CN106974915A - A kind of application of Celastrol in preparing treatment and delaying intervertebral disk retrogression lesion medicine - Google Patents
A kind of application of Celastrol in preparing treatment and delaying intervertebral disk retrogression lesion medicine Download PDFInfo
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Abstract
The invention discloses a kind of application of Celastrol in preparing treatment and delaying intervertebral disk retrogression lesion medicine, Celastrol is used as a kind of plant extracts with good bioactivity, antiphlogistic effects obvious the characteristics of low with dosage.Compared to Western medicine, Celastrol compares mitigation as a kind of Chinese medicine, its antiinflammatory action, and a kind of replacement therapy medicine can be provided for the complex treatment of intervertebral disc degeneration disease.
Description
(1) technical field
The present invention relates to a kind of application of Celastrol, more particularly to Celastrol is used to prepare treatment and delays vertebra
Between application in disc degradation medicine.
(2) background technology
Low back pain is orthopaedics common disease, is apt to occur in 40 years old to 80 years old crowd.Serious low back pain can make patient lose the job
Ability, serious burden is caused to society and family.More than 40% low back pain is by intervertebral disc degeneration (intervertebral
Disc degeneration, IVDD) cause.But so far, clinically there is no the medicine for intervertebral disc degeneration can
With.
Intervertebral disc degeneration can be caused by many factors, such as abnormal stress, local nutritional deficiency and congenital gene unconventionality,
Wherein inflammation is one of most important mechanism of causing a disease of intervertebral disc degeneration.The nucleus pulposus cell excessive Apoptosis mediated by inflammatory factor is recognized
To be an important ring in intervertebral disc degeneration process, therefore it is probably treatment intervertebral disc degeneration for the research of nucleus pulposus cell apoptosis
Important channel.
Celastrol (Celastrol) is that one kind is widely present in Celastraceae plant tripterygium wilfordii, celastrus orbiculatus and only son
Triterpene compound in rattan etc..Celastrol illustrates good bioactivity in multinomial pharmaceutical research, for example
Antitumor, immunosupress, anti-nerve degenerative diseases etc..But whether it has therapeutic action still not to intervertebral disc degeneration disease
It is clear.
(3) content of the invention
It is an object of the present invention to provide a kind of Celastrol in preparing treatment and delaying intervertebral disk retrogression lesion medicine
Application.The side effect larger compared to Western medicine, Celastrol can more leniently alleviate interverbebral disc and move back as a kind of Chinese medicine
Become.The discovery of this new effect, has also promoted the development of China's traditional Chinese medicine.
The technical solution adopted by the present invention is：
The present invention provides a kind of application of Celastrol in preparing treatment and delaying intervertebral disk retrogression lesion medicine,
Celastrol (Cel) molecular structural formula is shown in formula (I)：
Further, the medicine also includes pharmaceutical carrier, and the pharmaceutical carrier is micro emulsion, nano liposomes etc..
Further, the medicine is tablet, emulsion, capsule etc..
Further, the consumption that the consumption of Celastrol is 4mg/kg~0.213g/g in the medicine be 4mg/kg~
0.213g/g, preferred content is nano liposomes 4mg/kg, micro emulsion (ethyl oleate) 0.213g/g.The use of the Celastrol
Measure as 1~3mg/kg body weight.
Compared with prior art, beneficial effect of the present invention is mainly reflected in：Celastrol has well as a kind of
The plant extracts of bioactivity, antiphlogistic effects obvious the characteristics of low with dosage.Compared to Western medicine, Celastrol is made
For a kind of Chinese medicine, its antiinflammatory action compares mitigation, can provide a kind of replacement therapy for the complex treatment of intervertebral disc degeneration disease
Medicine.
(4) illustrate
Magnetic resonance compares figure of Fig. 1 Celastrols to the therapeutic effect of rat tail bone intervertebral disc degeneration acupuncture model；2W
Refer to culture 2 weeks, 6W represents culture 6 weeks, and Control is control, and IDD is intervertebral disc degeneration group, and Cel is intervertebral disc degeneration+thunder
Celastrol group.
The CCK8 toxicity trial compares figures of Fig. 2 Celastrols.
