Journal of Advanced Biochemistry

 

Chinese Herbal Formula Duhuo Jisheng Decoction in Treating Lumbar Disc Herniation: Clinical Evidence and Potential Mechanisms

Yixuan Li1, Qian Chen1, Xin Yuan1, Honghao Huang1, Qiuhong Zeng1, Guojun Bu1, Zhen Huang1, Lulu Cai1, and Shujie Tang1*ORCID ID 

1School of Chinese Medicine, Jinan University, Guangzhou 510632, China.

*Corresponding Author: Tang S, School of Chinese Medicine, Jinan University, Guangzhou 510632, China. E-mail:  [email protected]

Citation: Li Y, Chen Q, Yuan X, Huang H, Zeng Q et al. Chinese Herbal Formula Duhuo Jisheng Decoction in Treating Lumbar Disc Herniation: Clinical Evidence and Potential Mechanisms. Journal of Advanced Biochemistry. 2021;1(2):1-16.

 

Copyright: © 2021 Tang S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received On: 22nd December,2021     Accepted On: 29th December,2021    Published On: 10th January,2022

Abstract

Introduction: To investigate the effectiveness of DuHuo JiSheng decoction (DHJSD) versus Western medicine, and explore the mechanism of DHJSD in the treatment of lumbar disc herniation (LDH).

Methods. Eight databases were searched to retrieve the randomized controlled trials (RCTs), and a systematic review and meta-analysis was performed by Review Manager 5.4. Then, a network pharmacological analysis was carried out, in which core compounds and targets were identified, and protein-protein interaction (PPI) network was constructed. In addition, Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses as well as molecular docking were performed.

Results: Meta-analysis revealed, compared with Western medicine, both DHJSD plus Western medicine and DHJSD subgroups had better effectiveness in total effective rate, VAS and JOA scores, and DHJSD subgroup had a lower adverse event rate. Network pharmacology identified eight core compounds of DHJSD including quercetin, wogonin, kaempferol, formononetin, baicalein, 7-Methoxy-2-methyl isoflavone, beta-sitosterol, and beta-carotene, and nine core targets of LDH including IL6, TNF, ALB, IL1B, MMP9, VEGFA, AKT1, PTSG2, and FN1. Besides, 146 potential pathways of DHJSD were identified, including TNF and IL-17 signalling pathways, and molecular docking demonstrated the core compounds could bind to the core targets automatically.

Conclusions: In the treatment of LDH, DHJSD had better effectiveness in relieving pain, decreasing adverse event rate, and improving limb function than Western medicine, and DHJSD may mainly act on TNF, IL-17, and AGE-RAGE signalling pathways to exert immune regulation, anti-inflammatory, and analgesic effects.

Keywords: Duhuo Jisheng Decoction, Lumbar disc herniation, Network pharmacology, Meta-analysis, Systematic review.

Introduction

Lumbar disc herniation (LDH) is one of the most common spinal disorders caused by intervertebral disc degeneration (IVDD), which leads to low back pain (LBP) and sciatica [1]. It was reported that 30% of world population may suffer from LDH during their lifetime [2], and almost 85% of patients with sciatica may be attributed to LDH [3]. LDH imposes heavy burdens on patients, families, and governments in the world. Therefore, the treatment of LDH is an extensive concern in medical fields.

 

LDH can be treated via conservative or surgical therapies, and most of patients can recover based on conservative treatments, such as medication, exercise, epidural steroid injection, chiropractic manipulation, and physical therapy. Western medicine, including non-steroidal anti-inflammatory drugs, paracetamol, and opioids, play an important role in the treatment of LDH. However, these drugs have undesirable side effects and irreversible toxicity to digestive, urinary, and cardiovascular systems, leading to acute liver failure, myocardial infarction, and increased mortality [4-6].

