KR102006998B1 - A pharmaceutical composition for preventing or treating IL-6-mediated disease, comprising extract, fraction, or compounds derived from Ampelopsis brevipedunculata - Google Patents
A pharmaceutical composition for preventing or treating IL-6-mediated disease, comprising extract, fraction, or compounds derived from Ampelopsis brevipedunculata Download PDFInfo
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Abstract
본 발명은 개머루덩굴(Ampelopsis brevipedunculata) 추출물, 이의 분획물, 또는 이로부터 분리된 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6(interleukin-6) 매개성 질환의 예방 또는 치료용 약학적 조성물 및 상기 조성물을 IL-6 매개성 질환 의심 개체에 투여하는 단계를 포함하는, IL-6 매개성 질환의 치료 방법에 관한 것이다. 또한, 본 발명은 개머루덩굴 추출물, 이의 분획물, 또는 이로부터 분리된 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 식품 조성물, 의약외품 조성물, 사료 첨가제 및 음용수 첨가제에 관한 것이다.The present invention is a vine ( Ampelopsis) brevipedunculata ) extract, a fraction thereof, or a compound isolated therefrom or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for the prevention or treatment of IL-6 (interleukin-6) mediated diseases and the composition The present invention relates to a method for treating IL-6 mediated disease, comprising administering to a subject suspected of IL-6 mediated disease. In addition, the present invention includes a jasmine vine extract, fractions thereof, or a compound isolated therefrom or a pharmaceutically acceptable salt thereof as an active ingredient, a food composition for preventing or ameliorating IL-6 mediated diseases, quasi-drug compositions, It relates to feed additives and drinking water additives.
Description
본 발명은 개머루덩굴(Ampelopsis brevipedunculata) 추출물, 이의 분획물, 또는 이로부터 분리된 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6(interleukin-6) 매개성 질환의 예방 또는 치료용 약학적 조성물 및 상기 조성물을 IL-6 매개성 질환 의심 개체에 투여하는 단계를 포함하는, IL-6 매개성 질환의 치료 방법에 관한 것이다. 또한, 본 발명은 개머루덩굴 추출물, 이의 분획물, 또는 이로부터 분리된 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 식품 조성물, 의약외품 조성물, 사료 첨가제 및 음용수 첨가제에 관한 것이다.The present invention is a vine ( Ampelopsis brevipedunculata ) extract, a fraction thereof, or a compound isolated therefrom or a pharmaceutically acceptable salt thereof, as an active ingredient, a pharmaceutical composition for preventing or treating IL-6 (interleukin-6) mediated diseases, and the composition It relates to a method of treating an IL-6 mediated disease comprising administering to an individual suspected of an IL-6 mediated disease. In addition, the present invention is a food composition, quasi-drug composition for preventing or improving IL-6-mediated disease, comprising as an active ingredient a gorilla extract, a fraction thereof, or a compound isolated therefrom or a pharmaceutically acceptable salt thereof, It relates to feed additives and drinking water additives.
인터류킨-6(IL-6)는 B 세포 자극 인자 2(BSF2) 또는 인터페론-2(IFN-2)로도 불리는 사이토카인으로, B 임파구의 활성화에 관여하는 분화인자로 발견되었다. 그 후, 여러 가지 세포의 기능에 영향을 미치는 다기능 사이토카인이라는 것이 밝혀졌다. IL-6는 세포막 위에 두 종류의 단백질을 매개로 그 생물학적 활성을 전달한다. 하나는 IL-6가 결합하는 단백질인 IL-6 수용체로, IL-6 수용체는 세포막을 관통하여 발현되어 있으며 약 80kDa의 분자량을 가지는 막결합형 단백질이다. 다른 하나는, 비리간드 결합성의 시그날 전달에 속하는 약 130kDa의 분자량을 가지는 막단백질 gp130이다. IL-6와 IL-6 수용체는 IL-6/IL-6 수용체 복합체를 형성하고, 이어서 gp130과 결합한다. 이러한 리간드와 수용체들의 결합 후, 세포 내에서는 JAK2(Janus Kinase 2)가 인산전이반응(transphosphorylation)에 의해 활성화된다. 활성화된 JAK2에 의해 수용체 세포질 도메인(cytoplasmic domains)의 여러 타이로신 잔기(tyrosine residues)가 인산화(phosphorylation)되고, 이것은 SH2나 다른 인산타이로신 결합 모티프(phosphotyrosine binding motif)를 가지고 있는 STAT3(signal transducers and activators of transcription 3)와 같은 세포질 내 단백질의 도킹 사이트(docking site) 역할을 하게 된다. 수용체의 세포질 도메인(cytoplasmic domain)에 결합한 STAT3는 JAK2에 의해 인산화가 된 후 수용체에서 떨어져 나오며, 이러한 활성화된 STAT3들은 세포질 내에 서로서로 결합하여 호모다이머(homodimer) 또는 헤테로다이머(heterodimer)를 이룬 후 핵 내로 들어가 목적 유전자의 인식 서열(recognition sequence)에 결합하여 전사를 증가시킨다. Interleukin-6 (IL-6) is a cytokine, also called B cell stimulating factor 2 (BSF2) or interferon-2 (IFN-2), and was found to be a differentiation factor involved in the activation of B lymphocytes. After that, it was discovered that it is a multifunctional cytokine that affects the functions of several cells. IL-6 transmits its biological activity via two types of proteins on the cell membrane. One is the IL-6 receptor, which is a protein to which IL-6 binds. The IL-6 receptor is expressed through cell membranes and is a membrane-bound protein having a molecular weight of about 80 kDa. The other is the membrane protein gp130, which has a molecular weight of about 130 kDa, which belongs to the non-ligand-binding signal transmission. IL-6 and IL-6 receptors form an IL-6/IL-6 receptor complex, which then binds to gp130. After binding of these ligands and receptors, JAK2 (Janus Kinase 2) is activated by transphosphorylation in the cell. Activated JAK2 phosphorylates several tyrosine residues in the cytoplasmic domains of the receptor, which are signal transducers and activators of STAT3, which have SH2 or other phosphotyrosine binding motifs. It acts as a docking site for proteins in the cytoplasm, such as transcription 3). STAT3 bound to the cytoplasmic domain of the receptor is phosphorylated by JAK2 and then released from the receptor, and these activated STAT3s bind to each other in the cytoplasm to form a homodimer or heterodimer, and then the nucleus It goes inside and binds to the recognition sequence of the target gene to increase transcription.
이러한 IL-6에 의해 유도되는 신호전달체계와 염증성 질환, 자가면역질환 및 골다공증에 대한 관련성에 대하여 다양한 연구가 진행되어 왔다. 이에, 염증성, 자가면역질환 및 골다공증의 치료를 위해서 IL-6에 의해 유도되는 신호전달체계를 억제시키기 위한 연구가 활발히 진행되고 있으며, 현재 IL-6의 신호전달체계의 억제에 대하여 항 IL-6 R 항체(anti-IL-6 receptor antibody)를 이용한 것이 가장 많이 알려져 있다. 상기 항 IL-6 R 항체를 이용한 류마티스성 관절염에 대한 활액 세포 성장 억제제(국제특허공개 제96/011020호), 항 IL-6 R 항체를 이용한 형질구 증가증, 초면역 글로불린 혈증, 빈혈, 신염, 악액질, 류마티스성 관절염, 목축업자 질병 및 맥관증식신염과 같은 IL-6 산물에 기인하는 질병의 치료 등이 이미 알려진 바 있다(국제공개특허 제96/012503호). 또한, 항 IL-6 R 항체는 다발성 경화증, 포도막염, 만성 갑상선염, 지연성 과민증 및 아토피성 피부염과 같은 민감성 T 세포 관련 질병(국제특허공개공보 제98/042377호), 전신성 에리테마토스의 치료, 크론병의 치료(국제특허공개공보 제99/047170호), 췌장염의 치료(국제특허공개공보 제00/010607호), 건선의 치료(국제특허공개공보 제02/034292호) 및 연소성 만성 관절염의 치료(국제특허공개공보 제02/080969호)에 적용될 수 있음이 보고되었다. 그러나, 상기 항 IL-6 R 항체의 경우 개체 내에 도입되는 경우 외래 단백질로서 인지될 수 있는 부분인 에피토프를 가질 수 있으므로, 치료제로서 사용될 경우 여전히 면역원성으로 작용하는 단점이 있다. 상기와 같은 문제점을 해결하기 위하여 면역체계에 인지되지 않는 단백질이 아닌 작은 분자 화합물(small molecule compound)을 이용하여 IL-6에 의해 매개되는 질병의 치료제를 개발하기 위하여 많은 연구가 이루어지고 있다.Various studies have been conducted on the relationship between the signaling system induced by IL-6 and inflammatory diseases, autoimmune diseases, and osteoporosis. Accordingly, studies to suppress the signaling system induced by IL-6 for the treatment of inflammatory, autoimmune diseases and osteoporosis are actively being conducted, and currently, anti-IL-6 against inhibition of the signaling system of IL-6 It is most commonly known to use an R antibody (anti-IL-6 receptor antibody). Synovial cell growth inhibitor for rheumatoid arthritis using the anti-IL-6 R antibody (International Patent Publication No. 96/011020), plasmacytosis using anti-IL-6 R antibody, hyperimmune globulinemia, anemia, nephritis, Treatment of diseases caused by IL-6 products such as cachexia, rheumatoid arthritis, herder's disease, and vasculogenic nephritis, etc. have already been known (International Publication No. 96/012503). In addition, anti-IL-6R antibodies are sensitive T cell-related diseases such as multiple sclerosis, uveitis, chronic thyroiditis, delayed hypersensitivity and atopic dermatitis (International Patent Publication No. 98/042377), treatment of systemic erythematos, Treatment of Crohn's disease (International Patent Publication No. 99/047170), Pancreatitis (International Patent Publication No. 00/010607), psoriasis treatment (International Patent Publication No. 02/034292) and juvenile chronic arthritis It has been reported that it can be applied to treatment (International Patent Publication No. 02/080969). However, in the case of the anti-IL-6 R antibody, when introduced into an individual, it may have an epitope that is a part that can be recognized as a foreign protein, and thus, when used as a therapeutic agent, it still has a disadvantage of acting as immunogenicity. In order to solve the above problems, many studies have been conducted to develop therapeutic agents for diseases mediated by IL-6 using small molecule compounds rather than proteins that are not recognized by the immune system.
또한 암과 관련되어 IL-6 신호전달체계는 그 중간 매개인자인 STAT3(signal transducers and activators of transcription 3)와 많은 관련이 있다. STAT3는 골수종, 유방 암종, 전립선 암, 뇌 종양, 두경부 암종, 흑색종, 백혈병 및 림프종, 특히 만성 골수성 백혈병 및 다발성 골수종을 포함하여 여러 형태의 암에 관여하는 것으로 보고되었다(Niu, 등, Cancer Res., 1999, 59, 5059-5063). 쥐 및 인간 전립선 암 양쪽에서 유래된 세포들은 구조적으로 활성화된 STAT3을 갖는 것으로 밝혀졌으며, STAT3는 일부 급성 백혈병(Gouilleux-Gruart, V. 등, Leuk.Lymphoma, 1997, 28, 83-88) 및 T 세포 림프종(Yu,C.L.등, J.Immunol., 1997, 159, 5206-5210)에서 구조적으로 활성화되는 것으로 밝혀졌다. 흥미롭게도, STAT3은 만성 림프성 백혈병에서 세린 잔기 위에 구조적으로 인산화되는 것으로 밝혀졌다(Frank, D.A., 등, J.Clin.Invest., 1997, 100, 3140-3148). STAT3은, 다발성 골수종을 가진 환자로부터의 골수 단핵 세포 및 배양액 양쪽 모두에서, 골수종 종양 세포에서 구조적으로 활성인 것으로 밝혀졌다. 이러한 세포는 Fas-매개 세포고사에 내성이고 높은 수준의 Bcl-xL을 발현한다. STAT3 신호전달은 세포고사에 대한 내성을 부여함으로써 골수종 종양 세포의 생존을 위해 필수적인 것으로 밝혀졌다(Catlett-Falcone, R. 등, Immunity, 1999, 10, 105-115). 한편, 최근에는 췌장암을 비롯한 Ras에 의해 유도되는 암 환자군에서 이상적으로 IL-6가 분비되고, IL-6를 제거함으로서 Ras에 의한 종양세포의 성장과 혈관생성이 억제될 뿐 아니라 종양의 크기가 감소됨이 보고되었다 (Brooke Ancrile 등, Gene & Development, 2007, 21, 1714-1719). 또한 EGFR이 변이된 폐 선암(lung adenocarcinoma)에서 IL-6가 과발현됨으로서 STAT3가 활성화됨이 밝혀지면서 IL-6에 의한 gp130/JAK/STAT3 경로가 항암치료에 있어서 새로운 타켓으로 부각되고 있다(Sizhi Paul Gao 등, J. Clin. Invest. 2007, 117, 38463856).Also, related to cancer, the IL-6 signaling system is closely related to its intermediate mediator, STAT3 (signal transducers and activators of transcription 3). STAT3 has been reported to be involved in several forms of cancer, including myeloma, breast carcinoma, prostate cancer, brain tumor, head and neck carcinoma, melanoma, leukemia and lymphoma, especially chronic myelogenous leukemia and multiple myeloma (Niu, et al., Cancer Res. ., 1999, 59, 5059-5063). Cells derived from both murine and human prostate cancer have been found to have structurally activated STAT3, and STAT3 has some acute leukemia (Gouilleux-Gruart, V. et al., Leuk. Lymphoma, 1997, 28, 83-88) and T It has been found to be structurally activated in cellular lymphoma (Yu, CL et al., J. Immunol., 1997, 159, 5206-5210). Interestingly, STAT3 has been shown to be structurally phosphorylated on serine residues in chronic lymphocytic leukemia (Frank, D.A., et al., J. Clin. Invest., 1997, 100, 3140-3148). STAT3 has been found to be structurally active in myeloma tumor cells, both in myeloma mononuclear cells and cultures from patients with multiple myeloma. These cells are resistant to Fas-mediated apoptosis and express high levels of Bcl-xL. STAT3 signaling has been shown to be essential for the survival of myeloma tumor cells by conferring resistance to apoptosis (Catlett-Falcone, R. et al., Immunity, 1999, 10, 105-115). On the other hand, in recent years, IL-6 is secreted ideally in patients with Ras-induced cancer including pancreatic cancer, and by removing IL-6, the growth of tumor cells and angiogenesis by Ras are inhibited, as well as the size of the tumor is reduced. Has been reported (Brooke Ancrile et al., Gene & Development, 2007, 21, 1714-1719). In addition, as it was found that STAT3 is activated by overexpression of IL-6 in EGFR-mutated lung adenocarcinoma, the gp130/JAK/STAT3 pathway by IL-6 is emerging as a new target in chemotherapy (Sizhi Paul Gao et al., J. Clin. Invest. 2007, 117, 38463856).
