CN113476604A - Novel medical application of PLEKHQ1 protein - Google Patents
Novel medical application of PLEKHQ1 protein Download PDFInfo
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- CN113476604A CN113476604A CN202110580029.1A CN202110580029A CN113476604A CN 113476604 A CN113476604 A CN 113476604A CN 202110580029 A CN202110580029 A CN 202110580029A CN 113476604 A CN113476604 A CN 113476604A
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Abstract
The invention belongs to the field of biomedicine, and particularly relates to an application of a PLEKHQ1 protein as a target for inhibiting cell necrosis, and an application of an LEKHQ1 protein inhibitor in preparation of a product for inhibiting cell necrosis and screening and research of an anti-cell necrosis reagent and/or a medicament. Experiments prove that the PLEKHQ1 protein can promote programmed cell necrosis, the PLEKHQ1-/-MEF resists programmed cell necrosis induced by TNF-alpha, and the over-expression of the PLEKHQ1 promotes programmed cell necrosis. The PLEKHQ1 protein can be combined with RIPK1, RIPK3 and MLKL to promote programmed cell necrosis, so that the protein can be used as a target of an anti-cell necrosis medicament, is used for screening and developing the anti-cell necrosis medicament, and has clinical significance for searching a new target for preventing and treating various diseases (the cell necrosis has important pathological or physiological significance in various diseases) and related medicaments. The PLEKHQ1 protein inhibitor is expected to be applied to the intervention of cell necrosis participating in important diseases to improve the disease condition and prognosis of patients, and has important application value in the field of medical disease treatment.
Description
Technical Field
The invention belongs to the field of biomedicine, relates to a new medical application of PLEKHQ1 protein, and particularly relates to an application of the PLEKHQ1 protein as a target for inhibiting cell necrosis and an application of an LEKHQ1 protein inhibitor in preparation of a product for inhibiting cell necrosis and screening and developing an anti-cell-necrosis reagent and/or a medicament.
Background
Cell necrosis (cell necrosis) is an extreme physical (hyperthermia, radiation, etc.), chemical (strong acid, strong base, toxic substances, etc.), biological (pathogens, etc.) or other serious pathological factor-induced cell death, which is pathological. The increase of the membrane permeability of the necrotic cells leads to the swelling of the cells, the deformation or swelling of organelles, no obvious morphological change of early nuclei and finally the rupture of the cells. Necrotic cells are lysed to release the contents, causing inflammatory reactions; in the healing process, fibrosis of tissues and organs is often accompanied, and scars are formed. Chromatin is not agglutinated when cells die, a 200bp DNA degradation fragment is not generated, the random degradation is realized, no apoptotic bodies are formed, and the process is passive. However, in recent years, some proteins are considered to be involved in signal regulation of the process of cell necrosis, and the studies show that cell necrosis is also programmed, so that the protein is also called necroptosis (necroptosis).
Programmed cell necrosis or necroptosis (necroptosis) belongs to programmed cell death in a cell lysis mode, mainly occurs in the processes of body injury, cell stress, infection and inflammatory reaction, and is mainly characterized in that the permeability of cell membranes is increased, cells are swelled, and the cell membranes are broken to release cell contents. Programmed necrosis is mediated by the RIPK3-MLKL signaling pathway. Programmed necrosis may also be caused by activation of death receptors. After the formation of dead complexes, RIPK1 is combined with RIPK3 (Receptor-interacting protein kinase 3, RIPK 3) through RIPK Homology Interaction Motif (RHIM) to form a complex to form necrotic bodies (necropomes) if Caspase-8 activation is inhibited. In the necrotic bodies, RIPK3 is phosphorylated and activated, and continues to phosphorylate a downstream substrate MLKL, the phosphorylated MLKL is polymerized, and membrane pores are formed by combining phospholipid on the inner side of cell membranes, so that cell permeability is changed and necrosis is caused. Neocrostatin-1 (Nec-1) as an inhibitor of the kinase activity of RIPK1 was shown to block the progression of apoptosis. Activation of TLR3 and TLR4 also leads to apoptosis through the RIPK3-MLKL pathway. It has also been shown that cytoplasmic Z-DNA and Z-RNA can directly recruit and activate RIPK3 via Z-DNA binding protein 1 (ZBP 1) without relying on RIPK1, causing apoptosis. In addition, RIPK1 was again shown to inhibit apoptosis initiated by the latter two RIPKs 3. These findings demonstrate both the core-driven role of RIPK3-MLKL pathway in the process of programmed necrosis and the complexity of programmed necrosis regulation.
