KR20230052792A - Composition for preventing or treating liver fibrosis comprising beta-guanidinopropionic acid - Google Patents
Composition for preventing or treating liver fibrosis comprising beta-guanidinopropionic acid Download PDFInfo
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- KR20230052792A KR20230052792A KR1020220029238A KR20220029238A KR20230052792A KR 20230052792 A KR20230052792 A KR 20230052792A KR 1020220029238 A KR1020220029238 A KR 1020220029238A KR 20220029238 A KR20220029238 A KR 20220029238A KR 20230052792 A KR20230052792 A KR 20230052792A
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- preventing
- liver fibrosis
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Abstract
Description
본 발명은 간섬유화 예방 또는 치료 효과가 우수한 베타-구아니디노프로피온산(beta-guanidinopropionic acid, β-GPA)를 유효성분으로 포함하는 조성물에 관한 것이다. The present invention relates to a composition containing beta-guanidinopropionic acid (β-GPA) as an active ingredient, which is excellent in preventing or treating liver fibrosis.
섬유화(fibrosis)란 인체 내에서 조직이 여러 가지 스트레스 (감염, 화학적 자극, 방사선 등)에 의한 손상을 받은 후 창상치유(wound healing) 과정 중에 정상적인 통제가 불가능한 상태로, 특히 만성 질환에 공통적으로 거치게 되는 경로로서 그 기전이 매우 복잡하여 현재까지도 완전히 규명되고 있지 않다.Fibrosis is a state in which normal control is impossible during the wound healing process after tissue is damaged by various stresses (infection, chemical stimulation, radiation, etc.) in the human body, and is particularly common in chronic diseases. However, the mechanism is very complex and has not been fully elucidated to date.
간이 알코올, 바이러스 등의 여러 유해환경인자에 의해 자극을 받으면 쿠퍼세포(Kupffer cell)로부터 분비된 TGF-β(transforming growth factor beta)를 포함한 여러 사이토카인에 의하여 간성상 세포가 활성화된다. 분비된 TGF-β는 콜라겐 합성을 촉진시켜 세포외 기질을 축적시키고, 지속적으로 축적된 콜라겐에 의하여 간섬유화를 일으킬 뿐만 아니라, 간성상세포 자신 뿐만 아니라 주변의 간세포에도 영향을 주어 EMT(epithelial to mesenchymal transition)을 일으키는 것으로 알려져 있다. 계속되는 간섬유화(hepatic fibrosis)의 과정을 거쳐 결국은 간경변증이 유발되므로 간섬유화의 과정을 이해하고 연구하는 것은 간경변증을 유발할 수 있는 모든 질환을 해결하는 데 가장 기본적인 단계라고 할 수 있다.When the liver is stimulated by various harmful environmental factors such as alcohol and viruses, hepatic stellate cells are activated by various cytokines including TGF-β (transforming growth factor beta) secreted from Kupffer cells. The secreted TGF-β promotes collagen synthesis, accumulates extracellular matrix, causes hepatic fibrosis by continuously accumulated collagen, and affects not only hepatic stellate cells themselves but also surrounding hepatocytes, resulting in EMT (epithelial to mesenchymal known to cause a transition. Since liver cirrhosis is eventually induced through the continuous process of hepatic fibrosis, understanding and studying the process of hepatic fibrosis is the most basic step in solving all diseases that can cause liver cirrhosis.
일반적으로 간섬유화는 간경변증과는 달리 가역적이고, 얇은 원섬유(thin fibril)로 구성되며, 결절(nodule) 형성이 없는 것으로 알려져 있고, 간 손상의 원인이 소실되면 정상회복이 가능할 수 있으나, 이러한 간 섬유화증 과정이 반복적으로 지속되면 ECM(extra cellular matrix) 간의 교차결합(crosslinking)이 증가하여 결절(nodule)이 있는 비가역적인 간경변증으로 진행된다.In general, liver fibrosis is known to be reversible, composed of thin fibrils, and without nodule formation, unlike liver cirrhosis. If the fibrosis process continues repeatedly, crosslinking between ECM (extra cellular matrix) increases, leading to irreversible liver cirrhosis with nodules.
