CN116392522A - 黄连木香水煎剂在制备防治结肠炎相关肠癌药物中的应用 - Google Patents
黄连木香水煎剂在制备防治结肠炎相关肠癌药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种黄连木香水煎剂(香连汤，XLD)在制备防治结肠炎相关肠癌药物中的应用，所述香连汤可减轻AOM/DSS诱导小鼠结肠炎症及结肠肿瘤的发生；可减轻小鼠结肠炎症表达水平；可减少小鼠结肠上皮细胞的增殖；可减轻肠粘膜屏障损伤；可调节AOM/DSS引起的肠道菌群紊乱；可改善AOM/DSS引起的粪便代谢紊乱。本发明通过动物实验发现黄连木香水煎剂能显著增加AOM/DSS诱导小鼠体重及结肠长度，降低肠道内肿瘤个数，减轻肠道内炎症反应，修复肠粘膜损伤。本发明对结肠炎相关肠癌的临床防治、提高患者的生存质量和减少炎症复发具有十分重要的意义，为结肠炎相关肠癌的防治提供了一种安全、有效和经济的新方法。
Description
技术领域
本发明涉及中医药抗肿瘤领域领域，具体涉及黄连木香水煎剂在制备防治结肠炎相关肠癌药物中的应用。
背景技术
结直肠癌(Coloretal cancer，CRC)的发生发展与肠道微环境的改变密切相关。肠道微生物菌群，作为肠道微环境的重要组成部分，在肠道稳态调控中起着重要作用，其可通过调控肠道粘膜屏障、机体免疫状态、相关代谢功能及肠道炎症反应发挥疗效。研究发现，CRC患者肠道菌群通过调控模型小鼠肠道内Th1和Th17细胞的组成比例，增加肠道内炎症因子水平的表达，从而起到促进肠道腺瘤的生长。此外，随着菌群分离及培养技术的发展，研究发现乳杆菌通过抑制核因子NF-κB信号通路和促炎因子IL-17的表达，上调抗炎因子IL-10，从而起到抗CRC的作用；Akk菌通过减少脾脏、结肠及肠系膜淋巴结中浸润的巨噬细胞和降低肠组织内CD8细胞毒性T淋巴细胞的水平，进而起到减轻肠粘膜炎症反应，抑制CRC进展。以上研究表明不同肠道菌属在CRC疾病进程中发挥着不同的作用。
香连丸本是治疗下痢的古代名方，为现今临床常用的中成药。通过文献的初步考证，“香连丸”始见于唐·李绛《兵部手集方》(亡佚)，为治疗大冷洞痢肠滑，下赤白如鱼脑，日夜无节度，腹痛不可堪忍者。宋代杨士瀛在《仁斋直指方》中始有“香连丸”一名，治下痢：宜黄连、青木香，同捣筛，白蜜丸，如梧子……婴孺用之亦效。至宋代《太平惠民和剂局方》卷六中载有大香连丸一方，云：“黄连去芦须二十两，用茱萸十两同炒赤，去茱萸不用，木香不见火四两八钱八分”。自宋以后多以黄连(吴茱萸制)与木香(4∶1)制成丸剂，治疗湿热痢疾。现行《中国药典》所载“香连丸”的处方及治法为黄连(吴茱萸制)800g，木香200g，以上二味，粉碎成细粉，过筛，混匀，每100g粉末用米醋8g加适量的水泛丸，干燥，即得。功能与主治为清热燥湿，行气止痛。用于湿热痢疾，里急后重，腹痛泄泻；菌痢，肠炎。综上所述，现在所用之香连丸实质上是源于《太平惠民和剂局方》之大香连丸。考究于医学史，《太平惠民和剂局》确实为成药的发展和推广作出了巨大的贡献，然而深受仲景之学的影响，其用药特色明显存在不辨病机滥用湿热方药的流弊。因此，黄连和木香药对实乃湿热内蕴之证的核心用药。
中医学认为，CRC究其病因病机不外乎正虚邪实，其主要病理因素为“湿、热、瘀、毒、虚”。多项临床研究表明湿热内蕴证是CRC患者常见的中医证候，湿热病机始终贯穿于CRC发生发展的各个阶段。目前，实验研究发现湿邪可导致小鼠肠道菌群的失调，表现为有益菌表达的减少及致病菌丰度的增加。此外，张青等认为CRC多因饮食不节，恣食肥甘厚味，导致脾胃功能失调，气机升降失常，运化能力减弱，从而导致湿邪留滞机体，久则湿毒凝聚于肠道而成。同时，实验数据表明高脂饮食(肥甘厚味)可通过改变肠道菌群，影响肠道免疫微环境，促进肠道内炎症反应等途径促进CRC进展。
中医作为CRC综合治疗体系的一个重要组成部分，具有较好的临床疗效。针对湿热内蕴证CRC患者，中医治疗强调遵循清热化湿。黄连、木香组方，古来即有香连丸一用，是清热化湿，行气止痛的代表方剂，常用于治疗肠炎、细菌性痢疾等疾病，能有效缓解因湿热留滞大肠所致里急后重、泄泻、便血、腹胀腹痛等症状。值得关注的是，在临床实践过程中，我们发现湿热内蕴证CRC患者易出现上述相关症状(便血腹痛、里急后重等)，因此运用黄连木香水煎剂治疗湿热内蕴证CRC患者是临床上行之有效的中医治疗方案。
