CN104666313A - Application of ginkgolic acid in preparation of medicine for preventing and/or treating diseases caused by overactivity of osteoclast - Google Patents
Application of ginkgolic acid in preparation of medicine for preventing and/or treating diseases caused by overactivity of osteoclast Download PDFInfo
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Abstract
The invention belongs to the field of medicines, relates to novel pharmaceutical application of ginkgolic acid and particularly relates to application of ginkgolic acid (C17:1), which is a syzygiumtetragonum extract having a structural formula show in the specification, in preparation of a medicine for preventing and/or treating diseases caused by overactivity of osteoclast. The ginkgolic acid (C17:1) is capable of preventing nuclear translocation of NFATc1 and inhibiting differentiation and bone erosion of osteoclast and thus is used for preparing the medicine for preventing and treating the diseases including osteoporosis, osteolysis, rheumatoid arthritis, multiple myeloma, Paget's disease, hypercalcemia of tumors, osteogenesis imperfect, alveolar bone deficiency or bone loss caused during immunosuppressive therapy or long-term use of glucocorticoid.
Description
Technical field
The invention belongs to drug world, relate to the pharmaceutical usage that ginkgoic acid is new.Be specifically related to corner Jambul extract ginkgoic acid (C17:1) and prepare the application prevented and/or treated in osteoclast overactivity associated diseases medicine.Described ginkgoic acid (C17:1) is by stoping NFATc1 nuclear translocation, suppress differentiation of osteoclast and bone erosion ability, the hypercalcemia of malignant tumor, osteogenesis imperfecta, alveolar bone sick for the preparation of prevention and therapy osteoporosis, bone dissolvings, rheumatoid arthritis, multiple myeloma, Paget ' s lack or the medicine of the disease such as the bone loss caused of immunosuppressant therapy or life-time service glucocorticoid.
Background technology
Research display, osteoclast is the polarity apocyte with heavily absorption sclerotin ability from myeloid cell system.The osteoclast being attached to bone surface makes the calcareous dissolving in skeleton by the sour environment that the proton pump of ruffled border is set up, the substrate enzyme synthesized by osteoclast, comprises cathepsin K, MMP9 and TRAP, then degradable bone matrix.Large quantity research shows, the overactivity of osteoclast causes the imbalance of bone remodeling, causes the bone-related disorder such as hypercalcemia of the dissolving of osteoporosis, bone, rheumatoid arthritis, multiple myeloma, malignant tumor further.There is research in the arthritis animal model of induce by adjuvant, collagen, serum or TNF, in the pathological process that discovery osteoclast corrodes in ossa articularia, play vital effect; Then there is not bone erosion in the arthritic mice lacking osteoclast.Therefore, osteoclast is the key cells in bone erosion process.Focus at present by suppressing the above-mentioned various disease of osteoclast activity treatment to become drugmaker and each large pharmaceutical factory concern just gradually, wherein representative drugs is Denosumab, this medicine is humanized antibody, optionally in conjunction with activating T cell nuclear factor c1(nuclear factor of activated T cell1, NFATc1) differentiation of osteoclast is suppressed, stop the generation of bone erosion and periarticular bone-loss, this medicine listing in 2008, and is widely used in the treatment of above-mentioned various disease.
Current research shows nuclear factor of activated T cells c1(NFATc1) as transcription factor, in the atomization of osteoclast, play very crucial effect.Research display, intracellular calcium (Ca2+) wave energy of directly being induced by RANKL causes intracellular Ca2+ adjust phosphokinase phosphorylation and then optionally activate NFATc1, impel its transposition to enter core, thus start the gene expression depending on NFATc1 in differentiation of osteoclast process.NFATc1 can be induced to express, even if the embryonic stem cell RANKL path normal Activate of not expressing NFATc1 can not break up become osteoclast by Nuclear factor kappa B part (RANKL) receptor two downstream signaling pathway-TRAF6 and c-Fos.Because NFATc1 is as a kind of transcriptional regulatory factor, be mainly positioned in Cytoplasm when disactivation, once activation namely constantly transposition enter its biological effect of core competence exertion, thus NFATc1 becomes and suppresses the differentiation of osteoclast and the novel targets of bone erosion.
