TWI556822B - Use of compound extracted from raw polygonum multiflorum thunb. as ghrelin receptor agonist - Google Patents

Description

生何首烏萃取化合物做為飢餓素受體促效劑之應用 Application of Polygonum multiflorum extract compound as ghrelin receptor agonist

本發明係關於生何首烏萃取化合物做為飢餓素受體促效劑之應用。更特別地，本發明係關於生何首烏所含的特殊成分：大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷(命名為”Emoghrelin”)透過活化飢餓素受體而刺激生長激素分泌上升的用途。 The present invention relates to the use of a raw extract of Polygonum multiflorum as a ghrelin receptor agonist. More particularly, the present invention relates to a special component contained in Polygonum multiflorum: emodin-8- O- (6'- O -propionyl)-glucoside (designated "Emoghrelin") is activated by sensitizing ghrelin The use of body to stimulate the growth of growth hormone secretion.

人類生長激素的分泌會隨著年齡的增長而逐漸減少(Thorner and Nass,2007：[Thorner,M.O.,Nass,R.,2007.Human studies of growth hormone and aging.Pediatric Endocrinology Reviews 4,233-234.]；Ghigo et al.,1996：[Ghigo,E.,Arvat,E.,Gianotti,L.,Ramunni,J.,DiVito,L.,Maccagno,B.,Grottoli,S.,Camanni,F.,1996.Human aging and the GH-IGF-I axis.Journal of Pediatric Endocrinology & Metabolism 9,271-278.])，而生長激素分泌的減少目前認為與老年人常見的代謝與生理疾病的發生有重要的關連性，例如引發倦怠感、增加脂肪組織、心血管疾病的發生、學習認知能力與睡眠品質的降低等等(Aleman et al.,2000：[Aleman,A.,de Vries,W.R.,de Haan,E.H.,Verhaar,H.J.,Samson,M.M.,Koppeschaar,H.P.,2000.Age-sensitive cognitive function,growth hormone and insulin-like growth factor 1 plasma levels in healthy older men.Neuropsychobiology 41,73-78.]；Janssen et al.,2000：[Janssen,I.,Heymsfield,S.B.,Wang,Z.M.,Ross,R.,2000.Skeletal muscle mass and distribution in 468 men and women aged 18-88 yr.Journal of Applied Physiology 89,81-88.]；Sartorio et al.,1996：[Sartorio,A.,Conti,A.,Molinari,E.,Riva,G.,Morabito,F.,Faglia,G.,1996.Growth,growth hormone and cognitive functions.Hormone Research 45,23-29.]；Sattler,2013：[Sattler,F.R.,2013.Growth hormone in the aging male.Best Practice & Research.Clinical Endocrinology & Metabolism 27,541-555.]；Van Cauter et al.,2000：[Van Cauter,E.,Leproult,R.,Plat,L.,2000.Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men.Journal of the American Medical Association 284,861-868.])。目前對於老年人生長激素分泌減少的原因與機制並未完全瞭解，因此，透過刺激生長激素分泌以治療老化相關的疾病的醫療策略，目前仍在研究與開發測試當中。 The secretion of human growth hormone gradually decreases with age (Thorner and Nass, 2007: [Thorner, MO, Nass, R., 2007. Human studies of growth hormone and aging. Pediatric Endocrinology Reviews 4, 233-234.]; Ghigo et al., 1996: [Ghigo, E., Arvat, E., Gianotti, L., Ramunni, J., DiVito, L., Maccagno, B., Grottoli, S., Camanni, F., 1996. Human aging and the GH-IGF-I axis. Journal of Pediatric Endocrinology & Metabolism 9,271-278.]), and the reduction of growth hormone secretion is currently considered to be importantly related to the occurrence of metabolic and physiological diseases common in the elderly, such as Initiation of burnout, increased adipose tissue, cardiovascular disease, cognitive decline in learning and sleep quality, etc. (Aleman et al., 2000: [Aleman, A., de Vries, WR, de Haan, EH, Verhaar, HJ, Samson, MM, Koppeschaar, HP, 2000. Age-sensitive cognitive function, growth hormone and insulin-like growth factor 1 plasma levels in healthy older men. Neuropsychobiology 41, 73-78.]; Janssen et al., 2000: [Janssen, I., Heymsfield, SB, Wang, ZM, Ross, R., 2000. Skeletal muscle mass And distribution in 468 men and women aged 18-88 yr. Journal of Applied Physiology 89,81-88.]; Sartorio et al., 1996: [Sartorio, A., Conti, A., Molinari, E., Riva, G., Morabito, F., Faglia, G., 1996. Growth, growth hormone and cognitive functions. Hormone Research 45, 23-29.]; Sattler, 2013: [Sattler, FR, 2013. Growth hormone in the aging male .Best Practice & Research. Clinical Endocrinology & Metabolism 27, 541-555.]; Van Cauter et al., 2000: [Van Cauter, E., Leproult, R., Plat, L., 2000. Age-related changes in slow Wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. Journal of the American Medical Association 284, 861-868. At present, the causes and mechanisms for the reduction of growth hormone secretion in the elderly are not fully understood. Therefore, medical strategies for treating aging-related diseases by stimulating growth hormone secretion are still under research and development tests.

