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Find video protocols related to scientific articles indexed in Pubmed.
Giant enhancement of ferroelectric retention in BiFeO3 mixed-phase boundary.
Adv. Mater. Weinheim
PUBLISHED: 08-11-2014
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A large enhancement of nanodomain retention is shown in the mixed-phase region of a strained BiFeO3 epitaxial film. The superior ferroelectric retention is attributed to a lower elastic-energy density at the phase boundaries, which act as periodic pinning centers for the domain wall motion. This study delivers a new pathway of incorporating an elastic-energy term to assist ferroelectric retention.
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The epigenetic factor Kmt2a/Mll1 regulates neural progenitor proliferation and neuronal and glial differentiation.
Dev Neurobiol
PUBLISHED: 06-05-2014
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Multiple epigenetic factors play a critical role in cell proliferation and differentiation. However, their function in embryogenesis, especially in neural development, is currently unclear. The Trithorax group (TrxG) homolog KMT2A (MLL1) is an important epigenetic regulator during development and has an especially well-defined role in hematopoiesis. Translocation and aberrant expression of KMT2A is often observed in many tumors, indicating its proto-oncogenic character. Here, we show that Kmt2a was essential for neural development in zebrafish embryos. Disrupting the expression of Kmt2a using morpholino antisense oligonucleotides and a dominant-negative variant resulted in neurogenic phenotypes, including downregulated proliferation of neural progenitors, premature differentiation of neurons, and impaired gliogenesis. This study therefore revealed a novel function of Kmt2a in cell proliferation and differentiation, providing further insight into the function of TrxG proteins in neural development and brain tumors. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014.
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Simvastatin treatment exerts antidepressant-like effect in rats exposed to chronic mild stress.
Pharmacol. Biochem. Behav.
PUBLISHED: 05-09-2014
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Hyperlipidemia is associated with increased risk of coronary artery disease and stroke, both of which, in turn, are risk factors of old-age depression. Statins are extensively used for decreasing cholesterol levels. Clinical investigations revealed that long-term use of statins appeared to be associated with a lower risk of anxiety and depression. However, the antidepressant property of statins has not been well examined. This study aimed at examining the antidepressant-like effects of statins in rats exposed to chronic mild stress (CMS). We found that animals exposed to CMS for 4 weeks developed depressive-like state, shown by forced swim test and sucrose preference test. However, these CMS-induced behavioral changes were reversed by simvastatin (5 or 10mg/kg/day) for 14 days, comparable to imipramine (10mg/kg/day) treatment. Locomotor activity and anxiety-like behaviors were not altered by CMS or these treatments. These results demonstrated antidepressant-like effects of statin in CMS model of rats and suggested the potential that statins could be used to facilitate antidepressant treatment in clinical setting.
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Differentiation of neural stem/progenitor cells using low-intensity ultrasound.
Ultrasound Med Biol
PUBLISHED: 04-30-2014
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Herein, we report the evaluation of apoptosis, cell differentiation, neurite outgrowth and differentiation of neural stem/progenitor cells (NSPCs) in response to low-intensity ultrasound (LIUS) exposure. NSPCs were cultured under different conditions, with and without LIUS exposure, to evaluate the single and complex effects of LIUS. A lactic dehydrogenase assay revealed that the cell viability of NSPCs was maintained with LIUS exposure at an intensity range from 100 to 500 mW/cm(2). Additionally, in comparison with no LIUS exposure, the cell survival rate was improved with the combination of medium supplemented with nerve growth factor and LIUS exposure. Our results indicate that LIUS exposure promoted NSPC attachment and differentiation on a glass substrate. Neurite outgrowth assays revealed the generation of longer, thicker neurites after LIUS exposure. Furthermore, LIUS stimulation substantially increased the percentage of differentiating neural cells in NSPCs treated with nerve growth factor in comparison with the unstimulated group. The high percentage of differentiated neural cells indicated that LIUS induced neuronal networks denser than those observed in the unstimulated groups. Furthermore, the release of nitric oxide, an important small-molecule neurotransmitter, was significantly upregulated after LIUS exposure. It is therefore reasonable to suggest that LIUS promotes the differentiation of NSPCs into neural cells, induces neurite outgrowth and regulates nitric oxide production; thus, LIUS may be a potential candidate for NSPC induction and neural cell therapy.
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Phyllanthus urinaria induces mitochondrial dysfunction in human osteosarcoma 143B cells associated with modulation of mitochondrial fission/fusion proteins.
Mitochondrion
PUBLISHED: 04-14-2014
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Phyllanthus urinaria (P. urinaria), a widely used herbal medicine, has been reported to possess various biological characteristics including anti-inflammation, anti-virus, anti-bacteria, anti-hepatotoxicity and anti-cancer. This study provides molecular evidence associated with the dynamics and organization of mitochondria in osteosarcoma 143B cells resulted from P urinaria. Herein, P. urinaria-induced cytotoxicity and ROS associated with the inhibition of mitochondrial membrane potential were reversed by N-acetylcysteine (NAC). The endogenous antioxidant enzymes such as manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPX1) were activated by P. urinaria, but not correlated to catalase. P. urinaria decreased mitochondrial respiration activity as well as respiratory chain enzymes and HIF-1? in osteosarcoma 143B cells. Additionally, both adenosine triphosphate (ATP) synthase activation and ATP production were suppressed by P. urinaria. We further investigated changes of mitochondrial dynamic in osteosarcoma 143B cells. P. urinaria indeed fragmented the mitochondrial network of osteosarcoma 143B cells. We found a significant decrease in optic atrophy type 1 (Opa1) and mitofusin 1 (Mfn1) related to fusion proteins as well as increase mitochondrial fission 1 protein (Fis1) related to fission protein. It indicated that P. urinaria modulated the mitochondrial dynamics via fusion and fission machinery. Altogether, this study offers the evidence that mitochondrial dysfunction with dynamic change is essential components for the anti-cancer mechanism elicited by P. urinaria.
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Assessment of the potential of polyphenols as a CYP17 inhibitor free of adverse corticosteroid elevation.
Biochem. Pharmacol.
PUBLISHED: 04-07-2014
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Inhibition of 17?-hydroxylase/17,20-lyase (CYP17), which dictates the proceeding of androgen biosynthesis, is recommended as an effective treatment for androgen-dependent diseases. However, androgen depletion by selective CYP17 inhibition is accompanied with corticosteroid elevation, which increases risk of cardiovascular diseases. In this study, we evaluated the likelihood of polyphenols as a CYP17 inhibitor without cardiovascular complications. All examined polyphenols significantly inhibited CYP17 in human adrenocortical H295R cells, but their effects on androgen and cortisol biosynthesis were diverse. Resveratrol was the most potent CYP17 inhibitor with an approximate IC50 of 4 ?M, and the inhibition might weigh on the 17?-hydroxylase activity more than the 17,20-lyase activity. Resveratrol also inhibited 21?-hydroxylase (CYP21) essential for corticosteroid biosynthesis but to a lesser extent, thus preventing the occurrence of cortisol elevation following CYP17 blockade. Although transcriptional down-regulation was important for ?-naphthoflavone-mediated CYP17 inhibition, resveratrol inhibited CYP17 and CYP21 mainly at the level of enzyme activity rather than enzyme abundance and cytochrome P450 electron transfer. Daidzein also inhibited CYP17 and CYP21 although less potent than resveratrol. Daidzein was the only polyphenol showing inhibition of 3?-hydroxysteroid dehydrogenase type II (3?HSD2). The exceptional 3?HSD2 inhibition led to dehydroepiandrosterone accumulation alongside daidzein-caused androgen biosynthetic impairment. In contrast, androgen and cortisol secretion was increased or remained normal under ?-naphthoflavone and ?-naphthoflavone treatments, suggesting that CYP17 inhibition was counteracted by increased substrate generation. ?-naphthoflavone and ?-naphthoflavone also enhanced the formation of cortisol from 17-hydroxyprogesterone and testosterone from androstenedione. Our findings suggest a potential application of resveratrol in androgen deprivation therapy.
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Application of physiologically based absorption modeling to formulation development of a low solubility, low permeability weak base: mechanistic investigation of food effect.
