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WO2019168329A1 - Nanovésicules issues de bactéries acinetobacter et utilisation associée - Google Patents

Nanovésicules issues de bactéries acinetobacter et utilisation associée Download PDF

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Publication number
WO2019168329A1
WO2019168329A1 PCT/KR2019/002343 KR2019002343W WO2019168329A1 WO 2019168329 A1 WO2019168329 A1 WO 2019168329A1 KR 2019002343 W KR2019002343 W KR 2019002343W WO 2019168329 A1 WO2019168329 A1 WO 2019168329A1
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Prior art keywords
cancer
disease
vesicles
acinetobacter
derived
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English (en)
Korean (ko)
Inventor
김윤근
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MD Healthcare Inc
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MD Healthcare Inc
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Priority claimed from KR1020190022180A external-priority patent/KR102142327B1/ko
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/6851—Quantitative amplification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to nanovesicles derived from the genus Acinetobacter and its use. More specifically, malignant diseases such as gastric cancer, colorectal cancer, breast cancer, ovarian cancer and bladder cancer using nanovesicles derived from the genus Acinetobacter, myocardium
  • the present invention relates to a method for diagnosing cardiovascular diseases such as infarction, cardiomyopathy and stroke, diabetes, dementia, and Parkinson's disease, and a composition for preventing or treating the disease or inflammatory disease.
  • Inflammation is a local or systemic defense against damage or infection of cells and tissues, primarily by the direct response of humoral mediators that make up the immune system, or by stimulating local or systemic effector systems. It is caused by a cascade of biological reactions that take place.
  • Major inflammatory diseases include gastroenteritis, digestive diseases such as inflammatory bowelitis, oral diseases such as periodontitis, asthma, chronic obstructive pulmonary disease (COPD), respiratory diseases such as rhinitis, atopic dermatitis, hair loss, skin diseases such as psoriasis, degenerative arthritis, Arthritis, such as rheumatoid arthritis; And metabolic diseases such as obesity, diabetes, cirrhosis of the liver.
  • microbiota is a microbial community including microbes, archaea and eukarya that exist in a given settlement.
  • vesicles are absorbed through epithelial cells or keratinocytes of the mucosa to induce local inflammatory responses, as well as to regulate immune and inflammatory responses in the organs absorbed by the body and distributed to each organ. do.
  • vesicles derived from pathogenic Gram-negative bacteria such as Eshcherichia coli
  • vesicles derived from beneficial bacteria can control the disease by controlling immune and metabolic abnormalities caused by pathogenic vesicles.
  • Th17 immune response characterized by the secretion of IL-17 cytokines, which secrete IL-6 upon exposure to bacterial derived vesicles, which induce a Th17 immune response.
  • Inflammation by the Th17 immune response is characterized by neutrophil infiltration, and TNF-alpha secreted from inflammatory cells such as macrophages plays an important role in the process of inflammation.
  • Acinetobacter spp. Is an aerobic Gram-negative bacillus, which is widely distributed in nature and is isolated from soil, water, and clinical specimens. Among them, Acinetobacter baumannii is known as a major causative agent of infection in the hospital. However, no application has been reported for the diagnosis and treatment of intractable diseases such as cancer, cardiovascular diseases, metabolic diseases, and neuro-psychiatric diseases through extracellular vesicles derived from bacteria of the genus Acinetobacter.
  • the present inventors earnestly researched to solve the above-mentioned conventional problems.
  • the present inventors compared gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, And it was confirmed that the content of the bacterial vesicles of the genus Acinetobacter in the sample derived from Parkinson's disease patients significantly decreased.
  • vesicles were isolated from Acinetobacter Baumani bacteria belonging to the genus Acinetobacter and treated with macrophages, TNF-alpha secretion by pathogenic vesicles was significantly inhibited, and anticancer effects were confirmed in mouse cancer models. To this end, the present invention has been completed.
  • an object of the present invention is to provide a method for providing information for the diagnosis of gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, or Parkinson's disease.
