CN106872593A - Application of the lysophosphatidic acid as mark in endometriosis is detected - Google Patents
Application of the lysophosphatidic acid as mark in endometriosis is detected Download PDFInfo
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Abstract
Application the invention discloses lysophosphatidic acid as biomarker in the diagnostic reagent or detectable substance for preparing detection endometriosis.Meanwhile, present invention also offers one group of biomarker for being used to detect endometriosis, it is made up of following six kinds of lysophosphatidic acids：18:2 LPA；16:0 LPA；20:4 LPA；18:1 LPA；22:6 LPA；18:0 LPA.The present invention determines six kinds of levels of LPA in endometriosis patients and normal control's blood plasma using Ultra Performance Liquid Chromatography tandem mass spectrum method, and this six kinds of LPA concentration levels are significantly higher than normal control in as a result showing endometriosis patients blood plasma.Therefore, this six kinds of LPA can be applied as the biomarker of endometriosis, and this six kinds of LPA respectively reach 92% and 86% as the sensitivity and specificity of Combining diagnosis mark, the existing hematology biomarker of current endometriosis is all remarkably higher than.
Description
Technical field
The present invention relates to lysophosphatidic acid the diagnostic reagent of detection endometriosis is being prepared as biomarker
Or the application in detectable substance.
Background technology
Endometriosis (endometriosis, EMs) is that the endometrial tissue with growth function appears in son
A kind of continuation lesion disease at position beyond uterine cavity lining mucosa.EMs is about 10% in the incidence of disease of Women of Childbearing Age, and has
Obvious ascendant trend, with pelvic pain, 50% merges infertility to 80% EMs, be have a strong impact on WomanHealth common disease and
Frequently-occurring disease.At present, clinically EMs treatment methods mainly have the method that drug therapy, operative treatment and both treatments are combined,
Wherein, laparoscopic surgery removal of lesions is first-selected treatment method, but the method recurrence rate is higher, it has been reported that, it is 3 years
Recurrence rate is 7~30%, and recurrence rate is even as high as 50% within 5 years, has a strong impact on the quality of life of patient.
The means of current diagnosis EMs mainly include clinical symptoms diagnosis, biochemical indicator diagnosis, iconography ultrasonic examination, core
Magnetic resonant imaging examination etc..The typical clinical symptom of EMs includes dysmenorrhoea, pelycalgia, sexual intercourse pain and infertility, but other diseases such as mistake
Quick property bowel syndrome also has similar symptom with pelvic infecton, and the dystopy degree of EMs is tight with the pain symptom that it is showed
Weight degree correlation is poor so that diagnoses EMs according to clinical symptoms and has some limitations.U.S.'s reproductive medicine can be reported aobvious
Show that according to clinical symptoms diagnosis III phases and IV phases EMs there is preferable accuracy, and it is accurate for the diagnosis of I phases and II phases EMs
Property is poor.At present clinically frequently with cancer associated antigen CA125 as EMs biochemical diagnosis means, but many I phase EMs patients
The level of CA125 do not raise, and CA125 has rising in many other gynecological diseases such as oophoroma, fibroid etc.,
Therefore CA125 is not high as the specificity and sensitiveness of EMs diagnosis markers.Video ultrasound has very for ovary EMs tumours
Good diagnosis capability, but be difficult to diagnose the peritonaeum EMs adhesions related to EMs.Conventional examination per vagina also can not Accurate Diagnosis
EMs, because when many EMs patients carry out examination per vagina and no abnormal.The goldstandard of current EMs diagnosis is traumatic outer
Section's means, i.e. laparoscopic surgery.European EMs association are investigated 7025 EMs patients, as a result show that 65% patient is going out
Other diseases are misdiagnosed as when being gone to a doctor for the first time after existing EMs related symptoms, 46% EMs patient at least looked for 5 before making a definite diagnosis
Individual physician visits, this 7025 EMs patients from occur symptom to the average time made a definite diagnosis be up to 8 years.The investigation such as Hadfield is aobvious
Show that the U.S. and Britain EMs patient are respectively 11.7 and 8.0 to the time delay made a definite diagnosis from starting to occur symptom.Therefore, find
Specificity and sensitiveness EMs biomarkers high, set up noninvasive diagnostic model, and EMs patient can be carried out to examine in early days
Disconnected treatment symptom management in time, while the monitoring that can be used for after treatment.Current common hematology biomarker is shown in Table 1.
