original article system pharmacology-based …the molecular targets of bo-ai capsule for treating...

Int J Clin Exp Med 2019;12(7):8634-8644www.ijcem.com /ISSN:1940-5901/IJCEM0089778

Original Article System pharmacology-based approach to investigate the molecular targets of Bo-ai capsule for treating essential hypertension

Tao Han1*, Yanan Shi2*, Jing Zhang1, Zouji Bian1, Zhenyu Fan1, Jihan Huang1

1Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; 2Yueyang Hospital of Integrated Traditional Chinese and Western, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China. *Equal contributors.

Received December 13, 2018; Accepted April 9, 2019; Epub July 15, 2019; Published July 30, 2019

Abstract: Objective: This study aimed to identify bioactive compounds and molecular targets of Bo-ai capsule for treating hypertension using a system pharmacology approach. Method: Bioactive compounds were obtained by the absorption, distribution, metabolism, and excretion processes with oral bioavailability (OB) and drug-likeness (DL) evaluation. Subsequently, target prediction, pathway identification, and network construction were employed to clarify the mechanisms on the anti-hypertension effect of Bo-ai capsule. Results: Among 331 compounds, 34 com-pounds in Bo-ai capsule were identified as the potentially active compounds related to anti-hypertension through OB, DL, and 9 significant pathways were obtained by performing enrichment analyses of 15 protein targets using the DAVID 6.8. Conclusion: Active compounds and molecular targets of Bo-ai capsule were identified, showing that Bo-ai capsule may deliver anti-hypertensive effects through multi-components, multi-targets and multi-pathways. This study helps to reveal the synergistic effect on a systematic level.

Keywords: Bo-ai capsule, essential hypertension, system pharmacology, molecular targets, pathways

Introduction

Essential hypertension is a chronic disease which requires long-term treatment [1], and is one of the leading risk factors of cardiovascular disease [2]. It was estimated that the preva-lence of hypertension will be increased by 60% to more than 1.5 billion people by 2025 [3]. For preventing cardiovascular disease, it has been suggested that grade 1 hypertension (140-159/90-99 mmHg) with low to moderate abso-lute total cardiovascular risk should be treated with anti-hypertension drugs. Hypertension is a major risk factor for stroke, heart failure (HF), and heart disease (CHD). Evidence suggests that CHD is the most common outcome of hypertension [4].

Traditional Chinese Medicine (TCM), which is based on empirical applications and experi-ence distillation over thousands of years, has become a crucial component of the current medical system in China and has been exten-

sively used as complementary and alternative health care all over the world [5]. The results of some previous studies have already demon-strated that TCM can lower blood pressure and modify vascular risk factors in patients with hypertension [6, 7]. Some TCM medications might be effective in control cardiovascular risk factors such as hypertension, dyslipidemia, dia-betes/pre-diabetes, atherosclerotic cardiovas-cular disease (ASCVD), and chronic heart failure [8].

Chinese herbal products (CHPs), which derived from TCM decoction of herbal formulae are widely prescribed by TCM physicians for its con-venience and consistent quality [9]. Bo-ai cap-sule is one of the CHPs being used for control-ling high blood pressure which has approved by the China Food and Drug Administration (CFDA) (approval number Z20090750). Bo-ai capsule consists of four herbs: Rehmannia glutinosa li- bosch (RGL, Dihuang), Cacumen platycladi (CP, Cebaiye), Folium artemisiae argyi (FAA, Aiye),

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The molecular targets of Bo-ai capsule for treating essential hypertension

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lity (OB) [13], drug-likeness (DL) [14], target identifica-tion and network construction and analysis. The TCM network pharmacology not only offers an opportunity to discover bioactive ingre-dients and drug targets but also reveals the mechanisms of action between a TCM formula and relevant diseases. There are previ-ous studies that have suc-cessfully applied TCM net-work pharmacology in pre-diction of active ingredients and potential targets [14], uncovering the molecular and synergistic mechanism [15, 16]. Practically, this system pharmacology approaches have been success-fully established by our la- boratory to predict active compounds and molecular targets of TCMs, such as Yinchenhao decoction [17], Danlu Capsule for hyperplasia of mammary glands [18], and Xuangui dropping pill for treating primary dys-menorrhea [19].

