CN105517550A - 水稻的表征 - Google Patents
水稻的表征 Download PDFInfo
- Publication number
- CN105517550A CN105517550A CN201480042793.1A CN201480042793A CN105517550A CN 105517550 A CN105517550 A CN 105517550A CN 201480042793 A CN201480042793 A CN 201480042793A CN 105517550 A CN105517550 A CN 105517550A
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- Prior art keywords
- rice
- imines
- technique
- sugar
- oryza
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
用于生产包含来源于稻属植物种子的材料的组合物的方法,所述方法包括以下步骤:(a)提供来源于稻属种子的材料;和(b)在步骤(a)的所述材料中确定至少一种亚胺糖的存在或不存在和/或测量至少一种亚胺糖的量。还描述了来源于稻属植物种子的材料作为食品或饲料添加剂用于降低所述食品或饲料的升糖指数(GI)值的应用,所述材料包含至少一种亚胺糖。
Description
技术领域
本发明涉及产生基于水稻的组合物的方法,监控水稻质量的方法和选择在能量利用疾病(energyutilizationdisease)的治疗中具有应用的水稻品系(ricestrains)和品种的选择、育种、鉴别和筛选的方法。
背景技术
稻米是单子叶植物普通栽培稻(Oryzasativa)(亚洲稻)或非洲栽培稻(Oryzaglaberrima)(非洲稻)的种子。稻米主要有四类:籼米(籼稻,indica)(非粘性,长粒);粳米(粳稻,japonica)(粘性,短粒);以其坚果样香味和味道而著名的香米(aromatic)(中长粒),和具有不透明谷粒的糯米(glutinous)(也称为粘米(stickyrice))。
香米的品种包括:印度香米(basmati)、茉莉香米(jasmine)和野生山核桃香米(wildpecanrice)。当蒸煮时,米粒具有轻盈且蓬松质地。印度香米是在印度和巴基斯坦生长的香米。它具有坚果样味道并且具有奶油风味。它被认为是长粒白米并且淀粉含量比其它品种低。和大多数长粒米一样,蒸煮的印度香米的米粒特征性地自由流动,而不是粘性的。除了正常的(白色)印度香米之外,棕色印度香米是可获得的。由于其较低的升糖指数(GI)值,印度香米已经被视为比白米更健康的选择。
粳米的品种包括阿波罗米(Arboriorice)和Baldo米,它们是在意大利种植的栽培品系。
还根据颜色对稻米分类,其包括白色、棕色、黑色、紫色和红色品种。当使用水稻脱壳机磨碾水稻植物种子以脱除稻壳(稻粒的外壳)时,产生了糙米(棕色稻米,brownrice)。磨碾可以是连续的,从而除去米糠(其余的壳和胚芽(germ)),借此产生白米。白米具有相对长的货架寿命,但是缺少一些重要的营养物。米糠含有多种具有抵御疾病性质(包括调节肠道微生物群的能力)的生物活性成分。
科罗拉多州立大学的研究小组目前正在研究米糠如何提高粘膜免疫性(Kumar,A.等人.2012,BMCMicrobiology,12,71)。已发现在大鼠中米糠控制胃肠癌症、高脂血症和糖尿病(Cheng,H.H.等人,2010,InternationaljournalforvitaminandnutritionresearchInternationaleZeitschriftfurVitamin-undErnahrungsforschung,80(1):45-53;Tomita,H.等人,2008,OncolRep2008,19(1):11-15)并且在人中控制高胆固醇血症(Gerhardt,A.&Gallo,N.1998,JNutr.,128(5):865-869)。
长期以来,已知稻米具有一系列健康益处。除了作为食物的支柱作用外,亚洲种植水稻的国家,如泰国、中国、马来西亚、印度尼西亚和印度的古代文献表明稻米具有医学性质。根据阿育吠陀(Ayurvedictreaties)的遮罗迦集(Charaka)(c.700BC)和妙闻集(Susruta)(c.400BC),稻米在多种疾病的治疗中具有医学价值,如腹泻、呕吐、发烧、出血、胸痛、创伤和烧伤。甚至至今,在印度的一些部分仍使用某些品种来治疗皮肤疾病、血压、发烧、瘫痪和风湿病。喀拉拉邦(Kerala)著名的Nivara稻米在阿育吠陀实践中广泛用于身体富集(bodyenrichment)以排出有毒代谢产物、强健、恢复和激发身体、调节血压、预防皮肤疾病和延缓过早衰老(Ahuja,U.,等人.2008,AsianAgri-History12,93-108)。
在中国,稻米的医学价值最早可以追溯至2800BC,那时它被中国皇家医师用于治愈目的。中国人相信稻米强化脾胃,增强食欲并且治疗消化不良。在马来西亚,推荐将干燥的米粉用于皮肤疾病,而在柬埔寨,成熟植物的壳被认为对治疗痢疾有用。
与稻米有关的有利质量包括其淀粉的高可消化性、氨基酸的高生物价值、必需脂肪酸和硒的高含量。在急性腹泻的治疗中,基于稻米的口服补液溶液(ORS,oralrehydrationsolution)优于基于葡萄糖的ORS(GoreS.,等人.1992,BritishMedicalJournal304,287-291)并且已包含在WHO推荐中。稻米是低变应性食品并且推荐用于患有过敏性肠综合征的人(AhujaU.等人,2008,AsianAgri-History12,93-108)。
一些稻米品种声称具有低于其它品种的升糖指数(GI)。升糖指数或GI是食品中碳水化合物对血糖水平影响的量度。它估计了与葡萄糖消耗相比,在消耗食品后所述食品中每克有效碳水化合物(总碳水化合物减去纤维)升高人血液葡萄糖水平的程度高低(Jenkins,D.等人,1981,AmJClinNutr34,362–366)。根据定义,葡萄糖的升糖指数为100,而其它食品具有较低的升糖指数。具有在消化期间快速分解并将葡萄糖快速释放到血流中的碳水化合物的食品往往具有高GI;而具有具有更慢地分解并将葡萄糖较为逐渐释放到血流中的碳水化合物的食品往往具有低GI。较低的升糖指数表明所述食品的碳水化合物的消化和吸收速率较慢,并且还可以表明从肝脏和外周对碳水化合物消化产物的更大提取。较低的血糖反应通常等价于较低的胰岛素需要,但并非总是,并且可以改善长期血糖控制(Jenkins,D.等人2008,JAMA.300,2742-2753)和血脂。
对发表报道的系统综述(Barclay等人,2009,AmericanJournalofClinicalNutrition,87,627-637)推断低GI饮食与某些慢性疾病(包括糖尿病和心脏病)风险降低是独立相关的。在糖尿病患者中,中期研究的证据表明用低升糖指数形式替换高升糖指数碳水化合物将改善血糖控制,并且在用胰岛素治疗的人中,将减少低血糖发作(Willett,W.等人,2002,AmericanJournalofClinicalNutrition,76,274S-280S)。
已广泛研究了有色稻米并且它们的花青素和黄酮(类黄酮)含量与抗氧化性有关(Zhang,M.等人,2010,J.Agric.FoodChem.,58,7580–7587)。在兔中,与白米相比,红米和黑米表明将动脉粥样硬化斑块形成减少50%更多(Ling,W.等人200,:JournalofNutrition,131,1421-1426)。在最近的研究中(Das,S.和De,B.,2012,Nutrition&FoodScience,42,428-433),已将红米的酶抑制性质与白色品种的那些进行了比较。对α-淀粉酶和α-葡萄糖苷酶测试了两种类型的一些品种的甲醇水溶液提取物。白色品种显示出弱a-葡萄糖苷酶抑制和无a-淀粉酶抑制,而红色品种显示出良好的a-淀粉酶和a-葡萄糖苷酶抑制。尽管已报道有色稻米中的花青素具有a-葡萄糖苷酶抑制活性(Akkarachiyasit,S.等人,2010,Int.J.Mol.Sci.,11,3387-3396),但这里作者表明一些其它成分也可能有助于所观察到的抑制。在另一项研究中,已报道黑米提取物是比来自红米的那些更好的a-葡萄糖苷酶抑制剂(Yao,Y.等人,2010,J.Agric.FoodChem.,58,770–774)。
能量利用疾病
能量利用疾病涵盖了广泛的疾病,并且包括(例如)体内平衡病症(disordersofhomeostasis)、代谢疾病、糖代谢功能障碍和食欲障碍。
