CN106906278A - Predict biomarker of type ii diabetes cardiovascular complication risk and application thereof - Google Patents
Predict biomarker of type ii diabetes cardiovascular complication risk and application thereof Download PDFInfo
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6844—Nucleic acid amplification reactions
- C12Q1/686—Polymerase chain reaction [PCR]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
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Abstract
The invention belongs to biological and diagnostics technical field, be related to it is a kind of clearly, effectively, intuitively platelet reactivity biomarker P2Y12 acceptors, and its for diagnosing and predicting the purposes in type ii diabetes people's cardiovascular complication risk；The P2Y12 biomarkers can detect the P2Y12 contents in hematoblastic expression, and detection whole blood by quantitative fluorescent PCR, protein immunoblot, Enzyme-linked Immunosorbent Assay (ELISA), flow cytometry, ultraviolet spectrophotometry-near infrared spectroscopy, high performance liquid chromatography, colorimetric method, Mass Spectrometric Identification method etc..It is used to diagnose and predict the method for the risk of subject's cardiovascular complication present invention also offers biomarker P2Y12, and for treating the medicine of type ii diabetes patient's cardiovascular complication and the screening technique of such medicine.Individuation, the intervention stratege of the cardiovascular complication of precision treatment type ii diabetes patient are carried out the present invention further provides preferred P2Y12 inverse agonists.
Description
Technical field
The invention belongs to biological and diagnostics technical field, and in particular to type ii diabetes cardiovascular complication risk
Prediction and treatment technology field.More particularly, to diagnose and predict type ii diabetes patient's cardiovascular complication risk
Biomarker；And the method for diagnosing and predicting the risk of subject's cardiovascular complication.The present invention enters one
Step is related to the medicine for treating type ii diabetes patient cardiovascular complication (suffering from this sick risk to increase), and this
The screening technique of class medicine.
Background technology
In recent years, with the raising and aging population of China's Living consumption, the incidence of disease of type ii diabetes and dead
Rate of dying also is raised year by year.According to statistics, current China Adult type II diabetes illness rate is about 11.6%, type ii diabetes people
Number the first in the world, type ii diabetes have turned into the formidable enemy for threatening our people's life and health.Prior art discloses glycosuria
Old complaint is broadly divided into I types and type ii diabetes (T2DM) according to the difference of the cause of disease and clinical manifestation, wherein more than 90%
Patient is T2DM；The platelet reactivity that type ii diabetes patient more than half has atherosclerosis, patient increases,
The cardiovascular complications such as easy premature coronary heart disease, apoplexy.Data shows, in China, cardiovascular and cerebrovascular complication doubles to increase II
The direct medical cost of patients with type Ⅰ DM people, this is also the main cause for constituting death.Research display, II type glycosurias
The main cause of patient's Yi Faxin cerebrovascular complications is that platelet reactivity increases, but platelet reactivity is increased
Reason it is not immediately clear.As it was previously stated, cardiovascular complication is the major causes of death of diabetes, antiplatelet drug
It is the Main Means for preventing and treating diabetic cardiovascular complications, but because the reason for diabetic platelet reactivity increases
It is unclear, so there is no method to select that there is targetedly therapeutic scheme and medicine in clinical practice, and cannot carry out
Precision is treated, and causes that current type ii diabetes people cardiovascular and cerebrovascular complication therapeutic effect is not good enough, and the death rate is high.
It is a kind of classical g protein coupled receptor to have research to disclose P2Y12 acceptors.G protein coupled receptor is at least deposited
In the acceptor R and the acceptor R* of activated state of two kinds of configurations, i.e. non-live condition, the acceptor is in dynamic equilibrium：
R←→R*.Foundation is different with the selectivity that R is combined to R*, and part can be divided into activator, neutral antagonist, and reversely swash
Dynamic agent.To R* than having affinity higher to R, i.e., selectivity is combined activator with R*, makes balancing steering
The state of activation of acceptor is producing effect.Antagonist has identical parent to active acceptor R* and inactive receptive R
And power, and and R* and R combination keep dynamic equilibrium.Signal can be reduced to foundation level by antagonist, but can not
Signal is set to be reduced to below foundation level.Inverse agonist is selectively combined with inactive receptive R, is produced and endogenous
The opposite effect of activator.Different from neutral antagonist, inverse agonist can be reduced below signal to foundation level.When
When g protein coupled receptor level is raised, acceptor can be caused to be in a kind of spontaneous activation state so that basis of signals water
Flat abnormal rising.Inverse agonist can suppress the activity of constitutive activity acceptor, reduce the foundation level having built up, and
Neutral antagonist can not suppress the activity of constitutive activity acceptor, it is impossible to reduce the foundation level having built up.
