CN116440251B - 血吸虫来源多肽在制备预防和/或治疗缺血再灌注的药物中的应用 - Google Patents
血吸虫来源多肽在制备预防和/或治疗缺血再灌注的药物中的应用 Download PDFInfo
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Abstract
血吸虫来源多肽SjDX5‑271在制备预防和/或治疗缺血再灌注的药物、制备调节巨噬细胞极化的药物中的应用中的应用,所述血吸虫来源多肽SjDX5‑271的氨基酸序列如SEQ ID NO.1所示。本发明的血吸虫来源的多肽SjDX5‑271刺激小鼠骨髓源性巨噬细胞(BMDMs)后,可以抑制M1巨噬细胞极化,同时促进M2巨噬细胞极化;体内实验进一步证实上述血吸虫来源的多肽SjDX5‑271可促缓解小鼠肝脏缺血再灌注引起的肝损伤,能够缓解肝脏炎症进而发挥保肝的功效。体外证实本发明的血吸虫来源的多肽SjDX5‑271对人源巨噬细胞THP‑1同样存在抗炎作用,证实有转化前景。
Description
技术领域
本发明涉及生物医学领域,主要是血吸虫虫卵可溶性抗原来源的多肽,具有改善宿主肝脏缺血再灌注的肝损伤,可用于肝脏移植等肝脏手术之前的保肝药物中的应用。
背景技术
血吸虫宿主入侵后,在宿主肝脏形成虫卵肉芽肿。由于虫卵肉芽肿的持续存在,宿主的免疫反应逐渐趋向于2型为主的反应模式,包括Th2和M2细胞的增强,以及产生IL-4、IL-10等抗炎细胞因子,可显著减轻宿主的炎症反应。巨噬细胞是鸡蛋肉芽肿的主要细胞之一,在肉芽肿的缓解中起着重要作用。先前的研究表明IL-10可以减弱急性感染期造成的损伤。同时有研究表明,血吸虫卵抗原可诱导M2巨噬细胞极化,减轻小鼠炎症损伤。
库普弗细胞是肝脏中的常驻巨噬细胞,约占非实质细胞的20%。根据表型和功能的不同,巨噬细胞通常分为经典活化(M1)巨噬细胞和交替活化(M2)巨噬细胞。在肝脏缺血再灌注过程中,M1巨噬细胞产生TNF-α等促炎细胞因子促进炎症,M2巨噬细胞释放IL-10等抗炎细胞因子减少炎症。因此,了解巨噬细胞表型转化的调控是开发减少肝脏缺血再灌注炎症的新治疗策略的重要前提。
目前,M2巨噬细胞在脑卒中、器官移植等各种临床前模型中展现了治疗潜力。因此,寻求能在体内诱导M2巨噬细胞增强的生物制剂成为当下研究的热点。
发明内容
为解决现有技术中存在的上述技术问题,本发明提供血吸虫来源多肽在制备预防和/或治疗缺血再灌注的药物中的应用。
为了实现上述目的,本发明具体采用如下技术方案:
本发明的第一个目的是提供血吸虫来源多肽SjDX5-271在制备预防和/或治疗缺血再灌注的药物中的应用,所述血吸虫来源多肽SjDX5-271的氨基酸序列如SEQ ID NO.1所示:YKNLGGQQQSGSSQGQFPSGQMQQQQRPQQ。
进一步的,缺血再灌注为肝脏缺血再灌注。
进一步的,所述SjDX5-271来源于日本血吸虫虫卵。
进一步的,所述SjDX5-271为日本血吸虫卵通过细胞破碎分离纯化,或通过化学合成方法获得,或通过基因工程方法人工表达。
本发明的第二个目的是提供血吸虫来源多肽SjDX5-271在制备调节巨噬细胞极化的药物中的应用,所述血吸虫来源多肽SjDX5-271的氨基酸序列如SEQ ID NO.1所示。
进一步的,所述血吸虫来源多肽SjDX5-271能够促进M2巨噬细胞极化,同时抑制M1巨噬细胞极化。
作为本申请的优选技术方案,上述药物中可以包括药学上可接受的载体,所述药学上可接受的载体选自填充剂、润湿剂、粘合剂、崩解剂、润滑剂中的一种或多种。
作为本申请的优选技术方案,上述药物剂型包括口服制剂、注射制剂、经皮给药制剂或黏膜给药制剂。
进一步的,所述药物为注射制剂,血吸虫来源多肽SjDX5-271经注射施用。
有益效果
本发明提供的血吸虫来源多肽在制备预防和/或治疗缺血再灌注的药物中的应用,具有如下
