KR20160132611A - Composition for increasing amount of low density lipoprotein receptor by inhibition of PCSK9 gene expression comprising Rubi fructus extract as effective component and uses thereof - Google Patents
Composition for increasing amount of low density lipoprotein receptor by inhibition of PCSK9 gene expression comprising Rubi fructus extract as effective component and uses thereof Download PDFInfo
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- KR20160132611A KR20160132611A KR1020150065355A KR20150065355A KR20160132611A KR 20160132611 A KR20160132611 A KR 20160132611A KR 1020150065355 A KR1020150065355 A KR 1020150065355A KR 20150065355 A KR20150065355 A KR 20150065355A KR 20160132611 A KR20160132611 A KR 20160132611A
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- expression
- extract
- pcsk9 gene
- density lipoprotein
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Classifications
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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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/3262—Foods, ingredients or supplements having a functional effect on health having an effect on blood cholesterol
Abstract
The present invention relates to a composition containing an extract of Rubus coreanus as an active ingredient and for decreasing the expression of an increased PCSK9 gene by a statin compound or for increasing a low density lipoprotein receptor (LDLR) reduced by a statin compound.
The composition of the present invention can lower the blood cholesterol level by enhancing the expression of the low density lipoprotein receptor by inhibiting the expression of the PCSK9 gene. By lowering the amount of blood cholesterol, it can be used for prevention, improvement or treatment of metabolic diseases such as obesity, type 2 diabetes, hypertension, cardiovascular disease or hyperlipidemia.
Description
The present invention relates to a composition for enhancing the expression of a low density lipoprotein receptor (LDLR) by inhibiting the expression of PCSK9 gene and an expression of PCSK9 gene increased by a statin compound, By weight of the composition.
Due to economic growth and westernization of dietary habits, the intake of fat from food is increasing, and metabolic diseases such as hyperlipidemia, diabetes, hypertension, arteriosclerosis and fatty liver due to lack of exercise are increasing.
Hyperlipidemia is a hypercholesterolemia in which hypercholesterolemia, hypertriglyceridemia, and combined hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) occur in the blood with abnormally elevated levels of free lipid such as free cholesterol, cholesterol ester, phospholipid and triglyceride. It can be seen in the form of branches. Hyperlipidemia generally does not manifest itself in certain symptoms, but excessive lipid in the blood attaches to the walls of the blood vessels, narrowing blood vessels and causing atherosclerosis through inflammatory reactions. This can lead to coronary heart disease, cerebrovascular disease, and peripheral vascular occlusion. In addition, excess lipid in the blood accumulates in the liver tissue, which can lead to fatty liver.
Until now, there have been used diet, exercise, and medication to reduce the intake of cholesterol and fat-rich foods. However, diet and exercise therapy are difficult to manage and implement strictly, and their therapeutic effects are also limited. Drugs that reduce the lipid concentration developed to date include bile acid binding resins, drugs that lower the amount of cholesterol such as HMG-CoA reductase inhibitors, enzymes important for cholesterol biosynthesis, fibrin acid derivatives, nicotinic acid And other medicines that lower triglycerides have been developed.
Among them, the most commonly used drug as a therapeutic agent for hyperlipidemia is a statin-based compound (Goldstein, J. L. and Brown, M. S. 2009 Arterioscler Thromb Vasc Biol 29: 431-438). The statin compound inhibits the activity of HMG-CoA reductase, an enzyme that regulates the rate of cellular cholesterol synthesis, thereby decreasing the amount of intracellular cholesterol and consequently decreasing the amount of intracellular cholesterol. The amount of secreted cholesterol is lowered to lower the blood cholesterol level. Although statins are known to increase the amount of low density lipoprotein receptors, they also increase the expression of the PCSK9 gene at the transcription level (Janice Mayne et al., Lipids in health and Disease 2008, 7 : 22).