또한, STAT3는 류마티스성 관절염을 포함한 자가면역질환 또는 골다공증에 있어 NF-κB와는 또 다른 하나의 중요한 전사인자로서 역할을 하는 것이 알려져 있다. 특히, STAT3는 사이토카인인 IL-6에 의해서 활성화되는 것이 잘 알려져 있으며, 표피 성장 인자(Epidermal growth factor, EGF)에도 활성화되는 것으로 알려져있다. 최근, 골다공증과 IL-6와의 연관성에 대한 연구결과가 많이 보고되고 있으며, 특히 IL-6에 의해 유도되는 STAT3 활성이 파골세포의 분화와 뼈 생성에 중요한 역할을 한다는 것이 동물모델을 통하여 입증된바 있으며(Bone 2006, 39, 505-512), STAT3 결핍 마우스(STAT3-deficient mice)의 경우, 골밀도 및 골부피가 감소되어 있으며, 골다공증에 부정적인 영향을 미치는 파골세포 수의 증가가 관찰되었다(BBRC 2005, 328, 800-807). 반면, IL-6에 의해 유도되는 STAT3의 인산화를 저해하는 화합물인 마딘돌린 A(madindoline A)를 폐경기 골다공증 실험을 위한 동물모델인 OVX 마우스에 처리하면 뼈의 재흡수를 저해하는 활성이 나타난 났으며(PNAS, 2002, 99(23), 14728-14733), IL-6-/- 마우스 모델에서는 에스트로겐 고갈에 따른 뼈 손실과 파골세포의 전구체 수 증가 등의 변화가 나타나지 않았다(EMBO J 1994, 13, 1189-1196). 상기와 같은 사실은 IL-6가 특히, STAT3의 인산화를 통하여 뼈의 형성 및 재흡수에 중요하게 작용함을 나타내는 것이다.In addition, it is known that STAT3 plays a role as another important transcription factor different from NF-κB in autoimmune diseases including rheumatoid arthritis or osteoporosis. In particular, it is well known that STAT3 is activated by the cytokine IL-6, and it is also known to be activated by epidermal growth factor (EGF). Recently, many studies have been reported on the association between osteoporosis and IL-6, and in particular, it has been proven through animal models that STAT3 activity induced by IL-6 plays an important role in the differentiation of osteoclasts and bone formation. (Bone 2006, 39, 505-512), in the case of STAT3-deficient mice, bone mineral density and bone volume were decreased, and an increase in the number of osteoclasts, which negatively affects osteoporosis, was observed (BBRC 2005). , 328, 800-807). On the other hand, when madindoline A, a compound that inhibits IL-6-induced phosphorylation of STAT3, was treated in OVX mice, an animal model for postmenopausal osteoporosis experiments, the activity of inhibiting bone resorption was shown. (PNAS, 2002, 99(23), 14728-14733), in the IL-6-/- mouse model, no changes such as bone loss due to estrogen depletion and an increase in the number of osteoclast precursors were observed (EMBO J 1994, 13, 1189-1196). These facts indicate that IL-6 plays an important role in bone formation and resorption, in particular, through phosphorylation of STAT3.
이에 본 발명자들은 IL-6에 의해 활성화되는 STAT3 경로를 표적으로 하여 IL-6 매개성 질환 치료 기능이 있는 천연물을 찾기 위하여 예의 노력한 결과, 개머루덩굴 추출물 및 이의 분획물이 STAT3의 전사활성 및 인산화를 저해하여 IL-6에 의하여 매개되는 신호전달경로를 효과적으로 저해시키고, 특히, 파골세포의 분화를 저해하는 우수한 활성을 가짐을 확인하여, 이를 IL-6 매개성 질환의 예방 또는 치료에 사용할 수 있음을 확인하였다. 또한, 개머루덩굴 추출물로부터 IL-6 매개 신호전달경로를 효과적으로 저해하며, 또한 파골세포의 분화를 저해하는 활성을 가지는 유효 화합물을 규명하여 이를 골 대사성 질환을 비롯한 IL-6 매개성 질환의 치료에 적용할 수 있음을 확인하고, 본 발명을 완성하였다. Accordingly, the present inventors made intensive efforts to find a natural product capable of treating IL-6-mediated diseases by targeting the STAT3 pathway activated by IL-6. As a result, the extract and fractions thereof inhibited the transcriptional activity and phosphorylation of STAT3. Thus, it was confirmed that it has an excellent activity that effectively inhibits the signaling pathway mediated by IL-6 and, in particular, inhibits the differentiation of osteoclasts, and that it can be used for the prevention or treatment of IL-6-mediated diseases. I did. In addition, an effective compound having an activity of effectively inhibiting the IL-6-mediated signaling pathway and inhibiting the differentiation of osteoclasts has been identified from the extract of Asteraceae extract and applied to the treatment of IL-6-mediated diseases including bone metabolic diseases. It was confirmed that it could be done, and the present invention was completed.
본 발명의 하나의 목적은 개머루덩굴(Ampelopsis brevipedunculata) 추출물 또는 이의 분획물을 유효성분으로 포함하는, IL-6(interleukin-6) 매개성 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. One object of the present invention is a vine ( Ampelopsis brevipedunculata ) To provide a pharmaceutical composition for the prevention or treatment of IL-6 (interleukin-6) mediated disease, comprising an extract or a fraction thereof as an active ingredient.
본 발명의 다른 목적은 개머루덩굴 추출물 또는 이의 분획물을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 식품 조성물, 의약외품 조성물, 사료 첨가제 및 음용수 첨가제를 제공하는 것이다. Another object of the present invention is to provide a food composition for preventing or improving IL-6-mediated diseases, a quasi-drug composition, a feed additive and a drinking water additive, comprising an extract or a fraction thereof as an active ingredient.
본 발명의 또 다른 목적은 하기 화학식 1 내지 3 중 어느 하나로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. Another object of the present invention is to provide a pharmaceutical composition for preventing or treating IL-6 mediated diseases, comprising a compound represented by any one of the following
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
본 발명의 또 다른 목적은 상기 화학식 1 내지 3 중 어느 하나로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 식품 조성물, 의약외품 조성물, 사료첨가제 및 음용수 첨가제를 제공하는 것이다. Another object of the present invention is a food composition, quasi-drug composition for preventing or improving IL-6-mediated diseases, comprising a compound represented by any one of
본 발명의 또 다른 목적은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는, IL-6 매개성 질환의 치료 방법을 제공하는 것이다. Another object of the present invention is to provide a method for treating IL-6 mediated diseases, comprising administering the pharmaceutical composition to an individual.
상기의 목적을 달성하기 위한 하나의 양태로서, 본 발명은 개머루덩굴(Ampelopsis brevipedunculata) 추출물 또는 이의 분획물을 유효성분으로 포함하는, IL-6(interleukin-6) 매개성 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In some embodiments for achieving the above object, the present invention is a pharmaceutical for preventing or treating containing ampelopsis brevipedunculata vines (Ampelopsis brevipedunculata) extract or fractions thereof as an active ingredient, IL-6 (interleukin-6 ) mediated diseases The composition is provided.
본 발명에서 용어, "개머루덩굴(Ampelopsis brevipedunculata)"은 포도과 개머루속에 속하는 덩굴성 낙엽 관목이다. 상기 개머루덩굴은 약리학적 활성에 있어, 지혈작용, 항균작용, 항산화작용 등을 가지는 것으로 알려져 있지만, 개머루덩굴 추출물 또는 이의 분획물이 특히 염증성 질환, 골 대사성 질환, 아토피 및 암에서의 치료 용도에 대해서는 알려진 바 없으며, 본 발명자들에 의하여 최초로 규명된 것이다. 본 발명에서 개머루덩굴은 상업적으로 판매되는 것을 구입하거나, 자연에서 채취 또는 재배된 것을 사용할 수 있다. In the present invention, the term " Ampelopsis brevipedunculata )" is a vine deciduous shrub belonging to the genus Grapeaceae coccinus . The coccyx is known to have hemostatic action, antibacterial action, antioxidant action, etc. in its pharmacological activity, but the coriander extract or its fractions are particularly inflammatory diseases, There is no known use for treatment in bone metabolic diseases, atopy and cancer, and was first identified by the present inventors In the present invention, the honeysuckle can be purchased commercially, or harvested or cultivated in nature can be used. have.
본 발명에서 용어, "개머루덩굴 추출물"은 개머루덩굴을 추출하여 수득한 추출물을 의미한다. 상기 개머루덩굴 추출물은 개머루덩굴 분쇄물을 건조 중량의 약 2 내지 20배, 바람직하게는 약 3 내지 5배에 달하는 부피의 물, 메탄올, 에탄올 및 부탄올 등과 같은 탄소수 1(C1) 내지 6(C6)의 알코올 극성 용매, 바람직하게는 탄소수 1 내지 4의 저급알코올 극성 용매, 또는 이들의 약 1:0.1 내지 1:10의 혼합비를 갖는 혼합용매를 용출 용매로써 사용하고, 추출 온도는 20℃ 내지 100℃, 바람직하게는 실온에서, 추출 기간은 약 12시간 내지 4일, 바람직하게는 3일 동안 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등의 추출방법을 사용하여 추출할 수 있으나, IL-6 매개성 질환의 치료 활성이 있는 물질을 추출하는 방법이라면 제한없이 이용될 수 있다. 바람직하게는 냉침추출로 1회 내지 5회 연속 추출하여 감압여과하고, 그 여과추출물을 진공회전농축기로 20℃ 내지 100℃, 더 바람직하게는 실온에서 감압 농축하여 물, 저급 알콜 또는 이들의 혼합용매에 가용한 개머루덩굴 조추출물을 수득한 결과물이 될 수 있으나, 본 발명의 IL-6 매개성 질환의 치료 효과를 나타낼 수 있는 한, 이에 제한되지는 않고, 추출액, 추출액의 희석액 또는 농축액, 추출액을 건조하여 얻어지는 건조물, 또는 이들의 조정제물 또는 정제물의 형태를 모두 포함한다. 상기 개머루덩굴 추출물은 천연, 잡종, 변종식물의 다양한 기관으로부터 추출될 수 있고, 예를 들어, 뿌리, 지상부, 줄기, 잎, 꽃, 열매의 몸통, 열매의 껍질뿐만 아니라 식물 조직 배양물로부터 추출 가능하다. 본 발명의 일 실시예에서는 분말화된 개머루덩굴의 줄기에 에탄올을 넣고 7일간 냉침추출하였다(실시예 1).In the present invention, the term "black vine extract" refers to an extract obtained by extracting black vine. The extract is a carbon number of 1 (C 1 ) to 6 (C) such as water, methanol, ethanol, butanol, etc. in a volume of about 2 to 20 times, preferably about 3 to 5 times the dry weight of the crushed blackberry vine. 6 ) of an alcohol polar solvent, preferably a lower alcohol polar solvent having 1 to 4 carbon atoms, or a mixed solvent having a mixing ratio of about 1:0.1 to 1:10 thereof, as an elution solvent, and the extraction temperature is 20°C to At 100° C., preferably at room temperature, the extraction period can be extracted using an extraction method such as hot water extraction, cold needle extraction, reflux cooling extraction, or ultrasonic extraction for about 12 hours to 4 days, preferably 3 days, but IL -6 Any method of extracting a substance having therapeutic activity for a mediated disease can be used without limitation. Preferably, extraction is carried out under reduced pressure after 1 to 5 consecutive extractions by cold sedimentation, and the filtered extract is concentrated under reduced pressure at 20°C to 100°C with a vacuum rotary concentrator, more preferably at room temperature, and water, lower alcohol or a mixed solvent thereof Although it may be a result obtained by obtaining the crude extract of black stalk vine that can be used for, the extract is not limited thereto, as long as it can exhibit the therapeutic effect of the IL-6-mediated disease of the present invention, and the extract, a diluted solution or a concentrate of the extract, or an extract may be used. It includes all forms of dried products obtained by drying, or preparations or purified products thereof. The anteater extract can be extracted from various organs of natural, hybrid, and variant plants, and can be extracted from, for example, roots, above-ground parts, stems, leaves, flowers, trunks of fruits, shells of fruits, as well as plant tissue cultures. Do. In one embodiment of the present invention, ethanol was added to the stem of the powdered blackberry vine, and cold sediment was extracted for 7 days (Example 1).
본 발명에서 용어, "분획물"은 다양한 구성성분을 포함하는 혼합물로부터 특정 성분 또는 특정 그룹을 분리하는 분획방법에 의하여 얻어진 결과물을 의미한다. 본 발명의 개머루덩굴 분획물은 개머루덩굴 추출물을 물로 현탁한 후, 헥산, 에틸아세테이트와 같은 비극성 용매를 사용하여 분획함으로써 극성 용매 분획물과 비극성 용매 분획물을 각각 수득할 수 있다. 구체적으로, 개머루덩굴 조추출물을 증류수에 현탁한 후, 현탁액의 약 1 내지 100배, 바람직하게는 약 1 내지 5배 부피의 헥산 및 에틸아세테이트와 같은 비극성 용매를 가하여 1회 내지 10회, 바람직하게는 2회 내지 5회에 걸쳐 비극성 용매 가용층을 추출, 분리하여 수득할 수 있다. 또한 추가로 통상의 분획 공정을 수행할 수도 있다(Harborne J.B. Phytochemical methods: A guide to modern techniques of plant analysis, 3rd Ed. p6-7, 1998). 보다 구체적으로, 상기 개머루덩굴 조추출물을 물에 현탁한 후, 동량의 n-헥산 및 에틸아세테이트 용매를 이용하여 연속 추출로 개머루덩굴 각 용매 가용 추출물을 수득할 수 있고, 더욱 구체적으로는 개머루덩굴 조추출물을 물에 현탁한 후, 동량의 n-헥산을 혼합한 후 분획하여 n-헥산 가용성 분획물 및 수가용성 분획물을 수득할 수 있으며, 이 수가용성 분획물에 에틸아세테이트를 가하여 에틸아세테이트 가용성 분획물 및 수가용성 분획물을 수득할 수 있다. 본 발명의 일 실시예에서는 개머루덩굴 조추출물을 물에 현탁하여, 물 분획물, 헥산 분획물 및 에틸아세테이트 분획물을 수득하였다(실시예 1-2). In the present invention, the term "fraction" means a product obtained by a fractionation method for separating a specific component or a specific group from a mixture containing various constituents. In the fractions of the vines of the present invention, a polar solvent fraction and a fraction of a non-polar solvent can be obtained, respectively, by suspending the vine extract in water and then fractionating using a non-polar solvent such as hexane and ethyl acetate. Specifically, after suspending the crude blackberry vine extract in distilled water, about 1 to 100 times, preferably about 1 to 5 times the volume of the suspension, non-polar solvents such as hexane and ethyl acetate are added once to 10 times, preferably Can be obtained by extracting and separating the non-polar solvent soluble layer over 2 to 5 times. In addition, it is also possible to perform a conventional fractionation process (Harborne JB Phytochemical methods: A guide to modern techniques of plant analysis, 3rd Ed. p6-7, 1998). More specifically, after suspending the crude blackberry extract in water, continuous extraction using the same amount of n -hexane and ethylacetate solvent to obtain each solvent-soluble extract of the blackberry vine, more specifically, After the extract is suspended in water, the same amount of n -hexane is mixed and fractionated to obtain an n- hexane-soluble fraction and a water-soluble fraction, and ethyl acetate is added to the water-soluble fraction to obtain an ethyl acetate-soluble fraction and a water-soluble fraction. Fractions can be obtained. In one embodiment of the present invention, the crude extract of blackberry vine was suspended in water to obtain a water fraction, a hexane fraction, and an ethyl acetate fraction (Example 1-2).
또한, 상기 개머루덩굴 추출물 또는 이의 분획물은 대표적인 활성 성분으로 하기 화학식 1 내지 3으로 표시되는 화합물을 포함할 수 있다.In addition, the extract or a fraction thereof may include a compound represented by the following
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
본 발명의 일 실시예에서는, 개머루덩굴 추출물 또는 이의 분획물로부터 IL-6 신호전달경로를 효과적으로 차단하는 3종의 유효 화합물을 분리하였다. In one embodiment of the present invention, three kinds of effective compounds that effectively block the IL-6 signaling pathway were isolated from the extract or fractions thereof.
구체적으로, 3종의 유효 화합물은 화학식 1의 에틸 갈레이트(ethyl gallate), 화학식 2의 갈릭산(gallic acid) 및 화학식 3의 아로마덴드린(aromadendrin)으로, 에틸 갈레이트는 에틸 3,4,5-트리히드록시벤조에이트(ethyl 3,4,5-trihydroxybenzoate)로, 갈릭산은 4-히드록시-3-메톡시벤조산(4-hydroxy-3-methoxybenzoic acid)으로, 아로마덴드린은 3,5,7-트리히드록시-2-(4-히드록시페닐)크로만-4-온(3,5,7-trihydroxy-2-(4-hydroxyphenyl)chroman-4-one)으로 명명된다. Specifically, the three effective compounds are ethyl gallate of
상기 화합물들을 분리하기 위한 방법은 하기와 같이 수행될 수 있다.The method for separating the compounds may be carried out as follows.
