[go: up one dir, main page]

WO2008066064A1 - Régulation de l'activité du facteur transcriptionnel stat par un ion zinc - Google Patents

Régulation de l'activité du facteur transcriptionnel stat par un ion zinc Download PDF

Info

Publication number
WO2008066064A1
WO2008066064A1 PCT/JP2007/072921 JP2007072921W WO2008066064A1 WO 2008066064 A1 WO2008066064 A1 WO 2008066064A1 JP 2007072921 W JP2007072921 W JP 2007072921W WO 2008066064 A1 WO2008066064 A1 WO 2008066064A1
Authority
WO
WIPO (PCT)
Prior art keywords
zinc ion
substance
stat
activity
ion concentration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2007/072921
Other languages
English (en)
Japanese (ja)
Inventor
Toshio Hirano
Toshiyuki Fukada
Masaaki Murakami
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
RIKEN
Original Assignee
RIKEN
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by RIKEN filed Critical RIKEN
Publication of WO2008066064A1 publication Critical patent/WO2008066064A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to a STAT activity inhibitor and a prophylactic / therapeutic agent for diseases caused by excessive activation of STAT, which contain a substance that increases the intracellular zinc ion concentration.
  • IL-6 one of the site force-ins, activates multiple signaling molecules, including the transcription factor STAT3, via the gpl30 subunit of the IL-6 receptor expressed on the surface of target cells. It has been pointed out that it is important for homeostasis!
  • STAT is an important transcription factor involved in cell differentiation, proliferation, survival, and functional expression
  • Non-patent Document 2 excessive activation of STAT3 is caused by autoimmune diseases (Non-patent document 3), inflammatory diseases (Non-patent document 4, Non-patent document 5, Non-patent document 6), cancer (Non-patent document 7, Non-patent document). 8) It has been reported to be involved in etc. In other words, control of the signal transduction pathway involving STAT3 is extremely important from the viewpoint of prevention and treatment of such diseases.
  • Zinc (Zn) is involved in various biological responses, and zinc deficiency is sexual development delay, sperm depletion-amenorrhea, developmental abnormality, anemia, immune decline, night blindness, skin symptoms, taste disorders, olfaction It is known to cause various symptoms such as disability, chronic diarrhea, delayed wound healing, abnormal mental status and so on. So far, it has been reported that symptoms such as taste disorders and gastric ulcers are alleviated by zinc supplementation. In addition to various supplements, zinc supplementation uses Polaprezinc (Promac (registered trademark), a new zeria drug), etc. It is.
  • Non-patent document 1 Hirano et al., Signaling mechanisms through gpl30: a model of the cytokine system. Cytokine & Growth Factor Reviews, 8: 241-52, 1997.
  • Non-Patent Document 2 Sehgai PB et al., Signal transducers and activators of Trnascription (S TATs) Activation and Biology.luwer Academic Publishers. 2003.
  • Non-Patent Document 3 Sawa S et al., Autoimmune arthritis associated with mutated interleuk in (IL) _6 receptor g l30 is driven by STAT3 / IL_7_dependent homeostatic proliferat ion of CD4 + T cells., J Exp Med. 2006 Jun 12; 203 ( 6): 1459-70
  • Non-Patent Document 4 Mitsuyama, et al., STAT3 activation via interleukin 6 trans—signalli ng contributes to ileitis in SAMPl / Yit mice. Gut. 2006 Sep.55 (9): 1263-9.
  • Non-Patent Document 5 Suzuki A, et al., CIS3 / SOCS3 / SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med. 2001 Feb. 19; 193 (4): 471 -81.
  • Non-Patent Document 6 Lovato P et al., Constitutive STAT3 activation in intestinal T cells fr om patients with Crohn's disease., J Biol Chem. 2003 May 9; 278 (19): 16777-81.
  • Non-Patent Document 7 Bromberg JF et al., Stat3 as an oncogene., Cell. 1999 Aug 6; 98 (3): 2 95-303.
  • Non-Patent Document 8 Bromberg JF, Stat proteins and oncogenesis., J Clin Invest. 2002 May 1; 109 (9): 1139-1142.
  • An object of the present invention is to provide a novel STAT activity inhibitor and to prevent and treat a disease caused by excessive activation of STAT.
  • the present invention is as follows:
  • STAT force STATU STAT3 the agent according to [1], which is at least one selected from the group consisting of STAT4, STAT5, and STAT6,
  • a method for suppressing the activity of STAT comprising administering an effective amount of a substance that increases the concentration of intracellular zinc ions
  • a method for the prevention and treatment of a disease caused by excessive activation of STAT comprising administering to the subject a therapeutically effective amount of a substance that increases the intracellular zinc ion concentration, [10] Production of a STAT activity regulator Use of substances that increase intracellular zinc ion concentration, for
  • Substances that increase intracellular zinc ion concentration for use in the prevention and treatment of diseases caused by excessive activation of STAT [13] A screening method for a substance having an inhibitory action on STAT activity, comprising measuring the intracellular zinc ion concentration and selecting a substance that increases the intracellular zinc ion concentration as a substance capable of suppressing the STAT activity.
  • the agent of the present invention can be useful for suppressing / treating STAT activity and preventing / treating a disease caused by excessive activation of STAT.
  • a substance capable of suppressing S TAT activity can be obtained. Therefore, the method can be used as a prophylactic / therapeutic agent for diseases caused by STAT research and / or excessive activation of STAT. Can be useful in development.
