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 Table of Contents  
Year : 2022  |  Volume : 1  |  Issue : 1  |  Page : 39-47

A network pharmacology analysis to identify active components and targets of Moschus in treatment and rehabilitation of Bell’s palsy

1 Department of Acupuncture, Baoshan Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
2 Department of Rehabilitation, Baoshan Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
3 Engineering Research Center of Modern Preparation Technology of TCM, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Date of Submission10-Jan-2022
Date of Decision09-Feb-2022
Date of Acceptance02-Mar-2022
Date of Web Publication29-Mar-2022

Correspondence Address:
Zhi-Dan Liu
Department of Rehabilitation, Baoshan Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2773-2398.340143

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The traditional Chinese herb, Moschus (also called She Xiang in Chinese), is used to accelerate the rehabilitation of Bell’s palsy (BP) through acupoint sticking therapy in China. However, the mechanism of its effect is not clear. In this study, we explored the pharmacological mechanism using bioinformatics analysis. We identified 59 active ingredients in Moschus using the Traditional Chinese Medicine Integrated Database, including 17-beta-estradiol, testosterone, and 2,6-decamethylene pyridine. In total, 837 differently expressed genes were identified in blood of BP patients by RNA sequencing. Finally, 33 proteins were identified with overlapping predictions by the Comparative Toxicogenomics Database and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine. Proteins of interest were closely associated with 406 Gene Ontology biological processes and 4 pathways. The hub proteins in the protein–protein interaction network were FOS, JUN, proopiomelanocortin, and G protein-coupled estrogen receptor 1. A pharmacology network was constructed with 15 active components of Moschus, 33 protein targets and four pathways. The docking model of androst-4-ene-3,17-dione and FOS-JUN complexes was predicted and constructed. The results indicated testosterone as an effective component of Moschus that may enhance BP rehabilitation by targeting FUN and the mitogen-activated protein kinase and cyclic adenosine monophosphate signaling pathways, and that docking of androst-4-ene-3,17-dione and FOS-JUN complexes might play a critical role. The findings provide a direction for future research to verify the key targets of Moschus in the treatment of BP and an application prospect in the field of facial nerve rehabilitation.

Keywords: acupoint sticking therapy; Bell’s palsy; facial paralysis; Moschus; She Xiang; traditional Chinese medicineo

How to cite this article:
Li XY, Zhao C, Mao YR, Du RF, Liu ZD. A network pharmacology analysis to identify active components and targets of Moschus in treatment and rehabilitation of Bell’s palsy. Brain Netw Modulation 2022;1:39-47

How to cite this URL:
Li XY, Zhao C, Mao YR, Du RF, Liu ZD. A network pharmacology analysis to identify active components and targets of Moschus in treatment and rehabilitation of Bell’s palsy. Brain Netw Modulation [serial online] 2022 [cited 2023 Sep 22];1:39-47. Available from: http://www.bnmjournal.com/text.asp?2022/1/1/39/340143

Xiao-Yan Li, Chuang Zhao
Both authors contributed equally to this work.
Funding: This study was supported by Shanghai Municipal Health Commission (No. 201840303), Shanghai Talent Development Fund (No. 2020086), and Key discipline construction found of Baoshan Hospital, Shanghai University of Traditional Chinese Medicine (Nos. BSYYZDZK-2019-03, BSYYZDZK-2019-04).

  Introduction Top

Bell’s palsy (BP), also known as facial nerve paralysis, is caused by a loss of function of facial muscles innervated by the seventh cranial nerves in humans (Owusu et al., 2018) and in animals (Chan et al., 2020). BP is generally characterized by muscle dysfunction on one side of the face, and common symptoms include taste loss, hearing disorder and dry mouth. It commonly occurs with nonspecific pathogenesis. So BP is also identified as idiopathic facial paralysis (Somasundara and Sullivan, 2017). Other factors that can lead to BP include traumatic injury, metabolic disorders and leukemic infiltration (Seiff and Carter, 2002; Papan et al., 2019; Zhang et al., 2020). The underlying cause of BP is determined based on patient history and physical examination. However, the etiologies of some cases remain unclear, which can complicate treatment decisions.

