Chinese Medicine for Psoriasis Vulgaris Based on Syndrome Pattern: a Network Pharmacological Study

Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2020, Article ID 5239854, 16 pages https://doi.org/10.1155/2020/5239854

Research Article Chinese Medicine for Psoriasis Vulgaris Based on Syndrome Pattern: A Network Pharmacological Study

Dongmei Wang ,1,2,3 Chuanjian Lu ,2,3 Jingjie Yu,2,3 Miaomiao Zhang,2,3 Wei Zhu,2,3 and Jiangyong Gu 2,3,4

1Dermatology Hospital of Southern Medical University, Guangzhou 510091, China 2Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, China 3'e Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, China 4Department of Biochemistry, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

Correspondence should be addressed to Chuanjian Lu; [email protected] and Jiangyong Gu; [email protected]

Received 9 September 2019; Revised 13 January 2020; Accepted 23 January 2020; Published 28 April 2020

Academic Editor: Maria Camilla Bergonzi

Copyright © 2020 Dongmei Wang et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. -e long-term use of conventional therapy for psoriasis vulgaris remains a challenge due to limited or no patient response and severe side effects. Complementary and alternative treatments such as traditional Chinese medicine (TCM) are widely used in East Asia. TCM treatment is based on individual syndrome types. -ree TCM formulae, Compound Qingdai Pills (F1), Yujin Yinxie Tablets (F2), and Xiaoyin Tablets (F3), are used for blood heat, blood stasis, and blood dryness type of psoriasis vulgaris, respectively. Objectives. To explore the mechanism of three TCM formulae for three syndrome types of psoriasis vulgaris. Methods. -e compounds of the three TCM formulae were retrieved from the Psoriasis Database of Traditional Chinese Medicine (PDTCM). -eir molecular properties of absorption, distribution, metabolism, excretion and toxicity (ADME/T), and drug- likeness were compared by analyzing the distribution of compounds in the chemical space. -e cellular targets of the compounds were predicted by molecular docking. By constructing the compound-target network and analyzing network centrality, key targets and compounds for each formula were screened. -ree syndrome types of psoriasis vulgaris related pathways and biological processes (BPs) were enriched by the Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.8. Results. -e compounds of the three formulae exhibited structural diversity, good drug-like properties, and ADME/Tproperties. A total of 72, 97 and 85 targets were found to have interactions with compounds of F1, F2, and F3, respectively. -e three formulae were all related to 53 targets, 8 pathways, 9 biological processes, and 10 molecular functions (MFs). In addition, each formula had unique targets and regulated different pathways and BPs. Conclusion. -e three TCM formulae exhibited common mechanisms to some extent. -e differences at molecular and systems levels may contribute to their unique applications in individualized treatment.

1. Introduction decade, expanded understanding of psoriasis pathogenesis has led to the development of new systemic agents such as Psoriasis vulgaris is the most common type of psoriasis and biological drugs that have revolutionized the treatment of is characterized as sharply marginated, erythematous psoriasis [4, 5]. Moreover, the use of complementary and patches or plaques with silvery-white micaceous scales [1, 2]. alternative medicine including herbal medicine for subjects -e prevalence of psoriasis ranges from 0.91% to 8.5% across with psoriasis is increasing [6, 7]. Various traditional Chi- the world [3]. It causes a significant burden to patients nese medicines (TCMs) are widely used to treat psoriasis on including physical and psychological symptoms. Due to the basis of the unique clinical therapeutic theory and complex and unclear pathogenic factors, the treatment successful clinical applications [8–12]. -e clinical effec- options for psoriasis remain unsatisfactory. Over the last tiveness of TCMs for psoriasis has been validated by 2 Evidence-Based Complementary and Alternative Medicine controlled clinical trials [13] and meta-analysis [14]. Con- interactions with multiple targets make it difficult to elu- trolled trials also demonstrate that the combination of TCM cidate the mechanism of action (MoA) of TCM. In recent with traditional therapies for psoriasis is more efficacious years, network pharmacology is rapidly becoming a [15]. promising tool to reveal the pharmacodynamic material In the view of the therapeutic potential of Chinese basis and systematic features of TCM [28–30]. In this work, medicine, the diagnosis and treatment of psoriasis vulgaris a network pharmacology study was performed to explore are based on a group of individual symptoms, which is called the MoA of three TCM formulae for different syndrome as syndrome type or patterns [16, 17]. Psoriasis vulgaris is types of psoriasis by integrating ADME/T (absorption, classified as three main blood-related phenotypes in Chinese distribution, metabolism, excretion, and toxicity) analysis, medicine: blood heat, blood stasis, and blood dryness [8]. target prediction, drug-target network construction, and Blood heat is characterized by bright red papules with gene set enrichment analysis. -e results indicated that pruritus. Auspitz’s sign appears following removal of the multiple compounds of each formula could interact with scale. -e feature of blood dryness type manifests as light red multiple cellular targets and therefore regulate multiple and patchy particles, covered with plenty of dry silvery-white pathways and BPs. In addition, three TCM formulae were scales. With regard to blood stasis type, dull red, hard, and associated with the same group of targets, pathways, BPs, thick plaques are covered by thick, dry, silvery-white scales, and MFs, while each TCM formula also exhibited unique with itchiness [18]. -e syndrome type classification of profile. Our findings will provide a preliminary basis for patients with psoriasis vulgaris may vary according to the syndrome differentiation and treatment of psoriasis by changes of the symptoms. -e distribution of the three TCM. syndromes is closely related to the stage of psoriasis vulgaris. Blood heat, blood dryness, and blood stasis syndromes are 2. Materials and Methods commonly noted in progressive stage, extinction stage, and stationary stage of this disease, respectively [8]. -erefore, 2.1. Data Collection. -e herbal compositions of the three different syndrome types of psoriasis require different formulae were collected from the Chinese Pharmacopoeia therapeutic regimens. (2015 Edition). Subsequently, the chemical identifications, TCM formulae are mainly oral systematic drugs and the physicochemical properties, and 3D structures of com- selection of appropriate treatment is based on the different pounds (Table S1) which existed in each herb were retrieved syndrome type of psoriasis. -ese formulae can be used in from the Psoriasis Database of Traditional Chinese Medicine the form of Chinese herbal medicine decoction or com- (PDTCM) [31]. -e structures of the FDA-approved drugs mercial products, such as pills and tablets. for psoriasis were downloaded from DrugBank [32]. -e -ree commercially available herbal products are fre- psoriasis-associated proteins (Table S2) were collected from quently used in the oral treatment of psoriasis vulgaris. three sources: the targets of psoriasis drugs from DrugBank, According to the Chinese Pharmacopoeia (2015 Edition), the psoriasis-related targets from the -erapeutic Target Compound Qingdai Pills (F1), Yujin Yinxie Tablets (F2), and Database (TTD) [33] and PDTCM, and the targets sum- Xiaoyin Tablets (F3) are commonly used for blood heat, marized from the literature which have been reported in a blood stasis, and blood dryness type of psoriasis vulgaris, previous work [34]. respectively (Table 1). -ese formulae have been investigated in several clinical and experimental studies. Evidences from experimental studies suggest that F1 decreases the expres- 2.2. Analysis of ADME/T Properties, Drug-Likeness, and sion level of c-myc in keratinocytes, which can inhibit the Distribution in the Chemical Space. -e ADME/T descrip- hyperproliferation of these cells [19, 20]. Moreover, it has tors (Aqueous Solubility, Blood Brain Barrier Penetration, been reported that F1 modulates immunological function CYP2D6 Binding, Hepatotoxicity, Intestinal Absorption, [21]. A randomized controlled trial indicates that F1 could and Plasma Protein Binding) of the compounds in the three enhance the clinical efficacy and increase the number of TCM formulae were calculated by ADME/T Descriptors patients who achieve the psoriasis area and severity index 60 module of Discovery Studio (DS) v2.5 (Figure S1). A total (PASI 60) as an add-on therapy to acitretin and mometasone of eight molecular descriptors (molecular hydrophobicity furoate [22]. An in vivo study demonstrates that F2 could (AlogP), molecular weight, number of hydrogen bond decrease the expression levels of keratinocyte growth factor donors, number of hydrogen bond acceptors, number of and amphiregulin in Balb/c nude mice and downregulate the rotatable bonds, number of rings, number of aromatic expression levels of KGF and AREG mRNAs [23]. In ad- rings, and molecular fractional polar surface area) of the dition, F2 could inhibit the phagocytosis process of mac- compounds and drugs were calculated by the General rophages and thus modulates immunological response [24]. Purpose module of DS. Principal component analysis In a noncontrolled study, F2 has been proven to improve the (PCA) was conducted in the Library Analysis module of DS clinical outcome of 313 patients with psoriasis [25]. -e by using the aforementioned molecular descriptors. -e therapeutic efficacy of F3 for 60 patients with psoriasis is resulting three principal components (PC1, PC2, and PC3) validated by comparison with another TCM formula (Yin were used to reduce the dimension of molecular descrip- Xie Ping Granule) [26, 27]. tors, which can explain 89.5% of the total variance of these Each TCM formula consists of several herbs (Table 1). molecular descriptors. Subsequently, the distributions of -erefore, the presence of multiple components and their compounds and drugs in the chemical space were Evidence-Based Complementary and Alternative Medicine 3

