KR20230059919A - Senomorphic combination therapy - Google Patents
Senomorphic combination therapy Download PDFInfo
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- KR20230059919A KR20230059919A KR1020210143388A KR20210143388A KR20230059919A KR 20230059919 A KR20230059919 A KR 20230059919A KR 1020210143388 A KR1020210143388 A KR 1020210143388A KR 20210143388 A KR20210143388 A KR 20210143388A KR 20230059919 A KR20230059919 A KR 20230059919A
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract
본 발명은 KU-60019 및 Y-27632를 포함하는 세노모르픽(senomorphics)용 병용 조성물에 관한 것으로, 보다 상세하게는 노화에 의해 세포주기가 정지(senescent arrest)된 노화세포가 KU-60019와 Y-27632의 병용 처리에 의해 다양한 측면에서 다시 젊은 세포 수준으로 회복되는 상승 효과를 확인함으로써 KU-60019와 Y-27632을 포함하는 조성물을 세노모르픽(senomorphics)용 병용 약학조성물, 건강기능식품 조성물 및 화장료 조성물로 활용할 수 있다.The present invention relates to a combination composition for senomorphics containing KU-60019 and Y-27632, and more particularly, to a combination composition for senescent cells whose cell cycle is arrested by senescence by KU-60019 and Y-27632. - By confirming the synergistic effect of restoring to the level of young cells in various aspects by the combined treatment of 27632, the composition containing KU-60019 and Y-27632 is a combination pharmaceutical composition for senomorphics, a health functional food composition, and It can be used as a cosmetic composition.
Description
본 발명은 KU-60019 및 Y-27632를 포함하는 세노모르픽(senomorphics)용 병용 조성물에 관한 것이다.The present invention relates to a combination composition for senomorphics containing KU-60019 and Y-27632.
세포는 분열을 할수록 노화를 겪게 되며, 일정 횟수의 분열 후에는 더 이상 분열할 수 없는 상태의 헤이플릭스 한계(hayflick's limit)에 이르고, 이 한계에 도달한 세포를 노화된 세포(senescent cell)라고 한다.Cells undergo senescence as they divide, and after a certain number of divisions, they reach Hayflick's limit, a state in which they can no longer divide. Cells that have reached this limit are called senescent cells. .
과거 노화 연구는 노화의 원인 규명 및 분자 수준에서의 수명연장 방법에 편중되어 있었으나 최근 들어 노화 예방, 회복 및 치료 차원의 항노화에 관한 방법과 기술 개발 연구가 활발히 진행되고 있으며, 특히 노화 지연 및 노화관련 질병의 치료 물질 개발에 초점을 맞춘 연구가 증가하고 있다.In the past, aging research was focused on identifying the cause of aging and extending lifespan at the molecular level. However, recently, research on methods and technology development for anti-aging in terms of preventing, restoring, and treating aging is being actively conducted. In particular, aging delay and aging Research focusing on the development of therapeutic substances for related diseases is increasing.
노화 극복 약물 개발 전략으로는, 크게 노화세포만을 제거하는 약물(senolytics) 개발과 노화세포의 형질을 젊은 세포의 형질로 개선하는 약물(senomorphics) 개발로 나눌 수 있다. Strategies for developing drugs to overcome aging can be largely divided into development of drugs (senolytics) that remove only senescent cells and development of drugs (senomorphics) that improve the characteristics of senescent cells to those of young cells.
줄기세포를 통한 조직 재생이 활발하게 진행되지 않는 노화된 개체에서는, 노화세포를 제거하는 약물의 응용이 우려되기 때문에, 노화세포의 형질을 억제하는 약물이 상대적으로 더 절실히 필요한 상황이다.In aged individuals in which tissue regeneration through stem cells does not actively progress, since the application of drugs that remove senescent cells is a concern, drugs that inhibit the characteristics of senescent cells are relatively more urgently needed.
2010년 전후로 메트포르민(metformin), 라파마이신(rapamycin), NAD+ 부스터 등의 노화세포 형질 억제를 도모하는 약물들이 알려져 왔다. 하지만, 보고된 약물들은 모두 신진대사를 조절하거나 Sirt1, DNA 수선 단백질의 활성도를 조절하여 노화된 세포의 형질을 억제하기에, 노화된 세포의 세포분열기제(cell cycle mechanism) 재활성화에는 그다지 도움이 되지 못하며, 아직까지도 노화된 세포(senescent cell)의 전반적인 형질들을 회복시켜, 젊은 세포처럼 활발히 세포분열 가능하도록 유도하는 약물은 보고된 바 없다.Around 2010, drugs that promote the suppression of senescent cell traits, such as metformin, rapamycin, and NAD + booster, have been known. However, all of the reported drugs suppress the characteristics of senescent cells by regulating metabolism or regulating the activity of Sirt1 and DNA repair protein, so they are not very helpful in reactivating the cell cycle mechanism of senescent cells. However, no drug has been reported that restores the overall characteristics of senescent cells and induces them to actively divide like young cells.
따라서, 노화세포의 형질을 젊은 세포의 형질로 개선하는 약물(senomorphics) 개발이 여전히 필요한 실정이다.Therefore, there is still a need to develop drugs (senomorphics) that improve the characteristics of senescent cells to those of young cells.
본 발명의 목적은 노화세포의 형질을 젊은 세포의 형질로 개선하는 세노모르픽(senomorphics)용 병용 조성물을 제공하는 데에 있다.An object of the present invention is to provide a combination composition for senomorphics that improves the characteristics of senescent cells to those of young cells.