飢餓素(Ghrelin)是一段由28個胺基酸所組成的多胜肽激素，主要是在胃底基部的X/A樣細胞(X/A like cell)所分泌(Kojima等人，1999：[Kojima,M.；Hosoda,H.；Date,Y.；Nakazato,M.；Matsuo,H.；Kangawa,K.,Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature.1999,402,656-660]；Sakata等人，2002：[Sakata,I.；Nakamura,K.；Yamazaki,M.；Matsubara,M.；Hayashi,Y.；Kangawa,K.；Sakai,T.,Ghrelin-producing cells exist as two types of cells,closed-and opened-type cells,in the rat gastrointestinal tract.Peptides. 2002,23,531-6.])。其中第三個胺基酸serine有醯化的修飾(n-octanoylated modification)，而此轉譯後的修飾被認為是飢餓素具有生物活性的主要原因(Bednarek等人，2000：[Bednarek,M.A.,S.D.Feighner,et al.(2000)."Structure-function studies on the new growth hormone-releasing peptide,ghrelin：minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a." J Med Chem 43(23)：4370-4376.])。飢餓素被鑑定為一種G蛋白聯偶受體(G protein-couple receptor；GPCR)：生長激素分泌受體(Growth hormone secretagogue-1a receptor；GHSR)的配體(Howard等人，1996：[Howard,A.D.；Feighner,S.D.；Cully,D.F.；Arena,J.P.；Liberator,P.A.；Rosenblum,C.I.；Hamelin,M.；Hreniuk,D.L.；Palyha,O.C.；Anderson,J.；Paress,P.S.；Diaz,C.；Chou,M.；Liu,K.K.；McKee,K.K.；Pong,S.S.；Chaung,L.Y.；Elbrecht,A.；Dashkevicz,M.；Heavens,R.；Rigby,M.；Sirinathsinghji,D.J.S.；Dean,D.C.；Melillo,D.G.；Patchett,A.A.；Nargund,R.；Griffin,P.R.；DeMartino,J.A.；Gupta,S.K.；Schaeffer,J.M.；Smith,R.G.；VanderPloeg,L.H.T.,A receptor in pituitary and hypothalamus that functions in growth hormone release.Science.1996,273,974-7.]；Kojima等人，1999：[Kojima,M.；Hosoda,H.；Date,Y.；Nakazato,M.；Matsuo,H.；Kangawa,K.,Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature.1999,402,656-660.])。此受體主要分布在下視丘與腦下垂體(Zigman 等人，2006：[Zigman,J.M.；Jones,J.E.；Lee,C.E.；Saper,C.B.；Elmquist,J.K.,Expression of ghrelin receptor mRNA in the rat and the mouse brain.J.Comp.Neurol. 2006,494,528-48.])。生長激素分泌受體被飢餓素活化後，主要經由下視丘增加食慾以及刺激腦下垂體前葉釋放生長激素等生理作用(Castaneda等人，2010：[Castaneda,T.R.；Tong,J.；Datta,R.；Culler,M.；Tschop,M.H.,Ghrelin in the regulation of body weight and metabolism.Front.Neuroendocrinol.2010,31,44-60.]；Kojima與Kangawa,2008：[Kojima,M.；Kangawa,K.,Structure and function of ghrelin.Results.Probl.Cell.Differ. 2008,46,89-115.])，除此之外，飢餓素對於體內代謝、能量平衡與腸胃功能也具有調節的功能(Broglio等人，2003：[Broglio,F.；Gottero,C.；Benso,A.；Prodam,F.；Destefanis,S.；Gauna,C.；Maccario,M.；Deghenghi,R.；van der Lely,A.J.；Ghigo,E.,Effects of ghrelin on the insulin and glycemic responses to glucose,arginine,or free fatty acids load in humans.J.Clin.Endocrinol.Metab. 2003,88,4268-72.]；Ghigo等人，2005：[Ghigo,E.；Broglio,F.；Arvat,E.；Maccario,M.；Papotti,M.；Muccioli,G.,Ghrelin：more than a natural GH secretagogue and/or an orexigenic factor.Clin.Endocrinol.(Oxf) 2005,62,1-17.]；Kojima與Kangawa,2005：[Kojima,M.；Kangawa,K.,Ghrelin：structure and function.Physiol.Rev. 2005,85,495-522.])。 Ghrelin is a multi-peptide hormone consisting of 28 amino acids, mainly secreted by X/A like cells at the base of the stomach (Kojima et al., 1999: [ Kojima, M.; Hosoda, H.; Date, Y.; Nakazato, M.; Matsuo, H.; Kangawa, K., Ghrelin is a growth-hormone-releasing acifying peptide from stomach. Nature . 1999 , 402 ,656 -660]; Sakata et al., 2002: [Sakata, I.; Nakamura, K.; Yamazaki, M.; Matsubara, M.; Hayashi, Y.; Kangawa, K.; Sakai, T., Ghrelin-producing cells Exist as two types of cells, closed-and opened-type cells, in the rat gastrointestinal tract. Peptides. 2002 , 23 , 531-6.]). The third amino acid serine has an n- octanoylated modification, and this post-translational modification is considered to be the main reason for the biological activity of ghrelin (Bednarek et al., 2000: [Bednarek, MA, SDFeighner , et al. (2000). "Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a." J Med Chem 43 (23): 4370-4376 .]). Gourin is identified as a G protein-couple receptor (GPCR): a ligand for the growth hormone secretagogue-1a receptor (GHSR) (Howard et al., 1996: [Howard, AD;Feighner,SD;Cully,DF;Arena,JP;Liberator,PA;Rosenblum,CI;Hamelin,M.;Hreniuk,DL;Palyha,OC;Anderson,J.;Paress,PS;Diaz,C.;Chou ,M.;Liu,KK;McKee,KK;Pong,SS;Chaung,LY;Elbrecht,A.;Dashkevicz,M.;Heavens,R.;Rigby,M.;Sirinathsinghji,DJS;Dean,DC;Melillo, DG; Patchett, AA; Nargund, R;. Griffin, PR; DeMartino, JA; Gupta, SK; Schaeffer, JM; Smith, RG;. VanderPloeg, LHT, A receptor in pituitary and hypothalamus that functions in growth hormone release Science. 1996 , 273 , 974-7.]; Kojima et al., 1999: [Kojima, M.; Hosoda, H.; Date, Y.; Nakazato, M.; Matsuo, H.; Kangawa, K., Ghrelin is a Growth-hormone-releasing acifying peptide from stomach. Nature . 1999 , 402 , 656-660.]). This receptor is mainly distributed in the inferior colliculus and pituitary gland (Zigman et al., 2006: [Zigman, JM; Jones, JE; Lee, CE; Saper, CB; Elmquist, JK, Expression of ghrelin receptor mRNA in the rat and the Mouse brain. J.Comp.Neurol. 2006 , 494 , 528-48.]). After the growth hormone secretion receptor is activated by ghrelin, it mainly increases appetite through the hypothalamus and stimulates the release of growth hormone and other physiological effects in the anterior pituitary gland (Castaneda et al., 2010: [Castaneda, TR; Tong, J.; Datta, R .;Culler,M.;Tschop,MH,Ghrelin in the regulation of body weight and metabolism. Front.Neuroendocrinol . 2010 , 31 ,44-60.];Kojima and Kangawa,2008:[Kojima,M.;Kangawa,K ., Structure and function of ghrelin. Results.Probl.Cell.Differ. 2008, 46, 89-115.]), except for the ghrelin metabolism, energy balance and also having gastrointestinal function adjustment function (Broglio Et al., 2003: [Broglio, F.; Gottero, C.; Benso, A.; Prodam, F.; Destefanis, S.; Gauna, C.; Maccario, M.; Deghenghi, R.; van der Lely, AJ; Ghigo, E., Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans. J. Clin. Endocrinol. Metab. 2003 , 88 , 4268-72.]; Ghigo et al. , 2005: [Ghigo, E.; Broglio, F.; Arvat, E.; Maccario, M.; Papotti, M.; Muccioli, G., Ghrelin: more than a natu Ral GH secretagogue and/or an orexigenic factor. Clin . Endocrinol. (Oxf) 2005 , 62 , 1-17.]; Kojima and Kangawa, 2005: [Kojima, M.; Kangawa, K., Ghrelin: structure and function. Physiol. Rev. 2005 , 85 , 495-522.]).

