KR101959731B1 - A composition for preventing or treating menopausal disorder comprising extract from young barley leaves - Google Patents
A composition for preventing or treating menopausal disorder comprising extract from young barley leaves Download PDFInfo
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- KR101959731B1 KR101959731B1 KR1020170073728A KR20170073728A KR101959731B1 KR 101959731 B1 KR101959731 B1 KR 101959731B1 KR 1020170073728 A KR1020170073728 A KR 1020170073728A KR 20170073728 A KR20170073728 A KR 20170073728A KR 101959731 B1 KR101959731 B1 KR 101959731B1
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
- A61K36/8998—Hordeum (barley)
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/302—Foods, ingredients or supplements having a functional effect on health having a modulating effect on age
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/306—Foods, ingredients or supplements having a functional effect on health having an effect on bone mass, e.g. osteoporosis prevention
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Abstract
본 발명은 상기 새싹보리 추출물 또는 이의 분획물을 포함하는 갱년기 장애의 예방 또는 치료용 약학 조성물, 상기 약학 조성물을 투여하는 단계를 포함하는 갱년기 장애의 예방 또는 치료 방법, 및 상기 추출물 또는 이의 분획물을 포함하는 식품 조성물에 관한 것이다. 본 발명의 새싹보리 추출물은 골 항상성 장애를 대표하는 골다공증을 개선시키는 효과와 여성호르몬 분비를 조절하는 에스트로겐 수용체의 발현 촉진 활성을 보이므로, 상기 증상을 포함하는 갱년기 장애의 예방, 개선 또는 치료를 위한 또는 식품 및 의약품 등에 이용될 수 있다.The present invention relates to a pharmaceutical composition for preventing or treating a menopausal disorder comprising the above-mentioned germanium barley extract or a fraction thereof, a method of preventing or treating a menopausal disorder comprising administering the pharmaceutical composition, and a method for preventing or treating menopausal disorders comprising the extract or a fraction thereof ≪ / RTI > The germanium barley extract of the present invention exhibits an effect of improving osteoporosis, which is a bone homeostatic disorder, and an estrogen receptor-promoting activity of regulating female hormone secretion. Therefore, the present invention provides a method for preventing, ameliorating or treating a menopausal disorder Or foods and medicines.
Description
본 발명은 새싹보리 추출물을 포함하는 갱년기 장애의 예방 또는 치료용 조성물에 관한 것으로, 보다 구체적으로 본 발명은 상기 새싹보리 추출물 또는 이의 분획물을 포함하는 갱년기 장애의 예방 또는 치료용 약학 조성물, 상기 약학 조성물을 투여하는 단계를 포함하는 갱년기 장애의 예방 또는 치료 방법, 및 상기 추출물 또는 이의 분획물을 포함하는 식품 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating a menopausal disorder, which comprises a bud of a bud, and more specifically, the present invention relates to a pharmaceutical composition for preventing or treating a menopausal disorder comprising the bud of the bud or extract thereof, A method for preventing or treating menopausal disorders, and a food composition comprising the extract or a fraction thereof.
폐경이 나타난 이후의 약 1년까지를 폐경이행기, 더 흔히는 갱년기라고 하며 그 기간은 일반적으로 평균 4~7년 정도이다. 대한폐경학회에 따르면 우리나라 50대 여성 중 약 89%가 갱년기 증상을 겪는다. 폐경은 포도당 대사, 지질 대사, 골 항상성 및 에너지 대사에 대한 장애를 나타내며(Tiano and Mauvais-Jarvis, 2012; Wildman and Sowers, 2011), 이로 인해 폐경기 여성에서 구체적으로 안면홍조, 발한, 비뇨생식기계의 위축에 따른 증상(질 건조감, 반복적인 질 감염과 요로계 감염으로 인한 질염, 방광염, 배뇨통, 급뇨), 정신적 불안정(집중장애 및 단기 기억장애, 불안과 신경과민, 기억력 감소), 피부관절계 변화(피부 건조와 위축, 근육통, 관절통), 골다공증의 진행으로 인한 골절의 증가, 체질량지수(BMI)의 증가 등과 같은 갱년기 장애가 발생할 수 있다. Up to about one year after menopause is called menopausal transition, more commonly menopause, and the period is generally about 4-7 years. According to the Korean Society of Postmenopause, about 89% of Korean women in their 50s experience menopausal symptoms. Menopause appears to be a disorder of glucose metabolism, lipid metabolism, bone homeostasis, and energy metabolism (Tiano and Mauvais-Jarvis, 2012; Wildman and Sowers, 2011) (Vaginal dryness, repeated vaginal infections and urinary tract infection due to urinary tract infections, cystitis, dysuria, and urination), mental instability (intensive and short-term memory impairment, anxiety and nervous irritation, decreased memory) Dryness and atrophy, myalgia, arthralgia), increase in fractures due to progression of osteoporosis, increase in body mass index (BMI), and the like.
합성에스트로겐 호르몬제제의 투여는 이러한 장애들을 일부 해결할 수 있다고 알려져 있으나, 유방암, 자궁 내막암의 위험을 증가시키는 부작용이 있어 문제가 되고 있다. 이에 따라, 이소플라본, 플라보노이드, 리그난 등의 에스트로겐과 기능 및 구조가 유사한 식물 유래의 천연 에스트로겐인 피토에스트로겐(phytoestrogen)에 대한 관심이 높아지고 있다. 또한, 상기 이소플라보노이드와 같은 천연 화합물이 선택적 에스트로겐 수용체 조절제로 작용한다는 증거가 늘어감에 따라 갱년기 장애를 예방, 개선 및 치료하기 위한 후보 물질로서 천연 약초에 대한 연구가 활발히 진행되어, 여성 갱년기장애 개선에 효과를 갖는 홍삼 복합물 조성물(한국공개특허 10-2006-0061323) 등이 개발된 바 있다. 그러나, 그들의 효능은 여전히 확신할 수 없는 실정이다(Cano et al., 2008; Somjen et al., 2008).The administration of synthetic estrogen hormone preparations is known to solve some of these disorders, but it is problematic because of the side effects that increase the risk of breast cancer and endometrial cancer. Accordingly, phytoestrogen, which is a plant-derived natural estrogen similar in function and structure to estrogen such as isoflavones, flavonoids and lignans, is increasingly attracted. In addition, as evidence that natural compounds such as isoflavonoids act as selective estrogen receptor modulators, studies on natural herbs as a candidate substance for preventing, ameliorating, and treating menopausal disorders have been actively conducted, (Korean Patent Laid-Open No. 10-2006-0061323) and the like have been developed. However, their efficacy remains uncertain (Cano et al., 2008; Somjen et al., 2008).
따라서, 갱년기 여성에 있어서 상기 조절제와 같은 활성을 지니면서도, 갱년기 장애를 개선하는 피토에스트로겐을 포함하는 새로운 식물을 발굴하기 위한 연구가 절실하다. 그러나 갱년기 장애는 에스트로겐 분비 감소로 인한 포도당 대사, 지질 대사, 골 항상성 및 에너지 대사에 대한 복합적 장애를 포함하는 것이므로, 이 중 하나의 장애를 개선하더라도 다른 장애를 개선하는 효과가 나타나지 않는다면 전반적인 갱년기 장애 개선 효과를 기대할 수 없다는 문제가 있었다.Therefore, there is a desperate need to find new plants containing phytoestrogens that have the same activity as the above-mentioned modulators in menopausal women, but also improve menopausal disorders. However, since menopausal disorders include multiple disorders of glucose metabolism, lipid metabolism, bone homeostasis, and energy metabolism due to decreased estrogen secretion, if one of these disorders is ameliorated but does not improve other disorders, the overall menopausal disorder There is a problem that the effect can not be expected.
한편, 보리잎은 예전부터 약제로 사용되어 왔고, 비타민, 효소, 엽록소 등의 영양소가 풍부한 것으로 알려져 왔다. 최근에는, 보리에 함유되어있는 우수한 영양성분과 건강 기능성 물질의 다이어트 균형식,체질개선 등에 대한 효과가 알려지면서, 건강 기능성 원료 작물로서의 관심이 증대되고 있으며, 가축사료용 등으로도 우수한 평가를 받고 있다.On the other hand, barley leaves have long been used as medicines and have been known to be rich in nutrients such as vitamins, enzymes and chlorophyll. In recent years, interest in health functional raw material crops has been increasing, and it has been appreciated for livestock feeds and the like, as the effect of excellent nutritional ingredients contained in barley, a balanced diet of health functional substances, and improvement of constitution are known.
새싹보리는 보리에 싹을 틔워 약 15cm정도 자란 어린 식물체를 지칭하는데, 대체로 보리를 하루정도 물에 불린 후, 물기를 빼고 적당한 크기의 플라스틱 바구니나 스티로폼에 신문지 등을 깔고 보리를 파종하여, 싹이 날 때까지 종이로 덮어 두었다가 싹이 틔면 제거하고 수분을 유지하면서 7-10일 정도 지나서 l5cm크기가 되면 이를 사용하게 된다. 상기 새싹보리에는 식물섬유, 카로틴, 비타민C 등이 다른 채소 및 과일에 비하여 월등히 높은 함량으로 포함되어 있다고 알려져 있다. 뿐만 아니라, 약리활성의 측면에서 상기 새싹보리는 콜레스테롤 저하, 변비 예방, 동맥경화 예방, 항산화활성, 노화 방지, 골다공증 예방, 불면증 개선, 빈혈 예방 등의 효과를 나타낸다고 알려져 있다(장기창 및 강항원, 새싹보리의 영양학적 가치와 항산화, 항암, 항당뇨 및 미백 효과에 관한 연구, 지구촌 식품과 음식문화, 2010; 한국특허등록 제1174497호; 한국특허공개 제2013-0051181호). 특히, 새싹보리에 포함된 루테오린은 항산화제로 알려진 비타민C, 제니스테인 등에 비하여 월등히 우수한 항산화 활성을 나타낸다고 알려져 있고, 루테오린은 당뇨병 치료제인 아카보스보다 월등히 우수한 항당뇨 활성을 나타낸다고 알려져 있다. 그러나, 상기 새싹보리의 갱년기 장애에 대한 효과는 밝혀진 바 없다.A barley is a young plant that grows about 15cm in length and has been sprinkled on a barley for about a day. The barley is usually called water for a day, then drained and laid on a suitable size plastic baskets or styrofoam newspapers, It is covered with paper until it is blossomed, and if it shoots, it is removed after 7-10 days when it is removed and the moisture is retained. It is known that the germinated barley contains vegetable fiber, carotene, vitamin C and the like in a much higher content than other vegetables and fruits. In addition, from the viewpoint of pharmacological activity, it is known that the above-mentioned shoot barley has effects of cholesterol lowering, prevention of constipation, prevention of arteriosclerosis, antioxidant activity, prevention of aging, prevention of osteoporosis, improvement of insomnia and prevention of anemia Antioxidant, anticancer, anti-diabetic and whitening effect, Global Food and Food Culture, 2010; Korean Patent Registration No. 1174497; Korean Patent Publication No. 2013-0051181). In particular, it is known that rutheorin contained in the bud of barley has remarkably superior antioxidant activity than vitamin C and genistein, which are known as antioxidants, and rhetherin is known to exhibit superior antidiabetic activity than acabos, which is a treatment for diabetes, However, the effect on the menopausal disorders of the barley barley has not been disclosed.
