KR20190076437A - Composition for preventing or treating ischemic diseases comprising extract of Tozan as an active ingredient - Google Patents
Composition for preventing or treating ischemic diseases comprising extract of Tozan as an active ingredient Download PDFInfo
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- KR20190076437A KR20190076437A KR1020170178234A KR20170178234A KR20190076437A KR 20190076437 A KR20190076437 A KR 20190076437A KR 1020170178234 A KR1020170178234 A KR 1020170178234A KR 20170178234 A KR20170178234 A KR 20170178234A KR 20190076437 A KR20190076437 A KR 20190076437A
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- extract
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K36/18—Magnoliophyta (angiosperms)
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
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Abstract
Description
본 발명은 토사자 추출물을 유효성분으로 포함하는 허혈성 질환의 예방 또는 치료용 조성물에 관한 것으로, 구체적으로 토사자 추출물 또는 이의 분획물을 유효성분으로 포함하는 허혈성 질환의 예방 또는 개선용 건강기능식품 조성물; 약학 조성물; 의약외품 조성물; 또는 상기 약학 조성물을 이용하여 허혈성 질환을 치료하는 방법에 관한 것이다.The present invention relates to a composition for the prevention or treatment of ischemic diseases comprising an extract of Tozai as an active ingredient, and more particularly to a health functional food composition for preventing or ameliorating an ischemic disease comprising an extract of Tozan or a fraction thereof as an active ingredient; Pharmaceutical compositions; Quasi-drug composition; Or a method of treating ischemic diseases using the pharmaceutical composition.
허혈성 질환은 혈액의 유입이 감소하여 야기되는 혈행장애로서, 고령화, 외상, 합병증, 갱년기 등 다양한 요인에 의해 발병된다. 혈행장애는 호기성 대사장애, ATP 생산 저하를 야기하여 결국 세포를 기능부전 또는 괴사에 이르게 하는데, 허혈성 캐스케이드라고 불리우는 일련의 과정들이 촉발되면 조직이 영구적으로 손상될 수도 있어, 이를 치료하기 위한 많은 약제 및 치료방법이 개발되고 있다.Ischemic disease is a hematological disorder caused by a decrease in the inflow of blood, and is caused by various factors such as aging, trauma, complications, and menopausal period. Hematologic disorders lead to aberrant metabolic disturbances and ATP production, which ultimately leads to cell dysfunction or necrosis. If a series of processes called ischemic cascades are triggered, the tissue may be permanently damaged, and many medications and treatments Methods are being developed.
예로서, 노긴을 유효성분으로 함유하는 허혈성 질환의 예방 및 치료용 조성물(한국 공개특허공보 제10-2016-0086193호), VEGF 유래 펩타이드가 담지된 리포좀을 포함하는 허혈성 질환의 예방 또는 치료용 조성물(한국 공개특허공보 제10-2016-0141068호), 라이코펜을 포함하는 허혈성 질환의 치료 또는 예방용 조성물(한국 등록특허공보 제10-1293882호) 등이 개발된바 있다.For example, a composition for preventing or treating an ischemic disease comprising a noggin as an active ingredient (Korean Patent Laid-Open No. 10-2016-0086193), a composition for preventing or treating ischemic diseases comprising a liposome carrying a peptide derived from VEGF (Korean Patent Laid-Open No. 10-2016-0141068), and compositions for treating or preventing ischemic diseases including lycopene (Korean Patent Registration No. 10-1293882).
한편, 토사자는 새삼씨 또는 금사초라고도 불리우는 새삼의 씨앗으로서, 동의보감에서는 토사자가 정력을 좋게 해주고 원기를 복돋우며, 요통과 당뇨병에 효과가 있다고 기록되어있다. 또한, 토사자의 효능으로는 졍력증진, 신장기능 강화, 뼈 기능 강화, 이뇨 효과, 설과 효과, 야맹증 개선 등이 있어, 이와 관련된 질환의 한약재로도 널리 활용되고 있다. 그러나, 토사자의 허혈성 질환에 대한 치료 효과는 알려진바 없었다.On the other hand, it is said that the tosaja is the seed of the new ginseng which is also called the ginseng seed or the ginseng seed, and the ginseng boson is said to be effective for the back pain and the diabetes. In addition, the efficacy of humectants is widely used as medicinal herbs for improving diseases, improving kidney function, strengthening bones, improving diuretic effect, improving effect and night blindness. However, the therapeutic effect on the ischemic diseases of humans was not known.
이러한 배경하에, 본 발명자들은 허혈성 질환을 치료하기 위한 물질을 개발하고자 예의 연구 노력한 결과, 토사자 추출물이 난소가 절제되고 하지 허혈이 발병된 동물모델에서 하지 혈류를 개선시키고 상처 치유를 촉진시키고 염증을 감소시키며 혈관형성을 촉진함으로써 허혈성 질환을 개선/치료할 수 있음을 확인하여, 본 발명을 완성하였다.Under these circumstances, the present inventors have made intensive studies to develop a substance for treating ischemic diseases. As a result, the inventors of the present invention have found that the extract of Tozan extract improves the blood flow to the lower extremities and promotes wound healing and reduces inflammation And can improve / treat ischemic diseases by promoting angiogenesis, thus completing the present invention.
본 발명의 하나의 목적은 토사자 추출물 또는 이의 분획물을 유효성분으로 포함하는 허혈성 질환의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.It is an object of the present invention to provide a health functional food composition for preventing or ameliorating an ischemic disease comprising extracts or fractions thereof as an active ingredient.
본 발명의 다른 하나의 목적은 토사자 추출물 또는 이의 분획물을 유효성분으로 포함하는 허혈성 질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of ischemic diseases comprising extracts or fractions thereof as an active ingredient.
본 발명의 또 다른 하나의 목적은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 허혈성 질환의 치료 방법을 제공하는 것이다.It is another object of the present invention to provide a method for treating an ischemic disease comprising administering the pharmaceutical composition to a subject.
본 발명의 또 다른 하나의 목적은 토사자 추출물 또는 이의 분획물을 유효성분으로 포함하는 허혈성 질환의 예방 또는 개선용 의약외품 조성물을 제공하는 것이다.It is still another object of the present invention to provide a quasi-drug composition for preventing or ameliorating ischemic diseases comprising extracts or fractions thereof as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명의 하나의 양태는 토사자 추출물 또는 이의 분획물을 유효성분으로 포함하는 허혈성 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In order to accomplish the above object, one aspect of the present invention provides a health functional food composition for preventing or ameliorating ischemic diseases comprising extracts or fractions thereof as an active ingredient.
본 발명에서는, 토사자 추출물은 난소가 절제되고 하지의 혈관이 결찰되어 허혈성 질환이 야기된 동물모델의 하지 혈류를 개선시키고 상처 치유를 촉진키고 염증을 감소시키며 혈관형성을 촉진하므로, 허혈성 질환을 예방, 개선 또는 치료하는데 유용하게 사용될 수 있음을 확인하였다.In the present invention, the extract of the extracts of the ovary is used for prevention of ischemic diseases, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, It can be used for improving or treating diseases.
