KR102266125B1 - Composition for preventing or treating inflammatory diseases and cancer, including Hibiscus syriacus leaf callus extract as an active ingredient - Google Patents
Composition for preventing or treating inflammatory diseases and cancer, including Hibiscus syriacus leaf callus extract as an active ingredient Download PDFInfo
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- KR102266125B1 KR102266125B1 KR1020200049573A KR20200049573A KR102266125B1 KR 102266125 B1 KR102266125 B1 KR 102266125B1 KR 1020200049573 A KR1020200049573 A KR 1020200049573A KR 20200049573 A KR20200049573 A KR 20200049573A KR 102266125 B1 KR102266125 B1 KR 102266125B1
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- South Korea
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- callus
- mugunghwa
- composition
- cancer
- extract
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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Abstract
Description
본 발명은, 무궁화 잎 캘러스 추출물을 유효성분으로 포함하는 염증질환 및 암의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating inflammatory diseases and cancer comprising an extract of callus leaf from Mugunghwa as an active ingredient.
염증 반응은 세포 또는 조직의 손상이나 박테리아, 곰팡이, 바이러스, 다양한 종류의 알레르기 유발물질 등의 외부감염원에 감염되었을 때 국소 혈관과 체액 중 각종 염증 매개인자 및 면역세포가 관련되어, 효소 활성화, 염증 매개물질 분비, 체액 침윤, 세포 이동, 조직 파괴 등 일련의 복합적인 생리적 반응과 홍반, 부종, 발열, 통증 등 외적 증상을 나타낸다. 평상시의 염증 반응은 외부감염원을 제거하고 손상된 조직을 재생하여 생명체 기능회복작용을 하지만, 항원이 제거되지 않거나 내부물질이 원인이 되어 염증 반응이 과도하거나 지속해서 일어나면 오히려 점막 손상을 촉진하고, 그 결과 일부에서는 암 발생 등의 질환을 이끈다.Inflammatory reactions are caused by damage to cells or tissues or infection with external infectious agents such as bacteria, fungi, viruses, and various types of allergens. Various inflammatory mediators and immune cells in local blood vessels and body fluids are involved, and enzyme activation, inflammatory mediation It exhibits a series of complex physiological reactions such as substance secretion, body fluid infiltration, cell migration, and tissue destruction, and external symptoms such as erythema, edema, fever, and pain. The usual inflammatory reaction removes external infectious agents and regenerates damaged tissues to restore the function of living things, but if antigens are not removed or internal substances are the cause and the inflammatory reaction is excessive or continuous, it rather promotes mucosal damage. In some cases, it leads to diseases such as cancer.
대장암은 매년 거의 70만 명을 사망에 이르게 하는 세계에서 4번째로 발병률이 높은 치명적인 암이다. 2030년 까지 220만건 이상의 대장암 환자가 발생하고, 110만 명이 사망할 것으로 예상되어 지고 있다. 대장암을 치료하기 위하여, 주로 사용되는 화합물로는 5-플루오르 우라실(5-fluoro uracil, 5-FU)을 사용하고 있으며, 5-FU는 대장암에 대하여 상당히 강한 종양 증식효과를 나타내는 화합물로 알려져 있다. 그러나, 5-FU는 여러 가지 위장관, 혈액 학적, 심장독성을 유발하는 것으로 알려져 있으며, 메스꺼움, 구토, 식욕 부진, 변비, 설사, 탈모증 및 호중구 감소와 같은 부작용을 나타낸다. 따라서, 대장암을 치료하기 위하여, 대장암 종양의 세포사멸을 유도하는 새로운 메커니즘을 이용하는 화합물이 요구되고 있는 실정이다.Colorectal cancer is the fourth most common and deadly cancer in the world, killing nearly 700,000 people each year. By 2030, it is expected that more than 2.2 million cases of colorectal cancer will occur and 1.1 million people will die. In order to treat colorectal cancer, 5-fluoro uracil (5-FU) is used as a compound mainly used, and 5-FU is known as a compound that exhibits a fairly strong tumor proliferation effect on colorectal cancer. have. However, 5-FU is known to cause several gastrointestinal, hematological, and cardiotoxicities, and has side effects such as nausea, vomiting, anorexia, constipation, diarrhea, alopecia and neutropenia. Therefore, in order to treat colorectal cancer, there is a need for a compound using a novel mechanism for inducing apoptosis of colorectal cancer tumors.
그러나, 새로운 화합물 또한 5-FU와는 상이한 부작용을 나타낼 수 있어, 다양한 연구를 통해서, 강한 항암효과를 가지지만 부작용이 없는 천연물을 발굴하는 것이 점점 더 부각되고 있다. 실제로 일부 천연물이 약물로 직접적으로 사용되어 지고있으며, 실제로 현재 사용되는 항암제의 50% 이상이 천연물 또는 천연물 유래의 화합물로 구성되어 있어, 이러한 천연물을 이용한 대장암 치료는 지속적으로 연구될 전망이다.However, new compounds may also exhibit different side effects from 5-FU, and through various studies, it is increasingly being emphasized to discover natural products that have strong anticancer effects but have no side effects. In fact, some natural products are used directly as drugs, and in fact, more than 50% of currently used anticancer drugs are composed of natural products or compounds derived from natural products, so colorectal cancer treatment using these natural products is expected to be continuously studied.
이러한 천연 물질 중 최근 몇 년간, 세계적으로 식물 추출물이 주목받고 있었으며, 식물 추출물은 신체에 낮은 독성을 가지지만, 강한 항암활성을 가지는 활성 성분들이 다수 포함되어 있어, 다양한 식물종으로부터 효과적인 항암제를 찾는 연구들이 진행 중이다. 최근에는 인체에 효능이 뛰어나면서 독성이 낮은 천연물로부터 항암성분의 탐색과 개발에 관심이 집중되고 있다. 예를 들어, 미국 국립암연구소(NCI, Natrinal cancer institute)에서는 1982년까지 주로 식물체에 대하여 항암검색을 실시하여 약 30,000여종의 식물의 110,000개의 식물 추출물에 대하여 항암검색을 실시한 결과 탁서스 브레비폴리아(Tazusbrebifolia)로부터 탁솔(taxol)과 감프토테카 아커미나테(Camtotheca acuminate)로부터 캄프토테신(camptothecin)을 발견하였다.Among these natural substances, plant extracts have been attracting attention worldwide in recent years, and although plant extracts have low toxicity to the body, they contain many active ingredients with strong anticancer activity, so research to find effective anticancer drugs from various plant species are in progress Recently, attention has been focused on the search and development of anti-cancer ingredients from natural products that are effective in the human body and have low toxicity. For example, the U.S. National Cancer Institute (NCI) conducted an anticancer screening on plants mainly until 1982 and conducted a cancer screening on 110,000 plant extracts of about 30,000 plants. As a result, Taxus brevifolia Taxol (taxol) from (Tazusbrebifolia) and camptothecin from (Camtotheca acuminate) were found.
히비스커스 속(Hibiscus sp.)은 전세계예 분포되어 있으며 그 수가 약 220여종에 달하는 것으로 알려져 있다. 히비스커스 속 식물은 항당뇨, 항비만, 항염증제, 항암, 항균, 간보호 및 심장 보호에 효과가 있는 것으로 알려지고 있으며, 이러한 효과를 나타내는 유기산, 플라보노이드, 페놀 화합물, 트리 테르펜 유도체 및 피토스테리오드와 같은 잠재적인 생리활성 성분을 다량 함유하고 있는 것으로 보고되었다. 히비스커스속에서 많은 연구가 이루어진 로셀(roselle)은 전통 약초로서, 전세계 약 300여종이 포함되는 다년생 관목 또는 나무로서, 전세계 열대 및 아열대 지역에 분포되어 있다.The genus Hibiscus (Hibiscus sp.) is distributed worldwide and the number is known to reach about 220 species. Plants of the genus hibiscus are known to be effective in anti-diabetic, anti-obesity, anti-inflammatory, anti-cancer, antibacterial, hepatoprotective and cardiac protection, and organic acids, flavonoids, phenolic compounds, triterpene derivatives and phytosteroids, It has been reported to contain a large amount of the same potential bioactive ingredients. Roselle, a genus of hibiscus, is a traditional medicinal herb, a perennial shrub or tree that includes about 300 species worldwide, and is distributed in tropical and subtropical regions around the world.
우리나라의 국화인 무궁화(Mugunghwa; Hibiscus syriacus L.)는 대표적인 히비스커스 속 식물로서, 국내에서만 약 200 여종이 있는 것으로 알려져 있으며, 목근피(Hibiscus syriacus bark)는 무궁화의 뿌리 및 줄기 껍질 부분으로 예로부터 한방에서 소염, 항균 등의 효능을 가진 약용식물로 이용되고 있다. 그러나, 무궁화가 우리나라의 국화임에도 불구하고 현재까지 국내에서는 무궁화의 재배 및 육종에 관한 연구만 주로 이루어지고 있고, 무궁화를 이용한 다양한 생리활성 연구가 미흡하며, 특히 염증질환의 치료 및 암 치료제로서 이용하고자 하는 연구는 미비한 실정이다.Mugunghwa (Hibiscus syriacus L.), the national flower of Korea, is a representative plant of the genus hibiscus, and it is known that there are about 200 species in Korea alone. It is used as a medicinal plant with anti-inflammatory and antibacterial effects. However, despite the fact that Mugunghwa is Korea’s national flower, research on the cultivation and breeding of Mugunghwa has been mainly conducted in Korea so far, and research on various physiological activities using Mugunghwa is insufficient. In particular, it is intended to be used as a treatment for inflammatory diseases and cancer treatment. Research on it is scarce.