Present situation based on prior art, present inventor intends providing a kind of biomarker, further the biology
Label is used to diagnose and predict type ii diabetes patient's cardiovascular complication risk；And received for diagnosing and predicting
The method of the risk of examination person's cardiovascular complication and the medicine for screening treatment type ii diabetes patient's cardiovascular complication
Thing
The content of the invention
It is an object of the invention to provide a kind of biomarker for predicting type ii diabetes patient's cardiovascular complication risk
Thing, and be further used for diagnosing and predicting type ii diabetes patient's cardiovascular complication risk；And for diagnose and
Predict the method for the risk of subject's cardiovascular complication and for screening treatment type ii diabetes patient angiocarpy concurrently
The medicine of disease.
The present invention has carried out P2Y12 expression experimental studies, as a result shows, type ii diabetes human blood platelets P2Y12
Acceptor levels are significantly raised, acceptor spontaneous activation, acceptor elevated levels and the obvious positive correlation of platelet reactivity, show
It is the reason for diabetic platelet reactivity increases that P2Y12 acceptor levels are raised, therefore, P2Y12 acceptors can be made
To predict the biomarker of type ii diabetes patient's cardiovascular complication risk, it is used to predict that diabetic is cardiovascular
The risk that complication occurs, and further according to patient's P2Y12 acceptor levels, carry out personalization, the intervention of precision
Treatment.
Based on the studies above result：Type ii diabetes human blood platelets P2Y12 acceptor levels are significantly raised, and acceptor is spontaneous to swash
It is living, joint " inverse agonist can suppress the activity of constitutive activity acceptor, the foundation level that reduction has built up, and in
Property antagonist can not suppress the activity of constitutive activity acceptor, it is impossible to reduce the foundation level having built up " research foundation,
In the present invention further study show that, P2Y12 inverse agonists AR-C78511 is than P2Y12 Receptor neutral antagonists banks
Gray Lip river (AR-C69931MX, cangrelor), with more preferable anti-platelet activity；It is therefore proposed that for sugar
Urine patient's cardiovascular complication, P2Y12 inverse agonists possess bigger treatment than P2Y12 Receptor neutral antagonists
Advantage；For the elevated diabetic of P2Y12 acceptor levels, P2Y12 reverse excitement agent therapies can be used,
Carry out personalized and precision treatment.To sum up, the present invention is proposed：1) blood platelet P2Y12 acceptor levels during diabetes
Increase, acceptor spontaneous activation be diabetes patient's platelet reactivity increase, the major reason of vascular complication of easily making up one's mind；
2) blood platelet P2Y12 acceptor levels increase during diabetes, acceptor spontaneous activation is to cause the reduction of antiplatelet drug curative effect
Major reason；3) " clopidogrel Resistant " is relevant with its inverse agonist activity, i.e., for blood platelet P2Y12 acceptors
The patient that expression is increased, clopidogrel is low because of its inverse agonist activity, and antiplatelet effects are not good, cause to control curative effect
It is really poor；4) diabetes patient increased for blood platelet P2Y12 expression of receptor, P2Y12 receptor inverse agonists have more
Good antiplatelet advantage；5) II is instructed according to patient's blood platelet P2Y12 receptor expression levels in suggestion clinical practice
The selection of patients with type Ⅰ DM people's antiplatelet drug, i.e., the diabetes patient for increasing to blood platelet P2Y12 expression of receptor uses
P2Y12 reverse excitement agent therapies.
In the present invention, experimental data shows, type ii diabetes Platelet P2Y12 receptor expression levels substantially rise
Height, and increase positive correlation with platelet reactivity, explain type ii diabetes patient's cardiovascular complication risk and increase
The reason for；It is further proposed that " by detecting blood platelet P2Y12 receptor expression levels, prediction type ii diabetes people receives
Platelet reactivity level, the method for angiocardiopathy complication risk in examination person "；Be also found in the application：It is right
P2Y12 receptor expression levels diabetes patient's platelet reactivity high, P2Y12 inverse agonists AR-C78511 tools
Have than the P2Y12 more preferable inhibitory action of Receptor neutral antagonists cangrelor, with preferably preventing and treating type ii diabetes
The effect of patient's cardiovascular complication；Thus, the present invention proposes " P2Y12 reverse excitement agent therapies to be used, to P2Y12
Receptor expression level diabetes patient high, the method for carrying out precision treatment ".
