Limits...
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

Binding pattern of HSYA-XO complex. Autodock and AutoGrid were used to calculate the binding affinity. The grid procedure was handled by AutoGrid, in a grid box of 60∗60∗60 Å with a 1.0 Å to enclose all the active sites and to allow for the flexible rotations of HSYA. Then, the computation was performed 30 times using Autodock 4.0. (a) Overview. (b) Amplified binding pattern. (c) 3D interaction diagram between HSYA and XO. HSYA: green; hydrogen bond: yellow dash line.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4940575&req=5

fig5: Binding pattern of HSYA-XO complex. Autodock and AutoGrid were used to calculate the binding affinity. The grid procedure was handled by AutoGrid, in a grid box of 60∗60∗60 Å with a 1.0 Å to enclose all the active sites and to allow for the flexible rotations of HSYA. Then, the computation was performed 30 times using Autodock 4.0. (a) Overview. (b) Amplified binding pattern. (c) 3D interaction diagram between HSYA and XO. HSYA: green; hydrogen bond: yellow dash line.

Mentions: Since we confirmed that HSYA inhibits the activity of XO, we tried to further understand the interaction between HSYA and XO by computation docking. From the molecular docking data, we concluded HSYA directly implanted into the activity pocket of XO by hydrophobic characteristic and hydrogen bonds, which are essential to this interacting system with a binding energy of −5.77 kcal/M (Table 1). 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 in hydrophobic interactions (Figures 5(a) and 5(b)). Moreover, Glu 879, Asn 650, and His 875 were observed to form hydrogen bonds with the hydroxyl groups of HSYA (Figure 5(c)).


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)

Binding pattern of HSYA-XO complex. Autodock and AutoGrid were used to calculate the binding affinity. The grid procedure was handled by AutoGrid, in a grid box of 60∗60∗60 Å with a 1.0 Å to enclose all the active sites and to allow for the flexible rotations of HSYA. Then, the computation was performed 30 times using Autodock 4.0. (a) Overview. (b) Amplified binding pattern. (c) 3D interaction diagram between HSYA and XO. HSYA: green; hydrogen bond: yellow dash line.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Binding pattern of HSYA-XO complex. Autodock and AutoGrid were used to calculate the binding affinity. The grid procedure was handled by AutoGrid, in a grid box of 60∗60∗60 Å with a 1.0 Å to enclose all the active sites and to allow for the flexible rotations of HSYA. Then, the computation was performed 30 times using Autodock 4.0. (a) Overview. (b) Amplified binding pattern. (c) 3D interaction diagram between HSYA and XO. HSYA: green; hydrogen bond: yellow dash line.
Mentions: Since we confirmed that HSYA inhibits the activity of XO, we tried to further understand the interaction between HSYA and XO by computation docking. From the molecular docking data, we concluded HSYA directly implanted into the activity pocket of XO by hydrophobic characteristic and hydrogen bonds, which are essential to this interacting system with a binding energy of −5.77 kcal/M (Table 1). 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 in hydrophobic interactions (Figures 5(a) and 5(b)). Moreover, Glu 879, Asn 650, and His 875 were observed to form hydrogen bonds with the hydroxyl groups of HSYA (Figure 5(c)).

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