이러한 배경하에, 본 발명자들은 천연 약초를 이용하여 갱년기 장애를 개선하기 위한 방법을 개발하고자 예의 연구 노력한 결과, 새싹보리 추출물이 포도당 대사 장애, 지질 대사 장애, 골 다공증, 에너지 대사 장애 등을 포함하는 폐경기 또는 갱년기 장애를 예방 또는 개선할 수 있음을 확인하고 본 발명을 완성하였다.Under these circumstances, the present inventors have made extensive efforts to develop a method for improving menopausal disorders using natural herbs. As a result, the present inventors have found that the extract of bud from barley extract contains glucose metabolism disorder, lipid metabolism disorder, osteoporosis, And can prevent or ameliorate menopausal or menopausal disorders, thus completing the present invention.
본 발명의 하나의 목적은 새싹보리 추출물 또는 이의 분획물을 포함하는 갱년기 장애의 예방 또는 치료용 약학 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for preventing or treating a menopausal disorder comprising a germanium barley extract or a fraction thereof.
본 발명의 다른 하나의 목적은 상기 약학 조성물을 인간을 제외한 개체에 투여하는 단계를 포함하는 갱년기 장애의 예방 또는 치료 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating a menopausal disorder, which comprises administering the pharmaceutical composition to a subject other than a human.
본 발명의 또 다른 하나의 목적은 새싹보리 추출물 또는 이의 분획물을 포함하는 갱년기 장애의 예방 또는 개선용 식품 조성물을 제공하는 것이다.It is another object of the present invention to provide a food composition for preventing or ameliorating a menopausal disorder comprising a germanium barley extract or a fraction thereof.
상기 목적을 달성하기 위한 일 실시양태로서, 본 발명은 새싹보리 추출물 또는 이의 분획물을 포함하는 갱년기 장애의 예방 또는 치료용 약학 조성물을 제공한다.In one aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a menopausal disorder, which comprises a bud or a barley extract or a fraction thereof.
본 발명의 새싹보리 추출물은 RANKL에 의해 유도된 파골세포 분화를 억제하고, TRAP 활성 억제하며, 이러한 억제효과가 세포독성에 의하여 나타나는 것이 아님을 확인하였다. 따라서, 본 발명에서 제공하는 새싹보리 추출물은 골다공증, 여성호르몬 분비 장애, 비만, 홍조 등의 다양한 증상을 나타내는 갱년기 장애를 예방, 치료 또는 개선하는데 사용될 수 있다.The inventive shoot barley extract inhibited osteoclast differentiation induced by RANKL, inhibited TRAP activity, and confirmed that this inhibitory effect was not caused by cytotoxicity. Therefore, the germanium barley extract provided in the present invention can be used to prevent, treat or ameliorate menopausal disorders showing various symptoms such as osteoporosis, female hormone secretion disorder, obesity, flushing, and the like.
본 발명의 용어 "새싹보리"란, 보리에 싹을 틔워 약 15 내지 20cm정도 자란 어린 식물체를 의미한다. 통상적으로, 상기 새싹보리는 보리를 하루정도 물에 침지한 후, 수분을 제거하고, 수분의 손실을 방지한 조건에서 실내 재배의 경우 파종하여 발아시킨 다음, 7 내지 10일 동안 성장시켜서 수득할 수 있다.The term "sprout barley" of the present invention means a young plant which has grown on barley to about 15 to 20 cm. Normally, the barley is obtained by dipping the barley in water for one day, then removing water, and germinating in the case of indoor cultivation under the condition of preventing loss of water, and then growing it for 7 to 10 days have.
본 발명에 있어서, 상기 새싹보리의 추출물은 골다공증, 여성호르몬 분비 감소 등을 치료하는 효과를 나타낼 수 있으므로, 골다공증, 여성호르몬 분비 장애, 비만, 홍조 등의 다양한 증상을 나타내는 갱년기 장애를 예방, 치료 또는 개선하는데 사용될 수 있다.In accordance with the present invention, the extract of Sprout Barley can exhibit an effect of treating osteoporosis, reduction of female hormone secretion, and the like. Therefore, it is possible to prevent, treat, or prevent menopausal disorders that show various symptoms such as osteoporosis, female hormone secretion disorder, obesity, Can be used to improve.
본 발명의 용어 "추출물"이란, 목적하는 물질을 다양한 용매에 침지한 다음, 상온 또는 가온상태에서 일정시간 동안 추출하여 수득한 액상성분, 상기 액상성분으로부터 용매를 제거하여 수득한 고형분 등의 결과물을 의미한다. 뿐만 아니라, 상기 결과물에 더하여, 상기 결과물의 희석액, 이들의 농축액, 이들의 조정제물, 정제물 등을 모두 포함하는 것으로 포괄적으로 해석될 수 있다.The term "extract " of the present invention means a liquid substance obtained by immersing a desired substance in various solvents and then extracting the substance at room temperature or a constant temperature for a certain period of time, a solid matter obtained by removing the solvent from the liquid substance, it means. In addition, in addition to the above-mentioned results, the present invention can be broadly interpreted to include all of the diluted solution, the concentrated solution thereof, the adjusted product thereof, and the purified product.
본 발명에 있어서, 상기 추출물은 새싹보리 추출물을 의미한다. 상기 새싹보리 추출물은 상기 새싹보리의 식물전체, 이의 건조물, 가공물 등을 단독으로 또는 조합하여, 물 또는 다양한 유기용매 등으로 추출하여 수득할 수 있다. 이때, 사용되는 유기용매는 특별히 이에 제한되지 않으나, 바람직하게는 물, 극성용매 또는 비극성용매가 될 수 있고, 보다 바람직하게는 물, 탄소수 1 내지 4의 저급 알코올(메탄올, 에탄올, 주정, 프로판올 또는 부탄올 등), 이들의 혼합용매 등이 될 수 있으며, 가장 바람직하게는 에탄올 또는 그의 혼합용매를 사용할 수 있다. 또한, 상기 추출물을 수득하기 위한 방법 역시 특별히 이에 제한되지 않으나, 바람직하게는 상기 새싹보리의 식물전체, 이의 건조물, 가공물 등을 상기 용매에 침지하고, 10 내지 25℃의 상온에서 추출하는 냉침추출법, 40 내지 100℃로 가열하여 추출하는 가열추출법, 초음파를 가하여 추출하는 초음파추출법, 환류냉각기를 이용한 환류추출법 등의 방법을 사용할 수 있다.In the present invention, the above-mentioned extract means a barley extract. The above-mentioned germanium barley extract can be obtained by extracting the entire plant of the above-mentioned germanium bar, the dried product thereof, the processed product thereof, etc., alone or in combination thereof, with water or various organic solvents. The organic solvent may be water, a polar solvent or a nonpolar solvent, more preferably water, a lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, alcohol, propanol or the like) Butanol, etc.), mixed solvents thereof, etc., and most preferably, ethanol or a mixed solvent thereof can be used. Also, the method for obtaining the above extract is not particularly limited. However, it is preferable to use a cold extraction method in which the whole plant of the above-mentioned shoot barley, the dried product thereof, the processed product thereof and the like are dipped in the solvent and extracted at a room temperature of 10 to 25 ° C, A heating extraction method in which heating is carried out at 40 to 100 ° C, an ultrasonic extraction method in which ultrasonic waves are applied to the extraction, and a reflux extraction method using a reflux condenser.
본 발명의 용어 "분획물"이란, 다양한 구성성분을 포함하는 혼합물로부터 특정성분 또는 특정 그룹을 분리하는 분획방법에 의하여 얻어진 결과물을 의미한다.The term "fraction " of the present invention means a product obtained by a fractionation method for separating a specific component or a specific group from a mixture containing various constituents.
본 발명에 있어서, 상기 분획물은 상기 새싹보리 추출물을 다양한 분획방법에 적용하여 수득한 분획물로 해석될 수 있다. 상기 추출물의 분획물은 상기 추출물을 다양한 분획방법에 적용하여 수득할 수 있는데, 상기 분획방법은 특별히 이에 제한되지 않으나, 다양한 용매를 처리하여 수행하는 용매 분획법, 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 수행하는 한외여과 분획법, 다양한 크로마토그래피(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)를 수행하는 크로마토그래피 분획법 등이 될 수 있다. 특히, 상기 용매 분획법에 사용되는 용매는 특별히 이에 제한되지 않으나, 극성 용매 또는 비극성 용매를 사용할 수 있고, 바람직하게는 비극성 용매를 사용할 수 있다. 상기 용매 분획법은 비극성 수준이 높은 용매로부터 낮은 용매를 사용하여 상기 추출물을 순차적으로 분획하는 방식으로 수행될 수 있는데, 예를 들어 헥산 또는 에틸아세테이트를 이용하여 상기 추출물을 순차적으로 분획하는 방법을 사용할 수 있다.In the present invention, the fractions can be interpreted as fractions obtained by applying the germanium barley extract to various fractionation methods. The fraction of the extract can be obtained by applying the extract to various fractionation methods. The fractionation method is not particularly limited, but may be a solvent fractionation method which is carried out by treating various solvents, an ultrafiltration membrane having a constant molecular weight cut- , A chromatographic fractionation method in which various chromatographies (which are prepared for separation according to size, charge, hydrophobicity or affinity) are performed, and the like. In particular, the solvent used in the solvent fractionation method is not particularly limited, but a polar solvent or a nonpolar solvent can be used, and a nonpolar solvent can be preferably used. The solvent fractionation method may be carried out by sequentially fractionating the extract from a solvent having a high non-polarity level by using a low solvent. For example, a method of sequentially fractionating the extract using hexane or ethyl acetate may be used .
