CN110101698A - The application of jateorrhizine and pharmaceutical preparation - Google Patents
The application of jateorrhizine and pharmaceutical preparation Download PDFInfo
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- CN110101698A CN110101698A CN201910482193.1A CN201910482193A CN110101698A CN 110101698 A CN110101698 A CN 110101698A CN 201910482193 A CN201910482193 A CN 201910482193A CN 110101698 A CN110101698 A CN 110101698A
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- jateorrhizine
- pharmaceutical preparation
- treatment
- apoptotic cell
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
- A61K36/718—Coptis (goldthread)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Public Health (AREA)
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- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
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- Biotechnology (AREA)
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- Alternative & Traditional Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to pharmaceutical fields, in particular to a kind of application of jateorrhizine and pharmaceutical preparation.The pharmaceutical preparation includes the jateorrhizine and pharmaceutically acceptable carrier of therapeutically effective amount.Jateorrhizine can be activated effectively and promote the ability of macrophage phagocytosis apoptotic cell, then accelerate the removing of apoptotic cell, meanwhile jateorrhizine can also effectively inhibit the activity of increased MPO and the secretion of IL-6 during enteritis, then play the role for the treatment of colitis.
Description
Technical field
The present invention relates to pharmaceutical fields, in particular to a kind of application of jateorrhizine and pharmaceutical preparation.
Background technique
Currently, in nature, growth and development, tissue repair of any animals and plants etc. are directed to the new life of cell, wither
Die, and if the cell of apoptosis cannot be removed in time, be easy to cause the generation of various diseases.In inflammation disease such as inflammation
Property enteropathy during, the decline of apoptotic cell clearance ability can aggravate the state of an illness, therefore the removing for enhancing apoptotic cell is treatment inflammation
One new strategy of property disease.
Summary of the invention
The present invention provides a kind of application of jateorrhizine, it can activate and promote macrophage phagocytosis apoptotic cell
Ability then can quickly remove apoptotic cell, and can be applied to the treatment of inflammation, expand its use scope.
The present invention also provides a kind of pharmaceutical preparations, it is intended to improve the elimination effect for promoting apoptotic cell, and can treat
Inflammation.
The present invention is implemented as follows:
The present invention provides a kind of jateorrhizines as apoptotic cell clearance promotor, in preparation prevention and/or treatment
Colitis damages the application in the drug of related disease.
The present invention provides a kind of pharmaceutical preparations comprising the jateorrhizine of therapeutically effective amount and pharmaceutically acceptable
Carrier.
The beneficial effects of the present invention are: the application, which is provided, can effectively activate by jateorrhizine and promote macrophage
The ability of apoptotic cell is swallowed, the removing of apoptotic cell is then accelerated, meanwhile, jateorrhizine can also effectively inhibit enteritis dynamic
The activity of MPO in object model, reduces the secretion of IL-6, then plays the role for the treatment of colitis.
Detailed description of the invention
It, below will be to use required in embodiment in order to illustrate more clearly of the technical solution of embodiment of the present invention
Attached drawing be briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not to be seen as
It is the restriction to range, it for those of ordinary skill in the art, without creative efforts, can be with root
Other relevant attached drawings are obtained according to these attached drawings.
Fig. 1 is that the COL using various concentration that experimental example 1 of the present invention provides is handled BMDM12 hours, and then detection is remaining
The fluorogram of apoptotic cell；
Fig. 2 be after the apoptotic cell with CMFDA label that experimental example 1 of the present invention provides is handled 24 hours comparison BMDM with
The representative fluorescent image of BMDM after COL processing；
Fig. 3 is that the apoptosis for the CMFDA label for swallowing different number after 24 hours at every group that experimental example 1 of the present invention provides is thin
The distribution map of the macrophage of born of the same parents；
Fig. 4 is that the apoptotic cell for the CMFDA label that experimental example 1 of the present invention provides enters BMDM or COL by cell phagocytosis
The presentation graphics of the delay imaging of BMDM after processing；
Fig. 5 be experimental example 1 of the present invention provide with the apoptotic cell processing BMDM or COL of pHrodo label, treated
BMDM, representative fluorescent image in different time points；
Fig. 6 is the pHrodo of different time points apoptotic cell in the BMDM for the different COL processing that experimental example 1 of the present invention provides
The comparison figure of intensity；
Fig. 7 is the every daily weight record figure of separate groups of mice that experimental example 2 of the present invention provides；
Fig. 8 is the daily disease activity index figure of different groups (n=8-10) after the DSS treatment that experimental example 2 of the present invention provides；
Fig. 9 is the Midcolic presentation graphics of difference group that experimental example 2 of the present invention provides；
Figure 10 is the colon lengths schematic diagram for the different groups that experimental example 2 of the present invention provides；
Figure 11 is the comparison figure for the different group spleen weight indexes that experimental example 2 of the present invention provides；
Figure 12 is myeloperoxidase (MPO) activity in the colon lysate for the different groups that experimental example 2 of the present invention provides
Compare figure；
Figure 13 is the section of colon result schematic diagram for the HE dyeing that experimental example 2 of the present invention provides；
Figure 14 is the histological score figure according to HE coloration result that experimental example 2 of the present invention provides；
Figure 15 is IL-6 assay detection figure in the colon protein lysate of the offer of experimental example 2 of the present invention；
Figure 16 is the presentation graphics of TUNEL positive cell on the colon for the different groups that experimental example 2 of the present invention provides；
Figure 17 is the quantitative figure of TUNEL positive cell in each visual field of the offer of experimental example 2 of the present invention；
Figure 18 is the testing result figure for the jamaicin that experimental example 3 of the present invention provides.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
A kind of application of jateorrhizine is provided to the embodiment of the present invention below and pharmaceutical preparation illustrates.
