KR20200138904A - A composition comprising extracts of Dendropanax morbiferus for preventing or treating demyelinating disease - Google Patents
A composition comprising extracts of Dendropanax morbiferus for preventing or treating demyelinating disease Download PDFInfo
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- KR20200138904A KR20200138904A KR1020190065230A KR20190065230A KR20200138904A KR 20200138904 A KR20200138904 A KR 20200138904A KR 1020190065230 A KR1020190065230 A KR 1020190065230A KR 20190065230 A KR20190065230 A KR 20190065230A KR 20200138904 A KR20200138904 A KR 20200138904A
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Abstract
Description
본 발명은 황칠나무 추출물을 포함하는 탈수초 질환의 예방 또는 치료용 조성물 등에 관한 것이다.The present invention relates to a composition for preventing or treating demyelinating diseases, etc., comprising a hwangchil tree extract.
뇌의 신경섬유는 대부분 수초(미엘린, myelin)라는 지질단백질로 구성된 조직의 많은 층으로 둘러싸여 있는 구조를 이루고 있으며, 수초는 절연체와 비슷한 역할을 수행하기 때문에, 신경섬유를 따라 정확하고 빠른 신경 충동(neural impulse)을 전달하는데 중요한 역할을 수행하고 있다. 이러한 수초가 국소 손상, 면역 장애, 감염, 영양 결핍, 약물, 또는 알려지지 않은 원인 등에 의하여 손상, 파괴 등이 유발되게 되면, 내부에 있는 신경 섬유에 영구적인 손상이 유도된다. 따라서, 체내에서는 수초가 손상되면 이를 회복시키기 위하여 재수초화가 진행되나, 종종 재수초화가 실패하고 탈수초화로 진행되는 경우가 발생된다. 이러한 탈수초화로 인하여 발생되는 탈수초 질환(demyelinating disease)으로는 다발성 경화증(Multiple sclerosis), 급성 파종성 탈수초(acute disseminated demyelination), 레버 유전성 시각 신경병증(Leber hereditary optic neuropathy), 길랭-바레증후군(Guillain-Barre syndrome), 탈수초성 다발성 신경병증(demyelinating polyneuropathy), 샤르코 마리 투스병(Charcot Marie Tooth) 등이 있다. 이러한 탈수초 질환은 대부분이 난치성 질환으로서 치료가 용이하지 않을 뿐만 아니라, 효과적인 치료제가 미비한 실정이다. 최근 말초신경병증 동물모델에서 아스코르브산이 치료 효과를 나타내어 새로운 치료제로서 관심이 증가되었었으나, 임상시험에서 효과가 없는 것으로 확인된 바 있다.The nerve fibers of the brain form a structure surrounded by many layers of tissue, mostly composed of lipoproteins called myelin (myelin), and because myelin sheath plays a similar role as an insulator, it follows the nerve fibers with precise and fast nerve impulses ( neural impulse) plays an important role. When these myelin sheaths are damaged or destroyed by local damage, immune disorders, infections, nutritional deficiencies, drugs, or unknown causes, permanent damage to internal nerve fibers is induced. Therefore, in the body, when the myelin sheath is damaged, remyelination proceeds to recover it, but sometimes remyelination fails and demyelination occurs. Demyelinating diseases caused by such demyelination include multiple sclerosis, acute disseminated demyelination, Leber hereditary optic neuropathy, and Guillain-Barre syndrome. (Guillain-Barre syndrome), demyelinating polyneuropathy, and Charcot Marie Tooth. Most of these demyelinating diseases are intractable diseases and are not easy to treat, and effective treatments are insufficient. In recent years, ascorbic acid has shown a therapeutic effect in animal models of peripheral neuropathy, which has led to increased interest as a new therapeutic agent, but it has been confirmed to be ineffective in clinical trials.
따라서, 수초가 손상되었을 때 재수초화가 촉진되거나, 및/또는 탈수초화를 억제시키기 위해서 희소돌기아교세포 전구체세포를 모집(recruitment)하고, 모인 전구체세포를 희소돌기아교세포로 분화시킬 수 있는 신규 치료제의 개발이 절실히 필요한 실정이다. 이러한 치료제가 개발된다면 탈수초화로 인한 다양한 탈수초 질환의 효과적인 치료제로서 사용가능할 것으로 기대된다.Therefore, when the myelin sheath is damaged, remyelination is promoted, and/or in order to inhibit demyelination, recruitment of oligodendrocyte precursor cells, and a new therapeutic agent capable of differentiating the collected precursor cells into oligodendrocytes It is a situation in which the development of is desperately needed. If such a therapeutic agent is developed, it is expected to be used as an effective therapeutic agent for various demyelinating diseases caused by demyelination.
본 발명은 상기와 같은 종래 기술상의 문제점을 해결하기 위해 안출된 것으로, 황칠나무 추출물을 유효성분으로 포함하는 탈수초 질환의 예방, 개선, 또는 치료용 조성물 등을 제공하는 것을 그 목적으로 한다.The present invention has been conceived to solve the problems of the prior art as described above, it is an object of the present invention to provide a composition for preventing, improving, or treating demyelinating diseases comprising hwangchil tree extract as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 본 발명이 속하는 기술 분야의 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical task to be achieved by the present invention is not limited to the above-mentioned tasks, and other tasks that are not mentioned can be clearly understood by those of ordinary skill in the technical field to which the present invention belongs from the following description. will be.
본 발명은 황칠나무 추출물을 유효성분으로 포함하는 탈수초 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating demyelinating diseases comprising Hwangchil tree extract as an active ingredient.
또한, 본 발명은 황칠나무 추출물을 유효성분으로 포함하는 탈수초 질환의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving demyelination disease, comprising the extract of Hwangchil tree as an active ingredient.
또한, 본 발명은 황칠나무 추출물을 유효성분으로 포함하는 희소돌기아교세포 분화 촉진용 조성물을 제공한다.In addition, the present invention provides a composition for promoting differentiation of oligodendrocytes comprising the extract of Hwangchil wood as an active ingredient.
본 발명의 일 구체예에 있어서, 상기 황칠나무 추출물은 황칠나무 잎의 추출물인 것을 특징으로 한다.In one embodiment of the present invention, the hwangchil tree extract is characterized in that the extract of hwangchil tree leaves.
본 발명의 다른 구체예에 있어서, 상기 황칠나무 추출물은 당해 기술분야에 속하는 통상의 전문가에게 이미 알려진 공정에 의하여 추출될 수 있으며, 바람직하게는, 물, 에탄올, 부탄올, 아세톤, 에테르, 헥산, 벤젠, 에틸아세테이트 등을 단독으로 이용하여, 또는 혼합 용매를 이용하여 추출될 수 있으며, 더욱 바람직하게는 에탄올이나 이에 제한되지 않는다.In another embodiment of the present invention, the Hwangchil tree extract may be extracted by a process known to a person skilled in the art, preferably water, ethanol, butanol, acetone, ether, hexane, benzene , Ethyl acetate, etc. may be used alone, or may be extracted using a mixed solvent, more preferably ethanol, but not limited thereto.