  • the present invention from the group consisting of gastric cancer, colorectal cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, Parkinson's disease, and inflammatory diseases comprising an acinetobacter-derived vesicles as an active ingredient
  • Another object is to provide a composition for the prevention, treatment or amelioration of one or more diseases selected.
  • the present invention comprises the following steps, gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, or Parkinson's disease Provide informational methods for diagnosis:
  • the present invention also provides a method for diagnosing gastric cancer, colorectal cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, or Parkinson's disease, comprising the following steps:
  • the sample in step (a) may be feces, blood, or urine.
  • the primer pair in step (b) may be a primer of SEQ ID NO: 1 and SEQ ID NO: 2.
  • the present invention includes a cine vesicles of the genus Acinetobacter as an active ingredient, gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, Parkinson's disease, and It provides a pharmaceutical composition for the prevention or treatment of one or more diseases selected from the group consisting of inflammatory diseases.
  • the present invention includes a cine vesicles of the genus Acinetobacter as an active ingredient, gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, Parkinson's disease, and It provides a food composition for the prevention or amelioration of one or more diseases selected from the group consisting of inflammatory diseases.
  • the present invention includes a cine vesicles of the genus Acinetobacter as an active ingredient, gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, Parkinson's disease, and An inhalant composition for preventing or treating at least one disease selected from the group consisting of inflammatory diseases is provided.
  • the inflammatory disease is atopic dermatitis, acne, psoriasis, sinusitis, rhinitis, conjunctivitis, asthma, dermatitis, inflammatory collagen vascular disease, glomerulonephritis, encephalitis, inflammatory enteritis, chronic obstructive pulmonary disease, sepsis, plaque Blood shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthrosis, arthritis, inflammatory osteolysis, chronic inflammatory diseases caused by viral or bacterial infections, colitis, ulcerative colitis, inflammatory bowel disease, arthritis, rheumatoid arthritis, reactive arthritis, osteoarthritis , Scleroderma, osteoporosis, atherosclerosis, myocarditis, endocarditis, pericarditis, cystic fibrosis, Hashimoto's thyroiditis, Graves' disease, leprosy, syphilis, Lyme disease
  • the inflammatory disease may be a disease mediated by Interleukin-6 (IL-6) or Tumor necrosis factor alpha (TNF- ⁇ ).
  • IL-6 Interleukin-6
  • TNF- ⁇ Tumor necrosis factor alpha
  • the present invention also provides a cosmetic composition for the prevention or improvement of an inflammatory disease comprising a vesicle-derived vesicles of the genus Acinetobacter as an active ingredient.
  • the inflammatory disease may be at least one selected from the group consisting of atopic dermatitis, acne, and psoriasis.
  • the present invention comprises the step of administering to the subject a pharmaceutical composition
  • a pharmaceutical composition comprising an Acinetobacter genus bacteria-derived vesicles as an active ingredient, gastric cancer, colorectal cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, myocardium
  • the present invention is a group of vesicles derived from Acinetobacter genus, stomach cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, Parkinson's disease, and inflammatory diseases It provides a prophylactic or therapeutic use of one or more diseases selected from.
  • the vesicles may have an average diameter of 10 to 200 nm.
  • the vesicles may be secreted naturally or artificially from bacteria of the genus Acinetobacter.
  • the vesicle-derived vesicles of the genus Acinetobacter may be vesicles derived from Acinetobacter baumannii .
  • the present inventors confirmed that the intestinal bacteria are not absorbed into the body, but when the bacteria-derived vesicles are absorbed into the body through epithelial cells, they are distributed systemically and excreted in vitro through the kidneys, liver, and lungs.
  • Bacterial-derived vesicle metagenome analysis in the blood, blood, or urine may be used to detect feces, blood, or patients with gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, and Parkinson's disease. It was confirmed that the vesicle-derived bacteria of the genus Acinetobacter in urine were significantly reduced compared to normal individuals.
