WO2023068285A1 - 小胞体ストレス抑制剤、神経変性疾患予防改善剤および認知症の予防・進行防止・改善剤、並びに食品 - Google Patents

小胞体ストレス抑制剤、神経変性疾患予防改善剤および認知症の予防・進行防止・改善剤、並びに食品 Download PDF

Info

Publication number
WO2023068285A1
WO2023068285A1 PCT/JP2022/038842 JP2022038842W WO2023068285A1 WO 2023068285 A1 WO2023068285 A1 WO 2023068285A1 JP 2022038842 W JP2022038842 W JP 2022038842W WO 2023068285 A1 WO2023068285 A1 WO 2023068285A1
Authority
WO
WIPO (PCT)
Prior art keywords
endoplasmic reticulum
triglyceride
reticulum stress
formula
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2022/038842
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
誠 坪井
泰子 阪田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Refine Holdings Co Ltd
Original Assignee
Refine Holdings Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Refine Holdings Co Ltd filed Critical Refine Holdings Co Ltd
Priority to US18/702,472 priority Critical patent/US20240415797A1/en
Publication of WO2023068285A1 publication Critical patent/WO2023068285A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an endoplasmic reticulum stress inhibitor for improving the state of endoplasmic reticulum stress by means of triglycerides composed of saturated fatty acids mainly containing pentadecanoic acid. Furthermore, the present invention relates to agents for preventing, ameliorating, and treating diseases whose pathogenesis is associated with endoplasmic reticulum stress, and can be used as foods, pharmaceutical compositions, etc. containing these agents.
  • Endoplasmic reticulum stress is caused by the exposure of cells to various internal and external environmental changes, resulting in abnormal expression of the protein synthesis system in the lumen of the endoplasmic reticulum, which increases the amount of protein and stores proteins that are not normally eliminated. is no longer folded normally and accumulates as a defective protein.
  • Factors that cause endoplasmic reticulum stress are known to include nutritional starvation, perturbation of intracellular calcium concentration, hypoxia, expression of mutant proteins, and viral infection. Under endoplasmic reticulum stress, cells activate lipid synthesis and expand the endoplasmic reticulum to increase protein folding capacity for homeostasis.
  • Neurodegenerative diseases are diseases in which certain neuronal cell groups in the central nervous system are damaged and lost, thereby impairing neuronal function.
  • Typical neurodegenerative diseases include Alzheimer's disease and Creutzfeldt-Jakob disease causing cognitive dysfunction, Parkinson's disease causing motor dysfunction, amyotrophic lateral sclerosis (ALS) and Huntington's disease.
  • ALS amyotrophic lateral sclerosis
  • endoplasmic reticulum stress is also involved in the onset of these diseases. It is also called folding disease because accumulation of denatured proteins is observed as a common feature of the disease.
  • Alzheimer's disease extracellular amyloid ⁇ and intracellular tau protein accumulation are observed. Accumulation of ⁇ -synuclein is observed in Parkinson's disease, mutated superoxide dismutase in ALS, and huntingtin protein in Huntington's disease. Creutzfeldt-Jakob disease, which is classified as a prion disease, develops when abnormal prions accumulate. Thus, although the proteins that accumulate differ depending on the disease, there is a commonality that the accumulation of denatured proteins damages specific nerve cells and causes cell death.
  • Foods that suppress oxidative stress include polyphenols (Non-Patent Document 2), vitamins C and E (Non-Patent Document 3), and folic acid (Non-Patent Document 4). It is believed that antioxidants act to suppress neuronal cell death due to oxidative stress by removing active oxygen generated in the brain in the pre-dementia stage. In addition, it has been reported that circulating ketone bodies are increased by fatty acids with 7 carbon atoms constituting fatty acids and the triglyceride trihepranoin, thereby reducing amyloid ⁇ deposits in patients with Alzheimer's disease (Patent Document 1). However, the effects of these are unknown and cannot be said to be sufficient at present.
  • the problem to be solved by the present invention is an endoplasmic reticulum stress suppressing agent, a neurodegenerative disease preventive/improving agent, and a dementia preventive/progressive/improving agent that can be used as foods, drinks, and drugs suitable for such applications. , as well as providing food.
  • triglyceride composed of saturated fatty acids mainly containing pentadecanoic acid (C15) (pentadecanoic acid triglyceride: hereinafter referred to as "PdATG” ) acts on hippocampal-derived neurons to suppress the accumulation of denatured proteins in the endoplasmic reticulum caused by stress damage, thereby reducing the resulting cell death (apoptosis), thereby preventing or preventing neurodegenerative diseases.
  • PdATG pentadecanoic acid triglyceride
  • each of R 1 , R 2 and R 3 is a saturated fatty acid residue, at least one of which is a pentadecanoic acid residue.) as an active ingredient.
  • the triglyceride of formula (I) preferably has pentadecanoic acid residues in R 1 and R 2 or R 1 and R 3 .
  • any one of R 1 , R 2 and R 3 is tridecylic acid (C13), myristic acid residue (C14), palmitic acid residue (C16) or margaric acid residue (C17 ).
  • the triglyceride of formula (I) above wherein all of R 1 , R 2 and R 3 are pentadecane residues, and any two of R 1 , R 2 and R 3 are pentadecane triglycerides of formula (I) which are acid residues and the other one is a myristic acid or palmitic acid residue.
  • the triglyceride of formula (I) is derived from Aurantiochytrium or Schizochytrium algae, wherein R 1 , R 2 and R 3 may be triglycerides, each of which is a saturated fatty acid residue, at least one of which is a pentadecanoic acid residue. Furthermore, it may be a mixture containing unsaturated fatty acids derived from algae of the genus Aurantiochytrium or Schizochytrium.
  • a prophylactic/improving agent for neurodegenerative diseases which contains the triglyceride represented by the above formula (I) as an active ingredient.
  • an agent for preventing/preventing progression/amelioration of dementia containing the triglyceride represented by the above formula (I) as an active ingredient.
  • a food containing the triglyceride represented by the above formula (I) as an active ingredient is preferably used as, for example, a health food, a food with functional claims, or a food for specified health use, to improve the daily lives of people who tend to forget things.
