WO2021201303A1 - Functions of dapsone and derivatives of regulating nlrp3 inflammasome activation implicated in various human diseases, such as alzheimer's disease, prion diseases, type 2 diabetes, and infectious diseases - Google Patents

Functions of dapsone and derivatives of regulating nlrp3 inflammasome activation implicated in various human diseases, such as alzheimer's disease, prion diseases, type 2 diabetes, and infectious diseases Download PDF

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WO2021201303A1
WO2021201303A1 PCT/KR2020/004264 KR2020004264W WO2021201303A1 WO 2021201303 A1 WO2021201303 A1 WO 2021201303A1 KR 2020004264 W KR2020004264 W KR 2020004264W WO 2021201303 A1 WO2021201303 A1 WO 2021201303A1
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alzheimer
diseases
dapsone
nlrp3 inflammasome
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이종훈
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    • 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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • TLRs Toll-like receptors
  • the microbody also includes genetic variations in viruses and the TLR itself.
  • TLR-Arg677Trp was found in naive Hansen in Korea. Intracellular mutations in TLR2 may predispose to leprosy leprosy.
  • Hansen Indians having such a TLR-Arg677Trp genomic mutation is also treated with depsone (including rifampicin and clofazamine).
  • Depson is effective in molecular control of NLRP3 inflammasome in mild cognitive impairment, Parkinson's disease, and Alzheimer's disease (Lee, Choi et al. 2020).
  • depson can act as an allosteric regulation that can control the activity of the NLRP3 inflammasome even if there is a TLR-Arg677Trp genomic mutation.
  • TLR-Arg677Trp was reported to be present in Korean patients with lepromatous leprosy exclusively.
  • the mutation in the intracellular domain of TLR2 has a role in susceptibility to LL but LL was treated by dapsone with rifampicin, and clofazimine.
  • DDS among three antibiotics should be effective for molecular regulation of NLRP3 inflammasome activators such as MCI, PD and AD. (Lee, Choi et al. 2020)
  • NLRP3 itself or up-/downstream factors of NLRP3 inflammasome by DDS may produce therapeutic effects.
  • the human SARS virus and the MERS virus were identified as carriers of civets and camels, respectively. They are 99% genetically similar to the human coronavirus. However, it is known that COVID-19, which is found in humans, is genetically different from the coronavirus found in bats and pangolins.
  • the research team conducted a study to determine whether genetic mutation occurred through animal vectors or whether genetic mutation occurred due to infection in humans.
  • the research team suggested the possibility that the COVID-19 virus may have appeared as a lethal disease through genetic mutation in the process of adapting to humans after it was transmitted to humans years or decades ago.
  • the present invention is to save patients from acute pneumonia and premature death by inventing a substance that controls an immune response that causes fatal damage to the human body among the immune functions of the human body.
  • NLRP3 inflammasome which causes severe disease by causing inflammation in various human diseases, such as Alzheimer's disease, prion disease, type 2 diabetes, and various infectious diseases, is controlled.
  • Alzheimer's disease prion disease
  • type 2 diabetes a malignant neoplasm originating from a pre-neoplasm originating from a pre-neoplasm originating from a pre-neoplasm originating from a pre-neoplasm originating from a pre-neoplasm originating from a pre-neoplasm originating from a pre-neoplasm originating from a pre-neoplasm originating from various infectious diseases.
  • infectious diseases related to the inflammasome are Alzheimer's disease, prion disease, type 2 diabetes, and various infectious diseases.
  • Depsone is a therapeutic agent for Alzheimer's disease and can be used as a treatment for various infectious diseases such as COVID-19.
  • DDS was therapeutic substance of the Alzheirmers disease. (Namba, Kawatsu et al. 1992, Kimura and Goto 1993, Chui, Tabira et al. 1994, S Appleby and L Cummings 2013) And DDS may be a therapeutic preventive substance in COVID-19 .
  • CD4 and CD8 T cells were greatly reduced but highly activated in the biopsy tissue of a 50-year-old male.
  • High levels of proinflammatory CCR6+ Th17 were detected in CD4 T cells, and high concentrations of cytotoxic granules were detected in CD8 T cells. This means high activation of T cells.
  • TLRs confer a unique spiking function (by (S) entry protein) to the coronavirus and play a role in infecting mammalian cell receptors well.
  • SARS-CoV is the cause of its notorious high infectivity (Graham and Baric 2010).
  • MERS-CoV also binds well to dipeptidyl peptidase 4 (DPP4; also known as CD26) receptors and mainly infects the lower respiratory tract and other tissues. cling (Raj, Mou et al. 2013).
  • the innate immune system plays a role in the early infectious stages of an infectious disease. After a certain period of time, long-term immunity is acquired.
  • pro-inflammatory cytokines including interleukin (IL)-1 ⁇ and IL-6
  • IL-6 When COVID-19 infects the upper respiratory tract, pro-inflammatory cytokines (including interleukin (IL)-1 ⁇ and IL-6) is secreted and binds to TLR to secrete pro-IL-1 ⁇ , which is degraded by caspase-1 to activate the inflammasome causes Controlling pro-inflammatory IL-1 family members and IL-6 has therapeutic effects in many inflammatory diseases, including viral infections.
  • TLR Toll Like Receptor
  • NLRP3 protein 3 with NOD-, LRR- and pyrin domains
  • mitorondrial protein mitofusin 2 The microantiviral protein MAVS binds to NLRP3 and controls the inflammasome.
  • NLRP3 is an intracellular sensor. It detects a wide range of micromaterials, detects intrinsic danger signals and environmental substances, and forms and activates the NLRP3 inflammasome. When the NLRP3 inflammasome assembles, the pro-inflammatory cytokines IL-1 ⁇ and IL-18 are secreted by caspase-1, and gasdermin D mediated apoptosis by intracellular infectious agents.
  • Dysfunction of NLRP3 domain-containing protein 3 encoded by NOD-, LRR- and pyrin
  • causes various diseases Alzheimer's disease, prion disease, type 2 diabetes mellitus and infectious diseases).
  • cytokines or pathogen-associated molecular patterns induce genetic activation of known or unknown inflammasomes.
  • NLRP3 (NOD-, LRR- and pyrin domain- containing protein 3) inflammasome were activated by mitochondrial protein mitofusin 2.
  • the mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity.
  • NLRP3 is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome.
  • NLRP3 which encodes NOD-, LRR- and pyrin domain-containing protein 3
  • inflammasome activation is implicated in a variety of human diseases including Alzheimer's disease, Prion diseases, type 2 diabetes, and some infectious diseases (Yang, Wang et al. 2019)
  • PAMPs pathogen-associated molecular patterns
  • PAMPs pathogen-associated molecular patterns
  • DAMPs damage-associated molecular patterns
  • FIG. 2 Numerous pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) as shown in FIG. 2 are related to various particles and crystals and ATP and activate various signals.
  • RNA virus activates NLRP3, a mitochondrial antiviral signaling protein (MAVS) located in the outer mitochondrial membrane. Through this, the formation of inflammasome activates caspase 1 to degrade pro-IL-1 ⁇ and produce pro-IL-18 to cause inflammation.
  • MAVS mitochondrial antiviral signaling protein
  • RNA viruses activate NLRP3 through mitochondrial antiviral signaling protein (MAVS) on the mitochondrial outer membrane. Formation of the inflammasome activates caspase 1, which in turn cleaves pro-IL-1 ⁇ and pro-IL-18. (Swanson, Deng et al. 2019)
  • Impairment of TLR function due to gene diversity of TLR causes changes in immune response.
  • a variety of microligands, including gene diversity in viruses and TLR2 and TLR4 are implicated in human infectious diseases.
  • TLR-Arg677Trp was found in naive Hansen in Korea.
  • C is replaced with T.
  • Arg was substituted with Trp.
  • Such mutations were only found in leprosy leprosy and not in leprosy tuberculosis.
  • M. leprae causes leprosy.
  • there was a report that the cause of Alzheimer's disease in Hansen people is probably due to M. leprae bacteria. (Endoh, Kunishita et al. 1999)
  • TLRs Toll-like receptors
  • TLR-Arg677Trp was reported to be present in Korean patients with lepromatous leprosy exclusively.
  • DNA sequencing detected a C to T substitution at nucleotide 2029 from the start codon of the TLR2.
  • the mutation would substitute Arg to Trp at amino acid residue 677, one of the conserved regions of TLR2.
  • the mutation was involved in only lepromatous leprosy (LL), not tuberculoid leprosy and control.
  • leprosy can be cured by administering depsone, rifampicin, and clofazimine. Even if there is a mutation in TLR2 in Korean leprosy leprosy, leprosy can be cured by administering the above medicines.
  • Depsone has been reported to have therapeutic effects on mild cognitive impairment, Parkinson's disease and Alzheimer's disease by inhibiting the NLRP3 inflammasome promoter (allosteric regulation). (Lee, Choi et al. 2020)
  • the longevity index of male lepers on Sorok Island showed significantly higher life expectancy and lower mortality rates by age group than those of similar classes or average Koreans in Korea.
  • the upper panel is the mortality rate by age, and the lower panel is the percentage. There is nothing special about the comparison of the death rate of stagnant Koreans compared to Hansen people. The ratios for 2000 and 2005 are mutually inverted. (Cho, Shim et al. 2014)
  • Fig.4 suggests that leprosy-affected males have had a notably higher life expectancy than the least-educated subpopulation and even all Koreans for the past decade. Furthermore, leprosy-affected males aged 80 years and above have outlived their female counterparts.
  • Fig.5 compares the age-specific death rates of the three populations for 1995, 2000, and 2005. The upper panel presents ASDRs, and the bottom panel gives corresponding ratios.
  • depsone has a therapeutic effect by reducing the inflammatory response by binding at the molecular level to the inflammasome that causes mild cognitive impairment, Parkinson's disease, and Alzheimer's disease (allosteric regulation) (Lee, Choi et al. 2020).
  • Depson controls the inflammatory response by acting directly on the NLRP3 inflammasome, so it is a substance that can exert an anti-inflammatory effect by acting directly on the NLRP3 inflammasome regardless of NEK7, ASC, caspase-1, IL-1 ⁇ or other factors.
  • Depson has a therapeutic effect by reducing the inflammatory response by binding at the molecular level (allosteric regulation) (Lee, Choi et al. 2020) to inflammasomes that cause mild cognitive impairment and Parkinson's disease and Alzheimer's disease.
  • Depson is a substance capable of exhibiting an inflammatory treatment effect by directly acting on the NLRP3 inflammasome regardless of NEK7, ASC, caspase-1, IL-1 ⁇ or other factors by controlling the inflammatory response by acting directly on the NLRP3 inflammasome.
  • Depsone Dapsone, 4,4'-diaminodiphenylsulfone; hereinafter, Depsone or DDS
  • Depsone is a prophylactic treatment for Alzheimer's disease.
  • the group administered with Dapsone 100 mg/day and the control group 20 patients were administered for 52 weeks from mild to advanced patients. This is because, in patients with advanced disease, already extensive neurons are dead. There was an effect of improving cognitive function in patients with mild cognitive impairment and early Alzheimer's disease.
  • a study result was published that showed that there was no transition from mild cognitive impairment to Alzheimer's disease for 10 years, and the symptoms of Parkinson's disease patients improved. (Lee, Choi et al. 2020)
  • English - DDS is a therapeutic preventive substance in Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • Dapsone 100 mg/day
  • placebo placebo were administered orally, once daily for 52 weeks in 201 patients with mild-to-moderate AD.
  • dapsone and placebo were administered orally, once daily for 52 weeks in 201 patients with mild-to-moderate AD.
  • At the end of treatment there were no significant differences between dapsone and placebo on either cognitive or other measures of efficacy.
  • Those results are because patients with mild-to-moderate AD already have extensive neuronal death, and patients with mild cognitive impairment (MCI) and early AD patients were positive. MCI did not worsen from AD for 10 years, and Parkinson's disease (PD) symptoms were observed to change to mild.
  • MCI mild cognitive impairment
  • Depsone blocks nerve damage induced by glutamate agonists (mainly glutamate toxicity after ischemia).
  • glutamate agonists mainly glutamate toxicity after ischemia.
  • Depson has a regulatory effect on mRNA expression and cytokine production by LPS stimulating peripheral blood monocytes. Depson is an inhibitor that suppresses the expression of TNF- ⁇ mRNA and lowers the concentration of TNF- ⁇ in the culture medium.
  • Myeloparoxidase activity is increased 3.7-fold in the ischemic state compared to control mice. Although apoptosis was increased, depsone was effective for 72 hours after the onset of ischemic changes. Depsone showed significant antioxidant, anti-inflammatory, and anti-apoptotic effects during the overall ischemia and reperfusion period. (Diaz-Ruiz, Zavala et al. 2008)
  • English- DDS is effective in surgical stress induced by brain oxidative damage via down-regulating NADPH oxidase level in aged mice.
  • Zhang, Tian et al. 2015 propofol-induced cognitive alterations in aged rats (Yang, Li et al. 2017) ) and exerted anti-apoptotic effect after spinal cord injury.
  • Li et al. 2017 propofol-induced cognitive alterations in aged rats (Yang, Li et al. 2017)
  • English- DDS modulated the inflammatory cells, including granulocytes in LPS-treated BMs, by inducing cell death.
  • DDS decreased the mitochondrial membrane potential of LPS-treated BMs.(Kwon and Joo 2018) and DDS reduced acetic acid-induced inflammatory response in rat colon tissue through inhibition of NF-kB signaling pathway.(Rashidian, Rashki et al. 2019)
  • Depson is toxic to doxorubicin-doxorubicin in serum levels of CK-MB, electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals), papillary muscle contractility and excitation and the measurement of malondialdehyde (MDA), superoxide dismutase (SOD) As antioxidant enzyme and TNF- ⁇ tissue level- were reversibly reduced, which means that depson reduced oxidative stress and inflammatory response, and was consistent with histopathological findings.
  • ECG electrocardiographic
  • MDA malondialdehyde
  • SOD superoxide dismutase
  • Myeloperoxidase is a type of redox agent and induces the following reaction.
  • H2O2 + Cl - H2O + OCl -
  • Depsone binds to myelopharoxidase to regulate the production of hypochlorous acid and regulate the cellular inflammatory response.
  • van Zyl Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993
  • Depson interferes with virus-cell binding by alkalizing intracellular acidity.
  • Dapsone binds to myeloperoxidase and regulates the production of hypochlorite, thereby reducing the inflammatory response of cells.