Traditional Chinese Medicine (TCM), with satisfying effect and low toxicity, has been used to treat LDH for thousand years. DuHuo JiSheng Decoction (DHJSD), a TCM prescription recorded in the book Bei Ji Qian Jin Yao Fang written by Sun Simiao in Tang Dynasty, has remained the most popular TCM prescription in treating LDH [7]. DHJSD consists of fifteen herbs, including Duhuo (Radix Angelicae Pubescentis), Danggui (Radix Angelicae Sinensis), Sangjisheng (Herba Taxilli), Duzhong (Cortex Eucommiae), Fangfeng (Radix Saposhnikoviae), Xixin (Herba Asari), Chuanxiong (Rhizoma Chuanxiong), Baishao (Radix Paeoniae Alba), Dihuang (Radix Rehmanniae Glutinosae), Rougui (Cortex Cinnamomi), Renshen (Panax Ginseng), Fuling (Poria), Niuxi (Radix Achyranthis Bidentatae), Qinjiao (Radix Gentianae Macrophyllae), and Gancao (Radix Glycyrrhizae), which can eliminate rheumatism, nourish the kidney and liver, strengthen the muscles and bones, clear blood stasis, invigorate qi, and promote blood. Some randomized controlled trials (RCTs) have reported that the efficacy of DHJSD is better than Western medicine in the treatment of LDH [8-10]. However, few systematic review and meta-analysis articles have been published to investigate the effectiveness of DHJSD versus Western medicine in the treatment of LDH.

Moreover, the exact mechanism of DHJSD for LDH remains unclear, which can’t be clarified by traditional pharmacology, as the multi-compound, multi-target, and multi-pathway characteristics of Chinese herb decoction. In recent years, network pharmacology, an emerging field, can characterize the action mechanisms of complicated drug system in detail from molecular to pathway level by visualizing ‘multi-compound, multi-target, and multi-pathway’ interaction network [11]. As a result, we speculate that the active compounds, targets and signal pathways of DHJSD can be explored and analyzed by network pharmacology, and the mechanism of DHJSD may be clarified.

Therefore, a systematic review and meta-analysis as well as a network pharmacological analysis was performed in the current study. Our objectives were (1) to investigate the effectiveness of DHJSD versus Western medicine, and (2) to explore the treatment mechanism of DHJSD in treating LDH.

Methods

Meta-analysis

This systematic review has been developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [23] guidelines [12].

Search Strategy

Two researchers searched the databases including PubMed, the Cochrane Library, Embase, Web of Science, Science Direct, China National Knowledge Infrastructure (CNKI), Wanfang Database, and Chinese Science and Technology Periodical Database (VIP), from their inception to March 21, 2021, using Medical Subject Headings and key words. The language was limited to Chinese and English. The following terms were searched for English databases: (intervertebral disc displacement OR lumbar disc herniation OR herniated disc OR herniated disk OR disc prolapse OR disk prolapses OR disc prolapses OR disk prolapse OR slipped disc OR prolapsed disc OR prolapsed disk) AND (DuHuo JiSheng decoction OR DHJSD) AND (randomized controlled trial OR RCT OR RCTs OR randomization). The following terms were searched for Chinese databases: (Du huo ji sheng tang) AND (Yao zhui jian pan tu chu zheng OR Zhui jian pan tu chu OR Zhui jian pan peng tu OR Zhui jian pan tuo chui) AND (Sui ji dui zhao shi yan OR Sui ji).

Inclusion and exclusion criteria

The inclusion criteria were: (1) RCTs; (2) LDH was diagnosed based on symptoms, signs, and imaging examinations; (2) The experimental group was treated with DHJSD or DHJSD plus Western medicine, but the control group treated with Western medicine alone; (3) The outcome measurements, including visual analogue scale (VAS), Japanese orthopaedic association scores (JOA scores), and total effective rate were reported.

The exclusion criteria were: (1) Repetitive studies. (2) Patients have other complications, such as tumours, vertebral fracture, epidural abscess, spondylolisthesis, and lumbar stenosis. (3) The experimental group consists of acupuncture, manipulation or other external treatments as adjuvant therapy. (4) Data were incomplete or wrong.