  • endoplasmic reticulum stress can be suppressed in mammalian cells, particularly nerve cells, etc., and can be taken for a long period of time. can provide.
  • FIG. 1 shows the inhibitory effect of PdATG on cell death induced by tunicamycin, an endoplasmic reticulum stress inducer.
  • the vertical axis indicates cell viability (%), and the horizontal axis indicates tunicamycin treatment concentration. ** indicates that there is a significant difference compared with the control at the significance level of 1% and *, 5%. + indicates a significant trend.
  • PdATG means at least one ester of pentadecanoic acid and glycerol, and at least one, preferably any two of R 1 , R 2 and R 3 shown in formula (I) below,
  • R 1 and R 2 or R 1 and R 3 more preferably three of R 1 , R 2 and R 3 are pentadecanoic acid residues.
  • the binding position of pentadecanoic acid to glyceride may be any of the 1-3 positions.
  • R 1 , R 2 and R 3 are each saturated fatty acid residues, at least one of which is a pentadecanoic acid residue).
  • any one residue represented by R 1 , R 2 and R 3 may be a saturated fatty acid residue other than pentadecanoic acid residue.
  • “Saturated fatty acid” is a general term for fatty acids having no double bond or triple bond in the molecule, and is represented by the chemical formula of C n H 2n+1 COOH.
  • the saturated fatty acids are linear or branched saturated fatty acids, capric acid (C10), lauric acid (C12), tridecylic acid (C13), myristic acid (C14), pentadecanoic acid (C15), palmitic acid.
  • linear saturated fatty acids such as (C16), margaric acid (C17), stearic acid (C18), arachidic acid (C20), behenic acid (C22), lignoceric acid (C24) and cerotic acid (C26), and 2- Branched saturated fatty acids such as hexyldecanoic acid (C16), 13-methylpentadecanoic acid (C16), and 16-methylheptadecanoic acid (C18) are included.
  • PdATG in a preferred embodiment is a triglyceride of formula (I) above in which all of R 1 , R 2 and R 3 are pentadecanoic acid residues, and any two of R 1 , R 2 and R 3 are pentadecanoic acid residues and triglycerides, the other one being a myristic acid or palmitic acid residue.
  • the content ratio of the two in this mixture is not particularly limited, but it is preferably 1:2 to 2:1, more preferably approximately 1:1 in mass ratio.
  • each of these is contained in an amount of 10% by mass or more, preferably 20% by mass or more, based on the total amount of triglycerides.
  • a mixture of triglycerides containing two or more residues of pentadecanoic acid is contained in an amount of 50% by mass or more in the oil.
  • PdATG is represented by formula (II) or (III) below.
  • R is a saturated fatty acid of C14 to C16.
  • a mixture of triglycerides containing two or more pentadecanoic acid residues is contained in the fat or oil in an amount of 50% by mass or more. However, even if the content of triglycerides containing two or more pentadecanoic acid residues is 50% by mass or less, the purpose can be achieved by increasing the intake.
  • the active ingredient of the present invention may exist in the form of a mixture of triglycerides containing two or more residues of pentadecanoic acid, and at least 1% by mass, preferably 50% by mass or more, more preferably 50% by mass or more, relative to the total amount of triglycerides. When contained in a purity of 90% by mass or more, the mixture itself can function as an active ingredient.
  • the active ingredient of the present invention may be present in a mixture with triglycerides other than the compound of formula (I), and is at least 1% by mass, preferably 50% by mass or more, more preferably 90% by mass, based on the total amount of triglycerides. If it is contained at a purity of mass % or more, the mixture itself can exhibit its function as an active ingredient.
  • the active ingredient of the present invention has at least one, preferably two or more, odd-chain fatty acids, particularly pentadecanoic acid, in the molecule. It is thought that it suppresses abnormal proteins that cause cancer, reduces cell death, and exerts an action that leads to normality.
  • the active ingredient of the present invention has the effect of alleviating endoplasmic reticulum stress in various cells, thereby normally ameliorating diseases caused by endoplasmic reticulum stress and unhealthy conditions before the disease.
  • protein deposits with abnormal structures such as senile plaques and neurofibrillary tangles are observed.
  • Neuritic plaques are composed of peptide aggregates of about 40 amino acids called amyloid ⁇ , and these aggregates induce neuronal cell death. Deposition of amyloid ⁇ induces endoplasmic reticulum stress on neurons, which is the major cause of neuronal cell death (Ogen-Shtern N, et al., Protein aggregation and ER stress.
  • amyloid ⁇ causes the production of active oxygen in the brain by glial cells, and the resulting oxidative stress also causes neuronal cell death (Angelova PR, & Abramov AY. Interaction of neurons and astrocytes under the mechanism of A ⁇ -induced neurotoxicity. Biochem Soc Trans, 42, 1286-1290 (2014)).
  • the incubation period from the deposition of amyloid ⁇ to the onset of dementia is said to be 20 to 30 years. Because of the state of the disease, it is considered almost impossible to regenerate the neural circuits in the brain and completely cure the disease after the onset.
  • preventive measures it is conceivable to prevent neurodegeneration by ingesting preventive and alleviating ingredients before the onset of symptoms. At the same time, it is also important to treat early stages of suspected onset.
  • endoplasmic reticulum stress progresses due to environmental factors such as aging, genetic factors, and lifestyle habits, and insufficient repair causes gradual loss of homeostasis and cell death.
  • An age-related disease can be defined as an abnormally progressed state due to the addition of internal and external factors, and characteristic diseases occur in each organ.
  • metabolic syndrome is mentioned as a risk of cerebral/cardiovascular disease, diabetes, etc., and arteriosclerosis, decreased insulin sensitivity, and increased incidence of cancer.
  • oxidative stress hypothesis is a risk of aging progression, and the relationship between many diseases and active oxygen has been discussed, but in reality, the contribution of endoplasmic reticulum stress is considered.