간섬유화가 더욱더 진행되어 간경변증(cirrhosis)이 일어나는데, 어떤 원인에 의해 간세포 괴사가 일어나면 간세포 재생과 섬유조직의 증가가 일어나고, 이러한 과정이 오랫동안 반복하여 지속될 때 간경변증이 발생하게 된다. 지속적 또는 반복적인 미만성 간실질 손상, 섬유조직 증가와 간세포 재생에 의해 재생된 간 결절이나 결절로 형성된 간경변증은 병리학적으로 괴사(necrosis), 염증(inflammation) 및 섬유화(fibrosis)가 수반되는 만성질환이며 궁극적으로 간경변 합병증, 간암 등의 질환으로 진행되어 사망에 이르게 한다. 특히, 초기에 자각증상이 없어 상당히 진행되어서야 발견되기 때문에 간섬유화를 신속히 진단하고 치료하는 방법을 개발하기 위한 연구가 활발히 진행되고 있다.Liver fibrosis progresses further and cirrhosis occurs. When liver cell necrosis occurs for some reason, liver cell regeneration and fibrous tissue increase, and when this process continues repeatedly for a long time, liver cirrhosis occurs. Liver cirrhosis formed by liver nodules or nodules regenerated by persistent or repetitive diffuse liver parenchymal damage, fibrous tissue growth, and regeneration of hepatocytes is a chronic disease pathologically accompanied by necrosis, inflammation, and fibrosis. Ultimately, it progresses to diseases such as liver cirrhosis complications and liver cancer, leading to death. In particular, because there are no subjective symptoms in the early stages and it is discovered only after considerable progress, research is being actively conducted to develop methods for rapidly diagnosing and treating liver fibrosis.
간섬유화를 억제하는 물질로, 페니실라민, 16,16-디메틸 프로스티글라딘 E2, 비페닐 디메틸디카르복실산, 콜키친, 글루코코티코이드, 말로틸산(malotilate), 감마-인터페론, 펜톡시필린(pentoxifylline), 피리딘-2,4-디카르복실릭-디에틸아미드, 피리딘-2,4-디카르복실릭-디(2-메톡시에틸)아미드 등이 개발되었지만, 임상에 적용시 작용이 미약하거나 부작용이 심하여, 현재로서는 임상에 사용되고 있는 간섬유화 치료제는 없는 실정이다.As a substance that inhibits liver fibrosis, penicillamine, 16,16-dimethyl prostiglidin E2, biphenyl dimethyldicarboxylic acid, colchicine, glucocorticoid, malotilate, gamma-interferon, pentoxifylline ( pentoxifylline), pyridine-2,4-dicarboxylic-diethylamide, pyridine-2,4-dicarboxylic-di(2-methoxyethyl)amide, etc. have been developed, but their action is weak when applied clinically. or severe side effects, currently there is no treatment for liver fibrosis that is used clinically.
구아니디노프로피온산, 베타-구아니디노프로피온산 또는 N-(아미노이미노메틸)-베타-알라닌으로도 지칭되는 β-구아니디노프로피온산(β-GPA)은 크레아틴 유사체이다. 동물(래트, 원숭이, 햄스터) 연구는 산성 구아니딘 유도체, 예를 들면, β-GPA가 인슐린-비의존성 당뇨병의 동물 모델에서 고혈당증을 완화시킬 수 있다는 것을 보여준다. 따라서, 이는 때때로 혈당 수치를 조절하기 위하여 당뇨병 환자에서 식이 보충제로서 사용된다. β-GPA는 물에 고도로 용해성인(50 ㎎/㎖ 초과) 백색 결정질 분말이다.β-Guanidinopropionic acid (β-GPA), also referred to as guanidinopropionic acid, beta-guanidinopropionic acid, or N-(aminoiminomethyl)-beta-alanine, is a creatine analogue. Animal (rat, monkey, hamster) studies show that acidic guanidine derivatives, such as β-GPA, can alleviate hyperglycemia in animal models of non-insulin-dependent diabetes. Therefore, it is sometimes used as a dietary supplement in diabetic patients to control blood sugar levels. β-GPA is a white crystalline powder that is highly soluble (>50 mg/mL) in water.
한국등록특허 제190257호는 3-구아니디노프로피온산을 포함하는 대사질환 치료용 약학 조성물에 관한 내용을 개시하고 있고, 한국공개특허 제2018-0059446호는 개선된 특성의 β-구아니디노프로피오산의 약제학적으로 허용 가능한 염 및 이의 용도에 관해 개시하고 있다.Korean Patent Registration No. 190257 discloses a pharmaceutical composition for the treatment of metabolic diseases containing 3-guanidinopropionic acid, and Korean Patent Publication No. 2018-0059446 discloses β-guanidinopropionic acid with improved characteristics. Pharmaceutically acceptable salts of and uses thereof are disclosed.
