CN111053800A - Application of blueberries or extracts thereof in preparation of medicines or health-care products for preventing and treating pulmonary fibrosis - Google Patents
Application of blueberries or extracts thereof in preparation of medicines or health-care products for preventing and treating pulmonary fibrosis Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/31—Extraction of the material involving untreated material, e.g. fruit juice or sap obtained from fresh plants
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Abstract
The invention relates to application of blueberries or extracts thereof in preparation of medicines or health-care products for preventing and treating pulmonary fibrosis, and belongs to the field of medicines. The invention provides application of blueberries or extracts thereof in preparation of medicines or health-care products for preventing and treating pulmonary fibrosis. By establishing an in-vivo and in-vitro model, the blueberry extract provided by the invention proves that the blueberry can play an exact treatment role in pulmonary fibrosis. The blueberry has wide source, low cost and safe eating. The application of the invention is helpful for providing a medicine or health care product with good curative effect, low price and low toxicity for patients with pulmonary fibrosis, and has obvious clinical and social significance.
Description
Technical Field
The invention relates to application of blueberries or extracts thereof in preparation of medicines or health-care products for preventing and treating pulmonary fibrosis, and belongs to the field of medicines.
Background
Pulmonary fibrosis (Lung fibrosis) is a chronic, progressive Lung injury or the result of Lung disease to an advanced stage. The pathological characteristics of the lung cancer is that a great deal of fibroblasts are proliferated, extracellular matrix in lung tissues is accumulated and simultaneously accompanied with inflammatory injury, an alveolar structure is damaged, and scar formation is caused by abnormal repair after the tissues are injured, so that the exchange between the lung and external gas is blocked, and finally respiratory failure and death are caused. The clinical symptoms of pulmonary fibrosis are mainly manifested by dyspnea, hypoxemia, dry cough and the like. With the factors such as the deterioration and pollution of the living environment of human beings, the incidence of pulmonary fibrosis is increased with the time, the prognosis is poor, the average survival period after diagnosis is short, and the mortality is high.
The pathogenesis of pulmonary fibrosis is currently unknown and can be caused by a variety of factors including smoking, the environment, drugs, etc., which lead to inflammatory reactions and oxidative damage, destruction of the normal architecture of alveolar basal cells, simultaneous release of a range of cytokines, stimulation of fibroblast to myofibroblast transformation and proliferation, collagen deposition and massive extracellular matrix formation, ultimately leading to irreversible pulmonary fibrosis.
The current clinical drugs for pulmonary fibrosis are mainly pirfenidone and nintedanib, but the treatment effect and safety of the drugs are controversial. The traditional treatment mode mainly aims at inhibiting inflammation, but long-term use of drugs such as glucocorticoid, immunosuppressant, cyclophosphamide and the like can cause liver and kidney injury, so that the immunity of the organism is reduced, new lesions or other diseases can be induced, the risk of respiratory failure is increased, and even serious secondary infection is caused to cause death. Therefore, the search for new pulmonary fibrosis prevention and treatment drugs is urgently needed.
Disclosure of Invention
The invention aims to provide application of blueberries or extracts thereof in preparation of medicines or health-care products for preventing and treating pulmonary fibrosis.
The invention provides application of blueberries or extracts thereof in preparation of medicines or health-care products for preventing and treating pulmonary fibrosis.
Furthermore, the blueberry adopts at least one of whole fruit, any part of fruit, fruit juice or fruit juice concentrate.
Furthermore, the fruit juice is obtained by squeezing blueberry fruits and then carrying out solid-liquid separation.
Preferably, the fruit juice is prepared by the following method: juicing blueberry fruit, collecting pulp, centrifuging, and collecting supernatant.
Further preferably, the method further comprises the steps of: the supernatant was filtered and the filtrate was collected.
Further, the pulmonary fibrosis is chemical induced pulmonary fibrosis.
Preferably, the pulmonary fibrosis is pulmonary fibrosis caused by bleomycin.
Further, the medicine or the health care product reduces the expression level of at least one of fibrosis related proteins Collagen I, α -SMA and Vimentin in lung tissues.
Furthermore, the medicine or health care product inhibits the proliferation of fibroblasts and alveolar basal epithelial cells.