That is, although a statin compound is a very effective drug for hypercholesterolemia, it is clinically impossible to decrease the cholesterol in proportion to the dose even when the dose of the statin compound is doubled, It decreases to about 5 ~ 6% more. This is because the statin compound increases PCSK9 as described above.
On the other hand, PCSK9 (proprotein convertase subtilisin / kexin type 9) binds to the EGF-A domain of the low density lipoprotein receptor (LDLR) present in the cell membrane and migrates into the cell. (Horton, J. et al. 2007 Trends in Biochemical Sciences 32: 71-77). Increased expression of the PCSK9 gene leads to a decrease in LDLR and a rapid increase in the concentration of cholesterol in the blood. Patients with gain-of-function mutations with increased PCSK9 activity are more likely to develop autosomal dominant familial and cholesterolemia (Abifadel, M., et al., 2003 Nat. Genet., 34: 154-156) and, on the contrary, loss-of-function mutation in which the gene function of the PCSK9 gene is lost (Cohen, J., et al., 2005. Nat. Genet. 37: 161-165) reported that the levels of LDL-cholesterol in the blood are lower than those in normal subjects and that the incidence of coronary heart disease is very low . In addition, it has been reported that the expression of LDLR increases in mice lacking PCSK9, and that the concentration of LDL cholesterol in the blood is decreased (Rashid, S., et al., 2005 Proc Natl Acad Sci USA 102: 5374-5379) . Therefore, inhibition of the expression of PCSK9 gene can increase the amount of LDLR and decrease the cholesterol concentration in the blood, which is a new therapeutic target of hypercholesterolemia, which can remarkably lower the incidence of coronary artery disease.
Methods for inducing the decrease of cholesterol concentration in the blood by controlling the PCSK9 gene to date include a method of inhibiting the synthesis of PCSK9 gene using siRNA, a method of decreasing the amount of PCSK9 gene by using an antibody against PCSK9, A method of inhibiting the activity of the PCSK9 gene using a peptide that interferes with the binding of the PCSK9 gene and a method of inhibiting the activity of the PCSK9 gene or inducing a decrease in the expression level using a small compound.
An example of a method using a low molecular weight compound is berberine (Kong, W., et al. 2004 Nature Medicine 10: 1344-1351), chenodeoxycholic acid and FXR (farnesoid X receptor) It is reported that the expression of the gene is suppressed.
On the other hand, bokbunja is a medicinal material made of unripe berries of bokbunja berries of rosacea, and it is used as a kidney function, and it is used for urenjeong, 夢 精, 尿 尿, etc. It is used for weakening eyes, It makes the hair black and makes the skin soft and beautiful. Anti-inflammatory, antioxidant, and anti-helicobacter pylori activities have been reported, and mast cell activation inhibition, weight control effect, blood lipid component change, antioxidant effect, blood pressure inhibition effect and antibacterial effect have been reported. It has been known as a kidney function, infertility, moxibustion, liposuction, tonic, cleansing blood and eyes, protecting the liver, inhibiting carbohydrase activity, It contains a large amount of phosphorus, potassium, especially organic acids and vitamin C, and kaempferol, quercetin and phenolic compounds have been reported.
Korean Patent No. 1320371 discloses a technology relating to health functional foods including bokbunja having blood lipid-improving activity, Korean Patent Laid-Open Publication No. 2014-0031080 discloses an extract of bokbunja as an active ingredient The present invention relates to a composition for preventing and treating a metabolic syndrome disease, which comprises administering to a mammal in need thereof a composition for preventing and treating metabolic syndrome, which comprises administering to a mammal in need thereof a composition for inhibiting the expression of PCSK9 gene, Although there is disclosed a composition for inducing receptor uptake, there has been no report on a composition containing the bacterium extract of the present invention as an active ingredient and a composition for decreasing the expression of the PCSK9 gene or increasing the LDLR (low density lipoprotein receptor) .
