KR102592438B1 - Reagent composition for inhibiting AR and 5AR2 of androgen signaling related factors - Google Patents
Reagent composition for inhibiting AR and 5AR2 of androgen signaling related factors Download PDFInfo
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- KR102592438B1 KR102592438B1 KR1020220049607A KR20220049607A KR102592438B1 KR 102592438 B1 KR102592438 B1 KR 102592438B1 KR 1020220049607 A KR1020220049607 A KR 1020220049607A KR 20220049607 A KR20220049607 A KR 20220049607A KR 102592438 B1 KR102592438 B1 KR 102592438B1
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- centella asiatica
- prostate
- expression
- prostatic hyperplasia
- factors
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- A—HUMAN NECESSITIES
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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)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
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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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- 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
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat
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Abstract
본 발명은 병풀(Centella asiatica) 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방, 개선 또는 치료용 조성물에 관한 것이다. 이에 의하여 천연재료로 인체에 무해하고 부작용을 최소화할 수 있으며 특히 안드로겐 시그널링(androgen signaling) 관련 인자의 발현을 억제할 수 있는 효과가 있다.The present invention relates to a composition for preventing, improving, or treating benign prostatic hyperplasia or androgenic alopecia, comprising Centella asiatica extract as an active ingredient. As a result, it is a natural material that is harmless to the human body and can minimize side effects, and is especially effective in suppressing the expression of factors related to androgen signaling.
Description
본 발명은 전립선 비대증 또는 안드로겐성 탈모증 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating benign prostatic hyperplasia or androgenic alopecia.
전립선 비대증은 50 세 이상의 남성들에게 요로계의 흔한 만성 질환이다 (Berry S.J. et al., 1984). 전립선 비대증은 또한 요로 간헐적 증가, 요로 빈도 증가, 요로 응급, 요로 흐름 약화 및 불완전한 방광 비움을 포함한 요로 증상 저하(LUTS)와 관련이 있으며, 이로 인해 노인의 삶의 질이 나빠지며 일상 생활에 부정적인 영향을 미치게 된다 (Sarma, A.V. et al., 2012).Prostatic hyperplasia is a common chronic disease of the urinary tract in men over 50 years of age (Berry S.J. et al., 1984). Prostatic hyperplasia is also associated with lower urinary tract symptoms (LUTS), including increased urinary intermittency, increased urinary frequency, urinary emergencies, impaired urinary flow, and incomplete bladder emptying, which impairs quality of life in older adults and negatively impacts daily life. (Sarma, A.V. et al., 2012).
전립선 비대증의 근본적인 원인은 알려져 있지 않지만, 노화된 남성의 전립선은 안드로겐에 의해 영향을 받는다는 것이 잘 알려져 있다 (Kim S.K. et al., 2015). 전립선 비대증가 진행되는 동안, 안드로겐은 자가 분비 또는 파라 크린 방식으로 전립선에서 상피 세포 또는 기질 세포의 증식을 촉진하여 전립선 세포 증식 및 세포 자살의 불균형을 초래한다. 이것은 BPH의 중요한 원인으로 여겨져 왔다 (Choi, H.M. et al., 2016).Although the underlying cause of benign prostatic hyperplasia is unknown, it is well known that the prostate in aging men is affected by androgens (Kim S.K. et al., 2015). During the progression of prostatic hypertrophy, androgens promote the proliferation of epithelial or stromal cells in the prostate in an autocrine or paracrine manner, resulting in an imbalance in prostate cell proliferation and apoptosis. This has been considered an important cause of BPH (Choi, H.M. et al., 2016).
특히, 디하이드로테스토스테론(dihydrotestosteron, DHT)은 전립선 비대증의 발달과 관련이 있는 것으로 잘 알려져 있다. 나이가 들면서 남성의 성호르몬인 테스토스테론(testosteron)이 전립선에서 디하이드로테스토스테론(DHT)으로 높은 비율로 전환되기 시작하는데, 이것은 일차적으로 테스토스테론을 DHT로 전환시키는 효소인 리덕타아제(reductase) 효소의 농도가 높아지는 것이 원인이다. DHT는 안드로겐 수용체(AR)에 대한 결합력이 높기 때문에 TST와 비교하여 더 강력한 안드로겐이다. 5α환원효소 유형-2(5AR2)는 전립선에서 TST를 DHT로 변환하며, DHT는 AR과 결합하여 안드로겐-의존성 유전자의 전사를 증가시키고, 궁극적으로 전립선 증식과 관련된 단백질 합성의 자극을 유발하며, 전립선-특이적 항원(PSA) 수준을 향상시킨다. 한편, BPH 및 전립선암이 진행되는 동안 PSA 수준이 증가하는데, 이 때문에 PSA는 BPH의 진단에 널리 사용된다(Chen, Y. et al., 1996).In particular, dihydrotestosterone (DHT) is well known to be associated with the development of benign prostatic hyperplasia. As we age, the male sex hormone testosterone begins to be converted to dihydrotestosterone (DHT) at a high rate in the prostate. This is primarily due to the concentration of reductase, an enzyme that converts testosterone to DHT. The reason is that is rising. DHT is a more potent androgen compared to TST due to its high binding affinity to the androgen receptor (AR). 5α reductase type-2 (5AR2) converts TST to DHT in the prostate, and DHT binds to AR to increase transcription of androgen-dependent genes, ultimately leading to stimulation of protein synthesis associated with prostate hyperplasia. -Improves specific antigen (PSA) levels. Meanwhile, PSA levels increase during the progression of BPH and prostate cancer, which is why PSA is widely used in the diagnosis of BPH (Chen, Y. et al., 1996).
세포주기는 전립선 기질 및 상피 세포에서 발생하여 이들의 분열 및 복제로 이어진다. G1 / S 진행은 사이클린 D1 에 의해 고도로 규제된다. 또한 증식 세포핵 항원 (PCNA)은 세포주기에서 G1 / S 단계에 대한 조직 학적 마커로 인식된 산성 핵 단백질이다. 따라서 PCNA와 사이클린 D1의 발현은 BPH 동안 전립선 세포의 증식 상태를 반영할 수 있다 (Wang, W., et al., 2004).The cell cycle occurs in prostate stromal and epithelial cells, leading to their division and replication. G1/S progression is highly regulated by cyclin D1. Additionally, proliferating cell nuclear antigen (PCNA) is an acidic nuclear protein recognized as a histological marker for the G1/S phase of the cell cycle. Therefore, the expression of PCNA and cyclin D1 may reflect the proliferative state of prostate cells during BPH (Wang, W., et al., 2004).
반대로, 전립선 상피의 세포 자살은 전립선 비대증보다 정상적인 상태에서 전립선에서 더 자주 발생한다. 세포 자살을 억제하는 Bcl-2는 또한 전립선 상피에서 발견되며, 전립선 조직의 증식으로 이어진다 (Cardillo, M., et al., 1997).Conversely, apoptosis of the prostatic epithelium occurs more frequently in the prostate under normal conditions than in benign prostatic hyperplasia. Bcl-2, which inhibits apoptosis, is also found in the prostatic epithelium, leading to proliferation of prostatic tissue (Cardillo, M., et al., 1997).
