KR20200049999A - Composition for Preventing or Treating Secondary Osteoporosis Comprising Probiotics - Google Patents
Composition for Preventing or Treating Secondary Osteoporosis Comprising Probiotics Download PDFInfo
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- KR20200049999A KR20200049999A KR1020180131027A KR20180131027A KR20200049999A KR 20200049999 A KR20200049999 A KR 20200049999A KR 1020180131027 A KR1020180131027 A KR 1020180131027A KR 20180131027 A KR20180131027 A KR 20180131027A KR 20200049999 A KR20200049999 A KR 20200049999A
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- osteoporosis
- lactobacillus
- present
- strain
- composition
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Abstract
Description
본 발명은 프로바이오틱스를 유효 성분으로 포함하는 이차성 골다공증의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for the prevention or treatment of secondary osteoporosis comprising probiotics as an active ingredient.
골다공증(Osteoporosis)은 연령과 폐경 등 정상 생리적 변화에 기인하여 골량이 감소하는 일차성 골다공증(원발성, primary)과, 연령과 관계없이 질환이나 약물에 노출되어 초래되는 이차성 골다공증(속발성, secondary), 크게 두 가지로 분류된다. 흔히 골다공증은 노년기의 질병이라고 생각하기 쉽지만, 이차성 골다공증의 경우 노령이 아닌 경우에도 발병할 수 있고, 이 경우 향후 환자의 삶의 질에 미치는 영향이 매우 크기 때문에 이차성 골다공증의 치료 및 예방 방법을 개발하는 것은 매우 중요하다. Osteoporosis is primary osteoporosis (primary) in which bone mass decreases due to normal physiological changes such as age and menopause, and secondary osteoporosis (secondary) caused by exposure to diseases or drugs regardless of age. It is divided into two categories. Osteoporosis is often thought to be a disease of old age, but secondary osteoporosis can develop even if you are not old, and in this case, because it has a great impact on the quality of life of patients in the future, developing a method for treating and preventing secondary osteoporosis It is very important.
이차성 골다공증의 원인들은 매우 다양하다. 여러 전신 질환과 약물 등이 원인으로 알려져 있으나, 이 중 글루코코르티코이드 복용으로 인한 골다공증이 가장 흔하다. 글루코코르티코이드(Glucocorticoid: GC)는 항염증과 면역억제 기능이 있어 류마티스 관절염, 천식, 아토피 피부염, 관절염 등 여러 질병의 치료에 보편적으로 사용되는 약제이다. GC의 장기간 투여는 이러한 질병을 효과적으로 억제하지만, 대부분 환자에게서 조골세포와 파골세포의 정상적인 활성을 저해하여 골다공증을 초래한다. 통계적으로 살펴보면, GC를 투여하는 환자의 경우 1년 이내 골밀도의 12%가 급격히 감소되고 그 이후로는 뼈의 손실이 서서히 진행되어 2~5% 정도의 골밀도가 매년 점차적으로 감소됨이 보고된 바 있다. 위와 같은 GC 투여에 의한 이차성 골다공증을 예방하기 위해서는 GC의 투여를 중단하는 것이 가장 이상적인 방법이기는 하나, 해당 질병의 치료를 위해서는 소량이라도 복용이 지속되어야 한다는 점에서 문제가 된다. The causes of secondary osteoporosis are very diverse. Osteoporosis caused by taking glucocorticoids is the most common. Glucocorticoid (Glucocorticoid: GC) has anti-inflammatory and immunosuppressive functions, and is a drug commonly used to treat various diseases such as rheumatoid arthritis, asthma, atopic dermatitis, and arthritis. Long-term administration of GC effectively suppresses these diseases, but inhibits the normal activity of osteoblasts and osteoclasts in most patients, resulting in osteoporosis. Statistically, it has been reported that in the case of GC-administered patients, 12% of bone density decreases rapidly within 1 year, and bone loss gradually progresses after that, and 2-5% of bone density gradually decreases every year. . In order to prevent secondary osteoporosis by GC administration as described above, it is the most ideal method to stop GC administration, but it is problematic in that even a small amount should be continued to treat the disease.
GC의 장기 투여로 인한 골다공증을 예방할 수 있는 식품을 함께 섭취하는 것도 좋은 대안이 될 수 있지만, 시중에서 판매중인 제품들은 대부분 폐경기 여성, 및 노인성 골다공증과 같은 '원발성 골다공증'을 개선하기 위한 건강기능식품이며, 이차성 골다공증을 예방할 수 있는 제품은 아직까지 개발된 바 없다. 따라서 이차성 골다공증의 예방, 개선 또는 치료용도의 식품 또는 의약품의 개발이 절실히 필요한 실정이다. Eating foods that can prevent osteoporosis caused by long-term administration of GC may be a good alternative, but most commercially available products are health functional foods to improve 'primary osteoporosis' such as postmenopausal women and senile osteoporosis. , And a product capable of preventing secondary osteoporosis has not been developed. Therefore, there is an urgent need to develop food or pharmaceutical products for the prevention, improvement or treatment of secondary osteoporosis.
본 발명자들은 향후 골다공증의 예방, 개선 또는 치료용도의 식품 및 의약품으로 응용이 가능한 프로바이오틱스 균주 및 이를 이용한 발효유를 개발하고자 하였다. 그 결과, 프로바이오틱스 균주를 사용하여 발효유를 제조한 후 이를 글루코코르티코이드-유도 이차성 골다공증 실험동물에게 경구 투여하면 골밀도 및 골비율의 증가되고, 칼슘 관련 흡수 및 대사에 관련된 유전자의 발현이 증가됨을 규명함으로써, 본 발명을 완성하게 되었다. The present inventors tried to develop a probiotic strain and fermented milk using the same, which can be applied as food and pharmaceutical products for the prevention, improvement or treatment of osteoporosis in the future. As a result, by preparing a fermented milk using a probiotic strain and then orally administering it to a glucocorticoid-induced secondary osteoporosis experimental animal, the bone density and bone rate are increased and the expression of genes related to calcium absorption and metabolism is increased. The present invention has been completed.
따라서, 본 발명의 목적은 수탁번호 KCTC13686BP 인 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주를 제공하는 것이다. Accordingly, an object of the present invention is to provide a strain Lactobacillus plantarum A41 strain with accession number KCTC13686BP.
본 발명의 다른 목적은 상기 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주를 유효성분으로 포함하는 골다공증의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating osteoporosis, including the Lactobacillus plantarum A41 strain as an active ingredient.
본 발명의 또 다른 목적은 상기 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주를 유효성분으로 포함하는 골다공증의 예방 또는 개선용 식품조성물을 제공하는 것이다. Another object of the present invention is to provide a food composition for preventing or improving osteoporosis, including the Lactobacillus plantarum A41 strain as an active ingredient.
본 발명의 일 양태에 따르면, 본 발명은 수탁번호 KCTC13686BP 인 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주를 제공한다.According to an aspect of the present invention, the present invention provides Lactobacillus plantarum A41 strain with accession number KCTC13686BP.
본 발명자들은 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주(수탁번호 : KCTC13686BP)를 신규 분리하였다. 또한, 본 발명자들은 상기 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주(수탁번호 : KCTC13686BP)를 이용하여 발효유를 제조하였다. 상기 균주에 의해 제조된 발효유는 이차성 골다공증을 유도한 실험동물모델에 투여한 결과, 골밀도 및 골비율이 증가되는 효과가 있음을 확인하였다. 나아가, 상기 발효유를 투여한 실험동물모델의 장내에서 발현되는 칼슘 흡수 관련 단백질의 발현량이 증가되고, 혈중 칼슘농도가 증가되며, 파골세포 분화 억제 및 조골세포 분화 촉진과 관련된 유전자의 발현량을 조절함을 확인하였다. The present inventors newly isolated Lactobacillus plantarum A41 strain (Accession No .: KCTC13686BP). In addition, the present inventors prepared the fermented milk using the Lactobacillus plantarum A41 strain (Accession No .: KCTC13686BP). The fermented milk produced by the strain was administered to an experimental animal model inducing secondary osteoporosis, and it was confirmed that there is an effect of increasing bone density and bone proportion. Furthermore, the expression level of the calcium absorption-related protein expressed in the intestine of the experimental animal model administered with the fermented milk is increased, the blood calcium concentration is increased, and the expression level of genes related to suppressing osteoclast differentiation and promoting osteoblast differentiation is regulated. Was confirmed.
