WO2023243856A1 - Composition for preventing, ameliorating or treating blood dyscrasia comprising microorganism of genus euglena - Google Patents
Composition for preventing, ameliorating or treating blood dyscrasia comprising microorganism of genus euglena Download PDFInfo
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- WO2023243856A1 WO2023243856A1 PCT/KR2023/005907 KR2023005907W WO2023243856A1 WO 2023243856 A1 WO2023243856 A1 WO 2023243856A1 KR 2023005907 W KR2023005907 W KR 2023005907W WO 2023243856 A1 WO2023243856 A1 WO 2023243856A1
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- euglena gracilis
- composition
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- preventing
- cancer
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- UDEJEOLNSNYQSX-UHFFFAOYSA-J tetrasodium;2,4,6,8-tetraoxido-1,3,5,7,2$l^{5},4$l^{5},6$l^{5},8$l^{5}-tetraoxatetraphosphocane 2,4,6,8-tetraoxide Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P1(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)O1 UDEJEOLNSNYQSX-UHFFFAOYSA-J 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/02—Algae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
-
- 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
- A23V2250/00—Food ingredients
- A23V2250/20—Natural extracts
- A23V2250/202—Algae extracts
Definitions
- the present invention relates to the use of Euglena genus microorganisms to prevent, improve or treat hematopoietic disorders; and for use in preventing, improving or treating cancer.
- Anticancer drugs act on proliferating cells, such as hematopoietic stem cells and intestinal stem cells, in addition to target cancer cells. Therefore, some of the side effects of chemotherapy are leukopenia and mucositis. Moreover, dysbiosis of the intestinal microbial ecosystem occurs after chemotherapy. A healthy gut microbiome is necessary to maintain the intestinal barrier, colonization resistance, immunity and hematopoiesis. Defects in the stable microbial ecosystem in the intestines impair the physiological functions of the host, resulting in the invasion of endogenous bacteria and inhibition of hematopoiesis. Additionally, the use of antibiotics in cancer patients with leukopenia and mucositis after chemotherapy may worsen immunosuppression. Due to the role of intestinal bacteria in hematopoiesis, interest in non-drug supplements to restore intestinal microorganisms, such as prebiotics and probiotics, has recently increased.
- the present inventors completed the present invention by confirming that microorganisms of the Euglena genus restore the blood cell count reduced by anticancer drugs.
- an object of the present invention is to provide a composition for preventing, improving or treating blood dyscrasia containing Euglena gracilis .
- Another object of the present invention is to provide a composition for preventing, improving or treating cancer containing Euglena gracilis and an anticancer agent.
- Another object of the present invention is to provide an anticancer adjuvant composition containing Euglena gracilis.
- Another object of the present invention is to provide a method for promoting hematopoiesis, comprising administering Euglena gracilis to an individual in need thereof.
- Another object of the present invention is to provide a method of treating hematopoietic disorders comprising administering Euglena gracilis to an individual in need thereof.
- Another object of the present invention is to provide a method of treating cancer comprising administering Euglena gracilis and an anticancer agent to an individual in need thereof.
- the present invention provides a pharmaceutical composition for preventing or treating hematopoietic disorders containing Euglena gracilis.
- the present invention provides a food composition for preventing or improving hematopoietic disorders containing Euglena gracilis.
- the present invention provides a health functional food composition for preventing or improving hematopoietic disorders containing Euglena gracilis.
- the present invention provides a pharmaceutical composition for preventing or treating cancer containing Euglena gracilis and an anticancer agent.
- the present invention provides a food composition for preventing or improving cancer containing Euglena gracilis and an anticancer agent.
- the present invention provides a health functional food composition for preventing or improving cancer containing Euglena gracilis and an anticancer agent.
- the present invention provides an anti-cancer adjuvant composition containing Euglena gracilis.
- the present invention provides a method for promoting hematopoiesis, comprising administering Euglena gracilis to an individual in need thereof.
- the present invention also provides a method of treating hematopoietic disorders, comprising administering Euglena gracilis to an individual in need thereof.
- the present invention also provides a method of treating cancer comprising administering Euglena gracilis and an anticancer agent to an individual in need thereof.
- the Euglena genus microorganism according to the present invention restores blood cells reduced by anticancer drug administration to a normal level without affecting the spleen immune cell population.
- the Euglena genus microorganisms significantly increased the production of granulocyte/macrophage-colony stimulating factor, which is the basis of hematopoietic reaction. This means that the Euglena genus microorganism of the present invention promotes hematopoiesis, and can be used in various fields of treatment related to hematopoietic disorders and cancer.
- Figure 1a is a diagram showing the schedule of blood analysis experiments in mice administered a single dose of gemcitabine.
- Figure 1b is a diagram showing the results of confirming the white blood cell count following a single administration of gemcitabine in mice orally administered Euglena gracilis.
- Figure 1c is a diagram showing the results of confirming the number of neutrophils following a single administration of gemcitabine in mice orally administered Euglena gracilis.
- Figure 1d is a diagram showing the results of confirming the number of lymphocytes following a single administration of gemcitabine in mice orally administered Euglena gracilis.
- Figure 1e is a diagram showing the results of confirming the number of red blood cells following a single administration of gemcitabine in mice orally administered Euglena gracilis.
- Figure 2a is a diagram showing the schedule of the spleen immune cell analysis experiment in mice administered a single dose of gemcitabine.
- Figure 2b is a diagram showing the results of analyzing the number of CD11b (myeloid) and CD49b (NK cell) positive cells following a single administration of gemcitabine in mice orally administered Euglena gracilis.
- Figure 2c is a diagram showing the results of analyzing the number of CD4 and CD8 positive cells following a single administration of gemcitabine in mice orally administered Euglena gracilis.
- Figure 2d is a diagram showing the results of analyzing the expression of Dectin-1 following a single administration of gemcitabine in mice orally administered Euglena gracilis.
- Figure 3 shows the results of analyzing granulocyte/macrophage-colony-stimulating factor (GM-CSF) secretion following a single administration of gemcitabine in mice orally administered Euglena gracilis. .
- GM-CSF granulocyte/macrophage-colony-stimulating factor
- Figure 4a is a diagram showing the schedule of blood analysis experiments in mice administered multiple doses of gemcitabine.
- Figure 4b is a diagram showing the results of analyzing the number of white blood cells following multiple administrations of gemcitabine in mice orally administered Euglena gracilis.
- Figure 4c is a diagram showing the results of analyzing the number of lymphocytes following multiple administrations of gemcitabine in mice orally administered Euglena gracilis.
- Figure 4d is a diagram showing the results of analyzing the number of neutrophils following multiple administrations of gemcitabine in mice orally administered Euglena gracilis.
- Figure 4e is a diagram showing the results of analyzing the number of red blood cells following multiple administrations of gemcitabine in mice orally administered Euglena gracilis.
- the present invention provides a composition for preventing, improving or treating hematopoietic disorders (blood dyscrasia) containing Euglena gracilis .
- the composition of the present invention is a pharmaceutical composition for preventing or treating hematopoietic disorders; Food composition for preventing or improving hematopoietic disorders; Or it may be a health functional food composition for preventing or improving hematopoietic disorders.
- the present invention provides a composition for preventing, improving or treating cancer containing Euglena gracilis and an anticancer agent. More specifically, the composition of the present invention is a pharmaceutical composition for preventing or treating cancer; Food compositions for preventing or improving cancer; Or it may be a health functional food composition for preventing or improving cancer.
- Euglena gracilis is a single-celled eukaryote with flagella and chloroplasts, which are characteristic of plants and animals. As a food supplement, it is rich in essential amino acids, lipids, vitamins and beta glucans. Unlike the beta-glucans of bacteria, fungi, and plants, which are found in cell walls, the beta-glucans of Euglena gracilis are stored in granules called paramylons in the cytoplasm. This paramylon is a very pure beta-glucan composed of 100% glucose with linear beta-1,3 glycosidic linkages. It has high crystallinity and a molecular weight of 100 to 500 kDa. Euglena gracilis can accumulate large amounts of paramylon (more than 90% of dry weight) under dark conditions using glucose as a carbon source. Euglena is easy to culture, making it an inexpensive source of glucan.
- hematopoietic disorder refers to a disorder occurring in hematopoietic function in the bone marrow.
- Hematopoietic disorders are disorders in the production of blood cells, causing various blood cell-related diseases.
- the hematopoietic disorder includes leukopenia, neutropenia, lymphopenia, monocytopenia, granulocytopenia, aplastic anemia, malignant lymphoma, leukemia,
- leukopenia leukopenia
- neutropenia neutropenia
- lymphopenia lymphopenia
- monocytopenia granulocytopenia
- aplastic anemia malignant lymphoma
- leukemia leukemia
- diseases selected from the group consisting of chronic liver failure, renal failure, severe infections, myelopathogenic thrombocytopenia, idiopathic thrombocytopenic purpura (ITP), thrombocytopenia, myelodysplastic syndrome, and myeloproliferative disease It is not limited to this.
- the hematopoietic disorder may be a hematopoietic disorder caused by a side effect of an anticancer drug.
- the anticancer agent is Doxorubicin, Epirubicin, Gemsitabin, Cisplatin, Carboplatin, Procarbazine, and Cyclophos. Cyclophosphamide, Dactinomycin, Daunorubicin, Etoposide, Tamoxifen, Mitomycin, Bleomycin, Plicomycin , Transplatinum, Vinblastine, and Methotrexate, and most preferably gemcitabine, but the scope of the present invention is not limited thereto.
- Euglena gracilis of the present invention may be included in various forms such as its culture medium, dried product, or cell free supernatant, and may preferably be included in the form of Euglena gracilis dry powder, but is not limited thereto.
- the Euglena gracilis dry powder may contain Carbohydrate, Crude Protein, Crude Fat, Ash, Fiber, Beta-glucan, and Pheophorbide, and exemplary contents are shown in Table 1 of the present specification.
- prevention refers to all actions that inhibit or delay the onset of hematopoietic disorders or cancer by administering the composition according to the present invention.
- treatment refers to any action that improves or beneficially changes the symptoms of a hematopoietic disorder or cancer by administering the composition according to the present invention.
- improvement refers to any action that improves the bad condition of hematopoietic disorder or cancer by administering or ingesting the composition of the present invention to an individual.
- the pharmaceutical composition of the present invention can be formulated and used in various forms according to conventional methods.
- it can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and can be formulated and used in the form of external preparations, suppositories, and sterile injection solutions.
- composition of the present invention may contain one or more known active ingredients that have a preventive or therapeutic effect on hematopoietic disorders or cancer along with Euglena gracilis.
- composition of the present invention may further include pharmaceutically acceptable additives, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, and lactose. , mannitol, taffy, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, carnauba lead, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, White sugar, etc. may be used.
- the pharmaceutically acceptable additive according to the present invention is preferably contained in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
- composition of the present invention can be administered in various oral or parenteral formulations during actual clinical administration.
- diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants are used. It can be prepared by doing so, and it is preferable to use suitable preparations known in the art that are disclosed in the literature.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, or It is prepared by mixing lactose and gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.
- the liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. This may be included.
- Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
- Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
- injectable ester such as ethyl oleate.
- As a base for suppositories witepsol, macrogol, tween 61, cacao, laurin, glycerogeratin, etc. can be used.
