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. 2024 Mar 6;10(5):e27365. doi: 10.1016/j.heliyon.2024.e27365

Study on the mechanism of Shugan Lidan Xiaoshi granule in preventing acute pancreatitis based on network pharmacology and molecular docking

Jiaxing Wang a,b,1, Yang Wang a,b,1, Zitong Chen a,b, Bin Liu a,b, Wujie Wang a,b,⁎⁎, Yuliang Li a,b,⁎
PMCID: PMC10938120  PMID: 38486764

Abstract

Background

Shugan Lidan Xiaoshi granules (SLXG) is a herbal granule formulation developed by extensively modifying multiple traditional Chinese medicine compound prescriptions known for their ability to dissolve stones. It is primarily used for the prevention and treatment of cholelithiasis and possesses significant therapeutic potential in both preventing and treating acute pancreatitis. However, the preventive effects of SLXG on cholelithiasis-related complications, such as acute pancreatitis (AP), have been inadequately researched.

Methods

TCMSP database was searched to identify the active components and targets of SLXG's action. The disease gene databases (GeneCards, OMMI, PharmGKB, DrugBank) were used to retrieve the targets associated with AP. A TCM ingredient target network was then constructed by using the intersection of these two datasets. The overlapping targets underwent network analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG)and Protein-Protein Interaction (PPI) analyses. Molecular docking was performed to examine the interaction patterns between the active ingredients and central targets.

Results

A “Traditional Chinese Medicine-Component-Target” complex network consisting of 10 traditional Chinese medicines, 114 compounds, and 164 targets was constructed. GO and KEGG analysis showed that SLXG has the potential to regulate the response of oxygen-containing compounds, apoptosis, and inflammatory factors. Nine central genes were identified by the PPI network and subnetwork. IL6 was chosen as the most significant gene for molecular docking. The three active compounds of SLXG: quercetin, luteolin, and paeoniflorin, along with the active site of IL6 have a good binding ability and thus play a preventive role in AP.

Conclusion

This study provides evidence of the effective preventive role of SLXG against AP, as indicated by bioinformatics analysis. The preventive effect of SLXG is attributed to its multi-component, multi-target, and multi-pathway mechanisms. This finding provides a solid foundation for future research on the clinical application and mechanism of action of drugs.

Keywords: Acute pancreatitis, Shugan Lidan Xiaoshi granules, Molecular docking, Network pharmacology, Traditional Chinese medicine

1. Introduction

Acute pancreatitis (AP) is a prevalent cause of acute abdominal pain, with a fatality rate ranging from 1% to 5% [1]. Common causes of AP include gallstones (40%–70%), alcohol (25%–35%), hypertriglyceridemia (1%–14%), and endoscopic retrograde cholangiopancreatography (ERCP) (3%–5%) [2]. A prolonged follow-up study revealed that individuals with gallstones carry a 7% risk of developing biliary pancreatitis [3]. There are several hypotheses about the mechanism of gallstone-induced pancreatitis. Biliary pancreatitis can occur due to ampullary obstruction or local inflammation caused by stones, as well as temporary bile reflux into the pancreatic duct. Additionally, the risk of gallstone pancreatitis is higher when there are fewer gallstones [4,5]. Currently, the primary minimally invasive treatments for cholelithiasis are percutaneous transhepatic biliary drainage (PTPBD) and ERCP-related techniques. However, the incidence of acute pancreatitis after ERCP ranges from 1% to 9.8% and can reach up to 14% in high-risk patients [6,7]. Recent studies have indicated a potentially lower incidence of pancreatitis after PTPBD compared to ERCP [8,9]. Nonetheless, regardless of the method used (PTPBD or ERCP), the possibility of acute postoperative pancreatitis still exists. As a result, finding strategies to reduce the incidence of cholelithiasis-related or postoperative acute pancreatitis has become an urgent clinical challenge that requires attention.

Currently, the etiology and optimal treatment duration for acute pancreatitis (AP) remain poorly understood, and there is currently no specific medication that can alter the outcome of this condition [10]. The primary treatment for AP consists mainly of fluid resuscitation, pain management, and enteral nutrition support. Chinese herbal medicine has emerged as a significant non-surgical treatment modality for AP in recent years [11]. Multiple studies focusing on traditional Chinese medicine, including compound preparations such as Xiao Chaihu decoction, Dachengqi decoction, Shenmai injection, and Salvia miltiorrhiza, have demonstrated the efficacy of traditional Chinese medicine in ameliorating AP [[12], [13], [14], [15]]. However, considering the limited availability of effective pharmacotherapy options for acute pancreatitis, it is imperative to further explore potential drugs for the treatment of this condition.

