CRX-526(CRX-526) - 药物靶点：TLR4_在研适应症：围手术期缺血，再灌注损伤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

CRX-526 (X-In8)、CRX-526

靶点

TLR4

作用机制

TLR4拮抗剂(Toll样受体4拮抗剂)

治疗领域

心血管疾病其他疾病

在研适应症

围手术期缺血再灌注损伤

非在研适应症-

原研机构

University of North Carolina System

在研机构

X-In8 Corp

非在研机构-

最高研发阶段药物发现

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 CRX-526 相关的临床结果

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100 项与 CRX-526 相关的转化医学

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100 项与 CRX-526 相关的专利（医药）

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7

项与 CRX-526 相关的文献（医药）

2017-01-01·Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie2区 · 医学

Anti-inflammatory effect of miltirone on inflammatory bowel disease via TLR4/NF-κB/IQGAP2 signaling pathway

2区 · 医学

Article

作者: Gu, Junfei ; Jiang, Ziyu ; Chen, Juan ; Qiu, Huihui ; Feng, Liang ; Wang, Hongjian ; Du, Mei ; Luo, Yi ; Yang, Nan ; Liu, Ying ; Wang, Gang ; Hou, Xuefeng

Inflammatory bowel disease (IBD) is characterized by a radical imbalance in the activation of proinflammatory and anti-inflammatory signaling pathways in the gut. This study was conducted to evaluate the anti-inflammation effect of miltirone against IBD in vitro and in vivo, and try to explore the underlying mechanisms. Miltirone could extenuate the loss of colon length and weight caused by TNBS. Additionally, macroscopic scores and DAI were reduced significantly compared with the TNBS group. The levels of TNF-α, IL-1β, IL-6 and IL-8 were increased significantly with the induction by TNBS (100mg/kg) or LPS (0.5mg/mL). Interestingly, miltirone could down-regulate the levels of these increased pro-inflammatory factors in a dose-dependent manner both in vivo and in vitro. The protein and mRNA expressions of TLR4, MyD88, NF-κB p65 were up-regulated by TNBS or LPS stimulation. CRX-526, the TLR4 inhibitor, as well as miltirone could significantly suppress the increased protein and mRNA expressions. Miltirone could up-regulate the descreased IQGAP2 expression induced by LPS. All these revealed that the anti-inflammatory effect of miltirone on IBD may be via regulating TLR4/NF-κB/IQGAP2 signaling pathway. The findings might supply beneficial hints for the drug research to cure the IBD.

2015-09-01·Microvascular research3区 · 医学

Experimental TLR4 inhibition improves intestinal microcirculation in endotoxemic rats

3区 · 医学

Article

作者: Zimmermann, Katrin ; Pavlovic, Dragan ; Lehmann, Christian ; Zhou, Juan ; Soltow, Marieke ; Johnston, Brent

INTRODUCTION:

Toll like receptor 4 (TLR4) represents a critical cellular link for endotoxin-induced pathology. The aim of this study was to evaluate the potential role of TLR4 inhibition on the intestinal microcirculation during experimental endotoxemia.

MATERIALS AND METHODS:

The intestinal microcirculation was studied by intravital microscopy in four groups of Lewis rats (n=10 per group): healthy controls (CON group), endotoxemic animals (15mg/kg lipopolysaccharide, LPS group), endotoxemic animals treated with a TLR4 antagonist (1mg/kg CRX-526, LPS+CRX526 group), and controls treated with CRX-526 (C-CRX526 group). Plasma samples were obtained for cytokine measurements at the end of the experiments.

RESULTS:

Endotoxemia significantly increased leukocyte adhesion in intestinal submucosal venules (e.g., V1 venules: CON 20.4±6.5n/mm(2), LPS 237.5±36.2n/mm(2), p<0.05) and reduced capillary perfusion of the intestinal wall (e.g., longitudinal muscular layer: CON 112.5±5.9cm/cm(2), LPS 71.3±11.0cm/cm(2), p<0.05) at 2h. TLR4 inhibition significantly reduced endotoxemia-associated leukocyte adhesion (V1 venules: 104.3±7.8n/mm(2)) and improved capillary perfusion (longitudinal muscular layer: 111.0±12.3cm/cm(2)). Cytokine release was not significantly affected.

CONCLUSIONS:

The TLR4 pathway may be a target in clinical Gram-negative sepsis since administration of the TLR4 antagonist CRX-526 improved intestinal microcirculation parameters in experimental endotoxemia.

2014-01-01·European review for medical and pharmacological sciences

The TLR4/NF-κB signaling pathway mediates the growth of colon cancer.

Article

作者: Ren, X-J ; Qian, J ; Huang, H-Y ; Zhang, Z-J ; Cao, C-B ; Wang, N ; Peng, J-Q ; Liu, F-F

OBJECTIVE:

We studied the involvement of the TLR4/NF-κB pathway in the growth of colon cancer using human colon cancer specimens, human colon cancer SW620 cell line, and nude mouse xenograft model.

MATERIALS AND METHODS:

Tissue samples were surgically harvested. The human colon cancer SW620 cell line was pre-treated with the TLR4 inhibitor CRX-526 and stimulated with LPS. The nude mouse xenograft model was established by subcutaneous injection of SW620 cells with or without CRX-526, the TLR4 inhibitor. The study outcomes were mRNA and protein expressions of TLR4 and NF-κB p65 in specimens of colon cancer and adjacent normal tissue, SW620 cell line, and xenografts. In addition, we studied production of interleukin (IL)-6 and IL-8 in culture supernatants of LPS-stimulated SW620 cells.

RESULTS:

Both mRNA and protein expressions of TLR4 and NF-κB in colon cancer specimens were higher than those in the adjacent normal tissue. LPS up-regulated expression of TLR4 and NF-κB, and stimulated production of IL-6 and IL-8 in SW620 cells. These effects were attenuated by CRX-526. TLR4 inhibition was also effective in the nude mouse xenograft model, as tumor sizes were significantly smaller, and expressions of TLR4 and NF-κB significantly lower, in the mice treated with CRX-526.

CONCLUSIONS:

The TLR4/NF-κB signaling pathway is activated in colon cancer, causing production of IL-6 and IL-8, and, thereby, tumor growth and metastasization. Inhibition of TLR4 attenuates up-regulation of NF-κB and inhibits tumor growth.

100 项与 CRX-526 相关的药物交易

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