CN114947139A - 一种影响肿瘤生长的氨基酸组合物、功能性食品及其应用 - Google Patents
一种影响肿瘤生长的氨基酸组合物、功能性食品及其应用 Download PDFInfo
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Abstract
本发明提供了一种影响肿瘤生长的氨基酸组合物、功能性食品及其应用,属于氨基酸技术领域。本发明通过癌细胞培养和转录组、代谢机制研究,严格限制丝氨酸和甘氨酸的含量,提高丙氨酸含量能有效抑制癌细胞和肿瘤组织的生长。因此,本发明开发出的严格限制丝氨酸和甘氨酸含量增加丙氨酸含量的功能性蛋白质或食品有利于发挥抗肿瘤的作用。
Description
技术领域
本发明属于氨基酸技术领域,具体涉及一种影响肿瘤生长的氨基酸组合物、功能性食品及其应用。
背景技术
癌症是世界范围内重大的公共卫生问题之一,占全球死亡原因的前列。
癌症的治疗方法目前集中在手术治疗、放射治疗、化学药物治疗、生物治疗、激素疗法等,而膳食作为肿瘤患者疾病治疗的基础保障,却仅仅着眼于提高营养状况,本身无明确治疗作用。营养素的代谢在肿瘤细胞与正常细胞中存在差异。肿瘤是机体在各种致瘤因子作用下,细胞遗传物质发生改变、基因表达失常,细胞异常增殖而形成的非正常组织。肿瘤细胞会避开生长抑制,甚至利用正常细胞去创造利于肿瘤生长、避免免疫破坏的肿瘤微环境(tumormicroenvironment,TME),以保证其持续增殖和生存。肿瘤细胞的代谢不同于正常细胞。其中,氨基酸的代谢在肿瘤细胞的增殖过程中有着重要作用,肿瘤细胞中氨基酸代谢耗能比重大,占癌细胞增殖总耗能的33~58%,亮氨酸和丝氨酸的消耗位居前列[1]。氨基酸参与肿瘤细胞增殖过程中的蛋白质生物合成,同时为核糖核酸(ribonucleic Acid,RNA)、脱氧核糖核酸(deoxyribonucleic acid,DNA)的合成提供碳源和氮源,保证肿瘤细胞的快速生长,丝氨酸和甘氨酸是一碳单位的重要来源。理论上,我们可以通过限制食物中的氨基酸水平,即限制肿瘤细胞可获得的外源性氨基酸,来调节其代谢,达到抑制肿瘤细胞增殖和生长的目的。事实上,不少动物实验研究发现,限制某些非必需氨基酸可以降低血清氨基酸水平,抑制肿瘤细胞的生长[2-9],并能加强抗肿瘤药物的治疗效果[10]。
公布号CN 110214937 A的专利中公布了一种用于肿瘤患者的特殊医学用途配方营养粉及其配制方法,所涉及的营养粉剂混合了蛋白质、脂肪、碳水化合物、复合矿物质、复合维生素、牛磺酸、单双甘油脂肪酸、核苷酸、左旋肉碱,以及一些增稠剂、香精、甜味剂,具有高蛋白、高脂肪和低碳水化合物特点,蛋白质的组成为乳清蛋白粉、大豆分离蛋白、牛乳、奶粉、大豆低聚肽、海洋低聚肽,少量L-精氨酸、L-谷氨酰胺、L-亮氨酸,增加了免疫物质精氨酸和核苷酸,旨在提高患者营养状况,减少肿瘤细胞代谢所需糖类,“饿死”肿瘤细胞。然而,在营养成分的设计时,局限于三大营养素的配比的调整、脂肪来源和免疫营养的添加,主要目的是为了提高患者营养状况,以此促进肿瘤康复,无明确肿瘤治疗效果,对于不同的肿瘤采用同样配方粉,不考虑不同肿瘤类型的代谢差异,肿瘤营养干预无针对性。
再例如公布号AU 2016326347 B2的专利通过在小鼠癌细胞的培养基中限制某些氨基酸来找到寻找癌细胞的营养弱点,即限制了特定氨基酸后某些类型的癌细胞生长受到抑制,由此设计了针对肺癌、肝癌、乳腺癌、前列腺癌、结肠癌、淋巴瘤或白血病的氨基酸补充剂,该补充剂含所有必需氨基酸,限制了半胱氨酸,以及精氨酸、谷氨酰胺、丝氨酸、酪氨酸中至少一种,治疗方法为:为肿瘤患者提供预包装无蛋白膳食和上述氨基酸补充剂。再例如公布号US 2020/0297679 A1的专利基于小鼠实验,设计了结合限制氨基酸和/或透析的方式,以降低血清氨基酸水平,达到抑癌的效果,其食物组成严格限制半胱氨酸,包含至少一种必需氨基酸,以及丙氨酸、天冬氨酸、天冬酰胺、甘氨酸、脯氨酸中的至少一种非必需氨基酸,透析液根据需求含不同氨基酸组成,以透析出身体内的特定氨基酸。以上两个专利均基于细胞培养、小鼠模型直接观察到的肿瘤大小结果,其代谢及转录机制不清,无人群实验,不能确定限制特定氨基酸后是否对营养指标或其它指标有不良影响,仅由细胞培养或小鼠模型的结果推导至人身上风险较高。
目前,市面上尚无针对肿瘤患者限制/调整氨基酸来抑制肿瘤生长的食品,膳食是肿瘤患者的营养保障,有必要开发一种限制/调整氨基酸的食品,作为肿瘤患者的膳食选择,并用于肿瘤治疗。
参考文献
[1]Kang JS.Dietary restriction of amino acids for Cancer therapy.NutrMetab(Lond).2020;17:20.Published 2020Mar 14.doi:10.1186/s12986-020-00439-x