한편, 식물은 식물을 구성하는 잎, 줄기, 뿌리 등 그 일부만을 이식하여도 전체 개체가 다시 형성되는 전형성능(totipotency)이 뛰어나다. 식물세포는 식물의 조직으로부터 유도된 캘러스를 말하는데, 캘러스는 정상적인 기관형성이나 조직분화를 일으키는 능력을 잃은 무정형의 조직 또는 세포덩어리로서, 식물체에서 잘라낸 조직을 옥신(Auxin)이나 싸이토키닌(Cytokinins)을 함유한 배지에서 배양하거나 식물체에 상처를 내거나 또는 식물체의 상구를 옥신으로 처리하였을 때 생긴다. 캘러스는 식물세포 배양, 특히 조직배양을 통하여 잎, 줄기, 뿌리, 근경, 열매 등 식물의 어느 부분에서도 유도될 수 있으며, 계대배양에 의해 계속해서 만들어 낼 수 있다는 특징을 가지고 있다. 식물 세포의 배양의 기본 원칙은, 모든 식물 세포는 그 세포가 유래되는 전체 식물을 건설하는 능력을 갖는다는 생물학적 사실을 이용한다. 이 전형성능은 동물의 배아줄기세포의 다분화성과 비교가능하며, 캘러스는 그 캘러스가 유도된 식물의 생리 활성 성분도 동일하게 포함하고 있다. 이러한 캘러스의 성질 때문에, 최근 캘러스의 이용에 관해 관심이 고조되고 있고, 다양한 방면에서 연구중에 있으며, 캘러스와 관련된 공개특허로서, 제10-2008-0038068호 등이 있다.On the other hand, plants have excellent totipotency, in which entire individuals are re-formed even when only a part of the leaves, stems, and roots constituting the plant is transplanted. Plant cell refers to a callus derived from plant tissue. A callus is an amorphous tissue or cell mass that has lost the ability to cause normal organogenesis or tissue differentiation. Occurs when cultured in a medium containing Callus can be induced from any part of a plant such as leaves, stems, roots, rhizomes, and fruits through plant cell culture, especially tissue culture, and has the characteristic that it can be continuously produced by subculture. The basic principle of culturing plant cells takes advantage of the biological fact that every plant cell has the ability to build the whole plant from which it is derived. This typical performance is comparable to the multipotency of embryonic stem cells of animals, and the callus also contains the physiologically active ingredients of the plant from which the callus is derived. Due to these properties of the callus, interest in the use of the callus has recently been heightened, and research is being carried out in various fields, and as a callus-related publication patent, there is No. 10-2008-0038068 No.
본 발명의 목적은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for preventing or treating cancer comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
본 발명의 다른 목적은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 암의 예방 또는 개선용 건강 기능 식품을 제공하는 것이다.Another object of the present invention is to provide a health functional food for preventing or improving cancer comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
본 발명의 또 다른 목적은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 염증질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
본 발명의 또 다른 목적은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 염증질환의 예방 또는 개선용 건강기능식품을 제공하는 것이다.Another object of the present invention is to provide a health functional food for preventing or improving inflammatory diseases comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
또한, 본 발명은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 암의 예방 또는 개선용 건강 기능 식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving cancer comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
또한, 본 발명은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 염증질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
또한, 본 발명은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 염증질환의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving inflammatory diseases comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
본 발명의 무궁화 잎 캘러스 추출물은 무궁화 잎으로 분리된 캘러스를 배양하고, 이를 추출하여, 인간 대장암 세포주인 HT-29세포주에서 효과적으로 세포 증식, 세포 이동을 억제하고, 아폽토시스 인자인 Bax/Bcl-2 발현 비 및 시토크롬 c, 카스파제-9 및 카스파제-3의 발현을 효과적으로 억제하는 것을 확인하여, 항염제 및 항암제 관련 분야에서 유용하게 이용할 수 있다.Mugunghwa leaf callus extract of the present invention is obtained by culturing a callus separated from Mugunghwa leaf, extracting it, and effectively inhibiting cell proliferation and cell migration in the human colon cancer cell line HT-29 cell line, and Bax/Bcl-2, an apoptosis factor. By confirming that the expression ratio and the expression of cytochrome c, caspase-9 and caspase-3 are effectively inhibited, it can be usefully used in the fields related to anti-inflammatory and anticancer drugs.
도 1은 본 발명의 무궁화 잎 캘러스 추출물의 GC/MS 분석으로 성분을 분석한 것이다.
도 2는 본 발명의 무궁화 잎 캘러스 추출물의 GC/MS 분석으로 분석된 성분을 나타낸 도이다.
도 3은 본 발명의 GC/MS 분석 조건을 나타낸 도이다.
도 4는 본 발명의 무궁화 잎 캘러스 추출물의 HPLC 결과를 나타낸 도이다.
도 5는 본 발명의 무궁화 잎 캘러스 추출물에 의한 HT-29세포주의 세포 생존률을 MTT assay로 확인한 결과이다.
도 6은 본 발명의 무궁화 잎 캘러스 추출물에 의한 HT-29세포주의 세포 증식 억제를 확인한 도이다.
도 7은 본 발명의 무궁화 잎 캘러스 추출물에 의한 HT-29세포주의 아폽토시스를 Hoechst33258 및 PI 염색으로 확인한 도이다.
도 8은 본 발명의 무궁화 잎 캘러스 추출물에 의한 HT-29세포주의 아폽토시스를 Hoechst33258 및 Mito-Tracker 염색으로 확인한 도이다.
도 9는 본 발명의 무궁화 잎 캘러스 추출물에 의한 HT-29세포주의 아폽토시스를 Hoechst33258 및 Lyso-tracker 염색으로 확인한 도이다.
도 10은 본 발명의 무궁화 잎 캘러스 추출물에 의해 HT-29세포주에서 발현이 변화하는 유전자를 qRT-PCR로 확인한 도이다.
도 11은 본 발명의 무궁화 잎 캘러스 추출물에 의해 HT-29세포주에서 발현이 변화하는 단백질을 웨스턴블랏팅으로 확인한 도이다.
도 12는 본 발명의 무궁화 잎 캘러스 추출물을 40 μg/ml의 농도로 처리했을 때의 Scatter plot결과를 나타낸 도이다.
도 13은 본 발명의 무궁화 잎 캘러스 추출물을 80 μg/ml의 농도로 처리했을 때의 Scatter plot결과를 나타낸 도이다.
도 14는 본 발명의 무궁화 잎 캘러스 추출물을 처리하였을 때 대조군과 비교하여 차별적으로 발현하는 유전자를 volcano plot으로 나타낸 도이다.
도 15는 본 발명의 무궁화 잎 캘러스 추출물을 처리하였을 때 총 RNA중 대조군과 비교하여 차별적으로 발현하는 유전자의 히트맵을 나타낸 도이다.1 is an analysis of components by GC/MS analysis of a callus extract of Mugunghwa leaf of the present invention.
2 is a diagram showing components analyzed by GC/MS analysis of a callus extract from Mugunghwa leaf of the present invention.
3 is a diagram showing GC/MS analysis conditions of the present invention.
4 is a diagram showing the HPLC results of the callus extract of Mugunghwa leaf of the present invention.
5 is a result of confirming the cell viability of the HT-29 cell line by the Mugunghwa leaf callus extract of the present invention by MTT assay.
6 is a view confirming the cell proliferation inhibition of the HT-29 cell line by the extract of Mugunghwa leaf callus of the present invention.
7 is a diagram confirming apoptosis of the HT-29 cell line by a callus extract of Mugunghwa leaf of the present invention by Hoechst33258 and PI staining.
8 is a diagram confirming the apoptosis of the HT-29 cell line by the callus extract of Mugunghwa leaf of the present invention by Hoechst33258 and Mito-Tracker staining.
9 is a diagram confirming the apoptosis of the HT-29 cell line by the callus extract of Mugunghwa leaf of the present invention by Hoechst33258 and Lyso-tracker staining.
10 is a diagram confirming qRT-PCR of a gene whose expression is changed in HT-29 cell line by a callus extract of Mugunghwa leaf of the present invention.
11 is a diagram confirming the expression of a protein whose expression is changed in HT-29 cell line by a callus extract of Mugunghwa leaf of the present invention by Western blotting.
Figure 12 is a diagram showing the results of the Scatter plot when the Mugunghwa leaf callus extract of the present invention is treated at a concentration of 40 μg / ml.
13 is a view showing the results of the Scatter plot when the extract of Mugunghwa leaf callus of the present invention is treated at a concentration of 80 μg/ml.
Figure 14 is a diagram showing the genes differentially expressed as compared to the control group when treated with a callus extract of Mugunghwa leaf of the present invention as a volcano plot.
15 is a diagram showing a heat map of genes differentially expressed compared to a control group among total RNA when the callus extract of Mugunghwa leaf of the present invention is treated.