The common serum biomarkers of current endometriosis of table 1
Lysophosphatidic acid (lysophosphatidic acid, LPA) is the important intermediate of lipid-metabolism, can be mediated
Extensive biological effect, is referred to as multi-functional " phosphatide courier ".LPA passes through its g protein coupled receptor
(lysophosphatidic acid receptor, LPAR) activates many signal paths and produces many cell physiologicals to react,
Participate in the various kinds of cell functions such as motion, propagation, apoptosis, differentiation, invasion and attack, the secretion of regulating cell.Can confirm that at least 6 at present
Plant LPA acceptors, respectively LPAR1 (EDG2), LPAR2 (EDG4), LPAR3 (EDG7), LPAR4 (GPR23), LPAR5 (GPR92)
And LPAR6.Wherein LPAR1-3 is endothelial differentiation gene receptor family member, with 50-57% homologous amino acids series, they
It is the LPA acceptors of current most study with the affinity that LPA has height.Current research reports P2Y10, P2Y10 and GPR87
May be LPA acceptors, await further research and confirm.LPA is mainly sent out after being combined with acceptor by signals below transduction pathway
The effect of waving：(1) Gi-CAMP approach：The activity of adenyl cyclase can be suppressed so that intracellular cAMP concentration reduction, and then
Promote cell propagation；(2) Gq-PLC approach：Phospholipase C (PLC) can be activated, InsP3 (IP3) and diacylglycerol is formed
(DAG) temporary calcium ion concentration, is caused to raise and protein kinase C (PKC) activation；(3) Gi-Ras/Raf-MAPK approach：
LPA can activate Ras, Raf, so as to activate Raf/MAPK kinase cascades, cause cell division to be bred；(4) Rho signal pathways：LPA
By G12/13 protein activation Rho signal paths, reconstituted cell skeleton is played, change the effect such as cellular morphology；(5) PPAR γ are on the way
Footpath.LPAR is generally expressed in human normal tissue, and then research finds that LPAR sends out with tumour, cardio-cerebrovascular diseases
Exhibition is closely related.
Research shows that LPA has participated in the occurrence and development of many diseases.The research such as Wang finds that LPA can be with elicitor
Endometrial Carcinoma Cells HEC-1A increments, invasion and attack, migration and the expression and secretion of MMP-7 and uPA, show that LPA is endometrium
An important biomolecule activity regulating factor in cancer microenvironment.Seo H etc. have studied LPA signal paths in pig and cattle uterus,
The expression of COX-2 and PGs, research finds that LPA can stimulate the secretion of pig endometrium COX-2, shows that LPA is maintaining son
Important function has been played in the function of Endometrium；And in the uterus of ox, LPA is produced and discharged by endometrium, LPA can be lured
Lead progesterone and PGE2Secretion and increase PGE2/PGF2αRatio, and this effect can be by LPAR1 and 3 receptor antagonists
Ki16425 is suppressed, further study show that LPA is by raising PGE2Synthase activity causes Endometrial stromal cells PGE2
Increase with COX-2 secretions, show that LPA signal paths are played an important role in the gestation and fecundity of regulation and control ox.With just
Normal person is compared, and LPA levels are significantly raised in serum of ovarian cancer patients and ascites, and LPA can promote human epithelial ovarian carcinoma cells proliferation, is promoted
Infiltration, transfer and resistance etc., LPA can mediate the expression and activation of MMP amyloid protein precursors by COX-2, basilar memebrane of degrading, favorably
In the infiltration and transfer of cancer cell, the FasL expression of cell surface is raised, induced activation Lymphocyte Apoptosis are conducive to cancer cell
Immunologic escape；Induction vegf expression, promotes the formation of vascular tumor.Research shows LPA acceptors LPAR2 and LPAR3 in ovary
Expression high in cancer, and do not expressed or low expression in normal gonad cell.Research shows that LPA can be made by NF- kB pathways
The secretion of IL-8 is induced for the LPAR1 acceptors of Endometrial stromal cells, and IL-8 passes through as preceding angiogenesis factor
Acceptor combines the regulation for directly participating in angiogenesis.In sum, although lysophosphatidic acid LPA has participated in many diseases
Occurrence and development, but the research report about LPA value and application prospect in Diagnosis of Endometriosis treatment is there is no at present
Road.