Data Extraction and Quality Assessment

Data extraction and quality assessment of the included trials were carried out by two researchers independently. Data extraction included the information of first author, publication year, sample size, age of patients, gender, interventions, treatment duration, outcome measurements, and adverse events. Quality assessment was performed according to the Cochrane risk of bias tool, which consists of the following seven items: (1) randomization, (2) allocation concealment, (3) blinding of outcome assessment, (4) blinding of participants and personnel, (5) incomplete outcome data, (6) selective reporting, and (7) other bias. Each item has three levels, including high risk, low risk, and unclear risk. Discrepancies were resolved by discussion with a third researcher.

Statistical Analysis

 

The Review Manager 5.4 was used to perform the meta-analysis. Dichotomous data (total effective rate, adverse events) were analysed using risk ratio (RR) and 95% confidence interval (CI), while the continuous variables (VAS, JOA scores) using standard mean differences (SMD) and 95% CI. Statistical heterogeneity was calculated by I2 test. Fixed effect model was used when I2 50% and P0.1, otherwise random effect model was employed. When heterogeneity was high, a sensitivity analysis or subgroup analysis was performed. P< 0.05 was considered statistically significant.

 

Network pharmacology

Identification of active compounds and protein targets

The chemical compounds of DHJSD were screened out from Traditional Chinese Medicine Systems Pharmacology Database (TCMSP, http://tcmspw.com/), in which oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18 were set as criteria [13]. Based on the same platform, the targets corresponding to compounds were extracted. R and Strawberry Perl software were used to obtain gene symbols after standardizing gene names. The targets related with LDH were retrieved from Gene cards (https://www.genecards.org/) and OMIM (https://omim.org/). The drug-disease cross targets were identified in Venny (https://bioinfogp.cnb.csic.es/tools/venny/). The gene symbols of cross targets were uploaded into STRING database (https://string-db.org/), and the TSV files were exported to construct protein-protein interaction (PPI) network. The core targets were screened based on the frequency of occurrence.

Construction of Compounds-targets network

Compounds-targets network was visualized via Cytoscape software. Centi Scape, a plug-in in Cytoscape, was used to screen the main compounds in compounds-targets network by calculating “degree” score.

Gene ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses.

To clarify the function of targets and related signalling pathways, GO and KEGG pathway enrichment analyses were conducted by “DOSE”, “clusterProfiler”, “org.Hs.eg.db” and “pathview” packages in R software. GO enrichment analysis includes three parts of cellular component (CC), biological process (BP) and molecular function (MF). The bubble and bar charts of GO and KEGG pathway enrichment analyses were visualized via R software.

Compounds–targets molecular docking

 

Three-D structures of core targets were downloaded from RCSB PDB database (http://www.rcsb.org/) as receptors, and Mol2 format files of core compounds were downloaded in TCMID as ligands. Using AutoDock Tools, the receptor and ligand proteins were converted into PDBQT files, then the molecular docking was performed. PyMOL and Discovery studio software were utilized to visualize the best affinity conformation.

Results

Meta-analysis

Study Selection

Our initial search identified 2068 trials, and 218 were removed for duplications. The remaining trials were screened by reading titles and abstracts, during which 1446 were excluded because of failing to meet the inclusion criteria, and 404 were left. After reading the full texts, 137 trials were excluded for inappropriate interventions, 36 were excluded for non-RCTs, and 206 were excluded for review articles. As a result, a total of 25 trials were included in our analysis. The process of trial selection is shown in Figure 1.

Figure 1. Flow diagram of the study selection. CNKI, China National Knowledge Infrastructure; VIP, Chinese Science and Technology Periodical Database; RCTs, randomized controlled trials.