상기 새싹보리의 추출물 또는 그의 분획물은 상기 루토나린 또는 사포나린 이외의 다양한 화합물을 포함한다. 상기 새싹보리의 추출물 또는 그의 분획물에 포함된 화합물로는 사포나린, 루토나린, 3-FQA(3-O-Feruloylquinic acid), 이소오리엔틴(isoorientin), 루테올린-8-글루코시드(Luteolin-8-glucoside), 오리엔틴(Orientin), 이소비텍신(Isovitexin), 이소스코파린-7-O-[6-시나포일]-글루코시드(Isoscoparin-7-O-[6-sinapoyl]-glucoside), 이소스코파린-7-O-[6-페룰로일]-글루코시드(Isoscoparin-7-O-[6-feruloyl]-glucoside), 이소비텍신-7-O-[6-시나포일]-글루코시드(Isovitexin-7-O-[6-sinapoyl]-glucoside), 이소비텍신-7-O-[6-페룰로일]-글루코시드(Isovitexin-7-O-[6-feryloyl]-glucoside) 등을 들 수 있다.The extract or fraction thereof of the barley barley contains various compounds other than the above-mentioned lutonin or saponin. Examples of the compound contained in the extract or fraction thereof include saponin, 3-FQA (3-O-feruloylquinic acid), isoorientin, luteolin-8-glucoside -glucoside, Orientin, Isovitexin, isoscoparin-7-O- [6-cinapoyl] -glucoside, 7-O- [6-feruloyl] -glucoside, isovopressin-7-O- [6-cyapholyl] -glucoside Isovitexin-7-O- [6-sinapoyl] -glucoside, isoviticin-7-O- [6-feryloyl] -glucoside, And the like.
본 발명의 용어 "갱년기 장애"란, 월경이 중단되는 시기인 갱년기에 생기는 다양한 이상 증상들을 나타내는 질환을 의미하며, 대체로 난소의 기능이 노화로 인해 저하되어 여성호르몬을 적게 내기 때문에 몸속에 호르몬의 불균형이 일어나 생기게 된다. 상기 갱년기 장애는 에스트로겐 분비 감소로 인한 증상을 나타내며, 상기 증상은 포도당 대사 장애, 지질 대사 장애, 골 항상성 장애 및 에너지 대사 장애로 이루어지는 군에서 선택되는 1종 이상의 증상을 포함하지만, 이에 제한되는 것은 아니다. 구체적인 예로, 상기 포도당 대사 장애 및 상기 지질 대사 장애를 대표하는 증상으로는 비만; 상기 골 항상성 장애를 대표하는 증상으로는 골다공증; 및 상기 에너지 대사 장애를 대표하는 증상으로는 홍조를 들 수 있지만, 이에 제한되는 것은 아니며, 더욱 구체적인 예로 상기 갱년기 장애는 골다공증, 홍조 또는 그의 조합인 것일 수 있다.The term "menopausal disorder" of the present invention means a disease that manifests various abnormal symptoms occurring during the menopausal period when the menstruation is interrupted. In general, ovarian function is lowered due to aging and less female hormone, This is what happens. The menopausal disorder is indicative of a symptom due to decreased estrogen secretion, and the symptoms include, but are not limited to, one or more symptoms selected from the group consisting of glucose metabolism disorders, lipid metabolism disorders, bone homeostatic disorders and energy metabolism disorders . As a specific example, the symptoms representative of the glucose metabolism disorder and the lipid metabolism disorder include obesity; Symptoms that represent the bone homeostatic disorder include osteoporosis; And symptoms indicative of the energy metabolism disorder include, but are not limited to, flushing, and more specifically, the menopausal disorder may be osteoporosis, flushing, or a combination thereof.
본 발명의 일 실시예에 의하면, 본 발명의 새싹보리 추출물은 RANKL에 의해 유도된 파골세포의 마커인 TRAP의 발현을 감소시킬 뿐만 아니라(도 1), TRAP의 활성 자체를 농도의존적으로 감소시키고(도 2), 이러한 효과는 세포독성에 의한 것이 아님을 확인하였다.According to one embodiment of the present invention, the shoot barley extract of the present invention not only reduces the expression of TRAP, which is a marker of osteoclast induced by RANKL (Fig. 1), decreases the activity of TRAP itself in a concentration-dependent manner Figure 2), confirming that this effect is not due to cytotoxicity.
상기 결과로부터, 새싹보리 추출물은 파골세포의 분화를 억제하여, 골 항상성 장애를 대표하는 골다공증을 개선시키는 효과를 나타냄을 알 수 있었다. From the above results, it was found that the bud of the buds inhibited the differentiation of osteoclasts and improved the osteoporosis which is representative of bone homeostatic disorder.
또한, 새싹보리 추출물은 에스트로겐 수용체를 과다하게 발현시키는 것으로 알려진 암세포주에서 에스트로겐 수용체 알파, 베타를 활성화하여 여성호르몬 분비를 촉진하는 효과를 나타냄을 알수 있었다.In addition, it was found that the extract of bud of barley extract promotes female hormone secretion by activation of estrogen receptor alpha and beta in a cancer cell line known to overexpress the estrogen receptor.
따라서, 상기 증상을 포함하는 갱년기 장애의 예방, 개선 또는 치료를 위한 또는 식품 및 의약품 등에 이용될 수 있을 것으로 분석되었다.Therefore, it has been analyzed that it can be used for the prevention, improvement or treatment of the menopausal disorders including the above symptoms, or for foods and medicines.
본 발명의 용어, "예방"이란, 본 발명의 새싹보리 추출물 또는 이의 분획물을 포함하는 약학 조성물의 투여에 의해 갱년기 장애를 억제시키거나 또는 지연시키는 모든 행위를 의미한다.The term "prevention" of the present invention means any action that inhibits or delays a menopausal disorder by administration of a pharmaceutical composition comprising the bud or extract of the present invention or a fraction thereof.
본 발명의 용어, "치료"란, 상기 약학 조성물의 투여에 의해 갱년기 장애가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term "treatment" of the present invention means all the actions that the administration of the pharmaceutical composition improves or alters the menopausal disorder.
본 발명의 약학 조성물은 총 조성물의 중량 대비 갱년기 장애 0.0001 내지 50 중량%로 포함할 수 있으며, 구체적으로 0.01 중량% 내지 10 중량%로 포함할 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition of the present invention may contain 0.0001 to 50% by weight of the total composition, relative to the weight of the total composition, and may specifically include 0.01% to 10% by weight, but is not limited thereto.
상기 본 발명의 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있고, 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent conventionally used in the production of a pharmaceutical composition, and the carrier may include a non-naturally occuring carrier .
본 발명의 용어, "약학적으로 허용가능한"이란, 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다.The term "pharmaceutically acceptable" of the present invention means that the composition is free of toxicity to cells or humans exposed to the composition.
구체적으로, 상기 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명에서, 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. Specifically, the pharmaceutical composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method . In the present invention, the carrier, excipient and diluent which may be contained in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use may include various excipients such as wetting agents, sweetening agents, fragrances, preservatives, etc. in addition to water and liquid paraffin, which are simple diluents commonly used in suspension, liquid solutions, emulsions and syrups have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
다른 양태로서, 본 발명은 상기 약학 조성물을 갱년기 장애가 발병되거나 또는 발병될 가능성이 있는 인간을 제외한 개체에 투여하는 단계를 포함하는 갱년기 장애의 예방 또는 치료 방법을 제공한다. In another aspect, the present invention provides a method for the prevention or treatment of a menopausal disorder, comprising the step of administering the pharmaceutical composition to a subject other than a human who has or is likely to develop a menopausal disorder.
이때, 상기 새싹보리, 추출물, 분획물, 갱년기 장애, 예방 및 치료의 정의는 상기에서 설명한 바와 같다.Herein, the definitions of the above-mentioned barley, extract, fraction, menopausal disorder, prevention and treatment are as described above.
본 발명의 용어, "투여"란, 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미한다. The term "administering" of the present invention means introducing a given substance into a subject in an appropriate manner.
본 발명의 용어, "개체"란, 갱년기 장애가 발병하였거나 발병할 수 있는 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미한다. 구체적인 예로, 인간을 포함한 포유동물일 수 있다.The term "individual" of the present invention means all animals such as rats, mice, livestock, etc., including humans who have developed or may develop menopausal disorders. As a specific example, it may be a mammal including a human.
본 발명의 갱년기 장애의 예방 또는 치료 방법은 구체적으로, 인간을 제외한 개체에 새싹보리 추출물 또는 이의 분획물을 포함하는 갱년기 장애의 예방 또는 치료용 약학 조성물을 약학적으로 유효한 양으로 투여하는 단계를 포함할 수 있다. The method for preventing or treating a menopausal disorder according to the present invention specifically includes a step of administering a pharmaceutical composition for preventing or treating menopausal disorders comprising a bud of barley extract or a fraction thereof to a subject other than a human in a pharmaceutically effective amount .
본 발명의 용어, "약학적으로 유효한 양"이란, 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 성별, 연령, 체중, 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 및 배출 비율, 치료 기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 당업자에 의해 용이하게 결정될 수 있다.The term "pharmaceutically effective amount" of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, And other factors including drugs used in combination or at the same time, such as age, body weight, health status, type of disease, severity, activity of the drug, sensitivity to the drug, administration method, administration time, administration route, Can be readily determined by those skilled in the art according to factors well known in the medical arts.
구체적으로 본 발명의 조성물은 고형분을 기준으로 1일 0.0001 내지 100 mg/체중 kg으로, 더욱 구체적으로 0.001 내지 100 mg/체중 kg으로 투여할 수 있다. 투여는 상기 권장 투여량을 하루에 한 번 투여할 수도 있고, 수회 나누어 투여할 수도 있다.Specifically, the composition of the present invention may be administered at a dose of 0.0001 to 100 mg / kg body weight per day, more specifically 0.001 to 100 mg / kg body weight, based on the solid content. The administration may be such that the recommended dose is administered once a day or divided into several doses.
본 발명의 갱년기 장애의 예방 또는 치료 방법에서, 상기 조성물을 투여하는 투여 경로 및 투여 방식은 특별히 제한되지 않으며, 목적하는 해당 부위에 상기 조성물을 포함하는 조성물이 도달할 수 있는 한 임의의 투여 경로 및 투여 방식에 따를 수 있다. 구체적으로, 상기 조성물은 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있으며, 그 투여 경로의 비제한적인 예로는, 구강, 직장, 국소, 정맥내, 복강내, 근육내, 동맥내, 경피, 비측내 또는 흡입 등을 통하여 투여되는 것을 들 수 있다.In the method for preventing or treating menopausal disorders according to the present invention, the route of administration and the manner of administration of the composition are not particularly limited, and any route of administration may be used as long as the composition containing the composition can reach the desired site Depending on the mode of administration. Specifically, the composition may be administered orally or parenterally through various routes. Non-limiting examples of routes of administration include oral, rectal, topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, Intramuscularly or through inhalation or the like.