許多研究指出，在老化的人類與動物模式中，投予飢餓素與其口服合成衍生物之後發現能刺激食慾、增加生長激素分泌的脈衝、減少脂肪組織與提高骨質轉換率(Murphy et al.,1999：[Murphy,M.G.,Bach,M.A.,Plotkin,D.,Bolognese,J.,Ng,J.,Krupa,D.,Cerchio,K.,Gertz,B.J.,1999.Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults.The MK-677 Study Group.Journal of Bone and Mineral Research 14,1182-1188.]；Nass et al.,2008：[Nass,R.,Pezzoli,S.S.,Oliveri,M.C.,Patrie,J.T.,Harrell,F.E.,Jr.,Clasey,J.L.,Heymsfield,S.B.,Bach,M.A.,Vance,M.L.,Thorner,M.O.,2008.Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults：A randomized trial.Annals of Internal Medicine 149,601-611.]；Toshinai et al.,2007：[Toshinai,K.,Mondal,M.S.,Shimbara,T.,Yamaguchi,H.,Date,Y.,Kangawa,K.,Nakazato,M.,2007.Ghrelin stimulates growth hormone secretion and food intake in aged rats. Mechanisms of Ageing and Development 128,182-186.]；White et al.,2009：[White,H.K.,Petrie,C.D.,Landschulz,W.,MacLean,D.,Taylor,A.,Lyles,K.,Wei,J.Y.,Hoffman,A.R.,Salvatori,R.,Ettinger,M.P.,Morey,M.C.,Blackman,M.R.,Merriam,G.R.,Capromorelin Study,G.,2009.Effects of an oral growth hormone secretagogue in older adults.The Journal of Clinical Endocrinology and Metabolism 94,1198-1206.])；此外，飢餓素促效劑也被發現具有改善心血管疾病與學習認知的能力(Atcha et al.,2009：[Atcha,Z.,Chen,W.S.,Ong,A.B.,Wong,F.K.,Neo,A.,Browne,E.R.,Witherington,J.,Pemberton,D.J.,2009.Cognitive enhancing effects of ghrelin receptor agonists.Psychopharmacology(Berl).206,415-427.]；Li et al.,2006：[Li,L.,Zhang,L.K.,Pang,Y.Z.,Pan,C.S.,Qi,Y.F.,Chen,L.,Wang,X.,Tang,C.S.,Zhang,J.,2006.Cardioprotective effects of ghrelin and des-octanoyl ghrelin on myocardial injury induced by isoproterenol in rats.Acta Pharmacologica Sinica 27,527-535.])。 Many studies have indicated that in aging human and animal models, administration of ghrelin and its oral synthetic derivatives has been found to stimulate appetite, increase growth hormone secretion, reduce adipose tissue and increase bone turnover (Murphy et al., 1999). : [Murphy, MG, Bach, MA, Plotkin, D., Bolognese, J., Ng, J., Krupa, D., Cerchio, K., Gertz, BJ, 1999. Oral administration of the growth hormone secretagogue MK- 677 increases markers of bone turnover in healthy and functionally impaired elderly adults. The MK-677 Study Group. Journal of Bone and Mineral Research 14, 1182-1188.]; Nass et al., 2008: [Nass, R., Pezzoli, SS,Oliveri,MC,Patrie,JT,Harrell,FE,Jr.,Clasey,JL,Heymsfield,SB,Bach,MA,Vance,ML,Thorner,MO,2008.Effects of an oral ghrelin mimetic on body composition and clinical Outcomes in healthy older adults: A randomized trial. Annals of Internal Medicine 149,601-611.]; Toshinai et al., 2007: [Toshinai, K., Mondal, MS, Shimbara, T., Yamaguchi, H., Date, Y .Kangawa, K., Nakazato, M., 2007. Ghrelin stimulates growth ho Rmone secretion and food intake in aged rats. Mechanisms of Ageing and Development 128, 182-186.]; White et al., 2009: [White, HK, Petrie, CD, Landschulz, W., MacLean, D., Taylor, A., Lyles, K., Wei, JY ,Hoffman,AR,Salvatori,R.,Ettinger,MP,Morey,MC,Blackman,MR,Merriam,GR,Capromorelin Study,G.,2009.Effects of an oral growth hormone secretagogue in older adults.The Journal of Clinical Endocrinology And Metabolism 94, 1198-1206.]); In addition, ghrelin agonists have also been found to improve cardiovascular disease and cognitive ability (Atcha et al., 2009: [Atcha, Z., Chen, WS, Ong , AB, Wong, FK, Neo, A., Browne, ER, Witherington, J., Pemberton, DJ, 2009. Cognitive enhancing effects of ghrelin receptor agonists. Psychopharmacology (Berl). 206, 415-427.]; Li et al. , 2006: [Li, L., Zhang, LK, Pang, YZ, Pan, CS, Qi, YF, Chen, L., Wang, X., Tang, CS, Zhang, J., 2006. Cardioprotective effects of ghrelin And des-octanoyl ghrelin on myocardial injury induced by isoproterenol in rats. Acta Pharmacologica Sinica 27, 527-535.]).

