CN111529533B - Application of bromodomain protein4 inhibitor JQ1 or derivative thereof in preparation of medicines for treating sepsis intestinal barrier injury - Google Patents
Application of bromodomain protein4 inhibitor JQ1 or derivative thereof in preparation of medicines for treating sepsis intestinal barrier injury Download PDFInfo
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- CN111529533B CN111529533B CN202010505852.1A CN202010505852A CN111529533B CN 111529533 B CN111529533 B CN 111529533B CN 202010505852 A CN202010505852 A CN 202010505852A CN 111529533 B CN111529533 B CN 111529533B
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Abstract
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.
Description
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:
example 1
The animals selected for this experiment were 8-week C57BL/6 male mice, weighing approximately 25 grams, purchased from lakekshirta, grant no: SCXK (Xiang) 2019-. The C57BL/6 male mice are randomly divided into a normal saline control group (5 mice), an LPS model group (10mg/kg, 5 mice) and a JQ1 administration group (50mg/kg, 5 mice), wherein each group of animals are respectively injected with normal saline or JQ1 drugs with corresponding dose in the abdominal cavity, 10mg/kg of LPS is injected in the abdominal cavity after 1 hour, the mice are anesthetized by using 4% chloral hydrate in the abdominal cavity after 24 hours (timing is started after the LPS injection is finished), and intestinal tissues are taken after the anesthesia is finished and are placed in 4% paraformaldehyde for fixing overnight for tissue HE staining.
And (3) carrying out HE staining on intestinal tissues:
(1) and dehydrating the fixed intestinal tissue by gradient alcohol, and embedding paraffin to prepare paraffin sections.
(2) After deparaffinizing the sections with xylene, the sections were hydrated in a gradient.
(3) Staining with hematoxylin for 5min, and differentiating with 1% hydrochloric acid alcohol for 5-10 s.
(4) After rinsing with tap water for 15min, eosin staining was performed for 2 min.
(5) After gradient alcohol dehydration, xylene soaking for 2min, neutral resin mounting, and taking a picture under a microscope.
The experimental results are shown in fig. 1 and fig. 2.
The experimental results show that: JQ1 serving as a BRD4 inhibitor can obviously inhibit LPS-induced damage to the mucous layers of the small intestine and the colon of a septic mouse.
Example 2
The source of the experimental animals, the feeding conditions and the administration process were as described in example 1. After anesthetizing the mice, the intestinal tissue was taken and stored at-80 ℃ for fluorescent quantitative PCR detection.
Fluorescence quantitative PCR step of intestinal tissues:
(1) RNA extraction and reverse transcription: homogenizing tissue with 1ml Trizol lysate, adding 200 μ l chloroform, mixing well, standing for 5 min; centrifuging at 4 deg.C and 12000g for 15min, transferring upper water phase, adding isopropanol of the same volume, and mixing; centrifuging at 12000g for 10min at 4 ℃; discarding the supernatant, and adding 1ml of 75% ethanol; centrifuging at 4 deg.C for 5min at 7500g, and removing supernatant; after being dried, 20 mul of enzyme-removed water is added for dissolving; RNA was reverse transcribed into cDNA according to the instructions of the reverse transcription kit (Thermo, cat # K1621).
(2) RT-PCR: 10 μ l reaction: 5. mu.l of TB reaction solution, 0.2. mu.l of ROX dye and 0.4. mu.l of each of the upstream and downstream primers (10. mu.M); 1 μ l of cDNA; 3. mu.l of enzyme-removed water.
Step 1: 95 ℃ for 5min
Step 2: 95 ℃ for 15 s; 60 ℃ for 15 s; 72 ℃, 45s, 40 cycles
And step 3: GAPDH as reference gene by 2-ΔΔCT calculates the relative expression of the target gene.
The Q-PCR primers and sequences used are shown in Table 1:
TABLE 1
The results are shown in tables 2 to 4. Table 2 shows the effect of BRD4 inhibitor JQ1 on the expression level of inflammatory factor gene in intestinal tissue of septic mice; table 3 shows the effect of BRD4 inhibitor JQ1 on the expression level of inflammatory complex corpuscle gene NLRP3 in intestinal tissue of septic mice; table 4 shows the effect of BRD4 inhibitor JQ1 on the expression level of apoptosis marker genes in intestinal tissue of septic mice.