[2]Xiao F,Wang C,Yin H,et al.Leucine deprivation inhibitsproliferation and induces apoptosis of human breast cancer cells via fattyacid synthase.Oncotarget.2016;7(39):63679-63689.doi:10.18632/oncotarget.11626
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[4]Locasale JW.Serine,glycine and one-carbon units:cancer metabolismin full circle.Nat Rev Cancer.2013;13(8):572-583.doi:10.1038/nrc3557
[5]Sullivan MR,Mattaini KR,Dennstedt EA,et al.Increased SerineSynthesis Provides an Advantage for Tumors Arising in Tissues Where SerineLevels Are Limiting.Cell Metab.2019;29(6):1410-1421.e4.doi:10.1016/j.cmet.2019.02.015
[6]Sousa CM,Biancur DE,Wang X,et al.Pancreatic stellate cells supporttumour metabolism through autophagic alanine secretion[published correctionappears in Nature.2016Dec 1;540(7631):150].Nature.2016;536(7617):479-483.doi:10.1038/nature19084
[7]Maddocks ODK,Athineos D,Cheung EC,Lee P,Zhang T,van den Broek NJF,Mackay GM,Labuschagne CF,Gay D,Kruiswijk F,Blagih J,Vincent DF,Campbell KJ,Ceteci F,Sansom OJ,Blyth K,Vousden KH.Modulating the therapeutic response oftumours to dietary serine and glycine starvation.Nature.2017Apr 19;544(7650):372-376.doi:10.1038/nature22056.
[8]Gravel SP,Hulea L,Toban N,et al.Serine deprivation enhancesantineoplastic activity of biguanides.Cancer Res.2014;74(24):7521-7533.doi:10.1158/0008-5472.CAN-14-2643-T.
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发明内容
有鉴于此,本发明的目的在于提供一种影响肿瘤生长的氨基酸组合物,该组合物经转录和代谢通路研究证明能够产生抑制肿瘤细胞生产的作用,而对正常细胞而言为非必需氨基酸。
本发明的目的还在于提供一种针对肿瘤患者的功能性食品,通过调整氨基酸种类的组成以及含量高低,达到明显抗肿瘤的作用。
本发明提供了一种影响肿瘤生长的氨基酸组合物,包括丝氨酸和甘氨酸。
优选的,还包括丙氨酸。
本发明提供了所述氨基酸组合物在制备抗肿瘤产品中的应用。
优选的,所述氨基酸组合物中丝氨酸和甘氨酸是癌细胞生长必需氨基酸,所述产品中抑制丝氨酸和甘氨酸的含量发挥抗肿瘤的作用。
优选的,所述产品中提高所述氨基酸组合物中丙氨酸的含量达到抗肿瘤的目的。
本发明提供了一种功能蛋白质,包括以下质量百分含量的氨基酸:丝氨酸0~0.00108%、甘氨酸0~0.0015%、丙氨酸4%~20%,余量为正常细胞生长所需的氨基酸。
优选的,所述正常细胞生长所需的氨基酸包括质量百分含量的10%~94%必需氨基酸;所述必需氨基酸包括以下重量份的组分:亮氨酸16.1~26.5份、赖氨酸11.5~20.1份、缬氨酸11.04~15.65份、苯丙氨酸9.66~16.1份、甲硫氨酸4.6~11.5份、异亮氨酸8.74~13.8份、苏氨酸8.7~12.7份和色氨酸2.2~6.5份;