有益效果:
(1)血吸虫来源的多肽SjDX5-271可通过日本血吸虫卵通过细胞破碎分离纯化,或通过化学合成,或通过基因工程方法人工表达等方法获得。
(2)血吸虫来源的多肽SjDX5-271在缺血再灌注预防治疗药物中的应用。
(3)体外实验证实本发明的血吸虫来源的多肽SjDX5-271刺激小鼠骨髓源性巨噬细胞(BMDMs)后,可以抑制M1巨噬细胞极化,同时促进M2巨噬细胞极化;体内实验进一步证实上述血吸虫来源的多肽SjDX5-271可促缓解小鼠肝脏缺血再灌注引起的肝损伤,能够缓解肝脏炎症进而发挥保肝的功效。
(4)体外证实本发明的血吸虫来源的多肽SjDX5-271对人源巨噬细胞THP-1同样存在抗炎作用,证实有转化前景。
综上,本发明制备的血吸虫来源的多肽SjDX5-271,可显著减轻肝脏炎症,调控巨噬细胞极化,且无显著药物毒性和溶血活性,具有调节巨噬细胞极化作用,可用于缺血再灌注的预防治疗药物的应用。
附图说明
图1实施例1使用CCK8法和溶血活性实验检测不同浓度多肽SjDX5-271处理下小鼠巨噬细胞系RAW264.7活力变化以评估多肽药物毒性;其中,图1A为小鼠巨噬细胞系RAW264.7溶血活性实验红细胞溶血率,图1B为小鼠巨噬细胞系RAW264.7 CCK8细胞活性检测肝细胞活力。
图2实施例2使用血生化分析仪检测证明血吸虫来源的多肽SjDX5-271降低肝脏缺血再灌注后小鼠的ALT、AST水平,其中,图2A为小鼠血清ALT表达水平,图2B为小鼠血清AST表达水平。
图3实施例2使用苏木素伊红染色证明多肽SjDX5-271可使肝脏缺血再灌注小鼠肝脏坏死程度降低,其中,图3A为小鼠肝脏切片苏木素染色形态图片,图3B为肝脏切片坏死评分,图3C为肝脏切片中坏死面积统计。
图4实施例2使用TUNEL染色和蛋白印迹证明多肽SjDX5-271可使肝脏缺血再灌注小鼠肝细胞凋亡程度降低,多肽SjDX5-271抑制促凋亡相关蛋白Bax表达量,增加抑凋亡相关蛋白Bcl2的表达,其中,图4A为肝脏切片Tunel染色,图4B为肝脏切片Tunel染色阳性比例量化,图4C为凋亡相关蛋白Bax和Bcl2的检测。
图5实施例2使用实时荧光定量检测多肽SjDX5-271治疗可使肝脏缺血再灌注小鼠肝脏促炎相关基因表达降低,抑炎基因表达增高;其中,图5A为小鼠肝脏TNF-α表达量,图5B为小鼠肝脏IL-6表达量,图5C为小鼠肝脏IL-1β表达量,图5D为小鼠IL-10表达量。
图6实施例2使用免疫组化染色检测MPO证实多肽SjDX5-271治疗之后中性粒细胞浸润减轻。
图7实施例3虫卵来源多肽SjDX5-271可体外调控小鼠原代骨髓来源的巨噬细胞(BMDMs)极化;其中,图7A为小鼠BMDMs的TNF-α表达量,图7B为小鼠BMDMs的IL-6表达量,图7C为小鼠BMDMs iNOS的表达量,图7D为小鼠BMDMs IL-10的表达量,图7E为小鼠BMDMs Arg-1的表达量,图7F为小鼠BMDMs Ym-1的表达量,图7G为小鼠BMDMs细胞上清IL-6的表达量,图7H为小鼠BMDMs细胞上清IL-10的表达量。
图8实施例4虫卵来源多肽SjDX5-271可体外调控人源巨噬细胞THP-1极化;其中,图8A为THP-1的TNF-α表达量,图8B为THP-1的IL-10表达量,图8C为THP-1的Arg-1表达量。
具体实施方式
以下结合实施例来进一步解释本发明,但实施例并不对本发明做任何形式的限定。
本发明前期已通过高效液相色谱分离法分离出日本血吸虫虫卵的多肽混合物,并进行质谱分析,从中选择了丰度较高的其中一个肽段进行研究,命名为SjDX5-271。
SjDX5-271具体序列如下:
Seq ID NO.1:YKNLGGQQQSGSSQGQFPSGQMQQQQRPQQ;分子式C137H215N47O49S,平均分子量3336.5g/mol,理论等电点pI 10.39。