因此,能量利用疾病的实例包括胰岛素抵抗、各种糖尿病形式、代谢综合征、肥胖症、消耗综合征(wastingsyndromes)(例如,癌症相关性恶病质(cancerassociatedcachexia))、肌病(肌肉疾病,myopathies)、胃肠疾病、生长停滞(growthretardation)、高胆固醇血症(hypercholesterolemia)、动脉粥样硬化和年龄相关性代谢功能障碍。
能量利用疾病还包括与以下有关的病况:代谢综合征、肥胖症和/或糖尿病,包括(例如)高血糖症、葡萄糖耐受不良(glucoseintolerance)、高胰岛素血症(hyperinsulinaemia)、糖尿(glucosuria)、代谢性酸中毒(metabolicacidosis)、白内障、糖尿病性神经病变、糖尿病性肾病、糖尿病性视网膜病、黄斑变性(maculardegeneration)、肾小球硬化症(glomerulosclerosis)、糖尿病性心肌病、胰岛素抵抗、葡萄糖代谢障碍(葡萄糖代谢受损、葡萄糖代谢失调,impairedglucosemetabolism)、关节炎、高血压、高脂血症、骨质疏松症、骨质减少(osteopenia)、骨质流失(boneloss)、脆骨综合征(brittlebonesyndromes)、急性冠状动脉综合征(acutecoronarysyndrome)、不育、短肠综合征(shortbowelsyndrome)、慢性疲劳、进食障碍和肠运动功能障碍(intestinalmotilitydysfunction)。
胰岛素抵抗、代谢综合征和糖尿病
在健康个体中,通过两种胰腺激素:胰岛素(通过胰腺β-细胞产生)和高血糖素(glucagon)(通过胰腺α-细胞产生)将血糖水平维持在狭窄范围内。胰腺β-细胞感知血糖水平升高,并且通过分泌胰岛素进行应答。胰岛素促进身体组织的葡萄糖吸收,借此将血糖浓度恢复至生理范围。高血糖素相反地作用,在禁食条件下提高血糖水平,这主要是通过刺激肝脏中葡萄糖产生进行的。
胰岛素抵抗的特征在于胰岛素在骨骼肌、脂肪细胞和肝细胞中的作用降低,从而正常量的胰岛素不足以从这些组织的细胞中产生正常的胰岛素反应。在脂肪细胞中,胰岛素抵抗导致储存的甘油三酯水解,从而导致血浆中游离脂肪酸升高。在肌肉中,胰岛素抵抗降低葡萄糖吸收,而在肝细胞中,它降低葡萄糖储存。在后两种情况中,均导致血糖浓度升高。
由于胰岛素抵抗所造成的高胰岛素和葡萄糖血浆水平通常发展成代谢综合征和2型糖尿病。
代谢综合征是提高心血管疾病和糖尿病风险的异常和病症的集合。在许多发达国家中,发病率很高:一些研究表明美国的发病率多至人口的25%。该病症也称为(代谢)综合征X、胰岛素抵抗综合征、Reaven's综合征和CHAOS。可以通过存在三个或更多个下列症状来诊断代谢综合征:中心性肥胖(centralobesity)(男性腰围大于40英寸,女性腰围大于35英寸);高甘油三酯水平(150mg/dL以上);低HDL水平(男性低于40mg/dL,女性低于50mg/dL)和高血压(130/85mmHg以上)。相关疾病和病征为:脂肪肝(通常发展成非酒精性脂肪肝疾病)、多囊卵巢综合征(polycysticovariansyndrome)、血色沉着病(青铜色糖尿病、血色病、血色素沉着,hemochromatosis)(铁过载)和黑棘皮病(acanthosisnigricans)(皮肤暗块)。
代谢综合征的首选治疗(一线治疗,firstlinetreatment)是生活方式的改变(热量限制和身体活动)。然而,经常需要药物治疗。通常,单独治疗包含代谢综合征的各种疾病(例如,对于高血压的利尿剂和ACE抑制剂)。如果它们升高,胆固醇药物可以用于降低LDL胆固醇和甘油三酯水平,并且如果它们较低,则提高HDL水平。降低胰岛素抵抗的药物(例如,二甲双胍(metformin)和噻唑烷二酮(thiazolidinedione))的使用是有争议的。在小于31%的病例中,心血管运动(cardiovascularexercise)是治疗性的,并且通常不会产生空腹血糖或胰岛素抵抗降低。
因此,需要代谢综合征的新型和/或替代性治疗,特别是对肥胖症和/或甘油三酯水平升高有效的治疗。
2型糖尿病是其特征在于血糖水平持续升高的慢性疾病(高血糖症)。该疾病的特征在于胰岛素抵抗以及胰腺β-细胞中胰岛素分泌受损。胰岛素抵抗向2型糖尿病的发展的标志在于当胰腺β-细胞不能产生足够的胰岛素以维持正常血糖水平(血糖正常(euglycemia))时,出现进食后高血糖症。
目前用于治疗2型糖尿病的最重要的药物是二甲双胍(Glucophage、Diabex、Diaformin、Fortamet、Riomet、Glumetza、Cidophage等)。二甲双胍(Metformin)是双胍类口服抗高血糖剂。其它双胍类包括苯乙双胍和丁福明(buformin)(现在已撤回)。二甲双胍主要通过降低来自糖原储存的肝血糖释放起作用,并且在提高葡萄糖吸收中具有一些作用。其它广泛使用的药物种类包括磺酰脲(sulfonylurea)类(包括格列本脲(glibenclamide)和格列齐特(gliclazide))。这些药物提高葡萄糖刺激的胰腺胰岛素分泌。新药种类包括噻唑烷二酮(例如,罗格列酮(rosiglitazone)、吡格列酮(pioglitazone)和曲格列酮(troglitazone)),其通过结合至PPAR(过氧化物酶体增殖物激活受体(peroxisomeproliferator-activatedreceptors))起作用,所述PPAR是细胞核内的一类受体分子。其它种类包括α-葡萄糖苷酶抑制剂(阿卡波糖)、氯茴苯酸类(meglitinides)(其刺激胰岛素释放并且包括那格列奈(nateglinide)、瑞格列奈(repaglinide)以及它们的类似物)、肽类似物(例如,肠促胰岛素模拟物(incretinmimetics),其作为胰岛素促分泌素起作用,高血糖素样肽类似物(例如,艾塞那肽)、二肽基肽酶-4(DPP-4)抑制剂(其提高肠促胰岛素水平(例如,西他列汀)和淀粉不溶素(amylin)激动剂类似物(其减缓胃排空并且抑制高血糖素(例如,普兰林肽(pramlintide))。
然而,对于不同形式的2型糖尿病,现有疗法似乎不能改善β-细胞中关键内在因素的功能,并且所有现有疗法不能阻止疾病发展,并且随着时间推移,也不能使葡萄糖水平恢复正常和/或预防后续并发症。现有疗法还与不希望的副作用有关。例如,胰岛素促分泌素和胰岛素注射可以导致低血糖和体重增加。患者还可能随时间对胰岛素促分泌素变得不起反应。二甲双胍和α-葡萄糖苷酶抑制剂通常会导致胃肠问题,并且PPAR激动剂往往会导致提高的体重增加和水肿。还报道艾塞那肽(Exenatide)会导致恶心和呕吐。
糖基化在调节蛋白质性质中具有重要作用并且与多种疾病有关。Itoh,N.等人,2007(AmJPhysiolEndocrinolMetab293:E1069–E1077)报道了患有2型糖尿病的人受试者中血清N-聚糖谱并且发现具有带有平分型N-乙酰葡萄糖胺(bisectingN-acetylglucosamine)的α1,6-岩藻糖的双触角N-聚糖(biantennaryN-glycan)的量的提高。Copeland,R.J.等人,2008(AmJPhysiolEndocrinolMetab295:E17–E28)综述了O-连接的N-乙酰葡萄糖胺在糖尿病中的重要性并且推断GlcNAc糖基化和胰岛素抵抗的发展之间强烈的正相关。O-连接的-β-N-乙酰葡萄糖胺(O-GlcNAc)是动态翻译后修饰,与磷酸化类似,其在丝氨酸和/或苏氨酸羟基之间循环。O-GlcNAc的循环是通过O-GlcNAc转移酶和O-GlcNAc酶协同作用调控的。GlcNAc糖基化(GlcNAcylation)涉及葡萄糖毒性和慢性高血糖-引起的胰岛素抵抗(2型糖尿病的主要标志)的病因学。已表明氨基己糖苷酶活性在糖尿病患者血清中升高(例如,Agardh,C.D.等人,1982,ActaMedScand.212:39-41)。
1型糖尿病(或者胰岛素依赖型糖尿病)的特征在于胰腺中胰岛(isletsofLangerhans)的胰岛素产生β-细胞的损失,从而导致了胰岛素的缺乏。造成这种β-细胞损失的主要原因在于T细胞介导的自身免疫攻击。尚没有可以针对1型糖尿病(在北美洲和欧洲,其占糖尿病病例的多至10%)的已知预防措施。当疾病发生时,大部分受影响的人在其他方面是健康的或具有健康体重。对胰岛素的敏感性和反应性通常是正常的,特别是在早期。
