CN112076235A - 盐肤木果实在制备治疗或预防肝纤维化的药物中的应用 - Google Patents
盐肤木果实在制备治疗或预防肝纤维化的药物中的应用 Download PDFInfo
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Abstract
本发明涉及化学物质的新的医药用途领域,具体涉及一种盐肤木果实在制备治疗或预防肝纤维化的药物或者保健食品中的应用,本发明经研究发现盐肤木果实的醇提物在较低剂量下可以保护肝脏,有效地抑制CCl4模型小鼠的肝纤维化,盐肤木果实可作为哺乳动物肝纤维化的候选药物,且本发明药物原料来自于天然可食用的植物原材料,分布广泛,成本低廉,提取工艺及流程简单,提取物安全性高。
Description
技术领域
本发明涉及化学物质的新的医药用途领域,具体涉及一种盐肤木果实在制备治疗或预防肝纤维化的药物中的应用。
背景技术
肝脏是人体重要的代谢器官,承担着许多重要的生理生化功能,如脂质代谢、糖原储存、分泌蛋白合成等,其中解毒是肝脏重要的功能。肝脏作为最大的解毒器官,它对所有的外来化合物都能进行解毒和代谢,因此极易受到感染和损伤。酒精、苯并芘和四氯化碳等有毒物质会导致不同程度的肝损伤,如肝炎、肝纤维化,甚至肝癌。肝病病变过程一般分为连续的多个阶段,前期主要表现为肝损伤和慢性肝炎,如果不及时治疗将发展为第二阶段的肝纤维化;肝纤维化进一步加重将恶化成肝硬化和肝癌。在整个肝病过程中,肝纤维化是一个关键的节点。但是目前临床上还未有能够有效治疗肝纤维化的药物,因此,肝纤维化的预防具有非常重要的意义。
盐肤木(Rhus chinensis Mill.)果实又名盐麸子、叛奴盐、盐梅子等,是漆树科植物盐肤木的果实。生于海拔350-2300m的石灰山灌丛、疏林中。为我国常见的野生阳性树。分布东北及云南、四川、山西、安徽、江苏、广西等地。漆树对土壤条件要求不高,常见于未耕地,也是众所周知的五倍子的生产主体。盐肤木在中国古代各地早已用于治疗和预防疾病。例如,盐肤木叶用于治疗炎症和腹泻;根用于治疗疟疾和黄疸;果实和种子经常用于治疗痢疾。与其他部位相比,果实不仅可以作为草药使用,还可以作为鲜果、调味品和饮料使用,而且盐肤木果油在2013年已经被批准为新食品原料。此外,成熟果实在云南多个地方具有长期食用的历史。目前国内外对盐肤木果实防治肝纤维化的相关研究未见有专利文献报道。本发明将为开发安全有效的防治肝纤维化的保健食品或药品提供一定的科学依据。
发明内容
因此,发明人通过研究发现盐肤木果实对于CCl4所致小鼠肝纤维化具有明显的改善作用,可以保护肝脏,有效地预防或治疗哺乳动物的肝纤维化。
本发明提供了一种盐肤木果实在制备治疗或预防肝纤维化的药物或者保健食品中的应用。
优选地,所述药物或者保健食品还包括药学上可接受的载体。
进一步地,所述药学上可接受的载体选自药学上可接受的溶剂、增溶剂、助溶剂、乳化剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂、高分子骨架材料和成膜材料中的至少一种。
优选地,所述药物或者保健食品为口服溶液、注射剂、胶囊剂、片剂、药膜剂或喷雾剂。
进一步地,所述药物或者保健食品为盐肤木果实的水提物、醇提物,或者所述水提物或者醇提物经精制纯化后的精制物。
优选地,所述药物或者保健食品为盐肤木果实的乙醇溶液的提取物,优选地,所述乙醇溶液为体积百分数为80%的乙醇的水溶液。
