77 results about "Nuclear translocation" patented technology

The invention belongs to the technical field of cytotoxicity intervention, and particularly relates to application of an inhibitor JSH-23 in preparation of a medicine for preventing and / or treating ovarian toxicity caused by environmental toxin combined exposure. Aiming at the condition that MC-LR and NaNON combined exposure can activate NF-kappa B to induce KK-1 cell nitrification stress and cause mouse ovarian dysfunction, JSH-23 is selected as an intervention agent, and it is found that after KK-1 cells are pretreated by JSH-23, NF-kappa B nuclear translocation induced by the KK-1 cells due to MC-LR and NaNON combined exposure is remarkably inhibited, iNOS protein rising induced by toxin combined exposure is remarkably reduced, and NF-kappa B nuclear translocation induced by the KK-1 cells due to NF-kappa B combined exposure is remarkably inhibited. The increase of the levels of ONOO and 3-NT of nitration stress markers is effectively relieved, which indicates that JSH-23 can participate in the nitration stress of KK-1 cells caused by combined exposure of MC-LR and NaNO2 by inhibiting NF-kappa B activation, and a foundation is laid for screening antidotes after exposure of environmental toxins.

This invention discloses the application and method of a STAT1-targeting inhibitor in the treatment of immune thrombocytopenic purpura (ITP). It employs ivermectin, a STAT1 nuclear translocation inhibitor, and fludarabine, a STAT1 activation inhibitor. By injecting either the activation inhibitor or the nuclear translocation inhibitor, the platelet count in a mouse model of ITP is increased. Fludarabine, a fluorinated nucleotide analog of vidarabine, is non-radioactive and a small-molecule phosphorylation inhibitor. Ivermectin is a small-molecule inhibitor of nuclear translocation mediated by α / β1 introgression protein. Both have high bioavailability and are widely used to treat various hematological diseases with good safety profiles. Their application in treating ITP is safe, effective, and shows high compliance.

The invention relates to application of NMRK2 in regulating and improving myocardial ischemia reperfusion injury, and belongs to the technical field of biological medicine. Based on the lack of medicines for effectively preventing and treating myocardial ischemia-reperfusion injury at present, the invention develops a protection method based on NMRK2 signal regulation and control, specifically, a preparation for enhancing NMRK2 expression or activity is adopted to prepare the medicines for preventing or treating myocardial ischemia-reperfusion injury, and the medicines can systematically enhance the anti-oxidation defense capability of myocardial cells, so that the anti-oxidation defense capability of myocardial cells is enhanced. The tissue injury caused by reperfusion is improved, so that the myocardial ischemia reperfusion injury is effectively prevented and treated. Furthermore, it is found that the NMRK2 can inhibit excessive activation of MST1 / p-MST1 in a Hippo pathway and promote YAP nuclear translocation, so that NADK expression is up-regulated, a Trx1 antioxidant system is enhanced, and a new 'NMRK2-YAP-NADK-Trx1 antioxidant signal pathway' is formed.

The present invention discloses a plasmid vector and cell line that can induce targeted genomic DNA double-strand breaks. The present invention constructs a nuclease AscI expression plasmid based on a lentiviral vector backbone by integrating the Tet-on chemically inducible transcription control system and the ERT2 ligand-dependent nuclear localization control system. The vector regulates the transcription of AscI through the Tet-on system and uses the 4-hydroxytamoxifen-induced ERT2 system to achieve spatiotemporal specific nuclear translocation of the endonuclease AscI. The present invention also constructs and screens a cell line that stably expresses AscI. With the help of small chemical molecules, the spatiotemporal expression of the AscI endonuclease in cells can be precisely regulated, thereby inducing DNA double-strand breaks at specific sites in the genome. The present invention provides an efficient and accurate research tool for the field of DNA damage repair, which can be widely used in studying DNA damage repair mechanisms and high-throughput screening of related drugs.

The invention belongs to the technical field of medicine preparation, and particularly relates to application of DHGC in preparation of a medicine for treating acute kidney injury ferroptosis mediated by an SIRT3 / NRF2 axis. Experiments prove that DHGC can activate SIRT3 in a targeted manner, up-regulate the expression level of SIRT3, promote NRF2 deacetylation and drive NRF2 nuclear translocation, and further up-regulate the expression level of GPX4, so that the effect of resisting ferroptosis caused by acute kidney injury is achieved.