The typical therapies for BP include oral administration of corticosteroids, antiviral drugs, vitamins and physiotherapy (Holland and Bernstein, 2014; Madhok et al., 2016; Sullivan et al., 2016; Gagyor et al., 2019). Severe cases may need surgery for facial nerve decompression (Lee et al., 2019). Despite advances in treatments for BP, functional recovery remains incomplete in many cases. Traditional medicine serves as a traditional, complementary and alternative medicine, and is used worldwide, especially in Asia. In China, traditional Chinese medicine (TCM) is widely accepted for the advantages of fewer side effects, easy accessibility, low cost (Dashtdar et al., 2016). Moschus, a Chinese herb, has shown therapeutic effects in cardiovascular disorders (Rastogi et al., 2016; Chan et al., 2018; Li et al., 2020). The Compendium of Materia Medica, an ancient Chinese literature written by the well-known pharmacist Shi-Zhen Li, documented for the first time that Moschus is effective for dredging the channel and meridians. Recent evidence also supports the clinical application of Moschus for BP by application of acupoint sticking (Gu and Hao, 1995; Zhao, 1996; Wang and Chen, 1997; Meng et al., 2013), which refers to medicinal powder pasted on acupoints, such as Yifeng (SJ17) and Dicang (ST4), with or without a tiny incision. However, the underlining mechanism of Moschus for treating BP by acupoint sticking has not been clarified. In this study, the pharmacology network of Moschus was constructed using RNA sequencing and bioinformatics methods to explore the potential pharmacological mechanism of Moschus in BP treatment.

  Materials and Methods Top

Components of Moschus

Traditional Chinese Medicine Integrated Database (TCMID; http://www.megabionet.org/tcmid/) is a comprehensive database on TCM that bridges the gaps between TCM, common drugs and diseases (Xue et al., 2013). In our study, the chemical components of TCM Moschus were mined from TCMID.

Prediction of the targets for active ingredients of Moschus

Bioinformatics Analysis Tool for Molecular Mechanism of TCM (BATMAN-TCM) is the first bioinformatic analysis tool for studying the molecular mechanisms of TCM. The proteins targeted by the effective components of Moschus were predicted by the BATMAN-TCM online tool (http://bionet.ncpsb.org/batman-tcm/) (Liu et al., 2016). Protein-component interaction pairs with score > 20 were collected.

RNA sequencing and differential gene expression analysis

This study was approved by the Institutional Ethics Committee of Baoshan Hospital, Shanghai University of Traditional Chinese Medicine on September 28, 2018 (approval No. 201809-03). The research procedure has followed the tenets of the Declaration of Helsinki in protecting patients’ privacy from being exposed, and written informed consent had been collected by the researchers from all participants declaring the agreement about their blood being used for research purposes.

Whole blood samples were collected from veins in the left upper limb of five BP patients and five healthy controls. BP patients were recruited from diagnosed male or female BP patients aged 20–60 years without other diseases from Department of Acupuncture or Rehabilitaion, Baoshan Hospital, Shanghai University of Traditional Chinese Medicine. Healthy controls were recruited from male or female healthy hospital staff with age among 20–60 years. The total RNA was extracted from samples in the two groups using Trizol reagent following the manufacturer’s instructions (Invitrogen, Waltham, MA, USA, Cat# 15596-018) and then subjected to RNA sequencing. The raw reads were mapped to the human reference genome to generate a raw count. Then, the raw counts were normalized by the trimmed mean of M-values algorithm with the application of the edgeR package (Version 3.4) (Robinson et al., 2010), and then transformed to logarithm of counts per million reads (logCPM) to estimate the expression value of genes. Subsequently, the genes with differential expression between patients and controls were analyzed. The P values were evaluated by Benjamini-Hochberg method. Adjusted P value < 0.05 and |logFC (fold change)| > 2 were set as the cutoff values for screening differentially expressed genes. The volcano plot of differentially expressed genes was visualized by ggplot2 in R and the heatmap of differentially expressed genes was analyzed by heatmap 2.