PLEKHQ1 is a potential regulatory molecule for programmed cell death. PLEKHQ1 (pleckstrin homology. TM. Q member 1), also known as PLEKHO2, has the human PLEKHQ1 gene located on chromosome 15 and encodes a 490 amino acid protein. Bioinformatic analysis has shown that PLEKHQ1 may be involved in cytokine-receptor interaction, and contains a PH Domain at the N-terminus (Pleckstrin Homolgy Domain) that binds phospholipids and mediates protein-protein interactions. Previous studies have shown that PLEKHQ1 inhibits apoptosis, a key role in macrophage survival.
Cell necrosis is another mode of cell death distinct from apoptosis, and controls the growth, development, and homeostatic maintenance of multicellular organisms along with cell proliferation, differentiation, and the like. A large body of data suggests that cellular necrosis plays an important role in many physiological and pathological conditions, such as tissue development and damage, and the immune response of the body against viruses. Necrotic apoptosis offers yet another possible option and new avenue for disease treatment. Therefore, the research on the action target of inhibiting the cell necrosis and the related action mechanism thereof is a problem to be solved urgently.
Disclosure of Invention
In view of the problems in the prior art, the invention aims to provide the PLEKHQ1 protein as a target for inhibiting the action of cell necrosis, and the application of the PLEKHQ1 protein inhibitor in preparing products for resisting cell necrosis and screening and developing anti-cell necrosis agents and/or medicaments. Experiments prove that the PLEKHQ1 protein can promote programmed cell necrosis, the PLEKHQ1-/-MEF resists programmed cell necrosis induced by TNF-alpha, and the over-expression of the PLEKHQ1 promotes programmed cell necrosis. The PLEKHQ1 protein can be combined with RIPK1, RIPK3 and MLKL to promote cell programmed necrosis, so that the protein can be used as a target of an anti-cell necrosis medicament, is used for screening and developing the anti-cell necrosis medicament, and has important application value in the field of medical disease (cell necrosis has important pathological or physiological significance in various diseases) treatment.
The invention adopts the following technical scheme for achieving the aim.
Use of a PLEKHQ1 protein inhibitor for preparing an anti-cell necrosis product.
The PLEKHQ1 protein inhibitor is used as a drug target for preparing products for resisting cell necrosis.
The application of the PLEKHQ1 protein inhibitor in developing or screening anti-cell necrosis agents and/or medicaments.
Application of PLEKHQ1 protein inhibitor in preparing medicine for resisting cell necrosis is provided.
Application of a PLEKHQ1 protein inhibitor in preparing a medicament for preventing, relieving or treating diseases with important function of cell necrosis.
Further, the necrosis of cells is involved in important-acting diseases including inflammatory diseases, ischemia-reperfusion injury diseases, kidney diseases, cardiovascular diseases, liver diseases, diseases caused by infection of pathogenic microorganisms, tumors, nervous system-related diseases, and other diseases.
Further, the inflammatory disease includes sepsis, acute pancreatitis, inflammatory bowel disease, pneumonia, and the like.
Further, the ischemia reperfusion injury diseases comprise brain, retina, heart, kidney, liver, nerve injury diseases and the like.
Further, the cardiovascular diseases include coronary heart disease, cerebral infarction, peripheral vascular disease and the like.
Further, the kidney disease includes acute kidney injury, cisplatin-induced kidney injury, and the like.
Further, the liver diseases include liver injury, alcoholic liver disease, non-alcoholic steatohepatitis and the like.
