CN112040973A - 用作药物的骨桥蛋白和2’-岩藻糖基乳糖的组合 - Google Patents
用作药物的骨桥蛋白和2’-岩藻糖基乳糖的组合 Download PDFInfo
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Abstract
骨桥蛋白(OPN)和2'‑岩藻糖基乳糖(2‑FL)的组合用于预防或治疗影响人或动物受试者的由炎症因子分泌导致的免疫性疾病或紊乱。所述组合尤其可用于预防或治疗因细胞因子分泌，例如INF‑γ、IL‑2、IL‑4、IL‑17、IL‑6、IL‑10、TGF‑β、Tbet、GATA3和NFκB和/或免疫球蛋白分泌，例如IgE和Ig1而导致的疾病或紊乱。
Description
背景技术
骨桥蛋白(OPN)可高度浓缩于人母乳中，是一种广泛磷酸化的酸性糖蛋白，与炎症的发生有关，根据其细胞内或细胞外定位，影响细胞粘附、趋化性、免疫调节和对抗细胞凋亡的保护作用(2-6)。有趣的是，OPN被发现与许多免疫介导的疾病有关，包括多发性硬化症(7，8)、类风湿性关节炎(2)、系统性红斑狼疮(3)、炎症性肠病(4，9)、哮喘(5)和肝病(10)。
人乳低聚糖(HMO)是一个葡聚糖家族，是人母乳中含量第三高的组分(1)。最常见的HMO，2'-岩藻糖基乳糖(2FL)可以占母乳中所有HMO的30％。这种高度生物活性的HMO与免疫调节活性、对抗致病菌和病毒的保护作用以及改善的认知功能有关(1)。
已经发现，这两种目前可商购获得的人母乳成分可对免疫紊乱产生积极影响，这可能是由于(但不限于)对炎症细胞因子分泌的调节，特别是当以OPN和2-FL的组合形式使用时尤其如此，其中OPN和2-FL的含量与任何相关自然来源中存在的比例不同。
令人惊讶的是，进一步发现，OPN和2-FL，当以OPN和2-FL这种组合的形式使用时，可以协同作用来调节BALB/c炎症鼠模型的免疫反应。特别是观察到，OPN和2-FL组合使用可以协同作用以减轻炎症，调节诸如T细胞功能和细胞因子分泌等免疫参数。
这些成就使这两种成分的潜在应用范围出乎意料地扩大，无论是作为药物，还是以食物或营养或膳食补充剂的形式，适合于治疗或预防由人或动物免疫系统功能障碍引起的紊乱和疾病，特别是由炎症因子分泌导致的疾病或紊乱。
本发明在权利要求以及下面出现的说明书中进行限定。
发明内容
本发明的第一目的是骨桥蛋白(OPN)和2'-岩藻糖基乳糖(2-FL)的组合，其用于预防或治疗影响人或动物受试者的由炎症因子分泌导致的免疫性疾病或紊乱。
本发明的另一个目的是骨桥蛋白OPN和2'-岩藻糖基乳糖(2-FL)的组合，其用于预防或治疗影响人或动物受试者的由诸如IL-17和IL-4分泌等炎症细胞因子分泌，或诸如IgE分泌等免疫球蛋白分泌导致的免疫性疾病或紊乱。
本发明的又一个目的是预防或治疗影响人或动物受试者的由炎症因子分泌导致的免疫性疾病或紊乱的方法，该方法包括对有需要的受试者施用骨桥蛋白OPN和2'-岩藻糖基乳糖(2-FL)的组合，可选地与食物或营养或膳食补充剂结合或嵌入其中。
本发明的又一个目的是预防或治疗影响人或动物受试者的由诸如IL-17和IL-4分泌等炎症细胞因子分泌，或诸如IgE分泌等免疫球蛋白分泌导致的免疫性紊乱的方法，该方法包括对有需要的受试者施用骨桥蛋白OPN和2'-岩藻糖基乳糖(2-FL)的组合，可选地与食物或营养或膳食补充剂结合或嵌入其中。
定义
术语“OPN”定义人或动物来源的骨桥蛋白，以及当在本发明框架内应用时会产生相同或同等或类似效果的任何其衍生物或前体。该术语包括人或动物的OPN以及重组OPN。
术语“2-FL”定义了2'-岩藻糖基乳糖，其来源于天然的，最常见的哺乳动物来源；合成来源；或细菌发酵源，以及在本发明框架内应用时会产生相同或同等或类似效果的任何其衍生物或前体。该术语在某些情况下(但仍在本发明框架内)甚至可包括HMO，如3'-唾液乳糖和6'-唾液乳糖。
