CN116585300A - Application of cynarin in preparation of medicines for preventing or treating osteonecrosis of femoral head - Google Patents
Application of cynarin in preparation of medicines for preventing or treating osteonecrosis of femoral head Download PDFInfo
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- CN116585300A CN116585300A CN202310623622.9A CN202310623622A CN116585300A CN 116585300 A CN116585300 A CN 116585300A CN 202310623622 A CN202310623622 A CN 202310623622A CN 116585300 A CN116585300 A CN 116585300A
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- femoral head
- cynarin
- bone
- necrosis
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- YDDUMTOHNYZQPO-RVXRWRFUSA-N Cynarine Chemical compound O([C@@H]1C[C@@](C[C@H]([C@@H]1O)O)(OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C(O)=O)C(=O)\C=C\C1=CC=C(O)C(O)=C1 YDDUMTOHNYZQPO-RVXRWRFUSA-N 0.000 title claims abstract description 40
- YDDUMTOHNYZQPO-UHFFFAOYSA-N 1,3-bis{[(2E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy}-4,5-dihydroxycyclohexanecarboxylic acid Natural products OC1C(O)CC(C(O)=O)(OC(=O)C=CC=2C=C(O)C(O)=CC=2)CC1OC(=O)C=CC1=CC=C(O)C(O)=C1 YDDUMTOHNYZQPO-UHFFFAOYSA-N 0.000 title claims abstract description 38
- YDDUMTOHNYZQPO-BKUKFAEQSA-N cynarine Natural products O[C@H]1C[C@@](C[C@H](OC(=O)C=Cc2ccc(O)c(O)c2)[C@@H]1O)(OC(=O)C=Cc3ccc(O)c(O)c3)C(=O)O YDDUMTOHNYZQPO-BKUKFAEQSA-N 0.000 title claims abstract description 37
- SITQVDJAXQSXSA-CEZRHVESSA-N Cynarin Natural products O[C@@H]1C[C@@](C[C@H](O)[C@H]1OC(=O)C=Cc2ccc(O)c(O)c2)(OC(=O)C=Cc3cccc(O)c3O)C(=O)O SITQVDJAXQSXSA-CEZRHVESSA-N 0.000 title claims abstract description 36
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- JUHOZYRSRTUDPA-UHFFFAOYSA-N 1,3-di-O-caffeoyl quinic acid methyl ester Natural products C1C(C(=O)OC)(OC(=O)C=CC=2C=C(O)C(O)=CC=2)CC(O)C(O)C1OC(=O)C=CC1=CC=C(O)C(O)=C1 JUHOZYRSRTUDPA-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Emergency Medicine (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention belongs to application of cynarin in preparing medicines for preventing or treating the osteonecrosis of femoral head, and the cynarin has a structural formula of. The therapeutic effect of cynarin on the rat hormonal femoral head necrosis is observed by establishing a glucocorticoid-induced rat hormonal femoral head necrosis model. Through three-dimensional reconstruction analysis of the femoral head after Micro-CT scanning, H & E staining and active oxygen fluorescent probe marking femoral head tissue sections, serum bone metabolism markers and the like are combined, the cynarin can relieve the inhibition effect of the super-physiological dose glucocorticoid on the femoral head tissue, promote the differentiation of bone marrow mesenchymal stem cells to osteoblasts, improve the osteoblast activity, further reduce the femoral head necrosis degree, and provide a new way for preventing and treating the osteonecrosis of the femoral head by medicaments.
Description
Technical Field
The invention belongs to application of preparation of medicines related to hormonal necrosis of femoral head, and in particular relates to application of cynarin in preparation of medicines for preventing or treating hormonal necrosis of femoral head.
Background
Femoral head necrosis (Osteonecrosis of femoral head, ONFH) is a clinically common and serious orthopedic disorder. According to the etiology, the traumatic femoral head necrosis and the non-traumatic femoral head necrosis are classified into two categories. Traumatic injuries are mainly caused by hip trauma, femur and neck fracture and dislocation of the hip joint, and the latter is mostly caused by abuse of hormone drugs and excessive drinking and smoking. At present, the number of non-traumatic femoral head necrosis patients in China is over 750 ten thousand, the number of non-traumatic femoral head necrosis patients increases at a speed of 15-20 ten thousand each year, and the incidence rate tends to increase year by year.
