Original Article Utilizing Network Pharmacology to Explore the Scientific Connotation of Processing Technology About Rehmanniae Radix Praeparata

Int J Clin Exp Med 2019;12(12):13504-13513 www.ijcem.com /ISSN:1940-5901/IJCEM0100588

Original Article Utilizing network pharmacology to explore the scientific connotation of processing technology about Rehmanniae Radix Praeparata

Ruoqi Li, Guowei Zhou, Tianwei Xia, Yuxuan Wang, Chaoqun Ma, Jirong Shen

Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China Received August 5, 2019; Accepted October 8, 2019; Epub December 15, 2019; Published December 30, 2019

Abstract: Objective: Network pharmacology method was adopted in this study to establish differential component- target network of Rehmanniae Radix Praeparata before and after “steamed for nine times and dried for nine times”, explore the mechanism of the difference of pharmacological effect, reveal the scientific connotation of the processing method. Methods: The different components of Rehmanniae Radix Praeparata before and after “steamed for nine times and dried for nine times” were detected by consulting and screening the literature. PubChem database was used to convert all compounds to standard Canonical SMILES format. SMILES format files were imported into Swiss Target Prediction platform to predict potential targets for different components (possibility > 0). Targets with the highest confidence (score 0.900) were screened from STRING database to construct protein-protein interaction network. GO enrichment and KEGG pathway enrichment were analyzed by ClusterProfiler package in R language. Results: A total of 12 different components (catalpol, ajugol, Rehmannioside A, Acteoside, 5-hydroxymethy lfurfu- ral, Isoacteoside, stachyose, D(+)-Sucrose, raffinose, fructose, glucose and Manninotriose) were screened through literature review, and 101 potential targets were predicted. The GO analysis contained a total of 113 enrichment results. A total of 15 pathways were enriched by KEGG. Conclusion: The changes of glucoses (stachyose, raffinose and Manninotriose) in Rehmanniae Radix Praeparata may be the main reason for the enhancement of the tonifying effect (such as Notch signaling pathway, neuroactive ligand receptor interaction, etc.) after “steamed for nine times and dried for nine times”. The changes of iridoid terpenoids (catalpol, ajugol, rehmannin A, etc.) and carbohydrates (D(+)-Sucrose, raffinose, glucose, Manninotriose, etc.) may be the reasons for the loss of the hypoglycemic effect of Rehmanniae Radix Praeparata after “steamed for nine times and dried for nine times”. The change of pharmacological action is the result from chemical composition interaction of Rehmanniae Radix Praeparata.

Keywords: Rehmanniae Radix Praeparata, network pharmacology, steamed for nine times and dried for nine times, differential components, efficacy

Introduction manniae Radix Praeparata before and after “steamed for nine times and dried for nine Rehmannia glutinosa is root of Rehmannia glu- times”, but the specific mechanism is unclear. tinosa. The Rehmanniae Radix can be divided into fresh Rehmanniae Radix, Rehmanniae Ra- Network pharmacology abolish the traditional dix, Rehmanniae Radix Praeparata. “Rehman- research mode of “one target, one disease, one niae Radix Praeparata” and its processing drug” [1]. The strategy resonates well with the method are first recorded in “prepared qianjin holistic view of traditional Chinese medicine yaofang” and “qianjin yifang” written by Simiao (TCM), which is referred to as “multi-ingredient, Sun. Although processing technology of Re- multi-pathway and multi-target synergy”. In rehmanniae Radix Praeparata is controversial, cent years, many related research reports indi- herbalists regard “steamed for nine times and cate that exploring the molecular mechanism of dried for nine times” as processing criteria. Sci- TCM efficacy will become possible. This study entists have discovered the differences of the retrieved the difference of composition and content and pharmacological effects of Reh- its targets of Rehmanniae Radix Praeparata Processing technology and Rehmanniae Radix Praeparata

ncbi.nlm.nih.gov/pu), and fil- tered out the components that have been verified the content of Rehmanniae Radix Pr- aeparata before and after “steamed for nine times and dried for nine times”. All active compounds in Rehmanni- ae Radix Praeparata were input to the Pubchem database (https://pubchem.ncbi. nlm.nih.gov/) [4] to obtain the Canonical SMILES.

