KR101344086B1 - Composition for muscle fatigue resistance or muscle mass growth comprising celastrol - Google Patents
Composition for muscle fatigue resistance or muscle mass growth comprising celastrol Download PDFInfo
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- KR101344086B1 KR101344086B1 KR1020120034431A KR20120034431A KR101344086B1 KR 101344086 B1 KR101344086 B1 KR 101344086B1 KR 1020120034431 A KR1020120034431 A KR 1020120034431A KR 20120034431 A KR20120034431 A KR 20120034431A KR 101344086 B1 KR101344086 B1 KR 101344086B1
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- Prior art keywords
- muscle
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- celastrol
- composition
- cel
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- A—HUMAN NECESSITIES
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Abstract
본 발명은 셀라스트롤(celastrol)을 유효성분으로 포함하는 근피로 저항 또는 근질량 증가용 약학적 조성물에 관한 것으로, 셀라스트롤은 근세포 내에서 ATP를 안정적으로 공급하여 근피로에 대한 저항성을 높이고, 근단백질 분해 억제와 근단백질 생성을 촉진하여 근수축 단백질을 더 축적시켜 근질량을 증가시킴으로써, 운동경기력 향상에 효능을 나타내므로, 기능성 스포츠 음료 개발 등에 사용할 수 있다.The present invention relates to a pharmaceutical composition for muscle fatigue resistance or muscle mass increase, which includes celastrol as an active ingredient, which provides a stable supply of ATP in muscle cells, thereby increasing resistance to muscle fatigue, and muscle protein degradation. By inhibiting and promoting the production of muscle protein, by accumulating more muscle contraction protein to increase the muscle mass, it is effective in improving athletic performance, and thus can be used for the development of functional sports drinks.
Description
본 발명은 근세포 내에서 ATP를 안정적으로 공급하여 근피로에 대한 저항성을 높이고, 근단백질 분해 억제와 근단백질 생성을 촉진하여 근수축 단백질을 더 축적시켜 근질량을 증가시킴으로써, 운동경기력 향상에 효과를 가지는 셀라스트롤을 포함하는 조성물에 관한 것이다.
The present invention stably supplies ATP in muscle cells to increase resistance to muscle fatigue, inhibit muscle protein degradation and promote muscle protein production to further increase muscle mass by accumulating muscle contractile proteins, thereby having an effect on improving athletic performance. The present invention relates to a composition comprising celastrol.
최근 수십년 동안 스포츠 의학 분야의 과학자들은 운동 경기에서 운동경기력 향상 효과를 보기 위해 영양제 및 천연 화합물에 많은 관심을 가졌다. 운동경기력 향상은 그 경기 과정에서 근력을 얼마나 지속적으로 유지할 수 있느냐에 달려 있다. 근력의 지속성 여부는 단기적으로는 근세포 내의 적정 에너지(ATP) 공급과 젖산 생성 최소화(생화학적 능력)에, 장기적으로는 근수축 관련 단백질 축적에 의한 근질량 증가(생리학적 능력)에 의해 결정된다. 최근 연구들은 생화학적 및 생리학적 용량을 모두 증진시키는 화합물에 집중되고 있다. In recent decades, scientists in the field of sports medicine have paid much attention to nutritional and natural compounds to improve athletic performance in athletics. Improving athletic performance depends on how consistently you can maintain strength throughout the game. The persistence of muscle strength is determined in the short term by the provision of adequate energy (ATP) in muscle cells and minimization of lactic acid production (biochemical capacity), and in the long term by the increase in muscle mass (physiological capacity) by muscle contraction-related protein accumulation. Recent studies have focused on compounds that enhance both biochemical and physiological doses.
최근까지의 연구에서는 영양 보충제(예, 스테로이드제) 및 비타민과 같은 영양 성분이 운동경기력 향상에 효과를 발휘하는 것으로 나타났다. 예를들어, 근육 강화 스테로이드(eg., metandrostenolon)는 근육 운동 시 수축 단백질의 양을 증가시켜 운동 능력을 향상시키는 것으로 알려져있다. 그러나 개발된 비타민이나 영양 보충제는 복용금지(예, 스테로이드제)이거나 장기간 복용에 따른 부작용의 우려가 있으므로, 아직 더 많은 검증이 요구되고 있다. 특히, 이 연구들은 해당 약제를 근세포(in vitro)에 처리하여 효능을 조사한 것이 대부분으로, 근조직(ex vivo) 및 동물실험(in vivo)을 통한 검증은 미흡한 상태이다. Recent studies have shown that nutritional supplements, such as nutritional supplements (eg steroids) and vitamins, are effective in improving athletic performance. For example, anabolic steroids (eg, metandrostenolon) are known to increase exercise capacity by increasing the amount of contractile protein during muscle exercise. However, the development of vitamins and nutritional supplements is prohibited (eg, steroids) or may cause side effects from long-term use. In particular, these studies mostly examined the efficacy of the drug in the treatment of myocytes (in vitro), and the verification through ex vivo and animal experiments (in vivo) is insufficient.
더구나, 위에서 언급한 생리/생화학적 기능을 가진 식물성 천연물의 운동향상 효능성을 in vitro, ex vivo 및 in vivo 실험으로 조사한 연구는 사실상 전무한 상태이다.Moreover, there have been virtually no studies investigating the above-mentioned physiological / biochemical functions of plant natural motility in vitro, ex vivo and in vivo experiments.
셀라스트롤(Celastrol, CEL)은 노박덩굴과(Celastraceae) 식물 유래의 퀴논 메타이드 트리터펜계(quinone methide triterpene) 화합물로, 열 스트레스와 유사한 방식으로 열충격전사인자 1(heat shock transcription factor1(HSF1))을 활성화시키는 것으로 밝혀졌다. 또한, 상기 화합물은 항산화제 및 항-염증 활성, 신경보호 및 프로테아좀 활성 및 글루코코티코이드 수용체 활성에 대한 억제 효과 등 다양한 범위에서 기능을 나타낸다. 이들 활성들 모두 열충격 단백질의 강력한 유도제로서 셀라스트롤의 기능적 유의성을 나타내는 것이다.Celastrol (CEL) is a quinone methide triterpene compound from Celastraceae plants and heat shock transcription factor 1 (HSF1) in a manner similar to heat stress. It was found to activate. In addition, the compounds exhibit a range of functions, including antioxidant and anti-inflammatory activity, neuroprotective and proteasome activity, and inhibitory effects on glucocorticoid receptor activity. Both of these activities are indicative of the functional significance of Celastrol as a potent inducer of heat shock proteins.
셀라스트롤 기능에 대한 이들 구체적인 연구들에도 불구하고, 운동향상 효능에 대한 역할은 지금까지 밝혀진 바 없다.
In spite of these specific studies of cell trastol function, the role for exercise improvement efficacy has not been identified so far.
본 발명의 목적은 셀라스트롤의 근피로 저항 능력 및 근질량 증가 능력을 입증하여, 운동경기력 향상을 위한 용도를 제공하는 것이다.
It is an object of the present invention to demonstrate the ability of resistance to muscle fatigue and muscle mass increasing ability, thereby providing a use for improving athletic performance.
상기 목적을 달성하여 위하여, 본 발명은 셀라스트롤(celastrol)을 유효성분으로 포함하는 근피로 저항 또는 근질량 증가용 약학적 조성물을 제공한다.
In order to achieve the above object, the present invention provides a pharmaceutical composition for muscle fatigue resistance or muscle mass increase comprising celastrol as an active ingredient.
본 발명은 또한 셀라스트롤(celastrol)을 유효성분으로 포함하는 근피로 저항 또는 근질량 증가용 식품 조성물을 제공한다.
The present invention also provides a food composition for muscle fatigue resistance or muscle mass increase, which includes celastrol as an active ingredient.
본 발명은 또한 셀라스트롤(celastrol)을 유효성분으로 포함하는 근피로 저항 또는 근질량 증가용 화장품 조성물을 제공한다.
The present invention also provides a cosmetic composition for muscle fatigue resistance or muscle mass increase containing celastrol as an active ingredient.
본 발명은 셀라스트롤이 근세포 내에서 ATP를 안정적으로 공급하여 근피로에 대한 저항성을 높이고, 근단백질 분해 억제와 근단백질 생성을 촉진하여 근수축 단백질을 더 축적시켜 근질량을 증가시킴으로써, 운동경기력 향상에 효능을 지닌다. 따라서, 이러한 셀라스트롤의 운동경기력 향상 효능을 활용할 경우 스포츠 음료 개발에 유용하다.
The present invention provides a stable supply of ATP in muscle cells to increase resistance to muscle fatigue, inhibit muscle protein degradation, promote muscle protein production, and further increase muscle mass by accumulating muscle contractile proteins, thereby improving athletic performance. Has efficacy. Therefore, it is useful in the development of sports drinks when utilizing the athletic performance improvement effect of these cells.
도 1은 실시예 2에서 사용되는 랫트 그룹의 종류를 나타낸다.
도 2는 실시예 1에서 실험한 각 그룹의 가자미근에 대한 근력 데이터를 나타내는 그래프이다.
(A CON(대조군), B, C 및 D는 각각 셀라스트롤 0.1, 1.0 및 10.0 mM 포함)
도 3은 실시예 1에서 실험한 각 그룹의 시간에 따른 근육 장력(tension)의 변화를 나타내는 그래프이다.