Accordingly, the present invention provides a composition for inhibiting the expression of PCSK9 gene or for increasing a low density lipoprotein receptor (LDLR), which comprises an extract of Rubus coreanus as an active ingredient, Confirming that the composition increases the low density lipoprotein receptor (LDLR) through inhibition of the expression of the PCSK9 gene and increases the inflow of low density lipoprotein (LDL) into hepatocytes.
In order to achieve the above object, the present invention provides a composition containing an extract of Rubus coreanus as an active ingredient, for decreasing the expression of the PCSK9 gene or for increasing the LDLR (low density lipoprotein receptor).
In addition, the present invention provides a composition for containing an extract of Rubus coreanus as an active ingredient, for decreasing the expression of the PCSK9 gene increased by the statin compound or for increasing the low density lipoprotein receptor (LDLR).
In addition, the present invention provides a health functional food composition containing a bokbunja extract as an active ingredient and capable of decreasing the expression of the PCSK9 gene or increasing LDLR (low density lipoprotein receptor).
The present invention also provides a pharmaceutical composition for prevention or treatment of hypercholesterolemia comprising statin compound and brambone extract as an active ingredient and characterized by decreasing the expression of PCSK9 gene or increasing LDLR .
The present invention relates to a composition containing an extract of Rubus coreanus as an active ingredient and for decreasing the expression of the PCSK9 gene or for increasing a low density lipoprotein receptor (LDLR).
The composition of the present invention specifically inhibits the expression of the PCSK9 gene increased by the statin compound and has an effect of increasing the low density lipoprotein receptor. It can lower the blood level of cholesterol and can be used for prevention, improvement or treatment of metabolic diseases have.
1 is a schematic diagram of a luciferase assay system.
FIG. 2 is a result of confirming the operation of the luciferase assay system. In FIG. 2, (A) shows the results of cloning the promoter of the human PCSK9 gene into a firefly luciferase reporter and then transiently transfecting HepG2 cells (Coptis chinensis, 200 μg / ml) containing berberine (Berumine, 20 μM) and berberine, which are known to inhibit the expression of PCSK9 gene, and then subjected to luciferase assay using a luciferase assay It was confirmed that the azeotrope activity was operating normally.
(B) shows that the promoter activity is increased by co-transfection of a SREBP-1c expression vector, which is known to regulate human PCSK9 gene expression, with a reporter, so that the luciferase reporter activity used in the present invention is normally operating Fig.
FIG. 3 shows the results of transient transfection of human PCSK9 gene promoter (about 1.5 kb) reporter into
4 shows the results of transient transfection of a human PCSK9 gene promoter (about 1.5 kb) reporter into HepG2 cells, and 24 hours later, the ethanol extracted herbal medicine library (18 kinds of end products) was treated at a concentration of 200 μg / , And Luciferase assay. Berberine (20 μM) was used as a positive control, and the vehicle used to dissolve the substance was calibrated based on the negative control (Con) treated.
FIG. 5 is a graph showing the mRNA expression level of the PCSK9 gene after HepG2 cells were treated with 1 to 200 μg / ml of hot water extract of bokbunja for 24 hours together with 10 μM simvastatin or treated alone.
Figure 6 shows that HepG2 cells were treated with 1 ~ 200 ug / ml brambled hot-water extract for 24 hours with simuastatin (10 μM) or treated alone, followed by low density lipoprotein receptor (LDLR) mRNA And the amount of expression was confirmed.
Figure 7 shows that HepG2 cells were treated with 1 ~ 200 ug / ml brambled hot-water extract for 24 hours with simuastatin (10 μM) or treated with HMG-CoA reductase mRNA And the amount of expression was confirmed.
5 and 7, # and ## indicate statistically significant statistical significance when simvastatin alone was treated as compared to the negative control treated with the vehicle used for dissolving the substance. , And ## indicates that the p value is less than 0.001.
* And ** mean that simvastatin and brambone hydrothermal extracts treated with simvastatin alone were statistically treated together. * Indicates that the p value is less than 0.05, ** indicates the p value Is less than 0.001.