Firstly, jateorrhizine (Columbamine) provided by the invention, is denoted as COL, structural formula is as follows hereinafter:
Jateorrhizine have isoquinoline structure, can from Berberidaceae plant-Japan barberry, menispermaceous plants-herba fibraureae recisae,
It extracts and obtains in the plants such as bloodroot-Bock Nimu.
Further, jateorrhizine is the compound extracted from the coptis in the present invention.Extracting method is existing
Conventional extracting method, or the sold compound monomer of Chengdu Man Site Biotechnology Co., Ltd is directlyed adopt, it numbers
A0935。
Further, the embodiment of the present invention also provides a kind of jateorrhizine answering as apoptotic cell clearance promotor
With, it is preferable that apoptotic cell clearance is macrophage-mediated apoptotic cell clearance.It is highly preferred that macrophage is that BMDM is thin
Born of the same parents.
Further, the embodiment of the present invention also provides a kind of jateorrhizine in preparation prevention and/or treatment colitis damage
Hurt the application in the drug of related disease.And intestinal inflammation colitis is promoted with activity of myeloperoxidase and/or interleukin-6
Secretion increase it is related, therefore wherein important indicator include activity of myeloperoxidase promoted and/or interleukin-6 secretion increase.
Further, the embodiment of the present invention also provides a kind of for preventing and/or treating colitis damage related disease
Pharmaceutical preparation comprising the jateorrhizine and pharmaceutically acceptable carrier of therapeutically effective amount.
The therapeutically effective amount of the jateorrhizine is 10M~50M, preferably 20M on cell model.
The therapeutically effective amount of the jateorrhizine is 10-15mg/kg weight, preferably 10mg/kg body on animal model
Weight, and the animal model is the colitis model that mouse is established.
A kind of chemical activator provided by the invention and its application are specifically described below in conjunction with specific embodiment.
Embodiment
The present embodiment provides a kind of pharmaceutical preparation, active constituent is only jateorrhizine.The jateorrhizine is from the coptis
Middle extraction obtains.
Experimental example 1
The phagocytosis of macrophage is detected using the chemical activator of embodiment 1
(1) by the chemical activator of embodiment 1 match be dissolved in be made in culture medium various concentration medicament (respectively 1 μM, 5 μ
M, 10 μM, 20 μM), then 12 hours the chemicals treatment BMDM of above-mentioned various concentration, then detect the fluorescence of remaining apoptotic cell
(excitation: 492, transmitting: 519), obtain compare fluorogram, wherein n=6, average value ± S.D, i.e. Fig. 1.
As can be seen from FIG. 1, removing of the BMDM to apoptotic cell is enhanced after being handled with (1 μM -20 μM) of COL, and at dense
Spend gradient dependence.
(2) by the chemical activator of embodiment 1 match be dissolved in be made in culture medium various concentration medicament (respectively 1 μM, 5 μ
M, 10 μM, 20 μM), then 24 hours the chemicals treatment BMDM of above-mentioned various concentration, the apoptosis that CMFDA label is then added are thin
Born of the same parents are handled 24 hours, then detect fluorescent image, and it is thin in macrophage to detect the apoptotic cell (CMFDA label) swallowed for 24 hours
The distribution of born of the same parents, coloured moiety is apoptotic cell in-Fig. 3 referring to fig. 2, Fig. 2.
According to fig. 2 with Fig. 3 it is found that Fig. 2-3 is shown, the ability of COL treated BMDM phagocytosis apoptotic cell is significantly increased,
Containing BMDM quantity more than 15 apoptotic cells, quantity is obviously increased in COL processing group.