디하이드로테스토스테론 (DHT) 등의 남성 호르몬에 의한 또 다른 증상 중의 하나는 남성형 탈모증(male pattern baldness)이다. 탈모의 원인으로는 혈액순환 불량설, 남성호르몬 작용 과잉설, 피지 분비 과잉설, 비듬균 및 기타세균 등에 의한 두피기능 저하설, 유전적 요인, 노화 스트레스 등이 제시되어 왔으나, 현재까지 남성호르몬 과잉 분비에 직접적인 관계가 있는 탈모중의 가장 흔한 유형인 안드로겐성 탈모증(androgenic alopecia)의 원인이 밝혀지고 있다.Another symptom caused by male hormones such as dihydrotestosterone (DHT) is male pattern baldness. The causes of hair loss have been suggested to include poor blood circulation, excessive male hormone action, excessive sebum secretion, decreased scalp function due to dandruff and other bacteria, genetic factors, and aging stress. However, until now, excessive male hormone secretion has been suggested as the cause. The cause of androgenic alopecia, the most common type of hair loss directly related to hair loss, is being revealed.
안드로겐성 탈모증이 있는 경우 건강한 모발은 점차로 가늘어지고, 짧아지며, 모발이 약해져서 쉽게 부서지는 현상이 나타나게 되는데 이러한 현상을 축소화(miniaturization)라고 한다. 축소화가 일어나는 모낭은 결국 가늘고 눈에 잘 보이지 않으며 짧은 솜털로 변해 탈모가 진행되는 것이다. 이에 따라 최근 남성호르몬 활성 억제를 통한 탈모의 예방 및 치료를 위한 많은 연구가 보고 되고 있다.In cases of androgenetic alopecia, healthy hair gradually becomes thinner, shorter, and becomes weaker and more easily broken. This phenomenon is called miniaturization. Hair follicles that undergo miniaturization eventually become thin, hard to see, and turn into short downy hair, leading to hair loss. Accordingly, many studies have recently been reported on the prevention and treatment of hair loss by suppressing male hormone activity.
테스토스테론(testosterone)이 5α환원효소(5α-reductase)에 의해 활성형 남성호르몬인 디히드로테스토스테론(dihydrotestosterone, DHT)으로 전환되고, 이렇게 활성화된 디히드로테스토스테론이 안드로겐 수용체와 결합하여 모낭세포의 단백질 합성을 지연시켜 모낭의 생장기가 단축되고 모낭을 위축시켜 탈모를 유발한다. 또한 안드로겐성 탈모 과정에서 피지가 과잉 생성되기도 하며 그 결과로서 두피에서는 염증을 동반한 탈모가 나타나기도 한다 (Dennis A. Holt, et. al,. 1990).Testosterone is converted into dihydrotestosterone (DHT), an active male hormone, by 5α-reductase, and this activated dihydrotestosterone binds to androgen receptors to promote protein synthesis in hair follicle cells. Delaying this shortens the growth period of hair follicles and causes hair follicles to atrophy, causing hair loss. Additionally, sebum may be excessively produced during androgenetic alopecia, and hair loss accompanied by inflammation may occur on the scalp as a result (Dennis A. Holt, et. al,. 1990).
현재 개발된 테라조신, 독사조신, 탐술래신, 알푸조신 등과 같은 alpha-1 adrenergic blocker 로 사용되는 전립선 비대증 치료제의 경우 전립선 평활근을 이완시켜 요도 폐쇄 증상을 완화시키나 교감신경 차단으로 저혈압, 혈관 확장성 두통 등의 부작용이 보고되고 있다.Currently developed treatments for benign prostatic hyperplasia, such as alpha-1 adrenergic blockers such as terazosin, doxazosin, tamsulasin, and alfuzosin, relieve symptoms of urethral obstruction by relaxing prostatic smooth muscle, but block sympathetic nerves, causing hypotension and vasodilation. Side effects such as headaches have been reported.
5α환원효소 억제제인 피나스테라이드(Fi)와 두타스테라이드는 테스토스테론이 5α환원효소에 의해 활성 대사물질인 디하이드로테스토스테론 (DHT)으로의 전환을 억제하여 전립선 크기를 줄이고 BPH 및 탈모증에 사용되는 효과적인 것으로 알려져 있으나(Park, E.S., et al., 2018), 이들 약물은 발기 부전, 성욕 감소 및 사정에서의 정액 부피 감소와 같은 부작용을 일으키는 것으로 알려져 있다. 이렇듯 현재 사용하고 있는 약물치료가 다소 효과가 있다고는 하나, 그 부작용이 문제가 되며, 사실상, 전립선 비대증은 지속적인 노화현상 중 하나로 근본적 치료가 어려운 문제점이 있다.Finasteride (Fi) and Dutasteride, which are 5α reductase inhibitors, are known to be effective in reducing prostate size by inhibiting the conversion of testosterone to the active metabolite dihydrotestosterone (DHT) by 5α reductase and are used for BPH and alopecia. However (Park, E.S., et al., 2018), these drugs are known to cause side effects such as erectile dysfunction, decreased libido, and decreased semen volume in the ejaculate. Although currently used drug treatments are somewhat effective, their side effects are problematic, and in fact, benign prostatic hyperplasia is one of the persistent aging phenomena that makes fundamental treatment difficult.
따라서 부작용이 적은 효과적인 치료 전략을 찾는 연구자들은 천연 재료로 제조된 약제를 포함한 대체 의학에 관심이 증가되고 있다. 현재 천연 재료 중에서 쏘팔메토 추출물만이 전립선 비대증에 효과를 갖는 기능성 식품으로 널리 알려져 있다 (Marks, L.S., et al., 2000).Therefore, researchers looking for effective treatment strategies with fewer side effects are increasingly interested in alternative medicine, including drugs made from natural ingredients. Currently, among natural ingredients, only saw palmetto extract is widely known as a functional food with an effect on benign prostatic hyperplasia (Marks, L.S., et al., 2000).
본 발명의 목적은 천연재료로 인체에 무해하고 부작용을 최소화할 수 있는 병풀 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 치료용 약학 조성물을 제공하는 데 있다.The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating benign prostatic hyperplasia or androgenic alopecia, which contains as an active ingredient a centella asiatica extract, which is a natural material that is harmless to the human body and can minimize side effects.
본 발명의 목적은 천연재료로 인체에 무해하고 부작용을 최소화할 수 있는 병풀 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 개선용 식품 조성물을 제공하는 데 있다.The purpose of the present invention is to provide a food composition for preventing or improving benign prostatic hyperplasia or androgenic alopecia, which contains as an active ingredient Centella asiatica extract, which is a natural material that is harmless to the human body and can minimize side effects.
본 발명의 하나의 측면에 따르면,According to one aspect of the invention,
병풀(Centella asiatica) 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 치료용 약학 조성물이 제공된다.A pharmaceutical composition for preventing or treating benign prostatic hyperplasia or androgenetic alopecia is provided, comprising Centella asiatica extract as an active ingredient.
