23 results found
Valente P, Kiryushko D, Sacchetti S, et al., 2020, Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-D-aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro, ACS NANO, Vol: 14, Pages: 6866-6877, ISSN: 1936-0851
Gonzalez Carter D, Goode A, Kiryushko D, et al., 2019, Quantification of blood-brain barrier transport and neuronal toxicity of unlabelled multiwalled carbon nanotubes as a function of surface charge, Nanoscale, Vol: 11, Pages: 22054-22069, ISSN: 2040-3364
Nanoparticles capable of penetrating the blood-brain barrier (BBB) will greatly advance the delivery of therapies against brain disorders. Carbon nanotubes hold great potential as delivery vehicles due to their high aspect-ratio and cell-penetrating ability. Studies have shown multiwalled carbon nanotubes (MWCNT) cross the BBB, however they have largely relied on labelling methods to track and quantify transport, or on individual electron microscopy images to qualitatively assess transcytosis. Therefore, new direct and quantitative methods, using well-defined and unlabelled MWCNT, are needed to compare BBB translocation of different MWCNT types. Using highly controlled anionic (-), cationic (+) and non-ionic (0) functionalized MWCNT (fMWCNT), we correlate UV-visible spectroscopy with quantitative transmission electron microscopy, quantified from c. 270 endothelial cells, to examine cellular uptake, BBB transport and neurotoxicity of unlabelled fMWCNT. Our results demonstrate that: i) a large fraction of cationic and non-ionic, but not anionic fMWCNT become trapped at the luminal brain endothelial cell membrane; ii) despite high cell association, fMWCNT uptake by brain endothelial cells is low (< 1.5% ID) and does not correlate with BBB translocation, iii) anionic fMWCNT have highest transport levels across an in vitro model of the human BBB compared to non-ionic or cationic nanotubes; and iv) fMWCNT are not toxic to hippocampal neurons at relevant abluminal concentrations; however, fMWCNT charge has an effect on carbon nanotube neurotoxicity at higher fMWCNT concentrations. This quantitative combination of microscopy and spectroscopy, with cellular assays, provides a crucial strategy to predict brain penetration efficiency and neurotoxicity of unlabelled MWCNT and other nanoparticle technologies relevant to human health.
Kubankova M, Summers P, Lopez-Duarte I, et al., 2019, Microscopic viscosity of neuronal plasma membranes measured using fluorescent molecular rotors: effects of oxidative stress and neuroprotection., ACS Applied Materials and Interfaces, Vol: 11, Pages: 36307-36315, ISSN: 1944-8244
Molecular mobility in neuronal plasma membranes is a crucial factor in brain function. Microscopic viscosity is an important parameter that determines molecular mobility. This study presents the first direct measurements of the microviscosity of plasma membranes of live neurons. Microviscosity maps were obtained using fluorescence lifetime imaging of environment-sensing dyes termed 'molecular rotors'. Neurons were investigated both in the basal state and following common neurodegenerative stimuli, excitotoxicity or oxidative stress. Both types of neurotoxic challenges induced microviscosity decrease in cultured neurons, and the oxidant-induced membrane fluidification was counteracted by the wide-spectrum neuroprotectant, the H3 peptide. These results provide new insights into molecular mobility in neuronal membranes, paramount for basic brain function, and suggest that preservation of membrane stability may be an important aspect of neuroprotection in brain insults and neurodegenerative disorders.
Ruenraroengsak P, Kiryushko D, Theodorou IG, et al., 2019, Frizzled-7-targeted delivery of zinc oxide nanoparticles to drug-resistant breast cancer cells, Nanoscale, Vol: 11, Pages: 12858-12870, ISSN: 2040-3364
There is a need for novel strategies to treat aggressive breast cancer subtypes and overcome drug resistance. ZnO nanoparticles (NPs) have potential in cancer therapy due to their ability to potently and selectively induce cancer cell apoptosis. Here, we tested the in vitro chemotherapeutic efficacy of ZnONPs loaded via a mesoporous silica nanolayer (MSN) towards drug-sensitive breast cancer cells (MCF-7: estrogen receptor-positive, CAL51: triple-negative) and their drug-resistant counterparts (MCF-7TX, CALDOX). ZnO-MSNs were coated on to gold nanostars (AuNSs) for future imaging capabilities in the NIR-II range. Electron and confocal microscopy showed that MSN-ZnO-AuNSs accumulated close to the plasma membrane and were internalized by cells. High-resolution electron microscopy showed that MSN coating degraded outside the cells, releasing ZnONPs that interacted with cell membranes. MSN-ZnO-AuNSs efficiently reduced the viability of all cell lines, and CAL51/CALDOX cells were more susceptible than MCF7/MCF-7-TX cells. MSN-ZnO-AuNSs were then conjugated with the antibody to Frizzled-7 (FZD-7), the receptor upregulated by several breast cancer cells. We used the disulphide (S-S) linker that could be cleaved with a high concentration of glutathione normally observed within cancer cells, releasing Zn2+ into the cytoplasm. FZD-7 targeting resulted in approximately three-fold amplified toxicity of MSN-ZnO-AuNSs towards the MCF-7TX drug-resistant cell line with the highest FZD-7 expression. This study shows that ZnO-MSs are promising tools to treat triple-negative and drug-resistant breast cancers and highlights the potential clinical utility of FZD-7 for delivery of nanomedicines and imaging probes specifically to these cancer types.
