药学学报

基于中药超分子探究不同混合顺序对黄连解毒汤的物质形态及抗菌活性的影响

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谭心如 , 皮雯敏 , 赵一航 , 张景怡 , 汪志霞 , 徐冉 , 张留洋 , 黄雪梅 ^* , 王鹏龙 ^*

药学学报 | 研究论文 2025,60(6): 1948-1954

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药学学报 |研究论文 2025 , 60 (6) : 1948 -1954

基于中药超分子探究不同混合顺序对黄连解毒汤的物质形态及抗菌活性的影响

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谭心如, 皮雯敏, 赵一航, 张景怡, 汪志霞, 徐冉, 张留洋, 黄雪梅^*, 王鹏龙^*

作者信息

北京中医药大学中药学院, 北京 102488

通讯作者:

黄雪梅, E-mail: hxm3928@163.com

王鹏龙, E-mail: wpl581@126.com

作者简介:

作者贡献:

谭心如完成实验内容及论文撰写工作; 皮雯敏、赵一航、张景怡完成部分实验内容; 汪志霞、徐冉、张留洋辅助论文修改; 黄雪梅设计方案并指导论文撰写与修改; 王鹏龙设计方案、提供研究经费并指导论文的撰写和修改。

Effects of different mixing order on substance form and antibacterial activity of Huanglian Jiedu Decoction based on supramolecular Chinese medicine

Xin-ru TAN, Wen-min PI, Yi-hang ZHAO, Jing-yi ZHANG, Zhi-xia WANG, Ran XU, Liu-yang ZHANG, Xue-mei HUANG^*, Peng-long WANG^*

Affiliations

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China

出版时间: 2025-06-12 doi: 10.16438/j.0513-4870.2024-1065

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摘要

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中药超分子是中药复方的重要物质形态和显效形式, 超分子的形态与活性受多种因素影响, 混合顺序是其中关键要素之一。本研究采用动态光散射法、扫描电子显微镜、浊度仪及丁达尔效应等方法观察三组不同的混合顺序: 黄连组+栀子+黄芩(CGS)、黄连组+黄芩+栀子(CSG) 以及黄芩+栀子+黄连组(SGC) 汤剂之间的微观形态和物理性质差异, 利用高效液相色谱法分析其主要成分组成, 通过体外金黄色葡萄球菌(S. aureus) 模型对三组汤剂的抗菌活性进行初步对比, 并通过分子动力学模拟技术初步探讨三组汤剂中超分子的动态形成过程。研究表明, 不同混合顺序导致黄连解毒汤超分子部位形貌特征发生变化, 其宏观现象、电镜、粒径、电位、浊度等都伴随出现明显差异, 并显著影响其原有抗菌活性。此外, 分子动力学模拟结果也表明黄连解毒汤主要药效成分的不同混合顺序明显影响其自组装行为。本研究是对黄连解毒汤超分子物质基础形成的影响因素的进一步探索, 也为黄连解毒汤配方颗粒的临床合理服用提供了一定参考。

关键词

黄连解毒汤 / 中药超分子 / 混合顺序 / 物质形态 / 抗菌活性

Abstract

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Chinese medicine supramolecular is an important material form and effective form of Chinese medicine compound. The form and activity of supramolecular are affected by many factors, and the mixing order is one of the key factors. In this study, dynamic light scattering (DLS), scanning electron microscopy (SEM), turbidimeter and Tyndall effect were used to observe the differences of micromorphology and physical properties of three different groups of Coptidis Rhizoma group + Gardeniae Fructus + Scutellariae Radix (CGS), Coptidis Rhizoma group + Scutellariae Radix + Gardeniae Fructus (CSG) and Scutellariae Radix + Gardeniae Fructus + Coptidis Rhizoma group (SGC). The main components of the three groups of decoction were analyzed by high performance liquid chromatography (HPLC). The antibacterial activity of the three groups of decoction was preliminarily compared by in vitro Staphylococcus model, and the dynamic formation process of supramolecules in the three groups of decoction was preliminarily discussed by molecular dynamics simulation (MDS) technology. The results showed that different mixing sequences led to changes in the morphology of supramolecular parts of Huanglian Jiedu Decoction, with significant differences in macroscopic phenomena, electron microscopy, particle size, potential and turbidity, and significantly affected the original antibacterial activity. In addition, the results of molecular dynamics simulation also show that the different mixing order of the main components of Huanglian Jiedu Decoction will significantly affect its self-assembly behavior. This study is to further explore the factors affecting the formation of supramolecular substance basis of Huanglian Jiedu Decoction, also provides a reference for the clinical rational administration of Huanglian Jiedu Decoction formula granules.