그러나, 본 발명의 베타-구아니디노프로피오산이 간섬유화에 미치는 영향에 관해 보고된 바 없다. However, the effect of the beta-guanidinopropioic acid of the present invention on liver fibrosis has not been reported.
본 발명은 상기와 같은 요구에 의해 도출된 것으로서, 본 발명자들은 베타-구아니디노프로피오산을 유효성분으로 포함하는 조성물의 간섬유화 개선 또는 치료 효과를 확인하여 본 발명을 완성하였다. The present invention was derived from the above needs, and the present inventors completed the present invention by confirming the effect of improving or treating liver fibrosis of a composition containing beta-guanidinopropioic acid as an active ingredient.
상기 과제를 해결하기 위하여, 본 발명은 베타-구아니디노프로피온산(beta-guanidinopropionic acid, β-GPA)을 유효성분으로 포함하는 간섬유화 예방 또는 치료용 약학 조성물을 제공한다. In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating liver fibrosis comprising beta-guanidinopropionic acid (β-GPA) as an active ingredient.
본 발명의 일 예에서, 상기 베타-구아니디노프로피온산은 간조직 내에서 히드록시프롤린 및 알파 민무늬근육액틴 (alpha-smooth muscle actin) 단백질 발현을 감소시키는 것이고, 상기 베타-구아니디노프로피온산은 인터루킨 17 및 인터페론 감마의 발현을 감소시키는 것이며, 상기 베타-구아니디노프로피온산은 CD11b+Ly6C+ 단핵구의 분포를 감소시키는 것을 특징으로 하는 것이다.In one embodiment of the present invention, the beta-guanidinopropionic acid reduces the expression of hydroxyproline and alpha-smooth muscle actin proteins in liver tissue, and the beta-guanidinopropionic acid is an interleukin 17 and interferon gamma, and the beta-guanidinopropionic acid reduces the distribution of CD11b+Ly6C+ monocytes.
또한, 본 발명은 베타-구아니디노프로피온산(beta-guanidinopropionic acid, β-GPA)을 유효성분으로 포함하는 간섬유화 예방 또는 개선용 식품 조성물을 제공한다. In addition, the present invention provides a food composition for preventing or improving liver fibrosis comprising beta-guanidinopropionic acid (β-GPA) as an active ingredient.
본 발명의 다른 예에서, 본 발명은 베타-구아니디노프로피온산(beta-guanidinopropionic acid, β-GPA)을 투여하는 단계를 포함하는 인간을 제외한 개체에서 간섬유화 예방 또는 치료방법을 제공한다. In another embodiment of the present invention, the present invention provides a method for preventing or treating liver fibrosis in a non-human subject comprising administering beta-guanidinopropionic acid (β-GPA).
본 발명의 베타-구아니디노프로피온산(beta-guanidinopropionic acid, β-GPA)을 포함하는 조성물은 간조직 내에서 히드록시프롤린 및 알파 민무늬근육액틴 (alpha-smooth muscle actin) 단백질 발현, 인터루킨 17 및 인터페론 감마의 발현 및 CD11b+Ly6C+ 단핵구의 분포를 감소에 대한 효과가 있으므로 간섬유화 예방 또는 치료에 유용하게 사용될 수 있다. The composition containing beta-guanidinopropionic acid (β-GPA) of the present invention is effective in expressing hydroxyproline and alpha-smooth muscle actin proteins in liver tissue, interleukin 17 and interferon Since it has an effect on reducing the expression of gamma and the distribution of CD11b+Ly6C+ monocytes, it can be usefully used for preventing or treating liver fibrosis.
도 1은 본 발명의 일 구현 예에 따른 β-구아니디노프로피오산의 구조를 나타낸 것이다.
도 2는 본 발명의 일 구현 예에 따른 고지방고과당 식이 기반 지방간염/간섬유화 동물모델 실험 프로토콜을 나타낸 것이다.
도 3은 본 발명의 일 구현 예에 따른 지방간염/간섬유화 동물모델에서 β-구아니디노프로피오산에 의한 체중변화 그래프를 나타낸 것이다.
도 4는 본 발명의 일 구현 예에 따른 지방간염/간섬유화 동물모델에서 β-구아니디노프로피오산에 의한 먹이섭취 변화를 나타낸 것이다.
도 5는 본 발명의 일 구현 예에 따른 지방간염/간섬유화 동물모델에서 β-구아니디노프로피오산에 의한 간조직 hydroxyproline 측정 결과를 나타낸 것이다.