Kuimova M, Kubankova M, Kiryushko D, et al., 2018, Molecular rotors report on changes of live cell plasma membrane microviscosity upon interaction with beta-amyloid aggregates, Soft Matter, Vol: 14, Pages: 9466-9474, ISSN: 1744-683X
Amyloid deposits of aggregated beta-amyloid Aβ(1–42) peptides are a pathological hallmark of Alzheimer's disease. Aβ(1–42) aggregates are known to induce biophysical alterations in cells, including disruption of plasma membranes. We investigated the microviscosity of plasma membranes upon interaction with oligomeric and fibrillar forms of Aβ(1–42). Viscosity-sensing fluorophores termed molecular rotors were utilised to directly measure the microviscosities of giant plasma membrane vesicles (GPMVs) and plasma membranes of live SH-SY5Y and HeLa cells. The fluorescence lifetimes of membrane-inserting BODIPY-based molecular rotors revealed a decrease in bilayer microviscosity upon incubation with Aβ(1–42) oligomers, while fibrillar Aβ(1–42) did not significantly affect the microviscosity of the bilayer. In addition, we demonstrate that the neuroprotective peptide H3 counteracts the microviscosity change induced by Aβ(1–42) oligomers, suggesting the utility of H3 as a neuroprotective therapeutic agent in neurodegenerative disorders and indicating that ligand-induced membrane stabilisation may be a possible mechanism of neuroprotection during neurodegenerative disorders such as Alzheimer's disease.
Kiryushko D, Pankratova S, Klingelhofer J, et al., 2018, The S100A4 protein signals through the ErbB4 receptor to promote neuronal survival., Theranostics, Vol: 8, Pages: 3977-3990, ISSN: 1838-7640
Understanding the mechanisms of neurodegeneration is crucial for development of therapies to treat neurological disorders. S100 proteins are extensively expressed in the injured brain but S100's roleand signalling in neural cells remain elusive. We recently demonstrated that the S100A4 protein protects neurons in brain injury and designed S100A4-derived peptides mimicking its beneficial effects. Here we show that neuroprotection by S100A4 involves the growth factor family receptorErbB4 and its ligand Neuregulin 1 (NRG), key regulators of neuronal plasticity and implicated in multiple brain pathologies. The neuroprotective effect of S100A4 depends on ErbB4 expression andthe ErbB4 signalling partners ErbB2/Akt, and is reduced by functional blockade of NRG/ErbB4 in cell models of neurodegeneration. We also detect binding of S100A4 with ErbB1 (EGFR) and ErbB3. S100A4-derived peptides interact with, and signal through ErbB, are neuroprotective inprimary and immortalized dopaminergic neurons, and do not affect cell proliferation/motility - features which make them promising as potential neuroprotectants. Our data suggest that the S100- ErbB axis may be an important mechanism regulating neuronal survival and plasticity
Moldovan M, Pinchenko V, Dmytriyeva O, et al., 2013, Peptide Mimetic of the S100A4 Protein Modulates Peripheral Nerve Regeneration and Attenuates the Progression of Neuropathy in Myelin Protein P-0 Null Mice, MOLECULAR MEDICINE, Vol: 19, Pages: 43-53, ISSN: 1076-1551
Dmytriyeva O, Pankratova S, Owczarek S, et al., 2012, The metastasis-promoting S100A4 protein confers neuroprotection in brain injury, NATURE COMMUNICATIONS, Vol: 3, ISSN: 2041-1723
Pankratova S, Kiryushko D, Sonn K, et al., 2012, Neurotrophic and neuroprotective properties of non-hematopoietic EPO-derived peptides, Publisher: WILEY-BLACKWELL, Pages: E91-E91, ISSN: 0361-8609
