CN108403677A - Application of the crocin in preventing and treating Human Thoracic Aortic Dissection/aortic aneurysm - Google Patents
Application of the crocin in preventing and treating Human Thoracic Aortic Dissection/aortic aneurysm Download PDFInfo
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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Abstract
The present invention relates to application of the crocin in the drug for preparing prevention and/or treatment Human Thoracic Aortic Dissection/aortic aneurysm, the drug is：Drug, the drug through subcutaneously embedding administering mode administration of drug, intravenous administration administration through gastro-intestinal tract canal drug administration, the drug preferably through subcutaneous embedding administering mode administration.
Description
Technical field
The invention belongs to field of pharmaceutical biology, in particular to crocin prevention and treatment Human Thoracic Aortic Dissection/
Application in aortic aneurysm.
Background technology
Aortic aneurysm and the complication that dissection of aorta is diagnosis of thoracic aortic diseases most serious, most important feature is that have rupture
Tendency, the case fatality rate of TAD ruptures is up to 90%.With the continuous improvement of imaging diagnosis technology, incidence is found with detection
Patient's number rises year by year, in the therapeutic scheme of aortic aneurysm and dissection of aorta, it is intravascular repair, man-made support type blood vessel
Transplanting is main therapy, but operation wound is big, and the severe complications such as paraplegia and the death rate are up to 17% and 26%.
Other than operative treatment, the common treatment for aortic aneurysm and dissection of aorta further includes drug therapy,
Low danger patient can first drug application treatment, and carry out close observation.Common drug includes adrenergic beta receptor blockaders (beta receptor
Blocking agent), AngiotensinⅡ receptor1 antagonistic, angiotensin converting enzyme inhibitor, statins etc..Beta receptor blocks
Medicine can reduce myocardial contractive power, reduce blood pressure, and to reduce blood vessel wall tension, can postpone aneurysm of thoracic aorta progress, reduce blood vessel
The incidence of rupture and Human Thoracic Aortic Dissection improves survival rate.AngiotensinⅡ receptor1 antagonistic is common depressor
Object can inhibit the combination of angiotensinⅡ and its receptor 1, has been reported that and shows that such drug can postpone marfan's syndrome infant master
Artery root is broadening, and age smaller application effect is better.Angiotensin converting enzyme inhibitor can prevent vasotonia
Plain I is converted into the Angiotensin II of the upstreams ARBs, can reduce the expansion of aorta, the generation of MMP2 and TGF-β.Statins
Drug can reduce the generation of atherosclerosis, have protective effect to arterial wall.But above-mentioned various drugs, clinically also deposit
In many adverse reactions and side effect, for example, Bextra may reduce aorta elasticity, for young patient
There are potential side effect, the liver renal toxicity of statins, the incompatibility etc. of Bextra and some drugs for long-term treatment
Deng.Therefore, it is necessary to the safer drugs that effectively can prevent and alleviate aortic aneurysm and dissection of aorta.
For this problem, present inventor's first passage animal model to the traditional Chinese medicine of common plant origin at
Divide or compound is screened, obtains the new drug that can be directed to aortic aneurysm and dissection of aorta.
Invention content
Present invention firstly relates to a kind of crocins (also known as crocin I or safron glycosides) to Human Thoracic Aortic Dissection/chest
The treatment use of aortic aneurysm, the application are, for Human Thoracic Aortic Dissection/aneurysm of thoracic aorta patient of clinical definite, to lead to
The mode for crossing drug administration by injection applies crocin.
The invention further relates to crocin prepare treatment Human Thoracic Aortic Dissection/aneurysm of thoracic aorta drug in application,
The drug includes but not limited to the drug that drug, intravenous administration through gastro-intestinal tract canal drug administration are administered, through subcutaneously wrapping
Bury the drug of administering mode administration.
The invention further relates to crocin prepare prevent Human Thoracic Aortic Dissection/aneurysm of thoracic aorta drug in application,
The drug includes but not limited to the drug that drug, intravenous administration through gastro-intestinal digestion canal drug administration are administered, through subcutaneously embedding
The drug of administering mode administration.
The invention further relates to a kind of preparations for evaluating the animal model of the curative effect of medication of dissection of aorta/aortic aneurysm
Method, the method step is that 3 week old C57BL/6 background male mices is taken to give normal diet, by BAPN with 1g/kg/day
Dosage is dissolved in drinking-water, feeding mouse 4 weeks.
The invention further relates to a kind of preparation method for evaluating the animal model of the curative effect of medication of aortic aneurysm, the sides
Method step is：Take 6 week old Apoe-/-20~22g of male mice or so gives normal diet and drinking-water, to mouse subcutaneously to bury pump
Mode carry out human angiotensin II perfusions, the dosage and method of perfusion are：With 1.5 μ g/kg/min dosage, subcutaneous injection 6
Week.