- the dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time, and/or administration route of the pharmaceutical composition, and the type and degree of response to be achieved by administration of the pharmaceutical composition. , various factors including the type, age, weight, general health condition, symptoms or degree of disease, gender, diet, excretion, drugs used simultaneously or simultaneously with the subject, other components of the composition, etc. of the subject to be administered, and It may vary depending on similar factors well known in the pharmaceutical field, and a person skilled in the art can easily determine and prescribe an effective dosage for the desired treatment.
- the dosage of the pharmaceutical composition of the present invention is preferably administered at a concentration of, for example, 0.05 to 5 mg/kg, more preferably 0.1 to 0.4 mg/kg, and even more preferably 0.2 to 0.35 mg/kg. , and even more preferably 0.25 mg/kg, but the dosage does not limit the scope of the present invention in any way.
- the administration route and administration method of the pharmaceutical composition of the present invention may be independent, and are not particularly limited, and any administration route and administration method may be used as long as the pharmaceutical composition can reach the desired area. can be followed.
- the pharmaceutical composition can be administered orally or parenterally.
- the parenteral administration method includes, for example, intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration, or subcutaneous administration.
- composition of the present invention can be used alone or in combination with surgery, radiation therapy, hormone therapy, chemotherapy, and methods using biological response regulators for the prevention or treatment of hematopoietic disorders.
- food refers to food that has a bioregulatory function and is a concept that includes health functional foods.
- health functional food refers to a food group or food composition that provides added value to a food by using physical, biochemical, biotechnological methods, etc. to function and express the function of the food for a specific purpose, or a food group that regulates the biological defense rhythm and diseases. It refers to food that has been designed and processed to fully express the body's regulatory functions related to prevention and recovery in the living body.
- the health functional food is intended to enhance the activity of preventing or improving hematopoietic disorders or cancer.
- the food composition can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and components commonly added in the art. Additionally, the formulation of the food composition can be manufactured without limitation as long as it is a formulation recognized as a food composition.
- Foods according to the present invention include, for example, various foods, beverages, gum, tea, vitamin complexes, functional foods, etc. Additionally, foods include special nutritional foods (e.g., milk formula, infant and baby food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g., ramen, noodles, etc.), breads, health supplements, seasonings (e.g., soy sauce) , soybean paste, red pepper paste, mixed paste, etc.), sauces, confectionery (e.g., snacks), candy, chocolate, gum, ice cream, dairy products (e.g., fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various types of kimchi) , pickles, etc.), beverages (e.g., fruit drinks, vegetable drinks, soy milk, fermented drinks, etc.), natural seasonings (e.g., ramen soup, etc.), food additives, etc., but are not limited thereto.
- the food, beverage or food additive can
- the composition of the present invention When using the composition of the present invention as a health functional food additive, the composition can be added as is or used together with other health functional food ingredients, and can be used appropriately according to conventional methods.
- the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use.
- the composition of the present invention can be added in an amount of preferably 50 parts by weight or less, more preferably 25 parts by weight or less, based on the raw materials.
- the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
- the food or health functional food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like a typical food composition.
- natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol, and erythritol.
- the above-described flavoring agents include natural flavoring agents (thaumatin), stevia extracts (e.g. rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
- the food composition contains, in addition to Euglena gracilis, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and the like. It may contain salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the food composition of the present invention may contain pulp for the production of natural fruit juice and fruit juice drinks and vegetable drinks.
- the present invention provides an anticancer adjuvant composition containing Euglena gracilis.
- the anti-cancer adjuvant according to the present invention may be in the form of a pharmaceutical composition or food composition, and more specifically, may be an anti-cancer pharmaceutical adjuvant or an anti-cancer food adjuvant.
- anti-cancer adjuvant refers to an agent that can be used as an auxiliary agent to enhance the effect of a cancer treatment agent commonly used in the art, and the effect of a cancer treatment or anti-cancer treatment can be improved by using the adjuvant according to the present invention. It can improve or alleviate the side effects of cancer treatment or anti-cancer treatment.
- the term “food” refers to all foods that people consume on a daily basis, and includes health functional foods.
- Euglena gracilis of the present invention can be added to food compositions as an anti-cancer supplement, and can be added as the active ingredient or used together with other foods or food ingredients, and can be used appropriately according to conventional methods.
- the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
- the type of anticancer agent that can be used with the anticancer adjuvant of the present invention is not particularly limited.
- Anticancer drugs can be selected based on general principles that are considered when selecting anticancer drugs, such as the type of cancer cell, the absorption rate of the anticancer drug (treatment period and route of anticancer drug administration), the location of the tumor, and the size of the tumor.
- the present invention provides a method for promoting hematopoiesis comprising administering Euglena gracilis to an individual in need thereof.
- the subject may be an individual in need of blood cell formation, examples of which include individuals with reduced hematopoiesis and individuals with reduced blood cell counts due to various hematopoietic disorders.
- the entity may be an insect, fish, bird, or mammal, including humans, and may be a single cell or colony, but is not limited thereto.
- the present invention provides a method of treating hematopoietic disorders comprising administering Euglena gracilis to an individual in need thereof.
- the present invention also provides a method of treating cancer comprising administering Euglena gracilis and an anticancer agent to an individual in need thereof.
- the individual is an individual expected to develop a hematopoietic disorder; invented entity; It may be, but is not limited to, an entity that has been judged to be fully cured.
- Redundant content is omitted in consideration of the complexity of the present specification, and terms not otherwise defined in this specification have meanings commonly used in the technical field to which the present invention pertains.
- Euglena gracilis was provided in powder form from Daesang Co., Ltd.'s R&D Center (Icheon, Korea). The composition of Euglena gracilis powder was analyzed by the Korea Institute of Health Functional Foods (Seongnam, Korea), and the results are shown in Table 1.
- Euglena gracilis powder consists of 69.41% carbohydrates, which is approximately twice that reported elsewhere.
- the amount of paramylon (average molecular weight, 500 kDa) in Euglena gracilis was 597.88 mg/g.
- mice Male BALB/c mice aged 6–7 weeks were purchased from Coretech (Pyeongtaek, Korea). Animals were housed in a pathogen-free animal facility with temperature control (23°C ⁇ 3°C) and humidity control (55% ⁇ 15%), with sufficient ventilation and a 12-hour light/dark cycle. Mice were housed in polypropylene cages containing up to 5 mice each. Additionally, mice were provided with a commercial diet (Cargill Agri Purina Inc., Pyeongtaek, Korea) and water. The commercial diet contains 20% protein, 4.5% fat, 6% fiber, 0.5% calcium, 1% phosphorus, and 7% ash. All animals had a 1-week adjustment period prior to the experiment and were randomly assigned to the control or test group.
- mice For blood cell analysis, 8-10 animals per group were used, and for spleen isolation, 3-6 animals were used.
- the oral dose of Euglena gracilis was set at 3 g per kg body weight, which was set based on previous studies. Euglena gracilis suspended in saline solution was administered orally once a day until the mice were euthanized. Gemcitabine (120 mg/kg; Merck, Germany) dissolved in saline solution was administered intraperitoneally 2 weeks after the first oral administration of Euglena gracilis. Gemcitabine treatment was applied 1 to 4 times at 3-day intervals. Untreated mice received the same volume of saline. All experimental protocols were approved by the Sungkyunkwan University Animal Ethics Committee (SKKUIACUC2019-04-34-3). Animals were cared for in accordance with the National Research Council Guide for the Care and Use of Laboratory Animals (1996).
- Blood cells were collected at various time points after gemcitabine treatment.
- the specific administration schedule and blood collection schedule are as shown in Figure 1A.
- blood was collected on days 0, 3, 5, and 7 after a single dose of gemcitabine.
- mice were euthanized using Zoletil 50 (Virbac, Carros, France) and Rompen (Bayer Healthcare, Leverkusen, Germany), and blood was collected using cardiac puncture.
- the collected blood was collected in K2 EDTA tubes, and the number of white blood cells and cells was calculated using a ProCyte Dx hematology analyzer (IDEXX, Westbrook, ME, USA).
- IDEXX ProCyte Dx hematology analyzer
- the results of calculating the number of white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), and red blood cells (RBC) are shown in Figures 1b and 1d, respectively.
- Example 4 Analysis of spleen immune cells in mice administered a single dose of gemcitabine
- spleens were obtained 7 days after a single dose of gemcitabine was administered to mice.
- Splenocytes were prepared by dissociating spleen tissue using a glass mill under sterile conditions. Cells were collected in RPMI 1640 medium containing 1% fetal bovine serum (FBS) (HyClone, Logan, UT, USA) and 1% penicillin-streptomycin (WelGene, Gyeongsan, Korea), and filtered through a cell strainer (70 ⁇ m). filtered through. After centrifugation, red blood cells contained in the filtrate were lysed using BD PharmLyse lysis buffer (BD Biosciences, San Diego, CA, USA) to obtain only spleen cells. The obtained splenocytes were resuspended in RPMI 1640 containing 10% FBS and 1% penicillin-streptomycin to obtain a cell suspension.
- FBS fetal bovine serum
- penicillin-streptomycin WelGen
- a cell pellet was obtained from the cell suspension containing the spleen cells obtained in Example 4-1.
- the cell pellet was resuspended in FACS buffer (PBS/0.1% NaN 3 /1% FBS). Splenocytes were blocked with rat anti-mouse CD16/CD32 antibody (BD Biosciences) at 4°C for 5 minutes.
- splenocytes were stained with fluorescein isothiocyanate (FITC)-conjugated CD11b, phycoerythrin-conjugated CD49b, FITC-conjugated CD19, phycoerythrin-conjugated CD3, FITC-conjugated anti-mouse CD4, phycoerythrin-conjugated anti-mouse CD8a, and phycoerythrin-conjugated anti.
- FITC fluorescein isothiocyanate
- the proportion of bone marrow cells was confirmed to be increased after chemotherapy such as gemcitabine ( Figure 4b ).
- the ratio of NK cells in the gemcitabine-treated group (GEM) was higher than the control group, but the gemcitabine + Euglena gracilis-treated group (G+E) was confirmed to be lowered to the control group (CON) level ( Figure 4b). It was confirmed that there was no difference in subtypes of T cells, CD4 cells, and CD8 T cells ( Figure 4c).
- the gemcitabine-treated group (GEM) was also confirmed to have increased expression of Dectin-1.
- the gemcitabine treatment group (GEM) and gemcitabine + Euglena gracilis treatment group (G+E) were higher than the control group (CON) and Euglena gracilis treatment group (EUG), and there was a difference in Dectin-1 expression between groups. There was no.
- GM-CSF granulocyte/macrophage-colony-stimulating factor
- GM-CSF concentrations were determined using the mouse GM-CSF DuoSet ELISA kit (R&D Systems, Minneapolis, MN, USA). The results of analyzing GM-CSF secretion from splenocytes after a single administration of gemcitabine are shown in Figure 3.
- each group produced an almost undetectable amount of GM-CSF, and there was no difference between the groups.
- GM-CSF in the gemcitabine + Euglena gracilis group (G + E) was higher than that in the control group (CON) and gemcitabine (GEM) groups.
- GM-CSF in the gemcitabine + Euglena gracilis group (G+E) was higher than that in the control group (CON) and gemcitabine (GEM) groups, but there was a statistically significant difference between the groups. There was no.
- mice following multiple administrations of gemcitabine was analyzed.
- the specific administration schedule and blood collection schedule are shown in Figure 4A.
- gemcitabine was administered, and blood was collected on days 0, 1, 3, 5, and 7 after four administrations.
- mice were administered four doses of gemcitabine three days apart. Blood cells were obtained on days 1, 3, 5, and 7 after gemcitabine administration.
