CN107961234A - Ramosissimarin is preparing the application of drugs for rheumatoid arthritis - Google Patents
Ramosissimarin is preparing the application of drugs for rheumatoid arthritis Download PDFInfo
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- CN107961234A CN107961234A CN201810043917.8A CN201810043917A CN107961234A CN 107961234 A CN107961234 A CN 107961234A CN 201810043917 A CN201810043917 A CN 201810043917A CN 107961234 A CN107961234 A CN 107961234A
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- rheumatoid arthritis
- ramosissimarin
- synoviocytes
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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Abstract
The present invention relates to a kind of compound R amosissimarin to prepare the application of drugs for rheumatoid arthritis.First passage pharmacological evaluation of the present invention proves that ramosissimarin has the significant activity for suppressing synoviocytes in rheumatoid arthritis propagation and induction synoviocytes in rheumatoid arthritis apoptosis, available for the medicine for preparing prevention and/or treatment rheumatoid arthritis, therefore it has higher clinical value and development prospect.The invention discloses a kind of purposes of compound ramosissimarin in resisting rheumatoid arthritis medicine is prepared.Shown in formula I, it is isolated from Tamarix ramosissima branch to the structural formula of Ramosissimarin.Present invention firstly discovers that ramosissimarin can substantially suppress the propagation of synoviocytes in rheumatoid arthritis, the apoptosis of synoviocytes in rheumatoid arthritis is induced.
Description
Technical field
The present invention relates to a kind of compound R amosissimarin to prepare the application of drugs for rheumatoid arthritis.
Background technology
Rheumatoid arthritis (rheumatoid arthritis, RA) is a kind of chronic systemic based on arthropathy
Property autoimmune disease, at present its pathogenesis remain unknown, clinic think the morbidity of RA mainly due to patient itself
Immune dysfunction, causes allergic reaction, anti-inflammatory cells is gone bad denaturation, be deposited on joint part and make joint tissue deformity,
Disable.According to investigations, the incidence of RA is about 1-2% in world wide, and China RA patient populations fall ill more than 4,000,000
Rate is still in rising trend.
At present, mainly using non-steroidal anti-inflammatory drugs (diclofenac sodium, aspirin etc.) and it is immunized for rheumatoid arthritis
Inhibitor (Ismipur etc.) is treated, but these medicines are there are obvious adverse reaction, as the former damages intestines and stomach
Mucous membrane causes peptic ulcer, and the latter's selective action is poor, is easy to induce infection etc..Therefore, safe and effective control is researched and developed
It is a current urgent task to treat rheumatoid arthritis medicine.
In recent years, domestic and foreign scholars have made extensive and intensive studies in terms of autonomic drug treats RA, find many days
Right medicine such as tripterygium glycosides, total glucoside, malicious rattan alkali etc. have preferable RA therapeutic effects.Therefore, developed from autonomic drug
Go out safe and efficient RA medicines to have broad prospects.
The content of the invention
The object of the present invention is to provide a kind of compound R amosissimarin to prepare drugs for rheumatoid arthritis
Application, it, which has, significant suppresses synoviocytes in rheumatoid arthritis propagation and induction synoviocytes in rheumatoid arthritis apoptosis
Activity, can be used in prepare prevention and/or treatment rheumatoid arthritis medicine.
Applications of the Ramosissimarin in prevention or drugs for rheumatoid arthritis is prepared, wherein compound
The structural formula of Ramosissimarin is as follows：
Ramosissimarin is preparing the application in suppressing synoviocytes in rheumatoid arthritis hyperproliferation agent, wherein chemical combination
The structural formula of thing Ramosissimarin is as follows：
First passage pharmacological evaluation of the present invention proves that there is ramosissimarin the significant rheumatoid arthritis that suppresses to slide
Theca cell is bred and the activity of induction synoviocytes in rheumatoid arthritis apoptosis, available for preparation prevention and/or treatment rheumatoid
Arthritic medicine, therefore it has higher clinical value and development prospect.
