WO2022145710A1 - 마이크로코커스 루테우스 유래 세포외 소포를 포함하는 신경발달 질환, 신경질환, 또는 정신질환 예방 또는 치료용 조성물 - Google Patents
마이크로코커스 루테우스 유래 세포외 소포를 포함하는 신경발달 질환, 신경질환, 또는 정신질환 예방 또는 치료용 조성물 Download PDFInfo
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- micrococcus luteus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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- 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
Definitions
- the present invention relates to an extracellular vesicle derived from Micrococcus luteus and its use, and more particularly, to a neurodevelopmental disease, neurological disease, or mental disease prevention or It relates to a composition for treatment and the like.
- neurologic diseases including cognitive dysfunction such as Alzheimer's disease, and motor dysfunction such as Parkinson's disease and Lou Gehrig's disease; neurodevelopmental disorders such as autism, attention deficit hyperactivity disorder, and the like; Psychiatric diseases such as anxiety disorders, depression, and schizophrenia are major diseases that determine the quality of human life and are a major problem in public health.
- nerve cells causes abnormalities in the structure and function of brain-nerve tissue by abnormal death of nerve cells.
- Neurological diseases such as chronic inflammatory demyelinating polyneuropathy and diabetic neuropathy, occur as a result of neuronal degeneration or neuroinflammation.
- Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), MERRF syndrome ( Neurological diseases such as myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), Leigh syndrome (LS), and mitochondrial recessive ataxia syndrome (MIRAS syndrome) also caused by degenerative changes in
- Energy metabolism is the process of creating various substances by making energy necessary to perform cell functions. Proteins and lipids are produced in the endoplasmic reticulum (ER) through ATP made in mitochondria and supplied to necessary areas. Cells face various stresses from the moment they are created, and biological, chemical, physical, or mental stress induces endoplasmic reticulum (ER) stress, mitochondrial dysfunction, lysosomal damage, etc. abnormal substances are made in the cell, and the cells recognize this as a risk factor (danger signal) and induce an inflammatory response.
- ER endoplasmic reticulum
- ER endoplasmic reticulum
- mitochondrial dysfunction mitochondrial dysfunction
- lysosomal damage etc.
- abnormal substances are made in the cell, and the cells recognize this as a risk factor (danger signal) and induce an inflammatory response.
- Immunity is a defense mechanism of cells against biological, chemical, physical, and mental stress, and occurs through innate immunity and adaptive immunity. Recently, in relation to the pathogenesis of inflammatory diseases caused by immune dysfunction, a risk factor (danger signal) resulting from intracellular oxidative stress has been detected in the cytoplasmic pattern recognition receptor (PRR), Nucleotide-binding oligomerization domain (NLRP). It is known that NLRP3 protein forms an inflammasome and causes an inflammatory response and abnormal apoptosis. In particular, inflammation caused by activation of the NLRP3 inflammasome has become known as a key etiological mechanism of several neurodevelopmental diseases, neurological diseases, and psychiatric diseases.
- PRR cytoplasmic pattern recognition receptor
- NLRP3 protein forms an inflammasome and causes an inflammatory response and abnormal apoptosis.
- inflammation caused by activation of the NLRP3 inflammasome has become known as a key etiological mechanism of several neurodevelopmental diseases
- Microbiota or microbiome refers to a microbial community, including bacteria, archaea, and eukaryotes, present in a given habitat.
- Bacterial-derived vesicles secreted locally are absorbed through epithelial cells of the mucous membrane to induce a local inflammatory response, and vesicles that have passed through epithelial cells are systemically absorbed through lymphatic vessels and distributed to each organ. Regulates immune and inflammatory responses.
- vesicles derived from pathogenic Gram-negative bacteria such as Escherichia coli cause local colitis as pathogenic nanoparticles. It promotes inflammatory response and blood clotting, and is absorbed into muscle cells where insulin works, leading to insulin resistance and diabetes.
- vesicles derived from beneficial bacteria can control diseases by regulating abnormalities in immune and metabolic functions caused by pathogenic vesicles.
- Micrococcus luteus is a gram-positive bacterium belonging to the genus Micrococcus, and is a bacterium widely distributed in nature such as water, dust, soil, and the like. This bacterium is known to produce riboflavin when grown in toxic organic pollutants such as pyridine and to absorb ultraviolet light through lutein pigment. In addition, this fungus is isolated from dairy products and beer, grows in a dry environment or high salt environment, does not form spores, but is known to survive for a long time even at a refrigeration temperature such as a refrigerator.
- the present inventors significantly inhibited the secretion of inflammatory mediators by pathogenic factors and abnormal immune function caused by pathogenic factors when micrococcus luteus-derived vesicles were treated in cells. It was confirmed that micrococcus luteus-derived vesicles were effectively inhibited. In addition, it was confirmed that Micrococcus luteus-derived vesicles regulate immune function by suppressing the secretion of inflammatory mediators through NLRP3 protein expression and NLRP3 inflammasome formation, which are related to the pathogenesis of various diseases.
- the vesicles increase cellular homeostasis by activating eNOS (endothelial NO synthase), which is an important signal for cellular homeostasis.
- eNOS endothelial NO synthase
- the vesicles were treated in a mouse model of brain disease causing cognitive dysfunction by excessively inducing apoptosis of nerve cells, not only behavioral disorders related to cognitive functions but also abnormal protein deposition was inhibited.
- Micrococcus luteus-derived vesicles increase proliferation and differentiation of neural stem cells, and inter-neuronal intergrity, and thus have therapeutic effects on neurodevelopmental diseases, neurological diseases or mental disorders.
- BDNF brain-derived neurotrophic factor
- an object of the present invention is to provide a pharmaceutical composition for preventing or treating a neurodevelopmental disease, a neurological disease, or a mental disease, comprising vesicles derived from Micrococcus luteus as an active ingredient.
- the present invention is Micrococcus luteus ( Micrococcus luteus ) It is an object of the present invention to provide a food composition for preventing or improving neurodevelopmental disease, neurological disease, or mental disease, comprising vesicles derived from it as an active ingredient.
- Another object of the present invention is to provide an inhalant composition for preventing or treating a neurodevelopmental disease, a neurological disease, or a mental disease, comprising vesicles derived from Micrococcus luteus as an active ingredient.
- an object of the present invention is to provide a composition for drug delivery comprising vesicles derived from Micrococcus luteus as an active ingredient, for treatment of neurodevelopmental diseases, neurological diseases, or psychiatric diseases.
- an object of the present invention is to provide a pharmaceutical composition for anti-aging, comprising vesicles derived from Micrococcus luteus as an active ingredient.
- an object of the present invention is to provide a food composition for anti-aging, comprising a vesicle derived from Micrococcus luteus as an active ingredient.
- an object of the present invention is to provide a pharmaceutical composition for preventing or treating a neurodevelopmental disease, a neurological disease, or a mental disease, comprising a vesicle derived from bacteria of the genus Micrococcus as an active ingredient.
- the present invention provides a pharmaceutical composition for preventing or treating a neurodevelopmental disease, a neurological disease, or a psychiatric disease, comprising a micrococcus luteus -derived vesicle as an active ingredient provides
- the present invention provides a food composition for preventing or improving neurodevelopmental diseases, neurological diseases, or mental diseases, comprising vesicles derived from Micrococcus luteus as an active ingredient.