Traditional Chinese medicine decoctions based on the Shugan Lidan recipe are commonly used in the clinical treatment of cholelithiasis and have been shown to have a specific preventive effect on acute pancreatitis [[16], [17], [18]], although their mechanism remains unclear. SLXG is a comprehensive improved formulation of traditional Chinese medicines such as ShuganLidan decoction (SLD), Chaihu Shugan San (CSS), etc., which have the functions of soothing the liver, promoting bile excretion, and dissolving stones. The prescription consists of 11 traditional Chinese medicines: Bupleuri Radix (chaihu,CH), Chuanxiong Rhizoma (chuanxiong,CX), Aurantii Fructus (zhike,ZK), Glycyrrhizae Radix et Rhizoma (gancao,GC), Lysimachiae Herba (jinqiancao,JQC), Galli Gigerii Endothelium Coreneum (jineijin,JNJ), Curcumae Radix (yujin,YJ), Lygodii Spora (haijinsha,HJS), Artemisiae Scopariae Herba (yinchen,YC)，Lonicerae Japonicae Flos (erhua,EH)，Paeoniae Radix Alba (baishao,BS). Previous clinical experience has shown that combining ERCP with SLD in the management of choledocholithiasis significantly reduces the incidence of postoperative AP [18]. Additionally, studies have demonstrated the notable clinical efficacy of CSS therapy in the management of acute pancreatitis [19,20]. However, the mechanisms of these SLXG-related traditional Chinese medicine formulas in preventing and treating acute pancreatitis remain unclear. Accordingly, this study utilizes network pharmacology and molecular docking to explore the potential efficacy of SLXG in preventing acute pancreatitis. Furthermore, it provides an analysis of its potential mechanism, aiming to contribute to the development of effective prevention strategies and novel drug therapies for acute pancreatitis.

2. Materials and methods

2.1. Collection of components and targets of SLXG

Through the utilization of the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) [21], the active components of SLXG were identified. The database provided information on the chemical structure, half-life (HL), drug-like (DL), oral bioavailability (OB), drug targets, and other information of herbal components. In order to select compounds for further analysis, we performed a screening of candidate compounds according to the following parameters: OB ≥ 30%, HL and DL ≥ 0.18. The active components of JNJ were not included in TCMSP, it was screened by the BATMAN-TCM database [22]. In TCMSP, relevant drug targets for each active compound were obtained. All the targets found in the above search were standardized into gene names and UniProtIDs by searching “Homo sapiens” in the UniProt database [23]. Additionally, the content of various Chinese medicinal herbs in SLXG was provided in Table S1.

2.2. Collection of therapeutic targets related to AP

The keyword “acute pancreatitis” was used to search Genecards [24], OMIM database [25], PharmGKB database [26], and DrugBank database [27] to screen the target genes of AP. GeneCards identified multiple target genes associated with AP, which were subsequently screened using a relevance score cutoff of >5. The target genes associated with AP were determined by consolidating the findings from the four databases.

2.3. Network construction and enrichment analysis of “traditional Chinese medicine-component-target”

We utilized Cytoscape 3.9.1 [28] to construct the intricate target interaction network of SLXG. The network splitter module of the Cytoscape software was utilized for conducting the topological analysis. Utilizing the sangerbox platform [29], we conducted analyses on the GO and KEGG pathways to identify potential mechanisms involving cell components (CC), biological processes (BP), molecular functions (MF), and key signaling pathways.

2.4. Construction and topology analysis of PPI network

The STRING database [30] was used to ul the PPI network with SLXG targets and AP-related gene sets. The parameter was set to a confidence level >0.900. Subsequently, the PPI network of STRING was integrated into Cytoscape to build key subnetworks. Xia et al.'s method was consulted for the selection of core subnetworks, and two methods to screen core subnetworks were applied [31]. The PPI network was first analyzed in Cytoscape using the CytoNCA plug-in. In the primary score file generated by CytoNCA, each scoring metric including Betweenness, Closeness, Degree, Eigenvector, LAC, and Network, exceeded the median threshold. These parameters are also important indicators of new drug discovery and target prediction. The identified genes were then utilized to create a subnetwork, and the filtering procedure was repeated to obtain the ultimate key subnetwork. Another way for screening key subnetworks is to utilize the CytoHubba plug-in within Cytoscape to discover the top 17 most important genes within the PPI network.