AAPS PharmSciTech
PUBLISHED: 01-17-2014
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Physiologically based pharmacokinetic (PBPK) modeling has been broadly used to facilitate drug development, hereby we developed a PBPK model to systematically investigate the underlying mechanisms of the observed positive food effect of compound X (cpd X) and to strategically explore the feasible approaches to mitigate the food effect. Cpd X is a weak base with pH-dependent solubility; the compound displays significant and dose-dependent food effect in humans, leading to a nonadherence of drug administration. A GastroPlus Opt logD Model was selected for pharmacokinetic simulation under both fasted and fed conditions, where the biopharmaceutic parameters (e.g., solubility and permeability) for cpd X were determined in vitro, and human pharmacokinetic disposition properties were predicted from preclinical data and then optimized with clinical pharmacokinetic data. A parameter sensitivity analysis was performed to evaluate the effect of particle size on the cpd X absorption. A PBPK model was successfully developed for cpd X; its pharmacokinetic parameters (e.g., C max, AUCinf, and t max) predicted at different oral doses were within ±25% of the observed mean values. The in vivo solubility (in duodenum) and mean precipitation time under fed conditions were estimated to be 7.4- and 3.4-fold higher than those under fasted conditions, respectively. The PBPK modeling analysis provided a reasonable explanation for the underlying mechanism for the observed positive food effect of the cpd X in humans. Oral absorption of the cpd X can be increased by reducing the particle size (<100 nm) of an active pharmaceutical ingredient under fasted conditions and therefore, reduce the cpd X food effect correspondingly.
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Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy.
Int J Mol Sci
PUBLISHED: 01-08-2014
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Parkinson disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. Mitochondrial dysfunction, oxidative stress or protein misfolding and aggregation may underlie this process. Autophagy is an intracellular catabolic mechanism responsible for protein degradation and recycling of damaged proteins and cytoplasmic organelles. Autophagic dysfunction may hasten the progression of neuronal degeneration. In this study, resveratrol promoted autophagic flux and protected dopaminergic neurons against rotenone-induced apoptosis. In an in vivo PD model, rotenone induced loss of dopaminergic neurons, increased oxidation of mitochondrial proteins and promoted autophagic vesicle development in brain tissue. The natural phytoalexin resveratrol prevented rotenone-induced neuronal apoptosis in vitro, and this pro-survival effect was abolished by an autophagic inhibitor. Although both rotenone and resveratrol promoted LC3-II accumulation, autophagic flux was inhibited by rotenone and augmented by resveratrol. Further, rotenone reduced heme oxygenase-1 (HO-1) expression, whereas resveratrol increased HO-1 expression. Pharmacological inhibition of HO-1 abolished resveratrol-mediated autophagy and neuroprotection. Notably, the effects of a pharmacological inducer of HO-1 were similar to those of resveratrol, and protected against rotenone-induced cell death in an autophagy-dependent manner, validating the hypothesis of HO-1 dependent autophagy in preventing neuronal death in the in vitro PD model. Collectively, our findings suggest that resveratrol induces HO-1 expression and prevents dopaminergic cell death by regulating autophagic flux; thus protecting against rotenone-induced neuronal apoptosis.
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Identification of the proteins required for fatty acid desaturation in zebrafish (Danio rerio).
Biochem. Biophys. Res. Commun.
PUBLISHED: 09-18-2013
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Zebrafish ?-5/?-6 fatty acid desaturase (Z-FADS) catalyzes the cascade synthesis of long-chain polyunsaturated fatty acids (PUFAs), thereby playing a pivotal role in several biological processes. In the current study, we report that the Z-FADS protein exists in close proximity to certain cytochrome b5 reductases (CYB5R2 and 3) and elongases (ELOVL2, 4, 5 and 7) on the endoplasmic reticulum, as determined using fluorescence microscopy and fluorescence resonance energy transfer. HeLa cells co-transfected with zebrafish fads and elovl2, 4, and 5 produced docosahexaenoic acid (DHA), as detected by gas chromatography. In addition, immunofluorescence cytochemistry and Western blot data revealed that Z-FADS is present in the mitochondria of HeLa cells. Collectively, our results implicate that Z-FADS, the sole fatty acid desaturase ever been identified in zebrafish, can serve as a universal fatty acid desaturase during lipogenesis.
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Monolayer graphene dispersion and radiative cooling for high power LED.
Nanotechnology
PUBLISHED: 09-05-2013
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Molecular fan, a radiative cooling by thin film, has been developed and its application for compact electronic devices has been evaluated. The enhanced surface emissivity and heat dissipation efficiency of the molecular fan coating are shown to correlate with the quantization of lattice modes in active nanomaterials. The highly quantized G and 2D bands in graphene are achieved by our dispersion technique, and then incorporated in an organic-inorganic acrylate emulsion to form a coating assembly on heat sinks (for LED and CPU). This water-based dielectric layer coating has been formulated and applied on metal core printed circuit boards. The heat dissipation efficiency and breakdown voltage are evaluated by a temperature-monitoring system and a high-voltage breakdown tester. The molecular fan coating on heat dissipation units is able to decrease the equilibrium junction temperature by 29.1?° C, while functioning as a dielectric layer with a high breakdown voltage (>5 kV). The heat dissipation performance of the molecular fan coating applied on LED devices shows that the coated 50 W LED gives an enhanced cooling of 20% at constant light brightness. The schematics of monolayer graphene dispersion, undispersed graphene platelet, and continuous graphene sheet are illustrated and discussed to explain the mechanisms of radiative cooling, radiative/non-radiative, and non-radiative heat re-accumulation.
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Epigallocatechin gallate (EGCG), influences a murine WEHI-3 leukemia model in vivo through enhancing phagocytosis of macrophages and populations of T- and B-cells.
In Vivo
PUBLISHED: 08-31-2013
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Epigallocatechin gallate (EGCG) is the major polyphenol in green tea, and has been reported to have anticancer effects on many types of cancer cells. However, there is no report to show its effects on the immune response in a murine leukemia mouse model. Thus, in the present study, we investigated the effects of EGCG on the immune responses of murine WEHI-3 leukemia cells in vivo. WEHI-3 cells were intraperitoneally injected into normal BALB/c mice to establish leukemic BALB/c mice, which were then oral-treated with or without EGCG at 5, 20 and 40 mg/kg for two weeks. The results indicated that EGCG did not change the weight of the animals, nor the liver or spleen when compared to vehicle (olive oil) -treated groups. Furthermore, EGCG increased the percentage of cluster of differentiation 3 (CD3) (T-cell), cluster of differentiation 19 (CD19) (B-cell) and Macrophage-3 antigen (Mac-3) (macrophage) but reduced the percentage of CD11b (monocyte) cell surface markers in EGCG-treated groups as compared with the untreated leukemia group. EGCG promoted the phagocytosis of macrophages from 5 mg/kg treatment and promoted natural killer cell activity at 40 mg/kg, increased T-cell proliferation at 40 mg/kg but promoted B-cell proliferation at all three doses. Based on these observations, it appears that EGCG might exhibit an immune response in the murine WEHI-3 cell line-induced leukemia in vivo.
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Associations of mitochondrial haplogroups b4 and e with biliary atresia and differential susceptibility to hydrophobic bile Acid.
PLoS Genet.
PUBLISHED: 08-01-2013
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Mitochondrial dysfunction has been implicated in the pathogenesis of biliary atresia (BA). This study aimed to determine whether a specific mitochondrial DNA haplogroup is implicated in the pathogenesis and prognosis of BA. We determined 40 mitochondrial single nucleotide polymorphisms in 15 major mitochondrial haplogroups by the use of 24-plex PCR and fluorescent beads combined with sequence-specific oligonucleotide probes in 71 patients with BA and in 200 controls in the Taiwanese population of ethnic Chinese background. The haplogroup B4 and E prevalence were significantly lower and higher respectively, in the patients with BA than in the controls (odds ratios, 0.82 [p = 0.007] and 7.36 [p = 0.032] respectively) in multivariate logistic-regression analysis. The 3-year survival rate with native liver was significantly lower in haplogroup E than the other haplogroups (P = 0.037). A cytoplasmic hybrid (cybrid) was obtained from human 143B osteosarcoma cells devoid of mtDNA (?(0) cell) and was fused with specific mtDNA bearing E and B4 haplogroups donated by healthy Taiwanese subjects. Chenodeoxycholic acid treatment resulted in significantly lower free radical production, higher mitochondrial membrane potential, more viable cells, and fewer apoptotic cybrid B4 cells than parental 143B and cybrid E cells. Bile acid treatment resulted in a significantly greater protective mitochondrial reaction with significantly higher mitochondrial DNA copy number and mitofusin 1 and 2 concentrations in cybrid B4 and parental cells than in cybrid E cells. The results of the study suggested that the specific mitochondrial DNA haplogroups B4 and E were not only associated with lower and higher prevalence of BA respectively, in the study population, but also with differential susceptibility to hydrophobic bile acid in the cybrid harboring different haplogroups.
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Heat shock protein 70 protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus via inhibition of nuclear factor-?B activation-induced nitric oxide synthase II expression.
Neurobiol. Dis.
