CN102008474B - Application of nitidine chloride to preparation of medicament for treating autoimmune disease and graft rejection disease - Google Patents
Application of nitidine chloride to preparation of medicament for treating autoimmune disease and graft rejection disease Download PDFInfo
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- CN102008474B CN102008474B CN2010105622493A CN201010562249A CN102008474B CN 102008474 B CN102008474 B CN 102008474B CN 2010105622493 A CN2010105622493 A CN 2010105622493A CN 201010562249 A CN201010562249 A CN 201010562249A CN 102008474 B CN102008474 B CN 102008474B
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Abstract
The invention provides application of nitidine chloride to the preparation of a medicament for resisting autoimmunity disease and graft versus host disease. An experiment shows that the nitidine chloride can inhibit the proliferation of human dendritic cells in vitro, inhibit the human dendritic cells from promoting the proliferation reaction of allogeneic T cells and strengthen the capacity of secreting interleukin 10 of the human dendritic cells. Meanwhile, in an experimental autoimmunity disease cerebrospinal meningitis model, when used in vivo, the nitidine chloride can reduce the average clinical score of a mouse and inhibit the spinal marrow infiltration degree of monocytes and can obviously improve the secretion level of the interleukin 10 in the blood serum of the mouse. In a heart transplantation experiment, when used in vivo, the nitidine chloride can prolong the survival time of the transplanted heart. In a delayed type hypersensitivity reaction model, when used in vivo, the nitidine chloride can reduce the ear swelling degree of the mouse. Both in-vivo and in-vitro results show that the nitidine chloride has a certain effect of resisting the autoimmunity disease and the graft versus host disease. The medicament is a preparation which consists of the nitidine chloride serving as an active ingredient and a pharmaceutical carrier. The medicament can be prepared into an oral preparation, an injection, a suppository or an external preparation and the like.
Description
Technical field
The present invention relates to medicine.Be specifically related to prepare the medicine of new indication, relate in particular to the application of nitidine chloride (Nitidine) in anti-autoimmune disease of preparation and resisting transplant rejection disease medicament.
Background technology
Existing immunosuppressant mainly contains ciclosporin A (CsA), adrenocortical hormone, rapamycin etc., and they have tangible untoward reaction mostly, non-specific etc. like nephrotoxicity and pair cell, and also price is high, increases patient economy burden.How utilizing prevention of Chinese medicine and effective ingredient thereof and treatment autoimmune disease and transplant rejection is one of important directions of modernization of cmm.
Nitidine chloride is a kind of alkaloids substance, derives from rutaceae Radix Zanthoxyli rhizome.The structural formula of nitidine chloride is suc as formula shown in (I):
Formula (I)
Found that at present nitidine chloride has analgesia, antitumor, antifungal, also had pharmacological actions such as heart tonifying, blood pressure lowering.
BMDC (Dendritic cells; DC) be the strongest antigen presenting cell of function in the present known body; Can effectively activate the T cells proliferation and differentiation, regulate the function of inherent immunity responsive cell and adaptive immune response cell, in immunne response, play significant feature.And experimental autoimmune cerebrospinal meningitis (EAE), delayed hypersensitivity and heart transplantation repulsion etc. all are typical autoimmune disease and transplant rejection model.
The inventor studies the regulating and controlling effect of nitidine chloride to BMDC; Pharmacological action to nitidine chloride is studied; Through separation and cultivation to healthy human peripheral blood BMDC (DC), and inquired into nitidine chloride to DC in external evoked differentiation and the sophisticated influence of function.The discovery nitidine chloride can be participated in the inhibitory action to DC proliferation and differentiation and immunostimulatory potency, and can promote to press down the secretion of inflammatory cytokine IL-10.In addition, the inventor has also investigated prevention and the therapeutical effect of nitidine chloride to autoimmune disease and transplant rejection through zoopery.Based on above-mentioned pharmacological action, find that nitidine chloride has stronger effect to it, therefore intend the exploitation nitidine chloride and prepare immunosuppressant.
