CN114209837B - Medicament for treating erectile dysfunction and application thereof - Google Patents
Medicament for treating erectile dysfunction and application thereof Download PDFInfo
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- CN114209837B CN114209837B CN202111644037.4A CN202111644037A CN114209837B CN 114209837 B CN114209837 B CN 114209837B CN 202111644037 A CN202111644037 A CN 202111644037A CN 114209837 B CN114209837 B CN 114209837B
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- A—HUMAN NECESSITIES
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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Abstract
The invention discloses a medicine for treating erectile dysfunction and application thereof. The medicament for treating erectile dysfunction comprises an inhibitor of the Wnt signaling pathway. The invention discovers that the Wnt signal channel is a key channel activated by fibroblasts for the first time, proves that the inhibitor of the Wnt signal channel can obviously inhibit the expression of collagen in the fibroblasts from cavernous bodies, further inhibit the cavernous body fibrosis of the penis, and shows that the inhibitor of the Wnt signal channel has the potential of being used as a medicament for treating erectile dysfunction and provides a new thought for developing the medicament for treating the erectile dysfunction.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a medicine for treating erectile dysfunction and application thereof.
Background
The pathogenesis of Erectile Dysfunction (ED) is largely divided into two phases, early cavernous dysfunction and late cavernous structural changes. The morphological structure of the corpora cavernosa is not changed obviously, and the medicines such as sildenafil or tadalafil can be used for effectively treating the disease by improving the diastole state of smooth muscle by using a type 5 phosphodiesterase inhibitor (PDE 5 i); the latter major pathologies are manifested by cavernous tissue fibrosis, including endothelial cell injury, smooth muscle fibrosis and fibroblast proliferation, transforming growth factor- β (tgfβ) is currently considered to be the most important upstream signal leading to this process, but currently there is a lack of effective intervention for this signal in the ED treatment field, leading to advanced ED patients being treated usually by invasive procedures such as artificial cavernous implantation.
Development of a medicament for treating cavernous tissue fibrosis is one of the important points of research in the field, for example, CN112245414A discloses application of curcumin or a drug carrying system thereof in preparation of a medicament for treating penile erectile dysfunction, and experiments prove that curcumin and a curcumin slow-release drug film can promote growth of nerve axons by up-regulating expression of GAP-43 and MAP-2, promote synthesis of secretory myelin associated proteins by schwann cells by up-regulating expression of Oct-6 and Krox-20, and promote formation of myelin sheaths of the nerve axons. Meanwhile, the method can also effectively promote repair and regeneration of rat cavernous nerve after injury, restore cavernous nerve channel continuity and increase expression of penile tissue nerve ending nNOSmRNA and protein; it can further improve the penile erection function of rats with cavernous nerve injury, reduce the degree of penile tissue fibrosis, and effectively promote the recovery of the penis after the cavernous nerve injury, however, the effective drugs for the cavernous fibrosis of ED patients are still less at present.
The Wnt signaling pathway is a complex protein-acting network whose function is most common in embryonic development and cancer, but is also involved in normal physiological processes in adult animals. The Wnt signaling pathway is a signaling pathway of a set of multiple downstream channels stimulated by ligand protein Wnt and membrane protein receptor binding. Through this pathway, extracellular signals are transmitted into the cell by the activation process of the intracellular segment of the cell surface receptor.
In the prior art, the relationship between the Wnt signal pathway and erectile dysfunction has not been reported.
Disclosure of Invention
Aiming at the defects and actual demands of the prior art, the invention provides a medicament for treating erectile dysfunction and application thereof, wherein the medicament for treating erectile dysfunction comprises an inhibitor of a Wnt signal path, and the invention discovers that the inhibition of the Wnt signal path can inhibit cavernous body fibrosis for the first time and provides a new idea for developing the medicament for treating erectile dysfunction.
In order to achieve the above purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a medicament for treating erectile dysfunction comprising an inhibitor of the Wnt signaling pathway.