Also, @ and @@ signify statistically significant treatment of brambler hydrothermal extract alone versus a negative control without any treatment, @ indicates that p value is less than 0.05, and @@ indicates that p value is less than 0.001 .
8 is a graph showing the results of analysis of changes in LDL uptake amount of cells when treated with bokbunja extract alone or in combination with a statin compound. * Means statistically significant treatment of simvastatin and bokromatic hot-water extract in combination with simvastatin alone, and * means that the p-value is less than 0.05.
In addition, * means that statistical significance is obtained by treating the bokbunja extract alone with respect to the negative control treated with the vehicle used for dissolving the substance, and * means that the p value is less than 0.05.
$$ means statistically significant treatment of the bacterium extract alone compared to the negative control treated with the vehicle used to dissolve the material, and $$ means that the p value is less than 0.01.
The present invention relates to a composition containing an extract of Rubus coreanus as an active ingredient and for decreasing the expression of the PCSK9 gene or for increasing a low density lipoprotein receptor (LDLR). Since the composition increases the expression of low density lipoprotein receptor (LDLR) by decreasing the expression level of PCSK9 and consequently lowers the cholesterol level in the blood, it can be used for the treatment of metabolic diseases such as obesity,
The present invention also relates to a composition for containing a bramble extract as an active ingredient and for decreasing the expression of an increased PCSK9 gene by a statin compound or for increasing a low density lipoprotein receptor (LDLR) reduced by a statin compound will be.
The statin compound is not limited as long as it is a statin compound, but preferred examples thereof include simvastatin, atorvastatin, cerivastatin, lovastatin, pitavastatin, rosuvastatin, and may be one or more selected from rosuvastatin, pravastatin, fluvastatin and mevastatin.
The brambly extract may be a conventional extraction solvent known in the art, and examples of preferred extraction solvents include at least one selected from lower alcohols having 1 to 4 carbon atoms, water and mixtures thereof, more preferably water Or ethanol, and still more preferably water. In the case of hot water extraction using the above-mentioned water, water is added in an amount of 5 to 10 times the weight of the brambles and heated at 90 to 110 ° C for 2 to 3 hours for extraction. The extraction solution is filtered through a filter paper, and then freeze-dried is used, but it is not limited thereto. In the case of ethanol extraction, 80% ethanol is added by 5 to 10 times the volume of the bokbunum, and the mixture is dipped at room temperature for 20 to 25 ° C for 22 to 24 hours for extraction. The extraction solution is filtered through a filter paper, and then freeze-dried is used, but it is not limited thereto.
The present invention also relates to a health functional food composition containing an extract of Rubus coreanus as an active ingredient and capable of reducing the expression of PCSK9 gene or increasing LDLR (low density lipoprotein receptor).
The health functional food is not particularly limited and may be any type of food such as a health functional food, a nutritional supplement, a nutrient, a pharmafood, a health food, a nutraceutical, a designer food, a food additive, Preferably dairy products such as meat, sausage, bread, chocolates, candies, snacks, confectionery, pizza, ramen noodles and other noodles, gums and ice cream, soups, drinks, tea, drinks, alcoholic beverages, . At this time, the adding method is suitably used according to a conventional method, and the adding amount can be appropriately determined depending on the purpose of use.
The composition may further include various components other than the active ingredient. The various components are not particularly limited, but preferably include various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid, A salt thereof, an organic acid, a protective colloid thickener, a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, and a carbonating agent used in a carbonated drink. It may also contain flesh for the production of natural fruit juices, fruit juice beverages and vegetable beverages to add palatability or functionality, and these ingredients may be used independently or in combination.
