377 research outputs found
Design and optimization of nano-formulations for a novel colchicine derivative
No full textIntroduction: Chemotherapy is the most reliable approach to cancer treatment, but it is often
associated with side effects due to anti-cancer compounds' toxicity and non-selectivity [1]. CCI-
001 is a novel colchicine derivative, computationally designed by modifying colchicine’s basic
structure, that exploits the affinity with βIII-tubulin to impair the mitosis of cancer cells [1]. CCI-
001 showed lower general toxicity, increased selectivity and specificity [1]. Despite this, its
applications are limited by low water solubility and poor tumor uptake. [1]. This may reduce CCI-
001 efficacy and produce undesirable side effects. To solve this issue, this contribution describes
the design of new efficient transporters of CCI-001 (polymeric nanoparticles, NPs) to enhance
target accumulation and reduce the off-target effects.
Methods: CCI-001 was successfully loaded in core-shell pegylated NPs, using the
nanoprecipitation method [2]. In detail, a poly-ε-caprolactone (PCL)-based polyurethane
(NHSC2000) was solubilized in acetonitrile and precipitated in water containing a mix of
phospholipids (L-α- phosphatidylglycerol, PG and 1,2 – Distearoyl- sn – glycerol – 3 –
phosphoethanolamine – Poly (ethylene glycol), DSPE-PEG). In vitro efficacy of CCI-001 loaded-
NPs was analyzed against 2D and 3D cultures (spheroids) of three cell lines: U87MG (glioblastoma
multiforme), Mia-PaCa-2 (pancreatic adenocarcinoma) and OVCAR-3 (ovarian cancer).
Results: NPs of small size (~170 nm), narrow size distribution (PDI<0.3), high stability in aqueous
solution, and satisfying encapsulation efficiency (6 %) were obtained [3]. CCI-001-loaded NPs
caused a significant decrease in the viability of each cell line tested. The maximum effect was
exerted after 72h, at a concentration of 2,5 μM, where residual viabilities of 50%, 30%, and 26%
were reached for 2D culture of U87MG, Mia-PaCa-2, and OVCAR-3, respectively (Figure 1a). NPs
exhibited similar results on U-87 and Mia-PaCa-2 spheroids, while OVCAR-3 spheroids' viabilities
are higher than the corresponding 2D culture (as shown in Figure 1b). Also, empty NPs did not
elicit signs of toxicity on these cell lines, up to a concentration of 1 mg/ml.
Conclusions: Overall, our results demonstrate that nano-formulations of CCI-001 can be obtained
with satisfying loading efficacy without altering the anti-cancer effect of the drug, warranting
their further investigation
The causal roots of integration and the unity of consciousness
No full textA fundamental feature of consciousness is unity. The problem is whether unity is compatible both with the physical underpinnings of conscious experience and with the fabric of the physical world in general
Cytoskeletal signaling: is memory encoded in microtubule lattices by CaMKII phosphorylation?
No full textMemory is attributed to strengthened synaptic connections among particular brain neurons, yet synaptic membrane components are transient, whereas memories can endure. This suggests synaptic information is encoded and 'hard-wired' elsewhere, e.g. at molecular levels within the post-synaptic neuron. In long-term potentiation (LTP), a cellular and molecular model for memory, post-synaptic calcium ion (Ca²⁺) flux activates the hexagonal Ca²⁺-calmodulin dependent kinase II (CaMKII), a dodacameric holoenzyme containing 2 hexagonal sets of 6 kinase domains. Each kinase domain can either phosphorylate substrate proteins, or not (i.e. encoding one bit). Thus each set of extended CaMKII kinases can potentially encode synaptic Ca²⁺ information via phosphorylation as ordered arrays of binary 'bits'. Candidate sites for CaMKII phosphorylation-encoded molecular memory include microtubules (MTs), cylindrical organelles whose surfaces represent a regular lattice with a pattern of hexagonal polymers of the protein tubulin. Using molecular mechanics modeling and electrostatic profiling, we find that spatial dimensions and geometry of the extended CaMKII kinase domains precisely match those of MT hexagonal lattices. This suggests sets of six CaMKII kinase domains phosphorylate hexagonal MT lattice neighborhoods collectively, e.g. conveying synaptic information as ordered arrays of six "bits", and thus "bytes", with 64 to 5,281 possible bit states per CaMKII-MT byte. Signaling and encoding in MTs and other cytoskeletal structures offer rapid, robust solid-state information processing which may reflect a general code for MT-based memory and information processing within neurons and other eukaryotic cells
In silico Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting β-Tubulin Isotypes: A Search for a Selective and Specific β-III Tubulin Ligand