术语“人受试者”此处用于定义早产儿、新生儿、婴儿、儿童、青少年、成年人或老年人，特别是受其免疫功能不成熟或功能不全影响的婴儿受试者，后者需要恢复。
术语“动物受试者”主要定义哺乳动物，例如牛或宠物。
术语“由炎症因子分泌导致的免疫性疾病或紊乱”包括诸如特应性皮炎、银屑病、过敏、过敏性鼻炎、哮喘和慢性阻塞性肺病(COPD)等疾病或紊乱。然而，这种列举并不是限制性的。
术语“炎症因子”定义细胞因子，尤其是INF-γ、IL-2、IL-4、IL-17、IL-6、IL-10、TGF-β、Tbet、GATA3和NFκB，以及免疫球蛋白，例如IgE和IgGl。
术语“施用”包括口服或肠内、胃肠外或甚至局部施用。
术语“结合”和“嵌入”在本领域中是常见的。
具体实施方式
OPN和2-FL减轻了DNCB诱导的BALB/c小鼠的AD样症状
为探讨OPN或2-FL或OPN/2FL组合对特应性皮炎(AD)的炎症和出现的潜在治疗作用，通过在每只耳朵和背侧皮肤上局部施用DNCB建立BALB/c AD模型。经多次DNCB挑战后，DNCB致敏小鼠的皮肤出现水肿、表皮脱落、红斑和瘢痕。值得注意的是，与补充盐水的小鼠相比，在补充OPN(37.5或2.7mg/kg(bw)天)和2-FL(600或75mg/kg(bw)天)时，BALB/c小鼠的DNCB诱导AD样症状的严重程度得到了改善。瘙痒是AD的一个基本特征。抓挠行为已被确立为评价动物模型瘙痒的客观指标。
如图1所示，OPN和2-FL的口服施用显著降低了AD评分。有趣的是，2-FL/OPN的各种组合，特别是试验7和试验8所示的那些组合，显示出AD样症状的显著减少，表明在应用高剂量的OPN时存在协同作用。
如图2所示，OPN和2-FL的口服施用减少了抓挠行为。2-FL/OPN的组合-特别参见试验7和8-显示出AD样症状的最显著减少，表明具有协同作用。
OPN和2-FL降低了DNCB致敏小鼠的血清IgE升高并减轻肥大细胞浸润
与盐水对照组相比，在第27天测定补充了OPN和2-FL的小鼠的血清IgE浓度。与预期一样，局部施用DNCB可诱导BALB/c AD小鼠血清IgE的显著表达(1025.02±82.68μg/ml)，而OPN(388.22±61.28μg/ml)和2-FL(621.27±46.79μg/ml)补充组的血清IgE浓度均降低(图3)。
与其他处理相比，OPN/2-FL的高剂量组合(396.71±54.71μg/ml)-特别参见试验8-显著降低了IgE水平，突出了协同效应。
AD样小鼠中，OPN和2-FL处理后Thl、Th2和Th17细胞的百分比降低
测定DNCB处理的BALB/c小鼠(具有或不具有2FL和/或OPN补充)中的CD4+Th细胞的分化情况。通过细胞间染色法检测获自DNCB致敏小鼠的淋巴细胞的IFN-γ、IL-4和IL-17的表达，随后通过FACS分析确定。OPN和2-FL补充组中产生IFN-γ的CD4+Thl淋巴细胞的百分率明显低于盐水处理组。而与盐水处理组相比，补充组中产生IL-4的CD4+Th2淋巴细胞和产生IL-17的CD4+Th17淋巴细胞的值也明显降低(图4(a)和(b))。
这些数据-见图4a中的试验7和8以及图4b中的试验6、7和8-表明OPN和2-FL补充可通过调节Thl、Th2和Th17细胞极化来显著降低AD炎症。
OPN和2-FL降低BALB/c小鼠中DNCB诱导的TSLP和IL-17A的mRNA表达
从对照组小鼠和经处理的BALB/c小鼠的背部皮肤分离总RNA。随后，通过RT-PCR测定皮肤样品中细胞因子的mRNA表达。与盐水处理组相比，OPN和2-FL补充组中Th2相关细胞因子TSLP和IL-4的表达显著降低(图5)。此外，补充有OPN和2-FL的AD小鼠的皮肤中IL-17的mRNA表达也显著低于盐水处理的AD小鼠。
有趣的是，较低的表达水平与补充OPN/2FL的组合而非单个组分相关-参见试验6至8，尤其是图5a和图5b中的试验7和8。
