CN109528753A - The purposes of oligomerization hyaluronic acid or its salt in the drug of preparation treatment myocardial infarction - Google Patents
The purposes of oligomerization hyaluronic acid or its salt in the drug of preparation treatment myocardial infarction Download PDFInfo
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- CN109528753A CN109528753A CN201811564130.2A CN201811564130A CN109528753A CN 109528753 A CN109528753 A CN 109528753A CN 201811564130 A CN201811564130 A CN 201811564130A CN 109528753 A CN109528753 A CN 109528753A
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Abstract
The invention discloses the purposes of oligomerization hyaluronic acid or its salt in the drug of preparation treatment myocardial infarction.Oligomerization hyaluronic acid and its salt of the present invention can effectively treat myocardial infarction, significant in efficacy, provide a kind of new drug for clinical treatment myocardial infarction, potential applicability in clinical practice is good.
Description
Technical field
The present invention relates to the purposes of oligomerization hyaluronic acid or its salt in the drug of preparation treatment myocardial infarction.
Background technique
Myocardial infarction is to be called myocardial infarction, refers to that acute, duration ischemic, anoxic (coronary insufficiency) are drawn
The myocardial necrosis risen；Refer on the basis of coronary artery pathological changes, blood coronarius interrupts, and corresponding cardiac muscle occurs serious
And enduringly acute ischemia, eventually lead to the ischemic necrosis of cardiac muscle；The patient that acute myocardial infarction occurs, clinically often has
It has an intense pain, generate heat after lasting breastbone, white blood cell count(WBC) increases, Serum fibrosis markers increase and electrocardiogram reflecting myocardium is acute
The series of features of damage, ischemic and necrosis develops, and may occur in which arrhythmia cordis, shock and heart failure, belongs to coronary heart disease
Serious types, can the complication such as complicated by arrhythmia, shock or heart failure, often can threat to life.This disease is most common in America and Europe,
There are about the raw myocardial infarctions of 1,500,000 human hairs every year in the U.S..China is in obvious ascendant trend in recent years, is newly sent to few 500,000 every year, now
Suffer from least 2,000,000.
Have no the report of oligomerization hyaluronic acid and its salts for treating myocardial infarction.
Summary of the invention
The technical solution of the present invention is to provide oligomerization hyaluronic acid and its new applications of salt.
The present invention provides oligomerization hyaluronic acids or its salt in preparation treatment myocardial infarction and/or promotes the medicine of Myocardial Regeneration
Purposes in object.
Preferably, the oligomerization hyaluronic acid is the hyaluronic acid that molecular weight is less than 5000Da.
Preferably, the oligomerization hyaluronic acid is the hyaluronic acid that number-average molecular weight is 4750Da.
Preferably, the oligomerization hyaluronic acid is prepared as follows: being taken hyaluronic acid, is digested, molecule is collected in dialysis
Amount is the part 1000~5000Da, freeze-drying.
Preferably, the method for the enzymatic hydrolysis is: every 100mg hyaluronic acid is dissolved in the sodium-acetate buffer of 50mL 0.1M
In, be added 20000 unit of activity bovine testicular hyaluronidase, 37 DEG C of incubations 8h, addition trifluoroacetic acid in and hyaluronidase,
Supernatant is collected in centrifugation；The hyaluronic acid that the hyaluronic acid preferred molecular weight is 1,000,000.
Preferably, the drug is using a effective amount of oligomerization hyaluronic acid and/or its salt as active constituent, in addition pharmaceutically
The preparation that acceptable auxiliary material or complementary ingredient are prepared.
Preferably, the preparation is injection.
Preferably, the drug for promoting Myocardial Regeneration is to reduce cardiac muscle cell apoptosis, increase myocardial vascular quantity, promote
The drug of cardiomyocyte proliferation.
The present invention also provides a kind of drug for treating myocardial infarction, it with a effective amount of oligomerization hyaluronic acid and/or its
Salt is active constituent, in addition the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.
Preferably, the oligomerization hyaluronic acid is the hyaluronic acid that molecular weight is less than 5000Da.
Preferably, the oligomerization hyaluronic acid is the hyaluronic acid that number-average molecular weight is 4750Da.
Preferably, the preparation is injection.
