CN116445611A - Application of TRIM65 as target in screening medicines for preventing and treating atherosclerosis - Google Patents
Application of TRIM65 as target in screening medicines for preventing and treating atherosclerosis Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/136—Screening for pharmacological compounds
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses an application of TRIM65 as a target in screening medicines for preventing and treating atherosclerosis. The medicine acts on TRIM65 genes, and prevents and treats atherosclerosis by preventing the increase of the levels of serum inflammatory factors TNFalpha, IL-1 beta and IL-6, regulating and controlling JAK/STAT signal paths and PI3K-AKT/ERK1/2/NF- κB signal paths. According to the invention, the effect of TRIM65 in atherosclerosis occurrence and development is explored by using an atherosclerosis model mouse from which TRIM65 is knocked out for the first time; TRIM65 knockout is proposed to promote macrophage M1 type polarization by regulating JAK/STAT and PI3K-AKT/ERK1/2/NF- κB signaling pathways, thereby increasing inflammation and exacerbating the molecular mechanism of atherosclerosis development; the new effect of the novel compound in vascular diseases is revealed for the first time, and the novel compound is expected to become an effective target for preventing and treating atherosclerosis, so that theoretical basis and novel thinking are provided for development of atherosclerosis related medicines.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an application of TRIM65 serving as a target spot in screening medicines for preventing and treating atherosclerosis.
Background
At present, the death rate of cardiovascular diseases is still the first cause of the total death of urban and rural residents in China, the rural area is 46.66%, the city is 43.81%, and the continuous rising stage is realized. The current estimated national cardiovascular disease patients are 3.30 hundred million, which is higher than that of tumors and other diseases; the world health organization also predicts that by 2030 about 2.36 million people worldwide will die from cardiovascular related diseases. Cardiovascular disease has become a major public health problem, being the first killer of human health.
Atherosclerosis (AS) is a vascular chronic inflammatory disease driven by abnormal lipid metabolism, and is an important pathological basis for cardiovascular disease. At present, the first line means for clinically treating patients with cardiovascular diseases still uses statin lipid-lowering drugs to lower LDL-C (low density lipoprotein cholesterol), but epidemiological researches show that the therapeutic effect of the statin drugs to treat cardiovascular diseases by lowering the LDL-C level is less than 50%. Although non-statin drugs such as the siRNA drugs Inclisiran and PCSK9 monoclonal antibody Evolocumab, alirocuma targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) also play an important role in clinical treatment, cardiovascular mortality of chinese residents remains high and shows a trend of increasing year by year. Therefore, the research of new therapeutic targets and the elucidation of the molecular mechanisms affecting the development of atherosclerosis will provide theoretical and experimental basis for the development of new drugs for resisting atherosclerosis clinically.
TRIM65 is one of the important members of the TRIM (tripartite motif-containing protein) family, and has E3 ubiquitin ligase activity. It was found that TIRM65 plays an important regulatory role in carcinogenesis, innate immunity, inflammatory response, etc., but its role in atherosclerosis has not been studied at present. Thus, in the present invention, a model of atherosclerosis will be constructed by high fat diet induction using systemic TRIM65 knockout mice to explore the role of TRIM65 in atherosclerosis, while elucidating the molecular mechanisms that are responsible for atherosclerosis from the perspective of TRIM 65-mediated macrophage M1/M2-type regulation inflammation. The invention reveals the new function of TRIM65 in cardiovascular diseases, and provides new thought and theoretical basis for clinical prevention and treatment of atherosclerosis diseases and selection of related drug research and development molecular targets.
Disclosure of Invention
Aiming at the defects and the problems in the prior art, the invention aims to provide the application of TRIM65 serving as a target spot in screening medicines for preventing and treating atherosclerosis.
The invention is realized by the following technical scheme:
the TRIM65 is used as a target spot in screening medicines for preventing and treating atherosclerosis.
