CN114931574A - Iron death inhibitor and application thereof - Google Patents
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Abstract
The invention discloses an iron death inhibitor and application thereof, relates to the technical field of biomedicine, and adopts genistein as a novel iron death inhibitorTo NaIO 3 The AMD model established by the injured RPE cells has the protection effect, can remove oxygen free radicals and enhance the antioxidant capacity, thereby effectively protecting the photoreceptor cells from NaIO 3 Induced retinal damage; meanwhile, the composition can inhibit HO-1 expression, increase GPX4 antioxidant signal pathways, has an inhibiting effect on iron death-related signal pathways, and can be used for treating other diseases taking iron death as a target.
Description
The technical field is as follows:
the invention relates to the technical field of biological medicines, and particularly relates to an iron death inhibitor and application thereof.
Background art:
iron death (Ferroptosis) is an iron-dependent, novel programmed cell death mode distinct from apoptosis, necrosis, and autophagy. Iron death has been demonstrated in the development of various diseases such as neurodegenerative diseases, tumors, cardiovascular diseases, and the like. Iron death is closely related to Lipid peroxidation (Lipid peroxidation) and depends on Reactive Oxygen Species (ROS) levels and iron metabolism. Morphologically, iron death is mainly manifested by mitochondrial contraction, increased membrane density, and a reduction or disappearance of mitochondrial cristae, and thus, iron death is a new biological regulatory process distinct from other modes of cell death.
Age-related macular degeneration (AMD) is an important ocular fundus disease in which the elderly have irreversible vision impairment, even blindness.
The invention content is as follows:
the technical problem to be solved by the invention is to provide the application of Genistein (Genistein) as an iron death inhibitor, which not only can provide important reference value for the treatment of AMD, but also can be used as a novel inhibitor for treating other diseases (such as tumors, neurodegenerative diseases, cardiovascular and cerebrovascular diseases and the like) taking iron death as a target.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
one of the objects of the present invention is to provide the use of genistein as an inhibitor of iron death.
The invention also aims to provide the application of the genistein in preparing the medicine for treating the age-related macular degeneration.
The invention also aims to provide application of genistein in preparing a medicament for treating diseases taking iron death as a target. Preferably, the disease comprises diabetes, neurodegenerative diseases, tumors, cardiovascular diseases, respiratory diseases, parkinson's disease, ischemia reperfusion injury.
The medicine for treating age-related macular degeneration or treating diseases taking iron death as a target comprises genistein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers and/or auxiliary materials.
The dosage forms of the medicine are oral preparations, injection preparations, spraying agents and eye preparations. Preferably, the ophthalmic dosage forms comprise eye drops, eye ointments, eye sprays, eye gels, eye patches, intraocular injections, ophthalmic microspheres, ophthalmic implant tablets, periocular injections and ophthalmic sustained-release preparations
The invention utilizes NaIO 3 Establishing AMD model by injured RPE cells: sodium iodate (NaIO) 3 ) The antioxidant is an oxidant, can selectively act on RPE cells, inhibits the activities of an ion pump and II type carbonic anhydrase in the cells, increases the permeability of a membrane, enables organelles such as mitochondria and endoplasmic reticulum in the cells to be edematous, enables the RPE cells to have dysfunction, finally causes abnormal photoreceptor cell function, and establishes an age-related macular degeneration cell model.
The invention has the beneficial effects that: the invention adopts genistein as a novel iron death inhibitor, namely the genistein is prepared from NaIO 3 The AMD model established by the injured RPE cells has the protection effect, can remove oxygen free radicals and enhance the antioxidant capacity, thereby effectively protecting the photoreceptor cells from NaIO 3 Induced retinal damage; meanwhile, the composition can inhibit HO-1 expression, increase GPX4 antioxidant signal pathways, has an inhibiting effect on iron death-related signal pathways, and can be used for treating other diseases taking iron death as a target.