进一步地,所述药物包括其他治疗或预防肝纤维化的药物。
优选地,所述其他治疗或预防肝纤维化的药物选自乙肝键片、干扰素、无环鸟苷、拉米夫定、甘草次酸、片仔癀、三七总皂苷中的至少一种。
本发明还提供了一种用于治疗或预防肝纤维化的药物或者保健食品,所述药物或者保健食品以盐肤木果实、盐肤木果实的水提物或醇提物,或者所述水提物或者醇提物经精制纯化后的精制物为活性成分。
进一步地,向所述活性成分中加入常规辅料按照常规工艺制成临床上可接受的口服溶液、注射剂、胶囊剂、片剂、药膜剂、喷雾剂。
本发明技术方案,具有如下优点:
本发明通过实验发现盐肤木果实的醇提物在较低剂量下可以保护肝脏,有效地预防或治疗CCl4所致小鼠的肝纤维化,且原料来自于天然可食用的植物原材料,分布广泛,成本低廉,提取工艺及流程简单,提取物安全性高。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1是本发明实验例1中盐肤木果实对CCl4所致小鼠肝纤维化干预后的肝脏病理切片的HE染色图(HE×200),其中A为肝脏的组织形态图;B为HE染色图;C为Masson染色图;D和E为Sirius red染色图,其中D是在自然光源下拍摄照片,E是在偏振光源下拍摄照片。图中的K代表对照组,M代表模型组,AL代表醇提物低剂量组,AH代表醇提物高剂量组;
图2是本发明实验例1中盐肤木果实对肝纤维化相关蛋白的免疫组化图,A为P38MAPK蛋白免疫组化图;B为PPAR-γ蛋白免疫组化图。
具体实施方式
实施例1盐肤木果实的水提物
制法:取盐肤木果实按料液比为1:20加入水,煮沸1小时。煮沸以后趁热离心,转速4000r/min,上清液进行抽滤,抽滤以后的样品进行浓缩,最后冻干,得盐肤木果实的水提物。
实施例2盐肤木果实的醇提物
制法:取盐肤木果实按料液比为1:5加入80%的乙醇溶液(体积百分数),超声提取,提取温度为25℃,提取时间为30min,滤渣复提一次,然后4000r/min离心,取上清液浓缩冻干,得盐肤木果实的醇提物。
实施例3盐肤木果实的片剂
制法:取盐肤木果实按料液比为1:5加入80%的乙醇溶液(体积百分数),超声提取,提取温度为25℃,提取时间为30min,滤渣复提一次,然后4000r/min离心,取上清液浓缩冻干,得盐肤木果实的醇提物。取盐肤木果实的醇提物加入常规辅料按照常规工艺制成临床上可接受的片剂。
实施例4盐肤木果实的的胶囊剂
制法:取盐肤木果实按料液比为1:20加入水,煮沸1小时。煮沸以后趁热离心,转速4000r/min,上清液进行抽滤,抽滤以后的样品进行浓缩,最后冻干,得盐肤木果实的水提物。取盐肤木果实的水提物加入常规辅料按照常规工艺制成临床上可接受的胶囊剂。
其中上述实施例1-实施例4中,80%的乙醇溶液为80体积份的乙醇与20积份的水的混合溶液。
实验例1
1.实验材料
1.1实验动物
SPF级SD雄性小鼠,4-8周龄,共36只,体重在20g左右,体重偏差5%以内,由湖南斯莱克景达实验动物有限公司提供,小鼠的编号为SCXK(湘)2016-0002。小鼠购买以后,按照标准的小鼠饲养环境饲养小鼠,自由采食水和饲料。在该环境下适应七天后,随机把40只老鼠分成4组,每组10只。
1.2药物与试剂
盐肤木果实的醇提物(以下简称“醇提物”):按照实施例2所述的制法制备得到;AST检测试剂盒、ALT检测试剂盒、羟脯氨酸检测试剂盒、CAT检测试剂盒购自南京建成生物科技有限公司,GSH检测试剂盒、SOD检测试剂盒和MDA检测试剂盒购自碧云天生物技术有限公司。