Preferably, the medicament acts on TRIM65 gene to prevent the increase of the levels of serum inflammatory factors TNFa, IL-1 beta and IL-6, and inhibits the occurrence of inflammation to prevent atherosclerosis.
Preferably, the medicament acts on TRIM65 gene, inhibits polarization of macrophages to M1 type by regulating JAK/STAT signal pathway, and further prevents and treats atherosclerosis.
Preferably the agent acts on the TRIM65 gene while preventing the signal pathway from mediating macrophage to M1 type polarization by modulating the PI3K-AKT/ERK1/2/NF- κB signal pathway, thereby preventing and treating atherosclerosis.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the invention, an atherosclerosis model prepared by using a systemic TRIM65 knockout mouse is utilized for the first time, and the role of TRIM65 in atherosclerosis is systematically explored by adopting various research means;
2. the invention proposes a molecular mechanism of TRIM65 for improving atherosclerosis by influencing inflammatory reaction process;
3. the invention discloses a novel function of TRIM65 in cardiovascular diseases, and provides theoretical basis and novel thought for clinical prevention and treatment of atherosclerosis and selection of related drug research and development molecular targets.
Drawings
FIG. 1 shows the role and mechanism of TRIM65 as a target in preventing and treating atherosclerosis.
FIG. 2 is a graph showing the change in TRIM65 expression level with the development of atherosclerosis in the aorta of the mice according to the invention.
FIG. 3 is a graph showing the effect of the TRIM65 gene knockout on damage to the aorta and aortic root of mice in accordance with the invention.
FIG. 4 is a graph showing the effect of TRIM65 gene knockout on the levels of inflammatory factors TNFα, IL-1β and IL-6 in mice.
FIG. 5 is a graph showing the effect of TRIM65 gene knockout on macrophage polarization in mice in accordance with the present invention.
FIG. 6 is a graph showing the change of JAK/STAT signal pathway regulated by the TRIM65 gene knocked out according to the invention.
FIG. 7 is a graph showing the change of the signal path of the knocked-out TRIM65 gene regulated PI3K-AKT/ERK1/2/NF- κB.
Detailed Description
The invention will be further described with reference to the accompanying drawings.
As shown in figure 1, the invention takes mice as a target to establish the action and mechanism of TRIM65 as a target in preventing and treating atherosclerosis.
Analysis of changes in expression of trim65 in the progression of atherosclerosis:
systemic ApoE gene knockout (ApoE) -/- ) Mice were fed high fat diet for 0, 8, 16 weeks, the aorta of the mice was isolated, and the expression change of TRIM65 in the aorta was detected by Western Blot and qRT-PCR methods.
As can be seen from FIG. 2, high fat diet induced ApoE -/- Following mice, as atherosclerosis progresses, the levels of protein and mRNA expression of TRIM65 in the mouse aorta decrease, suggesting that TRIM65 may play a role in atherosclerosis.
Preparation of TRIM65 knockout mouse atherosclerosis model and phenotypic analysis:
systemic TRIM65 Gene knockout (TRIM 65) -/- ) Mice and ApoE -/- The mice are hybridized to obtain ApoE and TRIM65 double gene knockoutMouse (ApoE) -/- TRIM65 -/- I.e., the experimental mice of this example). With 8 weeks of age ApoE -/- Mice (control group) and ApoE -/- TRIM65 -/- After 13 weeks of feeding the mice (experimental group) with high fat diet, the aorta and aortic root of the mice were isolated, stained by oil red O and H&E, detecting the damage condition of the aorta by dyeing, and detecting the plaque stability by using sirius red dyeing; at the same time, the serum of the mouse is separated to detect inflammatory factors, and the abdominal cavity macrophages and bone marrow derived macrophages are separated.
As can be seen from fig. 3A-D, knocking out TRIM65 gene significantly increased the high fat diet induced damage of the whole aorta and aortic root in mice compared to control mice; as can be seen from fig. 3E-H, knocking out TRIM65 gene significantly reduced plaque stability compared to control mice. The results indicate that TRIM65 deficiency promotes the development of atherosclerosis while reducing plaque stability.
