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Analyte	Molecular weight	Precursor ion (m/z)	Product ion (m/z)	Declustering potential/V	Collision energy /eV
Baicalin	446.36	445.2	269.0	-60	-31
Geniposide	388.37	387.2	225.1	-80	-12
Luteolin	286.24	285.4	133.0	-120	-44
Coixol	165.15	164.0	149.0	-60	-20
Amygdalin	457.43	456.4	323.1	-60	-17
Paeoniflorin	480.47	479.00	120.6	-80	-30

Analyte	Molecular weight	Precursor ion (m/z)	Product ion (m/z)	Declustering potential/V	Collision energy /eV
Baicalin	446.36	445.2	269.0	-60	-31
Geniposide	388.37	387.2	225.1	-80	-12
Luteolin	286.24	285.4	133.0	-120	-44
Coixol	165.15	164.0	149.0	-60	-20
Amygdalin	457.43	456.4	323.1	-60	-17
Paeoniflorin	480.47	479.00	120.6	-80	-30

Compound	Regressive equation	Correlation coefficient (R²)	Linear range/ng·mL^-1	LOQ/ng·mL^-1
Baicalin	y = 0.028 9 x - 0.049 3	0.999 2	21.88-2 800	10.94
Geniposide	y = 0.003 58 x - 0.060 7	0.998 7	20.55-2 630	10.28
Luteolin	y = 0.013 8 x + 0.000 614	0.999 4	0.812 5-26.00	0.812 5
Coixol	y = 0.012 8 x + 0.036 3	0.997 9	0.429 7-55.00	0.429 7
Amygdalin	y = 0.004 01 x + 0.013 6	0.999 3	0.804 7-206.0	0.804 7

Compound	Regressive equation	Correlation coefficient (R²)	Linear range/ng·mL^-1	LOQ/ng·mL^-1
Baicalin	y = 0.028 9 x - 0.049 3	0.999 2	21.88-2 800	10.94
Geniposide	y = 0.003 58 x - 0.060 7	0.998 7	20.55-2 630	10.28
Luteolin	y = 0.013 8 x + 0.000 614	0.999 4	0.812 5-26.00	0.812 5
Coixol	y = 0.012 8 x + 0.036 3	0.997 9	0.429 7-55.00	0.429 7
Amygdalin	y = 0.004 01 x + 0.013 6	0.999 3	0.804 7-206.0	0.804 7

Parameter	Baicalin	Geniposide	Luteolin	Coxiol	Amygdalin
t_max/h	0.42 ± 0.13	1.08 ± 0.20	0.46 ± 0.10	0.58 ± 0.20	1.00 ± 0.00
C_max/ng·mL^-1	2 179.7 ± 196.9	77.7 ± 11.2	14.9 ± 2.3	12.0 ± 4.5	12.8 ± 2.0
t_1/2 /h	6.0 ± 1.0	5.5 ± 0.5	5.6 ± 1.1	4.6 ± 1.1	4.5 ± 1.7
AUC_0-t/μg·h·L^-1	15 564.1 ± 891.1	203.9 ± 23.6	39.6 ± 11.0	59.3 ± 19.8	36.6 ± 8.2
AUC_0-∞/μg·h·L^-1	15 764.5 ± 867.1	204.8 ± 23.6	39.9 ± 11.0	59.6 ± 20.1	38.4 ± 7.4
MRT_0-t /h	7.0 ± 0.5	3.09 ± 0.16	5.4 ± 0.5	5.9 ± 1.0	4.8 ± 0.8
MRT_0-∞ /h	7.6 ± 0.5	3.29 ± 0.2	5.7 ± 0.6	6.3 ± 1.5	5.9 ± 1.1

Parameter	Baicalin	Geniposide	Luteolin	Coxiol	Amygdalin
t_max/h	0.42 ± 0.13	1.08 ± 0.20	0.46 ± 0.10	0.58 ± 0.20	1.00 ± 0.00
C_max/ng·mL^-1	2 179.7 ± 196.9	77.7 ± 11.2	14.9 ± 2.3	12.0 ± 4.5	12.8 ± 2.0
t_1/2 /h	6.0 ± 1.0	5.5 ± 0.5	5.6 ± 1.1	4.6 ± 1.1	4.5 ± 1.7
AUC_0-t/μg·h·L^-1	15 564.1 ± 891.1	203.9 ± 23.6	39.6 ± 11.0	59.3 ± 19.8	36.6 ± 8.2
AUC_0-∞/μg·h·L^-1	15 764.5 ± 867.1	204.8 ± 23.6	39.9 ± 11.0	59.6 ± 20.1	38.4 ± 7.4
MRT_0-t /h	7.0 ± 0.5	3.09 ± 0.16	5.4 ± 0.5	5.9 ± 1.0	4.8 ± 0.8
MRT_0-∞ /h	7.6 ± 0.5	3.29 ± 0.2	5.7 ± 0.6	6.3 ± 1.5	5.9 ± 1.1

