CN116549472A - Picroside III在制备预防和/或治疗炎症性肠病药物中的应用 - Google Patents
Picroside III在制备预防和/或治疗炎症性肠病药物中的应用 Download PDFInfo
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- CN116549472A CN116549472A CN202310544011.5A CN202310544011A CN116549472A CN 116549472 A CN116549472 A CN 116549472A CN 202310544011 A CN202310544011 A CN 202310544011A CN 116549472 A CN116549472 A CN 116549472A
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Abstract
本发明公开了PicrosideIII在制备预防和/或治疗炎症性肠病药物中的应用,涉及药物技术领域。本发明提供的PicrosideIII在制备预防和/或治疗炎症性肠病药物中的应用属于首次公开,PicrosideIII属于纯天然制剂,安全可靠无毒副作用,可有效促进结肠粘膜伤口愈合和上皮屏障功能恢复,从而改善结肠炎。所述PicrosideIII可作为治疗炎症性肠病的药物,并可与可用药物载体制成各种剂型。
Description
技术领域
本发明涉及药物技术领域,尤其涉及Picroside III在制备预防和/或治疗炎症性肠病药物中的应用。
背景技术
溃疡性结肠炎(UC)是一种复发性炎症性肠病(IBD),病因不明,主要表现为结肠黏膜充血、水肿和血管模糊,伴有多处溃疡和表面带血分泌物。UC最常见于年轻人。UC复发很常见。因此,UC患者需要频繁和长期的药物治疗,严重影响其工作和生活。迄今为止,UC的确切病因尚不清楚,主要的临床策略是使用经典的治疗药物,如氨基水杨酸盐、皮质类固醇和免疫抑制药物来诱导缓解和减少复发。然而,由于这些药物的各种副作用,它们不能达到预期的效果。因此,迫切需要开发新的、安全有效的预防和治疗UC的药物。
虽然UC的确切发病机制尚不清楚,但科学界认为复发性炎症和难治性粘膜损伤是UC病理变化的关键事件。现有临床应用证实,氨基水杨酸盐、皮质类固醇、免疫抑制剂等常规药物确实能有效减轻结肠炎症并达到一定的缓解效果,但其促进肠黏膜愈合的作用有限。未愈合的黏膜便会受到致病因子的反复侵袭,诱发IBD复发。近年来,大量临床研究表明,粘膜愈合和屏障功能恢复是UC治疗的关键终点,不仅有助于减少炎症,促进上皮修复,缓解临床症状,防止疾病进展,而且有助于避免临床长期需要类固醇,减少住院和手术切除率。因此,促进粘膜屏障修复也是UC治疗的重要途径。目前临床上缺乏能够促进肠黏膜屏障修复的药物。
胡黄连(Picrorhiza scrophulariiflora Pennell)为玄参科多年生草本植物,现代药理学研究表明,胡黄连具有保肝利胆,抗菌消炎,抗哮喘,神经保护,免疫活性和降血糖等多种药理作用,具有广泛的药理活性。目前对胡黄连中的化学成份研究主要是针对胡黄连总苷或胡黄连苷II(Picroside II),对胡黄连苷III(Picroside III)的研究甚少。此外,CN114432330A公开了胡黄连苷II在制备预防和治疗炎症性肠病药物中的用途,但是胡黄连苷II和胡黄连苷III的化学结构差别很大,二者的活性基团不同,对于胡黄连苷III对抗炎症性肠病的治疗效果还不能根据现有技术简单推断后得出。
发明内容
本发明所要解决的技术问题是提供Picroside III在制备预防和/或治疗炎症性肠病药物中的应用。
为了解决上述问题,本发明提出以下技术方案:
本发明的第一个目的是提供Picroside III在制备预防和/或治疗炎症性肠病药物中的应用。
