阅读说明：本技术 溴结构域蛋白4抑制剂jq1或其衍生物在制备治疗脓毒症肠屏障损伤药物中的应用 (Application of bromodomain protein4 inhibitor JQ1 or derivative thereof in preparation of medicines for treating sepsis intestinal barrier injury ) 是由 陈玲 李威 钟小林 杨惠 曹文宇 徐杨 毛明莉 李梦琳 时萌萌 张圆 于 2020-06-05 设计创作，主要内容包括：本发明涉及医药技术领域,特别涉及溴结构域蛋白4(BRD4)抑制剂JQ1或其衍生物在制备治疗脓毒症肠屏障损伤药物中的应用。实验表明,在细菌脂多糖(LPS)诱导的脓毒症小鼠肠屏障损伤模型中,BRD4抑制剂JQ1可有效地抑制LPS诱导的脓毒症小鼠肠道黏膜层破损,炎症因子TNFα、IL1β和IL18的释放,NLRP3炎性复合小体的释放,以及细胞焦亡标志基因GSDMD、GSDME、P2X7及Aim2的高表达。结果显示,BRD4抑制剂JQ1可通过抑制肠道组织细胞焦亡,从而有效防止脓毒症小鼠肠屏障损伤,可用于制备治疗脓毒症肠屏障损伤的药物制剂。(The invention relates to the technical field of medicines, in particular to application of a bromodomain protein 4(BRD4) inhibitor JQ1 or a derivative thereof in preparing a medicine for treating sepsis intestinal barrier injury. Experiments show that in a sepsis mouse intestinal barrier injury model induced by bacterial Lipopolysaccharide (LPS), JQ1 serving as a BRD4 inhibitor can effectively inhibit LPS-induced damage of intestinal mucosa layers of sepsis mice, release of inflammatory factors TNF alpha, IL1 beta and IL18, release of NLRP3 inflammatory complex bodies and high expression of cell apoptosis marker genes GSDMD, GSDME, P2X7 and Aim 2. The results show that JQ1 serving as a BRD4 inhibitor can effectively prevent the intestinal barrier injury of mice with sepsis by inhibiting the scorching of intestinal tissue cells, and can be used for preparing a medicinal preparation for treating the intestinal barrier injury of sepsis.)

Use of an inhibitor of BRD4, JQ1, or a derivative thereof, in the manufacture of a medicament for the prevention and/or treatment of sepsis intestinal barrier injury.

2. The use of claim 1, wherein the sepsis intestinal barrier injury is LPS-induced sepsis intestinal barrier injury.

3. The use of claim 1 or 2, wherein JQ1 has a reparative effect on LPS-induced sepsis gut mucosal lesions.

4. The use according to any one of claims 1 to 3, wherein JQ1 inhibits apoptosis of intestinal tissue cells.

5. The use of any one of claims 1 to 4, wherein JQ1 inhibits LPS-induced release of inflammatory factors TNF α, IL1 β and/or IL18 from septic intestinal tissue.

6. The use according to any one of claims 1 to 5, wherein JQ1 inhibits LPS-induced release of inflammatory complex vesicles of sepsis intestinal tissue NLRP 3; the NLRP3 inflammatory complex corpuscle comprises one or more of NLRP3, Caspase1, or ASC.

7. The use according to any one of claims 1 to 6, wherein JQ1 inhibits LPS-induced high expression of the cell apoptosis marker genes GSDMD, GSDME, P2X7 and/or Aim2 in septic bowel tissue.

8. The use of any one of claims 1 to 7, wherein the medicament comprises an effective amount of JQ1 and a pharmaceutically acceptable excipient.

9. The use of claim 8, wherein the medicament is an injectable formulation.

10. The use of claim 9, wherein the infusion of the injectable formulation is intraperitoneal infusion.

Technical Field

The invention relates to the technical field of medicines, in particular to application of a bromodomain protein 4(BRD4) inhibitor JQ1 or a derivative thereof in preparing a medicine for treating sepsis intestinal barrier injury.

Background

Sepsis is a systemic inflammatory response syndrome caused by infection. Despite the great progress made by antibiotic therapy, surgery, etc., the morbidity and mortality of sepsis remains high. The gut serves as one of the earliest organs involved in the onset of sepsis, and its intestinal barrier damage plays an initiating role in the course of the sepsis outbreak. In severe sepsis, intestinal mucosa is damaged, permeability is increased, a large amount of bacteria and endotoxin enter blood and lymphatic circulation systems, and various inflammatory factors such as TNF alpha, IL1 and the like are activated and released, so that the function of multiple organs of the whole body is finally damaged. Therefore, how to effectively prevent the damage of the intestinal barrier becomes one of the important problems to be solved urgently in the research of sepsis.

Bromodomain-4 (BROMODOMAIN-CONTATING PROTEIN4, BRD4) is a key functional protein in bromodomain and super-terminal structure family, and mainly binds acetylated histone H3 and the like through two bromodomains of the bromodomain, recruits different transcription factors, regulates the expression of target genes, and further plays an important role in the regulation processes of inflammation, cell cycle, cell gene transcription and the like.

