CN113679709A - 丁香脂素在制备防治糖尿病肾病药物中的应用 - Google Patents
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Abstract
本发明公开了丁香脂素在制备防治糖尿病肾病药物中的应用，属于丁香脂素应用技术领域。丁香脂素结构式为：
丁香脂素的给药剂量25mg/kg，可制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂、喷雾剂、气雾剂等多种形式中的任意一种。本发明的有益效果是：丁香脂素在不影响糖尿病小鼠血糖的情况下能够显著改善糖尿病引起的肾损伤，为糖尿病肾病的新药研发提供了新思路，同时也拓展了丁香脂素的新用途。
Description
技术领域
本发明涉及丁香脂素在制备防治糖尿病肾病药物中的应用，属于丁香脂素应用技术领域。
背景技术
糖尿病肾病(diabetic nephropathy,DN)是引起终末期肾病(end stage renaldisease,ESRD)和糖尿病患者死亡的主要原因，与单纯糖尿病患者相比，其死亡风险要高3-12倍，已成为严重危害人类健康的全球公共卫生难题。DN是由糖尿病引起的一种微血管病变，以渐进性肾功能损伤为临床特征，伴随蛋白尿、水肿、高血压、肾小球滤过率降低等临床表现。细胞外基质(extracellular matrix,ECM)蛋白沉积、肾小球基底膜增厚以及电荷屏障丢失、肾小球系膜基质扩张、足突融合消失和足细胞丢失等是DN的主要病理学特征。DN发病机制极其复杂，目前认为与代谢异常、血液动力学变化、肾素-血管紧张素系统(renin–angiotensin system,RAS)激活、细胞程序性死亡、氧化应激、纤维化等多方面有关。因此，如何有效预防和治疗DN也是临床上亟待解决的重大难题。
丁香脂素(Syringaresinol,SYR)是一种天然多酚类化合物，是多种药用植物的重要活性成分，其中包括西花蓟马、杜仲、大血藤、刺五加等。研究发现，丁香脂素具有抗衰老、抗肿瘤、抗神经炎症以及心血管保护作用。迄今为止，尚未有关于丁香脂素在制备防治糖尿病肾病药物方面的相关报道。
本发明首次公开了丁香脂素对糖尿病引起的肾损伤的预防和治疗作用，启示丁香脂素有望用于防治糖尿病肾病药物的制备，开发了丁香脂素的新用途。
发明内容
本发明的目的在于，提供丁香脂素在制备防治糖尿病肾病药物中的应用。丁香脂素作为一种植物提取物，毒副作用小，用于制备防治糖尿病肾病的药物，临床应用前景可期。本发明为糖尿病肾病的新药研发提供新思路，也开辟了丁香脂素的新用途。
本发明解决上述问题的技术方案如下，丁香脂素在制备防治糖尿病肾病药物中的应用，所述丁香脂素化学结构式如下：
进一步的，本发明预防和/或治疗糖尿病肾病的产品为药物或保健品。所述药物或保健品包括丁香脂素和一种或多种药学上可接受的载体。所述载体为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂或润滑剂中的任意一种或几种。
进一步的，本发明所述药物或保健品可制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂、喷雾剂、气雾剂中的任意一种。
实验分为三组：对照组、模型组、药物治疗组。本发明首先构建糖尿病小鼠模型，然后对药物治疗组进行连续8周的丁香脂素灌胃治疗。观察丁香脂素是否具有治疗糖尿病肾病的作用。研究结果表明，丁香脂素对糖尿病小鼠血糖未产生显著影响，但丁香脂素治疗显著改善了糖尿病小鼠的肾功能(24h尿白蛋白排泄量减少、尿白蛋白/尿肌酐比值降低)；丁香脂素治疗减少了糖尿病引起的肾纤维化、氧化应激以及肾细胞焦亡等。综上，丁香脂素对糖尿病肾病具有显著的治疗效果。因此，丁香脂素可用于制备防治糖尿病肾病的药物。
所述丁香脂素的给药剂量是25mg/kg，经药理实验证明，采用上述剂量对糖尿病肾病有显著治疗效果。