1.3仪器
全自动生化分析仪,购自深圳雷杜生命科学股份有限公司。
2.方法与结果
2.1造模
将40只SPF级SD雄性小鼠分成4组,每组10只,各组编号如下:Group K:对照组(造模期间蒸馏水灌胃,记为K)、Group M:模型组(造模期间蒸馏水灌胃,记为M)、Group AL:醇提物低剂量组400mg/kg(造模期间醇提物灌胃,记为AL)、Group AH:醇提物高剂量组800mg/kg(造模期间醇提物灌胃,记为AH)。
第一次给药前所有动物禁食12h,并且在给药前记录各个老鼠的体重(禁水)。按照标准的小鼠饲养环境饲养小鼠(小鼠购买以后,在该环境下适应七天环境)。造模的方式如下:每天早上9点以5mL/kg的灌胃体积(每kg动物体重灌胃体积为5mL),灌入对应剂量的提取物或是蒸馏水,其中,K和M均以蒸馏水灌胃,AL以400mg/kg剂量的醇提物灌胃(每kg动物体重灌胃醇提物质量为400mg),AH以800mg/kg剂量的醇提物灌胃(每kg动物体重灌胃醇提物质量为800mg)。下午6点,除对照组以外,每组均以5mL/kg的灌胃体积(每kg动物体重灌胃体积为5mL),灌入浓度为35%的CCl4(用大豆油配制,体积百分数),一周两次,对照组灌入相应体积的大豆油。在饲养6周以后,对所有的小鼠禁食12h,使用10%的水合氯醛麻醉小鼠,称重,取血液制成血清待测,取肝脏称重,随后取肝左叶,浸没10%的福尔马林溶液中,待后续进行HE染色、Masson染色和Sirius red染色,另取肝脏放入液氮中保存用于后续肝脏生化指标测定。
2.2实验方法与结果
2.2.1盐肤木果实提取物对CCl4诱导肝纤维化小鼠的肝功能酶及肝系数的影响
小鼠中AST和ALT的测量分别使用南京建成AST检测试剂盒和ALT检测试剂盒进行有效的测量,具体步骤可以参照南京建成AST检测试剂盒和ALT检测试剂盒的说明书。肝系数计算方式是先称量小鼠禁食12小时后的体重,随后解剖小鼠取出小鼠肝脏并称重。肝系数等于肝脏重量除以对应小鼠体重。
表1.盐肤木果实提取物对CCl4诱导肝纤维化小鼠的肝功能酶及肝系数的影响
K | M | AL | AH | |
ALT(U/L) | 57.26±8.95<sup>a</sup> | 195.99±18.77<sup>b</sup> | 103.17±17.03<sup>c</sup> | 88.42±12.59<sup>ac</sup> |
AST(U/L) | 119.98±11.71<sup>a</sup> | 287.56±20.18<sup>b</sup> | 151.53±24.6<sup>a</sup> | 132.32±15.8<sup>a</sup> |
肝系数(g/100g) | 4.60±0.28<sup>a</sup> | 6.54±0.22<sup>b</sup> | 6.30±0.18<sup>b</sup> | 5.53±0.18<sup>c</sup> |
注:同一行不同字母代表具有显著性差异,标有相同字母表示与对应组没有显著性差异(p<0.05)
与对照组相比,CCl4模型组的肝功能酶和肝系数显著的增加;而给药组与CCl4模型组相比,高低剂量均可以有效地降低肝功能酶和肝系数,其中AH组的效果最好。在CCl4模型组中,血清中ALT和AST含量显著升高,说明肝脏受到了四氯化碳的损伤;但与模型组相比,各给药组的小鼠血清中ALT和AST含量均显著下降,说明盐肤木果实可以有效防治CCl4造成的肝纤维化,尤其是高剂量组效果最好。因此盐肤木果实可以防治肝纤维化。