본 발명의 용어, "토사자"는 메꽃과에 속하는 한해살이 덩굴성 식물인 새삼(Cuscuta japonica)의 씨앗을 말하며, 새삼씨 또는 금사초라고도 한다. 토사자는 주로 간과 신장을 보호하며 눈을 밝게 해주고, 양기를 도우며 신장 기능을 튼튼하게 해주는 약재로 알려져 있다. 그러나, 허혈성 질환에 대한 효과는 알려진바 없으며, 본 발명자들에 의해 처음으로 규명되었다. 본 발명에서 토사자는 상업적으로 판매되는 것을 구입하거나, 자연에서 채취 또는 재배된 것을 사용할 수 있다. The term " tosauja " of the present invention refers to the seed of Cuscuta japonica , a perennial plant belonging to the family Pinus densiflora, and is also called a seed or seedling. It is known as a medicine that protects the liver and kidneys, brightens the eyes, helps the Yangs and strengthens the kidneys. However, the effect on ischemic diseases is not known, and was first identified by the present inventors. In the present invention, the soil can be purchased commercially, sold or cultivated in nature.
본 발명의 용어, "추출물"은 상기 토사자를 추출 처리하여 얻어지는 추출액, 상기 추출액의 희석액이나 농축액, 상기 추출액을 건조하여 얻어지는 건조물, 상기 추출액의 조정제물이나 정제물, 또는 이들의 혼합물 등, 추출액 자체 및 추출액을 이용하여 형성 가능한 모든 제형의 추출물을 포함한다.The term "extract" of the present invention is intended to encompass an extract obtained by extracting the extract, a diluted or concentrated solution of the extract, a dried product obtained by drying the extract, a controlled preparation or a purified product of the extracted solution, And extracts of all formulations which can be formed using extracts.
상기 토사자를 추출하는 방법은 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 추출할 수 있다. 상기 추출 방법의 비제한적인 예로는, 열수 추출법, 초음파 추출법, 여과법, 환류 추출법 등을 들 수 있으며, 이들은 단독으로 수행되거나 2종 이상의 방법을 병용하여 수행될 수 있다.The method for extracting the soil-bearing material is not particularly limited and may be carried out according to a method commonly used in the art. Non-limiting examples of the extraction method include hydrothermal extraction, ultrasonic extraction, filtration, and reflux extraction. These may be performed alone or in combination with two or more methods.
본 발명에서, 상기 토사자를 추출하는데 사용되는 추출 용매의 종류는 특별히 제한되지 않으며, 당해 기술 분야에서 공지된 임의의 용매를 사용할 수 있다. 상기 추출 용매의 비제한적인 예로는 물, 탄소수 1 내지 4의 알코올 또는 이들의 혼합 용매 등을 들 수 있으며, 이들은 단독으로 사용되거나 1종 이상 혼합하여 사용될 수 있다. In the present invention, the type of the extraction solvent used for extracting the soil material is not particularly limited, and any solvent known in the art can be used. Nonlimiting examples of the extraction solvent include water, alcohols having 1 to 4 carbon atoms, and mixed solvents thereof. These solvents may be used alone or in combination.
구체적으로, 상기 추출 용매는 물 또는 에탄올일 수 있으나, 이에 제한되지 않는다.Specifically, the extraction solvent may be water or ethanol, but is not limited thereto.
본 발명의 용어, "분획물"은 여러 다양한 구성 성분들을 포함하는 혼합물로부터 특정 성분 또는 특정 성분 그룹을 분리하기 위하여 분획을 수행하여 얻어진 결과물을 의미한다.The term "fraction " of the present invention means a product obtained by performing fractionation to separate a specific component or a specific component group from a mixture containing various components.
본 발명에서, 상기 분획물을 얻는 분획 방법은 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 수행될 수 있다. 상기 분획 방법의 비제한적인 예로는, 다양한 용매를 처리하여 수행하는 용매 분획법, 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 수행하는 한외여과 분획법, 다양한 크로마토그래피(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)를 수행하는 크로마토그래피 분획법, 및 이들의 조합 등이 있다. 구체적으로, 본 발명의 토사자를 추출하여 얻은 추출물에 소정의 용매를 처리하여 상기 추출물로부터 분획물을 얻는 방법을 들 수 있다.In the present invention, the fractionation method for obtaining the fraction is not particularly limited and may be carried out according to a method commonly used in the art. Non-limiting examples of the fractionation method include a solvent fractionation method performed by treating various solvents, an ultrafiltration fractionation method performed through an ultrafiltration membrane having a constant molecular weight cut-off value, various chromatography (size, charge, hydrophobicity Or affinity-based separation), and a combination thereof, and the like. Specifically, a method of obtaining a fraction from the extract by treating the extract obtained by extracting the extract of the present invention with a predetermined solvent can be mentioned.
본 발명에서 상기 분획물을 얻는데 사용되는 분획 용매의 종류는 특별히 제한되지 않으며, 당해 기술 분야에서 공지된 임의의 용매를 사용할 수 있다. 상기 분획 용매의 비제한적인 예로는 물, 탄소수 1 내지 4의 알코올 등의 극성 용매; 헥산(Hexan), 에틸 아세테이트(Ethyl acetate) 등의 비극성 용매; 또는 이들의 혼합용매 등을 들 수 있다. 이들은 단독으로 사용되거나 1종 이상 혼합하여 사용될 수 있지만, 이에 제한되는 것은 아니다.The kind of the fraction solvent used for obtaining the fraction in the present invention is not particularly limited, and any solvent known in the art can be used. Non-limiting examples of the fraction solvent include polar solvents such as water and alcohols having 1 to 4 carbon atoms; Non-polar solvents such as hexane (Hexan) and ethyl acetate (Ethyl acetate); Or a mixed solvent thereof. These may be used alone or in combination of one or more, but the present invention is not limited thereto.
또한, 상기 추출물 또는 분획물은 추출 후 건조 분말 형태로 제조되어 사용될 수 있지만, 이제 제한되는 것은 아니다.In addition, the extract or fraction may be prepared and used in the form of a dry powder after extraction, but is not limited thereto.
본 발명의 용어, "허혈성 질환"(ischemic disease)은 혈류의 정지(허혈)에 의해 증상을 나타내는 질환으로서, 궁극적으로 비가역적인 세포 및 조직의 손상을 동반하는 질환을 의미한다. 혈류의 정지에 의해 조직 또는 세포로 공급되는 산소의 양이 감소하게 되는데, 이로 인해 세포의 사멸이 유발되어 조직, 기관의 기능이 저하된다. 따라서, 허혈성 질환은 일반적으로 혈류의 흐름을 증가시키거나, 혈관을 재생/신생시키는 기전으로 치료하고 있다. 상기 허혈성 질환은 다양한 하위 질환을 포함하고 있으며, 구체적으로 뇌허혈, 심장허혈, 당뇨병성 혈관심장 질환, 심부전, 심근비대증, 망막허혈, 허혈성 대장염, 허혈성 급성 신부전증, 뇌졸중, 뇌외상, 신생아 저산소증, 하지혈관 허혈성 질환 또는 사지말단부 허혈성 질환 등일 수 있으며, 더욱 구체적으로 하지혈관 허혈성 질환 또는 사지말단부 허혈성 질환일 수 있으나, 이에 제한되지 않는다.The term "ischemic disease " of the present invention refers to a disease that causes symptoms due to arrest of blood flow (ischemia), and ultimately a disease accompanied by irreversible cell and tissue damage. By stopping the blood flow, the amount of oxygen supplied to the tissue or cell is decreased, which causes the cell death, resulting in deterioration of tissue and organ function. Therefore, ischemic diseases are generally treated with a mechanism to increase the flow of blood flow or regenerate / regenerate blood vessels. The ischemic diseases include various sub-diseases, and specifically include cerebral ischemia, cardiac ischemia, diabetic cardiomyopathy, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, brain trauma, neonatal hypoxia, An ischemic disease or a limb ischemic disease, and more specifically, it may be, but not limited to, lower limb ischemic disease or limb ischemic disease.