本发明中,Picroside III胡黄连苷III是一种从传统中药胡黄连(Picrorhizascrophulariiflora Pennell)中分离出的环烯醚萜苷。
进一步地,炎症性肠病为复发性炎症性肠病。
进一步地,所述炎症性肠病为溃疡性结肠炎。
进一步地,所述炎症性肠病为克罗恩病。
本发明提供的Picroside III治疗溃疡性结肠炎的机理在于降低细胞通透性、抑制claudin-2的表达,增加ZO-1和occludin的表达,进而促进结肠粘膜伤口愈合和上皮屏障功能恢复,改善炎症状态。
本发明的第二个目的是提供一种抗炎症性肠病药物,包括Picroside III,炎症性肠病为复发性炎症性肠病。
进一步地,所述炎症性肠病为溃疡性结肠炎。
进一步地,所述炎症性肠病为克罗恩病。
本发明提供的Picroside III可与可用药物载体制成各种剂型;所述剂型包括片剂、丸剂、糖锭剂、颗粒剂、凝胶剂、膏剂、溶液剂、栓剂、注射剂、粉剂、胶囊剂、悬浮剂、吸入剂以及喷雾剂。
本发明提供的Picroside III制备的预防和治疗溃疡性结肠炎的药物可按各种制剂的常规工艺制备。在药物制备中使用的可药用的赋形剂和添加剂包括无毒的可相容的填料、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧化剂、润滑剂、矫味剂、增稠剂、着色剂、乳化剂或稳定剂。
Picroside III可以制成多种剂型,包括固体剂型,半固体剂型,液体制剂和气雾剂等。这几类剂型中的具体剂型包括包括片剂、丸剂、糖锭剂、颗粒剂、凝胶剂、膏剂、溶液剂、栓剂、注射剂、粉剂、胶囊剂、悬浮剂、吸入剂以及喷雾剂。这些剂型既能用于局部或全身给药又能用于速释或缓续给药,此类药物的给药方式有很多种,除了上述方式,还有口腔给药、面颊给药、直肠给药、腹膜给药、腹膜内给药、皮表给药、皮下给药和气管内给药等。
当Picroside III注射给药时,可以用水溶性或脂溶性的溶剂将此类化合物配制成溶液剂,悬浊剂和乳剂。脂溶性溶剂具体包括植物油及类似油类,合成脂肪酸甘油酯,高级脂肪酸酯以及乙二醇酯(proylene glycol)。这类化合物更易溶于Hank’s溶液、Ringer’s溶液或者生理盐水。
当Picroside III口服给药时,可以采用常用技术将其与药学可接受的赋形剂制成复合物。这些赋形剂可以将这些化合物制成多种可以被病人剂型,如片剂、丸剂、混悬剂、凝胶剂等。口服制剂的配制有多种方法,如先把化合物和固体赋形剂混匀,充分研磨混合物,添加适当的辅料,加工处理成颗粒。可以用于制成口服剂型的辅料包括:糖类如乳糖、蔗糖、甘露醇或山梨醇;纤维素类如玉米淀粉、小麦淀粉、马铃薯淀粉、明胶、西黄薯胶、甲基纤维素、羟甲基纤维素(hydroxyproylmethyl-cellulose)、羧甲基纤维素纳、聚乙烯吡咯酮等。
本发明涉及的Picroside III也可以制成喷雾剂,此种剂型是通过一个加压器和一个喷雾器或者一个干粉吸入装置而实现的。可以用作喷射器里合适的喷射剂如二氯二氟甲烷、氟三氯甲烷、二氯四氟乙烷、二氧化碳和二甲醚等。气雾剂给药的剂量可以通过喷射器的阀门来调节。
本发明涉及的各种剂型都关系到Picroside III的有效治疗剂量。所述抗炎症性肠病药物中,Picroside III的用量为15-1000mg/kg。需要说明的是,该化合物的有效治疗剂量取决于接受治疗的病人。在决定适宜的剂量时,病人的体重、病情、服药方式以及处方医师的主观判断因素都要纳入考虑。Picroside III的治疗有效量应该由有能力和丰富经验的处方医师决定。
粘膜愈合和屏障功能恢复是UC治疗的关键终点,其不仅有助于减少炎症,促进上皮修复,缓解临床症状,防止疾病进展,而且有助于避免临床长期需要类固醇,减少住院和手术切除率。Picroside III治能够降低细胞单层通透性、抑制claudin-2的表达,增加ZO-1和occludin的表达,进而促进结肠粘膜伤口愈合和上皮屏障功能恢复,改善炎症状态,因此具有治疗溃疡性结肠炎的功能。
与现有技术相比,本发明所能达到的技术效果包括:
