CN105497017B - The pharmaceutical applications of wedelolactone - Google Patents
The pharmaceutical applications of wedelolactone Download PDFInfo
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- CN105497017B CN105497017B CN201510808916.4A CN201510808916A CN105497017B CN 105497017 B CN105497017 B CN 105497017B CN 201510808916 A CN201510808916 A CN 201510808916A CN 105497017 B CN105497017 B CN 105497017B
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- wedelolactone
- angiogenesis inhibiting
- endometrial hyperplasia
- smooth muscle
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Abstract
The invention discloses the pharmaceutical applications of wedelolactone, purposes especially in angiogenesis inhibiting endometrial hyperplasia medicine and Antiatherosclerosis medicine is prepared, wedelolactone has the function that angiogenesis inhibiting endometrial hyperplasia, and this effect is mainly propagation and the migration realization by suppressing vascular smooth muscle cells.The present invention prepares angiogenesis inhibiting endometrial hyperplasia medicine and Antiatherosclerosis medicine provides Research Thinking for wedelolactone, and be expected to be applied to be performed the operation as coronary heart disease following percutaneous transluminal coronary angioplasty, Stent etc. and many reasons such as improper diet caused by blood vessel neointima hyperplasia and atherosclerosis prevention and treatment.
Description
Technical field
The present invention relates to the pharmaceutical applications of wedelolactone, especially prepare angiogenesis inhibiting endometrial hyperplasia medicine and
Purposes in Antiatherosclerosis medicine.
Background technology
Coronary artery bypass grafting, cardiac stent etc. are performed the operation because can effectively alleviate coronary atherosclerotic heart disease
The symptoms such as angina pectoris, heart infarction simultaneously extend the life-span and worldwide extensive use, but surgical procedure is inevitably made
Into blood vessel endothelium injury, vascular smooth muscle cells (vascular smooth musclecell, VSMC) proliferation apoptosis and cell
The accumulation of epimatrix causes blood vessel neointima hyperplasia, so as to cause subsequent atherosclerosis, the blood caused by this process
Manage and narrow have a strong impact on late result.VSMC abnormality proliferations and migration are the main reason for causing vascular lesion, are directly resulted in each
The generation of kind post-surgical vascular neointimal hyperplasia and ISR.
Wedelolactone is eclipta (Eclipta prostrata L.), golden small cup wedelia chinensis (Wedelia
A kind of natural lactone compound present in plant such as calendulacea), has many pharmacological actions, as liver protection,
Anti- snake venom, anti-immunity suppression, anti-inflammatory etc..But purposes of the wedelolactone in terms of angiogenesis inhibiting endometrial hyperplasia medicine is prepared
Temporarily have no report.
The content of the invention
It is an object of the invention in place of overcome the deficiencies in the prior art, there is provided the pharmaceutical applications of wedelolactone, especially
It is the purposes in angiogenesis inhibiting endometrial hyperplasia medicine and Antiatherosclerosis medicine is prepared.
One of the technical solution adopted for the present invention to solve the technical problems is：
Purposes of the wedelolactone in angiogenesis inhibiting endometrial hyperplasia medicine is prepared.
In one embodiment：The angiogenesis inhibiting endometrial hyperplasia refers to suppress to be drawn by platelet derived growth factor PDGF
The vascular smooth muscle cells VSMC risen propagation.
In one embodiment：Suppression vascular smooth muscle cells VSMC as caused by platelet derived growth factor PDGF
Propagation refers to suppress vascular smooth muscle cells VSMC from the G0/G1 phases of cell cycle to the transformation of S phases.
In one embodiment：The angiogenesis inhibiting endometrial hyperplasia refers to suppress to be drawn by platelet derived growth factor PDGF
The vascular smooth muscle cells VSMC risen migration.
In one embodiment：The angiogenesis inhibiting endometrial hyperplasia refers to Inhibit proliferaton activation antigen PCNA expression.
The two of the technical solution adopted for the present invention to solve the technical problems are：
Wedelolactone is preparing the purposes in preventing and treating atherosclerosis medicine.
In one embodiment：The preventing and treating atherosclerosis refers to angiogenesis inhibiting endometrial hyperplasia.
