KR20230079725A - A composition for preventing or treating immune diseases comprising zinc sulfate as an active ingredient - Google Patents
A composition for preventing or treating immune diseases comprising zinc sulfate as an active ingredient Download PDFInfo
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- KR20230079725A KR20230079725A KR1020210166787A KR20210166787A KR20230079725A KR 20230079725 A KR20230079725 A KR 20230079725A KR 1020210166787 A KR1020210166787 A KR 1020210166787A KR 20210166787 A KR20210166787 A KR 20210166787A KR 20230079725 A KR20230079725 A KR 20230079725A
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- zinc sulfate
- pharmaceutical composition
- immune diseases
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2250/00—Food ingredients
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- A23V2250/156—Mineral combination
- A23V2250/1642—Zinc
Abstract
본 발명은, 황산아연(Zinc sulfate)를 유효성분으로 포함하는 면역질환의 예방 또는 치료용 약학적 조성물에 관한 것으로서, 본 발명의 황산아연은, 루푸스 동물모델에서, 혈청 내 IgG2a 및 anti-dsDNA를 감소시키고, 신장조직을 보호하는 것을 확인하였으며, 전신 경화증 동물모델에서, 피부 진피층의 두께를 감소시키고, 피부 및 폐의 섬유화를 억제하는 것을 확인하였다. 또한, 황산아연이 루푸스 및 전신경화증과 관련된 면역세포인, double negative T cell, plasma cell, follicular B 및 Th17을 감소시키고, Treg를 증가시키는 것을 확인하여, 면역질환의 개선 효과가 있는 것을 확인하였다.The present invention relates to a pharmaceutical composition for preventing or treating immune diseases comprising zinc sulfate as an active ingredient, wherein the zinc sulfate of the present invention, in a lupus animal model, reduces serum IgG2a and anti-dsDNA. It was confirmed to reduce, protect renal tissue, and in an animal model of systemic sclerosis, reduce the thickness of the dermal layer of the skin and inhibit fibrosis of the skin and lungs. In addition, it was confirmed that zinc sulfate reduces double negative T cells, plasma cells, follicular B and Th17, which are immune cells related to lupus and systemic sclerosis, and increases Treg, confirming that there is an effect of improving immune diseases.
Description
본 발명은, 황산아연을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating immune diseases comprising zinc sulfate as an active ingredient.
전 세계적으로 면역과민반응으로 인한 질환이 증가하고 있지만, 이러한 질환들의 발생에 대한 근본적인 원인 규명이 충분히 이루어지지 않은 상태이다. 현재 과도한 면역반응에 의한 질환의 치료방법으로는 면역억제제를 단독 또는 병용 투여함으로써 상기 질환에 의해 야기되는 각종 증상을 완화 내지 감소시키는 것이다. Diseases caused by immune hypersensitivity reactions are increasing worldwide, but the fundamental causes of the occurrence of these diseases have not been sufficiently identified. Currently, as a treatment method for diseases caused by an excessive immune response, various symptoms caused by the diseases are alleviated or reduced by administering an immunosuppressive agent alone or in combination.
면역억제제란 항원의 작용에 대하여 숙주가 항체를 만드는 능력(체액성 면역반응) 또는 세포성 면역반응을 일으키는 능력을 저하시키거나 차단하기 위해 사용되는 다양한 물질들을 말한다. 이러한 면역억제제는 장기이식분야 뿐만 아니라 루푸스, 류마티스 관절염 등과 같은 자가면역질환과, 아토피, 알러지 등의 피부과민 반응에도 유용하게 사용될 수 있다. 우수한 면역억제제는 면역반응의 불균형을 조절할 수 있어야 하고, 인체에 대한 안전성이 확보되어야 하며, 장기간 치료시에 질환의 재발 발생 빈도가 낮아야 한다.Immunosuppressive agents refer to various substances used to reduce or block the ability of a host to produce antibodies against the action of an antigen (humoral immune response) or to induce a cellular immune response. These immunosuppressants can be usefully used not only in the field of organ transplantation, but also in autoimmune diseases such as lupus and rheumatoid arthritis, and skin hypersensitivity reactions such as atopy and allergy. An excellent immunosuppressive agent should be able to control the imbalance of the immune response, should be safe for the human body, and should have a low frequency of disease recurrence during long-term treatment.
현재 사용되고 있는 면역억제제로는 사이클로스포린 A와 FK506 등이 있는데, 이들은 복잡한 화학구조를 가진 천연물 유래의 화합물로서 원료 수급의 측면에서 고비용이 드는 문제점이 있어 비경제적이고, 장기투여로 인해 각종 부작용이 야기될 수 있다는 위험성을 내포하고 있다. 따라서 낮은 독성 및 면역관용 유도와 함께 경제적인 생산이 가능한 새로운 면역억제제의 개발이 절실히 요구되고 있는 실정이다. Currently used immunosuppressants include cyclosporin A and FK506, which are compounds derived from natural products with complex chemical structures that are uneconomical due to the high cost in terms of raw material supply and long-term administration, which can cause various side effects. There is a risk that there is Therefore, there is an urgent need for the development of new immunosuppressants capable of economical production with low toxicity and induction of immune tolerance.
한편, 각종 병원체에 대한 생체 방어 시스템으로 면역계에서 중심적 역할을 담당하는 세포군의 하나로 T 세포가 있다. T 세포는 인체의 흉선에서 생성되며 일련의 분화 과정을 거치면서 고유의 특성을 지닌 T 세포로 분화하게 되는데, 분화를 완료한 T 세포는 그 기능에 따라 크게 1형 보조 세포(Th1)와 2형 보조 세포(Th2)로 구분된다. 이 중에서 Th1 세포의 주된 기능은 세포 매개성 면역에 관여하고, Th2 세포는 체액성 면역에 관여하며, 면역계에서 이러한 두 세포 집단은 서로 과 활성화되지 않도록 서로 견제를 통해 면역계의 균형을 유지하고 있다. On the other hand, T cells are one of the cell groups that play a central role in the immune system as a biological defense system against various pathogens. T cells are produced in the human thymus and differentiate into T cells with unique characteristics through a series of differentiation processes. It is divided into helper cells (Th2). Among them, the main function of Th1 cells is involved in cell-mediated immunity, and Th2 cells are involved in humoral immunity.
따라서 면역질환의 대부분은 이러한 두 가지 면역 세포간의 불균형에 기인하는 것으로 볼 수 있는데, 예를 들어 Th1 세포의 활성이 비정상적으로 증가하는 경우 자가면역질환이 발생할 수 있고, Th2 세포의 활성이 비정상적으로 증가하는 경우 과민반응에 의한 면역질환이 발생하는 것으로 알려져 있다. Therefore, most of the immune diseases can be seen as being caused by an imbalance between these two immune cells. For example, when the activity of Th1 cells is abnormally increased, autoimmune diseases can occur, and the activity of Th2 cells is abnormally increased. It is known that immune diseases caused by hypersensitivity reactions occur.
