CN108611370A - A kind of PIMT expression plasmids, amplimer, construction method and application - Google Patents
A kind of PIMT expression plasmids, amplimer, construction method and application Download PDFInfo
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K38/45—Transferases (2)
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- C12N9/10—Transferases (2.)
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- C12Y201/00—Transferases transferring one-carbon groups (2.1)
- C12Y201/01—Methyltransferases (2.1.1)
- C12Y201/01077—Protein-L-isoaspartate(D-aspartate) O-methyltransferase (2.1.1.77)
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Abstract
The invention discloses a kind of PIMT expression plasmids, amplimer, construction method and applications.The sequence of the PIMT expression plasmids such as SEQ ID NO:Shown in 1.The construction method of the PIMT expression plasmids includes：According to the restriction enzyme site that people source PCMT, mRNA and pcDNA3.1 () Flag GFP plasmids provide, restriction enzyme site selection is carried out, the restriction enzyme site of the PCMT includes XhoI and BamHI, obtains PIMT expression plasmids.The sequence of amplimer for PIMT expression plasmids is respectively such as SEQ ID NO:2~SEQ ID NO:Shown in 7.The present invention constructs PIMT expression plasmids by gene technology, and expression quantity of the PIMT in RA FLS can be made to improve, and detection limit improves, and can be used as apoptosis and proliferation of the drug for regulating and controlling RA FLS, realizes the treatment to rheumatoid arthritis.
Description
Technical field
The present invention relates to a kind of PIMT (the different aspartoyl transmethylase of albumen, protein isoaspartyl-
Methyltransferase, abbreviation PIMT) expression plasmid, and in particular to the construction method of a kind of PIMT expression plasmids and used
Amplimer and its application in the drug for being used to prepare treatment rheumatoid arthritis, belong to technique for gene engineering neck
Domain.
Background technology
Under physiological condition, the altheine acyl residue (L-asparaginyl residues) in protein and L- asparagus ferns
Methionyl residues (L-aspartyl residues) meeting spontaneous deamination acyl or isomerization form abnormal L- aspartoyls
(abnormal l-isoaspartyl residues, L-isoAsp), this abnormal L-isoAsp collect cumulative in albumen and change
Become the structure of protein and influences protein function.Different aspartoyl transmethylase (the protein isoaspartyl- of albumen
Methyltransferase, PIMT) it is to be prevalent in prokaryotic cell and the repair enzyme in eukaryocyte, in physiological conditions
It can identify and shift in s-adenosyl-L-methionine (S-adenosyl-L-methionine, AdoMet) methyl group to exception
L- aspartoyls (L-isoaspartyl) residue in free carboxy on, repair abnormal L- aspartyl residues and be transformed into
Normal L- aspartoyls, and the structure and function of recoverin matter.In vitro study finds that the calmodulin of aging cannot activate
The reason of protein kinase is L- aspartyl residues becomes abnormal L- aspartoyls by spontaneous deamination acyl role transformation, with
After PIMT enzymes are incubated altogether, the activation of calmodulin is restored.The epidermal growth factor of aging, bacterial fluorescence carrier protein, Ah
It has been proved in the protein such as Er Cihai Gadamers-amyloid protein, prion protein and tissue plasminogen activator different
Normal L-isoAsp gathers the change with protein function, after being incubated altogether with PIMT enzymes, the functional rehabilitation of protein.The above research is aobvious
Show, PIMT can identify and repair exception L-isoAsp residues in protein peptide chain, and this identification repair can influence protein
Function.
People PIMT genes are by 1 (protein carboxyl-O- of protein carboxyl groups neighbour transmethylase
Methyltransferase-1, PCMT-1；EC 2.1.1.77) gene code.People's PIMT genes are located at human chromosome 6q22.3
On~6q24, overall length 1751bp, including 8 exons.People PIMT is 24500Da by the molecular weight that 226 amino acid form
Monomeric enzyme, sequence is highly conserved, containing there are three s-adenosyl-L-methionine (AdoMet) identification region, is located at 81
In~89,150~157 and 171~181 amino acids, N-terminal contains the alanine for the modification that can be acetylation.People PIMT has two
Kind hypotype, PIMT- I and PIMT- II, the structure of the two are slightly different, but have similar substrate specificity, for being located at cell
Interior substrate, catalytic action having the same.