본 발명의 또 다른 구체예에 있어서, 상기 탈수초 질환은 신경계의 수초가 파괴되는 증상을 동반하는 모든 질환을 포함하며, 바람직하게는 다발성 경화증(Multiple sclerosis), 급성 파종성 탈수초(acute disseminated demyelination), 레버 유전성 시각 신경병증(Leber hereditary optic neuropathy), 길랭-바레증후군(Guillain-Barre syndrome), 탈수초성 다발성 신경병증(demyelinating polyneuropathy), 샤르코 마리 투스병(Charcot Marie Tooth) 등이나, 수초의 재생을 촉진함으로써 치료할 수 있는 질환이라면 이에 제한되지 않는다.In another embodiment of the present invention, the demyelination disease includes all diseases accompanied by symptoms of destruction of the myelin sheath of the nervous system, preferably multiple sclerosis, acute disseminated demyelination ), Leber hereditary optic neuropathy, Guillain-Barre syndrome, demyelinating polyneuropathy, Charcot Marie Tooth disease, etc. If it is a disease that can be treated by promoting it is not limited thereto.
본 발명의 또 다른 구체예에 있어서, 상기 조성물은 수초화 재생을 촉진시키거나, 탈수초화를 억제시키는 것을 특징으로 한다.In another embodiment of the present invention, the composition is characterized in that it promotes myelinated regeneration or inhibits demyelinating.
본 발명의 또 다른 구체예에 있어서, 상기 희소돌기아교세포는 희소돌기아교세포 전구체세포(Oligodendrocyte precursor)로부터 분화되는 것을 특징으로 한다. 상기 희소돌기아교세포 전구체세포는 희소돌기아교세포로 분화될 수 있는 상태의 세포라면 제한이 없다.In another embodiment of the present invention, the oligodendrocyte is characterized in that it differentiates from oligodendrocyte precursor cells (Oligodendrocyte precursor). The oligodendrocyte precursor cell is not limited as long as it is a cell in a state capable of differentiating into oligodendrocytes.
또한, 본 발명은 황칠나무 추출물을 유효성분으로 포함하는 조성물을 개체에 투여하는 단계를 포함하는, 탈수초 질환의 치료 방법을 제공한다.In addition, the present invention provides a method for treating a demyelinating disease, comprising administering to an individual a composition containing Hwangchil tree extract as an active ingredient.
또한, 본 발명은 황칠나무 추출물을 유효성분으로 포함하는 조성물의 탈수초 질환의 예방 또는 치료 용도를 제공한다.In addition, the present invention provides a preventive or therapeutic use of a composition comprising a hwangchil tree extract as an active ingredient.
본 발명에 따른 황칠나무 추출물을 유효성분으로 포함하는 탈수초 질환의 예방, 개선, 또는 치료용 조성물은 희소돌기아교세포의 분화를 촉진시킬 수 있을 뿐만 아니라, 축삭돌기에의 접촉 및 수초화를 촉진시킨다. 또한, 수초화와 관련된 다양한 유전자의 발현량을 효과적으로 증가시킬 수 있기 때문에 탈수초화로 인하여 발생되는 다양한 탈수초 질환의 예방, 개선, 치료에 효과적으로 사용될 수 있을 것으로 기대된다.The composition for preventing, improving, or treating demyelination disease comprising the extract of Hwangchil tree according to the present invention can promote the differentiation of oligodendrocytes, as well as promote contact with axons and myelinization. . In addition, since it can effectively increase the expression levels of various genes related to myelinization, it is expected that it can be effectively used in the prevention, improvement, and treatment of various demyelinating diseases caused by demyelination.
도 1은 본 발명의 일 실시예에 따른 식물 추출물이 혼합 신경교세포의 수초화 형성에 미치는 영향을 면역염색법으로 확인한 결과를 나타낸 도면이다.
도 2는 본 발명의 일 실시예에 따른 식물 추출물이 희소돌기아교세포 분화에 미치는 영향을 면역염색법으로 확인한 결과를 나타낸 도면이다.
도 3은 본 발명의 일 실시예에 따른 황칠나무의 부위에 따른 추출물이 희소돌기아교세포의 수초화 형성에 미치는 영향을 면역염색법으로 확인한 결과를 나타낸 도면이다.
도 4는 본 발명의 일 실시예에 따른 황칠나무 잎 추출물이 희소돌기아교세포 분화에 미치는 영향을 실시간 중합효소연쇄반응으로 확인한 결과를 나타낸 도면이다.
도 5는 본 발명의 일 실시예에 따른 황칠나무 잎 추출물이 희소돌기아교세포 분화에 미치는 영향을 웨스턴블롯팅으로 확인한 결과를 나타낸 도면이다.
도 6은 본 발명의 일 실시예에 따른 황칠나무 잎 추출물이 후근신경절 신경세포와 희소돌기아교세포 전구체세포의 공동 배양에서 희소돌기아교세포의 분화에 미치는 영향을 면역염색법으로 확인한 결과를 나타낸 도면이다.
도 7은 본 발명의 일 실시예에 따른 황칠나무 잎 추출물이 축삭돌기 접촉에 미치는 영향을 면역염색법으로 확인한 결과를 나타낸 도면이다.
도 8은 본 발명의 일 실시예에 따른 황칠나무 잎 추출물이 수초화에 미치는 영향을 실시간 중합효소연쇄반응으로 확인한 결과를 나타낸 도면이다.1 is a view showing the result of confirming the effect of the plant extract according to an embodiment of the present invention on the formation of myelinated mixed glial cells by immunostaining.
2 is a view showing the result of confirming the effect of the plant extract according to an embodiment of the present invention on the differentiation of oligodendrocytes by immunostaining.
3 is a view showing the result of confirming the effect of the extract according to the portion of the hwangchil tree according to an embodiment of the present invention on the formation of myelinated oligodendrocytes by immunostaining.
4 is a view showing the result of confirming the effect of the Hwangchil tree leaf extract on the differentiation of oligodendrocytes according to an embodiment of the present invention by real-time polymerase chain reaction.
5 is a view showing the results of confirming the effect of the hwangchil tree leaf extract on the differentiation of oligodendrocytes according to an embodiment of the present invention by Western blotting.
6 is a view showing the result of confirming the effect of the Hwangchil tree leaf extract according to an embodiment of the present invention on the differentiation of oligodendrocytes in co-culture of dorsal root ganglion neurons and oligodendrocyte precursor cells by immunostaining .
7 is a view showing the result of confirming the effect of the hwangchil tree leaf extract on the axon contact according to an embodiment of the present invention by immunostaining.
8 is a view showing the result of confirming the effect of the Hwangchil tree leaf extract on myelinated plantation according to an embodiment of the present invention by real-time polymerase chain reaction.
