CN107041946A - 化合物ss‑31在制备治疗动脉粥样硬化及相关疾病药物或制剂上的应用 - Google Patents
化合物ss‑31在制备治疗动脉粥样硬化及相关疾病药物或制剂上的应用 Download PDFInfo
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Abstract
本发明提供了一种用于制备治疗患有动脉粥样硬化疾病，如颈动脉狭窄、下肢动脉硬化闭塞症及冠心病等相关疾病药物，即化合物Szeto‑Schiller‑31(SS‑31)在制备治疗动脉粥样硬化及相关疾病药物上的应用。本发明属于医药领域，具体指化合物新的医药用途领域。本发明通过实验发现SS‑31减轻动脉粥样硬化程度：显著降低小鼠动脉ROS水平，减少氧化损伤，提高ATP水平；显著减少动脉粥样硬化斑块处巨噬细胞含量，显著增加斑块处平滑肌细胞含量和胶原含量，稳定动脉粥样硬化斑块；显著改善炎症水平；显著降低主动脉斑块处脂质摄取蛋白的表达。结果表明SS‑31具有治疗动脉粥样硬化疾病及其相关疾病的作用。
Description
技术领域
本发明属于化学药物领域，涉及一种化合物Szeto-Schiller-31(SS-31)在制备治疗动脉粥样硬化疾病药物上的应用。
背景技术
动脉粥样硬化(Atherosclerosis,AS)是心血管疾病的病理基础，主要包括颈动脉狭窄、下肢动脉硬化闭塞症及冠心病。这类疾病的临床表现、病变特征虽不尽相同，但它们有共同的特征：病变缓慢发展，受累动脉管腔狭窄，远端组织血供不足，至今无理想预防药物，已成为世界范围内导致人类死亡的最主要原因。目前这类疾病的发病机制尚存争议，遗传、炎症、高脂饮食、老化等多种复合因素是该类疾病的共同致病因素，病理机制均包括血管内皮损伤、单核细胞粘附迁移形成巨噬细胞、巨噬细胞吞噬脂质形成泡沫细胞和代谢通路受损等。动脉粥样硬化疾病严重危害人类健康，给患者、家属和社会带来了极大的心理和经济负担，发展防治动脉粥样硬化的药物备受重视。
慢性炎症状态和高胆固醇血症是AS的重要特征。动脉内皮损伤是AS的起始步骤，受损的内皮细胞分泌粘附分子和细胞因子，募集白细胞。炎症持续存在会上调巨噬细胞清除剂受体的表达，增加ox-LDL摄取，促进泡沫细胞形成。泡沫细胞是AS斑块中最主要的炎症细胞。研究发现AS斑块处细胞内粘附分子、血管细胞粘附分子和单核细胞趋化因子等粘附分子高表达。白细胞经粘附分子粘附于内皮细胞后，经趋化因子介导，渗透进入血管内膜。
巨噬细胞脂质摄取和排出不平衡，细胞内脂质累积，泡沫细胞形成，是AS斑块形成的关键。CD36和LOX-1是氧化性低密度脂蛋白(ox-LDL)受体，是巨噬细胞表面的吸脂蛋白；ABCA1和ABCG1是巨噬细胞表面的排脂蛋白，胆固醇排出并与受体HDL或载脂蛋白A-Ⅰ结合。
Szeto-Schiller-31(SS-31)是一种新型靶向线粒体的化合物，由Szeto于2005年合成，在肾脏缺血动物模型中，可以作用于线粒体内膜心磷脂，保护线粒体的完整性，减少或抑制线粒体来源的活性氧(ROS)的产生，提高三磷酸腺苷(ATP)水平，达到减少氧化应激的目的。显然这些发现与抗动脉粥样硬化没有直接联系。目前SS-31已应用于多个人类疾病模型中并显示出一定的效果，比如研究显示SS-31对心衰和高血压性心肌病均有一定的保护作用，虽然心衰和高血压性心肌病与本申请所涉及的动脉粥样硬化疾病无论从疾病的发病机制，病理生理基础，还是对应的治疗药物、治疗靶点和治疗策略都完全不同，无法给出教导和启示，但是我们还是想大胆的尝试一下SS-31对动脉粥样硬化疾病是否具有保护作用。
但到目前为止，关于SS-31抗动脉粥样硬化及其相关疾病方面尚无报道。本申请首次通过模型评价SS-31在抗动脉粥样硬化方面的活性，并发现了其在控制动脉粥样硬化方面多方面的调控活性和功能。
Szeto-Schiller-31(SS-31)分子的结构式
发明内容
发明目的
本发明的目的是通过动脉粥样硬化疾病相关的疾病模型，发现SS-31在制备治疗动脉粥样硬化及相关疾病方面新的医药用途。
技术方案
