CN105640938A - Application of andrographalide in medicine for treating osteoarticular retrograde affection - Google Patents
Application of andrographalide in medicine for treating osteoarticular retrograde affection Download PDFInfo
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- CN105640938A CN105640938A CN201610038936.2A CN201610038936A CN105640938A CN 105640938 A CN105640938 A CN 105640938A CN 201610038936 A CN201610038936 A CN 201610038936A CN 105640938 A CN105640938 A CN 105640938A
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- rographolide
- retrograde affection
- osteoarticular retrograde
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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
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/19—Acanthaceae (Acanthus family)
Abstract
The invention discloses application of andrographalide in medicine for treating osteoarticular retrograde affection. The effect of andrographalide on osteoarticular retrograde affection is researched. Experiments show that andrographalide can act on multiple links or multiple target spots of osteoarticular retrograde affection, effectively restrain cartilago articularis matrix degradation, protect function completion of cartilage cells, restrain osteoarticular retrograde changes and finally promote repair of osteoarticular retrograde affection. Andrographalide is directly injected in articular cavities, has a better and more direct effect on improving osteoarticular retrograde affection, and is a new medicine which has potential value and is used for osteoarticular retrograde affection.
Description
Technical field
The present invention relates to medical field, specifically relating to rographolide to the provide protection of interleukin-1 �� (IL-1 ��) Induction of chondrocytes and take rographolide as the application of raw material in preparation treatment osteoarticular retrograde affection medicine.
Background technology
Osteoarticular retrograde affection is a clinical difficult problem urgently to be resolved hurrily, owing to wound and various disease such as osteoarthritis, osteonecrosis etc. cause osteoarticular retrograde affection very common on clinical. Osteoarticular retrograde affection treatment has become focus and the difficult point of orthopaedics and basis, relevant field and clinical study in recent years. Research at present shows, multiple somatomedin plays a significant role in the treatment of osteoarticular retrograde affection, comprises TGF-�� 1, IGF-1, FGF etc. But there is many drawbacks such as extraction process complexity, expensive, easy degraded at present conventional somatomedin, is unfavorable for clinical application widely. Owing to articular chondrocytes is unique cellular constituent in cartilage, and articular chondrocytes is the key of balance of cartilage matrix synthesis and function of organization's metabolism, it is seen that articular chondrocytes is to the importance of joint cartilage. Therefore, being badly in need of exploitation and find more easily extracting, with low cost, the medicine of the cartilage integrity effect that has protection chondrocyte simultaneously, improves cartilage metabolism, maintains is for improving osteoarticular retrograde affection.
Herba Andrographis (Andrographispaniculata (Burm.f) Ness) has another name called Chun Lianqiuliu, Radix Gentianae, gold tack etc., is Acanthaceae Herba Andrographis platymiscium, is the conventional herbal medicine of Zhuang nationality in Guangxi analgesic antiphlogistic among the people. Its main active ingredient rographolide (Andrographolide, AD) has thermal detoxification of dispelling, and the effect of osteoarticular retrograde affection be there is no report by effect of anti-inflammatory analgetic.
Summary of the invention
It is an object of the invention to provide a kind of safe and effective, cheap, the medicine that can apply that improve osteoarticular retrograde affection.
For completing above object, the present invention by the following technical solutions:
One, the preparation of rographolide
Extracting method: dry Folium Andrographis 10kg with the 75% cold leaching of ethanol of 100L, obtains leach liquor gac reflux decolour, takes out filter while hot after pulverizing. Reclaim ethanol, slowly add water, place analysis brilliant, take out filter, obtain coarse crystallization thing. The a small amount of water washing of coarse crystallization thing, 95% ethanol heating for dissolving, 1% gac backflow 30min, filters, and it is brilliant that filtrate places analysis, takes out filter, obtains white coarse crystallization 201.54g.
Purification process: white coarse crystallization is dissolved in methyl alcohol, is splined on neutral alumina column. With acetate-methanol-water different ratios and 25:0.1:0; 12:0.4:0; 0:1:0; 0:5:5; 0:3.5:6.5 carries out gradient elution. Thin-layer chromatography is followed the tracks of, and merges similar evaporate point. Evaporating point of merging 0:3.5:6.5 acetate-methanol-water elution, reclaims eluent, obtains white crystals 48.24mg.
