37 results about "Nf κb activation" patented technology

An antibody specifically binding to human BCMA, characterized in that the binding of said antibody is not reduced by APRIL and not reduced by BAFF, said antibody does not alter APRIL-dependent NF-κB activation, BAFF-dependent NF-κB activation, and does not alter NF-κB activation without BAFF and APRIL is useful as a therapeutic agent.

This invention relates to methods and compositions for the treatment and diagnosis of cardiac diseases and disorders, such as cardiac hypertrophy, myocardial infarction, stroke, arteriosclerosis and heart failure. The invention also relates to methods and compositions for the treatment of fibrosis-related diseases as well as methods and compositions for reducing apoptosis, increasing ST2L signaling, decreasing NF-κB activation, decreasing IκBα phosphorylation, decreasing P38MAPK phosphorylation, decreasing JNK phosphorylation, decreasing reactive oxygen species generation, decreasing macrophage infiltration and / or decreasing the expression of hypertrophic genes. More specifically, the invention relates to IL-33 and / or soluble ST2 inhibiting agents for use in the methods and compositions provided.

The present inventors used a model of intrasplenically induced liver metastasis to determine whether or not NF-κB activation in the liver is involved in the onset of metastatic tumors. When IKKβ was deleted from both liver cells and hematopoietically-derived cells, the onset of tumors was reduced remarkably. Tumor cells activated neighboring bone marrow cells (Kupffer cells) and produced mitogens such as interleukin (IL)-6, and this promoted angiogenesis and growth of tumors. The mitogen production depended on NF-κB in hematopoietically-derived Kupffer cells. Furthermore, treatment with an anti-IL-6 receptor antibody decreased the degree of metastatic tumor development. That is, the present inventors showed that tumor metastasis depends on inflammation, and proinflammatory intervention that targets Kupffer cells is useful for chemical prevention of metastatic tumors. Furthermore, it was shown that inhibition of the IKKβ / NF-κB signal transduction pathway, in particular IL-6 inhibition, can be utilized for anti-metastasis agents.

Disclosed are methods of treating, preventing, modulating, attenuating, or inhibiting a disease or a disorder associated with inflammation related to NF-κB activation in a subject which comprises administering to the subject at least one curcumin compound. Also disclosed are combination therapies comprising the administration of at least one curcumin compound and at least one ROS inhibitor. Pharmaceutical compositions and kits are also disclosed.

This invention pertains to the identification of two novel epithelial signaling pathways in ER-positive breast cancer s and the discovery that the cellular biology and (likely also the clinical outcome) of ER-positive breast cancer cells is unexpectedly altered when these signaling pathways are activated. The first pathway pertains to the discovery that NF-κB activation and / or DNA binding is implicated in the etiology of ER-positive breast (and other) cancers. The second pathway involves ligand-independent quinine-mediated ER activation by posphorylation (e.g. on SER-118 and SER-167 residues of ER) and nuclear translocation of full-length (67 kDA) ER as well as the phorphorylating activation of a truncated and nuclear-localized ER variant (˜52 kDa).

A medicament having inhibitory activity against NF-κB activation which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof:wherein X represents a connecting group whose number of atoms in a main chain is 2 to 5 (said connecting group may be substituted),“A” represents an acyl group which may be substituted, (provided that unsubstituted acetyl group and unsubstituted acryloyl group are excluded,) or a C1 to C6 alkyl group which may be substituted, or A may bind to connecting group X to form a cyclic structure which may be substituted,“E” represents an aryl group which may be substituted or a heteroaryl group which may be substituted,ring Z represents an arene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above.

A medicament having inhibitory activity against NF-κB activation which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof: wherein X represents a connecting group whose number of atoms in a main chain is 2 to 5 (said connecting group may be substituted), “A” represents an acyl group which may be substituted, (provided that unsubstituted acetyl group and unsubstituted acryloyl group are excluded,) or a C1 to C6 alkyl group which may be substituted, or A may bind to connecting group X to form a cyclic structure which may be substituted, “E” represents an aryl group which may be substituted or a heteroaryl group which may be substituted, ring Z represents an arene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above.

Methods for treating muscular wasting diseases such as Duchenne muscular dystrophy are disclosed. Specifically, the methods include administering to a subject in need of treatment for a muscular wasting disease, an NF-κB activation inhibitor capable of blocking the activation of NF-κB.

A method of inhibiting NF-κB activation in a mammal including a human, which comprises the step of administering an effective dose of a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof:

A medicament having inhibitory activity against NF-κB activation, which comprises a compound represented by the following general formula (I) or a pharmacologically acceptable salt as an active ingredient:wherein X represents a connecting group, A represents hydrogen atom or acetyl group, E represents an aryl group or a heteroaryl group, and ring X represents an arene or a heteroarene.

