CN107860830A - Application of the biomarker in its targeted drug in a kind of psoriasis vulgaris blood plasma - Google Patents
Application of the biomarker in its targeted drug in a kind of psoriasis vulgaris blood plasma Download PDFInfo
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- G—PHYSICS
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Abstract
The invention discloses biomarker in a kind of psoriasis vulgaris blood plasma its targeted drug application; characterized in that, the biomarker for threonine, leucine, phenylalanine, tryptophan, palmitamide, linoleamide, oleamide, oleic acid, stearic amide, arachidonic acid, cis 11 icosa alkene acid amides, trans 13 docosene acid amides, N sub-oleoyls taurine, Lysophosphatidylcholone (18:3), Lysophosphatidylcholone (18:2), uric acid, Lysophosphatidylcholone (16:0), Lysophosphatidylcholone (18:And Lysophosphatidylcholone (18 1):0) one kind or at least two in.The present invention finds patients with psoriasis vulgaris biomarker with UPLC/Q TOF MS technology combinations multi-variate statistical analysis, and method is feasible, scientific and reasonable, and the biomarker found contributes to the formulation of Individualized Dosing Regimen.
Description
Technical field
The present invention relates to the screening field of biomarker, and in particular to biological marker in a kind of psoriasis vulgaris blood plasma
Application of the thing in its targeted drug.
Background technology
Psoriasis is commonly called as " psoriasis ", is a kind of common chronic inflammation proliferative skin disorders easily recurred, and the whole world is ill
Number constitutes about 2%~3%.Its main tissue pathologies change is epidermal keratinocytes hyper-proliferative, dermal capillary
Blood vessel dilatation and growth and T cell, BMDC, neutrophil leucocyte and other inflammatory cell infiltrations.Clinically general point
For four types, i.e. homeliness type, pustule type, erythrodermic and arthropathica, wherein psoriasis vulgaris is most common, its typical skin
Damage to be covered with the multilayer silvery white scales of skin that peel off on red papules or patch.The course of disease of psoriasis vulgaris is longer, and skin lesion is extensive, Chang Fanfu
Breaking-out.The scales of skin that peel off, itch and visible patch are the subject matter for perplexing patient, and lack the method for radical cure for a long time, not only
Heavy financial burden is brought to patient, and adds the stress of patient, has a strong impact on its quality of life.More worth note
Meaning, psoriasis vulgaris can cause multiple complications, such as psoriatic arthritis, angiocardiopathy and metabolic syndrome
Deng.Therefore the disease is one of disease of current dept. of dermatology's primary study.
The metabolism group that the 1990s, mid-term grew up be after genomics, transcription group and proteomics it
Another systems biology branch risen afterwards, it be by investigate that biosystem is stimulated or disturbance after (such as some gene
Becoming under a certain pathological and physiological condition of XOR) metabolite collection of illustrative plates and its dynamic change study the one of the metabolism network of biosystem
Kind technology.Metabolism group has been developed rapidly, at present in biomarker due to its unique advantage since appearance
The research fields such as the accurate medication under instructing are widely used.
Accurate medication under biomarker guidance, it is the core realm generally acknowledged in accurate medical treatment.For grinding
The medicine of hair, biomarker helps to screen specified disease medicine composition, to filter out the drug ingedient to work well, because
Clinical data to there is specification proves that the medicine only has significant curative effect in the positive patient of biomarker.Here it is biology to mark
Will thing instructs lower to the effect precisely treated.
In more than ten years of past, the international big pharmaceutical factory in new drug field, especially tumour new medicine field, generally by biology
Label is as the emphasis for instructing its new medicine.Government also gives the support of height to this field, for there is biomarker
The personalized new drug that thing instructs can give acceleration examination ＆ approval, such as the ALK inhibitor gram azoles of Pfizer's treatment lung cancer replaces Buddhist nun, and government is simultaneously
The policy of the research and development declaration synchronous with new drug with diagnosis has also been put into effect in time.At the same time, precisely medical treatment also turns into biology doctor
Topic more and more popular, causes the great attention of government already in medicine field.