- the present invention provides an inhalant composition for preventing or treating neurodevelopmental diseases, neurological diseases, or mental diseases, comprising vesicles derived from Micrococcus luteus as an active ingredient.
- the present invention provides a composition for drug delivery comprising a vesicle derived from Micrococcus luteus as an active ingredient, for the treatment of neurodevelopmental diseases, neurological diseases, or mental disorders.
- the present invention provides a pharmaceutical composition for anti-aging, comprising a vesicle derived from Micrococcus luteus as an active ingredient.
- the present invention provides a food composition for anti-aging, comprising micrococcus luteus -derived vesicles as an active ingredient.
- the present invention provides a pharmaceutical composition for preventing or treating a neurodevelopmental disease, a neurological disease, or a psychiatric disease, comprising vesicles derived from bacteria of the genus Micrococcus as an active ingredient.
- the neurological disease may be a neurodegenerative disease or an inflammatory neurological disease, but is not limited thereto.
- the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotropic lateral sclerosis, Huntington's disease, epilepsy, Kearns -Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), MERRF syndrome (myoclonic epilepsy with It may be one or more diseases selected from the group consisting of ragged-red fibers; MERRF), NARP syndrome (neurogenic weakness with ataxia and retinitis pigmentosa; NARP), Leigh syndrome (LS), and MIRAS syndrome (mitochondrial recessive ataxia syndrome)
- the present invention is not limited thereto.
- the inflammatory neurological disease is one selected from the group consisting of multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, and diabetic neuropathy. It may be the above disease, but is not limited thereto.
- the mental disorder is major depressive disorder, bipolar disorder, anxiety disorder, schizophrenia, obsessive compulsive disorder, trauma
- At least one disease selected from the group consisting of post-traumatic stress disorder, dissociative disorder, eating disorder, substance use disorder, and personality disorder can, but is not limited thereto.
- the anxiety disorder is selected from the group consisting of panic disorder, social anxiety disorder, generalized anxiety disorder, and specific phobia. It may be one or more anxiety disorders, but is not limited thereto.
- the personality disorder is paranoid personality disorder, antisocial personality disorder, borderline personality disorder, narcissistic personality disorder , avoidant personality disorder, and one or more personality disorders selected from the group consisting of dependent personality disorder, but is not limited thereto.
- the neurodevelopmental disease is intellectual disability, communication disorder, autism spectrum disorder, attention deficit hyperactivity disorder (attention deficit hyperactivity disorder) , a specific learning disorder, and may be at least one selected from the group consisting of motor disorder, but is not limited thereto.
- the neurodevelopmental disease, neurological disease, or mental disease may be due to a neurogenesis dysfunction, but is not limited thereto.
- the neurodevelopmental disease, neurological disease, or mental disease may be mediated by NLRP3 inflammasome (NLR family pyrin domain containing 3 inflammasome), but is not limited thereto.
- NLRP3 inflammasome NLR family pyrin domain containing 3 inflammasome
- the composition may inhibit NLRP3 inflammasome formation, but is not limited thereto.
- the vesicle may have an average diameter of 10 to 200 nm, but is not limited thereto.
- the vesicle may be naturally secreted or artificially produced in Micrococcus luteus , but is not limited thereto.
- the composition may inhibit the aging of the brain or nerve cells, but is not limited thereto.
- the present invention includes the step of administering a composition comprising a vesicle derived from Micrococcus luteus as an active ingredient to an individual in need thereof, neurodevelopmental disease, neurological disease, or prevention or treatment of mental disease provide a way
- the present invention provides the use of a composition comprising vesicles derived from Micrococcus luteus as an active ingredient for preventing or treating neurodevelopmental disease, neurological disease, or mental disease.
- the present invention provides the use of micrococcus luteus -derived vesicles for the manufacture of a medicament for the treatment of neurodevelopmental diseases, neurological diseases, or mental diseases.
- the present invention comprises the steps of administering a composition comprising a vesicle derived from Micrococcus luteus carrying a desired neurodevelopmental disease, neurological disease, or psychiatric treatment drug as an active ingredient to an individual in need thereof. It provides a drug delivery method for treating a neurodevelopmental disease, a neurological disease, or a psychiatric disease, comprising:
- the present invention provides a drug delivery use of a composition comprising vesicles derived from Micrococcus luteus as an active ingredient for treating neurodevelopmental diseases, neurological diseases, or mental disorders.
- the present inventors confirmed that when micrococcus luteus-derived vesicles were orally administered, vesicles were absorbed into blood vessels and distributed in brain tissue.
- vesicles were treated with epithelial cells and inflammatory cells, secretion of inflammatory mediators caused by pathogenic factors was significantly inhibited, and when the cells were treated with the vesicles, NLRP3 protein expression and NF-kB ( p65) signal was confirmed to be inhibited.
- NF-kB p65
- BDNF gene expression suppressed by pathogenic factors was restored.
- sirtuin 1 and sirtuin 7 genes, which are suppressed by pathogenic factors were restored when the vesicles were treated in neurons.
- cognitive function was significantly restored.
- the vesicles were administered to the neurological disease mouse model, it was confirmed that the neurogenesis was significantly restored.
- the vesicles derived from Micrococcus luteus according to the present invention are Alzheimer's disease and Parkinson's disease.
- amyotropic lateral sclerosis Huntington's disease, epilepsy, multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, diabetic neuropathy neuropathy, autism spectrum disorder, attention deficit hyperactivity syndrome, major depressive disorder, bipolar disorder, anxiety disorder, schizophrenia ), obsessive compulsive disorder, post-traumatic stress disorder, dissociative disorder, eating disorder, substance use disorder, and personality disorder disorder
- 1 is a view showing the results of measuring the fluorescence intensity in each organ by extracting each organ for each time after oral administration of micrococcus luteus-derived vesicles to mice.
- FIG. 2 is a view showing the distribution of vesicles in brain tissue over time after oral administration of vesicles derived from Micrococcus luteus to mice.
- MDH-101 EV micrococcus luteus-derived vesicle
- Dex positive control drug dexamethasone
- FIG. 4A and 4B show the dose dependence of Micrococcus luteus-derived vesicles on the inhibition of IL-8 secretion by E. coli-derived vesicles by administration of Micrococcus luteus-derived vesicles (MDH-101) to epithelial cells.
- (a) is a diagram showing the experimental results
- E. coli-derived vesicles E. coli EV
- M. luteus EV Micrococcus luteus-derived vesicles
- E. coli EV E. coli-derived vesicles
- M. luteus EV Micrococcus luteus-derived vesicles
- FIG. 7 is a view showing the immune function-regulating proteins NLRP3, T-bet from tissues isolated from mice administered with lipopolysaccharide (LPS), an inflammatory causative factor, in order to evaluate the effect of modulating immune function by Micrococcus luteus-derived vesicles (MlEV). , A diagram showing the results of confirming the ROR- ⁇ t expression pattern.
