Analysis of the Material Basis and Efficacy of the Differences in the Preparation of Pinellia Ternate before and after Concoction Based on UPLC-Q-TOF-MS/MS and Network Pharmacology
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摘要:
目的 基于超高效液相色谱-四极杆-飞行时间质谱(UPLC-Q-TOF-MS/MS)和多变量统计分析, 筛选并鉴定半夏及其不同炮制品的差异性物质基础, 并针对共有及差异性物质基础进行网络药理学分析, 挖掘半夏炮制前后物质基础与功效变化的关系。 方法 采用UPLC-Q-TOF-MS/MS检测半夏及其炮制品共42批样品的主要物质基础并筛选差异性成分, 运用正交偏最小二乘判别分析(OPLS-DA), 以VIP>1.5、P<0.01、FC>2或<0.5为筛选标准, 通过数据库配对、文献比对鉴定得到差异性成分。进一步通过TCMIP数据库对差异性物质基础检索靶点, 对靶点进行蛋白互作分析, 最后通过GO富集和KEGG富集分析其代谢通路。 结果 生半夏与法半夏有14个差异性成分, 与生半夏相比, 法半夏含量升高的成分主要有甘草酸、甘草次酸、甘草素等, 含量降低的成分主要为酰胺类。生半夏与姜半夏有18个差异性成分, 主要为核苷类、黄酮类、氨基酸类。鸟苷、黄嘌呤及酪氨酸等含量降低, 磷酸腺苷含量升高。生半夏与清半夏有18个差异性成分, 清半夏中多种成分相对含量均降低, 如鞘氨醇。得到生半夏67个核心靶点,法半夏45个核心靶点,姜半夏38个核心靶点。 结论 建立的UPLC-Q-TOF-MS/MS方法能够较好地分离鉴定半夏中的化学成分, 结合多变量统计分析和网络药理学, 分析半夏及其炮制品的物质基础及潜在作用机制, 可为研究作用靶点提供思路, 为半夏及其炮制品的临床合理应用提供数据支持。 Abstract:OBJECTIVE To screen and identify the differential substance bases of Pinellia ternate and its different concoctions, conduct network pharmacological analysis on the common and differential substance bases, and explore the relationship between the substance bases and the changes in the efficacy of Pinellia ternate before and after concoction based on the UPLC-Q-TOF-MS/MS and multivariate statistical analysis. METHODS The main substance bases of 42 batches of samples were examined by UPLC-Q-TOF-MS/MS, and the differential components were screened by orthogonal partial least squares discriminant analysis (OPLS-DA) with VIP>1.5, P < 0.01 and FC>2 or < 0.5 as the screening criteria. The targets were further retrieved from the TCMIP database, and their protein interactions were analysed by GO enrichment and KEGG enrichment to visualise the "herbal-component-target-pathway" map. RESULTS Compared with Pinellia ternate, Pinelliae Rhizoma Praeparatum has 14 different components, mainly glycyrrhetinic acid, glycyrrhizic acid and glycyrrhizin, etc. The components with reduced content were mainly amides. There were 18 differential constituents between raw and ginger, mainly nucleosides, flavonoids and amino acids. The content of guanosine, xanthine and tyrosine was reduced, while the content of adenosine monophosphate was increased. There were 18 differential components between raw and Pinelliae Rhizoma Praeparatum Cum Alumine, and the relative content of many components in Pinelliae Rhizoma Praeparatum Cum Alumine was reduced, such as sphingomyelin. Further, the TCMIP database was used to retrieve targets from the differential substance base, and protein interaction analysis was performed on the targets, resulting in 67 core targets for Pinellia ternate, 45 core targets for Pinelliae Rhizoma Praeparatum, and 38 core targets for