CN108578398A - Macrophage element is preparing the application in preventing or treating the drug of rheumatoid arthritis - Google Patents
Macrophage element is preparing the application in preventing or treating the drug of rheumatoid arthritis Download PDFInfo
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- CN108578398A CN108578398A CN201810596398.8A CN201810596398A CN108578398A CN 108578398 A CN108578398 A CN 108578398A CN 201810596398 A CN201810596398 A CN 201810596398A CN 108578398 A CN108578398 A CN 108578398A
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The present invention relates to pharmaceutical technology field, specifically macrophage element is preparing the application in preventing or treating the drug of rheumatoid arthritis.The mouse model of rheumatoid arthritis that the present invention is induced by II Collagen Type VIs confirms that macrophage element significantly can improve rheumatoid arthritis mouse symptom by adjusting the balance of the Th17/Treg cells in CIA Mice Bodies, has good resisting rheumatoid arthritis effect.Compound macrophage element of the present invention is used as treatment medicine for treating rheumatoid arthritis, and a kind of new source is provided to seek safely and effectively resisting rheumatoid arthritis drug.
Description
Technical field
The present invention relates to pharmaceutical technology fields, specifically, being a kind of rush inflammatory resolution medium --- macrophage element
(maresin, MaR1) is preparing prevention or treatment rheumatoid arthritis disease drug by adjusting Th17/Treg cell balances
In application.
Background technology
A kind of chronic disabling autoimmune disease of rheumatoid arthritis (RA), China's illness rate are 0.32%-
0.36%.RA patient's pathology shows as multi-joint involvement, synovial membrane inflammation and hyper-proliferative formed pannus finally result in bone with it is soft
Osteoclasia and pain seriously affect the quality of life of patient, final 90% disability of patients with terminal and energy of taking care of oneself
Power (Xinyu Yang, Pengcheng Qiu, Bingbing Chen, Yaoyao Lin, Zhonghao Zhou, Renshan
Ge,Hai Zou,Jianmin Wang,*and Jianguang Wang,*KIAA1199as a potential
diagnostic biomarker of rheumatoid arthritis related to
angiogenesis.Arthritis Research&Therapy,2015,17:140).Rheumatoid arthritis is treated at present
Drug mainly has methopterin, non-steroidal antiinflammatory drugs and some biological agents, and (antibody of anti-IL-6 receptors, TNF-α inhibit
Agent), human body can be had larger side effect by taking these drugs for a long time, can cause upset,gastro-intestinal even bleeding, hepatic injury and high blood
(JF Lima-Garcia, RC Dutra, KABS da Silva, EM Motta, the MM Campos and JB such as pressure
Calixto.The precursor of resolvin D series and aspirin-triggered resolvin
D1display anti-hyperalgesic properties in adjuvant-induced arthritis in
rats.British Journal of Pharmacology,2011,164:278–293).Therefore, seek safely and efficiently anti-
The clinical medicine for the treatment of RA, which is medical field, important problem to be solved.
RA pathogenesis is intricate to be still not clear so far, recently result of study show when in vivo be inflamed reaction when,
Excitation inflammatory reaction factor be eliminated after, body will enter active inflammatory resolution process, if but inflammation cannot subside in time
Chronic inflammatory diseases, such as RA may occur.
Macrophage element (7R, 14S- dihydroxy -4Z, 8E, 10E, 12Z, 16Z, 19Z- docosahexaenoic acid, Maresin1,
MaR1) it is a kind of novel rush inflammatory resolution medium generated for source with the docosahexaenoic acid (DHA) of macrophages secrete,
Have in inflammatory reaction process of extinction and inhibit granulocyte infiltration, enhance macrophages phagocytic capacity, there is powerful anti-inflammatory recession
Act on (Serhan C N, Dalli J, Karamnov S, Choi A, Park CK, Xu ZZ, Ji RR, Zhu M, Petasis
NA.Macrophage proresolving mediator maresin 1stimulates tissue regeneration
and controls pain.FASEB J,2012,26(4):1755-1765.)。
Macrophage that so far there are no element (7R, 14S- dihydroxy -4Z, 8E, 10E, 12Z, 16Z, 19Z- docosahexaenoic acid,
Maresin1, MaR1) for treating the report in terms of rheumatoid arthritis.
Invention content
The purpose of the present invention is to provide a kind of rush inflammatory resolution media --- macrophage element (7R, 14S- dihydroxy -4Z, 8E,
10E, 12Z, 16Z, 19Z- docosahexaenoic acid, Maresin1, MaR) it is being prepared in advance by adjusting Th17/Treg cell balances
Application in anti-or treatment rheumatoid arthritis disease drug.