In one embodiment：The angiogenesis inhibiting endometrial hyperplasia refers to suppress to be drawn by platelet derived growth factor PDGF
The vascular smooth muscle cells VSMC risen propagation and/or migration.
The three of the technical solution adopted for the present invention to solve the technical problems are：
The dosage of above-mentioned wedelolactone, it is 3~60mg/kg.
Above-mentioned wedelolactone includes wedelolactone monomer, the clinically acceptable salt of wedelolactone monomer, Peng
The clinically acceptable preparation of Qi chrysanthemum internal ester monomers, the compound medicament composition containing wedelolactone monomer, its clinically
Acceptable salt and its clinically acceptable preparation.
Signified clinically acceptable salt of the invention means that wedelolactone monomer can be retained or contains wedelolactone
The property of compound medicament composition and the salt of biological effectiveness, including acid-addition salts formed with inorganic acid or organic acid；
The inorganic acid is such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid；The organic acids such as acetic acid, Vitamin C
Acid, trifluoroacetic acid, propionic acid, glycolic, (D) or (L) lactic acid, (D) or (L) malic acid, oxalic acid, fumaric acid, maleic acid, first sulphur
Acid, ethyl sulfonic acid, benzoic acid, p-methyl benzenesulfonic acid, salicylic acid, cinnamic acid, mandelic acid, tartaric acid, citric acid, butanedioic acid, hydroxyl second sulphur
Acid and malonic acid etc..
Signified clinically acceptable preparation of the invention, including oral formulations, ejection preparation etc., the oral formulations bag
Include but be not limited to tablet, capsule, oral liquid, granule, pill, powder, pill etc..
Compared with background technology, it has the following advantages that the technical program：
The invention provides effect evidence of the wedelolactone in angiogenesis inhibiting endometrial hyperplasia, and this effect is led
If being realized by the propagation and migration that suppress vascular smooth muscle cells, angiogenesis inhibiting inner membrance is prepared for wedelolactone
Anti-proliferative agent and Antiatherosclerosis medicine provide Research Thinking, and are expected to be applied to by coronary heart disease following percutaneous transluminal coronary angioplasty, stenter to implant
Art etc. is performed the operation and the prevention and treatment of blood vessel neointima hyperplasia and atherosclerosis caused by many reasons such as improper diet.
Brief description of the drawings
The invention will be further described with reference to the accompanying drawings and examples.
Fig. 1 a are the influence of wedelolactone rat aorta neointimal hyperplasia to caused by balloon injured, are freezed for blood vessel
The HE that cuts into slices dyes schematic diagram.
Fig. 1 b are the influence of wedelolactone rat aorta neointimal hyperplasia to caused by balloon injured, the amount for being Fig. 1 a
Change figure, i.e. neointimal area (neointima) and the statistical chart of medial smooth muscle (media) area ratio.### is represented and vacation
Operation group (Sham) is compared, model group (M) p ＜ 0.001；* * expressions are compared with model group, p ＜ 0.001.
Fig. 2 a are the influence for breeding activation antigen (PCNA) in wedelolactone rat aorta to caused by balloon injured, are
The western blot experimental result pictures of blood vessel.
Fig. 2 b are the influence for breeding activation antigen (PCNA) in wedelolactone rat aorta to caused by balloon injured, are
Fig. 2 a quantization figure, i.e. PCNA and internal reference GAPDH gray level ratio statistical chart.### expressions are compared with sham-operation group (Sham), mould
Type group (M) p ＜ 0.001；* represented with * * compared with model group, p ＜ 0.05 and p ＜ 0.01.
Fig. 3 is influence of the wedelolactone to the vascular smooth muscle cells number change of the PDGF in vitro cultures induced, ###
Represent compared with control group (c), induction group (pdgf) p ＜ 0.001；* * expressions are compared with model group, p ＜ 0.001.
Fig. 4 is the shadow that wedelolactone changes to the cell cycle of the vascular smooth muscle cells of the PDGF in vitro cultures induced
Ring, wherein Fig. 4 a are control group (c), and Fig. 4 b are PDGF inductions group (PDGF), and Fig. 4 c are WDL protections group (WDL5), and Fig. 4 d are WDL
Protection group (WDL10), Fig. 4 e are WDL protections group (WDL20), and Fig. 4 f are WDL protections group (WDL40).