所述正常细胞生长所需的氨基酸还包括0%~86%非必需氨基酸和条件必需氨基酸;所述非必需氨基酸和条件必需氨基酸包括以下一种或多种氨基酸:谷氨酸、天冬氨酸、天冬酰胺、谷氨酰胺、精氨酸、脯氨酸、酪氨酸、半胱氨酸和组氨酸。
本发明提供了一种功能性食品,包括所述功能蛋白质和辅料。
优选的,还包括膳食营养素。
本发明提供了所述功能蛋白质或所述功能性食品在改善肿瘤患者饮食中的应用;
优选的,所述肿瘤包括至少以下一种:结直肠癌、乳腺癌、淋巴瘤、胰腺癌、肺癌和肝癌。
本发明提供的影响肿瘤生长的氨基酸组合物,包括丝氨酸和甘氨酸。本发明以癌细胞为培养对照,分别评估缺乏13种氨基酸中一种或两种后对细胞生长的影响,培养基中省略添加丝氨酸和甘氨酸后,结直肠癌、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝癌、乳腺癌、胰腺导管腺癌细胞等多种癌细胞较为敏感,回补丝氨酸和甘氨酸后,癌细胞生长恢复。说明丝氨酸和甘氨酸为癌细胞生长所必需的氨基酸,培养基中缺乏丝氨酸和甘氨酸有利于抑制多种癌细胞的生长。
进一步的,本发明还限定了丙氨酸亦能影响肿瘤生长。通过转录和代谢机制研究,缺乏丝氨酸和甘氨酸的肿瘤组织中存在脂代谢的紊乱,而增加丙氨酸后,进一步促进肿瘤细胞中具有细胞毒性的doxSLs的合成,从而抑制癌细胞或肿瘤组织生长。
本发明提供了一种功能蛋白质,包括以下质量百分含量的氨基酸:丝氨酸0~0.00108%、甘氨酸0~0.0015%、丙氨酸4%~20%,余量为正常细胞生长所述的氨基酸。本发明细胞实验和动物水平实验表明,通过严格限制丝氨酸和甘氨酸含量,提高丙氨酸的含量后能有效抑制癌细胞或肿瘤组织的生长。因此,所述功能蛋白质能够作为唯一的膳食蛋白质为肿瘤患者提供蛋白质来源。
进一步的,为了保证人体细胞正常生长,预防营养不良的发生,本发明所述功能蛋白质还限定了必需氨基酸、非必需氨基酸和条件必需氨基酸。
本发明还提供了一种功能性食品,将上述功能蛋白质与与碳水化合物、脂肪、膳食纤维、维生素、矿物质等人体其他所需营养素组合,形成一种适合肿瘤患者的配方食品,可作为经口进食不便、管饲营养等特殊情况下肿瘤患者的全天膳食。经人群预实验证明,仅服用功能性食品的肿瘤患者血清中丝氨酸和甘氨酸水平呈先下降后上升的趋势,干预结束后丝氨酸和甘氨酸水平仍低于干预前;血清免疫水平指标在干预时间内,CD3+、CD4+指标呈上升趋势、CD8+呈下降趋势。
所述功能性食品还具有以下特点:
1)不同于目前市面上针对肿瘤患者的医疗食品仅着眼于提高患者营养状况,本发明通过研究限制氨基酸后肿瘤细胞的转录和代谢调控机制,调整氨基酸的构成,将营养治疗微观化、精准化,使得营养治疗对肿瘤疾病的辅助作用不仅仅局限于提升患者营养状况,为肿瘤的治疗提供了一种新思路、新方法。
2)不同于基于体外细胞培养或动物模型的发明,本发明基于转录和代谢调控机制的研究设计,更加有说服力,推导至人体身上的可行性更高,更安全,在人群中的预实验也得到了血清丝氨酸和甘氨酸会随着饮食中氨基酸的限制而下降,在肿瘤治疗中有继续研究的意义;
3)膳食是肿瘤患者每日最基础最必需的要求,本发明从分子层面为肿瘤患者的膳食提供了另一种更加适合的选择,经济且基础,加强临床治疗的效果。
附图说明
图1为转录组差异分析火山图;
图2为差异表达基因的功能富集分析结果;
图3为脂质代谢差异分析火山图;
图4为HCT116异种移植小鼠肿瘤体积变化趋势,*实验组3~5肿瘤生长速度显著小于实验组1和实验组2,P<0.05;#实验组1~5肿瘤生长速度显著小于对照组,P<0.01;
图5为异种移植HCT116小鼠喂养25天后血清氨基酸,*表示P<0.05,#表示P<0.01;
图6为异种移植HCT116小鼠喂养25天后肿瘤氨基酸相对水平(对照组生长水平为1);*表示P<0.05,#表示P<0.01;
图7为肿瘤患者服用功能食品后血清白蛋白水平变化;
图8为肿瘤患者服用功能食品后血浆前白蛋白水平变化;
图9为肿瘤患者服用功能食品后血清丝氨酸水平变化
图10为肿瘤患者服用功能食品后血清甘氨酸水平变化;
图11为肿瘤患者服用功能食品后血清丙氨酸水平变化;
图12为肿瘤患者服用功能食品后血清CD3+、CD4+、CD8+水平变化。
具体实施方式
本发明提供了一种影响肿瘤生长的氨基酸组合物,包括丝氨酸和甘氨酸。
在本发明中,经缺失特定种类氨基酸的培养基培养癌细胞发现,缺失丝氨酸和甘氨酸后抑制癌细胞的生长,回补丝氨酸和甘氨酸后癌细胞生长得到恢复。说明丝氨酸和甘氨酸为癌细胞生长所必需的氨基酸。丝氨酸和甘氨酸含量的提高有利于促进肿瘤生长,抑制丝氨酸和甘氨酸的含量能够抑制肿瘤生长。其中癌细胞包括结直肠癌、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝癌、乳腺癌、胰腺导管腺癌细胞。因此,从抗肿瘤角度制备药物或保健品或食品时,可通过严格抑制丝氨酸和甘氨酸的含量达到抗肿瘤的目的。