本发明将SS-31用于动脉粥样硬化疾病动物模型，结果显示皮下注射SS-31一方面延缓小鼠AS的发展，阻滞斑块的形成，另一方面可以稳定易损斑块。SS-31可以降低小鼠主动脉ROS水平、减少氧化损伤、提高ATP水平，改善小鼠全身炎症水平，降低小鼠主动脉斑块处脂质摄取蛋白(CD36和LOX-1)的表达。这些结果表明SS-31可以作为AS或者相关疾病的治疗药物用于临床。
SS-31本身或者其作为主要成分在治疗动脉粥样硬化疾病药物上的应用，所述动脉粥样硬化疾病包括颈动脉狭窄、下肢动脉硬化闭塞症及冠心病。
进一步的，SS-31本身或者其作为主要成分在制备下列药物上的应用：
(1)阻滞动脉粥样硬化斑块形成、延缓AS的发展；
(2)稳定易损动脉粥样硬化斑块、防止不稳定型心绞痛或/和心肌梗死的发生；
(3)降低主动脉ROS水平、减少主动脉氧化损伤、提高主动脉ATP水平，提高主动脉的生理机能与功能；
(4)降低主动脉或者全身炎症水平，阻滞AS的发生与发展；
(5)降低主动脉斑块处脂质摄取蛋白CD36的表达，阻滞AS的发生与发展；
(6)降低主动脉斑块处脂质摄取蛋白LOX-1的表达，阻滞AS的发生与发展。
本发明的优点：
1、本发明首次将新型靶向线粒体的化合物SS-31用于动脉粥样硬化及其相关疾病的治疗，可作为制备治疗动脉粥样硬化及其相关疾病药物的新用途申请，具有巨大的市场价值和社会效益。
2、本发明提供了SS-31作为药物主要成分在动脉粥样硬化疾病中的应用。SS-31延缓小鼠动脉粥样硬化疾病的发展，减少斑块的形成，另一方面可以稳定易损斑块。
3、降低主动脉ROS水平、减少主动脉氧化损伤、提高主动脉ATP水平，提高主动脉的生理机能与功能；
4、降低主动脉或者全身炎症水平，阻滞AS的发生与发展；
5、降低主动脉斑块处脂质摄取蛋白CD36的表达，阻滞AS的发生与发展；
6、降低主动脉斑块处脂质摄取蛋白LOX-1的表达，阻滞AS的发生与发展。
附图说明：
图1 SS-31对ApoE-/-小鼠主动脉斑块形成的影响(n＝15)，数据均以表示。
图2 SS-31对ApoE-/-小鼠主动脉窦区斑块形成的影响(n＝15)，数据均以表示。
图3 SS-31对ApoE-/-小鼠主动脉窦区斑块成分(巨噬细胞)的影响(n＝15)，数据均以表示。
图4 SS-31对ApoE-/-小鼠主动脉窦区斑块成分(平滑肌细胞)的影响(n＝15)，数据均以表示。
图5 SS-31对ApoE-/-小鼠主动脉窦区斑块成分(胶原)的影响(n＝15)，数据均以表示。
图6 SS-31对ApoE-/-小鼠主动脉活性氧(ROS)的影响。
图7 SS-31对ApoE-/-小鼠主动脉ATP的影响(n＝13)，数据均以表示。
图8 SS-31对ApoE-/-小鼠主动脉SOD2蛋白水平的影响(n＝1 4)，数据均以表示。
图9 SS-31对ApoE-/-小鼠主动脉总SOD2酶活性的影响(n＝1 3)，数据均以表示。
图10 SS-31对ApoE-/-小鼠主动脉窦区DNA损伤的影响(n＝15)，数据均以表示。
图11 SS-31对ApoE-/-小鼠主动脉窦区CD36的影响(n＝15)，数据均以表示。
图12 SS-31对ApoE-/-小鼠主动脉窦区LOX-1的影响(n＝15)，数据均以表示。
图13 SS-31对ApoE-/-小鼠主动脉窦区ABCA1的影响(n＝15)，数据均以表示。
具体实施方式：
SS-31对ApoE-/-小鼠的动脉粥样硬化的影响
1 材料和方法
1.1 实验分组与标本收集
雄性8周大ApoE-/-小鼠(遗传背景：C57BL/6)90只，从南京大学模式动物研究所购买。ApoE-/-小鼠饲养于SPF级动物房，并予高脂饮食。高脂饮食配方：0.2％胆固醇和20％脂肪混合常规饲料。ApoE-/-小鼠随机分为对照组(P)、低剂量药物组(M1，1mg/kg/d)和高剂量药物组(M3,3mg/kg/d)，每组30只。P组皮下注射生理盐水5mL·kg-1·d-1，M1组皮下注射SS-31 5mL·kg-1·d-1(SS-31粉末溶于生理盐水，浓度0.2mg·mL-1，上海强耀生物科技有限公司合成，剂量参考文献)，M3组皮下注射SS-31 5mL·kg-1·d-1(浓度0.6mg·mL-1)。