1型糖尿病的主要治疗(甚至在最早期阶段)是胰岛素替换结合使用血液测试检测器对血糖水平的小心监控。没有胰岛素时,可以出现丙酮血症(酮症,ketosis)和糖尿病性酮酸中毒(diabeticketoacidosis),并且将导致昏迷或死亡。除了常见的皮下注射,还可能通过泵递送胰岛素,其允许以预定水平一天24小时连续输注胰岛素,并且能够根据需要在进餐时间程序化施用胰岛素剂量(丸剂(大丸剂、推注剂,bolus))。最近,FDA已批准了胰岛素的吸入形式Exubera。
1型糖尿病的治疗必须是在长时期内连续的。尽管治疗不损害正常活动,但是必须在测试和药物治疗中注意深入认识、适当护理和规定。
因此,需要新型和/或替代性抗糖尿病药物治疗,具体地能够恢复β-细胞功能的那些。具体地,对于能够治疗2型和1型糖尿病两者以及相关病况同时比现有药物疗法具有更少的副作用的有效药物的临床需要仍是的确存在且显著未满足的。
亚胺糖
亚胺糖(iminosugar)是一类糖模拟物,其中糖的内环氧被碱性氮原子取代。多种亚胺糖是天然存在的,其构成了作为某些植物组织中的次级代谢产物出现的一类生物碱(在这些植物中,它们可能在防御中起作用)。
已显示亚胺糖具有不同的生物性质(通常由它们对天然底物的糖部分的结构类似性所造成,其在多数情况下反映在对多种酶,包括葡萄糖苷酶的抑制活性)。的确,目前认为亚胺糖是非常重要的一类治疗剂(参见IminosugarsFromSynthesistoTherapeuticApplications:Compain,Philippe&Martin,OlivierR(主编)ISBN-13:978-0-470-03391-3-JohnWiley&Sons)。的确,人们已将亚胺糖(通常以植物提取物的形式)作为毒药、麻醉药、兴奋剂(刺激剂,stimulant)和药物使用了数千年。
在Watson,A.A.等人,2001,Phytochemistry56:265-295中广泛地综述了多羟基化生物碱(polyhydroxylatedalkaloids)的治疗应用,应用包括癌症疗法、免疫刺激、糖尿病的治疗、感染(特别是病毒感染)的治疗、鞘糖脂溶酶体贮积症(glycosphingolipidlysosomalstoragediseases)的疗法和自身免疫病症(如关节炎和硬化症)的治疗。
在结构上,亚胺糖显示出较大的多样性。根据N-杂环的构型,它们可以在结构上进行分类。在Kutchan,T.M.1995,ThePlantCell7:1059-1070中描述了一些重要生物碱的实例以及它们的结构,而Watson,A.A.等人,2001Phytochemistry56:265-295将广泛范围的亚胺糖具体分为哌啶、吡咯啉、吡咯烷、吡咯里西啶(pyrrolizidine)、吲哚里西啶(indolizidine)和去甲茛菪烷生物碱(nortropanesalkaloids)(参见Watson,A.A.等人(2001)中的图1-7,该文献的公开内容作为参考并入本文)。
Watson,A.A.等人(2001)(同上)还表明基于它们的糖苷酶抑制谱,至少一些生物碱的功能分类是有可能的:多种多羟基化生物碱是有效力的并且是高度选择性的糖苷酶抑制剂。这些生物碱可以模拟吡喃糖基或呋喃糖基部分中存在的羟基的数目、位置和构型,并因此结合至同性质的(同类的,cognate)糖苷酶的活性部位,借此对其进行抑制。在Legler,G.,1990,Adv.Carbohydr.Chem.Biochem.48:319-384和Asano,N.等人,1995,J.Med.Chem.38:2349-2356中对该领域进行了综述。
发明内容
本发明至少部分基于某些水稻品种中亚胺糖的意外发现。因此,可以根据其亚胺糖谱(亚胺糖分布,iminosugarprofile)对水稻分类:在一些(但非所有)水稻品种中存在亚胺糖(包括某些生物活性亚胺糖)。
新近发现的水稻亚胺糖包括生物活性亚胺糖,其抑制葡萄糖吸收并且在能量利用疾病治疗中具有治疗活性,但也可能降低稻米的营养值。它们还可能有助于植物来源的害虫(有害体,pest)/病原体抵抗,并且还可能具有美容应用。
因此,该发现对全球水稻作物的利用具有深远意义,并且表明了对基于其亚胺糖谱对水稻分类的需要,从而可以选择适合于预期用途(例如,灾荒救助(faminerelief)、营养不良治疗、能量利用疾病控制、作物病害抵抗(croppestresistance)、美容应用等)的品系或品种。
显著地,新近发现的水稻亚胺糖包括亚胺糖fagomine(D-fagomine、FG、1,2-二脱氧野尻霉素(1,2-dideoxynojirimycin))和3,4,5-三羟基-2-羟甲基四氢吡啶(1-脱氧野尻霉素(1-deoxynojirimycin),DNJ):
已知DNJ通过抑制二糖酶和降低参与经上皮葡萄糖转运系统的蛋白表达来抑制小肠中葡萄糖的吸收,并且通过直接调控参与肝脏糖酵解和葡糖异生(糖质新生,gluconeogenesis)的酶蛋白的表达来维持稳定的血糖水平。提议将其作为糖尿病的治疗选择(参见Li,Y.等人1-deoxynojirimycininhibitsglucoseabsorptionandacceleratesglucosemetabolisminstreptozotocin-induceddiabeticmice.Sci.Rep.3,1377;DOI:10.1038/srep01377(2013))。已表明含有DNJ的桑树提取物控制啮齿类的体重增加并且抑制脂肪积累(Kong,W.H.等人,2008,J.Agric.FoodChem.56:2613-2619)。
Fagomine最初是在荞麦(甜荞)(FagopyrumesculentumMoench,双子叶蓼科(Polygonaceae))中鉴别的并且作为少量的亚胺糖在其它植物科中发现,包括桑科(Moraceae)、豆科(Fabaceae)和茄科(Solanaceae)。在全世界范围内,荞麦作为人的饮食存在,并且作为健康食品而闻名。Fagomine降低餐后血糖并调节细菌粘附(Gómez,L.等人,2012,D-Fagominelowerspostprandialbloodglucoseandmodulatesbacterialadhesion.BritishJournalofNutrition,107,第1739-1746页)。已建议将其作为膳食组成或者功能性食品成分以降低与快速消化碳水化合物的过度摄入或过量的可能病原细菌(同前)有关的健康风险。在啮齿类胰腺细胞研究中,Fagomine已显示加强了葡萄糖引起的胰岛素分泌(Watson,A.A.等人,2001,PolyhydroxylatedAlkaloids-NaturalOccurrenceandTherapeuticApplications.Phytochemistry56:265-295)。
不希望受任何理论束缚,本发明人假定新近发现的水稻亚胺糖(尤其包括fagomine和DNJ)有助于降低血糖,降低GI指数和控制体重增加。它们还可以控制皮肤中的糖水平和抑制黑色素形成。因此,本发明在水稻品系和品种的选择、育种、鉴定和筛选中获得应用,所述水稻品系和品种作为抗害虫/病原体作物、在能量利用疾病(如上所述)治疗、营养不良治疗、饥荒救济和作为化妆品(包含在局部施用于皮肤的特定组合物中)使用。
仍不希望受任何理论束缚,本发明人还假定水稻中亚胺糖的存在可能降低其营养价值,因此应针对亚胺糖含量筛选设计在用于饥荒救济或用于治疗营养不良的食物和食品增补剂中使用的水稻品种,并选择水稻品种以避免含有降低营养价值的亚胺糖的品系(strain)和品种(variety)。
因此,根据本发明,提供了用于生产包含来源于稻属(genusOryza)植物种子的材料的组合物的方法,所述方法包括以下步骤:(a)提供来源于稻属种子的材料;和(b)确定步骤(a)的所述材料中至少一种亚胺糖的存在或不存在和/或测量至少一种亚胺糖的量。
在另一个方面,提供了用于监控包含来源于稻属植物种子的材料的组合物的质量的方法,所述方法包括以下步骤:(a)提供来源于稻属种子的材料;和(b)确定步骤(a)的所述材料中至少一种亚胺糖的存在或不存在和/或测量至少一种亚胺糖的量。
在另一个方面,提供了通过根据前述权利要求中任一项所述的方法可获得的组合物,其在治疗营养不良或能量利用疾病(energyutilizationdisease)的方法中应用,或者当用作化妆品时(应用)。
在以下所述的权利要求中定义和描述了本发明的其它方面和优选实施方式。
具体实施方式
本文所提及的所有出版物、专利、专利申请及其它参考文献以它们的全部内容出于所有目的作为参考并入本文,就如同明确并且单独指明每一篇出版物、专利或专利申请作为参考并入并且完整描述了它们的内容。
定义