(3) apoptotic cell of CMFDA label is added to the BMDM of vesica normal BMDM or COL (concentration is 20 μM) processing
In, and the presentation graphics of delay imaging are formed, testing result is referring to fig. 4, wherein lesser circle bright spot is CMFDA dyeing
Apoptotic cell, other luminous positions are the BMDM for having contaminated Lysotracker, and scale bar, 100 μm.
As can be seen from FIG. 4, as shown in Figure 4, it is shown by the observation of realtime graphic, COL treated BMDM is compared to control
Group BMDM, can rapidly swallow a large amount of apoptotic cell.
(4) with concentration be 10 or 50 μM chemicals treatment BMDM 24 hours, then with pHrodo label apoptotic cell at
BMDM is managed, and records its representative fluorescent image in different time points, meanwhile, compare the pHrodo of different time points apoptotic cell
Intensity, testing result is referring to Fig. 5-Fig. 6, Fig. 5 medium scale, and 100 μm, average value ± S.D in Fig. 6.
Fig. 5-Fig. 6 display, after apoptotic cell is handled 2 hours, the pHrodo intensity continuous in BMDM increases.Obviously, COL
The BMDM of processing shows more apoptotic cells, emits with strong pHrodo intensity.
It should be noted that being analyzed by unidirectional ANOVA in Fig. 1 and Fig. 6 to analyze data.* P < 0.05, * * P <
0.001, ##P < 0.001.
Experimental example 2
Mouse experiment is carried out using the chemical activator of embodiment 1
Experimental method: to 8 weeks mouse (weight about 20g) apply 3%DSS 6 days, then with normal drinking water processing 5 days with
Inducing colitis damage.Using the method for intraperitoneal injection COL.COL injection concentration be 10mg/kg weight and 15mg/kg weight,
Injection is primary daily in whole experiment process.
The then variation of record mice weights daily, and the length of the colon of mouse is detected upon completion of the treatment,
It carries out dyeing detection to colon simultaneously to weigh the weight of spleen, to the myeloperoxidase in colon protein lysates
(MPO) activity is detected.By analyzing the daily weight loss degree of mouse, hematochezia situation and diarrhea state synthesis go out
The daily disease activity index (DAI) of mouse.
Testing result is referring to Fig. 7-15, and wherein Fig. 7 is daily for the mouse of groups (n=8-10) different after DSS or administered vehicle
Weight record, average value ± S.E.M.Fig. 8 is the daily disease activity index (DAI) of different groups (n=8-10) after DSS treatment,
Average value ± S.D；Fig. 9 is different groups of Midcolic presentation graphics.Figure 10 is to measure different groups of colon lengths, average value ±
S.D.Figure 11 is the comparison of different groups of spleen weight indexes, average value ± S.D.Figure 12 is the knot from different groups (n=8-10)
Myeloperoxidase (MPO) activity in intestines lysate, average value ± S.D.Figure 13 is the colon that the representative HE of each group is dyed
Slice, it is red: eosin, violet: hematoxylin, scale bar: 200 μm.Figure 14 is the histological score (8- according to HE coloration result
10), average value ± S.D.Figure 15 is IL-6 assay in colon protein lysate.Figure 16 is on different groups of colon
The presentation graphics of TUNEL positive cell, (left side bright spot part is TUNEL positive staining), scale bar, 200 μm.Figure 17 is every
TUNEL positive cell quantifies in a visual field, average value ± S.D.In figures 7 and 8, analysis number is analyzed by two-way ANOVA
According to.In D, E, F, H and J, analyzed by unidirectional ANOVA to analyze data.* P < 0.0001 P < 0.05, * * P < 0.001, * * *.
According to Fig. 7-Figure 17 it is found that COL processing significantly reduces the UC lesion of DSS induction, this can pass through weight loss
Mitigate (Fig. 7), lower DAI (Fig. 8) and longer colon lengths prove (Fig. 9, Figure 10).Figure 11 shows that COL is also alleviated
The spleen enlargement of DSS induction.Figure 12 shows that COL processing can inhibit MPO active.Figure 13 and 14 show the tissue of section of colon
Pathological analysis shows that COL treatment group shows that more complete colonic epithelium structure, less inflammatory cell infiltration and entirety are slow
Solve histological score.Figure 15 shows that COL can reduce the secretion of IL-6 in the colon protein lysate of DSS induction.Figure 16 and 17 is aobvious
Show, rarer apoptotic cell accumulation in the mouse Colon tissue of COL processing.COL is further demonstrated, it is a kind of that apoptosis can be promoted thin
The compound that born of the same parents remove alleviates the colitis damage in the mouse UC model of DSS induction.