Medicine corner Jambul, south (Syzygiumtetragonum) root that is Myrtaceae (Myrtaceae) Syzygium (Syzygium) plant corner Jambul (Syzygiumtetragonum), primary growth in Guangdong, Hainan, Guangxi, the ground such as Yunnan.Acrid in the mouth is bitter, slightly warm in nature.Have expelling wind and removing dampness, effect of reducing swelling and alleviating pain, cures mainly rheumatic arthralgia, the diseases such as treating swelling and pain by traumatic injury, is used for the treatment of various joint disease by among the people.Research at present for its active ingredient and therapeutic efficiency rarely has report.
Summary of the invention
The object of this invention is to provide the pharmaceutical usage that corner Jambul extract ginkgoic acid is new, be specifically related to ginkgoic acid (C17:1) and preparing the application prevented and/or treated in osteoclast overactivity associated diseases medicine.Described ginkgoic acid (C17:1) is by stoping NFATc1 nuclear translocation, suppress differentiation of osteoclast and bone erosion ability, the hypercalcemia of malignant tumor, osteogenesis imperfecta, alveolar bone sick for the preparation of prevention and therapy osteoporosis, bone dissolvings, rheumatoid arthritis, multiple myeloma, Paget ' s lack or the medicine of the disease such as the bone loss caused of immunosuppressant therapy or life-time service glucocorticoid.
Research design of the present invention targeting NFATc1 transposition enters the living cells screening system of core, screening active ingredients is carried out to the compound be separated in the Jambul of corner, result shows, wherein compound ginkgoic acid (C17:1) can obviously stop NFATc1 transposition to enter core, can obviously suppress myelomonocyte to the differentiation of osteoclast and bone erosion ability.
Compound ginkgoic acid (C17:1) structural formula of the present invention is as follows:
Its molecular formula is C
24h
38o
3, molecular weight is 374.561, chemistry 6-[10 ' (Z)-heptadecene base] salicylic acid by name.
Described ginkgoic acid (C17:1) is prepared by following method:
Adopt Chinese medicine corner Jambul medical material, through alcohol reflux 3 times, filtrate decompression is reclaimed, makes extractum evaporate to dryness and obtain crude extract, then become saturated solution with the dissolve with ethanol of 95%, filter with macroporous resin, use 95%EtOH eluting; With 1 times amount polycaprolactam after eluent concentrating under reduced pressure, with 95%EtOH eluting, monitor with TLC and concentrate effective site, being drying to obtain ginkgoic acid (C17:1) finished product.
In the present invention, our experiments show that, described ginkgoic acid (C17:1) can stop NFATc1 to transposition in core, obvious suppression myelomonocyte is to the differentiation of osteoclast, the characteristic enzyme Tartrate resistant acid phosphatase (TRAP) reducing osteoclast cell activation is expressed, lower expression and the enzymatic activity of the downstream target gene sclerotin digestive enzyme MMP9 of NFATc1, suppress the bone erosion ability of osteoclast.Further, the medicine of the diseases such as described ginkgoic acid (C17:1) is sick for the preparation of prevention and therapy osteoporosis, bone dissolving, rheumatoid arthritis, multiple myeloma, Paget ' s, the bone loss caused of the hypercalcemia of malignant tumor, osteogenesis imperfecta, alveolar bone disappearance or immunosuppressant therapy or life-time service glucocorticoid.
The invention provides compositions that ginkgoic acid (C17:1) containing effective dose and pharmacy can accept composition suppresses in differentiation of osteoclast and function medicament application in preparation.
The ginkgoic acid (C17:1) for the treatment of effective dose and any one adjuvant of pharmaceutically allowing can be made pharmaceutical composition according to the present invention, or add other and ginkgoic acid (C17:1) and make pharmaceutical composition without other anti-differentiation of osteoclasts of antagonism and function medicament.Or, in the medicine of suppression differentiation of osteoclast of the present invention, add one or more pharmaceutically acceptable carriers; Its preparation can be pharmaceutically any one dosage form, includes but not limited to last agent, powder, tablet, pill, drop, granule, suspending agent, solution, capsule, sugar-coat agent, oral liquid, injection, liposome, sublingual lozenge etc.
Instant invention overcomes the weak point that conventional Chinese medicine exists, find from Chinese medicine and obtain the compound monomer that pharmacological action target spot is clear and definite, have suppression osteoclast activity and function, be specifically related to corner Jambul extract ginkgoic acid, be further used for preparing the medicine that prevention and therapy osteoclast activity strengthens the diseases such as the various diseases that causes is as sick in osteoporosis, rheumatoid arthritis, multiple myeloma, Paget ' s, the hypercalcemia of malignant tumor.