도 6은 본 발명의 일 구현 예에 따른 지방간염/간섬유화 동물모델에서 β-구아니디노프로피오산에 의한 간조직 알파 민무늬근육액틴(alpha-smooth muscle actin) 단백질 발현 측정 결과를 나타낸 것이다.
도 7은 본 발명의 일 구현 예에 따른 지방간염/간섬유화 동물모델에서 β-구아니디노프로피오산에 의한 간조직의 기억(memory)/미접촉(naive) CD4+, CD8+T 세포의 분포를 나타낸 것이다.
도 8은 본 발명의 일 구현 예에 따른 지방간염/간섬유화 동물모델에서 β-구아니디노프로피오산에 의한 간조직 인터루킨 17(IL-17) 및 인터페론 감마(IFN-γ) 발현 T 세포의 분포를 나타낸 것이다.
도 9는 본 발명의 일 구현 예에 따른 지방간염/간섬유화 동물모델에서 β-구아니디노프로피오산에 의한 간내 단핵구 분포를 나타낸 것이다.1 shows the structure of β-guanidinopropioic acid according to an embodiment of the present invention.
2 shows an experimental protocol for a high-fat, high-fructose diet-based steatohepatitis/hepatic fibrosis animal model according to an embodiment of the present invention.
FIG. 3 shows a graph of weight change by β-guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
4 shows changes in food intake by β-guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
5 shows the results of measuring liver tissue hydroxyproline by β-guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
6 shows the results of measuring alpha-smooth muscle actin protein expression in liver tissue by β-guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
7 shows the distribution of memory/naive CD4+, CD8+ T cells in liver tissue by β-guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention. will be.
8 is a distribution of T cells expressing liver tissue interleukin 17 (IL-17) and interferon gamma (IFN-γ) by β-guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention. is shown.
9 shows the distribution of monocytes in the liver by β-guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
이하, 본 발명의 바람직한 구현예에 대하여 상세히 설명한다. 또한, 하기의 설명에서는 구체적인 구성요소 등과 같은 많은 특정 사항들이 도시되어 있는데, 이는 본 발명의 보다 전반적인 이해를 돕기 위해서 제공된 것일 뿐 이러한 특정 사항들 없이도 본 발명이 실시될 수 있음은 이 기술분야에서 통상의 지식을 가진 자에게는 자명하다 할 것이다. 그리고, 본 발명을 설명함에 있어서, 관련된 공지 기능 혹은 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.Hereinafter, preferred embodiments of the present invention will be described in detail. In addition, in the following description, many specific details such as specific components are shown, which are provided to help a more general understanding of the present invention, and it is common in the art that the present invention can be practiced without these specific details. It will be self-evident to those who have the knowledge of And, in describing the present invention, if it is determined that a detailed description of a related known function or configuration may unnecessarily obscure the subject matter of the present invention, the detailed description will be omitted.
본 발명에서 용어, "예방" 또는 "방지"라 함은 질환의 원인으로부터 발생을 억제하거나 지연시키는 것을 의미한다.In the present invention, the term "prevention" or "prevention" means suppressing or delaying the occurrence of a disease from its cause.
본 명세서에서, "치료"라 함은 완전히 치유하지 않아도 증상의 진전 및/또는 악화를 억제하여 손상의 진행을 멈추거나, 또는 증상의 일부 혹은 전부를 개선하여 치유의 방향으로 유도하는 것을 의미한다.As used herein, "treatment" means to stop the progression of damage by suppressing the progression and/or deterioration of symptoms even if not completely cured, or to improve some or all of the symptoms and lead them in the direction of healing.
본 발명에서 용어 “개선”은 증상이 호전 또는 이롭게 변경되는 모든 행위를 의미한다.In the present invention, the term "improvement" refers to all activities that improve or beneficially change symptoms.
본 발명은 베타-구아니디노프로피온산(beta-guanidinopropionic acid, β-GPA)을 유효성분으로 포함하는 간섬유화 예방 또는 치료용 약학 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing or treating liver fibrosis comprising beta-guanidinopropionic acid (β-GPA) as an active ingredient.
