CN117159521A - Application of shikonin as immunosuppressant used in allogeneic uterine transplantation - Google Patents
Application of shikonin as immunosuppressant used in allogeneic uterine transplantation Download PDFInfo
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- CN117159521A CN117159521A CN202311059541.7A CN202311059541A CN117159521A CN 117159521 A CN117159521 A CN 117159521A CN 202311059541 A CN202311059541 A CN 202311059541A CN 117159521 A CN117159521 A CN 117159521A
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- shikonin
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- transplantation
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- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 title claims abstract description 39
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 241001071917 Lithospermum Species 0.000 title claims abstract description 37
- 238000002054 transplantation Methods 0.000 title claims abstract description 21
- 239000003018 immunosuppressive agent Substances 0.000 title claims abstract description 17
- 229960003444 immunosuppressant agent Drugs 0.000 title claims abstract description 14
- 230000000735 allogeneic effect Effects 0.000 title claims abstract description 12
- 230000001861 immunosuppressant effect Effects 0.000 title claims abstract description 12
- 230000000694 effects Effects 0.000 abstract description 8
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- 231100000331 toxic Toxicity 0.000 abstract description 5
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- 239000003814 drug Substances 0.000 abstract description 2
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- 210000001744 T-lymphocyte Anatomy 0.000 description 6
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- 238000011282 treatment Methods 0.000 description 4
- 230000022131 cell cycle Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940124589 immunosuppressive drug Drugs 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000004229 Alkannin Substances 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 235000019232 alkannin Nutrition 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
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- 238000000034 method Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
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- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003409 anti-rejection Effects 0.000 description 1
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- 230000002496 gastric effect Effects 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011419 induction treatment Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
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- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
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- 230000001404 mediated effect Effects 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention discloses application of shikonin as an immunosuppressant used in allogeneic uterine transplantation, belonging to the technical field of biological medicine. The invention explores the application of the shikonin immunosuppressant used after the uterine transplantation for the first time, in a mouse uterine transplantation model, the single shikonin can obviously prolong the survival time of the transplant, greatly reduce the toxic and side effects, and can make a great contribution to the survival of the postoperative transplant of a patient and the improvement of the success rate of later pregnancy.
Description
Technical Field
The invention belongs to the technical field of biological medicine, and particularly relates to application of shikonin as an immunosuppressant used in allogeneic uterine transplantation.
Background
Organ transplantation is still the most effective treatment for the current treatment of end organ failure, and acute rejection is the most common type of rejection in clinical allogeneic organ transplantation. T cell mediated cellular immunity is one of the major mechanisms for acute rejection following organ transplantation. Pathological examination can see infiltration of inflammatory cells such as a large number of lymphocytes and macrophages within the graft. Early lymphocytes are predominantly CD4 + T cells, later on with CD8 having a killing function + T cells are the main factor, destroy the parenchymal cells of the graft, and if the immunosuppressive drugs are not controlled, the graft function is gradually lost. Immunosuppressive drugs such as tacrolimus, rapamycin, mycophenolic acid and the like directed against T cells play an important role in anti-rejection and immune tolerance induction treatment after transplantation. However, most immunosuppressants have strong toxic and side effects, which limit the clinical application. Finding immunosuppressive drugs with low toxic and side effects has been a focus of research in immunology.
Shikonin is used as one of the effective components of traditional Chinese herbal medicine radix Arnebiae, and has the functions of resisting inflammation and tumor, protecting uterus function and vasoconstriction, etc. Previous studies have demonstrated their potential for use in skin grafts, but their use in allogeneic uterine grafts has yet to be studied and developed.
Disclosure of Invention
The invention aims to solve the problem of strong toxic and side effects of immunosuppressants taken after the current uterine transplantation and provides application of Shikonin (SHK) as an immunosuppressant used in allogeneic uterine transplantation.
The invention is realized by the following technical scheme:
use of shikonin alone as an immunosuppressant for use in allogeneic uterine transplants.
Further, the dosage of shikonin is 10-20 mg/kg.d.
Further, the dosage of shikonin is 15 mg/kg.d.
Compared with the prior art, the invention has the following advantages:
1. in the mouse uterine transplantation model, the single shikonin can obviously prolong the survival time of the transplant, greatly reduce the toxic and side effects, and can make a great contribution to the survival of the postoperative transplant of a patient and the improvement of the success rate of later pregnancy.
2. The invention is the application of the immunosuppressant used after the uterine transplantation of alkannin for the first time.
Drawings
FIG. 1 is a graph showing the results of shikonin inhibiting proliferation of spleen cells in example 1 of the present invention;
FIG. 2 is a graph showing the CFSE results of shikonin inhibiting proliferation of spleen cells in example 1 of the present invention;
FIG. 3 is a flow chart showing the results of promoting apoptosis of spleen cells by shikonin in example 1 of the present invention;
FIG. 4 is a flow chart showing the results of shikonin blocking spleen cell cycle in example 1 of the present invention;
FIG. 5 is a photograph showing the steps of uterine implantation in example 2 of the present invention;
FIG. 6 is a graph showing the result of the alkannin extension of the survival of allograft uterus grafts in example 2 of the present invention;
FIG. 7 is a graph showing the effect of shikonin on post-operative body weight of a recipient mouse in example 2 of the present invention.
