KR101928881B1 - Compositions for Protecting or Treating Osteoarthritis - Google Patents
Compositions for Protecting or Treating Osteoarthritis Download PDFInfo
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- KR101928881B1 KR101928881B1 KR1020170142645A KR20170142645A KR101928881B1 KR 101928881 B1 KR101928881 B1 KR 101928881B1 KR 1020170142645 A KR1020170142645 A KR 1020170142645A KR 20170142645 A KR20170142645 A KR 20170142645A KR 101928881 B1 KR101928881 B1 KR 101928881B1
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- lactic acid
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Abstract
Description
본 발명은 골관절염의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating osteoarthritis.
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염증반응은 체내에서 발생한 산화스트레스에 의해 촉진되는데, 산화 스트레스에 의하여 세포 내의 유전자 주성분인 핵산(DNA), 근육의 주성분인 단백질, 세포막의 주성분인 지방 등이 변형을 일으키게 되거나 세포의 활성이 떨어져 결국은 신체 기능 자체에 문제가 생기며, 이는 세포사멸뿐만 아니라 퇴행성 질환을 일으키는 특정 세포의 유전자 발현을 증가시켜 염증 반응을 개시하거나 악화시킨다.The inflammation reaction is promoted by oxidative stress in the body. Oxidative stress causes degeneration of the nucleic acid (DNA), the main component of the muscle, and fat, the main component of the cell membrane, Has a problem with the body function itself, which initiates or exacerbates an inflammatory reaction by increasing gene expression of certain cells that cause degenerative diseases as well as apoptosis.
대식세포(macrophage)는 동물 체내 모든 조직에 분포하며 인체 내에서 선천적 면역반응을 담당하는 면역세포로, 인체 면역체계에서 중요한 역할을 하는 백혈구이다. 외부의 자극으로 인해 활성화된 대식세포는 염증매개물질 분비를 통해 염증반응을 유발함으로써 천식, 기관지염, 관절염, 다발성경화증, 동맥경화증, 뇌졸중, 알츠하이머병이나 파킨슨병과 같은 퇴행성 뇌질환 및 바이러스 감염으로 인한 염증질환등을 유발하고, 질환을 악화시키게 된다.Macrophages are macrophages that are distributed in all tissues of animals and are the immune cells responsible for the innate immune response in the human body. They are white blood cells that play an important role in the human immune system. The macrophages activated by external stimuli induce an inflammatory reaction through the secretion of inflammatory mediates, thereby causing degenerative brain diseases such as asthma, bronchitis, arthritis, multiple sclerosis, arteriosclerosis, stroke, Alzheimer's disease or Parkinson's disease, And the like, and the disease is worsened.
내독소의 하나인 지질다당체(lipopolysaccharide; LPS)는 Raw264.7 대식세포에서TNF-α(tumor necrosis factor-alpha), IL-6(interleukin-6), IL-1β(interleukin-1β)와 같은 전염증성 사이토카인(pro-inflammatory Cytokine)을 증가시키며, NO(nitric oxide), PGE2(prostaglandin E2) 등의 염증매개물질을 분비한다. 염증상태에서는 COX-2(cyclooxygenase-2)와 NOS(NO synthase)가 유도되어 과량의 PGE2, NO 등이 생성되며 여러가지 질병 및 암 발병(carcinogenesis)이 촉진된다.Lipopolysaccharide (LPS), one of the endotoxins, has been shown to inhibit the growth of Raw264.7 macrophages, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 and interleukin- Increases pro-inflammatory cytokines, and releases inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE 2 ). In the inflammatory state, COX-2 (cyclooxygenase-2) and NOS (NO synthase) are induced and excess PGE 2 and NO are produced, and various diseases and carcinogenesis are promoted.
이러한 전염증성 사이토카인의 생성 억제를 통한 염증반응을 초기 억제를 위한 항염증제 개발에 관한 연구가 진행되어 왔으며, 천연물 유래의 항염증 제제가 다수 개발되어 있다. 예를 들어, 톱니모자반 추출물의 IL-1β, IL-6 및 TNF-α 생성 억제 효과를 통한 관절염 예방 또는 치료용 조성물(등록특허 제10-1783525호), 부추 추출물의 IL-1β, IL-6, MIP-1α 및 TNF-α 생성 억제를 통한 염증성 질환 치료용 조성물(등록특허 제10-1447807호) 및 잔금분홍잎 추출물의 IL-12, IL-6, TNF-α를 통한 염증성 질환 치료용 조성물(등록특허 제10-1582320호) 등이 있다.Studies have been conducted on the development of anti-inflammatory drugs for the early suppression of inflammatory responses through inhibition of the production of proinflammatory cytokines, and many anti-inflammatory agents derived from natural products have been developed. For example, a composition for preventing or treating arthritis by inhibiting the production of IL-1β, IL-6 and TNF-α by an extract of Sawtooth mildew (Patent No. 10-1783525), a composition of IL-1β, IL-6 , Compositions for treating inflammatory diseases through inhibition of MIP-1α and TNF-α production (Patent No. 10-1447807), compositions for treating inflammatory diseases through IL-12, IL-6 and TNF-α (Registered patent No. 10-1582320).
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본 발명자들은 천연물의 염증 질환에 대한 개선 효과를 증가시키고자 노력하였다. 그 결과, 우슬 추출물 및 땅두릅 추출물의 혼합물을 유산균 발효물이, 발효 전 추출물과 비교하여 우수한 전염증성 사이토카인의 생성 억제 효과를 나타냄을 확인함으로써 본 발명을 완성하였다.The present inventors have sought to increase the improvement effect of natural products on inflammatory diseases. As a result, the present inventors have completed the present invention by confirming that the mixture of the extract of Chrysanthemum morifolium extract and Chrysanthemum morifolium extract has an effect of inhibiting the production of excellent proinflammatory cytokine by comparing the fermented product of lactic acid bacteria with the extract before fermentation.
따라서, 본 발명의 목적은 염증 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 데 있다.It is therefore an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of inflammatory diseases.
본 발명의 다른 목적은 염증 질환의 개선용 건강기능식품을 제공하는 데 있다.Another object of the present invention is to provide a health functional food for improving inflammatory diseases.
본 발명의 또 다른 목적은 전염증성 사이토카인의 생성 억제용 건강기능식품을 제공하는 데 있다.It is another object of the present invention to provide a health functional food for inhibiting the production of proinflammatory cytokines.
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본 발명의 일 양태에 따르면, 본 발명은 우슬(Achyranthes japonica) 추출물 및 땅두릅(Aralia continentalis) 추출물의 혼합물을 유산균으로 발효시킨 유산균 발효물을 유효성분으로 포함하는 염증 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.According to one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating an inflammatory disease comprising, as an active ingredient, a fermented product of lactic acid bacteria obtained by fermenting a mixture of Achyranthes japonica extract and Aralia continentalis extract with lactic acid bacteria .
본 명세서에서 용어 "염증 질환"은 생체 조직의 유해한 자극원, 예를 들어, 병원균, 손상된 세포, 자극원에 대한 생체반응 중 하나로 면역세포, 혈관, 분자생물학적인 중간체들이 관여되어 있는 보호반응으로, 미생물에 의한 감염 또는 상처, 수술, 화상, 동상, 전기자극, 화학물질 등 다양한 원인에 의하여 발생한다. 염증은 미생물, 조직 손상에 의한 급성염증, 및 병원균, 바이러스 이물질, 자가면역에 의한 만성 염증으로 나눌 수 있다.As used herein, the term " inflammatory disease " refers to a protective response involving immune cells, blood vessels, and molecular biological intermediates as one of the biological reactions to harmful stimulants of biological tissues such as pathogens, damaged cells, It is caused by various causes such as infection or wound by microorganism, surgery, burn, frostbite, electric stimulation, chemical substance. Inflammation can be divided into microorganisms, acute inflammation due to tissue damage, and chronic inflammation caused by pathogens, viral particles, and autoimmunity.