JQ1 is a specific BRD4 inhibitor with molecular weight of 456.99 and chemical formula C₂₃H₂₅ClN₄O₂S, CAS number 1268524-70-4, its structure is shown in formula I:

at present, no report is found about the application of JQ1 in the treatment of sepsis intestinal barrier injury.

Disclosure of Invention

In view of the above, the invention provides an application of a BRD4 inhibitor JQ1 or a derivative thereof in preparing a medicament for treating sepsis intestinal barrier injury. Experiments show that the BRD4 inhibitor JQ1 can effectively prevent the intestinal barrier injury of mice with sepsis by inhibiting the scorching of intestinal tissue cells, and can be used for treating the intestinal barrier injury induced by inflammatory factors in sepsis.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides application of an inhibitor JQ1 of BRD4 or a derivative thereof in preparing a medicament for preventing and/or treating sepsis intestinal barrier injury.

In some embodiments of the invention, the sepsis intestinal barrier injury is LPS-induced sepsis intestinal barrier injury.

In some embodiments of the invention, JQ1 has a repairing effect on LPS-induced sepsis intestinal mucosal lesions.

In some embodiments of the invention, JQ1 inhibits intestinal tissue cell apoptosis.

In some embodiments of the invention, JQ1 inhibits LPS-induced release of inflammatory factors TNF α, IL1 β and/or IL18 from septic intestinal tissue.

In some embodiments of the invention, JQ1 inhibits LPS-induced release of sepsis intestinal tissue NLRP3 inflammatory complex bodies; the NLRP3 inflammatory complex corpuscle comprises one or more of NLRP3, Caspase1, or ASC.

In some embodiments of the invention, JQ1 inhibits LPS-induced high expression of cell apoptosis marker genes GSDMD, GSDME, P2X7 and/or Aim2 in sepsis intestinal tissue.

In some embodiments of the invention, the medicament comprises an effective amount of JQ1 and a pharmaceutically acceptable excipient.

In some embodiments of the invention, the medicament is an injectable formulation.

In some embodiments of the invention, the infusion mode of the injection formulation is intraperitoneal infusion.

In conclusion, the invention provides application of a BRD4 inhibitor JQ1 or a derivative thereof in preparing a medicament for treating sepsis intestinal barrier injury. The invention has the technical effects that: according to the invention, the influence of a BRD4 inhibitor JQ1 on LPS-induced sepsis mouse intestinal barrier injury is observed, and JQ1 is found to have an obvious intestinal mucosa protection effect and effectively inhibit the release of inflammatory factors TNF alpha, IL1 beta, IL18 and NLRP3 inflammatory complex corpuscles and the high expression phenomena of cell apoptosis marker genes GSDMD, GSDME, P2X7 and Aim 2.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.

FIG. 1 shows HE staining showing the effect of the BRD4 inhibitor JQ1 on the intestinal mucosa layer of sepsis mice;

FIG. 2 shows HE staining showing the effect of the BRD4 inhibitor JQ1 on colonic mucosa in septic mice.

Detailed Description

The invention discloses application of a bromodomain protein4 inhibitor JQ1 or a derivative thereof in preparing a medicament for treating sepsis intestinal barrier injury, which can be realized by appropriately modifying process parameters by the skilled person with reference to the content in the specification. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

The invention provides application of a BRD4 inhibitor JQ1 or a derivative thereof in preparing a medicament for treating sepsis intestinal barrier injury.

In the invention, the NLRP3 inflammatory complex corpuscle is one or more of NLRP3, Caspase1 and ASC.

Preferably, the medicament also comprises pharmaceutically acceptable auxiliary materials.

Preferably, the dosage form of the medicament for treating the sepsis intestinal barrier injury is an injection administration dosage form.

Preferably, the injection administration dosage form is injection or powder injection.

In a particular embodiment of the invention, the infusion mode of the injectable dosage form is intraperitoneal.

Preferably, the dosage form of the medicament for treating the sepsis intestinal barrier injury is a gastrointestinal administration dosage form.

The invention provides application of a BRD4 inhibitor JQ1 or a derivative thereof in preparing a medicament for treating sepsis intestinal barrier injury. The invention has the technical effects that: according to the invention, the influence of a BRD4 inhibitor JQ1 on LPS-induced sepsis mouse intestinal barrier injury is observed, and JQ1 is found to have an obvious intestinal mucosa protection effect and effectively inhibit the release of inflammatory factors TNF alpha, IL1 beta, IL18 and NLRP3 inflammatory complex corpuscles and the high expression phenomena of cell apoptosis marker genes GSDMD, GSDME, P2X7 and Aim 2.

Reagents or instruments for the application of the bromodomain protein4 inhibitor JQ1 or the derivatives thereof in preparing the medicine for treating the sepsis intestinal barrier injury are all commercially available.

The invention is further illustrated by the following examples: