KR20040007380A - Food additive containing Agastache rugosa Extract - Google Patents
Food additive containing Agastache rugosa Extract Download PDFInfo
- Publication number
- KR20040007380A KR20040007380A KR1020030098547A KR20030098547A KR20040007380A KR 20040007380 A KR20040007380 A KR 20040007380A KR 1020030098547 A KR1020030098547 A KR 1020030098547A KR 20030098547 A KR20030098547 A KR 20030098547A KR 20040007380 A KR20040007380 A KR 20040007380A
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- KR
- South Korea
- Prior art keywords
- extract
- activity
- fraction
- inflammatory
- agastache rugosa
- Prior art date
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Classifications
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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
- A23V2250/00—Food ingredients
- A23V2250/20—Natural extracts
- A23V2250/21—Plant extracts
Abstract
Description
본 발명은 배초향 추출물이 함유된 식품첨가제에 관한 것으로서, 더욱 상세하게는 배초향(Agastache rugosa) 추출물이 염증반응인자로서의 보체계(complement system)의 활성 억제, 세포부착물질-1(intercellular adhesion molecule-1, ICAM-1)의 발현 억제 및 산화질소(nitric oxide, NO)의 생성 억제에 대한 활성이 우수함은 물론이고, 염증반응에 근거한 동맥경화성 병변의 발달을 현저하게 감소시키는효과를 가지고 있어 염증 질환 이외에도 염증반응과 관련된 동맥경화 그리고 이로 인한 순환기 질환의 예방 및 치료에 유용하므로 상기한 배초향 추출물을 식품첨가제로 사용하는 발명에 관한 것이다.The present invention relates to a food additive containing a pear pear extract, more specifically, Agastache rugosa extract inhibits the activity of the complement system as an inflammatory response factor, intercellular adhesion molecule-1, In addition to its excellent activity in inhibiting the expression of ICAM-1) and the production of nitric oxide (NO), it has the effect of significantly reducing the development of atherosclerotic lesions based on the inflammatory response. The invention relates to the use of the above-mentioned herbaceous extract as a food additive, as it is useful for the prevention and treatment of atherosclerosis and related circulatory diseases.
염증반응은 조직(세포)의 손상이나 외부감염원(박테리아, 곰팡이, 바이러스, 다양한 종류의 알레르기 유발물질)에 감염되었을 때 국소 혈관과 체액 중 각종 염증 매개인자 및 면역세포가 관련되어 효소 활성화, 염증매개물질 분비, 체액 침윤, 세포 이동, 조직 파괴 등 일련의 복합적인 생리적 반응과 홍반, 부종 발열 통증 등 외적 증상이 나타난다. 정상인 경우 염증반응은 외부감염원을 제거하고 손상된 조직을 재생하여 생명체 기능회복작용을 하지만, 항원이 제거되지 않거나 내부물질이 원인이 되어 염증반응이 과도하거나 지속적으로 일어나면 오히려 질환의 주요 병리현상(과민성 질환, 만성 염증)이 되며, 수혈, 약물투여, 장기이식 등 치료과정에서도 장해요인이 된다.Inflammatory reactions involve damage to tissues (cells) or external infectious agents (bacteria, fungi, viruses, various types of allergens), which involve various enzymes and immune cells in local blood vessels and body fluids. A series of complex physiological reactions, including substance secretion, fluid infiltration, cell migration and tissue destruction, and external symptoms such as erythema and edema fever pain. In normal cases, inflammatory reactions restore the function of life by removing external infectious agents and regenerating damaged tissues.However, if the inflammatory response is excessive or persistent due to the absence of antigens or internal substances, the major pathology of the disease (sensitizing disease) , Chronic inflammation) and also become a disorder in the treatment process such as blood transfusion, drug administration, and organ transplantation.
본 발명과 관련하여 염증반응에 관여하는 인자들의 작용을 기술하면 다음과 같다.Referring to the action of the factors involved in the inflammatory response in connection with the present invention.
보체계(complement system)는 면역반응의 초기에 염증 활성화 및 증폭작용을 하는 체액성 주요인자이다. 보체의 활성화 과정에서 생성되는 활성단백질(아나필라톡신류; C3a, C4a, C5a)과 복합단백질(membrane attack complex, MAC)은 다양한 염증 질환(류마치스성 관절염[Sato, Y. et al, Ann. Rheum. Dis. 52, 795-800, 1993], 전신홍반성낭창[Takematsu, H. et al, Clin. Exp. Rheumatol. 10, 433-438, 1992], 성인호흡기질환 증후군[Langlois, P. F. et al, Heart Lung. 18, 71-84,1989], 알쯔하이머성 치매[McGeer, D. L. et al, 8, 80-83 1995])과 관련이 있으며, 장기이식 초급성 거부반응의 직접적인 원인이 되고 있다[White, D. 14, 3-5, 1996].The complement system is a major humoral factor that activates and amplifies inflammation early in the immune response. The active proteins (anaphylatoxins; C3a, C4a, C5a) and membrane attack complex (MA) produced during the activation of complement are various inflammatory diseases (Sato, Y. et al, Ann. Rheum). 52, 795-800, 1993], systemic lupus erythematosus [Takematsu, H. et al, Clin.Exp. Rheumatol. 10, 433-438, 1992], adult respiratory disease syndrome [Langlois, PF et al, Heart Lung. 18, 71-84,1989], and Alzheimer's dementia (McGeer, DL et al, 8, 80-83 1995)), and are directly responsible for the organ transplant superacute rejection [White, D]. 14, 3-5, 1996].
ICAM-1은 내피세포(endothelial cells) 표면에서 발현되는 세포부착물질군의 대표적인 단백질이다. 정상적인 경우 매우 낮은 수준으로 발현되어 있으나 TNF-α, 인테페론-γ, 인터루킨-1β등 싸이토카인류 염증매개물질에 의하여 자극을 받으면 발현량이 급속히 증가되어 혈류 중 이동하는 단핵구나 임파구 등 염증세포를 부착하고 염증세포가 염증발생 조직으로 이동하는데 역할을 한다[Wegner C. D. et al, Science, 247(1941), 456-459, 1990; Dustin, M. L. et al, J. Immunol. 137(1) 245-254, 1986]. 따라서, ICAM-1의 발현은 염증세포가 염증발생 부위로 이동 및 집속하는 초기에 작용하여 염증반응의 증폭작용에 중요한 작용을 한다.ICAM-1 is a representative protein of the cell adhesion substance expressed on the surface of endothelial cells. Normally, they are expressed at very low levels, but when stimulated by cytokine-type inflammatory mediators such as TNF- α , inferon- γ , and interleukin-1 β , their expression levels rapidly increase and attach inflammatory cells such as monocytes or lymphocytes that move in the bloodstream. Inflammatory cells play a role in migration to inflammatory tissues [Wegner CD et al, Science, 247 (1941), 456-459, 1990; Dustin, ML et al, J. Immunol. 137 (1) 245-254, 1986]. Therefore, ICAM-1 expression plays an important role in the amplification of the inflammatory response by acting at the early stage when the inflammatory cells migrate and focus on the site of inflammation.
NO는 NO 합성효소(nitric oxide synthase, 이하 NOS)에 의해 L-알지닌(L-arginine)이 산화된 후 L-시트룰린(L-citrulline)과 함께 생성된다. NO는 혈관계에 작용하여 혈관확장, 혈소판 부착 및 응집, 신경전달, 소화기관 운동, 음경발기 등에 관여하는 매개물질이며, 염증세포 뿐만 아니라 비면역 세포에서도 생성되어 미생물 감염에 대한 방어작용을 한다. 한편, NO 생성에 관여하는 NOS 중 하나인 유도형-NOS(inducible-NOS, 이하 iNOS)는 칼슘이나 칼모듈린(calmodulin)에 비의존성으로서 지방다당질(lipopolysaccharide, 이하 LPS), 싸이토카인류(IFN-γ, TNF 등)의 자극으로 발현되는데[Dinerman, J. L. et al, Circ. Res. 73, 217-222, 1993], 이러한 자극에 의하여 싸이클로옥시게네이즈-2(cyclooxygenase-2, 이하COX-2)도 함께 활성화되어 염증매개물질인 프로스타글란딘류(prostaglandins, 이하 PGs)가 생성되기 때문에 iNOS 발현과 COX-2의 발현은 매우 밀접한 관련이 있으며, 생성된 NO는 COX-2 발현에 영향을 주기도 한다[Robert C. et al, J. Immunol. 165, 1582-1587, 2000; Daniela S. et al, Proc. Natl. Acad. Sci, USA, 90, 7240-7244, 1993]. 대식세포에서 NO의 생성은 선택적으로 iNOS의 발현에 의해서 유발되며, 그 결과 역시 다른 염증반응의 활성화를 유발하기 때문에 NO는 염증 질환의 중요한 인자라고 할 수 있다[Heirholzer, C. et al, J. Exp. Med. 187, 917-928, 1998; Nussler A. K. et al, J. Leukocyte Biol. 54, 171-178, 1993].NO is produced together with L-citrulline after L-arginine is oxidized by nitric oxide synthase (NOS). NO is a mediator involved in vasodilation, platelet adhesion and aggregation, neurotransmission, digestive system movement, penile erection, and so on, acting on the vascular system. Meanwhile, inducible-NOS (iNOS), one of NOSs involved in NO production, is independent of calcium or calmodulin, and thus lipopolysaccharide (LPS) and cytokines (IFN-). γ , TNF, etc.) [Dinerman, JL et al, Circ. Res. 73, 217-222, 1993], iNOS because these stimuli also activate cyclooxygenase-2 (COX-2) to produce prostaglandins (PGs), an inflammatory mediator. Expression is closely related to the expression of COX-2, and the NO produced also affects COX-2 expression [Robert C. et al, J. Immunol. 165, 1582-1587, 2000; Daniela S. et al, Proc. Natl. Acad. Sci, USA, 90, 7240-7244, 1993]. The production of NO in macrophages is selectively induced by the expression of iNOS, which also triggers the activation of other inflammatory responses, which is an important factor in inflammatory diseases [Heirholzer, C. et al, J. Exp. Med. 187, 917-928, 1998; Nussler AK et al, J. Leukocyte Biol. 54, 171-178, 1993.
동맥경화는 지질대사와 관련된 유전적 요인과 식습관, 흡연, 운동부족 등 환경적 요인에 의하여 동맥이 경화되는 질환으로서, 이로 인하여 심장질환, 뇌혈관 질환 등의 순환계 질환의 원인이 된다. 동맥경화의 초기 발생에 관한 가설은 "손상에 대한 반응(responce-to-injury hypothesis)"으로서, 유전적 변이, 과산화물, 고혈압, 당뇨, 혈장 호모시스테인 농도 증가, 미생물 감염 등의 원인에 의하여 혈관 내피세포가 정상적인 항상성을 유지하지 못하는 기능부전상태가 되는 것이다. 내피세포가 기능부전상태로 되면 세포부착물질이 크게 발현되고 세포 투과성이 증가되어 혈중 면역세포, 혈소판, 지방질 등의 부착 및 조직으로의 투과성이 증가되며, 이들 면역세포들의 염증매개인자 및 성장인자 분비 등 염증반응 때문에 동맥경화성 병변이 발생 및 발달하게 된다는 것이다[Russel R., New England J. of Med. 340(2), 115-126, 1999]. 이때 혈중 저밀도 지단백질(low density lipoprotein, 이하 LDL)이 산화, 당결합, 집적화, 당단백 결합 등의 원인으로변형-LDL(modified-LDL, 이하 MLDL)이 생성되고, 이들은 혈관 내피세포 및 평활근의 자극 및 손상을 유발한다[Steinberg D., J. Biol. Chem. 272, 20963-20966, 1997; Griendling K.K. et al., Circulation 96, 3264-3265, 1997; Bavab M. et al, Artheriosler. Thromb. Vasc. Biol. 16, 831-42, 1996]. 이로 인하여, 내피세포의 혈관세포부착물질-1(vascular cell adhesion molecule-1, VCAM-1) 발현 및 염증세포의 염증매개인자 방출이 촉진되면 LDL은 내피세포 아래에 유입 및 축적이 되고, 축적된 LDL 및 산화된 MLDL은 다시 대식세포, T 임파구 등 면역세포의 유입 및 활성화를 유발하는 과정을 되풀이하여 병변의 염증반응을 촉진하게 된다[Rajavashisth T.B. et al., Nature, 344, 254-257, 1990; Quinn M. T. et al., Proc. Natl. Acad. Sci. USA 84, 2995-2998, 1987]. 그 후 병변으로 유입된 대식세포나 임파구로부터 방출된 가수분해효소, 염증매개인자, 성장인자 등의 작용으로 병반은 괴사하게 되고, 괴사된 병소 부위로 단핵구의 유입, 평활근의 이동 및 분화, 섬유성 조직의 형성 등의 반복적인 과정을 통하여 병변 조직은 MLDL을 핵으로 한 괴사조직에 섬유질이 덮인 복잡한 구조의 섬유질 병변으로 발달하게 되며[Fuster V. et al. eds. Artherosclerosis and coronary artery disease. vol. 1, 539-555; 585-594; vol. 2, 492-510, Philadelphia, Lippincott-Raven, 1996], 발달된 병변 조직으로부터 혈전이 생성되고 동맥이 경화되어 혈류장애 등 순환기 질환이 나타나게 되는 것이다[Russel R., New England J. of Med. 340(2), 115-126, 1999; Wong, M.-L. et al, Proc. Natl. Acad. Sci. USA 97(15), 8681-8686, 2000].Arteriosclerosis is a disease in which arteries are hardened by genetic factors related to lipid metabolism and environmental factors such as eating habits, smoking, and lack of exercise, and thus cause circulatory diseases such as heart disease and cerebrovascular disease. The hypothesis of the early onset of atherosclerosis is "responce-to-injury hypothesis," which causes vascular endothelial cells due to genetic variations, peroxides, hypertension, diabetes, elevated plasma homocysteine levels, and microbial infections. Is a dysfunction that does not maintain normal homeostasis. When endothelial cells become dysfunctional, cell adhesion substances are greatly expressed and cell permeability is increased, and adhesion of immune cells, platelets, lipids, etc. and permeability to tissues are increased, and these immune cells secrete inflammatory mediators and growth factors. Atherosclerotic lesions develop and develop due to back inflammatory reactions [Russel R., New England J. of Med. 340 (2), 115-126, 1999]. At this time, low-density lipoprotein (LDL) in the blood produces modified-LDL (MLDL) as a cause of oxidation, glycemic binding, integration, glycoprotein binding, and the like, and they stimulate and stimulate vascular endothelial cells and smooth muscle. Cause damage [Steinberg D., J. Biol. Chem. 272, 20963-20966, 1997; Griendling K.K. et al., Circulation 96, 3264-3265, 1997; Bavab M. et al, Artheriosler. Thromb. Vasc. Biol. 16, 831-42, 1996. Because of this, when expression of vascular cell adhesion molecule-1 (VCAM-1) of endothelial cells and release of inflammatory mediators of inflammatory cells are promoted, LDL enters and accumulates under endothelial cells, LDL and oxidized MLDL in turn stimulate the inflammatory response of the lesions by inducing the influx and activation of immune cells such as macrophages and T lymphocytes. [Rajavashisth TB et al., Nature, 344, 254-257, 1990; Quinn M. T. et al., Proc. Natl. Acad. Sci. USA 84, 2995-2998, 1987. Thereafter, the lesions are necrotic by the action of hydrolase, inflammation mediator, growth factor, etc. released from the macrophages or lymphocytes introduced into the lesion, and monocytes are introduced into the necrotic lesions, smooth muscle migration and differentiation, and fibrous Through repetitive processes such as tissue formation, the lesion tissue develops into a complex fibrous lesion covered with fibers in the necrotic tissue with the MLDL nucleus [Fuster V. et al. eds. Artherosclerosis and coronary artery disease. vol. 1, 539-555; 585-594; vol. 2, 492-510, Philadelphia, Lippincott-Raven, 1996], the formation of thrombi from developed lesion tissue and the hardening of the arteries resulting in circulatory disorders such as impaired blood flow [Russel R., New England J. of Med. 340 (2), 115-126, 1999; Wong, M.-L. et al, Proc. Natl. Acad. Sci. USA 97 (15), 8681-8686, 2000].
따라서, 동맥경화는 혈중 콜레스테롤 및 LDL 등 지방질의 함량이 높을 경우 발생하게 되지만, 단순한 지방질 축적에 의해서만 발생되는 것이 아니라 동맥 내피세포 아래로 지방질의 유입 및 축적되는 과정과 그 후 일어나는 병변의 발달 및 세포괴사에 이르는 일련의 과정이 내피세포, 대식세포 및 임파구 등이 관여하는 전형적인 염증 반응인 것이다.Therefore, atherosclerosis occurs when the lipid content such as cholesterol and LDL in the blood is high, but it is not caused only by the accumulation of fat, but the process of the inflow and accumulation of fat under the arterial endothelial cells and the development and subsequent development of the lesion. A series of processes leading to necrosis are typical inflammatory reactions involving endothelial cells, macrophages and lymphocytes.