또한, 상기 허혈성 질환은 갱년기에 의해 유발되는 것일 수 있다.In addition, the ischemic disease may be caused by menopause.
상기 용어, "갱년기"는 여성의 생식기능이 소실하는 징후로 나타나는 월경폐지의 시기 또는 폐경기라고도 한다. 갱년기에는 난소의 기능이 노화로 인해 저하되어 여성호르몬을 적게 내기 때문에 호르몬의 불균형이 일어나 다양한 이상 증상들이 발병한다. 대표적으로, 갱년기에 의해 비만 등의 포도당 대사 장애 또는 지질 대사 장애; 골다공증 등의 골 항상성 장애; 홍조 등의 에너지 대사 장애; 또는 허혈성 질환 등의 혈류 장애 등이 야기된다.The term "menopausal period" is also referred to as a period of menstrual abolition or menopause, which is an indication that the reproductive function of a woman is lost. In menopause, ovarian function is lowered due to aging and fewer female hormones, resulting in hormonal imbalance, resulting in various abnormal symptoms. Typically, obesity is caused by menopausal glucose metabolism disorder or lipid metabolism disorder; Bone homeostatic disorders such as osteoporosis; Energy metabolism disorders such as flushing; Or blood flow disorders such as ischemic diseases.
본 발명의 목적상, 상기 토사자 추출물은 혈관내피세포의 이동 또는 증식을 유도하거나, 혈관내피세포의 혈관 형성을 촉진하거나, 또는 혈류량을 증가시키는 것일 수 있다.For the purpose of the present invention, the extract may be one which induces migration or proliferation of vascular endothelial cells, promotes angiogenesis of vascular endothelial cells, or increases blood flow.
상기 혈관내피세포의 이동 또는 증식, 혈관내피세포의 혈관 형성, 혈류량 증가 등을 유도/촉진시키는 것은 허혈성 질환의 치료에 활발히 활용되고 있는 기전인바, 이러한 효과를 나타내는 토사자 추출물은 허혈성 질환의 치료에 유용하게 사용될 수 있다.The induction / promotion of vascular endothelial cell migration or proliferation, vascular endothelial cell angiogenesis, and increase in blood flow is a mechanism that is actively utilized in the treatment of ischemic diseases, and the extract of the gut exhibiting such effects is useful for the treatment of ischemic diseases Lt; / RTI >
본 발명의 구체적인 일 실시예에서는, 난소가 절제되고 하지의 혈관이 결찰되어 허혈성 질환이 야기된 동물모델에 대하여, 토사자 추출물은 하지 혈류를 개선시키고, 말초혈관의 생성을 촉진시키며, 상처치유 관련 사이토카인의 발현을 증가시키고, 염증성 사이토카인의 발현을 감소시키며, 혈관내피세포의 이동 및 튜브형성을 촉진시킴을 확인하였다(도 1 내지 6).In an embodiment of the present invention, for animal models in which the ovaries are excised and the blood vessels of the lower limbs are ligated to cause ischemic diseases, the extract of Sorghum improves blood flow to the lower extremities, promotes the production of peripheral blood vessels, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 20, and 20, which increase expression of cytokines, decrease expression of inflammatory cytokines and promote vascular endothelial cell migration and tube formation.
이는, 상기 토사자 추출물을 포함하는 본 발명의 조성물은 허혈성 질환의 예방, 개선 또는 치료에 유용하게 사용될 수 있음을 시사하는 것이다.This suggests that the composition of the present invention comprising the extract of the extract of the present invention can be usefully used for prevention, improvement or treatment of ischemic diseases.
본 발명의 용어, "건강기능식품"(functional food)은 특정보건용 식품(food for special health use, FoSHU)과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 본 발명에서, 상기 건강기능식품은 건강식품 또는 건강보조식품과 호용된다.The term "functional food " of the present invention is the same term as " food for special health use (FoSHU) " Means high food. In the present invention, the health functional food is compatible with health food or health supplement.
본 발명의 건강기능식품 조성물은 일상적으로 섭취하는 것이 가능하며, 일반 약품과는 달리 천연물을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있으므로, 허혈성 질환의 예방 또는 개선 목적으로 매우 유용하게 사용될 수 있다.The health functional food composition of the present invention can be taken on a daily basis, and unlike general drugs, it has an advantage that natural products are used as raw materials and there are no side effects that may occur when a drug is taken for a long period of time. Can be very useful.
본 발명의 용어, "예방"은 상기 토사자 추출물 또는 이의 분획물을 포함하는 조성물의 투여로 증상을 억제 또는 지연시키는 모든 행위를 의미한다. The term "prophylactic" of the present invention refers to any act that inhibits or delays symptoms by administration of a composition comprising the extract or extract thereof.
본 발명의 용어, "개선"은 상기 식품 조성물의 투여로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 감소시키는 모든 행위를 의미한다.The term "improvement" of the present invention means any action that reduces the degree of the parameter associated with the condition being treated, such as the severity of symptoms, by administration of the food composition.
상기 건강기능식품은 허혈성 질환의 예방 또는 개선에 유용한 효과를 얻기 위하여 환제, 분말, 과립, 침제, 정제, 캡슐 및 음료 형태로 이루어지는 군에서 선택되는 것으로 제형화된 것으로 제조될 수 있다. 본 발명의 토사자 추출물 또는 이의 분획물을 포함하는 조성물을 첨가할 수 있는 식품의 종류에는 별다른 제한이 없으며, 예를 들어 각종 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있다. The health functional food may be formulated to be selected from the group consisting of pills, powders, granules, infusions, tablets, capsules and beverages in order to obtain a useful effect for prevention or improvement of ischemic diseases. There is no particular limitation on the kind of the food to which the composition containing the extract of the present invention or the fraction thereof can be added, and examples thereof include various drinks, gums, tea, vitamin complex, and health supplement foods.
상기 건강기능식품 조성물에는 건강기능식품의 예방 또는 개선 효과에 방해가 되지 않는 다른 성분을 추가할 수 있으며, 그 종류는 특별히 제한되지 않는다. 예를 들어, 통상의 식품과 같이 여러 가지 생약 추출물, 식품학적으로 허용가능한 식품보조첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.The health functional food composition may contain other ingredients that do not interfere with the preventive or improving effect of the health functional food, and the kind thereof is not particularly limited. For example, various herbal medicine extracts, food-acceptable food-aid additives or natural carbohydrates, such as ordinary foods, may be added as an additional ingredient.
또한, 상기 건강기능식품 조성물은 식품학적으로 허용가능한 담체를 추가로 포함할 수 있으며, 이는 당업자가 적절히 선택하여 사용할 수 있다. 예를 들어 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 그 종류가 제한되는 것은 아니다.In addition, the health functional food composition may further include a pharmaceutically acceptable carrier, which can be appropriately selected by those skilled in the art. For example, various kinds of nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, , A stabilizer, a preservative, a glycerin, an alcohol, a carbonating agent used in a carbonated drink, and the like, but the kind is not limited by the above examples.