한편, Th1 세포의 분화에 대한 최근 연구 결과에 따르면, Th1 세포의 활성을 조절할 수 있는 새로운 그룹인 면역조절 T 세포(Treg)의 존재가 알려지면서 이를 이용한 면역질환의 치료에 대한 연구가 대두되고 있는데, Treg 세포는 비정상적으로 활성화된 면역세포의 기능을 억제하여 염증 반응을 제어하는 특성이 있어, Treg 세포의 활성을 증가시키는 작용을 통해 면역질환을 치료하고자 하는 연구들이 많이 진행되고 있다.On the other hand, according to recent research results on the differentiation of Th1 cells, as the existence of immunoregulatory T cells (Tregs), a new group capable of regulating the activity of Th1 cells, has been known, research on the treatment of immune diseases using them has emerged. , Treg cells have the property of controlling the inflammatory response by suppressing the function of abnormally activated immune cells, and many studies are being conducted to treat immune diseases through the action of increasing the activity of Treg cells.
또한, Treg 세포 이 외에 T 세포의 분화 과정에서 만들어지는 또 다른 그룹으로 Th17 세포가 있는데, Th17 세포는 미분화 T세포의 분화 과정에서 Treg 세포의 분화와 유사한 과정을 거치며 형성되는 것으로 알려져 있다. 즉, Treg 세포와 Th17 세포의 분화는 공통적으로 TGF-β의 존재 하에서 이루어지지만, Treg 세포의 경우 IL-6을 필요로 하지 않는 반면, Th17 세포의 경우에는 TGF-β와 함께 IL-6가 존재하는 상황에서 분화를 한다. 또한, 분화된 Th17 세포는 IL-17을 분비하는 것을 특징으로 한다. In addition, there are Th17 cells as another group formed during the differentiation process of T cells other than Treg cells. It is known that Th17 cells are formed during the differentiation process of undifferentiated T cells through a process similar to that of Treg cells. That is, the differentiation of Treg cells and Th17 cells is commonly achieved in the presence of TGF-β, but IL-6 is not required for Treg cells, whereas IL-6 is present together with TGF-β for Th17 cells. differentiate in the circumstances. Also, differentiated Th17 cells are characterized by secreting IL-17.
Th17 세포는 Treg 세포와는 달리 면역질환에서 보이는 염증반응의 최전방에서 관여하여 염증 반응의 신호를 최대화시켜 질병의 진행을 가속화시키는 것이 밝혀지고 있다. 그러므로 자가면역질환 중 Treg 세포에 의해 제어되지 않는 자가면역질환의 경우, Th17 세포 활성의 억제를 표적으로 한 자가면역질환의 치료제 개발이 크게 부각되고 있다.It has been revealed that Th17 cells, unlike Treg cells, are involved in the forefront of the inflammatory response seen in immune diseases, maximizing the signal of the inflammatory response and accelerating the progression of the disease. Therefore, in the case of autoimmune diseases that are not controlled by Treg cells among autoimmune diseases, the development of a therapeutic agent for autoimmune diseases targeting inhibition of Th17 cell activity has been greatly highlighted.
현재 사용되고 있는 면역질환치료제로는 T 세포에서의 신호변환 경로를 차단하는 면역 억제제가 가장 많이 사용되고 있는데, 이러한 면역억제제들은 독성, 감염, 임파종, 당뇨병, 진전(tremor), 두통, 설사, 고혈압, 오심, 신기능 장애 등의 부작용이 발생하는 문제점이 있다.Immunosuppressants that block signal transduction pathways in T cells are most commonly used as immunosuppressive drugs currently used. However, there are problems in that side effects such as renal dysfunction occur.
또한, T 세포의 활성화를 억제하는 방법을 통해 면역질환을 치료하는 방법 이외에도 면역 세포로부터 분비되는 사이토카인의 양을 조절하는 치료법 및 면역 세포로부터 분비되는 사이토카인을 표적으로 하는 항체를 이용한 치료법이 개발 중에 있다. 그러나 이러한 방법은 실제적으로 임상실험을 거쳐 환자들에게 적용하기까지 많은 시간이 소요되어야 하고, 항체를 이용하는 방법은 항체 제작 과정에서 너무 많은 비용이 든다는 문제점이 있다.In addition to the method of treating immune diseases through suppression of T cell activation, therapies that regulate the amount of cytokines secreted from immune cells and therapies using antibodies targeting cytokines secreted from immune cells are developed. are among However, this method has a problem in that it takes a lot of time to actually apply to patients through clinical trials, and the method using antibodies requires too much cost in the antibody production process.
본 발명의 목적은 황산아연(Zinc sulfate)를 유효성분으로 포함하는 면역질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition for preventing or treating immune diseases comprising zinc sulfate as an active ingredient.
본 발명의 다른 목적은 황산아연(Zinc sulfate)를 유효성분으로 포함하는 면역질환의 예방 또는 개선용 식품조성물 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving immune diseases comprising zinc sulfate as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 황산아연(Zinc sulfate)를 유효성분으로 포함하는 면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating immune diseases comprising zinc sulfate as an active ingredient.
또한, 본 발명은 황산아연(Zinc sulfate)를 유효성분으로 포함하는 면역질환의 예방 또는 개선용 식품조성물 제공한다.In addition, the present invention provides a food composition for preventing or improving immune diseases comprising zinc sulfate as an active ingredient.
본 발명의 황산아연은, 루푸스 동물모델에서, 혈청 내 IgG2a 및 anti-dsDNA를 감소시키고, 신장조직을 보호하는 것을 확인하였으며, 전신 경화증 동물모델에서, 피부 진피층의 두께를 감소시키고, 피부 및 폐의 섬유화를 억제하는 것을 확인하였다. 또한, 황산아연이 루푸스 및 전신경화증과 관련된 면역세포인, double negative T cell, plasma cell, follicular B 및 Th17을 감소시키고, Treg를 증가시키는 것을 확인하여, 면역질환의 개선 효과가 있는 것을 확인하여, 관련 산업에 유용하게 이용할 수 있다.Zinc sulfate of the present invention was confirmed to reduce IgG2a and anti-dsDNA in serum and protect renal tissue in animal models of lupus, and in animal models of systemic sclerosis, reduce the thickness of the dermal layer of the skin and improve the appearance of the skin and lungs. It was confirmed that fibrosis was inhibited. In addition, it was confirmed that zinc sulfate reduces double negative T cells, plasma cells, follicular B and Th17, which are immune cells related to lupus and systemic sclerosis, and increases Treg, confirming that there is an effect of improving immune diseases, It can be usefully used in related industries.
