Striatal Dopamine Transmission Is Subtly Modified in Human A53Tα-Synuclein Overexpressing Mice

Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn), cause familial Parkinson's disease (PD). Mouse lines overexpressing the mutant human A53Tα-syn may represent a model of early PD. They display progressive motor deficits, abnormal cellular accumulation of α-syn, and deficits in dopamine-dependent corticostriatal plasticity, which, in the absence of overt nigrostriatal degeneration, suggest there are age-related deficits in striatal dopamine (DA) signalling. In addition A53Tα-syn overexpression in cultured rodent neurons has been reported to inhibit transmitter release. Therefore here we have characterized for the first time DA release in the striatum of mice overexpressing human A53Tα-syn, and explored whether A53Tα-syn overexpression causes deficits in the release of DA. We used fast-scan cyclic voltammetry to detect DA release at carbon-fibre microelectrodes in acute striatal slices from two different lines of A53Tα-syn-overexpressing mice, at up to 24 months. In A53Tα-syn overexpressors, mean DA release evoked by a single stimulus pulse was not different from wild-types, in either dorsal striatum or nucleus accumbens. However the frequency responsiveness of DA release was slightly modified in A53Tα-syn overexpressors, and in particular showed slight deficiency when the confounding effects of striatal ACh acting at presynaptic nicotinic receptors (nAChRs) were antagonized. The re-release of DA was unmodified after single-pulse stimuli, but after prolonged stimulation trains, A53Tα-syn overexpressors showed enhanced recovery of DA release at old age, in keeping with elevated striatal DA content. In summary, A53Tα-syn overexpression in mice causes subtle changes in the regulation of DA release in the striatum. While modest, these modifications may indicate or contribute to striatal dysfunction

Molecular psychiatry of zebrafish

Due to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling central nervous system (CNS) disorders. In particular, we outline recent genetic and technological developments allowing for in vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern molecular psychiatry research

Neurotransmitter Detection Using Corona Phase Molecular Recognition on Fluorescent Single-Walled Carbon Nanotube Sensors

ABSTRACT: Temporal and spatial changes in neurotransmitter concentrations are central to information processing in neural networks. Therefore, biosensors for neurotransmitters are essential tools for neuroscience. In this work, we applied a new technique, corona phase molecular recognition (CoPhMoRe), to identify adsorbed polymer phases on fluorescent single-walled carbon nanotubes (SWCNTs) that allow for the selective detection of specific neurotransmitters, including dopamine. We functionalized and suspended SWCNTs with a library of different polymers (n = 30) containing phospholipids, nucleic acids, and amphiphilic polymers to study how neurotransmitters modulate the resulting band gap, near-infrared (nIR) fluorescence of the SWCNT. We identified several corona phases that enable the selective detection of neurotransmitters. Catecholamines such as dopamine increased the fluorescence of specific single-stranded DNA- and RNA-wrapped SWCNTs by 58−80 % upon addition of 100 μM dopamine depending on the SWCNT chirality (n,m). In solution, the limit of detection was 11 nM [Kd = 433 nM for (GT)15 DNA-wrapped SWCNTs]. Mechanistic studies revealed that this turn-on response is due to an increase in fluorescence quantum yield and not covalent modification of the SWCNT or scavenging o

Investigation of Self-Diffusion of Titanium by Fluctuation Autocorrelation Method

Diffusion of titanium was examined in the field emission microscope using the fluctuation autocorrelation method. A thick titanium layer (about three monolayers) deposited on a tungsten tip was used. A temperature range of 1260-1410 K was found where diffusion can be described in a hydrodynamic approximation. In this temperature range the diffusion coefficient seems to comply with Arrhenius rule for the activation energy of 1.31 eV and D$\text{}_{0}$ = 3×10$\text{}^{-7}$ cm$\text{}^{2}$s

Anacardic acid enhances the anticancer activity of liposomal mitoxantrone towards melanoma cell lines – in vitro studies [Corrigendum]

