KR20160049909A - Composition for prevention or treatment of neurodegenerative brain diseases comprising Cosmos sulphureus - Google Patents
Composition for prevention or treatment of neurodegenerative brain diseases comprising Cosmos sulphureus Download PDFInfo
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- KR20160049909A KR20160049909A KR1020140147720A KR20140147720A KR20160049909A KR 20160049909 A KR20160049909 A KR 20160049909A KR 1020140147720 A KR1020140147720 A KR 1020140147720A KR 20140147720 A KR20140147720 A KR 20140147720A KR 20160049909 A KR20160049909 A KR 20160049909A
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- yellow cosmos
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- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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Abstract
Description
The present invention relates to a composition for preventing, ameliorating or treating brain diseases, and more particularly, to a composition for preventing, ameliorating or treating brain diseases, which comprises an extract of Yellow Cosmos as an active ingredient.
As the level of living improves and the average life span of humans increases, the number of diseases associated with aging increases, and the prevalence of degenerative brain diseases associated with the brain is increasing remarkably. Degenerative brain disease is a disease in which pathological features such as cognitive function and motor function develop due to premature death of brain cells in relation to pathological aging, and include diseases such as Alzheimer's syndrome, Parkinson's syndrome, Huntington's syndrome and the like . Although there are many studies on degenerative brain diseases, precise causes and fundamental treatment methods have not yet been developed.
To date, studies have shown that oxidative stress due to reactive oxygen species (ROS) is one of the important mechanisms responsible for degenerative brain diseases. Active oxygen species are generated in vivo by the redox enzyme system in mitochondria, by immune cells exposed to external antigens, and externally by radiation or various compounds. When the balance between the production and the removal of reactive oxygen species is destroyed by the production of too much active oxygen species or the deterioration of antioxidant system function, the living body is subjected to oxidative stress by active oxygen species. Oxidative stress promotes the development and progression of various diseases such as heart disease, cancer, and diabetes, and is known to be an important factor causing degenerative brain diseases including Alzheimer's syndrome. As one of the other causes of degenerative brain diseases, studies on the inflammatory reaction of microglia, which are immune cells in the brain, have been conducted. Microglial cells are activated microglia during brain injury and produce inflammatory mediators such as nitric oxide, cytokine, and prostaglandins. Since these inflammatory mediators act as a cause of neuronal cell death, understanding how microglial cell activation is regulated is one of the ways to reduce neuronal damage in degenerative brain diseases It can be an approach.
A number of studies have been carried out on mechanisms of protecting the brain from oxidative stress and inflammation. Of these, heme oxygenase-1 (HO-1) is involved. Hematinoxidase-1 catalyzes the decomposition of heme to produce carbon monoxide (CO), biliverdin, bilirbin, iron and the like, It protects cells from toxicity, protects cells, acts as antioxidant and anti-inflammation. Therefore, it is necessary to further study a substance inducing hematinoxidase-1 (HO-1) which has antioxidative and anti-inflammatory activities against oxidative stress and inflammation which are various degenerative brain diseases.
In order to solve the problems of the prior art as described above, the present invention provides a method for inhibiting brain cell damage and anti-inflammatory effect in microglia through the expression and activity of heme oxygenase-1 (HO-1) And an object of the present invention is to provide a composition for prevention, improvement or treatment of excellent brain diseases.
The present invention also relates to a method for preventing, ameliorating, or treating brain diseases, which is effective for protecting brain cells, by inhibiting glutamate-induced cell damage in hippocampal cell HT22 cells derived from mouse and suppressing inflammatory reaction by LPS in mouse derived microglia BV2 cells And to provide a composition.
In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating brain diseases, which comprises an extract of Yellow Cosmos as an active ingredient.
The yellow cosmos extract can be extracted with water or an organic solvent, and is preferably extracted with 70% ethanol.
The yellow cosmos extract may be extracted from petals, leaves, stems, roots, etc. of yellow cosmos, and is preferably yellow cosmos petal extract.
The yellow cosmos extract is preferably contained in an amount of 0.001 to 99.9% by weight based on the total weight of the composition.
The yellow cosmos extract may induce the expression of heme oxygenase-1 (HO-1) and increase its activity to prevent, ameliorate or treat brain diseases.
Wherein said brain disease is selected from the group consisting of aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Peak disease, Creutzfeldt-Jakob disease, depression, head trauma, stroke, CNS hypoxia, cerebral ischemia, encephalitis, forgetfulness, Nerve korsakov syndrome, drug addiction, epilepsy, epilepsy, hippocampal sclerosis, headache, brain aging, dementia, anterior temporal lobe degeneration, tumor, normal ICP, HIV, cerebrovascular disease, brain disease, cardiovascular disease, memory loss, Metabolic disorders, hypothyroidism, mild cognitive impairment, memory deficits due to cognitive deficits or attention deficit, cognitive, learning disabilities, and the like.