With the increasing clinical use of Glucocorticoids (GCs), hormonal femoral head necrosis (sonofh) caused by long-term, high-dose administration of Glucocorticoids GCs has become a major cause of non-traumatic femoral head necrosis. Of the current femoral head necrosis patients, about 45% are SONFH patients. In addition, in China, SONFH mainly affects adults of 30-60 years old, if effective intervention means are not adopted timely, 80% of patients can have bone destruction and femoral head collapse within 1-4 years, lower limb dysfunction is caused, and life quality of the patients is seriously affected. Although the occurrence of artificial joint replacement surgery solves the problem of movement disorder of patients suffering from femoral head collapse, as the life cycle of most patients is longer than the life cycle of the artificial joint, the risks of revision surgery are faced, and huge economic and mental pressures are born. So far, the pathogenesis of SONFH is not agreed, and effective prevention and treatment drugs are lacked, so that the pathogenesis of SONFH needs to be known, and the development of corresponding therapeutic drugs has important clinical significance.
Cynarin (Cynarin), also known as Cynarin, 1, 3-dicaffeoylquinic acid, 1, 5-dicaffeoylquinic acid, has a molecular formula of C 25 H 24 O 12 Molecular weight 516.4, CAS No. 30964-13-7, which is present in the Compositae plant Cynara scolymus L. Also known as Cynara scolymus, cynara scolymus), has the following structural formula:
。
globe artichoke is a functional plant used as both medicine and food from ancient times, and has biological activities of promoting bile flow, protecting liver, relieving spasm, reducing blood lipid, protecting gonad, resisting oxidation, etc. Among them, cynarin is the main active ingredient of cynara antioxidation and antimicrobial action, and the action is usually related to the content of cynarin. Studies have shown that GCs can affect the functions of bone marrow mesenchymal stem cells, osteoblasts, osteocytes, osteoclasts and vascular endothelial cells by inducing reactive oxygen species mediated oxidative damage, leading to programmed cell death and blood circulation dysfunction, disruption of bone homeostasis, impairment of mechanical support structure, altered bone microstructure, and ultimately glucocorticoid-induced osteoischemic necrosis. There is no study to find whether cynarin has a therapeutic effect on SONFH.
As hormonal femoral head necrosis (sonofh) still lacks effective pharmaceutical treatment and prevention means in clinical practice, there have been no reports of Guan Yangji and hormonal femoral head necrosis.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the application of cynarin in preparing the medicines for preventing or treating the hormonal necrosis of the femoral head, and provides a new way for preventing and treating the hormonal necrosis of the femoral head.
In order to solve the problems in the prior art, the technical scheme provided by the invention is as follows:
application of cynarin in preparing medicine for preventing and/or treating osteonecrosis of femoral head is provided.
As an improvement, the cynarin has the structural formula of
。
As an improvement, the hormonal femoral head necrosis is femoral head necrosis caused by the application of a super-physiological dose of glucocorticoid, wherein the glucocorticoid is the glucocorticoid commonly used in clinical prescriptions, such as dexamethasone, methylprednisolone and hydrocortisone.
A pharmaceutical composition for preventing or treating hormonal necrosis of the femoral head, comprising cynarin as an active ingredient of claim 1.
As an improvement, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
As an improvement, the pharmaceutical composition is suitable for gastrointestinal or parenteral administration.
As an improvement, the dosage form of the pharmaceutical composition is tablets, capsules, granules, pills, oral liquid or injection.
Advantageous effects
Compared with the prior art, the invention adopts a rat hormonal femoral head necrosis model induced by the hyper-physiological dose of glucocorticoid to observe the treatment effect of cynarin on the rat hormonal femoral head necrosis. Through three-dimensional reconstruction analysis of the femoral head after Micro-CT scanning, H & E staining and active oxygen (Reactive oxygen species, ROS) fluorescent probes are used for marking femoral head tissue slices, and serum bone metabolism marker detection is combined to prove that cynarin can relieve the inhibition effect of super-physiological dose glucocorticoid on femoral head tissues, promote bone marrow mesenchymal stem cells to differentiate into osteoblasts, improve osteoblast osteogenesis activity, further reduce femoral head necrosis degree, and provide a new way for preventing and treating the excimer femoral head necrosis by medicine.
