CN116874565B - 一种ceffe脱细胞脂肪活性蛋白的制备及在皮肤科和整形外科中的应用 - Google Patents
一种ceffe脱细胞脂肪活性蛋白的制备及在皮肤科和整形外科中的应用 Download PDFInfo
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Abstract
本发明涉及一种CEFFE脱细胞脂肪活性蛋白的制备及其在皮肤科和整形外科中的应用。本发明首先以脂肪抽吸物为样本，分离制备获得了CEFFE脂肪脱细胞活性蛋白，所述蛋白具有抗炎、抗氧化、促血管新生、促神经再生等功能。将其与本申请分离鉴定的抗氧化肽一起使用后，具有显著的促进新生血管生成、抗氧化、修复再生促进愈合的效果。
Description
技术领域
本申请涉及生物领域，具体的涉及一种CEFFE（脱细胞脂肪活性蛋白）的制备及在皮肤科和整形外科中的应用。
背景技术
衰老是生命过程中的一种自然现象，其本质是生物机体细胞、组织和器官等的结构和功能在内外众多因素刺激下，随着年龄的增长所发生的循序渐进的自然退化过程。近些年来，由衰老引发的糖尿病、脂质代谢异常等代谢性疾病及阿尔茨海默症、帕金森病等与认知相关的功能性障碍疾病发病率不断攀升，已经严重影响人们的生活，成为危害人类生命健康的主要挑战之一。随着科技的飞速发展，人们物质生活条件改善，医疗水平不断发展，人类平均寿命延长，人口老龄化不断加剧。
人体衰老的机制非常复杂，目前人体老化的9大标志性改变，包括基因组的不稳定性、端粒的磨损、表观遗传的改变、蛋白质内稳态的丧失、营养感知的失调、线粒体功能障碍、细胞衰老、干细胞耗竭，以及细胞间通信的改变。如果细分的话，前7项变化归于细胞和分子水平的变化，后2项则归于组织器官水平的变化。该报道进一步将衰老特征分为3类：主要特征、拮抗特征和综合特征。主要特征是指引起损伤的始动因素，包括了基因组的不稳定性、端粒的磨损、表观遗传的改变、蛋白质内稳态的丧失；拮抗特征是人体应对损伤的反应，包括了营养感知的失调、线粒体功能障碍、细胞衰老；综合特征是最终导致的结局，包括了干细胞耗竭和细胞间通信改变，并认为干细胞耗竭和细胞间通信改变是导致衰老的“罪魁祸首”。
衰老机体内氨基酸代谢紊乱，还可能涉及以下几个代谢通路：缬氨酸、亮氨酸和异亮氨酸的生物合成；丙氨酸、天门冬氨酸和谷氨酸代谢；甘氨酸、丝氨酸和苏氨酸代谢；苯丙氨酸、酪氨酸和色氨酸生物合成等。因衰老生物体内蛋白质和激素等合成速度降低，肠道菌群代谢活动紊乱，所以可能吸收缬氨酸、亮氨酸、异亮氨酸和苯丙氨酸等必需氨基酸利于自身合成蛋白，进而导致这些氨基酸的含量下降，影响机体正常代谢循环，加剧组织及器官的衰老。支链氨基酸包括缬氨酸、亮氨酸和异亮氨酸，在调节蛋白质合成、能量代谢等方面具有重要的作用，其中缬氨酸在体内酶作用下分解产生的琥珀酰辅酶A可作为三羧酸循环的底物参与反应，随着衰老的发生，机体能量代谢紊乱，可能降低缬氨酸的含量。研究发现，一些中药成分可回调衰老大鼠的血清中异亮氨酸的含量，表明衰老与支链氨基酸的降解与合成关系密切；给予甘草水提物后衰老大鼠肝组织中的缬氨酸含量升高，表明甘草水提物能够提高衰老机体对缬氨酸的吸收与利用。但是中药成分复杂，制备不便，使用起来具有诸多的不便。