  • Progression of the endoplasmic reticulum stress state develops age-related diseases, age-related neurodegenerative diseases, and the like. Progression of the endoplasmic reticulum stress state in each tissue is considered to be a major factor in the occurrence of adult diseases including cancer. In other words, it has been found that pharmaceuticals and food ingredients that can actually improve endoplasmic reticulum stress are indispensable for maintaining people's health.
  • the endoplasmic reticulum stress response is one of the mechanisms of stress adaptation response of cells, and it also plays an important role in the survival of cancer cells in the microenvironment such as hypoxia and low glucose in tumors.
  • Cancer is one of the leading causes of death in Japan.
  • the characteristics of cancer are 1) autonomous proliferation, 2) invasion and metastasis, and 3) cachexia (a state of malnutrition due to deprivation of nutrients by cancer tissue no matter how much nutrition is taken). Cancer cells can survive and proliferate in hypoxic and nutrient-poor environments.
  • This hypoxic and low-nutrient environment is exactly the environment that induces endoplasmic reticulum stress, and enhanced expression of endoplasmic reticulum molecular chaperones is observed in cancer cells, which is involved in cancer cell growth and metastasis. Also in breast cancer cells and hepatocellular carcinoma, increased expression of XBP-1 is considered to contribute to the survival of cancer cells. Suppression of XBP-1, which is abnormally expressed due to increased intracellular endoplasmic reticulum stress, may also suppress carcinogenesis.
  • XBP-1 X-box binding protein 1
  • XBP-1 X-box binding protein 1
  • the triglyceride mixture which is the active ingredient of the present invention, may be chemically synthesized or naturally occurring. If it is natural, its source is not particularly limited. Lipids produced by organisms in the body, such as livestock and poultry fats, fish and shellfish fats and oils, vegetable oils or lipid-producing microorganisms. From an industrial productivity point of view, microorganisms such as algae, bacteria, fungi (including yeast), and/or protists are preferred.
  • microorganisms include those selected from the group consisting of golden algae (such as microorganisms of the Stramenopile kingdom), green algae, diatoms, dinoflagellates, yeasts, and fungi of the genera Mucor and Mortiera.
  • golden algae such as microorganisms of the Stramenopile kingdom
  • green algae diatoms, dinoflagellates, yeasts, and fungi of the genera Mucor and Mortiera.
  • Members of the microbial community Stramenopile include microalgae.
  • Microalgae refer to organisms that perform oxygen-generating photosynthesis, excluding bryophytes, fern plants, and seed plants, and having a cell size of 1 ⁇ m to 100 ⁇ m in diameter.
  • Labyrinthulids, closely related protists of microalgae are also included.
  • Labyrinthulids are heterotrophic marine eukaryotic microorganisms that do not perform photosynthesis, and are widely distributed mainly in subtropical and tropical regions.
  • the Labyrinthula family is roughly divided into the family Labyrinthulidae and the family Thraustochytriidae, and the genus Labyrinthula, the genus Aurantiochytrium, the genus Schizochytrium ), the genus Thraustochytrium, the genus Aplanochytrium, the genus Oblongichytrium, the genus Botryochytrium, the genus Japonochytrium and the like.
  • Labyrinthula to be cultured are more preferably those of the genus Aurantiochytrium, Schizochytrium, or Thraustochytrium. These types have a relatively high ability to produce lipids and the like, and can produce hydrocarbons such as squalene, so they are suitably used for edible uses, biofuel raw materials, and the like.
  • Labyrinthula can be cultured by any culture method such as batch culture, continuous culture, or fed-batch culture.
  • Labyrinthula can be cultured by an appropriate culture method such as shaking culture, aerobic culture, aerobic stirring culture, airlift culture, and static culture. Among these culture methods, aeration and agitation culture or airlift culture is more preferable.
  • a culture apparatus used for culturing Labyrinthula for example, a mechanically stirred reactor, an airlift reactor, a packed bed reactor, a fluidized bed reactor, or the like can be used.
  • the culture vessel various vessels such as tanks, jar fermenters, flasks, dishes, culture bags, tubes, and test tubes can be used depending on the purpose of culture, culture capacity, and the like.
  • the culture vessel may be made of appropriate materials such as inorganic materials such as stainless steel and glass, and organic materials such as polystyrene, polyethylene terephthalate copolymer, and polypropylene.
  • Labyrinthula can be cultured under appropriate temperature conditions, pH conditions, aeration conditions, etc.
  • the culture temperature is preferably 5° C. or higher and 40° C. or lower, more preferably 10° C. or higher and 35° C. or lower, even more preferably 10° C. or higher and 30° C. or lower.
  • the pH is preferably 2 or more and 11 or less, more preferably 4 or more and 9 or less, and even more preferably 6 or more and 8 or less.
  • Labyrinthula can be cultured by subculturing at appropriate intervals according to the genus and species of the Labyrinthulea, medium composition, culture conditions, etc.
  • Labyrinthulids complete the logarithmic growth phase in about 2 days after starting the culture, and enter the death phase in about 7 days. Therefore, passage of Labyrinthula is preferably performed at intervals of 1 to 10 days, more preferably at intervals of 2 to 7 days, and preferably at intervals of 2 to 5 days. is more preferred.
  • the Labyrinthula can be cultured for an appropriate time depending on the genus and species of the Labyrinthula, medium composition, culture conditions, purpose of culture, and the like.
  • aurantiochytrium algae which are labyrinthulid algae, are heterotrophic algae that live in brackish waters, and are preferred because they have the characteristic of assimilating nutrients in water, producing lipids, and accumulating them in cells.
  • Aurantiochytrium algae it is preferable to use strains with excellent ability to produce desired triglycerides.
  • Such algal strains may be naturally collected and isolated, cloned through mutagenesis and screening, or established using genetic recombination techniques.
  • may For example, Aurantiochytrium Sp. Strains SA-96, NIES-3737, Aurantiochytrium NB6-3, or Aurantiochytrium mh1959 contain triglycerides containing the odd-chain fatty acid pentadecanoic acid (PDA) and the highly unsaturated fatty acid docosahexaenoic acid.