  • van Zyl Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993
  • DDS is to alkalize by increasing endosomal pH required for virus/cell fusion.
  • Depson can show the activity of myelopharoxidase in a stomatitis diagnostic tool on a sandwich test disk.
  • the activity of myelopharoxidase is controlled by depsons.
  • van Zyl Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993
  • Myeloparoxidase is a twin-shaped duplex, but when an inflammatory reaction occurs, a sulfonic group reacts to form a monoclonal
  • the monocytes function as oxidizing agents.
  • the shape of the red blood cells changes due to the monocyte formation of myelopharoxidase in the red blood cells. It appears as a microcirculation disorder.
  • Shamova Gorudko et al. 2020
  • SERP1 is a ⁇ -secretase activator that stimulates amyloid beta production in cells under endoplasmic reticulum (ER) stress.
  • ER endoplasmic reticulum
  • English- SERP1 is a ⁇ -secretase activator that stimulates A ⁇ generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes (inflammatory condition in cells).
  • ER endoplasmic reticulum
  • dapsone can be presumed to preserve cells by decreasing the inflammatory response of neutrophils and can regulate the production of hypochlorous acid. This response is associated with myeloperoxidase, a kind of reductase enzyme, and has the effect of reducing inflammatory reactions in Alzdheimer's disease, Parkinson's disease, mild cognitive impairment amd infectious disease.
  • ER endoplasmic reticulum
  • English- DDS might regulate NLRP3 inflammasome activators and a common signaling pathway targeted by NLRP3 inflammasome activation. But the specific targeting of NLRP3 itself may produce therapeutic effects for prevention and treatment of COVID-19 pneumonia.
  • depsone is a substance that acts on the NLRP3 inflammasome and exhibits anti-inflammatory effects.
  • DDS is a substance that acts on the NLRP3 inflammasome and exhibits an inflammatory treatment effect.
  • Depson to control the activity of inflammasomes such as NLRP3 is used in various human diseases in which symptoms are aggravated by the activity of inflamasoms such as NLRP3, and can be used as a therapeutic agent to prevent the worsening of infection symptoms. .
  • NLRP3 inflammasome activators From: The NLRP3 inflammasome: molecular activation and regulation to therapeutics, https://www.nature.com/articles/s41577-019-0165-0) (Swanson, Deng et al. 2019)
  • Depsone has been used worldwide for over 100 years and is an essential medicine designated by the World Health Organization (WHO). It is inexpensive and clinically safe. (Organization 2019) The NLRP3 inflammasome cohort is working to combat pneumonia and premature death from COVID-19.
  • the dosing of Depson for Hansen people was 50-100 g per day. However, 50 to 400 mg is used for the treatment of skin diseases, and 50 to 200 mg is used to treat mild cognitive impairment and Alzheimer's disease. 100mg was used together with pyrimethamine for the prevention of malaria.
  • the therapeutic serum concentration of dapsone is 0.5 to 5 mg/L. After oral dosing, it is slowly hydrated and reaches its maximum concentration after 4 hours.
  • DDS has been used worldwide for more than 100 years, and it is part of the World Health Organization (WHO) model list of essential medicines. It is also cheap and has an established clinical safety profile.
  • WHO World Health Organization
  • the daily dose of dapsone in leprosy is 50 to 100 mg, but varies from 50 to 400 mg in the treatment of other dermatological disorders; varies from 50 to 200mg in the treatment of in the treatment of MCI and AD.
  • malaria propylaxis a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly hematological effects.
  • the dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. The elimination half-life of dapsone is about 30 hours.(Zuidema, Hilbers-Modderman et al. 1986)
  • the daily dose of dapsone in COVID-19 may be 50 to 200mg, which permits monthly supervised administration as recommended by medical doctor.
  • Depsone has been used worldwide for over 100 years and is an essential medicine designated by the World Health Organization (WHO). It is inexpensive and clinically safe. (Organization 2019) The NLRP3 inflammasome cohort is working to combat pneumonia and premature death from COVID-19.
  • the dosing of Depson for Hansen people was 50-100 g per day. However, 50 to 400 mg is used for the treatment of skin diseases, and 50 to 200 mg is used to treat mild cognitive impairment and Alzheimer's disease. 100mg was used together with pyrimethamine for the prevention of malaria.
  • the therapeutic serum concentration of dapsone is 0.5 to 5 mg/L. After oral dosing, it is slowly hydrated and reaches its maximum concentration after 4 hours.
  • DDS has been used worldwide for more than 100 years, and it is part of the World Health Organization (WHO) model list of essential medicines. It is also cheap and has an established clinical safety profile.
  • WHO World Health Organization
  • the daily dose of dapsone in leprosy is 50 to 100 mg, but varies from 50 to 400 mg in the treatment of other dermatological disorders; varies from 50 to 200mg in the treatment of in the treatment of MCI and AD.
  • malaria propylaxis a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly hematological effects.
  • the dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. The elimination half-life of dapsone is about 30 hours.(Zuidema, Hilbers-Modderman et al. 1986)
  • the daily dose of dapsone in COVID-19 may be 50 to 200mg, which permits monthly supervised administration as recommended by medical doctor.
  • dapsone (4,4'-diaminodiphenylsulfone) is a sulfonamide mainly used for the treatment of leprosy and herpetic dermatitis
  • the chemical formula is C 12 H 12 N 2 O 2 S, and the structure is as follows like:
  • the composition of the present invention preferably contains 100 to 400 mg of the depson, more preferably 100 mg, and may contain the depson.
  • the composition may be administered 2-3 times a day.
  • Depsone an active ingredient of the present invention, reduces the inflammatory response of beta-amyloid deposited in brain cells causing Alzheimer's disease and neutrophils resulting therefrom, and by controlling the generation of hypochlorous acid that occurs, neurons (brain) cells) are considered to be preserved. In addition, it is judged that it has a function of regulating inflammation in a wide range of the human body by regulating the function of NLRP3.
  • the neuronal preservation effect responded to the cognitive function improvement effect, and after administration of 50 mg 2-3 times a day, rapidly improved cognitive function and dementia The effect was confirmed.
  • composition of the present invention may further contain one or more known active ingredients having an effect of preventing or treating Alzheimer's disease together with depsone.
  • composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions.
  • suitable carriers excipients and diluents commonly used in the preparation of pharmaceutical compositions.
  • it can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions.
  • Suitable formulations known in the art are preferably those disclosed in Remington's Pharmaceutical Science, recently Mack Publishing Company, Easton PA.
  • Carriers, excipients and diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, It is prepared by mixing gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc.
  • 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.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
  • the term “administration” means providing a given composition of the present invention to a subject by any suitable method.
  • the preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and weight of the individual, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art.
  • the depsone of the present invention may be administered in an amount of 1 mg/kg to 10000 mg/kg per day, may be administered once a day, or may be administered in several divided doses.
  • the pharmaceutical composition of the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection.
  • composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers for the prevention and treatment of Alzheimer's dementia.
  • health functional food refers to a food having bioregulatory functions such as prevention and improvement of disease, body defense, immunity, recovery from illness, and suppression of aging, and should be harmless to the human body when taken for a long time.
  • the composition of the present invention may be added to a health functional food for the purpose of preventing or improving Alzheimer's dementia, preventing and improving type 2 diabetes, preventing and improving Prion disease, and preventing and improving infectious diseases including COVID-19.
  • the depsone of the present invention When the depsone of the present invention is used as a food additive, the depson may be added as it is or may be used together 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 depsone of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw material.
  • it in the case of long-term intake for the purpose of health and hygiene or health control, it 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.
  • 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, vitamin complexes, and the like, and includes all health foods in the ordinary sense.
  • the health beverage composition of the present invention may include various flavoring agents or natural carbohydrates as additional ingredients, like conventional beverages.
  • natural carbohydrates monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, synthetic sweeteners such as saccharin and aspartame may be used.
  • the proportion of the natural carbohydrate is generally about 0.01 to 10 g, preferably about 0.01 to 0.1 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 included.
  • 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 very important, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
  • the above ingredients are mixed and filled in an airtight bag to prepare a powder.
  • tablets are prepared by tableting according to a conventional manufacturing method of tablets.
  • the above ingredients are mixed and filled in a gelatin capsule to prepare a capsule.
  • the content of the above ingredients per ampoule (2 ml) is prepared.
  • each component is added to purified water to dissolve, an appropriate amount of lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by adding purified water, and then filled in a brown bottle. Sterilize to prepare a solution.
  • the composition ratio of the vitamin and mineral mixture is a composition that is relatively suitable for health food in a preferred embodiment, but the mixing ratio may be arbitrarily modified. , to prepare granules, and can be used for preparing health food compositions according to a conventional method.
  • Vitamin B2 0.3g
  • the resulting solution is filtered and obtained in a sterilized 2 l container, sealed and sterilized, then refrigerated. It is used to prepare the health drink composition of the invention.
  • composition ratio is prepared by mixing ingredients suitable for relatively favorite beverages in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and national preferences such as demanding class, demanding country, and use.
  • the NLRP3 inflammasome is involved in various human diseases, including Alzheimer's disease, prion disease, type 2 diabetes, and various infectious diseases.
  • various complications and premature death are prevented by preventing the aggravation of diseases such as Alzheimer's disease, prion disease, type 2 diabetes, and various infectious diseases.
  • Diaz-Ruiz A., C. Zavala, S. Montes, A. Ortiz-Plata, H. Salgado-Ceballos, S. Orozco-Suarez, C. Nava-Ruiz, I. P ⁇ rez-Neri, F. Perez-Severiano. and C. R ⁇ os (2008). "Antioxidant, antiinflammatory and antiapoptotic effects of dapsone in a model of brain ischemia/reperfusion in rats.” Journal of Neuroscience Research 86(15): 3410-3419.
  • SERP1 is an assembly regulator of ⁇ in metabolic stress conditions. Science Signaling 13(623): eaax8949.
  • TLR2 Toll-like receptor 2

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Abstract

Dapsone having the ability to regulate the activation of inflammasomes such as NLRP3 can be used for various human diseases, the symptoms of which are worsened by the activation of inflammasomes such as NLRP3, and thus can be used as a medicinal product for preventing and treating worsening of infection symptoms and also as a functional health food.

Description

뎁손 및 유도체의 인류의 알츠하이머병, 프라이온병, 2형 당뇨병, 전염병 등 다양한 질병에 내재된 NLRP3 인플라마솜 활성 제어 기능{REGULATION FUNCTIONS OF INFLAMMASOME ACTIVATION IMPLICATED IN A VARIETY OF HUMAN DISEASE INCLUDING ALZHEIMER DISEASE PRION DISEASE TYPE 3 DIABETES AND SOME INFECTIOUS DISEASE BY DDS AND DERIVATIVES}Control function of NLRP3 inflammasome activity inherent in various diseases such as Alzheimer's disease, prion disease, type 2 diabetes, and infectious diseases of human beings of Depsone and its derivatives 3 DIABETES AND SOME INFECTIOUS DISEASE BY DDS AND DERIVATIVES}
내과학, internal medicine,
전염병, Epidemic,
면역학, immunology,
의약학, medicine,
감염병학, infectious disease,
당뇨병학, Diabetes,
프라이온병, prion bottle,
신경학, neurology,
MICROBIOLOGY,MICROBIOLOGY,
GENETICS.GENETICS.
TLR(Toll-like receptor)들은 다양한 TLR 유전체에 의하여 다양한 마이크로체(바이러스와 다양한 인간 전염 질병에 관계있는 TLR2와 TLR4의 다양성)에 대한 면역 반응을 바꿀 수 있다. 마이크로체에는 바이러스와 TLR 자체의 유전적 변이도 포함한다. 특히 TLR-Arg677Trp 는 한국의 나형 한센인에게서 발견되었다. TLR2의 세포내 변이로 나형 한센병에 더 잘 걸릴 수 있다. 그러나 이와 같은 TLR-Arg677Trp 유전체 변이가 있는 한센인도 뎁손(리팜피신, 클로파자민 포함)으로 치료된다는 점은 본 발명의 핵심 발견 중 하나이다. 뎁손은 경도인지장애, 파킨슨병, 알츠하이머병에서 NLRP3 인플라마섬의 분자 단위 조절에 효과적이다.(Lee, Choi et al. 2020) Toll-like receptors (TLRs) are capable of altering the immune response to various microbodies (the diversity of TLR2 and TLR4 involved in viruses and various human infectious diseases) by different TLR genomes. The microbody also includes genetic variations in viruses and the TLR itself. In particular, TLR-Arg677Trp was found in naive Hansen in Korea. Intracellular mutations in TLR2 may predispose to leprosy leprosy. However, it is one of the key findings of the present invention that Hansen Indians having such a TLR-Arg677Trp genomic mutation is also treated with depsone (including rifampicin and clofazamine). Depson is effective in molecular control of NLRP3 inflammasome in mild cognitive impairment, Parkinson's disease, and Alzheimer's disease (Lee, Choi et al. 2020).
뎁손은 TLR-Arg677Trp 유전체 변이가 있다고 하더라도 NLRP3 인플라마솜의 활성을 제어할 수 있는 알로스테릭 레귤레이션 작용을 할 수 있기 때문이다. This is because depson can act as an allosteric regulation that can control the activity of the NLRP3 inflammasome even if there is a TLR-Arg677Trp genomic mutation.
영문- TLRs due to polymorphisms of TLR genes can alter immune response to a wide variety of microbial ligands, including viruses, and polymorphisms in TLR2 and TLR4 have been linked to infectious diseases in human. In particular, TLR-Arg677Trp was reported to be present in Korean patients with lepromatous leprosy exclusively. The mutation in the intracellular domain of TLR2 has a role in susceptibility to LL but LL was treated by dapsone with rifampicin, and clofazimine. DDS among three antibiotics should be effective for molecular regulation of NLRP3 inflammasome activators such as MCI, PD and AD.(Lee, Choi et al. 2020) English- TLRs due to polymorphisms of TLR genes can alter immune response to a wide variety of microbial ligands, including viruses, and polymorphisms in TLR2 and TLR4 have been linked to infectious diseases in human. In particular, TLR-Arg677Trp was reported to be present in Korean patients with lepromatous leprosy exclusively. The mutation in the intracellular domain of TLR2 has a role in susceptibility to LL but LL was treated by dapsone with rifampicin, and clofazimine. DDS among three antibiotics should be effective for molecular regulation of NLRP3 inflammasome activators such as MCI, PD and AD. (Lee, Choi et al. 2020)
The specific targeting of NLRP3 itself or up-/downstream factors of NLRP3 inflammasome by DDS may produce therapeutic effects.The specific targeting of NLRP3 itself or up-/downstream factors of NLRP3 inflammasome by DDS may produce therapeutic effects.