Cross-validation of target proteins

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org) is a publicly available resource that records the association between chemicals, gene products, and disease. The BP-related gene products were retrieved from CTD (2019 update). Then, the results were compared with the target proteins of effective components of Moschus and differentially expressed gene products. The overlapping proteins were obtained for further analysis.

Gene Ontology function and pathway enrichment analysis

The Gene Ontology (GO) resource is widely used for providing functional annotation for genes and gene products in three categories: molecular function, cellular component, and biological process (Ashburner et al., 2000). The proteins of interest were subjected to GO enrichment analysis using clusterProfiler (Yu et al., 2012). The significant GO terms with P ≤ 0.05 in the biological process category were identified. The Kyoto Encyclopedia of Genes and Genomes is a resource containing the pathway terms for genes or gene products (Kanehisa and Goto, 2000). In our study, the significant pathways for proteins with P ≤ 0.05 were also analyzed with clusterProfiler in R (https://www.r-project.org/) (R Core Team, 2021).

Target protein interaction analysis

The protein-protein interactions (PPIs) were analyzed using the STRING database (version: 10.0, http://www.string-db.org/) (Szklarczyk et al., 2011; Szklarczyk et al., 2015). The protein interaction pairs were selected by Required Confidence (combined score) > 0.4 and the PPI network was constructed by Cytoscape software (https://cytoscape.org/index.html) (Shannon et al., 2003).

Construction for pharmacology network

Network pharmacology can illuminate a systematic understanding of drug actions. To explore the therapeutic action of Moschus, an integrated network with active components of Moschus, the network involving effective components of Moschus, their protein targets, and related pathways was constructed by Cytoscape software.

The Protein Data Bank is a worldwide repository that facilitates macromolecular structure studies by providing the three-dimensional (3D) structure of a given protein (Berman et al., 2014). PubChem is a public resource of chemical structures and corresponding biological activities, which contains three interlinked databases: Substance, Compound and BioAssay (Kim et al., 2019). In this study, the 3D structure of a key target protein was retrieved from the Protein Data Bank database and the molecular structure of the effective component was downloaded from the PubChem Compound database (https://pubchem.ncbi.nlm.nih.gov/). The raw SDF format file was transformed to mol2 format by pymol (Version 2.0 Schrödinger, LLC., New York, NY, USA). The docking possibility of the key protein and effective component was predicted by Lamarckian Genetic Algorithm with the application of AutoDock software (Center for Computational Structural Biology, La Jolla, CA, USA) (Morris et al., 2009).

  Results Top

Components of herb Moschus

The chemical components of herb Moschus were retrieved from TCMID with “She Xiang” (which is the Chinese Pinyin name of Moschus) as the keyword. As shown in Additional Table 1 [Additional file 1], there were 59 active ingredients in Moschus, including 17-beta-estradiol, testosterone, 2,6-decamethylene pyridine, 3,5-dihydroxybenzoic acid, and 3-methylcyclotridecan-1-one.

Differentially expressed genes associated with BP

A total of 837 genes were identified to be differentially expressed in the blood of BP patients compared with healthy controls. Of those, 457 genes were upregulated and 380 were downregulated. The differentially expressed genes were visualized in a volcano plot by combining significant P values and fold change [Figure 1]A. A heatmap of the differentially expressed genes illustrates that the BP and control groups were clearly distinguished based on their expression profiles [Figure 1]B.
Figure 1: Volcano plot and heatmap of differentially expressed genes in Bell’s palsy patients.
Note: The differentially expressed genes in the whole blood samples of five Bell’s palsy patients, compared with five healthy controls. (A) The volcano plot of differentially expressed genes was visualized by ggplot2 software using significant P values and fold change cutoff values. (B) The heatmap of differentially expressed genes was analyzed by heatmap 2 in R. The gene expression profiles were significantly different between patients and controls. N1-5 refers to the five normal control samples. SHEN1, WJF1, FEI1, SXL1 and ZXK1 refer to the name codes of five Bell’s palsy patients.