(A 기준(베이스라인) 장력, B 근육 장력, 평균 ± SEM (n = 6 per group); *, P < 0.05 (one-way ANOVA and Scheffe's multiple comparison tests))
도 4는 실시예 2에서 실험한 각 그룹의 근육 양의 증가를 나타내는 그래프이다.
도 5는 실시예 3에서 실험한 HSP72, Akt1-S6K 신호전달 축 및 ERK1/2의 겔 이미지를 나타낸다.
(t: triciribine(phospho-Akt1 억제제), u: u0126(phospho-ERK1/2 억제제), tDC: triciribine + DEX + CEL; uDC: u0126 + DEX + CEL; tuDC: triciribine + u0126 + DEX + CEL)
도 6은 실시예 3에서 실험한 C2C12 세포 직경에 대한 덱사메타손, 셀라스트롤과 Akt1 및 ERK1/2 활성 억제제의 영향을 나타내는 그래프이다.
(평균 ± SEM (n = 3); *, P < 0.05 (Kruskal-Wallis test and Langley post hoc comparison test) (t: triciribine(phospho-Akt1 억제제), u: u0126(phospho-ERK1/2 억제제), tDC: triciribine + DEX + CEL; uDC: u0126 + DEX + CEL; tuDC: triciribine + u0126 + DEX + CEL)
도 7은 실시예 3에서 실험한 C2C12 마우스 세포에 처리된 덱사메타손, 셀라스트롤 및 저해제에 의한 HSP72에서의 변화를 나타내는 그래프이다.
(평균 ± SEM (n = 3); *, P < 0.05 (Kruskal-Wallis and Langley's test)(Con: vehicle control; DEX: dexamethasone; CEL: celastrol)
도 8은 실시예 3에서 실험한 C2C12에서 26S 프로테아좀의 키모트립신 유사 활성에 대한 덱사메타손 및 셀라스트롤의 영향을 나타내는 그래프이다.
(평균 ± SEM (n = 6); *, P < 0.05 (one-way ANOVA and Duncan's post hoc tests) (t: triciribine(phospho-Akt1 억제제), u: u0126(phospho-ERK1/2 억제제), tDC: triciribine + DEX + CEL; uDC: u0126 + DEX + CEL; tuDC: triciribine + u0126 + DEX + CEL)1 shows the types of rat groups used in Example 2. FIG.
Figure 2 is a graph showing the muscle strength data for the soleus muscle of each group tested in Example 1.
(A CON (control), B, C, and D contain 0.1, 1.0, and 10.0 mM of Celastol, respectively)
Figure 3 is a graph showing the change in muscle tension (tension) with time of each group tested in Example 1.
(A baseline tension, B muscle tension, mean ± SEM (n = 6 per group); *, P <0.05 (one-way ANOVA and Scheffe's multiple comparison tests))
Figure 4 is a graph showing the increase in the amount of muscle of each group tested in Example 2.
5 shows gel images of HSP72, Akt1-S6K signaling axis and ERK1 / 2 tested in Example 3. FIG.
(t: triciribine (phospho-Akt1 inhibitor), u: u0126 (phospho-ERK1 / 2 inhibitor), tDC: triciribine + DEX + CEL; uDC: u0126 + DEX + CEL; tuDC: triciribine + u0126 + DEX + CEL)
6 is a graph showing the effect of dexamethasone, celastrol and Akt1 and ERK1 / 2 activity inhibitors on C2C12 cell diameters tested in Example 3. FIG.
(Mean ± SEM (n = 3); *, P <0.05 (Kruskal-Wallis test and Langley post hoc comparison test) (t: triciribine (phospho-Akt1 inhibitor), u: u0126 (phospho-ERK1 / 2 inhibitor), tDC: triciribine + DEX + CEL; uDC: u0126 + DEX + CEL; tuDC: triciribine + u0126 + DEX + CEL)
FIG. 7 is a graph showing changes in HSP72 by dexamethasone, celastrol and inhibitors treated in C2C12 mouse cells tested in Example 3. FIG.
(Mean ± SEM (n = 3); *, P <0.05 (Kruskal-Wallis and Langley's test) (Con: vehicle control; DEX: dexamethasone; CEL: celastrol)
FIG. 8 is a graph showing the effect of dexamethasone and celastrol on chymotrypsin-like activity of 26S proteasome in C2C12 tested in Example 3. FIG.
(Mean ± SEM (n = 6); *, P <0.05 (one-way ANOVA and Duncan's post hoc tests) (t: triciribine (phospho-Akt1 inhibitor), u: u0126 (phospho-ERK1 / 2 inhibitor), tDC : triciribine + DEX + CEL; uDC: u0126 + DEX + CEL; tuDC: triciribine + u0126 + DEX + CEL)
이하, 본 발명의 구성을 구체적으로 설명한다. EMBODIMENT OF THE INVENTION Hereinafter, the structure of this invention is demonstrated concretely.
본 발명은 셀라스트롤(celastrol)을 유효성분으로 포함하는 근피로 저항 또는 근질량 증가용 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for muscle fatigue resistance or muscle mass increase comprising celastrol as an active ingredient.
본 발명은 항산화, 항염증, 항암 및 세포보호 등의 기능을 갖는 셀라스트롤을 근피로 저항 또는 근질량 증가용 조성물의 용도로 사용한 것으로, 하기와 같은 메커니즘이 가능하다. The present invention uses a cellistrol having functions such as antioxidant, anti-inflammatory, anticancer and cytoprotective for use in a composition for muscle fatigue resistance or muscle mass increase, and the following mechanism is possible.
먼저, 셀라스트롤은 근세포 내에서 ATP를 안정적으로 공급하여 근피로에 대한 저항성을 높일 수 있다. 또한, 셀라스트롤은 프로테아좀의 활성을 감소시켜 근단백질 분해를 억제하며, 동시에 근단백질 생성 관련 신호전달분자인 Akt1과 p70/S6K의 활성을 증가시켜 근단백질 생성 촉진을 통해 근수축단백질을 더 축적시킴으로써 근질량을 증가시킬 수 있다. First, the cell trastol can stably supply ATP in muscle cells, thereby increasing resistance to muscle fatigue. In addition, Celastrol reduces the activity of proteasome to inhibit muscle protein degradation, and at the same time increases the activity of Akt1 and p70 / S6K, the signaling molecules related to muscle protein production, thereby promoting muscle protein production. By accumulating, the muscle mass can be increased.
일반적으로, 덱사메타손은 FoxO 단백질의 탈인산화를 유지시키며, 이에 따라 유비퀴틴 E3 리가아제의 발현 증가와 프로테아좀 활성도를 증가시켜 근단백질 분해를 촉진하는 것으로 보고되어 있다. 본 발명에서는 덱사메타손을 처리한 세포에서 근세포 직경이 유의한 수준으로 감소하였지만, 상기 덱사메타손과 셀라스트롤을 함께 처리했을 때는 대조군과 거의 동일하게 유지하는 것으로 나타났다. 또한 셀라스트롤이 근단백질 생성 관련 분자들의 활성화를 촉진시키는 것과 동시에 근단백질 분해 관련 신호분자들의 발현과 활성화를 억제시키는 결과를 확인하여 셀라스트롤의 근질량 효능을 확인하였다. 이에 따라, 셀라스트롤을 근피로 저항 및 근질량 증가용 조성물로 사용할 수 있으며, 궁극적으로 운동경기력 향상 효능을 가지는 조성물로 사용하게 한 것이다.
In general, dexamethasone maintains the dephosphorylation of FoxO protein, thus increasing the expression of ubiquitin E3 ligase and increasing the proteasome activity has been reported to promote muscle protein degradation. In the present invention, the dexamethasone-treated cells decreased the diameter of the myocytes to a significant level, but when treated with the dexamethasone and the celllastrol was shown to remain almost the same as the control group. In addition, the cell mass promotes the activation of molecules related to protein production and inhibits the expression and activation of signal molecules related to protein breakdown. Accordingly, it can be used as a composition for the resistance to muscle fatigue and muscle mass increase, and ultimately used as a composition having the effect of improving athletic performance.
본 발명에서 셀라스트롤은 의약품, 식품, 화장품 등의 용도로 사용할 수 있는데, 상기 셀라스트롤은 노박덩굴과(Celastraceae) 식물의 추출물 형태로 포함되거나, 상기 식물의 분쇄물 또는 건조 분쇄물로서 포함되어 사용할 수 있다.In the present invention, the cellulose can be used for pharmaceuticals, foods, cosmetics, etc. The cellulose can be included in the form of an extract of the plant of Nova Celastraceae , or used as a pulverized or dry pulverized product of the plant. Can be.
상기 셀라스트롤은 그 자체를 사용하거나 약제학적으로 허용이 가능한 산부가염 또는 금속 복합체, 예를 들어 아연, 철 등과 같은 염의 형태로 사용할 수 있다. 보다 구체적으로 산부가염은 염화수소, 브롬화수소, 황산염, 인산염, 말레산염, 아세트염, 시트로산염, 벤조산염, 숙신산염, 말린산염, 아스코로브산염 및 타르탈산염 등을 사용하는 것이 좋다.The celastrol can be used on its own or in the form of pharmaceutically acceptable acid addition salts or metal complexes such as salts such as zinc, iron and the like. More specifically, as acid addition salts, it is preferable to use hydrogen chloride, hydrogen bromide, sulfates, phosphates, maleates, acetates, citrates, benzoates, succinates, dried salts, ascorbates and tartalates.
