KR20080011921A - Compositions for treating autoimmune disease containing extracts of salviae miltiorrhizae radix - Google Patents
Compositions for treating autoimmune disease containing extracts of salviae miltiorrhizae radix Download PDFInfo
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- KR20080011921A KR20080011921A KR1020060072664A KR20060072664A KR20080011921A KR 20080011921 A KR20080011921 A KR 20080011921A KR 1020060072664 A KR1020060072664 A KR 1020060072664A KR 20060072664 A KR20060072664 A KR 20060072664A KR 20080011921 A KR20080011921 A KR 20080011921A
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- autoimmune disease
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A61K36/185—Magnoliopsida (dicotyledons)
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- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
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Abstract
Description
도 1 에서는 NZB/w F1 마우스에서 단삼투여군과 대조군 간의 체중의 비교를 보인다. Figure 1 shows a comparison of body weight between the group and the control group in NZB / w F1 mice.
도 2 에서는 NZB/w F1 마우스에서 단삼투여군과 대조군 간의 단백뇨와 소변의 단백질 수준의 비교를 보인다. 2 shows the comparison of proteinuria and urine protein levels between the group treated with the control group and the control group in NZB / w F1 mice.
도 3 에서는 NZB/w F1 마우스에서 단삼투여군과 대조군 간의 항-dsDNA IgG 의 혈청수준의 비교를 보인다. Figure 3 shows the comparison of the serum level of anti-dsDNA IgG between the mono-dose group and the control group in NZB / w F1 mice.
도 4 에서는 NZB/w F1 마우스에서 단삼투여군과 대조군 간의 항-dsDNA IgG1의 혈청수준의 비교를 보인다. Figure 4 shows the comparison of the serum level of anti-dsDNA IgG1 between the mono-administration group and the control group in NZB / w F1 mice.
도 5 에서는 NZB/w F1 마우스에서 단삼투여군과 대조군 간의 항-dsDNA IgG2a 의 혈청수준의 비교를 보인다. Figure 5 shows the comparison of the serum level of anti-dsDNA IgG2a between the short-term administration group and the control group in NZB / w F1 mice.
도 6 에서는 NZB/w F1 마우스의 비장임파구에서 단삼투여군과 대조군 간의 IFN-γ 발현량의 비교를 보인다. Figure 6 shows the comparison of IFN-γ expression level between the control group and the control group in the spleen lymphocytes of NZB / w F1 mice.
도 7 에서는 NZB/w F1 마우스의 비장임파구에서 단삼투여군과 대조군 간의 IL-4 발현량의 비교를 보인다. Figure 7 shows the comparison of IL-4 expression level between the control group and the control group in the spleen lymphocytes of NZB / w F1 mice.
도 8 에서는 NZB/w F1 마우스의 신장조직에서 단삼투여군과 대조군 간의 조직학적 검사결과를 보인다. A 는 대조군으로 27주된 NZB/w F1 쥐의 신장, B 는 단삼투여군이다. Figure 8 shows the histological examination results between the group and the control group in the renal tissue of NZB / w F1 mice. A is the height of 27-week-old NZB / w F1 rats, and B is the short osmotic group.
자가 면역 질환은 우리 몸의 면역 기능이 자신을 공격함으로써 일어나는 질병으로 자가 면역증 치료를 위하여는 우리 몸을 보호하는 면역 기능을 억제 하여야 되고 결과적으로 암이나 감염 질환에 노출되기 때문에 치료에 많은 어려움이 있다. 또한 자가 면역 질환은 오랜 기간에 걸쳐 형성되고 증상이 만성적으로 지속되며 대체로 장기의 영구손상을 초래하는 것이 일반 적인 예이며, 완치할 수 있는 방법이 거의 없는 것이 현실이다. 과거 20-30 년간 자가면역질환에 대한 지식은 많이 발전하였지만 아직도 정확한 생성 기작, 자가항원의 정체, 조절 유전인자 등은 여전히 불명확하다. 자가면역 질환은 장기특이(organ-specific) 질환과 전신성(systemic) 질환으로 크게 구분할 수 있다. Autoimmune disease is a disease caused by the body's immune function attacking itself. In order to treat autoimmune disease, the immune function that protects our body must be suppressed. have. In addition, autoimmune diseases are formed over a long period of time, the symptoms are chronic and usually cause permanent damage of the organ is a common example, the reality is that there is little way to cure. While knowledge of autoimmune diseases has evolved over the past 20-30 years, the exact mechanisms of production, the identity of autoantigens and regulatory genes are still unclear. Autoimmune diseases can be broadly divided into organ-specific diseases and systemic diseases.
장기 특이 자가면역 질환은 장기특이항원에 대한 면역반응이 일어 남으로서 생기며 우리 몸의 거의 모든 장기에서 발생할 수 있다. 전신성 자가면역 질환은 어떤 특정 세포에 대한 면역반응이 일어나는 것이 아니라 전신에 걸쳐 발현되는 항원에 대한 면역반응에 의해 야기 된다. 이런 전신성 자가면역 질환도 특이한 장기에 선택적으로 질병을 일으킬 수 있다(http://irc.ulsan.ac.kr/immunity/index.htm 참조,2006. 04. 11. 오후 4:30 접속). Organ-specific autoimmune diseases occur as a result of an immune response to organ-specific antigens and can occur in almost every organ in our body. Systemic autoimmune diseases are caused by immune responses to antigens expressed throughout the body rather than by an immune response to any particular cell. These systemic autoimmune diseases can also cause disease selectively in specific organs (see http://irc.ulsan.ac.kr/immunity/index.htm, accessed Apr. 11, 2006, 4:30 pm).
