CN115054609A - 甘草苷靶向sirt7/h3k122轴在制备银屑病药物中的应用 - Google Patents
甘草苷靶向sirt7/h3k122轴在制备银屑病药物中的应用 Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及甘草苷(liquiritin)及SIRT7/H3K122轴在制备银屑病药物中的应用。本发明利用生物信息分析及体内外实验验证，探究甘草苷(liquiritin)防治银屑病的作用机制。前期研究发现银屑病IMQ诱导的银屑病小鼠模型中SIRT7特异性升高，其组蛋白修饰底物H3K122表达下调。而甘草苷作用于银屑病小鼠模型后SIRT7的mRNA表达显著降低。过表达SIRT7的HaCaT细胞全转录组测序分析显示SITR7/H3K122显著下调PPAR‑γ表达。表明甘草苷可能通过介导SIRT7表达，降低组蛋白H3K122琥珀酰化修饰水平，调控PPAR‑γ改善炎症浸润，减弱细胞过度增殖，改善银屑病样皮损。甘草苷有望成为安全有效治疗银屑病和防治其复发的临床药物，而靶向SIRT7/H3K122轴可以作为一种新的防治方法，用于未来防治银屑病。
Description
技术领域
本发明涉及生物医药技术领域，具体地说，涉及甘草苷靶向SIRT7/H3K122轴在制备银屑病药物中的应用。
背景技术
银屑病是一种常见的慢性、复发性、免疫介导的皮肤疾病，影响全球约3％的人口(Michalek et al.,2017)。银屑病有多种临床皮损表现，但最常见的表现为慢性、对称性、红斑性、鳞屑性丘疹和斑块，斑块是角质形成细胞过度增殖和不完全分化的结果。除了影响皮肤本身外，各种并发症可能会影响患者的生活质量，对患者的情绪和心理健康产生显著的负面影响，增加死亡率(Langley et al.,2005)。
在银屑病的发病机制中，其核心过程是角质形成细胞(KCs)与免疫细胞之间异常且相互激活的交互串扰，主要的特征是KCs异常增殖、T淋巴细胞免疫细胞活性紊乱，和白细胞聚集(Lowes et al.,2014)。KCs被认为是几种趋化因子和细胞因子的来源，并能够调节银屑病的免疫表型，即使在免疫细胞正常的情况下，也足以引发银屑病(Armstrong andRead,2020)(Pasquali et al.,2019)(Gou et al.,2021)。因此，KCs是银屑病表型中的重要细胞类型，对于银屑病发生发展是至关重要的。
桃丹方被认为是治疗银屑病的有效方剂，已证实桃丹方可下调银屑病疾病相关炎症、增殖等表型，方中君药丹参有效成份Tanshinone IIA能抑制KC增殖，诱导细胞凋亡及细胞周期阻滞(Li et al.,2012)。银屑病血瘀证患者PASI评分改善率为76.64％。桃丹方下调IL-2、IL-4、IL-6表达和神经肽分泌等银屑病疾病表型(p<0.05)(范斌等,2006)(范斌等,2006)。为了进一步探究该方的核心成分及治疗银屑病的作用机制，申请人经LC-MS/MS分析发现甘草苷(95.87μg/mL)含量最高。前期研究显示甘草苷可以显著改善IMQ诱导的小鼠银屑病样皮损。IMQ诱导的病变表现出典型的红斑，鳞屑和增厚，在使用甘草苷治疗后，小鼠的皮肤病变得以减轻。H&E染色显示IMQ诱导的小鼠模型表皮明显增厚和真皮炎症细胞浸润，甘草苷干预后炎症明显减轻。但其分子机制有待阐释。
