CN106668001A - Application of cnidium lactone to preparation of osteoportic fracture drugs - Google Patents
Application of cnidium lactone to preparation of osteoportic fracture drugs Download PDFInfo
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- CN106668001A CN106668001A CN201510757726.4A CN201510757726A CN106668001A CN 106668001 A CN106668001 A CN 106668001A CN 201510757726 A CN201510757726 A CN 201510757726A CN 106668001 A CN106668001 A CN 106668001A
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Abstract
The invention relates to application of cnidium lactone to the preparation of osteoportic fracture drugs. According to the application, the cnidium lactone is discovered to promote osteogenesis in membranes and cartilages by regulating activities of cartilage cells and osteoblast, and promote the healing of osteoportic fracture. The mechanism that the cnidium lactone accelerates the healing of osteoportic fracture is to promote the proliferation of muscle-derived stem cells and osteoblast differentiation and migration by being applied to a beta-Catenin signal path. The cnidium lactone can be applied to the preparation of drugs for treating osteoportic fracture.
Description
Technical field
The present invention relates to application of the Osthole in treatment osteoporotic fracture medicine is prepared.
Background technology
Osteoporosis is a kind of common metabolic, complexity osteopathy.
With aging population, Chinese developing osteoporosis rate rises year by year, is apt to occur in postmenopausal women and elderly men.Chinese more than 40 years old population is up to 5.68 hundred million, and continent patients with osteoporosis has 1.12 hundred million, accounts for the 19.7% of total number of persons, and up to 13.2%, the male sex is up to 6.5% for wherein women.Its pathology is reduced with bone amount, the microstructure degeneration of bone is characterized, and causing the fragility of bone increases, and the positions such as fracture, common centrum, hip, humerus and distal radius fracture can be caused under the effect of slight external force.
The fracture that osteoporosis causes has the incidence of disease high, disable, fatal rate it is high, the characteristics of medical expense is high, it is 68.7 ten thousand people that China in 2006 occurs the number of Hip Fracture for more than 50 years old, estimated 2020 and the year two thousand fifty Hip Fracture number up to 163.8 and 590.8 ten thousand people, vertebral fracture is up to 3675 and 48,500,000 people, and the medical expense spent in terms of osteoporotic fracture was expected in the year two thousand twenty and the year two thousand fifty, 850 and 1,800,000,000,000 yuan will be risen to by 103.8 hundred million in 2006 yuan, therefore, osteoporotic fracture seriously threatens middle-aged and old health.Meanwhile, abnormal bone metabolism (osteoclast function is hyperfunction, function of osteoblast weakens) causes bone mass to decline., easily there is nonunion or malunion, or the complication such as operation again in the clinical treatment of osteoporotic fracture.
Therefore, need at present to find a kind of economy, safety, effectively, the medicine or mode of union of osteoportic fracture can be promoted, to solve fracture delayed union or disunion, reduce pain and the burden economically on patient's body.
The content of the invention
For the above-mentioned deficiency of prior art, embodiments in accordance with the present invention, it is desirable to provide a kind of economic, safety, effective, can promote the medicine or mode of union of osteoportic fracture, to solve fracture delayed union or disunion, pain and the burden economically on patient's body is reduced.
Osthole (Osthole) also known as osthole or osthole, are in the principle active component of the Chinese herbal medicine such as samphire frutus cnidii and levisticum.Modern pharmacological research finds that Osthole has various biological activity, such as anti-oxidant, anti-inflammatory, anti-osteoporosis, anti-apoptotic, estrogen-like and broad-spectrum antibacterial action.The present invention provides application of the Osthole individually in treatment osteoporotic fracture medicine is prepared.
Medical application of the present invention is by finding that Osthole draws to the effect curative effect of osteoporotic fracture animal model.