Table 1: Herbal compositions of three TCM formulae indicated for psoriasis vulgaris. Syndrome Formula Composition type Baphicacanthus cusia, Prunus mume, Taraxacum mongolicum, Arnebia euchroma, Angelica Compound Qingdai dahurica, Salvia miltiorrhiza, Dictamnus dasycarpus, Dryopteris crassirhizoma, Smilax glabra, Blood heat Pills (F1) Portulaca oleracea, Dioscorea hypoglauca, Crataegus pinnatifida, and Schisandra sphenanthera Gentiana macrophylla, Angelica sinensis, Acorus tatarinowii, Phellodendron amurense, Cyperus Yujin Yinxie Tablets rotundus, Curcuma wenyujin, Curcuma kwangsiensis, Strychnos nux-vomica, Gleditsia sinensis, Blood stasis (F2) Prunus persica, Carthamus tinctorius, Boswellia carterii, Rheum palmatum, Eupolyphaga sinensis, Baphicacanthus cusia, and Momordica cochinchinensis Rehmannia glutinosa, Isatis indigotica, Paeonia suffruticosa, Paeonia lactiflora, Angelica sinensis, Blood Xiaoyin Tablets (F3) Sophora flavescens, Lonicera japonica, Scrophularia ningpoensis, Arctium lappa, Cryptotympana dryness pustulata, Dictamnus dasycarpus, Saposhnikovia divaricata, and Carthamus tinctorius

6 20

3 10 0 PC3 PC3 0 –3

–10 20 –6 –8 6 0 3 10 0 20 0 0 8 PC1 40 PC2 PC1 –3 PC2 16 60 –10 –6

Drugs F1 F1_F2_F3 F2 F3 (a) (b)

50 40 60 40 30

30 40 20 20 10 20 Percentage in F1/F2/F3 Percentage in F1/F2/F3 10 Percentage in F1/F2/F3

0 0 0 012 34 012 3 4 5 012 ADMET absorption level ADMET solubility level ADMET hepatotoxicity level

F1-ADMET F1-ADMET F1-ADMET F2-ADMET F2-ADMET F2-ADMET F3-ADMET F3-ADMET F3-ADMET (c) (d) (e)

Figure 1: Drug-likeness and ADME/T properties of compounds in three TCM formulae for psoriasis. (a) Distributions in chemical space of FDA-approved drugs for psoriasis and compounds in three TCM formulae. (b) Distributions in chemical space of compounds in each TCM formula. Level of ADME/T absorption (c), solubility (d), and hepatotoxicity (e). illustrated by using these three principal components as 2.3. Molecular Docking. -e compound-target interaction coordinates (Figure 1). -e distributions of four drug-like was simulated by molecular docking. -e X-ray or NMR properties (AlogP, molecular weight, number of hydrogen structures were downloaded from the RCSB Protein Data bond acceptors, and that of and donors; see Table 2) were Bank and treated to be suitable for molecular docking by illustrated in Figure 2. AutoDock v4.2.6 [35] according to the protocols described 4 Evidence-Based Complementary and Alternative Medicine

Table 2: Statistics of molecular descriptors of compounds of three TCM formulae. Formula ALogP Molecular weight (Da) No. of hydrogen bond acceptors No. of hydrogen bond donors No. of compounds F1 2.65 ± 2.69 384.23 ± 163.12 6.54 ± 4.79 2.91 ± 2.91 857 F2 2.37 ± 3.32 428.06 ± 314.44 7.16 ± 8.09 3.86 ± 4.76 1084 F3 1.56 ± 3.37 431.31 ± 230.42 8.19 ± 6.19 4.33 ± 3.87 1295

14 30 12

10 20 8

6 10 Percentage in F1/F2/F3 4 Percentage in F1/F2/F3

0 0 –10 –5 0 51015 0 400 800 1200 1600 ALogP Molecular weight range

F1 F1 F2 F2 F3 F3 (a) (b) 25 16 20

12 15

8 10 Percentage in F1/F2/F3 Percentage in F1/F2/F3 4 5

0 0 0 10 20 30 40 0 5 10 15 20 Number of hydrogen bond acceptors Number of hydrogen bond donors

F1 F1 F2 F2 F3 F3 (c) (d)