Wherein, the concentration of the blueberry juice for inhibiting mouse embryo fibroblast (NIH3T3) and lung cancer human alveolar basal epithelial cell (A549) proliferation is 12.5-100 muL/mL.
Further, the medicine or health product inhibits epithelial-mesenchymal transition.
Preferably, the medicine or health care product reduces the expression of epithelial-mesenchymal transition related proteins α -SMA and Vimentin in alveolar basal epithelial cells and up-regulates the expression of E-cadherin.
The concentration of the blueberry juice for inhibiting the epithelial-mesenchymal transition of the lung cancer human alveolar basal epithelial cell (A549) cell strain is 50 mu L/mL.
Furthermore, the medicine or health care product is a preparation prepared by taking the blueberry or the extract thereof as an active ingredient and adding acceptable auxiliary materials or auxiliary ingredients.
Further, the preparation is an oral preparation, an injection preparation or an aerosol.
Furthermore, the unit preparation contains 5 mL-10 mL of blueberry juice. Wherein, the unit preparation of the invention corresponds to the daily dosage of the human body per kg body weight.
The invention provides application of blueberries or extracts thereof in preparation of medicines or health-care products for preventing and treating pulmonary fibrosis. By establishing an in-vivo and in-vitro model, the blueberry extract provided by the invention proves that the blueberry can play an exact treatment role in pulmonary fibrosis. The blueberry has wide source, low cost and safe eating. The application of the invention is helpful for providing a medicine or health care product with good curative effect, low price and low toxicity for patients with pulmonary fibrosis, and has obvious clinical and social significance.
Drawings
FIG. 1 is a graph showing the inhibition rate of blueberry juice on mouse embryonic fibroblast proliferation in example 1;
FIG. 2 is a graph showing the inhibition rate of blueberry juice in example 1 on proliferation of lung cancer human alveolar basal epithelial cells;
FIG. 3 is a graph showing the effect of blueberry juice on the morphological changes of TGF- β -stimulated A549 cells in example 1;
FIG. 4 is a graph showing the effect of blueberry juice on the expression of proteins associated with epithelial-mesenchymal transition of TGF- β -stimulated A549 cells in example 1;
FIG. 5 is a graph showing the change in expression of proteins associated with fibrosis of lung tissues of mice treated with blueberry juice for 28 days in example 2;
FIG. 6 is a graph showing the effect of 28 days of blueberry juice treatment on lung pathology and collagen deposition changes in mice in example 2.
Detailed Description
The blueberry also has the effects of preventing and treating pulmonary fibrosis and widening the application range of the blueberry, and an external model of a construct proves that the blueberry can inhibit the proliferation of mouse embryonic fibroblast (NIH3T3) and lung cancer human alveolar basal epithelial cells (A549) in a concentration and time dependent mode, can obviously improve the expression change of lung cancer human alveolar basal epithelial cell (A549) epithelial mesenchymal transition related protein caused by TGF- β stimulation, so that the expression of α -SMA and Vimentin is reduced, and the expression of E-Camerkin is increased.
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The blueberry juice (BBJ) is prepared by the following method: juicing blueberry fruit, collecting pulp, centrifuging, collecting supernatant, filtering, and collecting filtrate.
Example 1 in vitro cell experiment of blueberry juice for prevention and treatment of pulmonary fibrosis
The excessive proliferation of mouse embryonic fibroblasts (NIH3T3), lung cancer human alveolar basal epithelial cells (A549) causes the deposition of collagen, and thus, inhibiting their proliferation can inhibit the expression and deposition of collagen.
In the process of pulmonary fibrosis, TGF- β is a main fibrosis factor and can promote Epithelial-mesenchymal transition (EMT) in vitro, inhibit apoptosis of fibroblasts and promote generation of active oxygen, and in vivo research also shows that a large amount of TGF- β release can accelerate the process of pulmonary fibrosis, A549 is stimulated by TGF- β to accelerate the process of Epithelial-mesenchymal transition (EMT) and further accelerate the formation of pulmonary fibrosis, so that the inhibition of the transformation of EMT can reduce the formation of pulmonary fibrosis.
The experiment proves the effect of the blueberry juice on preventing and treating pulmonary fibrosis from the two aspects.