구체적으로, 개머루덩굴 헥산 분획물과 에틸아세테이트 분획물로부터 실리카겔 크로마토그래피로 화합물을 분리하고 정제하여 상기 화학식 1 내지 3의 화합물을 얻을 수 있다. 상기 화합물 분리를 위한 실리카겔 크로마토그래피를 수행하는 경우, 이동상으로는 n-헥산, n-헥산 에틸아세테이트, 클로로포름ㆍ아세톤 혼합용매 및 메탄올을 사용하는 것이 바람직하고, 추가되는 크로마토그래피에서는 n-헥산ㆍ아세톤 혼합용매를 사용할 수 있다. 이때 사용되는 n-헥산ㆍ에틸아세테이트 혼합용매의 부피비는 50 : 1 ~ 1 : 5 부피비가 바람직하며, 클로로포름ㆍ아세톤 혼합용매일 경우에는 150 : 1 ~ 1 : 4 부피비가 바람직하다. 상기 크로마토그래피는 단일 화합물이 정제될 때까지 1회 내지 수 회에 걸쳐 수행할 수 있으며, 필요에 따라 농축, 재결정을 실시할 수 있다. Specifically, the compound of
본 발명의 상기 3종의 유효 화합물은 IL-6 처리에 의한 STAT3 활성화를 효과적으로 저해하여(도 4), IL-6 매개성 질환의 예방 또는 치료에 적용될 수 있다. 또한, 상기 3종의 유효 화합물은 파골세포의 분화를 효과적으로 억제하여(도 11), 이를 골다공증을 비롯한 골 대사성 질환의 예방 또는 치료에 적용될 있는 효과를 지닌다. The three effective compounds of the present invention effectively inhibit STAT3 activation by IL-6 treatment (FIG. 4), and thus can be applied to the prevention or treatment of IL-6 mediated diseases. In addition, the three effective compounds effectively inhibit the differentiation of osteoclasts (FIG. 11), and thus have an effect that can be applied to the prevention or treatment of bone metabolic diseases including osteoporosis.
본 발명의 개머루덩굴 추출물, 이의 분획물 및 이로부터 분리된 상기 3종의 화합물은 STAT3(signal transducers and activators of transcription 3) 및 JAK2(Janus kinase 2) 저해 활성을 나타내어, IL-6 매개성 질환의 예방 또는 치료에 효과적으로 사용될 수 있다. The extract, a fraction thereof, and the three compounds isolated therefrom of the present invention exhibit inhibitory activities of STAT3 (signal transducers and activators of transcription 3) and JAK2 (Janus kinase 2), and prevent IL-6-mediated diseases. Or it can be effectively used for treatment.
본 발명에서 용어, "IL-6 매개성 질환"은 IL-6에 의한 신호전달경로가 활성화되어 발명하는 질환을 총칭하는 의미로서, 구체적으로 IL-6에 의하여 JAK2 및 STAT3가 인산화되어 활성화됨에 따라 발병하는 질병을 의미한다. 구체적으로, IL-6는 gp130, gp80과 같은 수용체에 결합하면, JAK2가 인산화되어 활성화되고, 이는 다시 STAT3 단백질의 인산화를 가져와 STAT3 단백질을 활성화시킨다. 활성화된 STAT3 단백질은 핵 내로 들어가 표적 유전자를 발현시킴을 통하여 IL-6 매개성 질환의 발병 또는 진행을 가져올 수 있다. 본 발명의 목적상 상기 IL-6 매개성 질환은 본 발명의 개머루덩굴 추출물 또는 이의 분획물에 의하여 예방 또는 치료될 수 있는 질환이라면 제한없이 포함하며, 그 예로 염증성 질환, 골 대사성 질환, 아토피 또는 암일 수 있으나, 이에 제한되지 않는다. In the present invention, the term "IL-6-mediated disease" is a generic term for a disease to be invented by activation of the signaling pathway by IL-6. Specifically, as JAK2 and STAT3 are phosphorylated and activated by IL-6 It means an onset disease. Specifically, when IL-6 binds to receptors such as gp130 and gp80, JAK2 is phosphorylated and activated, which in turn leads to phosphorylation of the STAT3 protein, thereby activating the STAT3 protein. Activated STAT3 protein can lead to the onset or progression of IL-6-mediated diseases by entering the nucleus and expressing the target gene. For the purposes of the present invention, the IL-6 mediated disease includes without limitation any disease that can be prevented or treated by the extract or fractions thereof of the present invention, such as inflammatory disease, bone metabolic disease, atopy or cancer. However, it is not limited thereto.
본 발명에서 용어, "염증성 질환"은 염증을 주병변으로 하는 질병을 총칭하는 것으로, 본 발명의 목적상 상기 IL-6에 의해 활성화된 STAT3에 의하여 매개되는 염증성 질환을 의미할 수 있다. 상기 염증성 질환의 예로 알레르기, 형질구 증가증, 초면역 글로불린 혈증, 빈혈, 신염, 악액질, 목축업자 질병, 맥관증식신염, 다발성 경화증, 포도막염, 만성 갑상선염, 지연과민증, 접촉피부염, 전신성 에리테마토스, 크론병, 건선, 연소성 특발성 위축증, 당뇨병 또는 알쯔하이머가 있으나, 이에 제한되지 않는다. 염증성 질환에서 활성화된 STAT3 단백질은 주요 전사인자로 작용하여 염증성 질환의 발병 및 진행을 가져오므로, STAT3 단백질의 활성화를 효과적으로 저해하는 본 발명의 조성물은 염증성 질환의 예방 및 치료에 있어 유용하게 사용될 수 있다.In the present invention, the term "inflammatory disease" refers to a disease whose main lesion is inflammation, and for the purposes of the present invention may mean an inflammatory disease mediated by STAT3 activated by IL-6. Examples of such inflammatory diseases include allergy, pheocytosis, hyperimmune globulinemia, anemia, nephritis, cachexia, herder's disease, vasculitis, multiple sclerosis, uveitis, chronic thyroiditis, delayed hypersensitivity, contact dermatitis, systemic erythematos, and Crohn Disease, psoriasis, juvenile idiopathic atrophy, diabetes or Alzheimer's, but is not limited thereto. Since the STAT3 protein activated in inflammatory diseases acts as a major transcription factor, leading to the onset and progression of inflammatory diseases, the composition of the present invention that effectively inhibits the activation of STAT3 protein can be usefully used in the prevention and treatment of inflammatory diseases. have.
본 발명에서 용어, "골 대사성 질환"은 조골세포 및 파골세포의 불균형으로 인해 유발되는 골 관련 질환을 의미한다. 이러한 질환의 예로는 과도한 파골세포의 골 흡수에 의한 골다공증(osteoprosis), 관절염(arthritis), 치주질환(periodontal disease), 골절 또는 파제트병(Paget disease) 등과 같은 병리학적 골 질환으로 골 파괴를 촉진하는 질환이 포함되나, 상기 골 대사성 질환에 한정되는 것은 아니다.In the present invention, the term "bone metabolic disease" refers to a bone-related disease caused by an imbalance of osteoblasts and osteoclasts. Examples of such disorders are pathological bone diseases such as osteoprosis, arthritis, periodontal disease, fractures, or Paget disease due to excessive bone resorption of osteoclasts, which promotes bone destruction. The disease includes, but is not limited to the bone metabolic disease.
그 중, "골다공증"은 뼈의 양이 감소하고 질적인 변화로 인해 뼈의 강도가 약해져서 골절이 일어날 가능성이 높은 상태를 의미한다. 뼈는 인체 내 여러 기관들을 보호하고 칼슘과 같은 체내에 필요한 물질들을 보관하는 저장소로서 기능하며, 뼈 조직에 존재하는 뼈를 분해하는 파골세포(osteoclast) 및 뼈를 생성하는 조골세포(osteoblast) 간의 균형에 이어 항상성이 유지된다. 골다공증의 경우에는 두 세포 활성이 균형이 깨지게 되면서 파골세포에 의한 지나친 뼈의 파괴가 일어나 발병 및 진행된다. 골다공증에서 주요한 분자로는 RANKL(receptor activator of nuclear factor kappa-B ligand)이 있으며, RANKL이 이의 수용체에 결합하여 다양한 전사인자를 활성화시켜 파골세포의 분화를 촉진시키며, 특히, IL-6는 RANKL에 의해 매개되는 파골세포 분화를 촉진시키는 것으로 알려져 있다(Kim K et al., J Immunol. 2007 May 1;178(9):5588-94.). 따라서, IL-6에 의해 활성화되는 신호전달을 억제시키고, 파골세포의 분화를 억제시켜 파골세포에 의한 뼈의 파괴를 감소시킬 수 있는 물질의 경우 골다공증의 치료제로서 이용될 수 있다. 본 발명의 개머루덩굴 추출물, 이의 분획물 또는 이로부터 분리된 화학식 1 내지 3의 화합물은 RANKL에 의해 유도되는 파골세포 분화 억제를 효과적으로 억제시키므로, 골다공증의 예방 또는 치료에 유용하게 이용될 수 있다.Among them, "osteoporosis" refers to a condition in which the amount of bone is decreased and the strength of the bone is weakened due to qualitative changes, so that a fracture is likely to occur. Bone protects various organs in the human body and functions as a reservoir to store necessary substances in the body, such as calcium, and balance between osteoclasts that break down bone and osteoblasts that produce bones in bone tissue. Subsequently, homeostasis is maintained. In the case of osteoporosis, the balance of the two cell activities is disrupted, causing excessive bone destruction by osteoclasts, leading to onset and progression. The major molecule in osteoporosis is RANKL (receptor activator of nuclear factor kappa-B ligand), and RANKL binds to its receptor and activates various transcription factors to promote the differentiation of osteoclasts. It is known to promote osteoclast differentiation mediated by (Kim K et al., J Immunol. 2007 May 1;178(9):5588-94.). Therefore, a substance capable of reducing the destruction of bone by osteoclasts by inhibiting the signal transduction activated by IL-6 and inhibiting the differentiation of osteoclasts can be used as a therapeutic agent for osteoporosis. The extract, a fraction thereof, or a compound of
상기 "관절염"은 하나 이상의 관절 부위에 염증을 수반하는 관절 질환을 의미한다. 상기 관절염의 일반적인 형태는 관절을 보고하고 있는 연골의 점진적인 손상이나 퇴행성 변화로 인해 관절을 이루는 뼈와 인대에 손상이 일어나서 염증과 통증이 생기는, 골관절염(osteoarthritis)이다. 본 발명의 목적상 상기 관절염은 관절 부위에 뼈 손실을 수반하는 질환으로, 그 종류가 특별히 제한되지는 않으나, 골관절염 또는 류마티스 관절염 등이 있다. The "arthritis" refers to a joint disease involving inflammation in one or more joint regions. The common form of arthritis is osteoarthritis, in which inflammation and pain occur due to damage to the bones and ligaments constituting the joint due to gradual damage or degenerative changes in cartilage reporting the joint. For the purposes of the present invention, the arthritis is a disease involving bone loss in the joint region, and the type is not particularly limited, but may include osteoarthritis or rheumatoid arthritis.
상기 "치주질환"은 세균에 의해 야기되는 치아지지 조직의 염증상태를 말하며, 치은염 및 치주염으로 분리할 수 있다. 발병원인은 불량한 구강 위생상태로 인한 구강 세균이 치면 세균막을 형성하는 데 있다. 치면 세균막이란 침에 있는 끈끈한 물질을 접착제로 이용하여 세균이 치아 표면에 달라붙은 후 증식한 세균덩어리를 말한다. 치면 세균막은 그냥 방치해 두면, 염증이 생겨 가끔 잇몸에서 피가 나고, 구취가 나는 경우가 있으며 이러한 증상을 치은염이라고 한다. 치은염이 더 진행되면, 치아와 잇몸 사이의 벌어진 틈이 더 깊어져서 치주낭이 생기고, 여기에 치주질환을 일으키는 세균들이 번식하여 치주염이 발생 된다. 치주염이 진행되면 칫솔질과 같은 약한 자극에도 잇몸에서 피가 나기도 하며 붓고, 종종 급성염증으로 변화되어 통증을 유발한다. 이러한 염증은 골을 만드는 기능은 저하시키고, 골을 흡수하는 작용이 높아져서 치조골이 점점 낮아지게 되어 치조골이 파괴되고 결국 치아를 상실하게 된다.The "periodontal disease" refers to an inflammatory state of the tooth supporting tissue caused by bacteria, and can be separated into gingivitis and periodontitis. The cause of the disease is the formation of a bacterial film when oral bacteria hit due to poor oral hygiene. The tooth surface bacterial film refers to a cluster of bacteria that has grown after bacteria adhere to the tooth surface by using a sticky substance in saliva as an adhesive. If left untreated, the bacterial membrane of the tooth may become inflamed, sometimes bleeding from the gums and bad breath. This symptom is called gingivitis. As gingivitis progresses further, the gap between the teeth and the gums becomes deeper, resulting in a periodontal sac, where bacteria that cause periodontal disease multiply, resulting in periodontitis. When periodontitis progresses, the gums bleed and swell even with weak stimuli, such as brushing, and often turn into acute inflammation, causing pain. This inflammation decreases the function of making bones, and increases the function of absorbing the bones, so that the alveolar bone is gradually lowered and the alveolar bone is destroyed and eventually the teeth are lost.
상기 "골절"은 뼈나 골단판 또는 관절면의 연속성이 비정상적으로 끊어진 상태로, 뼈의 깨짐을 일컫는다. 골절을 유발하는 원인으로는 교통사고 등의 외상, 산업장애에서 일어나는 안전사고, 골다공증, 골암, 대사이상증 등의 질병으로 인한 뼈의 변화 및 스포츠나 하중으로 인한 반복적인 뼈에 대한 스트레스 등이 있다. 또한, 골절 상태는 골절선(골 절단에 의해 발생된 뼈 끝단을 따른 선)에 근거하여, 균열 골절, 그린스틱(greenstick) 골절, 횡상 골절, 사상 골절, 나선상 골절, 분절 골절, 분쇄골절, 견열 골절, 압박 골절, 함몰 골절 등으로 분류된다.The "fracture" refers to a state in which the continuity of a bone or epiphysis plate or joint surface is abnormally broken, and refers to a fracture of a bone. The causes of fractures include trauma such as traffic accidents, safety accidents occurring in industrial disorders, bone changes due to diseases such as osteoporosis, bone cancer, and metabolic dystrophy, and repetitive stress on bones due to sports or loads. In addition, the fracture state is based on the fracture line (the line along the end of the bone caused by bone cutting), crack fracture, greenstick fracture, transverse fracture, sagittal fracture, spiral fracture, segmental fracture, comminuted fracture, avulsion fracture. , Compression fracture, depression fracture, etc.
상기 "파제트 병"은 골 재형성이 과도하게 항진되어 광범위한 부위의 골격계가 침범되는 국소성 골 질환을 의미한다. 파제트병의 병리학적인 기전은 뼈를 청소하는 기능을 가진 파골 세포에 의한 골 흡수의 과다한 증가와 이에 따른 보상작용으로 뼈를 만드는 기능을 가진 조골 세포에 의한 새로운 골 형성의 증가가 결합된 것으로 알려져 있으며, 또한, 골 파제트병에서 새롭게 형성된 뼈는 구조적으로 무질서하고 뼈 변형과 골절에 매우 취약한 상태로 알려져 있다. The "Paget's disease" refers to a localized bone disease in which bone remodeling is excessively promoted and the skeletal system in a wide area is invaded. The pathological mechanism of Paget's disease is known to be a combination of an excessive increase in bone resorption by osteoclasts, which have a function to clean the bones, and an increase in new bone formation by osteoblasts, which have a function of making bones, as a reward. In addition, bones newly formed in Bone Paget's disease are structurally disordered and are known to be very susceptible to bone deformation and fracture.
상기와 같은 골 대사성 질환의 예방 또는 치료에 있어, 본 발명의 개머루덩굴 추출물, 이의 분획물 또는 이로부터 분리된 화합물은 파골세포의 분화를 억제하며, 파골세포의 골 흡수를 저해하는 활성을 나타내므로 상기 질환들에 대해 예방 또는 치료 효과를 가져올 수 있다. In the prophylaxis or treatment of bone metabolic diseases as described above, the extract, a fraction thereof, or a compound isolated therefrom of the present invention inhibits the differentiation of osteoclasts and inhibits the bone resorption of osteoclasts. It can bring a prophylactic or therapeutic effect against diseases.
