CN108823151A - Application of the PLEKHQ1 albumen in the product that preparation inhibits Apoptosis - Google Patents
Application of the PLEKHQ1 albumen in the product that preparation inhibits Apoptosis Download PDFInfo
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- CN108823151A CN108823151A CN201810676373.9A CN201810676373A CN108823151A CN 108823151 A CN108823151 A CN 108823151A CN 201810676373 A CN201810676373 A CN 201810676373A CN 108823151 A CN108823151 A CN 108823151A
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- plekhq1
- apoptosis
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- albumen
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
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- C12N5/0602—Vertebrate cells
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Abstract
The invention discloses application of the PLEKHQ1 albumen in the product that preparation inhibits Apoptosis.It is demonstrated experimentally that on a cellular level, compared with the MEF cell of wild-type mice, the MEF apoptosis rate of PLEKHQ1 knock out mice is dramatically increased, and cytotoxicity also dramatically increases；On a molecular scale, derived from bone marrow macrophage missing PLEKHQ1 albumen causes the expression of cleaved caspase-3, cleaved caspase-8 and cleaved PARP to increase, illustrate that derived from bone marrow macrophage missing PLEKHQ1 albumen leads to caspase excessive activation, promotes the apoptosis of cell；In mouse living body level, compared with wild-type mice, the hepatic injury of PLEKHQ1 knock out mice is even more serious.It can be seen that PLEKHQ1 albumen is able to suppress Apoptosis.The present invention has great application value.
Description
Technical field
The invention belongs to fields of biomedicine, and in particular to PLEKHQ1 albumen is in the product that preparation inhibits Apoptosis
Application.
Background technique
Apoptosis is the apoptosis being realized at first, is mainly played during allelotaxis, tissue update etc.
Effect, is formed as main feature with cytoplasm concentration, chromatin margination, cell nuclear fragmentation, apoptotic body.Apoptosis be by
The apoptosis that Caspase (cysteine aspartic acic specific protease) is mediated, including by
Endogenous pathway caused by mitochondria and the exogenous route as caused by death receptor.It endogenous apoptosis or withers for the mitochondrial pathways
Die, apoptosis induction factor causes Mitochondrial outer membrane permeabilization to change, release cytochrome c (cytochrome c) etc. apoptosis because
Son induces Apaf-1 and Caspase 9 to form apoptosis complex, further Caspase-3 and Caspase-7 is activated to cause cell
Apoptosis.The Apoptosis that death receptor mediates originates in the combination of death ligand and receptor.Death ligand is mainly neoplasm necrosis
The factor (tumor necrotic factor, TNF) family.TNF-α can promote inflammatory reaction also to can induce Apoptosis.
After the TNF- receptor 1 (TNF receptor 1, TNF-R1) of tripolymer combines in TNF-α and cell membrane, the cytoplasm of TNF-R1
Part is combined by death domain (DD, death domain) and raises TRADD (TNFR1-associated death
Domain protein), RIPK1 (Receptor-interacting protein kinase 1, RIPK1), FADD (Fas-
Associated protein with death domain), FADD passes through Death Effector Domain DED (death again
Effector domain) raise proCaspase-8 (Caspase-8 proenzyme).ProCaspase-8 occurs certainly in the composite
Body cuts and is activated, and then cuts executor proCaspase-3, generates active Caspase-3, and Caspase-3 is into one
Step cutting stream substrates lead to Apoptosis.
Source of people plekhq1 gene is located on No. 15 chromosome, encodes PLEKHQ1 (pleckstrin homology
Domain containing, family Q member 1), also known as PLEKHO2 (pleckstrin homology domain
Containing, family O member 2).The N-terminal of PLEKHQ1 contains a PH structural domain, and PH structural domain is responsible for forming egg
Interaction between white-albumen and albumen-lipid.
Summary of the invention
How the purpose of the present invention inhibits Apoptosis.
The present invention protects PLEKHQ1 albumen preparing the application in product first；The function of the product can be following C1)
At least one of to C3)：C1) inhibit Apoptosis；C2) inhibit the activation of apoptosis correlation Caspase in cell；C3) inhibit
Hepatic injury.