PUBLISHED: 07-03-2013
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Status epilepticus induces subcellular changes that may eventually lead to neuronal cell death in the hippocampus. Based on an animal model of status epilepticus, our laboratory showed previously that sustained hippocampal seizure activity activates nuclear factor-?B (NF-?B) and upregulates nitric oxide synthase (NOS) II gene expression, leading to apoptotic neuronal cell death in the hippocampus. The present study examined the potential modulatory role of heat shock protein 70 (HSP70) on NF-?B signaling in the hippocampus following experimental status epilepticus. In Sprague-Dawley rats, kainic acid (KA) was microinjected unilaterally into the hippocampal CA3 subfield to induce prolonged bilateral seizure activity. Expression of HSP70 was elevated as early as 1h after the elicitation of sustained seizure activity, followed by a progressive elevation that peaked at 24h. Pretreatment with an antisense oligonucleotide against hsp70 decreased the HSP70 expression, and significantly augmented I?B kinase (IKK) activity and phosphorylation of I?B?, alongside enhanced nuclear translocation and DNA binding activity of NF-?B in the hippocampal CA3 neurons and glial cells. These cellular events were followed by enhanced upregulation of NOS II and peroxynitrite expression 3h after sustained seizure activity that led to an increase of caspase-3 and DNA fragmentation in the hippocampal CA3 neurons 7days after experimental status epilepticus. We concluded that HSP70 protects against apoptotic cell death induced by NF-?B activation and NOS II-peroxynitrite signaling cascade in the hippocampal CA3 and glial cells following experimental status epilepticus via suppression of IKK activity and deactivation of I?B?.
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The diagnostic value of ultrasonography in carpal tunnel syndrome: a comparison between diabetic and non-diabetic patients.
BMC Neurol
PUBLISHED: 06-21-2013
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To compare the value of ultrasonography for diagnosing carpal tunnel syndrome (CTS) in patients with and without diabetes mellitus (DM).
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Genetic algorithm-generated SNP barcodes of the mitochondrial D-loop for chronic dialysis susceptibility.
Mitochondrial DNA
PUBLISHED: 06-12-2013
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Abstract Background and aims: Single nucleotide polymorphism (SNP) interaction analysis can simultaneously evaluate the complex SNP interactions present in complex diseases. However, it is less commonly applied to evaluate the predisposition of chronic dialysis and its computational analysis remains challenging. In this study, we aimed to improve the analysis of SNP-SNP interactions within the mitochondrial D-loop in chronic dialysis. Material & method: The SNP-SNP interactions between 77 reported SNPs within the mitochondrial D-loop in chronic dialysis study were evaluated in terms of SNP barcodes (different SNP combinations with their corresponding genotypes). We propose a genetic algorithm (GA) to generate SNP barcodes. The ?(2) values were then calculated by the occurrences of the specific SNP barcodes and their non-specific combinations between cases and controls. Results: Each SNP barcode (2- to 7-SNP) with the highest value in the ?(2) test was regarded as the best SNP barcode (11.304 to 23.310; p?
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Single nucleotide polymorphisms in the mitochondrial control region are associated with metabolic phenotypes and oxidative stress.
Gene
PUBLISHED: 04-15-2013
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To identify the mitochondrial DNA (mtDNA) single nucleotide polymorphisms (SNPs) in the control region and elucidate their role in metabolic phenotypes and oxidative stress.
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Utility of physiologically based modeling and preclinical in vitro/in vivo data to mitigate positive food effect in a BCS class 2 compound.
AAPS PharmSciTech
PUBLISHED: 03-25-2013
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Physiologically based pharmacokinetic (PBPK) modeling has become a useful tool to estimate the performance of orally administrated drugs. Here, we described multiple in silico/in vitro/in vivo tools to support formulation development toward mitigating the positive food effect of NVS123, a weak base with a pH-dependent and limited solubility. Administered orally with high-fat meal, NVS123 formulated as dry filled capsules displayed a positive food effects in humans. Three alternative formulations were developed and assessed in in vitro and in vivo preclinical and/or clinical studies. By integrating preclinical in vitro and in vivo data, the PBPK model successfully estimated the magnitude of food effects and the predicted values were within ± 30% of the observed results. A model-guided parameter sensitivity analysis illustrated that enhanced solubility and longer precipitation times under fed condition were the main reason for enhanced NVS123s exposure in presence of food. Eventually, exposure after an amorphous formulation was found to be not significantly altered because of remarkably enhanced intestinal solubility and reduced precipitation. Gastroplus population simulations also suggested that the amorphous formulation is promising in mitigating a clinically significant food effect. Overall, these efforts supported the rationale of clinical investigation of the new formulation, and more importantly, highlighted a practical application of PBPK modeling solving issues of undesirable food effects in weakly basic compounds based on preclinical in vitro/in vivo data.
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Bcl-2 associated with positive symptoms of schizophrenic patients in an acute phase.
Psychiatry Res
PUBLISHED: 03-23-2013
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B cell lymphoma protein-2 (Bcl-2) may contribute to the pathophysiology of schizophrenia in the brain. The aim of this study was to investigate the serum levels of Bcl-2 in schizophrenic patients in an acute phase, and evaluate Bcl-2 level changes after antipsychotic treatment. We consecutively enrolled 41 schizophrenia patients in an acute phase; 28 were followed up with a 4-week antipsychotic treatment. Serum Bcl-2 levels were measured with assay kits. All patients were evaluated by examining the correlation between Bcl-2 levels and Positive and Negative Syndrome Scale (PANSS) scores, using Pearson correlation coefficients. In schizophrenic patients in an acute phase, positive PANSS subscores were significantly negatively correlated with Bcl-2 levels. In addition, we found Bcl-2 levels had a significantly negative correlation with PANSS total scores and positive subscores in male patients in an acute phase. Using the paired t-test, we found no significant changes in Bcl-2 levels in schizophrenia patients who had received the 4-week treatment with antipsychotic drugs (n=28). In conclusion, our results suggest that Bcl-2 might be an indicator of schizophrenia severity in the acute phase. In addition, Bcl-2 levels might be associated with positive symptoms in male patients with schizophrenia.
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Learning curve of single-port laparoscopic appendectomy for noncomplicated acute appendicitis: a preliminary analysis compared with conventional laparoscopic appendectomy.
J Laparoendosc Adv Surg Tech A
PUBLISHED: 03-21-2013
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The aim of this study was to delineate the learning curve of single-port laparoscopic appendectomy for noncomplicated appendicitis.
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Characterization of cross protection of Swine-Origin Influenza Virus (S-OIV) H1N1 and reassortant H5N1 influenza vaccine in BALB/c mice given a single-dose vaccination.
J. Biomed. Sci.
PUBLISHED: 03-18-2013
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Influenza virus has antigen drift and antigen shift effect, vaccination with some influenza vaccine might not induce sufficient immunity for host to the threat of other influenza virus strains. S-OIV H1N1 and H5N1 influenza vaccines in single-dose immunization were evaluated in mice for cross protection to the challenge of A/California/7/2009 H1N1 or NIBRG-14 H5N1 virus.
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Study of insulin resistance in cybrid cells harboring diabetes-susceptible and diabetes-protective mitochondrial haplogroups.
Mitochondrion
PUBLISHED: 01-27-2013
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This study aims to elucidate the independent role of mitochondria in the pathogenesis of insulin resistance (IR).
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Preventive SNP-SNP interactions in the mitochondrial displacement loop (D-loop) from chronic dialysis patients.
Mitochondrion
PUBLISHED: 01-24-2013
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Chronic dialysis association study involving individual single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) has previously been reported. However, possible SNP-SNP interactions for SNPs in the D-loop which could be associated with a reduced risk for chronic dialysis were not investigated. The purpose of this study was to propose an effective algorithm to identify protective SNP-SNP interactions in the D-loop from chronic dialysis patients. We introduce ISGA that uses an initialization strategy for genetic algorithms (GA) to improve the computational analysis for protective SNP-SNP interactions. ISGA generates genotype patterns with combined SNPs (SNP barcodes) for chronic dialysis. Using our previously reported 77 SNPs in the D-loop, the algorithm-generated protective SNP barcodes for chronic dialysis were evaluated. ISGA provides the SNP barcodes with the maximum frequency differences of occurrence between the cases and controls. The identified SNP barcodes with the lowest odds ratio (OR) values were regarded as the best preventive SNP barcodes against chronic dialysis. The best ISGA-generated SNP barcodes (two to nine SNPs) are more closely associated with the prevention of chronic dialysis when more SNPs are chosen (OR=0.64 to 0.32; 95% confidence interval=0.882 to 0.198). The cumulative effects of SNP-SNP interactions were more dominant in ISGA rather than in GA without the initialization strategy. We provide a fast identification of chronic dialysis-associated protective SNP barcodes and demonstrate that the SNP-SNP interactions may have a cumulative effect on prediction for chronic dialysis.
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Changes in oxidative stress markers in patients with schizophrenia: the effect of antipsychotic drugs.
