CN113616638A - Application of myricetin in preparation of transforming growth factor beta receptor 1 inhibitor - Google Patents
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Abstract
The invention discloses an application of myricetin in preparation of a transforming growth factor beta receptor 1 inhibitor, belonging to the technical field of medicines. The invention discloses the application of myricetin in preparing a transforming growth factor beta receptor 1 inhibitor for the first time, and experiments prove that the myricetin has the effect of inhibiting the expression of TGFBR1 and a downstream signal molecule Smad2/3 thereof in human vascular smooth muscle cells, and based on the natural and safe characteristics of the myricetin, the myricetin provides possibility for treating diseases caused by TGF beta pathway disorder, and particularly provides the application in medicines responding to TGFBR 1-related diseases.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of myricetin in preparation of a transforming growth factor beta receptor 1 inhibitor.
Background
Atherosclerosis (AS) is a common pathological basis for the increasing incidence, disability rate and mortality of cardiovascular and cerebrovascular related diseases, and the pathogenesis of AS mainly includes lipid infiltration theory, endothelial injury-response theory, platelet aggregation and thrombosis hypothesis, smooth muscle cell cloning theory and the like, wherein the phagocytosis of oxidation-modified low-density lipoprotein cholesterol, free cholesterol, microvesicles and apoptotic cells by vascular smooth muscle cells plays a key role in the development of Atherosclerosis. Migration and proliferation of vascular smooth muscle cells in the intima are also involved in plaque progression.
Transforming growth factor beta (TGF-beta) superfamily signal transduction plays an important role in the regulation of cell growth, differentiation and development in a number of biological systems. TGFBR1 is a transforming growth factor beta-specific receptor that mediates the pathophysiological functions of TGF-beta. TGF-beta can activate TGFBR1, the activated TGFBR1 phosphorylates downstream signal molecules Smad2 and Smad3, the formed Smad2/3 dimer and Smad4 are combined into trimer to enter a cell nucleus and regulate the transcription of a target gene, and TGFBR1 is a key node of TGF-beta signal transduction. In recent years, the TGF- β/Smad signaling pathway has been implicated in the development of a variety of cardiovascular diseases, such as restenosis, angiogenesis, and fibrosis. Genetic studies in animals and humans have shown that mutations in genes that functionally disrupt TGF-. beta.are associated with specific hereditary vascular syndromes, including Osler-Rendu-Weber disease, Marfan syndrome, and the like. Disturbances in TGF- β signalling can also lead to non-hereditary diseases such as atherosclerosis and myocardial fibrosis. Relevant studies have shown that TGF-. beta.including three subtypes of its superfamily (TGF-. beta.1, TGF-. beta.2, TGF-. beta.3) play an irreplaceable role in the development of atherosclerosis. TGF-. beta.plays a key role in the proliferation, differentiation, and migration of endothelial cells and smooth muscle cells.
At present, statins are main drugs for treating AS, can reduce the morbidity and mortality of coronary heart disease, delay the development of atherosclerotic plaques and even eliminate the plaques, but have many adverse reactions in clinical application, such AS liver injury, myalgia, gastrointestinal tract irritation and the like, so that the clinical application of the statins is limited, and under the condition, natural and safe compounds are particularly valuable.
Myricetin (Myricetin) is a natural polyhydroxy flavonoid compound existing in many fruits, vegetables, Chinese medicinal materials and other plants. In vitro studies show that myricetin has antioxidant, antibacterial, antiviral, antiinflammatory, antitumor, analgesic, hepatoprotective, blood glucose reducing, blood lipid reducing, heart protecting and nerve injury inhibiting effects. Based on its natural and safe characteristics, myricetin is widely used in medicine, food, health products and cosmetics. The pharmacological mechanism of myricetin is widely related, but the regulation and control of the transforming growth factor beta receptor 1(TGFBR1) are not reported.
Disclosure of Invention
The invention aims to provide application of myricetin in preparation of a transforming growth factor beta receptor 1 inhibitor, so as to solve the problems in the prior art, effectively prevent and treat diseases caused by TGF-beta pathway disorder, particularly diseases related to TGFBR1, and prevent and treat atherosclerosis.
