WO2011065657A2 - Compound comprising extracts or fractions of chrysanthemum boreale makino having anti-inflammation activity - Google Patents
Compound comprising extracts or fractions of chrysanthemum boreale makino having anti-inflammation activity Download PDFInfo
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- WO2011065657A2 WO2011065657A2 PCT/KR2010/006651 KR2010006651W WO2011065657A2 WO 2011065657 A2 WO2011065657 A2 WO 2011065657A2 KR 2010006651 W KR2010006651 W KR 2010006651W WO 2011065657 A2 WO2011065657 A2 WO 2011065657A2
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- WIPO (PCT)
- Prior art keywords
- composition
- chrysanthemum boreale
- boreale makino
- reduction
- extracts
- Prior art date
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Classifications
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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)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
- A61K36/287—Chrysanthemum, e.g. daisy
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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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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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
Definitions
- the present invention relates to a composition having an anti-inflammatory activity, comprising extracts or fractions of Chrysanthemum boreale Makino.
- atopic dermatitis is a skin disorder with multifactorial etiology, such as immunological, genetic, pharmacological, physiological, and environmental factors, is caused in particular, by infections, stress, changes in season and climate, stimuli, and allergens.
- Atopic dermatitis is a chronic inflammation of the skin that occurs in persons of all ages, from infants to adults.
- atopic dermatitis In general, approximately 80% of atopic dermatitis is associated with IgE, and atopic dermatitis can be categorized into the extrinsic (IgE-mediated) and the intrinsic (non-IgE-mediated) types.
- the elevated IgE response and eosinophilia are observed in patients with atopic dermatitis, which reflects increased responses of Th2 cytokines such as IL-4 and IL-5 with a concomitant decrease in the Th1 cytokine, IFN- ⁇ production.
- Th2 cytokines such as IL-4 and IL-5
- IFN- ⁇ production In this connection, the use of various immunomodulators such as pimecrolimus and tacrolimus has been attempted.
- Treg cells CD4+ CD25+ regulatory T cells (Treg cells) capable of directly suppressing immune responses has recently become known.
- Treg cells originate from the thymus and have an ability to control the activity of various T lymphocytes. Further, Treg cells transduce immune inhibitory signals or inhibit interaction between immune cells such as macrophages or B cells by the expression of CTLA4, GITR, CD25 and LAG3 on their surface. Treg cells induce immune suppression through the production of cytokines such as TGF- ⁇ and IL-35, in addition to IL-10.
- Th2 cytokines such as IL-4 and IL-5 are highly produced due to defects in Th2 cell development, whereas the production of Th1 cytokines such as IFN- ⁇ is suppressed.
- Th2 chemokines represented by TARC/CCL17, MDC/CCL22, and CTACK/CCL2, directly affect Th2 cell development.
- Cytokines are produced by various cells, and have many different actions. In particular, since an identical cytokine may exert different functions, cytokines are very difficult to classify. When T cells recognize antigens presented by macrophages and are activated to induce immune responses, numerous cytokines are involved in this process. Various cytokines are involved in each step of innate and adaptive immunity, from antigen recognition to effector steps, and some cytokines are also involved in the production of lymphocytes and other hemocytes. The actions of key cytokines are as follows.
- IL-1 (interleukin 1) is a cytokine that is produced by activated mononuclear phagocytes, epithelial cells, or endothelial cells, and mediates inflammation. There are two forms of IL-1, IL-1 ⁇ and IL-1 ⁇ . A small amount of IL-1 activates CD4-T cells and B cells and stimulates inflammatory cells. However, an excessive amount of IL-1 functions as a hormone to induce fever and acute phase response.
- IL-4 (interleukin 4) is a protein having a size of approximately 20 kDa, which is produced by CD4 T cells and activated mast cells, and functions as a B-cell growth factor. IL-4 also functions as a differentiation factor involved in immunoglobulin class switching in B cells, and may also activate CD4 T cells, mast cells, macrophages, etc.
- IL-10 (interleukin 10) induces differentiation of activated T cells into CTLs by a synergistic effect with IL-2, and also induces proliferation of NK cells, LAK cells, and activated T cells.
- IFN- ⁇ interferon- ⁇ , also known as type II interferon, is produced by CD4 T cells or CD8 T cells to regulate immune responses, and is thus also called immune interferon.
- IFN- ⁇ acts on T cells, B cells, NK cells, and endothelial cells to activate them, and functions as a macrophage-activating factor to increase the expression of MHC Class I and II.
- IFN- ⁇ is also able to inhibit viral replication, like other interferons.
- NO functions as a vasodilator under physiological conditions.
- iNOS inflammatory cytokines
- COX-2 cyclooxygenase-2
- COX-2 is a key modulator that produces prostaglandins from arachidonic acid.
- COX-2 converts arachidonic acid to PGG2.
- PGG2 is converted to PGE2, PGD2, PGF2, PGI2, or TXA2, which exert different functions in vivo.
- a representative COX-2 inhibitor is aspirin.
- the present inventors have demonstrated that the extracts and fractions of Chrysanthemum boreale Makino exhibit an effect of reducing serum IgE level and have an inhibitory effect on inflammation-related factors found in inflammatory diseases.
- the extracts and fractions of Chrysanthemum boreale Makino show prophylactic and therapeutic effects on various inflammatory diseases, in particular, on atopic dermatitis, thereby completing the present invention.
- composition according to the present invention has an anti-inflammatory activity, it can be used for the prevention or treatment of inflammatory diseases such as atopic dermatitis, and can also be applied to various fields, including quasi-drugs, cosmetics, foods, and water softeners.