This invention belongs to the field of biopharmaceutical technology, and specifically relates to the application of D724-0491 in the preparation of products for the prevention and treatment of breast cancer. D724-0491 inhibits the binding of HBXIP and KEAP1, reduces the level of NRF2 nuclear translocation, thereby inducing oxidative stress in tumor cells and promoting cancer cell death. It is a novel targeted therapy drug for breast cancer, improving the prognostic survival rate of breast cancer patients.

This invention proposes the application of psoralen as an Nrf2 agonist in drug preparation. This invention is the first to discover that psoralen is a specific Nrf2 agonist. Psoralen can directly target and bind to the Nrf2 protein, improving its stability, promoting its phosphorylation and nuclear translocation, thereby activating the Nrf2 signaling pathway, upregulating the expression of downstream antioxidant, anti-inflammatory, and anti-ferroptosis-related proteins, and achieving cell protection and tissue repair functions.

The application relates to the technical field of biological medicine, and provides an anti-GPC3 full humanization single-domain antibody and application thereof. The application uses phage display technology to obtain one anti-human GPC3 specificity full humanization monoclonal single-domain antibody through antibody screening by targeting human GPC3 protein. The obtained single-domain antibody can be specifically combined with human GPC3, and can effectively inhibit the nuclear translocation of YAP, provides an effective alternative antibody drug for GPC3-targeted HCC treatment, and has a potential clinical application prospect.

The invention relates to application of lentinan in preparation of a medicine for enhancing Kukuzhou cell immune function, and belongs to the technical field of immunopharmacology. The invention discloses a mechanism and application of lentinan LNT (Lentinan) based on a TLR2 (Toll-Liver Receptor 2) signal channel for enhancing the immune function of liver cumness cells and promoting lysosome maturation. By constructing an LNT fluorescence labeling system, a Kuptake cell in-vivo tracing model and a TLR2 function intervention model, it is proved that LNT can be directly combined with TLR2 and activate a TLR2 / MyD88 / NF-kappa B signal axis, and therefore the phagocytosis and immune response capacity of Kuptake cells is enhanced. Meanwhile, TLR2 signal-induced reactive oxygen species (ROS) up-regulation can promote TFEB dephosphorylation and nuclear translocation, lysosome maturation is driven, and degradation metabolism of LNT is accelerated. The invention provides a TLR2-based immune enhancement mechanism of the LNT, and provides a theoretical basis and an application basis for developing immunomodulatory targeted drugs.

The invention discloses an application of a P4HA1 inhibitor in preparation of a medicine for treating congenital megacolon-related enterocolitis, deeply clarifies an immune metabolic axis of 'P4HA1-hydroxyproline-eIF5A-IRF4-IL17', and discloses a new mechanism that metabolite hydroxyproline regulates the activity of eIF5A and promotes nuclear translocation of IRF4 so as to enhance TH17 cell mediated inflammatory response. Therefore, a brand new perspective is provided for understanding metabolic immune regulation of intestinal inflammation. By using the P4HA1 inhibitor (such as 1, 4-DPCA), secretion of IL-17 can be effectively inhibited, intestinal inflammation injury of HAEC model mice can be remarkably relieved, and a clear pharmacodynamic basis is achieved.

T lymphocytes play a key role in the immune response and their functions are intimately linked to metabolic programs. During immune responses, T cells undergo a metabolic reprogramming notably characterized by an increased aerobic glycolysis. Using a quantitative phosphoproteomic approach, the inventors have identified a new transcription factor called Foxk1 as being highly phosphorylated in T cells upon T Cell Receptor (TCR) engagement. The results also indicate that Foxk1 phosphorylation and nuclear translocation is dependent of the AKT-mTOR kinase activities. Using T-cell specific Foxk1 deficient mice (Foxk1- / -), we demonstrated that Foxk1 is required for full T cell activation. Foxk1-deficient T cells exhibited reduced proliferation and cytokine secretion following TCR stimulation. Furthermore, T cells from Foxk1- / - mice were less prone to acquire an effector like phenotype than wild-type cells when challenged in vivo. Conversely, Foxk1 overexpression in T cells enhanced their effector functions in a TCR-dependent manner. In CD8+ T cells, this effect also results into enhanced cancer cell killing capacity in vitro, and improved tumor rejection in vivo. Altogether, these results indicated that Foxk1 is a major regulator of T cell metabolism and thus, of T cell effector functions. Thus, the present invention relates to host immune cells engineered to overexpress a Foxk1 polypeptide and their use of the treatment of cancer.