The present invention also provides a food composition for preventing or ameliorating brain diseases, which comprises the yellow cosmos extract as an active ingredient.
According to the present invention, glutamate-induced cell damage is suppressed in mouse-derived hippocampal HT22 cells through expression and activity of heme oxygenase-1 (HO-1), and mouse-derived microglia BV2 cells Can be usefully used as a pharmaceutical composition and a health functional food for prevention, improvement and treatment of degenerative brain diseases through inhibition of inflammatory reaction by LPS and inhibition of brain cell damage and anti-inflammatory activity in microglial cells.
FIG. 1 is a graph showing cytotoxicity of hESC cells HT22 (A) and mouse-derived microspheres BV2 (B) derived from 70% ethanol extract of yellow cosmos petal according to an embodiment of the present invention.
FIG. 2 is a graph showing the cell survival rate of mouse-derived hippocampal cell HT22 induced by cytotoxicity by glutamate of a 70% ethanol extract of yellow cosmos petal according to an embodiment of the present invention.
FIG. 3 is a graph showing the inhibition rate of reactive oxygen species (ROS) production in a mouse-derived hippocampal cell HT22 in which cytotoxicity is inhibited by glutamate of a 70% ethanol extract of yellow cosmos petal according to an embodiment of the present invention.
4 is a graph showing inhibition of the expression of iNOS protein (A) and COX-2 protein (B) in mouse-derived microglia BV2 of a 70% ethanol extract of yellow cosmos petal according to an embodiment of the present invention.
5 is a graph showing inhibitory effect of NO production on mouse-derived microglia BV2 of a 70% ethanol extract of yellow cosmos petal according to an embodiment of the present invention.
FIG. 6 is a graph showing the effect of hematinoxidase-1 (HO-1) protein on mouse hippocampal cell HT22 (A) and mouse-derived microglia BV2 (B) of a 70% ethanol extract of yellow cosmos petal according to an embodiment of the present invention Fig.
FIG. 7 is a graph showing the cell survival rate (A) and the reactive oxygen species inhibition rate (hCG) of mouse-derived hippocampal cell HT22 induced by cytotoxicity by glutamate induced by HO-1 expression of 70% ethanol extract of yellow cosmos petal petal according to an embodiment of the present invention B).
FIG. 8 is a graph showing inhibitory effect of NO production on mouse-derived
Hereinafter, the present invention will be described in detail.
The inventors of the present invention studied a substance inducing hematinoxidase-1 (HO-1) having antioxidative and antiinflammatory activities against oxidative stress and inflammation which are various degenerative brain diseases, 1 < / RTI > expression-inducing activity and thus brain-protective activity, and thus completed the present invention.
The composition for preventing, ameliorating or treating brain diseases according to the present invention is characterized by containing a yellow cosmos extract as an active ingredient.
The yellow cosmos extract can be obtained by extracting and isolating from nature using an extraction and separation method known in the art, and the 'extract' defined in the present invention is extracted from yellow cosmos using an appropriate solvent , For example, crude extracts of yellow cosmos, polar solvent-soluble extracts, or non-polar solvent-soluble extracts.
As an appropriate solvent for extracting the extract from the yellow cosmos, any pharmaceutically acceptable organic solvent may be used, and water or an organic solvent may be used, but the present invention is not limited thereto. Examples of the solvent include alcohols having 1 to 4 carbon atoms such as purified water, methanol, ethanol, propanol, isopropanol, and butanol, acetone, ether various solvents such as ether, benzene, chloroform, ethyl acetate, methylene chloride, hexane and cyclohexane may be used alone or as a mixture of two or more thereof. Can be used. Particularly, the yellow cosmos extract is a 70% ethanol extract of yellow cosmos extracted with 70% ethanol (alcohol), and exhibits superior effects on hematinoxidase-1 expression and activity, It is further preferable that the anti-inflammatory activity in the glue cell can be further improved.
Examples of the extraction method include hot water extraction, cold extraction, reflux cooling, solvent extraction, steam distillation, ultrasonic extraction, elution, and compression. The desired extract may further be subjected to a conventional fractionation process or may be purified using a conventional purification method. The method for preparing the yellow cosmos extract of the present invention is not limited, and any known method may be used.
For example, the yellow cosmos extract contained as an active ingredient in the composition of the present invention may be prepared in a powder state by an additional process such as vacuum distillation, freeze drying, spray drying, or the like, by extracting the primary extract extracted with the hot water extraction method or the solvent extraction method can do. In addition, the primary extract can be further purified into a further purified fraction using various chromatographies such as silica gel column chromatography, thin layer chromatography, high performance liquid chromatography and the like Can be obtained.
