Use of sgc707 in the preparation of a medicament for treating myocardial fibrosis

Abstract

The application discloses application of SGC707 in preparation of anti-myocardial fibrosis drugs and belongs to the technical field of medicines.The experiment verifies that SGC707 can significantly reduce myocardial tissue collagen deposition of mice caused by ISO, obviously relieve the increase of mRNA expression levels of alpha-SMA, TGF-beta, PRMT3, p53 and PAI-1 caused by ISO, has the function of slowing down myocardial fibrosis, has important clinical guiding significance for treating myocardial fibrosis and provides a new way for exploring development of low-toxicity and high-efficiency anti-myocardial fibrosis drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the application of SGC707 in the preparation of anti-myocardial fibrosis drugs. Background Technology

[0002] Myocardial fibrosis is the end-stage pathological change in the development of various cardiovascular diseases. It results from persistent and recurrent myocardial ischemia and hypoxia caused by moderate to severe coronary atherosclerotic stenosis, gradually progressing to chronic ischemic heart disease and heart failure. Clinically, G protein-coupled receptor inhibitors, angiotensin-converting enzyme inhibitors, and diuretics are commonly used to treat myocardial fibrosis. Calcium channel blockers and angiotensin receptor blockers may also be used in combination. While these drugs can achieve significant short-term therapeutic effects, long-term use can lead to serious toxic side effects, such as nephrotoxicity, hepatotoxicity, elevated blood glucose and lipids, and electrolyte disturbances. Therefore, the search for highly effective and low-toxicity drugs for the treatment of myocardial fibrosis is receiving increasing attention.

[0003] SGC707 is a potent, selective, and non-competitive PRMT3 inhibitor with various beneficial biological effects, including anti-steatodendrostasis, anti-tumor, anti-apoptosis, and antiviral activity. It has potential applications in the treatment of non-alcoholic fatty liver disease, plasma lipid levels, atherosclerosis, and hepatocellular carcinoma. However, no research has been reported on the use of SGC707 in the preparation of anti-myocardial fibrosis drugs. Summary of the Invention

[0004] Therefore, the purpose of this invention is to provide the application of SGC707 in the preparation of anti-myocardial fibrosis drugs. This invention experimentally verified that SGC707 can significantly reduce collagen deposition in the myocardial tissue of mice induced by ISO, and significantly alleviate the increase in mRNA expression levels of α-SMA, TGF-β, PRMT3, p53, and PAI-1 induced by ISO, thus possessing the function of slowing down myocardial fibrosis and having important clinical guiding significance for the treatment of myocardial fibrosis.

[0005] The objective of this invention is achieved through the following means:

[0006] This invention provides the application of SGC707 in the preparation of anti-myocardial fibrosis drugs.

[0007] Based on the above technical solution, the drug further includes an effective amount of SGC707 and a pharmaceutically acceptable carrier.

[0008] Based on the above technical solution, the pharmaceutically acceptable carrier further includes fillers, diluents, binders, disintegrants, emulsifiers, and drug-carrying carriers without toxic side effects.

[0009] Based on the above technical solution, the drug is further prepared into a pharmaceutically permissible dosage form.

[0010] Based on the above technical solution, the dosage forms further include tablets, granules, oral liquid preparations, drops, injectable preparations, and capsule preparations.

[0011] Based on the above technical solution, the drug is further prepared in the form of a single-dose drug.

[0012] Based on the above technical solution, the single-dose drug further comprises 1-1000mg SGC707.

[0013] Based on the above technical solution, the drug can further reduce collagen deposition in myocardial tissue.

[0014] Based on the above technical solution, the drug can further downregulate the mRNA expression levels of α-SMA, TGF-β, PRMT3, p53, and PAI-1 in subjects with myocardial fibrosis.

[0015] The advantages of this invention over the prior art are as follows:

[0016] This invention experimentally verifies that SGC707 can significantly reduce collagen deposition in the myocardial tissue of mice induced by ISO, and significantly alleviate the increase in mRNA expression levels of α-SMA, TGF-β, PRMT3, p53, and PAI-1 induced by ISO, thus having the function of slowing down myocardial fibrosis. This has important clinical guiding significance for the treatment of myocardial fibrosis and provides a new approach for exploring the development of low-toxicity and highly effective anti-myocardial fibrosis drugs. Attached Figure Description

[0017] To more clearly illustrate the embodiments of the present invention, the accompanying drawings involved in the embodiments will be briefly described below.

[0018] Figure 1 MASSON collagen staining images of myocardial sections from mice in different experimental groups; where A is the CON group, B is the ISO group, C is the ISO+SGC707 group, and D is the ISO+PRO group.

[0019] Figure 2 The results show the mRNA expression levels of myocardial fibrosis-related genes α-SMA and TGF-β in mice from different experimental groups. In this table, A represents the mRNA expression level of α-SMA and B represents the mRNA expression level of TGF-β.

[0020] Figure 3The results show the mRNA expression levels of myocardial fibrosis-related genes PRMT3, p53, and PAI-1 in mice from different experimental groups. In the figures, A represents the mRNA expression level of PRMT3, B represents the mRNA expression level of p53, and C represents the mRNA expression level of PAI-1. Detailed Implementation

[0021] The present invention will be described in detail below with reference to the embodiments. However, the implementation of the present invention is not limited thereto. Obviously, the embodiments described below are only some embodiments of the present invention. For those skilled in the art, other similar embodiments can be obtained without creative effort and all fall within the protection scope of the present invention.