Summary of the invention
Technical problem to be solved by this invention is to study the regulating and controlling effect of nitidine chloride to BMDC, and design is at the medicine of anti-autoimmune disease and resisting transplant rejection disease.
The invention provides the application of nitidine chloride (Nitidine) in anti-autoimmune disease of preparation and resisting transplant rejection disease medicament.
Under vitro conditions; The present invention secretes the influence experiment of IL-10 (interleukin 10) to human dendritic cell through nitidine chloride; The concentration of the external mononuclearcell conversion of stimulating group BMDC secretion IL-10 is 435 ± 22pg/ml to find to reach the nitidine chloride stimulating group not; 92 ± 14pg/ml has differed significance gap (P＜0.05).Through the influence experiment of nitidine chloride, find to be starkly lower than the ability of the short propagation of handling without nitidine chloride of DC cell through the ability of the short Allogeneic T cell proliferation of the DC (BMDC) of nitidine chloride processing to the T cell transformation.Through MTT (tetramethyl azo azoles is blue) reducing process, the discovery nitidine chloride is external can obviously to suppress the prominent shape cell proliferation of people.In vivo under the condition; Through the preventive effect experiment of nitidine chloride to EAE (experimental autoimmune disease cerebrospinal meningitis); Average clinical score and the spinal cord monocyte infiltration degree of finding nitidine chloride lumbar injection group mice are starkly lower than not injection groups, and in the mice serum level of IL-10 apparently higher than injection groups not.To the experiment of the inhibitory action of mouse heart transplant rejection, the heart survival natural law of finding nitidine chloride lumbar injection group mice is apparently higher than injection groups not through nitidine chloride.Through the inhibition test of nitidine chloride, find that the auricle swelling degree of nitidine chloride lumbar injection group mice is starkly lower than not injection groups to delayed hypersensitivity.With external result, shown that all nitidine chloride can be used for preparing anti-autoimmune disease and resisting transplant rejection disease medicament in the body.
Medicine according to the invention is the preparation of being made up of as active component and pharmaceutical carrier nitidine chloride.Can be made into peroral dosage form, injection, suppository or the exterior-applied formulation etc. of different size according to different purposes.
Pharmaceutical carrier can be lactose, glucose, sucrose, Sorbitol, mannitol, xylitol, red tinea alcohol, maltose alcohol, starch, arabic gum, alginate, gel, calcium phosphate, calcium silicates, cellulose, methylcellulose, microcrystalline Cellulose, water, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, Talcum, magnesium stearate or mineral wet goods.
Described autoimmune disease and transplant rejection disease include but not limited to: chronic lymphocytic thyroiditis; Hyperthyroidism; Insulin-dependent diabetes; Primary biliary cirrhosis; Chronic ulcerative colitis; Pernicious anemia companion atrophic gastritis; Pneumorrhagia nephritis syndrome; Pemphigus; Multiple sclerosis; Acute idiopathic polyneuritis; Systemic lupus erythematosus (sle); Mouth xerophthalmia scheorma syndrome; Scleroderma; Polyarteritis nodosa; The Weganer granulomatosis; Myasthenia gravis; Rheumatoid arthritis; Nephritis; The nephrotic syndrome; Drug eruption; Urticaria; Solar dermatitis; Autoimmune disease such as anaphylactic shock or asthma or autoimmune response are diseases related; And acute, the subacute or chronic allograft rejection property disease that takes place during organ transplantation such as heart, liver, kidney, lung, skin, bone marrow.
The effective dose of nitidine chloride can be according to patient's state or body weight, dosage form, and the variation of route of administration and life cycle and changing can be determined by those of ordinary skill in the art.
The nitidine chloride that the present invention uses can be commercial, also can from the tuber of Radix Zanthoxyli plant, extract, and can also prepare with chemical synthesis.
