Biological interaction of alginetin

Alginetin is the major product formed from pentoses and hexurionic acids. Alginetin is producted by cooking process of food including pection, a naturally-occurring polysacharride found in many plants. However, the biological interaction and toxicity of alginetin are not known at all. The aim of the present study was to investigate the cellular actions of alginetin on rat thymic lymphocytes. The effects of alginetin on the cell were examined using flow cytometry with fluorescent probes. Alginetin increased cellular content of non-protein thiols ([NPT]i) and elevated intracellular Zn2+ levels ([Zn2+]i). Chelation of intracellular Zn2+ reduced the effect of alginetin on [NPT]i, and chelation of external Zn2+ almost completely diminished alginetin-induced elevation of [Zn2+]i, indicating that alginetin treatment increased Zn2+ influx. Increased [NPT]i and [Zn2+]i levels in response to alginetin were positively correlated. Alginetin protected cells against oxidative stress induced by hydrogen peroxide and Ca2+ overload by calcium ionophore. It is considered that the increases in [NPT]i and [Zn2+]i are responsible for the cytoprotective activity of alginetin because NPT attenuates oxidative stress and Zn2+ competes with Ca2+. Alginetin may be produced during manufacturing of jam, which may provide additional health benefits of jam

Conflicting actions of 4-vinylcatechol in rat lymphocytes under oxidative stress induced by hydrogen peroxide

4-Vinylcatechol (4VC) has been identified as an aroma compound in roasted foods, especially coffee. It is also a component in traditional herbal medicines. This compound may be subconsciously ingested through foods and herbs. Recent experimental evidence has shown that 4VC possesses an antioxidative action. However, the antioxidative action of 4VC at cellular levels is not well characterized. The effects of 4VC (0.1–100 μM) were examined on rat thymic lymphocytes without and with oxidative stress induced by 300 μM hydrogen peroxide (H2O2). Cell treatment with 100 μM 4VC alone for 4 hr significantly increased the population of dead cells. Thus, 4VC at 100 μM or above elicits cytotoxicity. However, 4VC at sublethal concentrations (1–10 μM) significantly attenuated the H2O2-induced increase in cell lethality in a concentration-dependent manner. While application of 10 μM 4VC slowed the process of cell death induced by H2O2, 4VC did not antagonize the H2O2-induced reduction of cellular nonprotein thiols. Although 4VC at 10 μM did not affect intracellular Ca2+ and Zn2+ levels, the agent potentiated the H2O2-induced increases in these levels. These actions of 10 μM 4VC are adverse to the cells under the oxidative stress. However, 10 μM 4VC partly attenuated the cell death induced by 100 nM A23187, a calcium ionophore. There are conflicting actions of 4VC at 1–100 μM on the cells under oxidative stress although the agent is used for an antioxidant. Thus, caution is required when using 4VC as a therapeutic agent

Zinc-dependent and independent actions of hydroxyhydroquinone

Coffee contains hydroxyhydroquinone (HHQ). HHQ is one of by-products released during bean roasting. Therefore, it is important to elucidate the bioactivity of HHQ to predict its beneficial or adverse effects on humans. We studied zinc-dependent and independent actions of commercially-procured synthetic HHQ in rat thymocytes using flow cytometric techniques with propidium iodide, FluoZin-3-AM, 5-chloromethylfluorescein diacetate, and annexin V-FITC. HHQ at 1050 μM elevated intracellular Zn2+ levels by releasing intracellular Zn2+. HHQ at 10 μM increased cellular thiol content in a Zinc-dependent manner. However, HHQ at 30–50 μM reduced cellular thiol content. Although the latter actions of HHQ (30–50 μM) were suggested to increase cell vulnerability to oxidative stress, HHQ at 0.3–100 μM significantly protected cells against oxidative stress induced by H2O2. The process of cell death induced by H2O2 was delayed by HHQ, although both H2O2 and HHQ increased the population of annexin V-positive living cells. However, HHQ at 10–30 μM promoted cell death induced by A23187, a calcium ionophore. HHQ at 10–30 μM exerted contrasting effects on cell death caused by oxidative stress and Ca2+ overload. Because HHQ is considered to possess diverse cellular actions, coffee with reduced amount of HHQ may be preferable to avoid potential adverse effects

Hydroxyhydroquinone, a by-product of coffee bean roasting, increases intracellular Ca2+ concentration in rat thymic lymphocytes

Hydroxyhydroquinone (HHQ) is generated during coffee bean roasting. A cup of coffee contains 0.1–1.7 mg of HHQ. The actions of HHQ on mammalian DNA were examined because HHQ is a metabolite of benzene, which causes leukemia. Currently, information on the cellular actions of HHQ is limited. We examined the effects of sublethal levels of HHQ on the concentration of intracellular Ca2+ in rat thymic lymphocytes by using a flow cytometric technique with fluorescent probes. HHQ at 10 μM or more significantly elevated intracellular Ca2+ levels by increasing the membrane permeability of divalent cations, resulting in hyperpolarization via the activation of Ca2+-dependent K+ channels. HHQ-induced changes in the intracellular Ca2+ concentration and membrane potential may affect the cell functions of lymphocytes. HHQ-reduced coffee may be preferable in order to avoid the possible adverse effects of HHQ