研究发现银屑病是由SIRT家族介导的炎症和新陈代谢相关疾病(Fan et al.,2019)。Sirtuins是进化保守的烟酰胺腺嘌呤二核苷酸(NAD)依赖性酶家族，具有去乙酰化酶和/或单ADP-核糖基转移酶活性，控制蛋白质的乙酰化或去琥珀酰化并调节细胞代谢。申请人前期发现甘草苷显著下调Sirtuin-7(SIRT7)的mRNA水平。SIRT7是一种NAD依赖性蛋白去乙酰化酶或去琥珀酰化酶，作用于调节炎性细胞因子释放，避免DNA损伤修复，适应环境挑战和细胞存活(Kiran et al.,2015)。最近的报道已经确定SIRT7与RNA聚合酶I相关联，并且是rDNA转录所必需的(Tsai et al.,2012)。其他研究还表明，SIRT7可能通过核编码线粒体基因的主调节剂GA重复结合蛋白β1(GABPβ1)的直接脱乙酰化来调节细胞代谢(Ryu etal.,n.d.)，这与银屑病及其合并症关系密切。综上，表明SIRT7在银屑病皮损中过度表达，导致KC生物学功能紊乱，与过度炎症相关，其抑制剂可能成为有效治疗银屑病的靶标。
组蛋白H3是在所有真核细胞染色质中发现的DNA结合蛋白之一，核小体是由四个核心组蛋白(H2A，H2B，H3和H4)中的每一个组成的八聚体。组蛋白在转录调控、DNA修复、DNA复制和染色体稳定性中起着核心作用。翻译后，组蛋白以多种方式进行修饰，以直接改变染色质结构或允许特定转录因子的结合。组蛋白H3的N端尾从球状核小体核心突出，可以经历几种不同类型的翻译后修饰，影响细胞过程。组蛋白3赖氨酸122(H3K122)位于核小体的二元轴上，这是组蛋白-DNA的侧表面部分结合达到其最大强度，定位于组蛋白八聚体表面并刺激转录，表明H3K122的潜在去琥珀酰化化可能起作用破坏组蛋白-DNA结合的稳定性。研究表明，H3K122ac能够刺激转录，其由共活性剂p300/CBP催化，可以由核激素受体信号传导诱导，且H3K122的突变会损害激活转录的过程(Tropberger et al.,2013)。Sirtuin 7(SIRT7)对H3K122succ的脱琥珀酰化已被证明与DNA双链断裂修复和基因组稳定性有关(Liet al.,2016)。表观遗传调节剂的组蛋白去琥珀酰化化已被证明可以激活肥厚反应基因的转录，从而导致心力衰竭的发展和进展，H3K122在左心室肥厚期不增加，但在心力衰竭期显著增加(Funamoto et al.,2021)。新研究发现，SIRT7能够通过催化cccDNA微染色体相关的组蛋白H3去琥珀酰化来限制HBV的转录和复制(Yu et al.,2021)。然而，H3K122在银屑病中的生物学功能有待进一步阐明。
目前，银屑病尚无特效疗法，适当的对症治疗可控制症状，但存在易反复发作的特点，且长期治疗容易导致不良反应。因此开发新的银屑病防治药物是非常必要的。目前未见甘草苷通过SIRT7/H3K122轴防治银屑病的报道。参考文献：
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发明内容
本发明的目的是针对现有技术中的不足，提供SIRT7/H3K122轴在制备银屑病防治药物中的应用及含有甘草苷的药物制备。
本发明的第一方面，提供甘草苷在制备防治银屑病的药物中的应用。
在本发明的另一方面，提供SIRT7或其抑制剂在制备防治银屑病的药物中的应用。
在本发明的另一方面，提供H3K122或其抑制剂在制备防治银屑病的药物中的应用。
在本发明的另一方面，提供一种防治银屑病的药物组合物，所述的药物组合物以甘草苷或其上调剂为活性成分，并进一步包含药学上可接受的载体。
在一个优选例中，所述药物组合物的剂型为外用剂型。
更优选地，所述药物组合物的剂型为贴剂、糊剂、软膏剂、微针剂、涂膜剂、巴布剂、喷雾剂。
在本发明的另一方面，提供一种防治银屑病的药物组合物，所述的药物组合物以赖氨酸去琥珀酰化酶Sirtuin-7(SIRT7)或其抑制剂为活性成分，并进一步包含药学上可接受的载体。
在一个优选例中，所述药物组合物的剂型为外用剂型或内用剂型。
更优选地，所述药物组合物的剂型为贴剂、糊剂、软膏剂、微针剂、涂膜剂、巴布剂、喷雾剂、胶囊剂、颗粒剂、片剂、丸剂、口服液或注射液。