또 다른 양태로서, 본 발명은 새싹보리 추출물 또는 이의 분획물을 포함하는 갱년기 장애의 예방 또는 개선용 식품 조성물을 제공한다.In another aspect, the present invention provides a food composition for the prevention or amelioration of a menopausal disorder comprising a germanium barley extract or a fraction thereof.
이때, 상기 새싹보리, 추출물, 분획물, 갱년기 장애 및 예방의 정의는 상기에서 설명한 바와 같다.Herein, the definitions of the above-mentioned barley, extract, fraction, menopausal disorder and prevention are as described above.
본 발명의 용어, "개선"이란, 본 발명의 새싹보리 추출물 또는 이의 분획물을 포함하는 조성물의 투여로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.The term "improvement" of the present invention means any action that at least reduces the degree of symptom associated with the condition to be treated by administration of the composition comprising the bud or extract of the present invention or its fractions.
본 발명의 용어 "식품"이란, 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료, 비타민 복합제, 건강 기능 식품 및 건강 식품 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.The term "food" of the present invention is intended to encompass all kinds of foods, including dairy products, soups, beverages, tea, drinks, alcoholic beverages including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, , A vitamin complex, a health functional food, and a health food, all of which include foods in a conventional sense.
본 발명의 식품 조성물은, 일상적으로 섭취하는 것이 가능하기 때문에 높은 갱년기 장애 개선 효과를 기대할 수 있으므로, 건강 증진 목적으로 매우 유용하게 사용될 수 있다.Since the food composition of the present invention can be routinely ingested, a high effect of improving menopausal symptoms can be expected, and thus it can be very usefully used for health promotion purposes.
상기 건강 기능(성) 식품(functional food)이란, 특정보건용 식품(food for special health use, FoSHU)과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 '기능(성)'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 식품의 제형 또한 식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나므로, 본 발명의 식품은 갱년기 장애 개선 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The term "functional food" as used herein means the same term as "food for special health use" (FoSHU). In addition to nutrition, It means food. Here, 'function (surname)' refers to the structure and function of the human body to obtain a beneficial effect for health use such as controlling nutrients or physiological action. The food of the present invention can be prepared by a method commonly used in the art and can be prepared by adding raw materials and ingredients which are conventionally added in the art. In addition, the formulations of the food can also be produced without restrictions as long as they are formulations recognized as food. The composition for food of the present invention can be manufactured in various formulations, and unlike general pharmaceuticals, it has an advantage that there is no side effect that may occur when a food is used as a raw material for a long period of taking a medicine, The inventive food can be taken as an adjuvant to improve the effect of improving the menopausal symptoms.
상기 건강 식품(health food)은 일반식품에 비해 적극적인 건강유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품(health supplement food)은 건강보조 목적의 식품을 의미한다. 경우에 따라, 건강 기능 식품, 건강식품, 건강보조식품의 용어는 호용된다.The health food refers to a food having an active health promotion or promotion effect compared with a general food, and a health supplement food refers to a food for health assistance. In some cases, the terms health functional foods, health foods, and health supplements are used.
구체적으로, 상기 건강 기능 식품은 본 발명의 화합물을 음료, 차류, 향신료, 껌, 과자류 등의 식품 소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용이 없는 장점이 있다.Specifically, the health functional food is a food prepared by adding the compound of the present invention to a food material such as a beverage, a tea, a spice, a gum, confectionery, or the like, or encapsulated, powdered or suspended therein. But it has the advantage that there is no side effect that can occur when the food is used as a raw material and long-term use of the drug.
상기 식품 조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 않으며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다.The food composition may further comprise a physiologically acceptable carrier. The type of carrier is not particularly limited, and any carrier conventionally used in the art can be used.
또한, 상기 식품 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예들 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu), 크륨(Cr) 등의 미네랄; 및 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다. In addition, the food composition may contain additional components that are commonly used in food compositions and can improve odor, taste, visual appearance, and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid and the like. Minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu) and chromium (Cr); And amino acids such as lysine, tryptophan, cysteine, valine, and the like.
또한, 상기 식품 조성물은 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨류엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산 나트륨, 아초산 나트륨 등), 표백제(아황산나트륨), 조미료(MSG 글루타민산나트륨 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(food additives)을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용될 수 있다.In addition, the food composition may contain at least one kind selected from the group consisting of preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate), disinfectants (such as bleaching powder and highly bleached white powder, sodium hypochlorite), antioxidants (butylhydroxyanisole (BHA) (Sodium nitrite), bleach (sodium sulfite), seasoning (sodium MSG glutamate, etc.), sweeteners (dicin, cyclamate, saccharin, etc.), coloring agents , Sodium, etc.), perfume (vanillin, lactones, etc.), swelling agents (alum, potassium hydrogen D-tartrate), emulsifiers, thickeners (foams), encapsulating agents, gum bases, foam inhibitors, solvents, And may include food additives. The additives may be selected and used in appropriate amounts depending on the type of food.
본 발명의 식품 조성물의 일 예로 건강음료 조성물로 사용될 수 있으며, 이 경우 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드; 말토스, 슈크로스와 같은 디사카라이드; 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드; 자일리톨, 소르비톨, 에리트리톨 등의 당알콜일 수 있다. 감미제는 타우마틴, 스테비아 추출물과 같은 천연 감미제; 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강음료 조성물 100 mL 당 일반적으로 약 0.01 ~ 0.04 g, 구체적으로 약 0.02 ~ 0.03 g이 될 수 있다.As an example of the food composition of the present invention, it can be used as a health beverage composition. In this case, various flavors or natural carbohydrates can be added as an additional ingredient like ordinary beverages. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose; Polysaccharides such as dextrin, cyclodextrin; Xylitol, sorbitol, erythritol, and the like. Sweeteners include natural sweeteners such as tau Martin and stevia extract; Synthetic sweetening agents such as saccharin and aspartame, and the like can be used. The ratio of the natural carbohydrate may be generally about 0.01 to 0.04 g, specifically about 0.02 to 0.03 g per 100 mL of the health beverage composition of the present invention.
상기 외에 건강음료 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산, 펙트산의 염, 알긴산, 알긴산의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올 또는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일주스, 과일주스 음료, 또는 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 혼합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 건강음료 조성물 100 중량부당 0.01 ~ 0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the health beverage composition may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acid, protective colloid thickener, pH adjuster, stabilizer, Alcohols or carbonating agents, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks, or vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the health beverage composition of the present invention.
본 발명의 새싹보리 추출물은 골 항상성 장애를 대표하는 골다공증을 개선시키는 효과와 여성호르몬 분비를 조절하는 에스트로겐 수용체의 발현 촉진 활성을 보이므로, 상기 증상을 포함하는 갱년기 장애의 예방, 개선 또는 치료를 위한 또는 식품 및 의약품 등에 이용될 수 있다.The germanium barley extract of the present invention exhibits an effect of improving osteoporosis, which is a bone homeostatic disorder, and an estrogen receptor-promoting activity of regulating female hormone secretion. Therefore, the present invention provides a method for preventing, ameliorating or treating a menopausal disorder Or foods and medicines.
도 1a는 새싹보리 추출물의 처리농도에 따른 RANKL에 의해 분화된 파골세포를 TRAP로 면역염색한 결과를 나타내는 현미경 사진이다.
도 1b는 도 1a에서 면역염색된 세포의 수를 정량분석한 결과를 나타내는 그래프이다.
도 1c는 새싹보리 추출물의 처리농도에 따른 TRAP의 활성변화를 비교한 결과를 나타내는 그래프이다.
도 1d는 새싹보리 추출물의 처리농도에 따른 BMM 세포의 세포생존율의 변화를 분석한 결과를 나타내는 그래프이다.
도 1e는 새싹보리 추출물의 처리농도에 따른 MCF-7(인체유방암세포)의 세포생존율의 변화를 분석한 결과를 나타내는 그래프이다.
도 2a는 새싹보리 추출물의 처리에 따른, 파골세포 분화와 연관된 전사인자인 c-Fos, TRAP, NFATc1 및 OSCAR의 발현수준의 변화를 분화유도 시간별로 분석한 결과를 나타내는 그래프로서, (□)는 새싹보리 추출물을 처리하지 않은 세포를 나타내고, (■)는 새싹보리 추출물을 처리한 세포를 나타내며, X 축은 분화유도 시간을 일별로 나타낸다.
도 2b는 새싹보리 추출물의 처리에 따른, 파골세포 분화와 연관된 전사인자인 c-Fos 및 NFATc1의 단백질 수준의 변화를 분화유도 시간별로 분석한 결과를 나타내는 웨스턴블럿 분석결과를 나타내는 사진이다.
도 3은 새싹보리 추출물의 처리에 따른, c-Fos와 NFATc1의 발현과 관련된 신호전달 경로를 구성하는 인자인 AKT, ERK, JNK 및 p38의 인산화수준 변화와 IκB-α의 수준 변화를 분화유도 시간별로 분석한 결과를 나타내는 전기영동사진이다.
도 4a는 새싹보리 추출물의 처리시간에 따른 효과를 검증하기 위한 실험과정을 나타내는 개략도로서, (0-1) 구간은 처음 1일 동안 새싹보리 추출물을 처리하는 구간이고, (1-2) 구간은 2일째에만 새싹보리 추출물을 처리하는 구간이며, (2-3) 구간은 3일째에만 새싹보리 추출물을 처리하는 구간이고, (3-4) 구간은 4일째에만 새싹보리 추출물을 처리하는 구간이다.
도 4b는 새싹보리 추출물의 처리시점에 따른 RANKL에 의해 분화된 파골세포를 TRAP로 면역염색한 결과를 나타내는 현미경 사진이다.
도 4c는 도 4b에서 면역염색된 세포 중에서 핵이 10개 이상인 세포의 수를 분석한 결과를 나타내는 그래프이다.
도 4d는 새싹보리 추출물의 처리시점에 따른 TRAP의 활성변화를 비교한 결과를 나타내는 그래프이다.
도 4e는 새싹보리 추출물의 처리시점에 따른 DC-STAMP의 발현수준변화를 비교한 결과를 나타내는 그래프이다.
도 5a는 파골세포 분화유도시 발현되는 카뎁신 K의 발현수준에 미치는 새싹보리 추출물의 효과를 처리시간의 경과에 따라 분석한 결과를 나타내는 그래프이다.
도 5b는 파골세포에 새싹보리 추출물을 처리하고, TRAP 염색을 수행한 결과 및 골 흡수 분석을 수행한 결과를 나타내는 현미경 사진이다.
도 5c는 상기 사진에서 TRAP 염색수준을 정량분석한 결과를 나타내는 그래프이다.
도 5d는 상기 사진에서 골 흡수 수준을 정량분석한 결과를 나타내는 그래프이다.
도 6은 에스트로겐 수용체를 과다하게 발현시키는 것으로 알려진 암세포주에서 에스트로겐 수용체 알파의 활성화에 대한 새싹보리 추출물의 효과를 분석한 결과를 나타내는 그래프이다.FIG. 1A is a photomicrograph showing immunostaining with TRAP of osteoclast differentiated by RANKL according to the treatment concentration of shoot barley extract. FIG.
FIG. 1B is a graph showing the results of quantitative analysis of the number of immunostained cells in FIG. 1A. FIG.
FIG. 1C is a graph showing the results of comparing the activity changes of TRAP with the treatment concentration of the barley extract. FIG.
FIG. 1D is a graph showing the results of analysis of changes in the cell survival rate of BMM cells according to the treatment concentration of the bud.
FIG. 1E is a graph showing the results of analysis of changes in cell survival rate of MCF-7 (human breast cancer cells) according to the treatment concentration of the extract of bud.
FIG. 2A is a graph showing the results of analysis of the expression levels of c-Fos, TRAP, NFATc1 and OSCAR, which are transcription factors involved in osteoclast differentiation, (■) represents cells treated with the barley extract, and the X-axis represents the differentiation induction time by day.
FIG. 2B is a photograph showing Western blot analysis showing the results of analysis of changes in the protein levels of c-Fos and NFATc1, which are transcription factors involved in osteoclast differentiation, according to the differentiation induction time according to the treatment with the bud.
FIG. 3 shows changes in phosphorylation levels and IκB-α levels of AKT, ERK, JNK, and p38, which are involved in signal transduction pathways involved in the expression of c-Fos and NFATc1, The results of electrophoresis are shown in Fig.
FIG. 4A is a schematic diagram showing an experimental procedure for verifying the effect of the barley extract on the treatment time. The (0-1) section is a section for treating the barley extract for the first day, and the section (1-2) (2-3) section is the section for treating the barley extract only on the 3rd day, and the section (3-4) is the section for treating the barley extract on the fourth day only.
FIG. 4B is a photomicrograph showing immunostaining with TRAP of osteoclast differentiated by RANKL according to the treatment time of the bud of the bud.
FIG. 4c is a graph showing the number of cells having 10 or more nuclei in the immunostained cells in FIG. 4b. FIG.
FIG. 4D is a graph showing the results of comparing the activity changes of TRAP with the treatment time of the barley extract of bud. FIG.
FIG. 4E is a graph showing the results of comparing the expression level of DC-STAMP with the treatment time of the barley extract.
FIG. 5A is a graph showing the results of analyzing the effect of the barley extract on the expression level of kadebsin K expressed upon osteoclast differentiation according to the elapsed time of treatment.
FIG. 5B is a micrograph showing the results of treatment of osteoclasts with barley extract, TRAP staining, and bone resorption analysis.
5c is a graph showing the results of quantitative analysis of TRAP staining level in the photograph.
FIG. 5D is a graph showing the result of quantitative analysis of bone resorption level in the photograph. FIG.
FIG. 6 is a graph showing the results of analysis of the effect of the barley extract on the activation of estrogen receptor alpha in cancer cell lines known to over-express the estrogen receptor.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예Example 1: 새싹보리 추출물의 수득 1: Obtain the extract of barley barley
광안 보리를 발아시키고, 5일이 경과한 시점에서 새싹보리를 수확하여 동결건조시켰으며, 이를 분말화하여 새싹보리 분말을 수득하였다.The ginseng barley was germinated, and after 5 days passed, the germanium barley was harvested and lyophilized, which was pulverized to obtain germinated barley powder.
상기 수득한 새싹보리 분말에 80% 에탄올을 가하여 추출하고, 이를 여과하여 액상성분을 수득하고, 상기 액상성분을 동결건조시켜 새싹보리 추출물을 수득하였다.The obtained germanium barley powder was extracted with 80% ethanol and filtered to obtain a liquid component, and the liquid component was freeze-dried to obtain a germanium barley extract.
실시예Example 2: 새싹보리 추출물의 파골세포 분화 억제효과 2: Inhibitory effect of shoot barley extract on osteoclast differentiation
상기 실시예 1에서 수득한 새싹보리 추출물이 갱년기 장애증상의 하나인 골다공증을 억제하는 효과를 나타내는지를 확인하고자 골수-유래 마크로파지(bone marrow-derived macrophage; BMM)를 파골세포로 분화시키고, 이러한 파골세포의 분화에 새싹보리 추출물이 나타내는 영향을 분석하였다.The bone marrow-derived macrophages (BMM) were differentiated into osteoclasts in order to confirm whether the germanium barberry extract obtained in Example 1 had an effect of inhibiting osteoporosis, which is one of the symptoms of menopausal disorder, The effect of barley extracts on the differentiation of.
실시예Example 2-1: 골수-유래 2-1: Bone marrow-derived 마크로파지의Macrophage 수득 purchase
5 주령의 수컷 ICR 마우스로부터 대퇴골(femur) 및 경골(tibia)을 적출하고, 이를 항생제(100 units/㎖ 페니실린 및 100 ㎍/㎖ 스트렙토마이신)을 포함하는 α-MEM으로 세척하여 골수세포(bone marrow cells)를 수득하였다. Femur and tibia were removed from 5-week-old male ICR mice and washed with α-MEM containing antibiotics (100 units / ml penicillin and 100 μg / ml streptomycin) to remove bone marrow cells.
상기 수득한 골수세포를 10% 소태아혈청(fetal bovine serum; FBS) 및 M-CSF(macrophage colony stimulating factor; 10 ng/㎖)를 포함하는 α-MEM에 접종한 후, 1일 동안 배양하였다. 배양 후, 수득한 비부착(non-adherent) 골수세포를 M-CSF(30 ng/㎖)를 포함하는 α-MEM에 접종한 후, 3일 동안 배양하였다. 배양 후, 비부착 세포를 제거하고, 배양용기에 부착된 세포(adherent cells)를 골수-유래 마크로파지(bone marrow-derived macrophage; BMM)로 사용하였다. The obtained bone marrow cells were inoculated into? -MEM containing 10% fetal bovine serum (FBS) and M-CSF (macrophage colony stimulating factor; 10 ng / ml) and cultured for 1 day. After culturing, the obtained non-adherent bone marrow cells were inoculated into? -MEM containing M-CSF (30 ng / ml) and cultured for 3 days. After incubation, non-adherent cells were removed and adherent cells were used as bone marrow-derived macrophages (BMM).
실시예Example 2-2: 파골세포의 분화에 미치는 새싹보리 추출물의 효과 2-2: Effect of barley extract on bud differentiation
상기 실시예 2-1에서 수득한 BMM 세포에 파골세포(osteoclast) 분화유도제인 RANKL(receptor activator of nuclear factor-kappaB ligand)을 처리하여, 상기 BMM 세포를 파골세포로 분화시키면서, 이러한 파골세포의 분화에 미치는 새싹보리 추출물의 효과를 검증하고자 하였다. The BMM cells obtained in Example 2-1 were treated with a receptor activator of nuclear factor-kappaB ligand (RANKL), an osteoclast differentiation inducer, to differentiate the BMM cells into osteoclasts, The effects of barley extracts on the growth of.
구체적으로, 10 ng/㎖의 RANKL과 30 ng/㎖의 M-CSF를 포함하고, 주정 또는 새싹보리 추출물을 다양한 농도 (0, 0.3, 1, 3 및 10 ㎍/㎖)로 포함하는 α-MEM에 접종한 후, 4일 동안 배양하여, 상기 BMM 세포를 다핵성 파골세포로 분화시켰다. Specifically, α-MEMs containing 10 ng / ml of RANKL and 30 ng / ml of M-CSF and containing either alcohol or spirulina barley extract at various concentrations (0, 0.3, 1, 3 and 10 μg / And then cultured for 4 days to differentiate the BMM cells into polynuclear osteoclasts.
상기 분화된 다핵성 파골세포를 3.7% 포르말린으로 10분간 고정하고 0.1% 트리톤 X-100으로 10분간 처리하여 투과성을 갖도록 하였다. 세포를 파골세포 분화의 주요한 바이오 마커인, TRAP(tartrate resistant acid phosphatase)을 염색 용액(sigma-Aldrich)을 이용하여 염색하여 가시화하였다(도 1a 및 1b).The differentiated polynuclear osteoclasts were fixed with 3.7% formalin for 10 minutes and treated with 0.1% Triton X-100 for 10 minutes to have permeability. Cells were visualized by staining with TRAP (tartrate resistant acid phosphatase), a major biomarker of osteoclast differentiation, using a staining solution (Sigma-Aldrich) (FIGS. 1A and 1B).
도 1a는 새싹보리 추출물의 처리농도에 따른 RANKL에 의해 분화된 파골세포를 TRAP로 면역염색한 결과를 나타내는 현미경 사진이고, 도 1b는 상기 면역염색된 세포의 수를 정량분석한 결과를 나타내는 그래프이다.FIG. 1A is a micrograph showing the results of immunoprecipitation of osteoclast differentiated with RANKL by TRAP according to the treatment concentration of bud of barberry extract, and FIG. 1B is a graph showing the result of quantitative analysis of the number of immunostained cells .
상기 도 1a 및 1b에서 보듯이, RANKL을 처리하여 BMM 세포를 파골세포로 분화시킬 때, 함께 처리된 새싹보리 추출물의 처리농도가 증가할수록 TRAP으로 염색된 파골세포의 수가 감소함을 확인하였다.As shown in FIGS. 1A and 1B, when the RANKL was treated to differentiate BMM cells into osteoclasts, the number of osteoclasts stained with TRAP decreased as the concentration of the treated barley extract increased.
따라서, RANKL에 의해 유도된 파골세포의 마커인 TRAP의 수준을 새싹보리 추출물이 농도의존적으로 억제할 것으로 분석되었다.Therefore, it was analyzed that the level of TRAP, which is a marker of osteoclast induced by RANKL, was inhibited in a dose dependent manner by the barley extract.
실시예Example 2-3: TRAP의 활성에 미치는 새싹보리 추출물의 효과 2-3: Effect of barley extract on the activity of TRAP
상기 실시예 2-2를 통하여, RANKL에 의해 유도된 파골세포의 마커인 TRAP의 수준을 새싹보리 추출물이 억제함을 확인하였으므로, 상기 TRAP의 활성에도 새싹보리 추출물이 효과를 나타내는지를 확인하고자 하였다.Through the above Example 2-2, it was confirmed that the level of TRAP, which is a marker of osteoclast induced by RANKL, is inhibited by the germanium barley extract, so that the effect of the germanium barley extract on the activity of TRAP was examined.
구체적으로, 상기 실시예 2-2의 방법으로 수득한 파골세포를 3.7% 포르말린으로 5분간 고정하고 0.1% 트리톤 X-100으로 10분간 처리하여 투과성을 갖도록 하였다. 이어, 상기 파골세포를 3 mM p-니트로페닐 포스페이트(p-nitropheyl phosphate, Sigma-Aldrich)를 포함하는 TRAP 완충액(100 mM 시트르산 나트륨 pH 5.0, 50 mM 주석산 나트륨(sodium tartrate))에 침지하고, 37℃에서 5분간 처리하였다. 반응혼합물을 동일한 부피의 0.1N NaOH를 포함하는 새 접시에 옮기고, 405 nm에서 광학밀도(optical density; OD) 값을 결정하였다. ###, p<0.001 (대 음성대조군), *, p<0.05; ***, p<0.001 (대 양성대조군). RANKL을 처리하되 새싹보리 추출물을 처리하지 않은 세포를 양성대조군으로, RANKL과 새싹보리 추출물 모두를 처리하지 않은 세포를 음성대조군으로 사용하였다. 실험군으로는 상기 실시예 2-2에서와 동일한 농도로 새싹보리 추출물을 처리한 세포를 사용하였다(도 1c). Specifically, the osteoclasts obtained by the method of Example 2-2 were fixed with 3.7% formalin for 5 minutes and treated with 0.1% Triton X-100 for 10 minutes to have permeability. The osteoclasts were then immersed in TRAP buffer (100 mM sodium citrate pH 5.0, 50 mM sodium tartrate) containing 3 mM p-nitropheyl phosphate (Sigma-Aldrich) Lt; 0 > C for 5 minutes. The reaction mixture was transferred to a new dish containing the same volume of 0.1 N NaOH and the optical density (OD) value at 405 nm was determined. ###, p < 0.001 (vs. negative control), *, p <0.05; ***, p < 0.001 (large positive control group). Cells treated with RANKL but not treated with barley extract were used as positive control, and cells not treated with RANKL and sprouted barley extract were used as negative control. As the experimental group, cells treated with the barley extract at the same concentration as in Example 2-2 were used (Fig. 1C).
도 1c는 새싹보리 추출물의 처리농도에 따른 TRAP의 활성변화를 비교한 결과를 나타내는 그래프이다. 상기 도 1c에서 보듯이, 새싹보리 추출물은 농도의존적으로 TRAP 활성을 억제함을 확인하였다.FIG. 1C is a graph showing the results of comparing the activity changes of TRAP with the treatment concentration of the barley extract. FIG. As shown in FIG. 1C, it was confirmed that the extract of bud from barley suppressed TRAP activity in a concentration-dependent manner.
실시예Example 2-4: 새싹보리 추출물의 세포독성 평가 2-4: Evaluation of cytotoxicity of barley extract
상기 실시예 2-2 및 2-3의 결과로부터, 새싹보리 추출물이 파골세포의 바이오마커인 TRAP의 발현과 활성을 농도의존적으로 억제함을 확인하고, 여성호르몬이 많은 인체유방암 세포 또한 이러한 효과가 새싹보리 추출물의 세포독성에 의한 것인지의 여부를 검증하고자 하였다.From the results of the above Examples 2-2 and 2-3, it was confirmed that the bud of the buds extract inhibited the expression and activity of TRAP, which is a biomarker of osteoclast, in a concentration-dependent manner, and the effect of the human hormone- And to investigate the cytotoxicity of the barley extract.
구체적으로, BMM 세포를 M-CSF (30 ng/㎖) 존재 하에 새싹보리 추출물을 다양한 농도 (0, 0.3, 1, 3 및 10 ㎍/㎖)로 처리하여 3일간 배양하였다. 새싹보리 추출물이 처리된 BMM 세포를 세포 증식을 여부를 확인하는 CCK-8 (Dojindo Lab., Japan) 시약을 첨가하고 37℃에서 4시간 배양하고, 450 nm에서 광학밀도값을 결정하였다. 이 광학 밀도값을 환산하여 세포의 생존률을 산출하였다(도 1d).Specifically, BMM cells were cultured for 3 days in the presence of M-CSF (30 ng / ml) treated with various concentrations (0, 0.3, 1, 3 and 10 占 퐂 / ml) of the shoot barley extract. BMM cells treated with shoot barley extract were incubated at 37 ° C for 4 hours with CCK-8 (Dojindo Lab., Japan) reagent to confirm cell proliferation and optical density was determined at 450 nm. The optical density value was converted to calculate the cell survival rate (Fig. 1D).
도 1d는 새싹보리 추출물의 처리농도에 따른 BMM 세포의 세포생존율의 변화를 분석한 결과를 나타내는 그래프이다. 상기 도 1d에서 보듯이, 새싹보리 추출물을 TRAP 발현과 활성을 억제하는 농도로 BMM 세포에 처리하여도, 세포독성이 나타나지 않음을 확인하였다.FIG. 1D is a graph showing the results of analysis of changes in the cell survival rate of BMM cells according to the treatment concentration of the bud. As shown in FIG. 1D, it was confirmed that the cytotoxicity was not observed even when BMT cells were treated with the bud-barley extract at a concentration that inhibited TRAP expression and activity.
또한, MCF-7 세포를 새싹보리 추출물을 다양한 농도 (0, 10, 25, 50, 및 100 ㎍/㎖)로 처리하여 2일간 배양하였다(도 1e).In addition, MCF-7 cells were treated with various concentrations (0, 10, 25, 50, and 100 占 퐂 / ml) of the barberry extract for 2 days (Fig.
도 1e는 새싹보리 추출물의 처리농도에 따른 MCF-7(인체유방암세포)의 세포생존율의 변화를 분석한 결과를 나타내는 그래프이다.FIG. 1E is a graph showing the results of analysis of changes in cell survival rate of MCF-7 (human breast cancer cells) according to the treatment concentration of the extract of bud.
도 1e에서 보듯이, 새싹보리 추출물을 농도의존적으로 처리하여도 MCF-7 세포에 독성이 나타나지 않음을 다시 확인하였다.As shown in Fig. 1 (e), it was confirmed again that MCF-7 cells did not show any toxicity even when treated with the bud-barley extract in a concentration-dependent manner.
실시예Example 3: 파골세포 분화에 관련된 3: related to osteoclast differentiation 바이오마커의Biomarker 발현수준에 미치는 새싹보리 추출물의 효과 Effect of barley extract on the level of expression
상기 실시예 2-2 내지 2-4의 결과로부터, 새싹보리 추출물이 파골세포의 분화를 억제하는 효과를 나타냄을 확인하였는 바, 상기 효과를 검증하고자, 파골세포 분화에 관련된 바이오마커의 발현수준에 미치는 새싹보리 추출물의 효과를 분석하였다.From the results of the above Examples 2-2 to 2-4, it was confirmed that the extract of sprout barley showed an inhibitory effect on the differentiation of osteoclasts. In order to verify the above effect, the expression levels of biomarkers related to osteoclast differentiation The effects of barley extracts were investigated.
대략적으로, 상기 실시예 2-2의 방법으로 3일 동안 파골세포 분화를 유도하면서, 각각의 분화일자별로 3 ㎍/㎖의 새싹보리 추출물을 처리한 세포와 처리하지 않은 세포를 각각 수득하였다.Approximately 3 days after osteoclast differentiation was induced for 3 days by the method of Example 2-2, cells treated with 3 μg / ml of the shoot barley extract and cells not treated with each of the differentiation dates were obtained.
상기 수득한 각 세포로부터 총 RNA를 수득한 다음, 상기 수득한 총 RNA를 역전사시켜서, cDNA를 수득하였다. 상기 수득한 cDNA를 주형으로 사용한 Sybr-green Real Time PCR 방법을 수행하여, 새싹보리 추출물의 처리에 따른, 파골세포 분화와 연관된 전사인자인 c-Fos, TRAP, NFATc1(Nuclear Factor Of Activated T-Cells 1) 및 OSCAR(Osteoclast-associated receptor)의 발현수준의 변화를 분석하였다(도 2a).Total RNA was obtained from each of the cells obtained above, and the obtained total RNA was reverse-transcribed to obtain cDNA. As a result of the Sybr-green Real Time PCR method using the obtained cDNA as a template, the transcription factors c-Fos, TRAP, NFATc1 (Nuclear Factor of Activated T-Cells 1) and OSCAR (osteoclast-associated receptor) expression levels (Fig. 2a).
도 2a는 새싹보리 추출물의 처리에 따른, 파골세포 분화와 연관된 전사인자인 c-Fos, TRAP, NFATc1 및 OSCAR의 발현수준의 변화를 분화유도 시간별로 분석한 결과를 나타내는 그래프로서, (□)는 새싹보리 추출물을 처리하지 않은 세포를 나타내고, (■)는 새싹보리 추출물을 처리한 세포를 나타내며, X 축은 분화유도 시간을 일별로 나타낸다. 도 2a에서 보듯이, 파골세포 분화와 연관된 전사인자인 c-Fos, TRAP, NFATc1 및 OSCAR의 발현수준은 RANKL의 처리에 의해 증가되지만, 이러한 각 전사인자의 발현수준 증가는 새싹보리 추출물의 처리에 의하여 억제됨을 확인하였다.FIG. 2A is a graph showing the results of analysis of the expression levels of c-Fos, TRAP, NFATc1 and OSCAR, which are transcription factors involved in osteoclast differentiation, (■) represents cells treated with the barley extract, and the X-axis represents the differentiation induction time by day. As shown in FIG. 2A, the expression levels of transcription factors c-Fos, TRAP, NFATc1 and OSCAR associated with osteoclast differentiation are increased by treatment with RANKL. However, the expression level of each transcription factor is increased in the treatment of the shoot barley extract Respectively.
한편, 상기 전사인자 중에서, TRAP에 영향을 미치는 c-Fos와, OSCAR에 영향을 미치는 NFATc1의 발현수준 변화를 단백질 수준에서 확인하기 위하여 웨스턴 블럿 분석을 수행하였다(도 2b).Among the transcription factors, Western blot analysis was performed to determine the level of expression of cFos, which affects TRAP, and NFATc1, which affects OSCAR, at the protein level (Fig. 2B).
