Search

Background: The term “addiction” encompasses both substance dependence and behavioral addiction and is associated with major societal problems. Measures to combat addiction are currently insufficient in Japan, and further research on addiction is necessary. Methods: Science Council of Japan (SCJ) has three subcommittees – the Addiction Subcommittee, Brain and Mind Subcommittee, and Neuroscience Subcommittee among others. Those three subcommittees are dealing directly or indirectly with addiction problems in Japan. Thus, all authors of this review, members of those subcommittees, collectively recommended what research activities are required in Japan for continuing effort in overcoming addiction problems in Japan. Results: We proposed the following measures. Proposal 1: Understand diversity in addiction and promote related research and education; Proposal 2: Promote personalized measures for patients with addiction disorders; Proposal 3: Foster addiction research personnel; Proposal 4: Develop new guidelines for the rehabilitation of patients with drug dependence; Proposal 5: Establish an institute specializing in addiction research and comprehensively handling information collection, research, countermeasures, treatment, and public relation related to addiction. Conclusion: The opinions of the review are based on the recommendations that were published in 2020 in Japanese by the Addiction Subcommittee, Brain and Mind Subcommittee, and Neuroscience Subcommittee of the SCJ. The authors here are sharing colleagues of Taiwanese Society of Psychiatry with these proposed research activities required to overcome addiction problems in Japan.

Purpose The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D2/D3 receptor occupancy induced by the serotonin–dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25–6 mg. Methods Occupancy was measured at 4 and 23.5 h post-dose using the D2/D3 receptor antagonist [11C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel. Results Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D2/D3 receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77–88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74–83%). Estimates of maximum obtainable receptor occupancy (Omax) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of Omax (EC50) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration–time curve (AUC∞) and maximum plasma concentration (Cmax) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort. Conclusion By extrapolating the observed single-dose D2/D3 receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder. Trial registration ClinicalTrials.gov NCT00805454 December 9, 2008.

Excessive loadings of terrestrial nitrogen and phosphorus, as well as their imbalances with silicon, have been recognized as one of the major causes of water quality and ecosystem deterioration in receiving waters. In this study, a periodic water quality monitoring was conducted in the rivers and streams of a tropical island (Ishigaki Island, Japan) to identify the factors controlling the concentrations of dissolved inorganic nitrogen (DIN), total phosphorus (TP) and dissolved silicon (DSi) with a special focus on the catchment characteristics (e.g., land use, surface geology, topography). Random Forest (RF) machine learning algorithm was employed to develop predictive models for nutrient concentrations from the catchment properties. The developed models could predict nutrient concentrations with sufficient accuracy, demonstrating that the studied nutrients are strongly affected by catchment properties. Agricultural land uses (e.g., livestock barn, sugarcane field) were ranked as the most important parameters for DIN and TP, while broadleaf forest was the most influential factor for DSi. Using the RF models, the contributions of DIN originating from sugarcane fields (i.e., fertilizers) and barns (i.e., manure) to riverine DIN were estimated, which were up to 60% in total in the studied river basins. Furthermore, the yield of DIN from sugarcane fields, calculated as the concentration of DIN derived from sugarcane fields divided by the percent area of sugarcane fields, strongly positively correlated with the areal coverage of limestone, suggesting that fertilizer-derived DIN is more prone to leaching out from cropland soil to groundwater and rivers in catchments with a higher dominance of calcareous geology. These results, including the methodology employed, have implications for water quality assessment and management in inland and coastal waters not only at the study site but also other regions.

We started a research of dendritic cell (DC) immunotherapy for malignant glioma in late 1997, and were continuing the clinical study for more than 20 years with making several improvements of methods. The presenter has been participating in this research from its inception, and has continued to conduct research as the life's work. We will present research history and the future prospects. Autologous cultured tumor cells were established from tumor tissue obtained from a surgery of patient with malignant glioma in our hospital. Mature DCs were induced from autologous peripheral blood mononuclear cells (PBMC), and were fused with the established tumor cells. Cell manufacturing performed at a cell processing facility (CPF) maintained and managed by our university. Before 2004, the tumor-fused DCs (TFDC) were co-administrated with rIL-12. Since 2014, TFDCs were stimulated with Poly(I:C) and IL-10-siRNA in order to increase IL-12 secretion levels of them. Since 2014, PBMCs were collected by the apheresis method. Since 2006, the TFDC immunotherapy was combined with temozolomide (TMZ) chemotherapy. 111 cases were enrolled in the clinical study. The TFDC-immunotherapy was combined with the TMZ chemotherapy in 88 cases enrolled after 2006. No serious problem was confirmed in the cell manufacturing. The therapeutic effect in this study will be compared with a historical control that were the cases of malignant glioma treated with a standard therapy at the other affiliated hospitals at the same period. The results will be reported in the presentation. The safety and efficacy of this treatment were confirmed in the previous study. We would like to establish a provision system of the TFDCs by use of our CPF by preparing product uniformity, transport safety, preservation methods, etc., and aim to expand the hospitals that can perform this immunotherapy.