The invention provides cardiovascular concurrent using the prediction of biomarker P2Y12 acceptors and diagnosis type ii diabetes people
The method of disease risk, and for the type ii diabetes people for the expression high of P2Y12 acceptors, using P2Y12 acceptors
Inverse agonist carries out individuation, the method for precision Antiplatelet therapy.Methods described includes that detection subject's blood is small
The method of P2Y12 receptor expression levels change in plate sample, and it is biological using blood platelet P2Y12 acceptors as one kind
Label is used to predict the risk of type ii diabetes cardiovascular complication, and according to blood platelet P2Y12 receptor expression levels,
Carry out personalized, precision treatment；Blood platelet P2Y12 expressions are increased patient (including type ii diabetes and its
Its arterial thrombotic disease such as apoplexy, coronary heart disease, peripheral vascular disease etc.), selection P2Y12 inverse agonists carry out anti-blood
Platelet is treated；In embodiments of the invention, preferably P2Y12 inverse agonists AR-C78511 reversely swashs as kind is potent
Dynamic agent, it has more preferable therapeutic advantage to type ii diabetes people's cardiovascular complication.
More specifically, utilization biomarker P2Y12 acceptors prediction of the invention and diagnosis type ii diabetes people's painstaking effort
The method of pipe complication risk, and for the type ii diabetes people for the expression high of P2Y12 acceptors, using P2Y12
Receptor inverse agonists carry out individuation, the method for precision Antiplatelet therapy, including：Determine P2Y12 acceptors
MRNA expressions in the platelet sample from the type ii diabetes people experimenter；P2Y12 acceptors exist
Protein expression level in platelet sample from the type ii diabetes people experimenter；Come from the II types sugar
Urinate the platelet aggregation rate level of the platelet sample of patient subject；And compare P2Y12 acceptors coming from
Protein expression level in the platelet sample of subject is stated with P2Y12 in the platelet sample of control group Healthy People
Expression；And determine protein expression of the P2Y12 acceptors in the platelet sample for coming from the subject
The relation of the platelet aggregation rate level of the corresponding sample of level；Determine and compare same concentrations simultaneously
The inhibition of AR-C78511 and cangrelor to the platelet aggregation rate of subject's platelet sample；And determine
The platelet aggregation rate inhibition of AR-C78511 and cangrelor is received with the P2Y12 in subject's platelet sample
The relation of body protein expression；Determine after testing, as a result show：It is tested in the Healthy People with P2Y12 acceptors
Expression in person's platelet sample is compared, and P2Y12 acceptors are in the blood platelet from type ii diabetes people experimenter
MRNA and protein expression level in sample are dramatically increased, and platelet aggregation is significantly increased, and P2Y12 acceptors
The platelet reactivity of expression quantity in the platelet sample for coming from subject and corresponding sample is into positive correlation；
AR-C78511 is similar to the inhibition of the platelet aggregation rate of Healthy People platelet sample with cangrelor, but
AR-C78511 is significantly stronger than cangrelor, and P2Y12 to the platelet aggregation rate inhibitory action of type ii diabetes people
Receptor protein expression is higher, and the platelet aggregation rate inhibition of AR-C78511 is got over and is better than cangrelor.