본 발명의 일 구현예에 따르면, 상기 염증 질환은 결막염, 치주염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병(Curr Drug Targets Inflamm Allergy. 2003 2(2):125-30), 대장염, 강직성척추염, 류마티스열, 루푸스(Ann Rheum Dis. 2005 64(6):849-853), 섬유근통(fibromyalgia, J Neuroimmunology 2016 290(15):22-25), 건선관절염, 골관절염, 류마티스관절염, 견관절주위염, 건염, 건초염, 건주위염, 근육염, 간염, 방광염, 신장염, 쇼그렌증후군(sjogren’s syndrome, J Rheumatol 1997 24(6):1089-91), 다발성경화증(Neurosci Lett. 2000 10;294(1):45-48) 및 급성 또는 만성 염증성 질환이다.According to one embodiment of the present invention, the inflammatory disease is selected from the group consisting of conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease ( Curr Drug Targets Inflamm Allergy . , Colitis, ankylosing spondylitis, rheumatic fever, lupus ( Ann Rheum Dis . 2005 64 (6): 849-853), fibromyalgia, J Neuroimmunology 2016 290 (15): 22-25), psoriatic arthritis, osteoarthritis, rheumatoid arthritis , Neuropathy, Sjogren's syndrome ( J Rheumatol 1997 24 (6): 1089-91), multiple sclerosis ( Neurosci Lett 2000 10; 294 (1) ): 45-48) and acute or chronic inflammatory disease.
본 명세서에서, 용어 "염증질환"은 최소한 후술할 전염증성 사이토카인인 IL-1β, IL-6, TNF-α 및 PGE2로 구성된 군으로부터 선택되는 하나 이상의 전염증성 사이토카인의 생성에 의해 적어도 부분적으로 유발되거나 악화되는 질환, 장애 (disorder), 또는 다른 의학적 증상을 모두 포함하는 것으로 이해될 수 있다.As used herein, the term " inflammatory disease " is intended to include, at least in part, by the generation of at least one proinflammatory cytokine selected from the group consisting of IL-1β, IL-6, TNF-α and PGE 2 , Disorder, or other medical condition that is caused or exacerbated by < RTI ID = 0.0 > a < / RTI >
본 발명의 염증 질환의 예방 또는 치료용 약제학적 조성물은 우슬 추출물 및 땅두릅 추출물의 혼합물을 유산균으로 발효시킨 유산균 발효물을 유효성분으로 포함한다.The pharmaceutical composition for preventing or treating inflammatory diseases according to the present invention comprises a fermented product of a lactic acid bacterium obtained by fermenting a mixture of a wheat extract and a cormorant extract with a lactic acid bacterium as an active ingredient.
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상기 우슬 추출물 및 땅두릅 추출물은 우슬 또는 땅두릅을 물, 및 탄소수 1 내지 4개의 직쇄 또는 분지형 알코올로 이루어진 군에서 선택된 1종 이상의 용매로 추출하여 얻어진 조추출물일 수 있다.The extract and the extract can be a crude extract obtained by extracting the wax or cormuta with at least one solvent selected from the group consisting of water and linear or branched alcohols having 1 to 4 carbon atoms.
우슬 또는 땅두릅의 조추출물 제조에 사용되는 한 용매에 물과 알코올의 혼합물을 사용하는 경우에는 10%이상 내지 100%(v/v)미만, 20%이상 내지 100%(v/v)미만, 30%이상 내지 100%(v/v)미만, 40%이상 내지 100%(v/v)미만, 50%이상 내지 100%(v/v)미만, 60%이상 내지 100%(v/v)미만, 70%이상 내지 100%(v/v)미만, 10%이상 내지 90%(v/v)미만, 20%이상 내지 90%(v/v)미만, 30%이상 내지 90%(v/v)미만, 40%이상 내지 90%(v/v)미만, 50%이상 내지 90%(v/v)미만, 60%이상 내지 90%(v/v)미만 또는 60%이상 내지 80%(v/v)의 탄소수 1 내지 4개의 직쇄 또는 분지형 알코올 수용액, 예를 들어, 70%(v/v)의 탄소수 1 내지 4개의 직쇄 또는 분지형 알코올 수용액일 수 있다.(V / v), 20% or more and 100% (v / v) or less, or 30% or less, when a mixture of water and alcohol is used in a solvent used for preparing crude extracts of water, (V / v), less than 100% (v / v), less than 100% (v / v), less than 100% , Less than 70% to less than 100% (v / v), less than 10% to less than 90% (v / v), more than 20% to less than 90% (v / , Less than 90% (v / v), less than 90% (v / v), less than 90% / v), for example, a linear or branched aqueous alcohol solution of 1 to 4 carbon atoms of 70% (v / v).
또한, 상기 알코올 수용액은 메탄올 수용액, 에탄올 수용액, 프로판올 수용액, 및 부탄올 수용액으로 이루어진 군에서 선택된 1종 이상일 수 있으며, 예를 들어, 에탄올 수용액인 것일 수 있으나, 이에 한정되는 것은 아니다.The alcohol aqueous solution may be at least one selected from the group consisting of an aqueous methanol solution, an aqueous ethanol solution, an aqueous propanol solution, and an aqueous butanol solution, and may be, for example, an aqueous ethanol solution, but is not limited thereto.
본 발명에 따른 우슬 추출물 및 땅두릅 추출물은 용매 조추출물을 추가의 용매로 분획한 용매 분획물일 수 있으며, 예를 들면 상기 용매 조추출물에 에틸에테르, 아세트산에틸, 및 부탄올로 이루어지는 군에서 선택된 1종 이상의 용매를 사용한 용매 분획물일 수 있다.The extract and the extract according to the present invention may be a solvent fraction obtained by fractionating the solvent crude extract with an additional solvent. For example, the solvent crude extract may contain at least one selected from the group consisting of ethyl ether, ethyl acetate, and butanol May be a solvent fraction using a solvent.
예를 들면, 상기 우슬 및 땅두릅을 물 및 탄소수 1 내지 4개의 직쇄 또는 분지형 알코올로 이루어지는 군에서 선택된 1종 이상의 용매로 추출한 용매 조추출물을 에틸에테르, 아세트산에틸, 및 부탄올로 이루어지는 군에서 선택된 1종 이상의 용매를 사용한 용매 분획물일 수 있다.For example, the solvent crude extract obtained by extracting the above-mentioned wax and puddle with at least one solvent selected from the group consisting of water and linear or branched alcohols having 1 to 4 carbon atoms is dissolved in a solvent selected from the group consisting of ethyl ether, ethyl acetate, and butanol Lt; / RTI > solvent fraction.
상기 우슬 추출물 및 땅두릅 추출물은 우슬 또는 땅두릅의 용매 조추출물, 용매 분획물을 포함하며 상술한 바와 같다.The above-mentioned water extracts and extracts of Chrysanthemum morifolium include solvent extracts and solvent fractions of mussel or cormorant as described above.
