CN109498659A - 沙虫酶解物在制备防治骨关节炎药物或保健品中的应用 - Google Patents
沙虫酶解物在制备防治骨关节炎药物或保健品中的应用 Download PDFInfo
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Abstract
本发明公开了沙虫酶解物在制备防治骨关节炎药物或保健品中的应用。药理实验研究证明，沙虫酶解物能够显著提高体外培养的软骨细胞的增殖活性，并且能够显著减轻大鼠骨关节损伤，表明沙虫酶解物有治疗或预防骨关节炎的潜力。本发明公开的沙虫酶解物的新用途扩大了沙虫酶解物的适应症或应用范围，有望开发成为新的防治骨关节炎的药物或保健品。
Description
技术领域
本发明涉及天然产物应用技术领域，具体涉及海产品酶解物在制备药物或保健品的应用。
背景技术
骨关节炎(Osteoarthritis，OA)是以关节软骨进行性损伤为特征的一种慢性关节退行性病变，好发于负重、活动频繁的关节。据统计，60岁以上人群OA的发病率可达50％，75岁以上人群高达80％，其致残率达53％，严重威胁居民健康。随着我国人口的老龄化趋势，预计到2050年，我国60岁以上老年人将达4.8亿，占总人口的34.1％，将成为全球老龄化最严重的国家。OA手术治疗存在费用高、疼痛、假体松动导致二次手术等问题，不易被患者接受。骨关节炎的常用药物氨基葡萄糖似乎并不比安慰剂组有效，其对骨关节炎的防治效果是不确定的，深海鱼油也并不能缓解膝骨关节炎的进展。因此，尽管骨关节炎给患者造成巨大痛苦并给社会带来巨大经济负担，但目前仍无治疗该疾病的有效措施。
作为最常见的关节疾病，OA随着人口老龄化而日益流行。虽然有关OA的研究众多，但其发病机制仍然没有充分阐明。研究认为其多因素病因包括氧化应激和活性氧(ROS)过量生成，ROS调节细胞内信号传导过程、软骨细胞衰老和细胞凋亡、细胞外基质合成和降解，并导致滑膜炎症及软骨下骨质功能障碍。鉴于此，以复杂的氧化应激信号通路为标靶，可能提供治疗这种破坏性疾病的潜在方法。许多各种不同的抗氧化剂，天然的或合成的，已经被建议用于OA治疗。褪黑激素及其代谢物是广谱抗氧化剂及自由基清除剂，一些研究显示褪黑激素对不同模型的OA均具有一定的防治效果。食物多酚，如白藜芦醇，其软骨保护作用与抗凋亡、抗炎特性有关，其机制涉及到ROS清除、NF-κΒ活性抑制及PGE2生成。一些草药通过其抗氧化功能也能够有助于OA治疗。异泽兰黄素通过抑制氧化应激并降低IL-1β、IL-6、硝基酪氨酸、iNOS及磷酸化JNK的表达水平，缓解软骨破坏；牛蒡根茶可降低膝骨关节炎患者血清MDA并提高总抗氧化力、SOD及GPX水平。自由基清除剂也已经被建议作为潜在治疗剂，用于对抗OA发展并保护关节软骨，如富勒烯，能使自由基失活并抑制氧化应激诱导的MMP-1、MMP-3及MMP-13生成、基质合成下调、人软骨细胞凋亡及早老，在手术诱导的OA动物模型中发挥了关节保护效果。此外，NADPH氧化酶抑制剂及iNOS抑制剂也对OA具有一定的治疗作用。另一方面，研究显示胶原蛋白肽作为药理营养素对关节和骨骼的某些退行性疾病具有防治的药理作用。无论是动物实验还是在临床研究中，胶原蛋白肽均可减轻OA症状，并能修复骨关节损伤或减缓退行性变，且无副作用。其作用机制主要包括：①作为软骨和滑液的基本成分，激发软骨的合成代谢；②延迟软骨炎症诱导的分解代谢，减缓软骨破坏进程，有助于关节软骨的再生，从而减少关节疼痛和增加受累关节的活动性。运动员服用膳食补充剂胶原蛋白多肽能够改善关节疼痛，表明胶原蛋白多肽有助于维持关节健康。狭鳕鱼皮胶原蛋白肽可以有效缓解大鼠骨关节炎的症状，其机制可能与调控体内的氧化-抗氧化的平衡体系以及抑制炎症因子的释放有关。而口服胶原蛋白多肽则能有效改善中老年女性膝骨关节炎患者的临床症状和功能，缓解疼痛，提高生活质量。以豚鼠为动物模型的实验也证明胶原蛋白多肽对骨关节炎具有潜在的治疗价值。