在本发明中,所述氨基酸组合物还优选包括丙氨酸。通过分析丝氨酸和甘氨酸对癌细胞抑制作用的转录和代谢机制发现,在缺乏丝氨酸和甘氨酸的肿瘤组织中存在脂代谢的紊乱,进一步对脂类代谢产物分析,发现doxSLs(deoxysphingolipids,doxSLs)水平显著升高,同时丝氨酸和甘氨酸缺乏的肿瘤细胞对丙氨酸的利用增加,因此推测在丝氨酸缺乏时,癌细胞会转向利用丙氨酸合成具有细胞毒性的doxSLs,从而表现为抑制癌细胞的生长。因此,丙氨酸作为丝氨酸的“替补品”,在严格限制丝氨酸和甘氨酸含量的基础上,进一步提高丙氨酸的含量能够显著抑制癌细胞和肿瘤组织的生长,从而达到抗肿瘤的目的。
基于上述氨基酸组合物含量能够有效调节癌细胞或肿瘤组织生长特性,本发明提供了所述氨基酸组合物在制备抗肿瘤产品中的应用。
在本发明中,所述氨基酸组合物中丝氨酸和甘氨酸是癌细胞生长必需的氨基酸,所述产品中抑制所述丝氨酸和甘氨酸的含量达到抗肿瘤的目的。所述产品中提高所述氨基酸组合物中丙氨酸的含量达到抗肿瘤的目的。本发明对所述产品没有特殊限制,制成本领域所熟知的抗肿瘤的产品形式即可,例如,药品、食品或保健品等。
本发明提供了一种功能蛋白质,包括以下质量百分含量的氨基酸:丝氨酸0~0.00108%、甘氨酸0~0.0015%、丙氨酸4%~20%,余量为正常细胞生长所需的氨基酸。
在本发明中,为了保证人体细胞的正常生长,预防营养不良的发生,所述正常细胞生长,所需的氨基酸优选包括所有必需氨基酸,质量百分含量为10%~96%。由于蛋白质的氨基酸模式与人体越接近,其生物价(biological value,BV)越高,即越容易被机体消化吸收和利用,为提高本发明所涉及的氨基酸组合物的生物价,所述必需氨基酸需符合以下重量份的组分:亮氨酸16.1~26.5份、赖氨酸11.5~20.1份、缬氨酸11.04~15.65份、苯丙氨酸9.66~16.1份、甲硫氨酸4.6~11.5份、异亮氨酸8.74~13.8份、苏氨酸8.7~12.7份和色氨酸2.2~6.5份。所述正常细胞生长所需的氨基酸优选还包括0%~86%非必需氨基酸和条件必需氨基酸;所述非必需氨基酸和条件必需氨基酸包括以下至少一种氨基酸:谷氨酸、天冬氨酸、天冬酰胺、谷氨酰胺、精氨酸、脯氨酸、酪氨酸、半胱氨酸和组氨酸。
本发明提供了一种功能性食品,包括所述功能蛋白质和辅料。
在本发明中,所述功能性食品作为蛋白质补充食品与无蛋白质饮食搭配食用,来作为特定肿瘤患者的全天膳食。在所述食品中,丝氨酸的质量不超过食物总量的0.00018wt%,甘氨酸质量不超过食物总量的0.00025wt%,即丝氨酸和甘氨酸的检出数值为0;丙氨酸含量占总氨基酸量的4wt%以上,占食物总量1.0wt%以上。
在本发明中,所述功能性食品的形式优选包括压片、固体粉剂、口服液、人造肉、饼干、面包、蛋糕、饮料和凝胶等。以人造肉为例,说明功能性食品的制备方法。所述人造肉的辅料优选为粘合剂、调味品和载体。所述载体优选包括食用菌、笋衣和调味品。所述食用菌优选包括至少以下菌的一种或几种:杏鲍菇、香菇和牛肝菌。所述调味品包括食盐、胡椒粉、肉味香精、葡萄糖浆等。所述粘合剂包括卡拉胶、淀粉等。所述人造肉包括以下重量份的组分:载体20~40份、卡拉胶2~4份,红薯淀粉15~30份,葡萄糖浆4~10份,功能性蛋白12~18份、食盐0.5~1.5份、胡椒粉0.7~2.1份和肉味香精0.01~0.1份;其中功能性蛋白质包含L-亮氨酸0.8~2.5份、L-盐酸赖氨酸0.6~2份、L-缬氨酸0.4~1.3份、L-苯丙氨酸0.3~1份、L-甲硫氨酸0.2~0.6份、L-异亮氨酸0.4~1.3份、L-苏氨酸0.3~1份、L-色氨酸0.2~0.6份、L-谷氨酰胺1~4.6份、L-天冬氨酸0.6~2.1份、L-盐酸精氨酸0.5~1.7份、L-丙氨酸0.05~0.15份、L-脯氨酸0.35~1.2份、L-组氨酸0.16~0.55份、L-酪氨酸0.3~1.0份、L-胱氨酸0.2~0.65份。人造肉中氨基酸组合物占总食品的约3wt%。功能性食品的制备方法,优选包括以下步骤:将所述载体制成絮状物与调味品、粘合剂和功能蛋白质混合,经谷氨酰胺转氨酶酶解,得到人造肉。所述人造肉可经煎,烤、蒸后食用,代替普通饮食中含蛋白质丰富的肉类,豆制品等,配合无蛋白饮食或极低蛋白饮食,作为肿瘤患者全天的膳食。