상기 우슬 추출물 및 땅두릅 추출물은 우슬 또는 땅두릅의 꽃, 잎, 줄기 및 뿌리로 이루어지는 군에서 선택된 1종 이상을, 물 및 탄소수 1 내지 4개의 직쇄 또는 분지형 알코올로 이루어진 군에서 선택된 1종 이상의 용매로 추출하여 얻어진 조추출물일 수 있다.The extracts and extracts of Chrysanthemum morifolium and Chrysanthemum morifolium may be at least one selected from the group consisting of flowers, leaves, stems and roots of wax or papillomum, and at least one solvent selected from the group consisting of water and linear or branched alcohols having 1 to 4 carbon atoms And may be a crude extract obtained by extraction.
상기 용매는 10%이상 내지 100%(v/v)미만, 20%이상 내지 100%(v/v)미만, 30%이상 내지 100%(v/v)미만, 40%이상 내지 100%(v/v)미만, 50%이상 내지 100%(v/v)미만, 60%이상 내지 100%(v/v)미만, 70%이상 내지 100%(v/v)미만, 10%이상 내지 90%(v/v)미만, 20%이상 내지 90%(v/v)미만, 30%이상 내지 90%(v/v)미만, 40%이상 내지 90%(v/v)미만, 50%이상 내지 90%(v/v)미만, 60%이상 내지 90%(v/v)미만 또는 60%이상 내지 80%(v/v)의 탄소수 1 내지 4개의 직쇄 또는 분지형 알코올 수용액, 예를 들어, 70%(v/v)의 탄소수 1 내지 4개의 직쇄 또는 분지형 알코올 수용액일 수 있다.(V / v), less than 100% (v / v), more than 30% and less than 100% (v / v), less than 50% to less than 100% (v / v), less than 60% to less than 100% (v / (v / v), 20% or more to less than 90% (v / v), 30% or more to less than 90% A linear or branched aqueous alcohol solution of from 1 to 4 carbon atoms of less than 90% (v / v), from 60% to less than 90% (v / v) or from 60% to less than 80% (v / v) Or a linear or branched alcohol aqueous solution of 1 to 70% (v / v) carbon atoms.
본 발명에 따른 우슬 추출물 및 땅두릅 추출물의 제조 과정을 보다 상세하게 설명하면 다음과 같다: 우슬 또는 땅두릅을 절단하고 물로 세척하여 협착물을 제거한 후, 상기 우슬 또는 땅두릅의 중량에 대하여 약 10 내지 20배 중량의 추출용매로 환류 추출한다. 추출 후 여과하여 여과액을 모은다. 추출 온도는 특별한 제한은 없지만 15 내지 110, 바람직하게는 20 내지 90인 것이 좋다.The process for producing the extract of Mullein and its extract according to the present invention will be described in more detail as follows: After cutting the mulberry or pelargonium and washing with water to remove the stenosis, about 10 to 20 times It is refluxed with a heavy extracting solvent. After extraction, the filtrate is collected by filtration. The extraction temperature is not particularly limited, but is preferably from 15 to 110, and more preferably from 20 to 90. [
추출 공정은 1회 또는 수회 반복할 수 있으며, 본 발명의 한 바람직한 예에서는 1차 추출 후 다시 재추출하는 방법을 채택할 수 있는데, 이는 생약추출물을 대량 생산하는 경우 효과적으로 여과를 한다 하더라도 생약 자체의 수분 함량이 높기 때문에 손실이 발생하게 되어 1차 추출만으로는 추출효율이 떨어지므로 이를 방지하기 위함이다. 또한, 각 단계별 추출효율을 검증한 결과 2차 추출에 의해 전체 추출량의 80 내지 90% 정도가 추출되는 것으로 밝혀졌다.The extraction process may be repeated once or several times. In a preferred example of the present invention, a method of re-extraction after the first extraction may be adopted. In the case of mass production of herbal extracts, The loss is generated due to the high water content, so that the extraction efficiency is lowered only by the first extraction. In addition, the extraction efficiency of each step was verified, and it was found that about 80 to 90% of the total extraction amount was extracted by the second extraction.
본 발명의 일 예에서, 추출공정을 2회 반복하는 경우, 상기 얻어진 잔사에 다시 추출용매, 약 5 내지 15 부피배, 바람직하게는 8 내지 12 부피배로 환류 추출한다. 추출 후 여과하고 이전에 얻어진 여과액과 합쳐서 감압농축을 하여 우슬 추출물 및 땅두릅추출물을 제조한다. 이와 같이 2차에 걸친 추출 및 각각의 추출 후 얻어진 여과액을 혼합함으로써 추출 효율을 높일 수 있으나, 본 발명의 추출물이 추출 회수에 한정되는 것은 아니다.In one example of the present invention, when the extraction step is repeated twice, the obtained residue is subjected to reflux extraction again with an extraction solvent, about 5 to 15 times by volume, preferably 8 to 12 times by volume. After the extraction, the filtrate is combined with the previously obtained filtrate, and the filtrate is concentrated under reduced pressure to prepare a crude extract and a crude extract. The extraction efficiency can be increased by mixing the extraction solution obtained after the second extraction and the filtrate obtained after each extraction, but the extract of the present invention is not limited to the extraction number.
상기 우슬 추출물 및 땅두릅 추출물 제조 시에 사용되는 용매의 양이 너무 적으면 교반이 어렵게 되고 추출물의 용해도가 낮아져 추출효율이 떨어지게 되고, 지나치게 많은 경우는 다음의 정제단계에서 사용되는 용매의 사용량이 많아져 경제적이지 못하여 취급상 문제가 발생할 수 있으므로, 용매의 사용량은 상기 범위로 하는 것이 좋다.If the amount of the solvent used in preparing the water extract and the extract is too small, the stirring becomes difficult and the solubility of the extract is lowered and the extraction efficiency becomes poor. When the amount is too large, the amount of the solvent used in the next purification step is increased It may not be economical and may cause handling problems. Therefore, the amount of the solvent used is preferably within the above range.
이와 같이 얻어진 여과된 추출물은 의약품 원료로 사용하기에 적합하도록 잔존하는 저급 알코올의 함량을 조절하기 위하여 농축물 총량의 약 10 내지 30중량배, 바람직하게는 15 내지 25중량배, 보다 바람직하게는 약 20 중량배의 물로 1 내지 5회, 바람직하게는 2 내지 3회 공비 농축하고 재차 동량의 물을 가하여 균질하게 현탁시킨 후 동결건조하여 분말상태의 우슬 추출물 및 땅두릅 추출물로서 제조될 수 있다.The thus-obtained filtered extract is used in an amount of about 10 to 30 times by weight, preferably 15 to 25 times by weight, more preferably about 15 times by weight, The mixture is concentrated by
본 발명에 사용된 추출 방법은 통상적으로 사용되는 모든 방법일 수 있으며, 예컨대, 냉침, 열수추출, 초음파 추출, 또는 환류 냉각 추출법일 수 있으나, 이에 한정되는 것은 아니다.The extraction method used in the present invention may be any conventionally used method such as, but not limited to, cold-water extraction, hot water extraction, ultrasonic extraction, or reflux-cooling extraction.
본 명세서에서 용어, '추출물'은 용매 조추출물, 특정 용매 가용 추출물(용매 분획물) 및 용매 조추출물의 용매 분획물을 포함하며, 상기 우슬 추출물 및 땅두릅 추출물은 용액, 농축물 또는 분말 상태를 모두 포함한다.As used herein, the term " extract " includes a solvent crude extract, a specific solvent soluble extract (solvent fraction) and a solvent fraction of a solvent crude extract, wherein the raspberry extract and the peony root extract include both a solution, a concentrate or a powder .
본 발명의 염증 질환의 예방 또는 치료용 약제학적 조성물은 상기 우슬 추출물 및 땅두릅 추출물을 혼합한 혼합물의 유산균 발효물을 유효성분으로 포함한다.The pharmaceutical composition for the prevention or treatment of inflammatory diseases of the present invention comprises a fermented product of a lactic acid bacterium as a mixture of a mixture of the wheat extract and the corn root extract as an active ingredient.
