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Based on Systematic Pharmacology: Molecular Mechanism of Siwei Jianbu Decoction in Preventing Oxaliplatin-Induced Peripheral Neuropathy.

ABSTRACT: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect caused by chemotherapy drugs, and its existence seriously affects the quality of life of patients. We first established an oxaliplatin-induced peripheral neuropathy (OIPN) model and then measured and evaluated mechanical hyperalgesia, thermal nociception, cold allodynia, and intraepidermal nerve fiber (IENF) density to determine Siwei Jianbu Decoction's role in preventing OIPN. Then, we conducted a systematic pharmacological study that revealed important roles for the MAPK signaling pathway and proinflammatory immune pathway and confirmed these roles by western blot, immunofluorescence, and qPCR. The data show that Siwei Jianbu Decoction can effectively prevent oxaliplatin-induced neuroinflammation by inhibiting an increase in NF-?B expression via downregulation of p-ERK1/2 and p-p38. The present study showed that SWJB may be beneficial in preventing oxaliplatin-induced peripheral neuropathy.

SUBMITTER: Zhang P

PROVIDER: S-EPMC7559195 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Based on Systematic Pharmacology: Molecular Mechanism of Siwei Jianbu Decoction in Preventing Oxaliplatin-Induced Peripheral Neuropathy.

Zhang Peng P Lu Yuting Y Yang Chao C Zhang Qiuyan Q Qian Yangyan Y Suo Jinshuai J Cheng Peng P Zhu Jing J

Neural plasticity 20201006

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect caused by chemotherapy drugs, and its existence seriously affects the quality of life of patients. We first established an oxaliplatin-induced peripheral neuropathy (OIPN) model and then measured and evaluated mechanical hyperalgesia, thermal nociception, cold allodynia, and intraepidermal nerve fiber (IENF) density to determine Siwei Jianbu Decoction's role in preventing OIPN. Then, we conducted a systematic pharma ...[more]

PMID: 33082779

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Project description:BackgroundTaohong Siwu decoction (THSWD) is a classic traditional Chinese medicine (TCM) formula known for its effects in promoting blood circulation, removing blood stasis, and rejuvenating energy. There have been clinical reports of THSWD treating chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel. We conducted a network pharmacology and molecular docking analysis to further clarify the molecular mechanisms by which THSWD exerts its protective effects against CIPN.MethodsChemical components of THSWD and their corresponding targets were obtained through the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), and related targets of CIPN were searched in disease databases including Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), GeneCards, and DrugBank. Common targets between THSWD and CIPN were identified using Venn diagrams. A protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. AutoDock and PyMOL were used for the molecular docking validation of the key components of THSWD with core targets.ResultsAt total of 69 chemical components of THSWD were identified, corresponding to 856 targets; 2,297 targets were associated with CIPN, with an intersection of 105 common targets. PPI analysis identified eight core targets: MYC, TNF, MAPK14, AKT1, ESR1, RELA, TP53, and HSP90AA1; KEGG enrichment analysis implicated signaling pathways such as PI3K-Akt, NF-κB, and HIF-1, etc. Molecular docking results indicated that the selected active components and their corresponding target proteins have good binding activity.ConclusionsThrough network pharmacology, this study found that THSWD has significant advantages in treating CIPN. By analyzing potential core targets, biological functions, and involved signaling pathways, we clarified the potential molecular biological mechanisms involved in THSWD's treatment effect. This study provides a theoretical basis for the clinical application of THSWD in treating CIPN.

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:BackgroundDanggui Sini decoction (DSD), a traditional Chinese medicine formula, has the function of nourishing blood, warming meridians, and unblocking collaterals. Our clinical and animal studies had shown that DSD can effectively protect against oxaliplatin (OXA)-induced peripheral neuropathy (OIPN), but the detailed mechanisms remain uncertain. Multiple studies have confirmed that gut microbiota plays a crucial role in the development of OIPN. In this study, the potential mechanism of protective effect of DSD against OIPN by regulating gut microbiota was investigated.MethodsThe neuroprotective effects of DSD against OIPN were examined on a rat model of OIPN by determining mechanical allodynia, biological features of dorsal root ganglia (DRG) as well as proinflammatory indicators. Gut microbiota dysbiosis was characterized using 16S rDNA gene sequencing and metabolism disorders were evaluated using untargeted and targeted metabolomics. Moreover the gut microbiota mediated mechanisms were validated by antibiotic intervention and fecal microbiota transplantation.ResultsDSD treatment significantly alleviated OIPN symptoms by relieving mechanical allodynia, preserving DRG integrity and reducing proinflammatory indicators lipopolysaccharide (LPS), IL-6 and TNF-α. Besides, DSD restored OXA induced intestinal barrier disruption, gut microbiota dysbiosis as well as systemic metabolic disorders. Correlation analysis revealed that DSD increased bacterial genera such as Faecalibaculum, Allobaculum, Dubosiella and Rhodospirillales_unclassified were closely associated with neuroinflammation related metabolites, including positively with short-chain fatty acids (SCFAs) and sphingomyelin (d18:1/16:0), and negatively with pi-methylimidazoleacetic acid, L-glutamine and homovanillic acid. Meanwhile, antibiotic intervention apparently relieved OIPN symptoms. Furthermore, fecal microbiota transplantation further confirmed the mediated effects of gut microbiota.ConclusionDSD alleviates OIPN by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment, which may influence its successful completion. The Huang-Qi-Gui-Zhi-Wu-Wu decoction (HQGZWWD) has been widely used to treat CIPN in China although the pharmacological mechanisms involved have not been clarified. Using the network pharmacology approach, this study investigated the potential pathogenesis of CIPN and the therapeutic mechanisms exerted by the HQGZWWD herbal formula in CIPN. The targets of HQGZWWD were identified using traditional Chinese medicine (TCM) databases (TCMSP and ETCM) and prediction platforms (PharmMapper and TargetNet), and the genes of CIPN were collected by DisGeNET, GeneCards, and literature search. The common target interaction network between herbal formula and diseases was constructed by using Cytoscape. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to reveal the mechanism and efficacy of HQGZWWD in the treatment of CIPN. A total of 153 CIPN-related genes were screened, and a protein-protein interaction (PPI) network with 96 nodes and 424 edges was constructed. Sixty-three active components were retrieved from HQGZWWD, with a herb-composite compound-target network including 748 nodes and 5448 edges. Forty-one targets belong to the above two networks. The analysis of network results and literature review shows that the main pathological processes of CIPN may be the inflammatory response and nerve injury, and HQGZWWD plays a therapeutic role in CIPN by regulating inflammatory response and repairing nerve injury, thus verifying the reliable efficacy of this herbal formula. In addition, we found two new potential therapeutic targets (CDK7 and GSTM2) warranting further investigation. This study fully illustrates that TCM has the characteristics of a multicompound, multitarget, and multipathway treatment, which is of great significance to study the curative effect of herbal formulations.

Dataset Information

Based on Systematic Pharmacology: Molecular Mechanism of Siwei Jianbu Decoction in Preventing Oxaliplatin-Induced Peripheral Neuropathy.

Publications

Based on Systematic Pharmacology: Molecular Mechanism of Siwei Jianbu Decoction in Preventing Oxaliplatin-Induced Peripheral Neuropathy.

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