OPN和2-FL降低小鼠中DNCB诱导的Thl、Th2和Th17反应增强
考虑到活化的CD4+T细胞在AD的发病机制中起重要作用，我们通过FACS分析检验了致敏小鼠dLNs中CD4+Th细胞亚群。OPN和2-FL处理的AD小鼠中产生IFN-γ的CD4+Th1淋巴细胞、产生IL-4的CD4+Th2淋巴细胞、产生IL-17的CD4+Th17淋巴细胞的百分比明显低于对照组小鼠。然而，组间Foxp3阳性CD4+Treg淋巴细胞的频率具有可比性(图8a-8c)。
另一方面，与对照AD小鼠相比，OPN和2-FL处理的AD小鼠皮肤损害中IFN-γ(Th1细胞因子)、IL-4(Th2细胞因子)和IL-17(Th17细胞因子)的mRNA水平被明显抑制(图15)。此外，我们测定了相应转录因子(即，T-bet、GATA3、ROR-γt)的水平，结果显示组间变化类似(图9a-9d)。
OPN和2-FL抑制DNCB处理的小鼠中肥大细胞和嗜酸性粒细胞对皮肤损害的浸润
所周知，肥大细胞和嗜酸性粒细胞因其对过敏性疾病的有害贡献而臭名昭著。
结果显示，OPN和2-FL处理的AD小鼠的皮肤损害中肥大细胞数明显低于WT对照组(图6)。
同样，免疫组化染色显示OPN和2-FL处理的AD小鼠皮肤损害中浸润的嗜酸性粒细胞数量与WT组相比明显减少(图7)。
一般而言，通过施用根据本发明的组合已取得良好结果，其向受试者提供OPN和2-FL，以约2.5至45mg/kg体重/天的相当广泛的剂量，以及约75至750mg/kg体重/天的剂量的2-FL。
当以高剂量向受试者提供OPN，尤其是在OPN剂量约为35至45mg/kg体重/天和2-FL剂量约为600mg/kg体重/天时，已获得最佳性能，尤其是证明具有协同效应的那些性能(参见下面的实施例)。
作为一种选择，并取决于需要该药物的人受试者，例如婴儿、儿童或老人，包含OPN和2-FL的组合的药物可以与食物或营养或膳食补充剂结合或嵌入其中。这可适用于口服和肠内给药。合适的食品、营养或膳食补充剂目前在市场上可商购。
上述内容同样适用于动物，如牛或宠物(如适用)。
1.方法
1.1动物处理
Balb/c小鼠购自南方医科大学(中国广州)动物中心。小鼠在特定的无病原体动物设施中，在控制温度(20-25℃)和湿度(50±5％)下维持12小时的光/暗循环。所有小鼠均以常规饮食和高压灭菌水喂养。本研究所有动物实验均经南方医科大学实验动物护理福利伦理委员会批准。为诱发AD样症状，将二硝基氯苯(DNCB)溶液(溶于丙酮和橄榄油的3:1混合物中)涂抹在小鼠背部皮肤和耳朵上(雌性，6-8周龄)。在完全去除背部毛发(约4cm2)后的第1天，在背部皮肤上涂抹150μl的2％DNCB溶液，在第1天分别在双耳背面各涂抹10μl。致敏4天后，涂抹溶解在丙酮：橄榄油混合物(3:1体积/体积)中的0.5％DNCB，刺激背部皮肤(150μl)和双耳背面(各10μl)，每两天一次(第5至27天)。将OPN和2-FL溶于0.9％的生理盐水中。用DNCB处理的小鼠从第0天到第27天胃内施用2-FL、OPN或2-FL加OPN。载体组和其他DNCB组的小鼠给予等量的生理盐水。
1.2AD得分评估
背部皮肤损害的严重程度根据以下四种症状进行宏观评估：水肿、红斑/出血、表皮脱落/糜烂、和疤痕/干燥，将各评分(0，无症状；1，轻度；2，中度；3，严重)之和定义为最终的皮炎评分，范围为0至12。这些视觉评估每两天进行一次，由至少两名独立的调查人员进行。
1.3抓挠行为的评估
将小鼠置于笼中1小时进行适应化。适应化后，宏观统计15分钟内抓挠发作次数。用爪子做的一系列抓挠动作算作一次抓挠发作。在15分钟内计算总的抓挠行为数。在实验的第7、14和21天进行抓挠行为测试。
1.4血清IgE水平的测定
实验最后一天采集单个小鼠的血清。根据制造商的说明，使用商用酶联免疫吸附试验(ELISA)试剂盒(美国圣地亚哥Invitrogen)对血清IgE水平进行定量。
