CN117338785A - Application of GSK-126 in preparation of hypolipidemic drugs - Google Patents
Application of GSK-126 in preparation of hypolipidemic drugs Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of GSK-126 in preparing hypolipidemic drugs. The GSK-126 has remarkable hypolipidemic effect, and can effectively reduce the weight of rodents; can effectively reduce the total cholesterol TC and the low-density lipoprotein cholesterol LDL-c level of rats; GSK-126 can effectively promote the expression of lipid peroxidation related genes, and can be prepared into safe and effective hypolipidemic drugs.
Description
Technical Field
The invention belongs to the technical field of drug development and application, and particularly relates to application of GSK-126 in preparation of a hypolipidemic drug.
Background
Unhealthy eating habits and lifestyle often lead to the occurrence of hyperlipidemia. Hyperlipidemia refers to a systemic blood lipid metabolism disorder in which the levels of components such as cholesterol (TC), triglycerides (TG), and low density lipoproteins (LDL-C) in the blood are elevated, with or without a concomitant decrease in the levels of high density lipoproteins (HDL-C). The accumulation of a large amount of lipids such as cholesterol and triglycerides in the body is not only a major cause of obesity, but also causes diseases such as hypertension, nonalcoholic fatty liver, myocardial infarction, arteriosclerosis and cerebral apoplexy in severe cases.
Currently, the blood lipid lowering drugs commonly used in clinic include statin drugs, ezetimibe, probucol and the like. The lipid-lowering drugs can lower blood lipid by interfering synthesis or absorption of cholesterol by the organism. Although the lipid components such as cholesterol and triglyceride in serum can be effectively reduced by taking the hypolipidemic drug for a long time, the side effect is obvious. If statin drugs are at risk of causing cardiovascular and cerebrovascular diseases, ezetimibe and plaucol are prone to cause gastrointestinal discomfort. Therefore, the development of novel lipid-lowering drugs has been a clinical medical research hotspot problem.
Disclosure of Invention
To overcome the disadvantages and shortcomings of the prior art, the invention aims to provide an application of GSK-126 in preparing hypolipidemic drugs.
The present invention is implemented by the use of GSK-126 in at least one of the following situations:
(1) The application in preparing hypolipidemic drugs;
(2) Use of a compound for the preparation of a medicament for enhancing the peroxidation capacity of mitochondrial lipids in cells and/or for inhibiting the level of active oxygen in cells.
Preferably, the GSK-126 is used for preparing medicines for reducing lipid by improving the peroxidation capacity of cell mitochondrial lipid.
Preferably, the medicament is a pharmaceutical composition of GSK-126 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
Preferably, the drug is modified by a carrier, and the carrier is one or more of microspheres, liposome, microemulsion, high molecular surfactant, nano particles and implant.
Preferably, the pharmaceutical dosage form is a capsule, tablet, powder, oral liquid, pill, tincture, syrup or injection.
The invention overcomes the defects of the prior art and provides an application of GSK-126 in preparing hypolipidemic drugs. GSK-126 has a molecular formula of C 31 H 38 N 6 O 2 The structural formula is as follows:
GSK-126 is a specific activity inhibitor of histone methyltransferase EZH2, whereas EZH2 is a specific methyltransferase of histone H3K27me 3. EZH2 is a therapeutic target of various diseases such as tumor, nervous system diseases and the like, and no report of adverse reaction of organisms after GSK-126 or EZH2 activity inhibition is currently seen. The invention provides GSK-126 which plays a role in reducing lipid by improving the lipid peroxidation capacity of cell mitochondria, and has good application prospect.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects: GSK-126 has remarkable hypolipidemic effect, and can effectively reduce the weight of rodents; can effectively reduce the TC and LDL-c levels of rats; GSK-126 can effectively promote the expression of lipid peroxidation related genes, and can be prepared into safe and effective hypolipidemic drugs.
Drawings
Fig. 1 is a graph showing the results of analysis of rat body weight by rat lateral ventricle injection GSK126, data expressed as mean ± standard deviation, p <0.001, p <0.01, p <0.05.
Fig. 2 is a graph showing the results of analysis of rat abdominal circumference before and after 1267 days of GSK injection into rat lateral ventricle, the data are expressed as mean ± standard deviation, p <0.001, p <0.01, p <0.05.
Fig. 3 is a graph showing the results of analysis of blood lipid levels in rat serum by seven consecutive days of rat lateral ventricular injection GSK126, data expressed as mean ± standard deviation, p <0.001, p <0.01, p <0.05.
FIG. 4 is a graphical representation of the results of the rat brain tissue ChIP-seq.
Fig. 5 is a schematic diagram of the results of PCR validation of genes associated with steroid negative regulated signaling pathways, data expressed as mean ± standard deviation, p <0.001, p <0.01, p <0.05.