Fig. 3 Celastrols are alleviating the qPCR experimental control figures that IL-1 β influence on nucleus pulposus cell functional parameter；A is
Expressions of the MMP3 in mRNA level in-site；B is expressions of the MMP9 in mRNA level in-site；C is expression of the MMP13 in mRNA level in-site
Situation；D is expressions of the ADAMTS-4 in mRNA level in-site；E is expressions of the ADAMTS-5 in mRNA level in-site.
Fig. 4 nucleus pulposus cells are under IL-1 β stimulations, and Celastrol improves the compares figure of its extracellular matrix complex functionality；a
For II Collagen Type VIs mRNA level in-site expression；B is expression of the proteoglycans in mRNA level in-site；C is II Collagen Type VIs
The expression fluorogram of (Collagen II) in protein level；D is expression fluorescence of the proteoglycans (Aggrecan) in protein level
Figure.
Fig. 5 Celastrols are alleviating qPCR, ELISA and Western that IL-1 β influence on nucleus pulposus cell inflammatory parameters
Blot experimental control figures；A is expressions of the IL-6 in mRNA level in-site；B is expression of the TNF-α in mRNA level in-site；C is
IL-6 is in extracellular secretion situation；D is the expression of TNF-α and IL-6 in protein level；E is TNF-α and β-actin ashes
Angle value ratio statistical chart；F is IL-6 and β-actin gray value ratio statistical charts；G is expressions of the COX-2 in mRNA level in-site；
H is expressions of the INOS in mRNA level in-site.
Fig. 6 nucleus pulposus cells are under IL-1 β stimulations, Western blot experiment pair of the Celastrol to its NF- κ B path
According to figure；A is expression of the NF- κ B signals paths in protein level；B is p-p65 and p65 gray value ratios statistical chart；C is
P-I κ B α and β-actin gray value ratios statistical chart；D is I κ B α and β-actin gray value ratios statistical chart.
Fig. 7 nucleus pulposus cells are under IL-1 β stimulations, and Celastrol enters the cellular immunofluorescence experiment pair of core situation to p65
According to figure；P65 is p65 distribution situation, and DAPI is nucleus, and Merge is each intracellular p65 distribution situation.
(5) embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This：
Embodiment 1
1st, experimental procedure：
(1) modeling method：Take (3.5ml/kg), iodine after 8 week old SD rats (about 200-220g), 10% chloral hydrate anesthesia
Volt sterilization, takes rat 7,8 to save tail bone (Co7/8), and 30g is punctured and is needled into, and piercing length is 5mm, is rotated by 360 ° and stays after piercing
Put and extracted after 30s, that is, obtain rat tail bone intervertebral disc degeneration model.15 SD rats are divided into 3 groups：1 (normal disc pair of group
According to group, control in Fig. 1), organize 2 (IDD in simple intervertebral disc degeneration group, Fig. 1), (Celastrol after intervertebral disc degeneration of group 3
Cel in treatment group, Fig. 1, the treatment of row Celastrol (distilled water preparation) gavage, 3mg/kg/d daily after modeling success).Respectively
The the 2nd and the 6th week after injury, centered on the section tail bone of rat 7,8, including interverbebral disc adjacent thereto, carry out rat tail bone magnetic
Resonance detection, compares the difference of normal disc and degeneration intervertebral disc magnetic resonance signal.
(2) choose clinically due to symptom is strong and iconography situation is lighter, it is desirable to pass through the trouble for relief of symptoms of performing the operation
The nucleus pulposus of person is cultivated.Nucleus pulposus withdrawal amount is about adult's little finger first knuckle size, and life is put in after taking-up
Manage in salt solution and preserve, be transported to laboratory within 30 minutes.First nucleus pulposus is washed 2 times with sterile PBS, impurity and bloodstain is removed.Nothing is used again
Bacterium apparatus is shredded into 1mm × 1mm × 1mm sizes, is transferred to 15ml centrifuge tubes.Washed once with sterile PBS again, from
The heart.Abandoning supernatant, adds 0.2%II Collagenase Types (Vetec) 20ml toward nucleus pulposus fragment is interior, is placed on 37 DEG C of cell culture incubators
Digested 5 hours, so as to fully digestion every 1 hour shaking test tube once.Then centrifugation, with 10ml PBS nucleus pulposus
Cell one time.Centrifuge again, add the penicillin streptomycin (Suo Lai of 15%FBS containing volumetric concentration (Hyclone)+mass concentration 1%
It is precious) DMEM/F12 basal mediums (GIBCO) suspension cell, be inoculated into 2 floor spaces for 25cm2Blake bottle in.After 7 days
It can be seen that nucleus pulposus cell is substantially adherent, you can change culture medium.Then change within 2-3 days a subculture.
