CN116370485A - Application of 2-hydroxyphenyl alpha-D-glucopyranoside in preparation of reagent for promoting vascular-bone formation - Google Patents
Application of 2-hydroxyphenyl alpha-D-glucopyranoside in preparation of reagent for promoting vascular-bone formation Download PDFInfo
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- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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Abstract
The invention relates to the technical field of regenerative medicine, and provides application of 2-hydroxyphenyl alpha-D-glucopyranoside in preparation of a reagent for promoting blood vessel-bone formation, wherein the action concentration of the 2-hydroxyphenyl alpha-D-glucopyranoside is 200-1600 ng/mL. The 2-hydroxyphenyl alpha-D-glucopyranoside can act on human umbilical vein endothelial cells, and can promote proliferation and migration of the endothelial cells and high expression of genes related to angiogenesis; the mouse experiment proves that the 2-hydroxyphenyl alpha-D-glucopyranoside has the efficacy of promoting the repair and regeneration of the bone tissue of the osteoporosis mouse. It is shown that the 2-hydroxyphenyl alpha-D-glucopyranoside can promote skeletal vascularization and promote bone tissue repair and regeneration.
Description
Technical Field
The invention relates to the technical field of regenerative medicine, in particular to application of 2-hydroxyphenyl alpha-D-glucopyranoside in preparation of a reagent for promoting blood vessel-bone formation.
Background
Generally, the human body reaches a peak of bone mass in life before and after age 30, and bone mass begins to be slowly lost after entering middle age. Women enter the early stage of bone mass loss from 40 years old to 49 years old, and the annual loss rate is 0.4% -0.6%; the bone mass loss rate of men is relatively slow, and the bone mass loss rate is usually kept at 0.3% -0.5% from 40 years old to 64 years old to the earlier stage of bone mass loss. The female will lose about 50% of the total bone during life and about 30% of the total bone during life. Epidemiological studies have shown that: as the aging of the population becomes more serious, diseases related to bone mass loss (such as osteoporosis, fracture, bone degeneration of periodontitis and the like) become an important public health problem in China. The prevalence of bone mass loss-related diseases is highly related to advanced age, and not only is the hazard enormous, but also related medical treatment and nursing require a great deal of input of manpower, material resources and financial resources, bringing about a heavy household burden and social burden.
Studies have shown that bone is a highly vascularized tissue, while neovascularization is a key factor in bone remodeling. New blood vessels carry oxygen, nutrients, minerals, growth factors, etc. into regenerated bone tissue, and in addition, it is a pathway for inflammatory cells, bone precursor cells, to the site of injury. Angiogenesis and osteogenesis are a highly coupled process, and good blood supply is a prerequisite for bone tissue regeneration.
In the process of implant osseointegration repair, the good angiogenesis capacity can obviously improve the repair speed of bone tissues and shorten the osseointegration time. After the implant is implanted into the jawbone, the composite structure on the surface of the implant can not only create a favorable bone immune microenvironment by stimulating macrophages, but also promote proliferation and differentiation of osteoblasts/endothelial cells. Therefore, in the osseointegration process after the implant is implanted into the human body, the osseogenesis ability and the neogenesis ability of blood vessels around bone tissue are indispensable, and are two very critical parts for promoting osseointegration. In the early stages of healing of chronic periodontitis, the invasive growth of alveolar bone blood vessels is a key factor in the bone metabolic process of periodontal tissue when tissue damage and blood circulation are established, and bone blood vessels not only provide nutrients to bone tissue, but also provide oxygen necessary for bone cell activity. Bone blood vessel growth and bone metabolism balance are coupled processes, bone blood vessels transport nutrient substances necessary for promoting bone formation and transport metabolic wastes in time, and bone cells can secrete angiogenesis promoting cytokines in the process of bone formation so as to regulate blood vessel proliferation and promote vascularization.