基于网络药理学结合药动学及靶点验证探究黄芩清热除痹胶囊治疗类风湿关节炎质量标志物

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董心同 ¹ , 柯江涛 ¹ , 甘珮荣 ¹ , 陈芳园 ¹ , 徐凤 ² , 陈建 ³ , 刘健 ⁴^,^* , 吴虹 ¹^,^*

药学学报 | 专题报道: 基于整合药理学的中医药现代化研究 2023,58(6): 1422-1429

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药学学报 |专题报道: 基于整合药理学的中医药现代化研究 2023 , 58 (6) : 1422 -1429

基于网络药理学结合药动学及靶点验证探究黄芩清热除痹胶囊治疗类风湿关节炎质量标志物

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董心同¹, 柯江涛¹, 甘珮荣¹, 陈芳园¹, 徐凤², 陈建³, 刘健⁴^,^*, 吴虹¹^,^*

作者信息

1.安徽中医药大学药学院, 新安医学教育部重点实验室, 中药研究与开发安徽省重点实验室, 安徽合肥 230012

2.安徽医科大学第二附属医院, 安徽合肥 230601

3.安徽中医药大学中西医结合学院, 安徽合肥 230012

4.安徽中医药大学第一附属医院, 安徽合肥 230031

通讯作者:

*刘健, Tel: 13955109537, E-mail: liujianahzy@126.com;

吴虹, Tel: 13485606565, E-mail: hongw@aliyun.com

To explore the quality markers of Huangqin Qingre Chubi capsule in the treatment of rheumatoid arthritis based on network pharmacology combined with pharmacokinetics and target verification

Xin-tong DONG¹, Jiang-tao KE¹, Pei-rong GAN¹, Fang-yuan CHEN¹, Feng XU², Jian CHEN³, Jian LIU⁴^,^*, Hong WU¹^,^*

Affiliations

1. School of Pharmacy, Anhui University of Chinese Medicine, Key Lab of Xin'an Medicine, Ministry of Education, Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Hefei 230012, China

2. The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China

3. School of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China

4. The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, China

出版时间: 2023-06-12 doi: 10.16438/j.0513-4870.2022-1447

文章导航

摘要

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黄芩清热除痹胶囊(Huangqin Qingre Chubi capsule, HQC) 作为临床治疗类风湿关节炎(rheumatoid arthritis, RA) 的有效方剂, 质量控制尚属空白。本研究拟通过网络药理学、药动学结合实验验证探究HQC治疗RA的质量标志物(quality markers, Q-marker)。通过构建“药效成分-靶点-通路”可视化网络, 初步预测HQC治疗RA潜在质量标志物。建立风湿热痹证胶原诱导性关节炎(collagen-induced arthritis, CIA) 大鼠模型, 阐明HQC药效成分在大鼠疾病状态下的动态量化规律。建立肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α) 诱导的RA成纤维样滑膜细胞(MH7A) 体外炎症模型, 检测活性成分对鞘氨醇激酶1 (sphingosin kinase-1, Sphk1)、p-SphK1蛋白表达影响。网络药理学结果显示, 黄芩苷、栀子苷、木犀草素、薏苡素和苦杏仁苷为HQC治疗RA的重要活性成分。定量分析结果进一步验证这5种成分的可测性。蛋白免疫印迹证实栀子苷和黄芩苷显著抑制Sphk1和p-SphK1蛋白表达。以上研究确定上述5种成分可作为HQC治疗RA的质量标志物。本实验经安徽中医药大学实验动物伦理委员会审核通过(批准号: AHUCM-rats-2021049), 所有程序均严格按照动物使用和护理的原则进行。

