1,736,481 research outputs found
Multifunctional role of PED/PEA15 in cell death and cell motility in human non small cell lung cancer (NSCLC)
No full textPED (phosphoprotein enriched in diabetes) is a 15 KDa protein involved in many cellular pathways and human diseases, including type II diabetes and cancer. We recently reported its overexpression in breast and lung cancers, and B-cell chronic lymphocytic leukemia (B-CLL). Furthermore, PED mediated resistance to chemotherapic agents in breast cancer cell lines and TRAIL (TNF-Related Apoptosis Inducing Ligand) treatment in primary B-CLL cells and lung cancer cell lines. Then, we show that PED function and expression are reguated by vitamin D3. To better understand its role in cancer, we focused on PED interactome characterization in non small cell lung cancer (NSCLC) cell line, A459. By the Tandem Affinity Purification (TAP), we have identified Rac1, member of mammalian Rho GTPase proteins family, as a PED-interacting protein, which is involved in many cellular processes, such as migration and invasion. Here we show that PED stimulates migration and invasion in Rac1-dependent manner in non small cell lung cancer. In conclusion, this is teh first report showing that PED and Rac1 interact and that this interaction regulates cell migration/invasion process through ERK1/2 pathway
Inside the function of the 67 kDa laminin receptor (67LR): a new promising target for cancer drug discovery by structure-based virtual screening
No full textThe 67 kDa laminin receptor (67LR) is a non-integrin cell-surface receptor for the extracellular matrix derived from the dimerization of a 37 kDa cytosolic precursor (37LRP). 67LR is highly expressed in human cancers and widely recognized as a molecular marker of metastatic aggressiveness.
Phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) is an anti-apoptotic protein whose expression is increased in several human cancers. In addition to apoptosis, PED/PEA-15 is involved in the regulation of other major cellular functions, including cell adhesion, migration, proliferation and glucose metabolism.
A yeast two-hybrid screening identified 67LR as a PED/PEA-15 interacting partner. PED/PEA-15 molecular interaction with 67LR was confirmed by pull-down experiments on lysates of PED/PEA-15 transfected HEK-293 cells. Overexpressed and endogenous PED/PEA-15 co-immunoprecipitated with 67LR in PED/PEA-15 transfected HEK-293 cells and in U-373 glioblastoma cells, respectively.
PED/PEA-15 overexpression significantly increased 67LR-mediated HEK-293 cell adhesion and migration to laminin that, in turn, determined PED/PEA-15 phosphorylation both in Ser-104 and Ser-116, through CamKII and PKC activation, thus enabling cell proliferation and resistance to apoptosis.
Therefore, 67LR binding to laminin induces, through interaction with PED/PEA-15, signals that may be crucial for tumor cell survival in a poor microenvironment. Indeed, high 67LR expression predicts for a more aggressive disease in several types of cancer.
These considerations prompted us to search for small molecules that might target 67LR activities. Since cancer cells overexpress 67LR, these compounds are expected to be cancer cell specific and minimally toxic. We conducted a computational screening of a diversity library of small molecules using the recently solved 67LR crystal structure, focusing on residues showed to be important for laminin binding. This analysis identified a lead compound that was characterized for its effects. This lead compound, NSC47924, could be the basis for the development of a new class of anti-cancer drugs, specifically targeting tumor invasion and metastasis
CLOZAPINE AND HALOPERIDOL INCREASE THE EXPRESSION OF PED/PEA-15: A PUTATIVE NOVEL MECHANISM FOR ANTIPSYCHOTIC-RELATED DIABETES
No full textSchizophrenia is a serious disorder that affects 1% of the population in the United States and Europe, and is associated with a significant reduction in life expectancy that approaches 20% compared with that of the general population. Current management of patients with schizophrenia involves the increasing use of atypical antipsychotic agents, such as risperidone, quetiapine, olanzapine, and clozapine. The use of these agents has been associated with increased morbidity from obesity,hyperlipidemia, development of new-onset diabetes, and, in rare instances, development of diabetic ketoacidosis. The precise mechanism for the abnormalities in carbohydrate and lipid metabolism is incompletely understood. We investigated whether haloperidol and clozapine, respectively a typical and an atypical antipsychotics, directly affect insulin action in cultured cell models and in vivo. In our experimental paradigms, both haloperidol and clozapine reduced insulin-stimulated glucose uptake in a time- and concentration dependent manner, although with a different efficacy. Indeed, pre-treatment with clozapine, but not with haloperidol, prevented insulin effect on insulin receptor (IR) and IR substrate-1/2 (IRS-1/2) tyrosine phosphorylation. Moreover, both drugs reduced insulin-dependent phosphorylation of protein kinase C-ζ (PKC- ζ), and induced an insulin- independent increase of phosphorylated Akt. These effects were paralleled by increased expression of Ped/Pea-15, an Akt substrate and inducer of insulin resistance. Similar changes of these signalling proteins were detected