The present invention also relates to a pharmaceutical composition for preventing or treating hypercholesterolemia, which comprises a statin compound and a bokbunja extract as an active ingredient. The bacterium extract is characterized by inhibiting the expression of the PCSK9 gene or increasing the expression of the LDLR. Since the expression of the PCSK9 gene is suppressed or the expression of the lipoprotein receptor is lowered, the blood level of cholesterol is lowered. And can be used as a pharmaceutical composition for the prevention or treatment of metabolic diseases such as
The brambly extract may be a conventional extraction solvent known in the art, and examples of preferred extraction solvents include at least one selected from lower alcohols having 1 to 4 carbon atoms, water and mixtures thereof, more preferably water Or ethanol, and still more preferably water. In the case of hot water extraction using the above-mentioned water, water is added in an amount of 5 to 10 times the weight of the brambles and heated at 90 to 110 ° C for 2 to 3 hours for extraction. The extraction solution is filtered through a filter paper, and then freeze-dried is used, but it is not limited thereto. In the case of ethanol extraction, 80% ethanol is added by 5 to 10 times as much as the weight of the bokbunum, and the mixture is dipped for 22 to 24 hours at room temperature of 20 to 25 캜 for extraction. The extraction solution is filtered through a filter paper, and then freeze-dried is used, but it is not limited thereto.
The statin compound is not limited as long as it is a statin compound, but preferred examples thereof include simvastatin, atorvastatin, cerivastatin, lovastatin, pitavastatin, rosuvastatin, and may be one or more selected from rosuvastatin, pravastatin, fluvastatin and mevastatin.
The pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier to be contained in the pharmaceutical composition of the present invention is one which is usually used at the time of formulation and includes saline solution, sterilized water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, But are not limited to, sucrose, sucrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, syrup, methylcellulose, methylhydroxybenzoate, Hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
The pharmaceutical composition of the present invention may further contain an antioxidant, a buffer, a bacteriostatic agent, a diluent, a surfactant, a binder, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent or a preservative.
The pharmaceutical composition of the present invention can be administered orally or parenterally, and is preferably administered orally. A suitable dose of the pharmaceutical composition of the present invention may be variously prescribed by factors such as the formulation method, the administration method, the age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate and responsiveness of the patient .
The pharmaceutical composition of the present invention may be prepared in unit dosage form by formulating it using a pharmaceutically acceptable carrier or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs, Into the container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not limited thereto.
Example 1. Liver cancer cell line ( HepG2 ) Culture
Liver cancer cell line (HepG2) was purchased from ATCC (American Type Culture Collection). Liver cancer cell line (HepG2) was cultured in DMEM / F-12 (Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12) medium containing 10% FBS and 1% penicillin-streptomycin. The cells were cultured in a 5% CO 2 incubator at 37 ° C. The cells were cultured in a number of cells (1 × 10 5 cells / 500 μl well) in a 24-well plate. The cells were dispensed into 24-well plates, and the cells were attached to 24 wells to form cells, which were then used when the cells reached 75% confluence.
Example 2. Preparation of bokbunja extract
1) Bokbunja Heat number Preparation of extract
2 L of water was added to 200 g of bokbunja, and the mixture was heated at 90 to 100 캜 for 2 to 3 hours, and then the extract was filtered. Then, the mixture was concentrated with a vacuum concentrator and dried in a freeze dryer under reduced pressure to obtain a hot water extract of bacterium, which was dissolved in 10% (v / v) DMSO.
2) Preparation of bokbunja ethanol extract
Two liters of 80% ethanol was added to 200 g of bokbunja, and the mixture was immersed at room temperature of 20 to 25 캜 for 22 to 24 hours, and the extract was filtered. After that, the extract was concentrated with a vacuum concentrator and dried in a freeze dryer under reduced pressure to obtain a bacterium ethanol extract. The extract was dissolved in 10% (v / v) DMSO.
Example 3. Luciferase Assay System construction
As shown in Fig. 1, in order to confirm the change in the expression level of the PCSK9 gene, a luciferase assay system was constructed and it was confirmed whether or not it was functioning normally.