Figure 2: Distributions of four drug-like properties. AlogP (a), molecular weight (b), number of hydrogen bond acceptors (c), and that of donors (d). in a previous work [34]. -e energy grid was a 30 × 30 × 30 A˚ and 0.02, respectively. Other parameters were set to default. cube centered on the occupied space of the original ligand -e binding energy calculated by AutoDock was used to with a spacing of 0.375 A˚ between the grid points. -e evaluate the aﬃnity between each compound and target Lamarckian genetic algorithm (LGA) was used to optimize protein. the conformation of each compound in the binding pocket. -e parameters for LGA were listed as follows: the number of individuals in population, the maximum number of 2.4. Construction of Compound-TargetNetwork. -e binding energy evaluations, the maximum number of generations, energy was used to evaluate the aﬃnity between the com- and the rate of gene mutation set as 150, 2.5 ×107, 2.7 ×104, pound and the target. In general, the binding energy can be Evidence-Based Complementary and Alternative Medicine 5

transferred to the inhibition constant Ki. In this work, the hydrogen bond donors of the compounds between F1 and threshold of binding energy was set to − 12.28 kcal/mol (the F2, F1 and F3, and F2 and F3 were 0.0056, 0.049, 0.13; 0.024, estimated inhibition constant Ki was approximately 1 nM) 0.12, 0.14; 4.8E − 12, 8.7E − 15, 7.4E − 11; and 0.20, 0.31, 0.27, for each compound and target (Table S3). respectively (Figure 2). In general, F2 had better similarity Subsequently, the data of the compound-target inter- with F3. Meanwhile, the compounds in three TCM formulae actions was imported into Cytoscape v3.6.0 [36] to construct exhibited significant differences in the distributions of hy- the compound-target network (CTN) for each TCM formula drogen bond acceptors. -e compounds of F1 had larger (Figure 3). -e network centralities of nodes (compounds average value of AlogP than the compounds of F2 and F3. and targets) were calculated by the Network Analyzer -erefore, similar ADME/T and physicochemical properties module of Cytoscape [37]. -e degree centrality was used to enabled the targeting of these compounds in the same group evaluate the importance of the targets and compounds in of proteins and the regulation of psoriasis-associated bio- CTNs (Tables 3 and 4). logical processes. Due to different properties and structural diversity, several compounds could also bind to different targets, which would lead to different molecular mechanisms 2.5. Gene Set Enrichment Analysis by DAVID. -e gene set for the treatment of different syndrome types of psoriasis by enrichment analysis was carried out on the web service of the each TCM formula. Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.8 [38]. -e gene list for each TCM formula was transferred from the CTN. -e KEGG pathways 3.2. Compounds in 'ree TCM Formulae Have Multiple and the Gene Ontology (GO) terms (biological processes Targets. -e TCM formula had multiple components and and molecular functions) were enriched for each gene list by can interact with multiple cellular targets. -erefore, mul- using the following parameters: the threshold of enriched tiple biological processes (BPs) would be regulated in a genes and P value were 3 and 0.05, respectively (Table S4). holistic manner. -e characteristics of “multicomponents -e top twenty GO terms and KEGG pathways which were and multitargets” of TCM can be illustrated by a bipartite significantly associated with the targets were further illus- CTN, which is composed of compounds and proteins linked trated by bubble diagrams (Figures 4–6) drawn by the by compound-target interactions [41, 42]. -e CTN of F1 ggplot2 package [39] in R 3.5.1. (Figure 3(a)) comprised 170 nodes (98 compounds and 72 targets) and 420 edges. -e CTN of F2 (Figure 3(b)) con- 3. Results sisted of 241 nodes (144 compounds and 97 targets) and 689 edges. A total of 189 nodes (104 compounds and 85 targets) 3.1. Compounds in 'ree TCM Formulae Have Good ADME/T and 354 edges were found in the CTN of F3 (Figure 3(c)). A and Drug-Like Properties. -e three TCM formulae (F1, F2, total of 53 common targets were associated with all three and F3) contained 857, 1084, and 1295 compounds, re- TCM formulae. In addition, a total of 6, 20, and 7 common spectively. -e statistics of the molecular properties dem- targets were associated with F1 and F2, F2 and F3 and, and onstrated that the majority of compounds obeyed Lipinski’s F1 and F3, respectively (Figure 3(d)). rule of five (Ro5) [40], which was frequently used to evaluate Typically, a compound would interact with several the drug-likeness of the compounds (Table 2). -e PCA proteins and the polypharmacological effects are highly results of the FDA-approved drugs and compounds in the enriched in those compounds with large degree centrality in three TCM formulae indicated a large overlap between their CTN [41, 43, 44]. -erefore, key targets (Table 3) and distributions in the chemical space (Figure 1(a)), which also compounds (Table 4) can be identified by degree centrality suggested that these compounds exhibited good drug-like in CTNs for F1, F2, and F3, respectively (Figures 3(a)–3(c)). properties. -ese key targets may participate in the same BP or a group -ese compounds also had good ADME/T properties, of related BPs. In addition, multiple compounds can bind to which can promote their oral bioavailability (Figure S1). -e a common protein and exert a synergistic or antagonistic ADME/Tand physicochemical properties of the compounds effect [45]. in the three TCM formulae were similar. First, the com- -e ingredients of F1, F2, and F3 have affinities with 12, pounds of each TCM formula exhibited approximately even 21, and 12 key targets (degree of target node ≥10), re- distribution in the chemical space (Figure 1(b)). -e scat- spectively (Table 3). Seven common key targets (Figure 3(e)) tered distributions indicated that these compounds were associated with all three TCM formulae as follows: appeared to have some degree of structural diversity. Second, Glucocorticoid receptor (UniProt: P04150), Adrenodoxin the ADME/T levels of absorption, solubility, and hepato- (UniProt: P10109), Retinaldehyde-binding protein 1 (Uni- toxicity in each TCM formula did not have significant Prot: P12271), Phospholipase A2 (UniProt: P14555), Cy- differences (Chi-squared test, P value >0.05) (Figures 1(c)– tochrome P450 11B2 (UniProt: P19099), Corticosteroid 11- 1(e)). -ird, four molecular properties (with the exception beta-dehydrogenase isozyme 1 (UniProt: P28845), and of the number of hydrogen bond acceptors) of Ro5 for ADP-ribosylation factor 1 (UniProt: P84077). -ese proteins each TCM formula exhibited broadly similar distributions would play critical roles in the treatment of psoriasis. With (Figure 2). P values of the Chi-squared tests for the dis- the exception of common key proteins, F1 and F2 had 3 and tributions of molecular hydrophobicity (AlogP), molecular 7 unique key targets, respectively. However, F3 was an weight, number of hydrogen bond acceptors, and number of exceptional case. -e target set of F3 was a part of that of F2 6 Evidence-Based Complementary and Alternative Medicine

M017130 P06126 Q07869 P11387 P09210 Q9UGN5 M006672 M025711 M006830 M007281 M018092 M024014 M028158 P12931 M017688 M014228 M013275 P52333 M017134 P26358 M020101 P20815 M014455 M024671 M017131 M023861 M027410 M017133 P19099 M027323 M015525 M009523 M010708 M023877 M027170 M021137 M021081M031368 O75469 M027461 M007272 Q9BTZ2 M024092 Q13946 M019514 M001191 P04049 M005695 M014063 M001968 M000208 P14555 M005571 M012765 M021322 M003009 M020920 P04150 P27815 M021791 M018967 P11388 M030466 P15328 M020498 P60763 M018528 P11473 M002504 M029090 M001859 M020662 Q8N8N7 P28845 M021602 M033307 P12271 M023507 P10109 Q08499 P35367 M013708 M014578 P05108 M009539 P84077 P08253 M015349 M032128 P05093 M020716 M011284 P15121 P56524 M003914 P08235 M026275 M014132 P42345 M002163 O14727 M028941 M030585 M017132 P37231 M013272 M002206 M014422 M002520 P06401 M004287 M014384 Q02763 P33261 Q9UNQ0P51580 P20839 P03956 M033147 P12104 P05106 M029686 M028141 Q02127 Q02750 M007243 M019381 M010568 M031236 M027665 Q03181 P10826 M004977 M001683 P07550 O67135 P27707 P09455 P13631 M027649 M031332 P04798 Q00535 Q16647 M024245 M004752 M024528 P08631 P04629 O43741 P13569 M020456 P04626 P00374 P17948 M010890 P39900 M015561 M012680 M000897 M004997 M027905 P35228 M024621P17612 P60484 O15379 P14780 (a)

