Dataset Information

Molecular network-based analysis of guizhi-shaoyao-zhimu decoction, a TCM herbal formula, for treatment of diabetic peripheral neuropathy.

ABSTRACT:

Aim

Guizhi-shaoyao-zhimu decoction (GSZ), a traditional Chinese medicine (TCM) herbal formula, has been shown effective in the treatment of diabetic peripheral neuropathy (DPN). In this study, network analysis was performed to decipher the molecular mechanisms of GSZ in the treatment of DPN.

Methods

The chemical components of the 3 herbs forming GSZ, ie, Ramulus Cinnamomi (Guizhi), Paeonia lactiflora (Shaoyao) and Rhizoma Anemarrhenae (Zhimu), were searched in Chinese medicine dictionaries, and their target proteins were identified in PubChem. DPN genes were searched in PubMed gene databases. Ingenuity Pathway Analysis (IPA) was used to build the GSZ pharmacological network and DPN molecular network. The canonical pathways between the two networks were compared to decipher the molecular mechanisms of GSZ in the treatment of DPN.

Results

Sixty-one protein targets for Guizhi, 31 targets for Shaoyao, 47 targets for Zhimu, as well as 23 genes related to DPN were identified and uploaded to IPA. The primary functions of the DPN molecular network were inflammatory response, metabolic disease, cellular assembly and organization. As far as the pharmacological network functions were concerned, Guizhi target proteins were involved in neurological disease, inflammatory disease, cellular growth and proliferation, cell signaling, molecular transport, and nucleic acid metabolism, Shaoyao target proteins were related to neurological disease, inflammatory disease, and Zhimu target proteins focused on cell death and survival, cellular movement, immune cell trafficking, DNA replication, recombination and repair, and cell cycle. In the three-herb combination GSZ, several new network functions were revealed, including the inflammatory response, gene expression, connective tissue development and function, endocrine system disorders, and metabolic disease. The canonical pathway comparison showed that Shaoyao focused on IL-12 signaling and production in macrophages, and Zhimu focused on TNFR2 signaling, death receptor signaling, ILK signaling, IL-17A in gastric cells, IL-6 signaling, IL-8 signaling, the role of JAK1, JAK2, and TYK2 in interferon signaling, IL-9 signaling, HMGB1 signaling, NO production and ROS production in macrophages, whereas GSZ focused aryl hydrocarbon receptor signaling and apoptosis signaling in addition to those pathways induced by Guizhi, Shaoyao and Zhimu.

Conclusion

Although each single herb can affect some DPN-related functions and pathways, GSZ exerts more effects on DPN-related functions and pathways. The effects of GSZ on aryl hydrocarbon receptor signaling and apoptosis signaling pathways may be the key components of its total molecular mechanisms.

SUBMITTER: Zhao N

PROVIDER: S-EPMC4594186 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Molecular network-based analysis of guizhi-shaoyao-zhimu decoction, a TCM herbal formula, for treatment of diabetic peripheral neuropathy.

Zhao Ning N Li Jian J Li Li L Niu Xu-yan XY Jiang Miao M He Xiao-juan XJ Bian Zhao-xiang ZX Zhang Ge G Lu Ai-ping AP

Acta pharmacologica Sinica 20150427 6

<h4>Aim</h4>Guizhi-shaoyao-zhimu decoction (GSZ), a traditional Chinese medicine (TCM) herbal formula, has been shown effective in the treatment of diabetic peripheral neuropathy (DPN). In this study, network analysis was performed to decipher the molecular mechanisms of GSZ in the treatment of DPN.<h4>Methods</h4>The chemical components of the 3 herbs forming GSZ, ie, Ramulus Cinnamomi (Guizhi), Paeonia lactiflora (Shaoyao) and Rhizoma Anemarrhenae (Zhimu), were searched in Chinese medicine dic ...[more]