- FIG. 1 is a flow chart showing the process of preparing the extracts and fractions of Chrysanthemum boreale Makino;
- FIG. 2 shows a sensitization schedule of DNCB-treated NC/Nga mice
- FIG. 3 shows changes of NC/Nga mouse model according to scores before and after drug treatment
- FIG. 4 shows changes in scratching behavior of atopic dermatitis-induced NC/Nga mouse model after treatment of the extracts of Chrysanthemum boreale Makino, Taraxacum mongolicum Hand-mazz, Phellodendron amurense Rupr, Acorus gramineus Soland, Ilex cornuta Lindl, and Prunus yedoensis Matsumura;
- FIG. 5 shows the results of clinical scoring of atopic dermatitis-induced NC/Nga mouse model after treatment of the extracts of Chrysanthemum boreale Makino, Taraxacum mongolicum Hand-mazz, Phellodendron amurense Rupr, Acorus gramineus Soland, Ilex cornuta Lindl, and Prunus yedoensis Matsumura;
- FIG. 6 shows changes in serum IgE level of atopic dermatitis-induced NC/Nga mouse model after treatment of the extracts of Chrysanthemum boreale Makino, Taraxacum mongolicum Hand-mazz, Phellodendron amurense Rupr, Acorus gramineus Soland, Ilex cornuta Lindl, and Prunus yedoensis Matsumura;
- FIG. 7 shows changes in atopic symptoms of NC/Nga mouse model according to scores before and after treatment with the extract of Chrysanthemum boreale Makino;
- FIG. 8 shows the results of clinical scoring of atopic dermatitis-induced NC/Nga mouse model after treatment with the extract of Chrysanthemum boreale Makino;
- FIG. 9 shows the results of scratching behavior of atopic dermatitis-induced NC/Nga mouse model after treatment with the extract of Chrysanthemum boreale Makino;
- FIG. 10 shows the results of measuring ear thickness (length: mm) of atopic dermatitis-induced NC/Nga mouse model after treatment with the extract of Chrysanthemum boreale Makino;
- FIG. 11 shows the results of measuring ear thickness (volume: %) of atopic dermatitis-induced NC/Nga mouse model after treatment with the extract of Chrysanthemum boreale Makino;
- FIG. 12 (a) shows the results of measuring serum IgE level of atopic dermatitis-induced NC/Nga mouse model after oral administration of the extract of Chrysanthemum boreale Makino; (b) shows the results of measuring serum IgE level of atopic dermatitis-induced NC/Nga mouse model after topical administration of the extract of Chrysanthemum boreale Makino;
- FIG. 13 shows the results of measuring serum IFN- ⁇ level of atopic dermatitis-induced NC/Nga mouse model after treatment with the extract of Chrysanthemum boreale Makino;
- FIG. 14 shows the results of measuring serum IL-4 level of atopic dermatitis-induced NC/Nga mouse model after treatment with the extract of Chrysanthemum boreale Makino;
- FIG. 15 shows photographs of ear tissue sections of atopic dermatitis-induced NC/Nga mouse model after treatment with the extract of Chrysanthemum boreale Makino;
- FIG. 16 shows LPS-induced intracellular nitric oxide production in RAW 264.7 cells after treatment with the fractions of Chrysanthemum boreale Makino;
- FIG. 17 shows LPS-induced intracellular iNOS (induced nitric oxide synthase) production in RAW 264.7 cells after treatment with the fractions of Chrysanthemum boreale Makino;
- FIG. 18 shows LPS-induced intracellular PGE2 production in RAW 264.7 cells after treatment with the fractions of Chrysanthemum boreale Makino;
- FIG. 19 shows LPS-induced intracellular COX-2 production in RAW 264.7 cells after treatment with the fractions of Chrysanthemum boreale Makino;
- FIG. 20 shows LPS-induced intracellular I ⁇ B production in RAW 264.7 cells after treatment with the fractions of Chrysanthemum boreale Makino;
- FIG. 21 shows LPS-induced intracellular P50 production in RAW 264.7 cells after treatment with the fractions of Chrysanthemum boreale Makino;
- FIG. 22 shows LPS-induced intracellular P65 production in RAW 264.7 cells after treatment with the fractions of Chrysanthemum boreale Makino;
- FIG. 23 shows LPS-induced intracellular nitric oxide production in RAW 264.7 cells after treatment with the fractions of Chrysanthemi Indici Flos;
- FIG. 24 shows LPS-induced intracellular iNOS (induced nitric oxide synthase) production in RAW 264.7 cells after treatment with the fractions of Chrysanthemi Indici Flos;
- FIG. 25 shows LPS-induced intracellular PGE2 production in RAW 264.7 cells after treatment with the fractions of Chrysanthemi Indici Flos;
- FIG. 26 shows LPS-induced intracellular COX-2 production in RAW 264.7 cells after treatment with the fractions of Chrysanthemi Indici Flos;
- FIG. 27 shows LPS-induced intracellular I ⁇ B production in RAW 264.7 cells after treatment with the fractions of Chrysanthemi Indici Flos;
- FIG. 28 shows LPS-induced intracellular P65 production in RAW 264.7 cells after treatment with the fractions of Chrysanthemi Indici Flos.
- FIG. 29 shows the results of MTS assay for cytotoxicity of extracts and fractions of Chrysanthemum boreale Makino.
- the present invention provides a composition having an anti-inflammatory activity, comprising extracts or fractions of Chrysanthemum boreale Makino.
- the present inventors have selected the extracts of Chrysanthemum boreale Makino, Taraxacum mongolicum Hand-mazz, Phellodendron amurense Rupr, Acorus gramineus Soland, Ilex cornuta Lindl, and Prunus yedoensis Matsumura, and examined their effects on inflammatory diseases. As a result, it was found that Chrysanthemum boreale Makino shows the most excellent effect.
- Example 1 when atopic dermatitis-induced models were treated with the extracts of Chrysanthemum boreale Makino, Taraxacum mongolicum Hand-mazz, Phellodendron amurense Rupr, Acorus gramineus Soland, Ilex cornuta Lindl, and Prunus yedoensis Matsumura, and then clinical scoring was performed, it was found that the extracts of Chrysanthemum boreale Makino were recorded showing low scores for erythema, edema, excoriation, pruritus, dry skin, erosion, and lichenification (Tables 1 and 2, and FIGs. 4 and 5), and showed a remarkably low serum immunoglobulin E level, compared to the other plants (Table 3 and FIG. 6).
- Chrysanthemum boreale Makino is a perennial plant, which belongs to the family Compositae and the order Campanulales, and is distributed in Korea, Japan, north China and Siberia, and is mainly found in valleys or fields. It grows to 1-1.5 m. Leaves are alternate, the bottom part falls when it blooms. The middle one is oblong, ovate, 5-7 cm long, 4-6 cm broad. The bottom part is cordate a bit or flat ended, and divided laminas have similar size, and are oblong, entire, sharp lobed serrates at the edge. Petiole is 1-2 cm long.
- the edge laminas are 2 pairs, and have a large gap between the laminas, hairs on the surface, and hairs in the middle of the backside. It is in flower from September to October, and the flower is 1.5 cm in diameter, and hangs on the end of the branches and main stems.
- the involucre is 4 mm long and 8 mm in diameter.
- the bract is in 3-4 lines, and the outer bract is linear or oblong and has hairs on its surface, and the inner bract is oblong and has a thin edge.
- Ligulate corolla is 5-7 mm long, yellow in color, and a tubular corolla’s edge is divided into 5 parts.
- An achene is obovate and 1 mm long, and has 5-6 lines and no pappus, and ripens in October-November. Its stalk is 1-1.5 m tall and has many branches with short white hairs. Its roots come out and twigs stretch out. The plant grows well in any soil, in particular in fertile soil, and prefers dry to wet places.
- the Chrysanthemum boreale Makino of the present invention is a scientific name, and may be purchased from commercially available sources, collected from nature, or cultivated. Further, the extracts of Chrysanthemum boreale Makino according to the present invention may be extracted from various organs of natural, hybrid, or mutant plants, for example, root, stalk, leaf, flower, fruit flesh and peel, and plant tissue culture, and is most preferably extracted from the flower of Chrysanthemum boreale Makino.
- the extracts of Chrysanthemum boreale Makino according to the present invention may be obtained by extraction with water, an organic solvent or a solvent mixture thereof.
- Chrysanthemum boreale Makino is dried for a predetermined time, and pulverized, followed by extraction according to the typical method known in the art, such as hot water extraction, cold water extraction, hot extraction, ultrasonic extraction, and cold extraction.
- the extraction method is not particularly limited, and it may be performed at room temperature or elevated temperature under the condition in which the active ingredients are not destroyed, or this destruction is minimized.
- the powder of Chrysanthemum boreale Makino obtained by pulverization of washed and dried Chrysanthemum boreale Makino, may be extracted using water, lower C 1 -C 4 alcohol, or a solvent mixture thereof, and more preferably, it is extracted using water or methanol.
- Hot water extraction of Chrysanthemum boreale Makino may be performed by the steps of heating Chrysanthemum boreale Makino with water, filtering Chrysanthemum boreale Makino, concentrating the filtrate and then pulverizing it with an excipient, and tabletting the extract powder of Chrysanthemum boreale Makino with a binder.
- the excipient may be exemplified by starch, calcium carbonate, sucrose, lactose, or gelatin.
- the binder may be exemplified by dextrin, hydroxypropyl methylcellulose, pregelatinized starch, povidone (polyvinylpyrrolidone), carboxymethyl cellulose, methylcellulose, or ethyl cellulose.
- the extraction time is not particularly limited, but may be approximately 2 to 5 hrs, and hot water extraction may be performed at 70 to 100°C, preferably 80 to 100°C. Based on the weight of Chrysanthemum boreale Makino, 10 to 30-fold, preferably, 15 to 25-fold, and more preferably, approximately 20-fold volume of water may be used to prepare a hot water extract of Chrysanthemum boreale Makino.
- the fractions of Chrysanthemum boreale Makino of the present invention may be obtained by fractionation of the extract of Chrysanthemum boreale Makino.
- solvents known in the art may be used, and preferably, organic solvents.
