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Application of annonaceous acetogenins polyether analog AA005 and structural analogs thereof to pharmacy

A technology similar to anemone lactone and structure, which is applied in the fields of biotechnology and medicine, can solve the problems of side effects and lack of pertinence, and achieve the effects of good stability, inhibition of fat accumulation, and easy absorption

Active Publication Date: 2014-10-29
RUIJIN HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, various lipid-lowering drugs have their own applicable conditions, have different degrees of side effects, and lack of pertinence

Method used

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  • Application of annonaceous acetogenins polyether analog AA005 and structural analogs thereof to pharmacy
  • Application of annonaceous acetogenins polyether analog AA005 and structural analogs thereof to pharmacy
  • Application of annonaceous acetogenins polyether analog AA005 and structural analogs thereof to pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: AA005 and its structural analogs can specifically inhibit the accumulation of triglyceride in preadipocyte 3T3-L1.

[0039] 3T3-L1 cells continued to grow until two days after complete contact inhibition, part of the cells were harvested as preadipocytes at day 0, and the other part was induced to differentiate in DMEM high-glucose medium containing 10% fetal bovine serum by adding MDI triple drug, and the cells in the treatment group Different concentrations of AA005 were added, and the cells were replaced every 48 hours. Oil red O staining showed that compared with the 0-day cells, the adipocytes on the 6th day of differentiation were generally observed, and there were obvious lipid droplets in the cells under the microscope, indicating that the induction of differentiation was successful. The cells in the control group and the AA005 treatment group that were induced to differentiate for 8 days were stained with Oil Red O, and then photographed grossly and ...

Embodiment 2

[0041] Example 2: AA005 and its structural analogs can down-regulate the protein expression of apoptosis-inducing factor AIF and mitochondrial complex I members in 3T3-L1 cells.

[0042] In order to study the mechanism of AA005 inhibiting triglyceride accumulation in preadipocytes 3T3-L1, cultured 3T3-L1 cells were continuously grown to complete contact inhibition for two days, some cells were harvested as preadipocytes at day 0, and the other part was added MDI triple drug to Differentiation was induced in the cell culture medium, and the cells in the drug-dosed group were treated with 330 nM AA005 at the same time, and the cell culture medium containing the drug was replaced every 48 hours. Cells in the control group and AA005 treatment group at different phases of induced differentiation were harvested, and the expression of apoptosis-inducing factor AIF, important member of mitochondrial complex Ⅰ NDUFS1 and mitochondrial marker protein COXⅣ were detected by Western blot ( ...

Embodiment 3

[0043] Example 3: AA005 and its structural analogs can specifically inhibit the accumulation of fat in nematodes.

[0044] Since C. elegans is a good biological model for studying fat metabolism, we thought of further verifying the effect of AA005 on fat metabolism in living organisms. Synchronize nematodes with double mutations of acs-20 and acs-22 genes to the L1 stage, culture the nematodes on the plate with OP50 bacteria to the L3 stage, transfer the nematodes to the liquid medium, and add 4 μM AA005, A1, A2, A3 treated the nematodes for 12 hours, removed the drug, cultured on the plate for 12 hours, fixed each group of nematodes when the nematodes were in early adulthood, stained with oil red O, and observed the fat accumulation in the nematodes under a microscope ( Figure 4 A). At the same time, according to literature reports, nematodes that inhibit the expression of daf-2 in nematodes by RNAi method increase fat accumulation, which is used as a positive control for o...

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Abstract

The invention discloses application of annonaceous acetogenins polyether analog AA005 and structural analogs thereof to pharmacy, and especially relates to application to prepare medicine for preventing or treating diseases about abnormal lipid metabolism. The inventor firstly discovers that AA005 is capable of inhibiting accumulation of triglycerides in preadipocyte 3T3-L1 and inhibiting accumulation of fat in nematodes, and apoptosis-inducing factor AIF is capable of specifically mutually acting with AA005 and participating the process of AA005 influencing lipid metabolism. AA005 may well provides a treatment method for selectively targeting adipocyte as a small molecule compound taking mitochondrial as target, and has good medicinal prospect to prepare medicines for preventing or treating diseases about abnormal lipid metabolism. The active substance AA005 and the structural analogs thereof are safe, low in toxicity and strong in pharmacological action, have the characteristics of absorption easiness, good stability and the like, and are relatively suitable for exploitation as novel medicines, food, health-care products and / or food additives.

Description

technical field [0001] The invention relates to the fields of biotechnology and medicine, in particular to the application of the active substance anemone lactone polyether analogue AA005 and its structural analogues in the preparation of drugs for the prevention or treatment of abnormal lipid metabolism diseases. Background technique [0002] In metazoans, energy homeostasis is regulated by cells and biological networks within the body. These networks control the behavior of the body and some complex and intertwined physiological functions, such as the absorption and transportation of nutrients, lipid synthesis, storage and utilization, etc. Fat is an important form of energy storage in the body, mainly composed of triglyceride (TG), whose synthesis and decomposition determine the body's fat mass. Fat cells are the "warehouse" where the body synthesizes and stores fat. When the body is in fasting, starvation or sympathetic stimulation, the fat stored in fat cells is hydro...

Claims

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Application Information

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IPC IPC(8): A61K31/365A61K31/4525A61P3/00A61P3/06A23L1/30
Inventor 王立顺韩冰吴朝霞姚祝军
Owner RUIJIN HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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