위 결과로부터, 본 발명의 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주(수탁번호 : KCTC13686BP)를 이용하여 제조된 발효유는 이차성 골다공증의 예방, 개선, 또는 치료에 유용하게 사용될 수 있음을 확인하였다. From the above results, it was confirmed that the fermented milk prepared using Lactobacillus plantarum A41 strain (Accession No .: KCTC13686BP) of the present invention can be useful for the prevention, improvement, or treatment of secondary osteoporosis.
본 명세서에서 용어 "골다공증(osteoporosis)"은 "골량의 감소와 미세구조의 이상을 특징으로 하는 전신적인 골격계 질환으로, 결과적으로 뼈가 약해져서 부러지기 쉬운 상태가 되는 질환"을 말한다. 골강도는 골량(quantity)과 골질(quality)에 의해 결정된다. 골량은 주로 골밀도 (BMD)에 의해 표현되고 골질은 구조, 골교체율, 무기질화, 미세 손상 축적 등으로 구성된다. 현재는 골밀도를 측정하여 골다공증을 진단하고 있다.As used herein, the term "osteoporosis" refers to a "systemic skeletal disease characterized by a decrease in bone mass and abnormalities in microstructure, and as a result, a weakened bone and a condition prone to breakage". Bone strength is determined by the quantity and quality. Bone mass is mainly expressed by bone density (BMD), and bone quality consists of structure, bone replacement rate, mineralization, and micro-damage accumulation. Currently, osteoporosis is diagnosed by measuring bone density.
골다공증은 일차성과 이차성 골다공증으로 분류된다. 일차성 골다공증 또는 원발성 골다공증은 폐경으로 인한 제1형 골다공증과 노화로 인한 제2형 골다공증으로 편의상 분류하지만 거의 같은 시기에 병합되어 진행되므로 정확히 분류하기 어려운 것으로 알려져 있다. 이차성 골다공증은 기저질환이나 약물에 의해 뼈의 미세구조가 변하고 골량이 감소하여 골절위험도가 증가한 것을 말한다. 이차성 골다공증의 원인으로 내분비질환(갑상선중독증, 당뇨병, 부갑상선기능항진증 등), 위장관질환(위절제줄, 만성 간질환, 흡수장애증후군, 염증성 장질환, 알코올 중독 등), 골수질환, 결체 조직질환(강직성 척추염, 류마티스 관절염, 골형성부전증 등), 약물 등이 있다. 남성에서 가장 흔한 원인은 성선기능 저하증, 글루코코르티코이드 투여 등이다.Osteoporosis is classified as primary and secondary osteoporosis. Primary osteoporosis or primary osteoporosis is classified as
본 발명의 일구현예에서, 상기 골다공증은 이차성 골다공증이고, 보다 구체적으로는 글루코코르티코이드계 약물 투여에 의한 이차성 골다공증이다. 상기 글루코코르티코이드계 약물은 코르티솔, 프레드니손, 프레드니솔론, 메틸프레드니솔론, 코르티손, 하이드록시코르티손, 트리암시놀론, 베타메타손, 또는 덱사메타손이나, 이에 한정되는 것은 아니다In one embodiment of the present invention, the osteoporosis is secondary osteoporosis, and more specifically, secondary osteoporosis by glucocorticoid drug administration. The glucocorticoid-based drug is, but is not limited to, cortisol, prednisone, prednisolone, methylprednisolone, cortisone, hydroxycortisone, triamcinolone, betamethasone, or dexamethasone.
본 발명에 있어서, 상기 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주는 "한국생명공학연구원 미생물자원센터(Korean Collection for Type Culture, KCTC)"에 수탁번호 "KCTC13686BP"로 기탁된 것이다. In the present invention, the Lactobacillus plantarum A41 strain is deposited with accession number "KCTC13686BP" to "Korean Collection for Type Culture (KCTC)", "Korea Research Institute of Bioscience and Biotechnology".
상기 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주의 균체 성상은 다음과 같다:The microbial properties of the Lactobacillus plantarum A41 strain are as follows:
- 서열번호 1의 16s rRNA 서열을 포함함-Contains the 16s rRNA sequence of SEQ ID NO: 1
- 그람 양성 막대모양 또는 구형 간균의 형태임-Gram-positive rod-shaped or spherical bacilli
- 인간의 입, 위장, 여성 성기관의 정상 세균총의 일부이며, 일반적으로 음식에 사용하는 것에 대해 안전하다고 여겨진다 (probiotics와 발효음식). L. plantarum은 Lactobacillus 속 구성원이며, 일반적으로 많은 발효 식품과 혐기성 식물의 물질에서 발견되며 타액에도 존재 하기도 한다.It is part of the normal microflora of the human mouth, stomach, and female sex organs and is generally considered safe for use in food (probiotics and fermented foods). L. plantarum is a member of the genus Lactobacillus , and is commonly found in many fermented foods and substances of anaerobic plants and is also present in saliva.
따라서, 본 발명의 다른 일 양태에 따르면, 본 발명은 수탁번호 KCTC13686BP인 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주, 또는 이의 배양물을 유효성분으로 포함하는 골다공증 예방 또는 치료용 약제학적 조성물을 제공한다. Accordingly, according to another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating osteoporosis comprising Lactobacillus plantarum A41 strain having accession number KCTC13686BP, or a culture thereof as an active ingredient. do.
본 발명의 또 다른 일 양태에 따르면, 본 발명은 수탁번호 KCTC13686BP인 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주, 또는 이의 배양물을 유효성분으로 포함하는 골다공증 예방 또는 개선용 식품조성물을 제공한다.According to another aspect of the present invention, the present invention provides a food composition for preventing or improving osteoporosis comprising Lactobacillus plantarum A41 strain having accession number KCTC13686BP, or a culture thereof as an active ingredient.
본 발명의 일구현예에서, 상기 조성물은 유효성분으로 락토바실러스 퍼멘텀(Lactobacillus fermentum), 락토바실러스 카제이(Lactobacillus casei), 락토바실러스 애시도필러스(Lactobacillus acidophilus), 락토바실러스 불가리쿠스(Lactobacillus delbrueckii ssp bulgaricus), 락토코커스 락티스(Lactococcus lactis), 엔테로코커스 페시움(Enterococcus faecium), 엔테로코커스 페칼리스(Enterococcus fecalis), 스트렙토코커스 써모필러스(Streptococcus thermophilus), 비피도박테리움 비피덤(Bifidobacterium bifidum), 및 비피도 박테리움 락티스(Bifidobacterium lactis) 로 이루어진 군으로부터 선택되는 1종 이상의 균, 또는 이의 배양물을 추가적으로 포함한다. In one embodiment of the present invention, the composition is Lactobacillus fermentum , Lactobacillus casei , Lactobacillus acidophilus , Lactobacillus acidophilus , Lactobacillus bulgaricus as an active ingredient ( Lactobacillus delbrueckii) ssp bulgaricus ), Lactococcus lactis , Enterococcus faecium , Enterococcus fecalis , Streptococcus thermophilus , Bifidobacterium bifidum ), and Bifidobacterium lactis ), or one or more bacteria selected from the group consisting of, or a culture thereof.
본 발명의 구체적인 구현예에서, 상기 락토바실러스 퍼멘텀은 락토바실러스 퍼멘텀 SRK414 균주(수탁번호 KCTC13687BP)일 수 있다. In a specific embodiment of the present invention, the Lactobacillus performance can be Lactobacillus performance SRK414 strain (Accession No. KCTC13687BP).
본 발명에 있어서, 상기 락토바실러스 퍼멘텀 SRK414 균주는 "한국생명공학연구원 미생물자원센터(Korean Collection for Type Culture, KCTC)"에 수탁번호 "KCTC13687BP"로 기탁된 것이다. In the present invention, the Lactobacillus performance SRK414 strain is deposited with the accession number "KCTC13687BP" to "Korean Microbiology Resource Center (KCTC)".
상기 락토바실러스 퍼멘텀 SRK414 균주의 균체 성상은 다음과 같다:The microbial properties of the Lactobacillus performance SRK414 strain are as follows:
- 서열번호 2의 16s rRNA 서열을 포함함 -Contains the 16s rRNA sequence of SEQ ID NO: 2
- 그람 양성 막대모양 또는 구형 간균의 형태임-Gram-positive rod-shaped or spherical bacilli
- 인간의 입, 위장, 여성 성기관의 정상 세균총의 일부이며, 일반적으로 음식에 사용하는 것에 대해 안전하다고 여겨진다 (probiotics와 발효음식). L. fermentum은 Lactobacillus 속 구성원이며, 이 속에 속하는 종들은 다양한 활용이 가능하다고 한다. 이러한 활용은 식품과 사료 발효를 포함한다. L. fermentum 중 몇 균주들은 항생제 및 화학요법제에 대해 자연내성을 갖는 것으로 밝혀져 있다. It is part of the normal microflora of the human mouth, stomach, and female sex organs and is generally considered safe for use in food (probiotics and fermented foods). L. fermentum is a member of the genus Lactobacillus , and species belonging to this genus are said to be versatile. These uses include food and feed fermentation. L. fermentum Several strains have been found to have natural resistance to antibiotics and chemotherapeutic agents.