Two, rographolide is to the protection of the beta induced chondrocyte of external IL-1
(1) extraction of chondrocyte: under aseptic condition, cartilaginous tissue is isolated from the epiphysis end of the four limbs bone of New Zealand breast rabbit, use trysinization 0.5h, damping fluid (PBS) adds Type �� collagen enzymic digestion 3h after washing, supernatant liquor is proceeded to the centrifugal 5min of centrifuge tube 1000r/min, adding the DMEM in high glucose substratum containing 15% foetal calf serum (FBS), 1% mycillin resuspended, cell cultures puts into 37 DEG C, 5%CO2And the incubator of moisture-saturated is cultivated, within every 2��3 days, change a not good liquor; When cell grows to 90% degrees of fusion, go down to posterity with trysinization, it is expanded to required cell quantity.
(2) cell toxicity test: the first-generation rabbit articular chondrocytes selecting growth conditions good, PBS rinses one time, collected by trypsinisation cell, is inoculated in 96 orifice plates after counting, and every porocyte amount is 5 �� 103Individual. After cell attachment, inhaling by liquid in hole, add the DMEM in high glucose substratum containing different concns rographolide (0��50mM), each concentration repeats 6 multiple holes. Cultivating after three days, every hole adds the tetrazolium bromide (MTT) of 20 �� L, and incubator hatches 4h, abandons supernatant liquor, and every hole adds DMSO200 �� L, and 570nm surveys absorption value. Filter out the rographolide of suitable concentration, for next step experiment.
(3) after first-generation cell dissociation counts, being inoculated in 24 and 6 orifice plates, every porocyte amount is respectively 2 �� 104��1��105Individual. After cell attachment; add the DMEM in high glucose perfect medium containing rographolide; the beta induced 24h of 10ng/mLIL-1 is added after 1h; related gene expression is detected by Fluorescent quantitative PCR (Realtime-PCR) method; the expression of immunohistochemical method detection associated protein, thus identify that rographolide is to the provide protection of the beta induced chondrocyte of IL-1.
Three, rographolide is improving the application of osteoarticular retrograde affection
To new zealand rabbit hind leg knee joint capable before and after ligamentaum cruciatum cut off art, formed osteoarticular retrograde affection model, by direct injection rographolide in joint cavity, observe it to the effect of osteoarticular retrograde affection. Getting rabbit bilateral knee joint, whether visual inspection has proud flesh and articular cartilage face ulceration, is observed by femur ankle joint cartilage surface under dissecting microscope, and joint cartilage is marked by Pelletier cardinal principle standards of grading. Direct injection rographolide in result display joint cavity, can obviously improve osteoarticular retrograde affection.
Matrix metalloproteinase (matrixmetalloproteinases is detected by qRT-PCR; MMPs) genetic expression; result display rographolide can obviously reduce MMPs expresses; comprise the expression level of MMP-1, MMP-3 and MMP-13 gene and albumen; significantly improve tissue inhibitor of metalloproteinase (tissueinhibitorofmetalloproteinases; Timp-1) expression of gene and albumen; prompting rographolide has the effect of antagonism joint cartilage substrate degradation, thus protects the integrity of bone articular cartilage.
The advantage of the present invention:
The present invention studies rographolide first to the effect of osteoarticular retrograde affection; experiment shows; rographolide can act on multiple link of osteoarticular retrograde affection or multiple target spot; effectively suppress joint cartilage substrate degradation, protection chondrocyte function complete, suppress Articular cartilage degeneration, the final reparation promoting osteoarticular retrograde affection. Direct injection in rographolide joint cavity, has better more directly act on improving osteoarticular retrograde affection, be a kind of new drug with potential value of osteoarticular retrograde affection.