Traditional Chinese medicines are receiving more and more attention due to their definite curative effect and low toxicity, and today, the traditional Chinese medicines have become hot spots for promoting angiogenesis. The Chinese medicinal formulas with good angiogenic effect, such as the Chinese angelica blood replenishing decoction, the peach red four-substance decoction, the single Chinese medicinal astragalus root and the like, are all prepared into medicines approved for marketing, and a large number of researches show that the Chinese medicinal materials have good curative effect on inducing angiogenesis. The traditional Chinese medicine formula has a synergistic effect, and the action mechanism is complex and is not clear through the combined action of multiple components, multiple targets and multiple ways. The traditional Chinese medicine extract is prepared by extracting the effective components to the maximum extent through a separation and purification technology, but simultaneously the non-effective components cannot be removed to the maximum extent, and often the impurities are more. The monomer is an effective component of the traditional Chinese medicine, often has higher biological activity, is easier to enter cells to exert the drug effect, has specific targets and has definite action mechanism. Therefore, the traditional Chinese medicine monomer has more remarkable effect in the aspect of inducing angiogenesis.
Disclosure of Invention
The invention aims to provide an application of 2-hydroxyphenyl alpha-D-glucopyranoside in preparing a reagent for promoting vascular-bone formation, wherein the 2-hydroxyphenyl alpha-D-glucopyranoside promotes proliferation and migration of human umbilical vein endothelial cells and high expression of genes related to vascular formation, and can promote skeletal vascularization and promote repair and regeneration of bone tissues.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides application of 2-hydroxyphenyl alpha-D-glucopyranoside in preparing a reagent for promoting endothelial cell proliferation and migration, wherein the structural formula of the 2-hydroxyphenyl alpha-D-glucopyranoside is shown as formula I:
preferably, the action concentration of the 2-hydroxyphenyl alpha-D-glucopyranoside is 200-1600 ng/mL.
The invention provides application of the 2-hydroxyphenyl alpha-D-glucopyranoside in promoting angiogenesis gene expression.
Preferably, the angiogenic genes include VEGF gene and TGF-beta gene.
The invention provides application of the 2-hydroxyphenyl alpha-D-glucopyranoside in preparing a reagent for promoting bone tissue repair and regeneration.
The invention provides application of the 2-hydroxyphenyl alpha-D-glucopyranoside in preparation of medicines for promoting vascular-bone formation.
Preferably, the medicine further comprises pharmaceutically acceptable auxiliary materials.
Compared with the prior art, the invention has the beneficial effects that:
the 2-hydroxyphenyl alpha-D-glucopyranoside can promote proliferation, migration and high expression of vascular endothelial cells of human umbilical vein. The experimental results of the mice show that: 2-hydroxy phenyl alpha-D-glucopyranoside is injected into an osteoporosis mouse body, does not cause the change of a mouse serum biochemical index (BUN, CK, ALT, AST), and has no chronic toxicological effect on internal organs. micro-ct scan and fluorescence double-standard results show that the density of mouse bone trabecula and the thickness of cortical bone are obviously increased, especially the thickness of cortical bone. Therefore, the 2-hydroxyphenyl alpha-D-glucopyranoside can promote skeletal vascularization and bone tissue repair and regeneration, has good application prospect, important clinical significance and commercial value, and provides a new candidate medicine for bone mass loss related diseases.
