Synthesis of Macrocyclic Hexaoxazole (6OTD) Dimers, Containing Guanidine and Amine Functionalized Side Chains, and an Evaluation of Their Telomeric G4 Stabilizing Properties

Structure-activity relationship studies were carried out on macrocyclic hexaoxazole (6OTD) dimers, whose core structure stabilizes telomeric G-quadruplexes (G4). Two new 6OTD dimers having side chain amine and guanidine functional groups were synthesized and evaluated for their stabilizing ability against a telomeric G4 DNA sequence. The results show that the 6OTD dimers interact with the DNA to form 1:1 complexes and stabilize the antiparallel G4 structure of DNA in the presence of potassium cation. The guanidine functionalized dimer displays a potent stabilizing ability of the G4 structure, as determined by using a FRET melting assay (ΔTm = 14°C)

Structure-Function of Serotonin in Bivalve Molluscs

It has been observed that 5-HT excites the heart nerves in hard clam and regulates contraction and relaxation of the anterior byssus retractor muscle in the blue mussel. It is now known that 5-HT regulates several neurobehavioral systems such as mood, appetite, sleep, learning, and memory. It also plays critical roles in the physiological functions of peripheral organs involved in stress, growth, and reproduction in the animal kingdom. The present study reviews conserved 5-HT biosynthesis and its localization in the nervous system, and its physiological contribution to regulate reproduction in bivalves. In the cytosol of neurons, tryptophan hydroxylase catalyzes hydroxylation of l-tryptophan to 5-hydroxytryptophan, which is converted to 5-HT by aromatic l-amino acid decarboxylase. A 5-HT transporter and a monoamine oxidase reuptakes and metabolizes 5-HT to control the amount of released 5-HT in the nervous system and peripheral organs. Perikarya and fibers of 5-HT neurons are mostly located in the cortices and neuropil of ganglia, respectively, and innervate the gonad. However, distribution and 5-HT content differ among species and sexes and undergo seasonal variations associated with gonadal development. The present review pays a special attention to future research perspectives to better understand 5-HT regulation of reproduction in bivalves

Pharmacology and Molecular Identity of Serotonin Receptor in Bivalve Mollusks

It is now known that 5-HT regulates several neurobehavioral systems such as mood, appetite, sleep, learning, and memory. It also plays critical roles in the physiological functions of peripheral organs involved in stress, growth, and reproduction in the animal kingdom. 5-HT content has seen to be higher in the nervous system of bivalves than those of other examined invertebrates and vertebrates. Thus, bivalves have been considered as an excellent model to investigate 5-HT functions in neurological and peripheral systems. The present study reviews knowledge on 5-HT signaling mediated through 5-HT receptor and its physiological contribution to regulate reproduction in bivalves. Two G-protein-coupled 5-HT1-like receptors have been cloned in bivalve species. However, binding affinities of the 5-HT agonists and antagonists to the isolated plasma membrane proteins and their effects on spawning in bivalves suggest the presence of a single or mixed 5-HT1-, 5-HT2-, and 5-HT3-like receptors. It has suggested that the 5-HT-like receptors in bivalves are distinct from those of mammalian 5-HT receptors due to pharmacological properties. The present review pays a special attention to future research perspectives to better understand 5-HT regulation of reproduction in bivalves, which can provide us with satisfactory knowledge to elucidate reproductive disorders associated with dysfunctions of the neurotransmitter system

Molybdenum sources and transport in the Alcator C-Mod tokamak

Additional file 6. Luciferase reporter assay results with or without L1H1-7OTD for G4 DNA sequences cloned in pGL4.23 vector

Inhibitory action of iron on erythropoietin via oxidative stress-HIF-2α pathway

Renal anemia is a major complication in chronic kidney disease (CKD). Iron supplementation, as well as erythropoiesis-stimulating agents, are widely used for treatment of renal anemia. However, excess iron causes oxidative stress via the Fenton reaction, and iron supplementation might damage remnant renal function including erythropoietin (EPO) production in CKD. EPO gene expression was suppressed in mice following direct iron treatment. Hypoxia-inducible factor-2 alpha (HIF-2α), a positive regulator of the EPO gene, was also diminished in the kidney of mice following iron treatment. Anemia-induced increase in EPO and HIF-2α expression was also inhibited by iron-treatment. In in vitro experiments using EPO-producing HepG2 cells, iron stimulation reduced the expression of the EPO gene, as well as HIF-2α. Moreover, iron treatment augmented oxidative stress, and iron-induced reduction of EPO and HIF-2α expression was restored by tempol, an anti-oxidant compound. HIF-2α interaction with the EPO promoter was inhibited by iron treatment, and was restored by tempol. These findings suggested that iron supplementation reduced EPO gene expression via an oxidative stress-HIF-2α-dependent signaling pathway

Iron accumulation causes impaired myogenesis correlated with MAPK signaling pathway inhibition by oxidative stress

Skeletal muscle atrophy is caused by disruption in the homeostatic balance of muscle degeneration and regeneration under various pathophysiological conditions. We have previously reported that iron accumulation induces skeletal muscle atrophy via a ubiquitin ligase-dependent pathway. However, the potential effect of iron accumulation on muscle regeneration remains unclear. To examine the effect of iron accumulation on myogenesis, we used a mouse model with cardiotoxin (CTX)-induced muscle regeneration in vivo and C2C12 mice myoblast cells in vitro. In mice with iron overload, the skeletal muscles exhibited increased oxidative stress and decreased expression of satellite cell markers. Following CTX-induced muscle injury, these mice also displayed delayed muscle regeneration with a decrease in the size of regenerating myofibers, reduced expression of myoblast differentiation markers, and decreased phosphorylation of mitogen-activated protein kinase signaling pathways. In vitro, iron overload also suppressed the differentiation of C2C12 myoblast cells, but the suppression could be reversed by superoxide scavenging using tempol. Excess iron inhibits myogenesis via oxidative stress, leading to an imbalance in skeletal muscle homeostasis

