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A Network Pharmacology Approach for the Identification of Common Mechanisms of Drug-Induced Peripheral Neuropathy.

ABSTRACT: Drug-induced peripheral neuropathy is a side effect of a variety of therapeutic agents that can affect therapeutic adherence and lead to regimen modifications, impacting patient quality of life. The molecular mechanisms involved in the development of this condition have yet to be completely described in the literature. We used a computational network pharmacology approach to explore the Connectivity Map, a large collection of transcriptional profiles from drug perturbation experiments to identify common genes affected by peripheral neuropathy-inducing drugs. Consensus profiles for 98 of these drugs were used to construct a drug-gene perturbation network. We identified 27 genes significantly associated with neuropathy-inducing drugs. These genes may have a potential role in the action of neuropathy-inducing drugs. Our results suggest that molecular mechanisms, including alterations in mitochondrial function, microtubule and cytoskeleton function, ion channels, transcriptional regulation including epigenetic mechanisms, signal transduction, and wound healing, may play a critical role in drug-induced peripheral neuropathy.

SUBMITTER: de Anda-Jauregui G

PROVIDER: S-EPMC6482281 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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A Network Pharmacology Approach for the Identification of Common Mechanisms of Drug-Induced Peripheral Neuropathy.

de Anda-Jáuregui Guillermo G McGregor Brett A BA Guo Kai K Hur Junguk J

CPT: pharmacometrics & systems pharmacology 20190220 4

Drug-induced peripheral neuropathy is a side effect of a variety of therapeutic agents that can affect therapeutic adherence and lead to regimen modifications, impacting patient quality of life. The molecular mechanisms involved in the development of this condition have yet to be completely described in the literature. We used a computational network pharmacology approach to explore the Connectivity Map, a large collection of transcriptional profiles from drug perturbation experiments to identif ...[more]

PMID: 30762308

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Project description:Compound XiongShao Capsule (CXSC), a traditional herb mixture, has shown significant clinical efficacy against diabetic peripheral neuropathy (DPN). However, its multicomponent and multitarget features cause difficulty in deciphering its molecular mechanisms. Our study aimed to identify the key active ingredients and potential pharmacological mechanisms of CXSC in treating DPN by network pharmacology and provide scientific evidence of its clinical efficacy. CXSC active ingredients were identified from both the Traditional Chinese Medicine Systems Pharmacology database, with parameters of oral bioavailability ≥ 30% and drug-likeness ≥ 0.18, and the Herbal Ingredients' Targets (HIT) database. The targets of those active ingredients were identified using ChemMapper based on 3D-structure similarity and using HIT database. DPN-related genes were acquired from microarray dataset GSE95849 and five widely used databases (TTD, Drugbank, KEGG, DisGeNET, and OMIM). Next, we obtained candidate targets with therapeutic effects against DPN by mapping active ingredient targets and DPN-related genes and identifying the proteins interacting with those candidate targets using STITCH 5.0. We constructed an "active ingredients-candidate targets-proteins" network using Cytoscape 3.61 and identified key active ingredients and key targets in the network. We identified 172 active ingredients in CXSC, 898 targets of the active ingredients, 110 DPN-related genes, and 38 candidate targets with therapeutic effects against DPN. Three key active ingredients, namely, quercetin, kaempferol, and baicalein, and 25 key targets were identified. Next, we input all key targets into ClueGO plugin for KEGG enrichment and molecular function analyses. The AGE-RAGE signaling pathway in diabetic complications and MAP kinase activity were determined as the main KEGG pathway and molecular function involved, respectively. We determined quercetin, kaempferol, and baicalein as the key active ingredients of CXSC and the AGE-RAGE signaling pathway and MAP kinase activity as the main pharmacological mechanisms of CXSC against DPN, proving the clinical efficacy of CXSC against DPN.

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

A Network Pharmacology Approach for the Identification of Common Mechanisms of Drug-Induced Peripheral Neuropathy.

Publications

A Network Pharmacology Approach for the Identification of Common Mechanisms of Drug-Induced Peripheral Neuropathy.

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