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Application of Eudesmin in preparation of drugs for preventing or curing renal fibrosis

A technology for renal fibrosis and eucalyptol, which is used in drug combinations, active ingredients of heterocyclic compounds, and diseases of the urinary system, etc., can solve the problems of cytotoxicity, large molecular weight of neutralizing antibodies, and failure to delay the progress of renal fibrosis. , to achieve the effect of broad clinical application prospects

Inactive Publication Date: 2018-09-14
SHANGHAI SIXTH PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, there are currently no drugs specifically targeting renal fibrosis in clinical practice.
In basic medical research, researchers often pay more attention to TGFβ1 neutralizing antibodies or small molecule inhibitors. However, neutralizing antibodies are difficult to reach the target site due to their large molecular weight; and small molecule inhibitors are mostly cytotoxic , and have serious toxic side effects on the body
Studies have shown that angiotensin II (Ang II) inhibitors, namely ACEI / ARB, can reduce the level of urinary TGFβ1, but the combination of the two does not show an additive effect, and cannot completely block the overexpression of TGFβ1, so it can only delay rather than completely arresting the progression of renal failure
In addition, clinical studies have shown that the clinical use of specific human monoclonal antibodies against TGFβ1 in patients with renal fibrosis failed to delay the progression of renal fibrosis

Method used

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  • Application of Eudesmin in preparation of drugs for preventing or curing renal fibrosis
  • Application of Eudesmin in preparation of drugs for preventing or curing renal fibrosis
  • Application of Eudesmin in preparation of drugs for preventing or curing renal fibrosis

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Experimental program
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Effect test

Embodiment 1

[0038] The Specimen Bank of Shanghai Sixth People's Hospital collected renal specimens from patients who signed the informed consent form and were pathologically diagnosed as renal fibrosis between 2015 and 2017. Immunohistochemical staining was performed on paraffin sections of renal biopsies , the specific steps are as follows: perform paraffin section, dewax to water with xylene and 95% alcohol; then, rinse with distilled water, and then remove endogenous peroxidase with 3% hydrogen peroxide aqueous solution (37°C for 30min); Then, wash with double distilled water and TBST, and then use sodium citrate solution for microwave repair; after the solution is cooled, normal sheep serum is blocked for 20 minutes, and primary antibody is added, incubated at 37°C for one hour, and overnight at 4°C; the next day , After the slices were equilibrated at room temperature, washed three times with TBST, added secondary antibody and incubated at 37°C for one hour, after color development by...

Embodiment 2

[0041] Construction of YY1 Overexpression Recombinant Virus

[0042] see Image 6 , the inventors used pHBAAV-CMV-MCS-3flag-T2A-ZsGreen, an adeno-associated virus vector, and used two restriction enzymes, BamH I and Kpn I, to digest with CutSmart buffer at 37°C for 1 hour. The gel was cut and recovered, and the purified linear vector was further obtained. At the same time, YY1 (SEQ ID NO.1) was amplified by PCR, the forward primer used was 5'-CCATAGAAGACACCGGGATCCGCCACCATGGCCTCGGGCGACACC-3'(SEQ ID NO.3), and the reverse primer used was 5'-GTAGTCGTTAATTAAGGTACCCTGGTTGTTTTTGGCCTTAGCATGT- 3' (SEQ ID NO.4); after PCR, the DNA was recovered to obtain a purified CDS fragment of linear YY1. Next, ligate the prepared linear vector with the CDS fragment of the linear YY1 (LigationHigh enzyme, 16°C for 1h), and then perform transformation, which specifically includes the following steps: add 10ul of the ligation product to Beijing Quanshijin Biotechnology Co., Ltd. Stable3 competent ...

Embodiment 3

[0045] Kidney-specific knockout of YY1 experiment

[0046] 4-week-old C57BL6 / J YY1 flox / flox Male rats were fed with a high-fat diet for 6 weeks and injected intraperitoneally with streptozotocin (STZ, 40 mg / kg), and injected every other day. Fasting blood glucose was measured after a total of three times. Male rats greater than 16.7 mmol / L were randomly divided into two groups. group, 12 rats in each group; one week later, the kidneys were injected with AAV-cre virus in situ: after the mice were anesthetized with pentobarbital sodium, the abdomen was opened, and the left kidney was carefully separated, and three points were taken from the lower border of the left renal cortex. Injection (10ul per point 1*10 12 AAV-cre virus); the control group was treated in the same way, the wound was sutured after injection of the same dose of AAV-GFP control virus, and the mice were sacrificed after continuing to feed for 12 weeks. During the feeding period of the mice, the body weight a...

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Abstract

The invention provides application of Eudesmin in preparation of drugs for preventing or curing renal fibrosis and further provides a drug composition for relieving renal fibrosis, and the drug composition comprises effective content of Eudesmin and a medically acceptable carrier. According to the provided technical scheme, renal fibrosis development is relieved on the TGF beta1 on the basis of transcription factor YY1 negative regulation, the key factor casing lowering of the TGF beta1 and target gene transcription level of the TGF beta1 is found, a specificity agonist-Eudesmin of the transcription factor YY1 is provided and can be used for preparing the drugs for preventing or curing renal fibrosis, therefore, the Eudesmin has a wide clinical application prospect in the aspect of preventing or curing renal fibrosis.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to the use of eucalyptol in the preparation of medicines for preventing or treating renal fibrosis, and also to a pharmaceutical composition for alleviating renal fibrosis. Background technique [0002] Renal fibrosis and sclerosis are one of the common causes of death in patients with end-stage renal failure, and various diseases can cause renal fibrosis, including but not limited to diabetic nephropathy, nephritis and renal tumors. The main pathological changes of renal fibrosis are the thickening of capillary basement membrane and the increase of basement membrane matrix, which eventually lead to diffuse or nodular glomerulosclerosis; the pathogenesis is accompanied by complex metabolic disorders Its pathogenesis is complex, including the interaction of hemodynamics, advanced glycation end products, oxidative stress, polyol pathway, protein kinase C, and activation of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/34A61P13/12
CPCA61K31/34A61P13/12
Inventor 刘军力高攀杨柳贾伟平
Owner SHANGHAI SIXTH PEOPLES HOSPITAL
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