The present invention also protects the application of PLEKHQ1 albumen, can be following C1) at least one of to C3)：C1) inhibit thin
Born of the same parents' apoptosis；C2) inhibit the activation of apoptosis correlation Caspase in cell；C3) inhibit hepatic injury.
The present invention also protects PLEKHQ1 albumen preparing the application in product as drug target；The function of the product
For can following C1) at least one of to C3)：C1) inhibit Apoptosis；C2) inhibit cell in apoptosis correlation Caspase swash
It is living；C3) inhibit hepatic injury.
The present invention also protects application of the PLEKHQ1 albumen in exploitation or screening reagent；The purposes of the reagent can be for such as
Lower C1) at least one of to C3)：C1) inhibit Apoptosis；C2) inhibit the activation of apoptosis correlation Caspase in cell；C3)
Inhibit hepatic injury.
In any of the above-described application, the C1) in, cell can be embryo fibroblast (MEF cell).It is described
C1 in), the embryo fibroblast of cell concretely mouse.The C2) in, cell can for embryo fibroblast and/or
Derived from bone marrow macrophage (BMDM cell).The C2) in, the embryo fibroblast and/or bone of cell concretely mouse
Marrow source macrophage.The C2) in, apoptosis correlation Caspase can be caspase-3 and/or caspase-8.The C3)
In, hepatic injury can be acute liver damage.The C3) in, acute liver damage can be caused by TNF-α and GalN induction.More specifically,
Acute liver damage can be：To mouse peritoneal injection TNF-α (injection dosage can be 10 μ g/kg) and GalN, (injection dosage can be 800
μ g/kg), induction causes acute liver damage.
The present invention also protects a kind of product, can contain PLEKHQ1 albumen；The function of the product can be following C1) extremely
At least one of C3)：C1) inhibit Apoptosis；C2) inhibit the activation of apoptosis correlation Caspase in cell；C3) inhibit liver
Damage.
In the said goods, the C1) in, cell can be embryo fibroblast (MEF cell).The C1) in, cell tool
Body can be the embryo fibroblast of mouse.The C2) in, cell can be embryo fibroblast and/or derived from bone marrow macrophage
Cell (BMDM cell).The C2) in, concretely the embryo fibroblast of mouse and/or derived from bone marrow macrophage are thin for cell
Born of the same parents.The C2) in, apoptosis correlation Caspase can be caspase-3 and/or caspase-8.The C3) in, hepatic injury can be
Acute liver damage.The C3) in, acute liver damage can be caused by TNF-α and GalN induction.More specifically, acute liver damage can
For：To mouse peritoneal injection TNF-α (injection dosage can be 10 μ g/kg) and GalN (injection dosage can be 800 μ g/kg), induction
Cause acute liver damage.
Any of the above-described mouse concretely mouse C57BL/6.
Above, the amino acid sequence of the PLEKHQ1 albumen can be as shown in sequence 2 in sequence table.The PLEKHQ1 egg
The nucleotide sequence of white encoding gene (i.e. plekhq1 gene) can be as shown in sequence 1 in sequence table.
Applicant of the present invention entrusts Cyagen (Suzhou) Biotechnology Co., Ltd. to prepare Plekho2 knock out mice
(mouse species C57BL/6), to obtain Plekho2 (TALEN) knock out mice；Plekho2 (TALEN) gene knockout
Mouse is referred to as PLEKHQ1 knock out mice.Compare the Apoptosis feelings of PLEKHQ1 knock out mice and wild-type mice
Condition is as a result as follows：On a cellular level, compared with the MEF cell of wild-type mice, the MEF of PLEKHQ1 knock out mice is thin
Born of the same parents' apoptosis rate dramatically increases, and cytotoxicity also dramatically increases；On a molecular scale, derived from bone marrow macrophage lacks PLEKHQ1
Cleaved caspase-3, the cleaved caspase-8 and cleaved PARP that albumen causes TNF-α and CHX to induce jointly
Expression increase, illustrate the derived from bone marrow macrophage missing PLEKHQ1 albumen caspase that causes TNF-α and CHX to induce jointly
Excessive activation promotes the apoptosis of cell；In mouse living body level, compared with wild-type mice, PLEKHQ1 gene knockout is small
The hepatic injury of mouse is even more serious, illustrates that PLEKHQ1 albumen is able to suppress the acute liver damage of TNF-α and GalN induction.Thus may be used
See, PLEKHQ1 albumen is able to suppress Apoptosis.The present invention has great application value.