Therefore, the yellow cosmos extract used in the present invention is a concept including all the extracts, fractions and tablets obtained in each step of extraction, fractionation or purification, their diluted solutions, concentrates or dried products.
The method for preparing the yellow cosmos extract according to one embodiment of the present invention will be described in more detail as follows.
In the present invention, the yellow cosmos is dried and pulverized, and then cooled to room temperature with a lower alcohol having 1 to 4 carbon atoms, preferably 70% ethanol, which is about 1 to 15 times the weight of the powdered yellow cosmos sample, It can be extracted at 25 ° C for 1 to 15 hours. Next, the yellow cosmos extract can be obtained through filtration and concentration under reduced pressure. At this time, the yellow cosmos extract can be used in all parts such as petals of yellow cosmos (petals, pistils such as pistils, stamens, and calyxes), leaves, stems and roots, and it is particularly preferable to use yellow cosmos petals.
The yellow Cosmos extract inhibits glutamate-induced cell damage in mouse-derived hippocampal HT22 cells by inducing the expression and activity of heme oxygenase-1 (HO-1) and increases the activity of mouse-derived microglia Cell BV2 cells can be used as a pharmaceutical composition or a food composition for preventing, ameliorating or treating brain diseases by suppressing inflammatory reaction by LPS to protect brain cells and without side effects.
Wherein said brain disease is selected from the group consisting of acute chronic aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Peak disease, Creutzfeldt-Jakob disease, depression, head trauma, stroke, CNS hypoxia, brain ischemia, encephalitis, , Cerebral vasculopathy, cerebral vascular disease, cardiovascular disease, amnesia, cerebral palsy, cerebral apoplexy, headache, brain aging, dementia, anterior temporal lobe degeneration, , Radiation exposure, metabolic disease, hypothyroidism, mild cognitive impairment, memory loss due to cognitive deficit or attention deficit, cognitive, learning impairment, and the like.
The present invention provides a pharmaceutical composition for preventing or treating brain diseases, which comprises an extract of Yellow Cosmos as an active ingredient.
The yellow cosmos extract is preferably included in the pharmaceutical composition of the present invention in an amount of 0.001 to 99.9% by weight, more preferably 0.1 to 99% by weight, and most preferably 1 to 80% by weight . When the content is less than 0.001% by weight, the efficiency of taking may be poor. When the content is more than 99.9% by weight, it is difficult to formulate the composition.
The compositions of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions. In addition, it can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, oral preparations such as syrups and aerosols, external preparations, suppositories and sterilized injection solutions according to a conventional method. Suitable formulations known in the art are preferably those as disclosed in Remington ' s Pharmaceutical Science, recently, Mack Publishing Company, Easton PA. Examples of carriers, excipients and diluents which may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like. When the composition is formulated, it is prepared using a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, Gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
The term "administering" as used herein is meant to provide any desired composition of the invention to a subject in any suitable manner.
The present invention relates to pharmaceutical compositions comprising an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, physician or other clinician, RTI ID = 0.0 > effective < / RTI > amount. It will be apparent to those skilled in the art that the therapeutically effective dose and frequency of administration for the pharmaceutical compositions of the present invention will vary with the desired effect. Thus, the optimal dosage to be administered can be readily determined by those skilled in the art and will vary with the nature of the disease, the severity of the disease, the amount of active and other ingredients contained in the composition, the type of formulation, and the age, The age, body weight, sex, diet, time of administration, route of administration and fraction of the composition, duration of treatment, concurrent medication, and the like. For a desired effect, the pharmaceutical composition of the present invention may be administered in an amount of 1 to 10,000 mg / kg / day, preferably 1 to 200 mg / kg / day, or may be administered once a day, It may be administered separately.
The pharmaceutical compositions of the present invention can be administered to a subject in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection.
In addition, the composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy or biological response modifiers for the prevention or treatment of brain diseases.
The present invention also provides a food composition for preventing or ameliorating brain diseases, which comprises the yellow cosmos extract as an active ingredient.
When the yellow cosmos extract of the present invention is used as a food additive, it can be suitably used according to a conventional method such as adding the yellow cosmos extract as it is or mixing it with other foods or food ingredients.
The yellow cosmos extract may be suitably modified according to the purpose of use (preventive, health or therapeutic treatment). It is particularly preferable that the yellow cosmos extract is contained in the food composition of the present invention in an amount of 0.001 to 99.9% by weight, Preferably 0.1 to 99% by weight, and most preferably 1 to 80% by weight. When the content is less than 0.001% by weight, the efficiency of taking may be poor. When the content is more than 99.9% by weight, it is difficult to formulate the composition.