상기 셀라스트롤 및 이의 약학적으로 허용가능한 염의 함량은 약학적 조성물 총 중량을 기준으로 2 내지 25 중량부로 포함되는 것이 바람직하다. 상기 함량 범위 내에서 근피로 억제 및 근질량 증가 효과가 우수하다.
The content of the cellulose and pharmaceutically acceptable salts thereof is preferably included in an amount of 2 to 25 parts by weight based on the total weight of the pharmaceutical composition. Within the above content range, the effect of inhibiting muscle fatigue and increasing muscle mass is excellent.
본 발명의 셀라스트롤 및 그의 염을 유효성분으로 함유하는 조성물은 투여방법, 투여형태 및 치료목적에 따라 상기 유효성분을 약제학적으로 허용 가능한 담체와 함께 혼합하여 희석하거나, 용기 형태의 담체 내에 봉입시킬 수 있다.The composition containing the celllastrol and its salts of the present invention as an active ingredient may be diluted or mixed with the pharmaceutically acceptable carrier or enclosed in a container form according to the administration method, dosage form and therapeutic purpose. Can be.
약학적으로 허용되는 담체는 완충액, 주사용 멸균수, 일반 식염수 또는 인산염 완충 식염수, 슈크로스, 히스티딘 및 폴리솔베이트 등과 같은 여러 성분을 함유할 수 있다.Pharmaceutically acceptable carriers may contain various components such as buffers, sterile water for injection, general saline or phosphate buffered saline, sucrose, histidine, polysorbate and the like.
본 발명의 약학적 조성물은 경구 또는 비경구로 투여할 수 있으며, 일반 의약품 제제의 형태, 예를 들어, 임상 투여 시 경구 및 비경구의 여러 가지 제형으로 투여할 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제할 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally, and may be administered in the form of a general pharmaceutical preparation, for example, in various dosage forms, orally and parenterally, in the case of clinical administration. Diluents or excipients such as extenders, binders, wetting agents, disintegrating agents, and surfactants may be used.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 약학적 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(Calcium carbonate), 수크로스(Sucrose), 락토오스(Lactose) 또는 젤라틴 등을 섞어 조제할 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the pharmaceutical composition of the present invention, for example, starch, calcium carbonate, Sucrose (Lucose), lactose (Lactose) or gelatin can be prepared by mixing.
단순한 부형제 이외에 마그네슘, 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러가지 부형제, 예를 들면 습윤제, 감미제, 방향제 및 보존제 등을 포함할 수 있다.In addition to simple excipients, lubricants such as magnesium, styrate and talc can also be used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin. .
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제를 포함할 수 있다. 비수성용제 및 현탁용제로는 프로필렌 글리콜(Propylene glycol), 폴리에틸렌 글리콜 또는 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등을 사용할 수 있다. 좌제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지 또는 글리세로제라틴 등이 사용될 수 있다.Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol or vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter or glycerogelatin may be used.
본 발명의 약학적 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도에 따라 그 범위가 다양하며, 일일 투여량은 통상 성인 체중 1kg 당 1 내지 5 mg을 하루에 연속적 또는 간헐적으로 투여할 수 있다.The dosage of the pharmaceutical composition of the present invention varies depending on the body weight, age, sex, health condition, diet, time of administration, administration method, excretion rate and severity of the disease, the daily dosage is usually
또한, 본 발명의 약학적 조성물은 단독으로 사용하거나, 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.
In addition, the pharmaceutical compositions of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.
또한, 본 발명은 셀라스트롤을 유효성분으로 포함하는 근피로 저항 또는 근질량 증가용 식품 조성물에 관한 것이다. In addition, the present invention relates to a food composition for muscle fatigue resistance or muscle mass increase, which contains celastrol as an active ingredient.
상기 셀라스트롤의 유효량을 기준으로, 본 발명은 셀라스트롤 그 자체 또는 식품학적으로 허용된 담체를 혼합한 조성물을 기본식이소재(其本食餌素材)로 포함하는 식품 또는 식품첨가제를 제공하는데, 상기 식품은 식육가공품, 어육제품, 두부, 묵, 죽, 라면이나 국수 등의 면류, 간장, 된장, 고추장, 혼합장 등의 조미식품, 소스, 과자, 발효유, 또는 치즈 등의 유가공품, 김치나 장아찌 등의 절임식품, 과실, 채소, 두유 및 발효음료 등의 음료수의 식품에 포함하여 사용할 수 있다. 이때, 상술한 형태의 식품은 해당 분야에서 통상의 지식을 가진 자(이하, 당업자라 함)라면 자명한 사항으로 이의 구체적인 조리 방법이나 생산 방법의 기재는 생략하기로 한다.Based on the effective amount of the cellulose trol, the present invention provides a food or food additive comprising the composition of the cellulose trol itself or a food-acceptable carrier as a basic dietary ingredient (其 本 食餌 素材), the food Processed meat products, fish products, tofu, jelly, porridge, noodles such as ramen or noodles, seasoned foods such as soy sauce, miso, red pepper paste, mixed soy sauce, dairy products such as sauces, sweets, fermented milk, or cheese, kimchi or pickles It can be used in foods such as pickles, fruits, vegetables, soy milk and fermented beverages. At this time, the food of the above-described form will be apparent to those of ordinary skill in the art (hereinafter, referred to as a person skilled in the art), and a description of its specific cooking method or production method will be omitted.
본 발명의 셀라스트롤을 식품 또는 식품첨가물로 사용하는 경우, 상기 셀라스트롤을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합양은 그의 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정할 수 있다. 일반적으로, 식품 또는 음료의 제조 시 본 발명의 조성물은 원료에 대하여 15 중량% 이하, 바람직하게는 10 중량% 이하의 함양으로 첨가할 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.In the case of using the celas trol of the present invention as a food or food additive, it can be added as it is or used with other food or food ingredients, and can be suitably used according to a conventional method. The mixed amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health or therapeutic treatment). In general, the composition of the present invention in the production of food or beverage may be added in a content of up to 15% by weight, preferably up to 10% by weight relative to the raw material. However, in the case of long-term consumption intended for health and hygiene purposes or for health control purposes, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range .
또한, 프로테아좀 활성 저해제로서 근질량 증가 효능을 활용할 경우 기능성 스포츠 음료 개발에도 유용할 것으로 사료된다. 본 발명의 셀라스트롤을 음료, 예를 들어, 기능성 스포츠 음료로 사용하는 경우, 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당 또는 과당과 같은 모노사카라이드, 말토스 또는 슈크로스와 같은 디사카라이드, 덱스트린 또는 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨 또는 에리트리톨과 같은 당알콜이 있다. 감미제는 타우마틴, 또는 스테비아 추출물과 같은 천연 감미제나, 사카린 또는 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 0.01 내지 0.04 g, 구체적으로는 약 0.02 내지 0.03 g 이다.
In addition, the use of muscle mass gain as a proteasome activity inhibitor may be useful for the development of functional sports drinks. In the case of using the celllatrol of the present invention as a beverage, for example, a functional sports beverage, various flavors or natural carbohydrates and the like may be contained as additional components, as in the conventional beverage. Natural carbohydrates described above include monosaccharides such as glucose or fructose, disaccharides such as maltose or sucrose, polysaccharides such as dextrin or cyclodextrin, sugar alcohols such as xylitol, sorbitol or erythritol. Sweeteners may be natural sweeteners such as taumartin, or stevia extract, or synthetic sweeteners such as saccharin or aspartame. The proportion of said natural carbohydrate is generally about 0.01 to 0.04 g, specifically about 0.02 to 0.03 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 음료 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올 및 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다.In addition to the above, the beverage composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols. And carbonation agents used in carbonated beverages.
또한, 본 발명의 음료 조성물은 천연 과일주스, 과일 주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 혼합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부당 0.01 내지 0.1 중량부의 범위에서 선택되는 것이 일반적이다.
In addition, the beverage composition of the present invention may contain fruit flesh for the production of natural fruit juice, fruit juice beverage and vegetable beverage. These components may be used independently or in combination. The proportion of such additives is not critical but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
또한, 본 발명은 셀라스트롤을 유효성분으로 포함하는 포함하는 근피로 저항 또는 근질량 증가용 화장료 조성물에 관한 것이다.In addition, the present invention relates to a cosmetic composition for muscle fatigue resistance or muscle mass increase, which comprises celastrol as an active ingredient.
유효량을 기준으로, 상기 셀라스트롤 자체 또는 화장품학적으로 허용된 담체를 혼합한 조성물을 기능성 성분으로 포함하는 화장료 또는 화장품을 제공하는데, 일반적인 유화 제형 및 가용화 제형의 형태로 제조할 수 있다. 유화 제형의 화장품으로는 영양화장수, 크림 및 에센스 등이 있으며, 가용화 제형의 화장품으로는 유연화장수가 있다. 적합한 화장품의 제형으로는 예를 들면 용액, 겔, 고체 또는 반죽 무수 생성물, 수상에 유상을 분산시켜 얻은 에멀젼, 현탁액, 마이크로에멀젼, 마이크로캡슐, 미세과립구 또는 이온형(리포좀), 비이온형의 소낭 분산제의 형태, 크림, 스킨, 로션, 파우더, 연고, 스프레이 또는 콘실 스틱의 형태로 제공될 수 있다.On the basis of the effective amount, to provide a cosmetic or cosmetics comprising the composition of the cellulose or itself or a cosmetically acceptable carrier as a functional ingredient, it can be prepared in the form of a general emulsion formulation and solubilized formulation. Cosmetics of the emulsified formulations include nutrient cosmetics, creams and essences, etc., and cosmetics of the solubilized formulations are soft cosmetics. Suitable cosmetic formulations include, for example, solutions, gels, solid or kneaded anhydrous products, emulsions obtained by dispersing the oil phase in water, suspensions, microemulsions, microcapsules, microgranules or ionic (liposomes) In the form of a dispersing agent, in the form of a cream, a skin, a lotion, a powder, an ointment, a spray or a conical stick.