본 발명은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cancer comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
본 발명에서 “약제학적으로 허용가능한”이란 생물체를 상당히 자극하지 않고 투여 활성 물질의 생물학적 활성 및 특성을 저해하지 않는 것을 의미한다."Pharmaceutically acceptable" in the present invention means that it does not significantly stimulate the organism and does not impair the biological activity and properties of the administered active substance.
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 the symptoms of a specific disease or delays the progression by administration of 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.As used herein, the term “treatment” refers to any action that improves or beneficially changes the symptoms of a specific disease by administration of the composition of the present invention.
본 발명에서 사용되는 용어 “개선”은 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소 시키는 모든 행위를 의미한다.As used herein, the term “improvement” refers to any action that at least reduces a parameter related to a condition to be treated, for example, the severity of symptoms.
본 발명에서 사용되는 용어 “캘러스”는 식물에 상처가 났을 때 생기는 유상조직 또는 유합조직을 뜻하며, 상처난 조직에 식물 호르몬 옥신을 처리하여 생기는 특수한 조직 또는 세포 덩어리를 뜻한다. 또한 캘러스는 조직배양을 함으로써 잎, 줄기 및 뿌리등 어느 부분에서도 생산할 수 있으며, 미분화된 세포덩어리를 지속적으로 계대할 수 있고, 배양 배지 내의 식물 호르몬을 조절하여, 불규칙한 도관이나, 체관으로의 분화, 부정아, 부정근의 형성 및 완전한 개체로 이를 수 있는 식물 세포의 덩어리를 의미한다. As used herein, the term “callus” refers to a callus or callus formed when a plant is injured, and refers to a special tissue or cell mass formed by treating the wounded tissue with the plant hormone auxin. In addition, callus can be produced from any part such as leaves, stems and roots by tissue culture, and can continuously pass undifferentiated cell masses, and regulate plant hormones in the culture medium to differentiate into irregular conduits or phloems, It refers to the mass of plant cells that can lead to the formation of irregular buds, irregular roots, and complete individuals.
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 a form in which the active ingredient is incorporated into a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, 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 in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., 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.In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the active ingredient, for example, starch, calcium carbonate, sucrose, lactose, gelatin. It can be prepared by mixing and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As the base of the suppository, witepsol, tween 61, cacao butter, laurin, glycerogelatin, etc. 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 may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by 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 테트라펩타이드 의 농도는 대상에 따라 다양하게 선택할 수 있음은 자명하며, 바람직하게는 약학 조성물에 0.01 ~ 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 individual's age, weight, sex, physical condition, and the like. It is self-evident that the concentration of the tetrapeptide contained in the pharmaceutical composition can be variously selected depending on the subject, and is preferably contained 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, pharmaceutical activity may not appear, and if it exceeds 5,000 μg/ml, it may be toxic to the human body.
본 발명의 일실시예에 따르면, 상기 무궁화 캘러스는 삼천리 무궁화 품종의 잎 캘러스인 것일 수 있다.According to an embodiment of the present invention, the Mugunghwa callus may be a leaf callus of Samchully Mugunghwa variety.
본 발명의 일실시예에 따르면, 상기 무궁화 캘러스는 수크로즈(sucrose), 2,4-디클로로페녹시아세트산(2,4-dichlorophenoxyacetic acid, 2,4-D), BA, MES 및 식물 한천(plant agar)을 포함하는 식물 우디 액체 배지(Woody plant media, WPM)에서 1차 배양된 캘러스인 것일 수 있다.According to an embodiment of the present invention, the Mugunghwa callus is sucrose, 2,4-dichlorophenoxyacetic acid (2,4-D), BA, MES and plant agar (plant). agar) may be a callus cultured primarily in a plant woody liquid medium (Woody plant media, WPM) containing the.
본 발명의 일실시예에 따르면, 상기 1차 배양된 캘러스는 30 g/L의 수크로즈, 1 mg/L의 2,4-D 및 0.5 mg/L의 BA를 포함하는 식물 우디 액체배지에서 2차 배양되는 것을 더 포함하는 캘러스인 것일 수 있다.According to an embodiment of the present invention, the primary cultured callus is 2 in a plant woody broth containing 30 g / L of sucrose, 1 mg / L of 2,4-D and 0.5 mg / L of BA It may be a callus that further comprises a tea cultured.
본 발명의 일실시예에 따르면, 상기 무궁화 잎 캘러스 추출물은, 암세포의 세포증식 및 세포 이동 억제 또는 세포의 핵형을 변화시키는 것일 수 있다.According to an embodiment of the present invention, the Mugunghwa leaf callus extract may inhibit cell proliferation and cell migration of cancer cells or change the karyotype of cells.
본 발명의 일실시예에 따르면, 상기 무궁화 잎 캘러스 추출물은, 암세포에서, Bax/Bcl-1 유전자의 발현 비 및 시토크롬 c(Cytochrome c), 카스파제-9(Caspase-9) 및 카스파제-3(Caspase-3)를 포함하는 유전자의 발현을 증가시켜 아폽토시스를 유도하는 것일 수 있다.According to an embodiment of the present invention, the Mugunghwa leaf callus extract, in cancer cells, the expression ratio of Bax/Bcl-1 gene and cytochrome c (Cytochrome c), caspase-9 (Caspase-9) and caspase-3 It may be to induce apoptosis by increasing the expression of a gene including (Caspase-3).
본 발명의 일실시예에 따르면, 상기 암은 이에 제한되지는 않으나 대장암, CTH 생성 종양, 급성 림프구성 또는 림프아구성 백혈병, 급성 또는 만성의 림포구성 백혈병, 급성 비림프구성 백혈병, 방광암, 뇌종양, 유방암, 경관암, 만성 골수성 백혈병, 장암, T-존 림프종, 자궁내막증, 식도암, 담즙 방광암, 에윙스 육종(Ewing's sarcoma), 두 및 목암, 설암, 홉킨스 림프종, 카포시스 육종, 신장암, 간암, 폐암, 중피종, 다발성 골수종, 신경아세포종, 비홉킨 림프종, 골육종, 난소암, 신경아세포종, 유선암, 경관암, 전립선암, 췌장암, 페니스암, 레티노블라스토마, 피부암, 위암, 갑상선암, 자궁암, 고환암, 윌름스 종양, 및 트로포블라스토마로 이루어진 군으로부터 선택된 1종 이상인 것일 수 있으며, 보다 상세하게는 대장암 일 수 있다.According to one embodiment of the present invention, the cancer is, but not limited to, colorectal cancer, CTH-producing tumor, acute lymphocytic or lymphoblastic leukemia, acute or chronic lymphocytic leukemia, acute non-lymphocytic leukemia, bladder cancer, brain tumor , breast cancer, cervical cancer, chronic myelogenous leukemia, bowel cancer, T-zone lymphoma, endometriosis, esophageal cancer, gall bladder cancer, Ewing's sarcoma, head and neck cancer, tongue cancer, Hopkins lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer , lung cancer, mesothelioma, multiple myeloma, neuroblastoma, non-Hopkin's lymphoma, osteosarcoma, ovarian cancer, neuroblastoma, mammary gland cancer, cervical cancer, prostate cancer, pancreatic cancer, penis cancer, retinoblastoma, skin cancer, stomach cancer, thyroid cancer, uterine cancer, testicular cancer, It may be at least one selected from the group consisting of Wilms' tumor and tropoblastoma, and more specifically, colorectal cancer.
또한, 본 발명은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 암의 예방 또는 개선용 건강 기능 식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving cancer comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
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 a conventional food composition.
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 above-mentioned 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 dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. The above-mentioned flavoring agents can advantageously use natural flavoring agents (Taumatin), stevia extract (eg rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). The food composition of the present invention may be formulated in the same manner 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, gums, candy, ice cream, alcoholic beverages, vitamin complexes, and health supplements. There is this.
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 includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavoring agents, colorants and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages.
본 발명의 기능성 식품 조성물은 염증질환 및 암의 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 유효The functional food composition of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or treating inflammatory diseases and cancer. In the present invention, the term 'health functional food composition' refers to a food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulating nutrients or physiological effects. The health functional food of the present invention may include normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to standards and standards. The items listed in the 'Food Additives Codex' 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, high pigment, and guar gum; Mixed preparations, such as a sodium L-glutamate preparation, a noodle-added alkali agent, a preservative preparation, and a tar dye preparation, etc. are mentioned. For example, a health functional food in tablet form is granulated by a conventional method by mixing the active ingredient of the present invention with an excipient, a binder, a disintegrant and other additives, followed by compression molding with a lubricant, etc. The mixture can be compression molded directly. In addition, the health functional food in the form of tablets may contain a corrosive agent and the like, if necessary. Among health functional foods in the form of capsules, hard capsules are effective in the present invention in ordinary hard capsules.
