CN112294792B - 化合物wzb117在制备治疗和/或预防肝损伤药物中的用途 - Google Patents
化合物wzb117在制备治疗和/或预防肝损伤药物中的用途 Download PDFInfo
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Abstract
本发明公开了化合物WZB117在制备治疗和/或预防肝损伤药物中的用途。本发明采用内毒素诱导的肝损伤小鼠模型，进行了大量实验研究。研究结果表明WZB117能够明显降低模型组小鼠血浆转氨酶水平，显著改善肝组织损伤，显著降低血浆TNF‑α、IL‑6等炎症因子水平，明显减轻肝细胞凋亡，具有显著的防治肝损伤的功效。
Description
技术领域
本发明涉及一种化合物WZB117在制备治疗和/或预防肝损伤药物中的用途，属于医药技术领域。
背景技术
内毒素是革兰阴性细菌的胞壁成分，是引起人体疾病的最重要的毒力因子之一，与多种临床疾病的发生发展密切关联。在多种疾病中，由于肠黏膜屏障受损，大量内毒素随门静脉进入肝内，可激发肝内强烈炎症反应，造成肝组织的严重损伤。肝脏受损后对于内毒素的清除功能降低，还可引起外周血中内毒素水平升高，即肠源性内毒素血症，导致全身性炎症反应和多脏器的损伤。因而，内毒素诱导的肝损伤是多种严重疾病中并发肝功能障碍乃至多器官功能障碍的关键环节。
目前临床上复方甘草酸苷、双环醇片等药物虽有一定的效果，但尚缺乏特效的治疗药物，因此急需研发治疗内毒素诱导肝损伤的药物。
发明内容
本发明的主要目的，在于提供WZB117在制备治疗和/或预防肝损伤药物中的用途，其中，本发明涉及的化合物WZB117的化学结构式如下：
其化学式为C20H13FO6，分子量为368.31；
该化合物是是葡萄糖转运蛋白1的抑制剂；目前尚未见化合物WZB117在防治肝损伤中的医用用途。
其中，优选地，本发明所述的肝损伤为内毒素引起的肝损伤。
优选地，所述药物中还包含药学上可接受的载体。
优选地，所述药学上可接受的载体选自下组：稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂中的至少一种。
优选地，WZB117，其药学上可接受的盐、溶剂合物、立体异构体、互变异构体或所述药物，配制为片剂、散剂、丸剂、注射剂、胶囊剂、膜剂、栓剂、膏剂或冲剂。
本技术方案与背景技术相比，具有如下优点：
本发明结果表明WZB117能够明显降低模型组小鼠血浆转氨酶水平，显著改善肝组织损伤，显著降低血浆TNF-α、IL-6等炎症因子水平，明显减轻肝细胞凋亡，具有显著的防治肝损伤的功效。
附图说明
下面结合附图和实施例对本发明作进一步说明。
图1为WZB117对LPS/D-Gal诱导的肝损伤小鼠转氨酶水平的影响。
图2为WZB117对LPS/D-Gal诱导的肝损伤小鼠肝组织病理的影响。
图3为WZB117对LPS/D-Gal诱导的肝损伤小鼠炎症因子的影响。
图4为WZB117对LPS/D-Gal诱导的肝损伤小鼠肝细胞凋亡的影响。
具体实施方式
1.实验材料
1.1实验用药物及试剂
WZB117购自Selleckchem公司，批号：S792701。
1.2实验动物及饲养
雄性C57BL/6小鼠，18-22g，雄性，由上海吉辉实验动物饲养有限公司提供，合格证号：20170012002547。饲养条件：室温20±2℃，湿度50％±5％，明暗交替，光照适度，通风洁净良好，自由饮水与进食。
2.方法
2.1内毒素诱导的肝损伤小鼠模型造模方法
采用C57BL/6小鼠，预先饲养一周，腹腔注射LPS(10μg/kg)及D-Gal(700mg/kg)复制内毒素诱导的肝损伤小鼠模型。脂多糖(lipopolysaccharides,LPS)/D-氨基半乳糖(D-Galactosamine,D-Gal)诱导小鼠肝损伤模型是一种公认的内毒素肝损伤动物模型，已被广泛应用。在本实验模型中，活化的枯否细胞分泌的大量的促炎因子，如肿瘤坏死因子-α(tumor necrosis factor alpha,TNF-α)、白细胞介素-6(Interleukin6,IL-6)是疾病发生发展的主要致病机制。
2.2实验分组
C57小鼠32只，随机分为4组，每组8只。分别为正常对照组，WZB117对照组，模型组，WZB117干预组。模型组及WZB117干预组采用上述方法造模。正常对照组及模型组给予0.5％羧甲基纤维素钠(含1％二甲基亚砜)；WZB117 2mg/kg溶于0.5％羧甲基纤维素钠(含1％二甲基亚砜)，于LPS(10μg/kg)及D-Gal(700mg/kg)造模前0.5h腹腔注射。实验终点时处死小鼠，留取血及肝组织备用。
2.3血浆生化检测
取小鼠血浆，使用商品化试剂盒检测谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate aminotransferase,AST)水平。
2.4肝组织HE染色
取小鼠肝组织标本，在4％多聚甲醛中固定，使用石蜡包埋、切片。使用苏木精-伊红染色，通过200倍光学显微镜观察肝组织病理变化。
2.5炎性因子检测
取小鼠血浆，使用ELISA试剂盒，检测血浆中TNF-α、IL-6水平。
