KR101937667B1 - Composition for reducing senescence of a cell - Google Patents
Composition for reducing senescence of a cell Download PDFInfo
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- KR101937667B1 KR101937667B1 KR1020170017477A KR20170017477A KR101937667B1 KR 101937667 B1 KR101937667 B1 KR 101937667B1 KR 1020170017477 A KR1020170017477 A KR 1020170017477A KR 20170017477 A KR20170017477 A KR 20170017477A KR 101937667 B1 KR101937667 B1 KR 101937667B1
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- cell
- present
- aging
- composition
- cells
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/999—Small molecules not provided for elsewhere
Abstract
본 발명은 세포 노화 억제용 조성물, 세포 노화 억제 방법 및 노화 관련 질환의 예방, 치료 또는 개선용 조성물에 관한 것으로, 특히 줄기세포에 있어서, 세포 증식 유도, 자가 재생 유도, 다분화능 회복 및 텔로머라제 활성 유도를 통하여 세포 노화를 현저하게 억제하는데 사용될 수 있다.The present invention relates to a composition for inhibiting cell senescence, a method for inhibiting cell senescence and a composition for preventing, treating or ameliorating senescence-related diseases. More particularly, the present invention relates to a composition for inducing cell proliferation, induction of self- Can be used to significantly inhibit cellular senescence through activity induction.
Description
본 발명은 세포 노화 억제용 조성물에 관한 것이다.The present invention relates to a composition for inhibiting cell senescence.
줄기세포(Stem cell)란, 다양한 조직을 구성하는 각 세포로 분화되기 전단계의 세포로서, 미분화 상태에서 무한 증식이 가능한 자가 증식능 및 특정 분화 자극에 의해 다양한 조직의 세포로 분화될 수 있는 잠재적 가능성인 다분화능을 가진 세포를 의미한다. 즉, 배양을 계속하여도 상기와 같은 자가 증식능 및 다분화능의 능력이 소멸되지 않는 세포를 의미한다.Stem cells are the cells of the pre-stage that are differentiated into cells constituting various tissues. As stem cells, they are capable of infinitely proliferating in an undifferentiated state, and potentially capable of being differentiated into cells of various tissues by a specific differentiation stimulus Means a cell with multiple differentiation potential. That is, it means a cell in which the self-renewal ability and the pluripotency retaining ability are not destroyed even if the culture is continued.
한편, 줄기세포는 분화 가능성에 따라 크게 배아 줄기세포(embryonic stem cell; ES cell)와 성체 줄기세포(adult stem cell)로 나뉜다. 정자와 난자가 만나 수정된 후 배아의 발생 과정 내에서, 형태 형성을 하게 되는데 이때 세포는 증식, 이동 및 분화 과정을 수행하게 된다. 배아 줄기세포는 수정란이 형성된 후 자궁 내막에 착상하기 전의 매우 초기 단계인 포배기(blastocyst)의 배아 중 태아로 발생하는 세포괴(inner cell mass; ICM)로부터 분리해낸 줄기세포로서, 내배엽, 외배엽 및 중배엽에 해당하는 3개의 배엽(embryonic germ layer)에 의해 생성되는 모든 조직의 세포로 분화될 수 있는 잠재력(pluripotent)을 갖는 세포를 의미한다. 상기 배아 줄기세포는 태아로 발생할 수 있는 세포괴로부터 분리해내는 과정 때문에 윤리적인 문제의 소지가 다분하다는 문제점이 존재한다.On the other hand, stem cells are divided into embryonic stem cells (ES cells) and adult stem cells depending on the possibility of differentiation. After the sperm and egg are met and fertilized, they undergo morphogenesis in the developmental process of the embryo, where the cells undergo proliferation, migration and differentiation. Embryonic stem cells are stem cells isolated from the inner cell mass (ICM) of the embryo of the blastocyst, which is a very early stage before implantation into the endometrium after embryo formation. The embryonic stem cells are endoderm, ectoderm and mesodermal Refers to a cell that has pluripotent potential to differentiate into cells of all tissues produced by the corresponding embryonic germ layer. The embryonic stem cell has a problem of being ethical problem due to the process of separating the embryonic stem cell from the cell mass that can occur in the fetus.
반면, 상기 성체 줄기세포는 발생 과정이 모두 끝난 성인 또는 배아 발생 과정이 진행되어 배아의 각 장기가 형성되는 단계의 태반에서 얻어지는, 각 장기의 특이적인 줄기세포로서, 일반적으로 그 분화능이 유래 되는 조직을 구성하는 세포로 한정되는 분화능(multipotent)을 갖게 된다. 상기 성체 줄기세포는 성인이 된 후에도 대부분의 장기에 남아 정상적 또는 병리학적으로 발생하는 세포의 손상을 보충하는 역할을 한다. 대표적인 성체 줄기세포는 골수에 존재하는 조혈 줄기세포(hematopoietic stem cell), 혈구 세포 이외의 결합 조직으로 분화되는 중간엽 줄기세포(mesenchymal stem cell)를 들 수 있다. On the other hand, the adult stem cells are adult stem cells whose development has been completed, or specific stem cells obtained from the placenta of the embryonic development stage where the embryonic development process proceeds, Which is defined by the cells constituting the cell. The adult stem cells remain in most organs after becoming adults, and serve to compensate for normal or pathologically occurring cell damage. Representative adult stem cells include hematopoietic stem cells present in the bone marrow and mesenchymal stem cells differentiated into connective tissues other than hemocytes.
최근, 인간으로부터 배아 줄기세포 분리가 성공한 뒤, 임상적 적용에 관심이 고조되고 있으나, 이러한 줄기세포는 다른 인체 초대배양 세포와 유사하게, 체외 배양 시 텔로미어의 소실과 무관한 노화(senescence) 기전에 의해 세포의 분열이 급격히 감소하는 것으로 보고되어 있다 (Shibata, K.R. etal.Stemcells, 25; 2371-2382, 2007). In recent years, there has been a growing interest in clinical applications after the successful isolation of embryonic stem cells from humans. However, these stem cells, similar to other human primary cultured cells, undergo senescence, which is independent of disappearance of telomere during in vitro culture (Shibata, KR et al. Stemcells, 25; 2371-2382, 2007).
따라서, 상기 배아 줄기세포를 세포 치료 등으로 이용하기 위해, 세포의 노화를 개선하여야 하나, 상기 세포의 노화는 환경적 스트레스의 축적으로 세포의 성장을 담당하는 단백질의 활성이 억제되는 현상이 주요 원인으로 지적되고 있을 뿐, 이를 개선할 수 있는 방안에 대하여는 현재까지 보고된 바 없다.Therefore, in order to use the embryonic stem cells for cell therapy or the like, it is necessary to improve the aging of the cells, but the aging of the cells is a phenomenon in which the activity of the protein responsible for cell growth is inhibited by accumulation of environmental stress, But there is no report on how to improve it.
본 발명의 일 목적은 세포 노화 억제용 조성물을 제공하는 것이다.It is an object of the present invention to provide a composition for inhibiting cell senescence.
본 발명의 다른 목적은 세포 노화 억제 방법을 제공하는 것이다.Another object of the present invention is to provide a method for inhibiting cell senescence.
본 발명의 또 다른 목적은 노화 관련 질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다.It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating aging-related diseases.
본 발명의 또 다른 목적은 노화 관련 질환의 예방 또는 개선용 화장료 조성물을 제공하는 것이다.It is still another object of the present invention to provide a cosmetic composition for preventing or improving aging-related diseases.