Psychiatry Res
PUBLISHED: 01-12-2013
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The aim of this study was to investigate the serum levels or activities of oxidative stress markers in patients with schizophrenia in acute phase and evaluate the changes in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) and thiobarbituric acid-reactive substances (TBARS) after treatment. We consecutively enrolled 41 patients with schizophrenia in acute phase, and 27 patients were followed up with a 4-week antipsychotic treatment. Serum oxidative stress markers were measured with assay kits. We found that Positive and Negative Syndrome Scale (PANSS) total scores were significantly negatively correlated with serum GPx activity and GSH levels and positively correlated with serum SOD activity in patients with schizophrenia in acute phase. In addition, serum GPx activity had a positive correlation with GSH levels and negative correlation with SOD activity. We also found that serum SOD activity was significantly negatively correlated with TBARS levels in patients in acute phase. Furthermore, we found significantly increased changes only in GPx activity in female patients receiving the 4-week treatment (P=0.006). In conclusion, our results suggest that SOD, GPX and GSH might be indicators of schizophrenia severity in acute phase. Furthermore, antipsychotic drugs might affect serum GPx activity in female patients receiving the 4-week treatment.
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2-Deoxyglucose treatment complements the cisplatin- or BH3-only mimetic-induced suppression of neuroblastoma cell growth.
Int. J. Biochem. Cell Biol.
PUBLISHED: 01-09-2013
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Neuroblastoma (NB) is characterized by pleomorphic molecular characteristics, which may influence cellular metabolism as well as the efficacy of glycolytic inhibitors in suppressing NB cell growth. We studied the metabolic profile of four NB cell lines without or with MYCN amplification and found no unanimous metabolic characteristics. The two NB cell lines with MYCN amplification exhibited a significantly higher HIF-1? expression level and ATP content compared to the two cell lines without MYCN amplification. MYCN amplification was associated with significantly greater inhibition of cellular proliferation and more apoptosis after treatment with the glycolytic inhibitor 2-deoxyglucose (2DG). Further analysis showed that 2DG increased PDK1 but decreased the ATP content and increased expression of the proapoptotic BH3-only protein Bad in both SK-N-AS (without MYCN amplification) and SK-N-DZ (with MYCN amplification) cells. In addition, 2DG decreased hexokinase II expression in SK-N-DZ cells and increased HIF-1?, Noxa, and PUMA expression in SK-N-AS cells. Pretreating SK-N-DZ cells with 2DG or cisplatin for 24 h, followed by cisplatin or 2DG for another 24 h, resulted in significantly greater suppression of cellular proliferation compared to treatment with 2DG or cisplatin for 48 h alone. Effective suppression of SK-N-AS proliferation occurred only when the cells were pretreated with cisplatin. Pretreatment of SK-N-DZ, but not SK-N-AS, with 2DG followed by the BH3-only mimetic ABT737 also resulted in significantly greater suppression of cellular proliferation compared to treatment with ABT737 or 2DG alone. A low dose of 2DG (2mM) was as effective as a high dose (20mM) in SK-N-DZ cells. In conclusion, the glycolytic inhibitor 2DG complemented the cisplatin- or ABT737-induced suppression of growth in NB cells, which are sensitive to glycolytic inhibition.
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Dner inhibits neural progenitor proliferation and induces neuronal and glial differentiation in zebrafish.
Dev. Biol.
PUBLISHED: 01-02-2013
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Delta/notch-like epidermal growth factor (EGF)-related receptor (DNER) is a single-pass transmembrane protein found to be a novel ligand in the Notch signaling pathway. Its function was previously characterized in the developing cerebellum and inner ear hair cells. In this study, we isolated a zebrafish homolog of DNER and showed that this gene is expressed in the developing nervous system. Overexpression of dner or the intracellular domain of dner was sufficient to inhibit the proliferation of neural progenitors and induce neuronal and glial differentiation. In contrast, the knockdown of endogenous Dner expression using antisense morpholino oligonucleotides increased the proliferation of neural progenitors and maintained neural cells in a progenitor status through inhibition of neuronal and glial differentiation. Through analysis of the antagonistic effect on the Delta ligand and the role of the potential downstream mediator Deltex1, we showed that Dner acts in Notch-dependent and Notch-independent manner. This is the first study to demonstrate a role for Dner in neural progenitors and neuronal differentiation and provides new insights into mediation of neuronal development and differentiation by the Notch signaling pathway.
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Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis.
Epilepsia
PUBLISHED: 11-15-2011
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Long-term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long-term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process.
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Roles of Oxidative Stress, Apoptosis, PGC-1? and Mitochondrial Biogenesis in Cerebral Ischemia.
Int J Mol Sci
PUBLISHED: 08-01-2011
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The primary physiological function of mitochondria is to generate adenosine triphosphate through oxidative phosphorylation via the electron transport chain. Overproduction of reactive oxygen species (ROS) as byproducts generated from mitochondria have been implicated in acute brain injuries such as stroke from cerebral ischemia. It was well-documented that mitochondria-dependent apoptotic pathway involves pro- and anti-apoptotic protein binding, release of cytochrome c, leading ultimately to neuronal death. On the other hand, mitochondria also play a role to counteract the detrimental effects elicited by excessive oxidative stress. Recent studies have revealed that oxidative stress and the redox state of ischemic neurons are also implicated in the signaling pathway that involves peroxisome proliferative activated receptor-? (PPAR?) co-activator 1? (PGC1-?). PGC1-? is a master regulator of ROS scavenging enzymes including manganese superoxide dismutase 2 and the uncoupling protein 2, both are mitochondrial proteins, and may contribute to neuronal survival. PGC1-? is also involved in mitochondrial biogenesis that is vital for cell survival. Experimental evidence supports the roles of mitochondrial dysfunction and oxidative stress as determinants of neuronal death as well as endogenous protective mechanisms after stroke. This review aims to summarize the current knowledge focusing on the molecular mechanisms underlying cerebral ischemia involving ROS, mitochondrial dysfunction, apoptosis, mitochondrial proteins capable of ROS scavenging, and mitochondrial biogenesis.
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The relationship between isolated dizziness/vertigo and the risk factors of ischemic stroke: a case control study.
Acta Neurol Taiwan
PUBLISHED: 07-09-2011
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Dizziness/vertigo are important public heath care issues especially in elderly patients. Isolated dizziness/vertigo without neurological deficits has seldom been considered a symptom/sign due to vascular origin. Recently, some studies have suggested that vascular origin should be considered in cases of positional vertigo and isolated vertigo or dizziness when the etiology remains unclear. In this study, we tried to delineate the correlation of dizziness/vertigo and risk factors of stroke.
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Statin pre-treatment is associated with lower platelet activity and favorable outcome in patients with acute non-cardio-embolic ischemic stroke.
Crit Care
PUBLISHED: 03-31-2011
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Statins reportedly have anti-inflammatory and anti-thrombotic effects aside from cholesterol-lowering. This study aimed to evaluate the effect of pre-existing statin use on platelet activation markers and clinical outcome in acute ischemic stroke patients.
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Dexamethasone decreases cholestatic liver injury via inhibition of intrinsic pathway with simultaneous enhancement of mitochondrial biogenesis.
Steroids
PUBLISHED: 01-31-2011
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Mitochondria are known to be involved in cholestatic liver injury. We tested the hypothesis that glucocorticoids can modulate mitochondrial function to alleviate cholestatic liver injury.
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Tissue-specific differences in mitochondrial DNA content in type 2 diabetes.
Diabetes Res. Clin. Pract.
PUBLISHED: 01-10-2011
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To investigate whether the effect of hyperglycemia on mitochondrial DNA (mtDNA) content is tissue-specific.
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Unsymmetrical squaraines incorporating the thiophene unit for panchromatic dye-sensitized solar cells.
Org. Lett.
PUBLISHED: 11-03-2010
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Two unsymmetrical squaraines, where the electron-rich 3,4-ethylenedioxythiophene or bithiophene conjugated fragment was used to link unconventionally the squaraine core and the hexyloxyphenyl amino group, were applied for DSCs. The corresponding photovoltaic devices exhibit an attractively panchromatic response and also convert a portion of the near-infrared photons into electricity.
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The value of serial plasma nuclear and mitochondrial DNA levels in patients with acute ischemic stroke.
Clin. Chim. Acta
PUBLISHED: 09-24-2010
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Elevated circulating cell-free DNA in plasma is reported in several critical diseases. This study hypothesized that since plasma nuclear and mitochondrial DNA substantially increase after acute ischemic stroke and decrease thereafter, their levels can predict treatment outcomes.