Brexpiprazole (Rexulti®) is the second antipsychotic agent in the world with dopamine D2 receptor partial agonist which was developed by Otsuka Pharmaceutical Co. Ltd. It is categorized as 〝Serotonin- dopamine Activity Modulator (SDAM)〟 that regulates both serotoninergic and dopaminergic systems by acting as a partial agonist for serotonin 5-HT1A receptors and D2 receptors and as an antagonist for 5-HT2A receptors. In preclinical pharmacological studies, brexpiprazole showed the equivalent antipsychotic-like effects to those of other atypical antipsychotics. And it was suggested that brexpiprazole has the low potentials to induce extrapyramidal symptoms, hyperprolactinemia and tardive dyskinesia, with improvement effects on cognitive dysfunction. Furthermore, brexpiprazole has the weak effects on histamine H1 receptors which are associated with sedation and weight gain in clinical. In the clinical trials in patients with schizophrenia in both acute and maintenance phase, brexpiprazole showed improvement of antipsychotic effects against placebo, and low incidence of adverse events, e.g., extrapyramidal symptoms, hyperprolactinemia, and weight gain, as suggested in preclinical studies. Furthermore, brexpiprazole showed low incidence of metabolic abnormalities. In particular, brexpiprazole showed relatively low incidences of akathisia, insomnia and agitation which has been commonly reported with aripiprazole. This would be based on the pharmacological features of brexpiprazole that is more potent antagonism at 5-HT2A receptors and D2 receptors partial agonism with lower intrinsic activity compared to those of aripiprazole. In conclusion, brexpiprazole could be one of the antipsychotics with the most rational mechanism of action, and the better efficacy and safety/tolerability profiles would contribute to the treatment of patients with schizophrenia.

Ferrous iron (Fe[II]) oxidation by dissolved oxygen was investigated in the Shizugawa Bay watershed with particular attention given to the effect of dissolved organic matter (DOM) properties on Fe(II) oxidation. To cover a wide spectrum of DOM composition, water samples were collected from various water sources including freshwater (e.g., river water and wastewater effluent) and coastal seawater. Measurement of nanomolar Fe(II) oxidation by using luminol chemiluminescence under dark, air-saturated conditions at 25 °C indicated that spatio-temporal variation of the second-order rate constant (6.7–74.5 M−1 s−1) was partially explained by the variation of the sample pH (7.5–8.6). However, at comparable pH values, the oxidation rates for freshwater were generally greater than those for coastal seawater. The substantial decline in oxidation rate constant after the removal of humic-type (allochthonous) DOM suggested that this hydrophobic DOM is a key factor that accelerates the Fe(II) oxidation in the freshwater samples. Observed lower oxidation rates for coastal seawater compared with freshwater and organic ligand-free seawater were likely associated with microbially derived autochthonous DOM, and the variation of Fe(II) oxidation at a fixed pH was best described by fluorescence index that represents the proportion of autochthonous and allochthonous DOM in natural waters. Consistently, Fe(II) oxidation was found to be slower in the presence of cellular exudates from phytoplankton. The present study highlighted the significant effect of DOM composition on the Fe(II) oxidation in inland and coastal waters.

Brexpiprazole (Rexulti

Fe(II) oxidation was investigated in samples from the Sagami River basin (Japan) with particular emphasis on the effect of dissolved organic matter (DOM) in an urban river system. Collected samples consisted of main stream and tributary waters impacted to a moderate and minor extent by anthropogenic activities, respectively, and treated effluents from adjacent municipal wastewater treatment plants (MWWTPs: as representative anthropogenic point source). Nanomolar Fe(II) oxidation was measured in air-saturated waters using luminol chemiluminescence in the dark at 25 °C. Second-order rate constant for Fe(II) oxidation (with respect to Fe(II) and O2 concentrations) showed spatial and temporal variation. Annual average of the rate constant was highest for MWWTP effluents, followed by reservoir and river waters, with tributary waters showing the lowest oxidation rate. Manipulation experiments indicated that, in addition to pH (7.8-8.4), DOM characteristics are important explanatory variable for the Fe(II) oxidation. For example, the addition of MWWTP-derived humic-type DOM to anthropogenically less-influenced tributary water resulted in substantial increase in the oxidation rate. Significant negative correlation observed between the specific UV absorbance (SUVA254) and Fe(II) oxidation rate constant (pH 8.0) suggests a potential effect of humic-type DOM with low SUVA254 (high aliphatic content) on Fe(II) oxidation in natural and engineered waters.

This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM). GBM patients were assigned to two groups: a group of recurrent GBMs after failing TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region. Toxicity, progression-free survival (PFS), and overall survival (OS) of this trial were evaluated. Expressions of WT-1, gp-100, and MAGE-A3, recognized as chemoresistance-associated peptides (CAP), were confirmed by immunohistochemistry of paraffin-embedded tumor samples. Patient’s PBMCs of pre- and post-vaccination were evaluated by tetramer and ELISPOT assays. FC-immunotherapy was well tolerated in all patients. Medians of PFS and OS of Group-R (n = 10) were 10.3 and 18.0 months, and those of Group-N (n = 22) were 18.3 and 30.5 months, respectively. Up-regulation and/or cytoplasmic accumulation of CAPs was observed in the recurrent tumors of Group-R patients compared with their initially excised tumors. Specific immune responses against CAPs were observed in the tetramer and ELISPOT assays. The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor effects in patients with GBM.