The invention relates to a PKM2-based nano glycopeptide activator and application thereof.The nano glycopeptide activator comprises three functional units, namely a PKM2 targeted activation unit R3, a self-assembly unit R2 and a response unit R1, and the chemical structure of the nano glycopeptide activator is shown in the formula (I). After administration, the nano glycopeptide activator can be enriched to a tumor site through targeting of sugar receptor transporter protein or an EPR effect; after entering tumor cells, the polypeptide is subjected to in-situ fibrosis deformation under the hydrolysis action of glycohydrolase, so that specific targeting and retention are realized; the nano-fiber with the PKM2 targeting activation unit can promote conversion of dimer PKM2 into tetramer PKM2, inhibit nucleation of PKM2, and prevent the DNA damage repair process of tumor cells.

The invention discloses application of Keratin5 low expression and PADI3 nuclear translocation in serving as a predictive marker for invasion and metastasis of head and neck squamous cell carcinoma, belongs to the technical field of biological medicine, verifies clinical applicability of KRT5 low expression and / PADI3 nuclear translocation (namely KRT5low / PADI3nucle) serving as a predictive index so as to fill the blank of the prior art, and provides a novel predictive marker for invasion and metastasis of head and neck squamous cell carcinoma. A novel molecular marker and an intervention target spot are provided for precise diagnosis and treatment of the head and neck squamous cell carcinoma; the KRT5 and PADI3 co-expression region forms a specific micro-domain difference and a specific mode in tumor tissues, can be used as an effective head and neck squamous cell carcinoma metastasis prediction marker, and has important scientific significance and application value for optimizing clinical diagnosis and treatment strategies.

The application belongs to the technical field of biological medicine and molecular biology, and particularly relates to application of umbilical cord blood plasma-derived extracellular vesicles and related bioactive molecules thereof in treatment of Alzheimer's disease. Specifically, the application isolates extracellular vesicles (UCBP-sEVs) from umbilical cord blood plasma, which has the effect of improving Alzheimer's disease. Further research finds that high enrichment of miR-16-2-3p therein is a key molecule for mediating treatment of Alzheimer's disease. miR-16-2-3p targets and inhibits expression of ROCK2, reduces phosphorylation level of TFEB and promotes nuclear translocation of the same, activates microglial autophagy-lysosome pathway, and thus promotes phagocytosis and degradation of intracerebral beta amyloid, and therefore has good practical application value.

The invention relates to the technical field of biological medicines, and particularly discloses a nanocapsule SMCPM and application thereof in medicines for treating or preventing osteosarcoma and pulmonary metastasis. The SMCPM is composed of a photosensitizer Ce6 carried by mesoporous silicon oxide-manganese oxide particles, an NRF2 inhibitor ML385 and an OS targeting peptide PT-7. Experiments prove that the SMCPM is high in penetrating power and strong in cell killing effect; by down-regulating NRF2 expression and reversing nuclear translocation, a biochemical inhibitory microenvironment can be effectively repaired, the tolerance of cells to active oxygen and epithelial-mesenchymal transition activated and induced by a NOTCH1 signal axis are remarkably reduced, the oxidative stress level of the cells is enhanced, and PIT-induced immunogenic cell death is promoted; the released Mn < 2 + > and double-stranded DNA can regulate and control an immunosuppressive microenvironment by activating an STING pathway in cells, thereby inhibiting the growth of osteosarcoma and preventing lung metastasis.

