CN-121987794-A - Application of USP7 as target in preparing medicament for treating vascular abnormal leakage diseases

Abstract

The application provides application of USP7 as a target in preparing medicines for treating vascular abnormal leakage diseases, relates to the technical field of biomedicine, and aims to regulate and control tumor, nerve and immune related diseases and closely relate to vascular endothelial cell functions by taking USP7 (ubiquitin-specific protease 7) as deubiquitinase. In vascular homeostasis, USP7 may maintain vascular barrier integrity and inhibit pathological leakage by stabilizing endothelial connective proteins such as VE-cadherein, beta-catenin, etc., while in inflammatory or hypoxic conditions, it may promote vascular endothelial cell activation by de-ubiquitinating HIF-1α or NF- κb pathway components (such as ikbα), exacerbate VEGF-signaling-driven aberrant angiogenesis or release of inflammatory factors, involved in diabetic retinopathy, tumor vascular proliferation and sepsis-related vascular leakage. The verification experiment proves that USP7 has a certain protection effect on vascular permeability, and provides a treatment strategy for clinical vascular abnormal leakage diseases.

Inventors

• MAO RENFANG
• JIANG YANHONG
• FAN YIHUI

Assignees

• 南通大学

Dates

Publication Date

20260508

Application Date

20260211

Claims (10)

1. Application of USP7 as target in preparing medicine for treating vascular abnormal leakage diseases.
2. 2. The use of USP7 as a target in the manufacture of a medicament for treating vascular abnormal leaky disease according to claim 1, wherein the medicament reduces permeability of vascular endothelial cells by overexpressing USP 7.
3. 3. The use of USP7 as target in the manufacture of a medicament for treating vascular abnormal leakage disease according to claim 1, wherein the vascular abnormal leakage disease comprises sepsis, acute lung injury or diabetic retinopathy-related vascular endothelial leakage.
4. 4. The use of USP7 as target in claim 3 for preparing a medicament for treating vascular leak diseases, wherein the medicament comprises a recombinant plasmid (such as pLV3-USP 7) containing over-expressed USP7, a lentiviral vector or a functional expression product thereof, which over-expresses USP 7.
5. 5. The use of USP7 as target in preparing medicine for treating vascular abnormal leakage disease according to claim 4, wherein the recombinant plasmid contains puromycin resistance screening marker gene and the vector skeleton is pLV3 series vector.
6. 6. The use of USP7 as target according to claim 5 for the manufacture of a medicament for the treatment of vascular abnormal leakage disease, wherein the medicament further comprises a pharmaceutically acceptable additional adjuvant.
7. 7. A pharmaceutical agent for inhibiting vascular endothelial cell infiltration, which is useful for over-expressing USP7.
8. 8. A pharmaceutical composition according to claim 7, wherein said pharmaceutical composition comprises a recombinant plasmid, lentiviral vector, or functional expression product thereof, over-expressing USP 7.
9. 9. A pharmaceutical composition according to claim 7, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.
10. 10. A pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is in the form of an injection, a lyophilized powder for injection or a sustained release preparation.

Description

Application of USP7 as target in preparing medicament for treating vascular abnormal leakage diseases Technical Field The application relates to the technical field of biomedicine, in particular to application of USP7 serving as a target in preparing a medicament for treating vascular abnormal leakage diseases. Background Vascular homeostasis is critical for maintaining the balance of the environment and tissue and organ functions in the human body, and leakage phenomena caused by impaired vascular barrier integrity under specific physiological or pathological conditions can lead to multiple system dysfunction. Pathological stimuli such as inflammatory reactions, infections, wounds, metabolic abnormalities (e.g., diabetes) or tumor microenvironments can induce loose vascular endothelial cell junctions and increased permeability, which in turn can lead to vascular leakage. The pathological leakage can cause tissue edema, plasma protein extravasation and abnormal infiltration of immune cells, further aggravate inflammatory spread and organ failure, and can cause irreversible damage and even death in diseases such as sepsis, acute lung injury, diabetic retinopathy and the like. Therefore, the key genes and molecular mechanisms for regulating and controlling vascular permeability are deeply analyzed, and the development of medicaments or intervention strategies for targeted repair of vascular barriers provides theoretical basis and clinical application prospect for treating vascular leakage related diseases. Disclosure of Invention The application aims to solve the technical problem that medicines or intervention strategies aiming at vascular barriers are lacked in the prior art. In order to solve the problems in the prior art, the application provides the following technical proposal The application of USP7 as a target in preparing medicaments for treating vascular abnormal leakage diseases. Preferably, the agent reduces vascular endothelial cell permeability by over-expressing USP 7. Preferably, the vascular abnormal leakage disease comprises sepsis, acute lung injury or diabetic retinopathy-related vascular endothelial leakage. Preferably, the medicament comprises a recombinant plasmid (e.g., pLV3-USP 7) comprising an over-expressed USP7, a lentiviral vector or a functional expression product thereof that over-expresses USP 7. Preferably, the recombinant plasmid comprises puromycin resistance selection marker gene and the vector backbone is a pLV3 series vector. Preferably, the medicament further comprises other auxiliary agents which are acceptable in medicine. The present application also provides a medicament for inhibiting the infiltration of vascular endothelial cells for over-expressing USP7. Preferably, the medicament comprises a recombinant plasmid that overexpresses USP7 (e.g., pLV3-USP 7), a lentiviral vector, or a functional expression product thereof. Preferably, the medicament further comprises other auxiliary agents which are acceptable in medicine. Preferably, the medicament is in the form of injection, freeze-dried powder injection or sustained release preparation. Compared with the prior art, the application at least comprises the following beneficial effects: 1. In the application, the in vitro experiment proves that the USP7 has a specific protection effect on the integrity of vascular endothelial barriers, can be definitely used as a core target for treating vascular abnormal leakage diseases, fills up the blank of the target research and development of the targeted drugs for the diseases in the prior art, and provides a brand-new action direction for treating the diseases. 2. The verification test proves that the over-expression of the USP7 can obviously reduce the glucan leakage amount (P < 0.0001) and weaken the fluorescent dye diffusion (P < 0.001) by reducing the permeability of vascular endothelial cells, directly inhibit vascular leakage, and inhibit the concentration dependence of the USP7 function to exacerbate leakage, and the positive and negative aspects verify the definite mechanism of regulating and controlling vascular leakage by the USP7, so that the reliability and scientificity of the treatment effect are ensured. 3. The USP7 provided by the application can be used for treating various clinical common and serious related diseases such as sepsis, acute lung injury, diabetic retinopathy and the like aiming at abnormal vascular leakage caused by various causes such as inflammation, infection, metabolic abnormality and the like, can cover the treatment requirements of multi-system vascular leakage lesions, and has wide application prospect. Drawings FIG. 1 shows that treatment of HUVEC cell lines with USP7 inhibitor increases vascular endothelial cell leakage pattern, A: statistical plot of FITC dextran leakage pattern after addition of HUVEC cell line to USP7 inhibitor FT671, and B: statistical plot of FITC dextran leakage pattern after addition of USP7 inhibitor P22077 to