有一种香连丸产物的新用途公开号为CN113730463A，新香连胶囊可按照如下方法制得：称取4份萸黄连、1份木香混合；样品粉碎；用5倍量30％～80％乙醇回流提取1～3次；合并提取液，回收溶剂，得到提取物浸膏，干燥，粉碎，装胶囊。具有抗幽门螺旋杆菌Hp的作用，其安全性比黄连和黄连提取物更高；还可以用于消化道肿瘤的治疗；此外，还具有预防包括动脉粥样硬化在内的心脑血管疾病的作用。但其未提及结肠炎相关肠癌的应用。
发明内容
本发明的目的在于提供黄连木香水煎剂在制备防治结肠炎相关肠癌药物中的应用，对结肠炎相关肠癌的临床防治、提高患者的生存质量和减少炎症复发具有十分重要的意义，为结肠炎相关肠癌的防治提供了一种安全、有效和经济的新方法。
为实现上述目的，本发明提供以下技术方案：
黄连木香水煎剂在制备防治结肠炎相关肠癌药物中的应用。
进一步的，所述黄连木香水煎剂由黄连和木香按重量比4∶1组成。
进一步的，所述黄连木香水煎剂抑制结肠炎症及结肠肿瘤的发生。
进一步的，所述黄连木香水煎剂抑制结肠组织内炎症因子的表达。
进一步的，所述黄连木香水煎剂抑制肠上皮细胞的增殖。
进一步的，所述黄连木香水煎剂抑制肠上皮细胞的凋亡活性。
进一步的，所述黄连木香水煎剂减轻结肠内肠粘膜损伤。
进一步的，所述黄连木香水煎剂通过调节调节炎症性肠病引起的肠道菌群及粪便代谢紊乱，进而抑制结肠炎相关肠癌的发生和发展。
发明提供的黄连木香水煎剂在制备防治结肠炎相关肠癌药物中的应用有益效果在于：
本发明通过动物实验发现黄连木香水煎剂能显著增加AOM/DSS诱导小鼠体重及结肠长度，降低肠道内肿瘤个数，减轻肠道内炎症反应，修复肠粘膜损伤，且未发现不良反应。其具体机制包括：香连汤通过调节肠道菌群(促进有AKK等益菌表达)及粪便代谢产物(胆汁酸及相关代谢产物)，上调肠屏障相关的蛋白(ZO-1等)、抑制细胞增殖、下调MPO及促炎因子的表达。本发明对结肠炎相关肠癌的临床防治、提高患者的生存质量和减少炎症复发具有十分重要的意义，为结肠炎相关肠癌的防治提供了一种安全、有效和经济的新方法。
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是本发明中实施例1中液相色谱质谱联用仪的检测结果；
A：黄连木香水煎剂相对含量排名前十的组成成份；
B：阳离子模式离子流图(Pattern of positive iron)和阴离子模式离子流图(Pattern of negative iron)；
图2是本发明中实施例2、3中实验组和对照组结肠肿瘤个数及长度对比图及PCNA蛋白表达对比结果；
A：实施例2中体重记录的结果(Body weight)；
B：实施例2中小鼠生存情况的记录结果；
C：实施例2中结肠长度(Length of colon)和肿瘤数量(number of tumor)的实验结果；
D：实施例2中病理评分结果；
E：实施例3中肠上皮增值(PCNA)及凋亡(Cleaved-caspase-3)相关蛋白的分析结果
图3是本发明中实施例3、4实验组和对照组肠道屏障指标，炎症因子的表达水平的结果，其中ns为p＞0.05，*p＜0.05(0.05水平的显著性)，**p＜0.01，***p＜0.001；
A：实施例3中肠屏障相关蛋白(ZO-1、Occludin)的检测结果；
B：实施例4中运用ELISA检测得到的肠组织炎症因子水平的结果，分别包括干扰素-γ(IFN)、白介素-17(IL-17)、白介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)；
C：实施例4中运用免疫组化检测肠组织髓过氧化物(MPO)水平表达结果；
图4是本发明中实施例5中利用粪便样本对肠道菌群进行检测的结果；
A：菌群的α-多样性结果，Observed-otus、Chao-1、Simpson和Shannon指标均体现了各组小鼠的丰富度水平；
B：β-多样性结果，体现了两组小鼠菌群的相似度；
C：两组小鼠在门水平上的菌群差异；
D：两组小鼠在种水平上的菌群差异；
图5是本发明中实施例5中小鼠门水平和种水平菌群动态变化图；