자가면역성 질환의 예로는 ⅰ) 면역계가 각종 관절의 조직을 공격하는 류마티스관절염(Rheumatoid Arthritis), ⅱ) T 세포에 의하여 유도되는 중추신경계의 자가면역증으로 대부분은 비교적 정상적인 생활이 가능하나, 심한 경우 실명, 마비, 조기사망(premature death)으로 이어질 수 있는 다발성 신경염(MS, Multiple Sclerosis), ⅲ) 췌장의 인슐린 생산 세포를 면역세포가 파괴하여 생기며 MHC 유전자가 중요한 면역매개 또는 타입1 당뇨병(Immune-Mediated or Type 1 Diabetes Mellitus), ⅳ) 면역계가 장을 공격하여 나타는 질환인 염증성 장질환(Inflammatory Bowel Diseases), ⅴ) 피부나 혈관의 경화(thickening)를 유도하는 피부경화증(Scleroderma), ⅵ) 전신성 자가면역증으로 깊은 피로감, 발진, 관절통 등의 증세를 수반하며, 심한 경우 면역계가 신장, 뇌, 폐 등에 손상을 끼칠 수 있는 전신성 홍반성 낭창(Systemic Lupus Erythematosus, SLE) 등이 있다(http://home.inje.ac.kr/~lecture/immunobiotech/ch6/6autoimmunity.htm 참조, 2006. 04. 11. 오후 4:30 접속).Examples of autoimmune diseases include i) rheumatoid arthritis, in which the immune system attacks tissues of various joints, and ii) autoimmunity of the central nervous system induced by T cells. Multiple sclerosis (MS), which can lead to blindness, paralysis, and premature death, is caused by the destruction of immune cells in the insulin-producing cells of the pancreas, and the MHC gene is important for immune mediating or
한편, 단삼(Salviae Miltiorrhizae Radix : SMR)은 순형과(꿀풀과, Labiatae)에 속한 다년생초본의 근으로서 적삼· 산삼· 목양유· 축마의 이명이 있다. 본 약재는 활혈조경· 행혈· 거어· 양혈소옹· 생신혈· 양혈안신· 익기 등의 효능이 있어 혈허혈어, 혈체경폐, 풍비불수, 징하적취, 심계실면, 혈사심번 등의 병증 치료에 유용하다. 또한, 단삼은 관상동맥 혈류량 증가, 말초혈관확장을 통한 혈압강하, 혈청지질감소, 항균작용, 혈당강하, 안정, 진통작용 등의 약리작용을 가지다고 알려져 있으나, 단삼 추출물 또는 단삼에 포함된 성분들이 SLE 치료에 사용된 바는 없다On the other hand, Salviae Miltiorrhizae Radix (SMR) is a perennial herb belonging to Sun-Hwa family (Lacaceae, Labiatae), which has the tinnitus of red ginseng, wild ginseng, shepherd's milk and horse breeding. This medicine is effective for the treatment of symptomatic such as hemoglobin, hematopoietic pulmonary disease, abundance of rain, infertility, cardiovascular system, blood death, etc. useful. In addition, although the salviae are known to have pharmacological effects such as increased coronary blood flow, lowering blood pressure through peripheral vasodilation, decreased serum lipid, antibacterial action, hypoglycemia, stabilization, analgesic effect, None has been used to treat SLE
이에 본 발명자들은 루푸스를 유발시킨 NZB/w F1(New Zealand Black/White F1) 마우스 모델에 단삼을 투여한 후 체중과 단백뇨, 신장과 간기능 검사, 혈액 검사, 비장에서의 임파구 검사, 엘리자(ELISA)를 이용한 사이토카인(Cytokine)발현량 측정 및 항-dsDNA 항체 발현량 측정, 신장의 조직학적 분석 등을 시행하여 단삼이 간과 신장에 미치는 장애 및 면역기능에 효과적으로 작용하는지를 검토하여 단삼에 SLE 치료 및 자가면역질환치료에 효과가 있음을 확인하고 본 발명을 완성하였다.Therefore, the inventors of the present invention, after administering the ginseng to lupus-induced NZB / w F1 (New Zealand Black / White F1) mouse model, body weight and proteinuria, kidney and liver function test, blood test, lymphocyte test in spleen, ELISA (ELISA) Cytokine expression, anti-dsDNA antibody expression level, and histological analysis of kidney were used to examine whether the ginseng effectively affects liver and kidney disorders and immune function. It was confirmed that the effect on the treatment of autoimmune diseases and completed the present invention.
본 발명의 목적은 단삼 추출물의 자가면역질환치료제로서의 용도를 제공하는 것이다.An object of the present invention is to provide a use of the extract as a therapeutic agent for autoimmune diseases.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings.
본 발명의 제 1 태양은 단삼의 추출물을 포함하는 자가면역질환 치료용 약학적 조성물에 관한 것이다. 보다 상세하게는, 상기 자가면역질환이 전신성 홍반성 낭창, 류마티스 관절염, 다발성신경염, 타입 1 당뇨병, 염증성 장질환 및 피부경화증인 것을 특징으로 하는 약학적 조성물에 관한 것이다.The first aspect of the present invention relates to a pharmaceutical composition for treating autoimmune disease, comprising an extract of Salvia ginseng. More specifically, the autoimmune disease relates to a pharmaceutical composition, characterized in that the systemic lupus erythematosus, rheumatoid arthritis, multiple neuritis,
본 발명에서 류마티스 관절염(Rheumatoid Arthritis)이라 함은 면역계가 각종 관절의 조직을 공격하여 관절염증이 대칭적으로 나타나며, 통증과 부기(swelling),관절경직을 수반하는 염증성 질환을 말한다. 류마티스 관절염 중 골관절염(osteoarthritis)은 퇴행성 질환으로 관절이 달아서 생기는 염증성 질환이며, 치료는 관절의 염증완화이다.In the present invention, rheumatoid arthritis refers to an inflammatory disease accompanied by pain, swelling, and joint stiffness due to symmetry of arthritis by the immune system attacking tissues of various joints. Osteoarthritis of rheumatoid arthritis is a degenerative disease and is an inflammatory disease caused by joint decoction. Treatment is an inflammation of the joint.
본 발명에서 다발성 신경염(Multiple Sclerosis)이라 함은 T 세포에 의하여 유도되는 중추신경계의 자가면역증으로, 대부분 비교적 정상적인 생활이 가능하나, 심한 경우, 실명, 마비, 조기사망(premature death)으로 이어질 수 있는 자가면역질환을 말한다. In the present invention, multiple neuritis (Multiple Sclerosis) is a central nervous system autoimmune induced by T cells, most of the relatively normal life, but can lead to severe blindness, paralysis, premature death Refers to autoimmune diseases.
본 발명에서 타입 1 당뇨병(Immune-Mediated or Type 1 Diabetes Mellitus)이라 함은 췌장의 인슐린 생산 세포를 면역세포가 파괴하여 나타나는 자가면역질환으로 인슐린의 생산 부족으로 인한 고포도당 혈증이 유도되고 그에 따른 복합증세(피로감, 잦은 소변, 갈증, 급성 착란 등)가 나타난다. 당뇨가 심한 경우는 신장손상, 실명, 사지절단, 사망에 이른다. In the present invention,
본 발명에서 염증성 장질환(Inflammatory Bowel Diseases)이라 함은 면역계가 장을 공격하여 나타나는 질환으로, 설사, 구토, 어지러움, 복부경련, 통증 등의 증세를 유도한다. Inflammatory Bowel Diseases in the present invention are diseases caused by the immune system attacking the intestine, and induce symptoms such as diarrhea, vomiting, dizziness, abdominal cramps, and pain.
본 발명에서 피부경화증(Scleroderma)이라 함은 피부나 혈관의 경화(thickening)를 유도하는 질병으로 운동기능의 상실되고, 호흡이 짧아지며, 드물게 신장, 심장, 폐의 부전으로 이어질 수 있다.In the present invention, sclerosis (Scleroderma) is a disease that induces the hardening of the skin or blood vessels (thickening), loss of motor function, shortening of breath, rarely lead to kidney, heart, lung failure.