关键词

类风湿关节炎 / 质量标志物 / 黄芩清热除痹胶囊 / 热痹 / 网络药理学 / 药动学

Abstract

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As an effective prescription for the treatment of rheumatoid arthritis (RA), Huangqin Qingre Chubi capsule (HQC) is still blank in quality control. This study aims to explore quality markers (Q-markers) for HQC in the treatment of RA by integrating network pharmacology and pharmacokinetics. By constructing the visualization network of "pharmacodynamic ingredient-target-pathway", the potential Q-Marker of HQC treatment for RA was preliminatively predicted. A rat model of rheumatic heat obstruction syndrome collagene-induced arthritis (CIA) was established to elucidate the dynamic quantification law of pharmacodynamic components of HQC in the disease state of rats. To establish the inflammatory model of RA synovial fibroblasts (MH7A) induced by tumor necrosis factor-α (TNF-α) in vitro. The effects of active ingredients on protein expression of sphingosin kinase-1 (Sphk1) and p-SphK1 were detected. The network pharmacological results showed that baicalin, geniposide, luteolin, coixol and amygdalin were the important active components of HQC treatment for RA. Quantitative analysis results further verified the measurability of these five components. The expression of Sphk1 and p-SphK1 was significantly inhibited by geniposide and baicalin by Western blotting. The above studies determined that the above 5 components could be used as Q-markers in the treatment of RA by HQC. This experiment was approved by the Experimental Animal Ethics Committee of Anhui University of Chinese Medicine (approval number: AHUCM-rats-2021049). All procedures were conducted in strict accordance with the principles of animal use and care.

Key words

rheumatoid arthritis / quality marker / Huangqin Qingre Chubi capsule / heat arthralgia / network pharmacology / pharmacokinetics

引用本文

董心同, 柯江涛, 甘珮荣, 陈芳园, 徐凤, 陈建, 刘健, 吴虹. 基于网络药理学结合药动学及靶点验证探究黄芩清热除痹胶囊治疗类风湿关节炎质量标志物. 药学学报, 2023 , 58 (6) : 1422 -1429 . DOI: 10.16438/j.0513-4870.2022-1447

Xin-tong DONG, Jiang-tao KE, Pei-rong GAN, Fang-yuan CHEN, Feng XU, Jian CHEN, Jian LIU, Hong WU. To explore the quality markers of Huangqin Qingre Chubi capsule in the treatment of rheumatoid arthritis based on network pharmacology combined with pharmacokinetics and target verification[J]. Acta Pharmaceutica Sinica, 2023 , 58 (6) : 1422 -1429 . DOI: 10.16438/j.0513-4870.2022-1447

正文

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类风湿关节炎(rheumatoid arthritis, RA) 作为自身免疫性疾病, 属中医学“痹证”范畴^[1]。黄芩清热除痹胶囊(Huangqin Qingre Chubi capsule, HQC) 包括黄芩、栀子、威灵仙、薏苡仁、桃仁, 全方发挥清热, 化湿之功效^[2], 常用于治疗RA风湿热证, 但其药效物质基础尚不明确。质量标志物(quality marker, Q-marker) 的提出为本研究探究HQC药效成分提供明确的方向^[3]。因此本研究整合网络药理学、药动学及实验验证挖掘活性成分, 确定HQC的质量标志物。

材料与方法

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数据库及软件 中药系统药理学数据库TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, http://lsp.nwu.edu.cn/tcmsp.php/), GeneCards基因组注释数据库平台(http://www.genecards.org/), Metascape基因富集分析数据库(http://metascape.org/), 网络可视化分析软件Cytoscape (Version 3.8.2)。

实验动物及细胞 雄性SPF级SD大鼠, 体重200~250 g, 购自济南朋悦实验动物繁育有限公司, 合格证号: SCXK (鲁) 20190003, 实验方案经安徽中医药大学实验动物伦理委员会审核通过(批准号: AHUCM-rats-2021049)。动物于自然光照、自由进食饮水、恒温、恒湿、整洁环境。RA滑膜成纤维细胞(MH7A细胞) 株购自广州吉妮欧生物科技有限公司。