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Activation of calcium/calmodulin-dependent protein kinase IV and peroxisome proliferator-activated receptor ? coactivator-1? signaling pathway protects against neuronal injury and promotes mitochondrial biogenesis in the hippocampal CA1 subfield after tra
J. Neurosci. Res.
PUBLISHED: 08-28-2010
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Delayed neuronal cell death occurs in the vulnerable CA1 subfield of the hippocampus after transient global ischemia (TGI). We demonstrated previously, based on an experimental model of TGI, that the significantly increased content of oxidized proteins in hippocampal CA1 neuron was observed as early as 30 min after TGI, followed by augmentation of PGC-1? expression at 1 hr, as well as up-regulation of mitochondrial uncoupling protein 2 (UCP2) and superoxide dismutases 2 (SOD2). Using the same animal model, the present study investigated the role of calcium/calmodulin-dependent protein kinase IV (CaMKIV) and PGC-1? in delayed neuronal cell death and mitochondrial biogenesis in the hippocampus. In Sprague-Dawley rats, significantly increased expression of nuclear CaMKIV was noted in the hippocampal CA1 subfield as early as 15 min after TGI. In addition, the index of mitochondrial biogenesis, including a mitochondrial DNA-encoded polypeptide, cytochrome c oxidase subunit 1 (COX1), and mitochondrial number significantly increased in the hippocampal CA1 subfield 4 hr after TGI. Application bilaterally into the hippocampal CA1 subfield of an inhibitor of CaMKIV, KN-93, 30 min before TGI attenuated both CaMKIV and PGC-1? expression, followed by down-regulation of UCP2 and SOD2, decrease of COX1 expression and mitochondrial number, heightened protein oxidation, and enhanced hippocampal CA1 neuronal damage. This study provides correlative evidence for the neuroprotective cascade of CaMKIV/PGC-1? which implicates at least in part the mitochondrial antioxidants UCP2 and SOD2 as well as mitochondrial biogenesis in ischemic brain injury.
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Nickel(II)-induced oxidative stress, apoptosis, G2/M arrest, and genotoxicity in normal rat kidney cells.
J. Toxicol. Environ. Health Part A
PUBLISHED: 04-15-2010
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In order to elucidate the effects of nickel (Ni) on oxidative stress, apoptosis, and genotoxicity in renal cells, the levels of intracellular oxidants, lipid peroxidation, apoptotic proteins, and DNA damage were measured in normal rat kidney (NRK) cells after nickel chloride (NiCl(2)) treatment. NiCl(2) appeared to increase the formation of the fluorescent oxidized compound (dichlorofluorescein, DCF) and levels of thiobarbituric acid-reactive substances (TBARS). In flow cytometric analysis, a rise in cell proportion in sub-G1 phase occurred in a concentration-dependent manner. After Ni treatment, there was reduced expression of Bcl-2 and Bcl-xL proteins, while induced Bad and Bax proteins expression was higher. Single-strand DNA breakage induced by Ni in NRK cells was determined by comet assay. Significant increase DNA damage score (arbitrary units) was noted in a concentration-related manner after treatment with Ni. Induction of intracellular oxidants by Ni was accompanied by an increasing frequency of DNA strand breakage. Our data indicate that Ni-induced oxidative stress and genotoxicity in NRK cells may involve reactive oxygen intermediates, and that Bcl family-mediated signaling pathway may be involved in positive regulation of Ni-induced renal cytotoxicity.
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A/H1N1 influenza vaccination in patients with systemic lupus erythematosus: safety and immunity.
Vaccine
PUBLISHED: 04-14-2010
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To determine the safety of and immunogenicity induced by A/H1N1 influenza vaccination in patients with systemic lupus erythematosus (SLE).
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Serum thiobarbituric acid-reactive substances and free thiol levels in schizophrenia patients: effects of antipsychotic drugs.
Psychiatry Res
PUBLISHED: 04-08-2010
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This study investigated the levels of serum thiobarbituric acid-reactive substances (TBARS) and free thiols in schizophrenia patients and healthy control subjects, and evaluated the effects of antipsychotic drugs. During a 2-year period, 77 schizophrenia patients and 110 healthy control subjects were recruited. Psychiatric diagnoses of schizophrenia were made according to DSM-IV criteria. Serum TBARS and free thiol levels were measured using the standard procedure in the laboratory room. Using analysis of covariance with body mass index adjustment, we found that schizophrenia patients had significantly lower serum levels of free thiols than the controls. Fifty-five patients were followed up and their serum TBARS and free thiol levels were measured at the end of the 4-week treatment with antipsychotic drugs. We found that there were significantly decreased changes in free thiol levels, but not in TBARS levels. Furthermore, patients taking risperidone had significantly decreased changes in free thiol levels. Additionally, the responders showed significantly decreased changes in free thiol levels, but not in TBARS levels. In conclusion, these analytical results suggested that serum free thiols might play an important role in the psychopathology of schizophrenia and could be used as markers for determining the treatment response in schizophrenia.
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An instrument for evaluation of performance of heat dissipative coatings.
Rev Sci Instrum
PUBLISHED: 04-08-2010
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An instrument is developed to evaluate the performance of heat dissipative coatings. The instrument has features to measure the apparent emissivity of a given surface under different input power settings. The emissivity of aluminum (Al Q-panel) and copper, as measured from 60-135 degrees C, showed a value of 0.15+/-0.03 and 0.42+/-0.05, respectively, consistent with reported values in literature. The relative emissivity of a heat dissipative coating, called as molecular fan carbon nanotube "MF-CNT," was found to be approximately 0.97. A simple mathematical model is built to evaluate the role of different heat transfer mechanisms (convection and radiation) on cooling performance, and it was observed that convection plays a dominant role in cooling, with more than 90% of heat transferred by convection. In presence of MF-CNT coating, radiation heat transfer increases to approximately 30% and lowers the steady state temperature by 10 degrees C. It is illustrated that radiative cooling could be a significant factor in thermal management.
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Transcriptional upregulation of nitric oxide synthase II by nuclear factor-kappaB promotes apoptotic neuronal cell death in the hippocampus following experimental status epilepticus.
J. Neurosci. Res.
PUBLISHED: 02-16-2010
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Whereas status epilepticus, or the condition of continuous epileptic seizures, produces a characteristic pattern of preferential neuronal cell loss in the hippocampus, the underlying mechanism is still unsettled. Based on an experimental model of temporal lobe status epilepticus, we demonstrated previously that prolonged seizures prompted an overproduction of nitric oxide (NO) by upregulation of NO synthase II (NOS II) in the hippocampal CA3 subfield, followed by the activation of mitochondrial apoptotic signaling cascade. Using the same animal model, the present study evaluated the hypothesis that transcriptional upregulation of NOS II gene by nuclear factor-kappaB (NF-kappaB) promotes apoptotic neuronal cell death in the hippocampus following status epilepticus. In Sprague-Dawley rats, significantly augmented nucleus-bound translocation of NF-kappaB p50 and p65 subunits and DNA binding activity of NF-kappaB were observed in hippocampal CA3 neurons as early as 30 min after elicitation of sustained seizure activity by microinjection of kainic acid into the CA3 subfield, followed by a progressive elevation that peaked at 90 min. In addition, application bilaterally into the hippocampal CA3 subfield of a selective NF-kappaB inhibitor, pyrrolidine dithiocarbamate or double-stranded kappaB decoy DNA significantly antagonized the activated NOS II-peroxynitrite signaling cascade (3 hr) and the associated manifestations of apoptotic cell death (7 days) in the hippocampus. We conclude that activation of NF-kappaB in hippocampal CA3 neurons upregulates NOS II gene expression following experimental temporal lobe status epilepticus, leading to apoptotic neuronal cell death in the hippocampus.
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Recurrent multiple cranial neuropathies in a diabetic patient.
Acta Neurol Taiwan
PUBLISHED: 01-18-2010
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Multiple cranial neuropathies is one of the neurological complications among diabetic patients. Symptoms of multiple cranial neuropathies may cause great anxiety for these patients and often appear to be a serious problem from a diagnostic and therapeutic point of view. A correct and timely diagnosis of the underlying cause of cranial nerve palsy in these patients is crucial because of the realistic threat of devastating neurologic conditions.
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Mitochondrial DNA variants in the pathogenesis of type 2 diabetes - relevance of asian population studies.
Rev Diabet Stud
PUBLISHED: 12-30-2009
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Mitochondrial dysfunction involves defective insulin secretion by pancreatic beta-cells, and insulin resistance in insulin-sensitive tissues such as muscle and adipose tissue. Mitochondria are recognized as the most important cellular source of energy, and the major generator of intracellular reactive oxygen species (ROS). Intracellular antioxidative systems have been developed to cope with increased oxidative damage. In case of minor oxidative stress, the cells may increase the number of mitochondria to produce more energy. A mechanism called mitochondrial biogenesis, involving several transcription factors and regulators, controls the quantity of mitochondria. When oxidative damage is advanced beyond the repair capacity of antioxidative systems, then oxidative stress can lead to cell death. Therefore, this organelle is central to cell life or death. Available evidence increasingly shows genetic linkage between mitochondrial DNA (mtDNA) alterations and type 2 diabetes (T2D). Based on previous studies, the mtDNA 16189 variant is associated with metabolic syndrome, higher fasting insulin concentration, insulin resistance index and lacunar cerebral infarction. These data support the involvement of mitochondrial genetic variation in the pathogenesis of T2D. Importantly, phylogeographic studies of the human mtDNAs have revealed that the human mtDNA tree is rooted in Africa and radiates into different geographic regions and can be grouped as haplogroups. The Asian populations carry very different mtDNA haplogroups as compared to European populations. Therefore, it is critically important to determine the role of mtDNA polymorphisms in T2D.
