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Application of RXR (Retinoid X receptor) in preparing medicine for treatment of vesicular stomatitis virus

A technology of stomatitis virus and blisters, applied in the field of biomedicine

Inactive Publication Date: 2016-04-27
宁波美丽人生医药生物科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

; For example, specific inhibitors of cyclooxygenase 1 increase the replication of pseudorabies virus PFV (Ray et al. 2004). Mice given cyclooxygenase 1 knockout but not given cyclooxygenase 2 knockout are more resistant to influenza virus Invasion (Carey et al 2005) and cyclooxygenase 1 promoter hyperacetylation produces interferon repression in histone deacetylation-deficient macrophages (Chen et al 2012) Although multiple studies have shown that cyclooxygenase 1 regulates Inhibition of type 1 interferons, but regulation of cyclooxygenase 1 by host antiviral responses remains poorly studied

Method used

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  • Application of RXR (Retinoid X receptor) in preparing medicine for treatment of vesicular stomatitis virus
  • Application of RXR (Retinoid X receptor) in preparing medicine for treatment of vesicular stomatitis virus
  • Application of RXR (Retinoid X receptor) in preparing medicine for treatment of vesicular stomatitis virus

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Experimental program
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Effect test

Embodiment 1

[0060] RXR expression regulates host susceptibility to vesicular stomatitis virus infection:

[0061] Our previous genetic studies have established a novel interferon regulator 3-dependent but interferon-independent mechanism to downregulate RXR expression (Chow et al. 2006). To determine RXR expression levels by infection with different types of viruses, bone marrow-derived macrophages were infected with vesicular stomatitis virus. The results showed that the expression of RXR was down-regulated after infection with the above viruses (such as figure 1 shown in A). Repression of the RXR gene was not due to changes in the cell state after infection, as the L32 control gene was unchanged (data not shown). Administration of the RNA virus analogue polyI:C and the DNA virus analogue polydA:dT can activate intracellular virus and also significantly inhibit the expression of RXR in bone marrow macrophages. (Such as figure 1 Shown in B) More importantly, it confirms that this su...

Embodiment 2

[0065] RXR agonists and their antagonists modulate host defense functions in vesicular stomatitis virus-injected macrophages:

[0066] Ligand binding to RXR can activate its downstream pathway and fully activate it. In order to explore whether RXR ligand activation can affect virus infection, RAW264.7 cells were pretreated overnight with RXR-specific agonists Ig268 and AGN194204, and then infected with vesicular stomatitis virus. Through plaque test analysis, the experimental results were consistent with the experimental results of RXR overexpression, and the RXR in the ligand activation group was given two stimulants, which significantly enhanced the level of vesicular stomatitis virus infection. (Such as Figure 8 A) Similarly, treatment with 9-cis retinoic acid (a novel ligand for RXR) also increased the susceptibility of RAW264.7 cell line to vesicular stomatitis virus infection in a dose-dependent manner ( Retinoic acid dose range 16nM-20nM) (eg figure 2 B and S1B), o...

Embodiment 3

[0068] Ligand activation of RXR inhibits the expression of multiple antiviral genes:

[0069] In order to study how RXR weakens the host immune response and facilitates virus infection, the inventors of the present invention performed gene chip detection on the RXR agonist pretreatment group and macrophage PolyI:C transfection group. The results showed that 9-cis retinoic acid can inhibit a variety of PolyΙ:C-induced genes, including type Ι interferon genes (such as IFN1, IFN2, IFN4, IFN5), Isg15, Ifit3 and Gbp3 (such as Figure 4 A) Considering that type Ⅲ interferon and its downstream interferon-stimulated gene ISGs play an important role in the host's immune response in antiviral infection, RXR-mediated inhibition of these antiviral genes may be the host's response to viral infection caused by susceptibility. In order to verify the genetic data and prove the hypothesis that RXR is beneficial to virus infection by inhibiting antiviral genes, the inventors pretreated RAW264....

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Abstract

The invention relates to the field of biological medicine, in particular to an application of RXR (Retinoid X receptor) in screening medicine for treatment of vesicular stomatitis virus. Not only the application of RXR (Retinoid X receptor) in screening the medicine for treatment of vesicular stomatitis virus but also a method for building an infection cell model of vesicular stomatitis virus caused by over-expression of RXR are provided; besides, it is found that COX infection pathway plays a key role in host defense to vesicular stomatitis virus in a RXR-dependent manner; and further, application of MHV68 in screening the medicine for treatment of vesicular stomatitis virus is verified.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the use of RXR in screening drugs for treating vesicular stomatitis virus infection. Background technique [0002] Immune activation during viral infection leads to downregulation of retinol X receptors, hereafter referred to as (RXR), RXR belongs to the nuclear receptors, which are essential in the metabolism of cells and the whole body. However, the role of RXR in host defense against viral infection remains unknown. Nuclear receptors (NRs) represent a large family of transcription factors involved in a broad spectrum of biological events, such as development, reproduction, and metabolism. (Robinson-Rechavi et al. 2003) Many members of the NR superfamily have emerged as key regulators of inflammation and immune responses (Daynes and Jones, 2002; Joseph et al. 2003; Ogawa et al. 2005), which enable macrophages and dendritic cells to sense its lipid environment and shapes its immune ...

Claims

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Application Information

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IPC IPC(8): A61K49/00A61K38/17C12N5/09A61P31/14
Inventor 田晓丽
Owner 宁波美丽人生医药生物科技发展有限公司
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