  • PDA odd-chain fatty acid pentadecanoic acid
  • the culture of the Aurantiochytrium genus algae is performed by a method established in the technical field. That is, normal maintenance culture is carried out by seeding algae in a medium whose components are appropriately prepared and following a standard method.
  • a medium for culturing Aurantiochytrium algae essentially contains salt, a carbon source and a nitrogen source.
  • GTY medium artificial seawater 10-40 g/L, D(+) glucose 20-100 g/L, tryptone 10-60 g/L, yeast extract 5-40 g/L
  • GTY medium artificial seawater 10-40 g/L, D(+) glucose 20-100 g/L, tryptone 10-60 g/L, yeast extract 5-40 g/L
  • Carbon sources include sugars such as glucose, fructose, and sucrose. These carbon sources are added, for example, at a concentration of 20-120 g per liter of medium.
  • Algae of the genus Aurantiochytrium are marine algae, and an appropriate amount of artificial seawater is added to the medium.
  • the artificial seawater has a final medium salinity of about 10% (v/v) to about 100% (v/v) of seawater (3.4% (w/v) salinity), such as It is added so that the concentration is about 1.0-3.0% (w/v).
  • microalgae culture media contain organic nitrogen such as sodium glutamate and urea, or inorganic nitrogen such as ammonium acetate, ammonium sulfate, ammonium chloride, sodium nitrate, ammonium nitrate, or yeast extract, corn steep liquor, polypeptone, Various nitrogen sources can be added, such as biological digests such as peptones, tryptones, and the like.
  • cell extracts obtained by extracting liquid components from cells of various animals are preferably used as nitrogen sources to be added to media used for culturing Aurantiochytrium algae.
  • Use of cell extracts that are rich in nutrients such as cell-derived amino acids, nucleic acids, vitamins, and minerals and that are available at low cost when cells must be mass-cultured on an industrial scale to obtain cultured cell products. is extremely advantageous.
  • the present inventors cultured Aurantiochytrium algae in an algae culture medium prepared by adding a strong acid-treated cell extract, and compared with the case where the cell extract without the treatment was added. have found that the production of odd-chain fatty acids dramatically increases, and have already reported a method for producing triglycerides containing odd-chain fatty acids as main components (Japanese Patent Application Laid-Open No. 2017-063633).
  • the basal medium for culturing Aurantiochytrium algae comprises 2% or more glucose, 0.5-4% sodium glutamate, and 0.1-2% yeast extract. , 1-3.3% sea salt, 2-20% whey (animal or vegetable) in medium supplemented with 10-50 mM valine and 10-50 mM sodium propionate.
  • Animal or vegetable whey is preferably tofu whey (soybean whey).
  • This basal medium contains at least 2% glucose and 0.5-4% monosodium glutamate, 0.1-2% yeast extract, 1-3.3% sea salt, 2-20% whey (animal or vegetable 2% or more of the culture solution of Aurantiochytrium precultured at 20 to 30° C. for 72 hours is added.
  • the Aurantiochytrium-loaded culture is aerated and gently agitated. Cultivation is carried out at 20 to 30° C. and a pH of 5.0 to 8.5 (using a 1.0 M NaOH solution for pH adjustment) for 48 to 200 hours.
  • Aurantiochytrium cells that have produced pentadecanoic acid triglyceride can be recovered by centrifugation (see WO2020/054804 pamphlet).
  • the pellet collected by centrifugation or filtration from the culture solution obtained by the above method is dried by freeze-drying or drying by heating.
  • the culture medium in which the algal cells are suspended may be directly used for the triglyceride extraction step. Extraction may be performed multiple times with different organic solvents.
  • the organic solvent a mixture of a polar solvent and a weakly polar solvent such as n-hexane/ethanol mixed solvent, chloroform/methanol mixed solvent, or ethanol/diethyl ether mixed solvent can be used.
  • the resulting extract is purified by methods known to those skilled in the art.
  • a fractionation technique known to those skilled in the art is adopted. Separation and purification may be carried out using various physicochemical properties such as polarity, solubility in solvents, melting point, specific gravity and molecular weight of triglyceride molecules to be fractionated, preferably using column chromatography techniques.
  • the conditions for the triglyceride separation means can be set by a person skilled in the art by routine examination of the conditions, depending on the composition of the triglyceride mixture and the types of triglycerides to be fractionated.
  • Algae of the genus Schizochytrium and Aurantiochytrium can synthesize and accumulate both odd-chain fatty acid triglycerides and polyunsaturated fatty acid triglycerides in their cells. Therefore, ethanol, hexane or ethyl acetate is added to the obtained algal cells to extract lipids, and then the solvent is distilled off to obtain algal lipids. Pentadecanoic acid triglyceride can be precipitated by allowing this lipid to stand at 5°C.
  • the composition of purified pentadecanoic acid triglyceride “PdATG” can be analyzed by HPLC-MS, HPLC, gas chromatography, and the like.
  • Algae of the genus Aurantiochytrium can synthesize and accumulate both odd-chain fatty acid triglycerides and polyunsaturated fatty acid triglycerides in their cells. Therefore, hexane or ethyl acetate is added to the obtained aurantiochytrium cells to extract lipids, and then hydrogen peroxide solution is added to the lipid solution or ozone is passed through it to oxidatively decompose the unsaturated fatty acids. After completion of the reaction, oxides are removed with sodium hydrogen carbonate and sodium carbonate or an ion exchange resin to obtain pentadecanoic acid triglyceride "PdATG".
  • the composition of purified pentadecanoic acid triglyceride “PdATG” can be analyzed by HPLC-MS, HPLC, gas chromatography, and the like.
  • the endoplasmic reticulum stress suppressing agent according to the first aspect of the present invention includes a preparation that suppresses neuronal cell death due to abnormal protein accumulation in the endoplasmic reticulum.
  • Neuronal cell death here encompasses neuronal necrosis and apoptosis.
  • inhibitor of neuronal cell death encompasses alleviating, reducing or abolishing neuronal cell death, inhibiting progression of neuronal cell death, and preventing and preventing neuronal cell death.
  • disorders diseases and aging changes