Experimental example 3
The measure of merit of phagocyte is carried out using jamaicin, testing result is referring to Figure 18.
It is the results show that homologue of the jamaicin as jateorrhizine, and not only no macrophage that increases is to apoptosis
The phagocytosis effect of cell, however reducing it swallows effect.
In conclusion chemical activator provided by the present application can effectively be activated by jateorrhizine and to promote macrophage thin
Endocytosis bites the ability of apoptotic cell, then accelerates the removing of apoptotic cell, meanwhile, jateorrhizine can also effectively inhibit enteritis
The activity of MPO in animal model, reduces the secretion of IL-6, then plays the role for the treatment of colitis.
The foregoing is merely the preferred embodiment of the present invention, are not intended to restrict the invention, for this field
For technical staff, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any
Modification, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. application of the jateorrhizine as apoptotic cell clearance promotor.
2. application according to claim 1, which is characterized in that the apoptotic cell clearance is macrophage-mediated apoptosis
Cell clearance.
3. application according to claim 2, which is characterized in that the macrophage is BMDM cell.
4. application of the jateorrhizine in the drug of preparation prevention and/or treatment colitis damage related disease.
5. application according to claim 4, which is characterized in that colitis be by activity of myeloperoxidase promoted and/
Or interleukin-6 secretion increase caused by inflammation.
6. a kind of for preventing and/or treating the pharmaceutical preparation of colitis damage related disease, which is characterized in that have including treatment
The jateorrhizine and pharmaceutically acceptable carrier of effect amount.
7. pharmaceutical preparation according to claim 6, which is characterized in that the treatment of the jateorrhizine on cell model
Effective quantity is 10 μM~50 μM.
8. pharmaceutical preparation according to claim 7, which is characterized in that the treatment of the jateorrhizine on cell model
Effective quantity is 20 μM.
9. pharmaceutical preparation according to claim 6, which is characterized in that there is the treatment of the jateorrhizine on animal model
Effect amount is 10-15mg/kg weight, preferably 10mg/kg weight, and the animal model is the colitis model that mouse is established.
10. pharmaceutical preparation according to claim 6, which is characterized in that the jateorrhizine is extracted from the coptis
The compound arrived.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910482193.1A CN110101698A (en) | 2019-06-04 | 2019-06-04 | The application of jateorrhizine and pharmaceutical preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910482193.1A CN110101698A (en) | 2019-06-04 | 2019-06-04 | The application of jateorrhizine and pharmaceutical preparation |
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| Publication Number | Publication Date |
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| CN110101698A true CN110101698A (en) | 2019-08-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201910482193.1A Pending CN110101698A (en) | 2019-06-04 | 2019-06-04 | The application of jateorrhizine and pharmaceutical preparation |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101155753B1 (en) * | 2010-09-29 | 2012-06-12 | 동아제약주식회사 | Pharmaceutical composition including quinoline derivative compound |
| CN108926561A (en) * | 2018-05-15 | 2018-12-04 | 吴正治 | Application of the jateorrhizine in prevention and treatment dementia or improvement memory class product |
| US20190105365A1 (en) * | 2013-04-23 | 2019-04-11 | University-Industry Cooperation Group Of Kyung Hee University | Composition for preventing, relieving or treating colitis, containing complex extracts |
-
2019
- 2019-06-04 CN CN201910482193.1A patent/CN110101698A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101155753B1 (en) * | 2010-09-29 | 2012-06-12 | 동아제약주식회사 | Pharmaceutical composition including quinoline derivative compound |
| US20190105365A1 (en) * | 2013-04-23 | 2019-04-11 | University-Industry Cooperation Group Of Kyung Hee University | Composition for preventing, relieving or treating colitis, containing complex extracts |
| CN108926561A (en) * | 2018-05-15 | 2018-12-04 | 吴正治 | Application of the jateorrhizine in prevention and treatment dementia or improvement memory class product |
Non-Patent Citations (3)
| Title |
|---|
| SHU DE-ZHONG等: "Effect of berberine chloriinduced by dextran sulfate sodiumde on expermi entalmurine colitis", 《JOURNAL OF CHINESE PHARMACEUTICAL SCIENCES》 * |
| 无: "无", 《KR101155753B1德温特摘要》 * |
| 李梦等: "UPLC-Q-TOFMS /MS 联用技术分析大鼠肠道微生物体外对小檗碱的代谢产物", 《信阳师范学院学报:自然科学版》 * |
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Application publication date: 20190809 |