본 발명의 조성물들의 유효성분인 상기 균주, 또는 이의 배양물은 상기 균주를 단리 및/또는 정제한 균체 외에 균체를 포함하는 배양물, 균체의 추출물, 배양물 상층액, 이들의 농축액, 농축물, 건조물, 또한 필요에 따라서 희석액, 희석물 등이며, 배양액, 배양물을 처리하여 얻어지는 모든 상태의 것을 포함한다. The strain, or a culture thereof, which is an active ingredient of the compositions of the present invention, is a culture medium containing cells in addition to the cells isolated and / or purified from the strain, an extract of cells, a culture supernatant, a concentrate thereof, a concentrate, It is a dried product, and if necessary, a diluent, a diluent, and the like, and includes all of the state obtained by treating the culture medium and the culture.
상기 균체의 배양법, 추출법, 분리법, 농축법, 건조법, 희석법 등은 특별히 한정되지 않는다. The culture method, extraction method, separation method, concentration method, drying method, dilution method, etc. of the above-mentioned cell body are not particularly limited.
균체를 배양하기 위한 배지로는 통상적으로 탈지유, 훼이, 카제인 등의 우유 단백질, 당류, 효모 엑기스 등을 포함하고 있으며, 배양 방법으로는 일반적인 각종 호기적 또는 혐기적인 방법을 적당히 사용할 수 있다. The medium for culturing the cells generally includes milk protein such as skim milk, whey, and casein, sugars, yeast extracts, etc., and various aerobic or anaerobic methods common to the culture method can be suitably used.
배양 온도로는 예를 들어 35~45℃를 설정하고, 배양 중에는 수산화나트륨 등의 알칼리를 사용하여 배지의 pH를 중성으로부터 산성, 예를 들어 pH가 5~6정도가 되도록 유지하는 중화배양법을 사용할 수도 있다. 이와 같은 중화배양법 외에 회분배양법 등의 임의의 배양 방법을 사용할 수 있으며, 배양한 후에는 필요에 따라서 배양물이나 그 상층액을 농축, 건조, 희석 등을 할 수도 있다. As the culture temperature, for example, 35 to 45 ° C is set, and during the culture, an alkali such as sodium hydroxide is used to use a neutralization culture method that maintains the pH of the medium from neutral to acidic, for example, about 5 to 6 pH. It might be. In addition to such a neutralization method, any culture method such as a batch culture method can be used. After cultivation, the culture or the supernatant may be concentrated, dried, or diluted, if necessary.
또한 원심분리법이나 막분리법을 사용하여 배양물의 상층액과 균체를 분리하여 균체를 농축한 상태로 회수할 수도 있다. 그리고 균체에 초음파 처리나 효소 처리 등을 행하여 균체 내의 성분을 추출하거나, 배양물이나 그 상층액, 균체나 그 추출물 등을 건조할 수도 있다. 이들은 본 발명의 상기 조성물의 유효 성분으로서 사용할 수 있다.In addition, the supernatant and the cells of the culture may be separated using a centrifugation method or a membrane separation method, and the cells may be recovered in a concentrated state. In addition, the cells may be subjected to ultrasonic treatment or enzyme treatment to extract components in the cells, or the culture or supernatant, the cells or the extract may be dried. These can be used as an active ingredient of the composition of the present invention.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로서 상기 유산균 뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있다. 상기 첨가성분은 예컨대 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상기 탄수화물로는 모노사카라이드(예를 들어, 포도당, 과당 등), 디사카라이드(예를 들어 말토스, 수크로스, 올리고당 등) 및 폴리사카라이드(예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 (타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등)) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.When the composition of the present invention is prepared as a food composition, as an active ingredient, as well as the lactic acid bacteria, it may include a component that is conventionally added in food production. The additive components include, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. Examples of the carbohydrate include monosaccharides (eg, glucose, fructose, etc.), disaccharides (eg, maltose, sucrose, oligosaccharides, etc.) and polysaccharides (eg, dextrins, cyclodextrins, etc.). Sugars and sugar alcohols such as xylitol, sorbitol, erythritol, etc. As flavoring agents, natural flavoring agents (taumatin, stevia extracts (e.g. rebaudioside A, glycyrrhizine, etc.)) and synthetic flavoring agents (saccharin, aspar Tom).
예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 유효성분인 상기 균주 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 대추 추출액 또는 감초 추출액 등을 추가로 포함시킬 수 있다.For example, when the food composition of the present invention is prepared as a drink agent, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, jujube extract or licorice extract may be additionally included in addition to the above-mentioned strain as an active ingredient of the present invention. have.
본 발명의 식품조성물은 식품, 기능성 식품(functional food), 영양보조제(nutritional supplement), 건강식품(health food) 및 식품 첨가제(food additives) 등의 모든 천연소재의 가공 형태를 포함한다. 상기 유형의 식품 조성물은 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조될 수 있다.The food composition of the present invention includes processing forms of all natural materials such as food, functional food, nutritional supplement, health food and food additives. Food compositions of this type can be prepared in various forms according to conventional methods known in the art.
예를 들면, 건강식품으로는 상기 유산균 자체를 차, 주스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화하여 섭취할 수 있다. 또한, 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예: 과일통조림, 병조림, 잼, 마아말레이드 등), 어류, 육류 및 그 가공식품(예: 햄, 소시지 콘비이프 등), 빵류 및 면류(예: 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예: 요거트, 발효유, 버터, 치즈 등), 식용식물유지, 마아가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예: 된장, 간장, 소스 등) 등 본 발명의 유산균을 첨가하여 제조될 수 있다. 또한, 본 발명의 유산균을 식품 첨가제의 형태로 사용하기 위해서는 분말 또는 농축액 형태로 제조하여 사용할 수 있다.For example, as a healthy food, the lactic acid bacteria themselves may be prepared in the form of tea, juice, and drink to be consumed or granulated, encapsulated, and powdered. In addition, food products include beverages (including alcoholic beverages), fruits and processed foods thereof (eg, canned fruits, canned foods, jams, marmalades, etc.), fish, meat, and processed foods (eg ham, sausage corn beef, etc.) ), Breads and noodles (e.g. udon, buckwheat noodles, ramen, spaghetti, macaroni, etc.), juice, various drinks, cookies, syrup, dairy products (e.g. yogurt, fermented milk, butter, cheese, etc.), edible vegetable oil, margarine, Vegetable protein, retort food, frozen food, various seasonings (eg, miso, soy sauce, sauce, etc.) can be prepared by adding the lactic acid bacteria of the present invention. In addition, in order to use the lactic acid bacteria of the present invention in the form of food additives, it may be prepared and used in the form of a powder or a concentrate.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로오스, 폴리비닐피롤리돈, 셀룰로오스, 물, 시럽, 메틸 셀룰로오스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 제한되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier included in the pharmaceutical composition of the present invention is commonly used in formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, but is not limited thereto It does not work. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.