(3) CCK8 methods determine drug cytotoxicity and medicine antiphlogistic effects：Take preceding 3 generation nucleus pulposus in selecting step (3) thin
Born of the same parents are with 5~6 × 103The amount in individual/hole is sowed in 96 orifice plates, after its is adherent, is divided into group 1 to totally 7 groups of group 7, wherein group 1 is
Control group (using 100 μ L basal mediums as control), 10 that DMEM/F12 basal mediums are prepared are used in the addition of group 2-5Mg/ml Thunder Gods
The μ L of rattan red pigment 100 (Celastrol addition is 10nM), 5 × 10 that DMEM/F12 basal mediums are prepared are used in the addition of group 3- 5The μ L of mg/ml Celastrols 100 (Celastrol addition is 50nM), the addition of group 4 is prepared with DMEM/F12 basal mediums
10-4Mg/ml Celastrol μ L (Celastrol addition is 100nM), the addition of group 5 is matched somebody with somebody with DMEM/F12 basal mediums
The 2 × 10 of system-4The μ L of mg/ml Celastrols 100 (Celastrol addition is 200nM), the addition of group 6 DMEM/F12 bases
The 4 × 10 of culture medium preparation-4The μ L of mg/ml Celastrols 100 (Celastrol addition is 400nM), the addition of group 7 is used
The 8 × 10 of DMEM/F12 basal mediums preparation-4The μ L of mg/ml Celastrols 100 (Celastrol addition is 800nM).
Then added in every hole with DMEM/F12 basal mediums configuration (basal medium containing mass concentration 10%：CCK8 working solutions=
9:1) the μ L of CCK8 (DOJINDO) Working dilutions 100.2h is incubated in 37 DEG C of incubators, its each hole absorbance is by ELIASA
Measure.
(4) nucleus pulposus cell of step (2) is divided into 4 groups again, and group 1 is control group (with 100% DMEM/F12 basal mediums
For control), the addition of group 3 10-4Mg/ml Celastrols (Celastrol addition is 100nM)+DMEM/F12 bases culture
Base, the addition of group 42 × 10-4Mg/ml Celastrols (Celastrol addition is 200nM)+DMEM/F12 basal mediums,
After 37 DEG C of culture 2h, group 2, group 3, group 4 abandon after culture medium the IL-1 β+DMEM/F12 bases for being separately added into final concentration 10ng/ml again
Culture medium, after 37 DEG C act on 24 hours, the ELISA for collecting supernatant to inflammatory factor is detected, cell precipitation separation cell egg
White and cell RNA carries out Western blot and qPCR respectively, to detect nucleus pulposus cell its intracellular NF- κ B under inflammatory stimulus
Expression situation of change, and with ELISA detect cell secrete inflammatory factor situation.
(5)Western blots：Take step (4) to act on the cell precipitation RIPA method leach proteins after 24h, and use BCA methods
Survey protein concentration.Take protein extract to add Loading buffer and water, make the quantification of 30 μ g of protein content, 100 DEG C of heating
5min makes albuminous degeneration.The protein liquid added in each hole of PAGE gel after 20 μ l denaturation, PAGE gel electricity
Transferring film is to pvdf membrane after swimming, and 5% skimmed milk power room temperature closes 2h, primary antibody (primary antibody：Primary antibody dilution volume ratio=1:1000)4℃
Overnight, TBST washs pvdf membrane 5min × 4 time, secondary antibody (secondary antibody：TBST volume ratio=1：1000) 2h, TBST washings are incubated at room temperature
5min × 4 time, the development of ECL systems.β-actin take purpose band as internal reference, the pick-up slips of Image lab 3.0 band gray value
Absorbance is used as relative expression quantity with internal reference band ratio.Anti- p-p65, p65, p-I κ B α, I κ B α primary antibodies are purchased in Cell
Signaling Technology, Inc. (Beverly, MA, USA), anti-tnf-alpha and IL-6 primary antibodies are purchased in Santa Cruz
Biotechnology (Santa Cruz, CA, USA), anti-collagen-II and aggrecan primary antibodies are purchased in Abcam
(Cambridge,MA,USA).Secondary antibody is purchased in Santa Cruz Biotechnology (Santa Cruz, CA, USA).
