CN103622939A - Application of compound for preparing drugs treating osteoarthritis - Google Patents
Application of compound for preparing drugs treating osteoarthritis Download PDFInfo
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- CN103622939A CN103622939A CN201310654109.2A CN201310654109A CN103622939A CN 103622939 A CN103622939 A CN 103622939A CN 201310654109 A CN201310654109 A CN 201310654109A CN 103622939 A CN103622939 A CN 103622939A
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- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 claims abstract description 28
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses new application of Trichostatin A treating the osteoarthritis. The osteoarthritis is one of the serious diseases harmful to human health; with the aging of the population, the number of patients suffering from the osteoarthritis is increased day by day, which brings the world an enormous social, medical and economic burden; although the relevant experts and scholars attach great importance to the prevention and the treatment of the disease, effective therapeutic drugs are still unavailable. Tests in vitro show that Trichostatin A has a significant anti-osteoarthritis effect. Experimental results show that Trichostatin A can suppress the expression of protein MMP3, protein MMP13 and mRNA induced by IL-1 in a human chondrosarcoma cell SW1353, and the suppressing effects are dose-dependent, so that the compound has a therapeutic effect on the osteoarthritis.
Description
Technical field
The present invention relates to the drug world that anti-osteoarthritis is relevant, relate in particular to Trichostatin A for preventing and treating the new purposes of osteoarthritis.
Background technology
Acetylation of histone can make nucleosomal structure relax thereby promote genetic transcription, otherwise suppresses.Acetylation of histone state is subject to two kinds of regulation and control, histone acetyltransferase (HAT) and histone deacetylase enzymes (HDAC) of acting on contrary enzyme.Deacetylase inhibitor is a class newtype drug of rising in recent years, can suppress the function of histone deacetylase enzyme in body, is used for treating cancer and neurodegenerative diseases.Because of its good therapeutic effect and less side effect, deacetylase inhibitor starts more and more being applied in the treatment of other diseases.The current clinical practice of deacetylase inhibitor (HDIs) is mainly aspect oncotherapy.Can be being divided into according to structure; 1, hydroxamic acid (hydroxamic acid) derivant, as Trichostatin A(TSA), SAHA, pyroxamide; 2, short-chain fatty acid, as: valproic acid (valproic acid), butyrate (butyrates) and phenylacetate (phenylacetate); 3, ring-type tetrapeptide class and epoxide, as: FK228; 4, synthetic heterocyclic carbamate derivatives, as: MS-275 and CI-994.In addition, also have sirtuin inhibitor also to belong to HDIs as sirtinol.Trichostatin A in the present invention belongs to wide spectrum hdac inhibitor.
Along with the aging of population, the sickness rate of osteoarthritis, also along with increasing sharply, has become the important diseases of harm humans health, and has brought huge society and financial burden to the whole world.Although relevant experts and scholars attach great importance to the control of this disease both at home and abroad, this disease still lacks effective medicine.Because osteoarthritis is a kind of chronic disease, need Long-term taking medicine, so low price, the micromolecular compound that toxic and side effects is little has become one of focus of research treatment osteoarthritis.
The compound Trichostatin A the present invention relates to belongs to open first for the purposes in the anti-medicine for treating arthritis of preparation the present invention relates to.
Summary of the invention
The invention provides the new purposes of anti-osteoarthritis of Trichostatin A (TSA).
The present invention finds the application in the anti-medicine for treating arthritis of Trichostatin A by experiment in vitro.
The present invention finds that by vitro tests Trichostatin A suppresses IL-1 induction MMP3 and MMP13 albumen and mrna expression in human cartilage sarcoma cell SW1353, and inhibitory action all presents dose dependent.Human cartilage sarcoma cell SW1353 is the cell model whether a classical in-vitro evaluation has anti-osteoarthritis effect, so Trichostatin A is a kind of desirable medicine of preventing and treating osteoarthritis.
Described compound Trichostatin A structure is as shown in formula I:
Formula I
The purposes of the Trichostatin A the present invention relates in the anti-medicine for treating arthritis of preparation belongs to open first.
Accompanying drawing explanation
Fig. 1 is the impact of TSA on MMP3 and MMP13 gene expression.
SW1353 cell is combined IL-1 under different TSA concentration, and to cultivate the mRNA level of 24h.MMP quantitative by RT-PCR.
Fig. 2 is the impact of TSA on MMP3 and MMP13 protein expression.
SW1353 cell is combined IL-1 and is cultivated 24h under different TSA concentration, and protein level is measured by western blotting.
The specific embodiment
Compound Trichostatin A involved in the present invention buys from Sigma company.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not subject to any restriction of specific embodiment, but be limited by claim.
Embodiment 1: the preparation of compound Trichostatin A tablet involved in the present invention:
Get 2 and digest compound Trichostatin A, add 198 grams of conventional adjuvants preparing tablet, mix, conventional tablet machine is made 1000.