PMID: 25948477

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Project description:Background and objectivesGuizhi-Shaoyao-Zhimu decoction (GSZD) is often applied to control rheumatoid arthritis (RA), gout, osteoarthritis, etc. In this study, bioinformatic analysis and experimental verification were used to uncover the integral mechanism profile of GSZD against RA.Materials and methodsThe chemical compositions of GSZD were identified by UPLC-QTOF-MS/MS. MH7A cell model was established to screen active compounds in GSZD, and potential targets of these compounds were predicted through online database retrieval. The differential expression genes (DEGs) in synovial tissue of RA patients and normal controls were retrieved from the GEO database. DEGs and the predicated compounds targets were overlapped, and the overlapped genes were subsequently enriched by GO and KEGG analysis. The pathways with significant enrichments were further experimentally verified.ResultsA total of 19 constituents were identified from GSZD, and 11 compounds showed obviously antiproliferative effects on MH7A cells with IC50 < 100 μg/mL. Bioinformatic analysis indicated that IL-1β, IL-6, MAPK8, JAK2, CXCL8, and CASP3 were the main targets of GSZD, and the integral pharmacological mechanisms profile of GSZD might be related to anti-inflammation and proapoptosis. GSZD can promote the loss of mitochondrial membrane potential (MOMP) and induce apoptosis in MH7A cells. Furthermore, in vitro experiments showed GSZD can not only downregulate mRNA expressions of IL-1β (p<0.05), IL-6 (p<0.05), MMPs (p<0.05) and CCL5 (p<0.05) but also inhibit the nuclear transcription of NF-κB. GSZD also reduced the expressions of Bcl-2 (p<0.05), JAK2 (p<0.05), STAT-3 (p<0.05), whereas increase Bax (p<0.05), Caspase-3 (p<0.05) and caspase-9 (p<0.05).ConclusionCollectively, inducing synovial fibroblast apoptosis and inhibiting inflammatory response are two important ways for GSZD to RA, and our study proved bioinformatic analysis combined with experimental verification is a feasible method to explore the drug targets and mechanism of actions of TCMs.

Project description:BackgroundGuiZhi-ShaoYao-ZhiMu decoction (GSZD), a traditional Chinese herbal medication, has been frequently used as an add-on medication to methotrexate (MTX) for rheumatoid arthritis (RA) treatment in China. This meta-analysis evaluated the efficacy and safety of adding GSZD to MTX for RA treatment.MethodsWe performed a systematic search of PubMed, Web of Science, EMBASE, and the Cochrane Library (all databases) for English-language studies and WanFang, VIP, and CNKI for Chinese-language studies up to 28 July 2020. Data from selected studies, mainly the response rates and rate of adverse events (AEs), were extracted independently by two authors, and a random-effects model (Mantel-Haenszel method) was used for the meta-analysis.ResultsA total of 14 randomized controlled trials and 1224 patients were included (623 patients in the GSZD + MTX group and 601 patients in the MTX group). For efficacy, the meta-analysis found that combining GSZD with MTX increased the effective rate [relative risk (RR) = 1.24, 95% confidence interval (CI): 1.18-1.30, based on 1069 patients], defined as >30% efficacy, American College of Rheumatology 20, or a decrease of disease activity score 28 >0.6. Adding GSZD reduced the swollen and tender joint counts, the duration of morning stiffness, the levels of C-reactive protein and rheumatoid factor, and erythrocyte sedimentation rate. The adjuvant therapeutic effect of GSZD was independent of the dose of MTX or the combined utilization of other drugs in both groups. For safety, adding GSZD was associated with a lower rate of total AEs (RR = 0.46, 95% CI: 0.26-0.83, based on 615 patients) and gastrointestinal tract AEs (RR = 0.46, 95% CI: 0.24-0.88, based on 537 patients).ConclusionCombining GSZD with MTX may be a more efficacious and safer strategy for treating RA compared with MTX alone. Further large studies are warranted to investigate the long-term efficacy and safety of adding GSZD to MTX for RA treatment.

Project description:BackgroundOxaliplatin-induced peripheral neurotoxicity (OIPN) limits the dose of chemotherapy and seriously affects the quality of life. Huangqi Guizhi Wuwu Decoction (HGWD) is a classical Traditional Chinese Medicine (TCM) formula for the prevention of OIPN. However, its specific pharmacological mechanism of action remains unknown. Our study found that HGWD can effectively alleviate chronic OIPN and regulate intestinal flora. Therefore, we explored the mechanism of action of HGWD in alleviating chronic OIPN from the perspective of intestinal flora.MethodsIn this study, we established an OIPN model in C57BL/6 mice treated with different concentrations of HGWD. Mechanical pain and cold pain were assessed at certain time points, and samples of mice colon, dorsal root ganglion (DRG), serum, and feces were collected. Associated inflammation levels in the colon and DRG were detected using immunohistochemical techniques; the serum lipopolysaccharide (LPS) levels and associated inflammation were assessed using the appropriate kits; and 16S rRNA sequencing was used to examine the dynamic changes in gut microorganisms. Finally, established fecal microbiota transplantation (FMT) and antibiotic (ABX) pretreatment models were used to validate flora's role in HGWD for chronic OIPN by pain scoring and related pathological analysis.ResultsHGWD treatment significantly alleviated pain sensitivity in chronic OIPN mice. Pathological results showed that HGWD treatment improved intestinal ZO-1 expression and reduced serum LPS levels and associated inflammatory factors in the colon, serum, and DRG. The 16S rRNA results showed that HGWD restored the composition of the intestinal flora in a time-dependent manner to alleviate OIPN. FMT and ABX experiments demonstrated that HGWD can alleviate chronic OIPN by regulating intestinal flora homeostasis.ConclusionsHGWD prevents chronic OIPN by dynamically regulating intestinal flora homeostasis, thereby ameliorating intestinal barrier damage and reducing serum LPS and relevant inflammatory factor levels in the colon, serum, and DRG.