脂肪脱细胞活性蛋白（Cell-freefatextract，CEFFE），是来源于脂肪组织的活性蛋白群，同样具有抗炎、抗氧化、促血管新生、促神经再生等功能，在神经、呼吸、生殖、运动等衰老性疾病的动物模型中，证实了其广泛的应用前景，其作用机制也是通过改善组织微环境发挥作用，有望成为未来抗衰老的“复合肥料”。CEFFE是人体脂肪组织提取的脂肪脱细胞活性蛋白，富含1700种以上生长因子，且已在多项临床研究中证实了其抗炎、抗氧化及促进组织再生的能力。基于CEFFE再生医学技术，纯化提取对肌肤促血管和神经再生的活性多肽，研发了CEFFEMedX®院线级产品和个护产品，使高浓度生长因子作用于肌肤细胞，使细胞重新恢复其机能与活性，加速细胞代谢，唤醒肌肤自我修复本能。
发明内容
本发明一方面，以脂肪抽吸物为样本，分离制备获得了CEFFE脂肪脱细胞活性蛋白，所述蛋白具有抗炎、抗氧化、促血管新生、促神经再生等功能。
进一步的，所述的CEFFE的分离方法为用盐水冲洗脂肪抽吸物以去除红细胞，然后以1200 ×离心g持续3分钟。第一次旋转后，弃去上层油性和下层流体层，收集中间脂肪层并进行机械乳化。乳化是通过将脂肪在两个10厘米长的注射器连通后来回移动40次实现。然后乳化脂肪在80℃冷冻，在37℃解冻，以进一步破坏脂肪组织。在冷冻/融化过程的一个循环后，脂肪再次以1500×g持续10分钟离心后，脂肪被分成四层。弃去上层油；第二层完整的脂肪和第四层碎片被丢弃；并且小心地吸出第三水层，即CEFFE（脂肪脱细胞活性蛋白）。通过将提取物通过0.22微米过滤器进行去除细胞碎片，得到最终提取物。
本发明进一步的，提供了CEFFE在制备抗氧化、促进伤口愈合的药物组合物中的用途。
进一步的，所述的药物组合物中进一步的还含有抗氧化多肽。
具体的，本发明的抗氧化肽分离自富含血浆蛋白、多肽的新鲜胎牛血清。
具体的，所述的抗氧化多肽其氨基酸序列如SEQ ID NO：1所示，命名为NQ-S34。
具体的，本发明还提供了NQ-S34多肽在制备抗氧化、促进皮肤伤口愈合的药物组合物中的用途。
具体的，所述多肽还可以被修饰，但是仍然保持多肽活性。
另外，本发明涉及含有这里所描述的多肽类似物的药物组合物，其可与药物学可接受的载体和赋形剂组合。本发明的组合物以可注射制剂、胶囊、药片、微粒、溶液、悬浮剂、糖浆、栓剂、鼻腔喷剂、霜、药膏、凝胶、缓释制剂或其它形式，通过口服、肠道、呼吸、直肠、蛛网膜下、膀胱内或局部给药。制备药物组合物的原则和方法在本领域已知并且被描述。
本发明的组合物可以以单元剂量形式给予人和其它动物，比如注射移植物、注射剂、片剂、胶囊、散剂、颗粒剂、无菌肠胃外溶液或混悬液、口服溶液或混悬液、包含有适量化合物的水包油或油包水乳液、栓剂或流体悬浮液或溶液。
在本说明书中，使用的术语“药物稀释剂”和“药物载体”具有相同的意思。口服给药，可制备成固体或流体单元剂量形式。制备固体组合物，如片剂，该化合物可以与常规组分如滑石粉、硬脂酸镁、磷酸二钙、硅酸铝镁、硫酸钙、淀粉、乳糖、阿拉伯胶、甲基纤维素及作为药学稀释剂或载体的功能上类似的材料混合。胶囊是通过将化合物与惰性药学稀释剂混合并将混合物填充入合适大小的硬明胶胶囊中而制备的。软明胶胶囊是通过将化合物与可接受的植物油、轻液体石蜡或其它的惰性油的浆液由机器包囊而制备的。可制备成流体单元剂量形式或口服给药如糖浆、酏剂和悬浮剂。该形式与糖、芳香调味剂和防腐剂一起溶于水性载体中制成糖浆。混悬液可借助于阿拉伯胶、黄芪胶、甲基纤维素等助悬剂用水性载体制备。采用化合物和灭菌载体可制备肠胃外给药流体单元剂量形式。在制备溶液中，可将化合物溶于注射用水中，过滤灭菌，然后装入适合的小瓶或安瓿中封口。可将辅助剂如局部麻醉剂、防腐剂和缓冲剂溶于载体中。将组合物装入小瓶后，冷冻组合物，真空除水，然后可以称重小瓶中的冷冻粉末，在使用前重构。