본 발명은 KU-60019 및 Y-27632를 포함하는, 노화세포의 형질을 젊은 세포의 형질로 개선하는 세노모르픽(senomorphics) 조성물을 제공한다.The present invention provides a senomorphic composition comprising KU-60019 and Y-27632 that improves the characteristics of senescent cells to those of young cells.
또한, 본 발명은 KU-60019 및 Y-27632를 포함하는, 세포 노화 관련 질환 치료 또는 예방용 약학조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for treating or preventing cellular aging-related diseases, including KU-60019 and Y-27632.
또한, 본 발명은 KU-60019 및 Y-27632를 포함하는, 리포푸신의 축적 관련 질환 치료 또는 예방용 약학조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for treating or preventing lipofuscin accumulation-related diseases, including KU-60019 and Y-27632.
또한, 본 발명은 KU-60019 및 Y-27632를 포함하는, 세포 노화 관련 질환 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cellular aging-related diseases, including KU-60019 and Y-27632.
또한, 본 발명은 KU-60019 및 Y-27632를 포함하는, 세포 노화 관련 질환 예방 또는 개선용 화장료 조성물을 제공한다.In addition, the present invention provides a cosmetic composition for preventing or improving cellular aging-related diseases, including KU-60019 and Y-27632.
본 발명에 따르면, 노화에 의해 세포주기가 정지(senescent arrest)된 노화세포가 KU-60019와 Y-27632의 병용 처리에 의해 다양한 측면에서 다시 젊은 세포 수준으로 회복되는 상승 효과를 확인함으로써 세노모르픽(senomorphics)용 병용 약학조성물, 건강기능식품 조성물 및 화장료 조성물로 활용할 수 있다.According to the present invention, by confirming the synergistic effect that senescent cells whose cell cycle is arrested by aging is restored to the level of young cells in various aspects by the combined treatment of KU-60019 and Y-27632, It can be used as a combination pharmaceutical composition for senomorphics, a health functional food composition, and a cosmetic composition.
도 1은 KU-60019(KU)와 Y-27632(Y)의 병용 처리에 따른 노화세포의 세포 분열 최적 농도를 결정한 CCK 분석법을 나타낸 것이고.
도 2는 KU 및 Y의 병용 처리에 따른 노화 세포의 세포 분열 가속화 정도를 HOECHST 염색으로 분석한 것이고,
도 3은 KU 및 Y의 병용 처리에 따른 노화 바이오마커 Senescence-associated-β-Galactosidase(SA-β-gal) 염색양 감소 유도 효과를 광학 현미경으로 확인한 것이고,
도 4는 KU 및 Y의 병용 처리에 따른 노화 바이오마커 SA-β-gal 염색양 감소 유도를 FDG assay 를 통해 SA-β-gal의 객관적 수치화 방법으로 분석한 것이고,
도 5는 KU 및 Y의 병용 처리에 따른 노화 세포 내 리포퓨신 양의 감소 유도를 세포의 자가형광 측정을 통해 분석한 것이고,
도 6은 KU 및 Y의 병용 처리에 따른 미토콘드리아 형태 변화 유도를 mitotracker 염색을 통해 분석한 것이고,
도 7은 KU 및 Y의 병용 처리에 따른 세포 내 활성산소 감소 유도를 MitoSox assay을 통해 분석한 것이고,
도 8은 KU 및 Y의 병용 처리에 따른 세포 내 미토콘드리아 막전위 회복을 TMRM assay을 통해 분석한 것이고,
도 9는 KU 및 Y의 병용 처리에 따른 미토콘드리아의 생합성 증가 유도를 mitotimer assay을 통해 분석한 것이고,
도 10은 KU 및 Y의 병용 처리에 따른 세포 내 DNA 손상 정도의 감소 유도를 γH2AX 및 53BP1의 면역화학법을 통해 분석한 것이고,
도 11 및 도 12는 KU 및 Y의 병용 처리에 따른 FOXM1과 E2F1의 활성화 유도를 각각 분석한 것이다.
도 13은 Y와 KU의 병용 처리에 따른 FOXM1 및 E2F1의 "순차적"인 활성화에 대한 작용기전의 모식도를 나타낸 것이다.1 shows a CCK assay method for determining the optimal concentration for cell division of senescent cells according to the combined treatment of KU-60019 (KU) and Y-27632 (Y).
Figure 2 is an analysis of the degree of cell division acceleration of senescent cells according to the combined treatment of KU and Y by HOECHST staining,
Figure 3 confirms the aging biomarker Senescence-associated-β-Galactosidase (SA-β-gal) staining reduction induction effect according to the combined treatment of KU and Y with an optical microscope,
Figure 4 analyzes the reduction of the aging biomarker SA-β-gal staining amount according to the combined treatment of KU and Y by an objective quantification method of SA-β-gal through FDG assay,
Figure 5 analyzes the induction of reduction in the amount of lipofuscin in senescent cells by the combined treatment of KU and Y through measurement of autofluorescence of cells,
Figure 6 analyzes the induction of mitochondrial morphological changes according to the combined treatment of KU and Y through mitotracker staining,
Figure 7 analyzes the induction of active oxygen reduction in cells according to the combined treatment of KU and Y through MitoSox assay,
Figure 8 analyzes the recovery of intracellular mitochondrial membrane potential according to the combined treatment of KU and Y through TMRM assay,
Figure 9 is an analysis of the induction of mitochondrial biosynthesis increase according to the combined treatment of KU and Y through mitotamer assay,
Figure 10 is an analysis of the induction of reduction of the degree of DNA damage in cells according to the combined treatment of KU and Y through the immunochemical method of γH2AX and 53BP1,
11 and 12 respectively analyze the induction of activation of FOXM1 and E2F1 according to the combined treatment of KU and Y.