1.5流式细胞术
在实验结束时制备皮肤引流淋巴结(dLNs)(腋窝和腹股沟)的单细胞悬浮液。对于Thl、Th2和TH17染色，根据制造商的方案，5x106淋巴细胞以500μl/孔的体积在96孔平板中与细胞刺激鸡尾酒和蛋白质抑制剂(美国圣地亚哥Invitrogen)一起培养5小时。用FITC标记的大鼠抗小鼠CD4(克隆RM4-5，BD Pharmingen，San Jose，CA，USA)进行表面染色后，透性化细胞用PE-Cy7标记的大鼠抗鼠IFN-γmAb(克隆XMG1.2，BD-Pharmingen)、APC标记的大鼠抗鼠IL-4mAb(克隆11B11，BD-Pharmingen)和PE标记的大鼠抗鼠IL-17mAb(克隆eBiol7B7，BD Pharmingen)染色。
1.6RNA分离与实时定量PCR
根据制造商的说明，使用TRIzol(TransGen Biotech，中国北京)从背部皮肤中分离出总RNA。用Transcript All-in-One First-Strand cDNA Synthesis SuperMix(TransGen Biotech，中国北京)对500ng RNA进行量化以用于逆转录反应，总体积为10μL。使用TransStart Green qPCR SuperMix(TransGen Biotech，中国北京)进行基因表达的实时定量PCR(RT-PCR)分析。靶基因水平相对于GAPDH基因表达标准化。
2.实施例
以下的实施例仅仅是对本发明的说明，它们并不视为代表对本发明的任何限制。
实施例1
图1：按照皮炎评分评估，OPN和2-FL减轻BALB/c小鼠中DNCB诱导的AD样症状。(1)对照组(2)DNCB组(3)DNCB组+高2FL(4)DNCB组+高OPN(5)DNCB组+低2FL+低OPN(6)DNCB组+高2FL+低OPN(7)DNCB组+低2FL+高OPN和(8)DNCB组+高2FL+高OPN。高OPN＝37.5mg/kg(bw)/天，低OPN＝2.7mg/kg(bw)/天，高2FL＝600mg/kg(bw)/天，并且低2FL＝75mg/kg(bw)/天。*p<0.05，**p<0.01。
实施例2
图2：在存在和不存在OPN和/或2FL的情况下，DNCB处理的BALB/c小鼠中15分钟的抓挠发作的次数。(1)对照组(2)DNCB组(3)DNCB组+高2FL(4)DNCB组+高OPN(5)DNCB组+低2FL+低OPN(6)DNCB组+高2FL+低OPN(7)DNCB组+低2FL+高OPN和(8)DNCB组+高2FL+高OPN。高OPN＝37.5mg/kg(bw)/天，低OPN＝2.7mg/kg(bw)/天，高2FL＝600mg/kg(bw)/天，以及低2FL＝75mg/kg(bw)/天。
实施例3
图3：第27天，在OPN和/或2FL存在和不存在的条件下，DNCB处理的BALB/c小鼠中血清IgE的水平。**p<0.01。(1)对照组(2)DNCB组(3)DNCB组+高2FL(4)DNCB组+高OPN(5)DNCB组+低2FL+低OPN(6)DNCB组+高2FL+低OPN(7)DNCB组+低2FL+高OPN和(8)DNCB组+高2FL+高OPN。高OPN＝37.5mg/kg(bw)/天，低OPN＝2.7mg/kg(bw)/天，高2FL＝600mg/kg(bw)/天，并且低2FL＝75mg/kg(bw)/天。
实施例4
图4(a)和(b)：在生理盐水处理的或OPN和2-FL处理的AD样小鼠(n＝6)中(a)产生IL-17的CD4+Th7淋巴细胞和(b)产生IL-4的CD4+Th2淋巴细胞的比率。*p<0.05，**p<0.01。(1)对照组(2)DNCB组(3)DNCB组+高2FL(4)DNCB组+高OPN(5)DNCB组+低2FL+低OPN(6)DNCB组+高2FL+低OPN(7)DNCB组+低2FL+高OPN和(8)DNCB组+高2FL+高OPN。高OPN＝37.5mg/kg(bw)/天，低OPN＝2.7mg/kg(bw)/天，高2FL＝600mg/kg(bw)/天，并且低2FL＝75mg/kg(bw)/天。