성분을 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.It can be prepared by filling a mixture in which the ingredients are mixed with additives such as excipients, and soft capsules can be prepared by filling a mixture of the active ingredient of the present invention with additives such as excipients in a capsule base such as gelatin. The soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary. A health functional food in the form of a ring can be prepared by molding a mixture of the active ingredient of the present invention with an excipient, a binder, a disintegrant, etc. by a conventionally known method, and can be coated with sucrose or other peeling agent if necessary, Alternatively, the surface may be coated with a material such as starch or talc. The health functional food in the form of granules can be prepared in granular form by a conventionally known method by mixing a mixture of the active ingredient excipients, binders, disintegrants, etc. of the present invention, and may contain flavoring agents, flavoring agents, etc. as needed. can
또한, 본 발명은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 염증질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
본 발명에서 “염증”이란, 어떤 자극에 대한 생체조직의 방어반응의 하나로, 각종 유해한 자극에 의한 상해를 제거하여 원래의 상태로 회복하려는 생체방어 기전이다. 염증의 자극에는, 감염 혹은 화학적, 물리적 자극이 있으며, 염증의 과정은 급성과 만성 염증의 2가지로 나눌 수 있다. 급성염증은 수일 이내의 단기적인 반응이며, 혈장성분이나 혈구 등이 미소순환계를 게재하여 이물 제거에 관련한다. 만성염증은 지속시간이 길며, 조직의 증식 등이 보여진다.In the present invention, "inflammation" is one of the defensive responses of biological tissues to certain stimuli, and is a biological defense mechanism that seeks to recover to the original state by removing injuries caused by various harmful stimuli. Inflammation stimuli include infection or chemical and physical stimuli, and the inflammatory process can be divided into acute and chronic inflammation. Acute inflammation is a short-term reaction within a few days, and plasma components or blood cells are involved in the removal of foreign substances by opening the microcirculation system. Chronic inflammation has a long duration, and tissue proliferation is seen.
본 발명의 일실시예에 따르면, 상기 염증질환은 이에 제한되지는 않으나 관절염, 비염, 간염, 각막염, 위염, 장염, 신장염, 기관지염, 흉막염, 복막염, 척추염, 췌장염, 염증성 통증, 요도염, 방광염, 화상 염증, 피부염, 치주염 및 치은염 군으로부터 선택된 1종 이상인 것일 수 있으며, 바람직하게는 관절염이다.According to an embodiment of the present invention, the inflammatory disease is, but not limited to, arthritis, rhinitis, hepatitis, keratitis, gastritis, enteritis, nephritis, bronchitis, pleurisy, peritonitis, spondylitis, pancreatitis, inflammatory pain, urethritis, cystitis, burns It may be one or more selected from the group consisting of inflammation, dermatitis, periodontitis and gingivitis, preferably arthritis.
또한, 본 발명은 무궁화 잎(Hibiscus syriacus leaves) 캘러스 추출물을 유효성분으로 포함하는 염증질환의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving inflammatory diseases comprising a callus extract of Hibiscus syriacus leaves as an active ingredient.
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 way of Examples. These examples are merely for illustrating 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> 사용 시약<Example 1> Reagent used
MRS(deMan, Rogosa, and Sharp) 액체 및 고체 배지는 Becton, Dickinson 및 Company (BD, San Jose, CA USA)에서 구입하였다. Dulbecco’s modified Eagle’s 배지(DMEM), 페니실린(penicillin), 스트렙토마이신(streptomycin) 및 우태아혈청(fetal bovine serum, FBS)은 무두 GenDEPOT(katy, TX, USA)에서 구입하였다. 크리시마린(Crisimarin), 히스피둘린(hispidulin), 크리스마틴(Crismartin), 2,2-디페닐-1-피크릴하이드라지일(2,2-diphenyl-1-picrylhydrazyl, DPPH), 디메틸설폭사이드(dimethyl sulfoxide, DMSO) 및 3-(4,5-디메틸티아졸-2-일)-2,5 디페닐테트라졸륨 브로마이드(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT)는 Sigma-Aldrich(St. Louism MO, USA)에서 구입하였다.MRS (deMan, Rogosa, and Sharp) liquid and solid media were purchased from Becton, Dickinson and Company (BD, San Jose, CA USA). Dulbecco's modified Eagle's medium (DMEM), penicillin, streptomycin, and fetal bovine serum (FBS) were purchased from tanned GenDEPOT (katy, TX, USA). Crisimarin, hispidulin, Crismartin, 2,2-diphenyl-1-picrylhydrazyl (DPPH), dimethyl sulfoxide (dimethyl sulfoxide, DMSO) and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide, MTT) was purchased from Sigma-Aldrich (St. Louism MO, USA).
<실시예 2> 통계학적 분석<Example 2> Statistical analysis
본 발명의 실시예와 관련된 실험은 모두 3회 수행하였으며, 데이터는 평균±표준 오차로 표시하였다. 통계분석은 SPSS 소프트웨어 버전 22.0(IBM, Armonk, NY, USA) 및 GraphPad Prism version 6 (GraphPad Software, Inc., La Jolla, CA, USA)을 사용하여 분석하였다. 일원 분산 분석(ANOVA)에 이어 Student’s t-test. P < 0.05, P< 0.01 및 P< 0.001은 통계적으로 유의한 것으로 간주하였다.All experiments related to Examples of the present invention were performed three times, and data were expressed as mean±standard error. Statistical analysis was performed using SPSS software version 22.0 (IBM, Armonk, NY, USA) and GraphPad Prism version 6 (GraphPad Software, Inc., La Jolla, CA, USA). One-way analysis of variance (ANOVA) followed by Student’s t-test. P < 0.05, P < 0.01 and P < 0.001 were considered statistically significant.
<실시예 3> 무궁화 잎 캘러스의 유도 및 추출<Example 3> Induction and extraction of Mugunghwa leaf callus
<3-1> 무궁화 잎 캘러스의 유도 및 수득<3-1> Derivation and obtaining of leaf callus of Mugunghwa
삼천리 품종의 무궁화(Hibiscus syriacus)의 잎(leave)을 70% 에탄올을 이용하여 1분간 표면 살균 하였으며, 에탄올 살균 후 3% 차아 염소산 나트륨 용액으로 10분간 추가 살균하였다. 살균된 무궁화 잎은 고압 멸균된 증류수로 10회 세척하여, 여과지를 이용하여, 수분을 제거하였다. 수분이 제거된 무궁화 잎은 무균적으로 0.5 cm의 조각으로 절편하고, 추가적으로 상처를 입혔으며, 캘러스를 유도하기 위하여, 30 g/L의 수크로즈(sucrose), 1 mg/L의 2,4-디클로로페녹시아세트산(2,4-dichlorophenoxyacetic acid, 2,4-D), 0.5 mg/L의 BA, 0.5 g/L의 MES 및 8 g/L의 식물 한천(plant agar)을 포함하는 pH 5.7의 멸균된 식물 우디 고체 배지(Woody plant media, WPM)에 절편된 무궁화 잎을 올려 23 ℃, 40% 습도 및 명조건 하에서 캘러스가 형성될 때까지 1차 배양 하였다.The leaves of Hibiscus syriacus of Samchully cultivar were surface sterilized for 1 minute using 70% ethanol, and then further sterilized with 3% sodium hypochlorite solution for 10 minutes after ethanol sterilization. Sterilized Mugunghwa leaves were washed 10 times with autoclaved distilled water, and moisture was removed using filter paper. Mugunghwa leaves from which moisture has been removed were aseptically sectioned into 0.5 cm pieces, further wounded, and to induce callus, 30 g/L sucrose, 1 mg/
캘러스가 유도되었을 때, 캘러스를 수득하고, 수득된 캘러스는 30 g/L의 수크로즈, 1 mg/L의 2,4-D 및 0.5 mg/L의 BA를 포함하는 포함하는 pH 5.7의 멸균된 식물 우디 액체 배지에서, 100 rpm, 23 ℃ 암조건에서 4주간 2차 진탕배양 하였다. 배양이 완료된 캘러스는 3000 rpm으로 10분간 원심분리하여, 상층액을 버리고 수득된 캘러스를 4℃에서 보관하여 추후 실험에 사용하였다.When the callus was induced, the callus was obtained, and the obtained callus was sterilized at pH 5.7 containing 30 g/L sucrose, 1 mg/
<3-2> 무궁화 잎 캘러스 추출물 제조<3-2> Preparation of Mugunghwa leaf callus extract
수득된 캘러스에 70% 에탄올을 첨가하여, 37℃의 진탕배양기에서 24시간 동안 교반하였다. 교반된 혼합물은 여과하여, 추출물을 분리하였으며, 분리된 무궁화 잎 캘러스 에탄올 추출물은 40℃의 회전 증발기로 에탄올을 증발시켰으며, 증발 후 남은 추출물에 증류수를 첨가하여 용해시킨 후 용해된 용액을 동결 건조하여, 무궁화 잎 추출물(Hibiscus syriacus extract, HSE)을 얻었으며, 4℃에 보관하여 추후 실험에 사용하였다.70% ethanol was added to the obtained callus and stirred for 24 hours in a shaker incubator at 37°C. The stirred mixture was filtered to separate the extract, and the separated Mugunghwa leaf callus ethanol extract was evaporated with a rotary evaporator at 40 ° C. After evaporation, distilled water was added to the remaining extract to dissolve it, and then the dissolved solution was freeze-dried. Thus, Mugunghwa leaf extract (Hibiscus syriacus extract, HSE) was obtained and stored at 4° C. to be used for further experiments.
