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Application of niclosamide and structural trim thereof in heart protection, pulmonary hypertension resistance and tumor resistance

A technology for pulmonary arterial hypertension and niclosamide, which is applied in the directions of antitumor drugs, medical preparations containing active ingredients, and drug combinations to achieve the effect of improving water solubility

Active Publication Date: 2018-11-16
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drugs for the treatment of pulmonary arterial hypertension urgently need to be developed

Method used

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  • Application of niclosamide and structural trim thereof in heart protection, pulmonary hypertension resistance and tumor resistance
  • Application of niclosamide and structural trim thereof in heart protection, pulmonary hypertension resistance and tumor resistance
  • Application of niclosamide and structural trim thereof in heart protection, pulmonary hypertension resistance and tumor resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 Niclosamide activates cardiomyocyte protection signal STAT3 and resists cardiomyocyte injury caused by doxorubicin

[0051] 1. Cells and experimental reagents:

[0052] Primary rat neonatal cardiomyocytes were cultured. Niclosamide was purchased from Sigma.

[0053] 2. Experimental method:

[0054] 2.1. Cultivate primary rat suckling mouse cardiomyocytes:

[0055] Take the heart of suckling mice (1-3 days), centrifuge "mixed collagenase + trypsin" at 37 degrees Celsius and 2500r / min, remove the supernatant, blow and beat the cells, collect them in a culture bottle, remove fibroblasts by differential adhesion, and continue to culture .

[0056] 2.2. Detection of STAT3 expression and activity

[0057] After the cells grew to a suitable density, niclosamide (0.05 μmol / L) was added, and samples were taken at 15 minutes, 30 minutes, 1 hour, and 2 hours to extract total protein. Protein concentration was determined using the BCA protein detection kit. Protein...

Embodiment 2

[0065] Example 2 Niclosamide (Niclosamide) increases cardiomyocyte ATP generation

[0066] 1. Cells and experimental reagents:

[0067] ditto

[0068] 2. Experimental method:

[0069] 2.1. Cultivate primary rat suckling mouse cardiomyocytes: same as above

[0070] 2.2. Determination of ATP content in cardiomyocytes

[0071] After the cells grew to a suitable density, niclosamide (0.05 μmol / L) was added, and after 12 hours, the ATP content of cardiomyocytes was measured with a kit.

[0072] 3. Results

[0073] 3.1 Niclosamide (Niclosamide) increases the ATP content of cardiomyocytes

[0074] Through research, the present invention finds that treating primary cardiomyocytes with niclosamide (0.05 μmol / L) for 12 hours can significantly increase the ATP content of cardiomyocytes. see results image 3 (*P<0.05, **P<0.01 vs Control. Nic, niclosamide).

Embodiment 3

[0075] Example 3 Niclosamide (Niclosamide) inhibits cardiac fibroblast proliferation and collagen secretion

[0076] 1. Experimental method:

[0077] 1.1. Culture primary rat neonatal cardiac fibroblasts

[0078] Take the heart of suckling mice (1-3 days), centrifuge "mixed collagenase + trypsin" at 37 degrees Celsius and 2500r / min, remove the supernatant, blow and beat the cells, collect them in culture flasks, and obtain cardiac fibroblasts by differential attachment method.

[0079] 1.2. Cardiac fibroblast proliferation and collagen secretion assay

[0080] Determination of collagen: extract primary SD neonatal rat myocardial fibroblasts, and starve the cells with complete medium for 12 hours after the cells are stably adhered to the wall. After adding the drug for 24 hours, absorb 32 μL of the supernatant culture solution, add 8 μL of 5×protein loading buffer, boil the sample at 100°C for 5 minutes, and use 7.5% SDS-PAGE gel for western blot experiment.

[0081] Cell pr...

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Abstract

The invention discloses application of niclosamide and a structural trim thereof in heart protection, pulmonary hypertension resistance and tumor resistance. The structural trim is an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-Niclosamide conjugate (HPMA-Nic) obtained by modifying niclosamide with N-(2-hydroxypropyl) methacrylamide. A research shows that the niclosamide increases generation of ATP of the myocardial cells, resists doxorubicin-induced myocardial cell injury, inhibits the multiplication and collagen secretion of fibroblasts and inhibits the multiplication and migration of pulmonary artery smooth muscle cells. The HPMA-Nic obviously improves the water solubility of the niclosamide; and intraperitoneal injection can inhibit pressure load-induced mouse myocardial hypertrophy and inhibit growth of a tumor in a naked mouse body. The invention provides a new effective technical measure for myocardial protection, cardiac fibrosis resistance, myocardial hypertrophy resistance, heart failure resistance, pulmonary artery hypertension resistance and anti-tumor treatment, and the application has a wide application prospect.

Description

technical field [0001] The present invention relates to the application of niclosamide (niclosamide) in myocardial protection, anti-cardiac fibrosis, anti-myocardial hypertrophy, anti-heart failure, anti-pulmonary hypertension and anti-other fibrotic diseases; also relates to N-(2-hydroxypropyl Niclosamide grafted 2-hydroxypropyl methacrylamide copolymer (N-(2-hydroxypropyl)methacrylamide(HPMA)copolymer-Niclosamide conjugates, HPMA-Nic ) and its applications in myocardial protection, anti-cardiac fibrosis, anti-cardiac hypertrophy, anti-heart failure, anti-pulmonary hypertension, anti-other fibrotic diseases and anti-tumor. The invention belongs to the field of biomedicine. Background technique [0002] Heart failure, referred to as heart failure, refers to the failure of the venous blood to fully discharge the heart due to cardiac systolic and / or diastolic dysfunction, resulting in blood stasis in the venous system and insufficient blood perfusion in the arterial system, r...

Claims

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Application Information

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IPC IPC(8): A61K31/167A61P9/00A61P9/12A61P9/04A61P35/00
CPCA61K31/167A61P9/00A61P9/04A61P9/12A61P35/00
Inventor 董德利
Owner HARBIN MEDICAL UNIVERSITY
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