Fig. 5 a are influence of the wedelolactone to the vascular smooth muscle cells migration of the PDGF in vitro cultures induced, are PDGF
Before addition (i.e. 0h), horizontal line represents the width of white space in figure.
Fig. 5 b are influence of the wedelolactone to the vascular smooth muscle cells migration of the PDGF in vitro cultures induced, are PDGF
When adding 12h, horizontal line represents the width of white space in figure.
Embodiment
Present disclosure is illustrated below by embodiment：
The wedelolactone of embodiment 1 rat aorta neointimal hyperplasia and atherosclerosis to caused by balloon injured
Inhibitory action
Using rat freshman endometrial hyperplasia and Atherosclerosis Model caused by balloon injured, wedelolactone pair is observed
The influence of the neointimal hyperplasia of the damage side arteria carotis communis of rat model.
It is as follows to test specific method step：
1) experimental animal and reagent
Rat 40, male, counterpoise 240-260g, purchased from Xiamen University's Experimental Animal Center.
Wedelolactone, purchased from Shanghai Yuan Ye bio tech ltd.
2) animal processing method
Rat feeding environment：23 ± 1 DEG C of temperature, humidity:40%-60%, natural lighting, free water, ad lib.It is suitable
After answering 1 week, be randomly divided into 5 groups, every group 8, be designated as respectively sham-operation group (being designated as sham groups), balloon injured group (be designated as M groups or
Model groups), wedelolactone low dose group (being designated as WDL1 groups), wedelolactone middle dose group (being designated as WDL2 groups), wedelia chinensis
Lactone high dose group (is designated as WDL3 groups).
Carry out balloon injured operation：After animal chloral hydrate anesthesia, median incision, separation left common carotid, neck are done
Interior and external carotid artery, make a kerf from external carotid artery, insert 2F foley's tube about 5cm, be filled with deionized water dilating sacculus, return
Pull catheter damages arteria carotis communis, damages repeatedly three times.Conduit is removed, ligatures external carotid artery, carries out skin of neck suture.
Start to be administered within second day after balloon injured.It is administered by the following method：
Sham-operation group and balloon injured group：Physiological saline, mode are given before feed is given when afternoon 14 daily：Gavage.
WDLI groups：It is administered once before giving feed when afternoon 14 daily, dosage 5mg/kg, mode：Gavage.
WDL2 groups：It is administered once before giving feed when afternoon 14 daily, dosage 25mg/kg, mode：Gavage.
WDL3 groups：It is administered once before giving feed when afternoon 14 daily, dosage 50mg/kg, mode：Gavage.
Successive administration is after 2 weeks according to the method described above, all animal physiological salt solution perfusions, takes and damages side arteria carotis communis, one
Divide paraformaldehyde to fix, make frozen section, HE dyeing；Another part crushes, ultrasound, extraction albumen, carries out western
Blot is tested.
Statistical analysis：The softwares of Graphpad Prism 5 (GraphPad Software Inc, USA) are used with data
Statistical analysis is carried out, compares between group with one-way analysis of variance, when variance analysis difference has conspicuousness, is further examined with t
Test and compare two-by-two.
3) result and analysis
3.1) influence of the wedelolactone to blood vessel neointima hyperplasia, as a result as shown in Fig. 1 a and Fig. 1 b, the result table
It is bright：
1. after balloon injured, the obvious hyperplasia of blood vessel neointima, illustrate modeling success.
2. the wedelolactone of middle dosage (WDL2 groups/WDL 25mg/kg) and high dose (WDL3 groups/WDL 50mg/kg)
Compared with balloon injury model group (M/model groups), blood vessel neointima hyperplasia significantly reduces, and it is poor to be respectively provided with conspicuousness for treatment group
It is different, illustrate that wedelolactone is notable for the inhibition of blood vessel neointima hyperplasia caused by balloon injured.
3.2) influence of wedelolactone pair and propagation activation antigen (PCNA), as a result as shown in Fig. 2 a and Fig. 2 b, the knot
Fruit shows：
1. after balloon injured, the obvious increase of blood vessel PCNA expression, illustrate that balloon injured causes the composition cell of blood vessel to be bred.