또한, 포말(foam)의 형태 또는 압축된 추진제를 더 함유한 에어로졸 조성물의 형태로도 제조될 수 있다.It can also be prepared in the form of a foam or an aerosol composition further containing a compressed propellant.
이때, 상술한 형태의 화장품 제조방법과 담체는 당업자에게 자명한 사항으로 구체적인 제조방법의 기재는 생략하기로 한다.At this time, the cosmetic preparation method and the carrier of the above-described form is obvious to those skilled in the art and description of the specific manufacturing method will be omitted.
또한, 상기 화장품은 본 발명의 셀라스트롤에 추가로 지방 물질, 유기 용매, 용해제, 농축제 및 겔화제, 연화제, 항산화제, 현탁화제, 안정화제, 발포제(foaming agent), 방향제, 계면활성제, 물, 이온형 또는 비이온형 유화제, 충전제, 금속이온봉쇄제 및 킬레이트화제, 보존제, 비타민, 차단제, 습윤화제, 필수 오일, 염료, 안료, 친수성 또는 친유성 활성제, 지질 소낭 또는 화장품에 통상적으로 사용되는 임의의 다른 성분과 같은 화장품학 분야에서 통상적으로 사용되는 보조제를 함유할 수 있다.
In addition, the cosmetics can be used in addition to the cellulose of the present invention, fatty substances, organic solvents, solubilizers, thickeners and gelling agents, softeners, antioxidants, suspending agents, stabilizers, foaming agents, fragrances, surfactants, water Commonly used in ionic or nonionic emulsifiers, fillers, metal ion sequestrants and chelating agents, preservatives, vitamins, blockers, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles or cosmetics It may contain adjuvants conventionally used in the cosmetic field, such as any other ingredient.
이하, 본 발명에 따르는 실시예 통하여 본 발명을 보다 상세히 설명하나, 본 발명의 범위가 하기 제시된 실시예에 의해 제한되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to Examples of the present invention, but the scope of the present invention is not limited by the following Examples.
실시예Example
1. 생체 밖(Ex vivo) 근피로 저항능(muscle fatigue resistance) 연구1. Ex vivo muscle fatigue resistance study
(1) 근 적출 (1) muscle extraction
항온항습(23 ± 1°C, 65%)과 12시간 간격의 낮-밤 주기를 갖는 사육실에서 관리된 11주령(40g 내외) ICR 마우스를 사용하였다. 실험 전 마우스는 사료와 물을 충분히 공급하였고, 사육실에서 1주간 안정기를 가졌다. 근수축 실험을 위하여 ICR 마우스를 펜토바르비탈 나트륨(pentobarbital sodium, 50 mg/kg 복강주사)으로 마취한 후, 오른쪽 가자미근(soleus m.)를 빠르게 적출하고, 상기 가자미근의 양쪽 끝, 인대 및 힘줄 부위를 명주실로 고정하여 근 수축실험을 위한 Krebs buffer solution에 담궜다. Eleven-week-old (40 g or so) ICR mice administered in a nursery with constant temperature and humidity (23 ± 1 ° C, 65%) and 12-hour day-night cycles were used. Before the experiment, the mice were supplied with sufficient feed and water, and had a stable period in the breeding room for 1 week. ICR mice were treated with pentobarbital sodium (50 mg / kg) for muscle contraction experiments. After anesthesia with abdominal injection, the right soleus muscle (soleus m.) Was quickly removed, and both ends, ligaments and tendons of the soleus were fixed in a silk thread soaked in Krebs buffer solution for muscle contraction experiments.
(2) 근 수축 실험 (2) muscle contraction experiment
상기 가지미근(이하, 근육)을 Krebs buffer solution(단위(mmol/L): NaCl 118; KCl 4.75; CaCl2 2.54; MgSO4 1.18; NaH2PO4 1.18; NaHCO3 24.8; 및 글루코오스 10(pH 7.4))이 담긴 5 ml 근수조(muscle bath)에 수평으로 넣어 5분간 안정시켰다. 근육 한쪽 끝의 명주실은 300C-LR 서보모터 암(servomotor arm, 고유 진동수 85 Hz) (Aurora Scientific Inc., Ontario, Canada)에 연결하고, 다른 끝은 마이크로미터(micrometer)에 연결한 뒤 적정 길이를 유지하였다. 상기 근수조에는 산소공급을 위해 95% O2 및 5% CO2 혼합가스를 주입하였다. 근수조의 온도는 TC-10 온도 조절기(temperature controller, Dagan Corporation, Minneapolis, MN, USA)를 통해 37 ± 0.01oC 로 유지 시켰다. 근수조 내에는 백금전극을 근육의 양 옆으로 평행하게 설치하였다. 근육은 DMC(Aurora Scientific) 프로그램과 Grass S48 Stimulator(Grass Instrument, Quincy, MA, USA)으로 적정 전기자극(자극 시간, 자극 빈도, 전압 등)을 주어 수축시켰다. 이때 발생하는 근력은 Dual-mode lever Arm system(Aurora scientific, inc., Ontario, Canada)을 이용하여 측정하였다. 근수축 실험 초기에 여러 번의 연축(twiches contraction)과 두 번의 강축(tetanus)을 통해 적정 근길이(optimum muscle length, Lo), 전압 그리고 자극빈도(stimulus frequency, 200Hz)를 결정하였다.
The dorsal muscle (hereinafter, muscle) was converted into Krebs buffer solution (unit (mmol / L): NaCl 118; KCl 4.75; CaCl 2 2.54; MgSO 4 1.18; NaH 2 PO 4 1.18; NaHCO 3 24.8; and glucose 10 (pH 7.4)). 5 ml muscle bath containing)) horizontally and stabilized for 5 minutes. A silk thread at one end of the muscle is connected to a 300C-LR servomotor arm (85 Hz natural frequency) (Aurora Scientific Inc., Ontario, Canada), the other end to a micrometer Maintained. The tank was injected with 95% O 2 and 5% CO 2 mixed gas for oxygen supply. The temperature of the water bath was maintained at 37 ± 0.01 o C through a TC-10 temperature controller (Dagan Corporation, Minneapolis, MN, USA). Platinum electrodes were installed in parallel to the sides of the muscle tank. Muscles contracted with the DMC (Aurora Scientific) program and the Grass S48 Stimulator (Grass Instrument, Quincy, Mass., USA) for proper electrical stimulation (stimulation time, stimulus frequency, voltage, etc.). Muscle strength was measured using a dual-mode lever arm system (Aurora scientific, inc., Ontario, Canada). On muscle contraction experiments Initial through multiple spasm (twiches contraction) and two gangchuk (tetanus) was determined fair muscle length (optimum muscle length, L o) , the voltage and frequency of stimuli (stimulus frequency, 200Hz).
(3) 셀라스트롤 효과 실험 (3) Cell trawl effect experiment
실험에 사용된 Krebs 용액은 DMSO에 녹인 셀라스트롤 농도에 따라 다음의 4종류로 준비하였다: 0.0 mM (대조군, CON), 0.1 mM, 1.0 mM 및 10 mM. 앞서 설명한대로 각 근육에 대한 적정 자극조건이 설정되면, 4 종류의 용액 중 하나를 근수조에 넣고 먼저 5분간 안정시켰다. 이후 1초간의 전기자극(수축)과 1초간의 휴식(이완)을 반복하면서 총 100초간 50회의 강축 수축작용을 일으켜 근피로를 유도하였다. 이후 수조 내 Krebs 용액을 교체해주고, 10분(600초)의 휴식(회복기)을 준 뒤 한번 전기자극(1초)을 주어 근수축을 일으켰으며, 다시 10분간 휴식을 준 뒤 동일한 자극으로 근수축을 유도하였다. 근력 데이터는 300C-LR servomotor arm를 통해 컴퓨터로 전송되고, 분석프로그램(DMA, Aurora Scientific)을 통해 근력을 분석하였으며, 근 횡단면적으로 나누어 근력 보정치를 얻었다.
Krebs solution used in the experiment was prepared in the following four kinds according to the concentration of the celllatroel dissolved in DMSO: 0.0 mM (control, CON), 0.1 mM, 1.0 mM and 10 mM. As described above, once the proper stimulation conditions for each muscle were established, one of the four solutions was placed in the water bath and allowed to stabilize for 5 minutes. After 1 second of electrical stimulation (contraction) and 1 second of relaxation (relaxation) were repeated, causing 50 contraction contractions for a total of 100 seconds to induce muscle fatigue. After replacing the Krebs solution in the tank, giving 10 minutes (600 seconds) of rest (recovery period) and then giving it an electrical stimulation (1 second) to cause muscle contraction. Induced. Muscle strength data was transferred to a computer via a 300C-LR servomotor arm and analyzed by strength analysis program (DMA, Aurora Scientific), and divided into muscle cross sections to obtain muscle strength corrections.