In order to achieve the purpose, the invention provides the following scheme:
the invention provides an application of myricetin in preparation of a transforming growth factor beta receptor 1 inhibitor.
Preferably, the myricetin regulates and controls the expression and transcription of a downstream signal gene of the transforming growth factor beta receptor 1 by inhibiting the phosphorylation levels of the transforming growth factor beta receptor 1 and downstream Smad2 and Smad3 thereof, thereby realizing the inhibition of the expression of the transforming growth factor beta receptor 1.
The invention also provides the application of myricetin in preparing a medicament for preventing and treating diseases caused by transforming growth factor beta signal pathway disorder.
The invention also provides the application of myricetin in preparing health-care food for preventing diseases caused by transforming growth factor beta signal pathway disorder.
Preferably, the disease comprises a condition associated with response to transforming growth factor beta receptor 1.
Preferably, the associated condition comprises atherosclerosis caused by abnormal expression of transforming growth factor beta receptor 1.
Preferably, the atherosclerosis also includes hypertension, coronary heart disease, cerebral infarction and peripheral vascular disease whose pathological mechanisms involve atherosclerosis.
The invention discloses the following technical effects:
the invention discloses application of myricetin in preparation of a transforming growth factor beta receptor 1(TGFBR1) inhibitor, which is proved by experiments to have the effect of inhibiting the expression of TGFBR1 and a downstream signal molecule Smad2/3 thereof in human vascular smooth muscle cells (HASMC). Therefore, the invention provides data basis for clinically preventing and treating TGFBR 1-related diseases, especially atherosclerosis and related diseases caused by atherosclerosis.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without creative efforts.
FIG. 1 is a molecular docking diagram of inhibitory effect of Myricetin Myricetin on TGFBR 1;
FIG. 2 is a surface plasmon resonance image of the in vitro binding affinity of Myricetin Myricetin and TGFBR 1;
FIG. 3 shows the effect of Myricetin Myricetin on the in vitro enzymatic activity of TGFBR 1; wherein, compared with control, P is less than 0.05, and there is statistical difference; p < 0.01, statistically different from control;
FIG. 4 shows that Myricetin Myricetin significantly inhibits the phosphorylation levels of human vascular smooth muscle cell TGBFBR1 and Smad2 and Smad3 downstream thereof; wherein, compared with control, P is less than 0.05, and there is statistical difference; p < 0.01, statistically different from control;
FIG. 5 shows that Myricetin Myricetin significantly inhibits neointimal hyperplasia in carotid artery of C57 mouse; wherein A is different groups of HE staining pathomorphology results; b is the column diagram analysis result of intimal hyperplasia condition of different groups; p < 0.05, statistically different from model; p < 0.01, statistically different from model.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
The molecular formula of the myricetin is C15H10O8Molecular weight is 318.24, and the structural formula is shown as follows:
example 1 molecular simulation virtual screening
The optimal conformation was simulated by using Sybyl-x2.1 software for the binding between Myricetin and TGFBR 1. This suggests a strong binding capacity between Myricetin and TGFBR 1. As shown in FIG. 1, Myricetin can hydrogen bond with ASP-351, ILE-211, GLU-245, SER-280, ASP-281, HIS-283 amino acid residues of TGFBR 1.
Example 2 Surface Plasmon Resonance Imaging (SPRi) molecular interaction assay analysis of the in vitro binding Capacity between Myricetin and TGFBR1
A3D Dextran chip was selected for spotting fixation. The specific operation flow is as follows:
(1) 0.765g EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and 0.115g NHS (N-N-hydroxysuccinimide) are respectively placed in two 50ml special centrifuge tubes, 10ml double distilled water is respectively added into each centrifuge tube to be fully dissolved and uniformly mixed, and when the two solutions are used, the two solutions are poured into a square box to ensure that the solutions are not over the surface of a chip to be activated, and then the square box is placed on a shaking table to react for 15 min.