PIMT gene delections have the function of inducing cell hyper-proliferative and Apoptosis, the study found that with normal small
Mouse compares, its CD4 of the mouse of knockout PIMT genes+T lymphocytes and splenocyte hyper-proliferative, and by the marrow of this mouse
Transplant the pathological change that will produce anti-DNA antibody and the typical lupus erythematosus nephritis of performance to normal mouse.And in tumour cell
The missing of PIMT genes can also cause cell Proliferation.Further researches show that PIMT to repair exception L-isoAsp residue functions pair
In normal mitogen-activated protein kinase (mitogen-activated protein kinase, the MAPK) signal transduction of maintenance
System is particularly significant, inhibits PIMT genes to be expressed in HEK-293 cell lines with SiRNA, can lead to abnormal L-isoAsp residues
Gather, and HEK-293 cells, Raf-1, MEK1/2 (mitogen-activated protein are stimulated with epidermal growth factor
) and 1/2 these three MAPK signals of extracellular regulated kinases (extracellular regulating kinase, ERK) kinase
Hyperphosphorylation is all presented in system cascade molecules, and high phosphorylation Raf-1, MEK1/2 and ERK1/2 are responsible for cell Proliferation.
The above result of study prompt：PIMT gene delections cause cell Proliferation to may be by what MAPK signal transduction pathways worked.
Studies have found that in cultured mouse cortical neurons cell and COS1 cell lines, PIMT can protect cell to resist withering for Bax inductions
It dies, this Anti-G values of PIMT rely on its adenosylmethionine calmodulin binding domain CaM, and this region is shifted in all methyl
It is highly conserved in enzyme.Recombination PIMT is transfected into endothelial cell, the apoptosis induced by oxidative stress, and PIMT can be inhibited
Protective effect be function by its transmethylase, rather than its non-enzymatic rhetorical function；Further researches show that PIMT to protect
Substrate specificity when protecting Apoptosis includes heat shock protein 70, heat shock protein 90, actin Actin and Bcl-xL.With
On researches show that：PIMT resists apoptosis by the function and protecting cell of its transmethylase.
But recombination to construct is carried out about by PIMT expression plasmids there has been no any at present, it is used for rheumatoid arthritis
Treatment in terms of report.
Invention content
The main purpose of the present invention is to provide a kind of PIMT expression plasmids, and in particular to a kind of structure of PIMT expression plasmids
Construction method and amplimer used and its application in the drug for being used to prepare treatment rheumatoid arthritis, to overcome
Deficiency in the prior art.
For realization aforementioned invention purpose, the technical solution adopted by the present invention includes：
An embodiment of the present invention provides a kind of PIMT expression plasmids, sequence such as SEQ ID NO:Shown in 1.
The embodiment of the present invention additionally provides a kind of recombinant expression carrier carrying PIMT expression plasmids above-mentioned.
The embodiment of the present invention, which additionally provides a kind of conversion or transfection, the host strain of aforementioned recombinant expression carrier.
The embodiment of the present invention additionally provides the construction method of aforementioned PIMT expression plasmids comprising：According to people source PCMT,
The restriction enzyme site that mRNA and pcDNA3.1 (-)-Flag-GFP plasmids provide, carries out restriction enzyme site selection, wherein the PCMT's
Restriction enzyme site includes XhoI and BamHI, obtains the PIMT expression plasmids of recombination.
The embodiment of the present invention additionally provides a kind of amplimer for aforementioned PIMT expression plasmids, the amplimer
Sequence is respectively such as SEQ ID NO:2~SEQ ID NO:Shown in 7.
The embodiment of the present invention additionally provides the expression albumen expanded by aforementioned PIMT expression plasmids.
The embodiment of the present invention additionally provides PIMT expression plasmids above-mentioned or expression albumen in regulation and control rheumatoid arthritis
(rheumatoid arthritis, RA) synovium ties up like cell (fibroblast-like synoviocytes, FLS)
Application in apoptosis and proliferation.
Further, the embodiment of the present invention additionally provides PIMT expression plasmids above-mentioned or expression albumen is controlled being used to prepare
Treat the application in the drug of rheumatoid arthritis.