- LPS lipopolysaccharide
- MlEV Micrococcus luteus-derived vesicles
- FIG. 8 is a view showing the results of confirming the effect of inhibiting the secretion of IL-1 ⁇ , an inflammatory mediator, by LPS by administering Micrococcus luteus-derived vesicles (M. luteus EV) to macrophages.
- M. luteus EV Micrococcus luteus-derived vesicles
- FIG. 9 is a view showing the innate immunity-related signals JNK and NF-kB (p65) in tissues isolated from mice administered with LPS, an inflammatory causative factor, in order to evaluate the effect of modulating the innate immune function by Micrococcus luteus-derived vesicles (MlEV). ) is a diagram showing the results of evaluating the degree of activation.
- MlEV micrococcus luteus-derived vesicles
- MDH-101 micrococcus luteus-derived vesicle
- Dexamethasone a positive control drug dexamethasone
- MDH-101 micrococcus luteus-derived vesicle
- a ⁇ amyloid protein
- MDH-101 micrococcus luteus-derived vesicle in cells to evaluate the effect of the micrococcus luteus-derived vesicle (MDH-101) on the expression of important neurotrophin and receptor-related genes in neurogenesis. It is a diagram showing the results of evaluating the effect of administering amyloid-beta protein (A ⁇ ), a causative factor, on the expression of neurotrophin and receptor genes, which are inhibited by A ⁇ .
- a ⁇ amyloid-beta protein
- FIG. 14 is a diagram showing an experimental protocol for evaluating the therapeutic efficacy of micrococcus luteus-derived vesicles (MDH-101) in a mouse model of brain disease (Tg-APP/PS1 mice) administered orally (WT+veh) : normal mouse group, Tg+veh: brain disease mouse group, Tg+MDH-101: mouse group in which Micrococcus luteus-derived vesicles (MDH-101) were orally administered to a brain disease mouse model, the same hereinafter).
- MDH-101 Micrococcus luteus-derived vesicles
- FIG. 16 is a water maze test for evaluating the therapeutic efficacy of Micrococcus luteus-derived vesicles (MDH-101) on learning ability in a Tg-APP/PS1 brain disease mouse model.
- MDH-101 Micrococcus luteus-derived vesicles
- FIG. 16 is a water maze test for evaluating the therapeutic efficacy of Micrococcus luteus-derived vesicles (MDH-101) on learning ability in a Tg-APP/PS1 brain disease mouse model.
- MDH-101 Micrococcus luteus-derived vesicles
- FIG. 17 shows the results of evaluating the therapeutic efficacy of Micrococcus luteus-derived vesicles (MDH-101) on the improvement of memory ability in a Tg-APP/PS1 brain disease mouse model by a passive avoidance test
- MDH-101 Micrococcus luteus-derived vesicles
- a ⁇ plaque fluorescence staining images and quantitative data in the parietal cortex, hippocampus, and Piriform cortex regions of the Tg-APP/PS1 brain disease mouse model pictures of A ⁇ plaque staining in the parietal lobe, hippocampus, and gourd cortex of the Tg+veh group (TG) and Tg+MDH-101 group (a), the number of A ⁇ plaques per unit area (b), and A ⁇ per unit area It is a figure which shows the area (C) of a plaque.
- a ⁇ plaque fluorescence staining images and quantitative data in the parietal cortex, hippocampus, and Piriform cortex regions of the Tg-APP/PS1 brain disease mouse model pictures of A ⁇ plaque staining in the parietal lobe, hippocampus, and gourd cortex of the Tg+veh group (TG) and Tg+MDH-101 group (a), the number of A ⁇ plaques per unit area (b), and A ⁇ per unit area It is a figure
- FIG. 19 is a marker of early neurogenesis in the brain showing the therapeutic efficacy of Micrococcus luteus-derived vesicles (MDH-101) on the proliferation of neural stem cells in the hippocampus of the Tg-APP/PS1 brain disease mouse model.
- the Ki-76 expression of phosphorus is shown through staining.
- the left side is a diagram showing the Ki-67 staining result, and the right side shows the Tg+veh group and Tg+MDH-101 group compared to the normal mouse group (WT+veh). It is a diagram showing the number of cells stained for Ki-67 in percentage (WT CON: normal mouse group, TG CON: brain disease mouse group, the same hereinafter).
- MDH-101 Micrococcus luteus-derived vesicles
- Tg-APP/PS1 brain disease mouse model related to the differentiation and migration of neural stem cells.
- the results of evaluation through staining of the marker doublecortin (DCX) are shown.
- the left side is a diagram showing the DCX staining results, and the right side is a diagram showing the average number of cells stained with DCX.
- Figure 21 shows the therapeutic efficacy of Micrococcus luteus-derived vesicles (MDH-101) on the formation of dendrites of neurons in the hippocampus of the Tg-APP/PS1 brain disease mouse model.
- MDH-101 Micrococcus luteus-derived vesicles
- the present invention relates to vesicles derived from Micrococcus luteus and uses thereof.
- the present inventors confirmed that when micrococcus luteus-derived vesicles were orally administered to mice, the vesicles were systemically absorbed and distributed in brain tissue (see Example 2).
- the present invention provides a pharmaceutical composition for preventing or treating a neurodevelopmental disease, a neurological disease, or a psychiatric disease comprising Micrococcus luteus-derived vesicles as an active ingredient.
- the present invention may provide a pharmaceutical composition for anti-aging, comprising a vesicle derived from Micrococcus luteus as an active ingredient.
- extracellular vesicle refers to a structure made of a nano-sized membrane secreted by various bacteria, for example, endotoxin (lipopolysaccharide) , vesicles or outer membrane vesicles (OMVs) from gram-negative bacteria such as Escherichia coli, which also contain toxic proteins and bacterial DNA and RNA, and peptidoglycan ( There are vesicles derived from gram-positive bacteria such as micrococcus bacteria that also contain peptidoglycan and lipoteichoic acid.
- endotoxin lipopolysaccharide
- OMVs outer membrane vesicles
- gram-negative bacteria such as Escherichia coli
- peptidoglycan There are vesicles derived from gram-positive bacteria such as micrococcus bacteria that also contain peptidoglycan and lipoteichoic acid.
- the extracellular vesicles or vesicles may collectively refer to all membrane structures naturally secreted or artificially produced in Micrococcus luteus , and in the present invention, MDH-101, MDH It can be variously expressed as -101 EV, M. luteus EV, or MlEV.
- the vesicles are heat-treated or high-pressure treated in the Micrococcus luteus culture process, or the bacterial culture medium is centrifuged, ultra-high-speed centrifugation, high-pressure treatment, extrusion, sonication, cell lysis, homogenization, freeze-thaw, electroporation, mechanical degradation,
- the separation may be performed using one or more methods selected from the group consisting of chemical treatment, filtration by a filter, gel filtration chromatography, pre-flow electrophoresis, and capillary electrophoresis. In addition, it may further include processes such as washing for removal of impurities, concentration of the obtained vesicles, and the like.