2.5. Detection of the binding ability of effective active components to key targets by molecular docking

Searching on the Pubchem website (https://pubchem.ncbi.nlm.nih.gov) yielded the 3D SDF structure file of the compound, which was then converted into a PDB file using the OpenBabel 2.4.1. The RSCB PDB database (https://www.rcsb.org/) was searched to obtain the receptor protein IL6 (PDB:1ALU), and PYMOL2.6.0 software was used to dehydrate and remove original ligand from the receptor protein [32]. The receptor protein was modified by hydrogenation and charge calculation using AutoDockTools1.5.7 software. The receptor protein was docked with small ligand molecules by AutoDockVina1.1.2 [33]. The grid boxes covering the entire protein were constructed to facilitate blind docking, and the binding energies were subsequently scored. A strong affinity between the active components and the action targets is represented by the binding energy < -5 kcal/mol [34,35].

3. Result

3.1. Effective components and target screening of SLXG

According to the criteria mentioned above, 117 active compounds and 260 drug targets were screened from the ten traditional Chinese medicines of SLXG using the TCMSP database. Octalupine was excluded in the above process because its drug targets could not be retrieved. The JNJ screened from the BATMAN-TCM database was excluded in the above method because of the low correlation between its active components and target genes with acute pancreatitis.

3.2. Acquisition of AP-related targets and intersection targets

The databases Genecards, OMIM, PharmGKB, and DrugBank provided information on 1804, 185, 112, and 6 genes associated with AP. After merging search results and eliminating duplicates, 1987 AP-related genes were obtained (Fig. 1A). Additionally, 164 intersection target genes were identified by intersecting disease-related genes with compound target genes (Fig. 1B).

Fig. 1.

Fig. 1

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The Wayne diagram of disease targets and drug targets.

3.3. Construction of herb-compound-target interaction pharmacology network

The data regarding intersection targets, active components, and traditional Chinese medicine was imported into Cytoscape 3.9.1 software for visual analysis, resulting in the generation of a compound target interaction network comprising 387 nodes and 2095 edges (Fig. 2). It was observed that multiple active compounds can target a single gene, whereas a single compound may target multiple genes, highlighting the multi-component, multi-target, and multi-pathway nature of SLXG, which contributes to the prevention and treatment of AP. Notably, among the 164 genes analyzed, PTGS2 stood out as the gene featuring the highest number of targeted components within the SLXG framework.

Fig. 2.

Fig. 2

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The Herb-compound-target interaction pharmacology network. compounds in SLXG are represented by circles. The ingredients of Traditional Chinese medicine are represented by an arrow. The AP-related target genes are represented by a diamond, and the interaction between compounds and the target genes is represented by the edges. According to topology analysis results, the size of the node is proportional to the value of the degree centrality.

3.4. GO enrichment analysis

The potential CC, BP, and MF of 164 target genes were identified by means of GO enrichment analysis. By setting the filter to P < 0.05 and FDR <0.1, 3807 significantly enriched GO terms were obtained, including 3401 BPs, 164 MFs, and 242 CCs. The top 15 terms are shown in Fig. 3A–C. GO terminology indicates that BPs are mainly involved in cellular response to oxygen-containing compounds, abiotic stimuli, cellular response to organic substance, chemical stimuli, apoptosis, etc.

Fig. 3.

Fig. 3

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GO enrichment analysis of the target genes. (A): BP (B): CC (C): MF. Gene counts are the total number of enriched genes, whereas gene ratio is the ratio of enriched genes to all target genes.

3.5. KEGG enrichment analysis

The enrichment analysis using KEGG identified pathways enriched for 164 target genes. The filter condition was set with adjusted P < 0.05 and FDR <0.1. There are 168 KEGG pathways that are significantly enriched, which suggests that these target genes have an impact on signal pathways related to viral infection, inflammatory factors, and the onset and progression of cancer. The bubble diagram depicting the 15 most significant KEGG pathways is presented in Fig. 4.

