Application of anethol trithione in preparation of medicine for preventing and/or treating toxic fatty acid-caused lipotoxicity of body cells

A technology of unsaturated fatty acid and anisitride, applied in the direction of organic active ingredients, drug combinations, antidote, etc., to achieve the effect of increasing beta oxidation, improving transport, and reducing damage

Pending Publication Date: 2020-05-26
THE SECOND XIANGYA HOSPITAL OF CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are currently no related drugs approved for the indication of reducing lipotoxicity

Method used

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  • Application of anethol trithione in preparation of medicine for preventing and/or treating toxic fatty acid-caused lipotoxicity of body cells
  • Application of anethol trithione in preparation of medicine for preventing and/or treating toxic fatty acid-caused lipotoxicity of body cells
  • Application of anethol trithione in preparation of medicine for preventing and/or treating toxic fatty acid-caused lipotoxicity of body cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 1. Effects of anetellitthioate (ADT) on fatty acids

[0043] 1. Preparation of drug

[0044] Add an emulsifier and a suspending agent to anetthio to prepare a suspension containing anetthio (concentrations are 0.07%, 0.14%, 0.28%, and 0.56%), and prepare a blank suspension in the same way for future use.

[0045] 2. Animals and diet

[0046] 54 male Syrian golden hamsters (80-100g) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. (certificate number: SCXK (Beijing) 2016-0011). The golden hamsters were kept in IVC cages, free to eat and drink, carried out a 12-hour light / dark cycle, and maintained a relative humidity of 50%±10%, and a temperature of 22°C to 25°C. Nantong Trofee Feed Technology Co., Ltd. provided a high-fat diet and a control diet, both of which were formulated based on purified raw materials. The control diet was designed to meet all nutritional needs of the hamsters. The cholesterol and lard in the high-fat diet are...

Embodiment 2

[0054] Effects of Anetetithione on Fatty Acids in High Fat Diet

[0055] 750 μl of a mixture of dichloromethane and methanol (CH2Cl2:CH3OH=2:1) ​​was added to the liver tissue and homogenized, followed by centrifugation to obtain a supernatant. Then, 100 μM butylated hydroxytoluene (BHT, to prevent lipid peroxidation), 250 μl CH2Cl2 and 250 μl water were sequentially added to the supernatant, and vortexed for 30 seconds. Transfer the lower phase, centrifuge again to get the supernatant, then evaporate it to dryness under nitrogen, dissolve the residue in n-hexane, add 10 μl of internal standard (heptadecanoic acid) and 2ml of 0.5M KOH-MeOH, place at 60 ℃ water bath heating for 20min. After cooling for 10 min, add 3 ml of 12.5% ​​H 2 SO4 methanol solution (to methylate the sample), and heated again in a water bath at 60° C. for 1 h. After the sample vial was cooled, 2ml of n-hexane and 1ml of saturated sodium chloride (NaCl) solution were added, and allowed to stand for 10 m...

Embodiment 3

[0061] Effects of anetthiorin on gene expression related to hepatic fatty acid metabolism (synthesis, desaturation, uptake, transport, and oxidation).

[0062]The expression of 12 genes involved in hepatic fatty acid metabolism (synthesis, desaturation, uptake, transport, and oxidation) was detected by RT-qPCR.

[0063] Total RNA was extracted from frozen liver tissue using TRIzol reagent (Invitrogen) and primed using PrimeScript according to the manufacturer's instructions. TM RT reagent kit (Takara BIO Inc., Code No. RR047A) was used for reverse transcription.

[0064] Use TB Premix Ex Taq TM II (Tli RNaseH Plus) (Takara BIO Inc., Code No. RR820A) and The system performs RT-qPCR. The total volume of the RT-qPCR reaction was 10 μL, and the cycle parameters were set as follows: pre-denaturation at 95°C for 30 s, followed by 40 cycles of 5 s at 95°C and 60 s at 60°C, followed by annealing extension at 60°C for 1 min. The expression level of each gene relative to GAPDH w...

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PUM

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Abstract

It is found that anethol trithione (H2S donor) can significantly reduce ACC1 and FAS expression and SCD1 expression, up-regulate FADS1 and FADS2 and inhibit de novo synthesis of toxic saturated fattyacid (palmitic acid), inhibit the synthesis of oleic acid, promote the desaturation of fatty acid and adjust the proportion of n-3/n-6 polyunsaturated fatty acid under the condition of high-fat diet.Meanwhile, PAQR3 is inhibited to promote peroxidase body oxidation of lipid and degradation of LDL; in addition, the expression quantity of RTN3 can be reduced, so that the overexpression of SREPB1c is reduced, and the formation of liver cell fat droplets is reduced; the reduced expression of FATP2, FATP4, FATP5 and L-FABP can be up-regulated, which indicates that the drug enhances fatty acid uptake of hepatocytes and promotes transport of the hepatocytes; it is particularly noticed that anethol trithione can remarkably increase the expression quantity of Mitofusin 1, Mitofusin 2 and CPT1a, mitochondrial fusion is promoted, beta-oxidation of fatty acid is enhanced, and the anethol trithione is widely applied to damage of toxic fatty acid to organs such as heart, brain, liver and kidney.

Description

technical field [0001] The invention relates to the field of pharmaceutical application, which is used to prevent damage to the body caused by toxic fatty acids, such as myocardial damage caused by lipotoxicity, fatty liver caused by lipotoxicity, and blood vessel damage caused by lipotoxicity. Background technique [0002] Fat is the most important energy source in the human body. The intake and oxidation of fatty acids (FA), especially free fatty acids, are maintained in a dynamic balance. However, excessive intake and insufficient oxidation can lead to lipid imbalance and lipotoxicity. [1] . Excessive accumulation of fatty acids can cause metabolic abnormalities, dysfunction and cell death in pancreatic islets, liver, muscle, heart, brain and other organs [2,3] , eventually causing dysfunction of the entire organ. [0003] Fatty acids are composed of saturated fatty acids and unsaturated fatty acids. Currently, long-chain saturated fatty acids such as palmitic acid (C16...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/385A61P39/02A61P9/00A61P25/00A61P1/16A61P13/12A61P3/10A61P9/10A61P35/00A61P3/00A61P3/06
CPCA61K31/385A61P39/02A61P9/00A61P25/00A61P1/16A61P13/12A61P3/10A61P9/10A61P35/00A61P3/00A61P3/06
Inventor 刘艺平赵程程唐密密蔡骅林李文群于楠楠刘谋泽原海燕周鹤俊刘盛
Owner THE SECOND XIANGYA HOSPITAL OF CENT SOUTH UNIV
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