The present invention provides an inhibitor of NF-κB, guggulsterone and its analogs. Guggulsterone suppresses NF-κB activation induced by TNF, phorbol ester, okadaic acid, cigarette smoke, H2O2 and IL-1β, as well as constitutive NF-κB activation expressed in most tumor cells. One mechanism by which guggulsterone inhibits activation of NF-κB is through suppression of IκBα phosphorylation and IκBα degradation. NF-κB-dependent gene transcription is modulated by guggulsterone and its analogs. In particular, induction by TNF, TNFR1, TRADD, TRAF2, NIK and IKK, is modulated by guggulsterone and its analogs. In addition, guggulsterone decreased the expression of genes involved in anti-apoptosis (IAP1, XIAP, Bfl-1 / A1, bcl-2, cFLIP, survivin), proliferation (cyclin D1, c-myc) and metastasis (MMP-9, COX2 and VEGF).

This invention relates to methods and compositions for the treatment and diagnosis of cardiac diseases and disorders, such as cardiac hypertrophy, myocardial infarction, stroke, arteriosclerosis and heart failure. The invention also relates to methods and compositions for the treatment of fibrosis-related diseases as well as methods and compositions for reducing apoptosis, increasing ST2L signaling, decreasing NF-κB activation, decreasing IκBα phosphorylation, decreasing P38MAPK phosphorylation, decreasing JNK phosphorylation, decreasing reactive oxygen species generation, decreasing macrophage infiltration and / or decreasing the expression of hypertrophic genes. More specifically, the invention relates to IL-33 and / or soluble ST2 inhibiting agents for use in the methods and compositions provided.

The present invention relates to the field of infection and inflammation and, more specifically, to the field of pathogen-induced nuclear factor kappa B activation. More specifically, a novel splice variant of MyD88, (MyD88S), which has been identified encoding a protein that inhibits LPS-induced NF-κB activation. MyD88S is a target to inhibit the phenomenon of endotoxin-tolerance that occurs in sepsis.

The invention provides an isolated, anti-inflammatory, cytoprotective compound that is soluble in aqueous fluid, is derivable from the conditioned medium of a probiotic culture, such as VSL#3, induces heat shock protein expression, and has shown the capacity to inhibit NF-κB activation. The compound is amenable to formulation in a pharmaceutical composition and to packaging in a kit form with instructions for use in methods according to the invention, which include methods of preventing, treating, or ameliorating a symptom of an inflammatory disorder, such as an inflammatory epithelial disease, e.g., inflammatory bowel disease, characterized by inflammation.

Provided are proteins having NF-κB activity, which are used for diagnosing, treating or preventing diseases associated with the excessive activation or inhibition of NF-κB. Using plasmid pNFκB-Luc, cDNA encoding a protein capable of activating NF-κB has been cloned from a cDNA library constructed from human lung fibroblasts, and the DNA sequence and the deduced amino acid sequence determined. The protein, the DNA encoding the protein, a recombinant vector containing the DNA, and a transformant containing the recombinant vector are useful for screening a substance inhibiting or promoting NF-κB activation.

The present invention provides pharmaceutical compositions of salicylanilide inhibitors of transcription factor NF-κB, and methods for treating diseases in which activation of NF-κB is implicated. More specifically, the present invention provides methods of treatment of a variety of diseases associated with NF-κB activation including inflammatory disorders; particularly rheumatoid arthritis, inflammatory bowel disease, and asthma; dermatosis, including psoriasis and atopic dermatitis; autoimmune diseases; tissue and organ rejection; Alzheimer's disease; stroke; atherosclerosis; restenosis; cancer, including Hodgkin's disease; certain viral infections, including AIDS; osteoarthritis; osteoporosis; and Ataxia Telangiestasia by administering to a patient in need thereof a compound of the present invention.

The present invention includes a method for the treatment of an advanced ovarian cancer, comprising: identifying a patient with advanced ovarian cancer; and administering to the patient an effective amount of truncated, dominant negative form of Galectin-3 sufficient to reduce the advanced ovarian cancer. In certain aspects, the truncated, dominant negative form of Galectin-3 is provided in an amount sufficient to reduce at least one of growth, motility, invasion, angiogenesis, or prevents Akt / NF-κB activation of the ovarian cancer.