Accompanying drawing explanation
Fig. 1, MTT detect rographolide to chondrocyte's toxicity test result (n=5, compares * p < 0.05, * * p < 0.01, * * * p < 0.001 with 0 ��M). Fig. 2, qRT-PCR detect rographolide chondrocyte's Timp-1, MMP-1, MMP-3 and MMP-13 gene expression results (n=6, Control group expression blank group that external IL-1 is beta induced; IL-1 �� group represents the IL-1 �� adding 10ng/mL; C1 group expression adds 1.56 ��Ms of rographolides and 10ng/mLIL-1 ��; C2 group expression adds 3.125 ��Ms of rographolides and 10ng/mLIL-1 ��; C3 group expression adds 6.25 ��Ms of rographolides and 10ng/mLIL-1 ��; Same time point, compares * p < 0.05, * * p < 0.01, * * * p < 0.001 with Control group). Fig. 3, to the beta induced chondrocyte MMP-1 of external IL-1 and Timp-1 protein expression detected result, (Control group represents blank group to Immunohistochemical detection rographolide; IL-1 �� group represents the IL-1 �� adding 10ng/mL; C1 group expression adds 1.56 ��Ms of rographolides and 10ng/mLIL-1 ��; C2 group expression adds 3.125 ��Ms of rographolides and 10ng/mLIL-1 ��; C3 group expression adds 6.25 ��Ms of rographolides and 10ng/mLIL-1 ��). Fig. 4, condyle of femur joint cartilage gross examination of skeletal muscle result (GroupA: sham operated rats, GroupB: model group, GroupC: rographolide group). Fig. 5, condyle of femur joint cartilage is appraisal result (same time point, compares * p < 0.05, * * p < 0.01, * * * p < 0.001 with GroupA for n=8, GroupA: sham operated rats, GroupB: model group, GroupC: rographolide group) substantially. Fig. 6, qRT-PCR detects rographolide to osteoarticular retrograde affection genes involved MMP-1, MMP-3, MMP-13 and Timp-1 expression of results (n=8, GroupA: sham operated rats, GroupB: model group, GroupC: rographolide group, same time point, compares * p < 0.05 with GroupA, * p < 0.01, * * * p < 0.001).
Embodiment
One, the preparation of rographolide
Extracting method: dry Folium Andrographis 10kg with the 75% cold leaching of ethanol of 100L, obtains leach liquor gac reflux decolour, takes out filter while hot after pulverizing. Reclaim ethanol, slowly add water, place analysis brilliant, take out filter, obtain coarse crystallization thing. The a small amount of water washing of coarse crystallization thing, 95% ethanol heating for dissolving, 1% gac backflow 30min, filters, and it is brilliant that filtrate places analysis, takes out filter, obtains white coarse crystallization 201.54g.
Purification process: white coarse crystallization is dissolved in methyl alcohol, is splined on neutral alumina column. With acetate-methanol-water different ratios and 25:0.1:0; 12:0.4:0; 0:1:0; 0:5:5; 0:3.5:6.5 carries out gradient elution. Thin-layer chromatography is followed the tracks of, and merges similar evaporate point. Evaporating point of merging 0:3.5:6.5 acetate-methanol-water elution, reclaims eluent, obtains white crystals 48.24mg.
Two, rographolide is to the protection of the beta induced chondrocyte of external IL-1
(1) extraction of chondrocyte: under aseptic condition, cartilaginous tissue is isolated from the epiphysis end of the four limbs bone of New Zealand breast rabbit, use trysinization 0.5h, damping fluid (PBS) adds Type �� collagen enzymic digestion 3h after washing, supernatant liquor is proceeded to the centrifugal 5min of centrifuge tube 1000r/min, adding the DMEM in high glucose substratum containing 15% foetal calf serum (FBS), 1% mycillin resuspended, cell cultures puts into 37 DEG C, 5%CO2And the incubator of moisture-saturated is cultivated, within every 2��3 days, change a not good liquor; When cell grows to 90% degrees of fusion, go down to posterity with trysinization, it is expanded to required cell quantity. Basis of microscopic observation can see multiangular chondrocyte.
(2) cell toxicity test: the first-generation rabbit articular chondrocytes selecting growth conditions good, PBS rinses one time, collected by trypsinisation cell, is inoculated in 96 orifice plates after counting, and every porocyte amount is 5 �� 103Individual. After cell attachment, inhaling by liquid in hole, add the DMEM in high glucose substratum containing different concns rographolide, each concentration repeats 6 multiple holes. Cultivating after three days, every hole adds the tetrazolium bromide (MTT) of 20 �� L, and incubator hatches 4h, abandons supernatant liquor, and every hole adds DMSO200 �� L, and 570nm surveys absorption value. Analyzing by SPSS statistical software result data, P value is less than 0.001 and represents with * * *, is less than 0.01 and represents with * *, is less than 0.05 and represents with *. Result shows, and rographolide is 1.56 ��Ms, 3.125 ��Ms and 6.25 ��Ms in concentration, obviously promotes chondrocyte proliferation. See Fig. 1.