본 발명의 또 다른 목적은 노화 관련 질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.It is still another object of the present invention to provide a food composition for preventing or ameliorating aging-related diseases.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당 업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
본 발명자들은 세포, 특히 줄기세포에 레스베라트롤(resveratrol) 및 터트-부틸하이드로퀴논(tert-butylhydroquinone)을 병용하여 투여하는 경우, 상기 줄기세포에서 세포 증식 유도, 자가 재생 유도, 다분화능 회복 및 텔로머라제 활성을 유도함으로써 세포의 노화를 현저하게 억제할 수 있음을 확인하여 본 발명을 완성하게 되었다.The present inventors have found that, when cells, particularly stem cells, are administered in combination with resveratrol and tert-butylhydroquinone, the stem cells can induce cell proliferation, induce self-renewal, And that the aging of the cells can be markedly inhibited by inducing the activity, thereby completing the present invention.
단, 본 발명에 있어서 상기 "세포 노화(cell senescence)"란, 정상 이배체 세포가 분열을 멈추는 현상으로, 염색체 말단의 텔로미어가 세포 분열 과정에서 점점 짧아져 DNA 손상이 발생함으로 유도될 수 있다. 텔로미어의 단축뿐만 아니라, 암 유전자 및 암 억제 유전자의 기능 이상, 염증반응, 산화 스트레스, 항암제, 자외선 및 방사선 등에 의해서도 세포 노화가 유도될 수 있다. 상기 세포 노화가 일어나는 경우, 노화된 세포의 특징은, ⅰ) 정상 세포에 비해 큰 크기, ⅱ) 정상 세포에 비해 편평한 모양, ⅲ) 세포의 성장이 멈춤, ⅳ) 핵내 DNA 다수의 손상 흔적, ⅴ) 다양한 염증성 단백질을 분비, ⅵ) 생화학적으로, 베타-갈락토시다제(β-galactosidase)의 활성이 증가가 일어날 수 있다.However, in the present invention, the term "cell senescence" refers to a phenomenon in which normal diploid cells stop dividing, and the telomere at the terminal of the chromosome may be shortened in the process of cell division, resulting in DNA damage. Cellular senescence can be induced not only by shortening of telomere, but also by dysfunction of cancer gene and cancer suppressor gene, inflammation reaction, oxidative stress, anticancer agent, ultraviolet ray and radiation. When the cell aging occurs, the aged cells are characterized by: i) a larger size compared to normal cells, ii) a flat shape compared to normal cells, iii) cell growth is stopped, iv) ) Secrete various inflammatory proteins, and vi) biochemically, an increase in the activity of β-galactosidase may occur.
본 발명의 일 실시예에서는 하이드로퀴논(Hydroquinone) 유도체 및 하기 화학식 1로 표시되는 화합물을 포함하는 세포 노화 억제용 조성물을 제공한다:In one embodiment of the present invention, there is provided a composition for inhibiting cell senescence comprising a hydroquinone derivative and a compound represented by the following Formula 1:
[화학식 1][Chemical Formula 1]
본 발명에 있어서, 상기 화학식 1로 표시되는 화합물은 식물이 곰팡이나 해충 같은 나쁜 환경에 직면했을 때 만들어내는 파이토알렉신으로, 폴리페놀계 물질에 해당하며, 항암, 항바이러스, 신경보호, 항노화, 항염 등의 효과를 나타낼 수 있다.In the present invention, the compound represented by the formula (1) is a phytoalexin produced when a plant is faced with a bad environment such as mold or insect pests. The compound corresponds to a polyphenol-based substance and has anticancer, antiviral, , And anti-inflammatory effects.
단, 본 발명에 있어서 상기 "하이드로퀴논(Hydroquinone) 유도체"란, 하이드로퀴논으로부터 유도된 화합물을 의미한다. 상기 하이드로퀴논은 피부 안에 있는 침체된 색소를 녹여 피부에 있는 잡티를 제거하는 데 사용될 수 있다. 본 발명의 목적상 상기 하이드로퀴논 유도체는 터트-부틸하이드로퀴논(tert-butylhydroquinone)일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the term "hydroquinone derivative" means a compound derived from hydroquinone. The hydroquinone can be used to dissolve stagnant pigment in the skin to remove dirt in the skin. For the purpose of the present invention, the hydroquinone derivative may be tert-butylhydroquinone, but is not limited thereto.
본 발명의 다른 실시예에서는 터트-부틸하이드로퀴논(tert-butylhydroquinone) 및 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 세포 노화 억제용 조성물을 제공한다.Another embodiment of the present invention provides a composition for inhibiting cell senescence comprising tert-butylhydroquinone and the compound represented by
본 발명의 일 구체 예에서, 본 발명에 따른 세포 노화 억제용 조성물은 줄기세포의 노화를 억제하는 조성물일 수 있고, 여기서, 상기 노화 억제의 대상이 되는 줄기세포는 중간엽 줄기세포(mesenchymal stem cell)일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the composition for inhibiting cell senescence according to the present invention may be a composition for inhibiting senescence of stem cells, wherein the stem cells to be inhibited by aging are mesenchymal stem cells ), But is not limited thereto.
단, 본 발명에 있어서, 상기 "중간엽 줄기세포"란, 골수와 제대혈에서 채취하는 줄기세포의 하나로, 실험관에서 이론적으로는 무한정 증식이 가능하며, 골아세포(osteoblast), 연골아세포(chondroblast), 지방 세포(adipocyte) 및 근아세포(myoblast) 등으로 분화될 수 있다. 본 발명의 목적상 계대 배양이 6회 이상 진행되어, 상기 노화된 세포의 특징을 나타내는 후기 단계(late passage)에 해당하는 줄기세포일 수 있고, 예를 들면 제대, 제대혈, 골수, 지방, 근육, 피부, 양막 및 태반으로 구성된 군에서 선택되는 1종 이상에서 유래된 것을 특징으로 하는 후기 중간엽 줄기세포 일 수 있으나, 이에 제한되는 것은 아니다.However, in the present invention, the term "mesenchymal stem cell" is one of stem cells to be harvested from bone marrow and umbilical cord blood. It can theoretically indefinitely proliferate in an experimental tube, and can be used for osteoblast, chondroblast, Adipocytes, myoblasts, and the like. For the purpose of the present invention, the stem cells may be a stem cell corresponding to a late passage showing the characteristics of the aged cells after the subculture has been performed 6 or more times, for example, cord, cord blood, bone marrow, But it is not limited to the late mesenchymal stem cell, which is derived from at least one selected from the group consisting of skin, amniotic membrane, and placenta.
본 발명의 다른 구체 예에서, 본 발명에 따른 조성물은 세포 내 텔로머라제(Telomerase) 활성, 세포 증식, 세포 주기(cell cycle) 활성 및 세포 분화(Differencication) 중 적어도 하나의 반응을 유도함으로써 줄기세포의 노화를 효과적으로 억제할 수 있다.In another embodiment of the present invention, the composition according to the present invention induces at least one of telomerase activity, cell proliferation, cell cycle activity, and cell differentiation, Can be effectively suppressed.
단, 본 발명에 있어서, 상기 "텔로머라제(Telomerase)"란, 염색체의 말단에 반복적으로 존재하는 유전 물질의 특이한 형태인 텔로미어가 세포 분열 시 길이가 짧아지는 것을 방지 또는 회복시키는 효소를 의미한다. 따라서, 본 발명의 목적상 본 발명에 따른 상기 세포 노화 억제용 조성물은 텔로머라제의 활성을 유도하여, 텔로미어의 길이가 짧아지는 현상을 방지하는 것일 수 있다.In the present invention, the term "telomerase " means an enzyme that prevents or restrains telomere shortening in cell division, which is a specific form of a genetic material repeatedly present at the end of a chromosome . Therefore, for the purpose of the present invention, the composition for inhibiting cell senescence according to the present invention may induce the activity of telomerase to prevent the shortening of the telomer length.