在本发明的另一方面，提供一种防治银屑病的药物组合物，所述的药物组合物组蛋白3赖氨酸122(H3K122)或其抑制剂为活性成分，并进一步包含药学上可接受的载体。
在一个优选例中，所述药物组合物的剂型为外用剂型或内用剂型。
更优选地，所述药物组合物的剂型为贴剂、糊剂、软膏剂、微针剂、涂膜剂、巴布剂、喷雾剂、胶囊剂、颗粒剂、片剂、丸剂、口服液或注射液。
在本发明的另一方面，提供SIRT7或H3K122作为靶点在筛选制备防治银屑病及防治银屑病样炎症药物中的应用。
本发明优点在于：
1、本发明利用动物实验结合生物信息分析，验证甘草苷防治银屑病的作用机制。发现甘草苷作用于IMQ诱导的小鼠模型后SIRT7的mRNA表达显著降低，提示SIRT7可能与银屑病发病密切相关，有望成为防治银屑病的新靶标。
2、采用慢病毒转染技术过表达HaCaT细胞中SIRT7并进行全转录组测序，结果显示SITR7/H3K122显著下调PPAR-γ表达。表明甘草苷可能通过介导SIRT7表达，降低组蛋白H3K122琥珀酰化修饰水平，调控PPAR-γ表达，改善炎症浸润，减弱细胞过度增殖，改善银屑病样皮损。这代表了银屑病病理中的一个新的分子特征，也是防治银屑病的一个有前途的靶点。
总的来说，本发明结果证明，甘草苷及靶向SIRT7/H3K122轴可以作为新的治疗方法，用于未来防治银屑病及其相关炎症损伤，减少疾病复发。甘草苷有望成为安全有效治疗银屑病和防治其复发的临床药物，而靶向SIRT7/H3K122轴可以作为一种新的防治方法，用于未来防治银屑病。
附图说明
图1.SIRT家族在临床组织中的表达差异箱型图。图为SIRT1-7在正常皮肤(n＝35)和银屑病皮损(n＝290)中差异性表达。其中横轴代表不同组样本，纵轴代表该基因表达分布情况，其中不同颜色代表不同组别，左上角代表显著性p值检验方法***p<0.001，**p<0.01，*p<0.05。
图2.甘草苷改善IMQ诱导的银屑病表型。A，小鼠外观；B，诱导8d后拍照，耳朵厚度定量分析。
图3.组织学染色分析,n＝5个样品/组。
图4.体内实验中检测SIRT7表达情况。A，第8天小鼠皮肤中SIRT家族的qPCR定量。***p<0.001，**p<0.01，*p<0.05。B，Western blot检测SIRT7和H3K122在银屑病皮损组织与正常组织中的表达。数据代表来自三个独立实验的平均值±SD。***P<0.001，**P<0.01，*P<0.05。
图5.SIRT7过表达HaCaT细胞的转录谱分析。A，差异基因火山图；B，差异基因热图；C，差异基因上调的KEGG通路气泡图；D，差异基因下调的KEGG通路气泡图；E，差异基因上调的GO富集柱状图；图5F，差异基因下调的GO富集柱状图。
具体实施方式
本申请发明人经过广泛而深入的研究，发现SIRT7/H3K122轴是甘草苷防治银屑病的重要作用靶标。
SIRT7、H3K1221
NAD依赖性蛋白去琥珀酰化酶Sirtuin-7(Sirtuin 7，SIRT7)是一个蛋白质编码基因。与SIRT7相关的疾病包括Monckeberg动脉硬化和体重指数定量性状位点11。其相关途径包括由HDAC III类介导的NAD代谢和信号传导事件。与该基因相关的基因本体(GO)注释包括染色质结合和NAD依赖性组蛋白去琥珀酰化酶活性(H3-K18特异性)。该基因的一个重要副基因是SIRT6。NAD依赖性蛋白赖氨酸脱酰酶，既可以作为脱乙酰酶，也可以作为脱乙酰酶或脱酰酶。
组蛋白H3是在所有真核细胞染色质中发现的DNA结合蛋白之一，核小体是由四个核心组蛋白(H2A，H2B，H3和H4)中的每一个组成的八聚体。组蛋白在转录调控、DNA修复、DNA复制和染色体稳定性中起着核心作用。组蛋白3赖氨酸122(H3K122)位于核小体的二元轴上，这是组蛋白-DNA的侧表面部分结合达到其最大强度，定位于组蛋白八聚体表面并刺激转录，表明H3K122可能起作用破坏组蛋白-DNA结合的稳定性。