The content of the invention
For above-mentioned prior art, the invention discloses a kind of new application of lysophosphatidic acid --- as biomarker
Application in the diagnostic reagent or detectable substance for preparing detection endometriosis.Meanwhile, present invention also offers one group of use
In the biomarker of detection endometriosis.
The present invention is achieved by the following technical solutions：
Lysophosphatidic acid is as biomarker in the diagnostic reagent or detectable substance for preparing detection endometriosis
Application, the lysophosphatidic acid is selected from any one or any several combination in following six kinds of lysophosphatidic acids：18:
2LPA；16:0LPA；20:4LPA；18:1LPA；22:6LPA；18:0LPA.
Described 18:2LPA；16:0LPA；20:4LPA；18:1LPA；22:6LPA；18:0LPA is the hypotype of LPA, and it contains
Justice is：N1:N2LPA, wherein, N1 refers to fatty acid carbon chain carbon atoms number, and N2 is fatty acid carbon chain carbon-carbon double bond number, and Fig. 3 is
18:0LPA and 18:The structural formula example of 2LPA.
Preferably, the lysophosphatidic acid is following six kinds of lysophosphatidic acids：18:2LPA；16:0LPA；20:4LPA；18:
1LPA；22:6LPA；18:0LPA.
Preferably, the diagnostic reagent or be Blood diagnosis reagent.
Further, during concrete application, lysophosphatidic acid levels in detection human plasma can use high performance liquid chromatography-string
Connection mass spectrography detection.
Further, after using six kinds of LPA concentration levels in high performance liquid chromatography-tandem mass method measure blood plasma, carry out
Multidimensional statistics is analyzed, such as principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA).
One group of biomarker for being used to detect endometriosis, is made up of following six kinds of lysophosphatidic acids：18:
2LPA；16:0LPA；20:4LPA；18:1LPA；22:6LPA；18:0LPA.
It is right with normal that the present invention determines endometriosis patients using Ultra Performance Liquid Chromatography-tandem mass spectrum method
According to six kinds of LPA (18 in person's blood plasma:2LPA；16:0LPA；20:4LPA；18:1LPA；22:Level 6LPA), as a result shows uterus
This six kinds of LPA concentration levels are significantly higher than normal control in endometriosis patients' blood plasma.Therefore, this six kinds of LPA can make
It is the biomarker of endometriosis, diagnostic reagent or detectable substance for preparing detection endometriosis, and
This six kinds of LPA respectively reach 92% and 86% as the sensitivity and specificity of Combining diagnosis mark, are all remarkably higher than at present
The existing hematology biomarker of endometriosis.Lysophosphatidic acid is used for uterus by the present invention
The detection of endometrium ectopia, testing result can be as the foundation of clinical diagnosis, with important medical value.
Brief description of the drawings
Fig. 1 a：It is used to distinguish diagnosis of endometriosis and control as Combining diagnosis mark using 6 kinds of LPA levels
PLS-DA figure (X-Y scheme).
Fig. 1 b：It is used to distinguish diagnosis of endometriosis and control as Combining diagnosis mark using 6 kinds of LPA levels
PLS-DA figure (graphics).
Fig. 2：Displacement number of times is the permutation test analysis chart under 1000 times, wherein, A is separating distance, and B is accurate for prediction
Degree.
Fig. 3：18:0LPA and 18:The structural formula example of 2LPA.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.
Involved instrument, reagent, material etc. in following embodiments, unless otherwise noted, are existing in the prior art
Conventional instrument, reagent, material etc., can be obtained by regular commercial sources.Involved experimental technique in following embodiments, inspection
Survey method etc., unless otherwise noted, is existing normal experiment method in the prior art, detection method etc..
Embodiment 1
Obtaining after healthcare hospital for women ＆ children of Jiangxi Province Medical Ethics Committee ratifies and obtain patient's informed consent, being managed with EDTA
Son collects healthcare hospital for women ＆ children of Jiangxi Province and makes a definite diagnosis endometriosis patients (30-42 Sui) and s.m.p endometriosis person (control
Group) each 30 parts of (30-42 Sui) blood, room temperature 1,750 × g be centrifuged 15 minutes, obtain blood plasma.Reference literature method (J
Chromatogr B Analyt Technol Biomed and Life Sci.2008；864(1-2):22-28.) carry out sample
Process and use high performance liquid chromatography-tandem mass spectrum to determine six kinds of LPA (18:2LPA；16:0LPA；20:4LPA；18:1LPA；
22:Level 6LPA).