Oligomerization hyaluronic acid and its salt of the present invention can effectively treat myocardial infarction, significant in efficacy, can also reduce the heart
Muscle cell apoptosis increases myocardial vascular quantity, promotes the survival of myocardium of left ventricle cell, can pass through regulation macrophage point
Type, and promote macrophages secrete growth factor VEGF, promote the proliferation of cardiac muscle cell, to promote Myocardial Regeneration, in turn
It prevents heart failure and improves disease treatment curative effect, potential applicability in clinical practice is good.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
The characterization of Fig. 1 .o-HA
Treatment effectiveness evaluation of Fig. 2 .o-HA to mouse.
The release of cTn I detects in mice serum after Fig. 3 .MI
The histopathological analysis of Fig. 4 cardiac muscular tissue.A, CD31；B, TUNEL；C, Ki67 expression.
The pathology HE dyeing of each main organs after Fig. 5 different experiments group processing mouse.
Influence detection of Fig. 6 different experiments group to macrophage migration, invasion.
Fig. 7 different experiments group detects the flow cytometer detection of macrophage parting and the WB of VEGF expression
Specific embodiment
The preparation of the oligomerization hyaluronic acid of the present invention of embodiment 1
The h-HA 100mg of 1000000 molecular weight is dissolved in the 0.1M sodium-acetate buffer (pH 5.4) of 50mL, and it is living to be added 20000
The bovine testicular hyaluronidase of unit of force, 37 DEG C of incubation 8h.10mL solution is taken out, the trifluoroacetic acid (TCA) of 1mL 100% is added
For neutralizing hyaluronidase.The enzyme precipitating of generation is removed by the method for centrifugation.Supernatant is collected, and in molecular weight 1000Da
Bag filter in, dialyse 72h under the conditions of 4 DEG C, midway at least change water 6 times.Liquid in bag filter is collected, molecular weight 5000Da's
In bag filter, continue the 72h that dialyses under the conditions of 4 DEG C.After dialysis, outer aqueous phase is collected, and be lyophilized, the o-HA sample storage after freeze-drying
It is spare there are 4 DEG C.
Molecular weight distribution and the homogeneity detection of product will be determined by gpc analysis.
As a result as shown in Figure 1, the preparation of o-HA is obtained by the method for enzyme degradation h-HA.It will be seen that o- in Fig. 1
The number-average molecular weight of HA is 4750Da, and PDI lower is 1.52, shows that the molecular weight distribution of o-HA oligosaccharides is uniform, thus proves o-
HA is successfully prepared.
Therapeutic effect of the 1 oligomerization Sodium Hyaluronate of test example to myocardial infarction and myocardial ischemia
1, experimental material
Oligomerization Sodium Hyaluronate, prepares according to the method for embodiment 1.
2, experimental method
2.1.MI surgical procedure is modeled
The male C57 mouse of 6-8 week old passes through intraperitoneal injection ketamine (100mg/kg as our modeling object-1)
With xylazine (10mg/kg-1) anaesthetize mouse, using toy ventilator row throacotomy, and following coronary artery occlusion is left
Descending anterior branch.Ligation, which finishes, sews up a wound, and mouse continues ventilation 30 minutes, until mouse lung is expanded again.Sham-operation group also by
Same operation does not ligature left anterior descending branch only.
Experiment is divided into 4 groups, Sham, PBS, h-HA and o-HA group, every group of 8 mouse.Administration mode is intravenous injection, h-HA
It is 5mg/kg with o-HA injection dosage.Treatment 28 days after, mouse put to death, collect the heart, liver, spleen, lung, kidney be used for subsequent experimental, one
Part is fixed in 4% formalin solution, is used for HE and MASSON pathological analysis (n=4)；Another part row frozen section,
For TUNEL, Ki67 and CD31 immunohistochemical analysis (n=4).
2.2.MI biological marker analyte detection
After mouse cardiac muscle ischemic injuries, in different time points, 6,8,12,24,28,72,96,120,144,168h, pass through
Eye socket takes blood, collects serum (n=6), the concentration of cTn I in different treatment group's mouse serums is detected by ELISA kit.
2.3. myocardium of left ventricle pathological analysis
After treating 28 days to mouse, the heart of each experimental mice is collected, a part is fixed in 4% formalin, stone
Wax slice is dyed by HE and MASSON, analyzes degree of myocardial ischemia.
The fresh heart of another part mouse is cut into the tissue block with a thickness of 3mm, carries out TTC dyeing, passes through digital phase
Machine is taken pictures, and myocardial ischemia-area is analyzed.