본 발명의 약학적 조성물에 포함되는 약학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다. The pharmaceutical composition of the present invention may be administered orally or parenterally, and in the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.
본 발명의 약학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. Suitable dosages of the pharmaceutical compositions of the present invention vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and response to response of the patient, Usually a skilled practitioner can easily determine and prescribe a dosage effective for the desired treatment or prophylaxis.
본 발명의 약학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화 함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical compositions of the present invention may be prepared in unit dosage form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporating into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or an aqueous medium, or may be in the form of extracts, powders, granules, tablets or capsules, and may further include a dispersant or stabilizer.
본 발명의 제 2 태양은 단삼의 추출물을 포함하는 자가면역질환에 효과적인 식품 조성물에 관한 것이다. 보다 상세하게는 상기 자가면역질환이 전신성 홍반성 낭창, 류마티스 관절염, 다발성신경염, 타입 1 당뇨병, 염증성 장질환 및 피부경화증인 것을 특징으로 하는 식품 조성물에 관한 것이다.The second aspect of the present invention relates to a food composition effective for autoimmune diseases comprising the extract of Salvia mildew. More specifically, the autoimmune diseases are systemic lupus erythematosus, rheumatoid arthritis, multiple neuritis,
본 발명의 단삼 추출물을 포함하는 식품은 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있다. 예컨대, 음료수로 제조되는 경우에는 본 발명의 식물 추출물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산 및/또는 과즙 등을 추가로 포함시킬 수 있다.Food containing the extract of the present invention may include ingredients that are commonly added at the time of food production. For example, when the beverage is prepared, in addition to the plant extract of the present invention, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid and / or juice may be further included.
한편, 본 발명의 기능성 식품 조성물은 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다. 예컨대, 드링크제로 제조되는 경우에는 본 발명의 단삼 추출물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다. 식품에 대한 용이한 접근성을 고려한다면, 본 발명의 식품은 신경성 질환의 치료 또는 예방, 산화 스트레스에 의해 초래되는 질환의 치료 또는 예방 및 인지 기능의 개선에 매우 유용하다.On the other hand, the functional food composition of the present invention includes components that are commonly added during food production, and include, for example, proteins, carbohydrates, fats, nutrients and seasonings. For example, when manufactured with a drink, it may further include citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, tofu extract, jujube extract, licorice extract, etc., in addition to the Dansam extract of the present invention. In view of easy access to food, the food of the present invention is very useful for the treatment or prevention of neurological diseases, for the treatment or prevention of diseases caused by oxidative stress, and for improving cognitive function.
본 발명에서 NZB/NZW F1 마우스는 일정 부분의 자가 항체를 만들어 내고, 인간의 SLE 질환의 연구모델로 많이 사용된다. NZB/NZW 마우스는 임상적으로는 정상적으로 태어나지만, 2-3개월 내에 용혈성 빈혈의 증상을 보인다. 항-적혈구 항체(anti-erythrocytic antibody), 항핵 항체(antinuclear antibody), 루푸스 세포, 면역 복합체 검사에서 모두 양성을 보인다.In the present invention, NZB / NZW F1 mice produce a part of autoantibodies and are widely used as a research model for human SLE disease. NZB / NZW mice are born normally clinically but show symptoms of hemolytic anemia within 2-3 months. Anti-erythrocytic antibodies, antinuclear antibodies, lupus cells, and immune complex tests are all positive.
본 발명에서 GOT(AST)와 GPT(ALT)는 간을 비롯해 장기에 존재하는 아미노산 합성 효소로 이는 정상적인 세포 파괴에 의해서도 혈액 중에 일정 수치정도가 존재하나 간과 특정장기가 손상되면 세포가 대량 파괴되고 결국 이러한 효소가 세포 외로 유출되어 이 효소의 수치가 상승하게 된다.In the present invention, GOT (AST) and GPT (ALT) is an amino acid synthase that exists in the organs, including the liver, which has a certain level in the blood even by normal cell destruction, but when the liver and certain organs are damaged, a large amount of cells are destroyed and eventually These enzymes leak out of the cell, causing the enzyme to rise.
본 발명에서 총단백은 혈청 내에 존재하는 각종 단백질의 합을 말하며 몸의 영양상태를 알 수 있다. 총단백은 탈수로 인한 혈액농축이 있을 시 다소 증가하나, 임상적 의의는 없고 드물게 나타나지만, 다발성 골수종시 병적으로 증가하고, 영양부족, 만성감염, 간경화, 신증후군 및 만성염증이 있을시 감소한다. 크레아티닌은 대부분 근육 내에 존재하며 신장을 통해서 배설한다. 그러므로 신부전증, 신장염 등의 신장질환이 있을 경우, 고단백식사, 조직붕괴 및 위장관 출혈시 혈중에 증가를 가져오며, 그 밖에 근육질환에도 증가한다. 간경화증 등 간질환시 다소 감소하나 임상적 의의는 없다. BUN(Blood Urea Nitrogen)은 신장질환이 있을 경우에 크레아티닌과 함께 증가하여 간경화와 같은 간질환이 있을 경우에 다소 감소하나, 특이한 임상적 의미는 없다. 주의할 것은 고단백 식사를 하거나, 조직붕괴, 위장관출혈, 탈수시에도 증가하므로 감별이 필요하다.In the present invention, the total protein refers to the sum of various proteins present in the serum, and the nutrition of the body can be known. Total protein is somewhat increased in case of blood concentration due to dehydration, but has little clinical significance and rarely, but increases in pathology in multiple myeloma and decreases in cases of malnutrition, chronic infection, liver cirrhosis, nephrotic syndrome and chronic inflammation. Creatinine is present in most muscles and is excreted through the kidneys. Therefore, in the case of kidney disease such as kidney failure, nephritis, high protein diet, tissue collapse and gastrointestinal bleeding increases in blood, and also increases in muscle diseases. It is somewhat decreased in liver disease such as cirrhosis but has no clinical significance. Blood Urea Nitrogen (BUN) increases with creatinine in kidney disease and decreases in liver disease such as cirrhosis, but has no specific clinical significance. Be careful not to eat high-protein meals, tissue breakdown, gastrointestinal bleeding, dehydration increases because it is necessary to discriminate.