또한, 상기 건강기능식품 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예를 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu) 등의 미네랄을 포함할 수 있다. 또한, 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다. In addition, the health functional food composition may contain additional components that are commonly used in food compositions and can improve odor, taste, visual appearance, and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid and the like. In addition, it may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn) and copper (Cu) It may also include amino acids such as lysine, tryptophan, cysteine, valine, and the like.
또한, 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨류엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산 나트륨, 아초산 나트륨 등), 표백제(아황산나트륨), 조미료(MSG 글루타민산나트륨 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(food additives)을 첨가할 수 있다.In addition, it is also possible to use antiseptics (such as potassium sorbate, sodium benzoate, salicylic acid, and sodium dehydroacetate), disinfectants (such as bleaching powder and highly bleached white powder, sodium hypochlorite), antioxidants (butylhydroxyanilide (BHA), butylhydroxytoluene BHT), etc.), coloring agents (such as tar pigments), coloring agents (such as sodium nitrite and sodium acetic acid), bleaching agents (sodium sulfite), seasoning (such as MSG sodium glutamate), sweeteners (such as hypoglycemia, , Food additives such as flavorings (vanillin, lactones, etc.), swelling agents (alum, potassium hydrogen D-tartrate), emulsifiers, emulsifiers, thickeners, encapsulating agents, gum bases, foam inhibitors, ) Can be added.
본 발명의 다른 하나의 양태는 토사자 추출물 또는 이의 분획물을 유효성분으로 포함하는 허혈성 질환의 예방 또는 치료용 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating an ischemic disease comprising an extract of Sorghum or a fraction thereof as an active ingredient.
이때, 상기 "토사자", "추출물", "분획물", "허혈성 질환" 및 "예방"의 정의는 전술한 바와 같다.Herein, the definitions of the above-mentioned "tobacco", "extract", "fraction", "ischemic diseases" and "prevention" are as described above.
본 발명의 용어, "치료"는 상기 토사자 추출물을 포함하는 조성물의 투여로 통증이 완화 또는 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term "treatment" of the present invention means any action in which the pain is relieved, improved or beneficially altered by the administration of the composition comprising the extract of the extract.
본 발명의 약학 조성물은 조성물 총 중량에 대하여 상기 토사자 추출물 또는 이의 분획물을 0.001 내지 80, 구체적으로 0.001 내지 70, 더욱 구체적으로 0.001 내지 60 중량%로 포함할 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition of the present invention may include, but is not limited to, 0.001 to 80, specifically 0.001 to 70, more specifically 0.001 to 60% by weight of the extract of the extract or fraction thereof, based on the total weight of the composition.
또한, 상기 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있고, 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다. In addition, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient or diluent conventionally used in the manufacture of a pharmaceutical composition, which carrier may comprise a non-naturally occuring carrier have.
상기 담체, 부형제 및 희석제의 구체적인 예로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있으나, 이에 제한되지 않는다.Specific examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, But are not limited to, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
또한, 상기 약학 조성물은 각각 통상의 방법에 따라 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결 건조제 및 좌제으로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있으며, 상기 제형은 경구 또는 비경구의 여러 가지 형태일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition may be formulated into tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze- And the formulations may be of various forms, such as oral or parenteral. In the case of formulation, it may be prepared by using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like which are usually used, but the present invention is not limited thereto.
구체적인 예로, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 사용될 수 있으며, 상기 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등이 사용될 수 있다. 또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제 등이 사용될 수 있으나, 이에 제한되지 않는다.As solid formulations for oral administration, tablets, pills, powders, granules, capsules and the like may be used. These solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like may be used. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may be used, but the present invention is not limited thereto.
또한, 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 사용될 수 있으며, 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 사용될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 또는 좌제 등이 사용될 수 있다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있으나, 이에 제한되지 않는다.As the liquid preparation for oral administration, suspensions, solutions, emulsions, syrups and the like may be used. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, Etc. may be used. For parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations or suppositories may be used. Examples of the non-aqueous solvent and suspension agent include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.
또한, 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있으나, 이에 제한되지 않는다.Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like, but the present invention is not limited thereto.
본 발명의 또 다른 하나의 양태는 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 허혈성 질환의 치료 방법을 제공한다.Another aspect of the present invention provides a method of treating an ischemic disease comprising administering the pharmaceutical composition to a subject.
이때, 상기 "허혈성 질환" 및 "치료"의 정의는 전술한 바와 같다.Herein, the definitions of the "ischemic diseases" and "treatment" are as described above.
본 발명의 용어, "투여"는 적절한 방법으로 개체에게 상기 토사자 추출물 또는 이의 분획물을 포함하는 조성물을 도입하는 것을 의미한다.The term "administering" of the present invention means introducing a composition comprising the soil extract or fraction thereof to a subject in an appropriate manner.
본 발명의 용어, "개체"는 허혈성 질환이 유발되거나 유발될 수 있는 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미한다. The term "individual" of the present invention means all animals such as mice, mice, livestock and the like, including humans, in which an ischemic disease can be induced or induced.
본 발명의 약학 조성물은 약학적으로 유효한 양으로 투여할 수 있다.The pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount.
상기 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the species and severity, age, sex, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts.
상기 약학 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여할 수 있고 종래의 치료제와는 순차적 또는 동시에 투여할 수 있다. 또한, 단일 또는 다중 투여할 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. In addition, it can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by a person skilled in the art.
또한, 상기 약학 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. In addition, the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may be determined depending on the condition and weight of the patient, , The type of drug, the route of administration, and the time, but may be suitably selected by those skilled in the art.
구체적인 예로, 상기 약학 조성물은 일반적으로 0.001 내지 1000 mg/kg, 더욱 구체적으로 0.05 내지 200 mg/kg, 가장 구체적으로 0.1 내지 100 mg/kg의 양을 1일 1회 내지 수회로 나누어 투여할 수 있으나, 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 당업자에 의해 적절하게 선택될 수 있다.As a specific example, the pharmaceutical composition may be administered in an amount of generally 0.001 to 1000 mg / kg, more particularly 0.05 to 200 mg / kg, most specifically 0.1 to 100 mg / kg, once / , The preferred dosage may be appropriately selected by those skilled in the art depending on the condition and the weight of the individual, the degree of disease, the type of drug, the route of administration and the period of time.
본 발명의 또 다른 하나의 양태는 토사자 추출물 또는 이의 분획물을 유효성분으로 포함하는 허혈성 질환의 예방 또는 개선용 의약외품 조성물을 제공한다.Another aspect of the present invention provides a quasi-drug composition for preventing or ameliorating an ischemic disease comprising extracts or fractions thereof as an active ingredient.
본 발명의 용어, "의약외품"은 사람이나 동물의 질병을 진단, 치료, 개선, 경감, 처치 또는 예방할 목적으로 사용되는 물품들 중 의약품보다 작용이 경미한 물품들을 의미한다. 예를 들어, 약사법에 따른 의약외품은 의약품의 용도로 사용되는 물품을 제외한 것으로, 사람/동물의 질병 치료나 예방에 쓰이는 제품, 인체에 대한 작용이 경미하거나 직접 작용하지 않는 제품 등이 포함된다.The term "quasi-drug product" of the present invention means products that are less active than drugs, among the products used for diagnosis, treatment, improvement, alleviation, treatment or prevention of diseases of human or animal. For example, quasi-drugs according to the Pharmaceutical Affairs Law include products used for the treatment and prevention of diseases of humans and animals, products which are mild to the human body or which do not act directly on the human body.