1. Cell culture
Mouse embryo fibroblast (NIH3T3) and lung cancer human alveolar basal epithelial cell (A549) are cultured in DMEM high-sugar medium containing 10% calf serum, 100U/mL penicillin and streptomycin are added into the culture medium in the cell culture and experiment process, and the culture is carried out at 37 ℃ and 5% CO2In an incubator.
2. MTT method for detecting influence of blueberry juice on proliferation of two cells
Cells in logarithmic growth phase in the plate are taken, digested, counted, laid on a 96-well plate and cultured normally. Selecting cells with good state in logarithmic growth phase, inoculating a 96-well plate according to the growth speed of the cells, wherein each well has 100 mu L, the number of the cells is about 1500-4000, and normally culturing. The following day of inoculation, blueberry juice diluted with culture medium was added to each well to give final concentrations of 0. mu.L/mL, 12.5. mu.L/mL, 25. mu.L/mL, 50. mu.L/mL, 100. mu.L/mL and 100. mu.L/mL control saline (SPS), 5 replicates per well, placed at 37 ℃ in 5% CO2The incubators are respectively cultured for 24 hours, 48 hours and 72 hours. Then 20. mu.L of MTT stock solution of 5mg/mL was added to each well, the mixture was incubated in an incubator for 2 to 4 hours, the cell supernatant in the wells was gently aspirated from the edge, 150. mu.L of DMSO was added to each well, the mixture was placed on a horizontal shaker and shaken at 150r/min for 10min, and then the OD at 570nm was measured with a microplate reader. Repeating the experiment for three times, sorting data, calculating concentration and growth inhibition rate of blueberry juice according to absorbance value, and calculating IC50. The experimental results are shown in fig. 1 and fig. 2.
As can be seen from FIG. 1, blueberry juice inhibited the proliferation of mouse embryonic fibroblasts (NIH3T3) in a concentration and time dependent manner.
As can be seen from FIG. 2, blueberry juice inhibited lung cancer human alveolar basal epithelial cell (A549) proliferation in a concentration and time dependent manner.
3. Determining influence of blueberry juice on morphological change of lung cancer human alveolar basal epithelial cells (A549) after stimulation of TGF- β
Taking logarithmically growing cells, digesting, collecting the cells, removing supernatant, adding a fresh culture medium, blowing and mixing uniformly, measuring the cell density, uniformly inoculating the cells into a 6-hole plate, wherein each hole is 2mL of cell suspension, the density is that the control hole can be fully filled after inoculation for 48h, after inoculation for 24h, starving the cells for 6h by using a serum-free culture medium, then stimulating the cells by using a completely fresh culture medium containing 5ng/mL of LTGF- β, after 1h, adding 50 mu L/mL of blueberry juice for continuous culture, after adding the sample for 24h, taking out the 6-hole plate, observing the change of cell morphology by using an inverted microscope under white light, and observing the result shown in figure 3.
As can be seen from FIG. 3, TGF- β stimulation causes the morphology of lung cancer human alveolar basal epithelial cells (A549) to change from short spindle to long spindle, and blueberry juice can inhibit the morphology change of A549 cells.
4. Detecting the influence of blueberry juice on the EMT (extracellular matrix transfer) protein expression of lung cancer human alveolar basal epithelial cells (A549) after stimulation of TGF- β
The method comprises the steps of taking cells in a logarithmic growth phase, carrying out cell passage, ensuring that the density of passaged cells is 80-90% after 48 hours of a control group, dividing the cells into 4 dishes and 24 hours, starving the cells for 6 hours by using a serum-free culture medium, adding a completely fresh culture medium containing 5ng/mL TGF- β for stimulation, adding 50 mu L/mL blueberry juice for intervention after 1 hour, continuously placing the cells in a culture box for culture after 24 hours of intervention, taking out a culture dish, placing the culture dish on ice for 10 minutes, discarding supernatant, lightly washing the cells twice by using precooled PBS, adding 1mLPBS into each dish, scraping the cells in a collection dish by using cells, centrifuging the cells for 3 minutes at 3000rpm, washing the precipitates for 2 times by using precooled PBS, fully draining the supernatant, adding a proper amount of RIPA lysate, blowing and uniformly mixing the lysate by using a transfer gun, enabling the lysate to fully contact with the cells, cracking the lysate, swirling the cells once every 15min, cracking for 60min, enabling the lysate to be subjected to the lysate, then to be transparent, then to 13500/15 min, adding a supernatant, adding a PVDF gel, placing the supernatant, performing a gel for a gel, placing the gel for a gel, after the gel, a gel is separated, a gel is prepared by using a gel, a gel for a gel, a gel is a gel, a gel is prepared by using a gel, a gel is prepared by using a gel, a gel is a gel, a gel-washing procedure of which is a gel-transfer procedure of which is performed after a gel-transfer procedure of which is performed after a gel, a gel-transfer procedure of which is performed after a gel-transfer procedure of a gel-transfer medium of a gel-transfer.
