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Hydroxysafflor Yellow A Inhibits LPS-Induced NLRP3 Inflammasome Activation via Binding to Xanthine Oxidase in Mouse RAW264.7 Macrophages.

Xu X, Guo Y, Zhao J, Wang N, Ding J, Liu Q - Mediators Inflamm. (2016)

Bottom Line: In this study, we predicted the potential interaction between HSYA and xanthine oxidase (XO) via PharmMapper inverse docking and confirmed the binding inhibition via inhibitory test (IC50 = 40.04 μM).Computation docking illustrated that, in this HSYA-XO complex, HSYA was surrounded by Leu 648, Leu 712, His 875, Leu 873, Ser 876, Glu 879, Phe 649, and Asn 650 with a binding energy of -5.77 kcal/M and formed hydrogen bonds with the hydroxyl groups of HSYA at Glu 879, Asn 650, and His 875.Moreover, we proved that HSYA markedly inhibited LPS-induced cleaved caspase-1 activation via suppressing the sensitization of NLRP3 inflammasome and prevented the mature IL-1β formation from pro-IL-1β form.

View Article: PubMed Central - PubMed

Affiliation: Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China; Beijing Institute of Traditional Chinese Medicine, Beijing 100010, China; Beijing Key Laboratory of Basic Research with Traditional Chinese Medicine on Infectious Diseases, Beijing 100010, China.

ABSTRACT
Hydroxysafflor yellow A (HSYA) is an effective therapeutic agent for inflammatory diseases and autoimmune disorders; however, its regulatory effect on NLRP3 inflammasome activation in macrophages has not been investigated. In this study, we predicted the potential interaction between HSYA and xanthine oxidase (XO) via PharmMapper inverse docking and confirmed the binding inhibition via inhibitory test (IC50 = 40.04 μM). Computation docking illustrated that, in this HSYA-XO complex, HSYA was surrounded by Leu 648, Leu 712, His 875, Leu 873, Ser 876, Glu 879, Phe 649, and Asn 650 with a binding energy of -5.77 kcal/M and formed hydrogen bonds with the hydroxyl groups of HSYA at Glu 879, Asn 650, and His 875. We then found that HSYA significantly decreased the activity of XO in RAW264.7 macrophages and suppressed LPS-induced ROS generation. Moreover, we proved that HSYA markedly inhibited LPS-induced cleaved caspase-1 activation via suppressing the sensitization of NLRP3 inflammasome and prevented the mature IL-1β formation from pro-IL-1β form. These findings suggest that XO may be a potential target of HSYA via direct binding inhibition and the combination of HSYA-XO suppresses LPS-induced ROS generation, contributing to the depression of NLRP3 inflammasome and inhibition of IL-1β secretion in macrophages.

No MeSH data available.


Related in: MedlinePlus

XO is a potential target of HSYA via PharmMapper inverse docking. 300 potential candidates out of 7302 were listed and sorted according to the fit score. The molecule and pharmacophore model of XO (PDB ID: 1F04) was exhibited right below the selected target. Note: pharmacophore features are schemed by color: hydrophobic, cyan; positive, blue; negative, red; donor, green; acceptor, magenta.
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fig2: XO is a potential target of HSYA via PharmMapper inverse docking. 300 potential candidates out of 7302 were listed and sorted according to the fit score. The molecule and pharmacophore model of XO (PDB ID: 1F04) was exhibited right below the selected target. Note: pharmacophore features are schemed by color: hydrophobic, cyan; positive, blue; negative, red; donor, green; acceptor, magenta.

Mentions: Via pharmacophore mapping approach, 300 potential candidates out of 7302 were listed and sorted according to the fit score (Submission ID 151015052728). Based on the disease information and potential roles in inflammation and redox related signaling pathways, endothelial nitric oxide synthase (PDB ID: 1P6M), NADPH cytochrome P450 reductase (PDB ID: 1J9Z), and XO (PDB ID: 1F04) were selected as potential targets of HSYA. Based on the pharmacophore model, endothelial nitric oxide synthase had one hydrophobic, four donors, and three acceptors; NADPH cytochrome P450 reductase had two hydrophobics, one positive, two negatives, one donor, eight acceptors, and one aromatic; XO had one negative, two donors, and five acceptors. However, since inhibition tests showed that HSYA possessed no depression effects on activities of endothelial nitric oxide synthase and NADPH cytochrome P450 reductase (data not shown), only the pharmacophore model of XO was exhibited in Figure 2.