目前醫學研究認為直接注射生長激素所引起的許多副作用(例如水腫、關節疼痛、腕隧道症候群與胰島素阻抗等症狀)，很有可能是因為直接改變人體生長激素分泌的頻率所導致(Ionescu and Frohman,2006：[Ionescu,M.,Frohman,L.A.,2006.Pulsatile secretion of growth hormone(GH)persists during continuous stimulation by CJC-1295,a long-acting GH-releasing hormone analog.The Journal of Clinical Endocrinology and Metabolism 91,4792-4797.]；Liu et al.,2007：[Liu,H.,Bravata,D.M.,Olkin,I.,Nayak,S.,Roberts,B.,Garber,A.M.,Hoffman,A.R.,2007.Systematic review：The safety and efficacy of growth hormone in the healthy elderly.Annals of Internal Medicine 146,104-115.])；然而，臨床研究顯示，透過活化飢餓素受體只會刺激生長激素分泌的脈衝，並不會改變其分泌的頻率，同時副作用的發生也輕微許多(Nass et al.,2008：[Nass,R.,Pezzoli,S.S.,Oliveri,M.C.,Patrie,J.T.,Harrell,F.E.,Jr.,Clasey,J.L.,Heymsfield,S.B.,Bach,M.A.,Vance,M.L.,Thorner,M.O.,2008.Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults：A randomized trial.Annals of Internal Medicine 149,601-611.]；White et al.,2009：[White,H.K.,Petrie,C.D.,Landschulz,W.,MacLean,D.,Taylor,A.,Lyles,K.,Wei,J.Y.,Hoffman,A.R.,Salvatori,R.,Ettinger,M.P.,Morey,M.C.,Blackman,M.R.,Merriam,G.R.,Capromorelin Study,G.,2009. Effects of an oral growth hormone secretagogue in older adults.The Journal of Clinical Endocrinology and Metabolism 94,1198-1206.])。因此，透過飢餓素受器活化的機制治療老化的相關疾病，目前被認為是十分具有潛力的治療模式。依據文獻報導，目前合成的飢餓素受體促效劑口服藥物仍有引發輕微水腫、肌肉疼痛、血糖增加、嘔吐與腹瀉的風險，在市面上也尚未出現適合用於臨床治療的飢餓素受體促效劑。 Current medical research suggests that many side effects (such as edema, joint pain, carpal tunnel syndrome, and insulin resistance) caused by direct injection of growth hormone are most likely due to the frequency of direct changes in human growth hormone secretion (Ionescu and Frohman, 2006: [Ionescu, M., Frohman, LA, 2006. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. The Journal of Clinical Endocrinology and Metabolism 91, 4792-4797.]; Liu et al., 2007: [Liu, H., Bravata, DM, Olkin, I., Nayak, S., Roberts, B., Garber, AM, Hoffman, AR, 2007. Systematic review :The safety and efficacy of growth hormone in the healthy elderly.Annals of Internal Medicine 146,104-115.]); however, clinical studies have shown that the activation of ghrelin receptors only stimulates the pulse of growth hormone secretion and does not change its The frequency of secretion, while the occurrence of side effects is also slightly more (Nass et al., 2008: [Nass, R., Pezzoli, SS, Oliveri, MC, Patrie, JT, Harrell, FE, Jr., Clasey, JL, Heymsfield , SB, Bach, MA, Vance, ML, Thorner, MO, 2008. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: A randomized trial. Annals of Internal Medicine 149,601-611.]; White et Al., 2009: [White, HK, Petrie, CD, Landschulz, W., MacLean, D., Taylor, A., Lyles, K., Wei, JY, Hoffman, AR, Salvatori, R., Ettinger, MP , Morey, MC, Blackman, MR, Merriam, GR, Capromorelin Study, G., 2009. Effects of an oral growth hormone secretagogue in older adults. The Journal of Clinical Endocrinology and Metabolism 94, 1198-1206.]). Therefore, the treatment of aging-related diseases through the mechanism of hunger receptor activation is currently considered to be a very promising treatment model. According to the literature, the current synthetic ghrelin receptor agonist oral drugs still cause mild edema, muscle pain, increased blood sugar, vomiting and diarrhea, and there is no ghrelin receptor suitable for clinical treatment in the market. An agonist.

何首烏為蓼科植物何首烏的塊根，為用於抗衰老的常見中草藥。許多研究也發現，何首烏的萃取物能改善高膽固醇血症、心血管疾病、認知能力降低等老化相關疾病(Chan et al.,2002：[Chan,Y.C.,Cheng,F.C.,Wang,M.F.,2002.Beneficial effects of different Polygonum multiflorum Thunb.extracts on memory and hippocampus morphology.Journal of Nutritional Science and Vitaminology(Tokyo).48,491-497.]；Chan et al.,2003：[Chan,Y.C.,Wang,M.F.,Chang,H.C.,2003.Polygonum multiflorum extracts improve cognitive performance in senescence accelerated mice.The American Journal of Chinese Medicine 31,171-179.]；Xiao et al.,1993：[Xiao,P.G.,Xing,S.T.,Wang,L.W.,1993.Immunological Aspects of Chinese Medicinal-Plants as Antiaging Drugs.Journal of Ethnopharmacology 38,167-175.]；Yim et al.,1998：[Yim,T.K.,Wu,W.K.,Mak,D.H.,Ko,K.M.,1998.Myocardial protective effect of an anthraquinone-containing extract of Polygonum multiflorum ex vivo.Planta Medica 64,607-611.])。而這些療效與飢餓素刺激生長激素分泌所產生的抗老化功效十分相似，因此本發明首先推測，生何首烏抗老化與延年益壽的功效，很有可能透過活化飢餓素受體的路徑所調控。 Polygonum multiflorum is the root of Polygonum multiflorum, a common Chinese herbal medicine used for anti-aging. Many studies have also found that extracts of Polygonum multiflorum can improve aging-related diseases such as hypercholesterolemia, cardiovascular disease, and cognitive decline (Chan et al., 2002: [Chan, YC, Cheng, FC, Wang, MF, 2002. Beneficial effects of different Polygonum multiflorum Thunb.extracts on memory and hippocampus morphology. Journal of Nutritional Science and Vitaminology (Tokyo). 48, 491-497.]; Chan et al., 2003: [Chan, YC, Wang, MF, Chang, HC 2003. Polygonum multiflorum extracts improve cognitive performance in senescence accelerated mice. The American Journal of Chinese Medicine 31, 171-179.]; Xiao et al., 1993: [Xiao, PG, Xing, ST, Wang, LW, 1993. Immunological Aspects Of Chinese Medicinal-Plants as Antiaging Drugs. Journal of Ethnopharmacology 38, 167-175.]; Yim et al., 1998: [Yim, TK, Wu, WK, Mak, DH, Ko, KM, 1998. Myocardial protective effect of an anthraquinone -containing extract of Polygonum multiflorum ex vivo. Planta Medica 64, 607-611.]). These effects are very similar to the anti-aging effects produced by ghrelin-stimulated growth hormone secretion. Therefore, the present invention first speculates that the anti-aging and longevity effects of Polygonum multiflorum are likely to be regulated by the pathway of activation of the ghrelin receptor.