Prediction of potential targets of different components and construction of compound- target network

Swiss Target Prediction (http://www.swisstarge tpredic- tion.ch/) is a network platform that can predict small mole- cule targets on the basis of the 2D and 3D similarity mea- Figure 1. Flowchart of utilizing network pharmacology to explore the scien- surements of ligands [5]. Fir- tific connotation of “steamed for nine times and dried for nine times” about stly, the Canonical SMILES of Rehmanniae Radix Praeparata. compounds were submitted to the platform. Then, the prop- before and after “steamed for nine times and erty was set to “Homo Sapiens” to obtain the dried for nine times”, used bioinformatics meth- predicted targets (Possibility > 0). The results ods to explore the scientific connotation of pro- are visualized using Cytoscape 3.2.1. cessing methods, “steamed for nine times and dried for nine times”, in order to provide a basis Construction of protein-protein interaction for further research and wide application in (PPI) network clinic. The workflow of this study was shown in STRING database (http://string-db.org) can as- Figure 1. sess and integrate direct (physical) and indirect Methods (chemical) associations among proteins [6]. The target data were uploaded to the STRING Screening of different components of database, the attribute was set to “Homo Sa- Rehmanniae Radix Praeparata before and af- piens”, the confidence score was set to the highest confidence (score 0.900), and the pro- ter “steamed for nine times and dried for nine tein-protein interaction network (PPI) was con- times” structed.

We consulted the literature related to the meth- Enrichment analysis of the GO function and od “steamed for nine times and dried for nine KEGG pathway times” about Rehmanniae Radix Praeparata (by the end of June 1, 2019, and removed the We used the org.Hs.eg.db packet in the R lan- non-“steamed for nine times and dried for ni- guage to convert the gene name to Entirez IDs, ne times” processing methods) in the China then used the ClusterProfiler packet to enrich National Knowledge Infrastructure (Http:// the network with GO enrichment and KEGG www.cnki.net/) and PubMed (Https://www. enrichment pathways [7]. The pathways whose

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P-values were less than 0.05 were considered Enrichment analysis of the GO function and statistically significant. KEGG pathway

Results A total of 113 enrichment results were analyzed in the GO analysis. 15 results were relat- Screening of different components of ed to cellular component (CC), 23 results were Rehmanniae Radix Praeparata before and af- related to molecular function (MF), 75 results ter “steamed for nine times and dried for nine were related to biological process (BP). The top times” 20 results were listed in Table 2 according to P value from low to high. Most of them were relat- The results showed the content of Catalpol, ed to the biological processes, such as Notch Acteoside, ajugol, stachyose, D(+)-Sucrose, Raf- receptor processing, adenylate cyclase-activat- finose decreased, and the content of Rehman- ing adrenergic receptor signaling pathway, ade- nioside_A, 5-hydroxymethylfurfural, Isoacteosi- nosine receptor signaling pathway, release of de, Fructose, glucose, Manninotriose in Rehm- sequestered calcium ion into cytosol, one-car- anniae Radix Praeparata increased after “stea- bon metabolic process, glycogen catabolic pro- med for nine times and dried for nine times” cess, and so on. Cell composition included inte- [8-10]. Cycloenedoid terpenoids D was not gral component of plasma membrane, gamma- included in the study due to the content re- secretase complex, extracellular matrix, and so mained controversial. on. G-protein coupled adenosine receptor activity, adrenergic receptor activity, endopepti- Prediction of potential targets of different dase activity, neurotransmitter receptor activi- components and construction of composition- ty, etc. were related to molecular functions. target network A total of 15 pathways were enriched by KEGG After obtaining the Canonical SMILES format of (Figure 4). Most of them were related to metab- the compound, the Swiss Target Prediction da- olism, such as starch and sucrose metabolism, tabase predicted a total of 280 potential tar- galactose metabolism, fructose and mannose gets and 101 potential targets (Table 1) after metabolism, nitrogen metabolism, and so on. removing duplication. All 101 potential targets In addition, many genes were enriched in ner- were used to build a component-target network vous system-related pathways, such as neuro- (Figure 2). There were a total of 113 nodes and active ligand-receptor interaction, Notch signal- 280 edges in the network. The green rectangle ing pathway, calcium signaling pathway, and so represented the difference between the ingre- on. dients before and after “steamed for nine times and dried for nine times”, the yellow oval repre- Discussion sented the predicted targets, and the edges between nodes represented the relationships Rehmannia glotinosa is widely used in tradi- between the components and the targets. tional Chinese medicine. Many active ingredi- ents of Rehmannia glotinosa have been stud- Construction of protein-protein interaction ied in recent years. For example, catalpol has (PPI) network been reported to have anti-inflammatory, anti- oxidative and other pharmacological activities, 101 targets were uploaded to STRING data- such as hypoglycemic [11, 12], anti-tumor [13, base, and the confidence score was set to the 14], protecting nervous system and cardiovas- highest confidence (score 0.9) to construct the cular system [15-18]. Rehmannioside A has a PPI network (Figure 3A). There were 69 nodes, significant effect on treating leukopenia model 173 edges, with an average node degree of mice [25]. Acteoside can protect brain, and has 3.43 in the PPI network. The network node rep- anti-hypertension, anti-oxidation, anti-apopto- resented the target, and the line represent- sis abilities [26-30]. Sugar is an important ed the interaction among the targets. Key tar- nutrient and efficacy component ofRehmanniae gets were (in order): APP, ADORA1, ADRA2A, Radix, including Rehmannia glotinosa oligosac- ADRA2B, ADRA2C, PTAFR, ADORA3, DRD2, charide (RGO) and Rehmannia glotinosa po- DRD3 and HTR1B according to the importance lysaccharide (RGP). The highest content of (Figure 3B). RGO in Rehmanniae Radix is salicose, while in

