Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome

doi:10.1007/s11684-019-0705-9

Front. Med.

2020, Vol. 14

Issue (3) : 335-356 https://doi.org/10.1007/s11684-019-0705-9

RESEARCH ARTICLE

Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome

Qiqi Zhao¹, Xin Gao¹, Guangli Yan¹, Aihua Zhang¹, Hui Sun¹, Ying Han¹, Wenxiu Li¹, Liang Liu², Xijun Wang^1,^2,³(

)

¹. National Chinmedomics Research Center, Sino-America Chinmedomics Technology Collaboration Center, National TCM Key Laboratory of Serum Pharmacochemistry, Laboratory of Metabolomics, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin 150040, China
². State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China
³. National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials, Guangxi Botanical Garden of Medicinal Plant, Nanning 530023, China

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Abstract

Sijunzi decoction (SJZD) is a Chinese classical formula to treat spleen qi deficiency syndrome (SQDS) and has been widely used for thousands of years. However, the quality control (QC) standards of SJZD are insufficient. Chinmedomics has been designed to discover and verify bioactive compounds of a variety of formula rapidly. In this study, we used Chinmedomics to evaluate the SJZD’s efficacy against SQDS to discover the potential quality-markers (q-markers) for QC. A total of 56 compounds in SJZD were characterized in vitro, and 23 compounds were discovered in vivo. A total of 58 biomarkers were related to SQDS, and SJZD can adjust a large proportion of marker metabolites to normal level and then regulate the metabolic profile to the health status. A total of 10 constituents were absorbed as effective ingredients that were associated with overall efficacy. We preliminarily determined malonyl-ginsenoside Rb2 and ginsenoside Ro as the q-markers of ginseng; dehydrotumulosic acid and dihydroxy lanostene-triene-21-acid as the q-markers of poria; glycyrrhizic acid, isoglabrolide, and glycyrrhetnic acid as the q-markers of licorice; and 2-atractylenolide as the q-marker of macrocephala. According to the discovery of the SJZD q-markers, we can establish the quality standard that is related to efficacy.

Keywords traditional Chinese medicine Sijunzi decoction spleen qi deficiency syndrome Chinmedomics quality-marker

Corresponding Author(s): Xijun Wang

Just Accepted Date: 08 August 2019 Online First Date: 26 November 2019 Issue Date: 08 June 2020

Cite this article:

Qiqi Zhao,Xin Gao,Guangli Yan, et al. Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome[J]. Front. Med., 2020, 14(3): 335-356.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0705-9
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I3/335

Fig.1 Model evaluation of spleen qi deficiency syndrome. (A) Body weight between the CON and MOD groups. (B) Spleen and thymus indices between the CON and MOD groups. (C) General state of model rats during model replication period. (D) Gastric food remnant and small intestine propulsive rates between the CON and MOD groups. (E) Gastric and small intestinal mucosa from the MOD group showed disorderly epithelial cells, unclearly muscular layer, slight erosion and exudation. (F) Serum D-xylose level and amylase level between CON and MOD groups. (G) GAS and MOT level between CON and MOD groups. *P<0.05 and **P<0.01 compared with the CON group.

Fig.2 SJZD efficacy evaluation on spleen qi deficiency syndrome. (A) Body weight of the control, model, and SJZD groups. (B) Spleen and thymus indices of the control, model, and SJZD groups. (C) Gastric food remnant and small intestine propulsive rates of the control, model, and SJZD groups. (D) GAS and MOT level of the control, model, and SJZD groups. (E) Gastric and small intestinal mucosa from the SJZD group showed improved epithelial cells and tissue lesion. (F) Serum D-xylose level, amylase level, GAS, and MOT level of the control, model, and SJZD groups. *P<0.05 and **P<0.01 compared with the control group; ^#P<0.05 and ^##P<0.01 compared with the model group.

Fig.3 Multivariate analysis in SQDS serum and urine metabolomics study. (A) PCA score plot (above) and OPLS-DA score plot (below) between different groups in serum metabolomics study. (B) Time trajectory of rat urine during the model replication. (C) PCA score plot (left) and OPLS-DA score plot (right) between different groups in urine metabolomics study.

Fig.4 Chemical structure and the mass fragment information of indole-3-carboxylic acid, identified as the SQDS rat urine biomarker in positive ion mode. The precise molecular mass and the fragments were detected by a mass spectrometer (UPLC-Q-TOF-MS) and determined within a reasonable degree of measurement error (<5 mDa).

