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Inhibitor capable of inhibiting excessive proliferation of keratinocytes, inhibitor composition, and applications of inhibitor

A cell-inhibiting and inhibitory technology, applied in drug combinations, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of unclear molecular mechanism, complex and diverse structure types, psoriasis chemical structure types and action targets The point and mechanism have not been fully elucidated to achieve the effect of inhibiting cell cycle progression, inhibiting abnormal immune function, and preventing excessive activation

Inactive Publication Date: 2017-06-23
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are more than 450 kinds of chemical components in Tripterygium wilfordii, and the structure types are complex and diverse. The chemical structure types, targets and mechanisms of the active ingredients for the treatment of psoriasis have not yet been fully elucidated.
Triptolide, triptolide ketone, and triptolide are three representative terpenoid compounds in Tripterygium wilfordii, which have a variety of pharmacological activities, but the application of monomer components to treat psoriasis has not been reported clinically, and The molecular mechanism is still unclear

Method used

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  • Inhibitor capable of inhibiting excessive proliferation of keratinocytes, inhibitor composition, and applications of inhibitor
  • Inhibitor capable of inhibiting excessive proliferation of keratinocytes, inhibitor composition, and applications of inhibitor
  • Inhibitor capable of inhibiting excessive proliferation of keratinocytes, inhibitor composition, and applications of inhibitor

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Experimental program
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Effect test

Embodiment 1

[0033] Detect the abnormal expression level of miR-17-92 in the clinical samples of patients with psoriasis and analyze the correlation with the severity of the disease. The results are as follows: figure 1 shown.

[0034] Take 30 skin lesions of psoriasis patients and 30 normal control skins respectively, cut off the subcutaneous tissue, about 100mg, freeze in liquid nitrogen and grind, then add 1mL Trizol, extract according to the instructions of the RNA extraction kit, and extract the total RNA with ultraviolet light Spectrophotometer was used to measure OD value and concentration. miR-17-92 exists in the form of mRNA when it is not processed into mature miRNA. The expression of miR-17-92 cluster is detected by the method of detecting mRNA, and the reverse transcription kit and SYBR fluorescence quantitative detection reagent of TAKARA company are used. kit; at the same time, the expression of miR-17-92 mature body was detected using the reverse transcription kit and SYBR ...

Embodiment 2

[0037] Using bioinformatics analysis technology to predict the upstream and downstream regulatory molecules of miR-17-92, the results are as follows figure 2 shown.

[0038] Through the website http: / / genome.ucsc.edu / , the promoter sequence of the upstream 5000bp of the miR-17-92 gene cluster was obtained, and at the same time, the website http: / / jaspar.genereg.net / was used to predict and discover the initiation of miR-17-92 Subregions present potential STAT1 binding sites, see figure 2 A in A, suggesting that STAT1 has a transcriptional activation effect on miR-17-92. Using bioinformatics prediction software Targetscan, miRbase, Pictar, etc. to predict and analyze, it was found that multiple mature miRNAs in miR-17-92 had sites that combined with the target gene CDKN2B and SOCS1 mRNA 3'UTR.

[0039] See results figure 2 In B, it is suggested that miR-17-92 may have a post-transcriptional regulatory effect on them.

Embodiment 3

[0041] CCK-8 method was used to detect the effect of 7 kinds of Tripterygium wilfordii monomer compounds on HaCaT cells alone on cell proliferation. For the results, see image 3 .

[0042] Test samples: representative compounds of Tripterygium wilfordii monomer, the main structural types are sesquiterpene alkaloids, diterpenoids and triterpenoids. (1) tripterine (LGT-1), (2) tripterine (LGT-2), (3) tripterine (LGT-3), (4) triptolide (LGT-4 ), (5) triptolide A (LGT-5), (6) triptolide (LGT-6), (7) triptolide ketone (LGT-7), (8) triptolide + triptolide Laclastin + triptolide ketone, the combination of three monomers (LGT-8). Sample preparation: DMSO was used as the solvent, and the initial concentration of the prepared compound was 1.0×10 -2 M; serially diluted to 6 concentration gradients as the test sample: 10 -3 M, 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M; in image 3 Among them, the effect of three kinds of tripterygium wilfordii monomer compounds on the cell pr...

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Abstract

The invention belongs to the fields of biotechnology and medicine, and relates to an inhibitor capable of inhibiting the excessive proliferation of keratinocytes, an inhibitor composition, and applications of the inhibitor. The inhibitor taking triptolide, triptonide or tripterine as the representative can inhibit the excessive proliferation of the keratinocytes, specifically, the expression levels of STAT1 and p-STAT1 can be inhibited, then the expression level of miR-17-92mRNA is down-regulated, then, miR-17-92 target gene CDKN2B is regulated, the secretion levels of inflammatory factors CXCL1, CXCL10, CXCL16 and IL-6 in cells are inhibited, and finally, the cell cycle progression and immune function abnormity are inhibited; triptolide, tripterine and triptonide can effectively inhibit the proliferation of the keratinocytes, and the effective doses respectively achieve 60nM, 100nM and 80nM.

Description

technical field [0001] The invention belongs to the field of biotechnology and medicine, and relates to an inhibitor and the application of the inhibitor in medicine, in particular to a method of regulating miR-17-92 and its downstream target genes through the STAT1 pathway to inhibit the excessive proliferation of keratinocytes and Inhibitors capable of inhibiting excessive proliferation of keratinocytes due to abnormal immunity, inhibitor composition and application thereof in the prevention and treatment of psoriasis. Background technique [0002] Psoriasis is an autoimmune skin disease with an incidence of about 2% in the natural population. The clinical manifestations of this disease are widespread skin erythema, desquamation, and severe itching, and even changes such as pustules, erythroderma, and joint damage; the main pathological features are accelerated proliferation of epidermal keratinocytes, and mitotic cycle Shortening, and resulting pathological manifestation...

Claims

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Application Information

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IPC IPC(8): A61K31/585A61K31/56A61P17/06
CPCA61K31/585A61K31/56A61K2300/00
Inventor 李春英安亚文郭森张伟刚高天文王刚
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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