Targets of hydroxychloroquine in the treatment of rheumatoid arthritis. A network pharmacology study

Xie, Bo; Lu, Haojie; Xu, Jinhui; Luo, Haixin; Hu, Yebei; Chen, Yi; Geng, Qingwei; Song, Xiuzu

doi:10.1016/j.jbspin.2020.105099

Cited by 11 publications

(8 citation statements)

References 30 publications

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“…The network pharmacology studies showed that multi-targets mechanism associated with HCQ treatment in SLE and RA. The related 3,316 proteins’ network data showed that ErbB, HIF-1, NF-κB, FoxO, chemokines, MAPK, JAK-STAT, PI3K-AKT pathways participate in the multi-targets mechanism of HCQ in RA ( Lyu et al, 2020 ; Xie et al, 2021 ). The efficacy of HCQ against SLE is mainly associated with the targets of cyclin dependent kinase 2 (CDK2), estrogen receptor alpha (ESR1) and CDK1, which regulate PI3K/AKT/GSK3β as well as IFN signaling pathway ( Xie et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes

et al. 2022

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Hydroxychloroquine (HCQ) is derivative of the heterocyclic aromatic compound quinoline, which has been used for the treatment of autoimmune diseases. The central purpose of this study was to investigate therapeutic effects and inflammatory immunological molecular mechanism of HCQ in experimental autoimmune hepatitis (AIH). Treatment with HCQ ameliorated hepatic pathologic damage, inflammatory infiltration, while promoted regulatory T cell (Treg) and down-regulated CD8+T cell differentiation in AIH mice induced by S-100 antigen. In vitro, HCQ also suppressed pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-12) secretion, promoted anti-inflammatory cytokine (TGF-β1) secretion. HCQ mainly impaired T cell lipid metabolism but not glycolysis to promote Treg differentiation and function. Mechanistically, HCQ down-regulated GRK2 membrane translocation in T cells, inhibited GRK2-PI3K interaction to reduce the PI3K recruiting to the membrane, followed by suppressing the phosphorylation of PI3K-AKT-mTOR signal. Pretreating T cells with paroxetine, a GRK2 inhibitor, disturbed HCQ effect to T cells. HCQ also reversed the activation of the PI3K-AKT axis by 740 Y-P (PI3K agonist). Meanwhile, HCQ inhibited the PI3K-AKT-mTOR, JAK2-STAT3-SOCS3 and increased the AMPK signals in the liver and T cells of AIH mice. In conclusion, HCQ exhibited specific and potent therapeutic effects on AIH and attendant liver injury, which was attributed to HCQ acted on GRK2 translocation, inhibited metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 signal in T lymphocytes, thereby modulating lipid metabolism of T cell function to regulate Treg differentiation and function.

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Section: Resultsmentioning

confidence: 99%

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes

et al. 2022

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“…The enrichment analysis was performed for the previously determined optimum target by the R package of “ClusterProfiler” on the biological process (BP), cellular component (CC), molecular function (MF) of gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways [ 39 , 40 ]. All data were visualized with histograms or bubble diagram [ 41 ].…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of Vitamin C Regulating Immune and Inflammation Associated with Neonatal Hypoxic-Ischemic Encephalopathy Based on Network Pharmacology and Molecular Simulation Technology

Zhao

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. There are still controversies about the curative effect of vitamin C in treating HIE, and its mechanism of action is not entirely clear. This study is designed to explore the potential molecular mechanism of vitamin C in treating neonatal hypoxic ischemic encephalopathy (HIE). Methods. The effect targets of vitamin C and the pathogenic targets of neonatal HIE were obtained via retrieval of public databases to screen out the molecular targets of vitamin C acting on neonatal HIE. Gene Ontology (GO) functional annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the main targets. Vitamin C and the optimum target structural components are subjected to molecular docking and molecular dynamics simulation analysis via computer software so as to verify their binding activity and stability. Result. Based on 16 overlapping targets of vitamin C and HIE, seven main targets were identified in this study. According to GO and KEGG analysis, molecular functions (top 25 items) and signal pathways (21 items) related to inflammatory reaction, immune response, and cell transcriptional control may be potential pathways for vitamin C to treat neonatal HIE. Molecular docking and molecular dynamics simulation were adopted to definitively determine the 4 optimum core target spots. Conclusion. The efficacy of vitamin C on HIE is involved in the immunoregulation and inflammation-related functional processes and signal pathways. These molecular mechanisms, including core targets, will contribute to the clinical practice of neonatal HIE in the future.

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“…A total of 1185 vitiligo-related proteins were screened. 26 , 27 The bisogenet plugin of Cytoscape was used for the PPI network construction. The intersected proteins between vitiligo and HCQ were entered into bisogenet.…”

Section: Methodsmentioning

confidence: 99%

Targets Exploration of Hydroxychloroquine for Pigmentation and Cell Protection Effect in Melanocytes: The Clue for Vitiligo Treatment

Xie¹,

Chen²,

Hu³

et al. 2022

DDDT

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Objective The treatment of vitiligo is often challenging to dermatologists. There is ample evidence to suggest that hydroxychloroquine (HCQ) is effective for vitiligo treatment; nonetheless, the underlying mechanism remains unknown. In the present study, we sought to uncover the molecular targets of HCQ by an integrated network-based pharmacologic and transcriptomic approach. Methods The potential targets of HCQ were retrieved from databases based on the crystal structure. Targets related to vitiligo were screened and intersected with potential targets of HCQ. A protein-protein interaction network of the intersected targets was generated. Interactions between the targets were verified by molecular docking. Moreover, human vitiligo immortalized melanocytes (PIG3V) were evaluated after treatment with HCQ (1μg/mL) for 24h. The total RNA of PIG3V was extracted and determined by RNA-seq transcriptomics for differential gene expression analysis. Network pharmacology was then used to identify the relationships between putative targets of HCQ and differentially expressed genes. Results Molecular docking analysis revealed four putative key targets (ACHE, PNMT, MC 1 R, and VDR) of HCQ played important roles in vitiligo treatment. According to the transcriptomic results, the melanosomal biogenesis-related gene BLOC1S5 was upregulated 138005.020 fold after HCQ treatment. Genes related to protein repair (MSRB3) and anti-ultraviolet (UV) effect (UVSSA) were upregulated 4.253 and 2.603 fold, respectively, after HCQ treatment. Conclusion The expression of the BLOC1S5 gene is significantly upregulated, indicating upregulated melanosomal biogenesis after HCQ treatment. In addition, HCQ yields a protective effect on melanocytes by upregulating genes associated with damaged protein repair (MSRB3) and anti-UV effect (UVSSA). The protective effects of HCQ are mediated by binding to putative targets ACHE, PNMT, MC 1 R, and VDR according to network pharmacology and docking verification.

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Targets of hydroxychloroquine in the treatment of rheumatoid arthritis. A network pharmacology study

Cited by 11 publications

References 30 publications

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes

Mechanisms of Vitamin C Regulating Immune and Inflammation Associated with Neonatal Hypoxic-Ischemic Encephalopathy Based on Network Pharmacology and Molecular Simulation Technology

Targets Exploration of Hydroxychloroquine for Pigmentation and Cell Protection Effect in Melanocytes: The Clue for Vitiligo Treatment

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