As can be seen from FIG. 4, TGF- β stimulation causes the lung cancer human alveolar basal epithelial cell (A549) epithelial mesenchymal transition related protein to be changed, the expression of α -SMA and Vimentin is up-regulated, and the expression of E-cadherin is inhibited, and blueberry juice can improve the change.
Example 2 in vivo animal experiment of blueberry juice for preventing and treating pulmonary fibrosis induced by bleomycin
Bleomycin (BLM) is an anti-squamous carcinoma drug, but causes pulmonary fibrosis. After bleomycin is instilled in bronchi, I-type alveolar epithelial cells are injured by inflammation to secrete proinflammatory factors, and the proliferation and differentiation of II-type epithelial cells can be observed on day 2, myofibroblasts are recruited, collagen is synthesized, extracellular matrix is accumulated, and tissue and interstitial fibrosis is caused. This is consistent with the induction of diffuse pulmonary fibrosis or fibro-alveolar inflammation in humans, suggesting that bleomycin-induced injury may provide a suitable model for this disease with unknown etiology and pathogenesis. Based on the results, a C57BL/6 mouse bleomycin-induced pulmonary fibrosis model (CNV) is established in the experiment, and the effect of the blueberry juice on treating pulmonary fibrosis in vivo is evaluated.
(1) Anesthesia: 10% chloral hydrate is administrated by intraperitoneal injection according to the weight of 5mL/kg of the mouse.
(2) Preparation of the experiment: injector, surgical instruments and suture, iodophor, 2mg/kg bleomycin, normal saline and alcohol cotton.
(3) Experimental procedures and precautions:
1) mice were anesthetized by intraperitoneal injection.
2) After the mice are successfully anesthetized, the neck skin of the mice is cut by a sterile instrument, the bronchus is exposed, and other important tissues such as blood vessels of the mice cannot be damaged.
3) After finding the bronchus, injecting 2mg/kg/10mL of bleomycin by using an injector, taking care not to leak, slowly injecting all the bleomycin, then slowly pulling out the needle point, lifting the forelimb of the mouse by two hands, and uniformly shaking up, down, left and right to uniformly distribute the bleomycin in the lung.
4) The cut neck skin was then sutured with surgical sutures and sterilized by spraying iodophor.
5) After the molding is finished, the mouse is placed in a clean cage for resuscitation, the head of the mouse is slightly raised, the mouse is kept warm, the heartbeat and the breathing condition of the mouse are observed, and the asphyxia is prevented.
(4) And (3) evaluating the anti-pulmonary fibrosis effect of the blueberry juice by applying a bleomycin model.
1) Grouping experiments: solvent group, high and low dose blueberry juice group (5, 10mL/kg) and sham group.
2) The administration method comprises the following steps: the medicine is administered through oral gavage. The administration of the high and low dose blueberry juice is started 24h after molding, and the administration of the blueberry juice is 5 mL/kg/day and 10 mL/kg/day for 28 days continuously. The solvent group was given the same dose of saline as the high dose group after modeling. The sham group was molded with the same volume of saline and then given the same dose of saline as the high dose group.
3) Evaluation indexes are as follows: at 28 days after administration, the status of the mice was observed, weighed and sacrificed, and lung tissues were taken out and soaked in formalin. Lung tissue was then paraffin embedded and sectioned. Measuring changes in expression of fibrosis-associated proteins in mouse lung tissue by western blotting; the histopathological structure and collagen deposition status of the mice were evaluated with H & E staining and Masson staining. The experimental results are shown in fig. 5 and 6.