상기 병풀 추출물은 물, 탄소수 1-4의 알코올, 또는 이들의 혼합용매에 의해 추출된 것일 수 있다.The Centella asiatica extract may be extracted with water, alcohol with 1 to 4 carbon atoms, or a mixed solvent thereof.
상기 약학 조성물은 안드로겐 시그널링(androgen signaling) 관련 인자의 발현 저해용일 수 있다.The pharmaceutical composition may be used to inhibit the expression of factors related to androgen signaling.
상기 안드로겐 시그널링 관련 인자는 SRC-1(steroid receptor coactivator), AR(androgen receptor), 5AR2(5alpha reductase), 및 PSA(prostate specific antigen) 중에서 선택된 어느 하나일 수 있다.The androgen signaling-related factor may be any one selected from SRC-1 (steroid receptor coactivator), AR (androgen receptor), 5AR2 (5alpha reductase), and PSA (prostate specific antigen).
상기 약학 조성물은 전립선 내 성장인자의 발현 억제용일 수 있다.The pharmaceutical composition may be used to inhibit the expression of growth factors in the prostate.
상기 전립선 내 성장인자는 EGF(Epidermal growth factor), IGF-1(Insulin like growth factor I), TGF-1β(Transforming growth factor beta 1), 및 VEGF(Vascular endothelial growth factor) 중에서 선택된 어느 하나일 수 있다.The growth factor within the prostate may be any one selected from Epidermal growth factor (EGF), Insulin like growth factor I (IGF-1), Transforming growth factor beta 1 (TGF-1β), and Vascular endothelial growth factor (VEGF). .
상기 약학 조성물은 PI3K/Akt 및 HIF-1 시그널링 관련 인자의 발현 억제용일 수 있다.The pharmaceutical composition may be used to inhibit the expression of PI3K/Akt and HIF-1 signaling related factors.
상기 PI3K/Akt 및 HIF-1 시그널링 관련 인자는 PI3K(phosphatidylinositol-3-kinase), Akt(protein kinase B), 및 HIF-1(Hypoxia-inducible factors) 중에서 선택된 어느 하나일 수 있다.The PI3K/Akt and HIF-1 signaling-related factors may be any one selected from PI3K (phosphatidylinositol-3-kinase), Akt (protein kinase B), and HIF-1 (Hypoxia-inducible factors).
상기 약학 조성물은 전립선 조직 내 세포증식 관련 인자 발현 억제용일 수 있다.The pharmaceutical composition may be used to inhibit the expression of factors related to cell proliferation in prostate tissue.
상기 전립선 조직 내 세포증식 관련 인자는 PCNA(Proliferating Cell Nuclear Antigen) 또는 사이클린 D1(Cyclin D1) 일 수 있다.The cell proliferation-related factor in the prostate tissue may be PCNA (Proliferating Cell Nuclear Antigen) or Cyclin D1.
본 발명의 다른 하나의 측면에 따르면,According to another aspect of the present invention,
병풀(Centella asiatica) 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 개선용 식품 조성물이 제공된다.A food composition for preventing or improving benign prostatic hyperplasia or androgenic alopecia is provided, containing Centella asiatica extract as an active ingredient.
본 발명의 다른 하나의 측면에 따르면,According to another aspect of the present invention,
병풀(Centella asiatica) 추출물을 유효성분으로 포함하는 식품 조성물을 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 개선용 건강기능식품이 제공된다.Provided is a health functional food for preventing or improving benign prostatic hyperplasia or androgenic alopecia, comprising a food composition containing Centella asiatica extract as an active ingredient.
본 발명의 병풀 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 치료용 약학 조성물은 천연재료로 인체에 무해하고 부작용을 최소화할 수 있으며 특히 안드로겐 시그널링(androgen signaling) 관련 인자의 발현을 억제할 수 있는 효과가 있다.The pharmaceutical composition for preventing or treating benign prostatic hyperplasia or androgenetic alopecia containing the centella asiatica extract of the present invention as an active ingredient is a natural material that is harmless to the human body and can minimize side effects, and especially inhibits the expression of factors related to androgen signaling. There is an effect that can be done.
본 발명의 병풀 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 개선용 식품 조성물은 천연재료로 인체에 무해하고 부작용을 최소화할 수 있으며 특히 안드로겐 시그널링(androgen signaling) 관련 인자의 발현을 억제할 수 있는 효과가 있다.The food composition for preventing or improving benign prostatic hyperplasia or androgenetic alopecia containing the centella asiatica extract of the present invention as an active ingredient is a natural ingredient that is harmless to the human body and can minimize side effects, and especially inhibits the expression of factors related to androgen signaling. There is an effect that can be done.
도 1은 실험예 1에 따른 웨스턴 블롯 결과이다.
도 2는 실험예 1에 따른 AR 단백질 발현량 측정 결과이다.
도 3은 실험예 1에 따른 5AR2 단백질 발현량 측정 결과이다.
도 4는 실험예 1에 따른 PSA 단백질 발현량 측정 결과이다.
도 5는 실험예 2에 따라 분리된 각 실험군의 전립선 사진과 전립선의 무게를 측정하여 비교한 결과이다.
도 6은 실험예 2에 따른 전립선 지수(prostate index) 측정결과이다.
도 7은 실험예 2에 따른 전립선 상피세포의 현미경 사진과 상피세포 두께를 측정한 결과이다.
도 8은 실험예 3에 따른 안드로겐 시그널링 관련 인자 발현 억제능 분석 결과이다.
도 9는 실험예 4의 참고문헌의 대표도이다.
도 10은 실험예 4에 따른 성장인자(Grow factor) 발현 억제능 분석 결과이다.
도 11은 PI3K/Akt 및 HIF 1 시그널링 경로의 개략도이다.
도 12는 실험예 5에 따른 웨스턴 블롯 실험결과이다.
도 13은 실험예 6에 따른 전립선 조직 내 세포증식 관련 인자 발현 억제능 분석 결과이다.Figure 1 shows the results of Western blot according to Experimental Example 1.
Figure 2 shows the results of measuring AR protein expression level according to Experimental Example 1.
Figure 3 shows the results of measuring 5AR2 protein expression level according to Experimental Example 1.
Figure 4 shows the results of measuring PSA protein expression level according to Experimental Example 1.
Figure 5 shows the results of comparing photos of the prostates of each experimental group separated according to Experimental Example 2 and the weight of the prostates.
Figure 6 shows the prostate index measurement results according to Experimental Example 2.
Figure 7 shows microscopic pictures of prostate epithelial cells and the results of measuring epithelial cell thickness according to Experimental Example 2.
Figure 8 shows the results of analysis of the ability to suppress the expression of androgen signaling-related factors according to Experimental Example 3.
Figure 9 is a representative diagram of the references in Experimental Example 4.
Figure 10 shows the results of analysis of growth factor expression inhibition ability according to Experimental Example 4.
Figure 11 is a schematic diagram of the PI3K/Akt and HIF 1 signaling pathways.
Figure 12 shows the results of a Western blot experiment according to Experimental Example 5.
Figure 13 shows the results of analysis of the ability to suppress expression of factors related to cell proliferation in prostate tissue according to Experimental Example 6.
이하, 본 발명을 상세하게 설명한다. Hereinafter, the present invention will be described in detail.