Furthermore, the tumor is breast cancer, colon cancer, acute myeloid leukemia, various melanomas, liver cancer, pancreatic cancer, cervical squamous cell carcinoma, esophageal cancer and the like.
Further, the nervous system related diseases include alzheimer's disease, parkinson's syndrome, amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury, stroke.
Further, the other diseases include gaucher's disease, organ transplantation, aging disease of the reproductive system, and the like.
Further, the medicament comprises an effective amount of PLEKHQ1 inhibitor and pharmaceutically acceptable auxiliary materials.
Further, the dosage form of the medicament is any pharmaceutically acceptable dosage form.
Preferably, the dosage form of the medicament is powder, tablets, granules, capsules, solutions, emulsions, suspensions, injections, external solutions, lotions, liniments, ointments, plasters, pastes, patches and the like.
The use of a PLEKHQ1 protein inhibitor as a drug target for an anti-cell necrosis drug.
Further, the drug includes small molecule compounds and large molecule compounds.
In any of the above applications, the PLEKHQ1 protein inhibitor is used for inhibiting the expression of PLEKHQ1 protein at the transcription level.
The PLEKHQ1 is used as target protein in protein therapy, and is used for designing and preparing medicines or biological preparations for resisting cell necrosis.
The pharmaceutical or biological agent comprises an inhibitor of the PLEKHQ1 protein.
In any of the above applications, the cell is an embryonic fibroblast, a skin fibroblast and/or a bone marrow-derived macrophage.
A product for inhibiting cell necrosis comprises PLEKHQ1 protein inhibitor.
Further, the cells are embryonic fibroblasts, skin fibroblasts and/or bone marrow-derived macrophages.
Compared with the prior art, the invention has the following beneficial effects.
The invention firstly discovers that the PLEKHQ1 protein can promote the programmed necrosis of cells, the PLEKHQ1-/-MEF resists the programmed necrosis of the cells induced by TNF-alpha, and the over-expression of the PLEKHQ1 promotes the programmed necrosis of the cells. The PLEKHQ1 protein is used as a target point for inhibiting cell necrosis, and the application of the PLEKHQ1 protein inhibitor in preparing products for inhibiting cell necrosis and screening and developing anti-cell necrosis medicines is provided. Experiments prove that the PLEKHQ1 protein can be combined with RIPK1, RIPK3 and MLKL to promote programmed cell necrosis, so that the protein can be used as a target of an anti-cell necrosis medicament and is used for screening and developing the anti-cell necrosis medicament.
Cell necrosis is a pro-inflammatory, programmed cell death process accompanied by the release of large amounts of cellular contents. For example, the release of injury-related model molecules (DAMPs) can activate the immune response of the body, so that the molecules are widely involved in the pathophysiological processes of various diseases, including neurodegenerative diseases, infectious inflammatory diseases, ischemia-reperfusion injury, tumorigenesis, metastasis and the like, and have clinical significance for searching new targets and related medicines for preventing and treating various diseases. The PLEKHQ1 protein inhibitor is expected to be applied to the intervention of the diseases to improve the disease condition and prognosis of patients, and has important application value in the field of medical disease treatment.
The term "sepsis" as used herein refers to the Systemic Inflammatory Response Syndrome (SIRS) caused by infection, which is clinically manifested mainly as inflammatory response and multiple organ failure.
The invention relates to 'Inflammatory Bowel Disease (IBD)' which is an idiopathic inflammatory intestinal tract disease related to ileum, rectum and colon. The clinical manifestations are diarrhea, abdominal pain, and even bloody stool. Two types are mainly included: ulcerative colitis (ulcerogenic colitis) and Crohn's disease.
In the invention, acute pancreatitis (acute pancreatitis) is an inflammatory reaction of pancreatic tissue autodigestion, edema, hemorrhage and even necrosis caused by pancreatic enzymes activated in pancreas due to various reasons. Pancreatic cells have both apoptotic and necrotic modes of death, but the severity of pancreatitis is directly related to necrosis.