当在本文中使用并且除非另外具体指明时,以下术语旨在具有除该术语在本领域中可具有的任何更广泛(或更狭窄)的含义之外的以下含义:
除非上下文中需要,否则本文中单数的使用表示包括复数,反之亦然。相关于实体所使用的术语“一个”或“一种”表示一个或多个该实体。照此,术语“一个”(或“一种”)、“一个或多个”和“至少一个”在本文中是可互换使用的。
如本文所使用的,术语“包括”或其变化形式如“包含”或“含有”表示包括任何所列举的整体(构成要素,integer)(例如,特征、元素、特性、性质、方法/工艺步骤或限制)或者整体(例如,特征、元素、特性、性质、方法/工艺步骤或限制)的组,但是不排除任何其它整体或整体的组。因此,如本文所使用的,术语“包括”是包含式的或者开放式的,并且不排除其它未列举的整体(构成要素,integer)或方法/工艺步骤。
在本文中使用短语“基本由……组成”来要求所指明的整体或步骤以及不实质上影响所主张发明的性质或功能的那些。
如本文所使用的,术语“组成”用来表示仅存在所列举的整体(例如,特征、元素、特性、性质、方法/工艺步骤或限制)或整体(例如,特征、元素、特性、性质、方法/工艺步骤或限制)的组。
术语亚胺糖(iminosugar)是本领域的术语,其定义了其中环氧被氮取代的糖类似物。如本文所使用的术语多羟基化生物碱定义了一类氧化的亚胺糖。通常,这些在环系核心上具有至少2、3、4、5、6或7(优选地,3、4或5)个羟基(或者具有一个或多个羟基取代基的烷基)。在本文中使用术语亚胺糖以包括亚胺糖酸(iminosugaracids)。术语亚胺糖酸定义了其中环氧被氮取代的糖酸类似物。
如本文所使用的,术语“疾病”用来定义损害生理机能并且与特定症状有关的任何异常情况。广泛地使用该术语来涵盖其中不管病原学性质(或者该疾病的病原学基础是否确实确立)而生理机能受到损害的任何病症、疾病、异常、病理、病、病况或综合征。因此,它涵盖了由感染、创伤、损伤、手术、放射性剥蚀(放射性切除,radiologicalablation)、中毒或营养不良所引起的病况。
如本文所使用的,术语“治疗(treatment)”或“处理(treating)”是指治愈、改善或减轻疾病症状或消除其病因(例如,病理学多样化状态)(或减轻病因影响)的干预(例如,将药剂施用于受试者)。在这种情况下,该术语与术语“疗法”同义使用。另外,术语“治疗(treatment)”或“处理(treating)”是指防止或延缓疾病发病或发展或者降低(或消除)其在治疗群体中的发病率的干预(例如,将药剂施用于受试者)。在这种情况下,所述术语治疗与术语“预防”同义使用。
术语“受试者”(其表示包括背景允许情况下的“个体”、“动物”、“患者”或“哺乳动物”)定义了指出进行治疗的任何受试者,具体地哺乳动物受试者。哺乳动物受试者包括(但不限于)人、家畜(domesticanimals)、农畜(farmanimals)、动物园动物、运动动物(sportanimals)和宠物。在优选的实施方式中,所述受试者是人。
如本文所使用的,化合物或组合物的有效量定义了可以施用于受试者而无过度毒性、刺激、过敏反应或者其它问题或并发症,与合理的效益/风险比相当的量,但是该量足以提供所期望的效果,例如,通过受试者状况的永久性或暂时性改善所表现出的治疗或预防。根据个体的年龄和一般条件、施用模式及其它因素,所述量在不同受试者之间也将是不同的。因此,尽管不可能指出确切的有效量,但是本领域那些技术人员将能够使用常规实验方法和背景常识在任何个体病例中确定适合的“有效”量。在本文中,治疗结果包括症状的消除或减轻、减轻的疼痛或不适、延长的存活时间、改善的活动能力以及临床改善的其它标志。治疗结果不必需是完全治愈。
在本文中使用术语“代谢综合征”来定义其特征为存在三个或更多个下列症状的病况:中心性肥胖(男性腰围大于40英寸,女性腰围大于35英寸);高甘油三酯水平(150mg/dL以上);低HDL水平(男性低于40mg/dL,女性低于50mg/dL)和高血压(130/85mmHg以上)。
因此,术语包括根据世界卫生组织的代谢综合征定义所定义的状况:(a)空腹血糖大于6.1mmol/L;(b)血压大于140/90mmHg;和(c)以下中的一种或多种:(i)血浆甘油三酯大于1.7mmol/L;(ii)HDL低于0.9和1.0mmol/L(分别针对男性和女性);(iii)体重指数大于30kg/m2。
在本文中,对代谢综合征治疗的提及将理解为包括与代谢综合征有关的任何或所有病症的治疗,具体地包括肥胖症(例如,中心性肥胖)和血清甘油三酯升高。
在本文中,对1型或2型糖尿病治疗的提及将理解为包括1型和2型糖尿病本身以及糖尿病前期(pre-diabetes)(前期糖尿病(incipientdiabetes))和胰岛素抵抗的治疗。
术语“糖尿病前期”或“前期糖尿病”定义了其中在没有糖尿病的情况下,存在葡萄糖或糖基化血红蛋白水平提高的情况。
本发明的医学用途
控制血液和组织中的糖以及减轻重量的健康益处很多,包括控制糖尿病、代谢综合征、减缓心血管系统破坏和减缓皮肤衰老。亚胺糖对健康具有多种潜在益处,其包括Th-1免疫应答调节、抗炎活性、抗癌和抗病毒活性,并且显示了改善功能性的蛋白质伴护(chaperoning)(Nash,R.J.,等人2011,Iminosugarsastherapeuticagents:recentadvancesandpromisingtrends.FutureMed.Chem.3(12):1513-1521)。亚胺糖还有可能控制昆虫及其它植物害虫(有害体,pest),并因此它们的存在还可以与水稻品种的抗害虫和病原体程度有关(Nash,R.J.,等人,1996,Polyhydroxylatedalkaloidsthatinhibitglycosidases.In:Alkaloids:ChemicalandBiologicalPerspectives.第11卷.S.W.Pelletier(主编).ElsevierScienceLtd.Oxford.第345-376页)。
本发明在营养不良的治疗和任何能量利用疾病中具有广泛应用。
因此,根据本发明可以治疗的疾病包括(例如)体内平衡病症、代谢疾病、糖代谢功能障碍和食欲障碍。
在优选的实施方式中,本发明在胰岛素抵抗、各种糖尿病形式、代谢综合征、肥胖症、消耗综合征(例如,癌症相关性恶病质)、肌病、胃肠疾病、生长停滞、高胆固醇血症、动脉粥样硬化和年龄相关性代谢功能障碍的治疗中具有应用。
本发明还可以用于与以下有关的病况的治疗:代谢综合征、肥胖症和/或糖尿病,包括(例如)高血糖症、葡萄糖耐受不良、高胰岛素血症(hyperinsulinaemia)、糖尿、代谢性酸中毒、白内障、糖尿病性神经病变、糖尿病性肾病、糖尿病性视网膜病、黄斑变性、肾小球硬化症、糖尿病性心肌病、胰岛素抵抗、葡萄糖代谢障碍、关节炎、高血压、高脂血症、骨质疏松症、骨质减少、骨质流失、脆骨综合征、急性冠状动脉综合征、不育、短肠综合征、慢性疲劳、进食障碍、肠运动功能障碍和糖代谢功能障碍。
本发明还可以用于抑制食欲。
特别优选胰岛素抵抗、代谢综合征、肥胖症和糖尿病(具体地,2型糖尿病)的治疗。
胰岛素抵抗、代谢综合征和糖尿病
本发明在胰岛素抵抗治疗中具有应用。胰岛素抵抗的特征在于胰岛素在骨骼肌、脂肪细胞和肝细胞中的作用降低,从而正常量的胰岛素不足以从这些组织的细胞中产生正常的胰岛素反应。在脂肪细胞中,胰岛素抵抗导致储存的甘油三酯水解,从而导致血浆中游离脂肪酸升高。在肌肉中,胰岛素抵抗降低葡萄糖吸收,而在肝细胞中,它降低葡萄糖储存。在后两种情况中,均导致血糖浓度升高。由于胰岛素抵抗所造成的高胰岛素和葡萄糖血浆水平通常发展成代谢综合征和2型糖尿病。
本发明在代谢综合征(如本文所定义的)的治疗中具有应用。该病症也称为(代谢)综合征X、胰岛素抵抗综合征、Reaven's综合征和CHAOS。
本发明在与代谢综合征有关的疾病的治疗中具有应用,其包括(例如):脂肪肝(通常发展成非酒精性脂肪肝疾病)、多囊卵巢综合征、血色沉着病(铁过载)和黑棘皮病(皮肤暗块)。
本发明在2型糖尿病治疗中具有应用。2型糖尿病是其特征在于血糖水平持续升高的慢性疾病(高血糖症)。该疾病的特征在于胰岛素抵抗以及胰腺β-细胞中胰岛素分泌受损。胰岛素抵抗向2型糖尿病的发展的标志在于当胰腺β-细胞不能产生足够的胰岛素以维持正常血糖水平(血糖正常)时,进食后高血糖症出现。
1型糖尿病
本发明在1型糖尿病(或胰岛素依赖型糖尿病)的治疗中具有应用。1型糖尿病的特征在于胰腺中胰岛的胰岛素产生β-细胞的损失,从而导致了胰岛素的缺乏。造成这种β-细胞损失的主要原因在于T细胞介导的自身免疫攻击。尚没有可以针对1型糖尿病(在北美洲和欧洲,其占糖尿病病例的多至10%)的已知预防措施。当疾病发生时,大部分受影响的人在其他方面是健康的或具有健康体重。对胰岛素的敏感性和反应性通常是正常的,特别是在早期阶段。
