CN112755020A - Small molecule compound for treating osteoarthritis and application thereof - Google Patents
Small molecule compound for treating osteoarthritis and application thereof Download PDFInfo
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- CN112755020A CN112755020A CN201910997792.7A CN201910997792A CN112755020A CN 112755020 A CN112755020 A CN 112755020A CN 201910997792 A CN201910997792 A CN 201910997792A CN 112755020 A CN112755020 A CN 112755020A
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Abstract
The invention relates to a small molecular compound for treating osteoarthritis, the effective component of the small molecular compound is Notopterol (Notopterol), the effective action concentration of the Notopterol is 5-25 mu M as a medicine for treating osteoarthritis. Mixing Notopterygii rhizoma alcohol with pharmaceutically acceptable adjuvants to obtain powder, unguent, powder, injection, aqua, enteric-coated sustained release preparation or injection. Animal experiments prove that the notopterygium alcohol can reduce OARSI scores, synovial membrane areas and cartilage defects of osteoarthritis mice, and reduce knee joint tissue damage and swelling of the osteoarthritis mice. The invention also discloses application of the notopterygium alcohol in preparing a medicament or a health-care product for treating osteoarthritis.
Description
Technical Field
The invention relates to a small molecular compound for treating osteoarthritis, and provides application of the small molecular compound in preparation of various forms of medicines or health-care foods for preventing and treating osteoarthritis.
Background
Osteoarthritis (OA) is a chronic degenerative disease of load-bearing joints, which is a common clinical disease of total joint diseases with progressive articular cartilage degeneration, narrow gap, synovial inflammation hyperplasia, subchondral bone remodeling as main pathological changes, and pain, swelling and joint deformity as main clinical manifestations. OA articular cartilage degeneration is irreversible, and an effective therapeutic drug is still lacked at present, so that the tibial high osteotomy and the joint replacement surgery are currently well-recognized effective therapies for treating KOA. While risk factors such as biomechanics, metabolism and genetics have been discovered, the exact pathogenesis of KOA remains unclear and the search for preventive and therapeutic KOA targets is a very popular area of research.
In recent years, our studies have confirmed that lymphatic return function plays an important role in the development and progression of osteoarthritis. When inflammation stimulates the proliferation of lymphatic vessels in tissues around joints and local transport lymph nodes, the inflammation also causes structural and functional abnormalities of collective lymphatic vessels, and leads to lymphatic return dysfunction around joints, further aggravating the symptoms of osteoarthritis. The idea of lymphatic return dysfunction in the inflammatory state, promoting lymphatic return and relieving osteoarthritis is consistent with the idea of pain caused by obstruction of arthralgia syndrome in traditional Chinese medicine and pain caused by obstruction of collaterals. The notopterygium alcohol researched by the invention can improve the lymphatic return function of osteoarthritis joints, reduce OARSI scores, synovial membrane areas and cartilage defects of osteoarthritis mice, and relieve tissue damage and swelling, thereby relieving osteoarthritis.
Disclosure of Invention
In view of the above-mentioned deficiencies of the prior art, according to the embodiments of the present invention, it is desirable to provide a small molecule compound for treating osteoarthritis with a definite therapeutic effect, and to propose a medical use thereof.
According to the embodiment, the small molecular compound for treating osteoarthritis provided by the technical scheme of the invention comprises the effective component of notopterygium alcohol, and the concentration of the notopterygium alcohol is 5-25 mu M. The notopterygium alcohol is an effective component extracted from dried root and rhizome of traditional Chinese medicine notopterygium, and can improve lymphatic return function of osteoarthritis joints, reduce OARSI score, synovial membrane area and cartilage defect of osteoarthritis mice, and relieve tissue injury and swelling, thereby relieving osteoarthritis.
According to the embodiment, the technical scheme of the invention is based on the effect of notopterygium alcohol as a medicament for treating osteoarthritis.
According to one embodiment, the invention proposes a medicament based on notopterygium alcohol as a therapeutic agent for osteoarthritis, the effective concentration of which is 5-25 μ M.
According to one embodiment, in the technical scheme of the invention, the notopterygium alcohol is mixed with pharmaceutically acceptable pharmaceutical excipients to form powder, paste, powder, injection, aqueous solution or injection.
According to one embodiment, the notopterygium alcohol as a therapeutic agent for osteoarthritis is prepared as a main active ingredient in various forms of drugs or health foods, which can be used for the prevention and treatment of the osteoarthritis. When in use, subcutaneous, intravenous injection or anorectal administration can be adopted; the injection can be selected from normal saline, glucose, stabilizer, antiseptic, suspending agent or emulsifier.