본 발명에서는 황칠나무 잎 추출물이 희소돌기아교세포 전구체세포의 단독 배양뿐만 아니라, 신경세포와의 공동 배양에서도 희소돌기아교세포의 분화를 촉진시키고, 수초화를 촉진하는 다양한 유전자의 발현을 촉진시킬 수 있을 뿐만 아니라, 축삭돌기 접촉도 유도함으로써 효과적으로 수초화를 촉진시킨다는 것을 확인하여 본 발명을 완성하였다.In the present invention, Hwangchil tree leaf extract promotes the differentiation of oligodendrocytes in co-culture with oligodendrocytes as well as oligodendrocyte progenitor cells alone, and can promote the expression of various genes that promote myelinization. In addition, the present invention was completed by confirming that it effectively promotes myelinization by inducing contact with the axon.
본 명세서에 있어서, “탈수초 질환(demyelinating disease)”이란 신경계의 미엘린 수초에서 비정상, 특히 수초의 파괴를 수반하는 질환을 총칭하는 의미로서, 수초의 파괴로 인한 모든 질환에는 제한이 없으나, 그 일례로는 다발성 경화증(Multiple sclerosis), 급성 파종성 탈수초(acute disseminated demyelination), 레버 유전성 시각 신경병증(Leber hereditary optic neuropathy), 길랭-바레증후군(Guillain-Barre syndrome), 탈수초성 다발성 신경병증(demyelinating polyneuropathy), 샤르코 마리 투스병(Charcot Marie Tooth) 등이 있다.In the present specification, the term "demyelinating disease" is a generic term for abnormalities in myelin sheaths of the nervous system, especially diseases involving destruction of myelin sheaths, and there is no limitation on all diseases caused by destruction of myelin sheaths, but an example thereof These include: Multiple sclerosis, acute disseminated demyelination, Leber hereditary optic neuropathy, Guillain-Barre syndrome, and demyelinating. polyneuropathy) and Charcot Marie Tooth.
본 명세서에 있어서, “예방(prevention)”이란 본 발명에 따른 조성물의 투여에 의해 탈수초 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.In the present specification, "prevention" refers to any action that suppresses or delays the onset of demyelinating disease by administration of the composition according to the present invention.
본 명세서에 있어서, “개선(improvement)”이란, 치료되는 상태와 관련된 파라미터, 예를 들면, 증상의 정도를 적어도 감소시키는 행위를 의미한다. 이때 상기 본 발명의 조성물을 탈수초 질환의 예방 또는 개선을 위하여 치료를 위한 약제와 동시에 또는 별개로서 사용될 수 있다.In the present specification, "improvement" refers to an action of at least reducing the severity of a parameter related to a condition to be treated, for example, symptoms. At this time, the composition of the present invention may be used simultaneously or separately with a drug for treatment in order to prevent or improve demyelinating disease.
본 명세서에 있어서, "치료(treatment)"란 본 발명에 따른 조성물의 투여에 의해 탈수초 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다. In the present specification, "treatment" refers to any action in which symptoms of a demyelinating disease are improved or beneficially changed by administration of the composition according to the present invention.
본 명세서에 있어서, “개체(individual)”란 본 발명의 조성물이 투여될 수 있는 대상을 말하며, 그 대상에는 제한이 없다. In the present specification, “individual” refers to a subject to which the composition of the present invention can be administered, and the subject is not limited.
본 명세서에 있어서, “약학적 조성물(pharmaceutical composition)”이란 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학적 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. 상기 약학적 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 약학적 조성물은 약제적으로 허용가능한 담체를 포함할 수 있다. 약제학적으로 허용되는 담체는 경구투여시에는 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 약학적 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구투여시에는 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 제형할 수 있다.In the present specification, the term "pharmaceutical composition" may be characterized in that it is in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition is intended for humans. I can. The pharmaceutical compositions are not limited thereto, but may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterile injectable solutions according to conventional methods. . The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be used as binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, flavoring agents, etc. for oral administration, and buffers, preservatives, painlessness, etc. for injections. Agents, solubilizers, isotonic agents, stabilizers, and the like can be mixed and used, and in the case of topical administration, a base agent, excipient, lubricant, preservative, etc. can be used. The formulation of the pharmaceutical composition of the present invention may be variously prepared by mixing with a pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixir, suspension, syrup, wafers, etc.In the case of injections, it can be prepared in the form of unit dosage ampoules or multiple dosage forms. have. Others, solutions, suspensions, tablets, capsules, can be formulated as sustained-release preparations.
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.On the other hand, examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, and the like may additionally be included.
본 발명에 따른 약학적 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. 본원에 사용된 용어 "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.The route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, local , Sublingual or rectal. Oral or parenteral administration is preferred. The term “parenteral” as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention can also be administered in the form of suppositories for rectal administration.
본 발명의 약학적 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 약학적 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 500 mg/kg 또는 0.001 내지 500 mg/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 제형화될 수 있다.The pharmaceutical composition of the present invention depends on a number of factors including the activity of the specific compound used, age, weight, general health, sex, formulation, time of administration, route of administration, excretion rate, drug formulation and the severity of the specific disease to be prevented or treated. It may vary in various ways, and the dosage of the pharmaceutical composition varies depending on the patient's condition, weight, degree of disease, drug type, administration route and duration, but may be appropriately selected by those skilled in the art, and 0.0001 to 500 mg per day /kg or 0.001 to 500 mg/kg. Administration may be administered once a day, or may be divided several times. The above dosage does not in any way limit the scope of the present invention. The pharmaceutical composition according to the present invention may be formulated as a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.
본 발명에 있어서 상기 식품 조성물은, 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등에 사용할 수 있으며, 환제, 분말, 과립, 침제, 정제, 캡슐 또는 음료의 형태로 사용할 수 있다. 상기 식품 조성물은 건강기능식품 조성물을 포함한다. 이때, 식품 또는 음료 중의 상기 황칠나무 추출물의 양은, 일반적으로 본 발명의 식품 조성물의 경우 전체 식품 중량의 0.01 내지 15 중량 %로 가할 수 있으며, 건강 음료 조성물의 경우 100 mL를 기준으로 0.02 내지 10g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.In the present invention, the food composition can be used in various foods, for example, beverages, gums, teas, vitamin complexes, health supplements, etc., and can be used in the form of pills, powders, granules, needles, tablets, capsules or beverages. I can. The food composition includes a health functional food composition. At this time, the amount of the Hwangchil tree extract in the food or beverage may be generally added in 0.01 to 15% by weight of the total food weight in the case of the food composition of the present invention, and 0.02 to 10g based on 100 mL in the case of a health drink composition, Preferably, it can be added in a ratio of 0.3 to 1 g.
본 발명의 식품 조성물은 당업계에 통상적인 식품첨가제, 예를 들어 향미제, 풍미제, 착색제, 충진제, 안정화제 등을 포함할 수 있다. 본 발명에 따른 식품 조성물은 필수 성분으로서, 상기 황칠나무 추출물 외에 첨가되는 성분에는 특별한 제한은 없으며 통상의 식품과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물의 예로는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린; 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제 (타우마틴, 스테비아 추출물(예를 들어, 레바우디오시드 A, 글리시르히진 등)) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 mL당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The food composition of the present invention may include food additives conventional in the art, such as flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like. The food composition according to the present invention is an essential ingredient, and there is no particular limitation on the ingredients added in addition to the Hwangchil tree extract, and may contain various flavoring agents or natural carbohydrates as an additional ingredient, as in a conventional food. Examples of the natural carbohydrate include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose, and the like; Polysaccharides such as dextrin, cyclodextrin; And common sugars such as xylitol, sorbitol, and sugar alcohols such as erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. I can. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 mL of the composition of the present invention.