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본 발명의 일 구현예에 따르면, 상기 혼합물의 우슬 추출물:땅두릅 추출물의 혼합비율은 1:0.1-10.0이다.According to one embodiment of the present invention, the mixing ratio of the mixture of the raspberry extract of the mixture and the extract of Pompeii is 1: 0.1-10.0.
본 발명의 다른 구현예에 따르면, 상기 혼합물의 우슬 추출물:땅두릅 추출물의 혼합비율은 1:0.1-9.0, 1:0.1-8.0, 1:0.1-7.0, 1:0.1-6.0, 1:0.1-5.0, 1:0.1-4.0, 1:0.1-3.0, 1:0.1-2.0, 1:0.1-1.0, 1:0.1-0.9, 1:0.1-0.8, 1:0.1-0.7, 1:0.1-0.6, 1:0.2-0.8, 1:0.3-0.7, 1:0.4-0.6 또는 1:0.5이다.According to another embodiment of the present invention, the mixing ratio of the mixture of the raspberry extract and the raspberry extract is 1: 0.1-9.0, 1: 0.1-8.0, 1: 0.1-7.0, 1: 0.1-6.0, 1: 0.1-5.0 1: 0.1 to 4.0, 1: 0.1 to 3.0, 1: 0.1 to 2.0, 1: 0.1 to 1.0, 1: 0.1 to 0.9, 1: 0.1 to 0.8, 1: 0.1 to 0.7, 1: 0.1 to 0.6, 1 : 0.2-0.8, 1: 0.3-0.7, 1: 0.4-0.6 or 1: 0.5.
본 명세서에서 용어 "유산균(또는 젖산균)"은 대사에 의해 탄수화물을 젖산으로 분해시키는 세균의 총칭이다. 유산균에 속하는 대표적인 속(genus)으로는 락토바실러스(Lactobacillus), 류코노스톡(Leuconostoc), 페디오코커스(Pediococcus), 락토코커스(Lactococcus), 스트렙토코커스(Streptococcus), 엔테로코커스(Enterococcus), 비피도박테리움(Bifidobacterium), 스포로락토바실러스(Sporolactobacillus), 웨이셀라(Weissella)등이 있으며, 이에 한정되지 않는다.As used herein, the term " lactic acid bacteria (or lactic acid bacteria) " is a collective term for bacteria that decompose carbohydrates into lactic acid by metabolism. Representative genuses belonging to the lactic acid bacteria include Lactobacillus , Leuconostoc , Pediococcus , Lactococcus , Streptococcus , Enterococcus , Bifidobacterium, But are not limited to, Bifidobacterium , Sporolactobacillus , Weissella , and the like.
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본 발명의 일 구현예에 따르면, 상기 유산균은 락토바실러스 속. (Lactobacillus sp.) 유산균이다.According to one embodiment of the present invention, the lactic acid bacterium is Lactobacillus sp. ( Lactobacillus sp.) Lactic acid bacteria.
본 발명의 다른구현예에 따르면, 상기 락토바실러스 속. 유산균은 락토바실러스 플란타럼(L. plantarum), 락토바실러스 락티스(L. lactis), 락토바실러스 크레모리스(L. cremoris), 락토바실러스 불가리쿠스(L. bulgaricus), 락토바실러스 카세이(L. casei), 락토바실러스 애시도필러스(L. acidophilus), 락토바실러스 람노서스(L. rhamnosus), 락토바실러스 루테리(L. reuteri) 및 락토바실러스 퍼멘텀(L. fermentum)로 구성된 군으로부터 선택되는 하나 이상의 락토바실러스 속. 유산균 일 수 있으며, 이에 제한되지 않는다.According to another embodiment of the present invention, the Lactobacillus sp. The lactic acid bacteria may be selected from the group consisting of L. plantarum , L. lactis , L. cremoris , L. bulgaricus , L. casei ), Lactobacillus acidophilus , L. rhamnosus , L. reuteri and L. fermentum , which are selected from the group consisting of Lactobacillus acidophilus , Lactobacillus acidophilus , Lactobacillus acidophilus , Lactobacillus acidophilus , Lactobacillus. Lactic acid bacteria, and the like.
본 발명의 특정 구현예에 따르면, 상기 락토바실러스 속. 유산균은 락토바실러스 플란타럼이다.According to a particular embodiment of the invention, the Lactobacillus sp. Lactic acid bacteria are lactobacillus plantarum.
상기 우슬 추출물 및 땅두릅 추출물을 혼합한 혼합물에 상기 유산균을 접종하고, 20 내지 40℃ 에서 12 내지 48시간동안 배양시켜 유산균 발효물을 제조한다.The lactic acid bacterium is inoculated into the mixture of the above-mentioned extract of rubella extract and the extract of Pompeii, and cultured at 20 to 40 ° C for 12 to 48 hours to prepare a lactic acid bacterium fermented product.
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본 발명의 조성물은 전염증성 사이토카인인 IL-1β, IL-6, TNF-α 및 PGE2로 구성된 군으로부터 선택되는 하나 이상의 전염증성 사이토카인의 생성을 저해한다.The compositions of the present invention inhibits the production of pro-inflammatory cytokines of IL-1β, IL-6, one or more pro-inflammatory cytokine is selected from the group consisting of TNF-α and PGE 2.
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본 발명의 약제학적 조성물은 우슬 추출물 및 땅두릅 추출물의 혼합물의 유산균 발효물의 약제학적 유효량 및/또는 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물로 이용될 수 있다.The pharmaceutical composition of the present invention can be used as a pharmaceutical composition comprising a pharmaceutically effective amount of a fermented product of lactic acid bacteria and / or a pharmaceutically acceptable carrier in a mixture of a wheat extract and a corn root extract.
본 명세서에서 용어 "약제학적 유효량"은 상술한 우슬 추출물 및 땅두릅 추출물의 혼합물의 유산균 발효물의 효능 또는 활성을 달성하는 데 충분한 양을 의미한다.As used herein, the term " pharmaceutically effective amount " means an amount sufficient to achieve efficacy or activity of a lactic acid fermentation product of a mixture of the above-mentioned wheat extract and cormorant extract.
본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.
본 발명에 따른 약제학적 조성물은 인간을 포함하는 포유동물에 다양한 경로로 투여될 수 있다. 투여 방식은 통상적으로 사용되는 모든 방식일 수 있으며, 예컨대, 경구, 피부, 정맥, 근육, 피하 등의 경로로 투여될 수 있으며, 바람직하게는 경구로 투여될 수 있다.The pharmaceutical compositions according to the present invention can be administered to mammals, including humans, in a variety of routes. The mode of administration may be any conventional manner and may be administered, for example, by oral, skin, intravenous, intramuscular, subcutaneous, and the like routes, preferably orally.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성별, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. 본 발명의 바람직한 구현예에 따르면, 본 발명의 약제학적 조성물의 1일 투여량은 0.001-1000 ㎎/㎏이다.The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate and responsiveness of the patient, Usually, a skilled physician can readily determine and prescribe dosages effective for the desired treatment or prophylaxis. According to a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001-1000 mg / kg.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질 중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제, 캅셀제 또는 젤(예컨대, 하이드로젤) 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets, capsules or gels (e.g., hydrogels), and may additionally contain dispersing or stabilizing agents.