- pentane, hexane, 2,2,4-trimethyl pentane, dicaine, cyclohexane, carbon disulfide, carbon tetrachloride, chlorobutane, diisopropyl ether, chloroform, acetone, nitropropane, butanone, dichloroethane, pyridine, propanol, methanol, and ethyl acetate are included.
- the preferred organic solvent includes non-polar organic solvents, in particular, chloroform, ethanol, ethyl acetate or a solvent mixture thereof, but is not limited thereto.
- non-polar organic solvents in particular, chloroform, ethanol, ethyl acetate or a solvent mixture thereof, but is not limited thereto.
- chloroform, ethanol, or a solvent mixture thereof is used to obtain each fraction, and all fractions showed the activity. Among them, the chloroform fraction showed the highest anti-inflammatory activity (Tables 8, 9, and 10).
- anti-inflammatory activity means to inhibit inflammation, which is one of the body’s internal defense mechanisms against certain stimulation, and refers to complicated lesions causing three changes: alteration of tissues, circulatory disturbances and exudation, and proliferation of tissues. More particularly, inflammation is part of innate immunity, and human innate immunity includes the perception of pathogens by recognition of specific cell-surface pattern, like in other animals. Phagocytes recognize the cells as non-self to attack pathogens. If pathogens penetrate physical barriers of the body, inflammation occurs. Inflammation is a nonspecific defense that creates an environment hostile to microbes at the site of injury. In inflammatory responses, when injury occurs or pathogens invade the body, cytokines are released by the recruitment of leukocytes involved in initial immune responses. Thus, the intracellular cytokine level is an index of inflammatory activation.
- the present inventors have performed experiments on Chrysanthemum boreale Makino, and demonstrated that the extracts and fractions of Chrysanthemum boreale Makino have an anti-inflammatory activity.
- the present inventors confirmed a reduction in serum IgE (immunoglobulin E), IFN- ⁇ (interferon- ⁇ ), and IL-4 (interleukin-4) levels (FIGs. 12, 13, and 14); a reduction in intracellular NO (nitric oxide) level (FIG. 16); a reduction in iNOS (induced nitric oxide synthase) level (FIG. 17); a reduction in intracellular PGE2 (prostaglandin E2) level (FIG.
- each of the methanol (MeOH) extract, chloroform (CHCl3) fraction, and ethyl acetate (EtOAc) fraction of Chrysanthemum boreale Makino was found to reduce the intracellular nitric oxide (NO) levels to approximately 38%, 78%, and 30% in inflammatory disease animal model (Example 3-2), whereas the methanol extract of Chrysanthemi Indici Flos was found to reduce the levels to 97.9%, 89.0%, 37.3%, and 17.8%, and the chloroform fraction of Chrysanthemi Indici Flos was found to reduce the levels to 50.6%, 19.2%, 16.6%, and 7.5% at
- Nitric oxide functions as a vasodilator under physiological conditions.
- NO a vasodilator
- macrophages are stimulated by inflammatory cytokines
- NO produced by iNOS induces inflammation under pathological conditions to increase COX-2 (cyclooxygenase-2) activity, leading to amplification of inflammation via arachidonic acid cascade.
- COX-2 cyclooxygenase-2
- IFN- ⁇ also known as type II interferon, is produced by CD4 T cells or CD8 T cells to regulate immune responses, and thus is also called immune interferon. IFN- ⁇ acts on T cells, B cells, NK cells, and endothelial cells to activate them, and functions as a macrophage-activating factor to increase the expression of MHC Class I and II. IFN- ⁇ is also able to inhibit viral replication, like other interferons.
- IL-4 is a protein having a size of approximately 20 kDa, which is produced by CD4 T cells and activated mast cells, and functions as a B-cell growth factor. IL-4 also functions as a differentiation factor involved in immunoglobulin class switching in B cells, and may also activate CD4 T cells, mast cells, and macrophages.
- the extracts or fractions of Chrysanthemum boreale Makino according to the present invention have excellent prophylactic and therapeutic activities on inflammatory diseases, in particular, allergic inflammatory diseases.
- the extracts and fractions of Chrysanthemum boreale Makino are not artificially-synthesized compounds, but based on the ingredients obtained from natural extracts. Thus, they are safe, non-toxic, and without side effects, and can be given over a long period of time. Further, the composition can be used for animals with inflammatory diseases, including monkeys, dogs, cats, rabbits, guinea pigs, rats, mice, cattle, sheep, pigs, and goats, as well as human.
- the present invention can be adopted for the preparation of a pharmaceutical composition for the prevention or treatment of inflammatory diseases comprising the extracts or fractions of Chrysanthemum boreale Makino as an active ingredient, and inflammatory diseases can be prevented or treated by the administration of the composition.
- the present invention relates to a pharmaceutical composition for the prevention or treatment of inflammatory diseases comprising the extracts or fractions of Chrysanthemum boreale Makino as an active ingredient, and a method for preventing or treating inflammatory diseases by the administration of the composition comprising extracts or fractions of Chrysanthemum boreale Makino to patients with inflammatory diseases or at risk for inflammatory diseases.
- the inflammatory diseases may be allergic inflammatory diseases, and the allergic inflammatory diseases may include chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, atopic dermatitis, and inflammatory bowel disease.
- COPD chronic obstructive pulmonary disease
- asthma chronic obstructive pulmonary disease
- rheumatoid arthritis atopic dermatitis
- inflammatory bowel disease any disease induced by inflammatory or allergic responses may be included without limitation, and preferably atopic dermatitis.
- prevention means all of the actions in which the disease is restrained or retarded by the administration of the composition comprising the extracts or fractions of Chrysanthemum boreale Makino according to the present invention.
- treatment means all of the actions in which the disease has taken a turn for the better or been modified favorably by the administration of the composition comprising the extracts or fractions of Chrysanthemum boreale Makino according to the present invention.
- Example 2 the present inventors confirmed 1) reduction in erythema, edema, excoriation, pruritus, dry skin, erosion, and lichenification (FIGs. 7 and 8); 2) reduction in ear edema (FIG. 10 and 11); 3) reduction in scratching behavior (FIG. 9); and 4) inhibition of fibroblast proliferation, collagen layer hyperplasia, and ulceration, reduction in mast cell infiltration, and reduction in inflammation by neutrophil and lymphocyte infiltration (FIG. 15) in inflammatory disease animal models after treatment with the extracts of Chrysanthemum boreale Makino, indicating therapeutic effects on inflammatory disease, in particular, atopic dermatitis.
- compositions for the prevention or treatment of inflammatory diseases comprising the extracts or fractions of Chrysanthemum boreale Makino according to the present invention can be administered to mammals including rats, mice, livestock, and humanS via various routes. All modes of administration are contemplated, for example, administration can be made orally, rectally or by intravenous, intramuscular, subcutaneous, epidural or intracerebroventricular injection. Preferably, the composition can be applied to the skin, and most preferably, oral administration.
- the pharmaceutical composition for the prevention or treatment of inflammatory diseases of the present invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount refers to an amount sufficient for the treatment of diseases, which is commensurate with a reasonable benefit/risk ratio applicable for medical treatment.
- An effective dosage of the present composition may be determined depending on the subject and severity of the diseases, age, gender, type of infected virus, drug activity, the patient’s drug sensitivity, administration time, administration routes, excretion rates, duration of treatment, simultaneously used drugs, and other factors known in the medical field.
- the effective amount may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and co-usage with other active agents.
- composition for the prevention or treatment of inflammatory diseases of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, and also used singly or in combination with other pharmaceutically active compounds.
- the pharmaceutical composition for the prevention or treatment of inflammatory diseases of the present invention may be prepared into a pharmaceutical formulation using the methods known in the art in order to provide rapid, prolonged or delayed release of the active ingredients after administration into mammals.
- the active ingredients may be mixed or diluted with carriers, or encapsulated in the container-type carrier.
- the pharmaceutical composition for the prevention or treatment of inflammatory diseases of the present invention may be formulated into formulations for oral administration, such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, etc., or as formulation for external application, suppository and sterile injectable solution, according to common methods.