As a specific example, the yellow cosmos extract of the present invention is added in an amount of not more than 15% by weight, preferably not more than 10% by weight based on the raw material. However, when it is intended for health and hygiene purposes or for the purpose of controlling health, it can be added in an amount below the above range, and there is no problem in terms of safety. Therefore, the active ingredient can be used in an amount exceeding the above range have.
There is no particular limitation on the kind of the food. Examples of the food to which the yellow cosmos extract of the present invention can be added include meat products, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Tea, a drink, an alcoholic beverage, a vitamin complex, and the like.
When the food composition of the present invention is prepared as a beverage, it may contain additional ingredients such as various flavors or natural carbohydrates such as ordinary beverages. Examples of the natural carbohydrate include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; Natural sweeteners such as dextrin and cyclodextrin, synthetic sweeteners such as saccharin and aspartame, and the like. The natural carbohydrate is contained in an amount of 0.01 to 10% by weight, preferably 0.01 to 0.1% by weight based on the total weight of the food composition of the present invention.
In addition to the above, the food composition of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, , Carbonating agents used in carbonated beverages, and the like. In addition, the compositions of the present invention may include flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of the above additives is not limited to a great extent, but may be in the range of 0.01 to 0.1% by weight based on the total weight of the food composition of the present invention.
The composition containing the yellow cosmos extract of the present invention as an active ingredient induces the expression and activity of heme oxygenase-1 (HO-1) Inhibits cell damage and suppresses inflammatory reaction by LPS in mouse derived microglia BV2 cells, and thus has a protective effect on brain cells, so that it can be effectively used for preventing, ameliorating or treating brain diseases. In addition, the present invention is free from toxicity and side effects including a yellow cosmos extract, which is a natural substance, and can be safely used for long-term use for the purpose of preventing, ameliorating or treating brain diseases.
Hereinafter, the present invention will be described in more detail with reference to examples. These embodiments are for purposes of illustration only and are not intended to limit the scope of protection of the present invention.
Example 1. Preparation of 70% ethanol extract of yellow cosmos petal
The petal part of the yellow Cosmos ( Cosmos sulphureus ) was selected, washed with water and dried. 50 g of the dried yellow cosmos petal sample was allowed to stand in 50 ml of 70% ethanol for 1 hour at room temperature and reflux-extracted for 2 hours. The extract was then filtered and concentrated with a rotary vacuum concentrator (BUCHI Labo-ratoriums Technik AG, Rotavapor RE-111, Germany) to give a yellow cosmos extract (1.5 g). Afterwards, a yellow cosmos extract was dissolved in DMSO (dimethyl sulfoxide) to prepare a sample.
Hereinafter, in order to test the effect of the 70% ethanol extract of yellow cosmos petal on the prevention, improvement and therapeutic effect of degenerative brain diseases, the damage of the brain hairs caused by oxidative damage and glutamate, In HT22 cells, a glutamate-induced brain cell damage model was used. It is known that microinflammatory cell progression leads to brain diseases caused by damage to nerve cells. Mouse mitochondria, well known as a major in vitro model of degenerative brain diseases Cell BV2 cells.
Example 2. Cytotoxicity of 70% ethanol extract of yellow cosmos petal
(Jeong GS et al., Natural Product Sciences, 13, pp. 268-272, 2007) to determine the cytotoxicity of the 70% ethanol extract of yellow cosmos leaf to mouse hippocampal cell (HT22) and mouse microglia ) Was used to perform the MTT test.
In order to investigate the protective effect against oxidative stress in cells in vitro, mouse hippocampal cell line (HT22) and mouse microglia cell line (BV2) were cultured in a 96-well plate, respectively, The 70% ethanol extracts of the obtained yellow cosmos petals were treated with 50, 100, 200, 400 and 500 μg / ml, respectively, and then cultured in a 5% CO 2 incubator for 24 hours. MTT (Sigma, M2128) reagent of 0.5 mg / ml was added to each well. After incubation in a 5% CO 2 incubator for 4 hours, the supernatant was discarded and 150 μl of DMSO (Junsei, 35535-0350) was added and shaken for 30 minutes. Using a ELISA reader (Bio-Rad, Microplate reader model 680) The cytotoxicity of 70% ethanol extract of yellow Cosmos was investigated by measuring the absorbance at.
As shown in FIG. 1, it was confirmed that the 70% ethanol extract of yellow cosmos petal, which is an active ingredient of the present invention, did not show cytotoxicity in both mouse hippocampal cell line (HT22) and mouse microglia cell line (BV2) .