Drawings
FIG. 1 is a graph showing the effect of 2-hydroxyphenyl α -D-glucopyranoside on proliferation of endothelial cells in human umbilical vein;
FIG. 2 is a graph showing the effect of 2-hydroxyphenyl α -D-glucopyranoside on endothelial cell migration in human umbilical vein;
FIG. 3 is a graph showing the effect of 2-hydroxyphenyl α -D-glucopyranoside on the expression of a angiogenesis-related gene in human umbilical vein endothelial cells;
FIG. 4 is a graph showing the effect of 2-hydroxyphenyl α -D-glucopyranoside on biochemical indicators in mouse serum, wherein "new monomer" refers to 2-hydroxyphenyl α -D-glucopyranoside;
FIG. 5 is a graph showing the effect of 2-hydroxyphenyl α -D-glucopyranoside on the organs of mice, wherein "new monomer" refers to 2-hydroxyphenyl α -D-glucopyranoside;
FIG. 6 is an effect of 2-hydroxyphenyl α -D-glucopyranoside on mouse bone tissue, wherein "new monomer" refers to 2-hydroxyphenyl α -D-glucopyranoside;
FIG. 7 is an effect of 2-hydroxyphenyl α -D-glucopyranoside on bone deposition in mice, wherein "new monomer" refers to 2-hydroxyphenyl α -D-glucopyranoside.
Detailed Description
The invention provides application of 2-hydroxyphenyl alpha-D-glucopyranoside in preparing a reagent for promoting endothelial cell proliferation and migration, wherein the structural formula of the 2-hydroxyphenyl alpha-D-glucopyranoside is shown as formula I:
in the present invention, the concentration of 2-hydroxyphenyl α -D-glucopyranoside is 200 to 1600ng/mL, preferably 400 to 1400ng/mL, and more preferably 600 to 1200ng/mL.
The invention provides application of the 2-hydroxyphenyl alpha-D-glucopyranoside in promoting angiogenesis gene expression.
In the present invention, the angiogenesis genes include VEGF gene and TGF-beta gene.
The invention provides application of the 2-hydroxyphenyl alpha-D-glucopyranoside in preparing a reagent for promoting bone tissue repair and regeneration.
The invention provides application of the 2-hydroxyphenyl alpha-D-glucopyranoside in preparation of medicines for promoting vascular-bone formation.
In the invention, the medicine also comprises pharmaceutically acceptable auxiliary materials.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
The embodiment provides a preparation method of 2-hydroxyphenyl alpha-D-glucopyranoside, which comprises the following steps:
(1) To the reaction flask was added (2S, 3R,4S,5R, 6R) -6- (acetoxymethyl) tetrahydro-2H-pyran-2, 3,4, 5-tetraacetic acid tetraester (2.5 g,6.40 mmol), catechol (2.5 g,22.70 mmol), zinc chloride (200 mg) and stirred under nitrogen at 140℃for 1.0H. Cooling, adding water (100 mL), extracting twice with ethyl acetate (100 mL. Times.2), drying with anhydrous sodium sulfate, filtering, spin-drying, subjecting the obtained mixture to silica gel column chromatography (PE: EA volume ratio of 5:1) to obtain white solid target compound (2R, 3R,4S,5R, 6R) -2- (acetoxymethyl) -6- (2-hydroxyphenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (1.0 g, extraction rate 30.5%), detecting by MS, MS (ESI, pos.ion) m/z:441.0[ M ] + H] + The white solid obtained was verified to be the target compound (2R, 3R,4S,5R, 6R) -2- (acetoxymethyl) -6- (2-hydroxyphenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetate.
(2) (2R, 3R,4S,5R, 6R) -2- (Acetoxymethyl) -6- (2-hydroxyphenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetate triester (500.0 mg,0.98 mmol), methanol (5.0 mL), sodium methoxide (16.0 mg,0.29 mmol) were added to the reaction flask at room temperature, stirred overnight at room temperature, pH was adjusted to neutral with acetic acid, and the mixture was purified with ion exchange resin (50 WX 8H + ) Filtering to obtain filtrate, spin-drying, concentrating under reduced pressure to obtain white solid target compound 2-hydroxyphenyl alpha-D-glucopyranoside (60.0 mg, extraction rate 25.1%), detecting with MS (ESI, neg. Ion) m/z 271.0[ M ] - H] - , 1 H NMR(500MHz,water-d 2 ): delta 7.26 (d, j=7.0 hz, 1H), 7.04-6.96 (m, 3H), 5.62 (s, 1H), 3.99-3.96 (m, 1H), 3.82-3.77 (m, 4H), 3.55-3.52 (m, 1H). The white solid obtained was verified to be the target compound 2-hydroxyphenyl α -D-glucopyranoside.