본 발명에서 인터페론(IFN, Interferones)은 IFN-α, IFN-β, IFN-γ의 3군으로 나뉘어 지고 IFN-γ는 주로 활성화된 T세포가 생성한다. 인터페론과 수용기가 결합하면 다양한 효과가 일어나고, 특히 IFN-γ는 면역 항진 효과가 있으며 항원제공과 대식세포, NK 세포, 세포 독성 T임파구의 활성을 증가시킨다. 또 다른 중요한 기능은 인터페론이 세포 표면의 MHC 분자 표현을 증가시키는 것인데 MHC I 분자 표현은 모든 인터페론이 증가시키는 반면 MHC II 분자는 IFN-γ가 유도한다. IL-4는 기능상 세포성 면역반응을 촉진시키는 Th1 세포가 분비하는 IFN-γ과 길항작용을 하여 과도한 Th1 반응에 의한 자가 면역질환 (제1형 당뇨병, 류마티스, 다발성 경화증 등)에 대한 면역치료제로서의 가능성이 확인되고 있으며, 난치성 질환인 악성 종양 (plasmacytoma, mammary adenocarcinoma, transformed fibroblast cell lines, a melanoma cell line, sarcoma cell line 등)의 성장을 억제하여, 새로운 항암 치료제로서 현재 임상 I/II단계 연구를 통해 안전성과 효과가 확인되고 있다. In the present invention, interferon (IFN, Interferones) is divided into three groups of IFN-α, IFN-β, IFN-γ and IFN-γ is mainly produced by activated T cells. The combination of interferon and receptor results in a variety of effects. In particular, IFN-γ has an immunosuppressive effect and increases antigen-providing and activity of macrophages, NK cells, and cytotoxic T lymphocytes. Another important function is that interferon increases the expression of MHC molecules on the cell surface. MHC I molecule expression is increased by all interferons, while MHC II molecules are induced by IFN-γ. IL-4 antagonizes IFN-γ secreted by Th1 cells, which promotes functional cellular immune responses, and acts as an immunotherapeutic agent for autoimmune diseases (
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. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .
모든 실험에서 나타낸 측정값은 평균± 표준평균오차(SEM, standard error of mean)로 표시하였으며, 통계학적 분석은 스튜던트 티-테스트(Student's t-test)로 수행하였다.*, p < 0.05 (n=8)Measurements presented in all experiments were expressed as mean ± standard error of mean (SEM), and statistical analysis was performed by Student's t-test. *, P <0.05 (n = 8)
<실시예 1> 단삼이 NZB/w F1 마우스의 체중에 미치는 영향의 확인Example 1 Identification of Effect of Salvia Miltiorrhiza on Body Weight of NZB / w F1 Mice
(1) 재료 및 방법(1) materials and methods
1) 실험동물1) Experimental Animal
본 발명에 사용된 실험동물은 생후 6주된 NZB/w F1 (New Zealand Black/White F1) 자성(雌性) 마우스이며 멸균 상태로 관리되어 온 것을 중앙실험동물(주) (Seoul, Korea)에서 구입하였다. 사료는 방사선 멸균 처리한 실험동물용 사료를 퓨리나(주) (경기도, )에서 구입하여 공급하였으며 음용수는 멸균 처리한 증류수를 사용하였다. NZB/w F1 마우스를 일반적인 조명과 22± 1℃의 온도 및 55± 5%의 습도를 유지 시키면서 사료와 음용수는 충분히 공급하여 자유롭게 섭취시켜 3개월간 사육하고 실험동물로 이용하였다. The experimental animals used in the present invention were 6 weeks old NZB / w F1 (New Zealand Black / White F1) magnetic mice, which were managed under sterile conditions and purchased from Central Experimental Animals (Seoul, Korea). . The feed was purchased from Purina Co., Ltd. (Gyeonggi-do,) and the sterilized distilled water was used. NZB / w F1 mice were kept in general lighting, 22 ± 1 ° C, and 55 ± 5% of humidity while feeding and drinking enough to feed freely for three months and used as experimental animals.
2) 시료의 제조 및 투여2) Preparation and Administration of Samples
본 발명에 사용된 단삼(丹蔘, Salviae Miltiorrhizae Radix : SMR)은 (Sunten Pharmaceutical Co. Lot No. 102401, Taipei, Taiwan)으로 부터 구입하여 사용하였다. 1 g당 단삼 0.66 g 과 전분 0.32g (yield : 66%) 혼합되어 있었다. 그래서 단삼 1 g당 물 66.7mL를 넣고 24시간동안 실온에서 추출하여 하였다. 수집된 추출액은 3000rpm에서 10분간 원심 분리한 후 상층액을 여과지 (whatman, No.2, Portland, OR, USA)를 이용하여 여과하여 하여 실험에 사용하였다. NZB/w F1 마우스에 대조군은 물을 투여하였고 단삼투여군은 1% 단삼추출액을 15주 동안 경구 투여 사용하였다. Salviae (Salviae Miltiorrhizae Radix: SMR) used in the present invention was purchased from (Sunten Pharmaceutical Co. Lot No. 102401, Taipei, Taiwan). 0.6 g of salvia and 0.32 g of starch (yield: 66%) were mixed per 1 g. Thus, 66.7 mL of water was added per 1 g of salvia, and extracted at room temperature for 24 hours. The collected extract was centrifuged at 3000 rpm for 10 minutes and the supernatant was filtered using filter paper (whatman, No. 2, Portland, OR, USA) and used for the experiment. In the NZB / w F1 mice, the control group was administered water, and in the group of the group administered with salvia, 1% salvia extract was used orally for 15 weeks.
3) 체중의 측정3) measurement of weight
15주 동안 1% 단삼추출액을 경구 투여한 NZB/w F1 마우스를 동물실험용 저울(OHAUS corporation, Pine Brook, NJ)을 이용하여 체중을 측정 하였다. NZB / w F1 mice orally administered with 1% Salvia Miltiorrhiza for 15 weeks were weighed using an animal laboratory scale (OHAUS corporation, Pine Brook, NJ).
(2) 결과(2) results
상기와 같이 생후 3개월 된 NZB/w F1 마우스에 1% 단삼추출액을 15주 동안 경구 투여한 후 대조군과 체중을 비교한 결과 거의 차이가 없음을 확인하였다(도 1).As described above, after oral administration of 1% salvia extract to NZB / w F1 mice at 3 months of age for 15 weeks, it was confirmed that there was almost no difference between the control and the body weight ( FIG. 1 ).
<실시예 2> 단삼의 단백뇨 감소 효과의 확인 <Example 2> Confirmation of the proteinuria reducing effect of salvia
(1) 재료 및 방법(1) materials and methods
실시예1의 (1)-1), 2)에서 와 같이 실험동물과 시료를 제조하고,Prepare experimental animals and samples as in Example 1 (1) -1), 2),
15주 동안 1% 단삼추출액을 NZB/w F1 마우스에 경구 투여한 후, 소변을 채취 하여 유리스칸(URiSCAN) 시험지(영동제약(주), 경기도, 대한민국)에 제조사의 프로토콜에 준하여 단백뇨를 측정하였다. 제조사에서 제공하는 발색표를 기준으로 하여 10∼29 ug/mL는 1, 30∼99 ug/mL는 2, 100∼299 ug/mL는 3, 300∼999 ug/mL는 4, 1000 ug/mL 이상은 5로 등급을 나누어 분석하였다. After 15 weeks of oral administration of 1% salvia extract to NZB / w F1 mice, urine was collected and proteinuria was measured according to the manufacturer's protocol on URiSCAN test paper (Youngdong Pharmaceutical Co., Ltd., Gyeonggi-do, South Korea). . 10-29 ug / mL is 1, 30-99 ug / mL is 2, 100-299 ug / mL is 3, 300-999 ug / mL is 4, 1000 ug / mL based on the color scheme provided by the manufacturer The results were analyzed by dividing the rating into five.