본 발명의 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 치료용 약학 조성물은 병풀(Centella asiatica) 추출물을 유효성분으로 포함한다.The pharmaceutical composition for preventing or treating benign prostatic hyperplasia or androgenetic alopecia of the present invention includes Centella asiatica extract as an active ingredient.
병풀(Centella asiatica)은 가장자리에 톱니를 두른 작은 부채 모양의 잎에 흰색 또는 연보라색의 꽃을 피우는 미나리과 식물이다. 인도에서는 상처를 입은 호랑이가 병풀나풀이 많이 난 곳에서 뒹굴어 치료하는 것을 보고 호랑이풀이라고 부르며 오래 전부터 약으로 활용해 왔다. Centella asiatica is a plant in the Apiaceae family that blooms white or light purple flowers on small fan-shaped leaves with serrated edges. In India, after seeing a wounded tiger rolling around in a place with a lot of Centella asiatica to heal, it was called tiger plant and has been used as medicine for a long time.
상기 병풀 추출물을 추출하는 추출용매는 물, 탄소수 1 내지 4의 저급알코올, 에틸렌글리콜, 에틸에테르 또는 이들의 혼합용매이다. 상기 저급알코올로는 20 내지 80%의 메탄올, 에탄올, 부탄올 또는 프로판올을 들 수 있다.The extraction solvent for extracting the Centella asiatica extract is water, lower alcohol having 1 to 4 carbon atoms, ethylene glycol, ethyl ether, or a mixed solvent thereof. The lower alcohol may include 20 to 80% methanol, ethanol, butanol, or propanol.
상기 추출용매로는 특별히 한정하는 것은 아니지만 60 내지 80%의 에탄올 수용액으로 추출된 추출물이 바람직하다.The extraction solvent is not particularly limited, but an extract extracted with a 60 to 80% aqueous ethanol solution is preferred.
본 명세서에서 병풀 추출물을 언급하면서 사용되는 용어 '추출물'은 추출용매를 처리하여 얻은 조추출물뿐만 아니라 병풀 추출물의 가공물도 포함한다. 예를 들어, 병풀 추출물은 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말 상태로 제조될 수 있다.The term 'extract' used in this specification while referring to the Centella asiatica extract includes not only the crude extract obtained by treatment with an extraction solvent, but also the processed product of the Centella asiatica extract. For example, Centella asiatica extract can be prepared in powder form by additional processes such as reduced pressure distillation and freeze-drying or spray drying.
또한, 본 발명의 병풀 추출물은 광의로는 병풀을 동물에게 투여할 수 있도록 제형화된 병풀 가공물, 예컨대, 병풀 분말도 포함하는 의미를 갖는다. 비록 본 발명에서 병풀로 실험을 진행하긴 하였으나, 병풀 가공물과 같은 형태로도 목적하는 효과를 달성할 수 있음은 당업자라면 예상 가능할 것이다.In addition, the Centella asiatica extract of the present invention, in a broad sense, also includes Centella asiatica processed products formulated so that they can be administered to animals, such as Centella asiatica powder. Although experiments were conducted with centella asiatica in the present invention, those skilled in the art would be able to predict that the desired effect can be achieved even in the form of a centella asiatica processed product.
한편, 본 명세서에서 용어 '유효성분으로 포함하는'이란 병풀 추출물 또는 이의 분획물의 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다. 일예로, 상기 병풀 추출물 또는 이의 분획물은 10 내지 1500 ㎍/㎖, 바람직하게는 100 내지 1000 ㎍/㎖의 농도로 사용된다. 병풀 추출물 또는 이의 분획물은 천연물로서 과량 투여하여도 인체에 부작용이 없으므로 본 발명의 조성물 내에 포함되는 병풀 추출물 또는 이의 분획물의 양적 상한은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.Meanwhile, in this specification, the term 'including as an active ingredient' means containing a sufficient amount to achieve the efficacy or activity of the Centella asiatica extract or fractions thereof. For example, the Centella asiatica extract or its fraction is used at a concentration of 10 to 1500 μg/ml, preferably 100 to 1000 μg/ml. Since the Centella asiatica extract or its fraction is a natural product and does not cause side effects to the human body even when administered in excessive amounts, the upper quantitative limit of the Centella asiatica extract or its fraction included in the composition of the present invention can be selected within an appropriate range by a person skilled in the art.
또한, 본 발명은 병풀(Centella asiatica) 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating benign prostatic hyperplasia or androgenic alopecia, comprising Centella asiatica extract as an active ingredient.
상기 약학 조성물은 안드로겐 시그널링(androgen signaling) 관련 인자의 발현 저해용으로 사용될 수 있다.The pharmaceutical composition can be used to inhibit the expression of factors related to androgen signaling.
상기 안드로겐 시그널링 관련 인자는 SRC-1(steroid receptor coactivator), AR(androgen receptor), 5AR2(5alpha reductase), 및 PSA(prostate specific antigen) 중에서 선택된 어느 하나일 수 있다.The androgen signaling-related factor may be any one selected from SRC-1 (steroid receptor coactivator), AR (androgen receptor), 5AR2 (5alpha reductase), and PSA (prostate specific antigen).
상기 약학 조성물은 전립선 내 성장인자의 발현 억제용으로 사용될 수 있다.The pharmaceutical composition can be used to inhibit the expression of growth factors in the prostate.
상기 전립선 내 성장인자는 EGF(Epidermal growth factor), IGF-1(Insulin like growth factor I), TGF-1β(Transforming growth factor beta 1), 및 VEGF(Vascular endothelial growth factor) 중에서 선택된 어느 하나일 수 있다.The growth factor within the prostate may be any one selected from Epidermal growth factor (EGF), Insulin like growth factor I (IGF-1), Transforming growth factor beta 1 (TGF-1β), and Vascular endothelial growth factor (VEGF). .
상기 약학 조성물은 PI3K/Akt 및 HIF-1 시그널링 관련 인자의 발현 억제용으로 사용될 수 있다.The pharmaceutical composition can be used to inhibit the expression of PI3K/Akt and HIF-1 signaling related factors.
상기 PI3K/Akt 및 HIF-1 시그널링 관련 인자는 PI3K(phosphatidylinositol-3-kinase), Akt(protein kinase B), 및 HIF-1(Hypoxia-inducible factors) 중에서 선택된 어느 하나일 수 있다.The PI3K/Akt and HIF-1 signaling-related factors may be any one selected from PI3K (phosphatidylinositol-3-kinase), Akt (protein kinase B), and HIF-1 (Hypoxia-inducible factors).
상기 약학 조성물은 전립선 조직 내 세포증식 관련 인자 발현 억제용으로 사용될 수 있다.The pharmaceutical composition can be used to inhibit the expression of factors related to cell proliferation in prostate tissue.
상기 전립선 조직 내 세포증식 관련 인자는 PCNA(Proliferating Cell Nuclear Antigen) 또는 사이클린 D1(Cyclin D1) 일 수 있다.The cell proliferation-related factor in the prostate tissue may be PCNA (Proliferating Cell Nuclear Antigen) or Cyclin D1.