When medicine according to the invention is used to treat autoimmune disease and transplant rejection property disease, can uses separately also and can unite use with medicine and the Therapeutic Method having ratified clinically to use at present or approval is from now on used.Its method for using includes but not limited to: behind use or the processing cell, cell is adopted and is treated use etc. in the direct body.Use when being used to treat autoimmune disease and transplant rejection property disease; Can be protectiveness or prophylactic treatment and treatment medicable or that palliate a disease, comprise that treatment is in the disease danger or the doubtful patient that disease taken place and ill or be diagnosed as the patient who suffers from disease or medical conditions.
In the present invention; Term " treatment (Treatment or Treat) " refers to protectiveness or prophylactic treatment and treatment medicable or that palliate a disease, comprises that treatment is in the disease danger or the doubtful patient that disease taken place and ill or be diagnosed as the patient who suffers from disease or medical conditions.
The present invention is used to prepare anti-autoimmune disease and resisting transplant rejection disease medicament with nitidine chloride; Can effectively suppress the generation and the development of autoimmune disease; Prolong the time-to-live of graft, reduce untoward reaction simultaneously, and the nitidine chloride source is abundant; Practice thrift medical expense, bigger clinical value is arranged.
Description of drawings
Fig. 1 nitidine chloride promotes human dendritic cell secretion IL-10
* expression: during the t check, p value＜0.05
Fig. 2 nitidine chloride suppresses the inhibitory action of DC to the Allogeneic T cell proliferation
* expression: during the t check, p value＜0.05
Fig. 3 nitidine chloride vitro inhibition people shape cell proliferation of dashing forward
* expression: during the t check, p value＜0.05
* representes: during the t check, and p value＜0.01
Fig. 4 nitidine chloride suppresses the clinical score and the monocytic spinal cord infiltration degree of EAE in mice, but promotes the level of mice serum IL-10
* expression: during the t check, p value＜0.05
Curve representation nitidine chloride lumbar injection reduces the clinical order of severity of EAE
Arrow is indicated monocytic infiltration degree
Fig. 5 nitidine chloride prolongs the life cycle of heart transplantation mice
Curve representation nitidine chloride lumbar injection prolongs the life cycle of heart transplantation mice
The specific embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention, if do not specialize the technological means that used technological means is well known to those skilled in the art.
The nitidine chloride nitidine chloride that the following example uses is commercially available, and available from Shanghai Tongtian Biotechnology Co., Ltd., purity is greater than 95%.Human peripheral is from Changhai hospital blood station.C57BL/6 mice and BALB/C mice are all available from Shanghai Bi Kai biotech firm.Used other reagent all can commercially availablely obtain.
Embodiment 1 human dendritic cell In vitro culture and nitidine chloride are to the processing of BMDC
Vein extracts the peripheral blood 50ml/ people of health adult, and anticoagulant heparin utilizes density to isolate PMNC, and with RPMI1640 (1640 culture medium) suspension cell that contains 10% calf serum, the adjustment cell concentration is 2 * 10
6/ ml adds in 24 well culture plates, the 0.5ml/ hole, and 37 ℃, the 5%CO2 incubator was cultivated 2 hours, made adherent mononuclear cells wherein, and warm serum-free RPMI1640 fine laundering culture plate promptly obtains adherent mononuclear cell to remove attached cell.In culture plate, add contain rhGM-SCF (people recombinate granule mononuclear cell colony stimulating factor) 1000IU/ml, rhIL-4 (people's recombinant interleukin 4) 800IU/ml contain serum RPMI1640; 37 ℃; The 5%CO2 incubator was cultivated 5 days; The adding final concentration is that the nitidine chloride of 1 μ mol/L was handled after 24 hours, and the adding final concentration is that the LPS (bacteria lipopolysaccharide) of 1000ng/ml continues to stimulate 24 hours.