Project description:BackgroundPaclitaxel-induced peripheral neuropathy (PIPN) is a challenging clinical problem during chemotherapy. Our previous work found that herbal formula Huangqi Guizhi Wuwu decoction (HGWD) could reduce oxaliplatin-induced neurotoxicity. However, its effect on PIPN remains unknown. In this study, we aim to investigate the therapeutic effect and the underlying mechanisms of HGWD against PIPN with pharmacological experiment and network pharmacology.MethodsMale Wistar rats were used to establish an animal model of PIPN and treated with different doses of HGWD for 3 weeks. Mechanical allodynia, thermal hyperalgesia and body weight were measured to evaluate the therapeutic effect of HGWD on PIPN rats. On the day of the sacrifice, blood, DRGs, sciatic nerve, and hind-paw intra-plantar skins were collected to assess neuroprotective effect of HGWD on PIPN. Next, network pharmacology was performed to decipher the potential active components and molecular mechanisms of HGWD, as were further verified by western blotting analyses in PIPN rats. Finally, the effect of HGWD on the chemotherapeutic activity of paclitaxel was evaluated in vitro and in vivo.ResultsIn rats with PIPN, HGWD reversed mechanical allodynia, thermal hyperalgesia, and ameliorated neuronal damage. Moreover, HGWD significantly increased the level of nerve growth factor, dramatically reduced IL-1β, IL-6, TNF-α levels and oxidative stress. Network pharmacology analysis revealed 30 active ingredients in HGWD and 158 candidate targets. Integrated pathway analysis identified PI3K/Akt and toll-like receptor as two main pathways responsible for the neuroprotective effect of HGWD. Further experimental validation demonstrated that HGWD expectedly inhibited the protein expression of TLR4, MyD88, IKKα, and p-NF-κB, and promoted PI3K, p-Akt, Nrf2, and HO-1 level in dorsal root ganglia. Last but not least, HGWD did not interfere with the antitumor activity of paclitaxel both in in vitro and in vivo models.ConclusionThese combined data showed that HGWD could inhibit paclitaxel-evoked inflammatory and oxidative responses in peripheral nervous system viaTLR4/NF-κB and PI3K/Akt-Nrf2 pathways involvement. The neuroprotective property of HGWD on PIPN provides fundamental support to the potential application of HGWD for counteracting the side effects of paclitaxel during chemotherapy.

Project description:PurposePaclitaxel-induced peripheral neuropathy (PIPN) is increasingly becoming one of the most widespread adverse effects in the treatment of cancer patients, and further precipitate neuroinflammation in the nervous system. Interestingly, Shaoyao Gancao Decoction (SGD), a traditional Chinese analgesic prescription, has emerged as a primary adjuvant to chemotherapy in relieving side effects, especially in the case of PIPN. However, the underlying mechanism of SGD functioning in PIPN remains elusive. Accordingly, the current study set out to explore the potential axis implicated in the functioning of SGD in PIPN.MethodsFirst, network pharmacology was adopted to predict the role of the transient receptor potential vanilloid type 1 (TRPV1) protein in treating PIPN with SGD. Subsequently, the effects of SGD treatment on mechanical allodynia and thermal hyperalgesia were evaluated in rat PIPN models. Based on the bioinformatics information and current literature, paclitaxel activates toll-like receptor 4 (TLR4) induces the sensitization of TRPV1 mechanistically. Thereafter, TLR4-myeloid-differentiation response gene 88 (MyD88) signaling and TRPV1 expression patterns in dorsal root ganglias (DRGs) were measured by means of Western blotting, qPCR and immunofluorescence.ResultsInitial bioinformatics reared a total of 105 bioactive compounds and 1075 target genes from SGD. In addition, 40 target genes intersected with PIPN were considered as potential therapeutic genes. Based on the network analysis, SGD was found to exert its analgesic effect by reducing the expression of TRPV1. Further experimentation validated that SGD exerted an analgesic effect on thermal hyperalgesia in PIPN models, such that this protective effect was associated with the suppression of TRPV1 and TLR4-MyD88 Signaling over-expression.ConclusionCollectively, our findings indicated that SGD ameliorates PIPN by inhibiting the over-expression of TLR4-MyD88 Signaling and TRPV1, and further highlights the use of SGD as a potential alternative treatment for PIPN.