As shown in FIG. 5, the Western blot results showed that blueberry juice could inhibit the expression of fibrosis-associated proteins Collagen I, α -SMA and Vimentin in lung tissue.
As shown in FIG. 6, H & E staining results show that the lung tissue structure of the mice in the sham operation group is complete and clear, the alveolar wall is not thickened, the alveolar cavity is bright, no obvious exudation is seen in the cavity, no inflammatory cell infiltration is caused, and no fibroblast proliferation is caused. The solvent group mice have damaged alveolar structures, widened alveolar spaces, a large amount of inflammatory cell infiltration and fibroblast proliferation, and pulmonary fibrosis. Compared with the solvent group, the administration groups of the blueberry juice have better conditions, the range of pathological changes is obviously reduced, and the lung parenchyma structure is less damaged. Masson staining results show that lung tissue structures of mice in a sham operation group are normal, a large amount of growing blue collagen fibers can be seen in mice in a solvent group at alveolar spaces, alveolar walls and surrounding walls of terminal bronchioles, respiratory bronchioles and bronchioles, and fibrosis degree of each dose group of blueberry juice is low compared with that of the solvent group, and the total content of collagen is low.
The experimental results show that the blueberry juice has the effects of reducing collagen fiber hyperplasia and improving pulmonary interstitial fibrosis.
It should be appreciated that the particular features, structures, materials, or characteristics described in this specification may be combined in any suitable manner in any one or more embodiments. Furthermore, the various embodiments and features of the various embodiments described in this specification can be combined and combined by one skilled in the art without contradiction.
Claims (10)
1. Application of blueberry or extract thereof in preparing medicines or health products for preventing and treating pulmonary fibrosis.
2. Use according to claim 1, characterized in that: the blueberry adopts at least one of whole fruit, any part of fruit, fruit juice or fruit juice concentrate.
3. Use according to claim 2, characterized in that: the fruit juice is obtained by squeezing blueberry fruits and then carrying out solid-liquid separation; preferably, the fruit juice is prepared by the following method: juicing blueberry fruit, collecting pulp, centrifuging, and collecting supernatant; further preferably, the method further comprises the steps of: the supernatant was filtered and the filtrate was collected.
4. Use according to claim 1, characterized in that: the pulmonary fibrosis is chemical pulmonary fibrosis; preferably, the pulmonary fibrosis is pulmonary fibrosis caused by bleomycin.
5. The use according to claim 1, wherein the pharmaceutical or health product reduces the expression level of at least one of the fibrosis-associated proteins Collagen I, α -SMA and Vimentin in lung tissue.
6. Use according to claim 1, characterized in that: the medicine or health product can inhibit proliferation of fibroblast and alveolar basal epithelial cell.
7. The use according to claim 1, wherein the medicament or health product inhibits epithelial-mesenchymal transition, preferably wherein the medicament or health product reduces the expression of the proteins α -SMA, Vimentin associated with epithelial-mesenchymal transition in alveolar basal epithelial cells, and up-regulates the expression of E-cadherin.
8. Use according to any one of claims 1 to 7, characterized in that: the medicine or health care product is a preparation prepared by taking blueberry or extract thereof as an active ingredient and adding acceptable auxiliary materials or auxiliary ingredients.
9. Use according to claim 8, characterized in that: the preparation is an oral preparation, an injection preparation or an aerosol.
10. Use according to claim 8, characterized in that: the unit preparation contains 5 mL-10 mL of blueberry juice.
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| CN112471503A (en) * | 2020-12-04 | 2021-03-12 | 浙江蓝美生物技术有限公司 | Blueberry powder compound solid preparation capable of enhancing immunity and nutritionally intervening colorectal cancer and preparation method and application thereof |
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| CN112471503A (en) * | 2020-12-04 | 2021-03-12 | 浙江蓝美生物技术有限公司 | Blueberry powder compound solid preparation capable of enhancing immunity and nutritionally intervening colorectal cancer and preparation method and application thereof |
| CN114558121A (en) * | 2022-03-11 | 2022-05-31 | 烟台新时代健康产业有限公司 | Composition for protecting respiratory tract and lung injury and preparation method and application thereof |
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