Figure 13 shows a schematic diagram of the mechanism of action for the "sequential" activation of FOXM1 and E2F1 according to the combined treatment of Y and KU.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
대부분의 세노모르픽(senomorphic) 약물들이 일부 노화 형질에서의 약효 유무에만 중점을 두고 다방면적인 조사와 세부적인 기작은 밝히지 않아 전반적인 노화 억제 효능이나 부작용이 우려되는 문제점을 해결하기 위해, 본 발명자는 새로운 세노모르픽(senomorphic) 약물 개발을 위해 예의 노력한 결과, KU-60019와 Y-27632의 병용 처리에 의해 노화세포에서는 불활성화 상태의 전사 인자인 FOXM1과 E2F1이 세포 주기 인자(cell cycle factor)들에 의해 재활성화되어 노화 극복에 필요한 대다수 유전자들의 전사를 촉진한다는 점을 밝혀 내어 본 발명을 완성하였다.In order to solve the problem that most senomorphic drugs focus only on the presence or absence of efficacy in some aging traits and do not reveal multidisciplinary investigations and detailed mechanisms, the overall anti-aging efficacy or side effects are concerned. As a result of diligent efforts to develop senomorphic drugs, the combined treatment of KU-60019 and Y-27632 resulted in the inactivation of transcription factors FOXM1 and E2F1 in senescent cells in the cell cycle factors. The present invention was completed by discovering that the gene is reactivated by the enzyme and promotes the transcription of most genes necessary for overcoming aging.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염; 및 하기 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 노화세포의 형질을 젊은 세포의 형질로 개선하는 세노모르픽(senomorphics) 조성물을 제공한다:The present invention relates to a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And a senomorphic composition for improving the characteristics of senescent cells to those of young cells, comprising a compound represented by
[화학식 1][Formula 1]
[화학식 2][Formula 2]
상기 조성물은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염; 및 하기 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 1 : (3~7)의 몰비율로 포함할 수 있고, 보다 바람직하게는 1 : 5의 몰비율로 포함할 경우 노화세포의 형질을 젊은 세포의 형질로 개선하는 세노모르픽(senomorphics) 상승 효과가 가장 우수한 것으로 확인되었다. The composition may include a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; and the compound represented by
이때, 화학식 1로 표시되는 화합물은 ATM(Ataxia telangiectasia mutated) 카이네이즈 억제제인 KU-60019이고, 화학식 2로 표시되는 화합물은 rho-연관 단백질 카이네이즈(Rho-associated, coiled-coil containing protein kinase; ROCK) 억제제인 Y-27632이다. At this time, the compound represented by Formula 1 is KU-60019, an ATM (Ataxia telangiectasia mutated) kinase inhibitor, and the compound represented by Formula 2 is a rho-associated, coiled-coil containing protein kinase (ROCK) inhibitor phosphorus Y-27632.
상기 약학적으로 허용가능한 염은 약학적으로 허용가능한 염기성 염 또는 산성 염 중 어느 하나의 형태로 사용할 수 있다. 염기성 염으로는 유기염기염, 무기염기염 중 어느 하나의 형태로 사용할 수 있으며, 예를 들어 나트륨염, 칼륨염, 칼슘염, 리튬염, 마그네슘염, 세슘염 및 아미늄(aminium)염, 암모늄염, 트리에칠아미늄염, 피리디늄염 등을 사용할 수 있으나, 이에 한정되는 것은 아니다.The pharmaceutically acceptable salt may be used in the form of either a pharmaceutically acceptable basic salt or acidic salt. The basic salt may be used in the form of any one of an organic base salt and an inorganic base salt, and examples thereof include sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, and ammonium salt. , triethylaminium salts, pyridinium salts, etc. may be used, but are not limited thereto.
또한, 산성 염은 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 벤젠설폰산, 캠퍼설폰산, 옥살산, 말론산, 글루타릭산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르탄산 등을 사용할 수 있다. 바람직하게는 무기산으로는 염산, 유기산으로는 메탄설폰산을 사용할 수 있다.Also, as the acid salt, an acid addition salt formed by a free acid is useful. Inorganic acids and organic acids can be used as free acids, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, and methanesulfonic acid as organic acids. , benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid etc. can be used. Preferably, hydrochloric acid may be used as an inorganic acid and methanesulfonic acid may be used as an organic acid.
또한, 상기 조성물은 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함할 수 있다.In addition, the composition may include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates that can be prepared by conventional methods.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1 또는 화학식 2의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기염기를 가하거나 무기염기의 염기 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 또는 이 혼합물에서 용매나 과량의 염기를 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by a conventional method. For example, a compound of Formula 1 or Formula 2 is dissolved in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, and an excess of an organic base is dissolved. It can be prepared by adding or precipitating or crystallizing after adding an aqueous base solution of an inorganic base. Alternatively, the solvent or excess base may be evaporated from the mixture and then dried to obtain an addition salt, or the precipitated salt may be suction filtered.
상기 조성물은 FOXM1의 활성화가 먼저 유도되고, 그 후 E2F1의 활성화가 유도되는 순차적인 활성화를 통해 세포 주기 인자를 재활성화 하여 노화세포의 형질을 젊은 세포의 형질로 개선할 수 있다.The composition can improve the traits of senescent cells to those of young cells by reactivating cell cycle factors through sequential activation in which FOXM1 activation is induced first and then E2F1 activation is induced.