본 발명의 다른 양태에 따르면, 본 발명은 우슬 추출물 및 땅두릅 추출물의 혼합물을 유산균으로 발효시킨 유산균 발효물을 유효성분으로 포함하는 염증 질환의 예방 또는 개선용 건강기능식품을 제공한다.According to another aspect of the present invention, there is provided a health functional food for preventing or ameliorating an inflammatory disease comprising, as an active ingredient, a fermented product of lactic acid bacteria obtained by fermenting a mixture of a wheat extract and a cormorant extract with a lactic acid bacterium.
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본 발명의 염증 질환의 예방 또는 개선용 건강기능식품은 식품 제조 시 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다. 예컨대, 드링크제로 제조되는 경우에는 유효성분으로서 우슬 추출물 및 땅두릅 추출물의 유산균 발효물이외에 향미제 또는 천연 탄수화물을 추가 성분으로 포함시킬 수 있다. 예를 들어, 천연 탄수화물은 모노사카라이드(예컨대, 글루코오스, 프럭토오스 등); 디사카라이드(예컨대, 말토스, 수크로오스 등); 올리고당; 폴리사카라이드(예컨대, 덱스트린, 시클로덱스트린 등); 및 당알코올(예컨대, 자일리톨, 소르비톨, 에리쓰리톨 등)을 포함한다. 향미제로서 천연 향미제(예컨대, 타우마린, 스테비아 추출물 등) 및 합성 향미제(예컨대, 사카린, 아스파르탐 등)을 이용할 수 있다.The health functional food for preventing or ameliorating the inflammatory disease of the present invention includes components that are conventionally added in the manufacture of foods, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings. For example, when it is prepared as a drink, a flavorant or a natural carbohydrate may be added as an active ingredient, in addition to the lactic acid bacteria fermented product of the extract of Chrysanthemum morifolium and the extract of Chrysanthemum morifolium extract. For example, natural carbohydrates include monosaccharides (e.g., glucose, fructose, etc.); Disaccharides (e.g., maltose, sucrose, etc.); oligosaccharide; Polysaccharides (e.g., dextrin, cyclodextrin and the like); And sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). Natural flavoring agents (e.g., tau marin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) may be used as flavorings.
본 발명의 상기 염증 질환의 예방 또는 개선용 건강기능식품은 상기 염증질환의 예방 또는 치료용 약제학적 조성물의 유효성분 및 효과가 동일하기 때문에, 이 둘 사이에 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여, 그 기재를 생략한다.The health functional food for preventing or ameliorating the inflammatory disease of the present invention has the same effective ingredient and effect as the pharmaceutical composition for the prevention or treatment of the inflammatory disease, so that the common content between the two avoids the excessive complexity of the present specification , The description thereof is omitted.
본 발명의 또 다른 양태에 따르면, 본 발명은 우슬 추출물 및 땅두릅 추출물의 혼합물을 유산균으로 발효시킨 유산균 발효물을 유효성분으로 포함하는 전염증성 사이토카인의 생성 억제용 건강기능식품을 제공한다.According to still another aspect of the present invention, there is provided a health functional food for inhibiting the production of proinflammatory cytokines, which comprises a fermented product of lactic acid bacteria obtained by fermenting a mixture of a wheat extract and a cormorant extract with a lactic acid bacterium as an active ingredient.
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본 발명의 일 구현예에 따르면, 상기 전염증성 사이토카인은 IL-1β, IL-6, TNF-α 및 PGE2로 구성된 군으로부터 선택되는 하나 이상의 전염증성 사이토카인이다.According to one embodiment of the invention, the proinflammatory cytokine is one or more pro-inflammatory cytokine is selected from the group consisting of IL-1β, IL-6, TNF-α and PGE 2.
본 발명의 상기 전염증성 사이토카인의 생성 억제용 건강기능식품은 상기 염증 질환의 예방 또는 개선용 건강기능식품의 유효성분 및 효과가 동일하기 때문에, 이 둘 사이에 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여, 그 기재를 생략한다.The health functional food for inhibiting the proinflammatory cytokine production of the present invention has the same effective ingredients and effects as the health functional food for preventing or ameliorating the inflammatory diseases, To avoid this, the description is omitted.
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본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 염증 질환의 개선, 예방 또는 치료용 약제학적 조성물 및 건강기능식품 조성물을 제공한다.(a) The present invention provides a pharmaceutical composition and a health functional food composition for improving, preventing or treating inflammatory diseases.
(b) 본 발명의 조성물은 우수한 전염증성 사이토카인의 생성 억제 활성을 제공한다.(b) The composition of the present invention provides excellent proinflammatory cytokine production inhibitory activity.
(c) 본 발명의 유효성분은 천연물 소재로, 화합물과 비교하여 인체 부작용이 적으며, 원재료의 수급이 용이하고, 생산비용이 경제적인 이점을 갖는다.(c) The active ingredient of the present invention is a natural material, which has fewer side effects on human body than the compound, has an advantage of easy supply and supply of raw materials, and is economical in production cost.
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도 1은 RAW264.7 대식세포의 세포생존율(%)에 대한 우슬(Aj) 및 땅두릅(Ac) 혼합물의 유산균 발효물의 혼합비율(1:2, 1:3, 1:5, 2:1, 3:1 및 5:1)의 영향을 나타낸다. 우슬 및 땅두릅 혼합물의 유산균 발효물의 농도는 0, 200, 400, 600, 800 및 1000 ug/ml이고, CCK 분석을 통해 세포생존율을 측정하였다.
도 2는 LPS-유도 RAW264.7 대식세포의 IL-1β 생성(pg/ml)에 대한 우슬(Aj) 및 땅두릅(Ac) 혼합물의 유산균 발효물의 혼합비율(1:2, 1:3, 1:5, 2:1, 3:1 및 5:1)의 영향을 나타낸다.
도 3은 LPS-유도 RAW264.7 대식세포의 IL-6 생성(pg/ml)에 대한 우슬(Aj) 및 땅두릅(Ac) 혼합물의 유산균 발효물의 혼합비율(1:2, 1:3, 1:5, 2:1, 3:1 및 5:1)의 영향을 나타낸다.
도 4는 LPS-유도 RAW264.7 대식세포의 TNFα 생성(pg/ml)에 대한 우슬(Aj) 및 땅두릅(Ac) 혼합물의 유산균 발효물의 혼합비율(1:2, 1:3, 1:5, 2:1, 3:1 및 5:1)의 영향을 나타낸다.
도 5는 SD 랫트의 혈중 TNFα(pg/ml)에 대한 우슬(Aj) 및 땅두릅(Ac) 혼합물의 유산균 발효물의 혼합비율(1:2, 1:3, 1:5, 2:1, 3:1 및 5:1)의 영향을 나타낸다.
도 6은 SD 랫트의 혈중 PGE2(pg/ml)에 대한 우슬(Aj) 및 땅두릅(Ac) 혼합물의 유산균 발효물의 혼합비율(1:2, 1:3, 1:5, 2:1, 3:1 및 5:1)의 영향을 나타낸다.
도 1 내지 6의 모든 그래프의 'P'는 양성대조군(LPS 처리), 'N'은 음성대조군(LPS 무처리)를 의미한다. 또한, 3번의 독립적 실험 결과의 평균±표준편차로 값을 산출하였고, ANOVA(p<0.05)에 따라,동일한 위 첨자를 공유하지 않는 유의한 차이를 갖는다.1 shows the mixing ratios (1: 2, 1: 3, 1: 5, 2: 1, 3: 1) of the lactic acid bacteria fermentation of the mixture of wax (Aj) and corn (Ac) to cell survival (%) of RAW264.7 macrophages : 1 and 5: 1). The concentration of lactic acid fermented product in the mixture of mussel and duckweed was 0, 200, 400, 600, 800 and 1000 ug / ml, and cell viability was measured by CCK analysis.