인간 사스 바이러스와 메르스 바이러스는 각각 사향고양이, 낙타가 매개체로 지목됐다. 이들은 인간 코로나바이러스와 유전적으로 99% 유사하다. 그러나 인간에게 발견되는 코로나19는 박쥐나 천산갑에서 발견된 코로나바이러스와 유전적 차이가 큰 것으로 알려져 있다. The human SARS virus and the MERS virus were identified as carriers of civets and camels, respectively. They are 99% genetically similar to the human coronavirus. However, it is known that COVID-19, which is found in humans, is genetically different from the coronavirus found in bats and pangolins.
연구진은 이같은 현상에 대해 동물 매개체를 거치면서 유전적 변이가 일어났는지, 아니면 인간에게 감염돼 유전적 변이가 일어났는지 확인하기 위한 연구를 진행했다. 연구진은 코로나19 바이러스가 수년 혹은 수십년 전에 인간에게 전파된 뒤 인간에 적응하는 과정에서 유전적 변이를 거쳐 치명적인 질환으로 나타났을 가능성을 제시했다.The research team conducted a study to determine whether genetic mutation occurred through animal vectors or whether genetic mutation occurred due to infection in humans. The research team suggested the possibility that the COVID-19 virus may have appeared as a lethal disease through genetic mutation in the process of adapting to humans after it was transmitted to humans years or decades ago.
그러나 급속히 변하는 유전적 병이로 인하여 유행하는 바이러스마다 일일이 항체를 만들고 생산할 수 없는 지경에 이르렀다. 이에 본 발명으로 인체의 면역 기능 중 인체에 치명적 손상을 일으키는 면역 반응을 제어하는 물질을 발명하여 급성 폐렴 및 조기 사망으로부터 환자를 구하기로 한다. However, due to rapidly changing genetic diseases, it has reached a point where it is impossible to make and produce antibodies for each epidemic virus. Accordingly, the present invention is to save patients from acute pneumonia and premature death by inventing a substance that controls an immune response that causes fatal damage to the human body among the immune functions of the human body.
또한 다양한 인류의 질병인 알츠하이머병, 프라이온병, 2형 당뇨병, 다양한 전염병의 염증을 일으켜서 중증 질환을 유발하는 NLRP3 인플라마솜의 활성을 뎁손을 투약하여 제어한다. In addition, by administering Depsone, the activity of NLRP3 inflammasome, which causes severe disease by causing inflammation in various human diseases, such as Alzheimer's disease, prion disease, type 2 diabetes, and various infectious diseases, is controlled.
1. 서론1. Introduction
코로나 바이러스는 TLR(Toll-like receptors) 에 결합한 후, caspase-1에 의해서, pro-IL-1β 을 배출하여 인플라마솜을 자극하여 폐 염증과 고열과 섬유화를 일으킨다. (Conti, Ronconi et al. 2020)After binding to TLR (Toll-like receptors), the corona virus releases pro-IL-1β by caspase-1 to stimulate the inflammasome, causing lung inflammation, high fever, and fibrosis. (Conti, Ronconi et al. 2020)
영문- The binding of COVID-19 to TLR causes the release of pro-IL-1β which is cleaved by caspase-1, followed by inflammasome which is a mediator of lung inflammation, fever and fibrosis. (Conti, Ronconi et al. 2020)English- The binding of COVID-19 to TLR causes the release of pro-IL-1β which is cleaved by caspase-1, followed by inflammasome which is a mediator of lung inflammation, fever and fibrosis. (Conti, Ronconi et al. 2020)
pro-inflammatory IL-1 family members 와 IL-6의 억제와 다양한 인류의 질병인 알츠하이머병, 프라이온병, 2형 당뇨병, 다양한 전염병에 관여하는 NLRP3 인플라마솜의 억제에 대한 것이다. 한센인의 뎁손과 알츠하이머병에 대한 연구를 통해서 가설을 증명하게 되었다. This study is about the inhibition of pro-inflammatory IL-1 family members and IL-6 and the inhibition of the NLRP3 inflammasome involved in various human diseases such as Alzheimer's disease, prion disease, type 2 diabetes, and various infectious diseases. The hypothesis was proved through the study of Hansen's Deppson and Alzheimer's disease.
영문- Suppressions of pro-inflammatory IL-1 family members and IL-6 and the formation and activation of the NLRP3 inflammasome which is implicated in a variety of human diseases including Alzheimer disease (AD), Prion diseases, type 2 diabetes, and some infectious diseases.(Yang, Wang et al. 2019) By examination of DDS and AD in Hansen disease, this study demonstrate the hypothesis. English- Suppressions of pro-inflammatory IL-1 family members and IL-6 and the formation and activation of the NLRP3 inflammasome which is implicated in a variety of human diseases including Alzheimer disease (AD), Prion diseases, type 2 diabetes, and some infectious diseases.(Yang, Wang et al. 2019) By examination of DDS and AD in Hansen disease, this study demonstrate the hypothesis.
2. NLRP3 인플라마솜과 질병2. NLRP3 Inflammasome and Disease
인플라마솜과 관계있는 대표적인 질환은 알츠하이머병, 프라이온병, 2형 당뇨병, 다양한 전염병이다. 뎁손은 알츠하이머병의 치료 물질이며 그리고 COVID-19와 같은 다양한 전염병 치료제로 사용될 수 있다. Representative diseases related to the inflammasome are Alzheimer's disease, prion disease, type 2 diabetes, and various infectious diseases. Depsone is a therapeutic agent for Alzheimer's disease and can be used as a treatment for various infectious diseases such as COVID-19.
영문- The activation of the NLRP3 inflammasome which is implicated in a variety of human diseases including Alzheimer disease (AD), Prion diseases, type 2 diabetes, and some infectious diseases. DDS was therapeutic substance of the Alzheirmers disease.(Namba, Kawatsu et al. 1992, Kimura and Goto 1993, Chui, Tabira et al. 1994, S Appleby and L Cummings 2013) And DDS may be a therapeutic preventive substance in COVID-19. English - The activation of the NLRP3 inflammasome which is implicated in a variety of human diseases including Alzheimer disease (AD), Prion diseases, type 2 diabetes, and some infectious diseases. DDS was therapeutic substance of the Alzheirmers disease. (Namba, Kawatsu et al. 1992, Kimura and Goto 1993, Chui, Tabira et al. 1994, S Appleby and L Cummings 2013) And DDS may be a therapeutic preventive substance in COVID-19 .
3. COVID-19 와 인플라마솜 3. COVID-19 and influenza
우리는 50세 남성의 생검 조직에서 CD4 and CD8 T 세포가 매우 감소하였으나 매우 활성화되어 있는 상태라는 것을 알게 되었다. CD4 T 세포에서 전염증 CCR6+ Th17가 높게 검출되었고, CD8 T 세포에서는 높은 농도의 cytotoxic granules이 검출되었다. 이는 T 세포의 높은 활성화를 의미한다. (Xu, Shi et al. 2020) We found that CD4 and CD8 T cells were greatly reduced but highly activated in the biopsy tissue of a 50-year-old male. High levels of proinflammatory CCR6+ Th17 were detected in CD4 T cells, and high concentrations of cytotoxic granules were detected in CD8 T cells. This means high activation of T cells. (Xu, Shi et al. 2020)
84세 여성의 생검 조직에서도 증가된 WBC count; 증가된 neutrophils; 감소된 lymphocytes; 감소된 eosinophils; 증가된 basophil 이 계수되었다. 이는 SARS and MERS-coronavirus 감염기의 사망자 코호트 연구 결과와 유사한 것이었다. (Tian, Hu et al. 2020) 두 건에서 모두 급성 폐 손상 - 부종, 면역물질 침투, 폐세포의 과증식과 조직화 현상이 관찰 되었다. (Ding, Wang et al. 2003, Ng, Al Hosani et al. 2016)increased WBC count in biopsy tissue from an 84-year-old woman; increased neutrophils; decreased lymphocytes; reduced eosinophils; Increased basophils were counted. This was similar to the results of a cohort study of deaths during SARS and MERS-coronavirus infection. (Tian, Hu et al. 2020) In both cases, acute lung injury - edema, infiltration of immune substances, hyperproliferation and organization of lung cells were observed. (Ding, Wang et al. 2003, Ng, Al Hosani et al. 2016)
적정하게 수행된 사후 부검 조직의 소견에서도 동일하였다. (Hanley, Lucas et al. 2020) The findings of the properly performed post-mortem autopsy tissue were the same. (Hanley, Lucas et al. 2020)
영문- We inspected carefully from peripheral blood of a 50-year-old man's biopsy samples that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated; was an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cell; CD8 T cells were found to harbor high concentrations of cytotoxic granules, which imply that over activation of T cells.(Xu, Shi et al. 2020)English - We inspected carefully from peripheral blood of a 50-year-old man's biopsy samples that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated; was an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells; CD8 T cells were found to harbor high concentrations of cytotoxic granules, which imply that over activation of T cells. (Xu, Shi et al. 2020)
Laboratory specimens from an 84-year-old female's biopsy samples revealed the following: increased WBC count; increased neutrophils; decreased lymphocytes; decreased eosinophils; and increased basophil count. (Tian, Hu et al. 2020) Laboratory specimens from an 84-year-old female's biopsy samples revealed the following: increased WBC count; increased neutrophils; decreased lymphocytes; decreased eosinophils; and increased basophil count. (Tian, Hu et al. 2020)
Compared with pathologic findings in a cohort of autopsy cases of SARS and MERS-coronavirus infections, the two cases presented here exhibited exudative and proliferative phases of acute lung injury, such as edema, inflammatory infiltrate, pneumocyte hyperplasia, and organization.(Ding, Wang et al. 2003, Ng, Al Hosani et al. 2016)Compared with pathologic findings in a cohort of autopsy cases of SARS and MERS-coronavirus infections, the two cases presented here exhibited exudative and proliferative phases of acute lung injury, such as edema, inflammatory infiltrate, pneumocyte hyperplasia, and organization.(Ding, Wang et al. 2003, Ng, Al Hosani et al. 2016)
Postmortem examination: respiratory tract samples, blood, urine and cerebrospinal fluid samples were deemed appropriate; should be taken prior to opening the body cavity and under as sterile conditions as possible to reduce contamination; may shed light on this COVID-19's disease.(Hanley, Lucas et al. 2020) Postmortem examination: respiratory tract samples, blood, urine and cerebrospinal fluid samples were deemed appropriate; should be taken prior to opening the body cavity and under as sterile conditions as possible to reduce contamination; may shed light on this COVID-19's disease. (Hanley, Lucas et al. 2020)
TLRs는 코로나 바이러스에 독특한 스파이크 기능(by (S) entry protein)을 부여하여 포유류의 세포 receptor에 잘 감염시키는 역할을 수행한다. SARS-CoV가 높은 전염력으로 악명이 높아진 원인이다.(Graham and Baric 2010) MERS-CoV 도 dipeptidyl peptidase 4 (DPP4; also known as CD26) receptors에 잘 달라붙으며 주로 하기도에 감염을 일으키고, 다은 조직에도 달라붙는다.(Raj, Mou et al. 2013)TLRs confer a unique spiking function (by (S) entry protein) to the coronavirus and play a role in infecting mammalian cell receptors well. SARS-CoV is the cause of its notorious high infectivity (Graham and Baric 2010). MERS-CoV also binds well to dipeptidyl peptidase 4 (DPP4; also known as CD26) receptors and mainly infects the lower respiratory tract and other tissues. cling (Raj, Mou et al. 2013).