Key words

Huanglian Jiedu Decoction / Chinese medicine supramolecule / mixing order / physical form / antibacterial activity

引用本文

谭心如, 皮雯敏, 赵一航, 张景怡, 汪志霞, 徐冉, 张留洋, 黄雪梅, 王鹏龙. 基于中药超分子探究不同混合顺序对黄连解毒汤的物质形态及抗菌活性的影响. 药学学报, 2025 , 60 (6) : 1948 -1954 . DOI: 10.16438/j.0513-4870.2024-1065

Xin-ru TAN, Wen-min PI, Yi-hang ZHAO, Jing-yi ZHANG, Zhi-xia WANG, Ran XU, Liu-yang ZHANG, Xue-mei HUANG, Peng-long WANG. Effects of different mixing order on substance form and antibacterial activity of Huanglian Jiedu Decoction based on supramolecular Chinese medicine[J]. Acta Pharmaceutica Sinica, 2025 , 60 (6) : 1948 -1954 . DOI: 10.16438/j.0513-4870.2024-1065

正文

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黄连解毒汤由三黄(黄连、黄芩、黄柏) 及栀子组成, 首见《肘后备急方》, 后《外台秘药》中也有记载, 是中医临床广为使用的清热解毒代表性方剂, 现代药理研究表明其具有抗菌消炎、降糖、降血压、抗肿瘤、降脂、调节肠道菌群等药理作用^[1-4]。现有研究表明, 黄连解毒汤煎煮后汤液呈现明显浑浊现象^[5], 并且以黄芩苷(baicalin, BA)、小檗碱(berberine, BBR) 为代表的主要成分会在浑浊部位中富集^[6], 而这种复杂多相态间成分含量分布不均的现象, 主要是因为其药效成分之间发生了相互作用后形成超分子态。不仅在黄连解毒汤中, 许多中药汤剂中的药效成分之间都可以通过氢键、静电作用等弱相互作用自组装形成形态不同的超分子, 且其生物活性也会有别于中药药效成分的简单叠加。例如麻杏石甘汤中存在的类球形纳米颗粒, 具有与全方相同的解热宣肺功效^[7]; 再如, 在麻黄附子汤中发现了大量的纳米球, 其抗炎活性强于麻黄附子汤原方^[8]。黄连解毒汤中“君-臣”药对黄芩-黄连配伍用药时也会产生中药超分子, 且超分子的形成受多种因素调控, 课题组前期研究表明, 不同的煎煮方式(单煎后混合和共煎) 会形成不同形貌的超分子, 进而产生抗菌活性的差异^[9]。

由此可见, 即使同一中药复方, 其汤液药理活性与形成中药超分子及其形貌变化等密不可分。因此, 为了进一步深入探究中药超分子形成的影响因素, 本研究以不同顺序混合黄连解毒汤中各味药的单煎液, 探讨不同顺序组的汤剂体系宏观浑浊现象和微观形貌差异以及对常见致病菌金黄色葡萄球菌的抗菌活性影响, 最后利用分子动力学模拟技术对超分子的形成过程进行分析, 对组装机制及活性差异内在原理进行探讨。本研究主要聚焦于黄连解毒汤中超分子形成的动态过程及活性差异, 以期为临床合理用药提供参考。

