Lovastatin inhibits Toll-like receptor 4 signaling in microglia by targeting its co-receptor myeloid differentiation protein 2 and attenuates neuropathic pain

Peng, Yinghua; Zhang, Xiaozheng; Zhang, Tianshu; Grace, Peter M.; Li, Hongyuan; Wang, Yibo; Li, Hang; Chen, Hongqian; Watkins, Linda R.; Hutchinson, Mark R.; Yin, Hang; Wang, Xiaohui

doi:10.1016/j.bbi.2019.09.013

Cited by 42 publications

(34 citation statements)

References 49 publications

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“…The cell surface MTS510 signal represents the remaining monomeric TLR4; i.e., the un‐activated TLR4/MD2 heterodimer. 200 ng/ml of LPS was used to activate TLR4 signaling based on the previous works (Peng et al., 2019; Wang et al., 2013; Zhang et al., 2019) and the LPS dose‐dependent NF‐κB activation and TLR4 downstream nitric oxide (NO) overproduction curves in BV‐2 microglia (Figure S6). Compared to the untreated control, approximately 17% of monomeric TLR4 was decreased 1 hr following treatment of BV‐2 cells with LPS (Figure 4a), while artemisinin completely blocked LPS‐induced decrease of TLR4 monomer (Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the classic ligand LPS, MD2 directly recognizes xenobiotics in a manner akin to LPS. Therefore, pharmacological targeting for TLR4 is an attractive approach for regulating innate immune TLR4 signaling (Hutchinson et al., 2012; Northcutt et al., 2015; Peng et al., 2019; Wang et al., 2012, 2013, 2019; Zhang et al., 2018, 2019, 2020). Herein, we demonstrate that MD2 is a direct molecular target of artemisinin responsible for the inhibition of innate immune TLR4 signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Lovastatin has been discovered to suppress LPS‐induced microglia activation but does not affect TLR4 signaling in other immunocompetent cells. V254I mutation in TLR4 impaired TLR4 expression and signaling in dendritic cells but not in macrophages (Peng et al., 2019; Tsukamoto et al., 2013). It seems that modulating TLR4 signaling by pharmacological agent or genetic manipulation appears not always to confer similar responsiveness on different immunocompetent cells (Peng et al., 2019; Tsukamoto et al., 2013).…”

Section: Discussionmentioning

confidence: 99%

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Artemisinin inhibits TLR4 signaling by targeting co‐receptor MD2 in microglial BV‐2 cells and prevents lipopolysaccharide‐induced blood–brain barrier leakage in mice

Zhang

Lin

et al. 2021

Journal of Neurochemistry

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Artemisinin and its derivatives have been the frontline drugs for treating malaria. In addition to the antiparasitic effect, accumulating evidence shows that artemisinins can alleviate neuroinflammatory responses in the central nervous system (CNS).However, the precise mechanisms underlying their anti-neuroinflammatory effects are unclear. Herein we attempted to delineate the molecule target of artemisinin in microglia. In vitro protein intrinsic fluorescence titrations and saturation transfer difference (STD)-NMR showed the direct binding of artemisinin to Toll-like receptor TLR4 co-receptor MD2. Cellular thermal shift assay (CETSA) showed that artemisinin binding increased MD2 stability, which implies that artemisinin directly binds to MD2 in the cellular context. Artemisinin bound MD2 showed much less collapse during the molecular dynamic simulations, which supports the increased stability of MD2 upon artemisinin binding. Flow cytometry analysis showed artemisinin inhibited LPS-induced TLR4 dimerization and endocytosis in microglial BV-2 cells. Therefore, artemisinin was found to inhibit the TLR4-JNK signaling axis and block LPS-induced pro-inflammatory factors nitric oxide, IL-1β and TNFα in BV-2 cells. Furthermore, artemisinin restored LPS-induced decrease of junction proteins ZO-1, Occludin and Claudin-5 in primary brain microvessel endothelial cells, and

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Artemisinin inhibits TLR4 signaling by targeting co‐receptor MD2 in microglial BV‐2 cells and prevents lipopolysaccharide‐induced blood–brain barrier leakage in mice

Zhang

Lin

et al. 2021

Journal of Neurochemistry

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“…It had been proven that Toll-like receptors were highly expressed in microglia of mice with neuropathy. When the Toll-like receptor signaling pathway was inhibited, it can effectively inhibit the occurrence of pain [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Investigating the Multitarget Mechanism of Traditional Chinese Medicine Prescription for Cancer‐Related Pain by Using Network Pharmacology and Molecular Docking Approach

