the safety of a fermented food using an extracellular endoplasmic reticulum derived from a fermented food.
본 발명의 예시적 구현예로, 상기 방법은 하기 단계를 포함할 수 있다: 발효식품으로부터 세포밖 소포체를 분리하는 단계; 상기 분리된 세포밖 소포체를 세포에 처리하여 배양하는 단계; 및 상기 세포 배양액 중의 염증성 매개체의 수준을 측정하는 단계. In an exemplary embodiment of the invention, the method may comprise the steps of: separating the extracellular endoplasmic reticulum from the fermented food; Treating the separated extracellular endoplasmic reticulum with cells and culturing the cells; And measuring the level of the inflammatory mediator in the cell culture fluid.
본 발명의 예시적 구현예로, 발효식품으로부터 세포밖 소포체를 분리하는 단계는 하기를 포함할 수 있다: 발효식품을 원심분리하여 불순물, 곰팡이 및 세균 등을 제거하는 단계; 및 초원심분리를 수행하여 세포밖 소포체를 분리하는 단계. In an exemplary embodiment of the invention, separating the extracellular endoplasmic reticulum from the fermented food product may comprise: centrifuging the fermented food to remove impurities, fungi, bacteria, and the like; And ultracentrifugation to isolate extracellular endoplasmic reticulum.
본 발명자들은 발효식품에서 분리된 세포밖 소포체가 염증성 질환과 관련된 염증성 매개체인 IL-6의 분비를 억제하는 항염증효과가 있으며, 또한 대장암 동물모델에서 암 발생을 억제하는 항암효과가 있음을 발견하였다. 따라서, 발효식품에서 유래된 세포밖 소포체를 유효성분으로 함유하는 본 발명의 조성물은 염증성 질환 및 암을 예방 또는 치료할 수 있는 약학적 조성물, 식품 조성물, 및 화장료 조성물 등으로 이용될 수 있다. The inventors of the present invention found that the extracellular endoplasmic reticulum isolated from the fermented food has an anti-inflammatory effect for inhibiting the secretion of IL-6, an inflammatory mediator associated with inflammatory diseases, and has an anti-cancer effect inhibiting cancer development in a colon cancer animal model Respectively. Therefore, the composition of the present invention containing the extracellular endoplasmic reticulum derived from the fermented food as an active ingredient can be used as a pharmaceutical composition, a food composition, and a cosmetic composition which can prevent or treat inflammatory diseases and cancer.
또한, 발효식품에서 유래된 본 발명의 세포밖 소포체는 염증세포의 염증성 매개체의 분비를 유발시킬 수 있기 때문에, 상기 세포밖 소포체를 이용하여 발효식품의 안전성을 진단할 수 있다. 이에 더하여, 발효식품에 존재하는 세포밖 소포체는 염증을 유도할 수 있기 때문에, 식품의 제조과정에서 세포밖 소포체를 제거함으로써 식품의 안전성을 높일 수 있다. In addition, since the extracellular endoplasmic reticulum of the present invention derived from a fermented food can induce the secretion of inflammatory mediators of inflammatory cells, the safety of the fermented food can be diagnosed using the extracellular endoplasmic reticulum. In addition, since the extracellular endoplasmic reticulum present in the fermented food can induce inflammation, the safety of the food can be improved by removing the extracellular endoplasmic reticulum during the production of the food.
도 1은 된장과 간장에서 세포밖 소포체를 추출하는 과정을 나타낸 프로토콜이다.
도 2는 세포밖 소포체 추출 과정 중에서 density gradient 초고속원심분리 후의 모습과 fraction을 분리 후 각 fraction의 단백질 농도 및 밀도를 측정한 결과이다.
도 3은 된장 (좌)과 간장 (우)에서 추출한 세포밖 소포체를 투과전자현미경 (transmission electron microscope, TEM)으로 관찰한 사진이다.
도 4는 우리나라 전통 된장에서 분리한 세포밖 소포체가 대장균 유래 세포밖 소포체 또는 LPS에 의한 염증성 매개체 분비에 미치는 영향을 평가하기 위하여 대식세포 (RAW 246.7 세포)에 처리한 뒤 세포 배양액에서 염증성 매개체 IL-6를 측정한 결과이다.
도 5는 우리나라 전통 간장에서 분리한 세포밖 소포체가 대장균 유래 세포밖 소포체 또는 LPS에 의한 염증성 매개체 분비에 미치는 영향을 평가하기 위하여 대식세포 (RAW 246.7 세포)에 처리한 뒤 세포 배양액에서 염증성 매개체 IL-6를 측정한 결과이다.
도 6은 일본식 된장에서 분리한 세포밖 소포체가 대장균 유래 세포밖 소포체 또는 LPS에 의한 염증성 매개체 분비에 미치는 영향을 평가하기 위하여 대식세포 (RAW 246.7 세포)에 처리한 뒤 세포 배양액에서 염증성 매개체 IL-6를 측정한 결과이다.
도 7은 일본식 간장에서 분리한 세포밖 소포체가 대장균 유래 세포밖 소포체 또는 LPS에 의한 염증성 매개체 분비에 미치는 영향을 평가하기 위하여 대식세포 (RAW 246.7 세포)에 처리한 뒤 세포 배양액에서 염증성 매개체 IL-6를 측정한 결과이다.
도 8은 일본식 간장에서 분리한 세포밖 소포체가 그람 양성균인 포도상구균 (S. aureus) 유래 세포밖 소포체에 의해 염증성 매개체 분비에 미치는 영향을 평가하기 위하여 대식세포 (RAW 246.7 세포)에 처리한 뒤 세포 배양액에서 염증성 매개체 IL-6를 측정한 결과이다.
도 9는 Lactobacillus acidophilus 유산균 음료에서 세포밖 소포체를 분리하여 동적광산란법으로 소포체의 크기를 측정한 그림이다.
도 10은 대장암세포에 의한 대장암동물모델에 Lactobacillus acidophilus 유산균음료에 포함된 세포밖 소포체를 투여하여 항암효과를 평가하기 위한 프로토콜이다.
도 11은 Lactobacillus acidophilus 유산균 음료에서 분리한 세포밖 소포체가 항암효과를 나타낸 결과이다. 1 is a protocol showing the process of extracting extracellular endoplasmic reticulum from soybean paste and soy sauce.
FIG. 2 shows the results of measuring the protein concentration and density of each fraction after separating the fraction and the shape after density gradient ultracentrifugation in the extracellular ER extraction process.