2. 생체 내(In vivo) 근육량 증가(muscle mass growth)2. In vivo muscle mass growth
(1) 실험 동물(1) experimental animals
4주차 Sprague-Dawley(SD) 랫트(rat)(~90g)를 앞에서 설명한 온도와 일주기 조건에서 사육하였다. 1주일간의 적응기를 거친 뒤, 하지현수(hindlimb unloading, HU), 트레드밀운동(treadmill exercise, T), 셀라스트롤(CEL) 투여량 등에 따라 다음과 같이 크게 4그룹으로 나누어 2주간의 실험에 들어갔다(도 1 참조).
① 대조군(CON 그룹): 운동이나 하지현수를 하지 않으며, DMSO만 경구투여함.① Control group (CON group): No exercise or lower extremity suspension, only DMSO orally.
② 하지현수그룹(HU 그룹) 그룹: 2주간 운동없이 하지현수를 유지하면서 DMSO 경구투여함.② Lower limb suspension group (HU group) Group: DMSO oral administration while maintaining lower limb suspension without exercise for 2 weeks.
③ (하지현수 + 트레드밀운동)군(HUT 그룹): 첫째 주는 HU 그룹과 동일하게 하며, 둘째 주는 매일 40분간 트레드밀운동을 병행하며 DMSO 경구투여함.③ (Hajisu + treadmill exercise) group (HUT group): The first week is the same as the HU group, the second week is orally administered DMSO with a treadmill exercise for 40 minutes every day.
④ (하지현수 + 트레드밀운동 + 셀라스트롤투여)군(CEL 그룹): 첫째 주는 HU와 동일하게 하며, 둘째 주는 매일 40분간 트레드밀운동과 셀라스트롤을 경구투여함. 또한, 셀라스트롤의 투여량에 따라 다시 다섯개의 소그룹으로 나눔. 이때, 셀라스트롤의 투여량은 0.5, 2, 5, 10 및 15 mg/kg body mass으로 정하여 실험하였으며, 이 중에서 가장 가장 효능이 뛰어난 양을 적정 투여량으로 정하였음.
④ (Hajisu + Treadmill Exercise + Celllas Troll Administration) Group (CEL Group): The first week is the same as HU, and the second week orally administers treadmill exercise and Celastro for 40 minutes every day. In addition, subdivided into five subgroups according to the dose of celatrol. At this time, the dose of celastrol was set to 0.5, 2, 5, 10 and 15 mg / kg body mass experiment, the most effective of these was determined as the appropriate dose.
실험시작 전에 랫트의 체중을 잰 뒤, 위와 같이 4그룹으로 무작위 분류하였다. 하지현수 그룹들(HU, HUT, CEL)은 테플론으로 코팅된 1 mm 스테인레스 고리를 랫트의 꼬리 하부 3분의 1되는 지점에 고정하였다. 고정 부위에는 소독된 면을 스트레치 테이프로 단단하게 싼 뒤 꼬리가 상하지 않도록 하였다. 외경 5.6 mm의 타이곤 튜브에 스테인레스 고리를 걸고 타이곤 튜브가 꼬리 전체를 감쌀 수 있게 한 뒤, 튜브의 반대쪽 끝을 사육장의 상부 중앙 부분의 카테터 장치에 연결하여 하지현수를 유지하였다. 이때 몸통의 각도가 지반과 약 35도로 랫트 머리를 아래로 향하도록 하체를 들어올렸다. 랫트는 앞발을 이용하여 자유롭게 사육장 내부를 돌아다닐 수 있었다. 그리고 트레드밀 운동을 위해서는 꼬리의 스테인레스 고리를 타이곤 튜브에서 분리하여 랫트를 트레드밀 위에 올려놓은 뒤 앞뒷발을 모두 이용하여 운동을 하도록 하였다.
Rats were weighed before starting the experiment and randomly divided into 4 groups as above. Lower extremity suspension groups (HU, HUT, CEL) fixed a 1 mm stainless ring coated with Teflon at the bottom third of the tail of the rat. The sterilized side was tightly wrapped with stretch tape and the tail was not damaged. A stainless ring was attached to the Tygon tube with an outer diameter of 5.6 mm to allow the Tygon tube to cover the entire tail, and then the other end of the tube was connected to the catheter device in the upper center portion of the kennel to maintain the suspension. At this time, the lower body was raised so that the torso angled the rat head down to about 35 degrees with the ground. Rats were able to roam freely inside the kennel using their paws. And for treadmill movement, the stainless ring of the tail was separated from the Tygon tube, and the rat was placed on the treadmill, and then exercised with both front and back legs.
(2) 트레드밀 운동 (2) treadmill exercise
트레드밀 운동기구(lxwxh = 430 mm x 95 mm x 165 mm)에 HUT 및 CEL 그룹 각개체(랫트)를 올려 놓은 뒤 12 m/min의 속도로 일주일 동안 매일 40분씩 운동을 시켰다. 트레드밀 내부의 온도는 실험 진행 시 20 내지 22℃ 상태로 유지하였다.
Treadmill exercise equipment ( L x W x H) = 430 mm x 95 mm x 165 mm), each individual HUT and CEL group (rat) was put into exercise for 40 minutes every day for a week at a speed of 12 m / min. The temperature inside the treadmill was maintained at 20-22 ° C. during the experiment.
(3) 근육 적출(3) muscle extraction
두번째 주 마지막 트레드밀 운동을 마친 뒤 24시간 후에 각 개체의 체중을 측정하고,펜토바비탈(50mg/kg, ip)로 마취시켰다. 그리고 두 하지의 가자미근을 적출하여 무게를 측정한 뒤, 체중당 근질량(muscle mass/body mass = Mm/Mb) 값을 얻었다. 이 Mm/Mb 값을 그룹 간 비교하여 셀라스트롤의 근발달 효과를 분석하였다.
Twenty four hours after the last treadmill exercise of the second week, each subject was weighed and anesthetized with pentobarbital (50 mg / kg, ip). The weights of the soles of the lower extremities were extracted and the weights were obtained. The muscle mass / body mass = Mm / Mb was obtained. The Mm / Mb values were compared between groups to analyze the effects of cell development on muscle development.
3. 시험관 내(in vitro) 분자 매카니즘(Molecular mechanism) 3. In vitro Molecular Mechanism
(1) 세포배양(Cell culture) (1) Cell culture
C2C12 근아세포(myoblastic cell)(American Type culture Collection)을 growth media(DMEM with 10% fetal bovine serum and 1% antibiotic-antimycotic)를 이용하여 각각 목적에 맞는 배양(culture) 용기(100 mm 배양접시(culture dishes)- 세포 직경 측정 및 프로테아좀 활성 분석(proteasome activity assay); 6 웰 플레이트(well plates)- 면역블로팅(immunoblotting))에서 증식 시켰다. 근원세포(Myoblast)가 용기 면적의 90%까지 증식되면 differentiation media(2% horse serum 및 1% antibiotic-antimycotic를 포함된 DMEM)로 갈아주어 5일간 분화를 유도하였다. 세포는 37℃, 5% CO2 인큐베이터에서 배양 되며 2일마다 새로운 배지(media)로 갈아 주었다.
C2C12 myoblastic cells (American Type culture Collection) were grown using growth media (DMEM with 10% fetal bovine serum and 1% antibiotic-antimycotic). dishes)-cell diameter measurement and proteasome activity assay; 6 well plates-immunoblotting. When myoblasts proliferated to 90% of the container area, they were changed to differentiation media (DMEM containing 2% horse serum and 1% antibiotic-antimycotic) to induce differentiation for 5 days. Cells were incubated in 37%, 5% CO 2 incubator and changed to fresh media every two days.
(2) 덱사메타손, 셀라스트롤 및 저해제 처리(2) treatment with dexamethasone, celastrol and inhibitor
5일간 분화시킨 근관세포(myotube)를 총 6개의 그룹으로 나누어 실험하였다.Myotubes differentiated for 5 days were divided into 6 groups.
① CON 그룹 - 24시간 동안 DMSO만 처리한 그룹인 vehicle control① CON group-vehicle control, which is a DMSO-treated group for 24 hours
② DEX 그룹 - 24시간 동안 150 μM의 덱사메타손(dexamethasone)을 처리한 그룹② DEX group-group treated with 150 μM of dexamethasone for 24 hours
③ CEL - 24시간 동안 DMSO를 처리하는 과정에서 마지막 6시간 동안 1.5 μM의 셀라스트롤을 처리한 그룹③ CEL-group treated with 1.5 μM of celllast during the last 6 hours of DMSO treatment for 24 hours
④ tDC - 10 μM의 tricirivine을 1시간 동안 전 처리한 후 24시간 동안 덱사메타손을 첨가하여 처리하는 과정에서 마지막 6시간 동안 셀라스트롤을 처리한 그룹④ tDC-10 μM tricirivine for 1 hour pretreatment followed by dexamethasone addition for 24 hours in the last 6 hours of treatment group
⑤ uDC - 10 μM의 u0126을 1시간 동안 전처리 한 후 24시간 동안 덱사메타손을 첨가 하여 처리하는 과정에서 마지막 6시간 동안 셀라스트롤을 처리한 그룹⑤ Pretreatment of uDC-10 μM u0126 for 1 hour, followed by dexamethasone for 24 hours
⑥ tuDC - 10 μM의 triciribine과 u0126을 1시간 동안 전처리 한 후 24시간 동안 덱사메타손을 첨가 하여 처리하는 과정에서 마지막 6시간 동안 셀라스트롤을 처리한 그룹⑥ tuDC-Cellulose treatment group for the last 6 hours during the treatment of 10 μM of triciribine and u0126 for 1 hour, followed by dexamethasone for 24 hours
각각의 처리가 끝난 세포들은 수거하여 세포직경 측정, 면역블로팅(immunoblotting) 분석에 사용되었다.