例证
现在,将参考具体的实施例来说明本发明。这些仅是示例性的并且仅出于说明性的目的:它们不意欲以任何方式限制所述本发明独占地主张的范围。这些实施例构成了目前对实践本发明所考虑的最佳方式。
实施例1:黑米(黑稻,BlackRice)中的亚胺糖
在通常用于蒸煮的沸水中提取来自意大利的黑米(GalloVenereRisoNero-26/04/15销售-80011420002782),并且将样品磨碎并在50%冷乙醇水溶液中提取。将两种提取物过滤并在处于H+形式的强酸型阳离子交换树脂IR120上分级。用水清洗后,用2M氨溶液替换保留的材料,并通过旋转蒸发减小体积。然后,将冷提取材料的IR120保留部分在阴离子交换树脂(CG400OH-形式)上进一步分离成结合和未结合样品。将所有部分(级分、馏分,fraction)对一组糖苷酶进行测定,并且它们显示出α和β-葡萄糖苷酶抑制,这可能是由于fagomine和DNJ造成的,但是另外它们强烈抑制α-和β-半乳糖苷酶(α-andβ-galactosidase)和两种N-乙酰基-β-D-氨基葡萄糖苷酶(N-acetyl-β-D-glucosaminidases),这可能不是由fagomine或DNJ造成的。
根据所述方法,通过气相色谱法(GC-MS)的所述部分的分析显示亚胺糖的复杂混合物包含16%的低分子量氨基酸部分(IR120树脂保留)。8.5mg/100g稻米似乎是fagomine加一些其它亚胺糖,一些可能是新型的(与质谱的报道结构不匹配)。Fagomine提供了独特的质谱图,这是由于三甲基甲硅烷基衍生物在144、170、260和348amu观察到了主要片段。这种稻米中其它亚胺糖的特征在于170、262、286和376amu处的独特亚胺糖片段。还观察到了具有类似光谱但更短保留时间(6.47分钟,相比之下fagomine为7.2分钟)的fagomine的差向异构体(可能是3-epifagomine)。
GC-MS
衍生化前,将所有样品冻干。使用六甲基二硅氮烷(hexamethyldisilazane)和三甲基氯硅烷在吡啶中的混合物(Pierce‘Tri-Sil’硅烷化试剂,HMDS:TMCS:吡啶的比值为2:1:10)制备三甲基甲硅烷基(TMS,Trimethylsilyl)衍生物。将样品在60℃加热15分钟,然后在室温下保持至少60分钟。通过离心使不溶的反应产物沉淀,并使用注射器将上清液转移到新的小瓶中。
使用具有高极性熔融石英柱(fused-silicacolumn)(Varian‘FactorFour’VF-5ms柱,25m×0.25mmi.d.,0.25μm相厚度)的PerkinElmerAutosystemXL气相色谱仪,通过GC-MS进行分析。载气(氦)流速为1mlmin-1。使用起始于160℃,5分钟,随后以10℃min-1的速度,线性提高至300℃的升温程序分离三甲基甲硅烷基-(TMS)衍生物。将温度在300℃保持另外10min;总分析时间为29分钟。在带有四极离子过滤系统的PerkinElmerTurboMassGold质谱仪进行柱洗脱液的电子碰撞质谱(electronimpactmassspectrometry),在分析期间以250℃持续运行。检测器质量范围设置为100至650amu。传输线(transferline)(GC至MS)的温度保持在250℃。通过装有去活化(deactivated)石英棉的熔融石英窄孔注射衬垫(afusedsilicanarrowboreinjectionliner),经由分流出口(分流比50:1)将样品注入所述柱上;进样口温度保持在200℃。进样体积为1μl。使用PerkinElmerTurboMass软件(TurboMassν.4.4)进行系统控制、数据收集和质谱分析。
对GalloVenere黑米的乙醇水溶液提取物进行糖苷酶抑制测定
除了来自Megazyme的β-甘露糖苷酶外,所有的酶和对硝基苯底物(对硝基苯基底物,para-nitrophenylsubstrate)购自Sigma。在处于酶的最适pH值的0.1M柠檬酸/0.2M磷酸氢二钠缓冲液中,在27℃测定酶。培育混合物包括10μl酶溶液、10μl10mg/ml的提取物水溶液和50μl在处于酶的最适pH值的缓冲液中构成的适当的5mM对硝基苯底物。在反应的指数期(使用其中水替代抑制剂的不受抑制的测定,在开始时已确定),通过加入70μl0.4M甘氨酸(pH10.4)终止反应。使用Versamax酶标仪(微板读取器,microplatereader)(MolecularDevices),在405nm读取最终的吸光值。测定重复三次,并且给出的数值表示为每次测定3个重复的平均值。方法的参考文献:-
Watson,A.A.等人.(1997).Glycosidase-inhibitingpyrrolidinealkaloidsfromHyacinthoidesnon-scripta.Phytochemistry46(2):255-259
表1:阴离子交换树脂分离的黑米提取物的平均糖苷酶抑制%
实施例2.商品化米粒(稻米谷粒,ricegrains)的fagomine含量
据称一些稻米品种具有低于其它品种(例如,棕色印度香米)的GI指数。
在50%乙醇水溶液中提取了一组挑选的超市稻米产品,并使用阳离子交换色谱法(IR120H+形式)浓缩氨基酸部分。发现在声称具有低GI指数的一些品种(例如,棕色印度香米和泰国茉莉香米)中存在Fagomine和可能的其它亚胺糖,并且在其它品种(例如,长粒白米)中没有或浓度显著更低。在一些品种中还存在1-脱氧野尻霉素(DNJ)。测量了葡糖醛酸酶(葡糖醛酸苷酶,glucuronidase)抑制,其表明还可以存在亚胺糖酸。亚胺糖可以通过减缓GI道中复合碳水化合物的降解来降低GI指数。
表2:商品化米粒的fagomine含量
使用可信的DMDP(2,5-二羟基甲基-3,4-二羟基吡咯烷)(每个样品0.1mg)作为内标,对fagomine定量。
使用如下所述的方法,通过GC-MS,fagomine(三甲基甲硅烷基衍生物)的保留时间为7.5分钟,DMDP为8.83分钟。
GC-MS
衍生化前,将所有样品冻干。使用六甲基二硅氮烷和三甲基氯硅烷在吡啶中的混合物(Pierce‘Tri-Sil’硅烷化试剂,HMDS:TMCS:吡啶的比值为2:1:10)制备三甲基甲硅烷基(TMS)衍生物。将样品在60℃加热15分钟,然后在室温下保持至少60分钟。通过离心使不溶的反应产物沉淀,并使用注射器将上清液转移到新的小瓶中。
使用具有高极性熔融石英柱(Varian‘FactorFour’VF-5ms柱,25m×0.25mmi.d.,0.25μm相厚度)的PerkinElmerAutosystemXL气相色谱仪,通过GC-MS进行分析。载气(氦)流速为1mlmin-1。使用起始于160℃,5分钟,随后以10℃min-1的速度,线性提高至300℃的温度程序分离三甲基甲硅烷基-(TMS)衍生物。将温度在300℃保持另外10min;总分析时间为29分钟。在带有四极离子过滤系统的PerkinElmerTurboMassGold质谱仪进行柱洗脱液的电子碰撞质谱,在分析期间以250℃持续运行。检测器质量范围设置为100至650amu。传输线(GC至MS)的温度保持在250℃。通过装有去活化(deactivated)石英棉的熔融石英窄孔注射衬垫,经由分流出口(分流比50:1)将样品注入所述柱上;进样口温度保持在200℃。进样体积为1μl。使用PerkinElmerTurboMass软件(TurboMassν.4.4)进行系统控制、数据收集和质谱分析。
尽管在棕色印度香米中fagomine含量相当低,每100g为约1mg,但是在这种稻米中,含有亚胺糖的总氨基酸部分重量不是很高,估计1.9%为fagomine。这使得fagomine成为低分子量口服可用含氮部分的显著成分。通过对比,在氨基酸部分中,所研究的大部分稻米样品不含fagomine(或者以长粒糙米为例,低于0.03%的检测限)。
表3:显示阳离子交换树脂保留部分(10mg/ml)的平均糖苷酶抑制%
购买的米粒的糖苷酶抑制测定
β-葡糖醛酸酶和对硝基苯底物购自Sigma。在处于酶的最适pH值的0.1M柠檬酸/0.2M磷酸氢二钠缓冲液中,在27℃测定酶。培育混合物包括10μl酶溶液、10μl10mg/ml的提取物水溶液和50μl在处于酶的最适pH值的缓冲液中构成的适当的5mM对硝基苯底物。在反应的指数期(使用其中水替代抑制剂的不受抑制的测定,在开始时已确定),通过加入70μl0.4M甘氨酸(pH10.4)终止反应。使用Versamax酶标仪(MolecularDevices),在405nm读取最终的吸光值。测定重复三次,并且给出的数值表示为每次测定3个重复的平均值。在Watson,A.A.,等人,1997,Glycosidase-inhibitingpyrrolidinealkaloidsfromHyacinthoidesnon-scripta.Phytochemistry46(2):255-259中描述了所述方法,该文献作为参考并入本文。