또한, 상기 조성물은 i) 세포 증식, ii) β-갈락토시다아제 (senescence-associated β-galactosidase)의 활성도 감소, iii) 리포퓨신의 발현양 감소, iv) 미토콘드리아 기능 향상, v) 활성산소 생성 감소 및 vi) DNA 손상 복구로 이루어진 군에서 선택된 하나 이상의 활성을 통해 노화세포의 형질을 젊은 세포의 형질로 개선할 수 있다.In addition, the composition can i) cell proliferation, ii) decrease the activity of β-galactosidase (senescence-associated β-galactosidase), iii) decrease the expression level of lipofuscin, iv) improve mitochondrial function, v) generate active oxygen The characteristics of senescent cells may be improved to those of young cells through at least one activity selected from the group consisting of reduction and vi) DNA damage repair.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염; 및 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 세포 노화 관련 질환 치료 또는 예방용 약학조성물을 제공한다.In addition, the present invention is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for treating or preventing cellular senescence-related diseases, including a compound represented by Formula 2 or a pharmaceutically acceptable salt thereof.
상기 세포 노화 관련 질환은 피부주름, 상처, 근감소증 및 조로증으로 이루어진 군에서 선택될 수 있다. 상기 조로증은 위너 증후군 및 허친슨 길포드 증후군에서 선택될 수 있지만, 이에 한정되는 것은 아니다.The cellular aging-related disease may be selected from the group consisting of skin wrinkles, wounds, sarcopenia, and premature aging. The progeria may be selected from Wiener syndrome and Hutchinson-Gilford syndrome, but is not limited thereto.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염; 및 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 리포푸신의 축적 관련 질환 치료 또는 예방용 약학조성물을 제공한다.In addition, the present invention is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for treating or preventing lipofuscin accumulation-related diseases, including a compound represented by Formula 2 or a pharmaceutically acceptable salt thereof.
상기 리포푸신의 축적 관련 질환은 신경 세로이드 리포푸신증 (neuronal ceroid lipofuscinoses: NCL), 나이관련황반변성 (Age-related macular degeneration), 신경근섬유의 엉킴 (neurofibrillary tangles), 심장의 갈색위축 (Brown atrophy of the heart), 알츠하이머병 (Alzheimer's disease), 파킨슨병 (Parkinson's disease), 루게릭병 (amyotrophic lateral sclerosis: ALS), 말단 비대증 (acromegaly), 탈신경 위축증 (denervation atrophy), 지질 축적 근질환 (lipid myopathy) 및 만성 폐쇄성 폐질환 (chronic obstructive pulmonary disease: COPD)으로 이루어진 군에서 선택될 수 있다.Diseases associated with the accumulation of lipofuscin include neuronal ceroid lipofuscinoses (NCL), age-related macular degeneration, neurofibrillary tangles, brown atrophy of the heart of the heart), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), acromegaly, denervation atrophy, lipid myopathy ) and chronic obstructive pulmonary disease (COPD).
본 발명의 한 구체예에서, 상기 약학조성물은 통상적인 방법에 따라 주사제, 과립제, 산제, 정제, 환제, 캡슐제, 좌제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있다.In one embodiment of the present invention, the pharmaceutical composition is any one selected from the group consisting of injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, emulsions, drops or liquids according to conventional methods. formulations can be used.
본 발명의 다른 구체예에서, 상기 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In another embodiment of the present invention, the pharmaceutical composition is a suitable carrier, excipient, disintegrant, sweetener, coating agent, swelling agent, lubricant, flavoring agent, antioxidant, buffer, bacteriostatic agent, diluent commonly used in the manufacture of pharmaceutical compositions , It may further include one or more additives selected from the group consisting of dispersants, surfactants, binders, and lubricants.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specifically, carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil may be used, and solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules. These solid preparations may be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions for oral use, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base material of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.
본 발명의 일실시예에 따르면 상기 약학조성물은 정맥내, 동맥내, 복강내, 근육내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to one embodiment of the present invention, the pharmaceutical composition is administered in a conventional manner through intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or intradermal routes. can be administered to the subject as
상기 조성물의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.A preferred dosage of the composition may vary depending on the condition and body weight of the subject, the type and severity of the disease, the type of drug, the route and duration of administration, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, but not limited thereto, the daily dosage may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or divided into several administrations, and the scope of the present invention is not limited thereby.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the 'subject' may be a mammal including a human, but is not limited to these examples.
또한, 본 발명은 화학식 1로 표시되는 화합물; 및 화학식 2로 표시되는 화합물을 포함하는, 세포 노화 관련 질환 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention is a compound represented by
상기 "건강기능식품"이라 함은 건강기능 식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The term "health functional food" refers to food manufactured and processed using raw materials or ingredients having useful functionality for the human body in accordance with the Health Functional Food Act, and "functional" refers to food that is not related to the structure and function of the human body. It refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients or physiological functions.
상기 건강기능식품 조성물은 통상의 식품 첨가물을 포함할 수 있으며, 상기 "식품 첨가물"로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전처에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional food composition may include conventional food additives, and the suitability as the "food additive" is determined in accordance with the General Rules and General Test Methods of Food Additives approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is judged according to the specifications and standards for the item.
상기 "식품 첨가물 공전"에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류들을 들 수 있다.Items listed in the "Food Additive Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigment, licorice extract, crystalline cellulose, goyang pigment, guar gum, and mixed preparations such as sodium L-glutamate preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations.
상기 건강기능식품에 함유된 화합물의 유효용량은 상기 치료제의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the compound contained in the health functional food may be used according to the effective dose of the therapeutic agent, but may be less than the above range in the case of long-term intake for the purpose of health and hygiene or health control, Since the active ingredient has no problem in terms of safety, it is certain that it can be used in an amount greater than the above range.
상기 건강기능식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제등을 들 수 있다.There is no particular limitation on the type of health functional food, and examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea , drinks, alcoholic beverages, and vitamin complexes.