FIG. 6 is a schematic representation of reactive oxygen species ROS results.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
1. Experimental materials
14 SD male rats with uniform body weight.
2. Principle of experiment
The weight measurement was performed daily by administering GSK-126 to the ventricles of rats, measuring the abdominal circumference, and observing the lipid-lowering effect of the drug.
It should be noted that, in this case, the application of GSK-126 in preparing lipid-lowering drugs indicates a series of lipid-lowering effects of GSK-126 on rat body weight, blood lipid and lipid peroxidation by lateral ventricle injection, but the lipid-lowering effects of GSK-126 are not dependent on lateral ventricle administration, and other administration modes (lateral ventricle, oral administration, etc.) also have equivalent efficacy.
3. Experimental method
3.1 grouping of animals
Random grouping: 21 SD male rats were randomly divided into 3 groups, namely a control group and a GSK-126 group.
3.2 administration and modeling period
GSK-126 rats of group 200mg/kg of GSK-126 were administered once daily by side ventricle injection, and rats of control group were administered with the same volume of blank solvent once daily by side ventricle injection. Daily body weight monitoring the body weight change of each group of rats was observed. Seven days of continuous injection.
3.3 main detection index
Rat body weight, abdominal circumference.
4. Experimental data and statistics
The experimental data are represented by mean value +/-standard error, and the comparison between the two groups adopts T test; p <0.05 indicates a significant difference. The experimental results were all counted using Graphpad Prism 5.0.
5. Experimental results
The results of body weight measurements for the two groups of rats are shown in FIG. 1, and the body weight of the GSK-126 group of mice is significantly reduced (p <0.05 vs control group) 7 days after GSK-126 treatment of the mice.
The results of the abdominal circumference detection of the two groups of rats are shown in fig. 2, and after 7 days of GSK-126 treatment, the abdominal circumference of the GSK-126 group of mice is significantly reduced (p <0.05 vs control group).
Example 2
1. Experimental materials
Each group of rat serum in example 1.
2. Principle of testing
2.1, total Cholesterol (TC) detection kit/(o-phthalaldehyde colorimetric method, purchased from Nanjing build) detection principle is that cholesterol and lipid thereof react with o-phthalaldehyde in the presence of strong acid to generate a mauve compound, the compound has a maximum absorption peak at 550nm wavelength, a spectrophotometer performs colorimetric determination at 550nm, and the cholesterol content has a good linear relation with absorbance within 4 mg/ml.
2.2, triglyceride (TG) detection kit (GPO-PAP) method, purchased from Nanjing build) detection principle is that triglyceride reacts with water under the action of lipase to generate glycerol and fatty acid, the generated glycerol reacts with ATP to generate glycerol-3-phosphoric acid and ADP under the action of glycerol kinase, the glycerol-3-phosphoric acid reacts with hydroxyacetone phosphate and hydrogen peroxide under the action of 3-phosphoglycerate oxidase, hydrogen peroxide, 4-AAP and parachlorophenol react with peroxidase to generate red quinoid, the color depth of the generated compound is proportional to the content of triglyceride, absorbance values of a standard tube and a sample tube are respectively measured, and the content of triglyceride in a sample can be calculated.
2.3, high Density lipoprotein cholesterol (HDL-c, purchased from Nanjing) detection kit detection principle is that after low density and very low density lipoprotein cholesterol in serum is inhibited by polyanion, the rest high density lipoprotein cholesterol reacts with 4-AA (4-aminoantipyrine), CHE (cholesterol esterase), CHO (cholesterol oxidase), POD (peroxidase) and TOPS (3-ethyl-N- (3-sulfopropyl) -3-methylpropylamine) to generate colored chelate. The color of the chelate is positively correlated with the content of high density lipoprotein cholesterol in serum, and the absorbance value is measured at 546nm wavelength to calculate the content.
2.4, the detection principle of the low-density lipoprotein cholesterol (LDL-c, purchased from Nanjing build) detection kit is that after the low-density lipoprotein cholesterol in serum is coated by polyanion, the residual very low-density high-density lipoprotein cholesterol reacts with 4-aminoantipyrine, cholesterol esterase, cholesterol oxidase and peroxidase to generate colorless water. After the surfactant is added, the encapsulated low density lipoprotein cholesterol is reopened. The opened low density lipoprotein cholesterol reacts with 4-aminoantipyrine, cholesterol esterase, cholesterol oxidase, peroxidase), 3-ethyl-N- (3-sulfopropyl) -3-methylpropylamine to produce a colored chelate. The color of the chelate is positively correlated with the content of low density lipoprotein cholesterol in serum, and the absorbance value is measured at 546nm wavelength to calculate the content.