实施例3.稻米饮料-RiceDream你的活力之源(RiceDreamyour
sourceofvitality)中的亚胺糖
RiceDream购自Waitrose超市(HainEuropeN.V.Industrielaan11A,9990Maidegem,BelgiumOrganic16.03.101L29-45-075)。
将100ml施加于处于H+形式的阳离子交换树脂IR120柱(2×20cm)上,并且保留部分(用2M氨溶液替换)获得了15mg含有亚胺糖的氨基酸部分。
如下所述,通过GC-MS分析的RiceDream乳含有保留时间(11.17分钟)类似于葡萄糖的1-脱氧野尻霉素(DNJ),并且具有在217、258、348amu具有离子的独特片段(在所述条件下的tms)。在10.6分钟(离子230、246、290和302amu)和11.4分钟(离子156、200和217amu)观察到了其它可能的亚胺糖。
GC-MS
衍生化前,将所有样品冻干。使用六甲基二硅氮烷和三甲基氯硅烷在吡啶中的混合物(Pierce‘Tri-Sil’硅烷化试剂,HMDS:TMCS:吡啶的比值为2:1:10)制备三甲基甲硅烷基(TMS)衍生物。将样品在60℃加热15分钟,然后在室温下保持至少60分钟。通过离心使不溶的反应产物沉淀,并使用注射器将上清液转移到新的小瓶中。
使用具有高极性熔融石英柱(Varian‘FactorFour’VF-5ms柱,25m×0.25mmi.d.,0.25μm相厚度)的PerkinElmerAutosystemXL气相色谱仪,通过GC-MS进行分析。载气(氦)流速为1mlmin-1。使用起始于160℃,5分钟,随后以10℃min-1的速度,线性提高至300℃的温度程序分离三甲基甲硅烷基-(TMS)衍生物。将温度在300℃保持另外10min;总分析时间为29分钟。在带有四极离子过滤系统的PerkinElmerTurboMassGold质谱仪进行柱洗脱液的电子碰撞质谱,在分析期间以250℃持续运行。检测器质量范围设置为100至650amu。传输线(GC至MS)的温度保持在250℃。通过装有去活化(deactivated)石英棉的熔融石英窄孔注射衬垫,经由分流出口(分流比50:1)将样品注入所述柱上;进样口温度保持在200℃。进样体积为1μl。使用PerkinElmerTurboMass软件(TurboMassν.4.4)进行系统控制、数据收集和质谱分析。
实施例4.BalanceFoodsFairtrade有机稻米饮料中的亚胺糖
在WaitroseAbergavenny购买稻米乳饮料(ricemilkdrink)。它由BalanceFoods出售,1升,BalanceFoodsLtd,ElsteadGU86LB06:44:24。
将100ml施加于处于H+形式的阳离子交换树脂IR120柱(2×20cm)上,并且保留部分(用2M氨溶液替换)获得了6.9mg含有亚胺糖的氨基酸部分。
样品含有fagomine和具有稍微更长保留时间的fagomine差向异构体(8.3分钟,而不是fagomine的8.1分钟);在所述条件下,两种化合物提供了fagomine的特征性三甲基甲硅烷基-断裂(片段化)方式,其中在144、170和260amu具有片段。
GC-MS
衍生化前,将所有样品冻干。使用六甲基二硅氮烷和三甲基氯硅烷在吡啶中的混合物(Pierce‘Tri-Sil’硅烷化试剂,HMDS:TMCS:吡啶的比值为2:1:10)制备三甲基甲硅烷基(TMS)衍生物。将样品在60℃加热15分钟,然后在室温下保持至少60分钟。通过离心使不溶的反应产物沉淀,并使用注射器将上清液转移到新的小瓶中。
使用具有高极性熔融石英柱(Varian‘FactorFour’VF-5ms柱,25m×0.25mmi.d.,0.25μm相厚度)的PerkinElmerAutosystemXL气相色谱仪,通过GC-MS进行分析。载气(氦)流速为1mlmin-1。使用起始于160℃,5分钟,随后以10℃min-1的速度,线性提高至300℃的温度程序分离三甲基甲硅烷基-(TMS)衍生物。将温度在300℃保持另外10min;总分析时间为29分钟。在带有四极离子过滤系统的PerkinElmerTurboMassGold质谱仪进行柱洗脱液的电子碰撞质谱,在分析期间以250℃持续运行。检测器质量范围设置为100至650amu。传输线(GC至MS)的温度保持在250℃。通过装有去活化(deactivated)石英棉的熔融石英窄孔注射衬垫,经由分流出口(分流比50:1)将样品注入所述柱上;进样口温度保持在200℃。进样体积为1μl。使用PerkinElmerTurboMass软件(TurboMassν.4.4)进行系统控制、数据收集和质谱分析。
实施例5.六种不同稻米样品的分析
在2012-13,在Aberystwyth购买了以下稻米样品:
表4:稻米样品
将30g稻米样品细磨,然后将20g每种样品在50%的乙醇水溶液中浸泡至少1天。将混悬液过滤,并向下通过处于H+形式的IR120柱(5×2cm)。用大量水清洗后,用2M氨溶液洗脱结合的材料。使用旋转蒸发和冷冻干燥使溶液干燥,并对残余物称重。获得了以下结合样品的重量:-
这些重量代表了20g每类稻米中存在的氨基酸和亚胺糖的量。对如上所述的每种样品进行三甲基甲硅烷基化样品的GCMS分析,并且在两种印度香米样品中检测到了鉴别为亚胺糖fagomine(通过144、170和260amu的特征离子)的7.08min时的峰值,但在其它样品中没有。为了确认该发现,对更大量的其它4种稻米类型进行GCMS,但是在这些样品中未检测到fagomine或1-脱氧野尻霉素。
实施例6:稻米中的Fagomine相关化合物。
已报道了D-fagomine作为膳食组成或功能性食品成分来降低与过量摄入快速消化碳水化合物有关的健康风险的可能(在1mg/kg有效),并且D-fagomine可以抑制潜在病原细菌(如大肠杆菌(Escherichiacoli)和肠沙门氏菌(Salmonellaenterica))对肠粘膜的粘附,同时促进乳酸杆菌属(Lactobacillusspp.)的粘附(Gomez,L.等人,Brit.J.Nutr.2012,107,1739-1746)。
进行进一步分析以表征与BBJ10-15(如以上实施例5中所列)和另外第7种稻米样品BBJ09中fagomine有关的化合物:
代码 | 供应商 | 商标名称 | 产品名称 | 批号 | 有效期限 | 国家 |
BBJ09 | Milbo Spa | Gallo Venere | 黑米 | 26.3.15 | 意大利 |
使用OH-形式的AmberliteCG400阴离子交换树脂对7种商品化稻米样品的阳离子交换树脂保留部分进一步分离。收集水洗脱部分(waterfractions),然后用1M乙酸清洗。碱性化合物(如fagomine和DNJ)存在于水清洗部分中,而酸性和中性化合物存在于酸清洗部分中。
将样品冻干,并通过向1mg干燥样品中加入30μlPierceTriSil来作为三甲基甲硅烷基衍生物进行分析。使用具有高极性熔融石英柱(Varian‘FactorFour’VF-5ms柱,25m×0.25mmi.d.,0.25μm相厚度)的PerkinElmerAutosystemXL气相色谱仪,通过GC-MS进行分析。载气(氦)流速为1mlmin-1。使用起始于160℃,5分钟,随后以10℃min-1的速度,线性提高至300℃的温度程序分离三甲基甲硅烷基-(TMS)衍生物。将温度在300℃保持另外10min;总分析时间为29分钟。在带有四极离子过滤系统的PerkinElmerTurboMassGold质谱仪进行柱洗脱液的电子碰撞质谱,在分析期间以250℃持续运行。检测器质量范围设置为100至650amu。传输线(GC至MS)的温度保持在250℃。通过装有去活化(deactivated)石英棉的熔融石英窄孔注射衬垫,经由分流出口(分流比50:1)将样品注入所述柱上;进样口温度保持在200℃。进样体积为1μl。
此外,相同稻米批次含有试验性地鉴别为N-乙基-fagomine(N-ethyl-fagomine)的化合物,其保留时间为8.10分钟,并且在144、170和260amu(如fagomine一样)具有独特的离子(tms),并且在198(100%)、288、376(分子离子-15)和391(分子离子)具有额外的离子。