Accompanying drawing explanation
Fig. 1: ginkgoic acid (C17:1) (YXS) suppresses the dose-effect relationship of NFATc1 nuclear translocation,
Wherein, EGFP-NFATc1U2OS cell strain uses 6.25 respectively, 12.5,25, and50 μM of ginkgoic acid (C17:1) processes 2h, afterwards with carbachol 2 μMs process 30min, cell is fixed and is carried out High content screening with after hochest dye core, (A) High content screening gained cytological map, (B) be caryoplasm fluorescence difference (* p<0.05, * * p<0.01 and after stimulating without compared with dosing group) quantitatively.
Fig. 2: ginkgoic acid (C17:1) (YXS) to the inhibitory action of the osteoclast precursor cells NFATc1 nuclear translocation that RANKL induces,
Wherein, adopt 50ng/ml RANKL and 0,6.25,12.5,25 μMs of ginkgoic acids (C17:1) (YXS) process RAW264.7 cell two days, extract nucleoprotein and plasmosin, and total protein carry out Western Blot analysis, with GAPDH as internal reference.
Fig. 3: ginkgoic acid (C17:1) on the impact of differentiation of osteoclast,
Wherein, osteoclast precursor cells 50ng/ml RANKL process 5 days, add 0 respectively simultaneously, 3.125,6.25,12.5,25 μMs of ginkgoic acid (C17:1) process, when the 6th day, taking-up is carried out TRAP dyeing, is taken pictures, (A) situation of osteoclast formation after TRAP dyeing under microscope, (B) TRAP Positive Cell Counts (* * p<0.01), (C) osteoclast precursor cells uses 12.5 respectively, 25,50 μMs of ginkgoic acids (C17:1) carry out CCK-8 method cytotoxicity experiment after processing 5 days.
Fig. 4: the expression of the significant gene of differentiation of osteoclast lowered by ginkgoic acid (C17:1),
Wherein, osteoclast precursor cells 50ng/ml RANKL and variable concentrations ginkgoic acid (C17:1) (0,3.125,6.25,12.5,25 μMs) after process, within the 6th day, carry out quantitative RT-PCR, analyze the amount of the mRNA of generation of transcribing, TRAP (A), Cts K, (B), MMP9, (C) (* p<0.05, * p<0.01), the culture medium supernatant that (D) collecting cell is cultivated carries out the experiment of gelatin zymogram, analyzes the activity of MMP9.
Fig. 5: ginkgoic acid (C17:1) on the impact of osteoclastic bone corrosion function,
Wherein, osteoclast precursor cells is inoculated on osteocomma, with 50ng/ml RANKL and ginkgoic acid (C17:1) 0,3.125,6.25,12.5 or 25 μMs process 6 days, after washing away cell, fix with cma staining, take pictures under simple microscope (A), bone erosion region Image-Pro Plus program software carries out areal calculation (B), (* p<0.05, * * * p<0.001).
Detailed description of the invention
Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned especially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
Embodiment 1: ginkgoic acid (C17:1) suppresses the dose-effect relationship of NFATc1 nuclear translocation
Principle: the change in fluorescence that what high intension instrument can be quantitative detect in endochylema and core.In the EGFP-NFATc1-U2OS stable cell strain adopted, NFATc1 is by green fluorescent protein (GFP) labelling, so according to the fluorescence change in endochylema and core and cell picture, can judge the distribution of NFATc1, thus judges that it enters core amount.Adopt carbachol to enter the stimulant of core as NFATc1 transposition, first preliminary experiment determines the best use of time and the dosage of stimulation.
Method: EGFP-NFATc1U2OS cell is inoculated in 96 orifice plate cultured cells, first use 6.25 respectively, 12.5,25,50 μMs of ginkgoic acids (C17:1) (YXS) process 2 hours, add carbachol 2 μMs process 30min again, cell is fixed and is utilized high intension instrument to detect fluorescence distribution inside and outside nucleus with after hochest dye core.Result and evaluation: Fig. 1 result shows, after 2M carbachol stimulation time 30min, endonuclear NFATc1 obviously increases; Through 6.25,12.5,25, the cell that ginkgoic acid (C17:1) (YXS) of 50 μMs processes, its endonuclear NFATc1 obviously reduces, and shows that ginkgoic acid (C17:1) can suppress NFATc1 transposition enter core in concentration dependent ground.