材料与方法

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仪器 BSA224S-CW型十万分之一电子天平(德国Sartorius公司); KDM型电热套(北京博凝生物科技有限公司); Zetasizer Nano ZS 90型马尔文粒度仪(英国Malvern仪器有限公司); ZEISS SUPRA55型场发射扫描电子显微镜(德国ZEISS公司); Beta 2-8 LDplus型真空冷冻干燥机(德国Christ公司); YKM-FZD型浊度仪(上海佑科仪器仪表有限公司); 1260 Infinity Ⅱ型高效液相色谱仪(美国Agilent科技有限公司); YXQ-LS-75SII型高压蒸汽灭菌锅(上海博讯实业有限公司); LRH-250型恒温生化培养箱(广州瑞明仪器有限公司); Multiskan GO型多功能酶标仪(芬兰热电科技仪器有限公司)。

药品与试剂 黄芩、黄连、黄柏和栀子均购自北京同仁堂(批号: 18092105、18121402、18052601、17121801), 经北京中医药大学任广喜副教授鉴定为唇形科植物黄芩(Scutellaria baicalensis Georgi) 的干燥根、毛茛科植物黄连(Coptis chinensis Franch.) 的干燥根茎、芸香科植物黄皮树(Phellodendron chinense Schneid.) 的干燥树皮及茜草科植物栀子(Gardenia jasminoides Ellis) 的干燥成熟果实; 盐酸小檗碱(批号O04HS196746) 和黄芩苷(批号A25HS192344) 均购自上海源叶生物科技有限公司; 京尼平苷(geniposide, GPS, 批号NP15-1) 购自上海笛柏生物科技有限公司; 甲醇(色谱级, 批号F24O9N213) 购自美国Fisher公司; 磷酸(色谱级, 批号20240430) 购自天津市大茂化学试剂厂。

样品制备

黄连与黄柏主要药效物质基础均为以小檗碱为代表的苄基异喹啉类生物碱^[10-13], 在本研究中将其二者近似为同组, 后统称为黄连组, 以在能够得到实验结果的同时简化实验对象。

单煎液的制备分别称量黄连(Coptidis Rhizoma)、黄芩(Scutellariae Radix)、黄柏(Phellodendri Chinensis Cortex) 以及栀子(Gardeniae Fructus) 各10 g装入无纺布煎药袋后以10倍量去离子水浸泡20 min后回流提取30 min, 趁热过滤, 按3∶2的比例合并黄连与黄柏水煎液, 分别得到黄连组(Coptidis Rhizoma and Phellodendri Chinensis Cortex, C)、黄芩(Scutellariae Radix, S)、栀子(Gardeniae Fructus, G) 水煎液。

机械混合液的制备将黄连组、黄芩、栀子三类水煎液冷却到室温后, 按5∶2∶3的配比以不同顺序进行机械混合, 得到三个组别: 黄连组+栀子+黄芩(CGS)、黄连组+黄芩+栀子(CSG)、黄芩+栀子+黄连组(SGC)。

形貌表征

宏观现象表征将CGS、CSG、SGC三组机械混合汤剂静置24 h后, 观察现象。

浊度测定以去离子水为空白溶剂, 取CGS、CSG、SGC三组机械混合液稀释相同倍数后取3 mL在浊度仪上测定样品的浊度值, 每组重复3次。

粒径测定取各组机械混合液1.5 mL于比色皿中, 马尔文粒度仪测量CGS、CSG、SGC三组机械混合液的粒径大小和分散性系数(polymer dispersity index, PDI), 温度为25 ℃, 每组平行3次。

电位测定取各组机械混合液各0.8 mL, 放入电位测定池, 测定各组电位值, 每组平行3次。

微观形貌表征取各组机械混合液, 用去离子水稀释, 分别取2.5 μL滴于干净的硅片上, 待水分自然挥干后, 于样品表面喷金, 置扫描电子显微镜(scanning electron microscope, SEM) 下观察其微观形貌。

高效液相色谱法测定(HPLC) 采用HPLC对CGS、CSG、SGC三组机械混合液的主要成分进行定性分析。

供试品溶液的制备分别称取CGS、CSG、SGC三组机械混合汤剂的冻干粉2 mg, 用去离子水将其浓度配置为2 mg·mL^-1, 置于水浴锅中加热溶解, 再以甲醇对倍稀释成1 mg·mL^-1, 经0.22 μm微孔滤膜过滤, 得到供试品溶液。