本发明提供的Picroside III在制备预防和/或治疗炎症性肠病药物中的应用属于首次公开,Picroside III属于纯天然制剂,安全可靠无毒副作用,可有效促进结肠粘膜伤口愈合和上皮屏障功能恢复,从而改善结肠炎。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1显示了Picroside III对dss诱导小鼠结肠炎的影响。图中,(A)为PicrosideIII的结构;(B)为各组小鼠的体重变化;(C)为各组DAI评分;(D)为各组小鼠的结肠及结肠长度代表性图像;(E)为结肠组织学评分及H&E染色图像(放大后,×100)。数据用均数±SEM表示(n=5),*p<0.05,**p<0.01,***p<0.001。Con为空白对照组;DSS为DSS模型组;DSS+CsA为阳性药环孢素A(CSA)组;DSS+Picroside III(L)为Picroside III低剂量组;DSS+Picroside III(H)为Picroside III高剂量组;Con+Picroside III(H)为无DSS的Picroside III治疗组;DAI指疾病活动指数。
图2显示了Picroside III对dss诱导结肠炎小鼠结肠组织ZO-1、claudin-3、occludin和claudin-2表达的影响。图中,(A)结肠炎小鼠结肠组织中ZO-1、claudin-3和occludin mRNA表达情况;(B)结肠炎小鼠结肠组织中ZO-1、claudin-2和occludin的蛋白表达。数据用均数±SEM表示(n=5),*p<0.05,**p<0.01。Con为空白对照组;DSS为DSS模型组;DSS+CsA为阳性药环孢素A(CSA)组;DSS+Picroside III(L)为Picroside III低剂量组;DSS+Picroside III(H)为Picroside III高剂量组;Con+Picroside III(H)为无DSS的Picroside III治疗组。
图3显示了Picroside III对TNF-α-处理Caco-2细胞单层通透性及创面愈合的影响。图中,(A)不同浓度的Picroside III对Caco-2细胞活力的影响。(B)不同浓度的Picroside III(5、10和20μM)对TNF-α-处理的Caco-2细胞对FD4透过率的影响。(C)不同浓度的Picroside III(5、10和20μM)对TNF-α-处理的Caco-2细胞单层创面愈合的影响。数据代表三个独立的体外实验。数据代表平均值±sem。*p<0.05,**p<0.01。CON:空白对照组。
图4显示了Picroside III对TNF-α-处理Caco-2细胞ZO-1、claudin-3、occludin和claudin-2表达的影响。图中,(A)TNF-α-处理Caco-2细胞中ZO-1、claudin-3、claudin-2mRNA表达情况。(B)TNF-α-处理Caco-2细胞中ZO-1、claudin-2和occludin的蛋白表达。数据代表三个独立的体外实验。数据以平均值±SEM表示。*p<0.05,**p<0.01。CON:空白组。
具体实施方式
下面结合附图和实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不用来限制本发明的范围。
本发明实施例所用的实验方法介绍如下:
结肠炎的诱导和评价:
将30只C57bl/6小鼠,雄性,18-22g,采用2%DSS饮用水5天诱导小鼠结肠炎,然后随机分成六组,分别为空白对照组、DSS模型组、阳性药环孢素A(CSA)组、Picroside III低剂量组、Picroside III高剂量组和无DSS的Picroside III治疗组。根据预实验,PicrosideIII低剂量处理组给予的Picroside III剂量设为15mg/kg,Picroside III高剂量处理组和无DSS的Picroside III治疗组给予的Picroside III剂量设为30mg/kg。同时,CSA组给予的剂量设定为25mg/kg。空白对照组和DSS模型组的小鼠给予相同体积的空白溶媒。所有小鼠从第0天开始连续灌胃11天。每天记录体重、腹泻程度和粪便隐血,然后计算疾病活动指数(DAI)。实验结束时,对所有小鼠实施安乐死,并切除结肠段。测量结肠长度后,收集结肠组织作进一步实验。