Fig. 4.

Fig. 4

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KEGG enrichment analysis of the target genes.

3.6. PPI network and critical subnetwork

The 164 target genes were imported into the STRING database, with the species Homo sapiens and the minimum confidence level set at 0.9. Simultaneously, the free points were hidden, and the information on target-protein interaction was transferred to cytoscope 3.9.1 software to visually analyze the PPI network diagram (Fig. 5A–B). The network diagram contains 149 nodes and 797 edges. Finally, by employing CytoNCA and CytoHubba, respectively, two significant subnetworks consisting of 17 target genes were discovered (Fig. 5C–F).

Fig. 5.

Fig. 5

Fig. 5

Fig. 5

Fig. 5

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Identification of key subnetwork using Cytoscape. (A) Analysis diagram illustrating the network of target-protein interactions (B) According to topology analysis results, the size and color of the node are proportional to the degree centrality value. (C) Performing the first filtering in the PPI network through Cyto-NCA, the screened yellow nodes with scores surpassing the median. (D) The subnetwork was built through a secondary filtration process using CytoNCA. Orange nodes were selected based on scores exceeding the median value. (E) Final key subnetwork identified after undergoing two rounds of filtration with CytoNCA. (F) Key subnetwork of top 17 nodes analyzed by CytoHubba.

3.7. Molecular docking of active compounds with proteins encoded by IL6

According to the Maximal Clique Centrality (MCC) values, which was regarded as the most effective method to find hub nodes [28]; two key subnetworks (Fig. 6A) and nine genes and their importance were examined (Table 1). Severe acute pancreatitis is associated with elevated levels of cytokines. IL6 is one of the best distinguishing markers for mild and severe acute pancreatitis, and blood IL6 levels are related to the mortality rate of organ failure [36]. IL6 was chosen as the most crucial gene for molecular docking. Afterward, three compounds that targeted the IL6 protein were isolated from the compound-target interaction network. The three compounds are quercetin, luteolin, and paeoniflorin. These compounds may all readily enter and bind to the active pocket of the IL6 protein, as demonstrated by the molecular docking (Fig. 6B–D). The docking score is recorded in Table 2.

Fig. 6.

Fig. 6

Fig. 6

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The selection of key genes within the subnetwork and molecular docking diagram of chemical composition to target. (A) The identification of key genes by the intersection of the two crucial subnetworks. (B) IL6-quercetin. (C) IL6-luteolin. (D) IL6-paeoniflorin.

Table 1.

The most critical nine genes and MMC values.

RANK 1 2 3 4 5 6 7 8 9
Gene IL6 STAT3 RELA MAPK3 MAPK1 TNF ERS1 FOS MYC
MCC 53368 51273 28258 24356 23234 22862 20556 20320 15422
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Table 2.

Molecular docking scores.

NO Mol ID Compound name Docking score (kcal/mol)
1 MOL000098 quercetin −7.1
2 MOL000006 luteolin −7.2
3 MOL001924 paeoniflorin −6.6
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4. Discussion

Cholelithiasis is the primary cause of acute pancreatitis globally, responsible for approximately 20–70% of all cases in Western countries [37,38]. Epidemiological studies have demonstrated an increasing prevalence of cholelithiasis with age. This suggests a correlation between the incidence of acute pancreatitis and demographic changes [39]. The obstruction of the Oddi sphincter by a stone is the initial reported cause of acute necrotizing pancreatitis. Experimental acute pancreatitis can be induced through pancreatic duct obstruction and/or bile acid infusion [10]. Women constitute approximately two-thirds of individuals with acute biliary pancreatitis, as they have a higher likelihood of developing gallstones compared to men [38]. Within this medical context, there is a growing research focus on the prevention and management of acute pancreatitis and its associated complications stemming from cholelithiasis.

Traditional Chinese medicine has the advantages of having many targets and few side effects, Consequently, it is increasingly being considered for clinical use. Traditional Chinese medicine can prevent and treat both cholelithiasis and pancreatitis. SLXG is composed of modified prescriptions based on the famous prescription of Shugan Lidan, which plays a key role in preventing and treating cholelithiasis in clinical settings. The previous studies on traditional Chinese medicine compound prescription of cholelithiasis primarily focus on the treatment and prevention of the disease itself. However, there are few reports that explain whether the treatment and prevention can influence the complications of the disease. Therefore, it was considered whether SLXG has the potential to prevent or treat AP. In recent years, studying and exploring the mechanism of action of traditional Chinese medicine compound prescriptions has been greatly aided by the analytical methods of network pharmacology and molecular docking. Therefore, we used the same strategy in this study.