(2) TGFBR1 protein spotting, placing the chip on a spotting instrument according to the operation process of the biological spotting instrument, performing spotting operation, attaching cover to the spotted chip, marking the serial number of the chip, and placing the chip in a biochemical reagent box (the humidity should be more than 50%) for incubation overnight at 4 ℃ in a refrigerator.
(3) The incubated chip was loaded on the SPR instrument and small molecule compounds were ready for flow through.
(4) The myricetin with the mother liquor concentration of 100mM is respectively prepared into flow-through phases with different concentration gradients of 7.5mM, 15mM and 30mM in the volume of 1mL by PBS, and the positive control SB431542 with the mother liquor concentration of 100mM is respectively prepared into flow-through phases with different concentration gradients of 5mM, 10mM, 20mM and 40mM in the volume of 1mL by PBS for later use.
(5) After a chip on which a target protein TGFBR1 sample is fixed, a flow sample, a buffer solution and a regeneration solution of myricetin and SB431542 with different concentration gradients are loaded and placed on a PlexArray HT A100 biomolecule interaction instrument, an intermolecular interaction experiment is carried out according to the operation flow of 'using SOP in a PlexArray HT high-throughput intermolecular interaction screening system'.
As shown in FIG. 2, it can be seen from the binding and dissociation process of TGFBR1 and myricetin, SB431542 that different concentrations of myricetin, SB431542 can rapidly bind to TGFBR 1. The kinetic parameters of the interaction between myricetin and TGFBR1 are respectively Ka-1.03E+03(1/Ms)，Kd＝0.0245(1/s)，KD＝2.38E-05(M). Kinetic parameters of the interaction between SB431542 and TGFBR1, Ka ═ 1.26E respectively+03(1/Ms)，Kd＝0.0311(1/s)，KD＝2.47E-05(M). The magnitude of intermolecular binding capacity is indicated by the KD value, with smaller KD indicating greater binding or affinity. As can be seen from the KD values, TGFBR1 has strong affinity for both myricetin and SB 431542.
EXAMPLE 3TGFBR1 in vitro enzyme Activity test
Referring to the TGFBR1 Kinase Assay protocol, 25ng TGFBR1(ALK5), 50. mu.M ATP, 0.2. mu.g/. mu.l TGFBR1 substrate, best shown in TGFBR1 Kinase and ATP titration experiments, were incubated at room temperature for 2 h. The specific operation flow is as follows:
(1) mu.l of different concentrations of myricetin (15, 30, 60. mu.M), 1. mu.l of different concentrations of SB431542 (15. mu.M, 30. mu.M, 60. mu.M) and 2. mu.l of TGFBR1 kinase, 2. mu.l of TGFBR1 substrate and ATP mix were added to 384 well plates, respectively.
(2) Incubate at room temperature for 120 min.
(3) Add 5. mu.l ADP-Glo to each wellTMReagent, incubate at room temperature for 40 min.
(4) Mu.l of Kinase Detection Reagent was added to each well and incubated at room temperature for 30 min.
(5) And detecting by using a multifunctional cell imaging microplate detector.
During the experiment, TGFBR1 Kinase, TGFBR1 substrate, ATP and Myricitin with different concentrations are diluted and prepared by Kinase Buffer.
As shown in fig. 3, the results show that: myricetin has the effect of inhibiting the in vitro enzyme activity of TGFBR1, the effect of Myricetin is equivalent to that of an inhibitor thereof (P is less than 0.05), and the difference between Myricetin and SB431542 in different concentration groups has no statistical significance (P is more than 0.05).
Experimental example 4 myricetin significantly inhibits phosphorylation levels of human vascular smooth muscle cell TGBFBR1 and Smad2 and Smad3 downstream thereof
4.1. Materials and methods
4.1.1 Experimental materials
Myricitin was purchased from Doctorite Biotech, Inc. and dissolved in sterile dimethyl sulfoxide DMSO to make the desired concentration.
4.1.2 cell lines
Human vascular smooth muscle cells (HASMCs) were provided by the Shanghai Life sciences cell Bank of the Chinese academy of sciences. The culture conditions are as follows: DMEM high-sugar medium (Gibco) containing 10% FBS (GIBCO), 37 ℃, 5% CO2A saturated humidity incubator.