본 발명의 약제학적 조성물은 경구 또는 비경구 투여할 수 있으며, 바람직하게는 경구 투여 방식으로 적용된다. 본 발명의 약제학적 조성물은 하기의 다양한 경구 또는 비경구 투여 형태로 제형화할 수 있으나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention can be administered orally or parenterally, and is preferably applied by oral administration. The pharmaceutical composition of the present invention may be formulated in various oral or parenteral dosage forms, but is not limited thereto.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제. 과립제, 엘릭시르제 등이 있는데, 이들 제형은 상기 유효성분 이외에 통상적으로 사용되는 충진제, 증량제, 습윤제, 붕해제, 활택제, 결합제, 계면활성제 등의 희석제 또는 부형제를 1종 이상 사용할 수 있다. 붕해제로는 한천, 전분, 알긴산 또는 이의 나트륨염, 무수인산일수소 칼슘염 등이 사용될 수 있고, 활택제로는 실리카, 탈크, 스테아르산 또는 이의 마그네슘염 또는 칼슘염, 폴리에틸렌 글리콜 등이 사용될 수 있으며, 결합제로는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로오스, 나트륨카복시메틸셀룰로오스, 폴리비닐피롤리딘, 저치환도 하이드록시프로필셀룰로오스 등이 사용될 수 있다. 이외에도 락토즈, 덱스트로오스, 수크로오스, 만니톨, 소르비톨, 셀룰로오스. 글리신 등을 희석제로 사용할 수 있으며, 경우에 따라서는 일반적으로 알려진 비등 혼합물, 흡수제, 착색제, 향미제, 감미제 등을 함께 사용할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, and syrups. There are granules, elixirs, and the like, and these formulations may use one or more diluents or excipients, such as fillers, extenders, wetting agents, disintegrating agents, lubricants, binders, and surfactants, which are commonly used in addition to the active ingredients. As a disintegrating agent, agar, starch, alginic acid or its sodium salt, calcium phosphate monohydrogen anhydride, etc. may be used, and as a lubricant, silica, talc, stearic acid or its magnesium salt or calcium salt, polyethylene glycol, etc. may be used. , As the binder, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low-substituted hydroxypropylcellulose, and the like can be used. In addition, lactose, dextrose, sucrose, mannitol, sorbitol, and cellulose. Glycine or the like can be used as a diluent, and in some cases, commonly known boiling mixtures, absorbents, colorants, flavoring agents, sweeteners and the like can be used together.
상기 조성물은 멸균되거나 또는 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염, 완충제 등의 보조제 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다. The composition may be sterilized or contain preservatives, stabilizers, hydration or emulsification accelerators, salts for osmotic pressure control, adjuvants such as buffers, and other therapeutically useful substances, conventional methods of mixing, granulating or coating methods It can be formulated according to.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. Suitable dosages of the pharmaceutical compositions of the invention are variously prescribed by factors such as formulation method, mode of administration, patient's age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion, and response sensitivity. Can be.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention is prepared in a unit dose form by formulating using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily carried out by those skilled in the art to which the present invention pertains. Or it can be manufactured by incorporating into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, syrup or emulsion in an oil or aqueous medium, or may be in the form of ex-agent, powder, granule, tablet or capsule, and may further include a dispersant or stabilizer.
본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 수탁번호 KCTC13686BP인 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주를 제공한다. (a) The present invention provides Lactobacillus plantarum A41 strain with accession number KCTC13686BP.
(b) 본 발명은 수탁번호 KCTC13686BP인 락토바실러스 플란타럼(Lactobacillus plantarum) A41 균주, 또는 이의 배양물을 유효성분으로 포함하는 약제학적 조성물 및 식품조성물을 제공한다.(b) The present invention provides a pharmaceutical composition and food composition comprising Lactobacillus plantarum A41 strain having accession number KCTC13686BP, or a culture thereof as an active ingredient.
본 발명의 균주 및 그 배양물은 골다공증, 특히 이차성 골다공증을 예방하거나 개선, 또는 치료하기 위한 목적의 식품조성물 및 약제학적 조성물로 유용하게 사용될 수 있다. The strain of the present invention and its culture can be usefully used as a food composition and pharmaceutical composition for the purpose of preventing, improving, or treating osteoporosis, particularly secondary osteoporosis.
도 1은 실험 그룹 별 골밀도(bone mineral density, mg/cm3)를 나타낸 도이다.
도 2는 실험 그룹 별 골비율(percent bone volume, %)을 나타낸 도이다.
도 3은 실험 그룹 별 장내 칼슘 수용 단백질인 TRPV6의 mRNA 발현량을 나타낸 도이다.
도 4는 실험 그룹 별 장내 칼슘 수용 단백질인 Calbindin-D9k의 mRNA 발현량을 나타낸 도이다.
도 5는 실험 그룹 별 장내 칼슘 수용 단백질인 PMCA1의 mRNA 발현량을 나타낸 도이다.
도 6은 실험 그룹 별 혈중 칼슘 농도를 나타낸 도이다.
도 7은 실험 그룹 별 RANKL mRNA의 발현량을 나타낸 도이다.
도 8은 실험 그룹 별 OPG mRNA의 발현량을 나타낸 도이다.
도 9는 실험 그룹 별 BSP mRNA의 발현량을 나타낸 도이다. 1 is a diagram showing bone mineral density (mg / cm 3 ) for each experimental group.
2 is a view showing the percentage of bone (percent bone volume,%) for each experimental group.
Figure 3 is a diagram showing the mRNA expression level of the intestinal calcium-accepting protein TRPV6 for each experimental group.
4 is a diagram showing the mRNA expression level of Calbindin-D9k, an intestinal calcium-accepting protein, for each experimental group.
5 is a diagram showing the mRNA expression level of the intestinal calcium-accepting protein PMCA1 by experimental group.
6 is a diagram showing the blood calcium concentration for each experimental group.
7 is a diagram showing the expression level of RANKL mRNA for each experimental group.
8 is a diagram showing the expression level of OPG mRNA for each experimental group.
9 is a diagram showing the expression level of BSP mRNA for each experimental group.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only intended to illustrate the present invention more specifically, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
본 명세서 전체에 걸쳐, 특정 물질의 농도를 나타내기 위하여 사용되는 "%"는 별도의 언급이 없는 경우, 고체/고체는 (중량/중량) %, 고체/액체는 (중량/부피) %, 그리고 액체/액체는 (부피/부피) %이다.Throughout this specification, "%" used to indicate the concentration of a specific substance, unless otherwise specified, solids / solids (weight / weight)%, solids / liquids (weight / volume)%, and The liquid / liquid is (volume / volume)%.
실시예Example 1: One: 프로바이오틱스Probiotics 균주 및 발효유의 제조 Preparation of strains and fermented milk
본 실험에 사용된 프로바이오틱스 균주들은 영유아의 분변과 전통 발효식품으로부터 분리되었다(표 2). 본 발명의 발효유를 제조하기 위하여, 탈지 우유(skim milk) 배지에 상기에서 분리한 프로바이오틱스 균주를 각각 접종하여 37℃에서 48시간 동안 배양하였다. 발효가 완료된 발효유는 동결건조 후 분말화 하여 PBS에 1×1010 CFU/ml 농도로 현탁하여 실험동물에게 급여하였다. 본 발명에 사용된 탈지 우유 배지의 조성과, 프로바이오틱스 균주 목록은 표 1 및 표 2에 나타내었다. Probiotic strains used in this experiment were isolated from feces and traditional fermented foods of infants and young children (Table 2). In order to prepare the fermented milk of the present invention, skim milk medium was inoculated with probiotic strains isolated from the above, and cultured at 37 ° C for 48 hours. After the fermentation was completed, the fermented milk was lyophilized and powdered, suspended in PBS at a concentration of 1 × 10 10 CFU / ml, and fed to the experimental animals. The composition of the skim milk medium used in the present invention and the list of probiotic strains are shown in Table 1 and Table 2.
실시예Example 2: 이차성 골다공증 동물모델의 제작 및 2: Production of secondary osteoporosis animal model and 실험군Experimental group 설정 Set
2.1 이차성 골다공증 동물모델의 제작2.1 Production of secondary osteoporosis animal model
이차성 골다공증 동물 모델은 다음과 같이 제작하였다. 체중 175~185 g 내외의 8주령 Wistar계 암컷 랫드(Samtako, South Korea)를 펠렛형 사료와 물을 충분히 공급하여 1주일 간 개별 케이지에 적응시킨 후 실험에 사용하였다. 이차성 골다공증 모델의 수립은 Lucinda et al.(PHYTOTHERAPY RESEARCH 27(4), (2012), 515-520) 와 Sousa et al.(Archives of Oral Biology 77 (2017) 55-61)에 의거하여 근육내 주사법으로 글루코코르티코이드의 일종인 덱사메타손(Dexamethasone, DEX)을 7 mg/kg BW의 농도로 주 1회씩 5주간 투여하였다. Animal models of secondary osteoporosis were constructed as follows. Eight week old Wistar female rats (Samtako, South Korea), weighing around 175 to 185 g, were sufficiently supplied with pellet-type feed and water to adapt to individual cages for one week before being used in the experiment. The establishment of a secondary osteoporosis model is an intramuscular injection method according to Lucinda et al. (PHYTOTHERAPY RESEARCH 27 (4), (2012), 515-520) and Sousa et al. (Archives of Oral Biology 77 (2017) 55-61). As a type of glucocorticoid, dexamethasone (DEX) was administered at a concentration of 7 mg / kg BW once a week for 5 weeks.