- the vesicles separated by the method have a spherical shape, and have an average diameter of 10-200 nm, 10-190 nm, 10-180 nm, 10-170 nm, 10-160 nm, 10-150 nm, 10 to 140 nm, 10-130 nm, 10-120 nm, 10-110 nm, 10-100 nm, 10-90 nm, 10-80 nm, 10-70 nm, 10-60 nm, 10-50 nm, 20 to 200 nm, 20 to 180 nm, 20 to 160 nm, 20 to 140 nm, 20 to 120 nm, 20 to 100 nm, or 20 to 80 nm, preferably, 20 to 200 nm, It is not limited thereto.
- the term “comprising as an active ingredient” means including an amount sufficient to achieve efficacy or activity of the Micrococcus luteus-derived vesicle.
- neurodevelopmental disorders refers to all developmental disorders that appear related to developmental delay or damage of the central nervous system, including the brain. It is known as a disease caused by a developmental disability, for example, intellectual disability, communication disorder, autism spectrum disorder, attention deficit hyperactivity disorder. ), specific learning disorder, and motor disorder.
- neurologic diseases refers to diseases caused by abnormalities in the nervous system, that is, the brain, spinal cord, nerves, etc.
- the neurologic disease is a degenerative neurological disease or inflammatory It may be a neurological disease, and may be included without limitation if it is a disease or condition caused by damage to nerve cells.
- the term “degenerative neurological disease” refers to a disease occurring in the brain among degenerative diseases that occur with aging, for example, Alzheimer's disease, Parkinson's disease. , amyotropic lateral sclerosis, Huntington's disease, epilepsy, Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), Melas syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MELAS), MERRF syndrome (myoclonic epilepsy with ragged-red fibers; MERRF), NARP syndrome (neurogenic weakness with ataxia and retinitis pigmentosa; NARP), Leigh syndrome syndrome (LS), and mitochondrial recessive ataxia syndrome (MIRAS).
- inflammatory neurological disease refers to a disease that occurs under the influence of neuroinflammation occurring in the central nervous system, for example, multiple sclerosis, chronic inflammatory demyelinating polyneuropathy ( chronic inflammatory demyelinating polyneuropathy, and diabetic neuropathy.
- Psychiatric Diseases refers to a pathological mental state that affects a person’s thoughts, emotions, and behavior, and refers to a state in which mental function is impaired, for example, For example, major depressive disorder, bipolar disorder, anxiety disorder, schizophrenia, obsessive compulsive disorder, post-traumatic stress disorder , dissociative disorder, eating disorder, substance use disorder, and personality disorder.
- anxiety disorder refers to a mental disorder in which a person feels anxious for no reason or the degree of anxiety is excessive, for example, panic disorder, social anxiety disorder. anxiety disorder), generalized anxiety disorder, and specific phobia.
- personality disorder used in the present invention refers to pathological emotions, thoughts and behaviors of an individual that gradually develop from childhood and solidify in adolescence or early adulthood, for example, paranoid Paranoid personality disorder, antisocial personality disorder, borderline personality disorder, narcissistic personality disorder, avoidant personality disorder, and dependent personality disorder (dependent personality disorder), etc. may be included.
- the neurodevelopmental disease, neurological disease, or mental disease may be a disease caused by a neurogenesis dysfunction, and more specifically, caused by a mitochondrial dysfunction caused by various stresses or NLRP3 inflammasome It may be a disease due to a disorder of neurogenesis caused by neuronal damage mediated by , neuroinflammation and/or neurodegeneration.
- neuralgenesis refers to a process in which nerve cells are generated from neural stem cells, and may include adult neurogenesis.
- the term “mediated by NLRP3 inflammasome (NLR family pyrin domain containing 3 inflammasome)” means that the excessively formed NLRP3 inflammasome induces a neuroinflammatory response through various signal transduction pathways.
- the Micrococcus luteus-derived vesicle can inhibit the NLRP3 inflammasome formation by inhibiting the signal transduction pathway priming the NLRP3 inflammasome formation. It is possible to effectively prevent, improve, or treat a neurodevelopmental disease, neurological disease, or mental disease mediated by inflammasome (NLR family pyrin domain containing 3 inflammasome).
- anti-aging means to delay aging as much as possible by preventing and inhibiting aging. It can suppress the aging of the brain or nerve cells.
- the content of the vesicles in the composition of the present invention can be appropriately adjusted depending on the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9% by weight, or 0.001 to 50% by weight based on the total weight of the composition.
- the content ratio is a value based on the dry amount from which the solvent is removed.
- the pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions.
- the excipient may be, for example, at least one selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a humectant, a film-coating material, and a controlled-release additive.
- the pharmaceutical composition according to the present invention can be prepared according to a conventional method, respectively, in powders, granules, sustained-release granules, enteric granules, liquids, eye drops, elsilic, emulsions, suspensions, alcohols, troches, fragrances, and limonaade.
- tablets, sustained release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusates, Warnings, lotions, pasta, sprays, inhalants, patches, sterile injection solutions, or external preparations such as aerosols can be formulated and used, and the external preparations are creams, gels, patches, sprays, ointments, warning agents , lotion, liniment, pasta, or cataplasma.
- Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- formulation it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
- water diluted hydrochloric acid, diluted sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (Twinester), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, etc.
- water diluted hydrochloric acid, diluted sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (Twinester), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone,
- sucrose solution other sugars or sweeteners may be used, and if necessary, a fragrance, colorant, preservative, stabilizer, suspending agent, emulsifying agent, thickening agent, etc. may be used.
- Purified water may be used in the emulsion according to the present invention, and if necessary, an emulsifier, preservative, stabilizer, fragrance, etc. may be used.
- Suspending agents such as acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose, HPMC 1828, HPMC 2906, HPMC 2910 may be used in the suspending agent according to the present invention. and, if necessary, surfactants, preservatives, stabilizers, colorants, and fragrances may be used.
- Injectables according to the present invention include distilled water for injection, 0.9% sodium chloride injection, ring gel injection, dextrose injection, dextrose + sodium chloride injection, PEG (PEG), lactated ring gel injection, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; Solubilizing aids such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tweens, nijeongtinamide, hexamine, and dimethylacetamide; Weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, buffers such as albumin, pepton
- the suppository according to the present invention includes cacao fat, lanolin, witepsol, polyethylene glycol, glycerogelatin, methyl cellulose, carboxymethyl cellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, Lecithin, Lanet Wax, Glycerol Monostearate, Tween or Span, Imhausen, Monolene (Propylene Glycol Monostearate), Glycerin, Adeps Solidus, Butyrum Tego -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydroxote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hydro Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium, A, AS, B, C, D, E, I, T, Massa-MF, Masupol, Masupol-15, Neos
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc.
- excipients for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc.
- lubricants such as magnesium stearate and talc are also used.
- Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc.
- various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
- Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- composition according to the present invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and type of the patient's disease; Sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs and other factors well known in the medical field may be determined.
- the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention pertains.
- the pharmaceutical composition of the present invention may be administered to an individual by various routes. All modes of administration can be contemplated, for example, oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, rectal insertion, vaginal It can be administered according to internal insertion, ocular administration, ear administration, nasal administration, inhalation, spraying through the mouth or nose, skin administration, transdermal administration, and the like.
- the pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient along with several related factors such as the disease to be treated, the route of administration, the patient's age, sex, weight, and the severity of the disease.
- the effective amount of the composition according to the present invention may vary depending on the patient's age, sex, and weight, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight, is administered daily or every other day, or 1 It can be administered in divided doses 1 to 3 times a day.