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Mitochondrial dysfunction and biogenesis in the pathogenesis of Parkinsons disease.
Chang Gung Med J
PUBLISHED: 12-29-2009
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Parkinsons disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration and development of cytoplasmic aggregates known as Lewy bodies. The impact of this disease is indicated by the fact that mortality is two to five times as high among affected persons as among age-matched controls. However, the cause of PD is still unknown and no cure is available at present. Several biochemical abnormalities have been described in the brains of patients with PD, including oxidative stress and mitochondrial dysfunction. Recent identification of specific gene mutations that cause PD has further reinforced the relevance of oxidative stress and mitochondrial dysfunction in the familial and sporadic forms of the disease. The proteins that are reported to be related to familial PD-PTEN-induced putative kinase 1 (PINK1), DJ-1, alpha- synuclein, leucine-rich repeat kinase 2 (LRRK2), and, possibly, parkin-are either mitochondrial proteins or are associated with mitochondria, and all are involved in pathways that elicit oxidative stress or free radical damage. Mitochondria are continually exposed to reactive oxygen species and accumulate oxidative damage more rapidly than the rest of the cell. Therefore, Parkinsons disease has been suggested to be associated with mitochondrial dysfunction. Since mitochondria are the major intracellular organelles that regulate both cell survival and death, clarifying the involvement of mitochondrial dysfunction and biogenesis during the process of PD could provide treatment strategies that might successfully intervene in the pathogenesis and slow the progression of the disease.
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Sleeping ECG and body position monitoring system.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 12-08-2009
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A textile-based ECG system for sleeper is presented. The electrode in the system is supported by a foam pad to ensure good contact as well as comfort to the wearer, and a flexible rubber to ensure that the electrode will electrically connect to the wearer only when pressed. Eight electrodes are multiplexed such that exactly two electrodes are pressed to connect the wearer no matter how the wearer lies. When the wearer lies in different positions, he/she will press different two electrodes, and then the morphology of the output ECG signal will be different accordingly. By this feature, the system can not only detect ECG but also determine the position of the sleeper.
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Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi).
J Clin Pharmacol
PUBLISHED: 11-23-2009
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Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) and multiple-dose (50-900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6-4.9 hours), AHU377 (0.5-1.1 hours), and its active moiety, LBQ657 (1.8-3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open-label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC(0-infinity) 0.90 [0.82-0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor-NEP inhibitor (ARNi) for hypertension and heart failure.
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Radiative cooling: lattice quantization and surface emissivity in thin coatings.
ACS Appl Mater Interfaces
PUBLISHED: 11-12-2009
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Nanodiamond powder (NDP), multiwall carbon nanotube (MWCNT), and carbon black (CB) were dispersed in an acrylate (AC) emulsion to form composite materials. These materials were coated on aluminum panels (alloy 3003) to give thin coatings. The active phonons of the nanomaterials were designed to act as a cooling fan, termed "molecular fan (MF)". The order of lattice quantization, as investigated by Raman spectroscopy, is MWCNT > CB > NDP. The enhanced surface emissivity of the MF coating (as observed by IR imaging) is well-correlated to lattice quantization, resulting in a better cooling performance by the MWCNT-AC composite. MF coatings with different concentrations (0%, 0.4%, 0.7%, and 1%) of MWCNT were prepared. The equilibrium temperature lowering of the coated panel was observed with an increase in the loading of CNTs and was measured as 17 degrees C for 1% loading of MWCNT. This was attributed to an increased density of active phonons in the MF coating.
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Effects of hepatic impairment on the pharmacokinetics of nilotinib: an open-label, single-dose, parallel-group study.
Clin Ther
PUBLISHED: 08-19-2009
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Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor approved for the treatment of patients who have imatinib-resistant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic or accelerated phase or who are unable to tolerate imatinib. Nilotinib is metabolized in the liver via oxidation and hydroxylation pathways, mediated primarily by the cytochrome P450 3A4 isozyme. Interpatient variability in systemic exposure to nilotinib has been reported to range from 32% to 64%.
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The role of mitochondria in cholestatic liver injury.
Chang Gung Med J
PUBLISHED: 08-12-2009
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There is increasing evidence that the integrity of antioxidant defenses is of vital importance in extrahepatic cholestasis, particularly with regard to the functioning of the livers mitochondria. Although the mechanisms by which cholestasis causes oxidant/antioxidant imbalance in mitochondria are poorly understood, hepatic injury caused by cholestasis may be due to oxidative stress from the mitochondria. The injury has been observed in experimental models of cholestasis, especial in a model of biliary cholestasis established in rats with bile duct ligation (BDL). In the BDL rat model, the mitochondrial DNA copy number is changed and apoptosis is activated in the liver. In addition, Peroxisome Proliferator-activated Receptor-Coactivator-1alpha and transcriptional factor A are impaired. Compared to sham-operated rats, glutathione activity is decreased after BDL. Peroxidation of the mitochondrial phospholipids may cause cell necrosis and the level of a by-product of this peroxidation, malondialdehyde, may contribute to cell death after BDL. The disturbance of the oxidant-antioxidant balance, especially in mitochondria, may be responsible for cholestatic liver injury in cholestasis rats. This review describes recent development in the pathogenesis of cholestasis from the viewpoint of mitochondrial biogenesis and suggests possible directions for future study.
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Gly482Ser polymorphism in the peroxisome proliferator-activated receptor gamma coactivator-1alpha gene is associated with oxidative stress and abdominal obesity.
Metab. Clin. Exp.
PUBLISHED: 07-09-2009
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The objective of the study was to o investigate the relationship of the Gly482Ser (G482S) polymorphism in the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PPARGC1A) gene and type 2 diabetes mellitus (T2DM), obesity, and oxidative status in Chinese adults. We enrolled 276 T2DM patients and 1049 nondiabetic subjects aged at least 35 years. The G482S variant was detected using polymerase chain reaction and restriction enzyme digestion. The levels of thiobarbituric acid reactive substance, an indicator of lipid peroxidation, were measured in plasma samples. The homeostasis model assessment-estimated insulin resistance (HOMA-IR) index was determined for nondiabetic subjects. P values were adjusted for age, sex, and body mass index by using a generalized linear model. In this series, there was no association between G482S polymorphism and T2DM and obesity (body mass index >25 kg/m(2)). However, the plasma fasting insulin levels and HOMA-IR indices were significantly higher in nondiabetic subjects harboring the variant (S/S) genotype than in those with the heterozygous (G/S) genotype. With regard to the effect of the different genotypes on body fat distribution, overweight nondiabetic subjects harboring the S/S or G/S genotype had a significantly higher waist-to-hip ratio than those with the wild-type (G/G) genotype. Furthermore, subjects with the S/S genotype had significantly higher serum thiobarbituric acid reactive substance levels than those with the G/G genotype; the diabetic group mainly contributed to this significant association (P < .001). In overweight, nondiabetic Chinese adults, G482S polymorphism in the PPARGC1A gene is associated with hyperinsulinemia, HOMA-IR indices, and abdominal obesity. Furthermore, in hyperglycemia, the S482 allele is related to increased oxidative stress.
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Early transcriptional deregulation of hepatic mitochondrial biogenesis and its consequent effects on murine cholestatic liver injury.
Apoptosis
PUBLISHED: 05-23-2009
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Mitochondria are known to be involved in cholestatic liver injury, but the damage and biogenesis of mitochondria in response to the early stage of cholestasis is unknown. A rat model of cholestasis was established by bile duct ligation (BDL), with simultaneous creation of the sham group receiving laparotomy without BDL. A significant decrease of liver peroxisome proliferators-activated receptor gamma coactivator-1alpha, mitochondrial transcriptional factor A (Tfam) and glutathione peroxidase (GPx) mRNA and Tfam protein from 6 to 72 h after BDL was found, which was associated with significant decrease of the glutathione, GPx and catalase activity at 72 h. At 72 h after BDL, mitochondrial DNA copy number reached the lowest level, while caspase 9 and 3 activity, but not caspase 8, Bax, Bcl(2), Fas L and Fas-Fas L complex, were upregulated significantly in the liver homogenates of BDL rats. The apoptotic liver cells appeared in large amounts in the rat liver by 72 h after BDL. Our results indicate that transcriptional regulation of the mitochondrial biogenesis is impaired within a few hours after complete bile duct obstruction, resulting in later mitochondrial dysfunction and consequent cholestatic liver injury via the intrinsic apoptosis pathway.