한편, 배초향은 순형과(Labiatae)에 속하는 다년생 초본으로서 한국, 중국, 일본 등 동북아에 분포하고 있으며 우리 나라에서는 주로 남부 지방에 야생하거나 일부 재배되고 있다. 한방에서는 지상부를 곽향(藿香)이라 하며 명의별록(名醫別錄)에는 "풍수독종을 치료하고 나쁜 기(氣)를 제거하며 곽란, 속이 쓰리고 아픈 증상을 치료"하는 약재로 사용하고 있으며, 민간에서는 잎(방아잎)을 추어탕 등 각종 찌개의 풍미재료로 사용하고 그 꽃은 밀원(蜜源)으로 이용하고 있다.Pearweed, on the other hand, is a perennial herb belonging to the labiatae, which is distributed in Northeast Asia such as Korea, China, and Japan. In oriental medicine, the upper part is called Gwahyang (藿香), and Myeongseol-rok is used as a medicine to "treat feng shui venom, remove bad flag, and curb kwaran, heartburn and painful symptoms." In folklore, leaves are used as flavoring materials for various stew, including chueotang, and the flowers are used as a wheat source.
배초향의 성분 연구로서는 정유성분[J. Essent. Oil Res. 8(2), 135-138, 1996;ibid4(6), 585-587, 1992; 한국식품과학회지 23(5), 582-586, 1991; J. Agric. Food Chem. 40(8), 1362-1366, 1992], 세스퀴테르펜류[Yakugaku zasshi 92(7), 908-909, 1972], 디테르펜류[대한민국 특허 제9608662호; Chin. Pharm. Sci. 6(3), 115-118, 1997; 생약학회지 25(4), 319-327, 1994;ibid18(2), 99-102, 1987], 트리테르펜류[Yaozue Xuebao 26(12), 906-910, 1991; 생약학회지 19(2), 97-98, 1988;ibid18(1), 50-53, 1987], 플라보노이드[Yaozue Xuebao 26(12), 906-910, 1991; Chem. Pharm. Bull. 29(6), 1777-1779, 1981], 페닐프로파노이드[Yakugaku Zasshi 106(12)1108-1111, 1986], 카로티노이드류[생약학회지30(4), 404-408, 1999]가 보고되었다. 배초향의 생리활성에 관한 연구로서는 추출물의 항균 활성[Phytother. Res. 14(3), 210-212, 2000; J. Food Sci. Nutr. 4(2), 97-102, 1999], 항바이러스 활성[Arch. Pharm. Res. 22(5), 520-523, 1999; US patent 5776462], 모노아민옥시데이즈 저해 활성[약학회지 42(6), 634-638, 1998]이 보고되었고, 배초향 성분 중 정유성분의 항균 활성[Zhongguo Yaozue Zazhi 35(1), 9-11, 2000; Weishengwuxue Zazhi 18(4), 1-4, 16, 1998] 및 모기기피 활성[중국특허 제1044205호], 카로티노이드 성분의 항암 활성[생약학회지 30(4), 404-408, 1999], 디테르펜류의 항암 활성[J. Nat. Prod. 58(11) 1718-1821, 1995] 및 항바이러스 활성[Arch. Pharm. Res. 22(1), 75-77, 1999], 페닐프로파노이드류의 항바이러스 활성[Arch. Pharm. Res. 22(5), 520-523, 1999], 항산화 활성[한국농화학회지 42(3), 262-266, 1999] 및 항보체 활성[생약학회지 27(1), 20-25, 1996; 한국농화학회지 39(2), 147-152, 1996]이 보고된 바 있다.Essential oil component [J. Essent. Oil Res. 8 (2), 135-138, 1996; ibid 4 (6), 585-587, 1992; Korean Journal of Food Science and Technology 23 (5), 582-586, 1991; J. Agric. Food Chem. 40 (8), 1362-1366, 1992] sesquiterpenes [Yakugaku zasshi 92 (7), 908-909, 1972], diterpenes (Korean Patent No. 9608662; Chin. Pharm. Sci. 6 (3), 115-118, 1997; Korean Journal of Pharmacognosy 25 (4), 319-327, 1994; ibid 18 (2), 99-102, 1987], triterpenes [Yaozue Xuebao 26 (12), 906-910, 1991; Korean Journal of Pharmacognosy 19 (2), 97-98, 1988; ibid 18 (1), 50-53, 1987], flavonoids [Yaozue Xuebao 26 (12), 906-910, 1991; Chem. Pharm. Bull. 29 (6), 1777-1779, 1981], phenyl propanoids (Yakugaku Zasshi 106 (12) 1108-1111, 1986), and carotenoids (Korean Journal of Pharmacognosy 30 (4), 404-408, 1999). Studies on the physiological activity of pear scents include the antimicrobial activity of extracts. Res. 14 (3), 210-212, 2000; J. Food Sci. Nutr. 4 (2), 97-102, 1999], antiviral activity [Arch. Pharm. Res. 22 (5), 520-523, 1999; US patent 5776462], monoamine oxidase inhibitory activity [Pharmaceutical Journal 42 (6), 634-638, 1998], reported the antimicrobial activity of essential oils in the herbaceous component [Zhongguo Yaozue Zazhi 35 (1), 9-11, 2000; Weishengwuxue Zazhi 18 (4), 1-4, 16, 1998] and mosquito repellent activity (Chinese Patent No. 1044205), anticancer activity of carotenoid components [Journal of Pharmacognosy 30 (4), 404-408, 1999], diterpenes Anticancer activity of [J. Nat. Prod. 58 (11) 1718-1821, 1995] and antiviral activity [Arch. Pharm. Res. 22 (1), 75-77, 1999], antiviral activity of phenylpropanoids [Arch. Pharm. Res. 22 (5), 520-523, 1999], antioxidant activity [Korean Journal of Agricultural Chemistry 42 (3), 262-266, 1999] and anticomplement activity [Journal of Pharmacognosy 27 (1), 20-25, 1996; Korean Journal of Agricultural Chemistry 39 (2), 147-152, 1996.
그러나, 배초향 추출물의 항염증 활성과 항동맥경화 활성에 관한 연구는 국내외적으로 보고된 바가 없다.However, studies on the anti-inflammatory activity and anti-arteriosclerosis activity of the herbaceous extract is not reported at home and abroad.
이에, 본 발명자들은 정상적인 지질대사를 저해하지 않고 항염증 활성에 근거한 동맥경화성 병변의 발달을 억제할 수 있는 생약재를 선발할 목적으로, 예로부터 식용 및 약용으로 사용되어온 생약재를 대상으로 항염증 활성 및 항동맥경화 활성을 조사하였다. 그 결과, 배초향 추출물이 다양한 염증인자에 대한 억제 활성을 가지고, 염증반응과 관련된 동맥경화성 병변을 현저하게 감소시키는 항동맥경화 활성이 뛰어남을 알게됨으로써 본 발명을 완성하게 되었다.Accordingly, the present inventors aimed at selecting herbal medicines capable of inhibiting the development of atherosclerotic lesions based on anti-inflammatory activity without inhibiting normal lipid metabolism, and anti-inflammatory activity and Anti-arteriosclerosis activity was investigated. As a result, the present invention was completed by knowing that the herbaceous extract has an inhibitory activity against various inflammatory factors, and excellent anti-arteriosclerosis activity that significantly reduces the atherosclerotic lesions associated with the inflammatory response.
따라서, 본 발명은 배초향 추출물이 함유되어 있어 항염증 활성과 항동맥경화 활성을 가지고 있어 염증성 질환, 염증반응과 관련된 동맥경화 및 이로 인한 순환기 질환의 예방 및 치료에 유용한 의약물 또는 식품첨가제를 제공하는데 그 목적이 있다.Accordingly, the present invention provides a pharmaceutical or food additive useful in the prevention and treatment of inflammatory diseases, arteriosclerosis associated with inflammatory reactions and the resulting circulatory diseases because it contains the herbaceous extract has anti-inflammatory activity and anti-arteriosclerosis activity. The purpose is.
도 1은 배초향 추출물 처리군과 무처리군에 대하여 8주 경과한 후의 심장대동맥 단면의 동맥경화성 병변을 비교한 사진(×40)이다.1 is a photograph (× 40) comparing the atherosclerotic lesions of the aortic cross-section after 8 weeks in the pearweed extract treatment group and the untreated group.
