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Application of SIRT3 mediated macrophage Fraxin deacetylation modification in improvement of inflammatory diseases

A technology of macrophage and acetylation, which is applied in the direction of medical preparations containing active ingredients, anti-inflammatory agents, non-central analgesics, etc., and can solve problems such as unclear internal mechanisms

Pending Publication Date: 2022-02-22
SHANGHAI INST OF HYPERTENSION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, in this field, the internal mechanism of how macrophages perceive the changes in the microenvironment, initiate the transformation of iron metabolic flux and induce the polarization of macrophages under the condition of inflammatory diseases is still unclear. A better understanding of the regulation of polarization in order to develop drugs that regulate the polarization of macrophages for clinical application

Method used

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  • Application of SIRT3 mediated macrophage Fraxin deacetylation modification in improvement of inflammatory diseases
  • Application of SIRT3 mediated macrophage Fraxin deacetylation modification in improvement of inflammatory diseases
  • Application of SIRT3 mediated macrophage Fraxin deacetylation modification in improvement of inflammatory diseases

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Effect test

Embodiment 1

[0286] Example 1. SIRT3 deficiency aggravates the accumulation of mitochondrial iron in macrophages and promotes the polarization of macrophages

[0287] The inventors used lentivirus to transfer SIRT3-shRNA into M1920 cells, and detected the efficiency of SIRT3 inhibition by qPCR and western blot experiments. Such as figure 1 As shown in A and B, the expression of SIRT3 was significantly inhibited at the mRNA and protein levels.

[0288] Angiotensin II (Ang II) has the effect of raising blood pressure in the body; at the cellular level, using it to stimulate cells can obtain a cell model that simulates the polarization of macrophages in the pathological state of hypertension.

[0289] The present inventors stimulated SIRT3-inhibited M1920 cells with angiotensin II (Ang II) for 24 hours, and found expression changes of some mitochondrial iron metabolism-related proteins. The mitochondrial iron metabolism-related proteins detected by the present inventors include Mito-ferrin,...

Embodiment 2

[0292] Example 2. The loss of Frataxin activity promotes the accumulation of mitochondrial iron in macrophages, increases the accumulation of lipid peroxides in cells, and leads to the polarization of macrophages

[0293] Synthesis of iron-sulfur clusters is central to mitochondrial iron metabolism. Frataxin is the key to the synthesis of iron-sulfur clusters and participates in multiple processes in mitochondrial iron metabolism. Therefore, in order to further explore the mechanism of mitochondrial iron metabolism in macrophage polarization, the inventors infected M1920 cells with lentivirus, inhibited the expression of Frataxin (Frataxin-shRNA), and observed changes in cell function and phenotype. Lipoflour is a fluorescent probe for the detection of intracellular lipid peroxides. Lipoflour staining and detection by flow cytometry, compared with the control group, Ang II can cause the increase of lipid peroxide, and after the expression of Frataxin was inhibited, the increa...

Embodiment 3

[0297] Example 3. SIRT3 regulates the acetylation modification of Frataxin protein Lysine 189 (Lys 189) and affects mitochondrial iron metabolism, and the iron metabolism mode mediated by Frataxin (K189) affects the inflammatory phenotype of macrophages

[0298] In order to explore the mechanism of the interaction between SIRT3 and Frataxin, the inventors used tool cells to transfect the human embryonic kidney 293T cell line with adenovirus E1A gene, precipitated SIRT3 and Frataxin respectively, and detected it by western blot. The derived SIRT3 forms a complex with Frataxin, suggesting that there is an interaction between SIRT3 and Frataxin ( image 3 A, B). The present inventors further clarified the interaction between exogenous SIRT3 and Frataxin. Using plasmids to introduce HA-SIRT3 and Flag-Frataxin into 293T cells, and immunoprecipitating Flag, the expression of SIRT3 protein can be detected ( image 3 C), and after immunoprecipitation of HA, the expression of Frataxi...

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Abstract

The invention provides an application of SIRT3 mediated macrophage Fraxin deacetylation modification in improvement of inflammatory diseases. The invention reveals that the SIRT3 and the Fraaxin can interact for the first time, and the SIRT3 can mediate the deacetylation modification of the Fraaxin, so that the polarization of the macrophage is regulated. M2-type polarization of macrophages can be adjusted by adjusting the interaction between SIRT3 and Frataxin, so that inflammation-related diseases such as hypertension can be relieved or treated. The invention has important significance for preventing and treating diseases related to mitochondrial metabolism and blood pressure disorder.

Description

technical field [0001] The present invention belongs to the technical field, and more specifically, the present invention relates to SIRT3-mediated Frataxin deacetylation modification and its application in inhibiting macrophage polarization and improving inflammatory diseases; preferably, the inflammatory diseases can be Inflammatory diseases associated with hypertension. Background technique [0002] Macrophages are representative innate immune regulatory cells. The activation of innate immunity and the release of a large number of inflammatory mediators mediated by them are considered to be one of the important pathogenesis of inducing inflammation and inflammation-related diseases. Macrophages possess the ability to polarize and deform, endowing them with distinct cellular phenotypes and functions. The concept of macrophage polarization stems from the observation that macrophages exposed to interferon-γ (Interferon gamma, IFN-γ and interleukin-4, IL-4) have different ge...

Claims

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Application Information

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IPC IPC(8): C12Q1/02A61K45/00A61P29/00
CPCG01N33/5055A61K45/00A61P29/00
Inventor 沈伟利高晶魏彤黄程淋
Owner SHANGHAI INST OF HYPERTENSION
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