CN108272789A - Ramosissimin is in the application for preparing drugs for rheumatoid arthritis - Google Patents
Ramosissimin is in the application for preparing drugs for rheumatoid arthritis Download PDFInfo
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- CN108272789A CN108272789A CN201810044099.3A CN201810044099A CN108272789A CN 108272789 A CN108272789 A CN 108272789A CN 201810044099 A CN201810044099 A CN 201810044099A CN 108272789 A CN108272789 A CN 108272789A
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- rheumatoid arthritis
- ramosissimin
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Abstract
The present invention relates to a kind of compound R amosissimin in the application for preparing drugs for rheumatoid arthritis.First passage pharmacological evaluation of the present invention proves that ramosissimin has the significant activity for inhibiting synoviocytes in rheumatoid arthritis proliferation and induction synoviocytes in rheumatoid arthritis apoptosis, it can be used for preparing and prevent and/or the drug for the treatment of rheumatoid arthritis, therefore it is with higher clinical value and development prospect.The invention discloses a kind of purposes of compound ramosissimin in preparing resisting rheumatoid arthritis drug, and the structural formula of Ramosissimin is shown in formula I, it is isolated from Tamarix ramosissima branch.Present invention firstly discovers that ramosissimin can obviously inhibit the proliferation 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 amosissimin in the application for preparing 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 RA morbidity mainly due to patient itself
Immune dysfunction leads to allergic reaction, makes the rotten denaturation of anti-inflammatory cells, 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.
Currently, mainly using non-steroidal anti-inflammatory drugs (diclofenac sodium, aspirin etc.) for rheumatoid arthritis and being immunized
Inhibitor (Ismipur etc.) is treated, but these drugs have apparent adverse reaction, as the former damages gastrointestinal tract
Mucous membrane leads to 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
Treat the urgent task that rheumatoid arthritis drug is current.
In recent years, domestic and foreign scholars have made extensive and intensive studies in terms of autonomic drug treats RA, find many days
Right drug such as tripterygium glycosides, total glucoside, malicious rattan alkali etc. has preferable RA therapeutic effects.Therefore, it is developed from autonomic drug
Go out safe and efficient RA medicines to have broad prospects.
Invention content
The object of the present invention is to provide a kind of compound R amosissimin to prepare drugs for rheumatoid arthritis
Using,
, Ramosissimin prepare prevent or drugs for rheumatoid arthritis in application, wherein compound
The structural formula of Ramosissimin is as follows：
Ramosissimin is preparing the application in inhibiting synoviocytes in rheumatoid arthritis hyperproliferation agent, wherein compound
The structural formula of Ramosissimin is as follows：
First passage pharmacological evaluation of the present invention proves that ramosissimin has significant inhibition rheumatoid arthritis synovial membrane
The activity of cell Proliferation and induction synoviocytes in rheumatoid arthritis apoptosis, can be used for preparing prevention and/or treatment rheumatoid is closed
Save scorching drug, therefore it is with higher clinical value and development prospect.
The invention discloses a kind of purposes of compound ramosissimin in preparing resisting rheumatoid arthritis drug,
The structural formula of Ramosissimin is shown in formula I, it is isolated from Tamarix ramosissima branch.Present invention firstly discovers that
Ramosissimin can obviously inhibit the proliferation of synoviocytes in rheumatoid arthritis, induce synoviocytes in rheumatoid arthritis
Apoptosis.Therefore, which can be used for preparing the drug for preventing and/or treating rheumatoid arthritis, and there is higher clinic to answer
With value and development prospect.
Description of the drawings
Fig. 1 is that the ramosissimin of various concentration in the embodiment of the present invention 1 is proliferated synoviocytes in rheumatoid arthritis
The statistical results chart of inhibiting effect；
Fig. 2 is the ramosissimin of various concentration in the embodiment of the present invention 2 to synoviocytes in rheumatoid arthritis apoptosis
The statistical results chart of facilitation.