Collect suspension cell, this suspension cell is BMDC.The BMDC of handling through nitidine chloride is nitidine chloride processed group BMDC; The BMDC of handling without the superchlorination nitidine is the untreated fish group BMDC
Embodiment 2 nitidine chlorides are to the influence of human dendritic cell secretion IL-10
The method of pressing embodiment 1 is cultivated nitidine chloride stimulating group and stimulating group BMDC not, and the collection supernatant detects the wherein content of IL-10 with ELISA (elisa) test kit of IL-10.The nitidine chloride stimulating group and not the external mononuclearcell of the stimulating group concentration that transforms BMDC secretion IL-10 be 435 ± 22pg/ml, 92 ± 14pg/ml has differed significance gap (P＜0.05) (see figure 1).
The separation of embodiment 3 T cells and nitidine chloride are to the influence of T cell transformation
Vein extracts the peripheral blood 50ml/ people of health adult, and anticoagulant heparin utilizes density to isolate PMNC; Cultivate 2h through the RPMI1640 serum-free medium; Collect suspension cell, centrifugal after, add the magnetic bead of anti-people CD4+T cell (anti-people CD4 positive T cell); Behind 4 ℃ of labelling 30min, PBS (phosphate buffer) washes one time.After the reuse PBS dilution, positive sorting CD4+T cell.Through the centrifugal 10min of 2000r/min, count and adjust to 2 * 10
6/ ml obtains the CD4+T cell.
Press the method for embodiment 1 and cultivate nitidine chloride processed group and untreated fish group BMDC; Collect the DC that each group is cultivated, act on 45 minutes for 37 ℃ with containing 50 μ g/ml ametycins (MMC), after reuse RPMI1640 culture medium is fully cleaned; Add culture plate at the bottom of 96 hole circles, cell number is 2 * 10
4/ hole adds Allogeneic T cell action effect cell respectively, and DC and T cytosis ratio are DC: T=1: 10; Cultivated altogether 96 hours; Group is as negative control with (PBMC (PMNC)+IL-2 (interleukin II) (30U/ml) half amount change night) every other day, and tritium mixes method and measures proliferation index (SI), and each sample is established three multiple holes; The result is value representation all, tests equal triplicate at every turn.
Stimulate the lymphopoietic ability of Allogeneic T through comparing nitidine chloride processed group and untreated fish group BMDC, find that nitidine chloride processed group BMDC promotes the ability of Allogeneic T cell proliferation to be starkly lower than the ability (see figure 2) that the untreated fish group BMDC promotes the Allogeneic T cell proliferation.
Embodiment 4MTT reducing process detects nitidine chloride and suppresses the prominent shape ability of cell proliferation of people
The method of pressing embodiment 1 obtains adherent mononuclear cell.In 96 well culture plates, add contain rhGM-SCF (people recombinate granule mononuclear cell colony stimulating factor) 1000IU/ml, rhIL-4 (people's recombinant interleukin 4) 800IU/ml contain serum RPMI1640 culture medium, add nitidine chloride simultaneously, make its final concentration be respectively 0,0.25,0.5,1,2 μ mol/L; 37 ℃; The 5%CO2 incubator was cultivated 5 days, added the MTT reagent of 5mg/ml, cultivated after 4 hours; After centrifuge is centrifugal; Supernatant is abandoned in suction, adds DMSO (dimethyl sulfoxide) cell lysis of 100 μ l, reads the light absorption value at 570nm place on the ELIASA.And calculate the vitro inhibition effect of nitidine chloride to the prominent shape cell proliferation of people, find that nitidine chloride can suppress the prominent shape cell proliferation (see figure 3) of people by the Concentraton gradient dependency.