A Correction to this paper has been published: 10.1007/s00228-020-03071-z

In this study, the relationships between the concentration and isotopic compositions (δ15NNO3 and δ18ONO3) of nitrate in river water and the land use and topographic characteristics of the watershed were analyzed for the tributaries of two major inflow rivers (Hokota River and Tomoe River) of Lake Kitaura (Ibaraki Prefecture, Japan). Modelling by the Random Forests machine learning algorithm in combination with statistical analyses (correlation analysis and principal component analysis) revealed that crop farming in dry fields (i.e., application of chemical fertilizers and manure) and swine farming (e.g., addition of swine manure to cropland soils over the basal application rate, leakage of swine manure from the stockyard to groundwater or river) in the watershed are the main drivers for increasing nitrate concentration in the river water of the studied river basins. Based on calculations using the Random Forests models, nitrate derived from swine farming was estimated to account for up to 28% of nitrate in the river water, and its contribution was proportional to the density of farmed swine (log-transformed value). Similarly, the percentage of nitrate removed in the riparian zone and the lotic environment (e.g., bottom sediment, water column and hyporheic zone within the river flow path) was estimated to be up to 34% and was also proportional to the topographic wetness index in the riparian zone (log-transformed value). In addition, significant negative correlations between log-transformed nitrate concentration and δ15NNO3 and δ18ONO3 were recognized in the combined data for all the tributaries as well as the single data for several tributaries, suggesting that biological processes (e.g., denitrification, assimilation) contribute to the removal of nitrate and associated changes in δ15NNO3 and δ18ONO3 of residual nitrate. These findings are applicable for planning measures to control nitrogen load from the watershed and for improving the accuracy in calculating the proportions of nitrate from different sources based on the isotope mixing models.

Deficiencies in social activities are hallmarks of numerous brain disorders. With respect to schizophrenia, social withdrawal belongs to the category of negative symptoms and is associated with deficits in the cognitive domain. Here, we used the N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) for induction of social withdrawal in rats and assessed the efficacy of several atypical antipsychotics with different pharmacological profiles as putative treatment. In addition, we reasoned that the marijuana constituent cannabidiol (CBD) may provide benefit or could be proposed as an adjunct treatment in combination with antipsychotics. Hooded Lister rats were tested in the three-chamber version for social interaction, with an initial novelty phase, followed after 3 min by a short-term recognition memory phase. No drug treatment affected sociability. However, distinct effects on social recognition were revealed. MK-801 reduced social recognition memory at all doses (>0.03 mg/kg). Predosing with aripiprazole dose-dependently (2 or 10 mg/kg) prevented the memory decline, but doses of 0.1 mg/kg risperidone or 1 mg/kg olanzapine did not. Intriguingly, CBD impaired social recognition memory (12 and 30 mg/kg) but did not rescue the MK-801-induced deficits. When CBD was combined with protective doses of aripiprazole (CBD-aripiprazole at 12 : or 5 : 2 mg/kg) the benefit of the antipsychotic was lost. At the same time, activity-related changes in behaviour were excluded as underlying reasons for these pharmacological effects. Collectively, the combined activity of aripiprazole on dopamine D2 and serotonin 5HT1A receptors appears to provide a significant advantage over risperidone and olanzapine with respect to the rescue of cognitive deficits reminiscent of schizophrenia. The differential pharmacological properties of CBD, which are seemingly beneficial in human patients, did not back-translate and rescue the MK-801-induced social memory deficit.

Brexpiprazole, a novel atypical antipsychotic drug, is currently being tested in clinical trials for treatment of psychiatric disorders, such as schizophrenia and major depressive disorder. The drug is known to act through a combination of partial agonistic activity at 5-hydroxytryptamine (5-HT)1A, and dopamine D2 receptors, and antagonistic activity at 5-HT2A receptors. Accumulating evidence suggests that antipsychotic drugs act by promoting neurite outgrowth. In this study, we examined whether brexpiprazole affected neurite outgrowth in cell culture. We found that brexpiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. The selective 5-HT1A receptor antagonist, WAY-100,635, was able to block the effects of brexpiprazole on neurite outgrowth, unlike the selective dopamine D2 receptor antagonist, raclopride. Furthermore, the selective 5-HT2A receptor antagonist M100907, but not DOI (5-HT2A receptor agonist), significantly potentiated NGF-induced neurite outgrowth. Moreover, xestospongin C and 2-aminoethoxydiphenyl borate (2-APB), both specific inhibitors of inositol 1,4,5-triphosphate (IP3) receptors, significantly blocked the effects of brexpiprazole. These findings suggest that brexpiprazole-induced neurite outgrowth is mediated through 5-HT1A and 5-HT2A receptors, and subsequent Ca2+ signaling via IP3 receptors.

This study aimed to investigate the spatial distribution of dissolved iron from river to coastal waters and iron bioavailability for coastal phytoplankton. Dissolved iron concentrations and other water quality parameters (e.g., pH, concentrations of dissolved organic carbon and trace metals, etc.) were determined in the Shizugawa Bay and its adjacent rivers, northeast Japan. Coastal dominant diatom (Chaetoceros sp.) isolated from the bay was used for incubational assay to examine growth kinetics in a range of iron concentrations. As a result, total dissolved iron concentrations of inland waters (75 ± 80 nM) were substantially higher than those of coastal waters (7.2 ± 4.8 nM). Among inland waters, iron concentrations from anthropogenic waters were relatively higher than those for forested river waters. In the bay, relatively higher concentrations of iron were observed in the inner part. From the growth experiment, half-saturation constant of iron for the growth of Chaetoceros sp. was determined to be 1.8 - 3.5 nM. The observed dissolved iron concentrations combined with growth response indicate that growth of Chaetoceros sp. is in some cases limited by iron availability. However, this study generally suggests that, while dissolved iron concentration largely decreased from river to coastal waters, terrestrial iron inputs potentially including both natural and anthropogenic sources contribute sufficient growth and iron availability by Chaetoceros sp. in the Shizugawa Bay.

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.