12周后，小鼠腹腔注射戊巴比妥(40mg·kg-1)麻醉，经下腔静脉取血，增加麻醉剂量(80mg·kg-1)后颈脱位处死，收集心脏及主动脉。心脏标本4％多聚甲醛固定24h，OCT包埋或石蜡包埋，在切片机连续切10张6μm厚石蜡或冰冻切片，主动脉窦石蜡切片常温保存备用。主动脉窦冰冻切片置于丙二醇中静置2min，油红O染色缸中染色16h，85％丙二醇分化1min，苏木素染色3min，封片，尽快在光学显微镜(德国ZEISS公司)下观察并拍照。每组小鼠主动脉进行大体油红染色(具体步骤见参考文献)，主动脉检测超氧化物歧化酶2(Superoxide dismutase2,SOD2)蛋白水平，主动脉检测总SOD活性，主动脉检测ATP水平。
1.2 血液标本处理
血液标本4℃过夜，2500g离心20min，取上清，获得血清标本。自动生化分析仪(Beckman Coulter AU542)检测血清中甘油三酯(Triglyceride,TG)和胆固醇(totalcholesterol，TC)的含量。酶联免疫吸附试验(Enzyme-linked immunosorbent assay,ELISA)试剂盒(武汉博士德生物工程有限公司)检测血清中细胞内粘附分子-1(Intracellular adhesion molecule，ICAM-1)、单核细胞趋化因子-1(Monocytechemoattractant protein，MCP-1)、白介素6(Interleukin,IL-6)和C-反应蛋白(C-reactive protein，CRP)水平。
1.3 DHE染色、ATP检测及SOD活性检测
主动脉离体后立即OCT包埋，急冻后冰冻切片机切6μm厚切片于载玻片上，荧光探针(Dihydroethidium,DHE,10μM,美国Sigma-Aldrich公司)37℃避光孵育30min，激光共聚焦显微镜(ZEISS HB050，德国ZEISS公司)观察荧光，荧光强弱反应ROS水平。主动脉离体后立即利用ATP检测试剂盒(上海碧云天生物技术有限公司)及SOD检测试剂盒(南京建成生物工程研究所)检测ATP水平及总SOD活性。
1.4 Western blotting
主动脉通过裂解液(英国Thermo Fisher Scientific公司)研磨裂解后，BCA法测定的蛋白浓度，35μg总蛋白提取物在12％SDS-PAGE凝胶中电泳分离，转至硝酸纤维素转印膜(Nitrocellulose membranes，NC)后一抗(SOD2，1：1000稀释，英国Abcam公司；Tubulin，1:2000稀释，美国Sigma-Aldrich公司)4℃过夜，二抗(羊抗兔或羊抗鼠，1:10000稀释)孵育1h。NC膜与ECL化学发光底物(上海碧云天生物技术有限公司)孵育后，立即用Westernblotting化学发光检测***(英国Thermo Fisher Scientific公司)进行曝光拍摄。采用Image J软件检测SOD2含量。
1.5 Masson特殊染色
小鼠的组织切片脱蜡，苏木素精染色4min，Masson氏改良三色染料染色8min，亮绿染色液染色8min，0.2％醋酸铵洗至无染料脱落，脱水，透明，封片，光学显微镜下观察并拍照。采用Image J软件分析斑块中胶原(蓝色)的含量。
1.6 免疫组织化学(Immunohistochemistry，IHC)
小鼠的组织切片脱蜡，抗原修复，3％H2O2抑制内源性过氧化酶，一抗(1:200稀释)室温孵育1.5h，二抗(1:200稀释)室温孵育30min，DAB显色，苏木素复染。染色完成后，在光学显微镜镜下观察并拍照。CD68(巨噬细胞分子标记)、α-SMA(平滑肌细胞分子标记)抗体购于英国Abcam公司；CD36抗体购于美国Proteintech Group公司；LOX-1抗体购于美国SantaCruz Biotech公司；ABCA1抗体购于美国Signalway Antibody LLC公司；二抗(羊抗兔或氧抗鼠)购于美国Santa Cruz Biotech公司。采用Image J软件分析IHC阳性区域的强度。
1.7 数据处理