A related gene set of SLXG targeting AP, consisting of 164 target genes, was constructed in this research through the analysis of the active components of 10 SLXG components. The association between active substances, targets, and traditional Chinese medicine is described by a complex target network. In the current study, 114 effective compounds and 164 candidate targets of SLXG for the treatment of acute pancreatitis (AP) were identified. Additionally, 87.80% of the 164 possible therapeutic targets for SLXG can overlap with at least two active compounds, suggesting that the effective compounds in SLXG may work together against AP by multi-target coordination. In addition, 92.98% of the 114 active compounds (106 out of 114) act on at least two candidate therapeutic targets. In addition, quercetin is found in five herbs (CH, YC, JQC, EH,GC). Luteolin is found in EH, and six herbs (CH, BS, GC, EH, JQC and HJS) contain kaempferol. They act on 108, 50, and 40 candidate AP therapeutic targets, respectively, indicating that SLXG effectively addresses acute pancreatitis (AP) by utilizing a synergistic blend of various herbal ingredients, compounds, and targeted therapeutic mechanisms.

It was speculated that quercetin would be crucial in the treatment of AP because it targets the most predictive targets. Quercetin, luteolin, kaempferol and paeoniflorin are part of the natural flavonoid compound family. Flavonoids have been shown to possess antioxidant properties by scavenging reactive oxygen species, bolstering endogenous antioxidants, downregulating the expression and synthesis of inflammatory cytokines such as IL-1β, IL-6, TNF-α, NF-κB, inhibiting inflammatory enzymes, and promoting the production of anti-inflammatory cytokines like IL-10 [40]. Previous research has demonstrated that quercetin is effective in treating acute pancreatitis by inhibiting the production of inflammatory and apoptotic factors (IL-6, TNF- α, and IL-1 β, as well as MAPK3 and TP53) [13,41]. Quercetin has been demonstrated in another study to provide protection against acute pancreatitis by up-regulating miR-216b and inhibiting both TNF-α and the p38/MAPK signaling pathway, consequently suppressing the release of inflammatory factors such as IL6 [42].Several studies have confirmed that luteolin can inhibit the expression of inflammatory factors such as TNF-α, IL-6, and IL-1β [[43], [44], [45]]. According to another study, luteolin reduces the severity of AP in mice by activating heme oxygenase (HO-1), which exerts anti-inflammatory and antioxidant effects [46]. This activity is linked to the suppression of NF-KB signaling pathway activation. Studies by Kim et al. have shown that kaempferol not only has free radical scavenging and anti-inflammatory activities in vitro but also can effectively inhibit the inflammatory symptoms in vivo [47]. A variety of inflammatory signaling components, such as Src, Syk, and IRAK4, which are essential for the activation of NF-kB and AP-1, can be inhibited by kaempferol, in particular. Kaempferol inhibits matrix metalloproteinase-1 (MMP-1) and down-regulates MMP-1 expression by inhibiting the activation of transcription factor-1 (AP-1) [48]. These studies suggest that there are a variety of active components in SLXG that can improve the symptoms of pancreatitis through different mechanisms. The effectiveness of SLXG in preventing AP can be predicted from numerous studies on the action mechanisms of these components, including the anti-inflammatory, antioxidant, and anti-apoptotic effects.