针对SjDX5-271,本发明设计了一段由相同数量氨基酸组成的无关肽Seq:GQQPQGSNKYNQQPSQSGFLQSGQQMRQQG。
本发明提供了如上两条氨基酸序列,除特别说明外,本实施例及以下实施例中的肽链均委托生工生物工程(上海)股份有限公司通过化学合成获得,纯度>95%。
实施例1虫卵来源多肽SjDX5-271的毒性评价
(1)溶血活性实验:
①制备无菌阿氏液,用含有肝素锂作为抗凝血剂的采血管收集C57BL6/J小鼠全血,并与阿氏液1:1混合均匀,从混合液中取出200μl,1000rpm离心15分钟,弃上清,将沉淀中的红细胞用灭菌生理盐水洗涤三次,使用生理盐水制成107-108的细胞悬液。将多肽使用生理盐水溶解至指定浓度,将上述红细胞悬液与样品按1:1混合,37℃培养30分钟,结束后1000rpm离心15分钟,上清液于540nm测OD值。
②将生理盐水作为阴性对照为,0.1%TritonX-100为阳性对照,并在分析时设定阳性对照溶血活性为100%。
③计算:I%=(AA-AB)/(AC-AB)*100。(I%:样品溶血活性,AA:样品组在540nm光吸收值,AB:阴性组540nm光吸收值,AC:阳性对照组540nm光吸收值)。
(2)CCK8细胞活性检测实验:
①在96孔板中加入200μl的密度为5000个/ml的细胞悬液,将培养板在37℃,5%CO2培养箱过夜。
②加入不同浓度的多肽,继续培养24h。
③到达刺激时间后,向每孔加入10μl CCK8溶液;在培养箱内孵育2小时后,酶标仪测定450nm处吸光度。
④计算细胞活力。
溶血实验结果表明,SjDX5-271从0.39μg/ml至100μg/ml浓度区间内,其红细胞溶血率与阳性组(溶血率100%)均有显著性差异(图1A)。
CCK8检测结果也显示,SjDX5-271刺激小鼠巨噬细胞系RAW264.7后,细胞活力均未发生显著性改变(图1B)。
图1展示了红细胞溶血实验和CCK8检测显示SjDX5-271无论在高浓度100μg/ml还是低浓度0.39μg/ml下,小鼠巨噬细胞系RAW264.7活力没有显著降低,说明SjDX5-271在0.39-100μg/ml浓度范围内无显著药物毒性。以上实验证明合成的多肽均无明显细胞毒性和溶血活性。
实施例2虫卵来源多肽SjDX5-271减轻缺血再灌注小鼠的肝损伤
以雄性6-8周C57BL6/J小鼠为研究对象,将30只小鼠随机分为6组,每组5只小鼠,其中假手术组分为:生理盐水组、无关肽组和SjDX5-271组;缺血再灌注组分为:生理盐水组、无关肽组和SjX5-271组。其中无关肽和SjDX5-271在手术24h经静脉注射,注射剂量为3mg/kg。造模过程为:使用血管夹闭塞包括肝动脉、门静脉和胆管的门脉三联体,以阻断肝中叶和左肝叶的血液供应,产生70%的肝缺血,肝缺血期持续90分钟,再灌注期持续6小时。假手术组进行相同的操作但不进行血管闭塞。再灌注结束后取小鼠外周血进行ALT和AST水平检测,以肝脏苏木素染色、TUNEL染色评估小鼠肝脏坏死程度,Western Blot实验检测凋亡相关蛋白Bax和Bcl2的表达、实时荧光定量检测小鼠肝脏TNF-α、IL-6、IL1β和IL-10表达水平,免疫组化染色MPO检测炎症细胞浸润程度,实时荧光定量和免疫组化染色评估小鼠肝脏炎症水平。
(1)苏木素染色:
①将肝脏组织包埋石蜡后,制成4μm的石蜡切片。
②二甲苯浸泡30min,进行脱蜡。
③入70%-90%酒精中脱水各10min。
④苏木素染色5分钟,之后用流水冲洗;返蓝液进行返蓝。
⑤伊红染色1分钟,入70%-90%酒精各5min,再置于二甲苯中两次,各5分钟,晾干后封片。
(2)TUNEL染色:
①肝脏石蜡切片使用二甲苯脱蜡30min。
②水化用梯度乙醇从90%-70%浸洗,各5min。
③使用蛋白酶k孵育30min。
④TUNEL反应液37℃避光孵育1h。