  • FIG. 1 is a diagram showing the effect of intracellular introduction of zinc ions in a mouse cell line.
  • the following results were obtained with the introduction of zinc ion:
  • C The transfer of STAT3 to the nucleus was significantly suppressed.
  • D The transcriptional activation of SOCS3 was remarkably suppressed.
  • FIG. 2 is a graph showing the effect of zinc ion administration in a mouse DSS-induced colitis model. It was revealed that administration of zinc ions significantly suppressed DSS-induced mouse body weight loss, ie, colitis.
  • SI AT signal lYansducer and Activator for ranscnption
  • STAT activation means that STAT is phosphorylated, translocates into the nucleus, and activates transcription of the target gene STAT T1 to STAT6 are currently cloned.
  • the STATs targeted by the invention are preferably STA Tl, STAT3, STAT4, STAT5 and STAT6, particularly preferably STAT3 Nucleotide sequences and amino acid sequences of STAT family members are available from various databases.
  • the STAT targeted in the present invention is usually a mammalian STAT.
  • mammals include, but are not limited to, primates, laboratory animals, livestock, pets, and the like, specifically humans, monkeys, rats, and the like.
  • the "substance that increases intracellular zinc ion concentration” directly and / or indirectly increases the concentration (ie, amount) of intracellular zinc ions regardless of the mechanism of action. Means any substance. In the present invention, a plurality of such substances may be used in combination. “Substances that increase intracellular zinc ion concentration” include “zinc ions”, “zinc ionophores”, “combinations of zinc ions and zinc ionophores”, “substances that regulate the expression and / or activity of zinc ion transporters” However, it is not limited to these.
  • Zinc ions Zinc ionophores
  • zinc ionophores and “combinations of zinc ions and zinc ionophores” directly increase the intracellular zinc ion concentration, and “substances that regulate the expression and / or activity of zinc ion transporters” It can indirectly increase the concentration of zinc ions in the cell.
  • the action of zinc ions on STAT may be direct or via other molecules.
  • expression means that a gene translation product (protein, polypeptide, etc.) is produced and functionally localized at its site of action.
  • the "zinc ion" may be in any form of ion (Zn 2+ ) / salt / complex.
  • zinc ions known zinc preparations can also be used.
  • Salts of zinc that can be used include physiologically acceptable salts with organic or inorganic acids such as trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citrate, gluconic acid.
  • Ascorbic acid benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamate, fumaric acid, phosphonic acid, malonic acid, malic acid, benzenesulfonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydrogen iodide Acid addition salts with acids such as acid, sulfamic acid, sulfuric acid and phosphoric acid Can be mentioned.
  • Examples of zinc complexes that can be used include physiologically acceptable complexes, such as the above-mentioned L-carnosine zinc complex (Pola Brenzing).
  • Zinc ions existing outside the cell are introduced into the cell by "zinc ionophore".
  • zinc ionophore examples include various compounds that are usually used in the art and are preferably commercially available.
  • examples of the zinc ionophore include, but are not limited to, pyrithione, heterocyclic amine, dithiocarbamate, and vitamins.
  • any combination force S of zinc ion and zinc ionophore is mentioned. You may use multiple types together, respectively as needed.
  • intracellular means (1) the whole cell or (2) "cytoplasm"
  • organelle refers to membranous organelles (meaning intracellular compartments separated from other spaces in the cytoplasm by the inner membrane)!
  • “increase in intracellular zinc ion concentration” includes (1) increase in zinc ion concentration in the whole cell, and (2) zinc ion concentration in the whole cell itself, Ubiquitous, i.e., causing a local increase in zinc ion concentration in the compartment (referred to as "cytoplasm” or "organelle”).
  • the “zinc ion transporter” includes “zinc ion importer” and “zinc ion transporter”.
  • the “zinc ion transporter” includes those responsible for zinc ion transport inside and outside the cell through the cell membrane and those responsible for zinc ion transport inside and outside the organelle. Specifically, in the case of (1) above, a molecule that takes zinc ions into the cell is called “zinc ion importer”, and a molecule that discharges zinc ions to the outside of the cell is called “zinc ion exporter”. .
  • a molecule that transports zinc ions from the organelle to the cytoplasm is included in the “zinc ion importer”, and a molecule that transports zinc ions from the cytoplasm to the organelle is “zinc ion”.
  • “modulating the expression and / or activity of a zinc ion transporter” includes, for example, “promoting the expression and / or activity of a zinc ion importer”, “expression of a zinc ion exporter” And / or “inhibiting activity” and the like, but is not limited to these as long as an “increase in intracellular zinc ion concentration” finally occurs.
  • the mechanism of action of the "substance that regulates the expression and / or activity of a zinc ion transporter” is not particularly limited, and may be regulation at the gene level or regulation at the protein level. Examples of regulation at the gene level include transcription regulation and gene expression regulation. Regulation at the protein level includes metabolic regulation, phosphorylation, dephosphorylation, glycosylation, lipid addition, coordinate bond with zinc, degradation, ubiquitination, acetylation, etc.