상기 외에 본 발명의 식품 조성물은 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, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid, and It may contain salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. These components may be used independently or in combination. The proportion of these additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, a preferred embodiment is presented to aid the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.
[실시예][Example]
실시예 1: 식물 추출물의 제조Example 1: Preparation of plant extract
식물 추출물을 제조하기 위하여, 마고영농조합에서 6 년산 황칠나무(Dendropanax morbiferus; DM)의 잎(leaves), 줄기 수피(stem barks) 및 뿌리(roots)를 제공받았다. 그리고 두충(Eucommia ulmoides; EU), 쇠무릎속(Achyranthes aspera; AcA), 도꼬마리(Xanthium strumarium; XS), 황기(Astragalus membranaceus; AM), 쑥(Artemisia princeps; ArP), 개다래(Actinidia polygama; AP), 지황(Rehmannia glutinosa, RG), 방풍(Ledebouriella seseloides; LS), 및 개똥쑥(Artemisia annua; AA)은 지리산 청정 약초에서 구매하였다. 각각의 시료는 건조시킨 후에 잘게 자르고, 갈아서 가루 형태로 제조하였다. 그리고 100 % 에탄올 50 mL에 8 g씩 첨가한 후에 실온에서 일주일 동안 shaking rotator에서 반응시키며 추출을 진행하였다. 그리고 일주일 후에 원심분리하여 침전물이 제거된 상층액을 획득하였다. 획득된 상층액은 70 ℃에서 evaporator를 이용하여 농축시킨 후에, 8 g/mL의 농도로 맞춰준 후에 사용 전까지 -20 ℃에서 보관하였다.To prepare plant extracts, leaves, stem barks, and roots of 6-year-old hwangchil tree (Dendropanax morbiferus; DM) were provided by Mago Farming Cooperative. And Eucommia ulmoides (EU), Achyranthes aspera (AcA), Xanthium strumarium (XS), Astragalus membranaceus (AM), Mugwort (Artemisia princeps; ArP), Actinidia polygama (AP), Rehmannia glutinosa (RG), windbreak (Ledebouriella seseloides; LS), and Artemisia annua (AA) were purchased from Jirisan Clean Herbs. Each sample was dried and then finely cut and ground to prepare a powder form. And after adding 8 g each to 50 mL of 100% ethanol, extraction was performed by reacting in a shaking rotator at room temperature for a week. And after a week, centrifugation was performed to obtain a supernatant from which the precipitate was removed. The obtained supernatant was concentrated at 70° C. using an evaporator, adjusted to a concentration of 8 g/mL, and stored at -20° C. until use.
실시예Example 2: 식물 추출물의 희소돌기아교세포의 2: of oligodendrocytes of plant extract 멤브레인Membrane 층 형성에 미치는 영향 확인 Checking the effect on layer formation
2.1. 혼합 신경교세포의 수초화 형성에 미치는 영향 확인2.1. Confirmation of effects on the formation of myelinated mixed glial cells
실시예 1과 동일한 방법으로 제조된 식물 추출물들이 희소돌기아교세포(oligodendrocyte; OL)의 멤브레인 층 형성에 영향을 미치는지 확인하기 위하여, 일차적으로 혼합된 신경교세포(주로, 희소돌기아교세포, 성상세포(astrocyte) 및 소교세포(microglia)가 포함된 혼합 신경교세포)를 배양하였다. 보다 자세하게는, 출생 후 0 내지 2 일된 마우스의 대뇌피질을 획득한 후에, poly-D-lysine(PDL)이 코팅된 커버슬립 위에 올려놓은 후에 10 % 우태아혈청(fetal bovine serum; FBS), 5 % 말혈청(horse serum), 및 1x 페니실린-스트렙토마이신(Gibco)이 첨가된 DMEM/F-12 배지에서 8 일간 배양하였다. 그리고 Sato 배지(DMEM containing 1× B-27 supplement, 1X Glutamax, 1X penicillin-streptomycin, 1 % horse serum, 1X sodium pyruvate, 0.34 μg/ml T3, 및 0.4 μg/ml T4)로 교체해준 후에, 실시예 1과 동일한 방법으로 제조된 식물 추출물들을 동량 처리한 후에 12 일(12 DIV; 12 days in vitro)간 배양하였다. 대조군으로는 에탄올을 동량 처리하였다. 그리고 수초 염기성 단백질(myelin basic protein; MBP)을 염색하여 브레인 층의 크기를 측정하였다. 수초 염기성 단백질은 성숙된 수초화의 주요 마커로 알려져 있다. 수초 염기성 단백질 염색을 위하여, 4 % 파라포름알데히드 용액을 이용하여 세포를 고정시킨 후에, 블록킹 용액(5 % normal donkey serum, 0.5 % Triton X-100, 및 0.05 % sodium azide가 첨가된 인산염완충용액(phosphate buffered saline))을 이용하여 세포를 블록킹하였다. 그리고 1 : 300의 농도로 희석된 rat monoclonal antibody to MBP(Chemicon)를 처리하고 4 ℃에서 16 시간 동안 반응시켜 1차 염색을 실시한 후에, 인산염완충용액을 이용하여 3 회 세척하여 결합되지 않은 항체를 제거하였다. 그리고 다시 2차 항체(Jackson Immunoresearch)를 처리하고 실온에서 45 분간 반응시킨 후에, 인산염완충용액을 이용하여 결합되지 않은 항체를 제거하였다. 그리고 마운팅 용액을 처리한 후에 현미경을 이용하여 형광 사진을 획득하였다. 획득된 형광 사진은 ImageJ를 이용하여 전체 세포의 면적 중에서 MBP양성 반응 면적의 퍼센트로 정량화하였다. 이후 모든 실험에서 p value가 0.05 이하이면 유의성이 있다고 확인하였다. 그 결과는 도 1에 나타내었다.In order to confirm whether the plant extracts prepared in the same manner as in Example 1 affect the formation of the membrane layer of oligodendrocytes (OL), primarily mixed glial cells (mainly, oligodendrocytes, astrocytes ( astrocyte) and mixed glial cells containing microglia) were cultured. In more detail, after acquiring the cerebral cortex of a
도 1에 나타난 바와 같이, 쑥(Arp)추출물과 황칠나무(DM) 추출물이 MBP 양성 반응이 가장 많이 증가된 것을 확인하였다. 상기 결과들을 통하여, 쑥 추출물과 황칠나무 추출물이 희소돌기아교세포, 성상세포 및 소교세포에 영향을 미쳐 수초화 형성을 촉진시킨다는 것을 확인할 수 있었다.As shown in Figure 1, it was confirmed that the Mugwort (Arp) extract and Hwangchil tree (DM) extract showed the greatest increase in MBP positive reaction. Through the above results, it was confirmed that the mugwort extract and Hwangchil tree extract affect oligodendrocytes, astrocytes, and microglia to promote myelin formation.