- Blood analysis was performed in the same manner as in Example 3 above.
- the control group in this experiment was the normal group (i.e., the group that did not receive gemcitabine).
- the results of analyzing blood collected 1 day after the last administration of gemcitabine are shown in Figures 4b to 4e, respectively.
- the gemcitabine + Euglena gracilis group had an increase in total white blood cells compared to the gemcitabine group (GEM), and in particular, there was a statistically significant increase in lymphocytes. There was no significant difference in neutrophil counts between the gemcitabine group (GEM) and the gemcitabine + Euglena gracilis group (G+E). Additionally, administration of Euglena gracilis to healthy mice (CON) had no significant effect on the white blood cell count.
- Euglena gracilis and the anticancer drug gemcitabine were administered to experimental animals, Euglena gracilis did not affect the spleen immune cell population and increased the number of white blood cells to the level of normal groups. Additionally, it was confirmed that Euglena gracilis improves the production of granulocyte/macrophage-colony stimulating factor. This means that Euglena gracilis has a significant effect of improving leukopenia, and Euglena gracilis of the present invention can be used in various fields in the field of treating anticancer drug side effects and leukopenia.
Abstract
The present invention relates to use of a microorganism of the genus Euglena for: preventing, ameliorating or treating blood dyscrasia; and preventing, ameliorating or treating cancer. The microorganism of the genus Euglena according to the present invention was confirmed to restore blood cells reduced by administration of an anticancer drug to a normal level, without affecting the spleen immune cell population. The microorganism of the genus Euglena was also confirmed to significantly increase the production of granulocyte/macrophage colony-stimulating factors underlying the hematopoietic response. This means that the microorganism of the genus Euglena according to the present invention promotes hematopoiesis, and thus can be used in the fields of blood dyscrasia and cancer-related treatment in various ways.
Description
본 발명은 유글레나 속 미생물의 조혈장애 예방, 개선 또는 치료 용도; 및 암 예방, 개선 또는 치료 용도;에 관한 것이다.The present invention relates to the use of Euglena genus microorganisms to prevent, improve or treat hematopoietic disorders; and for use in preventing, improving or treating cancer.
항암제는 표적 암세포 외에 조혈모세포, 장줄기세포 등 증식하는 세포에 작용한다. 따라서 화학 요법의 부작용 중 일부는 백혈구 감소증 및 점막염이다. 더욱이, 장내 미생물 생태계의 교란(dysbiosis)은 화학요법 후에 발생한다. 장내 장벽, 집락 저항성, 면역 및 조혈을 유지하기 위해서는 건강한 장내 미생물 군집이 필요하다. 장내 안정적인 미생물 생태계의 결함은 이러한 숙주의 생리적 기능을 손상시켜 내인성 세균의 침입과 조혈 억제를 초래한다. 또한 항암화학요법 후 백혈구감소증과 점막염이 있는 암 환자에서 항생제의 사용은 면역억제를 악화시킬 수 있다. 조혈작용에서 장내세균의 역할로 인해 최근 프리바이오틱스, 프로바이오틱스 등 장내미생물 복원을 위한 비약물 보충제에 대한 관심이 높아지고 있다.Anticancer drugs act on proliferating cells, such as hematopoietic stem cells and intestinal stem cells, in addition to target cancer cells. Therefore, some of the side effects of chemotherapy are leukopenia and mucositis. Moreover, dysbiosis of the intestinal microbial ecosystem occurs after chemotherapy. A healthy gut microbiome is necessary to maintain the intestinal barrier, colonization resistance, immunity and hematopoiesis. Defects in the stable microbial ecosystem in the intestines impair the physiological functions of the host, resulting in the invasion of endogenous bacteria and inhibition of hematopoiesis. Additionally, the use of antibiotics in cancer patients with leukopenia and mucositis after chemotherapy may worsen immunosuppression. Due to the role of intestinal bacteria in hematopoiesis, interest in non-drug supplements to restore intestinal microorganisms, such as prebiotics and probiotics, has recently increased.
이에 본 발명자들은 항암제 부작용 개선을 위해 연구한 결과, 유글레나 속 미생물이 항암제에 의해 감소된 혈구 수를 회복시키는 것을 확인함으로써 본 발명을 완성하게 되었다.Accordingly, as a result of research to improve the side effects of anticancer drugs, the present inventors completed the present invention by confirming that microorganisms of the Euglena genus restore the blood cell count reduced by anticancer drugs.
따라서 본 발명의 목적은, 유글레나 그라실리스(Euglena gracilis)를 포함하는 조혈장애(blood dyscrasia) 예방, 개선 또는 치료용 조성물을 제공하는 것이다.Therefore, an object of the present invention is to provide a composition for preventing, improving or treating blood dyscrasia containing Euglena gracilis .
본 발명의 다른 목적은, 유글레나 그라실리스 및 항암제를 포함하는 암 예방, 개선 또는 치료용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for preventing, improving or treating cancer containing Euglena gracilis and an anticancer agent.
본 발명의 또 다른 목적은, 유글레나 그라실리스를 포함하는 항암 보조제 조성물을 제공하는 것이다.Another object of the present invention is to provide an anticancer adjuvant composition containing Euglena gracilis.
본 발명의 또 다른 목적은, 유글레나 그라실리스를 이를 필요로 하는 개체에 투여하는 단계;를 포함하는 조혈 작용(hematopoiesis) 촉진 방법을 제공하는 것이다.Another object of the present invention is to provide a method for promoting hematopoiesis, comprising administering Euglena gracilis to an individual in need thereof.
본 발명의 또 다른 목적은, 유글레나 그라실리스를 이를 필요로 하는 개체에 투여하는 단계를 포함하는 조혈장애의 치료 방법을 제공하는 것이다.Another object of the present invention is to provide a method of treating hematopoietic disorders comprising administering Euglena gracilis to an individual in need thereof.
본 발명의 또 다른 목적은, 유글레나 그라실리스 및 항암제를 이를 필요로 하는 개체에 투여하는 단계를 포함하는 암의 치료 방법을 제공하는 것이다.Another object of the present invention is to provide a method of treating cancer comprising administering Euglena gracilis and an anticancer agent to an individual in need thereof.
상기 목적을 달성하기 위하여, 본 발명은 유글레나 그라실리스를 포함하는 조혈장애 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating hematopoietic disorders containing Euglena gracilis.
또한 본 발명은 유글레나 그라실리스를 포함하는 조혈장애 예방 또는 개선용 식품 조성물을 제공한다.Additionally, the present invention provides a food composition for preventing or improving hematopoietic disorders containing Euglena gracilis.
또한 본 발명은 유글레나 그라실리스를 포함하는 조혈장애 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving hematopoietic disorders containing Euglena gracilis.
또한 본 발명은 유글레나 그라실리스 및 항암제를 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다.Additionally, the present invention provides a pharmaceutical composition for preventing or treating cancer containing Euglena gracilis and an anticancer agent.
또한 본 발명은 유글레나 그라실리스 및 항암제를 포함하는 암 예방 또는 개선용 식품 조성물을 제공한다.Additionally, the present invention provides a food composition for preventing or improving cancer containing Euglena gracilis and an anticancer agent.
또한 본 발명은 유글레나 그라실리스 및 항암제를 포함하는 암 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cancer containing Euglena gracilis and an anticancer agent.
또한 본 발명은 유글레나 그라실리스를 포함하는 항암 보조제 조성물을 제공한다.Additionally, the present invention provides an anti-cancer adjuvant composition containing Euglena gracilis.
또한 본 발명은 유글레나 그라실리스를 이를 필요로 하는 개체에 투여하는 단계;를 포함하는 조혈 작용 촉진 방법을 제공한다.Additionally, the present invention provides a method for promoting hematopoiesis, comprising administering Euglena gracilis to an individual in need thereof.
또한 본 발명은 유글레나 그라실리스를 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 조혈장애의 치료 방법을 제공한다.The present invention also provides a method of treating hematopoietic disorders, comprising administering Euglena gracilis to an individual in need thereof.
또한 본 발명은 유글레나 그라실리스 및 항암제를 이를 필요로 하는 개체에 투여하는 단계를 포함하는 암의 치료 방법을 제공한다.The present invention also provides a method of treating cancer comprising administering Euglena gracilis and an anticancer agent to an individual in need thereof.
본 발명에 따른 유글레나 속 미생물은 비장 면역세포 집단에 영향을 미치지 않으면서, 항암제 투여에 의해 감소된 혈구를 정상 수준으로 회복시키는 것을 확인하였다. 또한 상기 유글레나 속 미생물은 조혈 반응의 기초가 되는 과립구/대식세포-콜로니 자극 인자의 생산을 현저히 증가시키는 것을 확인하였다. 이는 본 발명의 유글레나 속 미생물이 조혈 작용을 촉진한다는 것을 의미하는바, 조혈장애 및 암 관련 치료 분야에서 다양하게 활용될 수 있다.It was confirmed that the Euglena genus microorganism according to the present invention restores blood cells reduced by anticancer drug administration to a normal level without affecting the spleen immune cell population. In addition, it was confirmed that the Euglena genus microorganisms significantly increased the production of granulocyte/macrophage-colony stimulating factor, which is the basis of hematopoietic reaction. This means that the Euglena genus microorganism of the present invention promotes hematopoiesis, and can be used in various fields of treatment related to hematopoietic disorders and cancer.
도 1a는 젬시타빈 단회 투여 마우스의 혈액 분석 실험의 일정을 나타낸 도이다.Figure 1a is a diagram showing the schedule of blood analysis experiments in mice administered a single dose of gemcitabine.
도 1b는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 단회 투여에 따른 백혈구 수를 확인한 결과를 나타낸 도이다.Figure 1b is a diagram showing the results of confirming the white blood cell count following a single administration of gemcitabine in mice orally administered Euglena gracilis.
도 1c는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 단회 투여에 따른 호중구 수를 확인한 결과를 나타낸 도이다.Figure 1c is a diagram showing the results of confirming the number of neutrophils following a single administration of gemcitabine in mice orally administered Euglena gracilis.
도 1d는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 단회 투여에 따른 림프구 수를 확인한 결과를 나타낸 도이다.Figure 1d is a diagram showing the results of confirming the number of lymphocytes following a single administration of gemcitabine in mice orally administered Euglena gracilis.
도 1e는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 단회 투여에 따른 적혈구 수를 확인한 결과를 나타낸 도이다.Figure 1e is a diagram showing the results of confirming the number of red blood cells following a single administration of gemcitabine in mice orally administered Euglena gracilis.
도 2a는 젬시타빈 단회 투여 마우스의 비장 면역세포 분석 실험의 일정을 나타낸 도이다.Figure 2a is a diagram showing the schedule of the spleen immune cell analysis experiment in mice administered a single dose of gemcitabine.
도 2b는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 단회 투여에 따른 CD11b(myeloid) 및 CD49b(NK cell) 양성 세포수를 분석한 결과를 나타낸 도이다.Figure 2b is a diagram showing the results of analyzing the number of CD11b (myeloid) and CD49b (NK cell) positive cells following a single administration of gemcitabine in mice orally administered Euglena gracilis.
도 2c는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 단회 투여에 따른 CD4 및 CD8 양성 세포수를 분석한 결과를 나타낸 도이다.Figure 2c is a diagram showing the results of analyzing the number of CD4 and CD8 positive cells following a single administration of gemcitabine in mice orally administered Euglena gracilis.