2. the wedelolactone treatment group of middle dosage (WDL2 groups) and high dose (WDL3 groups) and balloon injury model group (M/
Model groups) compare, PCNA is substantially reduced, and is respectively provided with significant difference, illustrates wedelolactone for blood caused by balloon injured
Pipe propagation has significant inhibition.
Brief summary：The results show, wedelolactone have significantly to blood vessel neointima hyperplasia caused by balloon injured
Inhibitory action.
The wedelolactone of embodiment 2 is bred by the vascular smooth muscle cells (VSMC) of in vitro culture and the inhibitory action of migration
Using the rat chest aorta vascular smooth muscle cells of original cuiture, platelet derived growth factor (PDGF) is added to pierce
Swash its propagation and migration, the vascular smooth muscle cell proliferation and the inhibitory action of migration that observation wedelolactone is induced PDGF.
It is as follows to test specific method step：
1) primitive cell culture：
Rat, male, 130-150g, purchased from Xiamen University's Experimental Animal Center.
After rat chloral hydrate anesthesia, chest median incision is done, separates aorta pectoralis, cleans, is cut into small pieces in PBS,
It is attached on culture dish, treats its patch jail, add the DMEM medium cultures containing 20%FBS, change liquid within about 3 days, treat that cell climbs out of one
Passed on after fixed number amount.3-6 is used to test for VSMC, with the DMEM medium cultures containing 10%FBS.
2) cell experiment step：
MTS is tested：96 orifice plates are layered on certain density after cell dissociation, after its is adherent, are divided into control group (c), PDGF
Induction group (PDGF), WDL protections group (WDL5, WDL10, WDL20 and WDL40).With the culture medium starved cells 24h containing 1%FBS
Make its synchronization, control group continues hungry, and the PDGF that PDGF groups add 20ng/mL induces 24h, WDL each groups respectively with 5,10,
20th, after 40 μM of WDL protects 2h in advance, PDGF inductions 24h is added.Experiment adds MTS reagent colour developing, ELIASA measure after terminating
Absorbance OD values, compare the difference of vigor between each group cell.
Cell cycle determination is tested：6 orifice plates are layered on certain density after cell dissociation, after its is adherent, are divided into control group
(c), PDGF inductions group (PDGF), WDL protections group (WDL5, WDL10, WDL20 and WDL40).It is hungry with the culture medium containing 1%FBS
Starving cell 24h makes its synchronization, and control group continues hungry, PDGF groups addition 20ng/mL PDGF induction 12h, WDL each groups difference
After protecting 2h in advance with 5,10,20,40 μM of WDL, PDGF inductions 12h is added.Experiment terminates rear trypsin digestion cell, 80% second
Alcohol is fixed, and adds after PI is incubated half an hour and the cell quantity for being in each cell cycle is determined with flow cytometer.
Scratch experiment：Experimental implementation is same as above, and is induced preceding pipette tips cut in VSMC culture dishes adding PDGF, is inverted aobvious
Micro mirror, which is taken pictures, observes the change of scratch width when PDGF adds preceding and addition 12h, judges the transfer ability of cell.
3) result and analysis：
3.1) influence for the vascular smooth muscle cells number change that wedelolactone is induced PDGF, as a result as shown in figure 3,
The result shows：
1. after PDGF inductions, VSMC quantity substantially increases, and illustrates to induce successfully.
2. wedelolactone protection group, compared with PDGF induction groups, VSMC quantity is reduced, have during 40 μM of concentration notable
Sex differernce, illustrate that the inhibition that wedelolactone is bred for VSMC caused by PDGF is notable.
3.2) influence that wedelolactone changes to the cell cycle of the PDGF vascular smooth muscle cells induced, as a result as schemed
Shown in 4, the result shows：
1. after PDGF inductions, the cell quantity of the S phases in propagation increases to 22.0% from 1.5%, illustrates to induce successfully.
2. the 5th, 10,20,40 μM of wedelolactone protection group is compared with PDGF induction groups, the cell of the S phases in propagation
Quantity is reduced to 19.2%, 12.0%, 11.9% and 10.0% respectively from 22.0%, illustrates that wedelolactone causes for PDGF
VSMC have obvious inhibition from the G0/G1 phases to the transformation of S phases.
