WO2022050756A1 - Composition pour la prolifération hépatocellulaire ou l'efficacité anti-inflammatoire comprenant des exosomes dérivés du placenta - Google Patents

Composition pour la prolifération hépatocellulaire ou l'efficacité anti-inflammatoire comprenant des exosomes dérivés du placenta Download PDF

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WO2022050756A1
WO2022050756A1 PCT/KR2021/011922 KR2021011922W WO2022050756A1 WO 2022050756 A1 WO2022050756 A1 WO 2022050756A1 KR 2021011922 W KR2021011922 W KR 2021011922W WO 2022050756 A1 WO2022050756 A1 WO 2022050756A1
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placenta
liver
derived
exosome
exosomes
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PCT/KR2021/011922
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Korean (ko)
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임민주
정경수
한혜정
유영효
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(주)녹십자웰빙
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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
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/50—Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/20—Natural extracts
    • A23V2250/204—Animal extracts

Definitions

  • the present invention relates to a composition for hepatocellular proliferation or anti-inflammatory effect comprising a placenta-derived exosome, specifically, a pharmaceutical composition for improving liver function, preventing or treating liver disease, and treating or preventing a disease related to inflammation and It relates to a health functional food composition.
  • the secretome contains various bioactive factors that control the behavior of cells, and in particular, 'exosome' or 'extracellular vesicle' with many functions in the cellular secretion )', so research on its ingredients and functions is being actively conducted.
  • Cells release various membrane types of ERs to the extracellular environment, and these ERs are commonly referred to as extracellular vesicles (EVs).
  • EVs extracellular vesicles
  • the extracellular vesicles are also called cell membrane-derived ERs, ectosomes, shedding vesicles, microparticles, exosomes, and the like, and in some cases, they are used separately from exosomes.
  • Exosomes are nano-sized bi-lipid membrane vesicles secreted from living cells that play an important role in cell-to-cell communication.
  • the placenta plays an important role in regulating physiological homeostasis or supporting fetal development. It is known that extracellular vesicles and exosomes secreted from the placenta contribute to communication between the placenta and maternal tissues to maintain maternal-fetal resistance.
  • Exosomes contain active biological substances including lipids, cytokines, microRNAs, mRNAs and DNA, as well as proteins that may be present on the surface of exosomes.
  • Exosomes are known to be useful in a number of therapeutic approaches, including immune modulation, promotion of angiogenesis, and drug delivery. Therefore, the demand for more efficient methods that makes it possible to isolate large amounts of exosomes is clearly increasing recently.
  • the liver is one of the major human organs and is responsible for protein synthesis, metabolism, especially lipid metabolism.
  • Fatty liver caused by alcohol or metabolic syndrome causes general abnormalities in the body.
  • Dietary therapy is being implemented as a treatment for alleviating the symptoms of lipid or fat accumulation.
  • a method for fundamentally treating lipid or fat accumulation in the liver has not been developed.
  • inflammatory diseases can be acute, chronic, ulcerative, allergic or necrotic, whether any disease is acute, chronic, ulcerative, allergic or necrotic so long as it falls within the definition of an inflammatory disease as above. regardless of gender
  • Hepatitis is a disease caused by viruses, alcohol, drugs, and immune disorders. It can be interpreted as an all-inclusive term. Fatty hepatitis is diagnosed by distinguishing between non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH), in which an excessive amount of triglyceride is accumulated in the liver regardless of drinking. Fat Liver Disease) and non-alcoholic fatty liver (NAFLD, Non-alcoholic Fat Liver Disease) are being diagnosed.
  • NASH non-alcoholic steatohepatitis
  • NASH alcoholic steatohepatitis
  • Fat Liver Disease and non-alcoholic fatty liver
  • NAFLD Non-alcoholic Fat Liver Disease
  • An object of the present invention is to improve the symptoms of jaundice caused by hepatitis (NASH, ASH, NAFLD or AFLD), liver cirrhosis, liver fibrosis, cirrhosis, fatty liver or liver disease, including liver tissue regeneration including placental-derived exosomes, improvement of liver function , to provide a pharmaceutical composition or food composition for prevention or treatment.
  • NASH hepatitis
  • ASH ASH
  • NAFLD AFLD
  • AFLD AFLD
  • liver cirrhosis liver fibrosis
  • cirrhosis fatty liver or liver disease
  • liver tissue regeneration including placental-derived exosomes
  • Hepatocellular proliferation or anti-inflammatory efficacy pharmaceutical composition comprising placental-derived exosomes.
  • composition according to the above characterized in that the exosomes derived from dried placenta dried placenta.
  • hepatitis NASH, NAFLD or AFLD
  • liver cirrhosis liver fibrosis