(2) 결과(2) results
상기와 같이 사구체 손상으로 기능 장애가 발생했는지를 확인하기 위하여 단백뇨를 측정한 결과 단삼투여군이 대조군과 비교하여 유의성 있게 감소하였다(도 2). SLE환자의 대부분이 사구체에 면역글로불린 침착이 발생하게 되는데 이는 루푸스 신염의 주요 원인으로 작용하며, 환자의 반수는 단백뇨의 소견을 보인다. 뇨 분석 검사는 루푸스 신염을 진단하는데 가장 간단하고 흔히 이용되는 검사 방법이다. 단백뇨가 감소된 것은 루푸스가 개선되었기 때문으로 생각된다.As a result of measuring the proteinuria to confirm whether a dysfunction occurred due to glomerular damage, the group treated with the mononuclear group was significantly reduced compared to the control group ( FIG. 2 ). Most of the patients with SLE develop immunoglobulin deposition in the glomeruli, which is a major cause of lupus nephritis, and half of the patients show proteinuria. Urinalysis is the simplest and most commonly used test to diagnose lupus nephritis. The decrease in proteinuria is thought to be due to an improvement in lupus.
<실시예 3> 단삼이 간기능에 미치는 영향의 확인Example 3 Confirmation of Effect of Salvia Miltiorrhiza on Liver Function
(1) 재료 및 방법(1) materials and methods
실시예1의 (1)-1), 2)에서 와 같이 실험동물과 시료를 제조하고,생후 3개월 된 NZB/w F1 마우스에 1% 단삼추출액을 15주 동안 경구 투여한 후, 마우스에서 심장 채혈을 하였다. 채혈한 혈액을 실온에서 1시간 동안 방치한 후 3000 rpm에서 5분간 원심분리 하였다. 분리한 혈청은 -20℃에서 보관하여 실험에 이용하였다. 분리한 혈청을 DRI-CHEM 3500s (Fuji Photo Film Co., Ltd, Kamagwa-ken, Japan)을 이용하여 분석하였다. Experimental animals and samples were prepared as in Example 1 (1) -1) and 2), and NZB /
(2) 결과(2) results
간세포 손상과 담관 정체나 약물에 의한 효소 증가를 확인하기 위하여 GOT, GPT를 검사하였다. 단삼투여군이 대조군과 비교하여 유의성 있는 차이를 보이지 않았다. GOT and GPT were examined to confirm hepatocellular damage, bile duct stagnation, or drug-induced enzyme increase. The short osmotic group did not show any significant difference compared with the control group.
표 1. NZB/w F1 마우스에서 GOT, GPT농도 비교 Table 1 . Comparison of GOT and GPT Concentrations in NZB / w F1 Mice
<실시예 4> 단삼이 신장기능에 미치는 영향의 확인Example 4 Confirmation of Effect of Salvia Miltiorrhiza on Kidney Function
(1) 재료 및 방법(1) materials and methods
실시예1의 (1)-1), 2)에서 와 같이 실험동물과 시료를 제조하고,생후 3개월 된 NZB/w F1 마우스에 1% 단삼추출액을 15주 동안 경구 투여한 후, 실시예3의 (1)에서와 같이 심장채혈을 하고 혈청을 분리하여 DRI-CHEM 3500s (Fuji Photo Film Co., Ltd, Kamagwa-ken, Japan)을 이용하여 분석하였다. Experimental animals and samples were prepared as in Example 1 (1) -1) and 2), and 3% old NZB / w F1 mice were orally administered with 1% salvia extract for 15 weeks. As in (1), the blood was collected and the serum was separated and analyzed using DRI-CHEM 3500s (Fuji Photo Film Co., Ltd, Kamagwa-ken, Japan).
(2)결과(2) results
신장 기능 손상의 상태와 장애의 정도를 파악하기 위하여 BUN, 크레아티닌(Creatinine), 총단백(total protein)을 검사하였다. 그 결과 단삼투여군이 대조군과 비교하여 검사항목이 모두 감소하였으나 유의성은 없었다. BUN, creatinine, and total protein were examined to determine the status of renal impairment and the extent of the disorder. As a result, the test group decreased in all groups compared with the control group, but it was not significant.
표 2 . NZB/w F1 마우스에서 총단백, 크레아티닌, BUN 농도의 비교. Table 2 . Comparison of Total Protein, Creatinine, and BUN Concentrations in NZB / w F1 Mice.
<실시예 5> 단삼이 혈액학(Hematology)에 미치는 영향Example 5 Effect of Salvia Miltiorrhiza on Hematology
(1) 재료 및 방법(1) materials and methods
실시예1의 (1)-1), 2)에서 와 같이 실험동물과 시료를 제조하고,생후 3개월 된 NZB/w F1 마우스에 1% 단삼추출액을 15주 동안 경구 투여한 후, 실시예3의 (1)에서와 같이 심장 채혈 하여 얻은 혈액을 EDTA처리가 된 튜브에 담아서 롤 믹서(roll mixer)에서 30분간 롤링한 후 혈액학적 분석기 HEMAVET 시스템 (Hematology analyzer HEMAVET system, Drew Scientific Inc, Dallas, TX, USA)을 이용하여 분석하였다. Experimental animals and samples were prepared as in Example 1 (1) -1) and 2), and 3% old NZB / w F1 mice were orally administered with 1% salvia extract for 15 weeks. Hematology analyzer HEMAVET system, Drew Scientific Inc, Dallas, TX , USA).
(2) 결과(2) results
위와 같이 혈액학적 분석기를 이용하여 검사한 결과는 표 3과 같으며 혈구세포의 분포율은 거의 차이를 보이지 않았다.The test results using the hematological analyzer as shown above are shown in Table 3, and the distribution rate of the blood cells was almost insignificant.