试剂及仪器 HQC (批号: 20210601) 购自安徽中医药大学第一附属医院; 黄芩苷(批号: Z28S11X125952)、栀子苷(批号: C07N7Y24406)、薏苡素(批号: J26GB152842)、芍药苷(批号: X12A8C33672) 均购自上海源叶生物科技有限公司; 苦杏仁苷(批号: 29883-15-6); 木犀草素(批号: CHB180113) 购自成都克洛玛生物科技有限公司; 鸡Ⅱ型胶原(chick type Ⅱ collagen, CⅡ) (批号: 220184)、弗氏完全佐剂(freund's complete adjuvant, FCA) (批号: F5881) 购自美国Sigma公司; 辣根过氧化物酶标记山羊抗小鼠IgG (货号: A0216, H+L)、蛋白酶抑制剂混合物(货号: P1005)、磷酸酶抑制剂混合物A (货号: P1081, 50X)、BCA蛋白浓度测定试剂盒(货号: P0012) 均购自碧云天生物技术有限公司; 鼠单克隆β-actin一抗(货号: TA-09)、辣根酶标记兔抗山羊IgG (货号: ZB-2306, H+L) 购自北京中山金桥生物技术有限公司; PageRuler™ 预染蛋白分子量标准(货号: 26616) 购自赛默飞世尔科技有限公司; PVDF膜(货号: BS-PVDF-45) 购自白鲨Biosharp生物; 兔多克隆鞘氨醇激酶1 (sphingosin kinase-1, Sphk1) 一抗(货号: BA2865) 购自博士德生物; 兔多克隆p-SphK1一抗(货号: 19561-1-AP, Ser 25) 购自美国Proteintech; AB SCIEX QTRAP 5500三重四极杆质谱联用仪(型号: EB20711805, 美国AB SCIEX公司); 人工气候造模箱(型号: RXZ-160A, 宁波江南仪器厂); 红外热像仪(型号: T620, 美国Flir Systems公司)。

活性成分及靶点预测 通过TCMSP检索HQC成分, 以口服生物利用度≥ 30%及药物类药性≥ 0.18作为筛选条件, 同时纳入文献各单味药中发挥药效的成分。通过PharmMpaper平台预测成分靶点。利用DrugBank等数据库构建RA靶点数据库。通过Veeny在线平台获取成分与疾病交集靶点。通过Cytoscape软件分析中药、成分、靶点三者间相互关系, 获取重要活性成分及靶点。

交集靶点的通路富集分析 利用Metascape数据库对交集靶点进行基因本体(gene ontology, GO) 生物过程和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes, KEGG) 通路富集分析。根据P值显著性以气泡图形式展示前20条通路。

成分-靶点-通路网络构建 基于KEGG结果构建HQC“成分-靶点-通路”图, 明确HQC治疗RA的潜在质量标志物。

色谱及质谱条件 采用Waters Xbridge C18色谱柱(150 mm × 2.1 mm, 2.5 μm); 流动相: 含0.01 mol·L^-1甲酸铵的0.1%甲酸水溶液(A)-0.1%甲酸的乙腈(B) 为流动相, 洗脱梯度: 0~0.5 min, 95% A; 0.5~1.5 min, 95%~60% A; 1.5~3.0 min, 60% A; 3.0~4.5 min, 60%~0% A; 4.5~6.5 min, 0% A; 6.5~8.5 min, 0%~95% A; 8.5~10 min, 95% A。采用多反应监测扫描方式, 电喷雾负离子源模式。喷雾气为55 psi, 气帘气压力为25 psi, 碰撞气压力为中等, 辅助气为65 psi, 喷雾电压为-4 500 V, 离子源温度为450 ℃。重要质谱参数见表 1。

大鼠分组及造模 24只大鼠适应性喂养一周, 随机分为正常对照组、胶原诱导性关节炎(collagen-induced arthritis, CIA) 组、风湿热环境(rheumatic heat environment, FSR) 组、HQC组, 每组6只。CIA组模型制备: 在第0天, 将FCA乳化后的CⅡ于大鼠左后足趾及尾巴根部皮内注射0.2 mL, 第7天在背部多处注射0.1 mL乳剂加强刺激; FSR组及HQC组模型制备: 与CIA组同法注射乳剂, 并且在首次造模后接受持续28天, 一天4 h的环境刺激(干预条件: 湿度95 ℃; 风速5 m·s^-1; 温度37 ℃); 正常对照组: 注射生理盐水造模, 常温饲养。