图6是本发明中实施例6中实验组和对照组小鼠粪便代谢物质的对比结果；
A：利用火山图对两组上调和下调的代谢物进行了呈现，并呈现了排名前10的相关通路；
B：利用KEGG对相关通路进行了呈现；
C：展现了每组中的5只小鼠其代谢产物的相对含量(排名前11)，并具体展现了4中胆汁酸的相对含量，包括胆汁酸(cholic acid)、木里胆酸(muricholic acid)、牛磺酸脱氧胆酸(taurochenodeoxycholic acid)以及脱氧胆酸(deoxycholic acid)；
图7是本发明中实施例7中伪无菌小鼠的造模以及AOM/DSS造模的实验流程；
A：结肠长度(Colon Length)和肿瘤个数(Number of tumor)的结果；
B：小鼠体重的记录结果；
C：HE染色后得到的病理评分结果；
D：运用免疫组化对PCNA表达情况进行分析的结果；
E：增值(PCNA)、凋亡(Cleaved-caspase-3)及肠屏障(Occludin)相关蛋白水平的表达情况。
具体实施方式
下面结合附图和实施例对发明的技术方案做进一步的说明，以下实施例仅用于更加清楚地说明本发明的技术方案，因此只作为示例，而不能以此来限制本发明的保护范围。
实施例1
通过液相色谱质谱联用仪对药物有效成分进行鉴定，Q-TOF SYNAPT G2-Si高清晰度质谱仪(Waters，UK)采用电喷雾电离(ESI)作为电离源。采用Waters ACQUITY UPLCCortecs T3色谱柱(2.1 100mm；1.7m)和Cortecs T3 Van Guard(2.150mm，1.7μm)分离。在ESI-MS分析中，毛细管电压设定为3.0kV。MSE连续模态在mz 50-1500范围内进行。每个样品注入2L到柱中，用梯度洗脱。色谱柱和自动进样器温度分别保持在35℃和25℃。最后通过在数据库中进行对比分析，得到相应的成分。
实施例2
高脂饮食作为结直肠癌发生发展的高危因素之一，能够促进结直肠癌的进展。氧化偶氮甲烷(azoxymethane，AOM)/葡聚糖硫酸钠(dextran sodium sulfate，DSS)小鼠模型(高脂饲喂)是一种在致癌剂AOM和致炎剂DSS协同作用基础上，由炎症性肠病(inflammatory bowel disease，IBD)逐步发展为肠癌的炎症相关性癌症的研究模型。
动物饲养方法如下：
动物适应性饲养一周时即予以高脂饮食饲喂。
AOM溶于生理盐水：于实验正式开始第一周，根据每只小鼠的体重10mg/kg腹膜内注射；
DSS溶于饮用水至浓度2％：10g DSS+500ml过滤过的高压灭菌水；
黄连木香水煎剂(黄连4g，木香1g)：758mg/kg灌胃。
Balb/c 6week male小鼠(由浙江中医药大学动物研究中心代购)
2％DSS×7天，共给3个循环
黄连木香水煎剂每周7天×10周
实验期间每周对小鼠的体重进行记录，高脂饮食+AOM/DSS组(Model)和香连汤组(XLD)小鼠均于10周进行取材，取出所有肠管，用生理盐水冲洗后，滤纸吸干，测量结肠长度，观察并记录结肠肿瘤的形成情况。
各组取相同部位的结肠组织标本用多聚甲醛进行固定，用于制作石蜡切片，并对切片进行HE染色，以得到组织病理评分。
实验结果显示：相较于香连汤干预组(XLD)，高脂饮食+AOM/DSS组小鼠(Model)体重明显下降、结肠长度明显缩短(*p<；0.05，即0.05水平的显著性)，香连汤干预组肿瘤数有所减少、病理评分较低(**p<；0.01，即0.01水平的显著性)。
实施例3
各组取相同部位的结肠组织标本提取蛋白，测定浓度后依次进行变性、电泳、湿法转膜，用脱脂牛奶封闭，随后滴加一抗4℃过夜，二抗室温孵育1小时，通过化学发光、显影及定影获得蛋白条带，利用Image J软件对蛋白条带的灰度进行分析。实验结果显示：实验结果显示：相较于香连汤干预组(XLD)，高脂饮食+AOM/DSS组小鼠(Model)体重明显下降、结肠长度明显缩短(*p<；0.05)，香连汤干预组肿瘤数有所减少、病理评分较低(**p<；0.01)。进一步地，黄连木香水煎剂可以明显抑制高脂及AOM/DSS诱导的肠上皮细胞的增值及凋亡活性，具体表现为PCNA和Cleaved-caspase-3蛋白水平的下调(相较于模型组)。并且，香连汤可以有效保护肠屏障完整性，表现为上调ZO-1和Occludin的蛋白水平。