본 발명에서 용어, "아토피"는 피부질환의 일종으로서, 피부의 부스럼, 습진, 간지러움을 동반하는 질병이다. 상기 아토피의 발병에는 환경적 요인 및 유전학적 요인 모두가 관여하는 것으로 알려져 있으나, 정확한 발병기전은 규명되지 않았다. 상기 아토피는 케라틴세포 또는 내피세포에서 유래한 단백질을 항원을 인식하고 면역 반응을 일으키는 증상을 가질 수 있으나, 이에 제한되지 않는다. 기존에 보고된 바에 따르면 아토피는 CD28에 대한 자가항체를 가지는 것을 특징으로 하며, 상기 CD28 자가항체는 T 세포의 활성화를 가져올 수 있을 뿐만 아니라 아토피와 다른 염증성 피부 질환과 구별할 수 있는 특징으로 제시된 바 있다(Clin Exp Immunol. 2006 Nov;146(2):262-9.). 아토피는 최근에는 유소아 뿐만 아니라 성인에서도 빈번하게 발병하여, 그 예방 또는 치료가 중요한 사회적인 문제가 되고 있으나 그 원인이 명확하게 규명되지 않았다. 또한, 기존에 사용되고 있는 스테로이드 제제 등의 효과가 뛰어나지 않을 뿐만 아니라 부작용의 문제가 있어, 효과가 뛰어나면서도 유소아에도 사용가능한 안전한 아토피의 치료제의 개발이 요구되는 실정이다. 본 발명의 조성물은 천연물 유래로, 스테로이드 제제 등에 비하여 유소아에 적용하기 안전한 이점을 지닌다. 또한, 본 발명의 조성물에 있어, 아토피의 예방 또는 치료를 위해 포함되는 개머루덩굴 추출물 또는 이의 분획물은 IL-6 매개 경로를 차단함으로써, IL-6 매개 신호전달경로에 의한 부종을 비롯한 아토피 피부염에 수반되는 다양한 염증 현상을 완화시킴으로써 아토피 피부염을 효과적으로 치료할 수 있도록, 개머루덩굴의 줄기 부분으로부터 추출하여 수득한 것일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the term "atopy" is a kind of skin disease, and is a disease accompanied by swelling of the skin, eczema, and itching. It is known that both environmental and genetic factors are involved in the onset of atopy, but the exact pathogenesis has not been identified. The atopy may have symptoms of recognizing an antigen from a protein derived from keratinocytes or endothelial cells and causing an immune response, but is not limited thereto. According to previously reported, atopy is characterized by having an autoantibody against CD28, and the CD28 autoantibody is presented as a feature that can not only activate T cells, but also differentiate it from atopy and other inflammatory skin diseases. (Clin Exp Immunol. 2006 Nov;146(2):262-9.). In recent years, atopy is frequently onset not only in children but also in adults, and its prevention or treatment has become an important social problem, but its cause has not been clearly identified. In addition, there is a problem of side effects as well as ineffectiveness of the existing steroid preparations, and thus there is a need to develop a safe atopy therapeutic agent that is excellent in effect and can be used for children as well. The composition of the present invention is derived from a natural product and has a safe advantage to be applied to infants and toddlers compared to steroid preparations. In addition, in the composition of the present invention, atopic vine extract or a fraction thereof included for the prevention or treatment of atopy blocks the IL-6-mediated pathway, resulting in atopic dermatitis including edema by the IL-6-mediated signaling pathway. In order to effectively treat atopic dermatitis by mitigating various inflammatory phenomena, it may be obtained by extracting from the stem portion of the vine, but is not limited thereto.
본 발명에서 용어, "암"은 본 발명의 조성물에 의하여 치료될 수 있는 암이라면 제한없이 포함하며, 그 예로 췌장암, 유방암, 전립선암, 뇌종양, 두경부암종, 흑색종, 골수종, 백혈병, 림프종, 간암, 위암, 결장암, 골암, 자궁암, 난소암, 직장암, 식도암, 소장암, 항문부근암, 결장암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종 또는 중추신경계 종양일 수 있으나, 이에 제한되지 않는다. In the present invention, the term "cancer" includes without limitation any cancer that can be treated by the composition of the present invention, such as pancreatic cancer, breast cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, leukemia, lymphoma, liver cancer , Stomach cancer, colon cancer, bone cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, bladder cancer, kidney cancer , Ureteral cancer, renal cell carcinoma, renal pelvic carcinoma or central nervous system tumor, but is not limited thereto.
본 발명에서 용어, "예방"은 상기 조성물의 투여에 의해 IL-6 매개성 질환을 억제하거나 발병을 지연시키는 모든 행위를 의미하며, "치료"는 상기 조성물의 투여에 의해 IL-6 매개성 질환에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다. In the present invention, the term "prevention" refers to all actions of inhibiting or delaying the onset of IL-6-mediated disease by administration of the composition, and "treatment" refers to IL-6-mediated disease by administration of the composition. It refers to any action in which the symptoms caused by or are advantageously changed.
본 발명의 개머루덩굴 추출물 또는 이의 분획물을 포함하는 약학적 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형체 또는 희석제를 추가로 포함할 수 있다. 이때, 상기 조성물에 포함되는 개머루덩굴 추출물 또는 이의 분획물의 함량은 특별히 이에 제한되지 않으나, 조성물 총 중량에 대하여 0.0001 중량% 내지 10 중량%로, 바람직하게는 0.001 중량% 내지 1 중량%를 포함할 수 있다.The pharmaceutical composition comprising the extract or fractions thereof of the present invention may further include a suitable carrier, excipient, or diluent commonly used in the preparation of a pharmaceutical composition. At this time, the content of the extract or fractions thereof included in the composition is not particularly limited thereto, but may include 0.0001% by weight to 10% by weight, preferably 0.001% by weight to 1% by weight based on the total weight of the composition. have.
상기 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제으로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있으며, 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The pharmaceutical composition is any selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. It may have a single dosage form, and may be various oral or parenteral dosage forms. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, syrups, etc., but may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents. have. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.
본 발명의 조성물은 약학적으로 유효한 양으로 투여할 수 있다.The composition of the present invention can be administered in a pharmaceutically effective amount.
본 발명에서 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 투여경로 및 기간에 따라 다르지만, 바람직한 효과를 위해서, 본 발명의 개머루덩굴 추출물 또는 이의 분획물은 1일 0.0001 내지 100mg/kg으로, 바람직하게는 0.001 내지 100mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 조성물은 쥐, 가축, 인간 등의 다양한 포유동물에 다양한 경로로 투여할 수 있으며, 투여의 방식은 당업계의 통상적인 방법이라면 제한없이 포함하며, 예를 들어, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다.In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type and severity of the individual, age, sex, and disease. It can be determined according to the type, activity of the drug, sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all of the above factors, and can be easily determined by a person skilled in the art. The preferred dosage of the composition of the present invention varies depending on the condition and weight of the patient, the degree of the disease, the form of the drug, the route of administration and the duration, but for a desirable effect, the extract or fraction thereof of the present invention is 0.0001 to 100 mg per day. It is good to administer at /kg, preferably 0.001 to 100mg/kg. Administration may be administered once a day, or may be divided several times. The composition can be administered to various mammals such as mice, livestock, humans, etc. by various routes, and the mode of administration includes without limitation, if it is a conventional method in the art, for example, oral, rectal or intravenous, muscle, It can be administered by subcutaneous, intrauterine dura mater or intracerebrovascular injection.
또한, 본 발명의 약학적 조성물은 인간에 적용되는 의약품뿐만 아니라, 동물 의약품의 형태로도 사용될 수 있다. In addition, the pharmaceutical composition of the present invention can be used in the form of veterinary drugs as well as pharmaceuticals applied to humans.
본 발명의 일 실시예에서는 개머루덩굴의 에탄올 추출물; 이의 헥산, 에틸아세테이트 및 물 분획물; 및 헥산 분획물 또는 에틸아세테이트 분획물에 대한 크로마토그래피 분획이 IL-6에 의해 유도되는 STAT3 활성을 효과적으로 억제하는 것을 확인하였다(도 1 내지 3). 특히, 개머루덩굴의 에탄올 추출물은 STAT3의 인산화 및 JAK2의 인산화를 농도의존적으로 저해시키는 결과를 나타내어(도 5 및 6), 상기 개머루덩굴의 에탄올 추출물 및 이의 분획물을 IL-6에 의하여 매개되는 질환의 예방 또는 치료에 유용하게 사용할 수 있음을 확인하였다. 또한, 본 발명의 개머루덩굴 에탄올 추출물이 효과적으로 RANKL에 의해 유도되는 파골세포 분화를 억제시키는 것을 확인하였다(도 7). 파골세포는 골을 흡수하여 골다공증과 같은 골 질환을 유도 한다. 특히, 다핵성 파골세포의 수를 개머루덩굴 에탄올 추출물이 의미 있게 감소시킴을 확인할 수 있었으며(도 7B), 사용된 개머루덩굴 추출물 농도에서 세포독성이 없음을 확인할 수 있었다(도 7C). 또한, 본 발명의 일 실시예에 따르면 RANKL에 의해 발현되며 파골세포의 분화에 핵심적인 역할을 하는 전사인자인 c-Fos와 NFATc1의 유전자 및 단백질 발현이 개머루덩굴 에탄올 추출물 처리에 의해 효과적으로 억제되는 것을 볼 수 있었으며(도 8A, 8B), 파골세포의 분화에 중요한 유전자인 OSCAR, TRAP, cathepsin K, 그리고 DC-STAMP의 유전자 발현 모두 개머루덩굴 에탄올 추출물에 의해 효과적으로 억제됨을 볼 수 있었다(도 8C). 개머루덩굴 에탄올 추출물에 의한 파골세포 분화 억제 작용기전을 규명하기 위하여 RANKL의 하위신호전달기전인 p38, AKT, ERK, 그리고 IκB의 인산화를 측정한 결과, 개머루덩굴 에탄올 추출물은 RANKL에 의해 유도되는 p38과 IκB의 인산화를 억제하였으며 AKT와 ERK의 인산화에는 영향을 주지 않았다(도 9). 또한, 개머루덩굴 에탄올 추출물은 파골세포의 형성을 억제할 뿐만 아니라 파골세포의 골 흡수 작용 또한 억제함을 볼 수 있었다(도 10). 따라서, 본 발명의 개머루덩굴 추출물 또는 이의 분획물은 IL-6 매개성 질환의 예방 또는 치료, 특히 골다공증을 비롯한 골 대사성 질환의 예방 또는 치료에 유용하게 사용될 수 있다. In one embodiment of the present invention, ethanol extract of vines; Its hexane, ethyl acetate and water fractions; And it was confirmed that the chromatographic fraction for the hexane fraction or the ethyl acetate fraction effectively inhibited the STAT3 activity induced by IL-6 (FIGS. 1 to 3 ). Particularly, the ethanol extract of the blackberry vine showed a result of inhibiting the phosphorylation of STAT3 and the phosphorylation of JAK2 in a concentration-dependent manner (Figs. 5 and 6), so that the ethanol extract and its fractions of the blackberry vine were used to treat diseases mediated by IL-6. It was confirmed that it can be usefully used for prevention or treatment. In addition, it was confirmed that the ethanol extract of the present invention effectively inhibits the differentiation of osteoclasts induced by RANKL (FIG. 7). Osteoclasts absorb bone and induce bone diseases such as osteoporosis. In particular, it was confirmed that the number of polynuclear osteoclasts was significantly reduced by the Ethanol extract (Fig. 7B), and it was confirmed that there is no cytotoxicity at the concentration of the E. kelp extract used (Fig. 7C). In addition, according to an embodiment of the present invention, expression of genes and proteins of c-Fos and NFATc1, which are transcription factors that are expressed by RANKL and play a key role in the differentiation of osteoclasts, are effectively inhibited by treatment with ethanol extract of A. It can be seen (Figs. 8A, 8B), and all of the gene expressions of OSCAR, TRAP, cathepsin K, and DC-STAMP, which are genes important for the differentiation of osteoclasts, were effectively suppressed by the ethanol extract of syllium syllium (Fig. In order to investigate the mechanism of action for inhibiting osteoclast differentiation by ethanol extract of Ethanol extract, phosphorylation of p38, AKT, ERK, and IκB, the sub-signaling mechanisms of RANKL, was measured. It inhibited the phosphorylation of IκB and did not affect the phosphorylation of AKT and ERK (FIG. 9). In addition, it could be seen that the ethanol extract of A. vines inhibited the formation of osteoclasts, as well as the bone resorption action of osteoclasts (FIG. 10). Therefore, the extract or a fraction thereof of the present invention can be usefully used in the prevention or treatment of IL-6 mediated diseases, particularly in the prevention or treatment of bone metabolic diseases including osteoporosis.
또 다른 양태로서, 본 발명은 개머루덩굴 추출물 또는 이의 분획물을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 식품 조성물을 제공한다.In another aspect, the present invention provides a food composition for preventing or improving IL-6-mediated diseases, comprising an extract or a fraction thereof as an active ingredient.
상기 개머루덩굴, 이의 추출물, 분획물 및 IL-6 매개성 질환에 대해서는 상기에서 설명한 바와 같다. The vines, extracts, fractions, and IL-6-mediated diseases are as described above.
구체적으로, 본 발명의 추출물 또는 분획물을 IL-6 매개성 질환의 예방 또는 개선을 목적으로, 바람직하게는 염증성 질환, 골 대사성 질환, 아토피 또는 암의 예방 또는 개선을 목적으로 식품 조성물에 첨가할 수 있다. Specifically, the extract or fraction of the present invention may be added to a food composition for the purpose of preventing or improving IL-6-mediated diseases, preferably for the purpose of preventing or improving inflammatory diseases, bone metabolic diseases, atopy or cancer. have.
본 발명의 개머루덩굴 추출물 또는 이의 분획물을 식품 첨가물로 사용할 경우, 상기 추출물 또는 이의 분획물을 그대로 첨가하거나 다른 식품 또는 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효 성분의 혼합량은 사용 목적에 따라 적합하게 결정할 수 있다.When the extract or a fraction thereof of the present invention is used as a food additive, the extract or a fraction thereof may be added as it is or may be used with other foods or ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient can be appropriately determined according to the intended use.
본 발명의 식품의 종류에는 특별한 제한은 없다. 상기 개머루덩굴 추출물 또는 이의 분획물을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있고, 통상적인 의미에서의 식품을 모두 포함할 수 있으며, 동물을 위한 사료로 이용되는 식품을 포함한다.There is no particular limitation on the type of food of the present invention. Examples of foods to which the extract or fractions thereof can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages , Tea, drinks, alcoholic beverages, and vitamin complexes, and the like, may include all foods in the usual sense, and include foods used as feed for animals.
상기 외에 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄 산화제 등을 함유할 수 있다. 그밖에 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 또한, 상기 식품은 공지의 제조방법에 따라 정제, 과립, 분말, 캅셀, 액상의 용액 및 환 등의 제형으로도 제조될 수 있다. 본 발명에 의한 개머루덩굴 추출물 또는 이의 분획물을 유효성분으로 포함하는 것 이외에는 다른 성분에는 특별한 제한이 없으며, 통상의 여러 가지 향미제 또는 천연 탄수화물 등을 추가성분으로 포함할 수 있다. In addition to the above, the food composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, colorants, pectic acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols. , May contain a carbon oxidizing agent used in carbonated beverages. In addition, it may contain flesh for the manufacture of natural fruit juice, fruit juice beverage and vegetable beverage. In addition, the food may be prepared in formulations such as tablets, granules, powders, capsules, liquid solutions, and pills according to known manufacturing methods. There is no particular limitation on other components other than including the extract of the blackberry vine according to the present invention or a fraction thereof as an active ingredient, and various conventional flavoring agents or natural carbohydrates may be included as additional components.