FIG. 3 is a photograph of the extracellular endoplasmic reticulum (ER) extracted from soybean paste (left) and liver (right) by a transmission electron microscope (TEM).
Fig. 4 shows the effect of extracellular ERs isolated from Korean traditional soybean paste on the secretion of inflammatory mediators by E. coli-derived extracellular ER or LPS (RAW 246.7 cells) for evaluation and the inflammatory mediator IL-6 was measured in cell culture medium.
FIG. 5 shows the effect of extracellular ERs isolated from Korean traditional soy sauce on inflammatory mediator secretion by E. coli-derived extracellular ER or LPS (RAW 246.7 cells) for evaluation and the inflammatory mediator IL-6 was measured in cell culture medium.
6 shows the effect of the extracellular endoplasmic reticulum isolated from Japanese soybean paste on the secretion of inflammatory mediators by E. coli-derived extracellular endoplasmic reticulum or LPS (RAW 246.7 cells) for evaluation and the inflammatory mediator IL-6 was measured in cell culture medium.
Fig. 7 shows the effect of extracellular ERs isolated from Japanese soy sauce on inflammatory mediator secretion by E. coli-derived extracellular ER or LPS (RAW 246.7 cells) for evaluation and the inflammatory mediator IL-6 was measured in cell culture medium.
8 shows the effect of the extracellular endoplasmic reticulum isolated from Japanese soy sauce on the inflammatory mediator secretion by S. aureus- derived extracellular endoplasmic reticulum (RAW 246.7 cells) for evaluation and the inflammatory mediator IL-6 was measured in cell culture medium.
FIG. 9 is a photograph showing the size of the endoplasmic reticulum (ER) extracted from the extracellular endoplasmic reticulum in Lactobacillus acidophilus lactic acid beverage by dynamic light scattering.
10 is a protocol for evaluating the anti-cancer effect by administering an extracellular endoplasmic reticulum contained in a Lactobacillus acidophilus lactic acid bacterium to a colon cancer animal model by colon cancer cells.
FIG. 11 shows the results of the anticancer effect of the extracellular endoplasmic reticulum isolated from Lactobacillus acidophilus lactic acid beverage.
본 발명자들은 발효식품에 세포밖 소포체가 존재하고, 발효식품의 제조방법에 따라 발효식품에 존재하는 세포밖 소포체의 생물학적 활성이 다름을 발견하였다. 이와 관련하여, 우리나라의 전통적인 방법으로 제조한 간장에 존재하는 세포밖 소포체인 경우에는 소포체 자체에 의한 IL-6 분비기능이 현저히 증가되어 있었으나, 일본식으로 제조한 간장인 경우에는 반대로 염증질환을 유도하는 그람 음성균 유래 세포밖 소포체뿐만 아니라 그람 양성균 유래 세포밖 소포체에 의한 IL-6 분비를 효율적으로 억제한다는 사실을 발견하였다. 또한, 본 발명자들은 유산균음료에 세포밖 소포체가 존재함을 확인하고, 이를 분리하여 대장암 동물모델에 투여하였을 때 세포밖 소포체가 암의 발생을 효율적으로 억제함을 발견하여 본 발명을 완성하게 되었다. The present inventors have found that the extracellular endoplasmic reticulum is present in the fermented food and that the biological activity of the extracellular endoplasmic reticulum present in the fermented food is different depending on the method of producing the fermented food. In this regard, IL-6 secretion by the endoplasmic reticulum itself was remarkably increased in the case of the extracellular ER in the liver prepared by the conventional method in Korea. However, in the case of the soy sauce prepared in Japanese style, The present inventors have found that they efficiently inhibit the secretion of IL-6 by the extracellular endoplasmic reticulum derived from Gram-positive bacteria as well as the endoplasmic reticulum derived from Gram-negative bacteria. Further, the present inventors have found that the extracellular endoplasmic reticulum is present in the beverage of lactic acid bacteria, and that the extracellular endoplasmic reticulum effectively inhibits cancer when administered to an animal model of colon cancer by isolating it from the extracellular endoplasmic reticulum .
따라서, 본 발명은 발효식품에서 유래된 세포밖 소포체를 유효 성분으로 함유하는, 염증성 질환 및 암의 치료 또는 예방용 조성물을 제공한다. Accordingly, the present invention provides a composition for treating or preventing inflammatory diseases and cancer, comprising an extracellular endoplasmic reticulum derived from a fermented food as an active ingredient.
본 발명에서, "발효"란 식품의 제조과정시 무산소 상태에서 세균 혹은 효모 등에 의해 탄수화물이 알코올 및 이산화탄소 혹은 유기산 등으로 전환되는 것을 의미하며, 콩, 곡류, 채소, 과일, 생선, 육류 등에 세균 혹은 효모를 이용하여 발효식품을 제조할 수 있다. In the present invention, the term "fermentation" means that the carbohydrate is converted into alcohol, carbon dioxide, organic acid or the like by bacteria or yeast in an anaerobic state during the manufacturing process of food, and the bacteria, Fermented foods can be produced using yeast.
본 발명에서 "발효식품에서 유래된 세포밖 소포체"란 콩, 곡류, 채소, 과일, 생선, 육류 등의 발효식품에 존재하는 세포밖 소포체를 포함하며, 크기가 원래의 세포보다 작은 것을 특징으로 하나, 이에 제한되는 것은 아니다. 본 발명의 세포밖 소포체는 발효식품에 존재하는 세균 혹은 곰팡이에 의하여 분비되는 세포밖 소포체일 수 있다. 상기 발효식품에 존재하는 곰팡이는 발효를 유도하는 효모를 포함한다. The term " extracellular endoplasmic reticulum derived from a fermented food "in the present invention includes an extracellular endoplasmic reticulum present in a fermented food such as soybean, cereal, vegetable, fruit, fish, meat and the like and is smaller in size than the original cell , But is not limited thereto. The extracellular endoplasmic reticulum of the present invention may be an extracellular endoplasmic reticulum secreted by a bacterium or a fungus present in the fermented food. The fungi present in the fermented food include yeasts that induce fermentation.
