93 results about "Calcineurin phosphatase" patented technology

This invention relates to a method of treating transplant rejection comprising administering to a patient a pharmaceutical composition comprising an lck inhibitor and a calcineurin inhibitor or an immunosuppressant.

The present invention provides methods of treating and preventing cardiac hypertrophy and heart failure. MEF-2, NF-AT3, calcineurin, MCIP, and Class II HDACs have been shown to have a major role in cardiac hypertrophy and heart disease, and inhibition of many of these factors or the pathways mediated by these factors has been shown to have a beneficial, anti-hypertrophic effect. The present invention provides a link between these factors and the pathways they mediate through a family of non-voltage gated channels called TRP channels. The present invention further demonstrates that inhibitors of TRP channels can inhibit or treat heart failure and cardiac hypertrophy.

Methods and compositions are described for the modulation of hyperglycemia and / or one or more symptoms of hyperglycemia. Methods and compositions are described for the modulation of efflux transporter activity to increase the efflux of calcineurin inhibitors out of a physiological compartment and into an external environment. In particular, the methods and compositions disclosed herein provide for the increase of efflux transporter activity to increase the efflux of calcineurin inhibitor from physiological compartments.

The present invention discloses methods of using of compounds for the enhancement of the innate immune system of a patient. In particular, the active compounds of the present invention include at least one calcineurin inhibitor, mTOR inhibitor or non-immunosuppresive derivative, or a derivative, isomer, or pharmaceutically acceptable salt thereof; and optionally, at least one calciferol or LMW inhibitor, or a derivative, isomer, or pharmaceutically acceptable salt thereof. Pharmaceutical formulations comprising same are also disclosed.

Isolated peptide fragments of the conserved regulatory domain of NFAT protein capable of inhibiting protein-protein interaction between calcineurin and NFAT, or a biologically active analog thereof are described. Isolated polynucleotides and gene therapy vectors encoding such peptide fragments are also described. In addition, methods for treating immune-related diseases or conditions and methods for high throughput screening of candidate agents are described. Pharmaceutical compositions are also provided.

The present invention relates to a combination of agents, including an anti-proliferative agent, an anti-inflammatory agent, an anti-growth factor, and an extracellular matrix (ECM) molecule coated on a stent to prevent acute and subacute thrombosis, enhance endothelial in-growth, and prevent neointimal hyperplasia, and / or suppress neovascularization, and thereby reduce restenosis rates for drug eluting stents. The present invention also relates to methods of using such multiple drug eluting stents for the treatment of heart disease and other vascular conditions.

Provided are methods and compositions for maintaining the viability of photoreceptor cells following retinal detachment. The viability of photoreceptor cells can be preserved by administering a neuroprotective agent, for example, a substance capable of suppressing endogenous calcineurin or constitutively active calcineurin, inhibiting cleavage of calcineurin to constitutively active calcineurin, and / or directly or indirectly antagonizing calcineurin or constitutively active calcineurin (and combinations thereof), to a mammal having an eye with retinal detachment. The neuroprotective agent maintains the viability of the photoreceptor cells until such time that the retina becomes reattached to the underlying retinal pigment epithelium and choroid. The treatment minimizes the loss of vision, which otherwise may occur as a result of retinal detachment.

The present invention provides, inter alia, methods for treating or ameliorating the effects of a glioma. Methods of this invention include administering to a subject in need thereof an effective amount of a first active agent, such as e.g., an angiotensin receptor blocker, an antifungal agent, a bisphosphonate, an oxytocin inhibitor, an interleukin-1 (IL-1) inhibitor, a cyclooxygenase inhibitor, an α2δ voltage-dependent calcium channel (VDCC) inhibitor, a dihydroorotate dehydrogenase inhibitor, a calcium channel blocker, a renal sodium-chloride symporter inhibitor, an a2 adrenergic agonist, a phenothiazine antipsychotic, a calcineurin inhibitor, a 5-HT agonist, an angiotensin-converting enzyme (ACE) inhibitor, a direct rennin inhibitor, or combinations thereof, and a second active agent, which is a chemotherapeutic agent. Compositions for treating or ameliorating the effects of a glioma are also provided.

In accordance with the present invention, it has been discovered that glucose and incretin hormones promote pancreatic islet cell survival via the calcium and cAMP dependent induction, respectively, of the transcription factor CREB. Specifically, a signaling module has been identified which mediates cooperative effects of calcium and cAMP on islet cell gene expression by stimulating the dephosphorylation and nuclear entry of TORC2, a cytoplasmic CREB coactivator. The module comprises a cAMP regulated snf1-like kinase called SIK2 and the calcium regulated phosphatase calcineurin, both of which associate with TORC2 in the cytoplasm. TORC2 is repressed under basal conditions through a phosphorylation dependent interaction with 14-3-3 proteins. cAMP and calcium signals stimulate CREB target gene expression via complementary effects on TORC2 dephosphorylation; cAMP disrupts TORC2-associated activity of SIK2 or related family members, whereas calcium induces TORC2 dephosphorylation via calcineurin. These findings provide a novel mechanism by which CREB activates cellular gene expression, depending on nutrient and energy status, and facilitate development of assays to identify compounds which modulate the role of TORCs. In accordance with the present invention, it has been discovered that fasting and energy-sensing pathways regulate the gluconeogenic program in liver by modulating the nuclear entry of a transcriptional coactivator called Transducer of Regulated CREB Activity 2 (TORC2). Hepatic TORC2 over-expression induces fasting hyperglycemia, whereas knockdown of TORC2 leads to fasting hypoglycemia and silencing of the gluconeogenic program. Since a majority of individuals with Type II diabetes exhibit fasting hyperglycemia due to elevated hepatic gluconeogenesis, compounds that enhance TORC2 phosphorylation will find use as therapeutic agents in this setting.