(6) real-time fluorescence quantitative PCR：The cell precipitation for taking step (4) to act on after 24h carries RNA with Trizol methods, and determines
Concentration.Use PrimeScriptTMReverse Transcriptase kit carries out reverse transcription, is tested with SYBR (Shanghai life work) kit, and
Statistics, carries out differential expression analysis.
The target gene primer sequence of table 1
(7) ELISA detects the cellular inflammation factor：Step (4) is taken to act on the supernatant obtained after 24h, according to IL-6 reagents
Box (R＆D Systems, Inc., Minneapolis, MN, USA) operating procedure adds reagent, and detects absorbance with ELIASA.
(8) cellular immunofluorescence：The cell precipitation that step (4) is acted on after 24h is seeded in 6 orifice plate slides, passes through cell
The expression and p65 of Immunofluorescence test each group (packet synchronization rapid (4)) collagen II and proteoglycans it is intracellular
Positioning scenarios.Washed 5 minutes × 3 times, then fixed with 4% paraformaldehyde with PBS.Washed and added behind 5min × 3 time with PBS
0.5% TRITON X-100 processing 10min.5min × 3 time are washed with PBS, then 30min is closed with 5% BSA.Blot
PBS, is added dropwise p65 (1:200, CST) and II Collagen Type VIs antibody (1:200, Abcam), stay overnight for 4 DEG C.Next day, PBS washings 5min × 3
After secondary, with cell green fluorescence secondary antibody (1:400, Bioworld) room temperature lucifuge is incubated 1h.After being washed with PBS, then use DAPI
Contaminate core.Washed again with PBS behind 5min × 3 time, anti-fluorescence quenching, mounting is added dropwise.Take slide in fluorescence microscopy Microscopic observation simultaneously
Shoot.
2nd, experimental result：
(1) the magnetic resonance T2 weightings of simple intervertebral disc degeneration group (IDD in Fig. 1) are as display, and the interverbebral disc of regression is presented bright
Aobvious low signal.And after trypterygine extract for treating (Cel in Fig. 1), the signal of interverbebral disc is relative to intervertebral disc degeneration group (in Fig. 1
IDD) it is obviously improved, it was demonstrated that Celastrol can significantly delay the degree (Fig. 1) of intervertebral disc degeneration.
(2) show after absorbance that we count the ratio of each group absorbance/control group absorbance by CCK8 experiments, knot
Under fruit display 10,50,100, the effect of 200nM Celastrols, nucleus pulposus cell light absorption value and 0nM groups (no Celastrol group) nothing
Notable significant difference, show 10,50,100,200nM Celastrols to cell without notable toxicity；And 400,800nM Thunder Gods
Rattan red pigment group nucleus pulposus cell light absorption value is substantially less than 0nM groups, shows that 400,800nM Celastrols have significant nucleus pulposus cell
Toxicity.By this experiment, it is determined that Celastrol is to the safe concentration of nucleus pulposus cell, i.e. 0~200nM (Fig. 2).
(3) tested by qPCR, it has been found that under IL-1 β stimulations, the extracellular matrix breakdown enzyme table in nucleus pulposus cell
Up to rising, and it was found that after Celastrol processing, MMP and ADAMTS expression are presented dose dependent and declined, i.e. MMP3
(A in Fig. 3), MMP9 (B in Fig. 3), MMP13 (C in Fig. 3) and ADAMTS-4 (D in Fig. 3), ADAMTS-4-5 (E in Fig. 3) table
Raised up to amount under IL-1 β stimulation, decline after 100nMCel is added, further decline after 200nMCel is added,
The inflammatory degraded of extracellular matrix can be reduced by indicating Celastrol.In addition, cellular immunofluorescence experiment also demonstrates thunder
Celastrol can alleviate influences (Fig. 4) of the IL-1 β to nucleus pulposus cell epimatrix.