in caudate-putamen and in skeletal muscle of mice treated with either haloperidol or clozapine. Thus, antipsychotics may impair insulin action, at least in part, by upregulating Ped/Pea-15 and inhibiting activation of PKC- ζ
“PED/PEA-15 regulates wound healing and angiogenesis by affecting cytoskeletal organization and cell motility: a model for diabetic complications”
No full textFailure in wound healing is a common feature of diabetes mellitus which severely affects morbidity and mortality. We evaluated wound healing in the skin of transgenic mice (TgPED) over-expressing ped/pea-15, a gene over-expressed in patients with type 2 diabetes.Up to four days after the injury, the distance between wound edges was 3-fold higher in TgPED mice compared to their wild-type littermates (Wt). TgPED mice also presented significantly reduced granulation tissue formation as compared to Wt. Moreover, the wounded skin of TgPED exhibited also a reduced content of activated fibroblasts, collagen fibres and an increased detection of infiltrated inflammatory cells. These histological alterations were accompanied, in TgPED speciments, by an increased production of inflammatory cytokines and a defect of neo-angiogenesis process. Then we isolated endothelial cells and fibroblasts from TgPED and Wt mice, mainly involved in the formation of the granulation tissue, the first regenerative tissue that closes the skin gap. Endothelial cells and skin fibroblasts isolated from TgPED and Wt mice showed reduced healing ability in scratch wound healing assays compared to control cells. Furthermore, in time-lapse experiments, TgPED fibroblasts displayed about 2-fold lower velocity and diffusion coefficient, as compared with Wt. These changes were accompanied by reduced spreading and decreased formation of stress fibres and focal adhesion plaques. At molecular level, TgPED fibroblasts displayed decreased RhoA membrane content and increased cytosolic abundance of phosphorylated ERK1/2. Inhibition of ERK1/2 activity by PD98059 restored RhoA membrane translocation, cytoskeleton organization and cell motility and almost completely rescued wound healing ability of TgPED fibroblasts and can be expanded to endothelial cells. Interestingly, fibroblasts isolated from ped/pea-15 null mice (KO) displayed an increased motility and spreading compared to control cells. These results strongly support a role of PED/PEA-15 in the regulation of cell motility during skin wound healing. Moreover, the control exerted by PED/PEA-15 on cell migration is not restricted to fibroblasts. Considering the different known cellular function of PED/PEA-15 in a chronic disorder such as diabetes, the observation that PED/PEA-15 regulates cellular motility and skin wound healing in TgPED mice may suggest these mice as model to study the role of PED/PEA-15 in diabetic complications
Application of the amniotic membrane extract (AMX) for the persistent epithelial defect (PED) of the cornea [Primjena ekstrakta amnijske membrane (AMX) za perzistirajući epitelni defekt (PED) rožnice]
No full textA lot of pathological conditions could provoke damaging of the innervations of the cornea and lead to persistent epithelial defect (PED). AMX is lyophilized preparation of amniotic membrane (AM), which contains biological components and efficacy of AM for treatment of the corneal surface defects. In processing all the substances essential for biological effects of AM are preserved (growth factors, neutrophins, interleukins, receptors, fibronectins and different types of collagen). A patient can apply AMX as eye drops by himself in his home, thus avoiding surgical procedure. We presented two patients with PED; we treated them with eye drops of AMX, 2 drops every hour during day time. There was observed healing effect by reducing epithelial defect. Almost after a second day of application, and after 1-2 week period PED that persisted for weeks healed completely
Devise the concept of a virtual PED Lab for demonstrating new technologies and solutions (Concept on the development of a virtual PED Lab)
