CN111053770A - Application of berberine as immunosuppressant used in allogeneic heart transplantation - Google Patents
Application of berberine as immunosuppressant used in allogeneic heart transplantation Download PDFInfo
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- CN111053770A CN111053770A CN202010029483.3A CN202010029483A CN111053770A CN 111053770 A CN111053770 A CN 111053770A CN 202010029483 A CN202010029483 A CN 202010029483A CN 111053770 A CN111053770 A CN 111053770A
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- berberine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses application of berberine as an immunosuppressant used in allogeneic heart transplantation. In a mouse heart transplantation model, the berberine can obviously prolong the survival time of the allogeneic heart transplant by single use, the single use effect is superior to that of a first-line clinical immunosuppressant FK506, the toxic and side effects are greatly reduced, and the berberine can make a great contribution to the improvement of the postoperative life quality of a transplanted patient.
Description
Technical Field
The invention belongs to the technical field of organ transplantation medicines, and particularly relates to application of berberine as an immunosuppressant used in allogeneic heart transplantation.
Background
Organ transplantation remains the most effective treatment for end-organ failure at present, and acute rejection is the most common type of rejection in clinical allogenic organ transplantation. The acute rejection can be divided into cell type acute rejection and humoral type acute rejection according to different action mechanisms, the former is more important, and pathological examination shows infiltration of a large amount of inflammatory cells such as lymphocytes and macrophages in the graft, and neutrophilic granulocytes and eosinophilic granulocytes are also common. Early lymphocytes were predominantly CD4+T cells, late stage CD8 with killer function+T cells are the main and destroy the parenchymal cells of the graft, and if the immunosuppression drug is not used for control, the function of the graft is gradually lost. The immunosuppressive agents commonly used in clinic are widely applied to organ transplantation and disease treatment by blocking the functions of immune cells (T cells, B cells, macrophages and the like) and reducing the strength of immune response of organisms, but most immunosuppressive agents have strong toxic and side effects, so that the clinical application of the immunosuppressive agents is limited. The search for immunosuppressive drugs with low toxic and side effects has been the hot research of immunology.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides application of Berberine (BBR, Berberine, Berberine hydrochloride) as an immunosuppressant used in allogeneic heart transplantation.
The technical scheme of the invention is as follows:
use of berberine as an immunosuppressant for use in allogeneic heart transplantation.
In a preferred embodiment of the present invention, the berberine is used alone as an immunosuppressant for use in allogeneic heart transplantation.
In a preferred embodiment of the present invention, the berberine is administered in a dose of 4.5-5.5 mg/kg.d.
Further preferably, the berberine is used in a dose of 5mg/kg.
The invention has the beneficial effects that:
in a mouse heart transplantation model, the berberine can obviously prolong the survival time of the allogeneic heart transplant by single use, the single use effect is superior to that of a first-line clinical immunosuppressant tacrolimus (FK506), the toxic and side effects are greatly reduced, and the berberine can make a great contribution to the improvement of the postoperative life quality of a transplanted patient.
Drawings
FIG. 1 is a graph showing the results of inhibition of spleen cell proliferation by berberine in example 1 of the present invention.
FIG. 2 is a photograph showing the procedure of heart transplantation in example 2 of the present invention.
FIG. 3 is a graph showing the results of berberine in example 2 of the present invention to prolong survival of allograft.
FIG. 4 is a photograph showing the pathology of the major organs of the receptor in example 2 of the present invention.
FIG. 5 is a flow cytogram showing the effect on subpopulations of recipient spleen lymphocytes in example 2 of the present invention.
FIG. 6 is a graph showing the detection of the transcription level of the relevant inflammatory factor in the graft in example 2 of the present invention.
Fig. 7 is a graph showing detection of antigen-specifically induced T cell proliferation in example 2 of the present invention.
Fig. 8 is a pathological section of each graft group in example 2 of the present invention.
Detailed Description
The technical solution of the present invention will be further illustrated and described below with reference to the accompanying drawings by means of specific embodiments.
Example 1
Extraction of
Spleen cells of C57B/6 mice were stimulated with concanavalin (ConA) to stimulate T cells, and berberine was added at different concentrations to give final system berberine concentrations of 50. mu.M, 100. mu.M and 200. mu.M, NC was a negative control without ConA and berberine, PC was a positive pair without ConA and berberineAnd (4) performing group control. The effect of berberine at different concentrations on the proliferation capacity of T cells in a culture environment is detected by a Brdu method, and the result is shown in figure 1, wherein the inhibition effect of berberine is obvious at 50 mu M, and is further increased at 100 mu M and 200 mu M.
Example 2
The dosage of berberine is groped. 2.5, 5, 7.5 and 15mg/kg.d are respectively selected to carry out intraperitoneal injection on a receptor (a neck ectopic heart transplantation model: a neck ectopic heart transplantation operation is carried out by adopting a cannula method, the simplified steps of the heart transplantation are shown in a technical scheme 2;), and the results show that 2.5mg/kg.d does not prolong the survival time of the graft, the prolonging effects of 5mg/kg.d and 7.5mg/kg.d are consistent, but the 7.5mg/kg.d has higher lethality rate, and the lethality rate of 15mg/kg.d is as high as 100%.