도 2d는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 단회 투여에 따른 Dectin-1의 발현을 분석한 결과를 나타낸 도이다.Figure 2d is a diagram showing the results of analyzing the expression of Dectin-1 following a single administration of gemcitabine in mice orally administered Euglena gracilis.
도 3는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 단회 투여에 따른 과립구/대식세포-콜로니 자극 인자(granulocyte/macrophage-colony-stimulating factor, GM-CSF) 분비를 분석한 결과를 나타낸 도이다.Figure 3 shows the results of analyzing granulocyte/macrophage-colony-stimulating factor (GM-CSF) secretion following a single administration of gemcitabine in mice orally administered Euglena gracilis. .
도 4a는 젬시타빈 다회 투여 마우스의 혈액 분석 실험의 일정을 나타낸 도이다.Figure 4a is a diagram showing the schedule of blood analysis experiments in mice administered multiple doses of gemcitabine.
도 4b는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 다회 투여에 따른 백혈구 수를 분석한 결과를 나타낸 도이다.Figure 4b is a diagram showing the results of analyzing the number of white blood cells following multiple administrations of gemcitabine in mice orally administered Euglena gracilis.
도 4c는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 다회 투여에 따른 림프구 수를 분석한 결과를 나타낸 도이다.Figure 4c is a diagram showing the results of analyzing the number of lymphocytes following multiple administrations of gemcitabine in mice orally administered Euglena gracilis.
도 4d는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 다회 투여에 따른 호중구 수를 분석한 결과를 나타낸 도이다.Figure 4d is a diagram showing the results of analyzing the number of neutrophils following multiple administrations of gemcitabine in mice orally administered Euglena gracilis.
도 4e는 유글레나 그라실리스가 경구 투여된 마우스에서 젬시타빈 다회 투여에 따른 적혈구 수를 분석한 결과를 나타낸 도이다.Figure 4e is a diagram showing the results of analyzing the number of red blood cells following multiple administrations of gemcitabine in mice orally administered Euglena gracilis.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 양태에 따르면, 본 발명은 유글레나 그라실리스(Euglena gracilis)를 포함하는 조혈장애(blood dyscrasia) 예방, 개선 또는 치료용 조성물을 제공한다. 보다 상세하게는, 본 발명의 조성물은 조혈장애 예방 또는 치료용 약학적 조성물; 조혈장애 예방 또는 개선용 식품 조성물; 또는 조혈장애 예방 또는 개선용 건강기능식품 조성물;일 수 있다.According to an aspect of the present invention, the present invention provides a composition for preventing, improving or treating hematopoietic disorders (blood dyscrasia) containing Euglena gracilis . More specifically, the composition of the present invention is a pharmaceutical composition for preventing or treating hematopoietic disorders; Food composition for preventing or improving hematopoietic disorders; Or it may be a health functional food composition for preventing or improving hematopoietic disorders.
또한 본 발명의 다른 양태에 따르면, 본 발명은 유글레나 그라실리스 및 항암제를 포함하는 암 예방, 개선 또는 치료용 조성물을 제공한다. 보다 상세하게는, 본 발명의 조성물은 암 예방 또는 치료용 약학적 조성물; 암 예방 또는 개선용 식품 조성물; 또는 암 예방 또는 개선용 건강기능식품 조성물;일 수 있다.According to another aspect of the present invention, the present invention provides a composition for preventing, improving or treating cancer containing Euglena gracilis and an anticancer agent. More specifically, the composition of the present invention is a pharmaceutical composition for preventing or treating cancer; Food compositions for preventing or improving cancer; Or it may be a health functional food composition for preventing or improving cancer.
본 발명에 있어서, 유글레나 그라실리스(Euglena gracilis)는 동식물의 특징인 편모와 엽록체가 있는 단세포 진핵생물이다. 식품 보조제로 필수 아미노산, 지질, 비타민 및 베타 글루칸이 풍부하다. 세포벽에서 발견되는 박테리아, 균류 및 식물의 베타글루칸과 달리 유글레나 그라실리스의 베타글루칸은 세포질의 파라밀론이라는 과립에 저장된다. 이 파라밀론은 선형 베타-1,3 글리코시드 결합이 있는 100% 포도당으로 구성된 매우 순수한 베타-글루칸이다. 결정성이 높고 분자량이 100~500kDa이다. 유글레나 그라실리스는 포도당을 탄소원으로 하여 어두운 조건에서 많은 양의 파라밀론(건조 중량의 90% 이상)을 축적할 수 있다. 유글레나는 배양하기 쉽기 때문에 저렴한 글루칸 공급원이 된다.In the present invention, Euglena gracilis is a single-celled eukaryote with flagella and chloroplasts, which are characteristic of plants and animals. As a food supplement, it is rich in essential amino acids, lipids, vitamins and beta glucans. Unlike the beta-glucans of bacteria, fungi, and plants, which are found in cell walls, the beta-glucans of Euglena gracilis are stored in granules called paramylons in the cytoplasm. This paramylon is a very pure beta-glucan composed of 100% glucose with linear beta-1,3 glycosidic linkages. It has high crystallinity and a molecular weight of 100 to 500 kDa. Euglena gracilis can accumulate large amounts of paramylon (more than 90% of dry weight) under dark conditions using glucose as a carbon source. Euglena is easy to culture, making it an inexpensive source of glucan.
본 발명에 있어서, 조혈장애는 골수에서 조혈기능에 일어나는 장애를 의미한다. 조혈장애는 혈구 생성에 장애가 발생한 것으로, 다양한 혈구 관련 질환을 유발한다. In the present invention, hematopoietic disorder refers to a disorder occurring in hematopoietic function in the bone marrow. Hematopoietic disorders are disorders in the production of blood cells, causing various blood cell-related diseases.
본 발명의 구체예에서, 상기 조혈장애는 백혈구 감소증(leukopenia), 호중구 감소증(neutropenia), 림프구 감소증(lymphopenia), 단핵구 감소증(monocytopenia), 과립구 감소증(granulocytopenia), 재생 불량성 빈혈, 악성 림프종, 백혈병, 만성 간 장애, 신부전, 중증 감염증, 골수 장애성 혈소판 감소증, 특발성 혈소판 감소성 자반병(idiopathic thrombocytopenic purpura, ITP), 혈소판 무력증, 골수 형성이상 증후군 및 골수 증식성 질환으로 이루어진 군에서 선택된 1종 이상이나, 이에 제한되지 않는다.In an embodiment of the present invention, the hematopoietic disorder includes leukopenia, neutropenia, lymphopenia, monocytopenia, granulocytopenia, aplastic anemia, malignant lymphoma, leukemia, One or more diseases selected from the group consisting of chronic liver failure, renal failure, severe infections, myelopathogenic thrombocytopenia, idiopathic thrombocytopenic purpura (ITP), thrombocytopenia, myelodysplastic syndrome, and myeloproliferative disease, It is not limited to this.
본 발명의 구체예에서, 상기 조혈장애는 항암제 부작용에 의한 조혈장애일 수 있다.In an embodiment of the present invention, the hematopoietic disorder may be a hematopoietic disorder caused by a side effect of an anticancer drug.
본 발명의 바람직한 구체예에서, 상기 항암제는 독소루비신(Doxorubicine), 에피루비신(Epirubicin), 젬시타빈(Gemsitabin), 시스플라틴(Cisplatin), 카르보플라틴(Carboplatin), 프로카르바진(Procarbazine), 시클로포스파미드(Cyclophosphamide), 닥티노마이신(Dactinomycin), 다우노루비신(Daunorubicin), 에토포시드(Etoposide), 타목시펜(Tamoxifen), 미토마이신(Mitomycin), 블레오마이신(Bleomycin), 플리코마이신(Plicomycin), 트랜스플라티눔(Transplatinum), 빈블라스틴(Vinblastine) 및 메토트렉세이트(Methotrexate)로 이루어진 군으로부터 선택되는 1종 이상인 것이 바람직하고, 가장 바람직하게는 젬시타빈이나, 이에 본 발명의 범위가 제한되지 않는다.In a preferred embodiment of the present invention, the anticancer agent is Doxorubicin, Epirubicin, Gemsitabin, Cisplatin, Carboplatin, Procarbazine, and Cyclophos. Cyclophosphamide, Dactinomycin, Daunorubicin, Etoposide, Tamoxifen, Mitomycin, Bleomycin, Plicomycin , Transplatinum, Vinblastine, and Methotrexate, and most preferably gemcitabine, but the scope of the present invention is not limited thereto.
본 발명의 유글레나 그라실리스는 이의 배양액, 건조물 또는 무세포 상등액(cell free supernatant) 등의 다양한 형태로 포함될 수 있고, 바람직하게는 유글레나 그라실리스 건조 분말 형태로 포함될 수 있으나, 이에 제한되지 않는다. 상기 유글레나 그라실리스 건조 분말은 Carbohydrate, Crude Protein, Crude Fat, Ash, Fiber, Beta-glucan 및 Pheophorbide를 포함하는 것일 수 있고, 예시적인 함량은 본 명세서의 표 1과 같다.Euglena gracilis of the present invention may be included in various forms such as its culture medium, dried product, or cell free supernatant, and may preferably be included in the form of Euglena gracilis dry powder, but is not limited thereto. The Euglena gracilis dry powder may contain Carbohydrate, Crude Protein, Crude Fat, Ash, Fiber, Beta-glucan, and Pheophorbide, and exemplary contents are shown in Table 1 of the present specification.
본 발명에서 용어 “예방”이란 본 발명에 따른 조성물의 투여로 조혈장애 또는 암의 발병을 억제 또는 지연시키는 모든 행위를 말한다. 본 발명에서 용어 “치료”는 본 발명에 따른 조성물의 투여로 조혈장애 또는 암의 증세가 호전되거나 이롭게 변경하는 모든 행위를 말한다. 본 발명에서 용어 "개선"이란 본 발명의 조성물을 개체에 투여하거나 섭취시켜 조혈장애 또는 암의 나쁜 상태를 좋게 하는 모든 행위를 의미한다.In the present invention, the term “prevention” refers to all actions that inhibit or delay the onset of hematopoietic disorders or cancer by administering the composition according to the present invention. In the present invention, the term “treatment” refers to any action that improves or beneficially changes the symptoms of a hematopoietic disorder or cancer by administering the composition according to the present invention. In the present invention, the term "improvement" refers to any action that improves the bad condition of hematopoietic disorder or cancer by administering or ingesting the composition of the present invention to an individual.
본 발명의 조성물이 약학적 조성물로 이용되는 경우, 본 발명의 약학적 조성물은 통상의 방법에 따라 다양한 형태로 제형화하여 사용될 수 있다. 예컨대, 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽 등의 경구형 제형으로 제형화할 수 있고, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.When the composition of the present invention is used as a pharmaceutical composition, the pharmaceutical composition of the present invention can be formulated and used in various forms according to conventional methods. For example, it can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and can be formulated and used in the form of external preparations, suppositories, and sterile injection solutions.
본 발명의 조성물은 유글레나 그라실리스와 함께 조혈장애 또는 암에 대하여 예방 또는 치료 효과를 갖는 공지의 유효성분을 1종 이상 함유할 수 있다.The composition of the present invention may contain one or more known active ingredients that have a preventive or therapeutic effect on hematopoietic disorders or cancer along with Euglena gracilis.