M011674 P06702 M015525 M010816 P02774 P41743 P04271 M031837 M021875 M010872 Q07889 M014281 Q9Y6F1 P17252 P35222 M022588 M031458 M027425 Q02763 P27707 M013211 O14920 M018782 M002702 M005019 P13569 M033801 M010937 P11388 M026864 M012230 M004987 M016360 M001194 M016362 M025624 M010214 M008365 M006064 P20292Q16647 M007948 P37231 P00374 M024671 M013325 Q9UGN5 M016361 M012261 M028991 M022840 P60763 Q07869 P00439 M014582 Q03181 M003668 M009447 M004705 M019628 M028517 P11473 M012419 M013387 P19652 P09210 P15144 M025381 M033654 P28482 M032923 M028420 P05093 M010294 P14555 M003198 P05108 M007237 Q9UNQ0 P05106 P27815 Q08499 M030585 P09917 P00813 M000881 M031021 M030014 M029693 Q8N8N7 M005571 P19793 P08235 M006421 M026605 P04818 M006317 P35228 P26010 P28845 M002939 P29474 M032856 M007619 P08253 M020032 M027875 P04798 M001683 M004519 M020429 M001859 M024435 P10109 M021203 M002280 M002205 Q07343 M007187 P04150 P12271 M016866 M019624 P06401 M019201 P20701 P02741 M029426 M010232 M033909 P42345 P08631 M018773 P05771 M003338 M002163 P06126 M003214 M010231 M008874 M026718 M011995 P03956 M015955 M025306 M027410 P10826 P20815 Q13490 M008463 M032246 P15121 M025532 P11387 P00492 O14757 M031808 M025726 P13631 M008302 P07550 P47712 M007599 M025864 P14780 M021266 P33261 M024164 M012713 P39900 P56524 P23458 O75469 P19099 M003009 M014517 M026099 M024666 O14727 M004329 M034198 M024634 P35968 P09455 M029090 M011032 M024929 Q13946 M004842 M025298 P35354 M001215 M009135 M008764 P15328 M001790 M003669 M024758 P00519 P51580 M023117 Q08345 M008598 M028060 Q9BTZ2 O67135 P15309 M032629 M034061 M007663 M010708 M021732 M012665 M001762 M023861 M021181 M013715 P17948 M021319

M008658 M017584 M025414 M017778 Q02127 P11511 Q02750 P42684 P03372 P52333 P12104 M014910 M012982 M025438 P84077 M005541 P08183

M014455 M028033 M028329 M001099 M014267 (b) Figure 3: Continued. Evidence-Based Complementary and Alternative Medicine 7

M024095 M020216 O67135 Q03181 P04049 M011375 P00439 P15328

M011744 M008651P10721 F1 F2 M001118 M002414 P20839 M022651 M022262P39900 Q02763 Q08345 P37231 5 6 18 P04798 M004997 P14780 P09210 P00519 M004115 P17948 (4.4%) (5.3%) (15.8%) P15144 P10276 M023863 M030533 M022421 P35367 P42684 P26010 P02741 Q13490 Q00535 P05106 M004402M005940 P26358 Q9UNQ0 M012532 M000486 P51580 M030099 P03956 P15309 M004490 53 P47712 M019624 P00813 P13631 O14727 M008374 P08631 Q8N8N7 P12931 P35968 P29474 (46.5%) P00492 M017663 M000604 M034243 P27815 M002205 M023398 P06401 P10826 M010231 7 20 P08253 P12104 O14920 Q07343 M003214 P11387 M001683 M011161 M011831 Q08499M002146 M014910 P35228 (6.1%) (17.5%) M007243 P07550 P56524 M031485 P20292 P15121 P35354 P50613 P04150 P06126 P09455 M026782 M028923 M028060 Q16647 M030600 M007037 P12271M032246 M002031 O15379 M020101 M033909 M003009 P20815 M022800 P05108 P05093 M034322 M019114 M008793M030971 P11511 Q13946 M011330 M021771 M025532M024765 5 Q9UGN5 M005571 M010294 M023117 M020920 P08235M025624 M021065 M005746 P60763 P09874M014001 (4.4%) M034061 M020498M011886 P08183 M026718 P19099 M001859 M019816 M029090 M024671 P10109 M003682M018331 M000208 P11473 P14555 P52333 M021458 F3 P11388 M033351 M010283 M010708 M019514 M023861 M025438 P33261 M001239M023307 M021266 M015525 M011639M019343M020556 P84077 M019534 P28845 P27707 M020162 M021952 M006672 M024523 M019340M030304 P42345 M025643 M012483 M025991M010212 O75469 M015599 M027410 M012440P36507 M003342 M012665 (c) (d)

F1 F2 3 2 7 (12.5%) (8.3%) (29.2%)

7 (29.2%) 0 5 (0%) (20.8%)

0 (0%) F3

(e)

Figure 3: Compound-target networks. CTN for F1 (a), F2 (b), and F3 (c). -e ellipse and triangle represent target and compounds in three TCM formulae, respectively. -e color of target node represents the correlation between the target and three TCM formulae. If a target is related to only one TCM formula, the color is blue. If a target is related to F1 and F2, or F2 and F3, or F1 and F3, the color is yellow, green, and purple, respectively. And if a target is related to all three TCM formulae, the color is red. (d) Venn diagram of common targets in each formula. (e) Venn diagram of common key targets in each TCM formula.