Example 3: Protection of mouse hippocampal cell (HT22) and inhibition of reactive oxygen species by 70% ethanol extract of yellow cosmos petal
3-1. Protective effect of mouse hippocampal cell (HT22)
The protective effect of mouse hippocampal cell (HT22) of the 70% ethanol extract of yellow cosmos leaf was carried out by the same MTT method of Example 2 above.
The MTT method was carried out by culturing mouse hippocampal cells (HT22) at a concentration of 2 × 10 4 cells / well in a 96-well plate for 24 hours and culturing the cells in a culture medium containing 70% ethanol extract of
As shown in FIG. 2, it was confirmed that the 70% ethanol extract of yellow cosmos petal, an active ingredient of the present invention, exhibited significant cytoprotective activity against oxidative damage of glutamate-induced mouse hippocampal cell (HT22) .
3-2. Effect of inhibiting reactive oxygen species
(Royall J and H Ischiropoulos, Archives of Biochemistry and Biophysics, 302, 348-355, 1993) to measure the inhibitory effect of 70% ethanol extract of yellow cosmos petals on reactive oxygen species (ROS) Experiments were performed as well. Mouse hippocampal cells (HT22) were cultured for 24 hours at a concentration of 2 × 10 4 cells / well in a 96-well plate, and the extracts of the 70% ethanolic yellow cosmos petals obtained in Example 1 at 25, 50, 100 and 200 μg / Respectively. Each well was treated with 5 mM glutamate to induce cytotoxicity and then cultured in a 5% CO 2 incubator for 12 hours. As a positive control drug, 50 μM trolox was used.
Subsequently, the cultured cells were washed with PBS, and then incubated with 10 μM 2 ', 7'-dichlorodihydro-fluorescein diacetate (DCFDA, 35845, Fluka) (SpectramaxGemini XS, Molecular Devices, Sunnyvale, Calif., USA) were measured after reacting in Hank's balanced salt solution for 30 minutes in a dark room. The results are shown in FIG. At this time, the excitation wavelength is 490 nm and the emission wavelength is 525 nm.
As shown in FIG. 3, the 70% ethanol extract of yellow cosmos petal, which is an active ingredient of the present invention, significantly inhibited the production of reactive oxygen species in mouse hippocampal cell (HT22) induced oxidative stress by significant glutamate I was able to confirm.
Example 4. Anti-inflammatory effect of 70% ethanol extract of yellow cosmos petal on microglial cell (BV2)
4-1. Identification of anti-inflammatory effects of iNOS and COX-2-related microglia
In order to confirm the anti-inflammatory effect of the 70% ethanol extract of Yellow Cosmos petal which was confirmed to be safe because of no cytotoxicity through Example 2, the following experiment was carried out using mouse-derived macrophages.
First, COX-2 (cyclooxygenase 2) and NO (nitric oxide), which induce PGE2 (prostaglandin E2) production, are associated with the effect of 70% ethanol extract of yellow cosmos petals on the expression of anti- The amount of expression of inducible nitric oxide synthase (iNOS) inducing production was performed by Western blot analysis.
First, mouse-derived microglia (BV2) were suspended in 10% heat-inactivated fetal bovine serum (FBS) and penicillin G (100 IU / ml, Gibco co, USA) and streptomycin (100 μg / , USA) and cultured in a 5% CO 2 incubator (Sanyo, MCO175) at 37 ° C for 24 hours. Then, the cultured medium (5 x 10 6 cells / ml) was separated into 6-well plates by 1 ml each, and then the 70% ethanol extract of the yellow cosmos petal obtained in Example 1 was dissolved in 50, 100, 200 and 400 Mu] g / ml, and further cultured for 12 hours in a 5% CO 2 incubator. After the cultivation, 1 μg / ml of LPS (bacterial lipopoly-saccharide) was treated to induce an inflammatory reaction and further cultured for 18 hours. The protein content in the separated fractions was measured using a bicinchoninic acid protein kit (BCA), and the expression of iNOS and COX-2 was measured using the same amount of protein Western blot analysis was performed as follows.
First, the protein content contained in the cytoplasmic fractions obtained using the PER-Mammalian protein extraction buffer containing the protein degradation inhibitor and PMSF was measured using a Lowry protein assay kit (P5626, Sigma Chemical Co., USA) Respectively. The protein solution separated by the same amount as above was separated by SDS-PAGE using 12% dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and electrophoresis on ECL nitrocellulose membrane (Hybond enhanced chemiluminescence nitrocellulose membrane, Bio-Rad, USA). The ECL nitrocellulose membrane onto which the protein was transferred was blocked with 5% skim milk, washed, and analyzed by ECL detection system (Amersham Pharmacia Biotech, USA) according to the protocol provided. The amount of protein expression was confirmed, and the results are shown in FIG.