영문- Coronaviruses infect a wide range of mammals and birds. Their tropism is primarily determined by the ability of the spike (S) entry protein to bind to a cell surface receptor. Coronaviruses have zoonotic potential due to the adaptability of their S protein to receptors of other species, most notably demonstrated by SARS-CoV.(Graham and Baric 2010) MERS-CoV binds to dipeptidyl peptidase 4 (DPP4; also known as CD26) receptors that are primarily in the lower respiratory tract but also distributed in other tissues.(Raj, Mou et al. 2013)English - Coronaviruses infect a wide range of mammals and birds. Their tropism is primarily determined by the ability of the spike (S) entry protein to bind to a cell surface receptor. Coronaviruses have zoonotic potential due to the adaptability of their S protein to receptors of other species, most notably demonstrated by SARS-CoV. (Graham and Baric 2010) MERS-CoV binds to dipeptidyl peptidase 4 (DPP4; also known as CD26) receptors that are primarily in the lower respiratory tract but also distributed in other tissues. (Raj, Mou et al. 2013)
중간 숙주의 유전적 요소가 SARS-CoV에 영향을 쉽게 받는가와 임상 경과에 영향을 미치는가에 대한 연구가 중요하다. 타고난 면역계는 전염병의 초기 감염 단계에서 역할을 한다. 그리고 일정 기간이 지나고 장기 면역력을 획득하게 된다.(Yuan, Boehm et al. 2007) COVID-19가 상하기도에 감염되었을 때 pro-inflammatory cytokines (interleukin (IL)-1β and IL-6을 포함하여)이 분비되고 TLR에 결합하여 pro-IL-1β의 분비하는데, pro-IL-1β는 caspase-1에 의해 분해되어 인플라마솜을 활성화시키며 활성화된 IL-1β가 생산되어 폐에서 염증과 열과 섬유화를 일으킨다. pro-inflammatory IL-1 family members와 IL-6를 제어하면 바이러스 감염을 포함하여 많은 염증성 질환에 치료 효과가 있다. (Conti, Ronconi et al. 2020)It is important to study whether the genetic factors of the intermediate host are susceptible to SARS-CoV and affect the clinical course. The innate immune system plays a role in the early infectious stages of an infectious disease. After a certain period of time, long-term immunity is acquired. (Yuan, Boehm et al. 2007) When COVID-19 infects the upper respiratory tract, pro-inflammatory cytokines (including interleukin (IL)-1β and IL-6) is secreted and binds to TLR to secrete pro-IL-1β, which is degraded by caspase-1 to activate the inflammasome causes Controlling pro-inflammatory IL-1 family members and IL-6 has therapeutic effects in many inflammatory diseases, including viral infections. (Conti, Ronconi et al. 2020)
영문- It is important to investigate whether other host genetic factors could influence susceptibility to SARS-CoV infection and its subsequent clinical course. The innate immune system plays a role in limiting an infectious challenge in the early stages after exposure, during the lag time required to initiate long-lasting adaptive immunity. (Yuan, Boehm et al. 2007) When COVID-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6. The binding of COVID-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1β which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1β which is a mediator of lung inflammation, fever and fibrosis. Suppressions of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections.(Conti, Ronconi et al. 2020)English- It is important to investigate whether other host genetic factors could influence susceptibility to SARS-CoV infection and its subsequent clinical course. The innate immune system plays a role in limiting an infectious challenge in the early stages after exposure, during the lag time required to initiate long-lasting adaptive immunity. (Yuan, Boehm et al. 2007) When COVID-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6. The binding of COVID-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1β which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1β which is a mediator of lung inflammation , fever and fibrosis. Suppressions of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. (Conti, Ronconi et al. 2020)
RNA 바이러스 감염 후에는 NLRP3 (NOD-, LRR- 과 pyrin domain을 포함한 단백질 3번) 인플라마솜은 미토론드리아 단백질 mitofusin 2에 의해서 활성화된다. (Ichinohe, Yamazaki et al. 2013) 마이크로 항바이러스 단백질 MAVS는 NLRP3와 결합하고 인플라마솜을 제어한다. (Park, Juliana et al. 2013) After RNA virus infection, the NLRP3 (protein 3 with NOD-, LRR- and pyrin domains) inflammasome is activated by the mitorondrial protein mitofusin 2. (Ichinohe, Yamazaki et al. 2013) The microantiviral protein MAVS binds to NLRP3 and controls the inflammasome. (Park, Juliana et al. 2013)
도 1과 같이 NLRP3는 세포내 센서이다. 넓은 범위의 미세물질을 감지하고, 내재적 위험 신호와 환경물질을 감지하고 NLRP3 인플라마솜을 형성하고 활성화시킨다. NLRP3 인플라마솜이 모이면 caspase-1에 의하여 pro- inflammatory cytokines IL-1β 과 IL-18이 분비되고 gasdermin D가 매개하여 세포내 감염체에 의하여 세포사멸 된다. (Park, Juliana et al. 2013) NLRP3(NOD-, LRR- and pyrin으로 코딩된 domain-containing protein 3)의 기능이상은 다양한 질병(알츠하이머병, 프라이온병, 2형 당뇨병과 전염병들)을 유발한다.(Yang, Wang et al. 2019) cytokines 이나 병원체와 연계된 분자 패턴은 (PAMPs- pathogen-associated molecular patterns) 이미 알려져 있거나 아직 덜 알려져 있는 인플라마솜의 유전적 활성화를 유도한다. 1 , NLRP3 is an intracellular sensor. It detects a wide range of micromaterials, detects intrinsic danger signals and environmental substances, and forms and activates the NLRP3 inflammasome. When the NLRP3 inflammasome assembles, the pro-inflammatory cytokines IL-1β and IL-18 are secreted by caspase-1, and gasdermin D mediated apoptosis by intracellular infectious agents. (Park, Juliana et al. 2013) Dysfunction of NLRP3 (domain-containing protein 3 encoded by NOD-, LRR- and pyrin) causes various diseases (Alzheimer's disease, prion disease, type 2 diabetes mellitus and infectious diseases). (Yang, Wang et al. 2019) cytokines or pathogen-associated molecular patterns (PAMPs-pathogen-associated molecular patterns) induce genetic activation of known or unknown inflammasomes.
영문- After RNA virus infection, NLRP3 (NOD-, LRR- and pyrin domain- containing protein 3) inflammasome were activated by mitochondrial protein mitofusin 2.(Ichinohe, Yamazaki et al. 2013) The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. (Park, Juliana et al. 2013) NLRP3 is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro- inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D- mediated pyroptotic cell death. (Fig. 1) The dysfunction of NLRP3 (which encodes NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation is implicated in a variety of human diseases including Alzheimer's disease, Prion diseases, type 2 diabetes, and some infectious diseases.(Yang, Wang et al. 2019) The activation of cytokines or pathogen-associated molecular patterns (PAMPs) leads to the transcriptional upregulation of canonical and non-canonical inflammasome components.English- After RNA virus infection, NLRP3 (NOD-, LRR- and pyrin domain- containing protein 3) inflammasome were activated by mitochondrial protein mitofusin 2. (Ichinohe, Yamazaki et al. 2013) The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. (Park, Juliana et al. 2013) NLRP3 is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro- inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. (Fig. 1) The dysfunction of NLRP3 (which encodes NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation is implicated in a variety of human diseases including Alzheimer's disease, Prion diseases, type 2 diabetes, and some infectious diseases (Yang, Wang et al. 2019) The activation of cytokines or pathogen-associated molecular patterns (PAMPs) leads to the transcriptional upregulation of canonical and non-canonical inflammasome components.
도 2와 같은 수많은 PAMPs (pathogen-associated molecular patterns) 나 DAMPs (damage-associated molecular patterns)는 다양한 입자들과 결정들과 ATP와 관계하며 다양한 신호를 활성화시킨다. (K+ efflux, Ca+ flux, lysosomal disruption, mitochondrial reactive oxygen species (mtROS) production, the relocalization of cardiolipin to the outer mitochondrial membrane and the release of oxidized mitochondrial DNA (Ox-mtDNA), followed by Cl - efflux.) RNA 바이러스는 NLRP3를 마이토콘드리아 바깥 세포막에 있는 마이토콘드리아 신호 단백질 (mitochondrial antiviral signalling protein (MAVS)) 을 활성화시킨다. 이를 통한 인플라마솜의 형성은 caspase 1을 활성화시켜서 pro-IL-1β을 분해하고 pro-IL-18을 생산하여 염증을 일으킨다. (Swanson, Deng et al. 2019)Numerous pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) as shown in FIG. 2 are related to various particles and crystals and ATP and activate various signals. (K+ efflux, Ca+ flux, lysosomal disruption, mitochondrial reactive oxygen species (mtROS) production, the relocalization of cardiolipin to the outer mitochondrial membrane and the release of oxidized mitochondrial DNA (Ox-mtDNA), followed by Cl - efflux.) RNA virus activates NLRP3, a mitochondrial antiviral signaling protein (MAVS) located in the outer mitochondrial membrane. Through this, the formation of inflammasome activates caspase 1 to degrade pro-IL-1β and produce pro-IL-18 to cause inflammation. (Swanson, Deng et al. 2019)
영문- Next any of numerous PAMPs or damage-associated molecular patterns (DAMPs); such as particulates, crystals and ATP; activate multiple upstream signaling events. These include K+ efflux, Ca+ flux, lysosomal disruption, mitochondrial reactive oxygen species (mtROS) production, the relocalization of cardiolipin to the outer mitochondrial membrane and the release of oxidized mitochondrial DNA (Ox-mtDNA), followed by Cl- efflux. RNA viruses activate NLRP3 through mitochondrial antiviral signalling protein (MAVS) on the mitochondrial outer membrane. Formation of the inflammasome activates caspase 1, which in turn cleaves pro-IL-1β and pro-IL-18.(Swanson, Deng et al. 2019)English- Next any of numerous PAMPs or damage-associated molecular patterns (DAMPs); such as particulates, crystals and ATP; activate multiple upstream signaling events. These include K+ efflux, Ca+ flux, lysosomal disruption, mitochondrial reactive oxygen species (mtROS) production, the relocalization of cardiolipin to the outer mitochondrial membrane and the release of oxidized mitochondrial DNA (Ox-mtDNA), followed by Cl- efflux. RNA viruses activate NLRP3 through mitochondrial antiviral signaling protein (MAVS) on the mitochondrial outer membrane. Formation of the inflammasome activates caspase 1, which in turn cleaves pro-IL-1β and pro-IL-18. (Swanson, Deng et al. 2019)
4. 답손과 인플라마솜의 연관 고리 - 한센인의 알츠하이머병 4. The link between dapsone and the inflammasome - Hansen's Alzheimer's disease
TLR의 유전자의 다양성에 따른 TLR의 기능 손상은 면역 반응이 변하게 된다. 바이러스와 TLR2, TLR4에서 유전자의 다양성을 포함하여 다양한 미세 리간드는 인간 전염병에 관계 있다. 특별히 TLR-Arg677Trp 는 한국의 나형 한센인에게 발견되었다. TLR2의 시작 코돈에서 뉴클레오타이드 2029 번에서 C가 T로 바뀌어 있다. TLR2의 보존 지역 중 하나인 아미노산 가지 677번 에서 Arg이 Trp 으로 치환되었다. 이와 같은 변이는 오직 나형 한센병에서 발견되며 결핵형 한센병에서는 발견되지 않았다. (Kang and Chae 2001) M. leprae 균은 한센병을 유발한다. 그런데 알츠하이머병이 한센인에게 적은 원인이 M. leprae 균 때문인 것 같다는 보고가 있었다. (Endoh, Kunishita et al. 1999) Impairment of TLR function due to gene diversity of TLR causes changes in immune response. A variety of microligands, including gene diversity in viruses and TLR2 and TLR4, are implicated in human infectious diseases. In particular, TLR-Arg677Trp was found in naive Hansen in Korea. At nucleotide 2029 in the start codon of TLR2, C is replaced with T. At amino acid branch 677, one of the conserved regions of TLR2, Arg was substituted with Trp. Such mutations were only found in leprosy leprosy and not in leprosy tuberculosis. (Kang and Chae 2001) M. leprae causes leprosy. However, there was a report that the cause of Alzheimer's disease in Hansen people is probably due to M. leprae bacteria. (Endoh, Kunishita et al. 1999)
영문- The impairment of Toll-like receptors (TLRs) due to polymorphisms of TLR genes can alter immune response to a wide variety of microbial ligands, including viruses, and polymorphisms in TLR2 and TLR4 have been linked to infectious diseases in human. In particular, TLR-Arg677Trp was reported to be present in Korean patients with lepromatous leprosy exclusively. DNA sequencing detected a C to T substitution at nucleotide 2029 from the start codon of the TLR2. The mutation would substitute Arg to Trp at amino acid residue 677, one of the conserved regions of TLR2. The mutation was involved in only lepromatous leprosy (LL), not tuberculoid leprosy and control. (Kang and Chae 2001) M. leprae, which induces leprosy, was assumed as the cause of the low incidence of Alzheimer's disease in patients with Hansen's disease. '(Endoh, Kunishita et al. 1999) English- The impairment of Toll-like receptors (TLRs) due to polymorphisms of TLR genes can alter immune response to a wide variety of microbial ligands, including viruses, and polymorphisms in TLR2 and TLR4 have been linked to infectious diseases in human. In particular, TLR-Arg677Trp was reported to be present in Korean patients with lepromatous leprosy exclusively. DNA sequencing detected a C to T substitution at nucleotide 2029 from the start codon of the TLR2. The mutation would substitute Arg to Trp at amino acid residue 677, one of the conserved regions of TLR2. The mutation was involved in only lepromatous leprosy (LL), not tuberculoid leprosy and control. (Kang and Chae 2001) M. leprae, which induces leprosy, was assumed as the cause of the low incidence of Alzheimer's disease in patients with Hansen's disease. ' (Endoh, Kunishita et al. 1999)
그러나 한센병은 뎁손과 리팜피신, 클로파지민을 투약하면 치료된다. 한국의 나형 한센병에서 TLR2에 변이가 있다고 하더라도 상기 의약품을 투약하면 한센병은 치료된다. 세 가지 의약품 중에 뎁손은 NLRP3 인플라마섬 촉진자를 억제함으로써 (allosteric regulation) 경도인지장애와 파킨슨병과 알츠하이머병에 치료 효과가 있는 것으로 보고되었다. (Lee, Choi et al. 2020)However, leprosy can be cured by administering depsone, rifampicin, and clofazimine. Even if there is a mutation in TLR2 in Korean leprosy leprosy, leprosy can be cured by administering the above medicines. Among the three drugs, Depsone has been reported to have therapeutic effects on mild cognitive impairment, Parkinson's disease and Alzheimer's disease by inhibiting the NLRP3 inflammasome promoter (allosteric regulation). (Lee, Choi et al. 2020)