The compound mass spectrograph of triple quadrupole bar ion hydrazine is American AB SCIEX companies, and liquid chromatogram is Japan Shimadzu public
Department, LPA standard items and isotopic standard product are purchased from Avanti Polar Lipids companies.Scan pattern is MRM, monitors ion
To for [13C16]16:0LPA：m/z 425→153,22:6LPA：m/z 481→153,22:4LPA：m/z 457→153,18:
0LPA：m/z 437→153,18:1LPA：m/z 435→153,18:2LPA：m/z 433→153,16:0LPA：m/z 409→
153.The data obtained carries out PLS-DA analyses and substitutability analysis.
Result is as shown in table 2, Fig. 1, Fig. 2, from Table 2, it can be seen that LPA concentration in endometriosis patients serum
Level is significantly higher than the LPA concentration levels in collator's serum.As can be seen that six kinds of LPA can be as son from Fig. 1 and Fig. 2
The biomarker of Endometriosis, and this six kinds of LPA reach respectively as the sensitivity and specificity of Combining diagnosis mark
To 92% and 86%, sensitivity and specificity are higher than current existing endometriosis blood biomarker.Fig. 1 is mould
Type, Fig. 2 is that the model for showing this joint biomarker has specificity and sensitivity well.
The endometrium disease patient of table 2 and the horizontal contrast tables of collator LPA
The above results show that six kinds of LPA concentration levels are significantly higher than normal control in endometriosis patients blood plasma
Person, six kinds of LPA can be as the biomarker of endometriosis.And this six kinds of LPA are used as Combining diagnosis mark
Sensitivity and specificity respectively reach 92% and 86%, are all remarkably higher than the existing hematology of current endometriosis biological
Mark.
Although above-mentioned be described to specific embodiment of the invention in conjunction with the embodiments, not the present invention is protected
The limitation of scope, one of ordinary skill in the art should be understood that on the basis of technical scheme, those skilled in the art
The various modifications or deformation made by creative work need not be paid are still within protection scope of the present invention.
Claims (6)
1. lysophosphatidic acid as biomarker prepare detection endometriosis diagnostic reagent or detectable substance in
Using the lysophosphatidic acid is selected from any one in following six kinds of lysophosphatidic acids or any several combination：18:2 LPA；
16:0 LPA；20:4 LPA ；18:1 LPA；22:6 LPA ；18:0 LPA.
2. application according to claim 1, it is characterised in that：The lysophosphatidic acid is following six kinds of lysophosphatidic acids：
18:2 LPA；16:0 LPA；20:4 LPA ；18:1 LPA；22:6 LPA ；18:0 LPA.
3. application according to claim 1 and 2, it is characterised in that：The diagnostic reagent is Blood diagnosis reagent.
4. it is used to detect the biomarker of endometriosis, it is characterised in that：It is made up of following six kinds of lysophosphatidic acids：
18:2 LPA；16:0 LPA；20:4 LPA ；18:1 LPA；22:6 LPA ；18:0 LPA.
5. the biomarker of the detection endometriosis described in claim 4 detect endometriosis in should
With.
6. application according to claim 5, it is characterised in that：During concrete application, using high performance liquid chromatography-tandem mass
Lysophosphatidic acid levels in method detection human plasma.
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Cited By (3)
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| CN111983125A (en) * | 2017-08-23 | 2020-11-24 | 湖南省妇幼保健院 | Subclinical pelvic inflammatory disease marker and application thereof |
| CN112941169A (en) * | 2021-03-24 | 2021-06-11 | 浙江大学医学院附属邵逸夫医院 | Method for detecting internal abnormal disease related IVF fate based on granular cell gene expression |
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| CN112941169A (en) * | 2021-03-24 | 2021-06-11 | 浙江大学医学院附属邵逸夫医院 | Method for detecting internal abnormal disease related IVF fate based on granular cell gene expression |
| CN112941169B (en) * | 2021-03-24 | 2022-05-31 | 浙江大学医学院附属邵逸夫医院 | Method for detecting internal abnormal disease related IVF fate based on granular cell gene expression |
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