Figure 2 shows the mixing ratios (1: 2, 1: 3, 1: 1) of lactic acid bacteria fermentation of the mixture of mash (Aj) and corn (Ac) to IL- 5, 2: 1, 3: 1 and 5: 1).
Figure 3 shows the mixing ratios (1: 2, 1: 3, 1: 1) of lactic acid bacteria fermentation of the mixture of mash (Aj) and cormorant (Ac) to the production of IL-6 of pancreatic LPS- 5, 2: 1, 3: 1 and 5: 1).
Figure 4 shows the mixing ratios (1: 2, 1: 3, 1: 5, 1: 2) of lactic acid bacterial fermentations of the mixture of mash (Aj) and corn (Ac) to TNFα production (pg / ml) of LPS- 2: 1, 3: 1 and 5: 1).
FIG. 5 shows the mixing ratios (1: 2, 1: 3, 1: 5, 2: 1, 3: 1) of the lactic acid bacteria fermented product of the mixture of mash (Aj) and corn (Ac) to the blood TNFα (pg / ml) 1 and 5: 1).
Figure 6 shows the mixing ratios (1: 2, 1: 3, 1: 5, 2: 1, 3: 1) of lactic acid bacterial fermentations of the mixture of mash (Aj) and corn (Ac) to blood PGE 2 (pg / ml) : 1 and 5: 1).
'P' in all the graphs of FIGS. 1 to 6 means a positive control (LPS treatment) and 'N' means a negative control (no LPS treatment). In addition, the values were calculated as the mean ± standard deviation of three independent experiments, and according to ANOVA (p <0.05), there is a significant difference that does not share the same superscripts.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
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)%.
실시예Example
실험 재료 및 실험 방법Materials and Experiments
시료준비Sample Preparation
실험에 사용된 우슬(Achyranthes japonica nakai, Aj) 및 땅두릅(Aralia continentalis Kitagawa, Ac)은 ㈜제이앤디에서 파우더 형태로 구입하여 실험에 사용하였다. 실험에 사용된 락토바실러스 플란타럼(Lactobacillus plantarum, KCTC NO. 3108)은 생물자원센터(KCTC)에서 분양 받아 사용하였다. 분양 받은 L. plantarum를 락토바실러스 MRS 배지(Difco, Proteose Peptone No.3 10 g/L, Beef 추출물 10 g/L, 효모 추출물 5 g/L, 덱스트로오스 20 g/L, 폴리소르베이트(polysorbate) 80 1 g/L, 시트르산암모늄(ammonium citrate) 2 g/L, 초산나트륨(Sodium Acetate) 5 g/L, 황산마그네슘(Magnesium Sulfate) 0.1 g/L, 황산 망간(Manganese Sulfate) 0.05 g/L, 인산2칼륨(Dipotassium Phosphate) 2 g/L)에 접종하여 37℃, 250 rpm에서 7일 동안 배양 후 집균하여 사용하였다.( Achyranthes japonica nakai , Aj) and Aralia continentalis Kitagawa (Ac) were purchased in powder form from J & Andi Co., Ltd. and used in the experiment. The Lactobacillus plantarum (KCTC NO. 3108) used in the experiment was purchased from the BRC (KCTC). The cultured L. plantarum was treated with Lactobacillus MRS medium (Difco, 10 g / L Proteose Peptide No. 3, 10 g / L Beef extract, 5 g / L yeast extract, 20 g / L dextrose, polysorbate 2 g / L of ammonium citrate, 5 g / L of sodium acetate, 0.1 g / L of magnesium sulfate, 0.05 g / L of manganese sulfate, , 2 g / L of dipotassium phosphate), cultured at 37 DEG C and 250 rpm for 7 days, and then collected and used.
우슬과 땅두릅 파우더를 850 μm의 체로 거른 후, 우슬과 땅두릅의 비율을 1:2, 1:3, 1:5, 2:1, 3:1 그리고 5:1의 비율(질량비)로 각각 100 g씩 5 L 반응기에 투여 후 70% 주정(1 L, 10배수)으로 37℃에서 48시간 동안 추출하였다. 여과지를 이용하여 감압여과 한 후, 용액층을 회전진공증발기(vacuum rotary evaporator)로 농축하여 시료를 얻었다. 농축물의 1%(농축물 대비 균 1%에 해당하는 (W/W) 질량%)에 락토바실러스 플란타럼을 첨가하여 37℃에서 1시간 본배양 시킨 후 7일간 동결건조하여 최종시료로 사용하였다.The ratio of the ratio of water to the ratio of water to water was 1: 2, 1: 3, 1: 5, 2: 1, 3: 1 and 5: (1 L, 10-fold) at 37 ° C for 48 hours. After filtration under reduced pressure using a filter paper, the solution layer was concentrated with a rotary rotary evaporator to obtain a sample. Lactobacillus plantarum was added to 1% of the concentrate (mass% (W / W) corresponding to 1% of the bacteria compared to the concentrate), incubated at 37 ° C for 1 hour, and lyophilized for 7 days to be used as a final sample .
세포배양 및 세포독성 측정Cell culture and cytotoxicity measurement
RAW264.7 대식세포는 한국 세포주은행(Korea)에서 분양받아 사용하였다. 10% FBS(fetal bovine serum) 및 1% 항생제(페니실린-스트렙토마이신)을 첨가한 DMEM(Dulbecco's modified Eagle medium) 배지를 이용하여 37, 5% CO2 조건에서 배양하였다. 세포실험에 사용된 모든 시약은 웰진(Welgene)에서 구입하였다. 우슬 및 땅두릅 혼합물의 유산균 발효물을 세포에 처리하기 위한 최고농도를 결정하기 위하여, CCK(cell counting kits) 분석을 통해 세포독성을 확인하였다. RAW264.7 세포를 96 웰플레이트에 6*103 cells/well의 농도가 되도록 조절한 후 각 웰에 100 μL씩 분주하였다. 플레이트를 37℃, 5% CO2인큐베이터에서 24시간 배양하여 세포를 부착시킨 다음, 상기 혼합물의 유산균 발효물을 0, 200, 400, 600, 800, 1000 μg/mL 농도가 되도록 배지에 희석하여 첨가하였다. 24시간 동안 배양시킨 후 CCK 시약을 주입하고 37℃, 5% CO2인큐베이터에서 2시간 동안 반응시킨 후, 450 nm에서 흡광도를 측정하였다. 세포생존율(%) = (1-시료처리군의 흡광도 / 대조군의 흡광도) * 100의 계산식으로 정량화하였다.RAW264.7 macrophages were purchased from the Korean Cell Line Bank (Korea). The cells were cultured in DMEM (Dulbecco's modified Eagle medium) supplemented with 10% FBS (fetal bovine serum) and 1% antibiotic (penicillin-streptomycin) at 37.5% CO 2 . All reagents used in cell experiments were purchased from Welgene. Cytotoxicity was confirmed by CCK (cell counting kits) analysis in order to determine the highest concentration for treatment of lactic acid fermented product of the mixture of mussel and lean mixture. RAW264.7 cells were adjusted to a concentration of 6 * 10 3 cells / well in a 96-well plate, and 100 μL aliquots were added to each well. The plate was incubated in a 5% CO 2 incubator at 37 ° C for 24 hours to attach the cells. The fermented lactic acid bacteria of the mixture was diluted in the medium to a concentration of 0, 200, 400, 600, 800, 1000 μg / Respectively. After incubation for 24 hours, CCK reagent was injected, incubated at 37 ° C in a 5% CO 2 incubator for 2 hours, and absorbance was measured at 450 nm. Cell survival rate (%) = (1 - absorbance of sample treated group / absorbance of control group) * 100.