본 발명의 조성물은 약제학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약제학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당 등이 사용될 수 있다. 본 발명에 따른 약제학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 ~ 90 중량부 포함되는 것이 바람직하나 이에 한정되는 것은 아니다.The composition of the present invention may further include pharmaceutically acceptable additives, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, and lactose. , mannitol, taffy, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, carnauba lead, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, White sugar, etc. may be used. The pharmaceutically acceptable additive according to the present invention is preferably contained in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
본 발명의 조성물은 실제 임상투여 시에 경구 또는 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제할 수 있으며, 당해 기술 분야에 알려진 적합한 제제는 문헌에 개시되어 있는 것을 이용하는 것이 바람직하다.The composition of the present invention can be administered in various oral or parenteral formulations during actual clinical administration. When formulated, diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants are used. It can be prepared by doing so, and it is preferable to use suitable preparations known in the art that are disclosed in the literature.
상기 경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트(Calcium carbonate), 수크로스 (Sucrose) 또는 락토오스(Lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 또한, 상기 경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, or It is prepared by mixing lactose and gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. In addition, the liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. This may be included.
상기 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurin, glycerogeratin, etc. can be used.
본 발명의 약학적 조성물의 투여량은 상기 약학적 조성물의 제제화 방법, 투여 방식, 투여 시간 및/또는 투여 경로 등에 의해 다양해질 수 있으며, 상기 약학적 조성물의 투여로 달성하고자 하는 반응의 종류와 정도, 투여 대상이 되는 개체의 종류, 연령, 체중, 일반적인 건강 상태, 질병의 증세나 정도, 성별, 식이, 배설, 해당 개체에 동시 또는 이시에 함께 사용되는 약물 기타 조성물의 성분 등을 비롯한 여러 인자 및 의약 분야에서 잘 알려진 유사 인자에 따라 다양해질 수 있으며, 당해 기술 분야에서 통상의 지식을 가진 자는 목적하는 치료에 효과적인 투여량을 용이하게 결정하고 처방할 수 있다.The dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time, and/or administration route of the pharmaceutical composition, and the type and degree of response to be achieved by administration of the pharmaceutical composition. , various factors including the type, age, weight, general health condition, symptoms or degree of disease, gender, diet, excretion, drugs used simultaneously or simultaneously with the subject, other components of the composition, etc. of the subject to be administered, and It may vary depending on similar factors well known in the pharmaceutical field, and a person skilled in the art can easily determine and prescribe an effective dosage for the desired treatment.
본 발명의 약학적 조성물의 투여량은 예를 들어, 0.05 내지 5 mg/kg의 농도로 투여되는 것이 바람직하며, 더 바람직하게는 0.1 내지 0.4 mg/kg, 더욱 바람직하게는 0.2 내지 0.35 mg/kg, 더더욱 바람직하게는 0.25 mg/kg일 수 있으나, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition of the present invention is preferably administered at a concentration of, for example, 0.05 to 5 mg/kg, more preferably 0.1 to 0.4 mg/kg, and even more preferably 0.2 to 0.35 mg/kg. , and even more preferably 0.25 mg/kg, but the dosage does not limit the scope of the present invention in any way.
본 발명의 약학적 조성물의 투여 경로 및 투여 방식은 각각 독립적일 수 있으며, 그 방식에 있어 특별히 제한되지 아니하며, 목적하는 해당 부위에 상기 약학적 조성물이 도달할 수 있는 한 임의의 투여 경로 및 투여 방식에 따를 수 있다. The administration route and administration method of the pharmaceutical composition of the present invention may be independent, and are not particularly limited, and any administration route and administration method may be used as long as the pharmaceutical composition can reach the desired area. can be followed.
상기 약학적 조성물은 경구 투여 또는 비경구 투여 방식으로 투여할 수 있다. 상기 비경구 투여 방식으로는 예를 들어 정맥 내 투여, 복강 내 투여, 근육 내 투여, 경피 투여 또는 피하 투여 등이 포함된다.The pharmaceutical composition can be administered orally or parenterally. The parenteral administration method includes, for example, intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration, or subcutaneous administration.
본 발명의 약학적 조성물은 조혈장애의 예방 또는 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The pharmaceutical composition of the present invention can be used alone or in combination with surgery, radiation therapy, hormone therapy, chemotherapy, and methods using biological response regulators for the prevention or treatment of hematopoietic disorders.
본 발명에 있어서, 식품이란, 생체조절 기능을 가지는 식품을 말하는 것으로, 건강기능식품을 포함하는 개념이다. In the present invention, food refers to food that has a bioregulatory function and is a concept that includes health functional foods.
본 발명에 있어서, 건강기능식품이란 식품에 물리적, 생화학적, 생물공학적 수법 등을 이용하여 해당 식품의 기능을 특정 목적에 작용, 발현하도록 부가가치를 부여한 식품군이나 식품 조성이 갖는 생체방어리듬조절, 질병 방지와 회복 등에 관한 체내조절기능을 생체에 대하여 충분히 발현하도록 설계하여 가공한 식품을 의미한다. 본 발명의 목적상 상기 건강기능식품은 조혈장애 또는 암의 예방 또는 개선 활성을 증진시키기 위한 것이다.In the present invention, health functional food refers to a food group or food composition that provides added value to a food by using physical, biochemical, biotechnological methods, etc. to function and express the function of the food for a specific purpose, or a food group that regulates the biological defense rhythm and diseases. It refers to food that has been designed and processed to fully express the body's regulatory functions related to prevention and recovery in the living body. For the purpose of the present invention, the health functional food is intended to enhance the activity of preventing or improving hematopoietic disorders or cancer.
본 발명에 있어서 식품 조성물은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 식품 조성물의 제형 또한 식품 조성물로 인정되는 제형이면 제한 없이 제조될 수 있다.In the present invention, the food composition can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and components commonly added in the art. Additionally, the formulation of the food composition can be manufactured without limitation as long as it is a formulation recognized as a food composition.
본 발명에 따른 식품으로는 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 기능성 식품 등이 있다. 또한 식품에는 특수영양식품 (예, 조제유류, 영, 유아식 등), 식육가공품, 어육제품, 두부류, 묵류, 면류 (예, 라면류, 국수류 등), 빵류, 건강보조식품, 조미식품 (예, 간장, 된장, 고추장, 혼합장 등), 소스류, 과자류 (예, 스넥류), 캔디류, 쵸코렛류, 껌류, 아이스크림류, 유가공품 (예, 발효유, 치즈 등), 기타 가공식품, 김치, 절임식품 (각종 김치류, 장아찌 등), 음료 (예, 과실 음료, 채소류 음료, 두유류, 발효음료류 등), 천연조미료 (예, 라면 스프 등), 식품첨가제 등이 포함되나 이에 제한되지 않는다. 상기 식품, 음료 또는 식품첨가제는 통상의 제조방법으로 제조될 수 있다.Foods according to the present invention include, for example, various foods, beverages, gum, tea, vitamin complexes, functional foods, etc. Additionally, foods include special nutritional foods (e.g., milk formula, infant and baby food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g., ramen, noodles, etc.), breads, health supplements, seasonings (e.g., soy sauce) , soybean paste, red pepper paste, mixed paste, etc.), sauces, confectionery (e.g., snacks), candy, chocolate, gum, ice cream, dairy products (e.g., fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various types of kimchi) , pickles, etc.), beverages (e.g., fruit drinks, vegetable drinks, soy milk, fermented drinks, etc.), natural seasonings (e.g., ramen soup, etc.), food additives, etc., but are not limited thereto. The food, beverage or food additive can be manufactured by conventional manufacturing methods.
본 발명의 조성물을 건강기능식품 첨가물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 건강기능식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합량은 사용 목적에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 조성물은 원료에 대하여 바람직하게는 50 중량부 이하, 보다 바람직하게는 25 중량부 이하의 양으로 첨가할 수 있다. 그러나, 건강 조절 및 위생을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안정성 면에서 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용할 수 있다.When using the composition of the present invention as a health functional food additive, the composition can be added as is or used together with other health functional food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use. In general, when producing a food or beverage, the composition of the present invention can be added in an amount of preferably 50 parts by weight or less, more preferably 25 parts by weight or less, based on the raw materials. However, in the case of long-term intake for the purpose of health control and hygiene, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
본 발명의 식품 또는 건강기능식품 조성물은 유효성분인 유글레나 그라실리스를 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당 알코올이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.In addition to containing the active ingredient Euglena gracilis, the food or health functional food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like a typical food composition. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol, and erythritol. The above-described flavoring agents include natural flavoring agents (thaumatin), stevia extracts (e.g. rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
또한, 상기 식품 조성물은 유글레나 그라실리스를 외에 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 식품 조성물은 천연 과일 주스 및 과일 주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition, the food composition contains, in addition to Euglena gracilis, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and the like. It may contain salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the food composition of the present invention may contain pulp for the production of natural fruit juice and fruit juice drinks and vegetable drinks.
본 발명의 또 다른 양태에 따르면, 본 발명은 유글레나 그라실리스를 포함하는 항암 보조제 조성물을 제공한다.According to another aspect of the present invention, the present invention provides an anticancer adjuvant composition containing Euglena gracilis.
본 발명에 따른 항암 보조제는 약학적 조성물 또는 식품 조성물의 형태일 수 있으며, 보다 구체적으로는 항암 약학적 보조제 또는 항암 식품 보조제일 수 있다.The anti-cancer adjuvant according to the present invention may be in the form of a pharmaceutical composition or food composition, and more specifically, may be an anti-cancer pharmaceutical adjuvant or an anti-cancer food adjuvant.
본 발명에 있어서, “항암 보조제”는 당업계에서 일반적으로 사용되는 암치료제의 효과를 증진시키기 위하여 보조적으로 사용될 수 있는 제제를 말하며, 본 발명에 의한 보조제를 사용함으로써 암 치료제 또는 항암 치료의 효과를 증진시키거나, 암 치료제 또는 항암 치료의 부작용을 완화시킬 수 있다. In the present invention, “anti-cancer adjuvant” refers to an agent that can be used as an auxiliary agent to enhance the effect of a cancer treatment agent commonly used in the art, and the effect of a cancer treatment or anti-cancer treatment can be improved by using the adjuvant according to the present invention. It can improve or alleviate the side effects of cancer treatment or anti-cancer treatment.
상기 용어 "식품"은 사람이 일상적으로 섭취하는 음식물을 통틀어 이르는 말로, 건강기능식품을 포함하는 개념이다.The term “food” refers to all foods that people consume on a daily basis, and includes health functional foods.
본 발명의 유글레나 그라실리스는 항암보조제로 식품 조성물에 첨가될 수 있으며, 상기 유효성분을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 본 발명의 항암 보조제와 함께 사용될 수 있는 항암제의 종류는 특별히 한정되지 않는다. 항암제는 암세포의 종류, 항암제의 흡수 속도(치료기간과 항암제 투여 경로), 종양의 위치, 종양의 크기 등의 항암제 선택 시 고려하는 일반적인 원칙하에 선택될 수 있다.Euglena gracilis of the present invention can be added to food compositions as an anti-cancer supplement, and can be added as the active ingredient or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). The type of anticancer agent that can be used with the anticancer adjuvant of the present invention is not particularly limited. Anticancer drugs can be selected based on general principles that are considered when selecting anticancer drugs, such as the type of cancer cell, the absorption rate of the anticancer drug (treatment period and route of anticancer drug administration), the location of the tumor, and the size of the tumor.
본 발명의 또 다른 양태에 따르면, 본 발명은 유글레나 그라실리스를 이를 필요로 하는 개체에 투여하는 단계;를 포함하는 조혈 작용 촉진 방법을 제공한다.According to another aspect of the present invention, the present invention provides a method for promoting hematopoiesis comprising administering Euglena gracilis to an individual in need thereof.