Description of the drawings
Fig. 1, crocin are to the preventive effect of Human Thoracic Aortic Dissection/aortic aneurysm of mouse model.
Fig. 2, crocin are to the therapeutic effect of Human Thoracic Aortic Dissection/aortic aneurysm of mouse model
Specific implementation mode
Experimental animal, reagent and kit, instrument
Experimental animal
Human Thoracic Aortic Dissection/aortic aneurysm model：3 week old male wild-type mices (C57BL/6)；ApoE-/-Mouse
(C57BL/6J) it is purchased from Beijing HFK Bio-Technology Co., Ltd..All animals are in Beijing's cardiopulmonary and vascular disease
Research institute SPF grades of environment animals room carries out captive breeding.Wild mouse need to be to reach 3 week old, and male of the weight in 10g or so is small
Mouse.ApoE-/- mouse requires 6W or so, male mice of the weight in 20~22g or so.All experimental implementations all in accordance with NIH with
It formulates within 1996《Management of laboratory animal and guide for use》With reality as defined in the management of laboratory animal committee of the Capital University of Medical Sciences
Test flow progress.All experimental animals are grouped according to random device.
Biochemical reagents and kit title and supplier see the table below 1
Table 1, biochemical reagents and kit title and supplier
Experimental instrument and equipment title and supplier see the table below 2
Table 2, experimental instrument and equipment title and supplier
The structure of embodiment 1, Human Thoracic Aortic Dissection/aortic aneurysm mouse model (mouse TAD models)
BAPN feeds structure and the evaluation of water group mouse TAD models
3 week old C57BL/6 background male mices are taken to give normal diet,
BAPN feeds water group (n=16)：BAPN is dissolved in 1g/kg/day dosage in drinking-water.
It feeds BAPN the 14th day, randomly chooses 5 mouse and carry out aorta pectoralis ultrasound, judge whether to have existed aorta pectoralis
Broadening/interlayer.It is tested through being repeated several times, some animals have formed dissection of aorta/aortic aneurysm at 14 days, and start land
Continuous death.It is to model induction interlayer/aneurysmal effect assessment scheme：
1. the mouse aorta after pair death carries out HE or elastic fibers dyeing (specific method is shown in embodiment 2), measure
Vascular diameter whether thickening (interlayer)；Or it sees whether the disorder for elastic plate occur or aneurysm occurs；
2. pair intravital mouse carries out aortic arch ultrasound, calculated diameter sees whether thickening or interlayer occurs.
BAPN hello water group mouse add AII to be perfused after 4 weeks：It is perfused 24 hours with 1 μ g/kg dose subcutaneous, is such as perfused in AII
It is dead not yet after 24H, it is unified to put to death.
Embodiment 2 gives preventive effect of the crocin to dissection of aorta/aortic aneurysm
Crocin is ordered from rich letter (Beijing) Science and Technology Ltd. of middle peasant, and article No. is BP0406, and specific name is west
Carthamic acid I (Crocin I)
Water law, which is fed, using BAPN as described in Example 1 builds TAD mouse models.
The mouse of TAD will be induced to be randomly divided into two groups,
One group is crocin prevention group：From the first day for the water for feeding BAPN, it is injected intraperitoneally and hides according to the dosage of 50mg/kg
Carthamin, once every two days；
Another group is control group：Frequency same as crocin treatment group gives the life of same volume through intraperitoneal injection
Manage brine.
After four weeks, two groups of mouse all give Angiotensin II (AII) and fill pump, for 24 hours.
Observation index includes after administration：
1. weight：It weighs daily to two groups of mouse.Whether observation drug influences weight to increasing.
2.BAPN intakes：The drinking-water situation for substantially observing two groups of mouse daily, judges whether drug influences mouse weight
Variation
3. blood pressure：Since third week, the every 3 days measurement for carrying out a blood pressure, to exclude mouse due to blood pressure
Change cause its aneurysm to be not easily broken, influence survival rate
Observe terminal：
1. mouse natural death during modeling：Death time and the cause of death are noted down (whether because of interlayer/aneurysm rupture
And dead)；
2. not dead mouse：Mouse is put to death afterwards for 24 hours filling pump, the blood vessel for collecting all mouse is dyed, it is counted
Blood vessel diameter and interlayer incidence.