本发明的有益效果是：丁香脂素作为一种植物提取物，毒副作用小，能够显著改善糖尿病引起的肾损伤，可用于制备防治糖尿病肾病的药物，临床应用前景可期。为糖尿病肾病的新药研发提供了新思路，同时也拓展了丁香脂素的新用途。
附图说明
图1：小鼠血糖、尿白蛋白、尿肌酐检测结果。其中A为小鼠每周血糖值，B为小鼠24h尿白蛋白排泄量检测结果，C为小鼠尿白蛋白与尿肌酐比值(CON：对照组；DN：造模组；DN+SYR：药物治疗组；*P＜0.05；**P＜0.01；***P＜0.001)。
图2：肾脏组织Masson染色与天狼猩红染色图片(CON：对照组；DN：造模组；DN+SYR：药物治疗组)。
图3：肾脏组织透射电镜图片(CON：对照组；DN：造模组；DN+SYR：药物治疗组)。
图4：肾脏组织氧化应激相关指标检测结果。其中A为Westernblot检测抗氧化蛋白Nrf2与HO-1的表达水平，B为HDE染色检测肾脏组织中ROS浓度图片(CON：对照组；DN：造模组；DN+SYR：药物治疗组)。
图5：肾脏组织焦亡相关指标检测结果。其中A为Real-time PCR检测NLRP3、Caspase-1、GSDMD、IL-1β、IL-18基因表达水平，B为血清中IL-1βELISA检测结果，C为血清中IL-18ELISA检测结果(CON：对照组；DN：造模组；DN+SYR：药物治疗组；*P＜0.05；**P＜0.01；***P＜0.001)。
图6：丁香脂素治疗糖尿病肾病的作用比较图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，接下来将结合附图对本发明做进一步详尽地描述。
实施例一：血糖、尿白蛋白及尿肌酐的检测，附图1给出了小鼠血糖、尿白蛋白、尿肌酐检测结果。
随机将24只6-8周龄的雄性C57BL/6小鼠分为对照组(CON组，8只)和造模组(16只)；造模组小鼠连续5天按照50mg/kg的剂量腹腔注射STZ；注射STZ 1周后，剪断小鼠尾尖采集尾静脉血液检测小鼠血糖水平，血糖>11.4mM为造模成功的糖尿病小鼠；将糖尿病小鼠随机分为造模组(DCM组，8只)和药物治疗组(DCM+SYR组，8只)；药物治疗组小鼠按照25mg/kg剂量SYR灌胃处理8周，其它组小鼠按照同样剂量灌胃生理盐水作为对照，并且每周检测各组小鼠血糖。
丁香脂素治疗8周后，采集小鼠尿液，按照小鼠尿白蛋白及尿肌酐检测试剂盒说明书测定小鼠尿白蛋白及尿肌酐水平。
实施例二：肾脏组织Masson染色
将修剪好的肾脏组织浸泡在4％多聚甲醛中，室温固定24h以上，进行梯度脱水与包埋，制成6μm组织切片；经脱蜡复水后，苏木素染色染色5-10min；酸性乙醇分化5-15s；蓝化液返蓝3-5min；丽春红染色5-10min；脱水透明；中性树胶进行封片；400倍显微镜下观察、拍照，参见附图2。
实施例三：肾脏组织天狼猩红染色
将修剪好的肾脏组织浸泡在4％多聚甲醛中，室温固定24h以上，进行梯度脱水与包埋，制成6μm组织切片；经脱蜡复水后，天狼星红染色液染色1h；苏木素染细胞核8-10min；常规脱水透明；中性树胶封片；400倍显微镜下观察、拍照，参见附图2。
实施例四：肾脏组织透射电镜观察足细胞
丁香脂素治疗8周后，颈椎脱臼处死小鼠立即取出肾脏，于肾皮质处取2mm×2mm组织块浸泡到固定液里，交由科学指南针公司进行包埋、切片、染色及拍照，参见附图3。
实施例五：Westernblot检测肾脏组织蛋白表达
称取15-20mg肾脏组织放入2ml离心管中，加入裂解液，放入干净的磁珠，50Hz研磨2min；将离心管插入冰中每7min涡旋震荡1次，重复3次；4℃12000rpm离心30min；吸取上清即为总蛋白；使用BCA试剂盒检测蛋白浓度；10％SDS-PAGE凝胶进行电泳；将蛋白转至PDF膜；5％的脱脂牛奶封闭2h；加入Nrf2和HO-1抗体4℃孵育过夜；TBST洗涤3次后加入辣根素过氧化酶标记的二抗，室温孵育1h；TBST洗涤3次后进行发光检测。检测结果参见附图4的A图。