또한, 본 발명에 있어서, 상기 "세포 분화"란, 원시 세포에서 특정 성질을 갖는 세포로 변경되는 것을 의미하며, 생체 외(in vitro) 배양 시 줄기세포는 후기 단계로 갈수록 세포 분화능을 상실한다. 따라서, 본 발명의 목적상 본 발명에 따른 상기 세포 노화 억제용 조성물은 세포 분화능을 회복할 수 있도록 유도하여, 세포의 노화 현상을 억제할 수 있다.In the present invention, the term "cell differentiation" refers to a change from a primitive cell to a cell having a specific property. In vitro culturing, the stem cell loses its ability to differentiate into cells at a later stage. Therefore, for the purpose of the present invention, the composition for inhibiting cell senescence according to the present invention can induce the ability to regenerate cell differentiation, thereby suppressing the aging of cells.
또한, 본 발명에 있어서 상기 "세포 증식"이란, 세포수의 증가, DNA 복제, 세포분열 및 각종 세포 성분의 증가를 동반하는 세포내의 반응을 의미하며, 세포증식 속도는 생체 내에서 조절된다. 본 발명의 목적상 세포 주기의 반복으로 인하여 세포의 노화로 인한 세포 증식의 감퇴가 발생한 후기 단계(late passage)의 세포에서, 세포 증식을 유도하는 것일 수 있다.In the present invention, the term "cell proliferation" means an intracellular reaction accompanied by an increase in cell number, DNA replication, cell division, and an increase in various cellular components, and the cell proliferation rate is regulated in vivo. For the purpose of the present invention, it is possible to induce cell proliferation in late passage cells where cell cycle deterioration due to aging of cells due to repetition of cell cycle occurs.
본 발명의 다른 구현 예에서는, 하이드로퀴논(Hydroquinone) 유도체 및 상기 화학식 1로 표시되는 화합물을 포함하는 조성물을 세포에 투여하는 단계를 포함하는 세포 노화 억제 방법을 제공한다.In another embodiment of the present invention, there is provided a method for inhibiting cell senescence comprising the step of administering to a cell a composition comprising a hydroquinone derivative and a compound represented by the formula (1).
본 발명의 목적상, 본 발명에 따른 상기 조성물을 세포에 투여하는 단계는 인 비트로(in vitro)에서 수행될 수 있다. 이와 같이, 인 비트로 상에서 상기 조성물을 세포에 투여하는 경우에는 후기 단계의 세포에서 발생한 노화 현상을 억제하여, 다수의 계대 배양에 의해서도 상기 세포를 유지할 수 있어, 세포 치료제 등의 이용에 적극적으로 활용될 수 있다.For the purpose of the present invention, the step of administering the composition according to the invention to cells may be carried out in vitro. As described above, when the composition is administered to cells in vitro, it is possible to inhibit the aging phenomenon occurring in cells in later stages, to maintain the cells even in a number of subculture cultures, and to be actively utilized in the use of cell therapy agents and the like .
본 발명에서는 상기 조성물을 투여함으로써 텔로머라제(Telomerase) 활성, 세포 증식, 세포 주기(cell cycle) 활성 및 세포 분화(Differencication) 중 적어도 하나의 반응이 유도됨에 따라 줄기세포의 성장을 효과적으로 억제할 수 있다. In the present invention, at least one of telomerase activity, cell proliferation, cell cycle activity, and cell differentiation is induced by administration of the composition, thereby effectively inhibiting the growth of stem cells have.
본 발명의 일 구체 예에서, 상기 세포는 줄기세포일 수 있고, 본 발명의 목적상 상기 줄기세포는 중간엽 줄기세포(mesenchymal stem cell)일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the cell may be a stem cell, and for the purpose of the present invention, the stem cell may be a mesenchymal stem cell, but is not limited thereto.
단, 본 발명에서 하이드로퀴논, 중간엽 줄기세포, 텔로머라제 및 세포분화는 상기 세포 노화 억제용 조성물에 기재된 바와 중복되어, 그 기재를 생략한다.However, in the present invention, hydroquinone, mesenchymal stem cells, telomerase, and cell differentiation are overlapped with those described in the composition for inhibiting cell senescence, and the description thereof is omitted.
본 발명의 다른 실시예에서는 터트-부틸하이드로퀴논(tert-butylhydroquinone) 및 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 세포 노화 억제 방법일 수 있다.In another embodiment of the present invention, it may be a method for inhibiting cell senescence comprising tert-butylhydroquinone and a compound represented by
본 발명의 다른 구현 예에서는, 하이드로퀴논(Hydroquinone) 유도체 및 상기 화학식 1로 표시되는 화합물을 유효 성분으로 포함하는 노화 관련 질환의 예방 또는 치료용 약학 조성물을 제공한다.In another embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating an aging-related disease comprising a hydroquinone derivative and a compound represented by the formula (1) as an active ingredient.
단, 본 발명에서 하이드로퀴논, 중간엽 줄기세포, 텔로머라제 및 세포분화는 상기 세포 노화 억제용 조성물에 기재된 바와 중복되어, 그 기재를 생략한다.However, in the present invention, hydroquinone, mesenchymal stem cells, telomerase, and cell differentiation are overlapped with those described in the composition for inhibiting cell senescence, and the description thereof is omitted.
본 발명의 다른 실시예에서는 터트-부틸하이드로퀴논(tert-butylhydroquinone) 및 상기 화학식 1로 표시되는 화합물을 유효 성분으로 포함하는 노화 관련 질환의 예방 또는 치료용 약학 조성물일 수 있다.Another embodiment of the present invention may be a pharmaceutical composition for preventing or treating aging-related diseases comprising tert-butylhydroquinone and the compound represented by Formula 1 as an active ingredient.
본 발명의 다른 구체 예에서는, 본 발명에 따른 상기 노화 관련 질환은 피부 노화, 류마티스성 관절염, 골관절염, 간염, 만성 피부손상 조직 및 동맥경화로 이루어진 군으로부터 선택되는 1종 이상일 수 있으나, 세포의 노화로 기인하여 발생될 수 있는 질환이라면 특별히 제한하지 않는다. In another embodiment of the present invention, the aging-related diseases according to the present invention may be at least one kind selected from the group consisting of skin aging, rheumatoid arthritis, osteoarthritis, hepatitis, chronic skin damage tissue and arteriosclerosis, The present invention is not limited thereto.
본 발명에 있어서, "세포 노화 현상"이란, 암과 같은 질환을 억제하거나 촉진하기도 하며, 조직 재생과 복구, 조직/개체 노화와 노화 관련 질환의 중요한 기전으로 제시되고 있다. 아울러 세포 노화는 암, 동맥경화, 피부노화, 퇴행성 신경질환, 근감소증, 골다골증, 전립선비대증 등과 같은 다양한 노화 관련 질환의 병인에 기여할 수 있다. 노화가 빨리 진행되는 생쥐 모델에서, 노화 세포에서 발현이 증가하는 것으로 알려진 P16을 발현하는 세포를 선택적으로 제거한 결과 노화로 인한 조직 병변이 억제되며, 노화 관련 질환의 발생이 감소되는 것이 보고되어 있다. 생쥐에서 간 섬유화가 일어나는 과정에서 간 성상 세포의 노화가 나타나는데, 간성상세포의 노화가 과다한 간 섬유화를 억제하는 기능을 하는 것으로 알려져있다. P53 활성이 적절하게 조절되지 않은 상태에서 지나치게 높아지면 노화가 빨리 나타나지만, 적절한 P53의 활성은 오히려 노화를 억제하는 것으로 알려져 있다.In the present invention, "cell senescence phenomenon" refers to inhibition or promotion of diseases such as cancer, and is suggested as an important mechanism of tissue regeneration and restoration, tissue / individual senescence and aging-related diseases. In addition, cellular senescence can contribute to the pathogenesis of various aging-related diseases such as cancer, arteriosclerosis, skin aging, degenerative neurological diseases, myopenia, osteoporosis, and hypertrophy of the prostate. It has been reported that, in a mouse model in which aging proceeds rapidly, selective removal of cells expressing P16, which is known to increase expression in aging cells, inhibits aging-related tissue lesions and reduces the incidence of aging-related diseases. In the course of hepatic fibrosis in mice, aging of hepatic stellate cells occurs. It is known that aging of hepatic stellate cells inhibits excessive liver fibrosis. When P53 activity is not properly regulated, but too high, aging may occur rapidly, but proper P53 activity is known to inhibit aging.