도 2는 동맥경화성 병변조직에서 흰쥐 대식세포 단일클론 항체-2 (monoclonal antibody to mouse macrophages-2, MOMA-2, Serotec Inc. NC. USA)를 사용하여 8주 후에 면역조직학적 염색을 관찰한 사진(×100)을 나타낸 것이다.Figure 2 is a photograph of the immunohistostaining after 8 weeks using a rat macrophage monoclonal antibody-2 (MOMA-2, Serotec Inc. NC. USA) in atherosclerotic lesion tissue (X100) is shown.
본 발명은 배초향 추출물 또는 용매분획물이 함유되어 있는 의약물 또는 식품첨가제를 그 특징으로 한다.The present invention is characterized by a pharmaceutical or food additive containing the pear herb extract or solvent fraction.
이와 같은 본 발명을 상세히 설명하면 다음과 같다.The present invention will be described in detail as follows.
배초향 추출물 또는 용매분획물은 염증인자에 대한 억제활성 즉, 항보체 활성, ICAM-1 발현 억제 활성, NO의 생성 억제 활성을 가짐으로써 염증질환의 예방 및 치료에 유용할 뿐만 아니라, 염증반응과 관련된 동맥경화성 병변 억제 활성이 우수하여 동맥경화의 예방 및 치료에도 유용하다. 따라서, 본 발명은 상기한 배초향 추출물을 의약물 또는 식품첨가제로서 사용하는 용도에 관한 것이다.The herbaceous extract or solvent fraction has an inhibitory activity against inflammatory factors, that is, anti-complementary activity, ICAM-1 expression inhibitory activity, and NO production inhibitory activity, which is not only useful for the prevention and treatment of inflammatory diseases, It is also useful for the prevention and treatment of atherosclerosis due to its excellent curable lesion inhibiting activity. Accordingly, the present invention relates to the use of the above-mentioned pear herb extract as a pharmaceutical or food additive.
본 발명에 따른 배초향 추출물은 배초향 전초를 음건한 후 저급 알코올로 추출하여 농축함으로써 얻을 수 있다. 추출물의 수득률은 배초향 건조중량의 10 내지 20% 정도가 된다.Pearweed extract according to the present invention can be obtained by extracting and concentrated with a lower alcohol after drying the pear scented outpost. The yield of the extract is about 10 to 20% of the dry weight of the pear odor.
상기와 같이 얻은 배초향 추출물을 물에 현탁한 후 헥산(n-hexane)을 동일부피로 가하여 충분히 흔들어 준 다음 헥산층을 분획하고, 이어서 클로로포름(chloroform)과 부탄올(n-butanol)을 순차적으로 가하여 각각의 용매별 분획물을 얻었다.After the suspension of the pear fennel extract obtained as described above was added to the same volume of hexane ( n- hexane) and shaken sufficiently, the hexane layer was fractionated, and chloroform and n- butanol were added sequentially. A solvent-specific fraction of was obtained.
상기한 방법으로 얻은 배초향 추출물, 그리고 용매별 분획물 각각에 대하여 보체계에 대한 항보체 활성, ICAM-1 발현 억제 활성, NO의 생성 억제 활성 및 카라기난 유도-급성염증 동물모델에 대한 항염증 활성과 동맥경화성 병변의 억제 활성을 조사하였다.Anti-complementary activity against complement system, inhibitory activity of ICAM-1 expression, inhibitory activity of NO production and anti-inflammatory activity and atherosclerotic activity against carrageenan-induced acute-inflammatory animal models The inhibitory activity of the lesions was investigated.
배초향 추출물의 경우 면역복합체에 대한 사람 혈청의 보체 활성화 작용을 강하게 억제하는 항보체 활성을 나타낸다. 또한, 종양괴사인자-알파(tumor necrosis factor-α, 이하 TNF-α)로 ICAM-1의 발현을 유도한 단핵구 THP-1 세포주(THP-1 monocytic leukemic cells, 이하 THP-1 세포)에 대한 ICAM-1 발현을 강하게 억제한다. 그리고, 지방다당질(lipopolysaccharide, 이하 LPS)로 활성화를 유도한 쥐 단핵구/대식세포 세포주 RAW264.7(이하 RAW264.7 세포)의 NO 생성 작용에 대한 강한 억제 활성을 나타낸다. 또한, 카라기난 유도-급성염증 동물모델에서 강한 항염증 활성을 나타내며, 유전자 결핍 동물모델(LDLR-/- mice)에게 사료에 1%로 첨가하여 사육한 경우 무처리군 대동맥동(aortic sinus)에서 동맥경화성 병변이 현저하게 감소시킴을 알 수 있다The herbaceous extract exhibits anti-complement activity that strongly inhibits the complement activation activity of human serum on the immunocomplex. In addition, Tumor Necrosis Factor-alpha (tumor necrosis factor- α, TNF- α or less) to the ICAM for a monocytic THP-1 cell line (THP-1 monocytic leukemic cells, than THP-1 cells) induced the expression of ICAM-1 -1 strongly inhibits expression. In addition, it exhibits a strong inhibitory activity on the NO production action of the mouse monocyte / macrophage cell line RAW264.7 (hereinafter referred to as RAW264.7 cells) induced by activation with lipopolysaccharide (LPS). In addition, carrageenan-induced acute inflammatory animal models exhibited strong anti-inflammatory activity, and when the animals were fed at 1% in feed to the genetically deficient animal model (LDLR-/-mice), the arteries in the untreated group aortic sinus It can be seen that curable lesions are significantly reduced.
또한, 배초향 추출물의 헥산 분획물은 상기한 항보체 활성, ICAM-1 발현 억제 활성을 강하게 나타내고, 클로로포름 분획물은 ICAM-1 발현 억제 활성, NO 생성 저해 활성이 강하며, 부탄올 분획물은 ICAM-1 발현 억제 활성이 강하게 나타남을확인할 수 있다.In addition, the hexane fraction of the herbaceous extract showed strong anti-complement activity and ICAM-1 expression inhibitory activity, the chloroform fraction had a strong ICAM-1 expression inhibitory activity, NO production inhibitory activity, butanol fraction inhibited ICAM-1 expression It can be seen that the activity is strong.
한편, 본 발명은 배초향 추출물이 함유된 의약물 또는 식품첨가제를 그 특징으로 하는 바, 배초향 추출물의 의약물 또는 식품첨가제로의 제조방법은 공지방법을 따른다.On the other hand, the present invention is characterized in that the drug or food additive containing the medicinal herb extract, the method of producing the medicinal herb extract as a pharmaceutical or food additive according to the known method.
의약물으로 제조시에는 배초향 추출물 그 자체로도 사용할 수 있지만, 약학적으로 허용되는 담체(carrier), 부형제(forming agent), 희석제(diluent) 등과 혼합하여 분말, 과립, 캡슐 또는 주사제 등으로도 제조가 가능하다. 또한, 본 발명에 따른 배초향 추출물은 예로부터 식용 및 약용으로 사용되어온 것으로 그 투여용량에 특별한 제약은 없고, 체내 흡수도, 체중, 환자의 연령, 성별, 건강상태 식이, 투여시간, 투여 방법, 배설율, 질환의 중증도 등에 따라 변화될 수 있다. 일반적으로 배초향 추출물은 체중 1 ㎏당 0.1 내지 10 ㎎ 정도를 투여하는 것이 바람직하다. 따라서, 본 발명의 유효성분을 포함하는 조성물은 유효량 범위를 고려하여 제조하도록 하며, 이렇게 제형화된 단위투여형 제제는 필요에 따라 약제의 투여를 감시하거나 관찰하는 전문가의 판단과 개인의 요구에 따라 전문화된 투약법을 사용하거나 일정시간 간격으로 수회 투여할 수 있다.Although it can be used as a medicinal herb extract when used as a pharmaceutical, it is also prepared as a powder, granule, capsule or injection by mixing with a pharmaceutically acceptable carrier, forming agent, diluent, etc. Is possible. In addition, the herbaceous extract according to the present invention has been used for food and medicinal since ancient times, there is no particular restriction on the dosage, body absorption, weight, age, sex, health status of the patient, administration time, administration method, excretion Rate, the severity of the disease, and the like. In general, it is preferable to administer about 0.1 to 10 mg per kg body weight of the pear pear extract. Therefore, the composition containing the active ingredient of the present invention is to be prepared in consideration of the effective amount range, and the unit dosage form formulated in this way according to the judgment of the expert and the needs of the individual to monitor or observe the administration of the drug as needed Specialized medications can be used or administered at regular intervals.