In the invention, the corpora cavernosa of normal people and Erectile Dysfunction (ED) patients are detected by a single cell sequencing technology, a key channel activated by fibroblasts, namely a Wnt signal channel, is discovered for the first time, the expression of collagen in the fibroblasts from the cavernosa can be obviously inhibited by using the inhibitor treatment of the Wnt signal channel, and in the experiment of the cavernosa tissue level, the inhibitor of the Wnt signal channel can obviously inhibit the fibrosis of the cavernosa tissue, namely, the inhibitor of the Wnt signal channel is discovered for the first time to have the potential of being used as a medicament for treating erectile dysfunction, and a new idea is provided for developing the medicament for treating the erectile dysfunction.
According to the present invention, inhibitors capable of inhibiting YAP1 protein activity have potential as drugs for treating erectile dysfunction.
Preferably, the inhibitor of the Wnt signaling pathway comprises any one or a combination of at least two of ICG-001, XAV-939 or KY02111, preferably ICG-001.
In the present invention, ICG-001 has the chemical formula C 33 H 32 N 4 O 4 Is a small molecule compound which selectively antagonizes beta-catenin/TCF mediated transcriptional activity and specifically binds to CREB Binding Protein (CBP); XAV-939 of formula C 14 H 11 F 3 N 2 OS selectively inhibits Wnt/β -catenin mediated transcription by inhibiting tankyrase 1/2; KY02111 has the chemical formula of C 18 H 17 C l N 2 O 3 S, acts downstream of APC and GSK3 beta in the WNT pathway.
Preferably, the medicament for treating erectile dysfunction further comprises an adjuvant.
Preferably, the auxiliary material comprises any one or a combination of at least two of pharmaceutically acceptable carriers, excipients or diluents.
Preferably, the dosage form of the medicament for treating erectile dysfunction includes any one of suspension, granule, capsule, powder, tablet, emulsion, solution, drop pill, injection, suppository, enema, aerosol, patch or drop.
Preferably, the medicament for treating erectile dysfunction inhibits cavernous tissue fibrosis.
In a second aspect, the invention provides the use of an inhibitor of the Wnt signaling pathway in the manufacture of a medicament for the treatment of erectile dysfunction.
Preferably, the inhibitor of the Wnt signaling pathway comprises any one or a combination of at least two ICG-001.
In a third aspect, the invention provides the use of an inhibitor of the Wnt signaling pathway in the manufacture of a medicament for inhibiting fibrosis of cavernous tissue.
Preferably, the inhibitor of the Wnt signaling pathway comprises any one or a combination of at least two ICG-001.
In a fourth aspect, the invention provides the use of an inhibitor of the Wnt signaling pathway in the manufacture of a product for inhibiting cavernous tissue fibrosis for the purpose of non-disease diagnosis.
Preferably, the inhibitor of the Wnt signaling pathway comprises any one or a combination of at least two ICG-001.
In the invention, the inhibitor of the Wnt signal pathway is found to be capable of inhibiting the human corpora cavernosa fibrosis for the first time, and the inhibitor of the Wnt signal pathway can be applied to the preparation of a product for inhibiting the cavernosa tissue fibrosis for the purpose of non-disease diagnosis, and the product for inhibiting the cavernosa tissue fibrosis can be further applied to the fields of research on a cavernosa fibrosis mechanism and the like.
Compared with the prior art, the invention has the following beneficial effects:
in the invention, a key channel of fibroblast activation, namely a Wnt signal channel, is discovered for the first time, and the inhibition of the Wnt signal channel can obviously inhibit the expression of collagen in the cavernous fibroblast and activate autophagy of cells, and inhibit the human corpus cavernosum fibrosis, namely, the inhibitor of the Wnt signal channel is discovered for the first time to have the potential of being used as a medicament for treating erectile dysfunction, thereby providing a new thought for developing the medicament for treating the erectile dysfunction.
