CN116747213A - 大黄素在抑制皮脂腺合成与分泌中的应用 - Google Patents
大黄素在抑制皮脂腺合成与分泌中的应用 Download PDFInfo
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Abstract
本发明公开了大黄素在抑制皮脂腺合成与分泌中的应用,属于医药领域。大黄素在制备抑制皮脂腺分泌旺盛的药物中的应用,所述皮脂腺分泌旺盛的疾病包括痤疮、脂溢性皮炎、脂溢性脱发。所述药物中,大黄素的浓度为0.4‑2.4mg/g。本发明首次发现大黄素能直接抑制皮脂腺细胞增殖和脂质合成与分泌,且整个动物实验中并未观察到实验动物身体、生活状态及背部皮脂腺斑处皮肤的异常改变。该中药单体可为治疗皮脂合成与分泌过度的相关疾病提供新的有开发潜力的药物或为大健康产品的研发奠定物质基础。
Description
技术领域
本发明涉及大黄素在抑制皮脂腺合成与分泌中的应用,属于医药领域。
背景技术
皮脂腺是分布于除手掌、足底以外的全身皮肤的一种多腺泡全浆分泌组织,在头皮、面部的密度最高。皮肤表面正常的脂质可以起到屏障作用,能够滋润皮肤,抗感染和维持人体皮肤表面菌态平衡。皮脂腺过度分泌皮脂会导致皮肤出油过多而影响美观,也可能会促进痤疮或其他疾病的发展,严重影响了患者的心理健康和生活质量。近年来,饮食结构西方化、社会压力增加、熬夜等不良生活习惯导致的皮脂腺活性增高,脂质分泌旺盛,使得痤疮、脂溢性皮炎、脂溢性脱发等疾病的发病率攀升。抑制皮脂腺脂质合成与分泌分泌是治疗皮脂腺分泌旺盛疾病的重要途径。雄激素能直接刺激新生的皮脂腺细胞增殖和分化导致脂质合成与分泌增加;雄激素还可以激活胆固醇调节元件结合蛋白(Sterol RegulatoryElement Binding Protein,SREBP)相关的信号通路,该蛋白是皮脂腺细胞中脂质代谢多条信号传导通路的关键作用位点,能够直接作用于下游的脂质合成酶的表达,影响脂质代谢。因此抑制脂质分泌可通过以下三方面:①抑制皮脂腺细胞增殖,减少细胞个数;②抑制皮脂腺细胞生理学功能,降低单个细胞脂质合成量;③拮抗雄激素或抑制雄激素受体(androgenreceptor,AR)。目前临床以异维A酸为代表的抑制皮脂腺分泌药物会导致部分患者维a酸皮炎,肝功能、血糖、血脂、肌酸磷酸激酶异常,甚至出现抑郁、躁动、精神异常。
大黄素(Emodin)属于蒽醌类化合物,是中药大黄的主要有效成分之一,它的分子式为C15H10O5,是脂溶性物质,几乎不溶于水。大黄素来源中药大黄,具有抑制痤疮丙酸杆菌、抑制肝脏和血管脂质沉积、抗抑郁、抗肿瘤等作用。
现有技术虽然公开了大黄素可用于治疗痤疮,但主要依靠于抑制痤疮丙酸杆菌活性,而尚无大黄素对痤疮的发病部位皮脂腺的作用及其机制的相关研究报道。研发可以用于抑制皮脂腺分泌旺盛的药物,从而治疗痤疮等皮脂腺分泌过度的疾病则更为重要。因此有必要进行围绕毛囊皮脂腺单位的研究,进而为大黄素对皮脂腺作用的影响提供新的证据,并为治疗痤疮提供理论依据,同时为临床治疗皮脂腺合成与分泌过度相关疾病提供一种新的有开发潜力的药物或为大健康产品的研发奠定物质基础。
发明内容
为了解决现有技术存在的问题,本发明提供了大黄素在抑制皮脂腺合成与分泌中的应用,解决了缺少皮脂腺分泌旺盛相关疾病的治疗的技术问题。
本发明的技术方案为:
第一方面,本发明提供了大黄素在制备抑制皮脂腺分泌旺盛的药物中的应用。
进一步地,所述皮脂腺分泌旺盛的疾病包括痤疮、脂溢性皮炎、脂溢性脱发或毛囊炎。
所述痤疮是由皮脂腺分泌旺盛引起的疾病。
进一步地,所述药物中,大黄素的浓度为0.4-2.4mg/g。
进一步地,所述药物的剂型为乳膏。
优选地,所述药物包括大黄素、聚乙二醇和医用水包油乳膏基质。
配制方法如下:选择聚乙二醇400为促溶剂,在常温下,将大黄素先溶于聚乙二醇400中,再与乳膏基质充分搅拌混匀,待颜色均匀时装入避光试管中,4℃冷藏备用。所配制的乳膏中聚乙二醇400的终浓度为20wt%(包括基质乳膏),大黄素终浓度为0.4-2.4mg/g。
第二方面,本发明提供了大黄素在制备抑制皮脂腺分泌旺盛的化妆品中的应用。
进一步地,所述化妆品的剂型为水剂或膏剂。
优选地,所述化妆品包括美容外护产品。
第三方面,本发明提供了大黄素在制备抑制皮脂腺斑的增长或者抑制皮脂腺细胞的增殖或者抑制皮脂腺细胞脂质合成与分泌或者调节皮脂腺分泌旺盛的药物中的应用
第四方面,本发明提供了大黄素在制备抑制皮肤雄激素受体或者胆固醇调节元件蛋白SREBP-1的药物中的应用。
第五方面,本发明提供了大黄素在制备抑制皮脂腺分泌旺盛的食品中的应用。
有益效果:
本发明提供了可以外用治疗与皮脂腺分泌过度相关疾病的化合物,该化合物名称为大黄素,英文名Emodin,化学式为C15H10O5,能够显著抑制痤疮金黄地鼠模型皮脂腺斑的增长、皮脂腺细胞的增殖,也能显著抑制皮脂腺细胞脂质合成与分泌,达到抑制皮脂腺分泌旺盛的作用,从而治疗痤疮、脂溢性脱发等皮脂腺分泌旺盛的疾病。以上作用可能与大黄素外用抑制皮肤雄激素受体(AR)及胆固醇调节元件蛋白(SREBP-1)有关。本发明揭示了大黄素外用可以抑制皮脂腺的增殖和脂质合成与分泌,可为临床治疗如痤疮等皮脂分泌旺盛相关疾病提供新的候选药物。该组分除了可以作为治疗如痤疮等皮脂分泌旺盛相关疾病药物的主要原料,也可作为辅助成分添加到美容外护产品中。
本发明确认了中药单体——大黄素具有有效抑制皮脂腺分泌旺盛的作用,由于中药单体的化学组成是明确的,因而其质量也是可控的。其抑制皮脂分泌旺盛作用是通过研究皮脂腺合成与分泌旺盛的理想动物模型-金黄地鼠背部皮脂腺斑的动物试验确认,从而抑制皮脂过度分泌进而治疗痤疮的可靠性值得信赖。本发明首次发现大黄素能直接抑制皮脂腺细胞增殖和脂质合成与分泌,且整个动物实验中并未观察到实验动物身体、生活状态及背部皮脂腺斑处皮肤的异常改变。该中药单体可为治疗如痤疮等皮脂腺合成与分泌旺盛相关疾病提供新的有开发潜力的药物或为大健康产品的研发奠定物质基础。
附图说明
图1为用药30天后各组皮脂腺斑外观。
图2为用药后各组皮脂腺斑的组织病理表现(HE染色,x40);
其中,A:空白组;B:基质组;C:阳性对照(阿达帕林凝胶)组;D:大黄素乳膏低浓度组;E:大黄素乳膏中浓度组;F:大黄素乳膏中高浓度组;G:大黄素乳膏高浓度组。
图3为用药后各组金黄地鼠皮脂腺脂质分泌情况(油红O染色,x100);
其中,A:空白组;B:基质组;C:阳性对照(阿达帕林凝胶)组;D:大黄素乳膏低浓度组;E:大黄素乳膏中浓度组;F:大黄素乳膏中高浓度组;G:大黄素乳膏高浓度组。
图4为用药后各组金黄地鼠皮脂腺细胞PCNA蛋白表达水平比较(x±s,n=6);
*表示各浓度大黄素组与空白组相比具有明显差异,p<0.05;★表示大黄素高浓度组与阿达帕林组相比具有明显差异,p<0.05
