Mitoxantrone changes spectrin-aminophospholipid interactions

Understanding drug-membrane and drug-membrane protein interactions would be a crucial step towards understanding the action and biological properties of anthracyclines, as the cell membrane with its integral and peripheral proteins is the first barrier encountered by these drugs. In this paper, we briefly describe mitoxantrone-monolayer and mitoxantrone-bilayer interactions, focusing on the effect of mitoxantrone on the interactions between erythroid or nonerythroid spectrin with phosphatidylethanolamine-enriched mono- and bilayers. We found that mitoxantrone markedly modifies the interaction of erythroid and nonerythroid spectrins with phosphatidylethanolamine/phosphatitydcholine (PE/PC) monolayers. The change in Δπ induced by spectrins is several-fold larger in the presence of 72?nM mitoxantrone than in its absence: spectrin/mitoxantrone complexes induced a strong compression of the monolayer. Spin-labelling experiments showed that spectrin/mitoxantrone complexes caused significant changes in the order parameter measured using a 5′-doxyl stearate probe in the bilayer, but they practically did not affect the mobility of 16′-doxyl stearate. These results indicate close-to-surface interactions/penetrations without significant effect on the mid-region of the hydrophobic core of the bilayer. The obtained apparent equilibrium dissociation constants indicated relatively similar mitoxantrone-phospholipid and mitoxantrone-spectrin (erythroid and nonerythroid) binding affinities. These results might in part, explain the effect of mitoxantrone on spectrin distribution in the living cells.     

High dietary salt decreases antioxidant defenses in the liver of fructose-fed insulin-resistant rats

In this study we investigated the hypothesis that a high-salt diet to hyperinsulinemic rats might impair antioxidant defense owing to its involvement in the activation of sodium reabsorption to lead to higher oxidative stress. Rats were fed a standard (CON), a high-salt (HS), or a high-fructose (HF) diet for 10 weeks after which, 50% of the animals belonging to the HF group were switched to a regimen of high-fructose and high-salt diet (HFS) for 10 more weeks, while the other groups were fed with their respective diets. Animals were then euthanized and their blood and liver were examined. Fasting plasma glucose was found to be significantly higher (approximately 50%) in fructose-fed rats than in the control and HS rats, whereas fat liver also differed in these animals, producing steatosis. Feeding fructose-fed rats with the high-salt diet triggered hyperinsulinemia and lowered insulin sensitivity, which led to increased levels of serum sodium compared to the HS group. This resulted in membrane perturbation, which in the presence of steatosis potentially enhanced hepatic lipid peroxidation, thereby decreasing the level of antioxidant defenses, as shown by GSH/GSSG ratio (HFS rats, 7.098±2.1 versus CON rats, 13.2±6.1) and superoxide dismutase (HFS rats, 2.1±0.05 versus CON rats, 2.3±0.1%), and catalase (HFS rats, 526.6±88.6 versus CON rats, 745.8±228.7 U/mg ptn) activities. Our results indicate that consumption of a salt-rich diet by insulin-resistant rats may lead to regulation of sodium reabsorption, worsening hepatic lipid peroxidation associated with impaired antioxidant defenses.     

Structure and content of pollutants in temporal surface sediments in small watersheds

ABSTRACT

Formation of gel-like surface sediments has been observed during spring and autumn in small watersheds in boreal areas with pH <5.7 and concentrations of humic substances above 3 mg L^?1. This structure efficiently accumulates dissolved, colloidal and particulate constituents. The gel consists of ferric (hydr)oxides and fulvic acid and has high viable counts of bacteria (notably Gallionella spp.) as well as fungal hyphae. The solid/solution distribution (log K_d; l kg^?1) for trace metals (Cd, Cu, Pb, V, Zn) ranges from 4 to 6.5 which indicate an efficient accumulation during periods with gel. The concentrations of adsorbable organic halogens in the gel were not different from forest soils in general.     