  • endoplasmic reticulum stress such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Creutzfeldt-Jakob disease, amnesia, etc. It can be used for prophylaxis, prevention and/or amelioration.
  • the agent for preventing/improving neurodegenerative diseases according to the second aspect of the present invention and the agent for preventing/preventing/improving dementia according to the third aspect contain pentadecanoic acid triglyceride represented by the above formula (I) as an active ingredient. It can be used to improve the symptoms of neurodegenerative diseases such as Alzheimer's disease, and is useful as a drug therefor.
  • the term “pharmaceutical” means a therapeutic agent for preventing, progressing and/or improving symptoms such as dementia by suppressing endoplasmic reticulum stress in patients with Alzheimer's disease or the like.
  • pentadecanoic acid triglyceride represented by the above formula (I) is blended to produce a drug, for example, sugars such as dextrin and starch; proteins such as gelatin, soybean protein and corn protein; alanine, glutamine, isoleucine and the like; polysaccharides such as cellulose and gum arabic; oils and fats such as soybean oil and medium-chain fatty acid triglycerides.
  • a drug for example, sugars such as dextrin and starch; proteins such as gelatin, soybean protein and corn protein; alanine, glutamine, isoleucine and the like; polysaccharides such as cellulose and gum arabic; oils and fats such as soybean oil and medium-chain fatty acid triglycerides.
  • the amount of the pentadecanoic acid triglyceride represented by the above formula (I) in the pharmaceutical product according to the present invention is not particularly limited. It is preferable to adjust the amount to about 10 to 1000 mg per day.
  • the pharmaceutical of the present embodiment may contain only the compound of formula (I) as an active ingredient, or may contain other ingredients as long as they do not inhibit the nerve cell death inhibitory effect.
  • Other ingredients may be, for example, conventionally used therapeutic or prophylactic drugs for neurodegenerative diseases. Therefore, in a further aspect, the endoplasmic reticulum stress inhibitor of the present embodiment provides a pharmaceutical composition for preventing and improving neurodegenerative diseases.
  • the food according to the fourth aspect of the present invention contains pentadecanoic acid triglyceride represented by the above formula (I) as an active ingredient, and can be ingested for a long period of time as a preventive food or drink before the onset of neurodegenerative diseases. It is useful as a health food for that purpose. It has been reported that pentadecanoic acid, which constitutes PdATG, is contained in small amounts in edible parts such as beef, pork, chicken, and sheep meat, fish that live in rivers and seas, and mushrooms. Although it is contained in an extremely small amount, it is presumed to be highly safe based on long-term dietary experience.
  • the food of this embodiment is useful as a health food taken for health promotion.
  • “health food” refers to health promotion in daily life, forgetfulness due to aging, decline in comprehension/judgment, memory impairment, disorientation, executive dysfunction, aphasia/apraxia/agnosia, and dementia.
  • pentadecanoic acid triglyceride represented by the above formula (I) for example, sugars such as dextrin and starch; proteins such as gelatin, soybean protein and corn protein; alanine, glutamine, isoleucine and the like. polysaccharides such as cellulose and gum arabic; oils and fats such as soybean oil and medium-chain fatty acid triglycerides.
  • the amount of the pentadecanoic acid triglyceride represented by the above formula (I) in the food of the present invention is not particularly limited. It is preferable to adjust the intake of acid triglyceride to about 1 to 100 mg per day.
  • Specific examples of the above foods include beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit drinks, and lactic acid drinks (including concentrates and adjustment powders of these drinks); ice cream, ice sherbet, shaved ice, etc. Frozen desserts; Noodles such as buckwheat, udon, vermicelli, gyoza skin, steamed dumpling skin, Chinese noodles, instant noodles; Confectionery such as candy, candy, gum, chocolate, snacks, biscuits, jelly, jam, cream, baked goods; Fishery/livestock processed foods such as kamaboko, ham, and sausages; dairy products such as processed milk and fermented milk; oils and fats such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, and dressings; sauces, sauces, etc. health/dietary supplements in various forms such as tablets and granules; and other soups, stews, salads, side dishes, and pickles.
  • Noodles such as buckwheat,
  • Foods according to the present invention may contain various food additives such as antioxidants, fragrances, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, and preservatives. , seasonings, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, quality stabilizers, and other additives may be added alone or in combination.
  • various food additives such as antioxidants, fragrances, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, and preservatives.
  • seasonings, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, quality stabilizers, and other additives may be added alone or in combination.
  • the concentration of pentadecanoic acid triglyceride in the food according to the present invention is about 0.00001 to 100% by mass (hereinafter expressed as %), preferably about 0.0005 to 50% as a solid content. and good results.
  • Specific examples of the above-mentioned foods include foods for people with high blood sugar levels in terms of diabetes, foods for improving glaucoma and retinitis pigmentosa in terms of eye diseases, and dementia, improving memory, and improving cerebral blood flow in terms of neurodegenerative diseases.
  • High blood pressure headache, nausea, vomiting, disturbance of consciousness, convulsions, foods for people with high blood pressure; renal disorder; ), foods for normalizing growth such as stature such as skeletal dysplasia (chondrogenesis), and the like, but are not limited to these.
  • the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
  • the unit % of numerical values indicating the addition amount of various components means % by mass.
  • basal medium contains 3.6% glucose, 0.5% sodium glutamate, 0.2% yeast extract, 1% sea salt, 10% whey plus 50 mM valine and 25 mM sodium propionate.