본 발명의 약학 조성물은 상기 유효 성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.The pharmaceutical composition of the present invention can be prepared using pharmaceutically suitable and physiologically acceptable auxiliaries in addition to the active ingredients, and the auxiliaries include excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, and lubricants. Agents or flavoring agents can be used.
상기 약학 조성물은 투여를 위해서 상기 기재한 유효 성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약학 조성물로 바람직하게 제제화할 수 있다.For administration, the pharmaceutical composition may be preferably formulated as a pharmaceutical composition containing one or more pharmaceutically acceptable carriers in addition to the active ingredients described above.
상기 약학 조성물의 제제 형태는 과립제, 산제, 정제, 피복정, 캡슐제, 좌제, 액제, 시럽, 즙, 현탁제, 유제, 점적제 또는 주사 가능한 액제 등이 될 수 있다. 예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해, 유효 성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용 가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연 당, 옥수수 감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성 검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐 아세테이트, 소듐 클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸 셀룰로스, 아가, 벤토니트, 잔탄 검 등을 포함한다.The pharmaceutical composition may be in the form of granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops, or injectable solutions. For example, for formulation in the form of tablets or capsules, the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Additionally, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacance or sodium oleate, sodium stearate, magnesium stearate, sodium Includes benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.
액상 용액으로 제제화되는 조성물에 있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다.Acceptable pharmaceutical carriers for compositions formulated as liquid solutions include those that are sterile and biocompatible, such as saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and One or more of these ingredients can be mixed and used, and other common additives such as antioxidants, buffers, and bacteriostatic agents can be added as needed. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
본 발명의 약학 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있으며, 바람직하게는 경구 투여이다.The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc., and is preferably administered orally.
본 발명의 약학 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. 본 발명의 바람직한 구현예에 따르면, 본 발명의 약학 조성물의 1일 투여량은 0.001-10 g/㎏이다.The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity, and is usually A skilled doctor can easily determine and prescribe an effective dosage for desired treatment or prevention. According to a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001-10 g/kg.
본 발명의 약학 조성물은 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 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention can be prepared in unit dose form by formulating using a pharmaceutically acceptable carrier and/or excipient, or can be prepared by placing it in a multi-dose container. At this time, the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet, or capsule, and may additionally contain a dispersant or stabilizer.
또한, 본 발명은 병풀(Centella asiatica) 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving benign prostatic hyperplasia or androgenic alopecia, comprising Centella asiatica extract as an active ingredient.
본 발명에 따른 식품 조성물은 상기 약학 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 알코올 음료류, 과자류, 다이어트바, 유제품, 육류, 초코렛, 피자, 라면, 기타 면류, 껌류, 아이스크림류, 비타민 복합제, 건강보조식품류 등이 있다.The food composition according to the present invention can be formulated in the same way as the pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, alcoholic beverages, confectionery, diet bars, dairy products, meat, chocolate, pizza, ramen, other noodles, gum, ice cream, vitamin complexes, and health supplements. etc.
본 발명의 식품 조성물은 유효성분으로서 병풀 추출물 또는 이의 분획물 뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있으며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 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. 예컨대, 본 발명의 식품 조성물이 드링크제와 음료류로 제조되는 경우에는 본 발명의 병풀 추출물 또는 이의 분획물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 및 각종 식물 추출액 등을 추가로 포함시킬 수 있다.The food composition of the present invention may contain not only Centella asiatica extract or fractions thereof as an active ingredient, but also ingredients commonly added during food production, such as proteins, carbohydrates, fats, nutrients, seasonings, and flavoring agents. Includes. Examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, oligosaccharides, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. For example, when the food composition of the present invention is manufactured as a drink or beverage, in addition to the Centella asiatica extract or fractions thereof of the present invention, citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, and various plant extracts may be additionally included. You can.
본 발명은 병풀(Centella asiatica) 추출물을 유효성분으로 포함하는 전립선 비대증 또는 안드로겐성 탈모증 예방 또는 개선용 식품 조성물을 포함하는 건강기능식품을 제공한다. 건강기능식품이란, 병풀 추출물 또는 이의 분획물을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용시 발생할 수 있는 부작용 등이 없는 장점이 있다. 이와 같이 하여 얻어지는 본 발명의 건강기능식품은, 일상적으로 섭취하는 것이 가능하기 때문에 매우 유용하다. 이와 같은 건강기능식품에 있어서의 병풀 추출물의 첨가량은, 대상인 건강기능식품의 종류에 따라 달라 일률적으로 규정할 수 없지만, 식품 본래의 맛을 손상시키지 않는 범위에서 첨가하면 되며, 대상 식품에 대하여 통상 0.01 내지 50 중량%, 바람직하기로는 0.1 내지 20 중량%의 범위이다. 또한, 환제, 과립제, 정제 또는 캡슐제 형태의 건강기능식품의 경우에는 통상 0.1 내지 100 중량% 바람직하기로는 0.5 내지 80 중량%의 범위에서 첨가하면 된다. 한 구체예에서, 본 발명의 건강기능식품은 환제, 정제, 캡슐제 또는 음료의 형태일 수 있다.The present invention provides a health functional food containing a food composition for preventing or improving benign prostatic hyperplasia or androgenic alopecia, containing Centella asiatica extract as an active ingredient. Health functional foods are foods manufactured by adding Centella asiatica extract or its fractions to food ingredients such as beverages, teas, spices, gums, and confectionery, or by encapsulating, powdering, or suspending them, and when consumed, they have specific health effects. However, unlike regular drugs, it has the advantage of not having any side effects that may occur when taking the drug for a long time since it is made from food. The health functional food of the present invention obtained in this way is very useful because it can be consumed on a daily basis. The amount of Centella asiatica extract added in such health functional foods cannot be uniformly specified as it depends on the type of health functional food being targeted. However, it can be added within a range that does not damage the original taste of the food, and is usually 0.01% for the target food. to 50% by weight, preferably 0.1 to 20% by weight. In addition, in the case of health functional foods in the form of pills, granules, tablets, or capsules, it is usually added in the range of 0.1 to 100% by weight, preferably 0.5 to 80% by weight. In one embodiment, the health functional food of the present invention may be in the form of a pill, tablet, capsule, or beverage.
또한, 본 발명은 전립선 비대증 또는 안드로겐성 탈모증 예방, 치료 또는 개선을 위한 의약 또는 식품의 제조를 위한 병풀(Centella asiatica) 추출물의 용도를 제공한다. In addition, the present invention provides the use of Centella asiatica extract for the manufacture of medicine or food for preventing, treating or improving benign prostatic hyperplasia or androgenetic alopecia.
또한, 본 발명은 포유동물에게 유효량의 병풀(Centella asiatica) 추출물을 투여하는 것을 포함하는 아토피의 개선, 예방 또는 치료 방법을 제공한다.Additionally, the present invention provides a method for improving, preventing, or treating atopy comprising administering an effective amount of Centella asiatica extract to a mammal.
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다.As used herein, the term “mammal” refers to a mammal, preferably a human, that is the subject of treatment, observation or experiment.
