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Application of paeonol in preparing medicament for preventing and treating disease of TOPK activity abnormal elevation

A technology of paeonol and activity, which is applied in the field of new pharmacological effects of drugs and disease prevention and treatment, and can solve problems such as clinical application and obvious side effects

Inactive Publication Date: 2017-05-31
史飞
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs have obvious side effects and cannot be effectively clinically applied.

Method used

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  • Application of paeonol in preparing medicament for preventing and treating disease of TOPK activity abnormal elevation
  • Application of paeonol in preparing medicament for preventing and treating disease of TOPK activity abnormal elevation
  • Application of paeonol in preparing medicament for preventing and treating disease of TOPK activity abnormal elevation

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0035] Embodiment 1 Materials and methods included in the implementation of the present invention

[0036] 1. SUV equipment, reagents and antibodies

[0037] Solar UV equipment was purchased from Q-Lab Corporation (Cleveland, OH). The percentages of UVA and UVB were measured with an ultraviolet radiation meter and were 92.5% and 7.5%, respectively. Paeonol (purity>99%) was purchased from Chengdu Ruifengsi Biotechnology Co., Ltd. (Chengdu, China). PGEX-GST H2AX human plastids were purchased from addgene, and active TOPK was purchased from Millippore (Billerica, MA, USA). ELISA kits for TNF-α and IL-6 were purchased from Dakowei Biotechnology Co., Ltd. (Shenzhen, China). Total TOPK, total JNKs, total p38, H2AX antibody, phosphorylated TOPK (Thr9), phosphorylated JNKs (Thr183 / Tyr185), phosphorylated p38 (Thr180 / Tyr182), and phosphorylated H2AX (Ser139) were purchased from CellSignaling Technology (USA). β-actin antibody and horseradish peroxidase (HRP) secondary antibody wer...

Embodiment 2

[0055] Example 2 Paeonol binds to TOPK and inhibits its activity.

[0056] Based on comprehensive spectroscopic analysis and previously published data, paeonol was identified as a known 1-(2-hydroxy-4-methoxyphenyl)ethanone ( Figure 3A ). The toxicity of paeonol was determined by MTS method. HaCat and c141 JB6 cells were treated with different concentrations of paeonol (0, 50, 100, 200, 400μm) and different time (24, 48, 72h). The results showed that paeonol had no obvious cytotoxicity on JB6 c141 and HaCat cells (Fig. 3b).

[0057] To verify whether paeonol can bind to TOPK. The MST method is an optical method, which is characterized by a non-liquid phase and low sample consumption. It can quantify protein-protein interactions or small molecule protein interactions with high sensitivity. The affinity between paeonol and TOPK was tested by MST experiment. In this study, paeonol had a rather low equilibrium dissociation constant (Kd) of 7670 + / - 690 nm, indicating a stron...

Embodiment 3

[0058] Example 3 Paeonol inhibits SUV-induced activation of p38 and JNK.

[0059] JB6 cells are using 20kJ / m 2 Paeonol was pretreated for 12 hours under the SUV irradiation, and the thickness ranged from 25um to 100um, and p38 phosphorylation or JNKs levels were detected at the same time. The results showed that the levels gradually decreased ( Figure 4 A). Secondly, at 20kJ / m 2 The JB6 cells cultured with 100um paeonol under the SUV irradiation increased the culture time from 3 hours to 12 hours, and the phosphorylation of p38 or the level of JNKs also decreased gradually ( Figure 4 B). Similar results were obtained in HaCaT cells ( Figure 4 c, 4d). These data suggest that paeonol can inhibit the activation of JNK or p38 induced by SUV in vitro. Paeonol down-regulated the downstream TOPK signaling pathway induced by SUV in a time- and dose-dependent manner, and simultaneously inhibited the secretion of cytokines in JB6 c141 and HaCaT cells.

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Abstract

The invention discloses a novel effect and molecular mechanism of Paeonol and aims to provide an application of paeonol in preparing a medicament for preventing and treating a disease of TOPK activity abnormal elevation. Paeonol inhibits photodermatoses (sunburn and chronic actinic dermatosis) induced by ultraviolet rays (UV), which is realized by combining protein kinase (TOPK) originated from a T-LAK cell, inhibiting the activity thereof and blocking a TOPK signal channel. Immunopathology indicates that TOPK, P38 and JNK in skin lesion of photodermatoses are increased in expression. In a cell experiment, the activity of TOPK affects phosphorylation of P38 and JNK induced by UV. Through a molecular docking experiment, paeonol can be directly combined with TOPK to inhibit activation of TOPK and inhibit phosphorylation of p38, JNK and H2AX and secretion of inflammatory factors IL-6 and TNF-alpha. An animal experiment also verifies a cell experimental result.

Description

technical field [0001] The invention belongs to the field of new pharmacological action of medicine and disease prevention and treatment. It specifically relates to paeonol (Paeonol) inhibiting the biological activity of T-LAK cell-derived protein kinase (TOPK), and the application of paeonol in preventing and / or treating inflammation and tumor by regulating the abnormal increase of TOPK activity, including ultraviolet (UV) Induced actinic dermatoses such as sunburn and chronic actinic dermatosis. Background technique [0002] Clinical epidemiological investigations have shown that long-term exposure of the human body to sunlight ultraviolet (SUV) can produce skin inflammation and skin tumors, which seriously threaten human health. Ultraviolet radiation in sunlight can be divided into three categories according to the wavelength, long-wave ultraviolet (UVA) with a wavelength of 315-400nm, medium-wave ultraviolet (UVB) with a wavelength of 280-315nm, and short-wave ultraviol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/12A61P29/00A61P17/06A61P37/00A61P35/00A61P17/16
CPCA61K31/12
Inventor 史飞
Owner 史飞
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