The invention carries out animal experiments, 40 clean grade 3-month-old C57BL male mice are randomly divided into a Sham group (Sham group), a KOA group (osteoarthritis group), a positive control group and a notopterygium alcohol group (the latter is the drug of the invention and is also called a treatment group) according to the weight, the notopterygium alcohol group is intragastrically filled with notopterygium alcohol every day, the SHAM group and the KOA group are intragastrically filled with physiological saline with the same amount every day, and the positive control group is intragastrically filled with Mobi every day. The result of the histomorphometry analysis of animal experiments shows that the notopterygium alcohol can reduce OARSI score, synovial membrane area and cartilage defect of a mouse with osteoarthritis, and reduce tissue damage and swelling, thereby reducing the osteoarthritis. Therefore, various forms of drugs or health foods prepared with notopterygium alcohol as a main active ingredient can be used for preventing and treating the osteoarthritis.
Drawings
FIG. 1 shows a structural formula of Notopterygii rhizoma alcohol.
FIG. 2 is a graph showing the results of ABOG staining of knee joints in animal in vivo experiments.
FIG. 3 is a diagram showing the results of testing the reflux function of joint lymph in an animal body experiment.
FIG. 4 is a diagram showing the results of ultrasonic testing of synovial fluid in animal body.
FIG. 5 is a diagram showing the results of the COLII immunohistochemical staining assay for knee joint in animal experiments.
FIG. 6 is a graph showing the results of immunohistochemical staining detection of MMP13 in knee joints in animal experiments.
FIG. 7 is a graph showing the results of immunofluorescence staining of synovial lymph vessels of knee joints in animal in vivo experiments.
FIG. 8 is a graph showing the results of the assay of Notopterygii rhizoma alcohol for reducing the expression of mRNA of lymphatic endothelial cell inflammatory factor in vitro.
Detailed Description
The invention is further illustrated with reference to the following figures and specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
In the following examples of the present invention, notopterygium alcohol (shown in figure 1 in simplified structure) is extracted from the dried root and rhizome of Notopterygium incisum by commercially available methods or extraction methods commonly used in the field of Chinese medicine. M is a molar concentration, namely mol/L; μ M is micromoles per liter.
Examples of the experiments
Dividing 40 clean-grade 3-month-old C57BL male mice into Sham group, KOA group, positive control group and Notopterygii rhizoma alcohol group at random according to body weight, wherein the Notopterygii rhizoma alcohol group is intragastrically administered at 10mg/kg/d of Notopterygii rhizoma alcohol per day, the SHAM group and KOA group are intragastrically administered with equal amount of physiological saline per day, and the positive control group is intragastrically administered at Mobi per day. After 12 weeks of continuous gavage treatment, the swelling degree of the knee joint and the reflux function of the joint lymph are detected, then the knee joint is taken, a paraffin specimen is prepared, a 4-micron continuous section is taken, the conditions of tissue injury, synovium hyperplasia and joint cartilage damage are observed by carrying out Alcinia and orange G (ABOG) staining, and the cartilage COLII and MMP13 and the number of lymphatic vessels are observed by immunohistochemistry and immunofluorescence staining.
4.1 mouse Joint specimen ABOG staining detection
Fixing mouse knee joint with 4% paraformaldehyde for 24h after taking materials, decalcifying for 18 days after soaking and cleaning with PBS, changing decalcifying liquid every 2-3 days, soaking and cleaning with PBS, dehydrating for 18h in a tissue dehydrator, soaking and embedding in paraffin in a paraffin embedding machine, slicing (4 μm) in sagittal position, horizontally placing glass slide in a baking sheet machine for 5h for pasting, vertically placing in a 60 ℃ oven for 8h for wax flowing, and then dewaxing to water in a ventilation cabinet by a conventional method; 1% hydrochloric acid ethanol for 30 sec; performing Alsinoblue staining for 40min in hematoxylin staining solution (AB); washing with water for 3 times; differentiating with 1% ethanol hydrochloride for 3 sec; washing for three times; 2% ammonia water rewet for 15 sec; washing with water for 3 times; 95% ethanol for 2 min; soaking in orange red dye liquor (OG) for 2min30 sec; 95% ethanol for 2 min; absolute ethyl alcohol for 5 min; xylene 5minX 3; a neutral gum sealing sheet, which is placed on the paperboard; placing in a fume hood for 3-4h to volatilize the residual xylene; drying in an oven at 60 deg.C for 2 h; VS120 full slice scanner scan.