The invention discloses application of a targeted Nup85 inhibitor in preparation of a medicine for preventing or treating hepatocellular carcinoma, and relates to the technical field of biological medicine and tumor immunotherapy. The invention provides an application of a targeted Nup85 inhibitor in preparation of a medicine for preventing or treating hepatocellular carcinoma. The inhibitor prevents and / or treats hepatocellular carcinoma by enhancing CD8 + T cell functions, enhancement of the CD8 + T cell functions is realized by regulating STAT1 / CCL5 / CXCL10 pathways, and Nup85 reduces expression of CCL5 and CXCL10 by inhibiting nuclear translocation of phosphorylated STAT1, so that infiltration and activation of CD8 + T cells are inhibited. The invention discloses an immune escape mechanism that Nup85 inhibits CD8 + T cell infiltration by inhibiting p-STAT1 nuclear translocation and down-regulating CCL5 / CXCL10 expression in liver cancer for the first time, provides a new liver cancer immunotherapy target, and broadens the application of nucleopore protein in tumor immunotherapy; the target Nup85 inhibitor can be obtained through a conventional means, a new clinical application direction of the target Nup85 inhibitor is defined, and the target Nup85 inhibitor has good clinical transformation and development prospects.

The present invention discloses a method for constructing a transgenic mouse with systemic overexpression of human α-Syn-NLS. First, the human α-Syn coding sequence and the SV40 nuclear translocation signal sequence are obtained by PCR. Then, an entry clone vector containing the target sequence is constructed through a BP reaction. After digestion with enzymes, the entry clone vector is constructed into a recombinant expression vector containing the target sequence through an LR reaction. After digestion with enzymes again, using the lentiviral LV overexpression vector pLV-EGFP:T2A:Puro-EF1A as the backbone vector, the recombinant expression vector pDown-hSNCA / SV40NLS containing the target sequence is constructed into the lentiviral vector, and virus packaging and purification are carried out to obtain the pLV virus overexpressing nuclear import α-Syn. The virus is injected by the method of pronuclear injection of fertilized eggs to obtain a transgenic mouse with systemic overexpression of nuclear import human α-Syn protein, which can stably overexpress α-Syn for a long time and solve the problem of nuclear import at the same time. This model has important value for studying the comprehensive functions and mechanisms of α-Syn nuclear import.

The invention discloses a composition for improving skin inflammation as well as application and a production method of the composition. The composition is prepared from the following components in parts by weight: 2 to 6 parts of curcumin monocarbonyl analogue cyclodextrin inclusion compound and 0.3 to 0.5 part of allantoin. The curcumin monocarbonyl analogue cyclodextrin inclusion compound is prepared from the following components in parts by weight: 0.5 to 1.5 parts of curcumin monocarbonyl analogue and 98.5 to 99.5 parts of beta-cyclodextrin, and the composition is applied as a skin care product. Aiming at skin inflammation caused by chronic symptoms, NF-kappa B nuclear translocation is blocked, multi-target anti-inflammation is achieved, and the effect is better directly aiming at core pathogenic genes. The allantoin increases the dissolution and absorption of the curcumin monocarbonyl analogue cyclodextrin inclusion compound, promotes the hydration of cuticle and reduces the irritation to the skin; the use effect is milder, and the composition is more suitable for non-invasive dermatitis.

Non-viral gene therapy treatments have a number of advantages over viral vectors including typical non-antigenicity, low manufacturing cost, simplicity, and efficiency of delivering genetic cargo into the cytoplasm. The potency of non-viral gene therapy systems can be enhanced by providing them with means to more efficiently transport the delivered DNA from the cytoplasm to the nucleus. Provided herein, at least in part, are means of enhancing potency of non-viral gene therapies by including novel nuclear translocation enhancing sequences and compositions that can result in optimized nuclear translocation as well as related compositions and methods.

The invention discloses a probe set. The probe set comprises a first fusion protein and a second fusion protein, wherein the first fusion protein comprises a nuclear localization sequence and a first protein molecule, and the nuclear localization sequence is connected with the first protein molecule; the second fusion protein comprises a TFEB protein and a second protein molecule, the TFEB protein is connected with the second protein molecule, the second protein molecule is used for being combined with the first protein molecule, and a detectable signal is generated after the first protein molecule and the second protein molecule are combined. The probe set can rapidly, accurately and sensitively detect the TFEB nuclear transfer condition, can be used for high-throughput screening of TFEB regulation and control drugs, and reduces the drug screening cost.