TABLE 2 influence of JQ1 on the expression level of inflammatory factor genes in intestinal tissue of septic mice
| Inflammatory factors | TNFα | IL1β | IL18 |
| NS group | 1.0±0.235 | 1.0±0.161 | 1.0±0.197 |
| LPS group | 9.0±3.241* | 6.1±1.461** | 1.9±0.209** |
| LPS + JQ1 group | 0.6±0.098# | 0.3±0.090## | 0.4±0.115### |
| F | 7.13 | 11.35 | 19.13 |
| P | 0.008 | 0.0014 | 0.0001 |
*P﹤0.05，**P < 0.01vs NS group;#P﹤0.05，##P﹤0.01，###p < 0.001vs LPS group. Statistical analysis was performed using One-wayANOVA method.
TABLE 3 Effect of JQ1 on the expression level of inflammatory complex corpuscle Gene of sepsis mouse intestinal tissue NLRP3
| Small body of inflammation | NLRP3 | Caspase1 | ASC |
| NS group | 1.0±0.309 | 1.0±0.167 | 1.0±0.081 |
| LPS group | 3.0±0.550* | 1.6±0.178* | 1.4±0.127* |
| LPS + JQ1 group | 0.7±0.239## | 0.3±0.100### | 0.2±0.030### |
| F | 9.926 | 20.81 | 55.07 |
| P | 0.0021 | 0.0003 | ﹤0.0001 |
*P < 0.05vs NS group;##P﹤0.01，###p < 0.001vs LPS group. Statistical analysis was performed using One-way ANOVA.
TABLE 4 Effect of JQ1 on the expression level of gut tissue apoptosis marker genes in septic mice
*P﹤0.05，**P < 0.01vsNS group;##P﹤0.01，###p < 0.001vs LPS group. Statistical analysis was performed using One-way ANOVA.
The experimental results show that: JQ1, a BRD4 inhibitor, can effectively release inflammatory factors TNF alpha, IL1 beta, IL18 and NLRP3 inflammatory complex bodies of intestinal tissues of septic mice induced by LPS; JQ1 can obviously inhibit LPS-induced high expression phenomena of cell apoptosis marker genes GSDMD, GSDME, P2X7 and Aim2 in intestinal tissues of sepsis mice.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
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Claims (4)
- Use of an inhibitor JQ1 of BRD4 in the manufacture of a medicament for the prevention and/or treatment of sepsis intestinal barrier injury;the sepsis intestinal barrier injury is sepsis intestinal barrier injury induced by LPS;JQ1 has repairing effect on LPS-induced sepsis intestinal mucosa injury;JQ1 inhibits intestinal histiocyte apoptosis;JQ1 inhibits LPS-induced release of inflammatory factors TNF alpha, IL1 beta and/or IL18 from septic intestinal tissue;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;JQ1 inhibited LPS-induced high expression of cell apoptosis marker genes GSDMD, GSDME, P2X7 and/or Aim2 in sepsis intestinal tissue.
- 2. The use of claim 1, wherein the medicament comprises an effective amount of JQ1 and a pharmaceutically acceptable excipient.
- 3. The use of claim 2, wherein the medicament is an injectable formulation.
- 4. The use of claim 3, wherein the infusion of the injectable formulation is intraperitoneal.
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| CN104311562A (en) * | 2010-05-14 | 2015-01-28 | 达那-法伯癌症研究所 | Compositions and methods for treating neoplasia, inflammatory disease and other disorders |
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| WO2014202578A1 (en) * | 2013-06-17 | 2014-12-24 | Bayer Pharma Aktiengesellschaft | Substituted phenyl-2,3-benzodiazepines |
| US9505780B2 (en) * | 2014-05-05 | 2016-11-29 | Signalrx Pharmaceuticals, Inc. | Thienopyranones as kinase and epigenetic inhibitors |
| CN109568324A (en) * | 2018-12-25 | 2019-04-05 | 南华大学 | A kind of JQ1 or derivatives thereof is preparing the application in analgesic |
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| WO2009073300A1 (en) * | 2007-11-02 | 2009-06-11 | Vertex Pharmaceuticals Incorporated | [1h- pyrazolo [3, 4-b] pyridine-4-yl] -phenyle or -pyridin-2-yle derivatives as protein kinase c-theta |
| CN104311562A (en) * | 2010-05-14 | 2015-01-28 | 达那-法伯癌症研究所 | Compositions and methods for treating neoplasia, inflammatory disease and other disorders |
Non-Patent Citations (3)
| Title |
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| BET Protein Function Is Required for Inflammation: Brd2 Genetic Disruption and BET Inhibitor JQ1 Impair Mouse Macrophage Inflammatory Responses;Belkina, AC et al.;《The Journal of Immunology》;20130401;第190卷(第7期);第3670页摘要，第3677页最后一段 * |
| Dual transcriptome sequencing reveals resistance of TLR4 ligand-activated bone marrow-derived macrophages to inflammation mediated by the BET inhibitor JQ1;Amitabh Das et al.;《Scientific Reports》;20151119;第5卷;第1-14页 * |
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