2.2 2.2 실험군의Experimental 설정 및 발효유의 급여 Setting and feeding of fermented milk
본 발명의 프로바이오틱스 균주 및 발효유의 이차성 골다공증에 대한 치료효과를 확인하기 위하여, 실험군을 하기 표 3과 같이 총 9개의 그룹으로 분류하였다. 각 그룹별로 실험동물을 7마리씩 배정하였고, Normal 그룹을 제외한 모든 그룹은 상기 2.1의 방법대로 덱사메타손(DEX)을 주 1회 7 mg/kg(BW)의 농도로 5주간 투여하였다. In order to confirm the therapeutic effect of the probiotic strain and fermented milk of the present invention on secondary osteoporosis, the experimental groups were classified into a total of 9 groups as shown in Table 3 below. 7 experimental animals were assigned to each group, and all groups except the normal group were administered dexamethasone (DEX) once a week at a concentration of 7 mg / kg (BW) for 5 weeks as described in the above 2.1.
모든 발효유는 1×1010 CFU/ml의 농도로 PBS(Phosphate buffer saline)에 희석하여 위관 영양법(oral gavage)으로 경구 투여하였다. 한편, 본 실험의 목적이 프로바이오틱스를 이용한 우유 발효물의 항 골다공증 효과를 확인하기 위함이기 때문에 대조군으로는 발효를 진행하지 않은 Skim milk 투여군(SMP)을 사용하였다.All fermented milk was diluted or diluted in PBS (Phosphate buffer saline) at a concentration of 1 × 10 10 CFU / ml and orally administered by oral gavage. On the other hand, since the purpose of this experiment is to confirm the anti-osteoporosis effect of milk fermentation using probiotics, a Skim milk administration group (SMP) that did not undergo fermentation was used as a control.
실시예Example 3: 본 발명의 발효유 투여에 따른 골의 형태학적 분석 3: Morphological analysis of bone according to the administration of fermented milk of the present invention
골밀도(Bone mineral density)와 골비율(Percent bone volume)은 뼈의 강도를 측정할 때 가장 기본적으로 확인하는 지표이다. 본 발명의 프로바이오틱스 균주 및 발효유의 골밀도 개선효과를 측정하기 위하여, Micro Ct 영상분석기(Sky Scan 1176)와 이를 재구성하는 프로그램(NRecon), 그리고 이를 분석하는 프로그램(CTAn)을 이용하였다.Bone mineral density and percent bone volume are the most fundamental indicators when measuring bone strength. In order to measure the effect of improving the bone density of the probiotic strain and fermented milk of the present invention, a Micro Ct image analyzer (Sky Scan 1176) and a program to reconstruct it (NRecon), and a program to analyze it (CTAn) were used.
실험 결과, 덱사메타손을 투여한 DEX 그룹에서는 골밀도 및 골비율이 Normal 그룹 대비 유의적으로 감소한 것으로 보아 이차성 골다공증이 유도됨을 확인할 수 있었다. 이차성 골다공증 약물(alendronate)을 덱사메타손과 함께 투여한 Drug 그룹에서는 덱사메타손 투여로 인해 감소된 골밀도와 골비율이 회복된 것으로 나타났다. 본 발명의 프로바이오틱스 균주로 발효시킨 발효유를 투여한 A41 그룹, SRK414 그룹, B719 그룹, 및 393 그룹도 drug 그룹과 유사한 정도의 골밀도 및 골비율 회복 효과를 나타내었다. (도 1 및 도 2)As a result of the experiment, it was confirmed that secondary osteoporosis was induced in the DEX group administered with dexamethasone, as the bone density and bone ratio were significantly decreased compared to the normal group. In the drug group, in which the secondary osteoporosis drug (alendronate) was administered together with dexamethasone, it was shown that the reduced bone density and bone fraction were restored by administration of dexamethasone. The A41 group, the SRK414 group, the B719 group, and the 393 group to which the fermented milk fermented with the probiotic strain of the present invention were administered also exhibited similar bone mineral density and bone rate recovery effects. (FIGS. 1 and 2)
상기 결과로부터, 본 발명의 프로바이오틱스 균주인 L. plantarum A41, L. fermentum SRK414, L. plantarum B719, L. casei 393 으로 발효시킨 발효유가 덱사메타손의 투여로 유발된 이차성 골다공증의 증상인 골밀도, 골비율 감소를 회복시킴을 확인하였다.From the above results, the fermented milk fermented with the probiotic strains L. plantarum A41, L. fermentum SRK414, L. plantarum B719,
실시예Example 4. 본 발명의 발효유 투여에 의한 칼슘 흡수 관련 지표 분석 4. Analysis of indicators related to calcium absorption by administration of fermented milk of the present invention
혈중 칼슘농도가 부족할 경우, 뼈에 있는 칼슘이 혈중으로 유리되어 골소실이 증가하게 된다. 따라서 장내에서 칼슘 흡수를 촉진시킴으로써 혈중 칼슘 농도를 증가시키는 것은 골소실을 낮출 수 있는 중요한 예방책이 될 수 있다. 칼슘은 장에서 칼슘을 이동시키는 역할을 하는 단백질인 TRPV6, Calbindin-D9k, PMCA1 등에 의해 소장에서 혈관으로 유입되는데, 이들의 발현량이 증가한다면 칼슘 흡수가 원활히 진행된다고 볼 수 있다. 따라서 본 발명자들은 본 발명의 발효유 투여에 따른 장내 칼슘 수용 단백질의 mRNA 발현량을 알아보기 위해서 qRT-PCR 분석을 실시하였으며, 혈중 칼슘 농도와의 관련성을 확인하였다. When the calcium concentration in the blood is insufficient, the calcium in the bone is released into the blood, thereby increasing bone loss. Therefore, increasing calcium concentration in the blood by promoting calcium absorption in the intestine may be an important preventive measure to lower bone loss. Calcium is introduced into the blood vessels from the small intestine by TRPV6, Calbindin-D9k, PMCA1, etc., proteins that play a role in moving calcium from the intestine. Therefore, the present inventors performed qRT-PCR analysis to determine the mRNA expression level of the intestinal calcium-accepting protein according to the administration of fermented milk of the present invention, and confirmed the relationship with the blood calcium concentration.
4.1 장내 칼슘 수용체 유전자 발현 확인4.1 Confirmation of intestinal calcium receptor gene expression
발효유가 장내 칼슘 수용 단백질(TRPV6, Calbindin-D9k, PMCA1)의 발현량에 미치는 효과를 알아보기 위해서 qRT-PCR 분석을 진행하였다. 구체적으로, 실험 기간 종료 후 각 실험동물의 회장을 적출하여 균질화(homogenized)과정을 거친 후 TRIzol(Invitrogne)을 사용하여 조직에 포함되어 있는 RNA를 추출하였다. 정제된 RNA는 역전사효소 oligo(dT) 프라이머와 함께 cDNA합성에 사용되었으며, PCR 조건은 95 ℃에서 3분 이후, 94 ℃에서 10초 60 ℃에서 30초로, 총 44주기 반복하였다. qRT-PCT 분석을 위한 프라이머는 표 4에 나타내었다. 총 전사의 정도는 β-actin 전사 레벨로부터 정규화(normalization)하여 그래프로 나타내었다(도 3 내지 도 5). To investigate the effect of fermented milk on the expression level of intestinal calcium-accepting proteins (TRPV6, Calbindin-D9k, PMCA1), qRT-PCR analysis was performed. Specifically, after the end of the experimental period, the ileum of each experimental animal was extracted, subjected to a homogenized process, and then RNA contained in the tissue was extracted using TRIzol (Invitrogne). The purified RNA was used for cDNA synthesis together with reverse transcriptase oligo (dT) primer. PCR conditions were repeated for 3 cycles at 95 ° C., 3 seconds at 94 ° C., 10 seconds at 60 ° C., and 30 seconds at 60 ° C. for a total of 44 cycles. Primers for qRT-PCT analysis are shown in Table 4. The degree of total transcription was graphically normalized from the β-actin transcription level (FIGS. 3 to 5).
도 3 내지 5에서 나타낸 바와 같이, 본 발명의 발효유 투여 그룹 중에서 A41 그룹 및 SRK414 그룹이 다른 그룹에 비해 상대적으로 높은 장내 칼슘 수용 단백질(TRPV6, Calbindin-D9k, PMCA1)의 발현량을 나타내었다(도 3 내지 도 5).3 to 5, the A41 group and the SRK414 group in the fermented milk administration group of the present invention showed a relatively high expression level of intestinal calcium-accepting proteins (TRPV6, Calbindin-D9k, PMCA1) compared to other groups (FIG. 3 to 5).