组织学检查方法:
将小鼠结肠组织采用4%多聚甲醛固定,石蜡包埋,H&E(苏木精和伊红)染色后,采用盲法评估组织病理学损伤程度。
细胞培养方法:
Caco-2细胞从ATCC(Manassas,VA,USA)获得,在添加20%胎牛血清、1%非必需氨基酸和1%丙酮酸钠的MEM中,于37℃,5%CO2下培养。
渗透性评价方法:
FITC-葡聚糖(MW:4kDa,Sigma,USA)用于体外评估通透性。将2×104个/孔的Caco-2细胞接种于24孔传代孔的上腔,培养7~9d,获得传导稳定的Caco-2细胞单层。在此期间,每天都要更换培养基。之后,用TNF-α(100ng/mL)或/和Picroside III刺激24小时。随后,用PBS进行两次洗涤后,顶室用浓度为1mg/mL的fitc-葡聚糖孵育2小时。收集基底侧室培养基进行荧光分析。
伤口愈合试验及评价方法:
将Caco-2细胞置于12孔板中培养至细胞融合后,用250μL移液管尖轻轻划伤细胞单层。PBS洗涤后,将处理过的细胞单层暴露于含有TNF-α(100ng/mL)的Picroside III中24小时,并在显微镜下评估和记录细胞伤口愈合面积。
实时qPCR分析方法:
用(Thermo Fisher,USA)从细胞或结肠组织中提取总RNA,然后用逆转录试剂盒(Takara,Kusatsu,Shiga,Japan)转录成cDNA。在ABI 7500实时荧光定量PCR系统上使用SYBR Green Master Mix(Roche Diagnostics GmbH Mannheim,Germany)进行mRNA定量。以GAPDH为对照,准确定量基因表达。
Westernblot(WB)分析方法:
采用qPCR定量后,从细胞和结肠组织中获得的蛋白质进行SDS-PAGE凝胶电泳,随后转移到硝化纤维素膜上。然后用5%牛血清白蛋白阻断这些膜。然后应用一抗,然后应用相应的酶标二抗。用ECL底物(BIO-RAD,1705061,Hercules,CA,USA)实现蛋白条带的可视化。
结果统计分析:
使用Graph Pad Prism Version 8(Graph Pad Software Company,USA)对数据进行分析和处理,采用单因素方差分析(ANOVA)和Duncan多极差检验。P<0.05为差异有统计学意义。
实验结果说明:
结果1:Picroside III对dss诱导小鼠结肠炎的保护作用。
本发明的Picroside III的结构如图1A所示。本发明实施例采用dss诱导小鼠产生结肠炎的模型结果如图1B和1C所示,与对照组相比,DSS结肠炎小鼠体重明显下降,并伴有严重的血便和腹泻临床症状,导致疾病活动指数(DAI)评分明显升高。此外,dss诱导的结肠炎导致结肠长度缩短,并伴有严重的结肠组织损伤,如炎症细胞浸润、病变形成、隐窝破坏等,组织学评分较高,而Picroside III显著改善结肠缩短和损伤(图1D和1E)。这些数据表明,Picroside III对dss诱导的小鼠结肠炎有明显的改善作用。
结果2:Picroside III能够提高dss诱导结肠炎小鼠结肠组织ZO-1、claudin-3和occludin的表达,降低claudin-2的表达。
本实施例为了评估Picroside III对肠上皮屏障的保护作用,采用实时荧光定量PCR(RT-qPCR)或/和westernblot检测紧密连接蛋白的表达水平。结果如图2所示,与对照组小鼠相比,结肠炎小鼠结肠组织中ZO-1、occludin、claudin-3mRNA表达量以及ZO-1、occludin蛋白表达量均显著降低,而claudin-2蛋白表达量显著升高。然而,这些紧密连接蛋白的变化可被Picroside III显著逆转。这些数据表明,Picroside III在体内可有效促进紧密连接的完整性。