<실시예 4> GC/MS 분석<Example 4> GC/MS analysis
HSE는 가스크로마토그래피 질량 분석(gas chromatograph mass analysis, GC/MS)를 위하여, 5 mg을 GC 바이알에 넣은다음 피리딘 100 μl의 20000ppm 메틸 하이드록실 클로라이드 아민(Methyl hydroxyl chloride amine, MHCA)을 첨가하여 5분간 초음파 처리 하였다. 초음파 처리로 용해된 캘러스 추출물은 30℃의 오븐에서 90분간 산화시켰다. 산화된 샘플 50 μl를 유리 바이알에 옮긴 후 1% TMCS 용액을 함유한 BSTFA 50 μl와 500ppm 플루오란텐 50 μl를 첨가한 후 60℃의 오븐에서 30분 동안 반응시켰다. GC/MS 분석은 Thermo Xcalibur 기기 시스템(Thermo Fisher Scientific, Massachusetts, USA)을 이용하여 수행되었으며, Thermoscientific ISQ 질량분석기, TRACE 1300 시리즈 가스 크로마토그래피 v2.0 및 TriPlus 100 LS 액체 오토 샘플러 방법으로 분석을 설정하였으며, MS 수송라인 및 이온 소스 온도는 각각 310℃ 및 270℃로 설정하였다. 분석을 위해 초기 오븐 온도는 2분간 50℃에서 유지시켜 안정화 하였으며, 이후 20분간 320℃에 도달하도록 5℃/분의 송승속도로 설정하였다. 스플릿 온도는 300℃이며, 스플릿 및 캐리어 가스인 수소의 flow-rates는 각각 30 ml/분 및 20 ml/분 (2 분)의 조건으로 분석하였다(도 3). For HSE, for gas chromatograph mass analysis (GC/MS), 5 mg was placed in a GC vial, and then 100 μl of pyridine 20000 ppm methyl hydroxyl chloride amine (MHCA) was added. sonicated for minutes. The callus extract dissolved by sonication was oxidized in an oven at 30° C. for 90 minutes. After 50 μl of the oxidized sample was transferred to a glass vial, 50 μl of BSTFA containing 1% TMCS solution and 50 μl of 500 ppm fluoranthene were added, and then reacted in an oven at 60° C. for 30 minutes. GC/MS analyzes were performed using a Thermo Xcalibur instrument system (Thermo Fisher Scientific, Massachusetts, USA), set up for analysis with a Thermoscientific ISQ mass spectrometer, TRACE 1300 series gas chromatography v2.0 and
그 결과 도 1 및 도2에 나타낸 바와 같이, 무궁화 캘러스 추출물은 인산(Phosphoric acid)이 가장 풍부하게 10.61% 차지하였으며, 그 다음으로, 2-부텐디오산(2-Butenedioic acid) 이 3.13%, 부탄디오산(Butanedioic acid) 2.98% 순으로 차지하였다. 다른 지방산 및 조성의 경우 프로판산(Propanoic acid, 1.49%), D-(-)-락트산(D-(-)-Lactic acid, 1.49%), 부탄산(Butanoic acid, 1.33%), 벤조산(Benzoic acid, 1.28%), D-글루콘산(D-Gluconic acid, 1.11%), 1,2,3-프로판트리카르복실산(1,2,3-Propanetricarboxylic acid, 1.05%), 리놀레산(Linoleic acid, 0.97%), 팔미트산(Palmitic acid, 0.67%), 알파-리놀렌산(alpha-Linolenic acid, 0.63%), 아세트산(Acetic acid, 0.43%), 헥산(Hexanedioic acid, 0.33%), 노난산(Nonanoic acid, 0.24%), D-과당(D-Fructose, 5.01%), 3-이소프로핀-2-페닐인돌(3-Isopropyl-2-phenyl-indole, 4.89%), 이노시톨(Inositol, 1.69%)이 포함되었다.As a result, as shown in Figures 1 and 2, the Mugunghwa callus extract occupied the most abundant phosphoric acid 10.61%, followed by 2-butenedioic acid 3.13%, butane Dio acid (Butanedioic acid) accounted for in the order of 2.98%. For other fatty acids and compositions, propanoic acid (Propanoic acid, 1.49%), D-(-)-lactic acid (D-(-)-Lactic acid, 1.49%), butanoic acid (1.33%), benzoic acid acid, 1.28%), D-Gluconic acid (1.11%), 1,2,3-propanetricarboxylic acid (1,2,3-Propanetricarboxylic acid, 1.05%), linoleic acid (Linoleic acid, 0.97%), palmitic acid (0.67%), alpha-linolenic acid (0.63%), acetic acid (0.43%), hexane (Hexanedioic acid, 0.33%), nonanoic acid (Nonanoic) acid, 0.24%), D-fructose (D-Fructose, 5.01%), 3-Isopropyl-2-phenyl-indole (4.89%), Inositol (Inositol, 1.69%) this was included
추가 적으로 무궁화 잎 캘러스 추출물을 HPLC 분석하여, 그 결과를 도 4에 나타내었다.Additionally, HPLC analysis of the callus extract of Mugunghwa leaf was performed, and the results are shown in FIG. 4 .
<실시예 5> HT-29 세포주 배양<Example 5> HT-29 cell line culture
인간 HT-29 대장암 세포주는 한국 세포주 은행(서울)에서 분양받았다. 분양된 세포는 10% 우태아 혈청, 1%의 항생제(페니실린-스트렙토마이신) 및 L-글루타민(L-glutamine, GenDEPOT, Texas, USA)이 포함된 RPMI-1640 배지에 접종하였으며, 37℃ 및 5% 이산화탄소 조건으로 부란 배양기에서 배양하였다.The human HT-29 colorectal cancer cell line was purchased from the Cell Line Bank of Korea (Seoul). The distributed cells were inoculated in RPMI-1640 medium containing 10% fetal bovine serum, 1% antibiotics (penicillin-streptomycin) and L-glutamine (L-glutamine, GenDEPOT, Texas, USA), at 37°C and 5 It was cultured in a buran incubator under % carbon dioxide conditions.
<실시예 6> 세포 생존률 확인<Example 6> Confirmation of cell viability
<실시예 6-1> HT-29 세포 생장 억제 확인<Example 6-1> Confirmation of HT-29 cell growth inhibition
HSE의 세포독성을 확인하기 위하여 MTT 분석을 이용하여 세포 생존률을 확인하였다. 간략하게는, HT-29 세포를 96-well plate에 접종한 후 세포가 80%이상 부착되었을 때, HSE 40 μg/ml, 80 μg/ml 또는 시스플라틴 50 μg/ml 처리하여 37℃ 5% 이산화탄소를 공급한 가습 대기 조건에서 24시간 배양하였다. 배양완료 후 각 plate를 포스페이트 버퍼 식염수 (phosphate buffer saline, PBS)를 이용하여 2회 세척하였으며, 100 μl의 0.5 mg/ml 농도의 MTT 시약을 첨가하고 3시간 동안 추가 배양하였다. 배양된 세포에 100 μl의 DMSO를 첨가하여 자주색 포르마잔 결정을 용해 시켰으며, 각 well의 흡광도를 SpectraMax®ABS Plusmicroplate reader (Molecular Devices,San Jose, California, USA)를 이용하여 595 nm에서 측정하였다.In order to confirm the cytotoxicity of HSE, cell viability was confirmed using the MTT assay. Briefly, when HT-29 cells were inoculated into a 96-well plate and the cells adhered more than 80%,
그 결과 도 5에 나타낸 바와 같이 HT-29 세포주에 대하여 HSE의 세포독성의 용량 의존성은 HT-29세포주에 HSE를 처리하고 24시간 동안 배양하여 측정되었으며, 반수치사량(IC50)은 40 μg/ml인 것을 확인하였으며, HSE의 처리는 80 μg/ml까지 세포독성은 나타내지 않았다. As a result, as shown in FIG. 5 , the dose dependence of the cytotoxicity of HSE to the HT-29 cell line was measured by treating the HT-29 cell line with HSE and culturing for 24 hours, and the half-lethal dose (IC50) was 40 μg/ml. It was confirmed that HSE treatment did not show cytotoxicity up to 80 μg/ml.
<실시예 6-1> HT-29 콜로니 형성 억제 확인<Example 6-1> Confirmation of inhibition of HT-29 colony formation
HSE가 HT-29 세포주의 콜로니형성 및 세포 증식에 영향을 미치는지 평가하였다. 구체적으로, 세포 배양 접시 (35 x 10 mm)에 90%이상 부착될 때 까지 배양하였다. 세포 부착이 완료된 후, HT-29 세포주를 실시예 6-1에 기재된 농도와 동일한 농도로, HSE 및 시스플라틴을 처리하여, 24시간 동안 추가로 배양하였으며, 24 시간 후 들루타르 알데히드로 세포를 고정시키고, 크리스탈바이올렛 시약으로 염색하여, ToupView 3.7 현미경 카메라 소프트웨어가 장착된 Leica Mycrosystems(독일, Wetzlar)를 사용하여 관찰하였다.It was evaluated whether HSE affects colony formation and cell proliferation of the HT-29 cell line. Specifically, it was cultured until more than 90% adhered to the cell culture dish (35 x 10 mm). After cell attachment was completed, the HT-29 cell line was treated with HSE and cisplatin at the same concentration as described in Example 6-1, and further cultured for 24 hours, and cells were fixed with delutar aldehyde after 24 hours. and stained with crystal violet reagent, and observed using Leica Mycrosystems (Wetzlar, Germany) equipped with ToupView 3.7 microscope camera software.