  • cirrhosis fatty liver or liver disease, including liver tissue regeneration, liver function improvement, liver cell proliferation or hepatoprotective effect
  • a pharmaceutical composition for improving symptoms of jaundice A pharmaceutical composition for improving symptoms of jaundice.
  • Hepatocyte proliferation or anti-inflammatory functional food composition comprising placental-derived exosomes.
  • hepatitis NASH, NAFLD or AFLD
  • liver cirrhosis liver fibrosis
  • liver cirrhosis fatty liver or liver disease, including liver tissue regeneration, liver function improvement, liver cell proliferation or hepatoprotective effect
  • Functional food composition for improving symptoms of jaundice.
  • the exosome according to the present invention proliferates hepatocytes and has an anti-inflammatory effect, so the effect of regenerating liver tissue is excellent, so that hepatitis (NASH, ASH, NAFLD or AFLD), liver cirrhosis, liver It can be used for the purpose of preventing, improving, or treating the symptoms of jaundice caused by fibrosis, cirrhosis, fatty liver or liver disease.
  • hepatitis NASH, NAFLD or AFLD
  • liver cirrhosis liver cirrhosis
  • Figure 2 is a TEM (Transmission Electron Microscopy; Transmission Electron Microscopy) results of exosomes derived from the placenta.
  • 3 is a result of confirming the surface protein marker of the exosome derived from the placenta using an antibody.
  • the exosome derived from the placenta of the present invention prevents symptoms of jaundice caused by hepatitis (NASH, ASH, NAFLD or AFLD), cirrhosis, liver fibrosis, cirrhosis, fatty liver or liver disease, including liver tissue regeneration and improvement of liver function, It was found to have an effect of improving or treating, and thus the present invention was completed.
  • NASH hepatitis
  • ASH ASH
  • NAFLD AFLD
  • cirrhosis cirrhosis
  • liver fibrosis cirrhosis
  • cirrhosis fatty liver or liver disease, including liver tissue regeneration and improvement of liver function
  • the placenta-derived exosome according to the present invention may be obtained from, for example, drying or culturing the placenta, separating and purifying it, and the remaining culture medium or supernatant, but does not contain placental cells and does not contain culture supernatant.
  • purified exosomes are formulated into pharmaceutical compositions suitable for administration to a subject in need thereof.
  • the subject is a human.
  • the placental-derived exosome-containing pharmaceutical composition provided herein is administered to a subject in need thereof locally, subcutaneously, systemically, parenterally, intravenously, intramuscularly, externally (topical), orally, intradermally, It may be formulated for transdermal or intranasal administration.
  • a pharmaceutical composition containing placental derived exosomes provided herein is formulated for local administration.
  • the pharmaceutical compositions containing placental derived exosomes provided herein are formulated for systemic subcutaneous administration.
  • a pharmaceutical composition containing placental derived exosomes provided herein is formulated for parenteral administration. In certain embodiments, a pharmaceutical composition containing placental derived exosomes provided herein is formulated for intramuscular administration. In certain embodiments, a pharmaceutical composition containing placental-derived exosomes provided herein is formulated for topical administration. In certain embodiments, the placental-derived exosome-containing pharmaceutical compositions provided herein are formulated for oral administration. In certain embodiments, a pharmaceutical composition containing placental-derived exosomes provided herein is formulated for intradermal administration. In certain embodiments, a pharmaceutical composition containing placental-derived exosomes provided herein is formulated for transdermal administration.
  • a pharmaceutical composition containing placental derived exosomes provided herein is formulated for intranasal administration.
  • the placental-derived exosome-containing pharmaceutical composition provided herein is formulated for intravenous administration.
  • the placenta-derived exosome according to the present invention is obtained by using a commercially available exosome separation reagent (eg, ExoQuick-TCTM) or by using the TFF (Tangential Flow Filtration) method.
  • exosomes can be obtained from the placenta, a culture medium of the placenta, or a dry placenta using ultracentrifuge, ultrafiltration, or SEC (Size Exclusion Chromatography) methods. It is not limited only to the exosome obtaining method described in.
  • composition comprising exosomes derived from human placenta, wherein the exosomes are CD1c, CD20, CD24, CD25, CD29, CD2, CD3, CD8, CD9, CD11c, CD14, CD19, CD31, CD40, CD41b, CD42a, CD44, CD45, CD49e, CD4, CD56, CD62P, CD63, CD69, CD81, CD86, CD105, CD133-1, CD142, CD146, CD209, CD326, HLA-ABC, HLA-DRDPDQ, MCSP, ROR1, SSEA- 4 or a combination thereof.
  • exosomes are CD1c, CD20, CD24, CD25, CD29, CD2, CD3, CD8, CD9, CD11c, CD14, CD19, CD31, CD40, CD41b, CD42a, CD44, CD45, CD49e, CD4, CD56, CD62P, CD63, CD69, CD81, CD86, CD105, CD133-1, CD142, CD146