The protocol according to the ECL detection system was carried out by adding an antibody for COX-2 and iNOS (primary antibody, Santa Cruz Biotechnology, USA), reacting at 4 ° C for 24 hours, washing the membrane, (HRP conjugated anti-rabbit antibody) was added for 1 hour, followed by washing, and the signal was confirmed by antibody.
Experimental Results As shown in FIG. 4, β-actin, which is not related to inflammation, showed similar bands in all experimental groups, while the expression levels of iNOS and COX-2 protein related to inflammation were LPS and yellow cosmos petals 70 % Ethanol extracts were added. Specifically, when the expression of iNOS and COX-2 protein related to the inflammation was confirmed, the proteins were not found in a control group to which LPS was not added. However, when LPS was added, expression of iNOS and COX-2 protein rapidly Respectively. In addition, when 70% ethanol extract of yellow cosmos petal, which is an active ingredient of the present invention, was added, it was confirmed that the band of iNOS and COX-2 protein was blurred in a concentration-dependent manner. In particular, when compared to the control group treated with LPS alone, the band clearly blunted from the experimental group treated with 200 μg / ml of iNOS, and the band of COX-2 clearly showed a band of 200 μg / It was confirmed that it was blurred.
From the above results, it was found that the addition of the 70% ethanol extract of yellow cosmos petal, which is an active ingredient of the present invention, inhibited the expression of iNOS and COX-2 protein and had anti-inflammatory activity in microglial cells.
4-2. Inhibition of inflammation-related substance formation
In order to further confirm the anti-inflammatory effect of the 70% ethanol extract of yellow cosmos petal, which has been confirmed to have anti-inflammatory effects related to the inhibition of the production of iNOS and COX-2, the following experiment was carried out to further inhibit NO production, an inflammation-related substance.
First, as in Example 4-1, 70% ethanol extract of the yellow cosmos petal obtained in Example 1 was treated with 50, 100, 200 and 400 μg / ml of each of the microspheres in the same manner as in Example 4-1 and cultured for 12 hours , 1 μg / ml of LPS, and cultured for 18 hours to induce an inflammatory reaction. After the incubation, the supernatant was collected after centrifugation at 13,000 xg and 4 ° C for 2 minutes. The secretion amount of NO in the collected supernatant was measured according to the protocol provided by Promega using Griess reagent system (Promega, USA). Specifically, 100 μl of the supernatant of each control and experimental group was mixed with an equal amount of a 5% (v / v) phosphate solution of 0.1% (w / v) N- (1-naphathyl) -ethylene diamine and 1% / v) sulfanilamide) was mixed and reacted at room temperature (15 to 20 ° C) for 10 minutes. Then, the content of NO was measured by measuring the absorbance at 525 nm using an ELISA plate reader. The measurement results are shown in Fig.
As shown in FIG. 5, it was confirmed that the 70% ethanol extract of yellow cosmos petal, which is an active ingredient of the present invention, significantly inhibited NO production in microglial cells induced by inflammatory response by LPS From these results, it was confirmed that the 70% ethanol extract of yellow cosmos petal, which is an effective ingredient of the present invention, has an anti-inflammatory effect on microglial cells.
Example 5 Effect of 70% Ethanol Extract of Yellow Cosmos Flower on Expression of HO-1
(Heme oxygenase-1, HO-1) expression in mouse hippocampal cell HT22 and mouse microglia BV2 of a 70% ethanol extract of yellow cosmos petal, Western blot analysis (western blot analysis) as follows (Li B et al., European Journal of Pharmacology 614, pp. 58-65, 2009).
Experimental method using Western blot analysis (western blot analysis), on the 60㎜ dish 3 × 10 6 cells and incubated for 12 hours HT22 mouse hippocampus and mouse microglia BV2 respectively to a cell / ㎖ concentration Example 1 Were treated with 50%, 100%, 200%, and 400 μg / ml of the 70% ethanol extract of the yellow cosmos petal for 12 hours. At this time, 20 μM of cobalt protophorphyrin (CoPP), which is a strong inducer, was used as a positive control for the expression of HO-1, an enzyme showing antioxidative and cytoprotective effects. RIPA (89900, Thermo) buffer was added to mouse hippocampal cell HT22 and mouse microglia BV2, followed by centrifugation at 14,000 x g for 25 minutes at 4 DEG C, and the supernatant was transferred to a tube. Protein quantification was performed using a BSA protein kit (Pierce Biotechnology). Each sample was run on a 12.5% SDS-polyacrylamide gel for 2 hours and transferred to a nitrocellulose membrane (NC membrane) Respectively. The transferred nitrocellulose membrane was stopped for 1 hour in fresh blocking buffer (0.1
As shown in FIG. 6, the 70% ethanol extract of yellow cosmos petal, which is an active ingredient of the present invention, induced the expression of HO-1 in both mouse hippocampal cell HT22 and mouse microglia BV2 as the concentration increased .