그 결과 도 6에 나타낸 바와같이, HSE는 농도의존적으로 HT-29 세포의 콜로니 형성을 억제하였으며, 양성 대조군인 시스플라틴보다 높은 효과를 나타내는 것을 확인하였다.As a result, as shown in FIG. 6, HSE inhibited colony formation of HT-29 cells in a concentration-dependent manner, and it was confirmed that it exhibited a higher effect than cisplatin, a positive control.
<실시예 7> 세포 염색<Example 7> Cell staining
<7-1> Hoechst 33258 염색<7-1>
HT-29 세포에서 아폽토시스를 확인하기 위해 수정된 Hoechst 33258 염색으로 HT-29세포를 염색하여 관찰하였다. 구체적으로 커버 슬립 인셀 배양 plate(35 x 10 mm)에 2 x 105의 세포수가 되도록 HT-29 세포를 접종하고, 실시예 5와 동일한 농도로 HSE 또는 시스플라틴을 처리하여 배양하였다. 24시간 배양된 세포는 PBS로 2회 세척하고 37℃에서 30분 동안 10 mg/ml 농도의 Hoechst 33258 염색약을 처리하였다. 염색 후 축합 또는 단편화된 핵을 갖는 아폽토시스된 세포는 라이카 DMLS 형광 현미경(Mannheim, Germany)을 사용하여 관찰하였다.To confirm apoptosis in HT-29 cells, HT-29 cells were stained with modified
Hoechst 33258 염색은 이중가닥 DNA에 민감하기에 응축된 아폽토시스 세포를 정상 세포와 구별할 수 있으며, 도 7에 나타낸 바와 같이 HSE 추출물을 처리한 HT-29세포는 대조군과 비교하여, 핵형의 변화가 관찰되었고, 높은 형광을 나타내는 것을 확인하였다.Since
<7-2>프로피듐 아이오딘(PI) 염색<7-2> Propidium iodine (PI) staining
HT-29 세포에서 아폽토시스를 확인하기 위해 수정된 프로피듐 아이오딘 염색으로 HT-29세포를 염색하여 관찰하였다. 구체적으로 커버 슬립 인셀 배양 plate(35 x 10 mm)에 2 x 105의 세포수가 되도록 HT-29 세포를 접종하고, 실시예 5와 동일한 농도로 HSE 또는 시스플라틴을 처리하여 배양하였다. 24시간 배양된 세포는 PBS로 2회 세척하고 암조건에서 30분동안 PI dye solution 5 μl/ml을 처리하여 염색하였다. 염색된 세포는 라이카 DMLS 형광 현미경으로 시각화 하였다. Image-Pro plus 6.0 소프트웨어(Media Cybernetics, Maryland, USA)를 이용하여 축합 또는 단편화된 핵을 정량화 하여 HT-29 세포의 아폽토시스 정도를 평가하였다.To confirm apoptosis in HT-29 cells, HT-29 cells were stained with modified propidium iodine staining and observed. Specifically, HT-29 cells were inoculated to a cell number of 2 x 10 5 in a cover slip in-cell culture plate (35 x 10 mm), treated with HSE or cisplatin at the same concentration as in Example 5, and cultured. Cells cultured for 24 hours were washed twice with PBS and stained with 5 μl/ml of PI dye solution under dark conditions for 30 minutes. Stained cells were visualized with a Leica DMLS fluorescence microscope. The degree of apoptosis of HT-29 cells was evaluated by quantifying condensed or fragmented nuclei using Image-Pro plus 6.0 software (Media Cybernetics, Maryland, USA).
PI 염색약은 적색 형광을 나타내며, 살아있는 세포에는 침투할 수 없어, 사멸된 세포를 관찰할 때 사용된다. 따라서, 도 7에 나타낸 바와 같이 본 발명의 HSE를 HT-29세포주에 처리하였을 때 대조군과 비교하여, 적색형광이 증가한 것을 확인하여, HSE가 HT-29세포주에서 효과적으로 아폽토시스를 유도하는 것을 확인하였다.PI dye shows red fluorescence and cannot penetrate live cells, so it is used to observe dead cells. Therefore, as shown in FIG. 7 , when the HSE of the present invention was treated in the HT-29 cell line, compared to the control, red fluorescence was increased, and it was confirmed that HSE effectively induced apoptosis in the HT-29 cell line.
<7-3> Mito-tracker 및 Lyso-tracker 염색 <7-3> Mito-tracker and Lyso-tracker staining
HT-29 세포를 6-well plate에서 22-mm의 커버슬립상에서 성장시키고, 각각 상이한 농도로 HSE를 처리하였다. 상기 염색 시약의 제조사 가이드에 따라, HT-29 세포를 50 nM Mito-Tracker ™ Green FM (Ex/Em 490/516 nm) 및 Lyso-Tracker™ Green DND-26 (Ex/Em 504/511 nm)이 포함된 1 ml의 예열 배지와 함께 배양하였다. 30분간 배양한 후 라이카 DM IRB 역형광 현미경(Wetzlar, Germany)으로 염색된 HT-29 세포를 검출하였다. 그 결과를 도 8 및 도 9에 나타내었다.HT-29 cells were grown on a 22-mm coverslip in a 6-well plate, and each treated with HSE at different concentrations. According to the manufacturer's guide of the staining reagent, HT-29 cells were treated with 50 nM Mito-Tracker ™ Green FM (Ex/Em 490/516 nm) and Lyso-Tracker™ Green DND-26 (Ex/Em 504/511 nm). Incubated with 1 ml of pre-warmed medium included. After incubation for 30 minutes, HT-29 cells stained with a Leica DM IRB inverted fluorescence microscope (Wetzlar, Germany) were detected. The results are shown in FIGS. 8 and 9 .
<실시예 8> 유세포 분석<Example 8> Flow cytometry
HT-29 세포의 아폽토시스 상태는 Annexin V-fluorescein isothiocyanate(AnnexinV-FITC)와 PI 염색을 이용하여 세포막에서 포스파티딜 세린의 노출을 측정하여 분석되었다. 간략하게는 BD Pharmingen Annexin V-FITC ApoptosisDetection Kit I (BD Biosciences, San Jose, CA, USA)을 아폽토시스 분석에 사용하였으며, 상기 키트 제조사의 가이드에 따라, HT-29 세포를 세포 배양 접시(90 x 20 mm)에 접종하고, 24시간 배양한 후, 실시예 5와 동일한 농도의 HSE 또는 시스플라틴을 처리하여 24시간 추가로 배양하였다. 배양된 HT-29를 수득하고 차가운 PBS로 2회 세척하였다. 세척된 세포는 원심분리하여, 1 x 106 세포/ml의 농도에서 1x 결합 버퍼 100 μl에 세포를 재현탁 시키고 5 μl의 FITC Annexin V와 5 μl의 PI 염색약을 첨가하여, 암조건 하에서 실온(25 ℃)에서 15분간 배양하였다. 마지막으로 1x 결합 버퍼 400 μl를 FACS Ari aII flow 유세포 분석기(BD Biosciences, San Jose, CA, USA)로 분석 직전에 첨가하였다. 분석된 데이터는 DB Biosciences FACSD iva 소프트웨어를 사용하여 분석하였다.The apoptotic state of HT-29 cells was analyzed by measuring the exposure of phosphatidylserine in the cell membrane using Annexin V-fluorescein isothiocyanate (AnnexinV-FITC) and PI staining. Briefly, BD Pharmingen Annexin V-FITC ApoptosisDetection Kit I (BD Biosciences, San Jose, CA, USA) was used for apoptosis assay, and according to the kit manufacturer's guide, HT-29 cells were cultured in a cell culture dish (90 x 20 mm) and cultured for 24 hours, treated with HSE or cisplatin at the same concentration as in Example 5, and further cultured for 24 hours. Cultured HT-29 was obtained and washed twice with cold PBS. The washed cells were centrifuged, resuspended in 100 μl of 1x binding buffer at a concentration of 1 x 10 6 cells/ml, and 5 μl of FITC Annexin V and 5 μl of PI dye were added, followed by the addition of 5 μl of PI dye at room temperature ( 25 ℃) for 15 minutes. Finally, 400 μl of 1x binding buffer was added just before analysis with a FACS Ari aII flow flow cytometer (BD Biosciences, San Jose, CA, USA). Analyzed data were analyzed using DB Biosciences FACSD iva software.
<실시예 9> 상처 회복 마이그레이션 분석<Example 9> Wound recovery migration analysis
HT-29 세포 이동 능력에 대한 HSE의 효과를 평가하기 위해 상처 회복 분석을 수행하였다. 간략하게는 HT-29세포를 세포 배양 접시(35 x 10 mm)에 접종하고 90%이상 부착될 때까지 배양하였다. 각각의 배양 접시에서 동일한 영역에 200 μl 피펫팁을 사용하여 직선으로 긁어 상처를 유발하였으며, 부유 세포를 PBS로 세척하여 제거하였다. 그 후, HT-29세포를 HSE 또는 시스플라틴을 실시예 5에 기재된 농로 처리하였으며, 48시간 후에 라이카 Microsystems (Wetzlar, Germany)를 사용하여 관찰하였다.A wound healing assay was performed to evaluate the effect of HSE on HT-29 cell migration ability. Briefly, HT-29 cells were inoculated in a cell culture dish (35 x 10 mm) and cultured until more than 90% adherence. Wounds were induced by scraping in a straight line using a 200 μl pipette tip on the same area in each culture dish, and floating cells were removed by washing with PBS. Thereafter, HT-29 cells were treated with HSE or cisplatin at the concentration described in Example 5, and after 48 hours, they were observed using Leica Microsystems (Wetzlar, Germany).