Chang

Liu

Wang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Gu-tong formula (GTF) has achieved good curative effects in the treatment of cancer-related pain. However, its potential mechanisms have not been explored. We used network pharmacology and molecular docking to investigate the molecular mechanism and the effective compounds of the prescription. Through the analysis and research in this paper, we obtained 74 effective compounds and 125 drug-disease intersection targets to construct a network, indicating that quercetin, kaempferol, and β-sitosterol were possibly the most important compounds in GTF. The key targets of GTF for cancer-related pain were Jun proto-oncogene (JUN), mitogen-activated protein kinase 1 (MAPK1), and RELA proto-oncogene (RELA). 2204 GO entries and 148 pathways were obtained by GO and KEGG enrichment, respectively, which proved that chemokine, MAPK, and transient receptor potential (TRP) channels can be regulated by GTF. The results of molecular docking showed that stigmasterol had strong binding activity with arginine vasopressin receptor 2 (AVPR2) and C-X3-C motif chemokine ligand 1 (CX3CL1) and cholesterol was more stable with p38 MAPK, prostaglandin-endoperoxide synthase 2 (PTGS2), and transient receptor potential vanilloid-1 (TRPV1). In conclusion, the therapeutic effect of GTF on cancer-related pain is based on the comprehensive pharmacological effect of multicomponent, multitarget, and multichannel pathways. This study provides a theoretical basis for further experimental research in the future.

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“…129 Guo et al 130 confirmed the combination of Azacoccone E and 3-phosphoglycerate dehydrogenase (PHGDH) through microscale thermophoresis and cellular thermal shift assay (CETSA), which provided evidence for the treatment of cancer with this drug. Peng et al 131 used this technique to find that lovastatin targeted binding protein MD-2 relieves neuropathic pain through the TLR4 pathway. Therefore, this technique could measure the interaction forces between biomolecules in the natural state environment, requires low experimental cost and sample size, could achieve high-throughput and high-efficiency determination, and could provide research combined with energy free energy, enthalpy, and entropy, and more parameters, such as information.…”

Section: Confirmation Of “Active Ingredient-core Target”mentioning

confidence: 99%

Techniques and Strategies for Potential Protein Target Discovery and Active Pharmaceutical Molecule Screening in a Pandemic

Wang

et al. 2020

J. Proteome Res.

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Viruses remain a major challenge in the fierce fight against diseases. There have been many pandemics caused by various viruses throughout the world over the years. Recently, the global outbreak of COVID-19 has had a catastrophic impact on human health and the world economy. Antiviral drug treatment has become another essential means to overcome pandemics in addition to vaccine development. How to quickly find effective drugs that can control the development of a pandemic is a hot issue that still needs to be resolved in medical research today. To accelerate the development of drugs, it is necessary to target the key target proteins in the development of the pandemic, screen active molecules, and develop reliable methods for the identification and characterization of target proteins based on the active ingredients of drugs. This article discusses key target proteins and their biological mechanisms in the progression of COVID-19 and other major epidemics. We propose a model based on these foundations, which includes identifying potential core targets, screening potential active molecules of core targets, and verifying active molecules. This article summarizes the related innovative technologies and methods. We hope to provide a reference for the screening of drugs related to pandemics and the development of new drugs.

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Lovastatin inhibits Toll-like receptor 4 signaling in microglia by targeting its co-receptor myeloid differentiation protein 2 and attenuates neuropathic pain

Cited by 42 publications

References 49 publications

Artemisinin inhibits TLR4 signaling by targeting co‐receptor MD2 in microglial BV‐2 cells and prevents lipopolysaccharide‐induced blood–brain barrier leakage in mice

Artemisinin inhibits TLR4 signaling by targeting co‐receptor MD2 in microglial BV‐2 cells and prevents lipopolysaccharide‐induced blood–brain barrier leakage in mice

Investigating the Multitarget Mechanism of Traditional Chinese Medicine Prescription for Cancer‐Related Pain by Using Network Pharmacology and Molecular Docking Approach

Techniques and Strategies for Potential Protein Target Discovery and Active Pharmaceutical Molecule Screening in a Pandemic

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