Each treated cell was harvested and used for cell diameter measurement and immunoblotting analysis.
(3) 세포 크기(3) cell size
위의 6가지 그룹에 따른 세포 크기에 대한 영향을 알아보고자 근관세포(myotube)의 직경을 측정하였다. 임의로 16개의 구획을 나누어 100 배율의 현미경으로 물질의 처리가 끝난 세포들을 촬영 하였고, 각각의 구획에서 랜덤하게 세포를 선정하여 Image J program으로 근관세포(myotube)의 직경을 측정하였다.
The diameter of myotubes was measured to determine the effect on cell size according to the above six groups. Randomly divided 16 compartments were photographed cells of the material treated under a microscope of 100 magnification, the cells were randomly selected from each compartment and the diameter of the myotubes were measured by Image J program.
(4) 면역블로팅 분석(Immunoblotting analysis)(4) Immunoblotting analysis
물질의 처리가 끝난 후 수거한 세포에 cell lysis buffer[50 mM HEPES (pH 7.4), 150 mM NaCl, 2 mM EDTA, 1% Nonidet P-40, 20 mM β-glycerophosphate, 0.2 mM Na3VO4, 50 mM NaF, protease inhibitor Complete Mini, and phosphatase inhibitor cocktail]를 첨가하고 소니케이터를 이용하여 파쇄하였다. 샘플은 5분간 아이스(ice) 상태에서 인규베이션(incubation)하고 15분 동안 13,000 rpm으로 4℃에서 원심 분리 하였다. 그 후 상층액을 취한 뒤 bradford assay 방법으로 단백질의 농도를 측정하였다.After treatment, the collected cells were treated with cell lysis buffer [50 mM HEPES (pH 7.4), 150 mM NaCl, 2 mM EDTA, 1% Nonidet P-40, 20 mM β-glycerophosphate, 0.2 mM Na 3 VO 4 , 50 mM NaF, a protease inhibitor Complete Mini, and a phosphatase inhibitor cocktail] were added and disrupted using a sonicator. Samples were incubated on ice for 5 minutes and centrifuged at 4 ° C. at 13,000 rpm for 15 minutes. Then, the supernatant was taken and the protein concentration was measured by bradford assay.
HSP72, Akt1, phospho-Akt1, ERK1/2, phospho-ERK1/2, S6K 그리고 phosphor-S6K를 분석하기 위하여 30-50 ㎍의 단백질을 8% 내지 12% SDS-PAGE gel에서 분리하였고 분리된 단백질을 nitrocellulose 막(membrane)에 옮겼다. 막(Membrane)을 5% 탈지 분유(nonfat dry milk)로 1시간 동안 상온에서 bloking 한 뒤 10 ml의 TBS/T로 5분간 3번 워싱하였다. 다음으로 각각 목적에 맞게 일차 항체(primary antibody)를 1:1,000 - 1:10,000의 비율로 희석하고 막에 첨가하여 혼합기(shaker)로 4℃에서 하룻 밤(over-night)동안 인큐베이션(incubation)하였다. TBS/T로 5분간 3번 워싱한 뒤 HRP 결합 이차 항체를 목적에 맞게 1:1,000 내지 1:20,000의 비율로 희석하여 1시간 동안 상온에서 인큐베이션(incubation)하였다. 그 후 막(membrane)을 TBS/T로 5분간 3번 워싱하고 ECL 시스템(GE Healthcare, Fairfield, CT)으로 단백질을 발광시켜 X-ray 필름(film)으로 단백질의 밴드(band)를 얻어내었다. 다른 단백질의 밴드(band)를 얻기 위하여 10ml의 stripping buffer 로 상온에서 15분간 인큐베이션(incubation) 한 후 TBS/T로 5분간 3번 워싱하였다.
To analyze HSP72, Akt1, phospho-Akt1, ERK1 / 2, phospho-ERK1 / 2, S6K and phosphor-S6K, 30-50 μg of protein was isolated from 8% to 12% SDS-PAGE gel and the isolated protein was isolated. The nitrocellulose membrane was transferred to the membrane. Membrane was bloking at room temperature for 1 hour with 5% nonfat dry milk and then washed three times for 5 minutes with 10 ml of TBS / T. Next, primary antibodies were diluted at a ratio of 1: 1,000 to 1: 10,000 for each purpose, and added to the membrane, and incubated overnight at 4 ° C with a shaker. . After washing three times with TBS / T for 5 minutes, the HRP binding secondary antibody was diluted at a ratio of 1: 1,000 to 1: 20,000 according to the purpose, and incubated at room temperature for 1 hour. The membrane was then washed three times with TBS / T for 5 minutes and the protein was luminesed with an ECL system (GE Healthcare, Fairfield, CT) to obtain a band of protein with an X-ray film. In order to obtain a band of the other protein (incubation) at room temperature for 15 minutes in 10ml stripping buffer (washing) three times for 5 minutes with TBS / T.
(5) 프로테아좀 활성 분석 (5) Proteasome Activity Assay
덱사메타손으로 인한 프로테아좀 활성의 증가를 셀라스트롤을 처리함으로써 억제 할 수 있는지 증명하기 위하여 4가지 그룹(CON, DEX, CEL and DEX+CEL)의 근관세포(myotubes)에 목적에 맞는 물질을 처리한 후 트립신(trypsin)으로 세포를 접시(dish)에서 떼어내어 differentiation meidum으로 씻어 주었다. 본 연구에서는 단백질 가수 분해 능력(proteolytic capacity)를 확인하기 위하여 프로테아좀(proteasome)의 키모트립신-유사 사이트(chymotrypsin-like site의 activity)를 측정하였다. 50 ㎕의 differentiation medium안에 약 7,500개의 세포가 존재하도록 브라이트-라인 혈구계(bright-line hemocytometer)로 측정하고 Promega Proteasome- GloTM cell-based luminescent assay kit(Promega, Madison, WI, USA)를 이용하여 키모트립신-유사 사이트(chymotrypsin-like site)의 활성을 측정하였다. 측정된 결과가 프로테아좀(proteasome) 활성에 의한 결과인지를 확인 하기 위하여 같은 수로 희석된 세포를 프로테아좀 저해제(proteasome inhibitor)인 10 μM의 epoxomicin으로 30분간 전처리 한 후 같은 방법으로 키모트립신-유사 사이트(chymotrypsin-like site)의 활성을 측정하였다. Background signal은 제외 하였으며 luminescence는 GloMax 20/20 Luminometer(Promega)를 이용하였다.
In order to demonstrate that the increase in proteasome activity caused by dexamethasone can be suppressed by treatment with Celastrol, four groups (CON, DEX, CEL and DEX + CEL) of myotubes were treated with the desired material. After the cells were removed from the dish with trypsin (trypsin) and washed with differentiation meidum. In this study, the activity of chymotrypsin-like site of proteasome was measured to confirm the proteolytic capacity. Measured with a bright-line hemocytometer to provide approximately 7,500 cells in 50 μl of differentiation medium, and the Promega Proteasome-Glo TM The activity of chymotrypsin-like site was measured using a cell-based luminescent assay kit (Promega, Madison, Wis., USA). To determine if the measured results were due to proteasome activity, cells diluted with the same number were pretreated with 10 μM epoxomicin, a proteasome inhibitor for 30 minutes, followed by chymotrypsin- The activity of the chymotrypsin-like site was measured. Background signal was excluded and luminescence was used with
<데이터 분석><Data analysis>
모든 실험 수치는 평균 +/- 표준오차로 나타내었다. 평균 값의 그룹 간 차이는 표본 수가 3 또는 그 이하인 경우 Krusak-Wallis의 비모수(non-parametric) 검증법으로 유의성을 판단하였다. 표본 수가 5보다 큰 경우 변량분석 및 Duncan의 사후비교 분석법으로 그룹 간 차이의 유의성을 판단하였다. 통계분석은 SPSS 프로그램으로 실행하였으며, 평균값 차이의 유의성은 P = 0.05를 기준으로 결정하였다.
All experimental values are expressed as mean +/- standard error. Differences between groups of mean values were determined by Krusak-Wallis' non-parametric test method when the number of samples was 3 or less. If the number of samples was larger than 5, variance analysis and Duncan's post hoc analysis were used to determine the difference between the groups. Statistical analysis was carried out by the SPSS program, and the significance of the mean difference was determined based on P = 0.05.
본 발명에서 도 1은 실시예 1에서 대조군(CON) 그룹 및 0.1, 1.0 및 10.0 mM 농도의 셀라스트롤을 사용한 세그룹(CEL)에서의 가자미근의 근력 데이터를 나타내는 그래프이다. 기준 힘은 전기 자극이 없는 시간 동안 보여지는 힘의 휴식 수준(resting level)에서 결정되며, 100-초 동안의 반복적인 수축 동안 CON 그룹의 기준 힘은 꾸준히 증가하는 것과 비교하여 CEL 그룹은 안정적인 상태를 보여준다. 또한, 근력은 100-초 동안의 반복적인 수축뿐만 아니라 700 및 1300초에서 CON에 비해 세 CEL 그룹에서 매우 크게 나타났다. In the present invention, Figure 1 is a graph showing the muscle strength data of the soleus muscle in the control group (CON) group and the three groups (CEL) using the cell, the concentration of 0.1, 1.0 and 10.0 mM in Example 1. The reference force is determined at the resting level of the force seen during the absence of electrical stimulation, and the CEL group is in a stable state compared to the steady increase in the CON group during the 100-second repetitive contraction. Shows. In addition, muscle strength was very significant in the three CEL groups compared to CON at 700 and 1300 seconds as well as repetitive contractions for 100-seconds.