本發明基於以上之目的及發現，利用液相層析質譜儀(LC-MS)分析與鑑定生何首烏中所含成分(圖1)，並且比對其他文獻之質譜分析結果以確認各化合物之身分。其中6號化合物即為生何首烏所含的特殊成分大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷，於本發明將其命名為”Emoghrelin”。吾等認為這個特有的化合物很有可能是生何首烏抗老化的主要 活性成分。 Based on the above objects and findings, the present invention analyzes and identifies components contained in Polygonum multiflorum by liquid chromatography mass spectrometry (LC-MS) (Fig. 1), and compares the results of mass spectrometry analysis of other literatures to confirm the identity of each compound. . Among them, the compound No. 6 is the special component emodin-8- O- (6'- O -propanediyl)-glucoside contained in Polygonum multiflorum, and is named "Emoghrelin" in the present invention. We believe that this unique compound is likely to be the main active ingredient in the anti-aging of Polygonum multiflorum.

於是，本發明之一方面係關於，一種大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷作為一種飢餓素受體促效劑之用途。於本發明之具體實施態樣，所述之大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷係純化自生何首烏(Polygonum multiflorum Thunb.)，命名為emoghrelin(參首烏激素)。 Thus, one aspect of the invention relates to the use of an emodin-8- O- (6'- O -propanedithio)-glucoside as a ghrelin receptor agonist. In a specific embodiment of the present invention, the emodin-8- O- (6'- O -propionyl)-glucoside is purified from Polygonum multiflorum Thunb., and is named emoghrelin. Shouwu hormone).

本發明之另一方面，係關於一種用於活化飢餓素受體之組合物，其包含大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷作為飢餓素受體促效劑。於本發明之一些具體實施態樣，所述之組合物係用於刺激生長激素分泌。 Another aspect of the invention relates to a composition for activating a ghrelin receptor comprising emodin-8- O- (6'- O -propanedithio)-glucoside as a ghrelin receptor An agonist. In some embodiments of the invention, the composition is for stimulating growth hormone secretion.

本發明之另一方面，係關於一種用於抗老化之組合物，其包含大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷作為飢餓素受體促效劑。於本發明之一些具體實施態樣，所述之組合物係用於預防及/或治療因生長激素分泌降低所引起的老化相關疾病。 Another aspect of the invention relates to a composition for anti-aging comprising emodin-8- O- (6'- O -propanedithio)-glucoside as a ghrelin receptor agonist . In some embodiments of the invention, the composition is for preventing and/or treating an aging-related disease caused by a decrease in growth hormone secretion.

圖1為利用液相層析質譜儀(LC-MS)分析與鑑定生何首烏中所含成分。 Figure 1 shows the analysis and identification of the components contained in Polygonum multiflorum by liquid chromatography mass spectrometry (LC-MS).

圖2係顯示不同濃度之emoghrelin(10^-7~10^-4M)於加藥處理24小時(圖2A)，與48小時(圖2B)後，對於其細胞存活率並無顯著的影響。 Figure 2 shows that different concentrations of emoghrelin (10 ^-7 ~ 10 ^-4 M) had no significant effect on cell viability after 24 hours of dosing (Figure 2A) and 48 hours (Figure 2B).

圖3為emoghrelin與飢餓素受體促效劑之衍生物(GHRP-6)對於生長激素分泌的刺激活性分析。 Figure 3 is an analysis of the stimulatory activity of emoghrelin and a derivative of ghrelin receptor agonist (GHRP-6) for growth hormone secretion.

圖4係顯示飢餓素受體拮抗劑([D-Arg¹,D-Phe⁵,D-Trp^7,9,Leu¹¹]-受質P,0.5μM)會抑制GHRP-6與emoghrelin刺激生長激素分泌的活性。 Figure 4 shows that ghrelin receptor antagonists ([D-Arg ¹ , D-Phe ⁵ , D-Trp ^7,9 , Leu ¹¹ ]-substrate P, 0.5 μ M) inhibit GHRP-6 and emoghrelin-stimulated growth Hormone secretion activity.

圖5係GHRP-6(圖5A)及emoghrelin(圖5B)與飢餓素受體結合的分子模擬分析結果，顯示emoghrelin如同GHRP-6 能進入飢餓素受體的結合區。 Figure 5 shows the results of molecular simulation analysis of GHRP-6 (Fig. 5A) and emoghrelin (Fig. 5B) binding to ghrelin receptors, showing that emoghrelin is like GHRP-6. It can enter the binding region of the ghrelin receptor.

本發明之其他特色及優點將於下列實施範例中被進一步舉例與說明，而該實施範例僅作為輔助說明，並非用於限制本發明之範圍。 The other features and advantages of the present invention are further exemplified and illustrated in the following examples, which are intended to be illustrative only and not to limit the scope of the invention.

生何首烏中所含成分之分析與鑑定Analysis and Identification of the Components Contained in Polygonum multiflorum

利用液相層析質譜儀(LC-MS)分析與鑑定生何首烏中所含成分(圖1)，並且比對其他文獻之質譜分析結果以確認各化合物之身分(表1)。生何首烏藥材採自花蓮農改場與賓士農業生物科技有限公司，為一到兩年生的樣品。51.2g的藥材經粉碎機粉碎後，加入500mL甲醇，於室溫下以超音波萃取2小時，再利用抽氣過濾濾掉殘渣，此萃取流程重複兩次；將兩次的何首烏甲醇萃取液合併後經由0.22μm濾膜過濾，即為待測的樣品溶液。標準品溶液製備的部分，取適量THSG與emodin(純度>98%)，分別加入1mL甲醇溶解，以0.22μm濾膜過濾後即獲得標準品溶液。 The components contained in Polygonum multiflorum were analyzed and identified by liquid chromatography mass spectrometry (LC-MS) (Fig. 1), and the results of mass spectrometry were compared with other literatures to confirm the identity of each compound (Table 1). Raw Shouwu medicinal materials were collected from Hualien Agricultural Reformation and Binshi Agricultural Biotechnology Co., Ltd., which are samples for one to two years. After 51.2 g of the medicinal material was pulverized by a pulverizer, 500 mL of methanol was added, and ultrasonic extraction was performed at room temperature for 2 hours, and then the residue was filtered off by suction filtration. The extraction procedure was repeated twice; the twice extract of Polygonum multiflorum was combined. After filtration through a 0.22 μm filter, it is the sample solution to be tested. For the preparation of the standard solution, take appropriate amount of THSG and emodin (purity >98%), add 1 mL of methanol to dissolve, and filter with 0.22 μm filter to obtain the standard solution.