  • the vesicles were isolated by culturing Acinetobacter Baumani, a species of the genus Acinetobacter, in vitro and significantly inhibiting the secretion of inflammatory mediators by pathogenic vesicles when administered to inflammatory cells in vitro.
  • the bacterium-derived vesicles of the genus Acinetobacter according to the present invention are gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, and Parkinson's disease. It is expected that the present invention can be usefully used in diagnostic methods, and compositions for preventing or treating such diseases or inflammatory diseases.
  • Figure 1a is a photograph of the distribution of bacteria and vesicles by time after administration of bacteria and bacteria-derived vesicles (EV) to the mouth
  • Figure 1b is 12 hours after oral administration, blood, kidneys
  • the results were obtained by evaluating the distribution of bacteria, vesicles, and organs in the liver, liver, and various organs.
  • Figure 2 is a result of comparing the distribution of bacteria-derived vesicles of the genus Acinetobacter after analyzing the bacteria-derived vesicles metagenome present in gastric cancer patients and normal feces and urine.
  • Figure 3 is a result of comparing the distribution of the bacteria-derived vesicles of the genus Acinetobacter after analyzing the bacteria-derived vesicles metagenome present in colon cancer patients and normal urine.
  • Figure 4 is a result of comparing the distribution of bacteria-derived vesicles of the genus Acinetobacter after analyzing the bacteria-derived vesicle metagenome present in the breast cancer patients and normal blood and urine.
  • 5 is a result of comparing the distribution of vesicle-derived bacteria of the genus Acinetobacter after analysis of bacterial-derived vesicles metagenome present in ovarian cancer patients and normal urine.
  • Figure 6 is a result of comparing the distribution of bacteria-derived vesicles of the genus Acinetobacter after analyzing the bacteria-derived vesicles metagenome present in bladder cancer patients and normal urine.
  • Figure 7 is a result of comparing the distribution of bacteria-derived vesicles of the genus Acinetobacter after analysis of bacterial-derived vesicles metagenome present in patients with myocardial infarction and normal blood.
  • Figure 8 is a result of comparing the distribution of bacteria-derived vesicles of the genus Acinetobacter after analyzing the bacterial-derived vesicles metagenome present in cardiomyopathy patients and normal blood.
  • 9 is a result of comparing the distribution of vesicle-derived bacteria belonging to the genus Acinetobacter after analyzing the bacteria-derived vesicle metagenome present in blood and urine of diabetic patients and normal people.
  • Figure 10 is a result of comparing the distribution of bacteria-derived vesicles of the genus Acinetobacter after analyzing the bacteria-derived vesicles metagenome present in the stroke patients and normal blood.
  • 11 is a result of comparing the distribution of vesicle-derived bacteria belonging to the genus Acinetobacter after analysis of bacterial-derived vesicles metagenome present in Parkinson's disease patients and normal urine.
  • FIG. 13 is a result of evaluating the degree of cell death by administering the vesicles to macrophages (Raw264.7) in order to evaluate the apoptosis effect of Acinetobacter Baumani-derived vesicles.
  • E. coli EV Escherichia coli vesicles
  • Fig. 15 is an experimental protocol in which an acinetobacter Baumani-derived vesicle was administered to a mouse in order to evaluate the anticancer efficacy of the acinetobacter Baumani-derived vesicles.
  • FIG. 16 is a graph evaluating the effect on tumorigenesis by cancer cells by administering Acinetobacter Baumani vesicles intraperitoneally (IP) or orally (PO) in order to evaluate the anticancer efficacy of Acinetobacter Baumani vesicles. to be.
  • IP intraperitoneally
  • PO orally
  • Figure 17 is a tumor to evaluate the antitumor effect of Acinetobacter Baumani-derived vesicles, by administering Acinetobacter Baumani vesicles intraperitoneally (IP) or oral (PO), to evaluate the effect on tumor development by cancer cells It is a photograph.
  • the present invention relates to vesicles derived from the genus Acinetobacter and to their use.