It is prepared by tissue freezing section：
It uses amobarbital (100mg/kg) anesthesia to put to death mouse at the end of experiment, the heart is carried out using heparinized saline
Dirty perfusion removes heart remained blood.Continue to be perfused with 4% paraformaldehyde, makes vascular tissue's form fixation in situ.Stereoscopic aobvious
Detach clip aortic arch and drop portion under micro mirror, impregnated in 4% paraformaldehyde and fix 2 hours, after be transferred to 30% sucrose
It stays overnight for 4 DEG C in solution, is fully dehydrated.Blood vessel is taken out from sucrose solution within second day, tissue moisture is sufficiently absorbed through with filter paper, by blood
Pipe is embedded in OCT embedding mediums vertically, is slowly congealed in liquid nitrogen after masking foil wrapping, can be stored in -80 DEG C of refrigerators.Connected
Continuous frozen tissue section, 5 μm of thickness, with poly-D-lysine coating slide patch.
It is prepared by tissue paraffin section de
It uses amobarbital (100mg/kg) anesthesia to put to death mouse at the end of experiment, the heart is carried out using heparinized saline
Dirty perfusion removes heart remained blood.Clip aortic arch is detached under stereomicroscope, is put in 10% formalin solid
It is fixed；Normal aorta and TAD tissues are put in 10% formalin fixed.Blood vessel is taken out after at least 24 hours to carry out at dehydration
Reason, is used in combination paraffin-embedded tissue (blood vessel is straight down).Serial section, 5 μm of thickness, with poly-D-lysine coating are used when slice
Slide patch.
Histopathology：
I. observation elastic plate situation is dyed by elastic fibers,
Concrete operations are as follows：
1. frozen section：
(1) OCT is washed away in frozen section PBS；
(2) 1 drop (100 μ l) Lugol iodine solutions (reagent A) are added to be incubated 5 minutes, slightly wash；
(3) 1 drop (100 μ l) thio-acid sodium (reagent B) is added to handle 5 minutes；
(4) it is rinsed 5 minutes with flowing water, 70% alcohol is slightly washed；
(5) 1 drop (100 μ l) aldehyde-fuchsin dye liquor (reagent C) is added, carries out dyeing 10 minutes, is embathed 2 times with 70% alcohol
(about 30 seconds every time, until slice no longer decolourizes), are slightly washed；
(6) 1 drop (100 μ l) orange G dye liquor (reagent D) is added to dye 10 seconds, slightly washes；
(7) 95% dehydration of alcohol 5min；
(8) absolute alcohol is dehydrated 5min；
(9) the transparent 5min of dimethylbenzene, mounting；
2. paraffin section：
(1) paraffin section is routinely dewaxed with dimethylbenzene, and the ethyl alcohol through various concentrations at different levels is by paraffin section de-waxing to water：Two
Toluene I (20min) → dimethylbenzene II (20min) → dimethylbenzene III (20min) → 100% alcohol (5min) → 95% alcohol
(5min) → 80% alcohol (5min) → tap water washes away alcohol.
(2) 1 drop (100 μ l) Lugol iodine solutions (reagent A) are added to be incubated 5 minutes, slightly wash；
(3) 1 drop (100 μ l) thio-acid sodium (reagent B) is added to handle 5 minutes；
(4) it is rinsed 5 minutes with flowing water, 70% alcohol is slightly washed；
(5) 1 drop (100 μ l) aldehyde-fuchsin dye liquor (reagent C) is added, carries out dyeing 10 minutes, is embathed 2 times with 70% alcohol
(about 30 seconds every time, until slice no longer decolourizes), are slightly washed；
(6) 1 drop (100 μ l) orange G dye liquor (reagent D) is added to dye 10 seconds, slightly washes；
(7) 95% dehydration of alcohol 5min；
(8) absolute alcohol is dehydrated 5min；
(9) the transparent 5min of dimethylbenzene, mounting；
Using the micro- sem observations of Nikon ECLIPSE 90i, elastic fibers is in bluish violet, and background is in different degrees of yellow.
It is new intima part on the inside of elastic plate.
II. observation wall structures are dyed by HE and destroy situation,
Concrete operations are as follows：
1. frozen section：
(1) OCT is washed away in frozen section PBS；
(2) 4% paraformaldehyde fixes 10min, and PBS is washed 3 times.
(3) haematoxylin dyeing (1-2min), tap water rush three times removal loose colours.
(4) acidic alcohol differentiation liquid 2 seconds (being stained under two), the small flow velocity degree flushing of tap water return blue (5min).
(5) Yihong liquid dyeing (1-2min) contaminates endochylema, and tap water washes off loose colour (30 seconds).
(6) conventional dehydration, transparent, mounting：80% alcohol (5min) → 95% alcohol (5min) → 100% alcohol (5min)
→ 100% alcohol (5min) → dimethylbenzene I (5min) → dimethylbenzene II (5min) → neutral gum mounting.
(7) microscopically observation specimen morphology.
2. paraffin section：
(1) paraffin section is routinely dewaxed with dimethylbenzene, and the ethyl alcohol through various concentrations at different levels is by paraffin section de-waxing to water：Two
Toluene I (20min) → dimethylbenzene II (20min) → dimethylbenzene III (20min) → 100% alcohol (5min) → 95% alcohol
(5min) → 80% alcohol (5min).