在本发明中，所用的SIRT7、H3K122可以是天然存在的，比如其可以被分离或纯化自哺乳动物。此外，所述的SIRT7、H3K122也可以是人工制备的，比如可以根据常规的基因工程重组技术来生产重组SIRT7、H3K122。本发明优选采用重组SIRT7、H3K122。
任何适合的SIRT7、H3K122均可用于本发明。所述的SIRT7、H3K122包括全长的H3K122或其生物活性片段。经过一个或多个氨基酸残基的取代、缺失、或添加而成的SIRT7、H3K122的氨基酸序列也包括在本发明中。SIRT7、H3K122或其生物活性片段包括一部分保守氨基酸的替代序列，所述经氨基酸替换的序列并不影响其活性或保留了其部分的活性。适当替换氨基酸是本领域公知的技术，所述技术可以很容易地被实施并且确保不改变所得分子的生物学活性。这些技术使本领域技术人员认识到，通常在一种多肽的非必要区域改变单个氨基酸基本上不会改变生物活性见Watson，Molecular Biology of The Gene，第四版，1987，The Benjamin/Cummings Pub.Co.P224。
任何一种H3K122的生物活性片段都可以应用到本发明中。在这里，SIRT7、H3K122的生物活性片段的含义是指作为一种多肽，仍然能保持全长的SIRT7、H3K122的全部或部分功能。所述优选的生物活性片段至少保持50％的全长SIRT7、H3K122活性。在更优选的条件下，所述活性片段能够保持全长SIRT7、H3K122的60％、70％、80％、90％、95％、99％、或100％活性。
本发明也可采用经修饰或改良的SIRT7、H3K122，比如，可采用为了促进其半衰期、有效性、代谢、和/或蛋白的效力而加以修饰或改良的SIRT7、H3K122。所述经过修饰或改良的SIRT7、H3K122可以是一种SIRT7、H3K122的共轭物，或其可包含被取代的或人工的氨基酸。所述经过修饰或改良的SIRT7、H3K122可以是与天然存在的SIRT7、H3K122具有较小的共同点，但也能缓解银屑病或缓解银屑病样炎症，且不会带来其它不良影响或毒性。也就是说，任何不影响SIRT7、H3K122的生物活性的变化形式都可用于本发明中。
根据SIRT7、H3K122的氨基酸序列可以方便地得出其相应的核苷酸编码序列。
甘草苷
甘草苷是方剂桃丹方经过LC-MS/MS鉴定和定量出的核心化学成分，是一种黄酮类化合物，分子式为C21H22O9，分子量418.39，CAS号为551-15-5，具有强大的抗炎、促凋亡、抗氧化应激、抗癌的活性，可以用于治疗多种自身免疫性疾病及慢性炎症，包括银屑病和特应性皮炎等。据报道，甘草苷可抑制紫外线B诱导的促炎介质产生，对大鼠皮肤损伤的起到保护的作用(Li et al.,2021)；甘草苷可以诱导SGC7901/DDP细胞凋亡，导致细胞死亡(Wei etal.,2017)。同时，其强大的抗炎作用在体外实验中被验证与抑制炎症参数、KC增殖和减少MMPs的产生有关。此外，甘草苷被证明是NF-κB途径阻滞剂和对抗皮肤损伤的抗氧化剂。
用途
本发明提供甘草苷、SIRT7、H3K122在制备防治银屑病的药物中的用途。
银屑病是一种常见的慢性、复发性、免疫介导的皮肤和关节性疾病，影响约全球3％的人口。银屑病具有很强的遗传性，但环境因素如感染，在银屑病的发病因素中也起着重要的作用。银屑病有多种临床皮损表现，但最常见的表现为慢性、对称性、红斑性、鳞屑性丘疹和斑块，斑块是角质细胞过度增殖和不完全分化的结果。除了影响皮肤本身外，各种并发症可能会影响患者的生活质量，对患者的情绪和心理健康产生显著的负面影响，增加死亡率。
药物组合物