采用SPSS 22.0软件进行统计分析。计量资料以均数±标准差表示，组间两两比较采用Student t检验。p<0.05表示差异有统计学意义。
2 结果
2.1 SS-31可以延缓ApoE-/-小鼠AS发展
P组ApoE-/-小鼠8周和20周时体重与给药组(M1和M3)相似，给药组20周血清TC和TG与P组相似，如表1所示。主动脉大体油红染色发现M1和M3组ApoE-/-小鼠斑块面积显著减小，如图1所示，右方为其量化图。主动脉窦区冰冻切片油红染色发现M1和M3组ApoE-/-小鼠斑块大小显著减小，如图2所示，下方为其量化图。利用CD68、α-SMA免疫组织化学和Masson特殊染色研究斑块成分变化，如图3所示，M1和M3组CD68免疫组化阳性区域显著减少，下方为其量化图；图4为α-SMA免疫组化，M1和M3组ApoE-/-小鼠斑块处平滑肌细胞显著增多，下方为量化图；图5为Masson特殊染色，下方为蓝色面积量化，M1和M3组ApoE-/-小鼠斑块处胶原显著增多。以上结果表明SS-31组小鼠斑块面积明显减少减小，斑块表现更早期并且更加稳定，因此SS-31能够用于阻滞动脉粥样硬化斑块形成、延缓AS的发展。
2.2 SS-31减少ApoE-/-小鼠主动脉氧化应激水平并提高主动脉ATP合成
AS斑块处氧化应激水平升高，而SS-31作为一种抗氧化剂可以减少氧化应激水平，于是我们检测了各小鼠主动脉的ROS水平和ATP水平。图6是主动脉冰冻切片的DHE染色，M1和M3组ApoE-/-小鼠红色阳性区域明显减少，表明ApoE-/-小鼠主动脉细胞内ROS水平下降，氧化应激降低。主动脉ATP检测结果显示M1和M3组主动脉ATP含量显著升高，如图7所示。SOD是细胞清除ROS的主要蛋白，包括细胞中的SOD1和线粒体中的SOD2，SOD2发挥主要作用。主动脉Western blotting检测发现SOD2蛋白水平无变化，如图8所示，下方为其量化图；但是主动脉总SOD酶活性显著升高，如图9所示。ROS水平升高会损伤DNA，利用8-OHDG免疫组织化学检测动脉的DNA损伤，结果显示M1和M3组小鼠8-OHDG阳性区域面积显著降低，如图10所示，上方为8-OHDG免疫组织化学图像，下方为阳性区域量化图。以上结果表明SS-31降低了动脉氧化应激水平,因此可用于减少主动脉氧化损伤和粥样斑块的进一步扩张。
2.3 SS-31改善ApoE-/-小鼠全身炎症水平
AS是一种慢性炎症性疾病，ICAM-1和MCP-1是AS中主要的炎症因子，促进单核细胞/巨噬细胞向内皮细胞的粘附和向内膜的迁移。M1和M3组小鼠血清中ICAM-1和MCP-1显著降低(见表1)。迁移至血管内膜的巨噬细胞会分泌促炎因子，包括IL-6，IL-1β和肿瘤坏死因子(Tumor necrosis factor alfa，TNF-α)。这些炎症因子会介导全身的炎症反应，比如激活肝基因编码的急性期蛋白，包括CRP和血清淀粉样蛋白A(serum amyloid A，SAA)。M1和M3组ApoE-/-小鼠血清IL-6显著降低，CRP轻微降低，见表1。以上结果表明SS-31可以改善ApoE-/-小鼠全身炎症水平，有利于延缓粥样斑块的进一步发展。
2.4 SS-31降低ApoE-/-小鼠主动脉脂质摄取蛋白的表达
泡沫细胞形成是AS早期斑块出现的关键。氧化性低密度脂蛋白(Oxidized low-density lipoprotein，ox-LDL)摄取过多、胆固醇酯化过度和胆固醇释放受损均会导致胆固醇酯累积，形成脂滴，细胞逐渐向泡沫细胞转化。CD36(Cluster of differentiation36)和LOX-1(Lectin-like ox-LDL receptor-1)为ox-LDL受体，是重要的脂质摄取蛋白，ABCA1(ATP-binding cassette A1)是一种脂质排出蛋白。图11-13所示，M1和M3组ApoE-/-小鼠主动脉斑块处CD36和LOX-1表达显著降低，而ABCA1表达无改变。以上结果表明SS-31降低主动脉CD36和LOX-1的表达，抑制ox-LDL的摄取，预防脂质累积，减少泡沫细胞形成，因此SS-31可用于阻滞AS的发生和发展。