Drawings
FIG. 1 is a morphology of human cavernous fibroblasts;
FIG. 2 is a graph of human cavernous fibroblasts volume;
FIG. 3 is a graph showing the results of human cavernous fibroblast transcriptome sequencing, with fold change on the abscissa, with the right side of 0 representing the up-regulated gene and the left side of 0 representing the down-regulated gene;
FIG. 4 is a graph of Masson staining results of human cavernous tissue to a scale of 50. Mu.m;
fig. 5 is a graph of the white content ratio of smooth muscle to collagen in cavernous tissue, p < 0.05, p < 0.001, p < 0.0001.
Detailed Description
The technical means adopted by the invention and the effects thereof are further described below with reference to the examples and the attached drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting thereof.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or apparatus used were conventional products commercially available through regular channels, with no manufacturer noted.
In the examples of the present invention, ICG-001, XAV939 and KY02111 were purchased from selleck corporation.
Example 1
This example isolated human cavernous fibroblasts and cultured in vitro, comprising:
human cavernous tissue is isolated, the cavernous tissue obtained by the operation is rinsed 3 times by PBS to remove blood, then cut into block tissues with the size of 2mm multiplied by 2mm, digested for 30min by using digestive enzymes (comprising 4mg/mL type IV collagenase, 4mg/mL type I collagenase, 3mg/mL hyaluronidase and 1.5mg/mL pancreatin), then the block tissues are removed by using a tissue filter screen, and cell components are centrifugally reserved, and cultured after being resuspended by using DMEM culture medium of 10% fetal bovine serum.
Example 2
This example isolated human cavernous tissue and cultured in vitro, comprising:
fresh cavernous tissue obtained by the operation is cut into a size of about 2mm×2mm, a shaking table is placed in a culture box at 37 ℃ by using a low-sugar DMEM culture medium of 10% FBS, and the tissue is placed on the shaking table for culture.
Example 3
This example uses the human sponge fibroblasts cultured in example 1 to test the effect of inhibitors of the Wnt signaling pathway on treating human sponge fibroblasts.
Culturing human sponge fibroblasts cultured in example 1 with high sugar DMED medium containing 2% foetal calf serum at 37deg.C under 5% CO 2 When the cell growth density is 50%, ICG-001 with the concentration of 10 mu M is used for treatment, and the treatment is used as a control, and the treatment is carried out for 14 days by using the equivalent dimethyl sulfoxide (DMSO), the cell morphology is observed, as shown in figure 1, the cells are changed from long shuttles to thin strips, the internal refractive index is obviously improved, the cell volume is obviously reduced (figure 2), the cells are gradually changed to a non-fibrous morphology, the transcriptome sequencing is carried out on the treated fibroblasts, and the GO channel is obviously activated, including LAMP3, TRIB3, RAB39B and the like, as shown in figure 3; whereas "collagen fiber" related genes are significantly down-regulated, including COL1A1, COL3A1, COL5A1, and the like. The ICG-001 can inhibit the collagen expression of fibroblasts and activate autophagy, and the autophagy helps the cells to clear self metabolites and avoid the fibrosis progress caused by local inflammatory reaction. In summary, wnt pathway inhibitors inhibit fibroblast collagen expression and activate autophagy, thereby alleviating cavernous tissue fibrosis.
Example 4
This example tested the effect of inhibitors of different Wnt signaling pathways on inhibition of human cavernous tissue fibrosis using human cavernous tissue cultured in example 2.
Fresh isolated human cavernous tissue was rinsed 3 times with PBS to remove blood and cut into groups of approximately 2mm in sizeThe tissue mass is cultured in vitro in high sugar DMED medium containing 2% foetal calf serum and 10 μm ICG-001, XAV939 or KY02111 at 37deg.C and 5% CO 2 The comparison of the culture without Wnt inhibitor as control (NC) and the mass ratio of smooth muscle to collagen (main component of fibrosis) on day 3 of the culture was determined by Masson staining, the staining results are shown in fig. 4, the comparison of smooth muscle to collagen is shown in fig. 5, and it is clear from fig. 4 and 5 that the smooth muscle in the corpus cavernosum maintains a higher ratio after the culture with Wnt inhibitor under the condition of tissue culture in vitro, fibrosis is significantly inhibited, and furthermore, the fibrosis inhibiting effect of ICG-001 culture is significantly better than that of XAV-939 and KY02111, and the sum of the above shows that Wnt inhibitor can significantly delay the progress of fibrosis in the corpus cavernosum.