The subsequent experiment in vivo of the present invention finds, Osthole can remarkably promote healing of the senile osteoporosis fracture mouse in different times poroma, being included in 0-7 days early stage of fracture can promote intramembranous ossification and entochondrostosis, the neighbouring visible a large amount of hypertrophic chondrocyte hyperplasia of the broken ends of fractured bone；And in the fracture middle and later periods, 14-28 days, articular chondrocyte apoptosis promoted osteoblastic a large amount of hyperplasia, meanwhile, amount of osteoclast will not be suppressed, to play a part of the moulding reconstruction of poroma, ossis is led to again.Osthole promotes the expression of β-catenin in fracture site muscle and poroma.Osthole increases its increment of the quantity of Muscle-derived Stem Cells and promotion in fracture site muscle.Osthole promotes Muscle-derived Stem Cells to migrate to poroma, so as to stimulate skeletonization, accelerating union of bone fracture.
When Osthole of the present invention is used to treat osteoporotic fracture, its dosage is 5mg/kg/d.Wild type C57BL/6 mouse presses administration concentration 5mg/kg/d, maximum administration capacity 60ul/d (40ul lumbar injections, 20ul fracture site injection locations) administered volume gives Osthole solution, 7th, 14,28 days three observation periods time period,, there is not overt toxicity reaction in none dead mouse.In pharmacopeia, the daily highest consumption of people is 9g crude drugs to Osthole, and with the calculating of 70kg body weight, equivalent to 0.13g crude drugs/kg/d, institute's configuration concentration is 5g crude drugs/ml.Every time maximum administration capacity is 40ml/kg to mouse stomach, and single oral gavage is administered, and total amount is 200g crude drugs/kg, equivalent to 1538 times of people's pharmacopeia highest consumption per day.
The pharmaceutical composition that the present invention is provided can be prepared by methods known in the art, it is possible to be administered by approach such as oral, sublingual, percutaneous, muscle, subcutaneous, mucocutaneous, urethra, vagina or veins.Oral formulations include tablet, capsule, granule, pill chewing agent, solution etc..Non-intestinal drug delivery agent can make parenteral solution or freeze dried powder etc..Local administration can make creme, emulsion, ointment, patch or spray etc..But it is not limited thereto.
Description of the drawings
" effect curative effect of the Osthole to osteoporotic fracture animal model " of the invention will seem especially clear in following related experiment result, with reference to the following drawings：Wherein,
Fig. 1 is the X-Ray observation figures that Osthole intervenes the osteoporotic fracture fracture line of 7,14,28 days.
Fig. 2 is that Osthole intervenes the osteoporotic fracture poroma Micro-CT three-dimensional reconstruction figure of 7,14,28 days.
Fig. 3 is that Osthole intervenes the osteoporotic fracture Micro-CT scanning analysis Callus volumes of 7,14,2 days 8, Connection Density, bone density data comparison diagram.
Fig. 4 is that Osthole intervenes the osteoporotic fracture poroma biomethanics of 28 days --- finite element analysis figure.
Fig. 5 is that Osthole intervenes 7,14,28 days poroma Yihong haematoxylin (HE) of osteoporotic fracture dyeing observation figure.
Fig. 6 is that Osthole intervenes the osteoporotic fracture poroma alcian blue of 7,14,28 days/orange red (ABH/OG) dyeing observation figures.
Fig. 7 is that Osthole intervenes the osteoporotic fracture poroma osteoclast (Trap) of 7,14,28 days dyeing observation figure.
Fig. 8 is that Osthole intervenes osteoporotic fracture poroma osteoprotegerin (OPG) the Immunohistochemical study figure of 7,14,28 days.
Fig. 9 is that Osthole intervenes the osteoporotic fracture fracture site skeletal muscle β-catenin Immunohistochemical study figures of 7,14,28 days.
Figure 10 is that Osthole intervenes the osteoporotic fracture poroma β-catenin Immunohistochemical study figures of 7,14,28 days.
Figure 11 is that Osthole intervenes the osteoporotic fracture poroma Runx2 Immunohistochemical study figure of 7,14,28 days.
Figure 12 is that Osthole intervenes the osteoporotic fracture fracture site skeletal muscle Pax7 of 7,14,28 days (the unique tag protein moleculars of pairing box gene 7 --- skeletal muscle stem Cells) and the double fluorescent immunohistochemistry observation figures of Sca1 (Stem cell surface marker thing).
Figure 13 is that Osthole intervenes osteoporotic fracture fracture site the skeletal muscle Pax7 and Brdu of 7,14,28 days (5- bromodeoxyuridine nucleosides --- display cell propagation) double fluorescent immunohistochemistries observation figures.