한편, 식품첨가제로 제조 시에는 음료, 껌, 과자류 등의 식품소재에 본 발명의 배초향 추출물을 포함시켜 제조할 수 있다.On the other hand, when manufacturing as a food additive can be prepared by including the extract of the herbicide of the present invention in food materials such as beverages, gum, confectionery.
이상에서 설명한 배초향 추출물이 유효성분으로 함유된 의약품 및 식품첨가제는 염증질환과 동맥경화 및 이로 인한 순환기 질환의 예방효과는 물론 치료에도 탁월하다.Medicines and food additives containing the above-mentioned medicinal herb extract as an active ingredient are excellent in preventing as well as preventing inflammatory diseases and atherosclerosis and circulatory diseases caused by this.
이하, 본 발명을 다음 실시예에 의거하여 더욱 상세하게 설명하겠는바, 본 발명이 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited to the examples.
실시예 1: 배초향으로부터 추출물 제조 및 용매 분획Example 1 Extract Preparation and Solvent Fraction from Pearweed
농가에서 재배한 배초향(Agastache rugosa, Labiatae)의 지상부를 채취하여 음건하고 세절한 30 ㎏의 시료에 메탄올 120 L를 가하여 3일간 정치한 후 추출하였으며, 본 과정을 3 회 반복하여 얻은 추출액을 농축하여 추출물 3.5 ㎏을 얻었다. 추출물 중 2.5 ㎏을 물 10 L에 현탁시킨 후 헥산(n-hexane) 10 L를 가하여 헥산층을 분리한 다음 이를 2 회 반복하여 얻은 헥산층을 농축하여 헥산 분획물 380 g을 얻었다. 남은 수용액 층에 연이어 클로로포름(chloroform)과 부탄올(n-butanol)을 상기한 바와 같은 동일한 방법으로 분획한 후 농축하여 클로로포름 분획물 590 g, 부탄올 분획물 450 g, 물 분획물 980 g을 각각 얻었다.After extracting the ground parts of cultivated cultivated cultivars ( Agastache rugosa , Labiatae), 120 L of methanol was added to a dry and fine 30 kg sample and allowed to stand for 3 days. The extract was concentrated three times. 3.5 kg of extract was obtained. 2.5 kg of the extract was suspended in 10 L of water, 10 L of hexane ( n- hexane) was added thereto to separate the hexane layer, and the resulting hexane layer was concentrated twice. The hexane fraction was obtained 380 g. Subsequently, chloroform and n- butanol were fractionated in the same manner as described above in the remaining aqueous layer and concentrated to obtain 590 g of chloroform fraction, 450 g of butanol fraction, and 980 g of water fraction, respectively.
실시예 2: 배초향 추출물 및 용매 분획물의 항보체 활성Example 2: Anticomplement Activity of Pearweed Extract and Solvent Fraction
상기 실시예 1에서 얻은 추출물 및 각 용매 분획물에 대하여 보체계에 대한 항보체 활성을 조사하였다. 항보체 활성측정은 Meyer 등의 방법[Kabat, E. A. and Mayer M. M.(1961) in "Experimental Immunochemistry" 2nd ed. Charles and Thomas, USA]을 수정하여 사용하였으며 실험 과정은 다음과 같다.The anti-complement activity against the complement system was investigated for the extract obtained in Example 1 and each solvent fraction. Anti-complement activity was measured by Meyer et al. [Kabat, E. A. and Mayer M. M. (1961) in "Experimental Immunochemistry" 2nd ed. Charles and Thomas, USA] was modified and used as follows.
신선한 양 적혈구를 차가운 젤라틴-베로날 완충용액(1.8 mM 소듐 바비탈,3.1 mM 바비탈 산, 0.1% 젤라틴, 0.141 M 소금, 0.3% 나트륨아자이드, 0.5 mM 마그네슘클로라이드, 0.15 mM 칼슘클로라이드, pH 7.3)에서 3 회 세척한 후 5 ×108세포수/㎖로 농도를 맞추었다. 항체(anti-sheep red blood cell stroma rabbit antisera, S-1389, Sigma)를 1/100으로 상기 완충용액에서 희석한 후, 양 적혈구 희석액과 동일 부피로 섞고 37 ℃ 항온기에서 1시간동안 느리게 교반하여 면역복합체(sensitized erhthrocytes, EA)를 제조하였으며, 차가운 동일 완충용액으로 2회 세척하고 면역복합체 농도를 5 ×108세포수/㎖로 맞추었다. 인체혈액을 2500 ×g에서 원심분리하여 얻은 보체(혈청)를 상기 완충용액에서 1/90으로 희석하고, 면역복합체 용액 40 ㎕, 보체 희석액 80 ㎕ 및 완충용액 80 ㎕를 섞은 후 37 ℃ 항온기에서 반응시킨 다음, 즉시 원심분리하여 상등액 100 ㎕에 대하여 504 nm 파장에서 흡광도를 측정하였으며, 각 항체 및 보체(혈청) 농도별로 흡광도를 계산하여 50% 용혈(표준 용혈)을 일으키는데 필요한 항체 및 보체(혈청)의 희석 농도를 결정하였다. 그런 다음, 배초향 농축물 및 용매 분획물을 DMSO에 녹이고 표준용혈에 첨가하는 완충용액 80 ㎕에 2.5%로 희석한 후 상기한 방법으로 흡광도 측정을 3 회 반복하여 시료에 의한 흡광 저하도를 계산하였으며, 이를 보체의 용혈활성에 대한 배초향 농축물의 용혈억제 활성을 항보체 활성으로 환산하였다[수학식 1, 2].Fresh sheep erythrocytes were cold gelatin-veronal buffer (1.8 mM sodium barbital, 3.1 mM barbital acid, 0.1% gelatin, 0.141 M salt, 0.3% sodium azide, 0.5 mM magnesium chloride, 0.15 mM calcium chloride, pH 7.3 After washing 3 times), the concentration was adjusted to 5 × 10 8 cells / ml. After diluting the antibody (anti-sheep red blood cell stroma rabbit antisera, S-1389, Sigma) in 1/100 of the above buffer solution, mix it with the same volume with both erythrocyte dilutions and stir slowly for 1 hour at 37 ℃ thermostat. The complex (sensitized erhthrocytes, EA) was prepared, washed twice with the same cold buffer and the immunocomplex concentration was adjusted to 5 × 10 8 cells / ml. The complement (serum) obtained by centrifuging human blood at 2500 × g was diluted to 1/90 in the buffer solution, and 40 μl of the immunocomplex solution, 80 μl of the complement dilution solution and 80 μl of the buffer solution were reacted in a 37 ° C. thermostat. After centrifugation, the absorbance was measured at a wavelength of 504 nm for 100 μl of the supernatant, and the absorbance was calculated for each concentration of antibody and complement (serum) to generate 50% hemolysis (standard hemolysis). The dilution concentration of was determined. Then, after diluting the herbaceous concentrate and solvent fractions in DMSO and diluting 2.5% in 80 μl of the buffer solution added to the standard hemolysis, absorbance measurements were repeated three times to calculate the absorbance degradation by the sample. The hemolytic inhibitory activity of the herbicide concentrate on the hemolytic activity of complement was converted into anti-complement activity [Equation 1, 2].
그 결과, 다음 표 1과 같이 배초향 농축물 중 헥산 분획물 및 클로로포름 분획물에서 강한 항보체 활성이 나타남을 확인하였다.As a result, it was confirmed that strong anti-complement activity was observed in the hexane fraction and the chloroform fraction in the ethanol concentrate as shown in Table 1 below.
실시예 3: 배초향 추출물 및 용매 분획물의 ICAM-1 발현 억제 활성Example 3: ICAM-1 Expression Inhibitory Activity of Pearweed Extract and Solvent Fraction
상기 실시예 1에서 얻은 추출물 및 각 용매 분획물의 THP-1 세포에 대한 ICAM-1 발현 억제 활성을 조사하였다. 실험의 자세한 과정은 다음과 같다.The inhibitory activity of ICAM-1 expression on THP-1 cells of the extract and each solvent fraction obtained in Example 1 was investigated. The detailed process of the experiment is as follows.
