Application of EPCR pathway activator in preparation of anti-fibrosis agent

An anti-fibrosis and activator technology, applied in the field of biomedicine, can solve problems such as difficult to prevent or reverse fibrosis

Pending Publication Date: 2022-01-21
THE WEST CHINA SECOND UNIV HOSPITAL OF SICHUAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently existing drugs for the treatment of fibrosis are often only able to inhibit fibrosis to a certain extent, but it is difficult to prevent or reverse fibrosis

Method used

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  • Application of EPCR pathway activator in preparation of anti-fibrosis agent
  • Application of EPCR pathway activator in preparation of anti-fibrosis agent
  • Application of EPCR pathway activator in preparation of anti-fibrosis agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Embodiment one: materials and methods

[0080] Table 1 Key resources

[0081]

[0082]

[0083]

[0084] Animal care and mouse strains used. Floxed neuropilin 1 (Nrp1) mice and HIF2α (Hif2a) mice and mice lacking tissue inhibitor of metalloproteinase 1 (Timp1), platelet factor-Cre (Pf4-Cre) mice were obtained from the Jackson Laboratory. Expression of EC-specific Cdh5-(PAC)-Cre ERT2 / VE-cadherin-Cre ERT2 The mice were provided by Dr. Ralf Adams; this mouse line was crossed with floxed Nrp1 and Hif2a mice to generate Nrp1 iΔEC / iΔEC , Hif2a i ΔEC / iΔEC and control mice. Four-week-old mice were treated with intraperitoneal (i.p.) injections of 250 mg / kg tamoxifen for 10 days, followed by a one-week break after the 3rd and 6th dose (or 150 mg / kg for 6 days , and break for 3 days after the 3rd time). Quantitative polymerase chain reaction (PCR) confirmed the deletion of the target gene in ECs. Nrp1 iΔEC / iΔEC mice and Hif2a iΔEC / iΔEC Mice and age-matched li...

Embodiment 2

[0098] Example 2: The transition from "regeneration to fibrosis" in the lung of aged mice is related to the formation of "platelet-macrophage" colonies and the reprogramming of endothelial cells

[0099] Experimenters of the present invention use pneumonectomy (PNX) to compare the alveolar regeneration and fibrosis of mice of different ages ( Figure 1A ), including recovery of lung function, epithelial structure, and hydroxyproline content ( Figure 1B -C, Figure 8A -B). 20-month-old mice after PNX showed significant inhibition of alveolar regeneration and increased fibrosis compared to 2-, 3-, and 6-month-old mice. Therefore, the experimenters of the present invention defined 20-month-old mice as "old" mice, and compared the regenerative capacity of aged mice with 2-month-old (2-mon) or 3-month-old (3-mon) mice.

[0100] Platelets and macrophages play an important role in organ repair. Based on this, the experimenters of the present invention made CD41 in mouse lung aft...

Embodiment 3

[0102] Example 3: In aged lung, normalizing the NRP1-HIF2α-EPCR circuit in endothelial cells reduces the transition from "regeneration to fibrosis"

[0103] NRP1 is a co-receptor for various cytokines. In order to explore the role of NRP1 in aging-related fibrosis, the experimenters of the present invention constructed mice specifically deficient in NRP1 in endothelial cells (Nrp1 iΔEC / iΔEC ). Floxed NRP1 mice express EC-specific VE-cadherin (Cdh5)-Cre ERT2 mouse hybrids. Tamoxifen (Tamoxifen) treatment of the offspring deleted NRP1 in the endothelial cells of the offspring ( Figure 8E ). Aged Nrp1 iΔEC / iΔEC Mice received PNX, and 3-month-old (young) mice were compared with aged Nrp1 + / + Mice served as controls. Aged Nrp1 after PNX compared with aged control mice iΔEC / iΔEC Mouse PCECs showed lower HIF2α expression and higher EPCR levels ( Figure 1F , Figure 8F ). Deletion of NRP1 in endothelial cells suppresses the formation of "platelet-macrophage" colonies in p...

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Abstract

The invention relates to the field of biological medicines, in particular to an application of an EPCR pathway activator in preparation of an anti-fibrosis agent. The application is helpful for relieving organ fibrosis to a certain extent and promoting repair and regeneration of corresponding organs.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the application of an EPCR pathway activator in the preparation of an anti-fibrosis agent. Background technique [0002] Fibrosis can occur in multiple organs and is the final pathological outcome of many common chronic inflammatory, immune-mediated metabolic diseases and the main cause of morbidity and mortality in these diseases. A variety of noxious stimuli, including toxins, infectious pathogens, autoimmune responses, and mechanical stress, can induce fibrotic cellular responses. Fibrosis affects all tissues in the body and, if left unchecked, can lead to organ failure and death. [0003] Fibrosis is a repair response to protect the relative integrity of tissues and organs after tissue damage. In response to tissue injury, myofibroblasts derived from multiple sources including resident fibroblasts, mesenchymal cells, circulating fibroblasts, and transdifferentiation of other cell...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P43/00A61P1/16A61P11/00A61P13/12A61P9/00
CPCA61K45/00A61P1/16A61P11/00A61P13/12A61P9/00Y02A50/30
Inventor 丁楅森曹中炜
Owner THE WEST CHINA SECOND UNIV HOSPITAL OF SICHUAN
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