Aripiprazole is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D
2 receptors and serotonin-1A (5-hydroxytryptamine, 5-HT
1A) receptors and minimal ...side effects. Based on its pharmacological profile, including stabilization of mesocorticolimbic DA activity (a pathway implicated in drug addiction), we investigated the effects of aripiprazole on relapse to morphine seeking in rats. In experiment 1, rats underwent morphine-induced conditioned place preference (CPP) training with alternate injections of morphine (5 mg/kg, s.c.) and saline (1 ml/kg, s.c.) for 8 consecutive days. To examine the effect of aripiprazole on the expression of morphine-induced CPP, rats received aripiprazole (0, 0.03, 0.1, and 0.3 mg/kg, i.p.) 30 min before testing for the expression of CPP. In experiment 2, rats underwent the same CPP training as in experiment 1 and subsequent extinction training. To examine the effect of aripiprazole on reinstatement of morphine-induced CPP, rats received aripiprazole 30 min before testing for reinstatement of CPP. In experiment 3, to assess the effects of aripiprazole on locomotor activity, aripiprazole was administered 30 min before testing for locomotor activity. Aripiprazole significantly decreased the reinstatement of CPP induced by a priming injection of morphine but had no effect on the expression of morphine-induced CPP or locomotor activity. The D
2 and 5-HT
1A partial agonist and 5-HT
2A antagonist properties of aripiprazole likely account for the blockade of relapse to drug seeking. These findings suggest that aripiprazole may have therapeutic value for reducing craving and preventing relapse to drug seeking.
•(Co1−xNix)79.3B20.7 (x = 0, 0.25, 0.5, 0.75, 1) alloys were solidified at different undercoolings.•Partial substitution of Co by Ni reduces the possibility for metastable M2B.•All the Co-Ni-B alloys ...solidify into single metastable M23B6 phase at large undercooling.•The stability of metastable M23B6 phase becomes worse as the Ni content increases.•A vertical section of the Co-Ni-B phase diagram with a content of 20.7 at% B was drawn.
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(Co1−xNix)79.3B20.7 (x = 0, 0.25, 0.5, 0.75, 1) alloys were solidified at different undercoolings, aimed at the effect of Co/Ni atomic ratio on the metastable phase formation and stability. Substitution of Co by Ni reduces the possibility for metastable M2B (M = Co or/and Ni) phase to form as primary solid at medium undercoolings. As a result, M2B phase completely disappears from the solidification of the alloys with x = 0.5, 0.75 and 1. All the Co-Ni-B alloys investigated solidify into single metastable M23B6 phase at large undercooling. The stability of metastable M23B6 phase however becomes worse as the Ni content increases, due to which it is decomposed into α-M and M3B phases in the post-solidification cooling process when x ≥ 0.75. A vertical section of the Co-Ni-B phase diagram with a content of 20.7 at% B was drawn, including the liquidus temperatures of M3B, M2B and M23B6 phases and the eutectic temperatures of L → α-M + M3B and L → α-M + M2B.
Despite considerable advances in tissue engineering over the past two decades, solutions to some crucial problems remain elusive. Vascularization is one of the most important factors that greatly ...influence the function of scaffolds. Many research studies have focused on the construction of a vascular-like network with prevascularization structure. Sacrificial materials are widely used to build perfusable vascular-like architectures, but most of these fabricated scaffolds only have a 2D plane-connected network. The fabrication of three-dimensional perfusable branched networks remains an urgent issue. In this work, we developed a novel sacrificial molding technique for fabricating biocompatible scaffolds with a three-dimensional perfusable branched network. Here, 3D-printed poly(vinyl alcohol) (PVA) filament was used as the sacrificial material. The fused PVA was deposited on the surface of a cylinder to create the 3D branched solid network. Gelatin was used to embed the solid network. Then, the PVA mold was dissolved after curing the hydrogel. The obtained architecture shows good perfusability. Cell experiment results indicated that human umbilical vein endothelial cells (HUVECs) successfully attached to the surface of the branched channel and maintained high viability after a few days in culture. In order to prevent deformation of the channel, paraffin was coated on the surface of the printed structure, and hydroxyapatite (HA) was added to gelatin. In conclusion, we demonstrate a novel strategy toward the engineering of prevasculature thick tissues through the integration of the fused PVA filament deposit. This approach has great potential in solving the issue of three-dimensional perfusable branched networks and opens the way to clinical applications.