THP-1 세포는 RPMI-1640 배지[RPMI-1640(GibcoBRL 23400-021) 1.62% , 탄산수소나트륨 0.2%, 페니실린 및 스트렙토마이신 혼합 항생제 1%]에 소태반혈장(fetal bovine serum, GibcoBRL 26140-079, 이하 FBS)을 10% 첨가한 배양액을 사용하여 이산화탄소 배양기(5% 이산화탄소, 95% 상대습도, 37 ℃, 이하 CO2배양기)내에서 배양하였다. 검정용 시료는 DMSO에 녹이고 인산완충용액(phosphate buffered salin solution, 이하 PBS)에 5% 이하로 희석하고 반응액에 5%로 첨가하여, 시료를 녹인 DMSO 농도가 최종 반응액에서 0.25%를 넘지 않도록 하였다. THP1 세포(2.5 ×105cells/㎖)를 96-웰(well) 판에 각 웰당 200 ㎕씩 분주하고, 일정 농도로 제조된 시료용액 10 ㎕를 첨가하여 37 ℃의 CO2배양기 내에서 60분 동안 배양한 후, ICAM-1의 발현을 유도하기 위해 TNF-α(최종농도 10 ng/㎖)를 가하여 다시 CO2배양기 내에서 16 시간 동안 배양하였다. 반응액은 글루타르알데히드 완충액(glutaraldehyde 2.08% in PBS)을 25㎕를 가하여 세포를 판에 고정한 후, PBST(0.005% tween-20 in PBS)로 세척하고 3% 탈지유(skim milk)를 가하여 비특이적 결합부위가 차단되도록 하였으며, 다시 세척한 후 1차 항체(anti-human ICAM-1) 및 2차 항체(anti-mouse IgG peroxidase conjugate)를 순차적으로 가한 다음, 발색용 기질용액[OPD Peroxidase substrate,(Sigma P-9187), in 0.05M phosphate-citrate buffer] 200 ㎕를 가하고, 5 ∼ 10분 후 3 M HCl 50 ㎕를 가하여 반응을 정지시켰다. 그런 다음, 분광광도계를 사용하여 490 nm에서 반응액의 흡광도를 측정하여 TNF-α에 의한 THP-1 세포의 ICAM-1 발현율을 측정하고시료에 의한 발현 저해율을 계산하였다[수학식 3, 4].THP-1 cells were treated with fetal bovine serum (GibcoBRL 26140-079) in RPMI-1640 medium (1.6% of RPMI-1640 (GibcoBRL 23400-021), 0.2% sodium bicarbonate, 1% penicillin and streptomycin mixed antibiotics). Incubated in a carbon dioxide incubator (5% carbon dioxide, 95% relative humidity, 37 ° C., CO 2 incubator) using a culture solution to which 10% of FBS was added. The assay sample is dissolved in DMSO, diluted to 5% or less in phosphate buffered salin solution (PBS) and added to the reaction solution at 5% so that the dissolved DMSO concentration does not exceed 0.25% in the final reaction solution. It was. Dispense 200 μl of THP1 cells (2.5 × 10 5 cells / ml) into a 96-well plate for each well, and add 60 μl of the sample solution prepared at a constant concentration for 60 minutes in a CO 2 incubator at 37 ° C. After incubation, TNF- α (final concentration 10 ng / ml) was added to induce the expression of ICAM-1 and again incubated for 16 hours in a CO 2 incubator. The reaction solution was fixed with 25 μl of glutaraldehyde buffer (glutaraldehyde 2.08% in PBS) to fix the cells on the plate, washed with PBST (0.005% tween-20 in PBS), and 3% skim milk (non-specific binding). The site was blocked, washed again, and then the primary antibody (anti-human ICAM-1) and the secondary antibody (anti-mouse IgG peroxidase conjugate) were added sequentially, followed by OPD Peroxidase substrate (Sigma). P-9187), in 0.05 M phosphate-citrate buffer] 200 µl was added, and 5 to 10 minutes later, 50 µl of 3 M HCl was added to stop the reaction. Then, the absorbance of the reaction solution was measured at 490 nm using a spectrophotometer to measure the ICAM-1 expression rate of THP-1 cells by TNF- α and to calculate the expression inhibition rate by the samples [Equations 3, 4]. .
그 결과, 상기 표 2와 같이, 배초향 추출물 또는 용매 분획물이 염증치료제로 공지된 덱사메타손 보다 ICAM-1 발현 억제활성도가 조금 낮게 나타났지만, 특히 헥산 분획물과 클로로포름 분획물에서는 우수한 억제활성을 나타내고 있고, 덱사메타손은 스테로이드 염증제로서 효과는 강력하나 스테로이드 염증제가 장기간 사용시 공통적으로 수반하는 부작용(신장기능 억제, 감염 감수성 증가, 당뇨, 근육위축, 성장저해, 골다공증 등)이 있는 반면에 본 발명에 따른 배초향 추출물 또는 용매분획물은 부작용이 없어 사용시 안전하다.As a result, as shown in Table 2, although the herbaceous extract or solvent fraction showed slightly lower ICAM-1 expression inhibitory activity than dexamethasone, which is known as an inflammatory agent, especially the hexane fraction and chloroform fraction showed excellent inhibitory activity, and dexamethasone Although effective as a steroid inflammatory agent, steroid inflammatory agents have common side effects (inhibition of kidney function, increased susceptibility to infection, diabetes, muscle atrophy, growth inhibition, osteoporosis, etc.), whereas pear inflammatory extract or solvent fraction according to the present invention. Has no side effects and is safe to use.
실시예 4:Example 4: 배초향 추출물 및 용매 분획물의 NO 생성 억제 활성Inhibitory Activity of NOx Extract and Solvent Fraction on NO Production
상기 실시예 1에서 얻은 추출물 및 각 용매 분획물에 대하여 지방다당질(lipopolysaccharide, 이하 LPS)로 활성화를 유도한 쥐 단핵구/대식세포 세포주 RAW264.7(이하 RAW264.7 세포)의 시료에 의한 NO 생성 억제 활성을 조사하였으며 실험 과정은 다음과 같다.Inhibitory activity of NO production by a sample of the mouse mononuclear / macrophage cell line RAW264.7 (hereinafter referred to as RAW264.7 cells) induced activation with lipopolysaccharide (LPS) for the extract obtained in Example 1 and each solvent fraction. The experimental procedure is as follows.
실험은 Sherman 등의 방법[Sherman et al., Biochem. Biophys. Res. Commun. 191, 1301-1308, 1993]을 수정하여 사용하였으며, RAW264.7 세포를 대상으로 NO의 안정한 산화 생성물인 질산이온(NO3 -)의 생성을 측정하고 시료에 의한 생성 억제율을 측정하였다. 덜베코-수정-이글 배지(Dulbecco's Modified Eagle's medium, Gibco BRL, USA, 100 U/㎖ 페니실린, 100 ㎍/㎖ 스트렙토마이신, 10% FBS, 6 g/L HEPES, 3.7 g/L 탄산수소나트륨)에서 배양한 RAW264.7 세포(5 ×105cells/㎖)에 LPS(10 ㎍/㎖)를 첨가하여 활성화를 유도하고, 이산화탄소 항온기(5% 이산화탄소, 95% 상대습도, 37 ℃)에서 48시간 동안 배양하였다. 그런 다음, 배지를 원심분리(1000 rpm, 10 분)하여 얻은 상등액 100 ㎕에 그리스 시약[Griess reagent: 37.5mM 설파닐릭 산(sulphanilic acid), 12.5 mM N-(1-나프틸)에틸렌디아민디하이드로클로라이드[N-(1-naphthyl) ethylenediamine dihydrochloride), 6.5 mM 염산] 100 ㎕를 첨가하여 상온에서 10분간 반응시킨 후 분광광도계를 사용하여 540 nm에서 흡광도를 측정하였다. 이때 0 ∼ 50μM의 농도별로 제조한 질산염을 사용하여 NO3 -농도- 흡광도 상관 계수를 작성한 후 RAW264.7 세포에서 생성된 NO3 -농도를 계산하였다. 상기 실시예 1에서 제조한 시료의 NO 생성 억제 활성 측정은 시료를 DMSO에 녹인 후, RAW264.7 세포에 LPS를 처리하기 2시간 전에 0.1%로 첨가하여 반응 후 NO3 -농도를 측정하여 시료에 의한 NO3 -생성 억제율을 계산하였다[수학식 5, 6].Experiments were performed by Sherman et al. [Sherman et al., Biochem. Biophys. Res. Commun. 191, 1301-1308, 1993] was used, and the production of nitric acid (NO 3 − ), which is a stable oxidation product of NO, was measured in RAW264.7 cells and the inhibition rate of production by the samples was measured. In Dulbecco's Modified Eagle's medium, Gibco BRL, USA, 100 U / ml penicillin, 100 μg / ml streptomycin, 10% FBS, 6 g / L HEPES, 3.7 g / L sodium bicarbonate LPS (10 ㎍ / mL) was added to the cultured RAW264.7 cells (5 × 10 5 cells / mL) to induce activation, and for 48 hours in a carbon dioxide thermostat (5% carbon dioxide, 95% relative humidity, 37 ℃) Incubated. Then, 100 μl of the supernatant obtained by centrifugation (1000 rpm, 10 minutes) of the medium was added to a grease reagent [Griess reagent: 37.5 mM sulfanilic acid, 12.5 mM N- (1-naphthyl) ethylenediaminedihydro. 100 μl of chloride [N- (1-naphthyl) ethylenediamine dihydrochloride, 6.5 mM hydrochloric acid] was added and reacted at room temperature for 10 minutes, and then the absorbance was measured at 540 nm using a spectrophotometer. At this time, by using a nitrate produced by each concentration of 0 ~ 50 μ M NO 3 - concentration - Fill the absorbance coefficient of NO 3 generated by the RAW264.7 cells was calculated the concentration. In the measurement of NO production inhibitory activity of the sample prepared in Example 1, the sample was dissolved in DMSO, and added to 0.1% 2 hours before LPS treatment in RAW264.7 cells to measure NO 3 − concentration after the reaction. Inhibition rate of NO 3 − production was calculated [Equations 5, 6].