Modelling for rearrangement of fusiform initials during radial growth of the vascular cambium in Pinus sylvestris L.

In contrast to common belief, recent studies have confirmed that intrusive growth of fusiform cambial initials has a significant role in the rearrangement of the initials, but does not contribute to the cambial circumference increment. We observed a rapid rearrangement of cambial initials on a long series of transverse sections of the vascular cambium and the wood of a 50-year-old pine (Pinus sylvestris L.) tree. A comparison of cell arrangement in consecutive sections, as well as a critical analysis of tangential reconstructions, has confirmed that changes in cell locations in a group of cells on the tangential surface caused no change in the total tangential width of the whole group. Models illustrating changes in locations of the initials have been proposed, assuming that intrusive growth, which makes the growing initials intrude between the neighbouring initials and their immediate derivatives, is localized on the longitudinal edges of cells. We infer that intrusive growth of the cambial initials in P. sylvestris is not involved in the cambial circumference increment, but plays a significant role in the rearrangement of the initials, probably allowing for a relaxation of shearing strains generated during radial growth. The relationship of intrusive growth with the elimination of initials has been discussed with reference to the frequency of anticlinal divisions. It has been proposed that the occurrence of anticlinal divisions in excess over the actual requirement for increase in the cambial circumference could be due to internal shearing strains.     

Meeting report of the European mouse complex genetics network SYSGENET

The second scientific meeting of the European systems genetics network for the study of complex genetic human disease using genetic reference populations (SYSGENET) took place at the Center for Cooperative Research in Biosciences in Bilbao, Spain, December 10–12, 2012. SYSGENET is funded by the European Cooperation in the Field of Scientific and Technological Research (COST) and represents a network of scientists in Europe that use mouse genetic reference populations (GRPs) to identify complex genetic factors influencing disease phenotypes (Schughart, Mamm Genome 21:331–336, 2010). About 50 researchers working in the field of systems genetics attended the meeting, which consisted of 27 oral presentations, a poster session, and a management committee meeting. Participants exchanged results, set up future collaborations, and shared phenotyping and data analysis methodologies. This meeting was particularly instrumental for conveying the current status of the US, Israeli, and Australian Collaborative Cross (CC) mouse GRP. The CC is an open source project initiated nearly a decade ago by members of the Complex Trait Consortium to aid the mapping of multigenetic traits (Threadgill, Mamm Genome 13:175–178, 2002). In addition, representatives of the International Mouse Phenotyping Consortium were invited to exchange ongoing activities between the knockout and complex genetics communities and to discuss and explore potential fields for future interactions.     

High genetic diversity in southwest Asian populations of Philaenus spumarius (Hemiptera: Auchenorrhyncha)

The genus Philaenus is one of the best investigated among Auchenorrhyncha, and several morphological, ecological, karyological, and molecular data have led to a designation of up to 10 species, distributed mainly in the Mediterranean and south-western Asia. The only widespread Palaearctic species, P. spumarius, is known to be structured phylogeographically as it consists of two highly divergent mitochondrial clades (northeast, NE and southwest, SW), with several subclades. This study contributes to the species phylogeography through the study of the genetic diversity and affinity of P. spumarius populations from southwestern Asia. Mitochondrial DNA (cytochrome B) show a high level of genetic diversity within Turkish and Iranian populations, the majority of which belong to the SW clade, and only single populations from northeastern Turkey are found to be substantially highly divergent lineages within the NE clade. One of the NE populations also showed significant differences in the distribution and amount of heterochromatin compared to other populations. According to the results of this study and previous phylogenetic and phylogeographic works on this species, we conclude that Southwestern Asia is probably the place of origin of the Philaenus spumarius.     