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Table 1. Main compounds of Rehmanniae Radix Praeparata before and after “steamed for nine times and dried for nine times” Pubechem Category Compound Canonical SMILES Targets CID Cyrene ether terpenoids Catalpol 91520 C1=COC(C2C1C(C3C2(O3)CO) MGAM, SI, TREH, FOLH1, CA2, CA1, CA12, CA9, NAALAD2, ADA, HSP90AA1, AMY2A, OGA, O)OC4C(C(C(C(O4)CO)O)O)O GGH, ADORA1, ADORA2A, CA14, PYGM, HK2, HK1, SLC6A2 Cyrene ether terpenoids ajugol 6325127 CC1(CC(C2C1C(OC=C2)OC3C(C(C(C(O3) ADORA1, ADORA2A, MGAM, SI, TREH, FUCA1, CDA, FOLH1, LGALS3, LGALS9, CA2, CA1, CO)O)O)O)O)O CA12, CA9, TYR, CA14, HPRT1 Cyrene ether terpenoids Rehmannioside_A 78407230 C1=COC(C2C1C(C3C2(O3)CO)O) MGAM, SI, FOLH1, AMY2A, AMY1A, GAA, TREH, CA2, CA1, CA12, CA9, SLC6A2, CDK1, TYR, OC4C(C(C(C(O4)COC5C(C(C(C(O5)CO)O) CA14, FUCA1, NAALAD2, FPGS, ADORA2A, FDFT1 O)O)O)O)O Phenylethanol glycosides Acteoside 5281800 CC1C(C(C(C(O1)OC2C(C(OC(C2OC(=O) PRKCA, MMP2, MMP12, HSP90AA1, APP, AKR1B1, AKR1B10, CYP19A1 C=CC3=CC(=C(C=C3)O)O)CO) OCCC4=CC(=(C=C4)O)O)O)O)O)O Phenylethanol glycosides 5_hydroxymethylfurfural 237332 C1=C(OC(=C1)C=O)CO FUCA1, HSP90AA1, GBA Phenylethanol glycosides Isoacteoside 6476333 CC1C(C(C(C(O1)OC2C(C(OC(C2O) PRKCA, MMP2, MMP12, HSP90AA1, AKR1B1, MMP13, AKR1B10, APP, IMPDH1, IMPDH2, OCCC3=CC(=C(C=C3)O)O)COC(=O) MMP7, MMP8, ADORA1, ADORA2A, ADORA2B, ADORA3, EPHX2, TYR, IL2, MMP1, CYP19A1, C=CC4=CC(=C(C=C4)O)O)O)O)O)O TNF, TOP1, SLC5A1, PDE5A Carbohydrate stachyose 439531 