Substance P (SP) regulates multiple biological processes through its high-affinity neurokinin-1 receptor (NK-1R). While the SP/NK-1R signaling axis is involved in the pathogenesis of solid cancer, ...the role of this signaling pathway in hematological malignancy remains unknown. Here, we demonstrate that NK-1R expression is markedly elevated in the white blood cells from acute myeloid leukemia patients and a panel of human leukemia cell lines. Blocking NK-1R induces apoptosis in vitro and in vivo via increase of mitochondrial reactive oxygen species. This oxidative stress was triggered by rapid calcium flux from the endoplasmic reticulum into mitochondria and, consequently, impairment of mitochondrial function, a mechanism underlying the cytotoxicity of NK-1R antagonists. Besides anticancer activity, blocking NK-1R produces a potent antinociceptive effect in myeloid leukemia-induced bone pain by alleviating inflammation and inducing apoptosis. These findings thus raise the exciting possibility that the NK-1R antagonists, drugs currently used in the clinic for preventing chemotherapy-induced nausea and vomiting, may provide a therapeutic option for treating human myeloid leukemia.
Gold colloids with nanoparticles of different sizes were found to enhance the chemiluminescence (CL) of the luminol−H2O2 system, and the most intensive CL signals were obtained with 38-nm-diameter ...gold nanoparticles. UV−visible spectra, X-ray photoelectron spectra, and transmission electron microscopy studies were carried out before and after the CL reaction to investigate the CL enhancement mechanism. The CL enhancement by gold nanoparticles of the luminol−H2O2 system was supposed to originate from the catalysis of gold nanoparticles, which facilitated the radical generation and electron-transfer processes taking place on the surface of the gold nanoparticles. The effects of the reactant concentrations, the size of the gold nanoparticles. and some organic compounds were also investigated. Organic compounds containing OH, NH2, and SH groups were observed to inhibit the CL signal of the luminol−H2O2−gold colloids system, which made it applicable for the determination of such compounds.
There is a gap in knowledge how maternal exposure to environmental tobacco smoke (ETS) is associated with offspring congenital heart defects (CHDs). In this case-control study, we collected data on ...749 fetuses with CHDs and 880 fetuses without any congenital anomalies to examine the association of maternal ETS with fetal CHDs and the potentially moderating effect by maternal hazardous and noxious substances (HNS), periconceptional folate intake and paternal smoking. Maternal exposure to ETS in first trimester was associated with increased risk of CHDs in a dose-response gradient, with the AORs (95% CI) were1.38 (1.00-1.92), 1.60 (1.07-2.41), and 4.94 (2.43-10.05) for ETS < 1 h/day, 1-2 h/day, and ≥ 2 h/day, respectively. With the doubly unexposed group as reference categories, AORs for maternal ETS exposure ≥ 2 h/day in the absence of folate intake, in the presence of HNS exposure or paternal smoking, were 7.21, 11.43, and 8.83, respectively. Significant additive interaction between ETS exposure and maternal folate intake on CHDs was detected. Maternal ETS exposure during first trimester may increase the risk of offspring CHDs in a dose-response shape, and such effect may be modified by maternal folate intake or other potential factors.