MH7A细胞培养及分组 MH7A在含5%胎牛血清和1%青霉素-链霉素溶液的DMEM培养基中培养, 浓度为5% CO₂, 温度为37 ℃。组别为空白对照组、肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α) 组: TNF-α (10 ng·mL^-1)、栀子苷组: TNF-α (10 ng·mL^-1)+栀子苷(5×10^-5 mol·L^-1)、黄芩苷组: TNF-α (10 ng·mL^-1)+黄芩苷(1×10^-5 mol·L^-1)、木犀草素组: TNF-α (10 ng·mL^-1)+木犀草素(2×10^-5 mol·L^-1)、薏苡素组: TNF-α (10 ng·mL^-1)+薏苡素(1×10^-5 mol·L^-1)、苦杏仁苷组: TNF-α (10 ng·mL^-1)+苦杏仁苷(1×10^-5 mol·L^-1)。各单体给药浓度参照文献^[4-8]。

储备液制备 精密称取栀子苷、薏苡素、黄芩苷、木犀草素、苦杏仁苷对照品适量, 加入甲醇溶解稀释成浓度分别为0.263、0.550、0.280、0.260、0.206 mg·mL^-1的对照品储备液, 4 ℃保存备用。另精密称取芍药苷内标(internal standard, IS) 适量, 加甲醇稀释成3.230 μg·mL^-1。

血浆样品处理 精密吸取100 μL血浆样品, 移至2 mL离心管, 加入100 μL IS溶液, 涡旋混匀, 500 μL甲醇蛋白沉淀, 涡旋, 离心(12 000 ×g, 4 ℃, 10 min), 取上清500 μL, 真空浓缩仪挥干。残渣用100 μL甲醇复溶, 涡旋10 min, 离心2次(12 000 ×g, 4 ℃, 10 min), 取上清, 进样分析。

TNF-α刺激MH7A浓度优化 选取1.25、2.5、5、10、20 ng·mL^-1的TNF-α溶液刺激MH7A 24 h, 观察细胞增殖情况。

大鼠整体指标评价 炎症出现后, 每隔3天对各组大鼠进行全身表现评分、关节炎指数评分及足趾容积测量, 此外检测滑膜病理形态学。

热属性判断 通过红外热像仪每3天测量大鼠后肢关节表面温度。免疫第35天, 检测大鼠红细胞压积、血浆黏度、全血黏度。

专属性考察 分析空白血浆、空白血浆加5种混合对照品和IS溶液及口服HQC的血浆加IS溶液的色谱图, 评价专属性。

线性范围及定量下限考察 精密吸取对照品储备液, 混合, 甲醇逐级稀释配制成混合对照品溶液。取100 μL空白血浆, 加入各梯度混合对照品100 μL, 按照血浆样品方法处理, 评价线性关系。

精密度和准确度考察 3种浓度质控样品(n = 6), 通过同一天和连续三天检测, 考察日内、日间精密度和方法的准确度。

基质效应和提取回收率考察 比较处理前后空白血浆添加质控样品的峰面积, 考察提取回收率。纯溶剂与血浆中混合对照品的峰面积比, 考察基质效应。

稳定性考察 评估在不同储存条件下, 质控样品在血浆中化学性质变化。室温下储存24 h的短期稳定性, 经过3次冻融循环的冻融稳定性及-80 ℃下放置30天的长期稳定性。

药动学研究 造模第33天单次灌胃HQC 324 mg·kg^-1, 取给药后0、0.083、0.17、0.25、0.5、1、1.5、2、4、6、8、10、12、24、36 h采集的含药血浆, 液质联用分析, 绘制平均血浆药物浓度-时间曲线, DAS 2.0软件计算药动学参数。

蛋白免疫印迹法检测蛋白含量 分组给药干预, 加500 μL含1% PMSF蛋白酶抑制剂和磷酸酶抑制剂的RIPA裂解液裂解。BCA法蛋白定量试剂盒定量样品中总蛋白。用10%十二烷基硫酸钠-聚丙烯酰胺凝胶电泳分离等效蛋白样品。转移至200 mA PVDF膜上, 转膜后置于5%的脱脂奶粉中室温孵育封闭2 h时, 与一抗(1∶1 000) 在4 ℃下孵育过夜, 再次洗膜, 蛋白条带转移至二抗, 室温孵育1 h, 曝光。

结果

收起

1 活性成分及靶点预测

网络药理学结果显示获得HQC成分90种, RA靶点1 457个, 成分与RA交集靶点140个。此外纳入网络药理学中生物利用度较低但具有药效活性的成分黄芩苷、栀子苷、木犀草素、薏苡素、苦杏仁苷作为研究对象。分析中药、成分、靶点关系获得木犀草素、栀子苷、苦杏仁苷、薏苡素、黄芩苷等成分主要通过Sphk1、1-磷酸鞘氨醇(sphingosine 1-phosphate, S1P) 等靶点治疗RA。