3.3) influence of the wedelolactone to the PDGF vascular smooth muscle cells migrations induced, as a result such as Fig. 5 a and Fig. 5 b institutes
Show, the result shows：
1. after PDGF inductions 12h, lateral this white space migration of white space two of VSMC from original cut, white space
Constriction, illustrate to induce successfully.
2. the 5th, 10,20,40 μM of wedelolactone protection group is compared with PDGF induction groups, white space is elongated, i.e. constriction
Degree reduce, illustrate wedelolactone for caused by PDGF VSMC migrate have obvious inhibition.
Brief summary：The results show, the vascular smooth muscle cell proliferation that wedelolactone is induced PDGF have with migration
Obvious inhibitory action.
Therefore, wedelolactone can be used for the medicine for preparing angiogenesis inhibiting endometrial hyperplasia, specific as follows：
Purposes of the wedelolactone in angiogenesis inhibiting endometrial hyperplasia medicine is prepared.
The angiogenesis inhibiting endometrial hyperplasia refers to that suppressing the blood vessel as caused by platelet derived growth factor PDGF puts down
Sliding myocyte VSMC propagation.
Suppression vascular smooth muscle cells VSMC propagation as caused by platelet derived growth factor PDGF refers to press down
Vascular smooth muscle cells VSMC processed is from the G0/G1 phases of cell cycle to the transformation of S phases.
The angiogenesis inhibiting endometrial hyperplasia refers to that suppressing the blood vessel as caused by platelet derived growth factor PDGF puts down
Sliding myocyte VSMC migration.
The angiogenesis inhibiting endometrial hyperplasia refers to Inhibit proliferaton activation antigen PCNA expression.
One of due to blood vessel neointima hyperplasia is to cause atherosclerosis, therefore, wedelolactone may be used also
It is specific as follows for preparing the medicine of preventing and treating atherosclerosis：
Wedelolactone is preparing the purposes in preventing and treating atherosclerosis medicine.
The preventing and treating atherosclerosis refers to angiogenesis inhibiting endometrial hyperplasia.
The angiogenesis inhibiting endometrial hyperplasia refers to that suppressing the blood vessel as caused by platelet derived growth factor PDGF puts down
Sliding myocyte VSMC propagation.
Suppression vascular smooth muscle cells VSMC propagation as caused by platelet derived growth factor PDGF refers to press down
Vascular smooth muscle cells VSMC processed is from the G0/G1 phases of cell cycle to the transformation of S phases.
The angiogenesis inhibiting endometrial hyperplasia refers to that suppressing the blood vessel as caused by platelet derived growth factor PDGF puts down
Sliding myocyte VSMC migration.
The angiogenesis inhibiting endometrial hyperplasia refers to Inhibit proliferaton activation antigen PCNA expression.
In above-mentioned pharmaceutical applications, the dosage of the wedelolactone is 3~60mg/kg；The wedelolactone removes amphibious crab
Outside chrysanthemum internal ester monomer, the clinically acceptable salt of wedelolactone monomer is can also be, wedelolactone monomer is clinically
Acceptable preparation, the compound medicament composition containing wedelolactone monomer, its clinically acceptable salt and its clinically
Acceptable preparation.
It is described above, only present pre-ferred embodiments, therefore the scope that the present invention is implemented can not be limited according to this, i.e., according to
The equivalent changes and modifications that the scope of the claims of the present invention and description are made, all should still it belong in the range of the present invention covers.
Claims (11)
1. wedelolactone monomer or its clinically use of acceptable salt in angiogenesis inhibiting endometrial hyperplasia medicine is prepared
On the way, the purposes refers to the medicine for preparing treatment postangioplasty restenosis.
2. purposes according to claim 1, it is characterised in that：The angiogenesis inhibiting endometrial hyperplasia refers to suppress by blood
Vascular smooth muscle cells VSMC propagation caused by platelet derivative growth factor PDGF.