The invention discloses an HMGB3 inhibitor and application of the HMGB3 inhibitor in preparation of a medicine for treating liver cancer, and relates to the field of molecular biology and biological medicine. The application has the advantages that HCC cell proliferation and clone formation are inhibited through HMGB3shRNA, so that HCC transplanted tumor growth is inhibited, HMGB3 is knocked down to up-regulate expression of TNF, NFKBIA and other genes and down-regulate expression of CARD11 and other genes, NF-kappa B nuclear translocation degradation IKK is further inhibited, in-vitro proliferation and invasion ability of hepatocellular carcinoma cells can be seriously affected, development of liver cancer can be inhibited, and the application has a good application prospect. The compound can be used for preparing anti-hepatoma drugs.

The invention provides a rice bran protein source Keap1 inhibitory peptide as well as a preparation method and application thereof, and belongs to the technical field of biology. The invention provides a Keap1 inhibitory peptide. The Keap1 inhibitory peptide comprises a peptide 1 (SEQ ID NO: 1) and / or a peptide 2 (SEQ ID NO: 2). The Keap1 inhibitory peptide is a natural short peptide which is separated and identified from rice bran and can be directly combined with a Keap1 protein, can be used as a direct inhibitor of the Keap1 protein, and can be competitively combined with a Kelch structural domain of Keap1 to block interaction between Keap1 and Nrf2 and promote Nrf2 nuclear translocation and expression of a downstream antioxidant gene, so that endogenous antioxidant defense of cells is enhanced, and the Keap1 inhibitory peptide can be used for preparing a Keap1 inhibitor. The method can be widely applied to anti-oxidation product preparations.

The invention discloses a nano preparation for blocking malignant crosstalk of mechanical and biochemical signals of a lung. The preparation is composed of lipid nanoparticles composed of phospholipid, cholesterol and DSPE-PEG2K-NH2, the surfaces of the lipid nanoparticles are grafted with L-arginine and tannic acid, the two drugs are cooperatively loaded, and double intervention on mechanical and biochemical signal channels is achieved. Tannic acid modification can remove active oxygen and enhance lung targeting, and L-arginine is helpful to penetrate through a compact extracellular matrix and promote delivery of drugs to the deep part of pulmonary alveoli. On one hand, by promoting phenotype reversion of myofibroblast-like endothelial cells to endothelium, endothelial-mesenchymal transformation is reduced, and fibrosis progress is inhibited; on the other hand, nuclear translocation of mechanical conduction factors is blocked, and mechanical signal channels related to fibrosis are intervened. The nano preparation can effectively reverse malignant crosstalk of mechanical and biochemical signals in fibrotic lung tissues, and provides an innovative and efficient treatment strategy for pulmonary fibrosis.

Compounds having general formula I, a method for preparing same, a pharmaceutical composition thereof, and use thereof are provided. Specifically, a compound having a structure represented by general formula I, and a racemate, an R-isomer, an S-isomer and a pharmaceutically acceptable salt thereof, or a mixture thereof are provided. The compound promotes transcription factor EB (TFEB) nuclear translocation and lysosome generation, and can be used for preventing, treating, or assisting in treating various diseases related to lysosome dysfunction and biosynthesis insufficiency, especially neurodegenerative diseases caused by the accumulation of intracerebral pathological proteins (e.g., β-amyloid protein and α-synuclein), such as Alzheimer's disease (AD) and Parkinson's disease (PD).

This invention relates to the field of biomedical technology, and more particularly to the application of an isoflavone compound, specifically Corylifol A, in the preparation of drugs for the prevention and / or treatment of inflammatory diseases. When used to prepare drugs for the prevention and / or treatment of inflammatory diseases, this isoflavone compound can directly bind to the IκBα protein and specifically inhibit its phosphorylation, thereby blocking the phosphorylation and nuclear translocation of the NF-κB p65 subunit, ultimately inhibiting the overactivation of the NF-κB signaling pathway. Furthermore, the isoflavone compound can significantly reduce the mortality rate of lipopolysaccharide-induced septicemia in mice, inhibit the levels of inflammatory factors in serum and lung tissue, and effectively alleviate LPS-induced acute lung injury in mice. Simultaneously, when the isoflavone compound is controlled within an effective concentration range, it exhibits no significant cytotoxicity to mouse peritoneal macrophages and can significantly inhibit the production and release of lipopolysaccharide-induced inflammatory factors IL-1β, TNF-α, and IL-6.