Compared with prior art, beneficial effects of the present invention at least that：
The present invention constructs the PIMT expression plasmids of recombination by gene technology, can make expression quantity of the PIMT in RA-FLS
It improving, detection limit improves, and Effective Regulation RA-FLS proliferation improves the anti-invasion ability of RA-FLS cells, meanwhile, present invention structure
Recombination PIMT expression plasmids be to establish the basis of fluorescence quantitative PCR detection PIMT mRNA, and further study rheumatoid
Arthritic basis；Also, the PIMT expression plasmids that the present invention is built and expression albumen can be used as drug, for regulating and controlling RA-FLS
Apoptosis and proliferation, realize that treatment to rheumatoid arthritis, application prospect are extensive.
Description of the drawings
Fig. 1 is pcDNA3_1- multiple cloning sites schematic diagrames in a typical embodiments of the invention.
Fig. 2 is pcDNA3_1 carrier schematic diagrames in a typical embodiments of the invention.
Fig. 3 a- Fig. 3 b are expression of the PIMT in RA patient articulars synovial tissue in a typical embodiments of the invention respectively
Situation schematic diagram.
Specific implementation mode
As previously mentioned, in view of many defects of the prior art, inventor is carried through studying for a long period of time and largely putting into practice
Go out technical scheme of the present invention, a kind of PIMT expression plasmids of recombination is mainly built by gene technology, and for carrying medicine
The technical method of rheumatoid arthritis is treated, principle is the apoptosis that PIMT can protect cell to resist Bax inductions, PIMT
This Anti-G value relies on its adenosylmethionine calmodulin binding domain CaM.
A kind of PIMT expression plasmids that the one side of the embodiment of the present invention provides, sequence such as SEQ ID NO:Shown in 1.
The other side of the embodiment of the present invention additionally provides a kind of recombination table carrying PIMT expression plasmids above-mentioned
Up to carrier.
The other side of the embodiment of the present invention, which additionally provides a kind of conversion or transfection, the place of aforementioned recombinant expression carrier
Main bacterium.
The other side of the embodiment of the present invention additionally provides the construction method of aforementioned PIMT expression plasmids comprising：Root
According to the restriction enzyme site that people source PCMT, mRNA and pcDNA3.1 (-)-Flag-GFP plasmids provide, restriction enzyme site selection is carried out,
In, the restriction enzyme site of the PCMT includes XhoI and BamHI, obtains the PIMT expression plasmids of recombination.
The other side of the embodiment of the present invention additionally provides a kind of amplimer for aforementioned PIMT expression plasmids, institute
The sequence of amplimer is stated respectively such as SEQ ID NO:2~SEQ ID NO:Shown in 7.
Further, the amplimer includes the first primer group, the second primer sets and third primer sets, wherein described
Sequence such as SEQ ID NO in the first primer group for the sense primer in the sites XhoI:Shown in 2, it to be used for the downstream in the sites BamHI
The sequence of primer such as SEQ ID NO:Shown in 3, the sequence such as SEQ in second primer sets for the sense primer in the sites XhoI
ID NO:Shown in 4, the sequence such as SEQ ID NO of the downstream primer for the sites BamHI:Shown in 5, used in the third primer sets
In the sequence such as SEQ ID NO of the sense primer in the sites XhoI:Shown in 6, the sequence of the downstream primer for the sites BamHI is such as
SEQ ID NO:Shown in 7.
The other side of the embodiment of the present invention additionally provides the expression albumen expanded by aforementioned PIMT expression plasmids.
The other side of the embodiment of the present invention additionally provides PIMT expression plasmids above-mentioned or expression albumen in regulation and control class
Rheumatic arthritis (rheumatoid arthritis, RA) synovium ties up like cell (fibroblast-like
Synoviocytes, FLS) apoptosis and proliferation in application.
Further, the PIMT expression plasmids regulate and control rheumatoid arthritis synovial by Bax/Bcl-2 apoptosis pathway
The apoptosis of fibroblast-like cells, the PIMT expression plasmids regulate and control rheumatoid arthritis synovial into fibre by MAPK signal paths
Tie up the proliferation of like cell.
Further, the other side of the embodiment of the present invention additionally provides PIMT expression plasmids above-mentioned or expression albumen
Application in the drug for being used to prepare treatment rheumatoid arthritis.