영문- But Hansen's disease is treated with a combination of antibiotics. These are dapsone with rifampicin, and clofazimine is added for some types of the disease. Korean patients with lepromatous leprosy were treated by dapsone with rifampicin, and clofazimine, as well. So the mutation in the intracellular domain of TLR2 has a role in susceptibility to LL but LL was treated by dapsone with rifampicin, and clofazimine. DDS among three antibiotics should be effective for molecular regulation (allosteric regulation) of NLRP3 inflammasome activators such as MCI, PD and AD. (Lee, Choi et al. 2020)English - But Hansen's disease is treated with a combination of antibiotics. These are dapsone with rifampicin, and clofazimine is added for some types of the disease. Korean patients with lepromatous leprosy were treated by dapsone with rifampicin, and clofazimine, as well. So the mutation in the intracellular domain of TLR2 has a role in susceptibility to LL but LL was treated by dapsone with rifampicin, and clofazimine. DDS among three antibiotics should be effective for molecular regulation (allosteric regulation) of NLRP3 inflammasome activators such as MCI, PD and AD. (Lee, Choi et al. 2020)
4. 한센인의 수명 연구 (Cho, Shim et al. 2014) 4. Study on the lifespan of Hansen people (Cho, Shim et al. 2014)
기대치 않게 소록도 남성 나환자의 장수지수가 우리나라의 비슷한 계층 사람들이나 평균 한국인들보다도 현저히 높은 기대수명과 더 낮은 연령대별 사망률을 보였다. 1995년부터 2007년까지 보관되어 있는 한센협회 14,686여명의 자료(현재 363명 환자를 포함)를 토대로 세 가지의 장수 지표를 분석한 인구 통계 자료를 정리하였다. 6ㅇ세 이상 인구가 77.5%였고 평균 나이는 69세 였다. 지난 12년 간 한센인은 한국인보다 훨씬 더 수명이 길었다. 특히 기대수명은 남성 한센인이 높았다. (도 3) Unexpectedly, the longevity index of male lepers on Sorok Island showed significantly higher life expectancy and lower mortality rates by age group than those of similar classes or average Koreans in Korea. Based on the data of about 14,686 members of the Hansen Association (including 363 patients currently) stored from 1995 to 2007, demographic data analyzed by three longevity indicators were compiled. 77.5% of the population over the age of 6 was with an average age of 69. Over the past 12 years, Hansen people have lived much longer than Koreans. In particular, the life expectancy of male Hansen people was higher. (Fig. 3)
영문- Unexpectedly we found that the leprosy-affected elderly males have greater life expectancy and lower age-specific death rates than do their counterparts with the lowest level of education and even all Korean males. As of 1 January 2008, there were 14,686 welfare subjects,including 363 current patients with leprosy (The Korea Hansen Welfare Association, n.d.). The average age of leprosy-affected persons was 69 years old, with 77.5% of the population aged over 60. Over the past 12-year period, the longevity of leprosy-affected persons has been notably higher than that of all Koreans, and the advantage in longevity has been outstanding among leprosy-affected males. (Fig. 3)English- Unexpectedly we found that the leprosy-affected elderly males have greater life expectancy and lower age-specific death rates than do their counterparts with the lowest level of education and even all Korean males. As of 1 January 2008, there were 14,686 welfare subjects, including 363 current patients with leprosy (The Korea Hansen Welfare Association, n.d.). The average age of leprosy-affected persons was 69 years old, with 77.5% of the population aged over 60. Over the past 12-year period, the longevity of leprosy-affected persons has been notably higher than that of all Koreans, and the advantage in longevity has been outstanding among leprosy-affected males. (Fig. 3)
도 4는 60-85세 기대 수명을 1995년, 200년, 2005년 집단에서 분석하였다.세 그룹의 기대수명 비율은 아래 판넬에 제시하였다. 남성 한센인의 비율은 전체보다 높았다. 예로 2000년의 경우 60세에서 1.15였고 85세 이상에서 2.42였다. 이와같은 패턴은 유지되며 한센인 남성은 하류계층 인구보다 기대수명이 더 길다. 1995년과 2000년 여성의 경우 한센인은 모든 한국인과 하류계층보다 수명이 길다. 그러나 2005년에는 역전된다. 도 4는 한센인이 하층계층의 모든 한국인보다 기대수명이 길다. 더하여 80세 이상 한센인 남성은 같은 연령대 여성보다 더 오래 산다. 도 5는 연령대별 사망률을 1995, 2000, 2005년에 비교하였다. 위 판넬은 연령대별 사망률이고 아래 판넬은 비율이다. 한센인 대비 정체 한국인 사망률 비교는 특별한 점은 없다. 2000년과 2005년의 비율이 상호 역전되어 있다. (Cho, Shim et al. 2014) 4 shows the life expectancy of 60-85 years of age was analyzed in the 1995, 200, and 2005 groups. The life expectancy ratios of the three groups are presented in the panel below. The proportion of male Hansen people was higher than the total. For example, in 2000, it was 1.15 for 60 years old and 2.42 for 85 years old and older. This pattern holds, and Hansen men have a longer life expectancy than the lower-class population. For women in 1995 and 2000, Hansen people lived longer than all Koreans and lower classes. However, in 2005, it was reversed. 4 shows that Hansen people have a longer life expectancy than all Koreans in the lower classes. In addition, Hansen men over the age of 80 live longer than women of the same age. Figure 5 compares mortality rates by age group in 1995, 2000, and 2005. The upper panel is the mortality rate by age, and the lower panel is the percentage. There is nothing special about the comparison of the death rate of stagnant Koreans compared to Hansen people. The ratios for 2000 and 2005 are mutually inverted. (Cho, Shim et al. 2014)
영문- The upper panel of Fig.4 presents life expectancies from ages 60 to 85 of the three populations for 1995, 2000, and 2005. Ratios that compare the life expectancies across the three populations are presented in the lower panel. Among males, the ratios of leprosy-affected persons to all Koreans are greater than unity, and the value increases with age. For example, the ratio is 1.15 at age 60 but 2.42 at age 85 and over in 2000. This pattern is observable in all 3 years, although variation exists. The advantage of life expectancy among leprosy-affected males compared to another socially disadvantaged population (the least-educated subpopulation) is also substantial. For female populations, leprosy-affected persons have a higher life expectancy than all Koreans and the least-educated subpopulation across all ages in 1995 and 2000. The advantage, however, reverses in 2005. This Fig.4 suggests that leprosy-affected males have had a notably higher life expectancy than the least-educated subpopulation and even all Koreans for the past decade. Furthermore, leprosy-affected males aged 80 years and above have outlived their female counterparts. Fig.5 compares the age-specific death rates of the three populations for 1995, 2000, and 2005. The upper panel presents ASDRs, and the bottom panel gives corresponding ratios. Note that a ratio under unity indicates the mortality advantage of the population in the numerator over the population in the denominator, since the death rate is compared. In the ratios of leprosy-affected versus all Koreans, however, the pattern is unclear. Most ratios are under unity until 2000, but this reverses in 2005.(Cho, Shim et al. 2014) English- The upper panel of Fig.4 presents life expectancies from ages 60 to 85 of the three populations for 1995, 2000, and 2005. Ratios that compare the life expectancies across the three populations are presented in the lower panel. Among males, the ratios of leprosy-affected persons to all Koreans are greater than unity, and the value increases with age. For example, the ratio is 1.15 at age 60 but 2.42 at age 85 and over in 2000. This pattern is observable in all 3 years, although variation exists. The advantage of life expectancy among leprosy-affected males compared to another socially disadvantaged population (the least-educated subpopulation) is also substantial. For female populations, leprosy-affected persons have a higher life expectancy than all Koreans and the least-educated subpopulation across all ages in 1995 and 2000. The advantage, however, reverses in 2005. This Fig.4 suggests that leprosy-affected males have had a notably higher life expectancy than the least-educated subpopulation and even all Koreans for the past decade. Furthermore, leprosy-affected males aged 80 years and above have outlived their female counterparts. Fig.5 compares the age-specific death rates of the three populations for 1995, 2000, and 2005. The upper panel presents ASDRs, and the bottom panel gives corresponding ratios. Note that a ratio under unity indicates the mortality advantage of the population in the numerator over the population in the denominator, since the death rate is compared. In the ratios of leprosy-affected versus all Koreans, however, the pattern is unclear. Most ratios are under unity until 2000, but this reverses in 2005. (Cho, Shim et al. 2014)
그러므로 뎁손은 경도인지장애와 파킨슨병과 알츠하이머병을 일으키는 인플라마솜에 분자 단위에서 결합하여 (allosteric regulation)(Lee, Choi et al. 2020) 염증 반응을 줄여주는 것으로 치료효과를 나타낸다. 뎁손은 NLRP3 inflammasome에 직접 작용하여 염증 반응을 제어함으로써 NEK7, ASC, caspase-1, IL-1β나 다른 요소들과 관계없이 NLRP3 inflammasome에 직접 작용함으로써 염증 치료 효과를 나타낼 수 있는 물질이다. Therefore, depsone has a therapeutic effect by reducing the inflammatory response by binding at the molecular level to the inflammasome that causes mild cognitive impairment, Parkinson's disease, and Alzheimer's disease (allosteric regulation) (Lee, Choi et al. 2020). Depson controls the inflammatory response by acting directly on the NLRP3 inflammasome, so it is a substance that can exert an anti-inflammatory effect by acting directly on the NLRP3 inflammasome regardless of NEK7, ASC, caspase-1, IL-1β or other factors.
영문- Therefore, Depson has a therapeutic effect by reducing the inflammatory response by binding at the molecular level (allosteric regulation)(Lee, Choi et al. 2020) to inflammasomes that cause mild cognitive impairment and Parkinson's disease and Alzheimer's disease. Depson is a substance capable of exhibiting an inflammatory treatment effect by directly acting on the NLRP3 inflammasome regardless of NEK7, ASC, caspase-1, IL-1β or other factors by controlling the inflammatory response by acting directly on the NLRP3 inflammasome.English- Therefore, Depson has a therapeutic effect by reducing the inflammatory response by binding at the molecular level (allosteric regulation) (Lee, Choi et al. 2020) to inflammasomes that cause mild cognitive impairment and Parkinson's disease and Alzheimer's disease. Depson is a substance capable of exhibiting an inflammatory treatment effect by directly acting on the NLRP3 inflammasome regardless of NEK7, ASC, caspase-1, IL-1β or other factors by controlling the inflammatory response by acting directly on the NLRP3 inflammasome.
5. 뎁손(Dapsone, 4,4'-diaminodiphenylsulfone; 이하, 뎁손 또는 DDS)의 효능5. Efficacy of Depsone (Dapsone, 4,4'-diaminodiphenylsulfone; hereinafter, Depsone or DDS)
(1) 알츠하이머병의 예방 및 치료제(Therapeutic preventive substance in Alzheimer's disease) (1) Therapeutic preventive substance in Alzheimer's disease
뎁손은 알츠하이머병의 예방치료 물질이다. 답손 100mg/하루 투약한 군과 대조군 연구에서 52주 간 20명 환자를 대상으로 경증에서 진행된 환자에게 투약하였으나 뎁손을 투약한 군과 대조군 간 인지기능 개선 기능이 크게 차이나지 않았다. 이와같은 결과는 경증에서 진행된 환자에게는 이미 광범위한 뉴론이 죽은 상태이기 때문이다. 경도인지장애 와 초기 알츠하이머병 환자에게는 인지기능 개선 효과가 있었다. 경도인지장애에서 알츠하이머병으로 10년 간 이행되지 않았으며 파킨슨병 환자의 증상이 개선되었다는 연구 결과가 발표되었다. (Lee, Choi et al. 2020)Depsone is a prophylactic treatment for Alzheimer's disease. In the study of the group administered with Dapsone 100 mg/day and the control group, 20 patients were administered for 52 weeks from mild to advanced patients. This is because, in patients with advanced disease, already extensive neurons are dead. There was an effect of improving cognitive function in patients with mild cognitive impairment and early Alzheimer's disease. A study result was published that showed that there was no transition from mild cognitive impairment to Alzheimer's disease for 10 years, and the symptoms of Parkinson's disease patients improved. (Lee, Choi et al. 2020)
영문- DDS is a therapeutic preventive substance in Alzheimer's disease (AD). (Namba, Kawatsu et al. 1992, Kimura and Goto 1993, Chui, Tabira et al. 1994, S Appleby and L Cummings 2013) Dapsone (100 mg/day) and placebo were administered orally, once daily for 52 weeks in 201 patients with mild-to-moderate AD. At the end of treatment there were no significant differences between dapsone and placebo on either cognitive or other measures of efficacy. (Bain 2002, Imbimbo, Solfrizzi et al. 2010) Those results are because patients with mild-to-moderate AD already have extensive neuronal death, and patients with mild cognitive impairment (MCI) and early AD patients were positive. MCI did not worsen from AD for 10 years, and Parkinson's disease (PD) symptoms were observed to change to mild. (Lee, Choi et al. 2020)English - DDS is a therapeutic preventive substance in Alzheimer's disease (AD). (Namba, Kawatsu et al. 1992, Kimura and Goto 1993, Chui, Tabira et al. 1994, S Appleby and L Cummings 2013) Dapsone (100 mg/day) and placebo were administered orally, once daily for 52 weeks in 201 patients with mild-to-moderate AD. At the end of treatment there were no significant differences between dapsone and placebo on either cognitive or other measures of efficacy. (Bain 2002, Imbimbo, Solfrizzi et al. 2010) Those results are because patients with mild-to-moderate AD already have extensive neuronal death, and patients with mild cognitive impairment (MCI) and early AD patients were positive. MCI did not worsen from AD for 10 years, and Parkinson's disease (PD) symptoms were observed to change to mild. (Lee, Choi et al. 2020)
(2) 뎁손에 의한 NLRP3 인플라마섬 촉진자와 NLRP3의 전사 후 변화 관찰 (NLRP3 inflammasome activators and Post-transcriptional modifications of NLRP3 by DDS) (2) Observation of NLRP3 inflammasome activators and Post-transcriptional modifications of NLRP3 by DDS
뎁손은 glutamate agonists에 의하여 유발되는 신경 손상(주로 허혈 후에 오는 glutamate의 독성이다) 을 막는다. (Rios, Nader-Kawachi et al. 2004) 뎁손은 말초혈액 단구체를 자극하는 LPS에 의하여 mRNA의 발현과 싸이토카인의 생산에 조절 효과가 있다. 뎁손은 TNF-α의 mRNA의 발현을 억제하고 배양액에서 TNF-α의 농도를 낮추는 억제물질이다. (Abe, Shimizu et al. 2008) Depsone blocks nerve damage induced by glutamate agonists (mainly glutamate toxicity after ischemia). (Rios, Nader-Kawachi et al. 2004) Depson has a regulatory effect on mRNA expression and cytokine production by LPS stimulating peripheral blood monocytes. Depson is an inhibitor that suppresses the expression of TNF-α mRNA and lowers the concentration of TNF-α in the culture medium. (Abe, Shimizu et al. 2008)