  • the present inventors have found that the metagenome analysis shows that the bacterial vesicles of the genus Acinetobacter are significantly reduced in clinical samples of patients with cancer, cardiovascular disease, metabolic disease, and neuropsychiatric disease compared to normal people. Confirmed that it can. In addition, as a result of separating and characterizing the vesicles from the Acinetobacter Baumani strain, it was confirmed that the strain-derived vesicles can regulate immune function abnormalities caused by pathogenic vesicles.
  • the present invention provides an information providing method for diagnosing gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, or Parkinson's disease, comprising the following steps:
  • Diagnosis means, in a broad sense, to determine the actual condition of a patient in all aspects. The content of the judgment is the name of the disease, the etiology, the type of disease, the seriousness, the detailed mode of the condition, the presence or absence of complications, and the prognosis. Diagnosis in the present invention is to determine the onset of gastric cancer, colorectal cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, and Parkinson's disease and the level of the disease.
  • the sample may be feces, blood, or urine, but is not limited thereto.
  • the primer pair in step (b) may be a primer of SEQ ID NO: 1 and SEQ ID NO: 2.
  • metagenome also referred to as a military genome, refers to the sum total of the genome including all viruses, bacteria, fungi, etc. in an isolated area such as soil and animal intestine. It is used as a concept of genome to explain the identification of many microorganisms at once using sequencer for analysis.
  • the metagenome does not refer to one genome or genome, but to a kind of mixed dielectric as the genome of all species of one environmental unit. This is a term from the point of view of defining a species in the course of the evolution of biology in terms of functional species as well as various species that interact with each other to create a complete species.
  • rapid sequencing is used to analyze all DNA and RNA, regardless of species, to identify all species in one environment, and to identify interactions and metabolism.
  • the present invention comprises a vesicle derived from the genus Acinetobacter as an active ingredient, gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, Parkinson's disease And it provides a composition for the prevention or treatment of one or more diseases selected from the group consisting of inflammatory diseases.
  • the composition includes a pharmaceutical composition, an oral composition, or an inhalant composition, and may be a formulation of an oral spray or a nasal spray.
  • the term “inflammatory disease” refers to a disease caused by an inflammatory response in a mammalian body.
  • the inflammatory disease is atopic dermatitis, acne, psoriasis, sinusitis, rhinitis.
  • prophylaxis means any action that inhibits or retards the disease by administration of a composition according to the present invention.
  • improvement means any action that at least reduces the parameters associated with the condition being treated, for example, the extent of symptoms.
  • treatment refers to any action in which symptoms for the disease are improved or beneficially altered by administration of a composition according to the present invention.
  • nanovesicles Nanovesicle or vesicles (Vesicles) refers to the structure of the nano-size membrane secreted by various bacteria.
  • Vesicles or outer membrane vesicles (OMVs) derived from gram-negative bacteria have proteins, low molecular weight compounds, and bacterial DNA and RNA as well as lipopolysaccharides, and gram-positive bacteria.
  • the vesicles also contain peptidoglycan and lipoteichoic acid.
  • the nano vesicles or vesicles are naturally secreted or artificially produced from bacteria of the genus Acinetobacter, and have an average diameter of 20 to 100 nm.
  • the vesicle is centrifuged, ultra-fast centrifugation, high pressure treatment, extrusion, sonication, cell lysis, homogenization, freeze-thaw, electroporation, mechanical degradation, chemical treatment, filter by the culture medium containing bacteria of the genus Acinetobacter
  • the separation can be carried out using one or more methods selected from the group consisting of filtration, gel filtration chromatography, pre-flow electrophoresis, and capillary electrophoresis. In addition, it may further include a process for washing to remove impurities, concentration of the obtained vesicles and the like.
  • the pharmaceutical composition according to the invention may comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are conventionally used in the preparation, and include, but are not limited to, saline solution, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposomes, and the like. If necessary, other conventional additives such as antioxidants and buffers may be further included.
  • diluents, dispersants, surfactants, binders, lubricants and the like may be additionally added to formulate injectable formulations, pills, capsules, granules, or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • Suitable pharmaceutically acceptable carriers and formulations can be preferably formulated according to the individual components using methods disclosed in Remington's literature.