3. purposes according to claim 2, it is characterised in that：The suppression is caused by platelet derived growth factor PDGF
Vascular smooth muscle cells VSMC propagation refer to suppress vascular smooth muscle cells VSMC from the G0/G1 phases of cell cycle to the S phases
Transformation.
4. purposes according to claim 1, it is characterised in that：The angiogenesis inhibiting endometrial hyperplasia refers to suppress by blood
Vascular smooth muscle cells VSMC migration caused by platelet derivative growth factor PDGF.
5. purposes according to claim 1, it is characterised in that：The angiogenesis inhibiting endometrial hyperplasia refers to Inhibit proliferaton
Activation antigen PCNA expression.
6. wedelolactone monomer or its clinically acceptable salt prepare prevent and treat atherosclerosis medicine in purposes.
7. purposes according to claim 6, it is characterised in that：The preventing and treating atherosclerosis refers to angiogenesis inhibiting
Endometrial hyperplasia.
8. purposes according to claim 7, it is characterised in that：The angiogenesis inhibiting endometrial hyperplasia refers to suppress by blood
Vascular smooth muscle cells VSMC propagation and/or migration caused by platelet derivative growth factor PDGF.
9. purposes according to any one of claim 1 to 8, it is characterised in that：The wedelolactone monomer or its face
The dosage of acceptable salt is 3~60mg/kg on bed.
10. purposes according to any one of claim 1 to 8, it is characterised in that：The wedelolactone monomer or its face
Acceptable salt can be prepared into clinically acceptable preparation on bed.
11. purposes according to any one of claim 1 to 8, it is characterised in that：The wedelolactone monomer or its face
Acceptable salt can be prepared into compound medicament composition on bed.
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| CN201510808916.4A CN105497017B (en) | 2015-11-20 | 2015-11-20 | The pharmaceutical applications of wedelolactone |
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| CN201510808916.4A CN105497017B (en) | 2015-11-20 | 2015-11-20 | The pharmaceutical applications of wedelolactone |
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| CN105497017B true CN105497017B (en) | 2018-02-23 |
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| WO2008006118A2 (en) * | 2006-07-07 | 2008-01-10 | Bioassets Development Corporation | Novel regimens for treating diseases and disorders |
| CN103768117A (en) * | 2014-01-28 | 2014-05-07 | 中国药科大学 | Application of Eclipta prostrate extract in preparation of anti-pulmonary fibrosis drugs |
| CN104983884A (en) * | 2015-07-26 | 2015-10-21 | 黄萍 | Traditional Chinese medicine composition for treating arteriosclerosis obliterans caused by excessive noxious heat |
-
2015
- 2015-11-20 CN CN201510808916.4A patent/CN105497017B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008006118A2 (en) * | 2006-07-07 | 2008-01-10 | Bioassets Development Corporation | Novel regimens for treating diseases and disorders |
| CN103768117A (en) * | 2014-01-28 | 2014-05-07 | 中国药科大学 | Application of Eclipta prostrate extract in preparation of anti-pulmonary fibrosis drugs |
| CN104983884A (en) * | 2015-07-26 | 2015-10-21 | 黄萍 | Traditional Chinese medicine composition for treating arteriosclerosis obliterans caused by excessive noxious heat |
Non-Patent Citations (5)
| Title |
|---|
| Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression;Motoyuki Igata等;《Circulation Research》;20050908;第97卷;第837-844页 * |
| AMP-Activated Protein Kinase Inhibits Angiotensin II–Stimulated Vascular Smooth Muscle Cell Proliferation;Daisuke Nagata等;《Circulation》;20040719;第110卷;第444-451页 * |
| AMPK and cell proliferation – AMPK as a therapeutic target for atherosclerosis and cancer;Hiroyuki Motoshima等;《J Physiol》;20061231;第574卷(第1期);第63-71页 * |
| Wedelolactone Regulates Lipid Metabolism and Improves Hepatic Steatosis Partly by AMPK Activation and Up-Regulation of Expression of PPARα/LPL and LDLR;Yun Zhao等;《PLOS ONE》;20150713;第10卷(第7期);第1-17页 * |
| 特发性肺纤维化发病机制及血管新生作用的研究进展;龚玲;《医学研究生学报》;20140331;第27卷(第3期);第326-329页 * |
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