영문- DDS prevents neuronal damage induced by glutamate agonists (glutamate excitotoxicity is implicated in the damage after ischemia).(Rios, Nader-Kawachi et al. 2004) DDS has the effects of DDS on the mRNA expression and production of cytokines on lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells. DDS suppressed mRNA expression of tumor necrosis factor (TNF)-α and significantly decreased the level of TNF-α in culture supernatant.(Abe, Shimizu et al. 2008) English- DDS prevents neuronal damage induced by glutamate agonists (glutamate excitotoxicity is implicated in the damage after ischemia).(Rios, Nader-Kawachi et al. 2004) DDS has the effects of DDS on the mRNA expression and production of cytokines on lipopolysaccharide ( LPS)-stimulated peripheral blood mononuclear cells. DDS suppressed mRNA expression of tumor necrosis factor (TNF)-α and significantly decreased the level of TNF-α in culture supernatant.(Abe, Shimizu et al. 2008)
염증 반응의 지표인 마이엘로패록시다아제 활동은 대조군 쥐보다 허혈성 상태에서 3.7배 증가한다. 비록 세포사멸은 증가한다고 할지라도, 뎁손은 허혈성 변화가 발생한 후 72시간 동안 효과가 있었다. 뎁손은 전체적인 허혈과 재관류 기간 중 항산화, 항염증, 항사멸 효과를 크게 보여 주었다. (Diaz-Ruiz, Zavala et al. 2008)Myeloparoxidase activity, an indicator of the inflammatory response, is increased 3.7-fold in the ischemic state compared to control mice. Although apoptosis was increased, depsone was effective for 72 hours after the onset of ischemic changes. Depsone showed significant antioxidant, anti-inflammatory, and anti-apoptotic effects during the overall ischemia and reperfusion period. (Diaz-Ruiz, Zavala et al. 2008)
영문- Myeloperoxidase (MPO) activity, a marker of inflammatory response, increased 3.7-fold in ischemic animals vs. control rats, and dapsone treatment antagonized that effect. Although apoptosis was increased by the effect of ischemia at both evaluation times, DDS antagonized that effect only at 72 hr after surgery. Dapsone antagonized the entire ischemia-reperfusion end points measured, showing a remarkable ability to decrease markers of damage through antioxidant, anti-inflammatory, and anti-apoptotic effects.(Diaz-Ruiz, Zavala et al. 2008) English- Myeloperoxidase (MPO) activity, a marker of inflammatory response, increased 3.7-fold in ischemic animals vs. control rats, and dapsone treatment antagonized that effect. Although apoptosis was increased by the effect of ischemia at both evaluation times, DDS antagonized that effect only at 72 hr after surgery. Dapsone antagonized the entire ischemia-reperfusion end points measured, showing a remarkable ability to decrease markers of damage through antioxidant, anti-inflammatory, and anti-apoptotic effects. (Diaz-Ruiz, Zavala et al. 2008)
뎁손은 쥐에서 수술에 의한 뇌 산화 손상을 줄여주었고 이는 늙은 쥐에서 NADPH oxidase를 낮게 유지하여 가능했다. (Zhang, Tian et al. 2015) 늙은 쥐의 프로포폴에 의한 인지기능 개선에서도 동일한 효과가 있었으며 (Yang, Li et al. 2017), 뇌척수의 손상 후 세포 사멸을 가로막았다. (Rios, Orozco-Suarez et al. 2015) Depson reduced surgical brain oxidative damage in rats, which was possible by keeping NADPH oxidase low in older rats. (Zhang, Tian et al. 2015) The same effect was found in the improvement of cognitive function by propofol in elderly mice (Yang, Li et al. 2017), and prevented apoptosis after injury to the cerebrospinal cord. (Rios, Orozco-Suarez et al. 2015)
영문- DDS is effective in surgical stress induced by brain oxidative damage via down-regulating NADPH oxidase level in aged mice.(Zhang, Tian et al. 2015), propofol-induced cognitive alterations in aged rats (Yang, Li et al. 2017) and exerted anti-apoptotic effect after spinal cord injury.(Rios, Orozco-Suarez et al. 2015) English- DDS is effective in surgical stress induced by brain oxidative damage via down-regulating NADPH oxidase level in aged mice. (Zhang, Tian et al. 2015), propofol-induced cognitive alterations in aged rats (Yang, Li et al. 2017) ) and exerted anti-apoptotic effect after spinal cord injury.(Rios, Orozco-Suarez et al. 2015)
늙은 쥐에서는 파킨의 농도가 소뇌, 척수, 흑체, 선조체에서 낮다. 그러나 뎁손은 파킨의 농도를 회복시켰으며 뎁손은 늙은 쥐의 도파민 신경 감소를 막았고 SH-SY5Y 세포를 1-methyl-4-phenylpyridinium 과 hydrogen peroxide로 부터 보호했다. 뎁손은 유전 전사를 통하여 파킨을 활성화했는데 protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 (ATF4)를 작동시켰다. (Lee, Kang et al. 2016)In older mice, concentrations of Parkin are lower in the cerebellum, spinal cord, black body, and striatum. However, Depson restored the concentration of Parkin, and Depson prevented dopaminergic neuronal decline in aged mice and protected SH-SY5Y cells from 1-methyl-4-phenylpyridinium and hydrogen peroxide. Depson activated Parkin through genetic transcription, which activated protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 (ATF4). (Lee, Kang et al. 2016)
영문- The level of parkin was decreased in the cerebellum, brain stem, substantia nigra, and striatum of aged mice. But DDS restored the level of parkin, DDS prevented age-dependent DA neuronal loss, and DDS protected SH-SY5Y cells from 1-methyl-4-phenylpyridinium and hydrogen peroxide. DDS transcriptionally activated parkin via protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 (ATF4).(Lee, Kang et al. 2016)English- The level of parkin was decreased in the cerebellum, brain stem, substantia nigra, and striatum of aged mice. But DDS restored the level of parkin, DDS prevented age-dependent DA neuronal loss, and DDS protected SH-SY5Y cells from 1-methyl-4-phenylpyridinium and hydrogen peroxide. DDS transcriptionally activated parkin via protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 (ATF4). (Lee, Kang et al. 2016)
뎁손은 염증세포를 조절했고 LPS를 처리한 골수에서 과립구의 활동을 세포사멸을 통하여 조절했다. 이때 뎁손은 마이콘드리아 골수세포(LPS를 처리한) 세포막의 활동을 감소시켰다. (Kwon and Joo 2018) 그리고 뎁손은 쥐 내장에서 아세트산에 의해 유도된 염증 반응을 감소시켰는데 NF-kB signaling pathway를 중지시켰다. (Rashidian, Rashki et al. 2019)Depson regulated inflammatory cells and the activity of granulocytes in LPS-treated bone marrow through apoptosis. At this time, depson decreased the activity of the cell membrane of mychondrial bone marrow cells (LPS-treated). (Kwon and Joo 2018) And Depson reduced the acetic acid-induced inflammatory response in the rat gut, but stopped the NF-kB signaling pathway. (Rashidian, Rashki et al. 2019)
영문- DDS modulated the inflammatory cells, including granulocytes in LPS-treated BMs, by inducing cell death. DDS decreased the mitochondrial membrane potential of LPS-treated BMs.(Kwon and Joo 2018) and DDS reduced acetic acid-induced inflammatory response in rat colon tissue through inhibition of NF-kB signaling pathway.(Rashidian, Rashki et al. 2019)English- DDS modulated the inflammatory cells, including granulocytes in LPS-treated BMs, by inducing cell death. DDS decreased the mitochondrial membrane potential of LPS-treated BMs.(Kwon and Joo 2018) and DDS reduced acetic acid-induced inflammatory response in rat colon tissue through inhibition of NF-kB signaling pathway.(Rashidian, Rashki et al. 2019)
뎁손은 독소루비신에 의한 독성-doxorubicin in serum levels of CK-MB, electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals), papillary muscle contractility and excitation and the measurement of malondialdehyde (MDA), superoxide dismutase (SOD) as antioxidant enzyme and TNF-α tissue level-을 가역적으로 줄였는데, 이는 뎁손이 산화 스트레스와 염증 반응을 줄여주는 것을 의미하며 병리조직학적 소견과도 일치하였다. (Sheibani, Nezamoleslami et al. 2020)Depson is toxic to doxorubicin-doxorubicin in serum levels of CK-MB, electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals), papillary muscle contractility and excitation and the measurement of malondialdehyde (MDA), superoxide dismutase (SOD) As antioxidant enzyme and TNF-α tissue level- were reversibly reduced, which means that depson reduced oxidative stress and inflammatory response, and was consistent with histopathological findings. (Sheibani, Nezamoleslami et al. 2020)
영문- Administration of DDS with doxorubicin significantly reversed alterations induced by doxorubicin in serum levels of CK-MB, electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals), papillary muscle contractility and excitation and the measurement of malondialdehyde (MDA), superoxide dismutase (SOD) as antioxidant enzyme and TNF-α tissue level indicated that DDS significantly reduced oxidative stress and inflammation consistent with histopathological analysis.(Sheibani, Nezamoleslami et al. 2020)English- Administration of DDS with doxorubicin significantly reversed alterations induced by doxorubicin in serum levels of CK-MB, electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals), papillary muscle contractility and excitation and the measurement of malondialdehyde (MDA), superoxide dismutase (SOD) as antioxidant enzyme and TNF-α tissue level indicated that DDS significantly reduced oxidative stress and inflammation consistent with histopathological analysis.(Sheibani, Nezamoleslami et al. 2020)
마이엘로패록시다아제는 산화환원제의 한 종류로서 다음의 반응을 유도한다. H2O2 + Cl - = H2O + OCl - Myeloperoxidase is a type of redox agent and induces the following reaction. H2O2 + Cl - = H2O + OCl -
뎁손은 마이엘로패록시다아제와 결합하여 차아염소산의 생산을 조절하고 세포의 염증반응을 조절한다. (van Zyl, Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993) 뎁손은 세포내 산성도를 알칼리화하여 바이러스와 세포의 결합을 방해한다. Depsone binds to myelopharoxidase to regulate the production of hypochlorous acid and regulate the cellular inflammatory response. (van Zyl, Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993) Depson interferes with virus-cell binding by alkalizing intracellular acidity.
영문- Myeloperoxidase is a kind of oxidoreductase that catalyzes the chemical reaction of the following reaction: H2O2 + Cl - = H2O + OCl -. Dapsone binds to myeloperoxidase and regulates the production of hypochlorite, thereby reducing the inflammatory response of cells. (van Zyl, Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993) DDS is to alkalize by increasing endosomal pH required for virus/cell fusion. English- Myeloperoxidase is a kind of oxidoreductase that catalyzes the chemical reaction of the following reaction: H2O2 + Cl - = H2O + OCl - . Dapsone binds to myeloperoxidase and regulates the production of hypochlorite, thereby reducing the inflammatory response of cells. (van Zyl, Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993) DDS is to alkalize by increasing endosomal pH required for virus/cell fusion.
뎁손은 마이엘로패록시다아제의 활동도를 샌드위치테스트 디스크에서 구강염 진단기구에서 보여줄 수 있다. (Sakamoto, Fujii et al. 2008) 마이엘로패록시다아제의 활동은 뎁손에 의하여 제어된다. (van Zyl, Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993) 마이엘로패록시다아제는 쌍둥이 모양의 이중체이나 염증반응이 일어나면 설폰기가 반응하여 단구체로 바뀌고 단구체는 산화제로 작동하게 되는데 이때 적혈구 내 마이엘로패록시다아제의 단구체화에 의하여 적혈구의 모양이 변한다. 이는 미세혈류 순환 장애로 나타난다. (Shamova, Gorudko et al. 2020)Depson can show the activity of myelopharoxidase in a stomatitis diagnostic tool on a sandwich test disk. (Sakamoto, Fujii et al. 2008) The activity of myelopharoxidase is controlled by depsons. (van Zyl, Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993) Myeloparoxidase is a twin-shaped duplex, but when an inflammatory reaction occurs, a sulfonic group reacts to form a monoclonal The monocytes function as oxidizing agents. At this time, the shape of the red blood cells changes due to the monocyte formation of myelopharoxidase in the red blood cells. It appears as a microcirculation disorder. (Shamova, Gorudko et al. 2020)
영문- DDS revealed myeloperoxidase activity in whole saliva from subjects with periodontal disease in the sandwich test-disk.(Sakamoto, Fujii et al. 2008) Myeloperoxidase activity was inhibited by DDS.(van Zyl, Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993) Myeloperoxidase (MPO), a homodimer, consisting of two identical protomers (monomeric MPO) connected by a single disulfide bond but in inflammatory foci as a result of disulfide cleavage monomeric MPO (hemi-MPO) can also be produced. MPO, an oxidant-producing enzyme, was shown to red blood cell (RBC) deformability leading to abnormalities in blood microcirculation.(Shamova, Gorudko et al. 2020) English- DDS revealed myeloperoxidase activity in whole saliva from subjects with periodontal disease in the sandwich test-disk.(Sakamoto, Fujii et al. 2008) Myeloperoxidase activity was inhibited by DDS.(van Zyl, Basson et al. 1991, Bozeman, Learn et al. 1992, Uetrecht, Shear et al. 1993) Myeloperoxidase (MPO), a homodimer, consisting of two identical protomers (monomeric MPO) connected by a single disulfide bond but in inflammatory foci as a result of disulfide cleavage monomeric MPO (hemi) -MPO) can also be produced. MPO, an oxidant-producing enzyme, was shown to red blood cell (RBC) deformability leading to abnormalities in blood microcirculation. (Shamova, Gorudko et al. 2020)
염증 부위의 미세혈류 변화는 이중체와 단구체에 의하여 유도되며 이는 염증 부위에서 단구체의 발현을 조절하여서 적혈구의 순환을 관리조절하는 기전으로 사용되는 것으로 보인다. 이와같은 뎁손의 염증 조절 기전으로 볼 때 뎁손 분자단위에서 NLRP3 inflammasome activators의 조절 기능을 갖는 것으로 확인되었다. Changes in microcirculation at the site of inflammation are induced by duplexes and monocytes, and this appears to be used as a mechanism for managing and regulating the circulation of red blood cells by regulating the expression of monocytes at the site of inflammation. In view of such an inflammation control mechanism of depson, it was confirmed that it has a regulatory function of NLRP3 inflammasome activators at the depson molecular unit.
영문- Abnormalities in blood microcirculation in inflammatory foci can be induced by hemi-MPO and homodimer. It seems to reduce abnormalities on RBC response as a regulatory mechanism that regulates the development of hemi-MPO in inflammatory foci. It is presumed that DDS performs an anti-inflammatory reaction in various diseases by molecular regulation of NLRP3 inflammasome activators. English- Abnormalities in blood microcirculation in inflammatory foci can be induced by hemi-MPO and homodimer. It seems to reduce abnormalities on RBC response as a regulatory mechanism that regulates the development of hemi-MPO in inflammatory foci. It is presumed that DDS performs an anti-inflammatory reaction in various diseases by molecular regulation of NLRP3 inflammasome activators.