本发明的药物组合物可含有本文所述的活性试剂和药学上可接受的载体。药学上可接受的载体通常是安全、无毒的，包括各种赋形剂和稀释剂等。该术语指这样一些药剂载体：它们本身并不是必要的活性成分，且施用后没有过分的毒性。合适的载体是本领域普通技术人员所熟知的。在Remington'sPharmaceutical Sciences(Mack Pub.Co.N.J.1991)中可找到关于药学上可接受的赋形剂的充分解释。在组合物中药学上可接受的载体可含有液体，如水、盐水、甘油和乙醇。另外，这些载体中还可能存在辅助性的物质，如乳化剂、填充剂、粘合剂、润湿剂、崩解剂、促渗透剂、着色剂、助溶剂等。以上，所述的乳化剂诸如单甘油脂肪酸酯、双甘油脂肪酸酯、蔗糖酯、山梨糖醇脂、大豆磷脂、月桂酸单甘油酯、丙二醇脂肪酸酯、硬脂酰乳酸钙、双乙酰酒石酸、单硬脂酸甘油酯、改性大豆磷脂等；所述的赋形剂诸如硬脂酸镁、微晶纤维素、乳糖、奶糖、高分子量的聚乙二醇等；所述的填充剂诸如淀粉、甘露醇、硅酸、糊精、磷酸氢钙、纤维素等；所述的粘合剂诸如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、阿拉伯胶、淀粉浆、羟丙基淀粉、改良淀粉、预胶化淀粉、糊精、微晶纤维素、聚乙烯吡咯烷酮胶浆、明胶浆；所述的润湿剂诸如甘油等；所述的崩解剂诸如琼脂、碳酸钙、马铃薯淀粉、木薯淀粉、海藻酸、羟丙基淀粉、改良淀粉、羧甲基淀粉钠、微晶纤维素、瓜耳胶、苍耳胶、黄原胶等；所述的促渗透剂诸如薄荷脑、月桂氮酮、冰片等；所述的着色剂可以是植物着色剂、动物着色剂或者微生物着色剂，诸如甜菜红、姜黄、叶绿素、紫胶红、胭脂虫红、红曲着色剂等；所述的助溶剂诸如β-环糊精、麦芽糊精、吐温、乙醇、司盘类、十二烷基硫酸钠、丙二醇、聚乙二醇、甘油等。但对于本领域技术人员而言，还知晓可用于本发明的药用载体不仅限于上述类型。
剂型
对于本发明所述药物组合物的剂型没有特别限制，可以是任何适用于外用的剂型，包括但不限于贴剂、糊剂、软膏剂、微针剂、涂膜剂或巴布剂。也可以是任何适用于内用的剂型，包括但不限于胶囊剂、颗粒剂、片剂、丸剂、口服液或注射液等。
治疗方法
本发明提供一种防治银屑病的方法，所述方法包括给予需要的对象甘草苷；H3K122、SIRT7抑制剂；给予的量为治疗有效量，可根据个体的年龄、体重、性别、疾病种类和严重程度加以确定。对象可以是哺乳动物，尤其是人、鼠、兔子、猪、羊和狗等。给药方法是本领域常规的方法，例如涂抹、敷贴等，并可针对不同的试剂进行调整。
下面结合附图对本发明提供的具体实施方式作详细说明。
实施例1
一、方法和材料
1.生物信息学分析SIRTs家族在银屑病患者中的表达情况
使用的数据集包含来自GEO数据库中(https://www.ncbi.nlm.nih.gov/geo/)，数据集为GSE14905、GSE109248、GSE117239，下载数据格式为MINiML。分析方法为Wilcoxon秩和检验(rank sum test)非参数检验(nonparametric test)，以比较临床银屑病患者与正常组之间SIRTs家族的表达差异。箱线图通过boxplot进行绘制，并通过R软件包ggplot2实现可视化。上述所有分析方法和R包均由R语言实现，用于统计计算(2020)版本4.0.3。
2.银屑病样皮损在体模型的建立。
2.1小鼠建模及干预
采用IMQ诱导的银屑病样小鼠模型进行体内研究。为进行疗效实验，将小鼠随机分为3组(IMQ乳膏62.5mg/只，6h后给予不同治疗策略，连续8d)：空白组(62.5mg/只)，IMQ组(62.5mg/只)，IMQ+甘草苷组(62.5mg/只)。在复发实验中，将小鼠随机分成3组，连续用药8d，恢复12d，再用IMQ(20.8mg/只)再次激发，连续10d。所有动物实验均经上海中医药大学伦理委员会批准(no.YYLAC-2020-078-1)。