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Protein targets and cross-validation

Using the information in BATMAN, we identified 1081 protein targets for 26 active components. A total 11,862 records of gene products associated with BP were deposited in CTD. Then, the obtained proteins were compared with the differentially expressed genes. Finally, 33 overlapping proteins were obtained [Figure 2].
Figure 2: Venn diagram for the overlapping proteins associated with Bell’s palsy identified by cross-validation.
Note: The protein targets associated with Bell’s palsy were predicted using the BATMAN tool and CTD database. Then, the predicted proteins were compared with DEGs, which identified 33 overlapping proteins. BATMAN: Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine; CTD: Comparative Toxicogenomics Database; DEG: differentially expressed gene.

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Significant GO function and pathways enriched by proteins of interest

To understand the biological function and pathways of target proteins, the overlapping proteins were subjected to GO and pathway analysis. The proteins were significantly enriched in 406 GO biological processes and four pathways. The top 20 GO biological process terms, as displayed in [Figure 3], included response to metal ion, response to cyclic adenosine monophosphate (cAMP), and cellular response to calcium ion. The significantly enriched pathways included Endocrine resistance, mitogen-activated protein kinase (MAPK) signaling pathway, sulfur metabolism and cAMP signaling pathway [Figure 4].
Figure 3: Top 20 significant GO biological processes of protein targets associated with Bell’s palsy.
Note: The proteins of interest were subjected to GO function enrichment analysis by clusterProfiler. The significant GO terms with P ≤ 0.05 in the biological process category were analyzed. The top 20 GO terms were listed. The vertical axis represents GO terms or pathways and the horizontal axis indicates gene ratios enriched in a given GO term or pathway. The size of the nodes represents the ratio of enriched genes and color closer to red indicates a P value closer to 0. GO: Gene Ontology.

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Figure 4: Significant pathways of target protein associated with Bell’s palsy.
Note: The significant pathways for proteins with P ≤ 0.05 were also analyzed with clusterProfiler in R. The vertical axis represents GO terms or pathways and the horizontal axis indicates gene ratios enriched in a given GO term or pathway. The size of the nodes represents the ratio of enriched genes and color closer to red indicates a P value closer to 0. cAMP: Cyclic adenosine monophosphate; GO: Gene Ontology; MAPK: mitogen-activated protein kinase.

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PPI network

The interactions of overlapping proteins were predicted by the STRING database. Thirty-two protein interaction pairs were obtained. The PPI network was constructed with 32 edges connecting with 24 proteins [Figure 5]. The significant nodes with high degrees in the PPI network included Fos proto-oncogene, AP-1 transcription factor subunit (FOS; degree = 9), Jun proto-oncogene, AP-1 transcription factor subunit (JUN; degree = 8), proopiomelanocortin (POMC; degree = 6), G protein-coupled estrogen receptor 1 (GPER1; degree = 4), and calbindin 1 (CALB1; degree = 3).
Figure 5: Protein-protein interaction network of target proteins associated with Bell’s palsy.
Note: The protein pairs with combined score > 0.4 were retrieved from the STRING database, and the protein-protein interaction network was constructed by Cytoscape software. Yellow dot indicates upregulated target protein; blue square indicates downregulated protein.

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Pharmacology network for Moschus

A pharmacology network was constructed by integrating activated components, protein targets and pathways. As shown in [Figure 6], the network contained 52 nodes and 111 edges, of which there were 15 active components of Moschus, 33 protein targets and 4 pathways. The drug active components of androst-4-ene-3,17-dione (ADS; degree = 10), 5-cis-cyclopentadecen-1-one (degree = 10), testosterone (degree = 8) and 17-beta-estradiol (degree = 8) were significant nodes in the pharmacology network. The significant gene nodes included JUN (degree = 13), FOS (degree = 13) and GPER1 (degree = 11).
Figure 6: Pharmacology network of herb Moschus.
Note: The integrated network with active components of herb Moschus, their protein targets, and related pathways was constructed by Cytoscape software. Red rhombus indicates active ingredient; yellow dot indicates upregulated target protein; blue square indicates downregulated protein; green hexagon indicates pathway.