Project description:In this study, we predicted the core active compounds of Huangqi Guizhi Wuwu decoction in treatment of oxaliplatin-induced peripheral neuropathy and the related potential mechanism. Corresponding database was used to complete the interaction (PPI) network of key targets and the enrichment analysis of corresponding genmes. Molecular docking of key targets and key compounds was carried out using relevant software. The 60 chemical components corresponding to the oral absorption of Huangqi Guizhi Wuwu decoction correspond to 157 unique targets, and the 233 chemical components corresponding to percutaneous absorption in vitro correspond to 155 unique targets. There were 1074 unique targets for chemotherapy-induced peripheral neuropathy. Finally, three common key targets (SLC6A2, SLC6A3, and SLC6A4) and two key compounds (6-Gingerol and nuciferin) were screened according to the above three target datasets. The results showed that The PPI network of common key targets involved 23 associated proteins. In the related GO enrichment results, there were 33 items related to biological processes, 13 items related to cell composition, 21 items related to molecular function, and four KEGG pathway enrichments. L1000 kinase and GPCR perturbation analysis showed that the associated protein had an effect on the expression of multiple groups of kinase genes. HPA revealed that the enrichment of three common key targets was tissue-specific. The docking results showed that the 6 groups were structurally stable. The oral and topical use of Huangqi Guizhi Wuwu decoction can prevent and control peripheral neurotoxicity. The prevention and control effects may be related to its participation in the regulation of neurotransmitter transport, sympathetic activity, and transport. The histological parts of the mechanism are mainly distributed in the adrenal gland, placenta, brain, intestine, and lung, the blood is not specific. According to the prediction results of molecular docking, 6-Gingerol and nuciferin can closely bind to three common key targets.

Project description:BackgroundDiabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus and can lead to serious complications. Therapeutic strategies for pain control are available but there are few approaches that influence neurological deficits such as numbness.AimTo investigate the effectiveness of acupuncture on improving neurological deficits in patients suffering from type 2 DPN.MethodsThe acupuncture in DPN (ACUDPN) study was a two-armed, randomized, controlled, parallel group, open, multicenter clinical trial. Patients were randomized in a 1:1 ratio into two groups: The acupuncture group received 12 acupuncture treatments over 8 wk, and the control group was on a waiting list during the first 16 wk, before it received the same treatment as the other group. Both groups received routine care. Outcome parameters were evaluated after 8, 16 and 24 wk and included neurological scores, such as an 11-point numeric rating scale (NRS) 11 for hypesthesia, neuropathic pain symptom inventory (NPSI), neuropathy deficit score (NDS), neuropathy symptom score (NSS); nerve conduction studies (NCS) were assessed with a handheld point-of-care device.ResultsSixty-two participants were included. The NRS for numbness showed a difference of 2.3 (P < 0.001) in favor of the acupuncture group, the effect persisted until week 16 with a difference of 2.2 (P < 0.001) between groups and 1.8 points at week 24 compared to baseline. The NPSI was improved in the acupuncture group by 12.6 points (P < 0.001) at week 8, the NSS score at week 8 with a difference of 1.3 (P < 0.001); the NDS and the TNSc score improved for the acupuncture group in week 8, with a difference of 2.0 points (P < 0.001) compared to the control group. Effects were persistent in week 16 with a difference of 1.8 points (P < 0.05). The NCS showed no meaningful changes. In both groups only minor side effects were reported.ConclusionStudy results suggest that acupuncture may be beneficial in type 2 diabetic DPN and seems to lead to a reduction in neurological deficits. No serious adverse events were recorded and the adherence to treatment was high. Confirmatory randomized sham-controlled clinical studies with adequate patient numbers are needed to confirm the results.

Dataset Information

Molecular network-based analysis of guizhi-shaoyao-zhimu decoction, a TCM herbal formula, for treatment of diabetic peripheral neuropathy.

Aim

Methods

Results

Conclusion

Publications

Molecular network-based analysis of guizhi-shaoyao-zhimu decoction, a TCM herbal formula, for treatment of diabetic peripheral neuropathy.

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