In view of the foregoing it is apparent that personalized treatment is an inter-trade emerging field, metabolism group is ground with medicine
Hair organically combines, so as to reach the purpose of accurate medication.Can the most crucial part that the two success combines exactly find
The biomarker of predictable curative effect of medication.Although personalized treatment is into the common recognition of biomedicine field over more than ten years, a lot
Pharmaceutical factory is also paid much attention to, and some mechanisms even require that the project entered has been required for biomarker, but ratify to list in FDA
Individual new drugs up to a hundred in, granted as the biomarker with diagnosis only have more than ten.It can be seen that find correct biomarker
Thing is to be not easy very much, actually this bottleneck for having become personalized treatment.
Mainly include collection and pretreatment, the metabolism group data of sample using the flow of metabonomic analysis biomarker
The step such as collection and processing, multi-variate statistical analysis, the identification of mark and metabolic pathway analysis.The searching life of generally use
The assay method of substance markers thing has nuclear magnetic resonance (nuclear magnetic resonance, NMR), gas chromatography-mass spectrometry
With (gas chromatography-mass spectrometry, GC-MS), liquid chromatograph mass spectrography (liquid
Chromatography-mass spectrometry, LC-MS) etc., wherein, gas chromatography-mass spectrography, liquid chromatogram-matter
Spectrum combination is required for standard items to judge the structure of biomarker, and in the case of being biomarker known to requirement, measure is each
Mark content, the unknown situation of biomarker is not suitable for it.In addition, the sensitivity of 1H-NMR technology for detection is low, resolution ratio
It is not high.The biomarker report about psoriasis has much in recent years, but its Sensitivity and Specificity need into one
Step is demonstrate,proved.
The content of the invention
A kind of the defects of purpose of the present invention is aiming at prior art, there is provided biological marker in psoriasis vulgaris blood plasma
Application of the thing in its targeted drug.
The purpose of the present invention is achieved through the following technical solutions：
Biomarker is preparing the application of its targeted drug, the biomarker in a kind of psoriasis vulgaris blood plasma
For threonine, leucine, phenylalanine, tryptophan, palmitamide, linoleamide, oleamide, oleic acid, stearic acid
Acid amides, arachidonic acid, cis -11- icosa alkenes acid amides, anti-form-1 3- docosenes acid amides, N- sub-oleoyls taurine, haemolysis
Property phosphatidyl choline (LysoPC) (18:3)、LysoPC(18:2), uric acid, LysoPC (16:0)、LysoPC(18:1)、LysoPC
(18:0)。
Above-mentioned application, biomarker screen to obtain by following steps：
(1) mouse infection psoriasis model is established；
(2) collection and processing of mice plasma sample：Mouse blood sample is taken to centrifuge, supernatant is plasma sample；Take 1 part of blood
Slurry, 1~5 part of acetonitrile or methanol extraction albumen are added wherein, is centrifuged after mixing, takes supernatant to be dried up with nitrogen, residue second
Nitrile-water or methanol-water redissolve, and are centrifuged after mixing residue, take supernatant to be measured；
(3) machine processing on ultra performance liquid chromatography series connection quadrupole rod time of-flight mass spectrometer：The supernatant of step (2) is taken to enter
Row mass spectral analysis, gradient elution is carried out with mobile phase, and carry out negative ions using electro-spray ionization source and scan simultaneously；
(4) data processing and analysis；
(5) otherness metabolin and its Structural Identification.
The volume ratio of the blood plasma of step (2) and protein precipitant acetonitrile or methanol is 1:3.
The double solvents acetonitrile or the volume ratio of methanol and water of step (2) are 1:9.