여기에서 사용된 용어 "유효량"은 연구자, 수의사, 의사 또는 기타 임상의에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약학 조성물의 양을 의미하는 것으로, 이는 해당 질환 또는 장애의 증상의 완화를 유도하는 양을 포함한다. 본 발명의 유효 성분에 대한 유효량 및 투여횟수는 원하는 효과에 따라 변화될 수 있다. 그러므로, 투여될 최적의 투여량은 당업자에 의해 쉽게 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 본 발명의 예방, 치료 또는 개선 방법에 있어서, 성인의 경우, 추출물을 1일 1회 내지 수회 투여시, 0.001 g/kg 내지 10 g/kg의 용량으로 투여하는 것이 바람직하다.As used herein, the term "effective amount" means the amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal, or human, as believed by a researcher, veterinarian, physician, or other clinician, to cause the disease in question. or an amount that induces relief of symptoms of the disorder. The effective amount and frequency of administration of the active ingredient of the present invention may vary depending on the desired effect. Therefore, the optimal dosage to be administered can be easily determined by a person skilled in the art, and can be determined based on the type of disease, the severity of the disease, the content of the active ingredient and other ingredients contained in the composition, the type of dosage form, and the patient's age, weight, and general health. It can be adjusted according to various factors, including condition, gender and diet, administration time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs. In the prevention, treatment or improvement method of the present invention, for adults, it is preferable to administer the extract at a dose of 0.001 g/kg to 10 g/kg once or several times a day.
본 발명의 치료방법에서 병풀(Centella asiatica) 추출물을 유효 성분으로 포함하는 조성물은 경구, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 경피, 국소, 또는 피내 경로를 통해 통상적인 방식으로 투여할 수 있다.In the treatment method of the present invention, the composition containing Centella asiatica extract as an active ingredient is administered through conventional routes through oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, or intradermal routes. It can be administered in any way.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시하나, 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 범주 및 기술사상 범위 내에서 다양한 변경 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속하는 것도 당연한 것이다.Hereinafter, preferred embodiments are presented to aid understanding of the present invention. However, the following examples are merely illustrative of the present invention, and it is clear to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention. It is natural that such variations and modifications fall within the scope of the attached patent claims.
[실시예][Example]
실시예 1: 병풀 추출물 제조Example 1: Preparation of Centella asiatica extract
상업적으로 판매되는 건조된 인도네시아산 병풀(Centella asiatica)을 구입하여 100g의 시료에 D.W 1L를 가해 항온수조에 100℃에서 1시간 동안 추출하였다. 이 추출물을 여과지로 여과한 뒤 진공회전농축기를 이용하여 감압 농축하였다. 이후 딥 프리저(deep freezer)에서 하루 냉각하고 동결건조 하였다. 동결건조한 병풀 열수추출물은 DMSO(dimethyl sulfoxide)용매에 1 g/㎖ 농도로 용해시켜 세포실험에 사용하고 D.W에 용해시켜 동물실험에 사용하였다.Dried commercially sold Indonesian centella asiatica ( Centella asiatica ) was purchased, 1 L of DW was added to a 100 g sample, and extraction was performed in a constant temperature water bath at 100°C for 1 hour. This extract was filtered through filter paper and then concentrated under reduced pressure using a vacuum rotary concentrator. Afterwards, it was cooled in a deep freezer for a day and freeze-dried. Freeze-dried Centella asiatica hot water extract was dissolved in DMSO (dimethyl sulfoxide) solvent at a concentration of 1 g/ml and used in cell experiments, and dissolved in DW and used in animal experiments.
[실험예: 생체 외 실험][Experimental example: in vitro experiment]
실험예 1: 안드로겐 시그널링 관련 인자 발현 억제능 분석Experimental Example 1: Analysis of ability to suppress expression of androgen signaling-related factors
LNCaP 세포에 테스토스테론(testosterone propionate, TP)를 처리하여 세포증식을 유도하고 실시예 1의 병풀(Centella asiatica) 추출물을 처리한 후 AR(androgen receptor), 5AR2(5 alpha reductase), PSA(prostate specific antigen)의 발현억제 효능을 확인하였다.LNCaP cells were treated with testosterone (testosterone propionate, TP) to induce cell proliferation, and after treatment with the Centella asiatica extract of Example 1, AR (androgen receptor), 5AR2 (5 alpha reductase), and PSA (prostate specific antigen) ) was confirmed to suppress the expression of .
구체적으로, LNCaP 세포 내에서 병풀의 안드로겐 시그널링(androgen signaling) 관련 인자의 억제능 확인하였다. LNCaP 세포를 6 웰 플레이트에 2 x 106 개 시딩(seeding)한 뒤 100 nM의 테스토스테론(testosterone propionate, TP) 과 실시예 1의 병풀추출물(CA)을 농도별 250, 500 또는 1000 ㎍/㎖로 24시간 처리하였다. 이때 안드로겐 억제약물인 피나스테리드(finasteride, Fi) 1㎍/㎖ 처리군은 양성대조군으로 사용하였다. Specifically, the inhibitory ability of androgen signaling-related factors of Centella asiatica was confirmed in LNCaP cells. LNCaP cells were seeded in a 6 -well plate at 2 Treated for 24 hours. At this time, the group treated with 1㎍/㎖ of finasteride (Fi), an androgen inhibitor, was used as a positive control group.
세포에 처리가 끝난 후 웨스턴 블롯법을 이용하여 안드로겐 시그널링 관련 인자 AR, 5AR2 및 PSA 단백질 발현량을 측정하였으며 밴드 세기는 image J(NIH ver. 1.48, USA)를 이용하여 각 샘플의 면적을 설정한 후 상대되는 β-Actin의 면적을 동일한 방법으로 설정하여 그 값을 나누는 방식으로 계산함으로써 정량하였다. 이에 따른 웨스턴 블롯 실험 결과를 도 1에 나타내었으며, AR 단백질 발현량 측정 결과를 도 2에 나타내었고, 5AR2 단백질 발현량 측정 결과를 도 3에 나타내었고, PSA 단백질 발현량 측정 결과를 도 4에 나타내었다. After the cells were treated, the expression levels of androgen signaling-related factors AR, 5AR2, and PSA proteins were measured using Western blotting, and the band intensity was determined by setting the area of each sample using image J (NIH ver. 1.48, USA). Then, the relative area of β-Actin was set in the same way and quantified by calculating by dividing the value. The results of the Western blot experiment according to this are shown in Figure 1, the results of measuring AR protein expression levels are shown in Figure 2, the results of measuring 5AR2 protein expression levels are shown in Figure 3, and the results of measuring PSA protein expression levels are shown in Figure 4. It was.
이에 따르면, 실시예 1의 병풀추출물의 처리에 따라 AR, 5AR2 및 PSA 단백질 발현량이 농도 의존적으로 감소하는 경향을 나타내었으며, 특히 5AR2 및 PSA 단백질 발현량은 500 ㎍/㎖ 처리군에서 급격히 발현량이 감소하였고, 1000 ㎍/㎖ 처리군에서는 피나스테리드 약물처리군 보다 약간 높은 수준으로 매우 높은 발현량 억제능을 나타내었다.According to this, the expression levels of AR, 5AR2, and PSA proteins tended to decrease in a concentration-dependent manner upon treatment with the Centella asiatica extract of Example 1. In particular, the expression levels of 5AR2 and PSA proteins decreased sharply in the 500 μg/ml treatment group. The 1000 ㎍/㎖ treatment group showed a very high expression level inhibition ability at a slightly higher level than the finasteride drug treatment group.