In embodiments of the invention,
(1) using real time fluorescence quantifying PCR method in subject's type ii diabetes people and Healthy People platelet sample
P2Y12 Receptor mRNA level researchs, as a result show：P2Y12 in type ii diabetes human blood platelets sample
Receptor mRNA level (6.6 ± 4.6) is significantly higher than the P2Y12 expressions in Healthy People platelet sample
(1.5±0.9)；Normal reference value is less than 3.3, higher than this value for P2Y12 abnormal expressions increase；
(2) it is small to subject's type ii diabetes people and healthy human blood using the protein imprinted methods of Western Blot
P2Y12 receptor proteins expression research in plate sample, as a result shows：In type ii diabetes human blood platelets sample
P2Y12 receptor proteins expression quantity (0.68 ± 0.26) be significantly higher than in Healthy People platelet sample P2Y12 expression
Level (0.34 ± 0.16)；Normal reference value is less than 0.65, higher than this value for P2Y12 abnormal expressions increase；
(3) to subject's type ii diabetes people and the platelet aggregation rate result of study table of Healthy People platelet sample
It is bright：(1 μM) platelet aggregation rate (7.0 ± 1.6%) of induction type ii diabetes human blood platelets sample of low concentration ADP
It is significantly higher than the platelet aggregation rate (1.2 ± 0.9%) of Healthy People platelet sample；And high concentration ADP (10 μM)
It is small that the platelet aggregation rate (47 ± 13%) of induction type ii diabetes human blood platelets sample is equally significantly higher than healthy human blood
The platelet aggregation rate (38 ± 8%) of plate sample；
(4) the P2Y12 receptor proteins expression and platelet aggregation rate to subject's platelet sample carry out phase
The analysis of closing property, as a result shows：In subject's platelet sample, P2Y12 receptor protein expressions are higher,
Platelet aggregation rate is higher, and blood platelet P2Y12 receptor proteins expression is proportionate with platelet aggregation rate
Property (P (two-tailed)<0.01 | r |=0.89)；It is Concentration In Platelets of Diabetic Patients reaction to illustrate that P2Y12 acceptors increase
Property increase, the reason for cardiovascular complication risk increases；
(5) to AR-C78511 and cangrelor to (10 μM) subject's platelet sample platelet aggregations of induction of ADP
The inhibition of collection rate is analyzed, and as a result shows：The AR-C78511 and cangrelor of same concentrations (1nM)
To the platelet aggregation rate inhibition quite (P of Healthy People platelet sample>0.05)；But same concentration
AR-C78511 is significantly strong to the platelet aggregation rate inhibition (17 ± 9%) of type ii diabetes human blood platelets sample
In cangrelor (23 ± 11%)；Result illustrates inverse agonist AR-C78511 than neutral antagonist cangrelor
With the treatment advantage for preferably suppressing platelet reactivity, reduction cardiovascular complication risk；
(6) to AR-C78511 and cangrelor to (10 μM) subject's platelet sample platelet aggregations of induction of ADP
The inhibition of rate compares with P2Y12 receptor protein expressions in subject's platelet sample, as a result shows：
In subject's platelet sample, AR-C78511 and cangrelor are to platelet aggregation in subject's platelet sample
There is positive correlation (| r |=0.72 with P2Y12 receptor expression levels in subject's platelet sample in the inhibition of collection rate
P(two-tailed)<0.01；| r |=0.46P (two-tailed)<0.01)；And P2Y12 receptor protein expressions
Higher, the platelet aggregation rate inhibition of AR-C78511 is got over and is better than cangrelor.
Experimental result shows, in type ii diabetes people experimenter platelet sample, the mRNA and albumen of P2Y12
Expression and platelet aggregation rate are all significantly higher than normal volunteer；And as P2Y12 expressions increase
Plus, type ii diabetes human platelet aggregation rate is higher, there is positive correlation relation；In addition, AR-C78511 is to II
The platelet aggregation rate inhibition of patients with type Ⅰ DM people experimenter is significantly stronger than cangrelor, and P2Y12 albumen tables
Higher up to level, AR-C78511 gets over to the inhibition of platelet aggregation rate and is better than cangrelor.
The invention provides a kind of biomarker P2Y12 acceptors, its expression can as it is a kind of clearly, have
Effect, intuitively platelet reactivity biomarker, are further used for diagnosing and predicting that type ii diabetes people is cardiovascular
Complication risk；The P2Y12 acceptors can be by any effective way as platelet reactivity biomarker
Including, quantitative fluorescent PCR, protein immunoblot, Enzyme-linked Immunosorbent Assay (ELISA), flow cytometry, ultraviolet
AAS-near infrared spectroscopy, high performance liquid chromatography, colorimetric method, Mass Spectrometric Identification method etc. detected, institute
The method of stating can detect hematoblastic expression, also can detect the P2Y12 contents in whole blood.
Individuation, precision treatment are carried out the present invention further provides using P2Y12 inverse agonists：For treating blood
The cardiovascular complication of the increased type ii diabetes patient of platelet P2Y12 receptor expression levels, to height expression, spontaneous activation
The blood platelet of P2Y12 acceptors has more preferable inhibitory action；Wherein P2Y12 inverse agonists are included but is not limited to
AR-C78511。
In the present invention, can be administered by any effective way using P2Y12 inverse agonists, including oral, vein
Interior, intraperitoneal, part, transdermal, through eye, intranasal, part, suction, subcutaneous, intramuscular, mouth containing, sublingual, straight
Intestines etc., the P2Y12 inverse agonists can be administered alone, or be given with other active or inactive ingredient combinations
Medicine.
In the present invention, the P2Y12 inverse agonists can be prepared into any appropriate formulation, for example tablet, capsule,
Pill, granular preparation, parenteral solution etc..