进一步的，本发明的药物组合物中还添加有抗菌剂。
可以适用于根据本发明的用途的抗菌剂包括任何能有效地治疗和/或预防乳房疾病和/或耳疾病和/或与其有关的并发症的药剂。合适的抗菌剂包括但不限于：β-内酰胺抗菌剂例如天然的和合成的青霉素类药剂，包括青霉烷青霉素(例如苄青霉素，苯氧基青霉素，coxacillin，奈夫西林，甲氧西林，苯唑西林，阿莫西林，替莫西林，替卡西林等)，青霉素酶-稳定的青霉素，酰氨基和羧基青霉素(例如哌拉西林，阿洛西林，美洛西林，羧苄青霉素，替莫西林，替卡西林等)，和更广谱的青霉素(例如链霉素，新霉素，新霉素B，庆大霉素，阿泊拉霉素，丁胺卡那霉素，壮观霉素，阿莫西林，氨苄青霉素等)，头孢菌素类，大环内酯类(例如泰乐菌素，替米考星，aivlosin，红霉素，阿奇霉素，螺旋霉素，交沙霉素，北里霉素等)，林可胺类(例如林肯霉素，氯林肯霉素，吡利霉素等)，截短侧耳素(例如硫姆林，伐奈莫林等)，多肽，糖肽(例如万古霉素等)，多粘菌素(例如多粘菌素B，多粘菌素E等)，磺胺类(例如磺胺二甲基嘧啶，磺胺嘧啶，磺胺嘧啶银，磺胺曲沙唑，磺胺甲氧哒嗪，氨苯磺胺，磺胺甲基异噁唑，磺胺异噁唑，磺胺甲二唑，磺胺米隆等，单独地或与三甲氧苄二氨嘧啶组合)，氯霉素，甲砜氯霉素，氟苯尼考，四环素类药(例如四环素，金霉素，土霉素，甲氯环素，强力霉素，二甲胺四环素等)，喹诺酮和氟喹诺酮(例如环丙沙星，依诺沙星，格帕沙星，左氧氟沙星，洛美沙星，诺氟沙星，氧氟沙星，司帕沙星，曲伐沙星，cinocacin，萘啶酸等)，硫姆林，粘菌素，美罗培南，舒巴坦，三唑巴坦，美他环素，乙胺嘧啶，磺胺醋酰，噁唑烷酮，例如，依哌唑胺，利奈唑胺，N-((5S)-3-(3-氟-4-(4-(2-氟代乙基)-3-氧-1-哌嗪基)苯基-2-氧-5-噁唑烷基)甲基)乙酰胺，(S)-N-((3-(5-(3-吡啶基)噻吩-2-基)-2-氧-5-噁唑烷基)甲基)乙酰胺，2，2-二氟-N({(5S-3-[3-氟-4-(4-乙醇酰基哌嗪-1-基)苯基]-2-氧代-1，3-噁唑烷-5-基)甲基}硫代乙酰胺，(S)-N-((3-(5-(4-吡啶基)吡啶-2-基)-2-氧-5-噁唑烷基)甲基)乙酰胺盐酸盐等，氨基糖苷类(卡那霉素，妥布霉素，乙基西梭霉素等)，氨基环多醇，amphenicol，安沙霉素，碳青霉烯，头霉素，利福平，单酰胺菌素，氧头孢烯类，链霉杀阳菌素(例如奎奴普丁，达福普汀等)，环丝氨酸，莫匹罗星，脲氧肟酸盐，叶酸类似物(例如三甲氧苄二氨嘧啶等)，抗生素类抗肿瘤药(例如阿柔比星，放线菌素D，actinoplanone，aeroplysinin衍生物，NipponSoda茴香霉素，蒽环霉素，Azino-micyin-A，busucaberin，博来霉素硫酸盐，苔藓抑素-1，刺孢霉素，chromoximycin，更生霉素，柔红霉素，ditrisarubicinB，阿霉素，阿霉素-纤维蛋白原，elsamicin-A，表柔比星，erbstatin，依索比星，esperamicin-Alb，福司曲星，glidobactin，gregatin-A，grincamycin，除莠霉素，黄胆素，隐杯伞霉素，贝壳松，kesarirhodins，美诺立尔，丝裂霉素，mitoxantorone，突变霉素，霉酚酸酯，neoenactin，噁溶菌素，oxaunomycin，培洛霉素，pilatin，吡柔比星，porothramycin，pyrindamycinA，雷帕霉素，根霉素，罗多比星，西班米星，siwenmycin，sorangicin-A，稀疏霉素，斯堡霉素B，他利霉素，terpentecin，thrazine，tricrozarinA，佐柔比星，全身性抗菌剂(例如2，4-二氨基嘧啶)，硝基呋喃砜，马波沙星等，和其组合。