  • the pharmaceutical composition of the present invention is not particularly limited in formulation, but may be formulated as an injection, inhalant, external preparation for skin, oral ingestion, and the like.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, skin, nasal, airways) according to the desired method, and the dosage is determined by the condition and weight of the patient, disease Depending on the degree, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount.
  • the pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug and the drug. Sensitivity, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts.
  • the composition according to the present invention may be administered as a separate therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex and weight of the patient, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg daily or every other day, per kg of body weight Or divided into 1 to 3 times a day.
  • the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
  • the present invention comprises a vesicle derived from the genus Acinetobacter as an active ingredient, gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, Parkinson Provided is a food composition for preventing or ameliorating at least one disease selected from the group consisting of a disease and an inflammatory disease.
  • the food composition of the present invention includes a nutraceutical composition.
  • the food composition according to the present invention may be used as it is, or may be used in combination with other foods or food ingredients, or may be appropriately used according to conventional methods.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the compositions of the invention are added in amounts of up to 15% by weight, preferably up to 10% by weight relative to the raw materials.
  • the amount may be below the above range.
  • the food composition of the present invention in addition to containing the active ingredient as an essential ingredient in the indicated ratio, there are no particular restrictions on other ingredients, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract, for example, rebaudioside A, glycyrrhizin, etc.
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
  • these components can be used independently or in combination.
  • the proportion of such additives may also be appropriately selected by those skilled in the art.
  • the active ingredient may be added to the inhalant as it is, or may be used together with other ingredients, and may be appropriately used according to conventional methods.
  • the amount of the active ingredient to be mixed may be suitably determined depending on the purpose of use (prevention or treatment).
  • the inflammatory disease may be a disease mediated by IL-6 or TNF- ⁇ , but is not limited thereto.
  • the present invention provides a cosmetic composition for preventing or ameliorating an inflammatory disease comprising a vesicle-derived bacteria of the genus Acinetobacter as an active ingredient.
  • the cosmetic composition may be used for preventing or ameliorating an inflammatory disease selected from the group consisting of atopic dermatitis, acne, and psoriasis, but is not limited thereto.
  • Cosmetic compositions of the present invention may include components commonly used in cosmetic compositions, as well as vesicles derived from the genus Acinetobacter, and include, for example, conventional agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and perfumes. Adjuvants, and carriers.
  • composition of the present invention may be used in addition to the acetobacter bacteria-derived vesicles, and a combination of organic sunscreens that have been conventionally used insofar as they do not impair the skin protection effect by reacting with the acetobacter bacteria-derived vesicles.
  • organic sunscreen examples include glyceryl pava, drometrizole trisiloxane, drometrizole, digaloyltrioleate, disodium phenyldibenzimidazole tetrasulfonate, diethylhexyl butamidotriazone, diethylamino Hydroxybenzoylhexylbenzoate, die-methoxycinnamate, a mixture of lowson and dihydroxyacetone, methylenebis-benzotriazolyltetramethylbutylphenol, 4-methylbenzylidene camphor, menthyl anthranilate, benzophenone -3 (oxybenzone), benzophenone-4, benzophenone-8 (dioxyphenbenzone), butylmethoxydibenzoylmethane, bisethylhexyloxyphenol methoxyphenyltriazine, synoxate, ethyldihydroxypropylpava, Oct
  • Examples of products to which the cosmetic composition of the present invention may be added include, for example, cosmetics such as astringent cosmetics, soft cosmetics, nourishing cosmetics, various creams, essences, packs, foundations, and the like, cleansing agents, soaps, treatments, and essences.
  • Specific formulations of the cosmetic composition of the present invention include skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, essence, nutrition essence, pack, Formulations such as soaps, shampoos, cleansing foams, cleansing lotions, cleansing creams, body lotions, body cleansers, emulsions, lipsticks, makeup bases, foundations, press powders, loose powders, eye shadows and the like.
