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Application of ferroptosis inhibitor in preparation of medicine for preventing or treating osteoporosis or bone loss caused by iron overload

A technology for osteoporosis and inhibitors, applied in the field of application of ferroptosis inhibitors in the preparation of drugs for the prevention or treatment of osteoporosis or bone loss caused by iron overload, which can solve the problems of side effects and low specificity of drug use , to achieve the effect of good application prospects

Pending Publication Date: 2021-06-01
CHONGQING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These existing treatments can cause significant side effects and the use of drugs is less specific
In particular, there is an urgent need for specific treatments for iron overload-induced osteoporosis and bone loss.

Method used

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  • Application of ferroptosis inhibitor in preparation of medicine for preventing or treating osteoporosis or bone loss caused by iron overload
  • Application of ferroptosis inhibitor in preparation of medicine for preventing or treating osteoporosis or bone loss caused by iron overload
  • Application of ferroptosis inhibitor in preparation of medicine for preventing or treating osteoporosis or bone loss caused by iron overload

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Iron is one of the essential trace elements for the human body, but excessive accumulation of iron in tissues or cells can lead to diseases.

[0078] In this example, ferric ammonium citrate (FAC) is used to treat bone marrow stromal cells, and the concentration is selected from physiological concentration to the highest serum iron concentration range (i.e. 110 μg / dl to 1100 μg / dl) of iron overload patients found clinically at present, and the settings are 20 μM, 50 μM, 200 μM The microenvironment of iron overload was simulated in vitro, and sodium citrate was used as the control. Higher iron concentrations were not tested in this example because higher iron concentrations are not achievable in iron overload disease. FAC effectively mimics non-transferrin-bound iron (NTBI) in iron-overloaded patient plasma. Alkaline phosphatase (ALP) is a marker of early osteogenic differentiation. ALP activity plays a vital role in the early osteogenic process. Therefore, alkaline pho...

Embodiment 2

[0081] Preliminary experiments have found that the proliferation of iron-overloaded BMSCs is affected, and a large number of cells die, and its impact in iron-overloaded patients cannot be ignored. Therefore, in this embodiment, the morphological observation is directly performed through a high-definition microscope.

[0082] In this example, the effects of iron overload on cell viability and cell death of BMSCs were simultaneously studied. Cell viability was checked by CCK-8. On the 3rd day after FAC treatment, the percentage of cell death and cell proliferation were directly counted by placenta blue staining (the number of cells contained in 1 ul volume under the same conditions).

[0083] The experimental results showed that with the increase of FAC concentration, the morphology of BMSCs changed irregularly, with more shrunken cells and visible floating cells, especially at higher FAC concentration (ref. figure 2 shown in A). Cell viability decreased (see figure 2 Show...

Embodiment 3

[0091] The inventors provide whether ferroptosis, a new regulated form of cell death, is involved in the effects of iron overload on bone marrow mesenchymal stem cells. Initially, the inventors discovered that the iron transport-related protein DMT1, Tfr1, is involved in the intracellular Fe 2+ The expressions of divalent metal transporters and membrane proteins were significantly up-regulated by iron overload ( image 3 shown in A). Fluorescent probes were then used to detect intracellular Fe 2+ , showing intracellular Fe 2+ significantly increased in a dose-dependent manner ( image 3 shown in B).

[0092] Since excess intracellular iron may generate ROS through the Fenton reaction leading to ferroptosis, the cell-penetrating probe H2DCFDA was further used to assess ROS. The results showed that compared with the untreated group, the ROS level in the FAC-treated group was significantly increased ( image 3 shown in C).

[0093] Lipid peroxidation products (LPO), anothe...

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Abstract

The invention discloses application of a ferroptosis inhibitor in preparation of a medicine for preventing or treating osteoporosis or bone loss caused by iron overload, and relates to the field of osteoporosis treatment. According to the invention, it is found and confirmed for the first time that the cell mechanism for inhibiting osteogenic differentiation by iron overload is mainly ferroptosis instead of apoptosis or other death modes found by researchers at present, and a molecular mechanism for inhibiting osteogenic differentiation by reducing Wnt signals by ferroptosis is found. And four schemes for treating, preventing or reducing osteoporosis or bone loss caused by iron overload with high efficiency and low risk by reducing ferroptosis or activating a Wnt signal are provided. Specifically, melatonin or a ferroptosis inhibitor / drug inhibits ferroptosis, or a drug directly activating a Wnt signal removes the iron overload effect, and the bone marrow stromal cell osteogenic differentiation function is recovered. The invention provides experimental data and a research direction for clinically finding and treating osteoporosis or bone loss caused by iron overload under disease or environmental conditions.

Description

technical field [0001] The invention relates to the field of treatment of osteoporosis and bone loss caused by iron overload, in particular, the application of a ferroptosis inhibitor in the preparation of a medicament for preventing or treating osteoporosis or bone loss caused by iron overload. Background technique [0002] Iron is an essential element that plays a key role in DNA synthesis, electron / oxygen transport and other metabolic processes. Normal serum iron levels range from 50 μg / dL to 180 μg / dL. Ferroptosis is a form of regulated cell death (RCD) that depends on iron and reactive oxygen species (ROS), first proposed in 2012 by the laboratory of Dr. Brent R Stockwell. Ferroptosis differs from other types of RCD morphologically, biochemically, and genetically, and ferroptosis is distinct from pyroptosis, apoptosis, necrosis, and autophagic cell death. Ferroptosis is a process manifested by the accumulation of lethal ROS and lipid peroxidation products (LPO) during...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/4045A61K31/245A61K31/16A61K31/506A61P19/10A61P19/08
CPCA61K45/00A61K31/4045A61K31/245A61K31/16A61K31/506A61P19/10A61P19/08
Inventor 涂小林罗岑刘忻钰武异洵谢正松张一宁
Owner CHONGQING MEDICAL UNIVERSITY
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