In addition, present invention also offers the antiplatelet drug that expression high, spontaneous activation P2Y12 acceptors are directed to as screening
Method, and guide clinically such antiplatelet drug in type ii diabetes patient cardiovascular complication, other P2Y12
Receptor mutation or expression high cause the selection in the thrombotic diseases of P2Y12 acceptor spontaneous activations.
Below in conjunction with the accompanying drawings and specific embodiment, the present invention is expanded on further.It is emphasized that these embodiments are only
For illustrating the present invention rather than limitation the scope of the present invention.The experiment side of unreceipted actual conditions in the following example
Method, " Platelets " second edition (the New York for generally being edited according to normal condition such as Alan D.Michelson:
Elsevier Press, 2007) described in condition, or according to the condition proposed by manufacturer.Unless otherwise indicated,
Reagent comes from traditional Chinese medicines reagent Co., Ltd used in text, and percentage and number are calculated by weight.
Unless otherwise defined, all specialties are identical with meaning familiar to one skilled in the art institute with scientific words.Additionally,
Any method similar to described content or impartial and material all can be applied in the present invention.Preferable reality described in text
Applying method only presents a demonstration with material and is used.
Brief description of the drawings
P2Y12 Receptor mRNA levels are significantly higher than Healthy People, data in Fig. 1 .II patients with type Ⅰ DM human blood platelets
Represented with average value ± standard error.
P2Y12 receptor protein expressions are significantly higher than Healthy People in Fig. 2 .II patients with type Ⅰ DM people experimenter blood platelets,
Data average value ± standard error is represented.
Platelet aggregation rate is significantly improved in Fig. 3 .ADP induction type ii diabetes people experimenter platelet samples, wherein
It has been shown that, the platelet aggregation rate of (1 μM) induction type ii diabetes people experimenter platelet sample of low concentration ADP shows
It is higher than Healthy People to write；(10 μM) blood platelets of induction type ii diabetes people experimenter platelet sample of high concentration ADP
PAR is also significantly greater than Healthy People, and data average value ± standard error is represented.
P2Y12 receptor proteins expression and its platelet aggregation rate into positive correlation in Fig. 4 subject platelet sample
Linear relationship, wherein showing, P2Y12 receptor expression levels are higher in subject's platelet sample, its platelet aggregation
Rate is higher, and the expression of blood platelet P2Y12 can predict hematoblastic PAR.
Fig. 5 .AR-C78511 are significantly stronger than to the platelet aggregation rate inhibition of type ii diabetes human blood platelets sample
Cangrelor,
Wherein, A) same concentrations (1nM) AR-C78511 and cangrelor can substantially suppress healthy human blood
The platelet aggregation rate of platelet sample (n=12), and the similar (P of inhibition>0.05)；B it is) identical dense
Spend the platelet aggregation rate suppressions of the AR-C78511 to type ii diabetes human blood platelets sample (n=20) of (1nM)
Effect is significant processed is better than cangrelor (P<0.05).
Fig. 6 subject platelet sample P2Y12 receptor protein expressions are higher, and AR-C78511 is to platelet aggregation
Collection rate inhibition is got over and is better than cangrelor, wherein show, as P2Y12 receptor proteins expression is raised,
The antiplatelet platelet aggregation of AR-C78511 and cangrelor weakens, but when P2Y12 acceptor levels increase
The antiplatelet aggregative activity of Gao Shi, AR-C78511 is substantially better than cangrelor.
Specific embodiment
The real time fluorescence quantifying PCR method of embodiment 1. detects P2Y12 in type ii diabetes people experimenter blood platelet
Receptor mRNA level
The purpose of the present embodiment is to prove P2Y12 Receptor mRNA water in type ii diabetes people experimenter blood platelet
The flat P2Y12 receptor expression levels being significantly higher than in health volunteer's blood platelet.In the present embodiment, type ii diabetes
People and the hematoblastic preparation of normal volunteer：Blood platelet comes from the volunteer for having signed Informed Consent Form, volunteer
Any antiplatelet drug such as non-Aspirin, clopidogrel in 20 days before blood is taken.Anti-coagulants uses ACD
(85mmol L-1 sodium citrate,71.38 mmol L-1 citric acid,and 27.78mmol L-1 glucose)。
300g centrifugations obtain platelet rich plasma in 20 minutes, take after supernatant 900g further centrifugation to obtain blood within 10 minutes small
Plate.Trizol methods extract total mRNA, and reverse transcription obtains cDNA, the inspection of real time fluorescence quantifying PCR method relative quantification
Survey and determine P2Y12 Receptor mRNA levels.P2Y12 primers forward direction sequence be
TCACCCAGGTCCTCTTCCC, reverse sequence is TGTTCCCAGTTTGGCATCAC, internal reference
GAPDH primers forward direction sequence is GTCCACTGGCGTCTTCACCA, and reverse sequence is
GTGGCAGTGATGGCATGGAC.Computing formula is：
P2Y12 Receptor mRNAs level=2-ΔΔCt
P2Y12 Receptor mRNAs level result is as shown in figure 1, type ii diabetes in subject's platelet sample
P2Y12 Receptor mRNAs level (6.6 ± 4.6) are significantly higher than health in people experimenter (n=28) blood platelet
P2Y12 Receptor mRNA levels (1.5 ± 0.9, P in people experimenter (n=32) blood platelet<0.01),
P2Y12 Receptor mRNAs horizontal reference value is less than 3.3 in normal subjects's blood platelet, can determine higher than this reference value
Justice increases for P2Y12 Receptor mRNA horizontal abnormalities.