Tab.1 Detailed information of biomarkers tentatively identified by serum metabolomics

No.	Rt	M/Z ?determined	M/Z ?calculated	Adducts_H+	Adducts_H−	Actual_M	Proposed ?composition	Postulated identity	Trend
1	0.68	195.0504	195.0505	−	195.051	196.0583	C₆H₁₂O₇	Galactonic acid	↓
2	0.71	114.0661	114.0672	114.067	−	113.0589	C₄H₇N₃O	Creatinine	↑
3	0.76	300.0389	300.0389	−	300.039	301.0468	C₈H₁₅NO₉S	N-Acetylglucosamine 6-sulfate	↓
4	0.77	203.1508	203.1511	203.15	−	202.143	C₈H₁₈N₄O₂	Dimethyl-L-arginine	↓
5	0.79	335.0955	339.0961	335.096	−	334.0907	C₁₇H₁₉C_lN₂OS	Chlorpromazine-N-oxide	↓
6	0.8	243.0973	243.0971	243.098	−	242.0903	C₁₀H₁₄N₂O₅	Thymidine	↓
7	0.84	149.0451	149.0445	−	149.044	150.0528	C₅H₁₀O₅	β-D-ribopyranose	↑
8	0.89	70.0651	70.0655	70.0654	−	69.0578	C₄H₇N	1-Pyrroline	↑
9	0.89	132.0665	132.067	132.066	−	131.0582	C₅H₉NO₃	4-Hydroxy-L-proline	↑
10	0.9	191.0186	191.0191	−	191.019	192.027	C₆H₈O₇	Citric acid	↓
11	0.9	173.0079	173.0083	−	173.008	174.0164	C₆H₆O₆	Trans-aconitic acid	↓
12	1.21	121.065	121.0653	121.065	−	120.0575	C₈H₈O	Phenylacetaldehyde	↑
13	1.21	138.0915	138.0911	138.092	−	137.0841	C₈H₁₁NO	Tyramine	↑
14	1.29	111.0086	111.0081	−	111.008	112.016	C₅H₄O₃	2-Furoic acid	↓
15	1.29	173.0075	173.0081	−	173.008	174.0164	C₆H₆O₆	Dehydroascorbic acid	↓
16	1.69	238.0935	238.0929	238.094	−	237.0862	C₉H₁₁N₅O₃	Dyspropterin	↑
17	1.95	136.0753 ?/134.0591	136.0745 ?/134.0589	136.076	134.06	135.0684	C₈H₉NO	N-Acetylarylamine	↓
18	2.5	208.0969	208.0971	208.097	−	207.0895	C₁₁H₁₃NO₃	N-Acetyl-L-phenylalanine	↑
19	2.74	220.1183	220.118	220.118	−	219.112	C₁₀H₁₃N₅O	Cis-zeatin	↑
20	2.85	279.1335	279.1336	279.134	−	278.1267	C₁₄H₁₈N₂O₄	N1-(α-D-ribosyl)-5, 6-?dimethyl-benzimidazole	↓
21	2.94	216.9804	216.981	−	216.981	217.9885	C₇H₆O₆S	5-Sulfosalicylic acid	↑
22	3.02	162.0561 ?/160.0392	162.0555 ?/160.0399	162.055	160.039	161.0477	C₉H₇NO₂	Indole-3-carboxylic acid	↓
23	3.23	167.0335	167.0338	−	167.034	168.0423	C₈H₈O₄	Homogentisic acid	↑
24	3.41	206.0448 ?/204.0295	206.0455 ?/204.0289	206.045	204.029	205.0375	C₁₀H₇NO₄	Xanthurenic acid	↓
25	3.74	190.0449	190.0512	190.05	−	189.0426	C₁₀H₇NO₃	Kynurenic acid	↓
26	3.95	208.0607	208.0612	208.061	−	207.0532	C₁₀H₉NO₄	4-(2-Aminophenyl)-2, 4-?dioxobutanoic acid	↓
27	4.27	178.0492	178.0495	−	178.05	179.0582	C₉H₉NO₃	Hippuric acid	↓
28	4.57	164.0722 ?/162.0558	164.071 ?/162.0561	164.071	162.055	163.0633	C₉H₉NO₂	3-Methyldioxyindole	↓
29	4.57	340.1041 ?/338.0881	340.1042 ?/338.0882	340.104	338.088	339.0954	C₁₅H₁₇NO₈	6-Hydroxy-5-methoxyindole ?glucuronide	↓
30	4.8	192.0658	192.0661	−	192.066	193.0739	C₁₀H₁₁NO₃	Phenylacetylglycine	↓
31	5.18	229.143	229.1433	−	229.143	230.1518	C₁₂H₂₂O₄	Dodecanedioic acid	↓
32	5.37	173.0813	173.0809	−	173.081	174.0892	C₈H₁₄O₄	Suberic acid	↓
33	6.15	255.0671 ?/253.0514	255.0665 ?/253.0504	255.066	253.05	254.0573	C₇H₁₄N₂O₆S	5-L-Glutamyl-taurine	↑
34	6.23	297.0975	297.0983	−	297.098	298.1053	C₁₄H₁₈O₇	2-Phenylethanol glucuronide	↓
35	6.23	175.0241	175.0235	−	175.024	176.0321	C₆H₈O₆	D-Glucurono-6,3-lactone	↓
36	7.2	181.0862	181.086	181.086	−	180.0786	C₁₀H₁₂O₃	Coniferyl alcohol	↑
37	8.48	407.2785	407.2793	−	407.279	408.2876	C₂₄H₄₀O₅	Cholic acid	↑