Drawings
FIG. 1 is a three-dimensional reconstructed image of a femoral head of a rat, A is a Ctrl group, B is an MP model group, and C is a Cynarin treatment group;
FIG. 2 is a graph showing the results of the analysis of femoral head density (BMD) in rats of each experimental group;
FIG. 3 is a graph showing the analysis results of the thickness of the trabecular thickness (Tb.Th) of the femoral head bone of rats in each experimental group;
FIG. 4 is a graph showing the results of analysis of femoral head volume fraction (BV/TV) of rats in each experimental group;
FIG. 5 is a graph showing the results of analysis of the trabecular separation (Tb.Sp) of the femoral head bone of rats in each experimental group;
FIG. 6 is a graph of the results of femoral head H & E staining of rats in each experimental group, A being Ctrl group, B being MP model group, C being Cynarin treatment group;
FIG. 7 is a graph showing the ratio of femoral skull area to tissue area for rats in each experimental group, A being the Ctrl group, B being the MP model group, and C being the Cynarin treatment group;
FIG. 8 is a graph of the ROS staining results of femoral head of rats in each experimental group, A being the Ctrl group, B being the MP model group, and C being the Cynarin treatment group;
FIG. 9 is a graph of the results of analysis of the mean fluorescence intensity of ROS in the femoral head of rats in each experimental group;
FIG. 10 is a graph showing the results of detection of rat serum PINP in each experimental group;
FIG. 11 is a graph showing the results of the measurement of serum CTX in rats of each experimental group.
Detailed Description
The following examples will provide those skilled in the art with a more complete understanding of the invention, but are not intended to limit the invention in any way.
1. Materials and methods
1. Material
1.1 reagents and laboratory apparatus
1.1.1 Main medicine and reagent
Cynarin (Cynarin), purchased from aladine, china; lipopolysaccharide (Lipopolysaccharide), available from Sigma, usa; methylprednisolone (Methyl-prednisolone), available from Pfizer, belgium; rat type I procollagen amino terminal propeptide (PINP) and type I collagen cross-linked C-terminal peptide (CTX) enzyme-linked immunosorbent assay kit, purchased from Elabscience, china; decalcification solution of 10% ethylenediamine tetraacetic acid (10% EDTA) from source leaves, china; superoxide anion fluorescent probes (DHE) were purchased from bi yun, china; OCT embedding fluid (O.C.T Compound), available from Sakura Tissue Tek, U.S.A.; hematoxylin and eosin are purchased from source leaves, china; and 10% paraformaldehyde, sucrose, absolute ethanol, distilled water, paraffin, phosphate Buffer (PBS), 10% chloral hydrate, neutral resin, and anti-fluorescence quenching caplets.
1.1.2 major instruments
Micro-CT (SkyScan 1176, belgium), paraffin microtomes (Leica 2135, germany), cryomicrotomes (Leica CM1520, germany), flaker (Leica 1120, germany), paraffin embedding machine (BMJ-ii, china, state), axiovert 40C optical microscope (Zeiss, germany), enzyme-labeled instrument (Biotec, usa), surgical instrument suite, etc.
1.2 laboratory animals
Healthy SD rats 24, male, weight 350+ -20 g,10 week old, clean grade, supplied by the university of Suzhou animal experiment center. The feeding conditions were as follows: the room temperature is 18-20 ℃, the humidity is 50-60%, ventilation is good, and water is fed by free ingestion. All procedures were conducted according to the animal care committee and national institutes of health care and use of animal guidelines.
2. Experimental method
2.1 Grouping of laboratory animals
24 SD rats were randomly divided into the following 3 groups:
(1) Ctrl group (control group): 8, 3 continuous intraperitoneal injections of equal volumes of sterile PBS (in contrast to the MP group LPS injection volume), 8 continuous days of equal volumes of sterile PBS solution (in contrast to the MP group methylprednisolone injection volume) on bilateral gluteus maximus alternating muscle injection, and one gastric lavage equal volumes of sterile PBS solution (in contrast to the treatment group Cynarin) every two days on 12 days until sacrifice;
(2) MP group (model group): 8, continuously injecting LPS 40 mg/Kg/day into abdominal cavity for 3 days, alternately injecting MP 60 mg/Kg/day into bilateral gluteus maximus for 8 days continuously from 4 days, and injecting equal volume of sterile PBS solution (compared with the treatment group of Cynagin) once every two days from 12 days until the solution is killed;
(3) Cynagin group (treatment group): 8, first 3 continuous days of intraperitoneal injection of LPS 40 mg/Kg/day, 8 continuous days of bilateral gluteus maximus alternate intramuscular injection of MP 60 mg/Kg/day, 12 continuous days of every two days of gastric lavage of Cynagin 25mg/Kg until sacrifice.