세포의 상처가 회복되는 것은 세포의 이동이 증가된 것을 의미하며, 상처회복 마이그레이션 분석 결과, HT-29세포에 HSE를 처리하였을 때, 대조군과 비교하여, 세포이동이 유의미하게 감소하는 것을 확인하였다.Recovery of cell wounds means increased cell migration, and as a result of wound recovery migration analysis, it was confirmed that when HT-29 cells were treated with HSE, cell migration was significantly reduced compared to the control group.
<실시예 10> 정량적 실시간 역전사 PCR(Quantitative real-time reverse transcription-PCR) 분석<Example 10> Quantitative real-time reverse transcription-PCR analysis
HT-29 세포에서 RNA 추출 및 RT-PCR분석은 약간의 변형된 방법을 이용하여 수행하였다. HT-29세포는 세포 배양 접시(90 x 20 mm)에서 배양되었으며, HSE 또는 시스플라틴을 실시예 5에 기재된 농도로 처리하였다. HSE 또는 시스플라틴 처리 된 HT-29세포는 24시간 동안 배양하였으며, 배양 후 TRI sure 시약(Bioline, London, UK)을 이용하여 총 RNA를 추출하였다. 실시간 reverse transcription PCR(RT PCR)의 경우 1 μg의 총 RNA를 사용하여 역전사 올리고 dT 15 프라이머 (50 μM)를 이용하여 수행되었으며, cDNA는 AMV 역전사효소(10 U/μl)를 이용하여 제조사의 가이드에 따라 슈퍼 스크립트 First-Strand Synthesis Kit (Invitrogen, Carlsbad, CA)으로 합성되었다. 정량적 RT PCR(qRT PCR)은 SYBR® Green Sensimix Plus Master Mix (Quantace, Watford, England)를 이용하여, 20 μl의 반응 부피에서 100 ng의 cDNA를 사용하여 96 well plate에서 수행되었다. 상기 qRT PCR에서 사용한 프라이머 세트는 표 1에 나타내었다. qRT PCR 수행 조건으로는 95℃에서 10분 유지시킨 후 95℃에서 10초, 58℃에서 10초, 72℃에서 20초 동안을 한 사이클로 하여 40 사이클을 수행하였으며, 각 mRNA의 상대적 존재비는 2-ΔΔCt 방법으로 계산하였다. β-엑틴(β-actin)은 cDNA의 양을 표준화하기 위한 내부 표준 물질로 사용되었다.RNA extraction and RT-PCR analysis in HT-29 cells were performed using a slightly modified method. HT-29 cells were cultured in a cell culture dish (90 x 20 mm) and treated with HSE or cisplatin at the concentrations described in Example 5. HT-29 cells treated with HSE or cisplatin were cultured for 24 hours, and total RNA was extracted using TRI sure reagent (Bioline, London, UK) after culture. For real-time reverse transcription PCR (RT PCR), 1 μg of total RNA was used and reverse
그 결과, 도 10에 나타낸 바와 같이, 아폽토시스 조절 패밀리인 Bcl-2 패밀리에서, Bcl-2 유전자를 용량 의존적으로 하향조절하는 것이 관찰되었지만, 상기 패밀리 중 Bax 유전자의 발현은 현저하게 증가시켜, 본 발명의 HSE가 HT-29세포에서 Bax/Bcl-2 발현 비율을 대조군 대비 12배 까지 증가시켜, 아폽토시스를 유도하는 것을 확인하였다.As a result, as shown in FIG. 10, dose-dependent downregulation of the Bcl-2 gene was observed in the Bcl-2 family, which is a family of apoptosis regulation, but the expression of the Bax gene in the family was significantly increased, and the present invention of HSE increased the Bax/Bcl-2 expression ratio in HT-29 cells up to 12-fold compared to the control, and it was confirmed that apoptosis was induced.
또한 Bax/Bcl-2의 발현비가 높으면, 미토콘드라아 막 전위가 감소하게 되고, 막전위의 감소는 카스파제의 활성화를 유도하기에, 카스파제 활성과 관련된 시토크롬 c(Cytochrome c), 카스파제-9(Caspase-9) 및 카스파제-3(Caspase-3)의 발현도 확인하였다. In addition, when the expression ratio of Bax/Bcl-2 is high, the mitochondrial membrane potential decreases, and the decrease in membrane potential induces caspase activation, so cytochrome c (Cytochrome c), caspase- Expression of 9 (Caspase-9) and caspase-3 (Caspase-3) was also confirmed.
그 결과, 도 10에서 나타낸 바와 같이, HSE가 처리된 HT-29세포(80 μg/ml)에서, 대조군과 비교하여, 시토크롬 c(227.3%), 카스파제-9(301.2%) 및 카스파제-3(241.3%)의 발현이 유의적으로 증가한 것을 확인하여, 본 발명의 HSE가 아폽토시스와 관련된 인자를 조절하여, 아폽토시스를 유도하는 것을 확인하였다.As a result, as shown in FIG. 10 , in HT-29 cells (80 μg/ml) treated with HSE, cytochrome c (227.3%), caspase-9 (301.2%) and caspase- It was confirmed that the expression of 3 (241.3%) was significantly increased, and it was confirmed that the HSE of the present invention induces apoptosis by regulating factors related to apoptosis.
<실시예 11> RNA 시퀀싱<Example 11> RNA sequencing
<실시예 11-1> RNA 시퀀싱 및 발현 패턴 분석<Example 11-1> RNA sequencing and expression pattern analysis
RNA 서열 및 기능적 데이터 분석은, 총 RNA를 추출한 후 제조사의 가이드에 따라, Illumina® TruSeq stranded mRNA Prep Kit (San Diego, CA, USA)을 사용하여 RNA-seq 라이브러리를 제조한 다음, 구축된 RNA-seq 라이브러리를 Illumina® Hiseq2500으로 시퀀싱하여 101개의 염기쌍 쌍-말단 reads(101-base pair paired-end reads)를 얻었다. 또한, 획득된 고품질의 read(>2000만)는 디폴트 파라미터를 갖는 인간 지놈(hg19)서열과 정렬하였으며, 전사체 발현은 h19지놈을 주석으로 사용하여 cuffdiff v.2.2.0로 조립하였다. 전사 풍부도를 정규화하고 백만개 단편(FPKM)당 엑손 kb당 단편으로 측정하였다. 유의미한 차등 발현 유전자(DEG)는 대조군 및 HSE 처리군을 비교하여, 2이상 초과하는 접힘 변화의 임계값 및 0.05>P의 값을 가지는 유전자 중에서 선택하였다.For RNA sequence and functional data analysis, after extracting total RNA, according to the manufacturer's guide, an RNA-seq library was prepared using Illumina® TruSeq stranded mRNA Prep Kit (San Diego, CA, USA), and then the constructed RNA- The seq library was sequenced with Illumina® Hiseq2500 to obtain 101-base pair paired-end reads. In addition, the obtained high-quality reads (>20 million) were aligned with the human genome (hg19) sequence with default parameters, and transcript expression was assembled into cuffdiff v.2.2.0 using the h19 genome as an annotation. Transcription abundance was normalized and measured as fragments per kb exon per million fragments (FPKM). Significant differentially expressed genes (DEGs) were selected from genes having a fold change threshold value exceeding 2 and a value of 0.05>P by comparing the control group and the HSE-treated group.
생물학적 분석의 풍부도 및 Kyoto Encyclopedia of Genes and Genomes (KEGG)경로의 강화된 아폽토틱 관련 상대 유전자를 확인하기 위하여 DAVID v6.8 tool(https://david.ncifcrf.gov)을 이용하여 확인하였다. 또한 유전자 목록은 중요한 온톨로지(GO)를 식별하고 Cytoscape 소프트웨어 플랫폼(version 3.7.2)에서 STRING v.11.0 (https://string-db.org/) 애플리케이션을 활용하여 GO 상호작용 네트워크를 시각화 하였다. 히트맵은 Morpheus 소프트웨어를 사용하여 제작되었다(https://software.broadinstitute.org/morpheus/)(도 15).The abundance of biological analysis and the enriched apoptotic-related relative genes of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were identified using the DAVID v6.8 tool ( https://david.ncifcrf.gov ). The gene list also identified important ontology (GOs) and visualized GO interaction networks using the STRING v.11.0 (https://string-db.org/) application on the Cytoscape software platform (version 3.7.2). Heatmaps were created using Morpheus software ( https://software.broadinstitute.org/morpheus/ ) (FIG. 15).
<실시예 11-2> 차별 발현 유전자 분석.<Example 11-2> Differential expression gene analysis.
HT-29 세포주에, 시스플라틴 및 HSE가 처리되었을 때, 비처리 대조군과 비교하여, 차별발현되는 유전자를 확인하기 위해, 실시예 11에서 정량적 PCR로 분석한 유전자를 토대로, Scatter plot 분석 및 Volcano plot 분석을 시행하였다.When the HT-29 cell line was treated with cisplatin and HSE, compared to the untreated control group, in order to identify the differentially expressed genes, based on the genes analyzed by quantitative PCR in Example 11, Scatter plot analysis and Volcano plot analysis was implemented.