  • Examples of the "zinc ion transporter” include human ZIPs including the LIV family (BAB 70848, hZip4, BIGM103, IAA0062, IAA1265, hZip6, AAH08853, hZip7, XP_208 649, hZIPl, hZIP2, hZIP3, BAA92100, BAC04504, etc.), human CDF (cation diffusion facilitator) (hZnt_5, hZnt_7, hZnt_l, hZnt_6, hZnt_3, hZnt_2, hZnt_8, hZnt_4, hZnt-9, etc.).
  • human ZIPs including the LIV family (BAB 70848, hZip4, BIGM103, IAA0062, IAA1265, hZip6, AAH08853, hZip7, XP_208 649, hZIPl, hZIP2, hZIP
  • ZIPs belong to the “Zinc ion importer” and CDFs belong to the “Zinc ion importer”.
  • the zinc ion importer LIVl / Zip6 is regulated by STAT3 (Yamashita, S., Miyagi, C, Fukada, ⁇ , agara, N., Che, Y.-S. & Hirano, T. Zinc transporter LIVI controls epithelia mesenchymal tra nsition in zebrafish gastrula organizer. Nature 429, 298-302 (2004)).
  • Substances that suppress the expression of the zinc ion exporter gene may be used at any stage of transcription, post-transcriptional regulation, translation, post-translational modification, localization, and protein folding! / ,.
  • substances that suppress the expression of zinc ion exporter include transcriptional repressors, RNA polymerase inhibitors, RNA degrading enzymes, protein synthesis inhibitors, nuclear translocation inhibitors, proteolytic enzymes, protein denaturing agents, etc.
  • a substance that can specifically act on the target molecule is preferable.
  • One embodiment of a substance that suppresses the expression of a zinc ion exporter is a zinc ion etaspotter antisense nucleic acid.
  • Antisense nucleic acid refers to target mRNA (early transcription A nucleic acid comprising a base sequence capable of hybridizing with the target mRNA under physiological conditions of cells expressing the product, and capable of inhibiting the translation of the polypeptide encoded by the target mRNA in the hybridized state! /, However, it may bind to double-stranded RNA to form a triplex and inhibit transcription to mRNA.
  • the type of nucleic acid may be DNA or RNA, and may be a DNA / RNA chimera.
  • the length of the antisense nucleic acid is not particularly limited as long as it functions as an antisense nucleic acid.
  • the length of the antisense nucleic acid is short, about 15 bases, and the long one contains a sequence complementary to the full-length sequence of mRNA (initial transcription product). It may be.
  • the length of the antisense nucleic acid is, for example, about 15 bases or more, preferably about 18 bases or more, more preferably about 20 bases or more.
  • the length of the antisense nucleic acid is, for example, about 200 bases or less, preferably about 50 bases or less, more preferably about 30 bases or less. That is, examples of the antisense nucleic acid include oligonucleotides consisting of about 15 to about 200 bases, preferably about 18 to about 50 bases, more preferably about 20 to about 30 bases.
  • Ribozyme refers to RNA having an enzyme activity that cleaves nucleic acids !, but in the present invention, it is used as a concept including DNA as long as it has sequence-specific nucleic acid cleavage activity. Ribozymes include self-splicing RNAs found in infectious RNAs such as viroids and viruses, and hammerheads and hairpins are known.
  • a ribozyme when used in the form of an expression vector containing the RNA encoding the ribozyme, a hybrid ribozyme further linked with a tRNA-modified sequence is added to promote translocation to the cytoplasm. [Nucleic Acids Res., 29 (13): 2780-2788 (2001)].
  • Yet another embodiment of the substance that suppresses the expression of the zinc ion exporter is the nucleotide sequence of the mRNA or initial transcript of the zinc ion exporter or its partial partition ⁇ IJ (preferably within the coding region) (initial stage).
  • siRNA is typically a target gene mRNA or a nucleotide sequence of an initial transcript or a partial partition IJ (target nucleotide sequence).
  • shRNA small hairpin RNA is one of the preferred embodiments of siRNA.
  • the length of the portion of the siRNA that is homologous to the target nucleotide sequence is usually about 18 bases or more, for example, about 20 bases (typically about 2;! To 23 bases long). There is no particular limitation as long as it can cause a certain force RNA interference. If the siRNA is longer than 23 bases, the siRNA is degraded in the cell to produce siRNA of about 20 bases, so theoretically, the upper limit of the length of the portion homologous to the target nucleotide sequence is the target. The full length of the nucleotide sequence of the gene mRNA or early transcript.
  • the length of the homologous portion is, for example, about 200 bases or less, preferably about 50 bases or less, more preferably about 30 bases or less. That is, the length of the homologous portion is, for example, about 18 bases or more, preferably about 18 to about 200 bases, more preferably about 20 to about 50 bases, and further preferably about 20 to about 30 bases.
  • the total length of siRNA is usually about 18 bases or more, for example, about 20 bases (typically about 2;! To 23 bases long), as long as it can cause RNA interference.
  • the length of siRNA is, for example, about 200 bases or less, preferably about 50 bases or less, more preferably about 30 bases or less. That is, the length of siRNA is, for example, about 18 bases or more, preferably about 18 to about 200 bases, more preferably about 20 to about 50 bases, and further preferably about 20 to about 30 bases.