Figure 14 is that Osthole intervenes osteoporotic fracture poroma Pax7 of 7,14,28 days and the double fluorescent immunohistochemistry observation figures of Sca1.
Figure 15 is that Osthole intervenes osteoporotic fracture poroma Pax7 of 7,14,28 days and the double fluorescent immunohistochemistry observation figures of Sca1.
Specific embodiment
Below in conjunction with the accompanying drawings and specific embodiment, the present invention is expanded on further.These embodiments are interpreted as being merely to illustrate the present invention rather than limit the scope of the invention.After the content for having read record of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalence changes and modification equally fall into the scope of the claims in the present invention.
Osthole promotes the research of senile (12 monthly age) osteoporotic fracture mouse Healing
1 materials and methods
1.1 animals used as test
12 monthly age SPF level C57BL/6 mouse are bought in Chinese Academy of Sciences's Institute of Botany.
1.2 Experimental agents
Osthole is by Shanghai Yongheng Biological Science and Technology Co., Ltd., purity ＞ 98.5%, CAS NO:484-12-8；10% chloraldurate parenteral solution, lot number：20081027, Chemical Reagent Co., Ltd., Sinopharm Group；DMSO (dimethyl sulfoxide (DMSO)), CODE:0231amresco companies；Corn Oil (corn oil), sigma companies.
1.3 experiment equipments
UCT80 MicroCT (SCANCO Medical, CHE), DISCOVERY Dual-energy X-rays absorptionmetries, CMISA-99B graphical analysis management systems, LE-80K ultracentrifuges, Leica TP1020 tissue processors, the full-automatic paraffin wax embedding of Leica EG1160 types, Leica RM2135 cycle type slicers, Leica Histobath types HI1210 spread out piece machine, Leica Histoplate HI1220 types dry piece machine, Leica EMLBSLR microscopes and photographic system, the full tissue scanning instrument of Olympus, Olympus VS120-SL, Eppendorf 5415D supercentrifuges
1.4 animal packets and processing method
12 monthly age SPF level C57BL/6 mouse are selected, by 7,14,28 days, each time point was each 16, then was randomly divided into Osthole group and blank control group, each 8.Mouse is Jing after chloraldurate (0.3ml/100g) intraperitoneal injection of anesthesia, take dorsal position, left tibias, pick net mouse hair, iodophor disinfection, sterile working Jing anterior border of tibia cuts skin, passivity separates in shin bone, (tibial spine top) interior Outboard Sections manadesma at upper 1/3, muscle, in advance intramedullary needle head inserts (broken ends of fractured bone top) at 1/3 on shin bone by tibial plateau, operating scissors avoid tibial medial deep part muscle at 1/3, complete cross-section shin bone, in the bone cavity of syringe needle insertion broken ends of fractured bone bottom, about 3/4 length of insertion is cut off, support again into tibial plateau lower section, layer-by-layer suture manadesma, muscle, skin.Second day after operation, observation group gives respectively abdominal cavity and left tibias fracture site injection 40ul and 20ul Ostholes, put to death mouse, draw materials within 7 days, 14 days, 28 days in fracture surgery, after institute fixes 48 hours with 10% neutral formalin in a organized way, change 75% ethanol to fix for a long time, while carrying out index of correlation detection.
1.5 Testing index
1.5.1 imaging examination：
Left tibias fracture site X-ray inspections, left tibias poroma Micro-CT scanning analysis.
1.5.2 bone histomophormetry：
After iconography detection, decalcification process is carried out to left tibias with 14%EDTA, 20 days or so after it is calcareous take off completely after, Leica TP1020 tissue processors row serial dehydration, waxdip, embedding, slicer is along shin bone sagittal plane, the thick sections of 5mm are cut into, are dried, baked piece, carry out later stage Pathomorphologic credit analysis (such as HE, ABH/OG, Trap dyeing, SABC, immunofluorescence dyeing).
1.5.3 musculature slice analysis：
Take out fixed musculus soleus Jing PBS washings, immersion 1-2 hours, Leica TP1020 tissue processors row serial dehydration, waxdip, embedding, slicer is along muscle coronal-plane, it is cut into the thick sections of 5mm, dry, bake piece, carry out later stage Pathomorphologic credit analysis (such as HE, immunofluorescence dyeing).