또한, 본 발명은 발효식품에서 유래된 세포밖 소포체를 유효성분으로 함유하는, 염증성 질환 및 암의 치료 또는 예방용 백신을 제공한다. 상기 백신은 세포밖 소포체를 단독으로 사용하거나, 상기 세포밖 소포체와 병원성 소포체를 혼합하여 사용할 수 있다. 상기 병원성 소포체는 체내 공생 세균에서 유래한 병원성 소포체, 그람 양성 세균에서 유래한 병원성 소포체, 및 공기에 존재하는 병원성 소포체 등을 포함한다. The present invention also provides a vaccine for the treatment or prevention of inflammatory diseases and cancer, comprising an extracellular endoplasmic reticulum derived from a fermented food as an effective ingredient. The vaccine may be used by using the extracellular endoplasmic reticulum alone or by mixing the extracellular endoplasmic reticulum with a pathogenic endoplasmic reticulum. The pathogenic endoplasmic reticulum includes a pathogenic endoplasmic reticulum derived from a symbiotic bacterium in the body, a pathogenic endoplasmic reticulum derived from a gram-positive bacterium, and a pathogenic endoplasmic reticulum present in the air.
발효식품에서 상기 세포밖 소포체를 분리하는 방법은 세포밖 소포체를 순수하게 분리할 수 있다면 특별히 제한되지 않으며, 예컨대 발효식품에서, 원심분리, 초원심분리, 필터에 의한 여과, 겔 여과 크로마토그래피, 프리-플로우 전기영동, 모세관 전기영동 등의 방법 및 이들의 조합을 이용하여 세포밖 소포체를 분리할 수 있다. 또한, 불순물의 제거를 위한 세척, 수득된 세포밖 소포체의 농축 등의 과정을 추가로 포함할 수 있다. The method of separating the extracellular endoplasmic reticulum from the fermented food is not particularly limited as far as the extracellular endoplasmic reticulum can be separated purely. For example, in the fermented food, centrifugation, ultracentrifugation, filtration by filtration, gel filtration chromatography, - flow electrophoresis, capillary electrophoresis, etc., and combinations thereof can be used to separate the extracellular endoplasmic reticulum. Further, washing may be performed to remove impurities, and concentration of the obtained extracellular endoplasmic reticulum may be further included.
상기 방법에 의하여 분리된 세포밖 소포체는 평균 직경이 500 nm 이하일 수 있으며, 바람직하게는 20 nm 내지 200 nm 일 수 있다. The extracellular endoplasmic reticulum isolated by the above method may have an average diameter of 500 nm or less, preferably 20 nm to 200 nm.
본 발명의 일 구현예에 따르면, 상기 조성물은 약학적 조성물로 제조될 수 있다. 치료 및/또는 예방에 사용하기 위해 본 발명의 세포밖 소포체 자체를 투여하는 것이 가능할 수 있지만, 약학적 조성물의 활성 성분으로서 상기 세포밖 소포체가 포함되는 것이 바람직하다. According to one embodiment of the present invention, the composition may be prepared from a pharmaceutical composition. Although it may be possible to administer the extracellular endoplasmic reticulum of the present invention itself for use in therapy and / or prophylaxis, it is preferred that the extracellular endoplasmic reticulum is included as the active ingredient of the pharmaceutical composition.
상기 약학적 조성물은 상기 분리된 세포밖 소포체를 유효 성분으로 함유하며, 약학적으로 허용 가능한 담체를 포함할 수 있다. 상기 약학적으로 허용 가능한 담체는 제제 시에 통상적으로 이용되는 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 사이클로덱스트린, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올, 리포좀 등을 포함하지만 이에 한정되지 않으며, 필요에 따라 항산화제, 완충액 등 다른 통상의 첨가제를 더 포함할 수 있다. 또한, 희석제, 분산제, 계면활성제, 결합제, 윤활제 등을 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 적합한 약학적으로 허용되는 담체 및 제제화에 관해서는 레밍턴의 문헌 (Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA)에 개시되어 있는 방법을 이용하여 각 성분에 따라 바람직하게 제제화할 수 있다. 본 발명의 약학적 조성물은 제형에 특별한 제한은 없으나 주사제, 흡입제, 피부 외용제 등으로 제제화할 수 있다. The pharmaceutical composition contains the separated extracellular endoplasmic reticulum as an active ingredient, and may include a pharmaceutically acceptable carrier. Such pharmaceutically acceptable carriers are those conventionally used in the formulation and include, but are not limited to, saline, sterilized water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, And may further contain other conventional additives such as antioxidants and buffers as needed. In addition, it can be formulated into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like by additionally adding diluents, dispersants, surfactants, binders, lubricants and the like. Suitable pharmaceutically acceptable carriers and formulations can be suitably formulated according to the respective ingredients using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA. The pharmaceutical composition of the present invention is not particularly limited to a formulation, but may be formulated into injections, inhalants, external skin preparations, and the like.
본 발명의 약학적 조성물의 투여방법은 특별히 제한되는 것은 아니나, 목적하는 방법에 따라 정맥내, 피하, 복강 내, 흡입, 피부도포, 설하 투여, 비강투여, 항문 투여, 경구 복용 등을 선택할 수 있다. The method of administering the pharmaceutical composition of the present invention is not particularly limited, but it may be intravenously, subcutaneously, intraperitoneally, inhalation, skin application, sublingual administration, nasal administration, anal administration, oral administration etc. depending on the intended method .
투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양하다. 일일 투여량은 치료를 필요로 하는 개체에 투여됨으로서 경감된 질병 상태에 대한 치료에 충분한 본 발명의 치료용 물질의 양을 의미한다. 치료용 물질의 효과적인 양은 특정 화합물, 질병 상태 및 그의 심각도, 치료를 필요로 하는 개체에 따라 달라지며, 이는 당업자에 의해 통상적으로 결정될 수 있다. 비제한적 예로서, 본 발명에 의한 조성물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여 형태, 건강 상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로는 0.01 ~ 1000 ㎎/일, 바람직하게는 1 ~ 500 ㎎/일이며, 일정시간 간격으로 1일 1회 내지 수회에 분할 투여할 수도 있다. The dosage varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity. The daily dose refers to the amount of the therapeutic substance of the present invention which is sufficient to treat a relieved disease state by being administered to an individual in need of treatment. The effective amount of the therapeutic substance will depend on the particular compound, the disease state and its severity, the individual in need of treatment, which can be routinely determined by one of ordinary skill in the art. As a non-limiting example, the dosage for the human body of the composition according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient and is based on adult patients weighing 70 kg , It is generally 0.01 to 1000 mg / day, preferably 1 to 500 mg / day, and may be dividedly administered once to several times a day at predetermined time intervals.