Embodiment 2. is detected in type ii diabetes people experimenter blood platelet with the protein imprinted methods of Western Blot
P2Y12 receptor expression levels
The purpose of the present embodiment is to prove P2Y12 receptor protein expressions in type ii diabetes people experimenter blood platelet
It is significantly higher than the P2Y12 receptor protein expressions in normal volunteer's blood platelet.
In the present embodiment, type ii diabetes people and the hematoblastic preparation method of normal volunteer are with embodiment 1.Blood is small
Boiled after adding the cracking of SDS lysis buffers resuspended in plate standby.The protein imprinted method detections of WesternBlot are true
Determine P2Y12 receptor protein expressions, formula is：
P2Y12 receptor proteins expression=P2Y12 receptor proteins ribbon density/GAPDH protein ribbon densities
P2Y12 receptor proteins expression result in subject's platelet sample is as shown in Fig. 2 type ii diabetes people
P2Y12 receptor proteins expression (0.68 ± 0.26) are significantly higher than Healthy People in subject (n=20) blood platelet
P2Y12 receptor protein expressions (0.34 ± 0.16, P in subject (n=12) blood platelet<0.01).Just
P2Y12 receptor expression levels reference value is less than 0.65 in normal subject's blood platelet, be may be defined as higher than this reference value
P2Y12 receptor expression levels increase extremely.
The platelet aggregation rate of the type ii diabetes people experimenter platelet sample of embodiment 3.ADP inductions
The purpose of the present embodiment is to prove that type ii diabetes people experimenter platelet aggregation rate is significantly higher than Healthy People.
In the present embodiment, type ii diabetes people and the hematoblastic preparation method of normal volunteer are with embodiment 1.Blood is small
Plate resuspended (the 138mmol L of Tyrode buffer-1NaCl,2.7mmol L-1KCl,2mmol L-1MgCl2,0.42
mmol L-1NaH2PO4,5mmol L-1glucose,10mmol L-1HEPES, 0.2%bovine serum
albumin,and 0.02 unit mL-1Apyrase, pH7.4), platelet Counting, number of platelets is adjusted to 2.5 ×
108Individual blood platelet/mL；
Platelet aggregation is determined：It is hematoblastic be gathered in platelet aggregation instrument (Model 400VS, Chrono-Log,
Haverston, PA), parameter setting：Mixing speed 900rpm, 37 DEG C of temperature is adding various concentrations activator
Before ADP (1 μM, 10 μM), blood platelet solvent or medical preconditioning 3 minutes, curve of platelet aggregation monitoring
Time is 5 minutes, using maximum platelet aggregation rate as final platelet aggregation rate data；
Platelet aggregation rate result is as shown in figure 3, (1 μM) induction type ii diabetes people experimenter (n of low concentration ADP
=20) platelet aggregation rate (7.0 ± 1.6%) of platelet sample be significantly higher than normal volunteer (n=12) blood
Platelet aggregation rate (1.2 ± 0.9%, the P of platelet sample<0.05)；And (10 μM) induction II of high concentration ADP
The platelet aggregation rate (47 ± 13%) of patients with type Ⅰ DM people experimenter (n=20) platelet sample is equally significantly higher than
Platelet aggregation rate (38 ± 8%, P of normal volunteer (n=12) platelet sample<0.01).
The correlation of P2Y12 receptor proteins expression and its platelet aggregation rate in the subject's platelet sample of embodiment 4.
The purpose of the present embodiment is to prove that P2Y12 receptor protein expressions increase with subject's blood platelet, blood
The platelet aggregation rate of platelet sample is higher, and both have positive correlation.