2.2.2盐肤木果实提取物对CCl4诱导肝纤维化小鼠的肝脏中生化指标的影响
小鼠中羟脯氨酸和CAT的测量分别使用南京建成的羟脯氨酸检测试剂盒和CAT检测试剂盒进行有效的测量。小鼠中GSH、SOD和MDA测量分别使用碧云天GSH检测试剂盒、SOD检测试剂盒和MDA检测试剂盒进行有效的测量。具体步骤可以参照南京建成和碧云天对应试剂盒的说明书。
表2.盐肤木果实提取物对CCl4诱导肝纤维化小鼠的肝脏中生化指标的影响
K | M | AL | AH | |
GSH(nmol/mg prot) | 269.70±12.33<sup>a</sup> | 145.70±10.67<sup>b</sup> | 176.03±15.69<sup>b</sup> | 222.15±14.97<sup>c</sup> |
SOD(U/mg prot) | 180.81±22.2<sup>a</sup> | 70.50±29.69<sup>b</sup> | 103.68±25.46<sup>b</sup> | 138.64±7.08<sup>a</sup> |
CAT(U/mg prot) | 101.56±8.89<sup>a</sup> | 64.53±2.34<sup>b</sup> | 78.52±9.02<sup>c</sup> | 89.79±10.69<sup>ac</sup> |
MDA(mmol/mg prot) | 11.40±1.41<sup>a</sup> | 24.30±3.51<sup>b</sup> | 17.81±3.09a<sup>b</sup> | 15.62±2.04<sup>a</sup> |
羟脯氨酸(μg/g) | 202.17±29.12<sup>a</sup> | 417.47±30.42<sup>b</sup> | 303.74±28.47<sup>c</sup> | 271.65±20.37<sup>d</sup> |
注:同一行不同字母代表具有显著性差异,标有相同字母表示与对应组没有显著性差异(p<0.05)
从表2中可以看出,与对照组相比,CCl4模型组的GSH、SOD和CAT活力明显降低,说明肝脏的抗氧化系统受到了破坏;而给药组与CCl4模型组相比,高低剂量组均可以有效恢复抗氧化酶的活力,其中AH组的效果最好。另外,与对照组相比,CCl4模型组中的MDA和羟脯氨酸含量显著升高,说明肝脏受到了严重的脂质氧化损伤并诱发胶原纤维的合成;但是与模型组相比,各给药组的小鼠肝脏中MDA和羟脯氨酸含量均显著下降,说明盐肤木果实可以有效防治CCl4造成的肝脏脂质氧化损伤和肝纤维化发生,尤其是高剂量效果最好。因此盐肤木果实可以防治肝脏的氧化损伤和肝纤维化。
2.2.3盐肤木果实提取物对CCl4小鼠肝组织病理情况影响
分别取对照组、模型组、醇提物低剂量组和醇提物高剂量组的造模后的小鼠肝脏观察其形态,结果如图1所示,图1-A是肝脏组织的整体外观,K组肝脏形态特征正常,表面光滑,颜色鲜红有光泽。M组CCl4刺激后,肝脏泛黄,肝表面明显可见白色颗粒(即纤维化)。AL组和AH组纤维化程度明显减轻,白色颗粒消失,颜色为鲜红色,整体与K组没有显著的差异,说明盐肤木果实很好的保护了肝脏,未出现肝纤维化。