Pankratova S, Gu B, Kiryushko D, et al., 2012, A new agonist of the erythropoietin receptor, Epobis, induces neurite outgrowth and promotes neuronal survival, JOURNAL OF NEUROCHEMISTRY, Vol: 121, Pages: 915-923, ISSN: 0022-3042
Owczarek S, Soroka V, Kiryushko D, et al., 2011, Neuroplastin-65 and a mimetic peptide derived from its homophilic binding site modulate neuritogenesis and neuronal plasticity, JOURNAL OF NEUROCHEMISTRY, Vol: 117, Pages: 984-994, ISSN: 0022-3042
Pankratova S, Kiryushko D, Sonn K, et al., 2010, Neuroprotective properties of a novel, non-haematopoietic agonist of the erythropoietin receptor, BRAIN, Vol: 133, Pages: 2281-2294, ISSN: 0006-8950
Owczarek S, Kiryushko D, Larsen MH, et al., 2010, Neuroplastin-55 binds to and signals through the fibroblast growth factor receptor, FASEB JOURNAL, Vol: 24, Pages: 1139-1150, ISSN: 0892-6638
Sonn K, Pankratova S, Korshunova I, et al., 2010, A Metallothionein Mimetic Peptide Protects Neurons Against Kainic Acid-Induced Excitotoxicity, JOURNAL OF NEUROSCIENCE RESEARCH, Vol: 88, Pages: 1074-1082, ISSN: 0360-4012
Klingelhofer J, Moller HD, Sumer EU, et al., 2009, Epidermal growth factor receptor ligands as new extracellular targets for the metastasis-promoting S100A4 protein, FEBS JOURNAL, Vol: 276, Pages: 5936-5948, ISSN: 1742-464X
Kiryushko D, Dmytryeva O, Soroka V, et al., 2007, Search for novel targets of the A100A4 protein using S100A4-derived neuritogenic sequences, 21st Biennial Meeting of the International-Society-for-Neurochemistry/38th Annual Meeting of the American-Society-for-Neurochemistry, Publisher: BLACKWELL PUBLISHING, Pages: 273-273, ISSN: 0022-3042
Korshunova I, Novitskaya V, Kiryushko D, et al., 2007, GAP-43 regulates NCAM-180-mediated neurite outgrowth, JOURNAL OF NEUROCHEMISTRY, Vol: 100, Pages: 1599-1612, ISSN: 0022-3042
Kiryushko D, Bock E, Berezin V, 2007, Pharmacology of cell adhesion molecules of the nervous system, CURRENT NEUROPHARMACOLOGY, Vol: 5, Pages: 253-267, ISSN: 1570-159X
Kiryushko D, Korshunova I, Berezin V, et al., 2006, Neural cell adhesion molecule induces intracellular signaling via multiple mechanisms of Ca2+ homeostasis, MOLECULAR BIOLOGY OF THE CELL, Vol: 17, Pages: 2278-2286, ISSN: 1059-1524
Kiryushko D, Novitskaya V, Soroka V, et al., 2006, Molecular mechanisms of Ca2+ signaling in neurons induced by the S100A4 protein, MOLECULAR AND CELLULAR BIOLOGY, Vol: 26, Pages: 3625-3638, ISSN: 0270-7306
Kiryushko D, Berezin V, Bock E, 2004, Regulators of neurite outgrowth - Role of cell adhesion molecules, GASTROENTEROPANCREATIC NEUROENDOCRINE TUMOR DISEASE: MOLECULAR AND CELL BIOLOGICAL ASPECTS, Vol: 1014, Pages: 140-154, ISSN: 0077-8923
Kiryushko D, Kofoed T, Skladchikova G, et al., 2003, A synthetic peptide ligand of neural cell adhesion molecule (NCAM), C3d, promotes neuritogenesis and synaptogenesis and modulates presynaptic function in primary cultures of rat hippocampal neurons, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 278, Pages: 12325-12334, ISSN: 0021-9258
Soroka V, Kiryushko D, Novitskaya V, et al., 2002, Induction of neuronal differentiation by a peptide corresponding to the homophilic binding site of the second Ig module of the neural cell adhesion molecule, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 277, Pages: 24676-24683, ISSN: 0021-9258
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