生何首烏甲醇萃取液與標準品溶液皆利用高效能液相層析儀(HPLC)進行分析，層析管柱為Syncronis C18 column(4.6×250mm,5μm)，進樣量為20μL，流速為1mL/min，偵測波長為280nm；流動相A為純水，B為乙腈，兩者皆含0.5%乙酸，分離條件為0-45min,10 to 35% B；45-65min,35 to 100% B；65-80min,100% B進行梯度沖提。 Polygonum raw methanol extract using the standard solution are high performance liquid chromatography (HPLC) analysis, chromatography column is Syncronis C18 column (4.6 × 250mm, 5μm), injection volume was 20 μ L, flow rate 1mL/min, detection wavelength is 280nm; mobile phase A is pure water, B is acetonitrile, both contain 0.5% acetic acid, separation conditions are 0-45min, 10 to 35% B; 45-65min, 35 to 100% B; 65-80 min, 100% B for gradient elution.

本實驗所使用之液相層析串聯質譜儀為含自動進樣裝置的Surveyor LC system連接線性離子阱質譜儀(LTQ mass spectrometer)，並配備5μL樣品圈；液相層析條件與上述HPLC分析條件相同；離子源採用電灑游離法(electrospray ionization,ESI)正離子與負離子模式，離子源所使用的霧化氣體(sheath gas)、輔助氣體(auxiliary gas)和吹掃氣體(sweep gas)皆為氮氣，噴灑電壓(spray voltage)為4.5kV，毛細管溫度加熱至300℃，全掃描(full scan)的掃描範圍為m/z 150-1500；質量分析器為線性離子阱質量分析器(linear ion trap mass analyzer)，線性離子阱內所使用的碰撞氣體(collision gas)為氦氣，相對碰撞能量(relative collision energy)為27%，母離子隔離範圍為2Da。 The present experiment used a liquid chromatography tandem mass containing autosampler Surveyor LC system connecting means linear ion trap mass spectrometer (LTQ mass spectrometer), and equipped with 5 μ L sample loop; HPLC liquid chromatography conditions described above The analysis conditions are the same; the ion source adopts electrospray ionization (ESI) positive ion and negative ion mode, and the sheath gas, auxiliary gas and sweep gas used by the ion source are used. All are nitrogen, spray voltage is 4.5kV, capillary temperature is heated to 300 °C, full scan scan range is m/z 150-1500; mass analyzer is linear ion trap mass analyzer (linear Ion trap mass analyzer), the collision gas used in the linear ion trap is helium, the relative collision energy is 27%, and the parent ion isolation range is 2Da.

其中Peak 6號化合物即為生何首烏所含的特殊成分大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷，吾等將其命名為”Emoghrelin”，並認為此特有的化合物很有可能是生何首烏抗老化的主要活性成分，因此從生何首烏中純化出此化合物以進行相關的活性測試。 Among them, Peak 6 is the special component of eucalyptus 8- O- (6'- O -propanediyl)-glucoside contained in Polygonum multiflorum. We named it "Emoghrelin" and thought it The unique compound is likely to be the main active ingredient in the anti-aging of Polygonum multiflorum, so the compound was purified from Polygonum multiflorum for related activity testing.

”Emoghrelin”之純化Purification of "Emoghrelin"

生何首烏甲醇萃取液經由減壓濃縮與冷凍乾燥後，秤取4g的萃取物，以450mL純水回溶裝入分液漏斗中，利用液態分配萃取法依次以二氯甲烷、乙酸乙酯與正丁醇按照1：1的比例進行萃取3次，分別獲得不同極性之萃取物。之後取正丁醇萃取物，利用HPLC進一步純化出Emoghrelin，層析管柱為Syncronis C18 column(4.6×250mm,5μm)，流速為1mL/min，偵測波長為280nm；流動相A為純水，B為乙腈，兩者皆含0.5%乙酸，分離條件為0-10min,18 to 33% B；10-15min,33% B；15-35min,from 33 to 55% B進行梯度沖提，共獲得2.493mg的化合物以進行後續的細胞試驗。 The concentrated extract of Polygonum multiflorum was concentrated and lyophilized under reduced pressure, and 4 g of the extract was weighed and re-dissolved in 450 mL of pure water into a separatory funnel. The liquid distribution extraction method was followed by dichloromethane, ethyl acetate and positive The butanol was extracted three times in a ratio of 1:1 to obtain extracts of different polarities. Then, the n-butanol extract was taken, and the emogrelin was further purified by HPLC. The column was a Syncronis C18 column (4.6×250 mm, 5 μm), the flow rate was 1 mL/min, and the detection wavelength was 280 nm; the mobile phase A was pure water. B is acetonitrile, both containing 0.5% acetic acid, separation conditions are 0-10 min, 18 to 33% B; 10-15 min, 33% B; 15-35 min, from 33 to 55% B for gradient elution 2.493 mg of compound was used for subsequent cell assays.

”Emoghrelin”之細胞毒性分析Cytotoxicity analysis of "Emoghrelin"