  • the bacteria and bacterial-derived vesicles were orally administered to mice to observe the absorption, distribution, and excretion of the bacteria and vesicles in the body. It was confirmed that it was absorbed within 5 minutes of administration and distributed systemically and excreted through the kidneys, liver, and the like (see Example 1).
  • the stool, blood of a normal person matched age and sex to patients with gastric cancer, colorectal cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, Parkinson's disease, and dementia Bacterial metagenome analysis was performed using vesicles isolated from or urine. As a result, compared to normal samples, vesicles derived from Acinetobacter bacteria were more significant in samples of patients with gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, Parkinson's disease, and dementia. It was confirmed that it is reduced (see Examples 3 to 13).
  • the culture of the Acinetobacter Baumani culture was evaluated to evaluate whether the vesicles secreted therefrom exhibit an anticancer therapeutic effect.
  • a cancer model was made by subcutaneously injecting a cancer cell line, and the size of the cancer tissue was measured for 20 days after oral or intraperitoneal administration of the acinetobacter Baumani-derived vesicles to the mouse 4 days before the cancer cell line treatment. When the vesicles were administered orally, the size of the cancerous tissue was reduced compared to the control group (see Example 16).
  • the intestinal bacteria and enteric bacteria-derived vesicles were absorbed systemically, in order to evaluate the invasion of various organs, 50 ⁇ g of fluorescently labeled bacteria and vesicles derived from the fluorescein were administered as described above for 12 hours. Blood, heart, liver, kidneys, spleen, fat and muscle were collected later. As a result of fluorescence observation in the collected tissue, as shown in FIG. 1B, the vesicle-derived bacteria were distributed in blood, heart, lung, liver, kidney, spleen, fat, muscle and kidney, but bacteria were not absorbed. (See FIG. 1B).
  • DNA extracted by the above method was amplified using the above 16S rDNA primers, followed by sequencing (Illumina MiSeq sequencer), and the results were outputted in a Standard Flowgram Format (SFF) file, using GS FLX software (v2.9).
  • SFF Standard Flowgram Format
  • GS FLX Standard Flowgram Format
  • OTU operational taxonomy unit
  • clustering is performed according to sequence similarity using UCLUST and USEARCH, genus 94%, family 90%, order 85%, class 80%, phylum 75% sequence similarity
  • Clustering is based on the phylum, class, order, family, and genus levels of each OTU, and BLASTN and GreenGenes' 16S RNA sequence database (108,453 sequences) is used to identify bacteria with greater than 97% sequence similarity at the genus level.
  • Was profiled QIIME).
  • Example 2 the genes were extracted from the vesicles in the stool and 67 feces of gastric cancer patients and 198 normal controls matched with sex and age were subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicles of the genus Acinetobacter were significantly reduced in the stool of gastric cancer patients compared to the normal stool (see Table 2 and FIG. 2).
  • Example 2 In the method of Example 2, the urine of 61 patients with gastric cancer and the urine of 120 normal controls matched with sex and age were extracted from the vesicles present in the urine, followed by metagenome analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in the urine of gastric cancer patients compared to normal urine (see Table 3 and FIG. 2).
  • Example 2 In the method of Example 2, the urine of 52 colon cancer patients and the urine of 83 normal controls matched with sex and age were extracted from the vesicles present in the urine, followed by metagenome analysis. The distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in the urine of colorectal cancer patients compared to normal urine (see Table 4 and FIG. 3).
  • Example 2 the genes were extracted from vesicles in the blood of 96 breast cancer patients and 192 blood of the normal control group matched with sex and age, followed by metagenome analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in the blood of breast cancer patients compared to normal blood (see Table 5 and FIG. 4).
  • Example 2 the genes were extracted from vesicles in urine of 127 breast cancer patients and 220 urine control groups matched with sex and age, and then subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in the urine of breast cancer patients compared to normal urine (see Table 6 and FIG. 4).