Quinacrine reactivity with prion proteins and prion-derived peptides

Quinacrine is a drug that is known to heal neuronal cell culture infected with prions, which are the causative agents of neurodegenerative diseases called transmissible spongiform encephalopathies. However, the drug fails when it is applied in vivo. In this work, we analyzed the reason for this failure. The drug was suggested to “covalently” modify the prion protein via an acridinyl exchange reaction. To investigate this hypothesis more closely, the acridine moiety of quinacrine was covalently attached to the thiol groups of cysteines belonging to prion-derived peptides and to the full-length prion protein. The labeled compounds were conveniently monitored by fluorescence and absorption spectroscopy in the ultraviolet and visible spectral regions. The acridine moiety demonstrated characteristic UV–vis spectrum, depending on the substituent at the C-9 position of the acridine ring. These results confirm that quinacrine almost exclusively reacts with the thiol groups present in proteins and peptides. The chemical reaction alters the prion properties and increases the concentration of the acridine moiety in the prion protein.     

Neuroprotective role of taurine during aging

Aging of the brain is characterized by several neurochemical modifications involving structural proteins, neurotransmitters, neuropeptides and related receptors. Alterations of neurochemical indices of synaptic function are indicators of age-related impairment of central functions, such as locomotion, memory and sensory performances. Several studies demonstrate that ionotropic GABA receptors, glutamate decarboxylase (GAD), and somatostatinergic subpopulations of GABAergic neurons are markedly decreased in experimental animal brains during aging. Additionally, levels of several neuropeptides co-expressed with GAD decrease during aging. Thus, the age-related decline in cognitive functions could be attributable, at least in part, to decrements in GABA inhibitory neurotransmission. In this study, we showed that chronic supplementation of taurine to aged mice significantly ameliorated the age-dependent decline in spatial memory acquisition and retention. We also demonstrated that concomitant with the amelioration in cognitive function, taurine caused significant alterations in the GABAergic and somatostatinergic system. These changes included (1) increased levels of the neurotransmitters GABA and glutamate, (2) increased expression of both isoforms of GAD (65 and 67) and the neuropeptide somatostatin, (3) decreased hippocampal expression of the β3 subunits of the GABA_A receptor, (4) increased expression in the number of somatostatin-positive neurons, (5) increased amplitude and duration of population spikes recorded from CA1 in response to Schaefer collateral stimulation and (6) enhanced paired pulse facilitation in the hippocampus. These specific alterations of the inhibitory system caused by taurine treatment oppose those naturally occurring in the aging brain, suggesting a protective role of taurine in this process. An increased understanding of age-related neurochemical changes in the GABAergic system will be important in elucidating the underpinnings of the functional changes of aging. Taurine supplementation might help forestall the age-related decline in cognitive functions through interaction with the GABAergic system.     

Small molecules interacting with α-synuclein: antiaggregating and cytoprotective properties

Curcumin, a dietary polyphenol, has shown a potential to act on the symptoms of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, as a consequence of its antioxidant, anti-inflammatory and anti-protein aggregation properties. Unfortunately, curcumin undergoes rapid degradation at physiological pH into ferulic acid, vanillin and dehydrozingerone, making it an unlikely drug candidate. Here, we evaluated the ability of some curcumin by-products: dehydrozingerone (1), its O-methyl derivative (2), zingerone (3), and their biphenyl analogues (4–6) to interact with α-synuclein (AS), using CD and fluorescence spectroscopy. In addition, the antioxidant properties and the cytoprotective effects in rat pheochromocytoma (PC12) cells prior to intoxication with H₂O₂, MPP+ and MnCl₂ were examined while the Congo red assay was used to evaluate the ability of these compounds to prevent aggregation of AS. We found that the biphenyl zingerone analogue (6) interacts with high affinity with AS and also displays the best antioxidant properties while the biphenyl analogues of dehydrozingerone (4) and of O-methyl-dehydrozingerone (5) are able to partially inhibit the aggregation process of AS, suggesting the potential role of a hydroxylated biphenyl scaffold in the design of AS aggregation inhibitors.