首先利用大鼠腦下垂體腫瘤細胞株(RC-4B/C cells)測試emoghrelin之細胞毒性，細胞存活率的測定利用alamar blue試劑進行分析。大鼠腦下垂體腫瘤細胞株RC-4B/C(ATCC number：CRL-1903)以1×10⁵cell/well於24孔盤中進行培養，培養液組成為1：1的DMEM與α-MEM、0.01mM非必需胺基酸、15mM HEPES、0.2mg/ml牛血清白蛋白(BSA)、2.5ng/ml表皮細胞生長因子(EGF)、10%胎牛血清(FBS)。培養24小時後，置換成含有emoghrelin(10^-7~10^-4M)培養液於細胞培養箱中(37℃,5% CO₂)分別靜置24與48小時，之後再置換成含有10% alamar blue的培養液於細胞培養箱中反應3小時，利用光譜分析儀偵測其螢光值(激發光與散射光分別為560與590nm)，再換算其細胞存活率；细胞存活率(%)=(加藥组吸光值/對照组吸光值)×100%。 The cytotoxicity of emoghrelin was first tested using a rat pituitary tumor cell line (RC-4B/C cells), and the cell viability was measured using an alamar blue reagent. The rat pituitary tumor cell line RC-4B/C (ATCC number: CRL-1903) was cultured in a 24-well dish at 1×10 ⁵ cell/well. The medium consisted of 1:1 DMEM and α-MEM. , 0.01 mM non-essential amino acid, 15 mM HEPES, 0.2 mg/ml bovine serum albumin (BSA), 2.5 ng/ml epidermal growth factor (EGF), 10% fetal bovine serum (FBS). After 24 hours of culture, the cells were replaced with emoghrelin (10 ^-7 ~10 ^-4 M) in a cell culture incubator (37 ° C, 5% CO ₂ ) for 24 and 48 hours, respectively, and then replaced with 10%. The culture medium of alamar blue was reacted in a cell culture incubator for 3 hours, and the fluorescence value (excitation light and scattered light were 560 and 590 nm, respectively) was detected by a spectrum analyzer, and the cell survival rate was further converted; cell survival rate (%) = (absorbance value of the dosing group / absorbance of the control group) × 100%.

結果顯示，不同濃度之emoghrelin(10^-7~10^-4M)於加藥處理24與48小時後，對於其細胞存活率並無顯著的影響，參見圖2。 The results showed that different concentrations of emoghrelin (10 ^-7 ~10 ^-4 M) had no significant effect on cell viability after 24 and 48 hours of dosing, see Figure 2.

”Emoghrelin”之生長激素分泌刺激活性 Growth hormone secretion stimulating activity of "Emoghrelin"

利用大鼠腦下垂體前葉初代培養細胞測試emoghrelin刺激生長激素分泌之活性，生長激素分泌量的測定利用酵素免疫分析法(Enzyme-linked immunosorbent assay；ELISA)進行分析。使用250-300g的SD(Sprague Dawley)雄性大鼠，將大鼠以腹腔注射Zoletil 50(40mg/kg)麻醉後，取出大鼠的腦下垂體前葉組織，切碎後分別利用0.25%(w/v)collagenase type 1a、trypsin與DNase I三種不同的酵素作用將組織打散成單一細胞型態，最後經由100μm細胞過濾網過濾後，以細胞密度為4×10⁴cell/well於96孔盤中進行培養。於細胞培養箱中培養兩天(37℃,5% CO₂)待細胞穩定後，將原本培養液置換成無血清培養液於培養箱中靜置90分鐘，最後再置換成分別含有Emoghrelin(10^-7~10^-4M)與GHRP-6(GHSR agonist,10^-7M)的培養液，分別於藥物處理15與30分鐘後收集細胞培養液；飢餓素受體拮抗劑的測試採用[D-Arg¹,D-Phe⁵,D-Trp^7,9,Leu¹¹]-substance P(GHSR antagonist,0.5μM)，藥物測試的組別為含有GHSR antagonist(0.5μM)、GHRP-6(10^-7M)、GHRP-6(10^-7M)+GHSR antagonist(0.5μM)、Emoghrelin(10^-4M)與Emoghrelin(10^-4M)+GHSR antagonist(0.5μM)的培養基分別進行處理，於藥物處理15分鐘後收集細胞培養液。各組別之培養液以大鼠生長激素酵素免疫分析試劑[Rat growth hormone enzyme-linked immunosorbent assay(ELISA)kit]測定其生長激素分泌的含量。 The primary culture cells of the anterior pituitary of the rat brain were used to test the activity of emoghrelin to stimulate the secretion of growth hormone. The growth hormone secretion was measured by Enzyme-linked immunosorbent assay (ELISA). Using 250-300 g SD (Sprague Dawley) male rats, the rats were anesthetized with intraperitoneal injection of Zoletil 50 (40 mg/kg), and the anterior pituitary tissues of the rats were taken out and chopped and used with 0.25% (w/). v) Collagenase type 1a, trypsin and DNase I three different enzymes to break up the tissue into a single cell type, finally filtered through a 100 μm cell strainer, with a cell density of 4 × 10 ⁴ cell / well in 96 wells Cultivate in the pan. After culturing for two days (37 ° C, 5% CO ₂ ) in a cell culture incubator, the original culture solution was replaced with a serum-free medium in an incubator for 90 minutes, and finally replaced with Emogrelin (10, respectively). ^-7 ~10 ^-4 M) and GHRP-6 (GHSR agonist, 10 ^-7 M) culture medium, 15 and 30 minutes after drug treatment, cell culture medium was collected; ghrelin receptor antagonist was tested [D -Arg ¹ , D-Phe ⁵ , D-Trp ^7,9 , Leu ¹¹ ]-substance P (GHSR antagonist, 0.5 μ M), the drug test group consisted of GHSR antagonist (0.5 μ M), GHRP-6 ( ^{10 -7 M), GHRP-6} (10 -7 M) + GHSR antagonist (0.5 μ M), Emoghrelin (10 -4 M) and ^{Emoghrelin (10 -4 M) + GHSR} antagonist (0.5 μ M) of each medium The treatment was carried out, and the cell culture liquid was collected 15 minutes after the drug treatment. The culture medium of each group was assayed for the content of growth hormone secretion by a rat growth hormone enzyme-linked immunosorbent assay (ELISA) kit.

由圖3之結果顯示，emoghrelin與飢餓素受體促效劑之衍生物(GHRP-6)同樣於加藥處理15與30分鐘後發現生長激素分泌明顯上升，且emoghrelin(10^-7~10^-4M)刺激生長激素分泌的增加呈現藥物濃度依賴性。 From the results shown in Figure 3, emoghrelin and the ghrelin receptor agonist derivative (GHRP-6) were found to have a significant increase in growth hormone secretion after 15 and 30 minutes of dosing, and emoghrelin (10 ^-7 ~10 ^{- 4} M) Stimulation of growth hormone secretion increased in a drug concentration-dependent manner.

此外，飢餓素受體拮抗劑([D-Arg¹,D-Phe⁵,D-Trp^7,9,Leu¹¹]-受質P,0.5μM)也能抑制GHRP-6與emoghrelin刺激生長激素分泌的活性(圖4)。顯示，本發明之emoghrelin確實係 藉由活化飢餓素受體，而刺激生長激素的分泌。 In addition, ghrelin receptor antagonist ^{([D-Arg 1, D} -Phe 5, D-Trp 7,9, Leu 11] - subject matter P, 0.5 μ M) to suppress GHRP-6 can stimulate growth hormone and emoghrelin Secreted activity (Figure 4). It is shown that the emoghrelin of the present invention does stimulate the secretion of growth hormone by activating the ghrelin receptor.