The invention discloses a kind of use of compound ramosissimarin in resisting rheumatoid arthritis medicine is prepared
On the way.Shown in formula I, it is isolated from Tamarix ramosissima branch to the structural formula of Ramosissimarin.The present invention is first
It was found that ramosissimarin can substantially suppress the propagation of synoviocytes in rheumatoid arthritis, rheumatoid arthritis synovial membrane is induced
The apoptosis of cell.Therefore, which can be used for the medicine for preparing prevention and/or treatment rheumatoid arthritis, have higher
Clinical value and development prospect.
Brief description of the drawings
Fig. 1 is that the ramosissimarin of various concentrations in the embodiment of the present invention 1 increases synoviocytes in rheumatoid arthritis
Grow the statistical results chart of inhibitory action；
Fig. 2 is that the ramosissimarin of various concentrations in the embodiment of the present invention 2 withers synoviocytes in rheumatoid arthritis
Die the statistical results chart of facilitation.
Embodiment
The present invention provides a kind of compound ramosissimarin suppress synoviocytes in rheumatoid arthritis propagation with
And the application in prevention and/or treatment rheumatoid arthritis.
Compound ramosissimarin structural formulas according to the present invention are shown in formula I：
Above-claimed cpd be it is isolated from Tamarix ramosissima (Tamarix ramosissima Ledeb.) (ginger into
Handsome red buildings resisting rheumatoid disease arthritis chemical constitution study [D] Ningxia Medical University, 2016).Tamarix ramosissima is excellent windproof
Sand-fixation plant and the fine tree species of saline-alkali soil forestation, aboundresources extensive in NORTHWEST CHINA Area distribution.
The application of ramosissimarin provided by the present invention includes two aspects：1) preparing prevention for it and/or controlling
Treat the application in the product of rheumatoid arthritis；2) for its prepare suppress synoviocytes in rheumatoid arthritis propagation product in
Application.
It is in particular in that ramosissimarin can substantially suppress the propagation of synoviocytes in rheumatoid arthritis, induces class
The apoptosis of rheumathritis synovial cell, available for the medicine for preparing prevention and/or treatment rheumatoid arthritis.
In addition, the following products prepared using ramosissimarin as active ingredient：1) prevent and/or treat rheumatoid to close
Save scorching product；2) suppress the product of synoviocytes in rheumatoid arthritis propagation, fall within protection scope of the present invention.
Prevent and/or treat the medicine of rheumatoid arthritis in the present invention and suppress synoviocytes in rheumatoid arthritis and increase
The medicine grown can be imported by the method injecting, spray, permeate, absorb, physically or chemically mediate body for example muscle, it is intracutaneous,
Subcutaneously, vein, mucosal tissue；Or imported body after other material mixings or parcel.
When needs, one or more pharmaceutically acceptable carriers can also be added in said medicine.The load
Diluent of the body including pharmaceutical field routine, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surface
Activating agent, absorption carrier, lubricant etc..
A variety of shapes such as parenteral solution, tablet, pulvis, granule, capsule, oral liquid, paste, creme can be made in said medicine
Formula.The medicine of any of the above formulation can be prepared according to the conventional method of pharmaceutical field.
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1：
The inhibitory action that Ramosissimarin breeds synoviocytes in rheumatoid arthritis
Cell：Human rheumatoid arthritis synovial cell (RA-FLS)；
Medicine：ramosissimarin；
Method：The recovery of 1.RA-FLS
It is rapid from liquid nitrogen filling to take out RA-FLS cryopreservation tubes, put the thermostat water bath that temperature is 37 DEG C into, it is continual to shake
Shake, accelerate cell and thaw.After thawing completely, the RA-FLS suspension in cryopreservation tube is moved to pipettor in super-clean bench
In 10mL sterile centrifugation tubes, 5min, rotating speed 1000r/min are centrifuged.Supernatant is outwelled, 5mL complete culture solutions is added, uses pipettor
It is lasting to blow and beat to uniform cell suspension, RA-FLS is inoculated in 25mL Tissue Culture Flasks, is put into cell incubator and cultivates,
Incubator condition setting is 37 DEG C of temperature, CO2Concentration 5%.The growing state of RA-FLS is observed after 24h under the microscope, works as hair
When existing cell attachment, triangular in shape and irregular fusiformis, show that cell growth status is good.