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Peripheral blood mitochondrial DNA content and dysregulation of glucose metabolism.
Diabetes Res. Clin. Pract.
PUBLISHED: 04-28-2009
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The aim of this study was to examine the potential influence of insulin resistance (IR), hyperglycemia and oxidative stress on leucocytes mitochondrial DNA (mtDNA) content.
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Two-dimensional cell parameters of twisted nematic liquid crystal with an amplitude-sensitive heterodyne ellipsometer.
Appl Opt
PUBLISHED: 03-24-2009
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To be compared with the wavelength modulation technique for measuring two-dimensional (2D) cell parameters of a twisted nematic liquid crystal (TN-LC), we propose an amplitude-sensitive heterodyne ellipsometer (ASHE) of a single wavelength that is able to characterize TN-LC in 2D quantitatively. A quarter-wave plate (QWP) is rotated continuously in this setup to modulate the polarization state of the incident laser beam to obtain the amplitude ratio of the S and P waves versus the rotation angle of the QWP. Thus the cell parameters, including the twisted angle Phi, untwisted phase retardation Gamma, rubbing direction angle alpha, and cell gap d, of a TN-LC cell are obtained simultaneously by best fitting the detected amplitude ratio with a prediction based on the transfer matrix of TN-LC cell. 2D distributions of (Phi,Gamma,alpha,d) are then obtained either by scanning the TN-LC cell or by using a CCD camera for high-speed measurement. In this experiment, the stability of the amplitude-ratio measurement of the proposed ASHE was 0.5%. The goal is to integrate the rotating elliptical wave plate with the TN-LC cell in a heterodyne ellipsometer to obtain cell parameters at amplitude sensitivity. This increases not only the sensitivity of the measurement but also the possibility of extending the 2D distribution of cell parameters in real time.
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Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis.
Epilepsia
PUBLISHED: 03-09-2009
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Long-term antiepileptic drug (AED) therapy has been associated with an increase in risk of atherosclerosis. At issue is whether this risk is related to the duration of AED therapy. We evaluated the hypothesis that the cumulative effect of long-term exposure to AEDs plays a pivotal role in the pathogenesis of atherosclerosis in patients with epilepsy.
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Preservation of mitochondrial integrity and energy metabolism during experimental status epilepticus leads to neuronal apoptotic cell death in the hippocampus of the rat.
Seizure
PUBLISHED: 02-19-2009
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Status epilepticus results in mitochondrial damage or dysfunction and preferential neuronal cell loss in the hippocampus. Since a critical determinant of the eventual cell death fate resides in intracellular ATP concentration, we investigated whether mitochondrial integrity and level of energy metabolism are related with apoptotic cell death in specific hippocampal neuronal populations. A kainic acid (KA)-induced experimental temporal lobe status epilepticus model was used. Qualitative and quantitative analysis of DNA fragmentation, TUNEL immunohistochemistry, double immunofluorescence staining for activated caspase-3, electron microscopy or measurement of ATP level in the bilateral hippocampus was carried out 1, 3 or 7 days after microinjection unilaterally of a low dose of KA (0.5 nmol) into the CA3 hippocampal subfield. Characteristic biochemical (DNA fragmentation), histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were presented bilaterally in the hippocampus 7 days after the elicitation of sustained hippocampal seizure activity by microinjection of KA into the unilateral CA3 subfield. At the same time, CA3 or CA1 subfield on either side manifested a maintained ATP level; alongside relatively intact mitochondria, rough endoplasmic reticulum, Golgi apparatus or cytoplasmic membrane in hippocampal neurons that exhibited ultrastructural features of apoptotic cell death. Our results demonstrated that preserved mitochondrial ultrastructural integrity and maintained energy metabolism during experimental temporal lobe status epilepticus is associated specifically with apoptotic, not necrotic, cell death in hippocampal CA3 or CA1 neurons.
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Lack of association between mutations of gene-encoding mitochondrial D310 (displacement loop) mononucleotide repeat and oxidative stress in chronic dialysis patients in Taiwan.
J Negat Results Biomed
PUBLISHED: 02-11-2009
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Mitochondria (mt) are highly susceptible to reactive oxygen species (ROS). In this study, we investigated the association between a region within the displacement loop (D-loop) in mtDNA that is highly susceptible to ROS and oxidative stress markers in chronic dialysis patients. We enrolled 184 chronic dialysis patients and 213 age-matched healthy subjects for comparison. Blood levels of oxidative stress markers, such as thiobarbituric acid reactive substances (TBARS) and free thiol, and the mtDNA copy number were determined. A mononucleotide repeat sequence (CCCC...CCCTCCCCCC) between nucleotides 303 and 316-318 (D310) was identified in mtDNA.
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Contribution of nitric oxide, superoxide anion, and peroxynitrite to activation of mitochondrial apoptotic signaling in hippocampal CA3 subfield following experimental temporal lobe status epilepticus.
Epilepsia
PUBLISHED: 01-31-2009
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One cellular consequence of status epilepticus is apoptosis in the hippocampal CA3 subfield. We evaluated the hypothesis that the repertoire of cellular events that underlie such elicited cell death entails mitochondrial dysfunction induced by an excessive production of nitric oxide synthase II (NOS II)-derived NO, increased superoxide anion (O(2)(-)) production, and peroxynitrite formation.
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The creation of cybrids harboring mitochondrial haplogroups in the Taiwanese population of ethnic Chinese background: an extensive in vitro tool for the study of mitochondrial genomic variations.
Oxid Med Cell Longev
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Mitochondrial DNA (mtDNA) haplogroups may contribute to the development of aging-related diseases. A reliable in vitro cellular system for investigating the physiologic significance of mtDNA haplogroups is essential. This study aims to construct and characterize a series of cybrid cell lines harboring variant mtDNA haplogroups collected from healthy Taiwanese volunteers. Cybrid cells harboring different mtDNA haplogroups like B4a, B4b, B4c, B4d, B5, R, F1a, F2, D4e, D4a, D5b, D5a, E, M8, C, and N9a were prepared. Luminex 1000 and full-length mtDNA sequencing were used to confirm that mtDNA haplogroups of transmitochondrial cybrids were identical to their original donors. Cybrid B4b had a significantly lower oxygen consumption rate and higher mitochondrial membrane potential compared to F1a, B5, D5a, D4a, and N9a but had more susceptibility to H(2)O(2)-induced oxidative stress than cybrid F1a, D4a, and N9a. Cybrid N9a had better oxygen consumption and H(2)O(2)-challenged viability compared to B4b, F1a, B5, D5a, and D4a. A series of cybrid cells harboring the main haplogroups of the Taiwanese population with ethnic Chinese background has been developed in vitro. With this mtDNA haplogroup population, the underlying mechanisms of aging-related diseases may be better understood, and therapeutic interventions can be accelerated.
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Characterization of the dynamic mechanical stability of liquid-filled lenses.
Opt Express
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In this paper, the dynamic mechanical stability of the liquid-filled lenses was studied, in which acoustic excitation was used as broad band perturbation sources and the resultant response of the lens was characterized using non-contact laser Doppler vibrometer. To the best of our knowledge, its the first time that the mechanical stability of liquid-filled lenses was experimentally reported. Both experimental results and theoretical analysis demonstrate that the resonance of the lens will shift to higher frequency while the vibration velocity as well as its magnitude will be reduced accordingly when the pressure in the lens cavity is increased to shorten the focal length. All of these results will provide useful references to help researchers design their own liquid-filled lenses for various applications.
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Case studies for practical food effect assessments across BCS/BDDCS class compounds using in silico, in vitro, and preclinical in vivo data.
AAPS J
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Practical food effect predictions and assessments were described using in silico, in vitro, and/or in vivo preclinical data to anticipate food effects and Biopharmaceutics Classification System (BCS)/Biopharmaceutics Drug Disposition Classification System (BDDCS) class across drug development stages depending on available data: (1) limited in silico and in vitro data in early discovery; (2) preclinical in vivo pharmacokinetic, absorption, and metabolism data at candidate selection; and (3) physiologically based absorption modeling using biorelevant solubility and precipitation data to quantitatively predict human food effects, oral absorption, and pharmacokinetic profiles for early clinical studies. Early food effect predictions used calculated or measured physicochemical properties to establish a preliminary BCS/BDDCS class. A rat-based preclinical BCS/BDDCS classification used rat in vivo fraction absorbed and metabolism data. Biorelevant solubility and precipitation kinetic data were generated via animal pharmacokinetic studies using advanced compartmental absorption and transit (ACAT) models or in vitro methods. Predicted human plasma concentration-time profiles and the magnitude of the food effects were compared with observed clinical data for assessment of simulation accuracy. Simulations and analyses successfully identified potential food effects across BCS/BDDCS classes 1-4 compounds with an average fold error less than 1.6 in most cases. ACAT physiological absorption models accurately predicted positive food effects in human for poorly soluble bases after oral dosage forms. Integration of solubility, precipitation time, and metabolism data allowed confident identification of a compounds BCS/BDDCS class, its likely food effects, along with prediction of human exposure profiles under fast and fed conditions.