본 발명에 따른 토사자 추출물 또는 이의 분획물을 의약외품 첨가물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 의약외품 또는 의약외품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합량은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.When the extract of the extract or its fractions according to the present invention is used as a quasi-drug additive, the composition may be added as it is or may be used together with other quasi-drugs or quasi-drugs, and may be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment).
또한, 상기 의약외품 조성물은 특별히 이에 제한되지 않으나, 구체적으로 연고제, 로션제, 스프레이제, 패취제, 크림제, 산제, 현탁제, 겔제 또는 젤의 형태로 제조되어 사용될 수 있다.In addition, the quasi-drug composition may be prepared and used in the form of an ointment, a lotion, a spray, a patch, a cream, a powder, a suspension, a gel or a gel.
본 발명에 따른 토사자 추출물은 허혈성 동물 모델의 혈류를 개선시키고 상처 치유를 촉진키고 염증을 감소시키며 혈관형성을 촉진하는 효과를 나타내므로, 이를 포함하는 본 발명의 조성물은 허혈성 질환의 예방, 개선 또는 치료에 유용하게 사용될 수 있다.The extract of the present invention exhibits an effect of improving blood flow, accelerating wound healing, reducing inflammation and promoting angiogenesis in an ischemic animal model. Therefore, the composition of the present invention including the composition of the present invention can prevent, ameliorate or treat ischemic diseases . ≪ / RTI >
도 1은 토사자 추출물의 하지허혈 모델에서의 혈류량 개선 효과를 보여주는 그래프로서, 혈류량에 대한 허혈/비허혈 비율에 관한 것이다. 이때, OH는 토사자 추출물이 투여되지 않은 하지허혈 동물모델, OH+토사자150은 150mg/kg의 토사자 추출물이 투여된 하지허혈 동물모델, OH+토사자450은 450mg/kg의 토사자 추출물이 투여된 하지허혈 동물모델을 의미하며, OVX는 난소절제술 및 HLI는 하지허혈 결찰술을 의미한다. 또한, *는 P<0.05: vs. -7d, a는 P<0.05: OH vs. OH+토사자150, b는 P<0.05: OH vs. OH+토사자450, 및 c는 P<0.05: OH+토사자150 vs. OH+토사자450를 나타낸다.
도 2는 토사자 추출물의 말초혈관 생성 촉진 효과를 보여주는 그래프로서, 말초혈관의 밀도에 관한 것이다. 이때, OH는 토사자 추출물이 투여되지 않은 하지허혈 동물모델, OH+토사자150은 150mg/kg의 토사자 추출물이 투여된 하지허혈 동물모델, OH+토사자450은 450mg/kg의 토사자 추출물이 투여된 하지허혈 동물모델을 의미한다. 또한, a는 P<0.05: vs. OH, 및 b는 P<0.05: OH vs. OH+토사자150를 나타낸다.
도 3은 토사자 추출물의 상처 치유 관련 사이토카인(CXCL12, CD54)의 발현 증가 효과를 보여주는 이미지 및 그래프로서, 사이토카인 어레이 결과에 관한 것이다. 이때, 베히클(Vehicle)은 토사자 추출물이 투여되지 않은 하지허혈 동물모델(대조군), 토사자150은 150mg/kg의 토사자 추출물이 투여된 하지허혈 동물모델, 토사자450은 450mg/kg의 토사자 추출물이 투여된 하지허혈 동물모델을 의미한다. 또한, a는 P<0.05: vs. 베히클, 및 b는 P<0.05: vs. 토사자150를 나타낸다.
도 4는 토사자 추출물의 염증성 사이토카인(TNF-α, IL-6, IL-1b)의 발현 감소 효과를 보여주는 그래프이다. 이때, 베히클은 토사자 추출물이 투여되지 않은 하지허혈 동물모델(대조군), 토사자150은 150mg/kg의 토사자 추출물이 투여된 하지허혈 동물모델, 토사자450은 450mg/kg의 토사자 추출물이 투여된 하지허혈 동물모델을 의미한다. 또한, a는 P<0.05: vs. 베히클, 및 b는 P<0.05: vs. 토사자150을 나타낸다.
도 5는 토사자 추출물의 혈관내피세포 이동 촉진 효과를 보여주는 그래프로서, 이동 어세이(migration assay) 결과에 관한 것이다. 이때, Con은 혈관내피세포에 화합물/추출물이 처리되지 않은 대조군, VEGF 50 ng/㎖은 혈관내피세포에 VEGF 50 ng/㎖이 처리된 양성대조군 1, E2 1nM은 혈관내피세포에 E2 1nM이 처리된 양성대조군 2을 의미한다. 또한, a는 P<0.01, 및 b는 P<0.001: vs. 대조군을 나타낸다.
도 6은 토사자 추출물의 혈관내피세포 튜브 형성 촉진 효과를 보여주는 그래프이다. 이때, Con은 혈관내피세포에 화합물/추출물이 처리되지 않은 대조군, VEGF 50 ng/㎖은 혈관내피세포에 VEGF 50 ng/㎖이 처리된 양성대조군 1, Velbe 1 pM은 1 pM의 빈블라스틴(Vinblastine)이 처리된 양성대조군 2, E2 1nM은 혈관내피세포에 E2 1nM이 처리된 양성대조군 3을 의미한다. 또한, a는 P<0.05, 및 b는 P<0.01: vs. 대조군을 나타낸다.BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the blood flow improvement effect in the lower limb ischemic model of the extract of Sorghum, which relates to the ratio of ischemia / non-ischemia to blood flow. An ischemic animal model in which OH extractant was not administered, an ischemic animal model in which
FIG. 2 is a graph showing the peripheral vascularization-promoting effect of the extract of the extracts, which relates to the density of peripheral blood vessels. An ischemic animal model in which OH extractant was not administered, an ischemic animal model in which
FIG. 3 is an image and a graph showing the effect of increasing the expression of wound healing-related cytokines (CXCL12, CD54) in the soil extracts, and relates to cytokine array results. At this time, the vehicle was administered to the lower limb ischemia animal model (control group) to which the extract of Tozai was not administered, the lower limb ischemia animal model to which 150 mg / kg of the extract of Tozan was administered, and the extract of
FIG. 4 is a graph showing the effect of reducing the expression of inflammatory cytokines (TNF-.alpha., IL-6, and IL-1b) in the extract of T. ganoderma. The ischemic animal model in which 150 mg / kg of the extract of Tozan was administered and the
FIG. 5 is a graph showing the effect of accelerating vascular endothelial cell migration of a soil extract, and it relates to a migration assay result. At this time, Con is the control group,
FIG. 6 is a graph showing the promoting effect of vascular endothelial cell tube formation on the extract of T. ganoderma. At this time, Con was a control group in which vascular endothelial cells were not treated with compound / extract,
이하, 실시예를 통하여 본 발명을 보다 상세히 설명한다. 다만, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것에 불과하므로 본 발명의 범위가 이들 실시예에 의해 한정되는 것으로 해석되어서는 안된다. Hereinafter, the present invention will be described in more detail by way of examples. It should be understood, however, that these examples are for illustrative purposes only and that the scope of the present invention should not be construed as being limited by these examples.