4.2 혈중 칼슘 농도 조절효과4.2 Effect of regulating blood calcium concentration
본 발명의 발효유 투여가 혈중 칼슘 농도에 미치는 영향을 확인하기 위하여, 혈중 칼슘 농도를 확인하였다. 구체적으로, 동물실험 기간 종류 후 심장천자(heart puncture)법으로 혈액을 채취하였으며 원심분리(2500 g, 15분, 4℃)하여 수집한 혈청을 분석 전까지 -70 ℃에 보관하였다. 혈청 내에 있는 칼슘(Ca) 농도는 Calcium activity assay kit (㈜엠비엘, Korea)를 사용하여 분석하였다. 결과는 도 6에 나타내었다.In order to confirm the effect of the fermented milk administration of the present invention on the blood calcium concentration, the blood calcium concentration was confirmed. Specifically, blood was collected by a heart puncture method after a period of animal testing, and serum collected by centrifugation (2500 g, 15 minutes, 4 ° C) was stored at -70 ° C until analysis. Calcium (Ca) concentration in the serum was analyzed using a Calcium activity assay kit (MBL, Korea). The results are shown in FIG. 6.
도 6에 나타낸 바와 같이, 장내 칼슘 수용 단백질의 발현량과 마찬가지로 본 발명의 발효유 투여 그룹 중에서 A41 그룹 및 SRK414 그룹이 다른 그룹에 비해 상대적으로 높은 혈중 칼슘 농도를 나타냄을 확인하였다. 따라서 본 발명의 L. plantarum A41, 및 L. fermentum SRK414 균주에 의해 발효된 발효유는, 발효유가 투여된 동물의 소장 내 칼슘 흡수를 촉진시킴으로써 높은 혈중 칼슘 농도 유지하여 골소실을 효과적으로 예방할 수 있다고 사료된다.As shown in FIG. 6, it was confirmed that the A41 group and the SRK414 group in the fermented milk administration group of the present invention showed a relatively high concentration of calcium in the blood as compared with the other groups, similar to the expression level of the intestinal calcium-accepting protein. Therefore, it is considered that the fermented milk fermented by the L. plantarum A41 and L. fermentum SRK414 strains of the present invention can effectively prevent bone loss by maintaining high blood calcium concentration by promoting calcium absorption in the small intestine of animals to which fermented milk is administered. .
실시예Example 5. 본 발명의 발효유 투여에 따른 골 대사 관련 지표 분석 5. Analysis of bone metabolism related indicators according to the administration of fermented milk of the present invention
조골세포 또는 활성화된 면역세포에서 RANKL(Receptor Activator of Nuclear Factor Kappa B Ligand)이 발현되면 파골전구세포 세포막의 RANK(Receptor Activator of Nuclear Factor Kappa B)와 결합하여 파골세포의 분화가 이루어지는데, 이 경우 뼈 흡수가 촉진되어 골다공증이 유발될 수 있다. 반면 OPG(Osteoprotegerin)는 RANKL 대신 RANK에 수용되는 인자로, OPG가 RANK와 RANKL의 결합을 방해함으로써 파골세포의 분화를 억제시킬 수 있다. When Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) is expressed in osteoblasts or activated immune cells, osteoclast differentiation occurs by binding to Receptor Activator of Nuclear Factor Kappa B (RANK) of the osteoclast cell membrane. Bone absorption can be promoted, leading to osteoporosis. On the other hand, OPG (Osteoprotegerin) is a factor that is received by RANK instead of RANKL, and OPG can inhibit the differentiation of osteoclasts by interfering with the binding of RANK and RANKL.
본 발명자들은 본 발명의 발효유 투여가 골 대사에 미치는 영향을 확인하기 위하여, 골대사 관련 마커인 RANKL, OPG, 및 BSP의 mRNA 발현양을 qRT-PCR을 통해 분석하였다. 구체적으로, 실험동물의 넙다리뼈와 골피질을 균질화(homogenization)한 후 TRIzol reagent(Thermofisher, USA)를 이용해 총 RNA를 추출하였다. 정제된 총 RNA는 cDNA합성을 위해 사용하였다. PCR은 Biorad RT-PCR을 사용하였으며 95 ℃에서 3분간 처리한 후, 94 ℃에서 10초, 60 ℃에서 30초를 총 44주기 반복하였다. qRT-PCT 분석을 위한 프라이머는 표 5에 나타내었다. 총 전사의 정도는 β-actin 전사 레벨로부터 정규화(normalization)하여 그래프에 나타내었다(도 7 내지 9).The present inventors analyzed the mRNA expression levels of RANKL, OPG, and BSP, which are bone metabolism-related markers, through qRT-PCR to confirm the effect of fermented milk administration of the present invention on bone metabolism. Specifically, after homogenization of the thigh and bone cortex of the experimental animal, total RNA was extracted using TRIzol reagent (Thermofisher, USA). The purified total RNA was used for cDNA synthesis. PCR was performed using Biorad RT-PCR, and after processing at 95 ° C for 3 minutes, a total of 44 cycles were repeated at 94 ° C for 10 seconds and at 60 ° C for 30 seconds. Primers for qRT-PCT analysis are shown in Table 5. The degree of total transcription was normalized from the β-actin transcription level (Fig. 7 to 9).
도 7에 나타낸 바와 같이, A41 그룹, 및 SRK414 그룹에서 Dex 그룹에 비해 RANKL mRNA의 발현량이 유의미하게 감소하여 A41과 SRK414 발효유가 파골세포의 분화를 감소시키는 것을 확인하였다. As shown in FIG. 7, it was confirmed that the A41 and SRK414 fermented milk decreased the differentiation of osteoclasts by significantly reducing the expression of RANKL mRNA in the A41 group and the SRK414 group compared to the Dex group.
또한, 도 8에 나타낸 바와 같이, OPG mRNA 발현량도 393과 KSK을 제외한 모든발효유 투여 그룹에서 모두 유의미하게 증가하여 파골세포 분화의 억제를 확인하였다. In addition, as shown in FIG. 8, the expression level of OPG mRNA was also significantly increased in all fermented milk administration groups except 393 and KSK to confirm the inhibition of osteoclast differentiation.
마지막으로, 도 9에 나타낸 바와 같이, 궁극적인 조골세포 분화 표지인자인 BSP(Bone sialoprotein) 발현량 역시 A41, SRK414 그리고 B719 그룹에서 상대적으로 높은 발현량을 나타내어 조골세포 분화가 촉진되어 골다공증의 치료효과가 뛰어남을 확인할 수 있었다.Finally, as shown in FIG. 9, the ultimate osteoblast differentiation marker BSP (Bone sialoprotein) expression level also shows relatively high expression levels in the A41, SRK414 and B719 groups, thereby promoting osteoblast differentiation and promoting the therapeutic effect of osteoporosis. Was confirmed to be excellent.
상기 결과를 바탕으로 본 발명의 L. plantarum A41 균주, 및 L. fermentum SRK414 균주로 발효시킨 발효유를 동물모델에 투여하였을 때 체내 조골세포가 OPG 생성을 촉진시키고 RANKL의 생성을 억제시켜 파골세포의 분화를 억제하고, 조골세포의 분화를 촉진함으로써 이차성 골다공증에 대한 예방 효과를 나타내는 것을 확인하였다.Based on the above results, when the fermented milk fermented with the L. plantarum A41 strain and L. fermentum SRK414 strain of the present invention is administered to an animal model, osteoblasts in the body promote OPG production and inhibit the production of RANKL to differentiate osteoclasts It was confirmed that it exhibits a preventive effect against secondary osteoporosis by inhibiting and promoting differentiation of osteoblasts.