As shown in FIG. 2, Elsinoblue blue stained articular cartilage, and intact blue stained ankle cartilage was observed in SHAM mice. However, in the knee ankle joint of the KOA mouse, blue-stained cartilage was significantly damaged and the joint structure was destroyed. Notopterygium koreanum group had significantly reduced articular cartilage destruction compared to the KOA group. The area of articular cartilage was measured, showing that notopterygium alcohol significantly reduced cartilage defects in osteoarthritis. In the knee joint of the SHAM mouse, the blue articular cartilage is flat and full, and in the knee joint of the KOA mouse, more severe cartilage loss and synovitis occur. Notopterygium forbesii alcohol group has significantly reduced cartilage damage compared with KOA group. The research result of the notopterygium alcohol suggests that the notopterygium alcohol can reduce the inflammation degree of osteoarthritis.
4.2 near-infrared-indocyanine green imaging detection mouse knee joint lymphatic return function
Starting a Matrx anesthesia machine, putting a mouse into an anesthesia box, performing isoflurane inhalation anesthesia (the concentration is 1% -1.5%), putting the mouse on a constant-temperature heating plate (28 ℃), maintaining anesthesia of a mask, conventionally preparing skin by using a depilatory cream, and wiping the depilatory cream with warm water to protect the skin of the mouse; ICG dye (0.1. mu.g/mL ICG solution prepared in advance with distilled water and stored in the dark) extracted by a 30-gauge needle micro-syringe was injected into the mouse in the knee joint cavity, and the injection time was recorded. Strong light signals of the knee joint can be observed under near-infrared irradiation, and photographs of the knee joint are taken 3 hours and 6 hours after injection respectively; the ICG signal intensity of the region of interest of the knee joint in the photograph can be obtained by analyzing the ROI (region of interest) region with Image J software (National Institutes of Health). The Clearance (clearence) of lymphatic vessels around the knee joint was calculated from the signal intensity of ICG in photographs taken at two time points of the knee joint on one side of the same mouse, and it can represent the lymphatic return function in the knee joint cavity. As shown in figure 3, the clearance rate of indocyanine green in the joints of the Sham group is the highest, the clearance rate of the joints of the KOA group is reduced, and the clearance rate of the notopterygium alcohol group is obviously improved. The results suggest that notopterygium alcohol reduces osteoarthritis by promoting OA-joint lymphatic return function.
4.3 ultrasonic detection of synovial fluid volume of knee joint of mouse by using small animal
Starting a Matrx anesthesia machine, putting a mouse into an anesthesia box, performing isoflurane inhalation anesthesia (the concentration is 1% -1.5%), putting the mouse on a constant-temperature heating plate (28 ℃), maintaining anesthesia of a mask, conventionally preparing skin by using a depilatory cream, and wiping the depilatory cream with warm water to protect the skin of the mouse; the knee joint of the mouse is placed under a probe of vevo2100 animal ultrasound, the scanning of the knee joint fluid volume is completed through B-mode and 3D-mode, and 3D reconstruction is completed through the software of the mouse. As shown in fig. 4, the amount of synovial fluid in the KOA group was significantly increased compared to the Sham group, and the amount of synovial fluid in the KOA group was significantly decreased by the notopterol group. The results suggest that the notopterygium alcohol can relieve osteoarthritis by promoting the OA joint lymph reflux function, and the notopterygium alcohol is a medicine for preventing and treating osteoarthritis.
