CN115919886A - Application of quercetin-3-O-beta-D glucuronide in preparation of medicine for treating osteoarthritis - Google Patents
Application of quercetin-3-O-beta-D glucuronide in preparation of medicine for treating osteoarthritis Download PDFInfo
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Abstract
The invention discloses application of quercetin-3-O-beta-D glucuronide in preparation of a medicine for treating osteoarthritis. The experimental result proves that the quercetin-3-O-beta-D glucuronide can not only reduce the inflammation of cartilage cells and the generation of ROS; more importantly, the degradation of cartilage extracellular matrix can be inhibited; the treatment of osteoarthritis by reducing subchondral bone sclerosis and/or by alleviating articular cartilage degeneration is not available with conventional non-steroidal anti-inflammatory drugs. Quercetin-3-O-beta-D glucuronide has the advantages of small toxic and side effects, high safety and the like. Therefore, the invention provides a brand new thought and strategy for the research and development of the osteoarthritis treatment drug, and has wide application prospect.
Description
Technical Field
The invention belongs to the field of natural medicine compounds, and relates to application of quercetin-3-O-beta-D glucuronide in preparation of a medicine for treating osteoarthritis.
Background
Osteoarthritis (OA) is the most common degenerative joint disease, with the aging world population, OA incidence is increasing, and OA is one of the leading causes of disability in the elderly, which causes heavy economic burden to society and patients, and seriously affects people's healthy lives. Osteoarthritis is primarily manifested by loss of articular cartilage, osteophyte formation, subchondral bone changes, inflammation and pain. However, due to the complex pathogenesis of OA, current conservative treatment of OA focuses mainly on alleviating symptoms and alleviating patient suffering. At present, the types of medicines for conservative treatment of osteoarthritis are relatively single, and mainly comprise non-steroidal anti-inflammatory medicines, glucocorticoids, cartilage lubricants, antipyretic analgesics and the like. And these drugs are mainly used to relieve pain and inflammation symptoms, but fail to reverse the disease process of osteoarthritis, such as the relief of symptoms of articular cartilage loss, osteophyte formation, subchondral bone changes, and the like. Therefore, the use of non-steroidal anti-inflammatory drugs for osteoarthritis caused by articular cartilage loss, osteophyte formation, and subchondral bone changes has the problem of addressing both symptoms and root causes. In addition, these drugs are also prone to a variety of unavoidable side effects including hepatorenal toxicity, gastrointestinal reactions, and the like. Severe middle and advanced OA patients eventually can only select joint replacement surgery to improve quality of life. Therefore, the development of novel medicaments for treating osteoarthritis has important practical significance and social value.
Quercetin-3-O-beta-D glucuronide (Q3 GA) is a metabolite of Quercetin in vivo, and no report about the application of Quercetin-3-O-beta-D glucuronide in the preparation of osteoarthritis treatment drugs is found at present.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides application of quercetin-3-O-beta-D glucuronide in preparing a medicament for treating osteoarthritis.
The purpose of the invention can be realized by the following technical scheme:
Quercetin-3-O-beta-D glucuronide as a small molecular compound, and the structural formula is as follows:
the molecular formula is: C21H18O13.
Application of quercetin-3-O-beta-D glucuronide in preparing a medicament for treating osteoarthritis.
In a preferred embodiment of the present invention, the osteoarthritis includes, but is not limited to, interleukin-1 beta type osteoarthritis.
Application of quercetin-3-O-beta-D glucuronide in preparation of medicine for inhibiting osteoarthritis caused by degradation of cartilage extracellular matrix.
Application of quercetin-3-O-beta-D glucuronide in preparation of medicine for relieving osteoarthritis cartilage extracellular matrix degradation symptoms.
Application of quercetin-3-O-beta-D glucuronide in preparation of medicine for relieving subchondral bone sclerosis and/or articular cartilage degeneration symptoms.
Application of quercetin-3-O-beta-D glucuronide in preparation of medicine for relieving osteoarthritis cartilage extracellular matrix degradation, subchondral bone sclerosis and articular cartilage degeneration symptoms.
Has the advantages that:
the invention discloses application of quercetin-3-O-beta-D glucuronide in treating osteoarthritis for the first time. The experimental result proves that the quercetin-3-O-beta-D glucuronide not only can reduce the inflammation of cartilage cells and the generation of ROS; more importantly, the degradation of cartilage extracellular matrix can be inhibited; the treatment of osteoarthritis by reducing subchondral bone sclerosis and/or by alleviating articular cartilage degeneration is not available with conventional non-steroidal anti-inflammatory drugs. Quercetin-3-O-beta-D glucuronide has the advantages of small toxic and side effects, high safety and the like. Therefore, the invention provides a brand new thought and strategy for the research and development of the osteoarthritis treatment drug, and has wide application prospect.
Drawings
FIG. 1 is a graph of cytotoxicity of quercetin-3-O- β -D glucuronide on rat chondrocytes; wherein the left panel is the viability of the cells assessed in the 24 hour MTT assay and the right panel is the viability of the cells assessed in the 48 hour MTT assay.