在本发明中,所述功能性食品还优选与碳水化合物、脂肪、膳食纤维、维生素、矿物质等其他人体所需膳食营养素组合,设计一种适合特定肿瘤患者的特殊医学用途配方食品,可作为经口进食不便、管饲营养等特殊情况下肿瘤患者的全天膳食。特殊医学用途配方食品(foods for special medical purpose,FSMP)是指为了满足进食受限、消化吸收障碍、代谢紊乱或特定疾病状态人群对营养素或膳食的特殊需要,专门加工配制而成的配方食品(以下简称“特医食品”)。根据上述的发明原理、结合相关指南推荐[13]和《中国居民膳食营养素参考摄入量2013版》及《食品安全国家标准特殊医学用途配方食品通则》(GB29922-2013)的要求,设计一款适合特定肿瘤患者食用的特殊医学用途配方食品,可作为患者全天的营养素来源。本“特医食品”包含人体每日所需的碳水化合物、膳食纤维、蛋白质、脂肪、维生素和矿物质。本“特医食品”包括以下重量份的组分:碳水化合物170~533份,全部来自于麦芽糊精;膳食纤维23~80份,全部来自于果胶;植物源复合氨基酸粉(氨基酸组合物)90~270份,其中L-谷氨酰胺12~43份,L-亮氨酸10~25份,L-天冬氨酸10~22份,L-盐酸赖氨酸10~21份,L-精氨酸7~14份,L-缬氨酸6~13份,L-苯丙氨酸5~11份,L-丙氨酸7~15份,L-脯氨酸5~12份,L-异亮氨酸6~13份,L-苏氨酸5~12份,L-组氨酸2~6份,L-酪氨酸5~10份,L-甲硫氨酸3~6.5份,L-色氨酸3~6.5份,L-胱氨酸3~7份;脂肪160~520份,其中,辛酸10~30份,葵酸6~21份,棕榈酸7~22份,硬脂酸3~10份,油酸27~81份,亚油酸30~80份,α-亚麻酸10~25份;热带水果香精1.5~4.5份;三氯蔗糖0.2~0.6份。维生素和矿物质作为营养强化剂的添加份量为:维生素A醋酸酯0.002~0.02份、胆钙化醇0.00001~0.002份、dl-α-醋酸生育酚0.02~0.15份、植物甲萘醌0.00015~0.001份、盐酸硫胺素0.003~0.12份、核黄素0.0041~0.02份、盐酸吡哆醇0.008~0.03份、氰钴胺0.000005~0.0001份、L-抗坏血酸0.02~1份、叶酸0.0006~0.09份、烟酸0.01~0.1份;D-泛酸钙0.01~0.09份、D-生物素0.0001~0.009份、碳酸三钙10~40份、氯化钾3.3~12份,磷酸氢二钾0.06~0.3份,柠檬酸钠20~66份,氯化钠0.8~3份、硫酸镁2~8份、碘酸钾0.0003~0.0015份,焦磷酸铁0.3~1.1份、硫酸锌0.09~0.3份、亚硒酸钠0.00024~0.0008份、硫酸铜0.005~0.02份、硫酸锰0.003~0.01份。在特医食品中,氨基酸组合物占总食品的17.7wt%。所述“特医食品”中碳水化合物、蛋白质、脂肪供能比为30~50%:8~25%:30~50%。所述“特医食品”的制备方法,优选包括以下步骤:
1)维生素、食用香精、三氯蔗糖、总质量50%的麦芽糊精混合制备得到预混料1;其中维生素、食用香精、三氯蔗糖的总量与麦芽糊精按照质量比为10:1比例称量;
2)将矿物质和剩余的麦芽糊精混合,得到预混料2;
3)将预混料1和预混料2混合得到预混料3;
4)所述预混料3和剩余的组分混合,得到“特医食品”粉剂。
所述“特医食品”作为特定肿瘤患者的全天膳食;服用方法优选如下:45~80g/次,5~8次/日,粉剂与水的质量比例为1:4~8,温水冲调,可经口服用,可以进行管饲(鼻胃/肠管、胃/肠造瘘的肿瘤患者)。
本发明提供了所述功能蛋白质或所述功能性食品在改善肿瘤患者饮食中的应用;
在本发明中,所述肿瘤优选包括至少以下一种:结直肠癌、乳腺癌、淋巴瘤、胰腺癌、肺癌和肝癌。
下面结合实施例对本发明提供的一种影响肿瘤生长的氨基酸组合物、功能性食品及其应用进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
特医食品来源如表1所示。
表1原料来源说明
实施例1
通过细胞培养选择出缺乏对癌细胞生长有明显抑制效果的氨基酸。
实验选用缺乏不同非必需氨基酸的培养基培养不同的癌细胞系,以找出对癌细胞生长限制最显著的氨基酸。对照组培养基为含10%胎牛血清和1%双抗(青霉素和链霉素)等的RPMI 1640完全培养基(供应商:Procell,货号:PM150110B),培养基中含20种细胞生长所需的氨基酸,实验组培养基是从上述培养基中分离出需缺乏的非必需氨基酸的培养基,除缺失的氨基酸外,其他成分与对照组相同,缺乏非必需氨基酸的培养基添加等体积的EBSS。癌细胞系选择及实验组培养基氨基酸缺乏情况见下表2。
表2实验选择的癌细胞系
表3实验组培养基氨基酸缺乏情况
*由于丝氨酸和甘氨酸可相互转化,所以本实验增加了一个缺失丝氨酸+甘氨酸的培养基。
癌细胞系在不同的培养基中培养,用CellTiter-Glo试剂(供应商:Promega,目录号:G7570)测量3天后癌细胞的生长情况,得出实验组培养基中癌细胞的相对生长,计算公式如式I所示。
相对生长=读数(实验组)/读数(对照组) 式I
结果见表4。在生长受限的癌细胞系中后加入与完全培养基相同浓度的缺失氨基酸培养三日后,观测到明显的癌细胞生长恢复,表明细胞的生长抑制是由该氨基酸的缺失导致的。