Using the GEOS-Chem atmosphere-land-ocean coupled mercury model, we studied the significances of two processes, soil emission and atmospheric oxidation-reduction, in the global biogeochemical cycling of mercury and their parametrization to improve model performance. Implementing an empirical equation for soil emission flux (Esoil) including soil mercury concentration, solar radiation, and surface air temperature as parameters enabled the model to reproduce the observed seasonal variations of Esoil, whereas the default setting, which uses only the former two parameters, failed. The modified setting of Esoil also increased the model-simulated atmospheric concentration in the summertime surface layer of the lower- and midlatitudes and improved the model reproducibility for the observations in Japan and U.S. in the same period. Implementing oxidation of atmospheric gaseous elemental mercury (Hg(0)) by ozone with an updated rate constant, as well as the oxidation by bromine atoms (Br) in the default setting, improved the model reproducibility for the dry deposition fluxes observed in Japan. This setting, however, failed to reproduce the observed seasonal variations of atmospheric concentrations in the Arctic sites due to the imbalance between oxidation and reduction, whereas the model with Br as the sole Hg(0) oxidant in the polar atmosphere could capture the variations.

Oxidation and reduction kinetics of iron (Fe) and proportion of steady-state Fe(II) concentration relative to total dissolved Fe (steady-state Fe(II) fraction) were investigated in the presence of various types of standard humic substances (HS) with particular emphasis on the photochemical and thermal reduction of Fe(III) and oxidation of Fe(II) by dissolved oxygen (O2) and hydrogen peroxide (H2O2) at circumneutral pH (pH 7–8). Rates of Fe(III) reduction were spectrophotometrically determined by a ferrozine method under the simulated sunlight and dark conditions, whereas rates of Fe(II) oxidation were examined in air-saturated solution using luminol chemiluminescence technique. The reduction and oxidation rate constants were determined to substantially vary depending on the type of HS. For example, the first-order rate constants varied by up to 10-fold for photochemical reduction and 7-fold for thermal reduction. The degree of variation in Fe(II) oxidation was larger for the H2O2-mediated reaction compared to the O2-mediated reaction (e.g., 15- and 3-fold changes for the former and latter reactions, respectively, at pH 8). The steady-state Fe(II) fraction under the simulated sunlight indicated that the Fe(II) fraction varies by up to 12-fold. The correlation analysis indicated that variation of Fe(II) oxidation is significantly associated with aliphatic content of HS, suggesting that Fe(II) complexation by aliphatic components accelerates Fe(II) oxidation. The reduction rate constant and steady-state Fe(II) fractions in the presence of sunlight had relatively strong positive relations with free radical content of HS, possibly due to the reductive property of radical semiquinone in HS. Overall, the findings in this study indicated that the Fe reduction and oxidation kinetics and resultant Fe(II) formation are substantially influenced by chemical properties of HS.

Accumulating evidence suggests that inflammation may play a role in the pathophysiology of major depressive disorder (MDD). Antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), possess anti-inflammatory effects in vitro. Here, we examined the effects of SSRIs and SNRIs on lipopolysaccharide (LPS)-induced inflammation and depressive-like behavior in male mice. A single administration of LPS (0.5mg/kg, i.p.) increased serum levels of the pro-inflammatory cytokine, tumor necrosis factor-α (TNFα) and the anti-inflammatory cytokine, interleukin-10 (IL-10) in mice. Pretreatment with SSRIs (fluoxetine and paroxetine), SNRIs (venlafaxine and duloxetine), or 5-hydroxytryptophan (5-HTP), a precursor of serotonin, attenuated LPS-induced increases in TNFα, whereas it increased serum levels of IL-10, in mice treated with LPS. In the tail suspension test (TST), LPS increased the immobility time without affecting spontaneous locomotor activity, suggesting that LPS induced depressive-like behavior in mice. Treatment with fluoxetine (30 mg/kg) or paroxetine (10mg/kg) significantly shortened LPS-induced increases of immobility time. These results suggested that antidepressants exert anti-inflammatory effects in vivo, and that the serotonergic system may partially mediate these effects. In addition, the anti-inflammatory effects of antidepressants may help alleviate the symptoms of LPS-induced depression in mice.

BACKGROUND: Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors. MATERIALS AND METHODS: This study examined aripiprazole's interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties. RESULTS: Aripiprazole produced increases in [(35)S]GTPgammaS binding to rat hippocampal membranes. Its potency (pEC(50) = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT(1A)-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT(1A)-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT(1A) receptors (K (i) = 4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT(2A) receptors (K (i) = 3.4 nM), moderate affinity to 5-HT(2C) (K (i) = 15 nM) and 5-HT(7) (K (i) = 39 nM) receptors, and low affinity to 5-HT(6) receptors (K (i) = 214 nM) and 5-HT transporter (K (i) = 98 nM). In addition, aripiprazole potently blocked 5-HT(2A)-receptor-mediated increases in intracellular Ca(2+) levels in a rat pituitary cell line (IC(50) = 11 nM). DISCUSSION: These results support a partial agonist activity for aripiprazole at 5-HT(1A) receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.

The authors review presently available or potential biological methods to remove and detoxify toxic heavy metals and metalloids from polluted water and sediments (i.e., biosorption, bioaccumulation, oxidation/reduction, leaching, precipitation, volatilization, degradation, and phytoremediation). In addition, they describe the options for the recovery of metals sequestered by biosorbents (use of appropriate desorbing agents) and microbial and plant biomass (leaching by means of chemical reagents or biological processes, and thermal treatment in controlled systems).