It is shown by the above result of study, the present invention constructs the PIMT expression plasmids of recombination by gene technology, can make
Expression quantity of the PIMT in RA-FLS improves, and detection limit improves, and Effective Regulation RA-FLS proliferation improves the anti-of RA-FLS cells and invades
Ability is attacked, meanwhile, the recombination PIMT expression plasmids that the present invention is built are the bases for establishing fluorescence quantitative PCR detection PIMT mRNA,
It is also the basis of further research rheumatoid arthritis；Also, the PIMT expression plasmids that the present invention is built and expression albumen can
As drug, the apoptosis for regulating and controlling RA-FLS and proliferation realize that the treatment to rheumatoid arthritis, application prospect are extensive.
Below in conjunction with several preferred embodiments the technical solution of the present invention is further explained explanation, but reality therein
It tests condition and setup parameter is not construed as limitation to basic technical scheme of the present invention.And protection scope of the present invention is not limited to
Following embodiments.
Embodiment 1
The structure of PIMT expression plasmids
Select Homo sapiens protein-L-isoaspartate (D-aspartate) O-
Methyltransferase (PCMT1), mRNA, (NCBI Reference Sequence:NM_005389.2)
Expand CDs:74~757
According to Homo sapiens protein-L-isoaspartate (D-aspartate) O-
methyltransferase(PCMT1),mRNA(NCBI Reference Sequence:) and pcDNA3.1 NM_005389.2
The restriction enzyme site that (-)-Flag-GFP plasmids provide carries out restriction enzyme site selection, and only XhoI and BamHI can be used as PCMT1
Restriction enzyme site, separately design 3 pairs of primers and carry out PCR amplifications, and send product to sequencing, see shown in Fig. 1 and Fig. 2.
Wherein, primer sets sequence 1 is respectively：
PCMT1-XhoI-684F：TAACTCGAGACCATGGCCTGGAAATCCGGCG
PCMT1-BamHI-684R：TAAGGATCCTCACTTCCACCTGGACCACTGC
Primer sets sequence 2 is respectively：
PCMT-XhoI-858-F：TATCTCGAGATGCCGGGAGCGCGCAGT
PCMT-BamHI-858-R：TGTGGATCCTCACTTCCACCTGGACCACTG
Primer sets sequence 3 is respectively：
PCMT1-XhoI-855F：TAACTCGAGACCATGCCGGGAGCGCGCAGT
PCMT1-BamHI-855R:TAAGGATCCCTTCCACCTGGACCACTGCTTTTCTTTATCTG
Through sequencing, No. 3 primer extension product sequences (i.e. pcDNA-PIMT plasmid sequences) and the PIMT sequences in GeneBank
Arrange almost the same, but C is changed into T at 565bp, is compared through BLAST, is herein SNP site (rs17355457).
Performance detection：The relationship of PIMT and rheumatoid arthritis
Inventor is it has been investigated that different aspartoyl transmethylase (the protein isoaspartyl- of albumen
Methyltransferase, PIMT) in rheumatoid arthritis (rheumatoid arthritis, RA) synovium dimension sample
Expression is remarkably decreased in cell (fibroblast-like synoviocytes, FLS).