상기와 같은 결과는 도 2A 및 B에 요약된다. Such results are summarized in FIGS. 2A and B.
상기 도 2는 CON 및 세 CEL 그룹에서 시간에 따른 근육 장력(tension)의 변화를 나타내는 그래프이다. FIG. 2 is a graph showing changes in muscle tension over time in CON and three CEL groups.
CON 그룹에서 기준 힘의 증가는 마이오신 교차결합이 휴식(즉, 전기 자극이 아닌 시간) 동안 액틴필라멘트로부터 분리되지 않았음을 시사하며, 또한, 이전의 교차결합에 의해 설정된 짧아진 사르코메어(근절)의 위치에서부터 다음 교차결합 사이클이 시작될 것을 시사한다. 이는 100-초 반복적인 수축 동안 ATP를 계속적으로 소비하는 근육 세포로 인해 ATP 공급의 부족으로부터 나타나는 결과와 유사한 경직 상태이다. ATP의 균형 공급은 액틴필라멘트를 따라 이동하는 마이오신 교차결합의 파워 스트로크(power strokes)의 생산뿐만 아니라, SR 막에서 Ca2 +/ATPase 펌프를 통해 세포기질(cytosol)에서 sarcomplasmic reticulum(SR)로 Ca2 +의 재흡수를 위해서도 중요하다. 상기 Ca2 +는 휴식 상태에서 근형질에서 트로포닌(troponin) C에 결합된 상태이므로, ATP의 부족은 근원섬유의 경직과 같은 상태를 유발한다. 한편, SR에서 안정화된 기준 힘은 CEL-처리 그룹에서 Ca2 +의 빠른 재흡수가 나타나므로, Ca2+/ATPase 펌프는 이들 그룹에서 충분한 ATP의 공급에 의해 잘 작용할 것으로 예측된다. Increasing the baseline force in the CON group suggests that myosin crosslinking did not separate from the actin filament during rest (ie, non-electrical stimulation), and also shortened sarcomares established by the previous crosslinking (eradication). Suggests that the next crosslinking cycle begins. This is a stiff state similar to the results resulting from a lack of ATP supply due to muscle cells continually consuming ATP during 100-second repeated contractions. Balanced supply of ATP is to sarcomplasmic reticulum (SR) in the cell substrate (cytosol) via the Ca 2 + / ATPase pump, as well as production, in the SR membranes of the power stroke (power strokes) of a cross-linked myosin moving along the actin filament it is important for the uptake of Ca + 2. The Ca + 2 because it is bound to troponin in the sarcoplasmic at rest Nin (troponin) C state, the lack of ATP, results in a state, such as the stiffness of the myofibrils. On the other hand, the reference power is stabilized in the SR because the rapid reabsorption of Ca 2 + in the shown CEL- treated group, Ca 2+ / ATPase pump is expected to work well by supplying a sufficient ATP in these groups.
도 2B는 100-초 반복적인 수축활동과 700 및 1300초에서의 활동을 통해 CON 그룹이 세 CEL 그룹에 비해 더 빠른 경련 수축을 보이는 것으로 나타났다. 이러한 근육 수측의 중요한 감소는 CON 그룹의 근육의 근형질에서 ATP 수준이 낮다는 다른 증거를 제공한다. 이는 더 나아가 흥분-수축 사이클 동안 액틴 및 마이오신 필라멘트 사이의 활주운동이 불충분하므로, 교차결합 분해를 저해하도록 이끈다. 종합하면, 이러한 데이터는 CEL 처리가 새포 내의 ATP의 안정적인 유지와 함께 격렬한 수축성 활동에서 근피로에 저항하기 위해 가지미근을 도와줬을 것으로 예상된다.
FIG. 2B shows that the CON group showed faster constriction contractions than the three CEL groups through 100-second repetitive contraction activity and activity at 700 and 1300 seconds. This significant decrease in muscle medulla provides further evidence of low ATP levels in the muscle morphology of the CON group. This further leads to a lack of glide between actin and myosin filaments during the excitation-deflation cycle, thus inhibiting crosslink degradation. Taken together, these data suggest that CEL treatment assisted the pectoral muscles to resist muscle fatigue in intense contractile activity, with stable maintenance of ATP in the vesicles.
본 발명에서 도 3은 실시예 2의 CON, HU, HTU 및 CEL 그룹에서 근육 양의 증가를 나타내는 그래프이다. 상기 도 3에서는 운동 훈련 하에서 근육 양의 증가를 촉진하는 CEL의 잠재적인 운동경기력 향상 능력을 보여주고 있다. In the present invention, Figure 3 is a graph showing the increase in muscle mass in the CON, HU, HTU and CEL group of Example 2. 3 illustrates the potential athletic performance enhancement of CEL to promote an increase in muscle mass under athletic training.
체질량과 관계된 근육 양은 HU 그룹에서 상당히 감소하지만, 트레드밀 운동을 수행한 HUT에서는 덜 감소한다. 이 비율은 셀라스트롤의 양에 의존하여 0.5 내지 10 mg/kg까지 지속적으로 증가한다. 상대적인 근육양(RMM)은 10 mg/kg에 대하여 셀라스트롤 15 mg/kg이상에서는 증가하지 않으므로, in vivo에서 10 mg/kg이 최적의 투여라는 것을 확인할 수 있다.Muscle mass associated with body mass is significantly reduced in the HU group, but less in HUT with treadmill exercise. This ratio continues to increase from 0.5 to 10 mg / kg depending on the amount of celastrol. Relative muscle mass (RMM) does not increase over 15 mg / kg of Celasprol relative to 10 mg / kg, confirming that 10 mg / kg is the optimal dose in vivo.
CON과 비교하여 RMM은 HU 그룹에서 2.7배 감소했지만, HUT(P<0.05) 그룹에서는 1.9배만 감소했다. 이는 HU 그룹에 비해 1.4배 증가한 것과 같다. 중요한 것은 CEL 그룹(10 내지 15 mg/kg)에서 RMM이 HU(P<0.05) 그룹에 비해 1.7배 증가한 것이다. 이러한 결과는 셀라스트롤이 근력 생산을 위한 운동경기력 향상 효능을 제공할 수 있는 근육 단백질의 축적을 도울 것으로 예측된다. CON/CEL 그룹의 RMM은 CON(P> 0.05)와 차이가 없으므로, 셀라스트롤의 운동경기력 향상 효과는 근육 양 증가를 유도하는 운동 훈련과 같은 기계적인 자극이 필요할 것이다. 이는, 근육 재활을 위해 활용되는 어떠한 물리적 또는 전기적 자극의 종류는 셀라스트롤의 우수한 운동 경기력 향상 효과를 위한 전제조건 일 수 있다.
Compared to CON, RMM decreased 2.7 times in HU group, but only 1.9 times in HUT (P <0.05) group. This is equivalent to a 1.4-fold increase over the HU group. Importantly, RMM in the CEL group (10-15 mg / kg) was 1.7-fold higher than the HU (P <0.05) group. These results are expected to help the accumulation of muscle proteins that can provide the ability to enhance athletic performance for muscle production. Since the RMM of the CON / CEL group was not different from CON (P> 0.05), the performance improvement of Celastroll would require mechanical stimulation such as exercise training to induce muscle mass increase. This, any kind of physical or electrical stimulation utilized for muscle rehabilitation may be a prerequisite for the excellent athletic performance improvement effect of the cell trawl.
본 발명에서 도 4는 실시예 3의 (4)에서 수행된 HSP72, Akt1-S6K 및 ERK1/2의 겔 이미지를 나타낸다. 여기서, HSP72 표현 Akt1, S6K, 및 ERK1/2의 인산화 및 비인산화 수준은 관련 항체를 가지는 그룹의 whole-cell lysates를 사용한 면역블롯 분석에 의해 결정되며, GAPDH는 단백질 밀도의 정상화를 위해 사용된다. In the present invention, Figure 4 shows a gel image of HSP72, Akt1-S6K and ERK1 / 2 performed in Example 4 (4). Here, phosphorylation and nonphosphorylation levels of HSP72 expressing Akt1, S6K, and ERK1 / 2 are determined by immunoblot analysis using whole-cell lysates of the group with the relevant antibodies, and GAPDH is used for normalization of protein density.
또한, 도 5는 C2C12 세포 직경에 대한 덱사메타손, 셀라스트롤 및 억제제의 영향을 나타내는 그래프이다.5 is also a graph showing the effect of dexamethasone, celastrol and inhibitors on C2C12 cell diameter.