沙虫又叫海人参，学名方格星虫(Sipunculus nudus)，又称为光裸星虫，盛产于广东湛江和广西北部湾地区北海钦州等地。作为著名的海产珍品，沙虫味道鲜美脆嫩，富含多种活性成分，有待开发出更多后续产品，延长沙虫产品的产业链。研究证明，沙虫蛋白多肽具有极佳的抗氧化活性，而且沙虫胶原蛋白含量丰富，其含量占沙虫干基的9.00％。但是目前还没有沙虫蛋白多肽具有抗骨关节炎活性的相关报导。
发明内容
本发明的目的在于提供一种沙虫酶解物在制备防治骨关节炎药物或保健品中的应用。
为实现上述目的，本发明所采用的技术方案如下：
沙虫酶解物在制备防治骨关节炎药物或保健品中的应用。
作为进一步的方案，本发明所述的沙虫酶解物为沙虫蛋白经酶水解的产物。
作为进一步的方案，本发明所述的防治骨关节炎药物或保健品为胶囊剂、片剂、丸剂、颗粒剂或口服液中的一种。
作为进一步的方案，本发明所述的防治骨关节炎药物或保健品还包括制剂允许的辅料和/或活性成分。
沙虫富含胶原蛋白，沙虫酶解物是由沙虫蛋白经蛋白酶水解而制备的产物，其主要成分为氨基酸及多肽，具有较好的抗氧化、清除自由基和免疫调节活性。
实验结果显示，沙虫酶解物能够显著促进体外培养的软骨细胞增殖，能够显著减轻骨关炎模型大鼠的关节损伤，能够显著抑制骨关炎模型大鼠的血清炎性因子白介素-1β(IL-1β)水平。这些结果表明沙虫酶解物具有治疗或预防骨关节炎的功能。
本发明具有以下有益效果：
沙虫酶解物除了在体外可以促进软骨细胞增殖外，还能够在体内减轻骨关炎模型大鼠的关节损伤，并且该作用可能与抗炎效果有关。沙虫作为食材，无毒副作用，因此其酶解物在制备治疗或预防骨关节炎药物或保健品中具有较佳的应用潜力。
附图说明
图1为沙虫酶解物对软骨细胞增殖活性的影响，与空白对照组比较，P＜0.05＊(多重比较采用最小显著差异法即LSD法)；
图2为沙虫酶解物对关节肿胀度的影响，与模型组比较，P＜0.05＊(多重比较采用最小显著差异法即LSD法)；
图3为沙虫酶解物对IL-1β的影响，与模型组比较，P＜0.05＊(多重比较采用最小显著差异法即LSD法)。
具体实施方式
下面，结合具体实施方式，对本发明做进一步描述。
沙虫酶解物可以通过任意的、合适的蛋白酶水解技术获得。在本发明实施例中使用的沙虫酶解物可以通过以下方法获得：取新鲜沙虫(购于湛江东风水产品市场)，洗净、沥干、匀浆，按1∶3料水比加入蒸馏水(超纯水仪，Milli-Q)，调至pH7.2(HI2210酸度计，意大利哈纳)，按底物质量的0.1％的比例(w/w)分别将木瓜蛋白酶及胰酶混悬于蒸馏水中，于52℃恒温水浴6h，取出后在3000r/min条件下离心20min(台式低速离心机，湖南赫西仪器装备有限公司)，取上清液，冷冻干燥(冷冻干燥机，上海比朗)成干粉保存。
下面对本发明的优选实施例予以详细描述，实施例中未注明具体条件的实验方法，通常为常规条件。
实施例1沙虫酶解物对体外培养的软骨细胞增殖的影响
1.准备细胞实验用沙虫酶解物
取沙虫酶解物冻干品50mg，溶于10mL PBS溶液中，制得浓度为5mg/m L的沙虫酶解物溶液，0.22μm微膜(SLGPo33RB一次性过滤器，Millipore)除菌过滤。以高糖DMEM培养液(Thermo)逐级稀释，得到浓度为2、1、0.5、0.25、0.125mg/mL的沙虫酶解物溶液，置于-20℃冰箱保存备用。
2.大鼠关节软骨细胞分离、培养
取200g雌性SD大鼠(购自广东省医学实验动物中心)，脱臼处死，在无菌条件下取膝关节软骨，PBS漂洗，剪碎；置于浓度为0.2％的Ⅱ型胶原酶(Sigma公司)中，37℃水浴消化5h，可见软骨化成絮状；取200目不锈钢筛网过滤，3000r/min离心5min(微量高速冷冻离心机，湖南赫西仪器装备有限公司)，收集细胞加含FBS(Gibco公司)的高糖DMEM培养液，移入细胞培养瓶，置于37℃、5％CO2的细胞培养箱(Thermo)中进行单层培养，每3天更换1次培养液；当细胞铺满培养瓶底面积80％时，进行传代。
3.MTT法检测细胞增殖活性
取上述第3代软骨细胞，调整细胞浓度为5×105个/mL，接种于96孔板，每孔180μL细胞悬液，培养24h细胞贴壁后，依次加含不同浓度的上述冷冻保存的沙虫酶解物溶液(0.125，0.25，0.5，1，2mg/mL)20μL，空白对照组为不含沙虫酶解物的DMEM培养液，则沙虫酶解物终浓度为0、12.5、25、50、100、200μg/mL。每组均设6个复孔。孵育24h后，每孔加入20μLMTT(Sigma)，摇匀，37℃继续孵育5h后，弃培养液，每孔加入100μL DMSO(Sigma)，轻轻振荡10min。采用ELx800酶标仪(BIO-TEK)，于590nm波长处测各孔的吸光度值。结果采用SPSS软件进行统计分析。