2.2. 희소돌기아교세포의 수초화 형성에 미치는 영향 확인2.2. Confirmation of the effect on the formation of myelinated oligodendrocytes
실시예 1과 동일한 방법으로 제조된 식물 추출물들이 멤브레인 층 형성에 미치는 영향이, 성상세포 또는 소교세포를 통한 것인지, 아니면 희소돌기아교세포에 직접적으로 작용하는 것인지 확인하기 위하여 10 일 동안 배양된 혼합 신경교세포로부터 dish-panning 방법을 사용하여 희소돌기아교세포 전구체세포(oligodendrocyte precursor cell; OPC)를 분리하였다. 분리된 희소돌기아교세포 전구체세포는 PDL이 코팅된 커버슬립 위에 올려놓은 후 Sato 배지에서 배양하였다. 그리고 24 시간 동안 배양한 후에 각각의 식물 추출물이 첨가된 새로운 Sato 배지로 교체해준 후에 4 일 동안 추가로 배양하고, 실시예 2.1과 동일한 방법으로 수초 염기성 단백질을 염색하였다. 염색된 세포들은 ImageJ를 이용하여 MBP 양성 세포 수를 정량하였다. 그 결과는 도 2에 나타내었다.Mixed neurons cultured for 10 days to determine whether the effect of plant extracts prepared in the same manner as in Example 1 on the formation of the membrane layer is through astrocytes or microglia, or directly acts on oligodendrocytes. Ooligodendrocyte precursor cells (OPC) were isolated from glial cells using a dish-panning method. The isolated oligodendrocyte precursor cells were placed on a coverslip coated with PDL and cultured in Sato medium. And after culturing for 24 hours, after replacing with a new Sato medium to which each plant extract was added, it was further cultured for 4 days, and a myelinated basic protein was stained in the same manner as in Example 2.1. For stained cells, the number of MBP positive cells was quantified using ImageJ. The results are shown in FIG. 2.
도 2에 나타난 바와 같이, 다른 식물 추출물들의 경우에는 대조군인 에탄올과 비교하여 MBP 양성 세포의 수가 증가되었으나, 황칠나무 추출물의 경우 다른 식물 추출물과 비교하여 두 배 이상 증가된 것을 확인하였다. 또한 혼합 신경교세포에서 황칠나무 추출물과 유사하게 높은 수초 염기성 단백질 범위를 보여주었던 쑥 추출물의 경우에는 다른 식물 추출물과 유사한 결과를 나타낸다는 것을 확인하였다. 상기 결과를 통하여, 황칠나무 추출물은 쑥 추출물과는 상이하게 성상세포, 소교세포 등에 영향을 미치는 것이 아니라, 독립적으로 희소돌기아교세포의 수초화 형성을 촉진시키는 것을 확인할 수 있었다.As shown in FIG. 2, in the case of other plant extracts, it was confirmed that the number of MBP-positive cells was increased compared to ethanol as a control, but in the case of Hwangchil tree extract, it was confirmed that it was increased more than twice as compared to other plant extracts. In addition, it was confirmed that the mugwort extract, which showed a high myelin basic protein range, similar to that of Hwangchil tree extract in mixed glial cells, showed similar results to other plant extracts. Through the above results, it was confirmed that the Hwangchil tree extract did not affect astrocytes, microglia, etc. differently from the mugwort extract, but independently promotes the formation of myelinated oligodendrocytes.
실시예Example 3: 황칠나무 부위에 따른 추출물의 희소돌기아교세포의 3: Of the oligodendrocytes of the extract along the Hwangchil tree 멤브레인Membrane 형성에 미치는 영향 확인 Determine the impact on formation
황칠나무의 부위에 따른 추출물이 희소돌기아교세포의 수초화 형성에 미치는 영향을 확인하기 위하여, 실시예 1과 동일한 방법으로 제조된 황칠나무 잎 추출물, 줄기 수피 추출물, 및 뿌리 추출물을 실시예 2.2와 동일한 방법으로 1 일 동안 배양된 희소돌기아교세포 전구체세포에 처리하고 2일 동안 배양하였다. 황칠나무 추출물은 고농도(High)로는 배양 배지에 1 : 1,000의 농도로 희석되도록 처리하였고, 저농도(Low)로는 1 : 100,000의 농도로 희석되도록 처리하였다. 그 결과는 도 3에 나타내었다.In order to confirm the effect of the extract according to the part of the Hwangchil tree on the formation of myelinated oligodendrocytes, Hwangchil tree leaf extract, stem bark extract, and root extract prepared in the same manner as in Example 1 were the same as in Example 2.2. The oligodendrocyte precursor cells cultured for 1 day were treated by the method and cultured for 2 days. Hwangchil tree extract was treated to be diluted to a concentration of 1:1,000 in the culture medium at a high concentration (High), and treated to be diluted to a concentration of 1: 100,000 at a low concentration (Low). The results are shown in FIG. 3.
도 3에 나타난 바와 같이, 뿌리 추출물의 경우에는 MBP 양성 반응 면적이 약간 증가되었으며, 잎 추출물의 경우에는 다른 추출물의 두 배 정도 MBP 양성 반응 면적이 증가되었으며, 저농도와 비교하여 고농도로 처리하였을 때 MBP 양성 반응 면적이 현저히 증가된 것을 확인하였다. 상기 결과를 통하여, 황칠나무 중에서 잎 추출물의 성분이 희소돌기아교세포의 수초화 형성에 가장 큰 효과를 나타낸다는 것을 확인할 수 있었다.As shown in FIG. 3, in the case of the root extract, the MBP-positive reaction area was slightly increased, and in the case of the leaf extract, the MBP-positive reaction area was increased twice as much as that of other extracts, and when treated at a high concentration compared to the low concentration, MBP It was confirmed that the positive reaction area was significantly increased. Through the above results, it was confirmed that the component of the leaf extract among Hwangchil trees exhibited the greatest effect on the formation of myelinated oligodendrocytes.