염증 관련 사이토카인 생성량 측정Measurement of inflammation-related cytokine production
우슬과땅두릅 혼합물의 유산균 발효물이 LPS(lipopolysaccharides)의 자극에 의해 생성되는 IL-1β, IL-6 및 TNF-α의 생성량에 미치는 효과를 측정하기 위해 RAW264.7 대식세포를 1.5*106 cells/dish의 농도로 60 mm dish에 분주한 뒤 약 24시간 동안 배양하였다. LPS(1 μg/mL)를 처리하여 24시간 동안 염증을 유도시킨 후, 6가지 조합(우슬:땅두릅의 혼합비율, 1:2, 1:3, 1:5, 2:1, 3:1, 5:1)의 우슬과 땅두릅 혼합물의 유산균 발효물을 400 μg/mL의 농도로 처리하였다. 24시간 후, 세포 배양액을 수거하여 원심분리과정을 거친 상등액을 -20에 보관하여 시료로 사용하였다. 사이토카인 생성량 측정은 ELISA 키트(R&D system, Minneapolis, MN, USA)를 이용하여 제공된 실험방법에 따라 진행하였으며, 흡광도는 450 nm에서 ELISA 리더를 이용하여 측정하였다.To measure the effect of lactic acid fermentation on the production of IL-1β, IL-6 and TNF-α produced by LPS (lipopolysaccharides) stimulation, RAW264.7 macrophages were cultured in 1.5 × 10 6 cells / dish, and then cultured for about 24 hours. (1: 2, 1: 3, 1: 5, 2: 1, 3: 1, 1: 5: 1) were treated at a concentration of 400 μg / mL. After 24 hours, the cell culture medium was collected, centrifuged, and the supernatant was stored at -20 and used as a sample. The cytokine production was measured using an ELISA kit (R & D system, Minneapolis, MN, USA) and the absorbance was measured at 450 nm using an ELISA reader.
시험동물 및 사육환경Test animals and breeding environment
본 연구에 사용된 동물은 스프라그-다우리(Sprague-Dawley, SD)계의 6주령 된 흰 래트(암컷)로서 ㈜샘타코 바이오코리아에서 분양 받아 동물실험실 환경에 7일간 적응시킨 후 사용하였다. 적응기간 동안 동물실험실의 온도는 23±3℃, 습도 50±10% 내외, 명암주기는 12시간 단위로 조절하였다. 실험기간 내내 사료와 물을 제한 없이 적당량을 충분히 공급하였다.The animals used in this study were Sprague-Dawley (SD) 6-week-old white rats (female), which were purchased from Samtaco Bio Korea and used for 7 days in an animal laboratory environment. During the adaptation period, the temperature of the animal laboratory was adjusted to 23 ± 3 ℃, humidity of 50 ± 10% All feeds and water were supplied in sufficient quantity throughout the experiment.
시료의 투여 및 기간Sample administration and duration
총 40마리의 실험동물을 8 군[음성대조군, 양성대조군, 1:2, 1:3, 1:5, 2:1, 3:1및 5:1]으로 나누어 음성대조군을 제외한 모든 군에 LPS(300 μg/Kg)를 복강주사하여 염증을 유발시켰다. 24시간 뒤부터 음성대조군(normal군)과 양성대조군(control군)은 0.9% 증류수 2 ml을, 실험군은 각각의 시료 200 mg을 증류수 2 mL에 혼합하여 경구용 바늘(zonde needle)을 이용하여 매일 오전10시경에 1일 1회 2주간 경구투여 하였다.A total of 40 experimental animals were divided into 8 groups [negative control, positive control, 1: 2, 1: 3, 1: 5, 2: 1, 3: 1 and 5: 1] (300 μg / Kg) was injected intraperitoneally to induce inflammation. After 24 hours, the negative control (normal group) and the positive control group (control group) were mixed with 2 ml of 0.9% distilled water. In the experimental group, 200 mg of each sample was mixed with 2 mL of distilled water, And was orally administered once a day for about 2 weeks at about 10:00 am.
혈액분석Blood analysis
경구투여 종료 후 24시간 절식시킨 실험동물을 CO2챔버를 이용해 질식사 시킨 후, 혈액을 채취하고 12,000 rpm에서 20분 동안 원심분리하여 혈청을 분리하였다. 혈청으로 유리된 TNF-α 및 PGE2의 생성을 ELISA 키트(R&D systems Inc., Minneapolis, USA)를 사용하여 제공회사의 실험방법에 따라 측정하였다.After the oral administration, the animals were fasted for 24 hours and chased using a CO 2 chamber. Blood was collected and the serum was separated by centrifugation at 12,000 rpm for 20 minutes. Serum-liberated TNF- [alpha] and PGE 2 production were measured using an ELISA kit (R & D systems Inc., Minneapolis, USA) according to the supplier's experimental method.
통계분석Statistical analysis
본 실험에 대한 모든 데이터는 평균±표준편차로 나타내었으며, 연구 결과 얻어진 자료를 SPSS(statistical package for social science, version 20) 통계 프로그램을 사용하여 하위 그룹 각각의 기술통계치(mean, SD)를 산출하였다. 사후검증으로 Duncan's post-hoc test를 실시하였으며, p<0.05 수준에서 유의성을 검증하였다.All data for this experiment were expressed as means ± SD. The data obtained from the study were used to calculate the descriptive statistics (mean, SD) of each subgroup using the statistical package for social science, version 20 (SPSS) . Duncan's post-hoc test was performed by post-test, and significance was verified at p <0.05 level.
결과 및 고찰Results and Discussion
세포독성Cytotoxicity
우슬과 땅두릅 혼합물의 유산균 발효물의 세포독성 여부를 확인하기 위하여 CCK 분석을 이용하여 세포독성을 측정하였고, 결과를 도 1에 나타내었다. RAW264.7 세포에 각각 0, 200, 400, 600, 800, 1000 μg/mL의 우슬 및 땅두릅 혼합물의 유산균 발효물을 처리한 후, CCK 분석으로 세포생존률을 측정하였다. 모든 시료에서 400 μg/mL의 농도까지는 80% 이상의 생존율을 나타냈으므로 이후의 실험에서는 세포독성을 나타내지 않는 최고농도인 400 μg/mL의 농도에서 실험을 수행하였다.To determine the cytotoxicity of the fermented product of lactic acid bacteria in the mixture of mussel and duckweed, cytotoxicity was measured using CCK analysis. The results are shown in FIG. RAW264.7 cells were treated with 0, 200, 400, 600, 800, and 1000 μg / mL of lactic acid bacteria fermented with a mixture of wheat and triticale, respectively, and cell viability was measured by CCK analysis. In all the samples, the survival rate was more than 80% up to the concentration of 400 μg / mL. Therefore, the experiment was carried out at the maximum concentration of 400 μg / mL, which does not show cytotoxicity in subsequent experiments.
