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Application of sphingolipid inhibitor for preparing medicine of inhibiting iron overload disease

A technology of iron overload and inhibitor, applied in the field of medicine

Inactive Publication Date: 2019-03-08
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, known Myriocin has not been reported to treat ferroptosis

Method used

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  • Application of sphingolipid inhibitor for preparing medicine of inhibiting iron overload disease
  • Application of sphingolipid inhibitor for preparing medicine of inhibiting iron overload disease
  • Application of sphingolipid inhibitor for preparing medicine of inhibiting iron overload disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Intracellular iron concentration measurement.

[0055] 1) The day before the test, the human fibroblastosarcoma cancer cells that had grown to 80% to 90% were digested and centrifuged, and mixed with 2×10 cells per well. 5 The number of cells, inoculated into 6-well cell culture plate, and the cells were grown for 24 hours;

[0056] 2) Treat human fibroblastosarcoma cancer cells with medium containing 5 mM ferric ammonium citrate (calculated as iron) for 0 hour, 0.5 hour, 1 hour, and 2 hours;

[0057] 3) After the treatment time is up, discard the culture medium in the six-well plate, wash it twice with PBS gently, add 1 mL PBS containing 100nM Calcein-AM, and stain in the cell culture incubator for 15 minutes;

[0058] 4) After the staining time is up, add 600 μL Accutase cell digestion solution to each well to digest the cells, add 2 mL PBS to collect the cells into a centrifuge tube, centrifuge at 2500 rpm for 5 minutes, discard the supernatant and add 50...

Embodiment 2

[0060] Embodiment 2: Optical microscope observation and photographing.

[0061] 1) Cells grown to 80%-90% confluence were digested and centrifuged, and 2×10 5 The number of cells, inoculated into 6-well cell culture plate, and the cells were grown for 24 hours;

[0062] 2) Human fibroblastosarcoma cancer cells were treated with culture solution containing 0mM or 5mM ferric ammonium citrate (calculated as iron) for 24 hours

[0063] 3) After the treatment time, observe the cell morphology under a LEICA DCF295 inverted microscope, and select three random areas in the field of view to take pictures. Each trial was performed three independent manipulations. The result is as figure 2 Shown in B.

Embodiment 3

[0064] Example 3: Detection of cell activity.

[0065] 1) Digest and centrifuge the human fibroblastosarcoma cancer cells grown to 80%-90% fusion, 1×10 per well 4 The number of cells, each inoculated to a 96-well cell culture plate, cultivated for 24 hours;

[0066] 2) ①Add the control to the 96-well plate containing the cells, and culture the medium containing 1mM, 5mM, 10mM, 15mM FAC (calculated as iron) for 24 hours; ②Add the control (double distilled water) to the cells in the 96-well plate , 5mM FAC, 5mM FAC+10μM Fer-1, 5mM FAC+10μM Lip-1 medium to treat cells for 16 hours; ③Add control (DMSO), 2μM RSL3, 2μM RSL3+10μM Fer-1 to 96-well plate cells , 2μM RSL3+10μM Lip-1 medium for 8 hours; ④ medium containing control, 5mM FAC, 5mM FAC+100μM trolox, 5mM FAC+10μM U0126 medium for 24 hours; each treatment set 6 replicates;

[0067] 3) At 37°C, 5% CO 2 Conditioned cell culture incubator;

[0068] 4) Carefully pipette the treatment solution in the 96-well plate, and add the ...

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Abstract

The invention discloses application of a sphingolipid inhibitor for preparing a medicine of inhibiting an iron overload disease. The sphingolipid inhibitor is Myriocin. A new mechanism of ferroptosisis that excessive iron ions accelerate the synthesis of sphingolipid and activates a PDK1-SGK1 signal path to cause cell death. In addition, Myriocin inhibits serine palmitoyl transferase in a sphingolipid biosynthesis process to inhibit the synthesis of sphingolipid so as to rescue cell ferroptosis. The invention provides a theoretical basis for treating the iron overload disease which takes theferroptosis as a target, and especially provides a basis for researching and developing diseases caused by chronic iron overload.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to the application of sphingolipid inhibitors in the preparation of medicines for inhibiting iron overload diseases. Background technique [0002] Sphingolipids refer to a class of amphoteric lipids containing a sphingosine skeleton, one end of which is connected to a long-chain fatty acid, and the other end is a polar alcohol. Sphingolipids include sphingomyelin, cerebroside and ganglioside, which generally exist in the membranes of plants and animals, especially in the tissues of the central nervous system. They are involved in regulating many important signal transduction processes such as cell growth, differentiation, senescence and programmed cell death. [0003] Myriocin is a potent immunosuppressant and a specific serine palmitoyltransferase inhibitor. Serine palmitoyltransferase catalyzes the first step in de novo sphingolipid biosynthesis. Sphingolipids are involved ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/195A61P3/12
CPCA61K31/195A61P3/12
Inventor 冯杰丁浩轩方升林
Owner ZHEJIANG UNIV
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