Example 6. Cell protection and reactive oxygen species inhibition of mouse hippocampal cell HT22 by the expression of HO-1 in 70% ethanol extract of yellow cosmos petal
The mouse hippocampal cell HT22 was treated with 20 mM glutamate to induce cytotoxicity. Then, the 70% ethanol extract of the yellow cosmos petal obtained in Example 1 was treated at a concentration of 200, 400 / / ml for 12 hours And cultured in a 5% CO 2 incubator. At this time, 100 μM trolox was used as a positive control and 50 μM SnPP (Tin protophorphyrin, porphyrin products) was used as a negative control.
6-1. Cell protection
The cytoprotective effect by the HO-1 expression of the 70% ethanol extract of yellow cosmos petal was carried out by the same MTT method as in Example 2 above.
As shown in FIG. 7A, when the 70% ethanol extract of yellow cosmos petal, which is an active ingredient of the present invention, was treated with the ethanol extract, it was found that the effect of treating with SnPP, an inhibitor of HO-1, I could. Therefore, the 70% ethanol extract of the yellow cosmos petal, which is an active ingredient of the present invention, could be expected to have a protective effect on brain cells through expression of hematinoxidase-1 (HO-1) ( * P < compare).
6-2. Production of reactive oxygen species
To determine the effect of the 70% ethanol extract of yellow cosmos petal on the inhibition of reactive oxygen species by HO-1 expression, the production of reactive oxygen species was measured in the same manner as in Example 3 above.
As shown in FIG. 7B, the 70% ethanol extract of yellow cosmos petal, which is an active ingredient of the present invention, showed similar values to 100 μM Trolox used as a positive control, and treated with SnPP, an inhibitor of HO-1 ( * P <0.05 compared with glutamate treatment group, ** P <0.05 compared with 70% ethanol extract of yellow cosmos petals).
Example 6 Inhibitory Effect of HO-1 Expression of 70% Ethanol Extract of Yellow Cosmos Petal on Inflammatory NO Production in Microglial Cell BV2
Inhibitory effect on inflammatory NO production was observed in microglia BV2 in the same manner as in Example 4 above. First, as in Example 6, mice were treated with 200 μg / ml or 400 μg / ml of a 70% ethanol extract of yellow cosmos leaf with or without SnPP (50 μM) alone for 12 hours After treatment with 1 ㎍ / ㎖ of LPS, which is an inflammation inducer, the cells were further cultured for 18 hours to induce an inflammatory reaction.
As shown in FIG. 8, when the 70% ethanol extract of yellow cosmos petal was treated with the active ingredient of the present invention, the inhibitory effect on NO production was significant, but the treatment with SnPP, an inhibitor of HO-1 ( * P <0.05 compared with LPS treated group, ** P <0.05 compared with 70% ethanol extract of yellow cosmos petal).
From the above results, it can be seen that the yellow cosmos extract, which is an effective ingredient of the present invention, is well known as an in vitro experimental model of degenerative brain diseases
Application example 1: Parkinson's disease
Parkinson's disease is a degenerative nervous system disease that is accompanied by necrosis of dopaminergic neurons present in the black matter and exhibits various symptoms such as progression, muscle stiffness, exercise completion, abnormal posture, and inability to exercise. Clinical manifestations of Parkinson's disease other than these abnormal motility symptoms include autonomic nervous system symptoms, neuropsychiatric symptoms, cognitive dysfunction, and olfactory disorder. Oxidative toxicity is presented as a major cause of nerve cell necrosis, with increased levels of lipid peroxidation, DNA oxidation, protein carbonyl, and nitrotyrosine found in blacks (Bowling, AC and Beal, MF , Life Sci., 1995, 56 (14), 1151-1171). Therefore, the 70% ethanol extract of Yellow Cosmos which is an active ingredient of the present invention can be useful for preventing and treating Parkinson's disease.
Application example 2: Huntington's disease
The Huntington gene located on chromosome 4p16.3 has a unique sequence in which three bases of CAG are repeated. Huntington's disease is a disease in which the sequence of CAG repeat is abnormally increased, and it is the three major symptoms of dementia, mental symptoms and dementia. Accordingly, the 70% ethanol extract of Yellow Cosmos, which is an active ingredient of the present invention, can be useful for preventing and treating Huntington's disease.