In the present invention, ischemia-reperfusion Injury (IR), tissue damage caused by ischemia is a main cause of many fatal diseases, such as myocardial infarction caused by coronary arteriosclerosis, cerebral stroke, etc., however, the main cause of damage to tissue is not ischemia itself, but is caused by excessive free radicals attacking cells in the part of tissue which regains blood supply after blood supply is restored.
The pathogenic microorganism infection in the invention comprises virus (such as HIV, I type herpes simplex virus HSV-1, WNV, Coxsackie group B virus CVB, respiratory tract enterovirus prototype strain T3D, bacteria (such as pathogenic escherichia coli EPEC, staphylococcus aureus and the like) infection and parasite (such as Leishmania and the like) infection.
The research shows that the programmed cell necrosis promotes the generation and the metastasis of tumors, and the tumors in the invention are breast cancer, colon cancer, acute myeloid leukemia, various melanomas, liver cancer, pancreatic cancer, cervical squamous cell carcinoma, esophageal cancer and the like.
The nervous system related diseases in the present invention include Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Spinal Cord Injury (SCI), and stroke (stroke).
Other diseases in the present invention include Gaucher's Disease (GD), organ transplantation, diseases of aging of the reproductive system, and the like.
Drawings
FIG. 1 shows the ATP levels in embryonic fibroblasts from wild-type and PLEKHQ1 knockout mice were measured using CellTiter-Glo Luminescent Cell vitality Assay.
FIG. 2 shows the detection of ATP levels in embryonic fibroblasts from PLEKHQ1 knockout mice using CellTiter-Glo Luminescent Cell vitality Assay.
FIG. 3 is a graph showing the measurement of ATP levels in skin fibroblasts of wild-type and PLEKHQ1 knockout mice using CellTiter-Glo luminescennt Cell vitality Assay.
FIG. 4 shows the ATP levels in bone marrow-derived macrophages of wild-type, PLEKHQ1 knockout and MLKL knockout mice were measured using CellTiter-glonescent Cell vitality Assay.
FIG. 5 shows the ATP level measurement using CellTiter-Glo luminescennt Cell vitality Assay.
FIG. 6 shows the ATP level measurement using CellTiter-Glo luminescennt Cell vitality Assay.
FIG. 7 shows the expression of cytokines tnfa, IL-1b and IL-6 in mRNA cells extracted from embryo fibroblasts of wild type and PLEKHQ1 knockout mice detected by RT-PCR.
FIG. 8 shows the expression of cytokines tnfa, IL-1b and IL-6 in mRNA cells extracted from bone marrow-derived macrophages from wild-type and PLEKHQ1 knockout mice detected by RT-PCR.
FIG. 9 is a co-immunoprecipitation assay for the interaction of PLEKHQ1 with necrosis-modulating molecules.
FIG. 10 shows the detection of the interaction of PLEKHQ1 with necrosis-modulating molecules using GST-Pulldown.
FIG. 11 shows the effect of immunoblot detection of PLEKHQ1 deletion on the activation of necrosis-modulating molecules RIPK1 and RIPK 3.
FIG. 12 is a graph of the effect of immunoblot detection of PLEKHQ1 deletion on the activation of the necrosis-modulating molecule RIPK 3.
Detailed Description
The embodiments of the present invention will be described in detail below with reference to the drawings and examples. The following examples are given to facilitate a better understanding of the invention, but do not limit the invention. The experimental procedures in the following examples are conventional unless otherwise specified. The experimental materials used in the following examples were purchased from conventional biochemicals, unless otherwise specified.
Example 1 pleckhq 1 promotes apoptosis.
(1) Embryonic fibroblasts (MEF cells) from wild-type and PLEKHQ1 knock-out mice were taken, DMSO (1 ug/ml), TNF- α (50 ng/ml), TNF- α + Smac mimoic (100 nM), TNF- α + Smac mimoic + zVAD (20 mM), and TNF- α + Smac mimoic + zVAD + Neostatin 1 (30 mM) were added, and ATP levels were measured using CellTiter-Glo luminescence Cell vitality Assay after 12h at 37 ℃ as shown in FIG. 1.