⑤DAPI染色10min。
⑥冲洗后晾干封片。
(3)免疫组化染色
②肝脏石蜡切片使用二甲苯脱蜡30min。
②抗原修复:将柠檬酸抗原修复缓冲液加入切片盒内,淹没切片,放置微波炉中高档加热至沸腾5分钟,转至中火20分钟,取出切片盒,待冷却至室温后后用双蒸水漂洗3次,每次5分钟。
③把切片侵入到3%过氧化氢溶液中,25min后取出。
④用一抗稀释液稀释MPO抗体,在切片上滴加一抗,4℃摇床孵育过夜。
⑤滴加二抗,放置在37℃孵箱中,50min后取出。
⑥在切片上滴加DAB显色液。
⑦在切片上滴加苏木素染液复染3min,随后流水冲洗1分钟,然后用盐酸乙醇溶液分化1分钟,流动水冲洗,氨水返蓝,流水冲洗。
结果表明,血清生化检测表明SjDX5-271注射的小鼠肝损伤显著降低(图2A-B)。
图2A为经SjDX5-271多肽治疗后,小鼠血清ALT表达水平降低,图2B为经SjDX5-271多肽治疗后,小鼠血清AST表达水平降低。结果显示,经SjDX5-271治疗后,小鼠肝脏坏死程度显著降低。
苏木素伊红染色显示手术后小鼠肝脏坏死程度显著高于假手术组,提示造模成功。同时,小鼠的血清生化结果表明,经SjDX5-271注射后小鼠肝脏坏死程度显著减轻(图3A-C)。
其中,图3A为小鼠肝脏切片形态学的苏木素伊红染色显示,图3B显示小鼠肝脏切片Suziki评分,图3C显示小鼠肝脏切片的坏死面积统计。小鼠肝脏形态学的结果表明,经SjDX5-271注射后小鼠肝脏坏死程度显著减轻。
TUNEL染色证实多肽注射组小鼠肝细胞凋亡程度显著降低,蛋白印记实验证实SjDX5-271调节凋亡相关蛋白表达(图4)。
图4A为小鼠肝脏切片的Tunel染色实验,图4B为Tunel染色实验阳性结果的量化,证实经SjDX5-271治疗后,小鼠肝脏中肝细胞凋亡程度减轻。图4C为凋亡相关蛋白检测实验,结果表明经SjDX5-271治疗后,促凋亡蛋白Bax表达降低,抑凋亡蛋白Bcl2表达增加。
实时荧光定量结果证实,经SjDX5-271治疗后小鼠肝脏炎症减轻。
图5A-C为促炎性细胞因子(Tnf-α、Il6和Il1β)的mRNA水平检测,图5B为抗炎性细胞因子Il10的mRNA水平的检测,结果表明经SjDX5-271治疗后,小鼠肝脏促炎性细胞因子生成减少,抗炎性细胞因子生成增多,证实经SjDX5-271治疗后,小鼠肝损伤的炎症水平减低。
MPO免疫组化结果显示,多肽治疗组小鼠肝脏炎性细胞浸润减少。
图6A为小鼠肝脏切片MPO染色,检测中性粒细胞的表达,图6B为MPO染色阳性率的量化。结果证实,经多肽SjDX5-271治疗后,小鼠肝脏炎性浸润细胞减少。
实施例3虫卵来源多肽SjDX5-271调控小鼠巨噬细胞极化。
分离小鼠胫骨和股骨,冲出骨髓细胞后,1500rpm离心5min,弃上清后冰上红裂5min,之后加入含20ng/mL M-CSF的10% DMEM培养7天,细胞培养期间不更换培养基,培养第三天后更换一半骨髓巨噬细胞诱导培养基,第五天更换全部培养基,第七天即可用于后续实验。
在第七天时使用PBS冲洗三次以去除M-CSF残留和非贴壁细胞,留下贴壁的继续培养,并接受LPS(0.5μg/ml)存在或不存在刺激,诱导巨噬细胞向M1分化同时,以10μg/mL浓度的SjDX5-271和对照肽处理BMDMs 24h,收集细胞RNA和上清并进行炎症基因表达量分析。
结果显示,无论在LPS存在与否,SjDX5-271处理的BMDMs都可以抑制M1型巨噬细胞相关细胞因子的表达,同时促进M2型巨噬细胞细胞因子的表达(图7A-H)。
