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Application of BCAT2 inhibitor in preparation of medicine for preventing and/or treating BCAT2-mediated related metabolic diseases

A technology for metabolic diseases and inhibitors, applied in the field of medicine, can solve the problems that obesity cannot be found fundamentally, and the therapeutic effect of BCAT2 inhibitors on obesity has never been reported.

Active Publication Date: 2022-02-22
FUDAN UNIV SHANGHAI CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the role of BCAT2 in obesity deserves attention. However, the effect of BCAT2 on obesity has not been studied in adipose tissue, nor has the therapeutic effect of BCAT2 inhibitors on obesity been reported.
Therefore, it is impossible to fundamentally find a drug that can treat obesity

Method used

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  • Application of BCAT2 inhibitor in preparation of medicine for preventing and/or treating BCAT2-mediated related metabolic diseases
  • Application of BCAT2 inhibitor in preparation of medicine for preventing and/or treating BCAT2-mediated related metabolic diseases
  • Application of BCAT2 inhibitor in preparation of medicine for preventing and/or treating BCAT2-mediated related metabolic diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 Knockout of BCAT2 can suppress obesity

[0054] 1.1 Preparation of mouse model. A transgenic mouse model of conditional knockout of Bcat2 was prepared, and Aipoq-cre+Bcat2 was obtained by crossing the transgenic mice. flox / flox mouse (i.e. Bcat2 KO mice, such as figure 1 shown). Genotyping of mice using PCR and discovery of Bcat2 KO Mice are specific for Bcat2 knockout in adipose tissue (e.g. figure 2 shown), Bcat2 KO Mice no longer express Bcat2; Bcat2 KO In mice other organs outside the fat are not affected (eg image 3 shown).

[0055] 1.2 Effects on fat - improve obesity, blood sugar, triglycerides, fatty acids, cholesterol and leptin

[0056] (1) High-fat feed (60% fat in feed) feeding Bcat2 KO Mice and control mice (untreated normal mice) for 13 weeks. Bcat2 KO Mice are significantly resistant to high-fat diet-induced obesity, (e.g. Figure 4 shown, Figure 4 a Take pictures of the appearance of mice, Figure 4 b is the trend comparison o...

Embodiment 2

[0061] Example 2 Study on the mechanism that knocking out BCAT2 can inhibit obesity

[0062] 2.1 Discover the underlying mechanisms at the cellular level. The primary adipocytes of mice were isolated, 5-week-old male mice were taken, the abdomen was cut open, and the inguinal fat on both sides was cut off, minced in DMEM (containing 1% collagenase) medium, and shaken and digested at 37C for 2h. The supernatant was removed by centrifugation, the pellet was resuspended in DMEM medium, undigested tissue blocks were removed by filtration with a 45 μm membrane filter, and the filtrate was centrifuged and resuspended in DMEM cultured in a 10 cm cell culture dish in an incubator. After passage in 6-well plates, the induction of mature adipocytes begins after cell contact inhibition. Induction using 5mM 3-isobutyl-1-methylxanthine, 1mM dexamethasone, 125nM indomethacin, 850nM insulin, 1nM 3,3',5-Triiodo-L-thyronine (3,3',5-Triiodo-L-thyronine)| and 1 μM rosiglitazone (rosiglitazone)...

Embodiment 3

[0063] Example 3BCAT2 inhibitor screening.

[0064] 3.1BCAT2 protein purification. Using 293T cell cDNA as template, PCR reaction was performed to obtain the PCR product of human BCAT2 containing double restriction sites XbaI and Xhol. The digested PCR product and pET28a vector were separated by 1% agarose gel and the gel recovery kit was used for fragment recovery. The recovered fragment and vector were ligated in a molar ratio of 3:1. After obtaining the fragment, use restriction endonuclease to clone into pET28a vector, transform pET28a-Bcat2 into BL21(DE3) competent cells, take the plasmid and transform it into 50 μL BL21 competent cells, and put it into a 42°C water bath for 30s after ice bath for 30 minutes. . Add 250 μL of antibiotic-free LB liquid medium, pre-shake at 225 rpm for 40 min at 37° C., and then spread it on the LB solid medium plate supplemented with 50 μg / ml kanamycin, and culture at 37° C. overnight. Induce the expression of the protein. 1 L of bacte...

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Abstract

The invention provides application of a BCAT2 inhibitor in preparation of a medicine for preventing and / or treating BCAT2-mediated related metabolic diseases for the first time, wherein the BCAT2 inhibitor is telmisartan; the related metabolic diseases are selected from any one or more of fatty liver, obesity, hypertriglyceride, hyperglycemia, insulin resistance, hypercholesteremia, diabetes mellitus, inflammation caused by high expression of BCAT2 and tumors caused by high expression of BCAT2. The telmisartan can be applied to preparation of medicines for preventing and / or treating BCAT2-mediated related metabolic diseases, so that the metabolic diseases can be better resisted.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the use of a BCAT2 inhibitor in the preparation of a medicine for preventing and / or treating BCAT2-mediated related metabolic diseases. Background technique [0002] Branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) are essential amino acids for humans. Studies have found that branched-chain amino acids are significantly elevated in serum of patients with obesity and related metabolic diseases, and a diet high in branched-chain amino acids can increase the risk of obesity and related metabolic diseases, and a diet low in branched-chain amino acids can alleviate obesity and related metabolic diseases. . However, the metabolic function of branched-chain amino acids in obesity has remained unclear. [0003] Branched-chain amino acid transaminase (BCAT) is a key enzyme in the catabolism of branched-chain amino acids. BCAT is involved in the first step ...

Claims

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Application Information

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IPC IPC(8): A61K31/4184A61P1/16A61P3/04A61P3/06A61P3/10A61P5/50A61P29/00A61P35/00
CPCA61K31/4184A61P1/16A61P3/04A61P3/06A61P3/10A61P5/50A61P29/00A61P35/00
Inventor 雷群英马齐襄尹淼
Owner FUDAN UNIV SHANGHAI CANCER CENT
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