Effects of clozapine and N-desmethylclozapine on synaptic transmission at hippocampal inhibitory and excitatory synapses

Clozapine is the first atypical antipsychotic, and improves positive and negative symptoms of many patients with schizophrenia resistant to treatment with other antipsychotic agents. Clozapine induces minimal extrapyramidal side effects, but is more often associated with seizures. A large number of studies have been conducted to elucidate pharmacological profiles of clozapine and its major active metabolite, N-desmethylclozapine (NDMC). However, there are only a limited number of electrophysiological studies examining their effects on synaptic transmission. In this study, we examined effects of clozapine and NDMC on synaptic transmission by measuring inhibitory and excitatory postsynaptic currents in rat cultured hippocampal neurons. We found that clozapine and NDMC have qualitatively similar actions. They depressed the inhibitory transmission at 1-30 μM, and the excitatory transmission at 30 μM, the former being much more sensitive. The depression of IPSCs by 30 μM of these drugs was associated with an increase in the paired-pulse ratio. The GABA-induced currents were suppressed by these drugs, but less sensitive than IPSCs. The AMPA-induced currents were slightly potentiated by these drugs at 30 μM. At 30 μM, clozapine and NDMC slightly suppressed Ca2+ and Na+ channels. These results strongly suggest that clozapine and NMDC depress the inhibitory synaptic transmission mainly by antagonizing postsynaptic GABAA receptors, but at higher concentrations additionally by acting on presynaptic site, possibly in part through inhibition of presynaptic Ca2+ and Na+ channels. Preferential depression of inhibitory synaptic transmission by clozapine and NDMC might contribute to therapeutic actions and/or side-effects of clozapine. © 2011 Elsevier B.V. All rights reserved

Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice

Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD). Iron restriction exhibits protective effects against renal dysfunction; however, its effects against protein overload-induced tubulointerstitial damage remain unclear. Here, we investigated dietary iron restriction effect on tubulointerstitial damage in mice with protein-overload tubulointerstitial injury. Renal tubulointerstitial injury in animal model was induced by intraperitoneal injection of an overdose of bovine serum albumin (BSA). We divided mice into three groups: normal saline + normal diet (ND), BSA + ND, and BSA + iron-restricted diet (IRD). BSA overload induced renal tubulointerstitial injury in the ND mice, which was ameliorated in the IRD mice. Inflammatory cytokines and extracellular matrix mRNA expression was upregulated in BSA + ND mice kidneys and was inhibited by IRD. BSA-induced increase in renal superoxide production, NADPH oxidase activity, and p22phox expression was diminished in the IRD mice. IRD suppression increased BSA-induced renal macrophage infiltration. Moreover, BSA mice exhibited nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing protein (NLRP) inflammasome activation, which was inhibited by IRD. Ferrous iron increased in kidneys with BSA overload and was inhibited by IRD. Thus, iron restriction inhibited oxidative stress and inflammatory changes, contributing to the protective effect against BSA overload-induced tubulointerstitial injury

サボニウス風車の出力特性の改善

This paper describes an experimental study on improvement in output characteristics of Savonius wind turbine using guide vanes around the turbine rotor. One or two flat or curved vanes are used in this experiment. When one guide vane is properly placed in front of the turbine rotor, the maximum wind turbine output increased to about 1.2 times compared with that without guide vane. Furthermore, when two guide vanes are properly placed around the rotor, wind turbine output increased about 1.4 times compared with that without guide vane. To know the reason why such increase of the turbine output occurs, flow visualization was done about those flows. These results of the flow visualization showed that one guide vane placed in front of the. returning side of the rotor blade blocks the flow to the rotor, and another vane placed near the forward going rotor blade deflects flow to the rotor. The former vane decreases counter force to the blade and the latter one concentrates flow to the rotor, as the result wind turbine torque increases

A pH-Adjustable Tissue Clearing Solution That Preserves Lipid Ultrastructures: Suitable Tissue Clearing Method for DDS Evaluation

Visualizing biological events and states to resolve biological questions is challenging. Tissue clearing permits three-dimensional multicolor imaging. Here, we describe a pH-adjustable tissue clearing solution, Seebest (SEE Biological Events and States in Tissues), which preserves lipid ultrastructures at an electron microscopy level. Adoption of polyethylenimine was required for a wide pH range adjustment of the tissue clearing solution.The combination of polyethylenimine and urea had a good tissue clearing ability for multiple tissues within several hours. Blood vessels stained with lipophilic carbocyanine dyes were deeply visible using the solution. Adjusting the pH of the solution was important to maximize the fluorescent intensity and suppress dye leakage during tissue clearing. The spatial distribution of doxorubicin and oxidative stress were observable using the solution. Moreover, spatial distribution of liposomes in the liver was visualized. Hence, the Seebest solution provides pH-adjustable, rapid, sufficient tissue clearing, while preserving lipid ultrastructures, which is suitable for drug delivery system evaluations