Embodiment 2: the preparation of compound Trichostatin A capsule involved in the present invention:
Get 2 and digest compound Trichostatin A, add the conventional adjuvant of preparing capsule as 198 grams of starch, mix, encapsulatedly make 1000.
Below by experiment, further illustrate its pharmaceutically active.
1, experiment purpose: observe Trichostatin A(TSA by the experiment in vitro) therapeutic effect to osteoarthritis.
2, experimental technique:
The human cartilage sarcoma SW1353 that this experiment is used IL-1 to stimulate is OA cell model
[1-3], give TSA and process.Detect key enzyme MMP13 and the MMP3 of cartilage degradation
[4]albumen and mrna expression change.
Cell culture and processing: SW1353 cell is cultivated in DMEM/F12 culture medium (comprising 10% hyclone).Before experiment, first cell is inoculated in 6 orifice plates, after adherent spending the night, 24 hour cells are hungry processes.PBS washes 3 times to prevent affected by other cytokine, after in hole, add respectively according to schedule the TSA of IL-1 and various dose to process 24 hours.
PCR experiment: Trizol test kit is dissolved in DEPC after extracting total RNA, is stored in-80 degree with NANODROP after quantitatively.RNA carries out reverse transcription with HIScript reverse transcriptase by explanation, 10 microlitre reaction systems for the total RNA of 500ng.2 * Taq Master Mix increases to 1/10 product, reaction system 25 microlitres, amplified production gel electrophoresis analysis.Relevant primer information: MMP13-F AGGAGCATGGCGACTTCTAC; MMP13-R TAAAAACAGCTCCGCATCAA; MMP3-F CCTCTGATGGCCCAGAATTGA; MMP3-R GAAATTGGCCACTCCCTGGGT.
WESTERN BLOT:loading buffer cell lysis extracts SDS – polyacrylamide gel electrophoresis after total protein, transferring film primary antibodie hatch (rabbit anti-human-MMP3 and the anti-human MMP13 of rabbit) and spend the night after two anti-hatching and Protein Detection.
3, experimental result
As Fig. 1 and Fig. 2 finding, TSA suppresses IL-1 induction MMP3 and MMP13 albumen and mrna expression in human cartilage sarcoma cell SW1353, and inhibitory action all presents dose dependent.
4, conclusion
MMP3 and MMP13 all have high expressed and have been proved because its cartilage matrix Degradation promotes osteoarthritis progress in osteoarthritis (OA) patient chondrocyte, our experiment in vitro finds out that TSA can suppress important substrate hydrolytic enzyme MMP3 and the expression of MMP13, this shows that TSA may suppress osteoarthritis by the expression of reduction MMP and develop, and TSA can be for the control of osteoarthritis.
List of references:
[1]Cheng?W,Wu?D,Zuo?Q,et?al.Ginsenoside?Rb1prevents?interleukin-1beta?induced?inflammation?and?apoptosis?in?human?articular?chondrocytes[J].Int?Orthop,2013,37(10):2065-2070.
[2]Chang?C?C,Hsieh?M?S,Liao?S?T,et?al.Hyaluronan?regulates?PPARgamma?and?inflammatory?responses?in?IL-1beta-stimulated?human?chondrosarcoma?cells,a?model?for?osteoarthritis[J].Carbohydr?Polym,2012,90(2):1168-1175.
[3]Lu?Y?C,Jayakumar?T,Duann?Y?F,et?al.Chondroprotective?role?of?sesamol?by?inhibiting?MMPs?expression?via?retaining?NF-kappaB?signaling?in?activated?SW1353?cells[J].J?Agric?Food?Chem,2011,59(9):4969-4978.
[4]Wang?X,Li?F,Fan?C,et?al.Effects?and?relationship?of?ERK1and?ERK2?in?interleukin-1beta-induced?alterations?in?MMP3,MMP13,type?II?collagen?and?aggrecan?expression?in?human?chondrocytes[J].Int?J?Mol?Med,2011,27(4):583-589。
Claims (1)
- The application of 1.Trichostatin A in preparation treatment medicine for treating arthritis, described compound Trichostatin A structure as formula Ishown in:formula I.
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| CN201310654109.2A CN103622939A (en) | 2013-12-05 | 2013-12-05 | Application of compound for preparing drugs treating osteoarthritis |
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| CN201310654109.2A CN103622939A (en) | 2013-12-05 | 2013-12-05 | Application of compound for preparing drugs treating osteoarthritis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2586745B (en) * | 2018-03-13 | 2023-04-05 | Nuchido Ltd | Compositions |
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Non-Patent Citations (1)
| Title |
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| CHEN, WEI-PING; BAO, JIA-PENG; HU, PENG-FEI; FENG, JIE; WU, LI-D: "Alleviation of osteoarthritis by Trichostatin A, a histone", 《MOLECULAR BIOLOGY REPORTS 》 * |
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| GB2586745B (en) * | 2018-03-13 | 2023-04-05 | Nuchido Ltd | Compositions |
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Application publication date: 20140312 |