한편, 본 발명에서, "예방"은 본 발명에 따른 약학 조성물을 이용하여 노화 관련 질환의 증상을 차단하거나, 그 증상의 억제 또는 지연시키는 모든 행위라면 제한없이 포함할 수 있다. In the present invention, the term "prevention" may include, without limitation, any action that inhibits the symptoms of an aging-related disorder or inhibits or delays the symptoms using the pharmaceutical composition according to the present invention.
또한, 본 발명에서, "치료"는 본 발명에 따른 약학 조성물을 이용하여 노화 관련 질환의 증상이 호전되거나 이롭게 되는 모든 행위라면 제한없이 포함할 수 있다. Further, in the present invention, "treatment" can include without limitation any action that improves or alleviates symptoms of aging-related diseases using the pharmaceutical composition according to the present invention.
본 발명의 약학 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 상기 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약제학적 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of oral preparations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterilized injection solutions according to a conventional method, have. The pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizer, a suspending agent, a coloring matter, a perfume or the like in the case of oral administration. A wetting agent, an isotonic agent, an isotonic agent, an isotonic agent, a stabilizer and the like may be mixed and used. In the case of topical administration, a base, an excipient, a lubricant, a preservative and the like may be used. Formulations of the pharmaceutical compositions of the present invention may be prepared in a variety of ways by mixing with pharmaceutically acceptable carriers as described above. For example, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. In the case of injections, they may be formulated in unit dosage ampoules or in multiple dosage forms have. Other, solutions, suspensions, tablets, capsules, sustained-release preparations and the like.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltoditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.
본 발명에 따른 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical compositions according to the present invention may be, but is not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, Sublingual or rectal. Oral or parenteral administration is preferred.
본발명에 있어서, 상기 "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.In the present invention, the "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration.
본 발명의 약학 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여시간, 투여경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무형태, 투여경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형될 수 있다.The pharmaceutical composition of the present invention varies depending on various factors including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease to be prevented or treated. And the dosage of the pharmaceutical composition may be appropriately selected by a person skilled in the art depending on the condition of the patient, the body weight, the degree of disease, the type of administration, the route of administration and the period of time, and may be 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way. The pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.
본 발명의 또 다른 구현 예에서는, 하이드로퀴논(Hydroquinone) 유도체 및 상기 화학식 1로 표시되는 화합물을 유효 성분으로 포함하는 노화 관련 질환의 예방 또는 개선용 화장료 조성물을 제공한다.Another embodiment of the present invention provides a cosmetic composition for preventing or ameliorating an aging-related disease comprising hydroquinone derivatives and the compound represented by the formula (1) as an active ingredient.
단, 본 발명에서 하이드로퀴논, 중간엽 줄기세포, 텔로머라제, 노화 관련 질환, 세포분화 및 예방은 상기 세포 노화 억제용 조성물에 기재된 바와 중복되어, 그 기재를 생략한다.However, in the present invention, hydroquinone, mesenchymal stem cells, telomerase, aging-related diseases, cell differentiation and prevention are overlapped with those described in the composition for inhibiting cell senescence, and the description thereof is omitted.
본 발명의 다른 실시예에서는 터트-부틸하이드로퀴논(tert-butylhydroquinone) 및 상기 화학식 1로 표시되는 화합물을 유효 성분으로 포함하는 노화 관련 질환의 예방 또는 개선용 화장료 조성물일 수 있다.Another embodiment of the present invention may be a cosmetic composition for preventing or improving aging-related diseases comprising tert-butylhydroquinone and the compound represented by
한편, 본 발명에서, "개선"은 본 발명의 화장료 조성물을 이용하여 노화 관련 질환의 증상이 호전 또는 이롭게 변경되는 모든 행위라면 제한없이 포함할 수 있다.In the present invention, "improvement" may include, without limitation, any action that improves or alleviates symptoms of an aging-related disorder using the cosmetic composition of the present invention.
본 발명에 있어서, 상기 화장료 조성물은, 이에 제한되는 것은 아니지만, 화장수, 영양로션, 영양에센스, 마사지 크림, 미용목욕물첨가제, 바디로션, 바디밀크, 배스오일, 베이비오일, 베이비파우더, 샤워겔, 샤워크림, 선스크린로션, 선스크린크림, 선탠크림, 스킨로션, 스킨크림, 자외선차단용 화장품, 크렌징밀크, 탈모제화장용, 페이스 및 바디로션, 페이스 및 바디크림, 피부미백크림, 핸드로션, 헤어로션, 화장용크림, 쟈스민오일, 목욕비누, 물비누, 미용비누, 샴푸, 손세정제(핸드클리너), 약용비누비의료용, 크림비누, 페이셜 워시, 전신 세정제, 두피 세정제, 헤어린스, 화장비누, 치아미백용 겔, 치약 등의 형태로 제조될 수 있다. 이를 위해 본 발명의 조성물은 화장료 조성물의 제조에 통상적으로 사용하는 용매나, 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The cosmetic composition according to the present invention may be used in cosmetics, nutrition lotions, nutritional essences, massage creams, cosmetic bath additives, body lotions, body milks, bath oils, baby oils, baby powders, shower gels, Cream, sunscreen lotion, sunscreen cream, suntan cream, skin lotion, skin cream, sunscreen cosmetics, cleansing milk, hair loss shampoo, face and body lotion, face and body cream, skin whitening cream, hand lotion, hair lotion , Soap cream, jasmine oil, bath soap, water soap, soap, shampoo, hand cleanser (hand cleaner), medicinal soap medicine, cream soap, facial wash, whole body cleanser, scalp cleaner, hair rinse, Gel, tooth paste and the like. To this end, the composition of the present invention may further comprise a solvent commonly used in the production of a cosmetic composition, or a suitable carrier, excipient or diluent.
본 발명의 화장료 조성물 내에 더 추가될 수 있는 용매의 종류는 특별히 한정하지 않으나, 예를 들어, 물, 식염수, DMSO 또는 이들의 조합을 사용할 수 있고, 담체, 부형제 또는 희석제로는 정제수, 오일, 왁스, 지방산, 지방산 알콜, 지방산 에스테르, 계면활성제, 흡습제(humectant), 증점제, 항산화제, 점도 안정화제, 킬레이팅제, 완충제, 저급 알콜 등이 포함되지만, 이에 제한되는 것은 아니다. 또한, 필요에 따라 미백제, 보습제, 비타민, 자외선 차단제, 향수, 염료, 항생제, 항박테리아제, 항진균제를 포함할 수 있다. For example, water, saline solution, DMSO, or a combination thereof may be used. Examples of the carrier, excipient or diluent include purified water, oil, wax But are not limited to, fatty acids, fatty acid alcohols, fatty acid esters, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, lower alcohols and the like. Further, if necessary, it may contain a whitening agent, a moisturizing agent, a vitamin, an ultraviolet screening agent, a perfume, a dye, an antibiotic, an antibacterial agent, and an antifungal agent.