HE染色用于观察组织形态是否发生病变,染色步骤如下:分别取对照组、模型组、醇提物低剂量组和醇提物高剂量组的造模后的小鼠肝脏组织浸泡在组织固定液中,用低浓度到高浓度酒精作脱水剂,逐渐脱去组织块中的水份。将脱水的组织进行石蜡包埋、切片。染色前,二甲苯脱去切片中的石蜡,再用苏木精(Hematoxylin,H)和伊红(Eosin,E)染色2-5min,用无水乙醇分色与脱水,二甲苯透明,风干后中性树胶封片,最后用倒置显微镜观察。结果见图1-B所示,K组的肝脏,纹理清晰,细胞核居中,各细胞形态正常。而M组肝窦周围出现了大面积的肝细胞坏死和损伤。细胞间间隙变大,发生空泡变性和细胞核核聚集。在给药之后,无论是在低剂量组还是高剂量组,肝纤维化都明显降低。特别是AH组。说明盐肤木果实80%乙醇提取物很好的保护了肝脏,预防了纤维化发生。
Masson染色是最经典的组织染色方法之一,用于染色胶原,而胶原是肝脏纤维化组织病理学评价的重要参数。具体染色步骤如下:分别取对照组、模型组、醇提物低剂量组和醇提物高剂量组的造模后的小鼠肝脏组织浸泡在组织固定液中,用低浓度到高浓度酒精作脱水剂,逐渐脱去组织块中的水份。将脱水的组织进行石蜡包埋、切片。染色前,二甲苯脱去切片中的石蜡,用Masson丽春红酸性复染色5-10min,用无水乙醇分色与脱水,二甲苯透明,风干后中性树胶封片,最后用倒置显微镜观察。结果见图1-C所示,K组肝组织中几乎未见明显的胶原,而M组经过CCl4损伤,肝窦附近出现了大量的蓝色胶原,表明肝纤维化严重。灌以高低剂量盐肤木果实的两组小鼠的肝脏,胶原的含量均明显减少,尤其是高剂量组,只有少量胶原可见。说明盐肤木果实醇提取物很好的预防肝纤维化的发生。
Sirius red染色(天狼星红染色)是一种可以区分胶原类型的染色方法。操作如下:分别取对照组、模型组、醇提物低剂量组和醇提物高剂量组的造模后的小鼠肝脏组织浸泡在组织固定液中,用低浓度到高浓度酒精作脱水剂,逐渐脱去组织块中的水份。将脱水的组织进行石蜡包埋、切片。染色前,二甲苯脱去切片中的石蜡,天狼星红染液染15-30min,用无水乙醇分色与脱水,二甲苯透明,风干后中性树胶封片,最后用倒置显微镜观察。结果见图1D-E,其中,图1-D为自然光下拍摄的胶原,图1-E为偏振光下拍摄的胶原。在图1-D中,K组胶原含量较低,这一点在图1-E中再次得到证实,图1-D的K组只有肝窦周围出现了少量胶原。图1-D和1-E的M组中胶原含量明显升高,除肝窦附近,显示肝实质细胞周围也大量出现了胶原,说明肝纤维化严重。在两给药组中,胶原的含量都非常显著地降低。高剂量AH组的胶原含量比低剂量AL组减少更为明显,说明盐肤木果实80%乙醇溶液提取物对肝纤维化有很好的防治作用。
2.2.4盐肤木果实对肝纤维化相关蛋白表达的影响
P38 MAPK是丝裂原活化蛋白激酶(MAPK)家族中的一员,与体内的炎症、细胞应激、凋亡、细胞周期和生长等多种生理和病理过程中密切相关。它的激活会诱导肝内血管增生、肝窦样毛细血管、活化增殖肝星状细胞(HSCs),促进肝纤维化进程。PPAR(过氧化物酶体增殖物激活受体),是一类依赖配体活化的转录因子,属于核激素受体超家族成员。其中的一种亚型PPAR-γ具有抑制炎症因子生成及炎症形成的作用,及其免疫调节作用而备受关注。PPAR-γ还具有抗纤维化的作用,它的激活可以抑制细胞外基质(ECM)mRNA的表达,减少ECM的合成,同时加快了ECM分解,缓解肝纤维化。P38 MAPK和PPAR免疫组化染色的具体步骤如下:分别取对照组、模型组、醇提物低剂量组和醇提物高剂量组的造模后的小鼠肝脏组织浸泡在组织固定液中,用低浓度到高浓度酒精作脱水剂,逐渐脱去组织块中的水份,将脱水的组织进行石蜡包埋、切片的蜡块,使用二甲苯进行脱蜡处理,随后使用5%牛血清白蛋白封闭10-30分钟。使用对应一抗抗体进行有抗体的孵育。用PBS清洗后进行二抗的孵育(二抗是HRP偶联的IgG聚合物多克隆抗体)然后用水冲洗,在显微镜下观察。