  • the length of the nucleic acid of shRNA shall be shown as the length of the double-stranded part when it has a double-stranded structure.
  • the length of the loop portion of the hairpin loop of shRNA is not particularly limited as long as it can cause RNA interference, but is usually about 5 to 25 bases.
  • the nucleotide sequence of the loop portion is not particularly limited as long as it can form a loop and shRNA can cause RNA interference.
  • the agent of the present invention can express (encode) the effective nucleic acid molecule.
  • a vector can also be used as an active ingredient.
  • the expression vector that can be used in the present invention is not particularly limited, but as a vector suitable for administration to mammals such as humans, Examples thereof include viral vectors such as rovirus, adenovirus, and adeno-associated virus.
  • a nucleotide sequence encoding an effective nucleic acid molecule is usually operably linked to an appropriate promoter.
  • the promoter used is not particularly limited as long as it can function in the mammalian cells to be administered! /.
  • an appropriate promoter can be selected.
  • the expression vector of the present invention preferably contains a transcription termination signal (terminator region) downstream of the nucleotide sequence encoding the effective nucleic acid molecule, and further contains a selection marker gene (drug resistance gene, auxotrophic mutation).
  • a selection marker gene drug resistance gene, auxotrophic mutation.
  • Complementary gene, fluorescent protein gene, etc.), tag marker gene, etc. may be contained.
  • Administration of the prophylactic / therapeutic agent of the present invention comprising such an expression vector as an active ingredient is performed by an in vivo method in which the vector is directly introduced into the administration target body.
  • the inducer to a desired tissue, the expression of an effective nucleic acid molecule can be induced specifically in the tissue.
  • the substance that suppresses the activity of the zinc ion exporter is not particularly limited as long as it is a substance that can reduce the activity of the zinc ion exporter, but in order to minimize the adverse effect on other genes' proteins. Is preferably a substance that can act specifically on the target molecule.
  • Examples of the substance that specifically suppresses the activity of the zinc ion exporter include a dominant negative mutant of the zinc ion exporter, a nucleic acid encoding the same, an expression vector containing the nucleic acid, and a low molecular organic compound. .
  • the expression vector is the same as described above.
  • a dominant negative mutant of a zinc ion exporter is one whose activity has been reduced by introducing a mutation into the zinc ion exporter.
  • Dominant negative mutants of the zinc ion etaspotter can indirectly inhibit its activity by competing with the natural zinc ion exporter.
  • Dominant negative mutants of the zinc ion exporter can be made by introducing mutations into the zinc ion exporter.
  • Amino acid mutation is a method known per se using PCR or a known kit. Can be introduced.
  • Another preferred embodiment of the substance that suppresses the activity of a zinc ion exporter is an antibody (anti-zinc ion exporter antibody) that specifically recognizes a zinc ion exporter.
  • the antibody can be prepared by a well-known immunological technique, whether it is a polyclonal antibody or a monoclonal antibody.
  • the antibody may be an antibody fragment (eg, Fab, F (ab ′) 2) or a recombinant antibody (eg, a single chain antibody).
  • a nucleic acid encoding an anti-zinc ion exporter antibody and an expression vector containing the nucleic acid are also preferable as substances that suppress the activity of the zinc ion exporter.
  • the expression vector is the same as described above.
  • a substance that promotes the expression of a zinc ion importer is a nucleic acid encoding the zinc ion importer and an expression vector containing the nucleic acid.
  • nucleic acids include cDNA, mRNA, and chromosomal DNA encoding a zinc ion importer.
  • the nucleic acid encoding the zinc ion transporter may be DNA, RNA, or a DNA / RNA chimera, but is preferably DNA.
  • the nucleic acid may be double-stranded or single-stranded. In the case of double-stranded DNA, double-stranded DNA, double-stranded RNA or DNA: RNA nobled may be used.
  • Nucleic acid encoding a zinc ion importer is a polymer primer chain reaction (hereinafter referred to as “PCR”) using a synthetic primer having a part of the nucleotide sequence and a cage containing chromosomal DNA, mRNA, cDNA, etc. having the nucleotide sequence.
  • PCR polymer primer chain reaction
  • Method Reverse Transcriptase-PCR
  • RT_PCR method Reverse Transcriptase-PCR
  • the substance that promotes the activity of the zinc ion importer is not particularly limited as long as it is a substance that can promote the activity of the zinc ion importer. However, in order to minimize the adverse effect on other genes' proteins. It is preferable to be a substance that can act specifically on the target molecule.
  • Substances that specifically promote the activity of the zinc ion importer include constitutively active mutants of the zinc ion importer, nucleic acids encoding the same, and the nucleus. Examples include acid-containing expression vectors, low molecular organic compounds, and the like. Here, the expression vector is the same as described above.