도 2b는 새싹보리 추출물의 처리에 따른, 파골세포 분화와 연관된 전사인자인 c-Fos 및 NFATc1의 단백질 수준의 변화를 분화유도 시간별로 분석한 결과를 나타내는 웨스턴블럿 분석결과를 나타내는 사진이다. 도 2b에서 보듯이, RANKL의 처리에 의해 c-Fos 및 NFATc1의 단백질 수준이 증가되지만, 이러한 각 전사인자의 발현수준 단백질 수준 증가는 새싹보리 추출물의 처리에 의하여 억제됨을 확인하였다.FIG. 2B is a photograph showing Western blot analysis showing the results of analysis of changes in the protein levels of c-Fos and NFATc1, which are transcription factors involved in osteoclast differentiation, according to the differentiation induction time according to the treatment with the bud. As shown in FIG. 2B, although the protein levels of c-Fos and NFATc1 are increased by treatment with RANKL, it was confirmed that the expression level of each of these transcription factors is inhibited by treatment of the barley extract with the protein.
상기 도 2a 및 2b의 결과로부터, 새싹보리 추출물은 파골세포 분화에 필수적인 바이오마커인 c-Fos와 NFATc1의 발현을 억제함을 알 수 있었다.From the results shown in FIGS. 2A and 2B, it can be seen that the germanium barley extract inhibits the expression of c-Fos and NFATc1, which are biomarkers essential for osteoclast differentiation.
실시예Example 4: 파골세포 분화에 관련된 신호전달경로에 미치는 새싹보리 추출물의 효과 4: Effect of barley extract on the signaling pathways involved in osteoclast differentiation
상기 실시예 3의 결과로부터, 새싹보리 추출물이 파골세포 분화에 필수적인 바이오마커인 c-Fos와 NFATc1의 발현을 억제함을 확인하였으므로, 상기 c-Fos와 NFATc1의 발현과 관련된 신호전달 경로에 미치는 새싹보리 추출물의 효과를 분석하였다.From the results of Example 3, it was confirmed that the germanium barley extract inhibited the expression of c-Fos and NFATc1, which are essential biomarkers for osteoclast differentiation. Therefore, The effect of barley extract was analyzed.
대략적으로, 파골세포 분화를 30분 동안 유도하는 것을 제외하고는, 상기 실시예 3의 방법으로 각각의 분화된 파골세포를 수득하고, 이로부터 cDNA를 수득한 다음, c-Fos와 NFATc1의 발현과 관련된 신호전달 경로를 구성하는 인자인 AKT, ERK, JNK 및 p38의 인산화수준 변화와 IκB-α의 수준 변화를 분석하였다(도 3).Approximately, each of the differentiated osteoclasts was obtained by the method of Example 3, except that the osteoclast differentiation was induced for 30 minutes, from which cDNA was obtained and then the expression of c-Fos and NFATc1 Changes in phosphorylation levels and levels of IκB-α in AKT, ERK, JNK, and p38, which constitute related signal transduction pathways, were analyzed (FIG. 3).
도 3은 새싹보리 추출물의 처리에 따른, c-Fos와 NFATc1의 발현과 관련된 신호전달 경로를 구성하는 인자인 AKT, ERK, JNK 및 p38의 인산화수준 변화와 IκB-α의 수준 변화를 분화유도 시간별로 분석한 결과를 나타내는 전기영동사진이다. 도 3에서 보듯이, RANKL을 처리하여 파골세포로 분화시키면, IκB-α가 분해되고, AKT, ERK, JNK 및 p38의 인산화수준이 증가되었으나, 파골세포 분화시에 새싹보리 추출물을 처리하면, IκB-α의 분해가 억제됨을 확인하였다.FIG. 3 shows changes in phosphorylation levels and IκB-α levels of AKT, ERK, JNK, and p38, which are involved in signal transduction pathways involved in the expression of c-Fos and NFATc1, The results of electrophoresis are shown in Fig. As shown in FIG. 3, when RANKL was treated to differentiate into osteoclasts, IκB-α was degraded and phosphorylation levels of AKT, ERK, JNK and p38 were increased. However, when osteoclast differentiation was performed, -α was inhibited.
따라서, 새싹보리 추출물의 파골세포 분화억제 효과는 IκB의 분해와 연관될 것으로 분석되었다.Therefore, the effect of inhibiting the osteoclast differentiation of the germinated barley extract was analyzed to be related to the degradation of IκB.
실시예Example 5: 파골세포 분화 진행과정에서의 새싹보리 추출물의 효능 분석 5: Efficacy of bud-leaf extracts in osteoclast differentiation
파골세포의 분화 진행과정중에서 새싹보리 추출물의 항 파골세포 분화 효능을 더욱더 이해하기 위해서, 상기 실시예 2-1에서 수득한 BMM 세포에 RANKL을 4일 동안 처리하면서, 새싹보리 추출물을 시간 별로 처리하였다(도 4a).In order to further understand the anti-osteoclast differentiation efficacy of the germanium barley extract in the osteoclast differentiation progression process, the germanium barley extract was treated with time while treating RANKL for 4 days with the BMM cells obtained in Example 2-1 (Fig. 4A).
도 4a는 새싹보리 추출물의 처리시간에 따른 효과를 검증하기 위한 실험과정을 나타내는 개략도로서, (0-1) 구간은 처음 1일 동안 새싹보리 추출물을 처리하는 구간이고, (1-2) 구간은 2일째에만 새싹보리 추출물을 처리하는 구간이며, (2-3) 구간은 3일째에만 새싹보리 추출물을 처리하는 구간이고, (3-4) 구간은 4일째에만 새싹보리 추출물을 처리하는 구간이다.FIG. 4A is a schematic diagram showing an experimental procedure for verifying the effect of the barley extract on the treatment time. The (0-1) section is a section for treating the barley extract for the first day, and the section (1-2) (2-3) section is the section for treating the barley extract only on the 3rd day, and the section (3-4) is the section for treating the barley extract on the fourth day only.
이어, 상기 설정된 구간별로, 새싹보리 추출물을 처리한 다음, 처리된 세포를 대상으로 TRAP 염색을 수행하고, 염색된 세포의 수를 정량분석하였으며, TRAP의 활성을 측정하고, 파골세포의 말기 과정인 세포 융합과정에 관여하는 DC-STAMP의 발현수준을 분석하였다.Then, TRAP staining was carried out on the treated cells after treating the bud with the above-mentioned set intervals, the number of stained cells was quantitatively analyzed, the activity of TRAP was measured, and the end stage of osteoclast The expression level of DC-STAMP involved in the cell fusion process was analyzed.
실시예Example 5-1: TRAP 염색 분석 5-1: Analysis of TRAP staining
도 4a에서 설정한 바에 따라, BMM 세포에 RANKL을 4일 동안 처리하여 파골세포의 분화를 유도하면서, 분화의 초기, 중기 및 말기구간에서 새싹보리 추출물을 처리하고, 처리된 세포를 대상으로 TRAP 염색을 수행하고, 염색된 세포의 수를 정량분석하였다(도 4b).4A, BMM cells were treated with RANKL for 4 days to induce osteoclast differentiation, treated with the extracts of buds at the early, middle and late stages of differentiation, and treated with TRAP staining And the number of stained cells was quantitatively analyzed (Fig. 4B).
도 4b는 새싹보리 추출물의 처리시점에 따른 RANKL에 의해 분화된 파골세포를 TRAP로 면역염색한 결과를 나타내는 현미경 사진이다.FIG. 4B is a photomicrograph showing immunostaining with TRAP of osteoclast differentiated by RANKL according to the treatment time of the bud of the bud.
도 4b에서 보듯이, 새싹보리 추출물은 파골세포 분화의 초기, 중기, 말기 과정 모두에서 파골세포 분화 분자마커인 TRAP의 형성을 억제함을 확인하였다.As shown in FIG. 4B, it was confirmed that the shoot barley extract inhibited the formation of osteoclast differentiation marker, TRAP, in both early, middle and late osteoclast differentiation.
또한, 상기 염색된 세포중에서 핵이 10개 이상인 세포의 수를 분석하였다(도 4c).In addition, the number of cells having 10 or more nuclei in the stained cells was analyzed (FIG. 4C).
도 4c는 도 4b에서 면역염색된 세포 중에서 핵이 10개 이상인 세포의 수를 분석한 결과를 나타내는 그래프이다.FIG. 4c is a graph showing the number of cells having 10 or more nuclei in the immunostained cells in FIG. 4b. FIG.
도 4c에서 보듯이, (3-4) 구간에서는 핵이 10개 이상인 세포에서 발현된 TRAP의 수준이 급격히 저하됨을 확인하였다.As shown in FIG. 4C, it was confirmed that the level of TRAP expressed in cells having 10 or more nuclei was rapidly decreased in the (3-4) region.
상기 결과로부터 새싹보리 추출물이 파골세포의 분화과정중 말기과정에 더욱더 효과적으로 작용함을 알 수 있었다.From the above results, it can be seen that the barberry extracts are more effective for the late stage of osteoclast differentiation.
실시예Example 5-2: TRAP 활성 분석 5-2: Analysis of TRAP activity
상기 실시예 5-1을 통하여, RANKL에 의해 유도된 파골세포의 마커인 TRAP의 수준을 새싹보리 추출물이 파골세포 분화의 초기, 중기, 말기 과정 모두에서 TRAP의 형성을 억제함을 확인하였으므로, 상기 TRAP의 활성에도 새싹보리 추출물이 효과를 나타내는지를 실시예 2-3의 방법으로 확인하였다(도 4d).Through the above Example 5-1, it was confirmed that the level of TRAP, which is a marker of osteoclast induced by RANKL, suppresses the formation of TRAP in both early, middle and late stages of osteoclast differentiation, The effect of the barley extract on the activity of TRAP was confirmed by the method of Example 2-3 (Fig. 4d).
도 4d는 새싹보리 추출물의 처리시점에 따른 TRAP의 활성변화를 비교한 결과를 나타내는 그래프이다.FIG. 4D is a graph showing the results of comparing the activity changes of TRAP with the treatment time of the barley extract of bud. FIG.
도 4d에서 보듯이, 모든 기간에서 새싹보리 처리 시에 TRAP의 활성이 감소됨을 확인하였다.As shown in FIG. 4D, it was confirmed that the activity of TRAP was reduced during the treatment of barley barley in all the periods.
실시예Example 5-3: DC-STAMP의 발현수준 분석 5-3: Analysis of expression level of DC-STAMP
파골세포의 말기 과정인 세포 융합과정에 관여하는 DC-STAMP의 발현수준에 대한 새싹보리 추출물의 효과를 분석하였다(도 4e).The effect of the shoot barley extract on the expression level of DC-STAMP involved in the cell fusion process, which is an end stage of osteoclast, was analyzed (Fig. 4E).