- the dosage is not intended to limit the scope of the present invention in any way.
- the present invention includes the step of administering a composition comprising a vesicle derived from Micrococcus luteus as an active ingredient to an individual in need thereof, neurodevelopmental disease, neurological disease, or prevention or treatment of mental disease provide a way
- the present invention provides the use of a composition comprising vesicles derived from Micrococcus luteus as an active ingredient for preventing or treating neurodevelopmental disease, neurological disease, or mental disease.
- the present invention provides the use of micrococcus luteus -derived vesicles for the manufacture of a medicament for the treatment of neurodevelopmental diseases, neurological diseases, or mental diseases.
- “individual” means a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses, cattle, etc. It may be a mammal of, but is not limited thereto.
- administration means providing a predetermined composition of the present invention to an individual by any suitable method.
- prevention means any action that suppresses or delays the onset of a target disease
- treatment means that the target disease and its metabolic abnormalities are improved or It means all actions that are beneficially changed
- improvement means all actions that reduce the desired disease-related parameters, for example, the degree of symptoms by administration of the composition according to the present invention.
- the present invention provides a food composition for preventing or improving neurodevelopmental diseases, neurological diseases, or mental diseases, comprising vesicles derived from Micrococcus luteus as an active ingredient.
- the present invention can provide a food composition for anti-aging, comprising micrococcus luteus -derived vesicles as an active ingredient.
- the food composition may be a health functional food composition, but is not limited thereto.
- the vesicle of the present invention When the vesicle of the present invention is used as a food additive, it may be added as it is or may be used with other foods or food ingredients, and may be appropriately used according to a conventional method.
- the mixed amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment).
- the antifoam of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less based on the raw material.
- the amount may be less than 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.
- Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and includes all health functional foods in the ordinary sense.
- the health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, as in a conventional beverage.
- the above-mentioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
- natural sweeteners such as taumartin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like can be used.
- the proportion of the natural carbohydrate is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.
- the composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, Carbonating agents used in carbonated beverages, etc. may be contained.
- the composition of the present invention may contain the pulp for the production of natural fruit juice, fruit juice beverage, and vegetable beverage. These components may be used independently or in combination. The proportion of these additives is not critical, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.
- the present invention provides an inhalant composition for preventing or treating neurodevelopmental diseases, neurological diseases, or mental diseases, comprising vesicles derived from Micrococcus luteus as an active ingredient.
- inhalant compositions they may be formulated according to methods known in the art, using a suitable propellant, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- a suitable propellant for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- a suitable propellant for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- a suitable propellant for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- the present invention provides a composition for drug delivery comprising a vesicle derived from Micrococcus luteus as an active ingredient, for the treatment of neurodevelopmental diseases, neurological diseases, or mental disorders.
- drug delivery refers to the delivery of drugs such as proteins, antibodies, high molecular compounds, low molecular weight compounds, siRNA, and oligonucleotides to the vesicle according to the present invention in order to deliver the drug to a specific organ, tissue, cell or organelle. It means any means or action to load and deliver.
- the composition for drug delivery can deliver a drug to one or more organs selected from the group consisting of stomach, small intestine, large intestine, lung, liver, kidney, and brain, and preferably can deliver the drug to the brain, not limited
- the present invention comprises the steps of administering a composition comprising a vesicle derived from Micrococcus luteus carrying a desired neurodevelopmental disease, neurological disease, or psychiatric treatment drug as an active ingredient to an individual in need thereof. It provides a drug delivery method for treating a neurodevelopmental disease, a neurological disease, or a psychiatric disease, comprising:
- the present invention provides a drug delivery use of a composition comprising vesicles derived from Micrococcus luteus as an active ingredient for the treatment of neurodevelopmental diseases, neurological diseases, or mental disorders.
- the present invention provides a pharmaceutical composition for preventing or treating a neurodevelopmental disease, a neurological disease, or a psychiatric disease, comprising vesicles derived from bacteria of the genus Micrococcus as an active ingredient.
- Micrococcus luteus After culturing the Micrococcus luteus strain, its vesicles were isolated and characterized. Micrococcus luteus was sub-cultured in MRS (de Man-Rogosa and Sharpe) medium until the absorbance (OD 600) became 1.0 to 1.5 in an aerobic chamber at 37°C. Thereafter, the medium supernatant containing the strain was recovered, centrifuged at 10,000 g, 4° C. for 20 minutes, the strain was removed, and filtered through a 0.22 ⁇ m filter.
- MRS de Man-Rogosa and Sharpe
- the filtered supernatant was concentrated to a volume of 50 ml through microfiltration using a MasterFlex pump system (Cole-Parmer, US) with a 100 kDa Pellicon 2 Cassette filter membrane (Merck Millipore, US). Then, the concentrated supernatant was filtered again with a 0.22 ⁇ m filter. Thereafter, the protein was quantified using the BCA assay, and the following experiments were performed on the obtained vesicles.
- Example 2 Pharmacokinetic properties of vesicles derived from Micrococcus luteus
- Micrococcus luteus-derived vesicles stained with a fluorescent dye were orally administered to mice, and the fluorescence expressed in each organ was measured for 48 hours.
- FIG. 1 when the organ distribution over time of vesicles derived from Micrococcus luteus stained with an image was evaluated, it was confirmed that the vesicles were distributed in various organs. In addition, as shown in FIG. 2, the vesicles were distributed in the brain tissue within 1 hour after oral administration, and it was confirmed that the vesicles were continuously distributed in the brain tissue until 24 hours.
- Example 3 Anti-inflammatory effect of micrococcus luteus-derived vesicles in epithelial cells
- E. coli-derived vesicles E. coli EV
- an inflammatory factor were treated Accordingly, the secretion amount of IL-8, an inflammatory cytokine, was measured by ELISA (Enzyme-linked immunosorbent assay, R&D Systems).
- ELISA Enzyme-linked immunosorbent assay, R&D Systems.
- E. coli-derived vesicles were treated at a concentration of 1 ng/mL for 24 hours, and IL secreted into the medium The secretion amount of -8 was measured.
- micrococcus luteus-derived vesicles had better anti-inflammatory efficacy than dexamethasone, a representative anti-inflammatory drug, as well as anti-inflammatory effects of Micrococcus luteus-derived vesicles disappeared during heat treatment. It was found that the inflammatory action is mediated by the protein contained in the vesicle.
- Example 4 Anti-inflammatory effect of Micrococcus luteus-derived vesicles in inflammatory cells
- E. coli-derived vesicles E. coli EV
- TNF- ⁇ and IL-6 The secretion amount of TNF- ⁇ and IL-6 was measured by ELISA (R&D Systems) method.
- Micrococcus luteus-derived vesicles were pretreated to macrophages at various concentrations (1, 10, 100 ⁇ g/mL) for 24 hours, and then E. coli-derived vesicles were treated at a concentration of 1 ng/mL for 24 hours and secreted into the medium.
- the secretion amount of TNF- ⁇ and IL-6 was measured.