Detailed description of the invention
Fig. 1 is that PLEKHQ1 albumen inhibits Apoptosis.WT is wild-type mice, and PLEKHQ1-/- is PLEKHQ1 clpp gene
Except mouse.
Fig. 2 is that PLEKHQ1 albumen inhibits apoptosis correlation Caspase activation.WT is wild-type mice, PLEKHQ1-, and/- is
PLEKHQ1 knock out mice.
Fig. 3 is the acute liver damage that PLEKHQ1 albumen inhibits TNF-α and GalN induction.WT is wild-type mice,
PLEKHQ1-/- is PLEKHQ1 knock out mice.
Specific embodiment
Embodiment below facilitates a better understanding of the present invention, but does not limit the present invention.Experiment in following embodiments
Method is unless otherwise specified conventional method.The experimental materials used in the following example is unless otherwise specified certainly
What routine biochemistry reagent shop was commercially available.Quantitative experiment in following embodiment is respectively provided with three repeated experiments, as a result makes even
Mean value.
TNF-α is the product of U.S. Peprotech company, catalog number 315-01A.CHX(cycloheximide)
For the product of MCE company of the U.S., catalog number HY-12320.Smac mimetic is the product of U.S. MCE company, product
Catalog number (Cat.No.) is HY-12600.Annexin V-FITC Kit is the product of Xin Bosheng biotech firm, catalog number 12BJ01.
CellTiter-Glo Luminescent Cell Viability Assay is the product of Promega company, catalog number
For G1781.96 Non-Radio Cytotoxicity Assay of Cyto Tox is the product of Promega company, catalogue
Number be G7571.Caspase-3 antibody is the product of Cell Signaling Technology company, catalog number #
9665.Cleaved Caspase-3 antibody is the product of Cell Signaling Technology company, catalog number #
9664.Caspase-8 antibody is the product of Cell Signaling Technology company, catalog number #4927.
Cleaved Caspase-8 antibody is the product of Cell Signaling Technology company, catalog number #8592.
C-FLIP antibody is the product of Santa Cruz company, catalog number sc-5276.Cleaved PARP antibody is Cell
The product of Signaling Technology company, catalog number #9544.GAPDH antibody is Santa Cruz company
Product, catalog number sc-32233.RIPK1 antibody is the product of BD company, catalog number 610459.PLEKHQ1
Antibody is the product of Santa Cruz company, catalog number sc-100412.GalN(D(+)-Galactosamine
It hydrochloride is) product of Sigma Co., USA, catalog number G0500.3/7 Assay of Caspase-Glo is
The product of Promega company, catalog number G8093.ECL developing agents are the product of Thermo company, catalog number
For #32106.DMSO (dimethyl sulfoxide) is the product of ACROS company, catalog number 127790025.Protease inhibitors
For the product of Roche company, catalog number 04693116001.It is Pall Corporation public that protein, which transfers NC film,
The product of department, catalog number 66485.The secondary antibody of horseradish peroxidase label is Jackson ImmunoResearch Inc
The product of company.
Applicant of the present invention entrusts Cyagen (Suzhou) Biotechnology Co., Ltd. to prepare Plekho2 knock out mice
(mouse species C57BL/6), to obtain Plekho2 (TALEN) knock out mice.Plekho2 (TALEN) gene knockout
Mouse is hereinafter referred to as PLEKHQ1 knock out mice.