In this study, the aim was to predict active compounds

Folium nelumbinis (FN, Heye). Although the effi-cacy of Bo-ai capsule in anti-hypertension has been confirmed in phase II and phase III clinical trials, the identity of its active compounds and their molecular mechanisms are still unclear. Because of the complex composition of TCMs, it is unfortunately difficult to identify the effec-tive substances and their activities due to the multi-target and multi-pathway characteristics of TCMs [10]. However, a new emerged systems pharmacology [11] and network pharmacology [12] approaches may help to understand the mechanism of multiple targeted drugs across multiple scales ranging from molecular or cel-lular levels to tissue and organism levels. Based on genomics, proteomics, metabolomics, and some other technological platforms, it is able to study the function of herbal ingredients in a holistic way. Network pharmacology is applied in TCM by the combining oral bioavailabi-

of Bo-ai capsule and molecular targets on hypertension by using systems pharmacology methods, including prediction of OB, DL, and compound-target interactions, gene ontology (GO) and pathway enrichment analysis. The results not only illustrate the synergistic activities of Bo-ai capsule components and their targets, but also contribute to in-depth under-standing of the molecular mechanisms of the formula. Figure 1 shows the workflow of system pharmacological study of Bo-ai capsule.

Materials and methods

Candidate compound identification

Compound information of Bo-ai capsule were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) [20], which includes informa-

Figure 1. Workflow of system pharma-cology study of Bo-ai capsule.


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tion of all 500 Chinese herbal medicines regis-tered in the Chinese pharmacopoeia (2010 edi-tion) with a total of 30,069 ingredients collect-ed through literature mining and database integration.

Active compound screening

OB is one of the most crucial pharmacokinetic parameters in the ADME processes. High OB is often used as the key indicator to determine the drug-like property of bioactive molecules. Most of the ingredients in TCMs failed to reach the protein target sites of particular cells because of the lack of appropriate pharmaco-logical properties, particularly OB. In this study, molecules with OB ≥ 30% were considered to have favorable OB.

In early stages of drug development, evaluation of DL helps to screen excellent compounds and increases the hit rate of drug candidates. Therefore, the DL of the molecules in Bo-ai cap-sule was assessed using the Tanimoto coeffi-cient [21] through the following formula:

T ( )A A B

A,BBA B

2 2=

+ - )

)

Where A is the molecular descriptor of Bo-ai capsule on the basis of Dragon software (TA- LETE) and B is the average descriptor of all drugs in the DrugBank database. In this study, active molecules were defined as those with DL indices ≥ 0.12. The compounds with a DL index > 0.12 were considered to exhibit more favor-able DL and were selected as candidate mole-cules for further study.

Identification of associated proteins and gene names

The protein targets of the compounds were retrieved from the TCMSP database (http://lsp.nwsuaf.edu.cn/tcmsp.php). The dataset used for building these models includes 6511 drug molecules and 3987 targets with known com-pound-protein interactions in the DrugBank database. The targets prediction of TCMSP database were performed for the candidate com-pounds using the model which integrates the chemical, genomic and pharmacological infor-mation for drug targeting on a large scale, based on random forest (RF) and support vec-tor machine (SVM) [22]. The UniProt Know-

ledgebase (UniProtKB) is a protein database partially curated by experts and contains 54,247,468 sequence entries. Furthermore, the gene names were extracted from UniProtKB (http://www.uniprot.org). Finally, the targets were mapped to the Therapeutic Target Da- tabase (TTD, http://database.idrb.cqu.edu.cn/TTD/) to obtain the targets related to their cor-responding diseases.

Identification of significant pathways

The Database for Annotation, Visualization, and Integrated Discovery (DAVID) bioinformat-ics resource comprises an integrated online biological knowledge base and analytical tools for systematically extracting biological data from large gene and protein lists. (http://david.abcc.ncifcrf.gov/). To identify the pathways tar-geted by the compounds, the obtained genes were further analyzed using DAVID v6.8. Th- reshold count ≥ 2 and EASE scores ≤ 0.05 were selected for functional annotation clustering by a modified fisher exact method.