- FIGS. 6A and 6B when micrococcus luteus-derived vesicles were pretreated, the secretion of TNF- ⁇ ( FIG. 6a ) and IL-6 ( FIG. 6b ) by E. coli-derived vesicles, an inflammatory causative factor, was reduced. It was confirmed that vesicles derived from Micrococcus luteus were dose-dependently inhibited. This means that Micrococcus luteus-derived vesicles efficiently inhibit the secretion of inflammatory mediators by inflammatory causative factors from inflammatory cells that induce inflammation in neurodevelopmental diseases, neurological diseases or mental diseases.
- Example 5 Immune function modulating effect of Micrococcus luteus-derived vesicles on immune dysfunction caused by inflammatory factors
- NLRP3 protein present in the cytoplasm is known as a key signaling pathway in the pathogenesis of neurodevelopmental diseases, neurological diseases, or psychiatric diseases.
- NLRP3 NLR family pyrin domain containing 3
- t-box protein expressed in T cells was confirmed by western blotting.
- ROR- ⁇ t retineic-acid-receptor-related orphan nuclear receptor gamma
- NLRP3 protein expression was significantly increased in the LPS-administered group (LPS) compared to the negative control group, and Micrococcus luteus-derived vesicles were administered to the LPS-administered group (LPS+). MlEV), it was confirmed that NLRP3 protein expression was remarkably suppressed similarly to the group administered with dexamethasone (LPS+Dex).
- IL-1 ⁇ the effect on the secretion of IL-1 ⁇ was evaluated by pre-treating Micrococcus luteus-derived vesicles to macrophages by the method of Example 4, and then treating the macrophages with LPS.
- FIG. 8 when the vesicles were pretreated, it was confirmed that the secretion of IL-1 ⁇ by LPS, an inflammatory factor, was dose-dependently inhibited from Micrococcus luteus-derived vesicles (M. luteus EV).
- micrococcus luteus-derived vesicles efficiently inhibit the secretion of IL-1 ⁇ , an inflammatory mediator, secreted through the NLRP3 inflammasome from inflammatory cells that induce inflammation in neurodevelopmental diseases, neurological diseases, or mental diseases.
- Example 6 Modulating effect of micrococcus luteus-derived vesicles on innate immune dysfunction caused by inflammatory factors
- NLRP3 inflammasome Abnormalities in innate immune function against various metabolic stresses are known to be very important in the pathogenesis of neurodevelopmental diseases, neurological diseases, or psychiatric diseases.
- the acquired immune responses of Th1 and Th17 to specific antigens are key to immune dysfunction, whereas in the pathogenesis of neurodevelopmental diseases, neurological diseases or mental diseases, various risk factors that induce innate immunity (danger signals) ), the NLRP3 inflammasome is formed and disease is recently revealed.
- a priming process in which NLPR3 protein expression is induced by inflammatory factors such as LPS and TNF- ⁇ is important in advance.
- mice were excised from mice administered with LPS by the method of Example 5, and signals JNK and NF-kB ( p65) was evaluated by western blotting. 50 ⁇ g of protein was used to measure the expression level of each protein, and the expression of the above protein was evaluated in the tissues of the mouse group administered with dexamethasone (Dex) or Micrococcus luteus-derived vesicles.
- Dex dexamethasone
- LPS LPS-administered group
- MIEV Micrococcus luteus-derived vesicle
- Example 7 Modulating effect of Micrococcus luteus-derived vesicles on the generation of innate immune cells by inflammatory factors
- ILC3 immune cells through ROR- ⁇ t signaling are important in the pathogenesis of neurodevelopmental diseases, neurological diseases, or mental diseases caused by abnormalities in innate immune function against various stresses, which secrete IL-17, etc., and are involved in the pathogenesis of diseases This was recently revealed. In particular, it was found that ILC3 immune cells play a central role in the pathogenesis of multiple sclerosis, a representative inflammatory neurological disease.
- LPS was administered to mice according to the method of Example 5, and the number of immune cells in the tissues was evaluated by flow cytometry.
- the number of ILC3 cells secreting IL-17 was significantly increased compared to the negative control group, and the number of ILC3 cells increased by LPS was dexamethasone (Dex) and It was inhibited by Micrococcus luteus-derived vesicles (MIEV), and it was confirmed that the degree of inhibition was more significant when the vesicles were administered than when dexamethasone was administered. This means that the generation of innate immune cells induced by the NLRP3 inflammasome is efficiently inhibited by Micrococcus luteus-derived vesicles.
- Example 8 Efficacy of Micrococcus luteus-derived vesicles in the regulation of cellular homeostasis against oxidative stress
- NO nitric oxide
- eNOS endothelial NO synthase
- the degree of activation of eNOS signals after treating vascular endothelial cells with Micrococcus luteus-derived vesicles by the method described in Example 3 was evaluated.
- As a method for evaluating the expression of signaling proteins cells were lysed using a lysis buffer and proteins were extracted, and proteins were quantified using a BCA protein assay kit (Thermo, USA). The degree of protein activation was evaluated using antibodies specific for p-ERK, ERK, p-eNOS, eNOS, and ⁇ -actin.
- E. coli-derived vesicles E. coli
- Dex dexamethasone
- MDH-101 Micrococcus luteus-derived vesicles
- Micrococcus luteus-derived vesicles regulate the pathogenesis of neurological or psychiatric diseases by activating eNOS and ERK signals, which are important for vascular endothelial homeostasis and vascular health.
- Histone deacetylase is involved in the deacetylation of acetylated lysine residues of various proteins including histone proteins. Rather, it plays an important role in intracellular signaling processes.
- HDACs are divided into classes I, II, III and IV, and sirtuin belonging to class III is known as a signaling protein that maintains cellular homeostasis in a low-calorie stress situation.
- Sirtuin 1 which is present in the nucleus and cytoplasm, is an anti-aging protein that suppresses inflammation caused by metabolic stress as a deacetylase enzyme and increases cell survival
- Sirtuin 5 (Sirt5) is a protein that exists in mitochondria, has demalonylase, desuccinylase, and deacetylase enzyme functions, and maintains mitochondrial function by regulating ammonia toxicity in mitochondria
- Sirtuin 7 (Sirt7) is a protein that exists in neucleolus in the nucleus and has a deacetylase enzyme function to repair rDNA damage so that the protein can be properly produced in the ribosome.
- Neurotrophins are a group of growth factor proteins that play a key role in the survival and function of differentiated neurons, as well as in the development of neural stem cells. Most mammalian brains, including humans, produce neurons during the fetal period, but adult neurogenesis occurs even after birth due to the presence of neural stem cells in the hippocampus. Neurotrophins related to the survival and function of neural stem cells and neurons include brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), NT4/5, and nerve growth factor (NGF).
- BDNF brain-derived neurotrophic factor
- NT3 neurotrophin-3
- NGF nerve growth factor
- BDNF is present in the central nervous system and peripheral nervous system, and is a protein that not only increases survival and synapse formation of neurons present in the brain and peripheral nervous system through TrkB receptors, but also induces proliferation and differentiation of neural stem cells.
- Example 11 Cognitive function improvement effect of Micrococcus luteus-derived vesicles in brain disease mouse model
- the Tg-APP/PS1 mouse is a mouse model that induces brain disease by overexpressing abnormal APP (amyloid precursor protein) and PS1 (presenilin 1) proteins.