The amino acid sequence of PLEKHQ1 albumen is as shown in sequence 2 in sequence table, encoding gene (i.e. plekhq1 gene)
Nucleotide sequence as shown in sequence 1 in sequence table.
Mouse to be measured is PLEKHQ1 knock out mice or wild-type mice.
Embodiment 1, PLEKHQ1 albumen are inhibiting the application in Apoptosis
1, the preparation of TC system for handling, TS system for handling and control systems
The embryo fibroblast (i.e. MEF cell) of mouse to be measured is taken, TNF-α and CHX is added, obtains TC system for handling；
In TC system for handling, the concentration of TNF-α is that the concentration of 20ng/ μ L, CHX are 10 μ g/ μ L.
The embryo fibroblast (i.e. MEF cell) of mouse to be measured is taken, TNF-α and Smac mimetic is added, obtains TS
System for handling；In TS system for handling, the concentration that the concentration of TNF-α is 20ng/ μ L, Smac mimetic is 10nM.
The embryo fibroblast (i.e. MEF cell) of mouse to be measured is taken, DMSO is added, obtains control systems；Control systems
The concentration of middle DMSO is 1 μ g/mL.
2, it after completing step 1, takes system (TC system for handling, TS system for handling or control systems), 37 DEG C of processing 6h.
3, the system for taking into step 2, with flow cytometry using Annexin V-FITC Kit detection PI and
Annexin V positive cell ratio.
Part of test results is shown in A in Fig. 1 (DMSO is control systems, and TNF-α+CHX is TC system for handling).
4, the system for taking into step 2, using CellTiter-Glo Luminescent Cell Viability
It is horizontal that Assay detects ATP, and then investigates cell activity.
Part of test results is shown in B in Fig. 1 (DMSO is control systems, and TC is TC system for handling, and TS is TS system for handling).
5, the system for taking into step 2 is detected using 96 Non-Radio Cytotoxicity Assay of Cyto Tox
LDH (lactase dehydrogenase) emission levels, and then investigate cytotoxicity.
Part of test results is shown in C in Fig. 1 (DMSO is control systems, and TC is TC system for handling, and TS is TS system for handling).
TNF-α, CHX and Smac mimetic are to promote the apoptotic cell factor.The result shows that the MEF with wild-type mice
Cell is compared, and the MEF apoptosis rate of PLEKHQ1 knock out mice dramatically increases, and cytotoxicity also dramatically increases.Thus may be used
See, on a cellular level, PLEKHQ1 albumen can inhibit MEF Apoptosis.
Embodiment 2, PLEKHQ1 albumen inhibit apoptosis correlation Caspase activation
One, A is tested
1, the derived from bone marrow macrophage (BMDM cell) of mouse to be measured is taken, TNF-α and CHX is added, obtains system for handling；
In system for handling, the concentration of TNF-α is that the concentration of 20ng/ μ L, CHX are 10ug/ μ L.
2, after completing step 1, system for handling, 37 DEG C of processing 0h, 2h, 4h, 6h, 8h or 10h are taken.
3, the system of step 2 is taken into, RIPA lysate is added and is cracked, after then albumen is separated by electrophoresis in SDS-PAGE
Electrotransfer to protein transfers NC film.
RIPA lysate：Protease inhibitors containing 0.02table/mL, 150mM NaCl, 1% (v/v) NP-40,0.1%
(m/v) pH7.4 of SDS, 50mM Tris buffer.
4, after completing step 3, skim milk confining liquid is added and closes 1h.
5, after completing step 4, primary antibody (Cleaved Caspase-3 antibody, Caspase-3 antibody, Cleaved is added
Caspase-8 antibody, Caspase-8 antibody, Cleaved PARP antibody, c-FLIP antibody, PLEKHQ1 antibody or GAPDH are anti-
Body), incubation at room temperature 2h or 4 DEG C are incubated overnight.GAPDH is internal reference.
6, after completing step 5, with TBST buffer (Tris containing 30mg/mL, 88mg/mL Nacl, 1.7% (v/v) dense salt
The aqueous solution of acid and 0.5% (v/v) Tween 20) film 3 times are washed, each 10min.