상기 오일로서는 수소화 식물성유, 피마자유, 면실유, 올리브유, 야자인유, 호호바유, 아보카도유가 이용될 수 있으며, 왁스로는 밀랍, 경랍, 카르나우바, 칸델릴라, 몬탄, 세레신, 액체 파라핀, 라놀린이 이용될 수 있다.As the oil, hydrogenated vegetable oil, castor oil, cottonseed oil, olive oil, palm oil, jojoba oil and avocado oil may be used. Examples of the wax include wax, wax, carnauba, candelilla, montan, ceresin, liquid paraffin, Can be used.
또한, 지방산으로는 스테아르산, 리놀레산, 리놀렌산, 올레산이 이용될 수 있고, 지방산 알콜로는 세틸 알콜, 옥틸 도데칸올, 올레일 알콜, 판텐올, 라놀린 알콜, 스테아릴 알콜, 헥사데칸올이 이용될 수 있으며 지방산 에스테르로는 이소프로필 미리스테이트, 이소프로필 팔미테이트, 부틸 스테아레이트가 이용될 수 있다. 계면 활성제로는 당업계에 알려진 양이온 계면활성제, 음이온 계면활성제 및 비 이온성 계면활성제가 사용가능하며 가능한 한 천연물 유래의 계면활성제가 바람직하다.As the fatty acid, stearic acid, linoleic acid, linolenic acid and oleic acid may be used. As the fatty acid alcohol, cetyl alcohol, octyldodecanol, oleyl alcohol, panthenol, lanolin alcohol, stearyl alcohol and hexadecanol may be used Isopropyl myristate, isopropyl palmitate, and butyl stearate may be used as the fatty acid ester. As the surfactant, a cationic surfactant, an anionic surfactant and a nonionic surfactant known in the art can be used, and a surfactant derived from a natural material is preferably used as far as possible.
그 외에도 화장품 분야에서 널리 알려진 흡습제, 증점제, 항산화제 등을 포함할 수 있으며, 이들의 종류와 양은 당업계에 공지된 바에 따른다.In addition, it may contain a hygroscopic agent, a thickening agent, an antioxidant and the like widely known in the field of cosmetics, and the kind and amount thereof are well known in the art.
본 발명의 또 다른 구현 예에서는, 하이드로퀴논(Hydroquinone) 유도체 및 상기 화학식 1로 표시되는 화합물을 유효 성분으로 포함하는 노화 관련 질환의 예방 또는 개선용 식품 조성물을 제공한다.In another embodiment of the present invention, there is provided a food composition for preventing or ameliorating an aging-related disease comprising hydroquinone derivatives and the compound represented by the formula (1) as an active ingredient.
단, 본 발명에서 하이드로퀴논, 중간엽 줄기세포, 텔로머라제, 노화 관련 질환, 세포분화, 예방 및 개선은 상기 세포 노화 억제용 조성물에 기재된 바와 중복되어, 그 기재를 생략한다.However, in the present invention, hydroquinone, mesenchymal stem cells, telomerase, aging-related diseases, cell differentiation, prevention and improvement overlap with those described in the composition for inhibiting cell senescence, and the description thereof is omitted.
본 발명의 다른 실시예에서는 터트-부틸하이드로퀴논(tert-butylhydroquinone) 및 상기 화학식 1로 표시되는 화합물을 유효 성분으로 포함하는 노화 관련 질환의 예방 또는 개선용 식품 조성물일 수 있다.Another embodiment of the present invention may be a food composition for preventing or ameliorating an aging-related disease comprising tert-butylhydroquinone and the compound represented by
본 발명에 따른 상기 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. 발명의 상기 화합물이 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있다.The food composition according to the present invention may be prepared in the form of various foods such as beverages, gums, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes and breads. When the compound of the present invention is contained in the food composition, the amount thereof may be added in a proportion of 0.1 to 50% of the total weight.
본 발명에서, 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 포함하는 것 외에 특별한 제한은 없으며, 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물은 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등을 들 수 있다. In the present invention, when the food composition is prepared in the form of a beverage, there is no particular limitation other than that the food composition is contained at the indicated ratio, and it may contain various flavors or natural carbohydrates such as ordinary beverages as an additional ingredient have. The natural carbohydrates include conventional saccharides such as monosaccharides such as glucose, disaccharides such as fructose, sucrose and the like and polysaccharides, dextrins and cyclodextrins, and sugar alcohols such as xylitol, sorbitol and erythritol . Examples of the above-mentioned flavors include natural flavors (such as tau martin and stevia extract (for example, rebaudioside A and glycyrrhizin) and synthetic flavors (for example, saccharine and aspartame).
또한, 본 발명에서, 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 포함할 수 있다.Further, in the present invention, the food composition may be in the form of a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants, pectic acid and its salts, alginic acid and its salts, Colloid thickening agents, pH adjusting agents, stabilizers, antiseptics, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 본 발명의 핵심적인 요소에 해당하지 아니하지만, 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택되는 것이 일반적이다.These components may be used independently or in combination. The proportion of these additives is not a key element of the present invention, but is generally selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention.
또한, 본 발명에서 상기 식품 조성물은 밀크 또는 유장계 발효 유제품과 같은 식품 또는 영양 제품으로서 또는 식품 보조제 또는 건강기능성 식품으로 섭취될 수 있다. 구체적으로, 유제품, 음료수, 주스, 수프 또는 어린이용 식품과 같은 식품을 예로 들 수 있지만, 이에 제한되는 것은 아니다. 상기 유제품은 다양한 지방 함량을 갖는 임의의 액체 또는 반고체 밀크 또는 유장계 제품을 의미한다. 상기 유제품은 예를 들어 우유, 염소의 젖, 양의 젖, 크림, 전지유(full-fat milk), 전유(whole milk), 저지방유(low-fat milk) 또는 탈지유(skim milk), 한외여과유, 이중여과유(diafilteredmilk), 미세여과유(microfiltered milk), 임의의 가공을 통해 분유 또는 유장으로부터 얻은 재조합유, 가공 제품, 예를 들어, 요거트, 응유, 산유, 산전유(sour whole milk), 버터유, 기타 발효유 제품, 예를 들어 빌리(viili), 스낵바의 필링(filling of snack bars)등 일 수 있다. 또 다른 중요한 그룹은 유음료(milk beverage), 예를 들어, 유장 음료, 발효유, 농축유, 유아 및 아기용 밀크, 아이스크림, 단것과 같은 유함유 식품이 포함될 수 있다.In addition, in the present invention, the food composition may be ingested as food or nutritional products such as milk or dairy fermented milk products, or as food additives or health functional foods. Specifically, examples include foods such as dairy products, beverages, juices, soups or foods for children, but are not limited thereto. The dairy product means any liquid or semi-solid milk or liquid product having various fat contents. The milk product may be, for example, milk, goat's milk, positive milk, cream, full-fat milk, whole milk, low-fat milk or skim milk, Dyfiltered milk, microfiltered milk, recombinant milk obtained from milk powder or whey through any processing, processed products such as yoghurt, curd, milk oil, sour whole milk, , Buttermilk, other fermented milk products, e.g., viili, filling of snack bars, and the like. Another important group may include milk-based foods such as milk beverages, such as whey drinks, fermented milk, concentrated milk, infant and baby milk, ice cream, and sweets.
