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Application of POLR2A inhibitor in preparation of medicine

A technology for preparing drugs and inhibitors, which is applied in the field of biomedicine, and can solve problems such as the incomplete understanding of the pathological mechanism of estrogen and the increased risk of cardiovascular events

Active Publication Date: 2020-08-25
INST OF SPECIAL ANIMAL & PLANT SCI OF CAAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, taking estrogen has been reported to increase the risk of cardiovascular events and breast and uterine cancer
In addition, the pathological mechanism of estrogen is not fully understood

Method used

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  • Application of POLR2A inhibitor in preparation of medicine
  • Application of POLR2A inhibitor in preparation of medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] In vitro experiments demonstrate that POLR2A promotes osteoclast differentiation

[0095] The inventors of the present application first assessed the expression of POLR2A in bone marrow osteoclasts. After 4 days of culture, RANKL increased the expression of osteoclast marker tartrate-resistant acid phosphatase (TRAP), and the expression of TRAP was further increased after adding the osteoporosis-inducing drug rosiglitazone ( figure 1 Middle a). The expression of POLR2A increased in the RANKL group, and further increased under the stimulation of rosiglitazone ( figure 1 middle b~d).

[0096] The inventors of the present application then studied the growth cycle of osteoclasts ( figure 2 ). On the 3rd day from the start of culture, after staining with TRAP, almost no osteoclasts were detected in the RANKL and rosiglitazone groups. On day 4, the inventors of the present application detected the maximum number of osteoclasts in both groups. As the incubation time inc...

Embodiment 2

[0099] Bone is protected against Ovx-induced osteoporosis with α-Amanitin

[0100] The inventors of the present application demonstrated that the overexpression of POLR2A can promote bone loss in previous studies, so the inventors of the present application evaluated the curative effect after treatment with α-Amanitin, a specific inhibitor of POLR2A. It has been reported that α-Amanitin specifically inhibits POLR2A (Bensaude et al. 2011; Lindell et al., 1970), so the inventors of the present application evaluated the effect of α-Amanitin on osteoclastogenesis. It is reported that α-Amanitin has cytotoxicity (Letschert et al. 2006), so the inventors of the present application first tested the cytotoxicity of α-Amanitin at different concentrations. MTT results showed that there was no significant difference in cell viability between the control group and the α-Amanitin group (from 0 to 80ng / ml group ( Figure 5 middle a~b). Bone marrow osteoclast production assay showed that α...

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Abstract

The invention provides an application of a POLR2A inhibitor in preparation of a medicine. The medicine is used for at least one of the following effects: inhibiting osteoclast generation; inhibiting bone resorption; increasing bone mass; and increasing bone stability. Differentiation of osteoclasts from mouse bone marrow precursors and human peripheral blood mononuclear cells (hPBMN) is inhibitedby si-POLR2A, but is enhanced by Flag-POLR2A, which indicates that regulation of POLR2A on mouse bone resorption may be converted into human pathophysiology. The research of the invention shows that the treatment of alpha-Amanitin significantly reduces the size, quantity and nuclear rate of osteoclasts. In vivo studies show that: the treatment of the alpha-Amanitin almost completely inhibits boneresorption, and increases bone quality and stability. The invention provides a brand-new drug target and a new treatment means and thought for the development of a new generation of bone protection drugs through the identification of the alpha-Amanitin.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the application of POLR2A inhibitors in the preparation of medicines. Background technique [0002] Osteoporosis (Osteoporosis, OP) is a major public health problem, and its incidence is gradually increasing. It is characterized by an imbalance between osteoblastic bone formation and osteoclastic bone resorption. This leads to disturbances in bone microarchitecture, resulting in decreased bone stability and increased fracture risk. Conditions such as chronic inflammatory diseases, various drug treatments (including glucocorticoids), physical inactivity, and disability affect systemic bone turnover, leading to osteoporosis. However, the main cause of osteoporosis is estrogen deficiency. Loss of estrogen in postmenopausal women often promotes activation of osteoclastic bone resorption, leading to osteoporosis. [0003] Estrogen therapy has been widely used to improve postmenopausal o...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K38/12A61K31/7088A61K39/395A61P19/10G01N33/573
CPCA61K45/00A61K38/12A61K31/7088A61K39/395A61P19/10G01N33/573G01N2800/108G01N2333/91255
Inventor 李光玉刘春晓许丽文
Owner INST OF SPECIAL ANIMAL & PLANT SCI OF CAAS
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