The synthetic route of the 2-hydroxyphenyl alpha-D-glucopyranoside is as follows:
example 2
This example explores the effect of 2-hydroxyphenyl α -D-glucopyranoside on human umbilical vein endothelial cell proliferation, including the steps of:
immortalized human umbilical vein endothelial cells (HUVECs, purchased from Bode, beijing) were cultured to the third generation, cell suspensions (2000 cells/well) were inoculated in 96-well plates, 100. Mu.L of culture broth was added, and 2-hydroxyphenyl α -D-glucopyranoside, at gradient concentrations of 0ng/mL, 100ng/mL, 200ng/mL, 400ng/mL, 800ng/mL and 1600ng/mL, respectively, was added to the culture broth (3 multiplex wells were established for each concentration of drug). The culture plates of each concentration were divided into three culture times and placed in an incubator for culturing for 12 hours, 24 hours and 48 hours (37 ℃,5% CO) 2 ). To each well 10. Mu.L of CCK-8 solution was added and the plates incubated in an incubator for h. The absorbance at 450nm was measured with a microplate reader and the effective minimum concentration of 2-hydroxyphenyl α -D-glucopyranoside was selected. The results are shown in FIG. 1, and as can be seen from FIG. 1: 2-hydroxyphenyl alpha-D-glucopyranoside promotes proliferation of HUVECs and has a minimum effective concentration of 200ng/mL.
Example 3
This example explores the effect of 2-hydroxyphenyl α -D-glucopyranoside on vascular endothelial cell migration in human umbilical veins, including the steps of:
the ability of the lowest effective concentration of 2-hydroxyphenyl α -D-glucopyranoside to migrate to levels of immortalized HUVECs was assessed by in vitro scratch test. Firstly, uniformly marking transverse lines behind a 6-hole plate by using a marker pen, wherein the transverse lines are spaced by 1cm and cross through holes, and each hole at least passes through 5 lines. After HUVECs were fused to 80%, 0.25% trypsin was used to collect the cell suspension, and the cell suspension was collected at a rate of 2X 10 5 Inoculating the cells/well in 6-well plate at 37deg.C with 5% CO 2 Culturing in incubator for 24 hr. After the cells are fused, the cells are scratched, and after the scratches, the cells are washed 3 times by PBS washing liquid, and the scratched cells are removed. Adding a culture medium containing 200ng/mL of 2-hydroxyphenyl alpha-D-glucopyranoside at 37 ℃ and 5% CO 2 Culturing for 12h and 24h respectively in incubator. Observing under microscope, taking photo, and quantifying finenessCell migration. The results are shown in FIG. 2, and can be seen from FIG. 2: the immortalized HUVECs added with 200ng/mL of 2-hydroxyphenyl alpha-D-glucopyranoside culture medium have more obvious migration trend to scratch areas, and the difference has statistical significance, which shows that the 2-hydroxyphenyl alpha-D-glucopyranoside has the capacity of promoting the migration of the HUVECs.
Example 4
The present example explores the effect of 2-hydroxyphenyl alpha-D-glucopyranoside on human umbilical vein vascular endothelial cell angiogenesis-related gene expression, including the steps of:
RNA from HUVECs was extracted using TRizol extract (Invitrogen) and reverse transcribed into cDNA using a reverse transcription kit (Apexbio, USA). SYBR green-based real-time fluorescent quantitative nucleic acid amplification assays (quantification was performed at 95℃for 30s,1 cycle; 95℃for 30s and 55℃for 30s,39 cycles) were performed using 1. Mu.L of cDNA and qPCR Mix (purchased from the following holothurian, china) to detect differential expression of the cell angiogenesis-related gene VEGF and TGF-beta. The results are shown in FIG. 3, and the results are relatively quantified by the ΔCT method, as can be seen in FIG. 3: the culture medium containing 200ng/mL of 2-hydroxyphenyl alpha-D-glucopyranoside can promote the differential expression of the angiopoiesis related genes of the immortalized HUVECs.