结果见图2所示,图2-A是P38 MAPK免疫组化图。在K组中,切片表面平滑,纹理清晰,P38 MAPK几乎没有表达,表明肝脏没有炎症,细胞未出现应激和凋亡。而M组切片表面粗糙,肝窦附近明显病灶化,经抗体结合后出现大面积黄色的P38 MAPK,表明其含量明显提高,细胞核也出现了聚集,表面肝脏发生了严重的炎症和纤维化,细胞出现了凋亡。经过盐肤木果实干预的两组,黄色面积明显减小颜色也明显变浅,表明P38 MAPK表达降低,说明炎症得到了改善,肝纤维化得到了缓解。特别是高剂量AH组,黄色比AL组还浅,P38 MAPK表达量几乎与K组一致。图2-B是PPAR-γ免疫组化图。K组中,PPAR-γ表达量较高,肝组织未见有炎症和纤维化现象。M组PPAR-γ的表达明显被抑制,肝组织不能对炎症和肝纤维化进行有效的调节,肝纤维化严重。而经过盐肤木果实干预,PPAR-γ的表达得到了明显的回升,肝纤维化程度得到了缓解,其中,高剂量AH组的表达量恢复到了K组的水平。
综上所述,上述实验证明盐肤木果实的醇提取物可以有效地防治肝纤维化及其并发症,可以研发成防治肝纤维化方面的保健食品或药品。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.盐肤木果实在制备治疗或预防肝纤维化的药物或者保健食品中的应用。
2.根据权利要求1所述的应用,其特征在于,所述药物或者保健食品还包括药学上可接受的载体。
3.根据权利要求1或2所述的应用,其特征在于,所述药学上可接受的载体选自药学上可接受的溶剂、增溶剂、助溶剂、乳化剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂、高分子骨架材料和成膜材料中的至少一种。
4.根据权利要求1-3中任一所述的应用,其特征在于,所述药物或者保健食品为口服溶液、注射剂、胶囊剂、片剂、药膜剂或喷雾剂。
5.根据权利要求1-4中任一所述的应用,其特征在于,所述药物或者保健食品为盐肤木果实的水提物、醇提物,或者所述水提物或者醇提物经精制纯化后的精制物。
6.根据权利要求1-5中任一所述的应用,其特征在于,所述药物或者保健食品为盐肤木果实的乙醇溶液的提取物,优选地,所述乙醇溶液为体积百分数为80%的乙醇的水溶液。
7.根据权利要求1-6中任一所述的应用,其特征在于,所述药物还包括其他治疗或预防肝纤维化的药物。
8.根据权利要求7所述的应用,其特征在于,所述其他治疗或预防肝纤维化的药物选自乙肝键片、干扰素、无环鸟苷、拉米夫定、甘草次酸、片仔癀和三七总皂苷中的至少一种。
9.一种用于治疗或预防肝纤维化的药物或者保健食品,其特征在于,所述药物或者保健食品以盐肤木果实、盐肤木果实的水提物或醇提物,或者所述水提物或醇提物经精制纯化后的精制物为活性成分。
10.根据权利要求9所述的药物或者保健食品,其特征在于,向所述活性成分中加入常规辅料按照常规工艺制成临床上可接受的口服溶液、注射剂、胶囊剂、片剂、药膜剂、喷雾剂。
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