In summary, the invention first finds that a key channel of fibroblast activation, namely a Wnt signal channel, and in vitro cell experiments prove that inhibiting the Wnt signal channel can inhibit the collagen expression of the fibroblast and can activate autophagy; in an in vitro tissue culture experiment, the inhibition of the Wnt signal pathway can delay the human corpora cavernosa fibrosis, namely, the potential of the inhibitor of the Wnt signal pathway as a medicament for treating erectile dysfunction is discovered for the first time, and a new idea is provided for developing the medicament for treating erectile dysfunction.
The applicant states that the detailed method of the present invention is illustrated by the above examples, but the present invention is not limited to the detailed method described above, i.e. it does not mean that the present invention must be practiced in dependence upon the detailed method described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (2)
1. Use of an inhibitor of the Wnt signaling pathway in the manufacture of a medicament for the treatment of erectile dysfunction;
inhibitors of the Wnt signaling pathway include ICG-001 and XAV939.
2. The use of an inhibitor of the Wnt signaling pathway in the manufacture of a medicament for inhibiting cavernous tissue fibrosis;
inhibitors of the Wnt signaling pathway include ICG-001 and XAV939.
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| CN202111644037.4A CN114209837B (en) | 2021-12-29 | 2021-12-29 | Medicament for treating erectile dysfunction and application thereof |
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| CN114209837B true CN114209837B (en) | 2023-07-14 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008066627A2 (en) * | 2006-10-24 | 2008-06-05 | Board Of Regents, The University Of Texas System | Adenosine signaling in diagnosis, treatment and prevention of priapism and erectile dysfunction |
| KR20130021315A (en) * | 2011-08-22 | 2013-03-05 | 인하대학교 산학협력단 | Composition for preventing or treating erectile dysfunction comprising dkk2 protein or gene therefor and use thereof |
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| WO2013027911A1 (en) * | 2011-08-22 | 2013-02-28 | Inha Industry Partnership Institute | Composition for treatment or prevention of erectile dysfunction including dkk2 protein or dkk2 gene thereof and use of the composition |
| US11090385B2 (en) * | 2015-12-21 | 2021-08-17 | Gholam A. Peyman | Early cancer detection and enhanced immunotherapy |
| CN105854018B (en) * | 2016-03-28 | 2018-11-13 | 杭州师范大学 | Wnt inhibitor is preparing the application in treating hematopoiesis aplastic disease drug |
| CN109701026B (en) * | 2019-02-21 | 2021-02-09 | 四川大学华西第二医院 | Down syndrome treatment composition and application thereof |
| CN110317208B (en) * | 2019-05-15 | 2023-02-17 | 北京东方百奥医药开发有限公司 | Preparation method and medical application of icaritin derivative |
| CN111317734A (en) * | 2020-03-27 | 2020-06-23 | 广州医科大学附属第二医院 | Wnt signal pathway inhibitor and application |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008066627A2 (en) * | 2006-10-24 | 2008-06-05 | Board Of Regents, The University Of Texas System | Adenosine signaling in diagnosis, treatment and prevention of priapism and erectile dysfunction |
| KR20130021315A (en) * | 2011-08-22 | 2013-03-05 | 인하대학교 산학협력단 | Composition for preventing or treating erectile dysfunction comprising dkk2 protein or gene therefor and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| 高脂血症大鼠阴茎海绵体中NF-kB/ICAM-1表达与勃起功能障碍相关性研究;马运跃;郭玉刚;陈大印;牛文斌;迟宝进;董龙信;;世界最新医学信息文摘(第30期);全文 * |
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