Description of the drawings:
FIG. 1 is the expression of iron death markers in an AMD model;
FIG. 2 is the cell viability data of 5mM sodium iodate treated group after adding 12 small molecule compounds (10 μ M) for 24 h;
FIG. 3 shows the cell viability data of 10mM sodium iodate treated group after adding small molecule compounds Baicalein, Genistein and Quercetin (10 μ M) for 24 h;
FIG. 4 is the cell viability data of 20mM sodium iodate treated group after adding small molecule compounds Baicalein, Genistein and Quercetin (10 μ M) respectively for 24 h;
FIG. 5 is the expression of an RPE cell iron death marker following treatment with an iron death inhibitor or Genistein.
The specific implementation mode is as follows:
in order to make the technical means, the original characteristics, the achieved purposes and the effects of the invention easy to understand, the invention is further explained by combining the specific embodiments and the drawings.
The invention adopts the following small molecular compounds for inhibitor screening, including Baicalein (Baicalein), Genistein (Genistein), Deferoxamine (desferrioxamine), Apigenin (Apigenin), Bazedoxifene (Bazedoxifene), Puerarin (Puerarin), GSH-MEE (glutathione ethyl ester), Quercetin (Quercetin), Epigallocatechin (Epigallocatechin), Acetylcysteine (Acetylcysteine), Curcumin (Curcumin), Pinocembrin (Pinocembrin).
Example 1: cell iron death in AMD model
ARPE-19 cells were cultured one day earlier and seeded at 1X 10 in 100mm cell culture dishes 6 Cells in 10mL of medium, divided into 2 groups, control group and NaIO respectively 3 And (4) grouping. When the cell state is good and the cell density reaches about 80% the next day, the control group is replaced by new 10mL of cell culture medium, NaIO 3 Group Change with 10mM NaIO 3 The culture medium solution of (1). After culturing in a constant-temperature incubator for 24 hours, digesting cells, collecting cells, digesting by using a protein lysate, and extracting protein.
Western blot operation:
(1) loading and electrophoresis: prepare in advance 1 × electrophoretic fluid 900mL dd H 2 O +100mL of 10X electrophoresis solution. The protein denatured sample was removed from the freezer at-80 ℃ and thawed on ice, 500mL of 1 Xelectrophoresis buffer was added to the electrophoresis tank, and the prepared gel was placed in the electrophoresis tank and fixed. The comb in the glass plate was then pulled vertically, slowly upwards, and 5. mu.L of protein marker was added to the first well, and the denatured protein samples were added sequentially to the wells (20. mu.L/well). And the sample is slowly added, so that the overflow of the protein sample and the generation of bubbles are avoided. And supplementing a sufficient amount of electrophoretic liquid in the electrophoretic tank after the sample loading is finished, connecting an electrophoretic tank cover according to the positive electrode and the negative electrode, switching on a power supply, regulating the voltage to be constant voltage of 120V, stopping electrophoresis when the Marker and the protein run to the bottom end of the lower layer of gel, and switching off the power supply, wherein the whole process lasts for about 1.5 h.
(2) Film transfer: preparing 1L of membrane transferring solution (1 × 100mL of membrane transferring buffer solution), anhydrous methanol (200 mL) and dd H in advance 2 Pre-cooling with 700mL of water for later use; preparing filter paper, a spongy cushion and 1 PVDF membrane, trimming the PVDF membrane to be basically consistent with the size of gel, soaking the PVDF membrane in anhydrous methanol for about 1-2min for activation, and soaking the spongy cushion and the filter paper in a membrane conversion buffer solution to fully balance the PVDF membrane and the PVDF membrane. Separating the glue from the glass plate gently, arranging the sponge, the three layers of filter paper, the gel, the PVDF film, the three layers of filter paper and the sponge in order between the black clamping plate and the white clamping plate, assembling the rotary film clamp, exhausting bubbles in each layer, and clamping the rotary film clamp. Placing in a film-rotating groove, soaking in a film-rotating buffer solution of an ice box for cooling, adding the film-rotating solution to cover the film-rotating groove, plugging a power supply, placing the ice box around the film-rotating groove for cooling, turning on the power supply, setting the current at a constant current of 250mA, and rotating the film for about 60-80 min.
(3) And (3) sealing: after the membrane conversion is finished, the PVDF membrane is clamped by forceps, and is fully soaked in prepared 5% skimmed milk (1g skimmed milk powder +20mL TBST), and the membrane is slowly sealed for about 1 hour under the condition of room temperature on an inclined shaking bed.