Study characteristics and quality assessment

The 25 trials were all published in Chinese. A total of 2766 patients were enrolled, including 1683 males and 1083 females. In experimental groups (1397 patients), sixteen trials used DHJSD plus Western medicine, and nine trials used DHJSD alone as intervention. In control groups (1369 patients), eleven trials used diclofenac, four trials used celecoxib, one trial used lornoxicam, one trial used meloxicam, one trial used loxoprofen sodium, one trial used lysine Aspirin, one trial used diclofenac and Vitamin B12, and five trials used indomethacin, diclofenac, and ibuprofen. The treatment duration ranged from 14 to 42 days. All the trials reported total effective rate, eight trials reported VAS, two trials reported JOA scores, and seven trials reported adverse events.

In 25 trials, the patients were randomly assigned to experimental or control groups. In terms of the randomization sequence generation, two trials used random number tables, two trials used coin tossing, two trials used computer random number generator, and one trial used drawing of lots. Eighteen trials did not mention the randomization methods in details. No trials mentioned allocation concealment. One trial reported double blind method. Two trials reported follow-up. All the trials reported complete data. The basic characteristics and the quality assessment of the trials are shown in Appendix A and B.

Meta-analysis Results

As the heterogeneity was high between these trials, subgroup analysis was performed and the trials were divided into two subgroups according to different interventions in experimental group, i.e., DHJSD plus Western medicine and DHJSD subgroups.

Total Effective Rate

All the trials reported total effective rate (Figure 2a). In the subgroup of DHJSD plus Western medicine, nine trials were included and a significant difference was found between the groups (RR=1.18, 95% CI [1.12, 1.24]; P < 0.05). In the subgroup of DHJSD, sixteen trials were included and a significant difference (RR=1.31, 95% CI [1. 24, 1.38]; P < 0.05; I2 = 46%) was also found.

VAS scores

 

A total of eight trials reported VAS scores (Figure 2b). As both subgroups had high heterogeneity, a sensitive analysis was performed. In the subgroup of DHJSD plus Western medicine, after excluding any one of the three trials, the heterogeneity was still high. A significant difference was found between groups (SMD=-2.06, 95% CI [-2.90, -1.21]; P < 0.05; I2 = 97%). In the subgroup of DHJSD, after deleting Zou’s trial, the heterogeneity decreased to 3%, and the difference between groups was significant (SMD=-1.34, 95% CI [-1.70, -0.98]; P < 0.05; I2 = 3%).

JOA scores

Each subgroup had only one trial reporting JOA scores (Figure 2c), and each trial showed a significant difference between the groups (SMD=5.95, 95% CI [4.19, 7.71], P < 0.05 in the subgroup of DHJSD plus Western medicine; SMD= 2.72, 95% CI [1.99, 3.45], P < 0.05 in the subgroup of DHJSD).

Adverse Events

A total of seven trials reported adverse events (Figure 2d). Thirty-seven cases of gastrointestinal reaction, six cases of rash, and one case of facial edema occurred in control group; ten cases of gastrointestinal reaction and two cases of rash occurred in experimental group. In the subgroup of DHJSD plus Western medicine, no significant difference was found in adverse event rate between the groups (RR = 0.67, 95% CI [0.08, 5.72], P > 0.05). However, in the subgroup of DHJSD, a significant difference (RR = 0.2, 95% CI [0.09, 0.42], P < 0.05) was found between the groups.

Figure 2. Meta-analysis results. (a) Total effective rate. (b) VAS. (c) JOA score. (d) adverse event rate.

 

Network pharmacology

Active compounds and targets screening

A total of 240 active compounds were identified in Appendix C, including nine in Radix Angelica Pubescentis, two in Herba Taxilli, two in Radix Gentianae Macrophyllae, eighteen in Radix Saposhnikoviae, eight in Herba Asari, seven in Rhizoma Chuanxiong, two in Radix Angelicae Sinensis, two in Radix Rehmanniae Glutinosae, thirteen in Radix Paeoniae Alba, fifteen in Poria, twenty-eight in Cortex Eucommiae, twenty in Radix Achyranthis Bidentatae, twenty-two in Panax Ginseng, zero in Cinnanmomi Cortex, and ninety-two in Radix Glycyrrhizae, respectively. After standardization in Uniprot database, 179 potential active compounds and 292 DHJSD-related targets were predicted. 434 LDH-related targets were retrieved from GeneCards and OMIM databases. Subsequently, 56 drug-disease cross targets were obtained in Venny in Figure 3a. PPI network was visualized in STRING in Figure 3b. Top nine target proteins were identified as core targets, including IL6, TNF, ALB, IL1B, MMP9, VEGFA, AKT1, PTSG2, and FN1 in Figure 3c.