实施例六：肾脏组织DHE染色
取出的新鲜心脏组织依次浸没于10％、20％、30％的蔗糖溶液中进行梯度脱水；加入OCT包埋组织；以6μm的厚度进行切片；加入DHE工作液，37℃孵育40min；PBS洗涤3次后加入防荧光淬灭剂封片；100倍显微镜下观察，拍片。参见附图4的B图。
实施例七：Real-time PCR检测肾脏组织基因表达
称取15-20mg肾脏组织放入2ml无酶管，加入1ml Trizol裂解液和磁珠，50Hz研磨2min；组织裂解液室温放置10min；加入200μl的氯仿，震荡混匀后室温静置15min；4℃12000g离心30min；将上清转移到新的1.5ml无酶管中，加入与吸出上清等体积的异丙醇，颠倒混匀，室温静置10min；4℃12000g离心10min，倒掉上清；加入l mL 75％的乙醇，4℃8000g离心5min，倒掉上清，底部白色沉淀即为RNA；检测RNA浓度；使用反转录试剂盒将RNA反转成cDNA；通过Premier 5软件设计NLRP3、Caspae-1、GSDMD、IL-1β、IL-18引物序列；使用Real-time PCR试剂盒检测基因表达水平。检测结果参见附图5的A图。
实施例八：血清中IL-1β和LDH检测
丁香脂素治疗8周后，将眼球血收集到离心管中，室温静置3h；5000rpm离心15min。上层淡黄色透明液体即是血清。使用IL-1β和LDH检测试剂盒检测小鼠血清中IL-1β和LDH的浓度。检测结果参见附图5的B和C图。
所有数据均以平均值±SEM表示，使用SPSS 20软件进行统计学分析。采用t检验分析两组之间的差异。采用单因素方差分析(one-wayANOVA)分析多组之间的差异，P<0.05认为有统计学意义。使用GraphPad Prism 5软件制作柱状图等图表。
经过本发明具体实施，结果表明，丁香脂素对糖尿病小鼠血糖未产生显著影响，但丁香脂素治疗显著改善了糖尿病小鼠的肾功能(24h尿白蛋白排泄量减少、尿白蛋白/尿肌酐比值降低)；丁香脂素治疗减少了糖尿病引起的肾纤维化、氧化应激以及肾细胞焦亡等。比较结果参见附图6。因此，丁香脂素对糖尿病肾病具有显著的治疗效果，丁香脂素可用于制备防治糖尿病肾病的药物。具体的，本发明预防和/或治疗糖尿病肾病的产品为药物或保健品。所述药物或保健品包括丁香脂素和一种或多种药学上可接受的载体。所述载体为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂或润滑剂中的任意一种或几种。本发明所述药物或保健品可制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂、喷雾剂、气雾剂等多种形式中的任意一中。
Claims (7)
1.丁香脂素在制备防治糖尿病肾病药物中的应用，该应用包括制备预防和/或治疗糖尿病肾病药物。
2.根据权利要求1所述丁香脂素的化学结构式如下：
3.根据权利要求1所述的应用，其特征在于，所述丁香脂素的给药剂量25mg/kg。
4.根据权利要求1所述的应用，其特征在于，预防和/或治疗糖尿病肾病的产品为药物或保健品。
5.根据权利要求4所述的应用，其特征在于，所述药物或保健品包括丁香脂素和一种或多种药学上可接受的载体。
6.根据权利要求5所述的应用，其特征在于，所述载体为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂或润滑剂中的任意一种或几种。
7.根据权利要求4所述的应用，其特征在于，所述药物或保健品制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂、喷雾剂、气雾剂中的任意一种。
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