表4癌细胞相对生长
*癌细胞相对生长比例越低,表示生长被抑制的程度越高。
结果发现,某些癌细胞在缺乏胱氨酸(-Cys)、丝氨酸和甘氨酸(-SG)的培养基中受到明显抑制。-Cys培养基中,结直肠癌、急性T细胞白血病、肝癌、乳腺癌、前列腺癌细胞受到明显抑制;-SG的培养基中,结直肠癌、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝癌、乳腺癌、胰腺导管腺癌细胞对氨基酸的缺乏最敏感。培养基中缺乏丝氨酸和甘氨酸对多种癌细胞的抑制效果较好。
实施例2
限制丝氨酸和甘氨酸对癌细胞抑制作用的转录和代谢机制研究实验分别在完全限制丝氨酸和甘氨酸的培养基(-SG组)和完全培养基(Con组)中培养HCT116癌细胞系,利用RNA-seq技术检测出实验组与对照组样本的基因表达情况,基于DESeq算法以校正后p值小于0.05且logFC的绝对值大于1为阈值筛选差异表达基因,并对差异表达基因进行功能富集分析,部分差异表达基因经q-PCR实验验证。引物由上海生工合成,具体序列如表5所示。
表5各基因检测用引物序列信息
细胞转染12、24、48小时后收集样本,加入0.5ml MZ裂解液,按miRcute miRNA提取分离试剂盒说明书提取总RNA,并测量浓度,根据说明书将1ug RNA经iScript ReverseTranscription Supermix(Bio-Rad Laboratories)反转录,得到cRNA,将按SYBR GreenERQpcr SuperMix Universal(Bio-Rad)试剂盒说明检测目标基因的表达量,其中,每10μl反应体系包含:2μl稀释后的cRNA,5μl SYBR Green Supermix,上下游引物各1μl,同法制备内参18S rRNA的反应体系,放入CFX Connect Real time System(Bio-Rad CFXManagerv3.1)中进行3阶段反应程序:95℃3分钟,40周期95℃10秒,60℃30秒。
实验分为IN组(实验组),NC组(转染无意义寡核苷酸组)和空白组。结果发现,在-SG组的肿瘤组织中(图1和图2):
①与丝氨酸从头合成相关的基因PSAT1和PSPH的上调,反映了细胞内丝氨酸水平的降低;
②脂肪酸代谢关键酶SCD1表达下调,通过对失调基因功能富集显示丝氨酸和甘氨酸缺乏的肿瘤组织中存在脂代谢失衡;
③中性氨基酸转运体(ASCT1和ASCT2)表达上调,暗示着中性氨基酸摄取增多,通过对培养基中氨基酸含量的检测,发现-SG组培养基中丙氨酸含量显著降低,即丝氨酸和甘氨酸缺乏的肿瘤细胞对丙氨酸的利用增加;
④丝氨酸软脂酰转移酶(serine palmitoyltransferase,SPT)表达上调。
转录组学分析结果显示在缺乏丝氨酸和甘氨酸的肿瘤组织中存在脂代谢的紊乱,进一步,我们对脂类代谢产物进行了气相色谱质谱(GC-MS)分析,使用INCA算法计算各代谢物的丰度,经差异分析发现:在-SG组的肿瘤组织中,doxSLs(deoxysphingolipids,doxSLs)水平显著升高(图3)。
通过上述实验的结果可以推测,在缺乏丝氨酸和甘氨酸的培养基中,丙氨酸的利用会增加,并影响脂代谢通路,生成具有抗肿瘤作用的doxSLs,从而抑制癌细胞生长。
实施例3
探索不同剂量丙氨酸联合缺乏丝氨酸甘氨酸的抑癌效果
小鼠研究:
在上述实验中,我们发现癌细胞在缺乏丝氨酸和甘氨酸的培养基中会增加对丙氨酸的利用,生成具有细胞毒性的物质,接下来实验将注射了人结直肠癌细胞系(HCT116)的小鼠分为对照组和实验组,对照组进食含所有氨基酸配方的饲料(Control),实验组1的饲料相较于对照组不含丝氨酸和甘氨酸(-SG),丙氨酸含量(wt%)与对照组相同,实验组2~5的饲料相较于对照组不含丝氨酸和甘氨酸,并额外增加了丙氨酸含量,丙氨酸分别占氨基酸总量的4wt%,6wt%,8wt%,10wt%(小鼠饲料供应商:Biopike,M19053001)成分信息见表6。对照组和实验组总氨基酸量占饲料总量16.84~18.46wt%,实验组和对照组小鼠饮食干预之前均喂养普通饲料,喂养至可检测到肿瘤组织大小后开始干预饮食,观察实验小鼠肿瘤细胞生长的情况。
结果发现:实验组小鼠肿瘤组织的增长速度及肿瘤大小显著低于对照组(图4),当丙氨酸在总氨基酸中占比≥6wt%时,小鼠的肿瘤生长受到明显抑制,生长速度显著低于对照组、-SG组及-SG+A(4%)组;小鼠在饮食干预25日后,实验组血清丝氨酸和甘氨酸水平均显著下降,实验组3~5血清丙氨酸显著升高(图5);实验组小鼠肿瘤组织中的丝氨酸和甘氨酸水平显著下降,丙氨酸水平与对照组差异不显著(图6)
表6各组小鼠饲料主要成分对比