그 결과, 다음 표 3과 같이 배초향 농축물과 클로로포름 분획물 및 부탄올 분획에서 강한 NO 생성 억제 활성이 나타남을 확인하였다.As a result, as shown in Table 3, it was confirmed that strong NO production inhibitory activity was observed in the herbaceous concentrate, chloroform fraction and butanol fraction.
실시예 5:Example 5: 배초향 추출물의 카라기난-유도 급성염증 동물모델의 항염증 활성Anti-inflammatory Activity of Carrageenan-Induced Acute Inflammation Animal Model of Seaweed Extract
실험동물은 스프래그-돌리 수컷 쥐(male Sprague-Dawley rats, 210 ∼ 220 g)를 사용하였고 기염제로서는 카라기난을 사용하였으며, 실험동물에 부종을 유도한 후 상기 실시예 1에서 얻은 배초향 추출물에 의한 부종 억제율을 조사하였다. 실험의 자세한 과정은 다음과 같다.The experimental animals used male Sprague-Dawley rats (210-220 g) and used carrageenan as the base agent, and induced by the edible herb extract obtained in Example 1 after inducing edema in the experimental animals. Edema inhibition was investigated. The detailed process of the experiment is as follows.
배초향 추출물을 물에 현탁한 후 마리당 200 ㎎/㎏을 경구투여한 후 1시간 뒤에 카라기난 현탁액(1% carrageenan suspension in 0.85% 식염수) 0.1 ㎖를 실험동물 후지족척에 피하투여하였다. 실험동물은 7마리를 1군으로 하여 투여 직후부터 5시간까지 매시간마다 발바닥 두께를 측정하였으며, 이때 시료 대신에 생리식염수를 투여한 무처리군의 발바닥 두께를 함께 측정하여 시간별 무처리군의 부종 증가에 대한 시료 처리군의 부종 억제율을 조사하였다[수학식 7].After the suspension of the pear herb extract in water, orally administered 200 mg / kg per horse, 0.1 ml of carrageenan suspension (1% carrageenan suspension in 0.85% saline) was subcutaneously administered to the hind limbs. Experimental animals measured the thickness of the sole of each animal every hour from the immediate time of administration to 5 hours after the administration of 1 group. In this case, the thickness of the sole of the untreated group administered with saline instead of the sample was measured together to increase the edema of the untreated group. The rate of inhibition of edema of the sample treatment group was investigated.
그 결과, 다음 표 4와 같이 배초향 추출물은 카라기난-유도 급성염증 동물모델에서 용매투여 2시간 이후부터 매우 강한 항염증 활성을 나타내었으며, 측정한 5시간동안 부종 억제 효과가 지속되었다.As a result, as shown in Table 4, the pear herb extract showed very strong anti-inflammatory activity after 2 hours of solvent administration in the carrageenan-induced acute inflammatory animal model, and the edema inhibitory effect was continued for 5 hours.
실시예 6: 배초향 추출물의 동맥경화성 병변 억제 활성Example 6: Atherosclerotic Lesion Inhibitory Activity of the Herbal Fragrance Extract
상기 실시예 1에서 얻은 추출물의 동맥경화성 병변에 대한 억제 활성을 조사하였다. 실험의 자세한 과정은 다음과 같다.For atherosclerotic lesions of the extract obtained in Example 1 Inhibitory activity was investigated. The detailed process of the experiment is as follows.
(단계 1) 실험동물의 사육과 배초향 추출물의 동물 투여 실험(Step 1) Breeding of experimental animals and experiment of animal administration of pear herb extract
사용한 실험동물은 저밀도 지단백질 수용체 결핍 마우스 6 ∼ 8주령(평균체중 16.8 g) 암컷을 임의로 10마리씩 2그룹으로 나누었다. 한 그룹은 한 고지방 펠릿 사료(15% 지방, 1.25% 콜레스테롤 및 0.5% 소디움콜레이트 함유)를 섭취시켰고, 다른 한 그룹은 상기사료에 배초향 추출물이 0.1% 및 1%되게 섞은 펠릿 사료를 섭취시켰다. 실험기간 중에는 고형사료와 물을 자유롭게 공급하였다.The experimental animals used were divided into two groups of 10 low-density lipoprotein receptor deficient mice 6-8 weeks old (average weight 16.8 g) females. One group consumed one high fat pellet feed (containing 15% fat, 1.25% cholesterol and 0.5% sodium cholate), and the other group received a pellet feed mixed with 0.1% and 1% pear extract. During the experiment, solid feed and water were freely supplied.
(단계 2) 실험동물의 동맥경화성 병변의 측정(Step 2) Measurement of Atherosclerotic Lesions in Experimental Animals
실험 개시 8주 후에 모든 마우스에서 안구를 통한 채혈을 실시하였다. 이 후 이 마우스의 심장과 동맥을 인산완충용액(PBS)으로 10분간 관류를 하였고 다시 5분간 파라포름알데하이드로 관류하였다. 이러한 과정이 끝난 심장과 동맥을 떼어내고 10% 중성 포르말린에 24시간 담근 후 오씨티 배양액[OCT medium, 10.24% polyvinyl alcohol, 4.26% polyethylene glycol, 80.5% nonreactive ingredient, w/w, Life Science International, England, UK]으로 포매하였고 -70 ℃에서 냉동보관하였다. 냉동된 조직 절편을 -20 ℃가 유지되는 절편기를 이용하여 심장판막이 보이는 동맥부분을 기시점으로 하여 심장부분으로 9 ㎛씩 6장의 절편을 제조한 후, 염색약 오일 레드 O(Oil red O)로 염색하고 해리스 헤마토실린으로 카운터염색을 수행하였다. 염색된 절편을 이미지 분석기를 사용하여 각 동물 그룹의 평균 병변의 면적를 측정하여, 무처리군의 병변 발생에 대한 배초향추출물 처리군의 병변 억제 활성을 계산하였다[수학식 8].Eight weeks after the start of the experiment, all mice underwent ocular blood collection. Thereafter, the heart and arteries of the mouse were perfused with phosphate buffer solution (PBS) for 10 minutes and then perfused with paraformaldehyde for 5 minutes. After this procedure, the heart and arteries are removed and soaked in 10% neutral formalin for 24 hours, followed by OCT medium [OCT medium, 10.24% polyvinyl alcohol, 4.26% polyethylene glycol, 80.5% nonreactive ingredient, w / w, Life Science International, England , UK] and frozen at -70 ° C. The frozen tissue sections were prepared using a slicer maintained at −20 ° C., and 6 sections of 9 μm were prepared from the artery with visible heart valves at the starting point, and then stained with dye red O (Oil red O). Staining and counterstaining were performed with Harris hematocillin. Stained sections were measured using an image analyzer to measure the average lesion area of each animal group, and the lesion inhibition activity of the herbaceous extract-treated group against the development of the untreated group was calculated (Equation 8).
그 결과, 배초향 추출물을 첨가한 처리군은 8주의 실험 기간동안 무처리군과 비교할 때 섭취량 및 체중의 변화가 전혀 나타나지 않았다[표 5].As a result, the treated group to which the pear extract was added did not show any change in intake and body weight in comparison with the untreated group during the 8-week experimental period [Table 5].