This invention relates to methods and compositions for the treatment, management, reduction, or prevention of injuries to one or more major organs of the body, e.g., the brain, heart, lung, kidneys, liver, and gastrointestinal tract, of a mammal (e.g., a human) caused by one or more calcineurin or mammalian target of rapamycin (mTOR) complex inhibitors. The methods include administering an effective amount of one or more pituitary adenylate cyclase-activating polypeptide (PACAP)-like compounds to the mammal. Combination therapy with one or more PACAP-like compounds, either alone or in combination with one or more other prophylactic / therapeutic agents, plus one or more inhibitors of either calcineurin or the mTOR complexes can be used to treat organ transplantation, autoimmune diseases, graft-versus-host disease, Behçet's disease, hematological cancers, noninfectious uveitis, sarcoidosis, tuberous sclerosis complex, acute neurological diseases, age-related neurodegenerative diseases, Huntington's disease and other CAG codon repeat expansion diseases, keratoconjunctivitis sicca, and restenosis.

The invention discloses application of a calcineurin B protein interaction protein kinase gene HsCIPK17 of annual Hordeum spontaneum C. Koch in the Qinghai-Tibet Plateau: the HsCIPK17 is used for constructing Oryza sativa L.; the Oryza sativa L. has heavy metal stress tolerance and also has salt tolerance and abscisic acid stress tolerance; heavy metals are mercury, cadmium and chromium; a nucleotide sequence of the gene HsCIPK17 is that the GenBank accession number is JN655677.

The present invention describes a novel form of the MCIP protein, a 38 kDa version (MCIP-1-38) that predominates in the human heart, the upregulation of which is strongly suggested for the treatment or prevention of heart disease. The present invention provides for methods of treating and preventing cardiovascular diseases, in particular pathological cardiac hypertrophy and chronic heart failure, by applying a modulator of MCIP-1-38. The present invention also provides for methods of screening to find modulators of MCIP-1-38 and inhibitors of cardiac hypertrophy and heart failure.

A calcineurin activator, comprising the following protein (a) or (b) as an active ingredient and having the action of increasing intracellular calcium ion concentration through the influx of calcium ions into eukaryotic cells: (a) a killer protein (KLKP), being composed of 3 subunits consisting of amino acid sequences represented by SEQ ID NOS: 2, 3, and 4, respectively, and being produced by Kluyveromyces lactis killer yeast; or (b) a protein, being the same as protein (a) except for differing from protein (a) in that at least one of the 3 subunits consists of an amino acid sequence derived from the amino acid sequence represented by SEQ ID NO: 2, 3, or 4 by deletion, substitution, or addition of 1 or several amino acids, and having Kluyveromyces lactis killer protein (KLKP) activity.

Therapeutic compositions for treatment of protein serine / threonine phosphatase-related diseases are obtained by engineering amino acid sequences that disrupt interaction between the protein serine / threonine phosphatase and a protein inhibitor and are provided herein. Calcineurin and PPI are examples of protein serine / threonine phosphatases. RCAN1 is an inhibitor of calcineurin and is overexpressed in patients with serious diseases, such as Down syndrome and Alzheimer's disease. Molecules that bind RCAN1 at regions that interact with calcineurin selectively modulate functions of calcineurin to treat these diseases. Methods of treating a subject for a protein serine / threonine phosphatase-related disease by administering a molecule having an amino acid sequence selected from the group of SEQ ID NOs: 1-19 are further provided.

This invention provides compositions, organisms and methodologies employing a novel human gene encoding a protein that has sequence homology to a consensus sequence of calcineurin-like phosphoesterase family are disclosed. The novel protein is encoded by a human gene comprising 4 exons. The human gene is localized in the 10p15 locus of human chromosome 10. The sequence similarities between the novel human protein and the consensus sequence of calcineurin-like phosphoesterases indicate that the novel human protein may function as a calcineurin-like protein phosphatase.

The embodiments disclosed herein relate to ophthalmic compositions comprising calcineurin inhibitors or mTOR inhibitors, and more particularly to methods for treating an ocular disease and / or condition using the disclosed compositions. According to aspects illustrated herein, there is provided a pharmaceutical composition that includes a calcineurin inhibitor or an mTOR inhibitor; a first surfactant with an HLB index greater than about 10; and a second surfactant with an HLB index of greater than about 13, wherein an absolute difference between the HLB index of the first surfactant and the HLB index of the second surfactant is greater than about 3, and wherein the composition forms mixed micelles.