- Suitable carrier, excipient, and diluent that are typically used in the preparation of composition may be further included.
- Examples of the carrier, excipient, and diluent that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.
- commonly used filler, extender, binder, wetting agent, disintegrant, surfactant, etc. are used as diluent or excipient.
- Solid formulations for oral administration include tablet, pill, powder, granule, capsule, or the like.
- the solid formulation is prepared by mixing the extract with at least one excipient, e.g., starch, calcium carbonate, sucrose, lactose, gelatin, etc.
- excipient e.g., starch, calcium carbonate, sucrose, lactose, gelatin, etc.
- lubricants such as magnesium stearate and talc may be used, in addition to the excipient.
- Liquid formulations for oral administration include suspension, liquid for internal use, emulsion, syrup, or the like.
- various excipients e.g., wetting agent, sweetener, aromatic, preservative, etc., may be included.
- Formulations for parenteral administration include sterilized aqueous solution, non-aqueous solution, suspension, emulsion, freeze-dried preparation and suppository.
- the non-aqueous solution or suspension may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, or the like.
- a base for a suppository may be witepsol, macrogol, Tween 61, cocoa butter, laurin butter, glycerogelatin, etc.
- the present invention provides a food composition for the amelioration of inflammatory diseases, comprising the extracts or fractions of Chrysanthemum boreale Makino as an active ingredient.
- the food composition of the present invention may be prepared in the forms of pills, powders, granules, infusion, tablets, capsules or drinks, and may be added to various foods, for example, drinks, gum, tea, a vitamin complex, health promoting foods, etc.
- the food composition of the present invention may include other ingredients without particular limitations, and may include various herb medicine extracts, food additives, or natural carbohydrates in the same manner of conventional foods.
- the food composition may further include one or more herb medicine extracts selected from the group consisting of Chrysanthemum boreale Makino, Taraxacum mongolicum Hand-mazz, Phellodendron amurense Rupr, Acorus gramineus Soland, Ilex cornuta Lindl, and Prunus yedoensis Matsumura.
- herb medicine extracts selected from the group consisting of Chrysanthemum boreale Makino, Taraxacum mongolicum Hand-mazz, Phellodendron amurense Rupr, Acorus gramineus Soland, Ilex cornuta Lindl, and Prunus yedoensis Matsumura.
- a food supplement additive may be further included, and food additives include a fragrance agent, a flavouring agent, a coloring agent, a filler, a stabilizer or the like, which is conventionally known in the art.
- Examples of the natural carbohydrate include conventional sugar, such as monosaccharide (e.g., glucose, fructose, etc.); disaccharide (e.g., maltose, sucrose, etc.); polysaccharide (e.g., dextrin, cyclodextrin, etc.); and sugar alcohol such as xylitol, sorbitol, erythritol, etc.
- a natural fragrance agent such as thaumatin, a stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and a synthetic fragrance agent such as saccharine, aspartame, etc. may be appropriately used.
- the food composition of the present invention may contain various nutrients, vitamins, minerals (electrolytes), a flavor agent (such as a synthetic flavor agent, a natural flavor agent, etc.), a coloring agent, an extender (cheese, chocolate, etc.), pectic acid and salt thereof, alginic acid and salt thereof, organic acid, a protective colloid thickener, a PH adjuster, a stabilizer, a preservative, glycerin, alcohol, a carbonating agent used for a carbonated drink, etc.
- the food composition of the present invention may include flesh that may be used for preparing natural fruit juice, fruit juice drinks, and vegetable drinks. Each of the above such ingredients may be used independently or in any combination thereof.
- the present invention relates to a cosmetic composition, which includes the composition comprising the extracts or fractions of Chrysanthemum boreale Makino as an active ingredient.
- the cosmetic composition according to the present invention may formulated into cosmetic water, gel, water-soluble powder, oil-soluble powder, water-soluble liquid, cream, essence or the like, if necessary, to which pH- controlling substances, perfumes, emulsifiers, and antiseptics are added using conventional methods.
- the present invention relates to a quasi-drug composition, which includes the composition comprising the extracts or fractions of Chrysanthemum boreale Makino as an active ingredient. That is, the composition of the present invention may be added to a quasi-drug composition for the purpose of preventing or ameliorating inflammatory diseases.
- the extracts or fractions of Chrysanthemum boreale Makino of the present invention may be added as it is, or may be used in combination with other quasi-drugs or quasi-drug ingredients according to the typical method.
- Mixed amounts of active ingredients may be suitably determined depending upon the purpose of use (prophylactic, health or therapeutic treatment).
- the quasi-drug composition may be used in the preparation of disinfectant cleaner, shower foam, mouth freshener, wet tissue, cleaning soap, hand wash, humidifier filler, mask, ointment, coating agent, or filter filler.
- a filter including the filter filler according to the present invention may be applied to various fields, and used in any filtering apparatus known in the art.
- the present invention provides a water softener for the prevention or amelioration of inflammatory diseases, comprising the filter filler.
- water softener is an appliance that is designed to remove cations such as calcium and magnesium from hard water, and is also called a hard water softener. In addition to water softening functions, it may include air refreshing functions and water purifying functions.
- the water softener of the present invention includes a filter filler containing the composition which comprises the extracts or fractions of Chrysanthemum boreale Makino as an active ingredient, thereby being effective for the prevention and amelioration of inflammatory diseases, in particular, atopic dermatitis.
- the water softener of the present invention may contain various ingredients including oriental herbal medicines, depending on the purpose.
- NC/Nga mouse is known as a spontaneous atopic dermatitis mouse model, caused by enhanced IgE production due to hyperphosphorylation of JAK3 kinase. Recently, it was reported that atopic dermatitis is also spontaneously induced in STAT6 knockout NC/Nga mouse, in which STAT6 is essential for IgE and Th2 cytokine production, suggesting that dermatitis is induced by other unexpected mechanisms (J.I. 1999, 162: 1056-63). Despite these advantages, spontaneous dermatitis is induced at a low rate and there is a great difference in the severity of induced dermatitis. Actually, the mouse model is not a reliable model for evaluation.
- NC/Nga mouse model was introduced as an in vivo model for efficacy evaluation of therapeutic agents for atopic dermatitis.
- the spontaneous atopic dermatitis mouse model NC/Nga mouse was used to induce atopic dermatitis, and then evaluation was performed in the following manner to screen the most useful medicine.
- the drug screening was performed using the following experimental groups: a normal group which was not treated with DNCB so as not to develop atopic dermatitis, a control group which was treated with DNCB to develop atopic dermatitis, oral administration groups which were treated with the extract of Chrysanthemum boreale Makino (100 mg/kg, 400 mg/kg), and topical administration groups which were treated with the extract of Chrysanthemum boreale Makino (200 ⁇ l: 1% dilution, 2% dilution).
- Clinical scoring was performed twice each after DNCB (Sigma 23732-9) treatment, and treatment with candidate therapeutic agents (each 100 mg/kg and 400 mg/kg of Chrysanthemum boreale Makino, Ilex cornuta Lindl, Phellodendron amurense Rupr, Taraxacum mongolicum Hand-mazz, Acorus gramineus Soland, and Prunus yedoensis Matsumura).
- candidate therapeutic agents each 100 mg/kg and 400 mg/kg of Chrysanthemum boreale Makino, Ilex cornuta Lindl, Phellodendron amurense Rupr, Taraxacum mongolicum Hand-mazz, Acorus gramineus Soland, and Prunus yedoensis Matsumura.
- the clinical scoring of atopic dermatitis was performed and assessed by two or more experienced investigators. In particular, photographs were taken and stored, after completion of the drug treatment. The results of visual evaluation were expressed as the sum of individual scores of the following five items.