Figure 3. Analysis of the protein targets. (a) The Venny diagram. (b) The PPI network diagram. (c). The frequency of targets (X-axis: the number of edges joined by the target).

 

Core compounds obtained

The compounds-targets network was constructed via Cytoscape in Figure 4, which contained 210 nodes and 862 edges. The top eight compounds, including quercetin (MOL000098), wogonin (MOL000173), kaempferol (MOL000422), beta-carotene (MOL002773), formononetin (MOL000392), baicalein (MOL002714), 7-Methoxy-2-methyl isoflavone (MOL003896), and beta-sitosterol (MOL000358), were identified as core compounds based on corresponding degree score with 90,34,28,26,20,20,18, and 16, respectively.

Figure 4. Compounds-targets network. Pink circles, yellow circles, orange diamond, and green V represent the compounds, core targets, LDH, and DHJSD, respectively.

GO and KEGG Enrichment Analyses

GO function enrichment analysis involved 33 CC entries, 2156 BP entries, and 111 MF entries. The main CC entries included membrane raft, membrane microdomain, membrane region, vesicle lumen, secretory granule lumen collagen-containing, and extracellular matrix cytoplasmic vesicle lumen. The BP entries were mainly involved in the response to lipopolysaccharide, molecule of bacterial origin, chemical stress, oxidative stress, reactive oxygen species, and reactive oxygen species metabolic process. The MF entries mainly contained cytokine receptor binding, cytokine activity, receptor ligand activity, signaling receptor activator activity, and serine hydrolase activity. In addition, KEGG pathway enrichment analysis consisted of 146 signal pathways. The top ten entries in each part of GO and the top twenty KEGG signaling pathways were shown in Figure 5. The pathway map in treating LDH with DHJSD was obtained via KEGG Mapper tool in Figure 6. In TNF, IL17, and AGE signal pathways, the number of accumulated targets in DHJSD were 23, 22, and 21, which were higher than other pathways.

Figure 5. Enrichment Analyses. (a) Histogram of GO; (b) Bubble diagram of GO; (c) Histogram of KEGG; (d), Bubble diagram of KEGG.

Figure 6. TNF signal pathway map. Red rectangles represent the screened targets which mediate TNF signal pathway.

Results of molecular docking

There were strong binding effects between the eight ligands and nine receptors. The binding energies were all less than 5 kcal/mol in Table 1, and the interaction of van der Waals’ Forces was widely observed. In addition, hydrogen bonding was also the form of interaction in figure 7. IL6 and quercetin, TNF and wogonin, MMP9 and quercetin, and FN1 and wogonin were closely bound to residues via these hydrogen bonds: SER169, LEU64; GLY148; ALA242, ALA189, GLN227; ARG1491, respectively.

Figure 7. The conformations of receptor and ligand. (a) IL6 and quercetin. (b) TNF and wogonin. (c) MMP9 and quercetin. (d) FN1 and wogonin.

 

Target

PDB ID

Compound

Binding energy (kcal/mol)

IL6

4NI7

quercetin

-6.6

IL6

4NI7

wogonin

-6.4

IL6

4NI7

celecoxib

-6.5

IL6

4NI7

diclofenac

-5.8

TNF

5UUI

quercetin

-6.7

TNF

5UUI

wogonin

-7.1

TNF

5UUI

kaempferol

-6.5

TNF

5UUI

 

