KR102232072B1 - A Composition for Preventing or Treating Dermal Fibrosis Comprising Ethyl Pyruvate as an Active Ingredient - Google Patents
A Composition for Preventing or Treating Dermal Fibrosis Comprising Ethyl Pyruvate as an Active Ingredient Download PDFInfo
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- KR102232072B1 KR102232072B1 KR1020190053800A KR20190053800A KR102232072B1 KR 102232072 B1 KR102232072 B1 KR 102232072B1 KR 1020190053800 A KR1020190053800 A KR 1020190053800A KR 20190053800 A KR20190053800 A KR 20190053800A KR 102232072 B1 KR102232072 B1 KR 102232072B1
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Abstract
본 발명은 피부 섬유증(dermal fibrosis)의 예방 또는 치료용 약제학적 조성물, 피부 섬유증의 개선용 화장료 조성물 및 피부 섬유증의 예방 또는 치료용 조성물의 스크리닝 방법에 관한 것이다. 본 발명은 피부 섬유화를 원인으로 하는 켈로이드 등의 질환에 대해 섬유화의 진행 자체를 억제함으로써 근원적인 병인을 제거하는 효과적인 치료제로 유용하게 이용될 수 있다.The present invention relates to a pharmaceutical composition for preventing or treating skin fibrosis, a cosmetic composition for improving skin fibrosis, and a method for screening a composition for preventing or treating skin fibrosis. The present invention can be usefully used as an effective therapeutic agent for removing the underlying etiology by inhibiting the progression of fibrosis itself for diseases such as keloids caused by skin fibrosis.
Description
본 발명은 에틸 피루베이트를 유효성분으로 포함하는 피부 섬유증, 구체적으로는 켈로이드성 피부 섬유증의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating skin fibrosis, specifically, keloid skin fibrosis, comprising ethyl pyruvate as an active ingredient.
비정상적인 피부 섬유화에 이르는 섬유증식성(fibroproliferative) 양성 종양인 켈로이드는 콜라겐 섬유가 주성분인 ECM(extracellular matrix)의 과다한 축적으로 특징지워질 수 있다. 대게 이들 종양은 인접한 정상 조직에 침투하며 자발적으로 쇠퇴하는 경우가 거의 없다1. 최근, 켈로이드의 생성에 영향을 미치는 몇몇 매개체에 대한 관심이 증가하고 있음에도 이들의 메카니즘에 대한 명확한 이해는 이루어지지 않고 있다. 켈로이드성 섬유아세포(keloidal fibroblast: KF)의 과다 증식으로 인한 ECM의 과량 축적이 가장 잘 알려진 켈로이드 발달의 원인이다2-7. 따라서, 일반적으로 켈로이드성 섬유아세포의 증식률 증가 및 사멸률 감소가 켈로이드 형성의 원인으로 추정되고 있다8-10. 이에, 켈로이드성 섬유아세포의 증식을 억제하거나 병적인 섬유증을 되돌림으로써 적절한 치료가 이루어질 수 있다. A keloid, a fibroproliferative benign tumor leading to abnormal skin fibrosis, can be characterized by an excessive accumulation of the extracellular matrix (ECM), whose main component is collagen fibers. Usually, these tumors infiltrate adjacent normal tissues and rarely decay spontaneously 1 . Recently, although interest in several mediators that influence the formation of keloids is increasing, a clear understanding of their mechanisms has not been achieved. Excessive accumulation of ECM due to overproliferation of keloidal fibroblasts (KF) is the most well-known cause of keloid development 2-7 . Therefore, it is generally assumed that keloidal fibroblasts increase in proliferation and decrease in mortality as the cause of keloid formation 8-10 . Accordingly, appropriate treatment can be achieved by inhibiting the proliferation of keloid fibroblasts or reversing pathological fibrosis.
오토파지는 라이소좀 분해를 통한 세포 구성성분의 분해를 수반하는 매우 보존적인 세포사멸 과정이다. 이는 불필요하거나 손상된 세포 구성성분을 분해함으로써 세포 항상성을 유지하는데 기여한다11. 특히, 오토파지는 영양결핍, 장기 염증, 저산소 또는 항암 치료와 같은 세포 스트레스에 대한 적응성 생존 메카니즘으로 간주되어 왔다. 이에, 오토파지는 내부 기관의 섬유화, 조직 재형성 및 신경퇴행질환과 같은 다양한 인간 병태생리학과 관련되어 있다12. 스트레스 하에서의 세포 항상성 측면에서 오토파지의 중요성에 대한 많은 연구가 있었으나, 켈로이드 형성과 같은 병적인 피부 섬유증에서 오토파지의 작용에 대해서는 아직 연구된 바가 없다. 오토파지는 스트레스 상황 하에서도 세포의 생존성을 향상시키므로, 켈로이드에서의 세포사멸 감소가 켈로이드성 섬유아세포의 증식과 관련이 있을 것이라고 예측되었다. 이에, 본 발명자들이 첫 번째로 확인하고자 하는 것은 켈로이드에서 오토파지 활성이 변화하는지 여부였다.Autophagy is a very conservative apoptosis process that involves the degradation of cellular components through lysosome degradation. This contributes to maintaining cell homeostasis by breaking down unnecessary or damaged cellular components 11 . In particular, autophagy has been regarded as an adaptive survival mechanism to cellular stress such as malnutrition, long-term inflammation, hypoxia or chemotherapy. Thus, autophagy is associated with various human pathophysiology such as fibrosis of internal organs, tissue remodeling, and neurodegenerative diseases 12 . There have been many studies on the importance of autophagy in terms of cellular homeostasis under stress, but the action of autophagy in pathological skin fibrosis such as keloid formation has not been studied yet. Since autophagy improves cell viability even under stress conditions, it was predicted that the reduction of apoptosis in keloids may be related to the proliferation of keloid fibroblasts. Thus, the first thing the present inventors want to check was whether or not the autophagy activity changes in keloids.