본 발명의 구체예에서, 상기 개체는 혈구 형성이 필요한 개체일 수 있으며, 그 예로는 조혈 작용이 감소된 개체 및 다양한 조혈장애로 인해 혈구 수가 감소된 개체 등이 있다. 또한 상기 개체는 곤충류, 어류, 조류 또는 인간을 포함한 포유류일 수 있고, 단일 세포 또는 콜로니일 수 있으나, 이에 제한되지 않는다.In an embodiment of the present invention, the subject may be an individual in need of blood cell formation, examples of which include individuals with reduced hematopoiesis and individuals with reduced blood cell counts due to various hematopoietic disorders. Additionally, the entity may be an insect, fish, bird, or mammal, including humans, and may be a single cell or colony, but is not limited thereto.
본 발명의 또 다른 양태에 따르면, 본 발명은 유글레나 그라실리스를 이를 필요로 하는 개체에 투여하는 단계를 포함하는 조혈장애의 치료 방법을 제공한다. 또한 본 발명은 유글레나 그라실리스 및 항암제를 이를 필요로 하는 개체에 투여하는 단계를 포함하는 암의 치료 방법을 제공한다.According to another aspect of the present invention, the present invention provides a method of treating hematopoietic disorders comprising administering Euglena gracilis to an individual in need thereof. The present invention also provides a method of treating cancer comprising administering Euglena gracilis and an anticancer agent to an individual in need thereof.
본 발명의 구체예에서, 상기 개체는 조혈장애가 발병할 것으로 예상되는 개체; 발명한 개체; 또는 완치판정을 받은 개체;일 수 있으나, 이에 제한되지 않는다.In an embodiment of the present invention, the individual is an individual expected to develop a hematopoietic disorder; invented entity; It may be, but is not limited to, an entity that has been judged to be fully cured.
중복되는 내용은 본 명세서의 복잡성을 고려하여 생략하며, 본 명세서에서 달리 정의되지 않은 용어들은 본 발명이 속하는 기술분야에서 통상적으로 사용되는 의미를 갖는 것이다.Redundant content is omitted in consideration of the complexity of the present specification, and terms not otherwise defined in this specification have meanings commonly used in the technical field to which the present invention pertains.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.
실시예 1. 유글레나 그라실리스(Example 1. Euglena gracilis (
Euglena gracilisEuglena gracilis
) 준비) preparation
유글레나 그라실리스는 (주) 대상의 R&D Center(한국 이천)에서 분말 형태로 제공받았다. 유글레나 그라실리스 분말의 조성은 한국건강기능식품연구원(한국 성남)에서 분석하였으며, 그 결과는 표 1에 나타내었다.Euglena gracilis was provided in powder form from Daesang Co., Ltd.'s R&D Center (Icheon, Korea). The composition of Euglena gracilis powder was analyzed by the Korea Institute of Health Functional Foods (Seongnam, Korea), and the results are shown in Table 1.
| DescriptionDescription | AmountAmount |
| Energy (Kcal/100g)Energy (Kcal/100g) | 267.44267.44 |
| Carbohydrate (%)Carbohydrate (%) | 69.4169.41 |
| Crude Protein (%)Crude Protein (%) | 22.5822.58 |
| Crude Fat (%)Crude Fat (%) | 3.023.02 |
| Moisture (%)Moisture (%) | 2.762.76 |
| Ash (%)Ash (%) | 2.232.23 |
| Fiber (%)Fiber (%) | 63.8563.85 |
| Beta-glucan (mg/g)Beta-glucan (mg/g) | 597.88597.88 |
| Lead (mg/kg)Lead (mg/kg) | 0.03630.0363 |
| Cadmium (mg/kg)Cadmium (mg/kg) | 0.01350.0135 |
| Mercury (mg/kg)Mercury (mg/kg) | -- |
| Arsenic (mg/kg)Arsenic (mg/kg) | 0.01750.0175 |
| Pheophorbide (mg/kg)Pheophorbide (mg/kg) | 28.2428.24 |
| Escherichia coliEscherichia coli | -- |
표 1에 나타낸 바와 같이, 유글레나 그라실리스 분말은 69.41%의 탄수화물로 구성되어 있으며, 이는 다른 곳에서 보고된 것의 약 두 배이다. 유글레나 그라실리스에서 파라밀론(평균 분자량, 500kDa)의 양은 597.88mg/g이었다.As shown in Table 1, Euglena gracilis powder consists of 69.41% carbohydrates, which is approximately twice that reported elsewhere. The amount of paramylon (average molecular weight, 500 kDa) in Euglena gracilis was 597.88 mg/g.
실시예 2. 마우스 준비Example 2. Mouse preparation
6-7주령의 수컷 BALB/c 마우스를 코아텍(평택, 한국)에서 구입했다. 동물은 온도 조절(23℃ ± 3℃) 및 습도 조절(55% ± 15%)이 가능한 병원체가 없는 동물 시설에 수용하였고, 상기 동물 시설은 충분한 환기 및 12시간의 명암 주기가 있다. 마우스는 각각 최대 5마리의 마우스를 포함하는 폴리프로필렌 케이지에 보관되었다. 또한 마우스는 상업적인 식단(Cargill Agri Purina Inc., 평택, 한국)과 물을 제공받았다. 상업용 식단에는 단백질 20%, 지방 4.5%, 섬유질 6%, 칼슘 0.5%, 인 1%, 회분 7%가 포함되어 있다. 모든 동물은 실험 전에 조정 기간(adjustment prior) 1주를 가졌고, 대조군 또는 시험 그룹에 무작위로 할당하였다. 혈구 분석은 그룹 당 8-10마리로 구성하였고, 비장 분리를 위해 3-6마리로 구성하였다. 유글레나 그라실리스의 경구 용량은 체중 kg당 3g으로 설정하였고, 이는 이전 연구를 기반으로 설정하였다. 식염수에 현탁시킨 유글레나 그라실리스는 마우스가 안락사될 때까지 1일 1회 경구 투여하였다. 식염수에 녹인 젬시타빈(120 mg/kg; Merck, Germany)을 유글레나 그라실리스의 첫 경구 투여 2주 후에 복강 내 투여하였다. 젬시타빈 처리는 3일 간격으로 1~4회 적용되었다. 처리되지 않은 마우스는 동일한 부피의 식염수를 받았다. 모든 실험 프로토콜은 성균관대학교 동물윤리위원회(SKKUIACUC2019-04-34-3)의 승인을 받았다. 실험 동물의 관리 및 사용에 대한 미국 국립 연구 위원회 가이드(1996)에 따라 동물을 돌보았다.Male BALB/c mice aged 6–7 weeks were purchased from Coretech (Pyeongtaek, Korea). Animals were housed in a pathogen-free animal facility with temperature control (23°C ± 3°C) and humidity control (55% ± 15%), with sufficient ventilation and a 12-hour light/dark cycle. Mice were housed in polypropylene cages containing up to 5 mice each. Additionally, mice were provided with a commercial diet (Cargill Agri Purina Inc., Pyeongtaek, Korea) and water. The commercial diet contains 20% protein, 4.5% fat, 6% fiber, 0.5% calcium, 1% phosphorus, and 7% ash. All animals had a 1-week adjustment period prior to the experiment and were randomly assigned to the control or test group. For blood cell analysis, 8-10 animals per group were used, and for spleen isolation, 3-6 animals were used. The oral dose of Euglena gracilis was set at 3 g per kg body weight, which was set based on previous studies. Euglena gracilis suspended in saline solution was administered orally once a day until the mice were euthanized. Gemcitabine (120 mg/kg; Merck, Germany) dissolved in saline solution was administered intraperitoneally 2 weeks after the first oral administration of Euglena gracilis. Gemcitabine treatment was applied 1 to 4 times at 3-day intervals. Untreated mice received the same volume of saline. All experimental protocols were approved by the Sungkyunkwan University Animal Ethics Committee (SKKUIACUC2019-04-34-3). Animals were cared for in accordance with the National Research Council Guide for the Care and Use of Laboratory Animals (1996).
실시예 3. 젬시타빈 단회 투여 마우스의 혈액 분석Example 3. Blood analysis of mice administered single dose of gemcitabine
젬시타빈 처리 후 다양한 시점에서 혈액 세포를 수집했다. 구체적인 투여 스케줄 및 혈액 수집 일정은 도 1a과 같다. 구체적으로, 혈구 수의 시간 동역학 분석을 위하여, 젬시타빈 단회 투여 후 0, 3, 5 및 7일에 혈액을 수집하였다. 또한 Zoletil 50(Virbac, Carros, France) 및 Rompen(Bayer Healthcare, Leverkusen, Germany)을 사용하여 마우스를 안락사시키고, 심장 천자(cardiac puncture)를 이용하여 혈액을 채취하였다. 채취된 혈액을 K2 EDTA 튜브에 수집하고 ProCyte Dx 혈액학 분석기(IDEXX, Westbrook, ME, USA)를 사용하여 백혈구, 세포 수를 계산하였다. 백혈구(white blood cel,l WBC), 호중구(neutrophil, NEU), 림프구(lymphocyte, LYM) 및 적혈구(red blood cell, RBC) 수를 계산한 결과는 각각 도 1b 내지 d에 나타내었다.Blood cells were collected at various time points after gemcitabine treatment. The specific administration schedule and blood collection schedule are as shown in Figure 1A. Specifically, for temporal kinetic analysis of blood counts, blood was collected on days 0, 3, 5, and 7 after a single dose of gemcitabine. Additionally, mice were euthanized using Zoletil 50 (Virbac, Carros, France) and Rompen (Bayer Healthcare, Leverkusen, Germany), and blood was collected using cardiac puncture. The collected blood was collected in K2 EDTA tubes, and the number of white blood cells and cells was calculated using a ProCyte Dx hematology analyzer (IDEXX, Westbrook, ME, USA). The results of calculating the number of white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), and red blood cells (RBC) are shown in Figures 1b and 1d, respectively.
도 1b 내지 d에 나타낸 바와 같이, 젬시타빈 처리군(GEM)은 젬시타빈 처리 후 3일에서 5일 사이에 백혈구 감소증이 뚜렷하게 관찰되었으며, 7일에 총 백혈구 수가 대조군과 유사한 수준으로 회복되었다. 유글레나 그라실리스 처리군(G+E)은 젬시타빈 처리에 따라 백혈구 수가 다소 감소하였으나, 5일에 백혈구 수가 회복되었다. 특히, 유글레나 그라실리스에 의해 회복된 백혈구는 호중구와 같은 골수성 백혈구임을 확인하였다.As shown in Figures 1b to 1d, in the gemcitabine-treated group (GEM), leukopenia was clearly observed between 3 and 5 days after gemcitabine treatment, and on day 7, the total number of white blood cells recovered to a level similar to that of the control group. In the Euglena gracilis treatment group (G+E), the white blood cell count decreased slightly following gemcitabine treatment, but the white blood cell count recovered on day 5. In particular, it was confirmed that the white blood cells recovered by Euglena gracilis were myeloid white blood cells such as neutrophils.
젬시타빈 처리군(GEM)은 적혈구 수가 젬시타빈 처리 후 7일 동안 낮게 유지되는 것을 확인하였다. 또한 유글레나 그라실리스 처리군(G+E)은 적혈구 수를 회복하지 못했다. In the gemcitabine treated group (GEM), it was confirmed that the red blood cell count remained low for 7 days after gemcitabine treatment. Additionally, the Euglena gracilis treatment group (G+E) did not recover the red blood cell count.