有益效果
本发明首先以脂肪抽吸物为样本，分离制备获得了CEFFE脂肪脱细胞活性蛋白，所述蛋白具有抗炎、抗氧化、促血管新生、促神经再生等功能。将其与本申请分离鉴定的抗氧化肽一起使用后，具有显著的抗氧化、促进伤口愈合的效果。
附图说明
图1 多肽或CEFFE对H2O2损伤的HaCaT细胞损伤的保护能力结果图
图2 各实验组对伤口皮肤中SOD活性的影响结果图
实施方式
本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。以下实施案例中的方法、设备、材料，如果未进行特别说明，均为本领域常规方法、设备和材料，均可由市场购得。
实施例1 脂肪脱细胞活性蛋白的研制
用盐水冲洗脂肪抽吸物以去除红细胞，然后以1200 ×离心g持续3分钟。第一次旋转后，弃去上层油性和下层流体层，收集中间脂肪层并进行机械乳化。乳化是通过将脂肪在两个10厘米长的注射器连通后来回移动40次实现。然后乳化脂肪在80℃冷冻，在37℃解冻，以进一步破坏脂肪组织。在冷冻/融化过程的一个循环后，脂肪再次以1500×g持续10分钟离心后，脂肪被分成四层。弃去上层油；第二层完整的脂肪和第四层碎片被丢弃；并且小心地吸出第三水层，即CEFFE（脂肪脱细胞活性蛋白）。通过将提取物通过0.22-微米过滤器进行去除细胞碎片，得到最终提取物。然后将提取物储存在-20℃下以备将来使用。用BCA蛋白质测定试剂盒测量CEFFE的蛋白质浓度。
最终从 50 ml 离心脂肪抽吸物（第一次旋转后收集）中获得CEFFE的总蛋白浓度为 5622.14 ± 253.48μg/ml。
实施例2 抗氧化活性肽的筛选及制备
取新鲜的胎牛血清100ml，调节pH值为6.5，在温度为55摄氏度条件下，加0.5%的木瓜蛋白酶55℃条件下恒温酶解，控制反应时间为4h。100℃沸水浴灭酶后，10000r/min离心20min，取上清液，经0.45μm微孔滤膜真空抽滤，得到酶解液，利用超滤离心管对多肽溶液进行超滤分离，利用分子量截留范围不同的超滤膜对酶解产物进行分离，得到不同分子量的多肽，包括≥30000Da，3000-30000Da，≤3000Da等组分，测定各吸收峰对应的洗脱组分的抗氧化活性，因≤3000Da小肽抗氧化活性更强，故将收集的≤3000Da的组分再经过SephadexLH-20凝胶色谱柱进行分离，洗脱液为去离子水，流速为2.5mL/min，27mL接1管，在280nm下进行测量， DPPH自由基清除能力进行筛选，收集具有最佳抗氧化活性的组分，用SephadexG-25凝胶色谱柱进行二次分离，鉴定得到较好抗氧化特性的组分进一步的，再用高效液相色谱法进行分离，进一步的得到了抗氧化特性最好的多肽，通过质谱鉴定得到其氨基酸序列如SEQ ID NO：1所示，命名为NQ-S34。
实施例3 脂肪脱细胞活性蛋白CEFFE及抗氧化活性肽NQ-S34的抗氧化特性鉴定