- the evaluation items include erythema, pruritus and dry skin, edema and excoriation, erosion, and lichenification, which were individually scored as follows: absent (0), slight (1), moderate (2), and severe (3). Thus, the scores range from 0 to 15. The scores before and after drug treatment were compared to determine the reduction ratio, which was compared to that of vehicle-treated group for significance test.
- Serum IgE levels were determined by ELISA, after treating DNCB(Sigma 23732-9)-induced skin inflammation with the candidate therapeutic drugs (each 100 mg/kg and 400 mg/kg of Chrysanthemum boreale Makino, Ilex cornuta Lindl, Phellodendron amurense Rupr, Taraxacum mongolicum Hand-mazz, Acorus gramineus Soland, Prunus yedoensis Matsumura).
- the serum IgE levels before and after drug treatment were compared to determine the reduction ratio, which was compared to that of a vehicle-treated group for a significance test.
- A. Drug-treated group [IgE(drug) before treatment - IgE(drug) after treatment] / IgE(drug) before treatment
- Vehicle-treated group [IgE(Vehicle) before treatment - IgE(Vehicle) after treatment] / IgE(vehicle) before treatment
- Table 1 shows the clinical scoring of atopic dermatitis-induced NC/Nga mouse model (FIG. 5).
- Table 2 shows changes in the scratching behavior of atopic dermatitis-induced NC/Nga mouse model.
- 100 (mg/kg) and 400 (mg/kg) of Chrysanthemum boreale Makino were scored as 30.4 ⁇ 1.1 (point) and 21.8 ⁇ 2.8 (point), respectively. This result shows that the scores are remarkably lower than those of other drugs (FIG. 4).
- Chrysanthemum boreale Makino among the drug candidates showed the most significant effects in atopic dermatitis-induced NC/Nga mouse model, in accordance with the results of clinical scoring, scratching behavior, and serum IgE level. Therefore, Chrysanthemum boreale Makino was further studied on the basis of the above results. Detailed description and results of the experiments are as follows.
- NC/Nga mouse was used to test the effects of extracts and fractions of Chrysanthemum boreale Makino on major symptoms of atopic dermatitis (pruritus, increased IgE production, etc.).
- NC/Nga mouse Central Lab. animal Inc., Korea
- mice 5-week old NC/Nga mice used as experimental animals were supplied from Jung Ang Lab. Animal Inc., and after 1 week of acclimatization in the experimental facility, their body weight was measured (22 ⁇ 3 g). 6-8 mice were used for each group in the experiment. During the experimental period, animals were maintained at a temperature of 21 ⁇ 1 °C and humidity of 50 ⁇ 5% with free access to solid feed and water. One day before experiment, each animal’s back, from the lower portion of the ear to top portion of the tail, was shaved using a clipper (JC-4005, JOAS Elec. CO., Korea) to remove hairs completely. All experimental animal procedures were conducted with the prior approval of the Kyung Hee University Animal Ethics Committee in accordance with the Guide for the Care and Use of Laboratory Animals.
- Atopic dermatitis of NC/Nga mouse was assessed by the clinical visual evaluation method generally used. Clinical scoring was performed immediately before DNCB treatment, during DNCB treatment, immediately before drug treatment, during drug treatment, and after termination of drug treatment, respectively. The clinical scoring of atopic dermatitis was performed and assessed by two or more experienced investigators. In particular, photographs were taken and stored, after completion of drug treatment. The results of visual evaluation were expressed as the sum of individual scores of the following five items. The evaluation items include erythema, pruritus and dry skin, edema and excoriation, erosion, and lichenification, which were individually scored as follows: absent (0), slight (1), moderate (2), and severe (3). Thus, the scores range from 0 to 15. The scoring of atopic dermatitis was performed and assessed by two or more experienced investigators. In particular, photographs were taken and stored, after completion of drug treatment.
- the ear thickness was measured at the middle of the right ear using a micrometer (IP65 coolant proof, #293-240, mitutoyo, Japan).
- Serum IgE, IL-4, and IFN- ⁇ levels of Nc/Nga mice were determined using mouse ELISA kit (SHIBAYAGI Co., Ltd, Japan), IL-4 (R&D systems, Quantikine Immunoassay Kit, MN. USA), and IFN- ⁇ (R&D systems, Quantikine Immunoassay Kit, MN. USA), respectively.
- IgE level was determined in accordance with procedures of IgE mouse ELISA kit (SHIBAYAGI Co., Ltd, Japan). All reagents were prepared at room temperature, and immediately used.
- a plate was washed with a washing buffer three times, and 50 ⁇ l of IgE standard solution or sample solution (sample 5 ⁇ l + buffer 45 ⁇ l) was aliquoted to each well, and gently mixed using a microplate shaker. The plate was incubated at room temperature (20-25°C) for 2 hrs, and then washed with a buffer solution three times. 50 ⁇ l of biotin-conjugated anti-IgE antibody was aliquoted to each well, and gently mixed using a microplate shaker. The plate was incubated at room temperature for 2 hrs, and then washed with a washing buffer three times. 50 ⁇ l of HRP-avidin solution was aliquoted to each well, and gently mixed using a microplate shaker.
- the plate was incubated at room temperature for 1 hr. Subsequently, 50 ⁇ l of chromagenic substrate solution was aliquoted to each well, and gently mixed using a microplate shaker. The plate was incubated at room temperature for 20 min. Then, 50 ⁇ l of reaction stopper was added to each well and mixed well to stop further color development, and absorbance was measured at 450 nm within 30 min.
- IL-4 and IFN- ⁇ levels were determined in accordance with the procedures of IL-4 (R&D systems, Quantikine Immunoassay Kit, MN. USA) and IFN- ⁇ (R&D systems, Quantikine Immunoassay Kit, MN. USA).
- the plate was covered with a new adhesive cover sheet, incubated at room temperature for 2 hrs, and then washed five times. 100 ⁇ l of substrate solution was added to each well, and incubated at room temperature for 30 min in the dark. 100 ⁇ l of stop solution was added to each well, and the plate was gently tapped to mix completely. Within 30 min, the absorbance of each well was measured at 450 nm with correction at 540 nm (or 570 nm).
- mice were sacrificed and the back and ear tissues were removed and fixed in 10% neutral formalin.
- the tissues were embedded in paraffin to prepare paraffin-embedded blocks.
- the paraffin blocks were trimmed to a trimming thickness of 10 ⁇ m using a microtome (Microm-HM325), and then tissue sections were cut to a thickness of 3-4 ⁇ m.
- tissue sections were deparaffinized in xylene, immersed [100% alcohol(3 min) ⁇ 90% alcohol (3 min) ⁇ 80% alcohol (3 min) ⁇ 70% alcohol (3 min) ⁇ D.W (3 min)], and stained [Harris’ hematoxylin (4 min) ⁇ washing ⁇ 1% HCl alcohol (once) ⁇ washing (10 min) ⁇ eosin (10-20 sec)], and then dehydrated [70% alcohol (dipping) ⁇ 80% alcohol (dipping) ⁇ 95% alcohol(dipping) ⁇ 100% alcohol (dipping) ⁇ 100% alcohol (dipping)], and destained [xylene (3 min) ⁇ xylene (3 min)], followed by sealing.
- the normal group had healthy skin, and the control group developed apparent atopic symptoms such as erythema, edema, scaling, incrustation, and lichenification.
- atopic symptoms were remarkably inhibited, compared to the control group, but a more rapid amelioration of atopic dermatitis was observed in the oral administration groups than the topical administration groups by visual examination (FIG. 7).
- the normal group had healthy skin, and the atopic dermatitis-induced control group developed apparent atopic symptoms such as erythema, edema, scaling, incrustation, and lichenification.
- atopic symptoms were remarkably inhibited, compared to the atopic dermatitis-induced control group.
- NOR indicates the normal group
- CON indicates the control group
- CBP1 indicates the oral administration group (100 mg/kg of extract of Chrysanthemum boreale Makino)
- CBP4 indicates the oral administration group (400 mg/kg of extract of Chrysanthemum boreale Makino)
- CBS1 indicates the topical administration group (200 ⁇ l of 1% extract of Chrysanthemum boreale Makino)
- CBS2 indicates the topical administration group (200 ⁇ l of 2% extract of Chrysanthemum boreale Makino).