We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D2 and D3 receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D2L and D2S receptors (hD2L-Low, hD2L-High, hD2S-Low and hD2S-High, respectively) and human dopamine D3 Ser-9 and D3 Gly-9 receptors (hD3-Ser-9 and hD3-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D2 and D3 receptor full agonists and showed higher potencies in hD2L-High and hD2S-High compared to hD2L-Low and hD2S-Low. In hD3-Ser-9 and hD3-Gly-9 compared to hD2L-Low and hD2S-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD2L-Low; a low intrinsic activity partial agonist in hD2S-Low; a moderate partial agonist in hD3-Ser-9 and hD3-Gly-9; a robust partial agonist in hD2L-High; and a full agonist in hD2S-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD2S-Low and hD2S-High compared to hD3-Ser-9 and hD3-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with varying mechanisms of action, in the treatment of Parkinson's disease, depression and schizophrenia.

Apart from generating T-helper (Th) effector responses, dendritic cells (DCs) are capable of initiating tolerance against the inciting antigens. Therefore, successful DC-based immunotherapy against malignant tumors requires an additional strategy to activate antigen-processing DCs. We studied the antitumor immune responses conferred by fusions of DCs and glioma cells in vitro. Fusion cells (FCs) were stimulated with polyriboinosinic polyribocytidylic acid [Poly(I:C)] and/or small interference RNA (siRNA) of IL-10 (IL-10-siRNA). Increased IFN-β expression induced by Poly(I:C) transfection was accompanied by enhanced production of IL-10 and IL-12p70 in the FCs. We also found that the ability of Poly(I:C)-transfected FCs to produce IL-12p70, but not IFN-β, was preserved when endogenous IL-10 was suppressed by IL-10-siRNA. To analyze the antigen-presenting function further, DCs, glioma cells, and peripheral lymphocytes were established from patients newly diagnosed with glioma. In this experiment, peripheral lymphocytes were stimulated with autologous FCs and restimulated with autologous glioma cells. CD4T cells isolated from the stimulated lymphocytes were subjected to the ELISPOT and WST-1 assays, which revealed that the IL-10-siRNA/Poly(I:C)-cotransfected FCs elicit an efficient tumor-specific Th1 response. These findings support the relevance of using Poly(I:C) and IL-10-siRNA in clinical immunotherapy protocols with an FC-based vaccine for patients with malignant glioma as a means of promoting Th1-induced tumor antigen presentation.

Ho Tay (West Lake) in Hanoi, Vietnam receives wastewater from the city center and the surrounding residential areas, which can cause both eutrophication and enrichment of toxic heavy metals in the lake ecosystem. The aim of this study is to evaluate the recent trends of metal contamination in this lake from their spatial (horizontal and vertical) distributions in the lake sediments. Sediment cores with up to 70 cm in depth were sampled from four locations in the lake and analyzed for heavy metals (Cd, Cr, Cu, Mn, Ni, Pb and Zn) including a metalloid (As) and total organic carbon (TOC). High concentrations of the metals (except for Mn) and TOC have accumulated in sediment at the site where an inlet of sewage from the city center was located nearby. Increasing trends of the metal contents in the sediment profile toward the surface at the sites distant from the sewage inlets imply that the loads of these metals into this lake have been continuously increasing. In addition, Pb isotopic ratios in sediment profile could be used as an indicator of anthropogenic Pb pollution in the lake.

Amyloid precursor protein (APP) is strongly related to the onset of Alzheimer's disease. It possesses cleavage sites for beta- and gamma-secretases, and the resulting cleaved products (amyloid-beta peptides) are capable of causing neurotoxicity. Such cleavage is promoted by the Swedish and London mutations (APPSwe/Lon) inside the APP gene. Here, we characterized APPSL transgenic mice (APPSL-Tg) to determine the effects of this mutation. We observed that both the amount of insoluble amyloid-beta and the ratio of amyloid-beta 42/40 increased promptly in the brain during 6-16 months of age. Amyloid-beta plaques were observed in whole brain sections at 12 months. In contrast, the spatial memory assessed by the Morris water maze task was already impaired at 3 months, which suggested that the APPSL-Tg mice may represent an early-onset model of familial Alzheimer's disease. Furthermore, the levels of LAMP-1, a marker protein of lysosome, increased in the brain at 28 months. Such LAMP-1 protein was detected around the amyloid-beta plaques at the hippocampal regions of the APPSL-Tg mice. Our results suggested that the increase in LAMP-1 was enhanced by the accumulation of amyloid-beta occurring during aging. Our findings coincided with the pathological hallmarks of Alzheimer's disease.

In order to get a grasp of the current situation and characteristics of heavy metal pollution in the river environment of Hanoi City and its surrounding area, river sediment was sampled from the To Lich River (urban river) and the Nhue River (suburban/rural river) for three times during the period of October 2005 to June 2006 and analyzed for heavy metals. Accumulations of heavy metals in river sediment of the Nhue (in the suburban area of Hanoi) and the To Lich were found to have been progressing in the last 8 years due to wastewater discharge from the central part of Hanoi and urbanized areas along the rivers. Concentrations of As, Cr, Cu, Mn, Ni and Zn the in sediment of the Nhue were higher in the dry season than in the rainy season. However, multivariate analyses (principal component analysis and cluster analysis) revealed that, regardless of seasons, there were two characteristic areas with regard to heavy metal composition in river sediment: (1) the To Lich with high levels of Cd, Zn and TOC from anthropogenic origins, and (2) up- and down-stream parts of the Nhue with high concentrations of As, Mn and Pb derived from the Hong River, the headwater of the Nhue.

Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist approved for use in the treatment of psychiatric disorders including schizophrenia, bipolar disorder, and unipolar depression in the US. Aripiprazole has demonstrated a relatively favorable side effect profile compared to other commonly prescribed antipsychotics, including a low propensity for treatment-limiting extrapyramidal symptoms, hyperprolactinemia, and body weight gain. In an effort to elucidate aripiprazole's pharmacological activity in relation to clinically relevant fluctuation of dopamine D(2) receptor reserves, we compared the properties of aripiprazole to other antipsychotics, quetiapine, clozapine, olanzapine, ziprasidone, risperidone and haloperidol, a dopamine D(2) receptor partial agonist, bifeprunox, dopamine D(3) receptor modulators, BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide), and a 5-HT(1A) partial agonist, buspirone using forskolin-stimulated cAMP accumulation in clonal Chinese hamster ovary cell lines expressing low and high densities of human dopamine D(2S) receptors (hD(2S)-Low and hD(2S)-High, respectively). In hD(2S)-Low cells lacking receptor reserves for dopamine, all drugs antagonized dopamine responses, and their potencies correlated well with respective affinities. In hD(2S)-High cells possessing receptor reserves, all antipsychotics except aripiprazole antagonized dopamine responses, and their antagonist potencies were less than those in hD(2S)-Low cells treated with the equal dopamine concentration. In contrast, aripiprazole and bifeprunox acted as full agonists. BP897, GR103691 and buspirone acted as partial agonists. These data suggest that the level of receptor reserves influences antagonist potencies and side effects associated with antipsychotics. Aripiprazole's unique receptor reserve dependent properties may account for its favorable tolerability in the clinical setting.

The objective of this study is to assess the applicability of a commercial magnesium oxide (MgO) and a composite material containing MgO and natural minerals ('MgO-SH-A') as the soil amendments for suppression of cadmium (Cd) uptake and accumulation into rice grains. Firstly, the mineralogical and physicochemical properties, soil neutralizing capacities and Cd sorption characteristics of these materials were investigated. Both materials were strongly alkaline and possessed large surface areas. The X-ray diffraction pattern of MgO-SH-A indicated the presence of MgO and a magnesium-silicate mineral (antigorite) as the main components. MgO-SH-A showed a milder soil neutralizing capacity as compared to commercial MgO. The sorptions of Cd on commercial MgO and MgO-SH-A both fitted Langmuir isotherm. The maximum Cd sorption capacity of commercial MgO (46.8 mmol g(-1) DW) was higher than that of MgO-SH-A (5.87 mmol g(-1) DW), although the latter material showed higher affinity to Cd as compared to the former one. The dominant reaction involved in the Cd sorptions was suggested to be precipitation of Cd(OH)2 on the material surface. About 40% of Cd sorbed on MgO-SH-A was resistant to desorption by 0.1 M HCl, implying that this portion was strongly retained on the material surface.

The objective of this study is to assess the applicability of a commercial magnesium oxide (MgO) and a composite material containing MgO and natural minerals (‘MgO-SH-A’) as the soil amendments for suppression of cadmium (Cd) uptake and accumulation into rice grains. A cultivation experiment of rice plants ( Oryza sativa L. cv. Kinuhikari) was conducted in an actual Cd-contaminated alluvial paddy field to evaluate the effectiveness of these materials. The ‘plant available’ fractions of Cd in the paddy soil significantly decreased by application of commercial MgO at 2250 kg ha −1 or MgO-SH-A at 4500 kg ha −1 . These decreases would be primarily attributed to the increase in soil pH due to applications of the MgO materials because these soil Cd fractions were significantly negatively correlated with the soil pH. Even under a suppressive condition for Cd uptake by rice plants, i.e., continuous flooding of the paddy field around the heading stage, applications of these materials further reduced Cd concentration in brown rice as compared to that from the control. It was concluded that the two MgO materials examined would be effective in preventing Cd contamination of rice grains grown in Cd-polluted paddy fields.

Clinical evidence suggests that dopamine D(2) receptor partial agonists must have a sufficiently low intrinsic activity to be effective as antipsychotics. Here, we used dopamine D(2) receptor signaling assays to compare the in vitro functional characteristics of the antipsychotic aripiprazole with other dopamine D(2) receptor partial agonists (7-{3-[4-(2,3-dimethylphenyl)-piperazinyl]propoxy}-2(1H)-quinolinone [OPC-4392], (-)-3-(3-hydroxy-phenyl)-N-n-propylpiperidine [(-)3-PPP] and (+)terguride) and dopamine D(2) receptor antagonists. Aripiprazole and OPC-4392 were inactive in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTPgammaS) binding assay using Chinese Hamster Ovary (CHO) cell membranes expressing cloned human dopamine D(2Long) (hD(2L)) receptors, whereas (-)3-PPP and (+)terguride displayed low intrinsic activity. Aripiprazole also had no effect on [(35)S]GTPgammaS binding to CHO-hD(2L) cells, while OPC-4392, (-)3-PPP and (+)terguride were partial agonists. In contrast, aripiprazole, OPC-4392, (-)3-PPP, and (+)terguride were inactive in a [(35)S]GTPgammaS binding assay using rat striatal membranes. However, at a more downstream level of CHO-hD(2L) cell signalling, these drugs all behaved as dopamine hD(2L) receptor partial agonists, with aripiprazole displaying an intrinsic activity 2 to 3-fold lower (inhibition of forskolin-induced adenosine 3',5'-cyclic monophosphate accumulation) and almost half as high (enhancement of adenosine triphosphate-stimulated [(3)H]arachidonic acid release) as OPC-4392, (-)3-PPP and (+)terguride. Dopamine activity was blocked in each case by (-)raclopride, which was inactive on its own in every assay, as were the antipsychotics haloperidol, olanzapine, ziprasidone and clozapine. Together, these data, whilst preclinical in nature, are consistent with clinical evidence suggesting the favorable antipsychotic profile of aripiprazole, compared with the other clinically ineffective partial agonists, is dependent on its low intrinsic activity at dopamine D(2) receptors. This study also highlights the limitations of using [(35)S]GTPgammaS binding assays to identify dopamine D(2) receptor partial agonists.