실시예Example 4: 황칠나무 잎 추출물이 희소돌기아교세포의 분화에 미치는 영향 확인 4: Confirmation of the effect of Hwangchil tree leaf extract on the differentiation of oligodendrocytes
황칠나무 잎 추출물이 희소돌기아교세포의 분화에 미치는 영향을 확인하기 위하여, Olig1, ID2, Ascl1, 및 MBP 유전자의 발현량을 확인하였다. 보다 자세하게는, 황칠나무 잎 추출물을 실시예 2.2와 동일한 방법으로 희소돌기아교세포 전구체세포를 1 일 동안 배양한 후에, 추출물을 처리하고 2 일 동안 추가 배양하였다. 황칠나무 잎 추출물은 고 농도로는 배양 배지에 1 : 1,000의 농도로 희석되도록 처리하였고, 저 농도로는 1 : 100,000의 농도로 희석되도록 처리하였다. 유전자 발현량을 확인하기 위하여, TRIzol(Sigma)을 이용하여 배양된 세포로부터 RNA를 추출하고 추출된 RNA를 주형으로 하여 SuperScript II Reverse Transcriptase(Invitrogen)를 이용하여 cDNA를 합성하였다. 그리고 Step One Plus Real-Time PCR System(Applied Biosystems)을 이용하여 실시간 중합효소연쇄반응을 실시하였다. 유전자 발현량은 GAPDH 유전자 발현량을 이용하여 표준화(normalization)하였다. 중합효소연쇄반응에 사용한 프라이머는 하기 표 1에 기재하였으며, 그 결과는 도 4에 나타내었다.In order to confirm the effect of Hwangchil tree leaf extract on the differentiation of oligodendrocytes, the expression levels of Olig1, ID2, Ascl1, and MBP genes were confirmed. In more detail, after culturing the oligodendrocyte precursor cells in the same manner as in Example 2.2 in the Hwangchil tree leaf extract for 1 day, the extract was treated and further cultured for 2 days. Hwangchil tree leaf extract was treated to be diluted to a concentration of 1: 1,000 in the culture medium at a high concentration, and treated to be diluted to a concentration of 1: 100,000 at a low concentration. In order to check the gene expression level, RNA was extracted from cells cultured using TRIzol (Sigma), and cDNA was synthesized using SuperScript II Reverse Transcriptase (Invitrogen) using the extracted RNA as a template. And real-time polymerase chain reaction was performed using the Step One Plus Real-Time PCR System (Applied Biosystems). The gene expression level was normalized using the GAPDH gene expression level. Primers used in the polymerase chain reaction are shown in Table 1 below, and the results are shown in FIG. 4.
도 4에 나타난 바와 같이, Olig1 및 ID2 유전자의 경우에는 대조군인 에탄올과 비교하여 유의성 있게 발현량이 감소된 반면, MBP 유전자의 경우에는 유의성 있게 발현량이 증가된 것을 확인하였다. 상기 결과를 통하여, 황칠나무 잎 추출물이 희소돌기아교세포 전구체세포의 Olig1 및 ID2 유전자의 발현은 억제하고, MBP 유전자의 발현은 촉진시켜, 희소돌기아교세포로의 분화를 촉진시킨다는 것을 확인할 수 있었다.As shown in FIG. 4, in the case of the Olig1 and ID2 genes, it was confirmed that the expression level was significantly decreased compared to the control ethanol, whereas the MBP gene was significantly increased. Through the above results, it was confirmed that the Hwangchil tree leaf extract inhibited the expression of Olig1 and ID2 genes of oligodendrocyte precursor cells, and promoted the expression of MBP gene, thereby promoting differentiation into oligodendrocytes.
또한, 단백질 수준에서 재확인하기 위하여 1 : 500의 농도로 희석된 Rat antibody against MBP(Chemicon), 1 : 1,000의 농도로 희석된 rabbit antibodies against phospho-p42/44(Cell signaling), 및 1 : 5,000의 농도로 희석된 beta actin(Abcam)을 이용하여 웨스턴 블롯팅을 실시하였고, 발현량은 actin 발현량을 이용하여 표준화(normalization)하였다. 그 결과는 도 5에 나타내었다.In addition, to reconfirm at the protein level, the rat antibody against MBP (Chemicon) diluted at a concentration of 1: 500, rabbit antibodies against phospho-p42/44 (Cell signaling) diluted at a concentration of 1: 1,000, and 1: 5,000 Western blotting was performed using beta actin (Abcam) diluted to a concentration, and the expression level was normalized using the actin expression level. The results are shown in FIG. 5.
도 5에 나타난 바와 같이, 황칠나무 잎 추출물을 처리한 희소돌기아교세포 전구체세포에서는 MBP 단백질의 발현량이 증가되었으며, 세포외 신호조절 인산화효소 1/2(extracellular signal-regulated kinase 1/2; ERK 1/2)의 인산화를 촉진시켜 ERK 신호 전달 기작을 활성화시킨다는 것을 확인하였다. 상기 결과들을 통하여, 황칠나무 잎 추출물은 희소돌기아교세포 전구체세포의 ERK 기작을 활성화시켜 희소돌기아교세포의 분화를 촉진시킬 수 있다는 것을 확인할 수 있었다.As shown in Figure 5, in the oligodendrocyte precursor cells treated with Hwangchil tree leaf extract, the expression level of MBP protein was increased, and extracellular signal-regulated
실시예Example 5: 황칠나무 잎 추출물이 in 5: Hwangchil tree leaf extract in vivo에서in vivo 희소돌기아교세포의 분화에 미치는 영향 확인 Confirmation of effects on differentiation of oligodendrocytes
In vivo에서는 희소돌기아교세포의 분화 및 수초화 형성에 다양한 신경 신호전달 기작이 영향을 미치기 때문에, 황칠나무 잎 추출물이 신경세포(neuron)의 존재 하에서도 희소돌기아교세포의 분화에 영향을 주는지 확인하기 위하여, 일차적으로 마우스의 후근신경절 신경세포(dorsal root ganglion neuron; DRG neuron)에 희소돌기아교세포 전구체세포를 공동배양하였다. 보다 자세하게는, B-27 supplement, N-2 supplement, 5 μg/mL의 N-Acetyl-Cysteine, 5 μM의 forskolin, 및 페니실린-스트렙토마이신이 첨가된 DMEM 배지에서 배양한 후근신경절 신경세포에 희소돌기아교세포 전구체세포를 접종하여 공동배양하였다. 그리고 황칠나무 잎 추출물이 포함된 새로운 배지로 2 일 마다 교체하며 7 일간 배양하였다. 그리고 1 : 300의 농도로 희석된 rat monoclonal antibody to MBP(Chemicon), 1 : 5의 농도로 희석된 mouse hybridoma supernatants to O4(Chemicon), 및 1 : 500의 농도로 희석된 rabbit polyclonal antibodies to Olig2(Chemicon)를 이용하여 실시예 2.1과 동일한 방법으로 면역염색법을 실시하였다. 그리고 DAPI(Invitrogen)를 이용하여 세포의 핵을 염색하였다. Olig2는 희소돌기아교세포의 모든 단계에서 발현되는 마커로 알려져 있고, O4는 미성숙된 희소돌기아교세포의 마커로 알려져 있고, MBP는 성숙된 희소돌기아교세포의 마커로 알려져 있다. 그 결과는 도 6에 나타내었다.Since various nerve signaling mechanisms affect the differentiation of oligodendrocytes and myelinated formation in vivo, it was confirmed whether Hwangchil tree leaf extract affects the differentiation of oligodendrocytes even in the presence of neurons. For this purpose, oligodendrocyte precursor cells were co-cultured on mouse dorsal root ganglion neuron (DRG neuron). In more detail, B-27 supplement, N-2 supplement, 5 μg/mL of N-Acetyl-Cysteine, 5 μM of forskolin, and penicillin-streptomycin were added to DMEM medium cultured in dorsal muscle ganglion neurons. Glial precursor cells were inoculated and co-cultured. Then, it was cultured for 7 days, replacing every 2 days with a new medium containing Hwangchil tree leaf extract. And rat monoclonal antibodies to MBP (Chemicon) diluted at a concentration of 1: 300, mouse hybridoma supernatants to O4 (Chemicon) diluted at a concentration of 1: 5, and rabbit polyclonal antibodies to Olig2 ( Chemicon) was used to perform immunostaining in the same manner as in Example 2.1. Then, the cell nucleus was stained using DAPI (Invitrogen). Olig2 is known as a marker expressed in all stages of oligodendrocytes, O4 is known as a marker for immature oligodendrocytes, and MBP is known as a marker for mature oligodendrocytes. The results are shown in FIG. 6.