또한, 본 발명은 화학식 1로 표시되는 화합물; 및 화학식 2로 표시되는 화합물을 포함하는, 세포 노화 관련 질환 예방 또는 개선용 화장료 조성물을 제공한다.In addition, the present invention is a compound represented by
상기 화장료 조성물은 상기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염 이외에 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함할 수 있다.The cosmetic composition may include, in addition to the compound represented by
상기 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 썬 크림, 유연 화장수, 수렴 화장수, 영양 화장수, 영양 크림, 마사지 크림, 에센스, 아이 크림, 팩, 스프레이 또는 파우더의 제형으로 제조될 수 있다.The cosmetic composition may be prepared in any formulation commonly prepared in the art, for example, a solution, suspension, emulsion, paste, gel, cream, lotion, powder, oil, powder foundation, emulsion foundation, It may be formulated as a wax foundation and spray, but is not limited thereto. More specifically, it may be prepared in the form of sun cream, softening lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, essence, eye cream, pack, spray or powder.
상기 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜,실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as a carrier component. .
상기 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, additional chlorofluorohydrocarbon, propane/butane or a propellant such as dimethyl ether.
상기 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해 화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.When the formulation is a solution or emulsion, a solvent, solubilizing agent or emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -Butyl glycol oil, fatty acid esters of glycerol, polyethylene glycol or sorbitan.
상기 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, an ethoxylated isostearyl alcohol, a suspension agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose , aluminum metahydroxide, bentonite, agar or tracanth, and the like can be used.
본 발명에서 용어 "예방"이란 본 발명에 따른 조성물의 투여로 질환의 억제 또는 지연시키는 모든 행위를 의미한다. 본 발명에서 용어 "치료"는 본 발명에 따른 조성물의 투여로 질환의 증세가 호전되거나 이롭게 변경하는 모든 행위를 의미한다. 본 발명에서 "개선"이란 본 발명의 조성물을 개체에 투여하거나 섭취시켜 질환의 나쁜 상태를 좋게 하는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to any activity that suppresses or delays a disease by administering the composition according to the present invention. In the present invention, the term "treatment" refers to all activities that improve or beneficially change the symptoms of a disease by administering the composition according to the present invention. In the present invention, "improvement" means any action that improves the bad condition of a disease by administering or ingesting the composition of the present invention to a subject.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
<실시예> KU-60019와 Y-27632의 병용 처리에 따른 인간 피부 섬유아세포 (human dermal fibroblast)의 노화 형질 회복 효과 검토<Example> Examination of aging trait recovery effect of human dermal fibroblasts according to combined treatment of KU-60019 and Y-27632
1. 실험방법1. Experiment method
1) 세포 배양1) Cell culture
실험에서 사용된 인간 피부 섬유아세포(Human dermal fibroblast)는 신생아 피부에서 채취한 샘플(PCS-201-010; ATCC)이며, 세포는 Dulbecco's modified Eagle's medium [25 mM glucose, 10% FBS (S001-01; Welgene), 100 units/ml penicillin, 10 μg/ml streptomycin, and 25 ng/ml amphotericin B (LS203-01; Welgene)]의 배양액으로 37℃, 5% CO2 조건 하에서 배양되었다. Human dermal fibroblasts used in the experiment were samples taken from the skin of newborns (PCS-201-010; ATCC), and the cells were grown in Dulbecco's modified Eagle's medium [25 mM glucose, 10% FBS (S001-01; Welgene), 100 units/ml penicillin, 10 μg/ml streptomycin, and 25 ng/ml amphotericin B (LS203-01; Welgene)] at 37°C and 5% CO 2 conditions.
계대 배양은 세포의 confluency(세포 배양 통 바닥 면 세포 분포율)가 80%를 넘지 않을 때마다 진행되었으며 신생아 피부에서 채취된 1대부터 45대까지 1/4 만큼의 세포를 새로 배양함으로써 계대를 이어 나갔다. 45대부터 47대까지는 1/3만큼, 48대 이후로는 1/2로 진행하였다. Subculture was carried out whenever the cell confluency (cell distribution rate on the bottom of the cell culture tank) did not exceed 80%, and the passage was continued by newly culturing 1/4 of the cells from the 1st to 45th generations collected from the skin of newborns. . From the 45th to the 47th, it was 1/3, and from the 48th, it was 1/2.
population doubling time (DT)이 14일을 넘어가면서, SA-β-gal의 비율이 90%를 넘길 시 충분히 노화가 된 세포라 여기고 실험을 진행하였다. 반면에, population doubling time (DT)이 1일 이하인 세포만 젊은 세포로 여기고 실험을 진행하였다. 세포는 실험 전 MycoAlert Mycoplasma Detection Kit (LT07-318; Lonza) 오염 여부 실험을 통과하였다. When the population doubling time (DT) exceeded 14 days and the ratio of SA-β-gal exceeded 90%, the cells were considered sufficiently senescent and the experiment was conducted. On the other hand, only cells with a population doubling time (DT) of 1 day or less were regarded as young cells and the experiment was conducted. The cells passed the MycoAlert Mycoplasma Detection Kit (LT07-318; Lonza) contamination test prior to the experiment.