SERP1은 endoplasmic reticulum (ER) 스트레스 상황에서 세포에서 아밀로이드 베타 생산을 자극하는 γ-secretase activator이다. (Jung, Hyun et al. 2020) 뎁손의 분자 단위에서 알로스테릭 레귤레이션으로 보아 호중구에 의한 염증 반응을 조절하고 치아염소산의 생산을 조절하는 기능은 마이엘로패록시다아제와 관계 있으며 이는 알츠하이머병, 파킨슨병, 경도인지장애, 다양한 전염병에서 염증 반응을 줄이는 역할을 한다. (Lee, Choi et al. 2020)SERP1 is a γ-secretase activator that stimulates amyloid beta production in cells under endoplasmic reticulum (ER) stress. (Jung, Hyun et al. 2020) In terms of allosteric regulation at the molecular level of depsone, the function of regulating the inflammatory response by neutrophils and regulating the production of hypochlorous acid is related to myeloperoxidase, which is associated with Alzheimer's disease, Alzheimer's disease, It plays a role in reducing the inflammatory response in Parkinson's disease, mild cognitive impairment, and various infectious diseases. (Lee, Choi et al. 2020)
영문- SERP1 is a γ-secretase activator that stimulates Aβ generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes (inflammatory condition in cells).(Jung, Hyun et al. 2020) Considering the structure of dapsone and the allosteric regulation of the molecular unit, dapsone can be presumed to preserve cells by decreasing the inflammatory response of neutrophils and can regulate the production of hypochlorous acid. This response is associated with myeloperoxidase, a kind of reductase enzyme, and has the effect of reducing inflammatory reactions in Alzdheimer's disease, Parkinson's disease, mild cognitive impairment amd infectious disease.(Lee, Choi et al. 2020) English- SERP1 is a γ-secretase activator that stimulates Aβ generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes (inflammatory condition in cells).(Jung, Hyun et al. 2020) Considering the structure of dapsone and the allosteric regulation of the molecular unit, dapsone can be presumed to preserve cells by decreasing the inflammatory response of neutrophils and can regulate the production of hypochlorous acid. This response is associated with myeloperoxidase, a kind of reductase enzyme, and has the effect of reducing inflammatory reactions in Alzdheimer's disease, Parkinson's disease, mild cognitive impairment amd infectious disease. (Lee, Choi et al. 2020)
뎁손은 NLRP3 inflammasome 촉진자를 제어하고 NLRP3 inflammasome을 활성화시키는 공통경로를 제어한다. 그러나 NLRP3 inflammasome 자체를 가로막을 수 있는 알로스테릭 레귤레이션 기능은 COVID-19 폐렴의 치료 효과를 나타낼 수 있다. Depsons control the NLRP3 inflammasome promoter and the common pathway that activates the NLRP3 inflammasome. However, the allosteric regulation function, which can block the NLRP3 inflammasome itself, could have therapeutic effects in COVID-19 pneumonia.
영문- DDS might regulate NLRP3 inflammasome activators and a common signaling pathway targeted by NLRP3 inflammasome activation. But the specific targeting of NLRP3 itself may produce therapeutic effects for prevention and treatment of COVID-19 pneumonia.English- DDS might regulate NLRP3 inflammasome activators and a common signaling pathway targeted by NLRP3 inflammasome activation. But the specific targeting of NLRP3 itself may produce therapeutic effects for prevention and treatment of COVID-19 pneumonia.
(3)NLRP3 inflammasome cohort의 결론 ( Result of NLRP3 inflammasome cohort)(3) Result of NLRP3 inflammasome cohort
이와같은 데이터를 종합적으로 고려할 때 뎁손은 NLRP3 inflammasome에 작용하여 염증 치료 효과를 나타내는 물질이다. Considering these data comprehensively, depsone is a substance that acts on the NLRP3 inflammasome and exhibits anti-inflammatory effects.
영문- Considering these data comprehensively, DDS is a substance that acts on the NLRP3 inflammasome and exhibits an inflammatory treatment effect.English- Considering these data comprehensively, DDS is a substance that acts on the NLRP3 inflammasome and exhibits an inflammatory treatment effect.
이와 같은 뎁손의 NLRP3 등 인플라마솜의 활성을 제어할 수 있는 능력은 NLRP3 등 인플라마솜의 활성에 의하여 증상이 악화되는 다양한 인류의 질병에 사용되어 감염 증상의 악화를 예방하는 치료제로 사용될 수 있다. The ability of Depson to control the activity of inflammasomes such as NLRP3 is used in various human diseases in which symptoms are aggravated by the activity of inflamasoms such as NLRP3, and can be used as a therapeutic agent to prevent the worsening of infection symptoms. .
도 1. NLRP3 inflammasome activators (From: The NLRP3 inflammasome: molecular activation and regulation to therapeutics, https://www.nature.com/articles/s41577-019-0165-0) (Swanson, Deng et al. 2019)Figure 1. NLRP3 inflammasome activators (From: The NLRP3 inflammasome: molecular activation and regulation to therapeutics, https://www.nature.com/articles/s41577-019-0165-0) (Swanson, Deng et al. 2019)
도 2. Post-transcriptional modifications of NLRP3. (From: The NLRP3 inflammasome: molecular activation and regulation to therapeutics, https://www.nature.com/articles/s41577-019-0165-0)(Swanson, Deng et al. 2019)Figure 2. Post-transcriptional modifications of NLRP3. (From: The NLRP3 inflammasome: molecular activation and regulation to therapeutics, https://www.nature.com/articles/s41577-019-0165-0) (Swanson, Deng et al. 2019)
도 3. 소록도와 전국 장수 지수 비교Figure 3. Comparison of Sorok Island and the National Longevity Index
도 4. 일반 한국인과 한센인의 기대수명 장수지수(60세 인구 중 80세 이상의 인구 비)Figure 4. Life expectancy and longevity index of general Koreans and Hansen people (ratio of population over 80 among 60-year-old population)
도 5. 일반 한국인과 한센인의 사망률Fig. 5. Mortality of ordinary Koreans and Hansen people
도 6. 아급성 무릎 관절염 환자Fig. 6. Patients with subacute knee arthritis
뎁손은 100년 이상 전세계적으로 사용된 의약품이고 WHO에서 지정한 필수의약품이다. 가격이 저렴하고 임상 안정성도 확보되어 있다. (Organization 2019) NLRP3 inflammasome cohort에서는 COVID-19로부터 폐렴과 조기 사망을 위하여 노력하고 있다. 한센인에게 뎁손의 투약을 하루 50-100g 이었다. 그러나 피부 질환 등 치료를 위하여 50에서 400mg까지 사용되며 경도인지장애와 알츠하이머병 치료에는 50에서 200mg 사용되었다. 말라리아 예방을 위하여 pyrimethamine과 함께 100mg 사용되었다. 답손의 치료적 serum 농도는 0.5 to 5 mg/L이다. 경구 투약 후 천천히 습수되며 네 시간 후에 최고 농도에 도달한다. 흡수 반감기는 1.1시간이고 30시간이 지나면 제거된다. (Zuidema, Hilbers-Modderman et al. 1986) COVID-19 예방과 치료에는 하루 50-200mg을 의사의 처방과 관리 하에 투약할 것을 추천한다. Depsone has been used worldwide for over 100 years and is an essential medicine designated by the World Health Organization (WHO). It is inexpensive and clinically safe. (Organization 2019) The NLRP3 inflammasome cohort is working to combat pneumonia and premature death from COVID-19. The dosing of Depson for Hansen people was 50-100 g per day. However, 50 to 400 mg is used for the treatment of skin diseases, and 50 to 200 mg is used to treat mild cognitive impairment and Alzheimer's disease. 100mg was used together with pyrimethamine for the prevention of malaria. The therapeutic serum concentration of dapsone is 0.5 to 5 mg/L. After oral dosing, it is slowly hydrated and reaches its maximum concentration after 4 hours. It has an absorption half-life of 1.1 hours and is eliminated after 30 hours. (Zuidema, Hilbers-Modderman et al. 1986) For the prevention and treatment of COVID-19, it is recommended to administer 50-200 mg per day under the prescription and supervision of a doctor.
영문- NLRP3 inflammasome cohortEnglish - NLRP3 inflammasome cohort
DDS has been used worldwide for more than 100 years, and it is part of the World Health Organization (WHO) model list of essential medicines. It is also cheap and has an established clinical safety profile.(Organization 2019) In the NLRP3 inflammasome cohort, the goal was to prevent the exacerbation of COVID-19 to pneumonia and early death. The daily dose of dapsone in leprosy is 50 to 100mg, but varies from 50 to 400mg in the treatment of other dermatological disorders; varies from 50 to 200mg in the treatment of in the treatment of MCI and AD. In malaria prophylaxis, a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly hematological effects. The dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. The elimination half-life of dapsone is about 30 hours.(Zuidema, Hilbers-Modderman et al. 1986) The daily dose of dapsone in COVID-19 may be 50 to 200mg, which permits monthly supervised administration as recommended by medical doctor. DDS has been used worldwide for more than 100 years, and it is part of the World Health Organization (WHO) model list of essential medicines. It is also cheap and has an established clinical safety profile.(Organization 2019) In the NLRP3 inflammasome cohort, the goal was to prevent the exacerbation of COVID-19 to pneumonia and early death. The daily dose of dapsone in leprosy is 50 to 100 mg, but varies from 50 to 400 mg in the treatment of other dermatological disorders; varies from 50 to 200mg in the treatment of in the treatment of MCI and AD. In malaria propylaxis, a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly hematological effects. The dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. The elimination half-life of dapsone is about 30 hours.(Zuidema, Hilbers-Modderman et al. 1986) The daily dose of dapsone in COVID-19 may be 50 to 200mg, which permits monthly supervised administration as recommended by medical doctor.
NLRP3 inflammasome cohortNLRP3 inflammasome cohort
뎁손은 100년 이상 전세계적으로 사용된 의약품이고 WHO에서 지정한 필수의약품이다. 가격이 저렴하고 임상 안정성도 확보되어 있다. (Organization 2019) NLRP3 inflammasome cohort에서는 COVID-19로부터 폐렴과 조기 사망을 위하여 노력하고 있다. 한센인에게 뎁손의 투약을 하루 50-100g 이었다. 그러나 피부 질환 등 치료를 위하여 50에서 400mg까지 사용되며 경도인지장애와 알츠하이머병 치료에는 50에서 200mg 사용되었다. 말라리아 예방을 위하여 pyrimethamine과 함께 100mg 사용되었다. 답손의 치료적 serum 농도는 0.5 to 5 mg/L이다. 경구 투약 후 천천히 습수되며 네 시간 후에 최고 농도에 도달한다. 흡수 반감기는 1.1시간이고 30시간이 지나면 제거된다. (Zuidema, Hilbers-Modderman et al. 1986) COVID-19 예방과 치료에는 하루 50-200mg을 의사의 처방과 관리 하에 투약할 것을 추천한다. Depsone has been used worldwide for over 100 years and is an essential medicine designated by the World Health Organization (WHO). It is inexpensive and clinically safe. (Organization 2019) The NLRP3 inflammasome cohort is working to combat pneumonia and premature death from COVID-19. The dosing of Depson for Hansen people was 50-100 g per day. However, 50 to 400 mg is used for the treatment of skin diseases, and 50 to 200 mg is used to treat mild cognitive impairment and Alzheimer's disease. 100mg was used together with pyrimethamine for the prevention of malaria. The therapeutic serum concentration of dapsone is 0.5 to 5 mg/L. After oral dosing, it is slowly hydrated and reaches its maximum concentration after 4 hours. It has an absorption half-life of 1.1 hours and is eliminated after 30 hours. (Zuidema, Hilbers-Modderman et al. 1986) For the prevention and treatment of COVID-19, it is recommended to administer 50-200 mg per day under the prescription and supervision of a doctor.
영문- NLRP3 inflammasome cohortEnglish - NLRP3 inflammasome cohort
DDS has been used worldwide for more than 100 years, and it is part of the World Health Organization (WHO) model list of essential medicines. It is also cheap and has an established clinical safety profile.(Organization 2019) In the NLRP3 inflammasome cohort, the goal was to prevent the exacerbation of COVID-19 to pneumonia and early death. The daily dose of dapsone in leprosy is 50 to 100mg, but varies from 50 to 400mg in the treatment of other dermatological disorders; varies from 50 to 200mg in the treatment of in the treatment of MCI and AD. In malaria prophylaxis, a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly hematological effects. The dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. The elimination half-life of dapsone is about 30 hours.(Zuidema, Hilbers-Modderman et al. 1986) The daily dose of dapsone in COVID-19 may be 50 to 200mg, which permits monthly supervised administration as recommended by medical doctor. DDS has been used worldwide for more than 100 years, and it is part of the World Health Organization (WHO) model list of essential medicines. It is also cheap and has an established clinical safety profile.(Organization 2019) In the NLRP3 inflammasome cohort, the goal was to prevent the exacerbation of COVID-19 to pneumonia and early death. The daily dose of dapsone in leprosy is 50 to 100 mg, but varies from 50 to 400 mg in the treatment of other dermatological disorders; varies from 50 to 200mg in the treatment of in the treatment of MCI and AD. In malaria propylaxis, a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly hematological effects. The dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. The elimination half-life of dapsone is about 30 hours.(Zuidema, Hilbers-Modderman et al. 1986) The daily dose of dapsone in COVID-19 may be 50 to 200mg, which permits monthly supervised administration as recommended by medical doctor.
본 발명의 유효성분인 뎁손(dapsone, 4,4'-diaminodiphenylsulfone)은 주로 나병과 포진성 피부염의 치료에 사용되는 술폰아미드로서, 화학식은 C 12H 12N 2O 2S고, 그 구조는 하기와 같다:The active ingredient of the present invention, dapsone (4,4'-diaminodiphenylsulfone) is a sulfonamide mainly used for the treatment of leprosy and herpetic dermatitis, the chemical formula is C 12 H 12 N 2 O 2 S, and the structure is as follows like:
Figure PCTKR2020004264-appb-img-000001
Figure PCTKR2020004264-appb-img-000001
상기 뎁손은 헤모글로빈을 공격할 수 있어 투여되었을 때 용혈성 빈혈을 일으키고 헤모글로빈을 파괴하여 다양한 부산물을 인체에 남긴다고 보고되고 있어 인체에 투여시 반응과, 농도 및 pH 등을 고려함으로써 필요한 약리기능을 유도할 수 있는 투여 용법과 투여 용량을 한정하여야 한다.It has been reported that the depson can attack hemoglobin and, when administered, causes hemolytic anemia and destroys hemoglobin, leaving various by-products in the human body. The dosage regimen and dosage that can be administered should be limited.
이를 위하여, 본 발명자가 실험을 통해 최적의 투여 방법을 연구한 결과, 본 발명의 조성물은 바람직하게는 상기 뎁손을 100~400mg 포함하고, 더 바람직하게는 100mg 포함할 수 있으며, 상기 뎁손을 포함하는 조성물을 하루 2 내지 3회 투약할 수 있다. To this end, the present inventors have studied the optimal administration method through experiments, and as a result, the composition of the present invention preferably contains 100 to 400 mg of the depson, more preferably 100 mg, and may contain the depson. The composition may be administered 2-3 times a day.
본 발명의 유효성분인 뎁손은 알츠하이머병을 유발하는 뇌세포 내 침착된 베타 아밀로이드와 이로 인한 호중구(neutrophil)의 염증 반응을 감소시키고, 발생하는 하이포아염소산(hypochlorous acid) 생성을 조절함으로써 뉴런(뇌세포)을 보전하는 것으로 판단된다. 또한 NLRP3의 기능을 조절하여 광범위한 인체 내에서 염증 조절 기능을 갖고 있는 것으로 판단된다. Depsone, an active ingredient of the present invention, reduces the inflammatory response of beta-amyloid deposited in brain cells causing Alzheimer's disease and neutrophils resulting therefrom, and by controlling the generation of hypochlorous acid that occurs, neurons (brain) cells) are considered to be preserved. In addition, it is judged that it has a function of regulating inflammation in a wide range of the human body by regulating the function of NLRP3.