2.2 Preparation of rat hormonal femoral head necrosis model
The invention adopts a large-dose hormone impact induced rat hormonal femoral head necrosis model to simulate the pathological process of the hormonal femoral head necrosis after the clinical treatment by using the large-dose hormone impact. In order to truly simulate the in-vivo immune state of a clinical patient before using a large dose of hormone, the LPS is injected into the abdominal cavity of a rat for 40 mg/Kg/day in advance for 3 days continuously, the systemic inflammatory response is induced, and the success rate of femoral head necrosis modeling is improved. After successful induction of inflammatory response, 8 consecutive days were passed with alternating injections of MP 60 mg/kg/day into the bilateral gluteus maximus, with alternating injections being used to ensure bilateral consistency and reduce trauma at the site of intramuscular injection.
2.3 Specimen collection
Serum was collected first at week 8 after MP myonote was completed: collecting blood of a rat retroorbital venous plexus by using a capillary blood collection tube, standing the collected blood for 2 hours at a refrigerator of 4 ℃, centrifuging for 20 minutes at a rotating speed of 3000r/min after blood is coagulated and blood clots shrink, and collecting supernatant for detecting bone metabolic markers. The rats were then sacrificed to collect bilateral femoral heads, one side for staining of frozen sections and the other side for staining of paraffin sections. Taking out the frozen tissue, immediately dehydrating and embedding the femoral head; and after the paraffin embedded femoral head is fixed for 48 hours by 4% neutral paraformaldehyde, bone parameters are collected by Micro-CT scanning, and then the paraffin embedded femoral head is decalcified by 10% EDTA for 4 weeks and is used for histological staining analysis.
2.4 Micro-CT detection
Fixing for 48 hours, and performing Micro-CT scanning, wherein parameters are set as follows: resolution 18 μm, voltage 50kV; the current is 500 [ mu ] A; each exposure time was 100ms;0.9 °/8 images. Selecting femoral head of rat as region of interest, performing three-dimensional reconstruction and analysis on the image by using Micro-CT image analysis software, and recording bone density (Bone mineral density, BMD, g/cm) of femoral head in region of ROI 3 ) Bone volume to tissue volume ratio (Trabecular bone volume to total bone volume ratio, BV/TV), trabecular bone separation (Trabecular Separation/Spacing, tb. Sp, μm) -1 ) Bone trabecular thickness (Trabecular thickness, tb. Th, mm).
2.5 histological staining
After the collected femoral heads were fixed with 10% paraformaldehyde for 48h and 10% edta decalcified for 4 weeks, ethanol gradient dehydration was started: sequentially soaking in 60%, 70%, 80%, 90% and 100% ethanol solutions for 1 hr. The dehydrated femoral head is sequentially placed in xylene solution for 3h and paraffin for 8h at 70 ℃. Finally, placing the femoral head in a mould, filling paraffin, placing the mould on a cooling table at the temperature of minus 20 ℃ for cooling 1h, taking down the solidified tissue paraffin block, preserving at room temperature or slicing and dyeing, wherein the slice thickness is 6 mu m.
H & E staining step:
(1) Dewaxing and rehydrating: dewaxing the slices by using xylene (10 min multiplied by 3 times), and then sequentially rehydrating the slices by using 100%, 95%, 85% and 70% ethanol to deionized water for 10min each time;
(2) Washing with distilled water for 3min, staining with hematoxylin solution for 5min, and washing with tap water for 2min;
(3) Differentiating the 1% hydrochloric acid alcohol solution for 30s, and flushing with tap water for 1min;
(4) Reverse blue is carried out for 30s in 10% ammonia water solution, and tap water is used for washing for 1min;
(5) Counterstaining with l% eosin solution for 5min, and washing with tap water for 1min;
(6) Conventional dehydration, transparency and sealing.
The evaluation method comprises the following steps: a series of 5 sections were selected and the areas of interest were observed for ossification of bone tissue, trabecular alignment, and bone area to tissue area ratio under a 20 x optical field of view.
2.6 tissue ROS detection
And immediately placing the harvested femoral head in a 15% sucrose solution at 4 ℃ for 12 hours, transferring to a 30% sucrose solution at 4 ℃ for 24 hours, and finally placing the femoral head in a mold, covering the femoral head with OCT embedding liquid, and then placing the femoral head in a-20 ℃ for freezing or freezing for slicing, wherein the slicing thickness is 6 mu m.