- a normal mouse group WT+veh
- a sham-treated brain disease mouse group Tg+veh
- micrococcus luteus-derived vesicles 50 ⁇ g/mouse were orally administered to a mouse model of brain disease, divided into brain disease mouse groups (Tg+MDH-101), and behavioral and histological examinations were performed.
- Example 12 Learning ability improvement effect of Micrococcus luteus-derived vesicles in brain disease mouse model
- the WT+veh group had the fastest time to find the hidden platform during the 5-day training period, and the Tg+MDH-101 group to which Micrococcus luteus-derived vesicles were administered was the WT+veh group. It showed similar learning ability, but the Tg-veh group showed the slowest learning time.
- Example 13 Memory improvement effect of Micrococcus luteus-derived vesicles in brain disease mouse model
- mice in the WT+veh and Tg+MDH-101 groups did not enter the dark space until 300 seconds passed during the experiment at the time points of 24, 72, and 120 hours, but Tg+ It was confirmed that the time to enter the dark space gradually increased for the mice of the veh group.
- FIG. 17c when the mouse entered a dark space and received an electric shock, the mice in the WT + veh group were compared to the mice in the Tg + veh group in the case of the freezing time due to the shock.
- mice of the Tg+MDH-101 group administered with micrococcus luteus-derived vesicles had no significant difference from the mice of the Tg+veh group. From the above results, it can be seen that Micrococcus luteus-derived vesicles have an effect of inhibiting memory loss induced by abnormal proteins.
- Example 14 Efficacy of Micrococcus luteus-derived vesicles on abnormal plug formation in brain disease mouse model
- Amyloid beta (A ⁇ ) plaque is a protein typically found in the brain of Alzheimer's disease patients.
- a ⁇ plaque starts to accumulate in the mouse brain and is known to induce Alzheimer's symptoms.
- the brain sections of the mouse models of Example 11 were fluorescently stained with Thioflavin-S dye to analyze A ⁇ plaques deposited in the brain tissue.
- Example 15 Evaluation of adult neurogenesis efficacy of Micrococcus luteus-derived vesicles in a mouse model of brain disease
- the Tg+veh group compared to the WT+veh group As shown in FIG. 19 , as a result of confirming the number of cells stained for Ki-67 by fluorescently staining Ki-67, which is known as a marker for neural stem cell proliferation, the Tg+veh group compared to the WT+veh group It was confirmed that the number of cells stained for Ki-67 was significantly reduced. On the other hand, the Tg+MDH-101 group administered with micrococcus luteus-derived vesicles significantly increased the number of Ki-67-stained cells compared to the Tg+veh group, and it was confirmed that the group recovered to a similar extent to the WT+veh group.
- DCX double cortin
- Micrococcus luteus-derived vesicles induce new neurogenesis in a mouse model of brain disease, and by generating new neurons, a therapeutic effect on neurodevelopmental diseases, neurological diseases or mental disorders caused by abnormal protein production It can be seen that represents
- Example 16 Evaluation of neuronal dendrite formation ability of Micrococcus luteus-derived vesicles in a mouse model of brain disease
- MAP2 microtubule-associated protein 2
- the micrococcus luteus-derived vesicles of the present invention effectively inhibit the occurrence or course of neurodevelopmental diseases, neurological diseases or mental diseases.
- the vesicle controls the formation of NLRP3 inflammasome, which is a key immune-related signaling substance in neurodevelopmental diseases, neurological diseases, or psychiatric diseases, thereby suppressing inflammation caused by various inflammatory factors, thereby inhibiting abnormal death of neural stem cells and neurons. And it was found.
- the vesicle activates the eNOS signal and induces the generation of NO, which is a key signaling material for cellular homeostasis, and restores the expression of sirtuin 1 and sirtuin 7, which are suppressed by oxidative stress, to restore homeostasis of neural stem cells and neurons.
- NO is a key signaling material for cellular homeostasis
- sirtuin 1 and sirtuin 7 which are suppressed by oxidative stress
- micrococcus luteus-derived vesicles of the present invention can be used for the improvement, prevention, or treatment of neurodevelopmental diseases, neurological diseases, or mental diseases.
- the present inventors confirmed that when micrococcus luteus-derived vesicles were orally administered, vesicles were absorbed into blood vessels and distributed in brain tissue.
- vesicles were treated with epithelial cells and inflammatory cells, secretion of inflammatory mediators caused by pathogenic factors was significantly inhibited, and when the cells were treated with the vesicles, NLRP3 protein expression and NF-kB ( p65) signal was confirmed.
- eNOS signals inhibited by pathogenic factors were increased.
- BDNF gene expression suppressed by pathogenic factors was restored.
- the vesicles derived from Micrococcus luteus according to the present invention prevent neurodevelopmental diseases, neurological diseases, or mental diseases, It can be usefully used for the development of medicines or health functional foods for symptom improvement or treatment, as well as a drug delivery system for treating neurodevelopmental diseases, neurological diseases, or mental diseases. It is expected.
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Abstract
Description
명칭 | 구분 | 서열(5’→3’) | 서열번호 |
HDAC1 | FW | CAGTGTGGCTCAGATTCCCT | 1 |
RV | GGGCAGCTCATTAGGGATCT | 2 | |
HDAC2 | FW | GGGACAGGCTTGGTTGTTTC | 3 |
RV | GAGCATCAGCAATGGCAAGT | 4 | |
HDAC3 | FW | AGAGAGGTCCCGAGGAGAAC | 5 |
RV | ACTCTTGGGGACACAGCATC | 6 | |
HDAC4 | FW | CAATCCCACAGTCTCCGTGT | 7 |
RV | CAGCACCCCACTAAGGTTCA | 8 | |
HDAC5 | FW | TGTCACCGCCAGATGTTTTG | 9 |
RV | TGAGCAGAGCCGAGACACAG | 10 | |
Sirt1 | FW | GATCCTTCAGTGTCATGGTTC | 11 |
RV | ATGGCAAGTGGCTCATCA | 12 | |
Sirt5 | FW | ATCGCAAGGCTGGCACCAAGAA | 13 |
RV | CTAAAGCTGGGCAGATCGGACT | 14 | |
Sirt7 | FW | GAGAGCGAGGATCTGGTGAC | 15 |
RV | CGTGTAGACAACCAAGTGCC | 16 |
명칭 | 구분 | 서열(5’→3’) | 서열번호 |
tBDNF | FW | TGGCTGACACTTTTGAGCAC | 17 |
RV | GTTTGCGGCATCCAGGTAAT | 18 | |
NT3 | FW | TACTACGGCAACAGAGACG | 19 |
RV | GTTGCCCACATAATCCTCC | 20 | |
NT4/5 | FW | GGCTCCATCCTGAACATCAT | 21 |
RV | GCCATGATCTACCTGCCTGT | 22 | |
NGF | FW | AGCATTCCCTTGACACAG | 23 |
RV | GGTCTACAGTGATGTTGC | 24 | |
TrkB | FW | AAGGACTTTCATCGGGAAGCTG | 25 |
RV | TCGCCCTCCACACAGACAC | 26 |
Claims (25)
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는, 신경발달 질환, 신경질환, 또는 정신질환의 예방 또는 치료용 약학적 조성물.