도 5에 나타나듯이, 근육 세포 직경은 DEX 그룹에서 1.4 배 감소했지만, CEL 그룹(P <0.05)에서 CON 그룹과 유사하게 유지하고 있는 것을 확인할 수 있다. tDC 및 tuDC 그룹에서와 같이, 세포가 triciribine (phospho-Akt1 저해제)으로 처리되었을 때, 세포 크기는 DEX 그룹과 가깝게 줄었는데, 이는 Akt 신호전달 저해제는 세포 크기에서 CEL의 근육 강화 작용 효과를 대부분 억제하기 때문이다. As shown in FIG. 5, the muscle cell diameter was reduced 1.4 times in the DEX group, but it was confirmed that the CEL group (P <0.05) remained similar to the CON group. As in the tDC and tuDC groups, when cells were treated with triciribine (phospho-Akt1 inhibitors), the cell size decreased close to the DEX group, which inhibited most of the CEL's anabolic effects on cell size. Because.
u0126(phospho-ERK1/2 저해제)의 처리는 비록 triciribine(P <0.05)보다 덜 억제했더라도, CON 그룹과 비교하여 세포크기가 감소했다. 이것은 Akt1 경로는 CEL의 근육 강화 효과에 대한 세포 크기에서 ERK 경로 보다 더 영향력이 있음을 나타낸다.Treatment of u0126 (phospho-ERK1 / 2 inhibitor) decreased cell size compared to CON group, although less inhibited than triciribine (P <0.05). This indicates that the Akt1 pathway is more influential than the ERK pathway in cell size on the anabolic effects of CEL.
또한, 도 6은 C2C12 마우스 세포에 처리된 덱사메타손, 셀라스트롤 및 저해제에 의한 HSP72에서의 변화를 나타내는 그래프이다.6 is a graph showing changes in HSP72 by dexamethasone, celastrol and inhibitors treated in C2C12 mouse cells.
근육 양은 단백질 합성 속도 및 열화 속도 사이의 균형의 결과로 설명할 수 있다. 셀라스트롤 처리는 C2C12 근육 세포에서 HSP72을 상향조절 시키는 것을 알려져 있다. 셀라스트롤 처리는 또한, 근육 세포를 대조군과 유사한 직경으로 유지하도록 이끌지만, 덱사메타손 처리시 근육 세포는 직경이 감소한다. 구체적으로, 도 6을 통해 HSP72의 표현 수준이 덱사메타손에 의해 영향을 받지 않는 반면에, 셀라스트롤에 의해 3.6배 증가한다는 것을 확인할 수 있다. 세포가 triciribine 또는 u0126로 처리될 때, HSP 표현은 CON 그룹과 비교하여 tDC 그룹에서 2.3 배, uCD 그룹에서 3.0배 여전히 증가한다. 그러나, 두 억제제를 함께 처리했을 때(tuDC), HSP 수준은 CON(P> 0.05) 수준으로 감소한다. 이러한 결과는 HSP 표현에서 저해제 하나로는 셀라스트롤의 효과를 충분히 억제하지 못하며, 두 억제제를 함께 사용했을 때 거의 완벽하게 억제되는 것을 확인할 수 있다. 즉, Akt 신호는 HSP 표현에서 ERK 경로보다 더 큰 영향력을 가지지만, HSP72의 셀라스트롤-매개 상향 조절은 Akt 및 ERK1/2 경로의 활성화에 의해 달성될 수 있다. 두 경로의 활성화에 의한 HSP 상향조절의 범위가 어느 경로의 활성화에 의한 것보다 더 크므로, 두 경로의 효과는 CEL-매개 HSP 상향조절에서 더 많거나 적게 부가될 것으로 예측된다. Muscle volume can be explained as a result of the balance between the rate of protein synthesis and the rate of degradation. Cellular troll treatment is known to upregulate HSP72 in C2C12 muscle cells. Celllastrol treatment also leads to maintaining the muscle cells to a diameter similar to the control, but with dexamethasone treatment the muscle cells decrease in diameter. Specifically, it can be seen from FIG. 6 that the expression level of HSP72 is not affected by dexamethasone, but is increased 3.6-fold by celastrol. When cells are treated with triciribine or u0126, HSP expression is still increased 2.3-fold in the tDC group and 3.0-fold in the uCD group compared to the CON group. However, when treated with both inhibitors (tuDC), HSP levels decrease to CON (P> 0.05) levels. These results indicate that an inhibitor in HSP expression alone does not sufficiently inhibit the effects of celastrol and is almost completely inhibited when the two inhibitors are used together. That is, Akt signaling has a greater influence than the ERK pathway in HSP expression, but the celllast-mediated upregulation of HSP72 can be achieved by activation of the Akt and ERK1 / 2 pathways. Since the extent of HSP upregulation by activation of both pathways is greater than that by activation of either pathway, the effects of both pathways are expected to add more or less in CEL-mediated HSP upregulation.
셀라스트롤 처리는 p-Akt1/Akt1, p-S6K/S6K, 및 p-ERK/ERK의 중요한 증가에서 보여지듯이 단백질 합성 및 세포 생존에 관련한 신호전달 분자를 활성화하는 것을 보여준다. 한편, 덱사메타손 처리는 영향을 미치지 않고, 이들 분자의 활동을 억압하지 않는다. triciribine은 tDC 및 tuDC 그룹에서 보여지듯이 Akt1 및 그들 후속(drownstream) S6K활성을 거의 차단하나, tDC 그룹에 있어서 셀라스트롤에 의해 상향 조절된 ERK1/2의 활성화에는 영향을 미치지 않았다. ERK 억제제 u0126은 uDC 및 tuDC 그룹에 있어서 ERK 1/2의 활성을 완전히 지연시키지만, tDC에 있어서 Akt1 및 S6K의 활성화는 셀라스트롤의 효과에 의해 상향조절되어 유지된다.
Celllastrol treatment has been shown to activate signaling molecules related to protein synthesis and cell survival, as shown by significant increases in p-Akt1 / Akt1, p-S6K / S6K, and p-ERK / ERK. Dexamethasone treatment, on the other hand, has no effect and does not suppress the activity of these molecules. Tritricibine almost blocked Akt1 and their downstream S6K activity, as seen in the tDC and tuDC groups, but did not affect the activation of ERK1 / 2 up-regulated by celatrol in the tDC group. The ERK inhibitor u0126 completely delays the activity of
또한, 도 7은 C2C12에서 26S 프로테아좀의 키모트립신 유사 활성에 대한 덱사메타손 및 셀라스트롤의 영향을 나타내는 그래프이다. 7 is a graph showing the effect of dexamethasone and celastrol on chymotrypsin-like activity of 26S proteasome at C2C12.
근육 단백질 저하와 관련하여, 프로테아좀관련 시스템은 손상되거나 불필요한 단백질이 키모트립신 유사 활성과 같은 효소 활성에 의해 완전히 저하되는 최종 장소(site)이다. 도 7은 CON 그룹과 비교하여, 프로테아좀 활성(P <0.05)에서 DEX 그룹의 자극이 6.0배 증가한다는 것을 보여준다. 그러나, 셀라스트롤이 데사메타손과 별도 또는 함께 처리되었을 때, 프로테아좀 활성은 CON 그룹과 유사한 수준에서 유지된다. 이 결과는 CEL이 적극적인 주요 단백질 분해 시스템에 의해 분해 활동을 줄일 수 있음을 시사한다.
With regard to muscle protein degradation, proteasome-related systems are the final sites where damaged or unnecessary proteins are completely degraded by enzymatic activity, such as chymotrypsin-like activity. Figure 7 shows a 6.0-fold increase in stimulation of the DEX group in proteasome activity (P <0.05) compared to the CON group. However, when celastrol was treated separately or in combination with desamethason, proteasome activity is maintained at a similar level to the CON group. This result suggests that CEL can reduce degradation activity by an active major proteolytic system.
Claims (8)
Food composition for muscle fatigue resistance or muscle mass increase containing celastrol as an active ingredient.
음료 또는 음료첨가제인 근피로 저항 또는 근질량 증가용 식품 조성물.
5. The method of claim 4,
Food composition for muscle fatigue resistance or muscle mass increase which is a beverage or a beverage additive.
음료 또는 음료첨가제는 스포츠 음료 또는 이의 음료첨가제인 근피로 저항 또는 근질량 증가용 식품 조성물.
The method of claim 5, wherein
The beverage or beverage additive is a sports beverage or a beverage additive thereof, the composition for muscle fatigue resistance or muscle mass increase.
식품학적으로 허용 가능한 식품보조첨가제를 추가로 포함하는 근피로 저항 또는 근질량 증가용 식품 조성물.
5. The method of claim 4,
A food composition for muscle fatigue resistance or muscle mass increase, further comprising a food acceptable food additive.
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| US20080317886A1 (en) | 2005-11-03 | 2008-12-25 | Sparkman Dennis R | Compositions for Preventing and Reducing Delayed Onset Muscle Soreness |
| WO2010062658A1 (en) | 2008-10-28 | 2010-06-03 | Pablo Kizelsztein | Compositions and methods of treating demyelinating central nervous system diseases |
| KR101086642B1 (en) | 2009-02-27 | 2011-11-24 | 강원대학교산학협력단 | A composition having an effect of curing and preventing allergy disease by containing Celastrol |
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| US20080220084A1 (en) | 2007-03-09 | 2008-09-11 | Pfantastic Medical Research Institute, Llc | Combination therapy for alleviating pain-related conditions |
| WO2010062658A1 (en) | 2008-10-28 | 2010-06-03 | Pablo Kizelsztein | Compositions and methods of treating demyelinating central nervous system diseases |
| KR101086642B1 (en) | 2009-02-27 | 2011-11-24 | 강원대학교산학협력단 | A composition having an effect of curing and preventing allergy disease by containing Celastrol |
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