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Abstract

Eucommiae cortex (EC) and Achyranthis radix (AR) are herbal medicines widely used in combination for the treatment of intervertebral disc herniation (IDH). The mechanisms of action of the herbal combination have not been understood from integrative and comprehensive points of view. By adopting network pharmacological methodology, we aimed to investigate the pharmacological properties of the EC-AR combination as a therapeutic agent for IDH at a systematic molecular level. Using the pharmacokinetic information for the chemical ingredients of the EC-AR combination obtained from the comprehensive herbal drug-associated databases, we determined its 31 bioactive ingredients and 68 IDH-related therapeutic targets. By analyzing their enrichment for biological functions, we observed that the targets of the EC-AR combination were associated with the regulation of angiogenesis; cytokine and chemokine activity; oxidative and inflammatory stress responses; extracellular matrix organization; immune response; and cellular processes such as proliferation, apoptosis, autophagy, differentiation, migration, and activation. Pathway enrichment investigation revealed that the EC-AR combination may target IDH-pathology-associated signaling pathways, such as those of cellular senescence and chemokine, neurotrophin, TNF, MAPK, toll-like receptor, and VEGF signaling, to exhibit its therapeutic effects. Collectively, these data provide mechanistic insights into the pharmacological activity of herbal medicines for the treatment of musculoskeletal diseases such as IDH.

Keywords

herbal medicines network pharmacology intervertebral disc herniation molecular mechanisms multicomponent-multitarget drug

Introduction

Intervertebral disc herniation (IDH) is one of the most common musculoskeletal and orthopedic disorders affecting 1-3% of the worldwide population; it negatively impacts the quality of life (QoL) and health status of patients, and additionally places a significant economic burden on society.¹ IDH occurs when the intervertebral disc (IVD) components are displaced from the usual anatomical disc space; they protrude through the spinal canal and compress the spinal cord and nerve roots, resulting in pain in the arms, back, and legs, causing sciatica, tingling, numbness, and muscle weakness.² Pathomechanisms for IDH are suggested to be biological processes of disc cells and relevant materials, such as disc degeneration, angiogenesis, inflammation, degradation of extracellular matrix (ECM) components and collagen, and oxidative stress.^2–6 Presently, non-anti-inflammatory analgesics, nonsteroidal anti-inflammatory drugs, opioid analgesics, and muscle relaxants are used as conservative and non-operative therapies for IDH to enhance mobility and function, alleviate pain, and improve the QoL of patients.^7,8 However, the pharmacological strategies for IDH treatment remain limited.^7,8 Therefore, herbal medicines are increasingly being considered as effective non-operative therapies for IDH prevention and treatment due to their potent pharmacological activity and low toxicity.⁹

Eucommiae cortex (EC) and Achyranthis radix (AR) are herbal medicines widely used in a combination for the treatment of IDH.^9,10 Clinical studies have shown that the use of EC, AR, and herbal formulas containing EC and/or AR may enhance the total effective rate, cure rate, and alleviate pain intensity and relevant symptoms in patients with IDH.^9,11 It has been reported that EC and AR may exhibit diverse pharmacological effects such as analgesic, anti-inflammatory, antioxidant, antispasmodic, bone protective, immunomodulatory, nerve regenerative and functional restorative, and neuroprotective activities.^9,12–18 However, the systematic mechanisms underlying the pharmacological activity of the EC-AR combination for IDH treatment remain unexplored.

As the pharmacological effects of herbal medicines are conferred via the complex regulation of multiple therapeutic targets by various chemical ingredients, network pharmacology has been increasingly recognized as an effective and efficient methodology to investigate their therapeutic features in a systematic and comprehensive way.^19–23 This research method integrates biomedicine, pharmacochemistry, and computational network science and explores the multiple ingredient-multiple target mechanisms of herbal medicines in a network perspective.^19–23 Network pharmacology analysis investigates bioactive chemical ingredients and their targets that play major roles in the therapeutic effects of herbal medicines, constructs herbal medicine-related networks based on the relevant data, and explores their functional and topological characteristics.^19–23 This methodology is widely applied to studies regarding the mechanistic investigation of herbal medicines prescribed for various musculoskeletal diseases.^24–29 The goal of the present study was to dissect the systematic mechanisms of the EC-AR herbal combination for IDH treatment.