- 제1항에 있어서.상기 신경질환은 퇴행성 신경질환 또는 염증성 신경질환인 것을 특징으로 하는, 약학적 조성물.
- 제2항에 있어서,상기 퇴행성 신경질환은 알츠하이머병(Alzheimer’s disease), 파킨슨병(Parkinson’s disease), 근위축성 측삭 경화증(amyotropic lateral sclerosis), 헌팅턴병(Huntington’s disease), 뇌전증(epilepsy), 컨스-세이어증후군(Kearns-Sayre syndrome; KSS), 만성 진행성 외안근마비(chronic progressive external ophthalmoplegia; CPEO), 멜라스증후군(mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MELAS), MERRF증후군(myoclonic epilepsy with ragged-red fibers; MERRF), NARP증후군(neurogenic weakness with ataxia and retinitis pigmentosa; NARP), 리 증후군(Leigh syndrome; LS), 및 MIRAS증후군(mitochondrial recessive ataxia syndrome)으로 이루어진 군으로부터 선택된 하나 이상의 질환인 것을 특징으로 하는, 약학적 조성물.
- 제2항에 있어서,상기 염증성 신경질환은 다발성경화증(multiple sclerosis), 만성염증탈수초다발신경병증(chronic inflammatory demyelinating polyneuropathy), 및 당뇨병성 신경병증(diabetic neuropathy)으로 이루어진 군으로부터 선택된 하나 이상의 질환인 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서,상기 정신질환은 우울장애(major depressive disorder), 양극성기분장애(bipolar disorder), 불안장애(anxiety disorder), 조현병(schizophrenia) 강박장애 (obsessive compulsive disorder), 외상후스트레스장애(post-traumatic stress disorder), 해리장애(dissociative disorder), 섭식장애(eating disorder), 물질사용장애(substance use disorder), 및 성격장애(personality disorder)로 이루어진 군으로부터 선택된 하나 이상의 질환인 것을 특징으로 하는, 약학적 조성물.
- 제5항에 있어서,상기 불안장애는 공황장애(panic disorder), 사회적불안장애(social anxiety disorder), 범불안장애(generalized anxiety disorder), 및 특정 공포증(specific phobia)으로 이루어진 군으로부터 선택된 하나 이상의 불안장애인 것을 특징으로 하는, 약학적 조성물.
- 제5항에 있어서,상기 성격장애는 편집성 성격장애(paranoid personality disorder), 반사회적 성격장애(antisocial personality disorder), 경계성 성격장애(borderline personality disorder), 자기애 성격장애(narcissistic personality disorder), 회피성 성격장애(avoidant personality disorder), 및 의존성 성격장애(dependent personality disorder)로 이루어진 군으로부터 선택된 하나 이상 성격장애인 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서,상기 신경발달 질환은 지적장애(intellectual disability), 의사소통장애(communication disorder), 자폐 스펙트럼 장애(autism spectrum disorder), 주의력결핍/과잉행동장애(attention deficit hyperactivity disorder), 특정학습장애(specific learning disorder), 및 운동장애(motor disorder)로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서,상기 신경발달 질환, 신경질환, 또는 정신질환은 신경생성의 장애(neurogenesis dysfunction)로 인한 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서,상기 신경발달 질환, 신경질환, 또는 정신질환은 NLRP3 inflammasome(NLR family pyrin domain containing 3 inflammasome)에 의해 매개되는 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서,상기 조성물은 NLRP3 inflammasome 형성을 억제하는 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서,상기 소포는 평균 직경이 10 내지 200 nm인 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서,상기 소포는 마이크로코커스 루테우스(Micrococcus luteus)에서 자연적으로 분비 또는 인공적으로 생산되는 것을 특징으로 하는, 약학적 조성물.
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는, 신경발달 질환, 신경질환, 또는 정신질환의 예방 또는 개선용 식품 조성물.
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는, 신경발달 질환, 신경질환, 또는 정신질환의 예방 또는 치료용 흡입제 조성물.
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는, 신경발달 질환, 신경질환, 또는 정신질환 치료 약물 전달용 조성물.
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는, 항노화용 약학적 조성물.
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는, 항노화용 식품 조성물.
- 제18항에 있어서,상기 조성물은 뇌 또는 신경세포의 노화를 억제하는 것을 특징으로 하는, 식품 조성물.
- 마이크로코커스(Micrococcus) 속 세균 유래 소포를 유효성분으로 포함하는, 신경발달 질환, 신경질환, 또는 정신질환의 예방 또는 치료용 약학적 조성물.
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 신경발달 질환, 신경질환, 또는 정신질환의 예방 또는 치료 방법.
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는 조성물의 신경발달 질환, 신경질환, 또는 정신질환 예방 또는 치료 용도.
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포의 신경발달 질환, 신경질환, 또는 정신질환 치료용 약제의 제조를 위한 용도.
- 신경발달 질환, 신경질환, 또는 정신질환 치료 약물을 담지한 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 신경발달 질환, 신경질환, 또는 정신질환 치료 약물 전달 방법.
- 마이크로코커스 루테우스(Micrococcus luteus) 유래 소포를 유효성분으로 포함하는 조성물의 신경발달 질환, 신경질환, 또는 정신질환 치료 약물 전달 용도.
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CN202180088164.2A CN116806153A (zh) | 2020-12-28 | 2021-11-15 | 用于预防或治疗神经发育障碍、神经系统疾病或精神疾病的包含源自藤黄微球菌的细胞外囊泡的组合物 |
EP21915508.2A EP4268836A1 (en) | 2020-12-28 | 2021-11-15 | Composition for preventing or treating neurodevelopmental, neurological or psychiatric diseases, comprising extracellular vesicles derived from micrococcus luteus |
JP2023539322A JP2024501034A (ja) | 2020-12-28 | 2021-11-15 | マイクロコッカス・ルテウス由来細胞外小胞を含む神経発達疾患、神経疾患、または精神疾患の予防または治療用組成物 |
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KR1020210156079A KR102670461B1 (ko) | 2020-12-28 | 2021-11-12 | 마이크로코커스 루테우스 유래 세포외 소포를 포함하는 신경발달 질환, 신경질환, 또는 정신질환 예방 또는 치료용 조성물 |
KR10-2021-0156079 | 2021-11-12 |
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KR20180019482A (ko) * | 2016-08-16 | 2018-02-26 | 주식회사 엠디헬스케어 | 락토바실러스 속 세균 유래 소포를 포함하는 정신질환 예방 또는 치료용 조성물 |
US20190070225A1 (en) * | 2016-03-14 | 2019-03-07 | Holobiome, Inc. | Modulation of the gut microbiome to treat mental disorders or diseases of the central nervous system |
KR20190103962A (ko) * | 2018-02-28 | 2019-09-05 | 주식회사 엠디헬스케어 | 마이크로코커스 속 세균 유래 나노소포 및 이의 용도 |
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- 2021-11-15 WO PCT/KR2021/016633 patent/WO2022145710A1/ko active Application Filing
- 2021-11-15 JP JP2023539322A patent/JP2024501034A/ja active Pending
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