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Composition for preventing or treating valve calcification, containing dpp-4 inhibitor

A technology of DPP-4 and composition, applied in the directions of active ingredients of heterocyclic compounds, medical preparations containing active ingredients, gene therapy, etc.

Active Publication Date: 2018-01-02
THE ASAN FOUND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When eNOS dysfunction occurs, isoenzymes with similar structure and function to eNOS, such as neuronal NOS (nNOS) or inducible NOS (iNOS), increase compensatoryly to replace the action of eNOS, but cannot easily Continue to maintain normal vascular endothelial cell function

Method used

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  • Composition for preventing or treating valve calcification, containing dpp-4 inhibitor
  • Composition for preventing or treating valve calcification, containing dpp-4 inhibitor
  • Composition for preventing or treating valve calcification, containing dpp-4 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Analysis of DPP-4 Expression in Human Calcific Aortic Valve Disease (CAVD)

[0048] Human aortic valve samples were obtained from normal patients undergoing aortic valve replacement and from patients with severe calcified lesions at Seoul Asan Medical Center. Half of each sample was immediately stored in RNAlater (Life Technology), while the remaining half was fixed in OCT compound (Sakura Finetek, Inc.). The study protocol for collecting human samples was approved by the Institutional Review Board (IRB) of Asan Hospital, Seoul, Korea.

[0049] Gene expression profiles involved in cellular progression in human calcific aortic valve disease (CAVD) analyzed by microarray.

[0050] Analysis of gene expression profiles in aortic valve samples from non-calcified normal patients and calcified patients using Affymetrix Human Gene 2.0ST Array (Affymetrix, USA) was performed. Quantile normalization and data analysis were performed using Affymetrix GCOS software ...

Embodiment 2

[0057] Example 2: Analysis of DPP-4 expression in eNOS knockout mouse model

[0058] C57BL / 6J eNOS- / - (endothelial nitric oxide synthase knockout) mice (8 weeks old, n=10, TheJackson Laboratory, Bar Harbor, Me, USA) and C57BL / 6J wild-type mice (8 week old, wild type, WT, n=10). After purchase, mice were fed standard rodent chow until 3 months of age.

[0059] Mice were deeply anesthetized, and under this condition, PBS containing 4% paraformaldehyde was administered to the mice, and the heart and aorta were extracted. The extracted tissue was fixed overnight and embedded in paraffin, and the whole aortic valve was sectioned to a thickness of 5 μm. Mice were euthanized, and blood and aortic samples were stored for analysis.

[0060] To visualize calcium deposition in paraffin-embedded aortic valves and basal segments of the heart, von Kossa and Alizarin red staining were performed.

[0061] The result is, as Figure 4 As shown, dark-brown staining fractions indicative of...

Embodiment 3

[0062] Example 3: Observation of Calcification in Mouse Vascular Smooth Muscle Cells (VSMC)

[0063] The aortas extracted from eNOS- / - mice and wild-type mice together with the hearts in Example 2 were washed in serum-free medium M199 (Cellgro), cut into small pieces, and then placed in a water bath at 37° C. Incubate for 3 hours in M199 containing 20% ​​fetal calf serum and 3 mg / mL collagenase (Sigma). The isolated cells were found to be vascular smooth muscle cells by using anti-SM monoclonal antibody (Sigma). Isolated vascular smooth muscle cells were seeded at a concentration of 30%, and after 24 hours, the medium was replaced with osteogenic basal medium (Osteogenic SingleQuots, Lonza, USA). Medium was replaced at 3-day intervals during the 28-day culture.

[0064] For wild-type mice and eNOS KO mice, by using ALP staining as the staining method for the initial calcification stage, Alizarin red (AR) staining as the staining method for the intermediate calcification st...

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Abstract

The present invention relates to a composition for preventing or treating valve calcification, containing a dipeptidyl peptidase-4 (DPP-4) inhibitor. The DPP-4 inhibitor according to the present invention may include all of what can inhibit the expression of DPP-4 nucleotides or the activity of DPP-4 proteins, wherein: DPP-4 antibodies, sitagliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin, alogliptin, Anagliptin, evogliptin, Berberine, Diprotin, or Lupeol; DPP-4 mRNA anti-sense nucleotides, aptamers, small interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA (miRNA), or RNA interference (RNAi); or the like can be used.

Description

technical field [0001] The present invention relates to a pharmaceutical composition for preventing or treating valve calcification, comprising a dipeptidyl peptidase-4 (DPP-4) inhibitor. The present invention also relates to a food composition for preventing or improving valve calcification, which comprises a dipeptidyl peptidase-4 (DPP-4) inhibitor. Background technique [0002] Cardiovascular calcification contributes to the exacerbation of hypertension, heart failure, acute coronary syndrome, and valvular disease, and thus contributes to various complications. Also, various epidemiological studies have demonstrated that vascular calcification independently increases mortality. Vascular calcification occurs in a similar mechanism to the osteogenic program during normal prenatal stages or after fractures and is activated in diseases such as aging, diabetes, chronic renal failure and chronic inflammatory diseases. Mineral loss from bone is accelerated by an inflammatory r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61K39/395A61K31/4985A61P9/00
CPCA61K39/395A61K48/00A61K31/4985A61K31/40A61K31/403A61K31/495A61K31/513A61K31/522A23L2/52A61P13/02A61P13/12A61P29/00A61P3/06A61P43/00A61P5/30A61P9/00A61P9/04A61P3/10A23L33/10A23L33/13A23V2250/5434A23V2002/00A23V2200/30
Inventor 张恩珠宋在宽金美庭
Owner THE ASAN FOUND
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