본 발명의 일 예에서, 상기 베타-구아니디노프로피온산은 간조직 내에서 히드록시프롤린 및 알파 민무늬근육액틴 (alpha-smooth muscle actin) 단백질 발현을 감소시키는 것이고, 상기 베타-구아니디노프로피온산은 인터루킨 17 및 인터페론 감마의 발현을 감소시키는 것이며, 상기 베타-구아니디노프로피온산은 CD11b+Ly6C+ 단핵구의 분포를 감소시키는 것을 특징으로 하는 것이다.In one embodiment of the present invention, the beta-guanidinopropionic acid reduces the expression of hydroxyproline and alpha-smooth muscle actin proteins in liver tissue, and the beta-guanidinopropionic acid is an interleukin 17 and interferon gamma, and the beta-guanidinopropionic acid reduces the distribution of CD11b+Ly6C+ monocytes.
또한, 본 발명의 일 구현예에 따른 조성물에서, 상기 조성물은 간섬유화 예방 또는 치료에 유용한 추가 성분을 포함할 수 있고, 추가성분은 화합물, 천연물을 포함하는 간섬유화에 효과가 공지된 모든 성분을 포함할 수 있다.In addition, in the composition according to one embodiment of the present invention, the composition may include additional ingredients useful for preventing or treating liver fibrosis, and the additional ingredients include all ingredients known to be effective in liver fibrosis, including compounds and natural products. can include
본 발명의 조성물은 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함하여 모든 형태의 조성물로 제조될 수 있고, 바람직하게는 약학 조성물, 건강기능식품 조성물 또는 화장료 조성물의 형태로 제조될 수 있으나, 이에 제한되는 것은 아니다. The composition of the present invention may be prepared in any form of composition by further including appropriate carriers, excipients and diluents commonly used in the preparation of compositions, preferably in the form of pharmaceutical compositions, health functional food compositions or cosmetic compositions. It may be, but is not limited thereto.
본 발명의 약학 조성물은, 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제제화될 수 있으며, 산제, 정제, 캡슐제, 주사제 및 액제가 보다 바람직하다. 이러한 제제화는 약제학 분야에서 통상적으로 행하여지는 방법으로 수행될 수 있으며, Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다. The pharmaceutical composition of the present invention may be formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, and powders , tablets, capsules, injections and solutions are more preferred. Such formulation may be performed by a method commonly performed in the pharmaceutical field, and may be preferably formulated according to each disease or component using a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA.
상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 및 광물유 등을 포함한다.Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 추가로 사용하여 조제될 수 있다.When formulated, it may be prepared by additionally using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘카보네이트(calcium carbonate), 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
경구 투여를 위한 액상 제제로는 현탁액, 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. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween), 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included in addition to water and liquid paraffin, which are commonly used simple diluents. there is. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous agents and suspending agents. As the base of the suppository, witepsol, macrogol, tween, cacao butter, laurin paper, glycerogeratin and the like may be used.
본 발명의 약학 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서 본 발명의 약학 조성물은 1 일 0.01 내지 99.9 중량%, 바람직하게는 0.1 내지 99 중량%로 포함될 수 있다. 일일 투여량은 약 0.1 내지 1,000 mg/kg으로, 바람직하게는 100~300 mg/kg일 수 있다. The preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and body weight of the patient, the severity of the disease, the drug type, the route and duration of administration, but can be appropriately selected by those skilled in the art. However, for desirable effects, the pharmaceutical composition of the present invention may be included in an amount of 0.01 to 99.9% by weight, preferably 0.1 to 99% by weight per day. The daily dosage may be about 0.1 to 1,000 mg/kg, preferably 100 to 300 mg/kg.
또한, 또한, 본 발명은 베타-구아니디노프로피온산(beta-guanidinopropionic acid, β-GPA)을 유효성분으로 포함하는 간섬유화 예방 또는 개선용 식품 조성물을 제공한다. In addition, the present invention provides a food composition for preventing or improving liver fibrosis comprising beta-guanidinopropionic acid (β-GPA) as an active ingredient.
상기 조성물을 첨가할 수 있는 건강기능식품으로는 예를 들어, 각종 일반식품류, 음료, 껌, 차, 비타민 복합제 등이 있다.Health functional foods to which the composition can be added include, for example, various general foods, beverages, gum, tea, vitamin complexes, and the like.
또한, 상기 조성물은 질환의 예방 효과를 목적으로 식품 또는 음료에 첨가될 수 있다. 이때, 식품 또는 음료 중의 상기 추출물의 양은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 g을 기준으로 0.02 내지 5 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.In addition, the composition may be added to food or beverages for the purpose of preventing diseases. At this time, the amount of the extract in the food or beverage may be added at 0.01 to 15% by weight of the total food weight, and the health drink composition may be added at a rate of 0.02 to 5 g, preferably 0.3 to 1 g based on 100 g there is.