[실험예: 생체 내 실험][Experimental example: in vivo experiment]
8주령의 수컷 SD 래트(체중 200±5 g) 실험동물군을 아래의 표 1에 정리된 바와 같이 5그룹으로 나눈 다음, BPH 유발 그룹은 1주일 안정기 후 페노바비탈(phenobarbital) 50mg/kg을 복강 내 주사하여 마취한 후 고환과 부고환을 제거한 뒤 봉합실을 이용하여 수술 부위를 봉합하였다. 모든 실험은 무균 환경에서 이루어졌다. 3일간의 수술 안정기를 가진 다음 전립선 비대증(benign prostatic hyperplasia) 유발군(BPH)은 테스토스테론을 옥수수 오일(corn oil)에 녹여 3mg/kg의 농도로 매일 피하 주사하여 전립선 비대증을 유발시켰다. 병풀 투여군(BPH+CA200)은 실시예 1의 병풀 추출물을 멸균된 증류수에 녹여 200mg/k을 주간 존데를 이용하여 경구 투여하였다. 양성대조군인 쏘팔메토 투여군(BPH+Saw)은 쏘팔메토를 멸균된 증류수에 녹여 100mg/kg투여하였고, 피나스테리드 투여군(BPH+Fi)은 1mg/kg을 4주간 매일 존데를 이용하여 경구투여 했다. 실험 종료 후, 졸레틸(zoletil)을 이용하여 쥐를 희생시킨 후 심장 천공(heart puncture)를 통해 혈액을 수집한 뒤 혈청을 분리하여 -80℃에 보관하였다. RNAse가 제거된 수술기구로 전립선을 분리하여 -80℃에 보관한 뒤 웨스턴 블롯 실험을 실시하였다. The experimental animal group of 8-week-old male SD rats (body weight 200±5 g) was divided into 5 groups as summarized in Table 1 below, and the BPH-induced group was intraperitoneally administered 50 mg/kg of phenobarbital after a 1-week rest period. After anesthesia by injection, the testicles and epididymis were removed, and the surgical site was sutured using suture thread. All experiments were conducted in a sterile environment. After a 3-day surgical stabilization period, the benign prostatic hyperplasia (BPH) group was treated with testosterone dissolved in corn oil and injected subcutaneously every day at a concentration of 3 mg/kg to induce benign prostatic hyperplasia. For the Centella asiatica treatment group (BPH+CA200), the Centella asiatica extract from Example 1 was dissolved in sterilized distilled water and administered orally at 200 mg/k weekly using a sonde. The positive control group, the saw palmetto administration group (BPH+Saw), was administered 100 mg/kg of saw palmetto dissolved in sterilized distilled water, and the finasteride administration group (BPH+Fi) was orally administered 1 mg/kg using a sonde every day for 4 weeks. . After the experiment was completed, the mice were sacrificed using zoletil, blood was collected through heart puncture, and serum was separated and stored at -80°C. The prostate was separated using RNAse-free surgical instruments, stored at -80°C, and then subjected to Western blot experiment.
실험예 2: 전립선 크기 및 상피세포 두께 측정Experimental Example 2: Measurement of prostate size and epithelial cell thickness
분리된 각 실험군의 전립선 사진과 전립선의 무게를 측정하여 비교한 결과를 도 5에 나타내었으며, 전립선 지수(prostate index) 측정결과를 도 6에 타내었다.The results of comparing the photographs of the prostate and the weight of the prostate in each separated experimental group are shown in Figure 5, and the results of prostate index measurement are shown in Figure 6.
이에 따르면, 전립선 비대증 유발군(BPH)은 대조군에 비해 유의적으로 전립선의 크기가 증가함을 확인하였다. 반면 병풀 투여군(BPH+CA200)은 전립선 비대증 유발군(BPH)에 비해 전립선의 크기(무게)와 전립선 지수(prostate index)가 유의적으로 감소하였다.According to this, it was confirmed that the size of the prostate in the benign prostatic hyperplasia (BPH) group was significantly increased compared to the control group. On the other hand, the size (weight) and prostate index of the Centella asiatica administration group (BPH+CA200) were significantly reduced compared to the benign prostatic hyperplasia-induced group (BPH).
한편, 상기 각 실험군의 전립선 상피세포의 현미경 사진과 상피세포 두께를 측정한 결과를 도 7에 나타내었다.Meanwhile, microscopic pictures of prostate epithelial cells and the results of measuring epithelial cell thickness in each experimental group are shown in Figure 7.
이에 따르면, 전립선 비대증 유발군(BPH)은 대조군에 비해 유의적으로 전립선 상피세포 두께가 증가하였음을 확인하였다. 반면 병풀 투여군(BPH+CA200)은 전립선 비대증 유발군(BPH)에 비해 전립선의 상피세포 두께가 유의적으로 감소함을 확인하였다.According to this, it was confirmed that the prostate hyperplasia-induced group (BPH) had a significantly increased prostate epithelial cell thickness compared to the control group. On the other hand, it was confirmed that the epithelial cell thickness of the prostate was significantly reduced in the Centella asiatica administration group (BPH+CA200) compared to the benign prostatic hyperplasia-induced group (BPH).
**
실험예 3: 안드로겐 시그널링 관련 인자 발현 억제능 분석Experimental Example 3: Analysis of ability to suppress expression of androgen signaling-related factors
상기 동물실험군들에 대하여 안드로겐 시그널링(androgen signaling) 관련 인자 SRC-1(steroid receptor coactivator), AR(androgen receptor), 5AR2(5alpha reductase), PSA(prostate specific antigen)의 단백질 발현을 상술한 웨스턴 블롯 실험으로 분석한 결과를 도 8에 나타내었다.Western blot experiments detailing protein expression of androgen signaling-related factors SRC-1 (steroid receptor coactivator), AR (androgen receptor), 5AR2 (5alpha reductase), and PSA (prostate specific antigen) for the above animal test groups. The analysis results are shown in Figure 8.
이에 따르면, 병풀 투여군(BPH+CA200)에서 안드로겐 시그널링 관련 인자의 발현이 전립선 비대증 유발군(BPH)과 대비하여 전반적으로 유의적인 감소를 보였고, 특히 AR발현량이 현저히 감소하는 것으로 나타났다.According to this, the expression of androgen signaling-related factors in the Centella asiatica treatment group (BPH+CA200) showed a significant overall decrease compared to the benign prostatic hyperplasia-induced group (BPH), and in particular, the amount of AR expression was significantly reduced.