根据实验结果我们可以得出:饮食限制丝氨酸和甘氨酸能有效限制HCT116小鼠肿瘤生长,丙氨酸在氨基酸总量中的比例≥6wt%后,比单纯限制丝氨酸和甘氨酸能更有效限制肿瘤组织的增长。
实施例4
一种功能性全营养粉剂及其制备方法
营养粉剂中以氨基酸组合物作为蛋白质来源,其中氨基酸组合物种类及含量具体见表7,其中不含丝氨酸和甘氨酸,增加丙氨酸含量。营养粉剂中其他营养素按照《中国居民膳食营养素参考摄入量(2013版)》的建议设计,具体见表8。
表7氨基酸复配粉中的氨基酸含量
名称 | 比例(wt%) |
L-谷氨酰胺 | 18.44 |
L-亮氨酸 | 10.67 |
L-天冬氨酸 | 9.40 |
L-盐酸赖氨酸 | 8.69 |
L-盐酸精氨酸 | 7.28 |
L-缬氨酸 | 5.34 |
L-苯丙氨酸 | 4.46 |
L-丙氨酸 | 6.31 |
L-脯氨酸 | 4.85 |
L-异亮氨酸 | 5.34 |
L-苏氨酸 | 4.51 |
L-组氨酸 | 2.33 |
L-酪氨酸 | 4.08 |
L-甲硫氨酸 | 2.72 |
L-色氨酸 | 2.68 |
L-胱氨酸 | 2.91 |
丝氨酸 | 0 |
甘氨酸 | 0 |
表8全营养粉剂成分表
实施例5
人群预实验:
在胃肠道功能正常的10名实体瘤住院患者(患者信息见表9)中做了为期3个月的预实验。经伦理审核及患者知情同意后,受试者全天服用实施例4制备的营养粉剂,受试者每日服用量按25~35kcal/kg.d计算,营养制剂加入适量温水搅拌均匀后使用,不额外进食其他食物。定期收集受试者体重、血清白蛋白、前白蛋白、CD3+、CD4+、CD8+、血清丝氨酸、甘氨酸和丙氨酸指标,具体委托医院检验科完成。
结果发现:受试者全天能量摄入范围1500~1929kcal,蛋白质:62~80g,脂肪:61~78g。患者血清白蛋白和前白蛋白水平有上升趋势(图7、图8);血清丝氨酸和甘氨酸水平在饮食干预一个月后出现明显下降,干预三个月后,有所上升,但仍低于干预前,血清总丝氨酸水平变化:179.0±13.2μmol/L(0天)、149.8±10.4μmol/L(30天)、162.8±9.8μmol/L(90天),下降幅度为16.3%(30天)、9.1%(90天),甘氨酸水平变化:209.1±13.3μmol/L(0天)、156.8±11.9μmol/L(30天)、183.4±13.2μmol/L(90天),下降幅度为28.4%(30天)、12.3%(90天),丙氨酸水平实验前后无明显变化:363.8±13.2μmol/L(0天)、368.6±13.6μmol/L(30天)、366.6±12.5μmol/L(90天)(图9、图10、图11);免疫指标CD3+、CD4+指标呈上升趋势、CD8+呈下降趋势(图12);所有受试者干预期间体重无明显下降,其中有3位受试者体重升高超过5%。实验对象有2名患者出现恶心,1名出现呕吐,与实验前恶心呕吐发生率无显著差异(P>0.05)进行对症治疗后好转,进食第20天后对营养粉剂接受度明显下降,改变口味后接受度有所提升。
表9实体瘤患者基本信息
实施例6
适合肿瘤患者的特殊医学用途配方食品(粉剂)
“特医食品”的原料组成如下:碳水化合物355g,全部来自于麦芽糊精;膳食纤维51g,全部来自于果胶;植物源复合氨基酸粉(氨基酸组合物)177份,其中L-谷氨酰胺33g,L-亮氨酸19g,L-天冬氨酸17g,L-盐酸赖氨酸16g,L-精氨酸11g,L-缬氨酸10g,L-苯丙氨酸8g,L-丙氨酸11g,L-脯氨酸9g,L-异亮氨酸10g,L-苏氨酸8g,L-组氨酸4g,L-酪氨酸7g,L-甲硫氨酸5g,L-色氨酸5g,L-胱氨酸5g;脂肪174g,其中,辛酸21g,葵酸14g,棕榈酸14g,硬脂酸6g,油酸54g,亚油酸52g,α-亚麻酸14g;热带水果香精1.8g;三氯蔗糖0.1g。维生素和矿物质作为营养强化剂的添加份量为:维生素A醋酸酯0.004g、胆钙化醇0.00004g、dl-α-醋酸生育酚0.07g、植物甲萘醌0.0003g、盐酸硫胺素0.007g、核黄素0.009g、盐酸吡哆醇0.02g、氰钴胺0.00001g、L-抗坏血酸0.044g、叶酸0.0013g、烟酸0.0224g;D-泛酸钙0.0224g、D-生物素0.0002g、碳酸三钙24g、氯化钾7.4g,磷酸氢二钾0.17g,柠檬酸钠44.1g,氯化钠1.82g、硫酸镁5g、碘酸钾0.00075g,焦磷酸铁0.71g、硫酸锌0.20g、亚硒酸钠0.0005g、硫酸铜0.011g、硫酸锰0.007g。
本“特医食品”按照以下步骤备制:
1)配料称量:电子天平使用前校准,根据工艺规程,严格按照配方,准确称取各物料,对预混料进行精确称量,双人复核。其中预混料1包括维生素、食用香精、三氯蔗糖、部分麦芽糊精(与维生素、食用香精、三氯蔗糖按照10:1比例称量);预混料2包括矿物质、部分麦芽糊精(预混料2:预混料1=1:1);预混料3包括预混料1和预混料2混合后的终预混料。