본 발명에 따른 조성물은 단독으로 투여된 경우에 비하여, 세포 증식 유도, 자가 재생 유도, 다분화능 회복 및 텔로머라제 활성 유도를 통하여 세포 노화를 현저하게 억제하는 조성물로 사용될 수 있다.The composition according to the present invention can be used as a composition that significantly inhibits cell senescence through induction of cell proliferation, induction of self regeneration, recovery of pluripotency, and induction of telomerase activity, as compared with administration alone.
도 1은 본 발명의 일 실시예에 따른 줄기세포 세포 증식 정도를 그래프로 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른 줄기세포의 자가 재생 정도에 따른 사진을 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 줄기세포의 자가 재생된 세포의 수를 그래프로 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 자가 재생이 발생한 세포의 평균 사이즈를 그래프로 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른 텔로미어의 mRNA 발현 정도를 그래프로 나타낸 것이다.
도 6은 본 발명의 일 실시예에 따른 텔로미어의 mRNA 발현 정도를 그래프로 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른 텔로미어의 mRNA 발현 정도를 그래프로 나타낸 것이다.
도 8은 본 발명의 일 실시예에 따른 줄기세포의 골 분화 정도에 따른 사진을 나타낸 것이다.
도 9는 본 발명의 일 실시예에 따른 줄기세포의 골 분화 정도에 따른 흡광도를 그래프로 나타낸 것이다.
도 10은 본 발명의 일 실시예에 따른 줄기세포의 지방 세포로의 분화 정도에 따른 사진을 나타낸 것이다.
도 11은 본 발명의 일 실시예에 따른 줄기세포의 지방 세포로의 분화 정도에 따른 흡광도를 그래프로 나타낸 것이다.FIG. 1 is a graph showing the degree of stem cell proliferation according to an embodiment of the present invention.
FIG. 2 is a photograph showing the degree of self-renewal of stem cells according to an embodiment of the present invention.
FIG. 3 is a graph showing the number of self-regenerating cells of a stem cell according to an embodiment of the present invention.
4 is a graph illustrating an average size of cells in which self-regeneration has occurred according to an embodiment of the present invention.
FIG. 5 is a graph showing the degree of mRNA expression of telomere according to an embodiment of the present invention.
FIG. 6 is a graph showing the mRNA expression level of telomere according to an embodiment of the present invention.
FIG. 7 is a graph showing the degree of mRNA expression of telomere according to an embodiment of the present invention.
FIG. 8 is a photograph according to the degree of bone differentiation of stem cells according to an embodiment of the present invention.
FIG. 9 is a graph showing the absorbance according to the degree of bone differentiation of stem cells according to an embodiment of the present invention.
FIG. 10 is a photograph showing the degree of differentiation of stem cells into adipocytes according to an embodiment of the present invention.
11 is a graph showing the absorbance of the stem cells according to the degree of differentiation into adipocytes according to an embodiment of the present invention.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
실시예Example
[[ 준비예Preparation Example 1] 인간 유래 골수 세포 분리 및 배양 1] Isolation and culture of human-derived bone marrow cells
본 발명에 따른 조성물의 세포 노화 억제 효과를 확인하기 위해, 연세대학교 의과대학 재검사위원회(IRB)의 승인 하에, 7명의 성인 기증자의 장골에서 골수를 채취하여, 하기 실험에 사용하였다.In order to confirm the effect of the composition according to the present invention on the inhibition of cell senescence, bone marrow was collected from the iliac bone of seven adult donors under the approval of the Reinspection Committee (IRB) of Yonsei University College of Medicine and used for the following experiment.
통상의 방법에 의해 상기 골수에서 중간엽 줄기세포(Mesenchymal stem cell; 이하 'MSC'라 함)를 우선적으로 분리하고, 세포 배양 접시에 부착할 수 있는 능력을 갖는 세포를 선별하였다.Mesenchymal stem cells (hereinafter, referred to as MSCs) were preferentially separated from the bone marrow by a conventional method, and cells having the ability to attach to cell culture dishes were selected.
상기 선별된 MSC는 우태아혈청(FBS; hyclone, logan, UT) 10% 및 1%의 항생제를 포함하는 DMEM(Invitrogen Gibco, Grand Island, NY) 영양배지에서 37℃, 5 % CO2 배양기 내에서 배양하며, 3번째 계대에 해당하는 초기 단계(early passage)에서는 5000 cells/cm2의 밀도로 계대배양하였고, 9번째 계대에 해당하는 후기 단계(late passage)에서는 세포 배양 접시의 80%로 세포가 배양되었을 때 계대배양 하였다.The selected MSCs were cultured in DMEM (Invitrogen Gibco, Grand Island, NY) containing 10% of FBS (Hyclone, Logan, UT) and 1% of antibiotics at 37 ° C in a 5% CO 2 incubator And cultured at a density of 5000 cells / cm 2 in the early passage corresponding to the third passage. In the late passage corresponding to the 9th passage, 80% of the cells were cultured. When cultured, subculture was performed.
[[ 실시예Example 1] 세포 증식( 1] Cell proliferation ( cellcell proliferationproliferation ) 분석) analysis
본 발명에 따른 조성물의 세포 증식 유도 효과를 확인하기 위하여, 세포 증식률을 확인하였다. In order to confirm the cell proliferation inducing effect of the composition according to the present invention, the cell proliferation rate was confirmed.
상기 준비예 1의 후기 단계 MSC(이하 'LP MSC'라 함)를 1 X 103 cell/well로 96 well 세포 배양 접시에 분주한 뒤, 각각의 접시에 음성 대조군(vehicle)으로 DMSO, 아펠린(apelin) 20nM, 레스베라트롤(RSV) 1μM 및 터트-부틸하이드로퀴논(tert-butylhydroquinone; 이하 't-BHQ' 라함) 10 μM을 각각 투여하고, 아펠린 및 t-BHQ, 아펠린 및 레스베라트롤, 레스베라트롤 및 t-BHQ의 조합을 각각 병용하여 투여한 뒤, 0일 내지 7일에서 세포 증식률을 측정하였다.The MSC of the late phase of Preparation Example 1 (hereinafter, referred to as 'LP MSC') was dispensed into 96-well cell culture dishes at 1 × 10 3 cells / well. DMSO, Apelin apelin and t-BHQ, apelin and resveratrol, resveratrol and 1 μM of resveratrol (RSV) and 10 μM of tert-butylhydroquinone (hereinafter abbreviated as t-BHQ) t-BHQ, respectively, and then the cell proliferation rate was measured from 0 to 7 days.
상기 세포 증식률 측정은 EZ-cytox 세포 생존 어세이(cell viability assay) 시약을 10㎕씩 각각 분주한 뒤, 4시간 동안 반응이 끝난 후, 450nm에서 흡광도를 측정하여, 그 값을 도 1 및 표 1에 나타내었다.The cell proliferation rate was measured by dividing the EZ-cytox cell viability assay reagent by 10 μl each. After completion of the reaction for 4 hours, the absorbance at 450 nm was measured. Respectively.
도 1 및 표 1에서 보는 바와 같이, 아펠린, 레스베라트롤 또는 t-BHQ 각각을 단독으로 투여한 경우에는 7일째 약 1.2의 흡광도를 보였다. 또한, 아펠린과 t-BHQ을 병용 투여한 경우나, 아펠린과 레스베라트롤을 병용하여 투여한 경우 역시 약 1.2의 흡광도를 보였다. 반면, 레스베라트롤 및 t-BHQ를 병용 투여한 경우에는 7일에서 1.467의 흡광도를 나타내었다.As shown in Fig. 1 and Table 1, when apelin, resveratrol or t-BHQ alone was administered alone, the absorbance was about 1.2 at 7 days. In addition, when the combination of apelin and t-BHQ was administered or when apelin was administered in combination with resveratrol, the absorbance was also about 1.2. On the other hand, when resveratrol and t-BHQ were administered concomitantly, the absorbance was 1.467 at 7 days.