2.6TUNEL法细胞凋亡检测：肝组织石蜡切片，按TUNEL试剂盒说明的步骤进行染色。染色后细胞核棕黄(褐)为凋亡细胞，高倍镜下随机选取20个视野计数凋亡细胞数目。
3.统计分析
数据采用
表示，采用t检验或单因素方差分析进行检验，p<0.05为差异有统计学意义。
4.实验结果
4.1WZB117对LPS/D-Gal诱导的肝损伤小鼠转氨酶水平的影响。
转氨酶水平可反映小鼠急性肝损伤严重程度，正常对照组与WZB117对照组无明显差异，模型组小鼠血浆ALT和AST水平明显升高，与正常对照组比较，差异具有显著性；WZB117干预组与模型组比较，ALT和AST水平明显下降(图1)。上述结果提示：WZB117显著降低了LPS/D-Gal诱导的肝损伤小鼠血浆转氨酶水平。
4.2WZB117对LPS/D-Gal诱导的肝损伤小鼠肝组织病理的影响。
如图2肝组织切片的形态学结果显示：正常对照组与WZB117对照组无明显差异。模型组小鼠的肝小叶结构破坏，肝脏充血、出血，大量肝细胞变性、坏死伴有炎性细胞浸润。WZB117干预组的肝脏充血和肝细胞坏死等病理改变明显减轻。WZB117可明显减轻LPS/D-Gal诱导的肝组织形态学异常。
4.3WZB117对LPS/D-Gal诱导的肝损伤小鼠炎症因子的影响。
如图3，正常对照组和WZB117对照组之间血浆TNF-α、IL-6炎症因子水平无明显差异。LPS/D-Gal处理后，模型组TNF-α和IL-6水平显着高于正常对照组。WZB117干预组血浆TNF-α和IL-6水平显着低于模型组。WZB117显著抑制了LPS/D-Gal诱导的TNF-α、IL-6炎症因子产生。
4.4WZB117对LPS/D-Gal诱导的肝损伤小鼠肝细胞凋亡的影响。
如图4，与正常对照组比较，模型组小鼠肝组织凋亡细胞显著增加；给予WZB117干预后，肝组织凋亡细胞数量显著减少。WZB117显著减轻了LPS/D-Gal诱导的肝细胞凋亡。
LPS/D-Gal诱导的肝损伤小鼠模型是经典的肝损伤模型，精准的模拟了内毒素诱导的肝损伤的过程，具有良好的重现性，有效性和易用性。以上药效学试验结果显示，本发明提供的WZB117能够显著降低模型小鼠血浆转氨酶水平，显著减轻肝组织病理损伤，能显著抑制TNF-α、IL-6炎症因子水平，减轻LPS/D-Gal诱导的肝细胞凋亡。本发明研究结果证明，化合物WZB117具有很好的防治肝损伤的功效。
以上所述，仅为本发明较佳实施例而已，故不能依此限定本发明实施的范围，即依本发明专利范围及说明书内容所作的等效变化与修饰，皆应仍属本发明涵盖的范围内。
Claims (4)
1.化合物WZB117在制备治疗和/或预防肝损伤药物中的用途，其中，所述的WZB117结构如下：
所述的肝损伤为内毒素引起的肝损伤。
2.根据权利要求1所述的用途，其特征在于：所述药物中还包含药学上可接受的载体。
3.根据权利要求2所述的用途，其特征在于：所述药学上可接受的载体选自下组：填充剂、粘合剂、润湿剂、崩解剂、润滑剂中的至少一种。
4.根据权利要求1所述的用途，其特征在于：所述药物配制为片剂、散剂、丸剂、注射剂、胶囊剂、膜剂、栓剂、膏剂或冲剂。
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| CN108697729A (zh) * | 2016-02-04 | 2018-10-23 | 约翰霍普金斯大学 | 新型GLUT抑制剂rapaglutin及其用途 |
| WO2020086830A2 (en) * | 2018-10-26 | 2020-04-30 | Mayo Foundation For Medical Education And Research | Methods and materials for treating cancer |
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| CN108697729A (zh) * | 2016-02-04 | 2018-10-23 | 约翰霍普金斯大学 | 新型GLUT抑制剂rapaglutin及其用途 |
| WO2020086830A2 (en) * | 2018-10-26 | 2020-04-30 | Mayo Foundation For Medical Education And Research | Methods and materials for treating cancer |
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| Inhibition of GLUTs by WZB117 mediates apoptosis in blood-stage Plasmodium parasites by breaking redox balance;Meng Wei等;《Biochemical and Biophysical Research Communications》;20180802;第503卷;第1154-1159页 * |
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