Because beneficial effects of digitalis treatment in breast cancer patients have been suggested by epidemiological studies, we explored the mechanism of the growth inhibitory effects of these drugs ...on the estrogen receptor-negative human breast cancer cell line MDA-MB-435 s. Ouabain concentrations (100 nM or lower) that caused less than 25% inhibition of the pumping function of Na+/K+-ATPase had no effect on cell viability but inhibited proliferation. At the same concentrations, ouabain 1) activated Src kinase and stimulated the interaction of Src and Na+/K+-ATPase with epidermal growth factor receptor (EGFR); 2) caused a transient and then a sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2); 3) increased the expression of p21Cip1 but decreased that of p53; and 4) activated c-Jun NH2-terminal kinase (JNK) but not p38 kinase. These data, in conjunction with our previous findings on the signaling role of Na+/K+-ATPase in other cells, suggest that ouabain-induced activation/transactivation of Src/EGFR by Na+/K+-ATPase leads to activation of ERK1/2, the resulting increase in the level of cell cycle inhibitor p21Cip1, and growth arrest. Cooperation of JNK with ERK1/2 in this process is also suggested. Digoxin and digitoxin concentrations close to or at the therapeutic plasma levels had effects on proliferation and ERK1/2 similar to those of ouabain, supporting the proposed potential value of digitalis drugs for the treatment of breast cancer.
A novel model for three-dimensional (3D) global simulation of heat transfer in a Czochralski (CZ) furnace for silicon crystal growth was proposed. Convective, conductive and radiative heat transfers ...in the furnace are solved together in a conjugated way by a finite control-volume method. A mixed 2D/3D space discretization technique was developed, and concepts of 2D domain and 3D domain for a CZ furnace were proposed. This technique enables 3D global simulations to be conducted with moderate requirements of computer memory and computation time. A 2D global simulation was carried out to obtain good initial conditions for 3D global modeling to speed up the global iteration. The model was demonstrated to be valid and reasonable.
The incidence of prostate cancer is frequent, occurring in almost one-third of men older than 45 years. Only a fraction of the cases reach the stages displaying clinical significance. Despite the ...advances in our understanding of prostate carcinogenesis and disease progression, our knowledge of this disease is still fragmented. Identification of the genes and patterns of gene expression will provide a more cohesive picture of prostate cancer biology.
In this study, we performed a comprehensive gene expression analysis on 152 human samples including prostate cancer tissues, prostate tissues adjacent to tumor, and organ donor prostate tissues, obtained from men of various ages, using the Affymetrix (Santa Clara, CA) U95a, U95b, and U95c chip sets (37,777 genes and expression sequence tags).
Our results confirm an alteration of gene expression in prostate cancer when comparing with nontumor adjacent prostate tissues. However, our study also indicates that the gene expression pattern in tissues adjacent to cancer is so substantially altered that it resembles a cancer field effect.
We also found that gene expression patterns can be used to predict the aggressiveness of prostate cancer using a novel model.
We have shown that ouabain activates Src, resulting in subsequent tyrosine phosphorylation of multiple effectors. Here, we tested if the Na+/K+-ATPase and Src can form a functional signaling complex. ...In LLC-PK1 cells the Na+/K+-ATPase and Src colocalized in the plasma membrane. Fluorescence resonance energy transfer analysis indicated that both proteins were in close proximity, suggesting a direct interaction. GST pulldown assay showed a direct, ouabain-regulated, and multifocal interaction between the 1 subunit of Na+/K+-ATPase and Src. Although the interaction between the Src kinase domain and the third cytosolic domain (CD3) of 1 is regulated by ouabain, the Src SH3SH2 domain binds to the second cytosolic domain constitutively. Functionally, binding of Src to either the Na+/K+-ATPase or GST-CD3 inhibited Src activity. Addition of ouabain, but not vanadate, to the purified Na+/K+-ATPase/Src complex freed the kinase domain and restored the Src activity. Consistently, exposure of intact cells to ouabain apparently increased the distance between the Na+/K+-ATPase and Src. Concomitantly, it also stimulated tyrosine phosphorylation of the proteins that are associated with the Na+/K+-ATPase. These new findings illustrate a novel molecular mechanism of signal transduction involving the interaction of a P-type ATPase and a nonreceptor tyrosine kinase.
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