도 1은 본 발명의 황산아연을, 루푸스 마우스 모델에 투여하여, 체중 및 혈액 내 CD4-CD8- double negative T cell의 발현을 확인한 도이다(A: 체중 변화, B: CD4-CD8- double negative T cell 발현 정량화).
도 2는 본 발명의 황산아연을, 루푸스 마우스 모델에 투여하여, 혈청 IgG2a 및 anti-dsDNA의 발현을 확인한 도이다(A: IgG2a발현 확인, B: anti-dsDNA발현 확인).
도 3은 본 발명의 황산아연을, 루푸스 마우스 모델에 투여하여, 신장 조직에서의 사구체염 지수를 H&E 염색으로 평가한 도이다(A: H&E 염색 결과, B: membranous glomerulonephritis score 정량화).
도 4는 본 발명의 황산아연을, 루푸스 마우스 모델에 투여하여, TNF-α 및 IL-6 양성 세포의 수를 면역조직화학염색으로 확인한 도이다(A: 면역조직화학염색 결과, B: TNF-α 및 IL-6 양성 세포 수 정량화).
도 5는 본 발명의 황산아연을, 루푸스 마우스 모델에 투여하여, 혈액 내 조절 T 세포(regulatory T cell, Treg)의 발현을 확인한 도이다.
도 6은 본 발명의 황산아연을, 루푸스 마우스 모델에 투여하여, 비장 내 면역관련 세포의 변화를 확인한 도이다(A: plasma cell, B: follicular B cell, C: CD4-CD8- double negative T cell, D: Treg).
도 7은 본 발명의 황산아연을, 전신 경화증 마우스 모델에 투여하여, 피부 진피조직의 두께 변화를 H&E 염색으로 확인한 도이다(A: H&E 염색 결과, B: 진피 두께 정량화).
도 8은 본 발명의 황산아연을, 전신 경화증 마우스 모델에 투여하여, 피부 섬유화의 변화를 Masson’s Trichrome 염색으로 확인한 도이다.
도 9는 본 발명의 황산아연을, 전신 경화증 마우스 모델에 투여하여, 폐 섬유화의 변화를 Masson’s Trichrome 염색으로 확인한 도이다(A: Masson’s Trichrome 염색 결과, B: 폐 섬유화 정량화).
도 10은 본 발명의 황산아연을, 전신 경화증 마우스 모델에 투여하여, 혈액 내의 면역 관련 세포의 표현형을 분석한 도이다(A: Th17, B: Treg).
도 11은 본 발명의 황산아연을, 전신 경화증 마우스 모델에 투여하여, 비장 조직 내의 면역 관련 세포의 표현형을 분석한 도이다(A: Th17, B: Treg).1 is a diagram showing the expression of CD4 - CD8 - double negative T cells in body weight and blood by administering the zinc sulfate of the present invention to a lupus mouse model (A: weight change, B: CD4 - CD8 - double negative T cell) cell expression quantification).
2 is a diagram showing the expression of serum IgG2a and anti-dsDNA by administering the zinc sulfate of the present invention to a lupus mouse model (A: Confirmation of IgG2a expression, B: Confirmation of anti-dsDNA expression).
3 is a diagram illustrating the evaluation of the glomerulitis index in kidney tissue by H&E staining by administering the zinc sulfate of the present invention to a lupus mouse model (A: H&E staining result, B: quantification of membranous glomerulonephritis score).
4 is a diagram showing the number of TNF-α and IL-6 positive cells by immunohistochemical staining after administering the zinc sulfate of the present invention to a lupus mouse model (A: Immunohistochemical staining result, B: TNF- α and IL-6 positive cell count quantification).
5 is a diagram confirming the expression of regulatory T cells (Treg) in the blood by administering the zinc sulfate of the present invention to a lupus mouse model.
6 is a diagram illustrating changes in immune-related cells in the spleen by administering the zinc sulfate of the present invention to a lupus mouse model (A: plasma cell, B: follicular B cell, C: CD4 - CD8 - double negative T cell). , D: Treg).
7 is a view illustrating changes in the thickness of skin dermal tissue by H&E staining after administration of the zinc sulfate of the present invention to a systemic sclerosis mouse model (A: H&E staining result, B: quantification of dermal thickness).
8 is a diagram showing changes in skin fibrosis by Masson's Trichrome staining after administration of the zinc sulfate of the present invention to a systemic sclerosis mouse model.
9 is a diagram illustrating changes in lung fibrosis by Masson's Trichrome staining after administration of the zinc sulfate of the present invention to a systemic sclerosis mouse model (A: Masson's Trichrome staining result, B: quantification of lung fibrosis).
Fig. 10 is a diagram illustrating the analysis of the phenotype of immune-related cells in blood by administering zinc sulfate of the present invention to a systemic sclerosis mouse model (A: Th17, B: Treg).
11 is a diagram illustrating the analysis of phenotypes of immune-related cells in spleen tissue by administering the zinc sulfate of the present invention to a systemic sclerosis mouse model (A: Th17, B: Treg).
본 발명은 황산아연(Zinc sulfate)를 유효성분으로 포함하는 면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating immune diseases comprising zinc sulfate as an active ingredient.
본 발명에서 사용되는 용어 “예방”은 본 발명의 조성물의 투여로 특정 질환의 증상을 억제하거나 진행을 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" refers to any action that suppresses symptoms or delays the progression of a specific disease by administering the composition of the present invention.
본 발명에서 사용되는 용어 “치료”는 본 발명의 조성물의 투여로 특정 질환의 증상을 호전 또는 이롭게 변경시키는 모든 행위를 의미한다.The term "treatment" used in the present invention refers to all activities that improve or beneficially change the symptoms of a specific disease by administering the composition of the present invention.
본 발명의 약학 조성물에는 유효성분 이외에 보조제(adjuvant)를 추가로 포함할 수 있다. 상기 보조제는 당해 기술분야에 알려진 것이라면 어느 것이나 제한 없이 사용할 수 있으나, 예를 들어 프로인트(Freund)의 완전 보조제 또는 불완전 보조제를 더 포함하여 그 효과를 증가시킬 수 있다.The pharmaceutical composition of the present invention may further include an adjuvant in addition to the active ingredient. As long as the adjuvant is known in the art, any one may be used without limitation, but, for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the effect.
본 발명에 따른 약학 조성물은 유효성분을 약학적으로 허용된 담체에 혼입시킨 형태로 제조될 수 있다. 여기서, 약학적으로 허용된 담체는 제약 분야에서 통상 사용되는 담체, 부형제 및 희석제를 포함한다. 본 발명의 약학 조성물에 이용할 수 있는 약학적으로 허용된 담체는 이들로 제한되는 것은 아니지만, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The pharmaceutical composition according to the present invention may be prepared in the form of incorporating the active ingredient into a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers usable in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀전, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or sterile injection solutions according to conventional methods, respectively. .