HMGB1(High-mobility group box 1)은 DNA 복제, 재조합, 전사 및 수리에 관여하는 DNA 샤페론의 기능을 하는 유비쿼터스 핵단백질이다. 세포가 활성화되거나 손상되면, HMGB1는 핵 밖으로 이동하여 세포질이나 세포 외 공간으로 분비된다. 오토파지와 염증이 촉진되면서 HMGB1가 과발현되면 세포증식, 이동성, 혈관신생 및 세포사멸에 대한 저항성이 증가하게 된다13-17. 이에, 세포 외부의 HMGB1는 염증반응을 활성화하고 세포의 증식, 분화 및 이동을 촉진하는 DAMP(damage-associated molecular pattern) 단백질로 작용한다18. 세포질 HMGB1 및 세포외 HMGB1 모두 세포 스트레스에 대한 반응으로서 오토파지 활성을 증진시키기 때문에 HMGB1는 오토파지에 대한 핵심 조절자로 간주된다17,19. 핵 외부의 HMGB1가 오토파지를 유도함으로써 스트레스 상황에서 세포생존을 증진시키기 때문에, 본 발명자들은 HMGB1가 세포사멸 과정을 조절함으로써 켈로이드 발병에 관여하는지, 또한 오토파지 활성을 억제하면서 세포사멸을 유도하면 켈로이드에 대한 치료효과가 발휘될 수 있을지를 확인하고자 하였다.HMGB1 (High-mobility group box 1) is a ubiquitous nuclear protein that functions as a DNA chaperone involved in DNA replication, recombination, transcription and repair. When cells are activated or damaged, HMGB1 migrates outside the nucleus and is secreted into the cytoplasm or extracellular space. When HMGB1 is overexpressed as autophagy and inflammation are promoted, cell proliferation, mobility, angiogenesis, and resistance to apoptosis are increased 13-17 . Thus, HMGB1 outside the cell acts as a damage-associated molecular pattern (DAMP) protein that activates the inflammatory response and promotes cell proliferation, differentiation, and migration 18 . HMGB1 is considered a key regulator of autophagy because both cytoplasmic HMGB1 and extracellular HMGB1 enhance autophage activity in response to cellular stress 17,19 . Since HMGB1 outside the nucleus induces autophagy to promote cell survival in a stressful situation, the present inventors argue that HMGB1 is involved in the onset of keloids by regulating the apoptosis process, and induces apoptosis while inhibiting autophage activity. It was attempted to confirm whether the therapeutic effect of
피루브산에서 변형된 에틸 피루베이트는 HMGB1에 직접적으로 영향을 미쳐 세포외 공간에서의 화학주성 및 세포분열 활성을 억제하며, 나아가 HMGB1이 세포질로 이동하는 것을 막는다20.Ethyl pyruvate modified from pyruvic acid directly affects HMGB1, inhibits chemotaxis and cytokinetic activity in the extracellular space, and further prevents HMGB1 from migrating to the cytoplasm 20 .
본 발명자들은 섬유화를 조절하는 과정에서 켈로이드의 오토파지 활성 및 HMGB1의 관여에 주목하였으며, HMGB1의 강력한 억제자인 에틸 피루베이트가 유망한 켈로이드 치료제로 적용될 수 있음을 발견하였다.The present inventors paid attention to the autophagy activity of keloids and the involvement of HMGB1 in the process of controlling fibrosis, and found that ethyl pyruvate, a potent inhibitor of HMGB1, could be applied as a promising keloid treatment.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.Throughout this specification, a number of papers and patent documents are referenced and citations are indicated. The disclosure contents of the cited papers and patent documents are incorporated by reference in this specification as a whole, and the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly described.
본 발명자들은 피부조직에서 발생하는 섬유증식성 병변에 대해 외과적 수술, 방사선 치료 및 국소 스테로이드 주사법과 같은 피상적이고 대증적인 치료에서 벗어나 질환의 진행 메카니즘 자체를 차단하는 근원적 치료방법을 개발하기 위하여 예의 연구 노력하였다. 그 결과, 상기 화학식 1의 화합물을 약리성분으로 이용할 경우 피부 섬유아세포의 증식을 억제하고 섬유생성 조절인자들의 발현을 저해하여 섬유화의 진행이 차단된다는 것을 발견함으로써, 본 발명을 완성하게 되었다.The present inventors have made extensive research efforts to develop a fundamental treatment method that blocks the mechanism of progression of the disease itself away from superficial and symptomatic treatments such as surgical operation, radiation therapy, and local steroid injection for fibroproliferative lesions occurring in skin tissue. I did. As a result, when the compound of Formula 1 was used as a pharmacological component, it was found that the proliferation of skin fibroblasts was inhibited and the expression of fibrosis regulators was inhibited, thereby preventing the progression of fibrosis, thereby completing the present invention.
따라서 본 발명의 목적은 피부 섬유증(dermal fibrosis)의 예방 또는 치료용 약제학적 조성물을 제공하는 데 있다.Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating dermal fibrosis.
본 발명의 다른 목적은 피부 섬유증의 예방 또는 치료용 조성물의 스크리닝 방법을 제공하는 데 있다.Another object of the present invention is to provide a method for screening a composition for preventing or treating skin fibrosis.
본 발명의 또 다른 목적은 피부 섬유증의 개선용 화장료 조성물을 제공하는 데 있다.Another object of the present invention is to provide a cosmetic composition for improving skin fibrosis.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become more apparent by the following detailed description, claims and drawings.
본 발명의 일 양태에 따르면, 본 발명은 다음의 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는 피부 섬유증(dermal fibrosis)의 예방 또는 치료용 약제학적 조성물을 제공한다:According to one aspect of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of skin fibrosis comprising a compound represented by the following
화학식 1
상기 화학식에서, R1 및 R2는 각각 독립적으로 C1-C3 알킬이다.In the above formula, R 1 and R 2 are each independently C 1 -C 3 alkyl.
본 발명자들은 피부조직에서 발생하는 섬유증식성 병변에 대해 외과적 수술, 방사선 치료 및 국소 스테로이드 주사법과 같은 피상적이고 대증적인 치료에서 벗어나 질환의 진행 메카니즘 자체를 차단하는 근원적 치료방법을 개발하기 위하여 예의 연구 노력하였다. 그 결과, 상기 화학식 1의 화합물을 약리성분으로 이용할 경우 피부 섬유아세포의 증식을 억제하고 섬유생성 조절인자들의 발현을 저해하여 섬유화의 진행이 차단된다는 것을 발견함으로써, 본 발명을 완성하게 되었다.The present inventors have made extensive research efforts to develop a fundamental treatment method that blocks the mechanism of progression of the disease itself away from superficial and symptomatic treatments such as surgical operation, radiation therapy, and local steroid injection for fibroproliferative lesions occurring in skin tissue. I did. As a result, when the compound of Formula 1 was used as a pharmacological component, it was found that the proliferation of skin fibroblasts was inhibited and the expression of fibrosis regulators was inhibited, thereby preventing the progression of fibrosis, thereby completing the present invention.
본 발명에서 용어“피부 섬유증(dermal fibrosis)”은 피부조직 내 과도한 섬유성 연결조직이 형성되어 피부의 정상적인 구조와 기능이 손상되는 병적 상태를 의미한다. 피부 섬유증은 콜라겐 섬유를 주성분으로 하는 세포외 기질(ECM)의 과잉 축적으로 피부 조직이 딱딱해지거나 반흔이 형성되는 만성적 및 진행성 질환인데, 이는 복잡한 세포, 세포외 기질, 시토카인 및 성장 인자의 상호 작용을 통해 발달하며, 피부 섬유아세포의 증식률 증가 및 사멸률 감소를 수반한다. 따라서, 이의 병인(pathogenesis)을 제거하기 위해서는 섬유아세포의 증식 및 섬유 생성이 차단되어야 한다. In the present invention, the term "dermal fibrosis" refers to a pathological condition in which excessive fibrous connective tissue is formed in the skin tissue, thereby impairing the normal structure and function of the skin. Skin fibrosis is a chronic and progressive disease in which skin tissue hardens or scars are formed due to excessive accumulation of extracellular matrix (ECM), which is mainly composed of collagen fibers.It is the interaction of complex cells, extracellular matrix, cytokines, and growth factors. It develops through, and is accompanied by an increase in the proliferation rate of skin fibroblasts and a decrease in the mortality rate. Therefore, in order to eliminate its pathogenesis, fibroblast proliferation and fiber production must be blocked.