1.5.4 biomechanical detection：
Mechanical analysis is carried out to the 28d poroma of Micro-CT three-dimensional reconstructions by finite element analysis software, measurement parameter includes the rigidity of structure, cripping load, area of section and elastic modelling quantity, calculated by software.
1.6 statistical analyses：
Counting index is with mean ± standard deviationRepresent.By SPSS18.0 software kits, One-Way ANOVA analyses are carried out between multisample, carry out q inspections between sample two-by-two.Inspection level takes bilateral α=0.05.
2 results
2.1 Ostholes promote the formation of senile osteoporosis fracture mouse different time sections shin bone poroma, the effect of development
Fig. 1 X-Ray show that 7,14 days mouse tibia fracture lines of Osthole group are fuzzy compared with blank group, and 28 days fracture heading line offs, blank group still can be seen fracture line presence, and three time point fracture sites have no obvious healing trend.
The visible Osthole groups 7 of Fig. 2 Micro-CT, 14, the form of 28 days poroma is better than blank group with density, Fig. 3 data analyses further illustrate Osthole group in early stage (7, 14 days) promote mouse fracture site poroma formation, its TBV and Callus volume ratio (BV/TV), Connection Density (Conn-Dens), the indexs such as poroma bone density (BMD) are superior to blank group (the equal ＜ 0.01 of P), although the data of 28 days and blank group no significant difference, consider that Osthole group fracture site may substantially heal at 21 days, blank group heals substantially within 28 days, thus two groups have no notable difference.But Fig. 4 biomethanics --- Finite element analysis results, show that the rigidity of structure, breaking load, the elastic modelling quantity result of Osthole group poroma, higher than blank group, comprehensively illustrate that Osthole group poroma healing time and quality are superior to blank group.
The effect of 2.2 Ostholes regulation and control senile osteoporosis fracture Mouse cartilage and osteoblast activity
Fracture site cartilage a large amount of hyperplasia when Fig. 5 HE are dyeed and Fig. 6 ABH/OG dye visible Osthole group 7 days, articular chondrocyte apoptosis when 14 days, Gegenbaur's cell starts to increase, and blank group just formed cartilage scab at 14 days, and its healing was compared with Osthole group delay one week.Illustrate that Osthole can significantly raise cartilage and osteoblastic activity in different time sections, promote the intramembranous ossification and entochondrostosis of osteoporotic fracture, to improve the situation of osteoporotic fracture delayed union and disunion.
The effect of 2.3 Ostholes regulation and control senile osteoporosis fracture mouse osteoclast activity
There is the formation of a large amount of osteoclasts in the poroma of visible 7,14, the 28 days fracture sites of blank group of Fig. 7 Trap dyeing, and Osthole group only had a small amount of osteoclast formation at 7 days, osteoclast starts to increase when 14,28 days.
Fig. 8 OPG immunohistochemical staining results find out that the dark-brown positive staining of early stage (7 days) Osthole OPG SABCs is compared with blank group substantially high expression, and two groups unobvious in 14,28 days positive expression difference.
Fig. 7,8 two groups of result explanation Osthole early stages can suppress the hyperplasia of osteoclast, only on a small quantity with the downright bad bone tissue of absorption；14 days cartilage cells start apoptosis, Gegenbaur's cell substantial increase, and need certain amount osteoclast to absorb the cartilage cell of apoptosis, and proceed by poroma plastotype；The phase is reinvented into poroma within 28 days, need to absorb unnecessary poroma by osteoclast, so that ossis is led to again, form normal bone.Therefore, Chinese medicine (Osthole) has balance body cell, tissue, the effect of the normal function of organ, i.e. equilibrium between yin and yang.
2.4 Ostholes promote the Study on Molecular Mechanism of senile osteoporosis union
Figure 10 fracture site muscle β-catenin immunohistochemical stainings are visible, compare with blank group, Osthole group has more β-catenin positive expression cells when treating 7,14,28 days in fracture site muscle, shows that Osthole can activate fracture site muscle β-catenin signal paths.