NMR relaxation rate in the field-induced octupolar liquid phase of spin-1/2 J1-J2 frustrated chains

In the spin-1/2 frustrated chain with nearest-neighbor ferromagnetic exchange J1 and next-nearest-neighbor antiferromagnetic exchange J2 under magnetic field, magnetic multipolar-liquid (quadrupolar, octupolar, and hexadecapolar) phases are widely expanded from the saturation down to a low-field regime. Recently, we have clarified characteristic temperature and field dependence of the NMR relaxation rate 1/T_1 in the quadrupolar phase. In this paper, we examine those of 1/T_1 in the octupolar phase combining field theoretical method with numerical data. The relevance of the results to quasi one-dimensional J1-J2 magnets such as PbCuSO4(OH)2, Rb2Cu2Mo3O12 and Li2ZrCuO4 is shortly discussed.Comment: 6 pages (1 column), 3 figure

Disorganization of Semantic Brain Networks in Schizophrenia Revealed by fMRI

OBJECTIVES: Schizophrenia is a mental illness that presents with thought disorders including delusions and disorganized speech. Thought disorders have been regarded as a consequence of the loosening of associations between semantic concepts since the term "schizophrenia" was first coined by Bleuler. However, a mechanistic account of this cardinal disturbance in terms of functional dysconnection has been lacking. To evaluate how aberrant semantic connections are expressed through brain activity, we characterized large-scale network structures of concept representations using functional magnetic resonance imaging (fMRI). STUDY DESIGN: We quantified various concept representations in patients' brains from fMRI activity evoked by movie scenes using encoding modeling. We then constructed semantic brain networks by evaluating the similarity of these semantic representations and conducted graph theory-based network analyses. STUDY RESULTS: Neurotypical networks had small-world properties similar to those of natural languages, suggesting small-worldness as a universal property in semantic knowledge networks. Conversely, small-worldness was significantly reduced in networks of schizophrenia patients and was correlated with psychological measures of delusions. Patients' semantic networks were partitioned into more distinct categories and had more random within-category structures than those of controls. CONCLUSIONS: The differences in conceptual representations manifest altered semantic clustering and associative intrusions that underlie thought disorders. This is the first study to provide pathophysiological evidence for the loosening of associations as reflected in randomization of semantic networks in schizophrenia. Our method provides a promising approach for understanding the neural basis of altered or creative inner experiences of individuals with mental illness or exceptional abilities, respectively

Liquid-crystalline phase transition in organophosphazenes

Organophosphazenes with a similar mesogenic moiety were prepared and their mesogenicity was studied by differential scanning calorinetry (DSC) measurements and polarizing microsope observations. In cyclotriphosphazenes with alk-­oxybiphenyl and Schiff base moieties, mesomorphic phase transitions were observed, but no mesomorphic phase was observed for the corresponding cyclotetraphosphazenes. In polyphos-­phazenes with an alkoxybiphenyl moiety, no mesomorphic phase was observed. The molecular structure of cyclotriphosphazenes facilitated the formation of a mesomorphic layer structure; in contrast, the formation of a mesomorphic layer structure did not occur in cyclotetraphosphazenes and polyphosphazenes, even though they bore a similar mesogenic moiety. Moreover, in cyclotriphosphazenes with an optically active alkoxybiphenyl group, a smectic C* phase was observed. The spontaneous polarization of the compound was −190 μ C m −2 at 436 K in 25 μ in cell using the triangular-wave method. © 1998 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38314/1/785_ftp.pd

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81–127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81–127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure of TTR ex vivo in patient plasma. We conclude that our TTR81–127–based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis

Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice

We herein provide a thorough description of new transgenic mouse models for dentatorubral–pallidoluysian atrophy (DRPLA) harboring a single copy of the full-length human mutant DRPLA gene with 76 and 129 CAG repeats. The Q129 mouse line was unexpectedly obtained by en masse expansion based on the somatic instability of 76 CAG repeats in vivo. The mRNA expression levels of both Q76 and Q129 transgenes were each 80% of that of the endogenous mouse gene, whereas only the Q129 mice exhibited devastating progressive neurological phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiological studies of the Q129 mice demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and γ-aminobutyrate type A receptors in CA1 neurons were also observed. Neuropathological studies of the Q129 mice revealed progressive brain atrophy, but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyglutamine stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analyses demonstrated age-dependent down-regulation of genes, including those relevant to synaptic functions and CREB-dependent genes. These results suggest that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. Thus, our Q129 mice should be highly valuable for investigating the mechanisms of disease pathogenesis and therapeutic interventions