Neoprzewaquinone A from Salvia miltiorrhiza Bunge exerts anti-inflammatory activity by disrupting LPS binding to TLR4/MD2
10.16438/j.0513-4870.2023-1448
- VernacularTitle:丹参中甘西鼠尾新酮A通过干扰LPS与TLR4/MD2的结合发挥抗炎作用
- Author:
Hong-ying WANG
1
;
Xian-fang HE
1
;
Rui-xiu LIU
1
;
Qiong YI
2
;
Hang ZHONG
3
;
Lu WANG
2
Author Information
1. College of Pharmacy, Guizhou University, Guiyang 550025, China; Engineering Research Center of Ministry of Education for the Development and Utilization of Southwest Characteristic Medicinal Biological Resources, Guiyang 550025, China
2. Engineering Research Center of Ministry of Education for the Development and Utilization of Southwest Characteristic Medicinal Biological Resources, Guiyang 550025, China
3. College of Pharmacy, Guizhou University, Guiyang 550025, China
- Publication Type:Research Article
- Keywords:
italic>Salvia miltiorrhiza bunge;
neoprzewaquinone A;
lipopolysaccharide;
Toll like receptor 4/myeloid differentiation protein 2;
anti-inflammation
- From:
Acta Pharmaceutica Sinica
2024;59(6):1647-1655
- CountryChina
- Language:Chinese
-
Abstract:
This study investigates whether compounds in Salvia miltiorrhiza Bunge can bind to the Toll like receptor 4/myeloid differentiation protein 2 (TLR4/MD2) protein complex and exhibit anti-inflammatory activity. Virtual screening of reported chemical components of Salvia miltiorrhiza Bunge against TLR4/MD2 was conducted in this study. The selected compound, neoprzewaquinone A (Neo A), was tested for its impact on the binding of lipopolysaccharide (LPS) to receptors on the cell membrane, its affinity for the protein, its influence on the dimerization of TLR4 and MD2 in LPS-induced cells, and its effects on the phosphorylation of nuclear factor-κB (NF-κB) p65 protein and the secretion of inflammatory cytokines in cells. Results indicate that Neo A in Salvia miltiorrhiza Bunge exhibited the highest virtual binding affinity with TLR4/MD2, with a value of -12.8 kcal·mol-1. Neo A significantly inhibited the binding of LPS to receptors on the cell membrane (P < 0.01). Moreover, Neo A demonstrated affinity for rhTLR4/MD2, rhTLR4, and rhMD2, with KD values of 267, 534, and 228 nmol·L-1, respectively. Amino acid residues like TYR131 and PHE121 in TLR4/MD2 might play a role in the alkyl and π-alkyl hydrophobic interactions with Neo A. Neo A also significantly inhibited the dimerization of TLR4 and MD2 in LPS-mediated cells (P < 0.01) and markedly suppressed the phosphorylation of NF-κBp65 protein (P < 0.05). Furthermore, Neo A significantly or markedly inhibited the secretion of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in LPS-induced cells (P < 0.05, P < 0.01). In conclusion, Neo A exerts its anti-inflammatory effects by binding TLR4/MD2 then disrupting the binding of LPS to TLR4/MD2. It may serve as a TLR4/MD2 inhibitor with the potential to treat inflammation-related diseases targeting TLR4/MD2.