Embodiment 2: ginkgoic acid (C17:1) is to the inhibitory action of the osteoclast precursor cells NFATc1 nuclear translocation that RANKL induces
Principle: RANKL approach is considered to the critical path in differentiation of osteoclast forming process.The intracellular calcium fluctuation that RANKL directly induces causes intracellular Ca2+ adjust phosphokinase phosphorylation and then optionally activate NFATc1, impels its transposition to enter core, thus starts the gene expression depending on NFATc1 in differentiation of osteoclast process.Disappearance NFATc1, even if RANKL path normal Activate can not break up become osteoclast.
Method: osteoclast precursor cells RAW264.7 cell is inoculated in middle Tissue Culture Dish, adopts 50ng/ml RANKL and 0,6.25,12.5,25M ginkgoic acid (C17:1) (YXS) to process two days.Nucleoprotein separating kit extracts nucleoprotein and plasmosin, and total protein carries out Western Blot analysis, using GAPDH as internal reference.
Evaluation of result: after ginkgoic acid (C17:1) (YXS) process, in nucleus, NFATc1 protein content reduces successively with concentration rising (6.25,12.5,25 μMs), endochylema NFATc1 concentration presents contrary variation tendency, and the total protein NFATc1 extracted after identical pretreatment measures constant (Fig. 2).Ginkgoic acid (C17:1) also can very effectively suppress NFATc1 nuclear translocation in osteoclast precursor cells RAW264.7 cell as can be seen here.
Embodiment 3: ginkgoic acid (C17:1) is to the inhibitory action of differentiation of osteoclast
Principle: myelomonocyte is under the lasting stimulation of M-CSF (M-CSF) and RANKL, iuntercellular contacts with each other to merge and forms apocyte, and be differentiated to form the mature osteoclast with ring structure, and secrete osteoclast characteristic enzyme Tartrate resistant acid phosphatase (TRAP), by carrying out TRAP dyeing, the quantity of osteoclast formation can be detected.
Method: be separated myelomonocyte from C57/BL6 mouse femur, after counting, adjustment cell density is 100,000/mL, and add the recombined small-mouse M-CSF (M-CSF) of 30ng/mL, be inoculated in 96 well culture plates, every hole adds 100 μ L.Second day is the RANKL induction of 50ng/mL by concentration, adds 0 respectively, 3.125,6.25,12.5, the ginkgoic acid (C17:1) of 25 μMs simultaneously; Every other day change derivant and medicine, and observation of cell form.Cultivate after 6 days, carry out Tartrate resistant acid phosphatase (TRAP) dyeing.Taking pictures in the random selecting visual field, and counts stained positive cell number, carries out statistical analysis.Meanwhile, use 12.5 respectively to osteoclast precursor cells, 25,50 μMs of ginkgoic acids (C17:1) carry out CCK-8 method cytotoxicity experiment after processing 5 days.
Result and evaluation: as shown in figs 3 a andb, after variable concentrations ginkgoic acid (C17:1) (YXS) process, the quantity of osteoclast formation presents the reduction of dose dependent, 12.5, occurs significant suppression (* * p<0.01 is compared with last dosing group) when 25 μMs.CCK-8 method cytotoxicity experiment shows, ginkgoic acid (C17:1) in experimental concentration to osteoclast precursor cells no cytotoxicity.
Embodiment 4: the expression of the significant gene of differentiation of osteoclast lowered by ginkgoic acid (C17:1)
Principle: ripe osteoclast high expressed also secretes three kinds of significant enzymes, i.e. Tartrate resistant acid phosphatase (TRAP), cathepsin K (Ctsk), MMP-9 (MMP9), these three kinds of enzymes are key enzymes that osteoclast carries out bone erosion.
Method: be separated myelomonocyte from C57/BL6 mouse femur, after counting, adjustment cell density is 100,000/mL, and add the recombined small-mouse M-CSF (M-CSF) of 30ng/mL, be inoculated in 96 well culture plates, every hole adds 100 μ L.Second day is the RANKL induction of 50ng/mL by concentration, adds 0 respectively, 3.125,6.25,12.5, the ginkgoic acid (C17:1) of 25 μMs simultaneously; Every other day change derivant and medicine, and observation of cell form.Cultivate after 6 days, extract cell RNA, by PrimeScript
tMrT test kit (purchased from Takara, Dalian, China) illustrates that reverse transcription becomes cDNA.Carry out quantitative PCR reaction afterwards.(using SYBR Green II Master Mix, purchased from China) with β-actin for internal reference.Primer sequence (5' to 3'): TRAP, forward-GCAGTATCTTCAGGACGAGAAC, reverse-TCCATAGTGAAACCGCAAGTAG; MMP9, forward-TCCGTGTCCTGTAAATCTGC, reverse-TCCGTGTCCTGTAAATCTGC; Ctsk, forward-CTTAGTCTTCCGCTCACAGTAG, reverse-ACTTGAACACCCACATCCTG.Meanwhile, collect the culture fluid of above-mentioned cell, gelatin zymography detects the enzymatic activity of MMP9.