Example 5
The present example explores the effect of 2-hydroxyphenyl α -D-glucopyranoside on serum biochemical indicators in mouse blood, including the following steps:
12 female C57bl/6j mice of 12 weeks of age were selected and divided into 2 groups (OVX+ctrl group, OVX+2-hydroxyphenyl alpha-D-glucopyranoside group). The mice were anesthetized with sodium pentobarbital at a dose of 40mg/kg, the lower abdomen of the mice was prepared with skin, sterilized with iodophor, and iodophor was wiped off with 75% alcohol, and a 0.5cm long incision was made 0.5cm to the left of the midline of the abdomen 1cm below the ribs. The fascia and muscles are cut off, and the surgical field is passively widened. Finding white adipose tissue in the lower abdomen to pull out the body, and finding the oviduct and ovary along the ascending direction of uterus. After ligating the oviduct, the ovary and the oviduct are cut off, after bilateral excision, uterus and fat are put into the abdomen, and skin and muscle are sutured in layers. Model mice for osteoporosis were injected with 2-hydroxyphenyl α -D-glucopyranoside by tail vein for a total of 4 weeks, 3 times per week, at a dose of 5mg/kg three months after model stabilization. The control group is injected with the same amount of physiological saline, the doses of xylenol orange and calcein are 80mg/kg at the third weekend and the fourth weekend after injection, and the samples are collected after 12 hours of the last reagent injection. Serum: collecting eyeball blood, standing for 2h at 4deg.C and 3500r/min, centrifuging for 10min, and collecting serum at-80deg.C, and detecting Blood Urea Nitrogen (BUN), creatine phosphokinase (CK), alanine Aminotransferase (ALT), aspartic acid Aminotransferase (AST) in blood sample by automatic biochemical analyzer. The results are shown in FIG. 4, and as can be seen from FIG. 4: the 2-hydroxyphenyl alpha-D-glucopyranoside does not cause the change of the serum biochemical index BUN, CK, ALT, AST of the mice, which indicates that the 2-hydroxyphenyl alpha-D-glucopyranoside does not influence the mice.
Example 6
The present example explores the effect of 2-hydroxyphenyl α -D-glucopyranoside on the organs of mice, including the following steps:
taking heart, liver, spleen, lung and kidney tissue of mice, dividing into 0.5cm 3 The small pieces were rinsed with running water for 15min. And (3) placing the sample into a full-automatic tissue dehydrator for dehydration treatment, and after dehydration, utilizing a paraffin tissue embedding machine for paraffin embedding treatment of the sample. The tissue wax block was sectioned at a thickness of 8 μm and attached to an anti-drop slide H&E staining. The results are shown in FIG. 5, and as can be seen from FIG. 5: the 2-hydroxyphenyl alpha-D-glucopyranoside does not cause obvious pathological changes such as tumor or inflammatory infiltration of important organs of mice, and has no chronic toxicological effect.