3. Experimental method
The abdominal aorta of each group of rats was collected for blood, centrifuged (3000 r,20 min), and the supernatant was collected and tested using TC, TG, LDL-c and HDL-c kits. After the serum was treated according to the instructions, the absorbance was measured by an enzyme-labeled instrument, and the contents of TC, TG, LDL-c and HDL-c in the serum were calculated according to the formula, and the results were expressed in mmol/L.
4. Experimental data and results
4.1 data processing
The absorbance values measured using an enzyme-labeled instrument were used to calculate the amounts of TC, TG, LDL-c and HDL-c according to the kit instructions. The experimental data are represented by mean value + -standard error, the comparison among multiple groups is counted by using an One-wayANOVA method, and the comparison among the two groups is tested by using T; p <0.05 indicates a significant difference. The experimental results were all counted using Graphpad Prism 5.0.
4.2 experimental results
As shown in fig. 3, the change of blood lipid levels in serum is calculated according to the instruction of the kit, and compared with the control group, the levels of TC and LDL-c in the GSK-126 group rats are significantly reduced, the levels of TC (p < 0.05) and LDL-c (p < 0.01) in serum are significantly reduced after 200mg/kg of GSK126 is administered, and TG and HDL-c levels are not significantly changed.
Example 3
1. Experimental materials
Each group in example 1 had rat brain tissue.
2. Principle of testing
Chromatin co-immunoprecipitation technology in combination with second generation gene sequencing (Chromatin Immunoprecipitation sequencing, chIP-seq) is a well-established research method for studying protein-DNA interactions in vivo, the principle of which is: firstly, specifically enriching the DNA fragment combined with H3K27me3 by a chromatin co-immunoprecipitation (ChIP), and purifying and constructing a library; the enriched DNA fragments are then subjected to high throughput sequencing. GSK-126 is a well known inhibitor of histone methylase EZH2, whose use in brain tissue causes a decrease in the level of histone H3K27me3 methylation in brain cells. The level of enrichment of H3K27me3 on a segment of DNA marks the level of regulation of the expression of the DNA. The higher the level of H3K27me3 enrichment, the lower the level of gene expression; conversely, the lower the level of enrichment of H3K27me3, the higher the level of gene expression will be.
3. Experimental method
3.1, tissue preparation
After the rats are obtained from each group, the tissue of the same cerebral cortex part is cut into 1-3mm 3 The long pieces were transferred to 50ml tubes and 10ml PBS was added. Adding 1% formaldehyde to crosslink with chromatin, separating genomic DNA from tissue lysate, breaking DNA into small fragments with a certain length by ultrasound, adding 1ug H3K27me3 (purchased from abcam) antibody, and performing immunoprecipitation. And (3) after the cross-linking is removed, purifying DNA to obtain a DNA sample of chromatin immunoprecipitation, and carrying out DNA sequencing.
3.2 main detection index
GSK-126 was observed to inhibit the level of enrichment of H3K27me3 on DNA fragments before and after brain cells H3K27me 3.
4. Experimental results
As shown in FIG. 4, the ChIP-seq data suggested that GSK-126 inhibited brain H3K27me3 levels, and that H3K27me3 was enriched at gene DNA fragments that were predominantly in intracellular steroid negative regulation (negative regulation ofintracellular steroid hormone receptor signaling pathway) and other biological functions. It was suggested that H3K27me3 could no longer exert or attenuate the inhibition of intracellular levels of gene expression that degrade steroid function after the level of H3K27me3 methylation was inhibited by GSK-126. The level of expression of the above genes may increase and promote the ability of the intracellular steroid to degrade.
Example 4
1. Experimental materials
Each group of rat brain tissue in example 1
2. Principle of testing
By detecting the fluorescent signal intensity during PCR amplification, the relative initial number of target sequences can be determined. The abundance of a target sequence is typically measured by calculating the Ct value (the number of cycles that the fluorescence signal reaches a threshold). By constructing a standard curve or using the delta Ct method, the relative abundance of a target sequence in a sample to be measured can be compared to a reference gene or control.
3. Experimental method
3.1, tissue preparation
After the rats in each group were obtained, the same brain cortex tissue was cut into 1cm 3 Is a small block of (a). The cerebral cortex was placed in a homogenate mill, 1ml of trizol was added to homogenate and the tissue was broken, total RNA was extracted using chloroform extraction, and reverse transcription was performed using the hifscript cDNA (century well) synthesis kit. The primers used to amplify the cDNA are listed in Table 1. The cDNA was mixed with SYBR Green MasterMix (Nanjinopran) and synthetic primers for real-time quantitative PCR. And is carried out according to the following conditions: 5 minutes at 95 ℃; 10 seconds at 95 ℃, 30 seconds at 60 ℃;40 cycles at 95℃for 15 seconds, 60℃for 60 seconds, and 95℃for 15 seconds. Relative mRNA expression levels were quantified by normalization to the expression of the internal reference β -actin.