The receptor is female C57BL/6(B6, H-2K) with the body weight of 22 +/-2 g and the age of 8-12 weeksb) And BALB/c (H-2K)d) All purchased from Shanghai Si Laike laboratory animals Co., Ltd, China academy of sciences. All experimental animals were bred in the SPF-level environment of the institute of organ transplantation, university of Xiamen, and animals were anesthetized by intraperitoneal injection of sodium pentobarbital.
In this example, 5mg/kg. d was selected as the study dose, and the mice were treated by intraperitoneal injection of berberine at 5mg/kg per recipient per day from day 0 after heart transplantation (d0) to day 30 after surgery, and the negative control group was injected with physiological saline. After the operation, the neck pulsation condition judges whether the graft survives, and the pulsation stop is judged as complete rejection.
From the above experiments, as shown in FIG. 3, the median survival time of the graft of this example was 22 days, which was much more effective than tacrolimus (FK506, median survival time of 15 days, see Wang Y, Qin Q, Chen J, Kuang X, Xiaj, Xie B et al.Synthesis effects of Isatis tinctoria L.and tacrolimus in the prediction of acetic heart disease in micro. transfer Immunol 2009; 22 (1-2): 5-11. and Onsager DR, Canver CC, Jahania MS, Welter D, Michalski M, Hoffman AM et al.Effect of the graft in micro. transfer of the graft of reaction of the graft of 18. the first embodiment of FIGS. 23, 2. the first embodiment of the second embodiment of the graft of the first embodiment of the second, 2. the first embodiment of FIGS. 11. the first embodiment of FIGS. 23, 2, 3, 2
After 20 days, the patients were subjected to pathological analysis of heart, liver, lung and kidney, and the results are shown in FIG. 4, and no inflammatory cell infiltration and no histological and constitutive lesion were observed.
7 days after transplantation, recipient mouse spleen cells were collected and subjected to flow analysis, and as a result, as shown in FIG. 5, CD4/8 was found in the berberine group alone as compared with the Control group+A significant reduction in T cells occurred.
As shown in FIG. 6, the detection of inflammatory factors in heart transplant by qRT-PCR shows that IFN-gamma transcription level is reduced, which indicates that berberine inhibits Th1 pathway of receptor immune rejection, namely cell-mediated immune rejection.
Verification of berberine inhibiting T cell function: the effect of the drug administration on T cell response in each group was observed by separating spleen T cells from each group of mice as reactive cells on the 7 th day after heart transplantation and performing mixed lymphocyte culture using spleen cells of BALB/C treated with mitomycin C as stimulating cells. Three days later, each group of the responder cells was examined for proliferation (MLR) under stimulation with donor-derived alloantigen using 5-bromodeoxyuridine infiltration. As shown in FIG. 7, T cell responses were reduced in the berberine alone group compared to the control group.
Inflammatory cell infiltration of each group of grafts was observed by HE staining. As shown in fig. 8: 7 days after transplantation, the Control group graft had extensive necrosis of cardiomyocytes, massive infiltration of inflammatory cells, and massive thrombus formation. In the BBR group alone, the grafts showed moderate inflammatory cell infiltration and tissue damage, with less thrombus.
The above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, which is defined by the appended claims.
Claims (4)
1. Use of berberine as an immunosuppressant for use in allogeneic heart transplantation.
2. The use of claim 1, wherein: the berberine alone acts as an immunosuppressant used in allogeneic heart transplantation.
3. Use according to claim 1 or 2, characterized in that: the dosage of berberine is 4.5-5.5mg/kg.
4. The use of claim 4, wherein: the dosage of the berberine is 5mg/kg.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2019113413217 | 2019-12-23 | ||
| CN201911341321 | 2019-12-23 |
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| CN111053770B CN111053770B (en) | 2023-04-14 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6245781B1 (en) * | 1996-02-14 | 2001-06-12 | National Institute Of Immunology | Method for suppressing allogenic immune response or prevention/treatment of graft vs. host disease or graft rejection |
| CN1771944A (en) * | 2005-01-25 | 2006-05-17 | 吴开敏 | Application of high-solubility berberine in preparing medicine |
| CN104490876A (en) * | 2014-11-26 | 2015-04-08 | 中国药科大学 | Application of berberine hydrochloride in preparation of medicine used for preventing and/or treating acute hepatic failure |
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2020
- 2020-01-10 CN CN202010029483.3A patent/CN111053770B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6245781B1 (en) * | 1996-02-14 | 2001-06-12 | National Institute Of Immunology | Method for suppressing allogenic immune response or prevention/treatment of graft vs. host disease or graft rejection |
| CN1771944A (en) * | 2005-01-25 | 2006-05-17 | 吴开敏 | Application of high-solubility berberine in preparing medicine |
| CN104490876A (en) * | 2014-11-26 | 2015-04-08 | 中国药科大学 | Application of berberine hydrochloride in preparation of medicine used for preventing and/or treating acute hepatic failure |
Non-Patent Citations (4)
| Title |
|---|
| MOHSEN IMANSHAHIDI等: "Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine", 《PHYTOTHERAPY RESEARCH》 * |
| 刘幼英等: "黄连素对环孢素抗皮肤移植排斥反应的增强作用", 《中国药师》 * |
| 张振龙等: "盐酸小檗碱对心脏移植受者环孢素A药代动力学影响", 《中国中西医结合杂志》 * |
| 梁竹等: "免疫抑制剂在器官移植中的应用和研究进展", 《实用医药杂志》 * |
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