상기 결과는 유글레나 그라실리스가 적혈구 수에 영향을 미치지 않으면서, 화학 요법으로 인한 백혈구 감소증을 치료할 수 있음을 시사한다.The above results suggest that Euglena gracilis can treat leukopenia caused by chemotherapy without affecting red blood cell count.
실시예 4. 젬시타빈 단회 투여 마우스의 비장 면역세포 분석Example 4. Analysis of spleen immune cells in mice administered a single dose of gemcitabine
4-1. 비장 세포 준비4-1. Splenocyte preparation
도 2a와 같이, 젬시타빈을 마우스에 단회 투여한 후 7일째에 비장을 얻었다. 비장 세포는 멸균 조건에서 유리 분쇄기를 사용하여 비장 조직을 해리하여 준비했다. 세포는 1% FBS(fetal bovine serum)(HyClone, Logan, UT, USA)와 1% 페니실린-스트렙토마이신(WelGene, 경산, 한국)을 포함하는 RPMI 1640 배지에 수집하였고, 세포 여과기(70 μm)를 통해 여과되었다. 원심분리 후, 여과액에 포함된 적혈구를 BD PharmLyse 용해 완충액(BD Biosciences, San Diego, CA, USA)을 사용하여 용해시켜, 비장세포만을 얻었다. 수득된 비장세포를 10% FBS 및 1% 페니실린-스트렙토마이신이 포함된 RPMI 1640에 재현탁하여 세포 현탁액을 얻었다. As shown in Figure 2a, spleens were obtained 7 days after a single dose of gemcitabine was administered to mice. Splenocytes were prepared by dissociating spleen tissue using a glass mill under sterile conditions. Cells were collected in RPMI 1640 medium containing 1% fetal bovine serum (FBS) (HyClone, Logan, UT, USA) and 1% penicillin-streptomycin (WelGene, Gyeongsan, Korea), and filtered through a cell strainer (70 μm). filtered through. After centrifugation, red blood cells contained in the filtrate were lysed using BD PharmLyse lysis buffer (BD Biosciences, San Diego, CA, USA) to obtain only spleen cells. The obtained splenocytes were resuspended in RPMI 1640 containing 10% FBS and 1% penicillin-streptomycin to obtain a cell suspension.
4-2. 유세포 분석4-2. flow cytometry
상기 실시예 4-1에서 얻은 비장세포가 포함된 세포 현탁액으로부터 세포 펠릿을 얻었다. 상기 세포 펠릿을 FACS 완충액(PBS/0.1% NaN3/1% FBS)에 재현탁시켰다. 비장세포를 rat anti-mouse CD16/CD32 항체(BD Biosciences)로 4℃에서 5분간 블로킹하였다. 블로킹 후 비장세포를 fluorescein isothiocyanate (FITC)-conjugated CD11b, phycoerythrin-conjugated CD49b, FITC-conjugated CD19, phycoerythrin-conjugated CD3, FITC-conjugated anti-mouse CD4, phycoerythrin-conjugated anti-mouse CD8a, 및 phycoerythrin-conjugated anti-Dectin-1 (BD Biosciences)을 어둠 속에서 얼음 위에서 30분 동안 염색하였다. 일치하는 이소타입 항체는 비특이적 결합을 나타내는데 사용된다. 염색된 비장세포를 세척하고 FACS 완충액에 재현탁시켰다. Navios 유세포 분석기(Beckman Coulter, La Brea, CA, USA)에서 총 10,000개의 이벤트를 수집하고 Kaluza 소프트웨어(Beckman Coulter)를 사용하여 데이터를 처리하였다. 면역 세포 하위 집합의 백분율은 염색된 세포의 빈도로 계산하였고, Dectin-1 발현은 평균 형광 강도(mean fluorescence intensity, M.F.I.)로 결정하였다. 유세포 분석을 통해 CD11b(myeloid), CD49b(NK cell), CD4 및 CD8에 대해 염색 및 분석한 결과는 도 2b 및 c에 나타내었다.A cell pellet was obtained from the cell suspension containing the spleen cells obtained in Example 4-1. The cell pellet was resuspended in FACS buffer (PBS/0.1% NaN 3 /1% FBS). Splenocytes were blocked with rat anti-mouse CD16/CD32 antibody (BD Biosciences) at 4°C for 5 minutes. After blocking, splenocytes were stained with fluorescein isothiocyanate (FITC)-conjugated CD11b, phycoerythrin-conjugated CD49b, FITC-conjugated CD19, phycoerythrin-conjugated CD3, FITC-conjugated anti-mouse CD4, phycoerythrin-conjugated anti-mouse CD8a, and phycoerythrin-conjugated anti. -Dectin-1 (BD Biosciences) was stained for 30 min on ice in the dark. Matching isotype antibodies are used to indicate non-specific binding. Stained splenocytes were washed and resuspended in FACS buffer. A total of 10,000 events were collected on a Navios flow cytometer (Beckman Coulter, La Brea, CA, USA) and data were processed using Kaluza software (Beckman Coulter). The percentage of immune cell subsets was calculated as the frequency of stained cells, and Dectin-1 expression was determined as mean fluorescence intensity (MFI). The results of staining and analysis for CD11b (myeloid), CD49b (NK cell), CD4, and CD8 through flow cytometry are shown in Figures 2b and c.
도 4b 및 c에 나타낸 바와 같이, 골수 세포(CD11b(+) 세포)의 비율은 젬시타빈과 같은 화학 요법 후 증가된 것을 확인하였다(도 4b). NK 세포의 비율은 젬시타빈 처리군(GEM)이 대조군보다 높았으나, 젬시타빈+유글레나 그라실리스 처리군(G+E)은 대조군(CON) 수준으로 낮아진 것을 확인하였다(도 4b). T 세포, CD4 세포 및 CD8 T 세포의 하위 유형에는 차이가 없는 것을 확인하였다(도 4c). As shown in Figures 4b and c, the proportion of bone marrow cells (CD11b(+) cells) was confirmed to be increased after chemotherapy such as gemcitabine ( Figure 4b ). The ratio of NK cells in the gemcitabine-treated group (GEM) was higher than the control group, but the gemcitabine + Euglena gracilis-treated group (G+E) was confirmed to be lowered to the control group (CON) level (Figure 4b). It was confirmed that there was no difference in subtypes of T cells, CD4 cells, and CD8 T cells (Figure 4c).
다음으로, 유글레나 그라실리스의 경구 투여가 건강한 마우스 및 젬시타빈 처리된 마우스의 비장세포에 의한 Dectin-1 발현을 변경하는지 여부를 결정하였다. Dectin-1 분석 결과는 도 2d에 나타내었다.Next, we determined whether oral administration of Euglena gracilis alters Dectin-1 expression by splenocytes in healthy mice and gemcitabine-treated mice. The Dectin-1 analysis results are shown in Figure 2d.
도 2d에 나타낸 바와 같이, 유글레나 그라실리스(EUG)는 건강한 마우스에서 Dectin-1의 발현을 상향 조절했다(P = 0.053). 또한, 젬시타빈 처리군(GEM)도 Dectin-1의 발현이 증가된 것을 확인하였다. 젬시타빈 처리군(GEM) 및 젬시타빈+유글레나 그라실리스 처리군(G+E)은 대조군(CON) 및 유글레나 그라실리스 처리군(EUG)에 비해 높았으며, 그룹 간 Dectin-1 발현에는 차이가 없었다. As shown in Figure 2D, Euglena gracilis (EUG) upregulated the expression of Dectin-1 in healthy mice (P = 0.053). In addition, the gemcitabine-treated group (GEM) was also confirmed to have increased expression of Dectin-1. The gemcitabine treatment group (GEM) and gemcitabine + Euglena gracilis treatment group (G+E) were higher than the control group (CON) and Euglena gracilis treatment group (EUG), and there was a difference in Dectin-1 expression between groups. There was no.
상기 결과는 유글레나 그라실리스가 젬시타빈 단회 투여 후 비장 면역세포 집단에 영향을 미치지 않는다는 것을 의미한다.These results indicate that Euglena gracilis does not affect the splenic immune cell population after a single dose of gemcitabine.
실시예 5. 사이토카인 분석Example 5. Cytokine analysis
가용성 베타글루칸에 의해 유발되는 조혈 반응의 기초가 되는 기전은 화학요법 후 비장세포를 통한 내인성 과립구/대식세포-콜로니 자극 인자(granulocyte/macrophage-colony-stimulating factor, GM-CSF) 생산이다. 이 조사는 시험관 내에서 가용성 베타-글루칸으로 처리된 비장세포에서 수행되었다. 비장세포를 10% FBS가 포함된 RPMI 배지에 현탁하여 세포 현탁액을 제조하였다. 세포 현탁액을 24웰 플레이트에 시딩하고, 10μg/mL 지질다당류(lipopolysaccharide, LPS)(Sigma-Aldrich, St. Louis, MO, USA) 또는 2μg/mL 항-CD3e 항체(BD Biosciences)를 처리하여 48시간 동안 배양했다. 배양 후 상층액을 수확하고, 효소 결합 면역흡착 분석법(enzyme-linked immunosorbent assay, ELISA)을 사용하여 측정했다. GM-CSF 농도는 마우스 GM-CSF DuoSet ELISA 키트(R&D Systems, Minneapolis, MN, USA)를 사용하여 결정하였다. 젬시타빈 단회 투여 후 비장세포의 GM-CSF 분비를 분석한 결과는 도 3에 나타내었다.The mechanism underlying the hematopoietic response induced by soluble beta-glucan is the production of endogenous granulocyte/macrophage-colony-stimulating factor (GM-CSF) by splenocytes after chemotherapy. This investigation was performed on splenocytes treated with soluble beta-glucan in vitro. A cell suspension was prepared by suspending splenocytes in RPMI medium containing 10% FBS. The cell suspension was seeded in a 24-well plate and treated with 10 μg/mL lipopolysaccharide (LPS) (Sigma-Aldrich, St. Louis, MO, USA) or 2 μg/mL anti-CD3e antibody (BD Biosciences) for 48 hours. cultured for a while. After incubation, the supernatant was harvested and measured using enzyme-linked immunosorbent assay (ELISA). GM-CSF concentrations were determined using the mouse GM-CSF DuoSet ELISA kit (R&D Systems, Minneapolis, MN, USA). The results of analyzing GM-CSF secretion from splenocytes after a single administration of gemcitabine are shown in Figure 3.
도 3에 나타낸 바와 같이, 대조군(Media)에서 각 그룹은 거의 감지할 수 없는 양의 GM-CSF를 생성했고, 그룹 간에 차이가 없었다. LPS로 자극했을 때, 젬시타빈+유글레나 그라실리스 군(G+E)의 GM-CSF는 대조군(CON) 및 젬시타빈(GEM) 군의 수치보다 높았다. 항-CD3 항체 자극과 관련하여, 젬시타빈+유글레나 그라실리스 군(G+E)의 GM-CSF는 대조군(CON) 및 젬시타빈(GEM) 군의 수치보다 높았으나, 그룹 간에 통계유의한 차이가 없었다.As shown in Figure 3, in the control group (Media), each group produced an almost undetectable amount of GM-CSF, and there was no difference between the groups. When stimulated with LPS, GM-CSF in the gemcitabine + Euglena gracilis group (G + E) was higher than that in the control group (CON) and gemcitabine (GEM) groups. In relation to anti-CD3 antibody stimulation, GM-CSF in the gemcitabine + Euglena gracilis group (G+E) was higher than that in the control group (CON) and gemcitabine (GEM) groups, but there was a statistically significant difference between the groups. There was no.