No full textPED Labs act as catalysts to drive PED innovation and implementation, playing a crucial role in defining pathways towards climate-neutral and sustainable cities. The complexity of PED implementation requires advanced digital tools and methodologies to support design, planning, and decision-making processes. In this context, Virtual Positive Energy District Laboratories (VPEDLs) become essential digital platforms that facilitate these processes through simulation, stakeholder engagement, and regulatory testing. The main aim of this report is to define the concept of a Virtual PED Laboratory and to identify its main characteristics, applications and functionalities. The introduction, while summarising the differences between physical PED Labs and Virtual PED labs, highlights existing gaps in PED Labs that need to be addressed to accelerate the transition towards Positive Energy Districts. Section 2 presents a structured review of key concepts related to Virtual PED Labs. The review is organized according to two integrative aspects: PED Labs and their related concepts, and Virtual Labs and their related concepts. Main correlation to Digital Targets for 2030 EU Policy program, the “twin green and digital transition” and the urban digital twin are presented. Definitions, key characteristics and features are presented in section 3, while classification criteria and typologies in section 4. Section 5 provides a description of the digital tools, components and functionalities that characterize Virtual PED Labs. In the last section, 2 case studies are presented as representative of (Virtual) PED Labs: the Research Centre in Lubia (Spain) CEDER-CIEMAT and the Cascais Smar Pole Living Lab in Carcavelos (Portugal): technical information, key strategies and tools, as well as standardization and upscaling strategies are reported. This latest report of WG3 lays the foundation for future collaborations with all research groups involved in this project as a starting point for other collaborations aimed at improving processes for the achievement of the goals of climate-neutral cities and positive energy districts.COST Action 19126, Positive Energy Districts European Network, Deliverable 3.5Main Contributors and reviewers: Oscar Seco Calvo, Etminan Ghazal, Emanuela Giancola,
Maria Beatrice Andreucc
Multifunctional role of PED/PEA15 in cell death and cell motility in human non small cell lung cancer (NSCLC).
No full textPED (phosphoprotein enriched in diabetes) is a 15 KDa protein involved in many cellular pathways and human diseases, including type II diabetes and cancer. We recently reported its overexpression in breast and lung cancers, and B-cell chronic lymphocytic leukemia (B-CLL). Furthermore, PED mediated resistance to chemotherapic agents in breast cancer cell lines and TRAIL (TNF-Related Apoptosis Inducing Ligand) treatment in primary B-CLL cells and lung cancer cell lines. Then, we show that PED function and expression are reguated by vitamin D3. To better understand its role in cancer, we focused on PED interactome characterization in non small cell lung cancer (NSCLC) cell line, A459. By the Tandem Affinity Purification (TAP), we have identified Rac1, member of mammalian Rho GTPase proteins family, as a PED-interacting protein, which is involved in many cellular processes, such as migration and invasion. Here we show that PED stimulates migration and invasion in Rac1-dependent manner in non small cell lung cancer. In conclusion, this is teh first report showing that PED and Rac1 interact and that this interaction regulates cell migration/invasion process through ERK1/2 pathway
Comparison of PED/PED Flex and PED Shield in the treatment of unruptured intracerebral aneurysms.
No full textOBJECTIVE: The object of this study was to compare the efficacy and safety profile of the Pipeline embolization device (PED)/Pipeline Flex embolization device (PED Flex) with that of the Pipeline Flex embolization device with Shield Technology (PED Shield). After introducing the first-generation PED and the second-generation PED Flex with its updated delivery system, the PED Shield was launched with a synthetic layer of phosphorylcholine surface modification to reduce thrombogenicity.
METHODS: This is a retrospective review of unruptured aneurysms treated with PED/PED Flex versus PED Shield between 2017 and 2022 at the authors\u27 institution. Patients with ruptured aneurysms, adjunctive treatment, failed flow diverter deployment, and prior treatment of the target aneurysm were excluded. Baseline characteristics were collected for all patients, including age, sex, past medical history (hypertension, hyperlipidemia, diabetes mellitus), smoking status, aneurysm location, and aneurysm dimensions (neck, width, height) and morphology (saccular, nonsaccular). The primary outcome was procedural and periprocedural complication rates.
RESULTS: The study cohort comprised 200 patients with 200 aneurysms, including 150 aneurysms treated with the PED/PED Flex and 50 treated with the PED Shield. With respect to intraprocedural and periprocedural complications, length of stay, length of follow-up, and functional outcome at discharge, there was no significant difference between the two cohorts. At the midterm follow-up, the rate of in-stent stenosis (PED/PED Flex: 14.2% vs PED Shield: 14.6%, p = 0.927), aneurysm occlusion (complete occlusion: 79.5% vs 80.5%, respectively; neck remnant: 4.7% vs 12.2%; dome remnant: 15.7% vs 7.3%; p = 0.119), and the need for retreatment (5.3% vs 0%, p = 0.097) were comparable between the two cohorts.
CONCLUSIONS: This study suggests that, as compared to first- and second-generation PED and PED Flex, the third-generation PED Shield offers similar rates of complications, aneurysm occlusion, and in-stent stenosis at the midterm follow-up
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