2) 세포 증식 실험2) Cell proliferation experiment
실험에 사용될 세포는 실험 3일 전에 well plate에 이식되었다. KU-60019(이하, KU라고 함)와 Y-27632(이하, Y라고 함) 약물을 처리 후, D-Plus™ CCK reagent (Dongin)을 4시간 처리하여 세포의 양을 수치화 하였다. 450nm 파장대에서 플레이트 리더기(TECAN Infinite M200 PRO)을 이용하였다. Hoechst 33342의 경우, KU와 Y 약물을 처리한 세포에 10 μg/ml Hoechst 33342으로 30분 동안 염색 뒤, phosphate-buffered saline (PBS)로 2번 씻어주고 ex/em: 355/460nm 파장대에서 플레이트 리더기(TECAN Infinite M200 PRO)을 이용하여 세포의 양을 수치화 하였다.Cells to be used in the experiment were transplanted into
3) SA-β-gal 염색 실험3) SA-β-gal staining experiment
SA-β-gal 염색은 fluorescein di-β-d-galactopyranoside (FDG; Thermo Fisher Scientific) 혹은 X-gal-based Senescence β-Galactosidase Staining Kit (Cell Signaling Technology, #9860)를 이용하여 진행하였다. X-gal은 kit 제조사의 프로토콜대로 진행하였으며, FDG 같은 경우는 X-gal만 제외된 kit의 complete solution에서 FDG의 최종농도가 100 μM이 되도록 맞추어 세포에 처리하였다. 세포를 실험 수행 3일 전에 이식하였으며, 이미징을 위해서, X-gal 실험은 Olympus CKX41 현미경을 이용하여 세포가 분포해 있는 부위를 무작위로 사진 찍었고, FDG 실험은 ex/em: 495/520nm 파장대에서 플레이트 리더기(TECAN Infinite M200 PRO)을 이용하여 염색된 정도를 수치화 하였다. 그 다음으로, Hoechst 33342를 통해 세포의 양을 구해, 단위 세포 당 FDG가 염색된 정도를 계산하였다. SA-β-gal staining was performed using fluorescein di-β-d-galactopyranoside (FDG; Thermo Fisher Scientific) or X-gal-based Senescence β-Galactosidase Staining Kit (Cell Signaling Technology, #9860). X-gal was carried out according to the kit manufacturer's protocol, and in the case of FDG, cells were treated by adjusting the final concentration of FDG to 100 μM in the complete solution of the kit except for X-gal. Cells were transplanted 3 days before the experiment, and for imaging, the X-gal experiment randomly took pictures of the area where the cells were distributed using an Olympus CKX41 microscope, and the FDG experiment was plated in the ex/em: 495/520nm wavelength band. The degree of staining was quantified using a reader (TECAN Infinite M200 PRO). Next, the amount of cells was obtained using Hoechst 33342, and the degree of FDG staining per unit cell was calculated.
4) Lipofuscin 정량화 실험4) Lipofuscin quantification experiment
각 세포 당 lipofuscin 양을 LSR Fortessa (Beckton Dickson) flow cytometer를 이용하여 정량화 하였다. Lipofuscin이 autofluorescence라는 점을 응용하여 염색 없이 488 nm 파장대에서 530/30 nm bandpass filter (FITC channel)로 값을 측정하였다. The amount of lipofuscin per cell was quantified using an LSR Fortessa (Beckton Dickson) flow cytometer. By applying the point that Lipofuscin is autofluorescence, the value was measured with a 530/30 nm bandpass filter (FITC channel) in the 488 nm wavelength band without staining.
5) 면역화학법 실험5) Immunochemistry experiment
세포들은 4-well chamber cell culture slide (SPL)로 실험 3일 전에 이식되었다. Y와 KU 처리 후, 4% 파라포름알데히드로 10분 동안 세포를 고정시켰다. 1차 항체는 gelatin dilution buffer (GDB)에 희석한 다음 세포 위에 도포하고 4℃에서 밤새도록 반응시켰다. 2차례의 PBS 헹굼 후, 2차 항체를 GDB에 1:1,000으로 희석 후 1시간 동안 상온에 반응시켰다. Mounting solution with DAPI (Vector Laboratories)를 통해 DAPI 염색을 진행하였다. 마지막으로, ZEISS Axiocam 현미경으로 이미징 하였다. 위 실험에서 사용된 항체들은 다음과 같다. Cells were transplanted into 4-well chamber cell culture slides (SPL) 3 days before the experiment. After Y and KU treatment, cells were fixed with 4% paraformaldehyde for 10 minutes. The primary antibody was diluted in gelatin dilution buffer (GDB), applied onto the cells, and reacted overnight at 4°C. After two rounds of PBS rinse, the secondary antibody was diluted 1:1,000 in GDB and reacted at room temperature for 1 hour. DAPI staining was performed using a mounting solution with DAPI (Vector Laboratories). Finally, they were imaged with a ZEISS Axiocam microscope. Antibodies used in the above experiment are as follows.
rabbit anti-γH2AX (9218S; 1:500 dilution; Cell Signaling Technology), mouse anti-53BP1 (05-726; 1:500 dilution; MilliporeSigma)rabbit anti-γH2AX (9218S; 1:500 dilution; Cell Signaling Technology), mouse anti-53BP1 (05-726; 1:500 dilution; MilliporeSigma)
6) 미토콘드리아 기능 및 상태 측정6) Measurement of mitochondrial function and status
미토콘드리아의 형태나 총량을 측정하기 위해 세포를 30 nM MitoTracker Deep Red (M22426; Thermo Fisher)과 함께 30분 동안 37℃, 5% CO2 조건 하에서 반응시켰다. 해당 실험들은 모두 LSR Fortessa (Beckton Dickson) flow cytometer를 통해 측정되었으며, ROS 생성 양을 정량화하기 위해선 5 μM MitoSOX (M36008; Thermo Fisher) (excitation wavelength: 561 nm, 615/24 nm bandpass filter, PE-Texas Red channel), 37℃, 5% CO2 30분 반응을; 미토콘드리아 막 전위를 정량화하기 위해선 tetramethylrhodamine, methyl ester (TMRM; I34361; Thermo Fisher) (excitation wavelength: 561 nm, 615/24 nm bandpass filter, PE-Texas Red channel) 37℃, 5% CO2 30분 반응을 진행하였다. In order to measure the morphology or total amount of mitochondria, the cells were reacted with 30 nM MitoTracker Deep Red (M22426; Thermo Fisher) for 30 minutes at 37°C and 5% CO 2 conditions. All of the experiments were measured using an LSR Fortessa (Beckton Dickson) flow cytometer. To quantify the amount of ROS generation, 5 μM MitoSOX (M36008; Thermo Fisher) (excitation wavelength: 561 nm, 615/24 nm bandpass filter, PE-Texas Red channel), 37 ℃, 5% CO 2 reaction for 30 minutes; To quantify mitochondrial membrane potential, tetramethylrhodamine, methyl ester (TMRM; I34361; Thermo Fisher) (excitation wavelength: 561 nm, 615/24 nm bandpass filter, PE-Texas Red channel) 37°C, 5% CO 2 reaction for 30 minutes proceeded.