No full textThe cardinal role of microtubules in cell mitosis makes them interesting drug targets for many pharmacological treatments, including those against cancer. Moreover, different expression patterns between cell types for several tubulin isotypes represent a great opportunity to improve the selectivity and specificity of the employed drugs and to design novel compounds with higher activity only on cells of interest. In this context, tubulin isotype βIII represents an excellent target for anti-tumoral therapies since it is overexpressed in most cancer cells and correlated with drug resistance. Colchicine is a well-known antimitotic agent, which is able to bind the tubulin dimer and to halt the mitotic process. However, it shows high toxicity also on normal cells and it is not specific for isotype βIII. In this context, the search for colchicine derivatives is a matter of great importance in cancer research. In this study, homology modeling techniques, molecular docking, and molecular dynamics simulations have been employed to characterize the interaction between 55 new promising colchicine derivatives and tubulin isotype βIII. These compounds were screened and ranked based on their binding affinity and conformational stability in the colchicine binding site of tubulin βIII. Results from this study point the attention on an amide of 4-chlorine thiocolchicine. This colchicine-derivative is characterized by a unique mode of interaction with tubulin, compared to all other compounds considered, which is primarily characterized by the involvement of the α-T5 loop, a key player in the colchicine binding site. Information provided by the present study may be particularly important in the rational design of colchicine-derivatives targeting drug resistant cancer phenotypes
Large amplitude spatial fluctuations in the boundary region of the Bose-Einstein condensate in the Gross-Pitaevskii regime
No full textThe Gross-Pitaevskii regime of a Bose-Einstein condensate is investigated using a fully non-linear approach. The confining potential first adopted is that of a linear ramp. An infinite class of new analytical solutions of this linear ramp potential approximation to the Gross-Pitaevskii equation is found which are characterised by pronounced large-amplitude oscillations close to the boundary of the condensate. The limiting case within this class is a nodeless ground state which is known from recent investigations as an extension of the Thomas-Fermi approximation. We have found the energies of the oscillatory states to lie above the ground state energy but recent experimental work, especially on spatially confined superconductors, indicates that such states may be easily occupied and made manifest at finite temperatures. We have also investigated their stability using a Poincare section analysis as well as a linear perturbation approach. Both these techniques demonstrate stability against small perturbations. Finally, we have discussed the relevance of these quasi-one-dimensional solutions in the context of the fully three-dimensional condensates. This has been argued on the basis of numerical work and asymptotic approximations. (C) 2003 Elsevier Science B.V. All rights reserved
sj-pdf-1-tmj-10.1177_03008916221146208 – Supplemental material for Demystifying neuroblastoma malignancy through fractal dimension, entropy, and lacunarity
No full textSupplemental material, sj-pdf-1-tmj-10.1177_03008916221146208 for Demystifying neuroblastoma malignancy through fractal dimension, entropy, and lacunarity by Irene Donato, Kiran K Velpula, Andrew J Tsung, Jack A Tuszynski and Consolato M Sergi in Tumori Journal</p
Using the gibbs function as a measure of human brain development trends from fetal stage to advanced age
No full textWe propose to use a Gibbs free energy function as a measure of the human brain development. We adopt this approach to the development of the human brain over the human lifespan: from a prenatal stage to advanced age. We used proteomic expression data with the Gibbs free energy to quantify human brain’s protein–protein interaction networks. The data, obtained from BioGRID, comprised tissue samples from the 16 main brain areas, at different ages, of 57 post-mortem human brains. We found a consistent functional dependence of the Gibbs free energies on age for most of the areas and both sexes. A significant upward trend in the Gibbs function was found during the fetal stages, which is followed by a sharp drop at birth with a subsequent period of relative stability and a final upward trend toward advanced age. We interpret these data in terms of structure formation followed by its stabilization and eventual deterioration. Furthermore, gender data analysis has uncovered the existence of functional differences, showing male Gibbs function values lower than female at prenatal and neonatal ages, which become higher at ages 8 to 40 and finally converging at late adulthood with the corresponding female Gibbs functions
Structure based modeling of small molecules binding to the TLR7 by atomistic level simulations
No full textToll-Like Receptors (TLR) are a large family of proteins involved in the immune system response. Both the activation and the inhibition of these receptors can have positive effects on several diseases, including viral pathologies and cancer, therefore prompting the development of new compounds. In order to provide new indications for the design of Toll-Like Receptor 7 (TLR7)-targeting drugs, the mechanism of interaction between the TLR7 and two important classes of agonists (imidazoquinoline and adenine derivatives) was investigated through docking and Molecular Dynamics simulations. To perform the computational analysis, a new model for the dimeric form of the receptors was necessary and therefore created. Qualitative and quantitative differences between agonists and inactive compounds were determined. The in silico results were compared with previous experimental observations and employed to define the ligand binding mechanism of TLR7
Personalized anticancer therapy selection using molecular landscape topology and thermodynamics
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