3.2 main detection index
The mRNA expression level of the steroid negative regulation related gene in brain cells was observed before and after GSK-126 inhibits brain cells H3K27me 3.
4. Experimental results
The results are shown in FIG. 5. Compared to the control group, mRNA levels of the steroid negative regulation-related genes (TP 63, phb2, FOXP 1) were significantly elevated after GSK126 inhibited rat brain H3K27me3 levels. TP63, phb, FOXP1 are all mitochondrial membrane proteins and are involved in the process of mitochondrial lipid peroxidation. The above results not only verify the ChIP-seq results of example 3, but also suggest that the lipid lowering effect of GSK-126 might be achieved by increasing the lipid peroxidation capacity of mitochondria.
Example 5
1. Experimental materials
Mouse hippocampal neuronal cell line (HT 22)
2. Principle of testing
To demonstrate that GSK-126 exerts lipid lowering effects by increasing mitochondrial lipid peroxidation, this example used Palmitic Acid (PA) to construct a lipid toxicity model in vitro. Lipotoxicity is a phenomenon in which Free Fatty Acid (FFA) increases due to lipid metabolism disorder, and when the storage capacity of adipose tissue and the oxidation capacity of each tissue to the free fatty acid are exceeded, more free fatty acid is converted into triglyceride which is excessively deposited in non-adipose tissue, resulting in damage to the tissue. The palmitic acid model is a commonly used test method for constructing a lipotoxic cell model in vitro. After palmitic acid modeling, lipid accumulation causes impaired lipid peroxidation in cells, and intracellular Reactive Oxygen Species (ROS) accumulate in large quantities. By detecting intracellular Reactive Oxygen Species (ROS) levels, it is possible to characterize whether the lipid peroxidation capacity of a cell is impaired.
3. Experimental method
3.1, passage of cells and drug addition
Cell level experiments were performed using the mouse hippocampal neuronal cell line (HT 22), medium was discarded and 1mL of PBS was added, medium and cell metabolites were washed clean, liquid was blotted off, 1mL of pancreatin was added to the incubator for 3 minutes, then cells were taken out and observed under a microscope, cells were found to be completely digested, 1mL of DMEM complete medium was added to the cells to terminate digestion, cells were blown down into the medium with a bus tube, medium was aspirated into a centrifuge tube, centrifugation was performed for 5 minutes at 1000 rpm, excess liquid in the centrifuge tube was discarded, medium was blown down evenly, and 1:2 or 1:3 proportion is evenly distributed to new culture dishes for culture, 3mL of culture medium is added to the culture dishes, when the cells grow to 70%, the cells are treated by adding medicines, and 400uM palmitic acid is added to the cells for lipotoxicity model induction.
3.2 detection of cellular reactive oxygen species
Experimental operations refer to the instruction book of the active oxygen detection kit provided by Biyun. DCFH-DA was diluted in serum-free medium to a final concentration of 10 μΜ; DCFH-DA solution of cells after dilution, 37℃and 5% CO 2 Incubating for 20 minutes under the condition; then washing the cells three times with serum-free medium; cells were observed using a fluorescence microscope.
3.3 main detection index
Intracellular ROS fluorescence intensity.
4. Experimental results
As shown in fig. 6, the effect of PA and GSK126 on intracellular ROS staining level was detected using fluorescent probe DCFH-DA, and fluorescence microscopy showed that PA 400uM alone treated cells significantly enhanced green fluorescence intensity compared to control group, while GSK126 pretreatment of intracellular green fluorescence decreased, suggesting that GSK126 significantly enhanced lipid peroxidation ability of cells, inhibiting ROS production.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (5)
- Use of gsk-126 in at least one of the following:(1) The application in preparing hypolipidemic drugs;(2) Use of a compound for the preparation of a medicament for enhancing the peroxidation capacity of mitochondrial lipids in cells and/or for inhibiting the level of active oxygen in cells.
- 2. The use of claim 1, wherein GSK-126 is used in the manufacture of a medicament for use in lowering lipid by increasing the lipid peroxidation capacity of a cell's mitochondria.
- 3. The use of claim 1, wherein the medicament is GSK-126 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph thereof in combination with a pharmaceutically acceptable carrier, diluent or excipient.
- 4. The use according to claim 1, wherein the medicament is a medicament modified with a carrier, the carrier being one or more of microspheres, liposomes, microemulsions, polymeric surfactants, nanoparticles, implants.
- 5. The use according to claim 1, wherein the pharmaceutical dosage form is a capsule, a tablet, a powder, an oral liquid, a pill, a tincture, a syrup or an injection.
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