<110> CKD Bio Corp <120> Composition for Preventing or Treating Secondary Osteoporosis Comprising Probiotics <130> PN180362 <160> 14 <170> KoPatentIn 3.0 <210> 1 <211> 1487 <212> RNA <213> Artificial Sequence <220> <223> 16s rRNA of Lactobacillus plantarum A41 (KCTC13686BP) <400> 1 ggctcaggac gaacgctggc ggcgtgccta atacatgcaa gtcgaacgaa ctctggtatt 60 gattggtgct tgcatcatga tttacatttg agtgagtggc gaactggtga gtaacacgtg 120 ggaaacctgc ccagaagcgg gggataacac ctggaaacag atgctaatac cgcataacaa 180 cttggaccgc atggtccgag tttgaaagat ggcttcggct atcacttttg gatggtcccg 240 cggcgtatta gctagatggt ggggtaacgg ctcaccatgg caatgatacg tagccgacct 300 gagagggtaa tcggccacat tgggactgag acacggccca aactcctacg ggaggcagca 360 gtagggaatc ttccacaatg gacgaaagtc tgatggagca acgccgcgtg agtgaagaag 420 ggtttcggct cgtaaaactc tgttgttaaa gaagaacata tctgagagta actgttcagg 480 tattgacggt atttaaccag aaagccacgg ctaactacgt gccagcagcc gcggtaatac 540 gtaggtggca agcgttgtcc ggatttattg ggcgtaaagc gagcgcaggc ggttttttaa 600 gtctgatgtg aaagccttcg gctcaaccga agaagtgcat cggaaactgg gaaacttgag 660 tgcagaagag gacagtggaa ctccatgtgt agcggtgaaa tgcgtagata tatggaagaa 720 caccagtggc gaaggcggct gtctggtctg taactgacgc tgaggctcga aagtatgggt 780 agcaaacagg attagatacc ctggtagtcc ataccgtaaa cgatgaatgc taagtgttgg 840 agggtttccg cccttcagtg ctgcagctaa cgcattaagc attccgcctg gggagtacgg 900 ccgcaaggct gaaactcaaa ggaattgacg ggggcccgca caagcggtgg agcatgtggt 960 ttaattcgaa gctacgcgaa gaaccttacc aggtcttgac atactatgca aatctaagag 1020 attagacgtt cccttcgggg acatggatac aggtggtgca tggttgtcgt cagctcgtgt 1080 cgtgagatgt tgggttaagt cccgcaacga gcgcaaccct tattatcagt tgccagcatt 1140 aagttgggca ctctggtgag actgccggtg acaaaccgga ggaaggtggg gatgacgtca 1200 aatcatcatg ccccttatga cctgggctac acacgtgcta caatggatgg tacaacgagt 1260 tgcgaactcg cgagagtaag ctaatctctt aaagccattc tcagttcgga ttgtaggctg 1320 caactcgcct acatgaagtc ggaatcgcta gtaatcgcgg atcagcatgc cgcggtgaat 1380 acgttcccgg gccttgtaca caccgcccgt cacaccatga gagtttgtaa cacccaaagt 1440 cggtggggta accttttagg aaccagccgc ctaaagtggg acagatg 1487 <210> 2 <211> 1503 <212> RNA <213> Artificial Sequence <220> <223> 16s rRNA of Lactobacillus fermentum SRK414 (KCTC13687BP) <400> 2 gctcaggatg aacgccggcg gtgtgcctaa tacatgcaag tcgaacgcgt tggcccaatt 60 gattgatggt gcttgcacct gattgatttt ggtcgccaac gagtggcgga cgggtgagta 120 acacgtaggt aacctgccca gaagcggggg acaacatttg gaaacagatg ctaataccgc 180 ataacaacgt tgttcgcatg aacaacgctt aaaagatggc ttctcgctat cacttctgga 240 tggacctgcg gtgcattagc ttgttggtgg ggtaacggcc taccaaggcg atgatgcata 300 gccgagttga gagactgatc ggccacaatg ggactgagac acggcccata ctcctacggg 360 aggcagcagt agggaatctt ccacaatggg cgcaagcctg atggagcaac accgcgtgag 420 tgaagaaggg tttcggctcg taaagctctg ttgttaaaga agaacacgta tgagagtaac 480 tgttcatacg ttgacggtat ttaaccagaa agtcacggct aactacgtgc cagcagccgc 540 ggtaatacgt aggtggcaag cgttatccgg atttattggg cgtaaagaga gtgcaggcgg 600 ttttctaagt ctgatgtgaa agccttcggc ttaaccggag aagtgcatcg gaaactggat 660 aacttgagtg cagaagaggg tagtggaact ccatgtgtag cggtggaatg cgtagatata 720 tggaagaaca ccagtggcga aggcggctac ctggtctgca actgacgctg agactcgaaa 780 gcatgggtag cgaacaggat tagataccct ggtagtccat gccgtaaacg atgagtgcta 840 ggtgttggag ggtttccgcc cttcagtgcc ggagctaacg cattaagcac tccgcctggg 900 gagtacgacc gcaaggttga aactcaaagg aattgacggg ggcccgcaca agcggtggag 960 catgtggttt aattcgaagc tacgcgaaga accttaccag gtcttgacat cttgcgccaa 1020 ccctagagat agggcgtttc cttcgggaac gcaatgacag gtggtgcatg gtcgtcgtca 1080 gctcgtgtcg tgagatgttg ggttaagtcc cgcaacgagc gcaacccttg ttactagttg 1140 ccagcattaa gttgggcact ctagtgagac tgccggtgac aaaccggagg aaggtgggga 1200 cgacgtcaga tcatcatgcc ccttatgacc tgggctacac acgtgctaca atggacggta 1260 caacgagtcg cgaactcgcg agggcaagca aatctcttaa aaccgttctc agttcggact 1320 gcaggctgca actcgcctgc acgaagtcgg aatcgctagt aatcgcggat cagcatgccg 1380 cggtgaatac gttcccgggc cttgtacaca ccgcccgtca caccatgaga gtttgtaaca 1440 cccaaagtcg gtggggtaac cttttagagc cagccgccta agtgggacag atgattaggg 1500 tga 1503 <210> 3 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of TRPV6 <400> 3 gatggcacga ccctttgg 18 <210> 4 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of TRPV6 <400> 4 cttcgggagg tacttcgaga ca 22 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of Calbindin-D9k <400> 5 cgctaagaaa tctcccgaag 20 <210> 6 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of Calbindin-D9k <400> 6 ctccatcacc gttcttatcc a 21 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of PMCA1 <400> 7 actctggggc cagcttattt 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of PMCA1 <400> 8 gttcggcatg gtcaatctct 20 <210> 9 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of RANKL <400> 9 cccatcgggt tcccataaag tc 22 <210> 10 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of RANKL <400> 10 gcctgaagca aatgttggcg ta 22 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of OPG <400> 11 acggtttgca aaagatgtcc 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of OPG <400> 12 gtgagctgca gttggtgtgt 20 <210> 13 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of BSP <400> 13 agaaagagca gcacggttga gt 22 <210> 14 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of BSP <400> 14 gaccctcgta gccttcatag cc 22 <110> CKD Bio Corp <120> Composition for Preventing or Treating Secondary Osteoporosis Comprising Probiotics <130> PN180362 <160> 14 <170> KoPatentIn 3.0 <210> 1 <211> 1487 <212> RNA <213> Artificial Sequence <220> <223> 16s rRNA of Lactobacillus plantarum A41 (KCTC13686BP) <400> 1 ggctcaggac gaacgctggc ggcgtgccta atacatgcaa gtcgaacgaa ctctggtatt 60 gattggtgct tgcatcatga tttacatttg agtgagtggc gaactggtga gtaacacgtg 120 ggaaacctgc ccagaagcgg gggataacac ctggaaacag atgctaatac cgcataacaa 180 cttggaccgc atggtccgag tttgaaagat ggcttcggct atcacttttg gatggtcccg 240 cggcgtatta gctagatggt ggggtaacgg ctcaccatgg caatgatacg tagccgacct 300 gagagggtaa tcggccacat tgggactgag acacggccca aactcctacg ggaggcagca 360 gtagggaatc ttccacaatg gacgaaagtc tgatggagca acgccgcgtg agtgaagaag 420 ggtttcggct cgtaaaactc tgttgttaaa gaagaacata tctgagagta actgttcagg 480 tattgacggt atttaaccag aaagccacgg ctaactacgt gccagcagcc gcggtaatac 540 gtaggtggca agcgttgtcc ggatttattg ggcgtaaagc gagcgcaggc ggttttttaa 600 gtctgatgtg aaagccttcg gctcaaccga agaagtgcat cggaaactgg gaaacttgag 660 tgcagaagag gacagtggaa ctccatgtgt agcggtgaaa tgcgtagata tatggaagaa 720 caccagtggc gaaggcggct gtctggtctg taactgacgc tgaggctcga aagtatgggt 780 agcaaacagg attagatacc ctggtagtcc ataccgtaaa cgatgaatgc taagtgttgg 840 agggtttccg cccttcagtg ctgcagctaa cgcattaagc attccgcctg gggagtacgg 900 ccgcaaggct gaaactcaaa ggaattgacg ggggcccgca caagcggtgg agcatgtggt 960 ttaattcgaa gctacgcgaa gaaccttacc aggtcttgac atactatgca aatctaagag 1020 attagacgtt cccttcgggg acatggatac aggtggtgca tggttgtcgt cagctcgtgt 1080 cgtgagatgt tgggttaagt cccgcaacga gcgcaaccct tattatcagt tgccagcatt 1140 