Pinelliae Rhizoma Praeparatum cum Zingibere Et Alumine. Finally, the metabolic pathways were analyzed by GO enrichment and KEGG enrichment. CONCLUSION The UPLC-Q-TOF-MS/MS method established in this experiment can better isolate and identify the chemical components in Pinellia ternate. Combined with multivariate statistical analysis and network pharmacology, the material basis and potential mechanism of action of Pinellia ternate and its concoction products can provide ideas for the study of the action targets and provide data support for the rational clinical application of Pinellia ternate and its concoction products. -
表 1 半夏及其炮制品样品信息
Table 1. The information of Pinellia ternata and its processed products
编号 品名 批号/产地 提供厂家 1 生半夏 贵州妈姑镇 / 2 生半夏 贵州百纳 / 3 生半夏 湖北潜江 / 4 生半夏 贵州同镇乡 / 5 生半夏 山西运城 / 6 生半夏 贵州马场镇 / 7 生半夏 湖南新宁 / 8 生半夏 江苏泰州 / 9 生半夏 陕西商洛 / 10 生半夏 四川成都 / 11 法半夏 D2109074 四川新荷花中药饮片股份有限公司 12 法半夏 D2007020 四川新荷花中药饮片股份有限公司 13 法半夏 D2109125 四川新荷花中药饮片股份有限公司 14 法半夏 180301 安徽省万生中药饮片有限公司 15 法半夏 180704 安徽省万生中药饮片有限公司 16 法半夏 180703 安徽省万生中药饮片有限公司 17 法半夏 200301 安徽省万生中药饮片有限公司 18 法半夏 200601 安徽省万生中药饮片有限公司 19 法半夏 190901 安徽省万生中药饮片有限公司 20 法半夏 1807100 安徽鑫泰药业有限公司 21 法半夏 180601 安徽省万生中药饮片有限公司 22 法半夏 200802 安徽省万生中药饮片有限公司 23 姜半夏 D2110027 四川新荷花中药饮片股份有限公司 24 姜半夏 D1803063 四川新荷花中药饮片股份有限公司 25 姜半夏 200401 安徽鑫泰药业有限公司 26 姜半夏 201101 安徽鑫泰药业有限公司 27 姜半夏 200801 安徽省万生中药饮片有限公司 28 姜半夏 200301 安徽省万生中药饮片有限公司 29 姜半夏 180701 安徽省万生中药饮片有限公司 30 姜半夏 180702 安徽省万生中药饮片有限公司 31 姜半夏 D1804085 四川新荷花中药饮片股份有限公司 32 姜半夏 180302 安徽省万生中药饮片有限公司 33 姜半夏 180301 安徽省万生中药饮片有限公司 34 清半夏 D2108113 四川新荷花中药饮片股份有限公司 35 清半夏 D2110103 四川新荷花中药饮片股份有限公司 36 清半夏 D2106001 四川新荷花中药饮片股份有限公司 37 清半夏 D2003112 四川新荷花中药饮片股份有限公司 38 清半夏 2108033 四川新荷花中药饮片股份有限公司 39 清半夏 D2102069 四川新荷花中药饮片股份有限公司 40 清半夏 200601 安徽省万生中药饮片有限公司 41 清半夏 D2110062 四川新荷花中药饮片股份有限公司 42 清半夏 D1905059 四川新荷花中药饮片股份有限公司 表 2 QC样本峰面积RSD(%)
Table 2. RSD of peak area of QC sample(%)
正离子 负离子 RSD 比例 总计 RSD 比例 总计 0~10 50.80 0~10 46.53 10~20 15.56 74.48 10~20 25.06 78.94 20~30 8.16 20~30 7.52 表 3 生半夏及其炮制品差异性成分
Table 3. Analysis of the differences of Pinellia ternata and its processed products
序号 差异倍数 保留时间/min 化合物名称 分子式 离子模式 质荷比实测值 质荷比理论值 偏差ppm 二级碎片 文献 1 0.43 16.585 (2E, 4E)-N-(1, 3-Dihydroxy-3-methylpentan-2-yl)-2-methylhexa-2, 4-dienamide C13H23NO3 [M+H]+ 242.175 7 242.175 0 2.77 69.072 21, 85.030 5, 149.092 36, 192.024 34, 224.162 7 2 0.47 15.617 1-[(2S)-2-amino-3-phenylpropanoyl]-N-[(2S)-1-(4-ethylanilino)-1-oxopropan-2-yl]piperidine-4-carboxamide C26H34N4O3 [M+H]+ 451.269 0 451.271 0 -4.54 83.065 95, 110.069 11, 122.071 64, 220.113 4, 235.119 48, 253.133 71, 263.179 93, 336.202 94, 442.216 19 3 0.48 18.441 夏佛塔苷 C26H28O14 [M-H]- 563.136 8 563.140 6 -6.68 353.066 1, 383.076 6, 413.081 1, 443.100 7 4 2.41 1.923 [(2R, 3S, 4R)-5-(2, 