Specific implementation mode
The present invention provides a kind of compound ramosissimin inhibit synoviocytes in rheumatoid arthritis proliferation and
Prevent and/or treat the application in rheumatoid arthritis.
Compound ramosissimin structural formulas according to the present invention are shown in formula I：
Above compound be it is isolated from Tamarix ramosissima (Tamarix ramosissima Ledeb.) (ginger at
Handsome red buildings resisting rheumatoid disease arthritis chemical constitution study [D] Ningxia Medical University, 2016).Tamarix ramosissima is excellent windproof
The fine tree species of sand-fixation plant and saline-alkali soil forestation, in northwest China, Area distribution is extensive, resourceful.
The application of ramosissimin provided by the present invention includes two aspects：1) it is that it prevents and/or treat preparing
Application in the product of rheumatoid arthritis；2) be its prepare inhibit synoviocytes in rheumatoid arthritis proliferation product in
Using.
It is in particular in that ramosissimin can obviously inhibit the proliferation of synoviocytes in rheumatoid arthritis, induces class wind
The apoptosis of wet arthritis synovial cell can be used for preparing the drug for preventing and/or treating rheumatoid arthritis.
In addition, the following products prepared as active ingredient using ramosissimin：1) prevent and/or treat rheumatoid arthrosis
Scorching product；2) product for inhibiting synoviocytes in rheumatoid arthritis proliferation, also belongs to protection scope of the present invention.
Prevent and/or treat the drug of rheumatoid arthritis in the present invention and synoviocytes in rheumatoid arthritis is inhibited to increase
The drug grown can be imported by injection, injection, infiltration, absorption, the method that physically or chemically mediates body for example muscle, it is intradermal,
Subcutaneously, vein, mucosal tissue；Or imported body after other material mixings or package.
When needs, one or more pharmaceutically acceptable carriers can also be added in said medicine.The load
Body includes the diluent of pharmaceutical field routine, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surface
Activating agent, absorption carrier, lubricant etc..
A variety of shapes such as injection, tablet, pulvis, granule, capsule, oral solution, paste, creme can be made in said medicine
Formula.The drug of any of the above dosage form 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 inhibiting effect that Ramosissimin is proliferated synoviocytes in rheumatoid arthritis
Cell：Human rheumatoid arthritis synovial cell (RA-FLS)；
Drug：ramosissimin；
Method：The recovery of 1.RA-FLS
RA-FLS cryopreservation tubes are taken out rapidly from liquid nitrogen filling, put the thermostat water bath that temperature is 37 DEG C into, it is continual to shake
It shakes, accelerates 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 are added, use pipettor
RA-FLS is inoculated in 25mL Tissue Culture Flasks to uniform cell suspension, is put into cell incubator and cultivates by lasting piping and druming,
Incubator condition setting is 37 DEG C of temperature, CO2Concentration 5%.The growing state for observing RA-FLS after for 24 hours under the microscope, works as hair
Existing cell is adherent, triangular in shape and irregular fusiformis when, show that cell growth status is good.
The passage of 2.RA-FLS
It observes under the microscope, when RA-FLS adherent growths are to account for entire Tissue Culture Flask bottom 80% or so, i.e.,
It can carry out cell passage.The original fluid in culture bottle is outwelled, is rinsed 2 times with PBS, it is therefore an objective to original fluid be cleaned, avoided
Influence cell dissociation；0.25% tryptic digestive juice is added to be digested, and situation is digested in microscopically observation RA-FLS,
It waits for seeing that most cells become bowlder and suitable fetal calf serum (FBS) termination digestion is added under mirror, then be added a certain amount of complete
Full nutrient solution blows and beats culture bottle inner wall with aseptic straw repeatedly in culture bottle, is in uniform cell suspension；Use cell counting board
Cell is counted, after counting, RA-FLS is inoculated in 2 new culture bottles, and suitable complete culture is added
Liquid is put into cell incubator and cultivates, and incubator condition setting is 37 DEG C of temperature, and the mode of CO2 concentration 5%, i.e., one biography two passes
It is commissioned to train foster.