2 交集靶点的通路富集分析

GO富集结果显示药效成分通过调控激酶活性等作用参与RA多种生物学过程。KEGG富集结果显示药效成分主要参与鞘脂等信号通路的调控。前20条KEGG通路图见图 1A。

3 成分-靶点-通路网络分析

通过分析获得栀子苷、黄芩苷、苦杏仁苷、木犀草素、薏苡素的度值较高, 为HQC治疗RA的潜在质量标志物, “成分-靶点-通路”图如图 1B。

4 TNF-α浓度优化

通过检测MH7A细胞增殖, 最终选择10 ng·mL^-1的TNF-α作为后续造模浓度。不同浓度TNF-α对MH7A增殖能力的影响如图 2A。

5 大鼠整体指标评价

大鼠足爪肿胀图如图 3A。随造模时间延长, 大鼠背部溃烂、行动迟缓、体重减轻。病理结果(图 3B) 显示, 与正常组相比, CIA组滑膜细胞多层增厚, 大量炎性细胞充盈滑膜并伴有内膜下血管生成。正常组滑膜细胞整齐排列。FSR组大鼠较CIA组表现出更加明显的增殖及浸润, 且可观察多处新生血管。与正常组大鼠相比, CIA组及FSR组全身表现评分(图 3C)、关节炎指数(图 3D) 及足爪肿胀度(图 3E) 逐渐增加, 有显著差异, FSR组较CIA组大鼠症状明显。

6 热属性判断

免疫35天的血液流变学结果显示, 与正常组相比, CIA组及FSR组大鼠血浆黏度、红细胞压积及低剪切率下全血黏度显著升高。与CIA组相比, FSR组低剪切率下全血黏度、红细胞压积、血浆黏度有降低的趋势, 关节表面温度升高(图 4)。免疫接种期间, CIA组及FSR组大鼠关节表面温度较正常组高, FSR组最高。

7 专属性

5个化合物及IS的色谱图如图 5。内源性物质不干扰待测物及IS的测定。

8 线性关系及定量下限

血浆中5种化合物标准曲线方程、相关系数、线性范围及定量下限见表 2。

9 精密度及准确度

5种成分低、中、高3种浓度的质控样品日内精密度是2.0%~12.6%、日间精密度是3.3%~11.1%, 准确度分别是87.2%~112.2%, 93.9%~109.2%, 符合生物样品分析要求。

10 基质效应及提取回收率

5种成分的质控样品在大鼠血浆中的基质效应结果为85.7%~109.0%, 提取回收率为85.3%~99.6%, 结果符合体内样品定量方法要求。

11 稳定性

5种成分质控样品相对标准偏差在85.2%~111.3%之间, 生物样本基本稳定, 不影响定量测定结果。

12 药动学研究

平均血浆药物浓度-时间曲线图如图 6, 药动学参数见表 3。

13 HQC中5种活性成分对MH7A中SphK1、p-SphK1蛋白表达影响

蛋白免疫印迹结果见图 2B。结果显示, 与对照组相比, TNF-α组SphK1和p-SphK1蛋白显著升高(P < 0.01)。与TNF-α组相比, 栀子苷和黄芩苷显著抑制p-SphK1和SphK1蛋白表达, 而木犀草素、薏苡素和苦杏仁苷对SphK1和p-SphK1的表达均无影响(P > 0.05)。

讨论

收起

中药复方质量可控是临床疗效的重要保证, 因此寻求有效且适合的中药质控手段迫在眉睫。本研究基于网络药理学结合药动学及实验验证, 探究HQC抗RA的质量标志物。本研究通过“成分-靶点-通路”可视化网络分析, 发现HQC中5种活性成分可能通过影响Sphk1、S1P等靶点治疗RA。