In vitro In vitro 사이토카인 생성 저해능Cytokine generation is poor
우슬 및 땅두릅 혼합물의 유산균 발효물이 RAW264.7 대식세포에서 LPS에 의해 생성되는 사이토카인인 IL-1β, IL-6 및 TNF-α의 생성저해 효과에 대한 결과는 각각 도 2, 3 및 4와 같다. LPS만을 처리한 군(Control, 양성대조군)에서 IL-1β는 63.26 pg/mL로 LPS를 처리하지 않은 음성대조군(10.12 pg/mL)에 비해 높은 증가를 보였으나, 우슬:땅두릅=2:1, 1:5, 3:1 비율에서 각각 18.81, 37.35, 40.14 pg/mL로 IL-1β의 생성을 억제하는 것으로 확인되었다(도 2 및 표 1). 특히 2:1의 비율에서는 70% 수준까지 IL-1β의 생성이 감소되었다. IL-6의 경우는 LPS만을 처리한 군에서 774.49 pg/mL로 높은 증가를 보였으나, 2:1, 1:5, 1:2 비율에서 각각 542.68, 584.76, 633.52 pg/mL로 감소하였고, 특히 2:1 비율에서 LPS를 처리하지 않은 음성대조군에 비해 30% 감소 효과를 보였다(도 3 및 표 2). TNF-α의 경우 LPS만을 처리한 군에서 2275.68 pg/mL로 LPS를 처리하지 않은 군(1379.47 pg/mL) 보다 39% 높아졌지만, 1:5 비율에서 1847.02 pg/mL, 2:1 비율에서 1679.11 pg/mL로 각각 19%, 26% 감소 효과를 보였다(도 4 및 표 3).The results of inhibition of the production of IL-1β, IL-6 and TNF-α, which are cytokines produced by LPS in RAW264.7 macrophages, are shown in FIGS. 2, 3 and 4, respectively same. IL-1β was 63.26 pg / mL in the LPS-treated group (control, positive control group), but increased compared to the negative control group (10.12 pg / mL) 1β at a ratio of 1: 5 and 3: 1, respectively, to 18.81, 37.35, and 40.14 pg / mL, respectively (FIG. 2 and Table 1). In particular, at a ratio of 2: 1, the production of IL-1β was reduced to 70%. IL-6 was increased to 774.49 pg / mL in the LPS-treated group, but decreased to 542.68, 584.76 and 633.52 pg / mL in the 2: 1, 1: 5 and 1: 2: 1 ratio compared to the negative control without LPS treatment (FIG. 3 and Table 2). TNF-α was 2275.68 pg / mL in the LPS-treated group and 397% higher in the LPS treated group (1379.47 pg / mL) than in the LPS treated group, but the ratio of 1: 5 to 1847.02 pg / pg / mL by 19% and 26%, respectively (Fig. 4 and Table 3).
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혈관 관련 염증반응은 염증세포들(호중성 과립구, 림프구, 단핵구 및 대식세포), 내피세포, 혈관평활근 세포와의 복잡한 상호작용과 관련되고, 대식세포, T-세포, 단핵구, 혈소판, 내피세포에 의해 생성된 사이토카인은 염증성 혈관질환의 발병에 중요한 역할을 한다.The vascular-associated inflammatory response is associated with complex interactions with inflammatory cells (neutrophil granulocyte, lymphocyte, monocyte and macrophage), endothelial cells, and vascular smooth muscle cells, and is involved in macrophage, T-cell, mononuclear cell, platelet, The cytokines produced by these cells play an important role in the development of inflammatory vascular disease.
In vivo In vivo 사이토카인 생성 저해능Cytokine generation is poor
우슬과 땅두릅 혼합물의 유산균 발효물을 경구투여 한 SD 래트의 혈청으로 유리된 사이토카인 TNF-α 및 PGE2의 생성저해 효과에 대한 결과는 각각 도 5 및 6과 같다. TNF-α는 LPS만을 처리한 군(양성대조군)에서 17.25 pg/ml로 LPS를 처리하지 않은 음성대조군(10.88 pg/ml)에 비해 유의적인 증가를 보였다. 우슬:땅두릅=2:1, 1:5, 1:2 비율에서 각각 9.60, 10.85, 11.08 pg/ml로 TNF-α의 생성을 유의적으로 억제하였으며, 특히 2:1 비율에서 LPS만을 처리한 군보다 44% 감소 효과가 확인되었다(도 5 및 표 4). PGE2는 LPS만을 처리한 군에서 743.85 pg/ml로 LPS를 처리하지 않은 대조군(9.60 pg/ml)에 비해 높은 증가를 보였다. 우슬:땅두릅=2:1, 1:3, 3:1 비율에서 각각 208.86, 226.61, 276.45 pg/ml로 PGE2의 생성을 유의적으로 억제하는 것으로 확인되었다(도 6 및 표 5).The results of inhibiting the production of cytokines TNF-a and PGE 2 liberated with serum of SD rats orally administered with lactic acid bacteria fermented with a mixture of mussel and duckweed are shown in FIGS. 5 and 6, respectively. TNF-α was significantly increased in the LPS-treated group (positive control group) compared to the negative control group (10.88 pg / ml) treated with LPS at 17.25 pg / ml. The production of TNF-α was significantly inhibited at 9.60, 10.85 and 11.08 pg / ml at the ratio of 2: 1, 1: 5 and 1: 2, respectively, (Fig. 5 and Table 4). PGE 2 was increased to 743.85 pg / ml in the LPS-only group compared with the control group (9.60 pg / ml) in the LPS-untreated control group. Wooseul: udo = 2: 1, 1: 3, 3: 1 ratio was found to be 208.86, respectively, inhibit the production of PGE 2 significantly as 226.61, 276.45 pg / ml (Fig. 6 and Table 5).
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Claims (13)
The pharmaceutical composition for preventing or treating inflammatory diseases according to claim 1, wherein the extract of rumen extract and the extract of Pompeii are anhydrous or hydroalcoholic extracts having 1-4 carbon atoms.
The method of claim 1, wherein the composition is pro-inflammatory cytokine is IL-1β, IL-6, the prevention of TNF-α and inflammatory disorders for inhibiting one or more of the former production of inflammatory cytokine is selected from the group consisting of PGE 2 Or a pharmaceutical composition for therapeutic use.
[Claim 7] The health food according to claim 7, wherein the extract of rubella and the extract of Pompeii are anhydrous or hydrolyzed alcohol extracts having 1-4 carbon atoms.
The method of claim 7, wherein the lactic acid bacterium is selected from the group consisting of Lactobacillus sp. ( Lactobacillus sp.) For the prevention or amelioration of inflammatory diseases.
The method of claim 7, wherein the composition is pro-inflammatory cytokine is IL-1β, IL-6, the prevention of TNF-α and inflammatory disorders for inhibiting one or more of the former production of inflammatory cytokine is selected from the group consisting of PGE 2 Or health functional food for improvement.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR102007144B1 (en) * | 2019-04-26 | 2019-08-02 | 에스케이바이오랜드 주식회사 | A novel strain of Lactobacillus plantarum SKB1234 having an improving effect on arthritis and a method for producing a mixture of the fermented Achyranthes japonica Nakai extract using the Lactobacillus plantarum SKB1234, Angelica gigas Nakai extract and Eucommia ulmoides Oliver extract |
| KR102044659B1 (en) * | 2019-04-26 | 2019-11-13 | 에스케이바이오랜드 주식회사 | Comprising composition of fermented Achyranthes japonica Nakai extract Complex for preventing or treating arthritis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102007144B1 (en) * | 2019-04-26 | 2019-08-02 | 에스케이바이오랜드 주식회사 | A novel strain of Lactobacillus plantarum SKB1234 having an improving effect on arthritis and a method for producing a mixture of the fermented Achyranthes japonica Nakai extract using the Lactobacillus plantarum SKB1234, Angelica gigas Nakai extract and Eucommia ulmoides Oliver extract |
| KR102044659B1 (en) * | 2019-04-26 | 2019-11-13 | 에스케이바이오랜드 주식회사 | Comprising composition of fermented Achyranthes japonica Nakai extract Complex for preventing or treating arthritis |
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