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Application of TLR4 inhibitor in preparation of medicament for treating tooth extraction wound healing disorder caused by bisphosphonate-related osteonecrosis of the jaw (BRONJ)

A technology of inhibitors and tooth extraction wounds, applied in the field of medicine, can solve problems such as poor bone healing, achieve the effect of promoting the healing of tooth extraction wounds, improving speed and quality, and reducing the formation of sequestrum

Inactive Publication Date: 2019-10-15
AFFILIATED STOMATOLOGICAL HOSPITAL OF NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been reported that this long-term TLR4-mediated inflammatory response will lead to poor bone healing

Method used

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  • Application of TLR4 inhibitor in preparation of medicament for treating tooth extraction wound healing disorder caused by bisphosphonate-related osteonecrosis of the jaw (BRONJ)
  • Application of TLR4 inhibitor in preparation of medicament for treating tooth extraction wound healing disorder caused by bisphosphonate-related osteonecrosis of the jaw (BRONJ)
  • Application of TLR4 inhibitor in preparation of medicament for treating tooth extraction wound healing disorder caused by bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Experimental test of zoledronic acid promoting macrophage M1 polarization.

[0024] In order to simulate the effect of ZA on macrophages in the body, the inventors used ZA (zoledronic acid, 10 μM, Zometa, Novartis, USA) to treat primary macrophages derived from mouse bone marrow for 24 hours, then extracted the total protein of the cells, and used The expression of polarity conversion specific markers CD86 and CD206 was detected by western blot.

[0025] Methods as below:

[0026] ①Extraction of total cell protein

[0027] A. Take out the normal culture bottle of cells, pour off the culture medium, add 3ml 4 ℃ pre-cooled PBS solution (0.01mol / L, pH 7.4) to each bottle of cells, lay flat and gently shake for 1min to wash the cells, then discard the washing solution. Repeat the above operation three times, and turn the culture bottle upside down on absorbent paper to blot dry.

[0028] B. Add 10ul PMSF (100mM) to 1ml of the lysate, shake well and place on ice...

Embodiment 2

[0051] Example 2 Experimental test on the activation of TLR4 signaling pathway in macrophages after ZA treatment.

[0052] The inventors detected the activation of the TLR-4 signaling pathway and its downstream key targets in macrophages treated with ZA (10 μM, Zometa) for 24 hours, the method was the same as in Example 1.

[0053] figure 2 It is the western blot detection result of the activation of TLR-4 signaling pathway and its downstream key targets in macrophages after ZA treatment, figure 2 middle, figure 2 A is a western blot diagram, figure 2 B for figure 2 The quantitative statistical results of A, * means p<0.05, ** means p<0.01. It can be seen that macrophages treated with ZA promote the expression of TLR-4, MYD88, TRIF, and IRAK-4 at the protein level. It shows that the treatment of ZA can activate TLR-4 signaling pathway.

Embodiment 3

[0054] Example 3 Experimental test of zoledronic acid promoting macrophage NF-κB nuclear translocation.

[0055] Macrophages were treated with different concentrations of ZA (5 μM, 10 μM, 15 μM) for 30 min, and then nuclear proteins were extracted. Western blot was used to detect the nuclear translocation of NF-κB in macrophages after being stimulated by zoledronic acid.

[0056] The method of extracting nuclear protein is as follows:

[0057] a. Take the treated cells, centrifuge at 4°C, 500xg, and collect the cells for 3 minutes, discard the culture medium, and wash twice with pre-cooled PBS;

[0058] b. Aspirate the supernatant as much as possible without leaving residual liquid, add 200 μL pre-cooled Buffer A to each bottle of cells (add 1 μL DTT, 5 μL 100 mM PMSF, 5 μL protease inhibitors to each mL Buffer A, prepared before use), and vortex at the maximum speed Vigorously shake for 15s, place on ice for 10-15min;

[0059] c. Add 11 μL of cold Bμffer B, vortex vigorousl...

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Abstract

The invention discloses a novel application of a TLR4 inhibitor in preparation of a medicament for treating tooth extraction wound healing disorder caused by bisphosphonate-related osteonecrosis of the jaw. According to the invention, after the TLR4 inhibitor is used in a BRONJ mouse model in a preventive way, the healing speed and quality of the tooth extraction wound of mice are obviously improved. Experiments prove that: the TLR4 inhibitor TAK-242 can not only inhibit activation of a macrophage TLR-4 signal path caused by ZA in an in vitro experiment, but also promote healing of a tooth extraction wound of BRONJ and reduce local dead bone formation of the tooth extraction wound. Therefore, the TLR-4 inhibitor can be used for preparing preventive drugs or health products aiming at the tooth extraction wound healing disorder of the BRONJ.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the application of TLR4 inhibitors in the preparation of drugs for treating tooth extraction wound healing disorder caused by bisphosphonate osteonecrosis of the jaw (BRONJ). Background technique [0002] Nitrogen-containing bisphosphonates (NPBs) are widely used in patients with metastatic bone cancer, Paget's disease, and osteoporosis. However, after receiving high doses of intravenous bisphosphonates such as zoledronic acid (Zoledronic Acid, ZA), patients are prone to bisphosphonate-related osteonecrosis of the jaw (BRONJ). BRONJ refers to the phenomenon that the maxillofacial wounds caused by tooth extraction, periodontitis or trauma after the use of bisphosphonates last for more than eight weeks without radiation therapy. BRONJ is a rare but devastating disease that occurs in the mandible in 2 / 3 of cases. [0003] Previous studies have reported that inhibition...

Claims

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Application Information

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IPC IPC(8): A61K31/215A61P19/08A61P17/02
CPCA61K31/215A61P17/02A61P19/08
Inventor 朱伟文江宏兵张平傅瑜徐荣耀张玉超郭松松
Owner AFFILIATED STOMATOLOGICAL HOSPITAL OF NANJING MEDICAL UNIV
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