  • prepared by adding Cultivation was maintained at 25° C. and pH of 7.40 to 7.75 (1.0 M NaOH solution was used for pH adjustment) and cultured for 72 to 96 hours.
  • composition analysis of pentadecanoic acid triglyceride 0.50 mL of 14% BF 3 -methanol and 0.25 mL of methyl acetate were added to the lipid containing pentadecanoic acid triglyceride obtained in Production Example 1 and heated at 70° C. for 30 minutes to obtain a fatty acid methyl ester (FAME). rice field. Exactly 1.0 mL of n-hexane and 5 mL of physiological saline were added to the reaction solution and vigorously mixed. The mixture was centrifuged at 2800 rpm for 10 minutes, and the n-hexane layer was used as a sample for gas chromatography.
  • the above sample was analyzed using a gas chromatograph GC-2025 manufactured by Shimadzu Corporation.
  • the analysis conditions were to use an Agilent J&W GC column DB-23 (30 m x 0.25 mm), inject 1 ⁇ L of sample, and detect with an FID (flame ionization detector) with a carrier gas (He, 14 psi). bottom.
  • FID flame ionization detector
  • He carrier gas
  • the molecular species of FAME was identified based on the retention time of fatty acid methyl ester standards (manufactured by GL Sciences).
  • the fatty acid composition was obtained from the area ratio.
  • the calculated composition is a mass ratio.
  • the proportion of odd-chain fatty acids was determined by multiplying the total fatty acid content by the proportion (%) of odd-chain fatty acids (C13, C15, C17). The results obtained are shown in Table 1 below.
  • the content of odd-numbered chain fatty acids in the triglyceride obtained in Production Example 1 was 68.3% by mass. Moreover, it was found that the fatty acid is mainly a triglyceride composed of a pentadecanoic acid residue (C15) and a palmitic acid residue (C16).
  • the lipid containing pentadecanoic acid triglyceride obtained in Production Example 1 was analyzed by mass spectrometry using Thermo Fischer's Orbitrap mass spectrometer Exactive Plus (AMR's DART ion source).
  • AMR's DART ion source Thermo Fischer's Orbitrap mass spectrometer Exactive Plus (AMR's DART ion source).
  • the pentadecanoic acid triglyceride obtained in Production Example 1 was composed of a triglyceride formed only by the pentadecanoic acid residue (C15) and palmitin in 2 units of the pentadecanoic acid residue (C15). It was found to be a triglyceride mixture mainly containing triglycerides containing one unit of acid residue (C16).
  • Example 1 Investigation of cell death inhibitory effect by suppression of endoplasmic reticulum stress reduction by PdATG
  • a solution obtained by dissolving the pentadecanoic acid triglyceride obtained in Production Example 1 in ethanol was used as a test drug.
  • conducted the following experiments. ⁇ Test method Two mouse hippocampal neurons (HT22: hippocampal-derived cell line) were seeded in a 10-cm culture dish at a density of 4 ⁇ 10 5 cells/dish, and placed in an incubator at 37° C. and 5% CO 2 overnight. cultured.
  • test drug (50 ⁇ g/mL) treatment group and the solvent (ethanol) treatment group were treated, and the test drug or solvent was treated in the culture medium for 72 hours (3 days) at 37°C for 5 days. Cultured in an incubator with % CO2 . After confirming that both groups were 90% or more confluent (confirming that the drug treatment had no effect on cell division), they were newly seeded in a 96-well plate at a density of 4000 cells/well, Cultured in an incubator at 37° C., 5% CO 2 .
  • tunicamycin manufactured by Sigma
  • an endoplasmic reticulum stress inducer was added to the medium to a concentration of 0.1, 1, 5, 10, 25 or 50 ⁇ g/mL, and the mixture was incubated at 37°C. Cultured for 24 hours in a 5% CO 2 incubator. After that, the survival rate was measured by the MTT method. The cell viability in the other wells was calculated based on the viability of the tunicamycin-untreated cells in the solvent-treated group as 100%. The results are shown in Table 2 and FIG.
  • MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide) was added to cell culture, and the amount of the added MTT decomposed was measured. It is a chromogenic detection method for analyzing the number of viable cells by measuring. Specifically, when cells grown on a culture dish are incubated in an MTT solution, a water-insoluble formazan pigment is produced mainly depending on the enzymatic activity of mitochondria. After the formazan dye is solubilized, it is measured with a spectrophotometer. Since the obtained absorbance is proportional to the number of viable cells, it is possible to relatively compare the degree of cell proliferation.
  • Example 2 By treating pancreatic cells with tunicamycin, endoplasmic reticulum stressed pancreatic cells can be generated.
  • these cells were treated with the pentadecanoic acid triglyceride (PdATG) mixture obtained in Production Example 1, the expression gene level of the transcription factor XBP1 expressed in the pancreatic cells was measured by real-time PCR. The expression level was expressed as a relative expression level when the expression level of normal cells was set to 100.
  • PdATG pentadecanoic acid triglyceride
  • the PdATG according to the present invention is used to prevent, prevent progression, and improve forgetfulness, decline in comprehension/judgment, memory impairment, disorientation, executive dysfunction, aphasia/arpraxia/agnosia, and dementia. It is possible to provide an endoplasmic reticulum stress prevention/suppression agent that is capable of suppressing side effects and has no or few side effects. It is useful as a health food and medicine for preventing and alleviating nerve cell death, preventing the onset of dementia, preventing progression of symptoms, and alleviating and improving symptoms.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Biotechnology (AREA)
  • Mycology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Botany (AREA)
  • Emergency Medicine (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Toxicology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Nutrition Science (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Medicines Containing Plant Substances (AREA)
PCT/JP2022/038842 2021-10-20 2022-10-19 小胞体ストレス抑制剤、神経変性疾患予防改善剤および認知症の予防・進行防止・改善剤、並びに食品 Ceased WO2023068285A1 (ja)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/702,472 US20240415797A1 (en) 2021-10-20 2022-10-19 Endoplasmic reticulum stress inhibitor, neurodegenerative disease preventing/improving agent, agent for prevention/progression prevention/improvement of dementia, and food product