The chromatographic condition of step (3) is：ACQUITY UPLCTM BEH C18Post, model 2.1mm × 100mm, 1.7 μm；
Mobile phase is the formic acid acetonitrile of 0.1% formic acid water -0.1%, gradient elution：0~6min, 0.1% formic acid acetonitrile 5%~10%；6~
10min, 0.1% formic acid acetonitrile 10%~38%；10~15min, 0.1% formic acid acetonitrile 38%~100%；15~18min,
0.1% formic acid acetonitrile 100%；18~19min, 0.1% formic acid acetonitrile 100%~5%；19~22min, 0.1% formic acid acetonitrile
5%；Flow velocity 0.4mL/min；40 DEG C of column temperature；4 DEG C of sample room temperature；Sampling volume is 5 μ L.
The present invention is had the following advantages and beneficial effect relative to prior art：
(1) compared with common LC-MS technologies, UPLC/Q-TOF MS technologies are in resolution ratio, analyze speed and sensitivity
Etc. be all greatly improved.
(2) up to 19 kinds of biomarker of the invention, for the medicine in research and development, a variety of biomarkers contribute to essence
Quasi- screening specified disease medicine composition, to filter out the drug ingedient to be worked well to Different Individual.
Brief description of the drawings
Fig. 1 be healthy group (A, C) in the embodiment of the present invention 5 and psoriasis vulgaris group (B, D) positive ion mode (A,
B UPLC/Q-TOF MS base peaks intensity (Base Peak Intensity, BPI) chromatogram) and under negative mode (C, D)；
Fig. 2 be in the embodiment of the present invention 5 PCA shot charts (1, healthy group；2：Psoriasis vulgaris group；A：Cation mould
PCA shot charts under formula；B：PCA shot charts under negative ion mode)
Fig. 3 be in the embodiment of the present invention 5 OPLS-DA shot charts (1, healthy group；2：Psoriasis vulgaris group；A：Just from
OPLS-DA shot charts under subpattern；B：OPLS-DA shot charts under negative ion mode)
Fig. 4 is the OPLS-DA Model load figures (A in the embodiment of the present invention 5：OPLS-DA load under positive ion mode
Figure；B：OPLS-DA load diagrams under negative ion mode)；
Fig. 5 is the OPLS-DA models S figures (A in the embodiment of the present invention 5：OPLS-DA models S figures under positive ion mode；
B：OPLS-DA models S figures under negative ion mode)；
Fig. 6 is the potential source biomolecule mark metabolic pathway sketch in the embodiment of the present invention 5.
Embodiment
Embodiment 1
(1) foundation of imiquimod inducing mouse psoriasis model：24 female BAl BIcs/c mouse adaptability is fed into 3d
Afterwards with 4% chloraldurate (0.1ml/10g) intraperitoneal injection of anesthesia, its back hair is rejected, forms the sudden and violent of about 2cm × 3cm sizes
Reveal region, be randomly divided into 2 groups, every group 12, respectively blank group and model group.Blank group：Daily timing is in the exposed back of the body of mouse
Soft petroleum ointment 62.5mg is smeared in portion, while with physiological saline gavage, 0.2mL/ times/day, continuous 7 days.Model group：Daily timing
Smear 5%IMQ emulsifiable paste 62.5mg at the exposed back of mouse, while with physiological saline gavage, 0.2mL/ times/day, continuous 7 days.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Acetonitrile 600 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue acetonitrile-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000r/min, 10min, 4 DEG C), take
The μ L of supernatant 5 injection LC-MS instrument sample introduction analyses.
(3) UPLC/Q-TOF MS are analyzed：Chromatographic condition：ACQUITY UPLCTM BEH C18Post (2.1mm × 100mm,
1.7 μm, Waters, US)；Mobile phase is the formic acid acetonitrile (B) of 0.1% formic acid water (A) -0.1%, gradient elution：0~
6min, 5%~10%B；6~10min, 10%~38%B；10~15min, 38%~100%B；15~18min, 100%B；
18~19min, 100%B~5%B；19~22min, 5%B；Flow velocity 0.4mL/min；40 DEG C of column temperature；4 DEG C of sample room temperature；Enter
Sample volume is 5 μ L.Mass Spectrometry Conditions：Electro-spray ionization source (ESI)；Negative ions scan simultaneously；Mass scan range m/z 50
~1000Da, sweep time 0.6s；Capillary voltage is 3.0kV (ESI+), 2.8kV (ESI-)；Taper hole voltage is 30V；Extraction
Taper hole voltage 4V；Ion source temperature is 120 DEG C；Desolvation temperature is 350 DEG C；Desolventizing gas volume flow is 600Lh-1；
Taper hole gas volumetric flow is 50Lh-1.Exact mass correction ([M+H] is carried out using leucine-enkephalin+=556.277
1Da, [M-H]—=554.2615Da), flow velocity is 5 μ L/min.