The invention provides application of a CD5-targeting reagent in the aspects of reducing the drug resistance of tumor cells and improving the anti-tumor curative effect of drugs, and clarifies for the first time that CD5 molecules can promote high expression and cell nucleus displacement of transcription factors FOXO3a and FOXO4 in a forkhead cassette O signal channel; therefore, expression increase of the ABC drug-resistant protein family in diffuse large B-cell lymphoma tumor cells is mediated, and drug resistance of tumor cells to various chemotherapeutic drugs is promoted. Further, it is found that the celecoxib can significantly inhibit expression of CD5 molecule mediated ABC drug-resistant protein in B-cell lymphoma cells, then the celecoxib and chemotherapeutic drugs are combined for application, the killing effect of traditional chemotherapeutic drugs on diffuse large B-cell lymphoma tumor cells is significantly enhanced, and the chemotherapeutic drug resistance of diffuse large B-cell lymphoma is overcome. The anti-drug-resistant tumor strategy can overcome the problems of low treatment response rate and poor prognosis of the CD5-positive diffuse large B-cell lymphoma to the existing chemotherapy regimen due to multidrug resistance, and significantly improves the anti-tumor treatment effect.

The present invention discloses compounds containing general formula I, and methods for their preparation, pharmaceutical compositions and uses. Specifically, the present invention provides compounds having the structure shown in general formula I, and their racemic compounds, R-isomers, S-isomers, pharmaceutically acceptable salts or mixtures thereof. The said compounds have good effects on the nuclear translocation of transcription factor EB (TFEB) and the generation of lysosomes, and are used for the prevention, treatment or adjuvant treatment of various diseases related to lysosomal dysfunction and biosynthetic deficiency, especially neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), caused by the accumulation of pathological proteins (such as β-amyloid protein, α-synuclein) in the brain.

To provide a novel compound and use thereof.SOLUTION: A compound is used that comprises: a nuclear translocation unit having the property of migrating into a nucleus of a cell; a functional unit having a specific structure; and a linker unit that links the nuclear translocation unit and the functional unit .SELECTED DRAWING: None

The present invention relates to the field of biotechnology, and specifically to drugs and pharmaceutical compositions for treating APLAID. The drugs are inhibitors targeting the IFNβ signaling pathway, and the pharmaceutical compositions comprise inhibitors targeting the IFNβ signaling pathway, as well as pharmaceutically acceptable carriers and / or excipients. Molecular mechanism studies conducted using PLCγ2p.Leu845Ser mutant macrophages and mouse models indicate that upregulated IFNβ in macrophages is a key driver of APLAID. The p.Leu845Ser mutant PLCγ2 upregulates IFNβ expression by enhancing its binding to IRF5 and promoting IRF5 nuclear translocation. This invention reveals for the first time that activated IRF5 / IFNβ signaling in macrophages is a key driver of APLAID development and provides a new therapeutic target for APLAID patients.

The invention belongs to the technical field of genes and biomedicine, and particularly relates to a marker serving as a head and neck squamous cell carcinoma treatment target and application, the marker is an aerobic glycolysis key enzyme PFKP, and the aerobic glycolysis key enzyme PFKP promotes in-vivo glycolysis metabolism and head and neck squamous cell carcinoma progress through AMOTL1 / YAP / Hippo. The key enzyme PFKP for aerobic glycolysis is a key prognosis factor of the HNSCC, promotes aerobic glycolysis and epithelial-mesenchymal transition of the HNSCC, directly interacts with AMOTL1, inhibits ubiquitination degradation of the AMOTL1, promotes EMT and aerobic glycolysis of the HNSCC by depending on the AMOTL1, the PFKP targets the AMOTL1 to promote YAP nuclear translocation in the HNSCC, PFKP / AMOTL1 depends on the nuclear translocation of YAP to enhance the aerobic glycolysis and tumor progression of the HNSCC, and the HNSCC has the advantages that the key enzyme PFKP can be used for inhibiting the tumor progression of the HNSCC. The enhanced PFKP promotes the progress of the HNSCC in vivo through the AMOTL1 / YAP (AMOTL1 / YAP).