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Use of nitrine phlorizin in preparing drug for treating non-alcoholic fatty liver disease

A non-alcoholic, nitrogenated phlorizanin technology, applied in the field of medicine, can solve problems such as 4-AzGGPPS protein that has not been shown in research, and achieve the effect of protecting liver function, reducing lipid accumulation, and lowering levels

Inactive Publication Date: 2018-11-02
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Azide phloritin has been reported as an inhibitor of sodium-glucose co-transporter 2 (sodium-dependent glucose transporters 2, SGLT-2) expressed in the kidney, which can inhibit the reabsorption of glucose by the kidney, but no studies have shown Whether 4-Az can promote the degradation of GGPPS protein
Azidophloridin can directly target and bind GGPPS, trigger GGPPS degradation through the ubiquitination-proteasome pathway, thereby blocking the transmission of various signaling pathways involved in the GTPase family (GTPase), and inhibiting liver function. However, there is no report on the use of azide phlorizin in the treatment of non-alcoholic fatty liver disease

Method used

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  • Use of nitrine phlorizin in preparing drug for treating non-alcoholic fatty liver disease
  • Use of nitrine phlorizin in preparing drug for treating non-alcoholic fatty liver disease
  • Use of nitrine phlorizin in preparing drug for treating non-alcoholic fatty liver disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[0046] Example 3, 4-Az promotes ubiquitination and degradation of GGPPS

[0047] After administration of 4-Az, the ubiquitination-proteasome inhibitor MG132 and the lysosome-autophagosome fusion inhibitor CQ were treated respectively. When the two degradation pathways were respectively destroyed, only the treatment of MG132 prevented the expression of GGPPS decline. And the expression of GGPPS increased with the increase of MG132 concentration. We therefore concluded that the ubiquitination-proteasome inhibitor MG132 was able to reverse the decrease in GGPPS expression caused by 4-Az. The 293T co-transfected with GGPPS and Ub plasmids were divided into four groups: negative control group (DMSO), drug treatment group (4-Az, 10uM), proteasome inhibition group (DMSO+MG132), proteasome and drug combined Group (4-Az+MG132). MG132 prevents degradation by preventing the entry of target proteins tagged with ubiquitinated small molecules into the proteasome. When 4-Az and MG132 tre...

Embodiment 4、4

[0048] Example 4, 4-Az can directly bind to the mode of action of GGPPS

[0049] The concentration of the purified GGPPS-EGFP-His fluorescently expressed fusion protein was kept constant, and the concentration of the titrant used in each titration, that is, the concentration of FPP, the GGPPS positive control substrate, was changed. The thermophoretic movement of unbound GGPPS is different from that of the substrate FPP bound to GGPPS. The time shown is t=30 seconds. At different FPP concentrations, the normalized fluorescence signal of GGPPS is formed at Kd Fitted binding curve. The titrant was replaced with the natural active small molecule that needs to be identified. Compared with the control group EGFP, the fluorescence detection showed that 4-Az was directly combined with GGPPS. It can be seen that 4-Az promotes the degradation of GGPPS by directly combining with GGPPS to promote the ubiquitination of GGPPS.

[0050] Therapeutic effect of phlorizin azide on non-alcohol...

Embodiment 1

[0062] Embodiment 1, establishment of non-alcoholic fatty liver mouse model

[0063] Establishment of non-alcoholic fatty liver model mice by food-induced induction. The 4-week-old mice mentioned above in "General Materials and Methods" were fed with high-fat diet (containing 60% fat) for 8 weeks, and fatty liver was successfully induced after 8 weeks.

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Abstract

The invention discloses use of nitrine phlorizin (4-Az) as a key branching enzyme GGPPS inhibitor in an MVA pathway (mevalonate pathway), especially use in preparing a drug for treating non-alcoholicfatty liver disease. According to a series of experiments, the 4-Az can cause GGPPS protein to generate ubiquitin-proteasome pathway dependent degradation, has an inhibiting effect on GGPPS protein expression, and can be used as the inhibitor of GGPPS protein expression. More specifically, the nitrine phlorizin can reduce lipid accumulation and fatty degeneration of the livers, can reduce level ofglutamic-pyruvic transaminase and glutamic oxalacetic transaminase in blood, has the activity of protecting the liver function, and can be used for preparing the drug for treating the non-alcoholic fatty liver disease.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the use of azide phlorizin in the preparation of medicines for treating non-alcoholic fatty liver. Phloridizin azide can reduce lipid accumulation in the liver and has a significant effect on the treatment of non-alcoholic fatty liver. Background technique [0002] Non-alcoholic fatty liver disease refers to the excessive deposition of fat in liver cells caused by factors other than alcohol. Its development process generally includes simple steatosis, steatohepatitis, liver fibrosis and other lesions in the liver. In severe cases, liver cirrhosis will occur. , liver failure and even liver cancer. The prevalence of the disease continues to increase globally, paralleling increases in obesity, and is becoming a serious public health problem. [0003] Nonalcoholic fatty liver disease is the result of multiple factors such as genetics, environment, metabolism, and stress, and is ...

Claims

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Application Information

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IPC IPC(8): A61K31/7034A61P1/16
CPCA61K31/7034
Inventor 薛斌李朝军齐雅玲
Owner NANJING UNIV
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