There is disclosed a method for identifying a therapeutically responsive phenotype, as distinguished, e.g. from an alkylating agent resistant phenotype in a cell, which method may be used to evaluate the likelihood of successful outcome of treating a tumor cell with an alkylating agent. The method is directed to the NF-κB activation in response to DNA damage caused by alkylating agents. It comprises the step of measuring a level of expression of a protein, which participates in the NF-κB pathway. Preferably it comprises measuring the expression of TNFAIP3 in the cell, wherein a resistant phenotype has less expression of TNFAIP3 than a sensitive phenotype. Another particularly significant gene, which predicts survival, is NFKBIA. Other genes whose altered expression level is associated with resistance or prognosis are TNIP1, TNIP2, RIP, NFKBIB, Beta4GalNAc-T4, NFKBIE, C8orf4, LIF, CD44, FBXO32, and SDC1, and these are also measured in certain embodiments.

The present invention provides cell permeable NF-κB inhibitors consist of a polypeptide derived from the p65 subunit of NF-κB and a protein transduction domain derived from antennapedia third helix sequence. The inhibitor suppressed NF-κB activation induced by TNF, LPS, IL-1, okadaic acid, PMA, H2O2 and cigarette smoke condensate. NF-κB-regulated reporter gene expression induced by TNF, TNFR1, TRADD, TRAF2, NIK, IKK and p65 was suppressed by the inhibitor. The inhibitor enhanced TNF- and chemotherapeutic agent-induced apoptosis. Overall these results demonstrate a NF-κB inhibitor that can selectively inhibit NF-κB activation induced by various inflammatory stimuli, downregulate NF-κB mediated gene expression and upregulate apoptosis.

Compositions and methods are provided for treating NF-κB-related conditions. In particular, the invention provides a stimulus-inducible IKK signalsome, and components and variants thereof. An IKK signalsome or component thereof may be used, for example, to identify antibodies and other modulating agents that inhibit or activate signal transduction via the NF-κB cascade. IKK signalsome, components thereof and / or modulating agents may also be used for the treatment of diseases associated with NF-κB activation.

The transcription factor NF-κB is activated in response to various stimuli including ionizing radiation. Disruption of NFκB activation by mutant forms of the NF-κB inhibitor IκB-α or by proteasome inhibitors enhances both sensitivity to radiation and radiation-induced apoptasis. The present invention shows that expression of a dominant negative fragment of human p65 (p65DN) leads to down-regulation of both endogenous p65 protein and its mRNA. The dominant negative protein also inhibits radiation-induced NF-κB activation by preventing the proteolysis of IκB-α, resulting in enhancement of cellular radiosensitivity and radiation-induced apoptosis. The region of p65 in the dominant negative fragment is thus a molecular target for disruption of NF-κB activation and sensitization of tumors to radiotherapy.

Provided are proteins having NF-κB activity, which are used for diagnosing, treating or preventing diseases associated with the excessive activation or inhibition of NF-κB. Using plasmid pNFκB-Luc, cDNA encoding a protein capable of activating NF-κB has been cloned from a cDNA library constructed from human lung fibroblasts, and the DNA sequence and the deduced amino acid sequence determined. The protein, the DNA encoding the protein, a recombinant vector containing the DNA, and a transforrnant containing the recombinant vector are useful for screening a substance inhibiting or promoting NF-κB activation.

Methods for regulating NF-κB activation in cells comprising introducing into the cell a vector comprising a nucleic acid sequence encoding a NIK and IKK2 Binding Protein (NIBP) polypeptide, wherein the NIBP polypeptide is expressed in the cell, are provided. Also provided are methods for reversing the cancerous phenotype of a cancer cell and for modulating neuronal differentiation.

The present invention relates to the use of the A20-binding inhibitor of NF-κB activation (ABIN), or a functional fragment or variant thereof to protect against TNF-induced liver failure, such as viral hepatitis and alcoholic liver disease. More particularly, it relates to the prevention of the toxic effects of said diseases, including lethality, by overexpressing ABIN.

Methods for the treatment of osteolytic bone disease and for the inhibition of osteoclastogenesis are disclosed. The methods utilize COX-2 inhibitors and / or inhibitors of NF-κB activation, administered to patients in an amount effective to inhibit osteoclastogenesis. Also disclosed are methods to modulate the expression of MIP-1α in a subject.

The present invention concerns methods and means for identifying inhibitors of neuronal degeneration, and their use in the treatment of neurodegenerative disorders. In particular the invention concerns methods and means for identifying inhibitors of neuronal degeneration or cell death by taking advantage of the involvement of presenilin (PS) and Par-4 in NF-κB activation.

A method to identify selective inhibitors of antigen receptor-mediated NF-κB activation is provided, as well as compositions having one or more of those inhibitors and methods of using those inhibitors.