Result and evaluation: ginkgoic acid (C17:1) (YXS) dose-dependently can lower the expression (* p<0.05, * * p<0.01 and last dosing group contrast) of significant gene TRAP, Ctsk, MMP9mRNA of differentiation of osteoclast; And the MMP9 be secreted into outside born of the same parents obviously reduces, reduced activity.
Embodiment 5: ginkgoic acid (C17:1) is to the inhibitory action of osteoclast bone erosion
Principle: ripe osteoclast high expressed also secretes three kinds of significant enzymes, i.e. Tartrate resistant acid phosphatase (TRAP), cathepsin K (Ctsk), MMP-9 (MMP9), these three kinds of enzymes are key enzymes that osteoclast carries out bone erosion.
Method: be separated myelomonocyte from C57/BL6 mouse femur, after counting, adjustment cell density is 100,000/mL, be inoculated in osteocomma (purchased from Corning, US) surface, add the recombined small-mouse M-CSF (M-CSF) of 30ng/mL, second day is the RANKL induction of 50ng/mL by concentration, add 0 respectively, 3.125,6.25 simultaneously, the ginkgoic acid (C17:1) of 12.5,25 μMs; Every other day change derivant and medicine, and observation of cell form.Cultivate after 6 days, osteocomma is taken out and carries out cma staining, subsequently osteocomma is taken pictures, and corrode the gross area by Image-Pro Plus program computed in software.
Result and evaluation: ginkgoic acid (C17:1) (YXS) can dose-dependently reduce bone erosion area, the bone erosion ability (* p<0.05, * * * p<0.001 is compared with last dosing group) of osteoclast is significantly suppressed in 6.25 to 25 μMs of dosage ranges.
Claims (5)
1. ginkgoic acid (C17:1) compound of following structural formula is preparing the application prevented and/or treated in osteoclast overactivity associated diseases medicine,
2. purposes according to claim 1, is characterized in that, described ginkgoic acid (C17:1) compound suppresses differentiation of osteoclast and function.
3. purposes according to claim 1, it is characterized in that, described osteoclast overactivity associated diseases is selected from that osteoporosis, rheumatoid arthritis, multiple myeloma, Paget ' s are sick, the hypercalcemia of malignant tumor, osteogenesis imperfecta or alveolar bone disappearance are sick.
4. purposes according to claim 1, is characterized in that, described medicine contains the ginkgoic acid of effective dose (C17:1) and pharmacy can accept composition.
5. purposes according to claim 1, it is characterized in that, described medicine is that the ginkgoic acid (C17:1) for the treatment of effective dose and any one adjuvant of pharmaceutically allowing are made pharmaceutical composition, or adds other and ginkgoic acid (C17:1) and make pharmaceutical composition without other anti-differentiation of osteoclasts of antagonism and function medicament.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111991405A (en) * | 2020-08-28 | 2020-11-27 | 广州中医药大学第一附属医院 | Application of curdione and ginkgoneoic acid in preparation of bone formation promoting medicine |
| CN114980872A (en) * | 2019-12-30 | 2022-08-30 | 庆北大学校产学协力团 | Pharmaceutical composition for preventing or treating bone diseases comprising 4-hexylresorcinol as an active ingredient |
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| CN102641278A (en) * | 2012-04-06 | 2012-08-22 | 王青 | Application of ginkgolic acid in treating arthritis |
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| CN102641278A (en) * | 2012-04-06 | 2012-08-22 | 王青 | Application of ginkgolic acid in treating arthritis |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114980872A (en) * | 2019-12-30 | 2022-08-30 | 庆北大学校产学协力团 | Pharmaceutical composition for preventing or treating bone diseases comprising 4-hexylresorcinol as an active ingredient |
| CN111991405A (en) * | 2020-08-28 | 2020-11-27 | 广州中医药大学第一附属医院 | Application of curdione and ginkgoneoic acid in preparation of bone formation promoting medicine |
| CN111991405B (en) * | 2020-08-28 | 2021-10-29 | 广州中医药大学第一附属医院 | Application of curdione and ginkgoneoic acid in preparation of bone formation promoting medicine |
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