FIG. 2 is a graph showing the results of experiments on the release of IL-1 β (10 ng/ml) induced large chondrocyte NO by inhibition of quercetin-3-O- β -D glucuronide.
FIG. 3 is a graph showing the results of experiments on the IL-1 β (10 ng/ml) induced large chondrocyte ROS production by inhibition of quercetin-3-O- β -D glucuronide.
FIG. 4 is a graph showing the comparison of the expression level of OA chondrocyte-related protein.
FIG. 5 is a structure diagram of a micro-CT three-dimensional reconstructed posterior coronal plane of a right leg and knee joint of a rat.
FIG. 6 is a micro-CT analysis software for quantitatively analyzing the influence of quercetin-3-O-beta-D glucuronide on OA rat bone density (BV/TV), trabecular bone number (Tb.N) and trabecular bone separation degree (Tb.Sp).
Detailed Description
Example 1: cytotoxicity of Quercetin-3-O-beta-D glucuronide on primary rat chondrocytes.
Cartilage at knee joints of SD rats for 5-7 days is taken, and chondrocytes are extracted. Rat chondrocytes in logarithmic growth phase are taken, the culture medium is sucked and removed, PBS is washed for 2 times, 0.25% pancreatin containing EDTA is used for digestion for 5min, a cell counter is used for counting, the cells are inoculated in a 96-well plate, 5000 cells are placed in each well, after 24h of adherence, the rat chondrocytes are stimulated by quercetin-3-O-beta-D glucuronide (0, 0.625, 1.25,2.5,5, 10, 20, 40, 80 and 160 mu M) with different concentrations for 24h or 48h, after the culture is finished, 20 mu L of MTT solution is added in each well, the rat chondrocytes are placed in an incubator at 37 ℃ for incubation for 4h, the culture medium is slightly sucked and removed, 150 mu L of DMSO is added in each well, the rat chondrocytes are placed on a shaking table for 10min at room temperature, then OD value is measured by a Molecular Devices Max us384 microplate reader, the detection wavelength is set to be 570nm, and the reference wavelength is 630nm. The average value is obtained by measuring three times.
As shown in figure 1, when quercetin-3-O-beta-D glucuronide within 160 mu M intervenes in chondrocytes for 24 and 48 hours, no obvious growth inhibition phenomenon of the cells occurs.
Example 2: the inhibition effect of quercetin-3-O-beta-D glucuronide on IL-1 beta-stimulated primary chondrocyte inflammatory factors.
Rat chondrocytes in logarithmic growth phase were selected and seeded in 96-well plates at 1 million cells per well, pretreated 24h after attachment with different concentrations of quercetin-3-O- β -D glucuronide (1.25,2.5,5. Mu.M) for 2h, followed by IL-1 β (10 ng/mL) for a total of 48h. After 48h, cell supernatants were collected and added to 96-well plates with Griess reagent 1:1. Shaking on shaking table at room temperature in dark place for 10min. Finally, absorbance at 540nm (. P. <0.05,. P. <0.01,. P. < 0.001) was measured using a microplate reader.
The results (FIG. 2) show that the NO content in the model group (added with IL-1 beta) is higher than that in the control group, which indicates that the chondrocyte after IL-1 beta stem prognosis has an inflammatory state, and the NO content is reduced after administration, which indicates that quercetin-3-O-beta-D glucuronide inhibits the inflammation of the chondrocyte.
Example 3: quercetin-3-O-beta-D glucuronide inhibits ROS production in primary chondrocytes stimulated by IL-1 beta.
Following the same dosing regimen as described above, after incubation for 30min with DCFH-DA probe, 150. Mu.LPBS was added per well and the resulting suspension was used
The photograph was taken with a confocal microscope. The results (fig. 3) show that the fluorescence intensity of the model group is higher than that of the control group, which indicates that the ROS of the chondrocyte after IL-1 beta stem prognosis is increased, and the fluorescence intensity is reduced after administration, which indicates that the quercetin-3-O-beta-D glucuronide inhibits the generation of ROS of the chondrocyte and has the function of antioxidation.
Example 4: quercetin-3-O-beta-D glucuronide inhibits degradation of the chondrocyte extracellular matrix.
After the administration in the same manner as described above, chondrocyte proteins were extracted, and expression of matrix degradation-related proteins (Aggrecan, ADAMTS-5, MMP-13) in chondrocytes was detected by Western blot. Rat chondrocytes were lysed with RIPA lysate on ice, and after scraping the cells, they were transferred to a centrifuge tube, centrifuged to take the supernatant, and the protein concentration was determined by BCA method. 10% SDS-PAGE to separate the equivalent amount of protein and transfer to PVDF membrane, which was blocked with 5% skim milk powder for 2h. After washing the membranes 3 times with TBST, the membranes were incubated overnight at 4 ℃ with primary antibody, respectively. After washing the membranes 3 times with TBST, the membranes were incubated with the corresponding secondary antibodies for 2h at room temperature. And (3) developing by using a high-sensitivity ECL chemiluminescence detection kit. And calculating the gray value of the target protein band relative to the gray value of an internal reference by using the Image Lab, wherein the result is the relative expression quantity of the target protein of a certain sample.
