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Application of inhibitor of histone methyltransferase DOT1L in preparation of medicine for preventing and treating peritoneal fibrosis after peritoneal dialysis

A methyltransferase, peritoneal dialysis technology, applied in the direction of drug combinations, medical preparations containing active ingredients, antipyretics, etc., can solve problems such as poor effect, achieve significant technological progress, reduce inflammatory cell infiltration, reduce Effects of peritoneal pathological changes

Active Publication Date: 2020-12-18
SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Aiming at the clinical background and harm of peritoneal fibrosis related to peritoneal dialysis mentioned above, as well as the fact that there is no effective medicine for treating and alleviating peritoneal fibrosis clinically, the present invention provides a combination of Use of EPZ5676, an inhibitor of protein lysine methyltransferase DOT1L, in the preparation of drugs for preventing or treating peritoneal fibrosis after peritoneal dialysis, and the use of the inhibitor of histone lysine methyltransferase DOT1L To solve the technical problem of poor efficacy of drugs for the clinical treatment of peritoneal fibrosis associated with peritoneal dialysis

Method used

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  • Application of inhibitor of histone methyltransferase DOT1L in preparation of medicine for preventing and treating peritoneal fibrosis after peritoneal dialysis
  • Application of inhibitor of histone methyltransferase DOT1L in preparation of medicine for preventing and treating peritoneal fibrosis after peritoneal dialysis
  • Application of inhibitor of histone methyltransferase DOT1L in preparation of medicine for preventing and treating peritoneal fibrosis after peritoneal dialysis

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Embodiment 1 Materials and methods

[0017] 1) Reagent consumables

[0018] DOT1L, H3K79me2, Snail, and Slug antibodies were purchased from Abcam. Vimentin antibody was purchased from cell signalingTechnology company. Collagen I (A2), E-cadherin and GAPDH antibodies were purchased from Santa Cruz Company. F4 / 80 antibody was purchased from Sewell Company. EPZ5676 was purchased from APExBIO company. α-SMA antibody and other reagents were purchased from Sigma.

[0019] 2) Mouse peritoneal fibrosis model and experimental grouping

[0020] The mouse peritoneal fibrosis model was established by intraperitoneal injection of 4.25% high glucose peritoneal dialysis fluid. All animal experiments complied with the Chinese regulations on the management and use of laboratory animals.

[0021] 28-day mass percent concentration of 4.25% high-glucose peritoneal dialysis fluid induced mouse peritoneal fibrosis model

[0022] a. sham group (n=6): intraperitoneal injection of the s...

Embodiment 2

[0041] Example 2 EPZ5676 inhibits the occurrence of peritoneal fibrosis in mice induced by high-glucose peritoneal dialysis fluid

[0042] In the animal model, the present invention successfully establishes the animal model of peritoneal fibrosis after 28 days by giving mice an intraperitoneal injection of 3ml of high-glucose peritoneal dialysis solution with a mass percentage concentration of 4.25%. Masson staining shows that the subperitoneal area of ​​the mice in the dialysis group is significantly thickened. The mice in the treatment group were given intraperitoneal injection of EPZ5676 after daily injection of high-glucose peritoneal dialysis solution. It was found that EPZ5676 treatment could significantly reduce the peritoneal thickness and the positive area of ​​Masson staining ( figure 1 A-1C). The above results indicate that DOT1L may play an important regulatory role in the development of peritoneal fibrosis, and the DOT1L inhibitor EPZ5676 can alleviate the occur...

Embodiment 3

[0043] Example 3 EPZ5676 inhibits mouse peritoneal epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition induced by high-glucose peritoneal dialysis fluid

[0044] In the animal model of the present invention, the expression of ECM protein and EMT-related markers α-SMA, Collagen I and Vimentin in the peritoneal tissue is further detected by immunoblotting technology. The results showed that α-SMA, Collagen Ⅰ and Vimentin were highly expressed in the peritoneal tissue of mice injected intraperitoneally with high glucose dialysate for 28 days, and EPZ5676 could significantly down-regulate the expression levels of these proteins ( figure 2 A and 2B). Similarly, immunohistochemical staining showed that the expression of Collagen Ⅰ increased in the dialysis model group and decreased in the treatment group ( figure 2 C and 2D). These results indicated that EPZ5676 could inhibit high glucose peritoneal fluid-induced EMT and ECM deposition in mouse peri...

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Abstract

The invention provides application of an inhibitor of histone methyltransferase DOT1L in preparation of a medicine for preventing and treating peritoneal fibrosis after peritoneal dialysis. EPZ5676 isused for inhibiting histone lysine methyltransferase DOT1L, so that the peritoneal pathological change caused by high-glucose peritoneal dialysis fluid damage can be relieved, and the peritoneal function is improved. The inhibition mechanism is mainly characterized in that the EPZ5676 inhibits peritoneal mesothelial cell-mesenchymal transdifferentiation, and reduces inflammatory cell infiltration, especially macrophage infiltration. Therefore, DOT1L can become an important target spot for preventing or treating peritoneal fibrosis, and the related inhibitor is expected to become a clinical medicine and is used for preventing or treating peritoneal fibrosis related to peritoneal dialysis.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to histone lysine methyltransferase DOT1L, specifically, the preparation of a drug for preventing or treating peritoneal fibrosis after peritoneal dialysis by the inhibitor EPZ5676 of histone lysine methyltransferase DOT1L use in . Background technique [0002] Peritonealdialysis (PD) is one of the main alternative treatments for end-stage renal disease (ESRD). Metabolites and correct water-electrolyte, acid-base imbalance, and keep the internal environment of the body constant. Compared with hemodialysis, peritoneal dialysis is safe and simple, easy to operate, low in cost, can remove toxins and water more smoothly, retain residual renal function to the maximum extent, and improve the quality of life of ESRD patients. However, as the duration of peritoneal dialysis increases, various causes of peritoneal fibrosis (Peritoneal fibrosis, PF) lead to abnormal structure and function of the perit...

Claims

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Application Information

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IPC IPC(8): A61K31/7076A61P43/00A61P29/00
CPCA61K31/7076A61P43/00A61P29/00
Inventor 刘娜陶敏施映枫
Owner SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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