除了fagomine之外,Tilda印度香米和Tilda全粒印度香米还含有保留时间稍短(4-5分钟)的哌啶酸(pipecolicacid)衍生物,并将其试验性地鉴别为3,4-二羟基哌啶酸(3,4-dihydroxypipecolicacid)、3-羟基哌啶酸(3-hydroxypipecolicacid)和4-羟基哌啶酸(4-hydroxypipecolicacid)。所述化合物提供了独特的tms光谱,其在172(100%)以及130和156(两者均为30%)具有片段。
尽管不是葡萄糖苷酶抑制剂,但是哌啶酸在结构上与报道具有抗糖尿病活性的来自匙羹藤(Gymnemasylvestre)的3,4,5-三羟基哌啶酸(3,4,5-trihydroxypipecolicacid)(参见WO2009/103953)有关。有可能哌啶酸和fagomine在生物合成上是相关的。还声称羟基化哌啶酸(例如,(2R,3R,4R,5S)-3,4,5-三羟基哌啶-2-羧酸(6-epiBR1;2R,3R,4R,5S-三羟基哌啶酸;ido-BR1-参见Bashyal等人,(1986)TetrahedronLett.27:3205-3208)具有抗炎活性,并因此稻米还可能具有与降低炎性病症有关的益处。
在其它研究的米粒中,哌啶酸和N-乙基-fagomine不明显。
大鼠消化酶测定(表5)
大鼠的肠丙酮粉提取物购自Sigma(I1630lotSLBB6071V)以提供与消化更密切相关的结果。将100mg丙酮粉与1ml冷PBS混合,均质化,短暂超声处理,然后以12Krpm离心3min。大鼠肠提取物对PNPα-糖苷和PNPβ-半乳糖苷底物显示出良好的活性。它对PNPα-半乳糖苷底物显示出更强的活性,但是对PNPβ-糖苷的活性要弱许多。fagomine抑制α-葡萄糖苷酶活性,但是3-epifagomine和3,4-diepifagomine对所测量的活性均不抑制。
黑米提供了最强的消化酶抑制,不但对α-葡萄糖苷酶抑制,而且还强烈抑制α-半乳糖苷酶。黑米中来自不含fagomine的部分也提供了优良的α-葡萄糖苷酶抑制,如HS0816/78/10,其表明除了fagomine之外,它含有抑制α-葡萄糖苷酶的其它化合物(DNJ也不在该CG400阴离子交换树脂保留的部分中)。
两种印度香米样品提供了α-葡萄糖苷酶活性抑制。在该测定中,未测试另一种稻米样品(BBJ10-13)。
表5:糖苷酶抑制谱
底物抑制%
从这些大鼠消化结果能够清楚看出黑米和印度香米的成分可以抑制消化性糖苷酶。
等价内容
以上说明详细描述了本发明当前优选的实施方式。考虑到这些描述,对于本领域那些技术人员来说在本发明的实践中预期会发生多种改变和变化。那些改变和变化旨在涵盖在本发明所附的权利要求的范围内。
Claims (28)
1.一种用于产生包含来源于稻属(Oryza)植物种子的材料的组合物的工艺,所述工艺包括以下步骤:
(a)提供来源于稻属种子的材料;和
(b)在步骤(a)的所述材料中确定至少一种亚胺糖的存在或不存在和/或测量至少一种亚胺糖的量。
2.一种用于监控包含来源于稻属植物种子的材料的组合物的质量的方法,所述方法包括以下步骤:
(a)提供来源于稻属种子的材料;和
(b)在步骤(a)的所述材料中确定至少一种亚胺糖的存在或不存在和/或测量至少一种亚胺糖的量。
3.根据权利要求1所述的工艺或根据权利要求2所述的方法,其中确定至少一种亚胺糖存在。
4.根据权利要求3所述的工艺或方法,用于产生包含至少一种亚胺糖的组合物,还包括鉴别和/或分离所述亚胺糖的步骤。
5.根据前述权利要求中任一项所述的工艺或方法,其中确定至少一种亚胺糖不存在。
6.根据前述权利要求中任一项所述的工艺或方法,其中所述组合物选自:(a)食物;(b)膳食增补剂;(c)强化的食物或食品增补剂;(d)浓缩的食物或食品增补剂;(e)美容组合物;(f)高卡路里营养增补剂或食物;(g)功能性食品增补剂;(h)高GI食物或膳食增补剂;或(i)低GI食物或膳食增补剂。
7.根据前述权利要求中任一项所述的工艺或方法,其中所述至少一种亚胺糖具有选自以下的结构类别:
(a)哌啶;
(b)吡咯啉;
(c)吡咯烷;
(d)吡咯里西啶;
(e)吲哚里西啶;
(f)喹诺里西啶;
(g)去甲茛菪烷;
(h)开环亚胺糖;
(i)5,7稠合;
(j)环己亚胺;
(k)氮杂环丁烷;
(l)多羟基化生物碱;
(m)亚胺糖酸(例如,(聚)羟基哌啶酸);或
(n)(a)至(m)中任何两种或更多种的混合物。
8.根据前述权利要求中任一项所述的工艺或方法,其中所述至少一种亚胺糖选自:(a)哌啶;(b)吡咯烷;(c)亚胺糖酸(例如,(聚)羟基哌啶酸);和/或(d)任何上述的混合物。
9.根据前述权利要求中任一项所述的工艺或方法,其中所述至少一种亚胺糖在体外和/或体内起到以下糖苷酶类中的一种或多种酶的配体的作用,例如,作为所述酶的抑制剂:
(a)α-葡萄糖苷酶;
(b)β-葡萄糖苷酶;
(c)α-半乳糖苷酶;
(d)β-半乳糖苷酶;
(e)α-甘露糖苷酶;
(f)α-岩藻糖苷酶;或
(g)α-艾杜糖醛酸酶;或
(h)β-葡萄糖醛酸酶;或
(i)β-甘露糖苷酶;或
(j)氨基己糖苷酶;或
(k)α-N-乙酰氨基葡糖苷酶;或
(l)α-N-乙酰氨基半乳糖苷酶;或
(m)β-N-乙酰氨基葡糖苷酶;或
(n)β-N-乙酰氨基半乳糖苷酶;或
(o)唾液酸酶;或
(p)肝素酶;或
(q)神经氨酸苷酶;或
(r)透明质酸酶;或
(s)淀粉酶;或
(t)上述酶类的两种或更多种。
10.根据前述权利要求中任一项所述的工艺或方法,其中所述至少一种亚胺糖是:(a)葡萄糖苷酶抑制剂;和/或(b)α-半乳糖苷酶抑制剂;和/或(c)β-半乳糖苷酶抑制剂;和/或(d)N-乙酰-β-D-氨基葡糖苷酶抑制剂;和/或(e)葡萄糖醛酸酶抑制剂。
11.根据前述权利要求中任一项所述的工艺或方法,其中所述至少一种亚胺糖选自:(a)fagomine;(b)fagomine的差向异构体,例如,3-epifagomine;(c)N-乙基-fagomine;(d)DNJ;或(e)亚胺糖酸;或(f)(a)-(e)的组合。
12.根据权利要求11所述的工艺或方法,其中所述亚胺糖酸是(聚)羟基哌啶酸,例如,选自:(a)3,4-二羟基哌啶酸;(b)3-羟基哌啶酸;和(c)4-羟基哌啶酸。
13.通过根据前述权利要求中任一项所述的工艺可获得的组合物:(a)在治疗营养不良或能量利用疾病的方法中应用;或者(b)当作为化妆品应用。
14.根据权利要求13所述的组合物,其中所述能量利用疾病选自:(a)体内平衡病症;(b)代谢疾病;(c)糖代谢功能障碍;(d)食欲障碍;(e)胰岛素抵抗;(f)糖尿病(例如,1型或2型糖尿病);(g)糖尿病前期;(h)代谢综合征;(i)肥胖症;(j)消耗综合征(例如,癌症相关性恶病质);(k)肌病;(l)胃肠疾病;(m)生长停滞;(n)高胆固醇血症;(o)动脉粥样硬化;(p)年龄相关性代谢功能障碍;(q)高血糖症;(r)葡萄糖耐受不良;(s)高胰岛素血症;(t)糖尿;(u)代谢性酸中毒;(v)白内障;(w)糖尿病性神经病变;(x)糖尿病性肾病;(y)糖尿病性视网膜病;(z)黄斑变性;(aa)肾小球硬化症;(bb)糖尿病性心肌病;(cc)葡萄糖代谢障碍;(dd)关节炎;(ee)高血压;(ff)高脂血症;(gg)骨质疏松症;(hh)骨质减少;(ii)骨流失;(jj)脆骨综合征;(kk)急性冠状动脉综合征;(ll)不育;(mm)短肠综合征;(nn)慢性疲劳;(oo)进食障碍;(pp)肠运动功能障碍;(qq)糖代谢功能障碍;(rr)脂肪肝;(ss)多囊卵巢综合征;(tt)血色沉着病;和(uu)黑棘皮病。
15.一种用于选择稻属植物育种品系和/或品种的方法,所述方法包括以下步骤:
(a)提供材料,例如,来源于稻属植物的种子或营养部分;和
(b)确定步骤(a)的所述材料中至少一种亚胺糖的存在或不存在和/或测量至少一种亚胺糖的量,任选地其中所述至少一种亚胺糖如前述权利要求中任一项所定义的。
16.根据权利要求15所述的方法,其中所述方法用于针对以下各项来选择育种品系和/或品种:(a)害虫和/或病原体抗性;(b)作为用于饥荒救济的食物的植物来源;(c)作为低GI指数食物的植物来源;或(d)作为高GI指数食物的植物来源。
17.根据前述权利要求中任一项所述的工艺、方法或组合物,其中所述稻属植物选自:(a)普通栽培稻(Oryzasativa)(亚洲稻);(b)非洲栽培稻(Oryzaglabaerreima)(非洲稻);或(c)(a)和(b)的组合。