4.结果
由图1可知，随着沙虫酶解物浓度的增加，软骨细胞增殖活性也逐渐提高，并呈剂量依赖关系(软骨细胞增殖活性即OD值与沙虫酶解物剂量存在上升的线性趋势，P＜0.001)，表明沙虫酶解物对软骨细胞具有增殖促进作用。
实施例2：沙虫酶解物对大鼠骨关节炎的干预作用
1.准备动物实验用沙虫酶解物
取适量沙虫酶解物冻干品，并溶于蒸馏水，用于大鼠灌胃给药，沙虫酶解物溶液配制的原则是——每只大鼠每次灌胃量不得大于2mL，并且每日灌胃给药前需新鲜配制。
2.造模
大鼠腹腔注射水合氯醛(350mg/kg)(上海阿拉丁生化科技股份有限公司)麻醉，右后肢膝关节部位常规消毒，然后用1mL注射针穿过髌骨韧带向膝关节腔内注入灭菌生理盐水配制的40mg/mL的白陶土及20mg/mL的λ-鹿角菜胶(Sigma公司)的混悬液0.1mL，并缓慢曲伸关节持续5min。术后大鼠休息2天，第3天各组大鼠在跑台(ZH-PT动物实验跑台，安徽正华生物仪器设备有限公司)上以10～20m/min慢速跑步30min以适应跑道。5d后开始正式运动，20m/min，60min/d，跑台坡度为5°，运动6周后结束。
3.实验设计
取180g SD雄性大鼠分为4组，每组8只：①沙虫酶解物高剂量组(200mg/kg)，造模，并于造模开始日起开始给药，按200mg/kg的沙虫酶解物剂量每日灌胃给药1次；②中剂量组(100mg/kg)，造模，并于造模开始日起开始给药，按100mg/kg的沙虫酶解物剂量每日灌胃给药1次；③低剂量组(50mg/kg)，造模，并于造模开始日起开始给药，按50mg/kg的沙虫酶解物剂量每日灌胃给药1次；④模型组，造模，每日灌胃给与2mL蒸馏水1次。
4、关节肿胀度测定
6周跑台运动结束后，采用游标卡尺测量每组大鼠左右膝关节横向直径(mm)，并按以下公式计算膝关节肿胀度(％)：
关节肿胀度(％)＝(右腿膝关节直径－左腿膝关节直径)/左腿膝关节直径×100(％)。
结果采用SPSS软件进行统计分析。
5、大鼠处理及样本采集
测量完大鼠左右膝关节，100mg/mL水合氯醛麻醉大鼠(4mL/kg)，股动脉取血后处死。全血标本于室温静置30min后，3000r/min离心15min，取上清液，用于细胞因子检测。
6、炎性因子检测
用ELISA法测定大鼠血清中IL-1β质量浓度(武汉华美生物科技有限公司)。实验操作按照试剂盒所附说明书进行。结果采用SPSS软件进行统计分析。
7.实验结果
①沙虫酶解物高、中、低剂量组均能减轻大鼠关节肿胀损伤，但低剂量组与模型组相比没有显著性差异。大鼠关节肿胀度的减小与沙虫酶解物剂量增高之间存在剂量依赖关系(即关节肿胀度与沙虫酶解物剂量存在下降的线性趋势，P＜0.001)(图2)。
②与模型组相比，沙虫酶解物高、中、低剂量组均能减轻大鼠血清IL-1β质量浓度，但低剂量组与模型组相比没有显著性差异。大鼠血清炎性因子IL-1β质量浓度的减小与沙虫酶解物剂量增高之间存在剂量依赖关系(即血清IL-1β质量浓度与沙虫酶解物剂量存在下降的线性趋势，P＜0.001)(图3)。
对本领域的技术人员来说，可如以上描述的技术方案以及构思，做出其它各种相应的改变以及形变，而所有的这些改变以及形变都应该属于本发明权利要求的保护范围之内。
Claims (4)
1.沙虫酶解物在制备防治骨关节炎药物或保健品中的应用。
2.根据权利要求1所述的应用，其特征在于，所述沙虫酶解物为沙虫蛋白经酶水解的产物，其主要成分为氨基酸及多肽。
3.根据权利要求1所述的应用，其特征在于，所述的药物或保健品为胶囊剂、片剂、丸剂、颗粒剂或口服液。
4.根据权利要求3所述的应用，其特征在于，所述的药物或保健品由沙虫酶解物与制剂允许的辅料或其他任选的活性成分制成。
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