본 명세서에서 용어“알킬”은 직쇄 또는 분쇄의 포화 탄화수소기를 의미하며, C1-C3 알킬은 탄소수 1 내지 3의 알킬 유니트를 가지는 알킬기를 의미하며, C1-C3 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. In the present specification, the term “alkyl” refers to a linear or branched saturated hydrocarbon group, and C 1 -C 3 alkyl refers to an alkyl group having an alkyl unit having 1 to 3 carbon atoms, and when C 1 -C 3 alkyl is substituted, a substituent The carbon number of is not included.
본 발명의 구체적인 구현예에 따르면, 상기 화학식 1의 R1은 C1 알킬이고, R2는 C2 알킬이다. R1이 C1 알킬(메틸)이고 R2가 C2 알킬(에틸)인 화학식 1 화합물은 에틸 피부베이트(ethyl pyruvate, C5H8O3)이다.According to a specific embodiment of the present invention, R 1 in
본 명세서에서 용어“예방”은 질환 또는 질병을 보유하고 있다고 진단된 적은 없으나, 이러한 질환 또는 질병에 걸릴 가능성이 있는 대상체에서 질환 또는 질병의 발생을 억제하는 것을 의미한다. In the present specification, the term "prevention" has not been diagnosed as having a disease or disease, but refers to suppressing the occurrence of a disease or disease in a subject who is likely to have such a disease or disease.
본 명세서에서 용어“치료”는 (a) 질환, 질병 또는 증상의 발전의 억제; (b) 질환, 질병 또는 증상의 경감; 또는 (c) 질환, 질병 또는 증상을 제거하는 것을 의미한다. 본 발명의 조성물이 대상체에 투여되면 피부 섬유아세포의 증식 및 섬유생성 인자의 발현을 억제함으로써 피부에서의 과도한 섬유성 조직 생성을 개선시켜 증상의 발전을 억제하거나, 이를 제거하거나 또는 경감시키는 역할을 한다. 따라서, 본 발명의 조성물은 그 자체로 이들 질환 치료의 조성물이 될 수도 있고, 혹은 다른 약리성분과 함께 투여되어 상기 질환에 대한 치료 보조제로 적용될 수도 있다. 이에, 본 명세서에서 용어“치료”또는“치료제”는“치료 보조”또는“치료 보조제”의 의미를 포함한다. As used herein, the term “treatment” refers to (a) inhibition of the development of a disease, disease or condition; (b) alleviation of the disease, disease or condition; Or (c) to eliminate the disease, disease or condition. When the composition of the present invention is administered to a subject, it serves to suppress the development of symptoms by suppressing the proliferation of skin fibroblasts and the expression of fibroblasts and the expression of fibroblasts, thereby improving excessive fibrous tissue production in the skin, thereby inhibiting the development of symptoms, eliminating or alleviating them . Accordingly, the composition of the present invention may itself be a composition for treating these diseases, or may be administered together with other pharmacological ingredients and applied as a therapeutic adjuvant for the disease. Accordingly, the term "treatment" or "therapeutic agent" as used herein includes the meaning of "treatment aid" or "treatment aid".
본 명세서에서 용어“투여”또는“투여하다”는 본 발명의 조성물의 치료적 유효량을 대상체에 직접적으로 투여함으로써 대상체의 체내에서 동일한 양이 형성되도록 하는 것을 말한다.In the present specification, the term “administration” or “administer” refers to a therapeutically effective amount of the composition of the present invention being directly administered to a subject so that the same amount is formed in the subject's body.
본 발명에서 용어“치료적 유효량”은 본 발명의 약제학적 조성물을 투여하고자 하는 개체에게 조성물 내의 약리성분(예를 들어 에틸 피루베이트)이 치료적 또는 예방적 효과를 제공하기에 충분한 정도로 함유된 조성물의 함량을 의미하며, 이에“예방적 유효량”을 포함하는 의미이다. In the present invention, the term "therapeutically effective amount" refers to a composition containing a pharmacological component (for example, ethyl pyruvate) in the composition to an individual who intends to administer the pharmaceutical composition of the present invention to an extent sufficient to provide a therapeutic or prophylactic effect. It means the content of, and is meant to include "prophylactically effective amount".
본 명세서에서 용어“투여”또는“투여하다”는 본 발명의 조성물의 유효량을 대상체에 직접적으로 투여함으로써 대상체의 체내에서 동일한 양이 형성되도록 하는 것을 말한다.In the present specification, the term “administration” or “administer” refers to direct administration of an effective amount of the composition of the present invention to a subject so that the same amount is formed in the subject's body.
본 명세서에서 용어“대상체”는 제한없이 인간, 마우스, 래트, 기니아 피그, 개, 고양이, 말, 소, 돼지, 원숭이, 침팬지, 비비 또는 붉은털 원숭이를 포함한다. 구체적으로는, 본 발명의 대상체는 인간이다. As used herein, the term “subject” includes, without limitation, humans, mice, rats, guinea pigs, dogs, cats, horses, cows, pigs, monkeys, chimpanzees, baboons, or rhesus monkeys. Specifically, the subject of the present invention is a human.
본 발명의 구체적인 구현예에 따르면, 본 발명의 조성물로 예방 또는 치료되는 상기 피부 섬유증은 켈로이드성 피부 섬유증이다.According to a specific embodiment of the present invention, the skin fibrosis prevented or treated with the composition of the present invention is keloid skin fibrosis.
본 명세서에서 용어“켈로이드성 피부 섬유증(keloidal dermal fibrosis)”는 비정상적 피부 섬유화로 형성된 섬유증식성(fibroproliferative) 양성 종양을 의미하며, 켈로이드(keloid)라고도 불리운다.In the present specification, the term "keloidal dermal fibrosis" refers to a fibroproliferative benign tumor formed by abnormal skin fibrosis, and is also called a keloid.
본 발명의 구체적인 구현예에 따르면, 본 발명의 조성물은 피부 섬유아세포에서 HMGB1의 발현을 감소시킨다.According to a specific embodiment of the present invention, the composition of the present invention reduces the expression of HMGB1 in skin fibroblasts.
본 발명에 따르면, 본 발명의 조성물은 다양한 농도에서 피부 섬유아세포 및 켈로이드의 HMGB1 발현량을 유의하게 감소시킴으로써, 켈로이드의 세포 생존성을 감소시킨다. According to the present invention, the composition of the present invention significantly reduces the expression level of HMGB1 in skin fibroblasts and keloids at various concentrations, thereby reducing cell viability of keloids.
본 명세서에서 용어“발현의 감소”는 피부 섬유아세포 및 켈로이드에서 병적인 섬유화가 중단되거나 경감 또는 개선되거나 혹은 그 위험이 감소할 정도로, 섬유화의 지표 또는 원인이 되는 단백질 또는 유전자(예를 들어 HMGB1)의 발현량이 감소하는 것을 의미한다. 구체적으로는 대조군에 비하여 발현량이 15% 이상 감소한 상태, 보다 구체적으로는 20% 이상 감소한 상태, 더욱 구체적으로는 30% 이상 감소한 상태를 의미할 수 있다.As used herein, the term "reduction in expression" refers to a protein or gene (eg HMGB1) that is an indicator or cause of fibrosis to the extent that pathological fibrosis in skin fibroblasts and keloids is stopped, alleviated or improved, or the risk thereof is reduced. It means that the expression level of is decreased. Specifically, it may mean a state in which the expression level is reduced by 15% or more, more specifically, by 20% or more, and more specifically, by 30% or more compared to the control group.