4.4 mouse Joint specimen COLII immunohistochemical detection of cartilage degeneration
Dewaxing the paraffin tissue section to water conventionally, and washing for 3 times; absorbing water drops around the tissues by dust-free paper, assembling a pen drawing ring and putting the pen drawing ring into a wet box; dropwise adding 3% hydrogen peroxide, and keeping the temperature for 10 min; washing with water for 3 times, and dropwise adding trypsin for repairing at 37 deg.C for 10 min; washing with water for 3 times, and blocking with 4% BSA/PBS solution for 1 h; adding primary anti-dilution solution (anti-Collagen II, 1:1000 ratio, 0.4% BSA/PBS solution dilution) dropwise and incubating overnight in a refrigerator at 4 ℃; washing with PBS for 3 times, and soaking in PBS for 30 min; a second antibody, Goat Anti-Rabbit (diluted by 0.4% BSA/PBS solution at a ratio of 1: 200) is prepared at room temperature for 30min, and meanwhile, A + B diluent is prepared (diluted by two drops of A + two drops of B +5ml of 0.4% BSA/PBS solution at room temperature for 30 min); washing with PBS for 3 times, adding dropwise A + B mixed diluent, and standing at room temperature for 30 min; adding DAB color-developing agent for 3min (two drops of Buffer + two drops of H2O2 + four drops of DAB +5ml of distilled water, shaking and mixing uniformly, and using the mixture as ready; washing with water for 3 times, and dyeing with hematoxylin for 1min for 30 sec; washing with water for 3 times, and returning 2% ammonia water to blue for 15 sec; washing with water for 3 times, and dehydrating to obtain xylene; sealing neutral gum into a sheet; placing in a fume hood for 3-4h, and oven drying at 60 deg.C; VS120 full slice scanner scan. As shown in FIG. 5, COLII expression in the articular cartilage of the KOA group was significantly reduced compared to that of the Sham group, and the effect of COLII expression in the articular cartilage of the KOA group was significantly increased by using the notopterol group.
4.5 mouse Joint specimen MMP13 immunohistochemical detection of cartilage degeneration
Dewaxing the paraffin tissue section to water conventionally, and washing for 3 times; absorbing water drops around the tissues by dust-free paper, assembling a pen drawing ring and putting the pen drawing ring into a wet box; dropwise adding 3% hydrogen peroxide, and keeping the temperature for 10 min; washing with water for 3 times, and dropwise adding trypsin for repairing at 37 deg.C for 10 min; washing with water for 3 times, and blocking with 4% BSA/PBS solution for 1 h; adding primary anti-dilution solution (anti-Collagen II, 1:1000 ratio, 0.4% BSA/PBS solution dilution) dropwise and incubating overnight in a refrigerator at 4 ℃; washing with PBS for 3 times, and soaking in PBS for 30 min; a second antibody, Goat Anti-Rabbit (diluted by 0.4% BSA/PBS solution at a ratio of 1: 200) is prepared at room temperature for 30min, and meanwhile, A + B diluent is prepared (diluted by two drops of A + two drops of B +5ml of 0.4% BSA/PBS solution at room temperature for 30 min); washing with PBS for 3 times, adding dropwise A + B mixed diluent, and standing at room temperature for 30 min; adding DAB color-developing agent for 3min (two drops of Buffer + two drops of H2O2 + four drops of DAB +5ml of distilled water, shaking and mixing uniformly, and using the mixture as ready; washing with water for 3 times, and dyeing with hematoxylin for 1min for 30 sec; washing with water for 3 times, and returning 2% ammonia water to blue for 15 sec; washing with water for 3 times, and dehydrating to obtain xylene; sealing neutral gum into a sheet; placing in a fume hood for 3-4h, and oven drying at 60 deg.C; VS120 full slice scanner scan. As shown in fig. 6, the MMP13 of the articular cartilage of the KOA group was significantly increased compared to that of the Sham group, and the notopterol group significantly reduced the expression of MMP13 of the articular cartilage of the KOA group.
4.6 mouse Joint specimen PDPN/SMA immunofluorescence detection of lymphatic vessel number
Dewaxing the paraffin sections to water conventionally, and washing for 3 times; absorbing water drops around the tissues by dust-free paper, assembling pen-drawing rings and putting the pen-drawing rings into a wet box (a small amount of PBS can be dripped to prevent the specimens from being dried); adding trypsin dropwise, placing in a 37 ℃ thermostat, and repairing for 15 min; discarding trypsin, washing with water for three times, adding 4% BSA/PBS solution, and sealing at room temperature for 1 h; discarding the blocking solution, not washing, adding a mixed solution of primary anti-FITC alpha-SMA antibody (diluted by 0.4% BSA/PBS solution at a ratio of 1: 1500) and Podoplanin antibody (diluted by 0.4% BSA/PBS solution at a ratio of 1: 1000), and placing in a refrigerator at 4 ℃ for incubation overnight in the dark; taking out the wet box from the refrigerator, re-warming for 30min at room temperature, removing the primary antibody, and soaking and washing with PBS for 20minX 3; adding a secondary antibody Goat anti-hamster podoplanin (the proportion is 1:400, and the secondary antibody is diluted by 0.4% BSA/PBS solution), and incubating for 1h in a dark place at 4 ℃; discarding the secondary antibody, and washing for 3 times by PBS; soaking in 4 deg.C precooled PBS, and sealing with fluorescent sealing agent; VS120 full-scan scanner (fluorescence mode) scan. As shown in FIG. 7, the number of synovial lymph vessels in the joint of the KOA group was significantly reduced compared to that of the Sham group, and the number of synovial lymph vessels in the joint of the KOA group was significantly increased by the notopterygium alcohol.