The macrophage element for intervening RA animal models used in the present invention is purchased from Cayman companies, chemical structural formula such as formula
(I) shown in, purity >=95% is dissolved in ethyl alcohol, is diluted with PBS (PH=7.2) when use.
The first aspect of the present invention provides macrophage element and is preparing answering in preventing or treating the drug of rheumatoid arthritis
With.
Further, the macrophage element reduces arthritis index, inhibits ankle swelling degree.
Further, the macrophage element lowers serum Tumor Necrosis Factor (TNF-α), interleukin-11 β (IL-1 β), white
Interleukin 6 (IL-6), interleukin-17 (IL-17) and interferon (IFN γ) concentration raise IL-10 (IL-10) in serum and turn
Change growth factor-beta (TGF-β) concentration.
Further, the macrophage element reduces the generation of joint pannus and cartilage damage.
Further, the macrophage element is closed by adjusting the balance of Th17 cells and Treg cells to alleviate rheumatoid
The scorching disease development of section.
The second aspect of the present invention provides a kind of drug prevented or treat rheumatoid arthritis, including a effective amount of
Macrophage element and customary pharmaceutical excipients, carrier or diluent.
The third aspect of the present invention provides macrophage element in preparing the drug for adjusting Th17 cells and Treg cell balances
Using.
The present invention confirms macrophage element by promoting inflammatory resolution to RA therapeutic effects by many experiments.Sample clinical first
Product macrophage cellulose content, which measures, to be found, RA patients with active's serum macrophage elements concentration will be significantly lower than normal person, illustrate that macrophage element can
It can play an important role to the development of RA diseases.The Mechanism Study for delaying RA disease process followed by macrophage element, there is report
During road inflammatory resolution Th17/Treg cells it is unbalance play a significant role in RA disease development processes (Noack M,
Miossec P.Th17and regulatory T cell balance in autoimmune and inflammatory
diseases.Autoimmun Rev 2014,13:668-677), Th17 cells can by secrete cytokines (such as IL-1 β,
IL-6 etc.), chemotactic factor (CF) and matrix metalloproteinase promote inflammatory reaction, destroy cartilage or bone tissue；And Treg cells can be with
It secretes IL-10 and TGF-β inhibits inflammatory reaction, immune tolerance (Koenders MI, Joosten LA, van may finally be caused
den Berg WB.Potential new targets in arthritis therapy:interleukin(IL)-17and
its relation to tumour necrosis factor and IL-1in experimental arthritis.Ann
Rheum Dis 2006,65Suppl 3:iii29-33.).The present invention is based on the above theoretical foundations to have carried out macrophage element to RA diseases
Inhibiting effect of the macrophage element to CIA mouse arthroncus degree and internal proinflammatory factor is studied in the research of sick process influence on development,
Finally influence of the research macrophage element to Th17/Treg cell balances in CIA Mice Bodies.
The present invention uses rheumatoid arthritis animal model (Inglis JJ, Notley CA, Essex D, Wilson
AW,Feldmann M,Anand P,Williams R.Collagen-induced arthritis as a model of
hyperalgesia:functional and cellular analysis of the analgesic actions of
tumor necrosis factor blockade.Arthritis Rheum.2007,56(12):4015-4023), it observes huge
Bite the therapeutic effect that CIA mouse tail veins are administered in element.
Experimental result is shown, after macrophage element (0.8ug/kg (20ng/ is only), 4ug/kg (100ng/ is only)) tail vein administration,
CIA mouse mouse arthritis index can be significantly reduced, ankle swelling degree is inhibited；Lower tumor necrosis factor in CIA mice serums
Sub (TNF-α), interleukin-11 β (IL-1 β), interleukin 6 (IL-6), interleukin-17 (IL-17) and interferon (IFN γ) concentration, on
IL-10 (IL-10) and TGF β concentration in CIA mice serums are adjusted；Pathological section shows that it is small that macrophage element can substantially reduce CIA
Mouse joint pannus generates and cartilage damage.The studies above shows that macrophage element has good anti-RA activity.Further pass through stream
Formula cytometry experiment detects ratio of the macrophage element to Th17 cells and Treg cells in CIA Mice Bodies, the results showed that macrophage element can
To alleviate the development of RA diseases by improving the state that Th17/Treg is unbalance in CIA Mice Bodies.
The present invention has searched out that Th17/Treg is unbalance to treat the drug of RA by improving.
The invention has the advantages that：
1, the mouse model of rheumatoid arthritis that the present invention is induced by II Collagen Type VIs confirms that macrophage element can significantly lead to
The balance of the Th17/Treg cells in CIA Mice Bodies is overregulated to improve rheumatoid arthritis mouse symptom, is had good
Resisting rheumatoid arthritis acts on；
2, compound macrophage element of the present invention is used as treatment medicine for treating rheumatoid arthritis, to seek safety
Effective resisting rheumatoid arthritis drug provides a kind of new source.