实施例4
炎症因子的ELISA检测具体步骤如下：组织标本经研磨，3000-4000rpm，离心10min，留取上清，经BCA蛋白定量后，具体操作按照试剂盒说明书进行。MPO免疫组化检测采用SABC法，其实验步骤包括：(1)脱蜡；(2)封闭；(3)抗原修复；(4)血清封闭；(5)滴加一抗；(6)滴加二抗；(7)滴加SABC；(8)显色；(9)复染；(10)盐酸酒精分化；(11)脱水与透明；(12)封片：中性树胶封片，置于通风柜中晾干后显微镜拍照，并计数阳性细胞后续统计分析。主要抗体及来源：MPO(Wuhan Servicebio Technology，China)。酶联免疫结果显示：香连汤干预能显著下调IFN-γ、IL-17、IL-1b。免疫组化结果显示：香连汤(XLD group)干预后，MPO染色强度明显低于模型组(Model group)。
实施例5
小鼠粪便16S rDNA测序，上游引物为5′-CCTACGGGNGGCWGCAG-3′，下游引物为5′-GACTACHVGGGTATCTAATCC-3′，上游引物341f的碱基序列如SEQ ID NO.1所示，下游引物805R的碱基序列如SEQ ID NO.2所示。
使用上述引物对16S V3-V4区进行序列片段的扩增，PCR产物经2％琼脂糖凝胶电泳确证。在整个DNA提取过程中，使用的是超纯水，而不是样品溶液，以排除假阳性PCR结果作为阴性对照的可能性，PCR产物由AMPure XT beads(Beckman Coulter Genomics，Danvers，MA，USA)纯化，Qubit(Invitrogen，USA)定量。扩增子池用于测序，扩增子文库的大小和数量分别在Agilent 2100生物分析仪(Agilent，美国)和Illumina(KapaBiosciences，Woburn，MA，美国)的文库 定量试剂盒上进行评估。在NovaSeq PE250平台上对库进行排序。最后在Illumina NovaSeq平台上按照制造商的建议进行测序。
实施例6
粪便非靶向代谢组学分析
代谢物的提取需要根据实际的项目和样本(固体液体)选择性描述及调整，常规非靶向代谢组学(LC-MS/MS)，主要提取代谢的物方法，加入甲醇沉淀蛋白，静置过夜，离心80℃保存，准备上机。
一、液相部分
数据采集所用到的液相体系为SCIEX，UK公司的超高压液相。所用的色谱分析柱型号规格为ACQUITY UPLC T3(100mm*2.1mm，1.8μm，Waters，UK)。采集时，柱温设置为35度，流速为0.4ml/ml。采用的流动相为A相：水(1％甲酸)；B相：乙腈(1％甲酸)。液相梯度设置为：
时间 流动相成分
0～0.5min 5％B
0.5～7min5％～100％B
7～8min 100％B
8～8.1min 100％～5％B
8.1～10min 5％B
三、质谱部分
采集所用的高分辨率质谱仪为TripleTOF5600plus(SCIEX，UK)飞行时间质谱。每个样本进行一次正离子模式采集和一次负离子模式采集。离子源的遮蔽气压为30PSI(磅每平方英寸)，气体1(辅气)和气体2(鞘气)压力均设置为60PSI。源温度650度。正离子模式时电压为正5000伏，负离子模式时为-4500伏。采集数据的模式为IDA(信息依赖性采集)模式。
在一个采集循环中，一级采集范围为60-1200道尔顿，一级采集时间为150ms，然后从一级图谱中挑选带一个正电荷(负离子模式下为带一个负电荷)并且每秒信号积累强度超过100的前12个信号离子进行二级碎裂扫描。整个采集循环耗时0.56秒。
该质谱仪检测器有4个通道，脉冲射频电的频率为11kHz；检测器的检测频率为40GHz；每次扫描的粒子信号以四个通道分别记录共四次后合并转化成数据。扫描的动态排除时间设置为4秒。
在采集过程中，每间隔20个样本进行一次仪器准确度校正。同时，每间隔10个样本进行一次QC品的扫描。用QC间的质量差距来校正整批实验的系统误差。
实施例7
抗生素验证动物饲养方法如下：
动物适应性饲养一周时即予以高脂饮食饲喂。经适应性饲养，予四联抗生素饮水两周得到伪无菌处理，起后每隔两周予抗生素饮水干预。