滑膜炎症作为RA典型的病理特征, 研究表明, 多种炎性因子可作为推动炎症不断发展的始作俑者^[9]。S1P作为一类新型鞘脂分子, 通过SphKs磷酸化激活催化产生, 结合胞内或胞膜上S1P受体参与成纤维样滑膜细胞中炎症因子白细胞介素(interleukin, IL)-6释放, 介导RA炎症反应^[10]。本实验证实黄芩苷及栀子苷能够显著抑制细胞中p-SphK1和SphK1蛋白表达, 缓解炎症反应。细胞外信号调节激酶1/2 (extracel lular signal regulated kinase 1/2, ERK1/2) 通常参与RA中丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK) 介导的炎症、增殖和关节破坏^{[11, 12]}。在炎性环境中, TNF-α参与激活ERK1/2通路并诱导下游IL-6、基质金属蛋白酶-3释放, 加重滑膜炎症, 加速胞外基质降解^[13]。激活后的p38 MAPK同样释放IL-1β、TNF-α和IL-6等多种促炎细胞因子^{[14, 15]}。研究显示黄芩苷可有效降低p-p38, 阻断炎症通路, 缓解滑膜炎症^[16]。薏苡素通过抑制MAPK通路, 抑制NOD结构域样受体3炎性小体的激活, 发挥抗炎活性^[17]。3-磷酸肌醇激酶/蛋白激酶B (phosphoinositide 3-kinase/protein kinase B, PI3K/AKT) 通路可协助IL-17及IL-21炎性因子推动炎症发展^[9]。Hou等^[18]研究发现木犀草素通过下调p-AKT、p-ERK蛋白, 缓解CIA大鼠滑膜细胞增殖。此外黄芩苷可调控腺苷酸活化蛋白激酶/ERK/Akt通路减轻溃疡性结肠炎大鼠症状^[19]。

研究显示SphK1参与RA血管新生, 血管内皮生长因子(vascular endothelial growth factor, VEGF) 触发SphK1磷酸化位点激活, 介导VEGF-SphK1-S1P通路激活参与RA血管新生^[20]。ERK1/2可借助VEGF促进p-ERK1/2与SphK1的结合, 调控血管新生^{[21, 22]}。Deng等^[23]研究表明, 栀子苷通过抑制SphK1和p-ERK1/2结合, 减少S1P的释放, 抑制血管生成。鉴于药效作用与入血成分密切相关^[24], 本研究构建符合病证特点的FSR大鼠模型, 成功测定网络药理学预测的5种活性成分。

综上所述, 本研究通过体内外实验证实黄芩苷、栀子苷、苦杏仁苷、木犀草素、薏苡素是HQC抗RA的质量标志物, 其中黄芩苷、栀子苷可作为HQC主要成分抑制p-SphK1及S1P释放, 治疗RA。

作者贡献: 董心同负责完成相关实验及论文撰写; 柯江涛、甘珮荣、陈芳园、陈建、徐凤负责完成数据采集; 吴虹、刘健负责指导实验与修改论文。

利益冲突: 本文所有作者均声明无利益冲突。

基金

收起

国家自然科学基金面上项目(81874360)
安徽省高校自然科学基金重大项目(KJ2021ZD0060)
省级研究生学术创新项目(2022xscx101)

参考文献

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2023年第58卷第6期

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文章信息

doi: 10.16438/j.0513-4870.2022-1447

接收时间：2022-12-31
首发时间：2025-11-21
出版时间：2023-06-12

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出版历史

收稿日期：2022-12-31
修回日期：2023-04-23

基金

国家自然科学基金面上项目(81874360)

安徽省高校自然科学基金重大项目(KJ2021ZD0060)

省级研究生学术创新项目(2022xscx101)

作者信息

1.安徽中医药大学药学院, 新安医学教育部重点实验室, 中药研究与开发安徽省重点实验室, 安徽合肥 230012

2.安徽医科大学第二附属医院, 安徽合肥 230601

3.安徽中医药大学中西医结合学院, 安徽合肥 230012

4.安徽中医药大学第一附属医院, 安徽合肥 230031

通讯作者:

*刘健, Tel: 13955109537, E-mail: liujianahzy@126.com;

吴虹, Tel: 13485606565, E-mail: hongw@aliyun.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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TxT

Analyte	Molecular weight	Precursor ion (m/z)	Product ion (m/z)	Declustering potential/V	Collision energy /eV
Baicalin	446.36	445.2	269.0	-60	-31
Geniposide	388.37	387.2	225.1	-80	-12
Luteolin	286.24	285.4	133.0	-120	-44
Coixol	165.15	164.0	149.0	-60	-20
Amygdalin	457.43	456.4	323.1	-60	-17
Paeoniflorin	480.47	479.00	120.6	-80	-30

Analyte

Molecular weight

Precursor ion (m/z)

Product ion (m/z)