또 다른 양태로서, 본 발명은 개머루덩굴 추출물 또는 이의 분획물을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 의약외품 조성물을 제공한다.In another aspect, the present invention provides a quasi-drug composition for preventing or improving IL-6-mediated diseases, comprising an extract or a fraction thereof as an active ingredient.
상기 개머루덩굴, 이의 추출물, 분획물 및 IL-6 매개성 질환에 대해서는 상기에서 설명한 바와 같다. The vines, extracts, fractions, and IL-6-mediated diseases are as described above.
구체적으로, 본 발명의 개머루덩굴 추출물 또는 이의 분획물을 IL-6 매개성 질환의 예방 또는 개선을 목적으로 의약외품 조성물에 첨가할 수 있다.Specifically, the extract or fractions thereof of the present invention may be added to the quasi-drug composition for the purpose of preventing or improving IL-6-mediated diseases.
본 발명에서 용어, "의약외품"은 사람이나 동물의 질병을 치료, 경감, 처치 또는 예방할 목적으로 사용되는 섬유, 고무제품 또는 이와 유사한 것, 인체에 대한 작용이 약하거나 인체에 직접 작용하지 아니며, 기구 또는 기계가 아닌 것과 이와 유사한 것, 감염 예방을 위하여 살균, 살충 및 이와 유사한 용도로 사용되는 제제 중 하나에 해당하는 물품으로서, 사람이나 동물의 질병을 진단, 치료, 경감, 처치 또는 예방할 목적으로 사용하는 물품 중 기구, 기계 또는 장치가 아닌 것 및 사람이나 동물의 구조와 기능에 약리학적 영향을 줄 목적으로 사용하는 물품 중 기구, 기계 또는 장치가 아닌 것을 제외한 물품을 의미하며, 피부 외용제 및 개인위생용품도 포함한다.In the present invention, the term "quasi-drug" refers to fibers, rubber products, or the like, which are used for the purpose of treating, alleviating, treating, or preventing diseases of humans or animals, and their action on the human body is weak or does not directly act on the human body, and Or non-machine and similar, as an article corresponding to one of the preparations used for sterilization, insecticide, and similar purposes to prevent infection, and used for the purpose of diagnosing, treating, alleviating, treating or preventing diseases of humans or animals. It refers to items that are not instruments, machines, or devices among the items that are used, and items that are not instruments, machines, or devices among items used for the purpose of pharmacologically affecting the structure and function of humans or animals, and are intended for external use for skin and personal hygiene. Includes supplies.
본 발명의 개머루덩굴 추출물 또는 이의 분획물을 IL-6 매개성 질환의 예방 또는 개선을 목적으로 의약외품 조성물에 첨가할 경우, 상기 추출물 또는 분획물을 그대로 첨가하거나 다른 의약외품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효 성분의 혼합량은 사용 목적에 따라 적합하게 결정할 수 있다.When the extract or fraction thereof of the present invention is added to a quasi-drug composition for the purpose of preventing or improving IL-6-mediated disease, the extract or fraction may be added as it is or used with other quasi-drug components, and a conventional method It can be used appropriately according to. The mixing amount of the active ingredient can be appropriately determined according to the intended use.
상기 피부외용제는 특별히 이에 제한되지 않으나, 바람직하게는 연고제, 로션제, 스프레이제, 패취제, 크림제, 산제, 현탁제, 겔제 또는 젤의 형태로 제조되어 사용될 수 있다. 상기 개인위생용품에는 특별히 이에 제한되지 않으나, 바람직하게는 비누, 화장품, 물티슈, 휴지, 샴푸, 피부 크림, 얼굴 크림, 치약, 립스틱, 향수, 메이크업, 파운데이션, 볼터치, 마스카라, 아이섀도우, 선스크린 로션, 모발 손질 제품, 에어프레쉬너 겔 또는 세정 겔일 수 있다. 또한, 본 발명의 의약외품 조성물의 또 다른 예로 소독청결제, 샤워폼, 가그린, 물티슈, 세제비누, 핸드워시, 가습기 충진제, 마스크, 연고제 또는 필터충진제가 있다.The external preparation for skin is not particularly limited thereto, but may be preferably prepared and used in the form of an ointment, lotion, spray, patch, cream, powder, suspension, gel or gel. The personal hygiene products are not particularly limited thereto, but preferably soap, cosmetics, wet tissues, tissue paper, shampoo, skin cream, face cream, toothpaste, lipstick, perfume, makeup, foundation, cheek touch, mascara, eye shadow, sunscreen It can be a lotion, hair care product, air freshener gel, or cleaning gel. In addition, another example of the quasi-drug composition of the present invention is disinfectant cleaner, shower foam, gagrin, wet tissue, detergent soap, hand wash, humidifier filler, mask, ointment or filter filler.
또 하나의 양태로서, 본 발명은 개머루덩굴 추출물 또는 이의 분획물을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 사료 첨가제 또는 음용수 첨가제를 제공한다. In another aspect, the present invention provides a feed additive or a drinking water additive for preventing or improving IL-6-mediated diseases, comprising an extract or a fraction thereof as an active ingredient.
상기 개머루덩굴, 이의 추출물, 분획물 및 IL-6 매개성 질환에 대해서는 상기에서 설명한 바와 같다. The vines, extracts, fractions, and IL-6-mediated diseases are as described above.
본 발명에서 용어, "사료 첨가제"는 영양적 또는 특정 목적을 위하여 사료에 미량으로 첨가되는 물질을 총칭하는 것으로, 본 발명에서는 IL-6 매개성 질환의 예방 또는 개선을 목적으로 첨가되는 물질을 의미한다. 여기서, 동물이란 가축 및 애완동물을 포함하는 개념이다. In the present invention, the term "feed additive" is a generic term for substances added in trace amounts to feed for nutritional or specific purposes, and in the present invention, it means substances added for the purpose of preventing or improving IL-6 mediated diseases do. Here, an animal is a concept including livestock and pets.
본 발명의 사료첨가제에는 품질 저하를 방지하기 위해 첨가되는 결착제, 유화제, 보존제 등을 추가로 포함할 수 있고, 효용 증대를 위하여 첨가되는 아미노산제, 비타민제, 효소제, 생균제, 향미제, 비단백태 질소화합물, 규산염제, 완충제, 착색제, 추출제, 올리고당 등을 추가로 포함할 수 있으며, 그 외에도 사료 혼합제 등을 추가로 포함할 수 있으며, 이에 한정된 것은 아니다.The feed additive of the present invention may further include a binder, emulsifier, preservative, etc. added to prevent quality degradation, and amino acid, vitamin, enzyme, probiotic, flavoring, non-protein nitrogen added to increase utility A compound, a silicate, a buffer, a colorant, an extractant, an oligosaccharide, etc. may be additionally included, and in addition, a feed mixture may be additionally included, but the present invention is not limited thereto.
본 발명에서 용어, "음용수 첨가제"는 영양적 또는 특정 목적을 위하여 동물을 대상으로 하는 음용수에 미량으로 첨가되는 물질을 총칭하는 것으로, 본 발명에서는 IL-6 매개성 질환의 예방 또는 개선을 목적으로 첨가되는 물질을 의미한다. 여기서, 동물이란 가축 및 애완동물을 포함하는 개념이다. In the present invention, the term "drinking water additive" is a generic term for substances added in trace amounts to drinking water for animals for nutritional or specific purposes. In the present invention, for the purpose of preventing or improving IL-6-mediated diseases It means the substance to be added. Here, an animal is a concept including livestock and pets.
또 하나의 양태로서, 본 발명은 상기 화학식 1 내지 3 중 어느 하나로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 치료용 약학적 조성물을 제공한다.As another aspect, the present invention is a pharmaceutical composition for the prevention or treatment of IL-6-mediated diseases, comprising a compound represented by any one of
상기 화학식 1 내지 3의 화합물, IL-6 매개성 질환, 예방 또는 치료 및 약학적 조성물에 대해서는 상기에서 설명한 바와 같다. The compounds of
또한, 상기 화학식 1 내지 3의 화합물은 이를 포함하는 당업계에 공지된 천연물로부터 분리 정제하여 사용하거나, 또는, 상업적으로 시판되는 화합물을 구입하거나 합성하여 사용할 수 있으나, 이에 제한되지 않는다. In addition, the compounds of
또한, 상기 화학식 1 내지 3의 화합물은 약학적으로 허용가능한 염의 형태로 본 발명의 조성물에 포함될 수 있다. In addition, the compounds of
본 발명에서 용어, "약학적으로 허용가능한 염"은, 표적 개체가 생리학적으로 수인 가능한 본 발명의 화합물의 모든 염을 의미하며, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 화합물의 제형임이 바람직하다. 상기 약학적 염은, 약학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들어, 염산, 황산, 질산, 인산, 브롬화수소산, 요드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플로로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리신산 등과 같은 유기 카본산, 메탄설폰산, 에탄술폰산, 벤젠설폰산, p-톨루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 예를 들어, 약학적으로 허용되는 카르복실산 염에는, 리튬, 나트륨,칼륨, 칼슘, 마그네슘 등에 의해 형성된 금속염 또는 알칼리 토금속 염, 라이신, 아르지닌, 구아니딘 등의 아미노산 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸) 메틸아민, 디에탄올아민, 콜린 및 트리에틸아민 등과 같은 유기염 등이 포함된다.In the present invention, the term "pharmaceutically acceptable salt" refers to all salts of the compound of the present invention that the target individual is physiologically acceptable, and the biological activity of the compound does not cause serious irritation to the organism to which the compound is administered. It is preferable that it is a formulation of a compound that does not impair the properties and properties. The pharmaceutical salt is an acid forming a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbon acids such as citric acid, acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed by sulfonic acid and the like are included. For example, pharmaceutically acceptable carboxylate salts include metal salts or alkaline earth metal salts formed of lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N Organic salts such as -methyl-D-glucamine, tris(hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like.
또 하나의 양태로서, 본 발명은 상기 화학식 1 내지 3 중 어느 하나로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 식품 조성물을 제공한다. In another aspect, the present invention provides a food composition for preventing or improving IL-6-mediated diseases, comprising a compound represented by any one of
상기 화학식 1 내지 3의 화합물, IL-6 매개성 질환, 및 식품 조성물에 대해서는 상기에서 설명한 바와 같다.The compounds of
또 하나의 양태로서, 본 발명은 상기 화학식 1 내지 3 중 어느 하나로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 의약외품 조성물을 제공한다.In another aspect, the present invention provides a quasi-drug composition for preventing or improving IL-6-mediated diseases, comprising a compound represented by any one of
상기 화학식 1 내지 3의 화합물, IL-6 매개성 질환, 및 의약외품 조성물에 대해서는 상기에서 설명한 바와 같다. The compounds of
또 하나의 양태로서, 본 발명은 상기 화학식 1 내지 3 중 어느 하나로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, IL-6 매개성 질환의 예방 또는 개선용 사료 첨가제 또는 음용수 첨가제를 제공한다. In another aspect, the present invention is a feed additive for preventing or improving IL-6-mediated diseases, comprising a compound represented by any one of
상기 화학식 1 내지 3의 화합물, IL-6 매개성 질환, 사료 첨가제 및 음용수 첨가제에 대해서는 상기에서 설명한 바와 같다. The compounds of
또 다른 양태로서, 본 발명은 상기 개머루덩굴 추출물, 이의 분획물, 또는 상기 화학식 1 내지 3 중 어느 하나로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 조성물을 IL-6 매개성 질환 의심 개체에 투여하는 단계를 포함하는, IL-6 매개 질환의 치료 방법을 제공한다.In another aspect, the present invention provides a composition comprising the extract, a fraction thereof, or a compound represented by any one of
상기 조성물, IL-6 매개성 질환 및 치료에 대해서는 상기에서 설명한 바와 같다. The composition, IL-6 mediated disease and treatment are as described above.
구체적으로, 본 발명의 치료 방법은 상기 약학적 조성물을 약학적 유효량으로 IL-6 매개성 질환 의심 개체 내에 투여하는 것을 포함한다. 상기 개체는 개, 소, 말, 토끼, 마우스, 랫트, 닭 또는 인간을 포함하는 포유류 전체를 의미하나, 상기 예에 의해 본 발명의 포유류가 한정되는 것은 아니다. 상기 약학적 조성물은 비 경구, 피하, 복강 내, 폐 내 및 비강 내로 투여될 수 있고, 국부적 치료를 위해, 필요하다면 병변 내 투여를 포함하는 적합한 방법에 의하여 투여될 수 있다. 본 발명의 상기 약학적 조성물의 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.Specifically, the treatment method of the present invention includes administering the pharmaceutical composition in a pharmaceutically effective amount into an individual suspected of an IL-6 mediated disease. The individual refers to all mammals including dogs, cows, horses, rabbits, mice, rats, chickens, or humans, but the mammal of the present invention is not limited by the above examples. The pharmaceutical composition may be administered parenterally, subcutaneously, intraperitoneally, intraperitoneally and intranasally, and for local treatment, if necessary, may be administered by a suitable method including intralesional administration. The preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and weight of the individual, the degree of disease, the form of the drug, the route and duration of administration, but may be appropriately selected by those skilled in the art.
본 발명의 조성물은 IL-6에 의한 신호전달을 효과적으로 저해시키고 파골세포의 분화를 효과적으로 억제하므로, 상기 개머루덩굴 추출물 또는 이의 분획물을 포함하는 본 발명의 조성물은 IL-6 매개성 질환, 예컨대 염증성 질환, 골 대사성 질환, 아토피 또는 암의 예방 또는 치료에 있어 유용하게 이용될 수 있다. 특히, 개머루덩굴 추출물 또는 이의 분획물은 오랫동안 천연약재로 사용되어온 천연물에서 유래되어 부작용이 없이 상기 질환의 치료에 이용될 수 있는 이점이 있다. Since the composition of the present invention effectively inhibits signaling by IL-6 and effectively inhibits the differentiation of osteoclasts, the composition of the present invention comprising the extract or a fraction thereof is an IL-6 mediated disease, such as an inflammatory disease. , It can be usefully used in the prevention or treatment of bone metabolic disease, atopy or cancer. In particular, the extract or a fraction thereof is derived from a natural product that has been used as a natural medicine for a long time, and thus has an advantage that can be used for the treatment of the disease without side effects.
도 1은, 개머루덩굴 에탄올 추출물, 헥산, 에틸아세테이트 및 물 분획물의 IL-6 유도 루시퍼라제의 발현 저해활성을 나타낸 도이다.
도 2는, 개머루덩굴 헥산 분획물의 1차 컬럼크로마토그래피 분획(fraction)의 IL-6 유도 루시퍼라제의 발현 저해활성을 나타낸 도이다.
도 3은, 개머루덩굴 에틸아세테이트 분획물의 1차 컬럼크로마토그래피 분획의 IL-6 유도 루시퍼라제의 발현 저해활성을 나타낸 도이다.
도 4는, 개머루덩굴 추출물에서 분리한 유효 화합물들(에틸 갈레이트, 갈릭산 및 아로마덴드린)의 IL-6 유도 루시퍼라제의 발현 저해활성을 나타낸 도이다.
도 5는, 개머루덩굴 에탄올 추출물의 IL-6 유도 STAT3 인산화 저해 활성을 나타낸 도이다.
도 6은, 개머루덩굴 에탄올 추출물의 IL-6 유도 JAK2 인산화 저해 활성을 나타낸 도이다.
도 7은, 개머루덩굴 에탄올 추출물의 RANKL 유도 파골세포 분화 억제활성을 나타낸 도이다.
도 8은, 개머루덩굴 에탄올 추출물이 RANKL 유도 파골세포의 분화에 필요한 유전자 및 단백질의 발현을 억제하는 것을 보여주는 도이다.
도 9는, 개머루덩굴 에탄올 추출물이 RANKL의 하위신호전달기전인 p38과 IκB의 인산화 기전을 억제하여 파골세포의 분화를 억제한다는 것을 보여주는 도이다.
도 10은, 개머루덩굴 에탄올 추출물이 파골세포의 골 흡수를 저해하는 활성을 보여주는 도이다.