- Table 4 shows the results of clinical scoring of atopic dermatitis-induced NC/Nga mouse model.
- mice Scratching behavior of mice was observed as 63.0 ⁇ 2.9 times per 30 min in the control group, 30.4 ⁇ 1.4 times per 30 min and 21.8 ⁇ 2.9 times per 30 min in the oral administration groups (100 mg/kg and 400 mg/kg of Chrysanthemum boreale Makino), and 45.4 ⁇ 2.7 times per 30 min and 45.0 ⁇ 3.4 times per 30 min in the topical administration groups (1% and 2% Chrysanthemum boreale Makino).
- Table 5 shows the results of scratching behavior of atopic dermatitis-induced NC/Nga mouse model.
- mice To measure edema, the ear thickness of mice was measured every week after the initiation of experiment until the termination of experiment. There was no change in the ear thickness of the normal group, but a significant increase in the ear thickness was found in atopic dermatitis-induced control group. Inhibition of ear edema was observed in the oral and topical administration groups of Chrysanthemum boreale Makino. In particular, a remarkable inhibition of ear edema was observed in the oral administration groups. Table 6 (upper and lower Tables) shows the results of measuring ear thickness of atopic dermatitis-induced NC/Nga mouse model (FIGs. 10 and 11).
- Table 7 shows the results of ELISA to determine serum IgE, IFN- ⁇ and IL-4 levels in atopic dermatitis-induced mouse by DNCB sensitization and attack.
- serum IgE levels were 61.6 ⁇ 9.3 ng/ml in the control group, and 37.2 ⁇ 6.6 ng/ml and 46.7 ⁇ 7.1 ng/ml in the topical administration groups (1% and 2% Chrysanthemum boreale Makino), indicating a reduction in the level (FIG. 12 (b)).
- Serum IFN- ⁇ levels were 46.7 ⁇ 21.5 pg/ml in the control group, 3.3 ⁇ 0.4 pg/ml and 3.5 ⁇ 0.5 ng/ml in the oral administration groups (100 mg/kg and 400 mg/kg of Chrysanthemum boreale Makino), and 3.5 ⁇ 0.4 pg/ml and 3.6 ⁇ 0.4 pg/ml in the topical administration groups (1% and 2% Chrysanthemum boreale Makino), indicating a significant reduction (FIG. 13).
- Serum IL-4 levels were 5.4 ⁇ 0.7 pg/ml in the control group, 1.8 ⁇ 1.0 pg/ml and 2.3 ⁇ 1.0 pg/ml in the oral administration groups (100 mg/kg and 400 mg/kg of Chrysanthemum boreale Makino), and 1.7 ⁇ 0.5 pg/ml and 1.8 ⁇ 1.1 pg/ml in the topical administration groups (1% and 2% Chrysanthemum boreale Makino), indicating a significant reduction (FIG. 14).
- Table 7 shows the results of determination of serum IgE, IFN- ⁇ and IL-4 levels.
- mice used in the experiments were sacrificed after the termination of the experiments, and then the ear tissues were removed and fixed in 10% formalin solution.
- the tissues were embedded in paraffin, and then cut to a thickness of 3-4 ⁇ m, followed by H&E (Hematoxylin & Eosin) staining. Then, ulceration, epidermal thickness of atopic dermatitis-induced tissue, mast cell infiltration, eosinophil infiltration, neutrophil and lymphocyte infiltration, and fibroblast proliferation and collagen layer hyperplasia were investigated.
- Neutrophil and lymphocyte infiltration was not observed in the normal group, and severe neutrophil and lymphocyte infiltration was observed in the control group. Slight neutrophil and lymphocyte infiltration was observed in most of the oral administration groups (100 mg/kg and 400 mg/kg of Chrysanthemum boreale Makino) and the topical administration groups (1% and 2% Chrysanthemum boreale Makino), but the symptoms were ameliorated compared to those of the control group.
- Fibroblast proliferation and collagen layer hyperplasia were not observed in the normal group, but severe fibroblast proliferation and collagen layer hyperplasia were observed in the control group. No fibroblast proliferation and collagen layer hyperplasia were observed in the oral administration group (400 mg/kg of Chrysanthemum boreale Makino) and the topical administration group (2% Chrysanthemum boreale Makino), but various stages of fibroblast proliferation and collagen layer hyperplasia were observed in some subjects of the oral administration group (100 mg/kg of Chrysanthemum boreale Makino) and the topical administration group (1% Chrysanthemum boreale Makino), but the symptoms were ameliorated compared to those of the control group.
- 8.5 mast cells were observed in the topical administration group (1% Chrysanthemum boreale Makino), 8.85 mast cells in the topical administration group (2% Chrysanthemum boreale Makino), 7.15 mast cells in the oral administration group (100 mg/kg of Chrysanthemum boreale Makino), and 6.265 mast cells in the oral administration group (400 mg/kg of Chrysanthemum boreale Makino), indicating that the number of mast cells was ameliorated in the oral administration group (400 mg/kg of Chrysanthemum boreale Makino) than in the control group.
- murine macrophage RAW 264.7 cell line was obtained from the Korean Cell Line Bank (Korea) to perform the experiments.
- RAW 264.7 cells were grown in DMEM.
- RAW 264.7 cells were inoculated into a T-flask at a density of 2 ⁇ 105 cells/ml and cultured in a humidified CO2 incubator (5% CO2, 95% air) at 37°C for 24 hrs. Subsequently, the cells were treated with LPS (10 ⁇ g/ml) diluted in media without FBS for 24 hrs, and treated again with the drug (1 mg/ml) diluted in media without FBS. After 24 hrs, the cells were used for the experiments.
- iNOS induced nitric oxide synthase
- the membrane was blocked in 5% skim milk at room temperature for 1 hr, and incubated at 4°C overnight with iNOS primary antibody that was diluted in 5% skim milk to a predetermined ratio.
- the membrane was washed with TBST for 5 min three times, and then incubated with anti-mouse secondary antibody at room temperature for 1 hr.
- the membrane was washed with TBST for 10 min three times, and reacted with ECL Western Substrate (PIERCE, #3216) solution for 1 min, followed by development of X-ray film (Kodak).
- the prepared sample was electrophoresed on a 12% SDS-acrylamide gel, and then transferred onto PVDF membrane. Thereafter, the membrane was blocked in 5% skim milk at room temperature for 1 hr, and incubated at 4°C overnight with COX-2 primary antibody that was diluted in 5% skim milk to a predetermined ratio. The next day, the membrane was washed with TBST for 5 min three times, and then incubated with anti-mouse and goat secondary antibody at room temperature for 1 hr. Then, the membrane was washed with TBST for 10 min three times, and reacted with ECL Western Substrate (PIERCE, #3216) solution for 1 min, followed by development of the x-ray film (Kodak).
- PIERCE ECL Western Substrate
- the membrane was blocked in 5% skim milk at room temperature for 1 hr, and incubated at 4°C overnight with I ⁇ B ⁇ primary antibody that was diluted in 5% skim milk to a predetermined ratio. The next day, the membrane was washed with TBST for 5 min three times, and then incubated with anti-mouse secondary antibody at room temperature for 1 hr. Then, the membrane was washed with TBST for 10 min three times, followed by color development with BCIP-NBT solution (Nakanai Tesque, Japan).
- Each sample-treated experimental group and control group were harvested and washed with PBS twice.
- 0.4 ml of cell lysis buffer (10 mM HEPES (pH 7.9), 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 2.0 ⁇ g/ ⁇ l aprotinin) was added thereto, and left at 4°C for 15 min.
- 25 ⁇ l of 10% NP40 was added thereto, and vigorously mixed on a voltex for 10 sec.