도 6에 나타난 바와 같이, Olig2 양성 세포수 및 O4 양성 면적의 경우에는 유의성 있는 차이를 나타내지 않는 것을 확인하였다. 그러나, MBP 양성 면적의 경우에는 대조군으로 에탄올을 처리한 세포와 비교하여 황칠나무의 잎 추출물(Cultivation)을 처리한 경우에 유의성있는 증가를 나타내는 것을 확인하였다. 상기 결과를 통하여, 황칠나무 잎 추출물은 희소돌기아교세포 전구체세포의 단독 배양에서뿐만 아니라, 신경세포와의 공동 배양 시에도 희소돌기아교세포 전구체세포의 분화를 촉진시킬 수 있다는 것과 희소돌기아교세포 전구체세포의 증식에는 영향을 미치지 않는 것을 확인할 수 있었다.As shown in Fig. 6, it was confirmed that there was no significant difference in the number of Olig2 positive cells and the O4 positive area. However, it was confirmed that the MBP-positive area showed a significant increase in the case of treatment with the leaf extract (Cultivation) of Hwangchil tree compared to the cells treated with ethanol as a control. Through the above results, the Hwangchil tree leaf extract can promote the differentiation of oligodendrocyte precursor cells not only in single culture of oligodendrocyte precursor cells, but also in co-culture with nerve cells. It was confirmed that it did not affect the proliferation of.
또한, 수초화 촉진을 위하여 축삭돌기 접촉(axonal contact)이 유도되는지 확인하기 위하여 동일한 방법으로 12 일 동안 후근신경절 신경세포와 희소돌기아교세포 전구체세포와 공동배양한 후에 1 : 1,000의 농도로 희석된 Caspr 항체(Chemicon)를 이용하여 면역염색법을 실시하였다. 그 결과는 도 7에 나타내었다.In addition, to confirm whether axonal contact is induced to promote myelinization, Caspr diluted to a concentration of 1:1,000 after co-culture with dorsal root ganglion neurons and oligodendrocyte precursor cells for 12 days in the same way. Immunostaining was performed using an antibody (Chemicon). The results are shown in FIG. 7.
도 7에 나타난 바와 같이, 황칠나무 잎 추출물을 처리한 경우에 Caspr 양성 면적이 유의성있게 증가되는 것을 확인하였다. 상기 결과를 통하여, 황칠나무 잎 추출물은 희소돌기아교세포의 분화를 촉진할 뿐만 아니라, 축삭돌기 접촉 또한 촉진시켜 수초화를 효과적으로 촉진시킬 수 있다는 것을 확인할 수 있었다.As shown in FIG. 7, it was confirmed that the Caspr positive area was significantly increased when the Hwangchil tree leaf extract was treated. Through the above results, it was confirmed that the Hwangchil tree leaf extract not only promotes the differentiation of oligodendrocytes, but also promotes contact with axons, thereby effectively promoting myelinization.
면역염색법으로 확인한 결과를 재확인하기 위하여, 정량 실시간 중합효소연쇄반응을 실시하였다. 실시간 중합효소연쇄반응은 실시예 4와 동일한 방법으로 실시하였으며, 사용한 프라이머는 하기 표 2에 기재하였다. 그 결과는 도 8에 나타내었다.In order to reconfirm the results confirmed by the immunostaining method, quantitative real-time polymerase chain reaction was performed. Real-time polymerase chain reaction was carried out in the same manner as in Example 4, and the primers used are shown in Table 2 below. The results are shown in FIG. 8.
도 8에 나타난 바와 같이, 황칠나무 잎 추출물이 처리된 실험군의 경우 미엘린(myelin) 유전자들을 활성화시키는 전사인자인 Myrf, non-compact 미엘린 단백질인 CNP, compact 미엘린 단백질의 구조적 성분인 MBP 및 PLP 모두 유의성있게 발현이 증가된 것을 확인하였다. 상기 결과들을 통하여, 황칠나무 잎 추출물이 효과적으로 수초화를 촉진시킨다는 것 확인할 수 있었다. As shown in Figure 8, in the case of the experimental group treated with Hwangchil tree leaf extract, both Myrf, a transcription factor that activates myelin genes, CNP, a non-compact myelin protein, and MBP and PLP, which are structural components of the compact myelin protein, are significant. It was confirmed that the expression was increased. Through the above results, it was confirmed that the Hwangchil tree leaf extract effectively promotes myelinization.
실시예Example 6: 황칠나무 잎 추출물의 성분 확인 6: Confirmation of ingredients of Hwangchil tree leaf extract
황칠나무 잎 추출물에 포함되어 있는 성분을 확인하기 위하여, 실시예 1과 동일한 방법으로 준비한 황칠나무 잎 추출물을 LC-MS/MS(Liquid chromatography-mass spectrometry/mass spectrometry)로 분석하였다. 그 결과는 하기 표 3에 나타내었다.In order to confirm the components contained in the hwangchil tree leaf extract, the hwangchil tree leaf extract prepared in the same manner as in Example 1 was analyzed by LC-MS/MS (Liquid chromatography-mass spectrometry/mass spectrometry). The results are shown in Table 3 below.
[표 3][Table 3]
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that other specific forms can be easily modified without changing the technical spirit or essential features of the present invention will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not limiting.