Figure 11 poroma β-catenin immunohistochemical stainings are visible, compare with blank group, Osthole group has more β-catenin positive expression cells when treating 7,14,28 days in poroma, shows that Osthole can activate poroma β-catenin signal paths.
Figure 12 poroma Runx2 immunohistochemical stainings are visible, compare with blank group, and Osthole group has more Runx2 positive expressions cells when treating 7,14,28 days in poroma, shows that Osthole can promote skeletonization.
The double fluorescent immunohistochemistries of Figure 13 fracture site muscle Pax7 and Sca1 are visible, compare with blank group, Osthole group has the cell of more Pax7 and Sca1 DEs when treating 7,14,28 days in fracture site muscle, show that Osthole can increase the quantity of Muscle-derived Stem Cells in fracture site muscle.
The double fluorescent immunohistochemistries of Figure 14 fracture site muscle Pax7 and Brdu are visible, compare with blank group, Osthole group has the cell of more Pax7 and Brdu DEs when treating 7,14,28 days in fracture site muscle, show that Osthole can promote the propagation of Muscle-derived Stem Cells in fracture site muscle.
Figure 15 poroma Pax7 and the double fluorescent immunohistochemistries of Sca1 are visible, compare with blank group, Osthole group has the cell of more Pax7 and Sca1 DEs when treating 7,14,28 days in poroma, show that Osthole can promote Muscle-derived Stem Cells to migrate to fracture site, stimulate Osteoblast Differentiation to form poroma.
It is to increase the quantity of Muscle-derived Stem Cells by regulating and controlling β-catenin signal paths that Figure 10-15 results explanation Osthole promotes the molecular mechanism of senile osteoporosis union, promotes propagation and the migration of Muscle-derived Stem Cells, stimulates it to Osteoblast Differentiation.
Each experimental result more than comprehensive, can show that Osthole promotes the intramembranous ossification and entochondrostosis of osteoporotic fracture, accelerating union of bone fracture by β-catenin signal paths；And promote the propagation of Muscle-derived Stem Cells and differentiation in skeletal muscle near fracture site by acting on β-catenin signal paths, and promote Muscle-derived Stem Cells to migrate to poroma position, induce it to skeletonization specific differentiation, participate in the reparation of fracture.
Claims (4)
1. Osthole application individually in treatment osteoporotic fracture medicine is prepared.
2. purposes according to claim 1, is characterized in that, purity ＞ 98.5% of Osthole.
3. purposes according to claim 2, is characterized in that, administration concentration is 5mg/kg/d.
4. the purposes according to claim 1-3 any one, is characterized in that, Osthole passes through mouth
Clothes, sublingual, percutaneous, muscle, subcutaneous, mucocutaneous, urethra, vagina or intravenously administrable.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114344258A (en) * | 2022-02-15 | 2022-04-15 | 上海中医药大学附属龙华医院 | A special preparation of osthole for improving sarcopenia and muscular atrophy after fracture |
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| CN1080537A (en) * | 1992-07-01 | 1994-01-12 | 湛江医学院医药科技开发中心 | The goods of protect against osteoporosis and method for making thereof |
| CN1876642A (en) * | 2006-07-03 | 2006-12-13 | 杭州中药现代化研究中心 | Cnidium fruit essence crystal and preparation method and uses |
| CN1985817A (en) * | 2006-12-14 | 2007-06-27 | 广州中医药大学 | Cnidiadin liposome and its preparing process and application |
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2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1080537A (en) * | 1992-07-01 | 1994-01-12 | 湛江医学院医药科技开发中心 | The goods of protect against osteoporosis and method for making thereof |
| CN1876642A (en) * | 2006-07-03 | 2006-12-13 | 杭州中药现代化研究中心 | Cnidium fruit essence crystal and preparation method and uses |
| CN1985817A (en) * | 2006-12-14 | 2007-06-27 | 广州中医药大学 | Cnidiadin liposome and its preparing process and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114344258A (en) * | 2022-02-15 | 2022-04-15 | 上海中医药大学附属龙华医院 | A special preparation of osthole for improving sarcopenia and muscular atrophy after fracture |
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Application publication date: 20170517 |