Description of the drawings
Fig. 1：Macrophage element induces II Collagen Type VIs influence (CIA, the modeling group of RA model mice arthritis index；CIA+
20ng MaR1, modeling group give macrophage element and intervene 20ng/ only；CIA+100ng MaR1, modeling group give macrophage element intervention
100ng/ is only)；
Fig. 2：To II Collagen Type VIs induction RA model mice joint tissues pathological section, (HE is dyed macrophage element and toluidine blue contaminates
Color) influence；
Fig. 3：Macrophage element to II Collagen Type VIs induce RA model mice serum in IL-1 β (A), IL-6 (B), TNF-α (C),
IFN-γ (D), IL-17 (E), influence (* vs modeling groups, the p of IL-10 (F) and TGF-β (G)<0.05)；
Fig. 4：Macrophage element induces the influence of RA model mice Th17 cells and Treg cells to II Collagen Type VIs, and (A, macrophage element are right
The influence of Th17 cells in CIA Mice Bodies, B, influence of the macrophage element to Treg cells in CIA Mice Bodies, * vs model groups, p<
0.05)。
Specific implementation mode
It elaborates to specific implementation mode provided by the invention with reference to embodiment.
Embodiment 1：Macrophage element improves rheumatoid arthritis disease process by adjusting Th17/Treg cell proportions
1.1 experiment material
6-8 week old male DBA/1 mouse (Shanghai Si Laike biotech firms buy 30, mice serum IL-1 β, IL-6,
The ELISA kit (Sigma Co., USA) of TNF-α, IFN-γ, IL-17, IL-10 and TGF-β.Key instrument：Microplate reader
(BIO-RAD 550), centrifuge (Labofuge 400R, Heraeus companies), electronic balance (FA110A types, Shanghai precision section
Learn Instrument Ltd.), flow cytometer.
1.2 experiment modelings and administration
30 DBA/1 mouse are weighed before experiment, 3 groups are randomly divided by weight, every group 10, free diet, water inlet.
It is divided into only three groups of model group, macrophage element 20ng/ and macrophage element 100ng/.
Modeling group：0th day, ox II collagen types acetum is mixed with the Freund's complete adjuvant of equal capacity, fully
Emulsification, DBA/1 mouse root of the tails carry out intracutaneous injection (2mg/ml), every 0.1ml；After 21 days, by ox II collagen type acetic acid
Solution is mixed with the incomplete Freund's complete adjuvant of equal capacity, and fully emulsified booster immunization, DBA/1 mouse root of the tails carry out intradermal note
It penetrates (2mg/ml), every 0.1ml；
CIA+20ng MaR1 groups：Modeling same as model group after booster immunization, gives mouse tail vein once every three days
Macrophage element (20ng/ is only) is injected, is administered into always the 48th day；
CIA+100ng MaR1 groups：Modeling same as model group after booster immunization, gives mouse tail vein once every three days
Macrophage element (100ng/ is only) is injected, is administered into always the 48th day.
1.3 observation index
1.3.1 arthritis index scoring is carried out to mouse arthroncus degree, scoring in every 3 days is primary.
1.3.2 in experiment the 49th day, mouse is handled.Carry out following operation：
(1) mouse heart take a blood sample, set 37 DEG C be incubated 15 minutes after, with 1500r/min centrifuge 15min, take supernatant, use
ELISA method measures IL-1 β in three groups of mice serums, and IL-6, TNF-α, IFN-γ, IL-17, IL-10 and TGF-β are horizontal, press
ELISA kit specification is operated；
(2) three groups of mouse ankle joint bone tissues is taken to carry out check pathological section；
(3) three groups of mouse lymph nodes extraction lymph node cells are taken, Th17/Treg in every group of Mice Body of Flow cytometry
The ratio of cell.
1.4 experimental result
(1) rat arthritis index score
As shown in Figure 1, it is to prompt macrophage element can that two groups of macrophage element group arthritis index, which are below model group arthritis index,
Significantly reduce II Collagen Type VIs induction RA mouse arthritis indexes, show macrophage element to mouse model of rheumatoid arthritis have compared with
Good mitigation.
(2) pathological section
As shown in Fig. 2, model group mouse histopathologic slide shows that synovial hyperplasia, pannus and cartilage damage are serious, two
Group macrophage element group can substantially reduce synovial hyperplasia, pannus generation and cartilage damage, prompt macrophage element that can effectively inhibit RA moulds
The joint injury of type mouse.