C(C1C(C(C(C(O1)OCC2C(C(C(C(O2) CDK1, VEGFA, FGF1, FGF2, HPSE, HSP90AA1, LGALS4, LGALS3, LGALS8, PSEN2, PSENEN, OCC3C(C(C(C(O3)OC4(C(C(C(O4)CO)O)O) NCSTN, APH1A, PSEN1, APH1B, HTR2B, ADRA2A, ADRA2B, ADRA2C, DRD1, DRD2, ADRA1D, CO)O)O)O)O)O)O)O)O)O)O HTR2A, HTR2C, DRD3, CYP2D6, HTR6, ADRA1A, HTR1B, RORC, TRPV1, AMY2A, STAT3 Carbohydrate D(+)-Sucrose 5988 C(C1C(C(C(C(O1)OC2(C(C(C(O2)CO)O)O) CDK1, HSP90AA1, VEGFA, PSEN2, PSENEN, NCSTN, APH1A, PSEN1, APH1B, FGF1, HPSE, CO)O)O)O)O FGF2, LGALS4, LGALS3, LGALS8, CA2, CA1, CA12, CA9, HTR2B, ADRA2A, ADRA2B, ADRA2C, DRD1, DRD2, ADRA1D, HTR2A, HTR2C, DRD3, CYP2D6, HTR6, ADRA1A, HTR1B, FOLH1, RORC, MGAM, SI, TRPV1, STAT3, PYGL, PYGM, PYGB Carbohydrate Raffinose 439242 C(C1C(C(C(C(O1)OCC2C(C(C(C(O2) CDK1, VEGFA, FGF1, FGF2, HPSE, HSP90AA1, LGALS4, LGALS3, LGALS8, PSEN2, PSENEN, OC3(C(C(C(O3)CO)O)O)CO)O)O)O)O)O)O)O NCSTN, APH1A, PSEN1, APH1B, HTR2B, ADRA2A, ADRA2B, ADRA2C, DRD1, DRD2, ADRA1D, HTR2A, HTR2C, DRD3, CYP2D6, HTR6, ADRA1A, HTR1B, RORC, TRPV1, AMY2A, MGAM, AMY1A, GAA, STAT3 Carbohydrate Fructose 24310 C1C(C(C(C(O1)(CO)O)O)O)O GBA, HSP90AA1, VEGFA, PSEN2, PSENEN, NCSTN, APH1A, PSEN1, APH1B, FGF1, FGF2, HPSE, CDK1, LGALS4, LGALS3, LGALS8 Carbohydrate Glucose 107526 C(C(C(C(C(C=O)O)O)O)O)O CHRNA7, FDFT1, ACLY, NPC1L1, GBA, PTGER2, PTGER, PYGB, G6PD, HMGCR, SLC22A6, PYGM Carbohydrate Manninotriose 5461026 C(C1C(C(C(C(O1)OCC2C(C(C(C(O2) HTR2B, ADRA2A, ADRA2B, ADRA2C, DRD1, DRD2, ADRA1D, HTR2A, HTR2C, DRD3, CYP2D6, OCC(C(C(C(C=O)O)O)O)O)O)O)O)O)O)O)O HTR6, ADRA1A, HTR1B, RORC, CDK1, VEGFA, STAT3, GLRA1, GLRA2, PSEN2, PSENEN, NCSTN, APH1A, PSEN1, APH1B, PPM1A, LGALS4, LGALS3, LGALS8, VDR, PTAFR, HSP90AA1, MGAM, HSD11B2, HSD11B1, AMY2A, OPRK1, AMY1A, GAA, CA2, CA1, CA12, CA9