(4) data processing and analysis：Initial data carries out peak identification and peak using the softwares of Waters Markerlynx 4.1
Matching, obtains a three-dimensional data matrix for including retention time, mass-to-charge ratio and peak area.The data matrix is imported into
SIMCA-P12.0 software kits carry out multi-variate statistical analysis.Data are using mean center and Pareto is upscaled is pre-processed
Afterwards, principal component analysis (principal component analysis, PCA) is carried out first.To strengthen group difference, nothing is eliminated
Pass factor influences, further using orthogonal PLS discriminant analysis (orthogonal partial least-
Squares discriminant analysis, OPLS-DA).Statistical analysis uses SPSS17.0 statistical softwares, from OPLS-DA
Variable importance projection (Variable Importance in Projection, VIP) value is extracted in model>1 variable is carried out
Independent samples t test, p<0.05 is that difference is statistically significant, so as to be chosen as potential biomarker and be identified.
(5) identification of biomarker：The Structural Identification of biomarker is mainly the first mass spectrometric according to metabolin
(MS) accurate relative molecular mass, second order mses (MS/MS) intermediate ion fragment cracking rule and retention time search HMDB in
(http://www.hmdb.ca/), Mass Bank (http://www.massbank.jp/), KEGG (http://
) and METLIN (http www.kegg.com/://metlin.scripps.edu/) etc. database, with reference to pertinent literature
Or matched with Standard Metabolism thing, so that it is determined that the structure and title of biomarker.
Embodiment 2
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Acetonitrile 200 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue methanol-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of clear liquid 5 injection LC-MS instrument sample introduction analyses.
Embodiment 3
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Methanol 200 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue acetonitrile-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of clear liquid 5 injection LC-MS instrument sample introduction analyses.
Embodiment 4
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Methanol 200 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue methanol-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of clear liquid 5 injection LC-MS instrument sample introduction analyses.
Embodiment 5
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Acetonitrile 600 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue acetonitrile-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of clear liquid 5 injection LC-MS instrument sample introduction analyses.
Embodiment 6
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Acetonitrile 600 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue methanol-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of clear liquid 5 injection LC-MS instrument sample introduction analyses.
Embodiment 7
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to complete defrosting, draws, draws blood plasma 200
μ L, methanol 600 μ L, vortex 30s are added wherein, centrifuge (12000r/min, 10min, 4 DEG C), take the μ L of supernatant 750, use nitrogen
Air-blowing is done, by residue acetonitrile-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C),
Take the μ L of supernatant 5 injection LC-MS instrument sample introduction analyses.
Embodiment 8
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Methanol 600 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue methanol-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of clear liquid 5 injection LC-MS instrument sample introduction analyses.
Embodiment 9
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Plasma sample is placed on by mouse before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Acetonitrile 1000 μ L, vortex 30s are added wherein, are centrifuged (12000r/min, 10min, 4 DEG C), are taken the μ L of supernatant 750, use nitrogen
Drying, by residue acetonitrile-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of supernatant 5 injection LC-MS instrument sample introduction analyses.
Embodiment 10
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Acetonitrile 1000 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue methanol-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of clear liquid 5 injection LC-MS instrument sample introduction analyses.
Embodiment 11
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Methanol 1000 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue acetonitrile-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of clear liquid 5 injection LC-MS instrument sample introduction analyses.
Embodiment 12
In addition to step (2), remaining step is same as Example 1.