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021-171332 2021-10-20
JP2021171332A JP2023061448A (ja) 2021-10-20 2021-10-20 小胞体ストレス抑制剤、神経変性疾患予防改善剤および認知症の予防・進行防止・改善剤、並びに食品

Publications (1)

Publication Number Publication Date
WO2023068285A1 true WO2023068285A1 (ja) 2023-04-27

Family

ID=86059189

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/038842 Ceased WO2023068285A1 (ja) 2021-10-20 2022-10-19 小胞体ストレス抑制剤、神経変性疾患予防改善剤および認知症の予防・進行防止・改善剤、並びに食品

Country Status (3)

Country Link
US (1) US20240415797A1 (https=)
JP (1) JP2023061448A (https=)
WO (1) WO2023068285A1 (https=)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117298087A (zh) * 2023-10-17 2023-12-29 张岳峰 促血液药物颅内转运合剂及其应用
JP2025095964A (ja) * 2023-12-15 2025-06-26 リファインホールディングス株式会社 疲労回復剤、抗疲労作用剤および疲労回復用飲食物

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019052629A1 (en) * 2017-09-12 2019-03-21 Sunregen Healthcare Ag LIPIDS HAVING AN IMPERATIVE NUMBER OF CARBON ATOMS AND THEIR USE AS A PHARMACEUTICAL COMPOSITION OR FOOD SUPPLEMENT
JP2019518034A (ja) * 2016-06-08 2019-06-27 サンレーゲン ヘルスケア アーゲー 奇数個の炭素原子を有する脂質及び医薬組成物又は栄養補助食品としてのそれらの使用
WO2020054804A1 (ja) * 2018-09-13 2020-03-19 リファインホールディングス株式会社 奇数脂肪酸エステルの製造方法及び培養組成物
JP2020533019A (ja) * 2017-08-23 2020-11-19 シンプロミクス・リミテッド 制御可能なイントロンを用いる発現調節
WO2021020514A1 (ja) * 2019-07-31 2021-02-04 リファインホールディングス株式会社 コラーゲン産生促進剤、シワ改善剤、皮膚外用剤および美容飲食品
WO2021107084A1 (ja) * 2019-11-27 2021-06-03 リファインホールディングス株式会社 インスリン分泌促進剤並びにこれを用いた血糖値改善剤、糖尿病改善剤及び食品

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019518034A (ja) * 2016-06-08 2019-06-27 サンレーゲン ヘルスケア アーゲー 奇数個の炭素原子を有する脂質及び医薬組成物又は栄養補助食品としてのそれらの使用
JP2020533019A (ja) * 2017-08-23 2020-11-19 シンプロミクス・リミテッド 制御可能なイントロンを用いる発現調節
WO2019052629A1 (en) * 2017-09-12 2019-03-21 Sunregen Healthcare Ag LIPIDS HAVING AN IMPERATIVE NUMBER OF CARBON ATOMS AND THEIR USE AS A PHARMACEUTICAL COMPOSITION OR FOOD SUPPLEMENT
WO2020054804A1 (ja) * 2018-09-13 2020-03-19 リファインホールディングス株式会社 奇数脂肪酸エステルの製造方法及び培養組成物
WO2021020514A1 (ja) * 2019-07-31 2021-02-04 リファインホールディングス株式会社 コラーゲン産生促進剤、シワ改善剤、皮膚外用剤および美容飲食品
WO2021107084A1 (ja) * 2019-11-27 2021-06-03 リファインホールディングス株式会社 インスリン分泌促進剤並びにこれを用いた血糖値改善剤、糖尿病改善剤及び食品

