155,856 research outputs found
Zinc oxide nanoparticles as selective killers of proliferating cells
Background: It has recently been demonstrated that zinc oxide nanoparticles (ZnO NPs) induce death of cancerous cells whilst having no cytotoxic effect on normal cells. However, there are several issues which need to be resolved before translation of zinc oxide nanoparticles into medical use, including lack of suitable biocompatible dispersion protocols and a better understanding being needed of the mechanism of their selective cytotoxic action.
Methods: Nanoparticle dose affecting cell viability was evaluated in a model of proliferating cells both experimentally and mathematically. The key issue of selective toxicity of ZnO NPs toward proliferating cells was addressed by experiments using a biological model of noncancerous cells, ie, mesenchymal stem cells before and after cell differentiation to the osteogenic lineage.
Results: In this paper, we report a biocompatible protocol for preparation of stable aqueous solutions of monodispersed zinc oxide nanoparticles. We found that the threshold of intracellular ZnO NP concentration required to induce cell death in proliferating cells is 0.4 ± 0.02 mM. Finally, flow cytometry analysis revealed that the threshold dose of zinc oxide nanoparticles was lethal to proliferating pluripotent mesenchymal stem cells but exhibited negligible cytotoxic effects to osteogenically differentiated mesenchymal stem cells.
Conclusion: Results confirm the ZnO NP selective cytotoxic action on rapidly proliferating cells, whether benign or malignant
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Expression of proliferation-dependent antigens during cellular ageing of normal and progeroid human fibroblasts
Normal human fibroblasts display a limited lifespan in
culture, which is due to a steadily decreasing fraction of
cells that are able to proliferate. Using antibodies that react
with antigens present in proliferating cells only, in an
indirect immunofluorescence assay, we have estimated the
fraction of proliferating cells in cultures of normal human
fibroblasts. Furthermore, we have estimated the rate of
decline in the fraction of proliferating cells during the
process of cellular ageing by application of the assay to
normal human fibroblasts throughout their lifespan in
culture. Werner’s Syndrome is an autosomal recessive
disease in which individuals display symptoms of ageing
prematurely. Werner’s Syndrome fibroblasts display a
reduced lifespan in culture compared with normal human
fibroblasts. Like normal human fibroblasts, the growth of
Werner’s Syndrome fibroblasts is characterised by a
decreasing fraction of cells reacting with the proliferationassociated
antibodies throughout their lifespan in culture.
However, the rate of loss of proliferating cells in Werner’s
Syndrome fibroblasts during the process of cellular ageing
is accelerated 5- to 6-fold compared with the rate determined
for normal human fibroblasts
Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology
Aerobic glycolysis is a seemingly wasteful mode of ATP production that is seen both in rapidly proliferating mammalian cells and highly active contracting muscles, but whether there is a common origin for its presence in these widely different systems is unknown. To study this issue, here we develop a model of human central metabolism that incorporates a solvent capacity constraint of metabolic enzymes and mitochondria, accounting for their occupied volume densities, while assuming glucose and/or fatty acid utilization. The model demonstrates that activation of aerobic glycolysis is favored above a threshold metabolic rate in both rapidly proliferating cells and heavily contracting muscles, because it provides higher ATP yield per volume density than mitochondrial oxidative phosphorylation. In the case of muscle physiology, the model also predicts that before the lactate switch, fatty acid oxidation increases, reaches a maximum, and then decreases to zero with concomitant increase in glucose utilization, in agreement with the empirical evidence. These results are further corroborated by a larger scale model, including biosynthesis of major cell biomass components. The larger scale model also predicts that in proliferating cells the lactate switch is accompanied by activation of glutaminolysis, another distinctive feature of the Warburg effect. In conclusion, intracellular molecular crowding is a fundamental constraint for cell metabolism in both rapidly proliferating- and non-proliferating cells with high metabolic demand. Addition of this constraint to metabolic flux balance models can explain several observations of mammalian cell metabolism under steady state conditions