  • a constitutively active mutant of a zinc ion importer refers to a mutant that is always activated regardless of the presence or absence of an upstream signal.
  • Constitutively active mutants of the zinc ion importer can be made by introducing appropriate mutations in the sequence of the wild-type zinc ion importer. Amino acid mutations can be introduced by a method known per se using PCR or a known kit.
  • the "substance that increases the intracellular zinc ion concentration” may be a known compound or a new compound that will be developed in the future, in addition to the substances described above. Moreover, it does not matter whether it is a low molecular compound or a high molecular compound.
  • the low molecular weight compound is a compound having a molecular weight of less than 3000, and examples thereof include organic compounds that can be normally used as pharmaceuticals, derivatives and inorganic compounds thereof, and compounds that are produced by making full use of organic synthesis methods. Or a derivative thereof, a naturally derived compound or derivative thereof, a small nucleic acid molecule such as a promoter, or various metals.
  • polymer compound examples include compounds having a molecular weight of about 3000 or more, such as proteins, polynucleic acids, polysaccharides, and combinations thereof. These low-molecular compounds or high-molecular compounds can be obtained commercially if they are known, or can be obtained through steps such as collection, production, and purification according to each report literature. These may be naturally derived, prepared by genetic engineering, or obtained by semisynthesis.
  • Substances that increase intracellular zinc ion concentration are useful as STAT activity inhibitors and as preventive and therapeutic agents for diseases caused by excessive activation of STAT.
  • a “substance that increases intracellular zinc ion concentration” By administering a “substance that increases intracellular zinc ion concentration” to a patient with the disease in which STAT in the tissue or cells is excessively activated, the activation of STAT is suppressed and the disease is treated.
  • the term “excessive activation of STAT” means a state in which STAT power is normally received by STAT because of intrinsic and / or extrinsic reasons, and / or activity is increased by losing its activity control. .
  • STAT is constitutively active due to mutations in STAT itself, or activity is enhanced due to constitutive activation of upstream molecules in the signal transduction pathway that leads to STAT phosphorylation. A state etc. are illustrated. Excessive activation of each STAT can cause various diseases as described below.
  • Diseases caused by excessive activation of STAT1 by Type I Interferon, etc. include breast cancer, head and neck cancer, lung cancer, brain tumor, acute myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, red Examples include cancers such as leukemia, inflammatory diseases such as hepatitis, and the like.
  • diseases caused by excessive activation of STAT2 include inflammatory diseases such as hepatitis.
  • autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, Crohn's disease and ulcerative colitis.
  • Inflammatory bowel disease inflammatory diseases such as hepatitis C, hepatitis, breast cancer, head and neck cancer, prostate cancer, melanoma, ovarian cancer, lung cancer, brain tumor, triumphal cancer, renal carcinoma, kidney cancer, acute bone marrow Leukemia, chronic lymphocytic leukemia, mycosis fungoides, Burkitt lymphoma, large granular lymphocytic leukemia, myeloma, Hodgkin lymphoma, undifferentiated large cell lymphoma, cancer such as thyroid cancer, hepatocellular carcinoma, diabetes Etc. may be mentioned.
  • Diseases caused by excessive activation of STAT4 by IL-12 or IL-23 include inflammatory diseases such as hepatitis and arthritis, autoimmune diseases such as multiple sclerosis, Crohn's disease and ulcerative colitis Inflammatory bowel disease, allergic disease, Graves' disease etc. can be mentioned.
  • Diseases caused by excessive activation of STA T5 by IL-2 family site force-in, GCSF, EPO, TPO, IL-3 / IL-5 / GM-CSF, etc. include chronic myeloid leukemia, acute myeloid leukemia And acute lymphoblastic leukemia, chronic lymphocytic leukemia, cancer such as erythroleukemia, inflammatory diseases such as hepatitis, and the like.
  • Diseases caused by excessive activation of STAT6 by IL-4, etc. include atopic dermatitis, hay fever, allergic diseases such as bronchial asthma, inflammatory diseases such as hepatitis and arthritis, and multiple sclerosis. Autoimmune diseases, Graves' disease etc.
  • the STAT activity inhibitor of the present invention and diseases caused by excessive activation of STAT may contain a pharmaceutically acceptable excipient or additive as desired in addition to the above-mentioned active ingredient (that is, a substance that increases the intracellular zinc ion concentration).
  • Pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc. Can be mentioned.
  • Examples of pharmaceutically acceptable carriers include magnesium carbonate, magnesium stearate, talc, sugar, ratatose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low-melting wax, Examples include cocoa butter.
  • the tablet can be made into a tablet coated with a normal coating, for example, a sugar-coated tablet, an enteric-coated tablet, a film-coated tablet, a bilayer tablet, or a multilayer tablet as necessary.
  • Powders are formulated with a pharmaceutically acceptable powder base. Examples of the base include talc, ratatoose, and starch.
  • Drops can be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents, and the like.