표 3. NZB/w F1 마우스에서 혈액학적 비교 Table 3 . Hematological Comparison in NZB / w F1 Mice
최근에는 자가 조혈모세포를 이용하여 이식하여, 루푸스를 질환을 치료하는 방법이 연구되고 있다. 상기 방법은 병적인 임파구를 완전하게 제거한 후 이식된 자가 조혈모세포로부터 새로이 만들어진 임파구로 대체하여서 치료하는 방법이다. 본 발명에 따른 단삼추출물은 임파구의 양을 증가 시켰으나, 이 증가가 병적 림프구의 증가인지, 정상적인 면역기능을 수행하는 임파구인지는 불명하다. 다만, 단핵구, 호중성 백혈구 및 호산성 백혈구의 양을 감소시켰다. 임파구의 증가 및 감소와의 루푸스 질병과의 관계는 추가의 연구가 필요하다. Recently, a method of treating lupus with disease by transplantation using autologous hematopoietic stem cells has been studied. The method is to remove the pathological lymphocytes completely, and then replace them with the newly produced lymphocytes from the transplanted autologous hematopoietic stem cells. Salviae extract according to the present invention increased the amount of lymphocytes, it is not known whether the increase is an increase in pathological lymphocytes, lymphocytes performing a normal immune function. However, the amount of monocytes, neutrophils and eosinophils was reduced. The relationship between lupus disease with increasing and decreasing lymphocytes requires further study.
<실시예 6> 단삼이 항-dsDNA 항체 발현에 미치는 영향 확인Example 6 Effect of Salvia Miltiorrhiza on Anti-dsDNA Antibody Expression
(1) 재료 및 방법(1) materials and methods
1) 실시예1의 (1)-1), 2)에서 와 같이 실험동물과 시료를 제조하고, 생후 3개월 된 NZB/w F1 마우스에 1% 단삼추출액을 15주 동안 경구 투여한 후, 실시예3의 (1)에서와 같이 심장 채혈 하여 얻은 혈액에서 혈청을 분리하였다.1) Prepare experimental animals and samples as in Example 1 (1) -1) and 2), and after oral administration of 1% Salvia extract for 15 weeks to NZB /
2) 엘리자(ELISA)를 이용한 항-dsDNA 항체의 발현량 측정2) Determination of the expression level of anti-dsDNA antibody using ELISA
분리한 헐청에서 항-IgG, IgG1, IgG2a 발현량을 측정하기 위하여 마우스 IgG, IgG1, IgG2a 엘리자 정량 키트(ELISA Quantitation kit, Bethyl Laboratory, Montgomery, TX, USA)의 프로토콜을 이용하되 송아지 흉선(calf thymus) DNA (Sigma, Louis, MO, USA)를 코팅 완충용액(0.05M Carbonate-Bicarbonate, pH 9.6)로 100 ug/mL로 희석하여 96-웰 플레이트에 100 ㎕ 씩 분주한 후 실온에서 1시간 동안 코팅하였다. 코팅한 플레이트를 세척 완충용액 (50mM Tris, 0.14M Nacl, 0.05% Tween-20)으로 3번 세척한 후 블로킹 용액(Blocking solution, 50mM Tris, 0.14M Nacl, 1% BSA, pH 8.0)을 200 ㎕/웰 씩 분주한 후 실온에서 30분간 동안 블래킹(blacking) 하였다. 다시 세척 완충용액으로 3번 세척하고 표준과 시료를 100 ㎕씩 분주한 후 실온에서 1시간 반응시켰다. 세척 완충용액으로 5번 세척하고 HRP 감지 항체 (HRP Detection antibody)를 100 ㎕씩 각 웰에 첨가하였다. 실온에서 1시간 반응 후 세척 완충용액으로 5번 세척 한 후 기질용액 (Substrate Solution, TMB Substrate Reagent; Pharmingen, BD Bioscience, San Diego, CA, USA) 세트를 각 웰 마다 100 ㎕씩 첨가하였다. 실온의 어두운 곳에서 30분 동안 반응 한 후 2N H2SO4를 100 ㎕ 첨가 한 후 30분 안에 마이크로 플레이트 리더(Micropalte reader, Molecular Devices, Sunnyvale, CA, USA)로 450nm에서 읽었다.In order to measure the anti-IgG, IgG1, IgG2a expression levels in isolated herpes, the protocol of mouse IgG, IgG1, IgG2a ELISA Quantitation kit (ELISA Quantitation kit, Bethyl Laboratory, Montgomery, TX, USA) was used for calf thymus. ) Dilute DNA (Sigma, Louis, MO, USA) to 100 ug / mL with coating buffer (0.05M Carbonate-Bicarbonate, pH 9.6), dispense 100 μl into 96-well plates and coat for 1 hour at room temperature. It was. The coated plate was washed three times with washing buffer (50mM Tris, 0.14M Nacl, 0.05% Tween-20), and then 200 µl of blocking solution (50mM Tris, 0.14M Nacl, 1% BSA, pH 8.0) was added. After aliquoting per well, the cells were blacked for 30 minutes at room temperature. Again washed three times with the wash buffer, and 100 μl of standards and samples were dispensed for 1 hour at room temperature. Washed five times with wash buffer and 100 μl of HRP Detection antibody was added to each well. After 1 hour of reaction at room temperature, the solution was washed 5 times with washing buffer, and then 100 μl of substrate solution (Substrate Solution, TMB Substrate Reagent; Pharmingen, BD Bioscience, San Diego, CA, USA) was added to each well. After reacting for 30 minutes in a dark room temperature, 100 μl of 2N H 2 SO 4 was added and then read at 450 nm with a microplate reader (Micropalte reader, Molecular Devices, Sunnyvale, CA, USA) within 30 minutes.
(2) 결과(2) results
상기와 같이 엘리자 방법을 이용하여 측정한 결과 단삼투여군이 대조군과 비교하여 항-dsDNA 총 IgG는 유의성 있게 감소하였으며, 항-dsDNA IgG1은 감소하였으나 유의성은 없었다. 그에 반해 항-dsDNA IgG2a는 유의성 있게 증가하였다(도 3, 4, 5 ).As measured by the Eliza method as described above, the anti-dsDNA total IgG was significantly decreased and the anti-dsDNA IgG1 was decreased, but not significant. In contrast, anti-dsDNA IgG2a increased significantly ( FIGS. 3, 4, 5 ).
항-dsDNA항체는 우리 몸속에 중요한 구성 성분인 DNA에 관한 항체로서 이 항체는 루푸스 환자에서만 나타나기 때문에 루푸스 진단에 결정적인 역할을 한다. 뿐만 아니라 항-dsDNA 항체는 루푸스가 심하면 심할수록 수치가 올라가고 루푸스가 완화되면 그 수치가 내려가기 때문에 흔히 병원에서 루푸스 치료 반응의 지표로 많이 이용된다. 따라서 본 발명의 단삼추출물이 루푸스 질환에 효과적임을 보인다.Anti-dsDNA antibodies are antibodies to DNA, an important constituent in our body, and they play a decisive role in lupus diagnosis because they only appear in lupus patients. In addition, anti-dsDNA antibodies are often used as an indicator of lupus treatment response in hospitals because the higher the lupus, the higher the levels, and the lower the lupus, the lower the levels. Therefore, the salviae extract of the present invention is shown to be effective in lupus disease.