Tab.2 Detailed information of biomarkers tentatively identified by urine metabolomics

Fig.5 Serum and urine biomarker relative measurements before and after SJZD treatment. (A) 37 urine metabolites. (B) 21 serum metabolites. (*P<0.05 and **P<0.01 compared with the control group; ^#P<0.05 and ^##P<0.01 compared with the model group.)

Fig.6 Metabolite profile after orally administrated SJZD and the urine/serum metabolites relative-disordered pathway. (A) Urine metabolite profile. (B) Urine metabolite profile. (C) Urine metabolite relative pathways. 1. Glyoxylate and dicarboxylate metabolism; 2. Pentose and glucuronate interconversions; 3. Folate biosynthesis; 4. Phenylalanine metabolism; 5. Tyrosine metabolism; 6. Citrate cycle (TCA cycle); 7. Pyrimidine metabolism; 8. Starch and sucrose metabolism; 9. Ubiquinone and other terpenoid-quinone biosynthesis; 10. Taurine and hypotaurine metabolism; 11. Ascorbate and aldarate metabolism; 12. Riboflavin metabolism; 13. Tryptophan metabolism; 14. Primary bile acid biosynthesis. (D) Serum metabolite relative pathways. 1. Arachidonic acid metabolism; 2. Glycerophospholipid metabolism; 3. Tryptophan metabolism; 4. Primary bile acid biosynthesis; 5. Steroid hormone biosynthesis; 6. Linoleic acid metabolism; 7. Biosynthesis of unsaturated fatty acids; 8. Taurine and hypotaurine metabolism; 9. α-linolenic acid metabolism; 10. Retinol metabolism; 11. Fatty acid biosynthesis; 12. Arginine and proline metabolism; 13. Fatty acid elongation in the mitochondria.

Fig.7 Reconstructed pathways associated with the biomarkers that are abnormally expressed in SQDS rats. The red script substances are the metabolic markers tentatively identified in this experiment. They are mainly involved in bile acid metabolism, retinoid acid metabolism, fatty acid metabolism, amino acid metabolism, and carbohydrate metabolism.

Fig.8 Chromatograms and multivariate analysis in serum pharmacochemistry analysis. (A) Chromatograms of the SJZD, model group serum, and SJZD-dosed group. (B) PCA score plot between the dosed and model groups. (C) Trend plot of identified absorbed compound 3.117_257.0814.

Fig.9 ES-BPI rat serum chromatogram marked with characterized compounds after orally administrated SJZD. The compounds with yellow arrows were from Ginseng, with purple arrows from poria, with blue arrows from macrocephala, and with green arrows from licorice.

Fig.10 PCMS analysis between serum biomarkers and chemical constituents in the SJZD group. The vertical arrangement is the absorption components, and the transverse arrangement is the biomarkers. Red square: means extremely positive correlation. Black square: means extremely negative correlation. Pink square: means highly positive correlation. Blue square: means highly negative correlation. Green square: means minimal correlation. The absorbed compounds marked in red were the crucial compounds, which we further screened.

Fig.11 PCMS analysis between urine biomarkers and chemical constituents in the SJZD group. The vertical arrangement is the absorption components, and the transverse arrangement is the biomarkers. Red square: means extremely positive correlation. Black square: means extremely negative correlation. Pink square: means highly positive correlation. Blue square: means highly negative correlation. Green square: means minimal correlation. The absorbed compounds marked in red were the crucial compounds, which we further screened.

Fig.12 Research route of Sijunzi decoction’s quality-marker in this experiment.

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