(3) grouping and process: first-generation cell dissociation is inoculated in 6 orifice plates and is placed with in 24 orifice plates of sheet glass after counting, and every porocyte amount is respectively 1 �� 105��2��104Individual. After cell attachment, adding the DMEM in high glucose perfect medium containing rographolide, substratum contains the rographolide of three concentration respectively: C1 group, 1.56 ��Ms of rographolide+10ng/mLIL-1 ��; C2 group, 3.125 ��Ms of rographolide+10ng/mLIL-1 ��; C3 group, 6.25 ��Ms of rographolide+10ng/mLIL-1 ��; Blank group, 0 ��M of rographolide; IL-1 �� group, 0mM rographolide+10ng/mLIL-1 ��. Detect related gene expression by Fluorescent quantitative PCR (Realtime-PCR) method, the expression of immunohistochemical method detection associated protein, thus identify that rographolide is to the provide protection of the beta induced chondrocyte of IL-1.
(4) qRT-PCR test: extract total serum IgE according to the method for TIANGEN total RNA extraction reagent box (TIANGEN, Beijing), then adopt reverse transcription reaction test kit (Invitrogen company, the U.S.) to carry out reverse transcription. Concrete grammar reference reagent box explanation. The mensuration of sample relative expression quantity: by the condition groped and system, measures the Ct value of MMP-1, MMP-3, MMP-13 and Timp-1 tetra-genes in different sample respectively, adopts 2-����CtCalculate the difference of genetic expression. Analyzing by SPSS statistical software result data, P value is less than 0.001 and represents with * * *, is less than 0.01 and represents with * *, is less than 0.05 and represents with *. Experimental result shows, and relative to blank group and rographolide three concentration groups, MMP-1, MMP-3 and MMP-13 gene is expressed in IL-1 �� group to be increased, and the expression of Timp-1 gene reduces, and rographolide, when concentration is 3.25 ��Ms, acts on the most obvious. See Fig. 2.
(5) immunohistochemical staining: being taken out by cell climbing sheet, 0.01mol/LPBS washes 3 times, 3 minutes/time; 95% alcohol fixes 30 minutes, and PBS washes 3 times, 3 minutes/time; 3%H2O2Processing 15 minutes, PBS washes 3 times, 3 minutes/time; 15 minutes are closed with lowlenthal serum; After removing serum (not washing), drip and add II Collagen Type VI primary antibodie, be placed in 37 DEG C, wet box, 2��3 hours; Removing primary antibodie, PBS washes 3 times, 3 minutes/time; Dripping that to add two anti-, incubated at room 30 minutes, PBS washes 3 times, 3 minutes/time; Drip and add DAB four hydrochloride (DAB) solution now joined, basis of microscopic observation colour developing 3��5 minutes; Distillation washing 3 times, 3 minutes/time, Hematorylin redyed 15 seconds, and tap water returns indigo plant, dry, finally with neutral tree rubber seal sheet. Detect the expression of each group of II Collagen Type VI. Immunohistochemical staining result shows, and under the effect of rographolide, the secretion of MMP-1 albumen obviously reduces, and the secretion of Timp-1 increases. Generally speaking, rographolide suppresses the expression of MMPs by increasing the expression of matrix metallo-proteinase inhibitor (Timp-1), this imply that rographolide has the potential quality of antagonism joint cartilage substrate degradation. See Fig. 3.
Three, rographolide improves the pharmacodynamic experiment of osteoarticular retrograde affection
(1) experimental animal model preparation, grouping and process
44 healthy new zealand white rabbit 2.0-2.5kg, SPF level, randomly draws 8, does incision of skin, does not cut off ligamentaum cruciatum, makes sham operated rats (A group), and all the other 36 give the anesthesia of 5% vetanarcol (0.1mg/kg) auricular vein respectively. The rabbit formula of lying on the back is bundled in operating table, the hair of knee joint peripheral is shaved only, iodophor disinfection bonnet upper berth towel, outside knee joint, cut skin, manadesma, joint capsule arrival joint cavity by layer, kneecap is pushed to inner side flexing knee joint exposure anterior cruciate ligament as far as possible, and cuts off with scissors under looking at straight. Carry out drawer test and determine that anterior cruciate ligament ruptures completely, kneecap resets, otch normal saline flushing, No. 1 suture layer-by-layer suture closes joint cavity, after wound is wrapped up with auxiliary material, 5 day after surgery every day, subcutaneous 200,000 units injected penicillin preventing infection, and rabbit does not fix, directly send cage sub-cage rearing back to, rabbit one cage. Within after art 8 weeks, randomly draw 4 rabbits and carry out knee joint gross examination, get joint sample subsequently and carry out pathologic finding and genes involved inspection, after confirming osteoarticular retrograde affection model modeling success, carry out follow-up test.