본 발명의 건강기능음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물을 함유하는 것 외에 다른 성분에는 특별한 제한이 없으며, 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등의 추가 성분을 함유할 수 있다. 상술한 천연탄수화물의 예로는 모노사카라이드, 예를 들어 포도당, 과당 등; 디사카라이드, 예를들어 말토오스, 수크로오스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 솔비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제인 타우마틴, 스테비아 추출물, 예를 들어 레바우디오시드 A, 글리시르히진 등; 및 합성 향미제, 예를 들어 사카린, 아스파르탐 등을 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다. 상기 외에 본 발명의 추출물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 및 천연 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 추출물들은 천연 과일 쥬스, 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이때, 첨가제의 비율은 그다지 중요하지는 않지만 본 발명의 조성물 100 중량부 당 0.01 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.The health functional beverage composition of the present invention is not particularly limited in other components other than containing the extract as an essential component in the indicated ratio, and may contain additional components such as various flavoring agents or natural carbohydrates like conventional beverages. there is. Examples of the aforementioned natural carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. Examples of flavoring agents other than those described above include natural flavoring agents such as thaumatin and stevia extracts such as rebaudioside A and glycyrrhizin; and synthetic flavoring agents such as saccharin, aspartame, and the like can advantageously be used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention. In addition to the above, the extract of the present invention is various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective Colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like may be contained. In addition, the extracts of the present invention may contain fruit flesh for the production of natural fruit juice, fruit juice beverages and vegetable beverages. These components may be used independently or in combination. At this time, the proportion of the additive is not particularly important, but is generally selected in the range of 0.01 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명의 다른 예에서, 본 발명은 베타-구아니디노프로피온산(beta-guanidinopropionic acid, β-GPA)을 투여하는 단계를 포함하는 인간을 제외한 개체에서 간섬유화 예방 또는 치료방법을 제공한다. In another embodiment of the present invention, the present invention provides a method for preventing or treating liver fibrosis in a non-human subject comprising administering beta-guanidinopropionic acid (β-GPA).
본 발명의 이점 및 특징, 그리고 그것들을 달성하는 방법은 상세하게 후술되어있는 실시예들을 참조하면 명확해질 것이다. 그러나 본 발명은 이하에서 개시되는 실시예들에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 것이며, 단지 본 실시예들은 본 발명의 개시가 완전하도록 하고, 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이며, 본 발명은 청구항의 범주에 의해 정의될 뿐이다.The advantages and features of the present invention, and how to achieve them, will become clear with reference to the detailed description of the following embodiments. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various different forms, and only the present embodiments will complete the disclosure of the present invention and allow common knowledge in the art to which the present invention belongs. It is provided to fully inform the holder of the scope of the invention, and the present invention is only defined by the scope of the claims.
<실시예: 실험방법> <Example: Experimental method>
6주령 C57BL/6J 수컷 생쥐 총 12마리에 정상식이 혹은 고지방고과당 식이 (Rodent Diets With 40 kcal% Fat (Palm Oil), 20 kcal% Fructose and 2% Cholesterol; D09100310 새론바이오)를 투여하였다. 고지방고과당 식이는 지방간염에 의한 간섬유화를 유도하기 위하여 사용되었다.A total of 12 6-week-old C57BL/6J male mice were fed either a normal diet or a high-fat, high-fructose diet (Rodent Diets With 40 kcal% Fat (Palm Oil), 20 kcal% Fructose and 2% Cholesterol; D09100310 Saeron Bio). A high-fat, high-fructose diet was used to induce liver fibrosis caused by steatohepatitis.
생쥐가 21주령이 되었을 때, 정상식이 그룹과 고지방고과당 식이 그룹에서 각각 식수에 beta-Guanidinopropanoic acid (cat no : BD9459; BLD pharmatech Ltd.) 2 중량%의 농도로 처리하고 일주일에 2회 씩 식수 통을 갈아주어 자유롭게 마실 수 있도록 하였다(도 2). 식수에 2% beta-Guanidinopropanoic acid를 총 12주간 지속하고 난 뒤에, 생쥐를 부검하여 혈액, 간조직을 채취하였다. 결과적으로 지방간염에 의한 간섬유화 유도를 위한 고지방고과당 식이 투여기간은 27주 이었고, 항섬유화 효과를 판정하기 위해 2% beta-Guanidinopropanoic acid를 총 12주간 투여하였다(도 2).When the mice were 21 weeks old, the normal diet group and the high-fat, high-fructose diet group were treated with beta-Guanidinopropanoic acid (cat no: BD9459; BLD pharmatech Ltd.) at a concentration of 2% by weight in drinking water, respectively, and drank twice a week. The barrel was changed so that it could be freely drunk (Fig. 2). After a total of 12 weeks of 2% beta-Guanidinopropanoic acid in drinking water, mice were necropsied and blood and liver tissue were collected. As a result, the administration period of the high-fat, high-fructose diet for the induction of hepatic fibrosis by steatohepatitis was 27 weeks, and 2% beta-Guanidinopropanoic acid was administered for a total of 12 weeks to determine the antifibrotic effect (FIG. 2).