1. RA patient's body PIMT expressions reduce：Compared with healthy people, PIMT mRNA are in the periphery of RA patient
Expression in blood mononuclear cell is substantially reduced that (referring to Fig. 3 a, the mRNA of healthy volunteer PIMT expression is apparently higher than RA patient
MRNA expression, p<0.01)；To the Showed by immune group result PIMT of RA and OA patient articulars synovial tissue in RA patient articulars
(referring to Fig. 3 b, in RA and OA synovial tissues, PIMT albumen is expressed in cytoplasm, but in RA for expression reduction in synovial tissue
In synovial tissue, PIMT positive cells are substantially less than OA synovial tissues)；
2. PIMT regulates and controls RA-FLS apoptosis by Bax/Bcl-2 accesses：Specific SiRNA reduces the expression of PIMT, RA-
FLS increments increase, and apoptosis is reduced；It is overexpressed PIMT in RA-FLS, leads to the reduction of RA-FLS apoptosis；Detect apoptosis correlation egg
In vain, it is found that PIMT is the apoptosis for regulating and controlling RA-FLS by Bax/Bcl-2 apoptosis pathway；
3. PIMT regulates and controls the increment of RA-FLS cells by MAPK signal paths：PIMT plasmids are overexpressed in RA-FLS,
GAP-associated protein GAP in MAPK signal paths is measured, it is found that PIMT regulates and controls the increment of RA-FLS cells by MAPK signal paths；
4. influences of the PIMT to cell factor in RA-FLS cells：After being overexpressed PIMT, IL-1b, IL- in RA-FLS cells
6, IL-8, IL-17, TNF-α and vegf expression decline, and IL-10 expression is increased；After specific SiRNA lowers the expression of PIMT,
IL-10 expression in RA-FLS cells reduces；
5. PIMT expression, which declines, leads to the reduction of RA-FLS cell invasion abilities：Specific SiRNA reduces PIMT in RA-FLS
In expression, RA-FLS cell invasion abilities reduce；
6. demonstrating PIMT in the RAT-FLS of the rat RA models of II Collagen Type VIs induction can be by Bax/Bcl-2 apoptosis
Access regulates and controls the apoptosis of RAT-FLS and regulates and controls the increment of RA-FLS cells by MAPK signal paths.
And in the experiment of the actual clinical of the present invention, by the PIMT expression plasmids and expression albumen of the present invention as drug,
Apoptosis for regulating and controlling RA-FLS and proliferation play significant effect, and expression quantity of the PIMT in RA-FLS can be made to improve,
Detection limit improves, and Effective Regulation RA-FLS proliferation improves the anti-invasion ability of RA-FLS cells, realizes to rheumatoid arthritis
Treatment, application prospect is extensive.
Finally, it is to be noted that, the terms "include", "comprise" or its any other variant be intended to it is non-exclusive
Property include so that including a series of elements process, method, article or equipment not only include those elements, but also
Further include other elements that are not explicitly listed, or further include for this process, method, article or equipment it is intrinsic
Element.
It will be appreciated by those skilled in the art that the specific implementation mode of present invention described above, is not constituted to the present invention
The restriction of protection domain.Any technique according to the invention design made various other corresponding changes and deformation, should all
Including within the scope of the invention as claimed.
Sequence table
<110>Accurate medical science and technology Co., Ltd of Jiangsu Tianrui
<120>A kind of PIMT expression plasmids, amplimer, construction method and application
<160> 7
<170> SIPOSequenceListing 1.0
<210> 1
<211> 906
<212> DNA
<213>Artificial sequence (artificial sequence)
<400> 1
actcttggga aaactgctgg gcaccgtcgt cgcgctgaag gtggttctgt acctgctccg 60
agtgtgctta gcgatggcct ggaaatccgg cggcgccagc cactcggagc taatccacaa 120
tctccgcaaa aatggaatca tcaagacaga taaagtattt gaagtgatgc tggctacaga 180
ccgctcccac tatgcaaaat gtaacccata catggattct ccacaatcaa taggtttcca 240
agcaacaatc agtgctccac acatgcatgc atatgcgcta gaacttctat ttgatcagtt 300
gcatgaagga gctaaagctc ttgatgtagg atctggaagt ggaatcctta ctgcatgttt 360
tgcacgtatg gttggatgta ctggaaaagt cataggaatt gatcacatta aagagctagt 420
agatgactca gtaaataatg tcaggaagga cgatccaaca cttctgtctt cagggagagt 480
acagcttgtt gtgggggatg gaagaatggg atatgctgaa gaagcccctt atgatgccat 540
tcatgtggga gctgcagccc ctgttgtacc ccaggcgcta atagatcagt taaagcccgg 600
aggaagattg atattgcctg ttggtcctgc aggcggaaac caaatgttgg agcagtatga 660
caagctacaa gatggcagca tcaaaatgaa gcctctgatg ggggtgatat acgtgccttt 720
aacagataaa gaaaagcagt ggtccaggtg gaagtgattt tatcttctgc tctttcttct 780
tccacacatg caagtgaaag ggtgtgattt taagacatta gactacaaga gctgtttttg 840
gttgtcacct ttatgctcct ccattataac gtcagaaatt cattacatta aaaatgtgaa 900
aaatgt 906
<210> 2
<211> 31
<212> DNA
<213>Artificial sequence (artificial sequence)
<400> 2
taactcgaga ccatggcctg gaaatccggc g 31
<210> 3
<211> 31
<212> DNA
<213>Artificial sequence (artificial sequence)
<400> 3
taaggatcct cacttccacc tggaccactg c 31
<210> 4
<211> 27
<212> DNA
<213>Artificial sequence (artificial sequence)
<400> 4
tatctcgaga tgccgggagc gcgcagt 27
<210> 5
<211> 30
<212> DNA
<213>Artificial sequence (artificial sequence)
<400> 5
tgtggatcct cacttccacc tggaccactg 30
<210> 6
<211> 30
<212> DNA
<213>Artificial sequence (artificial sequence)
<400> 6
taactcgaga ccatgccggg agcgcgcagt 30
<210> 7
<211> 41
<212> DNA
<213>Artificial sequence (artificial sequence)
<400> 7
taaggatccc ttccacctgg accactgctt ttctttatct g 41
Claims (10)
1. a kind of PIMT expression plasmids, which is characterized in that its sequence such as SEQ ID NO:Shown in 1.