(3) serological index
As shown in figure 3, compared with model group, macrophage element can significantly reduce IL-1 β in serum, IL-6, TNF-α, IFN-γ,
The level of IL-17, IL-10 and TGF-β illustrate that the administration of macrophage element tail vein can significantly reduce rheumatoid arthritis animal model
The inflammatory reaction of RA mouse can be effectively relieved in the level of proinflammatory factor in serum.
(4) Flow cytometry Th17 and Treg cell proportions
As shown in figure 4, model group mouse Th17/Treg cell proportions are significantly increased compared to macrophage element processing group ratio.
The preferred embodiment of the invention is illustrated above, but the invention be not limited to it is described
Embodiment, those skilled in the art can also make various equivalent under the premise of without prejudice to the invention spirit
Modification or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.
Claims (7)
1. macrophage element is preparing the application in preventing or treating the drug of rheumatoid arthritis.
2. macrophage element according to claim 1 is preparing the application in preventing or treating the drug of rheumatoid arthritis,
It is characterized in that, the macrophage element reduces arthritis index, inhibit ankle swelling degree.
3. macrophage element according to claim 1 is preparing the application in preventing or treating the drug of rheumatoid arthritis,
It is characterized in that, the macrophage element lowers serum Tumor Necrosis Factor, interleukin-11 β, interleukin 6, interleukin-17 and interference
Plain concentration raises IL-10 and transforming growth factor-β concentration in serum.
4. macrophage element according to claim 1 is preparing the application in preventing or treating the drug of rheumatoid arthritis,
It is characterized in that, the macrophage element reduces the generation of joint pannus and cartilage damage.
5. macrophage element according to claim 1 is preparing the application in preventing or treating the drug of rheumatoid arthritis,
It is characterized in that, the macrophage element is by adjusting the balance of Th17 cells and Treg cells come rheumatoid arthritis disease
Disease development.
6. the drug of a kind of prevention or treatment rheumatoid arthritis, which is characterized in that including a effective amount of macrophage element, and routine
Pharmaceutical excipient, carrier or diluent.
7. application of the macrophage element in preparing the drug for adjusting Th17 cells and Treg cell balances.
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| CN201810596398.8A CN108578398A (en) | 2018-06-11 | 2018-06-11 | Macrophage element is preparing the application in preventing or treating the drug of rheumatoid arthritis |
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| CN201810596398.8A CN108578398A (en) | 2018-06-11 | 2018-06-11 | Macrophage element is preparing the application in preventing or treating the drug of rheumatoid arthritis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113712951A (en) * | 2021-08-05 | 2021-11-30 | 温州医科大学附属第二医院（温州医科大学附属育英儿童医院） | Macrophagemin 1 in preparation of medicine for treating pulmonary hypertension and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104684389A (en) * | 2012-05-10 | 2015-06-03 | 索卢泰克斯Na有限责任公司 | Oils with anti-inflammatory activity containing natural specialized proresolving mediators and their precursors |
| WO2017041094A1 (en) * | 2015-09-03 | 2017-03-09 | Solutex Na Llc | Compositions comprising omega-3 fatty acids, 17-hdha and 18- hepe and methods of using same |
-
2018
- 2018-06-11 CN CN201810596398.8A patent/CN108578398A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104684389A (en) * | 2012-05-10 | 2015-06-03 | 索卢泰克斯Na有限责任公司 | Oils with anti-inflammatory activity containing natural specialized proresolving mediators and their precursors |
| WO2017041094A1 (en) * | 2015-09-03 | 2017-03-09 | Solutex Na Llc | Compositions comprising omega-3 fatty acids, 17-hdha and 18- hepe and methods of using same |
Non-Patent Citations (3)
| Title |
|---|
| UNDURTI N DAS: "Lipoxins as biomarkers of lupus and other inflammatory conditions", 《DAS LIPIDS IN HEALTH AND DISEASE》 * |
| VALERIO CHIURCHIU等: "Pro-resolving lipid mediators resolvin D1, Resolvin D2 and Maresin 1 are critical in modulating T cell responses", 《SCI. TRANSL. MED.》 * |
| 唐诗 等: "Maresin1对高糖损伤肾小球系膜细胞的影响极其抗炎作用机制探讨", 《山东医药》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113712951A (en) * | 2021-08-05 | 2021-11-30 | 温州医科大学附属第二医院（温州医科大学附属育英儿童医院） | Macrophagemin 1 in preparation of medicine for treating pulmonary hypertension and application thereof |
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Address after: 325036 Wenzhou City National University Science Park incubator, No. 38 Dongfang South Road, Ouhai District, Wenzhou, Zhejiang Applicant after: Wenzhou Medical University Address before: 325000 No. 82 West College Road, Wenzhou, Zhejiang Applicant before: Wenzhou Medical University |
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