Materials and Methods

Determination of Active Chemical Ingredients in the EC-AR Combination

The absorption, distribution, metabolism, and excretion (ADME) pharmacokinetic parameters (such as oral bioavailability, drug-likeness, and Caco-2 permeability), key considerations used for drug design and development, of the chemical ingredients of EC and AR were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP),³⁰ Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM),³¹ and Traditional Chinese Medicine Integrated Database (TCMID).³² The chemical ingredients with oral bioavailability ≥30%, Caco-2 permeability ³−0.4, and drug-likeness ≥0.18 were determined as bioactive ingredients, as suggested previously.²¹ Oral bioavailability is the ratio of the amount of orally administered drug entering the systemic circulation and that reaching target tissues and organs; those with oral bioavailability ≥30% are considered to have effective absorptive capacity in the body.^30,33 Caco-2 permeability is a measure used to examine the permeability, diffusion, and absorption rates of a compound in human Caco-2 intestinal cells; a compound with Caco-2 permeability ³−0.4 is generally determined to be effectively permeable in the intestinal epithelium.^34,35 Drug-likeness is an indicator for qualitatively evaluating the suitability of a compound as a drug, considering its physical, chemical, and structural features using Tanimoto coefficients;^30,36 a compound with drug-likeness ≥0.18 is regarded a potential drug because the mean value of drug-likeness of all available drugs is 0.18.^30,36

Identification of Targets of Active Chemical Ingredients in the EC-AR Combination

The simplified molecular-input line-entry system (SMILES) notation for the active chemical ingredients of the EC-AR combination was obtained from the PubChem database.³⁷ Then, we imported the obtained SMILES information into the following tools and databases used for the analysis of chemical-protein interactions: Similarity Ensemble Approach (SEA),³⁸ PharmMapper,³⁹ SwissTargetPrediction,⁴⁰ and Search Tool for Interactions of Chemicals (STITCH) 5.⁴¹ In this way, we obtained the human targets of the bioactive ingredients of the EC-AR combination. The IDH-related human targets were retrieved from the databases, including the Therapeutic Target Database,⁴² DisGeNET,⁴³ Online Mendelian Inheritance in Man,⁴⁴ GeneCards,⁴⁵ Comparative Toxicogenomics Database,⁴⁶ and Pharmacogenomics Knowledgebase,⁴⁷ as well as from previous relevant literature.^27,48–54

Construction of Herbal Medicine-Related Networks

The herbal medicine-bioactive chemical ingredient-target (H-C-T) network was generated by linking the herbal medicines to their bioactive ingredients and the ingredients with their therapeutic targets. The herbal medicine-bioactive chemical ingredient-target-pathway (H-C-T-P) network was generated by linking the targets in the H-C-T network to their enriched disease-related pathways. The protein-protein interaction (PPI) network for the targets of herbal medicines was produced using the STRING database (interaction confidence score ≥0.7).⁵⁵ The generated networks were visualized and their properties were investigated using Cytoscape.⁵⁶ In a network, nodes describe herbal medicines, chemical ingredients, targets, or pathways, and links (or edges) describe the interaction relationships among them.⁵⁷ The number of links that a node has is called the degree.⁵⁷

Functional Enrichment Analysis

The g:Profiler⁵⁸ and Kyoto Encyclopedia of Genes and Genomes database⁵⁹ were used for the gene ontology (GO) and pathway enrichment analyses, respectively.

Molecular Docking Analysis

The structural information of the active chemical ingredients of the EC-AR combination and their therapeutic targets were investigated from the PubChem³⁷ and RCSB Protein Data Bank,⁶⁰ respectively. The information was imported into Autodock Vina,⁶¹ and the molecular docking scores of chemical ingredient-therapeutic target pairs were calculated. A chemical ingredient-target pair is considered to have potent binding activity if it exhibits a docking score £-5.0.^62,63

Results

Bioactive Chemical Ingredients in the EC-AR Combination and Their Targets

The ADME pharmacokinetic parameters of the chemical ingredients of the EC-AR combination were obtained from TCMSP,³⁰ BATMAN-TCM,³¹ and TCMID³² databases (Supplementary Table S1), and the ingredients with oral bioavailability ≥30%, drug-likeness ≥0.18, and Caco-2 permeability ³−0.4 were determined to be bioactive. Some chemical ingredients that did not fulfill the aforementioned criteria were also considered bioactive because of their presence in large amount in the EC-AR combination and their therapeutic effects.^64–72 Consequently, 49 bioactive chemical ingredients were identified in the EC-AR combination (Supplementary Table S2).