It is obvious that DA is an important neurotransmitter in vivo. It is involved in a variety of physiological processes such as mental processes, motor function and hormone regulation. In this context, it is quite understandable that a DA D2 receptor antagonist that inhibits the DA D2 receptor regardless of the state of activity of dopaminergic neurotransmission and inhibit the physiological function of DA can have a variety of adverse effects. In contrast to DA D2 antagonists, aripiprazole acts as an antagonist at the DA D2 receptor in the state of excessive dopaminergic neurotransmission, while it acts as an agonist at the DA D2 receptor in the state of low dopaminergic neurotransmission, and thus attempts to bring the state of dopaminergic neurotransmission to normal. This activity of aripiprazole to regulate dopaminergic neurotransmission is physiologically reasonable, and can be regarded as a stabilizing effect, for which aripiprazole is called a dopamine system stabilizer.

Background Vaccination with fusion cells (FCs) comprising dendritic cells and tumour cells as well as administration of interleukin-12 (IL-12) showed a significant therapeutic effect against established tumours in mouse experimental models. We conducted immunotherapy against various malignant tumours using the FCs and rhIL-12, and investigated the safety and efficacy of the therapy. Materials and methods Patients’ DCs were mixed with autologous irradiated tumour cells and treated with 50% polyethylene glycol to generate FCs. The FCs were inoculated intradermally, and then 30 ng kg−1 of rhIL-12 was injected at the same sites 2 and 6 days later. This process was carried out as one cycle, and three of these cycles were repeated at 1-week intervals to comprise one course. After completing the course, its safety and therapeutic effects were estimated. Results The most frequently observed adverse event was fever, observed in 26% of patients in the first cycle. Decrease in white blood cell and an increase in serum ALT were observed in 28% and 25%, respectively. Three out of 12 patients with a malignant brain tumour (25%) achieved a partial response (PR), but other patients with a malignant tumour showed no regression of their tumours. Thirteen out of 16 patients with a brain tumour (81%) showed cutaneous delayed hypersensitivity responses. However, only one of 16 patients (6%) with a malignant tumour other than a brain tumour developed such responses. Conclusions Immunotherapy using a FC vaccine and rhIL-12 induced no serious adverse reactions, and provided good therapeutic responses in some of the patients with a brain tumour.

The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated usingseveral pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to a typical antipsychotics. This profile may result from its high affinity partialagonist activity at D2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.

Vaccination of fusion cells (FCs) made from dendritic and tumor cells elicits anti-tumor effects. We investigated whether major histocompatibility complex (MHC) class I and II play an important role in the induction of anti-tumor immunity by FCs. Immunization with fusion cells composed of syngeneic, allogeneic, or MHC I−/−II−/− DCs and B16 cells inhibited tumor growth. Elispot assay showed a higher population of interferon-γ secreting T lymphocytes in mice immunized with fusion cells. These data suggest that anti-tumor effects of DCs and tumor cell fusions are not dependent on the expression of MHC class I and II on DCs.

Aripiprazole is a novel antipsychotic with a unique mechanism of action, which differs from currently marketed typical and atypical antipsychotics. Aripiprazole has been shown to be a partial agonist at the D(2) family of dopamine (DA) receptors in biochemical and pharmacological studies. To demonstrate aripiprazole's action as a partial D(2) agonist in pituitary cells at the molecular level, we retrovirally transduced the short (D(2S)) and the long (D(2L)) form of the human DA D(2) receptor gene into a rat pituitary cell line, GH4C1. [(3)H]-raclopride saturation binding analyses revealed a B(max) value approximately four-fold higher at D(2S) receptor-expressing GH4C1 cells than at D(2L) receptor-expressing GH4C1 cells, while a K(d) value was similar. Aripiprazole inhibited forskolin-stimulated release of prolactin in both D(2S) and D(2L) receptor-expressing GH4C1 cells, whereas the maximal inhibition of prolactin release was less than that of DA. Similarly, aripiprazole partially inhibited forskolin-induced cAMP accumulation in both D(2) receptor-expressing cells. Aripiprazole antagonized the suppression attained by DA (10(-7) M) in both D(2) receptor-expressing cells and, at the maximal blockade of cAMP, yielded residual cAMP levels equal to those produced by aripiprazole alone. These results indicate that aripiprazole acts as a partial agonist at both D(2S) and D(2L) receptors expressed in GH4C1 cells. These data may explain, at least in part, the observations that aripiprazole shows a novel antipsychotic activity with minimal potential for adverse events including no significant increase of serum prolactin levels in clinical studies.