실시예 1. 토사자 추출물의 제조 방법EXAMPLES Example 1 Preparation method of soil extract
토사자 추출물을 제조하기 위하여, 토사자 시료의 10배의 물 또는 에탄올을 첨가한 후, 환류추출 처리하여 토사자 열수 추출물을 얻었다. 상기 토사자 추출물을 No. 2 여과지(0.8 ㎛) 필터로 여과한 후, 진공회전농축기(rotary evaporator)를 이용하여 농축 및 동결건조하여 토사자 추출물을 제조하였다.To prepare the extract, 10 times as much water or ethanol as the sample was added to the extract, and the extract was subjected to reflux extraction to obtain hot water extract. The soil extract was applied to No. 2 filter paper (0.8 ㎛) filter, concentrated by using a rotary evaporator and lyophilized to prepare a soil extract.
실시예 2. 토사자 추출물의 혈류량 개선 효과 확인Example 2. Confirmation of blood flow improvement effect of extracts
허혈성 질환에 대한 토사자 추출물의 개선/치료 효과를 확인하기 위하여, 토사자 추출물의 하지허혈 모델에서의 혈류량 개선 효과를 확인하였다.In order to confirm the improvement / therapeutic effect of the extract of the extract on the ischemic diseases, the effect of improving the blood flow in the lower ischemic model of the extract of the extract was confirmed.
구체적으로, 암컷 C57BL/6 마우스 6주령을 수령하여 일주일의 순화기간을 거친 후 7주령에 난소절제술(ovariectomy; OVX)을 실시하였다. 이후, 상기 난소가 절제된 마우스에 대하여 8주령에 좌측 하지(left hind-limb; HLI) 두 구역의 혈관(동맥, 정맥)을 결찰 후 분리함으로써 허혈 모델을 완성하였다. 본 실험은 한국한의학연구원 실험동물 윤리위원회 심의(17-028)를 거쳤으며, 실험동물 사육 및 유지는 한국한의학연구원 실험동물연구센터의 동물 관리 및 사용 규정에 입각하여 온도 23±1℃ 습도 50±10% 내외, 12시간 명암주기로 일정하게 유지된 사육실에서 IVC(individually ventilated cage)에 사육하였다. 토사자는 각각 0.1%의 CMC(Carboxymethyl cellulose)에 희석하여 150mg/kg 또는 450mg/kg의 농도로 하루 중 오전에 경구 투여하였다. 하지허혈 모델 확립 후 14일 동안 레이저 도플러 영상장치를 이용하여 좌측 하지의 혈류(blood flow)를 측정하여, 모의수술 대조구인 우측 하지와 비교하여 허혈/비허혈 비율(ischemic/non-ischemic ratio)으로 혈류량(blood flow rate)을 구하였다.Specifically, ovariectomy (OVX) was performed at 7 weeks of age after receiving a 6-week-old female C57BL / 6 mouse for a week of purifying period. Thereafter, the ovariectomized mouse was ligated to the left hind limb (HLI) two-vessel blood vessels (artery, vein) at 8 weeks of age and then the ischemic model was completed. The experiment was carried out at the Korea Institute of Oriental Medicine (17-028), and the breeding and maintenance of experimental animals were conducted at 23 ± 1 ℃ and 50 ± 2 ℃, respectively, 10%, and 12 hours of light cycle, and maintained in an IVC (individually ventilated cage). The soil was diluted with 0.1% CMC (carboxymethyl cellulose) and administered orally at 150 mg / kg or 450 mg / kg / day in the morning. After the establishment of the lower limb ischemic model, the blood flow of the left lower limb was measured using a laser Doppler imaging device for 14 days. The ischemic / non-ischemic ratio was compared with that of the right lower limb, The blood flow rate was determined.
그 결과, 도 1에서 볼 수 있듯이, 하지허혈 직후의 혈류량(blood flow rate)은 하지허혈 유발 전(-7일)에 비하여 모든 대조군 및 실험군에서 유의적으로 감소하는 것을 확인하였다. 반면에, 토사자 추출물을 저농도/고농도로 처리한 실험군의 경우 하지허혈이 유도된 14일 후에 혈류량의 흐름이 유의적으로 증가하는 것을 확인하였다.As a result, as shown in FIG. 1, it was confirmed that the blood flow rate immediately after lower limb ischemia was significantly reduced in all the control and experimental groups compared to before ischemia induction (-7 days). On the other hand, it was confirmed that the flow of blood flow was significantly increased after 14 days of induction of lower limb ischemia in the experimental group treated with low concentration / high concentration of extract.
상기 결과를 통해, 토사자 추출물은 하지허혈에 의해 감소된 혈류량을 유의적으로 증가시키므로, 허혈성 질환의 예방, 개선 또는 치료에 유용하게 사용될 수 있음을 알 수 있었다.From the above results, it was found that the extract of Sorghum significantly increased blood flow reduced by ischemic insult, and thus can be effectively used for prevention, improvement or treatment of ischemic diseases.
실시예 3. 토사자 추출물의 말초혈관 생성 촉진 효과 확인Example 3 Confirmation of Peripheral Angiogenesis Promoting Effect of Sorghum Extract
허혈성 질환에 대한 토사자 추출물의 개선/치료 효과를 확인하기 위하여, 토사자 추출물의 하지허혈 모델에서의 말초혈관 생성 촉진 효과를 확인하였다.In order to confirm the improvement / therapeutic effect of the extract of the extract on the ischemic diseases, the effect of the extract of the extracts on the peripheral vascularization in the lower limb ischemic model was confirmed.
구체적으로, 혈관내피세포의 생체 표지자로 사용되는 CD31(cluster of differentiation 31)을 이용하여 하지허혈이 유발된 좌측 하지의 대퇴부(thigh) 및 장딴지 근육(calf muscle)에서 면역조직화학 염색을 실시하였다. 해당 조직은 파라핀 절편으로 5 ㎛의 두께로 절단하고, 자일렌을 이용하여 탈파라핀하였다. 고농도에서 저농도의 에탄올을 이용 최종적으로 수돗물에서 함수시킨 후 사용하였다. 사용한 항체로는 Abcam사의 항-CD31(rabbit polyclonal to CD31)을 이용하였으며, 최종 염색된 양성반응 세포(brown color)을 기준으로, 말초혈관(capillary)의 수를 세어 단위 면적(mm2)의 개수로 환산하였다.Specifically, immunohistochemical staining was performed on left lower limb thigh and calf muscle induced by lower limb ischemia using CD31 (cluster of differentiation 31) used as a biomarker of vascular endothelial cells. The tissue was cut into a thickness of 5 탆 with paraffin sections, and deparaffinized with xylene. Low concentration of ethanol was used at high concentration and finally water was used in tap water. Was used with the antibody is Abcam anti -CD31 (rabbit polyclonal to CD31) 's, the final staining positive cells (brown color) of, the number of peripheral blood vessel (capillary) for counting a unit area number (mm 2) of the reference Respectively.