Network construction and analysis

The compound-target network was constructed using candidate compounds and potential tar-gets. The target-pathway network was generat-ed by linking the potential targets and the sig-naling pathways participated. The networks were constructed using Cytoscape 3.3.0 soft-ware [23]. In this bilateral network, the nodes present the compounds, potential targets, or signal pathways, and the edges present the compound-target or targets-pathway interactions.

Results

Active compounds identification in Bo-ai cap-sule

The chemical composition database of the Bo-ai capsule was constructed through retriev-ing 390 compounds (352 compounds after deduplication) from the TCMSP including 76 from RGL, 86 from CP, 135 from FAA and 93 from FN. A total of 25 in the 76 RGL compounds 25 (32.9%) met the criterion of OB ≥ 30%, whereas 9 (11.8%) of them met the criteria of OB ≥ 30% and DL ≥ 0.12. Of the 86 CP com-pounds, 47 (54.6%) of them met the criterion of OB ≥ 30%, whereas 16 (18.6%) of them met the


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criteria of OB ≥ 30% and DL ≥ 0.12. Among the 135 FAA compounds, 81 (60.0%) of them met the criterion of OB ≥ 30%, whereas 15 (11.1%) of them satisfied the criteria of OB ≥ 30% and DL ≥ 0.12. Of the 93 FN compounds, 36 (38.7%) of them met the criterion of OB ≥ 30%, whereas 15 (16.1%) of them met the criteria of OB ≥ 30% and DL ≥ 0.12 (Table 1).

Finally 55 candidate compounds were screened from the 352 chemicals (13.1%) which pos-sessed not only satisfactory OB ≥ 30% and DL ≥ 0.12, and 46 compounds were obtained after removal of the duplicates.

Target and active compounds

In the 46 compounds that passed the OB and DL screening, 679 potential targets were ac- quired from the TCMSP. After abandoning dupli-cates, 253 target genes were selected. 34 tar-get-related compounds (Table 2) and 15 essen-tial hypertension -related genes (Table 3) were identified in TTD. A large number of compounds out of the 34 target-related compounds were reported to play a role of vital biological activi-ties such as resistance to oxidative stress and regulation of blood lipid metabolism, also including anti-atherosclerotic effect analysis. For instance, quercetin (MOL273, OB = 46.43, DL = 0.28) is confirmed to prevent atherosclerotic in patients at risk of coronary artery disease by regular consumption in diet [24]. Catechin (MOL350, OB = 49.68, DL = 0.24) has been demonstrated to reduce atherosclerosis in the apoE knockout mice [25]. Phytol (MOL149, OB = 33.82, DL = 0.13) is shown to significantly regulate whole body weight gain and hepatic lipid metabolism in TKO mice [26]. Isorhamnetin (MOL295, OB = 49.6, DL = 0.31) has been prov-en to relieve oxidative stress [27]. These com-pounds have indirect effects on reducing blood pressure and modify vascular risk factors.

Compound-target network analysis

In order to figure out the molecular mechanism of Bo-ai capsule clearly, a compound-target network was constructed (Figure 2). The results showed that a total of 49 nodes (34 com-pound nodes and 15 target nodes) were form- ed by 98 compound-target associations. Poten- tial pharmacological interaction relationships were predicted between compounds and tar-gets via the network. The nodes represented the compounds and targets while the edges represented the potential associations between them. By use of topological properties for analysis, the largest degree node was screened which means the most compounds or targets may play a role of the hub in the whole network. Hence, it is largely possible to think of it as a key compound and target.

The compounds (in Table 2) with the most potential targets were Cycloartenol (MOL307, degree = 9) with 9 potential targets; Armepavine (MOL322, degree = 8), Stigmasterol (MOL193, degree = 8), with 8 potential targets; o-Nornu-ciferine (MOL326, degree = 7) and Machiline (MOL323, degree = 7), with 7 potential targets; Nuciferin (MOL329, degree = 6), with 6 poten-tial targets.