미토콘드리아 생합성 실험을 위해서는, pLenti6.3/V5-DEST plasmid containing the MitoTimer reporter (#50547l, Addgene)를 45대 세포에 transduction 한 뒤, LSR Fortessa flow cytometer를 이용하여 green fluorescence (excitation wavelength of 488 nm with a 530/30 nm bandpass filter, FITC channel)/red fluorescence (excitation wavelength of 561 nm with a 583/22 nm bandpass filter, PE channel) 비율을 구해 정량화하였다. For mitochondrial biosynthesis experiments, pLenti6.3/V5-DEST plasmid containing the MitoTimer reporter (#50547l, Addgene) was transduced into 45 cells, and green fluorescence (excitation wavelength of 488 nm with a The 530/30 nm bandpass filter, FITC channel)/red fluorescence (excitation wavelength of 561 nm with a 583/22 nm bandpass filter, PE channel) ratio was obtained and quantified.
7) 웨스턴 블럿 기법 7) Western blot technique
세포들은 2ㅧLaemmli sample buffer (#161-0737, Bio-Rad) containing 5% β-mercaptoethanol (Sigma)로 용해된 후 95℃에서 5분 동안 끓여졌다. 용해된 단백질들은 크기 순차적으로 SDS-PAGE를 통해 전기 영동되고, SDS-PAGE gel에서 polyvinylidene difluoride (PVDF) membranes (Millipore)로 옮겨졌다. 항체들이 임의의 곳에서 달라붙지 않게 PVDF membrane을 미리 5% bovine serum albumin (BSA; Sigma)이 녹여진 tris-buffered saline + 0.05% Tween 20으로 blocking을 한 후 1차 항체가 처리되었다. 다음으로, membrane을 horseradish peroxidase (HRP)-conjugated 2차 항체에 1시간 동안 반응시켰다. 해당 단백질들을 검출하기 위해서, enhanced chemiluminescence solution (P90720, Millipore)으로 발광을 시키고 나서 ImageQuant LAS-4000 digital imaging system (GE Healthcare) 장비로 가시화하였다. 이미징 결과의 정량화는 ImageQuant TL software 8.1로 수행되었다. Cells were lysed in 2x Laemmli sample buffer (#161-0737, Bio-Rad) containing 5% β-mercaptoethanol (Sigma) and then boiled at 95°C for 5 minutes. Soluble proteins were electrophoresed through size-sequential SDS-PAGE and transferred to polyvinylidene difluoride (PVDF) membranes (Millipore) on SDS-PAGE gels. To prevent the antibodies from sticking anywhere, the PVDF membrane was blocked with tris-buffered saline + 0.05
2. 실험결과2. Experimental results
계대배양에 의해 헤이플릭 한계(Hayflick limit)에 도달한 노화 세포는 세포 분열을 더 이상 하지 않는다. 하지만, 도 1 및 도 2와 같이, Y와 KU 처리 시 노화세포의 세포 분열이 재개하는 것을 확인하였고, 특히 Y 2.5 μM과 KU 0.5 μM를 동시에 처리하였을 때, 세포분열 유도에 대한 상승효과가 발휘되었다.Senescent cells that have reached the Hayflick limit by subculture do not divide any more. However, as shown in FIGS. 1 and 2, it was confirmed that cell division of senescent cells resumed when Y and KU were treated, and in particular, when Y 2.5 μM and KU 0.5 μM were simultaneously treated, a synergistic effect on inducing cell division was exerted. It became.
노화 세포는 젊은 세포와는 다르게 바이오마커 중 하나인 senescence-associated-β-galactosidase 염색법에 의해 파랗게 염색된다. 도 3 및 도 4는 노화 세포에 Y와 KU를 동시에 처리하였을 때, 전체 세포 수 대비 염색의 되지 않는 세포들의 수가 감소를 확인하였다. Unlike young cells, senescent cells are stained blue by senescence-associated-β-galactosidase staining, one of the biomarkers. 3 and 4 confirm that when senescent cells were simultaneously treated with Y and KU, the number of unstained cells compared to the total number of cells decreased.
노화 세포는 세포 내 리소좀에서 다양한 대사물을 소화하거나 처리할 때 생성되는 일종의 대사 쓰레기인 리포퓨신(Lipofuscin)이 만들어진다. 황갈색 색소 과립인 리포퓨신은 대사 쓰레기 처리가 활발히 진행되는 젊은 세포에서는 생기지 않지만, 늙은 세포에 생성될 경우 여러 퇴행성 질환을 유발한다. 도 5와 같이, Y와 KU를 동시에 처리할 경우, 리포퓨신이 많이 감소하는 것을 확인하였다. Senescent cells produce lipofuscin, a kind of metabolic waste produced when they digest or process various metabolites in intracellular lysosomes. Lipofuscin, a tan pigment granule, does not occur in young cells where metabolic waste disposal is actively progressing, but when it is produced in old cells, it causes various degenerative diseases. As shown in FIG. 5, when Y and KU were simultaneously treated, it was confirmed that lipofuscin was greatly reduced.