对照品溶液的制备精密称取BA、BBR、GPS用色谱级甲醇溶解制成三者浓度均为0.20 mg·mL^-1的混标溶液, 经0.22 μm微孔滤膜过滤, 得到对照品溶液。

色谱条件色谱柱: LP-C18 (4.6 mm × 100 mm, 2.5 µm); 流动相: 0.1%磷酸-水(A) 和甲醇(B); 流速: 1 mL·min^-1; 检测波长: 238 nm; 进样量: 5 μL。梯度洗脱: 0~30 min, 20%~30% B; 30~80 min, 30%~40% B。

体外活性表征 采用营养肉汤稀释法表征CGS、CSG、SGC的体外抗菌活性。以抗菌活性最强的黄连为定量标准, 配置如下浓度梯度: 6、3、1.5、0.75、0.375 mg·mL^-1的含药营养肉汤, 然后每孔加入30 µL菌悬液(2×10⁷ CFU·mL^-1), 混合均匀后使其在恒温生化培养箱中自由生长12 h后使用酶标仪在600 nm测量吸光度值(A₆₀₀), 根据公式(1) 计算抑菌率。

$ \mathrm{抑}\mathrm{制}\mathrm{率}\left(\mathrm{\%}\right)\mathrm{ }=1-\frac{({A}_{\mathrm{样}\mathrm{品}}-{A}_{\mathrm{溶}\mathrm{剂}})}{({A}_{\mathrm{空}\mathrm{白}\mathrm{菌}}-{A}_{\mathrm{溶}\mathrm{剂}})} $

(1)

式1中, A_样品为给药之后的含菌营养肉汤在600 nm处的吸光度值; A_溶剂为营养肉汤在600 nm处的吸光度值; A_空白菌为细菌在营养肉汤中正常生长情况下在600 nm处的吸光度值。

收集上述48孔板中3 mg·mL^-1给药浓度下的细菌溶液并将其稀释1×10⁵倍, 最后取50 µL稀释液于营养琼脂板上, 用涂布棒迅速涂布均匀, 在37 ℃恒温生化培养箱中培养16 h后, 观察营养琼脂上的菌落情况。

分子动力学模拟 本文计算依靠分子动力学软件Gromacs 2020.6^[14]进行计算, 计算内容主要包括共轭梯度法进行能量最小化、NPT (粒子数: Number; 压力: Pressure; 温度: Temperature) 系综下共200 ps的退火平衡(0~100 ps, 0~298.15 K) 及298.15 K下50 ns的动力学模拟, 共进行两次, 总计100 ns。全程模拟采用tip3p水模型以模仿水溶剂条件。分子的力场参数基于GAFF^[15]力场, 有机分子拓扑文件获取及原子电荷的指认依靠Sobtop^[16]。

构建边长为5 nm的立方盒子, 将BA、BBR和GPS各20个, 以不同的加入顺序设定不同组别, 分别为以下三组: BA+BBR+GPS (BA与BBR先进行50 ns的动力学模拟后, 以最后一帧的稳定构象为初始模型, 继续加入GPS, 再进行50 ns的动力学模拟平衡, 共100 ns, 后同)、BA+GPS+BBR (BA与GPS先结合, 再加入BBR)、BBR+GPS+BA (BBR与GPS先结合, 再加入BA)。最后通过VMD将动力学过程进行可视化分析, 并抽取动力学轨迹。

统计学分析 应用软件IBM SPSS Statistics 20, 进行数据统计学分析, 测量值以平均±标准差(x ± s) 表示, P < 0.05具有统计学意义。