- the reactant was centrifuged at 4°C, 1,300 rpm for 2 min to obtain the supernatant containing cytoplasmic protein.
- ice-cold nuclear extraction buffer (containing 20 mM HEPES (pH 7.9), 0.4M NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 1 mM PMSF, 2.0 ⁇ g/ ⁇ l leupeptin, and 2.0 ⁇ g/ ⁇ l aprotinin) was added to the pellets, and incubated for 15 min at 4°C with intermittent mixing. Then, the sample was centrifuged at 4°C, 1,300 rpm for 2 min to obtain the nuclear protein supernatant. The obtained cytoplasmic and nuclear solutions were quantified using Pro-measureTM solution, and 30 ⁇ g of protein was mixed with the sample buffer.
- the mixture was heated at 95°C for 5 min, and then stored at -20°C.
- the prepared sample was electrophoresed on a 12% SDS-acrylamide gel, and then transferred onto PVDF membrane. Thereafter, the membrane was blocked in 5% skim milk at room temperature for 1 hr, and incubated at 4°C overnight with NF- ⁇ B p65 primary antibody that was diluted in 5% skim milk to a predetermined ratio. Next day, the membrane was washed with TBST for 5 min three times, and then incubated with anti-mouse secondary antibody at room temperature for 1 hr. Then, the membrane was washed with TBST for 10 min three times, followed by color development with BCIP-NBT solution (Nakanai Tesque, Japan).
- FBS Gibco BRL Co., U.S.A.
- cytoplasmic nitrite was measured using a Nitrate/Nitrite Colorimetric assay kit. The experiment was performed using a Griess reagent in accordance with the manufacturer’s instructions (Cayman Chemical Company). As a result, each nitrite production was reduced to approximately 38%, 78%, and 30% in the methanol (MeOH) extract, chloroform (CHCl3) fraction, and ethyl acetate (EtOAc) fraction at the concentration of 5 ⁇ g/ml, as compared to the control group (FIG. 16). Table 8 shows the effects of the extracts and fractions of Chrysanthemum boreale Makino on LPS-induced NO production in RAW 264.7 cells.
- Chrysanthemi Indici Flos used in the present experiment is a Korean chamomile, also called snow chamomile, golden chamomile, or yellow chamomile, and cultivated in youngchun, the North Kyungsang province, and collected on October 3, 2007.
- a part of the medicinal herb was stored at Dept. of Herbology, College of Oriental Medicine, Kyung Hee University.
- FBS Gibco BRL Co., U.S.A.
- iNOS induced nitric oxide synthase
- the membrane was blocked in 5% skim milk at room temperature for 1 hr, and incubated at 4°C overnight with iNOS primary antibody that was diluted in 5% skim milk to a predetermined ratio. The next day, the membrane was washed with TBST for 5 min three times, and then incubated with anti-mouse secondary antibody at room temperature for 1 hr. Then, the membrane was washed with TBST for 10 min three times, and reacted with ECL Western Substrate (PIERCE, #3216) solution for 1 min, followed by development of X-ray film (Kodak).
- PIERCE ECL Western Substrate
- Each sample-treated cells and control group were harvested and washed with PBS twice. 100 ⁇ l of Pro-prepTM reagent was added thereto, and left at -20°C for 10 min. Subsequently, centrifugation was performed at 4°C, 12,000 rpm for 10 min to obtain the supernatant. The obtained protein solution was quantified using Pro-measureTM solution, and 50 ⁇ g of protein was mixed with the sample buffer. The mixture was heated at 95°C for 5 min, and then stored at -20°C. The prepared sample was electrophoresed on a 12% SDS-acrylamide gel, and then transferred onto PVDF membrane.
- the membrane was blocked in 5% skim milk at room temperature for 1 hr, and incubated at 4°C overnight with COX-2 primary antibody that was diluted in 5% skim milk to a predetermined ratio.
- the membrane was washed with TBST for 5 min three times, and then incubated with anti-mouse secondary antibody at room temperature for 1 hr.
- the membrane was washed with TBST for 10 min three times, and reacted with ECL Western Substrate (PIERCE, #3216) solution for 1 min, followed by development of X-ray film (Kodak).
- Each sample-treated cell group and control group were harvested and washed with PBS twice. 100 ⁇ l of Pro-prepTM reagent was added thereto, and left at -20°C for 10 min. Subsequently, centrifugation was performed at 4°C, 12,000 rpm for 10 min to obtain the supernatant. The obtained protein solution was quantified using Pro-measureTM solution (Intron), and 50 ⁇ g of protein was mixed with the sample buffer. The mixture was heated at 95°C for 5 min, and then stored at -20°C. The prepared sample was electrophoresed on a 12% SDS-acrylamide gel, and then transferred onto PVDF membrane.
- Pro-measureTM solution Intron
- the membrane was blocked in 5% skim milk at room temperature for 1 hr, and incubated at 4°C overnight with I ⁇ B ⁇ primary antibody that was diluted in 5% skim milk to a predetermined ratio.
- the membrane was washed with TBST for 5 min three times, and then incubated with anti-mouse secondary antibody at room temperature for 1 hr.
- the membrane was washed with TBST for 10 min three times, followed by color development with BCIP-NBT solution (Nakanai Tesque, Japan).
- Each sample-treated experimental group and control group were harvested and washed with PBS twice.
- 0.4 ml of cell lysis buffer (10 mM HEPES (pH 7.9), 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 2.0 ⁇ g/ ⁇ l aprotinin) was added thereto, and left at 4°C for 15 min.
- 25 ⁇ l of 10% NP40 was added thereto, and vigorously mixed on a voltex for 10 sec.
- the reactant was centrifuged at 4°C, 1,300 rpm for 2 min to obtain the supernatant containing cytoplasmic protein.
- ice-cold nuclear extraction buffer (containing 20 mM HEPES (pH 7.9), 0.4M NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 1 mM PMSF, 2.0 ⁇ g/ ⁇ l leupeptin, and 2.0 ⁇ g/ ⁇ l aprotinin) was added to the pellets, and incubated for 15 min at 4°C with intermittent mixing. Then, the sample was centrifuged at 4°C, 1,300 rpm for 2 min to obtain the nuclear protein supernatant. The obtained cytoplasmic and nuclear solutions were quantified using Pro-measureTM solution, and 30 ⁇ g of protein was mixed with the sample buffer.
- the mixture was heated at 95°C for 5 min, and then stored at -20°C.
- the prepared sample was electrophoresed on a 12% SDS-acrylamide gel, and then transferred onto PVDF membrane. Thereafter, the membrane was blocked in 5% skim milk at room temperature for 1 hr, and incubated at 4°C overnight with NF- ⁇ B p65 primary antibody that was diluted in 5% skim milk to a predetermined ratio. Next day, the membrane was washed with TBST for 5 min three times, and then incubated with anti-mouse secondary antibody at room temperature for 1 hr. Then, the membrane was washed with TBST for 10 min three times, followed by color development with BCIP-NBT solution (Nakanai Tesque, Japan).
- each nitrite production was 97.9%, 89.0%, 37.3%, and 17.8% in the methanol extract and 50.6%, 19.2%, 16.6%, and 7.5% in the chloroform fraction at the sample concentrations of 12.5 ⁇ g/ml, 25 ⁇ g/ml, 50 ⁇ g/ml, and 100 ⁇ g/ml, as compared to the control group. That is, it can be seen that nitrite expression was inhibited to 50% or more at the methanol fraction of 50 ⁇ g/ml or more, and at the chloroform fraction of 25 ⁇ g/ml or more.
- Table 14 shows the effects of the extracts and fractions of Chrysanthemi Indici Flos on LPS-induced nitrite production in RAW 264.7 cells (FIG. 23).