노화 세포의 미토콘드리아는 젊은 세포의 미토콘드리아에 비해 길쭉하고 늘어진 형태를 갖는다. 도 6과 같이, Y와 KU를 같이 처리 시, 노화 세포의 미토콘드리아 모양이 젊은 세포의 미토콘드리아의 형태와 같이 단편적으로 존재함을 확인하였다. Mitochondria of senescent cells have an elongated and elongated shape compared to mitochondria of young cells. As shown in FIG. 6 , when Y and KU were treated together, it was confirmed that the shape of the mitochondria of the senescent cells was fragmentarily present like the shape of the mitochondria of the young cells.
노화된 세포의 미토콘드리아는 젊은 세포의 미토콘드리아에 비해 ROS 생성양이 높고, 미토콘드리아 막 전위가 낮으며, 미토콘드리아 회전율이 낮다. 하지만, 이러한 여러 노화된 미토콘드리아의 패턴들이 도 7 내지 도 9와 같이 Y와 KU를 처리해 주었을 때 젊은 세포와 비슷하게 변하는 것을 확인하였다. Compared to the mitochondria of young cells, the mitochondria of senescent cells have higher ROS production, lower mitochondrial membrane potential, and lower mitochondrial turnover. However, it was confirmed that the patterns of these various aged mitochondria changed similarly to those of young cells when Y and KU were treated as shown in FIGS. 7 to 9 .
노화된 세포는 DNA 손상을 복구할 능력이 없어, 부서진 상태의 DNA가 많다. 도 10과 같이, Y와 KU를 동시에 처리하였을 때 비정상적인 DNA가 상당히 복구되는 것을 확인하였다. Aged cells do not have the ability to repair DNA damage, so there is a lot of DNA in a broken state. As shown in FIG. 10, it was confirmed that abnormal DNA was considerably recovered when Y and KU were simultaneously treated.
상기 결과들을 종합하면, Y와 KU의 병용 처리에 따라 노화된 세포의 회복 작용이 크게 향상된 것을 확인할 수 있었다. Summarizing the above results, it was confirmed that the recovery action of senescent cells was greatly improved by the combined treatment of Y and KU.
한편, Y와 KU의 병용 처리에 의해 세포 주기 인자(cell cycle factor)들이 어떻게 영향을 받는지를 밝힘으로써 Y와 KU의 병용 처리에 따른 노화세포 회복 작용의 상승 효과를 규명하였고, 도 11 및 도 12와 같이, Y와 KU의 병용 처리에 따라 노화세포에서는 불활성화 상태의 전사 인자인 FOXM1과 E2F1이 세포 주기 인자(cell cycle factor)들에 의해 재활성화되어 노화 극복에 필요한 대다수 유전자들의 전사를 촉진하는 것으로 판단되었다. 특히, Y와 KU의 병용 처리에 따라 초반에 FOXM1의 활성화되고, 후반에 E2F1의 활성화되는 "순차적"인 활성화가 노화세포의 회복 작용에 매우 중요한 것으로 판단되었다.On the other hand, by revealing how cell cycle factors are affected by the combined treatment of Y and KU, the synergistic effect of the senescent cell recovery effect according to the combined treatment of Y and KU was identified, FIGS. 11 and 12 As shown, FOXM1 and E2F1, transcription factors in an inactive state, are reactivated by cell cycle factors in senescent cells according to the combined treatment of Y and KU, which promotes the transcription of most genes necessary for overcoming aging. It was judged to be In particular, according to the combined treatment of Y and KU, the "sequential" activation of FOXM1 in the early stage and E2F1 in the later stage was judged to be very important for the recovery function of senescent cells.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.Having described specific parts of the present invention in detail above, it is clear to those skilled in the art that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (11)
하기 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 노화세포의 형질을 젊은 세포의 형질로 개선하는 세노모르픽(senomorphics) 조성물:
[화학식 1]
[화학식 2]
A senomorphic composition for improving the characteristics of senescent cells into those of young cells, comprising a compound represented by Formula 2 or a pharmaceutically acceptable salt thereof:
[Formula 1]
[Formula 2]
하기 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 세포 노화 관련 질환 치료 또는 예방용 약학조성물:
[화학식 1]
[화학식 2]
A pharmaceutical composition for treating or preventing cellular senescence-related diseases comprising a compound represented by Formula 2 or a pharmaceutically acceptable salt thereof:
[Formula 1]
[Formula 2]
하기 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 리포푸신의 축적 관련 질환 치료 또는 예방용 약학조성물:
[화학식 1]
[화학식 2]
A pharmaceutical composition for treating or preventing lipofuscin accumulation-related diseases, comprising a compound represented by Formula 2 or a pharmaceutically acceptable salt thereof:
[Formula 1]
[Formula 2]
하기 화학식 2로 표시되는 화합물을 포함하는, 세포 노화 관련 질환 예방 또는 개선용 건강기능식품 조성물:
[화학식 1]
[화학식 2]
A health functional food composition for preventing or improving cellular aging-related diseases, comprising a compound represented by Formula 2 below:
[Formula 1]
[Formula 2]
하기 화학식 2로 표시되는 화합물을 포함하는, 세포 노화 관련 질환 예방 또는 개선용 화장료 조성물:
[화학식 1]
[화학식 2]
A compound represented by Formula 1 below; and
A cosmetic composition for preventing or improving cellular aging-related diseases, comprising a compound represented by Formula 2 below:
[Formula 1]
[Formula 2]
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