2.2甘草苷药物制备：
甘草苷(CAS：551-15-5)从中国食品药品检定研究院购买(中国北京)。公司购买(纯度≥98％)，溶解于乙醇和丙二醇(V：V＝3：7)。
2.3小鼠外观及H&E染色
将小鼠背部和耳朵的中部皮损外观对比，定量记录银屑病小鼠背部、耳部皮损厚度变化，观察IMQ诱导后小鼠皮损变化、以及甘草苷用药后表型是否缓解。用4％福尔马林溶液固定，并用H&E溶液染色，观察皮损组织病理变化情况。
2.4定量聚合酶链反应(q-PCR)
使用标准的TRIzol方案从皮肤和HaCaT细胞中提取总mRNA。通过用紫外分光光度计测量吸光度260/280比率来确定RNA的浓度和纯度。使用逆转录试剂盒制备cDNA，并使用逆转录酶进行逆转录。使用2-ΔΔCT方法分析相对定量数据。聚合酶链反应因雾显示在表1.
表1.qPCR引物
2.5Western blot分析
我们在银屑病皮损形成后第9天，对对照组、IMQ的小鼠实施安乐死。抗体包括抗SIRT7抗体(1:2000，ab259968，Abcam)，H3K122(1:2000，ab177306，Abcam)，将细胞与相关的二抗一起温育。检测各组细胞中的SIRT7、H3K122蛋白表达。
2.6统计分析
实验数据用GraphPad Prism 8进行分析，所有数据均表示为平均值±标准误差(S.E.M.)。用T检验或方差分析比较组间差异。p≤0.05和p≤0.01的值分别被认为有显著或非常显著的差异。
3.细胞培养和处理
HaCaT细胞系(300493)取自Cell Lines Service公司(Eppelheim,Germany)，在含10％胎牛血清、100U/ml青霉素和100μg/ml链霉素的DMEM中生长。NHEK(正常人表皮角质形成细胞,C-12006)细胞系购自Promo Cell(Heidelberg,Germany)，在角质形成细胞生长培养基2(D-39006,Heidelberg,Germany)中培养。上述细胞系于37℃培养箱中，在5％CO2的培养箱中。甘草苷以20mM的最终浓度作为治疗浓度，溶于DSMO；使用M5(添加IL-1α，IL-17A，IL-22，抑瘤素M和肿瘤坏死因子-α，2.5ng/ml)体外模拟银屑病的炎症特征。细胞样本内加入不同浓度的甘草苷溶液，而未经处理的样本接受等量的DMSO。
4.转录图谱检测
进行mRNA微阵列分析。用RNeasy Mini Kit(Cat#74106，Qiagen)根据制造商的方案从慢病毒转染SIRT7过表达的HaCaT细胞中提取总mRNA。RNA完整性用安捷伦生物分析仪4200(Agilent Technologies，nta Clara，CA，US)进行评估。用TruSeq链mRNA LT样品制备试剂盒(RS-122-2103，Illumina)构建cDNA文库。RNA测序由上海生物芯片有限公司完成。
根据p值＜0.05和|Log2F-C|≥2，鉴定SIRT7过表达细胞和正常HaCaT细胞中的差异mRNA，并进行GO和KEGG分析。
二、结果
1.生物信息分析
为了了解SIRTs家族在银屑病患者中的表达情况，我们通过Spearman相关系数评价银屑病与正常值的差异。结果显示，在银屑病患者中，除SIRT3外均具有显著差异，其中SIRT1(p＝0.0023)、SIRT4(p＝0.00069)、SIRT5(p＝3e-06)在银屑病患者中表达下调，SIRT6(p＝0.0017)、SIRT7(p＝2.4e-06)在银屑病患者中表达上调，SIRT7差异最为显著(图1)。
2.甘草苷显著改善IMQ诱导的小鼠银屑病样皮损