  • exosomes described herein contain specific markers. Such markers may be useful, for example, in the identification of exosomes, and in differentiating them from other exosomes, eg, exosomes not derived from the placenta. In certain embodiments, such exosomes are positive for one or more markers determinable by flow cytometry, such as fluorescence-activated cell sorting (FACS). In addition, the exosomes provided herein can be identified based on the absence of specific markers. Determination of the presence or absence of such markers can be determined using methods known in the art, for example, fluorescence-activated cell sorting (FACS).
  • FACS fluorescence-activated cell sorting
  • the exosomes are CD3-, CD11b-, CD14-, CD19-, CD33-, CD192-, HLA-A-, HLA-B-, HLA-C-, HLA-DR-, CD11c - or CD34-. In some embodiments, the exosomes are CD3-, CD11b-, CD14-, CD19-, CD33-, CD192-, HLA-A-, HLA-B-, HLA-C-, HLA-DR-, CD11c- and CD34 -am.
  • exosomes comprise non-coding RNA molecules.
  • inflammatory diseases include atopic dermatitis, psoriasis, dermatitis, allergy, arthritis, rhinitis, otitis media, sore throat, tonsillitis, cystitis, nephritis, pelvic inflammation, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematodes (SLE) , atherosclerosis, asthma, arteriosclerosis, edema, rheumatoid arthritis, delayed allergy (type IV allergy), transplant rejection, graft-versus-host disease, autoimmune encephalomyelitis, multiple sclerosis, arthritis, cystic fibrosis, diabetic retinopathy, rhinitis , ischemic-reperfusion injury, vascular restenosis, glomerulonephritis, gastrointestinal allergy, etc., but are not limited thereto.
  • SLE systemic lupus erythematodes
  • diseases associated with inflammation include acne vulgaris, asthma, autoimmune diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel disease inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis ) is included. Many diseases are associated with inflammation or are classified as autoimmune diseases.
  • Some different types of inflammatory diseases include gout, lupus, asthma, pleurisy, eczema, arthritis, gastritis, splenitis, sinusitis, hepatitis ( hepatitis, nephritis, psoriasis, vasculitis, laryngitis, thyroiditis, prostatitis, pharyngitis, sarcoidosis, atherosclerosis, allergic reactions, multiple sclerosis sclerosis, some myopathies, rheumatoid arthritis, seborrheic dermatitis, Wegener's granulomatosis, irritable bowel syndrome (IBS; Crohn's disease), ulcerative colitis colitis) and diverticulitis.
  • diseases related to inflammation include sepsis, polychondritis, scleroderma, periodontitis, gingivitis, Behcet's syndrome, vasculitis, Kawasaki disease, pancreatitis, bronchitis, inflammatory skin disease, stomatitis, peritonitis, stroke, cerebral infarction, Alzheimer's disease, Parkinson's disease, paresis Jet's disease, conjunctivitis, pneumonia, gastric ulcer, colitis, hemorrhoids, rheumatic lupus, parotiditis, tendinitis, myositis, Sjogren's syndrome, appendicitis, encephalitis, encephalomyelitis, biliary tract infection, mastitis, ulceris, scleritis, uveitis, aphthous stomatitis, etc. It is not limited to the diseases described in
  • the pharmaceutical composition of the present invention may be formulated as a pharmaceutical preparation for the prevention and treatment of skin diseases or liver diseases, including pharmaceutically acceptable carriers, diluents or excipients.
  • exosomes and/or pharmaceutical compositions comprising exosomes described herein can be used as hepatoprotective agents.
  • the exosomes and/or the pharmaceutical composition comprising the exosomes described herein may be provided in the form of a kit suitable for pharmaceutical use.
  • the carrier, excipient and diluent include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose. , microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition of the present invention is formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods to be prepared into pharmaceutical preparations.
  • oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods to be prepared into pharmaceutical preparations.
  • a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, etc. usually used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the pharmaceutical composition, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. It can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral use include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives are included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
  • the dosage of the pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, but generally in an amount of 0.1 to 100 mg/kg, preferably in an amount of 1 to 30 mg/kg, once a day to several It can be administered in divided doses. Also, the dosage may be increased or decreased according to the route of administration, the degree of disease, sex, weight, age, health status, diet, administration time, administration method, excretion rate, etc. Accordingly, the above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, dermal application, oral, rectal or intravenous, intramuscular, subcutaneous, intradermal, intrauterine dural administration, intranasal (nasal), inhalation administration using a nebulizer, etc. Alternatively, it may be administered by intracerebrovascular injection or the like. For the purpose of improving or preventing liver disease, the pharmaceutical composition of the present invention may be administered directly into the portal vein or hepatic vein.
  • the placenta prior to obtaining the exosome of the present invention is derived from a human, but is not limited thereto.