After the human PCSK9 gene promoter (about 1.5 kb) was cloned into a firefly luciferase reporter, transient transfection was performed on HepG2 cells, and 20 μM berberine and 200 μg berberine (Coptis chinensis) was treated and cultured for 24 hours. Thereafter, the degree of luminescence of firefly luciferase was measured and the results are shown in Fig. 2 (A). When treated with the extract of Coptis chinensis (200 μg / ml), which contains berberine (berberine, 20 μM) and berberine, which are known to inhibit the expression of PCSK9 gene, the amount of expression of PCSK9 gene Was significantly reduced compared to one negative control group.
In addition, the SREBP-1c expression vector, which is known to regulate the gene expression of the human PCSK9 gene, was co-transfected with a reporter, confirming that the promoter activity was increased, so that the luciferase reporter activity used in the present invention was normally operated (Fig. 2 (B)).
In the following examples, the luciferase assay system constructed in this example was used.
Example 4. PCSK9 Screening using the change in the transcriptional activity of the promoter region of the gene
Luciferase assay was performed to select herb extracts which can reduce the expression level of PCSK9 gene among 18 herb medicine library.
A luciferase reporter containing the human PCSK9 promoter (about 1.5 kb) was transiently transfected into HepG2 cells, followed by treatment with 18 kinds of herbal extracts of 200 μg / ml and culturing overnight. Then, the degree of luminescence of firefly luciferase was measured to select the herbal medicine extract which reduces the expression of PCSK9 gene. 3 and 4 that the selected herbal extract of # 24 reduces the expression level of the PCSK9 gene effectively in both hot water and ethanol extracts.
The herbal medicine extracts of # 24 disclosed in Figures 3 and 4 were identified as bramble extract.
Example 5. Bokbunja extract When administered alone or in combination with a statin compound PCSK9 , LDLR And HMG - CoA reductase Analysis of gene expression changes
In order to confirm the results of the luciferase assay screening conducted in Example 4, real-time PCR using a taqman probe was used to measure the activity of the PCSK9 protein when the brambler extract alone or the statin compound and the bacterium hot- , LDLR, and HMG-CoA reductase gene expression.
100 and 200 μg / ml of bokbule extracts were treated with
When treated with only 10 μM simvastatin, the expression of PCSK9 gene was increased (FIG. 5) and the expression of HMG-CoA reductase gene was increased. However, when the bokbunja extract alone or simvastatin and bokbunja extract were treated together, the expression of PCSK9 gene was decreased (Fig. 5), the expression of LDLR was increased (Fig. 6), and the expression of HMG-CoA reductase gene was decreased (Fig. 7). The positive control group in this example used berberine of 20 μM, and it was confirmed that the combination treatment of simvastatin and brambone extract of the present invention was more effective than berberine treatment.
Example 6. Bokbunja extract When cells are treated alone or in combination with a statin compound, LDL absorption( uptake ) Quantity change analysis
From the results of Examples 4 and 5, it was confirmed that the effect of suppressing the expression of PCSK9 and the expression of LDLR in Example 2 provided by the present invention was shown, and it was confirmed whether this effect had an effect on the change of absorption level to extracellular LDL To investigate the changes in the LDL uptake of cells in combination with bokbunja extract alone or with statin compounds using fluorescence-labeled LDL (fluorescence-labeled LDL).
Specifically, the cells were seeded in a 96-well white clear-bottom cell culture plate at 3 to 4 × 10 4 cells / well (FBS-containing media), cultured for 24 hours, and then exchanged with serum-free media I left it in starvation for 24 hours. After starvation, media was removed and washing was performed 3 times (100 쨉 l per well with assay buffer). 10 [mu] l of fluorescently-labeled LDL and 90 [mu] l of serum-free media were dispensed per well and treated for 24 hours. To confirm the specificity of LDL absorption, 10 μl of unlabeled (UN) LDL were treated in wells (UL-LDL, compete out the signal). After incubation for 24 hours, washing was carried out 4 times. After that, 100 μl of assay buffer was dispensed per well and the fluorescence expressed in each cell was measured (Ex / Em = 540 nm / 575 nm) The results are shown in Fig.