32 osteoarticular retrograde affection model rabbits are divided into 2 groups at random, model group (B group) and rographolide group (C group), often organize 16. A group does not do any process, B group: intraarticular injection 0.5mL physiological saline weekly, C group: intraarticular injection 0.5mL rographolide (3.25 ��Ms) weekly, 1 time/week. Respectively at administration 4W, 8W, putting to death, get knee joint fast, a part puts into DEPC water, for extracting RNA; A part is fixed with 10% formalin.
(2) Testing index
1) joint gross examination of skeletal muscle and scoring
2) Rt-PCR detects the expression of MMP-1, MMP-3, MMP-13 and Timp-1 gene
(3) experimental result
1) joint sample gross examination of skeletal muscle
Getting rabbit bilateral knee joint sample, whether whether joint has spur and synovial hyperplasia in visual inspection. Under dissecting microscope, femur ankle joint cartilage surface is observed, and by Pelletier substantially standards of grading joint cartilage is marked (0 point: articulum is complete, color and luster is as usual; 1 point: articulum is coarse, there are little crack and color and luster gloomy; 2 points: articulum is rotten to the corn, and cartilage defect reaches cartilage top layer or middle level deeply; 3 points: articulum ulceration, defect reaches cartilage deep layer deeply; 4 points: cartilage strips off, subchondral bone matter exposes. ). A group synovial fluid is normal, and cartilage surface bright color, flat smooth is without defect and crack, and edge clear is complete. 4 weeks B group knuckle synovia showed increased after administration, synovial hyperplasia is obvious, in femur, relatively A group is dim for condyle articulum color, surface forms big area ulcer, defect causes subchondral bone to expose, inside intraarticular condyle, edge and outside have obvious fiber spur to be formed, and by the 8th week, bone joint degeneration obviously increased. Administration is after 4 weeks, and C group knuckle synovia is more, has a small amount of synovial hyperplasia, and joint cartilage color and luster is dimmed, and articulum has small area ulcer, and a small amount of subchondral bone exposes, and when 8 weeks, joint cartilage ulcer surface increases a little. See Fig. 4.
By Pelletier substantially standards of grading three treated animal condyle of femur joint cartilage regressions are carried out rank scores, three groups of appraisal result are variant and have statistical significance (see figure 5).
2) qRT-PCR result
QRT-PCR detects the expression of cartilage matrix degraded genes involved MMP-1, MMP-3, MMP-13, Timp-1. Result shows, and the related gene expression of A group is all lower, and MMPs expression amount is less, and Timp-1 also can not be transferred; B group is in administration after 4 weeks, and the expression of MMPs gene is far away higher than C group, and the expression of Timp-1 gene is then contrary, and administration 8 weeks this difference rear is more remarkable; C group can significantly suppress the expression of MMPs, and greatly increases the expression of Timp-1. See Fig. 6.
Claims (2)
1. rographolide is in the application treated in osteoarticular retrograde affection medicine.
2. rographolide according to claim 1 is preparation in accordance with the following methods and obtains:
Extracting method: dry Folium Andrographis 10kg with the 75% cold leaching of ethanol of 100L, obtains leach liquor gac reflux decolour, takes out filter while hot after pulverizing; Reclaim ethanol, slowly add water, place analysis brilliant, take out filter, obtain coarse crystallization thing; The a small amount of water washing of coarse crystallization thing, 95% ethanol heating for dissolving, 1% gac backflow 30min, filters, and it is brilliant that filtrate places analysis, takes out filter, obtains white coarse crystallization 201.54g;
Purification process: white coarse crystallization is dissolved in methyl alcohol, is splined on neutral alumina column; With acetate-methanol-water different ratios and 25:0.1:0; 12:0.4:0; 0:1:0; 0:5:5; 0:3.5:6.5 carries out gradient elution; Thin-layer chromatography is followed the tracks of, and merges similar evaporate point; Evaporating point of merging 0:3.5:6.5 acetate-methanol-water elution, reclaims eluent, obtains white crystals 48.24mg.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020192232A1 (en) * | 2019-03-25 | 2020-10-01 | 深圳先进技术研究院 | Application of andrographolide in inhibiting formation and activation of osteoclasts |
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| CN1864704A (en) * | 2005-05-20 | 2006-11-22 | 先进基因股份有限公司 | Herbal composition for treatment of arthritic disorders, skin inflammatory disorders and pain |
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