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Figure 2. Component-target network of Rehmanniae Radix Praeparata before and after “steamed for nine times and dried for nine times”.

Rehmanniae Radix Praeparata is Mannino- and monosaccharides such as glucose and triose. RGP is mainly composed of glucose, ga- rhamnose were polymerized. Lots of scholars lactose, mannose and rhamnose, and has anti- believed that the Maillard reaction played an anxiety, anti-aging, anti-oxidation, immunity en- important role in the processing of Rehmanniae hancement, and anti-tumor effects. Studies Radix Praeparata [19]. However, the molecular have shown that the content of cycloenether- mechanism of the changes in pharmacological glycoside components such as catalpol, Reh- action before and after “steamed for nine times mannioside_D, and ajugol is decreased signifi- and dried for nine times” has not been clear cantly after “steamed for nine times and dried yet. In this study, 101 potential targets were for nine times”. The ester bond of the compo- predicted for 12 different components and a nent is fractured by heating. The content of PPI network was constructed. It is suggested mandiosin, a component of phenylethanolins, that the change in carbohydrate composition is also decreased, and the content of mandio- may be the main reason for the change to en- sin increased. Some scholars believed that this hancement of the tonic function (such as medi- was due to the reversible esterification reaction ating Notch signaling pathway, neuroactive that occurs during the processing process [31]. ligand-receptor interaction) after “steamed for 5-HMF is often considered to be a marker for nine times and dried for nine times”. quickly distinguishing between Rehmanniae Radix and Rehmanniae Radix Praeparata. Effect of Rehmanniae Radix Praeparata However, whether 5-HMF is a toxic ingredient or changing to “enhancement of the tonifying ef- a special active ingredient has not been con- fect” after “steamed for nine times and dried firmed yet. In addition, the content of polysac- for nine times” charides of Rehmanniae Radix Praeparata is increased obviously after “steamed for nine Rehmanniae Radix Praeparata has the cha- times and dried for nine times”. Scientists be- racteristics of promoting development, bone lieved the glycosides degraded during Z “stea- growth, and myelopoiesis. It plays an important med for nine times and dried for nine times” role in the differentiation of stem cells. Notch

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Figure 3. Protein-protein network of discrepant components and top 30 targets.

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Table 2. Main enriched GO terms related to Rehmanniae Radix Praeparata before and after “steamed for nine times and dried for nine times” Catalogy GO ID Description Genes P Value CC GO: 0005887 integral component of plasma membrane 30 1.71E-16 BP GO: 0007220 Notch receptor processing 5 7.62E-08 BP GO: 0071880 adenylate cyclase-activating adrenergic receptor signaling pathway 6 1.59E-07 BP GO: 0001975 response to amphetamine 5 1.51E-06 CC GO: 0070765 gamma-secretase complex 4 2.26E-06 BP GO: 0043085 positive regulation of catalytic activity 5 2.85E-06 MF GO: 0001609 G-protein coupled adenosine receptor activity 4 4.15E-06 MF GO: 0004935 adrenergic receptor activity 4 4.15E-06 BP GO: 0007200 phospholipase C-activating G-protein coupled receptor signaling pathway 6 6.17E-06 BP GO: 0001973 adenosine receptor signaling pathway 4 6.47E-06 MF GO: 0030246 carbohydrate binding 7 7.64E-06 BP GO: 0042493 response to drug 7 9.66E-06 MF GO: 0004175 endopeptidase activity 5 1.09E-05 MF GO: 0030594 neurotransmitter receptor activity 5 1.36E-05 BP GO: 0051209 release of sequestered calcium ion into cytosol 5 1.47E-05 BP GO: 0006730 one-carbon metabolic process 5 2.50E-05 BP GO: 0005980 glycogen catabolic process 4 2.68E-05 CC GO: 0031012 extracellular matrix 7 3.12E-05 MF GO: 0004993 G-protein coupled serotonin receptor activity 5 4.72E-05 MF GO: 0051378 serotonin binding 4 4.85E-05

Figure 4. Main enriched KEGG pathways related to Rehmanniae glotinosa before and after “steamed for nine times and dried for nine times”.

signaling pathway plays an important role in apoptosis. In recent years, scholars concen- regulating cell differentiation, proliferation, and trate on Notch signaling pathway because it is