본 발명의 구체적인 구현예에 따르면, 본 발명의 조성물은 피부 섬유아세포에서 콜라겐 I, 콜라겐 Ⅲ, 피브로넥틴 및 엘라스틴으로 구성된 군으로부터 선택되는 1개 이상의 단백질의 발현을 감소시킨다.According to a specific embodiment of the present invention, the composition of the present invention reduces the expression of one or more proteins selected from the group consisting of collagen I, collagen III, fibronectin and elastin in skin fibroblasts.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함한다.When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.
본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used at the time of formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. It does not become. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물은 경구 또는 비경구 투여할 수 있으며, 구체적으로는 비경구 방식으로 투여되고, 보다 구체적으로는 피하 또는 경피 투여될 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally, specifically administered in a parenteral manner, and more specifically administered subcutaneously or transdermally.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물의 바람직한 투여량은 성인 기준으로 0.001-100 ㎎/kg 범위 내이다.The appropriate dosage of the pharmaceutical composition of the present invention is prescribed in various ways depending on factors such as formulation method, administration mode, age, weight, sex, pathological condition, food, administration time, route of administration, excretion rate and response sensitivity. Can be. A preferred dosage of the pharmaceutical composition of the present invention is in the range of 0.001-100 mg/kg on an adult basis.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person having ordinary knowledge in the art. Or it can be prepared by incorporating it into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, syrup, or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, powder, granule, tablet or capsule, and may additionally include a dispersant or a stabilizer.
본 발명의 다른 양태에 따르면, 본 발명은 다음의 단계를 포함하는 피부 섬유증(dermal fibrosis)의 예방 또는 치료용 조성물의 스크리닝 방법을 제공한다:According to another aspect of the present invention, the present invention provides a method for screening a composition for preventing or treating dermal fibrosis comprising the following steps:
(1) 피부 섬유아세포를 포함하는 생물학적 시료에 시험물질을 접촉시키는 단계; (1) contacting a test substance with a biological sample including skin fibroblasts;
(2) 상기 시료 내 HMGB1의 활성 또는 발현량을 측정하는 단계, (2) measuring the activity or expression level of HMGB1 in the sample,
상기 HMGB1의 활성 또는 발현량이 감소한 경우, 상기 시험물질을 피부 섬유증의 예방 또는 치료용 조성물로 판정한다. When the activity or expression level of HMGB1 decreases, the test substance is determined as a composition for preventing or treating skin fibrosis.
켈로이드와 같이 피부 조직에서 발생하는 섬유화 질환을 치료함에 있어 HMGB1이 치료타겟이 될 수 있음은 아직까지 알려진 바가 없다. 본 발명에 따르면, 본 발명자들은 섬유화된 피부 조직에서 HMGB1이 고발현되며, 이의 발현을 저해할 경우 피부 섬유증이 치료될 수 있음을 처음으로 발견하였다. In the treatment of fibrotic diseases that occur in skin tissues such as keloids, it has not been known that HMGB1 can be a therapeutic target. According to the present invention, the present inventors have discovered for the first time that HMGB1 is highly expressed in fibrotic skin tissue, and if the expression thereof is inhibited, skin fibrosis can be cured.
본 발명의 스크리닝 방법에 따르면, 우선 피부 섬유아세포를 포함하는 생물학적 시료에 시험물질을 접촉시킨다. 본 발명에서 용어“생물학적 시료”는 인간을 포함한 포유동물로부터 얻어지는, 피부 섬유아세포를 포함하고 있는 모든 시료로서, 조직, 기관, 세포 또는 세포 배양액을 포함하나, 이에 제한되지 않는다.According to the screening method of the present invention, first, a test substance is brought into contact with a biological sample containing skin fibroblasts. In the present invention, the term "biological sample" is all samples including skin fibroblasts obtained from mammals including humans, and includes, but is not limited to, tissues, organs, cells, or cell culture fluids.
본 발명의 스크리닝 방법을 언급하면서 사용되는 용어“시험물질”은 HMGB1의 활성이나 발현량에 유전자 또는 단백질 수준에서 영향을 미치는지 여부를 검사하기 위하여 스크리닝에서 이용되는 미지의 물질을 의미한다. 상기 시험물질은 화합물, 뉴클레오타이드, 항체, 안티센스-RNA, siRNA(small interference RNA) 및 천연물 추출물을 포함하나, 이에 제한되는 것은 아니다. 이어, 시험물질을 처리한 생물학적 시료에서 HMGB1의 발현량 또는 활성을 측정하는데, 발현량의 측정은 당업계에 공지된 다양한 면역분석(immunoassay) 방법 또는 서열이 알려진 유전자를 타겟으로 통상적으로 설계된 프라이머 또는 프로브를 이용한 다양한 유전자 검출방법을 통해 이루어질 수 있다. 측정 결과, HMGB1의 발현량 또는 활성이 감소하는 경우 상기 시험물질은 피부 섬유증의 예방 또는 치료용 조성물로 판정될 수 있다.The term "test substance" used while referring to the screening method of the present invention means an unknown substance used in screening to examine whether the activity or expression level of HMGB1 has an effect at the gene or protein level. The test substance includes, but is not limited to, a compound, a nucleotide, an antibody, an antisense-RNA, a small interference RNA (siRNA), and a natural product extract. Next, the expression level or activity of HMGB1 is measured in the biological sample treated with the test substance, and the expression level is measured by various immunoassay methods known in the art or a primer or a commonly designed primer targeting a gene whose sequence is known. It can be achieved through a variety of gene detection methods using probes. As a result of the measurement, when the expression level or activity of HMGB1 decreases, the test substance may be determined as a composition for preventing or treating skin fibrosis.
본 발명의 또 다른 양태에 따르면, 본 발명은 다음의 화학식 1로 표시되는 화합물 또는 이의 화장품학적으로 허용되는 염을 유효성분으로 포함하는 피부 섬유증(dermal fibrosis)의 개선용 화장료 조성물을 제공한다:According to another aspect of the present invention, the present invention provides a cosmetic composition for improving dermal fibrosis comprising a compound represented by the following
화학식 1
상기 화학식에서, R1 및 R2는 각각 독립적으로 C1-C3 알킬이다.In the above formula, R 1 and R 2 are each independently C 1 -C 3 alkyl.
본 발명의 화학식 1 화합물 및 이를 통해 치료 또는 개선될 수 있는 피부 섬유증에 대해서는 이미 상술하였으므로, 과도한 중복을 피하기 위해 그 기재를 생략한다. Since the compound of the present invention and skin fibrosis that can be treated or ameliorated through the compound of the present invention have already been described above, description thereof will be omitted to avoid excessive redundancy.
본 발명의 화장료 조성물에 포함되는 성분은 유효 성분으로서의 상기 화학식 1 화합물 또는 이의 가수분해 산물 이외에 화장품 조성물에 통상적으로 이용되는 성분들을 포함하며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함한다.Ingredients included in the cosmetic composition of the present invention include ingredients commonly used in cosmetic compositions in addition to the compound of
본 발명의 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다.The cosmetic composition of the present invention may be prepared in any formulation conventionally prepared in the art, for example, solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing , Oil, powder foundation, emulsion foundation, wax foundation, and may be formulated as a spray, but is not limited thereto.