본 발명의 다른 구현예에 따르면, 본 발명의 조성물은 화장료 조성물로 제조될 수 있다. 본 발명의 화장료 조성물에 포함되는 성분은 유효 성분으로서의 상기 세포밖 소포체를 함유하는 것 이외에, 화장료 조성물에 통상적으로 이용되는 성분들을 포함하며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 및 담체를 포함할 수 있다. According to another embodiment of the present invention, the composition of the present invention can be prepared with a cosmetic composition. The components contained in the cosmetic composition of the present invention include components commonly used in cosmetic compositions in addition to those containing the above-described extracellular endoplasmic reticulum as an active ingredient, and examples thereof include antioxidants, stabilizers, solubilizers, vitamins, , ≪ / RTI > and carriers.
본 발명의 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 영양 크림, 수렴 화장수, 유연 화장수, 로션, 에센스, 영양젤 또는 마사지 크림의 제형으로 제조될 수 있다.The cosmetic composition of the present invention can be prepared into any of the formulations conventionally produced in the art and can be used as a solution, a suspension, an emulsion, a paste, a gel, a cream, a lotion, a powder, a soap, , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be prepared as a nutritional cream, a convergent lotion, a soft lotion, a lotion, an essence, a nutritional gel or a massage cream.
본 발명의 또 다른 구현예에 따르면, 본 발명의 조성물은 식품 조성물로 제조될 수 있다. 본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로서 상기 세포밖 소포체를 함유할 뿐만 아니라, 식품 제조시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함할 수 있다. 예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 세포밖 소포체 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙 등을 추가로 포함시킬 수 있다. According to another embodiment of the present invention, the composition of the present invention can be manufactured into a food composition. When the composition of the present invention is prepared as a food composition, it contains not only the extracellular endoplasmic reticulum as an active ingredient but also a component ordinarily added at the time of food production. For example, protein, carbohydrate, fat, Flavoring agents, flavoring agents and flavoring agents. For example, when the food composition of the present invention is prepared as a drink, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, and the like may be further included in addition to the extracellular endoplasmic reticulum of the present invention.
본 발명에서 "염증성 질환의 치료 또는 예방"이란, 염증성 질환의 경감, 완화 및 증상의 개선을 포함하며, 또한 염증성 질환이 걸릴 가능성을 경감하는 것을 포함하는 의미이다. The term " treatment or prevention of an inflammatory disease "in the present invention is meant to include relief of inflammatory diseases, alleviation, and improvement of symptoms, and also to alleviate the possibility of taking an inflammatory disease.
본 발명에서 "염증성 질환"이란, 포유동물 체내의 염증 반응에 의하여 유발되는 질환을 의미하며, 대표적인 예로는, 천식, 만성폐쇄성폐질환, 비염 등의 호흡기질환; 아토피피부염, 건선, 접촉피부염 등의 피부질환; 위염, 소화기궤양, 염증성장염 등의 소화기질환; 패혈증, 동맥경화증, 관절염, 뇌질환 등의 전신 염증질환, 및 이의 합병증 등을 포함한다. 또한, 상기 염증성 질환은 일반적인 염증성 질환 이외에도, 염증 반응과 관련된 암을 포함하는 의미로 사용되며, 예컨대, 폐암, 위암, 대장암 등을 포함한다. The term "inflammatory disease" in the present invention means a disease caused by an inflammatory reaction in a mammalian body. Typical examples thereof include respiratory diseases such as asthma, chronic obstructive pulmonary disease, rhinitis; Skin diseases such as atopic dermatitis, psoriasis and contact dermatitis; Gastrointestinal diseases such as gastritis, digestive ulcers, inflammatory bowel disease; Sepsis, arteriosclerosis, arthritis, systemic inflammatory diseases such as brain diseases, and complications thereof. In addition to the general inflammatory diseases, the inflammatory diseases include cancer associated with an inflammatory reaction, and include, for example, lung cancer, stomach cancer, colon cancer and the like.
본 발명의 조성물은 포유동물의 염증세포에서 염증성 매개체의 분비를 억제함으로써, 염증성 질환의 치료 또는 예방이 가능하다. 특히, 본 발명의 발효식품에서 분리한 세포밖 소포체가 염증성 질환 또는 암의 발생과 관련된 중요한 바이오마커인 IL-6의 분비를 억제하는 것이 가능하기 때문에, 본 발명의 조성물은 IL-6를 매개로 하는 Th17 염증성 질환 및 IL-6 또는 Th17 염증 반응에 의한 암을 치료 또는 예방하는 것이 가능하다. 이에 더하여, 본 발명자들은 유산균음료와 같은 발효식품에 존재하는 세포밖 소포체가 대장암 동물모델에서 암 발생을 효율적으로 억제함을 확인하였다. 따라서, 유산균음료와 같은 발효식품에 존재하는 세포밖 소포체를 포함하는 조성물을 투여함으로써 암 치료 및 예방 효과를 기대할 수 있다.The composition of the present invention inhibits the secretion of inflammatory mediators in the inflammatory cells of mammals, thereby enabling the treatment or prevention of inflammatory diseases. Particularly, since the extracellular endoplasmic reticulum isolated from the fermented food of the present invention can inhibit the secretion of IL-6, an important biomarker related to the development of inflammatory diseases or cancer, the composition of the present invention is mediated by IL-6 Lt; RTI ID = 0.0 > IL-6 < / RTI > or Th17 inflammatory response. In addition, the present inventors have confirmed that the extracellular endoplasmic reticulum present in fermented foods such as lactic acid bacteria beverage effectively inhibits cancer development in an animal model of colorectal cancer. Therefore, cancer treatment and prevention effects can be expected by administering a composition containing extracellular endoplasmic reticulum present in a fermented food such as a lactic acid bacterium drink.