In the present embodiment, by P2Y12 acceptors in subject (n=32) platelet sample for analyzing embodiment 2
The platelet aggregation rate number of protein expression level data and corresponding subject (n=32) platelet sample of embodiment 3
According to relation, linear regression analysis is carried out, calculate coefficient correlation；
Result is as shown in figure 4, within the specific limits, the P2Y12 receptor proteins of subject's platelet sample express water
Flat higher, its corresponding platelet aggregation rate is higher, and statistical analysis shows, two groups of data have positive correlation linear equation
Relation Y=36.74X+23.54 (P (two-tailed)<0.01), coefficient correlation | r |=0.89, subject's blood
There is high-positive correlation with platelet aggregation rate in the P2Y12 receptor proteins expression of platelet sample.
Embodiment 5.P2Y12 inverse agonists AR-C78511 and P2Y12 neutral antagonist cangrelor is to II type glycosurias
The inhibition of patient's platelet sample platelet aggregation rate
The purpose of the present embodiment is in order under proving same concentrations, P2Y12 inverse agonists AR-C78511 is to II types
The platelet aggregation rate inhibition of diabetes patient's platelet sample is significantly stronger than P2Y12 neutral antagonist cangrelors.
In the present embodiment, it is hematoblastic to prepare with platelet aggregation assay method with embodiment 3, as a result such as Fig. 5 institutes
Show, the platelet aggregation rate of the AR-C78511 and cangrelor of same concentrations (1nM) to Healthy People platelet sample
Inhibition quite (P>0.05)；But the AR-C78511 of same concentration is to type ii diabetes human blood platelets sample
Platelet aggregation rate inhibition is significantly stronger than cangrelor, and (platelet aggregation rate of 10 μM of ADP inductions is respectively 17
± 9% and 23 ± 11%, P<0.01, Fig. 5 B).
The blood platelet of embodiment 6.P2Y12 inverse agonist AR-C78511 and P2Y12 neutral antagonist cangrelors
The relation of PAR inhibition and subject's platelet sample P2Y12 receptor protein expressions
The purpose of the present embodiment is to prove that subject's platelet sample P2Y12 receptor protein expressions are higher,
AR-C78511 gets over to the inhibition of platelet aggregation rate and is better than cangrelor.
In the present embodiment, by P2Y12 acceptors in subject's blood platelet (n=32) sample for analyzing embodiment 2
Protein expression level data are with AR-C78511 in corresponding embodiment 5 and cangrelor to subject's platelet sample
(n=32) the inhibition data dependence of platelet aggregation rate, draws equation of linear regression, calculates straight line phase
Relation number, and check conspicuousness between straight line；
Result is as shown in fig. 6, AR-C78511 and cangrelor are small to the blood of subject's platelet sample (n=32)
There is positive correlation linear relationship, straight line side with P2Y12 receptor protein expressions respectively in the inhibition of plate PAR
Journey is respectively Y=12.58X+9.218, (P (two-tailed)<0.01)；Y=25.52X+7.076, (P
(two-tailed)<0.01)；Coefficient correlation is respectively (| r |=0.46；| r |=0.72).Two straight lines exist notable
Sex differernce (P<0.01).And when subject's platelet sample P2Y12 receptor protein expressions are higher,
AR-C78511 gets over to platelet aggregation rate inhibition and is better than cangrelor.
SEQUENCE LISTING
<110>
Fudan University
<120>
Predict biomarker of type ii diabetes cardiovascular complication risk and application thereof
<160>
4
<170>
PatentIn version 3.3
<210>
1
<211>
19
<212>
DNA
<213>
P2Y12 primers forward direction sequence
<400>
1
tcacccaggt cctcttccc 19
<210>
2
<211>
20
<212>
DNA
<213>
P2Y12 primer reverse sequences
<400>
2
tgttcccagt ttggcatcac
20
<210>
3
<211>
20
<212>
DNA
<213>
Internal reference GAPDH primers forward direction sequence
<400>
3
gtccactggc gtcttcacca 20
<210>
4
<211>
20
<212>
DNA
<213>
Internal reference GAPDH primer reverse sequences
<400>
4
gtggcagtga tggcatggac
20
Claims (10)
- Purposes of the 1.P2Y12 acceptors in the biomarker as prediction type ii diabetes cardiovascular complication risk.
- 2. purposes as described in claim 1, characterized in that, described biomarker is biological for platelet reactivity Mark；It is detected by any effective way, including：Quantitative fluorescent PCR, protein immunoblot, enzyme linked immunological Absorption (ELISA), flow cytometry, ultraviolet spectrophotometry-near infrared spectroscopy, high performance liquid chromatography, Colorimetric method and Mass Spectrometric Identification method.