상기 결과를 통하여, 레스베라트롤 및 t-BHQ를 병용하여 투여한 경우 LP MSC에서 세포 증식 유도에 있어 시너지 효과가 존재함을 알 수 있다.From the above results, it can be seen that there is a synergistic effect in inducing cell proliferation in LP MSC when resveratrol and t-BHQ are administered in combination.
[[ 실시예Example 2] 자기 재생( 2] Self-regeneration ( selfself -- renewalrenewal ) 능력 확인) Confirm ability
LP MSC에서 자기 재생 능력을 확인하기 위하여 콜로니-생성 유닛 섬유아세포(colony-forming unit-fibroblasts; CFU-F) 분석을 하였다.Colony-forming unit-fibroblasts (CFU-F) analysis was performed to confirm self-renewal ability in LP MSC.
상기 CFU-F 분석을 위해 음성 대조군(vehicle), 아펠린(apelin) 20nM 각각을 투여하고, 아펠린과 t-BHQ의 조합; 아펠린과 레스베라트롤의 조합; 레스베라트롤과 t-BHQ의 조합을 각각 병용 투여하고, 12일간 배양하였다. 그 뒤, 각각의 세포를 1회 PBS로 세척하고, 0.5% 크리스탈 바이올렛 용액(crystal violet solution)을 첨가 후, 30분간 실온에서 반응시킨 뒤, 염색된 콜로니의 수 및 크기를 확인하여, 그 결과를 도 2 내지 4에 나타내었다.For the CFU-F analysis, a negative control vehicle, 20 nM of apelin, was administered, and a combination of apelin and t-BHQ; A combination of apelin and resveratrol; The combination of resveratrol and t-BHQ was coadministered and cultured for 12 days. Then, each cell was washed once with PBS, added with 0.5% crystal violet solution, reacted at room temperature for 30 minutes, and the number and size of the stained colonies were confirmed. 2 to 4.
도 2 내지 3에서 보는 바와 같이, 아펠린과 t-BHQ를 병용 투여하였을 때 CFU-F 콜로니의 수는 40개에 해당하였으나, 레스베라트롤과 t-BHQ를 병용 투여하였을 때에는 콜로니 수가 60개에 해당하였다. As shown in FIGS. 2 to 3, when the combination of apelin and t-BHQ was administered, the number of CFU-F colonies was 40, but when the combination of resveratrol and t-BHQ was administered, the number of colonies was 60 .
또한, 도 4에서 보는 바와 같이, CFU-F 콜로니의 평균 크기는 대부분의 경우 음성 대조군과 차이가 없었지만, 레스베라트롤과 t-BHQ를 병용하여 투여한 경우 음성 대조군에 비하여 약 0.3 정도 크기가 증가되어 있었다.In addition, as shown in FIG. 4, the average size of CFU-F colonies was not different from the negative control group in most cases, but when administered with the combination of resveratrol and t-BHQ, the size of CFU-F colonies was increased by about 0.3 .
상기 결과를 통하여, 레스베라트롤과 t-BHQ를 병용하여 투여하는 경우 이들을 각각 투여한 경우, 혹은 다른 조합으로 병용 투여한 경우와 비교하여, LP MSC에서 줄기세포의 자가 재생 능력을 현저하게 유도시키는 것을 알 수 있다.The above results indicate that the administration of resveratrol and t-BHQ in combination leads to remarkable induction of self-renewal of stem cells in LP MSC, as compared with the case where they are administered individually or in combination with each other .
[[ 실시예Example 3] 3] 텔로머라제Telomerase (( telomeraseTelomerase ) 활성 확인) Active confirmation
세포 노화 억제 정도를 확인하기 위하여, 세포 노화 지표로 활용되는 텔로미어(telomere)를 생성하는 텔로머라제 활성 정도의 차이를 LP MSC 및 EP MSC 에서 확인하였다. 상기 텔로머라제(telomerase)의 활성도 확인을 위하여, 상기 실시예 2와 동일한 방법으로 조성물을 상기 준비예 1의 LP MSC 및 EP MSC에 투여한 뒤, 7일간 배양하였다. 그 뒤, 세포로부터 통상의 방법에 의해 mRNA를 추출하고, 실시간 중합효소 연쇄반응(real-time PCR)을 PCR 증폭 조건 95 10분간의 개시 단계, 95 5초, 56 20초로 이루어지는 40 사이클을 수행하여, 하기 텔로머라제 관련 유전자의 발현 정도를 확인하였다.In order to confirm the degree of cell senescence inhibition, the difference in telomerase activity level that produces telomeres used as an indicator of cell senescence was confirmed by LP MSC and EP MSC. In order to confirm the activity of the telomerase, the composition was administered to the LP MSC and EP MSC of Preparation Example 1 in the same manner as in Example 2, and then cultured for 7 days. Thereafter, mRNA was extracted from the cells by a conventional method and real-time PCR was performed for 40 cycles consisting of the initiation step of PCR amplification condition 95 10 minutes, 955 seconds, 5620 seconds, , And the degree of expression of the following telomerase-related gene was confirmed.
상기 텔로머라제 관련 유전자인 hTERT 유전자, CDK2 유전자 및 CCND1 유전자와 상보적으로 결합할 수 있는 프라이머를 이용하여 진행하였다. 또한, Applied Biosystem사로부터 구입된 ABI Step One Plus 시퀀스 탐지 시스템(Applied Biosystems)을 통해 정량적인 수치를 확인하여, 그 결과를 도 5 내지 7에 나타내었다.The primers were complementary to the telomerase related genes hTERT, CDK2 and CCND1. In addition, quantitative values were confirmed through an ABI Step One Plus sequence detection system (Applied Biosystems) purchased from Applied Biosystems, and the results are shown in FIGS. 5 to 7.
도 5 내지 7에서 보는 바와 같이, EP MSC에 비하여 감소되어 있던 LP MSC의 hTERT, CDK2 및 CCND1 유전자는 레스베라트롤과 t-BHQ를 병용하여 투여한 경우가 단독 또는 아펠린과 t-BHQ을 병용 투여한 경우나, 아펠린과 레스베라트롤을 병용 투여한 경우에 비하여 발현이 현저하게 증가되었다.As shown in FIGS. 5 to 7, hTERT, CDK2 and CCND1 genes of LP MSC, which were reduced compared to EP MSC, were treated with resveratrol and t-BHQ alone or in combination with apelin and t-BHQ , Or the administration of apelin and resveratrol in combination, the expression was remarkably increased.
상기 결과를 통하여, EP MSC가 후기 단계로 진행될수록, 레스베라트롤과 t-BHQ를 병용하여 투여하는 경우 MSC의 텔로머라제 활성이 감소되는 현상을 효과적으로 방지할 수 있고, 나아가 EP MSC 상태로 회복시킬 수 있음을 알 수 있다.As a result, the administration of resveratrol and t-BHQ in combination with EP MSC effectively prevented the telomerase activity of MSC from being reduced, .
[[ 실시예Example 4] 4] 골분화세포로의Into bone differentiation cells 다분화능Multiparameter (( multipotentmultipotent ) 확인) Confirm
본 발명에 따른 조성물을 투여하였을 때 줄기세포의 다분화능이 LP MSC에서 유지되는지 여부를 확인하기 위하여 골 분화능 정도를 확인하였다.When the composition according to the present invention was administered, the degree of bone differentiation was confirmed in order to determine whether the pluripotency of stem cells was maintained in the LP MSC.