(2) collection and processing of mice plasma sample：Each group mouse was drawn materials in the 8th day, with 4% chloraldurate solution
After (0.1ml/10g) intraperitoneal injection of anesthesia mouse, blood is taken to eyeball of mouse, is placed on inside the centrifuge tube containing EDTA, after blood sampling
Gently overturn and mix 5~6 times immediately, stand 2h, centrifuge (4 DEG C, 4000r/min, 10min), take supernatant to be placed in -80 DEG C of refrigerators
Freeze to be measured.Mice plasma sample is placed on before analysis and stands about 20min at room temperature to thawing completely, draws the μ L of blood plasma 200,
Methanol 1000 μ L, vortex 30s are wherein added, is centrifuged (12000r/min, 10min, 4 DEG C), is taken the μ L of supernatant 750, blown with nitrogen
It is dry, by residue methanol-water (10:90, v/v) 100 μ L redissolve, vortex 30s, centrifuge (12000rpm, 10min, 4 DEG C), take
The μ L of clear liquid 5 injection LC-MS instrument sample introduction analyses.
Biomarker in the psoriasis vulgaris blood plasma of table 1
VIP, variable importance projection；LysoPC, lysophosphatidyl choline；↑ increase compared with health is organized；↓ and healthy group
Compared to reduction.
Claims (5)
- A kind of 1. application of the biomarker in its targeted drug in psoriasis vulgaris blood plasma, it is characterised in that the biology Label for threonine, leucine, phenylalanine, tryptophan, palmitamide, linoleamide, oleamide, oleic acid, Stearic amide, arachidonic acid, cis -11- icosa alkenes acid amides, anti-form-1 3- docosenes acid amides, N- sub-oleoyl ox sulphurs Acid, Lysophosphatidylcholone (18:3), Lysophosphatidylcholone (18:2), uric acid, Lysophosphatidylcholone (16:0)、 Lysophosphatidylcholone (18:And Lysophosphatidylcholone (18 1):0) one kind or at least two in.
- 2. according to the application described in claim 1, it is characterised in that the biomarker is obtained by following steps：(1) mouse infection psoriasis model is established；(2) collection and processing of mice plasma sample：Mouse blood sample is taken to centrifuge, supernatant is plasma sample；1 part of blood plasma is taken, 1~5 part of acetonitrile or methanol extraction albumen are wherein added, is centrifuged after mixing, takes supernatant to be dried up with nitrogen, residue acetonitrile-water Or methanol-water redissolves, centrifuged after mixing residue, take supernatant to be measured；(3) machine processing on ultra performance liquid chromatography series connection quadrupole rod time of-flight mass spectrometer：The supernatant of step (2) is taken to carry out matter Spectrum analysis, gradient elution is carried out with mobile phase, and carry out negative ions using electro-spray ionization source and scan simultaneously；(4) data processing and analysis；(5) otherness metabolin and its Structural Identification.
- 3. application according to claim 2, it is characterised in that：The volume ratio of the blood plasma of step (2) and protein precipitant acetonitrile or methanol is 1:3.
- 4. application according to claim 2, it is characterised in that：The double solvents acetonitrile or the volume ratio of methanol and water of step (2) are 1:9.
- 5. application according to claim 2, it is characterised in that：The chromatographic condition of step (3) is：ACQUITY UPLCTM BEH C18Post, model 2.1mm × 100mm, 1.7 μm；Flowing It is mutually the formic acid acetonitrile of 0.1% formic acid water -0.1%, gradient elution：0~6min, 0.1% formic acid acetonitrile 5%~10%；6~ 10min, 0.1% formic acid acetonitrile 10%~38%；10~15min, 0.1% formic acid acetonitrile 38%~100%；15~18min, 0.1% formic acid acetonitrile 100%；18~19min, 0.1% formic acid acetonitrile 100%~5%；19~22min, 0.1% formic acid acetonitrile 5%；Flow velocity 0.4mL/min；40 DEG C of column temperature；4 DEG C of sample room temperature；Sampling volume is 5 μ L.
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