The GO enrichment analysis of this study showed that SLXG could participate in the process of cellular response to chemical stimulus,cellular response to organic substance,abiotic stimulation, response to oxygen containing compound, cell apoptosis, etc. KEGG pathway analysis shows that the target genes are mainly related to the PI3K-Akt signaling pathway, AGE-RAGE signaling pathway, etc., and play a role in prostate cancer, pancreatic cancer, bladder cancer, and other cancer pathways; Human cytomegalovirus infection, Kaposi sarcoma-associated herpesvirus infection and other virus-related pathways were also involved; and TNF signaling pathway and IL17 signaling pathway are related. PI3K/AKT is a crucial signal transduction pathway that regulates several signal transduction pathways, including stress, apoptosis, and proliferation. The expression of p-Akt and the activity of NF-kB in pancreatic tissue were significantly elevated in the AP model induced by pancreatic duct ligation [49]. Research showed that by inhibiting the PI3K pathway of SAP rats, the activity of NF-kB was decreased, the expression of the apoptosis inhibitory gene and the release of inflammatory factors were reduced, and the condition of rats was alleviated [50]. According to research by Sun et al. [12], AP can be improved by regulating the PI3K/AKT signal pathway, promoting apoptosis, and inhibiting the inflammatory response and pathological damage. TNF signaling pathway and IL-17 signaling pathway are classic inflammatory signal pathways crucial in the occurrence and development of pancreatitis [51]. Many of the key components, main targets, and pathways of SLXG are related to cancer, suggesting that SLXG might help to treat and prevent cancer. From the above enrichment analysis results, it can be seen that SLXG may improve the symptoms of pancreatitis through multiple signal pathways.

The PPI network and key network modules were constructed by 164 target genes. The topological analysis found the nine most critical central targets in the PPI network. This study centered on the crucial gene IL6, and molecular docking was carried out to confirm the interaction between the active compounds in SLXG and IL6. The findings of molecular docking showed that quercetin, luteolin, and paeoniflorin could bind well with IL6. In addition, the inhibitory effects of quercetin, luteolin, paeoniflorin, and other active ingredients in acute pancreatitis have been reported. Only a few studies have proved that paeoniflorin can improve acute pancreatitis and acute kidney injury and lung injury caused by acute pancreatitis in rats [52,53]. The findings of molecular docking showed that paeoniflorin might be crucial in treating acute pancreatitis; However, the specific mechanism of paeoniflorin in acute pancreatitis is still unclear, which needs further research and exploration.

5. Conclusion

In conclusion, this study conducted molecular docking validation and network pharmacological analysis to anticipate the action targets and main signal pathway of SLXG in treating AP. The key targets include IL6, STAT3, RELA, MAPK3, MAPK1, TNF, ESR1, FOS, MYC, etc. The key pathways mainly involve the PI3K-Akt signal pathway, IL17 signal pathway, TNF signal pathway, etc. Some potential active ingredients of SLXG may have a certain intervention effect on the clinical symptoms of AP. The therapeutic effect of SLXG may be achieved by affecting multiple targets and related pathways simultaneously, which also provides some references for further exploring its mechanism of action. In summary, the findings of this study demonstrate the perspective of bioinformatics on the efficacy of SLXG in the treatment of AP, offer a new prospect for SLXG application, and may also facilitate the basic research and design of targeted drugs for acute pancreatitis. It also provides a fresh concept for the development of a traditional Chinese medicine compound, that is, whether the traditional Chinese medicine compound can prevent and cure the related complications while treating the disease itself. The limitations of this study include that it only explores the theoretical level of the possibility; further animal tests and clinical trials are needed to verify the results of this research.

Ethics approval and consent to participate

As this study does not involve animal and patient experiments, the ethical approval and consent to participate are not applicable.

Consent for publication

Not applicable.

Availability of data and materials

All the data can be obtained from the open source platform provided in the article.

Founding

This study was supported by the Jinan New Support Projects for Universities (Talent Development Special Fund,Grant No:20228118) and Program for Integrated Traditional Chinese and Western Medicine in Shandong Province of China (Grant No:YXH2019ZXY007).

Data availability statement

Data included in article/supplementary material/referenced in article.

CRediT authorship contribution statement

Jiaxing Wang: Writing – original draft, Investigation. Yang Wang: Writing – original draft, Formal analysis. Zitong Chen: Software, Methodology. Bin Liu: Validation, Data curation. Wujie Wang: Writing – review & editing, Supervision, Data curation. Yuliang Li: Writing – review & editing, Supervision, Project administration.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We would like to thank everyone who contributed to this article.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e27365.

Contributor Information

Wujie Wang, Email: dr.wangwujie@sdu.edu.cn.

Yuliang Li, Email: lyl.pro@sdu.edu.cn.

Appendix A. Supplementary data

The following is/are the supplementary data to this article:

Multimedia component 1
mmc1.pdf (23.1KB, pdf)

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