그 결과, 도 2에서 볼 수 있듯이, 토사자 추출물을 처리하는 경우 난소가 절제된 하지허혈 모델의 말초혈관 형성이 유의하게 증가하며, 이는 농도 의존적으로 증가함을 확인하였다.As a result, as shown in FIG. 2, peripheral vascularization of the ovariectomized lower limb ischemia model was significantly increased in the case of the treatment with the extract of Sorghum extract, which was found to increase in a concentration-dependent manner.
상기 결과를 통해, 토사자 추출물은 말초혈관의 생성을 유의적으로 증가시키므로, 허혈성 질환의 예방, 개선 또는 치료에 유용하게 사용될 수 있음을 알 수 있었다.From the above results, it was found that the extract of Sorghum significantly increases the production of peripheral blood vessels and thus can be effectively used for prevention, improvement or treatment of ischemic diseases.
실시예 4. 토사자 추출물의 상처치유 사이토카인 발현 증가 효과 확인Example 4. Confirmation of wound healing cytokine expression enhancement of soil extracts
허혈성 질환에 대한 토사자 추출물의 개선/치료 효과를 확인하기 위하여, 토사자 추출물의 상처치유와 관련한 사이토카인의 발현 증가 효과를 확인하였다.In order to confirm the improvement / therapeutic effect of the extracts on the ischemic diseases, we confirmed the effect of increasing the expression of cytokines in relation to the wound healing of the extracts.
구체적으로, 난소절제 후 하지허혈을 시행한 동물모델에 토사자 추출물을 각 150mg/kg/일, 450mg/kg/일로 3주간 투여하였고, 상기 동물모델에서 얻은 혈청에 대하여 CXCL12, CD54의 사이토카인 발현 수준을 확인하였다. R&D SYSTEMS 사의 키트(Proteome Profiler, Mouse Cytokine Array Panel A, ARY006)를 사용하였고, 혈청을 분주한 후 각 사이토카인의 발현 변화를 스팟의 밀도를 통해 확인하였다.Specifically, the extracts were administered to the animal models subjected to lower limb ischemia after ovariectomy at 150 mg / kg / day and 450 mg / kg / day for 3 weeks, respectively. The serum levels of the CXCL12 and CD54 cytokines Respectively. A kit (Proteome Profiler, Mouse Cytokine Array Panel A, ARY006) from R & D SYSTEMS was used and the expression of each cytokine was determined by spot density after the serum was dispensed.
그 결과, 도 3에서 볼 수 있듯이, 토사자 추출물을 처리하는 경우 난소가 절제된 하지허혈 모델의 CXCL12, CD54 사이토카인 발현양이 현저하게 증가하며, 이는 농도 의존적으로 증가함을 확인하였다.As a result, as shown in FIG. 3, the amount of CXCL12 and CD54 cytokine expression in the ovariectomized lower limb ischemic model was remarkably increased when treated with the extract of soil extracts, which was found to increase in a concentration-dependent manner.
상기 결과를 통해, 토사자 추출물은 상처 치유에 관여하는 사이토카인의 발현을 증가시키므로, 허혈성 질환의 예방, 개선 또는 치료에 유용하게 사용될 수 있음을 알 수 있었다.From the above results, it was found that the extract of Sorghum increased the expression of cytokines involved in wound healing, and thus could be useful for preventing, improving or treating ischemic diseases.
실시예 5. 토사자 추출물의 염증성 사이토카인 발현 감소 효과 확인Example 5 Confirmation of Inflammatory Cytokine Expression Decreasing Effect of Sorghum Extract
허혈성 질환에 대한 토사자 추출물의 개선/치료 효과를 확인하기 위하여, 토사자 추출물의 염증성 사이토카인의 발현 증가 효과를 확인하였다.In order to confirm the improvement / therapeutic effect of the extract of the extract on the ischemic diseases, the effect of the extract of the extract on the expression of the inflammatory cytokine was confirmed.
구체적으로, 난소절제 후 하지허혈을 시행한 동물모델에 토사자 추출물을 각 150mg/kg/일, 450mg/kg/일로 3주간 투여하였고, 상기 동물모델에서 하지허혈이 유발된 좌측하지의 대퇴부 및 장딴지 근육의 환부 부위에서 토탈 RNA를 추출하였다. 상기 RNA의 역전사에 의해 합성된 cDNA 10g를 주형으로 사용하여, 염증 반응에 관련된 사이토카인(TNF-α, IL-6, IL-1b)을 PCR을 통해 증폭하였다.Specifically, the animal extracts were administered at 150 mg / kg / day and 450 mg / kg / day for 3 weeks to an animal model subjected to lower limb ischemia after ovariectomy. In the animal model, left lower thighs and calf muscles Total RNA was extracted from the affected area. The cytokines (TNF-α, IL-6, and IL-1b) involved in the inflammatory reaction were amplified by PCR using 10 g of the cDNA synthesized by reverse transcription of the RNA as a template.
그 결과, 도 4에서 볼 수 있듯이, 토사자 추출물을 처리하는 경우 난소가 절제된 하지허혈 모델의 TNF-α, IL-6, IL-1b 사이토카인 발현양이 현저하게 감소하며, 이는 농도 의존적으로 감소함을 확인하였다.As a result, as shown in FIG. 4, the expression of TNF-α, IL-6, and IL-1b cytokines in the ovariectomized lower limb ischemia model was significantly decreased when treated with extracts Respectively.
상기 결과를 통해, 토사자 추출물은 염증을 야기하는 사이토카인의 발현을 감소시키므로, 허혈성 질환의 예방, 개선 또는 치료에 유용하게 사용될 수 있음을 알 수 있었다.From the above results, it was found that the extract of Sorghum reduces the expression of cytokines causing inflammation, and thus can be effectively used for the prevention, improvement or treatment of ischemic diseases.
실시예 6. 토사자 추출물의 혈관내피세포 이동 촉진 효과 확인Example 6 Confirmation of Vascular Endothelial Cell Movement Promoting Effect of Sorghum Extract
허혈성 질환에 대한 토사자 추출물의 개선/치료 효과를 확인하기 위하여, 토사자 추출물의 혈관내피세포 이동 촉진 효과에 따른 혈관형성 촉진 효과를 확인하였다.In order to confirm the improvement / therapeutic effect of the extract of the extract on the ischemic diseases, the effect of accelerating the vascular endothelial cell migration of the extract of the extract was confirmed.
구체적으로, 트랜스웰(transwell)의 윗쪽 웰(upper well)에 혈관내피세포(HUVAC) 3×103 수의 세포를 분주하였고, 혈청이 포함되지 않은(serum free) EGM2 배양액에 토사자 추출물을 각각 1, 10 및 100 ㎍/㎖씩 첨가하여 세포를 6시간 동안 배양하였다. 이때, 대조군으로는 화합물 또는 추출물을 처리하지 않은 세포, 양성대조군 1으로는 50 ng/㎖의 VEGF를 처리한 세포, 양성대조군 2로는 1nM의 E2를 처리한 세포로 설정하였다. 이동한 혈관내피세포는 H&E 염색법으로 염색하여 본 발명의 토사자 추출물이 혈관내피세포 이동에 미치는 영향을 대조군과 비교하였다.Specifically, 3 × 10 3 cells of vascular endothelial cells (HUVAC) were dispensed into the upper well of the transwell and serum extracts were added to serum-free EGM2 medium , 10 and 100 [mu] g / ml, and the cells were cultured for 6 hours. At this time, as the control group, cells not treated with compound or extract, cells treated with 50 ng / ml VEGF as
그 결과, 도 5에서 볼 수 있듯이, 토사자 추출물을 처리하는 경우에는 아무것도 처리하지 않은 대조군에 비해 혈관내피세포의 이동이 현저하게 촉진되는 것을 확인하였으며, 이는 농도 의존적으로 증가함을 확인하였다. 또한, 토사자 추출물 100 ㎍/㎖을 처리하는 경우에는 양성대조군인 E2를 처리한 것과 유사한 효과를 나타냄을 확인하였다.As a result, as shown in FIG. 5, it was confirmed that the vascular endothelial cell migration was significantly accelerated in the case of treatment with the extract of the extracts, compared with the control group without any treatment, which was increased in a concentration-dependent manner. In addition, it was confirmed that treatment with 100 μg / ml of soil extract showed similar effect to treatment with E 2 as a positive control.