도 4e는 새싹보리 추출물의 처리시점에 따른 DC-STAMP의 발현수준변화를 비교한 결과를 나타내는 그래프이다.FIG. 4E is a graph showing the results of comparing the expression level of DC-STAMP with the treatment time of the barley extract.
도 4e에서 보듯이, 모든 기간에서 새싹보리 처리 시에 DC-STAMP의 발현수준이 감소됨을 확인하였다.As shown in FIG. 4E, it was confirmed that the expression level of DC-STAMP was decreased during the treatment of bud-barley treatment in all periods.
상기 도 4b 내지 4e의 결과로부터, 새싹보리 추출물이 파골세포의 분화과정중, 초기, 중기, 말기에 이르는 파골세포 분화의 전 과정을 억제하고, 분화말기에 더욱 효과적으로 작용함을 알 수 있었다.From the results shown in Figs. 4B to 4E, it can be seen that the bud of barberry extract inhibits the whole process of osteoclast differentiation during the differentiation process of osteoclast, early, middle and late, and acts more effectively at the end of differentiation.
실시예 6: 파골세포 골흡수 기능에 대한 새싹보리 추출물의 효과 분석Example 6: Analysis of the effect of the barley extract of bud on the osteoclast bone resorption function
새싹보리 추출물의 파골세포의 분화에 전반적인 과정에서의 억제 효능을 보였다면, 실제적으로 파골세포의 골흡수 기능에도 영향이 있는지를 알아보기 위하여, 골 흡수, 분화가 완료된 파골세포의 개수, 골 흡수와 관련된 유전자의 분석을 수행하였다. In order to investigate the effect of inhibiting osteoclast differentiation in the osteoclast differentiation, the number of osteoclasts, osteoclast, bone resorption, Analysis of related genes was performed.
실시예 6-1: 카뎁신 K(cathepsin K)의 발현수준에 미치는 효과Example 6-1: Effect on the expression level of cathepsin K (cathepsin K)
상기 실시예 2-1에서 수득한 BMM 세포에 RANKL을 3일 동안 처리하면서, 3㎍/㎖의 새싹보리 추출물을 처리하고, 파골세포의 골흡수와 연관된 유전자의 하나인 카뎁신 K의 발현수준을 분석하였다(도 5a).The BMM cells obtained in Example 2-1 were treated with RANKL for 3 days while treating with 3 μg / ml of the extract from buds, and the expression level of carvedil K, which is one of the genes involved in osteoclast bone resorption (Fig. 5A).
도 5a는 파골세포 분화유도시 발현되는 카뎁신 K의 발현수준에 미치는 새싹보리 추출물의 효과를 처리시간의 경과에 따라 분석한 결과를 나타내는 그래프이다.FIG. 5A is a graph showing the results of analyzing the effect of the barley extract on the expression level of kadebsin K expressed upon osteoclast differentiation according to the elapsed time of treatment.
도 5a에서 보듯이, 파골세포 분화유도시 카뎁신 K의 발현수준은 시간의 경과에 따라 현저히 증가하였으나, 새싹보리 추출물에 의해 이러한 발현수준의 증가가 억제됨을 확인하였다.As shown in FIG. 5A, the expression level of kadebesin K in osteoclast differentiation was remarkably increased with time, but it was confirmed that the increase in the expression level of osteoclastin K was inhibited by the barley extract.
실시예Example 6-2: 골 흡수 분석 6-2: Analysis of bone resorption
태어난 지 1~3일된 어린 쥐의 골에 0.1% 콜라게나제를 처리하여 조골세포를 분리하고, 상기 분리된 조골세포(3.5 × 105 cells/well)를 콜라겐 코팅된 배양접시에 BMMs(1 × 106 cells/well)와 함께 접종하였으며, VitD3(1α, 25-dihydroxyvitamin D3)와 PGE2(prostaglandin E2)를 포함하는 배지를 사용하여 6일동안 배양하여, 파골세포 분화를 유도하였다. 이어, 상기 분화된 파골세포에 10 ng/㎖의 RANKL과 3㎍/㎖의 새싹보리 추출물을 처리하고 24시간동안 배양하였다. 배양된 파골세포를 3.7% 포르말린으로 5분간 고정하고, 0.1% 트리톤 X-100으로 10분간 처리하여 투과성을 갖도록 처리한 다음, TRAP 염색을 수행하였다.The osteoblast cells were separated by treating with 0.1% collagenase at 1 to 3 days after birth of young rats and the separated osteoblasts (3.5 × 10 5 cells / well) were inoculated into collagen-coated culture dishes with
한편, 골 흡수 정도를 관찰하기 위하여, 상기 염색을 수행한 후, 세포를 PBS로 세척하고, 5% 차염소산나트륨을 5분간 처리하여 분화가 완료된 파골세포를 제거하였다. 그런 다음, 배양접시를 PBS로 세척한 후, 건조시켜 광학현미경으로 촬영하고, ImageJ 프로그램을 사용하여 촬영된 영상을 분석하여, 골 흡수 정도를 분석하였다(도 5b 내지 5d).On the other hand, to observe the degree of bone resorption, the cells were washed with PBS, and 5% sodium hypochlorite was treated for 5 minutes to remove the osteoclasts. Then, the culture dish was washed with PBS, dried and photographed with an optical microscope, and the images were analyzed using an ImageJ program to analyze the degree of bone resorption (Figs. 5B to 5D).
도 5b는 파골세포에 새싹보리 추출물을 처리하고, TRAP 염색을 수행한 결과 및 골 흡수 분석을 수행한 결과를 나타내는 현미경 사진이고, 도 5c는 상기 사진에서 TRAP 염색수준을 정량분석한 결과를 나타내는 그래프이며, 도 5d는 상기 사진에서 골 흡수 수준을 정량분석한 결과를 나타내는 그래프이다.FIG. 5B is a micrograph showing the result of treating the osteoclast with barley extract, TRAP staining, and bone resorption analysis. FIG. 5C is a graph showing the results of quantitative analysis of TRAP staining level And FIG. 5D is a graph showing the result of quantitative analysis of the bone resorption level in the photograph.
도 5b 및 5c에서 보듯이, 파골세포로 분화된 후에는 새싹보리 추출물을 처리하여도, 분화가 완료된 파골세포에 특별한 영향을 주지않음을 확인하였다.As shown in FIGS. 5B and 5C, it was confirmed that even after the differentiation into osteoclasts, the treatment with the barley extract did not affect the differentiated osteoclasts.
그러나, 도 5b 및 5d에서 보듯이, 분화된 파골세포의 골 흡수 활성을 새싹보리 추출물이 억제할 수 있음을 확인하였다.However, as shown in FIGS. 5B and 5D, it was confirmed that the extract of bud of the bud can inhibit the bone resorption activity of the differentiated osteoclasts.
상기 도 5b 내지 5d의 결과로부터, 새싹보리 추출물이 파골세포의 골 흡수 활성을 효과적으로 억제함을 알 수 있었다.From the results shown in Figs. 5B to 5D, it was found that the extract of bud of barberry effectively inhibited the osteoclastic bone resorption activity.
실시예Example 7: 여성 갱년기 질환의 원인이 되는 여성 호르몬 저하증에 대한 새싹보리 추출물의 개선 효과 7: Improvement of germinal barley extract on female hormone hypothyroidism which causes female climacteric disease
에스트로겐 수용체(에스트로겐 수용체 알파)를 과다하게 발현시키는 것으로 알려진 암세포주(MCF-7 human breast cancer cell)에 상기 실시예 1에서 수득한 새싹보리 추출물을 다양한 용량(10, 25, 50 또는 100 ㎍/㎖)으로 처리하고 배양한 후, 루시퍼라제가 결합된 항체를 이용하여, 활성화된 에스트로겐 수용체의 수준을 측정하였다(도 6). 이때, 음성 대조군으로는 아무것도 처리하지 않은 암세포주를 사용하고, 양성 대조군으로는 상기 암세포주에서 에스트로겐 수용체를 활성화시키는 것으로 알려진 17 베타-에스트로겐을 10 nM의 용량으로 처리한 암 세포주를 사용하였다.The MCF-7 human breast cancer cell, which is known to over-express the estrogen receptor (estrogen receptor alpha), is administered with various doses (10, 25, 50 or 100 占 퐂 / ml ) And cultured, the level of activated estrogen receptor was measured using an antibody conjugated with luciferase (FIG. 6). At this time, a cancer cell line in which no treatment was performed was used as a negative control, and a cancer cell line treated with a 10
도 6은 에스트로겐 수용체를 과다하게 발현시키는 것으로 알려진 암세포주에서 에스트로겐 수용체 알파의 활성화에 대한 새싹보리 추출물의 효과를 분석한 결과를 나타내는 그래프이다.FIG. 6 is a graph showing the results of analysis of the effect of the barley extract on the activation of estrogen receptor alpha in cancer cell lines known to over-express the estrogen receptor.
도 6에서 보듯이, 본 발명의 새싹보리 추출물을 처리할 경우, 활성화된 에스트로겐 수용체의 수준이 상기 추출물의 농도의존적으로 증가됨을 확인하였다.As shown in FIG. 6, when the extract of the present invention was treated with barberry extract, the level of activated estrogen receptor was increased in a concentration-dependent manner.
Claims (7)
A pharmaceutical composition for preventing or treating female hormone secretion disorders, comprising a barberry extract.
상기 새싹보리 추출물은 새싹보리를 물, 탄소수 1 내지 4의 알코올 및 이들의 혼합 용매로 이루어진 군에서 선택된 1종 이상의 용매로 추출하여 수득한 것인, 약학 조성물.
The method according to claim 1,
Wherein the extract of bud from barley is obtained by extracting bud of barley with at least one solvent selected from the group consisting of water, an alcohol having 1 to 4 carbon atoms and a mixed solvent thereof.
상기 조성물은 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함하는 것인, 조성물.
The method according to claim 1,
Wherein the composition further comprises a pharmaceutically acceptable carrier, excipient or diluent.
A method for preventing or treating a female hormone secretion disorder comprising administering a composition according to any one of claims 1, 2, and 5 to a subject other than a human who has or is likely to develop a female hormone secretory disorder Way.
A food composition for improving the secretion of female hormone secretion, comprising the extract of barley barley.
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KR20220152070A (en) | 2021-05-07 | 2022-11-15 | 대구가톨릭대학교산학협력단 | Composition for preventing or treating of osteoclast differentiation comprising barley grass extracts or alkaloids frction therefrom or alkaloid compounds isolated therefrom |
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