”Emoghrelin”之分子模擬分析 Molecular Simulation Analysis of "Emoghrelin"

人源GHSR(AAI13548)蛋白質序列被上傳至SWISS-Model網站供作為模擬之合適模板。β 1及β 2腎上腺素受體之結晶結構(編號：PDB 2YCY與3PDS)，其與相關配體(cyanopindolol及FAUC50)相結合，被用於建立GHSR之同源模擬。該相關配體結構於進行模擬前被合理移除，且可變鏈區域係透過Loop Refinement(MODELER)module於C116及C198修飾加上雙硫鍵。所建立出之GHSR結構具有最低之PDF總能量而進一步被使用於與GHRP-6及emoghrelin之分子對接。所有模擬程序係透過Discovery Studio 2.1軟體平台所完成。GHRP-6及emodin之三維結構係由PubChem所提供之資料庫中下載而得(於NCBI網址)。Emoghrelin則是基於emodin之結構於Chem3D軟體中重新予以建立所產生。鍵結口袋係依GHSR結構中III-VII細胞外跨模區連接之空腔加以定義，而配體於GHSR中之結合位置係以半徑為16Å之球體進行界定。GHSR與GHRP-6以及emoghrelin之分子對接程序係以Discovery Studio 2.1軟體中的LibDock模組進行電腦模擬，包含相關結構之最小化能量之計算係以CHARMm力場進行最佳化。 The human GHSR (AAI13548) protein sequence was uploaded to the SWISS-Model website for use as a suitable template for the simulation. The crystal structures of the β 1 and β 2 adrenergic receptors (numbers: PDB 2YCY and 3PDS), which bind to related ligands (cyanopindolol and FAUC50), were used to establish homologous simulations of GHSR. The related ligand structure was reasonably removed prior to the simulation, and the variable chain region was modified with a double-sulfur bond at C116 and C198 through a Loop Refinement (MODELER) module. The established GHSR structure has the lowest total PDF energy and is further used to interface with molecules of GHRP-6 and emoghrelin. All simulation programs are done through the Discovery Studio 2.1 software platform. The three-dimensional structure of GHRP-6 and emodin was downloaded from the database provided by PubChem (at the NCBI website). Emoghrelin was created based on the emodin structure re-established in the Chem3D software. The binding pockets are defined by the cavities of the III-VII extracellular translocation region in the GHSR structure, and the binding sites of the ligands in the GHSR are defined by spheres with a radius of 16 Å. The molecular docking program between GHSR and GHRP-6 and emoghrelin is computer simulated with the LibDock module in Discovery Studio 2.1 software. The calculation of the minimum energy of the relevant structure is optimized with the CHARMm force field.

由圖5之分子模擬分析結果顯示，emoghrelin如同GHRP-6能進入飢餓素受體的結合區，且產生足夠的氫鍵結合能力，故進一步證明，本發明之emoghrelin可作為有效的飢餓素受體促效劑。 The molecular simulation analysis shown in Figure 5 shows that emoghrelin can enter the binding region of ghrelin receptor as GHRP-6 and produce sufficient hydrogen bonding ability, thus further demonstrating that emoghrelin of the present invention can be used as an effective ghrelin receptor. An agonist.

綜合以上結果，顯示本發明之emoghrelin可透過活化飢餓素受體，作為一種飢餓素受體促效劑，而進一步刺激生長激素分泌的上升。 Taken together, the above results show that the emoghrelin of the present invention can further stimulate the increase of growth hormone secretion by activating the ghrelin receptor as a ghrelin receptor agonist.

因此，本發明係首先利用中藥何首烏，從其中純化及鑑定出天然、安全且具有飢餓素受體促效劑活性之化合物大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷(命名為 emoghrelin)，並證明其具有刺激生長激素分泌增加的功效，而將其應用於製備用以預防/治療高齡族群中因生長激素分泌降低所引起的老化相關疾病之組合物。 Therefore, the present invention first utilizes the traditional Chinese medicine Polygonum multiflorum, from which a natural, safe and ghrelin receptor agonist-like compound emodin-8- O- (6'- O -propanediyl) is purified and identified. Glucoside (designated emoghrelin) and proved to have an effect of stimulating an increase in growth hormone secretion, and is applied to the preparation of a composition for preventing/treating an aging-related disease caused by a decrease in growth hormone secretion in an elderly population.

Claims (7)

一種大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷用於製備活化飢餓素受體之組合物的用途，其中該大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷係作為飢餓素受體促效劑。 Use of emodin-8-O-(6'-O-propanedithio)-glucoside for the preparation of a composition for activating a ghrelin receptor, wherein the emodin-8- O- (6' -O -propanediyl)-glucoside is used as a ghrelin receptor agonist. 如請求項1所述的用途，其中該大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷係純化自生何首烏(Polyponum multiflorum Thunb.)，且命名為emoghrelin(參首烏激素)。 The use according to claim 1, wherein the emodin-8-O-(6'-O-propanedithio)-glucoside is purified from Polyponum multiflorum Thunb. and named emoghrelin. Shouwu hormone). 如請求項1所述的用途，其中該組合物係用於刺激生長激素分泌。 The use of claim 1, wherein the composition is for stimulating growth hormone secretion. 如請求項1所述的用途，其中該組合物為醫藥組合物。 The use of claim 1, wherein the composition is a pharmaceutical composition. 如請求項1所述的用途，其中該組合物為食品組合物。 The use of claim 1, wherein the composition is a food composition. 如請求項1所述的用途，其中該大黃素-8-O-(6’-O-丙二醯基)-葡萄糖苷係用於製備用於抗老化之醫藥組成物。 The use according to claim 1, wherein the emodin-8- O- (6'- O -propanedithio)-glucoside is used for the preparation of a pharmaceutical composition for anti-aging. 如請求6所述的用途，其中該醫藥組成物係用於預防及/或治療因生長激素分泌降低所引起的老化相關疾病。 The use according to claim 6, wherein the pharmaceutical composition is for preventing and/or treating an aging-related disease caused by a decrease in growth hormone secretion.