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Interactive docking of key proteins and effective components of herb Moschus

ASD, as the key effective component, and FOS and JUN, as the key proteins in the pharmacology network, were subjected to interactive docking prediction. The chemical structure of ASD was obtained from the PubChem Compound database [Figure 7]A. The 3D structure of the FOS-JUN complex (1FOS) was downloaded from the Protein Data Bank database [Figure 7]B and [Figure 7]C. Six docking models were predicted for 1FOS and ASD [Table 1]. Model 1 was the best docking model with the highest affinity and lowest root mean square deviation. The docking global graph based on Model 1 is visualized in [Figure 7]D. The interaction sequences between 1FOS and ASD were LYS267, ASN271, DC26 and DT14 [Figure 7]E.
Figure 7: Interactive docking prediction of key target proteins and effective components.
Note: The 3D structures of key target proteins were obtained from the Protein Data Bank database, and the molecular structures of effective components were predicted by the PubChem Compound database. The docking possibility of key proteins and effective components was predicted by AutoDock software. (A) Molecular structure of androst-4-ene-3,17-dione (ASD). Green indicates C atom; gray indicates H atom; red indicates O atom. (B) Linear 3D structure of FOS–JUN complexes (1FOS). (C) Surface 3D structure of 1FOS. (D) Global graph of molecule docking of 1FOS and ASD. Opaque white indicates 3D model of 1FOS; translucent molecule indicates ASD. (E) Local map of molecular docking model. Translucent molecule indicates ASD ligand. Spheres and secondary structure fragments represent hydrogen bonds or atoms with intimate contact with ASD ligand. Affinity is −7.9 and the interaction sequences between 1FOS and ASD include LYS267, ASN271, DC26 and DT14. 3D: Three-dimensional.

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Table 1: The docking models of ASD and 1FOS

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  Discussion Top

The traditional Chinese herb Moschus has been reported to facilitate the recovery of BP through acupoint sticking therapy. However, the mechanism of Moschus’s effect on BP through acupoint application is not understood. In the present study, the active ingredients of Moschus were predicted using the records of TCMID. The protein targets of the active ingredients were predicted by the BATMAN tool and differential expression analysis. Finally, a pharmacology network was constructed with 33 protein targets, 15 chemical components and 4 signaling pathways.

Our results showed that testosterone was an active ingredient of Moschus, which was validated in the pharmacology network. Testosterone is a primary male hormone and plays an essential role in human health and well-being (Bassil et al., 2009). Evidence has shown that testosterone, as an anabolic steroid, can be applied for male hypogonadism treatment and certain types of breast cancer (Cauley et al., 1999; Hankinson and Eliassen, 2007). In addition, testosterone has been implicated in muscle growth and human development (Rooyackers and Nair, 1997). It has been reported that androgens stimulate muscle generation, and facilitate reinnervation and angiogenesis (Hansen-Smith and Carlson, 1979). As a primary androgen, testosterone has been reported to activate androgen receptors on nerves to promote reinnervation in the process of muscle grafts (Kuiper et al., 1997; Bielecki et al., 2016). Previous evidence has suggested that testosterone plays a differential regulatory role in the regeneration of facial motoneurons (Kujawa et al., 1991). A study in male hamsters showed that testosterone mediated a faster recovery of BP (Kujawa et al., 1989), which is consistent with the therapeutic effect of Moschus on BP.

In the present study, the targets of Moschus in treating BP pointed to FOS and FUN genes. The FOS (also named c-Fos) gene family consists of four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. The FOS proto-oncogene has been reported as an immediate early gene is significantly associated with cell proliferation and differentiation, induced by a number of mitogens (Nephew et al., 2000). In addition, FOS protein has been associated with apoptotic cell death induced by anti-proliferative conditions (Smeyne et al., 1993).

In a repair-promoting low-intensity rTMS research (Lohof et al., 2022), low-intensity rTMS increased c-fos expression in Purkinje neurons, consistent with the production of reactive oxygen species by activated cryptochrome. It was proposed that weak magnetic fields act through cryptochrome, activating intracellular signals that induce climbing fiber-Purkinje cell reinnervation, rather than activating neurons via induced electric currents. The target of this study is strikingly consistent with current research that opens new routes to a connection with medicinal therapy, indicating that physical therapy and drug therapy, despite their different approaches, have some very surprising similarities. This may also indicate the neurological mechanism of the rehabilitation of BP.