表1 小鼠体重和血清脂质指标.
注：数据均用表示，*p<0.05，n＝15。
Claims (10)
1.化合物SS-31在制备治疗动脉粥样硬化疾病药物或者制剂上的应用。
2.根据权利要求1所述的化合物SS-31在制备治疗动脉粥样硬化疾病药物或者制剂上的应用，其特征在于所述动脉粥样硬化疾病包括颈动脉狭窄、下肢动脉硬化闭塞症及冠心病。
3.根据权利要求1或2所述的化合物SS-31在制备治疗动脉粥样硬化疾病药物或者制剂上的应用，其特征在于化合物SS-31在制备阻滞动脉粥样硬化斑块形成、延缓AS的发展药物或者制剂上的应用。
4.根据权利要求1或2所述的化合物SS-31在制备治疗动脉粥样硬化疾病药物或者制剂上的应用，其特征在于化合物SS-31在制备稳定易损动脉粥样硬化斑块、防止不稳定型心绞痛和心肌梗死发生药物或者制剂上的应用。
5.根据权利要求1或2所述的化合物SS-31在制备治疗动脉粥样硬化疾病药物或者制剂上的应用，其特征在于化合物SS-31在制备缓解机体具有的全身性的氧化应激和慢性炎症过程的药物或者制剂上的应用。
6.根据权利要求1或2所述的化合物SS-31在制备治疗动脉粥样硬化疾病药物或者制剂上的应用，其特征在于化合物SS-31在制备血管老化的病理特征的药物或者制剂上的应用。
7.化合物SS-31在制备降低主动脉ROS水平、减少主动脉氧化损伤、提高主动脉ATP水平、提高主动脉的生理机能与功能药物或者制剂上的应用。
8.化合物SS-31在制备降低主动脉或者全身炎症水平、阻滞AS的发生与发展药物或者制剂上的应用。
9.化合物SS-31在制备降低主动脉斑块处脂质摄取蛋白CD36的表达、阻滞AS的发生与发展药物或者制剂上的应用。
10.化合物SS-31在制备降低主动脉斑块处脂质摄取蛋白LOX-1的表达、阻滞AS的发生与发展药物或者制剂上的应用。
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Cited By (6)
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| WO2018171279A1 (zh) * | 2017-03-24 | 2018-09-27 | 南京大学 | 化合物ss-31在制备治疗动脉粥样硬化及相关疾病药物或制剂上的应用 |
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| CN115400201A (zh) * | 2021-05-26 | 2022-11-29 | 四川大学华西医院 | Ss-31在制备预防和/或治疗香烟诱导的气道炎症及慢性阻塞性肺疾病的药物中的用途 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1938042A (zh) * | 2004-01-23 | 2007-03-28 | 科内尔研究基金会 | 用于减轻氧化性损伤的方法 |
| CN104203262A (zh) * | 2012-02-23 | 2014-12-10 | 康奈尔大学 | 芳香族阳离子肽及其用途 |
| CN104324360A (zh) * | 2005-09-16 | 2015-02-04 | 科内尔研究基金会 | 用于减少cd36表达的方法 |
| CN104661670A (zh) * | 2012-08-02 | 2015-05-27 | 康肽德生物医药技术有限公司 | 用于治疗动脉粥样硬化的方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3443977A1 (en) * | 2009-12-31 | 2019-02-20 | Stealth Peptides International, Inc. | Methods for performing a coronary artery bypass graft procedure |