Embodiment 5 nitidine chlorides are to the preventive effect of EAE
EAE is the classical animal model of human multiple sclerosis (MS).Induce generation by mouse subcutaneous injection neurospongium oligochitosan protein polypeptide (MOG35-55).Abductive approach is: the MOG35-55 polypeptide lyophilized powder is dissolved among the PBS, and being made into final concentration is 3mg/ml.Bacillus calmette-guerin vaccine added (the bacillus calmette-guerin vaccine final concentration is 10mg/ml) is prepared into complete freund adjuvant in the incomplete freund adjuvant.The MOG35-55 polypeptide solution is mixed with isopyknic complete freund adjuvant, lash to the Water-In-Oil state, process the antigen Emulsion of inducing EAE with syringe.Each organizes mice respectively at back subcutaneous multi-point injection corresponding antigens Emulsion, and every injected in mice dosage is 200 μ l (about 300
μ g/ MOG35-55 polypeptide).Immunity was designated as the 0th day the same day, gave respectively to organize mouse peritoneal injection 400ng/ pertussis toxin, PT (PTX) in the 0th day and the 2nd day.The EAE standards of grading are international clinical score standard: 0 minute: asymptomatic; 1 minute: afterbody was unable; 2 minutes: a rear flank lower extremity paralysis; 3 minutes: lower extremity paralysis behind the bilateral; 4 minutes: acroparalysis before the lower extremity paralysis companion behind the bilateral; 5 minutes: moribund condition or morbidity back were dead.
C57BL/6 mice (a kind of mouse species), female, in age in 6-8 week, the 10mg/kgd nitidine chloride is injected after 7 days continuously in the abdominal cavity, induces the EAE morbidity.And after inducing 10 days, observe the average clinical score of mice, and measure the level of IL-10 in the mice serum.And do the bone marrow section, after the HE dyeing, observe the monocyte infiltration situation.Find that average clinical score and the spinal cord monocyte infiltration degree of nitidine chloride lumbar injection group mice are starkly lower than not injection groups, and in the nitidine chloride injection groups mice serum level of IL-10 apparently higher than injection groups (see figure 4) not.
Embodiment 6 nitidine chlorides are to the inhibitory action of mouse heart transplant rejection
With BALB/C mice (a kind of mouse species) is donor, is fixed in operating-table after the anesthesia of 0.1% pentobarbital sodium, behind the skin degerming, opens abdomen and exposes the abdominal cavity, and the heparin-saline by injecting the 50U/ml of 1ml in the postcava anaesthetizes sb. generally.Cut heart together with the front wall, place the Ru Suanlingeshi mixture of ice and water.Treat that heart stops to jump aorta posterior, pulmonary artery, pulmonary vein and superior and inferior vena cava fully, supply heart finishing to accomplish.
With the C57BL/6 mice, female, in age in 6-8 week, the 10mg/kgd nitidine chloride is injected after 7 days continuously in the abdominal cavity, as the receptor of heart transplant operation, is fixed in after the anesthesia on the operating-table, adopts the stringer otch, go up to mandibular bone down to clavicle, expose the left side cervical region.Excision lower jaw body of gland and part are excised sternocleidomastoid, free right side external jugular vein, and after the ligation, proximal part seals blood flow with vascular clamp, and nearly ligation section is cut off, the heparin-saline flushing of 50U/ml.Free as far as possible internal carotid artery, after the distal end ligation, proximal part is used the vascular clamp blocking blood flow, and in the proximal part cut-out of ligation point, the heparin-saline of 50U/ml washes, and the blood vessel bonder of 0.4mm is installed, and fixes with the suture of 11-0.The confession heart left pulmonary artery that installs the blood vessel bonder is inserted in receptor right side external jugular vein, and the suture of 10-0 is fixed, and receptor's the internal carotid artery that installs the blood vessel bonder is inserted in the aorta that supplies the heart, and the suture of 10-0 is fixed.In the rapid rewarming of hot salt brine, open blood flow.Behind the open blood flow about 30 seconds to 1 minute, heart began fibrillation, and recovers sinus rhythm rapidly.The suture of 7-0 is sewed up and is closed otch.
Postoperative direct touch heart transplant every day once judges whether to stop fighting, if stop fighting, and record heart survival natural law.The result finds, the heart survival natural law of nitidine chloride lumbar injection group mice is apparently higher than injection groups (see figure 5) not.