본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide may be used as a carrier component. I can.
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component. In particular, in the case of a spray, additionally chlorofluorohydrocarbon, propane / May contain propellants such as butane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.When the formulation of the present invention is a solution or emulsion, a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, an ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, and crystallites Sex cellulose, aluminum metahydroxide, bentonite, agar or tracanth, and the like can be used.
본 발명의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 라놀린 유도체 또는 에톡실화 글리세롤지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is a surfactant containing cleansing, as a carrier component, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters may be used.
본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 피부 섬유증(dermal fibrosis)의 예방 또는 치료용 약제학적 조성물 및 피부 섬유증의 개선용 화장료 조성물을 제공한다.(a) The present invention provides a pharmaceutical composition for preventing or treating skin fibrosis and a cosmetic composition for improving skin fibrosis.
(b) 본 발명은 또한 피부 섬유증의 예방 또는 치료용 조성물의 스크리닝 방법을 제공한다.(b) The present invention also provides a method for screening a composition for preventing or treating skin fibrosis.
(c) 본 발명은 피부 섬유화를 원인으로 하는 켈로이드 등의 질환에 대해 섬유화의 진행 자체를 억제함으로써 근원적인 병인을 제거하는 효과적인 치료제로 유용하게 이용될 수 있다.(c) The present invention can be usefully used as an effective therapeutic agent for removing the underlying etiology by inhibiting the progression of fibrosis itself against diseases such as keloids caused by skin fibrosis.
도 1은 에틸 피루베이트가 인간 정상 피부 섬유아세포(HDF)에 미치는 영향을 보여주는 그림으로, MTT 세포증식 어세이 결과 에틸 피루베이트가 HDF의 증식을 유의하게 억제하였음이 확인되었다.
도 2는 에틸 피루베이트가 켈로이드성 섬유아세포(KF)에 미치는 영향을 보여주는 그림으로, MTT 세포증식 어세이 결과 에틸 피루베이트가 KF의 증식을 유의하게 억제하였음이 확인되었다.
도 3은 에틸 피루베이트가 켈로이드 스페로이드에서의 HMGB1 발현에 미치는 영향을 보여주는 그림이다. 켈로이드 스페로이드에서 HMGB1를 동정하기 위해 웨스턴 블롯을 수행한 결과, 에틸 피루베이트를 첨가한 후 켈로이드 스페로이드에서 HMGB1 밀도가 눈에 띄게 감소하였음을 확인하였다(도 3a). 반정량적 분석(semi-quantitative analysis) 결과 에틸 피루베이트(20mM)를 처리한 켈로이드 스페로이드가 처리하지 않은 켈로이드 스페로이드에 비해 HMGB1가 유의하게 감소하였음을 확인하였다(도 3b).
도 4는 에틸 피루베이트가 인간 피부 섬유아세포에서 섬유증 마커의 발현에 미치는 영향을 보여주는 그림이다. 콜라겐 Ⅰ 및 p-smad 2/3는 에틸 피루베이트 처리 후 감소하였다. 인간 피부 섬유아세포에서 섬유증 마커에 대한 웨스턴 블롯을 수행한 결과 TGB-β 및 콜라겐 Ⅲ가 증가하였으나, 20mM 에틸 피루베이트 첨가 후 섬유증 마커는 유의하게 감소하였다(*p < 0.05, **p < 0.01).
도 5는 에틸 피루베이트가 켈로이드성 섬유아세포의 섬유증 마커 발현에 미치는 영향을 보여주는 그림이다. 에틸 피루베이트 처리 후 콜라겐 Ⅰ, Ⅲ, TGF-β 및 p-smad 2/3는 감소하였다. 켈로이드성 섬유아세포에서 섬유증 마커에 대한 웨스턴 블롯을 수행한 결과 TGB-β 및 콜라겐 Ⅲ가 증가하였으나, 20mM 에틸 피루베이트 첨가 후 섬유증 마커는 유의하게 감소하였다(p < 0.001).
도 6은 에틸 피루베이트-처리된 켈로이드 스페로이드에서의 콜라겐 I, Ⅲ, 피브로넥틴 및 엘라스틴의 조직화학적 분석결과를 보여주는 그림으로, 에틸 피루베이트를 각각 10, 20 및 40 mM 처리한 켈로이드 스페로이드의 콜라겐 Ⅰ, Ⅲ, 피브로넥틴 및 엘라스틴의 대표적인 면역화학염색 이미지를 나타낸다. 에틸 피루베이트 첨가 후 켈로이드 스페로이드에서의 콜라겐 I, Ⅲ, 피브로넥틴 및 엘라스틴은 유의하게 감소하였다. 1 is a diagram showing the effect of ethyl pyruvate on human normal skin fibroblasts (HDF). As a result of the MTT cell proliferation assay, it was confirmed that ethyl pyruvate significantly inhibited the proliferation of HDF.
2 is a diagram showing the effect of ethyl pyruvate on keloid fibroblasts (KF). As a result of the MTT cell proliferation assay, it was confirmed that ethyl pyruvate significantly inhibited the proliferation of KF.
3 is a diagram showing the effect of ethyl pyruvate on HMGB1 expression in keloid spheroids. As a result of performing Western blot to identify HMGB1 in keloid spheroids, it was confirmed that the HMGB1 density in the keloid spheroids markedly decreased after adding ethyl pyruvate (FIG. 3A). As a result of semi-quantitative analysis, it was confirmed that the keloid spheroid treated with ethyl pyruvate (20 mM) significantly reduced HMGB1 compared to the keloid spheroid not treated (FIG. 3b ).
