Speech illusions and working memory performance in non-clinical psychosis.

Psychotic disorders are characterized by auditory verbal hallucinations (AVHs), and research has shown that AVHs are linked to deficits in working memory. Our understanding of AVHs across the psychosis continuum is limited. To date, little research has tested whether hallucination proneness (HP) is linked with abnormalities on experimental multispeaker babble tasks. Few investigations have been conducted to determine how task performance might be linked to cognitive functioning. The objective of the current study is to better understand this empirical gap. A total of 70 adults (30 healthy controls and 40 HP individuals) were administered an experimental task in which they listened to multispeaker babble and were instructed to report any words or chains of consecutive words (CCWs) perceived. Participants also were administered nonverbal and verbal working memory tasks. Findings revealed that relative to the control group, the HP individuals perceived more words and longer CCWs during the task. While there were no significant differences in working memory tasks between the HP and control groups, longer CCW's were associated with decreased verbal working memory scores in the HP group. AVH proneness may occur across a continuum of psychosis and may be linked with other theoretically relevant cognitive vulnerability factors.

Green tea polyphenols precondition against cell death induced by oxygen-glucose deprivation via stimulation of laminin receptor, generation of reactive oxygen species, and activation of protein kinase Cε.

As the development of synthetic drugs for the prevention of stroke has proven challenging, utilization of natural products capable of preconditioning neuronal cells against ischemia-induced cell death would be a highly useful complementary approach. In this study using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in PC12 cells, we show that 2-day pretreatment with green tea polyphenols (GTPP) and their active ingredient, epigallocatechin-3-gallate (EGCG), protects cells from subsequent OGD/R-induced cell death. A synergistic interaction was observed between GTPP constituents, with unfractionated GTPP more potently preconditioning cells than EGCG. GTPP-induced preconditioning required the 67-kDa laminin receptor (67LR), to which EGCG binds with high affinity. 67LR also mediated the generation of reactive oxygen species (ROS) via activation of NADPH oxidase. An exogenous ROS-generating system bypassed 67LR to induce preconditioning, suggesting that sublethal levels of ROS are indeed an important mediator in GTPP-induced preconditioning. This role for ROS was further supported by the fact that antioxidants blocked GTPP-induced preconditioning. Additionally, ROS induced an activation and translocation of protein kinase C (PKC), particularly PKCε from the cytosol to the membrane/mitochondria, which was also blocked by antioxidants. The crucial role of PKC in GTPP-induced preconditioning was supported by use of its specific inhibitors. Preconditioning was increased by conditional overexpression of PKCε and decreased by its knock-out with siRNA. Collectively, these results suggest that GTPP stimulates 67LR and thereby induces NADPH oxidase-dependent generation of ROS, which in turn induces activation of PKC, particularly prosurvival isoenzyme PKCε, resulting in preconditioning against cell death induced by OGD/R.

Green tea polyphenols potentiate the action of nerve growth factor to induce neuritogenesis: possible role of reactive oxygen species.

Exogenously administered nerve growth factor (NGF) repairs injured axons, but it does not cross the blood-brain barrier. Thus, agents that could potentiate the neuritogenic ability of endogenous NGF would be of great utility in treating neurological injuries. Using the PC12 cell model, we show here that unfractionated green tea polyphenols (GTPP) at low concentrations (0.1 µg/ml) potentiate the ability of low concentrations of NGF (2 ng/ml) to induce neuritogenesis at a level comparable to that induced by optimally high concentrations of NGF (50 ng/ml) alone. In our experiments, GTPP by itself did not induce neuritogenesis or increase immunofluorescent staining for ß-tubulin III; however, it increased expression of mRNA and proteins for the neuronal markers neurofilament-L and GAP-43. Among the polyphenols present in GTPP, epigallocatechin-3-gallate (EGCG) alone appreciably potentiated NGF-induced neurite outgrowth. Although other polyphenols present in GTPP, particularly epigallocatechin and epicatechin, lack this activity, they synergistically promoted this action of EGCG. GTPP also induced an activation of extracellular signal-regulated kinases (ERKs). PD98059, an inhibitor of the ERK pathway, blocked the expression of GAP-43. K252a, an inhibitor of TrkA-associated tyrosine kinase, partially blocked the expression of these genes and ERK activation. Antioxidants, catalase (cell-permeable form), and N-acetylcysteine (both L and D-forms) inhibited these events and abolished the GTPP potentiation of NGF-induced neuritogenesis. Taken together, these results show for the first time that GTPP potentiates NGF-induced neuritogenesis, likely through the involvement of sublethal levels of reactive oxygen species, and suggest that unfractionated GTPP is more effective in this respect than its fractionated polyphenols.

Locally generated methylseleninic acid induces specific inactivation of protein kinase C isoenzymes: relevance to selenium-induced apoptosis in prostate cancer cells.

In this study, we show that methylselenol, a selenometabolite implicated in cancer prevention, did not directly inactivate protein kinase C (PKC). Nonetheless, its oxidation product, methylseleninic acid (MSA), inactivated PKC at low micromolar concentrations through a redox modification of vicinal cysteine sulfhydryls in the catalytic domain of PKC. This modification of PKC that occurred in both isolated form and in intact cells was reversed by a reductase system involving thioredoxin reductase, a selenoprotein. PKC isoenzymes exhibited variable sensitivity to MSA with Ca(2+)-dependent PKC isoenzymes (alpha, beta, and gamma) being the most susceptible, followed by isoenzymes delta and epsilon. Other enzymes tested were inactivated only with severalfold higher concentrations of MSA than those required for PKC inactivation. This specificity for PKC was further enhanced when MSA was generated within close proximity to PKC through a reaction of methylselenol with PKC-bound lipid peroxides in the membrane. The MSA-methylselenol redox cycle resulted in the catalytic oxidation of sulfhydryls even with nanomolar concentrations of selenium. MSA inhibited cell growth and induced apoptosis in DU145 prostate cancer cells at a concentration that was higher than that needed to inhibit purified PKC alpha but in a range comparable with that required for the inhibition of PKC epsilon. This MSA-induced growth inhibition and apoptosis decreased with a conditional overexpression of PKC epsilon and increased with its knock-out by small interfering RNA. Conceivably, when MSA is generated within the vicinity of PKC, it specifically inactivates PKC isoenzymes, particularly the promitogenic and prosurvival epsilon isoenzyme, and this inactivation causes growth inhibition and apoptosis.