13510 Int J Clin Exp Med 2019;12(12):13504-13513 Processing technology and Rehmanniae Radix Praeparata related to stem cell differentiation. Fu et al. fo- nine times and dried for nine times [23, 24]. We und that Rehmanniae Radix Praeparata poly- found that the potential targets of the different saccharide significantly inhibited the expres- components before and after “steamed for sion of Notch 1 protein and induced BMSCs to nine times and dried for nine times” were en- neurolike cells [21]. Du et al. believed that riched into glucose metabolism pathways, such some glycosyl components or ligand-receptor as starch and sucrose metabolism, galactose patterns in the ground yellow polysaccharide metabolism, fructose and mannose metabo- affected the extracellular subunit of the Notch lism. Catalpol can regulate these glycometa- protein, reducing the expression of the Note bolic pathways by regulating PYGM, MGAM, SI, receptor in the cell, thereby inhibiting the acti- HK1, HK2, and TREH. Other components, like vation of the signaling pathway and the expres- ajugol and Rehmannioside_A, also have hypo- sion of Hesl, hence promoting stem cells differ- glycemic effect by regulating MGAM, SI, TREH entiating to nerve cells [22]. This study found and other targets. The potential targets of sac- that the carbohydrate difference components charides are also enriched into the sugar me- changed (mainly salicose, cottonose, and man- tabolism pathway, such as sucrose [three gly- nose triose, etc.) before and after “steamed for cogen phosphatases (PYGB, PYGL, PYGM), MG- nine times and dried for nine times”, These AM, SI], cotton sugar (MGAM, GAA), glucose can mediate neuroactive ligand-receptor inter- (PYGB, PYGM) and so on. Changes in the com- actions by regulating DRD1, DRD2, DRD3, HTR- position of iridoids and sugars may be related 2A, HTR1B, HTR6, HTR2B, HTR2C, ADRA2A, to the weakening of the hypoglycemic effect of ADRA1A, ADRA2C, ADRA2B, ADRA1D, and TRP- Rehmanniae Radix Praeparata after “steamed V1. This type of carbohydrate component can for nine times and dried for nine times” [20]. participate in the Notch signal pathway through multiple targets such as PSEN1, PSEN2, PSE- Overall, we believed that the efficacy and phar- NEN, APH1A, and APH1N1 B. In addition, the macological effect of Rehmanniae Radix Prae- potential targets of different components of parata before and after “steamed for nine ti- sugar before and after “steamed for nine times mes and dried for nine times” is via multiple and dried for nine times” (NCSTN, APP, TNF, components, multiple targets, and multiple wa- PSEN1, APH1A, APH1N1 B, PSEN2, PSENEN) ys. We will do further experiment to validate the are also enriched into pathways involved in ner- predicted targets and underlying mechanisms vous system diseases, such as Alzheimer’s dis- of Rehmanniae Radix Praeparata in the future. ease. Those results show that these carbohydrate components may play an important role Acknowledgements in anti-aging and inducing BMSCs into neurolike cells through these pathways. This may pro- We are grateful to all the co-workers and part- vide a basis for further exploration of the mod- ners in this study. ern pharmacological mechanisms for the treatment of Alzheimer’s disease, promoting neural Disclosure of conflict of interest stem cell differentiation, paracrine, and the None. efficacy (“tonifying”) about Rehmanniae Radix Praeparata. Address correspondence to: Chaoqun Ma and Differences of hypoglycemic effect of Jirong Shen, Affiliated Hospital of Nanjing University Rehmanniae Radix Praeparata after “steamed of Chinese Medicine, Nanjing 210029, China. Tel: for nine times and dried for nine times” +86-13505195600; E-mail: [email protected] (CQM); Tel: +86-13813837751; E-mail: joint66118@ Rehmanniae Radix undergoing different pro- sina.com (JRS) cessing methods has a great influence on References the hyperglycemic and hyperlipemia. Wu et al. found that Rehmanniae Radix was better for [1] Hopkins AL. Network pharmacology: the next hypoglycemic effect and improving blood lipid paradigm in drug discovery. Nat Chem Biol than Rehmanniae Radix Praeparata in diabetic 2008; 4: 682-690. mice induced by streptozotocin, possibly due to [2] Zhang R, Zhu X, Bai H and Ning K. Network the loss of valid components after steamed for pharmacology databases for traditional Chi-

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