2. carrying the recombinant expression carrier of PIMT expression plasmids described in claim 1.
The host strain of recombinant expression carrier described in requirement 2 3. conversion or transfection are had the right.
4. the construction method of PIMT expression plasmids as described in claim 1, it is characterised in that including：According to people source PCMT, mRNA
The restriction enzyme site provided with pcDNA3.1 (-)-Flag-GFP plasmids carries out restriction enzyme site selection, wherein the digestion of the PCMT
Site includes XhoI and BamHI, obtains the PIMT expression plasmids of recombination.
5. a kind of amplimer for PIMT expression plasmids described in claim 1, which is characterized in that the sequence of the amplimer
Row are respectively such as SEQ ID NO:2~SEQ ID NO:Shown in 7.
6. the amplimer according to claim 5 for PIMT expression plasmids, which is characterized in that the amplimer packet
Include the first primer group, the second primer sets and third primer sets, wherein draw the upstream in the first primer group for the sites XhoI
The sequence of object such as SEQ ID NO:Shown in 2, the sequence such as SEQ ID NO of the downstream primer for the sites BamHI:It is described shown in 3
Sequence such as SEQ ID NO in second primer sets for the sense primer in the sites XhoI:Shown in 4, it to be used for the downstream in the sites BamHI
The sequence of primer such as SEQ ID NO:Shown in 5, the sequence such as SEQ in the third primer sets for the sense primer in the sites XhoI
ID NO:Shown in 6, the sequence such as SEQ ID NO of the downstream primer for the sites BamHI:Shown in 7.
7. the expression albumen that the PIMT expression plasmids described in claim 1 expand.
8. the expression albumen described in PIMT expression plasmids described in claim 1 or claim 7 is in regulation and control rheumatoid joint
Application in the apoptosis and proliferation of scorching synovium dimension like cell.
9. application according to claim 8, it is characterised in that：The PIMT expression plasmids are logical by Bax/Bcl-2 apoptosis
Road regulates and controls the apoptosis of rheumatoid arthritis synovial fibroblast-like cells, and the PIMT expression plasmids pass through MAPK signal path tune
Control the proliferation of rheumatoid arthritis synovial fibroblast-like cells.
10. the expression albumen described in PIMT expression plasmids described in claim 1 or claim 7 is being used to prepare treatment class wind
Application in the drug of wet arthritis.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2570167T3 (en) * | 2011-03-16 | 2016-05-17 | Probiodrug Ag | Benzimidazole derivatives as glutaminyl cyclase inhibitors |
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2018
- 2018-05-10 CN CN201810441546.9A patent/CN108611370A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2570167T3 (en) * | 2011-03-16 | 2016-05-17 | Probiodrug Ag | Benzimidazole derivatives as glutaminyl cyclase inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| GENBANK: "登录号：D25547.1", 《GENBANK》 * |
| 张慧等: "PIMT 对类风湿关节炎成纤维样滑膜细胞凋亡的影响", 《中国免疫学杂志》 * |
| 张慧等: "类风湿关节炎滑膜成纤维样细胞的蛋白质组学研究", 《中华临床医师杂志(电子版)》 * |
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Application publication date: 20181002 |