Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based ‘omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.
Antimicrobial textile products are developing rapidly as an important part of functional textiles.Silver nanoparticles (AgNPs) are nanotechnology products with antimicrobial properties. However, exposure to nanoparticles in daily life is an important issue for public health, still being updated. Aim was to evaluate the effects of AgNPs on the development of zebrafish embryos focusing on Wnt pathway, proliferation, oxidant-antioxidant status, and apoptosis. The expressions of ccnd1 and gsk3 were determined by RT-PCR, whereas -catenin and proliferative cell antigen (PCNA) expressions were determined immunohistochemically. Lipid peroxidation, superoxide dismutase, and glutathione-S-transferase activities were determined spectrophotometrically. Apoptosis was determined using acridine orange staining. Oxidant status, apoptosis, immunohistochemical PCNA, and catenin staining increased, whereas ccnd1 and antioxidant enzyme activities decreased in AgNPs-exposed embryos in a dose-dependent manner. Our results indicate the interaction of possible mechanisms that may be responsible for the toxic effects of AgNPs in zebrafish embryos.
Mesenchymal stem cells have the ability to transdifferentiate into neurons and therefore one of the potential adult stem cell source for neuronal tissue regeneration applications and understanding neurodevelopmental processes. In many studies on human mesenchymal stem cell (hMSC) derived neurons, success in neuronal differentiation was limited to neuronal protein expressions which is not statisfactory in terms of neuronal activity. Established neuronal networks seen in culture have to be investigated in terms of synaptic signal transmission ability to develop a culture model for human neurons and further studying the mechanism of neuronal differentiation and neurological pathologies. Accordingly, in this study, we analysed the functionality of bone marrow hMSCs differentiated into neurons by a single step cytokine-based induction protocol. Neurons from both primary hMSCs and hMSC cell line displayed spontaneous activity (�75%) as demonstrated by Ca ++ imaging. Furthermore, when electrically stimulated, hMSC derived neurons (hMd-Neurons) matched the response of a typical neuron in the process of maturation. Our results reveal that a combination of neuronal inducers enhance differentiation capacity of bone marrow hMSCs into high yielding functional neurons with spontaneous activity and mature into electrophysiologically active state. Conceptually, we suggest these functional hMd-Neurons to be used as a tool for disease modelling of neuropathologies and neuronal differentiation studies.
Purpose: Curcumin, a polyphenol isolated from the rhizomes of turmeric, holds great potential as a neuroprotective agent in addition to its anti-inflammatory and antioxidant characteristics. The poor bioavailability and low stability of curcumin are the greatest barriers to its clinical use. This study aims to investigate the neuroprotective effect of curcumin on axonal injury, by delivering the lipophilic polyphenol to a primary hippocampal neuron culture by means of a lipid-based drug delivery system, named emulsomes. Methods: To study neuroregeneration ex vivo, an injury model was established through single-cell laser axotomy on hippocampal neurites. Upon treatment with curcumin-loaded emulsomes (CurcuEmulsomes), curcumin and CurcuEmulsome uptake into neurons was verified by three-dimensional Z-stack images acquired with confocal microscopy. Neuron survival after axonal injury was tracked by propidium iodide (PI) and Hoechst staining. Alterations in expression levels of physiological markers, such as anti-apoptotic marker Bcl2, apoptotic marker cleaved caspase 3, neuroprotective marker Wnt3a and the neuronal survival marker mTOR, were investigated by immunocytochemistry analyses. Results: The results indicated significant improvement in the survival rate of injured neurons upon CurcuEmulsome treatment. Bcl2 expression was significantly higher for injured neurons treated with curcumin or CurcuEmulsome. Reduction in caspase 3 expression was seen in both curcumin and CurcuEmulsome treatment, whereas there were no significant changes in Wnt3a and mTOR expression. Conclusion: The established laser-axotomy model was proven as a reliable methodology to study neurodegenerative models ex vivo. CurcuEmulsomes delivered curcumin to primary hippocampal neurons successfully. Treated with CurcuEmulsomes, injured hippocampal neurons benefit from the neuroprotective effects of curcumin, exhibiting a higher survival rate and increased anti-apoptotic marker levels.
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