Application Example 3: Hypoxic-ischemic injury
Stroke is a disease caused by a deficiency of glucose and oxygen supplied by a certain amount of blood circulation disorder (thrombosis, embolism, stenosis) of the brain. It is caused by loss of body function regulation by a damaged brain, Cognitive dysfunction occurs. After stroke, membrane depolarization of the cell membrane causes calcium to enter the cell, which then enters the mitochondria, damaging the repiratory chain and increasing the production of reactive oxygen species do. The resultant active oxygen causes neuronal cell necrosis by inducing destruction of cell membrane lipids, genetic damage, protein denaturation, etc., whereas antioxidant has the effect of inhibiting necrosis of ischemic neurons (Holtzman et al., 1996 Et al., 2001, Acta neuropathol. (Berl.), 101 (3), 229-38; Hall et al., 1990, Stroke, 21, 11183-11187). Therefore, the 70% ethanol extract of Yellow Cosmos which is an active ingredient of the present invention can be effectively used for preventing and treating ischemic stroke.
Formulation Example 1. Preparation of pharmaceutical preparations
Acid production
20 mg of a yellow cosmos 70% ethanol extract, 100 mg of lactose and 10 mg of talt were mixed and filled in airtight bags to prepare powders.
Tablet manufacture
10 mg of yellow cosmos 70% ethanol extract, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were mixed and then tableted according to a conventional preparation method.
Capsule preparation
10 mg of a yellow Cosmos 70% ethanol extract, 3 mg of crystalline cellulose, 14.8 mg of lactose and 0.2 mg of magnesium stearate were mixed and filled in gelatin capsules according to a conventional capsule preparation method to prepare capsules.
Injection manufacturing
(2 ml) of yellow cosmos 70% ethanol extract, 180 mg of mannitol, 2,974 mg of sterilized distilled water for injection, and 26 mg of Na 2 HPO 4 .2H 2 O per one ampoule according to the usual injection preparation method.
Liquid preparation
20 mg of yellow cosmos 70% ethanol extract, 10 g of isomerized sugar, and 5 g of mannitol were added to purified water in accordance with the usual liquid preparation method to dissolve the lemon flavor, and the above components were mixed. Then, purified water was further added thereto, adjusted to a total volume of 100 ml, filled in a brown bottle, and sterilized to prepare a liquid preparation.
Formulation Example 2. Preparation of food preparation
Health food manufacturing
Yellow Cosmos 70
Health drink manufacturing
According to the normal health drink manufacturing method, 100 mg of yellow cosmos 70% ethanol extract, 15 g of vitamin C, 100 g of vitamin E (powder), 19.75 g of iron lactate, 3.5 g of zinc oxide, 3.5 g of nicotinic acid amide, 0.2 g of vitamin A, 0.25 g of vitamin B2, 0.3 g of vitamin B2 and a predetermined amount of water were mixed and heated at 85 DEG C for about 1 hour with stirring. The resulting solution was filtered to obtain a sterilized 2 L container, sealed sterilized, Respectively. At this time, although the composition ratio of the ingredients suitable for the beverage is comparatively mixed, the mixture ratio may be arbitrarily varied according to the demand, the demanded country, the intended use, and the regional or national preference.
Although the present invention has been described in terms of the preferred embodiments mentioned above, it is possible to make various modifications and variations without departing from the spirit and scope of the invention. It is also to be understood that the appended claims are intended to cover such modifications and changes as fall within the scope of the invention.
Claims (10)
Wherein the yellow cosmos extract is extracted with water or an organic solvent.
Wherein the yellow cosmos extract is a yellow cosmos 70% ethanol extract.
Wherein the yellow cosmos extract is extracted from at least one selected from petals, leaves, stems and roots of a yellow cosmos.
Wherein the yellow cosmos extract is a yellow cosmos petal extract.
Wherein the yellow cosmos extract is contained in an amount of 0.001 to 99.9% by weight based on the total weight of the composition.
Wherein the yellow cosmos extract induces expression of heme oxygenase-1 (HO-1).
Wherein said brain disease is selected from the group consisting of aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Peak disease, Creutzfeldt-Jakob disease, depression, head trauma, stroke, CNS hypoxia, cerebral ischemia, encephalitis, amnesia, Nerve korsakov syndrome, drug addiction, epilepsy, epilepsy, hippocampal sclerosis, headache, brain aging, dementia, anterior temporal lobe degeneration, tumor, normal cranial pressure hydrocephalus, HIV, cerebrovascular disease, brain disease, cardiovascular disease, amnesia, Wherein the composition is a memory, cognitive or learning disorder caused by exposure, metabolic disease, hypothyroidism, mild cognitive impairment, cognitive deficit or attention deficit.
Wherein the usual yellow cosmos extract is contained in an amount of 0.001 to 99.9% by weight based on the total weight of the composition.
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