AOM溶于生理盐水：于实验正式开始第三周，根据每只小鼠的体重10mg/kg腹膜内注射；
DSS溶于饮用水至浓度2％：10g DSS+500ml过滤过的高压灭菌水；
黄连木香水煎剂：758mg/kg灌胃。
Balb/e 6week male小鼠(由浙江中医药大学动物研究中心代购)
2％DSS×7天，共给3个循环
黄连木香水煎剂每周7天×10周
伪无菌组(Abx)和香连汤组(Abx+XLD)小鼠均于10周进行取材，取出所有肠管，用生理盐水冲洗后，滤纸吸干，测量结肠长度，观察并记录结肠肿瘤的形成情况。各组取相同部位的结肠组织标本用多聚甲醛进行固定，用于制作石蜡切片，并对切片进行HE染色，以得到组织病理评分。
各组取相同部位的结肠组织标本提取蛋白，测定浓度后依次进行变性、电泳、湿法转膜，用脱脂牛奶封闭，随后滴加一抗4℃过夜，二抗室温孵育1小时，通过化学发光、显影及定影获得蛋白条带，利用Image J软件对蛋白条带的灰度进行分析。运用免疫组化(具体方法参见实施例4)对肠组织PCNA表达情况进行检测。实验结果显示：实验结果显示：两组在体重变化、肿瘤个数、组织病理评分方面均无显著差异，但香连汤能够缓解抗生素引起的结肠缩短。进一步地，蛋白印迹结果显示，伪无菌组和香连汤组在上皮增值和肠屏障方面无显著差异，具体体现在Occludin、PCNA和Cleaved-caspase-3水平的无差异。
以上实验可知，黄连木香水煎剂能够通过调节肠道菌群及其代谢产物保护肠上皮的完整性、抑制局部炎症因子产生以及肠上皮的增值及凋亡活性，进一步抑制结肠癌的发生发展。
以上所述的具体实施例，对本发明解决的技术问题、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本发明的具体实施例而已，并不用于限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (8)
1.黄连木香水煎剂在制备防治结肠炎相关肠癌药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述黄连木香水煎剂由黄连和木香按重量比4∶1组成。
3.根据权利要求1所述的应用，其特征在于，所述黄连木香水煎剂抑制结肠炎症及结肠肿瘤的发生。
4.根据权利要求1所述的应用，其特征在于，所述黄连木香水煎剂抑制结肠组织内炎症因子的表达。
5.根据权利要求1所述的应用，其特征在于，所述黄连木香水煎剂抑制肠上皮细胞的增殖。
6.根据权利要求1所述的应用，其特征在于，所述黄连木香水煎剂抑制肠上皮细胞的凋亡活性。
7.根据权利要求1所述的应用，其特征在于，所述黄连木香水煎剂减轻结肠内肠粘膜损伤。
8.根据权利要求1所述的应用，其特征在于，所述黄连木香水煎剂通过调节炎症性肠病引起的肠道菌群及粪便代谢紊乱，进而抑制结肠炎相关肠癌的发生和发展。
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| CN115154505A (zh) * | 2022-07-20 | 2022-10-11 | 上海市中西医结合医院 | 香连丸在制备用于免疫治疗泛癌患者减毒增效的药物中的应用 |
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| CN113730463A (zh) * | 2020-05-28 | 2021-12-03 | 重庆伊士腾生物科技有限公司 | 香连丸产物的新用途 |
| CN115154505A (zh) * | 2022-07-20 | 2022-10-11 | 上海市中西医结合医院 | 香连丸在制备用于免疫治疗泛癌患者减毒增效的药物中的应用 |
Non-Patent Citations (1)
| Title |
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| 汤新民: "中药治疗消化道癌存活6年以上三例", 上海中医药杂志, no. 07, 15 July 1992 (1992-07-15), pages 35 * |
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