  • Capsenole can be produced by filling a compound as an active ingredient together with a pharmaceutically acceptable carrier.
  • the compound can be mixed with pharmaceutically acceptable excipients or filled into capsules without excipients.
  • a cachet agent can be produced by a similar method.
  • a base such as vegetable oil (castor oil, olive oil, peanut oil, etc.), mineral oil (petrol, white petrolatum, etc.), waxes, partially synthetic or fully synthetic glycerin fatty acid ester, etc. It is formulated by a commonly used technique.
  • injection solutions include solutions, suspensions, and emulsions.
  • examples thereof include an aqueous solution and a water propylene glycol solution.
  • the solution can also be prepared in the form of a solution of polyethylene glycol and / or propylene glycol, which may contain water.
  • a solution suitable for oral administration should be prepared by adding a compound as an active ingredient to water and adding a colorant, a fragrance, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary. Can do.
  • a solution suitable for oral administration can also be produced by adding the compound together with a dispersant to water to make it viscous.
  • the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.
  • the topical administration agent include the above liquid preparations, creams, aerosols, sprays, powders, mouths, ointments and the like.
  • the above-mentioned topical preparation can be produced by mixing a compound as an active ingredient with a pharmaceutically acceptable diluent and carrier.
  • Ointments and creams are formulated, for example, by adding a thickener and / or gelling agent to an aqueous or oily base.
  • the base include water, liquid paraffin, and vegetable oil.
  • the thickener for example, soft paraffin, aluminum stearate, cetostearyl anolanolate, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, beeswax and the like can be mentioned.
  • a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, cresol cresol, benzalkonium chloride, or a bacterial growth inhibitor can be added to the topical administration agent.
  • Lotions can contain one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, colorants, flavors, etc., in an aqueous or oily base. .
  • the agent of the present invention is administered orally or parenterally.
  • it can be administered in a dosage form commonly used in the art.
  • parenteral administration it is possible to administer in a dosage form such as a topical agent (transdermal agent, etc.), a rectal agent, an injection, or a nasal agent.
  • Examples of the oral preparation or rectal administration preparation include capsules, tablets, pills, powders, drops, cachets, suppositories, liquids and the like.
  • Examples of the injection include a sterile solution or a suspension.
  • Examples of the topical administration agent include creams, ointments, lotions, and skin preparations (ordinary patches and matrix agents).
  • the dose and frequency of administration of the agent of the present invention vary depending on the type of substance used to increase the zinc ion concentration used, the patient's symptoms, age, body weight, dosage form, etc., and can be appropriately set.
  • the present invention also provides a method of suppressing the activity of STAT, which comprises increasing intracellular zinc ion concentration in vitro.
  • the method includes the step of adding a substance that increases intracellular zinc ion concentration to an in vitro system in which suppression of STAT activity is desired.
  • the various substances described above can be used as substances that increase the intracellular zinc ion concentration.
  • Means to increase intracellular zinc ion concentration increase intracellular zinc ion concentration.
  • V it can be done by means of deviation! /.
  • Examples of in vitro systems to be used include systems such as tissue sections, cultured cells, cell debris, and cell extracts. As long as the system can function S and STAT and can suppress STAT activity, It is not limited to. As such an in vitro system used in the present invention, it is possible to use a primary cultured cell, a cell line derived from the primary cultured cell, etc. as such a cell. In this specification, even when using a cell-free system (cell debris, cell extract, etc.), “increasing intracellular zinc ion concentration” means increasing the zinc ion concentration of the system. It expresses.
  • the addition of a substance that increases the intracellular zinc ion concentration is performed in a culture medium.
  • the culture medium is appropriately selected depending on the cells to be used, and examples thereof include a minimum essential medium (MEM) containing about 5 to 20% urine fetal serum, Dulbecco's modified Eagle medium (DMEM), and the like.
  • MEM minimum essential medium
  • DMEM Dulbecco's modified Eagle medium
  • the culture conditions are appropriately determined in the same manner.
  • the pH of the medium is about 6 to about 8
  • the culture temperature is usually about 30 to about 40 ° C
  • the culture time is about 12 to about 72 hours. is there.
  • This method may be useful in studies of diseases involving STAT or STAT.
  • the present invention also provides a method for suppressing the activity of STAT, which comprises administering an effective amount of a substance that increases intracellular zinc ion concentration.
  • a substance that increases intracellular zinc ion concentration examples include the mammals described above.