4-dioxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] 4-hydroxy-2-methoxy-6-methylbenzoate C18H20N2O9 [M-H]- 407.174 9 407.174 0 2.26 149.048 34, 179.055 57 5 2.56 5.459 腺苷-3′-磷酸 C10H14N5O7P [M+H]+ 348.07 348.0704 -1.12 98.994 93, 119.045 77, 136.062 19 6 2.57 23.649 甘草酸 C42H62O16 [M+H]+ 823.413 8 823.411 1 3.27 189.163 47, 453.334 29, 647.374 57 [5] 7 2.69 24.677 (1R, 2R, 5S, 8R, 14R, 15R, 16S)-16-hydroxy-1, 2, 14, 17, 17-pentamethyl-8-(prop-1-en-2-yl)pentacyclo icosane-5, 15-dicarboxylic acid C30H46O5 [M+H]+ 487.343 9 487.340 8 6.44 121.103 81, 187.148 13, 317.212 62, 405.314 7, 423.332 37, 441.323 18, 469.321 96 8 2.78 2.911 (3R, 4S)-4, 6, 8-trihydroxy-7-methoxy-3-methyl-3, 4-dihydroisochromen-1-one C11H12O6 [M-H]- 239.058 239.056 8 4.85 96.965 62, 170.887 85 9 2.90 26.585 甘草次酸 C30H46O4 [M+H]+ 471.348 6 471.350 0 -3.06 135.116 3, 149.095 75, 189.165 66, 217.160 23, 235.164 96, 263.158 45, 317.196 29, 407.329 93, 425.346 74, 435.309 57, 453.339 57 10 3.22 23.248 甘草皂苷G2 C42H62O17 [M-H]- 837.389 3 837.391 4 -2.48 333.199 77, 351.034 12, 666.595 76, 826.739 62, 834.700 32 [6] 11 3.35 18.794 甘草素 C15H12O4 [M+H]+ 257.080 4 257.081 0 -2.14 81.035 03, 91.049 67, 109.027 37, 119.047 56, 137.023 54, 147.044 83, 163.041 18, 165.066 6, 183.074 89, 211.077 21, 239.069 24, 242.057 8 [7] 12 3.75 26.746 18β -甘草次酸 C30H46O4 [M-H]- 469.331 8 469.331 6 0.34 425.330 66 [6] 13 4.16 22.479 宝丹酮十一烯酸酯 C30H44O3 [M+H]+ 453.335 9 453.336 3 -0.99 107.085 49, 135.114 55, 149.131 88, 407.326 66 14 4.97 20.021 异甘草苷 C21H22O9 [M+H]+ 419.1315 419.134 0 -5.96 137.022 11, 147.042 01, 211.062 44, 236.202 32, 239.067 89, 242.056 44, 257.080 11 [5] 15 0.21 12.039 鸟苷 C10H13N5O5 [M-H]- 282.083 5 282.084 4 -3.23 108.019 29, 108.598 31, 133.014 6, 136.822 36, 150.041 66 16 0.38 15.617 1-[(2S)-2-amino-3-phenylpropanoyl]-N-[(2S)-1-(4-ethylanilino)-1-oxopropan-2-yl]piperidine-4-carboxamide C26H34N4O3 [M+H]+ 451.269 0 451.271 0 -4.54 83.065 95, 110.069 11, 122.071 64, 220.113 4, 235.119 48, 253.133 71, 263.179 93, 336.202 94, 442.216 19 17 0.39 4.794 黄嘌呤 C5H4N4O2 [M-H]- 151.026 1 151.026 2 -0.46 108.021 59 18 0.39 24.551 菊酸 C12H20O2 [M-H]- 195.138 6 195.139 1 -2.41 109.070 45, 138.070 42, 167.1387 9, 167.144 76, 183.329 06 19 0.39 18.441 夏佛塔苷 C26H28O14 [M-H]- 563.136 8 563.140 6 -6.68 353.066 1, 383.076 6, 413.081 1, 443.100 7 20 0.39 1.955 O-琥珀酰-L-高丝氨酸 C8H13NO6 [M-H]- 218.067 1 218.067 0.41 85.035 22, 88.042 75, 102.057 55, 103.340 35, 128.036 42, 146.060 03, 156.063 03, 200.045 53 21 0.41 15.183 N-Fructosyl phenylalanine C15H21NO7 [M+H]+ 328.140 3 328.138 8 4.57 97.027 67, 132.082 81, 144.080 67, 166.084 92, 178.084 09, 264.124 66, 292.105 16, 310.126 65 22 0.43 5.091 酪氨酸 C9H11NO3 [M-H]- 180.065 1 180.066 6 -8.50 93.040 19, 93.045 75, 119.056 