In terms of target analysis, prostaglandin G/H synthase 2 (PTGS2) was connected to 32 com-pounds; Beta-2 adrenergic receptor (ADRB2) was connected to 12 compounds; Alpha-1B adrenergic receptor (ADRA1B) was connected to 11 compounds and Alpha-1D adrenergic receptor (ADRA1D) was connected to 7 com-pounds; 5-hydroxytryptamine 2A receptor (HT- R2A) was connected to 6 compounds and Al- pha-2B adrenergic receptor (ADRA2B) was connected to 5 compounds. Each target in the net-work interacted with an average of 2.3 com-pounds. These findings indicate that multiple compounds could affect a single target in a potentially synergistic manner, supporting the results of studies on multi-component and mul-ti-target treatment of hypertension by TCM. Analysis of a single potential target that inter-acted with multiple drugs in the network could assist in uncovering additional synergistic drug combinations for the improved treatment of hypertension.

Table 1. The number of compounds in Bo-ai capsule satisfy OB ≥ 30% and DL ≥ 0.12Herbs Total OB ≥ 30% OB ≥ 30% and DL ≥ 0.12RGL 76 25 (32.9) 9 (11.8)CP 86 47 (54.6) 16 (18.6)FAA 135 81 (60.0) 15 (11.1)FN 93 36 (38.7) 15 (16.1)


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Table 2. Information for active compounds from Bo-ai formulaNumber Molecule Name OB (%) DL HerbsMOL018 Aeginetic acid 48.31 0.13 RGLMOL036 Jioglutin D 39.02 0.14 RGLMOL045 METHYL PALMITOLEATE 34.61 0.12 RGLMOL078 (5aR,8aS,9R)-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-isobenzofurano[5,6-f][1,3]benzodioxol-8-one 52.7 0.83 CPMOL090 9E,12Z-octadecadienoic acid 41.9 0.14 CPMOL099 Cedryl acetate 53.94 0.17 CPMOL102 DNOP 40.59 0.40 CPMOL105 Hinokinin 56.5 0.64 CPMOL109 Isopimaric acid 36.2 0.28 CPMOL113 METHYL LINOLEATE 41.93 0.17 CPMOL115 Methyllinolenate 46.15 0.17 CPMOL119 Oleic acid 33.13 0.14 CPMOL134 (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 42.36 0.21 FAAMOL147 EIC 41.9 0.14 FAA/RGLMOL149 Phytol 33.82 0.13 FAA/CPMOL150 Mandenol 42 0.19 FAAMOL184 Beta-sitosterol 36.91 0.75 FAA/CPMOL193 Stigmasterol 43.83 0.76 FAA/RGLMOL200 (-)-Caryophyllene oxide 32.67 0.13 FAA/CPMOL250 DBP 64.54 0.13 FAAMOL273 Quercetin 46.43 0.28 FN/CP/FAAMOL295 Isorhamnetin 49.6 0.31 FNMOL297 Sitosterol 36.91 0.75 FN/RGLMOL299 Kaempferol 41.88 0.24 FN/CPMOL307 Cycloartenol 38.69 0.78 FNMOL322 Armepavine 69.31 0.29 FNMOL323 Machiline 79.64 0.24 FNMOL326 O-Nornuciferine 33.52 0.36 FNMOL329 Nuciferin 34.43 0.40 FNMOL330 (+)-Leucocyanidin 37.61 0.27 FNMOL333 Leucodelphinidin 30.02 0.31 FNMOL334 Remerin 40.75 0.52 FNMOL346 Ent-Epicatechin 48.96 0.24 FNMOL350 (-)-catechin 49.68 0.24 FN


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GO biological process enrichment analysis

The GO enrichment analysis function of the DAVID 6.8 platform was used to study the pre-dicted protein target function. A total of 29 entries were confirmed in this analysis (P < 0.01, Figure 3). The results suggest that a num-ber of biological processes closely related to the hypertension such as adenylate cyclase-activating adrenergic receptor signaling path-way, cell-cell signaling, phospholipase c-acti-vating G-protein coupled receptor signaling pathway, norepinephrine-epinephrine vasocon-striction involved in regulation of systemic arte-rial blood pressure, positive regulation of smooth muscle contraction, regulation of blood pressure, negative regulation of blood pressure and regulation of smooth muscle contraction. These findings demonstrated that the corre-sponding targets of Bo-ai capsule and the cor-responding genes of hypertension have similar characteristics.