  • Trypsin-EDTA reagent was used in order to homogenize the dry placenta. 250 mg of dried placental tissue was mixed with 20 mL of Trypsin 0.25%-EDTA reagent and stirred vigorously. This mixture was incubated at 4 °C for 72 h. It was also possible to incubate at 37° C. when a trypsin reagent was used. Thereafter, centrifugation was performed at 6,000 rpm for 30 minutes to remove tissue and cellular impurities in the mixture, and the supernatant was purified using a 0.22 ⁇ m filter. If a 0.22 ⁇ m filter is used, cells and cell debris present in the pretreated dry placenta are removed.
  • ExoQuick-TCTM dry placenta solution from which cells and cellular impurities have been removed with ExoQuick-TCTM in a ratio of 5:1. This was incubated overnight at 4 °C. The next day, centrifuged at 1,500 x g at 4 °C for 30 min and the supernatant was removed. After centrifugation was performed once more at 1,500 x g at 4 °C for 5 minutes to remove all possible remaining fluid, the supernatant was completely removed. 200 ⁇ l of PBS was added to the exosome pellet and resuspended. The exosomes isolated in this process were named exosomes (EXQ) for convenience.
  • EXQ exosomes
  • Exosomes were isolated and concentrated using a TFF (Tangential Flow Filtration) method from the placenta filtered with a 0.22 ⁇ m filter.
  • a cassette filter Merck Millipore was used for the TFF method.
  • the TFF filter can be selected for the purpose of various molecular weight cutoff (MWCO), and in this experiment, a filter with a MWCO of 300,000 Da (Dalton) was used in consideration of the molecular weight of the exosome.
  • Exosomes were selectively separated and concentrated by the selected MWCO filter, and particles smaller than 300,000 Da, proteins, lipids, nucleic acids, and low molecular weight compounds were removed.
  • Exosomes isolated from the placenta were appropriately diluted in PBS, and the size distribution and concentration of exosome particles were measured using Nanosight (NS300, Malvern, UK) according to the device usage method.
  • the exosomes isolated from the placenta were fixed on a grid for 1 minute and washed with sterile water. After staining with 2% uranyl acetate for 20 seconds, the completely dried grid was photographed with a TEM (Transmission electron microscope, Talos L120C, FEI, Czech).
  • Exo-Check Exosome Antibody Arrays (EXORAY200A-4, System Bioscience, USA) were used to identify 8 types of surface protein markers (CD63, CD81, ALIX, FLOT1, ICAM1, EpCam, ANXA5, TSG101) of exosomes isolated from placenta. was used. Exosomes separated from the placenta and 1 X blocking buffer were added to the membrane provided by the Exo-Check Exosome Antibody Arrays kit and reacted at 2-8 °C for 24 hours. After the reaction, it was washed twice with 1 X Washing buffer at room temperature for 5 minutes each. Then, after adding 5ml Detection buffer and reacting at room temperature for 30 minutes, luminescence signals were obtained and the expression level of each protein was analyzed by chemiluminescence (FUSION_SOLO.6S, Vilber, France).
  • human hepatocellular carcinoma HepG2 cells were dispensed into a 96-well plate at 1 x 10 4 cells per well, and then Cell culture conditions were cultured for 24 hours.
  • the hepatocyte proliferation efficacy was confirmed by removing the existing medium, treating the test substance and culturing alone for 24 hours.
  • D-GalN D-Galactosamine
  • EXQ placental-derived exosome
  • hepatocyte proliferative capacity was increased in a concentration-dependent manner by placental-derived exosomes, and in particular, the 10% treatment group of placental-derived exosomes exhibited up to 179% of the proliferative capacity promotion compared to the control group.
  • the hepatocellular protection efficacy was confirmed by constructing a cytotoxicity model by treating D-GalN, known as a hepatotoxicity-inducing substance, by inhibiting RNA and protein synthesis in hepatocytes.
  • D-GalN known as a hepatotoxicity-inducing substance
  • the cell viability decreased by the D-GalN treatment was effectively recovered by the dry placenta-derived exosomes, which can be inferred to have hepatocellular protective efficacy against liver damage diseases.
  • the hepatocyte proliferation efficacy of placental-derived exosomes is due to growth factors or physiologically active substances present in the placenta. (Fig. 4)
  • Mouse macrophages (RAW264.7 cells) were seeded in a 96 well plate at 1 x 10 5 cells/well and cultured for 24 hours in cell culture conditions. The old medium was removed and lipopolysaccharide (LPS) and test substance (EXQ) were simultaneously treated and incubated for 24 hours. LPS used at this time is one of the components of the cell wall of Gram-negative bacteria and is a representative pathogenic substance that induces an inflammatory response in cells. Then, the cell culture solution and the Griess reagent were mixed in a 1:1 ratio and reacted at room temperature for 15 minutes. And the absorbance was measured at 540 nm using a spectrophotometer, and through this, the ability to inhibit nitric oxide (NO) production was measured. As a positive control group, diclofenac, a nonsteroidal anti-inflammatory drug used for inflammation treatment, was used, and the inhibition rate of NO production in each group was calculated as a percentage (%) compared to that of the control group.
  • LPS lip
  • test substance EXQ was diluted two-fold from 10% to 1.25% and treated, followed by NO assay.