  • An “effective amount” refers to an amount sufficient to increase the intracellular zinc ion concentration of a subject to be administered.
  • the present invention provides a method for the prophylaxis of a disease caused by excessive activation of STAT, preferably inflammatory bowel disease, which comprises administering an effective amount of a substance that increases the intracellular zinc ion concentration.
  • the “effective amount” is as described above. Specifically, for example, when ZnSO is administered as an aqueous solution, the 300 ppm solution is 5-10 ml / day.
  • the present invention relates to a substance containing a substance that increases intracellular zinc ion concentration, and a disease caused by excessive activation of STAT (for example, various diseases as described above, preferably inflammatory Can be used or used for prevention / treatment of bowel disease) It also includes commercial packages containing statements stating that they should be.
  • STAT various diseases as described above, preferably inflammatory Can be used or used for prevention / treatment of bowel disease
  • the present invention also includes a method for screening a substance having an inhibitory effect on STAT activity, comprising evaluating whether a test substance increases intracellular zinc ion concentration, and a substance obtainable by the method I will provide a.
  • a substance that increases the intracellular zinc ion concentration is selected as a substance having a STAT activity inhibitory action. This substance can prevent or treat diseases caused by excessive activation of STAT.
  • test substance used in the screening method of the present invention may be any known compound or new compound.
  • nucleic acids, carbohydrates, lipids, proteins, peptides, organic low molecular compounds, combinatorial chemistry examples thereof include compound libraries, random peptide libraries, natural components derived from microorganisms, animals and plants, marine organisms, and the like prepared using the technology.
  • the screening method of the present invention includes, for example, the following steps:
  • the cells to be used are not particularly limited as long as they are cells that can be used for measuring intracellular zinc ion concentration, and primary cultured cells, cell lines derived from the primary cultured cells, and the like should be used. Touch with force S.
  • the treatment of the cells with the test substance is usually performed in a culture medium.
  • the culture medium is appropriately selected depending on the cells to be used, and examples thereof include a minimum essential medium (MEM) containing about 5 to 20% urine fetal serum, Dulbecco's modified Eagle medium (DMEM), and the like.
  • MEM minimum essential medium
  • DMEM Dulbecco's modified Eagle medium
  • the culture conditions are also appropriately determined, for example, the pH of the medium is about 6 to about 8, the culture temperature is usually about 30 to about 40 ° C, and the culture time is about 12 to about 72 hours .
  • the treatment time of the cells with the test substance depends on the type and concentration of the cell test substance used. Set as appropriate. The concentration of the test substance for treating the cells is also set appropriately depending on the type of the test substance used and the treatment time.
  • the measurement of the intracellular zinc ion concentration can be carried out by using a method usually carried out in the art and according thereto.
  • a method usually carried out in the art for example, it can be measured directly by an atomic absorption method (frame method) or by a fluorescence spectrophotometer using a specific probe (for example, a fluorescent reagent).
  • the substance selected in the above step (3) can be used in the agent of the present invention as a substance having a STAT activity inhibitory action.
  • Example 1 Effect of zinc ion introduction on STAT in various cell lines
  • the antibodies used were as follows:
  • Primer sequences and reaction conditions used for real time PCR are as follows:
  • Example 2 Effect of zinc ion administration in a mouse DSS-induced colitis model
  • DSS-induced colitis is It is used as a model for inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
  • Wild-type C57BL / 6 mice were allowed to freely drink water with a zinc ion concentration of Oppm or 4000ppm from dayl4 to day9 in a water bottle. Colitis was induced by oral administration of lml of 5% DSS (molecular weight 4000) dissolved in water for 9 days from dayO. On day 9, mice were weighed, and weight loss was used as an indicator of DSS-induced colitis.
  • DSS molecular weight 4000
  • mice weight loss was significantly suppressed by administering zinc ions in a water bottle (Fig. 2).
  • Fig. 2 it was revealed that administration of zinc ions significantly suppressed STAT3 activation-dependent DSS-induced enteritis.
  • the agent of the present invention may be useful for suppressing / treating STAT activity and preventing / treating a disease caused by excessive activation of STAT.
  • a substance capable of suppressing S TAT activity can be obtained. Therefore, the method can be used as a prophylactic / therapeutic agent for diseases caused by STAT research and / or excessive activation of STAT. Can be useful in development.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Endocrinology (AREA)
  • Cell Biology (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Analytical Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Communicable Diseases (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Virology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)