7, after completing step 6, the secondary antibody of corresponding horseradish peroxidase label, incubation at room temperature 1h is added.
8, after completing step 7, film 3 times are washed with TBST buffer, each 10min.
9, after completing step 8, ECL developing agents is added on film, film is wrapped with preservative film, be placed in the change of Tanon 5200
Exposure in luminescence imaging analysis system, development are learned, and saves data.
Experimental result is shown in A in Fig. 2.
Two, B is tested
1, the MEF cell of mouse to be measured is taken, TNF-α and CHX is added, obtains system for handling；In system for handling, TNF-α
Concentration is that the concentration of 20ng/ μ L, CHX are 10ug/ μ L.
2, after completing step 1, system for handling, 37 DEG C of processing 0h, 4h or 6h are taken.
3, the system of step 2 is taken into, RIPA lysate is added and is cracked, after then albumen is separated by electrophoresis in SDS-PAGE
Electrotransfer to protein transfers NC film.
4, after completing step 3, skim milk confining liquid is added and closes 1h.
5, complete step 4 after, be added primary antibody (Cleaved Caspase-3 antibody, Cleaved Caspase-8 antibody,
Cleaved PARP antibody, RIPK1 antibody, c-FLIP antibody or GAPDH antibody), incubation at room temperature 2h or 4 DEG C are incubated overnight.
GAPDH is internal reference.
6, after completing step 5, film 3 times are washed with TBST buffer, each 10min.
7, after completing step 6, the secondary antibody of corresponding horseradish peroxidase label, incubation at room temperature 1h is added.
8, after completing step 7, film 3 times are washed with TBST buffer, each 10min.
9, after completing step 8, ECL developing agents is added on film, film is wrapped with preservative film, be placed in the change of Tanon 5200
Exposure in luminescence imaging analysis system, development are learned, and saves data.
Experimental result is shown in B in Fig. 2.
Three, C is tested
1, the preparation of TC system for handling, TS system for handling and control systems
With step 1 in embodiment 1.
2, it after completing step 1, takes system (TC system for handling, TS system for handling or control systems), 37 DEG C of processing 6h.
3, the system for taking into step 2, using in 3/7 Assay kit of Caspase-Glo detection MEF cell
The content of caspase-3.
Experimental result is shown in C in Fig. 2.
The result shows that derived from bone marrow macrophage missing PLEKHQ1 albumen causes TNF-α and CHX to induce jointly
The expression of cleaved caspase-3, cleaved caspase-8 and cleaved PARP increase, and illustrate derived from bone marrow macrophage
The caspase excessive activation that Cells Depletion PLEKHQ1 albumen causes TNF-α and CHX to induce jointly, promotes the apoptosis of cell.
Caspase-3 activity is higher in the MEF cell of apoptosis-induced PLEKHQ1 knock out mice, indicates Cells Depletion PLEKHQ1
It will accelerate itself apoptosis after albumen.It can be seen that on a molecular scale, PLEKHQ1 albumen is able to suppress Apoptosis.
Embodiment 3, PLEKHQ1 albumen inhibit the acute liver damage of TNF-α and GalN induction.
Test A, hepatocellular apoptosis guidance model
It taking and grows to 6-8 weeks mouse to be measured, TNF-α and GalN is injected intraperitoneally, the injection dosage of TNF-α is 10 μ g/kg,
The injection dosage of GalN is 800 μ g/kg.Then survival condition and the death time of mouse are observed, and counts survival rate.
TNF-α and GalN intraperitoneal injection are classical hepatocellular apoptosis guidance models.Survival rate statistical result is shown in A in Fig. 3.
The result shows that the survival rate of PLEKHQ1 knock out mice is lower compared with wild-type mice, it is easier to dead.
The level tested B, detect ALT and AST in mice serum
1, it takes and grows to 6-8 weeks mouse to be measured, TNF-α and GalN is injected intraperitoneally, the injection dosage of TNF-α is 10 μ g/
The injection dosage of kg, GalN are 800 μ g/kg.