또한, 배초향 추출물의 동맥경화성 병변에 대한 억제 효과에서는, 0.1% 및 1%의 배초향 추출물을 함유한 사료를 섭취한 실험군이 무처리군에 비하여 병변 크기가 각각 23.% 및 46.6% 감소한 결과를 나타내었다[표 6]. 그리고, 심장동맥의 단면 조직을 염색한 결과, 염증 반응에 의한 병변(괴사조직)의 크기가 무처리군에 비하여 1% 배초향 추출물 처리군은 현저하게 감소되었음이 관찰되었으며[도 1], 병변 조직의 대식세포만을 염색한 경우 1% 배초향 추출물 처리군은 무처리군보다 대식세포가 집적도가 현저하게 감소되었음을 확인하였다[도 2].In addition, the inhibitory effect on the atherosclerotic lesions of the herbaceous extract showed that the experimental group fed the feed containing 0.1% and 1% of the herbaceous extract showed 23.% and 46.6% reduction in lesion size compared to the untreated group, respectively. [Table 6]. In addition, as a result of staining the cross-sectional tissue of the coronary artery, it was observed that the size of the lesion (necrotic tissue) caused by the inflammatory response was significantly reduced in the 1% pear-flavored extract treated group compared to the untreated group [FIG. 1]. In the case of staining only macrophages of 1% baechuyang extract treatment group was confirmed that the density of macrophages significantly reduced than the untreated group [Fig. 2].
따라서, 동맥 내피세포 아래에서 대식세포 등 면역세포의 집적 및 염증반응으로 동맥경화성 병변이 발달하는 과정에서 배초향 추출물은 항염증 활성으로 병변의 발달을 현저하게 감소시키는 사실을 확인하였다.Therefore, it was confirmed that the herbaceous extract significantly reduced the development of the lesions due to anti-inflammatory activity during the development of atherosclerotic lesions due to the accumulation and inflammation of immune cells such as macrophages under the endothelial cells.
실시예 7 : 배초향 추출물 함유 정제의 제조Example 7: Preparation of Pear Extract
배초향 추출물 10 g10 g of pear fennel extract
락토스 70 g70 g of lactose
결정성 셀룰로오스 15 g15 g of crystalline cellulose
마그네슘 스테아레이트 5 g5 g of magnesium stearate
총 량 100 gTotal amount 100 g
상기에서 나열된 성분들을 잘게 부숴 혼합한 후 직타법(direct tableting method)에 의해 정제를 제조하였다. 각 정제의 총량은 100 ㎎이고, 그 중 배초향 추출물 성분의 함량은 10 ㎎이다.The tablets were prepared by direct tableting method after mixing the ingredients listed above finely. The total amount of each tablet was 100 mg, of which the content of the herbaceous extract component was 10 mg.
실시예 8 : 배초향 추출물 함유 분말제의 제조Example 8 Preparation of Pearweed Extract-Containing Powder
배초향 추출물 10 g10 g of pear fennel extract
옥수수 전분 50 g50 g of corn starch
카르복시 셀룰로오스 40 g40 g of carboxy cellulose
총 량 100 gTotal amount 100 g
상기에 나열된 성분들을 잘게 부숴 혼합하여 분말을 제조하였으며, 6 번 경질 캡슐에 분말 100 ㎎을 넣어 캡슐제를 제조하였다.A powder was prepared by crushing and mixing the ingredients listed above, and a capsule was prepared by putting 100 mg of powder into a 6 times hard capsule.
실시예 9: 독성시험Example 9: Toxicity Test
본 발명의 배초향 추출물에 대하여 독성실험을 다음과 같이 수행하였다. 구체적으로 상기 추출물을 디메틸설폭사이드(dimethylsulfoxide, 이하 DMSO)에 용해하고 물로 희석한 후 이를 마우스(군당 10마리)에 각각 1 g/㎏을 투여한 다음 7일간 관찰하였으나 사망하는 쥐는 없었다.Toxicity experiments were performed for the pear herb extract of the present invention as follows. Specifically, the extract was dissolved in dimethylsulfoxide (DMSO), diluted with water, and then administered to each mouse (10 mice per group) 1 g / kg and observed for 7 days, but no rats died.
실시예 10 : 배초향 추출물 함유 음료 조성물Example 10: Beverage Composition Containing Pear Herbal Extract
배초향 추출물 함유 음료 조성물에 사용된 성분들로 매실 추출물(매실농축물(고형분량 69oBx), 제조원: 하동 농업협동조합), 모과·당귀·건강·오미자·계피(서울 경동시장), 포도과즙(제조원: 코맥스(Comax international corp.), 고형분량 65oBx) 및 배과즙(제조원: 한미 향료화학(주), 고형분량 69oBx)을각각 구입하여 준비하였다.Ingredients used in beverage compositions containing pear flavour extracts are plum extract (plum concentrate (solid amount 69 o Bx), manufacturer: Hadong Agricultural Cooperative), quince, donkey, health, Schisandra chinensis (Seoul Kyungdong Market), grape juice (Manufacturer: Comax international corp., Solid content 65 o Bx) and pear juice (manufacturer: Hanmi Spice Chemical Co., Ltd., solid content 69 o Bx) were purchased and prepared respectively.
먼저, 생약재인 모과, 당귀, 건강, 오미자, 계피 각각은 10 중량배의 물을 첨가한 후, 100 ℃에서 30분간 열수 추출하였다. 이를 4 ℃에서 24시간 동안 방치하고 10,000 ×g에서 10분간 원심분리한 후 상등액을 취하여 생약재 추출물을 수득하여 사용하였다.First, the Chinese herbal medicine, Chinese Angelica, Angelica, Health, Schisandra chinensis, and Cinnamon, each added 10 wt. Times of water, and then hot water extracted at 100 ° C. for 30 minutes. This was allowed to stand at 4 ° C. for 24 hours, centrifuged at 10,000 × g for 10 minutes, and the supernatant was taken to obtain an herbal extract.
또한, 매실 추출물은 상기 매실농축물(69oBx)을 10oBx로 희석한 액을 사용하였으며, 포도과즙(65oBx)과 배과즙(69oBx)은 원액을 그대로 사용하였다.In addition, the plum extract was used to dilute the plum concentrate (69 o Bx) to 10 o Bx, grape juice (65 o Bx) and pear juice (69 o Bx) was used as the stock solution.
배초향 추출물 함유 음료 조성물로서는 배초향 추출물 0.1%, 매실 추출물 0.2%, 건강 추출물 0.3%, 당귀 추출물 0.3%, 계피 추출물 0.01%, 배과즙 5.0%, 고과당 17%를 사용하였으며 이들을 물에 희석하여 총 100 ㎖로 맞춘 후 95 ℃에서 15초간 살균, 냉각하여 드링크 타입의 음료 제품을 제조하였다.The beverage composition containing pear scent extract was used 0.1% pear extract, plum extract 0.2%, health extract 0.3%, Angelica extract 0.3%, cinnamon extract 0.01%, pear juice 5.0%, high fructose 17% and diluted them in water. After adjusting to ㎖ and sterilized for 15 seconds at 95 ℃, cooled to prepare a drink-type beverage product.
이상에서 상술한 바와 같이, 본 발명에 따른 배초향 추출물 및 용매분획물은 다양한 염증인자의 활성화, 생성 및 발현을 억제하며 동물모델에서도 항염증 활성을 나타내고 항염증 활성에 근거한 동맥경화 병변의 발생을 현저하게 억제하는 활성을 나타내므로 염증질환, 염증반응과 관련된 동맥경화 및 이로 인한 순환기 질환의 예방 및 치료 용도의 의약품 또는 식품첨가제로 유용하다.As described above, the herbaceous extract and solvent fraction according to the present invention inhibits the activation, production and expression of various inflammatory factors, exhibits anti-inflammatory activity in animal models, and significantly increases the occurrence of atherosclerotic lesions based on anti-inflammatory activity. Since it exhibits inhibitory activity, it is useful as a pharmaceutical or food additive for the prevention and treatment of inflammatory diseases, arteriosclerosis associated with inflammatory reactions and the resulting circulatory diseases.
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| US8019692B2 (en) | 2004-10-19 | 2011-09-13 | Yahoo! Inc. | System and method for location based social networking |
| KR20200078854A (en) * | 2018-12-24 | 2020-07-02 | 영농조합법인 부일식품 | Method for producing Agastache rugosa dry flower with increased acacetin and tilianin content and Agastache rugosa dry flower produced by the same method |
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