그 결과, 도 12, 13 및 도 14에 나타낸 바와 같이, 비처리 대조군과 비교하여, 시스플라틴 및 HSE가 처리된 HT-29 세포주는, 차별적인 유전자를 발현하느 것을 확인하였다.As a result, as shown in FIGS. 12, 13 and 14 , it was confirmed that the HT-29 cell line treated with cisplatin and HSE, compared to the untreated control group, expressed differential genes.
<실시예 12> 웨스턴 블랏 분석<Example 12> Western blot analysis
웨스턴블랏은 약간의 변형을 추가하여 시행하였다. 자세하게는 HT-29세포는 세포 배양 접시(90 x 20 mm)에 접종하였으며 24시간 후, HSE 또는 시스플라틴을 실시예 5에 기재된 농도로 처리하여 24시간 추가 배양하였다. 이후 세포를 수확하고 차가운 PBS로 2회 세척하였다. 수득된 세포 펠릿은 100 μl의 RIPA 용해 버퍼(Sigma-Aldrich)에 용해시켰다. 이어서 용해물을 4℃에서 20 분 동안 12000 rpm에서 원심분리하였다. 단백질 농도는 Bio-Rad Protein Assay kit (Bio-Rad Laboratories, Hercules, CA, USA)를 사용하여 분석하였고, 소 혈청 알부민(BSA)를 표준물질로 사용하였으며, 샘플로부터 동일한 단백질 추출물(50 μg)을 12% 처리 하였다. Invitrogen 2 mini electrophoresis tank system(Thermo Fisher Scientific, Massachusetts, USA)을 사용한 SDS-PAGE 후 iBlot™ 2 Gel Transfer Device (Thermo Fisher Scientific, Massachusetts, USA)를 사용하여 PVDF막에 로딩하였다. 이 후 인산화된 단백질을 0.1% 트윈-20(tween 20)을 갖는 PBS에서 5% 소혈청 알부민(BSA)으로 차단하고, 0.1% 트윈-20을 포함하는 5% 탈지우유 PBS를 1시간 처리하여 다른 단백질을 차단하였다. 차단된 단백질은 1차 항체와 함께 4℃에서 18시간 동안 반응시켰다. 1차 항체로는 β-actin (1:1000), NF-κB p65 (1:1000), p-p65(1:1000), TNF-α (1:1000), Bcl-2 (1:1000), Bax (1:1000), cytochrome-c(1:1000) 및 caspase-3/-9 (1:1000)을 사용하였다. 1차 항체와의 반응이 끝난 후 염소-항 토끼 또는 염소 pAb와 함께 배양된 막을 2차 항체인 마우스 IgG H&L(HRP) 항체(1:1000)와 함께 2시간 동안 반응시켰다. 반응이 끝난 후 2차 항체의 신호는 West-Q picoEmitter Coupled Logic (ECL) 기판(GenDEPOT, Texas, USA)으로 포착하고, Molecular Imager Gel DocTM XR+ system (Bio-Rad Laboratories, Hercules, CA, USA)에 노출시켰다. 단백질 밴드의 발현 정도는 QuantityOne 소프트웨어(Bio-Rad Laboratories, Hercules, CA, USA)로 확인하였다.Western blot was performed with slight modifications. Specifically, HT-29 cells were inoculated into a cell culture dish (90 x 20 mm) and 24 hours later, HSE or cisplatin was treated at the concentration described in Example 5 and further cultured for 24 hours. The cells were then harvested and washed twice with cold PBS. The obtained cell pellet was dissolved in 100 μl of RIPA lysis buffer (Sigma-Aldrich). The lysate was then centrifuged at 12000 rpm for 20 min at 4°C. Protein concentration was analyzed using the Bio-Rad Protein Assay kit (Bio-Rad Laboratories, Hercules, CA, USA), bovine serum albumin (BSA) was used as a standard, and the same protein extract (50 μg) from the sample was used. 12% was treated. After SDS-PAGE using the
그 결과를 도 11에 나타내었다.The results are shown in FIG. 11 .
Claims (12)
상기 무궁화 캘러스는 삼천리 품종의 무궁화 잎 캘러스인 것을 특징으로 하는 조성물.The method of claim 1,
The composition, characterized in that the Mugunghwa callus is a Mugunghwa leaf callus of the Samchully variety.
상기 무궁화 캘러스는, 수크로즈(sucrose), 2,4-디클로로페녹시아세트산(2,4-dichlorophenoxyacetic acid, 2,4-D), 6-벤질아미노퓨린(6-Benzylaminopurine, BA), 2-(N-모르폴리노) 에탄 설포닉산(2-(N-morpholino)ethane sulfonic acid, MES) 및 식물 한천(plant agar)을 포함하는 식물 우디 액체 배지(Woody plant media, WPM)에서 1차 배양된 캘러스인 것을 특징으로 하는 조성물.3. The method of claim 2,
The Mugunghwa callus is, sucrose, 2,4-dichlorophenoxyacetic acid (2,4-dichlorophenoxyacetic acid, 2,4-D), 6-benzylaminopurine (6-Benzylaminopurine, BA), 2-( Callus primary cultured in Woody plant media (WPM) containing N-morpholino) ethane sulfonic acid (2-(N-morpholino)ethane sulfonic acid, MES) and plant agar A composition, characterized in that
상기 1차 배양된 캘러스는, 수크로즈, 2,4-D 및 BA를 포함하는 식물 우디 액체배지에서 2차 배양되는 것을 더 포함하는 캘러스인 것을 특징으로 하는 조성물.4. The method of claim 3,
The primary cultured callus, sucrose, 2,4-D and composition, characterized in that the composition, characterized in that the callus further comprising a secondary culture in a plant woody liquid medium containing BA.
상기 무궁화 잎 캘러스 추출물은, 무궁화 잎 캘러스를 물, C1 내지 C4의 저급 알코올, C1 내지 C4의 저급 알코올 수용액 또는 핵산으로 이루어진 군에서 선택된 용매로 추출되는 것을 특징으로 하는 조성물.The method of claim 1,
The Mugunghwa leaf callus extract is a composition characterized in that the Mugunghwa leaf callus is extracted with a solvent selected from the group consisting of water, C1 to C4 lower alcohol, C1 to C4 lower alcohol aqueous solution, or nucleic acid.
상기 무궁화 잎 캘러스 추출물은, 암세포의 세포증식 및 세포 이동 억제 또는 세포의 핵형을 변화시키는 것을 특징으로 하는 조성물.The method of claim 1,
The composition, characterized in that the extract of Mugunghwa leaf callus, inhibits cell proliferation and cell migration of cancer cells or changes the karyotype of cells.
상기 무궁화 잎 캘러스 추출물은, 암세포에서, Bax/Bcl-1 유전자의 발현 비 및 시토크롬 c(Cytochrome c), 카스파제-9(Caspase-9) 및 카스파제-3(Caspase-3)를 포함하는 유전자의 발현을 증가시켜 아폽토시스를 유도하는 것을 특징으로 하는 조성물.The method of claim 1,
The Mugunghwa leaf callus extract, in cancer cells, the expression ratio of Bax/Bcl-1 gene and genes including cytochrome c (Cytochrome c), caspase-9 (Caspase-9) and caspase-3 (Caspase-3) A composition, characterized in that it induces apoptosis by increasing the expression of
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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KR20190067287A (en) * | 2017-12-06 | 2019-06-17 | 주식회사 더가든오브내추럴솔루션 | Anti-aging and anti-allergic cosmetic compositon comprising the extract of the flower, root, callus and seed of Hibiscus syriacus L. as an active ingredient and preparation method of the same |
KR102034844B1 (en) * | 2019-06-17 | 2019-10-21 | (주)에스디생명공학 | Compositions for Anti-Bacterial and Anti-Inflammatory Effect Comprising Callus Extract of Hibiscus Syriacus |
KR102047234B1 (en) * | 2019-06-17 | 2019-11-21 | (주)에스디생명공학 | Composition for Improving Skin Conditions with Improved Skin Whitening, Antioxidant, Moisturizing, Anti-wrinkling, and Regeneration Property Comprising Callus Extract of Hibiscus Syriacus |
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Publication number | Priority date | Publication date | Assignee | Title |
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KR20190067287A (en) * | 2017-12-06 | 2019-06-17 | 주식회사 더가든오브내추럴솔루션 | Anti-aging and anti-allergic cosmetic compositon comprising the extract of the flower, root, callus and seed of Hibiscus syriacus L. as an active ingredient and preparation method of the same |
KR102034844B1 (en) * | 2019-06-17 | 2019-10-21 | (주)에스디생명공학 | Compositions for Anti-Bacterial and Anti-Inflammatory Effect Comprising Callus Extract of Hibiscus Syriacus |
KR102047234B1 (en) * | 2019-06-17 | 2019-11-21 | (주)에스디생명공학 | Composition for Improving Skin Conditions with Improved Skin Whitening, Antioxidant, Moisturizing, Anti-wrinkling, and Regeneration Property Comprising Callus Extract of Hibiscus Syriacus |
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J BUON, 2017, 22(2), 543-551* |
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