실험에 사용한 그룹은 정상식이(정상식이-DW), 정상식이 + 2 중량% beta-Guanidinopropanoic acid가 포함된 식수(정상식이-β-GPA), 고지방고과당 식이(고지방/고과당식이-DW), 고지방고과당 식이 + beta-Guanidinopropanoic acid가 포함된 식수(고지방/고과당식이-β-GPA)를 투여한 군으로 분리하여 수행되었다(도 3).The groups used in the experiment were normal diet (normal diet-DW), normal diet + drinking water containing 2 wt% beta-Guanidinopropanoic acid (normal diet-β-GPA), and high-fat, high-fructose diet (high-fat/high-fructose diet-DW). , a high-fat high-fructose diet + beta-Guanidinopropanoic acid-containing drinking water (high-fat/high-fructose diet-β-GPA) was administered (Fig. 3).
매주 체중(도 3)과 식이 섭취량(도 4)을 측정하였고 간섬유화의 정도 평가를 위해 알파 민무늬근육액틴 (alpha-smooth muscle actin) 단백질 발현(도 6)과 간조직의 hydroxyproline의 양(도 5)을 평가하였다. 또한 간내 염증반응의 정량 평가를 위해 간내에 존재하는 면역세포의 분포와 활성을 유세포분석기술을 활용하여 평가하였다(도 7).Weekly weight (Fig. 3) and food intake (Fig. 4) were measured, and alpha-smooth muscle actin protein expression (Fig. 6) and the amount of hydroxyproline in liver tissue (Fig. 5) were evaluated to evaluate the degree of liver fibrosis. ) was evaluated. In addition, for quantitative evaluation of the intrahepatic inflammatory response, the distribution and activity of immune cells present in the liver were evaluated using flow cytometry (FIG. 7).
마우스 간조직을 collagenase로 digestion 한 후에, 40% Percoll (GE Healthcare, Buckingham, UK)을 활용하여 원심분리를 진행하였다. Cell pellet에 대하여 적혈구 제거 용액을 처리한 뒤에, Phosphate-buffered saline으로 희석하고 원심분리를 시행하여 간내에 존재하는 단핵세포를 얻었다. 이 세포들에 다양한 종류의 형광물질이 표지된 항체를 반응시켜서 유세포분석을 진행하였다.After digestion of mouse liver tissue with collagenase, centrifugation was performed using 40% Percoll (GE Healthcare, Buckingham, UK). After processing the red blood cell removal solution for the cell pellet, it was diluted with Phosphate-buffered saline and centrifuged to obtain mononuclear cells present in the liver. Flow cytometry was performed by reacting these cells with antibodies labeled with various types of fluorescent substances.
유세포분석에 활용된 항체: anti-CD3-PerCP-Cy5.5, anti-CD3-PE-Cy7, anti-CD4-AF700, anti-CD8-PE, anti-CD8-APC, anti-CD62L-APC, anti-CD44-FITC, anti-CD11b-PerCP-Cy5.5, anti-Ly6C-FITC, anti-IFN-γ-APC, anti-IL-17A-APC, fixable viability dye-APC-Cy7 (all supplied by eBioscience, San Diego, CA, USA)Antibodies used for flow cytometry: anti-CD3-PerCP-Cy5.5, anti-CD3-PE-Cy7, anti-CD4-AF700, anti-CD8-PE, anti-CD8-APC, anti-CD62L-APC, anti -CD44-FITC, anti-CD11b-PerCP-Cy5.5, anti-Ly6C-FITC, anti-IFN-γ-APC, anti-IL-17A-APC, fixable viability dye-APC-Cy7 (all supplied by eBioscience, San Diego, CA, USA)
<시험예: 결과> <Test Example: Results>
정상식이, 고지방고과당 식이 그룹 모두에서 beta-Guanidinopropanoic acid에 의하여 현저한 체중감소를 나타내었다(도 3).In both the normal diet and high-fat, high-fructose diet groups, significant weight loss was shown by beta-Guanidinopropanoic acid (FIG. 3).