为了鉴定甘草苷的浓度，采用CCK-8检测甘草苷在HaCaT和NHEK细胞。我们发现甘草苷显著抑制HaCaT细胞(IC50＝0.62μM)的生长。因此，0.62μM甘草苷刺激的HaCaT细胞被用作后续研究的实验条件。研究发现甘草苷可以显著改善IMQ诱导的小鼠银屑病样皮损。IMQ诱导的病变表现出典型的红斑，鳞屑和增厚，在使用甘草苷治疗后，小鼠的皮肤病变得以减轻(图2A)，将小鼠耳部、背部皮损厚度分别定量对比，发现咪喹莫特干预后小鼠皮损厚度明显增加，而甘草苷干预后显著缓解(图2B)。H&E染色显示IMQ诱导的小鼠模型表皮明显增厚和真皮炎症细胞浸润，甘草苷干预后炎症明显减轻(图3)。
3.体内实验发现甘草苷干预后可降低SIRT7表达
我们采用IMQ诱导的银屑病样小鼠模型作为研究对象探究甘草苷治疗银屑病的分子机制。结果证实：IMQ小鼠皮损中SIRT7显著上调(p＝0.0007)，同时甘草苷干预后SIRT7下调最显著(p＝0.0096)；在蛋白质水平，银屑病组SIRT7表达显著上调，同时其组蛋白赖氨酸去琥珀酰化修饰底物H3K122显著下调，提示银屑病可能一部分是由于SIRT7上调介导H3K122的修饰有关(图4)。
4.SIRT7过表达HaCaT细胞的转录谱分析
我们使用慢病毒来上调HaCaT细胞中SIRT7的表达，并检测SIRT7过表达的HaCaT细胞和正常HaCaT细胞的转录谱，并基于RNA测序进行了比较。在对测序数据进行初步质量控制后，共保留了15798个基因，其中3402个基因被鉴定为DE mRNAs，且1574个基因(46％)上调，1828个基因(54％)下调(图5A,B)。这一结果提示SIRT7过表达的细胞与正常细胞的mRNAs表达状态有很大的不同，SIRT7可能通过调节DE mRNA的表达，从而缓解银屑病炎症表型。
5.PPAR-γ是SIRT7下游效应基因
此外，我们进行了GO和KEGG途径富集分析。相关上调的差异mRNA相关的GO术语主要有生物过程、细胞器组织、分子函数、RNA结合、蜂窝组织、胞内膜界细胞器、细胞器部分、细胞内细胞器部分、含蛋白质复合物、胞质溶胶有关；而下调的差异mRNA则与生物过程、细胞氮化合物代谢过程、细胞芳香族化合物代谢过程、杂环代谢过程、含核碱基化合物代谢过程、RNA加工、分子函数、核酸结合、RNA结合、转移酶复合物等。这些与银屑病皮肤功能密切相关。
KEGG通路分析显示，差异上调mRNA相关的前10位KEGG通路主要与单纯疱疹感染、细胞粘附分子、药物代谢-细胞色素P450、补体和凝血级联、细胞色素P450对异生素的代谢、化学致癌、花生四烯酸代谢、炎症性肠病等的DE mRNAs。下调的主要与细胞因子-细胞因子受体相互作用、病毒蛋白与细胞因子和细胞因子受体的相互作用、神经活性配体-受体相互作用、味觉转导、系统性红斑狼疮、Jak-STAT信号通路、胆固醇代谢、IL-17信号通路、蛋白质消化吸收等途径相关。有趣的是，这些信号通路显示出与银屑病密切的相关性，且尤其与炎症有关。
值得注意的是，SIRT7过表达HaCaT细胞后显著下调PPAR-γ，表明SIRT7可能通过抑制PPAR-γ水平来改善银屑病表型。
这些结果表明，甘草苷可以抑制银屑病皮肤的过度炎症，改变SIRT7/H3K122轴相关基因表达。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
SEQUENCE LISTING
<110> 上海市皮肤病医院
<120> 甘草苷靶向SIRT7/H3K122轴在制备银屑病药物中的应用
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<213> 人工序列
<400> 10
cctctgaaag tgggaacccc 20
<210> 11
<211> 20
<212> DNA
<213> 人工序列
<400> 11
gaggggctaa tgggaacgag 20
<210> 12
<211> 20
<212> DNA