도 11은, 분리한 유효화합물인 에틸 갈레이트(EG), 갈릭산(GA) 및 아로마덴드린(AD)의 RANKL 유도 파골세포 분화 억제활성을 나타낸 도이다.1 is a diagram showing the activity of inhibiting the expression of IL-6-induced luciferase of ethanol extract, hexane, ethyl acetate, and water fractions.
FIG. 2 is a diagram showing the activity of inhibiting the expression of IL-6-induced luciferase in a primary column chromatography fraction of a hexane fraction of A. oleifera.
FIG. 3 is a diagram showing the activity of inhibiting the expression of IL-6-induced luciferase in the first column chromatography fraction of an ethylacetate fraction of A. oleifera.
FIG. 4 is a diagram showing the inhibitory activity of IL-6-induced luciferase expression of effective compounds (ethyl gallate, gallic acid, and aromadendrin) isolated from the extract of A.
Figure 5 is a diagram showing the IL-6-induced STAT3 phosphorylation inhibitory activity of ethanol extract of vines.
Figure 6 is a diagram showing the IL-6-induced JAK2 phosphorylation inhibitory activity of ethanol extract of blackberry vine.
Figure 7 is a diagram showing the RANKL-induced osteoclast differentiation inhibitory activity of ethanol extract of vines.
FIG. 8 is a diagram showing that the ethanol extract of Gamedica chinensis suppresses the expression of genes and proteins required for differentiation of RANKL-induced osteoclasts.
FIG. 9 is a diagram showing that the ethanol extract of A. vines inhibits the differentiation of osteoclasts by inhibiting the phosphorylation mechanisms of p38 and IκB, which are sub-signaling mechanisms of RANKL.
FIG. 10 is a diagram showing the activity of the ethanol extract of Gamerilla vine to inhibit bone resorption of osteoclasts.
11 is a diagram showing the RANKL-induced osteoclast differentiation inhibitory activity of the isolated effective compounds, ethyl gallate (EG), gallic acid (GA), and aromadendrine (AD).
이하, 본 발명을 하기 실시예 및 실험예에서 보다 구체적으로 설명한다. 그러나 이들 예는 본 발명의 이해를 돕기 위한 것일 뿐, 이들에 의해 본 발명이 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail in the following Examples and Experimental Examples. However, these examples are only intended to aid understanding of the present invention, and the present invention is not limited thereto.
실시예 1: 개머루덩굴 추출물 및 이의 분획물의 제조Example 1: Preparation of extract and fractions thereof
실시예 1-1: 개머루덩굴 추출물의 제조Example 1-1: Preparation of extract of black stalk vine
개머루덩굴은 줄기 부분을 물로 깨끗이 세척하여 그늘에서 건조한 후, 와링 브랜드로 분말화시켰다. 분말화된 개머루덩굴 6㎏을 에탄올 60ℓ에 넣고 실온에서 7일간 냉침 추출한 후, 여지(와트만사, 미국)로 감압 여과한 다음, 여과 추출물을 진공회전농축기로 실온에서 에탄올 용매를 제거하고, 추출된 잔사로서 개머루덩굴 조추출물 250g을 수득하였다.After washing the stem part of the stalk with water and drying it in the shade, it was powdered with a Waring brand. 6kg of powdered blackberry vine was put in 60ℓ of ethanol, extracted with cold for 7 days at room temperature, filtered under reduced pressure with filter paper (Whatman, USA), and then the filtered extract was removed from the ethanol solvent at room temperature with a vacuum rotary concentrator, and the extracted As a residue, 250 g of a crude extract of blackberry vine was obtained.
실시예 1-2: 개머루덩굴 분획물 및 1차 컬럼 크로마토그래피 분획(fraction)의 제조 Example 1-2: Preparation of a black honeysuckle fraction and a first column chromatography fraction
상기 조추출물에서 활성 분획물을 분리하기 위하여, 개머루덩굴 조추출물을 물 1ℓ에 현탁 시킨 후 동량의 헥산을 가하여 혼합하여 분획하고, 이 과정을 3회 반복하여 수가용성 분획물 1ℓ 및 헥산 가용성 분획물 3ℓ를 얻은 후, 이 헥산 가용성 분획물을 감압농축하여 헥산 가용 추출물 32g을 수득하였다. 이 수가용성 분획물 1ℓ에 에틸아세테이트를 가하여 혼합하여 분획하고, 이 과정을 3회 반복하여 수가용성 분획물 1ℓ 및 에틸아세테이트 가용성 분획물 3ℓ를 얻은 후, 이 에틸아세테이트 가용성 분획물을 감압농축하여 에틸아세테이트 가용 추출물 75g을 수득하였고, 남은 수가용성 분획물을 감압농축하여 100g을 수득하였으며, 이를 물 분획물로 사용하였다.In order to separate the active fraction from the crude extract, the crude blackberry vine extract was suspended in 1 liter of water and then fractionated by adding the same amount of hexane and mixing, and this process was repeated 3 times to obtain 1 liter of a water-soluble fraction and 3 liter of a hexane-soluble fraction. Thereafter, the hexane-soluble fraction was concentrated under reduced pressure to obtain 32 g of a hexane-soluble extract. Ethyl acetate was added to 1 liter of the water-soluble fraction and fractionated, and this process was repeated three times to obtain 1 liter of a water-soluble fraction and 3 liter of an ethyl acetate-soluble fraction. The ethyl acetate-soluble fraction was concentrated under reduced pressure to obtain 75 g of ethyl acetate-soluble extract. Was obtained, and the remaining water-soluble fraction was concentrated under reduced pressure to obtain 100 g, which was used as a water fraction.
상기 헥산 분획물을 클로로포름과 메탄올의 혼합 용매를 사용하여 실리카겔 컬럼 크로마토그래피를 행하였다. 이때, 클로로포름과 메탄올은 50:1 내지 0:100(v/v)인 용매를 사용하였다. 각각의 용출 용매를 TLC(Thin-layer chromatography)로 분석한 후 10개의 소분획으로 나누고, 이를 감압 농축하여 헥산 층 1차 컬럼 크로마토그래피 분획으로 사용하였다. 또한, 에틸아세테이트 분획물을 클로로포름과 메탄올의 혼합 용매를 사용하여 실리카겔 컬럼 크로마토그래피를 행하였다. 이때, 클로로포름과 메탄올은 50:1 내지 0:100(v/v)인 용매를 사용하였다. 각각의 용출 용매를 TLC로 분석한 후 13개의 소분획으로 나누고, 이를 감압 농축하여 에틸아세테이트 층을 1차 컬럼 크로마토그래피 분획(fraction)으로 사용하였다. The hexane fraction was subjected to silica gel column chromatography using a mixed solvent of chloroform and methanol. At this time, a solvent of 50:1 to 0:100 (v/v) was used for chloroform and methanol. Each elution solvent was analyzed by thin-layer chromatography (TLC), divided into 10 small fractions, concentrated under reduced pressure, and used as a hexane layer first column chromatography fraction. Further, the ethyl acetate fraction was subjected to silica gel column chromatography using a mixed solvent of chloroform and methanol. At this time, a solvent of 50:1 to 0:100 (v/v) was used for chloroform and methanol. Each elution solvent was analyzed by TLC, divided into 13 small fractions, concentrated under reduced pressure, and the ethyl acetate layer was used as a first column chromatography fraction.
실시예 2: 개머루덩굴 추출물 및 이의 분획물로부터 유효 화합물의 분리 및 구조 동정 Example 2: Isolation and Structure Identification of Active Compounds from Extracts and Fractions thereof
실시예 2-1: 유효화합물의 분리 및 정제Example 2-1: Separation and purification of an effective compound
상기 헥산 분획물과 에틸아세테이트 분획물을 합쳐서 얻은 107 g의 분획물을 가지고 헥산, 에틸아세테이트, 클로로포름과 메탄올의 혼합 용매를 사용하여 실리카겔 컬럼 크로마토그래피를 행하였다. 이때, 헥산, 에틸아세테이트, 클로로포름과 메탄올의 혼합용매 비율은 100 : 0 : 0 : 0 내지 0 : 0 : 0 : 100(v/v)인 용매를 사용하였다. 각각의 용출 용매를 TLC로 분석한 후 38개의 소분획으로 나누고, 이를 감압 농축하여 헥산과 에틸아세테이트 층 1차 컬럼 크로마토그래피 분획으로 사용하였다. 1차 컬럼 크로마토그래피 분획 중 23번째 소분획물 10.85g을 헥산, 아세톤의 혼합용매(100 : 0 ~ 1 : 1, v/v)를 이동상으로 하였으며, 중압 액체크로마토그래피를 사용하여 13개의 소분획물을 수득하였다. 이들 중 다섯 번째 분획물(Fr.5)에서 화합물 1(335 mg)을 수득하였다. A 107 g fraction obtained by combining the hexane fraction and the ethyl acetate fraction was subjected to silica gel column chromatography using a mixed solvent of hexane, ethyl acetate, chloroform and methanol. At this time, a mixed solvent ratio of hexane, ethyl acetate, chloroform and methanol was 100: 0: 0: 0 to 0: 0: 0: 100 (v/v). Each elution solvent was analyzed by TLC, divided into 38 small fractions, concentrated under reduced pressure, and used as a first column chromatography fraction of hexane and ethyl acetate layers. Among the first column chromatography fractions, 10.85 g of the 23rd small fraction was used as a mobile phase using a mixed solvent of hexane and acetone (100: 0 ~ 1: 1, v/v), and 13 small fractions were prepared by medium pressure liquid chromatography. Obtained. Compound 1 (335 mg) was obtained from the fifth fraction (Fr.5) of these.
헥산과 에틸아세테이트 층 1차 컬럼 크로마토그래피 분획 중 25번째 소분획물 2g을 클로로포름과 메탄올의 혼합용매(100 : 0 ~ 70 : 30, v/v)를 이동상으로 하였으며, 중압 액체크로마토그래피를 사용하여 6개의 소분획물을 수득하였다. 이들 중 네 번째 분획물(Fr.4)에서 화합물 2(453.1 mg)를 수득하였다.Hexane and ethyl acetate layer 2g of the 25th small fraction among the first column chromatography fractions was a mixed solvent of chloroform and methanol (100: 0 ~ 70: 30, v/v) as a mobile phase, using medium pressure liquid chromatography. A small fraction of dogs was obtained. Compound 2 (453.1 mg) was obtained from the fourth fraction (Fr.4) of these.
헥산과 에틸아세테이트 층 1차 컬럼 크로마토그래피 분획 중 23번째 소분획물 10.85 g으로부터 얻은 13개의 소분획물 중 일곱 번째 분획물(Fr.23-7)을 가지고 역상계 충전제(COSMOSIL 140C18-Prep.)를 이용한 크로마토그래피 분획을 실시하였다. 이를 통하여 6개의 소분획물을 얻었으며 이중 네 번째 분획물(Fr.23-7-4)에서 화합물 3(157.4 mg)을 수득하였다.Hexane and ethyl acetate layer chromatography using a reverse phase filler (COSMOSIL 140C18-Prep.) with the seventh fraction (Fr.23-7) of 13 small fractions obtained from 10.85 g of the 23rd small fraction among the first column chromatography fractions. The graphical fraction was carried out. Through this, 6 small fractions were obtained, and compound 3 (157.4 mg) was obtained from the fourth fraction (Fr.23-7-4).
실시예 2-2: 유효화합물의 구조 분석Example 2-2: Structural analysis of effective compounds
상기 실시예 2-1에서 얻은 화합물 1, 2, 3의 분자량 및 분자식을 액체크로마토질량분석기(AGILENT1100)를 사용하여 결정하였다. 또한, 핵자기공명(NMR) 분석 (JEOL, JNM EX-400)을 통한 1H NMR, 13C NMR의 분광학 자료를 이용하여 분자구조를 결정하였다.The molecular weights and molecular formulas of
이상의 기기분석 결과를 발표된 문헌의 것과 비교 분석한 결과, 하기 화학식 1로 표시되는 에틸갈레이트(Ethyl gallate), 하기 화학식 2로 표시되는 갈산(Gallic acid), 하기 화학식 3으로 표시되는 아로마덴드린(Aromadendrin)을 확인하였다. 구체적인 분석결과는 다음과 같았다.As a result of comparative analysis of the above instrumental analysis results with those of the published literature, ethyl gallate represented by the following formula (1), gallic acid represented by the following formula (2), aromadendrine represented by the following formula (3) (Aromadendrin) was confirmed. The detailed analysis results were as follows.
화합물 1 : 에틸 갈레이트(Ethyl gallate)Compound 1: Ethyl gallate
[화학식 1][Formula 1]
1) 물성 : white granular (m.p. 149-153 ℃)1) Physical properties: white granular (m.p. 149-153 ℃)
2) 분자량 : 198.172) Molecular weight: 198.17
3) 분자식 : C9H10O5 3) Molecular formula: C 9 H 10 O 5
4) 1H-NMR (methanol-d3, 400 ㎒) δ 1.35(t), 4.27(dd), 7.04(s) 13C-NMR (methanol-d3, 100 ㎒) δ 14.78, 61.80, 110.17, 121.95, 139.84, 146.64, 168.714) 1H-NMR (methanol-d 3 , 400 ㎒) δ 1.35(t), 4.27(dd), 7.04(s) 13C-NMR (methanol-d3, 100 ㎒) δ 14.78, 61.80, 110.17, 121.95, 139.84 , 146.64, 168.71
화합물 2 : 갈릭산(Gallic acid)Compound 2: Gallic acid
[화학식 2][Formula 2]
1) 물성 : White, yellowish-white crystals (m.p. 258 - 265 ℃)1) Physical properties: White, yellowish-white crystals (m.p. 258-265 ℃)
2) 분자량 : 170.122) Molecular weight: 170.12
3) 분자식 : C8H6O5 3) Molecular Formula: C 8 H 6 O 5
4) 1H-NMR (methanol-d3, 400 ㎒) δ 7.05(s) 13C-NMR (methanol-d3, 100 ㎒) δ 110.48, 122.28, 139.69, 146.53, 170.604) 1 H-NMR (methanol-d 3 , 400 ㎒) δ 7.05(s) 13 C-NMR (methanol-d 3 , 100 ㎒) δ 110.48, 122.28, 139.69, 146.53, 170.60
화합물 3 : 아로마덴드린(Aromadendrin)Compound 3: Aromadendrin
[화학식 3][Formula 3]
1) 물성 : White-gray, crystals (m.p. 228 ℃)1) Physical properties: White-gray, crystals (m.p. 228 ℃)
2) 분자량 : 288.252) Molecular weight: 288.25
3) 분자식 : C15H12O6 3) Molecular Formula: C 15 H 12 O 6
4) 1H-NMR (methanol-d3, 400 ㎒) δ 4.55(d), 5.88(d), 5.92(d), 6.83(d), 6.83(d), 7.35(d), 7.35(d). 13C-NMR (methanol-d3, 100 ㎒) δ 73.6, 85.0, 96.3, 97.4, 101.8, 116.1, 116.1, 129.3, 130.4, 130.4, 159.2, 164.6, 165.3, 168.9, 198.54) 1 H-NMR (methanol-d 3 , 400 ㎒) δ 4.55(d), 5.88(d), 5.92(d), 6.83(d), 6.83(d), 7.35(d), 7.35(d) . 13 C-NMR (methanol-d 3 , 100 ㎒) δ 73.6, 85.0, 96.3, 97.4, 101.8, 116.1, 116.1, 129.3, 130.4, 130.4, 159.2, 164.6, 165.3, 168.9, 198.5
실험예 1: 개머루덩굴 추출물, 이의 분획물 및 1차 컬럼 크로마토그래피 분 획의 IL-6에 의해 유도되는 STAT3의 전사활성 억제 효과 확인 Experimental Example 1: Confirmation of the effect of inhibiting the transcriptional activity of STAT3 induced by IL-6 in the extract, its fraction, and the first column chromatography fraction
개머루덩굴 추출물, 이의 분획물 및 1차 컬럼 크로마토그래피 분획의 IL-6에 의해 유도되는 STAT3의 활성 억제 효과를 측정하기 위해 하기와 같은 실험을 수행하였다. The following experiment was performed to measure the effect of inhibiting the activity of STAT3 induced by IL-6 of the extract, its fraction, and the first column chromatography fraction.