상기 결과를 통해, 토사자 추출물은 혈관내피세포의 이동을 촉진하여 혈관생성을 촉진하므로, 허혈성 질환의 예방, 개선 또는 치료에 유용하게 사용될 수 있음을 알 수 있었다.From the above results, it was found that the extract of Sorghum promotes the vascularization by promoting migration of vascular endothelial cells, and thus can be effectively used for prevention, improvement or treatment of ischemic diseases.
실시예 7. 토사자 추출물의 튜브 형성 촉진 효과 확인Example 7 Confirmation of Tube Formation Promotion Effect of Sorghum Extract
허혈성 질환에 대한 토사자 추출물의 개선/치료 효과를 확인하기 위하여, 토사자 추출물의 튜브 형성 촉진 효과에 따른 혈관형성 촉진 효과를 확인하였다.In order to confirm the improvement / therapeutic effect of the extract of the extracts on the ischemic diseases, the effect of accelerating the tube formation of the extract of the extracts was confirmed.
구체적으로, 혈관내피세포(HUVAC)를 세포외기질(extracellular matrix; ECM)로써 마트리겔(Matrigel)이 코팅된 24웰 플레이트에 3×105의 수로 분주하였다. 이후, 1% FBS(fetal bovine serum)가 포함된 EGM2 배지를 사용하여, 24시간 동안 37℃에서 혈관내피세포의 튜브(tube) 형성을 유도하였다. 24시간 후, 현미경으로 관찰 및 촬영하여 Image J 프로그램의 혈관생성(Angiogenesis) 분석기를 이용해 튜브 형성능을 측정하여 대조군과 비교하였다. 이때, 대조군으로는 화합물 또는 추출물을 처리하지 않은 세포, 양성대조군 1으로는 50ng/㎖의 VEGF를 처리한 세포, 양성대조군 2로는 1 pM의 빈블라스틴(Vinblastine; Velbe)을 처리한 세포, 및 양성대조군 3으로는 1nM의 E2를 처리한 세포로 설정하였다. Specifically, vascular endothelial cells (HUVAC) were dispensed into a 24-well plate coated with Matrigel as an extracellular matrix (ECM) in a number of 3 × 10 5 . Subsequently, tube formation of vascular endothelial cells was induced at 37 ° C for 24 hours using EGM2 medium containing 1% FBS (fetal bovine serum). After 24 hours, the tubes were observed and photographed with a microscope, and tube forming ability was measured using an Image J program Angiogenesis Analyzer and compared with the control group. At this time, as the control group, cells not treated with compound or extract, cells treated with 50ng / ml VEGF as
그 결과, 도 6에서 볼 수 있듯이, 토사자 추출물을 처리하는 경우에는 아무것도 처리하지 않은 대조군에 비해 혈관내피세포의 튜브 형성 정도가 유의하게 증가되는 것을 확인하였으며, 이는 농도 의존적으로 증가함을 확인하였다. 또한, 상기와 같은 토사자 추출물의 튜브 형성 촉진 효과는 1 ㎍/㎖의 낮은 농도에서도 빈블라스틴보다 우수하며, 100 ㎍/㎖을 처리하는 경우에는 양성대조군인 E2를 처리한 것과 유사한 효과를 나타냄을 확인하였다.As a result, as shown in FIG. 6, it was confirmed that the degree of tube formation of vascular endothelial cells was significantly increased in the case of treatment with the extract of the extracts, compared with the control without any treatment, and it was found to be increased in a concentration-dependent manner. In addition, the promoting effect on the tube formation of the extracts of the present invention was superior to Vinblastine even at a low concentration of 1 / / ml, and when treated with 100 / / ml, the effect was similar to that of the positive control E 2 Respectively.
상기 결과를 통해, 토사자 추출물은 혈관내피세포의 튜브 형성을 촉진하여 혈관생성을 촉진하므로, 허혈성 질환의 예방, 개선 또는 치료에 유용하게 사용될 수 있음을 알 수 있었다.From the above results, it was found that the extract of T. ganoderma facilitates the tube formation of vascular endothelial cells and promotes angiogenesis, so that it can be effectively used for the prevention, improvement or treatment of ischemic diseases.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.
Claims (9)
A health functional food composition for the treatment, prevention or amelioration of an ischemic disease comprising an extract of Tozan or a fraction thereof as an active ingredient.
The health functional food composition according to claim 1, wherein the extract is prepared by extracting the extract with at least one solvent selected from the group consisting of water, an alcohol having 1 to 4 carbon atoms, and a mixed solvent thereof.
[Claim 2] The method according to claim 1, wherein the fractions are prepared by fractionating the extract of the extracts with a solvent selected from the group consisting of water, an alcohol having 1 to 4 carbon atoms, hexane, ethyl acetate and a mixed solvent thereof ≪ / RTI >
The composition according to claim 1, wherein the ischemic disease is a lower limb ischemic disease or a limb ischemic disease.
2. The health functional food composition according to claim 1, wherein the ischemic disease is caused by menopausal period.
[Claim 2] The composition according to claim 1, wherein the extract of Tumor extract promotes migration or proliferation of vascular endothelial cells, promotes angiogenesis of vascular endothelial cells, or increases blood flow.
A pharmaceutical composition for preventing or treating an ischemic disease comprising an extract of Tozan or a fraction thereof as an active ingredient.
A method for treating an ischemic disease, comprising administering the pharmaceutical composition of claim 7 to a subject other than a human.
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PCT/KR2018/016526 WO2019125077A2 (en) | 2017-12-22 | 2018-12-21 | Composition for preventing or treating ischemic diseases comprising cuscuta japonica extract as active ingredient |
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KR101195109B1 (en) * | 2009-08-20 | 2012-10-29 | 화 례 임 | composition of health food |
KR101333090B1 (en) * | 2012-04-06 | 2013-11-27 | 동국대학교 경주캠퍼스 산학협력단 | Composition for preventing or treating postmenopausal syndrome comprising oriental herbal extract |
KR101544783B1 (en) * | 2014-08-19 | 2015-08-17 | 전북대학교산학협력단 | A composition comprising an extract of combined crude drugs for treating and preventing Male Infertility |
KR102028634B1 (en) * | 2015-11-11 | 2019-10-04 | 한국 한의학 연구원 | A composition for preventing or treating menopausal cardiovascular disease comprising Cuscuta japonica Chois extract |
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