实施例5
图5(a)、(b)和(c)：RT-PCR测定并以GAPDH比率表示的Th2相关细胞因子((a)TSLP和(b)IL-4)和IL17a的相对mRNA表达水平，在OPN和/或2FL存在和不存在的条件下，由DNCB处理的BALB/c小鼠中提取。*p<0.05，**p<0.01。(1)对照组(2)DNCB组(3)DNCB组+高2FL(4)DNCB组+高OPN(5)DNCB组+低2FL+低OPN(6)DNCB组+高2FL+低OPN(7)DNCB组+低2FL+高OPN和(8)DNCB组+高2FL+高OPN。高OPN＝37.5mg/kg(bw)/天，低OPN＝2.7mg/kg(bw)/天，高2FL＝600mg/kg(bw)/天，并且低2FL＝75mg/kg(bw)/天。
实施例6
图6：对DNCB处理的小鼠的皮肤进行甲苯胺蓝(TB)染色以鉴定肥大细胞。与DNCB+ns组相比，以在每个区域随机选择的四个视野内的平均值量化背部皮肤中肥大细胞的浸润量(**p<0.01)。
实施例7
图7：使用针对嗜酸性粒细胞过氧化物酶(EPX)的免疫组化染色以鉴定嗜酸性粒细胞。与DNCB+ns组相比，以在每个区域随机选择的四个视野内的平均值量化背部皮肤中嗜酸性粒细胞的浸润量(*p<0.05)。
实施例8
图8a-8c：通过定量RT-PCR分析，测定在2-FL和OPN处理存在或不存在条件下的AD小鼠的皮肤损害中IFN-γ、IL-4、IL-17的mRNA水平，并表示为相对于GAPDH的比率(*p<0.05，**p<0.01)，并与DNCB+ns组比较。
实施例9
图9a-9d：通过定量RT-PCR分析，测定在2-FL和OPN处理存在或不存在条件下的AD小鼠的皮肤损害中T-bet、GATA3、ROR-γt和Foxp3的mRNA水平，并表示为相对于GAPDH的比率(*p<0.05，**p<0.01)，并与DNCB+ns组比较。
参考
1.Bode,L.(2012)Human milk oligosaccharides:every baby needs a sugarmama.Glycobiology 22,1147-1162
2.Gravallese,E.M.(2003)Osteopontin:a bridge between bone and theimmune system.The Journal of clinical investigation 112,147-149
3.Kaleta,B.(2014)Role of osteopontin in systemic lupuserythematosus.Archivum immunologiae et therapiae experimentalis 62,475-482
4.Kourepini,E.,Aggelakopoulou,M.,Alissafi,T,Paschalidis,N.,Simoes,D.C,and Panoutsakopoulou,V.(2014)Osteopontin expression by CD103-dendriticcells drives intestinal inflammation.Proceedings of the National Academy ofSciences of the United States of America 111,E856-865
5.Konno,S.,Kurokawa,M.,Uede,T.,Nishimura,M.,and Huang,S.K.(2011)Roleof osteopontin,a multifunctional protein,in allergy and asthma.Clinical andexperimental allergy:journal of the British Society for Allergy and ClinicalImmunology 41,1360-1366