4.1.3 Western blot
Total protein was extracted by lysing cells or tissues with RIPA lysis solution (Biyuntian Biotechnology research institute) containing PMSF (Biyuntian Biotechnology Co., Ltd.) and phosphatase inhibitor (Biyuntian Biotechnology Co., Ltd.). 15. mu.g of cell protein was electrophoresed on 10% SDS-PAGE gel, transferred to PVDF membrane, and the membrane was incubated with specific antibody overnight at 4 ℃. Washing for 3 times, diluting with peroxidase-labeled secondary antibody (anti-rabbitIgG 1:2000 concentration), incubating for 1 hour at room temperature, washing for 3 times, soaking in HRP-ECL chemiluminescence solution (Millipore, USA, mixing solution A and solution B at a ratio of 1: 1), and imaging in an exposure apparatus.
The primary antibody used was as follows:
rabbit anti-p-Smad2 antibody (1:1000 concentration dilution; Abcam corporation, USA); rabbit anti-p-Smad3 antibody (1:1000 concentration dilution; Abcam corporation, USA); rabbit anti-p-TGFBR1antibody (1:1000 concentration dilution; Cell signalling, USA); rabbit anti-GAPDH antibody (1:1000 concentration dilution; Affinity, USA); rabbit anti-Smad2 antibody (1:1000 concentration dilution; Cell signalling, USA); rabbit anti-Smad3 antibody (1:1000 concentration dilution; Cell signalling, USA); rabbit anti-TGFBR 1antibody (1:1000 concentration dilution; Cell signalling, USA); rabbit anti-GAPDH antibody (1:1000 concentration dilution; Affinity, USA).
4.1.4 Image J Image analysis software analysis
The gray values of the bands after exposure were analyzed using Image J Image analysis software and gray value ratios were calculated for each of phospho-Smad2, phospho-Smad3, and phospho-TGFBR1 to the corresponding total proteins Smad2, Smad3, and TGFBR 1.
4.1.5 statistical analysis
The analysis was performed using the sps 22.0 statistical software, and the results were expressed as means ± standard deviation (Mean ± SD). The comparison among multiple groups uses one-factor variance analysis, an LSD method is adopted when the variance is uniform, Welch robust estimation is adopted when the variance is irregular, and pairwise comparison is carried out by a Tamhane T2 method, and P is less than 0.05, so that the statistical significance is realized.
As shown in fig. 4, the results show that: compared with a control group, myricetin can inhibit the phosphorylation levels of TGFBR1 and Smad2 and Smad3 downstream of the TGFBR1 in a concentration-dependent manner, and does not change the total protein levels of TGFBR1, Smad2 and Smad3 (P < 0.05).
The experiments prove that: myricetin can remarkably inhibit transforming growth factor beta receptor 1(TGFBR1), inhibit phosphorylation levels of Smad2 and Smad3 in a TGFBR 1-Smad signal pathway, and further regulate expression and transcription of downstream signal genes.
Experimental example 5 myricetin significantly inhibits carotid neointimal hyperplasia of C57 mice
Mouse left common carotid artery ligation animal model: intimal hyperplasia was simulated by ligating the left common carotid artery of the mice. Administering myricetin (20mg/kg, 40mg/kg) before molding, pre-intragastrically administering for 3 days, fasting one night before molding, performing abdominal anesthesia with 1% sodium pentobarbital (0.1ml/10g), after mouse anesthesia, fixing anesthetized mouse on dissecting table in supine position, removing hair on neck, disinfecting with iodophor, cutting skin along the center of neck, separating neck tissue layer by layer, fully exposing left common carotid artery, carefully separating artery and accompanying nerve, the Y-shaped blood vessels (common carotid artery, external carotid artery and internal carotid artery) are ligated by No. 6 aseptic braided suture (all operations are performed under microscope), then sutured (No. 5 aseptic braided suture), sterilized cut is placed on the heat insulation pad, animal house is continuously raised after reviving for observing subsequent conditions, and penicillin is injected into abdominal cavity for preventing infection. The shampooed group placed only sterile braided wire No. 6 at the bifurcation point without ligation. After the molding is finished, the gavage is continued to be given with myricetin (20mg/kg, 40mg/kg) for 4 weeks.