2,6h after completion step 1, takes the serum of mouse to be measured, then using bio-chemical detector detection serum alt and AST
Level.
Testing result is shown in B in Fig. 3.The result shows that PLEKHQ1 knock out mice has more compared with wild-type mice
High ALT and AST is horizontal, prompts hepatic injury even more serious.
The degree of injury tested C, evaluate murine liver tissue
1, it takes and grows to 6-8 weeks mouse to be measured, TNF-α and GalN is injected intraperitoneally, the injection dosage of TNF-α is 10 μ g/
The injection dosage of kg, GalN are 800 μ g/kg.
2,3h or 6h after completion step 1, takes the hepatic tissue of mouse to be measured, carries out HE dyeing.
3, it takes the hepatic tissue for growing to 6-8 weeks mouse to be measured, carries out HE dyeing (as control).
According to HE coloration result, the degree of injury of murine liver tissue is evaluated.HE dyes deeper, the then damage of murine liver tissue
Degree is more serious.
Experimental result is shown in C in Fig. 3 (0h is control).The result shows that compared with wild-type mice, PLEKHQ1 gene knockout
The hepatic injury of mouse is even more serious, illustrates that PLEKHQ1 albumen is able to suppress the acute liver damage of TNF-α and GalN induction.Thus
As it can be seen that PLEKHQ1 albumen is able to suppress Apoptosis in mouse living body level.
Claims (9)
1.PLEKHQ1 albumen is preparing the application in product；The function of the product is at least one of following C1) to C3)：
C1) inhibit Apoptosis；C2) inhibit the activation of apoptosis correlation Caspase in cell；C3) inhibit hepatic injury.
The application of 2.PLEKHQ1 albumen, at least one of following C1) to C3)：C1) inhibit Apoptosis；C2) inhibit thin
The activation of apoptosis correlation Caspase in born of the same parents；C3) inhibit hepatic injury.
3.PLEKHQ1 albumen is preparing the application in product as drug target；The function of the product is following C1) to C3)
At least one of：C1) inhibit Apoptosis；C2) inhibit the activation of apoptosis correlation Caspase in cell；C3) inhibit liver damage
Wound.
Application of the 4.PLEKHQ1 albumen in exploitation or screening reagent；The purposes of the reagent be following C1) into C3) extremely
Few one kind：C1) inhibit Apoptosis；C2) inhibit the activation of apoptosis correlation Caspase in cell；C3) inhibit hepatic injury.
5. the application as described in Claims 1-4 is any, it is characterised in that：
The C1) in, cell is embryo fibroblast；
The C2) in, cell is embryo fibroblast and/or derived from bone marrow macrophage；
The C2) in, apoptosis correlation Caspase is caspase-3 and/or caspase-8；
The C3) in, hepatic injury is acute liver damage.
6. application as claimed in claim 5, it is characterised in that：The C3) in, acute liver damage is induced by TNF-α and GalN
Cause.
7. a kind of product contains PLEKHQ1 albumen；The function of the product is at least one of following C1) to C3)：C1)
Inhibit Apoptosis；C2) inhibit the activation of apoptosis correlation Caspase in cell；C3) inhibit hepatic injury.
8. product as claimed in claim 7, it is characterised in that：
The C1) in, cell is embryo fibroblast；
The C2) in, cell is embryo fibroblast and/or derived from bone marrow macrophage；
The C2) in, apoptosis correlation Caspase is caspase-3 and/or caspase-8；
The C3) in, hepatic injury is acute liver damage.
9. product as claimed in claim 8, it is characterised in that：The C3) in, acute liver damage is induced by TNF-α and GalN
Cause.
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| CN111189808A (en) * | 2019-12-25 | 2020-05-22 | 宁夏医科大学总医院 | Screening method of specific protein molecular marker related to liver injury and hepatocyte apoptosis |
| CN113476604A (en) * | 2021-05-26 | 2021-10-08 | 鲲石生物科技(深圳)有限公司 | Novel medical application of PLEKHQ1 protein |
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