실험예 1-1: 형질전환체의 제조Experimental Example 1-1: Preparation of transformant
Hep3B 세포(ATCC HB-8064)에 STAT3에 의해 루시퍼라아제가 발현되는 pStat3-Luc, 및 pcDNA3.1(+)(Clontech laboratories, Palo Alto, CA)을 lipofectamin plus(Invitrogen, Carlsbad, CA, USA)로 함께 형질감염시켰다. 형질감염 이틀 후부터 하이그로마이신(hygromycin)을 처리(100㎍/㎖)하여 루시퍼라아제(luciferase)가 안정하게 발현되는 클론을 얻었다. 이 클론에서 루시퍼라아제가 안정하게 발현되는지는 루시퍼라아제 어세이를 통해 확인하였다.PStat3-Luc, in which luciferase is expressed by STAT3 in Hep3B cells (ATCC HB-8064), and pcDNA3.1(+) (Clontech laboratories, Palo Alto, CA) were added to lipofectamin plus (Invitrogen, Carlsbad, CA, USA) Were transfected together. Two days after transfection, hygromycin was treated (100 µg/ml) to obtain a clone stably expressing luciferase. Whether luciferase is stably expressed in this clone was confirmed through a luciferase assay.
실험예 1-2: IL-6 반응성 STAT3 리포터 유전자 검사Experimental Example 1-2: IL-6 responsive STAT3 reporter gene test
상기 형질감염된 세포를 DMEM 배지(GIBCO 119950965)로 무혈청 배양(serum starvation)하고 시료를 하기와 같이 1시간 처리한 후 10ng/㎖ IL-6(R&D system, USA)를 첨가하여 12시간 동안 배양하였다.The transfected cells were serum-free cultured with DMEM medium (GIBCO 119950965), and the samples were treated for 1 hour as follows, and then 10ng/ml IL-6 (R&D system, USA) was added and cultured for 12 hours. .
1: 음성대조군(비처리군);1: negative control group (non-treatment group);
2: 양성대조군(IL-6 10ng/㎖);2: positive control (IL-6 10 ng/ml);
3: 추출물, 분획물 및 헥산 층 1차 컬럼 크로마토그래피 분획(25, 50㎍/㎖), 에틸아세테이트 층 1차 컬럼 크로마토그래피 분획(10, 30㎍/㎖)3: Extract, fraction and hexane layer first column chromatography fraction (25, 50 μg/mL), ethyl acetate layer first column chromatography fraction (10, 30 μg/mL)
상기 반응한 세포를 PBS로 세척하고 50㎕ 용해 완충용액(luciferase assay system, promega, USA)을 넣고 20분간 교반한 후, 30㎕ 내지 100㎕의 루시퍼라제 기질(luciferase assay system, promega, USA)을 넣고 발색 정도를 루미노미터 (luminometer; EG&G BERTHOLD, USA)로 5분 안에 측정하였고, 그 결과를 도 1 및 2에 나타내었다.The reacted cells were washed with PBS, 50 µl lysis buffer (luciferase assay system, promega, USA) was added and stirred for 20 minutes, and then 30 µl to 100 µl of luciferase substrate (luciferase assay system, promega, USA) was added. The color development degree was measured within 5 minutes with a luminometer (EG&G BERTHOLD, USA), and the results are shown in FIGS. 1 and 2.
그 결과, 도 1에 나타낸 바와 같이, 본 발명의 개머루덩굴 에탄올 추출물, 및 헥산, 에틸아세테이트 및 물 분획물은 모두 IL-6에 의해 매개되는 STAT3의 활성을 저해되는 결과를 나타내었다. 구체적으로, 개머루덩굴 에탄올 추출물의 경우 25㎍/㎖ 및 50㎍/㎖ 각각에서 83.9%, 101.0%의 저해활성을 나타내었으며, 개머루덩굴 헥산 분획물은 25㎍/㎖ 및 50㎍/㎖ 각각에서 100.9%, 101.6%의 저해활성을 나타내었으며, 에틸아세테이트 분획물은 25㎍/㎖ 및 50㎍/㎖ 각각에서 89.1%, 101.1%의 저해활성을 나타내었고, 물 분획물은 25㎍/㎖ 및 50㎍/㎖ 각각에서 19.4%, 99.2%의 저해활성을 나타내었다.As a result, as shown in Figure 1, the ethanol extract of the present invention, and the hexane, ethyl acetate, and water fractions all showed a result of inhibiting the activity of STAT3 mediated by IL-6. Specifically, in the case of Ethanol extract, 83.9% and 101.0% at 25 ㎍ / ㎖ and 50 ㎍ / ㎖, respectively, and the hexane fraction of vinegar vine was 100.9% at 25 ㎍ / ㎖ and 50 ㎍ / ㎖, respectively. , 101.6% of inhibitory activity was shown, and the ethyl acetate fraction showed 89.1% and 101.1% inhibitory activities at 25 µg/ml and 50 µg/ml, respectively, and the
또한, 헥산 층 1차 컬럼 크로마토그래피 분획의 경우, 분획 1 내지 10 모두에서 25㎍/㎖ 및 50㎍/㎖ 농도에서 STAT3의 활성을 효과적으로 저해시키는 결과를 나타내었으며(도 2), 에틸아세테이트 층 1차 컬럼 크로마토그래피 분획의 경우, 10㎍/㎖ 및 30㎍/㎖ 모두에서 STAT3의 활성을 효과적으로 저해시키는 결과를 나타내었다(도 3). 분리한 유효화합물의 경우, 에틸 갈레이트와 갈릭산이 60㎍/㎖ 농도에서 각각 62.2%와 59.7%의 STAT3 저해활성을 나타내었으며, 아로마덴드린의 경우는 상기 두 화합물보다 좀 더 낮은 STAT3 저해활성을 나타내었다(도 4).In addition, in the case of the hexane layer primary column chromatography fraction, both
실험예 1-3: IL-6 유도 Stat3 및 JAK2 인산화 저해활성 검정Experimental Example 1-3: IL-6-induced Stat3 and JAK2 phosphorylation inhibitory activity assay
6웰 플레이트에 5×105세포/웰로 Hep3B 및 U266 세포를 배양접시에 80%의 분포(Confluency)로 배양한 후, 무혈청 배지로 교환하여 추가로 12시간 배양하고 하기와 같이 시료를 60분간 처리하였다.After culturing Hep3B and U266 cells in a 6-well plate at 5×10 5 cells/well at 80% confluency in a culture dish, exchanged for a serum-free medium and incubated for an additional 12 hours, and sampled as follows for 60 minutes. Processed.
1: 음성대조군(비처리군);1: negative control group (non-treatment group);
2: 양성대조군(IL-6 10ng/㎖);2: positive control (IL-6 10 ng/ml);
3: 추출물 및 분획물(10, 30, 60㎍/㎖) 3: Extracts and fractions (10, 30, 60 ㎍ / ㎖)
8: Genestein 처리군 (100μM)8: Genestein treatment group (100 μM)
그 다음, 20ng/㎖ IL-6를 처리하여 20분간 반응한 뒤 40㎕ 용해 완충용액 (pH 8, 20mM Tris-HCl, 137mM NaCl, 10% 글리세롤, 1% Triton X-100, 1mM Na3VO4, 2mM EDTA, 1mM PMSF, 20mM 류펩틴(leupeptin), 20mg/㎖ 아포토닌(aprotonin); Sigma, USA)을 사용하여 세포를 용해시킨 후, 원심분리(13,000g, 15분)하여 단백질이 녹아있는 상등액을 수득하였다. 단백질의 농도는 DC 단백질 검사 키트(Bio-Rad, USA)를 이용하여 정량하였고, 4 내지 12% SDS 폴리아크릴아마이드 겔(SDS-PAGE)에 단백질을 로딩하여 175mA에서 2시간 동안 전기영동 하였다. 전기영동이 끝난 후 겔의 단백질을 PVDF 멤브레인(Westran S, pore size 0.2 ㎜; Whatman, USA)으로 35 V에서 90분 동안 전사시켰다. 전사된 멤브레인을 Tris-완충용액(T-TBS; 50mM Tri-HCl, pH 7.6, 150mM NaCl, 0.2% Tween-20, 5% skim milk; Sigma, USA)으로 상온에서 1시간 차단하고 T-TBS로 5번 세척하였다. 상기 멤브레인에 일차항체로 phospho-JAK2, phospho-Stat3(1:1,000 희석)의 다중클론 항체를 4℃에서 12시간 동안 처리하였다. T-TBS로 5번 세척 후 이차항체로 HRP-결합 항-마우스 항체(1:5,000 희석)를 1시간 반응시켰다. 그 다음, T-TBS로 세척하고 암실에서 ECL 키트 (Amersham, USA)를 이용하여 필름을 현상시켰다. 상기 결과를 도 5 및 6에 나타내었다.Then, 20 ng/ml IL-6 was treated and reacted for 20 minutes, and then 40 µl lysis buffer (
그 결과, 본 발명의 개머루덩굴 에탄올 추출물은 IL-6에 의한 STAT3의 인산화를 농도의존적으로 효과적으로 저해시키는 결과를 나타내었으며(도 5), JAK2(Tyr1007/1008)의 인산화 역시 농도의존적으로 저해하는 결과를 나타내었다(도 6). As a result, the ethanol extract of the present invention showed a result of effectively inhibiting the phosphorylation of STAT3 by IL-6 in a concentration-dependent manner (FIG. 5), and the phosphorylation of JAK2 (Tyr1007/1008) was also inhibited in a concentration-dependent manner. Is shown (Fig. 6).
상기와 같은 결과는 본 발명의 개머루덩굴 에탄올 추출물이 IL-6에 의한 신호전달활성을 효과적으로 저해시킬 수 있음을 나타내는 것으로, 실험예 1-2의 결과와 종합하여 볼 때, 본 발명의 개머루덩굴 추출물 또는 이의 분획물을 사용하는 경우 IL-6 매개성 질환을 효과적으로 예방 또는 치료할 수 있음을 시사한다. The above results indicate that the ethanol extract of the present invention can effectively inhibit the signaling activity by IL-6. When viewed in combination with the results of Experimental Example 1-2, the extract of the present invention Alternatively, the use of a fraction thereof suggests that IL-6 mediated diseases can be effectively prevented or treated.
실험예 2: 개머루덩굴 추출물 및 분획물의 RANKL에 의해 유도되는 파골세포 분화 억제 효과 Experimental Example 2: Extracts and fractions of Amaranthus vines Osteoclast differentiation inhibiting effect induced by RANKL
골의 유지는 파골세포가 오래된 골을 흡수하고 조골세포가 새로운 골을 꾸준하게 생산함으로써 조절된다. 따라서 파골세포와 조골세포의 비정상적인 조화가 여러 가지 골 질환을 유발할 뿐만 아니라 파골세포의 증가는 골다공증, 류마티스 관절염, 치주염 등과 같은 골 질환을 유발한다. RANKL에 의해 유도되는 파골세포의 분화에서 IL-6/STAT3의 활성이 중요하게 관여하는 것으로 알려져 있다. 실험예 1을 통하여 본 발명의 개머루덩굴 추출물 및 이의 분획물이 IL-6에 의해 유도되는 STAT3의 활성을 효과적으로 저해시킬 수 있음을 확인하였다. 이에 RANKL에 의해 유도되는 파골세포의 분화에서 개머루덩굴 추출물이 억제효능이 있는지를 알아보기 위하여 하기와 같이 실험을 수행하였다.Bone maintenance is regulated by osteoclasts absorbing old bones and osteoblasts consistently producing new bones. Therefore, an abnormal combination of osteoclasts and osteoblasts not only causes various bone diseases, but an increase in osteoclasts causes bone diseases such as osteoporosis, rheumatoid arthritis, and periodontitis. It is known that the activity of IL-6/STAT3 is importantly involved in the differentiation of osteoclasts induced by RANKL. Through Experimental Example 1, it was confirmed that the extract and fractions thereof of the present invention can effectively inhibit the activity of STAT3 induced by IL-6. Accordingly, an experiment was carried out as follows to determine whether the extract of vinegar vines has an inhibitory effect in the differentiation of osteoclasts induced by RANKL.
실험예 2-1: RANKL 유도 파골세포 분화 억제 효능 검사Experimental Example 2-1: RANKL-induced osteoclast differentiation inhibition efficacy test
구체적으로, 5주령 생쥐의 넓적다리뼈와 정강이뼈를 분리하고 뼈 속질 공간을 1cc 주사기로 수세하여 골수세포를 얻었다. 분리된 골수세포는 10% FBS, 항생제, M-CSF(30ng/㎖)가 포함된 a-MEM 배지에서 3일간 배양하였다. 3일 후, 부착된 세포를 포식세포(bone marrow macrophage, BMM)로 사용하였다. 포식세포는 M-CSF(30ng/㎖)와 RANKL(50ng/㎖)을 첨가하여 배양하고 개머루덩굴 추출물(50, 25 및 10㎍/㎖) 및 분획물(50㎍/㎖)을 처리하였다. 4일 후, 배양한 세포는 TRAP 용액(Sigma Aldrich, USA)으로 염색하고 붉은색으로 염색된 세포를 분화된 뼈파골세포로 판단하였고 그 결과를 도 7에 나타내었다.Specifically, bone marrow cells were obtained by separating the thigh bone and shin bone of a 5-week-old mouse, and washing the inner space of the bone with a 1cc syringe. The isolated bone marrow cells were cultured for 3 days in a-MEM medium containing 10% FBS, antibiotics, and M-CSF (30 ng/ml). After 3 days, the attached cells were used as phagocytic cells (bone marrow macrophage, BMM). Phagocytic cells were cultured with the addition of M-CSF (30 ng/ml) and RANKL (50 ng/ml), and treated with extracts (50, 25 and 10 µg/ml) and fractions (50 µg/ml). After 4 days, the cultured cells were stained with a TRAP solution (Sigma Aldrich, USA), and the cells stained in red were judged as differentiated osteoclasts, and the results are shown in FIG. 7.
그 결과, 본 발명의 개머루덩굴 에탄올 추출물은 RANKL에 의해 유도되는 파골세포 분화를 효과적으로 억제하였다(도 7A 및 B).As a result, the ethanol extract of the present invention effectively inhibited the differentiation of osteoclasts induced by RANKL (Figs. 7A and B).
실험예 2-2: XTT 분석에 의한 세포독성 검사Experimental Example 2-2: Cytotoxicity test by XTT analysis
포식세포를 1X104 세포/웰의 밀도로 96-well plate에 첨가하고 개머루덩굴 에탄올 추출물과 M-CSF(30ng/㎖)를 첨가하여 3일간 배양하였다. 3일 후, XTT 용액 50㎕를 각각의 웰에 첨가하고 4시간 배양 후 ELISA reader(Molecular Devices, CA, USA)를 이용하여 450nm에서 흡광도를 확인하였고, 그 결과를 도 7C에 나타내었다.Phagocytic cells were added to a 96-well plate at a density of 1×10 4 cells/well, and ethanol extract and M-CSF (30 ng/ml) were added and cultured for 3 days. After 3 days, 50 µl of the XTT solution was added to each well, and after incubation for 4 hours, the absorbance at 450 nm was confirmed using an ELISA reader (Molecular Devices, CA, USA), and the results are shown in FIG. 7C.
그 결과, 본 발명의 개머루덩굴 에탄올 추출물은 세포독성을 전혀 나타내지 않았으며, 이는 개머루덩굴 에탄올 추출물이 세포독성과 무관하게 파골세포의 분화 억제 효능을 가진다는 것을 시사한다(도 7C). As a result, the Ethanol extract of the present invention did not show cytotoxicity at all, which suggests that the Ethanol extract has an effect of inhibiting the differentiation of osteoclasts irrespective of cytotoxicity (Fig. 7C).
