Targeting p38 MAPK signaling pathway and neutrophil extracellular traps: An important anti-inflammatory mechanism of Huangqin Qingre Chubi Capsule in rheumatoid arthritis
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作者:
Li, Yang
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Li, Yang
[1
,2
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Liu, Jian
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Acad Chinese Med, Inst Rheumatol, Hefei 230031, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Liu, Jian
[1
,3
]
Sun, Yue
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机构:
Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Acad Chinese Med, Inst Rheumatol, Hefei 230031, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Sun, Yue
[1
,3
]
Hu, Yuedi
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Hu, Yuedi
[1
,2
]
Cong, Chengzhi
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机构:
Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Cong, Chengzhi
[1
,2
]
Chen, Yiming
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Chen, Yiming
[1
,2
]
Fang, Yanyan
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Acad Chinese Med, Inst Rheumatol, Hefei 230031, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Fang, Yanyan
[1
,3
]
机构:
[1] Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
[2] Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R China
[3] Anhui Acad Chinese Med, Inst Rheumatol, Hefei 230031, Anhui, Peoples R China
Rheumatoid arthritis (RA) is a common chronic autoimmune disease. Neutrophils release and their extracellular traps (NETs) tend to result in synovial inflammation and cartilage damage. Huangqin Qingre Chubi Capsule (HQC) is an important herbal formulation for RA treatment and has been used for many years. This study applied an interdisciplinary and integrated strategy combining clinical data, integrative bioinformatics, molecular modeling, and both in vitro and in vivo experiments to elucidate the efficacy and potential anti-inflammatory mechanisms of HQC for RA. Retrospective clinical data mining demonstrated that patients with RA treated with HQC exhibited recovery of immuno-inflammatory markers and self-perception. By applying network pharmacological analysis, molecular docking, molecular dynamics simulation, and cellular thermal shift assays, we determined that HQC can directly bind to MAPK14 and target p38 MAPK signaling pathway and NETs formation. Treatment of an adjuvant-induced arthritis rat model combining damp-heat patterns using HQC demonstrated it's effectiveness in reducing the severity of inflammatory arthritis in a dose-dependent manner and downregulated phosphorylation of p38 MAPK and NETs release. In vitro co-culture system mimicking inflammatory microenvironment of RA in vivo revealed that crosstalk between neutrophils (PMNs) and fibroblast- like synoviocytes (FLSs) was manifested by activation of p38 MAPK signaling pathway, release of NETs, and amplification of inflammation, which was blocked by HQC. Mechanistic validation using the p38 MAPK agonist diprovocim demonstrated that HQC inhibited NET formation by modulating the p38 MAPK pathway (mainly by inhibiting its phosphorylation) to exert anti-inflammatory effects. In conclusion, our interdisciplinary and integrated study demonstrated that HQC can target the p38 MAPK signaling pathway to inhibit NET formation and inflammatory response, thereby blocking the crosstalk between PMNs and FLSs to ameliorating RA.
机构:
China Med Univ, Dept Anaesthesiol, Affiliated Hosp 4, Shenyang 110032, Peoples R ChinaChina Med Univ, Dept Anaesthesiol, Affiliated Hosp 4, Shenyang 110032, Peoples R China
Bai, Xuetao
Zhang, Hao
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China Med Univ, Dept Clin Lab, Affiliated Hosp 4, Shenyang 110032, Peoples R ChinaChina Med Univ, Dept Anaesthesiol, Affiliated Hosp 4, Shenyang 110032, Peoples R China
Zhang, Hao
Li, Zhiguo
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China Med Univ, Dept Clin Lab, Affiliated Hosp 4, Shenyang 110032, Peoples R ChinaChina Med Univ, Dept Anaesthesiol, Affiliated Hosp 4, Shenyang 110032, Peoples R China
Li, Zhiguo
Chen, Ou
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China Med Univ, Dept Clin Lab, Affiliated Hosp 4, Shenyang 110032, Peoples R ChinaChina Med Univ, Dept Anaesthesiol, Affiliated Hosp 4, Shenyang 110032, Peoples R China
Chen, Ou
He, Hengpeng
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China Med Univ, Dept Clin Lab, Affiliated Hosp 4, Shenyang 110032, Peoples R ChinaChina Med Univ, Dept Anaesthesiol, Affiliated Hosp 4, Shenyang 110032, Peoples R China
He, Hengpeng
Jia, Xiukun
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China Med Univ, Dept Clin Lab, Affiliated Hosp 4, Shenyang 110032, Peoples R ChinaChina Med Univ, Dept Anaesthesiol, Affiliated Hosp 4, Shenyang 110032, Peoples R China
Jia, Xiukun
Zou, Lijuan
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China Med Univ, Dept Clin Lab, Affiliated Hosp 4, Shenyang 110032, Peoples R China
China Med Univ, Dept Clin Lab, Affiliated Hosp 4, 4 Chongshan East Rd, Shenyang 110032, Liaoning Provin, Peoples R ChinaChina Med Univ, Dept Anaesthesiol, Affiliated Hosp 4, Shenyang 110032, Peoples R China
机构:
Peking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R ChinaPeking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R China
Yu, Qian
Zeng, KeWu
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Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R ChinaPeking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R China
Zeng, KeWu
Ma, XiaoLi
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Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R ChinaPeking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R China
Ma, XiaoLi
Song, FangJiao
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Peking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R ChinaPeking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R China
Song, FangJiao
Jiang, Yong
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Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R ChinaPeking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R China
Jiang, Yong
Tu, PengFei
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Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R ChinaPeking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R China
Tu, PengFei
Wang, XueMei
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Peking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R ChinaPeking Univ, Hosp 1, Res Studio Integrat Tradit & Western Med, Beijing 100034, Peoples R China