| US20170189429A1 (en) * | 2014-07-10 | 2017-07-06 | Rhode Island Hospital | Treating Arrhythmia with Mitochondrial-Targeted Antioxidants |
| CN107041946A (zh) * | 2017-03-24 | 2017-08-15 | 南京大学 | 化合物ss‑31在制备治疗动脉粥样硬化及相关疾病药物或制剂上的应用 |
-
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1938042A (zh) * | 2004-01-23 | 2007-03-28 | 科内尔研究基金会 | 用于减轻氧化性损伤的方法 |
| CN104324360A (zh) * | 2005-09-16 | 2015-02-04 | 科内尔研究基金会 | 用于减少cd36表达的方法 |
| CN104203262A (zh) * | 2012-02-23 | 2014-12-10 | 康奈尔大学 | 芳香族阳离子肽及其用途 |
| CN104661670A (zh) * | 2012-08-02 | 2015-05-27 | 康肽德生物医药技术有限公司 | 用于治疗动脉粥样硬化的方法 |
Non-Patent Citations (2)
| Title |
|---|
| SHEY-SHING SHEU等: "Targeting antioxidants to mitochondria: A new therapeutic direction", 《BIOCHIMICA ET BIOPHYSICA ACTA》 * |
| 李宽钰: "线粒体铁代谢与人类疾病的基础研究", 《医学研究生学报》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018171279A1 (zh) * | 2017-03-24 | 2018-09-27 | 南京大学 | 化合物ss-31在制备治疗动脉粥样硬化及相关疾病药物或制剂上的应用 |
| EP3771467A1 (en) * | 2019-07-30 | 2021-02-03 | Fundacio Institut de Recerca de l'Hospital de la Santa Creu i sant Pau | Ss-31 for the prevention and/or treatment of aneurysm |
| WO2021018862A1 (en) * | 2019-07-30 | 2021-02-04 | Fundació Institut De Recerca De L'hospital De La Santa Creu I Sant Pau | Ss-31 for the prevention and/or treatment of aneurysm |
| CN113143922A (zh) * | 2021-05-07 | 2021-07-23 | 广州医科大学 | Dhc在制备动脉粥样硬化治疗制剂中的应用 |
| CN115400201A (zh) * | 2021-05-26 | 2022-11-29 | 四川大学华西医院 | Ss-31在制备预防和/或治疗香烟诱导的气道炎症及慢性阻塞性肺疾病的药物中的用途 |
| CN113476587A (zh) * | 2021-07-19 | 2021-10-08 | 河南大学 | 一种脑靶向的神经保护剂ss31-ha-rt及其制备方法和应用 |
| CN113975402A (zh) * | 2021-07-19 | 2022-01-28 | 河南大学 | 靶向脑缺血区线粒体的神经保护药物ss31-ha-qt及其荧光探针和应用 |
| CN113476587B (zh) * | 2021-07-19 | 2022-07-12 | 河南大学 | 一种脑靶向的神经保护剂ss31-ha-rt及其制备方法和应用 |
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