The targets of the bioactive chemical ingredients of the EC-AR combination were identified from a variety of tools and databases used to analyze protein-chemical interactions (see Materials and Methods). As a result, 279 targets were determined for the EC-AR combination where 68 targets of 31 chemical ingredients were IDH-related (Supplementary Table S3).

Figure 1.

The herbal medicine-bioactive chemical ingredient-target network of the eucommiae Cortex-achyranthis radix combination. Green nodes, herbal medicines; red nodes, bioactive chemical ingredients; blue nodes, intervertebral disc herniation-related targets.

Network Pharmacological Investigation of EC-AR Combination

To carry out network pharmacological dissection of the therapeutic mechanisms of the EC-AR combination for IDH treatment, we generated an herbal medicine-bioactive chemical ingredient-target (H-C-T) consisting of 101 nodes (two herbal medicines, 31 bioactive chemical ingredients, and 68 IDH-related targets) and 190 edges (Figure 1 and Supplementary Table S3). Among the chemical ingredients in the network, quercetin (degree = 25), berberine (degree = 14), and kaempferol (degree = 11) had a large number of targets (Figure 1 and Supplementary Table S3), suggesting that they are potent contributors to the pharmacological effects of the EC-AR combination. Moreover, all chemical ingredients of the EC-AR combination shared one or more common targets, and 41 out of 68 targets interacted with two or more chemical ingredients (Figure 1), suggesting multiple ingredient-multiple target characteristics of herbal drugs.

Figure 2.

The protein-protein interaction network for the intervertebral disc herniation -related targets of the eucommiae Cortex-achyranthis radix combination. Pink nodes, hub targets.

To explore the interaction mechanisms underlying the targets of the EC-AR combination, we constructed a PPI network (60 nodes and 274 edges) where the targets served as the nodes (Figure 2). Further, based on the degree distribution of nodes in the network, we identified hubs, the high-degree nodes that play key biological roles and tend to be effective pharmacological targets.^73,74 As described previously, nodes whose number of links is ≥ two times the mean value of the degree of all the nodes in the network were defined as hubs.^75,76 Therefore, IL6 (degree = 32), MAPK1 (degree = 29), AKT1 (degree = 26), TP53 (degree = 25), EGFR (degree = 21), MMP9 (degree = 20), IL1B (degree = 19), and CCL2 (degree = 19) were regarded as hubs (Figure 2). These nodes may serve as crucial targets conferring the therapeutic effects of the EC-AR combination for IDH treatment.

Figure 3.

The herbal medicine-bioactive chemical ingredient-target-pathway network of the eucommiae Cortex-achyranthis radix combination. Green nodes, herbal medicines; red nodes, active chemical ingredients; blue nodes, intervertebral disc herniation-related targets; orange nodes, signaling pathways.

Thus, the results suggest the polypharmacological mechanisms of the EC-AR combination.

Functional Enrichment Analysis of the Therapeutic Mechanisms of the EC-AR Combination

To explore the therapeutic mechanisms of the EC-AR combination at the molecular level, we investigated the GO terms enriched with the targets of the EC-AR combination. The results showed that the targets of the EC-AR combination were involved in modulating important biological functions such as angiogenesis, cytokine and chemokine activity, oxidative and inflammatory stress responses, ECM organization, immune response, and cellular processes such as proliferation, apoptosis, autophagy, differentiation, migration, and activation (Supplementary Figure S1); this was consistent with the pathomechanisms of IDH and molecular activities of the herbal medicines reported in previous studies.^{2,5,6,9,16,77–90} Pathway enrichment analysis further demonstrated that the targets of the EC-AR combination were enriched in diverse signaling pathways implicated in the IDH pathology; these pathways include “cellular senescence”, “chemokine signaling pathway”, “FoxO signaling pathway”, “growth hormone synthesis”, “HIF-1 signaling pathway”, “IL-17 signaling pathway”, “leukocyte transendothelial migration”, “MAPK signaling pathway”, “mTOR signaling pathway”, “neurotrophin signaling pathway”, “osteoclast differentiation”, “PI3K-Akt signaling pathway”, “prolactin signaling pathway”, “Ras signaling pathway”, “TNF signaling pathway”, “toll-like receptor signaling pathway”, “VEGF signaling pathway”, and “JAK-STAT signaling pathway” (Figure 3 and Supplementary Figure S1).