Detailed Description
For a further explanation of the invention, reference is made to the following specific examples and figures.
Example 1
Extraction ofSpleen cells of C57BL/6J mice are stimulated by anti-CD3 and anti-CD28, and shikonin with different concentrations is added to ensure that the concentration of shikonin in a final system is respectivelyThe NC groups were negative control groups without anti-CD3 and anti-CD28 and shikonin, and the PC group was positive control group without shikonin and anti-CD3 and anti-CD 28.
The effect of Brdu insertion on T cell proliferation ability under different concentrations of shikonin culture environment was examined, and as shown in FIGS. 1 and 2, shikonin inhibition was evident at 0.50. Mu.M, inhibition was further increased at 0.75 and 1.00. Mu.M, and dose dependence was exhibited. CFSE flow cytometry at a suitable detection concentration of 0.75 μm was found to significantly reduce the proliferation fraction of T cells.
As shown in FIG. 3, when Annexin-v/PI detection is performed at a suitable detection concentration of 0.75. Mu.M, shikonin at this concentration significantly increases the T cell apoptosis ratio.
As shown in FIG. 4, cell cycle test was performed at a suitable test concentration of 0.75. Mu.M, which concentration of shikonin significantly blocked the cell cycle of T cells.
Example 2
The dosage of shikonin was fuzzed:
Balb/C female mice are selected as uterine transplantation donors, C57BL/6J female mice are selected as transplantation acceptors, and a sleeve method is adopted for uterine transplantation molding. The modeling simplified flow is shown in a technical roadmap 5; the shikonin of 10 mg/kg.d, 15 mg/kg.d and 20 mg/kg.d are respectively selected for carrying out gastric lavage treatment on the receptor, and the influence of the measurement of 10 mg/kg.d on the life of the uterine graft is not obvious, and the influence of shikonin of 15 mg/kg.d and 20 mg/kg.d on the life of the graft is obvious.
The receptor and the donor are respectively weight (22+ -2) g, and female C57BL/6J (B6, H-2K) of 8-12 weeks old b ) And BALB/c (H-2K) d ) All purchased from Beijing vitamin Torilhua laboratory animal Co., ltd. All experimental animals were bred in the SPF grade environment of Xiamen university organ transplantation institute and were anesthetized with pentobarbital sodium intraperitoneal injection.
In this example, 15mg/kg was selected as a study dose, and 15mg/kg shikonin treatment was administered to recipient mice by a intragastric technique every day from day 0 (d 0) after uterine transplantation to complete rejection of the postoperative graft, and physiological saline was used as a negative control group. And judging whether the implant survives or not through the peristaltic and blood supply conditions of the uterine implant after operation, and judging that the implant is completely repelled if no peristaltic and blood supply conditions exist. The lavage volume was obtained from the real-time body weight of the mice, recorded, and the real-time body weight of the mice was counted.
Through the above experiments, as shown in fig. 6, the median survival time of the grafts in this example was 12.5 days. The effect is obviously better than that of the control group (the median is 7 days). The SHK-treated group body weight recovered to a level comparable to that of the control group at 4-7 days after the operation, as shown in fig. 7, significantly higher than that of the experimental group using the same dose of FK 506.
The foregoing description is only illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the scope of the invention, i.e., the invention is not to be limited to the details of the invention.
Claims (3)
1. Use of shikonin as an immunosuppressant for allogeneic uterine transplantation, characterized in that shikonin alone is used as an immunosuppressant for allogeneic uterine transplantation.
2. Use of shikonin as an immunosuppressant for allogeneic uterine transplants according to claim 1, characterized in that the shikonin is used at a dose of 10-20 mg/kg-d.
3. Use of shikonin as an immunosuppressant for allogeneic uterine transplants according to claim 1, characterized in that the shikonin is used at a dose of 15 mg/kg-d.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311059541.7A CN117159521A (en) | 2023-08-22 | 2023-08-22 | Application of shikonin as immunosuppressant used in allogeneic uterine transplantation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311059541.7A CN117159521A (en) | 2023-08-22 | 2023-08-22 | Application of shikonin as immunosuppressant used in allogeneic uterine transplantation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117159521A true CN117159521A (en) | 2023-12-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311059541.7A Pending CN117159521A (en) | 2023-08-22 | 2023-08-22 | Application of shikonin as immunosuppressant used in allogeneic uterine transplantation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117159521A (en) |
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2023
- 2023-08-22 CN CN202311059541.7A patent/CN117159521A/en active Pending
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