(1) The dewaxing and rehydration steps are consistent with the H & E dyeing dewaxing and rehydration steps;
(2) Diluting the superoxide anion probe DHE to a working concentration of 3 mu M;
(3) Tissue sections were incubated with DHE working solution at 37 ℃ for 20min, rinsed 3 times with pbs to terminate staining;
(4) Immediately after the anti-fluorescence quenching capper was capped, images were acquired using a fluorescence microscope.
The evaluation method comprises the following steps: a series of 5 sections were selected and the region of interest was observed for red fluorescence intensity under a 20 x-ray microscope field of view, with a strong average fluorescence intensity representing transitional ROS production.
2.7 serum bone Metabolic marker detection
(1) Standard wells, blank wells and sample wells were set separately: standard 100 mu L of standard substance diluted by a ratio is added into a standard hole, 100 mu L of sample diluent is added into a blank hole, and 100 mu L of sample to be detected is added into the rest holes;
(2) Coating an ELISA plate, and incubating for 90 minutes at 37 ℃;
(3) Throwing out liquid in the holes without washing, adding 100 mu L of biotinylated antibody working solution into each hole, sealing the film, and incubating for 1h at 37 ℃;
(4) Throwing out liquid in the holes, adding 350 mu L of washing liquid into each hole, soaking for 1min, throwing out the liquid, and repeating the step of washing the plate for 3 times;
(5) Adding 100 mu L of enzyme conjugate working solution into each hole, sealing a film, and incubating for 1h at 37 ℃;
(6) The liquid in the holes is thrown out, and the plate is washed for 5 times, and the method is the same as that in the step 4;
(7) Adding 90 mu L of primer solution (TMB) into each hole, adding a coating film on an ELISA plate, sealing the coating film, and incubating for 15min at 37 ℃;
(8) The reaction was stopped by adding 50. Mu.L of stop solution to each well, and the optical density (OD value) of each well was measured at 450 nm by an enzyme-labeled instrument.
2.8 Statistical analysis
The result data are analyzed by using Graphpad Prism 9.0 statistical software, the data are expressed by mean ± standard deviation, the comparison of multiple groups is selected by single factor analysis of variance (one-way ANOVA test), and under the condition of uniform overall variance, the LSD and Dunnett-t method are selected for analysis.p<A difference of 0.05 is statistically significant.
2. Results
1. Activity and observations of laboratory animals
Animals of each group can freely move in the cage during molding, eat normally, and the mental state is not changed obviously. The injection site has no inflammatory reaction such as red swelling, liquid seepage and the like, and no animal death occurs in the experimental process.
2. Micro-CT detection result
Micro-CT scanning, 3D reconstruction and quantitative analysis can be performed, the bone mass and the change of the femoral head microstructure can be compared, and the bone microstructure can be visually presented, so that the degree of femoral head necrosis can be judged. The 3D reconstructed femoral head of fig. 1 shows a significant reduction in femoral head mass in MP compared to Ctrl, while after the administration of Cynarin, femoral head mass recovered and femoral head necrosis was reduced.
Bone density (BMD) changes are shown in fig. 2: the model femoral head BMD was significantly reduced, (0.135.+ -. 0.019 g/cm) 3 vs 0.067±0.01 g/cm 3 ) The differences are statistically significant (/ p)<0.01 A) is provided; compared with the model group, the bone density is increased (0.067+ -0.01 g/cm) after the administration of the Cynarin 3 vs 0.103±0.014 g/cm 3 ) The differences were statistically significant (.p)<0.05）。
The trabecular bone thickness (Tb. Th) is shown in fig. 3: compared with the control group, the thickness of bone trabecula is obviously reduced after MP intervention (0.21+/-0.02 mm vs 0.14+/-0.01 mm, p < 0.01); compared to the model group, bone trabecular thickness was significantly restored after the administration of Cynarin (0.14±0.01 mm vs 0.19±0.02 mm, < 0.05).
Bone volume fraction (BV/TV) is shown in fig. 4: the bone volume fraction of the model group was significantly reduced (82.8±6.5% vs 44.7±10.3%,. Times.p < 0.01) compared to the control group; the bone volume fraction of the Cynarin group was significantly increased (44.7±10.3% vs 70.7±11.2%,. Times.p < 0.01) compared to the model group.
The trabecular separation (Tb. Sp) is shown in fig. 5: compared with the control group, the trabecular bone separation degree of the model group is obviously increased (0.18+/-0.02 mm vs 0.43+/-0.04 and mm), and the difference is statistically significant (p < 0.01); and after the cynagin is given, the trabecular bone gap is obviously reduced (0.43+/-0.04 mm vs 0.2600 +/-0.04 mm), and the difference is statistically significant (p < 0.01).