图5为用药后各组金黄地鼠金黄地鼠皮脂腺细胞AR蛋白表达水平比较(x±s,n=6);
*表示各浓度大黄素组与空白组相比具有明显差异,p<0.05;★表示大黄素高浓度组与阿达帕林组相比具有明显差异,p<0.05。
图6为用药后各组金黄地鼠皮脂腺组织AR mRNA表达水平比较;
*表示各浓度大黄素组与空白组相比具有明显差异,p<0.05;★表示大黄素高浓度组与阿达帕林组相比具有明显差异,p<0.05。
图7为用药后各组皮脂腺组织SREBP-1mRNA表达水平比较;
*表示各浓度大黄素组与空白组相比具有明显差异,p<0.05;★表示大黄素高浓度组与阿达帕林组相比具有明显差异,p<0.05。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。实施例中未注明具体条件的实验方法,通常按照常规条件以及手册中所述的条件,或按照制造厂商所建议的条件;所用的通用设备、材料、试剂等,如无特殊说明,均可从商业途径得到。
本发明指出大黄素可用于治疗皮脂腺分泌旺盛的作用是经公认的研究皮脂腺分泌旺盛的理想模型-金黄地鼠背部皮脂腺斑的动物试验确认。(1)将42只雄性金黄地鼠随机分为空白组、基质组、阿达帕林凝胶阳性对照组、(低、中、中高、高浓度)大黄素乳膏组,共7组,每组6只。空白组不做处理,其余各组分别于背部双侧皮脂腺斑处涂抹1mL相应的药物30天,每日2次,于第0、10、20、30天测量皮脂腺斑面积并拍照记录皮脂腺斑外观,HE染色检测皮脂腺斑组织病理学改变,油红O染色检测脂质合成与分泌改变,免疫组化PCNA染色检测皮脂腺细胞增殖,AR染色检测雄激素受体蛋白表达水平,RT-PCR检测组织中AR mRNA、SREBP-1mRNA表达水平。
试验结果显示:乳膏基质组与空白组所有检测指标并无明显差异。外用不同浓度大黄素乳膏后皮脂腺斑面积均较用药前减小、皮脂腺组织病理学结构萎缩、脂质合成与分泌明显减少。各大黄素组皮脂腺斑组织中PCNA、AR蛋白表达均较空白组降低,高浓度大黄素组低于阿达帕林组;各浓度大黄素组皮脂腺斑组织中AR mRNA及SREBP-1mRNA的表达较基质组明显降低,高浓度组AR mRNA、SREBP-1mRNA表达明显低于阿达帕林组。表明:外用大黄素可抑制金黄地鼠皮脂腺斑增长和皮脂腺细胞增殖、抑制皮脂腺脂质合成与分泌、抑制AR蛋白合成和mRNA表达、抑制SREBP-1mRNA表达。综上所述,本发明证实了大黄素外用可以在解剖结构和生理学功能上抑制金黄地鼠皮脂腺细胞增殖、皮脂腺细胞脂质合成与分泌,具有一定的抑制皮脂腺分泌的功效,且可能与大黄素抑制皮脂腺组织AR进而降低SREBP-1mRNA的表达有关。
实施例1
1、药物配制
在常温下,将大黄素(式Ⅰ,分子式:C15H10O5,CAS号:518-82-1)先溶于聚乙二醇400中,再与乳膏基质(医用水包油乳膏基质)充分搅拌混匀,待颜色均匀时装入避光试管中,4℃冷藏备用。所配制的乳膏中聚乙二醇400的终浓度为聚乙二醇400和乳膏基质总量的20wt%,大黄素终浓度分别为0.4mg/g、0.8mg/g、1.6mg/g、2.4mg/g。为保证药物疗效,每次制作5g外用大黄素乳膏。
2、实验动物
42只SPF级,雄性,6-7周龄,体重110±10g的金黄地鼠,由辽宁长生生物技术有限公司提供,动物许可证号:SCXK(辽)2020-0001。置于22±2℃恒温,昼夜各12h的SPF级动物房分笼饲养,以金黄地鼠专用饲料喂养。