(Figure 3(e)), which was in accordance with their clinical in patients with psoriasis vulgaris [49]. Second, Phospho- applications. lipase A2 is implicated in lipid signaling and inflammatory -ese key proteins would play critical roles in the diseases [52], and the activity of phospholipase A2 in human treatment of psoriasis. First, three proteins (P04150, P10109, psoriatic skin is regulated by systematic treatment with a and P28845) were involved in metabolism and signaling of retinoic acid derivative [53]. -ird, Retinaldehyde-binding sterol and steroid. For example, Corticosteroid 11-beta- protein 1 is a soluble retinoid carrier and participates in the dehydrogenase reversibly converts cortisol to the inactive regeneration of active 11-cis-retinol and 11-cis-reti- metabolite cortisone and is related to glucocorticoid bio- naldehyde, which presumably leads to disruption of retinal synthetic process (Gene Ontology (GO): 0006704) [46]. vitamin-A metabolism (GO: 0006776) [54]. Fourth, ADP- Adrenodoxin is essential for the synthesis of various steroid ribosylation factor 1 is a GTP-binding protein that functions hormones and participates in the reduction of mitochon- as an allosteric activator of ADP-ribosyltransferase. -is drial cytochrome P450 for steroidogenesis [47, 48]. Glu- multifunctional protein can regulate cell proliferation, mi- cocorticoid receptor affects inflammatory responses, cellular gration, and fusion [55]. Finally, Cytochrome P450 (CYP) is proliferation, and differentiation [49–51]. Evidence indicates the sole enzyme responsible for the production of aldoste- that decreased expression of Glucocorticoid receptor may rone in humans [56] and participates in the metabolism of play an important role in the degeneration of keratinocytes therapeutic drugs, fatty acids, eicosanoids, sterols, steroids, 8 Evidence-Based Complementary and Alternative Medicine

Table 3: Key targets according to CTNs. Formula UniProt ID Degree Protein name F1 P19099 41 Cytochrome P450 11B2, mitochondrial F1 P28845 32 Corticosteroid 11-beta-dehydrogenase isozyme 1 F1 P84077 24 ADP-ribosylation factor 1 F1 P04150 19 Glucocorticoid receptor F1 P14555 16 Phospholipase A2, membrane associated F1 P12271 15 Retinaldehyde-binding protein 1 F1 P10109 14 Adrenodoxin, mitochondrial F1 P11388 14 DNA topoisomerase 2-alpha F1 P08235 14 Mineralocorticoid receptor F1 P37231 14 Peroxisome proliferator-activated receptor gamma F1 P11473 12 Vitamin D3 receptor F1 P33261 11 Cytochrome P450 2C19 F2 P19099 51 Cytochrome P450 11B2, mitochondrial F2 P28845 48 Corticosteroid 11-beta-dehydrogenase isozyme 1 F2 P84077 32 ADP-ribosylation factor 1 F2 P10109 28 Adrenodoxin, mitochondrial F2 P12271 28 Retinaldehyde-binding protein 1 F2 P03956 22 Interstitial collagenase F2 P14555 22 Phospholipase A2, membrane associated F2 P04150 22 Glucocorticoid receptor F2 P05108 21 Cholesterol side-chain cleavage enzyme, mitochondrial F2 P56524 18 Histone deacetylase 4 F2 P08235 17 Mineralocorticoid receptor F2 P39900 16 Macrophage metalloelastase F2 P10826 16 Retinoic acid receptor beta F2 O67135 14 Acetoin utilization protein F2 Q8N8N7 14 Prostaglandin reductase 2 F2 P08253 14 72 kDa type IV collagenase F2 O75469 13 Nuclear receptor subfamily 1 group I member 2 F2 P29474 11 Nitric oxide synthase, endothelial F2 P15121 11 Aldose reductase F2 P05093 10 Steroid 17-alpha-hydroxylase/17,20 lyase F2 P11473 10 Vitamin D3 receptor F3 P19099 41 Cytochrome P450 11B2, mitochondrial F3 P84077 20 ADP-ribosylation factor 1 F3 P10109 13 Adrenodoxin, mitochondrial F3 O67135 13 Acetoin utilization protein F3 P03956 13 Interstitial collagenase F3 P12271 12 Retinaldehyde-binding protein 1 F3 P04150 12 Glucocorticoid receptor F3 P05108 10 Cholesterol side-chain cleavage enzyme, mitochondrial F3 P56524 10 Histone deacetylase 4 F3 P39900 10 Macrophage metalloelastase F3 P28845 10 Corticosteroid 11-beta-dehydrogenase isozyme 1 F3 P14555 10 Phospholipase A2, membrane associated vitamin A, and vitamin D [57–60]. It has been reported that, Other four herbs (Arnebia euchroma, Dryopteris crassirhi- in some skin diseases, for example, in psoriasis, the ex- zoma, Portulaca oleracea, and Angelica dahurica) contained pressions of many types of CYP are elevated, and CYP is three, two, and one key compounds, respectively. F2 had 17 regarded as a target in the development of drugs for skin key compounds from seven herbs. F3 had 8 key compounds diseases [59]. from ﬁve herbs. Key compounds (Table 4) for each TCM formula were -ere were 14 key compounds of F1. -e biological screened by applying a somewhat arbitrary threshold (the activities related to the pathogenesis of psoriasis of several degree in CTN was greater than or equal to 10). F1 and F2 key compounds are known. For example, Schinalactone A had a common key compound ((24R)-24-ethylcholest-4-en- has signiﬁcant cytotoxicity against SK-BR-3, PANC-1, 3, 6-dione). F2 and F3 contained three common key com- and A-549 cell lines with IC50 values of 5.2, 5.9, and pounds (β-Carotene, 5-Phenylpentan-1,3, 4-triamine, and 17.7 μM, respectively [61]. Ergone exhibits inhibitory Clerosterol). A total of 14 key compounds were noted for F1. activity of nitric oxide production in RAW264.7 cells A total of eight key compounds were separated from stimulated by lipopolysaccharide with the IC50 value of Schisandra sphenanthera, which is worthy of attention. 28.96 μM [62]. Evidence-Based Complementary and Alternative Medicine 9

Table 4: Key compounds according to CTNs. Formula Compound ID Degree Chemical name Herb source F1 M014384 25 Schinalactone A Schisandra sphenanthera F1 M018528 19 Schisphendilactone B Schisandra sphenanthera F1 M004977 16 Dryocrassyl acetate Dryopteris crassirhizoma F1 M002520 14 β-Sitostenone Portulaca oleracea F1 M002163 13 (24R)-24-ethylcholest-4-en-3,6-dione Arnebia euchroma (F1) and Gleditsia sinensis (F2) F1 M031368 13 Schisanola Schisandra sphenanthera F1 M014132 12 Schisanola Schisandra sphenanthera F1 M027649 12 Dahuribirin D Angelica dahurica F1 M004287 11 Anwuweizic acidb Schisandra sphenanthera F1 M018092 11 Schisphendilactone A Schisandra sphenanthera F1 M011284 11 Schisandronic acid Schisandra sphenanthera F1 M020716 11 Anwuweizic acidb Schisandra sphenanthera F1 M013272 10 Ergone Arnebia euchroma F1 M010568 10 Dammara-18(28),21-diene Dryopteris crassirhizoma F2 M020429 32 Strychnoflavine Strychnos nux-vomica F2 M019628 32 Demethoxyguiaflavine Strychnos nux-vomica F2 M020032 32 N/A Strychnos nux-vomica F2 M018782 28 Nb-methyl-longicaudata Strychnos nux-vomica F2 M019201 18 Strychnochrysinec Strychnos nux-vomica F2 M024929 16 Luteoxanthin Prunus persica F2 M029426 16 5α-Stigmastan-3,6-dione Gleditsia sinensis F2 M010231 14 β-Carotene Lonicera japonica (F3) and Momordica cochinchinensis (F2) F2 M015955 13 Strychnochrysinec Strychnos nux-vomica F2 M002163 13 (24R)-24-ethylcholest-4-en-3,6-dione Arnebia euchroma (F1) and Gleditsia sinensis (F2) F2 M012713 13 α-Carotene Momordica cochinchinensis F2 M019624 11 5-Phenylpentan-1,3,4-triamine Angelica sinensis F2 M026864 11 Ergosterol peroxide Cyperus rotundus F2 M024435 11 Campesterol Prunus persica F2 M028420 10 Sitosterol Prunus persica F2 M002205 10 Clerosterol Carthamus tinctorius F2 M003669 10 Lutein Momordica cochinchinensis F3 M008651 18 4′-O-Methylochnaflavone Lonicera japonica F3 M030533 16 (8R,8′R)-Auroxanthin Lonicera japonica F3 M010231 14 β-Carotene Lonicera japonica (F3) and Momordica cochinchinensis (F2) F3 M019624 11 5-Phenylpentan-1,3,4-triamine Angelica sinensis F3 M023863 11 Lappaphen-b Arctium lappa F3 M011831 10 Pyropheophorbide Isatis indigotica F3 M000604 10 Lappaphen-a Arctium lappa F3 M002205 10 Clerosterol Carthamus tinctorius Note that a, b, c these two compounds were enantiomers.