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BOUREBABA LYNDA; MICHALAK IZABELA; ROCKEN MICHAEL; MARYCZ KRZYSZTOF: "Cladophora glomeratamethanolic extract decreases oxidative stress and improves viability and mitochondrial potential in equine adipose derived mesenchymal stem cells (ASCs)", BIOMEDICINE & PHARMACOTHERAPY, vol. 111, 1 January 1900 (1900-01-01), FR , pages 6 - 18, XP085604403, ISSN: 0753-3322, DOI: 10.1016/j.biopha.2018.12.020 *
MARYCZ KRZYSZTOF, MICHALAK IZABELA, KOCHEROVA IEVGENIIA, MARĘDZIAK MONIKA, WEISS CHRISTINE: "The Cladophora glomerata Enriched by Biosorption Process in Cr(III) Improves Viability, and Reduces Oxidative Stress and Apoptosis in Equine Metabolic Syndrome Derived Adipose Mesenchymal Stromal Stem Cells (ASCs) and Their Extracellular Vesicles (MV’s)", MARINE DRUGS, vol. 15, no. 12, pages 385, XP093057647, DOI: 10.3390/md15120385 *
SASAKI KAZUNORI, GERIBALDI-DOLDÁN NOELIA, WU QINGQING, DAVIES JULIE, SZELE FRANCIS G., ISODA HIROKO: "Microalgae Aurantiochytrium Sp. Increases Neurogenesis and Improves Spatial Learning and Memory in Senescence-Accelerated Mouse-Prone 8 Mice", FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, vol. 8, XP093057643, DOI: 10.3389/fcell.2020.600575 *
TSUBOI, MAKOTO ET AL.: "Alleviating endoplasmic reticulum stress in human skin cells caused by photoaging", FRAGRANCE JOURNAL, vol. 50, no. 7, 15 July 2022 (2022-07-15), pages 43 - 53 *
TSUBOI, MAKOTO.: "A new endoplasmic reticulum stress-relieving component produced by the microalga Aurantiochytrium limacinum", FRAGRANCE JOURNAL, vol. 50, no. 9, 15 September 2022 (2022-09-15), pages 37 - 42, XP009545367 *
TSUBOI, MAKOTO: "New Anti-Aging Science Food Ingredients that Alleviate Endoplasmic Reticulum Stress", FOOD PROCESSING AND INGREDIENTS, vol. 57, no. 7, July 2022 (2022-07-01), pages 88 - 89, XP009545375 *
TSUBOI, MAKOTO: "New Health Function Nutrients Included in Edible Microalgae: Hitherto Unknown Physical Health-Promoting Nutrients Made Clear", FOOD STYLE, vol. 26, no. 5, May 2022 (2022-05-01), pages 33 - 36, XP009545388 *
WANG FANG, LI HAILI, ZHAO HANG, ZHANG YA, QIU PENGCHENG, LI JIE, WANG SIWANG: "Antidiabetic Activity and Chemical Composition of Sanbai Melon Seed Oil", EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE, vol. 2018, 1 January 2018 (2018-01-01), US , pages 1 - 14, XP093057645, ISSN: 1741-427X, DOI: 10.1155/2018/5434156 *

Also Published As

Publication number Publication date
JP2023061448A (ja) 2023-05-02
US20240415797A1 (en) 2024-12-19

Similar Documents

Publication Publication Date Title
JP6705599B2 (ja) エイコサペンタエン酸生成微生物、脂肪酸組成物、ならびにそれらを作る方法およびそれらの使用
Kannan et al. Microbial production of omega‐3 fatty acids: an overview
AU2012285806B2 (en) Fatty acid compositions
JP7685134B2 (ja) インスリン分泌促進剤並びにこれを用いた血糖値改善剤、糖尿病改善剤及び食品
AU2016203427A1 (en) Thraustochytrids, fatty acid compositions, and methods of making and uses thereof
KR20140019840A (ko) 스키조키트리움 종의 돌연변이유발 방법 및 이의 생성되는 변이체 균주
WO2023068285A1 (ja) 小胞体ストレス抑制剤、神経変性疾患予防改善剤および認知症の予防・進行防止・改善剤、並びに食品
JP2007008863A (ja) 器質的脳障害に起因する高次脳機能の低下に対する改善作用を有する組成物
JP2015096494A (ja) 生体内酸化還元状態改善剤
US9687422B2 (en) Method for producing carotenoid-containing composition, and carotenoid-containing composition
JP2016172770A (ja) 器質的脳障害に起因する高次脳機能の低下に対する改善作用を有する組成物
JP2024176004A (ja) 小胞体ストレス抑制剤、慢性腎臓病疾患予防改善剤および食品
US20260060952A1 (en) Prophylactic, Progression Inhibitor, Ameliorant for Visual Field Defect Disorders, Light-Induced Ocular Tissue Disorders and Related Disorders, and Food Product
WO2025127147A1 (ja) 疲労回復剤、抗疲労作用剤および疲労回復用飲食物
Manjula et al. Biotechnology of microalgae: A green approach towards exploitation of omega-3 fatty acids
JP2014152118A (ja) 老化抑制剤
JP2025115705A (ja) 炎症性サイトカイン抑制剤
JP5496163B2 (ja) 脳機能の低下に起因する症状あるいは疾患の予防又は改善作用を有する組成物
CN104988078B (zh) 破囊壶菌、脂肪酸组合物和其制备方法及用途
JP6938163B2 (ja) 脂質組成物、その用途及びその製造方法
HK1241413A (en) Thraustochytrids, fatty acid compositions, and methods of making and uses thereof
JP2014205710A (ja) 器質的脳障害に起因する高次脳機能の低下に対する改善作用を有する組成物
HK40013094A (en) Thraustochytrids, fatty acid compositions, and methods of making and uses thereof
HK1166514B (en) Thraustochytrids, fatty acid compositions, and methods of making and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22883589

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 18702472

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22883589

Country of ref document: EP

Kind code of ref document: A1