aagttgggca ctctggtgag actgccggtg acaaaccgga ggaaggtggg gatgacgtca 1200 aatcatcatg ccccttatga cctgggctac acacgtgcta caatggatgg tacaacgagt 1260 tgcgaactcg cgagagtaag ctaatctctt aaagccattc tcagttcgga ttgtaggctg 1320 caactcgcct acatgaagtc ggaatcgcta gtaatcgcgg atcagcatgc cgcggtgaat 1380 acgttcccgg gccttgtaca caccgcccgt cacaccatga gagtttgtaa cacccaaagt 1440 cggtggggta accttttagg aaccagccgc ctaaagtggg acagatg 1487 <210> 2 <211> 1503 <212> RNA <213> Artificial Sequence <220> <223> 16s rRNA of Lactobacillus fermentum SRK414 (KCTC13687BP) <400> 2 gctcaggatg aacgccggcg gtgtgcctaa tacatgcaag tcgaacgcgt tggcccaatt 60 gattgatggt gcttgcacct gattgatttt ggtcgccaac gagtggcgga cgggtgagta 120 acacgtaggt aacctgccca gaagcggggg acaacatttg gaaacagatg ctaataccgc 180 ataacaacgt tgttcgcatg aacaacgctt aaaagatggc ttctcgctat cacttctgga 240 tggacctgcg gtgcattagc ttgttggtgg ggtaacggcc taccaaggcg atgatgcata 300 gccgagttga gagactgatc ggccacaatg ggactgagac acggcccata ctcctacggg 360 aggcagcagt agggaatctt ccacaatggg cgcaagcctg atggagcaac accgcgtgag 420 tgaagaaggg tttcggctcg taaagctctg ttgttaaaga agaacacgta tgagagtaac 480 tgttcatacg ttgacggtat ttaaccagaa agtcacggct aactacgtgc cagcagccgc 540 ggtaatacgt aggtggcaag cgttatccgg atttattggg cgtaaagaga gtgcaggcgg 600 ttttctaagt ctgatgtgaa agccttcggc ttaaccggag aagtgcatcg gaaactggat 660 aacttgagtg cagaagaggg tagtggaact ccatgtgtag cggtggaatg cgtagatata 720 tggaagaaca ccagtggcga aggcggctac ctggtctgca actgacgctg agactcgaaa 780 gcatgggtag cgaacaggat tagataccct ggtagtccat gccgtaaacg atgagtgcta 840 ggtgttggag ggtttccgcc cttcagtgcc ggagctaacg cattaagcac tccgcctggg 900 gagtacgacc gcaaggttga aactcaaagg aattgacggg ggcccgcaca agcggtggag 960 catgtggttt aattcgaagc tacgcgaaga accttaccag gtcttgacat cttgcgccaa 1020 ccctagagat agggcgtttc cttcgggaac gcaatgacag gtggtgcatg gtcgtcgtca 1080 gctcgtgtcg tgagatgttg ggttaagtcc cgcaacgagc gcaacccttg ttactagttg 1140 ccagcattaa gttgggcact ctagtgagac tgccggtgac aaaccggagg aaggtgggga 1200 cgacgtcaga tcatcatgcc ccttatgacc tgggctacac acgtgctaca atggacggta 1260 caacgagtcg cgaactcgcg agggcaagca aatctcttaa aaccgttctc agttcggact 1320 gcaggctgca actcgcctgc acgaagtcgg aatcgctagt aatcgcggat cagcatgccg 1380 cggtgaatac gttcccgggc cttgtacaca ccgcccgtca caccatgaga gtttgtaaca 1440 cccaaagtcg gtggggtaac cttttagagc cagccgccta agtgggacag atgattaggg 1500 tga 1503 <210> 3 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of TRPV6 <400> 3 gatggcacga ccctttgg 18 <210> 4 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of TRPV6 <400> 4 cttcgggagg tacttcgaga ca 22 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of Calbindin-D9k <400> 5 cgctaagaaa tctcccgaag 20 <210> 6 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of Calbindin-D9k <400> 6 ctccatcacc gttcttatcc a 21 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of PMCA1 <400> 7 actctggggc cagcttattt 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of PMCA1 <400> 8 gttcggcatg gtcaatctct 20 <210> 9 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of RANKL <400> 9 cccatcgggt tcccataaag tc 22 <210> 10 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of RANKL <400> 10 gcctgaagca aatgttggcg ta 22 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of OPG <400> 11 acggtttgca aaagatgtcc 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of OPG <400> 12 gtgagctgca gttggtgtgt 20 <210> 13 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of BSP <400> 13 agaaagagca gcacggttga gt 22 <210> 14 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Reverse primer of BSP <400> 14 gaccctcgta gccttcatag cc 22
Claims (8)
Lactobacillus plantarum A41 strain with accession number KCTC13686BP.
A pharmaceutical composition for preventing or treating osteoporosis comprising the strain of claim 1 or a culture thereof as an active ingredient.
A food composition for preventing or improving osteoporosis comprising the strain of claim 1 or a culture thereof as an active ingredient.
The composition of claim 3, wherein the food composition is fermented milk.
The method according to claim 2, wherein the composition is Lactobacillus fermentum , Lactobacillus casei , Lactobacillus acidophilus , Lactobacillus acidophilus , Lactobacillus delbrueckii ssp. bulgaricus ), Lactococcus lactis ), Enterococcus faecium , Enterococcus fecalis , Streptococcus thermophilus , Bifidobacterium bifidum ), and one or more bacteria selected from the group consisting of Bifidobacterium lactis , or a culture thereof.
The method of claim 3, wherein the composition is Lactobacillus fermentum , Lactobacillus casei , Lactobacillus acidophilus , Lactobacillus acidophilus , Lactobacillus delbrueckii ssp bulgaricus ), Lactococcus lactis ), Enterococcus faecium , Enterococcus fecalis , Streptococcus thermophilus , Bifidobacterium bifidum ), and one or more bacteria selected from the group consisting of Bifidobacterium lactis , or a culture thereof.
The pharmaceutical composition of claim 2, wherein the osteoporosis is secondary osteoporosis.
The food composition according to claim 3, wherein the osteoporosis is secondary osteoporosis.
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| KR101279852B1 (en) * | 2011-06-29 | 2013-07-09 | 주식회사 쎌바이오텍 | Composition for preventing or treating osteoporosis comprising multi-species pobiotic mixture |
| KR101349139B1 (en) * | 2012-02-27 | 2014-01-10 | 한국식품연구원 | Method for Preparing Vitamin K2 and Fermented Milk Using Lactobacillus fermentum LC272 |
| KR101771692B1 (en) * | 2015-09-03 | 2017-08-29 | 호서대학교 산학협력단 | Composition for Preventing, Treating or Improving Menopausal Syndrome comprising Sparassis crispa Wulf.: Fr. and Lactic Acid Bacteria as Active Ingredient |
-
2018
- 2018-10-30 KR KR1020180131027A patent/KR20200049999A/en not_active Application Discontinuation
-
2019
- 2019-06-18 WO PCT/KR2019/007320 patent/WO2020091180A2/en active Application Filing
Non-Patent Citations (4)
| Title |
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| Jung, H. Y., (2007) Osteoporosis Diagnosis and Treatment. Endocrinology and Metabolism. 23(2):76-108. |
| Kim, H. J., (2009) Pathological Mechanism of Glucocorticoid-induced Osteoporosis. Endocrinology and Metabolism. 24(4):231-235. |
| Lee, C. B., (2008) Effect of weight reduction and calcitriol treatment for the obese patients with glucocorticoid induced osteoporosis. Endocrinology and Metabolism. 17(4):161-168. |
| Park Y. S., Seo W. S., Joe J. L., Kim T. H., (2009) Long Term Use of Glucocorticoid Induced Osteoporotic Multiple Compression Fractures in Autoimmune Disease. Journal of Rheumatic Diseases. 16(3)228-231. |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020091180A9 (en) | 2021-02-18 |
| WO2020091180A2 (en) | 2020-05-07 |
| WO2020091180A3 (en) | 2020-07-23 |
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