F2 had 17 key compounds from seven herbs. effects [75]. Sitosterols may be related to cholesterol Luteoxanthin has antiproliferative effect in combination metabolism or anti-inflammatory effects via interference with the anticancer drug epirubicin [63]. 5α-Stigmastan- with prostaglandin metabolism [76]. Clerosterol inhibited 3, 6-dione has anti-inflammatory effect [64]. β-Carotene the growth of A2058 cells with an IC50 of 150 μM [77]. has close relationship with psoriasis [65] and is an ef- Lutein has antitumor and antiproliferative activities fective and safe treatment for patients with mild, chronic, [78, 79]. plaque-type psoriasis [66]. Patients with psoriasis have an F3 had 8 key compounds from five herbs. 4′-O-meth- increased risk of other health problems, and observational ylochnaflavone is a bioflavonoid which shows suppressive studies suggest that β-Carotene might help prevent these activity against lymphocyte proliferation [80]. Auroxanthin conditions, such as type 2 diabetes [67], rheumatoid ar- [81] and Pyropheophorbide [82] have antioxidant activity. thritis [68], asthma [69], and metabolic syndrome [70]. -ese key proteins were involved in the pathogenesis of Ergosterol peroxide suppresses inflammatory responses in psoriasis vulgaris and would be promising targets for the RAW264.7 macrophages [71] and has in vitro anti- discovery of novel drugs. -e key compounds for each TCM proliferative activity [72]. It also shows anticancer activity formula could play important roles in the treatment of this by downregulation of the β-catenin pathway in colorectal disease and contribute to the pharmacodynamic material cancer [73, 74]. Campesterol can inhibit proliferation and basis. Appropriate optimization of these compounds may has anti-inflammatory, antibacterial, and anticancer provide new leads. 10 Evidence-Based Complementary and Alternative Medicine

Top 20 pathways enriched by DAVID for F1 Top 20 pathways enriched by DAVID for F2 hsa05230 hsa05223 hsa05223 hsa05222 hsa05221 hsa05221 hsa05219 hsa05219 hsa05216 No. genes involved hsa05216 No. genes involved hsa05215 3 hsa05214 3 4 hsa05214 hsa04961 4 5 5 hsa05213 hsa04960 6 6 hsa05212 hsa04913 7 hsa05204 7 hsa04730 hsa04919 hsa04664 8 −log (P value) hsa04917 10 hsa04370 9 KEGG pathway hsa04915 KEGG pathway hsa04320 5 P hsa04913 hsa04150 −log10 ( value) hsa04912 4 hsa04066 6 hsa04370 3 hsa04012 5 hsa04066 2 hsa03320 4 hsa04012 hsa00591 3 hsa03320 hsa00590 2 hsa00140 hsa00140

10 15 7.5 10.0 12.5 15.0 Enrichment fold Enrichment fold (a) (b) Top 20 pathways enriched by DAVID for F3 hsa05230 hsa05222 F1 F2 hsa05221 No. genes involved hsa05220 4 3 5 hsa05219 3 (12.5%) (9.4%) (15.6%) 4 hsa05204 5 hsa04917 6 hsa04915 8 7 hsa04913 (25%) hsa04912 8 5 4 hsa04664 (15.6%) (12.5%) P hsa04662 –log10 ( value) KEGG pathway hsa04370 5 hsa04066 4 3 hsa04012 (9.4%) hsa03320 3 hsa00980 2 hsa00591 F3 hsa00590 hsa00140

5.0 7.5 10.0 12.5 Enrichment fold (c) (d)

Figure 4: Top twenty KEGG pathways enriched by DAVID. (a), (b), and (c) for F1, F2, and F3, respectively. Venn diagram of common pathways (d) for three TCM formulae.

3.3. TCM Formula Systematically Regulates Human Body. signaling pathway, and hsa04012: ErbB signaling pathway), -e compounds of each TCM formula can interact with two steroid-related pathways (hsa00140: steroid hormone different sets of cellular targets and subsequently regulate biosynthesis and hsa04913: ovarian steroidogenesis), and different biological processes. -e latter were presented by two cancer pathways (hsa05219: bladder cancer and gene set enrichment analysis (GSEA). In general, the targets of hsa05221: acute myeloid leukemia). In addition to these F1 were significantly enriched in 37 pathways in Kyoto eight common KEGG pathways, F1 and F2, F2 and F3, and Encyclopedia of Genes and Genomes (KEGG), 79 GO bio- F1 and F3 shared 3, 4, and 5 pathways, respectively. F1, F2, logical processes, and 38 GO molecular functions (Table S4 and F3 were associated with 4, 5, and 3 other unique and Figures 4(a), 5(a), and 6(a)). -e corresponding numbers pathways, respectively; see Figure 4(d). of enriched KEGG/GO terms for F2 and F3 were 68, 99, and A total of 9 GO biological processes were associated with 54 (Table S4 and Figures 4(b), 5(b), and 6(b)) and 35, 89, and all three TCM formulae (Figure 5) as follows: sterol meta- 46 (Table S4 and Figures 4(c), 5(c), and 6(c)), respectively. bolic process (GO:0016125), glucocorticoid biosynthetic -e top twenty KEGG/GO terms for each TCM formula process (GO:0006704), C21-steroid hormone biosynthetic were further studied. Eight common KEGG pathways were process (GO:0006700), response to vitamin A (GO: associated with all three TCM formulae (Figure 4) as follows: 0033189), vitamin A metabolic process (GO:0006776), four signaling pathways (hsa03320: PPAR signaling path- cAMP catabolic process (GO:0006198), negative regulation way, hsa04370: VEGF signaling pathway, hsa04066: HIF-1 of macrophage derived foam cell differentiation (GO: Evidence-Based Complementary and Alternative Medicine 11