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Abstract

La présente invention concerne une composition pharmaceutique ou une composition alimentaire fonctionnelle pour la santé pour l'amélioration, la prévention ou le traitement de maladies hépatiques et une efficacité anti-inflammatoire, qui, en comprenant des exosomes dérivés du placenta, a d'excellents effets de prolifération hépatocellulaire et anti-inflammation.
PCT/KR2021/011922 2020-09-03 2021-09-03 Composition pour la prolifération hépatocellulaire ou l'efficacité anti-inflammatoire comprenant des exosomes dérivés du placenta WO2022050756A1 (fr)

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KR20170103697A (ko) * 2016-03-03 2017-09-13 고려대학교 산학협력단 엑소좀 또는 엑소좀 유래 리보핵산을 포함하는 간섬유증 예방 또는 치료용 조성물

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US20170252379A1 (en) * 2014-10-09 2017-09-07 Anthrogenesis Corporation Placenta-derived adherent cell exosomes and uses thereof
KR20170103697A (ko) * 2016-03-03 2017-09-13 고려대학교 산학협력단 엑소좀 또는 엑소좀 유래 리보핵산을 포함하는 간섬유증 예방 또는 치료용 조성물

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CAO HONGMEI, YUE ZHIWEI, GAO HEQI, CHEN CHAO, CUI KAIGE, ZHANG KAIYUE, CHENG YUANQIU, SHAO GUOQIANG, KONG DELING, LI ZONGJIN, DING: "In Vivo Real-Time Imaging of Extracellular Vesicles in Liver Regeneration via Aggregation-Induced Emission Luminogens", ACS NANO, vol. 13, no. 3, 26 March 2019 (2019-03-26), US , pages 3522 - 3533, XP055907713, ISSN: 1936-0851, DOI: 10.1021/acsnano.8b09776 *
DUAN LIYUN, HUANG HAOYAN, ZHAO XIAOTONG, ZHOU MANQIAN, CHEN SHANG, WANG CHEN, HAN ZHIBO, HAN ZHONG-CHAO, GUO ZHIKUN, LI ZONGJIN, C: "Extracellular vesicles derived from human placental mesenchymal stem cells alleviate experimental colitis in�mice by inhibiting inflammation and oxidative stress", INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, vol. 46, GR , pages 1551 - 1561, XP055907724, ISSN: 1107-3756, DOI: 10.3892/ijmm.2020.4679 *
ZHANG HAN, SILVA ANA CAROLINE, ZHANG WEI, RUTIGLIANO HELOISA, ZHOU ANHONG: "Raman Spectroscopy characterization extracellular vesicles from bovine placenta and peripheral blood mononuclear cells", PLOS ONE, vol. 15, no. 7, pages e0235214, XP055907719, DOI: 10.1371/journal.pone.0235214 *

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