18.根据前述权利要求中任一项所述的工艺、方法或组合物,其中来源于稻属植物种子的材料包括:(a)籼米;(b)粳米;(c)香米;(d)糯米;(e)糙米;(f)白米;(g)黑米;(h)紫米;(i)红米;或(j)(a)-(i)的组合。
19.根据前述权利要求中任一项所述的工艺、方法或组合物,其中来源于稻属植物种子的材料包括米糠。
20.根据前述权利要求中任一项所述的工艺、方法或组合物,其中所述来源于稻属植物种子的材料包括:(a)非粘米;(b)粘米;(c)长粒米;(d)短粒米;(e)中粒米;或者(f)(a)-(e)的组合。
21.根据前述权利要求中任一项所述的工艺、方法或组合物,其中确定至少一种亚胺糖的存在或不存在和/或测量至少一种亚胺糖的量的步骤包括所述亚胺糖的功能和/或物理和/或化学表征。
22.根据权利要求21所述的工艺、方法或组合物,其中所述功能表征包括生物测定,例如,选自:
(a)体内或体外测定;和/或
(b)酶抑制测定(例如,糖苷酶和/或脂肪酶抑制);和/或
(c)受体结合测定;和/或
(d)细胞测定(例如,细胞复制、细胞-病原体、细胞-细胞相互作用和细胞分泌测定);和/或
(e)免疫测定;和/或
(f)抗微生物活性(例如,细菌和病毒细胞-结合和/或复制)测定;和/或
(g)毒性测定(例如,LD50测定)。
23.根据权利要求21或22所述的工艺、方法或组合物,其中所述物理表征选自:
(a)一种或多种植物化学成分的定量;和/或
(b)组分纯度的测量;和/或
(c)分子量(或者在包含多种不同植物化学成分的部分的情况下,分子量分布或其各个统计函数)的确定;和/或
(d)一种或多种分子式的确定(例如,通过核磁共振);和/或
(e)谱分析,例如,用以产生:(i)质谱和/或色谱数据和/或光电二极管阵列(PDA)谱和/或核磁共振(NMR)谱;和/或
(f)GC-MS和/或HPLC-PDA-MS。
24.根据权利要求21-23所述的工艺、方法或组合物,其中所述化学表征包括以下的测量:
(a)一种或多种植物化学成分的化学反应性;和/或
(b)一种或多种植物化学成分的溶解度;和/或
(c)一种或多种植物化学成分的稳定性和熔点。
25.来源于稻属植物种子的材料作为食品或饲料添加剂用于降低所述食品或饲料的升糖指数(GI)值的应用,所述材料包含至少一种亚胺糖。
26.权利要求25所述的应用,其中:(a)所述亚胺糖如权利要求1-24中任一项所定义;和/或(b)所述稻属植物如权利要求16所定义;和/或(c)来源于所述种子的所述材料如权利要求17-19中任一项所定义;和/或(d)来源于所述种子的所述材料是根据权利要求1-11或16-24中任一项所述的工艺或方法可获得的。
27.权利要求25或26所述的应用,其中所述材料富含所述至少一种亚胺糖。
28.根据权利要求25-27中任一项所述的应用,其中所述食品或饲料选自:(a)干燥的早餐谷类食品;(b)用于糖尿病患者的食品;(c)作为控制热量的饮食的一部分消费的减肥食品或饮料;(d)面包;(f)面粉;(g)运动饮料;(h)含咖啡因饮料;(i)含有稻米和/或谷类的小吃棒;或(j)干燥的稻米和/或谷物早餐食品。
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GB1313440.8 | 2013-07-29 | ||
GBGB1313440.8A GB201313440D0 (en) | 2013-07-29 | 2013-07-29 | Characterization of rice |
PCT/GB2014/052319 WO2015015186A1 (en) | 2013-07-29 | 2014-07-29 | Characterization of rice |
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EP (1) | EP3027185B1 (zh) |
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KR (1) | KR20160048089A (zh) |
CN (1) | CN105517550A (zh) |
GB (1) | GB201313440D0 (zh) |
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CN110099678A (zh) * | 2016-12-23 | 2019-08-06 | 欧莱雅 | 含有透明质酸和协同抗透明质酸酶活性剂的组合物 |
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CN111965278A (zh) * | 2020-08-07 | 2020-11-20 | 广西壮族自治区蚕业技术推广站 | 一种检测桑枝中1-脱氧野尻霉素含量的试剂盒及方法 |
CN113341032B (zh) * | 2021-07-22 | 2022-11-11 | 上海交通大学 | 一种鉴别粳籼稻品种的方法 |
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CA2752868C (en) | 2008-02-18 | 2018-11-27 | Summit Corporation Plc | Treatment of energy utilization disease |
WO2010049678A2 (en) * | 2008-10-31 | 2010-05-06 | Summit Corporation Plc | Treatment of energy utilization diseases |
KR20100104159A (ko) * | 2009-03-16 | 2010-09-29 | 김기호 | 미네랄, 한방제 강화 기능성 첨가제 |
CN101785544A (zh) * | 2010-03-03 | 2010-07-28 | 唐忠海 | 一种糯米桑叶糍粑的生产工艺技术 |
JP5526416B2 (ja) * | 2010-09-14 | 2014-06-18 | 独立行政法人国際農林水産業研究センター | α−グルコシダーゼ阻害活性を有する食品 |
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2014
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- 2014-07-29 JP JP2016530604A patent/JP2016531566A/ja active Pending
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2016
- 2016-01-27 US US15/008,336 patent/US20160213733A1/en not_active Abandoned
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I. A. ROSS等: "《MEDICINAL PLANTS OF THE WORLD. VOLUME 3:CHEMICAL CONSTITUENTS,TRADITIONAL AND MODERN MEDICAL USES》", 1 January 2005 * |
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CN110099678A (zh) * | 2016-12-23 | 2019-08-06 | 欧莱雅 | 含有透明质酸和协同抗透明质酸酶活性剂的组合物 |
CN110099678B (zh) * | 2016-12-23 | 2023-03-21 | 欧莱雅 | 含有透明质酸和协同抗透明质酸酶活性剂的组合物 |
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KR20160048089A (ko) | 2016-05-03 |
JP2016531566A (ja) | 2016-10-13 |
US20160213733A1 (en) | 2016-07-28 |
EP3027185A1 (en) | 2016-06-08 |
WO2015015186A1 (en) | 2015-02-05 |
EP3027185B1 (en) | 2020-01-22 |
GB201313440D0 (en) | 2013-09-11 |
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