3. Mechanism study of the promotion of atherosclerosis progression by knocking out TRIM65 Gene:
atherosclerosis is a chronic inflammatory disease, so we first examined the effect of TRIM65 knockout on inflammation. Detecting the content of inflammatory factors (TNF alpha, IL-1 beta and IL-6) in the serum of two groups of mice by an Elisa technology, and as shown in figure 4, knocking out TRIM65 gene obviously increases the levels of the inflammatory factors TNF alpha, IL-1 beta and IL-6 in the serum of the mice induced by high-fat diet; macrophage polarization plays an important role in regulating inflammation, and researches show that M1 type promotes inflammation and M2 type has anti-inflammatory effect, so that the expression level of M1 type markers (TNFa, IL-1 beta and IL-6) and M2 type markers (IL-10, CD206 and Arg-1) in peritoneal macrophages isolated by two groups of mice is further detected by qRT-PCR technology; as shown in fig. 5, knocking out TRIM65 gene significantly promoted polarization of macrophages to M1 type.
Further to explore the molecular mechanism of TRIM65 knockout to regulate macrophage M1 type polarization, we examined the effects of the TRIM65 knockout gene on the relevant signaling pathways (JAK/STAT and PI3K-AKT/MAPK/NF- κB) regulating macrophage M1/M2 type polarization at the animal and cellular levels, respectively. As shown in fig. 6, knocking out TRIM65 gene can activate JAK1/STAT1 signal pathway, mediate M1 type polarization of macrophages, and inhibit JAK2/STAT6 signal pathway to reduce M2 type polarization of macrophages, thereby promoting inflammation and further exacerbating atherosclerosis development; as shown in FIG. 7, the TRIM65 gene can be knocked out to regulate the PI3K-AKT/ERK1/2/NF- κB signal pathway to promote the polarization of macrophages to M1 type to promote the occurrence of inflammation and further exacerbate the development of atherosclerosis
By combining various research mechanisms and experimental analysis of the invention, TRIM65 can be used as a therapeutic target of atherosclerosis.
The foregoing description of the preferred embodiments of the present invention has been presented only in terms of those specific and detailed descriptions, and is not, therefore, to be construed as limiting the scope of the invention. It should be noted that modifications, improvements and substitutions can be made by those skilled in the art without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (7)
- Application of TRIM65 as target in screening medicines for preventing and treating atherosclerosis.
- 2. The use according to claim 1, characterized in that: the medicine acts on TRIM65 gene to prevent the increase of the levels of serum inflammatory factors TNFα, IL-1 beta and IL-6.
- 3. The use according to claim 2, characterized in that: the medicine can prevent increase of serum inflammatory factor, and prevent and treat atherosclerosis.
- 4. The use according to claim 1, characterized in that: the medicine acts on TRIM65 gene, and can prevent and treat atherosclerosis by regulating JAK/STAT signal pathway.
- 5. The use according to claim 4, characterized in that: the drugs inhibit JAK1/STAT1 signaling pathway mediated inhibition of macrophage polarization to M1 type, activate JAK2/STAT6 signaling pathway increase macrophage polarization to M2 type.
- 6. The use according to claim 1, characterized in that: the medicine acts on TRIM65 gene, and prevents and treats atherosclerosis by regulating and controlling PI3K-AKT/ERK1/2/NF- κB signal path.
- 7. The use according to claim 6, characterized in that: the medicine regulates and controls PI3K/AKT/ERK1/2/NF- κB signal path to inhibit macrophage from polarizing to M1 type.
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| CN202310562692.8A CN116445611A (en) | 2023-05-18 | 2023-05-18 | Application of TRIM65 as target in screening medicines for preventing and treating atherosclerosis |
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| CN202310562692.8A CN116445611A (en) | 2023-05-18 | 2023-05-18 | Application of TRIM65 as target in screening medicines for preventing and treating atherosclerosis |
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