Figure 4.

Molecular docking analysis of the bioactive chemical ingredients of eucommiae Cortex-achyranthis radix combination and their targets. (A) Baicalein-AKT1 (score = −6.2). (B) Berberine-AKT1 (score = −5.4). (C) Quercetin-AKT1 (score = −6.3). (D) Wogonin-CCL2 (score = −5.2). (E) Quercetin-EGFR (score = −7.9). (F) Aucubin-IL1B (score = −5.9). (G) Geniposide-IL6 (score = −6.3). (H) Berberine-MAPK1 (score = −7.1). (I) Baicalein-MMP9 (score = −6.3). (J) Caffeic acid-MMP9 (score = −6.4). (K) Quercetin-MMP9 (score = −6.3). (L) Wogonin-MMP9 (score = −5.9). (M) Berberine-TP53 (score = −6.8).

Together, the results of functional enrichment analysis suggested the comprehensive molecular and signaling mechanisms for the EC-AR combination for the treatment of IDH.

Molecular Docking Analysis for EC-AR Combination

To verify the binding activities among the bioactive chemical ingredients of the EC-AR combination and the targets, we carried out molecular docking analysis. The results indicated that the chemical ingredients and their hub targets may exhibit docking scores £-5.0 (Figure 4), suggesting their potential binding interactions.

Discussion

EC and AR are herbal medicines frequently used in combination as therapeutics for various musculoskeletal diseases such as osteoarthritis and IDH, with good efficacy and low toxicity.^9,24–26 Previous studies have analyzed their system-level mechanisms for the treatment of osteoarthritis;^24–26 however, their therapeutic properties in the case of IDH, from a view of network perspective, remain unexplored. This study aimed to dissect the comprehensive regulatory mechanisms of the EC-AR combination for IDH treatment based on the integrative network pharmacology methodology. By evaluating the pharmacokinetic characteristics of the chemical ingredients in the EC-AR combination, we determined 31 bioactive chemical ingredients and identified 68 IDH-related targets by investigating the protein-chemical binding interactions and performing network analysis. The 68 targets of the EC-AR combination were associated with the regulation of diverse biological activities, including angiogenesis, cytokine and chemokine activity, oxidative and inflammatory stress responses, ECM organization, immune response, and cellular processes such as proliferation, apoptosis, autophagy, differentiation, migration, and activation. These results were consistent with the previously reported pathological processes of IDH and the pharmacological mechanisms of the EC-AR herbal combination.^{5,6,9,16,77–90} Pathway enrichment analysis indicated that the targets of the EC-AR combination may be enriched in diverse pathways implicated in IDH pathology, such as those of cellular senescence, chemokine, neurotrophin, TNF, MAPK, toll-like receptor, and VEGF signaling.