<110> University of Brain Education Industrial Cooperation Group <120> A composition comprising extracts of Dendropanax morbiferus for preventing or treating demyelinating disease <130> MP19-064 <160> 16 <170> KoPatentIn 3.0 <210> 1 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Olig 1 forward primer <400> 1 gctcgcccag gtgttttgt 19 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Olig 1 reverse primer <400> 2 gcatggaacg tggttggaat 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Id2 forward primer <400> 3 cctgcatcac cagagacctg 20 <210> 4 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Id2 reverse primer <400> 4 ttcgacataa gctcagaagg gaa 23 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Ascl1 forward primer <400> 5 caaccgggtc aagttggtca 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Ascl1 reverse primer <400> 6 ctcatcttct tgttggccgc 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> MBP forward primer <400> 7 ccagagcggc tgtctcttcc 20 <210> 8 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> MBP reverse primer <400> 8 catccttgac tccatcgggc gc 22 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH forward primer <400> 9 ggtcggtgtg aacggatttg 20 <210> 10 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> GAPDH reverse primer <400> 10 tcgttgatgg caacaatctc cact 24 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Myrf forward primer <400> 11 tggcaacttc acctaccaca 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Myrf reverse primer <400> 12 gtggaacctc tgcaaaaagc 20 <210> 13 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> CNP forward primer <400> 13 gttctgagac cctccgaaaa 20 <210> 14 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> CNP reverse primer <400> 14 ccttgggttc atctccagaa 20 <210> 15 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> PLP forward primer <400> 15 ggtacagaaa agctaattga gacc 24 <210> 16 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> PLP reverse primer <400> 16 gatgacatac tggaaagcat ga 22 <110> University of Brain Education Industrial Cooperation Group <120> A composition comprising extracts of Dendropanax morbiferus for preventing or treating demyelinating disease <130> MP19-064 <160> 16 <170> KoPatentIn 3.0 <210> 1 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Olig 1 forward primer <400> 1 gctcgcccag gtgttttgt 19 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Olig 1 reverse primer <400> 2 gcatggaacg tggttggaat 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Id2 forward primer <400> 3 cctgcatcac cagagacctg 20 <210> 4 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Id2 reverse primer <400> 4 ttcgacataa gctcagaagg gaa 23 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Ascl1 forward primer <400> 5 caaccgggtc aagttggtca 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Ascl1 reverse primer <400> 6 ctcatcttct tgttggccgc 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> MBP forward primer <400> 7 ccagagcggc tgtctcttcc 20 <210> 8 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> MBP reverse primer <400> 8 catccttgac tccatcgggc gc 22 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH forward primer <400> 9 ggtcggtgtg aacggatttg 20 <210> 10 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> GAPDH reverse primer <400> 10 tcgttgatgg caacaatctc cact 24 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Myrf forward primer <400> 11 tggcaacttc acctaccaca 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Myrf reverse primer <400> 12 gtggaacctc tgcaaaaagc 20 <210> 13 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> CNP forward primer <400> 13 gttctgagac cctccgaaaa 20 <210> 14 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> CNP reverse primer <400> 14 ccttgggttc atctccagaa 20 <210> 15 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> PLP forward primer <400> 15 ggtacagaaa agctaattga gacc 24 <210> 16 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> PLP reverse primer <400> 16 gatgacatac tggaaagcat ga 22
Claims (14)
상기 황칠나무 추출물은 황칠나무 잎의 추출물인 것을 특징으로 하는, 약학적 조성물.The method of claim 1,
The hwangchil tree extract is characterized in that the extract of hwangchil tree leaves, pharmaceutical composition.
상기 황칠나무 추출물은 물, 에탄올, 부탄올, 아세톤, 에테르, 헥산, 벤젠, 및 에틸아세테이트로 이루어진 군으로부터 선택된 하나 이상의 용매를 이용하여 추출되는 것을 특징으로 하는, 약학적 조성물.The method of claim 1,
The Hwangchil tree extract is characterized in that it is extracted using one or more solvents selected from the group consisting of water, ethanol, butanol, acetone, ether, hexane, benzene, and ethyl acetate.
상기 탈수초 질환은 다발성 경화증(Multiple sclerosis), 급성 파종성 탈수초(acute disseminated demyelination), 레버 유전성 시각 신경병증(Leber hereditary optic neuropathy), 길랭-바레증후군(Guillain-Barre syndrome), 탈수초성 다발성 신경병증(demyelinating polyneuropathy), 및 샤르코 마리 투스병(Charcot Marie Tooth)으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 약학적 조성물.The method of claim 1,
The demyelination disease is multiple sclerosis, acute disseminated demyelination, Leber hereditary optic neuropathy, Guillain-Barre syndrome, and demyelination multiple neuropathy. A pharmaceutical composition, characterized in that it is at least one selected from the group consisting of demyelinating polyneuropathy, and Charcot Marie Tooth.
상기 조성물은 수초화 재생을 촉진시키거나, 탈수초화를 억제시키는 것을 특징으로 하는, 약학적 조성물.The method of claim 1,
The composition is characterized in that to promote myelinated regeneration or inhibit demyelinating, pharmaceutical composition.
상기 황칠나무 추출물은 황칠나무 잎의 추출물인 것을 특징으로 하는, 식품 조성물.The method of claim 6,
The hwangchil tree extract is characterized in that the extract of hwangchil tree leaves, food composition.
상기 황칠나무 추출물은 물, 에탄올, 부탄올, 아세톤, 에테르, 헥산, 벤젠, 및 에틸아세테이트로 이루어진 군으로부터 선택된 하나 이상의 용매를 이용하여 추출되는 것을 특징으로 하는, 식품 조성물.The method of claim 6,
The Hwangchil tree extract is characterized in that it is extracted using one or more solvents selected from the group consisting of water, ethanol, butanol, acetone, ether, hexane, benzene, and ethyl acetate.
상기 탈수초 질환은 다발성 경화증(Multiple sclerosis), 급성 파종성 탈수초(acute disseminated demyelination), 레버 유전성 시각 신경병증(Leber hereditary optic neuropathy), 길랭-바레증후군(Guillain-Barre syndrome), 탈수초성 다발성 신경병증(demyelinating polyneuropathy), 및 샤르코 마리 투스병(Charcot Marie Tooth)으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 식품 조성물.The method of claim 6,
The demyelination disease is multiple sclerosis, acute disseminated demyelination, Leber hereditary optic neuropathy, Guillain-Barre syndrome, and demyelination multiple neuropathy. Disease (demyelinating polyneuropathy), and Charcot Marie Tooth disease (Charcot Marie Tooth) characterized in that at least one selected from the group consisting of, a food composition.
상기 조성물은 수초화 재생을 촉진시키거나, 탈수초화를 억제시키는 것을 특징으로 하는, 식품 조성물.The method of claim 6,
The composition is characterized in that to promote myelinated regeneration or inhibit demyelinating, food composition.
상기 황칠나무 추출물은 황칠나무 잎의 추출물인 것을 특징으로 하는, 희소돌기아교세포 분화 촉진용 조성물.The method of claim 11,
The hwangchil tree extract is a composition for promoting differentiation of oligodendrocytes, characterized in that the extract of hwangchil tree leaves.
상기 황칠나무 추출물은 물, 에탄올, 부탄올, 아세톤, 에테르, 헥산, 벤젠, 및 에틸아세테이트로 이루어진 군으로부터 선택된 하나 이상의 용매를 이용하여 추출되는 것을 특징으로 하는, 희소돌기아교세포 분화 촉진용 조성물.The method of claim 11,
The hwangchil tree extract is a composition for promoting differentiation of oligodendrocytes, characterized in that it is extracted using one or more solvents selected from the group consisting of water, ethanol, butanol, acetone, ether, hexane, benzene, and ethyl acetate.
상기 희소돌기아교세포는 희소돌기아교세포 전구체세포(Oligodendrocyte precursor)로부터 분화되는 것을 특징으로 하는, 희소돌기아교세포 분화 촉진용 조성물.The method of claim 11,
The composition for promoting oligodendrocyte differentiation, characterized in that the oligodendrocytes are differentiated from oligodendrocyte precursor cells (Oligodendrocyte precursor).
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