The grouping is as follows: a Sham operation group (Sham), a left common carotid artery ligation Model group (Model), and a myricetin low-high dose group (20mg/kg, 40mg/kg), wherein each group contains 5 drugs, the administration group is respectively irrigated with 0.2ml of drugs every day, and the Sham operation group and the Model group: an equal amount of solvent control was given.
After 4 weeks, the mice were anesthetized (1% sodium pentobarbital, 0.1ml/10g, i.p.) and mounted in a supine position on a dissecting table. Cutting a mouse sternum, opening a chest cavity, exposing a heart, opening a LonggerPump peristaltic pump, inserting a LonggerPump peristaltic pump perfusion needle into a cardiac apex part and fixing, simultaneously quickly cutting a small opening (facilitating blood outflow) at the right auricle part, draining blood in a blood vessel of the mouse by PBS (phosphate buffer solution) through cardiac perfusion to avoid redundant residual blood from remaining in a blood vessel lumen, then fully exposing a left neck ligation blood vessel of the mouse, taking out the left neck blood vessel together with a ligation knot, quickly soaking the left neck blood vessel in a 4% paraformaldehyde solution for fixing, subsequently carrying out paraffin section preparation, and carrying out HE staining to observe pathological morphological changes.
And (4) prompting by a result: compared with the model group, the vessel wall of the blood vessel of the sham operation group is smooth, and no obvious intimal hyperplasia exists. Compared with the sham operation group, the model group has obvious hyperplasia of the blood vessel intima, obvious stenosis and reduction of the lumen diameter, and the difference has statistical significance. In addition, compared to the model group, as shown in fig. 5A and B, both the myricetin low dose group (20mg/kg) and the myricetin high dose group (40mg/kg) reduced the degree of intimal hyperplasia, with statistical significance of the difference.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.
Claims (7)
1. Application of myricetin in preparing transforming growth factor beta receptor 1 inhibitor is provided.
2. The use of claim 1, wherein myricetin regulates expression and transcription of a downstream signaling gene of transforming growth factor beta receptor 1 by inhibiting phosphorylation levels of transforming growth factor beta receptor 1 and Smad2 and Smad3 downstream thereof, thereby inhibiting expression of transforming growth factor beta receptor 1.
3. The application of myricetin in preparing medicine for preventing and treating diseases caused by transforming growth factor beta signal channel disorder is provided.
4. Application of myricetin in preparing health food for preventing diseases caused by transforming growth factor beta signal pathway disorder is provided.
5. The use of claim 3 or 4, wherein the disease comprises a condition associated with response to transforming growth factor beta receptor 1.
6. The use according to claim 5, wherein the related condition comprises atherosclerosis caused by abnormal expression of transforming growth factor beta receptor 1.
7. The use of claim 6, wherein said atherosclerosis further comprises hypertension, coronary heart disease, cerebral infarction and peripheral vascular disease whose pathological mechanisms involve atherosclerosis.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996030012A1 (en) * | 1995-03-24 | 1996-10-03 | Defeudis Francis V | Methods for treating conditions associated with excess nitric oxide |
| US20140221472A1 (en) * | 2013-02-05 | 2014-08-07 | Jilinsheng Jinziyuan Biotechnology Ltd | Use of myricetin or derivatives thereof as a cathepsin k inhibitor |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996030012A1 (en) * | 1995-03-24 | 1996-10-03 | Defeudis Francis V | Methods for treating conditions associated with excess nitric oxide |
| US20140221472A1 (en) * | 2013-02-05 | 2014-08-07 | Jilinsheng Jinziyuan Biotechnology Ltd | Use of myricetin or derivatives thereof as a cathepsin k inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| RICCARDO BERTIN等: "Activity of myricetin and other plant-derived polyhydroxyl compounds in human LDL and human vascular endothelial cells against oxidative stress", 《BIOMEDICINE & PHARMACOTHERAPY》 * |
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