结果

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1　CGS、CSG、SGC三组机械混合液形貌学表征

静置24 h后, CSG组呈现出明显的分层现象, 与其他两组(CGS组、SGC组) 的混悬现象不同(图1A)。经浊度仪测定(图1B): CSG组机械混合液的浊度值最小, 为86.33 ± 2.00 NTU, CGS组别的浊度值较大, 为120.48 ± 1.48 NTU, SGC组的浊度值最大, 为138.77 ± 0.95 NTU。三个组别丁达尔效应明显, 进一步利用马尔文粒度仪对CGS、CSG、SGC三组的粒径大小和电位值进行对比分析(图1C), CSG组的粒径较大, 为758.6 ± 28.38 nm, 粒径分布图呈双峰状, CGS组与SGC组的粒径较小, 分别为335.7 ± 5.50和263.9 ± 22.61 nm, 粒径分布图均呈现单峰。PDI值可以评判体系中粒子分布的均匀程度, PDI越小, 粒径分布越均匀, 在本研究中CSG组的PDI为0.7 ± 0.050, 而CGS组与SGC组的PDI都分布在0.4左右, 表明CGS组与SGC组的粒径分布更均匀, 不仅如此, zeta电位结果显示(图1D): CGS的电位值为-17.5 ± 0.26 mV, CSG电位值为-14.1 ± 0.45 mV, SGC的电位值为-14.4 ± 0.21 mV, 其中CGS组的电位绝对值最大, 该结果表明CGS组汤剂体系最稳定。为了进一步观测混合顺序对超分子物质形态造成的影响, 利用扫描电子显微镜对三组汤剂微观形貌进行观察, 图像显示(图1E), CGS组在镜下展现出类球状结构; CSG组在镜下呈现细碎且密集聚集的大颗粒状形态; SGC组则呈现出不规则的块状结构。上述实验结果提示, CSG组颗粒粒径大、分布不均匀, 故而易于下沉而聚集在底部, 导致其宏观呈现明显的上下分层现象; 相反, CGS组与CSG组的粒径小, PDI值较小, 且浊度值较高, 表明其超分子更倾向于混悬状态并且分布更加均匀, 因此表现为混悬不分层的状态; 此外, CGS组的电位绝对值最大, 表明该胶体溶液的分散性与稳定性更大以及其抗聚集能力更好, 更进一步地解释了CGS组不分层的原因。综上表明, 不同混合顺序会显著影响汤液宏观相态、物理性质等。

2　CGS、CSG、SGC三组机械混合液中的主要成分分析

为了探究黄连解毒汤不同混合顺序所导致的汤剂相态、物质形态、物理性质差异背后的化学成分组成变化趋势, 结合既往对黄连解毒汤主要成分的相关研究^[17-20], 通过高效液相色谱法, 对三组样品的主要成分组成进行分析。结果表明黄连解毒汤中主要三大类代表性成分为BA (t_R = 71.1 min)、BBR (t_R = 45.8 min) 和GPS (t_R = 16.8 min), 且不同混合顺序化学成分组成和比例关系基本一致(图2), 表明不同组装顺序并不会显著影响汤剂原有化学组成, 其造成差异的根本原因是不同混合顺序对组装行为带来的深层次影响。

3　CGS、CSG、SGC三组机械混合液的体外抑菌活性表征

金黄色葡萄球菌作为革兰阳性菌的代表, 是一种常见的食源性致病微生物。前期有诸多实验表明黄连解毒汤及主要成分对金黄色葡萄球菌有较强的抑制作用^{[21, 22]}。本研究通过比浊法、平板涂布法探究CGS、CSG、SGC三组汤剂在出现相态差异后其是否对金黄色葡萄球菌的体外抗菌活性造成影响。

首先, 利用比浊法测定CGS、CSG、SGC三组汤剂对金黄色葡萄球菌的抑菌活性(图3), 三组汤剂在6~0.375 mg·mL^-1时抑菌活性与浓度呈相关性, 在6 mg·mL^-1的高浓度下, 三组汤剂对金葡菌的抑制作用均较大, 抑菌率均达到90%以上且差异不明显; 但在3、1.5、0.75、0.375 mg·mL^-1时, 三组样品对细菌的抑制能力具有明显的差异, 抑菌效果为: CGS组 > CSG组 > SGC组(图3)。

进一步, 采用平板涂布法对上述实验结果进行了验证(图4)。将金黄色葡萄球菌和各样品共孵育后的菌悬液接种于平板上, 在样品浓度为3 mg·mL^-1时, CGS组有少量菌生长, 而SGC组能观察到大量明显的菌落, CSG组生长的菌落数量介于上述两组之间。进一步确证三组样品对细菌的抑制作用强弱为: CGS组 > CSG组 > SGC组, 这与比浊法的实验结果相一致。