(2) Embryonic fibroblasts (MEF cells) from PLEKHQ1 knock-out mice were taken, DMSO (1 ug/ml), TNF- α (50 ng/ml), TNF- α + Smac mimoic (100 nM), TNF- α + Smac mimoic + zVAD (20 mM) and TNF- α + Smac mimoic + zVAD + Neostatin 1 (30 mM) were added, and ATP levels were measured using CellTiter-Glo luminescence Cell Viability Assay after 12h treatment at 37 ℃ as shown in FIG. 2.
(3) Dermal fibroblasts (MDF cells) from wild-type and PLEKHQ1 knock-out mice were taken and added with DMSO (1 ug/ml), TNF- α (50 ng/ml), TNF- α + Smac mimoic (100 nM), TNF- α + Smac mimoic + zVAD (20 mM), and TNF- α + Smac mimoic + zVAD + Neostatin 1 (30 mM), respectively, and ATP levels were measured using CellTiter-Glo luminescence Cell vitality Assay after 12h treatment at 37 ℃ as shown in FIG. 3.
(4) Bone marrow-derived macrophages (BMDM cells) of wild-type, PLEKHQ1 gene knockout type and MLKL knockout type mice were taken, DMSO (1 ug/ml), LPS (100 ng/ml) + zVAD (20 mM), Poly (I: C) (100. mu.g/ml) + zVAD were added, and ATP levels were measured by CellTiter-Glo luminescence Cell vitality Assay after 12h treatment at 37 ℃ as shown in FIG. 4.
(5) Wild-type mice were divided into control and experimental groups, and were intraperitoneally injected with PBS and zVAD (20 mg/kg), 1h later with PBS and LPS (10 mg/kg), 16h later, peritoneal cells were collected by peritoneal lavage and analyzed by flow cytometry, as shown in FIG. 5.
The PLEKHQ1 knockout mice are divided into a control group and an experimental group, PBS and zVAD (20 mg/kg) are respectively injected into the abdominal cavity, PBS and LPS (10 mg/kg) are respectively injected into the abdominal cavity after 1h, peritoneal cells are collected by lavage of peritoneum after 16h, and the peritoneal cells are analyzed by a flow cytometer. The data obtained by flow cytometry in experiment (5) were subjected to quantitative analysis as shown in fig. 6.
Example 2 pleckq 1 promotes expression of pro-inflammatory genes in necrotic cells.
Taking embryo fibroblasts (MEF cells) of wild type and PLEKHQ1 gene knockout mice, respectively adding DMSO, TNF-alpha (50 ng/mL) + zVAD (20 mM) and TNF-alpha + zVAD + CHX (10 mg/mL), extracting cell mRNA after 6h and detecting the expression of cytokines tnfa, IL-1b and IL-6 by RT-PCR (reverse transcription-polymerase chain reaction) as shown in figure 7.
Bone marrow-derived macrophages (i.e., BMDM cells) from wild-type and PLEKHQ1 knockout mice were taken, DMSO, LPS (100 ng/mL) + zVAD (20 mM) and poly (I: C) (100. mu.g/mL) + zVAD (20 mM) were added, respectively, and after 6h, cellular mRNA was extracted and the expression of cytokines tnfa, IL-1b and IL-6 was detected by RT-PCR, as shown in FIG. 8.
Example 3 PLEKHQ1 binds to and promotes the activity of RIPKs.
The 293T cells were transfected with PLEKHQ1, RIPK1, RIPK3 and MLKL as indicated. After immunoprecipitation of the proteins with Flag antibodies, the Weston blot assay was performed, as shown in fig. 9.
L929 cell lysate was incubated with purified GST-PLEKHQ1 and its truncated fragment for GST-Pulldown detection of binding as shown in FIG. 10.
Embryonic fibroblasts (MEF cells) of wild-type and PLEKHQ1 knockout mice were taken, and after 2h or 4h stimulation with TNF-alpha (10 ng/mL) + zVAD (20 mM) + CHX (10 mg/mL), cellular proteins were extracted and expression of the proteins was detected by West Blot, as shown in FIG. 11.