Top 20 BPs enriched by DAVID for F1 Top 20 BPs enriched by DAVID for F2

GO:2000251 GO:0060440 GO:0071375 GO:0060020 GO:0060324 GO:0046697 −log (P value) −log (P value) GO:0048011 10 GO:0043401 10 10 GO:0046697 GO:0043101 8 10.0 GO:0043552 GO:0042908 7.5 GO:0043401 6 GO:0042359 GO:0043393 4 GO:0038083 5.0 GO:0043114 2 GO:0033189 2.5 GO:0033189 GO:0032331 GO:0031641 No. genes involved GO:0031641 No. genes involved GO:0030522 3 GO:0030949 3 4 5 GO:0016125 GO:0019372 GO: biological process 5 GO: biological process 7 GO:0010745 GO:0016125 6 9 GO:0008202 GO:0010863 7 11 GO:0007566 GO:0010745 8 GO:0006776 GO:0006776 9 GO:0006704 GO:0006704 GO:0006700 GO:0006700 GO:0006198 GO:0006198

25 50 75 100 30 40 50 60 70 80 90 Enrichment fold Enrichment fold (a) (b) Top 20 BPs enriched by DAVID for F3

GO:2000251 GO:1901216 F1 F2 GO:0071498 GO:0060324 7 1 6 −log (P value) GO:0048384 10 (20.6%) (2.9%) (17.6%) GO:0046697 7 6 GO:0043114 9 5 GO:0043101 (26.5%) GO:0042908 4 3 4 GO:0038083 3 (8.8%) (11.8%) GO:0033189 GO:0031641 No. genes involved GO:0016125 3 GO: biological process 4 4 GO:0010863 5 (11.8%) GO:0010745 6 GO:0006776 7 GO:0006704 F3 GO:0006700 GO:0006198 GO:0002068

50 100 150 200 Enrichment fold (c) (d)

Figure 5: Top twenty GO biological processes enriched by DAVID. (a), (b), and (c) for F1, F2, and F3, respectively. Venn diagram of common biological processes (d) for three TCM formulae.

0010745), regulation of myelination (GO:0031641), and (GO:0008144), 3′,5′-cyclic-nucleotide phosphodiesterase decidualization (GO:0046697). -ese findings were in ac- activity (GO:0004114), steroid hydroxylase activity (GO: cordance with the result of KEGG pathway enrichment 0008395), steroid binding (GO:0005496), growth factor analysis. -e associations between the KEGG pathways or binding (GO:0019838), oxygen binding (GO:0019825), and the GO biological processes and psoriasis were summarized nonmembrane spanning protein tyrosine kinase activity in Table S4. (GO:0004715). -ese molecular functions had close rela- Other than nine common GO biological processes, F1 tionships with the aforementioned KEGG pathways and GO and F2, F2 and F3, and F1 and F3 shared 1, 4, and 3 BPs, biological processes. respectively. F1, F2, and F3 were associated with 7, 6, and 4 -ree TCM formulae were associated with 8 common other unique BPs, respectively (Figure 5(d)). pathways, 9 common biological processes, and 10 common With regard to molecular functions, 10 GO terms were molecular functions (Figures 4(d), 5(d), and 6(d)). -ese associated with all three TCM formulae (Figure 6) as follows: findings indicated that the treatment of different syndrome retinoid X receptor binding (GO:0046965), 3′,5′-cyclic- types of psoriasis by three TCM formulae was associated AMP phosphodiesterase activity (GO:0004115), steroid with common mechanisms to some extent. Moreover, hormone receptor activity (GO:0003707), drug binding several unique factors were evident. For example, the 12 Evidence-Based Complementary and Alternative Medicine

Top 20 MFs enriched by DAVID for F1 Top 20 MFs enriched by DAVID for F2 GO:0046965 GO:0070330 GO:0020037 GO:0050544 GO:0019903 GO:0046965 GO:0019899 GO:0030552 GO:0019838 P GO:0019838 −log (P value) −log10 ( value) 10 GO:0019825 12 GO:0019825 GO:0016705 GO:0016712 9 10 GO:0008395 GO:0010181 GO:0008144 6 GO:0008395 5 GO:0005506 3 GO:0008144 GO:0005496 GO:0005542 GO:0004879 GO:0005496 No. genes involved No. genes involved GO:0004715 GO:0004879 5.0 5.0 GO: molecular function GO: molecular functionGO: molecular GO:0004714 7.5 GO:0004715 7.5 GO:0004713 10.0 GO:0004697 10.0 GO:0004497 GO:0004115 GO:0004175 GO:0004114 GO:0004115 GO:0003785 GO:0004114 GO:0003708 GO:0003707 GO:0003707

20 40 60 25 50 75 100 Enrichment fold Enrichment fold (a) (b) Top 20 MFs enriched by DAVID for F3 GO:0097110 GO:0070330 F1 F2 GO:0046965 GO:0030552 5 1 4 P (16.7%) (3.3%) (13.3%) GO:0020037 −log10 ( value) GO:0019838 10 GO:0019825 8 10 GO:0016712 6 (33.3%) GO:0016705 4 5 GO:0008395 4 (13.3%) (16.7%) GO:0008144 GO:0005496 No. genes involved GO:0004715 5.0 1 GO: molecular function GO:0004714 7.5 (3.3%) GO:0004497 10.0 GO:0004115 GO:0004114 F3 GO:0003785 GO:0003708 GO:0003707

25 50 75 100 125 Enrichment fold (c) (d)

Figure 6: Top twenty GO molecular functions enriched by DAVID. (a), (b), and (c) for F1, F2, and F3, respectively. Venn diagram of common molecular functions (d) for three TCM formulae. thyroid hormone signaling pathway (hsa04919), the mTOR pathway (GO: 0019372), negative regulation of chon- signaling pathway (hsa04150), and the B cell receptor drocyte differentiation (GO: 0032331), positive regulation signaling pathway (hsa04662) were only associated with F1, of vascular endothelial growth factor receptor signaling F2, and F3, respectively (Figure 4). With regard to the pathway (GO: 0030949), trachea formation (GO: 0060440), biological processes regulated by the three TCM formulae, and vitamin D metabolic process (GO: 0042359), were only great differences were found (Figure 5). Seven BPs, namely, associated with F2. Four BPs, namely, cellular response to cellular response to peptide hormone stimulus (GO: fluid shear stress (GO: 0071498), glandular epithelial cell 0071375), embryo implantation (GO: 0007566), intracel- development (GO: 0002068), positive regulation of neuron lular receptor signaling pathway (GO: 0030522), neuro- death (GO: 1901216), and retinoic acid receptor signaling trophin TRK receptor signaling pathway (GO: 0048011), pathway (GO: 0048384), were only associated with F3. It is positive regulation of phosphatidylinositol 3-kinase activity noteworthy that the vitamin D metabolic process (GO: (GO: 0043552), regulation of protein binding (GO: 0042359) was only associated with F2. Vitamin D plays an 0043393), and steroid metabolic process (GO: 0008202), essential role in cell proliferation, differentiation, apo- were only associated with F1. Six BPs, including Bergmann ptosis, and angiogenesis. Reduced vitamin D levels in glial cell differentiation (GO: 0060020), lipoxygenase psoriatic patients correlated with psoriasis duration. Evidence-Based Complementary and Alternative Medicine 13