4　分子动力学模拟

为了深层次探讨不同顺序混合后超分子组装行为及抗菌活性改变的内在机制, 基于既往对黄连解毒汤主要化学成分的研究和上述高效液相色谱的检测结果, 通过分子动力学(MD) 模拟进一步探讨宏观相态变化的内在分子机制, 对三个组别的超分子形成路径进行了初步的机制探究。本文将黄连水煎液与黄柏水煎液中的主要成分BBR与黄芩水煎液的主要成分BA、栀子水煎液中的主要成分GPS按照不同的顺序组合, 得到BBR+GPS+BA、BBR+BA+GPS、BA+GPS+BBR三组动态自组装视图, 分别代表了CGS、CSG、SGC组。并进一步分析了黄芩苷、小檗碱、京尼平苷因不同的加入顺序而导致的不同自组装过程和不同的组装结果。

BBR+GPS在0 ns时, 分子分布随机, 未有组装趋势(图5A1), 经过50 ns后, BBR+GPS两者通过弱相互作用形成二元聚集体(图5A2), 在此基础上加入BA (图5A3), 50 ns后, BA以插入的形式与上述二元聚集体相结合, 三者相互嵌入、交叉形成一种排布均匀的三元超分子(图5A4)。而BBR与BA先混合会因较强的相互作用力而发生了紧密的结合, 形成类似条带状的二元超分子(图5B2), 在此基础上加入GPS后, GPS与BBR+BA的二元超分子发生了聚集, 主要表现为黏附在二元组装体表面, 对原有超分子体系无明显破坏作用(图5B4)。此外, BA与GPS先混合后, 两者形成一定团簇, 且在此基础上, 再加入BBR, 大部分BBR呈现自我聚集状附着在BA+GPS的二元结合物的表面(图5C4)。

以上结果表明, 在多分子体系中, 成分间的不同混合顺序会影响分子之间的排列方式、结合强度等组装行为, 从而展现出不同形态的超分子结构。分子间可能会发生竞争性相互作用, 即争夺有限的相互作用位点。例如, 将BBR与BA先混合时, BA优先占据某些特定的结合位点, 致使GPS加入后, 只能在BBR+BA的二元超分子表面黏附, 故而呈现出上述结构。本研究发现混合顺序将影响分子组装行为, 其作用位点的相对占据及竞争可能是其组装行为差异的原因所在。

讨论

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单煎液混合顺序的不同对黄连解毒汤的相态、微观形貌、药理活性均具有影响。曾有研究表明, 与纤维状结构相比, 球状的纳米颗粒可以均匀地聚集在细菌周围, 将细菌紧紧包裹, 进而明显提高药效^[23]。CGS组抗菌活性最佳, 提示正是由于该组浊度较大、粒径较小, 微观下呈类球形纳米颗粒, 使其易均匀稳定悬浮于汤剂中, 尺寸较小的类球形纳米颗粒更容易发挥抗菌活性; 在此基础上, CGS组中BBR+GPS+BA的分子动力学模拟结果呈现排布均匀且有序的三元超分子结构, 在该结构中BA、GPS与BBR的结合较为松散, 进而促使BBR易于被释放, 笔者推测这是导致CGS组抑菌作用提高的内在原因。而在CSG组BBR+BA+GPS的模拟结构中, 因BBR与BA结合紧密, 且被GPS包裹在内部, 故BBR难以释放以发挥药效, 而SGC组BA+GPS+BBR结构中, BBR在外层排列, 糖苷类结构在内层, 提示该结构可能难以与细菌黏附, 因此其抗菌活性较差。本文初步发现药效成分组装行为不同-物质相态变化-药理活性改变的级联过程, 但相态改变对抗菌药效的影响机制仍待深入挖掘。

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2025年第60卷第6期

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doi: 10.16438/j.0513-4870.2024-1065

接收时间：2024-10-29
首发时间：2026-09-20
出版时间：2025-06-12

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收稿日期：2024-10-29
修回日期：2025-03-07

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北京中医药大学中药学院, 北京 102488

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黄雪梅, E-mail: hxm3928@163.com

王鹏龙, E-mail: wpl581@126.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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