Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Micelles were prepared from polymer-peptide block copolymer amphiphiles containing substrates for protein kinase A, protein phosphatase-1, and matrix metalloproteinases 2 and 9. We examine reversible switching of the morphology of these micelles through a phosphorylation-dephosphorylation cycle and study peptide-sequence directed changes in morphology in response to proteolysis. Furthermore, the exceptional uniformity of these polymer-peptide particles makes them amenable to cryo-TEM reconstruction techniques lending insight into their internal structure.
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PMID:Controlling and switching the morphology of micellar nanoparticles with enzymes. 2146 79

Early human allograft rejection can be initiated when circulating human host versus graft Ag-specific CD8 and CD4 effector memory T cells directly recognize MHC class I and II, respectively, expressed on the luminal surface by endothelium lining graft blood vessels. TCR engagement triggers both graft entry (TCR-driven transendothelial migration or TEM) and production of proinflammatory cytokines. Both TCR-driven TEM and cytokine expression are known to depend on T cell enzymes, myosin L chain kinase, and calcineurin, respectively, that are activated by cytoplasmic calcium and calmodulin, but whether the sources of calcium that control these enzymes are the same or different is unknown. Using superantigen or anti-CD3 Ab presented by cultured human dermal microvascular cells to freshly isolated peripheral blood human effector memory T cells under conditions of flow (models of alloantigen recognition in a vascularized graft), we tested the effects of pharmacological inhibitors of TCR-activated calcium signaling pathways on TCR-driven TEM and cytokine expression. We report that extracellular calcium entry via CRAC channels is the dominant contributor to cytokine expression, but paradoxically these same inhibitors potentiate TEM. Instead, calcium entry via TRPV1, L-Type Cav, and pannexin-1/P2X receptors appear to control TCR-driven TEM. These data reveal new therapeutic targets for immunosuppression.
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PMID:Divergent TCR-Initiated Calcium Signals Govern Recruitment versus Activation of Human Alloreactive Effector Memory T Cells by Endothelial Cells. 3034 Nov 83

The shortcomings of the currently available anti-breast cancer agents compel the development of the safer targeted drug delivery for the treatment of breast cancer. The aim of the present study was to evaluate the anti-breast cancer potential of Ipomoea turpethum extract loaded nanoparticles (NIPAAM-VP-AA) against breast cancer, together with the identification of the key proteins responsible for the caused cytotoxicity. For this, we explored the tumor microenvironment for targeted drug delivery and synthesized (temperature and pH responsive) double triggered polymeric nanoparticles by the free radical mechanism and characterized them by DLS and TEM. The extract which emerged as the best extract, i.e. root extract, was loaded on the nanoparticles and the cytotoxicity was evaluated in breast cancer cell lines (MCF-7 and MDA-MB-231) by various cytotoxic assays like MTT assay, CFSE cell proliferation assay, apoptosis assay, cell cycle study and DAPI nuclear staining. The key protein targets responsible for the caused cytotoxicity were identified by nano-LC-MS/MS analysis. The proteome analysis revealed that most of the significantly differentially expressed proteins have a role in proliferation, vesicular trafficking, apoptosis and tumor suppression. Finally, the interaction among the highly differentially expressed proteins was identified by using the STRING online tool, which showed that I. turpethum nanoparticles caused apoptosis in MCF-7 and MDA MB-231 cells by targeting nucleolysin TIAR, serine/threonine-protein phosphatase PP1 and ubiquitin-60S ribosomal protein L40.
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PMID:Identification of protein targets and the mechanism of the cytotoxic action of Ipomoea turpethum extract loaded nanoparticles against breast cancer cells. 3165 57

The etiology of preeclampsia (PE), a serious pregnancy complication, remains an enigma. We have demonstrated that proteinopathy, a pathologic feature of neurodegenerative diseases, is a key observation in the placenta and serum from PE patients. We hypothesize that the macroautophagy/autophagy machinery that mediates degradation of aggregated proteins and damaged organelles is impaired in PE. Here, we show that TFEB (transcription factor EB), a master transcriptional regulator of lysosomal biogenesis, and its regulated proteins, LAMP1, LAMP2, and CTSD (cathepsin D), were dysregulated in the placenta from early and late onset PE deliveries. Primary human trophoblasts and immortalized extravillous trophoblasts (EVTs) showed reduced TFEB expression and nuclear translocation as well as lysosomal protein content in response to hypoxia. Hypoxia-exposed trophoblasts also showed decreased PPP3/calcineurin phosphatase activity and increased XPO1/CRM1 (exportin 1), events that inhibit TFEB nuclear translocation. These proteins were also dysregulated in the PE placenta. These results are supported by observed lysosomal ultrastructural defects with decreased number of autolysosomes in hypoxia-treated primary human trophoblasts. Autophagy-deficient human EVTs exhibited poor TFEB nuclear translocation, reduced lysosomal protein expression and function, and increased MTORC1 activity. Sera from PE patients induced these features and protein aggregation in EVTs. Importantly, trophoblast-specific conditional atg7 knockout mice exhibited reduced TFEB expression with increased deposition of protein aggregates in the placenta. These results provide compelling evidence for a regulatory link between accumulation of protein aggregates and TFEB-mediated impaired lysosomal biogenesis and autophagy in the placenta of PE patients. Abbreviation: atg7: autophagy related 7; CTSD: cathepsin D; ER: endoplasmic reticulum; EVTs: extravillous trophoblasts; KRT7: keratin 7; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; mSt: mStrawberry; MTORC1: mechanistic target of rapamycin complex 1; NP: normal pregnancy; NPS: normal pregnancy serum; PE: preeclampsia; PES: preeclampsia serum; p-RPS6KB: phosphorylated ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; XPO1/CRM1: exportin 1.
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PMID:Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia. 3185 41