(4) Primary antibody incubation: an appropriate amount of primary antibody blocking solution is taken in advance and diluted according to a ratio of 1:1000 (primary antibody dilution/5% skimmed milk powder solution), and then added into an antibody incubation box and marked. After the membrane transfer is finished, the PVDF membrane is taken out, cut and respectively placed in corresponding antibody incubation boxes, and incubated overnight (12-16h) by slowly shaking at 4 ℃.
(5) And (3) secondary antibody incubation: the next day, the antibody incubation box was removed, the primary antibody dilution was recovered and frozen at-20 deg.C, and 1 XTSST was added to rapidly wash the membrane on a horizontal shaker for 10min each time, and repeated 3 times. Diluting a proper amount of secondary antibody with a confining liquid according to a ratio of 1:5000 (secondary antibody diluent/5% skimmed milk powder solution), adding the diluted secondary antibody into an antibody incubation box, and incubating for 1h in a horizontal shaker at room temperature. After the incubation is finished, the secondary antibody diluent is removed, and a1 XTSST horizontal shaking table is added to rapidly wash the membrane, each time for 10min, and the operation is repeated for 3 times.
(6) And (3) developing: the PVDF membrane is soaked by 1 XTBST, so that the PVDF membrane is prevented from being dried excessively. Opening and exposing a gel imaging system in advance, preparing Surpersignal West Pico Plus chemiluminescence substrate solution A and solution B according to a ratio of 1:1 in a dark room according to a specification, placing a PVDF membrane on a gel imaging analyzer, uniformly covering a proper amount of solution A and solution B mixed solution on the surface of the PVDF membrane in a dark place, exposing, developing and imaging, setting exposure time, selecting proper exposure imaging, and storing pictures. The experimental results were repeated at least three times.
As shown in figure 1, the iron death key proteins SLC7a11 and GPX4 were significantly decreased, while HO-1 was significantly upregulated, indicating that the cells underwent iron death.
Example 2: against 5mM NaIO 3 Small molecule inhibitor screening for injury
Mixing retinal ARPE-19 cells with a cell culture medium into a cell suspension one day in advance, counting (5000 cells/100 uL), inoculating the cell suspension to a 96-well cell culture plate, setting 5 multiple wells in each group, supplementing 100uL of the culture medium to each well, mixing uniformly, and putting the mixture into a constant-temperature incubator for culture. Next day, the cell condition was observed, and when the cell density reached about 80% and the cell condition was good, the experiment was performed. The cells were divided into 3 groups: control group, NaIO 3 Treatment group and inhibitor group. Control group: removing the culture medium, and adding new 100 μ L culture medium; NaIO 3 Treatment group: add 100. mu.L of 5mM NaIO 3 Putting the solution into a constant-temperature incubator for 24 hours; inhibitor group: add 90. mu.L of the prepared inhibitor solution to each well and after 2h add 10. mu.L (50mM) NaIO 3 Solution to a final concentration of 1uM inhibitor, NaIO 3 To a final concentration of 5And (5) culturing the cells in a constant temperature incubator for 24 hours by using mM, and detecting the activity of the cells by using CCK-8.
FIG. 2 is the data of cell viability after 24h of 5mM sodium iodate treatment with 12 small molecule compounds (10. mu.M), wherein the cell viability is maintained by Balcalein, Genistein, Quercetin and pinocembrin.
Example 3: resistance to 10mM NaIO 3 Impaired iron death inhibitor screening
The ARPE-19 cell plates were plated and after 24h the cell status was good, the cell culture medium was changed for each group (NaIO was added 3 Group and inhibitor group NaIO 3 The concentration is changed to 10mM to ensure that other conditions are unchanged), and after the culture in a constant-temperature incubator is carried out for 24 hours, the cell proliferation activity is detected by adopting a CCK-8 method.
As shown in FIG. 3, NaIO continues to be increased 3 After 10mM, Quercetin, Genistein was added to maintain 50% of the cell activity.