Target-pathway analysis

In order to investigate the effect of Bo-ai cap-sule in hypertension further, the pathway enrichment analysis was performed. The pathway enrichment analysis function of the DAVID 6.8 platform was used to identify the pathway associations of the 15 predicted proteins. A total of 9 pathways were identified (P < 0.05). To further elucidate the molecular mechanis-

ms, a target-pathway network was constructed on the basis of all targets and their corre-sponding significant signalling pathways (Fi- gure 4). As shown in Figure 4, the network was composed of 21 nodes (9 pathways and 12 proteins) and 45 interactions. The green nodes represent the pathways, the red nodes repre-sent the genes, and the edges represent the interactions between them.

As shown in Figure 4, 9 pathways enriched within multiple targets of Bo-ai capsule could be the key contributing factors to the anti- hypertension effect. In the pathways enriched with genes by compounds of Bo-ai capsule mainly involved in environmental information processing, organismal systems, cellular pro-cesses. The environmental information pro-cessing pathways including neuroactive ligand-receptor interaction (n = 9), cGMP-PKG signal-ing pathway (n = 7), calcium signaling pathway (n = 7) and cAMP signaling pathway (n = 4). The organismal systems pathways includes salivary secretion (n = 4), serotonergic synapse (n = 4), adrenergic signaling in cardiomyocytes (n = 4), and regulation of lipolysis in adipocytes (n = 3). The cellular processes pathway included gap junction (n = 3).

Discussion

Traditional Chinese Medicine plays a crucial role in curing diseases in the modern era. Similar to other complementary and alternative medicine, Traditional Chinese Medicine has developed a series of theoretical and practical ways to delineate the science of using com- posite herbal formula. Biomedical studies on Chinese Medicine formula have been exten-sively conducted, but it is still quite elusive for the people who are not familiar with Chinese Medicine. The mode of multiple components, targets and pathways is a prominent feature of TCM but obstacle of understanding the real action behind.

Bo-ai capsule is a newly CFDA-approved drug that is commonly used for treating anti-hyper-tension. Bo-ai capsule formula is composed of multiple compounds and has a complex mech-anism of action, which may be associated with multiple targets and multiple pathways. In this study, a systems pharmacology approach was applied to delineate the active compounds in Bo-ai capsule and its underlying mechanisms.

Table 3. Information regarding hypertension-related targets of Bo-ai capsuleNumber Protein GenesTAR01 Mineralocorticoid receptor NR3C2TAR02 Prostaglandin G/H synthase 2 PTGS2TAR03 Alpha-2A adrenergic receptor ADRA2ATAR04 Beta-2 adrenergic receptor ADRB2TAR05 Amine oxidase [flavin-containing] B MAOBTAR06 Beta-1 adrenergic receptor ADRB1TAR07 5-hydroxytryptamine 2A receptor HTR2ATAR08 Alpha-1B adrenergic receptor ADRA1BTAR09 Alpha-1D adrenergic receptor ADRA1DTAR10 Dopamine D1 receptor DRD1TAR11 Nitric-oxide synthase, endothelial NOS3TAR12 Neutrophil cytosol factor 1 NCF1TAR13 Alpha-2B adrenergic receptor ADRA2BTAR14 5-hydroxytryptamine 1B receptor HTR1BTAR15 Glutamyl aminopeptidase ENPEP


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nism of kaempferol and catechin was partially mediated by nitric oxide synthase/guanylate cyclase and large-conductance cal-cium-dependent potassi-um channels [30]. Some studies showed that cate-chin can be a potential anti-hypertension medicine [31].