[0022] Example 1

[0023] Seventy male 8-week-old C57BL / 6 mice were randomly divided into 5 groups: (1) Experimental control group (CON): free access to water and food; (2) Myocardial fibrosis model group (ISO): intraperitoneal injection of ISO (10mg / kg.day) to induce myocardial fibrosis for 14 days; (3) Drug treatment group (ISO+SGC707): mice were intraperitoneally injected with SGC707 (15mg / kg.day), specifically: intraperitoneal injection of ISO (10mg / kg.day) every day, followed by intraperitoneal injection of SGC707 (15mg / kg.day) 30 minutes later, for 14 days; (4) Positive control group (ISO+Propranolol, PRO): mice were intraperitoneally injected with ISO (10mg / kg.day), and intraperitoneal injection of propranolol PRO (40mg / kg.day) every day during the induction of myocardial fibrosis for 14 days; the mice were sacrificed after 14 days.

[0024] Masson staining: Myocardial tissue from mice euthanized in the above experimental group was subjected to Masson trichrome staining. The specific steps were as follows: (1) The sections were routinely dewaxed and hydrated, and stained with prepared Weigert iron hematoxylin for 5-10 min; (2) Differentiated with acidic ethanol differentiation solution and washed with water; (3) Rebounded with Masson blue solution and washed with water; (4) Washed with distilled water for 1 min; (5) Stained with Ponceau S and fuchsin for 5-10 min; (6) During the above operation, a weak acid working solution was prepared according to the ratio of distilled water: weak acid solution = 2:1, and washed with the weak acid working solution for 1 min; (7) Washed with phosphomolybdic acid solution for 1-2 min; (8) Washed with the prepared weak acid working solution for 1 min; (9) Stained directly in aniline blue staining solution for 1-2 min; (10) Washed with the prepared weak acid working solution for 1 min; (11) Rapidly dehydrated with 95% ethanol. Dehydrate with anhydrous ethanol 3 times, 5-10 seconds each time; (12) Clear with xylene 3 times, 1-2 minutes each time. Seal with neutral resin.

[0025] MASSON collagen staining images of myocardial sections from different experimental groups of mice are shown below. Figure 1 As shown, compared with the CON group, the MASSON collagen staining images of myocardial sections from the ISO group mice showed a large amount of collagen deposition. Figure 1 (A, 1B) In contrast, the MASSON collagen staining images of myocardial tissue in mice treated with SGC707 15mg / kg / day showed a significant reduction in collagen deposition, which was not significantly different from the experimental results after treatment with the positive drug propranolol PRO. Figure 1 C,1D).

[0026] The mRNA expression levels of TGF-β, α-SMA, PRMT3, p53, PAI-1 and GAPDH in the myocardial tissue of the mice sacrificed in the above experimental groups were detected by real-time quantitative qRT-PCR. The specific operation steps were as follows: (1) Primer design: follow the general primer design principles; (2) RNA extraction: follow the instructions of the kit; (3) Reverse transcription: 1. Genomic DNA removal reaction: prepare the reaction mixture on ice according to the instructions of the kit; 2. Reverse transcription reaction: the reaction solution is prepared on ice, and the reverse transcription reaction is performed immediately after the reagent is gently mixed; (4) Sample addition: prepare the premixed solution of TGF-β, α-SMA, PRMT3, p53, PAI-1 and GAPDH according to the kit and the number of samples, and then add the samples and premixed solution to the 96-well PCR plate in sequence according to the system, seal and centrifuge; (5) PCR test: open the software, put the PCR plate into BIO-RAD Real-Time In the System machine detection area, set the corresponding temperature and time cycle template, sample name, and detection factor, then click Start to wait for the results data and generate a graph.

[0027] The mRNA expression levels of myocardial fibrosis-related genes α-SMA and TGF-β in different experimental groups of mice are as follows: Figure 2 As shown, compared with the control group, the mRNA levels of α-SMA and TGF-β in the myocardial tissue of mice in the ISO group were significantly increased, and SGC70715mg / kg.day had a significant alleviating effect on the increase in α-SMA and TGF-β mRNA levels induced by ISO. Figure 2 (A, 2B) and slightly better than the experimental results after treatment with the positive drug propranolol PRO. The results showed that SGC707 could alleviate ISO-induced myocardial fibrosis in mice.

[0028] The mRNA expression levels of myocardial fibrosis-related genes PRMT3, p53, and PAI-1 in different experimental groups of mice are as follows: Figure 3As shown, compared with the control group, the mRNA levels of PRMT3, p53, and PAI-1 in the myocardial tissue of mice in the ISO group were significantly increased, and SGC707 15 mg / kg / day had a significant alleviating effect on the ISO-induced increase in PRMT3, p53, and PAI-1 mRNA levels. Figure 3 The results showed no significant difference between AC and the experimental results after treatment with the positive drug propranolol (PRO). These results suggest that PRMT3 may regulate p53 expression through PAI-1.

[0029] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. Application of SGC707 in the preparation of anti-myocardial fibrosis drugs.

2. The application according to claim 1, characterized in that, The drug comprises an effective amount of SGC707 and a pharmaceutically acceptable carrier.

3. The application according to claim 2, characterized in that, The pharmaceutically acceptable carriers include fillers, binders, disintegrants, and emulsifiers.

4. The application according to any one of claims 1-3, characterized in that, The drug is prepared into a pharmaceutically permissible dosage form.

5. The application according to claim 4, characterized in that, The dosage forms include tablets, granules, oral liquid preparations, drops, injectable preparations, and capsule preparations.

6. The application according to claim 5, characterized in that, The drug is prepared in single-dose form.

7. The application according to claim 6, characterized in that, The single-dose drug contains 1-1000 mg of SGC707.

8. The application according to claim 1, characterized in that, The drug described can reduce collagen deposition in myocardial tissue.

9. The application according to claim 1, characterized in that, The drug can downregulate the mRNA expression levels of α-SMA, TGF-β, PRMT3, p53, and PAI-1 in subjects with myocardial fibrosis.

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