제제화할 경우에는 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 그러한 고형 제제는 유효성분에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘 카르보네이트, 수크로스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 일반적으로 사용되는 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수용성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수용성용제, 현탁제로는 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브유와 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.When formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations contain at least one or more excipients such as starch, calcium carbonate, sucrose, lactose, and gelatin in addition to active ingredients. It can be prepared by mixing etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc. In addition to commonly used diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. can 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 solvents and suspending agents. As a base for suppositories, witepsol, tween 61, cacao paper, laurin paper, glycerogelatin, and the like may be used.
본 발명에 따른 약학 조성물은 개체에 다양한 경로로 투여될 수 있다. 투여의 모든 방식이 예상될 수 있는데, 예를 들면 경구, 정맥, 근육, 피하, 복강내 주사에 의해 투여될 수 있다.The pharmaceutical composition according to the present invention can be administered to a subject by various routes. All modes of administration are contemplated, eg oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
본 발명에 따른 약학 조성물의 투여량은 개체의 연령, 체중, 성별, 신체 상태 등을 고려하여 선택된다. 상기 약학 조성물 중 포함되는 유효성분의 농도는 대상에 따라 다양하게 선택할 수 있음은 자명하며, 바람직하게는 약학 조성물에0.01 ~ 5,000 ㎍/ml의 농도로 포함되는 것이다. 그 농도가 0.01 ㎍/ml 미만일 경우에는 약학 활성이 나타나지 않을 수 있고, 5,000 ㎍/ml를 초과할 경우에는 인체에 독성을 나타낼 수 있다.The dosage of the pharmaceutical composition according to the present invention is selected in consideration of the age, weight, sex, and physical condition of the subject. It is obvious that the concentration of the active ingredient included in the pharmaceutical composition can be variously selected according to the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 μg/ml. If the concentration is less than 0.01 μg/ml, pharmacological activity may not appear, and if the concentration exceeds 5,000 μg/ml, toxicity to the human body may be exhibited.
본 발명의 일실시예에 따르면, 상기 면역질환은, 전신성 홍반성 루푸스(systemic lupus erythematosus), 전신 경화증(systemic sclerosis) 류마티스 관절염 (Rheumatoid Arthritis), 골관절염(Osteoarthritis), 천식 (Asthma), 피부염 (Dermititis), 건선 (Psoriasis), 낭섬유증 (Cystic Fibrosis), 다발성 경화증 (Multiple Sclerosis), 뇌척수염(encephalomyelitis), 쇼그렌 증후군(Sjogren syndrome), 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 사구체신염(glomerulonephritis), 폐섬유증(pulmonary fibrosis), 염증성장질환 (Inflammatory Bowel Dieseses), 자가면역성 당뇨 (Autoimmune Diabetes), 당뇨 망막증 (Diabetic retinopathy), 비염 (Rhinitis), 혀혈-재관류 손상 (Ischemia-reperfusion injury), 혈관성형술후 재협착 (Post-angioplasty restenosis), 만성 폐색성 심장 질환 (Chronic obstructive pulmonary diseases; COPD), 그레이브병 (Graves disease), 위장관 알러지 (Gastrointestinal allergies), 결막염 (Conjunctivitis), 죽상경화증 (Atherosclerosis), 관상동맥질환 (Coronary artery disease), 협심증 (Angina), 이식거부질환, 이식편대숙주질환(GVHD) 및 소동맥 질환으로 이루어진 군으로부터 선택되는 것일 수 있고, 바람직하게는 전신 홍반성 루푸스 또는 전신 경화증이나, 이에 제한되지는 않는다.According to one embodiment of the present invention, the immune disease is systemic lupus erythematosus (systemic lupus erythematosus), systemic sclerosis (systemic sclerosis) rheumatoid arthritis (Rheumatoid Arthritis), osteoarthritis (Osteoarthritis), asthma (Asthma), dermatitis (Dermititis) ), Psoriasis, Cystic Fibrosis, Multiple Sclerosis, Encephalomyelitis, Sjogren syndrome, Hashimoto thyroiditis, Polymyositis, Scleroderma , Addison disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, inflammatory bowel diseases, autoimmune diabetes, Diabetic retinopathy, Rhinitis, Ischemia-reperfusion injury, Post-angioplasty restenosis, Chronic obstructive pulmonary diseases (COPD), Graves Graves disease, Gastrointestinal allergies, Conjunctivitis, Atherosclerosis, Coronary artery disease, Angina, Graft rejection disease, Graft-versus-Host disease (GVHD) and It may be selected from the group consisting of small artery disease, preferably systemic lupus erythematosus or systemic sclerosis, but is not limited thereto.
본 발명의 일실시예에 따르면, 상기 황산아연은, 혈청 내 IgG2a를 감소시키는 것일 수 있고, 혈청 내 항-이중가닥 DNA(anti-dsDNA) 항체를 감소시키는 것일 수 있다.According to one embodiment of the present invention, the zinc sulfate may decrease IgG2a in serum and may decrease anti-double-stranded DNA (anti-dsDNA) antibodies in serum.
본 발명의 일실시예에 따르면, 신장 조직의 손상을 보호하는 것일 수 있고, 바람직하게는, 막성 사구체신염 지수(membranous glomerulonephritis score)를 감소시키는 것일 수 있으며, 소변 내 알부민/크레아티닌 비율(albumin/creatinine ratio)을 감소시키는 것일 수 있다.According to one embodiment of the present invention, it may be to protect renal tissue damage, preferably, it may be to reduce the membranous glomerulonephritis score, and the albumin / creatinine ratio in urine (albumin / creatinine ratio) may be reduced.
본 발명의 일실시예에 따르면, 상기 황산아연은, 신장 조직 내 TNF-α 또는 IL-6 양성 세포의 침윤을 감소시키는 것일 수 있다.According to one embodiment of the present invention, the zinc sulfate may reduce infiltration of TNF-α or IL-6 positive cells into renal tissue.
본 발명의 일실시예에 따르면, 상기 황산아연은 피부 진피의 두께를 감소시키는 것일 수 있다.According to one embodiment of the present invention, the zinc sulfate may reduce the thickness of the skin dermis.
본 발명의 일실시예에 따르면, 상기 황산아연은, 조직의 섬유화를 억제하는 것일 수 있고, 상기 조직은 피부, 폐, 간, 근육, 신장, 장조직 및 비장으로 이루어진 군에서 선택된 조직일 수 있으며, 바람직하게는 피부 또는 폐 조직이나, 이에 제한되지는 않는다.According to one embodiment of the present invention, the zinc sulfate may inhibit fibrosis of a tissue, and the tissue may be a tissue selected from the group consisting of skin, lung, liver, muscle, kidney, intestinal tissue, and spleen; , preferably skin or lung tissue, but is not limited thereto.
본 발명의 일실시예에 따르면, 상기 황산아연은, 면역세포의 발현을 조절하는 것일 수 있다.According to one embodiment of the present invention, the zinc sulfate may regulate the expression of immune cells.