6.Uede,T.(2011)Osteopontin,intrinsic tissue regulator of intractableinflammatory diseases.Pathology international 61,265-280
Claims (18)
1.一种骨桥蛋白(OPN)和2'-岩藻糖基乳糖(2-FL)的组合，其用于预防或治疗影响人或动物受试者的由炎症因子分泌导致的免疫性疾病或紊乱。
2.如权利要求1所述的组合，其中，所述炎症因子选自细胞因子和免疫球蛋白。
3.如权利要求1和2中任一项所述的组合，其中，所述细胞因子选自INF-γ、IL-2、IL-4、IL-17、IL-6、IL-10、TGF-β、Tbet、GATA3和NFκB，并且所述免疫球蛋白选自IgE和IgG1。
4.如权利要求1至3中任一项所述的组合物，其中，所述免疫性疾病或紊乱选自包括特应性皮炎、银屑病、过敏、过敏性鼻炎、哮喘和慢性阻塞性肺病(COPD)的组。
5.如前述权利要求中任一项所述的组合，其中，骨桥蛋白(OPN)是人源性或动物源性或重组OPN。
6.如前述权利要求中任一项所述的组合，其中，2'-岩藻糖基乳糖(2-FL)是天然来源或合成来源或来自细菌发酵来源。
7.如前述权利要求中任一项所述的组合，其中，骨桥蛋白(OPN)以约2.5mg/kg体重/天至45mg/kg体重/天，优选约35mg/kg体重/天至40mg/kg体重/天的剂量提供给对其有需要的人或动物受试者。
8.如前述权利要求中任一项所述的组合，其中，2'-岩藻糖基乳糖(2-FL)以约75mg/kg体重/天至750mg/kg体重/天，优选约600mg/kg体重/天的剂量提供给对其有需要的人或动物受试者。
9.如前述权利要求中任一项所述的组合，其中，骨桥蛋白(OPN)和2'-岩藻糖基乳糖(2-FL)以一个或多个单一单位剂型的形式提供给有需要的人或动物受试者。
10.如前述权利要求中任一项所述的组合，当所述组合提供给有需要的人或动物受试者时，所述组合与食物或营养或膳食补充剂结合，或嵌入食物或营养或膳食补充剂中。
11.一种用于预防或治疗影响人或动物受试者的由炎症因子分泌导致的免疫性疾病或紊乱的方法，所述方法包括对所述受试者施用骨桥蛋白(OPN)和2'-岩藻糖基乳糖(2-FL)的组合。
12.如权利要求11所述的方法，其中，所述炎症因子选自细胞因子和免疫球蛋白。
13.如权利要求11和12中任一项所述的方法，其中，所述细胞因子选自INF-γ、IL-2、IL-4、IL-17、IL-6、IL-10、TGF-β、Tbet、GATA3和NFκB，并且所述免疫球蛋白选自IgE和IgG1。
14.如权利要求10至13中任一项所述的方法，其中，所述免疫性疾病或紊乱选自特应性皮炎、银屑病、过敏、过敏性鼻炎、哮喘和慢性阻塞性肺病(COPD)。
15.如权利要求10至14中任一项所述的方法，其中，骨桥蛋白(OPN)是人源性或动物源性或重组OPN。
16.如权利要求10至15中任一项所述的方法，其中，2'-岩藻糖基乳糖(2-FL)是天然来源或合成来源或来自细菌发酵来源。
17.如权利要求10至16中任一项所述的方法，其中，所述组合中的骨桥蛋白(OPN)以约2.5mg/kg体重/天至45mg/kg体重/天，优选约35mg/kg体重/天至40mg/kg体重/天的剂量提供给对其有需要的人或动物受试者。
18.如权利要求10至17中任一项所述的方法，其中，所述组合中的2'-岩藻糖基乳糖(2-FL)以约75mg/kg体重/天至750mg/kg体重/天，优选约600mg/kg体重/天的剂量提供给对其有需要的人或动物受试者。