金黄地鼠也称叙利亚仓鼠,其背部皮脂腺斑主要由毛囊、皮脂腺及黑素团块等组成,是雄激素依赖性器官。在解剖学结构和对激素的生理学反应上与人类相似,是研究皮脂代谢异常疾病的理想动物模型。42只金黄地鼠适应性饲养10天后开始实验。按照随机数字法,将动物进行分组,每组6只,共7组:空白组、基质组、大黄素乳膏低浓度组(0.4mg/g)、大黄素乳膏中浓度组(0.8mg/g)、大黄素乳膏中高浓度组(1.6mg/g)、大黄素乳膏高浓度组(2.4mg/g)、阳性对照组(阿达帕林凝胶),共7组,每组6只,每组分为两笼饲养。
3、动物干预方法
实验前给金黄地鼠背部剃毛,使皮脂腺斑块充分暴露。空白组不予任何干预;基质组外用基质乳膏(80wt%乳膏基质+20wt%聚乙二醇400),不同浓度大黄素乳膏组外用上述大黄素乳膏,阳性对照组外用阿达帕林凝胶,每次于每只金黄地鼠双侧皮脂腺斑外用药物1mL,每日2次,共30天。于第30天取金黄地鼠背部皮脂腺斑皮肤组织,进行病理组织学检查、油红O染色、免疫组化染色及Rt-PCR检测。
4、实验动物取材
各组实验动物末次给药后,禁食不禁水24h,采用异氟烷配合动物麻醉机麻醉金黄地鼠并剃毛,暴露皮脂腺斑块并用数码相机拍照,用游标卡尺精确测量并记录皮脂腺斑块的最大横径(DT)和最大纵径(DL),然后切取背部含完整皮脂腺斑的皮肤组织,将一部分皮肤组织在滤纸上展平后,置于4%甲醛中充分浸泡并做好标记,另一部分皮肤组织直接放置于-80℃冰箱保存待用。采集标本完毕后脱颈处死各组金黄地鼠,并按规定放置于动物尸体冷冻贮存室中。
5、皮脂腺斑面积测量
于用药第0、10、20、30天,在自然光下用游标卡尺分别测量金黄地鼠背部皮脂腺斑大小,以最大横径(DT)×最大纵径(DL)表示,计算皮脂腺斑面积,并用数码相机拍照存档。
6、皮肤组织HE染色观察皮脂腺斑组织病理学变化
于用药第30天取下金黄地鼠背部皮脂腺斑皮肤组织,置于4%甲醛中固定24h后开始常规进行蜡块和切片制作,于显微镜下观察。
7、油红O染色观察皮脂腺斑脂质分泌情况,常规方式进行冰冻切片制作及按油红O染色常规步骤进行染色;镜检:于显微镜下观察皮脂腺脂质分泌情况,并拍照记录。
8、免疫组化染色检测皮脂腺斑中PCNA、AR蛋白,其中一抗稀比例为PCNA 1:200、AR1:50;修复方式为采用pH6.0的柠檬酸盐缓冲液,微波修复法,高火10min;抗体用湿盒4℃过夜孵育;镜检:各切片随机选取3个高倍视野拍照,应用Image J软件测定相关蛋白的平均光密度值。
9、RT-qPCR法检测皮脂腺斑组织中AR、SREBP-1c的mRNA表达
操作步骤如下:组织总RNA提取、反转录、实时荧光定量PCR;采用参照基因△CT法,根据CT值计算目的基因mRNA相对定量值(RQ值),即RQ=2-△△CT。
引物名称、序列和长度如下:
10、统计学方法
使用SPSS26.0软件进行实验结果的统计分析,计量资料均用均数±标准差(x±s)表示,数据符合正态性分布及方差齐性时,采用单因素方差分析进行组间比较,各大黄素组间进一步两两比较采用LSD法。检验水准均为P<0.05有统计学意义。
11、实验结果显示:
1、用药后皮脂腺斑面积减小,具有统计学差异(P>0.05),见表1;皮脂腺斑外观颜色变浅、面积减小,见图1。