4.7 detection of mRNA expression of IL-1beta, TNF-alpha, iNOS by using notopterygium alcohol.
RNA extraction (Trizol method): washing a 6-hole plate by PBS, adding Trizol 1 ml/hole, repeatedly blowing, standing at room temperature for 5min to fully crack, transferring the lysate into a 1.5ml enzyme-free EP tube, and marking; adding 200 μ l chloroform, shaking thoroughly and mixing for 15sec, standing at room temperature for 3 min; centrifuging at 12000rpm at 4 deg.C for 15 min; after centrifugation, the solution was divided into three layers, 200. mu.l of the upper aqueous phase was taken to another 1.5ml of EP; adding 200 μ l isopropanol, mixing, and standing at room temperature for 10 min; centrifuging at 4 deg.C and 12000rpm for 15min, and discarding supernatant; adding 1ml of 75% ethanol, and suspending and precipitating; centrifuging at 4 deg.C and 7500rpm for 5min, discarding ethanol, and removing the residual supernatant with 20 μ l gun; drying at room temperature for 5 min; add 20. mu.l DEPC water to dissolve the RNA sample.
Reverse transcription: prepare 20 μ l reaction: 1.5ml of EP tube was placed on ice and formulated according to takara instructions: 5X PrimeScript 4. mu.l, Oligo dT Primer 1. mu.l, PrimeScript RT Enzyme Mix I1. mu.l, Random 6mers 1. mu.l, DEPC water + RNA sample 13. mu.l, the mixture was shaken well and mixed, and centrifuged. Reverse transcription was set for 15min at 37 ℃, 5sec at 85 ℃ and 4 ℃. The reverse transcribed cDNA sample was diluted 5-fold and ready for use.
And (3) PCR reaction: after the primers are centrifuged at high speed, corresponding DEPC water is added to prepare 100 mu M of concentration, then the primers are diluted to 10 mu M, and 20 mu l of PCR reaction system is prepared according to the takara specification: SYBR 10. mu.l, dd water 7. mu.l, cDNA 1. mu.l, upstream and downstream primers 1. mu.l each. 5min at 95 ℃, 30sec at 95 ℃ → 30sec at 58 ℃ → 40sec at 72 ℃, 30 cycles, 7min at 72 ℃ and 4 ℃ storage. The same sample is simultaneously used for beta-actin internal reference PCR reaction. After the reaction is finished, absolute quantitative analysis is automatically carried out by using Rotor Gene6.0 software, the result is calculated, and the ratio of the copy number of each gene contained in each sample body to the copy number of the beta-actin internal reference gene is compared. As shown in FIG. 8, Notopterygii rhizoma alcohol significantly reduced IL-1 beta-induced gene expression of IL-1, TNF and iNOS inflammatory factors in endothelial cells.
Claims (4)
1. A small molecular compound for treating osteoarthritis is characterized in that the small molecular compound is notopterygium alcohol, and the effective action concentration is 5-25 mu M.
2. The small molecule compound for treating osteoarthritis according to claim 1, wherein the small molecule compound is mixed with pharmaceutically acceptable pharmaceutical excipients to form powder, ointment, powder, injection, aqua, enteric sustained release preparation or injection.
3. Use of the small molecule compound for treating osteoarthritis according to claim 1 or 2 in preparation of a medicament or health product for preventing and treating osteoarthritis.
4. Use according to claim 3, wherein the effective concentration of notopterygium alcohol is 5-25 μ M.
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| CN114159454A (en) * | 2021-12-16 | 2022-03-11 | 中国药科大学 | Traditional Chinese medicine composition for preventing and treating Alzheimer disease and/or osteoporosis, preparation method and application |
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| CN114159454A (en) * | 2021-12-16 | 2022-03-11 | 中国药科大学 | Traditional Chinese medicine composition for preventing and treating Alzheimer disease and/or osteoporosis, preparation method and application |
| CN115844876A (en) * | 2022-11-23 | 2023-03-28 | 中国药科大学 | Medicine for preventing and treating rheumatoid arthritis and/or osteoarthritis and application thereof |
| CN115844876B (en) * | 2022-11-23 | 2023-09-29 | 中国药科大学 | Medicine for preventing and treating rheumatoid arthritis and/or osteoarthritis and application thereof |
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