- the extract of Chrysanthemi Indici Flos inhibited the nitrite production to 50% or more at the methanol extract of 50 ⁇ g/ml or more, and at the chloroform fraction of 25 ⁇ g/ml or more, but the extract of Chrysanthemum boreale Makino (Example 3-2) inhibited the nitrite production to 50% or more at the methanol extract of 10 ⁇ g/ml or more, at the chloroform fraction of 1.25 ⁇ g/ml or more, and at the ethyl acetate fraction of 10 ⁇ g/ml or more, indicating that much smaller amount of the extracts and fractions of Chrysanthemum boreale Makino showed the inhibitory effect on nitrite production that is equivalent to or higher than those of Chrysanthemi Indici. Flos.
- iNOS expression was determined at the concentration of 25 ⁇ g/ml. The iNOS expression was confirmed in RAW 264.7 cells by Western blotting.
- Each iNOS expression was 74.9% and 0.0% in the methanol extract and chloroform fraction, showing each reduction ratio of 25.1% and 100.0%, and 69.7% in the water fraction, showing the reduction ratio of 30.3% (FIG. 24).
- Table 15 shows the effects of the extracts and fractions of Chrysanthemi Indici Flos on LPS-induced iNOS expression in RAW 264.7 cells.
- the PGE2 production was 3250.3 ⁇ 22.8 pg/ml in the methanol extract at the sample concentration of 25 ⁇ g/ml, showing the reduction ratio of 5.1%, as compared to 3425.1 ⁇ 239.6 pg/ml of the control group.
- the PGE2 production was 3439.5 ⁇ 159.3 pg/ml in the water fraction, but 612.0 ⁇ 85.4 pg/ml in the chloroform fraction, showing the reduction ratio of 82.1% (FIG. 25).
- Table 16 shows the effects of the extracts and fractions of Chrysanthemi Indici Flos on LPS-induced PGE2 expression in RAW 264.7 cells.
- each p65 expression level was 71.6% and 87.9% in the methanol extract and chloroform fraction, showing each reduction ratio of 28.4% and 12.1%, and 86.1% in water fraction, showing each reduction ratio of 13.9%, as compared to the control group.
- the extract of Chrysanthemi Indici Flos showed inhibitory effect on NF- ⁇ B nuclear translocation, namely, a prominent reduction in NF- ⁇ B nuclear translocation (FIG. 28).
- Table 19 shows the effects of the extracts and fractions of Chrysanthemi Indici Flos on LPS-induced cytoplasmic and nuclear NF- ⁇ B expression in RAW 264.7 cells.
- MTS assay was performed in RAW 264.7 cell using MTS/PMS (Cell Titer 96TM Aqueous Non-Radioactive Cell Proliferation Assay, Cat. G5421-Promega).
- RAW 264.7 cell was inoculated into 96-well plate at a density of 5 ⁇ 104 cells/mL, and incubated for 24 hrs. The cells were cultured for 24 hrs in DMEM media without serum, containing the extracts of Chrysanthemum boreale Makino at the concentrations of 1.25 ⁇ g/mL, 2.50 ⁇ g/mL, and 5.00 ⁇ g/mL.
- the cells were treated with MTS and PMS in a mixing ratio of 20:1, and cultured for 3 hrs. Then, ELISA Reader (Versamax, Molecular Devices Co., U.S.A.) was used to measure absorbance at 490 nm.
- ELISA Reader Versamax, Molecular Devices Co., U.S.A.
- composition according to the present invention has an anti-inflammatory activity, it can be used for the prevention or treatment of inflammatory diseases such as atopic dermatitis, and can also be applied to various fields, including quasi-drugs, cosmetics, foods, and water softeners.
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Abstract
Description
Claims (19)
- A composition having an anti-inflammatory activity, comprising extracts or fractions of Chrysanthemum boreale Makino.
- The composition according to claim 1, wherein the extract of Chrysanthemum boreale Makino is a water extract of Chrysanthemum boreale Makino or a methanol extract of Chrysanthemum boreale Makino.
- The composition according to claim 1, wherein the extract of Chrysanthemum boreale Makino is extracted by hot water extraction.
- The composition according to claim 1, wherein the fraction is a fraction using any one of chloroform, ethanol, ethyl acetate or mixtures thereof.
- The composition according to claim 1, wherein the composition is a composition having one or more of the following properties:1) reduction in erythema, edema, excoriation, pruritus, dry skin, erosion and lichenification;2) reduction in ear edema;3) reduction in scratching behavior;4) reduction in serum immunoglobulin E (IgE), interferon- γ (IFN-γ) or interleukin-4 (IL-4) level;5) reduction in intracellular nitric oxide (NO) expression;6) reduction in intracellular Nitric oxide synthases (iNOS) expression;7) reduction in intracellular prostaglandin E2 (PGE2) production;8) reduction in intracellular COX-2 expression;9) inhibition of IκB phosphorylation and reduction in NF-κB nuclear translocation; and10) inhibition of fibroblast proliferation, collagen layer hyperplasia, and ulceration, reduction in mast cell infiltration, and reduction in inflammation by neutrophil and lymphocyte infiltration.
- A pharmaceutical composition for the prevention or treatment of inflammatory diseases, comprising the composition of any one of claims 1 to 5 as an active ingredient.
- The pharmaceutical composition according to claim 6, wherein the inflammatory disease is allergic inflammatory disease.
- The pharmaceutical composition according to claim 7, wherein the allergic inflammatory disease is atopic dermatitis.
- The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition for the prevention or treatment of inflammatory diseases has any one formulation selected from the group consisting of tablet, pill, powder, granule, capsule, suspension, liquid for internal use, emulsion, syrup, sterilized aqueous solution, non-aqueous solution, lyophilized formulation, and suppository.
- A cosmetic composition for the prevention or amelioration of inflammatory diseases, comprising the composition of any one of claims 1 to 5 as an active ingredient.
- A food composition for the prevention or amelioration of inflammatory diseases, comprising the composition of any one of claims 1 to 5 as an active ingredient.
- The food composition according to claim 11, wherein the food composition is any one selected from the group consisting of meats, sausages, bread, chocolate, candies, snacks, cookies, pizza, ramyun, gums, ice cream, soups, beverages, tea, functional water, drinks, alcoholic drinks, and vitamin complex.
- A quasi-drug composition for the prevention or amelioration of inflammatory diseases, comprising the composition of any one of claims 1 to 5 as an active ingredient.
- The quasi-drug composition according to claim 13, wherein the quasi-drug composition is any one selected from the group consisting of disinfectant cleaner, shower foam, mouth freshener, wet tissue, cleaning soap, hand wash, humidifier filler, mask, ointment, coating agent, or filter filler.
- A water softener for the prevention or amelioration of inflammatory diseases, comprising a filter filler containing the composition of any one of claims 1 to 5 as an active ingredient.
- A method for preventing or treating inflammatory diseases by the administration of the composition of any one of claims 1 to 5 to patients with inflammatory diseases or at risk for inflammatory diseases.
- The method according to claim 16, wherein the composition is orally or topically administered.
- The method according to claim 16, wherein the inflammatory disease is allergic inflammatory disease.
- The method according to claim 18, wherein the allergic inflammatory disease is atopic dermatitis.
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US13/512,283 US8518462B2 (en) | 2009-11-27 | 2010-09-30 | Compound comprising extracts or fractions of chrysanthemum boreale makino having anti-inflammation activity |
CN2010800589001A CN102686230A (en) | 2009-11-27 | 2010-09-30 | Compound comprising extracts or fractions of chrysanthemum boreale makino having anti-inflammation activity |
JP2012540999A JP2013512235A (en) | 2009-11-27 | 2010-09-30 | Nochiku extract or composition having anti-inflammatory activity containing this fraction |
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KR20220096527A (en) * | 2020-12-31 | 2022-07-07 | 두리화장품 주식회사 | The cosmetic composition containing Chrysanthemum boreale extract and its fermentation product |
KR102482119B1 (en) | 2020-12-31 | 2022-12-28 | 두리화장품 주식회사 | The cosmetic composition containing Chrysanthemum boreale extract and its fermentation product |
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WO2011065657A3 (en) | 2011-09-15 |
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