人永生化上皮角质形成细胞系HaCaT用DMEM细胞培养基（含体积分数10%胎牛血清）在37℃ 5% CO2环境下培养，每2d进行换液。取汇合度到80%的细胞接种于6孔板中，当细胞密度达到板孔2/3时，将其分成空白组（细胞正常生长）、模型组（800µmol/L的H2O2作用24h)、NQ-S34多肽加样组（分别加入10、50、100µg/mL的NQ-S34预处理2h后，再加入800µmol/L的H2O2作用24h）。CEFFE实验组（分别加入0.1%、1%、5%的实施例1制备的CEFFE预处理2h后，再加入800µmol/L的H2O2作用24h）。阳性对照组（分别加入10µg/L的Vc预处理2h后，再加入800µmol/L的H2O2作用24h）。24h后，弃旧培养基，加入质量浓度为1mg/mL的MTT溶液，每个孔加100μL，4h后，弃MTT溶液，在96孔板中加入DMSO溶液，每孔100μL，摇床摇晃10min（避光操作），使每孔中的液体呈蓝紫色透明状无沉淀，在540nm处测OD值。根据OD值，计算实验组与对照组比值，评价多肽或CEFFE对H2O2损伤的HaCaT细胞损伤的保护能力，结果如图1所示。
由图1可见，与正常生长的空白组比较，加入H2O2损伤细胞以后，细胞相对活力与空白组差异极显著性（P﹤0.01）。实验组相对活力均显著性高于模型组（P﹤0.01），且随着多肽或者CEFFE浓度的增加，相对活性与浓度呈现正相关关系，说明加入样品保护细胞后，细胞的活力逐渐提升。尤其是多肽浓度达到了100ug/mL时其保护能力达到了97%。而5%浓度的CEFFE其保护能力也达到了89%。这说明，多肽和CEFFE都对H2O2诱导的氧化损伤有保护作用，其保护强度在一定范围随样品浓度的提高而增强。
实施例4 小鼠实验
小鼠烫伤模型的制备：试验前24h在小鼠背部剃毛，用10%硫化钠涂抹剃毛区进行脱毛，待毛脱干净时用生理盐水清洗干净，单笼饲养。小鼠静脉注射3%戊巴比妥钠（30mg/kg）进行麻醉，背部脱毛区皮肤以75%乙醇消毒后，使用烫伤仪在鼠背部中线外侧1cm各制备1个烫伤创面，创面面积为1.5cm2，烫伤条件为：烫头温度100℃、作用压力1000g、烫头与皮肤接触时间为5s。试验分组和给药：模型小鼠随机分为5组，分别是模型对照组、阳性对照组、实验组1、实验组2、实验组3，10只/组（雌雄各半）。模型对照组造模后不进行给药；阳性对照组造模后1d开始，烫伤创面以1%Vc水溶液进行涂抹治疗，每天涂抹1次（约1mL），连续涂抹15d；实验组1造模后1d开始，烫伤创面以1%CEFFE进行涂抹治疗，每天涂抹1次，连续涂抹15d。实验组2造模后1d开始，烫伤创面以100µg/mL的多肽水溶液进行涂抹治疗，每天涂抹1次，连续涂抹15d。实验组3造模后1d开始，烫伤创面以100µg/mL的多肽水溶液联合1%CEFFE进行涂抹治疗，每天涂抹1次，连续涂抹15d。烫伤创面愈合率测定：分别于造模后以及第15d使用标准半透明称量纸覆盖在鼠背部的烫伤创面，将创面边缘描绘在半透明的称量纸上，剪出创面形状，计算纸片的面积，按照公式：创面愈合率（%）=（原始创面面积-未愈合创面面积）/原始创面面积×100%，计算创面愈合率。结果如表1所示。
表1 各组烫伤创面不同时间的创面愈合率比较
| 组别 | 创面愈合率（%） |
| 模型组 | 52.46±3.58 |
| 阳性对照组 | 70.23±8.07# |
| 实验组1 | 88.53±7.53## |
| 实验组2 | 93.49±5.54## |
| 实验组3 | 98.67±6.89## |
注：与模型对照组比较，#表示差异显著，##表示差异极显著。