Vitamin D is highly effective in the treatment of psoriasis. extinction stage, and stationary stage, respectively. -e results Calcipotriol and other vitamin D analogues are frequently indicated the underlying mechanisms with regard to three used for the treatment of psoriasis due to their immu- different aspects. First, a high percentage (46.5%, Figure 3(d)) noregulating and antiproliferation activity [83]. -is evi- of the targets noted for the three TCM formulae was the same, dence indicated that vitamin D was notably required for the which was in accordance with the common pathogenesis of treatment of the blood stasis type of psoriasis vulgaris. psoriasis vulgaris. Second, F1, F2, and F3 exhibited indepen- dent MoA by interacting with different sets of targets and by 4. Discussion regulating different biological processes. -ese findings were further supported by the GSEA results (Figures 4(d), 5(d), and -e TCM formula is a complicated drug system; thus 6(d)). Finally, three TCM formulae exhibited common targets complex interactions between multicomponents and mul- between each other, which reflected their associations with titargets can lead to the regulation of multiple pathways and different stages of psoriasis vulgaris. biological processes. In clinical practice of TCM, the selection of an appropriate formula is particularly important. 5. Conclusions Most commonly, the remedy will be modified along with the change of the syndrome pattern of the disease. In this work, -e clinical practice of TCM involves treatment of blood network pharmacology was adopted to explore the thera- heat, blood stasis, and blood dryness type of psoriasis vul- peutic mechanisms of three TCM formulae which were garis by Compound Qingdai Pills, Yujin Yinxie Tablets, and indicated for different syndrome patterns of psoriasis vul- Xiaoyin Tablets, respectively. Based on the evidence pre- garis. Similarities and differences among all three TCM sented in the current study, the compounds of the three formulae were both identified at different scales. TCM formulae exhibited good ADME/T and drug-like -e majority of the ingredients exhibited good ADME/T properties. Multiple compounds of each formula can in- and drug-like properties, which provided the diversity and teract with multiple cellular targets and thus regulate effectiveness of pharmacodynamic material basis for each TCM multiple pathways and BPs. -ree TCM formulae were formula. A number of compounds have demonstrated affinities associated with the same group of targets, pathways, BPs, for multiple cellular targets. A total of 98 compounds of F1 and MFs, while each TCM formula exhibited unique profile. were associated with 72 targets. -e targets of F1 were sig- -ese findings reveal that different syndrome types of nificantly enriched in 37 KEGG pathways, 79 GO BPs, and 38 psoriasis vulgaris not only have common pathogenesis to GO MFs. A total of 144 compounds of F2 were associated with some extent, but also exert inherent differences that require 97 targets. -e targets of F2 were significantly enriched in 68 elaborate therapies. KEGG pathways, 99 GO BPs, and 54 GO MFs. A total of 104 compounds of F3 were associated with 85 targets. -e targets of Abbreviations F3 were significantly enriched in 35 KEGG pathways, 89 GO BPs, and 46 GO MFs. Although the presence of common ADME/T: Absorption, distribution, metabolism, excretion, compounds in three TCM formulae was rare, considerable and toxicity intersections were noted in their targets, including 53 common BPs: Biological processes proteins (red nodes in Figures 3(a)–3(c)) and 7 key targets. CTN: Compound-target network Meanwhile, F1 and F2, F2 and F3, and F1 and F3 shared 3, 4, DAVID: Visualization and Integrated Discovery and 5 KEGG pathways, 1, 4, and 3 GO BPs, and 1, 5, and 4 GO F1: Compound Qingdai Pills MFs, respectively. In addition, F1, F2, and F3 were associated F2: Yujin Yinxie Tablets with 5, 18, and 5 unique targets, 4, 5, and 3 KEGG pathways, 7, F3: Xiaoyin Tablets 6, and 4 GO BPs, and 5, 4, and 1 GO MFs, respectively. GO: Gene Ontology All three TCM formulae can regulate steroid hormone GSEA: Gene set enrichment analysis biosynthesis, PPAR signaling pathway, VEGF signaling KEGG: Kyoto Encyclopedia of Genes and Genomes pathway, HIF-1 signaling pathway, and ErbB signaling LGA: Lamarckian genetic algorithm pathway. Only F1 can regulate thyroid hormone signaling PCA: Principal component analysis pathway. Compared with F1, F2 can regulate mTOR sig- PDTCM: Psoriasis Database of Traditional Chinese naling pathway and Aldosterone-regulated sodium reab- Medicine sorption alone. F3 can regulate B cell receptor signaling TCM: Traditional Chinese medicine pathway uniquely. Seven common key targets (Glucocor- TTD: -erapeutic Target Database. ticoid receptor, Adrenodoxin, Retinaldehyde-binding protein 1, Phospholipase A2, Cytochrome P450 11B2, Data Availability Corticosteroid 11-beta-dehydrogenase isozyme 1, and ADP- ribosylation factor 1) were associated with all three TCM Additional data to the manuscript will be available upon formulae. F1 and F2 and F2 and F3 had 2 and 5 common request. targets, respectively. However, the targets of F1 did not overlap except the above mentioned 7 key proteins. Conflicts of Interest In clinical practice, blood heat, blood dryness, and blood stasis syndromes are commonly seen in progressive stage, -e authors have no conflicts of interest to declare. 14 Evidence-Based Complementary and Alternative Medicine

Authors’ Contributions Journal of the American Academy of Dermatology, vol. 60, no. 3, pp. 419–425, 2009. J. Y. G. and C. J. L. conceived the study. D. M. W., M. M. Z., [8] S. Meng, Z. Lin, Y. Wang, Z. Wang, P. Li, and Y. Zheng, and W. Z. collected the data, performed data analysis, and “Psoriasis therapy by Chinese medicine and modern agents,” interpreted the results. J. Y. G., D. M. W., and J. J. Y. wrote Chinese Medicine, vol. 13, no. 1, p. 16, 2018. the manuscript. All authors read and approved the [9] B. Farahnik, D. Sharma, J. Alban, and R. K. Sivamani, “Topical manuscript. botanical agents for the treatment of psoriasis: a systematic review,” American Journal of Clinical Dermatology, vol. 18, no. 4, pp. 451–468, 2017. Acknowledgments [10] B. Farahnik, D. Sharma, J. Alban, and R. Sivamani, “Oral (systemic) botanical agents for the treatment of psoriasis: a -e calculations were performed on high-performance review,” 'e Journal of Alternative and Complementary computer cluster of Guangdong Provincial Hospital of Medicine, vol. 23, no. 6, pp. 418–425, 2017. Traditional Chinese Medicine. -is study was supported by [11] C. S. Zhang, J. J. Yu, S. Parker et al., “Oral Chinese herbal the start-up support for scientific research of Xinglin Young medicine combined with pharmacotherapy for psoriasis Scholar in Guangzhou University of Chinese Medicine (A1- vulgaris: a systematic review,” International Journal of Der- AFD018161Z04), the National Natural Science Foundation matology, vol. 53, no. 11, pp. 1305–1318, 2014. of China (81804111 and 81904198), Guangdong Science and [12] S. Parker, A. L. Zhang, C. S. 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