본 발명의 일실시예에 따르면, 상기 면역세포는, double negative T cell, regulatory T cell (Treg), plasma cell, follicular B cell 및 Th17로 이루어진 군에서 선택된 면역세포일 수 있다.According to one embodiment of the present invention, the immune cells may be immune cells selected from the group consisting of double negative T cells, regulatory T cells (Treg), plasma cells, follicular B cells, and Th17.
또한, 상기 면역세포의 발현을 조절하는 것은, double negative T cell, plasma cell, follicular B cell 및 Th17로 이루어진 군에서 선택된 면역세포의 발현을 감소시키는 것일 수 있고, Treg의 발현을 증가시키는 것일 수 있으나, 이에 제한되지는 않는다.In addition, regulating the expression of the immune cells may be to reduce the expression of immune cells selected from the group consisting of double negative T cells, plasma cells, follicular B cells and Th17, or to increase Treg expression. , but is not limited thereto.
또한, 본 발명은 황산아연(Zinc sulfate)를 유효성분으로 포함하는 면역질환의 예방 또는 개선용 식품조성물 제공한다.In addition, the present invention provides a food composition for preventing or improving immune diseases comprising zinc sulfate as an active ingredient.
본 발명에서 사용되는 용어 “개선”은 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term "improvement" refers to any action that at least reduces the severity of a parameter related to the condition being treated, for example, a symptom.
본 발명의 식품 조성물은 본 발명의 유효성분을 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.In addition to containing the active ingredient of the present invention, the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like conventional food compositions.
상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 본 발명의 식품 조성물은 상기 약학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등이 있다.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. As the flavoring agents described above, natural flavoring agents (thaumatin), stevia extracts (eg rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can advantageously be used. The food composition of the present invention can be formulated in the same way as the pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gum, candy, ice cream, alcoholic beverages, vitamin complexes and health supplements, etc. there is
또한 상기 식품 조성물은 유효성분인 추출물 외에 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 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, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition, the food composition, in addition to the active ingredient extract, various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors 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 food composition of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages, and vegetable beverages.
본 발명의 기능성 식품 조성물은 면역질환의 예방 또는 치료 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공될 수 있다. 본 발명에서 '건강기능성 식품 조성물'이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. 상기 '식품 첨가물 공전'에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료 제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다. 예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다. 캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다. 환 형태의 건강기능식품은 본 발명의 유효성분과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다. 과립 형태의 건강기능식품은 본 발명의 유효성분의 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The functional food composition of the present invention may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or treating immune diseases. In the present invention, 'health functional food composition' refers to a food manufactured and processed using raw materials or ingredients having useful functionality for the human body according to Health Functional Food Act No. 6727, and the structure and function of the human body It refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients or physiological functions. The health functional food of the present invention may contain ordinary food additives, and the suitability as a food additive is determined according to the general rules of the Food Additive Code and General Test Methods approved by the Food and Drug Administration, unless otherwise specified. It is judged according to standards and standards. Examples of the items listed in the 'Food Additive Code' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, kaoliang pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations. For example, a health functional food in the form of a tablet is obtained by granulating a mixture obtained by mixing the active ingredient of the present invention with an excipient, a binder, a disintegrant, and other additives in a conventional manner, and then adding a lubricant or the like to compression molding, or as described above. The mixture can be directly compression molded. In addition, the health functional food in the form of a tablet may contain a flavoring agent and the like as needed. Among health functional foods in the form of capsules, hard capsules can be prepared by filling a mixture in which the active ingredient of the present invention is mixed with additives such as excipients in a normal hard capsule. It can be prepared by filling the mixture mixed with gelatin in a capsule base. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary. The health functional food in the form of a pill can be prepared by molding a mixture of the active ingredient of the present invention mixed with an excipient, a binder, a disintegrant, etc. by a conventionally known method, and can be coated with sucrose or other coating agent if necessary, Alternatively, the surface may be coated with a material such as starch or talc. Health functional food in the form of granules can be prepared in granular form by a conventionally known method of mixing the active ingredient of the present invention with excipients, binders, disintegrants, etc., and, if necessary, flavoring agents, flavoring agents, etc. can
이하, 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail by examples. These examples are merely for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
<실시예 1> 황산아연의 루푸스 질환에 대한 효과 확인<Example 1> Confirmation of the effect of zinc sulfate on lupus disease
<1-1> 루푸스 동물모델<1-1> Lupus animal model
본 발명의 황산아연(Zinc sulfate, ZnSO4)의 루푸스(Lupus)의 치료 효과를 확인하기 위하여, 루푸스 동물모델을 이용하였다. 구체적으로 루푸스 동물모델인 8주령의 MRL/lpr 마우스에 황산아연 100 μg을 증류수 200 μl에 희석하여 매일 경구 투여 하였다. 실험 전 소변과 혈청을 수득하였고, 이후 약물 투여를 시작한 시점부터 2주 간격으로 소변과 혈청을 추가로 수득하였다. 체중은 약물투여 시작부터 4주 간격으로 측정하였으며, 약물 투여 후 16주차에 마우스를 희생하였다. 대조군으로는 증류수를 경구투여한 질병 대조군(Con)을 이용하였다.In order to confirm the lupus treatment effect of the zinc sulfate (ZnSO 4 ) of the present invention, a lupus animal model was used. Specifically, 100 μg of zinc sulfate diluted in 200 μl of distilled water was orally administered daily to 8-week-old MRL/lpr mice, which are lupus animal models. Urine and serum were obtained before the experiment, and then urine and serum were additionally obtained at intervals of 2 weeks from the start of drug administration. Body weight was measured at 4-week intervals from the start of drug administration, and mice were sacrificed at 16 weeks after drug administration. As a control group, a disease control group (Con) orally administered with distilled water was used.
<1-2> 황산아연의 루푸스 제어 확인<1-2> Confirmation of Lupus Control by Zinc Sulfate
상기 실시예 1-1의 마우스 동물모델의 체중을 측정하고, 혈액 및 혈청으로부터 루푸스와 관련된 인자들을 분석하였다. 구체적으로는, 수득된 혈액으로부터, CD4-CD8- 이중 음성 T 세포(CD4-CD8- double negative T cell)을 측정하였으며, 혈청 내에서, 루푸스의 주요한 마커인 anti-dsDAN 및 IgG2a를 측정하였다.The body weight of the mouse animal model of Example 1-1 was measured, and factors related to lupus were analyzed from blood and serum. Specifically, CD4 - CD8 - double negative T cells were measured from the obtained blood, and anti-dsDAN and IgG2a , which are major markers of lupus, were measured in serum.