상기 실시예 2과 동일한 방법으로 조성물을 상기 준비예 1의 LP MSC에 투여한 뒤, 14일간 골아세포 분화 배지에서 배양하여 골 분화를 유도하고, 석회화 정도를 확인할 수 있는 알리자린 레드 S(Alizarin red S) 시약으로 염색하여 현미경으로 측정하였고, 10% 세틸피리디니움 클로라이드(Cetylpyridinium chloride ) 용액으로 탈색하고, 595nm에서의 흡광도를 측정하여, 도 8 및 도 9에 나타내었다.In the same manner as in Example 2, the composition was administered to the LP MSC of Preparation Example 1, and then cultured in an osteoblast differentiation medium for 14 days to induce bone differentiation. Alizarin red S ) were stained with the reagent was measured under a microscope, 10% cetylpyridinium nium chloride (cetylpyridinium decolorized with chloride) solution, followed by measuring the absorbance at 595nm, are shown in FIGS.
도 8 및 도 9에서 보는 바와 같이, 음성 대조군 또는 아펠린을 단독으로 투여한 경우에는 석회화 정도가 높지 않았으며, 아펠린과 t-BHQ를 병용 투여하거나, 아펠린과 레스베라트롤을 병용 투여한 경우에도 석회화 정도 가 높지 않았다. 반면, 레스베라트롤과 t-BHQ를 병용하여 투여한 경우에는 2.144의 값으로 가장 석회화 정도가 높았다.As shown in Figs. 8 and 9, when the negative control or apelin was administered alone, the degree of calcification was not high. When apelin and t-BHQ were administered concomitantly or when apelin and resveratrol were administered concomitantly The degree of calcification was not high. On the other hand, the combination of resveratrol and t-BHQ showed the highest degree of calcification at a value of 2.144.
상기 결과를 통해 레스베라트롤과 t-BHQ를 병용하여 투여하는 경우, 다른 조성물에 비하여 후기 단계에서 상실된 다분화능 회복에 현저한 효과가 존재함을 알 수 있다.These results indicate that when resveratrol and t-BHQ are administered in combination, there is a remarkable effect on the recovery of the multipotential regeneration lost in the later stage compared to other compositions.
[[ 실시예Example 5] 지방세포로의 5] 다분화능Multiparameter (( multipotentmultipotent ) 확인) Confirm
또한, 본 발명에 따른 조성물을 투여하였을 때 줄기세포의 다분화능이 LP MSC에서 유지 여부를 확인하기 위하여 지방세포로의 분화능을 확인하였다.In addition, when the composition according to the present invention was administered, the ability to differentiate into adipocytes was confirmed in order to confirm whether the pluripotency of stem cells was maintained in LP MSCs.
상기 실시예 2과 동일한 방법으로 조성물을 상기 준비예 1의 LP MSC에 투여한 뒤, 21일간 지방세포 분화 배지에서 배양하여 지방 분화를 유도하고, 지방 분화 정도를 확인할 수 있는 오일-레드 O(oil-red O) 시약으로 염색한 뒤 현미경 관찰하였고, 이소프로페놀(isopropanol)으로 탈색한 뒤, 500nm에서의 흡광도를 측정하여, 도 10 및 도 11에 나타내었다.The composition was administered to the LP MSC of Preparation Example 1 in the same manner as in Example 2, and then cultured in an adipocyte differentiation medium for 21 days to induce lipid differentiation. The oil-red O (oil -red O) reagent, followed by microscopic observation, discoloration with isopropanol, and measurement of the absorbance at 500 nm, as shown in FIGS. 10 and 11. FIG.
도 10 및 도 11에서 보는 바와 같이, 대조군 또는 아펠린을 단독으로 투여한 경우 및 아펠린과 t-BHQ를 병용 투여하거나, 아펠린과 레스베라트롤을 병용 투여한 경우에는 지방세포로의 분화 정도가 대조군에 비하여 큰 차이가 존재하지 않았지만, 레스베라트롤과 t-BHQ를 병용하여 투여한 경우에는 0.365로 지방세포로의 분화 정도가 3배 증가 하였다.As shown in Figs. 10 and 11, when the control or apelin was administered singly or when apelin and t-BHQ were co-administered, or when apelin and resveratrol were administered in combination, the degree of differentiation into adipocytes was increased There was no significant difference between the two groups, but when resveratrol was administered in combination with t-BHQ, the degree of differentiation into adipocytes increased 3-fold to 0.365.
상기 결과를 통해 레스베라트롤과 t-BHQ를 병용하여 투여하는 경우, 다른 조성물에 비하여 후기 단계에서 상실된 다분화능 회복에 현저한 효과가 존재함을 알 수 있다.These results indicate that when resveratrol and t-BHQ are administered in combination, there is a remarkable effect on the recovery of the multipotential regeneration lost in the later stage compared to other compositions.
이상에서 본 발명에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고, 청구범위에 기재된 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 다양한 수정 및 변형이 가능 하다는 것은 당 기술분야의 통상의 지식을 가진 자에게는 자명할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the scope of the present invention is not limited to the disclosed exemplary embodiments, but various changes and modifications may be made without departing from the scope of the invention. It will be obvious to those who have knowledge of
Claims (18)
상기 세포 노화 억제는 세포 내 텔로머라제(Telomerase) 활성, 세포 증식, 세포 주기(cell cycle) 활성 및 세포 분화(Differencication) 중 적어도 하나의 반응을 유도하는 것인, 세포 노화 억제 방법:
[화학식 1]
Wherein said inhibition of cell senescence induces at least one of telomerase activity, cell proliferation, cell cycle activity, and cell differentiation.
[Chemical Formula 1]
상기 세포는 줄기세포인 것인, 세포 노화 억제 방법.8. The method of claim 7,
Wherein said cell is a stem cell.
상기 줄기세포는 후기 중간엽 줄기세포인 것인, 세포 노화 억제 방법.10. The method of claim 9,
Wherein the stem cell is a late mesenchymal stem cell.
상기 후기 중간엽 줄기세포는 제대, 제대혈, 골수, 지방, 근육, 피부, 양막 및 태반으로 구성된 군에서 선택되는 1종 이상에서 유래된 것을 특징으로 하는, 세포 노화 억제 방법.11. The method of claim 10,
Wherein said late mesenchymal stem cells are derived from at least one selected from the group consisting of umbilical cord, umbilical cord blood, bone marrow, fat, muscle, skin, amnion and placenta.
상기 노화 관련 질환은 골관절염인, 약학 조성물:
[화학식 1]
Wherein said aging-related disease is osteoarthritis.
[Chemical Formula 1]
상기 노화 관련 질환은 골관절염인, 화장료 조성물:
[화학식 1]
Wherein said aging-related disease is osteoarthritis.
[Chemical Formula 1]
상기 노화 관련 질환은 골관절염인, 식품 조성물:
[화학식 1]
Wherein said aging-related disease is osteoarthritis.
[Chemical Formula 1]
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| KR102647264B1 (en) | 2023-11-01 | 2024-03-14 | 주식회사 아리바이오 | Composition for drug delivery comprising nanoparticle carrying telomerase activator and composition for preventing, improving or treating hair loss |
| KR102647261B1 (en) | 2023-05-04 | 2024-03-14 | 주식회사 아리바이오 | Composition for drug delivery comprising nanoparticle carrying telomerase activator and composition for preventing, improving or treating hair loss |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR102647261B1 (en) | 2023-05-04 | 2024-03-14 | 주식회사 아리바이오 | Composition for drug delivery comprising nanoparticle carrying telomerase activator and composition for preventing, improving or treating hair loss |
| KR102647264B1 (en) | 2023-11-01 | 2024-03-14 | 주식회사 아리바이오 | Composition for drug delivery comprising nanoparticle carrying telomerase activator and composition for preventing, improving or treating hair loss |
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