3.MTT methods measure cell inhibitory rate
Suitable ramosissimin is taken to be made into 0.01,0.1,1,5,10 μM of culture solution respectively with DMEM.Take in pair
The RA-FLS in number growth period, outwells the original fluid in culture bottle, is rinsed 2 times with PBS, and 0.25% tryptic digestive juice is added
It is digested, and situation is digested in microscopically observation RA-FLS, wait for seeing that cell major part change bowlder addition is suitable under mirror
FBS terminates digestion, and a certain amount of culture solution is then added in culture bottle, culture bottle inner wall is ceaselessly blown and beaten with aseptic straw,
It in uniform cell suspension, is counted with cell counting board, it is 1 × 10 to adjust cell concentration with culture solution5A/mL, by 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 setting is
37 DEG C of temperature, CO2Concentration 5%.Be incubated for 24 hours after, by 96 orifice plates be divided into 6 groups (i.e. blank control group, 0.01,0.1,1,5,10 μM
Medicine group, every group of 6 multiple holes), the original fluid in hole is sopped up, the drug containing culture of the DMEM and various concentration of equivalent are separately added into
Base is put into cell incubator and intervenes.Intervene for 24 hours and after 48h, 20 μ L MTS, 37 DEG C of incubation 1.5h are added in each hole and use enzyme
Connection immune detector measures absorbance of each hole at 540nm wavelength, 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：A concentration of 0.1~10 μM of ramosissimin can obviously inhibit the proliferation of RA-FLS, and inhibiting effect
Enhance with the increase of drug concentration.
Embodiment 2：
Facilitations of the Ramosissimin to synoviocytes in rheumatoid arthritis apoptosis
Cell：Human rheumatoid arthritis synovial cell (RA-FLS)；
Drug：ramosissimin；
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+
It under the endonuclease enzyme effect of dependence, is cut off at random between nucleosomal units, forms 180~200bp nucleosome DNA polies
Body.As long as a series of 3 ' ends-OH for the DNA for notch occur on DNA double chain fracture or a chain and generating 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 the 3 '-ends of DNA, so as to carry out the detection of apoptotic cell, such methods one
As be known as deoxyribonucleotide terminal enzyme (DNA) mediate Nick End labelling method (TUNEL).
Take suitable ramosissimin to be made into 0.1 and 1 μM of culture solution respectively with DMEM, RA-FLS cells in blank and
It is incubated 48h in drug containing culture solution, uses 4% paraformaldehyde to fix 30min at room temperature.3 are rinsed with phosphate buffer (PBS)
Time, cell membrane penetration liquid (0.1% sodium citrate, 0.1%TritonX-100) is added and acts on 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%.
The agent of Ramosissimin of the present invention Ramosissimin in the application for preparing drugs for rheumatoid arthritis
Amount is 0.1~0.5mg/kg/day, and usage is oral.
Claims (2)
- Applications of the 1.Ramosissimin in preparing prevention or drugs for rheumatoid arthritis, wherein compound The structural formula of Ramosissimin is as follows：
- 2.Ramosissimin is preparing the application in inhibiting synoviocytes in rheumatoid arthritis hyperproliferation agent, wherein compound The structural formula of Ramosissimin is as follows：
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810044099.3A CN108272789B (en) | 2018-01-17 | 2018-01-17 | Application of Ramosissimin in preparation of medicine for treating rheumatoid arthritis |
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| CN201810044099.3A CN108272789B (en) | 2018-01-17 | 2018-01-17 | Application of Ramosissimin in preparation of medicine for treating rheumatoid arthritis |
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| CN108272789B CN108272789B (en) | 2020-08-18 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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2018
- 2018-01-17 CN CN201810044099.3A patent/CN108272789B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|
| YA-RU LIU等: "NLRC5 promotes cell proliferation via regulating the NF-κB signaling pathway in Rheumatoid arthritis", 《MOLECULAR IMMUNOLOGY》 * |
| 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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