또한, 본 발명은 발효식품에서 유래된 세포밖 소포체를 이용하여 식품의 안전성을 진단하는 방법을 제공한다. 발효식품에서 분리된 세포밖 소포체는 염증세포의 염증성 매개체의 분비를 유발시킬 수 있다. 따라서, 상기 진단 방법은, 발효식품에서 세포밖 소포체를 분리하는 단계; 상기 분리된 세포밖 소포체를 염증세포에 처리하여 배양하는 단계; 및 상기 세포 배양액 중의 염증성 매개체의 수준을 측정하는 단계를 포함할 수 있다. 즉, 상기 분리된 세포밖 소포체를 체외에서 염증세포에 투여하여 함께 배양하고, 상기 염증세포에서 분비되는 염증성 매개체의 종류 및 수준을 측정하여, 식품의 안전성을 진단하는 것이 가능하다. The present invention also provides a method for diagnosing the safety of foods using extracellular endoplasmic reticulum derived from a fermented food. The extracellular endoplasmic reticulum isolated from fermented food can induce the secretion of inflammatory mediators of inflammatory cells. Accordingly, the diagnostic method comprises: separating the extracellular endoplasmic reticulum from the fermented food; Treating the isolated extracellular endoplasmic reticulum with an inflammatory cell; And measuring the level of the inflammatory mediator in the cell culture fluid. That is, it is possible to diagnose the safety of the food by measuring the type and level of inflammatory mediators secreted from the inflammatory cells by administering the separated extracellular endoplasmic reticulum to the inflammatory cells in vitro and culturing them together.
예컨대, 상기 분리된 세포밖 소포체를 대식세포 배양액 중에 첨가하여 함께 배양하고, 상기 대식세포가 분비하는 IL-6의 수준을 측정함으로써 식품에 의한 염증성 질환의 발생 혹은 악화 여부를 진단할 수 있다. 또한, 상기 분리된 세포밖 소포체를 실험동물에 직접 투여하여, 실험동물의 체내에 생성되는 염증성 매개체(예컨대, IL-6)의 수준을 측정함으로써, 세포밖 소포체를 분리한 대상 개체의 염증성 질환의 발생 혹은 악화 여부를 예측하는 것이 가능하다. For example, the separated extracellular endoplasmic reticulum may be cultured together with a macrophage culture solution, and the level of IL-6 secreted by the macrophage may be measured to diagnose whether the inflammatory disease is caused or exacerbated by the food. Further, by directly administering the separated extracellular endoplasmic reticulum to an experimental animal and measuring the level of an inflammatory mediator (for example, IL-6) produced in the body of the experimental animal, an inflammatory disease of a subject isolated from the extracellular endoplasmic reticulum It is possible to predict whether it occurs or deteriorates.
또한, 본 발명은 발효식품에 존재하는 세포밖 소포체를 제거하여 식품의 안전성을 높이는 방법을 제공한다. 발효식품에 존재하는 세포밖 소포체는 염증을 유도할 수 있으므로, 다양한 방법으로 발효식품에 존재하는 세포밖 소포체를 제거하여 보다 안전한 식품을 제조할 수 있다. The present invention also provides a method for enhancing the safety of a food by removing extracellular endoplasmic reticulum present in a fermented food. Since the extracellular endoplasmic reticulum present in the fermented food can induce inflammation, a safer food can be produced by removing the extracellular endoplasmic reticulum present in the fermented food by various methods.
이하, 본 발명의 이해를 돕기 위하여 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, embodiments are described to help understand the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.
[[ 실시예Example ]]
실시예Example 1. 발효식품인 간장 (soy sauce) 및 된장 (soybean paste) 유래 1. Derived from fermented soy sauce and soybean paste 세포cell 밖 소포체의 분리 및 이의 특성Separation of outer envelope and its properties
도 1에 나타낸 프로토콜에 따라, 간장 60 ml을 고속원심분리 튜브 (high speed centrifuge tube)에 담은 후, 4℃, 10,000 x g에서 15분 동안 고속원심분리 (high speed centrifugation)를 연속으로 2번 수행하였다. 상층액을 70 ml 용량의 초원심분리 튜브 (ultracentrifuge tube)에 담고 4℃, 100,000 x g에서 4시간 동안 초원심분리 (ultracetrifugation)를 하였다. 상층액은 버리고 튜브 아래에 존재하는 침전물을 50% Optiprep solution으로 녹여내었다. 이후 Optiprep density gradient 방법으로 추가 정제를 수행하였다. 5 ml 용량의 초원심분리 튜브에 침전물이 함유된 50% Optiprep solution, 40%, 30%, 20%, 10%의 Optiprep solution을 각각 1 ml씩 순서대로 넣고, 4℃, 100,000 x g에서 4시간 동안 초원심분리를 하였다(도 1 참조). 초원심분리 후 세포밖 소포체는 밀도에 따라 20% Optiprep solution과 30% Optiprep solution 층 사이에 위치하였다 (도 2 참조). 튜브의 윗쪽부터 용액을 제거하여 세포밖 소포체가 포함된 층을 분리하였다. According to the protocol shown in Fig. 1, 60 ml of soy sauce was placed in a high-speed centrifuge tube and then subjected to two consecutive high-speed centrifugations at 4O < 0 > C and 10,000 xg for 15 minutes . The supernatant was placed in a 70 ml ultracentrifuge tube and subjected to ultracetrifugation at 4,000C for 4 hours at 100,000 x g. The supernatant was discarded and the precipitate present under the tube was dissolved in 50% Optiprep solution. Then further purification was carried out by Optiprep density gradient method. Optiprep solution containing 50% Optiprep solution containing 40%, 40%, 30%, 20%, and 10% of the precipitate was placed in a 5 ml ultracentrifuge tube in the order of 1 ml each at 4 ° C and 100,000 xg for 4 hours Followed by ultracentrifugation (see Fig. 1). After ultracentrifugation, the extracellular endoplasmic reticulum was located between the 20% Optiprep solution and the 30% Optiprep solution layer according to density (see FIG. 2). The solution was removed from the top of the tube to separate the layer containing the extracellular endoplasmic reticulum.
된장에서 세포밖 소포체 분리 시, 된장 10 g을 100 ml PBS가 들어있는 비커에 4℃, 1시간 동안 녹여내고 거즈를 이용하여 큰 이물질들을 걸러냈다. 이후 과정은 간장에서 세포밖 소포체 분리와 동일하게 수행하였다. 상기의 방법으로 추출한 세포밖 소포체의 투과전자현미경 (transmission electron microscope, TEM)으로 관찰한 결과, 세포밖 소포체는 지질 이중층으로 이루어져 있으며, 크기가 50-100 nm이고 대체로 구형을 이루고 있음을 확인하였다 (도 3 참조). For isolation of extracellular ER from doenjang, 10 g of doenjang were dissolved in beaker containing 100 ml of PBS at 4 ℃ for 1 hour and gauze was used to filter out large foreign matter. The subsequent procedure was performed in the same manner as the extracellular ER removal in the liver. Transmission electron microscopy (TEM) of the extracellular endoplasmic reticulum extracted by the above method revealed that the extracellular endoplasmic reticulum was composed of a lipid bilayer and had a size of 50-100 nm and a generally spherical shape 3).