As a result, as shown in Fig. 8, the treatment of Example 6 showed a statistically significant increase in the inflow of LDL into HepG2 cells when the bokbunja extract alone or simvastatin and bokbunja extract were used together.
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| PCT/KR2015/013365 WO2016182161A1 (en) | 2015-05-11 | 2015-12-08 | Composition containing rubus coreanus extract or fraction thereof as active ingredient for increasing low-density lipoprotein receptor by inhibiting pcsk9 gene expression, and use thereof |
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| KR101956805B1 (en) * | 2019-02-21 | 2019-03-11 | 한국식품연구원 | Composition for Inhibiting PCSK9 Gene Expression or Increasing Amount of Low Density Lipoprotein Receptor Comprising Butein or Isoeugenol |
| KR20190041832A (en) * | 2017-10-13 | 2019-04-23 | 한국식품연구원 | Composition for Inhibiting PCSK9 Gene Expression or Increasing Amount of Low Density Lipoprotein Receptor Comprising Butein or Isoeugenol |
| KR20210030192A (en) | 2019-09-09 | 2021-03-17 | (주)리즈바이오텍 | Pharmaceutical composition containing complex Rubus crataegifolius, Crataegus pinnatifida Bunge, Cinnamomum cassia extracts for prevention or treatment of metabolic syndrome |
| KR20220126387A (en) | 2021-03-09 | 2022-09-16 | (주)리즈바이오텍 | Pharmaceutical composition comprising Rubus, Crataegus and Cinnamomum Genus extracts for prevention or treatment of metabolic syndrome |
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| KR101158739B1 (en) * | 2010-04-19 | 2012-06-22 | 주식회사 참선진 종합식품 | Manufacturing method of herbal medicine vegetable juice for improvement of blood circulation, herbal medicine vegetable juice for improvement of blood circulation manufactured by the same |
| KR101173172B1 (en) * | 2010-05-28 | 2012-08-14 | 한국식품연구원 | A composition for improving lipid metabolism which includes extract of rubus coreanus as an active constituent by major |
| WO2014003352A1 (en) * | 2012-06-29 | 2014-01-03 | (주)리즈바이오텍 | Composition containing immature fructus extract of rubus coreanus miquel as active ingredient for improving blood circulation |
| KR20140140674A (en) * | 2013-05-29 | 2014-12-10 | 재단법인 고창복분자연구소 | Method for Cholesterol Inhibition in Blood Using Extract of Rubus occidentalis ＆ Red Ginseng |
| KR20140141845A (en) * | 2013-05-31 | 2014-12-11 | 재단법인 고창복분자연구소 | Composition for Improving of Blood Coagulation from Main Component Using Extract of Stem of Rubus occidentalis |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190041832A (en) * | 2017-10-13 | 2019-04-23 | 한국식품연구원 | Composition for Inhibiting PCSK9 Gene Expression or Increasing Amount of Low Density Lipoprotein Receptor Comprising Butein or Isoeugenol |
| KR101956805B1 (en) * | 2019-02-21 | 2019-03-11 | 한국식품연구원 | Composition for Inhibiting PCSK9 Gene Expression or Increasing Amount of Low Density Lipoprotein Receptor Comprising Butein or Isoeugenol |
| KR20210030192A (en) | 2019-09-09 | 2021-03-17 | (주)리즈바이오텍 | Pharmaceutical composition containing complex Rubus crataegifolius, Crataegus pinnatifida Bunge, Cinnamomum cassia extracts for prevention or treatment of metabolic syndrome |
| KR20220126387A (en) | 2021-03-09 | 2022-09-16 | (주)리즈바이오텍 | Pharmaceutical composition comprising Rubus, Crataegus and Cinnamomum Genus extracts for prevention or treatment of metabolic syndrome |
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