정상식이, 고지방고과당 식이 그룹 모두에서 beta-Guanidinopropanoic acid는 마우스 사료 섭취에 영향을 주지 않았다(도 4).In both the normal diet and high-fat, high-fructose diet groups, beta-Guanidinopropanoic acid did not affect mouse feed intake (FIG. 4).
beta-Guanidinopropanoic acid는 고지방고과당 식이 그룹에서 현저한 간조직 hydroxyproline의 감소를 유도하였다(도 5). 이 결과는 beta-Guanidinopropanoic acid가 간섬유화 억제기능을 가지고 있다는 것을 시사하는 결과이다.Beta-Guanidinopropanoic acid induced a significant decrease in liver tissue hydroxyproline in the high-fat, high-fructose diet group (FIG. 5). This result suggests that beta-Guanidinopropanoic acid has the function of inhibiting liver fibrosis.
간섬유화의 정도를 대변하는 단백질인 알파 민무늬근육액틴의 발현이 beta-Guanidinopropanoic acid 처리 그룹에서 유의미하게 감소하였다(도 6).The expression of alpha-smooth muscle actin, a protein representing the degree of hepatic fibrosis, was significantly decreased in the beta-Guanidinopropanoic acid-treated group (FIG. 6).
정상식이에 비하여 고지방고과당 식이 처리 그룹은 간조직 기억 CD4+, CD8+ T세포가 증가하는데 반해 미접촉 CD4+, CD8+ T세포는 감소하는 경향을 나타내었다(도 7). 이 결과는 beta-Guanidinopropanoic acid를 처리하면 간조직 기억 CD4+, CD8+ T세포의 감소와 미접촉 CD4+, CD8+ T세포의 증가를 유도하여 간내 염증 반응 감소에 기여하는 것을 나타내는 것이다. Compared to the normal diet, in the group treated with the high-fat, high-fructose diet, liver tissue memory CD4+ and CD8+ T cells increased, whereas non-contact CD4+ and CD8+ T cells decreased (FIG. 7). These results indicate that treatment with beta-Guanidinopropanoic acid contributes to the reduction of the hepatic inflammatory response by inducing a decrease in hepatic tissue memory CD4+ and CD8+ T cells and an increase in non-contact CD4+ and CD8+ T cells.
고지방고과당 식이를 처리하면 간내 CD4+ T세포에서 인터루킨 17 및 인터페론 감마의 발현양이 증가하였고, beta-Guanidinopropanoic acid를 처리하면 간내 CD4+ T세포에서 인터루킨 17 및 인터페론 감마의 발현 정도가 현저히 감소하였다(도 8). 이 결과는 beta-Guanidinopropanoic acid가 간내 염증반응을 유도하는 염증성 사이토카인 (인터루킨 17, 인터페론 감마)을 감소시켜 결과적으로 도 5 및 도 6에서 나타난 섬유화의 감소를 유도했다는 것을 시사하는 것이다.Treatment with a high-fat, high-fructose diet increased the expression of interleukin 17 and interferon gamma in intrahepatic CD4+ T cells, and treatment with beta-Guanidinopropanoic acid markedly decreased the expression of interleukin 17 and interferon gamma in intrahepatic CD4+ T cells (Fig. 8). This result suggests that beta-Guanidinopropanoic acid reduced inflammatory cytokines (interleukin 17, interferon gamma) inducing an intrahepatic inflammatory response, resulting in a reduction in fibrosis shown in FIGS. 5 and 6 .
CD11b+Ly6C+를 나타내는 단핵구(monocyte)는 고지방고과당 식이에 의한 지방간염/간섬유화에서 증가하는 경향을 보였고, beta-Guanidinopropanoic acid는 CD11b+Ly6C+ 단핵구의 분포를 감소시켰다(도 9). 이는 간내 염증반응 감소 및 섬유화 억제에 기여했을 것을 시사하는 것이다.Monocytes expressing CD11b+Ly6C+ tended to increase in steatohepatitis/hepatic fibrosis caused by the high-fat, high-fructose diet, and beta-Guanidinopropanoic acid reduced the distribution of CD11b+Ly6C+ monocytes (FIG. 9). This suggests that it may have contributed to reducing the inflammatory response in the liver and inhibiting fibrosis.
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