3. H & E staining results
The result is shown in fig. 6, the femoral head of the control group has normal ossification, and the trabeculae are orderly arranged; the model group has incomplete femoral head ossification and irregular arrangement of trabeculae; after the cynagin is given, ossification of bone tissue appears, and trabecula is repaired, thickened and arranged regularly.
Bone area/tissue area (%) is shown in fig. 7: the ratio of the bone tissue area of the model group is obviously reduced (34.5+/-12.9%) compared with the control group (74.8+/-7.2%), and the difference is statistically significant (p < 0.01); compared with the model group, the bone area of the cynagin group is obviously increased (34.5+/-12.9% vs 60.7+/-14.1%), and the difference is statistically significant (p < 0.01).
4. Tissue ROS assay results
The total ROS content of the femoral head was detected using a ROS fluorescent probe, and observed under a fluorescence microscope, the results are shown in FIG. 8.
ROS mean fluorescence intensity (Mean fluorescence intensity, MFI) is shown in fig. 9: compared with the control group (1+/-0.14), the fluorescence intensity of the model group (3+/-0.26) is obviously enhanced, and the difference is statistically significant (p < 0.01); compared to the MP group, the fluorescence intensity was significantly reduced (1.7±0.26) after the cynagin treatment, and the difference was statistically significant (p < 0.05). See fig. 9.
5. Serum bone metabolism marker detection result
The change in bone formation capacity is further understood by detecting the change in serum bone metabolism marker content, such as serum PINP, which is the collagen synthesized by osteoblasts, and serum CTX, which reflects the bone resorption activity of osteoclasts.
PINP: compared with the comparison group, the PINP content of the model group is obviously reduced (1+/-0.12 vs 0.52+/-0.19), and the difference is statistically significant (p < 0.01); compared with the model group, the recovery of PINP content (0.52±0.19 vs 0.87±0.16) after the cynagin treatment was statistically significant (p < 0.05), see fig. 10.
CTX: compared to the control group (1±0.09), the model group (2.76±0.31) had statistically significant differences in CTX levels up-regulated (p < 0.01); compared to the model group, the CTX levels were down-regulated in the treatment group (1.8±0.36), and the differences were statistically significant (p < 0.05), see in particular fig. 11.
Experiments prove that compared with a control group, the model group has obvious reduction of bone density, bone volume fraction and bone trabecular thickness, and has statistical difference in that the bone trabecular clearance is increased; the femoral head necrosis degree in the treatment group is obviously reduced, the bone density, the bone volume fraction and the bone small thickness are obviously increased, and compared with the model group, the statistical difference exists. The inhibition of bone cell osteogenesis by large doses of hormones plays an important role in femoral head necrosis. And the cynagin reduces the oxidative stress of osteoblasts and slows down the development of femoral head necrosis by removing ROS. Experimental results indicate that the level of ROS in the femoral head of rats receiving Cynarin is significantly reduced compared to the model group. Serum bone metabolism marker detection also proves that compared with a control group, the intervention of the model group inhibits the function of osteoblasts and promotes the activity of the osteoclasts; and after the administration of Cynarin, serum osteogenic marker levels increased and osteoclastic marker levels decreased. The rat femoral head necrosis model treated by using the cynagin proves that the cynagin has an improvement effect on femoral head necrosis induced by large-dose hormone.
In conclusion, animal experiments prove that the Cynarin can promote and relieve oxidative stress, promote osteogenesis and relieve hormone-induced femoral head necrosis. The Cynarin has the effect of improving the femoral head necrosis induced by hormone, and can be used as an effective component for preparing related medicines to intervene in the femoral head necrosis.
Claims (7)
1. Application of cynarin in preparing medicine for preventing or treating osteonecrosis of femoral head is provided.
2. The use according to claim 1, wherein the cynarin has the formula
。
3. The use according to claim 1, wherein the hormonal femoral head necrosis is a femoral head necrosis caused by a supraphysiologic dose of glucocorticoid application.
4. A pharmaceutical composition for preventing or treating hormonal necrosis of the femoral head, wherein the active ingredient of the pharmaceutical composition is cynarin according to claim 1.
5. The pharmaceutical composition of claim 4, further comprising a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is suitable for gastrointestinal or parenteral administration.
7. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, pill, oral liquid, or injection.
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