실험예 2-3: RANKL에 의해 유도되는 파골세포 분화에서 중요한 역할을 하는 유전자/단백질들의 발현 분석 Experimental Example 2-3: Expression analysis of genes / proteins that play an important role in osteoclast differentiation induced by RANKL
RANKL은 세포막의 RANK와 결합한 후 세포 내 신호 전달 체계를 거쳐 전사인자인 c-Fos와 NFATc1의 발현을 촉진하고 파골세포의 지표인 TRAP 유전자의 발현을 유도시킨다. RANKL로 자극한 BMM에서 Real-time PCR 분석법에 의하여 c-Fos, NFATc1, OSCAR, TRAP, cathepsin K, 및 DC-STAMP의 mRNA 발현을 정량하였다. 실험예 2-1과 같이 BMM을 준비한 후 개머루덩굴 에탄올 추출물 (50㎍/㎖)을 1시간 동안 전처리하고 RANKL (100ng/㎖)을 첨가한 후 12, 24, 그리고 48시간 배양하였다. 배양 후 각각의 세포에서 TRIzol(Invitrogen) 용액으로 RNA를 분리하고 분리한 RNA 1 ㎍을 사용하여 cDNA를 합성하였다. 합성된 cDNA는 다음과 같은 프라이머를 사용하여 PCR 증폭하였다.After RANKL binds to RANK in the cell membrane, it promotes the expression of transcription factors c-Fos and NFATc1 through intracellular signaling system and induces the expression of the TRAP gene, an indicator of osteoclasts. In RANKL stimulated BMM, mRNA expression of c-Fos, NFATc1, OSCAR, TRAP, cathepsin K, and DC-STAMP was quantified by real-time PCR analysis. After preparing BMM as in Experimental Example 2-1, ethanol extract (50 µg/ml) was pretreated for 1 hour, and RANKL (100 ng/ml) was added, followed by incubation for 12, 24, and 48 hours. After cultivation, RNA was isolated from each cell with a TRIzol (Invitrogen) solution, and cDNA was synthesized using 1 μg of the isolated RNA. The synthesized cDNA was amplified by PCR using the following primers.
c-Fos
NFATc1
OSCAR
TRAP
cathepsin K
DC-STAMP
GAPDH
PCR 분석 결과, 본 발명의 개머루덩굴 에탄올 추출물이 파골세포의 분화에 중요한 유전자인 c-Fos, NFATc1, OSCAR, TRAP, cathepsin K, 및 DC-STAMP의 mRNA 발현을 모두 효과적으로 억제함을 볼 수 있었다(도 8). 특히, 개머루덩굴 에탄올 추출물은 전사인자 c-Fos보다 전사인자 NFATc1의 발현을 더 효과적으로 억제함을 볼 수 있었다.As a result of PCR analysis, it was found that the ethanol extract of the present invention effectively inhibited the mRNA expression of all genes important for the differentiation of osteoclasts, c-Fos, NFATc1, OSCAR, TRAP, cathepsin K, and DC-STAMP ( Fig. 8). In particular, it could be seen that the ethanol extract of Asteraceae vine more effectively inhibited the expression of the transcription factor NFATc1 than the transcription factor c-Fos.
실험예 2-4: RANKL의 하위신호전달기전 활성 분석; p38, AKT , ERK , 그리고 IκB의 인산화 측정 Experimental Example 2-4: Analysis of the activity of RANKL prior to subsignaling; Measurement of phosphorylation of p38, AKT , ERK , and I κB
실험예 2-1과 같이 BMM을 준비한 후 무혈청 배지로 교환해주었다. 무혈청 배지에서 3시간 동안 배양한 후 개머루덩굴 에탄올 추출물을 각각의 농도별로 1시간 동안 전 처리하였다. 이 후 RANKL(100ng/㎖)을 첨가하여 15분 자극한 후 각각의 세포를 모아서 실험예 1-3과 같은 방법으로 각 단백질의 인산화를 측정하였다.After preparing BMM as in Experimental Example 2-1, it was replaced with a serum-free medium. After incubation in a serum-free medium for 3 hours, the ethanol extract of the vine was pretreated for 1 hour at each concentration. Thereafter, RANKL (100ng/ml) was added and stimulated for 15 minutes, and then each cell was collected and phosphorylation of each protein was measured in the same manner as in Experimental Example 1-3.
그 결과, 개머루덩굴 에탄올 추출물은 RANKL에 의해 유도되는 p38과 IκB의 인산화를 억제하였으나, AKT와 ERK의 인산화에는 영향을 주지 않았다(도 9).As a result, the ethanol extract of blackberry vine inhibited the phosphorylation of p38 and IκB induced by RANKL, but did not affect the phosphorylation of AKT and ERK (FIG. 9).
실험예 2-5: 골 흡수 검사Experimental Example 2-5: Bone resorption test
골 흡수 검사를 위하여, 조골세포는 생후 1일령 생쥐의 안와(calvaria)를 떼어서 0.1% 콜라게나아제(collagenase)와 0.2% 디스파아제(dispase)를 첨가 후 추출된 세포를 10% FBS와 항생제(penicillin/streptomycin)가 들어있는 α-MEM 배양액에서 3일간 배양하여 얻었다. 골수세포와 조골세포를 콜라겐으로 코팅한 90-mm 배양접시에 첨가하고 비타민 D3(10-8M)와 PGE2(10-6M)를 처리한 후 6일간 동조 배양하였다. 6일 후, 콜라게나아제를 이용하여 부착된 성숙 파골세포를 떼어낸 후, 하이드록시아파타이트(hydroxyapatite)가 코팅된 48-웰 플레이트에 넣고 1시간 동안 배양하였다. 1시간 배양 후, 트립신을 처리하여 조골세포를 제거하고 순수 파골세포에 RANKL(100 ng/㎖)을 처리하고 개머루덩굴 에탄올 추출물을 농도별로 처리해 24시간 배양했다. 파골세포는 0.1% Triton X-100을 처리해 제거하고 광학 현미경으로 촬영했다. 골 흡수 영역의 정량화는 Image Pro-plus program version, version. 4.0(Media Cybernetics)을 이용했다.For the bone resorption test, osteoblasts were removed from the orbit (calvaria) of 1-day-old mice, and 0.1% collagenase and 0.2% dispase were added, and the extracted cells were mixed with 10% FBS and antibiotics ( penicillin/streptomycin) was obtained by incubating for 3 days in α-MEM culture solution. Bone marrow cells and osteoblasts were added to a 90-mm culture dish coated with collagen, treated with vitamin D 3 (10 -8 M) and PGE2 (10 -6 M), followed by synchronous culture for 6 days. After 6 days, the attached mature osteoclasts were removed using collagenase, and then placed in a 48-well plate coated with hydroxyapatite and incubated for 1 hour. After incubation for 1 hour, trypsin was treated to remove osteoblasts, RANKL (100 ng/ml) was treated on pure osteoclasts, and ethanol extracts were treated with different concentrations for 24 hours. The osteoclasts were removed by treatment with 0.1% Triton X-100 and photographed with an optical microscope. The quantification of the bone resorption area is based on the Image Pro-plus program version, version. 4.0 (Media Cybernetics) was used.
그 결과, 본 발명의 개머루덩굴 에탄올 추출물이 50㎍/㎖의 농도에서 파골세포의 골 흡수 작용을 효과적으로 억제함을 볼 수 있었다(도 10).As a result, it can be seen that the ethanol extract of the present invention effectively inhibits the bone resorption action of osteoclasts at a concentration of 50 µg/ml (FIG. 10).
또한, 본 발명에서는 실험예 1-3을 통하여 개머루덩굴로부터 분리한 유효화합물인 에틸 갈레이트, 갈릭산 및 아로마덴드린이 우수한 STAT3 저해활성을 나타내는 것을 확인하였으며, 이에 이들 화합물들이 RANKL에 의해 유도되는 파골세포의 분화에서도 억제효능이 있는지를 알아보았다. In addition, in the present invention, it was confirmed that ethyl gallate, gallic acid, and aromadendrin, which are effective compounds isolated from black stalks through Experimental Example 1-3, exhibit excellent STAT3 inhibitory activity, whereby these compounds are induced by RANKL. It was examined whether there is an inhibitory effect in the differentiation of osteoclasts.
이때, 실험예 2-1과 같이 검사하여 RANKL에 의해 유도되는 파골세포 분화 억제 효능을 검사하였고, 그 결과, STAT3 저해활성과 유사하게 에틸 갈레이트와 갈릭산은 10μM과 30μM의 농도에서 우수한 파골세포 분화 억제 효능을 나타내었으며, 아로마덴드린은 두 화합물보다는 낮았으나, 60μM 농도에서 파골세포의 분화를 효과적으로 저해하는 결과를 보였다(도 11).At this time, as in Experimental Example 2-1, the efficacy of inhibiting osteoclast differentiation induced by RANKL was examined.As a result, similar to the STAT3 inhibitory activity, ethyl gallate and gallic acid were excellent in osteoclast differentiation at concentrations of 10 μM and 30 μM. The inhibitory effect was shown, and aromadendrin was lower than that of the two compounds, but showed a result of effectively inhibiting the differentiation of osteoclasts at a concentration of 60 μM (FIG. 11).
상기와 같은 결과를 종합하면, 본 발명의 개머루덩굴 추출물, 이의 분획물 및 이로부터 분리한 화합물들이 IL-6 매개성 질환을 치료할 수 있음을, 특히 파골세포의 분화를 효과적으로 억제하여 골다공증을 비롯한 골 대사성 질환을 효과적으로 치료할 수 있음을 시사하는 것이다.Summarizing the above results, it was found that the extract, its fractions, and the compounds isolated therefrom of the present invention can treat IL-6-mediated diseases. This suggests that the disease can be effectively treated.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시 예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그 리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing the technical spirit or essential features thereof. In this regard, the embodiments described above are illustrative in all respects and should be understood as non-limiting. The scope of the present invention should be construed as including the meaning and scope of the claims to be described later rather than the above detailed description, and all changes or modifications derived from the equivalent concepts within the scope of the present invention.
<110> Korea Research Institute of Bioscience and Biotechnology <120> A pharmaceutical composition for preventing or treating IL-6-mediated disease, comprising extract, fraction, or compounds derived from Ampelopsis brevipedunculata <130> PA130871-KR-D1 <150> KR 10-2012-0112093 <151> 2012-10-09 <160> 14 <170> KopatentIn 2.0 <210> 1 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Primer for c-Fos (sense) <400> 1 ctggtgcagc ccactctggt c 21 <210> 2 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Primer for c-Fos (antisense) <400> 2 ctttcagcag attggcaatc tc 22 <210> 3 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Primer for NFATc1 (sense) <400> 3 caacgccctg accaccgata g 21 <210> 4 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Primer for NFATc1 (antisense) <400> 4 ggctgccttc cgtctcatag t 21 <210> 5 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Primer for OSCAR (sense) <400> 5 ctgctggtaa cggatcagct ccccaga 27 <210> 6 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Primer for OSCAR (antisense) <400> 6 ccaaggagcc agaaccttcg aaact 25 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for TRAP (sense) <400> 7 acttccccag cccttactac 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for TRAP (antisense) <400> 8 tcagcacata gcccacaccg 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for cathepsin K (sense) <400> 9 cagcagaacg gaggcattga 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for cathepsin K (antisense) <400> 10 cctttgccgt ggcgttatac 20 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for DC-STAMP (sense) <400> 11 gcaaggaacc caaggagtcg 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for DC-STAMP (antisense) <400> 12 cagttggccc agaaagaggg 20 <210> 13 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for GAPDH (sense) <400> 13 accacagtcc atgccatcac 20 <210> 14 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for GAPDH (antisense) <400> 14 tccaccaccc tgttgctgta 20 <110> Korea Research Institute of Bioscience and Biotechnology <120> A pharmaceutical composition for preventing or treating IL-6-mediated disease, comprising extract, fraction, or compounds derived from Ampelopsis brevipedunculata <130> PA130871-KR-D1 <150> KR 10-2012-0112093 <151> 2012-10-09 <160> 14 <170> KopatentIn 2.0 <210> 1 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Primer for c-Fos (sense) <400> 1 ctggtgcagc ccactctggt c 21 <210> 2 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Primer for c-Fos (antisense) <400> 2 ctttcagcag attggcaatc tc 22 <210> 3 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Primer for NFATc1 (sense) <400> 3 caacgccctg accaccgata g 21 <210> 4 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Primer for NFATc1 (antisense) <400> 4 ggctgccttc cgtctcatag t 21 <210> 5 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Primer for OSCAR (sense) <400> 5 ctgctggtaa cggatcagct ccccaga 27 <210> 6 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Primer for OSCAR (antisense) <400> 6 ccaaggagcc agaaccttcg aaact 25 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for TRAP (sense) <400> 7 acttccccag cccttactac 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for TRAP (antisense) <400> 8 tcagcacata gcccacaccg 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for cathepsin K (sense) <400> 9 cagcagaacg gaggcattga 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for cathepsin K (antisense) <400> 10 cctttgccgt ggcgttatac 20 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for DC-STAMP (sense) <400> 11 gcaaggaacc caaggagtcg 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for DC-STAMP (antisense) <400> 12 cagttggccc agaaagaggg 20 <210> 13 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for GAPDH (sense) <400> 13 accacagtcc atgccatcac 20 <210> 14 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Primer for GAPDH (antisense) <400> 14 tccaccaccc tgttgctgta 20
Claims (11)
[화학식 1]
[화학식 2]
.A pharmaceutical for preventing or treating atopic dermatitis, which is an interleukin-6 mediated inflammatory disease, comprising an extract of Ampelopsis brevipedunculata stem or a fraction thereof including the compound represented by Formula 1 or 2 as an active ingredient Composition:
[Formula 1]
[Formula 2]
.
[화학식 1]
[화학식 2]
.Food for preventing or improving atopy, an IL-6 (interleukin-6) mediated inflammatory disease comprising an extract of Ampelopsis brevipedunculata stem or a fraction thereof including the compound represented by Formula 1 or 2 as an active ingredient Composition:
[Formula 1]
[Formula 2]
.
[화학식 1]
[화학식 2]
.A quasi-medicinal product for the prevention or improvement of atopic dermatitis, which is an IL-6-mediated inflammatory disease, comprising an extract of Ampelopsis brevipedunculata stem or a fraction thereof including the compound represented by Formula 1 or 2 as an active ingredient Composition:
[Formula 1]
[Formula 2]
.
[화학식 1]
[화학식 2]
.Feed for the prevention or improvement of atopic dermatitis, IL-6 (interleukin-6) -mediated inflammatory disease, comprising an extract of Ampelopsis brevipedunculata stem or a fraction thereof including the compound represented by Formula 1 or 2 as an active ingredient additive:
[Formula 1]
[Formula 2]
.
[화학식 1]
[화학식 2]
.Cosmetics for the prevention or improvement of atopic dermatitis, IL-6 (interleukin-6) -mediated inflammatory disease comprising an extract of the extract Ampelopsis brevipedunculata stem or a fraction thereof containing the compound represented by Formula 1 or 2 as an active ingredient Composition:
[Formula 1]
[Formula 2]
.
A method of treating atopy, which is an IL-6 (interleukin-6) mediated inflammatory disease, comprising administering the composition of claim 1 to an individual except a human.
[화학식 1]
[화학식 2]
.Drinking water for the prevention or improvement of atopy, an IL-6 (interleukin-6) mediated inflammatory disease, comprising an extract of Ampelopsis brevipedunculata stem or a fraction thereof including the compound represented by Formula 1 or 2 as an active ingredient additive:
[Formula 1]
[Formula 2]
.
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CN104383383A (en) * | 2014-12-11 | 2015-03-04 | 李学存 | Chinese medicinal wine for promoting healing of bone fracture and preparation method thereof |
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JP6861955B2 (en) * | 2017-01-11 | 2021-04-21 | 日本メナード化粧品株式会社 | Hyaluronic acid synthesis accelerator |
KR101957369B1 (en) * | 2017-11-14 | 2019-03-12 | 한국생명공학연구원 | A composition for preventing or treating Porcine reproductive and respiratory syndrome, comprising an Ampelopsis brevipedunculata extract, a fraction thereof, or a compound isolated therefrom |
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WO2005000330A1 (en) | 2003-05-28 | 2005-01-06 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Angiogenic agents from plant extracts, gallic acid, and derivatives |
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KR101673265B1 (en) | 2016-11-07 |
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