Embryonic fibroblasts (MEF cells) of wild-type and PLEKHQ1 knockout mice were taken, and after stimulation for 4h with TNF-alpha (10 ng/mL) + zVAD (20 mM), cellular proteins were extracted and expression of the proteins was detected by West Blot, as shown in FIG. 12.
Claims (25)
- Use of a PLEKHQ1 protein inhibitor for the preparation of an anti-cell necrosis product.
- Application of the PLEKHQ1 protein inhibitor as a drug target in preparing an anti-cell necrosis product.
- Use of a PLEKHQ1 protein inhibitor in the development or screening of anti-cell necrosis agents and/or drugs.
- Application of the PLEKHQ1 protein inhibitor in preparing anti-cell necrosis medicines.
- Application of the PLEKHQ1 protein inhibitor in preparing medicines for preventing, relieving or treating diseases with important function of cell necrosis.
- 6. The use of claim 5, wherein the cellular necrosis is involved in important-acting diseases including inflammatory diseases, ischemia-reperfusion injury diseases, kidney diseases, cardiovascular diseases, liver diseases, diseases caused by infection with pathogenic microorganisms, tumors, diseases related to the nervous system, and other diseases.
- 7. The use of claim 6, wherein the inflammatory disease comprises sepsis, acute pancreatitis, inflammatory bowel disease, pneumonia.
- 8. The use of claim 6, wherein the ischemia-reperfusion injury disease comprises brain, retina, heart, kidney, liver, nerve injury disease.
- 9. The use of claim 6, wherein the cardiovascular disease comprises coronary heart disease, cerebral infarction, peripheral vascular disease.
- 10. The use of claim 6, wherein the kidney disease comprises acute kidney injury, cisplatin-induced kidney injury.
- 11. The use of claim 6, wherein the liver disease comprises liver injury, alcoholic liver disease, non-alcoholic steatohepatitis.
- 12. The use of claim 6, wherein the tumor is breast cancer, colon cancer, acute myeloid leukemia, multiple melanomas, liver cancer, pancreatic cancer, cervical squamous carcinoma, esophageal cancer.
- 13. The use of claim 6, wherein the neurological-related disorder comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury, stroke.
- 14. The use according to claim 6, wherein the other diseases include gaucher's disease, organ transplantation, diseases of the aging reproductive system.
- 15. The use of any one of claims 4 to 14, wherein the medicament comprises an effective amount of a PLEKHQ1 inhibitor, and a pharmaceutically acceptable excipient.
- 16. The use of any one of claims 4 to 15, wherein the medicament is in a form of any pharmaceutically acceptable dosage form.
- 17. The use of claim 16, wherein the medicament is in the form of a powder, tablet, granule, capsule, solution, emulsion, suspension, injection, topical solution, lotion, liniment, ointment, plaster, paste, patch.
- Use of a PLEKHQ1 protein inhibitor as a drug target for an anti-cell necrosis drug.
- 19. The use of claim 16, wherein the medicament comprises small molecule compounds and large molecule compounds.
- 20. The use of any one of claims 1 to 19, wherein the inhibitor of the PLEKHQ1 protein inhibits the expression of the PLEKHQ1 protein at the transcriptional level.
- Use of PLEKHQ1 as a target protein in protein therapy for the design and manufacture of a medicament or biological preparation against cell necrosis.
- 22. The use of claim 21, wherein the pharmaceutical or biological agent comprises an inhibitor of the PLEKHQ1 protein.
- 23. Use according to any one of claims 1 to 22, wherein the cells are embryonic fibroblasts, skin fibroblasts and/or bone marrow derived macrophages.
- 24. A product for inhibiting cell necrosis, said product comprising an inhibitor of PLEKHQ1 protein.
- 25. The product of claim 24, wherein the cells are embryonic fibroblasts, skin fibroblasts, and/or bone marrow derived macrophages.
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Application publication date: 20211008 |