A method for decreasing the level of restenosis following a stent placement medical intervention involves the continuous administration of a dose of an immunosuppressant or anti-inflammatory agent from reservoirs in a stent to vascular tissue in need of treatment in a controlled, two phase drug release profile. It is envisioned that the vascular tissue in need of treatment is arterial tissue, specifically coronary arterial tissue. The agent or drug can be the calcineurin inhibitor Pimecrolimus. The drug can be held within reservoirs in the stent in a drug delivery matrix comprised of the drug and a bioresorbable polymeric material and optionally additives to regulate the drug release.

The present invention concerns methods of treating fungal infections and methods of screening compounds for activity in treating fungal infections. Methods of the invention include using an active compound such as fludioxonil to treat a Cryptococcus neoformans infection. Also included are methods and pharmaceutical compositions useful for treating fungal infections using a Hog1 activator such as fludioxonil and a calcineurin inhibitor in combination.

The invention discloses application of gentiopicroside and a gentiopicroside preparation, particularly discloses non-treatment application of the gentiopicroside serving as a calcineurin (CAN)-NF-AT pathway blocker and application of the gentiopicroside to preparation of the calcineurin (CAN)-NF-AT pathway blocker, and further discloses application of the gentiopicroside to preparation of an external preparation or daily chemical product for preventing or treating skin hypersensitivity inflammatory reaction. The gentiopicroside stemming from dried roots and rhizomes of Gentiana lutea is capable of blocking a CAN-NF-AT pathway to effectively prevent or treat skin allergy symptoms such as eczema and contact dermatitis caused by excessive immune response and can be prepared into various daily chemical products or external preparations. A gentiopicroside synthetic process used herein is mature, preparation cost is low, popularization and application are benefited, and accordingly the gentiopicroside is promising in application prospect.

Provided are methods and compositions for maintaining the viability of photoreceptor cells following retinal detachment. The viability of photoreceptor cells can be preserved by administering a neuroprotective agent, for example, a substance capable of suppressing endogenous calcineurin or constitutively active calcineurin, inhibiting cleavage of calcineurin to constitutively active calcineurin, and / or directly or indirectly antagonizing calcineurin or constitutively active calcineurin (and combinations thereof), to a mammal having an eye with retinal detachment. The neuroprotective agent maintains the viability of the photoreceptor cells until such time that the retina becomes reattached to the underlying retinal pigment epithelium and choroid. The treatment minimizes the loss of vision, which otherwise may occur as a result of retinal detachment.

The invention provides a maize calcineurin B albuminoid ZmCBL10 gene. The coding amino acid sequence of the gene is shown as SEQ ID No.1. The nucleotide sequence of a coding sequence of the gene is shown as SEQ ID No.2. The ZmCBL10 gene participates in plant salt tolerance processes through gene regulation and control, and has significant importance for culturing of high-output genetically modified crops.

The present invention provides for methods of treating and preventing cardiac hypertrophy and heart failure. The present invention provides the link between ERK1 / 2 and calcineurin and CamKII. The present invention further demonstrates that inhibitors of ERK1 / 2 inhibit cardiac hypertrophy and heart disease by inhibiting, in part, the fetal cardiac gene expression that occurs when Ca2+-dependent signalling occurs in the heart.

The invention relates to applications of a regulator of calcineurin 1.4 (RCAN1.4) or analogues of RCAN1.4 in preparing medicines for inhibiting liver cancer. According to the applications, RCAN1.4 orup-regulators of RCAN1.4 can be used for inhibiting liver cancer; and the functional analogue medicines such as cyclosporin A of RCAN1.4 also can obviously reduce the in-vivo pulmonary metastasis capacity of liver cancer cells.

The present invention relates to a conjugate that specifically targets a calcineurin inhibitor to T cells, such as Th17 cells, for use in a method for the treatment of an inflammatory disease. The invention also relates to a method for treating an inflammatory disease by administering a conjugate that specifically targets a calcineurin inhibitor to T cells, such as Th17 cells. In addition, the invention relates to a method for identifying a subject likely to be resistant to steroid treatment, as well as a subject likely to benefit from treatment with a calcineurin inhibitor.

The present invention provides for a transgenic nonhuman mammal whose germ or somatic cells contain a nucleic acid molecule which encodes calcineurin or a variant thereof under the control of a regulatable promoter, introduced into the mammal, or an ancestor thereof, at an embryonic stage. The present invention also provides for a method of evaluating whether a compound is effective in improving long-term memory in a subject suffering from impaired long-term memory which comprises: (a) administering the compound to the transgenic nonhuman mammal of claim 1 wherein the mammal has increased brain-specific calcineurin activity due to expression of the nucleic acid, and (b) comparing the long-term memory of the mammal in step (a) with the long-term memory of the mammal in the absence of the compound so as to determine whether the compound is effective in rescuing the long-term memory defect in the subject.