9, 119.059 41, 121.494 9, 163.043 17 23 0.44 3.308 5-羟甲基胞苷 C10H15N3O6 [M-H]- 272.089 1 272.088 8 0.99 185.0915 4, 189.053 71, 212.052 57 24 0.45 1.593 2′-脱氧腺苷 C10H13N5O3 [M-H]- 250.093 9 250.094 6 -2.68 73.041 15, 88.041 81, 88.046 13, 88.050 45, 88.066 67, 88.566 77, 88.819 53, 89.130 26 25 0.45 17.816 5, 7-dihydroxy-2-(4-hydroxyphenyl)-8-[3, 4, 5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]-6-(3, 4, 5-trihydroxyoxan-2-yl)chromen-4-one C26H28O14 [M+H]+ 565.156 9 565.154 3 4.53 295.054 66, 307.058 5, 325.067 41, 349.052 95, 379.083 53, 409.073 3, 427.083 19, 481.113 65, 511.122 65, 547.148 93 26 0.47 22.083 (9Z, 12E)-15, 16-dihydroxyoctadeca-9, 12-dienoic acid C18H32O4 [M+H]+ 313.239 6 313.237 3 7.28 68.057 05, 81.031 75, 91.056 22, 93.067 46, 97.100 23, 105.071 43, 109.063 64, 111.081 59, 137.092 91, 145.100 97, 151.108 18, 259.199 22, 277.217 74, 295.221 92 27 0.48 24.692 N-甲基酪氨酸 C10H13NO3 [M-H]- 194.082 5 194.082 3 1.39 179.053 82 28 0.48 16.585 (2E, 4E)-N-(1, 3-dihydroxy-3-methylpentan-2-yl)-2-methylhexa-2, 4-dienamide C13H23NO3 [M+H]+ 242.175 7 242.175 0 2.77 69.072 21, 85.030 5, 149.092 36, 192.024 34, 224.162 7 29 0.49 16.565 泰吡培南酯 C22H31N3O6S2 [M+H]+ 498.173 9 498.173 0 1.73 294.115 48, 298.091 13, 323.111 88, 369.132 14, 410.184 66, 480.165 95 30 0.49 19.745 苯异戊二酮 C11H14O4 [M+H]+ 211.096 1 211.096 0 0.28 194.116 8 31 2.13 5.459 3′-磷酸腺苷 C10H14N5O7P [M+H]+ 348.070 0 348.070 4 -1.12 98.994 93, 119.045 77, 136.062 19 32 2.33 3.460 5-磷酸腺苷 C10H14N5O7P [M-H]- 346.055 0 346.055 8 -2.40 78.964 9, 78.966 94, 78.970 02, 96.978 29, 96.979 43, 134.055 76, 222.076 33 0.19 12.039 鸟苷 C10H13N5O5 [M-H]- 282.083 5 282.084 4 -3.23 108.026 7, 133.018 4, 150.044 5 34 0.30 5.091 酪氨酸 C9H11NO3 [M-H]- 180.065 1 180.066 6 -8.50 93.040 19, 93.045 75, 119.056 9, 119.059 41, 121.494 9, 163.043 17 35 0.31 4.794 黄嘌呤 C5H4N4O2 [M-H]- 151.026 1 151.026 2 -0.46 108.021 59 36 0.33 3.308 5-羟甲基胞嘧啶 C10H15N3O6 [M-H]- 272.089 1 272.088 8 0.99 185.091 54, 189.053 71, 212.052 57 37 0.36 18.441 异牡荆素-2″-O-阿拉伯糖苷 C26H28O14 [M-H]- 563.136 8 563.139 8 -5.20 293.043 79, 413.081 12 38 0.41 15.183 N-Fructosyl phenylalanine C15H21NO7 [M+H]+ 328.140 3 328.138 8 4.57 97.027 67, 132.082 81, 144.080 67, 166.084 92, 178.084 09, 264.124 66, 292.105 16,310.126 65 39 0.42 24.551 菊酸 C12H20O2 [M-H]- 195.138 6 195.139 1 -2.41 109.070 45, 138.070 42, 167.138 79, 167.144 76, 183.329 06 40 0.43 1.955 O-琥珀酰-L-高丝氨酸 C8H13NO6 [M-H]- 218.067 1 218.067 0.41 85.035 22, 88.042 75, 102.057 55, 103.340 35, 128.036 42, 146.060 03, 156.063 03, 200.045 53 41 0.44 16.565 泰吡培南酯 C22H31N3O6S2 [M+H]+ 498.173 9 498.173 1.73 294.115 48, 298.091 13, 323.111 88, 369.132 14, 410.184 66, 480.165 95 42 0.45 5.561 阿糖尿苷 C9H12N2O6 [M-H]- 243.061 3 243.062 3 -4.11 66.041 