从表1的结果可以看出，与模型对照组相比，实验组和阳性对照组的创面愈合率显著高于模型对照组。实验组1的CEFFE与实验组2的多肽都具有较好的促进皮肤愈合的效果，而将二者组合使用后，具有更好的促进伤口愈合的效果。
取等量的各组伤口皮肤提取蛋白质，采用BCA法检测蛋白质浓度，然后95℃10min对其变性。以体积分数10%的SDS-PAGE胶分离蛋白，转膜，牛奶封闭4h，TBST缓冲液洗涤10min，重复3次，4℃一抗孵育过夜，TBST缓冲液洗涤10min，重复3次，二抗孵育4h，TBST缓冲液洗涤10min，重复3次，化学发光液作用后，在化学放光系统下进行显影。测量SOD的灰度值，以空白组为基础来表示目的蛋白的表达量。结果如图2所示。
从图2可以看出，模型组经H2O2处理，细胞中SOD活性降低，而实验组中加入不同浓度的多肽或者CEFFE或者二者的组合进行涂抹治疗后，能使伤口皮肤中的SOD含量上调，提高了抗氧化活性。
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。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，但本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (5)
1.一种抗氧化的药物组合物，其特征在于含有NQ-S34多肽，其氨基酸序列如SEQ IDNO：1所示。
2.一种抗氧化的药物组合物，其特征在于含有NQ-S34多肽和CEFFE脱细胞脂肪活性蛋白，其中所述多肽的氨基酸序列如SEQ ID NO：1所示，所述的CEFFE脱细胞脂肪活性蛋白的制备方法为：用盐水冲洗脂肪抽吸物以去除红细胞，然后以1200×g离心持续3分钟；弃去上层油性和下层流体层，收集中间脂肪层并进行机械乳化；乳化是通过将脂肪在两个10厘米长的注射器连通后来回移动40次实现；然后乳化脂肪在80℃冷冻，在37℃解冻，以进一步破坏脂肪组织；脂肪再次以1500×g持续10分钟离心后，脂肪被分成四层，弃去上层油；第二层完整的脂肪和第四层碎片被丢弃；并且小心地吸出第三水层，通过将提取物通过0.22微米过滤器进行去除细胞碎片，得到最终提取物即CEFFE脂肪脱细胞活性蛋白。
3.NQ-S34多肽在制备促进皮肤伤口愈合或促进皮肤抗氧化的药物组合物中的用途，其中，NQ-S34多肽氨基酸序列如SEQ ID NO：1所示。
4.NQ-S34多肽和CEFFE脂肪脱细胞活性蛋白在制备促进皮肤伤口愈合或促进皮肤抗氧化的药物组合物中的用途，其中，NQ-S34多肽氨基酸序列如SEQ ID NO：1所示；所述的CEFFE脱细胞脂肪活性蛋白的制备方法为：用盐水冲洗脂肪抽吸物以去除红细胞，然后以1200×g离心持续3分钟；弃去上层油性和下层流体层，收集中间脂肪层并进行机械乳化；乳化是通过将脂肪在两个10厘米长的注射器连通后来回移动40次实现；然后乳化脂肪在80℃冷冻，在37℃解冻，以进一步破坏脂肪组织；脂肪再次以1500×g持续10分钟离心后，脂肪被分成四层，弃去上层油；第二层完整的脂肪和第四层碎片被丢弃；并且小心地吸出第三水层，通过将提取物通过0.22微米过滤器进行去除细胞碎片，得到最终提取物即CEFFE脂肪脱细胞活性蛋白。
5.如权利要求3或4所述的用途，其特征在于所述的药物组合物为乳剂。
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