Example 4: resistant to 20mM NaIO 3 Impaired iron death inhibitor screening
The ARPE-19 cell plates were plated and after 24h the cell status was good, the cell culture medium was changed for each group (NaIO was added 3 Group and inhibitor group NaIO 3 The concentration is changed to 20mM to ensure that the rest conditions are unchanged), and after the culture in a constant temperature incubator is carried out for 24 hours, the cell proliferation activity is detected by adopting a CCK-8 method.
As shown in FIG. 4, NaIO continues to be increased 3 After a concentration of 20mM, the addition of Genistein maintained cell activity at 50%.
Example 5: detection of expression of iron death-related protein
As shown in fig. 5, NaIO 3 In the AMD model of induced ARPE-19 injury, the iron death key proteins SLC7A11 and GPX4 were significantly decreased, while HO-1 was significantly upregulated, indicating that the cells underwent iron death. The iron death inhibitor group (Ferrostatin-1) shows that 3 Compared with SLC7A11 and GPX4, HO-1 is obviously reduced, and the effect of the iron death inhibitor is shown. Interestingly, the Genistein group agreed with the iron death inhibitor group, suggesting that Genistein is resistant to NaIO by inhibiting iron death-related genes 3 Induced cell death, therefore Genistein is a potential inhibitor of iron death.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. Use of genistein as an inhibitor of iron death.
2. Application of genistein in preparing medicine for treating senile macular degeneration is provided.
3. Application of genistein in preparing medicine for treating diseases targeting iron death is provided.
4. Use according to claim 3, characterized in that: the diseases include diabetes, neurodegenerative diseases, tumors, cardiovascular diseases, respiratory diseases, Parkinson's disease, and ischemia-reperfusion injury.
5. Use according to claim 2 or 3, characterized in that: the medicine comprises genistein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers and/or auxiliary materials.
6. Use according to claim 5, characterized in that: the dosage forms of the medicine are oral preparations, injection preparations, spraying agents and eye preparations.
7. Use according to claim 6, characterized in that: the ophthalmic preparation comprises eye drops, eye ointment, eye spray, eye gel, eye patch, intraocular injection, ophthalmic microspheres, ophthalmic implant, periocular injection and ophthalmic sustained-release preparation.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210667785.2A CN114931574A (en) | 2022-06-14 | 2022-06-14 | Iron death inhibitor and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116832030A (en) * | 2023-08-07 | 2023-10-03 | 首都医科大学附属北京妇产医院 | Application of baicalein in preparing medicaments related to PCOS ovarian dysfunction |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6001368A (en) * | 1998-09-03 | 1999-12-14 | Protein Technologies International, Inc. | Method for inhibiting or reducing the risk of macular degeneration |
| WO2000067738A2 (en) * | 1999-05-07 | 2000-11-16 | Johns Hopkins University School Of Medicine | The use of a protein tyrosine kinase pathway inhibitor in the treatment of ocular disorders |
| JP2008303199A (en) * | 2007-06-11 | 2008-12-18 | Heimat Ltd | Anti-neovascularization composition containing lipid extract of grifola frondosa and genistein |
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- 2022-06-14 CN CN202210667785.2A patent/CN114931574A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6001368A (en) * | 1998-09-03 | 1999-12-14 | Protein Technologies International, Inc. | Method for inhibiting or reducing the risk of macular degeneration |
| WO2000067738A2 (en) * | 1999-05-07 | 2000-11-16 | Johns Hopkins University School Of Medicine | The use of a protein tyrosine kinase pathway inhibitor in the treatment of ocular disorders |
| JP2008303199A (en) * | 2007-06-11 | 2008-12-18 | Heimat Ltd | Anti-neovascularization composition containing lipid extract of grifola frondosa and genistein |
Non-Patent Citations (1)
| Title |
|---|
| YU XIAN GOH ET AL.: "Genistein: A Review on its Anti-Inflammatory Properties", 《FRONTIERS IN PHARMACOLOGY》, pages 13 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116832030A (en) * | 2023-08-07 | 2023-10-03 | 首都医科大学附属北京妇产医院 | Application of baicalein in preparing medicaments related to PCOS ovarian dysfunction |
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