机构:
Tianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R ChinaTianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R China
Liu, Yixin
Wei, Wei
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Tianjin Med Univ, Gen Hosp, Dept Rheumatol, Tianjin 300052, Peoples R ChinaTianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R China
Wei, Wei
Hong, Chengcheng
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Childrens Hosp Tianjin, Dept Lab Med, Tianjin 300203, Peoples R ChinaTianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R China
Hong, Chengcheng
Wang, Yang
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Tianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R ChinaTianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R China
Wang, Yang
Sun, Xuguo
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Tianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R ChinaTianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R China
Sun, Xuguo
Ma, Jun
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Tianjin Med Univ, Dept Hlth Stat, Coll Publ Hlth, Tianjin 300070, Peoples R ChinaTianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R China
Ma, Jun
Zheng, Fang
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Tianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R ChinaTianjin Med Univ, Dept Clin Immunol, Sch Med Lab, Tianjin 300203, Peoples R China
机构:
Shanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
Shanxi Univ Tradit Chinese Med, Shanxi Key Lab Innovat Drug Treatment Serious Dis, Taiyuan, Peoples R ChinaShanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
Tang, Li
Luo, Jie-ran
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Shanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R ChinaShanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
Luo, Jie-ran
Wang, Xiao-yan
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Shanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R ChinaShanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
Wang, Xiao-yan
Zhao, Bei
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Shanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R ChinaShanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
Zhao, Bei
Ge, Rui
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Shanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R ChinaShanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
Ge, Rui
Liang, Tai-gang
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Shanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R ChinaShanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
Liang, Tai-gang
Ban, Shu-rong
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Shanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R ChinaShanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
Ban, Shu-rong
Li, Qing-shan
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Shanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
Shanxi Univ Tradit Chinese Med, Shanxi Key Lab Innovat Drug Treatment Serious Dis, Taiyuan, Peoples R ChinaShanxi Med Univ, Sch Pharmaceut Sci, Taiyuan 030001, Peoples R China
机构:
Univ Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, FranceUniv Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, France
Ribon, Matthieu
Seninet, Sarra
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Univ Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, FranceUniv Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, France
Seninet, Sarra
Matyja, Katarzyna
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Univ Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, FranceUniv Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, France
Matyja, Katarzyna
Sebbag, Mireille
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Univ Toulouse, UMR 5165, CNRS 1056, INSERM, Toulouse, FranceUniv Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, France
Sebbag, Mireille
Clavel, Cyril
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Univ Toulouse, UMR 5165, CNRS 1056, INSERM, Toulouse, FranceUniv Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, France
Clavel, Cyril
Mussard, Julie
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Univ Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, FranceUniv Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, France
Mussard, Julie
Serre, Guy
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Univ Toulouse, UMR 5165, CNRS 1056, INSERM, Toulouse, FranceUniv Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, France
Serre, Guy
Boissier, Marie-Christophe
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Avicenne Hosp, AP HP, Rheumatol Dept, Bobigny, FranceUniv Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, France
Boissier, Marie-Christophe
Decker, Patrice
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Univ Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, FranceUniv Paris 13, INSERM, UMR 1125, Li2P,Sorbonne Paris Cite, Bobigny, France
机构:
Sangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South Korea
AmcoBio Inc, Seoul 08758, South KoreaSangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South Korea
Cheon, Se-Yun
Kang, Hyun-Ae
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Sangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South KoreaSangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South Korea
Kang, Hyun-Ae
Jin, Bo-Ram
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Sangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South KoreaSangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South Korea
Jin, Bo-Ram
Kim, Hyo-Jung
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机构:
Sangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South KoreaSangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South Korea
Kim, Hyo-Jung
Park, Yea-Jin
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h-index: 0
机构:
Sangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South KoreaSangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South Korea
Park, Yea-Jin
An, Ren-Bo
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机构:
Yanbian Univ, Coll Pharm, Yanji 133002, Peoples R ChinaSangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South Korea
An, Ren-Bo
Kim, Soo-Yong
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机构:
Korea Res Inst Biosci & Biotechnol, Int Biol Mat Res Ctr, 125 Gwahak Ro, Daejeon 34141, South KoreaSangji Univ, Dept Pharmacol, Coll Korean Med, Wonju 26339, South Korea