Extracellular vesicle-induced differentiation of neural stem progenitor cells
Neural stem progenitor cells (NSPCs) from E13.5 mouse embryos can be maintained in culture under proliferating conditions. Upon growth-factor removal, they may differentiate toward either neuronal or glial phenotypes or both. Exosomes are small extracellular vesicles that are part of the cell secretome; they may contain and deliver both proteins and genetic material and thus play a role in cell–cell communication, guide axonal growth, modulate synaptic activity and regulate peripheral nerve regeneration. In this work, we were interested in determining whether NSPCs and their progeny can produce and secrete extracellular vesicles (EVs) and if their content can affect cell differentiation. Our results indicate that cultured NSPCs produce and secrete EVs both under proliferating conditions and after differentiation. Treatment of proliferating NSPCs with EVs derived from differentiated NSPCs triggers cell differentiation in a dose-dependent manner, as demonstrated by glial-and neuronal-marker expression
Morphology of Proliferating Epithelial Cellular Tissue
We investigate morphologies of proliferating cellular tissue using a newly
developed numerical simulation model for mechanical cell division. The model
reproduces structures of simple multi-cellular organisms via simple rules for
selective division and division plane orientation. The model is applied to a
bimodal mixture of stiff cells with a low growth potential and soft cells with
a high growth potential. In an even mixture, the soft cells develop into a
tissue matrix and the stiff cells into a dendrite-like network structure. For
soft cell inclusion in a stiff cellular matrix, the soft cells develop to a
fast growing tumour like structure that gradually evacuates the stiff cell
matrix. With increasing inter-cell friction, the tumour growth slows down and
parts of it is driven to self-inflicted cell death
Lung adenocarcinoma originates from retrovirus infection of proliferating type 2 pneumocytes during pulmonary post-natal development or tissue repair
Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer
Quantum Destruction of Spiral Order in Two Dimensional Frustrated Magnets
We study the fate of spin-1/2 spiral-ordered two-dimensional quantum
antiferromagnets that are disordered by quantum fluctuations. A crucial role is
played by the topological point defects of the spiral phase, which are known to
have a Z2 character. Previous works established that a nontrivial quantum
spin-liquid phase results when the spiral is disordered without proliferating
the Z2 vortices. Here, we show that when the spiral is disordered by
proliferating and condensing these vortices, valence-bond solid ordering occurs
due to quantum Berry phase effects. We develop a general theory for this latter
phase transition and apply it to a lattice model. This transition potentially
provides a new example of a Landau-forbidden deconfined quantum critical point.Comment: 12 pages (Extended and appendix added
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Internal iamin structures within G1 nuclei of human dermal fibroblasts
The nuclear lamina is a mesh-like network of fibres subjacent
to the inner nuclear membrane that is believed
to be involved in the specific spatial reorganisation of
chromatin after mitosis. To determine how the lamina
might be involved in chromatin reorganisation, we have
performed indirect immunofluorescence studies on quiescent
and proliferating human dermal fibroblasts
(HDF). Two monoclonal antibodies recognising human
lamins A and C and three different fixation methods
were employed. In indirect immunofluorescence studies,
cultures of quiescent cells displayed a uniform perinuclear
distribution of the antibodies. In proliferating cultures
two distinct populations of cells were observed:
one population displayed a typical perinuclear antibody
distribution, while the second population displayed an
unusual pattern consisting of a series of spots and fibres
within the nucleus. By inducing cell-cycle synchrony in
cultures we were able to determine that the unusual
internal distribution of the lamin antibodies was
restricted to cells in G1. Optical sectioning and 3-D
reconstruction of the lamina structures in G1 nuclei was
performed with a confocal laser scanning microscope
(CLSM). This revealed that the internal lamin structures
consisted of small foci and fibres proliferating
throughout the nucleus. These structures were shown to
be closely associated with areas of condensed chromatin
but not nuclear membrane. As cells progress towards S
phase the internal lamin foci disappear
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