The passage of 2.RA-FLS
Observe under the microscope, when RA-FLS adherent growths are to account for whole Tissue Culture Flask bottom 80% or so, i.e.,
It can carry out cell passage.The original fluid in blake bottle is outwelled, is rinsed 2 times with PBS, it is therefore an objective to original fluid is cleaned, is avoided
Influence cell dissociation；Add 0.25% tryptic digestive juice to be digested, and situation digested in micro- Microscopic observation RA-FLS,
Treat to see that most cells become bowlder and add suitable hyclone (FBS) termination digestion under mirror, then add a certain amount of complete
Full nutrient solution blows and beats blake bottle inner wall with aseptic straw repeatedly in blake bottle, in uniform cell suspension；Use cell counting count board
Cell is counted, after counting, RA-FLS is inoculated in 2 new blake bottles, and adds suitable culture completely
Liquid, is put into cell incubator and cultivates, and incubator condition setting is 37 DEG C of temperature, CO2 concentration 5%, i.e., one mode for passing two passes
It is commissioned to train foster.
3.MTT methods measure cell inhibitory rate
The nutrient solution for taking suitable ramosissimarin to be made into 0.01,0.1,1,5,10 μM respectively with DMEM.Take and be in
The RA-FLS of exponential phase, outwells the original fluid in blake bottle, is rinsed 2 times with PBS, adds 0.25% Trypsin Induced
Liquid is digested, and digests situation in micro- Microscopic observation RA-FLS, treats to see that cell largely becomes bowlder and adds in right amount under mirror
FBS terminate digestion, then add a certain amount of nutrient solution in blake bottle, ceaselessly blown and beaten with aseptic straw in blake bottle
Wall, in uniform cell suspension, is counted with cell counting count board, and it is 1 × 10 to adjust cell concentration with nutrient solution5A/mL, will
RA-FLS is inoculated in 96 hole steril cell culture plates, per 100 μ L of hole, is put into cell incubator and is cultivated, incubator condition is set
It is set to 37 DEG C of temperature, CO2Concentration 5%.Be incubated 24h after, by 96 orifice plates be divided into 6 groups (i.e. blank control group, 0.01,0.1,1,5,
10 μM of medicine groups, every group of 6 multiple holes), the original fluid in hole is sopped up, is separately added into the DMEM of equivalent and the drug containing of various concentrations
Culture medium, is put into cell incubator and intervenes.After intervening 24h and 48h, 20 μ L MTS, 37 DEG C of incubation 1.5h are added in each hole,
Absorbance of each hole at 540nm wavelength is measured with enzyme-linked immunosorbent assay instrument, calculates the inhibiting rate of each group cell.
Calculation formula is as follows：
Cell inhibitory rate/%=(1- blank control group OD values/each acute drug group OD values) × 100%
As a result：Concentration is that 0.1~10 μM of ramosissimarin can substantially suppress the propagation of RA-FLS, and suppresses to make
Strengthened with the increase with drug concentration.
Embodiment 2：
Facilitations of the Ramosissimarin to synoviocytes in rheumatoid arthritis apoptosis
Cell：Human rheumatoid arthritis synovial cell (RA-FLS)；
Medicine：ramosissimarin；
Method：The recovery of 1.RA-FLS
It is same as Example 1.
The passage of 2.RA-FLS
It is same as Example 1.