(4) tested by Western blot, qPCR and ELISA, Celastrol can be reduced under IL-1 β stimulations
The content of the nucleus pulposus cell cellular inflammation factor, it was confirmed that Celastrol has antiinflammatory action (Fig. 5) really.
(5) further protein blot analysis of experiments is passed through, it has been found that Celastrol can be by suppressing NF- κ B signals
Antiinflammatory action (Fig. 6) is played in the activation of path, and this result is also able to checking (figure in p65 cellular immunofluorescence experiment
7)。
In addition, Celastrol of the present embodiment as known structure, can contain directly from market purchasing or chemical synthesis
The pharmaceutical composition of Celastrol can be some long-acting or local sustained release preparations, for example, it is possible to use modern medicine
Some biomaterials, including polycaprolactone, polylactic acid-polyglycol, polyvinyl alcohol etc., Celastrol is contained, is formed
Compound formulation.Also there are some researches show tripterygium wilfordii has certain cytotoxicity.Matched somebody with somebody under instruction of Chinese Medicine theory by Chinese medicine
The toxicity of 5 reduction tripterygium wilfordiis, is an important method of tripterygium wilfordii attenuation, for example, can mitigate liver poison with root of herbaceous peony combination drug
Property, its genotoxicity to male etc. can be reduced with barrenwort combination drug.Drug matching attenuation research need to will be traditional in
Medical knowledge opinion is combined with modern diseases pathogenesis, sets up appropriate theoretical evaluation index, using modern detection means and method,
Carry out tripterygium wilfordii compatibility attenuation Mechanism Study, filter out the optimal compatibility of attenuation synergistic, deeply recognize the toxic action of tripterygium wilfordii
With workaround so that preferably improve tripterygium wilfordii application security and clinical value.
Claims (6)
1. a kind of application of Celastrol in preparing treatment and delaying intervertebral disk retrogression lesion medicine.
2. application as claimed in claim 1, it is characterised in that the Celastrol molecular structural formula is shown in formula (I)：
3. application as claimed in claim 1, it is characterised in that the medicine also includes pharmaceutical carrier.
4. application as claimed in claim 3, it is characterised in that the pharmaceutical carrier is micro emulsion or liposome.
5. application as claimed in claim 4, it is characterised in that the medicine is tablet, capsule or emulsion.
6. application as claimed in claim 3, it is characterised in that in the medicine consumption of Celastrol be 4mg/kg~
0.213g/g。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114533703A (en) * | 2022-03-08 | 2022-05-27 | 河南省人民医院 | Tripterine composite membrane and preparation method and application thereof |
| CN115252811A (en) * | 2022-07-13 | 2022-11-01 | 山西医科大学 | Activatable diagnosis and treatment integrated nanoprobe and preparation method and application thereof |
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| WO2008148016A1 (en) * | 2007-05-25 | 2008-12-04 | University Of Pittsburgh- Of The Commonwealth System Of Higher Education | Inhibiting the signs of aging by inhibiting nf-kappa b activation |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008148016A1 (en) * | 2007-05-25 | 2008-12-04 | University Of Pittsburgh- Of The Commonwealth System Of Higher Education | Inhibiting the signs of aging by inhibiting nf-kappa b activation |
Non-Patent Citations (2)
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| 孙中仪等: "NF－kB信号通路与椎间盘退变的研究进展", 《中国矫形外科杂志》 * |
| 梁鹤等: "NF － κB 信号通路的激活与椎间盘退变的关系", 《中国矫形外科杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114533703A (en) * | 2022-03-08 | 2022-05-27 | 河南省人民医院 | Tripterine composite membrane and preparation method and application thereof |
| CN114533703B (en) * | 2022-03-08 | 2024-05-31 | 河南省人民医院 | Tripterine composite film and preparation method and application thereof |
| CN115252811A (en) * | 2022-07-13 | 2022-11-01 | 山西医科大学 | Activatable diagnosis and treatment integrated nanoprobe and preparation method and application thereof |
| CN115252811B (en) * | 2022-07-13 | 2024-02-09 | 山西医科大学 | Activatable diagnosis and treatment integrated nano probe and preparation method and application thereof |
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