The results (FIG. 4) show that the expression of ADAMTS-5 and MMP-13 is reduced and the expression of ADAMTS-5 and MMP-13 is increased in the model group relative to that of Aggrecan in the blank group, which shows that the phenomenon that the stimulation of the IL-1 beta to chondrocytes can cause the reduction of the expression of extracellular matrix anabolism related proteins and the increase of the expression of extracellular matrix catabolism related proteins is reversed after the administration of the model group, and shows that the quercetin-3-O-beta-D glucuronide can effectively inhibit the degradation of the extracellular matrix.
Example 5: in vivo application of quercetin-3-O-beta-D glucuronide for relieving articular cartilage degeneration
The experimental animals are male SD rats 200 +/-10 g, and the groups are as follows: control group, arthritis + Q3GA (2.5 mg/ml), and arthritis + Q3GA (5 mg/ml). Performing resection (DMM) of medial meniscus of knee joint of right rat, dissolving quercetin-3-O-beta-D glucuronide with 40% PEG 400, performing articular cavity injection treatment for one week after operation, administering 2 times per week, and collecting knee joint specimen for subsequent detection 5 weeks after administration. The effect of quercetin-3-O-beta-D glucuronide on subchondral bone sclerosis was evaluated by imaging. The specific implementation steps are that the knee joints of the mice are fixed in formalin for 48 hours. And then scanning by adopting micro-CT equipment, wherein the region of interest is the medial tibial platform. And carrying out quantitative analysis by using analysis software and a three-dimensional reconstruction platform. The parameters tested were: bone density (BV/TV), trabecular number (Tb.N), trabecular resolution (Tb.Sp). The OA modeled group showed statistical differences of <0.05, significant differences of <0.01, and very significant differences of <0.001, compared to the blank control group. Compared with the OA model group, the Q3GA treatment group # p <0.05 is statistically different, the # p <0.01 is significantly different, and the # p <0.001 is significantly different.
The 3D reconstruction results show (fig. 5) that quercetin-3-O- β -D glucuronide reduces the extent of wear of articular surface cartilage, alleviating the progression of osteoarthritis, and at higher doses, the articular cartilage surface is less worn, compared to the model group (OA). Therefore, the quercetin-3-O-beta-D glucuronide can relieve the degeneration of the articular cartilage. The BV/TV results are shown in FIG. 6, where the model group showed a lower significance than the normal group and increased after administration of quercetin-3-O- β -D glucuronide. Tb.N gave results consistent with BV/TV results. The Tb.Sp model group is higher in significance than the normal group, and is lower after quercetin-3-O-beta-D glucuronide is given. These results indicate that the knee joint is unstable after the medial meniscal model of the knee joint of the rat is removed, and the microstructure of the subchondral bone at the early stage is changed, mainly the cartilage is destroyed, which shows that the subchondral bone has bone remodeling. Quercetin-3-O-beta-D glucuronide can relieve bone destruction and absorption, and protect bone structure of subchondral bone, thereby playing the role of protecting articular cartilage.
The quercetin-3-O-beta-D glucuronide can inhibit the generation of cartilage cells NO and ROS, inhibit the generation of inflammation related proteins (iNOS), inhibit the generation of cartilage extracellular matrix catabolic proteins (ADAMTS-5 and MMP-13), promote the generation of cartilage extracellular matrix synthesis proteins (Aggrecan), inhibit inflammation and cartilage degradation in osteoarthritis, reduce the progress of osteoarthritis and achieve the effect of treating osteoarthritis. The quercetin-3-O-beta-D glucuronide can relieve the development of osteoarthritis caused by the removal of medial menisci of rats in vivo, relieves the wear of articular cartilage, has a protective effect on the articular cartilage, and further explains that the quercetin-3-O-beta-D glucuronide can be used as a potential medicament for treating osteoarthritis, and has a very good development and application prospect.
Claims (6)
1. Application of quercetin-3-O-beta-D glucuronide in preparation of medicine for treating osteoarthritis is provided.
2. The use according to claim 1, characterized in that said osteoarthritis includes but is not limited to interleukin-1 β type osteoarthritis.
3. Application of quercetin-3-O-beta-D glucuronide in preparation of medicine for inhibiting osteoarthritis caused by degradation of cartilage extracellular matrix.
4. Application of quercetin-3-O-beta-D glucuronide in preparation of a medicine for relieving osteoarthritis cartilage extracellular matrix degradation symptoms.
5. Application of quercetin-3-O-beta-D glucuronide in preparation of medicine for relieving subchondral bone sclerosis and/or articular cartilage degeneration symptoms.
6. Application of quercetin-3-O-beta-D glucuronide in preparation of medicines for relieving osteoarthritis cartilage extracellular matrix degradation, subchondral bone sclerosis and articular cartilage degeneration symptoms.
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| CN104717965A (en) * | 2012-09-06 | 2015-06-17 | 岭南大学校产学协力团 | Composition for inhibiting cellular senescence comprising quercetin-3-O-beta-D-glucuronide |
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