JUN, also named c-Jun, is the putative transforming gene of avian sarcoma virus 17. It encodes a protein that is highly similar to the viral protein and interacts directly with specific target DNA sequences to regulate gene expression. In the current study, JUN was predicted to be a protein target for testosterone. The JUN protein family plays a regulatory role in collagenase expression after stimulation by various extracellular signals (Angel and Karin, 1992). JUN has been found to be selectively expressed in peripheral nerves of rats after axotomy and to play a role in nerve generation and facial paralysis rehabilitation (Thanos et al., 1999). JUN protein expression is increased after the activation of the MAPK pathway induced by ultraviolet radiation in the skin (Yang et al., 2009). A previous report suggested that MAPK is activated in mice with facial pain induced by occlusal interference (Cao et al., 2013b). Furthermore, the MAPK signaling pathway has been suggested to be involved in the evolution of facial palsy in a mouse model (Fang et al., 2015). A previous study suggested that MAPK signaling was one downstream pathway underlying the role of ciliary neurotrophic factor and brain-derived neurotrophic factor in improving facial nerve regeneration and functional recovery (Cao et al., 2013a). In the present study, an interaction was identified between JUN protein and the MAPK signaling pathway. Taken together, we suggest that JUN protein and the MAPK signaling pathway play a role in the recovery of facial nerve disorders.

Furthermore, our data showed that the cAMP signaling pathway also interacted with JUN protein. cAMP is a second messenger involved in central nervous system axonal regeneration. cAMP levels increase during advanced neurite growth induced by neurotrophins such as brain-derived neurotrophic factor and glia-derived neurotrophic factor (Teng and Tang, 2006). In addition, upregulated cAMP induced by Trk receptor signaling plays a key role in improving axonal outgrowth of peripheral nerves. Testosterone has been suggested to show promise for the treatment of peripheral nerve injury (Chan et al., 2014). In our study, JUN was predicted to be the target for testosterone, and pathway analysis showed that the cAMP signaling pathway was a significant pathway involved with JUN. Thus, we suggest that testosterone may improve the recovery of BP by targeting JUN involved in the cAMP signaling pathway.

Testosterone and ASD coexist in human plasma (Rivarola and Migeon, 1966). In our study, the interactive docking of 1FOS-ASD was predicted. ASD has been reported to have a proliferative effect on androgen-sensitive LNCaP cells (Laplante and Poirier, 2008), but there is little evidence for a therapeutic role of ASD on BP. Our data show that ASD targeting 1FOS may play a key role in treating BP. However, further analyses are urgently needed.

In conclusion, testosterone, as an active ingredient of herb Moschus, may advance the recovery of BP by targeting JUN protein. Docking of ASD and 1FOS, and the MAPK and cAMP signaling pathways involved with JUN may play key roles in the therapeutic effect of Moschus in BP recovery. However, this study also had its limitations. For example, the expression of predicted target genes and proteins was not verified in human experiments, and the interaction between Moschus and the predicted target genes or proteins was not clear in pharmacology. Thus, further pharmacological studies are warranted. These findings provide a direction for future research to verify the key targets of Moschus in treating BP.


We would like to express our thanks to Mrs. Yan-Yan Hao and Jian-Ying Xu for blood sample collection and Miss Lu Zhang for RNA experiment preparation, and financial support from Shanghai Municipal Health Commission.

Author contributions

Study conception and design and administrative support: ZDL; study materials or patients preparation: XYL; data collection: XYL, CZ; data analysis and interpretation: XYL, CZ, YRM, RFD. All authors wrote the manuscript and approved the final version of the manuscript.

Conflicts of interest

The authors declare that they have no competing interests.

Author statement

This paper has been posted as a preprint on Research Square with doi: https://doi.org/10.21203/rs.3.rs-92118/v1 which is available from: https://www.researchsquare.com/article/rs-92118/v1.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Additional file

Additional Table 1: The effective components of traditional Chinese herb Moschus.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]

  [Table 1]


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