실시예Example 2. 한국 된장 및 간장 (혹은 조선 된장 및 간장)에서 분리한 2. Isolate from Korean soybean paste and soy sauce (or Korean soybean paste and soy sauce). 세포밖Extracellular 소포체에 의한 염증성 매개체 분비 및 Inflammatory mediator secretion by the endoplasmic reticulum LPSLPS 혹은 대장균 유래 Or Escherichia coli derived 세포밖Extracellular 소포체에 의한 염증성 매개체 분비에 미치는 영향 Influence on the secretion of inflammatory mediators by the endoplasmic reticulum
마우스 대식세포 (RAW264.7)에 한국 된장 및 간장에서 분리한 세포밖 소포체 (0.1, 1 μg/ml)를 단독으로 처리하거나 LPS(10 ng/ml) 또는 대장균 유래 세포밖 소포체(100 ng/ml)와 함께 처리하고 15시간 동안 배양한 뒤 세포 배양액에서 염증성 매개체 IL-6의 발현 정도를 확인 하고 그 결과를 도 4 및 도 5에 나타내었다. (10 ng / ml) or Escherichia coli-derived extracellular endoplasmic reticulum (100 ng / ml) alone or in combination with mouse macrophages (RAW264.7) ) And cultured for 15 hours. The expression level of the inflammatory mediator IL-6 was confirmed in the cell culture medium. The results are shown in FIGS. 4 and 5.
도 4 및 도 5에 나타난 바와 같이, 대조군과 비교하여 한국 된장 및 간장에서 분리한 세포밖 소포체를 처리해준 실험군에 염증성 매개체인 IL-6가 증가하는 것을 알 수 있다. 또한, 한국 된장 및 간장에서 분리한 세포밖 소포체를 LPS 또는 대장균 유래 세포밖 소포체와 함께 처리한 실험군에서는 함께 처리한 한국 된장 및 간장 유래 세포밖 소포체의 양이 증가함에 따라 대장균 유래 세포밖 소포체나 LPS를 단독으로 처리한 실험군에 비해 IL-6가 증가하는 것을 확인 하였다. As shown in FIGS. 4 and 5, IL-6, which is an inflammatory mediator, is increased in the experimental group treated with the extracellular endoplasmic reticulum isolated from Korean soybean and soy sauce, as compared with the control group. In the experimental group treated with LPS or E. coli-derived extracellular endoplasmic reticulum isolated from Korean soybean and soy sauce, the amount of extracellular extracellular and extracellular endoplasmic reticulum derived from E. coli and LPS IL-6, IL-6, IL-6, IL-6 and IL-6.
상기 결과는 한국 된장 및 간장 유래 세포밖 소포체는 단독으로도 염증성 매개체 분비를 증가시킬 수 있으며 대장균 유래 세포밖 소포체 및 LPS에 의한 염증성 매개체의 발현 증가를 더욱 촉진 시킬 수 있음을 의미한다. These results indicate that Korean soybean and soy-derived extracellular ER can increase inflammatory mediator secretion alone and further promote the expression of inflammatory mediators by E. coli-derived extracellular ER and LPS.
실시예 3. 일본식 된장에서 분리한 세포밖 소포체에 의한 염증성 매개체 분비 및 LPS, 혹은 대장균유래 세포밖 소포체에 의한 염증성 매개체 분비에 미치는 영향Example 3: Inflammatory mediator secretion by extracellular endoplasmic reticulum isolated from Japanese soybean paste and effect on the inflammatory mediator secretion by LPS or E. coli-derived extracellular endoplasmic reticulum
마우스 대식세포 (RAW264.7)에 일본식 된장에서 분리한 세포밖 소포체 (0.1, 1, 10 μg/ml)를 단독으로 처리하거나, LPS(10 ng/ml), 대장균 유래 세포밖 소포체(10 ng/ml)와 함께 처리하고 15시간 동안 배양한 뒤 세포 배양액에서 염증성 매개체 IL-6의 발현 정도를 확인 하고 그 결과를 도 6에 나타내었다. (10 ng / ml), extracellular endoplasmic reticulum (10 ng / ml) from Escherichia coli, and mouse embryonic kidney cells (RAW264.7) ml) and cultured for 15 hours. Then, the expression level of the inflammatory mediator IL-6 was confirmed in the cell culture medium, and the results are shown in Fig.
도 6에 나타난 바와 같이, 일본식 된장에서 분리한 세포밖 소포체만을 투여한 경우에는 IL-6 분비가 증가하지 않았으나, LPS 혹은 대장균 유래 세포밖 소포체와 함께 일본 된장 유래 세포밖 소포체를 10 μg/ml 농도로 처리한 실험군에서는 대조군 (LPS 또는 대장균 유래 세포밖 소포체만을 처리한 실험군)에 비교하여 IL-6가 증가함을 알 수 있다. As shown in FIG. 6, IL-6 secretion did not increase when only the extracellular endoplasmic reticulum isolated from Japanese soybean paste was administered, but the endoplasmic reticulum-derived extracellular endoplasmic reticulum from LPS or E. coli was incubated with 10 μg / ml , IL-6 is increased in comparison with the control group (the group treated with LPS or E. coli-derived extracellular endoplasmic reticulum only).
상기 결과는, 일본식 된장 유래 세포밖 소포체는 염증 반응을 유도하는 LPS, 대장균 유래 세포밖 소포체에 의한 염증성 매개체의 발현을 증가시킬 수 있음을 의미한다. The above results indicate that the Japanese extant extracellular ERCs can increase the expression of inflammatory mediators by LPS and E. coli-derived extracellular ER that induce an inflammatory response.