表1用药前后各组金黄地鼠皮脂腺斑面积比较(x±s,mm2)
注:a与空白组比较,P<0.05,b与空白组比较,P<0.01,c与高浓度组比较,P<0.05。
2、用药后皮脂腺斑组织病理学变化,大黄素组皮脂腺出现不同程度萎缩,见图2。
3、用药后大黄素组金黄地鼠皮脂腺细胞脂质分泌均有不同程度减少,见图3。
4、用药后大黄素组皮脂腺细胞中PCNA、AR蛋白合成被抑制,具有统计学差异(P>0.05),见图4、图5。
5、用药后大黄素组皮脂腺斑组织ARmRNA、SREBP-1mRNA表达被抑制,具有统计学差异(P>0.05);见图6、图7。
结果表明,外用大黄素可抑制金黄地鼠皮脂腺斑增长和皮脂腺细胞增殖、抑制皮脂腺脂质合成与分泌、抑制AR蛋白合成和mRNA表达、抑制SREBP-1mRNA表达。
综上所述,本发明证实了大黄素外用可以在解剖结构和生理学功能上抑制金黄地鼠皮脂腺细胞增殖、皮脂腺细胞脂质合成与分泌,具有一定的抗痤疮等皮脂腺分泌旺盛疾病的功效,且可能与大黄素抑制皮脂腺组织AR进而降低SREBP-1mRNA的表达有关。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明的保护范围。
Claims (9)
1.大黄素在制备抑制皮脂腺分泌旺盛的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述皮脂腺分泌旺盛的疾病包括痤疮、脂溢性皮炎、脂溢性脱发或毛囊炎。
3.根据权利要求1所述的应用,其特征在于,所述药物中,大黄素的浓度为0.4-2.4mg/g。
4.根据权利要求1所述的应用,其特征在于,所述药物的剂型为乳膏。
5.大黄素在制备抑制皮脂腺分泌旺盛的化妆品中的应用。
6.根据权利要求5所述的应用,其特征在于,所述化妆品的剂型为水剂或膏剂。
7.大黄素在制备抑制皮脂腺斑的增长或者抑制皮脂腺细胞的增殖或者抑制皮脂腺细胞脂质合成与分泌或者调节皮脂腺分泌旺盛的药物中的应用。
8.大黄素在制备抑制皮肤雄激素受体或者胆固醇调节元件蛋白SREBP-1的药物中的应用。
9.大黄素在制备抑制皮脂腺分泌旺盛的食品中的应用。
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WO2017142368A2 (ko) * | 2016-02-19 | 2017-08-24 | 전북대학교 산학협력단 | 알레르기성 또는 염증성 피부질환의 예방 또는 치료용 조성물 |
CN111372597A (zh) * | 2017-10-19 | 2020-07-03 | 耶鲁大学 | 通过药用草药提取物及其组合物抑制雄激素受体 |
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WO2017142368A2 (ko) * | 2016-02-19 | 2017-08-24 | 전북대학교 산학협력단 | 알레르기성 또는 염증성 피부질환의 예방 또는 치료용 조성물 |
CN111372597A (zh) * | 2017-10-19 | 2020-07-03 | 耶鲁大学 | 通过药用草药提取物及其组合物抑制雄激素受体 |
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