Among all the 15 potential targets, PTGS2, ADRB2, ADRA1B, ADRA1D, HTR2A, and ADRA2B are consid-ered to be associated with hypertension. The higher number of compound-tar-get interactions on these targets further proved its key role in the treatment of hypertension. For example, PTGS2 is one of the two known isoforms of Prosta- glandin G/H synthase (PG- HS) which is an important regulator of vascular func-

A total of 34 compounds, 15 protein targets, and 9 pathways were implicated in the anti-hypertension effect of Bo-ai capsule. The study showed that the Bo-ai capsule was highly con-nected to the pathways, biological processes, and organs of hypertension. A pharmacological approach was used to identify the actions of Bo-ai capsule at the systemic network level.

Among the 34 active compounds, a few com-pounds have been verified to possess multiple pharmacological actions including anti-hyper-tension. For example, isorhamnetin and quer-cetin exert their hypotensive and protective effects on target organs of hypertension patients through decreasing the levels of Ca(2+) in vascular smooth muscle cells (VSMC) by block-ing both voltage-dependent calcium channels (VDC) and receptor-operated calcium channels (ROC) in physiological and pathological condi-tions [28]. Beta-sitosterol, a very abundant plant phytosterol, is effective in restoring basal liver and kidney functions of hypertension in hypertensive animals and has been an impor-tant phytosterol in the therapeutic manage-ment of CVDs [29]. The hypotensive mecha-

tion [32]. ADRB2 is a cell membrane-spanning beta-adrenergic receptor that interacts with epinephrine, a hormone and neurotransmitter which mediated smooth muscle via a down-stream interaction with L-type calcium channel. ADRB2 gene is associated with hypertension susceptibility in Han Chinese population [33]. As hypertension is a multifactorial disease in- fluenced by genetic and environmental compo-nents [34], these targets may synergistically mediate the hypertension disease from differ-ent mechanisms and make the body restore to a healthy state [35].

Bo-ai capsule was approved for treating essen-tial hypertension by the CFDA, but the active compounds and their molecular mechanisms in anti-hypertension treatment are still unclear. In the present study, the possible chemical compounds analyzed that can enter the circula-tion system were predicted along with possible targets using system pharmacology. The ingre-dients of TCM are complex, and these ingredi-ents, with particular effects and targets, can act on the various aspects of the disease through multiple systems, and they interact with

Figure 2. Compound-target network. Blue represents the compounds and red represents the targets.


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Figure 3. Gene analysis of treatment targets. The x-axis represents enrichment analysis ratings (P < 0.05) and the y-axis represents the enrichment analysis of significant types of biological processes.


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Acknowledgements

This study were supported by the College Students innovative activities pro-gram (2017SHUTCM117) and Shanghai S&T Innova- tion Plan (17401970900).

Disclosure of conflict of interest

None.

Address correspondence to: Jihan Huang and Zhenyu Fan, Center for Drug Clinical Re- search, Shanghai University of Traditional Chinese Medi- cine, 1200 Cailun Road, Pu dong New District, Shanghai 201203, China. Tel: +86 21 5132 2420; Fax: +86 21 5132 2750; E-mail: huangji-

each other to produce synergistic effects. A TCM formula is a multi-component and multi-target agent with synergistic effects that ac- counts for this relationship. The system phar-macology can be used as tool to predict the tar-get profiles and pharmacological actions of herbal compounds. Network construction approaches were used in this study to identify the bioactive compounds of Bo-ai capsule and their potential targets and we preliminarily explored to the anti-hypertension of Bo-ai capsule. Fur- thermore, herein is reported multi-component therapeutics by Bo-ai capsule to provide multi-target, multi-pathway regulation of anti-hyper-tension activity. Additional experiments are necessary to validate the prediction results in the future.

Conclusion

The mechanism of anti-hypertensive action of Bo-ai capsule involves multiple compounds, targets, and pathways. The anti-hypertensive effects of Bo-ai capsule may depend on the regulation of the proteins and pathways related to metabolism, organismal systems, and environmental information processing. Systems pharmacology approaches developed here pro-vide an alternative strategy for the comprehen-sive understanding of the mechanisms of Bo-ai capsule in anti-hypertension therapy.

[email protected] (JHH); [email protected] (ZYF)

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