Embodiment 7 nitidine chlorides are to delayed hypersensitivity
The continuous lumbar injection 10mg/kgd of mice nitidine chloride is after 7 days.Acetone and Oleum Sesami are pressed 1: 4 volume mixing, and with 2,4-dinitrofluorobenzene (DNFB) is dissolved in wherein, processes 2 of 1% concentration, 4-dinitrofluorobenzene (DNFB) solution, i.e. 1%DNFB.Administration the 8th day, with mice stomach wall QUMAO, and with 1%DNFB in depilation place sensitization, every Mus 50 μ L smoothen, reuse is strengthened sensitization 1 time with method behind the 24h.Mouse sensitization continued lumbar injection 10mg/kgd nitidine chloride was evenly smeared auris dextra with 1%DNFB 10 μ L and is attacked after 5 days.Mice is put to death in cervical vertebra dislocation behind the 24h, and the left and right auricle of 8mm is weighed towards the cut-off footpath, with the difference of two auricle weight as swelling degree (mg).The result finds that the auricle swelling degree of nitidine chloride lumbar injection group mice is starkly lower than not injection groups.
Claims (7)
1. the application of nitidine chloride in the anti-autoimmune disease disease medicament of preparation.
2. nitidine chloride repels the application in the disease medicament in the anti-heart transplantation of preparation.
3. application according to claim 1 and 2 is characterized in that, the preparation that said medicine is made up of as active component and pharmaceutical carrier nitidine chloride.
4. application according to claim 3 is characterized in that, said medicine is peroral dosage form, injection, suppository or exterior-applied formulation.
5. application according to claim 3; It is characterized in that said pharmaceutical carrier is lactose, glucose, sucrose, Sorbitol, mannitol, xylitol, red tinea alcohol, maltose alcohol, starch, arabic gum, alginate, gel, calcium phosphate, calcium silicates, cellulose, water, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, Talcum, magnesium stearate or mineral oil.
6. application according to claim 5 is characterized in that, said cellulose is methylcellulose or microcrystalline Cellulose.
7. application according to claim 1; It is characterized in that said medicine is the medicine of treatment chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, primary biliary cirrhosis, chronic ulcerative colitis, pernicious anemia companion atrophic gastritis, pneumorrhagia nephritis syndrome, multiple sclerosis, systemic lupus erythematosus (sle), myasthenia gravis, rheumatoid arthritis, nephritis, the nephrotic syndrome, drug eruption, urticaria, anaphylactic shock or asthma.
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| CN103316025B (en) * | 2013-06-08 | 2015-03-11 | 中国人民解放军第二军医大学 | Application of p-hydroxyl acetophenone glycosidase to medicine for autoimmunity disease and transplant rejection disease |
| CN104800216B (en) * | 2015-01-26 | 2019-03-22 | 东北师范大学 | The application of Nitidine Chloride and its derivative in preparation prevention and treatment dermatosis treating medicine |
| CN106389432B (en) * | 2016-04-07 | 2019-06-07 | 刘倩 | Nitidine Chloride is preparing the application in anti-osteoporosis and bone loss diseases |
| CN107648233A (en) * | 2017-11-16 | 2018-02-02 | 上海壹志医药科技有限公司 | The medicinal usage of dihydronitidine |
| CN115160448B (en) * | 2022-07-07 | 2023-08-25 | 广州梵之容化妆品有限公司 | Graded polysaccharide and application thereof in whitening and preparing whitening cosmetics |
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| CN101564393A (en) * | 2008-04-25 | 2009-10-28 | 中国科学院化学研究所 | Novel application of nitidine |
| CN101708314A (en) * | 2009-12-10 | 2010-05-19 | 中国人民解放军第二军医大学 | Chinese medicinal essential oil injection solution, injection and preparation method thereof |
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| CN1712051A (en) * | 2005-06-08 | 2005-12-28 | 叶耀良 | Quality control of Gongyanping preparation |
| CN101564393A (en) * | 2008-04-25 | 2009-10-28 | 中国科学院化学研究所 | Novel application of nitidine |
| CN101708314A (en) * | 2009-12-10 | 2010-05-19 | 中国人民解放军第二军医大学 | Chinese medicinal essential oil injection solution, injection and preparation method thereof |
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