In vivo microdialysis was used to monitor the effects of oral aripiprazole and olanzapine on basal extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) in the medial prefrontal cortex and striatum of conscious, freely moving rats. Acute aripiprazole administration did not affect dopamine output, but produced moderate increases in DOPAC and HVA concentrations, in medial prefrontal cortex or striatum of drug-naïve rats. Similarly, aripiprazole did not affect dopamine output but produced moderate elevations in DOPAC and HVA concentrations in the striatum of chronic aripiprazole-pretreated rats. Olanzapine produced comparatively larger elevations in dopamine, DOPAC, and HVA in both regions, which, in the striatum, were diminished after chronic olanzapine exposure. Aripiprazole reduced extracellular 5-HIAA concentrations in the medial prefrontal cortex and striatum of drug-nai;ve rats, but not in chronic aripiprazole-pretreated rats. Together, these data provide in vivo evidence of aripiprazole-induced changes in forebrain dopaminergic and serotonergic function that may reflect its partial agonist activity at presynaptic dopamine D(2) and 5-HT(1A) receptors and antagonist activity at 5-HT(2A) receptors.

Shedding of growth-suppressive gangliosides from glomerular mesangial cells undergoing apoptosis. Background Apoptosis of glomerular mesangial cells is a common feature in several types of glomerular diseases. However, its pathophysiologic significance is not known. We recently identified gangliosides as a major growth-inhibitory substance in the conditioned medium of mesangial cells. In this report, we tested whether biologically distinct forms of cell fate, apoptosis and necrosis, could modulate ganglioside shedding from mesangial cells. Methods Mesangial cells were exposed to low (10 to 40 mJ/cm 2 ) and high (400 mJ/cm 2 ) doses of ultraviolet light to induce apoptosis and necrosis, respectively. Conditioned media were collected and examined for its growth-inhibitory activity for mesangial cells. Ganglioside shedding was analyzed using metabolic labeling and thin-layer chromatography (TLC). Results Shedding of gangliosides as well as growth-inhibitory activity in the conditioned medium predominantly increased when mesangial cells were undergoing apoptosis in contrast to that of viable or necrotic mesangial cells. The inhibitory substance in the conditioned medium from apoptotic mesangial cells completely fulfilled the characteristic criteria of gangliosides. This substance was less than 3 kD and was sensitive to neuraminidase digestion. Shedding of gangliosides from mesangial cells reduced significantly when apoptosis was inhibited by overexpression of antiapoptotic gene, Bcl-XL . In addition, ganglioside shedding also increased when mesangial cells were exposed to other inducers of apoptosis for mesangial cells (i.e., H 2 O 2 and staurosporin). Conclusion These results provide the novel link between masangial cell apoptosis and increased release of gangliosides that potentially suppress mesangial cell proliferation and thus indicate a mechanism for the negative regulation of mesangial cell growth by apoptosis.

Malignant astrocytoma is the most common primary brain tumor in adults. The median survival of patients with malignant astrocytomas (high-grade astrocytomas) is about 1-2 years, despite aggressive treatment that includes surgical resection, radiotherapy and cytotoxic chemotherapy. Therefore, novel therapeutic approaches are needed to prolong survival. We investigated antitumor immunity conferred by the intratumoral injection of dendritic (DC) and irradiated glioma cells (IR-GC) in a mouse brain tumor model. Intratumorally injected DC migrated to the lymph nodes and elicited systemic immunity against autologous glioma cells. In a treatment model, intratumoral injection of DC and IR-GC prolonged the survival of brain tumor-bearing mice. Efficacy was reduced when studies were performed in mice depleted of CD8(+) T cells. Administration of DC or IR-GC alone had no effect on survival of brain tumor-bearing mice. CTL activity against glioma cells from immunized mice was also stimulated by coadministration of DC and IR-GC compared with the controls. These results support the therapeutic efficacy of intratumoral injection of DC and IR-GC.

We investigated whether Candida beta-D-glucan (CSBG) alters the maturation of dendritic cells (DCs). DC phenotypes were analyzed using FACScan. The expression of surface molecules, including major histocompatibility complex (MHC) classes I and II, as well as CD80 and CD86, increased on DCs that were stimulated with lipopolysaccaride (DCs/LPS), in comparison with unstimulated bone marrow-derived DCs (BM-DCs). Furthermore, the level of surface molecule expression on DCs stimulated with CSBG (DCs/CSBG) was between that of DCs and DCs/LPS. Phagocytosis was assessed by the uptake of FITC-dextran. There were no differences in the uptake of dextran among DCs/LPS and DCs/CSBG. The ability of BM-DCs to uptake dextran was higher than that of DCs/LPS and DCs/CSBG. We analyzed the concentration of IL-12 secreted by DCs using ELISA. BM-DCs secreted a low concentration of IL-12, while DCs/LPS and DCs/CSBG secreted higher levels of IL-12 than BM-DCs. There were no remarkable differences in the concentrations of IL-12 produced by DCs/LPS and DCs/CSBG. This data suggests that CSBG may augment DC maturation.

Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans.

We investigated whether glioma cells affected the maturation of dendritic cells (DCs). First, DCs phenotypes were analyzed using FACScan. Incubation of both human and mouse immature DCs with glioma cells altered their expression of cell surface molecules, whereas expression of cell surface molecules by mature mouse and human DCs was not affected by exposure to glioma cells. Subsequently, phagositosis was assessed by uptake of FITC-dextran. Coculture with glioma cells did not inhibit phagositosis of either mature or immature DCs relative to the controls. We also analyzed the concentration of IL-12 secreted by mature DCs using enzyme-linked immunoabsorbent assay (ELISA). IL-12 production by DCs was inhibited by coculture with glioma cells. However, stimulation with lipopolysaccharide restored the production of IL-12 by both human and mouse DCs. These data suggest that glioma cells suppress the maturation of DCs.