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Application of doxycycline in preparing medicines for enhancing PAC1-R (Pituitary Adenylate Cyclase Activating Polypeptide Type 1 Receptor) dimer dependent constitutive activity

A doxycycline, inherently active technology, applied in drug combinations, active ingredients of tetracycline, diseases, etc., can solve the problems that the target of action has not been elucidated, and the mechanism of action of doxycycline is unclear

Inactive Publication Date: 2013-11-20
余榕捷
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the mechanism of action of doxycycline at the cellular and molecular levels is unclear, and its target has never been elucidated so far

Method used

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  • Application of doxycycline in preparing medicines for enhancing PAC1-R (Pituitary Adenylate Cyclase Activating Polypeptide Type 1 Receptor) dimer dependent constitutive activity
  • Application of doxycycline in preparing medicines for enhancing PAC1-R (Pituitary Adenylate Cyclase Activating Polypeptide Type 1 Receptor) dimer dependent constitutive activity
  • Application of doxycycline in preparing medicines for enhancing PAC1-R (Pituitary Adenylate Cyclase Activating Polypeptide Type 1 Receptor) dimer dependent constitutive activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 Doxycycline promotes the proliferation of PAC1-CHO cells expressing PAC1-R dimers

[0027] Published articles (PLoS One. 2012;7(12):e15811) have clarified that PAC1-R can form dimers, and the formation of dimers depends on the first Cys at the N-terminal (position 25), if By mutating Cys to Ala, the mutant M-PAC1-R cannot dimerize. The structural model of PAC1-R is shown in the figure figure 1 ; PAC1-R and M-PAC1-R dimer model diagram figure 2 .

[0028] The established CHO cell line PAC1-CHO stably expressing PAC1-R and the CHO cell M-PAC1-CHO stably expressing Cys / Ala mutant M-PAC1-R were used in the experiment. The effect of doxycycline on the proliferation activity of the two cell lines was determined by MTT assay. Results (such as image 3 ) found that after incubating cells with 100-1000ng / mL doxycycline for 48 hours, the cell viability was measured by MTT method, and the ratio of cell viability compared with the untreated control group was c...

Embodiment 2

[0029] Example 2 Comparison of doxycycline and PAC1-R agonist maxadilan

[0030] In order to further determine whether doxycycline is an agonist of PAC1-R, the specific agonist maxadilan (1nM) of PAC1-R was used to compare the activity of doxycycline (100ng / mL). The results are as follows Figure 4 As shown, after incubating the cells for 48 hours, the cell viability was measured by MTT method, and it was found that both PAC1-CHO and M-PAC1-CHO were positive for the PAC1-R specific agonist maxadilan (P<0.01, PAC1-CHO treated with maxadilan and M-PAC1 -PAC1-CHO vs PAC1-CHO and M-PAC1-CHO of the blank control), and maxadilan has a more significant effect on the proliferation of M-PAC1-CHO (may be related to dimer steric hindrance that hinders ligand binding); and strong Mycin only had proliferative effects on PAC1-CHO, but basically had no effect on M-PAC1-CHO (P<0.01, PAC1-CHO vs. M-PAC1-CHO and CHO). This result indicates that doxycycline is not an agonist of PAC1-R, but ac...

Embodiment 3

[0031] Example 3 Doxycycline promotes anti-apoptosis of PAC1-CHO cells

[0032] The auxotrophic-induced apoptosis model was prepared by serum-free culture, and the effect of doxycycline on the anti-apoptotic activity of cells expressing PAC1-R dimer was detected. The result is as Figure 5 As shown, after 24 hours of serum-free culture, the activities of the three types of cells all decreased significantly, the residual activity of M-PAC1-CHO cells was 41.6±11.6%, the residual activity of PAC1-CHO was 51.4±8.8%, and the residual activity of CHO was 33.3±10.4%; When the serum was removed and doxycycline (100ng / mL) was added to culture, the residual activity of PAC1-CHO cells was significantly increased to 74.5±9.4% (P<0.01, serum-doxycycline+ group vs. serum-doxycycline-group) . However, the same concentration of doxycycline did not promote the anti-apoptotic function on M-PAC1-CHO and CHO that could not produce PAC1-R dimer. It can be seen that doxycycline only has an ef...

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Abstract

The invention discloses an application of doxycycline for preparing medicines for enhancing PAC1-R (Pituitary Adenylate Cyclase Activating Polypeptide Type 1 Receptor) dimer dependent constitutive activity. The doxycycline is used as a B type G-protein-coupled receptor PAC1-R dimmer for enhancing the PAC1-R dimer dependent constitutive activity so as to exert the biological functions through a PAC1-R mediated signal transduction pathway. As PAC1-R is a specific receptor of neuropeptide PACAP (Pituitary Adenylate Cyclase Activating Polypeptide), and PAC1-R mediates various important biological functions, so that the activity of the doxycycline to the PAC1-R dimer indicates that the doxycycline can be applied to treatment and medicinal development of diseases taking PAC1-R as target spots, for example, memory impairment, oligospermia, asthenozoospermia, posttraumatic stress disorder and the like.

Description

technical field [0001] The present invention relates to doxycycline, in particular, relates to the application of doxycycline in the preparation of drugs for enhancing the intrinsic activity dependent on PAC1-R dimer. Background technique [0002] Doxycycline is a broad-spectrum tetracycline antibiotic, which is a semi-synthetic tetracycline obtained by deoxygenating the 6α-position of the parent ring of tetracycline. At present, studies have proved that the main principle of tetracycline antibacterial drugs is 1) inhibiting bacterial protein synthesis by binding to bacterial ribosomes; 2) changing the permeability of bacterial cell membranes and inhibiting bacterial DNA replication. [0003] In recent years, doxycycline has been found to have a variety of new effects other than antibiotics, including promoting thymocyte proliferation, anti-thymocyte apoptosis, promoting nerve cell proliferation, and anti-neuron cell apoptosis. Doxycycline has also been found clinically th...

Claims

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Application Information

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IPC IPC(8): A61K31/65A61P25/28A61P25/16A61P25/00A61P15/08
Inventor 余榕捷陈建环
Owner 余榕捷
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