그 결과, 황산아연이 투입된 루푸스 동물모델은, 대조군과 비교하여, 체중이 유의적으로 감소하는 것을 확인하였으며(도 1A), 혈액 내 CD4-CD8- 이중 음성 T 세포가 유의적으로 감소하는 것을 확인하였다(도 1B). 또한, 혈청 내 루푸스 마커인 anti-dsDAN 및 IgG2a가 대조군과 비교하여 유의적으로 감소한 것을 확인하였다(도 2A 및 도 2B).As a result, it was confirmed that the lupus animal model injected with zinc sulfate had a significant decrease in body weight compared to the control group (FIG. 1A), and a significant decrease in CD4 - CD8 - double negative T cells in the blood. (FIG. 1B). In addition, it was confirmed that anti-dsDAN and IgG2a, which are lupus markers in serum, were significantly decreased compared to the control group (FIGS. 2A and 2B).
<실시예 2> 황산아연의 신장 보호 효과 확인<Example 2> Confirmation of the renal protective effect of zinc sulfate
상기 실시예 1-1에서 희생된 마우스로부터, 신장을 수득하고, 이를 절편으로 제작하여, 헤마톡실린 & 에오신(Hematoxylin & Eosin, H&E) 염색으로 황산아연이 신장의 손상을 보호하는지 막성 사구체신염 지수(membranous glomerulonephritis score)로 확인하고자 하였다. 또한, 상기 실시예 1-1에서 수득된 소변 샘플로부터, 사구체 기능을 확인할 수 있는 마커인 알부민/크레아티닌 비율(albumin/creatinine ratio)을 측정하였다.Kidneys were obtained from mice sacrificed in Example 1-1, and sections were prepared to determine whether zinc sulfate protects kidney damage by hematoxylin & eosin (H&E) staining. Membrane glomerulonephritis index (membranous glomerulonephritis score). In addition, from the urine samples obtained in Example 1-1, the albumin/creatinine ratio, which is a marker for confirming glomerular function, was measured.
그 결과, 도 3에 나타낸 바와 같이, 황산아연이 투여된 루푸스 동물모델은, 대조군과 비교하여, 막성 사구체신염 지수가 유의적으로 감소한 것을 확인하였으며, 사구체 기능과 관련된 알부민/크레아티닌 비율 또한 유의하게 감소한 것을 확인하였다. As a result, as shown in FIG. 3, in the lupus animal model administered with zinc sulfate, it was confirmed that the membranous glomerulonephritis index was significantly reduced compared to the control group, and the albumin / creatinine ratio related to glomerular function was also significantly reduced. confirmed that
<실시예 3> 루푸스 동물모델에서의 면역조직화학염색<Example 3> Immunohistochemical staining in lupus animal models
상기 실시예 1-1에서 희생된 마우스의 신장 조직에서, 염증과 관련된 세포의 발현을 확인하고자 하였다. 구체적으로, 수득된 신장조직의 절편을 제작하고, 이를 면역조직화학염색으로 염색하여, TNF-alpha 및 IL-6를 발현하는 세포를 분석하였다.In the kidney tissue of the mouse sacrificed in Example 1-1, the expression of cells related to inflammation was confirmed. Specifically, sections of the obtained kidney tissue were prepared, stained with immunohistochemical staining, and cells expressing TNF-alpha and IL-6 were analyzed.
그 결과, 도 4에 나타낸 바와 같이, 황산아연을 투여한 루푸스 동물모델에서는 대조군과 비교하여, 신장 조직 내의 TNF-alpha 및 IL-6를 발현하는 세포가 유의적으로 감소한 것을 확인하였다.As a result, as shown in FIG. 4, it was confirmed that in the lupus animal model administered with zinc sulfate, cells expressing TNF-alpha and IL-6 in the kidney tissue were significantly reduced compared to the control group.
<실시예 4> 황산아연의 면역세포 조절 확인(루푸스, Ex vivo)<Example 4> Confirmation of immune cell regulation by zinc sulfate (lupus, ex vivo)
<4-1> 혈액내 면역세포 조절 확인<4-1> Confirmation of regulation of immune cells in blood
상기 실시예 1-1에서 희생된 마우스의 세포 표현형을 분석하여, 황산아연이 면역세포를 조절하는지 확인하고자 하였다. 구체적으로, 상기 마우스로부터 수득된 혈액에서, 루푸스와 관련된 면역세포인, 조절 T 세포 (regulatory T cell, Treg)의 발현을 유세포분석으로 분석하였다.By analyzing the cellular phenotype of the mice sacrificed in Example 1-1, it was attempted to determine whether zinc sulfate regulates immune cells. Specifically, the expression of regulatory T cells (Tregs), which are immune cells related to lupus, in the blood obtained from the mice was analyzed by flow cytometry.
그 결과, 황산아연을 루푸스 투여한 마우스 군에서는, 대조군과 비교하여 Treg가 유의적으로 증가한 것을 확인하였다(도 5).As a result, in the mouse group to which zinc sulfate was administered with lupus, it was confirmed that Treg significantly increased compared to the control group (FIG. 5).
<4-2> 비장내 면역세포 조절 확인<4-2> Confirmation of regulation of immune cells in the spleen
상기 실시예 4-1과 동일한 방법으로, 비장 내 면역세포 표현형을 확인하였다. 구체적으로, 상기 마우스로부터 수득된 비장에서, 루푸스와 관련된 CD19-CD138+ 세포(plasma cell)와 CD19+CD21 middle CD23+ 세포(follicular B cell), CD4-CD8-double negative T cell 및 Treg를 분석하였다.In the same manner as in Example 4-1, the phenotype of immune cells in the spleen was confirmed. Specifically, in the spleen obtained from the mouse, lupus-related CD19 - CD138 + cells (plasma cells), CD19 + CD21 middle CD23 + cells (follicular B cells), CD4 - CD8 - double negative T cells and Tregs were analyzed. .
그 결과, 황산아연을 투여한 루푸스 마우스 군에서는, 대조군과 비교하여, CD19-CD138+ 형질세포 및 CD19+CD21 middle CD23+ follicular B 세포의 수는 감소하였으며, Treg는 유의적으로 증가한 것을 확인하였다(도 6A 내지 도 6D).As a result, in the lupus mouse group administered with zinc sulfate, compared to the control group, the number of CD19 - CD138 + plasma cells and CD19 + CD21 middle CD23 + follicular B cells decreased, and it was confirmed that Tregs significantly increased ( 6A to 6D).