실험예 4: 성장인자(Grow factor) 발현 억제능 분석Experimental Example 4: Analysis of growth factor expression inhibition ability
British journal of cancer, 101(12), 1949-1956 에 따르면, 표피성장인자(Epidermal growth factor)가 전립선 암에서 안드로겐의 제어를 벗어나도록 하는 역할을 한다고 알려져 있으며, 참고로 상기 논문의 대표도를 도 9에 나타내었다. 안드로겐 시그널링으로 인해 ARE(androgen response element) 에서 성장인자(Grow factor)의 전사가 이루어져 발현량이 증가되는 경향을 보인다. 성장인자는 전립선 비대증을 유도하는 큰 요인으로 볼 수 있다. According to British journal of cancer, 101(12), 1949-1956, epidermal growth factor is known to play a role in preventing androgen control in prostate cancer. For reference, a representative diagram of the above paper is provided. Shown in 9. Due to androgen signaling, growth factor transcription occurs in the ARE (androgen response element), and the expression level tends to increase. Growth factors can be seen as a major factor that induces benign prostatic hyperplasia.
이에 따라 본 실험예에서 병풀 추출물 투여가 전립선 비대증을 유도시킨 쥐의 전립선 내 성장인자의 발현을 감소시키는지 확인하기 위하여 상기 실험군들에 대해 상술한 바와 같이 웨스턴 블롯 실험을 수행하고 그 결과를 도 10에 나타내었다. 이에 따르면, 전립선 비대증은 병풀 투여군(BPH+CA200)에서 성장인자인 EGF(Epidermal growth factor), IGF-1(Insulin like growth factor I), TGF-1β(Transforming growth factor beta 1), VEGF(Vascular endothelial growth factor)의 발현량이 전립선 비대증 유발군(BPH)에 비해 유의적으로 감소한 것을 확인할 수 있었다.Accordingly, in this experimental example, to determine whether administration of Centella asiatica extract reduces the expression of growth factors in the prostate of mice that induced benign prostatic hyperplasia, a Western blot experiment was performed on the experimental groups as described above, and the results are shown in Figure 10 shown in According to this, benign prostatic hyperplasia was caused by growth factors such as EGF (Epidermal growth factor), IGF-1 (Insulin like growth factor I), TGF-1β (Transforming growth factor beta 1), and VEGF (Vascular endothelial growth factor) in the Centella asiatica group (BPH+CA200). It was confirmed that the expression level of (growth factor) was significantly decreased compared to the benign prostatic hyperplasia-induced group (BPH).
실험예 5: PI3K/Akt 및 HIF-1 시그널링 경로(signaling pathway) 관련 인자 발현 억제능 분석Experimental Example 5: Analysis of the ability to suppress expression of factors related to the PI3K/Akt and HIF-1 signaling pathways
앞서 실험예 4에서 병풀 투여군(BPH+CA200)은 안드로겐 시그널링을 억제하고 이로 인해 표피성장인자(EGF)의 발현을 억제함을 확인하였다. 한편, 이로 인한 PI3K/Akt 및 HIF-1 시그널링 경로(signaling pathway) 관련 인자인 PI3K(phosphatidylinositol-3-kinase), Akt(protein kinase B), PTEN(phosphatase and tensin homologue), HIF-1(Hypoxia-inducible factors)의 발현이 억제되는지 확인하기 위하여 상술한 바와 같이 웨스턴 블롯 실험을 수행하였다. 참고로 PI3K/Akt 및 HIF-1 시그널링 경로의 개략도를 도 11에 나타내었으며, 웨스턴 블롯 실험결과를 도 12에 나타내었다.Previously, in Experimental Example 4, it was confirmed that the group administered with Centella asiatica (BPH+CA200) suppressed androgen signaling, thereby suppressing the expression of epidermal growth factor (EGF). Meanwhile, factors related to the PI3K/Akt and HIF-1 signaling pathways, such as PI3K (phosphatidylinositol-3-kinase), Akt (protein kinase B), PTEN (phosphatase and tensin homologue), and HIF-1 (Hypoxia- To confirm whether the expression of inducible factors was suppressed, a Western blot experiment was performed as described above. For reference, a schematic diagram of the PI3K/Akt and HIF-1 signaling pathways is shown in Figure 11, and the results of the Western blot experiment are shown in Figure 12.
이에 따르면, 병풀 투여군(BPH+CA200)에서 표피성장인자(EGF)로부터 유도된 PI3K/Akt 및 HIF-1 시그널링 경로의 관련 인자들 중 PI3K를 억제해주는 인자인 PTEN을 제외하고 모든 관련 인자 단백질의 발현이 높은 것으로 나타났다.According to this, among the factors related to the PI3K/Akt and HIF-1 signaling pathways induced by epidermal growth factor (EGF) in the Centella asiatica treatment group (BPH+CA200), the expression of all related factor proteins except PTEN, a factor that inhibits PI3K, was expressed. This was found to be high.
실험예 6: 전립선 조직 내 세포증식 관련 인자 발현 억제능 분석Experimental Example 6: Analysis of the ability to suppress expression of factors related to cell proliferation in prostate tissue
전립선 조직 내 세포증식과 관련된 대표적인 인자인 PCNA(Proliferating Cell Nuclear Antigen)와 사이클린 D1(Cyclin D1) 단백질 발현을 상술한 웨스턴 블롯 실험으로 분석하여 그 결과를 도 13에 나타내었다. 이에 따르면, 분석했다. 병풀 투여군(BPH+CA200)에서 전립선 비대증 유발군(BPH)에 비해 PCNA와 Cyclin D1 단백질 발현이 감소한 것을 확인할 수 있었다.The expression of PCNA (Proliferating Cell Nuclear Antigen) and Cyclin D1 (Cyclin D1) proteins, which are representative factors related to cell proliferation in prostate tissue, were analyzed by the Western blot experiment described above, and the results are shown in Figure 13. According to this, it was analyzed. It was confirmed that PCNA and Cyclin D1 protein expression was decreased in the Centella asiatica administration group (BPH+CA200) compared to the benign prostatic hyperplasia-induced group (BPH).
이상, 본 발명의 실시예들에 대하여 설명하였으나, 해당 기술 분야에서 통상의 지식을 가진 자라면 특허청구범위에 기재된 본 발명의 사상으로부터 벗어나지 않는 범위 내에서, 구성 요소의 부가, 변경, 삭제 또는 추가 등에 의해 본 발명을 다양하게 수정 및 변경시킬 수 있을 것이며, 이 또한 본 발명의 권리범위 내에 포함된다고 할 것이다.Although the embodiments of the present invention have been described above, those skilled in the art can add, change, delete or add components without departing from the spirit of the present invention as set forth in the patent claims. The present invention may be modified and changed in various ways, and this will also be included within the scope of rights of the present invention.
Claims (3)
상기 병풀 추출물은 열수 추출물이고,
생체 외(in vitro) 조건의 LNCaP 세포에서 안드로겐 시그널링(androgen signaling) 관련 인자인 AR(androgen receptor) 및 5AR2(5alpha reductase) 중에서 선택된 1종 이상의 발현 저해용 시약 조성물.Contains Centella asiatica extract as an active ingredient,
The Centella asiatica extract is a hot water extract,
A reagent composition for inhibiting the expression of at least one selected from AR (androgen receptor) and 5AR2 (5alpha reductase), factors related to androgen signaling, in LNCaP cells under in vitro conditions.
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