실시예 4. 일본식 간장에서 분리한 세포밖 소포체에 의한 염증성 매개체 분비 및 LPS, 대장균유래 세포밖 소포체, 혹은 포도상구균유래 세포밖 소포체에 의한 염증성 매개체 분비에 미치는 영향Example 4. Inflammatory mediator secretion by extracellular endoplasmic reticulum isolated from Japanese soy sauce and influence on the secretion of inflammatory mediators by LPS, E. coli-derived extracellular endoplasmic reticulum or extracellular endoplasmic reticulum-derived endoplasmic reticulum-derived endoplasmic reticulum
마우스 대식세포 (RAW264.7)에 일본식 간장에서 분리한 세포밖 소포체 (0.1, 1, 10 μg/ml)를 단독으로 처리하거나, LPS(10 ng/ml), 대장균 유래 세포밖 소포체(10 ng/ml), 혹은 포도상구균 유래 세포밖 소포체(1 μg/ml)와 함께 처리하고 15시간 동안 배양한 뒤 세포 배양액에서 염증성 매개체 IL-6의 발현 정도를 확인하였다. 이 결과, 일본 간장에서 분리한 세포밖 소포체만을 투여한 경우에는 IL-6 분비가 증가하지 않았으나, LPS 혹은 대장균 유래 세포밖 소포체 또는 포도상구균 유래 세포밖 소포체와 함께 일본 간장 유래 세포밖 소포체를 10 μg/ml 농도로 처리한 실험군에서는 대조군 (LPS, 대장균 유래 세포밖 소포체 또는 포도상구균 유래 세포밖 소포체만을 처리한 실험군)에 비교하여 IL-6가 현저히 감소한 것을 확인하였다 (도 7 및 도 8 참조). (10 ng / ml), E. coli-derived extracellular endoplasmic reticulum (10 ng / ml), and mouse embryonic kidney cells (RAW264.7) ml) or staphylococcal extracellular endoplasmic reticulum (1 μg / ml), and cultured for 15 hours. The expression level of inflammatory mediator IL-6 was confirmed in the cell culture medium. As a result, IL-6 secretion did not increase when only the extracellular extracellular fluid isolated from Japanese soy sauce was administered. However, the extracellular endoplasmic reticulum or endoplasmic reticulum-derived extracellular endoplasmic reticulum-derived extracellular endoplasmic reticulum from LPS, / ml, the IL-6 level was significantly reduced in the experimental group treated with the control (LPS, E. coli-derived extracellular endoplasmic reticulum or staphylococcal-derived endoplasmic reticulum-derived endoplasmic reticulum only group) (FIGS. 7 and 8).
상기 결과는, 일본식 간장 유래 세포밖 소포체는 염증 반응을 유도하는 LPS, 대장균 유래 세포밖 소포체 또는 포도상구균 유래 세포밖 소포체에 의한 염증성 매개체의 발현을 길항 할 수 있음을 의미한다. The above results indicate that the Japanese extracellular extracellular endoplasmic reticulum can antagonize the expression of inflammatory mediators by LPS, E. coli-derived endoplasmic reticulum or staphylococcal endoplasmic reticulum-derived endoplasmic reticulum.
실시예Example 5. Lactobacillus acidophilus 유산균 음료에서 5. Lactobacillus acidophilus in lactic acid beverage 세포밖Extracellular 소포체 분리 및 특성 Elastomeric separation and characterization
Lactobacillus acidophilus에 의한 유산균 음료에서 세포밖 소포체를 분리하기 위하여 상기 유산균 음료 1L를 거즈로 걸러내었다. 거즈로 걸러낸 유산균 발효에서 유산균 및 기타 부유물을 제외한 상층액을 얻어내기 위하여 12,000 x g의 속도로 30분간 원심 분리를 수행하였다. 원심 분리 수행 후 얻어낸 상층액은 0.22 ㎛의 필터를 이용하여 0.22㎛초과 물질을 제거하였다. 얻어낸 0.22 ㎛ 미만의 용액에서 세포밖 소포체를 얻어내기 위해서 150,000 x g의 속도로 2시간 동안 초고속 원심 분리를 수행하였다. 초고속 원심 분리 수행 후 가라앉은 세포밖 소포체를 200 μl의 생리 식염수로 풀어내어 Bradford assay로 정량을 수행하였으며, 분리해낸 세포밖 소포체의 크기를 측정하기 위하여 동적 빛 산란법을 이용하였다. 그결과 얻어낸 세포밖 소포체는 평균 29.34nm이 크기를 가지고 있다는 것을 확인하였다 (도 9 참조). To separate the extracellular endoplasmic reticulum from the lactic acid bacteria drink by Lactobacillus acidophilus , 1 L of the lactic acid bacterium drink was filtered with a gauze. In the fermentation of lactic acid bacteria filtered with gauze, centrifugation was carried out at a speed of 12,000 xg for 30 minutes to obtain supernatant except for lactic acid bacteria and other suspended substances. After the centrifugation, the supernatant was removed by using 0.22 ㎛ filter to remove excess 0.22 ㎛. Ultracentrifugation was performed for 2 hours at a rate of 150,000 x g to obtain extracellular endoplasmic reticulum in the resulting solution of less than 0.22 탆. After extracorporeal centrifugation, the extracellular endoplasmic reticulum was eluted with 200 μl of physiological saline and quantitated by Bradford assay. Dynamic light scattering method was used to measure the size of extracellular ER. The resulting extracellular endoplasmic reticulum was found to have an average size of 29.34 nm (see FIG. 9).
실시예Example 6. Lactobacillus acidophilus 유산균 음료에서 분리한 6. Lactobacillus acidophilus isolated from lactic acid beverage 세포밖Extracellular 소포체의 항암효과 Anticancer effect of the endoplasmic reticulum
실시예 5의 방법에 의해서 분리된 Lactobacillus acidophilus 유산균 음료 유래 세포밖 소포체가 항암효과를 가지고 있는지 확인하기 위하여 colon 26 종양 세포를 이용한 in vivo 종양 모델에서 활성을 확인하였다. The activity of the extracellular endoplasmic reticulum derived from Lactobacillus acidophilus Lactobacillus beverage isolated by the method of Example 5 was confirmed in an in vivo tumor model using colon 26 tumor cells to confirm the anticancer effect.
