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Application of fingolimod or salts thereof in treatment of cystic diseases

A cyst and purpose technology, applied in the field of medicine, can solve problems such as no drug for delaying the disease, no effective treatment for ADPKD, and impact on the quality of life of patients

Inactive Publication Date: 2016-05-11
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, patients with ADPKD often need to treat various concurrent cystic diseases in other parts at the same time, such as surgical resection of liver cysts, pancreatic cysts, etc., and the quality of life of patients is also seriously affected
[0005] So far, there is still no effective treatment for ADPKD, and there is no therapeutic drug to delay the progression of the disease. In clinical practice, symptomatic and supportive treatments such as antihypertensive and pain relief are mainly used. After the disease progresses to the end stage, dialysis or kidney transplantation is used. bring a heavy burden

Method used

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  • Application of fingolimod or salts thereof in treatment of cystic diseases
  • Application of fingolimod or salts thereof in treatment of cystic diseases
  • Application of fingolimod or salts thereof in treatment of cystic diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1: Effect of fingolimod on proliferation of human polycystic kidney cyst lining epithelial cell line WT9-12

[0083] Human polycystic kidney cyst lining epithelial cell line WT9-12 was cultured in DMEM / F12 medium with 10% fetal bovine serum, added with double antibodies, digested with trypsin and passaged. After about 70% of cell confluence, trypsinize, make cell suspension, count cells under microscope, and then inoculate in 96-well plate, 6×10 per well 3 cells. After synchronization, fingolimod treatment was given, and the concentration gradient of fingolimod was 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.175 μM, 1.588 μM, and 0.781 μM. The changes of cell proliferation after administration for 24, 48 and 72 hours were observed by MTT method. Aspirate the culture medium at each time point, add 10 μl MTT (5 mg / ml aqueous solution) to 100 μl medium in each well, incubate at 37°C for 3 hours, suck out the culture medium, add 100 μl DMSO to each well, shake at room tempe...

Embodiment 2

[0088] Example 2: Effects of fingolimod on apoptosis and cell cycle of human polycystic kidney cyst lining epithelial cells WT9-12

[0089] WT9-12 cells were treated with 2×10 5 Cells / well were seeded in a 6-well plate, and when 60-70% confluence was reached, the cells were treated with 1 μM, 2 μM, and 10 μM of fingolimod for 24 hours. Cells and supernatant were collected, trypsinized and centrifuged, washed with cold 1×PBS and then centrifuged at 1000 rpm / min for 10 minutes. Discard the supernatant, add 1×binding buffer, adjust the cell concentration to 1×10 6 cells / ml. Add 5 μl AnnexinV and 1 μl PI (100 μg / ml) working solution to every 100 μl cell suspension, incubate at room temperature in the dark for 15 minutes, add 400 μl 1× binding buffer, mix well and place on ice, then use flow cytometry to measure apoptosis as soon as possible death, the results are shown in Table 2 and figure 2 , fingolimod can significantly induce apoptosis in WT9-12 cells.

[0090] Table 2 E...

Embodiment 3

[0097] Example 3: Effect of fingolimod on HDACs in human polycystic kidney cyst lining epithelial cell line WT9-12

[0098] WT9-12 cells in 8×10 5 Cells / dish were seeded in a 10 cm culture dish, and when 60-70% confluence was reached, the cells were treated with 0 μM or 2.5 μM of fingolimod for 24 hours. Trypsinize and harvest the cells. Wash the cells with cold 1×PBS and centrifuge at 1000rpm / min for 10 minutes to remove the PBS. Add 1ml Trizol solution to dissolve the cells completely and extract RNA. Use HisScript1 st The strandcDNA synthesis kit (Vazyme) reverse transcribed RNA into cDNA. The cDNA obtained by reverse transcription was used for Realtime-PCR analysis. Such as Figure 4 As shown, fingolimod can inhibit the transcription of some HDACs.

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Abstract

The invention provides application of fingolimod (2-amino-2-[2-(4-octylphenyl) ethyl]-1,3-propanediol) or salts thereof in preparation of medicinal compositions for treating cystic diseases. Particularly, the inventor finds that fingolimod or salts thereof have the effects of inducing the apoptosis and / or inhibiting the proliferation of a cystic cell by inhibiting HDACs and arresting the cell cycle of the cystic cell at G2 / M so as to reduce the cystic volume and restore the renal function. In addition, cytotoxicity experiments also confirm that during the treatment of the cystic diseases, fingolimod, as a known marketed medicine, has no obvious toxicity under the therapeutic dose. Fingolimod, as a medicine for treating the cystic diseases, especially an autosomal dominant polycystic kidney disease, has a wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine. Specifically, the application of Flingolimod or a salt thereof in the treatment of cystic diseases, especially the application of HDACs inhibitor in the treatment of autosomal dominant polycystic kidney disease. Background technique [0002] Autosomal dominant polycystic kidney disease (autosomaldominantpolycystickidneydisease, ADPKD) is the most common hereditary kidney disease, with an incidence of about 1 / 400-1 / 1000. There are currently about 1.5-3 million patients in my country. ADPKD mainly manifests as numerous cysts of different sizes in the bilateral kidneys. The cysts are similar to benign tumors and progressively enlarge, eventually destroying the structure and function of the kidneys, leading to end-stage renal failure. 50% of patients over 60 years old progress to uremia, which accounts for 5-10% of the causes of end-stage renal failure. As a genetic disease, the patient's children...

Claims

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Application Information

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IPC IPC(8): A61K31/137A61P35/00A61P13/12A61P1/16A61P1/18
Inventor 罗成李林柳红陈丽敏李昕卢俊彦林岱宗付莉莉孔祥谦李国王雪琦梅长林蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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