<실시예 5> 황산아연의 전신 경화증에 대한 효과 확인<Example 5> Confirmation of the effect of zinc sulfate on systemic sclerosis
<5-1> 전신 경화증 동물 모델<5-1> Systemic sclerosis animal model
본 발명의 황산아연이 전신 경화증에 효과가 있는지 확인하기 위하여, 전신 경화증 동물모델을 제작하였다. 구체적으로, B6 마우스의 목 뒷덜미에, 가로 x 세로 2cm x 2cm의 부위를 클리퍼(clipper)를 이용해 제모하였다. 제모 후 블레오마이신(Bleomycin, BLM)을 50 μg/100 μl (PBS)의 농도로 매일 2주간 피하 주사(subcutaneous injection)하여 전신 경화증을 유도하였다.In order to confirm whether the zinc sulfate of the present invention is effective for systemic sclerosis, an animal model for systemic sclerosis was prepared. Specifically, on the nape of the neck of the B6 mouse, an area measuring 2 cm x 2 cm in width x length was depilated using a clipper. After hair removal, systemic sclerosis was induced by subcutaneous injection of bleomycin (BLM) at a concentration of 50 μg/100 μl (PBS) every day for 2 weeks.
<5-2> 황산 아연에 의한 진피층 두께변화 확인<5-2> Confirmation of dermal layer thickness change by zinc sulfate
상기 실시예 5-1의 동물모델에서, BLM 투여 후 일주일 후부터 황산아연을 100 μg/200 μl (증류수)의 농도로 매일 경구투여하였다. 약물투여 4주 후 마우스를 희생하여 피부 조직을 수득하였다, 수득된 피부조직을 H&E 염색하여, 피부 진피층의 두께변화를 확인하였다. 대조군으로는 증류수만을 경구투여한 질병대조군을 이용하였다.In the animal model of Example 5-1, zinc sulfate was orally administered daily at a concentration of 100 μg/200 μl (distilled water) one week after BLM administration. After 4 weeks of drug administration, mice were sacrificed to obtain skin tissues. The obtained skin tissues were stained with H&E to confirm changes in the thickness of the dermal layer of the skin. As a control group, a disease control group in which only distilled water was orally administered was used.
그 결과, 질병대조군과 비교하여, 황산아연을 투여한 마우스군에서는, 피부 진피층의 두께가 유의적으로 감소한 것을 확인하였다(도 7).As a result, it was confirmed that the thickness of the dermal layer of the skin was significantly reduced in the mouse group administered with zinc sulfate compared to the disease control group (FIG. 7).
<실시예 6> 전신 경화증 동물 모델에서 황산아연의 섬유화(fibrosis) 억제 확인<Example 6> Confirmation of inhibition of fibrosis by zinc sulfate in an animal model of systemic sclerosis
<6-1> 피부 섬유화 억제 확인<6-1> Confirmation of inhibition of skin fibrosis
본 발명의 황산아연이 전신 경화증의 주요한 증상인 섬유화를 억제하는지 확인하고자, 상기 실시예 5-1에서 희생된 마우스의 피부조직을 Masson’s Trichrome 염색으로, collagenous connective tissue의 변화를 확인하였다. 구체적으로, Masson’s Trichrome 염색으로, collagenous connective tissue가 많을수록 푸른색으로 염색되는 것을 확인할 수 있다.In order to confirm whether the zinc sulfate of the present invention inhibits fibrosis, which is a major symptom of systemic sclerosis, the skin tissue of the mouse sacrificed in Example 5-1 was stained with Masson's Trichrome to confirm changes in collagenous connective tissue. Specifically, with Masson's Trichrome staining, it can be confirmed that the more collagenous connective tissue is, the bluer the staining is.
그 결과, 본 발명의 황산아연이 투여된 전신 경화증 마우스에서는, 질병 대조군과 비교하여, collagenous connective tissue 유의적으로 감소하는 것을 확인하였다(도 8).As a result, in mice with systemic sclerosis to which the zinc sulfate of the present invention was administered, it was confirmed that collagenous connective tissue significantly decreased compared to the disease control group (FIG. 8).
<6-2> 폐 섬유화 억제 확인<6-2> Confirmation of inhibition of pulmonary fibrosis
본 발명의 황산아연이 전신 경화증의 주요한 증상인 섬유화를 억제하는지 확인하고자, 상기 실시예 6-1과 동일한 Masson’s Trichrome 염색으로, 폐 섬유화를 확인하였다.In order to confirm whether the zinc sulfate of the present invention inhibits fibrosis, which is a major symptom of systemic sclerosis, pulmonary fibrosis was confirmed by the same Masson's Trichrome staining as in Example 6-1.
그 결과, 본 발명의 황산아연이 투여된 전신 경화증 마우스에서는, 질병대조군과 비교하여, 폐 조직의 섬유화가 유의적으로 감소한 것을 확인하였다(도 9).As a result, it was confirmed that fibrosis of lung tissue was significantly reduced in mice with systemic sclerosis to which the zinc sulfate of the present invention was administered, compared to the disease control group (FIG. 9).
<실시예 7> 황산아연의 면역세포 조절 확인(전신 경화증, Ex vivo)<Example 7> Confirmation of immune cell regulation by zinc sulfate (systemic sclerosis, ex vivo)
<7-1> 혈액내 면역세포 조절 확인<7-1> Confirmation of regulation of immune cells in blood
상기 실시예 5-1에서 희생된 마우스의 세포 표현형을 분석하여, 황산아연이 면역세포를 조절하는지 확인하고자 하였다. 구체적으로, 상기 마우스로부터 수득된 혈액에서, 전신 경화증과 관련된 면역세포인 CD4+ IL-17+ T 세포(Th17), 조절 T 세포 (regulatory T cell, Treg)의 발현을 유세포분석으로 분석하였다.By analyzing the cell phenotype of the mice sacrificed in Example 5-1, it was attempted to determine whether zinc sulfate regulates immune cells. Specifically, the expression of CD4+ IL-17+ T cells (Th17) and regulatory T cells (Treg), which are immune cells related to systemic sclerosis, in the blood obtained from the mice was analyzed by flow cytometry.
그 결과, 황산아연을 투여한 전신 경화증 마우스 군에서는, 대조군과 비교하여, Th17의 수는 감소하였으며(도 10A), Treg는 유의적으로 증가한 것을 확인하였다(도 10B).As a result, in the systemic sclerosis mouse group administered with zinc sulfate, compared to the control group, the number of Th17 decreased (FIG. 10A), and it was confirmed that Tregs significantly increased (FIG. 10B).
<7-2> 비장내 면역세포 조절 확인<7-2> Confirmation of regulation of immune cells in the spleen
상기 실시예 7-1과 동일한 방법으로, 비장 내 면역세포 표현형을 확인하였다. 구체적으로, 상기 마우스로부터 수득된 비장에서, 전신 경화증과 관련된 Th17 및 Treg를 분석하였다.In the same manner as in Example 7-1, the phenotype of immune cells in the spleen was confirmed. Specifically, Th17 and Tregs associated with systemic sclerosis were analyzed in the spleen obtained from the mouse.