상기 결과는 유글레나 그라실리스에 의한 강화된 GM-CSF 생산이 화학요법 약물에 대한 반응으로 조혈 줄기 세포로부터 분화된 선천 면역 골수 세포에 특이적임을 의미한다. 즉, 유글레나 그라실리스는 젬시타빈 처리 마우스의 비장 세포를 통해 GM-CSF 생산을 향상시켰다.These results indicate that enhanced GM-CSF production by Euglena gracilis is specific for innate immune myeloid cells differentiated from hematopoietic stem cells in response to chemotherapy drugs. In other words, Euglena gracilis enhanced GM-CSF production through spleen cells of gemcitabine-treated mice.
실시예 6. 젬시타빈 다회 투여 마우스의 혈액 분석Example 6. Blood analysis of mice administered multiple doses of gemcitabine
젬시타빈 다회 투여에 따른 마우스의 혈액을 분석하였다. 구체적인 투여 스케줄 및 혈액 수집 일정은 도 4a와 같다. 구체적으로, 혈구 수의 시간 동역학 분석을 위하여, 젬시타빈을 투여하였고, 4회 투여 후 0, 1, 3, 5 및 7일에 혈액을 수집하였다. 이 실험에서, 마우스에 3일 간격으로 4회 용량의 젬시타빈을 투여했다. 젬시타빈 투여 후 1일, 3일, 5일 및 7일에 혈액 세포를 얻었다. 상기 실시예 3과 동일한 방법으로 혈액 분석을 수행하였다. 본 실험의 대조군은 정상군(즉, 젬시타빈을 투여하지 않은 그룹)이다. 젬시타빈 마지막 투여 1일 후 채취된 혈액을 분석한 결과는 각각 도 4b 내지 e에 나타내었다.The blood of mice following multiple administrations of gemcitabine was analyzed. The specific administration schedule and blood collection schedule are shown in Figure 4A. Specifically, to analyze the temporal dynamics of blood count, gemcitabine was administered, and blood was collected on days 0, 1, 3, 5, and 7 after four administrations. In this experiment, mice were administered four doses of gemcitabine three days apart. Blood cells were obtained on days 1, 3, 5, and 7 after gemcitabine administration. Blood analysis was performed in the same manner as in Example 3 above. The control group in this experiment was the normal group (i.e., the group that did not receive gemcitabine). The results of analyzing blood collected 1 day after the last administration of gemcitabine are shown in Figures 4b to 4e, respectively.
도 4b 내지 e에 나타낸 바와 같이, 젬시타빈+유글레나 그라실리스 군(G+E)는 젬시타빈 군(GEM)에 비해 총 백혈구가 증가하였고, 특히 림프구가 통계 유의적으로 증가했다. 호중구 수는 젬시타빈 군(GEM) 및 젬시타빈+유글레나 그라실리스 군(G+E) 사이에 유의한 차이가 없었다. 또한 건강한 마우스(CON)에 유글레나 그라실리스를 투여하여도 백혈구 수에는 유의한 영향을 미치지 않았다. As shown in Figures 4b to 4e, the gemcitabine + Euglena gracilis group (G + E) had an increase in total white blood cells compared to the gemcitabine group (GEM), and in particular, there was a statistically significant increase in lymphocytes. There was no significant difference in neutrophil counts between the gemcitabine group (GEM) and the gemcitabine + Euglena gracilis group (G+E). Additionally, administration of Euglena gracilis to healthy mice (CON) had no significant effect on the white blood cell count.
상기 결과는 유글레나 그라실리스가 정상적인 조혈에 영향을 미치지 않고, 장기간 젬시타빈에 노출되었을 때, 림프구에 대한 유글레나 그라실리스의 조혈 활성이 두드러진다는 것을 의미한다.The above results indicate that Euglena gracilis does not affect normal hematopoiesis, and that the hematopoietic activity of Euglena gracilis on lymphocytes is prominent when exposed to gemcitabine for a long period of time.
실시예 7. 통계 분석Example 7. Statistical analysis
통계적 유의성은 SPSS 소프트웨어 버전 25.0(IBM, Chicago, IL, USA)을 사용하여 결정하였다. 데이터가 적절하게 정규 분포를 따르는 경우 Student's t-test, 최소 유의차 검정을 사용한 analysis of variance (ANOVA) 또는 Dunnett T3 test를 사용한 Welch's ANOVA를 사용하여 값을 비교했다. 데이터가 정규 분포를 따르지 않는 경우 non-parametric ANOVA(Kruskal-Wallis)에 이어 Mann-Whitney U test를 적용하였다. PRIMER7을 사용하여 PERMANOVA를 통해 베타 다양성의 상당한 차이를 계산했다. 통계적 유의성은 P < 0.05로 설정하였다.Statistical significance was determined using SPSS software version 25.0 (IBM, Chicago, IL, USA). If the data were appropriately normally distributed, values were compared using Student's t-test, analysis of variance (ANOVA) using the least significant difference test, or Welch's ANOVA using the Dunnett T3 test. If the data did not follow a normal distribution, non-parametric ANOVA (Kruskal-Wallis) followed by the Mann-Whitney U test was applied. Significant differences in beta diversity were calculated via PERMANOVA using PRIMER7. Statistical significance was set at P < 0.05.
종합적으로 본 발명자들은 실험동물에 유글레나 그라실리스 및 항암제 젬시타빈을 투여할 경우 유글레나 그라실리스가 비장 면역세포 집단에 영향을 미치지 않으면서, 백혈구 수를 정상군 수준으로 증가시키는 것을 확인하였다. 또한 유글레나 그라실리스가 과립구/대식세포-콜로니 자극 인자의 생산을 향상시키는 것을 확인하였다. 이는 유글레나 그라실리스가 현저한 백혈구 감소증 개선 효과가 있음을 의미하는바, 본 발명의 유글레나 그라실리스는 항암제 부작용 및 백혈구 감소증 치료 분야에서 다양하게 활용될 수 있다.Overall, the present inventors confirmed that when Euglena gracilis and the anticancer drug gemcitabine were administered to experimental animals, Euglena gracilis did not affect the spleen immune cell population and increased the number of white blood cells to the level of normal groups. Additionally, it was confirmed that Euglena gracilis improves the production of granulocyte/macrophage-colony stimulating factor. This means that Euglena gracilis has a significant effect of improving leukopenia, and Euglena gracilis of the present invention can be used in various fields in the field of treating anticancer drug side effects and leukopenia.
이상, 본 발명내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적인 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의해 정의된다고 할 것이다. As above, specific parts of the present invention have been described in detail, and it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (13)
- 유글레나 그라실리스(Euglena gracilis)를 포함하는 조혈장애(blood dyscrasia) 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating blood dyscrasia containing Euglena gracilis.
- 제1항에 있어서,According to paragraph 1,상기 조혈장애는 백혈구 감소증(leukopenia), 호중구 감소증(neutropenia), 림프구 감소증(lymphopenia), 단핵구 감소증(monocytopenia), 과립구 감소증(granulocytopenia), 재생 불량성 빈혈, 악성 림프종, 백혈병, 만성 간 장애, 신부전, 중증 감염증, 골수 장애성 혈소판 감소증, 특발성 혈소판 감소성 자반병(idiopathic thrombocytopenic purpura, ITP), 혈소판 무력증, 골수 형성이상 증후군 및 골수 증식성 질환으로 이루어진 군에서 선택된 1종 이상인, 조성물.The hematopoietic disorders include leukopenia, neutropenia, lymphopenia, monocytopenia, granulocytopenia, aplastic anemia, malignant lymphoma, leukemia, chronic liver failure, renal failure, and severe A composition that is one or more selected from the group consisting of infectious diseases, bone marrow dysfunction thrombocytopenia, idiopathic thrombocytopenic purpura (ITP), thrombocytopenia, myelodysplastic syndrome and myeloproliferative disease.
- 제1항에 있어서,According to paragraph 1,상기 조혈장애는 항암제 부작용에 의한 조혈장애인, 조성물.The hematopoietic disorder is a hematopoietic disorder caused by side effects of anticancer drugs, composition.
- 제3항에 있어서,According to paragraph 3,상기 항암제는 독소루비신(Doxorubicine), 에피루비신(Epirubicin), 젬시타빈(Gemsitabin), 시스플라틴(Cisplatin), 카르보플라틴(Carboplatin), 프로카르바진(Procarbazine), 시클로포스파미드(Cyclophosphamide), 닥티노마이신(Dactinomycin), 다우노루비신(Daunorubicin), 에토포시드(Etoposide), 타목시펜(Tamoxifen), 미토마이신(Mitomycin), 블레오마이신(Bleomycin), 플리코마이신(Plicomycin), 트랜스플라티눔(Transplatinum), 빈블라스틴(Vinblastine) 및 메토트렉세이트(Methotrexate)로 이루어진 군으로부터 선택되는 1종 이상인, 조성물.The anticancer drugs include Doxorubicin, Epirubicin, Gemsitabin, Cisplatin, Carboplatin, Procarbazine, Cyclophosphamide, and Dactino. Dactinomycin, Daunorubicin, Etoposide, Tamoxifen, Mitomycin, Bleomycin, Plicomycin, Transplatinum, A composition comprising at least one member selected from the group consisting of Vinblastine and Methotrexate.
- 유글레나 그라실리스를 포함하는 조혈장애 예방 또는 개선용 식품 조성물.A food composition for preventing or improving hematopoietic disorders containing Euglena gracilis.
- 유글레나 그라실리스를 포함하는 조혈장애 예방 또는 개선용 건강기능식품 조성물.A health functional food composition for preventing or improving hematopoietic disorders containing Euglena gracilis.
- 유글레나 그라실리스 및 항암제를 포함하는 암 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer containing Euglena gracilis and an anticancer agent.
- 유글레나 그라실리스 및 항암제를 포함하는 암 예방 또는 개선용 식품 조성물.A food composition for preventing or improving cancer containing Euglena gracilis and an anticancer agent.
- 유글레나 그라실리스 및 항암제를 포함하는 암 예방 또는 개선용 건강기능식품 조성물.A health functional food composition for preventing or improving cancer containing Euglena gracilis and an anticancer agent.
- 유글레나 그라실리스를 포함하는 항암 보조제 조성물.Anti-cancer adjuvant composition containing Euglena gracilis.
- 유글레나 그라실리스를 이를 필요로 하는 개체에 투여하는 단계;를 포함하는 조혈 작용(hematopoiesis) 촉진 방법.A method of promoting hematopoiesis comprising administering Euglena gracilis to an individual in need thereof.
- 유글레나 그라실리스를 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 조혈장애의 치료 방법.A method of treating a hematopoietic disorder comprising administering Euglena gracilis to a subject in need thereof.
- 유글레나 그라실리스 및 항암제를 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 암의 치료 방법.A method of treating cancer, comprising administering Euglena gracilis and an anticancer agent to a subject in need thereof.
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| JP2017128568A (en) * | 2016-01-20 | 2017-07-27 | 株式会社ユーグレナ | Anti-tumor agent, tumor cell proliferation inhibitor, anti-breast cancer agent, and method for producing anti-tumor agent |
| CN105901714A (en) * | 2016-04-27 | 2016-08-31 | 青岛旭能生物工程有限责任公司 | Euglena compound tablet and preparation method thereof |
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