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Nilotinib preclinical pharmacokinetics and practical application toward clinical projections of oral absorption and systemic availability.
Biopharm Drug Dispos
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Nilotinib is a highly potent and selective bcr-abl tyrosine kinase inhibitor used for the treatment of patients who are in the chronic and accelerated phases of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Nilotinib preclinical data and its use for practical predictions of systemic exposure profiles and oral absorption are described. The systemic clearance (CL) of nilotinib was relatively low in rodents with a value of less than 25% of hepatic blood flow (Q(H)), while it was moderate in monkeys and dogs (CL/Q(H) ?=?32-35%). The steady state volume of distribution (V(ss) ) ranged from 0.55 to 3.9 l/kg across the species tested. The maximum concentration (C(max)) of nilotinib occurred at 0.5-4 h and the bioavailability was moderate (17-44%). The plasma protein binding was high (> 97.5%) in preclinical species and humans. The human CL (~ 0.1 l/h/kg) and V(ss) (~2.0 l/kg) were best predicted by the rat-dog-human proportionality method and allometric scaling method, respectively. The human intravenous pharmacokinetic profile was projected by the Wajima C(ss)-MRT method. The predicted micro-constants from human intravenous profiles were incorporated into the advanced compartmental absorption and transit model within the GastroPlus program to simulate the oral concentration-time curves in humans. Overall, the simulated oral human pharmacokinetic profiles showed good agreement with observed clinical data, and the model predicted that the C(max) , AUC, t(½) , V(z) /F and CL/F values were within 1.3-fold of the observed values. The absolute oral bioavailability of nilotinib in healthy humans was predicted to be low (< 25%).
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Mitochondrial Dysfunction and Oxidative Stress Promote Apoptotic Cell Death in the Striatum via Cytochrome c/Caspase-3 Signaling Cascade Following Chronic Rotenone Intoxication in Rats.
Int J Mol Sci
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Parkinsons disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration. Evidence suggests that mitochondrial dysfunction may be linked to PD through a variety of different pathways, including free-radical generation and dysfunction of the mitochondrial Complex I activity. In Lewis rats, chronic systemic administration of a specific mitochondrial Complex I inhibitor, rotenone (3 mg/kg/day) produced parkinsonism-like symptoms. Increased oxidized proteins and peroxynitrite, and mitochondrial or cytosol translocation of Bim, Bax or cytochrome c in the striatum was observed after 2-4 weeks of rotenone infusion. After 28 days of systemic rotenone exposure, imunohistochemical staining for tyrosine hydroxylase indicated nigrostriatal dopaminergic neuronal cell degeneration. Characteristic histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were present in the striatal neuronal cell after chronic rotenone intoxication. We conclude that chronic rotenone intoxication may enhance oxidative and nitrosative stress that induces mitochondrial dysfunction and ultrastructural damage, resulting in translocation of Bim and Bax from cytosol to mitochondria that contributes to apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade.
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Serum level and prognostic value of neopterin in patients after ischemic stroke.
Clin. Biochem.
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We hypothesized that serum level of neopterin is significantly predictive of prognostic outcome in patients after acute ischemic stroke (IS).
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The association of statin therapy and high-sensitivity C-reactive protein level for predicting clinical outcome in acute non-cardioembolic ischemic stroke.
Clin. Chim. Acta
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Statins reportedly have anti-inflammatory effects aside from their cholesterol-lowering effect. We investigated the effects of statins on serum hs-CRP level and clinical outcome of acute ischemic stroke (IS) patients.
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Mitochondrial DNA coding and control region variants as genetic risk factors for type 2 diabetes.
Diabetes
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Both the coding and control regions of mitochondrial DNA (mtDNA) play roles in the generation of diabetes; however, no studies have thoroughly reported on the combined diabetogenic effects of variants in the two regions. We determined the mitochondrial haplogroup and the mtDNA sequence of the control region in 859 subjects with diabetes and 1,151 normoglycemic control subjects. Full-length mtDNA sequences were conducted in 40 subjects harboring specific diabetes-related haplogroups. Multivariate logistic regression analysis with adjustment for age, sex, and BMI revealed that subjects harboring the mitochondrial haplogroup B4 have significant association with diabetes (DM) (odds ratio [OR], 1.54 [95% CI 1.18-2.02]; P < 0.001), whereas subjects harboring D4 have borderline resistance against DM generation (0.68 [0.49-0.94]; P = 0.02). Upon further study, we identified an mtDNA composite group susceptible to DM generation consisting of a 10398A allele at the coding region and a polycytosine variant at nucleotide pair 16184-16193 of the control region, as well as a resistant group consisting of C5178A, A10398G, and T152C variants. The OR for susceptible group is 1.31 (95% CI 1.04-1.67; P = 0.024) and for the resistant group is 0.48 (0.31-0.75; P = 0.001). Our study found that mtDNA variants in the coding and control regions can have combined effects influencing diabetes generation.
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Peroxisome proliferator-activated receptors ?/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus.
J Neuroinflammation
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Status epilepticus induces subcellular changes that may lead to neuronal cell death in the hippocampus. However, the mechanism of seizure-induced neuronal cell death remains unclear. The mitochondrial uncoupling protein 2 (UCP2) is expressed in selected regions of the brain and is emerged as an endogenous neuroprotective molecule in many neurological disorders. We evaluated the neuroprotective role of UCP2 against seizure-induced hippocampal neuronal cell death under experimental status epilepticus.
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Sequence-based polymorphisms in the mitochondrial D-loop and potential SNP predictors for chronic dialysis.
PLoS ONE
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The mitochondrial (mt) displacement loop (D-loop) is known to accumulate structural alterations and mutations. The aim of this study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) within the D-loop among chronic dialysis patients and healthy controls.
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Renin inhibitor aliskiren exerts neuroprotection against amyloid beta-peptide toxicity in rat cortical neurons.
Neurochem. Int.
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Accumulation of amyloid ?-peptide (A?) in senile plaques, a pathological hallmark of Alzheimers disease (AD), has been implicated in neuronal degeneration. Renin-angiotensin system (RAS) blockers, including the renin inhibitor aliskiren, are a group of clinically relevant anti-hypertensive agents. The present study was initiated to investigate whether aliskiren may modulate A? neurotoxicity as an additional function aside from its established property of lowering blood pressure. We found aliskiren conferred neuronal resistance to A? toxicity in primary rat cortical cultures. Moreover, both A?25-35 and A?1-42 induced renin expression in cortical neurons; in parallel, a heightened expression of renin was detected in the cerebral cortices of 9-month-old AD transgenic mice. Notably, aliskiren blocked A?-mediated neuronal induction of renin. We therefore concluded that aliskiren may carry neuroprotective action against A? toxicity. Furthermore, the aliskiren effects may involve downregulation of renin expression induced by A?.
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The effect of the red wine polyphenol resveratrol on a rat model of biliary obstructed cholestasis: involvement of anti-apoptotic signalling, mitochondrial biogenesis and the induction of autophagy.
Apoptosis
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Mitochondria are known to be involved in cholestatic liver injury. The potential protective effect of resveratrol in cholestatic liver injury and the possible roles of autophagy and apoptosis induction in this process are not yet clear. The aim of this study is to determine whether resveratrol administration after bile duct ligation can reduce cholestasis-induced liver injury through modulating apoptosis, mitochondrial biogenesis and autophagy. A rat model of cholestasis was established by bile duct ligation (BDL) and compared with a sham group receiving laparotomy without BDL, with resveratrol or control treatments following BDL. The expression of proteins involved in the apoptotic and autophagic pathways were analyzed by western blotting. Apoptosis was examined by TUNEL staining. In the resveratrol/BDL group LC3-II upregulation persisted for 1-7 days, Bax was downregulated and catalase was upregulated at 3-7 days after resveratrol treatment. The decline in mitochondrial DNA copy number was reversed at 3-7 days. Caspase 3 expression was significantly downregulated at 3-7 days in the resveratrol group. TUNEL staining showed significant numbers of apoptotic liver cells appeared in livers 3-7 days after BDL and that was decreased by resveratrol treatment. Our results indicate that early resveratrol treatment reverses impaired liver function within hours of BDL.
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Novel physiologically based pharmacokinetic modeling of patupilone for human pharmacokinetic predictions.
Cancer Chemother. Pharmacol.
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Patupilone (EPO906) is a novel potent microtubule stabilizer, which has been evaluated for cancer treatment. A novel physiologically based pharmacokinetics (PBPK) model was developed based on nonclinical data to predict the disposition of patupilone in cancer patients.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.