그 결과, 황산아연을 투여한 전신 경화증 마우스 군에서는, 대조군과 비교하여, Th17의 수는 감소하였으며(도 11A), Treg는 유의적으로 증가한 것을 확인하였다(도 11B).As a result, in the systemic sclerosis mouse group administered with zinc sulfate, compared to the control group, the number of Th17 was decreased (FIG. 11A), and it was confirmed that Tregs were significantly increased (FIG. 11B).
따라서, 본 발명의 황산아연은, 루푸스 동물모델에서, 혈청 내 IgG2a 및 anti-dsDNA를 감소시키고, 신장조직을 보호하는 것을 확인하였으며, 전신 경화증 동물모델에서, 피부 진피층의 두께를 감소시키고, 피부 및 폐의 섬유화를 억제하는 것을 확인하였다. 또한, 황산아연이 루푸스 및 전신경화증과 관련된 면역세포인, double negative T cell, plasma cell, follicular B 및 Th17을 감소시키고, Treg를 증가시키는 것을 확인하여, 면역질환의 개선 효과가 있는 것을 확인하였다.Therefore, it was confirmed that the zinc sulfate of the present invention reduces serum IgG2a and anti-dsDNA in serum and protects renal tissue in lupus animal models, reduces the thickness of the dermal layer of skin in systemic sclerosis animal models, and reduces skin and It was confirmed that fibrosis of the lung was inhibited. In addition, it was confirmed that zinc sulfate reduces double negative T cells, plasma cells, follicular B and Th17, which are immune cells related to lupus and systemic sclerosis, and increases Treg, confirming that there is an effect of improving immune diseases.
Claims (15)
상기 면역질환은 전신성 홍반성 루푸스(systemic lupus erythematosus), 전신 경화증(systemic sclerosis), 류마티스 관절염 (Rheumatoid Arthritis), 골관절염(Osteoarthritis), 천식 (Asthma), 피부염 (Dermititis), 건선 (Psoriasis), 낭섬유증 (Cystic Fibrosis), 다발성 경화증 (Multiple Sclerosis), 뇌척수염(encephalomyelitis), 쇼그렌 증후군(Sjogren syndrome), 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 사구체신염(glomerulonephritis), 폐섬유증(pulmonary fibrosis), 염증성장질환 (Inflammatory Bowel Dieseses), 자가면역성 당뇨 (Autoimmune Diabetes), 당뇨 망막증 (Diabetic retinopathy), 비염 (Rhinitis), 혀혈-재관류 손상 (Ischemia-reperfusion injury), 혈관성형술후 재협착 (Post-angioplasty restenosis), 만성 폐색성 심장 질환 (Chronic obstructive pulmonary diseases; COPD), 그레이브병 (Graves disease), 위장관 알러지 (Gastrointestinal allergies), 결막염 (Conjunctivitis), 죽상경화증 (Atherosclerosis), 관상동맥질환 (Coronary artery disease), 협심증 (Angina), 이식거부질환, 이식편대숙주질환(GVHD) 및 소동맥 질환으로 이루어진 군으로부터 선택되는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 1,
The immune disease is systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, osteoarthritis, asthma, dermititis, psoriasis, cystic fibrosis Cystic fibrosis, multiple sclerosis, encephalomyelitis, Sjogren syndrome, Hashimoto thyroiditis, polymyositis, scleroderma, Addison disease, vitiligo (vitiligo), pernicious anemia, glomerulonephritis, pulmonary fibrosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis ( Rhinitis), Ischemia-reperfusion injury, Post-angioplasty restenosis, Chronic obstructive pulmonary diseases (COPD), Graves disease, gastrointestinal allergy ( selected from the group consisting of gastrointestinal allergies), conjunctivitis, atherosclerosis, coronary artery disease, angina, transplant rejection disease, graft versus host disease (GVHD) and small artery disease Phosphorus, a pharmaceutical composition for the prevention or treatment of immune diseases.
상기 황산아연은, 혈청 내 IgG2a를 감소시키는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 1,
The zinc sulfate, to reduce IgG2a in serum, a pharmaceutical composition for preventing or treating immune diseases.
상기 황산아연은, 혈청 내 항-이중가닥 DNA(anti-dsDNA) 항체를 감소시키는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 1,
The zinc sulfate, anti-double-stranded DNA (anti-dsDNA) antibody in the serum to reduce, the pharmaceutical composition for the prevention or treatment of immune diseases.
상기 황산아연은, 신장 조직의 손상을 보호하는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 1,
The zinc sulfate is a pharmaceutical composition for preventing or treating immune diseases, which protects renal tissue from damage.
상기 신장 조직의 손상 보호는, 막성 사구체신염 지수(membranous glomerulonephritis score)를 감소시키는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 5,
Protection against damage to the renal tissue is to reduce the membranous glomerulonephritis index (membranous glomerulonephritis score), a pharmaceutical composition for preventing or treating immune diseases.
상기 황산아연은, 신장 조직 내 TNF-α 또는 IL-6 양성 세포의 침윤을 감소시키는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 1,
The zinc sulfate is a pharmaceutical composition for preventing or treating immune diseases, which reduces the infiltration of TNF-α or IL-6 positive cells in renal tissue.
상기 황산아연은 피부 진피의 두께를 감소시키는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 1,
The zinc sulfate is to reduce the thickness of the skin dermis, a pharmaceutical composition for preventing or treating immune diseases.
상기 황산아연은, 조직의 섬유화를 억제하는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 1,
The zinc sulfate, to inhibit fibrosis of tissue, a pharmaceutical composition for the prevention or treatment of immune diseases.
상기 조직은, 피부, 폐, 간, 근육, 신장, 장 및 비장으로 이루어진 군에서 선택된 조직인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 9,
The tissue is selected from the group consisting of skin, lung, liver, muscle, kidney, intestine and spleen, a pharmaceutical composition for preventing or treating immune diseases.
상기 황산아연은, 면역세포의 발현을 조절하는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 1,
The zinc sulfate is a pharmaceutical composition for preventing or treating immune diseases, which regulates the expression of immune cells.
상기 면역세포는, double negative T cell, regulatory T cell (Treg), plasma cell, follicular B cell 및 Th17로 이루어진 군에서 선택된 면역세포인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 11,
The immune cells are immune cells selected from the group consisting of double negative T cells, regulatory T cells (Treg), plasma cells, follicular B cells and Th17, a pharmaceutical composition for preventing or treating immune diseases.
상기 면역세포의 발현 조절은, double negative T cell, plasma cell, follicular B cell 및 Th17로 이루어진 군에서 선택된 면역세포의 발현을 감소시키는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 11,
Regulating the expression of the immune cells, to reduce the expression of immune cells selected from the group consisting of double negative T cells, plasma cells, follicular B cells and Th17, the pharmaceutical composition for preventing or treating immune diseases.
상기 면역세포의 발현 조절은, Treg의 발현을 증가시키는 것인, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 11,
Regulating the expression of the immune cells, to increase the expression of Treg, a pharmaceutical composition for the prevention or treatment of immune diseases.
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