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Therapeutic drug target for preventing and treating skeletal muscle atrophy and application of therapeutic drug target

A technology of skeletal muscle and drug action, applied in the biological field, can solve the problem of not disclosing the association of BCKDC skeletal muscle atrophy

Pending Publication Date: 2018-09-07
SHANGHAI SIXTH PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the prior art does not disclose an association between BCKDC or BCKDK and skeletal muscle atrophy

Method used

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  • Therapeutic drug target for preventing and treating skeletal muscle atrophy and application of therapeutic drug target
  • Therapeutic drug target for preventing and treating skeletal muscle atrophy and application of therapeutic drug target
  • Therapeutic drug target for preventing and treating skeletal muscle atrophy and application of therapeutic drug target

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] This embodiment is to detect the metabolic changes of tumor patients, and its experimental method is as follows:

[0037] (1) The clinical data and serum / urine samples of 222 tumor patients (including 84 tumor cachexia patients, 33 cachexia early stage patients and 105 tumor patients with stable body weight) and 74 healthy controls were collected, and the patients were divided into experimental groups. After the set and validation set, the diagnosis model is constructed.

[0038] (2) Whole blood was collected into EP tubes without anticoagulants, and centrifuged to collect the light yellow serum in the upper layer.

[0039] (3) Take 200μl of serum and add it to EP tube, then add 400μl containing D 2 O and NaN 3 PBS buffer solution, vortexed to mix, centrifuged to remove impurities in the serum, and only retained small molecular metabolites.

[0040] (4) After centrifugation, absorb the supernatant and transfer it to a 5mm NMR tube for measurement.

[0041] See the e...

Embodiment 2

[0044] This embodiment is to detect the metabolic changes of the tumor cachexia animal model, and its experimental method is as follows:

[0045] (1) To establish an animal model of tumor cachexia: when the B16 melanoma carcinoma cells were subcultured to the fourth passage, they were washed with PBS and made into 1×10 7 / ml density suspension, inoculated subcutaneously on the dorsal upper rear side of the right forelimb of male C57BL / 6J mice, each mouse was inoculated with 0.1-0.2ml. The mice were sacrificed about 3 weeks after the inoculation, and the tumor blocks were taken for passage. After the third passage, a stable tumor cachexia model was obtained.

[0046] (2) On the 11th day of inoculation in the experimental mice, obvious tumor masses were seen, and then the length and width of the tumor masses were measured every other day or every day, and the tumor weight was calculated.

[0047] (3) On the 21st day, the blood was collected, and the animals were sacrificed at t...

Embodiment 3

[0052] This example is to study the relationship between BCKDC and myotube atrophy in vitro, and the experimental method is as follows:

[0053] (1) Purchase DMEM high-sugar medium without leucine, add 52.5mg of Leucine- 13 C6 (CLM-2262-H-PK, Cambridge Isotope Laboratories, Inc., Andover, MA), cultured differentiated multinucleated myotubes.

[0054] (2) Cell grouping, C2C12 multinucleated myotubes were treated with dexamethasone and serum from patients with tumor cachexia, and cultured for 48 hours.

[0055] (3) Collect the medium supernatant and cell lysate, add the solvent containing internal standard after the sample is concentrated and freeze-dried, conduct qualitative and quantitative analysis of leucine intermediate metabolites by nuclear magnetic resonance or mass spectrometry, and compare the metabolite change level to analyze metabolites Expression of upstream and downstream proteases.

[0056] (4) For the experimental results see image 3 , treatment of C2C12 mul...

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Abstract

The invention relates to a therapeutic drug target for preventing and treating skeletal muscle atrophy and an application of the therapeutic drug target, and provides the application of a BCKDC (branched-chain alpha-ketoacid dehydrogenase complex) or BCKDK (branched-chain alpha-ketoacid dehydrogenase kinase) as the therapeutic drug target to prevention or treatment of skeletal muscle atrophy and an application of the BCKDC or BCKDK to preparation of drugs for preventing or treating skeletal muscle atrophy and particularly provides a method for screening skeletal muscle atrophy resistant drugsin vivo and in vitro. According to the method, the BCKDC or a gene of the BCKDC is taken as a drug action object or BCKDK or a gene of BCKDK is taken as the drug action object, and an inhibitor of theBCKDC or an activator of BCKDK is selected as a primarily screened drug candidate for preventing or treating skeletal muscle atrophy. The key restrictive metabolic enzyme regulation mechanism of thetherapeutic drug target is analyzed from the perspective of tumor cachexia metabolism regulation, the drug intervention target is determined, the therapeutic drug target has potential clinical application value in treatment of skeletal muscle atrophy, and a new platform is provided for screening of the drugs for treating skeletal muscle atrophy.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to a drug target for preventing and treating skeletal muscle atrophy and its application. Background technique [0002] Skeletal muscle atrophy is common in cachexia patients (including cachexia induced by malignant tumors, chronic heart failure, chronic obstructive pulmonary disease, chronic kidney disease, rheumatoid arthritis and other diseases), elderly patients and patients with muscular dystrophy. It is manifested by increased protein catabolism and insufficient anabolism, leading to severe weight loss and muscle loss. The occurrence of skeletal muscle atrophy not only reduces the quality of life of patients and shortens the survival period of patients, but also seriously affects the implementation of the treatment plan for patients' underlying diseases, reduces the sensitivity of drug treatment, and increases the incidence of complications. [0003] The pathogenesis ...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P21/00C12Q1/6883C12Q1/32C12Q1/48
CPCA61K45/00A61P21/00C12Q1/32C12Q1/485C12Q1/6883G01N2333/90203G01N2333/912C12Q2600/136
Inventor 杨全军郭澄陈力陈林林
Owner SHANGHAI SIXTH PEOPLES HOSPITAL
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