结果3:Picroside III具有降低细胞单层通透性,促进TNF-α-处理的Caco-2细胞创面愈合的作用。
本实施例在确定了用于Caco-2细胞的Picroside III的安全浓度后(图3A),在TNF-α(肿瘤坏死因子-α)的刺激下进行细胞单层通透性测定。如图3B所示,TNF-α处理导致Caco-2细胞对fitc-葡聚糖(mw 4kda,FD4)透过率显著增加,而Picroside III处理显著降低了FD4透过率,且呈剂量依赖性。同时,在TNF-α-诱导的Caco-2细胞中进行划痕实验,研究Picroside III对细胞单层创面愈合的影响。如图3C所示,TNF-α处理显著降低Caco-2细胞单层创面闭合的百分比,而Picroside III处理后这种降低明显逆转。综上所述,这些数据表明Picroside III在体外有效促进伤口愈合和降低细胞单层通透性。
结果4:Picroside III在TNF-α-处理的Caco-2细胞中增加ZO-1和occludin的表达,降低claudin-2的表达。
本实施例为了研究Picroside III对紧密连接细胞完整性的影响,采用RT-qPCR或/和western blot检测紧密连接蛋白ZO-1、occludin和claudin-2的水平。结果如图4A和4B显示,TNF-α侵袭后,ZO-1mRNA水平以及ZO-1和occludin蛋白表达均显著下调,而Picroside III治疗可显著挽救这种下降。此外,TNF-α在mRNA和蛋白水平上急剧刺激了claudin-2的表达,而这种增加被Picroside III处理有效地抑制。这些数据表明,Picroside III可有效促进TNF-α-处理的Caco-2细胞紧密连接的完整性。
综上,Picroside III治能够降低细胞单层通透性、抑制claudin-2的表达,增加ZO-1和occludin的表达,进而促进结肠粘膜伤口愈合和上皮屏障功能恢复,改善炎症状态,因此具有治疗溃疡性结肠炎的功能。
在上述实施例中,对各个实施例的描述都各有侧重,某个实施例中没有详细描述的部分,可以参见其他实施例的相关描述。
以上所述,为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到各种等效的修改或替换,这些修改或替换都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以权利要求的保护范围为准。
Claims (8)
1.Picroside III在制备预防和/或治疗炎症性肠病药物中的应用,所述PicrosideIII的结构式如式(1)所示:
2.如权利要求1所述的应用,其特征在于,所述炎症性肠病为溃疡性结肠炎或克罗恩病。
3.如权利要求1所述的应用,其特征在于,所述炎症性肠病为溃疡性结肠炎。
4.如权利要求1所述的应用,其特征在于,所述炎症性肠病为克罗恩病。
5.如权利要求1-4任一项所述的应用,其特征在于,所述Picroside III可单独或与其他药物组合制备预防和/或治疗炎症性肠病的药物。
6.如权利要求1-4任一项所述的应用,其特征在于,所述Picroside III可与可用药物载体制成各种剂型。
7.如权利要求6所述的应用,其特征在于,所述剂型包括片剂、丸剂、糖锭剂、颗粒剂、凝胶剂、膏剂、溶液剂、栓剂、注射剂、粉剂、胶囊剂、悬浮剂、吸入剂以及喷雾剂。
8.一种预防和/或治疗炎症性肠病的药物,其特征在于,包括Picroside III,且以Picroside III作为唯一活性成份,所述炎症性肠病为溃疡性结肠炎或克罗恩病。
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