2.4. mouse heart Myocardial Regeneration is analyzed
The heart tissue for the remaining part collected, by frozen section immunohistochemical analysis items Testing index, including
TUNEL, Ki67 and CD31 are analyzed in cardiac muscular tissue, cardiac muscle cell apoptosis, new vessels and cardiomyocyte proliferation situation.
2.5. safety and toxicity assessment
After treatment 28 days, each main organs of the liver of collection, spleen, lung, kidney are fixed in 4% formalin, are cut by paraffin
Piece carries out HE dyeing, for evaluating o-HA toxicity.In addition, carrying out blood biochemistry analysis to the mouse blood of collection.
2.7.o-HA to the Mechanism Study of Myocardial Regeneration
By migration, invasion, streaming, Protein Assav, migration and invasion of the o-HA to inducing macrophage are analyzed, macrophage is thin
The polarized influence of born of the same parents.
3, experimental result
3.1o-HA reduces myocardial infarction area
Shown in Fig. 2A, after myocardium of left ventricle tissue T TC dyeing, white area shows that more greatly myocardial infarction area is bigger, compared with
NS and h-HA group, myocardial infarction area reduces about 90% after o-HA treatment.The result shows that o-HA substantially reduces myocardial fibrosis
Area can effectively treat MI.HE dyeing display (2C), o-HA treatment group compare other treatment group, myocardium cell necrosis degree
It is substantially reduced, and without obvious inflammatory cell infiltration in cardiac muscular tissue.Shown in Fig. 2 D, the MASSON of heart paraffin section is dyed
It is displayed in blue occupied area reflection left ventricle degree of fibrosis, shows o-HA treatment group than other experimental group myocardium of left ventricle fibers
Change degree significantly reduces, and myocardial infarction area significantly reduces.
Experimental result illustrates that oligomerization hyaluronic acid of the present invention can effectively treat myocardial infarction, and significant effect is better than general
The hyaluronic acid of logical molecular weight.
3.2MI biological marker analyte detection
CTn I is the marker of the specificity generated after cardiomyocyte cell death caused by MI, the content back in serum
Reflect the irreversible dead degree of cardiac muscle cell.As shown in figure 3, NS group and h-HA group be when for 24 hours, concentration of the cTn I in serum
It is 598.2 ± 37.1and, 489.5 ± 8.2Pg/mL respectively, then reduces and continued with higher concentration to 28 days.And o-HA group,
CTn I concentration will be low than above-mentioned two groups when for 24 hours, 378 ± 12.5Pg/mL, and equally lower dense to be similar to Sham group
Degree level was to 28 days.
The experimental results showed that o-HA is capable of the death of effective protection and reduction cardiac muscle cell
For 3.3 cardiomyocyte apoptosis with shown in regeneration analysis chart 4A, we use TUNEL staining analysis, and o-HA treatment group TUNEL is positive
Cardiac muscle cell's ratio be substantially reduced；As shown in Figure 4 B and 4C, in cardiac muscular tissue, o-HA treatment group CD31 positive cell ratio compared with
Other groups dramatically increase, and the cardiac muscle cell of the Ki67 positive increased significantly relative to other treatment group in cardiac muscular tissue.The result shows that
O-HA being capable of effective protection cardiac muscle cell reduction cardiac muscle cell apoptosis, increase cardiac muscular tissue's angiogenesis and increase cardiac muscle cell's increasing
It grows.
3.4 safeties and toxicity assessment
After treatment is finished, HE stained tissue pathological observation is shown, small a main organs do not occur pathology after o-HA treatment
Variation, and the not infiltration (Fig. 5) of inflammatory cell.The result shows that o-HA is carried out, MI Therapeutic safety is high, and toxic side effect is low.
Mechanism Study of the 3.5o-HA to macrophage
It is tested by scratch and Transwell, it has been found that o-HA can promote migration and the invasion (figure of macrophage
6)；Flow cytometry discovery o-HA can promote macrophage to polarize to M2 type, and promote vascular endothelial growth factor
The expression (Fig. 7) of VEGF.It is considered that this will be the main reason for o-HA promotes Myocardial Regeneration.
4 conclusions
Present invention experiment confirms oligomerization hyaluronic acid o-HA, can effectively treat myocardial infarction, and significant effect is excellent
In the hyaluronic acid h-HA of conventional molecular weight.