Anacardic acid enhances the anticancer activity of liposomal mitoxantrone towards melanoma cell lines – in vitro studies [Corrigendum]Legut M, Lipka D, Filipczak N, et al. Int J Nanomedicine. 2014;9:653–668.The authors advise the Acknowledgment on page 666 is missing the final sentence:This study was supported by: the Wrocław Research Centre EIT+ under the Biotechnologies and Advanced Medical Technologies project; BioMed (POIG.01.01.02-02-003/08), financed by the European Regional Development Fund (Operational Programme Innovative Economy, 1.1.2) #8221.Read the original articl

Vitamin C-driven epirubicin loading into liposomes

Dominik Lipka,1 Jerzy Gubernator,1 Nina Filipczak,1 Sabine Barnert,2 Regine Süss,2 Mateusz Legut,1 Arkadiusz Kozubek1 1Department of Lipids and Liposomes, University of Wroclaw, Wroclaw, Poland; 2Department of Pharmaceutical Technology, Albert Ludwigs University, Freiburg, Germany Abstract: The encapsulation of anticancer drugs in a liposome structure protects the drug during circulation and increases drug accumulation in the cancer tissue and antitumor activity while decreasing drug toxicity. This paper presents a new method of active drug loading based on a vitamin C pH/ion gradient. Formulations were characterized in terms of the following parameters: optimal external pH, time and drug-to-lipid ratio for the purpose of remote loading, and in vitro stability. In the case of the selected drug, epirubicin (EPI), its coencapsulation increases its anticancer activity through a possibly synergistic effect previously reported by other groups for a free nonencapsulated drug/vitamin C cocktail. The method also has another advantage over other remote-loading methods: it allows faster drug release through liposome destabilization at the tumor site, thanks to the very good solubility of the EPI vitamin C salt, as seen on cryogenic transmission electron microscopy images. This influences the drug-release process and increases the anticancer activity of the liposome formulation. The liposomes are characterized as stable, with very good pharmacokinetics (half-life 18.6 hours). The antitumor activity toward MCF-7 and 4T-1 breast cancer cells was higher in the case of EPI loaded via our gradient than via an ammonium sulfate gradient. Finally, the EPI liposomal formulation and the free drug were tested using the murine 4T-1 breast cancer model. The antitumor activity of the encapsulated drug was confirmed (tumor-growth inhibition over 40% from day 16 until the end of the experiment), and the free drug was shown to have no anticancer activity at the tested dose. Keywords: liposomes, epirubicin, vitamin C, antitumor activity, remote loading, ascorbic aci

Novel Liposomal Formulation of Baicalein for the Treatment of Pancreatic Ductal Adenocarcinoma: Design, Characterization, and Evaluation

Pancreatic cancer (PC) is one of the deadliest cancers so there is an urgent need to develop new drugs and therapies to treat it. Liposome-based formulations of naturally-derived bioactive compounds are promising anticancer candidates due to their potential for passive accumulation in tumor tissues, protection against payload degradation, and prevention of non-specific toxicity. We chose the naturally-derived flavonoid baicalein (BAI) due to its promising effect against pancreatic ductal adenocarcinoma (PDAC) and encapsulated it into a liposomal bilayer using the passive loading method, with an almost 90% efficiency. We performed a morphological and stability analysis of the obtained BAI liposomal formulation and evaluated its activity on two-dimensional and three-dimensional pancreatic cell models. As the result, we obtained a stable BAI-encapsulated liposomal suspension with a size of 100.9 nm ± 2.7 and homogeneity PDI = 0.124 ± 0.02, suitable for intravenous administration. Furthermore, this formulation showed high cytotoxic activity towards AsPC-1 and BxPC-3 PDAC cell lines (IC50 values ranging from 21 ± 3.6 µM to 27.6 ± 4.1 µM), with limited toxicity towards normal NHDF cells and a lack of hemolytic activity. Based on these results, this new BAI liposomal formulation is an excellent candidate for potential anti-PDAC therapy