2)过筛:所有物料经60目振荡筛进行分散混合,以保证产品中无异物。
3)第一次预混:将预混料1的物料投入三维混合机中进行预混合,混合时间20分钟,混合完成后装入袋中备用。
4)第二次预混:将预混料1与预混料2的物料投入三维混合机中进行预混合,混合时间20分钟,获得最终预混料3,装入袋中备用。
5)总混:将预混料3从三维混合机中转移至锥形混合机中,加入剩余物料进行总混,混合时间30分钟,制得成品。
本“特医食品”碳水化合物、蛋白质、脂肪供能比为30~50%:8~25%:30~50%。
营养成分如下:
使用方法:
①本“特医食品”作为特定肿瘤患者的全天膳食;
②45~80g/次,5~8次/日,粉剂与水的质量比例为1:4.5g,温水冲调,
可经口服用,可以进行管饲(鼻胃/肠管、胃/肠造瘘的肿瘤患者)。
实施例7
一种作为膳食蛋白质补充的“人造肉”及制备方法
人造肉制作步骤:
1)将晒干的杏鲍菇和笋衣30g,用150份清水将其充分泡发,约3h,捞出泡好软化的笋衣和杏鲍菇絮状物,沥干待用;
2)在沥干的笋衣和杏鲍菇絮状物中加入卡拉胶3g,红薯淀粉25g,葡萄糖浆7g,氨基酸组合物15g(供应商:大连医诺生物股份有限公司),包含L-亮氨酸1.7g、L-盐酸赖氨酸1.3g、L-缬氨酸0.83g、L-苯丙氨酸0.7g、L-甲硫氨酸0.42g、L-异亮氨酸0.83g、L-苏氨酸0.7g、L-色氨酸0.4g、L-谷氨酰胺2.34g、L-天冬氨酸1.47g、L-盐酸精氨酸1.1g、L-丙氨酸0.1g、L-脯氨酸0.8g、L-组氨酸0.36g、L-酪氨酸0.65g、L-胱氨酸0.43g,食盐1g,胡椒粉1.4g,肉味香精0.05g;
3)将谷氨酰胺转氨酶0.4g,加入5g蒸馏水中溶解,导入2)中的混合物中,搅拌均匀后放入模型中,在40℃水浴中静置3h,使酶反应充分;
4)从模型中取出人造肉,中火蒸30分钟后取出,冷藏保存。
上述食品每100g含蛋白质3g,丝氨酸0.15mg,丝氨酸在食物总量占比0.00015wt%,甘氨酸0.23mg/100g,甘氨酸在总氨基酸中占比0.00023wt%(丝氨酸和甘氨酸的理论值均低于检出限),丙氨酸1114mg,丙氨酸在总氨基酸中占比6.8wt%,占食物总量的1.114wt%。
使用方法:
上述制备的人造肉经煎烤后食用,代替普通饮食中含蛋白质丰富的肉类,豆制品等,配合无蛋白饮食或极低蛋白饮食,作为肿瘤患者全天的膳食。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
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Claims (10)
1.一种影响肿瘤生长的氨基酸组合物,其特征在于,包括丝氨酸和甘氨酸。
2.根据权利要求1所述氨基酸组合物,其特征在于,还包括丙氨酸。
3.权利要求1或2所述氨基酸组合物在制备抗肿瘤产品中的应用。
4.根据权利要求3所述应用,其特征在于,所述氨基酸组合物中丝氨酸和甘氨酸是癌细胞生长必需氨基酸,所述产品中抑制丝氨酸和甘氨酸的含量发挥抗肿瘤的作用。
5.根据权利要求3所述应用,其特征在于,所述产品中提高所述氨基酸组合物中丙氨酸的含量达到抗肿瘤的目的。
6.一种功能蛋白质,其特征在于,包括以下质量百分含量的氨基酸:丝氨酸0~0.00108%、甘氨酸0~0.0015%、丙氨酸4%~20%,余量为正常细胞生长所需的氨基酸。
7.根据权利要求6所述功能蛋白质,其特征在于,所述正常细胞生长所需的氨基酸包括质量百分含量的10%~96%必需氨基酸;所述必需氨基酸包括以下重量份的组分:亮氨酸16.1~26.5份、赖氨酸11.5~20.1份、缬氨酸11.04~15.65份、苯丙氨酸9.66~16.1份、甲硫氨酸4.6~11.5份、异亮氨酸8.74~13.8份、苏氨酸8.7~12.7份和色氨酸2.2~6.5份;
优选的,所述正常细胞生长所需的氨基酸还包括0%~86%非必需氨基酸和条件必需氨基酸;所述非必需氨基酸和条件必需氨基酸包括以下一种或多种氨基酸:谷氨酸、天冬氨酸、天冬酰胺、谷氨酰胺、精氨酸、脯氨酸、酪氨酸、半胱氨酸和组氨酸。
8.一种功能性食品,其特征在于,包括权利要求6所述功能蛋白质和辅料。
9.根据权利要求8所述功能性食品,其特征在于,还包括膳食营养素。
10.权利要求6或7所述功能蛋白质或权利要求8或9所述功能性食品在改善肿瘤患者饮食中的应用;
优选的,所述肿瘤包括至少以下一种:结直肠癌、乳腺癌、淋巴瘤、胰腺癌、肺癌和肝癌。
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