In addition, present invention experiment, which has also demonstrated oligomerization hyaluronic acid o-HA, can reduce cardiac muscle cell apoptosis, increase cardiac muscle
Blood vessel number promotes the survival of myocardium of left ventricle cell, can be by regulating and controlling macrophage parting, and promotes macrophage point
Growth factor VEGF is secreted, promotes the proliferation of cardiac muscle cell, and significant effect is better than the hyaluronic acid h-HA of common molecular weight, this
Invention oligomerization hyaluronic acid o-HA can promote Myocardial Regeneration, and can be used in treatment becomes the material for promoting Myocardial Regeneration.
To sum up, oligomerization hyaluronic acid and its salt of the present invention can effectively treat myocardial infarction, significant in efficacy, Small side effects,
A kind of new drug is provided for clinical treatment myocardial infarction, potential applicability in clinical practice is good.
Claims (10)
1. the purposes of oligomerization hyaluronic acid or its salt in preparation treatment myocardial infarction and/or the drug for promoting Myocardial Regeneration.
2. purposes according to claim 1, it is characterised in that: the oligomerization hyaluronic acid is that number-average molecular weight is less than
The oligomerization hyaluronic acid of 5000Da.
3. purposes according to claim 2, it is characterised in that: the oligomerization hyaluronic acid is that number-average molecular weight is 4750Da
Oligomerization hyaluronic acid.
4. purposes according to claim 1, it is characterised in that: the oligomerization hyaluronic acid is prepared as follows: being taken
Hyaluronic acid digests, dialysis, and collection molecular weight is the part 1000~5000Da, freeze-drying.
5. purposes according to claim 1, it is characterised in that: the method for the enzymatic hydrolysis is: every 100mg hyaluronic acid, it is molten
In the sodium-acetate buffer of 50mL 0.1M, the bovine testicular hyaluronidase of 20000 unit of activity is added, 37 DEG C of incubation 8h add
Enter in trifluoroacetic acid and supernatant is collected in hyaluronidase, centrifugation；The hyaluronic acid preferred molecular weight be 1,000,000 it is transparent
Matter acid.
6. purposes described in any one according to claim 1~5, it is characterised in that: the drug is with a effective amount of oligomerization
Hyaluronic acid and/or its salt are active constituent, in addition the system that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared
Agent.
7. purposes according to claim 6, it is characterised in that: the preparation is injection.
8. purposes described in any one according to claim 1~7, it is characterised in that: it is described promote Myocardial Regeneration drug be
The drug for reducing cardiac muscle cell apoptosis, increasing myocardial vascular quantity, promoting cardiomyocyte proliferation.
9. a kind of drug for treating myocardial infarction, it is characterised in that: it is to live with a effective amount of oligomerization hyaluronic acid and/or its salt
Property ingredient, in addition the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.
10. drug according to claim 7, it is characterised in that: the oligomerization hyaluronic acid is that number-average molecular weight is less than
The hyaluronic acid of 5000Da；Preferably, the oligomerization hyaluronic acid is the hyaluronic acid that number-average molecular weight is 4750Da.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007291133A (en) * | 2007-07-09 | 2007-11-08 | Seikagaku Kogyo Co Ltd | Therapeutic agent containing hyaluronic acid oligosaccharide as active ingredient |
| US7507723B2 (en) * | 2000-07-07 | 2009-03-24 | Seikagaku Corporation | Hyaluronic acid oligosaccharide fractions and drugs containing the same |
| CN105055440A (en) * | 2012-02-21 | 2015-11-18 | 华熙福瑞达生物医药有限公司 | Application and composition of poly-hyaluronic acid or oligo-hyaluronate |
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- 2018-12-20 CN CN201811564130.2A patent/CN109528753B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7507723B2 (en) * | 2000-07-07 | 2009-03-24 | Seikagaku Corporation | Hyaluronic acid oligosaccharide fractions and drugs containing the same |
| JP2007291133A (en) * | 2007-07-09 | 2007-11-08 | Seikagaku Kogyo Co Ltd | Therapeutic agent containing hyaluronic acid oligosaccharide as active ingredient |
| CN105055440A (en) * | 2012-02-21 | 2015-11-18 | 华熙福瑞达生物医药有限公司 | Application and composition of poly-hyaluronic acid or oligo-hyaluronate |
Non-Patent Citations (2)
| Title |
|---|
| S. MATOU-NASRI等: "Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and γ-adducin", 《INTERNATIONAL JOURNAL OF ONCOLOGY》 * |
| 张晓鸥等: "透明质酸支架材料：应用研究与产品转化前景", 《中国组织工程研究》 * |
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