4 is a diagram showing the effect of ethyl pyruvate on the expression of fibrosis markers in human skin fibroblasts. Collagen I and p-
5 is a diagram showing the effect of ethyl pyruvate on the expression of fibrosis markers in keloid fibroblasts. Collagen I, III, TGF-β and p-
6 is a diagram showing the results of histochemical analysis of collagen I, III, fibronectin, and elastin in ethyl pyruvate-treated keloid spheroids. Collagen of keloid spheroids treated with 10, 20 and 40 mM ethyl pyruvate, respectively Representative immunochemical staining images of I, III, fibronectin and elastin are shown. Collagen I, III, fibronectin and elastin in keloid spheroids were significantly reduced after addition of ethyl pyruvate.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
실험방법Experiment method
1. 세포의 준비 1. Preparation of cells
정상 인간 피부 섬유아세포(HDFs) 및 켈로이드성 섬유아세포(KF)는 ATCC (American Type Culture Collection; Manassas, VA, USA)로부터 수득하였다. 세포들은 10% 우태아혈청(FBS; Sigma-Aldrich, St. Louis, MO, USA), 페니실린(30 U/mL) 및 스트렙토마이신(300 μg/mL)을 함유하는 DMEM(Dulbecco’s modified Eagle’s medium; Gibco, Grand Island, NY, USA)에서 배양하였다. 배양은 가습 배양기에서 37℃, 5% CO2 하에서 2일마다 배양액을 교체해가며 수행하였다. 모든 실험에서, 세포는 7계대 이전의 것을 사용하였다. Normal human skin fibroblasts (HDFs) and keloid fibroblasts (KF) were obtained from ATCC (American Type Culture Collection; Manassas, VA, USA). Cells were DMEM (Dulbecco's modified Eagle's medium; Gibco) containing 10% fetal bovine serum (FBS; Sigma-Aldrich, St. Louis, MO, USA), penicillin (30 U/mL) and streptomycin (300 μg/mL). , Grand Island, NY, USA). Cultivation was performed in a humidified incubator at 37° C. and 5% CO 2 , replacing the culture solution every 2 days. In all experiments, cells before
2. 켈로이드 스페로이드의 제작2. Production of keloid spheroids
활성단계 켈로이드를 가지는 환자의 외과수술 과정에서 켈로이드 및 인접한 정상 피부조직을 수득하였다. 켈로이드 스페로이드는 살균한 21-게이지 바늘로 켈로이드의 중앙 피부조직을 2mm 직경의 조작으로 절개함으로써 종래 보고된 방법21대로 제작하였다. 외식편을 HydroCell® 24 멀티-웰 플레이트(Nunc, Rochester, NY, USA)에 플레이팅하고 4시간 동안 5% FBS(fetal bovine serum), 10 μM 인슐린 및 1μM 하이드로코르티손이 보충된 Iscove 변형 Dulbecco 배지(Gibco)에서 배양하였다. HMGB1의 억제제인 에틸 피루베이트를 0, 1, 10, 20 및 40 mM의 켈로이드 스페로이드를 함유하는 플레이트에 첨가하고 37℃, 5% CO2에서 3일간 배양하였다. 처리된 켈로이드 스페로이드를 4% 포르말린에 고정하고 파라핀에 포매시킨 후 5μm 두께의 절편으로 잘랐다.A keloid and adjacent normal skin tissue were obtained during the surgical procedure of a patient with an active stage keloid. The keloid spheroid was manufactured according to the previously reported method 21 by incising the central skin tissue of the keloid with a sterilized 21-gauge needle with a 2 mm diameter operation. Explants were plated on HydroCell ® 24 multi-well plates (Nunc, Rochester, NY, USA) and Iscove modified Dulbecco's medium supplemented with 5% fetal bovine serum (FBS), 10 μM insulin and 1 μM hydrocortisone for 4 hours ( Gibco). Ethyl pyruvate, an inhibitor of HMGB1, was added to a plate containing 0, 1, 10, 20 and 40 mM keloid spheroids and incubated at 37°C and 5% CO 2 for 3 days. The treated keloid spheroid was fixed in 4% formalin, embedded in paraffin, and cut into 5 μm-thick sections.
3. MTT (Methyl Thiazolyl-Diphenyl-Tetrazolium Bromide) 분석 3. MTT (Methyl Thiazolyl-Diphenyl-Tetrazolium Bromide) Analysis
KF 및 HDF에 에틸 피루베이트를 처리한 후의 세포 생존성을 측정하기 위해, 3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라졸리움 브로마이드(MTT) 분석을 수행하였다: 1 X 104 cells/cm2의 KF 및 HDF를 3배수 96 웰에 씨딩하였다. 0, 1mM, 5mM, 10nM 및 20mM의 에틸 피루베이트(Sigma-Aldrich)에 세포를 48시간 동안 노출시킨 후, 200μL의 0.5 mg/mL MTT 용액(Boehringer, Mannheim, Germany)을 각 웰에 첨가하고 플레이트를 37℃에서 3시간 동안 배양하였다. 수득된 포르마잔을 용해시키기 위해, MTT 용액 제거 후 200μL의 디메틸 설폭사이드(Sigma-Aldrich)를 각 웰에 첨가하였다. 마이크로플레이트 리더(Bio-Rad, Hercules, CA, USA)를 이용하여 570nm에서 흡광도를 측정하였다.To measure cell viability after treatment with ethyl pyruvate on KF and HDF, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis was performed. Then: 1
4. 켈로이드 스페로이드의 조직학 및 IHC 4. Histology and IHC of keloid spheroids
켈로이드 스페로이드에 0, 10, 20 및 40mM의 에틸 피루베이트를 48시간 동안 처리하였다. 이후 스페로이드를 세척하고 4% 포르말린으로 고정한 다음 파라핀으로 포매한 뒤, 5μm 두께의 절편으로 잘랐다. 대표적인 단면을 PicroSirius 레드로 염색하고, 광학현미경으로 조사하였다. IHC 염색을 위해, 켈로이드 스페로이드 단면을 마우스 항-HMGB1(Abcam), 마우스 항-콜라겐 type I (Abcam), 마우스 항-콜라겐 type Ⅲ(Sigma-Aldrich), 마우스 항-엘라스틴 (Sigma-Aldrich), 마우스 항-피브로넥틴(Santa Cruz Biotechnology), 래빗 항-TGF (transforming growth factor)-β(Abcam), 콜라게나아제 억제제(MMP1)(Abcam) 또는 래빗 항-Smad 2/3 1차 항체와 함께 4℃에서 밤새 배양하였다. 이후 단면을 차 항체인 Envision™ kit(Dako, Glostrup, Denmark)과 함께 상온에서 20분 간 배양하였다. 디아미노벤지딘/하이드로겐 퍼옥시다제(Dako)이 크로모겐 기질로 사용되었다. 모든 슬라이드는 Meyer 헤마톡실린으로 대조염색하였다. HMGB1, 콜라겐 I, 콜라겐 Ⅲ, 엘라스틴, 피브로넥틴, TGF-β, MMP1 및 Smad 2/3의 발현량은 Metamorph® 이미지 분석 소프트웨어를 이용하여 반정량적으로 분석하였다. 분석결과는 상이한 디지털 이미지의 평균 광학밀도로 표현하였다. The keloid spheroid was treated with 0, 10, 20 and 40 mM of ethyl pyruvate for 48 hours. Afterwards, the spheroids were washed, fixed with 4% formalin, embedded in paraffin, and cut into 5 μm-thick sections. Representative cross sections were stained with PicroSirius red and examined with an optical microscope. For IHC staining, the keloid spheroid section was subjected to mouse anti-HMGB1 (Abcam), mouse anti-collagen type I (Abcam), mouse anti-collagen type III (Sigma-Aldrich), mouse anti-elastin (Sigma-Aldrich), 4℃ with mouse anti-fibronectin (Santa Cruz Biotechnology), rabbit anti-TGF (transforming growth factor)-β (Abcam), collagenase inhibitor (MMP1) (Abcam) or
5. 콜라겐 마커 및 전섬유성 (profibrotic) 마커에 대한 웨스턴 블롯팅5. Western blotting for collagen markers and profibrotic markers