<213> 人工序列
<400> 12
ggaggagtac agagtggggt 20
<210> 13
<211> 20
<212> DNA
<213> 人工序列
<400> 13
tccagccaaa gcccagatta 20
<210> 14
<211> 20
<212> DNA
<213> 人工序列
<400> 14
cctgaacaag ggtcaagcca 20
Claims (9)
1.甘草苷或其上调剂在制备防治银屑病的药物中的应用。
2.SIRT7或其抑制剂在制备防治银屑病的药物中的应用。
3.H3K122或其抑制剂在制备防治银屑病的药物中的应用。
4.一种防治银屑病的药物组合物，其特征在于，所述的药物组合物以甘草苷为活性成分，并进一步包含药学上可接受的载体。
5.一种防治银屑病的药物组合物，其特征在于，所述的药物组合物以SIRT7或其抑制剂为活性成分，并进一步包含药学上可接受的载体。
6.一种防治银屑病的药物组合物，其特征在于，所述的药物组合物以H3K122或其抑制剂为活性成分，并进一步包含药学上可接受的载体。
7.根据权利要求4-6任一所述的药物组合物，其特征在于，所述药物组合物的剂型为外用剂型或内用剂型。
8.根据权利要求6所述的药物组合物，其特征在于，所述药物组合物的剂型为贴剂、糊剂、软膏剂、微针剂、涂膜剂、巴布剂、喷雾剂、胶囊剂、颗粒剂、片剂、丸剂、口服液或注射液。
9.SIRT7或H3K122作为靶点在筛选防治银屑病或缓解银屑病样炎症的药物中的应用。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117582444A (zh) * | 2023-10-12 | 2024-02-23 | 中国科学院微生物研究所 | Gs-9620在制备预防和/或治疗银屑病的药物中的应用 |
Citations (1)
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|---|---|---|---|---|
| CN102125576A (zh) * | 2010-01-14 | 2011-07-20 | 北京联合大学应用文理学院 | 甘草苷在制备防治心脑血管疾病药物中的应用 |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102125576A (zh) * | 2010-01-14 | 2011-07-20 | 北京联合大学应用文理学院 | 甘草苷在制备防治心脑血管疾病药物中的应用 |
Non-Patent Citations (2)
| Title |
|---|
| 吴钉红: "治疗银屑病中药的网络药理学研究", 《中国博士学位论文全文数据库 医药卫生科技辑》, no. 05, pages 057 - 30 * |
| 范晓晶: "SIRTs在银屑病中的异常表达", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》, no. 01, pages 075 - 53 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117582444A (zh) * | 2023-10-12 | 2024-02-23 | 中国科学院微生物研究所 | Gs-9620在制备预防和/或治疗银屑病的药物中的应用 |
| CN117582444B (zh) * | 2023-10-12 | 2024-04-30 | 中国科学院微生物研究所 | Gs-9620在制备预防和/或治疗银屑病的药物中的应用 |
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