3.TUNEL methods measure Apoptosis
The fracture of chromosomal DNA is a progressive process stage by stage in Apoptosis, and chromosomal DNA is first in endogenous
Hydrolase nucleic acid under the action of be degraded to the large fragment of 50-300kb.Then about 30% chromosomal DNA is in Ca2+And Mg2+
Under the endonuclease enzyme effect of dependence, cut off at random between nucleosomal units, form 180~200bp nucleosome DNA polies
Body.As long as a series of 3 '-OH ends for the DNA for occurring notch on DNA double chain fracture or a chain and producing can be in deoxyribose
Under the action of nucleotide terminal enzyme (DNA) (TdT), by deoxyribonucleotide and fluorescein, peroxidase, alkaline phosphatase
The derivative that enzyme or biotin are formed is tagged to 3 '-end of DNA, so as to carry out the detection of apoptotic cell, this kind of method one
As be known as deoxyribonucleotide terminal enzyme (DNA) mediation Nick End labelling method (TUNEL).
The nutrient solution for taking suitable ramosissimarin to be made into 0.1 and 1 μM respectively with DMEM, RA-FLS cells are in blank
And 48h is incubated in drug containing nutrient solution, at room temperature 30min is fixed using 4% paraformaldehyde.3 are rinsed with phosphate buffer (PBS)
Time, add cell membrane penetration liquid (0.1% sodium citrate, 0.1%TritonX-100) effect 2min.Deoxidation core is used at 37 DEG C
Reaction is marked in ribotide terminal enzyme (DNA) (TdT) and biotin -11- deoxyuridine triphosphates (biotin-11-dUTP)
1h.Using fluorescence microscope cellular morphology and calculate apoptotic index.
Calculation formula is as follows：
Apoptotic index/%=(apoptosis cell/1000 in 1000 cells) × 100%.
Ramosissimarin of the present invention Ramosissimarin in the application for prepare drugs for rheumatoid arthritis
Dosage be 0.1~0.5mg/kg/day, usage is oral.
Claims (2)
- Applications of the 1.Ramosissimarin in prevention or drugs for rheumatoid arthritis is prepared, wherein compound The structural formula of Ramosissimarin is as follows：
- 2.Ramosissimarin is preparing the application in suppressing synoviocytes in rheumatoid arthritis hyperproliferation agent, wherein compound The structural formula of Ramosissimarin is as follows：
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810043917.8A CN107961234B (en) | 2018-01-17 | 2018-01-17 | Application of Ramosissimarin in preparation of medicine for treating rheumatoid arthritis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810043917.8A CN107961234B (en) | 2018-01-17 | 2018-01-17 | Application of Ramosissimarin in preparation of medicine for treating rheumatoid arthritis |
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| CN107961234A true CN107961234A (en) | 2018-04-27 |
| CN107961234B CN107961234B (en) | 2020-08-18 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3449372A (en) * | 1967-02-09 | 1969-06-10 | Union Carbide Corp | Process for the production of coumarins |
| CN106581092A (en) * | 2016-11-28 | 2017-04-26 | 宁夏医科大学 | Tamarix ramosissima Ledeb extract and application thereof in preparation of medicine for treatment of rheumatoid arthritis |
-
2018
- 2018-01-17 CN CN201810043917.8A patent/CN107961234B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3449372A (en) * | 1967-02-09 | 1969-06-10 | Union Carbide Corp | Process for the production of coumarins |
| CN106581092A (en) * | 2016-11-28 | 2017-04-26 | 宁夏医科大学 | Tamarix ramosissima Ledeb extract and application thereof in preparation of medicine for treatment of rheumatoid arthritis |
Non-Patent Citations (3)
| Title |
|---|
| E. MARCUS等: "Novel Condensation Products of Diketene", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| 姜成帅: "红柳抗类风湿关节炎化学成分研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 李娟等: "多枝柽柳中的酚酸类化学成分", 《中国中药杂志》 * |
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| CN107961234B (en) | 2020-08-18 |
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