35, 82.033 26, 110.025 82, 111.022 42, 122.028 31, 140.036 53, 152.034 04, 200.051 94 43 0.45 22.083 (9Z, 12E)-15, 16-Dihydroxyoctadeca-9, 12-dienoic acid C18H32O4 [M+H]+ 313.239 6 313.237 3 7.28 68.057 05, 81.031 75, 91.056 22, 93.067 46, 97.100 23, 105.071 43, 109.063 64, 111.081 59, 137.092 91, 145.100 97, 151.108 18, 259.199 22, 277.217 74, 295.221 92 44 0.46 3.033 桉树素 C19H18O5 [M+H]+ 327.114 8 327.116 -3.82 98.981 98, 235.044 66, 237.083 24 45 0.46 15.617 1-[(2S)-2-amino-3-phenylpropanoyl]-N-[(2S)-1-(4-ethylanilino)-1-oxopropan-2-yl]piperidine-4-carboxamide C26H34N4O3 [M+H]+ 451.269 451.271 -4.54 83.065 95, 110.069 11, 122.071 64, 220.113 4, 235.119 48, 253.133 71, 263.179 93, 336.202 94, 442.216 19 46 0.48 17.816 5, 7-dihydroxy-2-(4-hydroxyphenyl)-8-[3, 4, 5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]-6-(3, 4, 5-trihydroxyoxan-2-yl)chromen-4-one C26H28O14 [M+H]+ 565.156 9 565.154 3 4.53 295.054 66, 307.058 5, 325.067 41, 349.052 95, 379.083 53, 409.073 3, 427.083 19, 481.113 65, 511.122 65, 547.148 93 47 0.48 19.745 苯异戊二酮 C11H14O4 [M+H]+ 211.096 1 211.096 0.28 194.116 8 48 0.49 23.856 鞘胺醇 C18H39NO3 [M+H]+ 318.301 5 318.299 4 6.41 60.046 04, 300.295 84 [5] 49 0.50 23.81 茉莉酸甲酯 C13H20O3 [M-H]- 223.134 8 223.134 3.59 166.076 8 50 0.50 16.773 N-L-γ-谷氨酰-L-亮氨酸 C11H20N2O5 [M+H]+ 261.144 261.144 5 -1.88 86.096 95, 130.051 28, 132.101 73, 142.047 68, 152.110 18, 169.086 55, 198.116 35, 244.115 69 注: 1~14.法半夏与生半夏比较; 15~32.姜半夏与生半夏比较; 33~50.清半夏与生半夏比较。与生半夏相比, 差异倍数FC>1表示炮制品中该成分相对含量升高, FC<1表示相对含量下降。 表 4 生半夏及其炮制品前10个核心靶点拓扑参数
Table 4. Topological parameters of the first 10 core targets of Pinellia ternata and its processed products
序号 基因名 度值 介数 紧密性 备注 1 AKT1 148 12 956.91 0.257 142 87 生半夏 2 EPRS 126 5 024.252 0.247 706 43 3 ALDH18A1 110 3 675.666 3 0.243 442 62 4 GOT2 100 1 591.117 6 0.235 714 29 5 GAD2 98 3 681.418 0.243 044 18 6 EARS2 96 2 784.839 8 0.236 842 11 7 GAD1 94 2 064.456 3 0.240 097 02 8 GLUL 92 1 650.316 9 0.239 130 44 9 GOT1 92 1 350.233 8 0.234 227 14 10 DLG4 90 1 630.903 7 0.242 251 22 11 GAPDH 218 9 785.235 0.6 法半夏 12 ACTB 216 9 337.987 0.602 484 13 AKT1 198 7 279.958 0.583 166 14 HSP90AA1 180 7 483.474 0.568 359 15 TNF 154 3 854.105 0.532 967 16 JUN 134 2 084.546 0.530 055 17 ESR1 128 2 437.737 0.524 324 18 HSPA8 124 3 703.567 0.525 271 19 CREB1 124 2 073.461 0.503 46 20 MAPK3 122 2 698.677 0.507 853 21 GAPDH 200 14 555.67 0.570 611 姜半夏 22 AKT1 178 10 780.17 0.553 704 23 INS 134 7 123.225 0.527 337 24 MAPK3 110 3 435.675 0.491 776 25 SRC 108 3 872.972 0.496 678 26 HIF1A 106 5 117.919 0.489 362 27 PPARG 102 2 801.175 0.489 362 28 CREB1 92 1 693.218 0.481 482 29 HSPA8 92 3 750.292 0.477 636 30 IDH1 82 1 841.436 0.462 848 -
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