celecoxib

-6.7

TNF

5UUI

diclofenac

-6.8

ALB

6HSC

beta-carotene

-9.8

ALB

6HSC

celecoxib

-5.8

ALB

6HSC

diclofenac

-6.2

IL1B

1L2H

quercetin

-7.3

MMP9

6ESM

quercetin

-10

MMP9

6ESM

baicalein

-9.7

MMP9

6ESM

celecoxib

-8.8

MMP9

6ESM

diclofenac

-7.4

VEGFA

3QTK

quercetin

-8.3

VEGFA

3QTK

beta-carotene

-9.2

VEGFA

3QTK

baicalein

-8

VEGFA

3QTK

celecoxib

-8.4

VEGFA

3QTK

diclofenac

-6.6

AKT1

3O96

quercetin

-9.2

AKT1

3O96

wogonin

-9

AKT1

3O96

kaempferol

-9.3

AKT1

3O96

beta-carotene

-10.7

AKT1

3O96

baicalein

-9.4

AKT1

3O96

celecoxib

-10.1

AKT1

3O96

diclofenac

-7.8

PTGS2

5IKR

quercetin

-9.4

PTGS2

5IKR

wogonin

-8.4

PTGS2

5IKR

beta-carotene

-10.2

PTGS2

5IKR

formononetin

-7.8

PTGS2

5IKR

baicalein

-9.3

PTGS2

5IKR

7-Methoxy-2-methyl isoflavone

-8.8

PTGS2

5IKR

beta-sitosterol

-8.4

PTGS2

5IKR

celecoxib

-9

PTGS2

5IKR

diclofenac

-7.6

FN1

4LXO

wogonin

-6.9

FN1

4LXO

celecoxib

-7.3

FN1

4LXO

diclofenac

-6.1

                             Table 1. Binding energy between receptor and ligand.

Discussion

Evidence Summary

In this systematic review and meta-analysis, we found, compared with Western medicine alone, DHJSD or DHJSD plus Western medicine had better effectiveness in total effective rate, VAS, and JOA scores. As to the adverse event rate, a significant difference was found in the subgroup of DHJSD, demonstrating DHJSD had a lower toxicity than Western medicine alone. However, in the subgroup of DHJSD plus Western medicine, there was no significant difference. In our opinion, the use of Western medicine led to a higher adverse event rate in the subgroup. Thus, we concluded that DHJSD had better effectiveness in relieving pain, decreasing adverse event rate, and improving limb function than Western medicine alone.

Main Pharmacological Mechanisms

Based on this network pharmacological study, the main core compounds of DHJSD, including quercetin, wogonin, kaempferol, formononetin, baicalein, 7-Methoxy-2-methyl isoflavone, beta-sitosterol and beta-carotene were identified. Both quercetin and kaempferol have anti-oxidative activities, which can protect nucleus pulposus cells from apoptosis, and avoid annulus fibrosus degeneration induced by oxidative stress. Also, quercetin can suppress the secretion and expression of pro-inflammatory cytokines as well as M1 macrophages/microglia-mediated immune response, which might prevent nociceptive hypersensitivity and exert anti-inflammatory effects [14-17]. Wogonin, formononetin, and baicalein have the functions of inhibiting neuro-inflammatory responses, mitigating progression of disc degeneration, and alleviating pain by suppressing the secretion of inflammatory mediators including IL-1β, IL-6, and TNF-α [18-20]. In addition, beta-sitosterol can improve the swelling symptoms caused by pro-inflammatory cytokines [21], and beta-carotene can postpone the occurrence of intervertebral disc degeneration [22]. These results demonstrated in the treatment of LDH DHJSD may exert anti-oxidation, anti-inflammatory, immune regulation, and analgesic effects through abovementioned multiple compounds.