- 3. purposes as described in claim 1 or 2, characterized in that, described biomarker P2Y12 expressions, Compared with Healthy People, the P2Y12 expressions of the type ii diabetes patient are raised.
- 4. purposes as described in claim 2, characterized in that, described blood platelet is present in peripheral blood in patients, it is huge Nucleus is present in candidate stem cell.
- 5. purposes as described in claim 2, characterized in that, the platelet reactivity biomarker P2Y12 Expression is used to diagnosing or predicting type ii diabetes Platelet reactivity, platelet aggregation rate.
- 6. a kind of method for predicting the cardiovascular complication risk of type ii diabetes patient, it is characterised in that it includes： Determine P2Y12 acceptors expression in the type ii diabetes individuals blood platelet sample；Compare P2Y12 acceptors Expression in the sample from the type ii diabetes individuals is with P2Y12 acceptors in the control subject Expression in blood platelet sample；Compared with expression wherein with P2Y12 acceptors in the check sample, P2Y12 Expression increase of the acceptor in the sample from the type ii diabetes individuals is that the angiocardiopathy is concurrent The instruction that disease risk is improved, so as to predict that the onset risk of type ii diabetes patient's angiocardiopathy complication increases.
- 7. method according to claim 6, it is characterised in that wherein described type ii diabetes people cardiovascular complication Positive correlation is raised with platelet reactivity.
- 8. method according to claim 6, it is characterised in that wherein by P2Y12mRNA and protein expression Level detects increasing for blood platelet P2Y12 expressions.
- 9.P2Y12 receptor inverse agonists are for preparing prevention, the increased II types sugar for the treatment of P2Y12 receptor expression levels Purposes in the antiplatelet drug that urine patient's cardiovascular complication risk increases；Wherein, described P2Y12 acceptors are anti- Suppress the increased type ii diabetes Platelet reactivity of P2Y12 receptor expression levels and preventing and treating II type glycosurias to activator Sick cardiovascular complication.
- 10. purposes according to claim 9, it is characterised in that described P2Y12 receptor inverse agonists are AR-C78511。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107519500A (en) * | 2017-09-11 | 2017-12-29 | 南昌大学 | Application of the short hairpin ribonucleic acid of purine 2Y12 acceptors in diabetes and complication medicine is prepared |
| CN107625782A (en) * | 2017-09-11 | 2018-01-26 | 南昌大学 | Application of the short hairpin ribonucleic acid of purine 2Y12 acceptors in diabetes nerve pathology pain medicine is prepared |
| RU2695322C2 (en) * | 2017-10-16 | 2019-07-23 | Елизавета Олеговна Дзантиева | Method of selecting men at pre-diabetes risk group and type 2 diabetes mellitus |
| CN112553323B (en) * | 2020-12-25 | 2022-05-13 | 福建农林大学 | COL1A1 as biomarker of type 2 diabetes and application thereof |
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| CN101213456A (en) * | 2005-05-05 | 2008-07-02 | 菲布罗根公司 | Diagnostic marker for diabetic vascular complications |
| CN101563597A (en) * | 2006-09-01 | 2009-10-21 | 美国菌种保藏中心 | Compositions and methods for diagnosis and treatment of type 2 diabetes |
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| CN101213456A (en) * | 2005-05-05 | 2008-07-02 | 菲布罗根公司 | Diagnostic marker for diabetic vascular complications |
| CN101563597A (en) * | 2006-09-01 | 2009-10-21 | 美国菌种保藏中心 | Compositions and methods for diagnosis and treatment of type 2 diabetes |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107519500A (en) * | 2017-09-11 | 2017-12-29 | 南昌大学 | Application of the short hairpin ribonucleic acid of purine 2Y12 acceptors in diabetes and complication medicine is prepared |
| CN107625782A (en) * | 2017-09-11 | 2018-01-26 | 南昌大学 | Application of the short hairpin ribonucleic acid of purine 2Y12 acceptors in diabetes nerve pathology pain medicine is prepared |
| RU2695322C2 (en) * | 2017-10-16 | 2019-07-23 | Елизавета Олеговна Дзантиева | Method of selecting men at pre-diabetes risk group and type 2 diabetes mellitus |
| CN112553323B (en) * | 2020-12-25 | 2022-05-13 | 福建农林大学 | COL1A1 as biomarker of type 2 diabetes and application thereof |
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