도 10에 나타낸 프로토콜에 따라, Colon 26 종양 세포를 이용한 in vivo 종양 모델을 만들기 위해서 5주령의 Balb/c(male) 마우스에 1 x 106 개의 colon 26 세포를 피하 주사로 주입하였다. 이후 유산균 음료 유래 세포밖 소포체의 항암효과를 확인하기 위하여 종양 주입 후 7일 후부터 3일 간격으로 유산균 음료 유래 세포밖 소포체 10㎍을 꼬리 정맥을 통해서 주사 하였다. 마지막 주사 후 3일 뒤, 마우스를 해부하여 종양을 절제하고 종양의 부피를 측정하여 유산균 음료 유래 세포밖 소포체의 항암 효과를 평가 하였다. According to the protocol shown in Fig. 10, in vivo using Colon 26 tumor cells To create a tumor model, 1 x 10 6 colon 26 cells were injected subcutaneously into 5-week-old Balb / c (male) mice. In order to confirm the anticancer effect of the extracellular endoplasmic reticulum from the lactic acid bacteria beverage, 10 μg of the extracellular endoplasmic reticulum derived from the lactic acid bacterium was injected through the tail vein at intervals of 3 days from the 7th day after the tumor injection. Three days after the last injection, the mice were dissected to excise the tumor, and the volume of the tumor was measured to evaluate the anticancer effect of the extracellular endoplasmic reticulum from the lactic acid bacteria beverage.
그 결과, 유산균 음료 유래 세포밖 소포체를 주사한 그룹에서 주사하지 않은 그룹에 비교하여 종양의 크기가 현저히 감소하였음을 확인하였다 (도 11 참조).As a result, it was confirmed that the size of the tumor was significantly reduced in the group injected with the extracellular endoplasmic reticulum derived from the lactic acid bacteria drink as compared with the group injected with no injection (see FIG. 11).
상기 실시예 등을 통하여, 본 발명자들은 대표적인 발효식품인 일본식 간장에서 분리한 세포밖 소포체가 염증성 질환 및 암을 일으키는데 중요한 바이오마커인 IL-6 분비를 억제함을 최초로 규명하였으며, 이에 더하여, Lactobacillus acidophilus 유산균음료에서 분리한 세포밖 소포체가 대장암 발생을 효율적으로 억제함을 최초로 규명하였다.Through the above examples, the inventors of the present invention firstly confirmed that the extracellular endoplasmic reticulum isolated from Japanese typical soybean fermented food inhibits IL-6 secretion, which is an important biomarker for causing inflammatory diseases and cancer. In addition, Lactobacillus acidophilus We first elucidated that the extracellular endoplasmic reticulum isolated from lactic acid bacteria beverage effectively suppresses colon cancer development.
또한, 본 발명자들은 간장 등의 발효식품에서 발효를 일으키는 세균 등이 콩과 같은 기질을 이용하여 발효하는 과정에서 세포밖 소포체를 분비하고, 이는 IL-6 등에 의해 매개되는 염증성 질환 및 암 등의 발생 및 진행을 막을 수 있다는 것을 확인하였다. In addition, the present inventors secrete extracellular endoplasmic reticulum in the process of fermenting bacteria such as soybean fermented by using a substrate such as soybean, which causes inflammatory diseases mediated by IL-6, cancer and the like And prevent progression.
본 발명의 세포밖 소포체는 된장 및 간장에서 분리했으나, 이에 제한하는 것은 아니다. 또한, 한국간장 (혹은 조선간장)에서 분리한 세포밖 소포체 자체가 염증세포에서 염증성 매개체 분비를 유도하는 정도가 LPS나 대장균 유래 세포밖 소포체에 의한 정도와 비슷함은 발효식품 내에 존재하는 세포밖 소포체 자체가 염증성 질환을 유도함을 의미하며, 이는 발효식품 내 세포밖 소포체에 의한 염증세포에서 IL-6 등의 분비를 측정함으로써 발효식품의 안전성을 진단할 수 있다는 것을 의미한다. 이는 간장 등의 발효식품에 초점을 맞추었으나, 이에 제한하는 것은 아니다. The extracellular endoplasmic reticulum of the present invention was isolated in soybean paste and soy sauce, but is not limited thereto. In addition, the extracellular endoplasmic reticulum isolated from Korean soy sauce (or Korean soy sauce) itself is similar in level to that of LPS or E. coli-derived endoplasmic reticulum from inflammatory cells, This means that the safety of the fermented food can be diagnosed by measuring the secretion of IL-6 and the like in the inflammatory cells caused by the extracellular endoplasmic reticulum in the fermented food. This focuses on fermented foods such as soy sauce, but is not limited thereto.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.
Claims (9)
상기 염증성 질환은 천식, 만성폐쇄성폐질환, 염증성 대장염, 아토피피부염, 패혈증, 및 동맥경화증으로 이루어지는 군에서 선택되는 것을 특징으로 하는, 염증성 질환 치료용 약학적 조성물.
A pharmaceutical composition for the treatment of inflammatory diseases, comprising an extracellular endoplasmic reticulum derived from Japanese soy sauce as an active ingredient,
Wherein said inflammatory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, inflammatory colitis, atopic dermatitis, sepsis, and arteriosclerosis.
The composition of claim 1, wherein said extracellular endoplasmic reticulum inhibits secretion of interleukin-6 (IL-6) as an inflammatory mediator in mammalian epithelial or inflammatory cells.
4. The composition of claim 3, wherein said inflammatory cells are macrophages or eosinophils.
The composition of claim 1, wherein the extracellular endoplasmic reticulum has an average diameter of 20 nm to 200 nm.
상기 염증성 질환은 천식, 만성폐쇄성폐질환, 염증성 대장염, 아토피피부염, 패혈증, 및 동맥경화증으로 이루어지는 군에서 선택되는 것을 특징으로 하는, 염증성 질환 개선용 식품 조성물.
An extracellular endoplasmic reticulum derived from Japanese soy sauce as an active ingredient,
Wherein said inflammatory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, inflammatory colitis, atopic dermatitis, sepsis, and arteriosclerosis.
상기 염증성 질환은 천식, 만성폐쇄성폐질환, 염증성 대장염, 아토피피부염, 패혈증, 및 동맥경화증으로 이루어지는 군에서 선택되는 것을 특징으로 하는, 염증성 질환 개선용 화장료 조성물.A cosmetic composition for improving an inflammatory disease, comprising an extracellular endoplasmic reticulum derived from a Japanese soy sauce as an active ingredient,
Wherein the inflammatory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, inflammatory colitis, atopic dermatitis, sepsis, and arteriosclerosis.
상기 염증성 질환은 인터루킨 6(IL-6) 과발현을 특징으로 하는, 염증성 질환 개선용 화장료 조성물.
A cosmetic composition for the treatment of inflammatory diseases, which comprises an extracellular endoplasmic reticulum derived from a liver fermented by a bacterium or a fungus as an active ingredient,
Wherein said inflammatory disease is characterized by overexpression of interleukin-6 (IL-6).
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