Moreover, the core targets of LDH, including IL-6, TNF, ALB, IL-1β, MMP9, VEGFA, AKT1, PTGS2 and FN1, were found in the current network pharmacological study. TNF, IL-6, IL-1β are key inflammatory mediators, which induce inflammatory response, matrix destruction, autoimmune response, and hyperalgesia [23-27]. MMP9, one member of matrix metalloproteinases family, can hydrolyse and degrade intervertebral disc tissues, leading to IVDD and associated pain symptoms [28]. VEGFA can promote the neovascularization and infiltration to accelerate IVDD [29]. AKT1, activated by VEGF, can promote neuronal and vascular ingrowth and result in pain [30]. PTGS2 (COX2), upregulated by inflammatory cytokines, plays an important role in disc degeneration and painful radiculopathy [31]. FN1 can increase the expression of pro-inflammatory cells, accelerating the degeneration and promoting radicular pain [32, 33]. Thus, these core targets were closely related to the symptoms of LDH, and DHJSD may exert its therapeutic effects by intervening these targets.

 

In addition, to investigate the role of the active targets of DHJSD in gene function and signalling pathways, GO and KEGG enrichment analyses were carried out. GO enrichment analysis indicated that the effectiveness of DHJSD was mainly reflected in the regulation of receptor and ligand activities, plasma membrane, and biological oxidation processes. In KEGG pathway enrichment analysis, TNF, IL-17 and AGE-RAGE signalling pathways are associated with inflammatory response, immune regulation and extracellular matrix degradation. TNF and IL-17 can activate NF-kappa B pathway to cause inflammation response and immune process via binding to TNFR2 [25, 34] or ACT1 [35]. Also, the activation of NF- kappa B in the spinal cord can cause nociceptive hypersensitivity and pain-related neuropeptide expression to aggravate pain [36, 37]. Moreover, both TNF and IL-17 can induce inflammatory cytokines into degenerated NP tissues and degrade extracellular matrix, which is the main reason of low back pain and sciatica symptoms [38-40].  AGE-RAGE pathway has similar function to TNF and IL-17 pathways [41]. Subsequently, we speculate the active compounds of DHJSD may act on TNF, IL-17, and AGE-RAGE signalling pathways via core targets to exert immune regulation, anti-inflammatory and analgesic effects.

In molecular docking, the main active compounds could bind to the core targets automatically. We found the binding energies of eight core ligands were lower than diclofenac and celecoxib. The lower the energies, the higher the affinities and the greater the possibility of interactions between ligands and receptors [41], this may be one of the explanations why DHJSD has better effectiveness. Moreover, the affinities between PTGS2 and quercetin, wogonin, kaempferol, beta-carotene, baicalein, 7-Methoxy-2-methyl isoflavone and beta-sitosterol, as well as between MMP9 and quercetin and baicalein were strong, suggesting PTGS2 and MMP9 may be the major pharmacotherapeutic targets in treating LDH. Some experiments have confirmed the production of MMPs and PTGS2 in TNF signal pathway can induce IVDD, sciatica, and hyperalgesia [34, 43]. Besides, the expression of MMP9 and PTGS2 can be potentiated via the activation of NF- kappa B, and further induce autoimmune response in IL17 signal pathway [44, 45] or inflammatory response in AGE-RAGE signal pathway [46, 47]. Briefly, the results of molecular docking further confirmed the effectiveness of DHJSD in treating LDH.

Limitations

 

There were some limitations in this study. Firstly, the quality of the included trials was low, as most trials lacked details of random sequence generation, allocation concealment, blinding methods, long-term follow-up, and dropouts. Secondly, the heterogeneity was high. After excluding one or two trials, the heterogeneity was decreased in some subgroups. However, in terms of VAS and adverse event rate, the heterogeneity in the subgroup of DHJSD plus Western medicine couldn’t be decreased by sensitive analysis. The high heterogeneity may due to patients’ characteristics, different doses and frequencies of DHJSD and Western medicine used in groups. Thirdly, the current conclusions were concluded based on multiple databases, and further experimental researches should be performed to confirm the conclusions. Therefore, more studies need to be carried out in the future.

Conclusions

In the treatment of LDH, DHJSD had better effectiveness in reducing pain, decreasing adverse event rate, and improving limb function than Western medicine, and DHJSD may mainly act on TNF, IL17, and AGE-RAGE signalling pathways to exert immune regulation, anti-inflammatory and analgesic effects.

Conflict of Interest (COI)

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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