  • Example 2 136 urine patients with ovarian cancer and 136 urine in the normal control group matched with sex and age were extracted from the vesicles present in the urine, followed by metagenome analysis. The distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the bacterial vesicles of the genus Acinetobacter were significantly reduced in the urine of ovarian cancer patients compared to normal urine (see Table 7 and FIG. 5).
  • the urine of 95 patients with bladder cancer and the urine of 157 normal controls matched with sex and age were extracted from the vesicles present in the urine, followed by metagenome analysis.
  • the distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in the urine of bladder cancer patients compared to normal urine (see Table 8 and FIG. 6).
  • the blood of 57 patients with myocardial infarction and the blood of 163 normal controls matched with sex and age were extracted from the vesicles present in the blood and subjected to metagenome analysis, followed by acinetobacter.
  • the distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the vesicles derived from Acinetobacter bacteria were significantly reduced in the blood of myocardial infarction patients compared to normal blood (see Table 9 and FIG. 7).
  • Example 2 In the method of Example 2, the blood of 72 patients with cardiomyopathy and the blood of 163 normal controls matched with sex and age were extracted from the vesicles present in the blood, followed by metagenome analysis, followed by acinetobacter. The distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter was significantly reduced in the blood of cardiomyopathy patients compared to normal blood (see Table 10 and FIG. 8).
  • Example 2 blood was extracted from vesicles in the blood of 61 diabetic patients and 122 blood of the normal control group which matched gender and age. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in the blood of diabetic patients compared to normal blood (see Table 11 and FIG. 9).
  • the urine of 60 diabetic patients and the urine of 134 normal controls matched with gender and age were extracted by the method of Example 2, and the genes were extracted from the vesicles present in the urine, followed by metagenome analysis.
  • the distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in urine of diabetic patients compared to normal urine (see Table 12 and FIG. 9).
  • Example 2 the genes were extracted from the vesicles in the blood of 115 stroke patients and 109 blood of the normal control group matched with sex and age, followed by metagenome analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in the blood of stroke patients compared to normal blood (see Table 13 and FIG. 10).
  • the urine of 39 Parkinson's disease patients and urine of 76 normal controls matched to gender and age was extracted by extracting genes from vesicles present in urine, followed by metagenome analysis. Distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in the urine of Parkinson's disease patients compared to normal urine (see Table 14 and FIG. 11).
  • Example 2 blood was collected from 67 blood of dementia patients and 70 blood of the normal control group which matched gender and age, and the genes were extracted from the vesicles present in the blood, followed by metagenome analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of the genus Acinetobacter were significantly reduced in the blood of dementia patients compared to normal blood (see Table 15 and FIG. 12).
  • the Acinetobacter Baumani strain was cultured in NB (Nutrient broth) medium until the absorbance (OD 600) was 1.0-1.5 in an aerobic chamber at 37 ° C. and then sub-cultured to LB (Luria Bertani broth) medium. Then, the culture medium supernatant containing the strain was recovered and centrifuged at 10,000 g, 4 ° C. for 20 minutes, and then the strain was removed and filtered through a 0.22 ⁇ m filter.
  • the filtered supernatant was concentrated to 50 ml volume by microfiltration using a MasterFlex pumpsystem (Cole-Parmer, US) with a 100 kDa Pellicon 2 Cassette filter membrane (Merck Millipore, US). The concentrated supernatant was once again filtered through a 0.22 ⁇ m filter. Thereafter, the protein was quantified by BCA assay, and the following experiments were performed on the obtained vesicles.
  • A. baumannii EVs ( A. baumannii EV) were collected in raw 264.7 cells of mouse macrophage. 10 ⁇ g / ml), followed by Cell viability test. More specifically, the raw 264.7 cells divided into 4 x 10 4 cells in 48-well cell culture plates were treated with various concentrations of Acinetobacter Baumani-derived vesicles loaded with DMEM serum-free medium and cultured for 12 hours. After the cells were treated with EZ-CYTOX (Dogen, Korea) for 4 hours, the absorbance was measured at 450 nm using a SpectraMax M3 microplate reader (Molecular Devies, USA).