<실시예 7> 단삼이 비장 임파구에서 사이토카인 발현에 미치는 영향 확인Example 7 Effect of Salvia Miltiorrhiza on Cytokine Expression in Spleen Lymphocytes
(1) 재료 및 방법(1) materials and methods
1) 실시예1의 (1)-1), 2)에서 와 같이 실험동물과 시료를 제조하고, 생후 3개월 된 NZB/w F1 마우스에 1% 단삼추출액을 15주 동안 경구 투여한 후, 비장을 적출한다.1) Prepare the experimental animals and samples as in Example 1 (1) -1), 2), and after oral administration of 1% salvia extract for 15 weeks to NZB /
2) 비장 임파구 준비 및 배양2) preparation and culture of spleen lymphocytes
적출한 NZB/w F1 마우스의 비장을 멸균된 주사기로 파쇄한 후 세포 스트레이너(cell strainer, BD Bioscience, San Diego, CA, USA)로 걸러낸다. 균질화된 비장세포에 적혈구 제거를 위하여 5㎖ 팜 라이즈(PharM Lyse, BD Bioscience, San Diego, CA, USA)를 넣고 5분간 반응시킨다. 세포가 부유되어 있는 튜브에 5㎖의 배지를 첨가한 후 1,000 rpm에서 10분간 원심분리하고 상층액을 제거한다. 남은 세포 덩어리(pellet)는 1㎖의 배지로 서스펜션(suspension)한 후 트리판 블루(trypan blue)로 염색하여 세포수를 측정하였다.The spleens of the isolated NZB / w F1 mice are crushed with a sterile syringe and then filtered with a cell strainer (BD Bioscience, San Diego, CA, USA). Into homogenized splenocytes, 5 ml of palm rise (PharM Lyse, BD Bioscience, San Diego, CA, USA) was added to remove red blood cells and allowed to react for 5 minutes. 5 ml of medium is added to the tube in which the cells are suspended, centrifuged at 1,000 rpm for 10 minutes, and the supernatant is removed. The remaining cell pellet was suspended in 1 ml of medium and stained with trypan blue to measure the number of cells.
분리한 비장 임파구를 2×106 cells/㎖의 농도로 1 mL씩 24-웰 플레이트에 분주(seeding)하였다.2㎍/㎖ 항-CD3e(clone:145-2C11, BD Bioscience, San Diego, CA, USA)가 코팅된 플레이트에 비장 임파구를 분주(seeding)한 후 2㎍/㎖ 항-CD28(clone:37.51, BD Bioscience, San Diego, CA, USA)로 상호자극하였다. 상기의 혼합물을 48시간 동안 37℃, 5% CO2 배양기(Nuaire, Plymouth, MN, USA)에서 배양한 뒤 상층액을 얻어서 -20℃ 보관한 후 실험에 이용하였다.The isolated spleen lymphocytes were seeded into 24-well plates at a concentration of 2 × 10 6 cells / mL in 24-well plates. 2 μg / mL anti-CD3e (clone: 145-2C11, BD Bioscience, San Diego, CA, USA) coated spleen lymphocytes on coated plates and were then stimulated with 2 μg / ml anti-CD28 (clone: 37.51, BD Bioscience, San Diego, Calif., USA). The mixture was incubated for 48 hours at 37 ℃, 5% CO 2 incubator (Nuaire, Plymouth, MN, USA) and then obtained a supernatant and stored in -20 ℃ was used in the experiment.
3) 엘리자(ELISA)를 이용한 사이토카인 발현량 측정3) Measurement of cytokine expression using ELISA
NZB/W F1 마우스의 비장 임파구 세포를 배양한 상층액에서 IFN-γ, IL-4의 발현량을 측정하기 위하여 OptEIA 마우스 IFN-γ세트, OptEIA 마우스 IL-4 세트(BD Bioscience, San Diego, CA, USA)의 프로토콜을 이용하되 포획 항체 (항-마우스 IFN-γ 또는 IL-4)를 코팅 완충용액(0.1M Carbonate, pH 9.5)으로 희석하여 96-웰 플레이트에 100㎕씩 분주한 후 4℃에서 하룻밤동안 코팅하였다. 코팅한 플레이트를 세척 완충용액(PBS/Tween-20 0.05%)로 3번 세척한 후 분석 희석액(Assay Diluent, BD Bioscience, San Diego, CA, USA)을 200㎕/웰 씩 분주한 후 실온에서 1시간 동안 블로킹하였다. 다시 세척 완충용액으로 3번 세척하고 표준 또는 샘플을 100㎕씩 각각 분주한 후 실온에서 2시간 동안 반응시켰다. 세척 완충용액으로 5번 세척하고 작용 감지물질(Working Detector, 감지 항체 +아비딘(Avidin)-HRP)을 100㎕씩 각 웰에 첨가하여 실온에서 1시간 반응 후 세척 완충용액으로 10번 세척한 후 기질 용액(Substrate Solution, TMB Substrate Reagent; Pharmingen, BD Bioscience, San Diego, CA, USA)을 각 웰마다 100㎕씩 첨가하였다. 실온의 어두운 곳에서 30분 동안 반응시킨 후 2N H2SO4를 50㎕ 첨가 한 후 30분 안에 다중효소면역측정기(흡광분석기, Microplate Reader , Molecular Devices, Sunnyvale, CA, USA)로 450㎚/570㎚에서 읽었다.In order to measure the expression level of IFN-γ and IL-4 in supernatant cultured spleen lymphocyte cells of NZB / W F1 mice, OptEIA mouse IFN-γ set and OptEIA mouse IL-4 set (BD Bioscience, San Diego, CA) , USA) protocol, but the capture antibody (anti-mouse IFN-γ or IL-4) is diluted with coating buffer (0.1M Carbonate, pH 9.5) and dispensed 100μL in 96-well plate and then 4 ℃ Coated overnight at. The coated plate was washed three times with washing buffer (PBS / Tween-20 0.05%), followed by dispensing the assay diluent (Assay Diluent, BD Bioscience, San Diego, Calif., USA) at 200 μl / well, then at room temperature. Blocking for time. Again washed three times with the wash buffer and the standard or sample was dispensed each 100μL and reacted for 2 hours at room temperature. After washing 5 times with washing buffer and adding 100 μl of each working detector (Working Detector, detection antibody + avidin-HRP) to each well, the reaction was performed at room temperature for 1 hour and then washed 10 times with washing buffer. 100 μl of each solution (Substrate Solution, TMB Substrate Reagent; Pharmingen, BD Bioscience, San Diego, Calif., USA) was added to each well. After reacting for 30 minutes in a dark place at room temperature, 50 μl of 2N H 2 SO 4 was added and within 30 minutes, 450 nm / 570 with a multi-enzyme immunoassay (absorber, Microplate Reader, Molecular Devices, Sunnyvale, CA, USA). Read at nm.