图7Tnfα(A)、Il6(B)和Inos(C)为M1型巨噬细胞的标志位,我们发现BMDMs细胞经SjDX5-271刺激后,M1型巨噬细胞标志物mRNA表达水平减低,Il10(D)、Arg1(E)和Ym1(F)为M2型巨噬细胞标志物,我们发现经SjDX5-271刺激后,M2型巨噬细胞标志物mRNA表达水平增高。图7G-H为经SjDX5-271刺激后,细胞上清蛋白水平的检测。结果显示,经SjDX5-271刺激后,IL-6(M1型巨噬细胞标志物)蛋白表达水平降低,而IL-10(M2型巨噬细胞标志物)蛋白水平表达增高。以上结果证实,SjDX5-271可以诱导M2巨噬细胞极化同时抑制M1巨噬细胞极化。
实施例4虫卵来源多肽SjDX5-271调控人源巨噬细胞极化。
首先将培养好的处于对数生长期的THP-1巨噬细胞在室温条件下,300g离心5min,弃上清废液,使用不加血清的1640培养基重悬,按照终浓度50ng/ml的浓度加入PMA,将细胞吹打均匀后铺板,放于37℃、5%CO2培养箱孵育24-48h诱导分化成巨噬细胞,然后更换新鲜培养基继续培养细胞。接受LPS(100ng/ml)存在或不存在刺激,诱导巨噬细胞向M1分化同时,以10μg/mL浓度的SjDX5-271和对照肽处理THP-1细胞24h,收集细胞RNA进行炎症基因表达量分析。
结果显示,SjDX5-271处理的THP-1可以抑制促炎性相关细胞因子的表达,同时促进抗炎性细胞因子的表达(图8A-C)。
图8Tnfα(A)为M1型巨噬细胞的标志物,我们发现THP-1细胞经SjDX5-271刺激后,M1型巨噬细胞标志物mRNA表达水平减低,Il10(B)和Arg1(C)为M2型巨噬细胞标志物,我们发现经SjDX5-271刺激后,M2型巨噬细胞标志物mRNA表达水平增高。证实SjDX5-271诱导巨噬细胞M2极化同时抑制M1巨噬细胞极化的特性对人源巨噬细胞依旧存在作用,有转化价值。
本发明制备的血吸虫来源肽可用于治疗缺血再灌注损失的耀武应用,具有重要的临床价值。
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。
Claims (2)
1.血吸虫来源多肽SjDX5-271在制备预防和/或治疗肝脏缺血再灌注的药物中的应用,所述血吸虫来源多肽SjDX5-271的氨基酸序列如SEQ ID NO.1所示。
2.根据权利要求1所述的应用,其特征在于,所述血吸虫来源多肽SjDX5-271经注射施用。
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CN112707959A (zh) * | 2020-11-11 | 2021-04-27 | 南京医科大学 | 一种多肽、制备方法及应用 |
CN113160983A (zh) * | 2021-04-09 | 2021-07-23 | 南京医科大学附属逸夫医院 | 一种代谢相关脂肪性肝病临床预测模型 |
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CN112707959A (zh) * | 2020-11-11 | 2021-04-27 | 南京医科大学 | 一种多肽、制备方法及应用 |
CN113160983A (zh) * | 2021-04-09 | 2021-07-23 | 南京医科大学附属逸夫医院 | 一种代谢相关脂肪性肝病临床预测模型 |
Non-Patent Citations (2)
Title |
---|
A target-based discovery from a parasitic helminth as a novel therapeutic approach for autoimmune diseases;Yangyue Ni等;eBioMedicine;第95卷;104751 * |
日本血吸虫40 kDa 热休克蛋白对巨噬细胞活化的影响;李莎莎等;中国血吸虫病防治杂志;第24卷(第2期);137-141,149 * |
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