  • PBST PBS containing 0.05% tween-20
  • RD PBS containing 1% BSA
  • Samples and standards were dispensed 50 ⁇ l according to the concentration and reacted at room temperature for 2 hours.
  • the detection antibody was diluted in RD, and 50 ⁇ l was dispensed at a working concentration for 2 hours at room temperature.
  • vesicles derived from the Acinetobacter Baumani strain were administered intraperitoneally or orally to 6-week-old C57BL / 6 male mice, and injected subcutaneously with a cancer cell line (CT26 cell) on day 4 of administration.
  • CCT26 cell cancer cell line
  • a cancer model was created. After administration of the cancer cell line, vesicles derived from the Acinetobacter Baumani isolate were administered daily by intraperitoneal injection or orally, and the size of the cancer tissue was measured until the 24th day (see FIG. 15).
  • the size of the cancer tissue was significantly decreased in the mouse orally administered vesicles compared to the control group oral saline administration group, and the size of the cancer tissue was increased intraperitoneally (Fig. 16 and FIG. 17). This means that administration of acinetobacter Baumani-derived vesicles to the mucosa can effectively inhibit the growth of cancerous tissues.
  • the vesicles derived from the genus Acinetobacter according to the present invention are gastric cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, myocardial infarction, cardiomyopathy, stroke, diabetes, dementia, or a method for diagnosing Parkinson's disease, and the disease or inflammatory disease. It is expected that the present invention can be usefully used in the composition for preventing, treating or improving food or drugs.

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Abstract

La présente invention concerne des vésicules issues de bactéries Acinetobacter et une utilisation associée. Les présents inventeurs ont confirmé expérimentalement que les vésicules sont significativement réduites dans des échantillons cliniques dérivés de patients atteints de maladies malignes telles que le cancer gastrique, le cancer colorectal, le cancer du sein, le cancer de l'ovaire et le cancer de la vessie, des maladies cardiovasculaires telles que l'infarctus du myocarde, la cardiomyopathie et l'accident vasculaire cérébral, le diabète sucré, la démence et la maladie de Parkinson par rapport à celle d'une personne normale, et que les vésicules inhibent significativement la sécrétion d'un médiateur inflammatoire par les vésicules pathogènes. Les présents inventeurs ont confirmé que les vésicules ont un effet anticancéreux dans un modèle de cancer de souris. Par conséquent, des vésicules issues de bactéries Acinetobacter selon la présente invention peuvent être efficacement utilisées pour développer un procédé de diagnostic pour des maladies malignes telles que le cancer gastrique, le cancer colorectal, le cancer du sein, le cancer de l'ovaire et le cancer de la vessie, des maladies cardiovasculaires telles que l'infarctus du myocarde, la cardiomyopathie et l'accident vasculaire cérébral, le diabète sucré, la démence et la maladie de Parkinson, et pour développer une composition destinée à prévenir ou traiter les maladies susmentionnées ou des maladies inflammatoires.
PCT/KR2019/002343 2018-02-28 2019-02-27 Nanovésicules issues de bactéries acinetobacter et utilisation associée Ceased WO2019168329A1 (fr)

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KR20160073157A (ko) * 2014-12-16 2016-06-24 이화여자대학교 산학협력단 세균 유래의 나노소포체를 이용한 세균성 감염질환 원인균 동정방법
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KR101632896B1 (ko) * 2015-07-29 2016-06-23 한국생명공학연구원 Lps가 결여된 아시네토박터 바우마니 유래 외막소포체를 포함하는 항암용 조성물
KR20180006303A (ko) * 2016-07-08 2018-01-17 주식회사 엠디헬스케어 프로피오니박테리움 속 세균 유래 나노소포 및 이의 용도
KR20180018354A (ko) * 2016-08-12 2018-02-21 주식회사 엠디헬스케어 바실러스 속 세균 유래 나노소포 및 이의 용도

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