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BCAR3 inhibitors and their use in prevention and treatment of fibrotic diseases

A fibrotic disease and inhibitor technology, applied in the field of disease prevention and treatment, can solve the problems of high surgical risk, high surgical cost, clinical treatment effect and safety that cannot meet the treatment needs, etc. high effect

Active Publication Date: 2022-05-24
TONGJI HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Organ transplantation is the only final treatment option for patients with fibrotic diseases, and its application and promotion are limited by the difficulty in obtaining donors, high surgical risks, and high surgical costs
However, existing drugs cannot reverse the course of fibrosis, and their clinical efficacy and safety cannot meet the treatment needs.

Method used

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  • BCAR3 inhibitors and their use in prevention and treatment of fibrotic diseases
  • BCAR3 inhibitors and their use in prevention and treatment of fibrotic diseases
  • BCAR3 inhibitors and their use in prevention and treatment of fibrotic diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 The effect of airway injection of BCAR3 siRNA on the degree of pulmonary fibrosis;

[0043] Experimental animals and materials:

[0044] 1. Experimental animals:

[0045] Source: Wild-type mice (WT, C57BL / 6) bred in the animal room of Tongji Medical College;

[0046] Childbearing age: 8 to 10 weeks old;

[0047] 2. Experimental method:

[0048] Wild-type mice were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (70 mg / kg), followed by airway injection of FITC at a final concentration of 0.021 mg / kg, which was purchased from sigma and dissolved in normal saline for use In , mice injected with the same volume of Scr siRNA using the airway were used as controls. On the 14th and 17th days after the administration of FITC, BCAR3siRNA and Scr siRNA were injected into the airway again, and the mice were sacrificed 21 days later to analyze the degree of pulmonary fibrosis in each mouse.

[0049] The severity of interstitial fibrosis was indep...

Embodiment 2

[0054] Example 2 Effects of airway injection of BCAR3 siRNA on fibronectin, type I collagen, α-SMA protein, BCAR3 protein and mRNA levels;

[0055] In order to further evaluate the degree of fibrosis in the lungs of each mouse after FITC injection, the present invention detected fibronectin, type I collagen, α-SMA protein, BCAR3 protein in the lung tissue of each mouse by western blot and RT-PCR respectively. protein and mRNA levels.

[0056] Specifically, the lung tissue of the mice after the experiment in Example 1 was collected, the protein in the tissue was extracted by RIPA lysis solution, and the protein expression levels of target proteins, such as fibronectin, type I collagen, α-SMA and BCAR3, were detected by Western blot. The result is as image 3 shown. For the specific method of the Western blot, please refer to Hu Y et al., 2022, Nature communications, 13:114.

[0057] At the same time, SYBR Premix Ex Taq (TaKaRa) was used for quantitative RT-PCR, and β-actin w...

Embodiment 3

[0061] Example 3 Effect of airway injection of BCAR3 siRNA on hydroxyproline levels;

[0062] 1. Experimental materials:

[0063] Hydroxyproline detection kit: Nanjing Jiancheng Biotechnology Co., Ltd.

[0064] 2. Experimental method:

[0065] The expression levels of hydroxyproline in the lung tissue of each group of mice in Example 1 were determined by using a hydroxyproline detection kit.

[0066] The results are as Figure 5 shown, combined with Figure 5 It can be seen that, as the above-mentioned expression results of Example 2 are consistent, compared with the mice injected with BCAR3 siRNA into the airway, the Scr siRNA mice injected into the airway have more severe fibrosis after induction by FITC, and the hydroxyproline in the lung tissue is more serious. Acid levels were significantly up-regulated.

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Abstract

The invention discloses a BCAR3 inhibitor and application thereof in prevention and treatment of fibrosis diseases, and belongs to the technical field of disease prevention and treatment. Specifically, BCAR3siRNA is injected into the airway of a wild type mouse, mice injected with Scr siRNA in the airway are used as a contrast, the pulmonary fibrosis degree of each mouse is analyzed, and the result shows that the pulmonary fibrosis degree of the mice injected with BCAR3siRNA in the airway is remarkably reduced. Further exploration finds that on one hand, the BCAR3 inhibitor inhibits polarization of M2 type macrophages, and on the other hand, the BCAR3 inhibitor can reduce differentiation of fibroblasts so as to slow down the fibrosis process. The invention provides a novel BCAR3-targeting treatment strategy for fibrotic diseases, and further lays a foundation for developing novel high-safety medicines capable of effectively treating fibrotic diseases.

Description

technical field [0001] The invention relates to a medicine for preventing or treating various fibrotic diseases and conditions, belonging to the technical field of disease prevention and treatment, in particular to a BCAR3 inhibitor and its use in preventing and treating fibrotic diseases. Background technique [0002] BCAR3, English full name Breast cancer anti-estrogen resistance 3, also known as AND-34 or NSP2, is a member of the NSP family, as described in Makkinje A, et al., 2009, Cell Signal, 21:1423-35. Although a large number of research results have shown that BCAR3, as an adaptor protein downstream of several growth factor receptors, promotes cell proliferation and migration, and is involved in various diseases, such as endometriosis (Meng X, et al., 2019, Mol. Cell Endocrinol, 494: 110486.) and breast cancer, ovarian cancer, endometrial cancer and other tumors (Arras J, et al., 2021, Am J Cancer Res, 11: 4768-4787), but it is not clear that BCAR3 is involved in th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P43/00
CPCA61K45/00A61P43/00
Inventor 王宜王琪熊维宁喻钧
Owner TONGJI HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI TECH
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