웨스턴 블롯팅을 이용하여 대표적인 전섬유성 마커인 콜라겐 I, 콜라겐 Ⅲ, 피브로넥틴, 엘라스틴, MMP1 및 TGF-β에 대한 정량측정을 수행하였다. 0mM, 10mM, 20mM 및 40mM 에틸 피루베이트를 처리한 HDF 및 KF(세포는 105 cells/well로 씨딩됨)를 100 mm × 20 mm 디쉬에서 48시간 배양하였다. 세포를 프로테아제 억제제 존재 하에서 50 mM Tris-HCl(pH 7.6), 1% Nonidet P-40, 150 mM NaCl 및 0.1 mM 아세트산 아연에서 용해시켰다. 단백질 농도는 Lowry 방법(Bio-Rad)으로 측정하고, 각 시료 20 μg을 10% SDS 젤 전기영동으로 분리하였다. 이후 단백질을 전기영동을 통해 폴리비닐리덴 디플루오라이드(PVDF) 막(Millipore, Billerica, MA)으로 이동시켰다. 막을 블로킹 완충제로 1시간 동안 블로킹한 뒤, 콜라겐 I, 콜라겐 Ⅲ, 피브로넥틴, 엘라스틴, MMP1 및 TGF-β에 대한 1차 항체와 함께 4℃에서 밤새 배양하였다. 2차 항체(호스래디시 퍼옥시다제-접합 항-래빗 또는 항-마우스;Santa Cruz Biotechnology)와 함께 2시간 동안 상온에서 배양한 뒤, 화학형광 시약(Amersham Pharmacia Biotech, Piscataway, NJ, USA)을 이용하여 제조자의 설명서에 따라 단백질 밴드를 시각화하였다. Image J 소프트웨어 (National Institutes of Health, Bethesda, MD, USA)를 이용하여 단백질 발현을 분석하였다. Quantitative measurements were performed on representative prefibrous markers of collagen I, collagen III, fibronectin, elastin, MMP1 and TGF-β using Western blotting. HDF and KF (cells were seeded with 10 5 cells/well) treated with 0mM, 10mM, 20mM and 40mM ethyl pyruvate were cultured in 100 mm×20 mm dishes for 48 hours. Cells were lysed in 50 mM Tris-HCl (pH 7.6), 1% Nonidet P-40, 150 mM NaCl and 0.1 mM zinc acetate in the presence of a protease inhibitor. Protein concentration was measured by the Lowry method (Bio-Rad), and 20 μg of each sample was separated by 10% SDS gel electrophoresis. Then, the protein was transferred to a polyvinylidene difluoride (PVDF) membrane (Millipore, Billerica, MA) through electrophoresis. After blocking the membrane with a blocking buffer for 1 hour, it was incubated overnight at 4° C. with primary antibodies against collagen I, collagen III, fibronectin, elastin, MMP1 and TGF-β. After incubation with a secondary antibody (horseradish peroxidase-conjugated anti-rabbit or anti-mouse; Santa Cruz Biotechnology) for 2 hours at room temperature, use a chemofluorescent reagent (Amersham Pharmacia Biotech, Piscataway, NJ, USA) The protein band was visualized according to the manufacturer's instructions. Protein expression was analyzed using Image J software (National Institutes of Health, Bethesda, MD, USA).
실험결과Experiment result
1. 에틸 피부베이트는 인간 피부 섬유아세포의 증식을 억제한다. 1. Ethyl dermatate inhibits the proliferation of human skin fibroblasts.
에틸 피루베이트를 이용한 HMGB1 억제가 피부세포 증식에 영향을 주는지를 조사하기 위해 MTT 어세이를 수행하였다. 에틸 피루베이트 처리 후의 세포 생존성을 조사하기 위해, 에틸 피루베이트 다양한 농도(0, 1, 5 및 10 mM)의 에틸 피루베이를 MTT 어세이 48시간 전에 인간 피부 섬유아세포에 처리하였다. 그 결과, 모든 에틸 피루베이트 처리농도에서 HDF 증식이 유의하게 감소함을 확인함으로써(도 1), 에틸 피루베이트가 인간 피부 섬유아세포의 생존성을 감소시킴을 확인할 수 있었다. MTT assay was performed to investigate whether HMGB1 inhibition using ethyl pyruvate affects skin cell proliferation. In order to investigate the cell viability after ethyl pyruvate treatment, various concentrations of ethyl pyruvate (0, 1, 5 and 10 mM) of ethyl pyruvate were treated on human skin fibroblasts 48 hours before the MTT assay. As a result, it was confirmed that HDF proliferation significantly decreased at all ethyl pyruvate treatment concentrations (FIG. 1), thereby confirming that ethyl pyruvate reduced the viability of human skin fibroblasts.
2. 에틸 피부베이트는 켈로이드성 섬유아세포 증식을 억제한다. 2. Ethyl dermatate inhibits keloid fibroblast proliferation.
에틸 피루베이트를 이용한 HMGB1 억제가 켈로이드 섬유아세포의 증식에 영향을 미치는지를 조사하기 위해 MTT 어셍를 수행하였다. 에틸 피루베이트 처리 후의 세포 생존성을 측정하기 위해 다양한 농도(0, 10 및 20 mM)의 에틸 피루베이트를 MTT 어세이 48시간 전에 켈로이드성 섬유아세포에 처리하였다. 그 결과, 모든 농도의 에틸 피루베이트에서 켈로이드성 섬유아세포의 증식이 유의하게 감소하였다(도 2). 이러한 결과는 에틸 피루베이트가 켈로이드성 섬유아세포의 생존성을 감소시킴을 보여준다. MTT assay was performed to investigate whether HMGB1 inhibition with ethyl pyruvate affects the proliferation of keloid fibroblasts. In order to measure the cell viability after ethyl pyruvate treatment, various concentrations (0, 10 and 20 mM) of ethyl pyruvate were treated on keloid fibroblasts 48 hours before the MTT assay. As a result, the proliferation of keloid fibroblasts was significantly reduced in all concentrations of ethyl pyruvate (FIG. 2). These results show that ethyl pyruvate reduces the viability of keloid fibroblasts.
3. 에틸 피루베이트는 인간 피부 섬유아세포에서 HMGB1의 발현을 감소시킨다.3. Ethyl pyruvate decreases the expression of HMGB1 in human skin fibroblasts.
외부에서 도입된 HMGB1가 켈로이드의 오토파지 활성을 증가시킨다면 HMGB1를 억제할 경우 켈로이드의 세포 생존성이 감소할 것이라는 가정을 시험하기 위해, 에틸 피루베이트를 처리하여 HMGB1의 세포 외 활성 및 세포질로의 이동을 억제하였다. 에틸 피루베이트가 강력한 HMGB1 억제제로 인식되고 있음에도, 이 물질이 켈로이드에 미치는 영향은 연구된 바가 없다. 따라서, 본 발명자들은 켈로이드 스페로이드를 이용하여 에틸 피루베이트가 켈로이드에서 HMGB1 발현을 억제하는지 여부를 조사하였다. 확립된 프로토콜21에 따라 켈로이드 미세환경을 모방하고, 다양한 농도(0, 10, 20, and 40 mM)의 에틸 피루베이트를 켈로이드 스페로이드에 처리한 뒤 HMGB1에 대한 IHC 염색을 수행하였다. 도 3에서 보는 바와 같이, 비-처리 켈로이드 스페로이드는 HMGB1의 높은 발현을 보인 반면, 에틸 피루베이트-처리 켈로이드 스페로이드는 HMGB1 발현이 크게 감소하였다. Metamorph® 이미지 분석 소프트웨어를 이용해 데이터를 그래프화한 결과, 10, 20 또는 40 mM의 에틸 피루베이트를 처리한 켈로이드 스페로이드에서 HMGB1 발현이 유의하게 감소함을 확인하였다.To test the hypothesis that if HMGB1 introduced from the outside increases the autophagy activity of keloids, inhibition of HMGB1 will decrease the cell viability of keloids, treatment with ethyl pyruvate for extracellular activity and migration of HMGB1 to the cytoplasm. Was suppressed. Although ethyl pyruvate is recognized as a potent HMGB1 inhibitor, its effect on keloids has not been studied. Therefore, the present inventors investigated whether ethyl pyruvate inhibits HMGB1 expression in keloids using keloid spheroids. In accordance with the established protocol 21 , the keloid microenvironment was mimicked, and various concentrations (0, 10, 20, and 40 mM) of ethyl pyruvate were treated with the keloid spheroid, followed by IHC staining for HMGB1. As shown in FIG. 3, the non-treated keloid spheroid showed high expression of HMGB1, while the ethyl pyruvate-treated keloid spheroid significantly reduced HMGB1 expression. As a result of graphing the data using Metamorph ® image analysis software, it was confirmed that HMGB1 expression was significantly reduced in keloid spheroids treated with 10, 20 or 40 mM ethyl pyruvate.