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| PCT/IB2019/000297 WO2019207355A1 (en) | 2018-04-25 | 2019-04-24 | Combinations of osteopontin and 2'-fucosyllactose for use as medicaments |
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| CN112890200A (zh) * | 2021-03-08 | 2021-06-04 | 合生元（广州）健康产品有限公司 | 用于促进低体重婴幼儿生长追赶的一种营养组合物 |
| CN112914104A (zh) * | 2021-03-08 | 2021-06-08 | 合生元（广州）健康产品有限公司 | 用于预防婴幼儿肥胖的一种营养组合物 |
| CN114586983A (zh) * | 2022-03-07 | 2022-06-07 | 黑龙江飞鹤乳业有限公司 | 一种促神经发育营养组合物及其制备和应用 |
| CN115399480A (zh) * | 2021-09-26 | 2022-11-29 | 黑龙江飞鹤乳业有限公司 | 含泛酸的促神经发育营养组合物及其制备和应用 |
| CN115843880A (zh) * | 2022-11-29 | 2023-03-28 | 黑龙江飞鹤乳业有限公司 | 含母乳低聚糖和骨桥蛋白的营养组合物、食品及用途 |
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| WO2023144416A1 (en) * | 2022-01-31 | 2023-08-03 | Société des Produits Nestlé S.A. | Compositions comprising osteopontin (opn) |
| KR102527378B1 (ko) | 2022-04-28 | 2023-05-02 | (주)에이피테크놀로지 | 2'-fl을 함유하는 도파민 감소로 말미암아 발생하는 질환의 개선, 예방 또는 치료용 조성물 |
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| CN112890200A (zh) * | 2021-03-08 | 2021-06-04 | 合生元（广州）健康产品有限公司 | 用于促进低体重婴幼儿生长追赶的一种营养组合物 |
| CN112914104A (zh) * | 2021-03-08 | 2021-06-08 | 合生元（广州）健康产品有限公司 | 用于预防婴幼儿肥胖的一种营养组合物 |
| CN112890200B (zh) * | 2021-03-08 | 2021-11-12 | 合生元（广州）健康产品有限公司 | 用于促进低体重婴幼儿生长追赶的一种营养组合物 |
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| CN116268412A (zh) * | 2021-09-26 | 2023-06-23 | 黑龙江飞鹤乳业有限公司 | 含酵母β-葡聚糖的促神经发育营养组合物及其制备和应用 |
| CN114586983A (zh) * | 2022-03-07 | 2022-06-07 | 黑龙江飞鹤乳业有限公司 | 一种促神经发育营养组合物及其制备和应用 |
| CN115843880A (zh) * | 2022-11-29 | 2023-03-28 | 黑龙江飞鹤乳业有限公司 | 含母乳低聚糖和骨桥蛋白的营养组合物、食品及用途 |
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