Declustering potential/V

Collision energy /eV

Baicalin

446.36

445.2

269.0

-60

-31

Geniposide

388.37

387.2

225.1

-80

-12

Luteolin

286.24

285.4

133.0

-120

-44

Coixol

165.15

164.0

149.0

-60

-20

Amygdalin

457.43

456.4

323.1

-60

-17

Paeoniflorin

480.47

479.00

120.6

-80

-30

Compound	Regressive equation	Correlation coefficient (R²)	Linear range/ng·mL^-1	LOQ/ng·mL^-1
Baicalin	y = 0.028 9 x - 0.049 3	0.999 2	21.88-2 800	10.94
Geniposide	y = 0.003 58 x - 0.060 7	0.998 7	20.55-2 630	10.28
Luteolin	y = 0.013 8 x + 0.000 614	0.999 4	0.812 5-26.00	0.812 5
Coixol	y = 0.012 8 x + 0.036 3	0.997 9	0.429 7-55.00	0.429 7
Amygdalin	y = 0.004 01 x + 0.013 6	0.999 3	0.804 7-206.0	0.804 7

Compound

Regressive equation

Correlation coefficient (R²)

Linear range/ng·mL^-1

LOQ/ng·mL^-1

Baicalin

y = 0.028 9 x - 0.049 3

0.999 2

21.88-2 800

10.94

Geniposide

y = 0.003 58 x - 0.060 7

0.998 7

20.55-2 630

10.28

Luteolin

y = 0.013 8 x + 0.000 614

0.999 4

0.812 5-26.00

0.812 5

Coixol

y = 0.012 8 x + 0.036 3

0.997 9

0.429 7-55.00

0.429 7

Amygdalin

y = 0.004 01 x + 0.013 6

0.999 3

0.804 7-206.0

0.804 7

Parameter	Baicalin	Geniposide	Luteolin	Coxiol	Amygdalin
t_max/h	0.42 ± 0.13	1.08 ± 0.20	0.46 ± 0.10	0.58 ± 0.20	1.00 ± 0.00
C_max/ng·mL^-1	2 179.7 ± 196.9	77.7 ± 11.2	14.9 ± 2.3	12.0 ± 4.5	12.8 ± 2.0
t_1/2 /h	6.0 ± 1.0	5.5 ± 0.5	5.6 ± 1.1	4.6 ± 1.1	4.5 ± 1.7
AUC_0-t/μg·h·L^-1	15 564.1 ± 891.1	203.9 ± 23.6	39.6 ± 11.0	59.3 ± 19.8	36.6 ± 8.2
AUC_0-∞/μg·h·L^-1	15 764.5 ± 867.1	204.8 ± 23.6	39.9 ± 11.0	59.6 ± 20.1	38.4 ± 7.4
MRT_0-t /h	7.0 ± 0.5	3.09 ± 0.16	5.4 ± 0.5	5.9 ± 1.0	4.8 ± 0.8
MRT_0-∞ /h	7.6 ± 0.5	3.29 ± 0.2	5.7 ± 0.6	6.3 ± 1.5	5.9 ± 1.1

Parameter

Baicalin

Geniposide

Luteolin

Coxiol

Amygdalin

t_max/h

0.42 ± 0.13

1.08 ± 0.20

0.46 ± 0.10

0.58 ± 0.20

1.00 ± 0.00

C_max/ng·mL^-1

2 179.7 ± 196.9

77.7 ± 11.2

14.9 ± 2.3

12.0 ± 4.5

12.8 ± 2.0

t_1/2 /h

6.0 ± 1.0

5.5 ± 0.5

5.6 ± 1.1

4.6 ± 1.1

4.5 ± 1.7

AUC_0-t/μg·h·L^-1

15 564.1 ± 891.1

203.9 ± 23.6

39.6 ± 11.0

59.3 ± 19.8

36.6 ± 8.2

AUC_0-∞/μg·h·L^-1

15 764.5 ± 867.1

204.8 ± 23.6

39.9 ± 11.0

59.6 ± 20.1

38.4 ± 7.4

MRT_0-t /h

7.0 ± 0.5

3.09 ± 0.16

5.4 ± 0.5

5.9 ± 1.0

4.8 ± 0.8

MRT_0-∞ /h

7.6 ± 0.5

3.29 ± 0.2

5.7 ± 0.6

6.3 ± 1.5

5.9 ± 1.1