Hydroxysafflor Yellow A Inhibits LPS-Induced NLRP3 Inflammasome Activation via Binding to Xanthine Oxidase in Mouse RAW264.7 Macrophages.

Xu X, Guo Y, Zhao J, Wang N, Ding J, Liu Q - Mediators Inflamm. (2016)

XO is a potential target of HSYA via PharmMapper inverse docking. 300 potential candidates out of 7302 were listed and sorted according to the fit score. The molecule and pharmacophore model of XO (PDB ID: 1F04) was exhibited right below the selected target. Note: pharmacophore features are schemed by color: hydrophobic, cyan; positive, blue; negative, red; donor, green; acceptor, magenta.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4940575&req=5

fig2: XO is a potential target of HSYA via PharmMapper inverse docking. 300 potential candidates out of 7302 were listed and sorted according to the fit score. The molecule and pharmacophore model of XO (PDB ID: 1F04) was exhibited right below the selected target. Note: pharmacophore features are schemed by color: hydrophobic, cyan; positive, blue; negative, red; donor, green; acceptor, magenta.
Mentions: Via pharmacophore mapping approach, 300 potential candidates out of 7302 were listed and sorted according to the fit score (Submission ID 151015052728). Based on the disease information and potential roles in inflammation and redox related signaling pathways, endothelial nitric oxide synthase (PDB ID: 1P6M), NADPH cytochrome P450 reductase (PDB ID: 1J9Z), and XO (PDB ID: 1F04) were selected as potential targets of HSYA. Based on the pharmacophore model, endothelial nitric oxide synthase had one hydrophobic, four donors, and three acceptors; NADPH cytochrome P450 reductase had two hydrophobics, one positive, two negatives, one donor, eight acceptors, and one aromatic; XO had one negative, two donors, and five acceptors. However, since inhibition tests showed that HSYA possessed no depression effects on activities of endothelial nitric oxide synthase and NADPH cytochrome P450 reductase (data not shown), only the pharmacophore model of XO was exhibited in Figure 2.

Bottom Line: In this study, we predicted the potential interaction between HSYA and xanthine oxidase (XO) via PharmMapper inverse docking and confirmed the binding inhibition via inhibitory test (IC50 = 40.04 μM).Computation docking illustrated that, in this HSYA-XO complex, HSYA was surrounded by Leu 648, Leu 712, His 875, Leu 873, Ser 876, Glu 879, Phe 649, and Asn 650 with a binding energy of -5.77 kcal/M and formed hydrogen bonds with the hydroxyl groups of HSYA at Glu 879, Asn 650, and His 875.Moreover, we proved that HSYA markedly inhibited LPS-induced cleaved caspase-1 activation via suppressing the sensitization of NLRP3 inflammasome and prevented the mature IL-1β formation from pro-IL-1β form.

View Article: PubMed Central - PubMed

Affiliation: Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China; Beijing Institute of Traditional Chinese Medicine, Beijing 100010, China; Beijing Key Laboratory of Basic Research with Traditional Chinese Medicine on Infectious Diseases, Beijing 100010, China.

ABSTRACT
Hydroxysafflor yellow A (HSYA) is an effective therapeutic agent for inflammatory diseases and autoimmune disorders; however, its regulatory effect on NLRP3 inflammasome activation in macrophages has not been investigated. In this study, we predicted the potential interaction between HSYA and xanthine oxidase (XO) via PharmMapper inverse docking and confirmed the binding inhibition via inhibitory test (IC50 = 40.04 μM). Computation docking illustrated that, in this HSYA-XO complex, HSYA was surrounded by Leu 648, Leu 712, His 875, Leu 873, Ser 876, Glu 879, Phe 649, and Asn 650 with a binding energy of -5.77 kcal/M and formed hydrogen bonds with the hydroxyl groups of HSYA at Glu 879, Asn 650, and His 875. We then found that HSYA significantly decreased the activity of XO in RAW264.7 macrophages and suppressed LPS-induced ROS generation. Moreover, we proved that HSYA markedly inhibited LPS-induced cleaved caspase-1 activation via suppressing the sensitization of NLRP3 inflammasome and prevented the mature IL-1β formation from pro-IL-1β form. These findings suggest that XO may be a potential target of HSYA via direct binding inhibition and the combination of HSYA-XO suppresses LPS-induced ROS generation, contributing to the depression of NLRP3 inflammasome and inhibition of IL-1β secretion in macrophages.

No MeSH data available.


Related in: MedlinePlus