Abstract

L'invention a pour but de prévenir et de traiter une maladie induite par l'hyperactivation de STAT en proposant un nouveau régulateur de l'activité STAT. A cet effet, l'invention porte sur un régulateur de l'activité STAT et un remède préventif/remède pour une maladie induite par l'hyperactivation de STAT qui contiennent une substance capable d'élever la concentration de zinc intracellulaire, et sur un procédé de criblage d'une substance ayant un effet de régulation de l'activité STAT.
PCT/JP2007/072921 2006-11-28 2007-11-28 Régulation de l'activité du facteur transcriptionnel stat par un ion zinc Ceased WO2008066064A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006320811A JP2008133222A (ja) 2006-11-28 2006-11-28 亜鉛イオンによる転写因子ｓｔａｔの活性制御
JP2006-320811 2006-11-28

Publications (1)

Publication Number Publication Date
WO2008066064A1 true WO2008066064A1 (fr) 2008-06-05

Family

ID=39467854

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/072921 Ceased WO2008066064A1 (fr) 2006-11-28 2007-11-28 Régulation de l'activité du facteur transcriptionnel stat par un ion zinc

Country Status (2)

Country Link
JP (1) JP2008133222A (fr)
WO (1) WO2008066064A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03135919A (ja) * 1989-07-20 1991-06-10 Derek Bryce-Smith 抗アレルギースプレー製剤
JPH0469338A (ja) * 1990-07-06 1992-03-04 Zeria Pharmaceut Co Ltd 炎症性腸疾患予防・治療剤
JP2002348244A (ja) * 2001-05-23 2002-12-04 Fancl Corp 抗糖尿病組成物
WO2005063301A1 (fr) * 2003-12-26 2005-07-14 Toshio Hirano Inducteur emt
WO2006080581A1 (fr) * 2005-01-31 2006-08-03 Riken Agent de regulation de la reaction de degranulation et de la production de cytokine
WO2006080582A1 (fr) * 2005-01-31 2006-08-03 Riken Agent de regulation de la fonction d'une cellule presentant l'antigene

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03135919A (ja) * 1989-07-20 1991-06-10 Derek Bryce-Smith 抗アレルギースプレー製剤
JPH0469338A (ja) * 1990-07-06 1992-03-04 Zeria Pharmaceut Co Ltd 炎症性腸疾患予防・治療剤
JP2002348244A (ja) * 2001-05-23 2002-12-04 Fancl Corp 抗糖尿病組成物
WO2005063301A1 (fr) * 2003-12-26 2005-07-14 Toshio Hirano Inducteur emt
WO2006080581A1 (fr) * 2005-01-31 2006-08-03 Riken Agent de regulation de la reaction de degranulation et de la production de cytokine
WO2006080582A1 (fr) * 2005-01-31 2006-08-03 Riken Agent de regulation de la fonction d'une cellule presentant l'antigene

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LIU S. ET AL.: "Effect of zinc protoporphyrin on apoptosis in planted breast carcinoma", ZHONGHUA SHIYAN WAIKE ZAZHI (CHINESE JOURNAL OF EXPERIMENTAL SURGERY), vol. 23, no. 5, May 2006 (2006-05-01), pages 525 - 527 *
STURNIOLO G.C. ET AL.: "Effect of zinc supplementation on intestinal permeability in experimental colitis", THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE, vol. 139, no. 5, 2002, pages 311 - 315, XP055069504, DOI: doi:10.1067/mlc.2002.123624 *
TANBA H.: "Hi-tokui-sei Ensho-sei Cho Shikkan to Biryo Kinzoku", DIGESTION & ABSORPTION, vol. 13, no. 1, 1990, pages 5 - 15 *

Also Published As

Publication number Publication date
JP2008133222A (ja) 2008-06-12

Similar Documents

Publication Publication Date Title
US11939374B2 (en) Treatment of fibrosis
Du et al. The LPS-inducible lncRNA Mirt2 is a negative regulator of inflammation
Kang et al. Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization
Zhang et al. MicroRNA-377 inhibited proliferation and invasion of human glioblastoma cells by directly targeting specificity protein 1
TW200413725A (en) Method for diagnosing non-small cell lung cancers
CN113677706B (zh) 肝毒性的治疗
US9453050B2 (en) Compositions for treating glioma
JP2011506274A (ja) ファスチンを阻害するための方法
Yin et al. Elevated chemokine CC-motif receptor-like 2 (CCRL2) promotes cell migration and invasion in glioblastoma
Kwon et al. Secreted frizzled-related protein 5 suppresses inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes through down-regulation of c-Jun N-terminal kinase
Kuo et al. A Fc-VEGF chimeric fusion enhances PD-L1 immunotherapy via inducing immune reprogramming and infiltration in the immunosuppressive tumor microenvironment
JP7025034B2 (ja) 膵臓炎、腎損傷および腎臓癌を治療および予防するための組成物および方法
CN101151274A (zh) 促进Bmal1的诱导表达的RORα
WO2008066064A1 (fr) Régulation de l'activité du facteur transcriptionnel stat par un ion zinc
WO2023183822A1 (fr) Perte hématopoïétique du chromosome y provoquant une fibrose cardiaque et un dysfonctionnement et étant associée à la mort causée par une insuffisance cardiaque
KR102099335B1 (ko) Prox1의 발현 또는 활성 조절제를 포함하는 텔로머라제 역전사효소의 발현 조절용 조성물 또는 텔로머라제 역전사효소 조절제의 스크리닝 방법
US20250171786A1 (en) COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF THE SIGNAL REGULATORY PROTEIN ALPHA (SIRPa) GENE
WO2010084668A1 (fr) Procédé de diagnostic du syndrome néphrotique, agent prophylactique ou thérapeutique pour le syndrome néphrotique, et procédé de criblage de l'agent prophylactique ou thérapeutique
TWI546075B (zh) 以微小去氧核醣核酸為基礎用於抗大腸直腸癌及大腸直腸癌預後的方法
JP7325799B2 (ja) 神経新生の低下抑制剤
JP5382746B2 (ja) 抗癌剤耐性を獲得した癌細胞の抗癌剤感受性を回復する方法
EP1774031A2 (fr) Procédé de traitement du cancer par inhibition de l'expression ou de la fonction du gène mage
CN120361217A (zh) Anxa2抑制剂在食管癌治疗中的应用
Vishwamitra Multilevel Deregulation Of Survival Mechanisms In Npm-Alk+ T-Cell Lymphoma
KR100992239B1 (ko) Ｍｉｇ１２ 유전자의 신규한 용도

Legal Events

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

Ref document number: 07832643

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07832643

Country of ref document: EP

Kind code of ref document: A1