(2) 결과(2) results
상기와 같은 방법으로 측정한 사이토카인 발현량은 단삼투여군이 대조군과 비교하여 IFN-γ는 감소하였으나 유의성이 없었으나 IL-4는 유의성 있게 증가하였다(도 6, 7).The cytokine expression level measured by the above method was significantly decreased in IFN-γ but not significantly increased in IL-4 compared to the control group compared with the control group ( FIGS. 6 and 7 ).
IFN-γ는 류마티스 관절염환자에서는 관해를 유도하는 작용을 하지만 SLE 환자나 SLE 마우스에서는 반대로 질환을 악화시키는 것으로 알려져 있는데, 주 기전은 IgG2a의 생산을 촉진해 사구체 장애를 가속화하는 것으로 알려져 있다. IL-4는 Th2에서 유발되는 사이토카인으로 주로 IgG1과 IgE를 분비 유도하며 SLE 환자에게서 증가된다. IgG2a전환에 관여하는 IFN-γ의 경우 단삼추출물 투여군은 대조군에 비해 유의성 있게 감소하여 루푸스 질환에 효과적임을 보였다. 반면에 본 발명에 따른 단삼추출물은 IgG1전환에 관여하는 IL-4는 단삼 추출물 투여군은 대조군에 비교하여 증가하였으나 유의성은 없었다(?).IFN-γ plays a role in inducing remission in rheumatoid arthritis patients, but it is known to exacerbate the disease in SLE patients and SLE mice. The main mechanism is known to accelerate the production of IgG2a and accelerate glomerular disorder. IL-4 is a cytokine induced by Th2 and mainly secretes IgG1 and IgE and is increased in SLE patients. In case of IFN-γ, which is involved in IgG2a conversion, the saliva extract was significantly reduced compared to the control group, indicating that it was effective in lupus disease. On the other hand, the salviae extract according to the present invention, IL-4 involved in IgG1 conversion increased in comparison with the control group in the saliva extract administration group, but was not significant (?).
<실시예 8> 단삼이 신장에 미치는 영향 확인Example 8 Checking the Effect of Salvia Miltiorrhiza on Kidney
(1) 재료 및 방법 (1) materials and methods
실시예1의 (1)-1), 2)에서 와 같이 실험동물과 시료를 제조하고, 생후 3개월 된 NZB/w F1 마우스에 1% 단삼추출액을 15주 동안 경구 투여한 다음, 실험군과 대조군을 희생시킨 후 신장 조직을 적출하여 식염수으로 수세한 후 10% 중화 포르말린에 고정 후 수세, 탈수하여 파라핀으로 고정하였다. 고정한 조직을 4㎛ 두께로 분할하고 피에이에스(PAS, Periodic Acid-Schiff staining system, Sigma, ouis, MO, USA)의 프로토콜을 이용하여 PAS 염색을 하였다.Experimental animals and samples were prepared as in Example 1 (1) -1) and 2), and NZB / w F1 mice aged 3 months were orally administered with 1% salvia extract for 15 weeks. After sacrifice, kidney tissue was extracted, washed with saline, fixed in 10% neutralized formalin, washed with water, dehydrated, and fixed with paraffin. The fixed tissue was divided into 4 μm thick and PAS stained using a protocol of PAS (PAC, Periodic Acid-Schiff staining system, Sigma, ouis, MO, USA).
(2) 결과(2) results
상기와 같은 실험 결과, 단삼투여군이 대조군과 비교하여 사구체의 손상이 적었으며 대식세포의 침윤도 보이지 않았음을 확인할 수 있었다(도 8).As a result of the above experiments, it was confirmed that the dan-sam administered group had less glomerular damage and no invasion of macrophages compared to the control group (FIG. 8).
도 8 에서 A는 대조군의 신장으로 짧고 넓은 화살표는 경화한 사구체이고, 긴 화살표는 표면혈관 백혈구의 침윤을 보이고 있으며, B 는 단삼투여군의 신장으로 짧은 두줄의 화살표가 사구체를 나타낸다 . In Figure 8 , A is the kidney of the control group, the short and wide arrow is a hardened glomeruli, the long arrow shows the surface vascular leukocyte infiltration, B is the kidney of the short-term administration group, two short arrows represent the glomeruli.
피에이에스 염색(PAS, Periodic acid-Schiff hematoxylin stain)으로 염색하였으며. 배율× 400이다.It was stained with PAS (Periodic acid-Schiff hematoxylin stain). Magnification × 400.
본 발명에서 NZB/W F1 마우스에 단삼추출액을 경구 투여한 후 단백뇨 수치를 측정한 결과, 단삼투여군에서 유의성있게 단백뇨가 감소하였으며, 임파구를 증가시키고, 루푸스 질환의 중요한 척도인 항-dsDNA 총 IgG 감소시켰다. In the present invention, the proteinuria level was measured after oral administration of the salvia extract to NZB / W F1 mice, and significantly decreased proteinuria, increased lymphocytes, and decreased anti-dsDNA total IgG, an important measure of lupus disease, in the administration group. I was.
또한, 본 발명에 따른 단삼추출물이 NZB/W F1 마우스의 비장 임파구에서 사이토카인 발현에 미치는 영향을 알아본 결과 IgG2a전환에 관여하는 IFN-γ의 경우 단삼추출물 투여군은 대조군에 비해 유의성 있게 감소하여 루푸스 질환에 효과적임을 보였으며, 사구체의 손상과 대식세포의 침윤을 억제하는 효과를 나타내므로 루푸스 치료제로서 유용하게 사용될 수 있다.In addition, as a result of examining the effect of Salvia extract according to the present invention on cytokine expression in spleen lymphocytes of NZB / W F1 mice, the group treated with Salvia extract was significantly decreased compared to the control group in IFN-γ involved in IgG2a conversion. It has been shown to be effective in the disease, and since it shows an effect of inhibiting the damage of glomeruli and invasion of macrophages, it can be usefully used as a treatment for lupus.
본 발명에 따른 단삼 추출물은 자가면역성 질환의 중요한 표지 인자인 항-dsDNA 총 IgG의 양을 감소시켰고, IFN-γ의 양을 감소시켰다. 따라서 상기 단삼추출물은 류마티스관절염, 다발성신경염, 타입 1 당뇨병, 염증성 장질환, 및 피부경화증 등의 자가면역질환치료에도 유용할 것으로 예상이 된다. Salviae extract according to the present invention reduced the amount of anti-dsDNA total IgG, an important marker of autoimmune disease, and decreased the amount of IFN-γ. Therefore, the extract is expected to be useful in the treatment of autoimmune diseases such as rheumatoid arthritis, polyneuritis,
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.
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