(2) tap water rinses, and washes away alcohol.
(3) haematoxylin dyeing (3-5min), tap water rush three times removal loose colours.
(4) acidic alcohol differentiation liquid 2 seconds (being stained under two), the small flow velocity degree flushing of tap water return blue (5min).
(5) Yihong liquid dyeing (2-3min) contaminates endochylema, and tap water washes off loose colour (30 seconds).
(6) conventional dehydration, transparent, mounting：80% alcohol (5min) → 95% alcohol (5min) → 100% alcohol (5min)
→ 100% alcohol (5min) → dimethylbenzene I (5min) → dimethylbenzene II (5min) → neutral gum mounting.
(7) microscopically observation specimen morphology.
The results show that the life span of the mouse of intraperitoneal injection crocin group has significantly compared with the mouse of TAD control groups
(Figure 1A) the arteriorrhexis rate of improvement has apparent reduction (Figure 1B), interlayer incidence to reduce apparent (Fig. 1 C), and blood vessel diameter expands
The rate of opening reduces apparent (Fig. 1 D), and the blood vessel colored graph of mouse model is shown in Fig. 1 E, it is seen then that the rat aorta pipe of crocin prevention group
Chamber is relatively complete mellow and full, does not expand, and positive controls (BAPN induces the mouse of TAD) blood vessel elastic plate is disorderly, blood
Pipe diameter thickening is more than 150% (apparent aortic aneurysm symptom), while part blood vessel elastic plate cut, arterial blood tube wall
It is middle a large amount of interlayer thrombus occur.
Embodiment 3 gives therapeutic effect of the crocin to dissection of aorta/aortic aneurysm
Water law, which is fed, using BAPN as described in Example 1 builds TAD mouse models.
The mouse of TAD will be induced to be randomly divided into two groups,
One group is crocin treatment group：From feeding the 14th day of the water containing BAPN, noted according to the dosage abdominal cavity of 80mg/kg
Hide-out phenomena carthamin, once every two days；
Another group is control group：Frequency same as crocin treatment group gives the life of same volume through intraperitoneal injection
Manage brine.
After four weeks, two groups of mouse all give Angiotensin II (AII) and fill pump, for 24 hours.
Observation index includes after administration：
1. weight：It weighs daily to two groups of mouse.Whether observation drug influences weight to increasing.
2.BAPN intakes：The drinking-water situation for substantially observing two groups of mouse daily, judges whether drug influences mouse weight
Variation
3. blood pressure：Since third week, the every 3 days measurement for carrying out a blood pressure, to exclude mouse due to blood pressure
Change cause its aneurysm that should not rupture, influence survival rate
Observe terminal：
1. mouse natural death during modeling：Note down death time and the cause of death (whether dead because of aorta rupture)；
2. not dead mouse：Mouse is put to death afterwards for 24 hours filling pump, the blood vessel for collecting all mouse is dyed, it is counted
Blood vessel diameter and interlayer incidence.
Frozen section, paraffin section, histopathology method are the same as embodiment 3.
The results show that the life span of the mouse of intraperitoneal injection crocin group has significantly compared with the mouse of TAD control groups
Improve (Fig. 2A), aorta rupture rate has apparent reduction (Fig. 2 B), interlayer incidence to reduce apparent (Fig. 2 C), and blood vessel diameter expands
Opening rate (aortic aneurysm) reduces apparent (Fig. 2 D), and the blood vessel colored graph of mouse model is shown in Fig. 1 E, it is seen then that crocin treatment group
Rat aorta tube chamber is smooth, and diameter is normal, and it is more than 150% (for apparent artery that BAPN, which induces the rat aorta lumen distention of TAD,
Tumor symptom), while part blood vessel elastic plate cut, there are a large amount of thrombus interlayers.
Finally, it should be noted that above example is used only as helping skilled in the art to understand technical solution of the present invention
Essence, limiting the scope of the present invention that it goes without doing.
Claims (4)
1. application of the crocin in the drug for preparing treatment Human Thoracic Aortic Dissection/aortic aneurysm.
2. application according to claim 1, which is characterized in that the drug is：Medicine through gastro-intestinal tract canal drug administration
Object, the drug of intravenous administration administration, the drug through subcutaneously embedding administering mode administration, preferably through subcutaneous embedding administering mode
The drug of administration.
3. application of the crocin in preparing the drug for preventing Human Thoracic Aortic Dissection/aortic aneurysm.
4. application according to claim 3, which is characterized in that the drug is：Medicine through gastro-intestinal tract canal drug administration
Object, the drug of intravenous administration administration, the drug through subcutaneously embedding administering mode administration, preferably through subcutaneous embedding administering mode
The drug of administration.
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