4. 에틸 피루베이트는켈로이드 섬유아세포 및 켈로이드 조직에서의 콜라겐 Ⅰ, Ⅲ, TGF-β 및 p-smad 2/3에 영향을 미친다.4. Ethyl pyruvate affects collagen I, III, TGF-β and p-
켈로이드에서 에틸 피루베이트로 유도된 오토파지에 의한 세포사멸 결과를 평가하기 위해, 섬유아세포에서의 콜라겐 Ⅰ, Ⅲ, TGF-β 및 p-smad 2/3 발현을 웨스턴 블롯으로 측정하였다. 그 결과, 켈로이드성 섬유아세포에서 콜라겐 Ⅰ, Ⅲ, TGF-β 및 p-smad 2/3 발현은 정상 피부 섬유아세포에 비해 1.2배 및 1.1배 높았다. 나아가, 켈로이드성 섬유아세포에서 크게 증가한 콜라겐 Ⅲ 및 TGF-β 수준은 20 mM 에틸 피루베이트 처리 후 유의하게 감소하였다. 이러한 결과는 에틸 피루베이트 처리 후 콜라겐 Ⅲ 및 TGF-β의 유의한 감소를 보여준 IHC 데이터와 일치하는 것이다(도 5). 20 mM 에틸 피루베이트를 처리한 켈로이드 조직에서 콜라겐 Ⅰ 및 p-smad 2/3 발현은 비처리 켈로이드 조직에 비해 각각 18.11% 및 24.64%가 감소하였다(***p < 0.001, 도 5). In order to evaluate the result of apoptosis by autophagy induced by ethyl pyruvate in keloid, collagen I, III, TGF-β and p-
5. 에틸 피루베이트는 켈로이드 스페로이드에서 콜라겐 I, Ⅲ, 피브로넥틴 및 엘라스틴을 억제한다.5. Ethyl pyruvate inhibits collagen I, III, fibronectin and elastin in keloid spheroids.
추가적으로, 에틸 피루베이트가 섬유생성의 핵심 조절 분자인 콜라겐 Ⅰ, Ⅲ, 피브로넥틴 및 엘라스틴의 발현에 미치는 영향을 조사하였다. 면역조직화학 염색 결과 에틸 피루베이트(40 mM)-처리 켈로이드 스페로이드에서 콜라겐 I, Ⅲ, 피브로넥틴 및 엘라스틴이 각각 50.67%, 64.81%, 63.42% 및 62.30%가 감소하였음을 확인하였다(p<0.001, 도 6). 이들 데이터로부터 에틸 피루베이트가 TGF-β 및 이의 신호경로를 조절함으로써 켈로이드 섬유증을 완화시킴을 알 수 있다. Additionally, the effect of ethyl pyruvate on the expression of collagen I, III, fibronectin and elastin, which are key regulatory molecules of fibrosis, was investigated. As a result of immunohistochemical staining, it was confirmed that collagen I, III, fibronectin and elastin decreased by 50.67%, 64.81%, 63.42% and 62.30%, respectively, in ethyl pyruvate (40 mM)-treated keloid spheroids ( p <0.001, p <0.001, Fig. 6). From these data, it can be seen that ethyl pyruvate relieves keloid fibrosis by regulating TGF-β and its signaling pathway.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As described above, specific parts of the present invention have been described in detail, and it is obvious that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereto for those of ordinary skill in the art. Accordingly, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.
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Claims (11)
화학식 1
상기 화학식에서, R1 및 R2는 각각 독립적으로 C1-C3 알킬이다.
A pharmaceutical composition for preventing or treating keloidal dermal fibrosis comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
Formula 1
In the above formula, R 1 and R 2 are each independently C 1 -C 3 alkyl.
The composition of claim 1, wherein R 1 in Formula 1 is C 1 alkyl, and R 2 is C 2 alkyl.
The composition of claim 1, wherein the composition reduces the expression of HMGB1 in skin fibroblasts.
The composition of claim 1, wherein the composition reduces the expression of one or more proteins selected from the group consisting of collagen I, collagen III, fibronectin and elastin in skin fibroblasts.
화학식 1
상기 화학식에서, R1 및 R2는 각각 독립적으로 C1-C3 알킬이다.
A cosmetic composition for improving keloidal dermal fibrosis comprising a compound represented by the following Formula 1 or a cosmetically acceptable salt thereof as an active ingredient:
Formula 1
In the above formula, R 1 and R 2 are each independently C 1 -C 3 alkyl.
The composition of claim 1, wherein R 1 in Formula 1 is C 1 alkyl, and R 2 is C 2 alkyl.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20230019795A (en) | 2021-08-02 | 2023-02-09 | 셀라이온바이오메드 주식회사 | A composition for treating hypertrophic scar and keloid comprising benzhydrylthio acetamide compounds as an active ingredient |
| WO2023014003A1 (en) | 2021-08-02 | 2023-02-09 | 셀라이온바이오메드 주식회사 | Composition for treating hypertrophic scars and keloids comprising benzhydryl thioacetamide compound as active ingredient |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20090239947A1 (en) * | 2008-01-25 | 2009-09-24 | Weixang Dai | Inhibition of proliferation and fibrotic response of activated corneal stromal cells |
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| US5091171B2 (en) | 1986-12-23 | 1997-07-15 | Tristrata Inc | Amphoteric compositions and polymeric forms of alpha hydroxyacids and their therapeutic use |
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| US20090239947A1 (en) * | 2008-01-25 | 2009-09-24 | Weixang Dai | Inhibition of proliferation and fibrotic response of activated corneal stromal cells |
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| Journal of Investigative Dermatology, 138, 2322-2332, 2018.* |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20230019795A (en) | 2021-08-02 | 2023-02-09 | 셀라이온바이오메드 주식회사 | A composition for treating hypertrophic scar and keloid comprising benzhydrylthio acetamide compounds as an active ingredient |
| WO2023014003A1 (en) | 2021-08-02 | 2023-02-09 | 셀라이온바이오메드 주식회사 | Composition for treating hypertrophic scars and keloids comprising benzhydryl thioacetamide compound as active ingredient |
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