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Method for obtaining medicament with mitochondrial uncoupling effect

A mitochondrial uncoupling, mitochondrial technology, applied in the field of biology and medicine, to achieve high cell-specific effects

Inactive Publication Date: 2018-08-14
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far no safe mitochondrial uncoupler has been found for clinical application

Method used

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  • Method for obtaining medicament with mitochondrial uncoupling effect
  • Method for obtaining medicament with mitochondrial uncoupling effect
  • Method for obtaining medicament with mitochondrial uncoupling effect

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0148] 6.5 Preparation of mouse cerebral hemorrhage model, cerebral edema and behavioral detection

[0149] 6.5.1 Method for making cerebral hemorrhage model caused by injection of autologous blood into striatum

[0150] Select ICR (CD-1) male mice with a body weight of about 25g-30g, anesthetize them with chloral hydrate, place them in a stereotaxic instrument, fix them, and start the operation. Apply iodophor to the top of the head, and cut a wound with a length of 1cm on the top of the head. , Use hydrogen peroxide slurry to find the position of the anterior bregma. After determining the position of the anterior bregma, open 0.5mm in the front and 2.0mm in the side. Find the position of the needle in the left brain, and then gently drill the hole with a dental drill. For blood collection, use tail blood collection, cut an opening on the tail, draw 15 μl of arterial blood with a 50 μl micro-syringe, quickly move the syringe to the stereotaxic instrument, slowly insert the ne...

Embodiment 1

[0204] Example 1: Preliminary Screening

[0205] The inventors have found through research that the oxidation of specific sulfur-containing compounds (or the products of these sulfur compounds transformed / metabolized in vivo or in cells) by SQR can lead to reverse electron transfer (RET) at the level of complex I in the respiratory chain, resulting in mitochondrial Uncoupling. Therefore, inhibition of respiratory chain complex I can specifically inhibit SQR-mediated mitochondrial uncoupling: including inhibiting the decrease of transmitochondrial inner membrane potential (abbreviated as mitochondrial membrane potential), inhibiting the decrease of intracellular ATP level and Increase in OCR values ​​in the presence of oligomycin. The mitochondrial uncoupling agents that have been discovered so far are protons or ionophores, and their uncoupling effects do not depend on complex I of the respiratory chain. Using this feature, the mitochondrial uncoupler or AMPK activator based...

Embodiment 2

[0211] Example 2: Confirmation that the mitochondrial uncoupling effect of candidate substances is dependent on the function of mitochondrial respiratory chain complex I

[0212] The inventors further tested whether the mitochondrial respiratory chain complex I inhibitor rotenone could block the other two important features of mitochondrial uncoupling caused by the candidate substance on microglial cells: 1) reduce intracellular ATP levels (and increase ADP / ATP ratio); 2) Increased cellular oxygen consumption (OCR) in the presence of oligomycin.

[0213] After the BV2 microglial cells endogenously expressing SQR were treated with the substances to be screened or solvents, the intracellular ATP level and ADP / ATP ratio were detected. The results showed that simple rotenone (Rot) treatment could lead to a decrease in ATP levels in BV2 microglia ( figure 2 A, 2C, 2E) and ADP / ATP ratio increased ( figure 2 B, 2D, 2F). The proton-type mitochondrial uncoupler FCCP also caused a...

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Abstract

The invention belongs to the fields of biology and medicine and discloses a method for generating mitochondria uncoupling and activating adenosine monophosphate activated protein kinase (AMPK). The method is characterized in that horizontal reversed electron transfer of a mitochondrial respiratory chain complex I is caused by oxidation of a sulfur-containing compound through SQR, cross-mitochondrial inner membrane potential is reduced, and thereby mitochondrial uncoupling is generated; by the mitochondrial uncoupling, the synthesis level of ATP in cells can be reduced and further the AMPK is activated. The invention also discloses a method for obtaining a mitochondria uncoupling agent and an AMPK activator based on the SQR. The experiment verifies that the method disclosed by the inventionhas the advantages that firstly, oxidation of the sulfur-containing compound by the SQR is a novel method for generating the mitochondria uncoupling or activating the AMPK; secondly, a novel mitochondria uncoupling agent or the AMPK activator can be obtained on the basis of the SQR; thirdly, an obtained compound has the mitochondria uncoupling of cell specificity or AMPK activating effect as wellas low toxic and side effects, and can be used for treating related diseases.

Description

technical field [0001] The invention belongs to the field of biology and medicine, discloses a new method leading to mitochondrial uncoupling or AMPK activation, and discloses a method based on sulfide-quinone oxidoreductase (SQR, Sulfide:quinone oxidoreductase) to obtain mitochondrial uncoupling or AMPK activating substances, and the use of the substances obtained by this method in the preparation of medicines for treating related diseases. Background technique [0002] Mitochondria are the key organelles of cell metabolism and the main place for the synthesis of high-energy substance adenosine triphosphate (ATP) in cells. ATP provides the main energy for life activities. In general, the process of releasing energy by oxidation of substrates such as glucose in cells is coupled with the process by which mitochondrial ATP synthase uses the energy released by oxidation of substrates to phosphorylate adenosine diphosphate (ADP) to generate ATP, that is, substrates such as gluc...

Claims

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Application Information

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IPC IPC(8): G01N33/52G01N33/50A61K31/385A61K31/255A61P7/04A61P25/00A61P3/00A61P3/04A61P39/06A61P9/10A61P3/10A61P35/00
CPCA61K31/255A61K31/385A61P3/00A61P3/04A61P3/10A61P7/04A61P9/10A61P25/00A61P35/00A61P39/06G01N33/5079G01N33/52
Inventor 程坚
Owner SUZHOU UNIV
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