The key hub targets of the EC-AR combination were associated with IHD-related pathological processes and may act as pharmacological targets for the disease treatment. Interleukin (IL)-6 (encoded by IL6) is a proinflammatory cytokine crucially involved in the IDH-associated pathogenesis and pain development; the expression, activity, and polymorphisms of Il-6 are correlated with the risk, progression, and clinical prognosis of IDH and its inhibition may result in the alleviation of pain.^78,91–95 Extracellular signal-regulated kinase (ERK)-2 (encoded by MAPK1) activates proinflammatory cytokines that may contribute to IDH progression by promoting inflammation and apoptosis of IVD cells.^88,96–98 Inhibition of ERK2 activity may block the degeneration of IVDs and restore the disc function.^88,96–98 Akt1 (encoded by AKT1) is a key regulator of the proliferation of IVD cells and its transcript level is associated with IDH progression and deterioration.^50,99–101 Abnormal regulation of matrix metalloproteinase (MMP)-9 activity plays a role in IDH development and progression by inducing disc matrix degradation and collagen loss; it is further related to the prognosis and disease severity in patients with IDH.^102–109 p53 (encoded by TP53) is a mediator of senescence, oxidative stress response, apoptosis, and inflammation in IVD cells and is implicated in neovascularization and infiltration associated with IDH pathogenesis; furthermore, p53 may have potential as a therapeutic target for IDH treatment.^110–117 Aberrant activity of epidermal growth factor receptor (encoded by EGFR) is reported in degenerative IVDs and its inhibition may suppress the degeneration of IVDs and ameliorate IDH.^118,119 IL-1β (encoded by IL1B) is an IDH-associated proinflammatory cytokine, and its genetic variability may influence the clinical outcome of patients with IDH.¹²⁰ The chemokine (C-C motif) ligand 2 (CCL2; encoded by CCL2) is associated with the persistence and prolongation of IDH-induced pain and pain intensity in patients with IDH.^121,122

Various pathways targeted by the EC-AR combination are reportedly involved in the pathophysiology of IDH. Cellular senescence of IVD cells is the most important pathophysiological mechanism underlying IVD degeneration leading to IDH, and the antisenescence-based pharmacological strategies may be effective in preventing or attenuating the disease onset and progression.^123–134 The chemokine pathway is an inflammatory pathomechanism associated with IDH development and its activity is related to the generation, persistence, and severity of neuropathic and radicular pain induced by IDH; additionally, targeting this pathway may hold therapeutic potential.^{122,135–139} The Fork head box O (FoxO) pathway has an antioxidant effect that can protect IVDs against their degeneration induced by oxidative stress.¹⁴⁰ The synthesis, expression, and activity of various growth factors and hormones, cytokines, and chemokines associated with osteoclast differentiation in IVD cells are related to IDH severity.¹⁴¹ Hypoxia inducible factor (HIF)-1 pathway is a key regulator of the resorption of herniated discs and survival and apoptotic cell death of disc cells in IVDs.¹⁴² The autoimmunity- and inflammation-associated interleukin (IL)-17 pathway acts as a key mediator of IVD deterioration and IDH progression, and its higher activity is observed in the IVD tissues of patients with IDH.^143,144 Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway acts as an inflammation regulator and causes IDH-associated symptoms that are important for the degeneration of herniated IVDs.¹⁴⁵ The migration and infiltration of leukocytes into IVD tissues, accompanied by angiogenesis, neovascularization, and appearance of nerve fibers, may accelerate the inflammatory IVD degeneration and IDH-related disease processes.⁹⁷ Mitogen activated protein kinase (MAPK) and Ras pathways are involved in the development and persistence of radicular pain and motor dysfunction by modulating the activities of pro-inflammatory, autophagic, and apoptotic cytokines and regulators, and targeting them can alleviate such pathological responses and further induce resorption of IVDs.^146–152 The repression of the mammalian target of rapamycin (mTOR) pathway can attenuate IDH-induced pain and radiculopathies.¹⁵³ The activity of the neurotrophin pathway is related to inflammatory IVD degeneration and its associated pain responses.^154–157 Deregulation of the phosphatidylinositol 3-kinase (PI3 K)-Akt signaling pathway is implicated in IVD degeneration and IHD pathogenesis; its pharmacological intervention reduced IDH-associated pain by inhibiting inflammation responses.^99,158 The prolactin pathway may prevent the progression of IVD degeneration by suppressing inflammation and apoptosis of IVD cells via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis.¹⁵⁹ Improper regulation of the tumor necrosis factor (TNF) pathway may correlate with an increased susceptibility to severity of IVD degeneration and herniation by modulating inflammation, disc cell apoptosis, disc resorption, macrophage infiltration, radiculopathy, onset, persistence, and chronicity of pain.^160–172 The toll-like receptor (TLR) pathway may promote the upregulation of inflammatory cytokines and signaling pathways and also macrophage infiltration, thereby contributing to inflammation, apoptosis, oxidative stress, and degeneration of IVDs.^173–179 Proangiogenic vascular endothelial growth factor (VEGF) signaling is involved in neovascularization, ECM degradation, and resorption of herniated IVDs.^4,5,180,181

Previous studies have shown the regulatory activities of the bioactive chemical ingredients of the EC-AR combination in the disc components and their pharmacological effects on IDH and disc degeneration. Aucubin suppresses the degradation of ECM in disc cells of IVDs, thereby inhibiting their degeneration.¹⁸² Baicalein exerts anti-inflammatory effects on disc cells by inactivating inflammation-inducing cytokines and other mediators and alleviates disc degeneration.¹⁸³ Chlorogenic acid may block oxidative stress-induced apoptosis of disc cells and protect against degeneration of IVDs.¹⁸⁴ Berberine suppresses ECM degradation, oxidative stress, inflammatory processes, and apoptotic cell death of disc cells by inhibiting matrix-degrading enzymes, oxidative stress- and inflammation-associated cytokines and regulators, and by inducing autophagy; these pharmacological effects may lead to the attenuation of IDH and IVD degeneration.^185–187 Kaempferol alleviates the IVD degeneration by inhibiting ECM degradation and inflammation, increasing the viability of bone-marrow-derived mesenchymal stem cells (BMSCs), and reducing the lipid accumulation and adipogenesis in BMSCs.¹⁸⁸ Quercetin exerts inhibitory effects on various senescence-related mechanisms and ameliorates IVD degeneration via regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/NF-κB axis.¹⁸⁹ Wogonin reduces the activities of Nrf2/ARE and MAPK signaling, matrix-degrading proteinases, and inflammatory mediators to upregulate key disc components, while suppressing ECM loss and progression of disc degeneration.¹⁹⁰ The overall findings of this study present experimental evidence for the therapeutic effects of the EC-AR combination for IDH.

The present study has certain limitations. The study lacked experimental validation regarding the molecular regulatory mechanisms of the EC-AR combination and the contribution of its individual bioactive ingredients to the therapeutic effects. Future studies are warranted to address the aforementioned issues and assess the efficacy and safety of the administration of EC-AR combined with IDH therapeutics such as acetaminophen, ibuprofen, muscle relaxants, and opioids.^7,8

To conclude, this network pharmacology-based study revealed the systematic mechanisms of the EC-AR herbal combination for IDH treatment based on network and functional enrichment analyses. The overall findings offer a comprehensive and integrative basis and evidence for the pharmacological effects of the EC-AR herbal combination against musculoskeletal diseases.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X211055024 - Supplemental material for Network Pharmacological Dissection of the Mechanisms of Eucommiae Cortex-Achyranthis Radix Combination for Intervertebral Disc Herniation Treatment

Supplemental material, sj-docx-1-npx-10.1177_1934578X211055024 for Network Pharmacological Dissection of the Mechanisms of Eucommiae Cortex-Achyranthis Radix Combination for Intervertebral Disc Herniation Treatment by Ho-Sung Lee, In-Hee Lee, Kyungrae Kang, Minho Jung and Seung Gu Yang, Tae-Wook Kwon, Dae-Yeon Lee in Natural Product Communications

Footnotes

Acknowledgments

Not applicable.

Author Contributions

Conceptualization: Ho-Sung Lee, In-Hee Lee, Dae-Yeon Lee.

Methodology: Ho-Sung Lee, In-Hee Lee, Dae-Yeon Lee.

Data collection: Ho-Sung Lee, In-Hee Lee, Kyungrae Kang, Minho Jung, Seung Gu Yang, Tae-Wook Kwon.

Data analysis and investigation: Ho-Sung Lee, In-Hee Lee, Dae-Yeon Lee.

Writing: Ho-Sung Lee, In-Hee Lee, Dae-Yeon Lee.

All authors read and approved the final manuscript.

Data Statement

All data generated or analyzed during this study are included in this published article and its Supplemental materials file.

Declaration of Competing Interests

The authors declare that there is no conflict of interest.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval

Ethical Approval is not applicable for this article.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

Trial Registration

Not applicable, because this article does not contain any clinical trials.

ORCID iD

Dae-Yeon Lee

Supplemental material

Supplemental material for this article is available online.

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