뎁손이 치매 및 인지기능에 미치는 영향을 확인하기 위하여 임상 실험을 다섯 명 이상에게 시행한 결과, 상기 뉴런 보존효과가 인지기능 개선효과로 반응하여 하루 50mg 2-3회 투여 후 급격히 인지기능 및 치매 개선 효과가 확인되었다. 이 결과로 보아 상기 판단과 같이 뎁손이 고장난 단백질을 박테리아로 인식해서 배출함으로써, 뇌세포에 단백질이 축적되고 배출되지 않아서 발생하는 치매의 진행을 중단시킬 수 있음을 확인하였다. 또한 NLRP3의 기능을 조절하여 염증으로 인한 독성이 더이상 진행되지 전신에서 작용 하였다. 통상적인 염증 치료(약물 치료, 신경차단술 등)로는 치료할 수 없는 아급성 관절 질환이 있는 40대 남성의 무릎 관절 내 상세불명의 윤활막염 및 힘줄윤활막염 및 아래다리 무릎뼈힘줄염에 작용하여 염증을 제어하여서 무릎 질병을 치료하였다. (도6)As a result of conducting a clinical trial on five or more people to confirm the effect of Depson on dementia and cognitive function, the neuronal preservation effect responded to the cognitive function improvement effect, and after administration of 50 mg 2-3 times a day, rapidly improved cognitive function and dementia The effect was confirmed. As a result of this, it was confirmed that, as determined above, by recognizing and discharging the broken protein as bacteria, it was possible to stop the progression of dementia caused by accumulating and not excreting the protein in brain cells. In addition, by regulating the function of NLRP3, it acted in the whole body, where inflammation-induced toxicity no longer progresses. Inflammation by acting on unspecified synovitis and tendon synovitis in the knee joint of a man in his 40s with subacute joint disease that cannot be treated with conventional inflammatory treatment (drug treatment, nerve block, etc.) Knee disease was treated by controlling. (Fig. 6)
본 발명의 조성물은 뎁손과 함께 알츠하이머성 치매 대하여 예방 또는 치료의 효과를 갖는 공지의 유효성분을 1종 이상 더 함유할 수 있다. The composition of the present invention may further contain one or more known active ingredients having an effect of preventing or treating Alzheimer's disease together with depsone.
본 발명의 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 또한, 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 당해 기술 분야에 알려진 적합한 제제는 문헌 (Remington's Pharmaceutical Science, 최근, Mack Publishing Company, Easton PA)에 개시되어 있는 것을 사용하는 것이 바람직하다. 포함될 수 있는 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등이 있다. 상기 조성물을 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로오스, 락토오스, 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. The composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. In addition, according to a conventional method, it can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions. Suitable formulations known in the art are preferably those disclosed in Remington's Pharmaceutical Science, recently Mack Publishing Company, Easton PA. Carriers, excipients and diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil. When formulating the composition, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, It is prepared by mixing gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, 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. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명에서 사용되는 용어 "투여"는 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.As used herein, the term “administration” means providing a given composition of the present invention to a subject by any suitable method.
본 발명의 약학적 조성물의 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 바람직한 효과를 위해서, 본 발명의 뎁손은 1일 1 mg/ kg 내지 10000 mg/kg의 양으로 투여할 수 있으며, 하루에 한번 투여할 수도 있고, 수 회 나누어 투여할 수도 있다. The preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and weight of the individual, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. For a desirable effect, the depsone of the present invention may be administered in an amount of 1 mg/kg to 10000 mg/kg per day, may be administered once a day, or may be administered in several divided doses.
본 발명의 약학적 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection.
본 발명의 조성물은 알츠하이머성 치매 예방 및 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers for the prevention and treatment of Alzheimer's dementia.
본 발명에서, "건강기능식품"이란, 질병의 예방 및 개선, 생체방어, 면역, 병후의 회복, 노화 억제 등 생체조절 기능을 가지는 식품을 말하는 것으로, 장기적으로 복용하였을 때 인체에 무해해야 한다. In the present invention, "health functional food" refers to a food having bioregulatory functions such as prevention and improvement of disease, body defense, immunity, recovery from illness, and suppression of aging, and should be harmless to the human body when taken for a long time.
본 발명의 조성물은 알츠하이머성 치매의 예방 또는 개선과 2형 당뇨병의 예방 및 개선과 Prion 질병의 예방 및 개선과 COVID-19를 포함한 전염병의 예방 및 개선을 목적으로 건강기능식품에 첨가될 수 있다. 본 발명의 뎁손을 식품 첨가물로 사용할 경우, 상기 뎁손을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 사용 목적 (예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 뎁손은 원료에 대하여 15중량% 이하, 바람직하게는 10 중량% 이하의 양으로 첨가된다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The composition of the present invention may be added to a health functional food for the purpose of preventing or improving Alzheimer's dementia, preventing and improving type 2 diabetes, preventing and improving Prion disease, and preventing and improving infectious diseases including COVID-19. When the depsone of the present invention is used as a food additive, the depson may be added as it is or may be used together 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). In general, in the production of food or beverage, the depsone of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, it 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.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 수프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the type of the food. 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, vitamin complexes, and the like, and includes all health foods in the ordinary sense.
*본 발명의 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 포함할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토오스, 수크로오스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ml 당 일반적으로 약 0.01 내지 10 g, 바람직하게는 약 0.01 내지 0.1 g 이다.* The health beverage composition of the present invention may include various flavoring agents or natural carbohydrates as additional ingredients, like conventional beverages. As the above-mentioned natural carbohydrates, monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, synthetic sweeteners such as saccharin and aspartame may be used. The proportion of the natural carbohydrate is generally about 0.01 to 10 g, preferably about 0.01 to 0.1 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 포함할 수 있다. 그 밖에 본 발명의 조성물은 천연 과일주스, 과일주스 음료 및 야채 음료의 제조를 위한 과육을 포함할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01 내지 0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, 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 included. In addition, 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 very important, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
이하 본 발명의 이해를 돕기 위하여 바람직한 준비예, 실시예 및 제제예를 제시한다. 그러나 하기 준비예, 실시예 및 제제예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 이에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred preparation examples, examples and formulation examples are presented to help the understanding of the present invention. However, the following preparation examples, examples, and formulation examples are only provided for easier understanding of the present invention, and thus the content of the present invention is not limited thereto.
이하 본 발명의 약학적 조성물과 식품 조성물의 제제예를 설명하나, 이는 본 발명을 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, formulation examples of the pharmaceutical composition and the food composition of the present invention will be described, but this is not intended to limit the present invention, but merely to describe it in detail.
제제예 1. 약학적 제제의 제조Formulation Example 1. Preparation of a pharmaceutical formulation
1. 산제의 제조 1. Preparation of powder
뎁손 50 mgDepsone 50 mg
유당 100 mg Lactose 100 mg
탈크 10 mgtalc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight bag to prepare a powder.
2. 정제의 제조2. Preparation of tablets
뎁손 50 mgDepsone 50 mg
*옥수수전분 100 mg* Cornstarch 100 mg
유당 100 mg Lactose 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above ingredients, tablets are prepared by tableting according to a conventional manufacturing method of tablets.
3. 캡슐제의 제조3. Preparation of capsules
뎁손 50 mgDepsone 50 mg
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mg0.2 mg magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled in a gelatin capsule to prepare a capsule.
4. 주사제의 제조4. Preparation of injections
뎁손 50 mgDepsone 50 mg
만니톨 180 mgmannitol 180 mg
주사용 멸균 증류수 2974 mg2974 mg of sterile distilled water for injection
Na 2HPO 42H 2O 26 mgNa 2 HPO 4 2H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당 (2 ml) 상기의 성분 함량으로 제조한다.According to a conventional method for preparing injections, the content of the above ingredients per ampoule (2 ml) is prepared.
5. 액제의 제조5. Preparation of liquid formulations
뎁손 50 mg Depsone 50 mg
이성화당 10 g10 g isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water appropriate amount
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ml로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.According to a conventional liquid preparation method, each component is added to purified water to dissolve, an appropriate amount of lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by adding purified water, and then filled in a brown bottle. Sterilize to prepare a solution.
[제제예 2. 식품 제제의 제조][Formulation Example 2. Preparation of food preparations]
1. 건강식품의 제조1. Manufacture of health food
뎁손 50 mgDepsone 50 mg
비타민 혼합물 적량appropriate amount of vitamin mixture
비타민 A 아세테이트 70 g 70 g vitamin A acetate
비타민 E 1.0 mgVitamin E 1.0 mg
비타민 B1 0.13 mgVitamin B1 0.13 mg
비타민 B2 0.15 mgVitamin B2 0.15 mg
비타민 B6 0.5 mg0.5 mg of vitamin B6
비타민 B12 0.2 g 0.2 g of vitamin B12
비타민 C 10 mgVitamin C 10 mg
비오틴 10 g 10 g of biotin
니코틴산아미드 1.7 mg1.7 mg of nicotinic acid amide
엽산 50 g 50 g folic acid
판토텐산 칼슘 0.5 mgCalcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture appropriate amount
황산제1철 1.75 mgferrous sulfate 1.75 mg
산화아연 0.82 mgZinc Oxide 0.82 mg
탄산마그네슘 25.3 mgMagnesium carbonate 25.3 mg
제1인산칼륨 15 mgpotassium phosphate monobasic 15 mg
제2인산칼슘 55 mgDicalcium Phosphate 55 mg
구연산칼륨 90 mgPotassium citrate 90 mg
탄산칼슘 100 mg100 mg of calcium carbonate
염화마그네슘 24.8 mgMagnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.The composition ratio of the vitamin and mineral mixture is a composition that is relatively suitable for health food in a preferred embodiment, but the mixing ratio may be arbitrarily modified. , to prepare granules, and can be used for preparing health food compositions according to a conventional method.
2. 건강음료의 제조2. Manufacture of health drinks
뎁손 50 mgDepsone 50 mg
비타민 C 15 g15 g vitamin C
비타민 E(분말) 100 g100 g vitamin E (powder)
젖산철 19.75 g19.75 g of iron lactate
산화아연 3.5 g3.5 g zinc oxide
니코틴산아미드 3.5 g3.5 g of nicotinic acid amide
비타민 A 0.2 g0.2 g vitamin A
비타민 B1 0.25 g0.25 g of vitamin B1
비타민 B2 0.3gVitamin B2 0.3g
물 정량water metering
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 l 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다.After mixing the above ingredients according to the usual health drink manufacturing method, after stirring and heating at 85°C for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 l container, sealed and sterilized, then refrigerated. It is used to prepare the health drink composition of the invention.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is prepared by mixing ingredients suitable for relatively favorite beverages in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and national preferences such as demanding class, demanding country, and use.
NLRP3 인플라마솜은 다양한 인류의 질병인 알츠하이머병, 프라이온병, 2형 당뇨병, 다양한 전염병에 관여한다. 뎁손을 투약하여 알츠하이머병, 프라이온병, 2형 당뇨병, 다양한 전염병 등등의 질병의 악화를 방지하여 다양한 합병증과 조기사망을 방지한다. The NLRP3 inflammasome is involved in various human diseases, including Alzheimer's disease, prion disease, type 2 diabetes, and various infectious diseases. By administering Depsone, various complications and premature death are prevented by preventing the aggravation of diseases such as Alzheimer's disease, prion disease, type 2 diabetes, and various infectious diseases.
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Claims (6)

  1. 뎁손 및 유도체를 유효성분으로 함유하는, NLRP3 인플라마솜(inflammasome) 염증에 의한 알츠하이머병, 파킨슨병, 경도인지장애 및 전염병의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating Alzheimer's disease, Parkinson's disease, mild cognitive impairment and infectious diseases caused by NLRP3 inflammasome inflammation, containing depsone and derivatives as active ingredients.
  2. 제1항에 있어서, 상기 조성물은 뎁손 및 유도체를 50~200mg 포함하는 것을 특징으로 하는, 알츠하이머병, 파킨슨병, 경도인지장애 및 전염병의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating Alzheimer's disease, Parkinson's disease, mild cognitive impairment and infectious diseases according to claim 1, wherein the composition contains 50 to 200 mg of depsone and derivatives.
  3. 제2항에 있어서, 상기 조성물은 하루 2 내지 3회 투여되는 것을 특징으로 하는, 알츠하이머병, 파킨슨병, 경도인지장애 및 전염병의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating Alzheimer's disease, Parkinson's disease, mild cognitive impairment and infectious diseases according to claim 2, wherein the composition is administered 2 to 3 times a day.
  4. 제1항에 있어서, 상기 조성물은 세포 내 NLRP3 인플라마섬 및 NLRP3 인플라마섬 촉진자 및 NLRP3 인플라마섬 촉진시키는 공통 경로를 제어하여 염증을 감소시키는 것을 특징으로 하는, 알츠하이머병, 파킨슨병, 경도인지장애 및 전염병의 예방 또는 치료용 약학적 조성물.The method of claim 1, wherein the composition reduces inflammation by controlling a common pathway that promotes intracellular NLRP3 inflammasome and NLRP3 inflammasome promoter and NLRP3inflammasome, Alzheimer's disease, Parkinson's disease, mild cognitive A pharmaceutical composition for the prevention or treatment of disorders and infectious diseases.
  5. 뎁손 및 유도체를 유효성분으로 함유하는, 염증에 의한 알츠하이머병, 파킨슨병, 경도인지장애 및 전염병 개선용 건강 기능식품. A health functional food for improving Alzheimer's disease, Parkinson's disease, mild cognitive impairment and infectious diseases caused by inflammation, containing depsone and derivatives as active ingredients.
  6. 제5항에 있어서, 상기 조성물은 세포 내 NLRP3 인플라마섬 및 NLRP3 인플라마섬 촉진자 및 NLRP3 인플라마섬 촉진시키는 공통 경로를 제어하여 염증을 감소시키는 것을 특징으로 하는, 알츠하이머병, 파킨슨병, 경도인지장애 및 전염병 개선용 건강 기능식품.The method of claim 5, wherein the composition reduces inflammation by controlling a common pathway that promotes intracellular NLRP3 inflammasome and NLRP3inflammasome promoter and NLRP3inflammasome, Alzheimer's disease, Parkinson's disease, mild cognitive Health functional food for improving disability and infectious diseases.
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