Example 7
This example explores the effect of 2-hydroxyphenyl α -D-glucopyranoside on bone tissue in mice, including the steps of:
the femur of the mouse is dissected, and after the femur is placed into 4% paraformaldehyde for 24 hours, the femur is transferred into 0.5% paraformaldehyde solution to prevent crystals from forming in bone tissues to influence sample scanning. And placing the sample in a Micro-CT special scanning tube with the tube diameter of 14mm, horizontally placing the sample, and placing the scanning tube in a Micro-CT scanning case sample tray, wherein the transverse axis of the scanning tube is perpendicular to the Micro-CT scanning axis. The scan procedure related parameters are as follows: the scan voltage was 70kVp, the scan energy power was 14W, the scan current was 200 μA, the exposure time was 300ms, the scan BH 1200mg HA/cc, the scan accuracy was 10 μm, and the scan Filter (Filter) was 0.5mmAI Filter. Later image data was reconstructed and analyzed using the chemicals 13.0 software. During femur data reconstruction, bone trabecular data analysis is carried out on all bone trabeculae of the inner layer of cortical bone, wherein the bone trabecular data is selected from the initial 1mm below a femur growth plate; cortical bone data analysis cortical bone was selected at 7-7.5 mm below the growth plate. The results are shown in FIG. 6, and the micro-ct scan results show that: after adding 2-hydroxyphenyl alpha-D-glucopyranoside, the density of the trabecular bone of the mouse is obviously increased, and the thickness of cortical bone is increased. The volume fraction (BV/TV) of the femur bone of the mice and the number (Tb.N) of the trabeculae are obviously increased, the separation degree (Tb.Sp) of the trabeculae is reduced, which indicates that the femur bone density of the mice is increased, and the trabeculae are distributed more densely.
Example 8
This example explores the effect of 2-hydroxyphenyl α -D-glucopyranoside on bone formation in mice, including the steps of:
the femur specimen of example 7 (xylenol orange and calcein were injected intraperitoneally at a dose of 80mg/kg, at 1 week intervals) was hard tissue sectioned to a slice thickness of about 15 μm. Hard tissue section was added dropwise 1:1000 volumes of diluted DAPI dye solution were used for 5min. Soaking and washing in PBS for 5min for 3 times. An anti-fluorescence quenching tablet sealer is used. And observing the red-green double-color fluorescent marks under an inverted fluorescent microscope, and counting the bone deposition rate. The results are shown in FIG. 7, and as can be seen from FIG. 7: after mice were injected with 2-hydroxyphenyl α -D-glucopyranoside, the bone formation rate (BFR/BS) and the bone mineralization deposition rate (MAR) were both significantly increased.
From the above examples, the present invention provides the use of 2-hydroxyphenyl alpha-D-glucopyranoside for preparing a reagent for promoting vascular-bone formation, wherein the 2-hydroxyphenyl alpha-D-glucopyranoside promotes proliferation and migration of human umbilical vein endothelial cells and high expression of genes related to vascular formation, and can promote skeletal vascularization and promote repair and regeneration of bone tissues.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (7)
- 2. the use according to claim 1, wherein the concentration of 2-hydroxyphenyl α -D-glucopyranoside is in the range of 200 to 1600ng/mL.
- 3. Use of 2-hydroxyphenyl α -D-glucopyranoside according to claim 1 or 2 for promoting the expression of angiogenic genes.
- 4. The use according to claim 3, wherein the angiogenic genes comprise a VEGF gene and a TGF- β gene.
- 5. Use of the 2-hydroxyphenyl α -D-glucopyranoside according to claim 1 or 2 for the preparation of an agent for promoting repair and regeneration of bone tissue.
- 6. Use of a 2-hydroxyphenyl α -D-glucopyranoside according to claim 1 or 2 for the preparation of a medicament for promoting vascular-bone formation.
- 7. The use according to claim 6, wherein the medicament further comprises pharmaceutically acceptable excipients.
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WO2001001996A1 (en) * | 1999-06-29 | 2001-01-11 | University Of Western Australia | Compositions and methods for treating or preventing osteoporosis |
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WO2001001996A1 (en) * | 1999-06-29 | 2001-01-11 | University Of Western Australia | Compositions and methods for treating or preventing osteoporosis |
KR20220151480A (en) * | 2021-05-06 | 2022-11-15 | 제주대학교 산학협력단 | Composition comprising anthocyanin isolated from an Hibiscus syriacus L. for preventing or treating bone disease |
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